Clinical trial NCT02875834
Conditions: Hyperkalemia
Sponsor: AstraZeneca
Start date: 2017-03-03; Completion date: 2018-02-14
Enrollment: 267 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 two days of initial ZS therapy (10g TID).

Detailed description:

Arms: arm 1: Suspension administered 5g orally once daily for 28 days after the first 48-hour open label initial phase. arm 2: Suspension administered 10g orally once daily for 28 days after the first 48-hour open label initial phase. arm 3: Suspension administered orally placebo once daily for 28 days after the first 48-hour open label initial phase.
Interventions: intervention 1: Sodium Zirconium Cyclosilicate (ZS) 10g intervention 2: Sodium Zirconium Cyclosilicate (ZS) 5g intervention 3: Sodium Zirconium Cyclosilicate (ZS) 10g intervention 4: Placebo
Intervention descriptions: intervention 1: Suspension administered 10g orally three times per day, in the first 48-hour of the study for all patients (48-hour open label initial phase) intervention 2: Suspension administered 5g orally once daily for 28 days after the first 48-hour open label initial phase. intervention 3: Suspension administered 10g orally once daily for 28 days after the first 48-hour open label initial phase. intervention 4: Suspension administered orally placebo once daily for 28 days after the first 48-hour open label initial phase.

Protocol documents:
Prot_001.pdf: 
1 (86)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
VERSION HISTORY
Version 3.0, 22 Sep 2016
The main reason for the protocol amendment was to clarify guidance with respect to 
concomitant use of ZS and drugs with gastric pH-dependent bioavailability. Additional 
changes made to the protocol include multiple minor improvements. The main changes are 
summarized as below.
Section 3.9 (Discontinuation of investigational product): The discontinuation criteria for 
significant increase in PR interval was updated to better reflect that “new onset peak T-
wave”.
Section 4.2.3 (48-hour open-label initial phase Day 3 (Visit 4)): The section was updated to 
reflect that relevant assessments also to be performed if the i-STAT potassium value is < 
3.5 mmol/L during the Visit 4.
Section 6.3.1 (Time period for collection of adverse events): The section was further 
updated to specify the follow up for adverse events.
Section 7.7.1 (Oral medications with gastric pH-dependent bioavailability): The section was 
added to clarify guidance with respect to concomitant use of ZS and drugs with gastric pH-
dependent bioavailability. For a specific list of drugs the recommendation is to administer 
those at least 2 hours before or 2 hours after study drug to mitigate the risk of drug 
interactions.
Section 8.5.1 (Analysis of the primary variable): Minor typographical error was updated in 
this section.
Section 8.5.3 (Safety analysis): Minor typographical errors and formatting was updated in 
this section.
Clinical Study Protocol 
Drug Substance
ZS
Study Code
D9480C00002
Version
3.0
Date
22 Sep 2017
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
Global


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Version 2.0, 07 Dec 2016
The main reasons for the protocol amendment were to clarify how patients developing 
hypokalemia during the 48h initial open label treatment phase are to be monitored and 
handled, and to update the Benefit Risk section with additional information. Additional 
changes made to the protocol include multiple minor improvements. The main changes are 
summarized below.
Study Synopsis:  The synopsis was updated to align with the amendments made in the body 
of the CSP.
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
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 QT prolongation begins to 
represent a medical risk.


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Section 4 (Table 1): The study plan and timing of procedures for the 48h 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 visitif 
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.
Section 4.3 (Follow-up period): Vital signs were added to the study procedures in this 
section to align with Table 2.
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 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 5.3 (Other assessments): This section was updated to modify the timepoint when 
the EQ-5D questionnaire will be completed.


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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 8.3 (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 the 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. 
Section 8.5.2 (Analysis of the secondary and additional variables): This section was 
updated to clarify the health state of the study population will be assessed on initial phase
Day 1, and on 28-day randomized treatment study phase Day 29 using the EQ-5D 
questionnaire.
Section 8.5.3 (Safety analysis): This section was updated to include the physical 
examinations and ECGs as the safety analysis.
Section 8.5.4 (Subgroup analysis): This section was revised to clarify that subgroup 
analysis, for the purpose of regulatory submission, will only be performed in Japanese 
patients.


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Version 1.0, 17 June 2016
Initial creation
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
6 (86)
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 
Global
International Co-ordinating Investigator
Dr. Faiez Zannad, Professor of therapeutics and cardiology, director of the Clinical 
Investigation Centre at the Institut National de la Santé et de la Recherche Médicale, INSERM, 
Centre d'Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de 
Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France
Study site(s) and number of patients planned
This study will be conducted in approximately 50 centers in several different countries. Before 
patients are randomized to the double-blind study phase, they will receive open-label ZS for 
48 hours during the initial phase. It is expected that approximately 443 patients will need to be 
enrolled, to have approximately 269 patients entered into the 48-hour open-label initial phase, 
resulting in approximately 255 patients being randomized in the 28-day treatment study phase.
Enrolment will be stopped when approximately 255 patients have been initiated with the 28-
day randomized treatment study phase.
Study period
Phase of development
Estimated date of first patient enrolled
Q1 2017
Phase 3
Estimated date of last patient completed
Q1 2018
Study design
This is a prospective, randomized, double-blind, placebo-controlled, phase 3 study to 
determine the safety and efficacy of ZS in patients with hyperkalemia. This study consists of 
screening period (1 day), 48-hour open-label initial phase, 28-day randomized treatment study 
phase, and follow-up period (7±1 days after the last administration of study medication).
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 48-hour open-label initial phase. In the initial 
phase, patients will receive open-label ZS at a dose of 10g per os (PO) three times a day (tid) 
for 48 hours. Patients who achieve normokalemia (i-STAT [A portable blood analyser] 
potassium values between 3.5 to 5.0 mmol/L, inclusive) by the morning of Day 3 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 every day (qd), 10g qd, or placebo qd for the following 28 days.


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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Treatment will end on the study 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 48-hour 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 48h 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 D9480C00002
Version 3.0
Date 22 Sep 2017
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Secondary Objectives:
Outcome Measures:
48-hour open-label initial phase:
!
To evaluate the proportion of patients 
who achieve normokalemia after 48 
hours 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
Patient reported outcomes:
!
To evaluate the health state in the study 
population using EQ-5D
48-hour open-label initial phase efficacy endpoints:
!
Proportion of patients who achieve 
normokalemia during the initial phase at 24 and 
48 hours
!
Exponential rate of change in S-K levels 
(blood) during the 48-hour open-label initial 
phase
!
Change (absolute and percent change) from 
baseline in S-K levels (blood) at all measured 
time intervals (See Table 1) post dose in 48-
hour open-label initial phase
!
Time to normalization in S-K levels 
(normalization defined as S-K levels between 
3.5-5.0 mmol/L, inclusive) in 48-hour open-
label initial 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
Patient reported outcomes:
!
EQ-5D questionnaire 
*       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 subgroups. More details will be 
provided in the SAP


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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Safety Objectives:
Outcome Measures:
!
To evaluate the effect of ZS on other 
serum electrolytes in both 48-hour open-
label initial phase and 28-day 
randomized treatment study phase
!
To evaluate the safety and tolerability 
profiles of ZS in both 48-hour open-
label initial phase and 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 hypokalaemia
Target patient population
The target patient population consists of male and female patients aged ≥ 18 to ≤ 90 years
with hyperkalemia, defined as two consecutive i-STAT potassium values, measured 60-
minutes apart, both ≥5.1 mmol/L within 1 day of the first ZS dose.
Duration of treatment
The study will start with the screening period, and all baseline parameters should be 
measured/collected up to 1 day prior to administration of first dose of study drug on initial 
phase Day 1. During the 48-hour open-label initial phase patients will receive ZS per os (PO) 
at a dose of 10g three times a day (tid) for 48 hours. Patients who achieve normokalemia (i-
STAT potassium values between 3.5 to 5.0 mmol/L, inclusive), by the morning of Day 3 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 initial phase. The total expected study duration for each individual 
patient is approximately 5-6 weeks.
Investigational product, dosage and mode of administration
48-hour open-label initial phase:
!
ZS 10g will be administered orally three times a day (tid) for 48 hours as 
an oral suspension
28-day randomized treatment study phase:
!
ZS 5g will be administered orally once daily (qd) for 28 days as an oral 
suspension


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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!
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 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), dosing during the 28-day randomized treatment study phase will be reduced 
from qd to once every other day (qod).
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 3.4 
mmol/L, inclusive during the 48h initial open label treatment phase the subject will be 
directed to not take any more ZS for the remainder of the day and return the next day to 
continue in the study, if the potassium is then between 3.5 and 5.0 mmol/L.
Patients with confirmed i-STAT potassium <3.0 mmol/L should discontinue from therapy.
Statistical methods
Separate efficacy and safety analyses will be performed for the 48-hour open-label initial 
phase and 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 including separate evaluability rules 
for the 48-hour open-label initial phase and 28-day randomized treatment study phase.
For the initial phase, the full analysis set will include all patients registered in the 48 hours 
open label initial phase. The safety analysis set, for the initial phase, will include all patients 
with at least one dose of IP during this treatment phase, and will be analysed 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 28-day randomized treatment study 
phase IP among those randomized, and will be analysed on an as-treated basis. 
Unless otherwise specified, all efficacy analyses will be carried out on the full analysis sets 
and all safety analyses will be based on the safety analysis sets.
The null hypothesis for the study is that there is no difference 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 48-hour 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 to 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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reflect the mean difference between i-STAT and S-K values from all available paired lab 
samples. 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 of all available 
S-K values during 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 
mean Day 8-29 values stratified by country; the model will include all S-K data collected at 
the scheduled visits between Day 8-29 as response variables, and baseline covariates for initial 
phase eGFR and initial phase and 28-day randomized treatment study phase S-K values as 
well as age (<55, 55-64, ≥65 years), country and baseline binary indicators for RAAS 
inhibitors, chronic kidney disease, heart failure, and diabetes mellitus. 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 3.5-5.0mmol/L, inclusive) at the end of the 28-day randomized 
treatment study phase and during 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 
EQ-5D will be used to assess the health state of the patient population.
Safety endpoints will include adverse events, serious AEs (SAEs), vital signs, clinical 
laboratory evaluations, physical examinations, ECGs, and other serum electrolytes 
(specifically, calcium [S-Ca], magnesium [S-Mg], serum sodium [S-Na], phosphate [S-PO4], 
bicarbonate [S-HCO3], and blood urea nitrogen [BUN]).
The confirmed i-STAT potassium value on Study Day 3 of the 48-hour open-label initial 
phase will be used to establish the patient’s eligibility into the 28-day randomized treatment 


Clinical Study Protocol Synopsis
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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study phase, however central laboratory S-K values will be used for all analyses. The baseline 
S-K for the 28-day randomized treatment study phase will use the first S-K measurement 
taken the morning of 48-hour open-label initial phase on Study Day 3. Baseline for all other 
parameters will be the fasting parameter value measured within 1 day of the first study drug 
administration in the initial phase.
There is no planned interim analysis in this study.
A sample size of approximately 255 patients (i.e. 102 patients for each active treatment arm
and 51 patients for placebo control arm) will provide >90% power to detect a 0.30 mean 28-
day randomized treatment study phase Day 8-29 S-K difference, assuming a 0.5 intra-subject 
standard deviation, comparing each active dose (high to low) vs. placebo control using a two-
sided t-test at significance level of 5%. Assuming 95% of enrolled patients will be 
normokalemic after treatment with at least 1 dose of ZS 10g (see Section 7.2), approximately 
269 patients will be needed to enter 48-hour open-label initial phase.


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS.....................................................................................6
TABLE OF CONTENTS...................................................................................13
1.
INTRODUCTION ............................................................................................. 21
1.1
Background and rationale for conducting this study ...........................................21
1.2
Rationale for study design, doses and control groups..........................................26
1.3
Benefit/risk and ethical assessment ....................................................................28
1.3.1
Clinical benefits.................................................................................................29
1.3.2
Clinical risks......................................................................................................29
1.3.3
Clinical benefit-risk balance...............................................................................30
1.3.4
Conclusions ....................................................................................................... 30
1.4
Study Design...................................................................................................... 30
2.
STUDY OBJECTIVES...................................................................................... 33
2.1
Primary objective...............................................................................................33
2.2
Secondary objectives..........................................................................................34
2.3
Safety objectives................................................................................................35
2.4
Exploratory objectives .......................................................................................35
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL.....................35
3.1
Inclusion criteria ................................................................................................35
3.2
Exclusion criteria ............................................................................................... 36
3.3
Patient enrolment and randomization .................................................................37
3.4
Procedures for handling incorrectly enrolled or randomized patients..................37
3.5
Methods for assigning treatment groups.............................................................37
3.6
Methods for ensuring blinding ...........................................................................38
3.7
Methods for unblinding......................................................................................38
3.8
Restrictions........................................................................................................38
3.9
Discontinuation of investigational product .........................................................39
3.9.1
Procedures for discontinuation of a subject from investigational product............40
3.10
Criteria for withdrawal....................................................................................... 40
3.10.1
Screen failures ...................................................................................................41
3.10.2
Withdrawal of the informed consent...................................................................41


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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3.11
Discontinuation of the study............................................................................... 41
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................42
4.1
Enrolment/screening period (Visit 1)..................................................................46
4.2
Treatment period................................................................................................ 46
4.2.1
48-hour open-label initial phase Day 1 (Visit 2) .................................................46
4.2.2
48-hour open-label initial phase Day 2 (Visit 3) .................................................48
4.2.3
48-hour open-label initial phase Day 3 (Visit 4) .................................................48
4.2.4
28-day randomized treatment study phase Day 1 (Visit 4)..................................49
4.2.5
28-day randomized treatment study phase Day 2 (Visit 5)..................................49
4.2.6
28-day randomized treatment study phase Day 5 (Visit 6)..................................50
4.2.7
28-day randomized treatment study phase Day 8 (Visit 7)..................................50
4.2.8
28-day randomized treatment study phase Day 12 (Visit 8)................................51
4.2.9
28-day randomized treatment study phase Day 15 (Visit 9)................................51
4.2.10
28-day randomized treatment study phase Day 19 (Visit 10) ..............................52
4.2.11
28-day randomized treatment study phase Day 22 (Visit 11) ..............................52
4.2.12
28-day randomized treatment study phase Day 26 (Visit 12) ..............................53
4.2.13
28-day randomized treatment study phase Day 29 (Visit 13) ..............................53
4.3
Follow-up period (EOS)..................................................................................... 54
5.
STUDY ASSESSMENTS..................................................................................55
5.1
Efficacy assessments..........................................................................................55
5.1.1
Potassium...........................................................................................................55
5.2
Safety assessments.............................................................................................55
5.2.1
Laboratory safety assessments............................................................................ 55
5.2.2
Physical examination .........................................................................................57
5.2.3
ECG...................................................................................................................57
5.2.3.1
Resting 12-lead ECG .........................................................................................57
5.2.4
Vital signs.......................................................................................................... 58
5.2.4.1
Pulse rate and blood pressure .............................................................................58
5.3
Other assessments.............................................................................................. 58
5.4
Pharmacokinetics (Not applicable).....................................................................58
5.5
Pharmacodynamics (Not applicable) ..................................................................58
5.6
Pharmacogenetics (Not applicable) ....................................................................58
5.7
Biomarker analysis (Not applicable)...................................................................58
5.8
Storage, re-use and destruction of biological samples......................................... 58
5.9
Labeling and shipment of biological samples ..................................................... 58
5.10
Volume of blood................................................................................................ 59
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT.............................60
6.1
Definition of adverse events............................................................................... 60


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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6.2
Definitions of serious adverse event ................................................................... 61
6.3
Recording of adverse events............................................................................... 61
6.3.1
Time period for collection of adverse events ......................................................61
6.3.2
Follow-up of unresolved adverse events.............................................................61
6.3.3
Variables............................................................................................................ 61
6.3.4
Causality collection............................................................................................62
6.3.5
Adverse events based on signs and symptoms....................................................63
6.3.6
Adverse events based on examinations and tests ................................................63
6.4
Reporting of serious adverse events ................................................................... 63
6.5
Overdose............................................................................................................64
6.6
Pregnancy .......................................................................................................... 64
6.6.1
Maternal exposure..............................................................................................64
6.6.2
Paternal exposure...............................................................................................65
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ...................65
7.1
Identity of investigational product(s)..................................................................65
7.2
Dose and treatment regimens .............................................................................66
7.3
Labelling............................................................................................................66
7.4
Storage............................................................................................................... 67
7.5
Compliance........................................................................................................67
7.6
Accountability....................................................................................................67
7.7
Concomitant and other treatments ...................................................................... 67
7.7.1
Oral medications with gastric pH-dependent bioavailability...............................68
7.8
Post Study Access to Study Treatment (Not Applicable) .................................... 68
8.
STATISTICAL ANALYSES BY ASTRAZENECA..........................................68
8.1
Statistical considerations....................................................................................68
8.2
Sample size estimate ..........................................................................................69
8.3
Definitions of analysis sets................................................................................. 69
8.3.1
Full analysis sets (FAS)......................................................................................69
8.3.2
Safety analysis sets (SAF)..................................................................................69
8.4
Outcome measures for analyses..........................................................................70
8.4.1
Primary efficacy variable ...................................................................................70
8.4.2
Secondary efficacy variables..............................................................................70
8.4.3
Safety Variables.................................................................................................71
8.5
Methods for statistical analyses..........................................................................71
8.5.1
Analysis of the primary variable......................................................................... 72
8.5.2
Analysis of the secondary and additional variables.............................................73
8.5.3
Safety analysis ................................................................................................... 74


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8.5.4
Subgroup analysis..............................................................................................74
8.5.5
Interim analysis..................................................................................................75
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.........................75
9.1
Training of study site personnel .........................................................................75
9.2
Monitoring of the study...................................................................................... 75
9.2.1
Source data ........................................................................................................76
9.2.2
Study agreements............................................................................................... 76
9.2.3
Archiving of study documents............................................................................ 76
9.2.4
Deviation from the clinical study protocol..........................................................76
9.3
Study timetable and end of study........................................................................76
9.4
Data management by AstraZeneca or delegate ................................................... 77
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................78
10.1
Ethical conduct of the study ...............................................................................78
10.2
Patient data protection........................................................................................78
10.3
Ethics and regulatory review ..............................................................................78
10.4
Informed consent ...............................................................................................79
10.5
Changes to the protocol and informed consent form...........................................79
10.6
Audits and inspections .......................................................................................80
11.
LIST OF REFERENCES ...................................................................................80
LIST OF TABLES
Table 1
Study Plan detailing the procedures: 48-hour open-label initial 
phase.....................................................................................................42
Table 2
Study Plan detailing the procedures: 28-day randomized treatment 
study phase ...........................................................................................44
Table 3
Laboratory Safety Variables..................................................................56
Table 4
Volume of blood to be withdrawn from each patient: 48-hour 
open-label initial phase..........................................................................59
Table 5
Volume of blood to be withdrawn from each patient: 28-day 
randomized treatment study phase.........................................................60
Table 6
Confirmatory Testing Sequence ............................................................72


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LIST OF FIGURES
Figure 1.               Multivariable-adjusted mortality by serum potassium level in a 
cohort of 55,266 patients with eGFR <60 ml/min per 1.73 m2
during median follow up 2.76 years (Lou J et al 2016) ..........................28
Figure 2
Forest plot of benefits (green) and risks (red) for ZS 10g and 15g..........30
Figure 3
Study flow chart....................................................................................32
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................81
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................83
Appendix C           EQ-5D Health Questionnaire ................................................................84


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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 48-hours Open Label Initial Phase
FAS-RTP
Full Analysis Set for the double blind Randomized Treatment Phase
GCP
Good Clinical Practice


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Abbreviation or 
special term
Explanation
GFR
Glomerular Filtration Rate
GGT
Gamma-glutamyl transferase
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
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 48-hours Open Label Phase
SAF-RTP
Safety Analysis Set for the double blind Randomized Treatment Phase
SAP
Statistical Analysis Plan
SARs
Suspected Adverse Reactions
S-Ca
Serum calcium
S-HCO3
Serum bicarbonate 
S-K
Serum potassium
S-Mg
Serum magnesium 


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Abbreviation or 
special term
Explanation
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


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Potassium is a ubiquitous ion, involved in numerous processes in the human body. It is the
most abundant intracellular cation and is critically important for numerous physiological
processes, including maintenance of cellular membrane potential, homeostasis of cell volume, 
and transmission of action potentials. The 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 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 (eg, amiloride, spironolactone), nonsteroidal anti-inflammatory
drugs (eg, ibuprofen, naproxen, celecoxib), heparin, and certain cytotoxic and antibiotic drugs
(eg, 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.


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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]; eg, 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.
!
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 


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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.
Four clinical studies of ZS have been completed (ZS-002, ZS-003, ZS-004, and ZS-004E) in 
patients with hyperkalemia.
As ZS is not systemically absorbed, traditional phase 1 studies of the pharmacokinetics of ZS 
in healthy patients were not conducted. However, a phase 1 pharmacodynamic study (Study 
ZS-006) was conducted to characterize the potential effect of ZS on sodium and potassium 
excretion.
Completed Phase 2 and 3 Studies 
Four clinical phase 2 and 3 studies (ZS-002, ZS-003, ZS-004, and ZS-004E) of ZS in patients 
with hyperkalemia have been completed. ZS-002 was a proof-of-concept phase 2 study to 
assess the safety and efficacy of acute dosing in patients with chronic kidney disease (CKD) 
and hyperkalemia. ZS-003 and ZS-004 were phase 3 studies to assess the safety and efficacy 
of acute and extended dosing with ZS in patients with hyperkalemia. ZS-004E was an open-
label, long-term extension (11 months) of Study ZS-004. 
Study ZS-002 was a multicenter, prospective, randomized, placebo-controlled, double-blind, 
dose-escalating phase 2 study to investigate the safety, tolerability, and pharmacodynamics of 
ZS in patients with CKD (defined by an estimated glomerular filtration rate [GFR, eGFR] 
between 30 and 60 mL/min) and hyperkalemia (defined by S-K values between 5.0 and 6.0 
mmol/L, inclusive). A total of 90 patients were enrolled and, in a dose-escalating fashion, 
received ZS doses of 0.3, 3.0 or 10.0 g tid or placebo for a minimum of 48 hours or a 
maximum of 96 hours. Of the 90 randomized patients, a total of 30 patients were randomized 
to placebo, 12 to ZS 0.3 g tid, and 24 each to ZS 3 g tid and ZS 10 g tid. 
Study ZS-003(Packham DK et al 2015, Luo J et al 2016) was a phase 3, multicenter, 
prospective, randomized, placebo-controlled, double-blind, dose-ranging study to investigate 
the safety and efficacy of ZS in patients with hyperkalemia (i-STAT potassium values at entry 
between 5.0 and 6.5 mmol/L, inclusive). Patients were randomized to receive 1 of 4 doses of 
ZS (1.25 g, 2.5 g, 5 g, and 10 g) or placebo, administered tid with meals for the initial 48 
hours (Acute Phase), followed by a randomized dose of ZS (1.25 g, 2.5 g, 5 g, and 10 g) or 
placebo administered qd in the morning for 12 days (Subacute Phase). There was a one-time 
randomization to assign the Acute Phase and the Subacute Phase (in the event that normalized 
S-K was achieved after completion of the Acute Phase) treatments. The Subacute Phase 
randomized normokalemic patients to 1 of the 4 active doses in a 1:1 ratio between the same 
Acute Phase dose administered qd and placebo administered qd, whereas patients who 
received placebo in the Acute Phase were randomized to receive either 1.25 g or 2.5 g of ZS 
administered qd in the Subacute Phase. A total of 753 patients were randomized and treated in 
the Acute Phase of the study (158 placebo, 154 ZS 1.25 g tid, 141 ZS 2.5 g tid, 157 ZS 5 g tid, 


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and 143 ZS 10 g tid). Of the 579 ZS-treated patients who completed the Acute Phase, 447 
continued into the Subacute Phase and were randomized to continue on the same ZS dose they 
received in the Acute Phase but administered qd or placebo (49 ZS 1.25 g qd and 41 placebo; 
54 ZS 2.5 g qd and 46 placebo; 65 ZS 5 g qd and 68 placebo; and 63 ZS 10 g qd and 61 
placebo). 
ZS-004(Kosiborod M et al 2014) was a phase 3, multicenter, prospective, randomized, 
placebo-controlled, double-blind, dose-ranging maintenance study to investigate the safety 
and efficacy of ZS in patients with hyperkalemia (i-STAT potassium values ≥ 5.1 mmol/L). 
Patients were enrolled in the Open-label Acute Phase (Acute Phase) and treated with ZS 10 g 
tid for the initial 48 hours (6 doses). Patients who achieved normokalemia during the Acute 
Phase were randomized in a double-blind manner in a 4:4:4:7 ratio to 1 of 3 doses of ZS (5 g, 
10 g, or 15 g) or placebo administered qd for a further 28 days (Maintenance Phase). A total 
of 258 patients were enrolled in the Acute Phase of the study and were treated with ZS 10 g 
tid. Of the 251 patients who completed ZS 10 g tid dosing during the Acute Phase, 237 
continued into the Maintenance Phase and were randomized to either placebo (85 patients) or 
ZS (5 g [45 patients], 10 g [51 patients], or 15 g [56 patients] qd). 
ZS at doses of 3 g and 10 g tid in Study ZS-002, 2.5 g, 5 g, and 10 g tid in Study ZS-003, and 
10 g tid in Study ZS-004 demonstrated highly statistically significant and clinically 
meaningful dose-dependent decreases in S-K within 48 hours of treatment. Following S-K 
normalization via acute tid administration, extended dosing maintained normokalemia for up 
to 12 days with ZS qd doses of 5 g and 10 g in Study ZS-003, and for up to 28 days with ZS 
qd doses of 5 g, 10 g, and 15 g in Study ZS-004. The effectiveness of acute and extended 
dosing with ZS was evident across all predefined subpopulations (diabetes mellitus, heart 
failure [HF], CKD, and concurrent use of renin-angiotensin-aldosterone system [RAAS] 
inhibitor medication). Importantly, there was a close correlation between starting S-K and 
effect so that the higher starting S-K, the greater the effect. For example, in Study ZS-003, 
patients with a starting S-K > 5.5 mmol/L demonstrated a mean reduction in S-K of -1.1 
mmol/L at 48 hours versus a reduction of -0.57 mmol/L at 48 hours in patients with a starting 
S-K ≤ 5.3 mmol/L. This effect was also observed in Study ZS-004 with the mean reductions 
in S-K at 48 hours increasing with higher baseline S-K values (S-K ≥ 6.0: -1.49 mmol/L; S-K 
≥ 5.5 to < 6.0: -1.19 mmol/L; S-K < 5.5: -0.78 mmol/L). (Kosiborod M et al 2014, Packham 
DK et al 2015, Luo J et al 2016)
Study ZS-004E was a long-term (up to an additional 11 months), open-label extension to 
Study ZS-004. Patients who completed extended dosing in Study ZS-004 or who discontinued 
due to hypo- or hyperkalemia, and had a mean i-STAT potassium value between 3.5 and 6.2 
mmol/L, inclusive, were eligible to participate. If the i-STAT potassium value was between 
3.5 and 5.5 mmol/L, inclusive, at the end of Study ZS-004, the patient entered the Extended 
Dosing Phase and started open-label ZS at a dose of 10 g qd. If the i-STAT potassium value 
was > 5.5 mmol/L at the end of Study ZS-004, the patient entered an Acute Phase, where they 
received ZS 10 g tid for 24 (3 doses) or 48 hours (6 doses), depending on their daily i-STAT 
potassium measurement. Patients who attained normokalemia (i-STAT potassium between 3.5 
and 5.0 mmol/L, inclusive) after either 24 or 48 hours of treatment entered the Extended 


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Dosing Phase. The starting dose of ZS was 10 g qd, which could be titrated according to a 
patient’s i-STAT potassium value from a maximum dose of 15 g qd to a minimum dose of ZS 
5 g every other day (qod). Not all patients who completed Study ZS-004 and who were 
eligible for Study ZS-004E per protocol criteria continued in Study ZS-004E as drug product 
was not available for 77 patients who completed Study ZS-004. Hence, only 123 patients were 
enrolled and treated in Study ZS-004E.
In Study ZS-004E, extended dosing with ZS for up to 11 months was effective in maintaining 
normokalemia. Across Study Days 8 to 337, 88.3% (95% Confidence Interval [CI]: 81.2%, 
93.5%) of patients had average S-K values ≤ 5.1 mmol/L, which is statistically significantly 
higher than the 50% null hypothesis. The least squares mean from a logistic regression 
analysis, which adjusted for baseline covariates, was 92.8% (95% CI: 84.7%, 96.8%). Results 
were consistent across subgroups defined by age and baseline presence of CKD, HF, diabetes 
mellitus, and RAAS inhibitor use. In addition, the proportions of patients with S-K values ≤ 
5.1 mmol/L were relatively constant among the extended dosing time points, ranging from 
77.1% to 87.5%. The effectiveness of ZS in maintaining normokalemia was also demonstrated 
by the proportion of patients with average S-K values ≤ 5.5 mmol/L during Study Days 8 to 
337, as 100% (95% CI: 97.0%, 100.0%) of patients had average S-K values ≤ 5.5 mmol/L, 
which is statistically significantly higher than the 60% null hypothesis. The proportions of 
patients with S-K values ≤ 5.5 mmol/L were relatively constant across the extended dosing 
time points, ranging from 91.4% to 98.5%. 
Given the potency of ZS in reducing S-K levels, the reductions were not associated with 
events of significant hypokalemia or other clinically significant changes in electrolytes. Dose-
related increases in bicarbonate and reductions in blood urea nitrogen (BUN) were 
consistently observed in ZS-treated patients. There were no clinically important changes in 
other clinical laboratory tests, including no dose-related changes in serum magnesium, 
sodium, or calcium. 
ZS treatment was well tolerated at all dose levels administered in Studies ZS-002, ZS-003, 
ZS-004, as well as the long-term Study ZS-004E. In these studies, commonly reported 
treatment-emergent adverse events among patients who received ZS or placebo were 
gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, and dyspepsia). The 
majority of the treatment-emergent adverse events reported were mild or moderate in severity 
and most were considered unrelated to study drug. In Study ZS-004, an increased incidence of 
events associated with peripheral edema was reported with the ZS 15 g qd dose during 
extended dosing; however, this might be explained by more severe disease at baseline in the 
ZS 15 g group as compared to placebo (greater proportions of patients with HF [45% versus 
31%]). Edema was also monitored in long-term Study ZS-004E and the exposure-corrected 
edema rate (taken into consideration total exposure days) was comparable to the placebo rate 
in Study ZS-004. Furthermore, peripheral edema did not increase with duration of treatment 
with ZS, indicating that edema is unlikely to be related to ZS. No dose-response relationship 
has been observed for the occurrence of any other specific treatment-emergent adverse event. 


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No clinically significant dose-related changes in vital signs have been observed in ZS-treated 
patients. Consistent with the decrease in S-K, a small dose-related increase in QTc interval has 
been observed in patients during treatment with ZS. The level of increase in QTc is considered 
clinically insignificant and no increase in cardiac arrhythmias has been observed. 
Completed Phase 1 Study 
ZS is not systemically absorbed, as was confirmed from blood and urine samples collected as 
part of Study ZS-004. Thus, traditional phase 1 studies of the pharmacokinetics of ZS in 
healthy patients were not conducted. However, a phase 1 pharmacodynamic study (Study ZS-
006) was conducted to characterize the potential effect of ZS on sodium and potassium 
excretion in 30 healthy patients on a fixed, low-sodium and high-potassium diet. A total of 30 
patients received 4 days of dosing with ZS during this trial; 15 patients were dosed with 5 g qd
and 15 were dosed with 10 g qd. Overall, the small dose-dependent reduction in urine sodium 
excretion (5 g: -0.93 mmol/24 hours; 10 g: -5.47 mmol/24 hours) observed in this study 
suggests that ZS does not increase urinary sodium output in this patient population and study 
conditions. The decreases in urinary potassium with concomitant increases in fecal potassium 
are consistent with the mechanism of action of ZS. The decreases in urinary potassium of 
~379 and ~829 mg correspond to an in vivo KEC of 9.7 and 21.2 mEq potassium for the 5 g 
and 10 g doses of ZS, respectively.
Ongoing Clinical Studies 
One open-label phase 3 study (ZS-005) is currently ongoing, evaluating the long-term (up to 1 
year) safety and efficacy of ZS in maintaining normokalemia. The study contains an Acute 
Phase, in which patients are dosed with ZS 10 g tid for 24 to 72 hours, followed by a long-
term Extended Dosing period in which patients are dosed with ZS starting at 5 g qd, which 
may be increased or decreased in increments/decrements of 5 g qd up to a maximum of 15 g 
qd or a minimum of 5 g qod based on i-STAT potassium measurements. As of 7 December 
2015, a total of 751 patients had been included in the Acute Phase, of whom 746 patients 
entered Extended Dosing. 
In the Acute Phase of the study, 99% of patients achieved normokalemia. Of the 746 patients 
who entered Extended Dosing, 488 have completed ≥ 3 months of therapy, 436 have 
completed ≥ 6 months, 287 have completed ≥ 9 months, and 155 have completed 12 months. 
The vast majority of patients maintained normal serum potassium on ZS, with 87.9% and 
98.8% of patients reporting mean serum potassium ≤5.1 and ≤5.5 mmol/L throughout months 
3-12. Similar results were observed in pre-specified subgroups of patients with CKD, HF, 
diabetes mellitus, and those receiving RAAS inhibitor therapy. Mean S-K levels were 
maintained at 4.7 mmol/L. Safety data were consistent with other ZS studies.
1.2
Rationale for study design, doses and control groups
This phase 3 study is intended to be included in applications for marketing authorization in the 
countries where the study is performed.


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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 
48-hour 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 (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, double-blind treatment 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 48-hour 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 (ie, 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 studied 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.
The patient selection criteria allows for the assessment of both efficacy and safety of ZS in a 
relevant population of patients with hyperkalemia. Since hyperkalemia affects both men and 
women, the inclusion criteria allows equal access to the protocol for both sexes. Exclusion 
criteria are developed based on consideration of safety concerns and to prevent enrollment of 
patients who are unsuitable for the study. In order to ensure the study population reflect ‘real 
life’, the exclusion criteria are not extensive, as the Sponsor want to ensure that the patient


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
28 (86)
population enrolled is representative of the patient population receiving the drug post-approval. 
Hence, a large number of concomitant diseases and concomitant treatments are allowed, 
recognizing that many patients with hyperkalemia would also suffer from a range of 
concomitant diseases. This approach was further justified by the favorable safety and 
tolerability profile observed in Study ZS-003 and Study ZS-004, combined with the fact that 
ZS is not systemically absorbed.
1.3
Benefit/risk and ethical assessment
Hyperkalemia is common in patients with chronic kidney disease or heart failure, particularly 
when treated with renin angiotensin aldosterone system inhibitors (RAASi). Mortality risk 
with hyperkalemia parallels the magnitude of potassium elevation. 
Figure 1.               Multivariable-adjusted mortality by serum potassium level in a cohort 
of 55,266 patients with eGFR <60 ml/min per 1.73 m2 during median 
follow up 2.76 years (Lou J et al 2016)
0
1
2
3
4
5
<3.5
3.5-3.9
4.0-4.4
4.5-4.9
5.0-5.4
5.5-5.9
>6.0
Mortality- Adjusted IRR ± 95% CI
Serum K+ (mEq/L) 
1.49
[1.34, 1.65]
3.05
[2.53, 3.68]
1.06
[0.98, 1.14]
1.14
[1.04, 1.26]
1.60
[1.37, 1.88]
3.31
[2.52, 4.34]
Reference
For acute treatment, intravenous glucose/insulin and inhaled beta-adrenergic agonists drive 
potassium into cells. Potassium can be removed from the body by dialysis or with non-
absorbed polymers which non-selectively bind potassium and are excreted. Polymers do not 
lower potassium rapidly and cause significant gastrointestinal (GI) side effects (colonic 
necrosis, bowel obstruction, GI bleeding, ischemic colitis, perforation), bind to many oral 
medications and to other cations, lowering magnesium and calcium levels. Thus, an unmet 
need remains for safe, rapid, and an effective treatment for hyperkalemia.
Sodium zirconium cyclosilicate (ZS) is a non-absorbed, inorganic crystal that selectively 
exchanges hydrogen and sodium cations for potassium in a dynamic process throughout the 
upper and lower gastrointestinal tract. Bound potassium ions are excreted from the body. ZS is 
a white, insoluble, powder provided in 5g and 10g sachets to be suspended in water for oral 
administration.


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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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 normokalaemia 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
In double-blind, placebo-controlled trials 1009 patients received ZS. Subjects were 22 to 93 
years of age, 42% female, 86% white, 12% black and nearly all had chronic kidney disease, 
heart failure and/or diabetes mellitus.
Hypokalemia: During treatment up to 12 months at doses titrated to maintain normokalemia, 
hypokalemia was identified in 5.7% (7/123) of subjects in ZS-004E and 2.5% (17/684) in ZS-
005. Only 1 patient developed K+<3.0 mmol/L. 
Edema: Among subjects randomized to placebo, ZS 5, 10 or 15g QD, edema was reported by 
1.7, 0.9, 4.4 and 14.3%, respectively (ZS-003 & -004). Edema was untreated in 47% (7/15) of 
ZS-treated subjects and managed with diuretic initiation or dose adjustment and/or 
discontinuation of calcium channel blocker in the remainder. Although ZS exchanges protons 
and sodium for potassium, ZS did not increase urine sodium excretion in study ZS-002, -004 
or -006 indicating no increase in sodium absorption; the mechanism underlying edema 
remains uncertain.


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
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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
10g
15g
10g
15g
10g
15g
10g
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. 
No serious safety risks have so far been identified. Serum potassium should be periodically 
monitored.
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. 
1.4
Study Design 
This is a 2-phase, prospective, randomized, double-blind, placebo-controlled, phase 3 study to 
determine the safety and efficacy of ZS in patients with hyperkalemia.


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
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This study consists of screening period (1 day), 48-hour open-label initial phase,  28-day 
randomized treatment study phase and 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 48-hour 
open-label initial phase.
The study comprises 14 visits: enrolment visit (Visit 1), entering visit to 48-hour open-label 
initial phase (Visit 2), treatment visit in initial phase (Visit 3), randomization visit to 28-day 
randomized treatment study phase (Visit 4), treatment visit in 28-day randomized treatment 
study phase (Visit 5-12), safety visit in 28-day randomized treatment study phase (Visit 13), 
and end of study (EOS) visit. For details on timing of visits, see Figure below:


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
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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 EOS occurs 7±1 day after the last administration of study medication (same applies if patients leave the study during 48-hour open-label initial phase)
b  Study Day for 48-hour open-label initial phase
c Study Day for 28-day randomized treatment study phase; Day 3 of the 48-hour open-label initial phase is the same day as Day 1 for 28-day randomized treatment study phase
Screening
Treatment Period
ZS 10g tid
R
(2:2:1)
DB
ZS 5g qd
ZS 10g qd
Placebo qd
EOS a
48-hour open-label 
initial phase
28-day randomized treatment 
study phase
EOS
V 1
V 2
V 3
V 8
V 7
V 6
V 5
V 4
V 9
V 10
V 11
V 12
V 13
D -1
D 1b
D 2b
D 3b/D1c
D 2c
D 5c
D 8c
D12 c
D 15c
D 19c
D 22c
D 26c
D 29c


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Study Code D9480C00002
Version 3.0
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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 48h 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


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Study Code D9480C00002
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2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
48-hour open-label initial phase:
!
To evaluate the proportion of patients 
who achieve normokalemia after 48 
hours 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
Patient reported outcomes:
!
To evaluate the health state in the study 
population using EQ-5D
48-hour open-label initial phase efficacy endpoints:
!
Proportion of patients who achieve 
normokalemia during the initial phase at 24 and 
48 hours
!
Exponential rate of change in S-K levels 
(blood) during the 48-hour open-label initial 
phase
!
Change (absolute and percent change) from 
baseline in S-K levels (blood) at all measured 
time intervals (See Table 1) post dose in 48-
hour open-label initial phase
!
Time to normalization in S-K levels 
(normalization defined as S-K levels between 
3.5-5.0 mmol/L, inclusive) in 48-hour open-
label initial 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 
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
Patient reported outcomes:
!
EQ-5D questionnaire 
*       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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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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2.3
Safety objectives
Safety Objectives:
Outcome Measures:
!
To evaluate the effect of ZS on other 
serum electrolytes in both 48-hour open-
label initial phase and 28-day 
randomized treatment study phase
!
To evaluate the safety and tolerability 
profiles of ZS in both 48-hour open-
label initial phase and 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 hypokalaemia
2.4
Exploratory objectives
Not applicable.
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures 
2.
Female and male patients aged ≥18 and ≤90 years
3.
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 48-hour 
open-label initial phase Day 1
4.
Ability to have repeated blood draws or effective venous catheterization
5.
Female patients must be 1 year post-menopausal, surgically sterile, or using an 
acceptable method of contraception (an acceptable method of contraception is 
defined as a barrier method in conjunction with a spermicide) for the duration of the 
study (from the time they sign consent) and for 3 months after the last dose of 
ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, 
approved contraceptive implant, long-term injectable contraception, intrauterine 
device, or tubal ligation are allowed. Oral contraception alone is not acceptable; 
additional barrier methods in conjunction with spermicide must be used


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
2.
Participation in another clinical study with an investigational product during the last 
3 months
3.
Pseudohyperkalemia signs and symptoms, such as hemolyzed blood specimen due 
to excessive fist clenching to make veins prominent, difficult or traumatic 
venipuncture, or history of severe leukocytosis or thrombocytosis.
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
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
6.
Patients with a life expectancy of less than 3 months
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
8.
Female patients who are pregnant, lactating, or planning to become pregnant
9.
Patients with diabetic ketoacidosis
10.
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
11.
Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
12.
Patients with cardiac arrhythmias that require immediate treatment
13.
Patients on dialysis
14.
Patients who are blood donors should not donate blood during the study and for 3
months following their last dose of ZS
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.


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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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3.3
Patient enrolment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient or their guardian/legal 
representative before any study specific procedures are performed. Patient is 
considered enrolled in the study after she/he has signed the informed consent form 
(ICF).
2.
Assign potential patients a unique enrolment number via IVRS/IWRS, beginning 
with ‘E#’.
3.
Patients will remain associated with the same enrolment number throughout the 
entire study, and patients should NOT receive any new E-code if re-screened. If a 
patient signs the ICF but does not meet the inclusion/exclusion criteria the patient 
will be marked as a screen failure on the Screening and Enrolment Log provided by 
the Sponsor and will be entered in WBDC as a screen failure. Patients can be re-
screened once . A new ICF does not need to be signed before re-screening if the 
original ICF was signed within 30 days and the ICF has not been revised.
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment.  The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
The randomization codes will be computer generated using the AZ global randomization 
system (AZRand) and loaded into the IVRS/IWRS database. Randomization codes will be 
generated in blocks to ensure approximate balance (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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Study Code D9480C00002
Version 3.0
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3.6
Methods for ensuring blinding
The 28-day randomized treatment phase will have a double blind design. Patients will take by 
mouth the entire contents of a single sachet per day containing either ZS 5g, ZS 10g or 
placebo. The exterior appearance of the sachets are identical, but the volume of study drug 
will differ depending upon the randomized treatment group. Individual sachets are enclosed 
in a carton with a tamper evident seal intended to be broken exclusively by patients just before 
taking the study drug. 
A designated individual (e.g. pharmacist) at each study site will be responsible for performing 
study drug accountability and if required, this person will answer questions from patients 
related to the IP administered during the 28-day randomized treatment phase. The designated 
individual will not participate in patient management or patient assessments.
No member of the study team at AZ, or representative, personnel at study centers or any 
clinical research organization (CRO) handling data will have access to the randomization 
scheme during the conduct of the study, with the exception of the AZ personnel generating the 
randomization scheme as well as AZ Supply Chain, and the CRO companies providing the 
IVRS/IWRS and carrying out the packaging and labeling of study medication. This 
documentation will be kept in a secure location until the end of the study.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient in 28-day randomized treatment study phase, will be available to the Investigator(s) or 
pharmacists from the IVRS/IWRS in case of unblinding situation. Routines for this will be 
described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff.
AstraZeneca 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 inhibitor and/or diuretic therapy during the study, in addition, patients are not allowed 
to start dialysis while in the study. For concomitant medications which are restricted during 
the study, please see Section 7.7


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
39 (86)
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
!
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 > 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 48-hour open-label initial phase or 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


Clinical Study Protocol
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
40 (86)
∀
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.
Patients who discontinue from study medication but agree to remain in the study should 
continue to follow protocol-specified procedures and assessments except for dispensing of 
study medication for the study. 
Note: Discontinuation of investigational product does not necessarily imply discontinuation of 
follow-up or termination of all study participation.
3.9.1
Procedures for discontinuation of a subject from investigational product 
At any time, patients are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments – see Section 3.10), without prejudice to 
further treatment.  A patient that decides to discontinue investigational product will always be 
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
Any patient who is withdrawn from the study medication prior to study completion will return 
to the clinic 7 (± 1) days after the last IP administration for an EOS visit. Dosing schedule 
cards and all study drugs should be returned by the patient.


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
41 (86)
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 recieving 
open label treament. These patients should have the reason for study withdrawal recorded as 
‘Eligibility criteria not fulfilled’ (i.e., patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures. 
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
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/randomisation 
code cannot be reused. Withdrawn patients will not be replaced.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that are assessed as causally related to 
study drug and are not considered to be consistent with continuation of the study.
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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4.
STUDY PLAN AND TIMING OF PROCEDURES
Table 1
Study Plan detailing the procedures: 48-hour open-label initial phase
Study Visit
Visit 1
Visit 2
Visit 3
Visit 46
EOS8
Initial Phase Day
Screen
Day 112
Day 212
Day 312
Day 912
Written informed consent
X
Eligibility criteria
X9
Demographics
X
Medical History
X9
EQ-5D questionnaire
X
Physical exam including weight
X9, 13
X13
X13
Access IVRS/IWRS
X
X
X10
Study drug (IP) dispensation
X
Study drug (IP) administration
X
X
ECG
X9
X
X
Vital signs
X9
X
X
Concomitant medications
X9
X
X
X
Adverse events
X14
X
X
X
Potassium4, 11
X2
X3
X7
X7
Clinical Chemistry1,4
X9
X
X
Hematology1,4
X9
X
X
Urinalysis1,4
X9
X
X
Urine HCG
X5,9
X5
IP Reconciliation
X
1.
Parameters to be measured are detailed in Table 3. 
2.
Potassium will be measured twice 60 (±10) minutes apart within 1 day prior to any dose administration, and 
on initial phase Day 1 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 minutes) after taking the second dose for patients with i-STAT 
potassium ≥6.1 mmol/L or <4.0 mmol/L 4 hours after the first dose
3.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) after the first dose on initial phase Day 
2 (Visit 3)
4.
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 initial phase Day 1(Visit 2), the 
Central Laboratory clinical chemistry and hematology samples will be collected at the same time as the 60 
minutes i-STAT screening potassium sample;
5.
For women of childbearing potential, urine-HCG will be measured at clinic, using the tube provided by 
Central Laboratory


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
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6.
Visit 4 (Day 3 for 48-hour open-label initial phase) is the same visit of  Day 1 in 28-day randomized 
treatment study phase;  i-STAT and S-K for all patients, remaining procedures only for patients with i-
STAT potassium values >5.0 mmol/L as measured fasting
7.
Central laboratory S-K sample collected as part of the serum clinical chemistry
8.
EOS in 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
9.
Baseline parameters should be measured/collected up to 1 day prior to administration of the 1st dose of 
study drug on initial phase Day 1(Visit 2)
10. Access IVRS/IWRS on initial phase Day 3 (Visit 4) or if patient permanently discontinuous dosing before 
the end of initial phase dosing period
11. All potassium samples are analyzed by i-STAT and by the Central Laboratories on all occasions.             
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 potassium samples should be 
collected prior to insulin administration whenever possible.    
12. Study Day in Table 1 is for 48-hour open-label initial phase
13. A complete physical examination should be performed within 1 day prior to administration the first dose of 
study drug on initial phase Day 1, and targeted physical examination will be conducted on initial phase Day 
3 and 9 for patients not entering the 28-day randomized treatment study phase. Please refer to section 5.2.2
14. AEs will be collected after the patient has signed informed consent, so during the Day 1 (Visit 2), 
investigator need to check if any AE happened since from inform consent


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Study Code D9480C00002
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Table 2
Study Plan detailing the procedures: 28-day randomized treatment 
study phase
Study Visit
Visit  
4
Visit  
5
Visit  
6
Visit  
7
Visit  
8
Visit  
9
Visit 
10
Visit 
11
Visit 
12
Visit 
13
(EO
S)8
28-day
randomized 
treatment 
study phase
Day7
Day
110
Day
210
Day
510
Day  
810
Day
1210
Day
1510
Day
1910
Day
2210
Day
2610
Day
2910
Day
3510
Eligibility 
criteria
X
EQ-5D
X
Physical exam
including 
weight3, 11
X
X
X
X
Access 
IVRS/IWRS9
X
X
X
X
Study drug 
(IP) 
dispensation
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
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
Urinalysis1,3
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 


Clinical Study Protocol
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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 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 at the patient has been upright for at least 2 hours and before the ECG 
4.     IP administration may not happen during some scheduled visits in patients for which the dose was reduced 
to EOD dosing.
5.
For women of Childbearing potential, urine-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 Laboratories on all occasions.             
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 potassium samples should be 
collected prior to insulin administration whenever possible
7.
If a scheduled clinic visit falls on a weekend or National 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 28-day randomized treatment study phase Days 5, 8, 12, 15, 19, 22, 26 and 35, up to 2 
days late for 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.
EOS occurs 7±1 day after the last administration of IP
9.
Access IVRS/IWRS on visit indicated or if patient permanently discontinues dosing before the end of 28-
day randomized treatment study phase
10.    Study Day in Table 2 is for 28-day randomized treatment study phase
11.    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 5.2.2


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4.1
Enrolment/screening period (Visit 1)
Procedures will be performed according to the Study Plan in Table 1.
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be entered in the study. 
Patients can be re-screened once during the clinical trial period. A new ICF does not need to 
be signed before re-screening if the original ICF was signed within 30 days and has not been 
revised.
After a patient has signed the ICF at Visit 1 the site investigator will use the IVRS/IWRS to 
obtain a unique patient enrolment number after collecting the demographic parameters from 
the patient (including sex, date of birth, race, ethnic group).
4.2
Treatment period
Table 1 and Table 2 provide an overview of the procedures performed at each visit during the 
treatment period, and further details are provided below. Changing the order of the procedures 
at a visit, e.g. for logistical reasons, would not constitute a protocol violation if agreed in 
advance and in writing between the site and the sponsor study physician.
4.2.1
48-hour open-label initial phase Day 1 (Visit 2)
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 assessments 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 discontinue 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)
!
Administer the EQ-5D questionnaire


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!
Patient medical and surgical history including co-morbidities will be obtained with 
the review of selection criteria
!
Perform 12-lead Electrocardiogram (ECG)
!
Perform a complete physical examination including weight, see Section 5.2.2;
!
Review and record the concomitant medications and AEs/SAEs
Note: The above procedures should be performed within 1 day of the first administration of 
study drug and before any IP administration.
Patients who meet all inclusion/exclusion criteria will be entered into the trial and the 
following procedures will take place: 
!
The site will access the IVRS/IWRS and the system will assign the patient an 
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 potassium sample (i-STAT and 
Central Laboratory) will be collected, following which the patient is allowed to 
break the fast
!
Two additional potassium samples (i-STAT and Central Laboratory) will then be 
taken at 2 and 4 hours (±15 min) after dose administration. 
!
Patients with i-STAT potassium levels < 6.1 and ≥4.0 mmol/L at the 4 hour (± 15 
minutes) post Dose 1 blood draw will be sent home with instructions on how to take 
the IP. They will be requested to fill out a dosing schedule card indicating when 
they took the IP; The patient will return to the clinic the following morning for the 
initial Phase Day 2 (Visit 3)
!
Patients with i-STAT potassium ≥ 6.1 or <4.0 mmol/L at the 4 hour post Dose 1 
blood draw will stay in the clinic and take the second dose of study drug
approxtimately 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 as determined by i-STAT, and the 
ECG does not show any of the ECG withdrawal criteria, the patient will be sent 
home with the 3rd dose of study drug and the dosing card and return to the clinic in 
the morning of initial phase Day 2 (Visit 3). 
!
See section 7.2 regarding how to handle patients with potassium < 3.5 mmol/L.


Clinical Study Protocol
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Study Code D9480C00002
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4.2.2
48-hour open-label initial phase Day 2 (Visit 3)
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 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. 
!
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, 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 IP and 
dosing schedule card with them. 
4.2.3
48-hour open-label initial phase Day 3 (Visit 4)
Please note, the initial phase Day 3 is also the same day as the 28-day randomized treatment 
study phase Day 1 (Visit 4).
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 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 4.2.4). However if the i-STAT 
potassium value is > 5.0 mmol/L or <3.5 mmol/L the below assessments will be 
performed:


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Version 3.0
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∀
Samples will be collected: Blood samples for the standard assessment of clinical 
chemistry; blood sample for standard assessment of heamatology; Urine for
standard assessment of urinalysis parameters
∀
An ECG will be performed (Section 5.2.3)
∀
Perform target physical examination including weight (Section 5.2.2)
∀
Withdraw the patient from the 48-hour open-label initial phase
∀
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 
4.2.4
28-day randomized treatment study phase Day 1 (Visit 4)
The Day 1 of 28-day randomized treatment study phase is the same day as the Day 3 of 48-
hour open-label initial phase. Patients whose i-STAT potassium value is within the normal 
range (3.5 to 5.0 mmol/L, inclusive) at Day 3 of 48-hour open-label initial phase, will be 
randomized into the double-blind 28-day randomized treatment study 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 national 
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 IP and dosing 
schedule card with them when they return to the clinic.
4.2.5
28-day randomized treatment study phase Day 2 (Visit 5)
If the scheduled 28-day randomized treatment study phase Day 2 clinic visit falls on a 
weekend or National holiday the Day 2 visit (Visit 5) may occur up to 2 days late.


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Study Code D9480C00002
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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 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 (28-day 
randomized treatment study phase Day 5) and bring the used IP and dosing 
schedule card with them.
4.2.6
28-day randomized treatment study phase Day 5 (Visit 6)
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 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 (28-day 
randomized treatment study phase Day 8) and bring the used IP and dosing 
schedule card with them.
4.2.7
28-day randomized treatment study phase Day 8 (Visit 7)
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 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 and an ECG will be performed (Section 5.2.3). 


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Study Code D9480C00002
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!
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 (28-day 
randomized treatment study phase Day 12) and bring the used IP and dosing 
schedule card with them. 
4.2.8
28-day randomized treatment study phase Day 12 (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 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 (28-day 
randomized treatment study phase Day 15) and bring the used IP and dosing 
schedule card with them.
4.2.9
28-day randomized treatment study phase Day 15 (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 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 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 


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
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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 (28-day 
randomized treatment study phase Day 19 and bring the used IP and dosing 
schedule card with them.
4.2.10
28-day randomized treatment study phase Day 19 (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 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 (28-day 
randomized treatment study phase Day 22) and bring the used IP and dosing 
schedule card with them. 
4.2.11
28-day randomized treatment study phase Day 22 (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 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.


Clinical Study Protocol
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Study Code D9480C00002
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!
Patients will return to the clinic, in the morning, four (4) days later (28-day 
randomized treatment study phase Day 26) and bring the used IP and dosing 
schedule card with them
4.2.12
28-day randomized treatment study phase Day 26 (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 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 IP and dosing schedule 
card with them.
4.2.13
28-day randomized treatment study phase Day 29 (Visit 13)
Please note: If the Day 29 visit is conducted early, the patient must take IP through 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 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 


Clinical Study Protocol
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Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
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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 EQ-5D questionnaire will be administered
!
Patients will be instructed to return to the clinic, in the morning, 7 ±1 days 
following the last study IP administration (28-day randomized treatment study 
phase Day 35) for an EOS visit.
4.3
Follow-up period (EOS)
Follow up visit will be performed at Day 9 for 48-hour open-label initial phase, and Day 35 
for 28-day randomized treatment study phase, or 7 ±1 days following the last study IP 
administration for patients who are withdrawn from the study medication.
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 48-hour open-label initial phase or 28-day randomized treatment 
study phase falls on a weekend, the EOS visit can be performed either on the preceding Friday 
or the following Monday.


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Study Code D9480C00002
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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
Potassium
Blood samples for determination of potassium will be taken at the times indicated in the Study 
Plan (see Table 1 and Table 2). Potassium samples will be analyzed locally using i-STAT 
devices, and serum samples will be prepared and shipped to the Central Laboratory. All serum 
samples should be examined and any hemolyzed samples MUST be redrawn. In the event that 
hemolyzis or other artefacts are suspected based on the reported i-STAT result the sample 
may be re-drawn to confirm the result. Only the confirmatory sample result needs to be 
reported in the eCRF.
5.2
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.
Sample tubes and sample sizes may vary depending on laboratory method used and routine 
practice at the site.


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Table 3
Laboratory Safety Variables
Haematology
Clinical Chemistry (serum/plasma)
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)
U- Human chorionic gonadotropin (HCG) (only 
for females of childbearing potential) 2
S-Alanine transaminase (ALT)
S-Aldosterone
P-Renin
1.
Potassium will be tested by i-STAT and Central Laboratory
2.
Urine-HCG will be measured at clinic, used the tube provided by Central Laboratory
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
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 initial phase Days 1, 3 and 9 (EOS visit) for patients NOT entering the double-
blind 28-day randomized treatment study phase and on 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 initial phase Day 1 (60 
minute baseline sample), initial phase Days 3 and 9 (EOS) for patients not entering the 28-day 


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randomized treatment study phase, and on 28-day randomized treatment study phase Days 
1,15, 29 and 35 (EOS) 
Urine samples will also be collected during the study. The 48-hour 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 48-hour open-label initial phase Day 9, or on28-day randomized treatment study 
phase Day 35.
Urinalysis will be performed by the Central Laboratory at 48-hour open-label initial phase
Day 1 for all patients and on initial phase Days 3 and 9 for patients NOT entering the 28-day 
randomized treatment study phase, and on 28-day randomized treatment study phase Days 1, 
15, 29 and 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 examination
A complete physical examination should be performed within 1 day of administing the first 
dose of study drug on initial phase Day 1 (Baseline: all patients), and targeted physical 
examination will be conducted on 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
5.2.3.1
Resting 12-lead ECG
A 12-lead ECG will be performed after the patient has been lying down for 5 minutes at the
times indicated in the Study Plan in Table 1 and Table 2. Heart rate, P and QRS durations, PR
and QT intervals will be recorded from standard lead of the computerized quantitative 12-lead
ECG.
ECGs will be recorded at initial phase Day 1, initial phase Day 3 and Day 9 (EOS) for patients 
NOT entering the double-blind 28-day randomized treatment study phase, and on 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 at 


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the 1 hour post 1st dose time point on 48-hour open-label initial phase Day 1, an additional 
ECG will be recorded 1.5 hours post 2nd dose. 
5.2.4
Vital signs
5.2.4.1
Pulse rate and blood pressure
Pulse rate and systolic and diastolic blood pressure (BP) will be assessed using non-invasive 
equipment by an adequately trained health care professional. Measurements with a calibrated 
sphygmomanometer are preferred. If not available, another device calibrated carefully in 
proportion to a mercury sphygmomanometer is preferred. Use of aneroid manometers should 
be avoided. Appropriate cuff size must be used to ensure accurate measurement. 
The disappearance of sound (Korotkov phase V) should be used for the diastolic reading. 
Three (3) readings separated by 2 minutes should be averaged, and the average result will be 
recorded in the eCRF. If the first two readings of SBP differ by more than 5 mmHg, additional 
readings should be obtained.Blood pressure should be checked in both arms at the first visit. 
Subsequent blood pressure measurements should be recorded in the arm with the higher 
pressure. Blood pressure should be measured in either supine or sitting position. No shift from 
one position to another should be made during the study. Supine or sitting posture should be 
adopted for at least 5 minutes before measurement.The patient should be relaxed and with the 
arm outstretched and supported. Blood pressure should be measured under standardized 
conditions, as nearly as possible at the same time each visit, on the same arm, by the same 
personnel, and with the same apparatus.
5.3
Other assessments
The EQ-5D questionnaire in the local language will be administered on initial phase Day 1, 
and on 28-day randomized treatment study phase Day 29. The results will be recorded in the 
eCRF. See Appendix C.
5.4
Pharmacokinetics (Not applicable)
5.5
Pharmacodynamics (Not applicable)
5.6
Pharmacogenetics (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.


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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: 48-hour open-
label initial phase
Assessment
Sample 
Volume 
(mL)
Number of Samples
Maximum 
blood volume 
Total (mL)
V 2
(D 16)
V 3
(D 26)
V 4
(D 36)
EOS
(D 96)
Hematology
2
12
0-14
1
6
Clinical 
Chemistry
8.5
12
0-14
1
25.5
Potassium (i-
STAT and 
Central Lab S-K)
4.5
5-61,5
23
15
15
45
Maximum 
blood volume 
Total (mL)
37.5
9
15
15
76.5
V= Visit; D=Day
1.
Potassium will be measured twice 60 (±10) minutes apart within 1 day of first dose administration on initial 
phase Day 1(Visit 2) 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
2.
On initial phase Day 1(Visit 2), the Central Laboratory clinical chemistry and hematology samples will be 
collected at the same time as the 60 minutes i-STAT screening potassium sample
3.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) post 1st dose on initial phase Day 2 
(Visit 3)
4.
Clinical chemistry and hematology samples only for patients with i-STAT potassium values >5.0 mmol/L 
as measured fasting on initial phase Day 3 (Visit 4)
5.
Central laboratory S-K sample collected as part of the clinical chemistry
6.
Study Day in Table 4 is day for 48-hour open-label initial phase


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Table 5
Volume of blood to be withdrawn from each patient: 28-day randomized 
treatment study phase
Assessment
Sample 
Volum
e (mL)
Number of Samples
Maxi
mum 
blood 
volum
e 
Total 
(mL)
V4
D12
V5
D22
V6
D52
V7
D82
V8
D122
V9
D152
V10
D192
V11
D222
V12
D262
V13
D292
EOS
D352
Hematology
2
1
1
1
1
8
Clinical 
Chemistry
8.5
1
1
1
1
34
Potassium 
(i-STAT and 
Central Lab 
S-K1)
4.5
1
1
1
1
1
1
1
1
1
1
1
49.5
Maximum 
blood 
volume 
Total (mL)
15
4.5
4.5
4.5
4.5
15
4.5
4.5
4.5
15
15
91.5
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 28-day randomized treatment study phase
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.


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The term AE is used to include both serious and non-serious AEs.
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 or substantial 
disruption of the ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the subject or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events (including SAEs) will be collected from the time of informed consent, 
throughout the treatment period and including the EOS visit, and followed up to resolution of 
the Adverse Event.
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


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!
Maximum intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or 
no)
!
Action taken with regard to investigational product
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
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?’


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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 
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.


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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, an overdose is defined as more than 30g per day.
!
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.
!
An overdose without associated symptoms is only reported on the 
Overdose CRF module.
If an overdose on ZS occurs in the course of the study, then the Investigator or other site 
personnel inform appropriate AstraZeneca representatives immediately, or no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
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 


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contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
When the CRF module is used include the following:  The PREGREP module in the CRF is 
used to report the pregnancy and the PREGOUT is used to report the outcome of the 
pregnancy.
6.6.2
Paternal exposure 
Nonclinical data with ZS-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.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product and 
strength
Dosage form
Manufacturer
Sodium Zirconium
Cyclosilicate (ZS) 5 g
Powder for Oral Suspension in 
a sachet
AstraZeneca 
Sodium Zirconium
Cyclosilicate (ZS) 10 g
Powder for Oral Suspension in 
a sachet
AstraZeneca


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Placebo 
Powder for Oral Suspension in 
a sachet
AstraZeneca
7.2
Dose and treatment regimens
During the 48-hour 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 initial phase Days 1 and 2, but for other dose during the 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) on the morning of 48-hour open-label 
initial phase 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 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), dosing during the 28-day randomized treatment study phase will be reduced from qd 
to every other day.
If a patient develops confirmed i-STAT potassium values between 3.0 mmol/L and 3.4 
mmol/L, inclusive during the 48h initial open label treatment phase the subject will be 
directed to not take any more ZS during the rest of the day and return the next day to continue 
in the study. E.g. patients with potassium values between 3.0 mmol/L and 3.4 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 
and continue their therapy as per the study schedule if the potassium has is then between 3.5 
and 5.0 mmol/L. 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.
Patients with confirmed potassium <3.0 mmol/L should discontinue from therapy as per 
section 3.9.
For doses administered in the clinic during the 48-hour open label initial phase each dose will 
be individually dispensed by designated, trained site staff.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.


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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 48-hour open-label 
initial phase Day 1 until 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 48-hour open-label initial phase Day 1 through 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).
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 


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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.
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
7.7.1
Oral medications with gastric pH-dependent bioavailability
When co-administered with ZS, some oral medications with gastric pH-dependent 
bioavailability may exhibit a clinically meaningful increase or decrease in their 
bioavailability. Therefore, these drugs should be administered at least 2 hours before or 2 
hours after study drug,  to mitigate the risk of drug interactions. 
Drugs that should be taken 2 hours before or after study drug to avoid a possible raised gastric 
pH drug interaction are listed below:
Class of Drug
Drugs
Azole antifungals
Ketoconazole, Itraconazole, Posaconazole or 
Voriconazole
Anti-HIV drugs
Atazanavir, Nelfinavir, Indinavir, Ritonavir, 
Saquinavir, Raltegravir, Ledipasvir, 
Rilpivirine
Tyrosine kinase inhibitors
Erlotinib, Dasatinib, Nilotinib
7.8
Post Study Access to Study Treatment (Not Applicable)
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
All personnel involved with the analysis and conduct of the study will remain blinded until 
protocol violators have been identified, and database is locked. Analyses will be performed by 
AstraZeneca or its representatives.   


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A detailed Statistical Analysis Plan (SAP) will be prepared prior to first patient randomized 
and any subsequent amendments will be documented, with final amendments completed prior 
to unblinding of the data.
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 28-day randomized treatment study phase Study Days 8-29 
between each active dose (high to low) vs. placebo control. Assuming an intra-subject 
standard deviation of 0.50, approximately 255 patients, or 102 patients per active dose 
treatment arm and 51 patients for placebo control arm, will provide >90% power to detect a 
0.30 mean 28-day randomized treatment study phase Day 8-29 S-K difference, comparing 
each active dose (high to low) vs. placebo control using a two-sided t-test at a significance 
level of 5%. Assuming 95% of patients will be normokalemic after treatment with at least 1 
dose of ZS 10g (see section 7.2) , approximately 269 patients will be needed to enter 48-hour 
open-label initial phase. 
The assumptions used in the above sample size estimations are taken from the ZS-004 study.
8.3
Definitions of analysis sets
All efficacy analyses will be performed using the full analysis set (FAS) based on the Intent-
to-Treat (ITT) principle. The FAS includes all randomized patients. The main analysis will be 
analysed according to their randomized treatment assignment. 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.
This study will have prospectively defined analysis sets including separate evaluability rules 
for the 48-hour open-label initial phase and 28-day randomized treatment study phase. 
8.3.1
Full analysis sets (FAS)
FAS-OLP: For the 48-hour open-label initial phase, the full analysis set will include all 
patients registered in the 48h 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 48-hour open-label initial phase, the safety analysis set will include all 
patients as treated with at least one dose of IP in the 48h open label initial phase. 
SAF-RTP: For the subsequent 28-day randomized treatment study phase, the safety analysis 
set will include all patients as treated with at least one dose of 28-day randomized treatment 
study phase IP among those randomized. 


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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 
(LSMEAN) of all S-K value during the 28-day randomized treatment study phase Study Days 
8-29.
8.4.2
Secondary efficacy variables
For the 48-hour open-label initial phase, the secondary efficacy endpoints will include the 
following parameters:
!
Exponential rate of change in S-K levels (blood)
!
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 48-hour 
open-label initial phase at 24 and 48 hours
!
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 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 48-hour open-lable initial phase and 28-day randomized 
treatment study phase baselines
!
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
Analysis of data from the 28-day randomized treatment study phase will be performed after all 
patients have completed or discontinued from this phase. In addition, all relevant queries must 
be answered and the database must be locked and unblinded for the 28-day randomized 
treatment study phase prior to the analysis.
All efficacy analyses will be performed separately for the 48-hour open-label initial phase and 
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 initial 
phase and 28-day randomized treatment study phase, respectively.
All efficacy and safety data will be listed by patient. Descriptive statistics will consist of the 
number of patients (n), mean, standard deviation, median, minimum, and maximum for 
continuous variables and counts and percentage for categorical variables. Within-treatment 
group changes will be analysed using paired t-tests, and comparisons between each active 
dose treatment group vs. placebo control group will be performed using a 2-sample t-tests.
Results of all statistical analysis will be presented with a 95% confidence interval (CI) and 
two-sided p-value, unless otherwise stated.
For the initial phase, the baseline S-K will be established on initial phase Study Day 1 (pre-
treatment) by taking the mean of 2 different S-K values, recorded 60 ± 10 minutes apart.
For the subsequent 28-day randomized treatment study phase, the baseline S-K will be 
established in the morning of initial phase Study Day 3 and will use the first S-K measurement 
performed on Study Day 3, that establishes patient eligibility into the 28-day randomized 
treatment study phase.
The baseline for all other parameters will be the fasting parameter value measured within 1 
day of the first study drug administration in the initial phase.
Multiple testing strategy
An overall Type I error rate of 5% accounting for efficacy analyses, in both phases of the 
study, will be maintain 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. 


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Specifically, the following fixed hierarchical sequence (see Table 6; progressing to the next 
test in the sequence till a 2-sided p-value of > 0.05 is encountered.  At which point further 
testing will cease.  Explicitly, Table 6 will be implemented:
Table 6
Confirmatory Testing Sequence
Seq
Study Phase 
Efficacy variable
Comparison
1
Acutei
48-hour open label phase mean change from baseline 
48 hours after first dose of ZS 10g
2
Maintenanceii
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/Exitiii
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 
Days 8 to 29, inclusive
ZS 10g QD vs. 
Placebo
7
Maintenance
Number of days patients remain normokalemic 
during the 28-day randomized treatment study phase
Days 8 to 29, inclusive
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
i     Acute Study Phase refers to the 48-hour Open Label Initial Phase.
ii    Maintenance Study Phase refers to the 28-day randomized treatment Study Phase.
iii   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 LSMEAN 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 study treatment period to 
estimate the least squares mean Day 8-29 values stratified by country; the model will include 


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all S-K data collected at the schedule visits between Day 8-29 as response variables, and 
baseline covariates for initial phase eGFR and open label and double-blind randomized phase
baseline S-K values as well as age (<55, 55-64, ≥65 years), country and baseline binary 
indicators for RAAS inhibitors, chronic kidney disease, heart failure, and diabetes mellitus. In 
addition, the primary efficacy endpoint will be evaluated in patients with hyperkalemia 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 outcome. If 
Central Laboratory data are missing, they will be replaced by i-STAT values adjusted to 
reflect the mean difference between i-STAT and S-K values from all available paired lab 
samples collected in this study.  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 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.
For the 28-day randomized treatment study phase, the same modelling strategy (as described 
in Section 8.5.1) will be applied to the secondary efficacy endpoint to compare each active 
dose (high to low) vs. placebo control.
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 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
The health state of the study population will be assessed on initial phase Day 1, and on 28-day 
randomized treatment study phase Day 29 using the EQ-5D questionnaire. 
In addition, the secondary efficacy endpoint at the end of the 28-day randomized treatment 
study phase will be evaulated in patients with hyperkalemia for the subgroups defined in 
Section 8.5.4. More details will be specified in the SAP.


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8.5.3
Safety analysis
Separate safety analyses will be performed for the initial phase and 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]).
The respective safety analysis will be undertaken on the safety analysis sets, separately for the 
initial phase and for the 28-day randomized treatment study phase. Safety and tolerability data 
will be presented by treatment arm. 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]). For each study treatment, safety data will be collected and 
analysed while on initial phase or 28-day randomized treatment study phase treatment, and 
follow up until adverse events are resolved. The type, incidence, timing (onset, duration), 
relationship, and severity of AEs will be reported for treatment-emergent and SARs. Reasons 
for 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.
The time frames of interest will be from 28-day randomized treatment study phase Study Day 
1 through the end of 28-day randomized treatment study phase Day 28. Unresolved adverse 
event outcomes at the end of 28-day randomized treatment study phase will be followed for an 
additional seven days or until resolution, whichever occurs earlier.
8.5.4
Subgroup analysis
To facilitate a benefit-risk assessment for the purpose of regulatory submission in Japan, 
subgroup of patients from Japan will be analyzed separately, with respect to all efficacy and 
safety variables for both phases of the study. More details will be presented in the SAP.
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 
following subgroups:
!
chronic kidney disease (CKD)
!
diabetes mellitus (DM)
!
Heart failure (HF)


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!
those on RAAS inhibitors
More details will be described in the SAP.
8.5.5
Interim analysis
No interim analyses are planned.
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 


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disposed of/destroyed accordingly, and the action is documented, and 
reported to the subject.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.2.4
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 2017 and to end by Q1 2018.


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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.  
Data will be entered into the WBDC system at the study site. Trained site staff will be 
entering the data as specified in the protocol and according to the eCRF instructions. Data 
entered into the WBDC system will be immediately saved to a central database and changes 
tracked to provide an audit trail. The data will then undergo quality control and be validated as 
described in the Data Management Plan.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the AZ Drug Dictionary or WHODRUG. Classification coding will be 
performed by the Medical Coding Team at the AZ Data Management Center or other party.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
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.


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Management of external data
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to the clinical database. Data Management will assure that the 
data collection tools for IVRS are tested and validated. External data reconciliation will be 
done with the clinical database as defined in the Data Management Plan.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An 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.
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.


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AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports 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
!
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 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 study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment 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 revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 10.3.


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If a protocol amendment 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
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, GCP, 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements.  The Investigator will contact AstraZeneca immediately if contacted 
by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
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.


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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the 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 (eg, 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 (eg, 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 (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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!
Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
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 D9480C00002
Version 3.0
Date 22 Sep 2017
83 (86)
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
84 (86)
Appendix C           EQ-5D Health Questionnaire
Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walking about 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 
            
I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 
            


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
85 (86)
I have severe problems doing my usual activities 

I am unable to do my usual activities 
            
PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 
            


Clinical Study Protocol Appendix B
Drug Substance ZS
Study Code D9480C00002
Version 3.0
Date 22 Sep 2017
86 (86)
!
We would like to know how good or bad your health is 
TODAY.
!
This scale is numbered from 0 to 100.
!
100 means the best health you can imagine.
0 means the worst health you can imagine.
!
Mark an X on the scale to indicate how your health is TODAY.
!
Now, please write the number you marked on the scale in the box 
below. 
YOUR HEALTH TODAY  =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health       
you can imagine
The worst health     
you can imagine


Document Name:
                                                                   
Document Title:
                                                                                                    
                                                                                                                                     
                                                                                                                              
                                                                                                                                             
                                                                                                                 
Document ID:
                                                                                          
Version Label:
                  
 
 
 
 
 
 
 
     
            
                                          
              
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
Signed By
Meaning of Signature
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
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SAP_000.pdf: 
Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
1
Statistical Analysis Plan
Study Code
D9480C00002
Edition Number
2.0
Date
15 March 2018
A phase 3 multicenter, prospective, randomised, double-blind, placebo-
controlled study to investigate the safety and efficacy of ZS (sodium 
zirconium cyclosilicate), in patients with hyperkalemia-HARMONIZE 
Global


PPD


PPD


PPD


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
5
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................1
SIGNATURE OF STUDY STATISTICIAN.............................................................2
SIGNATURE OF STUDY STATISTICIAN.............................................................3
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .......................................4
TABLE OF CONTENTS..........................................................................................5
LIST OF ABBREVIATIONS ...................................................................................8
AMENDMENT HISTORY.....................................................................................10
1
STUDY DETAILS..................................................................................16
1.1
Study objectives......................................................................................16
1.2
Study design ...........................................................................................18
1.2.1
Schedule of Visits ...................................................................................20
1.2.1.1
Enrolment/screening period (Visit 1).......................................................24
1.2.1.2
48-hour open-label initial phase Days 1-3 (Visit 2-4) ..............................24
1.2.1.3
28-day randomised treatment study phase Days 1-29 (Visit 4-13) ...........24
1.2.1.4
Follow-up period (EOS)..........................................................................25
1.3
Number of patients..................................................................................25
1.3.1
Sample size estimate ...............................................................................26
2
ANALYSIS SETS ..................................................................................26
2.1
Definition of analysis sets .......................................................................26
2.1.1
Full analysis sets.....................................................................................26
2.1.2
Safety analysis sets .................................................................................27
2.2
Violations and deviations ........................................................................27
2.2.1
Important protocol deviations..................................................................27
2.2.2
Screen failures ........................................................................................28
3
PRIMARY AND SECONDARY VARIABLES......................................28
3.1
Primary efficacy variable ........................................................................28
3.2
Secondary efficacy variables...................................................................28
3.2.1
48-hour open-label initial phase ..............................................................28
3.2.2
28-day randomised treatment phase.........................................................28
3.3
Other variables........................................................................................29
3.4
Safety Variables......................................................................................29
3.4.1
Adverse Events (AEs).............................................................................29


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
6
3.4.1.1
Recording of adverse events....................................................................30
3.4.1.2
Variables.................................................................................................30
3.4.2
Vital Signs ..............................................................................................31
3.4.3
Physical Examination..............................................................................31
3.4.4
Electrocardiogram ECG).........................................................................31
3.4.5
Laboratory Assessments..........................................................................32
3.4.6
Visit windows.........................................................................................33
4
ANALYSIS METHODS.........................................................................34
4.1
General principles...................................................................................34
4.1.1
Definition of Baseline and Post Baseline.................................................35
4.1.2
Definition of change from baseline..........................................................36
4.1.3
Definition of percent change from baseline .............................................36
4.1.4
Mixed Model: Terms and Estimation ......................................................36
4.1.5
Log-transformation of S-K values ...........................................................37
4.1.6
Handling of missing data.........................................................................37
4.1.6.1
S-K efficacy endpoint .............................................................................37
4.1.6.2
Missing start and stop dates – AEs and concomitant medications ............37
4.1.7
Definition of subgroups...........................................................................37
4.2
Hypotheses .............................................................................................38
4.2.1
Primary hypotheses.................................................................................38
4.2.2
Secondary hypotheses .............................................................................38
4.2.3
Multiple testing strategy..........................................................................39
4.3
Analysis methods....................................................................................41
4.3.1
Demographics and baseline characteristics..............................................41
4.3.2
Patient disposition and study population..................................................41
4.3.3
Medical History ......................................................................................41
4.3.4
Prior and/or Concomitant Medication......................................................42
4.3.5
48-hour open-label initial phase efficacy analyses ...................................42
4.3.5.1
Exponential rate of change ......................................................................42
4.3.5.2
Mean change from baseline and mean percent change from baseline.......42
4.3.5.3
Proportion of normokalemic patients.......................................................42
4.3.5.4
Time to normalisation in S-K values .......................................................42
4.3.6
28-day randomised treatment study phase (RTP) efficacy analyses .........43
4.3.6.1
Primary efficacy analysis ........................................................................43
4.3.6.2
Secondary efficacy analysis ....................................................................43
4.3.7
Sensitivity analyses of primary and selected secondary efficacy variable.44
4.3.7.1
Sensitivity analysis replacing central laboratory S-K with i-STAT ..........44
4.3.7.2
Sensitivity analysis to assess impact of change to potassium assay..........45
4.3.8
Other secondary analysis.........................................................................45
4.3.9
Safety analyses........................................................................................45
4.3.9.1
Treatment Duration, Treatment Compliance, and Exposure.....................46
4.3.9.2
Adverse Events (AEs).............................................................................46
4.3.9.3
Analyses for Laboratory Tests.................................................................48
4.3.9.4
Vital Signs ..............................................................................................48


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
7
4.3.9.5
Physical Examination..............................................................................48
4.3.9.6
Pregnancy Test........................................................................................49
4.3.10
Subgroup analyses ..................................................................................49
5
INTERIM ANALYSES ..........................................................................49
6
CHANGES OF ANALYSIS FROM PROTOCOL ..................................50
7
REFERENCES .......................................................................................50
8
APPENDIX ............................................................................................51
8.1
Appendix A: Partial date conventions for AE..........................................51
8.2
Appendix B: Algorithm for prior/concomitant medications: ....................52
8.3
Appendix C: Definition of subgroups......................................................54
8.4
Appendix D: Change in calibration of the potassium assay......................58


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AZ
AstraZeneca
BUN
Blood Urea Nitrogen
CHF
Congestive heart failure 
CI
Confidence Interval 
CKD
Chronic Kidney Disease
CTCAE
Common Terminology Criteria for Adverse Event
DM
Diabetes mellitus 
ECG
Electrocardiogram
eCRF
electronic Case Report Form 
eGFR
Estimated Glomerular Filtration Rate
EOS
FAS
FAS-OLP
FAS-RTP
End of Study
Full Analysis Set
Full Analysis Set for the 48-hours Open Label Initial Phase
Full Analysis Set for the double blind Randomised Treatment Phase
GFR
Glomerular Filtration Rate
ITT
Intent-to-Treat 
IPD
Important protocol deviation
HCG
Human chorionic gonadotropin
HF
Heart Failure
IP
Investigational Product 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
OLP
the 48-hours Open Label Initial Phase
P-Renin
Plasma-Renin
qd
Once Daily
qod
Every other day 
RAAS
Renin-angiotensin-aldosterone system 
RTP
Double-blind 28 Day Randomised Treatment Phase
SAE
Serious Adverse Event 


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
9
Abbreviation or 
special term
Explanation
SAF
SAF-OLP
SAF-RTP
Safety Analysis Set
Safety Analysis Set for the 48-hours Open Label Initial Phase
Safety Analysis Set for the double blind Randomised Treatment 
Phase
S-HCO3
Serum bicarbonate 
S-K
Serum potassium
S-Mg
Serum magnesium 
S-Na
Serum sodium 
S-PO4
Serum phosphate 
Tid
three times a day
VS 
Vital signs
WHO 
World Health Organization
ZS
Sodium zirconium cyclosilicate


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
10
AMENDMENT HISTORY
Date
Brief description of change
23 November 
2017
The SAP was updated to better reflect AZ standards on the presentation 
of safety variables. Additionally, sensitivity analyses and subgroup 
analyses were updated. Evaluations of endpoints where updated to be 
analysed using only one method per endpoint. Various minor typos 
corrected. Harmonization in the use of RTP. See below for further 
details on the updates. 
List of abbreviations: Clarified that the RTP refers to the 28-day 
randomized treatment phase. WHO added to the list.
Section 2.1.1: ”Enrolled” changed to ”entered” in the definition of the 
SAF-OLP.
Section 2.2.1: Clarified that the number of patients with IPDs will be 
presented by study phase.
Section 4.1.7.1: Following section was removed:
”If a patient’s Day 29 S-K assessment is made more than one day after 
the last dose, it will be treated as missing in data analysis and handled 
as defined above.”
Section 4.2.2: The following hypotheses added to the list of secondary 
hypotheses to be tested:
The mean change in P-Renin in the ZS 10g treatment group;
The mean change in P-Renin in the ZS 5g treatment group.
Section 4.3.2: “All screened patients” changed into “all enrolled 
patients” in the description of the patient disposition summary. 
”Number of OLP registered patients” changed into ”Number of patients 
entered in OLP”.
Section 4.3.4: ”AstraZeneca Drug Dictionary” replaced by ”WHO Drug 
Dictionary”.
Section 4.3.5: Description of presentation of ”Expected exponential rate 
of change” removed from this section. Clarified that the nominal and 
percent changes referenced should be for the S-K values.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
11
Date
Brief description of change
Section 4.3.5.1: Formula for Expected exponential rate of change is 
removed. Clarified that the time estimate from the linear mixed model 
will be presented. ”Expected” is removed from this and other section 
referencing this endpoint.
Section 4.3.5.3: Clarified that the Clopper-Pearson method for exact 
confidence interval for proportion will be used.
Section 4.3.6.1: Removed text describing that that LSMEANs will be 
provided for each study visit. Added that results will also be provided 
back-transformed to the original scale.
Section 4.3.6.2.1: Removed Fisher’s Exact Test for proportion of 
patients remaining normokalemic at Day 29/Exit. ”Day 29/EOS” 
changed to ”Day 29/Exit” to be in line with title. Text added to clarify 
that proportion of patients remaining normokalemic will be presented 
by study visit.
Section 4.3.6.2.2: Clarified that LSMEANs will be provided for the 
number of normokalemic days. 
Section 4.3.6.2.3: Log-rank test for time to hyperkalemia removed.
Section 4.3.7.1: Following two sensitivity analyses was removed:
i)
Including patients discontinuing before day 8 having a Day 8 
measurement imputed using an interpolation based on an 
EM algorithm.
ii)
Repeating the primary analysis model on non-logged K 
values.
Section renumbered to 4.3.7
Section 4.3.7.2: Sensitivity analysis for the secondary endpoint of 
number of normokalemic patients was removed. Section removed.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
12
Date
Brief description of change
Section 4.3.9.2: Section re-phrased to clarify that only AEs considered 
as treatment emergent will be included in summaries. Definition of 
treatment-emergent added. Clarified how to present AEs using the date 
of onset. Text not referring to the analysis or presentation removed. 
General updates to section 4.3.9.2 and subsections:
TEAE replaced by AE. 
“Overall” removed from descriptions of presentations.
Section 4.3.9.2.1: Added the following two bullets to the categories in 
the overall AE summary:
!
Number and percentage of patients experiencing AEs with 
outcome of death
!
Number and percentage of patients experiencing AEs leading to 
treatment withdrawal
The following two bullets were removed:
!
the number and percentage of patients experiencing a TEAE by 
strongest relationship to study medication
the number and percentage of patients experiencing a TEAE by greatest 
intensity
Text referring to presentation of AEs leading to permanent 
discontinuation moved to 4.3.9.2.2.
Section 4.3.9.2.2: Repetitions removed from the text.
Section 4.3.9.2.3: SOC removed from description of presentation. 
Removed text describing that separate presentations will be provided 
for AEs classified as related and non-related by investigator.
Section 4.3.9.2.4: SOC removed from description of presentation.
Section 4.3.9.2.5: ”Other SAEs” removed from title. Added description 
that AEs with outcome of death will be tabulated by SOC and PT.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
13
Date
Brief description of change
Section 8.1 Appendix A: Clarified that imputation of incomplete or 
missing onset date of an AE will be set to the day of the first dose of 
study medication only if the end date is on or after the first dose of 
study medication.  
Imputation rules for incomplete AE end dates removed as it has no 
impact on presentation of adverse events.
Section 4.3.10: The presentation of subgroup analyses for CKD, CHF, 
DM and RAASi use has been modified. An interaction effect for 
treatment by subgroup was included.
29 November 2017
IPD added to list of abbreviations.
Section 2.2: Corrected cross-reference to section 2.2.1.
Section 3.4: Repeating information removed.
Section 4.1: Clarified that Eq. 2 for eGFR will be used for Japan 
specific analyses alone.
Section 4.1.5: Section regarding visit windows is moved to section 
3.4.6. 
Section 4.1: Added description that p-values from tests not included in 
the closed testing procedures are considered exploratory and not called 
significant.
Section 4.1.6.1: Removed paragraph describing imputation of Day 8 S-
K values. This related to a now removed sensitivity analysis.
Section 4.3.2: Added clarification for enrolled and entered into the 
OLP.
Section 4.3.6.2.4: Clarified that t-tests will be performed for mean 
change from baseline for S-Aldo and P-Renin.
Section 4.3.9.2: Study treatment exposure added.
Section 4.3.10: Clarified that output for Japanese subgroup will be 
included in Japan specific CSR.
16 February 2018
Secondary efficacy variable of Exponential rate of change updated. 
Mention of 24-hour and 48-hour removed from Sections 3.2.1 and 
4.2.2.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
14
Date
Brief description of change
Section 3.2.2: Clarified that change in S-K levels is computed as 
compared to OLP and RTP baselines.
Section 3.4.5: New paragraph describing a change to the potassium 
assay calibration.
Section 4.1.6.1: Imputation method modified to, in addition to the visit 
number, take into account the calibration method for the potassium 
assay at the central laboratory.
Section 4.1.7: New section describing the definition of subgroups of 
patients with heart failure, chronic kidney disease and diabetes mellitus.
Section 4.2.2: Hypotheses for mean change or percent change in S-K 
levels during RTP removed.
Section 4.3.2: Language updated so that definition of entered patients 
does not contradict the definition given in section 2.1.1.
Section 4.3.3: Removed paragraph describing a listing for prior and 
current medical history.
Section 4.3.4: Analysis set for prior and concomitant medication 
changed to FAS.
Section 4.3.5: Language updated to include all pre-planned time points 
in summary of S-K levels during OLP.
Section 4.3.7: New subsection 4.3.7.2 describing sensitivity analyses to 
assess impact of a change to the calibration method of the potassium 
assay the central laboratory.
Section 4.3.9.1: Sorting criteria for listing removed.
Section 8.3: New Appendix added for definition of subgroups.
Section 8.4: New Appendix added for details regarding the change to 
the potassium assay.
15 March 2018
Section 2.1.1: Clarified that patients that were entered and received 
study medication in OLP without meeting eligibility criteria will be 
included in the full Analysis Set for OLP.
Section 4.3.5.1: Rephrased section to clarify the fixed and random 
effects used in the model.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
15
Date
Brief description of change
Section 4.3.9.2: Clarified that AEs occurring on OLP Day 3 (day of 
randomisation) should be summarised for OLP since it would not be 
possible to distinguish whether AE occurred before or after intake of 
randomised study medication.
Sections 4.3.6.2.1-3: Clarified that effects for visit and visit-by-
treatment interaction are not included in modelling.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
16
1
STUDY DETAILS
HARMONIZE Global is a Phase 3 multicentre, prospective, randomised, double-blind, 
placebo-controlled study to investigate the safety and efficacy of ZS in patients with
hyperkalemia. It is intended to be included in applications for marketing authorisation in the 
countries where the study is performed. For details on study background and rationale, please 
refer to the Clinical study protocol for HARMONIZE Global (CSP, D9480C00002, Version 
2.0 (07 Dec 2016)).
This Statistical Analysis Plan (SAP) provides details of the summaries and analyses to be 
performed to report the findings of the study. This SAP, which will be finalised prior to 
database lock (DBL), should be read in conjunction with the HARMONIZE Global CSP. 
1.1
Study 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 48h 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 randomised
treatment study phase Days 8-29


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
17
Secondary Objectives:
Outcome Measures:
48-hour open-label initial phase:
!
To evaluate the proportion of patients 
who achieve normokalemia after 48 hours 
of open-label initial phase treatment
28-day randomised 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
Patient reported outcomes:
!
To evaluate the health state in the study 
population using EQ-5D
48-hour open-label initial phase efficacy endpoints:
!
Proportion of patients who achieve 
normokalemia during the initial phase at 24 and 
48 hours
!
Exponential rate of change in S-K levels 
(blood) during the 48-hour open-label initial 
phase
!
Change (absolute and percent change) from 
baseline in S-K levels (blood) at all measured 
time intervals (See Table 1)  post dose in 48-
hour open-label initial phase
!
Time to normalisation in S-K levels 
(normalisation defined as S-K levels between 
3.5-5.0 mmol/l, inclusive) in 48-hour open-label 
initial phase
28-day randomised 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 
randomised treatment study phase and during 
the 28-day randomised treatment study phase
!
The number of days patients remain 
normokalemic during the 28-day randomised 
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
Patient reported outcomes:
!
EQ-5D questionnaire


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
18
Safety Objectives:
Outcome Measures:
!
To evaluate the effect of ZS on other 
serum electrolytes in both 48-hour open-
label initial phase and 28-day randomised 
treatment study phase
!
To evaluate the safety and tolerability 
profiles of ZS in both 48-hour open-label 
initial phase and 28-day randomised 
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
*       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 randomised 
treatment study phase will be evaluated in patients with hyperkalemia for the subgroups.
1.2
Study design
This is a 2-phase, prospective, randomised, double-blind, placebo-controlled, Phase 3 study to 
determine the safety and efficacy of ZS in patients with hyperkalemia.
This study consists of a screening period (1 day), 48-hour open-label initial phase (OLP), 28-
day randomised treatment study phase (RTP), and follow-up period (7±1 days after the last 
administration of study medication). 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 the first dose of study drug in the 
OLP. 
During the OLP all patients will receive ZS per os (PO) at a dose of 10g three times a day (tid) 
for a maximum of 6 doses.  If a patient develops confirmed i-STAT (as measured by a 
portable blood analyser) potassium values between 3.0 mmol/L and 3.4 mmol/L inclusive 
during the OLP, the patient will be directed to not take any more ZS during the rest of the day 
and return the next day to continue in the study.  For patients who do not enter the RTP, the 
end of study (EOS) follow-up visit will be 7±1 days after the last administration of study 
medication in the 48-hour open-label initial phase.
Patients who achieve normokalemia (i-STAT potassium values between 3.5 to 5.0 mmol/l, 
inclusive) on the morning of Day 3 will then be randomised 2:2:1 into the double-blind 28-day 
randomised treatment study phase to receive ZS 5g, 10g or placebo, PO qd for the following 
28 days.  If the potassium level remains low (e.g., if a patient develops i-STAT potassium 
values between 3.0 mmol/L and 3.4mmol/L, inclusive as confirmed by taking a second 
potassium measurement after a 10 ± 2 minute interval), dosing during the RTP will be reduced 
from qd to every other day.  Patients will then be required to complete the study Day 29 visit, 
and the EOS visit which is 7±1 days after the last administration of study medication. 


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
19
Figure 1.               Study flow diagram
R=Randomization; DB=Double-blind; EOS=End of study; V=Visit; D=Day; tid=three times a day; qd=once daily
a  EOS occurs 7±1 day after the last administration of study medication (same applies if patients leave the study during 48-hour open-label initial phase)
b  Study Day for 48-hour open-label initial phase
c Study Day for 28-day randomized treatment study phase; Day 3 of the 48-hour open-label initial phase is the same day as Day 1 for 28-day randomized treatment study phase
Screening
Treatment Period
ZS 10g tid
R
(2:2:1)
DB
ZS 5g qd
ZS 10g qd
Placebo qd
EOS a
48-hour open-label 
initial phase
28-day randomized treatment 
study phase
EOS
V 1
V 2
V 3
V 8
V 7
V 6
V 5
V 4
V 9
V 10
V 11
V 12
V 13
D -1
D 1b
D 2b
D 3b/D1c
D 2c
D 5c
D 8c
D12 c
D 15c
D 19c
D 22c
D 26c
D 29c


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
20
1.2.1
Schedule of Visits
The study will be conducted according to the study flow diagram (Figure 1) and the Study 
Plan (Table 1 and Table 2). The study plan tables provide an overview of the procedures 
performed at each visit during the treatment period, and further details are provided in the 
protocol (CSP, D9480C00002, Version 2.0 (07 Dec 2016)). 
Table 1
Study Plan detailing the procedures: 48-hour open-label initial phase
Study Visit
Visit 1
Visit 2
Visit 3
Visit 46
EOS8
Initial Phase Day
Screen
Day 112
Day 212
Day 312
Day 912
Written informed consent
X
Eligibility criteria
X9
Demographics
X
Medical History
X9
EQ-5D questionnaire
X
Physical exam including weight
X9, 13
X13
X13
Access IVRS/IWRS
X
X
X10
Study drug (IP) dispensation
X
Study drug (IP) administration
X
X
ECG
X9
X
X
Vital signs
X9
X
X
Concomitant medications
X9
X
X
X
Adverse events
X14
X
X
X
Potassium4, 11
X2
X3
X7
X7
Clinical Chemistry1,4
X9
X
X
Hematology1,4
X9
X
X
Urinalysis1,4
X9
X
X
Urine HCG
X5,9
X5
IP Reconciliation
X
1.
Parameters to be measured are detailed in Table 3                 Laboratory Safety Variables. 
2.
Potassium will be measured twice 60 (±10) minutes apart within 1 day prior to any dose administration, and 
on initial phase Day 1 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 minutes) after taking the second dose for patients with i-STAT 
potassium ≥6.1 mmol/L or <4.0 mmol/L 4 hours after the first dose
3.
Potassium will be measured predose (0 hour) and 1 hour (±15 min) after the first dose on initial phase Day 2 
(Visit 3)
4.
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 initial phase Day 1(Visit 2), the 


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
21
Central Laboratory clinical chemistry and hematology samples will be collected at the same time as the 60 
minutes i-STAT screening potassium sample;
5.
For women of childbearing potential, urine-HCG will be measured at clinic, using the tube provided by 
Central Laboratory
6.
Visit 4 (Day 3 for 48-hour open-label initial phase) is the same visit of  Day 1 in 28-day randomised 
treatment study phase;  i-STAT and S-K for all patients, remaining procedures only for patients with i-
STAT potassium values >5.0 mmol/L as measured fasting
7.
Central laboratory S-K sample collected as part of the serum clinical chemistry
8.
EOS in initial phase only for patients NOT entering the 28-day randomised treatment study phase, and 
occurs 7±1 day after the last administration of IP
9.
Baseline parameters should be measured/collected up to 1 day prior to administration of the 1st dose of 
study drug on initial phase Day 1(Visit 2)
10. Access IVRS/IWRS on initial phase Day 3 (Visit 4) or if patient permanently discontinues dosing before the 
end of initial phase dosing period
11. All potassium samples are analysed by i-STAT and by the Central Laboratories on all occasions.           
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 potassium samples should be collected 
prior to insulin administration whenever possible.    
12. Study Day in Table 1 is for 48-hour open-label initial phase
13. A complete physical examination should be performed within 1 day prior to administration the first dose of 
study drug on initial phase Day 1, and targeted physical examination will be conducted on initial phase Day 
3 and 9 for patients not entering the 28-day randomised treatment study phase.
14. AEs will be collected after the patient has signed informed consent, so during the Day 1 (Visit 2), 
investigator need to check if any AE happened since from inform consent


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
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Table 2
Study Plan detailing the procedures: 28-day randomised treatment study 
phase
Study Visit
Visit  
4
Visit  
5
Visit  
6
Visit  
7
Visit  
8
Visit  
9
Visit 
10
Visit 
11
Visit 
12
Visit 
13
(EOS)8
28-day 
randomised 
treatment 
study phase
Day7
Day 
110
Day 
210
Day 
510
Day  
810
Day 
1210
Day 
1510
Day 
1910
Day 
2210
Day 
2610
Day 
2910
Day 
3510
Eligibility 
criteria
X
EQ-5D
X
Physical exam
including 
weight3, 11
X
X
X
X
Access 
IVRS/IWRS9
X
X
X
X
Study drug 
(IP) 
dispensation
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
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
Urinalysis1,3
X
X
X
X
Urine HCG
X5
IP 
Reconciliation
X
1.
Parameters to be measured are detailed in Table 3 Laboratory Safety Variables..
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 randomised treatment study phase. 


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
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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 28-day randomised 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 at the patient has been upright for at least 2 hours and before the ECG 
4.      IP administration may not happen during some scheduled visits in patients for which the dose was reduced 
to EOD dosing.
5.
For women of Childbearing potential, urine-HCG will be measured at clinic, using the tube provided by 
Central Laboratory
6.
All potassium samples are analysed by i-STAT and by the Central Laboratories on all occasions.             
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 potassium samples should be collected 
prior to insulin administration whenever possible
7.
If a scheduled clinic visit falls on a weekend or National holiday during the 28-day randomised 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 28-day randomised treatment study phase Days 5, 8, 12, 15, 19, 22, 26 and 35, up to 2 
days late for 28-day randomised 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.
EOS occurs 7±1 day after the last administration of IP
9.
Access IVRS/IWRS on visit indicated or if patient permanently discontinues dosing before the end of 28-
day randomised treatment study phase
10.    Study Day in Table 2 is for 28-day randomised treatment study phase
11.    Targeted physical examination will be conducted on Days 1, 15, 29, and Day 35 (EOS) during the 28-day 
randomised treatment study phase.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
24
1.2.1.1
Enrolment/screening period (Visit 1)
Procedures will be performed according to the Study Plan in Table 1. At screening, consenting 
patients are assessed to ensure that they meet the study 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 and will remain associated 
with the same enrolment number throughout the entire study.  
1.2.1.2
48-hour open-label initial phase Days 1-3 (Visit 2-4)
On Day 1, 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). Patients who meet all 
inclusion and none of the exclusion criteria will be entered into the trial and treated with ZS 
10g for 48-hour. 
1.2.1.3
28-day randomised treatment study phase Days 1-29 (Visit 4-13)
Patients whose i-STAT potassium value is within the normal range (3.5 to 5.0 mmol/L, 
inclusive) at Day 3 of the OLP will be randomised into the double-blind RTP to one of three 
treatment arms (i.e. ZS 5g, ZS 10g or placebo) and treated for 28 days. Note that the OLP Day 
3 is also the RTP Day 1 (Visit 4).
a) Treatment Assignment and Randomisation Procedure
The randomisation codes will be computer generated using the AZ global randomisation 
system (AZRand) and loaded into the IVRS/IWRS database. Randomisation codes will be 
generated in blocks to ensure approximate balance (2:2:1) between the three treatment arms
(ZS 5g, ZS 10g or placebo). Randomisation will be stratified by country.
No member of the study team at AZ, or representative, personnel at study centres or any 
clinical research organisation (CRO) handling data will have access to the randomisation 
scheme during the conduct of the study, with the exception of the AZ personnel generating the 
randomisation scheme as well as AZ Supply Chain, and the CRO companies providing the
IVRS/IWRS and carrying out the packaging and labeling of study medication. This 
documentation will be kept in a secure location until the end of the study.
b) Blinding
The RTP will have a double blind design.  In order to ensure a double-blind randomised study, 
patients and Investigators will remain blinded to treatment assignment throughout the entire 
study.  Personnel involved with the analysis and conduct of the study will remain blinded until 
protocol deviators have been identified and the database in locked.  


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
25
To ensure blinding of the treatments, the actives and placebo will be identical in appearance 
and identical packaging and labeling will be used.  Patients will take by mouth the entire 
contents of a single sachet per day containing either ZS 5g, ZS 10g or placebo. The exterior 
appearance of the sachets are identical, but the volume of study drug will differ depending 
upon the randomised treatment group. 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.
c) Un-blinding
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient in the 28-day randomised treatment study phase, will be available to the Investigator(s) 
or pharmacists from the IVRS/IWRS in case of an un-blinding situation. Routines for this will 
be described in the IVRS/IWRS user manual that will be provided to each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to the patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for Serious Adverse Events (SAEs) that are 
unexpected and are suspected to be causally related to the 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.
1.2.1.4
Follow-up period (EOS)
A follow up visit will be performed at Day 9 in the OLP, and Day 35 in the RTP; or, 7 ±1 
days following the last study medication administration for patients who are withdrawn from 
the study medication. 
1.3
Number of patients
This study will be conducted in approximately 50 centres in several different countries. Before 
patients are randomised to the double-blind study phase, they will receive open-label ZS 10g 
for 48 hours during the initial phase. It is expected that approximately 443 patients will need 
to be enrolled, to have approximately 269 patients entered into the OLP, resulting in 
approximately 255 patients being randomised in the RTP. Enrolment will be stopped when 
approximately 255 patients have been initiated with the 28-day randomised treatment study 
phase.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
26
1.3.1
Sample size estimate
The sample size is determined to detect a clinically meaningful difference in the primary 
endpoint of the mean S-K during 28-day randomised treatment study phase (Study Days 8-29) 
between each active dose (high to low) vs. placebo control. Assuming an inter-patient 
standard deviation of 0.50, a total of approximately 255 patients, or 102 patients per each 
active dose treatment arm and 51 patients for placebo control arm, will provide >90% power 
to detect a 0.30 mean 28-day randomised treatment study phase Day 8-29 S-K difference, 
comparing each active dose (high to low) vs. placebo control for a two-sided t-test at a 
significance level of 5%. Assuming 95% of patients will be normokalemic after treatment 
with at least 1 dose of ZS 10g (See CSP, Version 2.0 (Date: 07 Dec2016) Section 7.2), 
approximately 269 patients will be needed to enter 48-hour 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 48-hour open-label phase mean change from baseline of S-K 48 hours after first dose of 
ZS 10g will be evaluated first. A sample size of 225 patients will provide >99% power to 
detect 1.05 absolute reduction (0.5 standard deviation of the change) in mean change from 
baseline of S-K 48 hours after the first dose of ZS 10g during the open label initial phase.
2
ANALYSIS SETS
2.1
Definition of analysis sets
The study will have prospectively defined analyses sets including separate evaluability rules 
for the OLP and RTP. The analyses sets defined below will be used for all data analyses in 
this study.
2.1.1
Full analysis sets
All efficacy analyses, unless otherwise specified, will be performed using the full analysis set 
(FAS), which is based on the Intention-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.
FAS-OLP: for the OLP, the full analysis set will include all patients entered in the initial study 
phase (i.e. patients entered into the trial after meeting the eligibility criteria for the study), 
regardless of whether they took study medication or not. Patients who did not meet eligibility 
criteria but entered the OLP and received study medication will be included in FAS-OLP and 
will be identified as a protocol deviation
FAS-RTP: for the RTP, the full analysis set will include all patients who are randomised to the 
28-day randomised treatment phase, regardless of whether they took study medication or not.  
In this set, patients will be analysed according to their randomised treatment assignment.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
27
2.1.2
Safety analysis sets 
All safety analyses will be performed using the safety analysis set (SAF). Safety analyses will 
be performed for each study phase, OLP and RTP.
SAF-OLP: For the OLP, the safety analysis set will include all patients in the FAS-OLP who 
receive at least 1 dose of study medication.  Patients will be assigned on an as-treated basis for 
safety analyses.
SAF-RTP: For the subsequent RTP, the safety analysis set will include all patients in the FAS-
RTP who receive at least 1 dose of study medication.  Patients will be assigned on an as-
treated basis for safety analyses.  If a patient receives more than one treatment during the 
RTP, they will be analysed according to the highest dose of study medication received during 
the phase. 
2.2
Violations and deviations
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.
A protocol deviation occurs when a patient fails to adhere to pre-specified protocol eligibility 
criteria, and/or compliance during the course of the trial. It is anticipated that most of the 
deviations will be able to be determined programmatically from the data.
Protocol deviations relating to patient-level as well as patient-visit-level events will be 
reviewed by appropriate medical, clinical, data management, and statistical personnel and 
documented prior to un-blinding the study. All deviations considered as important (including, 
but not limited to, those defined in Section 2.2.1 ) will be tabulated and listed in the CSR. 
2.2.1
Important protocol deviations
The following deviations are considered as important protocol deviations (IPDs):
!
Study drug compliance < 80% or > 120%. 
!
Administration of wrong type of study drug (i.e. the one not randomised to) cumulatively 
for more than 1 week.
!
Patients randomised who fail to receive treatment.
!
Administration of prohibited concomitant medication or non-drug therapy.
!
Eligibility criteria not fulfilled but patient still randomised and subsequently discovered to 
have failed the eligibility criteria, and where the failure to meet the eligibility criteria may 
have a negative impact on the analysis of the study.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
28
The number and percentage of patients with any of these IPDs will be summarised for both 
study phases (OLP and RTP, respectively). The summary will display the number of patients 
with an important protocol deviation in each study phase.
2.2.2
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. These patients should be withdrawn from the 
study 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.
Note that screen failure patients can be re-screened once during the clinical trial period and 
will remain associated with the same enrolment number throughout the entire study.  
3
PRIMARY AND SECONDARY VARIABLES
3.1
Primary efficacy variable
The primary efficacy parameter in this study will be the model-based least squares means 
(LSMEAN) of all S-K values during the RTP, Study Days 8-29.
3.2
Secondary efficacy variables
3.2.1
48-hour open-label initial phase 
For the OLP, 24-hour assessments are those made on OLP Study Day 2; 48-hour assessments 
are those made on OLP Study Day 3.  The following secondary efficacy endpoints will be 
included in the analysis:
!
Exponential rate of change in S-K levels from baseline.
!
Nominal and percent change from baseline in S-K levels at all measured time intervals 
post-dose
!
Proportion of patients who achieve normokalemia during the OLP at 24 and 48 hours
!
Time to normalisation in S-K levels (normalisation defined as S-K levels between 3.5-5.0 
mmol/l, inclusive)
3.2.2
28-day randomised treatment phase 
For the subsequent 28-day randomised treatment study phase, the following secondary 
efficacy endpoints will be included in the analysis.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
29
!
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 RTP and during the RTP
!
The number of days patients remain normokalemic during the 28-day randomised 
treatment study phase
!
The mean change and mean percent change from baseline in S-K levels evaluated relative 
to both 48-hour open-label initial phase and 28-day randomised treatment study phase
baselines. 
!
The time to hyperkalemia (defined as S-K ≥5.1 mmol/l)
!
The mean changes in S-Aldo and P-Renin levels
3.3
Other variables
The health state of the study population will be assessed at Visit 2 and Visit 13 using the EQ-
5D questionnaire. The EQ-5D comprises five questions about mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression with five possible answers for each item 
(see appendix 3 in the protocol - CSP, D9480C00002, Version 2.0 (07 Dec 2016)). In 
addition, there is a visual analogue scale (VAS) to indicate the general health status with 100 
indicating the best health status and 0 the worst.
3.4
Safety Variables
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]).
3.4.1
Adverse Events (AEs)
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.
Events will be defined as treatment emergent if they onset, or worsen (by investigator report 
of a change in intensity), during the treatment period (by summarising based on date of onset). 
If partial dates of onset occur, a conservative approach will be followed and events will be 
assumed to be treatment emergent unless there is convincing evidence to the contrary.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
30
A serious adverse event (SAE) 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 hospitalisation or prolongation of existing hospitalisation
!
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
!
Is a congenital abnormality or birth defect. 
!
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above
3.4.1.1
Recording of adverse events
AEs (including SAEs) will be collected from the time of informed consent, throughout the 
treatment period, including the EOS visit.
Any AEs that are unresolved at the patient’s last AE assessment (EOS visit) 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.
3.4.1.2
Variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Max intensity (mild, moderate or severe)
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or no)
!
Action take with regard to investigational product
!
Outcome
The following variables will be collected for each SAE:
!
Date AE met criteria for serous AE
!
Date Investigator became aware of serious AE
!
AE is serous due to 


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
31
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedures(s)
!
Description of AE
3.4.2
Vital Signs
Pulse rate and systolic and diastolic blood pressure (BP) will be assessed at Visits 2, 4, 9, 13 
and the EOS visit using non-invasive equipment.  Three (3) readings separated by 2 minutes 
will be averaged and the averaged result will be recorded in the eCRF. 
3.4.3
Physical Examination
A complete physical examination will be performed within 1 day of administration of the first 
dose of study drug on initial phase Day 1 (Baseline: all patients), and targeted physical 
examination will be conducted on OLP Day 3 for all patients and on Day 9 for patients not 
entering the 28-day randomised treatment study phase. During the RTP targeted physical 
examination will be conducted on Days 1, 15, 29, and Day 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.
3.4.4
Electrocardiogram ECG)
A 12-lead ECG will be performed at the times indicated in the Study Plan in Table 1 and 
Table 2.  Heart rate, P and QRS durations, PR and QT intervals will be recorded from 
standard lead of the computerised quantitative 12-lead ECG.
ECGs will be recorded at OLP Days 1, 3 and 9 (EOS) for patients NOT entering the double-
blinded RTP, and on RTP Days 1, 8, 15, 22, 29 and 35 (EOS) for those entering the RTP. For 
patients who have i-STAT potassium levels ≥ 6.1 mmol/L at the 1 hour post first dose time 
point in the 48h OLP Day 1, an additional ECG will be recorded 1.5 hours post second dose. 


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3.4.5
Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken during the OLP at Visits 2, 4 and the EOS visit for patients not entering the 
double-blind 28-day randomised treatment study phase and at Visits 4, 9, 13 and EOS visit for 
the RTP phase. The clinical chemistry, hematology and urinalysis will be performed at a 
central laboratory. Laboratory safety variables are described in Table 3.
Table 3                 Laboratory Safety Variables
Haematology
Clinical Chemistry (serum/plasma)
B-Haemoglobin (Hb)
S-Total Protein
B-Haematocrit
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)
U- Human chorionic gonadotropin (HCG) (only for 
females of childbearing potential) 2
S-Alanine transaminase (ALT)
S-Aldosterone
P-Renin
1.
Potassium will be tested by i-STAT and Central Laboratory
2.
Urine-HCG will be measured at clinic, used the tube provided by Central Laboratory
The calibration of the S-K assay was changed during the course of the study. Measurements 
analysed using the new calibration method are on average higher than when analysed by the 
old calibration method. Covance, the central laboratory provider, have performed analysis of 
the correlation and relationship between the old and new calibration methods and have 


Statistical Analysis Plan 
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concluded that the bias is small enough to be within the variability of the assay and also small 
enough to leave the reference ranges unchanged. See Section 8.4, Appendix D for details on 
the change to the calibration of the potassium assay.
3.4.6
Visit windows
In the absence of nominal visits, the 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. In the event that both 
a scheduled and 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.
Table 5     Time windows for allocation of data to visits for statistical analysis 
Study Visit (Target Day)
Nominal Target 
Day
Study Visit Window (Days)
Lower
Upper
Open-Label Phase 
Visit 1 (Screening)
-1
---
-1
Visit 2 (OLP-Day 1)
1
1
1
Visit 3 (OLP-Day 2)
1
2
2
Visit 4 (OLP-Day 3)
1
3
3
End of Study Visit (OLP-Day 9)1
9
4
16
Randomised Treatment Phase 
Visit 4 (RTP-Day 1)
1
1
1
Visit 5 (RTP-Day 2)
1
2
2
Visit 6 (RTP-Day 5)
3
3
6
Visit 7 (RTP-Day 8)
3
7
9
Visit 8 (RTP-Day 12)
4
10
13
Visit 9 (RTP-Day 15)
3
14
17
Visit 10 (RTP-Day 19)
4
18
20
Visit 11 (RTP-Day 22)
3
21
24
Visit 12 (RTP-Day 26)
4
25
27
Visit 13 (RTP-Day 29)
3
28
31
End of Study Visit (RTP-Day 35)2
9
32
43
1. Note: End of Study Visit (OLP-Day 9) in initial phase only for patients NOT entering the 28-day randomised 
treatment study phase, and occurs 7±1 day after the last administration of  IP.
2. Note: End of Study Visit (RTP-Day 35) occurs 7±1 day after last administration of IP in RTP.
The pre-dose S-K measurements at Visit 3 and Visit 4 will be used to calculate the proportion 
of patients who achieve normokalemia during the 48-hour open-label initial phase at 24 and 
48 hours, respectively. If there are multiple S-K measurements at the same time-point, the first 
measurement will be used.


Statistical Analysis Plan 
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Edition Number 2.0
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4
ANALYSIS METHODS
4.1
General principles
The SAS® software, version 9.2 or higher, will be used in order to generate all the statistical 
outputs. Analysis of data from the OLP and the RTP will be performed after all patients have 
completed or discontinued from the study. In addition, all relevant data queries must be 
answered and the database must be locked and un-blinded for the 28-day randomised 
treatment study phase prior to the analysis.
Unless otherwise specified, all efficacy analyses will be carried out on the FAS-OLP or FAS-
RTP, respectively. Safety analyses will be based on the SAF-OLP or SAF-RTP, respectively. 
Efficacy summary results during the RTP will be presented based on randomised treatment 
group (ZS 5g, ZS 10g or placebo).  Safety summary results will be presented based on 
treatment actually received. For Safety analyses, if a patient receives more than one treatment 
during the RTP, they will be analysed according to the highest dose of study medication 
received during the phase. 
Individual patient data will be presented in patient listings. Unless otherwise specified, data 
listings will at least include patient ID, age, gender and race, and will be presented sorted by 
treatment group, centre/site, patient ID, and date/time of observations, by visit, where 
appropriate.  Patient characteristics (e.g. demographics and baseline characteristics) and study 
medication information will be listed for all enrolled patients and flagged by analysis 
population (FAS-OLP or FAS-RTP) and treatment group in each phase, if appropriate.
The number and percentage of patients in each analysis set will be presented in summary 
tables, with the total number of patients in each study phase serving as the denominator for the 
respective summaries.  
The number and percentages of patients within each important protocol deviation type will be 
summarised by study phase, OLP and RTP, respectively. In the RTP, summaries will be 
presented overall and by treatment group.  All individual patients with important protocol 
deviations will be listed as well for OLP and RTP, respectively.
Continuous variables will be summarised by descriptive statistics, including number of non-
missing observations (n), mean, standard deviation, median, minimum, and maximum. The 
means and medians will be presented to one further degree of precision than the raw data. 
Standard deviations will be reported to one further degree of precision than the means, and 
medians. Minimums and maximums will be displayed with the same number of decimal 
places as the collected data. 
Categorical variables will be summarised by frequency counts and percentages. Percentages 
will be presented to 2 decimal places, unless most percentages in a particular table are small 


Statistical Analysis Plan 
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Edition Number 2.0
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(i.e. < 5%). All percentages within a table will be consistent. Any data presentation that 
includes percentages should clearly indicate the denominator used for the calculation of each 
percentage (e.g., in the footnote). The denominator will normally be the total number of 
patients with non-missing data (e.g., number entered in the OLP or in a treatment group for 
the RTP), unless otherwise stated.
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 rounded to 3 decimal places. 
If the fourth digit of the p-value is less than or equal to 4, the p-value will be rounded down. If 
the fourth digit of the p-value is greater than or equal to 5, the p-value will be rounded up. All 
p-values rounded to 0.000 will be presented as ‘< 0.001’ and p-values that are rounded to 
1.000 will be presented as ‘> 0.999’. A sequential closed testing procedure is used to adjust 
for multiplicity. 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.
The eGFR will be calculated as in Equation 1 for all patients:
1. eGFR = 175 x (0.011312 x Creatinine umol/L)**(-1.154) x (age in years)
**(-0.203) x 1.212 (if patient is black) x 0.742 (if female).
Additionally, for the Japan specific analyses alone, the eGFR will be calculated using both 
Equations 1 and 2 for the Japanese subpopulation to reflect muscle volume in Japanese 
patients (and potentially in East Asian) and also to facilitate comparison with Japan stand-
alone studies:
2. eGFR = 194 x (0.011312 x Creatinine umol/L)**(−1.094 )× (age in years)       
**(−0.287 ) x 0.739 (if female).
4.1.1
Definition of Baseline and Post Baseline
For the OLP, the baseline S-K will be established on initial phase Study Day 1 (pre-treatment) 
by taking the mean of 2 different S-K values, recorded 60 ± 10 minutes apart (time 0 and time 
60 minutes). Post baseline for the OLP will be all S-K measurements taken after first dose.
For the subsequent RTP, the baseline S-K will be established on the morning of OLP Study 
Day 3 as the first S-K measurement performed on Study Day 3, which establishes patient 
eligibility into the 28-day randomised treatment study phase. Post baseline for the RTP will be 
all S-K measurements taken after patient randomisation in the randomised treatment phase.
The baseline for all other parameters will be the fasting parameter value measured within 1 
day before the first study drug administration in the OLP.


Statistical Analysis Plan 
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Edition Number 2.0
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4.1.2
Definition of change from baseline
The change from baseline will be calculated as follows:
ΔBaseline = Post baseline value – Baseline value
4.1.3
Definition of percent change from baseline
%∆= 	
 	  −	 
	 
∗100%
4.1.4
Mixed Model: Terms and Estimation
The form of the mixed effects model employed in the analyses in this study is as follows:
ln( ) =  ! + # + ɛ,
where ln(SK Level)ij is the S-K level in the natural log scale for the jth measurement for the 
ith patient, Xij is the matrix of fixed effects covariates, β is a vector containing the fixed-
effects regression coefficients, Zi represents the random effects covariates, bi is a normally 
distributed random effect parameter, and ɛij is a normally distributed random error term. 
Unless otherwise stated, all mixed effects models used in the evaluation of the study
objectives will use the covariates in Table 4 in estimating the model parameters:  
Table 4     Fixed and Random Effects
Fixed Effects
Random 
Effects
!
visit (treated as a categorical variable)
!
treatment groups (ZS 10g qd, ZS 5g qd and placebo)
!
visit-by-treatment interaction
!
both baseline S-K values (48-hour open-label initial phase and 
double-blind randomised phase)
!
baseline eGFR (during 48-hour open-label initial phase)
!
age category (<55, 55-64, ≥65 years)
!
country 
!
baseline binary indicators for RAAS inhibitors
!
baseline chronic kidney disease status (CKD)
!
baseline congestive heart failure status (CHF)
!
baseline diabetes mellitus status (DM)
!
Patient


Statistical Analysis Plan 
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Variance components will be estimated using a restricted maximum likelihood method 
(REML) and an unstructured covariance structure will be assumed.  Should the specified 
model fail to converge, the final covariance structure will be determined by Akaike’s 
information criterion: Toeplitz, first-order autoregressive and compound symmetry.  The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.
  
4.1.5
Log-transformation of S-K values
For the purpose of statistical modeling, a natural log transformation will be applied to the S-K 
level since historical data shows that S-K measurements follows a log-normal distribution, and 
will then stabilise the variance.  
4.1.6
Handling of missing data
4.1.6.1
S-K efficacy endpoint
In the event of missing S-K data from the central laboratory, the i-STAT data will be 
used to replace missing data by adjusting for the average paired difference between the 
central and i-STAT levels collected at the same visit and with the same calibration 
method for the potassium assay. For details on the change to the potassium assay 
calibration assay, see Section 3.4.5 or Section 8.4, Appendix D.
If a patient is missing both the central laboratory and i-STAT values for the last visit on 
treatment, the EOS value will be used if it is within 1 day of a target study day and the last 
dose date.   
No other data will be imputed or inferred for either missing baseline or on-study data for any 
other efficacy endpoint.
4.1.6.2
Missing start and stop dates – AEs and concomitant medications
AE and concomitant medication missing start/stop dates will appear as missing in the patient 
data listings, but will be imputed to permit the proper tabulation of AE data. The imputation of 
missing AE and concomitant medication onset/start and end/stop dates will be used to 
determine the status of each AE and the previous/concomitant status of each medication.
Please refer to Section 8.1, Appendix A, for the method of imputation of missing AE 
onset/start and end/stop dates and Section 8.2, Appendix B, for the method of imputation of 
missing concomitant medication onset/start and end/stop dates.
4.1.7
Definition of subgroups
The definition of the subgroup of patients with heart failure, chronic kidney disease and 
diabetes mellitus will be coded from medical history using the narrow MedDRA SMQs. The 
full list of Preferred Terms is found in Section 8.3, Appendix C.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
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4.2
Hypotheses
4.2.1
Primary hypotheses
The null hypothesis is that there is no treatment difference in the mean S-K levels (Days 8-29) 
compared to placebo as follows (two null hypotheses):
)
(
)
10
_
(
:
0
Placebo
g
ZS
H
sk
sk
∀
∀
#
vs. 
)
(
)
10
_
(
:
Placebo
g
ZS
H
sk
sk
A
∀
∀
∃
)
(
)
5
_
(
:
0
Placebo
g
ZS
H
sk
sk
∀
∀
#
vs. 
)
(
)
5
_
(
:
Placebo
g
ZS
H
sk
sk
A
∀
∀
∃
4.2.2
Secondary hypotheses
For the 48-hour open-label initial phase, the following null hypotheses will be tested versus 
two-sided alternative:
Exponential rate of change in S-K levels =0;
Mean S-K change from baseline at 24hours of first dose = 0
Mean S-K change from baseline at 48 hours of first dose=0;   
Mean S-K percent change from baseline at 24 hours = 0
Mean S-K percent change from baseline at 48 hours=0;
For the subsequent 28-day randomised treatment study phase, the following null hypotheses 
will be tested versus two-sided alternative relative to placebo:
The proportion of patients in the ZS 10g treatment group who remain normokalemic;
The proportion of patients in the ZS 5g treatment group who remain normokalemic;
The mean number of days patients in the ZS 10g treatment group remain normokalemic;
The mean number of days patients in the ZS 5g treatment group remain normokalemic;
The median time (days) to hyperkalemia in the ZS 10 g patients;
The median time (days) to hyperkalemia in the ZS 5 g patients;
The mean change in S-Aldo in the ZS 10g treatment group;
The mean change in S-Aldo in the ZS 5g treatment group.
The mean change in P-Renin in the ZS 10g treatment group.
The mean change in P-Renin in the ZS 5g treatment group.


Statistical Analysis Plan 
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Edition Number 2.0
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4.2.3
Multiple testing strategy
An overall Type I error rate of 5% accounting for efficacy analyses, in both phases of the 
study, will be maintained using a sequential closed testing procedure.
The analyses for the 28-day randomised treatment study phase will focus on randomised 
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 until a 2-sided p-value >0.05 is encountered, at which 
point further testing will cease.  Explicitly, Table 6 will be implemented.


Statistical Analysis Plan 
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Edition Number 2.0
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Table 6                           Confirmatory Testing Sequence
Seq
Study phase
Efficacy variable
Comparison
1
Acutei
48-hour open label phase mean change from 
baseline of S-K 48 hours after first dose of ZS 10g
2
Maintenanceii
28-day randomised treatment study phase Days 8-
29 mean S-K
ZS 10g QD vs. 
Placebo
3
Maintenance
28-day randomised 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 randomised treatment 
study phase at Study Day 29/Exitiii
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 randomised treatment 
study phase at Study Day 29/Exitiii
ZS 5g QD vs. 
Placebo
6
Maintenance
Number of days patients remain normokalemic 
during the 28-day randomised treatment study 
phase
ZS 10g QD vs. 
Placebo
7
Maintenance
Number of days patients remain normokalemic 
during the 28-day randomised 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 randomised 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 randomised treatment 
study phase)
ZS 5g QD vs. 
Placebo
i    Acute Study Phase refers to the 48-hour Open Label Initial Phase.
ii    Maintenance Study Phase refers to the 28-day randomised treatment Study Phase.
iii   Study Day 29/Exit refer to day of last dose of study treatment


Statistical Analysis Plan 
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Edition Number 2.0
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4.3
Analysis methods
4.3.1
Demographics and baseline characteristics
Demographic and baseline characteristics of age (at screening), age categories (<55, 55-64, 
≥65 years), country, sex, race, ethnicity, weight, height, BMI will be summarised by study 
phase using their respective full analysis sets. For the RTP, the baseline will be summarised 
by treatment groups as well as overall. 
The number and percent of patients with the following baseline disease characteristics will 
also be summarised: 
-
chronic kidney disease (CKD)
-
diabetes mellitus (DM)
-
heart failure (HF)
-
use of renin-angiotensin-aldosterone system (RAAS) inhibitors.
4.3.2
Patient disposition and study population
All enrolled patients will be included in summaries of patient disposition and patient 
availability for analysis populations by treatment group. Patients signing the ICF are 
considered enrolled. Patient accounting will be provided for the following parameters:
!
Number of patients entered in the OLP and OLP completers. A completer is defined as 
a patient who were treated with study drug during the OLP and have both OLP 
baseline and 48-hour S-K assessments. Those who do not enter the randomised phase 
and have completed the EOS visit will be defined as OLP completers;
!
Number of RTP-eligible patients defined as an OLP completer with S-K levels 
between 3.5 and 5.0 mmol/L, inclusive, at the OLP 48-hour time point;
!
Number of RTP randomised patients, completion status, and reasons for 
discontinuations, where a completer is defined as patients who were randomised and 
completed Day 29 and EOS procedures.
Also, patient exclusions from analysis populations will be tabulated.
4.3.3
Medical History
Prior medical conditions/diseases are those medical conditions/diseases that are taken within 7 
days before start of study medication while current medical conditions/diseases are those 
medical conditions/diseases that are still present when receiving first treatment of ZS or after 
first treatment. 
The number of patients with any past and current medical conditions/diseases will be 
tabulated by MedDRA SOC and PT for OLP and RTP respectively. A patient will only be 
counted once within a particular SOC (or PT) even if he/she has multiple conditions/diseases 
in the same SOC (or PT). For RTP, the summary statistics will be displayed by treatment 
groups as well as overall.


Statistical Analysis Plan 
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4.3.4
Prior and/or Concomitant Medication
Prior medications are defined as medications taken with a start date that falls before the first 
dose of study medication (ZS). Concomitant medications include medications that started 
prior to, but continued after, the first day of a study phase, or medication changes (including 
newly initiated medications) during a study phase. All prior medication and concomitant 
medications will be coded with the WHO Drug Dictionary, and summarised by phase for their 
respective safety data sets (FAS-OLP or FAS-RTP). For the RTP, the summary statistics will 
be displayed overall as well as by treatment groups.
The number and percentage of patients with prior and concomitant medications will be 
tabulated by Anatomic Therapeutic Chemical classification system (ATC) Term and Drug
Preferred Name. A summary table for disallowed (and allowed) concomitant medication taken 
during the study will also be provided.
4.3.5
48-hour open-label initial phase efficacy analyses
Descriptive statistics will be presented for S-K level at baseline, Day 1 (1, 2 and 4 hours post 
first dose) and Day 2 (pre-dose and 1 hour post the first dose in the day), including the 
nominal and percent changes from baseline.
4.3.5.1
Exponential rate of change
The exponential rate of change in S-K levels will be derived from a mixed effects model (SAS 
PROC MIXED) of serial, log-transformed S-K levels during the OLP. In addition to the fixed 
effects in table 4 (with the exception of the visit and treatment effects) time will be included as 
a fixed effect. A random intercept and slope (for time) will be used in the model. The time 
effect estimate will be presented with corresponding standard errors and p-values.
4.3.5.2
Mean change from baseline and mean percent change from baseline
For changes from baseline and percent changes from baseline in S-K levels at Visit 3 (24 
hours) and Visit 4 (48 hours), one sample, two-sided t-tests will be applied to test the null 
hypotheses that the means equal zero. The p-value for the change from baseline at Visit 4 will 
be used in the sequential closed testing procedure (the first test in the sequential closed testing 
procedure).
4.3.5.3
Proportion of normokalemic patients
The observed proportions of patients achieving normokalemia at Visit 3 (24 hours) and Visit 4 
(48 hours) will be provided along with 95% two-sided Clopper-Pearson exact confidence 
intervals. 
4.3.5.4
Time to normalisation in S-K values
The time to normalisation in S-K levels will be summarised using Kaplan-Meier life table 
curves and associated 95% CI points will be provided in the figure. All S-K assessments 


Statistical Analysis Plan 
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during OLP (e.g., not just those at 24 and 48 hours) will be used. Patients who fail to achieve 
normalisation will be censored at last measurement (the last measurement before the first dose 
of 28-day randomised treatment study phase). Patients who discontinued 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 patients who fail to achieve normalisation and will be censored at 
48 hours. Other discontinued patients will be censored at the last S-K evaluation.
4.3.6
28-day randomised treatment study phase (RTP) efficacy analyses
4.3.6.1
Primary efficacy analysis
The primary endpoint in this study will be the model-based LSMEAN of available S-K values 
during the 28-day randomised treatment study phase for Study Days 8-29. The longitudinal 
model specified in Section 4.1.4 (SAS PROC MIXED) will be used to estimate the least 
squares means for Days 8-29 and compare each active dose (ZS 10g and ZS 5g) versus the 
placebo.  The response variables will be S-K values (natural log scale) during Days 8-29.  
Fixed and random treatment effects are those in Table 4.
The p-value from two sample t-tests (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 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 95% confidence intervals.  
The results from the above analysis will be presented both as modelled and back-transformed 
to their original scale.
Descriptive statistics will be presented for S-K values at the OLP baseline, RTP baseline and 
Visit 5 (Day 1) through Visit 13 (Day 29), and the EOS visit. Nominal changes and percent 
changes from each baseline (OLP and RTP) will be summarised by treatment groups (ZS 5g, 
ZS 10g and placebo). 
4.3.6.2
Secondary efficacy analysis
4.3.6.2.1 Number of patients who remain normokalemic at Study Day 29/Exit
For the Day 29/Exit time point, the percentage of normokalemic patients at RTP Day 29/Exit 
will be compared using a logistic regression model containing the same baseline covariates, 
with the exception of visit and visit-by-treatment interaction, as for the primary efficacy 
endpoint (See Section 4.1.4). The p-value at the Day 29/Exit time point will be used in the 
sequential closed testing procedure (fourth and fifth tests in the sequential closed testing 


Statistical Analysis Plan 
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procedure). Additionally, the proportion of patients who remain normokalemic will be 
presented by study visit.
4.3.6.2.2 Number of days patients 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.  If an 
intermediate assessment time point is missing, the time interval will be extended until the next 
non-missing time point.
The number of normokalemic days will be analysed using a linear regression model with the 
same covariates, with the exception of visit and visit-by-treatment interaction, as for the 
primary efficacy endpoint analysis (See Section 4.1.4). The p-value (two-sided) will be 
provided to compare the LSMEANs of the normokalemic days between each active treatment 
versus placebo (sixth and seventh tests in the sequential closed testing procedure).
Descriptive statistics for the number of normokalemic days will be provided for each 
treatment group.
4.3.6.2.3 Time to hyperkalemia
Kaplan-Meier curves of the time to hyperkalemia will be displayed for each treatment group. 
A proportional hazards model (SAS PROC PHREG) will be assessed with the same 
covariates, with the exception of visit and visit-by-treatment interaction, as for the primary 
efficacy endpoint analysis (See Section 4.1.4). The hazard ratio between each active treatment 
versus placebo will be reported along with a 95% confidence interval. 
4.3.6.2.4 S-Aldo and P-Renin levels
Descriptive statistics will be presented for nominal values, change from baseline and percent 
change from baseline in S-Aldo and P-Renin levels during 28-day randomised treatment study 
phase at Visits 4, 9, 13 and EOS for each treatment group. 
Treatment group differences (each active treatment vs. placebo) for the mean change from 
baseline will be assessed by two-sided, two sample t-test at each visit for both S-Aldo and P-
Renin.
4.3.7
Sensitivity analyses of primary and selected secondary efficacy variable
4.3.7.1
Sensitivity analysis replacing central laboratory S-K with i-STAT
A sensitivity analysis will be conducted to assess the robustness of the results of the primary 
efficacy analysis. This will be performed by using the same longitudinal model on patients 
Day 8 to Day 29 i-STAT measurements.


Statistical Analysis Plan 
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Edition Number 2.0
Date 15 March 2018
45
4.3.7.2
Sensitivity analysis to assess impact of change to potassium assay
Sensitivity analyses will be conducted to assess the impact of the change to the calibration 
method for the potassium assay. The calibration method for the potassium assay at the central 
laboratory was changed during the study, and the new calibration method is on average 0.208 
mmol/L larger compared to the old calibration method. Details are provided in Section 3.4.5
and Section 8.4, Appendix D. Because the change to the calibration was done late in the 
study, the majority of potassium measurements will be analysed by the old calibration. 
In order to assess the impact of this change, sensitivity analyses will be conducted for the 
primary analysis of mean S-K during RTP Days 8-29 and for the secondary efficacy analyses 
included in the sequential closed testing procedures:
!
Proportion of patients who remain normokalemic (as defined by S-K between 3.5-5.0 
mmol/L, inclusive) during the 28-day randomised treatment study phase at Study Day 
29/Exit
!
Number of days patients remain normokalemic during the 28-day randomised 
treatment study phase
!
Time to hyperkalaemia (defined as S-K ≥ 5.1 mmol/L during the 28-day randomised 
treatment study phase)
Sensitivity analyses will be performed by subtracting the average bias between the old and 
the new calibrations from all the S-K measurements analysed by the new assay. By doing 
this, results will reflect what could have been observed had the assay not been changed. 
Analyses will be repeated on this new data containing all original S-K measurements 
analysed by the old calibration method and the adjusted measurements analysed by the new 
method calibration. 
4.3.8
Other secondary analysis
The health state of the study population will be assessed at Visit 2 and Visit 13 using the EQ-
5D questionnaire. EQ-5D will be summarised separately using their respective full analysis 
sets at their respective study phases.  
The five subscores of EQ-5D on mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression at Visit 2 and Visit 13 will be summarised by presenting the number of 
patients and percentage for each category.  Visual analogue scale (VAS) at Visit 2 and Visit 
13 will be summarised by presenting the number of non-missing observations, mean, standard 
deviation, median, inter-quartile range, minimum and maximum.  
4.3.9
Safety analyses
Separate safety analyses will be performed for the OLP and the RTP presented by treatment. 
Safety endpoints will include adverse events (AEs), serious AEs (SAEs), vital signs (VS), 
physical examinations, ECGs, clinical laboratory evaluations, and other electrolytes 


Statistical Analysis Plan 
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Edition Number 2.0
Date 15 March 2018
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(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 respective safety analyses will be undertaken on the safety analysis sets, separately for the 
initial phase (SAF-OLP) and for the 28-day randomised treatment study phase (SAF-RTP).
4.3.9.1
Treatment Duration, Treatment Compliance, and Exposure
Summary statistics (number of non-missing observations, mean, median, standard deviation, 
minimum and maximum values) will be presented for the total duration of exposure, study 
treatment exposure and compliance for the actual dose received in the OLP and for each of the 
randomised treatment groups (ZS 5g, ZS 10g and placebo) in the RTP
Total duration of exposure in each study phase will be calculated as:
[&
 ' 	
 &	 ' 	
&( &)* −&
 ' ')	
 &	 ' 	
&( &)* + 1 &(].
Study treatment exposure in each study phase is the total duration of exposure minus the sum 
of days where the drug was not taken due to interruption.
Compliance will be calculated as:
,-./ (%) =
0
 -) ' 	/ℎ
	 
2
34./
& -) ' 	/ℎ
	 
2 × 100% ,
where the expected number of sachets is calculated over the patient’s actual duration in the 
trial and not the planned duration. 
A patient listing which describes dose regimen (the planned dose, the actual dose, the unit, 
frequency) and exposure will be provided.  
A listing of patients with dose adjustments during the RTP will be provided.  This listing will 
include the days when such change happened and the confirmed i-STAT potassium values that 
resulted in the dose adjustment.
4.3.9.2
Adverse Events (AEs)
Adverse Events will be presented separately for the OLP and the RTP. Only AEs considered 
treatment-emergent will be presented in summary tables. Treatment-emergence is defined as 
AEs occurring during treatment. That is, with an onset date on or after the day of first dose of 
study medication and no later than the day of last dose of study medication + 1 day. AE 
summaries will display the number of patients experiencing the event and not the total number 
of events. Adverse events will be classified into system organ class (SOC) and preferred term 
(PT) using the latest version of MedDRA. All AEs, including those not considered treatment-
emergent, will be included in safety listings.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
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The onset date of the AE determines the phase in which the AE will be summarised. AEs with 
an onset date prior to administration of the first randomised study medication in the RTP will 
be included in the summary for the OLP. If a patient has an AE with an onset date that occurs 
after administration of the first dose of randomised study medication in the RTP, the AE will 
be included in the summary for the RTP. In order to have a consistent “worst case” allocation 
of AEs, any AE with an onset on OLP Day 3 (day of randomisation) will be summarized for 
the OLP, because it will not be able to distinguish AEs occurring before or after the actual 
intake of randomised IP.
Narratives will be written for every AE classified as serious or leading to withdrawal of IP. 
All AEs will be presented in individual listings. The listing will contain the following 
information: phase, treatment group, verbatim term, PT, intensity, relationship to study 
medication, day of onset and duration of AE, treatment given to treat the adverse event, the 
outcome, whether the event was an SAE, whether it led to withdrawal and whether it is a 
TEAE. If the onset date is completely missing, then these events will be presented first. If the 
onset date is missing a month or a day, then these events will be presented before any 
complete dates.
4.3.9.2.1 Overall Summary of Adverse Events
AEs will be summarised by treatment group for the OLP phase and the RTP and will include 
the following:
!
the number and percentage of patients experiencing an AE
!
the number and percentage of patients experiencing an AE with an outcome of death
!
the number and percentage of patients experiencing an SAE
!
the number and percentage of patients experiencing an AE leading to treatment 
withdrawal
4.3.9.2.2 AEs and SAEs by System Organ Class (SOC) and Preferred Term (PT)
The number and percentage of patients with AEs will be summarised by SOC and PT, by 
treatment group. 
A patient with more than one type of AE in a particular SOC will be counted only once in the 
total of patients experiencing AEs in that particular SOC.  Since a patient could have more 
than one type of AE within a particular SOC, the sum of patients experiencing different AEs 
within the SOC could be larger than the total number of patients experiencing AEs in that 
SOC.  Similarly, a patient who has experienced an AE in more than one SOC will be counted 
only once in the total number of patients experiencing AEs in all SOCs.
The number of AEs and the number and percentage of patients with AEs that led to permanent 
discontinuation of study drug will be summarised by SOC and PT, by treatment group.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
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4.3.9.2.3 AEs and SAEs by PT, and Relationship
The number and percentage of patients with AEs will be summarised by PT, relationship to 
study drug, and treatment group. 
4.3.9.2.4 AEs by PT, and Severity
The number and percentage of patients with AEs will be summarised by PT, intensity (mild, 
moderate, or severe), and treatment group.
4.3.9.2.5 Deaths
The number and percentage of patients with AEs with outcome of death will be summarised 
by SOC, PT, and treatment group.
Patient listings of all deaths and their causes will be provided by phase and treatment group.
4.3.9.3
Analyses for Laboratory Tests
Descriptive statistics by time of assessment will be presented for each laboratory parameter 
described in Table 3 separately for the initial phase (SAF-OLP) and for the 28-day 
randomised treatment study phase (SAF-RTP). Changes from baseline for continuous 
variables as well as shift tables for categorical variables will be presented, separately for the 
initial phase (SAF-OLP) and for the 28-day randomised treatment study phase (SAF-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 
standardised 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 phase and 
by treatment group.
Bivariate plots for AST and ALT vs. Total Bilirubin will be provided.
4.3.9.4
Vital Signs
Vital sign measurements will be summarised at selected visits.  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 or RTP).
4.3.9.5
Physical Examination
Physical examination is stated as a safety endpoint in the CSP. However, no separate analyses 
will be provided. Physical examinations are performed by the investigator according to the 
schedule of assessments (Table 1 and Table 2). If there are new or aggravated findings, as 
compared with baseline, these are to be reported as AEs.


Statistical Analysis Plan 
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4.3.9.6
Pregnancy Test
A by-patient listing of all pregnancy tests will be provided by phase as well as by treatment 
group.
4.3.10 Subgroup analyses
To facilitate a benefit-risk assessment for the purpose of regulatory submission in Japan, the 
subgroup of patients from Japan will be analysed separately, with respect to efficacy and 
safety variables for both phases of the study and presented in a Japanese specific Clinical 
Study Report.
For all summary tables, descriptive statistics will be generated for Japan patients.  The 
selected models described in Section 4.2 will be separately applied to Japanese patients. The 
country-related covariates will be excluded when fitting the analysis models. For example, in 
the longitudinal models (SAS PROC MIXED), a term for country will be excluded from the 
models.  
In addition, analyses will be performed for 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 randomised treatment study phase 
in order to explore the variation of the treatment effect in the following subgroups:
!
baseline chronic kidney disease status 
!
baseline diabetes mellitus status
!
baseline heart failure status
!
Those on RAAS inhibitors
Separate models will be fitted for each subgroup with a treatment by subgroup interaction 
term in addition to the covariates in the original analysis. Estimates of the treatment by 
subgroup interaction will be provided with corresponding p-values and confidence intervals. 
Additionally, for the analysis of the primary endpoint on the subgroups, LSMEANs for the 
combinations of treatment by subgroup levels will be presented with corresponding 
confidence intervals.
5
INTERIM ANALYSES
No applicable.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
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6
CHANGES OF ANALYSIS FROM PROTOCOL
In table 6 of the protocol, the sixth and seventh tests in the sequence were number of days 
patients remaining normokalemic during the 28-day randomised treatment study phase Days 8 
to 29, inclusive. In SAP, the number of days patients remaining normakalemic will be 
calculated from day 1 to day 29 in RTP. It was revised in the table 6 of SAP.
7
REFERENCES
No applicable.


Statistical Analysis Plan 
Study Code D9480C00002
Edition Number 2.0
Date 15 March 2018
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8
APPENDIX
8.1
Appendix A: Partial date conventions for AE
Missing type
Action
If only the day part of the AE onset date is 
missing and occurs in the same month and 
year as the first dose of study medication
If AE’s ending date is before the date of the 
first dose, the first day of the month will be 
used to complete the onset date of the AE.
If AE’s end date is on or after the first dose 
of study medication, the date of first dose of 
study medication will be used as the onset 
date of the AE. 
If the day and month parts of the AE onset 
date are missing and occur in the same year 
as the first dose of study medication
If AE’s end date is on or after the first dose 
of study medication, the date of the first 
dose of study medication will be used as 
the onset date of the AE. Otherwise, 
January 1st will be used to complete the 
onset date of the AE.
If the AE onset date is completely missing
If the end date is on or after the first dose of 
study medication,the date of the first dose of 
study medication will be used as the onset 
date of the AE.


Statistical Analysis Plan 
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Edition Number 2.0
Date 15 March 2018
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8.2
Appendix B: Algorithm for prior/concomitant medications:
START 
STOP 
ACTION
Known
Known
If stop date < study med start date, assign as prior;
If stop date ≥ study med start date and start date ≤ study med 
last date + 30 days, assign as concomitant; 
If stop date > study med start date and start date > study med 
last date + 30 days, assign as post study.
Partial
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then:
If stop date < study med start date, assign as prior
If stop date ≥study med start date and start date ≤ study med 
last date + 30 days, assign as concomitant
If stop date > study med start date and start date > study 
med last date + 30 days, assign as post treatment
Missing
If stop date is missing could never be assumed a 
prior medication
If start date ≤ study med last date + 30 days, assign 
as concomitant
If start date > study med last date + 30 days, assign as 
post treatment
Known 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month 
are unknown), then:
If stop date < study med start date, assign as prior
If stop date≥  study med start date and start date ≤ study 
med last date + 30 days, assign as concomitant
If stop date > study med start date and start date > study 
med last date + 30 days, assign as post treatment


Statistical Analysis Plan 
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Edition Number 2.0
Date 15 March 2018
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Partial
Partial
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown) and impute stop date as latest possible date 
(i.e. last day of month if day unknown or 31st December 
if day and month are unknown), then: If stop date < study 
med start date, assign as prior
If stop date ≥ study med start date and start date ≤ study 
med last date + 30 days, assign as concomitant
If stop date > study med start date and start date > study 
med last date + 30 days, assign as post treatment
Missing
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month 
are unknown), then:
If stop date is missing could never be assumed a prior 
medication
If start date ≤ study med last date + 30 days, assign as 
concomitant
If start date > study med last date + 30 days, assign as 
post treatment


Statistical Analysis Plan 
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Edition Number 2.0
Date 15 March 2018
54
8.3
Appendix C: Definition of subgroups
The narrow SMQs for cardiac failure, CKD and diabetes, found in Table 5, Table 6 and Table 
7, respectively, will be used for the definition of the subgroups for heart failure, chronic 
kidney disease and diabetes mellitus.  
Table 5 Definition of Heart Failure
Preferred term
Acute left ventricular failure
Acute pulmonary oedema
Acute right ventricular failure
Cardiac asthma
Cardiac failure
Cardiac failure acute
Cardiac failure chronic
Cardiac failure congestive
Cardiac failure high output
Cardiogenic shock
Cardiopulmonary failure
Cardiorenal syndrome
Chronic left ventricular failure
Chronic right ventricular failure
Cor pulmonale
Cor pulmonale acute
Cor pulmonale chronic
Ejection fraction decreased
Hepatic congestion
Hepatojugular reflux
Left ventricular failure
Low cardiac output syndrome
Neonatal cardiac failure
Obstructive shock
Pulmonary oedema
Pulmonary oedema neonatal
Radiation associated cardiac failure
Right ventricular ejection fraction decreased
Right ventricular failure
Ventricular failure


Statistical Analysis Plan 
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Edition Number 2.0
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Table 6 Definition of Chronic Kidney Disease
Preferred term
Artificial kidney device user
Azotaemia
Chronic kidney disease
Chronic kidney disease-mineral and bone disorder
Coma uraemic
Diabetic end stage renal disease
Dialysis
Dialysis device insertion
End stage renal disease
Glomerulonephritis chronic
Haemodialysis
Haemofiltration
Hepatorenal failure
High turnover osteopathy
Hyperparathyroidism secondary
Kidney fibrosis
Low turnover osteopathy
Nephrogenic anaemia
Nephrogenic systemic fibrosis
Nephrosclerosis
Oedema due to renal disease
Pericarditis uraemic
Peritoneal dialysis
Renal and liver transplant
Renal and pancreas transplant
Renal failure
Renal replacement therapy
Renal rickets
Renal transplant
Uraemia odour
Uraemic acidosis
Uraemic encephalopathy
Uraemic gastropathy
Uraemic myopathy
Uraemic neuropathy
Uraemic pruritus
Uridrosis


Statistical Analysis Plan 
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Table 7 Definition of Diabetes Mellitus
Preferred Term
Acquired lipoatrophic diabetes
Blood 1,5-anhydroglucitol decreased
Blood glucose increased
Diabetes complicating pregnancy
Diabetes mellitus
Diabetes mellitus inadequate control
Diabetes with hyperosmolarity
Diabetic arteritis
Diabetic coma
Diabetic hepatopathy
Diabetic hyperglycaemic coma
Diabetic hyperosmolar coma
Diabetic ketoacidosis
Diabetic ketoacidotic hyperglycaemic coma
Diabetic ketosis
Diabetic metabolic decompensation
Euglycaemic diabetic ketoacidosis
Fructosamine increased
Fulminant type 1 diabetes mellitus
Gestational diabetes
Glucose tolerance impaired
Glucose tolerance impaired in pregnancy
Glucose urine present
Glycosuria
Glycosuria during pregnancy
Glycosylated haemoglobin increased
Hyperglycaemia
Hyperglycaemic hyperosmolar nonketotic syndrome
Hyperglycaemic seizure
Hyperglycaemic unconsciousness
Impaired fasting glucose
Insulin resistance
Insulin resistance syndrome
Insulin resistant diabetes
Insulin-requiring type 2 diabetes mellitus
Ketoacidosis


Statistical Analysis Plan 
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Edition Number 2.0
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Ketonuria
Ketosis
Ketosis-prone diabetes mellitus
Latent autoimmune diabetes in adults
Metabolic syndrome
Monogenic diabetes
Neonatal diabetes mellitus
Pancreatogenous diabetes
Type 1 diabetes mellitus
Type 2 diabetes mellitus
Type 3 diabetes mellitus
Urine ketone body present


Statistical Analysis Plan 
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Edition Number 2.0
Date 15 March 2018
58
8.4
Appendix D: Change in calibration of the potassium assay
Attached to this Appendix is communication from central laboratory provider Covance 
regarding the change to the calibration of the potassium assay. It contains the results from an 
analysis of the correlation and relationship between the old and new calibration methods 
performed by Covance.


PPD
PPD
PPD
PPD
PPD


PPD
PPD
PPD