An Open-Label, Randomised, Phase 4 Study of Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge in Participants With Chronic Kidney Disease Treated for Hyperkalaemia
Phase: PHASE4
Conditions: Hyperkalaemia, Chronic Kidney Disease
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1  of 1 1 2  
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  
St u d y C o de  
D 9 4 8 0 C 0 0 0 2 3  
Ve r s i o n  
4 . 0 
Date  
1 6  Oct 2 0 2 3  
A n O pe n -L a bel, R a n d o mi se d, P h ase 4 St u d y of C o nti n ui n g 
S o di u m Zirc o ni u m C ycl osilic ate ( S Z C) after Disc h ar ge i n 
P artici p a nts wit h C hr o nic Ki d ne y Dise ase tre ate d f o r 
H y per k al ae mi a  
S p o ns or N a me: Astra Z e neca A B  
Le g al Re gistere d A d dress: 1 5 1 8 5 S ö dertälje, S we de n  
Re g ul at or y A g e nc y I de ntifier N u m ber(s): 2 0 2 1- 0 0 3 5 2 7- 1 4  
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 h e 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 
discl ose d a n d/ or p u blis he d acc or di n g t o t he Astra Z e neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o m plia nce wit h pre v aili n g la ws a n d re g ul ati o ns. 
Pr ot oc ol N u m ber:  4. 0 
A me n d me nt N u m ber:  3. 0  
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); bra n d na m e L O K E L M A®  
St u d y P h ase:  4 
S h ort Title: C o nti n ui n g S o di u m Zirc o ni u m C ycl osilicate ( S Z C) after dis c h ar ge st u d y 
Acr o n y m:  C O N TI N UI T Y  
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. 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol  - 4. 0 
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2  of 1 1 2  
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  
D O C U M E N T HI S T O R Y  
D oc u m e nt  
D ate  
A me n d me nt 3  
1 6 Oct 2 0 2 3  
A me n d me nt 2  
0 7 J ul 2 0 2 2 
A me n d me nt 1  
0 2 A u g  2 0 2 1  
Ori gi nal Pr ot oc ol  
1 2  J ul 2 0 2 1 
A me n d me nt 3. 0: 1 6 Oct o ber 2 0 2 3 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n. 
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 1. 1  S y n o psis  
Secti o n 2. 1 St u d y Rati o nale  
Secti o n 3 O bjecti ves a n d 
E n d p oi nts  
Secti o n 4. 2 Scie ntific Rati o nale f or 
St u d y Desi g n  
Secti o n 8. 1. 2 Mai n Sec o n dar y 
E n d p oi nts  
Secti o n 9. 1 Statistical H y p ot hesis  
9. 2 Sa m ple Size Deter mi nati o n  
9. 2. 2 Mai n Sec o n dar y E n d p oi nt  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
I n t he defi niti o n of t he first sec o n dar y 
o bjecti ve a n d e n d p oi nt, “ti me t o first 
occ urre nce of h os pital a d missi o ns or 
E D visits wit h H K as a c o ntri b uti n g 
fact or” was c ha n ge d t o “ occ urre nce of 
all-ca use h os pital  a d missi o ns, or  E D 
visits wit h H K as a c o ntri b uti n g 
fact or”. I n relati o n t o t his c ha n ge , a 
se nsiti vit y a nal ysis wit h h os pital 
a d missi o n wit h H K as a c o ntri b uti n g 
fact or has bee n a d de d as well as 2 
sec o n dar y o bjecti ves a n d e n d p oi nts.  
T o e x pa n d t he defi niti o n of t he 
mai n sec o n dar y e n d p oi nt t o 
e nc o m pass a wi der ra n ge of 
h os pital a d missi o ns t o facilitate a 
lar ger, cli nicall y mea ni n gf ul 
effect size f or detecti o n i n or der  
t o re d uce sa m ple size. 
Secti o n 1. 1  S y n o psis  
Secti o n 4. 1 O verall Desi g n  
Secti o n 9. 2. 2 Mai n Sec o n dar y 
E n d p oi nt  
Secti o n 1 1 Refere nces  
Sa m ple size was re -calc ulate d base d 
o n t he ne w defi niti o n of t he sec o n dar y 
e n d p oi nt. 
T o ali g n wit h c ha n ges i n t he mai n 
sec o n dar y e n d p oi nt. 
Secti o n 1. 1  S y n o psis  
Secti o n 5. 1 I ncl usi o n Criteria  
C ha n ge i n i ncl usi o n criteri o n # 3 t o 
all o w e nr ol me nt of partici pa nts wit h 
a n y c hr o nic ki d ne y disease ( C K D ) 
sta ge or  a hi g her esti mate d gl o mer ular 
filtrati o n rate (e G F R). 
Alt h o u g h H K is less c o m m o n i n 
earl y sta ges of C K D, t hese 
patie nts ma y alrea d y ha ve ha d 
H K e pis o des, ha ve bee n usi n g 
R A A SI me dicati o ns a n d are at 
hi g h ris k of H K rec urre nce. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 1 1 2  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 1. 1  S y n o psis  
Secti o n 4. 1 O verall Desi g n  
G ui da nce o n so di u m zirc o ni u m 
c ycl osilicate (S Z C ) i nitiati o n at 
baseli ne ha ve bee n m o difie d . 
At t he ti me of e nr ol me nt, 
par tici pa nts are bei n g treate d f or 
H K & t heref ore s witc h t o S Z C  is 
wit hi n la bel . 
Secti o n 1. 1 S y n o psis  
Secti o n 1. 2 Sc he ma  
Secti o n 1. 3 Sc he d ule of Acti vities  
Clarificati o ns o n visit wi n d o ws a n d 
ot her mi n or e dit orial c ha n ges.  
Clarificati o n e dit . 
Secti o n 1. 3 Sc he d ule of Acti vities  
Secti o n 2. 1 St u d y Rati o nale  
Re ni n -a n gi ote nsi n -al d oster o ne s yste m 
i n hi bit or d ose 
c ha n ges/ disc o nti n uati o ns has bee n 
a d de d i n t he list of data t o be c ollecte d 
o n h os pital a d missi o n a n d E D visit.  
Clarificati o n e dit.  
Secti o n  1. 3 Sc he d ule of Acti vities  
A d de d assess me nt of l ocal la b orat or y 
K +  at f oll o w-u p p hase  
Clarificati o n e dit.  
Secti o n 2. 3. 1 Ris k Assess me nt  
C o nsti pati o n has bee n a d de d as 
p ote ntial ris k of cli nical si g nifica nce . 
T o ali g n wit h u p date d S Z C 
specific safet y re q uire me nts. 
Secti o n 1. 1 S y n o psis  
Secti o n 1. 2 Sc he ma  
Secti o n 5. 1 I ncl usi o n Criteria  
Secti o n 6. 1 Scree ni n g a n d 
I n patie nt P hase 
C ha n ge i n i ncl usi o n criteri o n # 4 t o 
clarif y t hat patie nts treate d f or c urre nt 
e pis o de of H K ca n be N K at ti me of 
e nr ol me nt 
Clarificati o n e dit.  
Secti o n 5. 2 E xcl usi o n Criteria  
E xcl usi o n criteri o n # 1 is si m plifie d t o 
e xcl u de a n y partici pa nt wit h a 
h os pitalisati o n f or a n ac ute 
car di o vasc ular e ve nt wit hi n 1 2 wee ks 
pri or t o scree ni n g.  
T he rati o nale f or t his e xcl usi o n 
criteria is t o a v oi d patie nts at hi g h 
ris k of re-a d missi o n f or reas o ns 
u nrelate d t o  H K, t heref ore 
w or di n g was si m plifie d.  
Secti o n 5. 2 E xcl usi o n Criteria  
W or di n g of e xcl usi o n criteri o n # 5 is 
si m plifie d. 
Clarificati o n e dit . 
Secti o n 5. 2 E xcl usi o n Criteria  
E xcl usi o n criteria # 6 a n d 1 0 are 
p o ole d i n a si n gle e xcl usi o n criteri o n  
( # 1 0). 
Clarificati o n e dit.  
Secti o n 5. 2 E xcl usi o n Criteria  
E xcl usi o n criteri o n  # 1 2 is delete d t o 
a v oi d d u plicati o n wit h ne w e xcl usi o n 
criteri o n # 5. 
Clarificati o n e dit . 
Secti o n 1. 1 S y n o psis  
Secti o n 1. 2 Sc he ma  
Secti o n 4. 2 Scie ntific St u d y 
Rati o nale  
E xcl usi o n criteri o n  # 1 3 is m o difie d t o 
s pecif y w hic h  K-bi n ders are 
pr o hi bite d bef ore c urre nt E D 
visit/ h os pitalisati o n prece di n g 
e nr ol me nt. It is als o s pecifie d t hat 
Clarificati o n e dit . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4  of 1 1 2  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n 5. 2 E xcl usi o n Criteria  
i nitiati o n of S Z C or patir o mer d uri n g 
t he c urre nt E D visit/h os pitalis ati o n 
prece di n g e nr ol me nt is all o we d . 
Secti o n 5. 2 E xcl usi o n Criteria  
E xcl usi o n criteri o n  # 1 4 is m o difie d t o 
all o w e mer ge nc y/ u nsc he d ule d 
hae m o dial ysis t o treat H K d uri n g t he 
c urre nt E D visit/ h os pitalisati o n 
prece di n g e nr ol me nt . 
Clarificati o n e dit . 
Secti o n 5. 2 E xcl usi o n Criteria  
E xcl usi o n criteri o n # 1 5 is m o difie d t o 
re m o ve n ot e re gar di n g partici pa nts 
vacci nate d wit h C O VI D -1 9 vacci ne 
w hile still u n der e mer ge nc y use 
utilizati o n.  
C o nsiste nc y wit h c urre nt 
sta n dar ds. 
Secti o n 5. 2 E xcl usi o n Criteria  
E xcl usi o n criteri o n # 2 0  is u p date d t o 
a d d t he e xcl usi o n of W O C B P w h o are 
n ot sta ble o n t he c o ntrace pti ve met h o d 
f or t he last m o nt h a n d t o clarif y 
c o ntrace pti o n m ust be use d u ntil 7 
da ys after last d ose  
Clarificati o n e dit  
Secti o n 8. 3. 9 Me dicati o n Err or, 
Dr u g A b use, a n d Dr u g Mis use  
A p pe n di x B 4  
T he w h ole secti o n has bee n m o difie d 
t o i ncl u de dr u g a b use a n d dr u g mis use 
secti o ns. 
U p date re q uire d d ue t o  E U 
“Detaile d g ui da nce o n t he 
c ollecti o n, verificati o n a n d 
prese ntati o n of a d verse 
e ve nt/reacti o n re p orts arisi n g 
fr o m cli nical trials o n me dici nal 
pr o d ucts f or h u ma n use (‘ C T -3’) ” 
a n d  Astra Ze neca c or p orate safet y 
C A P A . 
Secti o n 9. 4. 4 Safet y  
Re d uce d ti me wi n d o w of A E 
occ urre nce p ost -last d ose fr o m 1 4 
da ys t o 7 da ys f or a n e ve nt t o be 
c o nsi dere d treat me nt e mer ge nt.  
T o c orrect a n err or i n t he pr ot oc ol 
a n d t o ali g n wit h t he f oll o w -u p 
vis it 7 da ys after E O T. 
Secti o n 9. 5 I nteri m A nal yses  
T he pla n ne d i nteri m a nal ysis has bee n 
ca ncelle d. 
D ue t o decrease d sa m ple size, 
r u n ni n g a n i nteri m a nal ysis is n ot 
j ustifie d. 
A p pe n di x A 1  
A d de d s u b -hea di n g “ Re g ulat or y 
Re p orti n g Re q uire me nts f or Seri o us 
B reac hes”. 
U p date re q uire d t o c o m pl y wit h 
re g ulat or y re q uire me nt (e. g. E U 
C T R ) a n d gl o bal c o m pa n y 
re q uire me nt. 
A p pe n di x A 6  
U p date d i nf or mati o n a b o ut ti meli nes 
f or s u b missi o n of trial res ults 
s u m maries t o E U C TI S. 
U p date re q uire d t o c o m pl y wit h 
E U C T R . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 1 1 2  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
A p pe n di x A 7  
U p date d i nf or mati o n a b o ut rete nti o n 
ti meli nes of rec or ds a n d d oc u me nts t o 
2 5 years after st u d y arc hi vi n g or as 
re q uire d b y l ocal re g ulati o ns. 
U p date re q uire d t o c o m pl y wit h 
E U C T R  a n d gl o bal c o m pa n y 
re q uire me nt. 
T hr o u g h o ut  
H os pital a d missi o n has bee n re place d 
b y h os pitalisati o n prece di n g 
e nr ol me nt. 
Clarificati o n e dit.  
 
Mi n or e dit orial a n d d oc u me nt 
f or matti n g re visi o ns. 
Mi n or, t heref ore ha ve n ot bee n 
s u m marise d. 
 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6  of 1 1 2  
 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  ....................................... 2 
T A B L E O F C O N T E N T S  ........................................................................................................... 6 
LI S T O F FI G U R E S  ................................................................................................................... 8 
LI S T O F T A B L E S  ..................................................................................................................... 8 
LI S T O F A P P E N DI C E S  ............................................................................................................ 9 
1  
P R O T O C O L S U M M A R Y  .................................................................................... 1 0 
1. 1  
S y n o psis ................................................................................................................ 1 0  
1. 2  
Sc he ma  .................................................................................................................. 1 8 
1. 3  
Sc he d ule of Acti vities  ........................................................................................... 1 9 
2  
I N T R O D U C TI O N ................................................................................................ 2 3 
2. 1  
St u d y Rati o nale ..................................................................................................... 2 3  
2. 2  
Bac k gr o u n d ........................................................................................................... 2 3  
2. 3  
Be nefit/ Ris k Assess me nt  ...................................................................................... 2 5 
2. 3. 1  
Ris k Assess me nt  ................................................................................................... 2 5 
2. 3. 2  
Be nefit Assess me nt  ............................................................................................... 2 6 
2. 3. 3  
O verall Be nefit: Ris k C o ncl usi o n  ......................................................................... 2 7 
3  
O BJ E C TI V E S A N D E N D P OI N T S  ...................................................................... 2 7 
4  
S T U D Y D E SI G N  ................................................................................................. 4 2 
4. 1  
O verall Desi g n  ...................................................................................................... 4 2 
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  .................................................................. 4 3 
4. 2. 1  
Partici pa nt I n p ut i nt o Desi g n ................................................................................ 4 4  
4. 3  
J ustificati o n f or D ose ............................................................................................ 4 4 
4. 4  
E n d of St u d y Defi niti o n ........................................................................................ 4 5  
5  
S T U D Y P O P U L A TI O N  ....................................................................................... 4 5 
5. 1  
I ncl usi o n Criteria .................................................................................................. 4 5 
5. 2  
E xcl usi o n Criteria  ................................................................................................. 4 6 
5. 3  
Lifest yle C o nsi derati o ns ....................................................................................... 4 8  
5. 4  
Scree n Fail ures ...................................................................................................... 4 8 
6  
S T U D Y I N T E R V E N TI O N  ................................................................................... 4 8 
6. 1  
Scree ni n g a n d I n patie nt P hase  .............................................................................. 4 8 
6. 2  
O ut patie nt P hase ................................................................................................... 4 9  
6. 3  
St u d y I nter ve nti o ns A d mi nistere d  ........................................................................ 5 1 
6. 3. 1  
I n vesti gati o nal Pr o d ucts........................................................................................ 5 1 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7  of 1 1 2  
6. 4  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...................................................... 5 2  
6. 5  
Meas ures t o M i ni mise Bias: Ra n d o misati o n a n d Bli n di n g .................................. 5 2 
6. 6  
St u d y I nter ve nti o n C o m plia nce ............................................................................ 5 3  
6. 7  
C o nc o mita nt T hera p y  ........................................................................................... 5 3 
6. 7. 1  
Resc ue Me dici ne  ................................................................................................... 5 4 
6. 8  
D ose M o dificati o n ................................................................................................ 5 5  
6. 9  
I nter ve nti o n After t he E n d of t he St u d y ................................................................ 5 6 
7  
DI S C O N TI N U A TI O N  O F  S T U D Y I N T E R V E N TI O N  A N D  P A R TI CI P A N T  
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ............................................................. 5 6 
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................................. 5 6  
7. 1. 1  
Per ma ne nt Disc o nti n uati o n of St u d y I nter ve nti o n ............................................... 5 6  
7. 1. 2  
Te m p orar y Disc o nti n uati o n  .................................................................................. 5 7 
7. 2  
Partici pa nt Wit h dra w al fr o m t he St u d y  ................................................................ 5 7 
7. 3  
L ost t o F oll o w- u p ................................................................................................. 5 8  
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ................................................ 5 9 
8. 1  
Efficac y Assess me nts  ............................................................................................ 5 9 
8. 1. 1  
Pri mar y E n d p oi nt .................................................................................................. 5 9  
8. 1. 2  
Mai n Sec o n dar y E n d p oi nts ................................................................................... 6 0  
8. 1. 3  
A d diti o nal Efficac y Ass ess me nts  ......................................................................... 6 0 
8. 2  
Safet y Assess me nts  ............................................................................................... 6 0 
8. 2. 1  
P h ysical E xa mi nati o ns .......................................................................................... 6 0  
8. 2. 2  
Vital Si g ns  ............................................................................................................. 6 0 
8. 2. 3  
Electr ocar di o gra ms  ............................................................................................... 6 1 
8. 2. 4  
Cli nical Safet y La b orat or y Assess me nts  .............................................................. 6 1 
8. 2. 5  
Ot her Safet y Assess me nts  ..................................................................................... 6 3 
8. 3  
A d verse E v e nts a n d Seri o us A d vers e E ve nts  ....................................................... 6 3 
8. 3. 1  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E I nf or mati o n ................. 6 4  
8. 3. 2  
F oll o w- u p of A Es a n d S A Es ................................................................................. 6 4  
8. 3. 3  
Ca usalit y C ollecti o n .............................................................................................. 6 5 
8. 3. 4  
A d verse E v e nts Base d o n Si g ns a n d S y m pt o ms .................................................. 6 5  
8. 3. 5  
A d verse E v e nts Base d o n E xa mi nati o ns a n d Tests .............................................. 6 5  
8. 3. 6  
Re p orti n g of Seri o us A d verse E ve nts ................................................................... 6 6  
8. 3. 7  
Re p orti n g of A Es/ S A Es i n Relati o n t o C O VI D- 1 9 .............................................. 6 7  
8. 3. 8  
Pre g na nc y  ............................................................................................................. 6 7 
8. 3. 8. 1  
Mater nal E x p os ur e ................................................................................................ 6 7  
8. 3. 8. 2  
Pater nal E x p os ure ................................................................................................. 6 8  
8. 3. 9  
Me dicati o n Err or, Dr u g A b use, a n d Dr u g Mis use ................................................ 6 8  
8. 3. 9. 1  
Ti meli nes  .............................................................................................................. 6 8 
8. 3. 9. 2  
Me dicati o n Err or ................................................................................................... 6 8  
8. 3. 9. 3  
Dr u g A b us e  ........................................................................................................... 6 8 
8. 3. 9. 4  
Dr u g Mis use .......................................................................................................... 6 8 
8. 4  
O ver d ose ............................................................................................................... 6 9  
8. 5  
H u ma n Bi ol o gical Sa m ples  .................................................................................. 6 9 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8  of 1 1 2  
8. 5. 1  
P har mac o ki netics .................................................................................................. 6 9  
8. 5. 2  
I m m u n o ge nicit y Assess me nts ............................................................................... 6 9 
8. 5. 3  
P har mac o d y na mics  ............................................................................................... 6 9 
8. 6  
H u ma n Bi ol o gical Sa m ple Bi o mar kers  ................................................................ 6 9 
8. 7  
O pti o nal Ge n o mics I nitiati ve Sa m ple  ................................................................... 6 9 
8. 8  
Me dical Res o urce Utilisati o n a n d Healt h Ec o n o mi cs  .......................................... 6 9 
8. 8. 1  
Data S o urce  ........................................................................................................... 6 9 
8. 8. 2  
O utc o me varia bl es  ................................................................................................ 7 0 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................... 7 1 
9. 1  
Statistical H y p ot heses  ........................................................................................... 7 1 
9. 2  
Sa m ple Size Deter mi nati o n  .................................................................................. 7 1 
9. 2. 1  
Pri mar y E n d p oi nt .................................................................................................. 7 1  
9. 2. 2  
Mai n Sec o n dar y E n d p oi nt .................................................................................... 7 2  
9. 3  
P o p ulati o ns f or A nal yses  ...................................................................................... 7 2 
9. 4  
Statistical A nal yses  ............................................................................................... 7 3 
9. 4. 1  
Ge ner al C o nsi derati o ns ......................................................................................... 7 3  
9. 4. 2  
C O VI D - 1 9 C o nsi derati o ns ................................................................................... 7 5 
9. 4. 3  
Efficac y  ................................................................................................................. 7 5 
9. 4. 3. 1  
Pri mar y E n d p oi nts ................................................................................................ 7 5  
9. 4. 3. 2  
Sec o n dar y E n d p oi nts ............................................................................................ 7 6  
9. 4. 3. 3  
E x pl orat or y E n d p oi nts .......................................................................................... 8 0  
9. 4. 4  
Safet y  .................................................................................................................... 8 6 
9. 5  
I nteri m A nal ys es ................................................................................................... 8 7 
9. 6  
A dj u dicati o n C o m mittee  ....................................................................................... 8 7 
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  ............................................................................................ 8 8 
1 1  
R E F E R E N C E S  ................................................................................................... 1 1 0  
 
LI S T O F FI G U R E S  
Fi g ure 1  
St u d y Desi g n ............................................................................................... 1 8  
 
LI S T O F T A B L E S  
Ta ble  1 
Sc he d ule of A cti vities  ................................................................................. 1 9 
Ta ble 2  
Ris k Assess me nt  .......................................................................................... 2 6 
Ta ble 3   
O bjecti ves a n d E n d p oi nts ............................................................................ 2 8 
Ta ble 4   
D ose Titrati o n a n d Disc o nti n uati o n Criteria D uri n g t he O ut patie nt P hase . 4 9 
Ta ble 5   
I n v esti gati o nal Pr o d ucts .............................................................................. 5 1 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9  of 1 1 2  
Ta ble 6  
La b orat or y Safet y Varia bles  ....................................................................... 6 2 
Ta ble 7   
P o p ulati o ns f or A nal ysis ............................................................................. 7 3 
Ta ble 8   
A nal ysis Peri o ds .......................................................................................... 7 3 
 
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 nsi derati o ns .......................... 8 9 
A p pe n di x  B  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, E val u ati n g, 
F oll o w- u p, a n d Re p orti n g ........................................................................... 9 5  
A p pe n di x  C  
Ma na ge me nt of St u d y Pr oce d ures D uri n g t he C O VI D- 1 9 Pa n de mic ...... 1 0 1 
A p pe n di x  D  
Pr ot oc ol A me n d me nt Hist or y ................................................................... 1 0 3 
A p pe n di x  E  
A b bre viati o ns ............................................................................................ 1 0 8 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2  of 1 1 2  
•  
Occ urre nce/ fre q ue nc y 
•  
Relati o ns hi p t o S Z C as 
assesse d b y i n vesti gat or. 
•  
I nte nsit y 
•  
Seri o us ness  
•  
Deat h  
•  
A E s lea di n g t o disc o nti n uati o n 
of S Z C . 
F or e x pl orat or y o bjecti ves a n d e n d p oi nts, s ee S ecti o n 3  of t he pr ot oc ol.  
O ver all Desi g n : 
T his is a P hase 4, ra n d o mise d, c o ntr olle d, o pe n-l a bel, parallel gr o u p, m ultice ntre st u d y i n 
partici pa nts wit h C K D tr eate d f or H K, w hilst a d mitte d t o t he h os pital. T here will be 3 p hases:  
•  T he i n- h os pital p hase: 
 
Scree ni n g visit: W ill occ ur w hile t he partici p a nts are i n a n i npatie nt u nit, i n 
or der t o c h ec k eli gi bilit y criteria. Partici p a nts will be eli gi ble if:  t he y ha ve a 
dia g n osis of C K D (a n y st a ge) or esti mate d gl o mer ular filtrati o n rate (e G F R ) 
< 9 0 ml/ mi n/ 1. 7 3 m 2; a n d t he y are H K  (as d efi ne d b y site’s l ocal practice  
a n d K +  ≤ 6. 5 m m ol/ L ) or t he y were H K  a n d are n o w N K  w hile recei vi n g 
treat me nt f or H K. T he st u d y pla ns t o e nr ol a p pr o xi matel y e q ual n u m bers of 
p artici pa nts  wit h mil d H K ( K +  bet wee n > 5. 0 a n d ≤ 5. 5 m m ol/ L) a n d wit h 
m o derate/se v ere H K ( K +  bet wee n > 5. 5 a n d ≤ 6. 5 m m ol/ L), wit h a mi ni m u m 
of 3 0 % of t he e nr olle d partici pa n ts i n eit her gr o u p. Partici pa nts  will be 
eli gi ble if t he y are n ot o n S Z C or patir o mer bef ore  t his c urre nt E D 
visit/ h os pital  a d missi o n a n d f ulfill all i ncl usi o n/e xcl usi o n criteria.  
Parti ci pants i n w h o m S Z C or patir o mer has bee n i nitiate d d uri n g  t his 
c urre nt E D visit/ h os pitalisati o n prece di n g e nr ol me nt  ca n be e nr ol le d i n t he 
st u d y. 
 
T he i n patie nt p hase: 
B aseli ne visit : Ca n occ ur t he sa me da y as t h e scree ni n g visit  if all 
i ncl usi o n/e xcl usi o n criteria are f ulfille d . Treat me nt wit h S Z C will be i nitiate d 
as per l ocal la bel  at bas eli ne visit  a n d will be base d o n K+  meas ure me nt 
perf or me d wit hi n t he pre vi o us 2 4 h o urs :  
•  Partici pa nts wit h  H K ( K + bet wee n > 5. 0 a n d ≤ 6. 5 m m ol/ L): 1) st o p 
c urre nt K- bi n der if a n y, 2) start S Z C c orrecti o n d ose (n ote: partici pa nts 
c urre ntl y o n S Z C s h o ul d c o nti n ue S Z C c orrecti o n  d ose, u p t o 7 2 h o urs). 
•  Partici pa nts c urre ntl y recei vi n g a n y treat me nt f or t he c urre nt e pis o de of 
H K a n d are alrea d y N K at baseli ne ( K + ≤ 5. 0 m m ol/ L): 1) st o p a n y 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3  of 1 1 2  
c urre nt K - bi n der, 2) start S Z C mai nte na nce  d ose ( n ote: partici pa nts 
c urre ntl y o n S Z C mai nte na nce d ose s h o ul d c o nti n ue S Z C mai nte na nce 
d ose). 
•  All treat me nt decisi o ns, i ncl u di n g m o dificati o n t o t he o n g oi n g t hera p y 
f or H K, m ust be bas e d o n t he i n vesti gat or’s me di cal j u d ge me nt of t he 
partici pa nt’s best i nterest . 
T y picall y, N K is ac hie v e d wit hi n 2 4 t o 4 8 h o urs. If partici pa nts are still 
h y per kalae mic after 4 8 h o urs of treat me nt, t he s a me re gi me n ca n be c o nti n ue d 
f or a n a d diti o nal 2 4 h o urs. If N K is n ot ac hie v e d after 7 2  h o urs of treat me nt, 
ot her treat me nt a p pr oac h es s h o ul d be c o nsi dere d, a n d t he partici pa nt  
disc o nti n ue d fr o m t he st u d y.  
 
Partici pa nts reac hi n g N K ( K +  bet wee n 3. 5 a n d 5. 0 m m ol/ L, i ncl usi ve) wit hi n 
7 2 h o urs will be starte d o n mai nte na nce d os e of S Z C u ntil disc har ge. 
 
Disc har ge visit: T he da y t he y get disc har g e d fr o m t he h os pital, partici pa nts 
will be ra n d o mise d  t o o ne of t he 2 parallel ar ms at t his visit a n d e nter t he 
o ut patie nt p hase. T o be ra n d o mise d, p artici pa nts ha ve t o be N K ( K+  bet wee n 
3. 5 a n d 5. 0 m m ol/ L, i ncl usi ve) a n d s h o ul d be start e d o n a mai nte na n ce d os e 
f or S Z C. T he disc har g e visit will ta ke place 1 t o 2 1 da ys after t h e baseli ne 
visit. Me dical m o nit or’s a p pr o val ma y be s o u g ht f or all o wi n g l o n ger 
d urati o n h os pital sta ys f or s pecific p artici pa nt s.  
•  T he o ut patie nt p hase: 
 
Partici pa nts will be treate d wit h eit her S Z C, as per l ocal la bel , or S o C, as per 
l ocal practice f or 1 8 0 d a ys. 
 
Visits will occ ur 7, 3 0, 6 0, 9 0, 1 2 0, 1 5 0, 1 8 0 (e n d of treat me nt [ E O T]) d a ys 
after disc h ar ge visit (ra n d o misati o n ). O nl y visits at 7, 9 0, a n d 1 8 0 da ys will 
be o n- site visits: t he re mai ni n g bei n g tele p h o ne visits.   
•  T he f oll o w- u p p has e: 
 
A f oll o w- u p site vis it (e n d of st u d y visit) will occ ur a p pr o xi matel y 7 da ys 
after E O T.  
Data will be c ollecte d at o n -site visits, via tele p h o ne visits a n d me dical c hart re vie ws.  
T he st u d y will be c o n d ucte d i n a p pr o xi matel y 3 0 t o 5 0 sites i n 4 t o 7 c o u ntries i n E ur o pe. 
Discl os ure St ate m e nt : T his is a parallel - gr o u p treat me nt st u d y wit h 2 treat me nt ar ms t hat are 
o pe n la bel.   
M as ki n g: N o mas ki n g  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4  of 1 1 2  
N u m ber of P artici p a nts:  
Ass u mi n g a 2 0 % dr o p- o ut rate fr o m e nr ol me nt t o ra n d o misati o n a n d a 2 0 % dr o p o ut 
p ost- disc har ge ( p ost-ra n d o misati o n), a p pr o xi matel y 1 6 3 partici pa nts will be e nr olle d, 
res ulti n g i n a p pr o xi matel y 1 3 0 partici pa nts disc har ge d a n d ra n d o mis e d, t o ac hie ve 1 0 4 
e val ua ble p artici pa nts ( 5 2 per ar m ). 
N ote : “ E nr olle d ” mea ns a partici pa nt's, or t heir le gall y acce pta ble re pres e ntati ve’s, a gree me nt 
t o partici pate i n a cli nical st u d y f oll o wi n g c o m pleti o n of t he i nf or me d c o ns e nt pr ocess. 
P ote ntial partici pa nts w h o are scree n e d f or t h e p ur p ose of deter mi ni n g eli gi bilit y f or t he st u d y, 
b ut are n ot assi g ne d tr eat me nt i n t he st u d y, are c o nsi dere d “scree n fail ures ”, u nless ot her wise 
s pecifie d b y t he pr ot o c ol.  
I nter ve nti o n Gr o u ps  a n d D ur ati o n: 
All  partici pa nts will be treate d wit h S Z C as per l o cal la bel (c orrecti o n a n d / or mai nte n a nce 
treat me nt) d uri n g t he i n- h os pital p hase. T he d urati o n of i n- h os pital p hase will be 1 t o 2 1 da ys 
p ost-e nr ol me nt; me dical m o nit or’s a p pr o val ma y be s o u g ht f or all o wi n g l o n ger d urati o n 
h os pital sta ys f or s pecific partici pa nt s. 
At disc har ge, p artici pa nts w h o are N K ( K+  bet w ee n 3. 5 a n d 5. 0 m m ol/ L, i ncl usi ve) a n d ha v e 
bee n starte d o n a mai nte n a nce d ose f or S Z C will be ra n d o mise d i n a 1: 1 rati o t o o ne of t he 
f oll o wi n g ar ms a n d s u bs e q ue ntl y e nter t he o ut p atie nt p hase:  
•  Ar m A: P artici pa nts  disc har ge d wit h S Z C, as per l ocal la bel, t o ma na g e H K u ntil e n d of 
o ut patie nt p hase 
•  Ar m B: P artici pa nts  disc har ge d wit h S o C, as per l ocal practice, t o ma na g e H K u ntil e n d of 
t he st u d y.  
N ote: Partici pa nts i nte n de d t o recei ve a K - bi n der at disc har ge (as per t he site r o uti ne me dical 
practice) will n ot be ra n d o mise d a n d will be disc o nti n ue d fr o m t he st u d y. Still, it is all o we d 
t hat partici pa nts ra n d o mise d i nt o Ar m B ha ve a n y K- bi n der prescri b e d at D a y 7 
p ost- disc har ge  ( or after Da y 7 p ost-disc har g e),  t o treat c o nfir m e d H K or i n case t here is a n 
i ncreas e i n K +  le vel si nce disc har ge t hat, i n t he i n v esti gat or’s o pi ni o n, re q uires t hera p y. 
T he d urati o n of o ut patie nt p hase will be a p pr o xi m atel y 1 8 0 da ys. 
After t he o ut patie nt p h ase, partici pa nts will e nter i nt o t he f oll o w - u p p hase w hic h will last 
7 da ys. St u d y dr u g will be disc o nti n ue d f or partici pa nts i n Ar m A. T hese p artici pa nts will be 
treate d as p er l ocal practi ce ( S o C). Partici pa nts i n Ar m B will c o nti n ue S o C treat me nt.  
T he t otal st u d y d urati o n f or eac h p artici pa nt will t he n be a p pr o xi mat el y 6 m o nt hs. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 5  of 1 1 2  
A dj u dic ati o n C o m mittee: Yes   
St atistic al Met h o ds : 
A nal yses will be f urt her detaile d i n t he statistical a nal ysis p la n w hic h will be fi nalise d wit hi n 
9 0 da ys of first partici p a nt  e nr olle d. It s h o ul d be n ote d t hat deat h wit h o ut pri or h os pitalis ati o n 
or E D visits is  see n as ne gli gi ble. As s uc h, t he wa y deat h is treate d (as o utc o me or ce ns ori n g) 
will n ot dra maticall y aff ect t he o utc o mes.  
Pri mar y E n d p oi nt 
Occ urre n ce ( yes/ n o) of N K ( K+ bet wee n  3. 5 a n d 5. 0 m m ol/ L, i ncl usive) at 1 8 0 d ays 
p ost- disc h ar ge will be a n al yse d usi n g a l o gistic re gressi o n m o del wit h res p o nse as t he 
de pe n de nt varia ble a n d r a n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. Partici pa nts 
w h o disc o nti n ue treat me nt wit h a K +  meas ure m e nt at 1 8 0 da ys p ost- disc har ge will ha ve t his 
val ue use d irr es pecti ve of treat me nt disc o nti n uati o n. Use of resc ue t hera p y f or H K will be 
c o nsi dere d t o be n o n-res p o nse. D o w n -titrati o n (i n cl u di n g disc o nti n uati o n) of R A A Si  
(ie, a n gi ote nsi n-c o n v erti n g e nz y me i n hi bit ors, a n gi ote nsi n rece pt or bl oc k ers, a n d 
mi neral oc ortic oi d r ece pt or a nta g o nists) will be c o nsi dere d t o be n o n- res p o nse. Partici pa nts 
w h o die of a n y ca use pri or t o 1 8 0 da ys p ost- disc h ar ge or w h o are l ost t o f oll o w- u p f or a n y 
reas o n will be c o nsi dere d t o be n o n-res p o nse. Se nsiti vit y a nal yses will e val uate t he i m pact of 
c o nsi deri n g t his as n o n-r es p o nse vers us o nl y e v al uati n g c o m pleters will be assesse d. 
Sec o n dar y Efficac y E n d p oi nts 
1.  Ti me t o first occ urre nce of a ny c o m p o n e nt of all- c a use h os pit al a d missi o n, or E D visit wit h 
H K as a c o ntri b uti n g f act or, or all-c a use de at h, or use of resc ue t her a p y f or H K  at a ny ti me 
p ost- disc h ar ge u p t o 1 8 0 d ays  will be a nal yse d usi n g a l o g-ra n k test. I n a d diti o n, a C o x 
pr o p orti o nal hazar ds m o del will be use d f or esti m ati o n wit h ra n d o mise d treat me nt gr o u p as 
t he i n de pe n de nt varia ble. Partici pa nts w h o disc o nti n ue treat me nt will c o nti n ue t o be f oll o we d  
u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt. Resc ue t hera p y f or H K will be 
c o nsi dere d a n e ve nt. Partici pa nts w h o re q uire h os pital a d missi o n or E D visits wit h o ut H K as a 
c o ntri b uti n g fact or will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite 
e n d p oi nt. Partici pa nts w h o die of a n y ca use will be c o nsi dere d a n e ve nt. Partici pa nts w h o are 
l ost t o f oll o w- u p will be ce ns ore d at t he date of l oss t o f oll o w- u p. Partici pa nts w h o ha ve 
R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt.  
2.  Ti me t o first occ urre nce of a ny c o m p o n e nt of all- c a use h os pit alis ati o n a d missi o n or E D 
visit wit h H K as a c o ntri b uti n g f act or, at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays will be 
a nal yse d usi n g a l o g-r a n k test. I n a d diti o n, a C o x pr o p orti o nal hazar ds m o del will be use d f or 
esti mati o n wit h ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt vari a ble. Parti ci pa nts w h o 
disc o nti n ue treat me nt or w h o ha ve E D visit wit h o ut H K as a c o ntri b uti n g fact or will c o nti n ue 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 6  of 1 1 2  
t o be f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt. Partici pa nts w h o die of 
a n y ca use, us e res c ue t hera p y f or H K or are l ost t o f oll o w -u p will be ce ns ore d at t he date of 
deat h, use of r esc u e t hera p y , or l oss t o f oll o w- u p, res pecti vel y. Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt.    
3.  N u m ber of all-c a use h os pit al a d missi o n, or E D visit wit h H K as a c o ntri b uti n g f act or, at 
a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays will be a nal yse d usi n g a ne gati ve bi n o mial re gressi o n 
m o del. Partici pa nts w h o disc o nti n ue treat me nt, us e resc u e t hera p y f or H K or w h o ha ve a n E D 
visit wit h o ut H K as a c o ntri b uti n g fact or, will c o nti n ue t o be f oll o we d u p f or t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt. Partici pa nts w h o die of a n y ca use or are l ost t o 
f oll o w- u p will be ce ns or e d at t he date of deat h or l oss t o f oll o w- u p. Partici pa nts w h o ha ve 
R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt.  
4.  Ti me t o first occ urre nce of a ny c o m p o n e nt of h os pit al a d missi o n or E D visit, b ot h wit h H K 
as a c o ntri b uti n g f act or, at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays will be a nal yse d usi n g a 
l o g-ra n k test. I n a d diti o n, a C o x pr o p orti o nal hazar ds m o del will be use d f or esti mati o n wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n dent v aria ble. Partici pa nts w h o disc o nti n ue 
treat me nt or w h o h a ve h os pital a d missi o n or E D visit wit h o ut H K as a c o ntri b uti n g fact or will 
c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt. Partici pa nts w h o 
die of a n y ca use, use resc ue t hera p y f or H K or are l ost t o f oll o w - u p will be ce ns ore d at t he 
date of deat h, use of r esc ue t hera p y, or l oss t o f oll o w- u p, res p ecti vel y. Partici pa nts w h o ha ve 
R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt.    
5.  N u m ber of h os pit al a d missi o n or E D visit b ot h wit h H K as a c o ntri b uti n g f act or, at a ny 
ti me p ost- disc h ar ge u p t o 1 8 0 d ays will be a nal yse d usi n g a ne gati ve bi n o mi al re gressi o n  
m o del. Partici pa nts w h o disc o nti n ue treat me nt, us e resc u e t hera p y f or H K or w h o ha ve a 
h os pital a d missi o n, or a n E D visit wit h o ut H K as a c o ntri b uti n g fact or, will c o nti n ue t o be 
f oll o we d u p f or t he first c o m p o ne nt of t he c o m p osite e n d p oi nt. Partici pa nts w h o die of a n y 
ca use or are l ost t o f oll o w -u p will be ce ns ore d at t he date of deat h or l oss t o f oll o w- u p. 
Partici pa nts w h o ha v e R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt.  
6. Ti me t o first occ urre nce of R A A Si d o w n -titr ati o n (i ncl u di n g disc o nti n u ati o n) at a ny ti me 
p ost- disc h ar ge u p t o 1 8 0 d ays  will be a nal yse d usi n g a l o g-ra n k test. I n a d diti o n, a C o x 
pr o p orti o nal hazar ds m o del will be use d f or esti m ati o n wit h ra n d o mise d treat me nt gr o u p as 
t he i n de pe n de nt varia ble. Partici pa nts w h o disc o nti n ue treat me nt will c o nti n ue t o be f oll o we d  
u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt. Partici pa nts w h o die of a n y ca us e or are 
l ost t o f oll o w- u p will be ce ns ore d at t heir date of deat h or l oss t o f oll o w- u p , res pecti vel y.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 7  of 1 1 2  
Safet y E n d p oi nts 
Safet y will be assesse d i n ter ms of A Es, seri o us a d verse e v e nts (S A Es ), A Es lea di n g t o 
treat me nt disc o nti n uati o n, cli nical la b orat or y d ata, vital si g ns, a n d E C G. A p pr o priate 
s u m maries of t hese dat a will be prese nte d b y treat me nt gr o u p. 
A d verse e ve nts  will be pr ese nte d f or eac h treat me nt gr o u p b y s yste m or ga n class, a n d 
preferre d t er m  c o veri n g n u m ber a n d perce nt a ge of partici pa nts re p orti n g at least 1 e ve nt a n d 
n u m ber of e v e nts w her e a p pr o priate. A n o ver vie w of A Es will prese nt f or eac h  treat me nt 
gr o u p t he n u m ber a n d p erce nta g e of partici pa nts wit h a n y A E, A Es wit h o utc o me of deat h, 
S A Es, a n d A Es lea di n g t o disc o nti n uati o n of i n vesti gati o nal me dici nal pr o d uct (I M P). 
Se parate A E ta bles will  be pr o vi de d ta ke n i nt o c o nsi derati o n relati o ns hi p as assesse d b y t he 
i n vesti gat or, ma xi m u m i nte nsit y, seri o us ness, deat h a n d e ve nts lea di n g t o disc o nti n uati o n of 
I M P. 
S a m ple Size : 
Sa m ple size deter mi nati o n is base d o n t he mai n  sec o n dar y efficac y e n d p oi nt (Ti me t o first 
occ urr e nce of a n y c o m p o ne nt of all-ca use h os pital a d missi o n, or E D visit wit h H K as a 
c o ntri b uti n g fact or, or all-ca use d eat h or us e of res c ue t hera p y f or H K at a n y ti me p ost -
disc har ge u p t o 1 8 0 d a ys). Usi n g a l o g-ra n k t est f or e q ualit y of s u r vi val c ur ves, a si g nifica n ce 
le vel of 5 %, a p o wer of 8 0 % a n d a hazar d rati o of 0. 3 2 9 wit h s ur vi val pr o p orti o ns of 8 3% f or 
S Z C a n d 5 6. 8 % f or S o C, a sa m ple size of 5 2 e val ua ble partici pa nts p er ar m ( N  = 1 04 t otal) 
w o ul d be re q uir e d. Ass u mi n g a 2 0 % dr o p- o ut rat e fr o m e nr ol me nt t o ra n d o mis ati o n, a n d a 
2 0 % dr o p o ut p ost- disc h ar ge ( p ost-ra n d o mis ati o n ), a t otal of a p pr o xi mat el y 1 6 3 partici pa nts 
will be e nr olle d. 
A n al ysis P o p ul ati o ns : 
S afet y Set O pe n: All partici pa nts w h o recei ve d at least o ne d ose of S Z C d uri n g t he st u d y u p 
u ntil disc har ge/ra n d o mis ati o n. 
S afet y Set R a n d o mise d:  All ra n d o mise d partici pa nts w h o recei v e d at least 1 d ose of S Z C 
p ost- disc har ge i n Ar m A a n d all ra n d o mise d partici pa nts i n Ar m B. 
F ull A n al ysis Set ( F A S): All ra n d o mise d partici pa nts . T he F A S  will be use d as t he pri mar y 
p o p ulati o n f or t he pri mar y, sec o n dar y, a n d e x pl orat or y efficac y e n d p oi nts.  
Per Pr ot oc ol Set ( P P S): T he F A S partici pa 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. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 8  of 1 1 2  
1. 2  
Sc he m a  
Fi g ure 1 
St u d y Desi g n   
      
A b bre viati o ns: C K D = c hr o nic ki d ne y disease;  E D = e mer ge nc y de part me nt; H K = h y per kalae mia; 
K/ K +  = p otassi u m; N K = n or m o kalae mia; S o C = sta n dar d of care; S Z C = s o di u m zirc o ni u m c ycl osilicate . 
* St u d y me dical m o nit or’s a p pr o val ma y be s o u g ht f or all o wi n g l o n ger d urati o n h os pital sta ys f or s pecific 
par tici pa nts. 
* *  K+  meas ure me nt wit hi n 2 4 h o urs of treat me nt i nitiati o n s h o ul d be o btai ne d bef ore starti n g treat me nt.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 9  of 1 1 2  
1. 3  
Sc he d ule of Acti vities  
 
Ta ble  1  
Sc he d ule of Acti vities  
Pr oce d ure  
I n-h os pit al p h ase  
( 1 t o 2 1 d a ys) a 
 
O ut p atie nt p h ase ( Visit s 4 t o 1 0)  
E/ D h  
F oll o w -u p 
p h ase  
Det ails i n C S P 
Secti o n or 
A p pe n di x  
 
Scree ni n g  
 
B aseli ne a 
 
D a y of 
disc h a r g e 
fr o m t he 
h os pit al b  
+ 7 
d a ys  
n 
 
+ 3 0 
d a ys c, h, 
n 
+ 6 0 
d a ys c, h, 
n 
 
+ 9 0 
d a ys c, h, 
n  
 
+ 1 2 0 
d a ys c, h,n 
 
+ 1 5 0 
d a ys c, h,n 
 
+ 1 8 0 
d a ys c, h,n  
( E O T) 
 
+ 7 d a ys 
after 
E O T h, o 
 
 
Visit  
1 
2 
3 
4 
5       
( p h o n e) 
6 
( p h o n e) 
7 
8 
( p h o n e) 
9 
( p h o ne)  
1 0  
 
1 1  
 
Visit Wi n d o w ( +/ -) 
 
 
 
1   
6   
6   
6   
6   
6   
6   
 
3 
 
I nf or me d c o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n a n d e x cl usi o n 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Secti o n s 5. 1  
an d 5. 2  
Ra n d o misati o n  
 
 
X 
 
 
 
 
 
 
 
 
 
Secti o n  6. 2  
R o uti ne Cli nic al Pr o ce d ures  
De m o gra p h y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
C o m plete p h ysical 
e xa mi nati o n d 
X 
 
 
 
 
 
 
 
 
 
 
 
Secti o n  8. 2. 1  
Tar gete d p h ysical 
e xa mi nati o n e 
 
 
X 
X 
 
 
X 
 
 
X 
X 
X 
Secti o n  8. 2. 1  
Me dical hist or y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt me dicati o n  
At e v er y visit a n d ma y b e c o n d u cte d b y p h o n e if n ot tie d t o a visit  
Secti o n  6. 7  
Vital si g ns f 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Secti o n  8. 2. 2  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 0  of 1 1 2  
 
Pr oce d ure  
I n-h os pit al p h ase  
(1 t o 2 1 d a ys) a 
 
O ut p atie nt p h ase ( Visit s 4 t o 1 0)  
E/ D h  
F oll o w -
u p p h ase  
Det ails i n C S P 
Secti o n or 
A p pe n di x  
 
Scree ni n g  
 
B aseli ne a 
 
D a y of 
disc h a r g e 
fr o m t he 
h os pit al b  
+ 7 
d a ys n  
 
+ 3 0 
d a ys c, h, n 
+ 6 0 
d a ys c, h, n 
 
+ 9 0 
d a ys c, h, n 
 
+ 1 2 0 
d a ys c, h, n 
 
+ 1 5 0 
d a ys c, h, n 
 
+ 1 8 0 
d a ys c, h, n 
( E O T) 
 
+ 7 d a ys 
after 
E O T h , o 
 
 
Visit  
1 
2 
3 
4 
5       
( p h o n e) 
6 
( p h o n e) 
7 
8 
( p h o n e) 
9 
( p h o ne)  
1 0  
 
1 1  
 
Visit Wi n d o w ( +/ -) 
 
 
 
1 
6 
6   
6   
6   
6   
6   
 
3 
 
R o uti ne S afet y Me as ure m e nts  
A d verse e ve nts  
At e v er y visit a n d ma y b e c o n d u cte d b y p h o n e if n ot tie d t o a visit  
Secti o n  8. 3  
Uri ne pre g na nc y test 
(w o me n of c hil d -beari n g 
p ote ntial o nl y)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical safet y la b orat or y 
assess me nts (i ncl u di n g uri n e 
di pstic k) g 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
Secti o n  8. 2. 4  
Electr oca r di o gra m 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
X 
Secti o n  8. 2. 3  
St u d y Ass ess m e nts 
L ocal la b orat or y  K+  i 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
X 
Secti o n  8. 1. 1  
Ce ntral l a b orat or y K+ j 
 
X 
X 
 
 
 
X 
 
 
X 
X 
 
Secti o n  8. 1. 1  
Data collecti o n o n h os pital 
a d missi o ns a n d E D visits 
( wit h H K a n d all-ca use), 
I C U visits, o ut patie nt visits, 
use of resc ue t hera p y,  
R A A Si d ose 
c ha n ges/ disc o nti n uati o ns , 
dial ysis i nitiati o n, a n d e G F R 
(site visits)   
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Secti o n  8. 8  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m  zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 1  of 1 1 2  
A b bre viati o ns: C S P = cli nical st u d y pr ot o c ol; E/ D = earl y st u d y inter v e nti o n  disc o nti n u ati o n; E D = e mer g e n c y d e p art me nt; e G F R = esti mate d gl o mer ular filtrati o n 
rate; E O T = e n d of treat me nt;  H K = h y p er k alae mia ; I C U = i nte nsi ve care u nit; K +  = p otassi u m ; R A A Si = re ni n-a n gi ote nsin- al d oster o ne s yste m i n hi bit ors . 
a 
Baseli ne a n d scree ni n g ca n o cc ur t h e sa me d a y.  
b 
W ill be mi ni m u m 2 4 h o urs after treat me nt i nitiati o n (f or p artici p a nt s w h o ac hie v e n or m o k alae mia [ K+  b et wee n 3. 5  a n d 5. 0 m m ol/ L , i ncl usi ve]). Partici pa nt s wit h 
K +  > 5. 0  m m ol/ L or  K+  < 3. 5 m m ol/ L at disc h ar g e will b e disc o n ti n u e d fr o m st u d y treat me nt a n d will b e f oll o we d p er pr ot oc ol . 
c 
After d ate of disc h ar g e. 
d 
A c o m plete p h ysical e x a mi n ati o n will b e p erf or me d at scree ni n g ( Visit 1) a n d i n cl u d e a n assess me nt of t h e f oll o wi n g: ge neral a p peara nce, res pirat or y, car di o vasc ular, 
a b d o me n s ki n, h ea d a n d n ec k (i n cl u di n g  ears, e y es, n ose a n d t hr o at), l y m p h n o d es, t h yr oi d, m usc ul os k eletal (i n cl u di n g s pi ne a n d e xtre mities) , a n d ne ur ol o gical s yste ms.  
e 
T he tar gete d p h ysical e x a mi n ati o n i n cl u d es t h e f oll o wi n g: s ki n, e xtre mities, car di o v asc ular i n cl u di n g assess m e nt of si g ns of heart fail ure, l u n gs, a n d a b d o me n . 
f 
T he vital si g ns i n cl u d e s yst olic a n d diast olic bl o o d press ure , a n d p ulse rate. B o d y wei g ht a n d h ei g ht will b e meas ure d at t he scree ni n g visit. Wei g ht ( wei g he d o n t he sa me 
scale i n t h e sa me state of dress) c ollecte d at eac h site visit. 
g 
Cli nical safet y la b orat or y assess m e nts via ce ntral la b orat or y: B - Hae m o gl o bi n ( H b), B -Le u k o c yte c o u nt, B -Le u k o c yte differe ntial c o u nt (a bs ol ute c o u nt), B -Platelet c o u nt, 
B- He mat ocrit ( Hct), S -S o di u m ( Na + ), S-P otassi u m ( K + ), S-Bicar b o n ate ( T otal C O 2), S-C hl ori d e ( Cl -), S-Gl u c ose, S -Creati ni ne, S -Bl o o d Urea Nitr o ge n ( B U N), Urea 
( B U N)/ Creati ni n e Rati o, e G F R usi n g t h e C K D-E PI f or m ula, S -A ni o n g a p , S -Al b u mi n, S -T otal Pr otei n, S -Calci u m ( Ca + + ), S-Ma g nesi u m ( M g
+ + ), S-P h os p hate ( P O 4), 
S- Bilir u bi n, t otal, S -Al k ali n e p h os p h atase ( A L P), S -Ala ni n e a mi n o tra nsferase ( A L T), S -As p artate a mi n o tra nsferase ( A S T). Cli nical safet y la b orat or y assess me nts via l ocal 
la b orat or y: uri n al ysis ( di pstic k), ie, U-H b/ Er yt hr o c ytes/ Bl o o d, U -Pr otei n/ Al b u mi n, a n d U- Gl u c ose . 
h 
Data c ollecte d d uri n g o n -site a n d tele p h o n e visits will b e c o m bi n e d wit h d ata c ollecte d fr o m p artici pa nt me dical c h art re vie w, if dee me d necessar y . 
Pr oce d ure  
I n-h os pit al p h ase  
(1 t o 2 1 d a ys) a 
 
O ut p atie nt p h ase ( Visit s 4 t o 1 0)  
E/ D h  
F oll o w -
u p p h ase  
Det ails i n C S P 
Secti o n or 
A p pe n di x  
 
Scree ni n g  
 
B aseli ne a 
 
D a y of 
disc h a r g e 
fr o m t he 
h os pit al b  
+ 7 
d a ys n  
 
+ 3 0 
d a ys c, h, n 
+ 6 0 
d a ys c, h, n 
 
+ 9 0 
d a ys c, h, n 
 
+ 1 2 0 
d a ys c, h, n 
 
+ 1 5 0 
d a ys c, h, n 
 
+ 1 8 0 
d a ys c, h, n 
( E O T) 
 
+ 7 d a ys 
after 
E O T h , o 
 
 
Visit  
1 
2 
3 
4 
5       
( p h o n e) 
6 
( p h o n e) 
7 
8 
( p h o n e) 
9 
( p h o ne)  
1 0  
 
1 1  
 
Visit Wi n d o w ( +/ -) 
 
 
 
1 
6 
6 
6 
6 
6 
6 
 
3 
 
St u d y Tre at m e nt A d mi nistr ati o n j 
St u d y i nter ve nti o n 
dis pe nsati o n i n -h os pital 
p hase k 
 
X l 
 
 
 
 
 
 
 
 
 
 
Secti o n  6. 4  
St u d y i nter ve nti o n 
dis pe nsati o n o ut patie nt 
p hase m  
 
 
X 
X 
 
 
X 
 
 
 
 
 
Secti o n  6. 4  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 2  of 1 1 2  
i 
F or scree ni n g, K +  res ults o btai n e d d uri n g r o uti n e me dical care ma y b e use d ( H K as d efi n e d b y site’s l o cal practice a n d K +  m ust bet wee n > 5 . 0 a n d ≤ 6. 5  m m ol/ L). Still a 
l ocal K+  meas ure me nt s h o ul d b e o btai n e d wit hi n 2 4 h o urs of st u d y treat me nt i nitiati o n. D uri n g t h e c orrect i o n treat me nt p hase K+  le vel is assesse d at least o nce a da y, b y l ocal 
la borat or y  or a n y ot h er v ali d ate d met h o d.  L o cal la b orat or y ( or a n y ot h er v ali d ate d met h o d) o nl y ma y b e use d at all ot her visits, i ncl u di n g a n y u nsc he d ule d visit. P otassi u m  
m a y be c h ec k e d m ore ofte n t h a n i n dicate d h ere, if me dicall y a p pr o priate.  
j 
Baseli ne sa m ples f or K +  are a n al yse d at t h e ce ntral la b orat or y a n d t h e res ults are n ot n ee d e d t o assess eli gi bilit y. Sa m ples will be a nal yse d b y ce ntral a n d l ocal la b orat ories at 
da y of disc h ar g e, +  9 0, +  1 8 0 d a ys, a n d E/ D visits w hile ce ntral la b orat or y o nl y will b e use d at b aseli n e . 
k 
T reat me nt wit h s o di u m zirc o ni u m c y cl osilicate (S Z C ) will b e esta blis h e d w hile t h e p artici p a nt is i n t he h os pital. O nl y partici pa nts ra n d o mise d t o S Z C will be di s pe nse d 
st u d y i nter v e nti o n d uri n g t h e o ut patie nt p h ase . A n y ti me st u d y dr u g d ose is a dj uste d, or if i n eit h er treat me nt ar m a c o nc o mita nt me dicati o n w hic h ma y affect K +  le vels is 
c ha n ge d (e g , use of re ni n a n gi ote nsi n -al d oster o n e s yste m i n hi bit ors [a n gi ote nsi n -c o n v erti n g e n z y me i n hi bit ors , a n gi ote nsi n rece pt or bl oc ker , mi neral oc ortic oi d rece pt or 
a nta g o nists] or di uretics), t h e p artici p a nt n ee ds t o ret ur n t o t h e site 7 ( ± 2) d a ys later f or a K +  meas ure me nt a n d rec or di n g of a d verse e ve nts a n d c o nc o mita nt me dicati o ns. 
D uri n g t he i n p atie nt ph ase, dr u g dis p e nsati o n will o cc ur e v er y d a y.  
l 
Ce ntral la b orat or y K +  res ults at baseli n e are n ot n ecessar y t o i nitiate t h e st u d y i nter v e nti o n as l o n g as all eli gi bilit y criteria are met  ( o nl y l ocal assess me nt of K+  wit hi n 
2 4  h o urs of treat me nt i nitiati o n is re q uire d) . 
m  
If d ose titrati o n o cc urs at a n y ti me d uri n g t h e o ut p atie nt p h ase, u nsc h e d ule d dis p e nsati o n visits will b e p erf or me d . 
n 
Relati ve t o t h e d ate of ra n d o misati o n ( Visit 3)  
o 
Relati ve t o t h e d ate of Visit 1 0/ E O T.  
 
 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 3  of 1 1 2  
2  
I N T R O D U C TI O N 
S o di u m zirc o ni u m c ycl osilicate ( S Z C) is as a n orall y -a d mi nistere d, n o n- p ol y mer 
n o n-a bs or ba bl e, i n or ga ni c, cr ystalli ne cati o n- e xc h a n ger t hat re pres e nts a n o vel t hera p y f or 
h y per kalae mia ( H K ). It s electi vel y bi n ds p otassi u m ( K+ ) i o ns i n e xc ha n ge f or h y dr o ge n a n d 
s o di u m i o ns t hr o u g h o ut t he gastr oi ntesti nal tract, t here b y re d uci n g ser u m K +  c o nce ntrati o n 
(S pi n o witz et al, 2 0 1 9 ). T he  K+  is re m o ve d fr o m t he b o d y t hr o u g h fecal e x creti o n. S o far, S Z C 
(re gister e d u n der t he tra d e na me of L o k el ma® ) has bee n re gistere d i n se v eral c o u ntries 
w orl d wi de, i ncl u di n g U nite d Ki n g d o m, Ger ma n y, Fra nce, It al y, Net herla n ds, Bel gi u m, a n d 
S pai n. 
2. 1  
St u d y R ati o n ale  
H y per kalae mia  is a c o m m o n pr o ble m see n i n h os pital patie nts. C urre ntl y, fe w patie nts treate d 
f or H K i n h os pital ar e disc har g e d wit h treat me nt t o mai ntai n n or m o kalae mia ( N K). F oll o wi n g 
disc har ge, t h ese patie nts are at ris k f or h os pital a d missi o n  a n d e mer ge nc y d e part me nt ( E D) 
visits f or rec urre nt H K. A rece nt o bs er vati o nal st u d y i n Ja pa n de m o nstrate d t hat patie nts wit h 
H K wer e m ore ofte n rea d mitte d t o h os pital, sta ye d l o n ger, a n d ha d m ore E D/ o ut patie nt visits 
t ha n patie nts wit h N K  (K a n da et al, 2 0 2 0 ). I n patie nts s ufferi n g fr o m c hr o ni c ki d ne y disease 
( C K D), t his tra nslate d i nt o healt hcare c osts w hic h were n earl y 3 ti mes hi g h er f or p atie nts wit h 
H K c o m par e d t o patie nts ha vi n g N K . Si milar fi n di n gs ha ve als o bee n re p orte d fr o m t he 
U nite d States  (Betts et al, 2 0 2 0 ). I n a d diti o n, it was s h o w n t hat i ncreas e d H K se verit y was 
ass ociate d wit h a n i ncreasi n g occ urre n ce of h os pital a d missi o n s (Da vis et al, 2 0 1 9 ).  
S o di u m zirc o ni u m c ycl osilicate  is a n o vel K+  bi n der t hera p y t o c orrect H K a n d mai ntai n N K. 
Efficac y a n d s afet y of S Z C has bee n esta blis he d t hr o u g h a r o b ust cli nical de vel o p me nt 
pr o gra m. H o w e ver, t h ere is c urre ntl y n o o utc o me st u d y t hat has i n vesti gate d w het her 
c o nti n ue d use of S Z C re d uces healt h care res o urce utilisati o n vers us sta n dar d of care ( S o C). 
T he c urr e nt st u d y will e xa mi ne t he c o nti n ue d use of S Z C i n a C K D p o p ulati o n wit h H K. T he 
pri mar y o bjecti ve of t h e st u d y is t o e val uate t he efficac y of c o nti n ui n g S Z C, as per l ocal la bel, 
as part of t he disc h ar g e me dicati o ns c o m pare d t o S o C, as per l ocal practice, i n mai ntai ni n g 
N K i n partici pa nts wit h C K D treate d f or H K. T he st u d y will als o asse ss w het her c o nti n ue d 
use of S Z C at disc har g e will re d uce t he i nci d e nce of all -ca us e h os pital a d missi o ns a n d E D 
visits  wit h H K as a c o ntri b uti n g fact or, or all-ca use deat h , or use of res c ue t hera p y f or H K, or 
re ni n-a n gi ote nsi n- al d oster o ne s yste m i n hi bit ors (R A A Si) d o w n -titrati o n (i ncl u di n g 
disc o nti n uati o n) c o m pare d t o S o C as per l ocal practice , w hic h ma y s u p p ort healt h tec h n ol o g y 
assess me nt.  
2. 2  
B ac k gr o u n d  
H y per kalae mi a is a p ote ntiall y life-t hreate ni n g el ectr ol yte dis or der a n d  is pri maril y ca use d b y 
re nal d ysf u ncti o n lea di n g t o re d uce d e xcreti o n of K+ . T he i nci de nce of H K i n C K D patie nts 
has bee n r e p orte d t o r a n g e bet wee n 7. 7 % a n d 7 3 % ( K o ves d y, 2 0 1 7 ). 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 4  of 1 1 2  
I n a st u d y of a p pr o xi mat el y 3 6, 0 0 0 patie nts wit h a n esti mate d gl o mer ular filtrati o n rate 
(e G F R ) < 6 0 ml/ mi n per 1. 7 3 m 2, H K  was ass ociate d wit h i ncreas e d all -ca use m ortalit y  
(Na k h o ul et al, 2 0 1 5 ). 
Beca use H K ca n i n d u ce or w orse n car diac arr h yt h mias, it is ass ociate d wit h si g nifica ntl y 
i ncreas e d m ortalit y (K o v es d y, 2 0 1 7 ). 
Treat me nt of se vere H K is t he n a me dical e m er ge n c y b ut it s h o ul d be f oll o we d b y c o nti n u o us 
l o n g-ter m treat me nt t o pr e ve nt rec urre nce. S o far, t he c o m m o n practice f or ma na gi n g c hr o nic 
H K is f oc use d o n eli mi nati n g H K pre dis p osi n g fact ors. Patie nts are t he n a d vise d t o re d uce 
hi g h K +  i nta ke i n diets b ut als o t o wit h dra w or re d uce me dicati o ns k n o w n t o raise K+  le vels. 
A m o n g t hese me dicati o ns, R A A Si , f or e xa m ple, are c o m m o nl y prescri be d i n patie nts wit h 
C K D, a n d ar e ofte n disc o nti n ue d t o ma na ge H K, i n s pite of t heir rec o g nise d car di o vas c ular 
a n d re nal b e nefits i n t his p o p ulati o n (K o ves d y, 2 0 1 7 ). F urt her m ore, wit h h ol di n g R A A Si ma y 
lea d t o i ncre me nt al healt hcare c osts ass ociate d wit h p o or o utc o mes, s uc h as e n d-sta ge re nal 
disease, h os pitalisati o ns d ue t o car di o vas c ular ca uses, a n d car di o vasc ular m ortalit y  (D u n n et 
al, 2 0 1 5). 
Mai ntai ni n g t he use of t hese be neficial me dicati o ns w hile i m ple me nti n g vari o us strate gies t o 
c o ntr ol K +  bala nce is d esira ble  a n d c o ul d b e o btai ne d b y l o n g-ter m use of K +  bi n ders 
(K o ves d y, 2 0 1 7 ). A treat me nt of u p t o 1 2 m o nt hs wit h S Z C utilisi n g a d ose titrati o n sc he me 
wit h t he starti n g d ose of 5 or 1 0 g dail y, titrate d t o a ma xi m u m of 1 5 g dail y or a mi ni m u m of 
5 g e ver y ot her da y, was eff ecti ve i n mai ntai ni n g N K i n t he maj orit y of s u bjects i n a l o n g -ter m 
st u d y (S pi n o witz et al, 2 0 1 9 ). H o we v er, i n t he U S, o nl y 0. 1 % of patie nts wit h a H K-relate d 
i npatie nt sta y recei v e d a bi n der at disc har ge ( Da vis et al, 2 0 1 9 ). 
H y per kalae mia  is re p orte d i n less t ha n 5 % of t he p o p ulati o n, w orl d wi de 
(Le der er  a n d al, 2 0 2 0) b ut ma y aff ect u p t o 1 0 % of h os pitalise d patie nts ( R ossi g n ol et al, 
2 0 1 6 ). I n a d diti o n t o cli nical c o nse q ue n ces, H K  is ass ociate d wit h i ncrease d healt h care c osts 
a n d healt hcare res o ur ce utili sati o n ( H R U):  
•  Betts et al. f o u n d t hat patie nts wit h H K i nc urre d $ 1 5, 9 8 3 hi g her t otal healt hcare c osts a n d 
$ 9, 2 9 3 hi g her i n patie nt c osts ( 5 8 % of t he t otal c ost differe n ce) t h a n patie nts wit h o ut H K 
wit hi n 1 year. W he n h os pitalise d, patie nts wit h H K were 4 0 % m ore li kel y t o be 
re-a d mitte d wit hi n 1 year  c o m pare d wit h matc h e d patie nts wit h o ut H K . Si milar t o t he 
fi n di n gs fr o m a n ot her w or k (Fitc h et al, 2 0 1 7 ), t he st u d y als o s h o we d t hat t he differe nce i n 
H R U a n d healt hcare c osts bet wee n patie nts wit h a n d wit h o ut H K i ncreas e d wit h C K D 
se verit y (Betts et al, 2 0 1 8 ). 
•  T here is li mite d e vi de nce re gar di n g o utc o m es  f oll o wi n g disc har ge fr o m a H K -rel ate d 
h os pitalisati o n.  P ost- disc har ge h os pital a d missi o n rates are  i m p orta nt h os pital q ualit y 
metrics t o meas ure t h e  effecti ve ness of h os pital care wit h s ocietal ec o n o mic i m plicati o ns . 

Cli nical St u d y Pr ot o c ol - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 5  of 1 1 2  
I n an ot her st u d y , Betts assesse d t he p ost- disc har ge ec o n o mic a n d h os pital a d missi o n  
b ur de ns ass ociat e d wit h H K- rel ate d h os pitalisati o ns i n t he real w orl d (Betts et al,  2 0 2 0). 
C o m pare d t o patie nts h os pitalise d f or reas o ns u nrelate d t o H K, patie nts wit h H K- rel ate d 
h os pitalisati o ns  ha d 5 6 % t o 5 8 % hi g her rates of h os pital a d missi o n  wit hi n 3 0, 6 0 , a n d 9 0 
da ys after dis c har g e. I n t his st u d y, t he t otal i n patie nt da ys wit hi n 1 year w as nearl y t wice 
hi g her f or h os pitalisati o ns relate d t o H K as c o m pare d t o h os pitalisati o ns n o t relate d t o H K. 
2. 3  
Be nefit/ Ris k Assess me nt  
2. 3. 1  
Ris k Assess m e nt 
T his st u d y will recr ui t partici pa nts w h o ha ve mil d-t o-m o derate H K. T h ere is a ris k of H K i n 
t h ose partici pa nts w h o ar e ra n d o mise d t o S o C a n d a ris k of h y p o kalae mia i n partici pa nts 
ra n d o mise d t o S Z C. He nce, H K a n d h y p o kalae mia are t h e maj or me dical ris ks f or partici pa nts 
i n t his st u d y. T he f oll o wi n g st u d y desi g n feat ures were i ncl u d e d t o mi ni mise t he ris k t o 
partici pa nts:  
•  
All partici pa nts will recei ve acti ve treat me nt wit h S Z C d uri n g t he i n patie nt p hase a n d 
o nl y partici pa nts t hat ha v e n or malis e d K +  will be ra n d o mise d i nt o t he st u d y, mi ni misi n g 
t he ris k of H K i n t he r a n d o mise d treat me nt p hase. 
•  
Visit 7 da ys p ost- disc har ge e ns ures t hat t he p artici pa nt 's K+  le vel is sta ble p ost- disc har ge, 
a n d me dicati o ns ca n b e c ha n ge d as nee de d . S uc h a dj ust me nt ma y i n v ol ve i nitiati o n of a n y 
K- bi n der i n t he S o C ar m ( N ote: I n t he S Z C ar m, c o nc o mita nt use of ot her K- bi n ders is 
pr o hi bite d alt h o u g h resc u e t hera p y wit h K- bi n der is all o we d, see Secti o n  6. 7. 1 ). 
•  
T he K +  meas ure m e nts at o n -site st u d y visits will pr o vi de i n vesti gat ors wit h u p-t o-date K +  
val ues , t here b y all o wi n g d ose a dj ust me nts/ disc o nti n uati o n t o occ ur as a p pr o priate d uri n g 
t he st u d y visit. 
•  
A n y ti me st u d y dr u g d ose is a dj uste d, or i n eit her treat me nt ar m, if a c o nc o mita nt 
me dicati o n w hic h ma y affect K +  le vels is c ha n g e d (e g, use of R A A Si or di uretics), t he 
partici pa nt nee ds t o r et ur n t o t he site 7 ( ± 2) da ys later f or a K +  meas ure me nt a n d 
rec or di n g of a d verse e v e nts ( A Es) a n d c o n c o mita nt me dicati o ns.   
•  
H y p o kalae mia h as bee n r e p orte d wit h S Z C. T he S Z C d ose titrati o n a n d st o p pi n g r ules, 
a n d resc u e t her a p y r ules base d o n K +  m o nit ori n g, are i ncl u de d i n t his pr ot o c ol t o 
mi ni mi se t he ris k of H K a n d h y p o kalae mia.  
•  
T he ris k of se v er e H K u p o n ra n d o mis ati o n t o S o C will be miti gate d wit h m o nit ori n g of 
K +  fr o m t he be gi n ni n g of t he ra n d o mise d treat me nt t hr o u g h t he e n d of treat me nt (E O T ) 
visit.  
•  
T he ris k of H K after t h e E O T visit will be miti gate d b y m o nit ori n g K + , 1 wee k aft er t he 
E O T . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 6  of 1 1 2  
•  
Oe d e ma-relat e d e ve nts ( gr o u pe d ter ms i ncl u de preferre d ter ms ( P Ts) of o e de ma, o e de m a 
peri p her al, ge ner alize d o e de ma, fl ui d rete nti o n, h y per v ole mia, l ocalize d o e de ma, a n d 
peri p her al s welli n g) ha ve bee n re p orte d b y p atie nt s treate d wit h S Z C, i n partic ular at 
hi g her d oses. P h ysical e x a mi nati o ns t o assess oe de ma will be perf or me d a n d t he 
partici pa nt will be wei g h e d at pre -s pecifi e d visits t o e ns ure de v el o p me nt of oe de ma will 
be detect e d earl y a n d a p pr o priatel y ma na g e d.  
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits a n d p ote ntial ris ks of S Z C 
ma y be f o u n d i n t he I n v esti gat or’s Br oc h ure ( I B). 
Ta ble 2 
Ris k Assess me nt  
P ote nti al ris k of cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or 
ris k  
Miti g ati o n str ate g y  
 
S Z C  
H y p o kalae mia  
  
C o m m o n ( ≥ 1/ 1 0 0 t o <  1/ 1 0) . 
I n cli nical trials, 4. 1 % of S Z C 
patie nts de vel o pe d h y p o kalae mia 
wit h a K +  val ue less t ha n 
3. 5  m m ol/ L . 
M o nit ori n g K
+  a n d d ose 
a dj ust me nts.   
Oe de ma relate d e ve nts  
(i ncl u des fl ui d rete nti o n, 
g e neralise d oe de ma, 
h y per v olae mia, localise d oe de ma, 
o e de ma,  oe de ma peri p heral, 
p eri p heral s welli n g) 
C o m m o n ( ≥ 1/ 1 0 0 t o <  1/ 1 0) . 
I n cli nical trials wit h S Z C, t he 
m ost c o m m o nl y re p orte d a d verse 
reacti o n was oe de ma relate d 
e ve nts w hic h were re p orte d b y 
5. 7 % S Z C patie nts; 1. 7 % , 2. 7% , 
5. 2 % , a n d 1 4. 3 % of patie nts 
ra n d o mise d t o place b o, or S Z C 5, 
1 0, or 1 5 g o nce dail y u p t o o ne 
m o nt h, res pecti vel y .  
P h ysical e xa mi nati o ns t o assess 
oe de ma will be perf or me d a n d t he 
partici pa nt will be wei g he d at 
pre -s pecifie d visits t o e ns ure 
de vel o p me nt of oe de ma will be 
detecte d earl y.  
 
Oe de ma ma na ge me nt as per 
i n vesti gat ors me dical j u d ge me nt.  
 
C o nsti pati o n  
C o m m o n ( ≥1/ 1 0 0 t o < 1/ 1 0)  
I n cli nical st u dies c o n d ucte d i n 
c o u ntries wit h a pre d o mi na ntl y 
Asia n p o p ulati o n, c o nsti pati o n 
wit h a n esti mate d fre q ue nc y of 
8. 9 % occ urre d i n patie nts 
recei vi n g S Z C ; a n d was res ol ve d 
wit h d ose a dj ust me nt or treat me nt 
disc o nti n uati o n.  
D ose a dj ust me nt or 
di sc o nti n uati o n as per 
i n vesti gat ors me dical j u d ge me nt. 
A b bre viati o ns: K +  = p otassi u m ; S Z C = so di u m zirc o ni u m c ycl osilicate .  
2. 3. 2  Be nefit Assess m e nt 
Cli nical st u dies i n patie nts wit h H K ha ve de m o nstrate d t he efficac y a n d s afet y of S Z C i n t he 
c orrecti o n of H K a n d mai nte na nce of N K. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 7  of 1 1 2  
T he pri mar y be n efit f or p artici pa nts ra n d o mise d t o S Z C treat me nt is e x pect e d t o be t he 
mai nte na nce of N K after disc har ge fr o m t he h os pital. F urt her, s h o ul d t he st u d y h y p ot hesis 
pr o ve tr ue, p artici pa nts ta ki n g S Z C will be nefit fr o m less fre q ue nt h os pitalisati o ns.  
T he a p pr o v e d d ose a dj ust me nt al g orit h m will be use d as per l ocal la bel w h e ne ver a  K+  
meas ure me nt is a v aila ble, e na bli n g partici pa nts t o ac hie ve a n d mai ntai n N K. I n acc or da n ce 
wit h t he al g orit h m, t he d ose ma y be i ncrease d, re d uce d, or ke pt u n c ha n ge d, de pe n di n g o n t he 
c urre nt K +  le v els, a da pti n g t he d osi n g re gi me n t o eac h partici p a nt a n d pre ve nti n g 
u n necessaril y hi g h e x p os ure t o t he pr o d uct. 
Partici pa nts treate d wit h S o C ma y n ot o btai n t he sa me be nefit i n ter ms of H K ma na ge m e nt  b ut 
ma y be nefit fr o m a cl oser f oll o w-u p. Partici pa nts will recei ve resc u e me dici ne w he ne v er 
cli nicall y i n dicate d.  
Partici pa nts, irres pecti ve of t heir treat me nt all ocati o n, ma y be nefit fr o m m ore i nte nse 
m o nit ori n g a n d atte nti o n t o t heir u n derl yi n g c o n diti o n.  
I n t he lar g er pers pecti ve, t he mai n p ote ntial be nefit of c o n d ucti n g t his st u d y lies i n t he 
p ossi bilit y t o ge nerate scie ntific e vi de nce f or i m pr o ve d ma na ge m e nt of pati e nts wit h C K D 
treate d f or H K , a n d p ote ntiall y re d uce t he ti me s p e nt at t he h os pital. 
2. 3. 3  O ver all Be nefit: Ris k C o ncl usi o n 
Base d o n t he k n o w n p ote ntial ris ks t o st u d y partici pa nts, t he e x peri e nce of S Z C o ver t he 
4  years p ost-a p pr o val, t h e ris k miti gati o ns i ncl u de d i n t his pr ot oc ol, a n d t he l o n g-ter m 
p ote ntial be nefits of si m plif yi n g ma na ge me nt of p artici pa nts wit h H K ass o ciate d wit h C K D, it 
is c o ncl u de d t hat t he st u d y as pr o p ose d e x p os es recr uite d partici pa nts t o a n acce pta ble ris k.  
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits a n d p ote ntial ris ks of S Z C 
ma y be f o u n d i n t he I B. 
3  
 O B J E C TI V E S A N D E N D P OI N T S  
T he pr ot oc ol o bjecti ves a n d e n d p oi nts are pr o vi de d i n  Ta ble 3 .  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 0  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of all-ca use h os pita l a d missi o n s or E D 
visit s wit h H K as a c o ntri b uti n g fact or  
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: Ti me t o first occ urre nce of all-ca use 
h os pital a d missi o n , or E D visit wit h H K as a 
c o ntri b uti n g fact or at a n y ti me p ost -disc har ge u p t o 
1 8 0 da ys.  
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt or w h o ha ve E D visit wit h o ut 
H K as a c o ntri b uti n g fact or will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite 
e n d p oi nt (treat me nt p olic y strate g y). Partici pa nts 
w h o die  of a n y ca use , use resc ue t hera p y f or H K or 
are l ost t o f oll o w -u p will be ce ns ore d at t he date of 
dea t h, use of resc ue t hera p y or l oss t o f oll o w-u p , 
res pecti vel y. Partici pa nts w h o ha ve R A A Si d o w n -
titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o 
be f oll o we d u p t o t he first c o m p o ne nt of t he 
c o m p osite e n d p oi nt (treat me nt p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n -Meier 
pl ots of t he s ur vi val f u ncti o n f or t he S Z C a n d S o C 
treat me nt gr o u ps will be prese nte d. L o g -ra n k test f or 
testi n g will be use d t o calc ulate a t w o -si de d p-val ue , 
C o x pr o p orti o nal hazar ds rati o f or esti mati o n , wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble.  T he H R a n d t he t w o -si de d 9 5 % c o nfi de nce 
i nter val will be prese nte d. T he ris k differe nce a n d 
t w o-si de d 9 5 % c o nfi de nce i nter val will be prese nte d. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 1  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part  of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he n u m ber  
of all-ca use h os pital  a d missi o ns or  E D 
visits wit h H K as a c o ntri b uti n g fact or  
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: N u m ber  of all-ca use h os pital  a d missi o n , or  
E D visits wit h H K as a  c o ntri b uti n g fact or at a n y 
ti me p ost-disc har ge u p t o 1 8 0 da ys.  
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt , use resc ue t hera p y f or H K or 
w h o  ha ve a n E D visit wit h o ut H K as a c o ntri b uti n g 
fact or, will c o nti n ue t o be f oll o we d u p to t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt 
p olic y strate g y). Partici pa nts w h o die  of a n y ca use or 
are l ost t o f oll o w -u p will be ce ns ore d at t he date of 
deat h or l oss t o f oll o w -u p.  Partici pa nts w h o ha ve 
R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) 
will c o nti n ue t o be f oll o we d u p  to t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt  (treat me nt 
p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Mea n n u m ber 
of all-ca use h os pital a d missi o n s or E D visits, wit h 
H K as a c o ntri b u ti n g fact or b y ra n d o mise d treat me nt 
gr o u p. Ne gati ve bi n o mial re gressi o n m o del  wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble  a n d i ncl u di n g d urati o n of ti me i n st u d y as a n 
offset. T he i nci de nce rate ( S Z C/ S o C), al o n g wit h 
9 5 % c o nfi de nce i nter val s a n d t w o-si de d p-val ues 
will be dis pla ye d . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 2  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of h os pital a d missi o ns or E D visit s wit h 
H K as a c o ntri b uti n g fact or  
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: Ti me t o first occ urre nce of h os pital 
a d missi o n or E D visit, b ot h wit h H K as a 
c o ntri b uti n g fact or at a n y ti me p ost -disc har ge u p t o 
1 8 0 da ys.  
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt or w h o ha ve h os pital 
a d missi o n or  E D visit wit h o ut H K as a c o ntri b uti n g 
fact or will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt 
p olic y strate g y). Partici pa nts w h o die  of a n y ca use , 
use resc ue t hera p y f or H K or are l ost t o f oll o w -u p 
will be ce ns ore d at t he date of deat h , use of resc ue 
t hera p y or l oss t o f oll o w-u p , res pecti vel y. 
Partici pa nts w h o ha ve R A A Si d o w n -titrati o n 
(i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite 
e n d p oi nt (treat me nt p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n -Meier 
pl ots of t he s ur vi val f u ncti o n f or t he S Z C a n d S o C 
treat me nt gr o u ps will be prese nte d. L o g -ra n k test f or 
testi n g will be use d t o calc ulate a t w o -si de d p-val ue , 
C o x pr o p orti o nal hazar ds rati o f or esti mati o n , wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble.  T he H R a n d t he t w o -si de d 9 5 % c o nfi de nce 
i nter val will be prese nte d. T he ris k differe nce a n d 
t w o-si ded 9 5 % c o nfi de nce i nter val will be prese nte d.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 3  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he n u m ber  
of h os pital a d missi o n s or  E D visits wit h 
H K as a c o ntri b uti n g fact or  
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: N u m ber  of h os pital a d missi o n or  E D visits 
wit h H K as a c o ntri b uti n g fact or, at a n y ti me 
p ost -disc har ge u p t o 1 8 0 da ys.  
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt , use resc ue t hera p y f or H K or 
w h o  ha ve a h os pital  a d missi o n, or a n E D visit 
wit h o ut H K as a c o ntri b uti n g fact or, will c o nti n ue t o 
be f oll o we d  u p to t he first c o m p o ne nt of t he 
c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o die  of a n y ca use or are l ost t o 
f oll o w-u p will be ce ns ore d at t he date of deat h or 
l oss t o f oll o w-u p.  Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will 
c o nti n ue t o be f oll o we d u p  to t he first c o m p o ne nt of 
t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Mea n n u m ber 
of h os pital a d missi o ns or E D visits, wit h H K as a 
c o ntri b uti n g fact or b y ra n d o mise d treat me nt gr o u p. 
Ne gati ve bi n o mial re gressi o n m o del  wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble  a n d i ncl u di n g d urati o n of ti me i n st u d y as a n 
offset. T he i nci de nce rate ( S Z C/ S o C), al o n g wit h 
9 5 % c o nfi de nce i nter vals a n d t w o -si de d p-val ues 
will be dis pla ye d . 
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns c o m pare d 
t o S o C o n  re d uci n g t he ris k of R A A Si 
d o w n -titrati o n (or  disc o nti n uati o n)  
•  
P o p ulati o n: F ull anal ysis set 
•  
E n d p oi nt: Ti me t o first occ urre nce of R A A Si 
d o w n -titrati o n ( or disc o nti n uati o n) at a n y ti me p ost -
disc har ge  u p t o 1 8 0 da ys.  
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt will c o nti n ue t o be f oll o we d u p 
t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt 
(treat me nt p olic y strate g y). Partici pa nts w h o die of 
a n y ca use  or are l ost t o f oll o w-u p will be ce ns ore d at 
t heir date of deat h or l oss t o f oll o w-u p , res pecti vel y. 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): L o g -ra n k test 
f or testi n g, C o x pr o p orti o nal hazar ds rati o f or 
esti mati o n wit h ra n d o mise d treat me nt gr o u p as t he 
i n de pe n de nt varia ble. 
 
 
 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osil icate - D 9 4 8 0 C 0 0 0 2 3  
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 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of h os pital a d missi o ns  wit h H K as a 
c o ntri b uti n g fact or or all -ca use deat h 
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: Ti me t o first occ ur re nce of eit her h os pital 
a d missi o n wit h H K as a c o ntri b uti n g fact or or all -
ca use deat h at a n y ti me p ost -disc har ge u p t o 1 8 0 
da ys . 
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt, ha ve a n E D visit wit h o ut 
h os pital a d missi o n  wit h H K as a c o ntri b uti n g fact or , 
h os pital a d missi o n or E D visits wit h o ut H K as a 
c o ntri b uti n g fact or or use resc ue t hera p y f or H K  will 
c o nti n ue t o be f oll o we d  u p t o t he first c o m p o ne nt of 
t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o are l ost t o  f oll o w-u p will be 
ce ns ore d at t he date of l oss t o f oll o w -u p. Partici pa nts 
w h o die of a n y ca use will be c o nsi dere d a n e ve nt 
(c o m p osite varia ble strate g y). Partici pa nts w h o ha ve 
R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) 
will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt 
p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis):  Ka pla n -Meier 
pl ots of t he s ur vi val f u ncti o n f or t he S Z C a n d S o C 
treat ment gr o u ps will be prese nte d. L o g -ra n k test f or 
testi n g will be use d t o calc ulate a t w o-si de d p-val ue, 
C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble. T he H R a n d t he t w o -si de d 9 5 % c o nfi de nce 
i nter val will be prese nte d. T he ris k differe nce a n d 
t w o-si de d 9 5 % c o nfi de nce i nter val will be prese nte d. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of E D visits wit h H K as a c o ntri b u ti n g 
fact or or all -ca use deat h 
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: Ti me t o first occ urre nce of eit her E D visit 
wit h H K as a c o ntri b uti n g fact or or all -ca use deat h at 
a n y ti me p ost-disc har ge u p t o 1 8 0 da ys.  
•  
I nterc urre nt e ve nt strateg y:  Partici pa nts w h o 
disc o nti n ue of treat me nt will c o nti n ue t o be f oll o we d 
u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt 
(treat me nt p olic y strate g y). Partici pa nts w h o re q uire 
a n y h os pital a d missi o n or E D visits wit h o ut H K as a 
c o ntri b uti n g fact or or w h o use resc ue t hera p y will 
c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of 
t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o die of a n y ca use will be c o nsi dere d 
a n e ve nt (c o m p osite varia ble strate g y). Partici pa nts 
w h o are l ost t o f oll o w -u p will be ce ns ore d at t he date 
of l oss t o f oll o w -u p.  Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will 
c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of 
t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n -Meier 
pl ots of t he s ur vi val f u ncti o n f or t he S Z C a n d S o C 
treat me nt gr o u ps will be prese nte d. L o g-ra n k test f or 
testi n g will be use d t o calc ulate a t w o-si de d p-val ue, 
C o x pr o p orti o nal hazar ds rati o f or esti mati o n,  wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble. T he H R a n d t he t w o -si de d 9 5 % c o nfi de nce 
i nter val will be prese nte d. T he ris k differe nce a n d 
t w o-si de d 9 5 % c o nfi de nce i nter val will be prese nte d. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 8  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of t he c o m p osite o utc o me of all -ca use 
h os pitalisati o ns, E D visits, all -ca use deat h , 
or use of resc ue t hera p y f or H K  
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: Ti me t o first occ urre nce of a n y c o m p o ne nt 
of all-ca use h os pitalisati o ns , E D visits , use of resc ue 
t hera p y f or H K or all-ca use deat h  i n eac h ar m at a n y 
ti me p ost-disc har ge u p t o 1 8 0 da ys . 
•  
I nterc urre nt e ve nt strate gy: Partici pa nts w h o 
disc o nti n ue of treat me nt will c o nti n ue t o be  f oll o we d 
u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt 
(treat me nt p olic y strate g y). Resc ue t hera p y f or H K 
will be c o nsi dere d a n e ve nt (c o m p osite varia ble 
strate g y). Partici pa nts w h o re q uire a n y h os pital 
a d missi o n or E D visit will be c o nsi dere d a n e v e nt 
(c o m p osite varia ble strate g y). Partici pa nts w h o die of 
a n y ca use will be c o nsi dere d a n e ve nt (c o m p osite 
varia ble strate g y). Partici pa nts w h o are l ost t o 
f oll o w-u p will be ce ns ore d at t he date of l oss t o 
f oll o w-u p.  Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will 
c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of 
t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis):  Ka pla n -Meier 
pl ots of t he s ur vi val f u ncti o n f or t he S Z C a n d S o C 
treat me nt gro u ps will be prese nte d. L o g -ra n k test f or 
testi n g will be use d t o calc ulate a t w o-si de d p-val ue, 
C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt 
varia ble. T he H R a n d t he t w o -si de d 9 5 % c o nfi de nce 
i nter val will be prese nte d. T he ris k differe nce a n d 
t w o-si de d 9 5 % c o nfi de nce i nter val will be prese nte d. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 9  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, o n mea n K +  le vels 
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: K +  le vel u p t o 1 8 0 da ys p ost-disc har ge.  
•  
I nterc urre nt e ve nt strate g y: K+  le vels fr o m 
partici pa nts after disc o nti n uati o n of treat me nt, 
h os pital a d missi o ns or E D visits f or a n y reas o n will 
be i ncl u de d i n t he a nal ysis (treat me nt p olic y 
strate g y). Partici pa nts w h o use resc ue t hera p y f or 
H K will ha ve K +  le vels pri or t o resc ue t hera p y f or 
H K use d i n t he a nal ysis ( w hile o n treat me nt 
strate g y). Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will ha ve 
K +  le vels pri or t o t he R A A Si d o wn- titrati o n use d i n 
t he a nal ysis ( w hile o n treat me nt strate g y). 
Partici pa nts w h o die of a n y ca use or w h o are l ost t o 
f oll o w-u p pri or t o 1 8 0 da ys p ost -disc har ge  will  ha ve 
all a vaila ble K +  i ncl u de d i n t he a nal ysis (treat me nt 
p olic y strate g y).  
•  
P o p ulati o n le ve l s u m mar y (a nal ysis): Mi xe d m o del 
re peate d meas ures a nal ysis wit h ra n d o mise d 
treat me nt gr o u p as a n i n de pe n de nt varia ble. T he 
c oefficie nt esti mates, sta n dar d err or, 9 5 % c o nfi de nce 
i nter vals f or c oefficie nt esti mate, a n d p-val ues will 
be re p orte d.  
•  
T o e val ua te t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he n u m ber 
of h os pital a d missi o ns wit h H K as a 
c o ntri b uti n g fact or 
•  
P o p ulati o n: F ull a nal ysis set  
•  
E n d p oi nt: N u m ber of h os pital a d missi o ns wit h H K 
as a c o ntri b uti n g fact or, at a n y ti me p ost -disc har ge 
u p t o 1 8 0 da ys.  
•  
I nterc urre nt e ve nt strate g y: Partici pa nts w h o 
disc o nti n ue treat me nt, use resc ue t hera p y f or H K, 
ha ve R A A Si d o w n -titrati o n (i ncl u di n g 
disc o nti n uati o n ), e x perie nce all -ca use deat h or l oss 
t o f oll o w-u p pri or t o 1 8 0 da ys p ost -disc har ge will 
ha ve all a vaila ble h os pital a d missi o n data use d 
irres pecti ve of t he i nterc urre nt e ve nt (treat me nt 
p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y: Mea n n u m ber of h os pital 
a d missi o ns wit h H K as a c o ntri b uti n g fact o r, b y 
ra n d o mise d treat me nt gr o u p. Ne gati ve bi n o mial 
re gressi o n m o del wit h ra n d o mise d treat me nt gr o u p 
as a mai n effect a n d i ncl u di n g d urati o n of ti me i n 
st u d y as a n offset. T he i nci de nce rate rati o 
( S Z C/ S o C), al o n g wit h 9 5 % c o nfi de nce i nter vals a n d 
t w o-si ded p -val ues will be dis pla ye d.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o n i u m c ycl osilicate - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 0  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he t otal L O S 
i n h os pitalisati o ns wit h H K as a 
c o ntri b uti n g fact or 
•  
C o nti n u o us varia ble s u m mar y statistics ( me dia n a n d 
mea n) of t otal L O S wit h H K as a c o ntri b uti n g fact or 
b y ra n d o mise d treat me nt gr o u p. Wilc o x o n ra n k -s u m 
test b y ra n d o mise d treat me nt gr o u p. 
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he t otal L O S 
i n all-ca use h os pitalisati o ns  
•  
C o nti n u o us varia ble s u m mar y statistics ( me dia n a n d 
mea n) of t otal L O S i n all -ca use h os pitalisati o ns b y 
ra n d o mise d treat me nt gr o u p. Wilc o x o n ra n k-s u m test 
b y ra n d o mise d treat me nt gr o u p.   
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of disc har ge me dicati o ns, c o m pare d t o 
S o C i n re d uci n g t he i nci de nce of K -bi n der 
use  
•  
Ti me t o first occ urre nce of K -bi n der use i n eac h ar m 
at a n y ti me p ost -disc har ge u p t o 1 8 0 da ys . 
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of disc har ge me dicati o ns, c o m pare d t o 
S o C i n re d uci n g t he fre q ue nc y a n d d urati o n 
of K -bi n der use  
•  
Ti me t o disc o nti n uati o n of K -bi n der fr o m i nitiati o n 
i n eac h ar m i n t he first i nsta nce of K-bi n der use 
p ost -disc har ge u p t o 1 8 0 da ys . 
•  
Fre q ue nc y of t he use of K -bi n der t o treat H K at a n y 
ti me p ost-disc har ge u p t o 1 8 0 da ys i n eac h ar m . 
•  
T o e val uate t he effect of c o nti n ui n g S Z C  as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of resc ue t hera p y f or H K use  
•  
Ti me t o first occ urre nce of resc ue t hera p y use i n 
eac h ar m at a n y ti me p ost -disc har ge u p t o 1 8 0 da ys .  
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of t he c o m p osite o utc o me of all -ca use 
h os pitalisati o ns, E D visits, or o ut patie nt 
visits  
•  
Ti me t o first occ urre nce of all -ca use h os pitalisati o ns, 
E D visits, or o ut patie nt visits i n eac h ar m at a n y ti me 
p ost -disc har ge u p t o 1 8 0 da ys . 
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n t he c ha n ge i n e G F R  
•  
Rate of c ha n ge i n (sl o pe) e G F R fr o m i n patie nt p hase 
t o 9 0 a n d 1 8 0 da ys p ost-disc har ge res pecti vel y, i n 
eac h ar m . 
•  
T o e val uate t he effect of c o nti n ui n g S Z C as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n t he i nci de nce of 
dial ysis i nitiati o n  
•  
Ti me t o first occ urre nce of dial ysis i nitiati o n i n eac h 
ar m at a n y ti me p ost -disc har ge u p t o 1 8 0 da ys . 
•  
T o e val uate t he effect of c o nti n ui n g S Z C  as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce 
of I C U a d missi o ns  
•  
Ti me t o first occ urre nce of I C U a d missi o ns i n eac h 
ar m at a n y ti me p ost -disc har ge u p t o 1 8 0 da ys . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 1  of 1 1 2  
•  
T o e val uate t he effect of c o nti n ui n g S Z C  as 
part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, o n t he a bilit y t o c o nti n ue 
R A A Si  
•  
Descri pti ve s u m mar y of use of , a n d c ha n ges i n use 
of, R A A Si, at u p t o 9 0 a n d 1 8 0 da ys p ost -disc har ge , 
res pecti vel y, i n eac h ar m. 
A b bre viati o ns: A E = a d verse e ve nt; E C G = electr ocar di o gra m; E D = e mer ge nc y de part me nt; e G F R = esti mate d 
gl o mer ular filtrati o n rate; H K =  h y per kalae mia;  H R = hazar d rati o; I C U = i nte nsi ve care u nit; K+  = p otassi u m; 
L O S = le n gt h of sta y; N K = n or m o kalae mia or n or m o kalae mic; R A A Si  = re ni n-a n gi ote nsi n -al d oster o ne s yste m 
i n hi bit or; S o C = sta n dar d of care; S Z C = s o di u m zirc o ni u m c ycl osilicate. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 2  of 1 1 2  
4  
S T U D Y D E SI G N  
4. 1  
O ver all  Desi g n  
•  
T his is a P hase 4, ra n d o mise d, c o ntr olle d, o pe n- l a bel, parallel- gr o u p, m ultice ntre st u d y i n 
partici pa nts wit h C K D tr eate d f or H K  w hilst i n h os pital . 
•  
Partici pa nts fr o m 3 0 t o 5 0 sites i n 4 t o 7 c o u ntries will be scree n e d f or e nr ol me nt. 
Ass u mi n g a 2 0 % dr o p o ut rate fr o m e nr ol me nt t o ra n d o misati o n a n d a 2 0 % dr o p o ut p ost-
disc har ge ( p ost-ra n d o mis ati o n), a p pr o xi matel y 1 6 3 partici pa nts will ha ve t o be e nr olle d t o 
ac hie ve 1 0 4 e val ua ble partici pa nts ( 5 2 per ar m).  I n t otal, u p t o a ma xi m u m of 1 6 3 
p artici pa nts  will be e nr olle d, res ulti n g i n a p pr o xi matel y 1 3 0 partici pa nts disc har ge d a n d 
ra n d o mise d a n d 1 0 4 e v al ua ble partici pa nts  ( 5 2 p er ar m). 
•  
T he st u d y pla ns t o e nr ol a p pr o xi matel y e q ual n u m bers of partici pa nt s wit h mil d H K 
( K+  bet wee n > 5 . 0 a n d ≤ 5. 5 m m ol/ L ) a n d wit h m o derate/se v ere  H K ( K +  b et wee n > 5. 5 
a n d ≤ 6. 5 m m ol/ L ), wit h a mi ni m u m of 3 0 % of t he e nr olle d partici pa nts i n eit her gr o u p. 
•  
D uri n g t he i n- h os pital p hase, partici p a nts will be treate d wit h S Z C as per l o cal la bel 
(c orr ecti o n a n d/ or mai nte na nce treat me nt, see S ecti o n  6. 1 ), starti n g at baseli ne a n d base d 
o n l ocal K +  meas ure m e nt o btai ne d wit hi n 2 4 h o urs of treat me nt i nitiati o n:  
- 
P artici pa nts wit h  H K  ( K + bet wee n > 5. 0 a n d ≤ 6. 5 m m ol/ L): 1) st o p c urre nt K- bi n der 
if a n y, 2) start S Z C c orr ecti o n  d ose ( n ote: partici p a nts c urre ntl y o n S Z C s h o ul d 
c o nti n ue S Z C c orrecti o n  d ose, u p t o 7 2 h o urs). 
- 
Partici pa nts c urr e ntl y recei vi n g a n y treat me nt f or t he c urre nt e pis o de of H K a n d are 
alrea d y N K at bas eli ne ( K + ≤ 5. 0 m m ol/ L): 1) st o p a n y c urre nt K - bi n der, 2) start 
S Z C mai nte na nce  d ose ( n ote: partici pa nts c urre ntl y o n S Z C mai nte na nce d ose s h o ul d 
c o nti n ue S Z C mai nte na nce d ose). 
- 
All treat me nt decisi o ns, i ncl u di n g m o dificati o n of t he o n g oi n g t hera p y f or H K, m ust 
be base d o n t he  i n vesti gat or’s me dical j u d ge me nt of t he partici pa nt’s b est i nterest. 
•  
At disc har ge, N K partici pa nts  w h o ha ve b ee n treate d wit h S Z C f or bet wee n 1 a n d 2 1 da ys 
w hilst i n h os pital a n d are starte d o n S Z C mai nte na nce d ose will be ra n d o mise d i n a 1: 1 
rati o t o o ne of t he f oll o wi n g ar ms: 
- 
Ar m A: P artici pa nts  disc har ge d wit h S Z C, as per l ocal la bel, t o ma na g e H K u ntil t he 
e n d of t he o ut patie nt p hase 
- 
Ar m B: P artici pa nts  disc har ge d wit h S o C, as per l ocal practice, t o ma na g e H K u ntil 
t he e n d of st u d y. 
•  N ote: Partici pa nts i nte n de d t o be disc har g e d wit h a K- bi n der (as per t he site r o uti ne 
me dical practice) will  n ot be ra n d o mise d a n d will be disc o nti n ue d fr o m t he st u d y. Still, 
partici pa nts ra n d o mise d i nt o Ar m B ma y ha ve a K- bi n der pres cri be d at Da y 7 
p ost- disc har ge  ( or after Da y 7 p ost-disc har g e ), t o treat c o nfir m e d H K or i n case t here 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 3  of 1 1 2  
is a n i ncreas e i n K+  le vel si nce disc har g e t hat, i n t he i n vesti gat or’s o pi ni o n, re q uires 
t hera p y. 
•  
T he t otal d urati o n of t he st u d y f or eac h partici pa nt will be u p t o a p pr o xi matel y 6 m o nt hs.  
•  
St u d y visit sc he d ule is as f oll o ws: 
•  I n- h os pital p hase: 
- 
T he scree ni n g visit will occ ur w hile t he p artici pa nt is at t he h os pital ( u p t o 
2 1 da ys bef or e disc har ge; me dical m o nit or’s a p pr o val ma y be s o u g ht f or 
all o wi n g l o n ger d urati o n h os pital sta ys f or s pecific partici pa nt s) i n or der t o c hec k 
eli gi bilit y criteria 
- 
I n p atie nt p hase: 
o  
T he baseli ne visit (ca n occ ur t he sa me d a y as t he s cree ni n g visit) w here 
treat me nt wit h S Z C will be i nitiate d 
o  
T he disc har g e visit, 1 t o 2 0 da ys after baseli ne ; m e dical m o nit or’s a p pr o v al 
ma y be s o u g ht f or all o wi n g l o n ger d urati o n h os pital sta ys f or s pecific 
partici pa nt s). Ra n d o misati o n will occ ur  at da y of disc har ge. 
•  O ut patie nt p hase: 
- 
Visits  will occ ur at 7, 3 0, 6 0, 9 0, 1 2 0, 1 5 0, a n d 1 8 0 ( E O T) da ys after 
ra n d o misati o n. O nl y visits at 7, 9 0 a n d 1 8 0 da ys after ra n d o misati o n will be 
o n- site visits, t he re mai ni n g bei n g tele p h o ne visits. If d ose titrati o n occ urs at a n y 
ti me d uri n g t he o ut patie nt p hase, u nsc he d ule d dis p e nsati o n visits will be 
perf or me d.  
•  F oll o w- u p p hase: 
- 
A f oll o w- u p o n- site visit (e n d of st u d y visit ) will occ ur a p pr o xi matel y 7 da ys 
after E O T . 
•  
Data  will be c ollecte d at o n -site visits, via tele p h o ne visits a n d me dical c hart re vie ws.  
•  
A n a dj u dicati o n c o m mittee will be i n v ol ve d i n t he st u d y (see A p pe n di x A 5 ). 
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n  
H os pitalise d C K D patie nts wit h H K are at hi g her ris k of rec urre nt H K a n d of rea d missi o n t ha n 
h os pitalise d C K D patie nts wit h o ut H K.  
C O N TI N UI T Y will recr uit h os pitalise d partici pa nts wit h C K D (see i ncl usi o n criteri o n # 3  f or 
details) a n d H K (see i ncl usi o n criteri o n # 4  f or det ails). After treat me nt wit h S Z C, t he 
partici pa nts reac hi n g N K will be ra n d o mise d t o eit her S Z C or S o C treat me nt at disc har ge . T he 
st u d y ai ms t o s h o w t hat prescri bi n g S Z C as a part of t he disc har g e me dicati o ns i n t his 
p o p ulati o n will res ult i n a n i ncrease d li keli h o o d of mai ntai ne d N K a n d a re d uce d i nci de n ce of 
all-ca use h os pital a d missi o ns or E D visits  wit h H K as a c o ntri b uti n g fact or, c o m pare d wit h 
partici p a nts disc har ge d wit h S o C. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 4  of 1 1 2  
T he st u d y i nter ve nti o ns are S Z C (as per l o cal la bel) a n d S o C (as per l o cal practice) gr o u ps. 
Partici pa nts i n b ot h gr o u ps will ha ve K +  n or malise d at t he be gi n ni n g of t he o ut patie nt p hase 
a n d m o nit ori n g of K +  will occ ur d uri n g st u d y. Titrati o n of S Z C will be base d o n K+  val ues, 
acc or di n g t o Secti o n  6. 2  to e ns ure partici p a nts recei ve S Z C at a n i n di vi d uall y o pti mise d d ose. 
Clear g ui da nce is i n place f or r esc ue t h era p y f or H K (see Secti o n 6. 7. 1 ) as well as f or st u d y 
disc o nti n uati o n (see Secti o n 7 ). 
T he S o C as per l ocal pr actice is use d as c o m p arat or as t here is c urre ntl y n o sta n dar dise d 
t hera p y t o treat patie nts wit h C K D a n d H K aft er disc har ge  fr o m t he h os pital. 
T he st u d y is desi g ne d t o ali g n as m uc h as p ossi ble wit h real- w orl d cli nical practice, wit h l o w 
n u m ber of ma n dat e d o n- site f oll o w-u p visits (at D a ys 7, 9 0, a n d 1 8 0 p ost- disc har ge ) a n d b y 
usi n g me dical c hart r e vie ws a n d tele p h o ne c o ntacts i n bet wee n f or c o m ple me ntar y data 
c ollecti o n. 
C O N TI N UI T Y  is a P has e 4 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 d eter mi ne if t here is a n a d diti o nal be nefit of pres cri bi n g S Z C at disc har ge i n 
t he selecte d p o p ulati o n. T he pri mar y o bjecti ve is t o e val uate t he efficac y of c o nti n ui n g S Z C as 
part of t he disc har ge m e dicati o ns, c o m pare d t o S o C, i n mai ntai ni n g N K . T he mai n sec o n dar y 
o bjecti ve is t o e val uate t h e effect of c o nti n ui n g S Z C as part of t he disc har ge me dicati o ns, 
c o m pare d t o S o C, i n re d uci n g t he i nci de nce of t h e c o m p osite o utc o me of all-ca use h os pital 
a d missi o n s or E D visits wit h H K as a c o ntri b uti n g fact or. Ot her s ec o n dar y o bjecti ves i ncl u de 
t he o utc o me of h os pital a d missi o ns wit h H K as a c o ntri b uti n g fact or. T he defi niti o n of 
h os pital a d missi o n s a n d E D visits wit h H K as a c o ntri b uti n g f act or , rat her t ha n d ue t o  H K, is 
base d o n t he f act t hat H K is rarel y deter mi ne d as t he pri mar y ca use of t h ese healt h care 
e nc o u nters. A n  a dj u dicati o n c o m mittee will be f or me d t o deter mi ne w het h er H K was a 
c o ntri b uti n g ca use of t he e nc o u nter. N ote: T his a dj u dicati o n c o m mittee will als o re vie w t he 
re p orte d c o nc o mita nt me dicati o ns t o deter mi ne R A A Si d o w n-titrati o n/ disc o nti n uati o n e ve nts 
a n d use of r esc ue t h era p y f or H K . 
4. 2. 1  
P artici p a nt I n p ut i nt o Desi g n 
N ot a p plica ble. 
4. 3  
J ustific ati o n f or D ose  
D uri n g b ot h i n- h os pital a n d o ut patie nt p hases, S Z C will be d ose d acc or di n g t o its l ocal la bel; 
see Secti o ns 6. 1  a n d 6. 2 .  
Cli nical st u dies i n partici pa nt s wit h H K c o nsiste ntl y de m o nstrate d t hat i nitial treat me nt wit h 
S Z C 1 0 g t hree ti mes dail y (TI D ) f or 2 4 h o urs u p t o 7 2 h o urs res ulte d i n cli nicall y mea ni n gf ul 
K +  re d ucti o n wit h a maj orit y of partici pa nts ac hie vi n g N K wit hi n 2 4 t o 4 8 h o urs. M ore o ver, 
partici pa nts  wit h hi g her baseli ne K+  le vels ha d greater re d ucti o ns i n K+  le v els (H o y, 2 0 1 8 ). 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 5  of 1 1 2  
O nset of efficac y was r a pi d wit h K +  re d ucti o n o bser ve d as earl y as 1 h o ur after d ose i nta ke 
(H o y, 2 0 1 8 ). 
After c orrecti o n of H K, c o nti n ue d mai nte na nce treat me nt f or 2 8 da ys wit h S Z C 5, 1 0, or 1 5 g 
dail y res ulte d i n c o nti n ue d effecti ve c o ntr ol of K +  wit hi n t he N K ra n ge. T h e pr o p orti o n of 
partici pa nts  w h o re m ai ne d N K at t he E O T  wit h S Z C 5, 1 0, a n d 1 5 g dail y i ncreas e d d ose-
de pe n de ntl y (r a n ge: 7 1 % t o 8 5 %) a n d was s u p eri or t o place b o.  
L o n g- ter m mai nte na n ce treat me nt wit h S Z C f or u p t o 1 2 m o nt hs has als o bee n st u die d. Once 
dail y ( Q D) d osi n g wit h S Z C, starti n g fr o m 5 g Q D a n d s u bse q ue ntl y i n di vi d ualize d, pr o vi de d 
mai nte na nce of N K  f or u p t o 1 2 m o nt hs, wit h 8 7 % of partici pa nts ac hie vi n g K+  ≤ 5. 1 m m ol/ L 
at Da y 3 6 5 (S pi n o witz et al, 2 0 1 9 ). 
4. 4  
E n d of St u d y  Defi niti o n  
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y if he/s he has c o m plete d all p hases of 
t he st u d y i ncl u di n g t he last sc he d ule d pr oce d ure at visit 1 1, as s h o w n i n t he Sc he d ule of 
Acti vities  ( S o A; Ta ble  1). 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast sc he d ule d pr o ce d ure s h o w n i n t he S o A 
f or t he last partici p a nt i n t he st u d y. 
5  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o v al of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d. Rescree ni n g of partici p a nts is all o we d as 
detaile d i n Secti o n  5. 4 . 
T he distri b uti o n of partici pa nts acr oss t he ra n ge of K +  le vels will be o perati o nall y c o ntr olle d 
b y e ns uri n g t hat t he f oll o wi n g rati os are met: 
•  
A p pr o x i matel y 5 0 % e nr olle d partici pa nt s wit h mil d H K (K +  bet wee n > 5. 0 a n d 
≤ 5. 5 m m ol/ L ) a n d a p pr o xi matel y 5 0 % wit h m o derate/se vere  H K ( K+  bet w ee n > 5. 5 a n d 
≤ 6. 5 m m ol/ L )  
•  
A mi ni m u m of 3 0 % of e nr olle d partici pa nt s i n eac h gr o u p.  
5. 1  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be i n cl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y: 
A ge  
1  
M ust be 1 8 years of a ge or ol der, at t he ti me of si g ni n g t he i nf or me d c o nse nt 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 6  of 1 1 2  
T y pe of P artici p a nt a n d Dise ase C h ar acteristi cs  
2  
A d mitte d t o h os pital (i n patie nt care; directl y or fr o m E D)  
3  
Wit h:  
- 
Dia g n ose d C K D ( a n y sta ge)  
or 
- 
e G F R < 9 0 m L/ mi n/ 1. 7 3 m2 at, or wit hi n 3 m o nt hs of, st u d y scree ni n g, b ase d o n t he 
C hr o nic Ki d ne y Diseas e E pi de mi ol o g y C olla b orati o n ( C K D- E PI) e q u ati o n (Le ve y et 
al, 2 0 0 9). N ote : Race/et h nicit y s h o ul d n ot be i ncl u de d i n C K D- E PI e q uati o n 
calc ulati o n.  
4  
L ocal la b or at or y K +  meas ure me nt wit hi n 2 4 h o urs of baseli ne visit ( visit 2), w here res ult 
is eit her: 
•  H y per kalae mic  as d efi ne d b y site’s l ocal practi ce a n d K+  ≤ 6. 5 m m ol/ L 
•  Or,  n or m o kalae mic: K +  bet wee n ≥ 3. 5 a n d ≤ 5. 0 m m ol/ L, w here patie nt starte d a n d is 
recei vi n g tr eat me nt f or t his e pis o de of H K.  
Se x  
5  
Male or fe m ale  
I nf or m e d C o nse nt 
6  
Ca pa ble a n d willi n g of gi vi n g si g ne d i nf or me d c o nse nt as descri b e d i n  A p pe n di x A  w hic h 
i ncl u des c o m plia nce wit h t he re q uire m e nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt 
f or m (I C F) a n d i n t his pr ot oc ol. 
5. 2  
E xcl usi o n Criteri a  
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y: 
Me dic al C o n diti o ns  
1  
H os pitalisati o n f or a n ac ute car di o vas c ular e ve nt wit hi n 1 2 wee ks pri or t o scree ni n g  
2  
U na ble t o ta ke or al S Z C  dr u g mi x  
3  
-  
4  
Wit h a life e x pecta nc y of less t ha n 6 m o nt hs  
5  
A n y me dical c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or ma kes t he partici pa nt n ot 
s uita ble f or i ncl usi o n 
6  
- 
7  
Q T i nter val c orrecte d b y t he Fri dericia met h o d ( Q Tc F) > 5 5 0 msec 
8  
Hist or y of Q T pr ol o n gati o n ass ociate d wit h ot her me dicati o ns t hat re q uire d 
disc o nti n uati o n of t hat me dicati o n 
9  
C o n ge nital l o n g Q T s y n dr o me 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 7  of 1 1 2  
1 0  Cli nicall y si g nifica nt arr yt h mias  as j u d ge d b y t he i n vesti gat or 
1 1  - 
1 2  - 
Pri or/ C o nc o mit a nt T her a p y  
1 3  O n g oi n g treat me nt wit h S Z C or patir o mer bef ore c urre nt E D visit/ h os pital a d missi o n  
( o n g oi n g treat me nt wit h ot her K- bi n ders bef ore c urre nt E D visit/ h os pital a d missi o n is 
all o we d). N ote: I nitiati o n of S Z C  or patir o mer d uri n g t he c urre nt E D visit/ h os pitalisati o n 
prece di n g e nr ol me nt  is all o we d.  
1 4  C hr o nic hae m o dial ysis or perit o neal dial ysis  or t h e reci pie nt of or sc h e d ule d date f or a 
ki d ne y tra ns pla nt. N ote: E mer ge nc y/ u nsc h e d ule d hae m o dial ysis t o treat H K d uri n g t he 
c urre nt E D visit/ h os pitalisati o n prece di n g e nr ol me nt is all o we d. 
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce  
1 5  Partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal me dici nal pr o d uct (IM P)  
a d mi nistere d d uri n g t he m o nt h bef ore scree ni n g.  
1 6  K n o w n h y perse nsiti vit y t o S Z C or a n y of t he e xci pie nts of t he pr o d uct 
Ot her E xcl usi o ns  
1 7  I n v ol ve m e nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o b ot h Astra Ze neca 
staff a n d/ or staff at t he st u d y site) 
1 8  J u d g me nt b y t he i n vesti gat or t hat t he partici pa nt s h o ul d n ot partici pate i n t he st u d y if t he 
partici pa nt is u nli kel y t o c o m pl y wit h st u d y pr oce d ures, restricti o ns, a n d re q uire me nts 
1 9  Pre vi o us ra n d o misati o n i n t he prese nt st u d y  
2 0  F or w o me n o nl y: W o me n of c hil d- beari n g p ote ntial ( W O C B P; ie, t h ose w h o are n ot 
c he micall y or s ur gicall y sterilise d or w h o are n ot p ost- me n o pa usal) w h o are n ot willi n g t o 
use o ne of t he met h o ds of c o ntrace pti o n descri be d hereafter, or w h o are n ot sta ble o n t he 
c o ntrace pti o n met h o d f or t he last o ne m o nt h, fr o m t he ti me of si g ni n g t he i nf or me d 
c o nse nt t hr o u g h o ut t he st u d y a n d 7 da ys aft er t he l ast d ose: 
a)  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n: oral, i ntra va gi nal, tra ns der mal 
b)  Pr o gest o ge n- o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n: oral, 
i njecta ble, i m pla nta ble 
c)  I ntr a uteri ne d e vice 
d)  I ntr a uteri ne h or m o ne-rel easi n g s yste m 
e)  Bilateral t u b al occl usi o n  
f) Vasect o mise d part ner ( v asect o mise d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d 
pr o vi de d t hat part ner is t he s ole se x ual part ner of t he W O C B P partici pa nt a n d t hat t he 
vasect o mise d part n er has recei v e d me dical assess me nt of t he s ur gical s uccess  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 8  of 1 1 2  
g)  Se x ual a bsti ne nce: it is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as 
refr ai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d 
wit h t he st u d y treat me nts. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n 
relati o n t o t he d urati o n of t he st u d y a n d t he preferre d a n d us ual lifest yle of t he 
partici pa nt.  
2 1  F or W O C B P  o nl y: W o me n w h o ha ve a p ositi ve pre g na nc y t est at scree ni n g O R w o me n 
w h o are breastf ee di n g . 
5. 3  
Lifest yle C o nsi der ati o ns  
N o lifest yle restricti o ns are re q uir e d i n t he st u d y. 
5. 4  
Scree n F ail ures  
Scree n f ail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
are n ot s u bse q u e ntl y e ntere d i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns p are nt r e p orti n g of scree n fail ure partici pa nts t o meet t he C o ns oli date d 
Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts a n d t o res p o n d t o q u eries fr o m 
re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, 
eli gi bilit y criteria, a n d a n y seri o us a d vers e e v e nt ( S A E ) a n d s h o ul d be rec or de d i n t he 
electr o nic Cas e Re p ort F or m (e C R F ). 
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y (scree n fail ure) ma y b e 
rescr ee ne d ( ma xi m u m t wice) if:  
•  scree n fail ure is d ue t o n ot meeti n g K +  or e G F R i ncl usi o n criteria  
•  excl usi o n criteria are n o  l o n ger a p plica bl e 
•  tec h nical iss ues are e n c o u ntere d at e nr ol me nt site visit . 
Partici pa nts w h o are rescree ne d s h o ul d b e assi g ne d t he sa me partici p a nt n u m ber as f or t h e 
i nitial scree ni n g. 
6  
S T U D Y I N T E R V E N TI O N  
St u d y i nter ve nti o n is defi ne d as a ny i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s) or 
place b o i nte n de d t o b e a d mi nistere d t o or me dical de vice(s) utilise d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol. 
6. 1  
Scree ni n g a n d I n p atie nt P h ase  
Partici pa nts wit h H K ( see i ncl usi o n criteri o n # 4 ) a n d n ot o n S Z C or patir o mer bef ore t his 
c urre nt E D visit/ h os pital a d missi o n (i nitiati o n of S Z C or patir o mer d uri n g E D 
visit/ h os pitalisati o n prece di n g e nr ol me nt is all o w e d), will start S Z C, as per l ocal la bel, d uri n g 
t he i n patie nt p hase. I nitiati o n of S Z C treat me nt will be base d o n l ocal meas ure me nt of K+ , 
o btai ne d wit hi n 2 4 h o urs pri or t o first d ose of o n-st u d y S Z C: 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 9  of 1 1 2  
•  
C orrecti o n  treat me nt: 1 0 g, TI D f or u p t o 7 2 h o urs. T y picall y, N K is ac hie v e d wit hi n 
2 4 t o 4 8 h o urs. If partici p a nts are still h y per kal ae mic after 4 8 h o urs of treat me nt, t he sa me 
re gi me n ca n b e c o nti n ue d f or a n a d diti o nal 2 4 h o urs. If N K is n ot ac hie ve d after 7 2 h o urs 
of treat me nt, ot her treat m e nt a p pr oac hes s h o ul d be c o nsi dere d, a n d t he parti ci pa nt 
disc o nti n ue d fr o m t he st u d y d ue t o lac k of S Z C effect. Partici pa nts w h o recei ve d a n y H K 
treat me nt d uri n g c urre nt E D visit/ h os pitalisati o n prece di n g e nr ol me nt a n d are N K at 
baseli ne  ca n directl y start t he mai nte na nce d ose of S Z C (see hereafter).   
•  
Mai nte na nce treat me nt  ( o nce N K  [ K+ bet wee n  3. 5 a n d 5. 0 m m ol/ L, i ncl usi ve ] is reac he d): 
5 g, Q D . D ose will be a dj uste d base d o n K+  (see T a ble 4 ). T he rec o m me n d e d 
mai nte na nce d os e ra n g e is fr o m 5 g e ver y ot h er da y t o 1 0 g dail y. 
Partici pa nts wit h N K  a n d w h o ha ve bee n  starte d o n a mai nte na nce d ose f or S Z C ( per l ocal 
la bel) at t he ti me of disc h ar ge will be ra n d o mise d at disc har g e t o eit her Ar m A ( S Z C per l ocal 
la bel) or Ar m B ( S o C, as per l ocal practice) a n d e nter t he o ut patie nt p hase. 
T he f oll o wi n g partici pa nts will n ot be eligi ble f or ra n d o mis ati o n: 
•  
Partici pa nt i nte n de d t o be disc har g e d o n a K- bi n der as per t he site r o uti ne me dical 
practice ( disc o nti n ue d fr o m t he st u d y) 
•  
Partici pa nt wit h a n i n - h os pital p hase e xcee di n g 2 1  da ys (i ncl u di n g scree ni n g), e xce pt 
w he n st u d y me dical m o nit or’s a p pr o val w as s o u g ht f or l o n ger d urati o n of h os pital sta ys 
f or s pecifi c partici pa nts  
•  
Partici pa nts wit h K +  > 5. 0 m m ol/ L at disc har ge; t hese partici p a nts will be disc o nti n ue d 
fr o m t he st u d y treat me nt a n d f oll o we d u p as p er pr ot oc ol 
•  
Partici pa nts wit h K +  < 3. 5 m m ol/ L at disc har ge; t hese partici p a nts will be disc o nti n ue d 
fr o m st u d y treat me nt a n d will be f oll o we d per pr ot oc ol. 
6. 2  
O ut p atie nt P h ase  
Partici pa nts ra n d o mise d t o Ar m A will be disc har g e d wit h S Z C d ose d per l ocal la bel ( fr o m 5 g 
e ver y ot her da y t o 1 0 g d ail y)  t o ma na ge K +  u ntil t he E O T  ( 1 8 0 d a ys p ost-disc har ge ). 
As per la bel, S Z C d ose titrati o n will be all o we d base d o n K +  le vels as detail e d i n Ta ble 4 .  
Ta ble 4  
D ose Tit r a ti o n a n d Disc o nti n u ati o n Criteri a D uri n g t he O ut p atie nt P h ase 
K +  ( m m ol/ L) 
D ose Titr ati o n a n d Disc o nti n u ati o n Criteri a f or A b n or m al K +  
< 3. 0  
•  Treat me nt per ma ne ntl y disc o nti n ue d (see Secti o n  7. 1. 1 ). C hec k E C G a n d treat acc or di n g t o 
me dical j u d g me nt.  
3. 0 - 3. 4  
•  C hec k E C G, per ma ne ntl y disc o nti n ue treat me nt if seri o us arr h yt h mia f o u n d a n d treat 
acc or di n g t o me dical j u d g me nt.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 0  of 1 1 2  
K +  ( m m ol/ L) 
D ose Titr ati o n a n d Disc o nti n u ati o n Criteri a f or A b n or m al K +  
•  If n o seri o us arr h yt h mia f o u n d, i n vesti gat or t o c o nsi der t o d o w n -titratea or pa use S Z C a n d 
treat acc or di n g t o me dical j u d g me nt. Partici pa nts wit h heart fail ure s h o ul d pa use st u d y dr u g.  
•  I ncrease m o nit ori n g u ntil K+  ≥ 3. 5 m m ol/ L .a 
•  E val uate f or u n derl yi n g ris k f or h y p o kal ae mia. If h y p o kalae mia res ol ves a n d partici pa nt  
dee me d a p pr o priate t o restart treat me nt (f or partici pa nts  w h o ha ve pa use d S Z C), t he n t he 
i n vesti gat or s h o ul d c o nsi der t o restart S Z C at a l o wer d ose.a 
3. 5 - 5. 0  
•  N o c ha n ge i n S Z C d ose  is rec o m me n de d. 
5. 1 – 5. 5  
•  I ncrease S Z C d ose b y 5 g Q D i ncre me nts u p t o a ma xi m u m of 1 0 g Q D. a 
•  I ncrease m o nit ori n g u ntil K+  i n n or mal ra n ge. 
5. 6 – 6. 0  
•  C hec k E C G, disc o nti n ue treat me nt if seri o us arr h yt h mia f o u n d a n d treat acc or di n g t o 
me dical j u d g me nt.  
•  If n o seri o us arr h yt h mia, i ncrease S Z C d ose b y 5 g Q D i ncre me nts u p t o a ma xi m u m of 1 0 g 
Q D. a 
•  F urt her K +  m o nit ori n g a n d treat me nt per i n vesti gat or me dical j u d g me nt base d o n partici pa nt 
ris k a n d be nefit. 
•  I ncrease m o nit ori n g fre q ue nc y u ntil K+  i n n or mal ra n ge. 
> 6. 0  
•  Treat me nt per ma ne ntl y disc o nti n ue d (see Secti o n  7. 1. 1 ); i nitiate resc ue t hera p y (see Secti o n 
6. 7. 1  f or resc ue t hera p y). 
•  C hec k E C G a n d treat acc or di n g t o me dical j u d g me nt.  
A b bre viati o ns: E C G = electr ocar di o gra m; K +  = p otassi u m; Q D = o nce dail y; R A A Si = re ni n a n gi ote nsi n-
al d oster o ne s yste m i n hi bit or ; S Z C = s o di u m zirc o ni u m c ycl osilicate. 
a A n y ti me st u d y dr u g d ose is a dj uste d, or if i n eit her treat me nt ar m, a c o nc o mita nt me dicati o n w hic h ma y 
affect K +  le vels is c ha n ge d (e g, use of R A A S i or di uretics), t he parti ci pa nt nee ds t o ret ur n t o t he site 7 ( ± 2) 
da ys later f or a K +  meas ure me nt a n d rec or di n g of a d verse e ve nts a n d c o nc o mita nt me dicati o ns.  
Partici pa nts ra n d o mise d t o Ar m B will be disc har g e d wit h o ut S Z C a n d will recei v e S o C per 
l ocal practice f or m a na gi n g t heir K+  u ntil t he E O T  ( 1 8 0 da ys p ost- disc har ge). T he S o C will be 
at t he discreti o n of t he tr eati n g p h ysicia n ; h o we ver, partici pa nts i nte n de d t o be disc har g e d 
wit h a K- bi n der will n ot be ra n d o mise d. H o w e ver, partici pa nts i n Ar m B m a y ha ve a K- bi n der 
prescri be d at  Da y 7 p ost-disc har ge ( or after D a y 7 p ost- disc har ge) t o treat c o nfir me d H K or i n 
case t here is a n i ncreas e i n K +  le vel si nce disc har g e t hat, i n t he i n vesti gat or’s o pi ni o n, re q uires 
t hera p y. 
T he K +  le vels will be meas ure d at o n-site visits at D a ys 7 (l ocal la b orat or y), 9 0 (l ocal a n d 
ce ntral la b orat ories) , a n d 1 8 0 (l ocal a n d ce ntral la b orat ories) (s ee Secti o ns 8. 1. 1  an d  8. 2. 4 ). 
O verall m o nit ori n g fre q u e nc y will de pe n d u p o n a variet y of fact ors i ncl u di n g ot her 
me dicat i o ns, pr o gressi o n of C K D, a n d dietar y K+  i nta ke. It is t he res p o nsi bilit y of t he treati n g 
p h ysicia ns t o c hec k t he p artici pa nt K +  as me dicall y a p pr o priate/i n acc or d a n ce wit h t he la bel 
(f or b ot h S Z C a n d S o C ar ms). I n a d diti o n t o t he sc he d ule d o n-site visits, partici pa nts s h o ul d 
ret ur n t o t he site f or a l ocal K +  meas ure me nt 7 ( ± 2) da ys after a n y d os e a dj ust me nt t o S Z C. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 1  of 1 1 2  
A d diti o nall y, partici pa nts  i n eit her treat me nt ar m s h o ul d ha ve t heir K+  meas ure d l ocall y 
7 ( ± 2) da ys after c h a n ges are ma d e t o me dicati o ns t hat affect  K+  le vels (e g, use of R A A Si  or 
di uretics).  
S uc h a d diti o nal K +  c hec ks a n d site visits  will ta ke place as cli nicall y i n dicat e d  a n d t he 
res ulti n g data, i ncl u di n g A Es a n d c o nc o mita nt me dicati o n i nf or mati o n, relati n g t o t hese visits  
will als o be c ollecte d d uri n g t he st u d y.   
6. 3  
St u d y I nter ve nti o ns A d mi nistere d  
6. 3. 1  
I n vesti g ati o n al Pr o d u cts 
Ta ble 5  pr o vi des i nf or m ati o n o n t he I M P.  
Ta ble 5  
I n vesti g ati o n al Pr o d ucts 
I nter ve nti o n N a me 
S o di u m zirc o ni u m c ycl osilicate ( S Z C)  
D ose F or m ul ati o n/ U nit D ose Stre n gt h  
W hite t o gre y cr ystalli ne p o w der f or oral s us pe nsi o n 
i n 5 g sac hets 
R o ute of A d mi nistr ati o n  
Oral  
Use  
I n vesti gati o nal pr o d uct 
S o urci n g  
Pr o vi de d ce ntrall y b y t he s p o ns or  
P ac k a gi n g a n d L a beli n g  
St u d y treat me nt will be pr o vi de d i n sac het s. Eac h 
sac het will be la bele d i n acc or da nce wit h G o o d 
Ma n ufact uri n g Practice A n ne x 1 3 a n d per c o u ntr y 
re g ulat or y re q uire me nt.  
La bel te xt will be tra nslat e d i nt o l ocal la n g ua ge. 
D uri n g t he i n patie nt p has e, S Z C will be dis pe nse d dail y t o all partici pa nts. 
D uri n g t he o ut patie nt p hase, S Z C will be s u p plie d , at t he site, t o t he partici pa nts ra n d o mise d 
t o Ar m A at t he ti me p oi nts i n dicate d i n t he S o A (Ta ble  1), in t he a m o u nt e x pecte d t o acc o u nt 
f or its usa ge as p er t he i n vesti gat or’s prescri pti o n, i ncl u di n g p ossi ble d ose m o dificati o ns t hat 
mi g ht occ ur bef or e t he n e xt sc he d ule d dis pe nsati o n visit. S o di u m zirc o ni u m c ycl osilicate ma y 
als o be dis pe nse d at u nsc he d ule d visits. H o me deli ver y ma y be c o nsi dere d as alter nati ve m o de 
of s u p pl yi n g dr u g w here l ocal re g ulati o ns all o w.  
F or eac h partici pa nt, t he i n vest i gat or will select t he S o C treat me nt ( base d o n t he m ost 
a p pr o priate o pti o n f or t he partici pa nt) t hat t he p artici pa nt w o ul d recei v e if ra n d o mise d t o t he 
S o C ar m pri or t o ra n d o misati o n of t he partici pa nt. T his m ust be c o m plete d f or all partici pa nts. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 2  of 1 1 2  
T he i nf or mati o n will be r ec or de d i n t he I nteracti ve Res p o nse Tec h n ol o g y/ R a n d o misati o n a n d 
Trial S u p pl y Ma na ge me nt (I R T/ R T S M) s yste m.  
6. 4  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y  
T he oral s us pe nsi o n t o be a d mi nistere d t o partici pa nts d uri n g t he i n patie nt p hase of t he st u d y 
s h o ul d be pre pare d i n t he f oll o wi n g wa y: t he e ntire c o nte nts of t he sac het s h o ul d be e m ptie d 
i n a dri n ki n g glass c o ntai ni n g a p pr o xi matel y 4 5 ml of water a n d stirre d w ell. T he tasteless 
li q ui d s h o ul d be dr u n k w hile still cl o u d y. T he p o w der will n ot diss ol ve. If t he p o w der s ettles, 
t he li q ui d s h o ul d be stirre d a gai n a n d ta k e n. If n ee de d, ri nse t he glass wit h m ore water t o 
e ns ure t hat all of t he c o nt e nt is ta ke n. If 2 sac hets (t otal d ose of 1 0 g) are nee de d, t he sa me 
v ol u me of water ( 4 5 ml) s h o ul d be use d (ie, n o i ncrease i n v ol u me of water). 
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit a n d st ora ge f or all st u d y i nter ve nti o n recei ve d a n d a n y discre p a ncies 
are r e p orte d a n d res ol ve d bef ore us e of t he st u d y i nter ve nti o n. 
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n a n d o nl y a ut h orise d site 
staff ma y s u p pl y or a d mi nister st u d y i nter ve nti o n. All st u d y i nter ve nti o n m ust be st ore d i n a 
sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mat e d) area i n acc or da n ce 
wit h t he la belle d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orise d site 
staff. 
T he i n vesti gat or, i n stit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o ns will 
de pe n d o n l ocal r e g ulati o ns i n a gi ve n st u d y c o u ntr y . 
6. 5  
Me as ures t o Mi ni m ise Bi as: R a n d o mis ati o n a n d Bli n di n g  
T his is a n o pe n-la bel st u d y; h o we ver, t he s p ecific i nter ve nti o n t o be ta ke n b y a partici pa nt will 
be ra n d o ml y assi g ne d usi n g a n I R T/ R T S M. Bef ore t he st u d y is i nitiate d, call-i n directi o ns f or 
t he I R T a n d/ or t he l o g-i n i nf or mati o n a n d directi o ns f or t he R T S M will be pr o vi de d t o eac h 
site. T he site will c o ntact t he I R T/ R T S M pri or t o t he start of st u d y i nter ve nti o n a d mi nistrati o n 
f or eac h partici p a nt. T he site will rec or d t he i nter v e nti o n assi g n me nt o n t he a p plica ble e C R F, 
if re q uire d. O nce a ra n d o misati o n n u m ber has bee n assi g ne d it m ust n ot be re-assi g ne d. 
P ote ntial bias will be re d uce d b y ce ntral ra n d o misati o n. 
St u d y i nter ve nti o n will be dis pe nse d at t he st u d y visits s u m marise d i n t he S o A (Ta ble  1) a n d 
ma y als o be dis pe nse d at u nsc he d ule d visits.    
Dis pe nse d b ut n ot use d st u d y i nter ve nti o n i n u n o pe ne d sac h ets ma y be re- dis pe nse d t o t he 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 3  of 1 1 2  
sa me or ot her st u d y partici pa nts i n t he i n patie nt p hase. 
Ret ur ne d st u d y i nter ve nti o n i n u n o pe ne d pac k ets or sac hets ma y b e re- dis pe nse d t o t he sa me 
st u d y partici pa nt d uri n g t he o ut patie nt p hase. 
6. 6  
St u d y I nter ve nti o n C o m pli a nce  
W he n partici p a nts are d ose d at t he site, w hic h will occ ur d uri n g t he i n p atie nt p hase, t he y will 
recei v e S Z C directl y fr o m t he i n vesti gat or or desi g nee, u n der m e dical s u per visi o n. T he date, 
a n d ti me if a p plica ble, of d ose a d mi nistere d i n t he h os pital will be rec or de d i n t he s o urce 
d oc u me nts a n d rec or de d i n t he e C R F. T he d ose of S Z C a n d st u d y partici pa nt i de ntificati o n 
will be c o nfir me d at t he ti me of d osi n g b y a me m ber of t he st u d y site staff ot her t h a n t he 
pers o n a d mi nisteri n g t he st u d y i nter ve nti o n. 
W he n partici p a nts self -a d mi nister st u d y i nter ve nti o ns at h o me ( S Z C or S o C), c o m plia nce wit h 
st u d y i nter ve nti o ns will be assesse d at eac h visit ( b ot h o n-site a n d tele p h o ne visits). 
C o m plia nce will be asses se d b y c o u nti n g ret ur ne d sac hets a n d direct q uesti o ni n g d uri n g t he 
visits a n d d oc u me nte d i n t he s o urce d o c u me nts a n d e C R F. De viati o n(s) fr o m t he prescri be d 
d osa ge re gi me n s h o ul d b e rec or de d i n t he e C R F a n d i n t he s o urce d oc u m e ntati o n. 
A rec or d of t h e n u m be r of S Z C sac hets f or S Z C dis pe nse d t o a n d ta ke n b y eac h p artici pa nt 
m ust be mai ntai ne d a n d r ec o ncile d wit h st u d y i nter ve nti o n a n d c o m plia nce rec or ds. 
I nter ve nti o n start a n d st o p dates, i ncl u di n g dates f or i nter ve nti o n dela ys a n d/ or d ose 
re d ucti o ns or i ncr eases will als o be rec or d e d i n t he e C R F.  
T here will n ot be acc o u nt a bilit y f or partici pa nts all ocate d t o S o C. 
6. 7  
C o nc o mit a nt T her a p y  
S o di u m zirc o ni u m c ycl osilicate  ca n tra nsie ntl y i ncrease g astric p H b y a bs or bi n g h y dr o ge n 
i o ns t hat ca n lea d t o c h a n ges i n s ol u bilit y a n d a bs or pti o n ki netics f or c o-a d mi nistrate d dr u gs 
wit h p H- de pe n d e nt bi oa vaila bilit y. T heref ore, S Z C s h o ul d be a d mi nistere d at least 2 h o urs 
bef ore or 2 h o urs after or al me dicati o ns wit h gastric p H- de pe n d e nt bi oa vail a bilit y. 
E xa m ples of dr u gs t hat s h o ul d be ta ke n 2 h o urs b ef ore or aft er S Z C t o a v oi d p ossi ble raise d 
gastric p H dr u g i nter acti o n are liste d bel o w: 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 4  of 1 1 2  
Cl ass of Dr u g  
Dr u gs  
Az ole a ntif u n gals  
Ket oc o naz ole, itrac o naz ole, p osac o naz ole  
A nti -h u ma n i m m u n o deficie nc y  dr u gs  
Ataza na vir, nelfi na vir, i n di na vir, rit o na vir, sa q ui na vir, ralte gra vir,  
le di pas vir, ril pi viri ne 
T yr osi ne ki nase i n hi bit ors  
Erl oti ni b, dasati ni b, nil oti ni b  
N ote, t his list is n ot e x ha usti ve. Please refer t o t he S m P C of c o nc o mita nt me dicati o ns t he partici pa nt  gets 
a d mi nistere d f or p H de pe n de nt bi oa vaila bilit y.  
S o di u m zirc o ni u m c ycl osilicate  ca n be c o-a d mi nistere d wit h oral me di cati o ns t hat d o n ot 
e x hi bit p H- de pe n de nt bi o a vaila bilit y wit h o ut s paci n g of d osi n g ti mes. 
I n a dr u g- dr u g i nteracti o n st u d y i n healt h y v ol u nteers, c o-a d mi nistrati o n of S Z C  1 5 g wit h 
tacr oli m us 5 m g res ulte d i n a decr ease d t acr oli m us area u n d er c o nce ntrati o n c ur ve a n d 
ma xi m u m o bser ve d plas ma c o nce ntr ati o n  b y 3 7 % a n d 2 9 %, res pecti vel y. T heref ore, 
tacr oli m us s h o ul d be ta ke n at least 2 h o urs bef ore or after S Z C . I n t he s a me st u d y, 
c o-a d mi nistrati o n of S Z C  a n d c ycl os p ori n di d n ot s h o w a cli nicall y mea ni n gf ul i nteracti o n. 
P otassi u m bi n ders will n ot be a ut h orize d i n Ar m A, u nless t he y are pres cri be d as res c ue 
t hera p y (see Secti o n 6. 7. 1 ). 
A n y me dicati o n or vacci ne (i ncl u di n g o ver- t h e-c o u nter or pres cri pti o n me dici nes, vita mi ns, 
a n d/ or her b al s u p ple me nts) or ot her s pecific cate g ories of i nterest t hat t he p artici pa nt is 
recei vi n g at t he ti me of e nr ol me nt or recei ves d uri n g t he st u d y m ust be rec or de d al o n g wit h: 
•  
Reas o n f or use 
•  
Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates 
•  
D osa ge i nf or m ati o n i ncl u di n g d ose a n d fre q ue nc y. 
If t he partici p a nt recei ve d o ne ( or m ore) C or o na vir us disease 2 0 1 9 ( C O VI D - 1 9) 
vacci n ati o n(s) pri or t o e nr ol me nt, t he n t his nee ds t o be rec or de d i n t he e C R F. 
T he s p o ns or or c o ntr act r esear c h or g a nizati o n st u d y p h ysicia n s h o ul d be c o ntacte d if t her e are 
a n y q uesti o ns re gar di n g c o nc o mita nt or pri or t hera p y. 
6. 7. 1  Resc ue Me dici ne  
Resc ue t her a p y  is all o we d a n d is at t he discreti o n of t he treati n g p h ysicia n (see Ta ble 4  f or 
g ui da nce f or partici pa nts recei vi n g S Z C). F or b ot h ar ms, resc u e t hera p y is defi ne d as a n y 
t hera pe utic i nter v e nti o n c o nsi dere d necessar y i n acc or da nce t o l ocal practice patter ns t o 
ma na ge hi g h K +  i n t he setti n g of se vere H K as defi ne d b y t he treati n g p h ysi cia n a n d site.  T his 
ma y i ncl u de, b ut n ot li mite d t o: 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 5  of 1 1 2  
1)  beta -a dre ner gic a g o nists 
2)  calci u m gl uc o nate  
3)  s o di u m bicar b o nate 
4)  i ntra ve n o us i ns uli n/ gl uc ose 
5)  K- bi n ders 1 
6)  a n y e mer g e nc y dial ysis or ot her f or ms of re n al re place me nt treat me nts gi ve n wit h t he 
g oal of c o ntr olli n g t he H K.  
Resc ue t her a p y s h o ul d be f oll o we d b y t he a p pr o priate S Z C d ose a dj ust me nt a n d pr o per 
d oc u me ntati o n of t he e v e nt.  
T he s p o ns or will n ot  s u p pl y resc ue t hera p y t hat will be o btai ne d l ocall y.  
T he date a n d ti me of res c ue t hera p y  a d mi nistrati o n , as well as t he na m e a n d d osa ge re gi me n 
of t he resc u e t her a p y , m ust be rec or d e d  i n t he e C R F. A d diti o nall y, t he a dj u dicati o n c o m mittee 
will re vie w re p orte d c o n c o mita nt me dicati o ns t o deter mi ne if a n y s h o ul d b e i ncl u de d as resc ue 
t hera p y f or H K. 
Use of r esc ue t hera p y will be treate d statisticall y as descri be d i n t he statistical a nal ysis pla n 
( S A P). See Statistical C o nsi derati o ns, Secti o n  9 , for i m plicati o ns of t he use of resc u e t hera p y 
a n d/ or ot her K- bi n ders t o t he a nal ysis of e n d p oi nts.  
6. 8  
D ose M o dific ati o n  
F or Ar m A, s ee  Ta ble 4  for S Z C d ose titrati o n. 
F or Ar m B, S o C will be a dj uste d at t he discreti o n of t he treati n g  p h ysicia n or t he i n vesti gat or. 
 
 
 
 
 
 
1 W hile partici pa nts  i nte n de d t o be disc har ge d o n a bi n der will n ot be eli gi ble f or ra n d o misati o n, a bi n der ma y be 
nee de d as resc ue t hera p y. Resc ue t hera p y wit h bi n der is defi ne d as t he a d diti o n of a n y bi n der, e xcl u di n g S Z C, t o 
Ar m A  or  t he a d diti o n of a n y bi n der, i ncl u di n g S Z C, t o Ar m B. T he st u d y is o pe n la bel, ie, t he i n vesti gat or s hall 
be a ware of w het her p artici pa nts are treate d wit h S Z C. As per l ocal practice, S Z C s h o ul d be wit h dra w n if a n d 
w he n a n ot her bi n der is i nitiate d.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 6  of 1 1 2  
6. 9  
I nter ve nti o n After t he E n d of t he St u d y  
N o i nter ve nti o n will f oll o w t he e n d of t he st u d y. Decisi o n t o c o nti n ue o n S Z C treat me nt or 
S o C will be at i n vesti gat or’s discreti o n.  
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N/ WI T H D R A W A L  
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n 
7. 1. 1  
Per m a ne nt Disc o nti n u ati o n of St u d y I nter ve nti o n 
It ma y be necessar y f or a partici pa nt t o per ma n e ntl y disc o nti n ue ( defi niti ve disc o nti n uati o n) 
st u d y i nter ve nti o n. If st u d y i nter ve nti o n is per ma ne ntl y disc o nti n ue d, t he partici pa nt will be 
f oll o we d u p acc or di n g t o t he S o A (Ta ble  1). See t he S o A f or data t o be c oll ecte d at t he ti me of 
disc o nti n uati o n of st u d y i nter ve nti o n a n d f oll o w- u p f or a n y f urt her e val uati o ns t hat nee d t o be 
c o m plete d.  
To mi ni mize  ris k f or e ve nts relate d t o se vere h y p okalae mia , t he f oll o wi n g disc o nti n uati o n 
criteri o n will be f oll o we d:  
•  
C o nfir me d K +  < 3. 0 m m ol/ L b y ta ki n g a sec o n d meas ure me nt after a ≥ 1 0-mi n ute 
i nter val, at a n y ti me d uri n g t he st u d y, t he partici p a nt s h o ul d i m me diatel y recei ve 
a p pr o priate m e dical i nter ve nti o n a n d st u d y i nter ve nti o n s h o ul d be per ma ne ntl y 
disc o nti n ue d. 
To mi ni mize  ris k f or e ve nts relate d t o se vere H K , t he f oll o wi n g disc o nti n uati o n criteri o n will 
be f oll o we d: 
•  
C o nfir me d K +  > 6. 0 m m ol/ L b y ta ki n g a sec o n d meas ure me nt after a ≥ 1 0-mi n ute 
i nter val, at a n y ti me d uri n g t he st u d y, t he partici p a nt s h o ul d i m me diatel y recei ve 
a p pr o priate m e dical i nter ve nti o n a n d st u d y i nter ve nti o n s h o ul d be per ma ne ntl y 
disc o nti n ue d. 
To mi ni mize ris k f or e ve nts relate d t o p r ol o n gati o n of Q T i nter val c orrecte d (Q Tc ), t h e 
f oll o wi n g disc o nti n uati o n criteria will be f oll o w e d: 
•  
If a n a bs ol ute Q Tc > 5 5 0 ms, or a n i ncrease i n Q T c i nter val > 6 0 ms fr o m baseli ne t o 
m ore t ha n 5 0 0 ms is reac he d, t he partici pa nt s h o ul d i m me diatel y recei v e a p pr o priate 
me dical i nter ve nti o n a n d be per ma n e ntl y disc o nti n ue d fr o m t he st u d y i nter v e nti o n. T he 
Q Tc F al g orit h m is rec o m me n de d. All partici pa nts meeti n g t he Q Tc >  5 0 0 ms criteri o n 
s h o ul d i m me diatel y ha ve K +  assesse d, if n ot alrea d y d o ne wit hi n 1 h o ur of perf or mi n g t he 
electr ocar di o gr a m ( E C G).  
F or seri o us arr h yt h mia ( e g, ass ociate d wit h K +  < 3. 5 or > 5. 6 m m ol/ L), st u d y dr u g s h o ul d be 
per ma ne ntl y disc o nti n ue d. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 7  of 1 1 2  
Ot her reas o ns f or disc o nti n uati o n of st u d y i nter ve nti o n ma y i ncl u de: 
•  
Partici pa nt decisi o n ; the partici pa nt is at a n y ti me free t o disc o nti n ue treat me nt, wit h o ut 
prej u dice t o f urt h er treat me nt.  
•  
I n c orr ectl y ra n d o mise d p artici pa nt, i n w h o m t he i ncl usi o n/e xcl usi o n criteri a vi olati o n 
w o ul d p ut t he partici pa nt at u n d ue ris k. T his will re q uire a disc ussi o n  wit h t he me dical 
tea m, w h o will pr o vi de a fi nal o utc o me / acti o n. 
•  
A d verse e ve nt f or w hic h t he i n vesti gat or j u d ges c o nti n ue d treat me nt ma y p ut t he 
partici pa nt at u n d ue ris k. 
•  
Se vere n o nc o m plia n ce wit h t he cli nical st u d y pr ot oc ol ( C S P ) 
•  
Pre g na nc y ( s ee Secti o n  8. 3. 8 ). 
F or disc o nti n uati o n pertai ni n g t o C O VI D- 1 9, pl ease see  A p p e n di x C . 
N ote t hat disc o nti n uati o n fr o m st u d y i nter ve nti o n is N O T t he sa me as a wit h dra wal fr o m t he 
st u d y. 
7. 1. 2  
Te m p or ar y Disc o nti n u ati o n 
If K +  ra n g es fr o m 3. 0 t o 3. 4 m m ol/ L , t he i n vesti gat or will  c o nsi der S Z C a d mi nistrati o n t o  be 
eit her d o w n-titrate d or pa use d a n d h y p o kalae mia s h o ul d be ma na ge d as per sta n dar d practice. 
Partici pa nts wit h heart f ail ure s h o ul d pa use st u d y dr u g. T he partici pa nt s h o ul d be e val uate d 
f or a n y ris k f act ors f or h y p o kalae mia, i ncl u di n g a n y i nterc urre nt ill ness or c o m or bi dit y. 
S o di u m zirc o ni u m c ycl osilicate a d mi nistrati o n ca n be res u me d  (if pa use d), if i n dicate d, b ut 
o nl y after t he i nter c urr e nt me dical c o n diti o n t hat preci pitate d t he h y p o k alae mia has i m pr o ve d 
a n d K +  has ret ur n e d t o t he tar get ra n ge of n or mal l e vels ( 3. 5 t o 5. 0 m m ol/ L, i ncl usi ve). T he 
i n vesti gat or will c o nsi der re-starti n g S Z C wit h a l o wer d ose. 
If partici pa nt te m p oraril y (≤ 1 4 da ys) disc o ntin ues st u d y i nter ve nti o n f or reas o ns ot her t ha n 
h y p o kalae mia, S Z C a d mi nistrati o n ca n be res u me d o nce partici p a nt c o n diti o n is sta bilise d 
acc or di n g t o i n vesti gat or j u d ge me nt, a n d if t he partici pa nt is willi n g t o ta ke treat me nt.  
A n y ti me st u d y dr u g d ose is a dj uste d, or if a c o nc o mita nt me dicati o n w hic h ma y affect K +  
le vels is c ha n ge d  ( e g, use of R A A S i or di uretics),  t he partici pa nt nee ds t o ret ur n t o t he site 7 
( ± 2) da ys later f or a K +  meas ure me nt a n d rec or di n g of A Es a n d c o nc o mita nt me dicati o ns.  
7. 2  
P artici p a nt Wit h dr a w al fr o m t he St u d y  
•  
A partici pa nt ma y wit h dr a w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest, or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi o ural, 
c o m plia nce, or a d mi nistrati ve reas o ns. T his is e x p ecte d t o be u n c o m m o n. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 8  of 1 1 2  
•  
A partici pa nt w h o c o nsi d ers wit h dra wi n g fr o m t he st u d y m ust be i nf or me d b y t he 
i n vesti gat or a b o ut m o difie d f oll o w- u p o pti o ns (e g, tele p h o ne c o ntact, a c o nt act wit h a 
relati ve or tr eati n g p h ysicia n, or i nf or mati o n fr o m me dical rec or ds). 
•  
At t he ti me of wit h dra wal fr o m t he st u d y, if p ossi ble, a n e arl y st u d y i nter ve nti o n 
disc o nti n uati o n visit s h o ul d be c o n d ucte d, as s h o w n i n t he S o A (Ta ble  1). See S o A f or 
data t o be c ollect e d at t he ti me of st u d y wit h dra wal a n d f oll o w- u p a n d f or a n y f urt her 
e val uati o ns t hat nee d t o b e c o m plete d. 
- 
T he partici pa nt will disc o nti n ue t he st u d y i nter ve nti o n a n d be wit h dra w n fr o m t he 
st u d y at t hat ti me. 
•  
If t he partici p a nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati o n, t he s p o ns or ma y 
retai n a n d c o nti n ue t o us e a n y data c ollecte d b ef ore s uc h a wit h dra w al of c o nse nt. 
•  
If a partici pa nt wit h dra ws fr o m t he st u d y, it s h o ul d be c o nfir me d if h e/s he still a grees f or 
e xisti n g sa m ples t o be use d i n li ne wit h t he ori gi n al c o nse nt. If h e/s he re q u ests wit h dra wal 
of c o nse nt f or us e of sa m ples, destr ucti o n of a n y s a m ples ta ke n a n d n ot test e d s h o ul d be 
carri e d o ut i n li ne wit h w hat was state d i n t he i nf or me d c o nse nt a n d l o cal re g ulati o n. T he 
i n vesti gat or m ust d oc u me nt t he decisi o n o n use of e xisti n g sa m ples i n t he site st u d y 
rec or ds a n d i nf or m t he Gl o bal St u d y Tea m. 
7. 3  
L ost t o F oll o w - u p 
A partici pa nt  will be c o nsi dere d l ost t o f oll o w - u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d n o c o ntact has bee n esta blis he d b y t he ti me t he st u d y is c o m plete d (see 
Secti o n  4. 4 ), s uc h t hat t here is i ns uffici e nt i nf or m ati o n t o deter mi ne t he partici pa nt’s stat us at 
t hat ti me. 
Partici pa nts w h o decli ne t o c o nti n ue partici pati o n i n t he st u d y, i ncl u di n g tele p h o ne c o ntact, 
s h o ul d be d oc u me nte d as ‘ wit h dra wal of c o nse nt” rat her t ha n “l ost t o f oll o w- u p’. I n v esti gat ors 
s h o ul d d oc u me nt atte m pts t o re-esta blis h c o ntact wit h mi ssi n g partici pa nts t hr o u g h o ut t he 
st u d y peri o d. If c o ntact wit h a missi n g partici pa nt is re-esta blis he d, t he partici pa nt s h o ul d n ot 
be c o nsi der e d l ost t o f oll o w- u p a n d e v al uati o ns s h o ul d res u me acc or di n g t o t he pr ot oc ol. 
 T he f oll o wi n g acti o ns m ust be ta ke n if a p artici pa nt  fails t o ret ur n t o t he cli nic or t o a ns wer a 
p h o ne call f or a re q uire d st u d y visit: 
•  
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he partici pa nt o n t he i m p orta nce of m ai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he p artici p a nt wis hes t o a n d/ or s h o ul d c o nti n ue i n 
t he st u d y. 
•  
Bef ore a  p artici pa nt  is dee me d l ost t o foll o w- u p, t he i n vesti gat or or desi g n ee m ust ma ke 
e ver y eff ort t o r e gai n c o ntact wit h t he partici pa nt  ( w here p ossi ble, 3 tele p h o ne calls a n d, 
if necessar y, a certifie d l etter t o t he partici pa nt ’s last k n o w n maili n g a d dress or l ocal 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
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e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he p artici pa nt ’s 
me dical rec or d . 
Disc o nti n uati o n of s pecific sites or of t he st u d y as a w h ole are ha n dle d as p art of A p pe n di x A . 
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
St u d y pr oce d ures a n d t heir ti mi n g are s u m mar ised i n t he S o A ( Ta ble  1). Pr ot oc ol wai ver s or 
e xe m pti o ns are n ot all o w e d. 
I m me diat e saf et y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o det er mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y i nter ve nti o n. 
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A (Ta ble  1), is 
esse ntial a n d re q uire d f or st u d y c o n d uct. 
All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nt s meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d d etails of all parti ci pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g f ail ure, as a p plica ble. 
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge m e nt (e g, bl o o d 
c o u nt) a n d o btai ne d b ef ore si g ni n g of t he I C F ma y be util ised f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures m et t he pr ot oc ol- s pecifie d criteria a n d w ere perf or m e d 
wit hi n t he ti me fra me defi ne d i n t he S o A ( Ta ble  1). 
8. 1  
Effic ac y Assess me nts  
8. 1. 1  
Pri m ar y E n d p oi nt  
P otassi u m will be meas ure d aft er vital si g ns, E C G ( w he n a p plica ble), a n d p h ysical 
e xa mi nati o n ( w he n a p plica ble) , at ti me p oi nts i n dicate d i n t he S o A (see  Ta ble  1). Sa m ples will 
be a nal yse d b y c e ntr al a n d l ocal la b orat ories at da y of disc har g e, + 9 0 d a ys , + 1 8 0 da ys, a n d 
earl y disc o nti n uati o n ( E/ D) visits . Ce ntral la b orat or y will o nl y be use d at b aseli ne . Local  
la b orat or y o nl y ma y be use d at  all ot her visits, i ncl u di n g  + 7 da ys a n d a n y u nsc he d ule d visit, 
f or treat me nt d ecisi o n. 
Ce ntral la b orat or y K +  val ues will be use d f or st u d y e n d p oi nt assess me nts w hile l ocal 
la b orat or y ass ess me nts ma y be use d f or i ncl usi o n/e xcl usi o n criteria, titrati o n decisi o ns, a n d 
cli nical decisi o ns. 
All K +  sa m ples s h o ul d be e xa mi ne d a n d a n y o vertl y hae m ol yse d sa m ples m ust be re dra w n. 
P otassi u m will be meas ure d t o assess N K  ( 3. 5 t o 5. 0 m m ol/ L i ncl usi ve) occ urre n ce at 
1 8 0 da ys p ost- disc har g e .  

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N ote:  K+  res ults will als o be use d f or st u d y i nter v e nti o n titrati o n. A n y ti me st u d y dr u g d ose is 
a dj uste d, a l ocal K +  meas ure me nt will nee d t o be p erf or me d  7 ( ±  2) da ys lat er. A d diti o nall y, 
partici pa nts  i n eit her treat me nt ar m s h o ul d ha ve t h eir K +  meas ure d l o call y 1 wee k 
after c ha n ges are m a de t o me dicati o ns t hat affect  K+  le vels (e g, use of R A A Si  or 
di uretics) . T hese K +  c hec ks will be perf or me d i n a d diti o n t o t he sc he d ule d st u d y assess me nts, 
a n d t he res ulti n g data will als o be c ollecte d i n t he st u d y.  
See t he la b orat or y ma n ual f or details o n dra wi n g, pre parati o n, a n d a n al ysis of bl o o d sa m ples. 
8. 1. 2  
M ai n Sec o n d ar y E n d p oi nt s 
•  
H os pit al a d missi o ns  wit h H K as a c o ntri b uti n g fact or ( base d o n cli nical j u d ge me nt a n d 
c o nfir me d b y a dj u dicati o n c o m mittee, see A p pe n di x A 5 ), a n d all-ca use, res pecti vel y, 
i ncl u di n g ti me of e ve nt a n d n u m ber of e v e nts, as well as le n gt h of sta y ( L O S) (as a n 
e x pl orat or y e n d p oi nt). 
•  
E D visits  wit h H K as a c o ntri b uti n g fact or ( bas e d o n cli nical j u d ge me nt a n d c o nfir me d b y 
a dj u dicati o n c o m mittee, see A p pe n di x A 5 ), i ncl u di n g ti me of e ve nt. 
•  
All -ca use d eat hs, i ncl u di n g ti me of e ve nt. 
•  
Use of r esc ue t hera p y f or H K ( base d o n cli nical j u d ge me nt a n d c o nfir me d b y a dj u dicati o n 
c o m mittee, see A p pe n di x A 5 ), i ncl u di n g ti me of e ve nt. 
8. 1. 3  
A d diti o n al Effic ac y Assess m e nts 
T he a d diti o nal efficac y assess me nts f or t he re m ai ni n g sec o n dar y a n d all e x pl orat or y 
o bjecti ves ar e o utli ne d i n Secti o n  8. 8. 2 . 
8. 2  
S afet y Assess me nts  
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A ( Ta ble  1). 
8. 2. 1  
P h ysic al E x a mi n ati o ns  
•  
A c o m plete p h ysical e x a mi nati o n will i ncl u de assess me nts of t he f oll o wi n g: ge neral 
a p pear a nce,  res pirat or y, car di o vasc ular, a b d o me n, s ki n, hea d a n d nec k (i ncl u di n g ears, 
e yes, n ose a n d t hr oat), l y m p h n o des, t h yr oi d, m usc ul os keletal (i ncl u di n g s pi ne a n d 
e xtre mities), a n d ne ur ol o gical s yste ms.  
•  
A tar gete d p h ysical e xa mi nati o n will i ncl u de  assess me nts of t he f oll o wi n g: s ki n, 
e xtre mities, car di o v asc ul ar i ncl u di n g assess me nt of si g ns of heart fail ure, l u n gs, a n d 
a b d o me n. 
P h ysical e xa mi nati o n will be perf or m e d at ti me p oi nts as s pecifie d i n t he S o A  (Ta ble  1).  
8. 2. 2  
Vit al Si g ns 
T he vital si g ns i ncl u de wei g ht, hei g ht, s yst olic a n d diast olic bl o o d press ure ( B P ), a n d p ulse 

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rate a n d will be assesse d as o utli ne d i n t he S o A (Ta ble  1).  
Bl o o d press ure a n d p ulse rate s h o ul d be meas ure d wit h a c o m pletel y a ut o mate d de vice i n 
tri plicate wit h at least 1-mi n ute i nter vals bet wee n meas ure me nts after b ei n g c o mf orta bl y at 
rest i n a seate d p ositi o n wit h t he bac k a n d feet s u p p orte d (ie, b y c h air bac k a n d fl o or or 
platf or m, res pecti vel y) q uietl y f or at least 5 mi n utes. Ma n ual tec h ni q u es will be use d o nl y if 
a n a ut o mate d de vi ce is n ot a vaila ble.  
T he p ositi o n of t he partici pa nt s h o ul d be c o mf orta ble wit h t he ar m w here t he B P is rec or de d t o 
be wit hi n t he le vel of heart (t he mi d dle of t he c uff o n t he u p per ar m is at t he le vel of t he ri g ht 
atri u m [t he mi d p oi nt of t he ster n u m]). T h e partici pa nt will be i nstr ucte d t o rela x as m uc h as 
p ossi ble a n d t o n ot tal k d uri n g t he meas ure m e nt pr oce d ure. T he s a me de vi ce s h o ul d 
prefera bl y be us e d f or t h e partici pa nt  d uri n g t he c o urse of t he st u d y a n d i n t he sa me ar m.  
T he first rea di n g of t he B P a n d p ulse rate s h o ul d b e rejecte d. T he sec o n d a n d t hir d rea di n gs 
s h o ul d be a ver a ge d t o gi ve t he meas ure me nt t o be rec or d e d i n t he e C R F. 
Hei g ht a n d wei g ht meas ure d at scr ee ni n g visit. F or s u bse q ue nt visits c ollecti o n of wei g ht o nl y, 
usi n g t he sa me scale a n d i n t he sa me state of dress.  
8. 2. 3  
Electr oc ar di o gr a ms 
A n E C G will be perf or me d at ti me p oi nts as s pecifie d i n t he S o A (Ta ble  1) a n d acc or di n g t o 
cli nical j u d g me nt i n c o n necti o n wit h se vere h y p o k alae mia  ( K+  < 3. 0 m m ol/ L), se vere H K  
( K+  > 6. 0 m m ol/ L), or a n y s y m pt o ms or cli nical e ve nts s u g gesti n g car diac arr h yt h mia. 
T he Q Tc F s h o ul d be r ec or de d at eac h E C G meas ure me nt.  
T he E C G data s h o ul d be rec or d e d i n t he e C R F, i ncl u di n g Q Tc F, i n c o n necti o n wit h re p orti n g 
A Es t hat c o ncer n arr h yt h mia.  
F or st u d y partici pa nts wit h pace ma k ers:  
•  All E C G varia bles, i ncl u di n g Q T/ Q Tc F, s h o ul d b e rea d m a n uall y a n d be rec or de d i n t he 
e C R F. 
•  If n ot f ulfilli n g t he i ncl usi o n/e xcl usi o n criteria or f ulfilli n g t he disc o nti n uati o n criteria, 
pace ma k er partici pa nts s h o ul d be ma na ge d as rec o m me n de d b y pr ot oc ol ( wit h o ut 
e xce pti o ns). 
8. 2. 4  
Cli nic al S afet y L a b or at or y Assess m e nts 
Uri nal ysis a n d bl o o d f or t he deter mi nati o n of cli ni cal c he mistr y a n d h e mat ol o g y, as well as 
uri ne pre g n a nc y test, will be ta ke n at t he visits i n dicate d i n t he S o A (Ta ble  1). N ote: I n case of 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
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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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false p ositi ve, false n e gati ve or i n deter mi nate res ults of t he uri ne pre g n a nc y test, i n vesti gat ors 
s h o ul d c o nfir m res ults wit h w hate ver s uita ble m et h o d i n vesti gat or feels is a p pr o priate. 
Assess me nts of he mat ol o g y a n d cli nical c h e mistr y will be perf or me d b y a ce ntral la b orat or y 
w hile uri nal ysis, a n d uri n e pre g na n c y tests will be a nal yse d l ocall y. P otassi u m will be 
a nal yse d ce ntrall y at bas eli ne a n d b ot h ce ntral l y a n d l ocall y at da y of disc h ar ge, + 9 0 da ys, 
+ 1 8 0 da ys, a n d E/ D visits . At +  7 da ys, K+  will be meas ure d l ocall y, o nl y.  
P otassi u m meas ure d l ocall y ( b y a vali date d met h o d, e g, bi oc he mistr y meas ure me n t or bl o o d 
gas a nal yser ) will be use d f or partici pa nt  ma n a ge me nt a n d f or st u d y i ncl usi o n a n d will be 
re p orte d i n t he eC R F, b ut sa m ples c ollecte d at t he sa me ti me a n d a nal ys e d at t he ce ntral 
la b orat or y will be use d f or t he mai n statistical a nal yses. 
Sites a re e nc o ura ge d t o use l ocal la b orat ories t hat ca n pr o vi de K+  res ults as ra pi dl y as 
p ossi ble. At + 7 a n d + 9 0 da ys, i f t he site ca n o btai n t he res ults i n a reas o na ble ti me (as 
deter mi ne d b y t he i n vesti gat or a n d t he partici pa nt), t he sa m ples f or t he l ocal la b orat or y ca n be 
dra w n at t he b e gi n ni n g of eac h visit, a n d t he n t h e partici pa nt  me dicati o ns titrate d a n d/ or  I M P 
dis pe nse d bef or e t he partici pa nt lea ves t he cli nic. 
T he ma xi m u m a m o u nt of ti me bet wee n l ocal la b orat or y sa m ple c ollecti o n a n d o btai n me nt of 
data res ults s h o ul d be 1 d a y. If bl o o d sa m ples f or l ocal la b orat or y testi n g are ta ke n at t he st u d y 
visit a n d t he res ults are n ot k n o w n pri or t o t he partici pa nts  lea vi n g t he visit, t he i n vesti gat or 
ma y call t he partici p a nts  or bri n g t he m bac k t he f oll o wi n g da y f or i nstr ucti o ns re gar di n g 
c o nc o mita nt me dicati o n titrati o n a n d I M P d osi n g. Alter nati vel y, if m ore feasi ble f or t he 
p artici pa nt a n d i n vesti gat or, bl o o d sa m ples f or t he l ocal la b orat or y tests ma y be c ollecte d 
1 da y bef or e st u d y pr oce d ure i n cas es w he n t he l o cal la b orat or y sa m ple a n al ysis ti me is 
e x pecte d t o b e l o n ger t ha n t he d urati o n of t he partici pa nt ’s cli nic visit. 
T h e res ults of K +  le vels p erf or me d l o call y usi n g l ocal la b orat ories will be pr o vi de d t o t he 
i n vesti gat or t he sa me da y a n d a nal yse d b ef ore assess me nt a gai nst t he i ncl usi o n criteria a n d 
ra n d o misati o n. 
A d diti o nal safet y sa m ples ma y be c ollecte d (‘ u nsc he d ule d’) if cli nicall y i n dicate d at t he 
discreti o n of t he i n vesti g at or. T he date, ti me of c ollecti o n , a n d res ults ( val u es, u nits, a n d 
refere nce r a n ges) will be rec or d e d o n t he a p pr o pri ate e C R F. 
A listi n g of la b orat or y safet y varia bl es is pr o vi de d i n  Ta ble 6 .  
Ta ble 6  
L a b or at or y S afet y Va ri a bles  
He m at ol o g y/ He m ost asis ( w h ole bl o o d)  
Cli nic al C he mistr y (ser u m)  
B- He m o gl o bi n ( H b)  
S- S o di u m ( Na + ) 
B- Le u k oc yte c o u nt  
S- P otassi u m ( K + ) 

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B- Le u k oc yte differe ntial c o u nt (a bs ol ute c o u nt)  
S- Bicar b o nate ( T otal C O 2) 
B- Platelet c o u nt  
S- C hl ori de ( Cl -) 
B- He mat ocrit ( Hct)  
S- Gl uc ose  
 
S- Creati ni ne  
 
S- Bl o o d Urea Nitr o ge n ( B U N)  
 
Urea ( B U N)/ Creati ni ne Rati o  
 
E sti mate d gl o mer ular filtrati o n rate  usi n g t he C hr o nic 
Ki d ne y Disease E pi de mi ol o g y C olla b orati o n  f or m ula 
Uri n al ysis  ( di pstic k) 
S- A ni o n ga p  
U- H b/ Er yt hr oc ytes/ Bl o o d  
S- Al b u mi n  
U- Pr otei n/ Al b u mi n  
S- T otal Pr otei n  
U- Gl uc ose  
S- Calci u m ( Ca + + ) 
 
S- Ma g nesi u m ( M g
+ + ) 
 
S- P h os p hate ( P O 4) 
 
S- Bilir u bi n, t otal  
 
S- Al kali ne p h os p hatase ( A L P)  
 
S- Ala ni ne a mi n o tra nsferase ( A L T)  
 
S- As partate a mi n o tra nsferase ( A S T)  
T he i n vesti gat or s h o ul d ma ke a n ass ess me nt of t he a vaila ble res ults wit h re gar d t o cli nicall y 
rele va nt a b n or malities. T he la b orat or y res ults s h o ul d be retai ne d as s o urce data. F or 
i nf or mati o n o n h o w A Es base d o n la b orat or y tests s h o ul d be rec or de d a n d re p orte d (see 
Secti o n  8. 3. 5 ). 
8. 2. 5  
Ot her S afet y Assess m e nts 
T he e G F R will be calc ul ate d usi n g t he C K D - E PI f or m ula as pre vi o usl y p u blis he d 
(Le ve y  et al, 2 0 0 9).  
8. 3  
A d verse E ve nts  a n d  Seri o us A d verse E ve nts  
T he p ri nci pal i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are 
fa miliar wit h t he c o nte nt of t his secti o n 
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n  A p pe n di x B . 
A d verse e ve nts  will be re p orte d b y t he partici p a nt  ( or, w he n a p pr o priat e, b y a care gi ver, 
s urr o gate, or t h e partici p a nt 's le gall y a ut h orised re prese ntati ve) .  
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi niti o n of a n A E. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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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8. 3. 1  
Ti m e Peri o d a n d Fre q ue nc y f o r C ollecti n g A E a n d S A E 
I nf or m ati o n 
A d verse eve nts will be c ollecte d fr o m ti me of si g nat ure of t he I C F, t hr o u g h o ut t he treat me nt 
peri o d a n d i ncl u di n g t he f oll o w- u p peri o d. 
Seri o us A Es  will be rec or de d fr o m t he ti me of si g ni n g of t he I C F. 
If t he i n vesti gat or bec o m es a ware of an S A E  wit h a s us pecte d ca usal relati o ns hi p t o t he I M P 
t hat occ urs after t he e n d of t he cli nical st u d y i n a partici pa nt treat e d b y hi m or her, t he 
i n vesti gat or s hall, wit h o ut u n d ue dela y, re p ort t he S A E t o t he s p o ns or. 
8. 3. 2  
F oll o w- u p of A Es a n d S A Es 
A n y A Es t hat are u nr es ol ve d at t he f oll o w- u p visit i n t he st u d y are f oll o we d u p b y t he 
i n vesti gat or f or as l o n g as me dicall y i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he eC R F . 
Astra Ze neca retai ns t he ri g ht t o re q uest a d diti o nal i nf or mati o n f or a n y p artici pa nt  wit h 
o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if j u d ge d necessar y. 
A d verse e v e nt v ari a bles  
T he f oll o wi n g varia bles will be c ollecte d f or eac h A E;  
•  
A E ( ver b ati m)  
•  
T he date w h e n t he A E st arte d a n d st o p pe d 
•  
Ma xi m u m A E i nte nsit y ( mil d, m o derate, se vere)  
•  
W het her t he A E is seri o us or n ot 
•  
I n v esti gat or ca us alit y rati n g a gai nst t he I M Ps ( yes or n o) 
•  
Acti o n ta ke n wit h re g ar d t o I M Ps 
•  
O utc o me . 
I n a d diti o n, t he f oll o wi n g varia bles will be c ollecte d f or S A Es: 
•  
Date A E met criteria f or S A E  
•  
Date i n vesti gat or beca me a war e of S A E  
•  
Reas o n w h y A E  is classe d as seri o us  
•  
Date of h os pitalisati o n  
•  
Date of disc h ar ge  
•  
Pr o ba ble ca us e of deat h  
•  
Date of deat h  
•  
A ut o ps y perf or me d 

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•  
Ca usalit y assess me nt i n relati o n t o st u d y pr oce d ure(s) 
•  
Ca usalit y assess me nt t o ot her me dicati o n . 
8. 3. 3  C a us alit y C ollecti o n 
T he i n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n st u d y treat me nt a n d eac h A E, a n d 
a ns wer ‘ yes’ or ‘ n o’ t o t h e q uesti o n ‘ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y t hat 
t he e ve nt ma y ha v e bee n ca use d b y t he st u d y treat me nt?’. 
F or S A Es, ca usal rel ati o ns hi p s h o ul d als o be assesse d f or ot her m e dicati o n a n d st u d y 
pr oce d ur es. F or S A Es t hat c o ul d be ass oci ate d wit h a n y st u d y pr oce d ure, t he ca usal 
relati o ns hi p is i m plie d as ‘ yes’. 
A g ui de t o t he i nter pretati o n of t he ca usalit y q uesti o n is f o u n d i n  A p pe n di x B . 
8. 3. 4  A d verse E ve nts B ase d o n Si g ns a n d S y m pt o ms 
All A Es s p o nta ne o usl y re p orte d b y t he partici p a nt, re p orte d i n res p o nse t o t he o pe n q uesti o n 
fr o m t he st u d y site staff, or re veale d b y o bser vati o n will be c ollecte d a n d rec or de d i n t he 
e C R F. W he n c ollecti n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n p ossi ble) t o 
rec or di n g a list of si g ns a n d s y m pt o ms. H o we ver, if a dia g n osis is k n o w n a n d t here are ot her 
si g ns or s y m pt o ms t hat are n ot ge nerall y part of t h e dia g n osis, t he dia g n osis a n d eac h si g n or 
s y m pt o m will be rec or de d se parat el y. 
8. 3. 5  A d verse E ve nts B ase d o n E x a mi n ati o ns a n d Tests 
If a partici pa nt’s K +  val ue is c o nfir me d at <  3. 5 m m ol/ L, t he e ve nt s h o ul d be re p ort e d as a n 
A E.  
T he res ults fr o m t he C S P- ma n date d la b orat or y tests , vital si g ns , a n d E C G will be s u m marise d 
i n t he cli nical st u d y re p ort.  
Deteri or ati o n as c o m par e d t o baseli ne i n C S P- ma n date d la b orat or y val ues a n d vital si g ns  
s h o ul d o nl y be re p orte d as A Es if t he y f ulfil a n y of t he S A E criteria, are t h e reas o n f or 
disc o nti n uati o n of treat me nt wit h t he I M P, or are c o nsi dere d t o be cli nicall y rele va nt as j u d g e d 
b y t he i n vesti gat or ( w hic h ma y i ncl u de b ut n ot li mite d t o c o nsi derati o n as t o w het her 
treat me nt or n o n- pla n n e d visits were re q uire d or ot her acti o n was t a ke n wit h t he st u d y 
treat me nt, e g, d ose a dj ust me nt or dr u g i nterr u pti o n).  
If deteri orati o n i n a la b or at or y val ue/ vital si g n is ass ociate d wit h cli nical si g ns a n d s y m pt o ms, 
t he si g n or s y mpt o m will be re p ort e d as a n A E a n d t he ass ociate d la b orat or y res ult/ vital si g n 
will be c o nsi dere d as a d diti o nal i nf or mati o n. W here ver p ossi ble t he re p orti n g i n vesti gat or 
uses t he cli nical, rat h er t ha n t he la b orat or y ter m (e g, a n a e mia vers us  l o w hae m o gl o bi n val ue). 
I n t he a bse n ce of cli nical si g ns or s y m pt o ms, cli nicall y rele v a nt deteri orati o ns i n 

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n o n- ma n date d para met ers s h o ul d be re p orte d as A E(s). 
Deteri or ati o n of a la b or at or y val ue, w hic h is u ne q ui v ocall y d ue t o disease pr o gressi o n, s h o ul d 
n ot be re p orte d as a n A E/ S A E. 
A n y ne w or a g gra v ate d cli nicall y rele va nt a b n or m al me dical fi n di n g at a p h ysical e xa mi nati o n 
as c o m par e d wit h t he bas eli ne assess me nt will be re p orte d as a n A E u nl ess u ne q ui v ocall y 
relate d t o t he disease u n d er st u d y. 
8. 3. 6  
Re p orti n g of Seri o us A d verse E ve nts 
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relat e d t o t he  I M P, or t o t he 
st u d y pr oce d ur e(s). All S A Es will be rec or de d i n t he eC R F.  
If a n y S A E occ urs i n t he c o urse of t he st u d y, i n vesti gat ors or ot her site pers o n nel will i nf or m 
t he a p pr o priat e Astr a Ze n eca r e pr ese ntati ves wit hi n 1 da y, ie, i m me diatel y b ut n o l ater t h a n 
2 4 h o urs of w he n he or s he bec o mes a ware of it . 
T he desi g nate d Astra Z e n eca r e pr ese ntati ve will w or k wit h t he i n vesti gat or t o e ns ure t hat all 
t he necess ar y i nf or mati o n is pr o vi de d t o t he Astra Ze neca Patie nt Safet y dat a e ntr y site wit hi n 
1  c ale n d ar d a y  of i nitial recei pt f or fat al a n d life-t hreate ni n g e v e nts a n d wit hi n 5 c ale n d ar 
d a ys of i nitial recei pt f or all ot her S A Es.  
F or fatal or life -t hreate ni n g A E s w here i m p orta nt or rele v a nt i nf or mati o n is missi n g, acti ve 
f oll o w- u p will be u n derta ke n i m me diatel y . I n vesti gat ors or ot her site pers o n nel will i nf or m 
Astra Ze neca re pr ese ntati ves of a n y f oll o w - u p i nf or mati o n o n a pre vi o usl y re p orte d S A E 
wit hi n 1 cale n dar d a y, ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n he or s he bec o mes 
a war e of it . 
O nce t he i n vesti gat ors or ot her site pers o n nel i n di cate a n A E is seri o us i n t he electr o ni c data 
ca pt ure ( E D C) s yste m, a n a ut o mate d e mail alert is se nt t o t he desi g nate d Astra Ze neca 
re pres e ntati ve. If t h e E D C s yste m is n ot a vaila ble, t he n t he i n vesti gat or or ot her st u d y site 
staff r e p orts a S A E t o t he a p pr o priate Astra Ze neca re pres e ntati ve b y tele p h o ne. T he 
Astra Ze neca re pr ese ntati ve will a d vise t he i n vesti gat or/st u d y site staff h o w t o pr ocee d. 
I n vesti gat ors or ot her site pers o n nel will se n d rel e va nt e C R F m o d ules b y fa x t o t he desi g nate d 
Astra Ze neca re pr ese ntati ve.  
F or f urt her g ui da n ce o n t he defi niti o n of a n S A E, see  A p p e n di x B . 
T he ref er e nce d o c u me nt f or defi niti o n of e x p ecte d ness/liste d ness is t he I B f or t he Astra Ze neca 
dr u g.  

Cli nical St u d y Pr ot oc o l - 4. 0  
Astra Ze neca  
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8. 3. 7  
Re p orti n g of A Es/ S A Es i n Rel ati o n t o C O VI D- 1 9 
All A Es/ S A Es s h o ul d be re p orte d i n li ne wit h i nstr ucti o ns f or safet y re p orti n g d oc u me nte d i n 
t he C S P. F or partici pa nts  e x perie n ci n g si g ns a n d s y m pt o ms i n dicati n g a n i nfecti o n, a n atte m pt 
will be ma de t o deter mi n e w het her t h e C O VI D - 1 9 vir us is t he i nfecti o us or ga nis m a n d t he A E 
will be rec or d e d acc or di n gl y. If a partici pa nt prese nts wit h cli nical si g ns a n d s y m pt o ms 
s u g gesti ve of C O VI D- 1 9, a test will be re q ueste d w here p ossi ble: 
•  If t he test is p ositi ve, rec or d “ C O VI D- 1 9 p ositi ve” i n t he A d vers e E ve nt Fi el d. 
•  If t he test is ne gati ve, r ec or d “ C O VI D - 1 9 ne gati ve” i n t he A d vers e E ve nt Fi el d, al o n g wit h 
t he A E/ S A E si g ns a n d s y m pt o ms a n d/ or ot her dia g n osis. 
If a test has n ot bee n perf or me d or res ult is n ot a vaila ble a n d si g ns a n d s y m pt o ms, as j u d ge d 
b y t he I n vesti gat or, are s u g gesti ve of C O VI D- 1 9 i nfecti o n, rec or d “ C O VI D- 1 9 s us pecte d ” i n 
t he A E fiel d . If t he i n vesti gat or has ot her c o n c urre nt dia g n oses f or t he partici pa nt’s si g ns a n d 
s y m pt o ms (e g, p ne u m o nia), t hese will be rec or de d as se parate A Es.  
8. 3. 8  
Pre g n a nc y 
All pre g na ncies a n d o utc o mes of pre g n a nc y s h o ul d be re p ort e d t o Astra Ze n eca e xce pt f or: 
•  
Pre g na nc y disc o v ere d b ef ore t he st u d y partici pa nt has recei ve d a n y st u d y i nter ve nti o n 
•  
Pre g na nc y i n t he part ner of male partici pa nts . 
8. 3. 8. 1  
M ater n al E x p os ure 
Wo me n of c hil d beari n g p ote ntial w h o are pla n ni n g o n bec o mi n g pre g na nt are n ot all o we d t o 
be i ncl u de d i n t his st u d y. S h o ul d a pre g na nc y still occ ur, t he I M P u n der st u d y s h o ul d be 
disc o nti n ue d i m me diatel y, a n d t he pre g na n c y re p orte d t o Astra Z e neca. 
Pre g na nc y  itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t h e I M P ma y ha ve 
i nterfer e d wit h t he effecti ve ness of a c o ntrace pti ve me dicati o n. C o n ge nital a n o malies/ birt h 
defects a n d s p o nta ne o us miscarria ges s h o ul d be re p orte d a n d ha n dle d as S A Es. Elec ti ve 
a b orti o ns wit h o ut c o m plicati o ns s h o ul d n ot be ha n dle d as A Es. T h e o utc o m e of all 
pre g na nci es (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, ect o pic pre g na nc y, n or mal birt h 
or c o n ge nital a n o mal y) s h o ul d be f oll o we d u p a n d d oc u me nte d e v e n if t he partic i pa nt was 
disc o nti n ue d fr o m t he st u d y. 
If a n y pr e g na nc y occ urs i n t he c o urse of t he st u d y, t he n t he i n vesti gat or or ot her site pers o n nel 
i nf or ms t he a p pr o priat e Astra Ze neca re prese ntati ves wit hi n 1 d a y , ie, i m me diatel y b ut n o 
l ater t h a n 2 4 h o urs of w he n he or s he b ec o mes a ware of it . 
T he desi g nate d Astra Z e n eca r e pr ese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or m ati o n is pr o vi de d t o t he Astra Z e neca Patie nt Safet y data e ntr y site wit hi n 

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1 or 5 cale n d ar da ys f or S A Es (see Secti o n  8. 3. 6 ) a n d wit hi n 3 0 da ys f or all ot her pre g na n cies. 
T he sa me ti meli nes a p pl y w he n t he o utc o me i nf or mati o n is a vaila ble.  
T he P R E G R E P m o d ule i n t he e C R F is use d t o re p ort t he pre g na n c y a n d t he pa per- b ase d 
P R E G O U T m o d ule is use d t o re p ort t he o utc o m e of t he pre g n a nc y. 
8. 3. 8. 2  
P ater n al E x p os ure  
T here is n o r estricti o n o n fat heri n g c hil dre n or d o n ati n g s per m d uri n g t he st u d y. 
8. 3. 9  
Me dic ati o n E rr or, Dr u g A b us e, a n d Dr u g Mis use  
8. 3. 9. 1  
Ti meli nes  
If an e v e nt of me dicati o n err or , dr u g a b use, o r  dr u g mis use occ urs d uri n g t he st u d y, t he n t he 
i n vesti gat or or ot her site pers o n nel i nf or ms t he a p pr o priate Astra Z e neca re prese ntati ves wit hi n 
o ne c ale n d ar d a y , ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs  of w he n t he y bec o me a ware of 
it.  
T he desi g nate d Astra Z e n eca r e pr ese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or mati o n is c o m plete d wit hi n o ne  (initial fatal/life-t hreate ni n g or f oll o w- u p 
fatal/life-t hreate ni n g) or 5  ( ot her seri o us i nitial a n d f oll o w- u p) c ale n d ar d a ys  if t here is an 
S A E ass ociate d wit h t he e ve nt of me dicati o n err or, dr u g a b use, or mis use (s ee Secti o n  8. 3. 6 ) 
a n d wit hi n 3 0 d a ys  f or all ot her e ve nts. 
8. 3. 9. 2  
Me dic ati o n Err or  
F or t he p ur p oses of t his cli nical st u d y, a me dicati o n err or is a n u ni nte n de d  fail ure or mista ke 
i n t he treat me nt pr ocess as per pr ot oc ol i n a d mi nisteri n g a n y st u d y dr u g t hat eit her ca us es 
har m t o t he partici pa nt or has t he p ote ntial t o ca us e har m t o t he partici pa nt. 
T he f ull defi niti o n a n d e x a m ple of a me dicati o n e rr or ca n b e f o u n d i n A p pe n di x B 4 .  
8. 3. 9. 3  
Dr u g A b use  
Dr u g a b use is t he p ersiste nt or s p ora dic i nte nti o n al, n o n-t hera pe utic e xcessi ve use of st u d y 
dr u g as per pr ot oc ol f or a percei v e d re war d or desire d n o n- t hera pe utic effect. 
T he f ull defi niti o n a n d e x a m ples of dr u g a b us e ca n be f o u n d i n A p p e n di x B 4 . 
8. 3. 9. 4  
Dr u g  Mis use  
Dr u g mis use is t he i nte nti o n al a n d i na p pr o priate use ( b y a st u d y partici p a nt) of t he st u d y dr u g 
f or me dici nal p ur p os es o utsi de of t he a ut h orise d pr o d uct i nf or mati o n a n d i ncl u des deli berate 
a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute. 
T he f ull defi niti o n a n d e x a m ples of dr u g mis use ca n be f o u n d i n  A p p e n di x B 4 . 

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8. 4  
O ver d ose  
D uri n g t he c orrecti o n treat me nt, a n y S Z C d ose greater t ha n 3 0 g wit hi n 1 da y, or c o nti n uati o n 
of t he c orr ecti o n d ose ( 1 0 g TI D) f or m ore t ha n 7 2 h o urs will be c o nsi dere d a n o ver d ose. 
D uri n g t he mai nte na nce peri o d , a d ose hi g her t ha n 1 0 g per da y will be c o nsi dere d a n 
o ver d ose. 
•  
A n o ver d ose wit h ass o ciate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
rele va nt A E m o d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule. 
•  
A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y re p orte d o n t he O ver d os e e C R F 
m o d ule. 
If a n o ver d ose o n a n Astr a Ze neca st u d y i nter ve nti o n occ urs i n t he c o urse of t he st u d y, t he 
i n vesti gat or or ot her site pers o n nel will i nf or m a p pr o priate Astra Z e neca re prese ntati ves 
i m me diatel y, b ut n o l ater t h a n 2 4 h o urs  of w he n he or s he bec o mes a ware of it. 
T he desi g nate d Astra Z e n eca r e pr ese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or m ati o n is pr o vi de d t o t he Astra Z e neca Patie nt Safet y data e ntr y site wit hi n 
1 or 5 cale n d ar da ys f or o ver d oses ass o ciate d wit h a n S A E (see Secti o n  ) a n d wit hi n 3 0 da ys 
f or all ot her e v e nts. 
8. 5  
H u m a n Bi ol o gic al S a m ples  
8. 5. 1  
P h ar m ac o ki netics 
P har mac o ki netic  para met ers ar e n ot e val uat e d i n t his st u d y. 
8. 5. 2  
I m m u n o ge nicit y Assess me nts 
I m m u no ge nicit y assess me nts are n ot e v al uate 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 mic p ara m eters ar e n ot e val u ate 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  
S a m ples f or b i o mar kers are n ot e v al uate d i n t his st u d y. 
8. 7  
O pti o n al Ge n o mics I niti ati ve S a m ple  
O pti o nal Ge n o mics I nitiati ve researc h is  n ot a p plica ble i n t his st u d y.  
8. 8  
Me dic al Res o urce Utilis ati o n a n d He alt h Ec o n o mics  
8. 8. 1  
D at a S o u rce 
T his st u d y i nte n ds t o c ollect pri mar y a n d sec o n d ar y data  o n healt h care res o urce utilisati o n 

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ass ociate d wit h me dical e nc o u nters. T h e data will be c ollecte d at o n -site visits ( pri mar y data) 
or via telep h o ne visits ( pri mar y data) or m e dical c hart re vie ws (sec o n dar y data) as d escri be d 
i n t he S o A ( Ta ble  1). D ata c ollecti o n will be carrie d o ut b y mea ns of a w e b-base d data ca pt ure 
s yste m (e C R F) w hic h will a d here t o all a p plica ble data pr otecti o n re g ulati o ns a n d 
re q uire me nts wit h r e gar d t o electr o nic rec or ds a n d data base v ali dati o n.  
Ge ner all y, at eac h visit, t he partici pa nt  will be as k e d a b o ut a n y healt h care e nc o u nters si nce 
t he last visit. T he partici pa nt  will be as ke d t o pr o vi de details, a n d per missi o n t o c o ntact t he 
treati n g p h ysicia n f or access t o me dical rec or ds. T he i n vesti gat or ma y nee d t o re q uest tra nsfer 
of rec or ds fr o m o ut patie nt visits or a d missi o n t o  h os pitals n ot ha vi n g j oi nt electr o nic me di cal 
rec or ds. 
8. 8. 2  
O utc o m e v ari a bles 
Pr ot oc ol- ma n date d pr o ce d ures, tests, a n d e n c o u nters are e xcl u d e d . 
T he o utc o me assess me nts f or t he pri mar y e n d p oi nt a n d t he mai n sec o n dar y e n d p oi nt are 
descri be d i n S ecti o ns 8. 1. 1  an d  8. 1. 2 , res pecti vel y. T he o utc o me ass ess me nts f or t he 
re mai ni n g sec o n d ar y e n d p oi nts a n d all e x pl orat or y e n d p oi nts are liste d bel o w.  
Sec o n d ar y o utc o m e v ari a bles 
•  
H os pital a d missi o n s wit h H K as a c o ntri b uti n g fact or ( base d o n cli nical j u d ge me nt a n d 
c o nfir me d b y a dj u dicati o n c o m mittee, see A p pe n di x A 5 ) a nd all -ca use, res pecti vel y, 
i ncl u di n g ti me of e ve nt, n u m ber of e v e nts, a n d L O S . 
H os pital a d missi o n s w here H K w as n ot a c o ntri b uti n g fact or will als o be c ollecte d.  
•  
E mer ge nc y d e part me nt  visits wit h H K as a c o ntri b uti n g fact or ( bas e d o n cli nical 
j u d ge me nt a n d c o nfir m e d b y a dj u dicati o n c o m mittee, see A p p e n di x A 5 ) a n d all-ca use, 
res pecti vel y, i ncl u di n g ti me of e ve nt a n d n u m b er of e ve nts. 
E mer ge nc y d e part me nt  visits w here H K w as n ot a c o ntri b uti n g fact or will als o be 
c ollecte d.  
•  
O ut patie nt visits (all -ca use)  
•  
Mea n K
+  le vels 
•  
Use of r esc ue t hera p y (s ee  Secti o n  6. 7. 1 ) 
•  
All -ca use d eat h . 
E x pl or at or y o utc o m es v ari a bles 
•  
I nte nsi v e care u nit (I C U) visits 
•  
e G F R  
•  
Use of K - bi n d ers t o treat H K p ost-disc har g e  
•  
Dial ysis i nitiati o n  

Cli nical S t u d y Pr ot oc ol - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 1  of 1 1 2  
•  
Use of R A A Si . 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1  
St atistic al H y p ot heses  
T he statistical h y p ot hesis f or t he pri mar y e n d p oi nt is: 
N ull: N o differe n ce i n t h e occ urre n ce ( y es/ n o) of a partici pa nt  bei n g N K at 1 8 0 da ys 
p ost- disc har ge b et wee n t he S Z C a n d S o C ar ms.  
Alter nate: Differ e nce i n t he occ urre n ce ( y es/ n o) of a partici pa nt  bei n g N K  at 1 8 0 da ys 
p ost- disc har ge b et wee n t he S Z C a n d S o C ar ms.  
T he statistical h y p ot hes e s f or t he ti me t o e ve nt sec o n dar y e n d p oi nts ( # 1, # 2, # 4, a n d # 6) are: 
N ull: N o differe n ce i n e v e nt rates c orres p o n di n g t o ti me t o first occ urre n ce of a n y c o m p o ne nt 
of t he c o m p osite o utc o m e bet wee n t he S Z C a n d S o C ar ms. 
Alter nate: Differ e nce i n e ve nt rate s c orres p o n di n g t o ti me t o first occ urre n ce of a n y 
c o m p o ne nt of t he c o m p osite o utc o me bet wee n t h e S Z C a n d S o C ar ms. 
T he statistical h y p ot hesis f or sec o n d ar y e n d p oi nt # 3 is: 
•  
N ull: N o differe n ce i n t h e i nci de nce rate s of h os pital a d missi o n or E D visit  wit h H K as a 
c o ntri b uti n g fact or bet w ee n t he S Z C a n d S o C ar ms. 
Alter nate:  A differ e nce i n t he i nci de nce rate of h os pital a d missi o n or E D visit  wit h H K as a 
c o ntri b uti n g fact or bet w ee n t he S Z C a n d S o C ar ms. 
9. 2  
S a m ple Size Deter mi n ati o n  
T he sa m ple size calc ulati o n f or t his st u d y is base d o n t he mai n sec o n dar y e n d p oi nt (Ti me t o 
first occ urr e nce of a n y c o m p o ne nt of all-ca us e h os pital a d missi o n , or E D visit wit h H K as a 
c o ntri b uti n g fact or, or all-ca use d eat h or us e of res c ue t hera p y f or H K at a n y ti me p ost -
disc har ge u p t o 1 8 0 d a ys) ; t he sa m ple size w o ul d be s maller if bas e d o n t he pri mar y e n d p oi nt 
of mai ntai ne d N K .  
9. 2. 1  
Pri m ar y E n d p oi nt  
F or t he pri mar y e n d p oi nt a sa m ple size esti mate w o ul d calc ulate;  
•  
T w o gr o u p χ² test  
•  
Si g nifica nce le vel: 5 % (t w o -si de d) 
•  
P o wer: 8 0 %  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 2  of 1 1 2  
•  
Pr o p orti o ns wit h N K ( K +  bet wee n 3. 5 a n d 5. 0 m m ol/ L, i ncl usi ve) at 1 8 0 da ys 
p ost- disc har ge), ( Da vis et al, 2 0 1 9 ; S pi n o witz et al, 2 0 1 9 ): 
- 
Ar m A ( S Z C): 0. 8 8  
- 
Ar m B ( S o C): 0. 5 9 
T he a b o ve test s pecifics a n d ass u m pti o ns yiel d a sa m ple size of 3 6 p artici p a nts per ar m 
(t otal N = 7 2). Ass u mi n g a 2 0 % dr o p o ut rate fr o m e nr ol me nt t o ra n d o misati o n a n d a 2 0 % 
dr o p o ut p ost- disc har g e ( p ost-ra n d o mis ati o n), a t otal of a p pr o xi matel y 1 1 3 partici pa nts will be 
e nr olle d. T his is e xcee de d b y t he n u m ber of partici pa nts re q uire d f or t he sec o n dar y e n d p oi nt 
sa m ple size calc ulati o n ( Secti o n 9. 2. 2 ) 
T he a b o ve eff ect -size ass u m pti o ns d o n ot c o nte m plate t he p ote ntial i m pact of R A A Si 
d o w n -titrati o n o n res p o nse. Si nce t his is e x pecte d t o di mi nis h t he res p o nse rate i n t he S o C ar m 
relati ve t o t he treat me nt ar m, t hese c o nser vati ve ass u m pti o ns s h o ul d pr o vi de a sli g ht 
u n deresti mate of p o w er. 
9. 2. 2  
M ai n Sec o n d ar y E n d p oi nt  
Pri or data:  Base d o n ass u m pti o ns o ver a 6- m o nt h peri o d of 1 6. 2 % all-ca us e h os pitali sati o n f or 
S Z C ar m ( P ollac k et al, 2 0 2 3 ) a n d 4 0 % f or S o C ar m (T h o mse n et al; 2 0 1 7 , Ka n da et al; 2 0 2 0 , 
H or ne et al; 2 0 1 9 ), 0. 8 % E D visits wit h H K as a c o ntri b uti n g fact or i n t he S Z C ar m (P ollac k 
et al; 2 0 2 3) a n d 3. 2 % f or S o C (Tafesse et al; 2 0 2 0 , Kas hi hara et al; 2 0 1 9 , Ka n da et al; 2 0 2 0 ), 
it is ass u me d t hat 1 7 % a n d 4 3. 2 % of patie nts i n t he S Z C a n d S o C ar m will e x perie n ce a n 
e ve nt res p ecti vel y.  
Sa m ple size esti mate:  
•  
L o g - Ra n k Test f or E q u alit y of S ur vi val C ur ves 
•  
Si g nifica nce le vel: 5 %  
•  
P o wer: 8 0 % 
•  
Hazar d rati o (H R; S Z C/ S o C): 0. 3 2 9 
•  
Pr o p orti o ns wit h o ut t he mai n sec o n dar y c o m p osite o utc o me (e v e nt-free) at 1 8 0 da ys 
p ost- disc har ge:  
- 
Ar m A ( S Z C): 8 3 % ( 1 7 % wit h t he o utc o me/e ve nt of i nterest)  
- 
Ar m B ( S o C): 5 6. 8 % ( 4 3. 2 % wit h t he o utc o me/e v e nt of i nterest) . 
T he a b o ve test s pecifics a n d ass u m pti o ns yiel d a sa m ple size of 5 2 e val ua bl e partici pa nts per 
ar m (t otal  N = 1 0 4). Ass u mi n g a 2 0 % dr o p- o ut rat e fr o m e nr ol me nt t o ra n d o misati o n, a n d a 
2 0 % dr o p o ut p ost-ra n d o misati o n, a t otal of a p pr o xi matel y 1 6 3 partici pa nts will be e nr olle d. 
9. 3  
P o p ul ati o ns f or A n al yses  
T he f oll o wi n g p o p ulati o ns are defi ne d: 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 3  of 1 1 2  
Ta ble 7 
P o p ul ati o ns f or A n al ysis  
A n al ysis Set  
Descri pti o n  
Tre at me nt Assi g n me nt  
F ull A nal ysis Set ( F A S)  
T he F A S, t he pri mar y, sec o n dar y , a n d 
e x pl orat or y efficac y a nal ysis set, will i ncl u de 
all ra n d o mise d partici pa nts  
Partici pa nts will be 
a nal y se d  acc or di n g t o t heir 
ra n d o mise d treat me nt. 
Per Pr ot oc ol Set ( P P S)  
T he F A S partici pa 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. 
Partici pa nts will be 
a nal y se d  acc or di n g t o t heir 
ra n d o mise d treat me nt. 
Safet y Set O pe n ( S S O)  
T he S S O will i ncl u de all partici pa nts w h o 
recei ve at least o ne d ose of so di u m zirc o ni u m 
c ycl osilicate (S Z C ) d uri n g t he st u d y u p u ntil 
disc har ge/ra n d o misati o n.  
Partici pa nts will be 
a nal y se d  as a si n gle gr o u p.  
Safet y Set Ra n d o mise d 
( S S R) 
T he S S R will i ncl u de all ra n d o mise d 
partici pa nts recei vi n g at least 1 d ose of S Z C 
p ost -dis c har ge i n Ar m A, a n d all ra n d o mise d 
partici pa nts i n Ar m B.  
Partici pa nts will be 
a nal y se d  acc or di n g t o 
treat me nt act uall y recei ve d. 
T he n u m ber of p artici pa nts i n eac h a nal ysis set, a n d t he n u m ber e xcl u d e d a n d ass ociate d 
reas o ns, will be s u m marise d b y trea t me nt gr o u p a n d o verall. I n a d diti o n, t h e f oll o wi n g peri o ds 
will be defi ne d f or t h e p ur p ose of r e p orti n g: 
Ta ble 8  
A n al ysis Peri o ds 
Peri o d  
Descri pti o n  
I n patie nt peri o d  
T he i n patie nt peri o d  refers t o t he peri o d fr o m t he date of first st u d y 
i nter ve nti o n dis pe nsati o n of s o di u m zirc o ni u m c ycl osilicate u ntil t he date 
of ra n d o misati o n at disc har ge  (e xcl usi ve). 
O ut patie n t peri o d 
T he o ut patie nt  peri o d refers t o t he peri o d fr o m t he date of ra n d o misati o n 
u ntil t he earliest date of last assess me nt d uri n g t he f oll o w -u p peri o d, 
wit h dra wal of c o nse nt, last c o ntact wit h t he partici pa nt, or deat h  
(i ncl usi ve). 
 
9. 4  
St atistic al A n al yses  
T he S A P will be drafte d a n d a p pr o ve d wit hi n 9 0 da ys of t he date of t he first partici pa nt 
e nr olle d, a n d a n y f urt her c ha n ges d uri n g t he c o urs e of t he st u d y will be fi nalise d pri or t o 
Data b ase L oc k. T h e S A P will i ncl u de a m ore tec h nical a n d detaile d d escri pti o n of t he 
statistical a nal yses descri be d i n t his secti o n. T his secti o n is a s u m mar y of t h e pla n ne d 
statistical a nal yses of t he m ost i m p orta nt e n d p oi nts i ncl u di n g pri mar y a n d k e y sec o n dar y 
e n d p oi nts. 
9. 4. 1  
Ge ner al C o nsi de r ati o ns 
T he f ull a nal ysis set (F A S ) will be t he pri mar y a n al ysis set f or t he efficac y a nal yses, w hile t he 
safet y set r a n d o mise d (S S R ) will be use d f or t he s afet y a n al yses. Safet y a n al yses will als o be 
perf or me d f or t he s afet y set o pe n (S S O ). Data fr o m all scree n e d partici pa nts will be use d t o 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 4  of 1 1 2  
descri be t he fl o wc hart of partici pa nt s fr o m scree ni n g t o f ulfil me nt of eli gi bilit y criteria a n d 
ra n d o misati o n. 
All baseli ne c haracteristics, effi cac y , a n d s afet y v aria bles will be s u m mari se d usi n g 
descri pti ve statistics as a p pr o priate. C o nti n u o us varia bles will be s u m marise d b y descri pti ve 
statistics (i ncl u di n g n u m ber of partici pa nt s [ n], m ea n, sta n dar d de viati o n, mi ni m u m, me dia n, 
a n d ma xi m u m). Cate g ori cal varia bl es will be s u m marise d wit h fre q u e ncies a n d perce nta ges. 
T he e xte nt of missi n g dat a will be re p ort e d. 
To c o ntr ol f or t y pe I err or, a hier arc hical testi n g pr oce d ure will be f oll o we d w he n f or mall y 
testi n g t he pri mar y a n d s ec o n dar y efficac y a nal ysis e n d p oi nts. T he hierarc hical testi n g 
pr oce d ur e will f oll o w a ste p wise al g orit h m w here eac h e n d p oi nt is o nl y f or mall y teste d if t he 
prece di n g n ull h y p ot hesis is rejecte d (t w o-si de d p- val ue <  0. 0 5). If t he prece di n g n ull 
h y p ot hesis is n ot rejecte d, t he n t he e val uati o n of t h e e n d p oi nt will be re d uce d t o t hat of a n 
e x pl orat or y e n d p oi nt. A draft or der f or hi erarc hical testi n g is o utli ne d i n t he c urre nt or d er 
descri be d f or t he pri mar y a n d sec o n dar y o bjecti ves ( see S ecti o n 3 ), a n d t he fi nal or der will be 
detaile d i n t he S A P.  
T he e n d p oi nt a n d statistical a nal ysis secti o ns f oll o w t he I C H E 9 ( R 1) a d d e n d u m o n e sti ma n ds 
a n d se nsiti vit y a nal yses i n cli nical trials, i ncl u di n g t he la n g ua ge f or strate gi es t o a d dress 
i nterc urr e nt e ve nts: 
Treat me nt P olic y Strate g y  
T he occ urre n ce of t h e i nterc urre nt e v e nt is c o nsi dere d irrele va nt i n defi ni n g t he treat me nt 
eff ect of i nter est: t he val ue f or t he v aria ble of i nterest is use d re g ar dless of w het her or n ot t he 
i nterc urr e nt e ve nt occ urs. F or e xa m ple, w he n s p ecif yi n g h o w t o a d dress t he use of a d diti o nal 
me dicati o n as a n i nter c urre nt e ve nt, t he v al ues of t he varia ble of i nterest are use d re gar dless of 
w het her or n ot t he p artici pa nt  ta kes a d diti o nal me dicati o n. 
H y p ot hetical Strate gies  
A sce nari o is e n visa ge d i n w hic h t he i nterc urre nt e ve nt w o ul d n ot occ ur, or t hat differe nt 
i nterc urr e nt e ve nts w o ul d occ ur or t h at i nterc urre nt e ve nts w o ul d occ ur wit h alter nati ve 
fre q ue n c y: t he val ue of t he varia ble t o reflect t he cli nical q uesti o n of i nterest is t he val ue 
w hic h t he varia bl e w o ul d ha ve ta ke n i n t he h y p ot h etical sce n ari o defi n e d. A wi de variet y of 
h y p ot hetical sce nari os ca n be e n visa ge d. F or e xa m ple, f or a partici pa nt t hat will s uffer a n A E 
a n d disc o nti n ue treat me nt, it mi g ht be c o nsi dere d w het her t he s a me partici pa nt w o ul d n ot 
ha ve t he A E  or c o ul d c o nti n ue treat me nt i n s pite of t he A E . 
C o m p osite Varia ble Strat e gies  
A n i nterc urr e nt e ve nt is c o nsi dere d i n itself t o be i nf or mati ve a b o ut t he p artici pa nt’s  o utc o me 
a n d is t heref ore i nc or p or ate d i nt o t he defi niti o n of t he varia ble. F or e xa m pl e, a partici p a nt  
w h o disc o nti n ues treat me nt beca use of t o xicit y ma y be c o nsi dere d n ot t o ha ve bee n 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 5  of 1 1 2  
s uccessf ull y treate d. If t h e o utc o me vari a ble was alrea d y s uccess or fail ure, disc o nti n uati o n of 
treat me nt f or t o xicit y w o ul d si m pl y be c o nsi dere d a n ot her m o de of fail ure. Ter mi nal e ve nts, 
s uc h as deat h, are p er ha ps t he m ost salie nt e xa m ple of t he nee d f or t he c o m p osite strate g y. 
W hile O n Treat me nt Strate gies  
F or t his strate g y, res p o nse t o treat me nt pri or t o t he occ urre nce of t he i nterc urre nt e v e nt is of 
i nterest. Ter mi n ol o g y f or t his strate g y will de pe n d o n t he i nterc urre nt e ve nt of i nterest 
(e g, “ w hile ali ve”, w h e n c o nsi deri n g deat h as a n i nterc urre nt e ve nt ). If a varia ble is meas ure d 
re peat e dl y, its val ues u p t o t he ti me of t he i nterc urre nt e ve nt ma y b e c o nsi d ere d rele va nt f or 
t he cli nical q uesti o n, rat h er t ha n t he val u e at t he sa me fi xe d ti me p oi nt f or all partici pa nt s. Li ke 
t he c o m p osite strate g y, t he w hile o n treat me nt strate g y ca n b e t h o u g ht of as i m pacti n g t he 
defi niti o n of t he varia ble. 
9. 4. 2  
C O VI D- 1 9 C o nsi der ati o ns 
It is a ntici pate d t hat a d diti o nal se nsiti vit y a n d s u p ple me ntar y a n al yses will be re q uire d t o 
deter mi ne t he i m pact of t he C O VI D - 1 9 p a n de mic o n t his trial a n d its e n d p oi nts. Pla n ne d 
se nsiti vit y a nal yses will disti n g uis h bet wee n pa n d e mic a n d n o n-pa n d e mic -relate d i nterc urre nt 
e ve nts i n ter ms of t he a p pr oac h ta k e n f or s e nsiti vit y a nal y ses i ncl u di n g a p pr oac hes relate d t o 
esti ma n ds, missi n g data, vali dit y a n d m o dificati o n of statistical a nal ysis met h o ds.  F urt her 
details will be i ncl u de d wit hi n t he S A P.  
9. 4. 3  
Effic ac y 
9. 4. 3. 1  
Pri m ar y E n d p oi nts  
Occ urre n ce ( yes/ n o) of N K ( K+  bet wee n 3. 5 a n d 5. 0 m m ol/ L , i ncl usive) at 1 8 0 d ays 
p ost- disc h ar ge 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Occ urre n ce ( y es/ n o) of N K ( K +  bet wee n 3. 5 a n d 5. 0 m m ol/ L, i ncl usi ve ) at 
1 8 0 da ys p ost- disc har g e  
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt wit h a K +  
meas ure me nt at 1 8 0 da ys p ost- disc har ge will ha v e t his val ue use d irres pecti ve of 
treat me nt disc o nti n uati o n (treat me nt p olic y strate g y). Use of resc u e t hera p y f or H K will 
be c o nsi der e d t o be n o n-r es p o nse (c o m p osite varia ble strate g y). T h e R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will be c o nsi dere d t o be n o n-res p o nse 
(c o m p osite varia ble str at e g y). Partici pa nts w h o di e of a n y ca use pri or t o 1 8 0 da ys 
p ost- disc har ge or w h o ar e l ost t o f oll o w- u p f or a n y reas o n will be c o nsi dere d t o be 
n o n- res p o nse (c o m p osite varia ble strat e g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): L o gistic re gressi o n a nal ysis wit h res p o nse 
( occ urre nce) as t he de pe n de nt varia ble a n d ra n d o mise d treat me nt gr o u p as t he 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 6  of 1 1 2  
i n de pe n de nt vari a ble. T h e o d ds rati o al o n g wit h t he t w o-si de d 9 5 % c o nfi de nce i nter vals 
a n d t w o-si de d p- v al ue (si g nifica nce d eclare d <  0. 0 5) will be dis pla ye d. 
Se nsiti vit y A n al yses 
T he a nal yses of t he pri m ar y e n d p oi nt will be re p eate d b y var yi n g t he esti ma n d:  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Pr o vi di n g t here are s ufficie nt partici pa nts wit hi n  
eac h c o variat e t o s u p p ort t he a nal ysis, t he l o gistic re gressi o n m o del will i ncl u de 
ra n d o mise d treat me nt gr o u p a n d t he f oll o wi n g baseli ne varia bles: a g e (as a s pli ne), se x, 
prese nce of heart f ail ure, dia betes, R A A Si use, C K D sta ge, a n d b aseli ne K +  (mil d H K 
defi ne d b y K +  bet w ee n >  5. 0 a n d ≤ 5. 5 m m ol/ L a n d m o derate/se v ere H K defi ne d b y K +  
bet wee n > 5. 5 a n d ≤ 6. 5 m m ol/ L) as i n de pe n de nt varia bles. 
•  
I nterc urre nt e v e nt strate g y: As pri mar y esti ma n d, b ut partici pa nts nee di n g resc ue t hera p y 
f or H K will f oll o w t he tr eat me nt p olic y strate g y (i e, re gar dless of t he i nterc urre nt e v e nt). 
•  
I nterc urre nt e v e nt strate g y: As pri mar y esti ma n d, b ut partici pa nts wit h R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will f oll o w t he treat me nt p olic y strate g y 
(ie, re g ar dless of t he i nterc urr e nt e ve nt). 
•  
I nterc urre nt e v e nt strate g y: As pri mar y esti ma n d b ut partici pa nts w h o die or are l ost t o 
f oll o w- u p pri or t o 1 8 0 da ys p ost-disc har ge will n ot be e val uate d (c o m pleters a nal ysis 
o nl y). 
•  
H y p ot hetical strate g y: As pri mar y esti ma n d, b ut partici pa nts w h o are l ost t o f oll o w- u p 
after 9 0 d a ys will ha ve t h eir K +  stat us at 9 0 da ys, if a vaila ble, carrie d f or war d t o 1 8 0 da ys 
a n d i ncl u de d i n t he a n al ysis. 
•  
Alter nati ve p o p ulati o n: As pri mar y esti ma n d b ut t he per pr ot oc ol set ( P P S) will be use d 
as t he p o p ulati o n f or a n al ysis. 
9. 4. 3. 2  
Sec o n d ar y E n d p oi nts  
F or eac h sec o n dar y e n d p oi nt, se nsiti vit y a nal ysis will be c o n d ucte d i ncl u di n g a n a nal ysis 
usi n g t he P P S  p o p ulati o n. 
1. Ti me t o first occ urre nce of a ny c o m p o n e nt of all- c a use h os pit al a d missi o n, or E D visit s 
wit h H K as a c o ntri b uti n g f act or, or a ll-c a use de at h , or use of resc ue t her a py f or H K at a ny 
ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Ti me t o first occ urr e nce of eit her c o m p o ne nt of t he c o m p osite o utc o me at a n y 
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts  w h o disc o nti n ue of treat me nt will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Resc ue t her a p y f or H K will be c o nsi dere d a n e ve nt (c o m p osite varia ble strat e g y). 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 7  of 1 1 2  
Partici pa nts w h o re q uir e E D visits wit h o ut H K as a c o ntri b uti n g fact or will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o die of a n y ca use will be c o nsi d ere d a n e v e nt (c o m p osite v aria ble 
strate g y). Partici pa nts w h o are l ost t o f oll o w - u p will be ce ns ore d at t he date of l oss t o 
f oll o w- u p. Partici pa nts w h o ha ve R A A Si do w n -titrati o n (i ncl u di n g disc o nti n uati o n) will 
c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt 
p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o -si de d p- v al ue, C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T h e H R a n d t he t w o-si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o -si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d. 
Se nsiti vit y A n al ysis  
(i) 
Partici pa nts wit h  all-ca us e h os pital a d missi o ns will o nl y be i ncl u de d w here H K is a 
c o ntri b uti n g fact or. 
(ii) 
Partici pa nts w h o d o w n- titrate R A A Si ( or disc o nti n ue) will be ce ns ore d at t he date 
of d o w n- titrati o n. 
(iii) 
Pr o vi di n g t here are s ufficie nt e ve nts wit hi n eac h c o variate ( > 5 e v e nts) t o s u p p ort 
t he a nal ysis, t he a nal yses of ti me-t o-e ve nt sec o n dar y e n d p oi nts will be re peate d i n 
t he F A S usi n g a n alter n ati ve p o p ulati o n le vel s u m mar y w here t he C o x pr o p orti o nal 
hazar ds m o d el will i ncl u de ra n d o mise d treat me nt gr o u p a n d t he f oll o wi n g baseli ne 
varia bles: a g e (as a s pli ne), se x , prese nce of heart fail ure, dia b etes, R A A Si use, 
C K D sta ge a n d bas eli ne K +  ( mil d H K defi ne d b y K+  bet wee n >  5. 0 a n d 
≤ 5. 5 m m ol/ L  a n d m o derate/se vere H K d efi ne d b y K +  bet wee n > 5. 5 a n d 
≤ 6. 5 m m ol/ L) as i n de pe n de nt varia bles.  
(i v) 
A d diti o nall y, t he a nal ysis will be re peat e d wit h t he P P S a nal ysis p o p ulati o n. A n 
a d diti o nal se nsiti vit y a nal ysis will be c o n d ucte d w here partici pa nts w h o are l ost t o 
f oll o w- u p will be acc o u nte d f or usi n g a n i n vers e pr o ba bilit y wei g hti n g a p pr oac h 
w here si milar partici pa nts w h o were n ot l ost t o f oll o w- u p will be re- wei g hte d 
( h y p ot hetical strate g y). F ull details re gar di n g se nsiti vit y a nal yses will be descri be d 
i n t he S A P. 
S u b gr o u p a nal yses will be perf or me d of t he pri mar y e n d p oi nt a n d of t he m ai n sec o n dar y 
e n d p oi nt, e g, b y a ge, se x, prese nce of heart fail ure, dia betes, R A A Si use, C K D sta ge, a n d 
baseli ne K +  ( mil d H K defi ne d b y K+  bet wee n >  5. 0 a n d ≤ 5. 5 m m ol/ L a n d m o derate/se v ere 
H K defi ne d b y K +  bet wee n > 5. 5 a n d ≤ 6. 5 m m ol/ L) at baseli ne, a n d b y d urati o n of 
h os pitalisati o n. A d diti o nal partici pa nt s u b gr o u ps ma y be c o nsi dere d, a n d f urt her details o n 
t hese a nal yses will be pr o vi de d i n t he S A P. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilic ate - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 8  of 1 1 2  
2. Ti me t o first occ urre nce of a ny c o m p o n e nt of all- c a use h os pit al a d missi o n, or E D visit wit h 
H K as a c o ntri b uti n g f act or at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Ti me t o first occ urr e nce of eit her c o m p o ne nt of t he c o m p osite o utc o me at a n y 
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt or w h o ha ve E D visit 
wit h o ut H K as a c o ntri b uti n g fact or will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt 
of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). Partici pa nts w h o die of a n y ca us e, 
use resc u e  t her a p y f or H K or ar e l ost t o f oll o w- u p will be ce ns ore d at t he d ate of deat h, 
use of res c ue t her a p y or l oss t o f oll o w- u p, res pecti vel y. Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p o i nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o -si de d p- v al ue, C o x pr o p orti onal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T h e H R a n d t he t w o-si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o -si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1 e xcl u di n g t he 
se nsiti vit y a nal ysis f or R A A Si d o w n-titrati o n. 
3. N u m ber of all- c a use h os pit al a d missi o n, or E D visits wit h H K as a c o ntri b uti n g f act or, at 
a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: N u m ber of all-ca use h os pital a d missi o n s or E D visits wit h H K as a c o ntri b uti n g 
fact or at a n y ti me p ost- disc har ge u p t o 1 8 0 d a ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt, use resc ue t hera p y f or 
H K or w h o ha v e a n E D visit wit h o ut H K as a c o ntri b uti n g fact or, will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Par tici pa nts w h o die of a n y ca use or are l ost t o f oll o w- u p will be ce ns ore d at t he date of 
deat h or l oss t o f oll o w- u p. Partici pa nts w h o ha ve R A A Si d o w n -titrati o n (i ncl u di n g 
disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osi te 
e n d p oi nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Mea n n u m b er  of all-ca use h os pital a d missi o n s or 
E D visits wit h H K as a c o ntri b uti n g fact or b y ra n d o mise d treat me nt gr o u p. Ne gati ve 
bi n o mial re gressi o n m o del wit h ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt varia ble 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 9  of 1 1 2  
a n d i ncl u di n g d urati o n of ti me i n st u d y as a n offset. T he i nci de nce rate ( S Z C/ S o C), al o n g 
wit h  9 5 % c o nfi de nce i nter vals a n d t w o-si de d p-v al ues  will be dis pla ye d . 
•  
Se nsiti vit y a nal yses will be c o n d ucte d usi n g t he P P S a nal ysis p o p ulati o n a n d a 
m ulti varia ble ne gati ve bi n o mial re gressi o n m o del i ncl u di n g a ge (as a s pli ne), se x, 
prese nce of heart f ail ure, dia betes, R A A Si use, C K D sta ge a n d b aseli ne K +  ( mil d H K 
def i ne d b y K+  bet w ee n >  5. 0 a n d ≤ 5. 5 m m ol/ L a n d m o derate/se v ere H K defi ne d b y K +  
bet wee n > 5. 5 a n d ≤ 6. 5 m m ol/ L ) as i n de pe n de nt varia bles. 
4. Ti me t o first occ urre nce of a ny c o m p o n e nt of h os pit al a d missi o n or E D visit, b ot h wit h H K 
as a c o ntri b uti n g f act or at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S 
•  
E n d p oi nt: Ti me t o first occ urr e nce of eit her c o m p o ne nt of t he c o m p osite o utc o me at a n y 
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt or w h o ha ve h os pital 
a d missi o n or E D visit wit h o ut H K as a c o ntri b uti n g fact or will c o nti n ue t o be f oll o we d u p 
t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). Partici pa nts 
w h o die of a n y ca use, us e resc u e  t hera p y f or H K or are l ost t o f oll o w - u p will be ce ns ore d 
at t he date of d eat h, use of resc u e t hera p y or l oss t o f oll o w- u p, res pecti vel y. Partici pa nts 
w h o ha ve R A A Si d o w n-titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d 
u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strat e g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o -si de d p- v al ue, C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T h e H R a n d t he t w o-si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o-si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1 e xcl u di n g t he 
se nsiti vit y a nal ysis f or R A A Si d o w n-titrati o n. 
5. N u m ber of h os pit al a d missi o ns or E D visits wit h H K as a c o ntri b uti n g f act or, at a ny ti me 
p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S 
•  
E n d p oi nt: N u m ber of h os pital a d missi o ns or E D visits wit h H K as a c o ntri b uti n g fact or at 
a n y ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt, use resc ue t her a p y f or 
H K or w h o ha v e a h os pit al a d missi o n, or a n E D visit wit h o ut H K as a c o ntri b uti n g fact or, 
will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt 
(treat me nt p olic y strate g y). Partici pa nts w h o die of a n y ca us e or are l ost t o f oll o w-u p will 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 0  of 1 1 2  
be ce ns or e d at t he d ate of deat h or l oss t o f oll o w- u p. Partici pa nts w h o ha ve R A A Si 
d o w n-titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Mea n n u m b er of h os pital a d missi o ns or E D visits, 
wit h H K as a c o ntri b uti n g fact or b y ra n d o mise d treat me nt gr o u p. Ne g ati ve bi n o mial 
re gressi o n m o del wit h ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v ari a ble a n d 
i ncl u di n g d urati o n of ti me i n st u d y as a n offs et. T he i nci de nce rate ( S Z C/ S o C), al o n g wit h 
9 5 % c o nfi de n ce i nter v als a n d t w o-si de d p- v al ues will be dis pla ye d. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d usi n g t he P P S a nal ysis p o p ulati o n a n d a 
m ulti varia ble ne gati ve bi n o mial  re gressi o n m o del i ncl u di n g a ge (as a s pli ne), se x, 
prese nce of heart f ail ure, dia betes, R A A Si use, C K D sta ge a n d b aseli ne K +  ( mil d H K 
defi ne d b y K +  bet w ee n > 5. 0 a n d ≤ 5. 5 m m ol/ L a n d m o derate/se v ere H K defi ne d b y K +  
bet wee n > 5. 5 a n d ≤ 6. 5  m m ol/ L) as i n de pe n de nt varia bles.  
6.  Ti me t o first occ urre nce of R A A Si d o w n- titr ati o n (or disc o nti n uati o n)  at a ny ti me p ost-
disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Ti me t o first occ urr e nce of R A A Si d o w n- titrati o n ( or disc o nti n uati o n) at a n y 
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o die of a n y ca use or are l ost t o f oll o w- u p will be ce ns ore d at t heir date of 
deat h or l oss t o f oll o w- u p , res pecti vel y. 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): L o g-ra n k test f or testi n g, C o x pr o p orti o nal hazar ds 
rati o f or esti mati o n wit h ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1, e xcl u di n g t he 
se nsiti vit y a nal ysis f or R A A Si do w n -titrati o n. 
9. 4. 3. 3  
E x pl or at or y E n d p oi nts  
F ull a nal ysis details f or t he e x pl orat or y e n d p oi nts will be descri be d i n t he S A P.  
1. Ti me t o first occ urre nce of a ny c o m p o n e nt of h os pit al a d missi o n or E D visit, b ot h wit h H K 
as a c o ntri b uti n g f act or, or all-c a use de at h at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Ti me t o first occ urr e nce of a n y c o m p o ne nt of t he c o m p osite o utc o me at a n y 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 1  of 1 1 2  
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue of treat me nt will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o re q uir e h os pital a d missi o n or E D visits wit h o ut H K as a c o ntri b uti n g 
fact or or us e res c ue t hera p y will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he 
c o m p osite e n d p oi nt (treat me nt p olic y strate g y). Partici pa nts w h o die of a n y ca use will b e 
c o nsi dere d a n e ve nt ( c o m p osite varia ble strate g y). Partici pa nts w h o are l ost t o f oll o w- u p 
will be ce ns ore d at t he date of l oss t o f oll o w- u p. Partici pa nts w h o ha v e R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o-si de d p- v al ue, C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T h e H R a n d t he t w o-si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o -si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d.  
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1. 
2. Ti me t o first occ urre nce of eit her h os pit al a d missi o n wit h H K as a c o ntri b uti n g f act or or 
all- c a use de at h at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Ti me t o first occ urr e nce of eit her c o m p o ne nt of t he c o m p osite o utc o me at a n y 
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue of treat me nt will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o re q uir e h os pital a d missi o n wit h o ut H K as a c o ntri b uti n g fact or or a n y 
E D visits or w h o use resc ue t hera p y will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). Partici p a nts w h o die of 
a n y ca use will be c o nsi dere d a n e v e nt (c o m p osite varia ble strat e g y). Partici pa nts w h o are 
l ost t o f oll o w- u p will be ce ns ore d at t he date of l oss t o f oll o w- u p. Partici pa nts w h o ha ve 
R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he 
first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o -si de d p- v al ue, C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 2  of 1 1 2  
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T h e H R a n d t he t w o-si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o -si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1. 
3. Ti me t o first occ urre nce of eit her E D visit wit h H K as a c o ntri b uti n g f act or or all- c a use 
de at h at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: Ti me t o first occ urr e nce of eit her c o m p o ne nt of t he c o m p osite o utc o me at a n y 
ti me p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue of treat me nt will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Partici pa nts w h o re q uir e a n y h os pital a d missi o n or E D visits wit h o ut H K as a c o ntri b uti n g 
fact or or w h o use r esc ue t hera p y will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of 
t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). Partici pa nts w h o die of a n y ca use will 
be c o nsi der e d a n e v e nt (c o m p osite varia ble strate g y). Partici pa nts w h o are l ost t o 
f oll o w- u p will be ce ns or e d at t he date of l oss t o f oll o w- u p. Partici pa nts w h o ha ve R A A Si 
d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first 
c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o -si de d p- v al ue, C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T he H R a n d t he t w o -si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o-si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1. 
4. Ti me t o first occ urre nce of a ny c o m p o n e nt of all-c a use h os pit alis ati o ns, E D visits, use of 
resc ue t her a p y f or H K, or all-c a use de at h i n e ac h ar m at a ny ti me p ost- disc h ar ge u p t o 1 8 0 
d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt : Ti me t o first occ urr e nce of a n y c o m p o ne nt of all- ca use h os pitalisati o ns, E D 
visits, use of resc ue t hera p y f or H K or all- ca us e deat h i n eac h ar m at a n y ti me 
p ost- disc har ge u p t o 1 8 0 da ys.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 3  of 1 1 2  
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue of treat me nt will c o nti n ue t o be 
f oll o we d u p t o t he first c o m p o ne nt of t he c o m p osite e n d p oi nt (treat me nt p olic y strate g y). 
Resc ue t her a p y f or H K will be c o nsi dere d a n e ve nt (c o m p osite varia ble strat e g y). 
Partici pa nts w h o re q uir e a n y h os pital a d missi o n or E D visit will be c o nsi dere d a n e v e nt 
(c o m p osite varia ble str at e g y). Partici pa nts w h o di e of a n y ca use will be c o nsi dere d a n 
e ve nt (c o m p osite varia bl e strate g y). Partici pa nts w h o are l ost t o f oll o w- u p will be 
ce ns ore d at t he date of l oss t o f oll o w- u p. Partici pa nts w h o ha ve R A A Si d o w n -titrati o n 
(i ncl u di n g disc o nti n uati o n) will c o nti n ue t o be f oll o we d u p t o t he first c o m p o ne nt of t he 
c o m p osite e n d p oi nt (treat me nt p olic y strate g y).  
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Ka pla n- Mei er pl ots of t he s ur vi val f u ncti o n f or t he 
S Z C a n d S o C treat me nt gr o u ps will be prese nte d. L o g- ra n k test f or testi n g will be use d t o 
calc ulate a t w o -si de d p- v al ue, C o x pr o p orti o nal hazar ds rati o f or esti mati o n, wit h 
ra n d o mise d treat me nt gr o u p as t he i n de pe n de nt v aria ble. T h e H R a n d t he t w o-si de d 9 5 % 
c o nfi de nce i nter val will be prese nt e d. T he ris k differe n ce a n d t w o -si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d. 
•  
Se nsiti vit y a nal yses will be c o n d ucte d as per s ec o n dar y e n d p oi nt # 1. 
5. P ot assi u m level u p t o 1 8 0 d ays p ost- disc h ar ge. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: K +  le vels u p t o 1 8 0 da ys p ost-disc har g e.  
•  
I nterc urre nt e v e nt strate g y: K +  le vels fr o m partici p a nts after disc o nti n uati o n of treat me nt, 
h os pital a d missi o ns, or E D visits f or a n y reas o n will be i ncl u de d i n t he a nal ysis (treat me nt 
p olic y strate g y). Partici p a nts w h o use res c ue t hera p y f or H K will ha ve K +  le vels pri or t o 
resc ue t h era p y f or H K us e d i n t he a nal ysis ( w hile o n treat me nt strate g y). Partici pa nts w h o 
ha ve R A A Si d o w n -titrati o n (i ncl u di n g disc o nti n uati o n) will ha ve K+  le vels pri or t o t he 
R A A Si d o w n -titrati o n use d i n t he a nal ysis ( w hile o n treat me nt strate g y). Partici pa nts w h o 
die of a n y ca use or w h o are l ost t o f oll o w- u p pri or t o 1 8 0 da ys p ost- disc har g e will ha ve 
all a vaila ble K +  i ncl u de d i n t he a nal ysis (treat me nt p olic y strate g y). 
•  
P o p ulati o n le vel s u m mar y (a nal ysis): Mi xe d m o del re peate d meas ures ( M M R M) a nal ysis 
wit h ra n d o mise d treat me nt gr o u p as a n i n de pe n d e nt varia ble. T h e c oefficie nt esti mates, 
sta n dar d err or, 9 5 % c o nfi de nce i nter v al  f or c oefficie nt esti mate, a n d p-val u es will be 
re p orte d. 
Se nsiti vit y A n al ysis  
•  
Pr o vi di n g t here are s ufficie nt partici pa nts wit hi n eac h c o v ariate t o s u p p ort t he a nal ysis a n 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 4  of 1 1 2  
alter nati ve p o p ulati o n le v el s u m mar y usi n g t he F A S p o p ulati o n w here t he M M R M 
a nal ysis will i ncl u de ra n d o mise d treat m e nt gr o u p a n d t he f oll o wi n g baseli ne varia bles: 
a ge (as a s pli ne), se x, prese nce of h eart fail ure, dia betes, R A A Si use, C K D sta ge a n d 
baseli ne K +  (mil d H K defi ne d b y K +  bet wee n >  5. 0 a n d ≤ 5. 5 m m ol/ L a n d 
m o derate/se v ere H K defi ne d b y K +  bet wee n > 5. 5 a n d ≤ 6. 5 m m ol/ L ) as i n de pe n de nt 
varia bles.  
6. N u m ber of h os pit al a d missi o ns wit h H K as a c o ntri b uti n g f act or at a ny ti me p ost- disc h ar ge 
u p t o 1 8 0 d ays. 
•  
P o p ulati o n: F A S  
•  
E n d p oi nt: N u m ber of h os pital a d missi o ns wit h H K as a c o ntri b uti n g fact or, at a n y ti me 
p ost- disc har ge u p t o 1 8 0 da ys. 
•  
I nterc urre nt e v e nt strate g y: Partici pa nts w h o disc o nti n ue treat me nt, use resc ue t hera p y f or 
H K, ha ve R A A SI d o w n -titrati o n (i ncl u di n g disc o nti n uati o n), e x perie n ce all -ca use d eat h 
or l oss t o f oll o w- u p pri or t o 1 8 0 da ys p ost- dis c har ge will ha ve all a v aila ble h os pital 
a d missi o n a n d E D visit data use d irres pecti ve of t he i nterc urre nt e v e nt (treat me nt p olic y 
strate g y). 
•  
P o p ulati o n le vel s u m mar y: Mea n n u m ber of h os pital a d missi o ns wit h H K as a 
c o ntri b uti n g fact or, b y r a n d o mise d treat me nt gr o u p. Ne gati ve bi n o mial re gressi o n m o del 
wit h ra n d o mise d treat me nt gr o u p as a mai n effect a n d i ncl u di n g d urati o n of ti me i n st u d y 
as a n offset. T he i nci d e nce rate rati o ( S Z C/ S o C), al o n g wit h 9 5 % c o nfi de nce i nter vals a n d 
t w o-si de d p-val ues will b e dis p la ye d. 
Se nsiti vit y A n al ysis  
•  
Pr o vi di n g t here are s ufficie nt, a n alter nati ve p o p ul ati o n le vel s u m mar y usi n g t he F A S 
p o p ulati o n w here t he n e g ati ve bi n o mial re gressi o n m o del will i ncl u de ra n d o mise d 
treat me nt gr o u p a n d t h e f oll o wi n g baseli ne varia bl es: a ge (as a s pli ne), se x, prese nce of 
heart f ail ure, dia bet es, R A A Si use, C K D sta ge, a n d baseli ne K +  (mil d H K defi ne d b y K +  
bet wee n >  5. 0 a n d ≤ 5. 5 m m ol/ L  a n d m o derate/se vere H K defi ne d b y K +  bet wee n > 5. 5 
a n d ≤ 6. 5 m m ol/ L ) as i n de pe n de nt varia bles. 
•  
T he pr o p orti o n of partici pa nts per ar m w h o are l ost t o f oll o w- u p will be s u m marise d. If a 
greater t ha n 1 0 % differ e n ce b y treat me nt ar m i n t he pr o p orti o n w h o are l ost t o f oll o w- u p 
is o bser ve d, t he n a s e nsiti vit y a nal ysis will be c o n d ucte d utilisi n g t he mea n c u m ulati ve 
c o u nt met h o d (D o n g et al, 2 0 1 5 ) whic h reflects a s u m marisati o n of all e ve nts t hat occ ur 
i n a p o p ulati o n b y a gi ve n ti me (e g, b y 9 0 da ys). 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 5  of 1 1 2  
7. Tot al L O S f or h os pit alis ati o ns (i ncl u di n g m ulti ple h os pit alis ati o ns) wit h H K as a 
c o ntri b uti n g f act or i n e ac h ar m at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
T he Wilc o x o n r a n k-s u m test b y ra n d o mise d treat me nt gr o u p will be use d t o calc ulate a 
t w o-si de d p- val ue. C o nti n u o us varia ble s u m mar y statistics ( me dia n a n d mea n) of t otal L O S 
wit h H K  as a c o ntri b uti n g fact or b y ra n d o mise d treat me nt gr o u p will be prese nte d.  
8. Tot al L O S f or all-c a use h os pit alis ati o ns (i ncl u di n g m ulti ple h os pit alis ati o ns) i n e ac h ar m at 
a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays. 
A nal yse d as per e x pl or at or y e n d p oi nt # 7 b ut d urati o n of h os pitalisati o n w here H K is n ot a 
c o ntri b uti n g fact or will b e part of t he e n d p oi nt, a n d n ot treate d as a n i nterc urre nt e v e nt 
9. Fre q ue ncy of t he use of K- bi n ders t o tre at H K at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays i n 
e ac h ar m. 
A ne gati ve bi n o mial re gr essi o n m o del wit h ra n d o mise d treat me nt gr o u p as a mai n effect a n d 
d urati o n of ti me i n st u d y as a n offset will be use d t o a nal yse t he n u m ber of uses of K- bi n ders 
t o treat H K. 
1 0 . Ti me t o first occ urre n ce of K- bi n der use t o tre at H K p ost- disc h ar ge at a ny ti me 
p ost- disc h ar ge u p t o 1 8 0 d ays i n e ac h ar m. 
Ka pla n - Mei er pl ots of t he s ur vi val f u ncti o n f or t h e S Z C a n d S o C treat me nt gr o u ps will be 
prese nte d. A l o g- ra n k test will be use d t o calc ulate a t w o-si de d p-v al ue. A C o x pr o p orti o nal 
hazar ds rati o will be use d f or a nal ysis wit h ra n d o mise d treat me nt gr o u p, a n d ot her c o variates 
descri be d i n t he S A P . T h e H R a n d t he t w o-si de d 9 5 % c o nfi de n ce i nter v al will be prese nte d.  
1 1. D ur ati o n of ti me o n K- bi n ders fr o m i niti ati o n i n t he first i nst a nce of K- bi n der use 
p ost- disc h ar ge u p t o 1 8 0 d ays i n e ac h ar m. 
Ka pla n -Mei er p l ots of t he s ur vi val f u ncti o n f or t h e S Z C a n d S o C treat me nt gr o u ps will be 
prese nte d. A l o g- ra n k test will be use d t o calc ulate a t w o-si de d p-v al ue. T his e x pl orat or y 
e n d p oi nt will be a nal yse d usi n g a C o x pr o p orti o nal hazar ds rati o wit h ra n d o mise d treat me nt 
gr o u p, a n d ot her c o variat es descri be d i n t he S A P. T he H R a n d t he t w o-si de d 9 5 % c o nfi de n ce 
i nter val will be prese nt e d.  
1 2. Ti me t o first occ urre nce of resc u e t her a py use t o tre at H K at a ny ti me p ost- disc h ar ge u p t o 
1 8 0 d ays i n e ac h ar m. 
T his e x pl orat or y e n d p oi nt will be a nal yse d per e x pl orat or y e n d p oi nt # 1 0. 
1 3 . Ti me t o first occ urre n ce of all-c a use h os pit alis ati o ns , E D visits or o ut p atie nt visits at a ny 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o d i u m zirc o ni u m c ycl osilicate - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 6  of 1 1 2  
ti me p ost- disc h ar ge u p t o 1 8 0 d ays i n e ac h ar m. 
T his e x pl orat or y e n d p oi nt will be a nal yse d per e x pl orat or y e n d p oi nt # 1 0. 
1 4. R ate of c h a n ge i n (sl o pe) e G F R b et wee n tre at me nt ar ms. 
A n M M R M a nal ysis wit h ra n d o mise d treat me nt gr o u p as a mai n effect, da ys p ost- disc har ge, 
a n i nteracti o n eff ect bet w ee n ra n d o mise d treat me nt gr o u p a n d da ys p ost- dis c har g e, as w ell as 
ot her c o variates des cri be d i n t he S A P will be use d t o esti mate t he sl o pe of e G F R b y 
ra n d o mise d treat me nt gr o u p. 
1 5 . Ti me t o first occ urre n ce of di alysis i niti ati o n at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays i n 
e ac h ar m. 
T his e x pl orat or y e n d p oi nt will be a nal yse d per e x pl orat or y e n d p oi nt # 1 0. 
1 6. Ti me t o first occ urre n ce of I C U a d missi o ns at a ny ti me p ost- disc h ar ge u p t o 1 8 0 d ays i n 
e ac h ar m. 
T his e x pl orat or y e n d p oi nt will be a nal yse d per e x pl orat or y e n d p oi nt # 1 0. 
1 7. Use of R A A Si at 9 0 a n d 1 8 0 d ays p ost- disc h ar ge by tre at m e nt ar m. 
T his e x pl orat or y e n d p oi nt will descri pti vel y s u m marise t he use of R A A Si i n eac h treat me nt 
ar m. T his will i ncl u de, b ut nee d n ot be li mite d t o: fre q ue n c y ( %) of partici pa nts o n R A A Si at 
disc har ge w h o re mai n e d o n R A A Si at 9 0 a n d 1 8 0 da ys p ost- disc har g e , res p ecti vel y; fre q u e nc y 
( %) of p artici pa nts o n R A A Si at disc har ge w h o h a ve i ncrease d R A A Si d ose b y 9 0 a n d 
1 8 0 da ys p ost- disc har g e , res pecti vel y; fre q ue n c y ( %) of partici pa nts o n RA A Si at disc har ge 
w h o ha ve decrease d R A A Si d ose b y 9 0 a n d 1 8 0 da ys p ost- disc har g e , res p ecti vel y; fre q u e nc y 
( %) of p artici pa nts w h o i nitiate d R A A Si b y 9 0 a n d 1 8 0 da ys p ost-disc har g e , res pecti vel y. 
9. 4. 4  
S afet y 
Safet y will be assesse d i n ter ms of A Es, S A Es, A Es lea di n g t o treat me nt disc o nti n uati o n, 
cli nical la b orat or y d ata, vital si g ns, a n d E C G. A p pr o priate s u m maries of t hese data will be 
prese nte d b y tr eat me nt gr o u p. 
A d verse e ve nts  will be cl assifie d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
s yste m or ga n class ( S O C) a n d P T. A treat me nt-e merge nt A E ( T E A E) is d efi ne d as a n A E wit h 
t he start date o n or after t he first d ose date a n d u p t o (a n d i ncl u di n g) 7 da ys after t he l ast d ose 
date. O nl y T E A Es will b e i ncl u de d i n ta ble s u m maries.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 7  of 1 1 2  
A d verse e ve nts  will be pr ese nte d f or eac h treat me nt gr o u p b y S O C, a n d P T c o veri n g n u m ber 
a n d perce nta ge of partici pa nts re p orti n g at least 1 e ve nt a n d n u m ber of e v e nts w here 
a p pr o priate. 
A n o ver vie w of A Es will prese nt f or eac h treat me nt gr o u p t he n u m ber a n d perce nt a ge of 
partici pa nts wit h a n y A E, A Es wit h o utc o me of deat h, S A Es, a n d A Es lea di n g t o 
disc o nti n uati o n of I M P. 
Se parate A E ta bles  will be pr o vi de d ta ke n i nt o c o nsi derati o n relati o ns hi p as assesse d b y t he 
i n vesti gat or, ma xi m u m i nte nsit y, seri o us ness, deat h, a n d e ve nts lea di n g t o disc o nti n uati o n of 
I M P.  
Ke y partici pa nt i nf or mati o n  will be prese nte d f or partici pa nts wit h A Es wit h o utc o me of 
deat h, S A Es, a n d A Es lea di n g t o disc o nti n uati o n of I M P. 
A n A E listi n g f or t he saf et y a nal ysis set will c o ver details f or eac h i n di vi d ual A E; a n A E 
listi n g f or partici pa nts w h o were n ot e x p ose d t o I M P is prese nte d se paratel y. 
F ull details of A E a n al yses will be pr o vi de d i n t he S A P.  
A n o ver vie w of oe de m a -relate d A Es a n d i nsta nces of K+  < 3. 5 will be pres e nte d. 
All A E data will be liste d f or all partici pa nts. I n a d diti o n, S A Es a n d A Es t hat le d t o 
wit h dra wal or d eat h a n d treat me nt -relate d A Es will be liste d. 
Cli nical safet y la b orat or y assess me nts will be s u m marise d a n d liste d. S hift ta bles will be 
pr o vi de d f or sel ect tests, w here s hift fr o m scree ni n g baseli ne t o t he w orst val ue wit hi n eac h 
part of t he st u d y a n d o verall will be s u m marise d. La b orat or y d ata o utsi de t he refere n ce ra n ges 
will be i n dicate d i n all listi n gs.  
All safet y a nal yses will be perf or me d o n t he S S O a n d S S R. I n ge neral, safet y assess me nts will 
be re p ort e d descri pti vel y b y treat me nt gr o u p. F ull details o n safet y a n al yses will be pr o vi de d 
i n t he S A P. 
9. 5  
I nteri m A n al yses  
N o i nteri m a nal ysis is pla n ne d f or t his st u d y. 
9. 6  
A dj u dic ati o n C o m mittee  
F or details o n t he A dj u dicati o n C o m mittee, refer t o A p pe n di x A 5 . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 8  of 1 1 2  
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  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 9  of 1 1 2  
A p pe n di x  A Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns  
A 1  
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
•  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g: 
- 
C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declar ati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces  I nter nati o nal Et hical G ui deli nes 
- 
A p plica ble I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) G o o d Cli nical Practice 
( G C P) G ui deli nes 
- 
A p plica ble la ws a n d re g ulati o ns. 
•  
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vesti gat or Br oc h ure (I B), a n d ot her rele v a nt 
d oc u me nts ( e g, a d v ertise me nts) m ust be s u b mitte d t o a n I nstit uti o nal Re vie w B oar d  
(I R B)/I n d e pe n d e nt Et hics C o m mittee (IE C ) b y t h e i n vesti gat or a n d re vie w e d a n d 
a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d. 
•  
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a n d a p plica ble Re g ulat or y 
A ut h orit y a p pr o val bef or e i m ple me ntati o n of c ha n ges ma de t o t he st u d y desi g n, e xce pt 
f or c ha n g es necessar y t o eli mi nate a n i m me diate h azar d t o st ud y partici pa nts. 
•  
Astra Ze neca will be res p o nsi ble f or o btai ni n g t he re q uire d a ut h orisati o ns t o c o n d uct t he 
st u d y fr o m t he c o ncer ne d Re g ulat or y A ut h orit y. T his res p o nsi bilit y ma y be dele gate d t o a 
c o ntract r esearc h or g a nizati o n, b ut t he acc o u nta bilit y re mai n s wit h Astra Ze neca. 
•  
T he i n vesti gat or will be r es p o nsi ble f or pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at 
t he site a n d a d here nce t o re q uire me nts of 2 1 C o de of Fe d eral Re g ulati o ns (C F R ), I C H 
g ui deli nes, t he I R B/I E C, E ur o pea n Re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if 
a p plica ble), E ur o pea n M e dical De vi ce Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice res earc h 
(if a p plica ble), a n d all ot her a p plica bl e l ocal re g ulati o ns 
Re g ul at or y Re p orti n g Re q u ire m e nts f or Seri o us A d verse E ve nts 
•  
Pr o m pt n otificati o n b y t he i n vesti gat or t o t he s p o ns or of a n S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of 
a st u d y i nter ve nti o n u n der cli nica l i n vesti gati o n are met. 
•  
T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical 
i n vesti gati o n. T he s p o ns or will c o m pl y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts 
relati n g t o safet y r e p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors. 
•  
F or all st u dies e xce pt t h ose utilizi n g me dical de vices , i n vesti gat or safet y re p orts m ust be 
pre par e d f or s us p ecte d u ne x pecte d s eri o us a d vers e rea cti o ns acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d s p o ns or p olic y a n d f or war d e d t o i n vesti gat ors as necessar y. 
- 
E ur o pea n Me dical De vi ce Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice res earc h (if 
a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 0  of 1 1 2  
•  
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will re vie w 
a n d t he n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priat e acc or di n g t o 
l ocal re q uir e me nts. 
Re g ul at or y Re p orti n g Re q uire m e nts f or Seri o us Bre ac hes  
•  
Pr o m pt n otificati o n b y t he i n vesti gat or t o Astra Ze neca of a n y ( p ote ntial) s eri o us breac h of 
t he pr ot oc ol or re g ul ati o ns is esse ntial s o t hat le gal a n d et hical o bli gati ons are met.  
•  
A ‘seri o us br eac h’ mea ns a breac h li kel y t o affect t o a si g nifica nt de gree t he safet y a n d 
ri g hts of a partici pa nt or t he relia bilit y a n d r o b ust n ess of t he data g e nerate d i n t he cli nical 
st u d y. 
•  
If a n y ( p ote ntial) seri o us breac h o cc urs i n t he c o urse of t he st u d y, i n vesti gat ors or ot her 
site pers o n nel will i nf or m t he a p pr o priate Astra Z e neca re prese ntati ves i m me diatel y after 
he or s he bec o mes a war e of it. 
•  
I n cert ai n re gi o ns/c o u ntri es, Astra Ze n eca has a le g al res p o nsi bilit y t o n otif y b ot h t he l ocal 
re g ulat or y a ut h orit y a n d ot her re g ulat or y a ge n cies a b o ut s uc h breac hes. 
•  
Astra Ze neca will c o m pl y wit h c o u ntr y -s pecifi c re g ulat or y re q uire m e nts rel ati n g t o seri o us 
breac h re p orti n g t o t he r e g ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors. If E ur o pea n 
U ni o n ( E U ) Cli nical Trials Re g ulati o n 5 3 6/ 2 0 1 4 a p plies, Astra Ze neca is re q uire d t o e nter 
details of seri o us breac h es i nt o t he E ur o pea n Me di ci nes A ge nc y Cli nical Trial 
I nf or mati o n S yste m ( C TI S). It is i m p orta nt t o n ote t hat re dact e d versi o ns of seri o us 
breac h re p ort s will be a v aila ble t o t he p u blic via C TI S. 
•  
T he i n vesti gat or s h o ul d ha ve a pr o cess i n place t o e ns ure t hat: 
- 
T he site staff or s er vice pr o vi ders dele g ate d b y t he i n vesti gat or/i nstit uti o n are a ble t o 
i de ntif y t he occ urre nce of a ( p ote ntial) s eri o us breac h 
- 
A ( p ote ntial) seri o us br eac h is pr o m ptl y re p orte d t o Astra Ze neca or dele g ate d part y, 
t hr o u g h t he c o ntacts ( e mail a d dress or tel e p h o ne n u m ber) pr o vi de d b y Astra Ze neca. 
A 2  
Fi n a nci al Discl os ure  
I n vesti gat ors a n d s u b-i n v esti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi n a ncial 
i nf or mati o n as re q u este d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na n cial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n vesti gat ors 
are r es p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 year after c o m pleti o n of t he st u d y. 
A 3  
I nf or me d C o nse nt Pr ocess 
•  
T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ure of t h e st u d y t o t he 
partici pa nt or his/ her le g all y a ut h or ised re pre se nt ati ve a n d a ns w er all q uesti o ns re gar di n g 
t he st u d y. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 1  of 1 1 2  
•  
Partici pa nts m ust be i nf or me d t hat t heir partici p ati o n is v ol u ntar y  a n d t he y are free t o 
ref use t o partici pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me a n d f or a n y reas o n 
d uri n g t he st u d y . Partici pants or t heir le gall y a ut h or ised re prese ntati ve will be re q uire d t o 
si g n a state me nt of i nf or me d c o nse nt t hat meets t he re q uire me nts of 2 1 C F R  5 0, l ocal 
re g ulati o ns, I C H g ui deli nes, Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
re q uire me nts, w h ere a p plica ble, a n d t he IR B/I E C or st u d y ce ntre. 
•  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d 
bef ore t h e partici pa nt w as e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h or ised pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F. 
•  
Partici pa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y. 
•  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y 
a ut h orised re prese ntati ve. 
•  
Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.  
A 4  
D at a Pr otecti o n  
•  
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y partici pa nt rec or ds or 
datasets t hat ar e tra nsf err e d t o t he s p o ns or will c o ntai n t he i de ntifier o nl y; partici pa nt 
na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de nti fia ble will n ot be 
tra nsferre d. 
•  
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y- relate d d ata will be use d b y 
t he s p o ns or i n acc or da nce wit h l ocal data pr ot ecti o n la w. T he le vel of discl os ure a n d use 
of t heir data m ust als o b e e x plai ne d t o t he partici p a nt i n t he i nf or me d c o nse nt.  
•  
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y 
Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h or ised pers o n nel a p p oi nte d b y t he 
s p o ns or, b y a p pr o priat e I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
A 5  
C o m mittees Str uct ure  
A n a dj u dicati o n c o m mittee will be f or m e d. T his c o m mittee will be c o m p ose d of i n de pe n d e nt 
ne p hr ol o gists, bli n de d t o st u d y treat me nt assi g n me nt. T he o bjecti ve of t his c o m mittee is t o 
e val uate w h et her t he h os pital a d missi o n s or E D  visits meet t he pre -s pecifie d C harter 
defi niti o n of H K  as c o ntri b uti n g fact or f or t hes e e nc o u nters. T he c o m mittee will als o re vie w 
t he re p orte d c o nc o mita nt me dicati o ns t o deter mi ne R A A Si d o w n- titrati o n/ disc o nti n uati o n 
e ve nts a n d use of res c ue t hera p y f or H K. 
A 6  
Disse mi n ati o n of Cli nic al St u d y D at a  
A n y res ults b ot h tec h nical a n d la y s u m maries f or t his trial, will be s u b mitte d t o E U C TI S 
wit hi n a year fr o m gl o bal E n d of Trial Date i n all partici pati n g c o u ntries, d ue t o scie ntific 
reas o ns, as ot her wise statistical a nal ysis is n ot rele va nt. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 2  of 1 1 2  
A descri pti o n of t his cli nical st u d y will be a vaila bl e o n 
htt p:// w w w.astraze necac li nicaltrials.c o m a n d htt p:// w w w.cli nicaltrials. g o v as will t he 
s u m mar y of t he st u d y res ults w he n t he y are a vaila ble. T he cli nical st u d y a n d/ or s u m mar y of 
st u d y res ults ma y als o be a vaila ble o n ot her we bsites acc or di n g t o t he re g ul ati o ns of t he 
c o u ntries i n w hic h t he st u d y is c o n d ucte d. 
A 7  
D at a Q u alit y Ass ur a nce  
•  
All partici pa nt data r elati n g t o t he st u d y will be rec or de d o n e C R F u nless tra ns mitte d t o 
t he s p o ns or or desi g nee electr o nicall y (e g, l a b orat or y data). T h e i n vesti gat or is 
res p o nsi ble f or v erif yi n g t hat data e ntries are acc urate a n d c orrect b y electr o nicall y 
si g ni n g t he e C R F. 
•  
T he i n vesti gat or m ust mai ntai n acc urate d oc u me nt ati o n (s o urce d ata) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e e C R F. 
•  
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a g e nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d o c u me nts. 
•  
M o nit ori n g details descri bi n g strate g y ( e g, ris k- b ase d i nitiati ves i n o perati o ns a n d q ualit y 
s uc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gies a n d A nal ytical Ris k-B ase d 
M o nit ori n g), met h o ds, res p o nsi bilities a n d re q uire me nts, i ncl u di n g ha n dli n g of 
n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n- site m o nit ori n g) 
are pr o vi d e d i n t he M o nit ori n g Pla n. 
•  
T he s p o ns or or desi g nee is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y i ncl u di n g 
q ualit y c hec ki n g of t he d ata. 
•  
T he s p o ns or ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals 
(e g, co ntr act res ear c h o r g a nizati o ns [C R Os ]). 
•  
St u d y m o nit ors will perf or m o n g oi n g s o urce data ve rificati o n t o c o nfir m t hat data e ntere d 
i nt o t he e C R F b y a ut h orise d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m 
s o urce d oc u m e nts; t hat t he safet y a n d ri g hts of partici pa nts are b ei n g pr otecte d; a n d t hat 
t he st u d y is bei n g c o n d ucte d i n acc or d a nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y 
ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
•  
Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he i n vesti gat or f or a mi ni m u m of  2 5 years after st u d y arc hi vi n g or as 
re q uire d b y l ocal re g ulati o ns, acc or di n g t o t he Astra Ze n eca Gl o bal rete nti o n a n d Dis p osal 
Sc he d ule. N o r ec or ds ma y be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n 
a p pr o val of t he s p o ns or. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y 
wit h o ut writte n n otificati o n t o t he s p o ns or. 
•  S o urce D oc u m e nts 
•  
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he p artici pa nt a n d s u bsta ntiate 
t he i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he i n v esti gat or’s site.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 3  of 1 1 2  
•  
Data e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u m e nts m ust be c o nsiste nt 
wit h t he s o urce d oc u m e nts or t he discre pa n cies m ust be e x plai ne d. T he i n v esti gat or ma y 
nee d t o re q u est pre vi o us me dical rec or ds or tra nsfer rec or ds, de p e n di n g o n t he st u d y. 
Als o, c urre nt me dical rec or ds m ust be a vaila ble. 
•  
All i nf or mati o n i n ori gi nal rec or ds a n d certifie d c o pies of ori gi nal rec or ds of cli nical 
fi n di n gs, o bser vati o ns, or ot her acti vities i n a cli nical st u d y necess ar y f or t he 
rec o nstr ucti o n a n d e val u ati o n of t he st u d y are d efi ne d as s o urce d oc u me nts. S o urce data 
are c o nt ai ne d i n s o urce d oc u me nts ( ori gi nal rec or ds or certifie d c o pies). 
A 8  
St u d y a n d Site St art a n d Cl os ure  
T he st u d y start date is t he date o n w hic h t h e cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts.  
T he first act of recr uit me nt is t he first site acti vate d will be t he st u d y start date.  
T he s p o ns or desi g nee res er ves t he ri g ht t o cl ose t h e st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti o n of t he s p o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl os e d w he n all re q uire d d o c u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d a n d a st u d y-site cl os ure visit has bee n perf or m e d. 
T he i n vesti gat or ma y i nitiate st u d y -site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or or i n vesti gat or ma y i ncl u de b ut are 
n ot li mite d t o:  
1)  Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes 
2)  I n a de q uat e recr uit me nt of partici pa nts b y t he i n vesti gat or 
3)  Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt. 
 
If t he st u d y is pre mat ur el y ter mi nate d or s us pe n d e d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y C R O(s) use d i n t he st u d y of 
t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y 
re q uire me nts. T h e i n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt a n d s h o ul d ass ure 
a p pr o priate p artici pa nt t h era p y a n d/ or f oll o w- u p. 
Partici pa nts fr o m ter mi nate d sites will ha ve t he o p p ort u nit y t o be tra nsferre d t o a n ot her site t o 
c o nti n ue t he st u d y. 

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A 9  
P u blic ati o n P olic y  
•  
T he res ults of t his st u d y ma y be p u blis he d or pres e nte d at scie ntific meeti n gs. If t his is 
f oresee n, t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or 
bef ore s u b missi o n. T his all o ws t he s p o ns or t o pr otect pr o prietar y i nf or mati o n a n d t o 
pr o vi de c o m me nts. 
•  
T he s p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. I n 
acc or d a nce wit h sta n dar d e dit orial a n d et hical practice, t he s p o ns or will ge n erall y s u p p ort 
p u blicati o n of m ultice ntre  st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site data. I n 
t his case, a c o or di nati n g i n vesti gat or will be desi g nate d b y m ut ual a gree me nt. 
•  
A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nt er nati o nal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts. 
 
 

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A p pe n di x  B A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g  
B 1  
Defi niti o n of A d verse E ve nts  
A n A E is t he de v el o p me nt of a n y u nt o war d me di cal occ urre n ce i n a p artici pa nt  or cli nical 
st u d y partici pa nt  a d mi nistere d a me di ci nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a 
ca usal r elati o ns hi p wit h t his treat me nt . A n A E ca n t heref ore be a n y u nfa v o ura ble a n d 
u ni nte n de d si g n ( e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na usea, c hest 
pai n), or diseas e te m p orall y ass ociate d wit h t he use of a me dici n al pr o d uct, w het her or n ot 
c o nsi dere d r elate d t o t he me dici nal pr o d uct.  
T he ter m A E is use d t o i ncl u de b ot h seri o us a n d n o n-seri o us A Es a n d ca n i ncl u de a 
deteri orati o n of a pre- e xisti n g me dical occ urre nce . A n  A E ma y occ ur at a n y ti me e ve n if n o 
st u d y i nter ve nti o n has bee n a d mi nistere d. 
B 2  
Defi niti o ns of Seri o us A d verse E ve nt  
A seri o us a d verse e ve nt ( S A E) is a n A E o cc urri n g d uri n g a n y st u d y p hase (i e, r u n-i n, 
treat me nt, was h o ut, f oll o w- u p), t hat f ulfils o ne or m ore of t he f oll o wi n g criteria: 
•  
Res ults i n deat h  
•  
Is i m me diatel y life-t hreate ni n g 
•  
Re q uires i n -partici pa nt  h os pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n  
•  
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y   
•  
Is a c o n ge nital a n o mal y or birt h defect 
•  
Is a n i m p orta nt me dical e ve nt t hat ma y je o par dise t he partici pa nt  or ma y re q uire me dical 
treat me nt t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
 
A d verse E v e nts f or m ali g n a nt t u m o urs  re p orted d uri n g a st u d y s h o ul d ge nerall y be ass esse d 
as S A Es . If n o ot her seri o us ness criteria a p pl y, t he ‘I m p orta nt Me di cal E v e nt’ criterio n s h o ul d 
be use d. H o w e ver, i n cert ai n sit uati o ns, me dical j u d ge me nt o n a n i n di vi d ual e ve nt basis 
s h o ul d be a p plie d t o clarif y t hat t he mali g na nt t u m o ur e ve nt s h o ul d be ass esse d a n d re p orte d 
as a n o n- seri o us A E . F or e xa m ple, if t he t u m o ur is i ncl u de d as me dical hist or y a n d 
pr o gressi o n occ urs d uri n g t he st u d y, b ut t he pr o gressi o n d oes n ot c ha n ge treat me nt a n d/ or 
pr o g n osis of t he mali g na nt t u m o ur, t he A E ma y n ot f ulfil t he attri b utes f or bei n g assesse d as 
seri o us, alt h o u g h re p orti n g of t he pr o gressi o n of t he mali g na nt t u m o ur as a n A E is vali d a n d 
s h o ul d occ ur. Als o, s o me t y pes of mali g na nt t u m o urs, w hic h d o n ot s prea d re m otel y after a 
r o uti ne treat me nt t hat d o es n ot re q uire h os pitalisati o n, ma y be assesse d as n o n-seri o us; 
e xa m ples i n a d ults i ncl u de Sta ge 1 basal cell carci n o ma a n d Sta ge 1 A 1 cer vical ca n cer 
re m o ve d via c o n e bi o ps y. 

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Life -t hre at e ni n g 
‘ Life-t hreate ni n g’ mea ns t hat t he partici pa nt was at i m me diate ris k of deat h fr o m t he A E as it 
occ urr e d,  or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d u ct w o ul d res ult i n t he 
partici pa nt’s deat h . ‘ Lif e-t hreate ni n g’ d oes n ot mea n t hat ha d a n A E occ urre d i n a m ore se v ere 
f or m it mi g ht ha ve ca use d deat h (e g, h e patitis t hat res ol ve d wit h o ut he patic fail ure).  
H os pit alis ati o n  
O ut patie nt treat me nt i n a n e mer ge n c y  r o o m is n ot i n itself an S A E, alt h o u g h t he reas o ns f or it 
ma y be (e g , br o nc h os pas m, lar y n geal oe d e ma). H os pital a d missi o ns a n d/ or s ur gical o perati o ns 
pla n ne d bef ore or d uri n g a st u d y are n ot c o nsi dere d A Es if t he ill ness or dis ease e xiste d b ef ore 
t he partici pa nt was e nr oll e d i n t he st u d y, pr o vi de d t hat it di d n ot deteri orate i n a n u ne x pect e d 
wa y d uri n g t he st u d y. 
I m p ort a nt M e dic al E ve nt or M e dic al T re at me nt 
Me dical a n d sci e ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her a case is seri o us i n 
sit uati o ns w here i m p orta nt me dical e ve nts ma y n ot be i m me diatel y life-t hreate ni n g or res ult i n 
deat h, h os pitalisati o n, disa bilit y , or i nca pacit y b ut ma y je o par dise t he p artici pa nt  or ma y 
re q uire me di cal treat me nt t o pre ve nt o ne or m ore o utc o mes liste d i n t he defi niti o n of seri o us. 
T hese s h o ul d us uall y be c o nsi dere d as seri o us. 
Si m pl y st o p pi n g t he s us pect dr u g d oes n ot mea n t hat it is a n i m p orta nt me dical e ve nt; me dical 
j u d ge me nt m ust be use d. 
•  
A n gi oe de ma n ot se vere e n o u g h t o re q uire i nt u bati o n b ut re q uiri n g i ntra ve n o us 
h y dr oc ortis o ne treat me nt 
•  
He pat ot o xicit y ca use d b y paraceta m ol (aceta mi n o p he n) o ver d os e re q uiri n g treat me nt wit h 
N- acet ylc ystei ne  
•  
I nte nsi v e treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m 
•  
Bl o o d d yscrasias ( e g, n e utr o pe nia or a n ae mia re q uiri n g bl o o d tra nsf usi o n, etc.) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisati o n 
•  
De vel o p me nt of dr u g d e pe n de nc y or dr u g a b us e. 
I nte nsit y R ati n g S c ale: 
•  
Mil d (a ware n ess of si g n or s y m pt o m, b ut easil y t olerate d) 
•  
M o derate ( dis c o mf ort s ufficie nt t o ca use i nterfere n ce wit h n or mal acti vities) 
•  
Se vere (i n ca pacitati n g, wit h i na bilit y t o perf or m n or mal acti vities). 
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d s e vere A Es. Se v erit y is a meas ure of 
i nte nsit y, w hereas seri o us ness is de fi ne d b y t he criteria i n A p pe n di x B 2 . A n A E of se v ere 

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i nte nsit y nee d n ot necess aril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or 
se veral h o urs m a y be c o nsi dere d se vere n a usea, b ut n ot a S A E u nless it meets t he criteria 
s h o w n i n A p pe n di x B 2 . H o we ver,  a str o ke t h at res ults i n o nl y a li mite d de gree of disa bilit y 
ma y be c o nsi der e d a mil d str o ke b ut w o ul d be a S A E w he n it satisfies t he criteria s h o w n i n 
A p pe n di x B 2 . 
B 3  
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n  
W he n ma ki n g a n assess me nt of ca usalit y c o nsi der t he f oll o wi n g fact ors w he n deci di n g if t here 
is a ‘reas o n a ble p ossi bilit y’ t hat a n A E ma y h a ve b ee n ca use d b y t he dr u g. 
•  
Ti me c o urse. E x p os ur e t o s us pect dr u g. Has t he p artici pa nt  act u all y recei ve d t he s us pect  
dr u g? Di d t he A E o cc ur i n a reas o n a ble te m p oral relati o ns hi p t o t he a d mi nistrati o n of t he 
s us pect dr u g? 
•  
C o nsiste nc y wit h k n o w n dr u g pr ofile. Was t he A E c o nsiste nt wit h t he pre vi o us 
k n o wle d ge of t he s us p ect dr u g ( p har mac ol o g y a n d t o xic ol o g y) or dr u gs of t h e sa me 
p har mac ol o gical class? Or c o ul d t he A E b e a ntici pate d fr o m its p har mac ol o gical 
pr o perties? 
•  
De -c h alle n ge e x p erie n ce. Di d t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he d ose 
of t he s us pect dr u g ? 
•  
N o alter nati ve ca use . T h e A E ca n n ot be reas o n a bl y  e x plai ne d b y a n ot her aeti ol o g y s uc h 
as t he u n derl yi n g diseas e, ot her dr u gs, ot her h ost or e n vir o n me ntal fact ors. 
•  
Re -c halle n g e e x perie nce. Di d t he A E re o cc ur if t h e s us pecte d dr u g was rei ntr o d uce d after 
ha vi n g bee n st o p pe d? Astra Ze neca w o ul d n ot n or mall y rec o m me n d or s u p p ort a 
re-c h alle n ge. 
•  
La b orat or y tests. A s p ecific la b orat or y i n v esti gati o n (if perf or me d) h as c o nfir me d t he 
relati o ns hi p. 
I n diffic ult cas es, ot her f act ors c o ul d be c o nsi dere d s uc h as: 
•  
Is t his a r ec o g nised feat ure of o ver d ose of t h e dr u g? 
•  
Is t here a k n o w n mec h a nis m? 
Ca usalit y of ‘relate d’ is ma de if f oll o wi n g a re vie w of t he rel e va nt data, t h ere is e vi de n ce f or a 
‘reas o n a ble p ossi bilit y’ of a ca us al relati o ns hi p f or t he i n di vi d ual case. T he e x pressi o n 
‘reas o n a ble p ossi bilit y’ of a ca us al relati o ns hi p is mea nt t o c o n ve y, i n ge neral, t hat t here are 
facts (e vi d e nce) or ar g u m e nts t o s u g gest a ca usal relati o ns hi p. 
T he ca us alit y assess me nt is perf or me d b ase d o n t h e a vaila ble d ata i ncl u di n g e n o u g h 
i nf or mati o n t o ma ke a n i nf or me d j u d g me nt. Wit h n o a vaila ble facts or ar g u me nts t o s u g gest a 
ca usal r elati o ns hi p, t he e ve nt(s) will be assess e d as ‘ n ot relate d’ . 

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Ca usal relati o ns hi p i n cases w her e t he diseas e u n der st u d y has deteri orate d d ue t o lac k of 
eff ect s h o ul d be classifi e d as n o reas o n a ble p ossi bilit y.  
B 4  
Me dic ati o n Err or, Dr u g A b use, a n d Dr u g Mis use  
F or t he p ur p oses of t his cli nical st u d y, a me dicati o n err or is a n u ni nte n d e d fail ure or mista ke 
i n t he treat me nt pr ocess f or a n Astr a Ze n eca st u d y i nter ve nti o n t hat eit her ca uses har m t o t he 
partici pa nt or has t he p ot e ntial t o ca use har m t o t he partici pa nt.  
A me dicati o n err or is n ot lac k of efficac y of t h e dr u g, b ut rat her a h u m a n or pr ocess- relate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y site staff or p artici pa nt. 
Me dicati o n err or i ncl u des sit uati o ns w here a n err or.  
•  
O cc urre d  
•  
W as i de ntifie d a n d i nterce pte d bef ore t he p artici pa nt recei ve d t h e dr u g  
•  
D i d n ot occ ur, b ut cir c u msta nces were rec o g nise d t hat c o ul d ha ve le d t o a n err or. 
 
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors: 
•  
Dr u g na me c o nf usi o n 
•  
Dis pe nsi n g err or ( e g, me dicati o n pre pare d i nc orrectl y, e ve n if it was n ot act uall y gi ve n t o 
t he partici pa nt) 
•  
Dr u g n ot a d mi nistere d as i n dicate d (e g, wr o n g r o ute or wr o n g site of a d mi nistrati o n) 
•  
Dr u g n ot ta ke n as i n dic ate d (e g, ta blet  diss ol ve d i n water w h e n it s h o ul d be ta ke n as a 
s oli d ta blet)  
•  
Dr u g n ot st ore d as i nstr u cte d ( e g, k e pt i n t he fri d g e w he n it s h o ul d be at r o o m 
te m perat ur e)  
•  
Wr o n g partici p a nt recei v e d t he me dicati o n (e xcl u di n g I nteracti ve Res p o ns e 
Tec h n ol o g y/ Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt [ I R T/ R T SM] err ors)  
•  
Wr o n g dr u g a d mi nister e d t o partici pa nt (e x cl u di n g I R T/ R T SM err ors). 
 
E xa m ples of e ve nts t hat d o n ot  re q uire re p orti n g as me dicati o n err ors i n cli nical st u dies: 
•  
Err ors r elate d t o or r es ulti n g f r o m I R T/ R T SM, i ncl u di n g t h ose w hic h lea d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha v e bee n a me dicati o n err or  
•  
Partici pa nt acci d e ntall y misse d dr u g d ose(s) (e g, f or g ot  t o ta ke me dicati o n) 
•  
Acci de ntal o v er d ose ( will be ca pt ure d as a n o v er d ose)  
•  
Partici pa nt faile d t o ret ur n u n use d me dicati o n or e m pt y pac ka gi n g 

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Me dicati o n err ors ar e n ot re gar d e d as A Es b ut A Es ma y occ ur as a c o ns e q ue nce of t he 
me dicati o n err or.  
Dr u g A b use  
F or t he p ur p ose of t his st u d y, dr u g a b use is defi ne d as t he persiste nt or s p ora dic i nte nti o nal, 
n o n- t hera p e utic e xcessi ve use of I M P or Astra Ze n eca n o n- i n v esti gati o nal me dici nal pr o d uct 
(NI M P ) f or a per cei ve d r e war d or desire d n o n-t hera pe utic effect. 
A n y e ve nts of dr u g a b use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ure d a n d f or w ar de d t o 
t he Data E ntr y Site ( D E S) usi n g t he Dr u g A b us e Re p ort F or m. T his f or m s h o ul d be use d b ot h 
if t he dr u g a b use h a p pe n e d i n a st u d y partici pa nt or if t he dr u g a b us e i n v ol ves a pers o n n ot 
e nr olle d i n t he st u d y (s uc h as a rel ati ve of t he st u d y partici pa nt). 
E xa m ples of dr u g a b us e i ncl u de b ut are n ot li mite d t o: 
•  
T he dr u g is use d wit h t he i nte nt of getti n g a percei ve d re w ar d ( b y t h e st u d y partici pa nt or 
a pers o n n ot e nr olle d i n t he st u d y) 
•  
T he dr u g i n t he f or m of a ta blet is cr us he d a n d i njecte d or s n orte d wit h t he i nte nt of 
getti n g hi g h  
 
Dr u g Mis use  
Dr u g mis use is t he i nte nti o nal a n d i na p pr o priat e use ( b y a st u d y partici p a nt) of I M P or 
Astra Ze neca NI M P f or m e dici nal p ur p oses o utsi de of t he a ut h orise d pr o d u ct i nf or mati o n, or 
f or u na ut h orise d I M Ps or Astra Z e neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute. 
E ve nts of dr u g mis use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ure d a n d f or war de d t o 
t he D E S usi n g t he Dr u g Mis use Re p ort F or m. T his f or m s h o ul d be use d b ot h if t he dr u g 
mis use ha p pe ne d i n a st u d y partici pa nt or if t he dr u g mis use re gar ds a pers o n n ot e nr olle d i n 
t he st u d y (s uc h as a relati ve of t he st u d y partici pa nt). 
E xa m ples of dr u g mis use i ncl u de b ut are n ot li mite d t o: 
•  
T he dr u g is use d wit h t he i nte nti o n t o ca use a n effect i n a n ot her p ers o n 
•  
T he dr u g is s ol d t o ot her pe o ple f or recreati o nal p ur p oses  
•  
T he dr u g is use d t o f acilitate assa ult i n a n ot her p ers o n  
•  
T he dr u g is deli ber atel y a d mi nistere d b y t he wr o n g r o ute 

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•  
T he dr u g is s plit i n half beca use it is easier t o s wall o w, w he n it is state d i n t he pr ot oc ol 
t hat it m ust be s wall o we d w h ole 
•  
O nl y half t he d ose is ta ke n beca use t h e st u d y parti ci pa nt feels t hat h e/s he is feeli n g better 
w he n n ot ta ki n g t he w h ol e d ose 
•  
S o me o ne w h o is n ot e nr olle d i n t he st u d y i nte nti o nall y ta kes t he dr u g. 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl o silicate - D 9 4 8 0 C 0 0 0 2 3  
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 1  of 1 1 2  
A p pe n di x  C M a n a ge me nt of St u d y Pr oce d ures D uri n g t he C O VI D -1 9 
P a n de mic  
C 1  
I ntr o d ucti o n 
Safe g uar di n g t he h ealt h  a n d well bei n g of o ur partici pa nts a n d e ns uri n g t he c o nti n ue d s u p pl y 
of o ur me dici nes t o partici pa nts re mai ns of p ara m o u nt i m p orta nce f or Astra Ze neca t hr o u g h 
t he o n g oi n g C O VI D-1 9 o ut brea k.  
N ote: C ha n ges bel o w s h o ul d be i m ple me nte d o nl y d uri n g st u d y disr u pti o ns d ue t o a n y of or a 
c o m bi nati o n of ci vil crisis, nat ural disaster, or p u blic healt h crisis (e g, d uri n g q uara nti nes a n d 
res ulti n g site cl os ures, re gi o nal tra vel restri cti o ns, a n d c o nsi derati o ns if site pers o n nel or st u d y 
partici pa nts bec o m e i nfecte d wit h se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
(S A R S - C o V- 2) or si milar pa n de mic i nfecti o n) d uri n g w hic h partici pa nts m a y n ot wis h t o or 
ma y be u na ble t o visit t he st u d y site f or st u d y visits. T hese c ha n g es s h o ul d o nl y be 
i m ple me nte d if all o wa ble b y l ocal/re gi o nal g ui deli nes a n d f oll o wi n g a gree me nt fr o m t he 
s p o ns or. 
C 2  
Ris k Assess me nt f or C O VI D -1 9 P a n de mic  
S o di u m zirc o ni u m c ycl osilicate  is a K- bi n der acti n g i n t he gastr oi ntesti nal tract a n d i s n ot 
a bs or be d. N o a d diti o nal ris k fr o m C O VI D- 1 9 is e x pecte d d ue t o S Z C. 
H o we ver, t he ris k of e x p os ure t o i nfecte d p e o ple ca n n ot be c o m plet el y e xcl u de d d uri n g st u d y 
partici pati o n as t he partici pa nts ma y nee d t o e x p os e t he msel ves t o p u blic areas (e g, c o m m ut e 
t o t he site) a n d ha ve a d diti o nal h u ma n c o ntact (e g, wit h site staff). 
C 3  
Me as ures t o Miti g ate t he Ris ks Ass oci ate d wit h C O VI D -1 9  
•  
T his st u d y will start or res u me e nr ol me nt o nl y w h e n t he s p o ns or a n d i n vesti gat or dee m it 
a p pr o priate. I n a d diti o n, t he e nr ol me nt at a site le v el will o nl y start or res u me w he n l ocal 
re g ulati o ns a n d g ui deli nes all o w. 
•  
Nati o nal la ws a n d l ocal r ec o m me n dati o ns re g ar di n g t he pa n de mic will be strictl y a d here d 
t o. 
•  
Site is e nc o ura ge d t o c o ntact t he partici pa nt wit hi n 1 da y pri or t o a st u d y visit t o as k f or 
si g ns a n d s y m pt o ms relate d t o C O VI D- 1 9. 
C 4  
S us pecte d C O VI D -1 9 After Scree ni n g  
P artici p a nt is Se verel y Ill or H os pit alise d  
If t he partici p a nt bec o mes s y m pt o matic after scree ni n g a n d has s us pecte d C O VI D- 1 9 
(re gar dless of a n y S A R S - C o V-2 test res ults t hat ma y be a vaila ble), a n d is se verel y ill a n d/ or 
h os pitalise d, t he partici pa nt ma y te m p oraril y  (≤ 1 4 da ys), or per ma ne ntl y disc o nti n ue st u d y 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 2  of 1 1 2  
i nter ve nti o n at t he discreti o n of t he site i n vesti gat or.  
P artici p a nt is N O T Se verel y Ill  or H os pit alise d  
If t he partici p a nt bec o mes s y m pt o matic after scree ni n g a n d has s us pecte d C O VI D- 1 9 
(re gar dless of w h et her a n y S A R S- C o V-2 test res ults are a v aila ble or n ot), a n d is N O T se verel y 
ill a n d/ or h os pitalise d, t he i n vesti gat or s h o ul d deter mi ne if co nti n uati o n of treat me nt wit h 
st u d y i nter ve nti o n is i n t he best i nterest of t he p arti ci pa nt. 
Re gar dless if st u d y i nter ve nti o n is c o nti n ue d or n ot, t he partici pa nt is e nc o ura ge d t o atte n d t he 
st u d y visits acc or di n g t o t he sc he d ule. 
C 5  
C O VI D -1 9 D uri n g t he St u d y  
Re -c o nse nt of St u d y P a rtici p a nts D uri n g St u d y I nterr u pti o ns  
D uri n g st u d y i nterr u pti o ns, it ma y n ot be p ossi ble f or t he partici p a nts t o c o m plete o n- site 
st u d y visits a n d assess me nts a n d alter nati ve mea ns f or carr yi n g o ut t he visits a n d assess me nts 
ma y be necessar y (e g, r e m ote visits). Re-c o nse nt s h o ul d be o btai ne d f or t h e alter nati ve m ea ns 
of carr yi n g o ut visits a n d assess me nts a n d s h o ul d be o btai ne d pri or t o perf or mi n g t he 
pr oce d ur es descri be d i n t he S o A ( Secti o n 1. 3 ). Local a n d re gi o nal re g ulati o ns a n d/ or 
g ui deli nes re gar di n g re- c o nse nt of st u d y partici pa nts s h o ul d be c hec ke d a n d f oll o we d. 
Visiti n g t he st u d y sites f or t he s ole p ur p ose of o btai ni n g re-c o nse nt s h o ul d b e a v oi de d. 
Tele m e dici ne Visit t o Re pl ace O n -site Visit ( W here A p plic a ble) 
I n t his a p pe n di x, t he ter m tele me dici ne visit refers t o re m ote c o ntact wit h t he st u d y 
partici pa nts usi n g telec o m m u nicati o ns tec h n ol o g y i ncl u di n g p h o ne calls, virt ual or vi de o 
visits, a n d m o bile healt h de vices. 
D uri n g a ci vil crisis, nat ural disaster, or p u blic h ealt h crisis, visits t hat are sc he d ule d t o be o n 
site ma y be re place d b y a tele me dici ne visit if all o we d b y l ocal/re gi o n al g ui deli nes. Ha vi n g a 
tele me dici ne c o ntact wit h t he partici pa nts will all o w A Es a n d c o nc o mita nt me dicati o ns t o be 
re p orte d a n d d oc u me nte d. 
D at a C a pt ure D uri n g Tele m e dici ne Visits  
Data c ollecte d d uri n g tel e me dici ne visits will be ca pt ure d b y t he q ualifi e d healt h care 
pr ofessi o nal f r o m t he st u d y site. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 3  of 1 1 2  
A p pe n di x  D Pr ot oc ol A me n d me nt Hist or y  
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y bef or e t he Ta ble of C o nte nts. 
A me n d me nt 1. 0 : 0 2 A u g ust  2 0 2 1 
T his a me n d me nt is c o nsi dere d t o be n o n- s u bsta ntial base d o n t he criteria s et f ort h i n Article 
1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n 
U ni o n beca us e it neit her si g nifica ntl y i m pacts t he safet y or p h ysical/ me ntal i nte grit y of 
partici pa nts n or t he sci e ntific val ue of t he st u d y.  
O ver all R ati o n ale f or t he A m e n d me nt:
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3 Sc he d ule of 
Acti vities  
St u d y i nter ve nti o n dis pe nsati o n has bee n 
a d de d at visit 4 ( 7 da y s after disc har ge ). 
T o all o w f or st u d y i nter ve nti o n 
dis pe nsati o n if d ose nee ds t o be 
a dj uste d  
 
 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 4  of 1 1 2  
A me n d me nt 2. 0: 0 7 J ul y 2 0 2 2 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n. 
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1 S y n o psis  
3 O bjecti ves a n d E n d p oi nts  
4. 2 Scie ntific Rati o nale f or St u d y 
Desi g n  
9. 1 Statistical H y p ot hesis  
9. 2. 1 Pri mar y E n d p oi nt  
9. 4. 3. 1 Pri mar y E n d p oi nts  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
9. 4. 3. 3 E x pl orat or y E n d p oi nts  
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 nsi derati o ns  
D o w n -titrati o n (i ncl u di n g 
disc o nti n uati o n) of 
re ni n-a n gi ote nsi n -al d oster o ne s yste m 
i n hi bit ors ( R A A Si; ie, 
an gi ote nsi n -c o n verti n g e nz y me 
i n hi bit ors, an gi ote nsi n rece pt or 
bl oc ker s, a n d mi neral oc ortic oi d 
rece pt or a nta g o nists) is n o w defi ne d 
as a n o n‑res p o nse. C ha n ges i n 
R A A Si d oses d uri n g t he st u d y will be 
re vie we d a n d assesse d b y t he 
A dj u dicati o n C o m mittee.  
D ue t o t he k n o w n p ote ntial 
of R A A Si d o w n -titrati o n t o 
ac hie ve n or m o kalae mia, it is 
nee de d t o i ncl u de t his i n t he 
pri mar y c o m p osite as 
treat me nt fail ure 
1. 1 S y n o psis  
3 O bjecti ves a n d E n d p oi nts  
9. 1 Statistical H y p ot hesis  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
Sec o n dar y o bjecti ve # 2 is e dite d a n d 
is n o w f oc usi n g o n i nci de nce of 
h os pitalisati o n prece di n g e nr ol me nt s 
or e mer ge nc y de part me nt ( E D) visits, 
b ot h wit h h y per kalae mia ( H K) as a 
c o ntri b uti n g fact or.  
T o be m ore rele va nt t o 
cli nical decisi o n ma ki n g   
1. 1 S y n o psis  
3 O bjecti ves a n d E n d p oi nts  
9. 1 Statistical H y p ot hesis  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
Sec o n dar y o bjecti ve # 3 is e dite d a n d 
is n o w f oc usi n g o n n u m ber of 
h os pitalisati o n prece di n g e nr ol me nt s 
or E D visits, b ot h wit h H K as a 
c o ntri b uti n g fact or.  
T o be m ore rele va nt t o 
cli nical decisi o n ma ki n g   
1. 1 S y n o psis  
3 O bjecti ves a n d E n d p oi nts  
9. 1 Statistical H y p ot hesis  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
A ne w sec o n dar y o bjecti ve is a d de d 
t o e val uate effect of s o di u m 
zirc o ni u m c ycl osilicate ( S Z C) o n 
re d uci n g t he ris k of R A A Si 
d o w n -titrati o n.  
T h o u g h u n desira ble, R A A Si 
d o w n -titrati o n is a treat me nt 
o pti o n f or ma na gi n g H K: 
rece nt g ui deli nes descri be 
re d uci n g R A A Si as a last 
res ort 
1. 1 S y n o psis  
3 O bjecti ves a n d E n d p oi nts  
9. 1 Statistical H y p ot hesis  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
9. 4. 3. 3 E x pl orat or y E n d p oi nts  
Sec o n dar y o bjecti ves # 4 t o # 1 0 are 
m o ve d t o e x pl orat or y o bjecti ves.  
T o si m plif y t he sec o n dar y 
e n d p oi nts  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zir c o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 5  of 1 1 2  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1 S y n o psis  
1. 2 Sc he ma  
1. 3 Sc he d ule of Acti vities  
4. 2 Scie ntific Rati o nale f or St u d y 
Desi g n  
5. 1 I ncl usi o n Cri teria 
6. 1 Scree ni n g a n d I n patie nt P hase  
I ncl usi o n criteri o n #4 : Defi niti o n of 
H K f or eli gi bilit y is m o difie d . 
Clarificati o ns are als o pr o vi de d f or 
s o urces of t hese p otassi u m  ( K+ ) 
val ues . 
T o better descri be t he 
a p pr o priate a n d a d dressa ble 
p o p ulati o n  
1. 1 S y n o psis  
1. 2 Sc he ma  
4. 1 O verall Desi g n  
5 St u d y P o p ulati o n  
9. 4. 3. 1 Pri mar y E n d p oi nts  
9. 4. 3. 2 Sec o n dar y E n d p oi nts  
9. 4. 3. 3 E x pl orat or y E n d p oi nts  
 
T he st u d y n o w pla ns t o e nr ol 
a p pr o xi matel y e q ual n u m bers of 
partici pa nts wit h mil d H K ( K +  
bet wee n > 5 . 0 a n d ≤ 5. 5 m m ol/ L) a n d 
wit h m o derate/se vere H K ( K +  
bet wee n > 5. 5 a n d ≤ 6. 5  m m ol/ L), 
wit h a mi ni m u m of 3 0 % of t he 
e nr olle d partici pa nts i n eit her gr o u p . 
As a c o nse q ue nce, K +  le vels were 
a dj uste d i n se nsiti vit y a nal yses 
secti o ns f or pri mar y, sec o n dar y, a n d 
e x pl orat or y e n d p oi nts.  
T o descri be t he be nefit see n 
f or mil d H K vers us 
m o derate/se vere H K wit h 
S Z C p ost -disc har ge  
1. 1 S y n o psis  
4. 1 O verall Desi g n  
4. 2 Scie ntific Rati o nale f or St u d y 
Desi g n  
5. 2 E xcl usi o n Criteria  
6. 1 Scree ni n g a n d I n patie nt P hases  
It is clarifie d t hat partici pa nts treate d 
b y a K -bi n der at t he c urre nt E D 
visit/ h os pital a d missi o n ca n be 
e nr olle d i n t he st u d y u n der certai n 
c o n diti o ns. 
 
Clarificati o n e dit  
1. 1 S y n o psis  
1. 2 Sc he ma  
1. 3 Sc he d ule of Acti vities  
4. 1 O verall Desi g n  
6. 1 Scree ni n g a n d I n patie nt P hases  
Disc har ge ca n n o w occ ur u p t o 
2 1  da ys after baseli ne (i nstea d of 1 4, 
pre vi o usl y ). 
Base d o n fee d bac k fr o m 
i n vesti gati ve sites, 
partici pa nts  sta yi n g f or m ore 
t ha n 1 4 da ys i n h os pital ma y 
still be  g o o d  ca n di dates f or 
t his st u d y 
1. 1 S y n o psis  
2. 3. 1 Ris k Assess me nt  
4. 1 O verall Desi g n  
6. 2 O ut patie nt P hase  
It is clarifie d t hat partici pa nts 
ra n d o mise d t o Ar m B ca n be 
prescri be d a K -bi n der at, or after 
Da y  7 p ost -disc har ge t o treat H K.  
Clarificati o n e dit  
1. 1 S y n o psis  
9. 4. 4 Safet y  
Clarificati o ns o n a d verse e ve nt 
a nal yses.  
Clarificati o n e dit  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 6  of 1 1 2  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3 Sc he d ule of Acti vities  
6. 2 O ut patie nt P hase  
8. 1. 1 Pri mar y E n d p oi nts  
8. 2. 4 Cli nical Safet y La b orat or y 
Assess me nts  
Clarificati o ns are a d de d a b o ut w hic h 
la b orat or y (l ocal or ce ntral 
la b orat or y) will a nal yse t he sa m ples.  
Clarificati o n e dit  
1. 3 Sc he d ule of Acti vities  
6. 3. 1 I n vesti gati o nal Pr o d ucts  
6. 5 Meas ures t o Mi ni mise Bias: 
Ra n d o misati o n a n d Bli n di n g  
It is clarifie d t hat d uri n g in patie nt 
p hase, S Z C will be dis pe nse d dail y . 
Clarificati o n e dit  
1. 1 S y n o psis  
1. 2 Sc he ma  
1. 3 Sc he d ule of Acti vities  
4. 1 O verall Desi g n  
6. 1 Scree ni n g a n d I n patie nt P hase   
It is clarifie d t hat ce ntral la b orat or y 
res ults f or K+  are n ot ma n dat or y t o 
start S Z C treat me nt at t he baseli ne 
visit as l o n g as all eli gi bilit y criteria 
are met ( o nl y a K+  meas ure me nt n ot 
ol der t ha n 2 4 h o urs is necessar y) . 
Clarificati o n e dit  
2. 3. 1 Ris k Assess me nt  
Fl ui d o verl oa d is delete d fr o m  t he 
preferre d te r ms i ncl u de d i n 
o e de ma -relate d e ve nts. 
T o be ali g ne d wit h t he latest 
I n vesti gat or’s Br oc h ure 
5. 2 E xcl usi o n C riteria 
E xcl usi o n criteria # 3 a n d # 1 4 are 
c o m bi ne d i nt o o ne e xcl usi o n 
criteri o n. 
Clarificati o n e dit  
5. 2 E xcl usi o n C riteria 
T he ne w e xcl usi o n criteri a (# 3 a n d 
# 1 4 c o m bi ne d) are  e dite d t o e xcl u de 
all ki d ne y tra ns pla nt reci pie nts. 
T o c orrect a mista ke i n t he 
pre vi o us versi o n of t he 
pr ot oc ol w here o nl y li vi n g 
d o n or ki d ne y tra ns pla nt 
reci pie nts were e xcl u de d 
5. 2 E xcl usi o n C riteria 
A p pe n di x  C 4 C O VI D -1 9 pri or t o 
Scree ni n g  
E xcl usi o n criteri o n # 1 1 (e xcl usi o n of 
partici pa nts  wit h e vi de nce of 
C or o na vir us disease 2 0 1 9 wit hi n 2 
wee ks pri or t o scree ni n g ) is delete d. 
A ne w ris k assess me nt was 
perf or me d a n d le d t o t he 
c o ncl usi o n t hat t his 
e xcl usi o n c riteri o n was n ot 
nee de d a n y m ore  
5 St u d y P o p ulati o n  
5. 4 Scree n Fail ures  
A p pe n di x A 3 I nf or me d C o nse nt  
T o all o w f or re -scree ni n g ( u p t o 2 ). 
T o facilitate recr uit me nt  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 7  of 1 1 2  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
6. 4  Pre parati o n/ Ha n dli n g/ St ora ge/ 
Acc o u nta bilit y  
A d diti o nal i nf or mati o n f or t he fi nal 
dis p ositi o n of u n use d st u d y 
i nter ve nti o ns is pr o vi de d. 
Clarificati o n e dit  
6. 7 C o nc o mita nt T hera p y  
Tacr oli m us is a d de d i n t he list of 
dr u gs t hat s h o ul d be ta ke n 2 h o urs 
bef ore or after S Z C t o a v oi d p ossi ble 
dr u g i nteracti o n.  
T o matc h u p date d E ur o pea n 
S m P C of L o kel ma  
1. 3 Sc he d ule of Acti vities  
8. 2. 4 Cli nical Safet y La b orat or y 
Assess me nts  
It is clarifie d t hat i n case of false 
p ositi ve, false ne gati ve or 
i n deter mi nate res ult f or uri ne 
pre g na nc y test, a sec o n d assess me nt 
will be perf or me d. It is als o clarifie d 
t hat K+  assesse d  l ocall y s h o ul d be 
meas ure d wit h  a vali date d met h o d, 
e g , bi oc he mistr y meas ure me nt or 
bl o o d gas a nal yser .    
Clarificati o n e dit  
8. 4 O ver d ose  
Defi niti o n of o ver d ose d uri n g S Z C 
mai nte na nce p hase is m o difie d fr o m 
1 5 t o 1 0 g/ da y.  
T o be ali g ne d wit h t he 
ma xi m u m dail y d ose d uri n g 
t he mai nte na nce p hase 
T hr o u g h o ut  
Mi n or e dit orial a n d d oc u me nt 
f or matti n g re visi o ns. 
Mi n or, t heref ore ha ve n ot 
bee n s u m marise d  
 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 8  of 1 1 2  
A p pe n di x  E A b bre vi ati o ns  
A b bre vi ati o n or s peci al ter m  
E x pl a n ati o n  
A E  
a d verse e ve nt 
B P  
bl o o d press ure  
C F R  
C o de of Fe deral Re g ulati o ns  
C K D  
c hr o nic ki d ne y disease  
C K D -E PI  
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R O  
c o ntract researc h or ga nizati o n  
C S P  
cli nical st u d y p r ot oc ol 
C TI S  
Cli nical Trial I nf or mati o n S yste m  
D E S  
Data E ntr y Site  
E C G  
electr ocar di o gra m 
e C R F  
electr o nic Case Re p ort F or m  
E D  
e mer ge nc y de part me nt 
E/ D  
earl y disc o nti n uati o n  
E D C  
electr o nic data ca pt ure 
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E O T  
e n d of treat me nt 
E U  
E ur o pea n U ni o n  
F A S  
f ull a nal ysis set 
G C P  
G o o d Cli nical Practice  
H K  
h y per kalae mia  
H R  
hazar d rati o  
H R U  
healt hcare res o urce utilisati o n  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I C U 
i nte nsi ve care u nit 
I E C 
I n de pe n de nt Et hics C o m mittee 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B/I E C 
I nstit uti o nal Re vie w B oar d 
I R T/ R T S M 
I nteracti ve Res p o nse Tec h n ol o g y/Ra n d o mis ati o n a n d Trial S u p pl y 
Ma na ge me nt  
K +  or K  
p otassi u m  
L O S  
le n gt h of sta y 

Cli nical St u d y Pr ot oc ol  - 4. 0 
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
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 9  of 1 1 2  
A b bre vi ati o n or s peci al ter m  
E x pl a n ati o n  
M M R M  
mi xe d m o del re peate d meas ures  
NI M P  
n o n -i n vesti gati o nal me dici nal pr o d uct 
N K  
n or m o kalae mia or n or m o kalae mic  
P P S  
per pr ot oc ol set  
P T  
preferre d ter m  
Q D  
o nce dail y  
Q Tc  
Q T i nter val c orrecte d  
Q Tc F  
Q T i nter val c orrecte d b y t he Fri dericia met h o d  
R A A Si  
re ni n-a n gi ote nsi n -al d oster o ne s yste m i n hi bit or  
S A E  
seri o us a d verse e ve nt  
S A P  
statistical anal ysis p la n 
S A R S -C o V - 2 
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2  
S o A  
Sc he d ule of Acti vities  
S o C  
sta n dar d of care 
S O C  
s yste m or ga n class 
S S O  
safet y set o pe n 
S S R  
safet y set ra n d o mise d 
S Z C  
s o di u m zirc o ni u m c ycl osilicate 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt 
TI D  
t hree ti mes dail y 
W O C B P  
W o ma n of c hil d beari n g p ote ntial  
 
 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 0  of 1 1 2  
1 1  
R E F E R E N C E S  
Betts et al, 2 0 1 8 
Betts K A, Wo olle y J M, M u F, et al. T he c ost of h y per kalae mia  i n t he U nite d States. Ki d ne y 
I nt Re p. 2 0 1 8; 3: 3 8 5 – 3 9 3. 
Betts et al, 2 0 2 0 
Betts K A, Wo olle y J M, M u F, et al. P ost disc har ge Healt h care c osts a n d h os pital rea d missi o n  
i n patie nts wit h h y perkal ae mia -r elate d h os pitalisati o ns. Ki d ne y I nt Re p. 2 0 2 0 
J u n 1 1; 5( 8): 1 2 8 0- 1 2 9 0. d oi: 1 0. 1 0 1 6/j.e kir. 2 0 2 0. 0 6. 0 0 4. 
D a vis et al, 2 0 1 9 
Da vis J, Isra ni R, M u F, et al. Ma na ge me nt of h y p er kale mic p atie nts i n t he i n patie nt setti n g b y 
h y per kalae mia  se verit y. P oster prese nte d at t he A ca de m y of M a na ge d Care P har mac y 
( A M C P) A n n ual Meeti n g 2 0 1 9, Marc h 2 5- 2 8, Sa n Die g o, Calif or nia, U S A. 
D o n g et al, 2 0 1 5 
D o n g H, R o bis o n L L, Leise nri n g W M, Marti n LJ, Ar mstr o n g G T, Yas ui Y. Esti mati n g t he 
b ur de n of r ec urre nt e v e nts i n t he prese nce of c o m p eti n g ris ks: t he met h o d of mea n c u m ulati ve 
c o u nt. A merica n j o ur nal of e pi de mi ol o g y. 2 0 1 5 A pr 1; 1 8 1( 7): 5 3 2- 5 4 0.  
D u n n et al, 2 0 1 5 
D u n n J D, Be nt o n W W, Er nest o O r ozc o- Torre ntera, E, et al. T he b ur d e n of h y per kalae mia  i n 
patie nts wit h car di o vasc ular a n d r e nal diseas e. A m J Ma na g Care.  2 0 1 5; 2 1: S 3 0 7- S 3 1 5. 
Fitc h et al, 2 0 1 7 
Fitc h K, Wo olle y J M, E n gel T, et al. T he cli nical a n d ec o n o mic b ur de n of h y per kalae mia  o n 
me dicare a n d c o m mer cial pa yers. A m Healt h Dr u g Be nefits. 2 0 1 7; 1 0( 4): 2 0 2- 2 1 0. 
H or ne et al, 2 0 1 9 
H or ne L, As hfa q A, Mac Lac hla n S. et al. E pi de mi ol o g y a n d healt h o utc o m es ass ociate d wit h 
h y per kalae mia  i n a pri mar y car e setti n g i n E n gla n d. B M C Ne p hr ol. 2 0 1 9; 2 0( 8 5). 
htt ps:// d oi. or g/ 1 0. 1 1 8 6/s 1 2 8 8 2- 0 1 9- 1 2 5 0- 0 . 
H o y, 2 0 1 8 
H o y S. S o di u m Zirc o ni u m C ycl osilicate: A Re vie w i n H y per kal ae mia. Dr u gs. 
2 0 1 8; 7 8: 1 6 0 5- 1 6 1 3. 
I C H E 9 w or ki n g gr o u p, 2 0 2 0 
I C H E 9 w or ki n g gr o u p. I C H E 9 ( R 1): a d de n d u m o n esti ma n ds a n d se nsiti vit y a nal ysis i n 
cli nical trials t o t he g ui deli ne o n statistical pri nci ples f or cli nical trials.  
K a n d a et al, 2 0 2 0 
Ka n da E, K as hi har a N, K o hsa ka S, et al. Cli nical a n d ec o n o mic b ur de n of h y per kalae mia: a 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 1  of 1 1 2  
nati o n wi de h os pital- b ase d c o h ort st u d y i n Ja pa n. Ki d ne y Me d. 2 0 2 0; 2( 6): 7 4 2- 7 5 2. 
d oi: 1 0. 1 0 1 6/ j. x k me. 2 0 2 0. 0 9. 0 0 3. 
K as hi h ar a et al, 2 0 1 9 
Kas hi hara  N, K o hsa k a S, Ka n da E. H y p er kal e mia i n Real -Worl d Patie nts  U n der C o nti n u o us 
Me dical Care i n J a pa n . Ki d ne y I nt Re p. 2 0 1 9; 4, 1 2 4 8 – 1 2 6 0 
K o ves d y, 2 0 1 7 
K o ves d y C P. U p dates i n h y per kalae mia : O utc o mes a n d t hera p e utic strate gi es. Re v E n d ocr 
Meta b Dis or d. 2 0 1 7 Mar; 1 8( 1): 4 1- 4 7.  
Le derer et  al, 2 0 2 0 
Le der er E, Bat u ma n V, Alsa us kas Z, et al. W h at is t he gl o bal pre vale n ce of h y per kalae mia  
( hi g h ser u m p otassi u m le vel)? Me dsca pe 2 0 2 0: htt ps:// w w w. me dsca pe.c o m/a ns wers/ 2 4 0 9 0 3-
1 0 9 9 5/ w hat- is-t he- gl o bal-pre val e nce - of-h y p er kal ae mia - hi g h-ser u m- p ot assi u m-le vel. 
Le ve y et al, 2 0 0 9 
Le ve y A S, Ste ve ns L A, Sc h mi d C H, et al. A ne w e q uati o n t o esti mate gl o m er ular filtrati o n 
rate. A n n I nter n M e d. 2 0 0 9; 1 5 0( 9): 6 0 4- 6 1 2. 
N a k h o ul et al, 2 0 1 5 
Na k h o ul G N, H ua n g H, Arri gai n S, et al. Ser u m p otassi u m, e n d- sta ge re n al disease a n d 
m ortalit y i n c hr o nic ki d ne y disease. A m J Ne p hr ol . 2 0 1 5; 4 1: 4 5 6- 4 6 3. 
R ossi g n ol et al, 2 0 1 6 
R ossi g n ol P, Le gra n d M, K osi b or o d M, et al. E mer ge nc y ma na g e me nt of se vere 
h y per kalae mia : G ui deli ne f or best practice a n d o p p ort u nities f or t he f ut ure. P har mac ol Res. 
2 0 1 6 N o v; 1 1 3( Pt A): 5 8 5 - 5 9 1. 
P oll ac k et al, 2 0 2 3 
P ollac k C V, A gir o A, Fa n M u F, et al. I m pact o n h os pitalizati o ns of l o n g-ter m vers us s h ort-
ter m t hera p y wit h s o di u m zirc o ni u m c ycl osilicat e d uri n g r o uti ne o ut patie nt care of patie nts 
wit h h y per kale mia: t he r ec o g nize I st u d y, E x pert Re vie w of P har mac oec o n o mics & O utc o mes 
Researc h . 2 0 2 3; 2 3: 2, 2 4 1- 2 5 0. 
S pi n o witz et al, 2 0 1 9 
S pi n o witz B S, Fis h ba ne S, Per g ola P E, et al. S o di u m zirc o ni u m c ycl osilicate  a m o n g 
i n di vi d uals wit h h y per kale mia: a  1 2- m o nt h P hase 3 st u d y. Cli n J A m S oc Ne p hr ol. 2 0 1 9; 
1 4 ( 6): 7 9 8- 8 0 9. 
T afesse et al, 2 0 2 0 
Tafesse E, H urst M, H os ki n L, et al. Ris k fact ors ass ociate d wit h t he i nci d e nce a n d rec urre nce 
of h y per kal ae mia i n patie nts wit h car di ore nal c o n diti o ns. I nt J Cli n Pract. 2 0 2 0; 0 0:e 1 3 9 4 1. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 2 3  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 2  of 1 1 2  
T h o mse n et al, 2 0 1 7 
T h o mse n R W , Nic olaise n S K , Has v ol d P et al . Ele vate d p otassi u m le vels i n patie nts wit h 
c hr o nic ki d ne y disease: o cc urr e nce, ris k fact ors a n d cli nical o utc o mes  - a D a nis h p o p ulati o n-
base d c o h ort st u d y.  Ne p hr ol Dial Tra ns pla nt . 2 0 1 7; 1 – 1 0. 

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 0 C 0 0 0 2 3-cs p- v 4
D oc u me nt Title:
D 9 4 8 0 C 0 0 0 2 3 Cli nical St u d y Pr ot oc ol versi o n 4
D oc u me nt I D:
D oc I D- 0 0 4 6 2 1 5 1 1
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)
Si g ne d b y
Me a ni n g of Si g n at ure
2 3- Oct- 2 0 2 3 1 6: 3 2 U T C
C o nte nt A p pr o val
0 2- N o v- 2 0 2 3 1 1: 1 9 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