Clinical trial NCT04727528
Conditions: Hyperkalaemia Metabolic Acidosis Chronic Kidney Disease
Sponsor: AstraZeneca
Start date: 2021-03-22; Completion date: 2022-09-14
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to evaluate the efficacy of SZC as compared to placebo in maintaining normal sK+ in patients with hyperkalemia and metabolic acidosis associated with CKD

Detailed description:
NEUTRALIZE is a prospective, randomized, double-blind, placebo-controlled, parallel, multicenter, Phase IIIb study to investigate the safety and efficacy of SZC in patients with hyperkalemia and low bicarbonate (metabolic acidosis ).

The study will be conducted in the United States (US) at approximately 35 investigative sites.

After screening on Day 1, all eligible patients will receive open-label SZC for up to 48 hours. Patients who achieve normokalemia within 48 hours will be randomized 1:1 into the double-blind randomized treatment phase to receive SZC or placebo. Study treatment will end with the Day 29 visit, which will be followed by a follow-up visit 7 days after the last administration of study medication.

Arms: arm 1: All eligible patients will receive SZC 10 g TID for up to 48 hours. Patients with POCT (Point-of-Care-Test) K+ ≥5.1 mmol/L after 24 hours will continue on SZC 10 g TID for another 24 hours. Patients who achieve normokalemia (defined as POCT K+ between 3.5 and 5.0 mmol/L inclusive) after receiving SZC 10 g TID for up to 48 hours will proceed to randomization.

Patients with POCT K+ \<3.5mmol/L at any time during the open-label phase will be withdrawn from study treatment and will be followed per protocol. arm 2: Patients will be randomized to SZC 10 g QD or placebo 10 g QD. The dose of SZC/placebo will be titrated by increasing or decreasing the dose by 5 g increments at 1-week intervals to between 5 g every other day (QOD) and 15 g QD of the randomized phase to maintain normokalemia by POCT K+.
Interventions: intervention 1: Sodium zirconium cyclosilicate intervention 2: Placebo
Intervention descriptions: intervention 1: Investigational medicinal product intervention 2: Plabeco comparator

Protocol documents:
Prot_000.pdf: 
Cli nical St u d y Pr ot oc ol - 6. 0
Astr a Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
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Cli nic al St u d y Pr ot oc ol 
St u d y I nter ve nti o n
S o di u m Zirc o ni u m C ycl osilicate ( S Z C)
St u d y C o de
D 9 4 8 0 C 0 0 0 2 2
Ve rsi o n
6. 0
Date
3 Marc h 2 0 2 2
A D o u ble -bli n d R a n d o mize d Pl ace b o -c o ntr olle d P ar allel Desi g n 
M ultice nter P h ase III b St u d y of t he Effect of S o di u m Zirc o ni u m 
C ycl osilic ate ( S Z C) o n Ser u m P ot assi u m a n d Ser u m Bic ar b o n ate 
i n P atie nts wit h H y per kale m i a a n d Met a b olic Aci d osis Ass oci ate d 
wit h C hr o nic Ki d ne y Di se ase ( N E U T R A LI Z E)
S p o ns or  N a me: Astra Ze neca P har mace ut icals L P
Le g al Re gister e d A d dress : 1 8 0 0 C o nc or d Pi ke, W il mi n gt o n, D E 1 9 8 0 3, U S
Re g ul at or y A ge nc y I de ntifier  N u m ber: I N D 1 0 8 9 5 1
T his Cli nical St u d y  Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
Sta n dar d pr oce d ures. T he Cli nical St u d y Pr ot oc ol is p u blicl y re gistere d a n d t he res ults are 
di s close d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o mplia nce wi t h pre vaili n g la ws a n d re g ulatio ns.
P r ot oc ol N u m ber : D 9 4 8 0 C 0 0 0 2 2
A me n d me nt N u m ber : n ot a p plica ble
St u d y I nter ve nti o n : s o diu m  zirc o ni u m c yclosilicate ( S Z C)
St u d y P h ase : III b
S h ort Title : N E U T R A LI Z E
St u d y p h ysici a n n a me a n d c o nt act i nf or m ati o n will be pr o vi de d se p ar atel y .
Pri nci p al i n ve sti g at or:
 
P P D


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DOCUMENT HISTORY
Document
Date
Amendment, CSP version 6.0
3 March 2022
Amendment, CSP version 5.0
3 February 2022
Amendment, CSP version 4.0
10 June 2021
Amendment , CSP version 3.0
16 Apr 2021
Amendment, CSP version 2.0
18 Nov 2020
Amendment 6.0, 3 March 2022
Section # and Name
Description of Change
Brief Rationale
Section 5.1
Inclusion criteria 3 - Inclusion criteria 
number 3 had a typographical error. The 
range of POCT bicarbonate inclusion 
criteria is not changed, in line with 
protocol revision history for version 5.0
but has a typographical error.  The correct 
wording should be “POCT K+ level >5 
mmol/L to ≤5.9 mmol/L and POCT 
bicarbonate levels between 16-20 mmol/L 
inclusive prior to the first SZC dose on 
study Day 1.
Correcting typographical error


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TABLE OF CONTENTS
1
PROTOCOL SUMMARY .................................................................................. 7
1.1
Synopsis ............................................................................................................. 7
1.2
Schema............................................................................................................. 11
1.3
Schedule of Activities ....................................................................................... 12
2
INTRODUCTION............................................................................................ 14
2.1
Study Rationale ................................................................................................ 14
2.2
Background ...................................................................................................... 15
2.2.1
Risk Assessment ............................................................................................... 17
2.2.2
Benefit Assessment........................................................................................... 17
2.2.3
Overall Benefit/Risk Conclusion....................................................................... 18
3
OBJECTIVES AND ENDPOINTS................................................................... 19
4
STUDY DESIGN ............................................................................................. 22
4.1
Overall Design.................................................................................................. 22
4.1.1
Open-label Correction Phase............................................................................. 22
4.1.2
Randomized Placebo-controlled Phase.............................................................. 22
4.2
Scientific Rationale for Study Design ............................................................... 22
4.2.1
Rationale for Patient Population........................................................................ 22
4.2.2
Rationale for Blinding and Randomization........................................................ 23
4.2.3
Rationale for Treatment Groups........................................................................ 23
4.2.4
Rationale for Objectives and Endpoints ............................................................ 23
4.3
Justification for Dose........................................................................................ 24
4.4
End of Study Definition.................................................................................... 24
5
STUDY POPULATION.................................................................................... 25
5.1
Inclusion Criteria .............................................................................................. 25
5.2
Exclusion Criteria ............................................................................................. 26
5.3
Lifestyle Considerations ................................................................................... 27
5.4
Screen Failures ................................................................................................. 27
6
STUDY INTERVENTION ............................................................................... 28
6.1
Open-label Correction Phase (Visits 1 and 2) .................................................... 28
6.2
Randomized Placebo-controlled Phase (Visits 3 to 5)........................................ 28
6.3
Randomized Placebo-controlled Phase (Visits 6 and 7) ..................................... 29
6.4
Study Intervention(s) Administered................................................................... 30
6.4.1
Investigational Products.................................................................................... 30
6.5
Preparation/Handling/Storage/Accountability ................................................... 31
6.6
Measures to Minimize Bias: Randomization and Blinding ................................ 31
6.7
Study Intervention Compliance......................................................................... 32
6.8
Concomitant Therapy........................................................................................ 32
6.8.1
Rescue Therapy ................................................................................................ 34


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6.9
Dose Modification ............................................................................................ 34
6.10
Intervention After the End of the Study............................................................. 34
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 35
7.1
Discontinuation of Study Intervention............................................................... 35
7.2
Participant Withdrawal from the Study.............................................................. 36
7.3
Lost to Follow-up ............................................................................................. 36
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 38
8.1
Efficacy Assessments........................................................................................ 38
8.1.1
Potassium ......................................................................................................... 38
8.1.2
Bicarbonate....................................................................................................... 39
8.1.3
Chloride............................................................................................................ 39
8.1.4
Urine Analysis .................................................................................................. 39
8.2
Safety Assessments........................................................................................... 39
8.2.1
Physical Examinations...................................................................................... 40
8.2.2
Vital Signs ........................................................................................................ 40
8.2.3
Electrocardiograms........................................................................................... 40
8.2.4
Clinical Safety Laboratory Assessments............................................................ 41
8.3
Adverse Events and Serious Adverse Events..................................................... 42
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 42
8.3.2
Follow-up of AEs and SAEs ............................................................................. 42
8.3.3
Causality Collection.......................................................................................... 43
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 43
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 44
8.3.6
Reporting of Serious Adverse Events ................................................................ 44
8.3.7
Reporting of AEs/SAEs in Relation to COVID-19 ............................................ 45
8.3.8
Pregnancy......................................................................................................... 45
8.3.8.1
Maternal Exposure............................................................................................ 46
8.3.8.2
Paternal Exposure............................................................................................. 46
8.3.9
Medication Error............................................................................................... 46
8.4
Overdose .......................................................................................................... 47
8.5
Human Biological Samples............................................................................... 47
8.5.1
Pharmacokinetics.............................................................................................. 47
8.5.2
Immunogenicity Assessments ........................................................................... 48
8.5.3
Pharmacodynamics........................................................................................... 48
8.6
Human Biological Sample Biomarkers ............................................................. 48
8.7
Optional Genomics Initiative Sample................................................................ 48
8.8
Health Economics............................................................................................. 48
9
STATISTICAL CONSIDERATIONS................................................................ 49
9.1
Statistical Hypotheses....................................................................................... 49
9.2
Sample Size Determination............................................................................... 49
9.3
Populations for Analyses................................................................................... 50


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9. 4
Stati stical A nal yses ...........................................................................................5 0
9. 4. 1
Ge neral C o nsi derati o ns .....................................................................................5 0
9. 4. 2
C O VI D -1 9 C o nsi derat i ons ................................................................................5 1
9. 4. 3
Ef ficac y ............................................................................................................5 1
9. 4. 3. 1
Pri mar y E n d p o i nt..............................................................................................5 1
9. 4. 3. 2
Sec o n dar y  E n d p oi nts ........................................................................................5 2
9. 4. 4
S af et y ...............................................................................................................5 8
9. 5
I nteri m A nal yses ...............................................................................................5 8
9. 6
Data M o nit ori n g C o m mittee .............................................................................5 9
1 0
S U P P O R TI N G 
D O C U M E N T A TI O N 
A N D 
O P E R A TI O N A L
C O N SI D E R A TI O N S ........................................................................................6 0
1 1
R E F E R E N C E S ................................................................................................. 8 0
LI S T O F FI G U R E S
Fi g ure 1
St u d y  desi g n............................................................................................1 1
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of Act i vities..............................................................................1 2
Ta ble 2
Ris k Assess me nt ......................................................................................1 7
Ta ble 3
O bject i ves a n d E n d p oi nts.........................................................................1 9
Ta ble 4
D ose Ti tr atio n a n d Disc o nt i n uati on Cri t eria D uri n g t he Ra n d o mize d 
Pl ace b o -c o ntr olle d P hase: first 2 wee ks ...................................................2 8
Ta ble 5
Di sc o ntin uati o n Cri teria D uri n g t he Ra n d o mize d Place b o-c o ntr olle d 
P hase: l ast 2 wee ks ..................................................................................2 9
Ta ble 6
I n vesti gati onal Pr o d ucts ...........................................................................3 0
Ta ble 7
S u m mar y  of Restricte d Me dicati ons D uri n g Pre -st u d y a n d/ or Treat me nt 
P eri o d ......................................................................................................3 3
Ta ble 8
La b orat or y  S afet y Varia bles .....................................................................4 1
Ta ble 9
P o p ul atio ns f or A nal ysis ..........................................................................5 0
LI S T O F A P P E N DI C E S
A p pe n di x A
Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsid er ati o ns .........................6 1
A p pe n di x B
A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or Rec or di n g, E val uati n g, 
F o ll ow- u p, a n d Re p orti n g ........................................................................6 6
C CI


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Appendix C
Handling of Human Biological Samples .................................................. 70
Appendix D
Optional Genomics Initiative Sample....................................................... 72
Appendix E
Management of Study Procedures During the COVID-19 Pandemic........ 75
Appendix F
Abbreviations .......................................................................................... 78






Cli nical St u d y Pr ot oc ol - 6. 0
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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O bjecti ves
E n d p oi nts
H y p ot heses
A Es lea di n g t o 
disc o nti n uati o n of S Z C/
place b o
A b bre viati o ns : A E = a d verse e ve nt; C K D = c hr o nic ki d ne y disease; E C G = electr ocar di o gra m; E O T = e n d of 
treat me nt; s K + = ser u m p otassi u m; S Z C = s o di u m zirc o ni u m c ycl osilicate .
F or t he 
 e n d p oi nts, a n d h y p ot heses, see Secti o n 3 of  t he pr ot oc ol.
O ver all Desi g n
T his is a pr os pecti ve, ra n d o mize d, d o u ble -bli n d, place b o -c o nt r olle d, parallel, mul tice nter, 
P hase III b st u d y  t o i n vesti gate t he safety a n d efficac y of S Z C i n patie nts wit h h y per kale mia 
a n d l o w bicar b o nate ( or meta b o lic aci d osis). 
T he st u d y  will be c o n d ucte d i n t he U nite d States ( U S) at a p pr o xi matel y 3 5 i n vesti gati ve sites.
After scree ni n g o n Da y 1, all patient s will recei ve o pe n-label S Z C f or u p t o 4 8 h o urs, a n d t he n 
be ra n d o mize d t o d o u ble - bli n d treat me nt of S Z C or place b o f or 4 wee ks. F oll o w -u p will 
c o nti n ue f or 7 da ys after t he last a d mi nistrati o n o f st u d y me dicat i on.
Discl os ur e St ate me nt : T hi s is a parallel-gr o u p treat m e nt st u d y wit h 2 ar ms t hat is partici pa nt -
a n d i n vest i gat or-bli n de d.
N u m ber  of P artici p a nts:. A p pr o xi matel y 4 7 7 patie nts will be scree ne d. A p pr o xi matel y  14 8
pati e nts will be e nr olle d t o t he o pe n-label p hase o f t he st u d y t o ac hie ve 1 3 6 ra n d oml y 
assi g ne d t o st u d y int er ve ntio n.
I nter ve nti o n Gr o u ps a n d D ur ati o n
T his st u d y  c o nsists of a s h ort scree ni n g peri o d ( Da y 1), a n o pe n-la bel c orrecti o n p hase ( u p t o 
4 8 h o urs), a 4 -wee k ra n d o mize d treat me nt p hase, a n d a f oll ow- u p peri o d ( 7 da ys after t he last 
a d mi nistrati o n of st u d y me dicatio n) . T he t otal st u d y  tr e at me nt perio d c o nsist i n g of o pe n-label 
a n d ra n d o mize d p hases will be 2 8 da ys.
Scree ni n g will be perf or me d usi n g p ot assi u m  a n d bicar b o nate val ues fr om a st u d y-ap pr o ve d 
p oi nt -of - care bl o o d a nal yzer (P oi nt -of -Care -Te st, P O C T), t o deter mi ne eli gi bility of  
c o nse nt i n g patie nts t o e nter t he o pe n-lab el  c orrecti o n p hase. Pati e nts w h o meet t he P O C T
eli gi bilit y crit eria of ser u m p ot assiu m  (s K +) bet wee n 5 -5. 9 m m o l/ L i ncl usi ve, A N D ser u m 
bicar b o nate bet wee n 1 6 -2 0 m m ol / L incl usi ve, will be e nr olle d i nt o t he o pe n -label c orrecti o n 
p hase . All baseli ne para meters s h o ul d be meas ure d/c ollecte d pri or t o a d mi nistrati o n of t he first 
d ose of st u d y  dr u g i n t he o pe n-label i nit ial phase. 
I n t he o pe n-la bel i nitial p hase, patie nts will recei ve o pe n-lab el  S Z C orall y at a d ose of 1 0 g 
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three times daily (TID) for up to 48 hours, depending on POCT potassium value..
Patients who achieve normokalemia (POCT K+ between 3.5 and 5.0 mmol/L inclusive) within 
48 hours will be randomized 1:1 into the double-blind randomized treatment phase to receive 
10 g SZC or placebo once daily (QD) starting dose for the following 26 or 27 days. Patients 
who achieve normokalemia after 24 hours will be randomized and will not need to continue 
on 10 g SZC TID for another 24 hours.
Study treatment will end with the Day 29 visit, which will be followed by the Follow-up 
Phase visit, 7 days after the last administration of study medication.
Data Monitoring Committee: No
Statistical Methods
The analysis of the primary endpoint will be conducted according to the intention-to-treat 
principle using the full analysis set (FAS). All randomized patients will be included in the 
analyses, irrespectively of whether they do, or do not, receive treatment or do, or do not, 
experience a particular type of protocol deviation, such as failure to fulfill one or more 
eligibility criteria. Thus, the population under study consists of all patients who are deemed as 
suitable for randomization by the investigator(s).
The primary endpoint is a classification of each randomized patient into a responder or a non-
responder category (ie, a 0-1 type of response), with a patient being a responder if they:
a.
Are normokalemic (central laboratory sK+ between 3.5 and 5.0 mmol/L inclusive) at 
the EOT visit (Day 29)
b. Did not receive any rescue therapy for hyperkalemia during the randomized phase
The following rules will be implemented to account for missing laboratory results: 
a.
If Visit 7 central laboratory sK+ is missing, then Visit 6 central laboratory sK+ will 
be used in its place (last observation carried forward [LOCF]).
b.
If central laboratory sK+ is missing for Visits 6 and 7, then sK+ will be replaced by 
POCT value adjusted to reflect the mean difference between POCT and sK+ values 
from all available paired laboratory samples. (Visit 7 POCT will be used unless 
missing, in which case Visit 6 POCT will be used.)
c.
If no results (central laboratory sK+ or POCT K+) are available for Visits 6 and 7, 
then classify as non-evaluable. 
A sensitivity analysis will be conducted based on the Per Protocol Set (PPS). Additional 
sensitivity analyses will also be carried out related to the proportion of patients achieving 
normokalemia in the SZC versus placebo arm.


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1.2
Schema
Figure 1
Study design
* Open-label phase will be Day 1 or Days 1 and 2. Randomization to double-blind placebo-controlled phase 
will start Day 2 or 3. 
#
Visit 3 procedures will occur on Day 2 for patients who achieve normokalemia (POCT K+ 3.5-5.0 mmol/L) at 
Visit 2 (Day 2) and on Day 3 for patients who achieve normokalemia at Visit 3. Patients who achieve 
normokalemia at 24 hours will not need to remain on SZC 10 g TID and will be enrolled in the randomized 
placebo-controlled phase at Day 2. Patients who achieve normokalemia at 48 hours will be enrolled in the 
randomized placebo-controlled phase at Day 3.
Patients with POCT K+ <3.5 mmol/L at Day 2 or 3 and patients with POCT K+ >5.0 mmol/L at Day 3 will be 
discontinued from the study and followed up as per protocol.
Abbreviations: h = hours; K+ = potassium; R = randomization; SZC = sodium zirconium cyclosilicate; TID = 
three times daily.


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1.3
Schedule of Activities
Table 1
Schedule of Activities
Procedure
Screening
Open-Label Phase
(up to 2 days)a
Randomized Phase (Visit 2 or 3 to Visit 7)
E/D
Follow-
up Phase
Details in CSP 
section
Visit
1
1
2
Randomiza-
tion (Day 2 
or 3)
4
5
6
7 
(EOT)
8
2
3 a
Week
1
1
1
1
2
3
4
5
6
Day (Window)
1
1
2
2 or 3
8(±1)
15(±1)
22(±1)
29(±1)
36(±3)
Informed consent
X
Section 5.1
Inclusion and exclusion criteria
X
Sections 5.1 & 5.2
Routine Clinical Procedures
Demography
X
Section 5.1
Physical examination (including 
heightb)
X
X
X
Section 8.2.1
Medical history
X
Section 5.2
Concomitant medication
At every visit and may be conducted by phone if not tied to a visit
Section 6.8
Vital signs
X
X
X
X
X
X
X
X
Section 8.2.2
Weight
X
X
X
X
X
X
X
X
Section 8.2.1
Routine Safety Measurements
Adverse events
At every visit and may be conducted by phone if not tied to a visit
Section 8.3
Urine pregnancy test (females only)
X
Section 8.2.4
Clinical safety laboratory assessments 
(including urine dipstick)c
X
X
X
X
X
Section 8.2.4
Electrocardiogram
X
X
X
X
X
Section 8.2.3
Efficacy Lab Assessmentsd
Central laboratory potassium,
bicarbonate, and chloridee
(X)e
(X)
X
X
X
(X)
(X)
(X)
Section 8.2.4


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A b bre viati o ns : C S P = cli nical st u d y pr ot oc ol; E/ D = Earl y St u d y I nter ve nti o n/ Disc o nti n uati o n; E O T = e n d of treat me nt; K + = p otassi u m; S Z C = s o di u m zirc o ni u m c ycl osilicate; 
TI D = t hree ti mes dail y; U A C R = uri ne al b u mi n-t o-creati ni ne -rati o.
a
O pe n -la bel will be Da y 1 or Da ys 1 a n d 2; ra n d o mizati o n will start Da y 2 or 3. V isit 3 pr oce d ures will occ ur o n Da y 2 f or patie nts w h o ac hie ve n or m o kale mia (P O C T K + 
bet wee n 3. 5 -5. 0 m m ol/ L i ncl usi ve) at Visit 2 ( Da y 2) a n d o n Da y 3 f or patie nts w h o ac hie ve n or m o kale mia at Visit 3. Patie nts w h o ac hie ve n or m o kale mia at 2 4 h o urs will n ot 
nee d t o re mai n o n S Z C 1 0 g TI D a n d will be e nr olle d i n t he ra n d o mize d place b o-c o ntr olle d p hase at Da y 2 . Patie nts wit h P O C T K + < 3. 5 m m ol/ L at Da y 2 or 3 will be 
disc o nti n ue d fr o m t he st u d y a n d f oll o we d u p as per pr ot oc ol . Patie nts w h o ac hie ve n or m o kale mia at 4 8 h o urs will be e nr olle d i n t he ra n d o mize d place b o -c o ntr olle d p hase at 
Da y 3 . Patie nts wit h P O C T K + > 5. 0 m m ol/ L at Da y 3 will be disc o nti n ue d fr o m t he st u d y a n d f oll o we d u p as per pr ot oc ol.
b
Hei g ht will be c ollecte d o nl y at t he scree ni n g visit.
c
Cli nical safet y la b orat or y assess me nts at scree ni n g t o be dra w n at t he sa me ti me p oi nt as P O C T . Dra w n sa m ples will be discar de d if patie nt d oes n ot meet criteria f or e nr ol me nt 
i nt o o pe n la bel p hase.
d
Fasti n g is rec o m me n de d ( b ut n ot ma n dat or y) as meals ca n tra nsie ntl y c ha n ge aci d -base stat us.
e
P otassi u m , bicar b o nate , a n d c hl ori de will be meas ure d as part of t he cli nical safet y la b orat or y assess me nts f or Visits 1, 3, 7, a n d 8.
f
P O C T assess me nt will i ncl u de bicar b o nate as t otal car b o n di o xi de ( T C O 2), p otassi u m, creati ni ne, s o di u m, c hl ori de, a n d a ni o n ga p .
g
Uri nar y al b u mi n, a m m o ni u m, citrate, p H, creati ni ne, a ni o n ga p , a n d calc ulate d U A C R a n d a m m o ni u m -t o-creati ni ne rati o will be meas ure d at t he ce ntral la b orat or y .
h
O pti o nal ge n o mics sa m ple t o be dra w n at t he sa me ti me p oi nt as t he sec o n d P O C T . Dra w n sa m ples will be discar de d if patie nt d oes n ot meet criteria f or e nr o lme nt i nt o o pe n 
la bel p hase.
i
A sta ble d ose of S Z C/ place b o is rec o m me n de d d uri n g t he last 2 wee ks of t he ra n d o mize d p hase . H o we ver, d ose titrati o n will be all o we d f or o pti mal patie nt care a n d/ or if ris k 
f or disc o nti n uati o n or as per i n vesti gat or j u d g me nt, a cc or di n g t o S ecti o n 6. 3 .
P O C T assess me nts f
X
X  
X  
X  
X  
X  
X  
X  
X
Secti o n  8. 2. 4
S p ot uri ne (ce ntral la b) g
X
X  
X  
X  
X  
X  
X  
X
Secti o n  8. 1. 4
O pti o nal ge n o mics bl o o d sa m ple
X h
Secti o n  8. 7
St u d y Tre at me nt A d mi nistr ati o n
Dr u g dis pe nsati o n o pe n -la bel p hase
X  
X
Secti o n  6. 1
Dr u g dis pe nsati o n ra n d o mize d p hase
X  
X  
X  
X
Secti o n  6. 2
Ra n d o mizati o n ( 1: 1 S Z C or place b o)
X
Secti o ns  6. 2 -6. 3
Titrati o n, if nee de d
X  
X  
X i
Secti o n  6. 2
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2
INTRODUCTION
Sodium zirconium cyclosilicate (SZC) is as an orally-administered, non-polymer non-
absorbable, inorganic, crystalline cation-exchanger that represents a novel therapy for 
hyperkalemia. It selectively binds potassium in exchange for hydrogen and sodium ions 
throughout the gastrointestinal (GI) tract, thereby reducing serum potassium (sK+) 
concentration.1,2 The potassium is removed from the body through fecal excretion. 
The efficacy of SZC to rapidly correct hyperkalemia and maintain normokalemia irrespective 
of underlying morbidity, and its favorable safety profile, have been well documented in the 
clinical program. In clinical studies, three times daily (TID) administration of 10g SZC rapidly 
normalizes sK+ (between 3.5 and 5.0 mmol/L inclusive) within 48 hours3,4,5 and is associated 
with maintenance of normokalemia for up to 1 year with continued administration of titrated 
SZC dose.6
SZC treatment has also been associated with dose-dependent increases in serum bicarbonate 
based on existing data including Phase II, open-label Phase III, and post-hoc analyses of 
randomized Phase III trials.1,2,3
2.1
Study Rationale
A significant proportion of patients with chronic kidney disease (CKD) and hyperkalemia 
have low serum bicarbonate. Based on recent studies, low serum bicarbonate and associated 
metabolic acidosis have been associated with an increased risk for CKD progression, 
metabolic bone disease, and mortality; and recent evidence has bolstered the need to increase 
serum bicarbonate.7
Post-hoc analyses of Phase III studies for SZC showed a dose-dependent increase in serum 
bicarbonate and the increase was greater in patients with lower serum bicarbonate at 
baseline.1,8
However, patients in SZC studies were included on the basis of their elevated POCT or sK+; 
serum bicarbonate level was not part of the inclusion criteria.1,4,5 Though a portion of the 
patients in the studies (39.4% in ZS-004 and 31.4% in ZS-005) also had a low serum 
bicarbonate, the population of CKD patients with hyperkalemia and low serum bicarbonate 
was not systematically identified or studied. In addition, these studies did not:
a.
restrict use of sodium bicarbonate, thus confounding the effect of SZC on serum 
bicarbonate; OR
b. evaluate the impact of SZC on urine ammonium excretion.
Therefore, the full benefit of SZC in patients with hyperkalemia and metabolic acidosis 
associated with CKD is not known.


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A double-blind randomized study that demonstrates SZC’s ability to treat hyperkalemia and 
increase serum bicarbonate in this patient population could potentially improve health and 
reduce the complexity of care management. Measuring change in urine ammonium will 
further elucidate the mechanism behind the increase in serum bicarbonate seen with SZC. This 
study aims to investigate if SZC can increase serum bicarbonate in a clinically meaningful 
way. Increases in serum bicarbonate with SZC treatment may provide potential benefits in
terms of correcting metabolic acidosis, as well as reducing the need for alkali supplementation 
with sodium bicarbonate.
2.2
Background
Metabolic acidosis associated with CKD is defined as a serum bicarbonate <22 mmol/L (per 
KDIGO guidelines)9 and occurs in about 1 in 3 patients with CKD stage 3-5 with 
hyperkalemia.10 An even larger proportion of CKD patients have a negative acid balance 
despite having serum bicarbonate levels ≥22 mmol/L;11 therefore, the optimal serum 
bicarbonate level in CKD remains to be determined. Recent studies suggest treatment of 
metabolic acidosis by increasing serum bicarbonate appears to improve muscle mass and 
preserve kidney function by decreasing protein catabolism and may slow progression of 
CKD.7,12
However, current treatment with sodium bicarbonate is limited by high pill burden needed to 
correct the serum bicarbonate.7 Given the evidence that SZC treats hyperkalemia and also 
causes a dose-dependent increase in serum bicarbonate, patients with both these 
electrolyte/acid-base complications may observe efficacy from treatment with SZC. 
In post-hoc analysis of ZS-004, patients with a baseline serum bicarbonate level of <22 
mmol/L observed mean increase in serum bicarbonate of 5.1 mmol/L at Day 29 with SZC 
versus 1.5 mmol/L increase for placebo (p<0.001).2,3 In ZS-005, a mean increase in serum 
bicarbonate of 2.5 mmol/L was observed at Day 29 in patients with baseline serum 
bicarbonate <22 mmol/L compared to a 0.77 mmol/L increase in all patients.1
The exact mechanism behind the increase in serum bicarbonate seen with SZC has not been 
fully elucidated. There are 2 potential mechanisms: a) correction of hyperkalemia leads to 
increased renal ammoniagenesis effectively increasing renal excretion of acid6,13 or b) SZC 
binds ammonium ions in the GI tract, given that the mean binding site is 3 Angstroms and the 
size of ammonium is 2.96 Angstroms in the dehydrated form. This leads to less ammonium 
absorption from the GI tract which would otherwise be metabolized to urea, a process that 
consumes bicarbonate.14,15 A pathways analysis evaluating the 2 potential mechanisms using 
data from prior SZC studies shows that serum urea levels decreased and urine pH is slightly 
increased. The mechanism responsible for an increase in serum bicarbonate could be related 
to, at least in part, SZC binding ammonium in the GI tract.16 Prior SZC studies have not 
studied the impact of SZC on urine ammonium. If the urine ammonium does not increase 


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markedly with SZC, that would suggest that the mechanism of the correction of hyperkalemia 
is related to an increased excretion of ammonium in the GI tract. Additional confirmatory 
studies, eg, measurement of fecal ammonia, will be needed. Such evidence would differentiate 
SZC from other potassium binders, as an increase in serum bicarbonate was not seen in the 
patiromer clinical trials.17
A detailed description of the chemistry, pharmacology, efficacy, and safety of SZC is provided 
in the Investigator’s Brochure (IB)8. Benefit/Risk Assessment
This study will recruit patients who have mild-to-moderate hyperkalemia. There is a risk of 
hyperkalemia in those patients who are randomized to placebo and risk of hypokalemia in 
patients randomized to SZC. Additionally, there is theoretical risk of worsening metabolic 
acidosis (low bicarbonate). Hence, hyperkalemia, hypokalemia, and potentially worsening 
metabolic acidosis are the major medical risks for patients participating in this trial. The 
following study design features were included to minimize the risk to patients:

All patients will receive active treatment with SZC (10 g TID, up to 48 hours) during 
the open-label phase and only patients that have normalized POCT K+ will be 
randomized into the study, minimizing the risk of hyperkalemia in the randomized 
treatment phase.

POCT will be used by sites to measure K+ and bicarbonate at each visit, providing 
investigators with up-to date K+ and bicarbonate measurements thereby allowing dose 
adjustments/discontinuation to occur as appropriate during the study visit.

SZC dose titration and stopping rules and rescue therapy rules based on POCT K+ 
monitoring are included in this protocol to minimize the risk of hyperkalemia and 
hypokalemia.

The risk of severe hyperkalemia upon randomization to placebo will be mitigated with 
close monitoring of K+ from the beginning of the randomized treatment through the 
EOT visit.

The risk of hyperkalemia after the EOT visit will be mitigated by monitoring of K+ for 
1-week post-study conclusion.

Hypokalemia has been reported with SZC. SZC dose titration and stopping rules based 
on K+ monitoring are included in this protocol to minimize the risk of hypokalemia in 
patients receiving SZC. 

Rules for rescue medication treatment based on POCT bicarbonate monitoring are 
included in the protocol to minimize the risk of severe metabolic acidosis.

Edema-related events (grouped terms include preferred terms of edema, edema
peripheral, generalized edema, fluid overload, fluid retention, hypervolemia, localized
edema, and peripheral swelling) have been reported by patients treated with SZC, in 


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particular at higher doses. Physical examinations to assess edema will be performed 
and the patient will be weighed at prespecified visits to ensure development of edema
will be detected early and appropriately managed (see Section 8.2.1).
More detailed information about the known and expected benefits and potential risks of SZC 
may be found in the IB.8
2.2.1
Risk Assessment
Table 2
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention
Common (≥1/100 to <1/10) 
ADR observed in SZC clinical 
studies: edema-related events
Edema-related events were reported by 
5.7% of SZC subjects; 2.7%, 5.2%, 
14.3%, and 1.7% of subjects randomized 
to SZC 5 g, 10 g, 15 g, and placebo, 
respectively.  Grouped terms include 
preferred terms of Edema, Edema 
peripheral, Generalized edema, Fluid 
overload, Fluid retention, Hypervolemia, 
Localized edema, and Peripheral 
swelling.  (Refer to IB Section 5.4-5.5 
and 6.4)
Of the edema-related events, 
53% were managed with 
initiating diuretic treatment or 
adjusting the diuretic dose, 
while the remainder did not 
require treatment.  
Common (≥1/100 to <1/10) 
ADR observed in SZC clinical 
studies: hypokalemia
Hypokalemia (serum K+ <3.5 mmol/L), 
a result of the pharmacological action of 
the drug, was observed in 4.1% of 
subjects treated with SZC.  
Resolved with dose adjustment 
or discontinuation of SZC 
treatment.
Abbreviations: ADR = adverse drug reaction; IB= Investigator’s Brochure; QD = once daily; sK+ = serum 
potassium; SZC = sodium zirconium cyclosilicate
2.2.2
Benefit Assessment
Clinical studies in patients with hyperkalemia have demonstrated the efficacy and safety of 
SZC in the correction of hyperkalemia and maintenance of normokalemia.
Participants, irrespective of their treatment allocation, may benefit from more intense 
monitoring and attention to their underlying condition. Patients randomized to SZC may 
benefit by being able to maintain normokalemia according to recommended target doses of 
SZC. In the larger perspective, the main potential benefit of conducting this study lies in the 
possibility to generate scientific evidence for improved management of patients with 
hyperkalemia and metabolic acidosis associated with CKD, and potentially improve health 


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and reduce the complexity of care management.
2.2.3
Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with SZC are justified by the anticipated benefits that 
may be afforded to participants with hyperkalemia and metabolic acidosis.
In previous studies, SZC has proven to effectively and safely correct hyperkalemia to the 
normal sK+ range and maintain normokalemia for up to 12 months in a broad patient 
population with hyperkalemia, including those on hemodialysis. In these studies, treatment 
with SZC was associated with dose-dependent increases in serum bicarbonate. Unfavorable 
effects were limited, and the adverse drug reactions (ADRs) of edema-related events and 
hypokalemia were generally mild and easily managed. Dose titration during maintenance 
treatment allows individualized treatment to maintain normokalemia. Based on the available 
clinical data, the benefit/risk assessment is favorable for correction of hyperkalemia with SZC 
10 g TID for up to 2 days, and for maintenance treatment of patients with hyperkalemia across 
the dose range 5 g every other day (QOD) to 5 to 15 g QD. Data from these studies 
demonstrate that the majority of patients can be adequately maintained on the 5 g QD or 10 g 
QD dose. Based on the limited potential risks to study participants, the risk mitigations 
included in this protocol, and the long-term potential benefits of simplifying management of 
patients with hyperkalemia and metabolic acidosis associated with CKD, it is concluded that 
the study as proposed exposes recruited patients to an acceptable risk.






Cli nical St u d y Pr ot oc ol - 6. 0
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A b bre viati o ns: A E = a d verse e ve nt; C K D = c hr o nic ki d ne y disease; E C G = electr ocar di o gra m; E O T = e n d of 
treat me nt; s K + = ser u m p otassi u m; S Z C = s o di u m zirc o ni u m c ycl osilicate.
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4
STUDY DESIGN
4.1
Overall Design
NEUTRALIZE is a Phase IIIb multicenter, placebo-controlled, randomized, double-blind, 
parallel-designed clinical trial which includes a screening visit, a treatment period 
(approximately 4 weeks), and an off-treatment follow-up visit 1 week later. The treatment 
period will be divided into an open-label correction phase of up to 48 hours’ duration where 
all patients will receive SZC followed immediately by a randomized, placebo-controlled phase 
from Day 3 to Day 29. 
4.1.1
Open-label Correction Phase
All patients fulfilling inclusion/exclusion criteria will enter the initial open-label correction 
phase and receive SZC. During the correction phase, the dose of SZC will be 10 g TID up to 
48 hours. Patients meeting normokalemia (POCT K+ between 3.5 and 5.0 mmol/L inclusive) 
at Day 2 (after 24 hours in the open-label correction phase) will be eligible for the randomized 
phase. Patients not meeting normokalemia at Day 2 will continue in the open-label correction 
phase for an additional 24 hours and repeat POCT on the next day (Day 3). If normokalemia is 
achieved on Day 3, the patient is eligible for the randomized phase. If normokalemia is not 
achieved (POCT K+ value is ≥5.1 mmol/L), the patient will have treatment discontinued, be 
withdrawn from the study, and complete follow-up per the Schedule of Activities (SoA). 
Patients with POCT K+ <3.5 mmol/L at Day 2 or 3 will be discontinued from the study and 
followed up as per protocol.
4.1.2
Randomized Placebo-controlled Phase
Patients who achieve normokalemia (defined as POCT K+ between 3.5 and 5.0 mmol/L 
inclusive) after receiving SZC 10 g TID for up to 48 hours during the open-label correction 
phase will be randomized 1:1 to receive either SZC or placebo in the 4-week double-blind, 
placebo-controlled phase. Patients will be randomized to SZC 10 g QD or placebo 10 g QD. 
The dose of SZC/placebo will be titrated by increasing or decreasing the dose by 5 g 
increments at 1-week intervals to between 5 g every other day (QOD) and 15 g QD during the 
first 2 weeks of the randomized phase to maintain normokalemia by POCT K+. A stable 
SZC/placebo dose is recommended during the last 2 weeks of the randomized placebo-
controlled phase (see Section 6.3).
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Patient Population
The study will exclusively recruit patients who have hyperkalemia and low serum bicarbonate 
associated with CKD. The study will examine the effect of SZC, a commercially available 
drug with the indication for treatment of hyperkalemia, on increasing serum bicarbonate. 
Currently, there are no approved single agents shown to treat both hyperkalemia and raise 


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ser u m bicar b o nate.
Eli gi ble pat ient s will u n der g o a n o pe n-label peri o d of treat me nt wit h S Z C 1 0 g TI D f or u p t o 
4 8 h o ur s t o n or malize K + ( o n-label d osi n g) . T his met h o d ol o g y  has bee n use d i n ot her S Z C 
trials f or t his patient  p o p ulati o n. P O C T K + le vels will be m onit ore d d uri n g t he o pe n -lab el  
p eri o d a n d t h ose w h o n or malize t he K + le vel will be eli gi ble t o be ra n d o mize d; t h ose w h o d o 
n ot n or m alize K + will n ot be eli gi ble f or ra n d o mizati o n. 
4. 2. 2
R ati o n ale f or Bli n di n g a n d R a n d o miz ati o n
T he st u d y  e mpl o y s bli n di n g t o mi ni mize t he ris k f or bias i ntr o d uce d b y patient s, i n vesti gat ors,
a n d s p o ns or or s p o ns or re prese ntati ves . Mi ni mizi n g bi as i ntr o d uce d b y in vesti gat ors a n d 
pati e nts is i m perati ve as t he pri mar y a n d sec o n dar y e nd p oi nts of t he tri al ca n be i nfl ue nce d 
sig nifica nt l y b y treat m e nt c h oices ma de b y t he i n vesti gat ors i n t he trial a n d a gree d wit h 
parti ci pat i n g patie nts. Ra n d o mizat i on is e m pl oye d t o mi ni mize t he ris k f or bias a n d pr o d uce 
c o mpara ble gr o u ps, a n d a 1: 1 ra n d o mizat i on sc he me was selecte d t o ma xi mize p o wer a n d 
t here b y mi ni mize t he n u m ber of pat ient s nee de d t o be recr uite d.
4. 2. 3
R ati o n ale f or Tre at me nt Gr o u ps
T he treat me nt gr o u ps f or t hi s P hase III b st u d y  incl u de S Z C a n d place b o gr o u ps . B ot h gr o u ps 
will ha ve K + n or malize d at t he be gi n ni n g o f t he ra n d o mize d trial a n d cl ose m o nit ori n g of K + 
a n d bicar b o nate will occ ur d uri n g t he d urati o n of t he st u d y. Tit rati o n will occ ur d uri n g t he first 
2 wee ks of t hera p y  t o ac hie ve o pti mal st u d y dr u g d ose acc or di n g t o Secti o ns 6. 2 a n d 6. 3 . 
Tit rati o n of S Z C will be base d o n P O C T K + val ues at eac h visit t o e ns ure patie nts recei ve 
S Z C at a n i n di vi d uall y o pti mize d d ose . Patie nts ra n d o mize d t o recei ve place b o will u n der g o 
m o c k titr atio n t o m ai ntai n t he st u d y bli n di n g. A si milar met h o d olo g y  has bee n use d i n ot her 
S Z C tri als f or si milar st u d y p o p ulatio ns wi t h mai nt e na nce of n or m o kale mia . Clear g ui da nce is 
i n place f or resc ue t hera p y for b ot h h y per kale mia ( > 6. 0 m m o l/ L) a n d l o w ser u m bicar b o nate 
( ≤1 5 m m o l/ L) as well as f or st u d y disc o nti n uati on.
Pl ace b o is use d as c om parat or i n N E U T R A LI Z E as t he pri mar y a n d sec o n dar y efficac y 
e n d p o i nts c o uld be affecte d b y  treati n g p h ysicia ns k n o wi n g t he treat me nt all ocati o n of 
i n di vi d ual patient s, a n d as t her e is n o dr u g c urre ntl y a p pr o ve d t o treat patie nts wit h 
h y per kale mia ass ociate d wit h C K D a n d t o raise t heir ser u m bicar b o nate.
4. 2. 4
R ati o n ale f or O bjecti ves a n d E n d p oi nts
N E U T R A LI Z E is a P hase III b st u d y, a n d as s uc h it is desi g ne d t o pr o vi de necessar y a n d 
s ufficie nt data t o deter mi ne if t here is a n a d diti onal be nefit of i ncreasi n g ser u m bicar b o nate i n 
pati e nts wit h h y per kale mia ass ociat e d wit h C K D. T he pri mar y  o bjecti ve is t o e val uate t he 
efficac y of S Z C as c o m pare d t o place b o i n mai ntai ni n g n or mal s K + i n pat ient s wit h 
h y per kale mia a n d meta b o lic aci d osis ass ociate d wit h C K D. Sec o n dar y  e n d p oi nts will f oc us o n 
t he a bilit y of S Z C t o raise ser u m bicar b o nate . 
 
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4. 3
J u stific ati o n f or D ose
I n n o n-dial ysis pat ient s, t he a p pr o ve d S Z C d ose i n t he U S f or c orrecti o n of h y per kale mia is 
1 0 g TI D ta ke n orall y f or u p t o 4 8 h o urs . F or mai nte na nce of n or m o kale mia, a d ose of 1 0 g 
Q D i s a p pr o ve d, a n d ca n be a dj uste d at 1-wee k i nter vals as nee de d ( b y 5 g i ncre me nts) t o 
o btai n desire d s K + tar get ra n ge ( bet wee n 3. 5 a n d 5. 0 m m o l/ L incl usi ve) . T he rec o m me n de d 
mai nte na nce d ose ra n ge is fr o m 5 g Q O D t o 1 5 g Q D.
Cli nical st u dies i n patie nts wit h h y per kale mia c o nsiste nt l y de m onstrate d t hat  i nitial o pe n-la bel 
treat me nt wit h S Z C 1 0 g TI D f or 2 4 h o urs u p t o 4 8 h o urs res ulte d i n cli nicall y mea ni n gf ul 
s K + re d ucti o n wit h a maj ority of  patient s ac hie vi n g n or m o kale mia wit hi n 2 4 t o 4 8 h o urs . 
M ore o ver, patie nts wit h hi g her baseli ne s K + le vels ha d greater re d ucti o ns i n s K + le vels . O nset 
of  efficac y was ra pi d wit h s K + re d ucti on o bser ve d as earl y  as 1 h o ur after d ose i nta ke.
After c orrecti o n of h y per kale mia, c o nti n ue d mai nt e na nce treat me nt f or 2 8 da ys wit h S Z C 
5 g, 1 0 g, or 1 5 g Q D res ulte d i n c o nt i nue d effecti ve c o ntr ol of s K + wit hi n t he n or m o kale mic 
ra n ge. T he pr o p orti o n of  p atie nts w h o re mai ne d n or m o kale mic at E O T wit h S Z C 5 g, 1 0 g, 
a n d 1 5 g Q D i ncrease d d ose -de pe n de nt l y (ra n ge: 7 1 % t o 8 5 %) a n d was s u peri or t o place b o . I n 
a d ditio n, l o n g- t er m mai nt e na nce treat me nt of u p t o 1 2 m o nt hs wit h S Z C utilizi n g a d ose 
titr atio n sc he me wi t h t he starti n g d ose of 5 g Q D or 1 0 g Q D, titrate d t o a ma xi m u m of 1 5 g 
Q D or a mi ni m u m o f 5 g Q O D was effecti ve i n mai ntai ni n g n or m o kale mia i n t he maj orit y of  
pati e nts.
4. 4
E n d of St u d y Defi niti o n
A partici pa nt i s c o nsidere d t o ha ve c o m plete d t he st u d y  if he/s he has c o m p lete d all p hases of 
t he st u d y or if he/s he recei ve d resc ue treat me nt f or h yper kale mia or l o w ser u m  bicar b o nate 
i ncl u di n g t he last sc he d ule d pr oce d ure s h o w n i n t he S o A  (Ta ble 1 ).
T he e n d o f t he st u d y is defi ne d as t he date of t he last sc he d ule d pr oce d ure s h o w n i n t he S o A 
f or t he last partici pa nt i n t he st u d y.
C CI


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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be 18 years of age or older, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Participants with stage 3-5 CKD and not on dialysis, with an estimated glomerular 
filtration rate (eGFR) ≤59 mL/min/m2 based on the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation.
3
POCT K+ level >5 mmol/L to ≤5.9 mmol/L and POCT bicarbonate levels between 16-20
mmol/L inclusive prior to the first SZC dose on study Day 1
4
Ability to have repeated blood draws or effective venous catheterization.
Sex
5
Male and/or female.
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.

Female participants of childbearing potential must have a negative urine 
pregnancy test at screening. 

Female participants must be 1 year post-menopausal, surgically sterile, or using 
one highly effective form of birth control (defined as one that can achieve a 
failure rate of less than 1% per year when used consistently and correctly). They 
should have been stable on their chosen method of birth control for a minimum 
of 3 months before entering the study and willing to remain on the birth control 
until 12 weeks after the last dose.
Informed Consent
6
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
7
Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports the 
Genomic Initiative. The patient may opt out on the genomic blood sample.


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5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Participants with pseudohyperkalemia.
2
Dialysis requirement or anticipated by the investigator to require dialysis therapy within 1 
month, history of renal transplant, or life expectancy less than 3 months.
3
Cardiac arrhythmias requiring immediate treatment.
4
Active or suspected diabetic ketoacidosis.
5
POCT bicarbonate low enough to need emergency intervention or treatment as judged by 
the investigator.
6
Acute/chronic worsening renal function (eg, ≥30% decline in eGFR) in the 3 months 
before screening.
7
Current acute decompensated HF, hospitalization due to decompensated HF within 4 
weeks prior to screening, or myocardial infarction (MI), unstable angina, stroke or 
transient ischemic attack (TIA) within 12 weeks prior to screening.
8
Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery 
bypass grafting [CABG]) or valvular repair/replacement within 12 weeks prior to 
screening or planned to undergo any of these operations. 
9
Symptomatic hypotension.
10 Current exacerbation of chronic obstructive pulmonary disease (COPD)/asthma or 
hospitalization due to exacerbation of COPD/asthma within 4 weeks of screening. 
11 Severe constipation, bowel obstruction or impaction, including abnormal post-operative 
bowel motility disorders..
12 Active malignancy requiring treatment.
13 History of QT prolongation associated with other medications that required 
discontinuation of that medication.
14 Congenital long QT syndrome.
15 Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication 
are permitted.
16 QTcF (QT interval corrected by the Fridericia method) >550 msec.
Prior/Concomitant Therapy
17 Active treatment (within 7 days prior to screening) with SZC, sodium bicarbonate, 
sodium polystyrene sulfonate, lactulose, or patiromer.


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Prior/Concurrent Clinical Study Experience
18 Participation in another clinical study with an investigational product (IP) administered in 
the last month1.
19 Participants with a known hypersensitivity to SZC.
Other Exclusions
20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
21 Patients who are severely physically or mentally incapacitated and who in the opinion of 
the investigator are unable to perform the patients’ tasks associated with the protocol.
22 Previous enrolment in the present study. 
23 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
24 If the participant has evidence of Coronavirus disease 2019 (COVID-19) within 2 weeks 
prior to screening (see Appendix E), the participant cannot be enrolled in the study.
5.3
Lifestyle Considerations
No lifestyle restrictions are required in the study. 
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
fail inclusion/exclusion criteria and are not entered into the open-label correction phase. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after >2 weeks if screen failure was due to patient not meeting inclusion criterion 
#3 (POCT K+ level >5 mmol/L to ≤5.9 mmol/L and POCT bicarbonate levels between 16-20 
mmol/L) and/or met exclusion criterion #24 [if the participant has evidence of COVID-19
infection within 2 weeks prior to screening]). Further, participants who failed due to not 
meeting inclusion criteria #3 may be rescreened more than once at investigator’s discretion if 
sK+ and bicarbonate obtained during routine patient care subsequent to the last screening are 
consistent with screening criteria. Rescreened participants should be assigned the same 
participant number as the initial screening.
                                               
1 Participants who received a COVID-19 vaccine whilst still under Emergency Use Utilization will not be 
excluded from the study.


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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to or medical device(s) utilized by a study participant 
according to the study protocol.
6.1
Open-label Correction Phase (Visits 1 and 2)
All eligible patients will receive SZC 10 g TID for up to 48 hours. Patients with POCT K+ 
≥5.1 mmol/L at Visit 2 will continue on SZC 10 g TID for another 24 hours. Patients who 
achieve normokalemia (POCT K+ between 3.5 and 5.0 mmol/L inclusive) at Visit 2 will 
proceed to randomization. Patients with POCT K+ <3.5 mmol/L at any time during the open-
label phase will be withdrawn from study treatment and will be followed per protocol. 
Open-label phase failures are defined as participants who enter the open-label correction 
phase and receive at least 1 dose of SZC but who fail to achieve normokalemia (POCT K+ 
between 3.5 and 5.0 mmol/L inclusive) after the 48-hour correction phase. Individuals who 
fail the open-label phase will not be eligible to be rescreened.
6.2
Randomized Placebo-controlled Phase (Visits 3 to 5)
Patients who achieve normokalemia during the open-label correction phase will be 
randomized in a 1:1 double-blind fashion to SZC 10 g QD or placebo 10 g QD. Dose can be 
titrated during the first 2 weeks of the randomized phase based on POCT K+. Table 4
describes the titration of SZC and placebo and discontinuation criteria for abnormal K+ during 
the first 2 weeks of the randomized phase.
Table 4
Dose Titration and Discontinuation Criteria During the Randomized 
Placebo-controlled Phase: first 2 weeks 
Note: If needed, dose titrations will be made on Day 8 and Day 15 (Visits 4 and 5).
SZC/Placebo
POCT K+ 
(mmol/L) on 
Day 8 or 15
Dose Titration and Discontinuation Criteria for Abnormal K+
SZC/placebo: 
All patients 
start on 10 g 
QD, then titrate 
from there 
based on POCT
K+
<3.0
Treatment permanently discontinued. Obtain ECG and treat according to 
medical judgment.
3.0 - 3.4 
Obtain ECG, permanently discontinue treatment if serious arrhythmia 
found and treat according to medical judgment.
If no serious arrhythmia found, pause treatment and treat according to 
medical judgment. 
Increase monitoring until POCT K+ ≥3.5 mmol/L.
Evaluate for underlying risk for hypokalemia. If hypokalemia resolves 
and patient deemed appropriate to restart treatment, then initiate 
SZC/placebo 5 g QOD for the rest of the treatment period.


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SZC/Placebo
POCT K+ 
(mmol/L) on 
Day 8 or 15
Dose Titration and Discontinuation Criteria for Abnormal K+
3.5 - 5.0
No change in SZC/placebo dose.
5.1 – 5.5
Increase SZC/placebo dose by 5 g QD increments up to a maximum of 
15 g QD.*
5.6 – 6.0 
Obtain ECG, discontinue treatment if serious arrhythmia found.
If no serious arrhythmia, increase SZC/placebo dose by 5 g QD 
increments up to a maximum of 15 g QD.*
Further K+ monitoring and treatment per investigator medical judgment 
based on patient risk and benefit.
Increase monitoring frequency until K+ ≤5.5 mmol/L.
>6.0
Treatment permanently discontinued; initiate rescue treatment (see 
Section 6.8.1 for rescue treatment).
Obtain ECG and treat according to medical judgment.
* Uptitration (based on K+ levels) will occur at 1-week intervals.
6.3
Randomized Placebo-controlled Phase (Visits 6 and 7)
A stable dose of SZC/placebo is recommended during the last 2 weeks of the randomized 
phase. However, dose titration will be allowed for optimal patient care and/or if risk for 
discontinuation or as per investigator judgment. Patients with POCT K+ excursions outside of 
between 3.5 and 5.0 mmol/L inclusive during the last 2 weeks of the randomized phase (Days 
16-28) will be managed as detailed in Table 5.
Table 5
Discontinuation Criteria During the Randomized Placebo-controlled 
Phase: last 2 weeks 
SZC/Placebo
POCT K 
(mmol/L), 
Day 22
Discontinuation Criteria for Abnormal K+
SZC/placebo
<3.0
Treatment permanently discontinued. Obtain ECG and treat according to 
medial judgment.
3.0 - 3.4 
Obtain ECG, discontinue treatment if serious arrhythmia found and treat 
according to medical judgment.
If no serious arrhythmia found, temporarily interrupt treatment and treat 
according to medical judgment.
Increase monitoring until POCT K+ ≥3.5 mmol/L.
Evaluate for underlying risk for hypokalemia. If hypokalemia resolves and 
patient is deemed appropriate to restart treatment, then initiate 
SZC/placebo 5 g QOD for the rest of the treatment period.
3.5 - 5.5
No change in SZC/placebo dose.


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SZC/Placebo
POCT K 
(mmol/L), 
Day 22
Discontinuation Criteria for Abnormal K+
5.6 – 6.0
No change in SZC/placebo dose except for optimal patient care and/or if 
risk for discontinuation or as per investigator judgment.
Obtain ECG, permanently discontinue treatment if serious arrhythmia 
found.
Further K+ monitoring and treatment per investigator medical judgment* 
based on patient risk and benefit. 
Increase monitoring frequency until K+ ≤5.5 mmol/L.
>6.0
Treatment permanently discontinued, initiate rescue treatment (see Section 
6.8.1 for rescue treatment).
Obtain ECG and treat according to medical judgment.
* Could include rescue therapy or discontinuation from study treatment. To be followed up and recorded as per 
protocol.
6.4
Study Intervention(s) Administered
During the open-label correction phase, all patients will receive SZC orally at a dose of 10 g 
TID for a maximum of 6 doses over 48 hours. Study drug will be administrated orally with or 
without food. The individual kit will be assigned through Interactive Response 
Technology/Randomization and Trial Supply Management (IRT/RTSM).
For patients with POCT K+ values within the normokalemic range (between 3.5 to 5.0 
mmol/L inclusive) on open-label correction phase Day 2 or Day 3, the site will contact 
IRT/RTSM 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 IRT/RTSM 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.
For doses administered in the clinic during both study phases, each dose will be individually 
dispensed by designated trained site staff.
Refer to Table 4 and Table 5 for dose titration and discontinuation criteria.
6.4.1
Investigational Products
Table 6
Investigational Products
Intervention Name
Sodium zirconium cyclosilicate 
(SZC)
Placebo
Dose Formulation/Unit 
Dose Strength
White to grey crystalline powder 
for oral suspension in 5 g and 10 g 
sachets
Powder for oral suspension in a 
sachet


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Route of 
Administration
Oral 
Oral
Use
Investigational product
Placebo comparator
Sourcing
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and Labeling
Study treatment will be provided in sachet. Each sachet will be labeled 
in accordance with Good Manufacturing Practice (GMP) Annex 13 and 
per country regulatory requirement. 
Labels will be prepared in accordance with GMP and local regulatory 
guidelines. The labels will fulfill GMP Annex 13 requirements for 
labeling. Label text will be translated into local language.
6.5
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study or their legally authorized representative may receive 
study intervention and only authorized site staff may supply or administer study intervention. 
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Reference Manual.
6.6
Measures to Minimize Bias: Randomization and Blinding
All participants achieving normokalemia during the open-label correction phase and entering 
the double-blind placebo-controlled phase will be centrally assigned to randomized study 
intervention using an IRT/RTSM. Before the study is initiated, the telephone number and call-
in directions for the IRT and/or the log in information and directions for the RTSM will be 
provided to each site.
Study intervention will be dispensed at the study visits summarized in the SoA (Table 1). 
Returned study intervention should not be re-dispensed to the participants.


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The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification number 
to be allocated to the participant at the dispensing visit.
Routines for this will be described in the IRT/RTSM user manual that will be provided to each 
center.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The investigator will document and report the action to AstraZeneca, without 
revealing the treatment given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented.
6.7
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the 
electronic case report form (eCRF). The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention.
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning 
during the site visits and documented in the source documents and eCRF. Deviation(s) from 
the prescribed dosage regimen should be recorded in the eCRF.
A record of the number of sachets dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the eCRF.
6.8
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrolment or 
receives during the study must be recorded along with:

Reason for use


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
Dates of administration including start and end dates

Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
SZC can transiently increase gastric pH by absorbing hydrogen ions that can lead to changes 
in solubility and absorption kinetics for co-administrated drugs with pH-dependent 
bioavailability. Therefore, SZC should be administered at least 2 hours before or 2 hours after 
oral medications with gastric pH-dependent bioavailability.
Examples of drugs that should be taken 2 hours before or after SZC to avoid possible raised 
gastric pH drug interaction are listed below:
Class of Drug
Drugs
Azole antifungals
ketoconazole, itraconazole, posaconazole
Anti-HIV drugs
atazanavir, nelfinavir, indinavir, ritonavir, saquinavir, raltegravir, ledipasvir, 
rilpivirine
Tyrosine kinase inhibitors
erlotinib, dasatinib, nilotinib
SZC can be co-administered with oral medications that do not exhibit pH-dependent 
bioavailability without spacing of dosing times.
Table 7
Summary of Restricted Medications During Pre-study and/or Treatment 
Period
Type of Medication/Treatment
Timeline/Instructions
Renin–Angiotensin–Aldosterone System Inhibitor 
(RAASi) therapy 
Patients cannot be started on RAASi therapy during 
the trial. 
For patients receiving RAASi at baseline:
ACEi, ARB or ARNI: To be continued at the dose 
the patient was taking at baseline (Day 1).
MRAs: Dose reductions from baseline permitted for 
MRAs 
Sodium-glucose transport protein 2 inhibitor 
(SGLT2i) therapy
Patients receiving SGLT2i therapy at baseline will be 
allowed to continue stable dosing throughout the trial. 
Patients cannot be started on SGLT2i therapy during 
the trial.


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Type of Medication/Treatment
Timeline/Instructions
Sodium bicarbonate or sodium citrate
Except if used as rescue therapy to treat metabolic 
acidosis (POCT bicarbonate <15 mmol/L) per 
investigator discretion (see Section 6.8.1).
Sodium polystyrene sulfonate (SPS), patiromer
Except if used as rescue to treat hyperkalemia 
according to medical judgment and if SZC/placebo 
has been discontinued.
K+ supplements or other drugs administered to raise 
sK+ (eg, K+ chloride)
Except if used to treat hypokalemia according to 
medical judgment.
Drugs with pH-dependent absorption
Drugs with pH-dependent absorption should be 
administered at least 2 hours before or 2 hours after 
SZC to mitigate the risk of drug interactions.
6.8.1
Rescue Therapy
Rescue therapy for hyperkalemia is defined as any therapeutic intervention considered 
necessary in accordance to local practice patterns to reduce sK+ in the setting of severe 
hyperkalemia (>6 mmol/L). This includes insulin/glucose, beta adrenergic agonists, calcium 
gluconate, sodium bicarbonate, and any dialysis or other forms of renal replacement 
treatments given with the goal of controlling the hyperkalemia. 
Rescue therapy for low bicarbonate (<15 mmol/L) will be according to standard of care, such 
as use of sodium bicarbonate.
In order to be considered confirmed for meeting the rescue criteria, the POCT K+ or 
bicarbonate measurement must be repeated after a ≥10-minute interval, with both 
measurements meeting the cut-off value.
The patient will discontinue treatment and be discontinued from study drug following rescue. 
Rescue will be counted as an endpoint event with applicable end of study assessments, and 
proper documentation of the type of rescue will be recorded.
6.9
Dose Modification
All randomized patients start on 10 g QD, then titrate from there based on POCT K+. See 
Table 4 for dose titration.
6.10
Intervention After the End of the Study
Poststudy access to study treatment is not applicable. Patients are to be managed as per 
standard of care after study completion.


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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will be 
followed up according to the SoA (Table 1). See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up for any further evaluations that need to be 
completed.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
To minimize risk for events related to severe hypokalemia, the following discontinuation 
criterion will be followed:

Confirmed POCT K+ <3.0 mmol/L by taking a second measurement after a ≥10-
minute interval, at any time during the study, the patient should immediately receive
appropriate medical intervention and study drug should be permanently discontinued.
To minimize risk for events related to severe hyperkalemia, the following discontinuation 
criterion will be followed:

Confirmed POCT K+ >6.0 mmol/L by taking a second measurement after a ≥10-
minute interval, at any time during the study, the patient should immediately receive 
appropriate medical intervention and study drug should be permanently discontinued.
To minimize risk for events related to prolongation of QTc, the following discontinuation 
criteria will be followed:

If an absolute QTc >550 ms, or an increase in QTc interval >60 ms from baseline to 
more than 500 ms is reached, the patient should immediately receive appropriate 
medical intervention and be permanently discontinued from the study drug treatment. 
The QTcF algorithm is recommended. All patients meeting the QTc >500 ms criterion 
should immediately have K+ assessed, if not already done within 1 hour of performing 
the electrocardiogram (ECG).
For serious arrhythmia (eg, associated with POCT K+ <3.5 mmol/L or >5.6 mmol/L), study 
drug should be permanently discontinued.
To minimize risk for events related to severe metabolic acidosis, the following discontinuation 


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criterion will be followed:

Confirmed POCT bicarbonate ≤15 mmol/L by taking a second measurement after a 
≥10-minute interval, at any time during the study, the patient should immediately 
receive appropriate medical intervention and study drug should be discontinued.
For discontinuation pertaining to COVID-19, please see Appendix E.
7.2
Participant Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon.
A participant who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, home visit, telephone contact, a contact with a relative 
or treating physician, or information from medical records).
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA (Table 1). See the SoA for 
data to be collected at the time of study withdrawal and follow-up and for any further 
evaluations that need to be completed.
The participant will discontinue the study intervention and be withdrawn from the study at 
that time.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be carried 
out in line with what was stated in the informed consent and local regulation. The investigator 
must document the decision on use of existing samples in the site study records and inform the 
Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:


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
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow- up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to be lost 
to follow-up. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.


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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
For management of study procedures during the COVID-19 pandemic, please see Appendix E.
At screening, some of the variables that will be collected will include demographics (eg, age, 
gender, race, ethnicity), a comprehensive medical and surgical history (eg, presence of 
diabetes mellitus type 1 or 2, HF, hypertension, CKD, prior history of hyperkalemia), baseline 
laboratory results (see Table 8). For measurement of K+ and bicarbonate, POCT K+ and 
POCT bicarbonate will be utilized for study inclusion criteria, eligibility for the randomized 
placebo-controlled phase and for titration of SZC/placebo. Central laboratory sK+ and POCT
bicarbonate will be utilized for study assessments.
8.1
Efficacy Assessments
8.1.1
Potassium
Whole blood samples will be analyzed locally using POCT devices to generate K+ for the 
purposes of study inclusion, dose adjustments, and monitoring. Samples drawn at the same 
timepoints will be prepared and shipped to the central laboratory for analysis of sK+. All 
serum samples should be examined and any hemolyzed samples must be redrawn. In the event 
that hemolysis or other artifacts are suspected based on the reported POCT K+ result, the 
blood samples must be re-drawn to confirm the result. Only the confirmatory sample result 
needs to be reported in the eCRF. The primary endpoint will use the central laboratory sK+ 
measurement from Visit 7 if available. If Visit 7 central laboratory sK+ is missing, then Visit 6 
central laboratory sK+ will be used in its place under the principle of last observation carried 


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forward (LOCF). If central laboratory sK+ is missing for Visits 6 and 7, then sK+ will be 
replaced by POCT values adjusted to reflect the mean difference between POCT and sK+ 
values from all available paired laboratory samples. (Visit 7 POCT will be used unless 
missing, in which case Visit 6 POCT will be used).
See the laboratory manual for details on drawing, preparation, and analysis of blood samples.
8.1.2
Bicarbonate
As bicarbonate measurement levels can decrease with exposure to the air, this study will 
utilize POCT to measure bicarbonate instead of central laboratory serum bicarbonate to 
improve accuracy.18 The POCT measurement will be used to determine inclusion of patients in 
the study and in determining endpoints related to bicarbonate. The POCT blood analyzers
along with the appropriate chemistry panels measure TCO2 which includes CO2 in several 
states: CO2 in physical solution and loosely bound to proteins, bicarbonate (HCO3-), 
carbonate (CO3) anions, and carbonic acid (H2CO3).19 The serum bicarbonate measured by 
most central laboratories is actually the TCO2; thus, the POCT bicarbonate measurement is 
equivalent to measuring the serum bicarbonate reported by central laboratories.
8.1.3
Chloride
Serum chloride will be measured as part of the clinical safety laboratory assessments for Visits 
1, 3, 7, and 8. 
8.1.4
Urine Analysis
When possible, the first morning void spot urine will be collected at the timepoints indicated 
in the SoA (Table 1). Urinary albumin, ammonium, citrate, pH, and creatinine will be 
measured at the central laboratory and reported. Urine anion gap will be calculated based on 
sodium, potassium, and chloride ions. Albumin-to-creatinine-ratio (UACR), which will be 
calculated based on the measured urinary albumin and creatinine, will be reported. 
Ammonium-to-creatinine ratio will be calculated based on the measured urinary ammonium 
and creatinine and reported.
8.2
Safety Assessments
Safety will be assessed throughout the study. A complete baseline profile of each patient will 
be established through demographics, medical history, clinical laboratory values, vital signs, 
and physical assessments. During the course of the study, vital signs, ECG, and laboratory 
tests will be performed as specified in the SoA (Table 1). Adverse events (AEs), SAEs, and 
ongoing concomitant medication usage will be monitored and recorded throughout the study. 
Serious adverse event reports will be evaluated individually to assess the impact of the event, 
if any, on the overall safety of the product and on the study itself. Cumulative AEs will be 
monitored throughout the study. All AEs will be followed until resolved, stable or until the 


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patient’s end of study visit. See Section 8.3 for details on AE and SAE reporting.
Planned timepoints for all safety assessments are provided in the SoA (Table 1). 
8.2.1
Physical Examinations
A complete physical examination will be performed at screening (Visit 1) and include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal
(including spine and extremities) and neurological systems. Body weight and height will be 
measured at the screening visit. Weight will be measured as specified in the SoA. Patients 
should be in light indoor clothes without shoes. 
Physical examination will be performed at the timepoints as specified in the SoA (Table 1).
8.2.2
Vital Signs
The vital signs include tympanic temperature, systolic and diastolic BP, pulse rate and 
respiratory rate and will be assessed as outlined in the SoA (Table 1). Blood pressure and 
pulse rate should be measured with a completely automated device in triplicate with at least 1-
minute intervals between measurements after being comfortably at rest in a seated position 
with the back and feet supported (ie, by chair back and floor or platform, respectively) quietly 
for at least 5 minutes. Manual techniques will be used only if an automated device is not 
available. The position of the patient should be comfortable with the arm where the BP is 
recorded to be within the level of heart (the middle of the cuff on the upper arm is at the level 
of the right atrium [the midpoint of the sternum]). The patient will be instructed to relax as 
much as possible and to not talk during the measurement procedure. The same device should 
preferably be used for the patient during the course of the study and in the same arm. The first 
reading of the BP and pulse rate should be rejected. The second and third readings should be 
averaged to give the measurement to be recorded in the eCRF.
Vital signs will be performed at the timepoints as specified in the SoA (Table 1).
8.2.3
Electrocardiograms
An ECG will be performed at screening, randomization, end of treatment, and follow-up (as 
specified in the SoA [Table 1]), and according to clinical judgment in connection with severe 
hypokalemia (sK+ <3.0 mmol/L), severe hyperkalemia (sK+ >6.0 mmol/L), or any symptoms 
or clinical events suggesting cardiac arrhythmia.
QTcF should be recorded at each ECG measurement.
The ECG data should be recorded in the eCRF, including QTcF, in connection with reporting 
AEs that concern arrhythmia.


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For study patients with pacemakers: 

All ECG variables, including QT/QTcF, should be read manually and be recorded in 
the eCRF.

If not fulfilling the inclusion/exclusion criteria or fulfilling the discontinuation criteria, 
pacemaker patients should be managed as recommended by protocol (without 
exceptions).
8.2.4
Clinical Safety Laboratory Assessments
Urinalysis and blood for the determination of clinical chemistry and hematology as well as 
urine pregnancy test, will be taken at the visits indicated in the SoA. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The following variables will be measured and analyzed.
Table 8
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum)
B-Hemoglobin (Hb)
S-Sodium (Na+)
B-Leukocyte count
S-Potassium (K+)
B-Leukocyte differential count (absolute count)
S-Bicarbonate (Total CO2)
B-Platelet count
S-Chloride (Cl-)
B-Hematocrit (Hct)
S-Glucose
S-Creatinine
S-Blood Urea Nitrogen (BUN)
Urea (BUN)/Creatinine Ratio
eGFR using the CKD-EPI formula
Urinalysis (dipstick)
Anion gap (blood, from POCT or calculated based on 
POCT)
U-Hb/Erythrocytes/Blood 
S-Albumin
U-Protein/Albumin 
S-Total Protein
U-Glucose
S-Calcium (Ca++)
S-Magnesium (Mg++)
S-Phosphate (PO4)
S-Bilirubin, total
S-Alkaline phosphatase (ALP)
S-Alanine amino transferase (ALT)


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S-Aspartate amino transferase (AST)
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 the 
center as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 8.3.5.
8.3
Adverse Events and Serious Adverse Events
The investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from the start of the open-label correction phase throughout 
the treatment period and including the follow-up period.
SAEs will be recorded from the time of signing of the ICF.
If the investigator becomes aware of a SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the follow-up visit 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 participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse Event Variables
The following variables will be collected for each AE:

AE (verbatim)


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
The date when the AE started and stopped

Maximum AE intensity (mild, moderate, severe)

Whether the AE is serious or not

Investigator causality rating against the IP(s) (yes or no)

Action taken with regard to IP(s)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

SAE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.3
Causality Collection
The investigator should assess causal relationship between study treatment and each AE, 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 study treatment?’
For SAEs, causal relationship should 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 B.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant, reported in response to the open question 
from the study site staff, 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 


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symptom will be recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarized 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, are the reason 
for discontinuation of treatment with the IP or are considered to be clinically relevant as 
judged by the investigator (which may include but not limited to consideration as to whether 
treatment or non-planned visits were required or other action was taken with the study 
treatment, eg, dose adjustment or drug interruption).
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 (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should
not be reported as an AE/SAE.
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 unless unequivocally 
related to the disease under study.
8.3.6
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 


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AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, 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 electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative. If the EDC system is not available, then the investigator or other study site 
staff reports a SAE to the appropriate AstraZeneca representative by telephone. The 
AstraZeneca representative will advise the investigator/study site staff how to proceed. 
Investigators or other site personnel will send relevant eCRF modules by fax to the designated 
AstraZeneca representative.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
8.3.7
Reporting of AEs/SAEs in Relation to COVID-19
All AEs/SAEs should be reported in line with instructions for safety reporting documented in 
the CSP. For patients experiencing signs and symptoms indicating an infection, an attempt will 
be made to determine whether the COVID-19 virus is the infectious organism and the AE will 
be recorded accordingly. If a patient presents with clinical signs and symptoms suggestive of 
COVID-19, a test will be requested where possible:

If the test is positive, record “COVID-19 positive” in the Adverse Event Field.

If the test is negative, record “COVID-19 negative” in the Adverse Event Field, along 
with the AE/SAE signs and symptoms and/or other diagnosis.
If a test has not been performed or result is not available and signs and symptoms, as judged 
by the Investigator, are suggestive of COVID-19 infection, record “COVID-19 suspected” in 
the Adverse Event Field. If the investigator has other concurrent diagnoses for the patient’s 
signs and symptoms (eg, pneumonia), these will be recorded as separate AEs.
8.3.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
intervention


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8.3.8.1
Maternal Exposure
Women of childbearing potential who are planning on becoming pregnant are not allowed to 
be included in this study. Should a pregnancy still occur, the IP should be discontinued 
immediately, and the pregnancy reported to AstraZeneca.
If a participant becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the participant 
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 1 day, ie, 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 8.3.8) and within 30 days for all other pregnancies.
The same timelines apply when the outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.8.2
Paternal Exposure
There is no restriction on fathering children or donating sperm during the study.
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose until a time period of 
12 weeks after last dose as indicated by previous studies (pre-clinical and clinical) should, if 
possible, be followed up and documented in the Pregnancy Report Form. Consent from the 
partner must be obtained before the Pregnancy Report Form is completed.
8.3.9
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 


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but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B.
8.4
Overdose
During the initial open-label correction phase, any SZC dose greater than 30 g within 1 day, or 
continuation of the correction dose (10 g TID) for more than 48 hours will be considered an 
overdose.
During the randomized maintenance period, a dose higher than 15 g per day will be 
considered an overdose.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel will inform appropriate AstraZeneca representatives 
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 overdoses associated with an SAE (see Section 8.3.6) and within 30 days for 
all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific laboratory manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples, see Appendix C.
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.


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8. 5. 2
I m m u n o ge nicit y Assess me nts
I mm u n o ge nicit y will  not be assesse d i n t his st u d y.
8. 5. 3
P h ar m ac o d y n a mics
P har mac o d y na mics are n ot e val uate d i n t his st u d y .
8. 6
H u m a n  Bi ol o gic al S a m ple Bi o m ar kers
 will be c ollecte d at scree ni n g.
8. 7
O pti o n al Ge n o mics I niti ati ve S a m ple
C ollect i on of o pti o nal  sa m ples f or Ge n o mics I nitiati ve researc h is als o part of t his st u d y as 
s pecifie d i n t he S o A a n d is s u bject t o agree me nt i n t he I C F a d de n d u m.
A bl o o d sa mpl e f or D N A is olati o n will be c ollecte d fr om parti ci pa nts w h o ha ve c o nse nte d t o 
parti ci pate i n t he ge net ic a nal ysis c om p o ne nt of t he st u d y . Parti ci pat i on is o pti o nal. 
P arti cipa nts w h o d o n ot wi s h t o partici pate i n t he ge net ic researc h ma y still partici pate i n t he 
st u d y.
See  A p pe n di x D f or i nf or mati on re gar di n g t he Ge n o mics I nit iati ve ge netic sa m ple. Details o n 
pr ocesses f or c ollect i on, s hi p me nt, a n d destr ucti o n of t hese sa m ples ca n be f o u n d eit her i n t he 
a p pe n dices or i n t he la b orat or y ma n ual. 
F or st ora ge a n d destr ucti o n of ge netic sa m ples , see A p pe n di x D.
8. 8
He alt h Ec o n o mics
Heal t h Ec o n o mics para meters are n ot e val uate d in t hi s st u d y.
C CI


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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The statistical hypotheses for the primary endpoint are:
Null: No difference in the Occurrence (yes/no) of patients having a normal sK+ on Day 29 
(Visit 7) without need for rescue treatment for hyperkalemia at any point during the 
randomized phase between SZC and placebo.
Alternate: Difference in the occurrence of patients having a normal sK+ on Day 29 without 
need for rescue treatment for hyperkalemia at any point during the randomized phase.
Hypotheses for the secondary endpoints are provided in Section 9.4.3.2.
9.2
Sample Size Determination

Prior data: Proportion of patients with serum bicarbonate between16-20 mmol/L 
inclusive who had a 3 mmol/L or greater increase in serum bicarbonate with SZC 
versus placebo from ZS-004,20 Global Harmonize trial,21 and ZS-005.22

SZC: 92/235 = 0.39 achieved an increase in serum bicarbonate ≥3 mmol/L

Placebo: 7/40 = 0.175 achieved an increase in serum bicarbonate ≥3 mmol/L

Sample size estimate*
o
20% absolute difference:
o
Alpha=0.05, Power=80%
o
Control=0.175 with serum bicarbonate increase of 3mmol/L or more
o
SZC=0.39 with serum bicarbonate increase of 3mmol/L or more
*Actual effect size = 0.215 
o
N=68 per group (136).
o
N=148 (accounting for 8% drop-out from initial phase to randomized-withdrawal 
phase) 
*Sample size would be smaller if based on primary endpoint of mean sK+ (N=18 per arm
@90% power).
Approximately 477 patients will be screened. Approximately 148 patients will be enrolled to 
the open-label phase of the study to achieve 136 randomly assigned to study intervention.


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9. 3
P o p ul ati o ns f or A n al yses
Ta ble 9 
P o p ul ati o ns f or  An al ysis
A n al ysi s Set
Descri pti o n
F ull A nal y sis Set
( F A S)
T he pri mar y a nal ysis set f or t he pri mar y, sec o n dar y, 
 will 
i ncl u de patie nts w h o ac hie ve n or m o kale mia at t he e n d of t he o pe n-la bel c orrecti o n p hase 
a n d e nter t he ra n d o mize d place b o -c o ntr olle d p hase. Patie nts will be a nal yze d o n a n 
i nte nt-t o-treat basis acc or di n g t o t heir ra n d o mize d i n vesti gati o nal pr o d uct (I P).
Safet y Set O pe n
( S S O)
All patie nts e nr olle d i n t he o pe n -la bel c orrecti o n p hase w h o t o o k at least 1 d ose of st u d y 
dr u g . Patie nts will be a nal yze d as a si n gle gr o u p.
Safet y Set 
Ra n d o mize d
( S S R)
All patie nts w h o ac hie ve n or m o kale mia at t he e n d of t he o pe n -la bel c orrecti o n p hase a n d 
e nter t he ra n d o mize d place b o-c o ntr olle d p hase. Patie nts will be a nal yze d acc or di n g t o t he 
I P recei ve d.
Per Pr ot oc ol Set 
( P P S)
F A S patie nts wit h o ut a n y i m p orta nt pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m t he 
P P S . Patie nts will be a nal yze d acc or di n g t o t heir ra n d o mize d I P.
9. 4
St atistic al A n al yses
T he stati stical a nal ysis pla n ( S A P) will be fi nalize d pri or t o data base l oc k a n d it will i ncl u de a 
m o re tec h nical a n d detaile d descri pti on of t he statistical a nal yses descri be d i n t his sect i on . 
T his sect i on is a s u m mar y of t he pla n ne d statistical a nal yses of  t h e most i m p orta nt e n d p oi nts 
i ncl u di n g pri mar y a n d ke y sec o n dar y e n d p oi nts.
9. 4. 1
Ge ner al C o nsi der ati o ns
All data pr ocessi n g, s u m marizat i on, a n d a nal yses will be perf or me d usi n g Versio n  9. 3 ( or 
later) of t he S A Sstatistical s oftware pac ka ge.
T he S A P will det ail a n y a p pr oac h t o be ta ke n t o c o ntr ol f or m ulti plicity f or t he pri mar y a n d 
sec o n dar y e n d p oi nts. T he pri mar y a n d sec o n dar y e nd p oi nts will prese nt t w o -side d p -val ues i n 
li ne wit h t he st u d y o bjecti ves a n d t he c orres p o n di n g si g nifica nce le vel of t he h y p ot hes es will 
be re p orte d al o n gsi de t hese p -val ues s u bject t o t he met h o ds use d t o c o n tr ol for m ul tiplici t y.
C o nti n u o us data will be s u m marize d b y  tr e at me nt gr o u p usi n g t he n u m ber of o bser vat i ons 
a vaila ble ( n), mea n, sta n dar d de viat i on ( S D), mi ni m u m, q uartile 1, me d ia n, q uartile 3 a n d 
ma xi m u m . Cate g ori cal data will be s u m marize d b y treat me nt gr o u p usi n g t he c o u nt of patie nts 
a n d perce nta ge.
Scree ni n g baseli ne is defi ne d as t he last a vaila ble assess me nt pri or t o t he first d ose of o pe n -
la bel treat me nt. Meas ure me nts ma de o n t he sa me date as t he first d ose of o pe n- la bel treat me nt 
will n ot be c o nsi dere d u nless t he meas ure me nt is c o nfir me d t o be pre -d ose b y t he ti mes t he 
meas ure me nt a n d d ose are rec or de d . Ra n d o mizat i on baseli ne is defi ne d as t he last a vaila ble 
assess me nt pri or t o or o n t he date of t he ra n d o mizati o n visit f or all pat ient s, u nless ot her wise 
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specified.
Post-hoc analysis will be considered depending on study findings.
9.4.2
COVID-19 Considerations
COVID-19 is anticipated to have a minimal impact on this study due to the 36-day follow-up 
period and the analysis approaches outlined below for the primary and secondary endpoints. 
For the primary and secondary endpoints, a Visit 6 value for sK+ is used if a Visit 7 value is 
unavailable due to a missed visit or drop-out related to COVID-19 and an approach to use 
POCT values is also used.
Any other analytic strategies needed to assess and address issues pertaining to COVID-19 
related to estimands, missing data, validity, and modifications of statistical analysis methods 
or need for additional analyses will be described in the SAP.
9.4.3
Efficacy 
9.4.3.1
Primary Endpoint
The Occurrence (yes/no) of patients having normal sK+ (between 3.5 and 5.0 mmol/L 
inclusive) on Day 29 (Visit 7) without rescue treatment for hyperkalemia at any point during 
the randomized phase in the SZC versus placebo arm.
Analysis Methods
The occurrence of patients having normal sK+ will be analyzed using a logistic regression 
analysis with response as the dependent variable and randomized treatment group as the 
independent variable. The odds ratio along with the 95% confidence intervals and two-tailed 
p-value (significance declared <0.05) will be displayed. The analysis will be based on the 
FAS. 
The following rules will be implemented to account for missing laboratory results:
a.
If Visit 7 central laboratory sK+ is missing, then Visit 6 central laboratory sK+ will 
be used in its place (last observation carried forward [LOCF])
b.
If central laboratory sK+ is missing for Visits 6 and 7, then sK+ will be replaced by 
POCT value adjusted to reflect the mean difference between POCT and sK+ values 
from all available paired laboratory samples. (Visit 7 POCT would be used unless 
missing in which case Visit 6 POCT will be used.)
c.
If no results (central lab sK+ or POCT K) are available for Visit 6 and 7, then classify 
as non-evaluable.
A sensitivity analysis will be conducted which will include the following characteristics as 
independent variables in the logistic regression analysis: race, gender, age at baseline (<65, 


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≥65), CKD stage at baseline (3, 4, or 5) and diabetes status at baseline. Additional sensitivity 
analyses will also be carried out related to the proportion of patients achieving normokalemia 
in the SZC versus placebo arm. A sensitivity analysis will be conducted repeating the primary 
analysis but conducted in the PPS.
9.4.3.2
Secondary Endpoints
1
Mean change in serum bicarbonate from baseline (Day 1) to Day 29 (Visit 7) in SZC 
versus placebo arm
Hypotheses
Null: No difference in mean change in serum bicarbonate from baseline to Day 29 between 
SZC and placebo.
Alternate: Difference in mean change in serum bicarbonate from baseline to Day 29 between 
SZC and placebo.
Analysis Methods
The mean change in serum bicarbonate from baseline (Day 1) will be analyzed using analysis 
of covariance (ANCOVA) analyses at the significance level 5% (2-sided), with randomized 
treatment as main effect and baseline bicarbonate as covariate. For patients needing rescue 
treatment for low bicarbonate, the last value of POCT bicarbonate during the randomized 
period prior to rescue treatment will be analyzed. The analysis will be based on the FAS. A 
sensitivity analysis will be conducted based on the PPS.
An additional sensitivity analysis will be carried out using another ANCOVA analysis that 
replaces missing POCT bicarbonate values with central laboratory serum bicarbonate values 
and includes a covariate in the model to control for central laboratory values.
2
Occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥2 mmol/L 
on Day 29 (Visit 7) from baseline without need for rescue treatment for low bicarbonate 
in SZC versus placebo arm
Hypotheses
Null: No difference in the occurrence of patients having an increase in serum bicarbonate of 
≥2 mmol/L from baseline to Day 29 without need for rescue treatment for metabolic acidosis 
(low bicarbonate) between SZC and placebo.
Alternate: Difference in the occurrence of patients having an increase in serum bicarbonate of 
≥2mmol/L from baseline to Day 29 without need for rescue treatment for metabolic acidosis 
(low bicarbonate) between SZC and placebo.


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Analysis Methods
The occurrence of patients having an increase in serum bicarbonate of ≥2 mmol/L on Day 29 
(Visit 7) from baseline without need for rescue treatment for low bicarbonate will be analyzed 
using a logistic regression analysis with response as the dependent variable and randomized 
treatment group as the independent variable. The odds ratio along with the 95% confidence 
intervals and two-tailed p-value (significance declared <0.05) will be displayed. The analysis 
will be based on the FAS. A sensitivity analysis will be conducted based on the PPS.
The following rules will be implemented for missing laboratory results:
a.
If Visit 7 POCT bicarbonate data is missing, then Visit 6 POCT bicarbonate will be 
used in its place (LOCF).
b.
If POCT bicarbonate is missing for Visits 6 and 7, then POCT will be replaced by 
central laboratory bicarbonate value adjusted to reflect the mean difference between 
POCT and central laboratory bicarbonate values from all available paired laboratory 
samples. (Visit 7 central laboratory bicarbonate will be used unless missing, in which 
case Visit 6 central laboratory bicarbonate will be used.)
c.
If no results (POCT or central laboratory bicarbonate) are available for Visits 6 and 7, 
then classify as non-evaluable.
A sensitivity analysis will be conducted which will include the following characteristics as 
independent variables in the logistic regression analysis: race, gender, age at baseline (<65, 
≥65), CKD stage at baseline (3, 4, or 5), and diabetes status at baseline. 
3
Occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥3 mmol/L 
on Day 29 (Visit 7) from baseline without need for rescue treatment for low bicarbonate 
in SZC versus placebo group
Hypotheses
Null: No difference in the occurrence of patients having an increase in serum bicarbonate of 
≥3 mmol/L from baseline to Day 29 without need for rescue treatment for metabolic acidosis 
(low bicarbonate) between SZC and placebo.
Alternate: Difference in the occurrence of patients having an increase in serum bicarbonate of 
≥3mmol/L from baseline to Day 29 without need for rescue treatment for metabolic acidosis 
(low bicarbonate) between SZC and placebo.
Analysis Methods


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The occurrence of patients having an increase in serum bicarbonate of ≥3 mmol/L on Day 29 
(Visit 7) from baseline without need for rescue treatment for low bicarbonate will be analyzed 
using a logistic regression analysis with response as the dependent variable and randomized 
treatment group as the independent variable. The odds ratio along with the 95% confidence 
intervals and two-tailed p-value (significance declared <0.05) will be displayed. The analysis 
will be based on the FAS. A sensitivity analysis will be conducted based on the PPS.
The rules for missing POCT bicarbonate implemented for the secondary endpoint #2 will also 
be implemented for this endpoint. Sensitivity analysis and subsequent subgroup analyses will 
be implemented as described for secondary endpoint #2.
4
Occurrence (yes/no) of patients having a normal sK+ (between 3.5 and 5.0 mmol/L 
inclusive) on Day 29 (Visit 7) and an increase in serum bicarbonate of ≥3 mmol/L on Day 
29 (Visit 7) from baseline without need for rescue treatment for hyperkalemia or low 
bicarbonate 
Hypotheses
Null: No difference in the occurrence (yes/no) of patients having normal sK+ (between 3.5 
and 5.0 mmol/L inclusive) and an increase in serum bicarbonate of ≥3 mmol/L from baseline 
to Day 29 between SZC and placebo.
Alternate: Difference in the proportion of patients achieving normal sK+ (between 3.5 and 5.0 
mmol/L inclusive) and an increase in POCT bicarbonate of ≥3 mmol/L from baseline to Day 
29 between SZC and placebo.
Analysis Methods
The occurrence of patients having a normal sK+ (between 3.5 and 5.0 mmol/L inclusive) on 
Day 29 (Visit 7) and a serum bicarbonate of ≥3 mmol/L on Day 29 (Visit 7) without need for 
rescue treatment will be analyzed using a logistic regression analysis with response as the 
dependent variable and randomized treatment group as the independent variable. The odds 
ratio along with the 95% confidence intervals and two-tailed p-value (significance declared 
<0.05) will be displayed. The analysis will be based on the FAS. A sensitivity analysis will be 
conducted based on the PPS.
The rules for missing K+ laboratory results for the primary endpoint and POCT bicarbonate 
for secondary endpoint #2 above will also be implemented for this endpoint. Sensitivity 
analysis and subsequent subgroup analyses will be implemented as described for secondary 
endpoint #2.
5
Occurrence (yes/no) of patients having serum bicarbonate ≥22 mmol/L on Day 29 (Visit 
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Hypotheses
Null: No difference in the occurrence of patients having serum bicarbonate ≥22 mmol/L at 
Day 29 from without need for rescue treatment for metabolic acidosis (low bicarbonate) 
between SZC and placebo.
Alternate: Difference in the occurrence of patients having serum bicarbonate ≥22 mmol/L at 
Day 29 without need for rescue treatment for metabolic acidosis (low bicarbonate) between 
SZC and placebo.
Analysis Methods
The occurrence of patients with serum bicarbonate of ≥22 mmol/L at Day 29 (Visit 7) without 
need for rescue treatment for low bicarbonate will be analyzed using a logistic regression 
analysis with response as the dependent variable and randomized treatment group as the 
independent variable. The odds ratio along with the 95% confidence intervals and two-tailed 
p-value (significance declared <0.05) will be displayed. The analysis will be based on the 
FAS. A sensitivity analysis will be conducted based on the PPS.
The rules for missing POCT bicarbonate implemented for the secondary endpoint #2 will also 
be implemented for this endpoint. Sensitivity analysis and subsequent subgroup analyses will 
be implemented as described for secondary endpoint #2.
6
Occurrence (yes/no) of patients having a normal sK+ (between 3.5 and 5.0 mmol/L 
inclusive) on Day 29 (Visit 7) and a serum bicarbonate of ≥22 mmol/L on Day 29 (Visit 7) 
without need for rescue treatment for low bicarbonate or hyperkalemia
Hypotheses
Null: No difference in the occurrence of patients having normal sK+ (between 3.5 and 5.0 
mmol/L inclusive) and serum bicarbonate of ≥22 mmol/L on Day 29 between SZC and 
placebo.
Alternate: Difference in the occurrence of patients having normal sK+ (between 3.5 and 5.0 
mmol/L inclusive) and serum bicarbonate of ≥22 mmol/L from baseline to Day 29 between
SZC and placebo.
Analysis Methods
The occurrence of patients having a normal sK+ (between 3.5 and 5.0 mmol/L inclusive) on 
Day 29 (Visit 7) and serum bicarbonate of ≥22 mmol/L on Day 29 (Visit 7) without need for 
rescue treatment will be analyzed using a logistic regression analysis with response as the 


Cli nical St u d y Pr ot oc ol - 6. 0
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de pe n de nt varia ble a n d ra n d o mize d treat me nt gr o u p as t he i n de pe n de nt varia ble. T he o d ds 
r atio al o n g wi t h t he 9 5 % c o nfi de nce i nter vals a n d t w o-taile d p-val ue (si g nifica nce declare d 
< 0. 0 5) will be dis pla ye d. T he a nal ysis will be base d o n t he F A S. A se nsitivit y a nal ysis will be 
c o n d ucte d base d o n t he P P S.
T he r ul es f or missi n g K + la b orat or y res ults for t he pri mar y  e n d p oi nt a n d P O C T bicar b o nate 
f or sec o n dar y e n d p oi nt # 2 a b o ve will als o be i m ple me nte d f or t his e nd p oi nt . Se nsit i vity 
a nal ysis a n d s u bse q ue nt s u b gr o u p a nal yses will be i m ple me nte d as descri be d f or sec o n dar y  
e n d p o i nt # 2.
7
Occ urre nce (yes/ n o) of p atie nts nee di n g resc ue tre at me nt f or l o w bic ar b o n ate ( P O C T ≤1 5 
m m ol/ L) d uri n g t he r a n d o mize d p h ase bet wee n S Z C a n d pl ace b o.
H y p ot heses
N ull: N o differe nce i n t he occ urre nce of  patie nts nee di n g resc ue treat me nt f or l o w bicar b o nate 
d uri n g t he ra n d o mize d p hase bet wee n S Z C a n d place b o.
Alt er nate: Differe nce i n t he o c c urre nce of  patie nts nee di n g resc ue treat me nt f or l o w 
bicar b o nate d uri n g t he ra n d o mize d p hase bet wee n S Z C a n d place b o.
A n al ysis Met h o ds
T he occ urre nce of  p atie nts nee di n g resc ue treat me nt f or l o w bicar b o nate will be a nal yze d 
usi n g a l o gist ic re gressi on a na l ysis with resc ue treat me nt as t he de pe n de nt varia ble a n d 
ra n d omize d treat me nt as t he i n de pe n de nt varia ble. T he o d ds rati o al o n g wit h t he 9 5 % 
c o nfi de nce i nter vals a n d t w o -taile d p-val ue (si g nifica nce declare d < 0. 0 5) will be dis pla ye d. 
T he a nal ysis will be base d o n t he FA S. A  se nsiti vity a nal ysis will be c o n d ucte d base d o n t he 
P P S.
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9.4.4
Safety
Safety will be assessed in terms of AEs, SAEs, AEs leading to treatment discontinuation, 
laboratory data, vital signs, ECG, and full physical examinations during the open-label phase, 
the randomized phase, and through to follow-up. These assessments will be collected for all 
patients.
Appropriate summaries of these data will be presented by treatment group. The AEs will be 
classified using the Medical Dictionary for Regulatory Activities (MedDRA) system of 
nomenclature system organ class (SOC) and preferred term (PT).
A treatment emergent AE (TEAE) will be defined as an AE with the start date on or after the 
first dose date and up to (and including) 7 days after the last dose date. Similarly, the number 
of patients experiencing SAEs, AEs that led to withdrawal, AEs that led to death and treatment 
related AEs, and number of such events, will be summarized by treatment group.
An overview of edema-related AEs and instances of sK+ <3.5 will be presented.
The identified risk of hypokalemia is defined by laboratory values and not by specific 
MedDRA terms.
All AE data will be listed for all patients. In addition, SAEs and AEs that led to withdrawal or 
death, and treatment-related AEs will be listed.
Clinical safety laboratory assessments (including sK+ and serum creatinine) will be 
summarized and listed. Shift tables will be provided for select tests, where shift from 
screening baseline to the worst value within each part of the study and overall will be 
summarized. Laboratory data outside the reference ranges will be indicated in all listings.
All safety analyses will be performed on the Safety Sets. In general, safety assessments will be 
reported descriptively by treatment group and separately for the open-label and randomized-
withdrawal phases. Full details on safety analyses will be provided in the SAP.
9.5
Interim Analyses 
An informal interim analysis for the purpose of Sample Size Re-estimation (SSR) will be
conducted when approximately 68 person-months of follow-up time of the total 136 person-
months have occurred (an information time of 0.5) to adjust for potential deviations from the 
pre-specified expected effect sizes based on updated knowledge provided by the observed 
effect sizes which inform the key secondary efficacy endpoint (occurrence of patients having 
an increase in serum bicarbonate of ≥3 mmol/L from baseline (Day 1) to Day 29 without need 
for rescue treatment for metabolic acidosis). This analysis will estimate the true effect size and 


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re-estimate the additional number of subjects that need to be accrued to achieve sufficient 
power based on this new information.  Enrolment may be extended to accrue this number of 
additional subjects if it is determined this can be achieved in a cost-effective manner. The 
analysis will be unblinded to the party who executes it but blinded to the study team. The 
complete details of the SSR will be described in the SAP.
9.6
Data Monitoring Committee
No Data Monitoring Committee is planned for this study. Study is on-label for an approved 
drug. 


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other applicable 
local regulations.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
o
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations


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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during 
the study. Participants or their legally authorized representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorized
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 


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time and for any reason during the retention period. 
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with the Patient Safety function at AstraZeneca. 
Issues identified will be addressed, for example, by amending the CSP and letters to 
Investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. 
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to
the sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of non-


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compliance issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 


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not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the participant or may require 
medical treatment to prevent one of the outcomes listed above.
Life-threatening
‘Life-threatening’ means that the participant 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 
participant’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).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.


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Important medical event or medical treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the participant or may
require medical treatment 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 
judgment 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 anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
Intensity rating scale:

mild (awareness of sign or symptom, but easily tolerated)

moderate (discomfort sufficient to cause interference with normal activities)

severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 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 an SAE unless it meets the criteria 
shown in Appendix B 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 an SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
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 participant 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 etiology 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 no available facts or arguments to suggest a 
causal relationship, 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.
B 4
Medication Error
For the purposes of this clinical study, a medication error is an unintended deviation from the 
allowable schedule as per protocol in administering any study drug that either causes harm to 
the participant or has the potential to cause harm to the participant. 


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A medication error is not lack of efficacy of the drug, but rather a human or process-related 
failure while the drug is in control of the study site staff or participant.

Medication error includes situations where an error:

Occurred

Was identified and intercepted before the participant received the drug 

Did not occur, but circumstances were recognized that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given 
to the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of 
the above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team for the 
remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.


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
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650.
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry ice content.


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Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments, or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA (ie, the entire genome). 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
All participants will be asked to participate in this genetic research. Participation is voluntary 
and if a participant declines to participate there will be no penalty or loss of benefit. The 
participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfill all of the inclusion criteria
described in the main body of the Clinical Study Protocol and provide informed consent for 
the Genomics Initiative sampling and analyses.
Exclusion Criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:
o
Previous allogeneic bone marrow transplant
o
Non-leukocyte depleted whole blood transfusion within 120 days of genetic 
sample collection
o
Healthy Volunteers and pediatric patient samples will not be collected for the 
Genomics Initiative.


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Withdrawal of Consent for Genetic Research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary withdrawal 
will not prejudice further treatment. Procedures for withdrawal are outlined in Section 7.2.
Collection of Samples for Genetic Research
The blood sample for this genetic research will be obtained from the participants at Visit 1. 
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding participants who may withdraw due to an AE. If for any reason the sample is not 
drawn at Visit 1, it may be taken at any visit until the last study visit. Only one sample should 
be collected per participant for genetics during the study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA).

The link between the participant enrolment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.


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Informed Consent
The genetic component of this study is optional and the participant may participate in other 
components of the main study without participating in this genetic component. To participate 
in the genetic component of the study, the participant must sign and date both the consent 
form for the main study and the addendum for the Genomics Initiative component of the 
study. Copies of both signed and dated consent forms must be given to the participant and the 
original filed at the study center. The investigator(s) is responsible for ensuring that consent is 
given freely and that the participant understands that they may freely withdrawal from the 
genetic aspect of the study at any time.
Participant Data Protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. For 
example, in the case of a medical emergency, an AstraZeneca Physician or an investigator 
might know a participant’s identity and also have access to his or her genetic data. 
Regulatory authorities may require access to the relevant files, though the participant’s 
medical information and the genetic files would remain physically separate.
Data Management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.

AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organizations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research purposes. 
Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.


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Appendix E
Management of Study Procedures During the COVID-19 
Pandemic
E 1
Introduction 
Safeguarding the health and wellbeing of our participants and ensuring the continued supply 
of our medicines to participants remains of paramount importance for AstraZeneca through 
the ongoing COVID-19 outbreak. 
Management described in this appendix related to study visits and SARS-COV-2 testing 
should be implemented only during the COVID-19 pandemic and will apply until further 
notice, as communicated by the sponsor. Changes to study visits due to participants not 
wishing to or being unable to visit sites should only be implemented if allowable by 
local/regional guidelines and following agreement from the sponsor. 
Changes that may affect the study participants’ participation in the study should be 
communicated to the participant. It is the investigator’s responsibility to inform the study 
participants of any change in the study conduct that may be implemented. The participants’ 
assent and/or consent to any such change in study conduct should also be documented. 
E 2
Risk Assessment for COVID-19 Pandemic 
SZC is a K+ binder acting in the GI tract and is not absorbed. No additional risk from 
COVID-19 is expected due to SZC. However, the risk of exposure to infected people cannot 
be completely excluded during study participation as the participants may need to expose 
themselves to public areas (eg, commute to the site) and have additional human contact (eg, 
with site staff). 
Measures to mitigate the risks associated with COVID-19

This study will start or resume enrolment only when the sponsor and investigator deem it 
is appropriate. In addition, the enrolment at a site level will only start or resume when 
local regulations and guidelines allow. 

National laws and local recommendations for regarding the pandemic will be strictly 
adhered to. 

The site is encouraged to contact the participant within 1 day prior to a study visit, see 
next section. Study visits may be modified where appropriate and permitted by local 
practice, see Section E 4.
E 3
COVID-19 Assessment
In order to limit potential infection at the site, the site is recommended to contact the 
participant within 1 day prior to any study visit to ask for signs and symptoms related to 
COVID-19. COVID-19 symptoms include, but are not limited to: fever or chills, cough, 


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shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss 
of taste or smell, sore throat, congestion or runny nose, nausea or vomiting and diarrhea.
Recommended questions to determine risk of COVID-19 are included below for information: 
1
Have you experienced unexplained fever, cough, shortness of breath, chills, muscle pain, 
headache, sore throat, and/or new loss of taste or smell within the past 14 days?
2
Have you been in contact with anyone who is sick with or exhibiting Covid-19 symptoms 
in the last 14 days?
3
Have you been in contact in the last 14 days to someone who was diagnosed with Covid-
19 within 14 days from your contact?
COVID-19 prior to screening
It is important that participants with possible ongoing or not completely resolved COVID-19 
infection are not to be enrolled in the study. If the participant has evidence of COVID-19 
within 2 weeks prior to screening (eg, a positive COVID-19 test or a clinical risk that has not 
been satisfactorily excluded), the participant cannot be enrolled and will be treated according 
to standard of care. 
Suspected COVID-19 after screening
Participant is severely ill or hospitalized:

If the participant becomes symptomatic after screening, and has suspected COVID-19 
(regardless of any SARS-Cov-2 test results that may be available), and is severely ill 
and/or hospitalized, IP will be permanently discontinued. 

If possible, the participant is encouraged to attend the study visits according to 
schedule even if off treatment. Visits may be modified per guidance in Section E 4 and 
per local regulations and guidelines related to COVID-19.
Participant is NOT severely ill or hospitalized:

If the participant becomes symptomatic after enrolment, and has suspected COVID-19 
(regardless of whether any SARS-Cov-2 test results are available or not), and is NOT 
severely ill and/or hospitalized the investigator should determine if continuation of 
treatment with IP is in the best interest of the patient.
Regardless if IP is continued or not, the participant can attend the study visits according to 
schedule IF the investigator discerns ability of participant or in accordance to institution 
policy keeping in mind social distancing and potential exposure to other people. Visits may be 


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modified per guidance in Section E 4 and per local regulations and guidelines related to 
COVID-19. See Modified Visits below.
E 4
Modified Visits
As a general rule, the sponsor’s expectation is that as long as conditions permit, the participant 
should remain in the study and complete visits as per the schedule. Of note, when directly 
interacting with a participant within the boundaries set by this guidance document (eg, study 
visit of any kind) it is expected and assumed by the sponsor that it is done in accordance with 
‘social distancing’ and protection requirements as set by local orders to manage the COVID-
19 pandemic. The specifics of such conduct are not part of the scope of this document. 
Visits may be modified if needed due to the COVID-19 pandemic, if an on-site visit is not 
possible due to participants not wishing to or being unable to visit sites. Modified visits can 
only replace a site visit if allowed by local/regional guidelines and regulations. 
The sponsor should be notified of any deviation from the regular scheduled visits and planned 
study procedures, and of the alternative plan the site will implement. Any deviation from the 
protocol should be documented in the participant file with a comment explaining the relation 
to COVID-19. A modified visit may for example be a home visit. Regardless of the modified 
visit approach, every effort should be made to complete the full scope of the study visit 
activities and procedures (see the SoA, Table 1). If this is not possible, the minimum safety 
measurements should always include sK+ measurements and, where indicated, an ECG, in 
addition to collection of AEs and concomitant medication.
If an in-person visit with the participant is not possible, the site may consider having a 
telemedicine visit. The term telemedicine visit refers to remote contact with the participants 
using telecommunications technology such as phone calls, virtual or video visits, and mobile 
health devices. Having a telemedicine contact with the participant will allow AEs, and 
concomitant medication to be reported and documented. At the earliest possibility, the 
minimum safety measurements including sK+ measurements and, where indicated, an ECG 
must be done.


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Appendix F
Abbreviations
Abbreviation or special term
Explanation
AE
adverse event
ACEi
angiotensin-converting enzyme inhibitor
ADR
adverse drug reaction
ANCOVA
analysis of covariance
ARB
angiotensin II receptor blocker
ARNi
angiotensin receptor-Neprilysin inhibitor
BP
blood pressure
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CPS
calcium polystyrene sulfonate
CSP
Clinical Study Protocol
CV
cardiovascular
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
FAS
Full Analysis Set
GCP
Good Clinical Practice
GI
gastrointestinal
GMP
Good Manufacturing Practice
HF
heart failure
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IRT/RTSM
Interactive Response Technology/Randomization and Trial Supply 
Management
K+
potassium
MedDRA
Medical Dictionary for Regulatory Activities
MRA
mineralocorticoid receptor antagonist
NK
normokalemia or normokalemic


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Abbreviation or special term
Explanation
POCT
Point of Care Test
PPS
Per Protocol Set
QD
once daily
QOD
every other day
QTcF
QT interval corrected by the Fridericia method
RAASi
renin-angiotensin-aldosterone system inhibitor
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SGLT2i
sodium-glucose transport protein 2 inhibitor
sK+
serum potassium
SMQ
standardized MedDRA queries
SoA
Schedule of Activities
SOC
Standard of Care
SPS
sodium polystyrene sulfonate
SSO
Safety Set Open
SSR
Safety Set Randomized
SZC
sodium zirconium cyclosilicate
TID
three times daily
UACR
urine albumin-to-creatinine ratio
US
United States


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11
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hyperkalemia. N Engl J Med. 2015;372:222-231.
5. 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;312:2223-2233.
6. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol.
2009;20:251-254.
7. Di lorio BR, Bellasi A, Raphael KL et al. Treatment of metabolic acidosis with sodium 
bicarbonate delays chronic kidney disease: the UBI study. J Nephrol. 2019;32:989-1001.
8. LOKELMA® (sodium zirconium cyclosilicate) powder for oral suspension. Product 
Monograph (PM). AstraZeneca Canada, Inc. August 2020. 
9. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2012). 
KDIGO clinical practice guideline for the evaluation and management of chronic kidney 
disease. Kidney Int Suppl. 2013;(3):1-150.
10. Cook E, Davis J, Israni R, et al. Prevalence of metabolic acidosis among patients with 
CKD and hyperkalemia. Abstract accepted for National Kidney Foundation 2020 Spring 
Clinical Meetings; March 25-29, 2020; New Orleans, LA, USA. 
11. Vallet M, Metzger M, Haymann JP et al. Urinary ammonia and long-term outcomes in 
chronic kidney disease. Kidney Int. 2015;88:137-145. 
12. Kraut JA, Madias NE. Metabolic acidosis of CKD: An update. Am J Kidney Dis. 
2016;67(2):307-317.
13. Pourafshar N, Pourafshar S, Soleimani M. Urine ammonium, metabolic acidosis and 
progression of chronic kidney disease. Nephron. 2018;138:222-228.
14. Stavros F, Yang A, Leon A, et al. Characterization of structure and function of ZS-9, a K+ 
selective ion trap. PLoS One. 2014;9:e114686.
15. McCullough PA, Costanzo MR, Silver M, et al. Novel agents for the prevention and 
management of hyperkalemia. Rev Cardiovasc Med. 2015;16:140-155.
16. Roger SD, Spinowitz BS, Lerma EV, et al. Sodium zirconium cyclosilicate increases 
serum bicarbonate concentrations among patients with hyperkalemia: exploratory analyses 
from three randomized, multi-dose, placebo- controlled trials. Nephrol Dial Transplant. 


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2020 Jun 26;gfaa158. 
17. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and 
hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372:211-221.
18. Centro RM. ‘Chapter 196 Serum Total Carbon Dioxide’. In Clinical Methods: The 
History, Physical, and Laboratory Examinations. 3rd Edition. Boston: Buttersworth. 
1990;888-889. 
19. In House Data; AstraZeneca Pharmaceuticals LP. Data source: R262.ZS004
20. In House Data; AstraZeneca Pharmaceuticals LP. Data source: R262.H-GL
21. In House Data; AstraZeneca Pharmaceuticals LP. Data source: R262.ZS005


SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 9 4 8 0c 0 0 0 2 2-cs p- v 6
D oc u me nt Title:
D 9 4 8 0 C 0 0 0 2 2 Cli nical St u d y Pr ot oc ol versi o n 6
D oc u me nt I D:
D oc I D- 0 0 4 3 9 6 3 2 8
Versi o n L a bel:
6. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
0 7- Mar- 2 0 2 2 1 2: 2 2 U T C
C o nte nt A p pr o val
0 7- Mar- 2 0 2 2 1 2: 4 3 U T C
C o nte nt A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan  
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Statistical Analysis Plan 
Study Code 
D9480C00022 
Edition Number 
External 4.0 
Date 
01/DEC/2022 
A Double-blind Randomized Placebo-controlled Parallel Design 
Multicenter Phase IIIb Study of the Effect of Sodium Zirconium 
Cyclosilicate (SZC) on Serum Potassium and Serum Bicarbonate 
in Patients with Hyperkalemia and Metabolic Acidosis Associated 
with Chronic Kidney Disease (NEUTRALIZE) 
  
 


Statistical Analysis Plan  
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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS .......................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................... 4 
AMENDMENT HISTORY ....................................................................................................... 5 
1 
STUDY DETAILS ................................................................................................. 7 
1.1 
Study objectives ...................................................................................................... 7 
1.2 
Study design ........................................................................................................... 8 
1.2.1 
Randomization ........................................................................................................ 9 
1.3 
Number of subjects ................................................................................................. 9 
2 
ANALYSIS SETS ................................................................................................ 10 
2.1 
Definition of analysis sets ..................................................................................... 10 
2.2 
Violations and deviations ..................................................................................... 11 
2.3 
Analysis Periods ................................................................................................... 12 
3 
PRIMARY AND SECONDARY VARIABLES ................................................. 13 
3.1 
Time Points and Visit Windows ........................................................................... 13 
3.2 
Subject Disposition ............................................................................................... 13 
3.3 
Efficacy Variables ................................................................................................ 14 
3.3.1 
Potassium .............................................................................................................. 14 
3.3.2 
Bicarbonate ........................................................................................................... 15 
3.3.3 
Additional serum measurements........................................................................... 16 
3.3.4 
Urine analysis ....................................................................................................... 16 
3.4 
Safety Variables .................................................................................................... 16 
3.4.1 
Exposure and dose interruptions ........................................................................... 16 
3.4.2 
Adverse Events ..................................................................................................... 17 
3.4.3 
Laboratory Data .................................................................................................... 18 
3.4.4 
Vital Signs ............................................................................................................ 19 
3.4.5 
Electrocardiograms ............................................................................................... 20 
3.4.6 
Physical Exam ...................................................................................................... 20 
4 
ANALYSIS METHODS ...................................................................................... 20 
4.1.1 
Handling of missing dates .................................................................................... 21 
4.1.1.1 
Partial start dates ................................................................................................... 21 
4.1.1.2 
Partial end dates .................................................................................................... 22 
4.2 
Analysis methods .................................................................................................. 22 
4.2.1 
Subject Disposition and Analysis Sets Analyzed ................................................. 22 
4.2.2 
Protocol Deviations .............................................................................................. 23 
4.2.3 
Demographics and Other Baseline Characteristics............................................... 23 
4.2.4 
Medical History .................................................................................................... 24 
4.2.5 
Previous and Concomitant Medications ............................................................... 24 
4.2.6 
Measurements of Study Treatment Compliance................................................... 25 


Statistical A nal ysis Pla n  
Astra Ze neca  
D 9 4 8 0 C 0 0 0 2 2  - E xter nal 4. 0  
0 1/ D E C/ 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3  of 4 2  
 
 
4. 2. 7  
Efficac y  ................................................................................................................. 2 6  
4. 2. 7. 1  
Pri mar y Efficac y A nal ysis  .................................................................................... 2 6  
4. 2. 7. 2  
Pri mar y Efficac y A nal ysis –  Se nsiti vit y A nal ys es  ............................................... 2 8  
4. 2. 7. 3  
Sec o n dar y Efficac y A nal ys es  ............................................................................... 2 9  
4. 2. 7. 4  
Sec o n dar y Efficac y A nal ysis  –  Se nsiti vit y A nal ys es  ........................................... 3 5  
4. 2. 8  
Safet y  .................................................................................................................... 3 7  
4. 2. 8. 1  
A d verse E v e nts  ..................................................................................................... 3 7  
4. 2. 8. 2  
Deat hs  ................................................................................................................... 3 8  
4. 2. 8. 3  
La b orat or y D ata  .................................................................................................... 3 9  
4. 2. 8. 4  
Vital Si g ns  ............................................................................................................ 3 9  
4. 2. 8. 5  
Electr ocar di o gra ms  ............................................................................................... 3 9  
4. 2. 8. 6  
P h ysical E x a mi nati o n  ........................................................................................... 4 0  
4. 2. 8. 7  
E x p os ure  ............................................................................................................... 4 0  
4. 2. 8. 8  
Pre g n a nc y T est ...................................................................................................... 4 0  
5  
I N T E RI M A N A L Y S E S ........................................................................................ 4 0  
6  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L  .............................................. 4 1  
7  
R E F E R E N C E S  ..................................................................................................... 4 1  
8  
A P P E N DI X  .......................................................................................................... 4 2  
 
LI S T O F T A B L E S  
N o ta ble of fi g ures e ntries f o u n d.  
LI S T O F FI G U R E S  
N o ta ble of fi g ures e ntries f o u n d.  
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LIST OF ABBREVIATIONS 
Abbreviation or special term 
Explanation 
AE 
Adverse Event 
ACEi 
Angiotensin-Converting Enzyme inhibitor 
ANCOVA 
ANalysis of COVAriance 
ARB 
Angiotensin II Receptor Blocker 
ARNi 
Angiotensin Receptor-Neprilysin inhibitor 
CKD 
Chronic Kidney Disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
COVID-19 
COronaVIrus Disease 2019 
CSP 
Clinical Study Protocol 
ECG 
ElectroCardioGram 
eCRF 
electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
EOT 
End Of Treatment 
FAS 
Full Analysis Set 
IP 
Investigational Product 
LOCF 
Last Observation Carried Forward 
K+ 
Potassium 
MedDRA 
Medical Dictionary for Regulatory Activities 
POCT 
Point-of-Care Test 
PPS 
Per Protocol Set 
QD 
once daily 
QTcF 
QT interval corrected by the Fridericia method 
RAASi 
Renin-Angiotensin-Aldosterone System Inhibitor 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
sK+ 
serum potassium 
SoA 
Schedule of Activities 
SSO 
Safety Set Open 
SSR 
Safety Set Randomized 
SZC 
Sodium Zirconium Cyclosilicate 
TCO2 
Total carbon dioxide 
TID 
Three times daily 
UACR 
urine albumin-to-creatinine ratio 


Statistical A nal ysis Pla n  
Astra Ze neca  
D 9 4 8 0 C 0 0 0 2 2  - E xter nal 4. 0  
0 1/ D E C/ 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5  of 4 2  
 
 
A M E N D M E N T HI S T O R Y  
C ate g or y *:  
C h a n ge refers t o  
D ate  
Descri pti o n of c h a n ge  
I n li ne wit h t he 
C S P ?  
R ati o n ale  
Ot her  
0 1 -Dec -2 0 2 2  
A me n de d  s u b gr o u p a n d 
se nsiti vit y a nal yses t o be 
c o n d ucte d. A me n de d 
c o variates t o be i ncl u de d 
i n se nsiti vit y a nal ysis of 
pri mar y e n d p oi nt.  
N o  
D ue t o t he earl y ter mi nati o n of 
st u d y s o me pla n ne d a nal yses c a n n ot 
be perf or me d d ue t o s mall sa m ple 
size. U p dati n g S A P t o clarif y w hic h 
s u b gr o u p a n d se nsiti vit y a nal yses 
are n o l o n ger bei n g perf or me d.  
M ulti ple T esti n g Pr oce d ure  
0 1 -Dec -2 0 2 2  
Clarifie d data 
prese ntati o n of  
m ulti plicit y pr ocess d ue 
t o earl y ter mi nati o n of 
t he st u d y   
N o  
Clarif yi n g h o w p -val ues will b e 
dis pla ye d  i n data prese ntati o ns d ue 
t o earl y ter mi nati o n of st u d y. 
Ot her  
3 0 -Ma y -2 0 2 2  
U p date d la n g ua ge t o 
reflect c ha n ges i n 
pr ot oc ol v 6. 0. A d de d 
details re gar di n g i nteri m 
a nal ysis.  
Yes, v 6. 0  
Pr ot oc ol u p date i ncl u des i nteri m 
a nal ysis t o be descri be d i n t he S A P.  
Pr i mar y or sec o n dar y  e n d p oi nts 
0 9 -A u g -2 0 2 1  
C ha n ge d i -S T A T t o 
P oi nt of Care T est 
( P O C T) t hr o u g h o ut S A P 
i n li ne wit h C S P 
Yes, v 4. 0  
Pr ot oc ol u p date d t o e x pa n d P O C T 
o pti o ns i n a d diti o n t o i -S T A T.  
Statistical a nal ysis met h o d f or t he 
pri mar y of sec o n dar y e n d p oi n ts 
0 9 -A u g -2 0 2 1  
A d de d P O C T t y pe t o 
m ulti varia ble a nal yses of 
pri mar y a n d sec o n dar y 
e n d p oi nts  
Yes,  v 4. 0  
C o nsi dere d i m p orta nt t o c o ntr ol f or 
c o nf o u n di n g differe nce fr o m P O C T 
t y pe use d b y site. 
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gap results but providing variables 
needed to enable calculation. 
Addition of analysis visit windows 
09-Aug-2021 
Added analysis visit 
windows 
No 
This change expands visit windows 
to allow additional assessments to 
be included in summaries by visit. 
* Pre-specified categories are  
Primary or secondary endpoints; Statistical analysis method for the primary or secondary endpoints; Derivation of primary or secondary endpoints; Multiple 
Testing Procedure; Data presentations; Other 
 






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inclusive, will be enrolled into the open-label correction phase. All baseline parameters should 
be measured/collected prior to administration of the first dose of study drug in the open-label 
initial phase.  
In the open-label initial phase, patients will receive open-label SZC orally at a dose of 10 g 
three times daily (TID) for up to 48 hours, depending on POCT potassium value. 
Patients who achieve normokalemia (K+ between 3.5 and 5.0 mmol/L inclusive) within 24-48 
hours will be randomized 1:1 into the double-blind randomized treatment phase to receive 10 
g SZC or placebo once daily (QD) starting dose for the following 28 days. Patients who 
achieve normokalemia after 24 hours will be randomized and will not need to continue on 10 
g SZC TID for another 24 hours. 
Study treatment will end with the Day 29 visit, which will be followed by the end of study 
visit 7 days after the last administration of study medication. 
1.2.1 
Randomization 
Subjects who are normokalaemic (NK; 3.5≤sK+≤5.0 mmol/L) within 24 to 48 hours of 
enrolment in the open-label correction phase will be randomized 1:1 to either SZC 10g QD or 
placebo 10g QD. Randomization will be performed using randomly permuted blocks. The 
randomization codes will be computer generated and loaded into the IxRS database. 
1.3 
Number of subjects 
 Prior data: Proportion of patients with serum bicarbonate between 16-20 mmol/L 
inclusive who had a 3 mmol/L or greater increase in serum bicarbonate with SZC 
versus placebo from ZS-004,20 Global Harmonize trial,21 and ZS-005.22 
 SZC: 92/235 = 0.39 achieved an increase in serum bicarbonate ≥3 mmol/L 
 Placebo: 7/40 = 0.175 achieved an increase in serum bicarbonate ≥3 mmol/L 
 Sample size estimate* 
o 
20% absolute difference: 
o 
Alpha=0.05, Power=80% 
o 
Control=0.175 with serum bicarbonate increase of 3mmol/L or more 
o 
SZC=0.39 with serum bicarbonate increase of 3mmol/L or more 
 
*Actual effect size = 0.215  
o 
N=68 per group (136) 
o 
N=148 (accounting for 8% drop-out from initial phase to randomized placebo-
controlled phase)  
*Sample size would be smaller if based on primary endpoint of mean sK+ (N=18 per arm). 


Statistical A nal ysis Pla n  
Astra Ze neca  
D 9 4 8 0 C 0 0 0 2 2  - E xter nal 4. 0  
0 1/ D E C/ 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 0  of 4 2  
 
 
A p pr o xi matel y 4 7 7  p atie nts will be scree ne d. A p pr o xi matel y 1 4 8 p atie nts will be e nr olle d t o 
t he o pe n-la bel p h ase of t he st u d y t o ac hie ve 13 6  ra n d o ml y assi g ne d t o st u d y i nter ve nti o n. 
2  
A N A L Y SI S S E T S  
2. 1  
De fi niti o n of a n al ysis sets 
Scree ne d Set  
All s u bjects w h o were scree ne d f or i ncl usi o n i n t he o pe n -la bel r u n-i n peri o d of t he st u d y. T his 
a nal ysis s et will be use d t o descri be t he de m o gra p hics of s u bjects c o nsi dere d f or i ncl usi o n i n 
t he st u d y. T he assi g n m e nt of s u bjects t o a treat me nt gr o u p f or a n al ysis is n ot a p plica ble.  
S afet y Set O pe n  
All patie nts e nr olle d i n t he o pe n -la bel c orrecti o n p hase w h o t o o k at least 1 d ose of st u d y dr u g. 
T he Safet y Set O pe n ( S S O) a nal ysis set will be us e d t o descri be t h e safet y c ha racteristics of 
S Z C d uri n g t he o pe n – la b el peri o d. Patie nts will be a nal yze d as a si n gle gr o u p. 
S afet y Set R a n d o mize d  
All patie nts w h o ac hie ve n or m o kale mia at t he e n d of t he o pe n -la bel c orrecti o n p hase a n d w h o 
recei v e d at least o ne d ose of eit her S Z C or place b o d uri n g t he ra n d o mize d place b o -c o ntr olle d 
p hase. T he Safet y Set Ra n d o mize d ( S S R) a nal ysis set will be use d t o descri be t he safet y 
c haracteristics of S Z C or place b o d uri n g t he ra n d o mize d place b o -c o ntr olle d p hase. Patie nts 
will be a nal yze d acc or di n g t o t he i n vesti gati o nal pr o d uct (I P) recei v e d d uri n g t he ra n d o mize d 
place b o -c o ntr olle d p hase.  
F ull A n al ysis Set  
All patie nts w h o ac hie ve n or m o kale mia ( K + bet w ee n 3. 5 a n d 5. 0 m m ol/ L i ncl usi ve) at t he e n d 
of t he o pe n -la b el c orrecti o n p hase a n d e nter t he ra n d o mized place b o -c o ntr olle d p hase. T he 
F ull A nal ysis Set ( F A S) will be t he pri mar y a n al ysis set use d f or t he pri mar y, s ec o n dar y a n d 
. Patie nts will be a nal yze d o n a n i nte nt-t o-treat b asis acc or di n g t o t heir 
ra n d o mize d I P. 
Per Pr ot oc ol Set  
T he  Per Pr ot oc ol Set ( P P S) is defi ne d as all patie nts i n t he F A S wit h o ut a n y i m p orta nt 
pr ot oc ol de viati o ns lea di n g t o e x cl usi o n fr o m t he P P S. Patie nts will be a nal yse d acc or di n g t o 
t heir ra n d o mize d I P. T h e P P S will be use d f or se nsiti vit y a n al ysis of t h e pri mar y a n d 
sec o n dar y e n d p oi nts. 
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Protocol deviations are defined as any change, divergence, or departure from the study design 
of procedures defined in the clinical study protocol (CSP). Important protocol deviations are a 
subset of protocol deviations and may significantly impact the correctness, accuracy, and/or 
reliability of the study data or that may significantly affect a subject’s rights, safety, or well-
being.  Important protocol deviations which should lead to exclusion from the PPS will be 
defined by the Sponsor before database lock by judging the importance of the deviations upon 
the primary efficacy endpoint. 
2.2 
Violations and deviations 
Subjects will be assessed by comparison of their electronic case report form (eCRF) data with 
the criteria below; protocol waivers will not be taken into consideration (e.g. if a subject 
younger than 18 enters the study on a protocol waiver, the subject would still be excluded 
from the PPS). 
The following criteria may be considered as important protocol deviations which have a major 
effect on efficacy or that could potentially affect the interpretability of the study results and 
which should lead to exclusion from the PPS. 
  Subjects who failed any of the inclusion or exclusion criteria of the study. 
 Inappropriate compliance with study treatment during the randomized placebo-
controlled phase of the study, e.g. treatment compliance of less than 80% or greater 
than 120% 
 All prohibited medications which are administered during the randomized placebo-
controlled phase of the study. Prohibited medications include patients starting on 
renin-angiotensin-aldosterone system inhibitor (RAASi) therapy during the trial Note: 
RAASi therapies: Angiotensin-converting enzyme inhibitor (ACEi), angiotensin II 
receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNi) are 
permitted to be continued at the same dose as baseline. 
 Errors in treatment allocation. Any subject who received incorrect study treatment 
compared with randomized study treatment at any time during the study 
 Any subject unblinded during the study 
 Rules for rescue medication for hyperkalemia or metabolic acidosis violated 
 Start of double-blind study medication prior to randomization date 
 Subject with first dose prior to baseline evaluations. 


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In addition, protocol deviations will be defined by the Sponsor before database lock as 
coronavirus disease 2019 (COVID-19) pandemic related or not by judging the root cause of 
the protocol deviation, in line with FDA guidance (FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency; March 2020). The 
following criteria may be considered as indicative of a protocol deviation related to the 
COVID-19 pandemic. 
 Missed in-person visit due to COVID-19 illness and/or COVID-19 public health 
control measures 
 Study visit out of window due to COVID-19 illness and/or COVID-19 public health 
control measures 
 Missed doses due to COVID-19 illness and/or COVID-19 public health control 
measures 
 Missed sK+ measurements due to COVID-19 illness and/or COVID-19 public health 
control measures 
 Missed bicarbonate measurements due to COVID-19 illness and/or COVID-19 public 
health control measures 
2.3 
Analysis Periods 
Analysis periods defined in this section are distinct from those used to describe the study 
design in the CSP and section 1.2 of the SAP. 
Screening Period 
The screening period is defined as the period from informed consent to the first dose of open-
label study or screen failure. 
Open-label correction period 
The open-label correction period refers to the period from first dose of open-label study 
treatment to the earliest date of randomization, withdrawal of consent, last contact with the 
subject or death. 
Randomized placebo-controlled period 
The randomized placebo-controlled period refers to the period from randomization to the 
earliest date of rescue treatment for hyperkalemia or low serum bicarbonate, last assessment 
during follow-up (day 36 +/- 3), withdrawal of consent, last contact with the subject, or death. 


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3 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Time Points and Visit Windows 
For all populations, assessments will be assigned to visits and analysis periods for categorical 
summaries as follows: 
 
Assessments with missing data and assessments marked “Not Done” will be considered 
as providing a missing response and are not permitted to be assigned to a visit window. 
 
The worst value (e.g. out of reference range preferred to within range; abnormal preferred 
to normal) will be used in each window. If multiple assessments fall within the same 
window with equal value, then the first non-missing will be used for the summary. 
 
Scheduled day and visit window during the open-label period in Table 1 are with respect to 
the first dose of open-label study treatment. Baseline is defined as measurements taken at the 
screening visit on day 1 of the study. 
Table 1 Definition of visit windows 
Visit 
Scheduled 
Day of 
Visit 
Analysis Period 
Protocol Visit 
Windows 
Visit title in 
TFLs 
Analysis Visit 
Windows 
Visit 1 
1 
Screening/ 
Open-Label 
Day 1 
Visit 1 (Baseline) 
Day 1 
Visit 2 
2 
Open-Label 
Day 2* 
Visit 2 
Day 2* 
Visit 3 
2 or 3 
Randomized 
Days 2 – 3* 
Visit 3 
(Randomization) 
Days 2 – 3* 
Visit 4 
8 
Randomized 
Days 7 – 9 
Visit 4 
Days 4 – 11 
Visit 5 
15 
Randomized 
Days 14 – 16 
Visit 5 
Days 12 – 18 
Visit 6 
22 
Randomized 
Days 21 – 23 
Visit 6 
Days 19 – 25 
Visit 7 
29 
Randomized 
Days 28 – 30 
Visit 7 (EOT) 
Days 26 – 32 
Visit 8 
36 
Randomized 
Days 33 – 39 
Visit 8 (Follow-up) Days 33 - 39 
* Assessments conducted on day 2 and day 3 will be assigned to visit 2 or 3 based on the 
nominally entered visit on the eCRF. 
3.2 
Subject Disposition 
Screen failures are defined as subjects who consent to participate in the clinical study but fail 
inclusion/exclusion criteria and are not entered into the open-label correction phase. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after >2 weeks if screen failure was due to not meeting inclusion criterion #3 
(POCT K+ level >5 mmol/L to ≤5.9 mmol/L and POCT bicarbonate levels between 16-20 
mmol/L inclusive prior to the first SZC dose on study Day 1) and/or met exclusion criterion 
#24 (If the participant has evidence of Coronavirus disease 2019 (COVID-19) within 2 weeks 
prior to screening). Further, participants who failed, due to not meeting inclusion criteria #3 


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may be rescreened more than once at investigator’s discretion if sK+ and bicarbonate obtained 
during routine patient care subsequent to the last rescreening are consistent with study entry 
criteria. Rescreen participants will be assigned the same participant number as in the initial 
screen so that each participant will appear once in disposition summaries. 
3.3 
Efficacy Variables 
3.3.1 
Potassium 
Whole blood samples will be analyzed locally using POCT devices to generate K+ for the 
purposes of study inclusion, dose adjustments, and monitoring. Samples drawn at the same 
timepoints will be prepared and shipped to the central laboratory for analysis of sK+. In the 
event that hemolysis or other artifacts are suspected based on the reported POCT K+ result, 
the blood samples must be re-drawn to confirm the result and only the confirmatory sample 
result will be reported. 
The primary endpoint will use the central laboratory sK+ measurement from Visit 7 if 
available and no use of rescue medication for hyperkalaemia has occurred. Missing 
measurements at Visit 7 will be imputed as follows: 
(i) 
If Visit 7 central laboratory sK+ is missing 
Visit 6 (or an unscheduled assessment which occurs between visits 6 and 7) central 
laboratory sK+ will be used in its place under the principle of last observation 
carried forward (LOCF). If multiple measurements are available, the closest 
measurement to the scheduled date of Visit 7 will be used. 
(ii) 
If central laboratory sK+ is missing for Visits 6 and 7 
sK+ will be replaced by POCT values adjusted to reflect the mean difference 
between POCT and sK+ values from all available (including screening, baseline 
and unscheduled visits) paired laboratory samples in both treatment groups. The 
mean difference will be estimated using a summary statistic of the difference in all 
pairs and will not adjust for baseline characteristics.  If a Visit 7 POCT value is 
available the adjusted value for this will be used unless missing, in which case the 
adjusted Visit 6 POCT will be used. If an unscheduled POCT assessment which 
occurs between visits 6 and 7 is available, then the closest POCT assessment to the 
scheduled date of visit 7 will be used. 
(iii) 
No sK+ or POCT K available for Visits 6 or 7 
The subject will be classified as non-evaluable for primary and secondary efficacy 
endpoints which include sK+ measurements in their definition. 


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Normokalaemia is defined as 3.5 ≤ sK+ ≤ 5.0 and hyperkalaemia is defined as sK+ >5.0 
where the sK+ value used will be the result of the imputation approach described above. 
3.3.2 
Bicarbonate 
Whole blood samples will be analyzed locally using POCT devices to generate POCT serum 
bicarbonate measurements (TCO2). The secondary endpoints will use the POCT serum 
bicarbonate measurement from Visit 7 if available. For the first secondary endpoint analysing 
the mean change in serum bicarbonate from baseline, missing measurements at visit 7 will be 
imputed as follows: 
(i) 
If Visit 7 POCT serum bicarbonate measurements are unavailable 
Visit 6 (or an unscheduled assessment which occurs between visits 6 and 7) POCT 
serum bicarbonate will be used in its place under the principle of LOCF. If 
multiple measurements are available, the closest measurement to the scheduled 
date of Visit 7 will be used. 
As a sensitivity analysis for the secondary endpoint #1, and as standard imputation approach 
for the other secondary endpoints which include serum bicarbonate measurements, the 
additional imputation rule will be applied: 
(ii) 
If POCT bicarbonate is missing for Visits 6 and 7 
POCT bicarbonate will be replaced by central laboratory bicarbonate values 
adjusted to reflect the mean difference between POCT and central laboratory 
bicarbonate values from all available (including screening, baseline and 
unscheduled visits) paired laboratory samples in both treatment groups. The mean 
difference will be estimated using a summary statistic of the difference in all pairs 
and will not adjust for baseline characteristics.  If a visit 7 central laboratory value 
is available the adjusted value for this will be used unless missing, in which case 
the adjusted Visit 6 central laboratory measurement will be used. If an unscheduled 
central laboratory assessment which occurs between visits 6 and 7 is available, 
then the closest available assessment to the scheduled date of visit 7 will be used. 
(iii) 
No POCT or central laboratory bicarbonate available for Visits 6 or 7 
The subject will be classified as non-evaluable for secondary efficacy endpoints 
which include serum bicarbonate measurements in their definition. 
Thresholds for the change from baseline for the imputed serum bicarbonate value described 
above of ≥2 mmol/L and ≥3 mmol/L will be calculated and an absolute value of ≥22 mmol/L 
or <15 mmol/L. 


Statistical A nal ysis Pla n  
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3. 3. 3  
A d diti o n al ser u m me as ure me nts  
W h ole bl o o d sa m ples will be a nal y z e d l ocall y usi n g P O C T  de vices t o ge nerate P O C T  
creati ni ne a n d a ni o n ga p meas ure me nts. If P O C T d oes n ot ge nerate a ni o n ga p val ues, t he n 
a ni o n ga p will be deri ve d usi n g t he f or m ula:  
A ni o n ga p ( m E q/ L) = s o di u m ( m E q/ L) –  (c hl ori d e ( m E q/ L) + bicar b o nat e ( m E q/ L)) 
W here s o di u m, c hl ori de a n d bicar b o nate are meas ure d at t he sa m e visits as disc usse d bel o w.  
3. 3. 4  
Uri ne a n al ysis  
W he n p ossi ble, first m or ni n g v oi d s p ot uri ne will be c ollecte d at visits 1, 3 -8 a n d i n t he e ve nt 
of earl y wit h dr a wal. Uri nar y al b u mi n, a m m o ni u m, citrate, p H, a n d creati ni ne will be 
meas ure d at t he ce ntr al la b orat or y. Uri n e a ni o n ga p will be calc ulate d base d o n s o di u m, 
p otassi u m, a n d c hl ori de i o ns  usi n g t he f or m ulat e pr o vi de d i n secti o n 3. 3. 3 . Uri ne al b u mi n-t o-
creati ni ne -rati o ( U A C R) will be calc ulate d base d o n t he meas ure d uri nar y al b u mi n a n d 
creati ni ne. A m m o ni u m -t o-creati ni ne rati o will be calc ulate d base d o n t he meas ure d uri n ar y 
a m m o ni u m a n d creati ni n e. T he uri ne a ni o n ga p, U A C R a n d a m m o ni u m -t o-creati ni ne rati o 
will be calc ulate d b y t he c e ntral la b orat or y.  
If visit 7 ce ntral la b orat or y me as ure me nts are u n a v aila ble, t he n visit 6 val ues will be use d 
u n der t he pri nci ple of L O C F.  
3. 4  
S afet y V ari a bles  
3. 4. 1  
E x p os ure a n d d ose i nterr u pti o ns  
E x p os ure (i.e. d urati o n of treat me nt) will be defi n e d as f oll o ws:  
T otal ( or i nte n de d) e x p os ure of st u d y treat me nt  
C CI


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 
Total (or intended) exposure = min (last dose date where dose > 0 [units], date of death, 
date of discontinuation) – first dose date + 1 
Actual exposure of study treatment 
 
Actual exposure = total (or intended) exposure – total duration of dose interruptions, 
where intended exposure will be calculated as above and a dose interruption is defined as 
any length of time where the subject has not taken any of the planned daily dose. The 
duration of each dose interruption will be calculated as interruption stop date – 
interruption start date + 1. 
The actual exposure calculation makes no adjustment for any dose reduction that may have 
occurred. 
3.4.2 
Adverse Events 
Adverse events (AEs) and Serious adverse events (SAEs) will be collected from start of the 
open-label correction phase, throughout the treatment period and including during the follow-
up period. In addition, SAEs will be recorded from the time of signing the informed consent 
form and will continue throughout the clinical study until the end of any follow-up prior; this 
applies even if the subject has not received any study treatment (as per the SOP: Reporting of 
Individual Safety Events in Clinical Studies). SAEs which occur after the end of the clinical 
study but with a suspected causal relationship to the IP will be reported by the investigator but 
will not be included in summary tables and listings. 
A treatment emergent AE (TEAE) will be defined as an AE with the start date on or after the 
first dose date and up to (and including) 7 days after the last dose date or an AE which starts 
prior to first dose of IP (i.e. before study day 1) which subsequently worsen in severity on or 
after the date of first dose of IP and up to and including 7 days following the date of last dose 
of study medication. AEs which occur more than 7 days after the last dose date will only be 
listed. Similarly, the number of patients experiencing SAEs, AEs that led to withdrawal, AEs 
that led to death and treatment related AEs, and number of such events, will be summarized 
by treatment group. 
AEs will be further categorized as either occurring during the open-label period, if the start date 
is on or after the first dose date during the open-label correction period and prior to the date of 
the first dose of treatment during the randomized placebo-controlled period, or occurring during 
the randomized placebo-controlled period if the start date is on or after the date of the first dose 
of treatment during the randomized placebo-controlled period. 
The Medical Dictionary for Regulatory Activities (MedDRA) (using the latest or current 
MedDRA version) will be used to classify AEs system organ class (SOC) and preferred term 
(PT). 
If the relationship to treatment is missing, then the AE will be considered as possibly related 
to treatment. 


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Other significant adverse events 
An overview of edema-related events (grouped terms include preferred terms of edema, 
edema peripheral, generalized edema, fluid overload, fluid retention, hypervolemia, localized 
edema, and peripheral swelling)and instances of sK+ <3.5 will be presented.  
Deaths 
All AEs leading to death will be collected until the end of the study. 
Laboratory Data 
Deterioration as compared to baseline in protocol-mandated laboratory values will only be 
reported as AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of 
treatment with the IP or are considered to be clinically relevant as judged by the investigator 
(which may include but not limited to consideration as to whether treatment or non-planned 
visits were required or other action was taken with the study treatment, e.g., dose adjustment 
or drug interruption). 
Vital Signs Data 
Deterioration as compared to baseline in protocol-mandated vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the IP or are considered to be clinically relevant as 
judged by the investigator (which may include but not limited to consideration as to whether 
treatment or non-planned visits were required or other action was taken with the study 
treatment, eg, dose adjustment or drug interruption). 
3.4.3 
Laboratory Data 
Absolute change from baseline in haematology and clinical chemistry variables will be 
calculated for each post-dose visit. CTC and maximum post-baseline grade will be calculated 
at each visit, where appropriate. Absolute values will be compared to the local laboratory 
reference range and classified as low (below range), normal (within range or on limits of 
range) and high (above range). All values classified as high or low will be flagged on the 
listings. 
Urinalysis and blood for the determination of clinical chemistry and haematology will be 
taken at the visits indicated in the Schedule of Activities (SoA) Tables 1 of the CSP. 
Presentations and summaries will use central laboratory results except for urinalysis dipstick 
results which will be local. Laboratory parameters include: 


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Table 2: Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum) 
B-Haemoglobin (Hb) 
S-Creatinine (sCr) 
B-Leukocyte count 
S-Potassium (K+) 
B-Leukocyte differential count (absolute count) 
S-Bicarbonate (Total CO2) 
B-Platelet count 
S-Chloride (Cl-) 
B-Hematocrit (Hct) 
S-Glucose 
 
S-Creatinine 
Urinalysis (dipstick, non central) 
S-Blood Urea Nitrogen (BUN) 
U-Hb/Erythrocytes/Blood  
Urea (BUN)/Creatinine Ratio 
U-Protein/Albumin  
eGFR using the CKD-EPI formula 
U-Glucose  
Anion gap (blood, from POCT if available) 
 
S-Albumin 
 
S-Total Protein 
 
S-Calcium (Ca++) 
 
S-Magnesium (Mg++) 
 
S-Phosphate (PO4) 
 
S-Bilirubin, total 
 
S-Alkaline phosphatase (ALP) 
 
S-Alanine amino transferase (ALT) 
 
S-Aspartate amino transferase (AST) 
Estimated eGFR will be calculated using the CKD-EPI (chronic kidney disease epidemiology 
collaboration equation) formula for each time-point and will be analysed as provided by 
Covance Central Laboratory Services: 
eGFR (CKD-EPI)= 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 
1.159 [if Black] 
Where SCr (standardized serum creatinine) = mg/dL,  κ = 0.7 (females) or 0.9 (males), α = -
0.329 (females) or -0.411 (males), min = indicates the minimum of SCr/κ or 1, max = indicates 
the maximum of SCr/κ or 1 and age = years. eGFR at study entry will be calculated based on 
either POCT or local laboratory creatinine values. 
3.4.4 
Vital Signs 
Vital signs will be evaluated and assessed at screening, randomization and all further study 
visits according to the SoA, Tables 1 of the CSP. Vital signs include tympanic temperature 
(ºC), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate (beats per 
minute), respiratory rate (breaths per minute), height (cm, baseline only) and weight (kg). 
Absolute change from baseline will be calculated for each post-dose visit. 


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3.4.5 
Electrocardiograms 
Electrocardiogram (ECG) assessments will be performed at screening, randomization, EOT, 
and follow-up (as specified in the SoA), and according to clinical judgement in connection 
with severe hypokalaemia (sK+ <3.0 mmol/L), severe hyperkalemia (sK+>6.0 mmol/L) or 
any symptoms or clinical events suggesting cardiac arrhythmia. ECG parameters will include 
mean, minimum and maximum heart rate (beats/min), aggregate PR interval (msec), P wave 
duration (msec), QRS duration (msec), QT interval (msec), QTcB interval (msec), QT interval 
corrected by the Fridericia method (QTcF) interval (msec) and RR interval (msec). The 
absolute change from baseline will be calculated for each post-dose visit. 
3.4.6 
Physical Exam 
A complete physical examination is performed at screening, randomization and all further 
study visits according to the SoA, Tables 1 of the CSP. Physical examination will include an 
assessment of general appearance, respiratory, cardiovascular, abdomen skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine 
and extremities) and neurological systems. Body weight and height are measured at the 
screening visit and weight will then be measured at randomization and all further study visits 
according to the SoA. 
4 
ANALYSIS METHODS 
The principal analyses outlined in this statistical analysis plan will be conducted by Covance 
Inc., in accordance with the contract with AstraZeneca Pharmaceuticals LP and following the 
Excellence in Medical Partnership for Outsourced Worldwide Evidence Research 
(EMPOWER) description of services.  
The below mentioned general principles will be followed for analyses: 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will 
be summarised by the number of observations, mean, standard deviation, median, Q1, Q3, 
minimum and maximum. Categorical variables will be summarized by frequency counts and 
percentages for each category. 
Unless otherwise stated, percentages will be calculated out of the analysis set total for the 
treatment group. 
For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional decimal 
places compared to the original data. Minimum and maximum will be displayed with the same 
accuracy as the original data. 
For categorical data, percentages will be rounded to 1 decimal place. 


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SAS® version 9.3 or higher will be used for all analyses 
It is acceptable to present large numerical values in more appropriate units. For example, an 
AUC value of 123,000 ng h/mL may be reported as 123 µg h/mL instead. It is however, 
important to keep the units consistent within the report and the precision consistent with that 
prior to conversion. 
In general, for all endpoints the last observation before the first dose of study treatment in the 
open-label period will be considered the baseline measurement, unless otherwise specified. 
For assessments on the day of first dose, where time is not captured, a nominal pre-dose 
indicator, if available, will serve as sufficient evidence that the assessment occurred prior to 
first dose. 
Assessments on the day of the first dose when neither time nor a nominal pre-dose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
protocol to be conducted before first dose. 
In all quantitative summaries from baseline, variables will be calculated as the post-treatment 
value minus the value at baseline. The percentage change from baseline will be calculated as 
(post-baseline value – baseline value) / baseline value x 100. Absolute and percentage change 
will be summarized. 
Safety and treatment exposure data will be summarised based upon the SSO and SSR analysis 
sets separately. Analyses using the SSO analysis set will be restricted to visits 1 and 2 (if 
applicable). Study population and demography data will also be summarized using the SSO 
and SSR analysis sets. 
4.1.1 
Handling of missing dates 
Incomplete dates (partial or missing dates where a full date is permissible) will be presented in 
the data listings as recorded on the eCRF. However, for use in calculations (for instance in 
calculation of the duration of an AE or medication use), dates will be estimated as follows: 
4.1.1.1 
Partial start dates 
If the year is unknown, then: 
 
The date will not be imputed, and will be assigned a missing value 
If the month is unknown, then: 
 
If the year matches the year of the first dose date in the open-label period, then impute the 
month and day of the first dose date. 
 
Otherwise, assign the month as January 
If the day is unknown, then: 


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 
If the month and year match the month and year of the first dose date in the open-label 
period, then impute the day of the first dose date. 
 
Otherwise, assign the day as 1st of the month. 
4.1.1.2 
Partial end dates 
If the year is unknown, then the date will not be imputed and will be assigned a missing value. 
If the month is unknown, then assign December. 
If the day is unknown, then assign the last day of the month. 
If the above rules for end dates result in an illogical date with regard to the dates the subject 
was in the study, then the end date will be replaced with the subject’s date of 
completion/discontinuation. 
4.2 
Analysis methods 
4.2.1 
Subject Disposition and Analysis Sets Analyzed 
Subject disposition will be listed and summarized by treatment group and overall. The number 
and percentage of subjects in the following categories will be summarized for subjects in the 
screened set: 
 Screened; 
 Did not enter open-label period (Screening failures) and associated reasons; 
 Entered the open-label period and received treatment 
 Entered the open-label period and did not receive treatment and associated reasons 
 Randomized; 
 Not randomized (Open-label period failure) and associated reasons; 
 Randomized and received treatment; 
 Randomized, did not receive treatment and associated reasons; 
 Completed the study; 
 Discontinued treatment and associated reasons (including use of rescue treatment); 
 Terminated study and associated reasons; 


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The denominator used for percentages will be calculated as follows. The denominator for 
subjects who are screened or who did not enter the open-label period (and associated reasons) 
will be calculated using the number of screened subjects. The denominator for subjects who 
entered the open-label period and received treatment, who entered the open-label period and 
did not receive treatment (and associated reasons), randomized and not randomized (and 
associated reasons) will be calculated using the number of subjects who entered the open-label 
period. The remaining subject disposition categories will use the number of subjects who were 
randomized for the denominator. Categories will still be presented if 0 subjects satisfy the 
criteria. 
The number of subjects in each of the analysis sets and the reasons for exclusion from each 
will be summarized for all screened subjects by treatment group and overall. 
4.2.2 
Protocol Deviations 
All important protocol deviations (Section 2.2) leading to exclusion from the PPS will be 
listed and summarized by treatment group and overall for the FAS. Important protocol 
deviations will be further classified as either pandemic-related or excluding pandemic related 
important protocol deviations and will be summarized by treatment group and overall for the 
FAS. 
4.2.3 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized in total for the SSO 
and by treatment group and total for the SSR and FAS. The demographic and baseline 
characteristics include the following: 
 Age (years); 
 Age groups (>18 to ≤65, >65 to ≤85 and >85 years); 
 Sex (male, female); 
 Race category (White, Black or African American, Asian, Native Hawaiian or Other 
Pacific Islander, American Indian or Alaskan Native, Other); 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 
 CKD status at baseline (3, 4 or 5); 
 Chronic Heart Failure at baseline (No, Yes) [Determined as medical history with 
MedDRA coded preferred term of cardiac failure chronic] 
 Diabetes status at baseline (No, Yes); 


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No formal tests of statistical significance will be performed on the demographic and baseline 
data. 
A separate table will summarize the subject characteristics at baseline and will be listed and 
summarized in total for the SSO and by treatment group and total for the SSR and FAS. They 
will include: 
 Baseline height (cm); 
 Baseline weight (kg); 
 Baseline body mass index (kg/m2) [calculated as (baseline weight/baseline height2 
where weight is in kg and height is in m]; 
Other baseline measurements, such as vital signs and ECG results, will be reported with post-
baseline measurements. 
4.2.4 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 23.0 (or a later version if updated during the study)]. The number and 
percentage of subjects with any medical history will be summarized for the SSO by system 
organ class (SOC) and preferred term (PT) overall. The number and percentage of subjects 
with any medical history will be summarized for the SSR by system organ class (SOC) and 
preferred term (PT) for each treatment group overall. 
4.2.5 
Previous and Concomitant Medications 
Medications received prior to or concomitantly with study treatment will be coded using the 
WHO Drug Dictionary [Version March 2020 (or a later version if updated during the study)], 
Anatomical Therapeutic Chemical (ATC) Classification codes. 
Prior medications and concomitant medications are as defined as follows: 
Prior medications are those taken with a stop date prior to the first dose date of study 
treatment during the open-label correction period. 
Concomitant medications during the open-label correction period are those with a start date 
anytime before the first dose date of study treatment during the randomized placebo-
controlled period and a stop date on or after the first dose of study treatment during the open-
label correction period. 


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Concomitant medications during the randomized placebo-controlled period are those with a 
stop date on or after the first dose date of study treatment during the randomized  placebo-
controlled period. 
If a medication cannot be classified as “prior” or “concomitant during the open-label 
correction period” or “concomitant during the randomized placebo-controlled period” after 
applying imputation rules for missing/incomplete dates, it will be classified as concomitant 
during the randomized placebo-controlled period. 
Concomitant medications during the open-label correction and randomized placebo-controlled 
periods will be further categorized by those allowed and disallowed. Disallowed concomitant 
medications are defined in the CSP Section 6.8 as starting on RAASi therapy during the trial 
(ATC level 2 code C09) or sodium-glucose transport protein 2 inhibitor therapy. Furthermore, 
several medications which are described as restricted will also be included as disallowed 
concomitant medications.  
Prior medications, allowed/disallowed concomitant medications during the open-label 
correction period and allowed/disallowed concomitant medications during the randomized 
placebo-controlled period will be listed together. Allowed/disallowed concomitant 
medications during the open-label correction period will be summarized using the SSO and 
presented in total. Allowed/disallowed concomitant medications during the randomized 
placebo-controlled period will be summarized separately by treatment group and overall using 
the SSR. 
The number and percentages of subjects using each medication will be displayed together with 
the number and percentage of subjects using at least one medication within each therapeutic 
class (ATC-Level 2), chemical subgroup (ATC-Level 4), and generic term. 
4.2.6 
Measurements of Study Treatment Compliance 
The percentage compliance for SZC and placebo is calculated for each analysis period as: 
100*actual sachets taken/expected sachets taken 
, where: 
Actual sachet taken is defined as: 
Sum of the sachets taken throughout the respective analysis period 
And the expected sachets taken throughout the respective analysis period is derived using the 
study intervention and drug dispensation records to calculate the number of sachets expected 
accounting for changes to the prescribed dosage level (from 10g three times daily to 5g every 
other day) and the unit dose strength dispensed (5g and 10g sachets). 


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The percentage compliance for SZC and placebo will be calculated separately for the open-
label and placebo-controlled periods and will be summarized descriptively overall using the 
SSO and treatment group using the SSR respectively. 
Furthermore, for SZC/placebo the number and percentage compliance will be presented 
separately for the open-label and placebo-controlled periods using the SSO and SSR 
respectively with the following compliance categories: 
 <50% 
 ≥50% to <80% 
 ≥80% to <120% 
 ≥120% 
Furthermore, at each study visit during the open-label and placebo-controlled periods there 
will be a categorical summary of the number and percentage of subjects assigned to each dose 
of SZC/placebo (e.g. 5g every other day, 5g daily, 10g daily, 15g daily). 
4.2.7 
Efficacy 
To control for type I error, a hierarchical testing procedure will be followed when formally 
testing primary and secondary efficacy analysis endpoints. The hierarchical testing procedure 
will follow a stepwise algorithm where each endpoint is only formally tested if the preceding 
null hypothesis is rejected (p<0.05). The first secondary endpoint will only be formally tested 
if the null hypothesis for the primary endpoint is rejected at p<0.05. Endpoints which are not 
formally tested will have a p-value displayed when one can be calculated. However, a 
footnote will indicate that the “P-value is descriptive only due to a previous endpoint in the 
hierarchical testing procedure failing to have the null hypothesis rejected (p≥0.05). The final 
order for hierarchical testing will be the order displayed below. 
4.2.7.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the occurrence (yes/no) of patients having normal sK+ 
(between 3.5 and 5.0 mmol/L inclusive) on Day 29 (Visit 7) without rescue treatment for 
hyperkalemia at any point during the randomized phase in the SZC versus placebo arm. 
Patients with missing sK+ will have these imputed as described in section 3.3.1. The number 
and percentage of subjects who achieved a response (Yes, No, Non-evaluable) will be 
summarized by randomized treatment group in the FAS. 
The occurrence will be compared between treatment groups in the FAS using a logistic 
regression model (excluding non-evaluable responses) including response as the dependent 
variable and randomized treatment as an independent factor, it will be tested using a two-sided 


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alpha = 0.05. The common odds ratio will be derived together with the two-sided 95% 
confidence interval. 
Documentation will be provided to check the underlying assumptions for the logistic 
regression model. Standardized residuals will be presented in a scatter plot by alphanumerical 
subject ID. Subjects with standardized residuals > 3.0 will be listed. Influential observations 
on the regression coefficients will be detected by calculating Cook’s D statistic (In SAS 
applied with proc reg with the plots=cooksd option) and presented in a diagnostic plot by 
alphanumerical subject ID. Subjects with Cook’s D statistic > 4/sqrt(n) will be listed. 
Estimand Attributes 
In line with ICH E9 (R1) addendum, 5 attributes (treatment, population, endpoint, intercurrent 
events, and population-level summary) have been specified to translate the primary and key 
secondary efficacy objectives into treatment effects that are to be estimated (estimands). 
Endpoint: 
 Hyperkalaemia response, defined as an observed sK+ within 3.5-5.0 mEq/L at Day 29 
(Visit 7) 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the randomized placebo-
controlled period (Composite variable strategy, i.e. considered to be non-response). 
 Use of rescue therapy for low bicarbonate at any point during the randomized placebo-
controlled period (Treatment policy strategy, i.e. regardless of the intercurrent event). 
 Death prior to Day 29 (Visit 7) (Composite variable strategy, i.e. considered to be non-
response). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no sK+ or POCT K measurement at visit 6 or visit 7 (Hypothetical 
strategy, i.e. assume response is not evaluable). 
Population Level Summary: 


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 Odds ratio of the proportion of responders in the SZC treatment group compared to the 
placebo group. 
4.2.7.2 
Primary Efficacy Analysis – Sensitivity Analyses 
Three sensitivity analyses will be pre-specified to be conducted for the primary efficacy 
endpoint. Upon review of the trial data, additional post-hoc or subgroup analyses may be 
performed. 
(i) 
Primary analysis as described above. In addition to randomized treatment, the 
originally specified logistic regression model would have included: race, gender, 
age at baseline (<65, ≥65), CKD stage at baseline (3, 4), diabetes status (Yes, No), 
POCT bicarbonate level at entry (16-18, 19-20), POCT type (i-STAT, Piccolo) and 
baseline use of RAASi therapy (Yes, No) as independent factors. Due to the early 
termination of the study only POCT type will be included as an independent factor. 
(ii) 
Primary analysis as described above but conducted in the PPS. 
(iii) 
The intercurrent event strategy will be altered to describe the treatment effect in a 
COVID-19 pandemic-free world. 
Intercurrent Event Strategy: 
 Discontinuation of treatment not related to the COVID-19 pandemic 
(Treatment policy strategy, i.e. regardless of the intercurrent event). 
 Discontinuation of treatment related to the COVID-19 pandemic (Hypothetical 
strategy, i.e. assume response is missing). 
 Use of rescue therapy for hyperkalaemia at any point during the randomized-
withdrawal period (Composite variable strategy, i.e. considered to be non-
response). 
 Use of rescue therapy for low bicarbonate at any point during the randomized 
placebo-controlled period (Treatment policy strategy, i.e. regardless of the 
intercurrent event). 
 Death prior to Day 29 (Visit 7) not related to the COVID-19 pandemic 
(Composite variable strategy, i.e. considered to be non-response). 
 Death prior to Day 29 (Visit 7) related to the COVID-19 pandemic 
(Hypothetical strategy, i.e. considered to be non-response). 
 Subject lost to follow-up prior to Day 29 (Visit 7) irrespective of relationship to 
COVID-19 pandemic (Hypothetical strategy, i.e. assume response is not 
evaluable). 
 Subject with no sK+ or POCT K measurement at visit 6 or visit 7 irrespective 
of relationship to COVID-19 pandemic (Hypothetical strategy, i.e. assume 
response is not evaluable). 


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4.2.7.3 
Secondary Efficacy Analyses 
1 
Mean change in serum bicarbonate from baseline (Day 1) to Day 29 (Visit 7) in SZC 
versus placebo arm. 
Serum bicarbonate will be summarized and listed in the FAS using the visits of Baseline (Visit 
1), randomization (Visit 3) and Day 29 (Visit 7). Patients with missing serum bicarbonate 
values at visit 7 will have these imputed with serum bicarbonate values from visit 6 if 
available, as described in section 3.3.2. The mean change in serum bicarbonate from baseline 
(Day 1) will be analyzed using analysis of covariance (ANCOVA) analyses at the significance 
level 5% (2-sided), with randomized treatment as main effect and baseline bicarbonate as 
covariate. For patients needing rescue treatment for low bicarbonate, the last value of the 
POCT bicarbonate during the randomized period prior to rescue treatment will be analyzed. 
The analysis will be based on the FAS. 
Documentation will be provided on the underlying assumptions for the ANCOVA model. This 
will include a check that the residuals are approximately normally distributed by plotting a 
histogram of the residuals for the model as well as a Shapiro-Wilk test which will reject the 
null hypothesis that the residuals are normally distributed if p<0.05. Secondly, the 
homogeneity of variance will be visually checked through an inspection of a plot of residuals 
versus predicted values from the model. Finally, the homogeneity of slopes will be determined 
by conducting an ANCOVA analysis where the dependent variable is Day 29 (Visit 7) serum 
bicarbonate and the independent variables are randomized treatment group, baseline serum 
bicarbonate and an interaction term between randomized treatment group and baseline serum 
bicarbonate. If p>0.05 for the interaction term, then we will accept the homogeneity of the 
treatment slopes. 
Estimand Attributes 
Endpoint: 
 Change in serum bicarbonate at Day 29 (Visit 7) from baseline 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (Treatment policy strategy, i.e. regardless of the intercurrent event). 


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 Use of rescue therapy for low bicarbonate at any point during the randomized 
controlled period (While on treatment strategy, e.g. last observation carried forward). 
 Death prior to Day 29 (Visit 7) (While on treatment strategy, e.g. last observation 
carried forward). 
 POCT bicarbonate measurement unavailable for Visits 6 and 7 (Hypothetical strategy, 
assume response is missing). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, assume 
response is missing). 
Population Level Summary: 
 Least squares mean estimate in the SZC treatment group compared to the placebo 
group. 
2 
Occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥2 mmol/L 
on Day 29 (Visit 7) from baseline without need for rescue treatment for low bicarbonate 
in SZC versus placebo arm. 
For secondary efficacy endpoints #2 - #7 the number and percentage of subjects with the 
endpoint (Yes, No, Non-evaluable) will be summarized by randomized treatment group in the 
FAS. Patients with missing sK+ or serum bicarbonate values at visit 7 will have these imputed 
as described in sections 3.3.1 and 3.3.1. The occurrence of each secondary efficacy endpoint 
will be compared between treatment groups in the FAS using a logistic regression model 
including the binary response endpoint as the dependent variable and randomized treatment as 
an independent factor, it will be formally tested using a two-sided alpha = 0.05 if the 
hierarchical testing strategy supports conducting a formal hypothesis test. The common odds 
ratio will be derived together with the two-sided 95% confidence interval. 
For each secondary efficacy endpoint #2 - #7, documentation will be provided to check the 
underlying assumptions for the logistic regression model. Standardized residuals will be 
presented in a scatter plot by alphanumerical subject ID. Subjects with standardized residuals 
> 3.0 will be listed. 
Endpoint: 
 Serum bicarbonate response, defined as an increase from baseline in serum 
bicarbonate value ≥2 mmol/L at Day 29 (Visit 7) 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 


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 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (Treatment policy strategy, i.e. regardless of the intercurrent event). 
 Use of rescue therapy for low bicarbonate at any point during the randomized 
controlled period (While on treatment strategy, e.g. last observation carried forward). 
 Death prior to Day 29 (Visit 7) (Composite variable strategy, i.e. considered to be non-
response). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no POCT or central laboratory bicarbonate measurements at visit 6 or 
visit 7 (Hypothetical strategy, i.e. assume response is not evaluable). 
Population Level Summary: 
 Odds ratio of the proportion of responders in the SZC treatment group compared to the 
placebo group. 
3 
Occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥3 mmol/L 
on Day 29 (Visit 7) from baseline without need for rescue treatment for low bicarbonate 
in SZC versus placebo group. 
Endpoint: 
 Serum bicarbonate response, defined as an increase in serum bicarbonate value ≥3 
mmol/L at Day 29 (Visit 7) from baseline 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (Treatment policy strategy, i.e. regardless of the intercurrent event). 
 Use of rescue therapy for low bicarbonate at any point during the randomized 
controlled period (While on treatment strategy, e.g. last observation carried forward). 
 Death prior to Day 29 (Visit 7) (Composite variable strategy, i.e. considered to be non-
response). 


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 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no POCT or central laboratory bicarbonate measurements at visit 6 or 
visit 7 (Hypothetical strategy, i.e. assume response is not evaluable). 
Population Level Summary: 
 Odds ratio of the proportion of responders in the SZC treatment group compared to the 
placebo group. 
4 
Occurrence (yes/no) of patients having a normal sK+ (between 3.5 and 5.0 mmol/L 
inclusive) on Day 29 (Visit 7) and an increase in serum bicarbonate of ≥3 mmol/L on Day 
29 (Visit 7) from baseline without need for rescue treatment for hyperkalemia or low 
bicarbonate. 
Endpoint: 
 Hyperkalaemia response, defined as an observed sK+ within 3.5-5.0 mEq/L at Day 29 
(Visit 7) and serum bicarbonate response, defined as an increase in serum bicarbonate 
value of ≥3 mmol/L at Day 29 (Visit 7) from baseline. 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (While on treatment strategy, e.g. last observation carried forward). 
 Use of rescue therapy for low bicarbonate at any point during the randomized 
controlled period (While on treatment strategy, e.g. last observation carried forward). 
 Death prior to Day 29 (Visit 7) (Composite variable strategy, i.e. considered to be non-
response). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no sK+ or POCT K measurement at visit 6 or visit 7 (Hypothetical 
strategy, i.e. assume response is not evaluable). 
 Subject with no POCT or central laboratory bicarbonate measurements at visit 6 or 
visit 7 (Hypothetical strategy, i.e. assume response is not evaluable). 


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Population Level Summary: 
 Odds ratio of the proportion of responders in the SZC treatment group compared to the 
placebo group. 
5 
Occurrence (yes/no) of patients having serum bicarbonate ≥22 mmol/L on Day 29 (Visit 
7) without need for rescue treatment for low bicarbonate in SZC versus placebo group 
Endpoint: 
 Serum bicarbonate response, defined as a serum bicarbonate value of ≥22 mmol/L at 
Day 29 (Visit 7) 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (Treatment policy strategy, i.e. regardless of the intercurrent event). 
 Use of rescue therapy for low bicarbonate at any point during the randomized 
controlled period (While on treatment strategy, e.g. last observation carried forward). 
 Death prior t Day 29 (Visit 7) (Composite variable strategy, i.e. considered to be non-
response). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no POCT or central laboratory bicarbonate measurements at visit 6 or 
visit 7 (Hypothetical strategy, i.e. assume response is not evaluable). 
Population Level Summary: 
 Odds ratio of the proportion of responders in the SZC treatment group compared to the 
placebo group. 
6 
Occurrence (yes/no) of patients having a normal sK+ (between 3.5 and 5.0 mmol/L 
inclusive) on Day 29 (Visit 7) and a serum bicarbonate of ≥22 mmol/L on Day 29 (Visit 7) 
without need for rescue treatment for low bicarbonate or hyperkalemia 
Endpoint: 


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 Hyperkalaemia response, defined as an observed sK+ within 3.5-5.0 mEq/L at Day 29 
(Visit 7) and serum bicarbonate response, defined as a serum bicarbonate value of ≥22 
mmol/L at Day 29 (Visit 7). 
Population: 
 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (While on treatment strategy, e.g. last observation carried forward). 
 Use of rescue therapy for low bicarbonate at any point during the randomized 
controlled period (While on treatment strategy, e.g. last observation carried forward). 
 Death prior to Day 29 (Visit 7) (Composite variable strategy, i.e. considered to be non-
response). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no sK+ or POCT K measurement at visit 6 or visit 7 (Hypothetical 
strategy, i.e. assume response is not evaluable). 
 Subject with no POCT or central laboratory bicarbonate measurements at visit 6 or 
visit 7 (Hypothetical strategy, i.e. assume response is not evaluable). 
Population Level Summary: 
 Odds ratio of the proportion of responders in the SZC treatment group compared to the 
placebo group. 
7 
Occurrence (yes/no) of patients needing rescue treatment for low bicarbonate (serum 
bicarbonate from POCT ≤15 mmol/L) during the randomized phase between SZC and 
placebo. 
Endpoint: 
 Use of rescue treatment for low bicarbonate, where low bicarbonate is defined as a 
serum bicarbonate value of ≤15 mmol/L during the randomized placebo-controlled 
period 
Population: 


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 All subjects who achieve normokalemia at the end of the open-label correction phase, 
meet inclusion/exclusion criteria and are randomized 
Treatment: 
 SZC or Placebo. Patients with sK+ ≥ 6.0 mmol/L will be managed with rescue therapy 
employing local standard of care. 
Intercurrent Event Strategy: 
 Discontinuation of treatment (Treatment policy strategy, i.e. regardless of the 
intercurrent event) 
 Use of rescue therapy for hyperkalaemia at any point during the placebo-controlled 
period (Treatment policy strategy, i.e. regardless of the intercurrent event). 
 Death prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume response is not 
evaluable). 
 Subject lost to follow-up prior to Day 29 (Visit 7) (Hypothetical strategy, i.e. assume 
response is not evaluable). 
 Subject with no POCT or central laboratory bicarbonate measurements at visit 6 or 
visit 7 (Hypothetical strategy, i.e. assume response is not evaluable). 
Population Level Summary: 
 Odds ratio of the proportion with rescue treatment for low bicarbonate in the SZC 
treatment group compared to the placebo group. 
4.2.7.4 
Secondary Efficacy Analysis – Sensitivity Analyses 
Two sensitivity analyses will be conducted for secondary efficacy endpoint #1: 
(i) Analysis as described for secondary endpoint #1 using PPS 
(ii) Analysis as described above but with full imputation of bicarbonate using central 
laboratory measurements, as described in section 3.3.2, is conducted before the 
response is assumed to be missing. In addition, the ANCOVA model will include 
a binary variable to indicate if the dependent variable is  central laboratory 
measurement. 
Two sensitivity analyses will be conducted for each of the secondary efficacy endpoints #2-
#7. 
 Principal secondary analysis as described where the logistic regression model will 
include: race, gender, age at baseline (<65, ≥65), CKD stage at baseline (3, 4), diabetes 
status at baseline (Yes, No), POCT bicarbonate level at entry (16-18, 19-20), POCT 
type (i-Stat, Piccolo) and baseline use of RAASi therapy (Yes, No) as independent 
factors. 
 Principal secondary analysis as described but conducted in the PPS. 


Statistical A nal ysis Pla n  
Astra Ze neca  
D 9 4 8 0 C 0 0 0 2 2  - E xter nal 4. 0  
0 1/ D E C/ 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 6  of 4 2  
 
 
D ue t o t he e arly ter mi n ati o n of t he tri al, t he se nsitivity a n alyses descri be d a b ove will n ot be 
c o n d ucte d d ue t o a n i ns ufficie nt s a m ple size.  
C CI
C CI


Statistical A nal ysis Pla n  
Astra Ze neca  
D 9 4 8 0 C 0 0 0 2 2  - E xter nal 4. 0  
0 1/ D E C / 2 0 2 2 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 7  of 4 2  
 
 
4. 2. 8  
S afet y  
4. 2. 8. 1  
A d verse E ve nts  
A n o verall s u m mar y ta bl e of t he n u m ber of s u bjects e x perie nci n g eac h cate g or y of A Es will 
be pr o d uce d usi n g t he S S O a n d S S R. A nal yses usi n g t he S S O will be  restri cte d t o A Es w hic h 
occ urre d d uri n g t he o pe n -la bel c orrecti o n peri o d a n d will be prese nte d o verall. A nal ys es usi n g 
t he S S R will i ncl u de A Es w hic h occ urre d d uri n g t he ra n d o mize d place b o-c o ntr olle d peri o d 
a n d will be prese nt e d b y treat me nt gr o u p recei v e d d uri n g t he ra n d o mize d place b o -c o ntr olle d 
peri o d a n d o verall.  
A n y A E occ urri n g wit hi n t he defi ne d 7 -d a y f oll o w -u p peri o d aft er disc o nti n uati o n of I P will 
be i ncl u de d i n t he A E s u m maries. Treat me nt e mer ge nt a d verse e v e nts ( T E A Es) occ urri n g 
pri or t o first d ose of I P (i.e. bef ore st u d y da y 1) w hic h s u bse q ue ntl y w orse n i n se verit y 
f oll o wi n g d osi n g will be prese nte d i n t he s u m mar y ta bles. 
A n o ver vie w t a ble will s u m mariz e t he n u m ber a n d perce nt a ge of s u bjects wit h at least o ne of 
t he f oll o wi n g A Es, w here patie nts wit h m ore t ha n o ne A E i n a partic ular cate g or y are c o u nte d 
o nl y o nce i n t hat cate g or y, as well as t he a bs ol ute c o u nts of n u m ber of A Es. F or t he o v erall 
s u m mar y of s u bjects wit h a n y A Es, i n t he safet y s et ra n d o mize d a nal ysis gr o u p, t he e ve nt r ate 
will be dis pla ye d. T his will be calc ulate d as t h e N u m ber of s u bjects wit h A Es di vi de d b y t he 
t otal n u m ber of da ys at ris k f or A Es acr oss all s u bjects i n gi ve n gr o u p, m ulti plie d b y 3 6 5. 2 5 
m ulti plie d b y 1 0 0.  
 
A n y A Es  
 
A n y A Es assesse d b y i n v esti gat or as p ossi bl y relat e d t o treat me nt  
 
A n y A Es wit h o utc o me of deat h  
 
A n y S A Es (i n cl u di n g e v e nts wit h o utc o me of deat h)  
 
A n y S A Es le a di n g t o treat me nt disc o nti n uati o n  
 
A n y A Es lea di n g t o treat me nt disc o nti n uati o n  
 
A n y A Es lea di n g t o d ose re d ucti o n of st u d y treat me nt  
 
A n y A Es lea di n g t o d ose i nterr u pti o n of st u d y tr eat me nt 
C CI


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 
Any AEs leading to study discontinuation 
 
The number and percentage of subjects reporting each AE will be summarized by system 
organ class (SOC) and preferred term (PT). Tables will be sorted by international order for 
SOC and PTs will be sorted alphabetically. The following summaries will be produced using 
the SSO and SSR: 
 
AEs by SOC and PT; 
 
Most common AEs (>5% in any treatment group) by SOC and PT; 
 
AEs assessed by investigator as possibly related to treatment, by SOC and PT; 
 
AEs by relationship to treatment, by SOC and PT; 
 
AEs by maximum intensity, by SOC and PT; 
 
AEs assessed by investigator as possibly related to treatment, by maximum intensity, 
SOC and PT; 
 
AEs leading to treatment discontinuation, by SOC and PT; 
 
AEs assessed by investigator as possibly related to treatment leading to treatment 
discontinuation, by SOC and PT; 
 
SAEs, by SOC and PT; 
 
SAEs related to treatment, by SOC and PT; 
 
AEs leading to death, by SOC and PT; 
 
All AE data will be listed appropriately for all subjects including information on AE duration, 
intensity, seriousness, action taken, outcome, relationship as assessed by investigator, timing 
of onset of AE in relation to the first dose of study treatment in the open-label correction 
period, study treatment at the time of event. 
4.2.8.2 
Deaths 
A summary of deaths will be provided with number and percentage of subjects categorized as: 
 
Number of subjects with any AE with outcome = death 
 
AEs related to disease under investigation and with AE outcome of death 
 
AEs with outcome of death only (AE start date falling > 21 days after last treatment dose) 
 
Deaths > 21 days after last treatment dose, unrelated to AE or disease under investigation 
 
Deaths > 21 days after last treatment dose, AE related to disease under investigation and 
with AE outcome of death 
All deaths will be listed. 


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4.2.8.3 
Laboratory Data 
Laboratory data (clinical chemistry, haematology and urinalysis) will be summarized and 
listed. Laboratory data outside the reference ranges will be indicated in the listings. If a 
subject has multiple results for a particular test at a particular time point, the first non-missing 
scheduled value will be used for the summary. System international (SI) units will be reported 
for all analytes. 
Laboratory data absolute and change from baseline values for continuous chemistry, 
haematology and urinalysis parameters will be summarized at each scheduled assessment 
time. Separate tables will be provided for the SSO, restricted to visits during the open-label 
period and presented overall and for the SSR which will include all visits and be presented by 
treatment received during the randomized placebo-controlled period. 
Shift tables will be provided for select tests, where shift from baseline to the maximum value 
will be summarized. These will be provided separately for the SSO which will be limited to 
visits during the open-label period and the SSR which will summarize the worst overall value 
across all visits. Shift tables for laboratory values by worst common toxicity criteria (CTC) 
grade will be produced for all parameters with grading. These will be provided separately for 
the SSO which will be limited to visits during the open-label period and be presented overall 
and the SSR which will summarize the worst CTC grade across all visits and be presented by 
treatment received during the randomized-withdrawal period. 
In addition, the number and percentage of subjects with markedly abnormal clinical laboratory 
values will be summarized for each parameter by timepoint. These will be provided separately 
for the SSO, which will be limited to visits during the open-label period and be presented 
overall, and the SSR, which will summarize abnormal clinical laboratory values across all 
visits and be presented by treatment received during the randomized placebo-controlled 
period. 
4.2.8.4 
Vital Signs 
Vital sign values will be summarized and listed. Vital sign data absolute and change from 
baseline will be summarized at each scheduled timepoint. The continuous vital sign 
parameters will be summarized with descriptive statistics. If a subject has multiple results for 
a particular test at a particular time point, the first non-missing scheduled value will be used 
for the summary. These will be provided for the SSO, limited to visits during the open-label 
correction period and presented overall, and the SSR which will include all visits with 
scheduled vital sign assessment and be presented by treatment received during the randomized 
placebo-controlled period. 
4.2.8.5 
Electrocardiograms 
ECG data will be summarized and listed. Absolute and change from baseline in ECG 
parameters will be summarized at each scheduled timepoint. The continuous ECG parameters 


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will be summarized with descriptive statistics. If a subject has multiple results for a particular 
test at a particular time point, the first non-missing scheduled value will be used for the 
summary. These will be provided for the SSO, limited to visits during the open-label 
correction period and presented overall, and the SSR which will include all visits with ECG 
assessments and be presented by treatment received during the randomized placebo-controlled 
period. 
4.2.8.6 
Physical Examination 
Physical examination assessments where a new or worsening abnormality is observed will be 
reported as an AE.  
Height (Screening visit only), weight and BMI will be summarized overall for the SSO, 
restricted to visits during the open-label correction period, and by treatment received during 
the randomized placebo-controlled period using the SSR. 
4.2.8.7 
Exposure 
Exposure (in days) to IP i.e. total amount of study drug will be summarized overall for the 
SSO and by treatment group for the SSR. 
Actual and total exposure (days) will be summarized by the following: mean, standard 
deviation, minimum, maximum, median and number of observations. 
The dosage will be calculated for the open-label correction period and randomized placebo-
controlled periods respectively: 
The total cumulative dose received (g)/Number of days receiving study drug (i.e. excluding 
dose interruptions). 
SZC/Placebo will be summarized by the following: range, mean, range of mean doses. Total 
cumulative dose received (g) will be summarized by mean and range. The range of the 
maximum dose received (g/day) will be summarized. For each study visit period (e.g. from 
visit 1 to visit 2, visit 2 to visit 3) the total number (%) of subjects who received dose will be 
presented and the prescribed daily dose. 
4.2.8.8 
Pregnancy Test 
Serum pregnancy and urine pregnancy test results will be listed only using the SSO analysis 
set. 
5 
INTERIM ANALYSES 
An informal interim analysis for the purpose of Sample Size Re-estimation (SSR) will be 
conducted when approximately 68 person-months of follow-up time of the total 136 person-
months have occurred (an information time of 0.5) to adjust for potential deviations from the 


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pre-specified expected effect sizes based on updated knowledge provided by the observed 
effect sizes which inform the key secondary efficacy endpoint (occurrence of patients having 
an increase in serum bicarbonate of ≥3 mmol/L from baseline (Day 1) to Day 29 without need 
for rescue treatment for metabolic acidosis). 
This analysis will estimate the true effect sizes and re-estimate the additional numbers of 
subjects that need to be accrued to achieve sufficient power based on this new information. At 
sponsor’s discretion, enrolment may be extended to accrue this number of additional subjects 
if it is determined that this can be achieved in a cost-effective manner. The analysis will be 
unblinded to the party who executes it but blinded to the study team. 
The SSR will follow the approach outlined in Herson and Wittes (1993). Once 68 person-
months of follow-up time have elapsed an analysis will be conducted by a separate unblinded 
team. The current proportion of subjects in the placebo arm for secondary endpoint #3 “The 
occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥3 mmol/L on Day 
29 (Visit 7) from baseline without need for rescue treatment for low” will be estimated as 𝜃𝐶
̂. 
The sample size, N, required to detect a difference between: 
𝜃𝐸= 𝜃𝐶
̂ versus 𝜃𝐸= min( (𝜃𝐶
̂ + .215, 1) 
will be calculated using nQuery to determine the suggested sample size requires adjustment 
and a report provided to the sponsor detailing this calculation. Nmin, the minimum sample size 
for the trial will be set at the original sample size calculation of 136. Based on estimates of the 
total sample size needed to detect a difference of 0.215 with 80% power for varying 
proportions for the control arm (𝜃𝐶
̂), a maximum sample size of 168 is required when 𝜃𝐶
̂=0.4, 
so Nmax, the maximum proposed sample size for the trial will be set at 168. The sponsor will 
have oversight and will make the decision whether an increase in sample size is economically 
and scientifically viable. 
However, due to the early termination of the study the interim analysis will not be conducted. 
6 
CHANGES OF ANALYSIS FROM PROTOCOL 
Due to the early termination of this study all sensitivity analyses described in section 4.2.7.4, 
subgroup analyses described in section 4.2.7.5 and the interim analysis described in section 5 
will not be conducted due to insufficient sample size. 
7 
REFERENCES 
FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic: Guidance for Industry, Investigators, and Institutional Review Boards. 
https://www.fda.gov/media/136238/download. Accessed 25 May 2021. 


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Herson, J. and Wittes, J., 1993. The use of interim analysis for sample size adjustment. Drug 
Information Journal, 27(3), pp.753-760. 
8 
APPENDIX 
Not applicable. 
 


SI G N A T U R E P A G E
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electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 9 4 8 0c 0 0 0 2 2-sa p-e d- 4
D oc u me nt Title:
Statistical A nal ysis Pla n E diti o n 4
D oc u me nt I D:
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Versi o n L a bel:
4. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
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0 5- Dec- 2 0 2 2 1 4: 4 3 U T C
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N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D