Clinical trial NCT04997161
Conditions: Hyperkalaemia
Keywords: Hyperkalaemia Dialysis Patients
Sponsor: AstraZeneca
Start date: 2021-08-17; Completion date: 2021-11-17
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prescribing Sodium zirconium cyclosilicate (SZC) with enhanced nutritional advice to participants with hyperkalaemia on haemodialysis will reduce serum K+ (S-K+ ) and enable the consumption of more fruit and vegetables and more satisfying diet. The study aims to show that participants using SZC achieve S-K+ reduction as well as participants on SoC (other than K+ binders), without the need for restricting K+ in the diet.

Detailed description:
This is a Phase IV, randomised, controlled, open-label, parallel-group, multicentre, prospective study to evaluate the effect of the combination of SZC and enhanced nutritional advice to consume fruit and vegetables as compared to SoC in reducing S-K+ levels in participants with hyperkalaemia on haemodialysis. Following 7-day screening, all participants who are enrolled will begin an up to 1-month HK Treatment Phase with SZC as per local label. Participants will receive dietary advice consistent with SoC at that site, including K+ restriction. A 4-month Diet Comparison Phase will begin next with participants being randomised to either continue taking SZC, which can be titrated as needed to maintain target S-K+ , and receive enhanced nutritional advice to consume fruit and vegetables (SZC arm), or SZC will be withdrawn and participants will receive SoC, including dietary K+ restriction (SoC arm).

Arms: arm 1: Participants will continue taking Sodium Zirconium Cyclosilicate (SZC), which can be titrated up or down to maintain S-K+ in the range 3.5-5.5 mmol/L; participants will also receive enhanced nutritional advice to consume fruit and vegetables. Advice will be provided by dietitians at study visits and by Noom app between visits. arm 2: SZC will be withdrawn and participants will receive SoC as per site practice, including dietary K+ restriction. Dietary advice will be given by dietitians at study visits and by Noom app between study visits.
Interventions: intervention 1: Sodium Zirconium Cyclosilicate (SZC) intervention 2: Enhanced dietary advice intervention 3: Standard dietary advice including K+ restriction.
Intervention descriptions: intervention 1: Participants in the active arm will receive SZC dosed as per the local label to control hyperkalaemia and maintain normokalaemia. intervention 2: Participants will receive enhanced dietary advice in addition to taking SZC. This will include advice from dietitians to consume fruit and vegetables. Participants will be encouraged to consume up to 70 mmol K+ per day. intervention 3: Participants randomised to the SoC arm of the Diet Comparison Phase will receive standard dietary advice including K+ restriction.

Protocol documents:
Prot_002.pdf: 
D oc u me nt T y pe:  
D oc u me nt Dat es: 
St u d y Title: 
Fi nal Pr ot oc ol  
D 9 4 8 0 C 0 0 0 1 4 Pr ot oc ol Versi o n 3. 0 ( 1 2 A u g ust 2 0 2 1) 
A n  O pe n- La bel, Ra n d o mise d, C o ntr olle d, Parallel- Desi g n, 
M ultice ntre, P hase I V St u d y of S o di u m Zirc o ni u m C ycl osilicate a n d 
E n ha nce d N utriti o n A d vice C o m pare d t o Sta n dar d of Care i n 
Dial ysis P atie nts wit h Hy per kalae mia  ( GR A Z E) 
Pr ot oc ol Refere nce  N u m ber: D 9 4 8 0 C 0 0 0 1 4 
N C T N u m ber:    
N C T 0 4 9 9 7 1 6 1 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 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 1 4  
 
Ve r s i o n  
3. 0  
 
Date  
1 2  A u g 2 0 2 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A n O pe n -L a bel, R a n d o mi se d, C o ntr olle d, P ar allel -Desi g n, 
M ultice ntre, P h ase I V St u d y of S o di u m Zirc o ni u m C ycl osilic ate  
a n d E n h a nce d N utriti o n A d vice C o m p are d t o St a n d ar d of C are i n 
Di al ysis P atie nts wit h H y per k al ae mi a ( G R A Z E)  
 
S p o ns or N a me: Astra Ze 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 ge nc y I de ntifier N u m ber(s) : U S I N D : 1 0 8 9 5 1 / E u dra C T: 2 0 2 1 - 0 0 0 4 5 7- 8 1  
T his Cli nical St u d y Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
sta n dar d pr oce d ures. T he Cli nical St u d y Pr ot oc ol is p u blicl y re gistere d a n d t he res ults are 
discl ose d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o m plia nce wit h pre vaili n g la ws a n d re g ulati o ns. 
Pr ot oc ol 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 n a me L O K E L M A ®  
St u d y P h ase:  4 
S h ort Title:  S o di u m Zirc o ni u m C ycl osilicate  a n d E n ha nce d N utriti o n St u d y 
St u d y p h ysici a n a n d i n vesti g at or n a mes 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. 
 
Redacted for Public Disclosure


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 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 me nt  
D ate  
A me n d me nt, C S P Versi o n 3. 0  
1 2 -A u g -2 0 2 1  
A me n d me nt , C S P V ersi o n 2. 0  
0 5 -Ma y -2 0 2 1  
C S P V ersi o n 1. 0 
1 6 - Mar-2 0 2 1  
 
A me n d me nt 2 1 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 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 beca use 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 scie ntific 
val ue of t he st u d y.  
O ver all R ati o n ale f or t he A me n d me nt:
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
S u bst a nti al/ N o n -s u bst a nti al 
Secti o n 5. 1 
I ncl usi o n 
Criteria  
Clarificati o ns o n t he birt h 
c o ntr ol met h o ds all o we d f or 
fe male partici pa nts of 
c hil d beari n g p ote ntial  
e nr olle d i n t he U nite d -
Ki n g d o m  
Me dici nes a n d 
healt hcare pr o d uct 
Re g ulat or y A ge nc y 
re q uest 
N o n -s u bsta ntial 
Secti o n 9. 3 
P o p ulati o ns f or 
A nal yses  a n d 
A p pe n di x A  3 
Clarificati o n o n scree ni n g 
p hase  defi niti o n  
T o all o w f or partici pa nts 
w h o are n ot c o nse nte d 
o n a LI DI da y t o still be 
eli gi ble 
N o n -s u bsta ntial 
Secti o n 1. 3 
Sc he d ule of 
Acti vities  a n d 
A p pe n di x A 3 
F urt her t o t he c ha n ge i n 
scree ni n g p hase  defi niti o n, 
t he date of o btai ni n g t he I C F 
has bee n clarifie d  
I C F ca n be o btai ne d u p 
t o 7 da ys pri or t o st u d y 
s pecific assess me nts 
N o n -s u bsta ntial 
Secti o n 9. 4. 3. 2 
Sec o n dar y 
E n d p oi nts  
Mi n or e dit orial re visi o ns  o n 
t he statistical testi n g 
state me nt f or t he n o n-
i nferi orit y test  
T y p os, t heref ore ha ve 
n ot bee n s u m marise d  
N o n -s u bsta ntial 
Secti o n 9. 4. 3. 2 
Sec o n dar y 
E n d p oi nts  
U p date i n t he c o n diti o n t o 
reject t he n ull h y p ot hesis 
T he c o n diti o n t o reject 
t he n ull h y p ot hesis needs 
t o matc h wit h t he 
c orrecte d statistical 
testi n g state me nt f or t he 
n o n -i nferi orit y test 
N o n -s u bsta ntial 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Secti o n # a n d 
N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
S u bst a nti al/ N o n -s u bst a nti al 
A p pe n di x C  3 
A b bre viate d 
Treat me nt 
Satisfacti o n 
Q uesti o n naire 
f or Me dicati o n 
T S Q M - 9 
Deleti o n of si de -effects i n t he 
i nstr ucti o n te xt 
T o clarif y t hat 
partici pa nts are n ot 
re q ueste d t o assess si de-
effects i n t his versi o n of 
t he T S Q M 
N o n -s u bsta ntial 
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  
N o n -s u bsta ntial 
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 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  ........................................................................................................... 4 
1  
P R O T O C O L S U M M A R Y  ...................................................................................... 8 
1. 1  
S y n o psis .................................................................................................................. 8  
1. 2  
Sc he ma  .................................................................................................................. 1 1  
1. 3  
Sc he d ule of Acti vi ties ........................................................................................... 1 1  
2  
I N T R O D U C TI O N ................................................................................................ 1 5 
2. 1  
St u d y Rati o nale ..................................................................................................... 1 5  
2. 2  
Bac k gr o u n d ........................................................................................................... 1 5  
2. 3  
Be nefit/ Ris k Assess me nt  ...................................................................................... 1 6 
3  
O BJ E C TI V E S A N D E N D P OI N T S  ...................................................................... 1 7 
3. 1  
Esti ma n ds f or Pri mar y O bjecti ve  ......................................................................... 1 9 
4  
S T U D Y D E SI G N  ................................................................................................. 2 0 
4. 1  
O verall Desi g n  ...................................................................................................... 2 0 
4. 1. 1  
St u d y C o n d uct Miti gati o n D uri n g St u d y Disr u pti o ns D ue t o Cases of Ci vil 
Cr isis, Nat ural Disaster, or P u blic Healt h Crisis .................................................. 2 0 
4. 1. 2  
U p t o 1- m o nt h H K Treat me nt P hase (all partici pa nts)  ......................................... 2 0 
4. 1. 3  
4- m o nt h Diet C o m paris o n P hase ( 2 ar ms) ........................................................... 2 1  
4. 1. 4  
F oll o w- u p P hase (all partici pa nts)  ........................................................................ 2 1 
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  .................................................................. 2 1 
4. 3  
J ustificati o n f or D ose ............................................................................................ 2 1 
4. 4  
E n d of St u d y Defi niti o n ........................................................................................ 2 2  
5  
S T U D Y P O P U L A TI O N  ....................................................................................... 2 2 
5. 1  
I ncl usi o n Criteria .................................................................................................. 2 2 
5. 2  
E xcl us i o n Criteria ................................................................................................. 2 3 
5. 3  
Lifest yle C o nsi derati o ns  ....................................................................................... 2 5 
5. 4  
Scree n Fail ures  ..................................................................................................... 2 5 
6  
S T U D Y I N T E R V E N TI O N  ................................................................................... 2 5 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistere d  ...................................................................... 2 5 
6. 1. 1  
I n vesti gati o nal Pr o d ucts ....................................................................................... 2 5 
6. 1. 2  
S o C Dietar y A d vice  .............................................................................................. 2 6 
6. 1. 3  
E n ha nce d Dietar y A d vice  ..................................................................................... 2 6 
6. 1. 4  
Diet M o bile A p p ( N o o m) ..................................................................................... 2 6  
6. 2  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ...................................................... 2 7 
6. 3  
Meas ures t o Mi ni mise Bias: Ra n d o misati o n a n d Bli n di n g  .................................. 2 7 
6. 4  
St u d y I nter ve nti o n C o m plia nce ............................................................................ 2 7  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
6. 5  
C o nc o mita nt T hera p y  ........................................................................................... 2 8 
6. 5. 1  
Resc ue Me dici ne  ................................................................................................... 2 9 
6. 5. 2  
Dial ys ate P otassi u m C o nce ntrati o n Prescri pti o n  .................................................. 2 9 
6. 6  
D ose M o dificati o n  ................................................................................................ 3 0 
6. 7  
I nter ve nti o n After t he E n d of t he St u d y ................................................................ 3 0 
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  ............................................................. 3 0 
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................................. 3 0  
7. 1. 1  
Te m p orar y Disc o nti n uati o n .................................................................................. 3 1  
7. 2  
Partici pa nt Wit h dra wal fr o m t he St u d y  ................................................................ 3 1 
7. 3  
L ost t o F oll o w- u p ................................................................................................. 3 2  
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  ................................................ 3 2 
8. 1  
Efficac y Assess me nts  ............................................................................................ 3 3 
8. 1. 1  
P otassi u m  .............................................................................................................. 3 3 
8. 1. 2  
Patie nt -Re p orte d O utc o mes ( P R Os)  ..................................................................... 3 3 
8. 1. 2. 1  
K D Q O L ™- 3 6 ....................................................................................................... 3 3  
8. 1. 2. 2  
E Q - 5 D- 5 L ............................................................................................................. 3 3 
8. 1. 2. 3  
T S Q M - 9 ................................................................................................................ 3 3 
8. 1. 2. 4  
P GI C  ..................................................................................................................... 3 4 
8. 1. 2. 5  
A d mi nistrati o n of Electr o nic Patie nt -Re p orte d O utc o mes (e P R Os)  .................... 3 4 
8. 2  
Safet y Assess me nts  ............................................................................................... 3 5 
8. 2. 1  
P h ysical E xa mi nati o ns  .......................................................................................... 3 5 
8. 2. 2  
Vital Si g ns  ............................................................................................................. 3 5 
8. 2. 3  
Electr ocar di o gra ms  ............................................................................................... 3 5 
8. 2. 4  
Cli nical Safet y La b orat or y Assess me nts  .............................................................. 3 6 
8. 2. 5  
Ot her Assess me nts  ................................................................................................ 3 7 
8. 2. 5. 1  
Dial ysis Prescri pti o n  ............................................................................................. 3 7 
8. 2. 5. 2  
Dial ysis A de q uac y  ................................................................................................ 3 7 
8. 2. 5. 3  
I nter dial ytic Wei g ht Gai n (I D W G) ....................................................................... 3 7 
8. 3  
A d verse E ve nts a n d Seri o us A d verse E ve nts ....................................................... 3 7  
8. 3. 1  
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or mati o n  ................. 3 7 
8. 3. 2  
F oll o w- u p of A Es a n d S A Es ................................................................................. 3 8  
8. 3. 3  
Ca usalit y C ollecti o n  ............................................................................................. 3 9 
8. 3. 4  
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms .................................................. 3 9  
8. 3. 5  
A d verse E ve nts Base d o n E xa mi nati o ns a n d Tests  .............................................. 3 9 
8. 3. 6  
Re p orti n g of Seri o us A d verse E ve nts ................................................................... 4 0  
8. 3. 7  
Pre g na nc y ............................................................................................................. 4 0  
8. 3. 7. 1  
Mater nal E x p os ure ................................................................................................ 4 1  
8. 3. 7. 2  
Pater nal E x p os ure ................................................................................................. 4 1  
8. 3. 8  
Me dicati o n Err or  ................................................................................................... 4 2 
8. 4  
O ver d ose ............................................................................................................... 4 2  
8. 5  
H u ma n Bi ol o gical Sa m ples  .................................................................................. 4 2 
8. 6  
H u ma n Bi ol o gical Sa m ple Bi o mar kers  ................................................................ 4 3 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
8. 7  
O pti o nal Ge n o mics I nitiati ve Sa m ple  ................................................................... 4 3 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................... 4 3 
9. 1  
Statistical H y p ot heses  ........................................................................................... 4 3 
9. 2  
Sa m ple Size Deter mi nati o n  .................................................................................. 4 3 
9. 3  
P o p ulati o ns f or A nal yses  ...................................................................................... 4 3 
9. 4  
Statistical A nal yses  ............................................................................................... 4 4 
9. 4. 1  
Ge neral C o nsi derati o ns  ......................................................................................... 4 4 
9. 4. 2  
C O VI D -1 9 C o nsi derati o ns  ................................................................................... 4 5 
9. 4. 3  
Efficac y  ................................................................................................................. 4 5 
9. 4. 3. 1  
Pri mar y E n d p oi nt .................................................................................................. 4 5  
9. 4. 3. 2  
Sec o n dar y E n d p oi nts ............................................................................................ 4 6  
9. 4. 3. 3  
E x pl orat or y E n d p oi nts  .......................................................................................... 4 8 
9. 4. 4  
Safet y  .................................................................................................................... 4 8 
9. 5  
I nteri m A nal yses ................................................................................................... 4 9 
9. 6  
Data M o nit ori n g C o m mittee  ................................................................................. 4 9 
1 0  
S U P P O R TI N G
 D O C U M E N T A TI O N
 A N D
 O P E R A TI O N A L
 
C O N SI D E R A TI O N S  ............................................................................................ 4 9 
1 1  
R E F E R E N C E S  ..................................................................................................... 8 1 
 
LI S T O F FI G U R E S  
Fi g ure 1  
St u d y Desi g n ............................................................................................... 1 1  
 
LI S T O F T A B L E S  
Ta ble  1 
Sc he d ule of Acti vities  ................................................................................. 1 2 
Ta ble 2   
O bjecti ves a n d E n d p oi nts ............................................................................ 1 7 
Ta ble 3   
I n vesti gati o nal Pr o d uct ................................................................................ 2 5 
Ta ble 4  
Restricte d Me dicati o ns  ................................................................................ 2 9 
Ta ble 5  
La b orat or y Safet y Varia bles  ....................................................................... 3 6 
Ta ble 6  
P o p ulati o ns f or A nal ysis  ............................................................................. 4 3 
Ta ble 7   
A nal ysis Peri o ds .......................................................................................... 4 4 
 
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 .......................... 4 9  
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 val uati n g, 
F oll o w- u p, a n d Re p orti n g ........................................................................... 5 5  
A p pe n di x C 
Electr o nic Patie nt -Re p o rte d O utc o mes ....................................................... 6 0 
A p pe n di x D  
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 ........ 7 6  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
A p pe n di x E  
A b bre viati o ns .............................................................................................. 7 8  
A p pe n di x F  
Pr ot oc ol A m e n d me nt Hist or y ..................................................................... 8 0 






Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0  of 8 2  
Discl os ure St ate me nt:  
T his is a  parallel -gr o u p, n o n -i n dicati o n-see ki n g inter ve nti o n - m o del n utriti o n st u d y wit h 
2 a r ms t hat is o pe n-la bel. 
N u m ber of P artici p a nts:  
A p pr o xi matel y 3 8 2 partici pa nts will be scree ne d  a n d 1 9 1 e nr olle d t o ac hie ve 1 6 2 ra n d o mise d 
( 8 1 per treat me nt ar m) t o st u d y i nter ve nti o n. Secti o n 9. 2, Sa m ple Size Deter mi nati o n, e x plai ns 
h o w scree ni n g fail ures are defi ne d.  
N ote : ‘E nr olle d ’ mea ns a partici pa nt ’s, or t heir le gall y acce pta ble re prese ntati ve’s, a gree me nt 
t o partici pate i n a clinical 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 nse nt pr ocess. 
P ote ntial partici pa nts w h o are scree ne d f or t he 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 ra n d o ml y assi g ne d/assi g ne d i n t he st u d y, are c o nsi dere d ‘scree n failures’, u nless 
ot her wise s pecifie d b y t he pr ot oc ol.  
I nter ve nti o n Gr o u ps  a n d D ur ati o n : 
T he st u d y has a d urati o n of 5 m o nt hs of partici pa nt partici pati o n a n d c o nsists of u p t o 7- da ys 
scree ni n g, u p t o 1- m o nt h H K Treat me nt P hase  (all partici pa nt s ta ke S Z C wit h sta n dar d dietar y 
a d vice), 4- m o nt h Diet C o m paris o n P hase ( partici pa nt s are ra n d o mise d t o So C ar m wit h 
sta n dar d dietar y a d vice or t o S Z C ar m wit h e n ha nce d dietar y a d vice), a n d e n ds wit h a 
f oll o w- u p visit ( 2 wee ks [ 1 4 ± 3 da ys] t o matc h dial ysis sc he d ule).  
D at a M o nit ori n g C o m mittee: N o  
St atistic al Met h o ds  
Sa m ple size deter mi nati o n is base d u p o n t he pri mar y o bjecti ve of t he pri mar y esti ma n d, ie, T o 
ev al u ate t he effect of t he c o m bi n ati o n of S Z C a n d e n h a nce d n utriti o n al a dv ice t o c o ns u me 
fr uit a n d ve get a bles as c o m p are d t o S o C i n re d uci n g S- K+ . Wit h 8 0 % p o wer t o reject t he 
pri mar y h y p ot hesis, 8 1 ra n d o mise d partici pa nt s per treat me nt ar m ( 1 6 2 i n t otal) w o ul d be 
re q uire d wit h a 1-si de d al p ha of 0.0 2 5 , ass u mi n g a c o m m o n sta n dar d de viati o n acr oss 
treat me nt gr o u ps of 0. 4 5 a n d a n o n-i nferi orit y mar gi n of 0. 2. It is e x pecte d t hat 1 5 % of 
partici pa nts w h o e nter t he H K Treat me nt  P hase  will n ot c o nti n ue t o t he Diet C o m paris o n 
P hase , a n d c o nse q ue ntl y it is a ntici pate d t hat a p pr o xi matel y 1 9 1 partici pa nts will e nter t he H K 
Treat me nt P hase  i n or der t o ac hie ve 1 6 2 ra n d o mise d. F urt her, t he scree ni n g fail ure rate is 
esti mate d t o be 5 0 %, mea ni n g 3 8 2 partici pa nt s will be e nr olle d. Partici pa nts will be 
ra n d o mise d i nt o t he 4- m o nt h Diet C o m paris o n P hase u ntil t he re q uire d n u m ber of ra n d o mis e d 
partici pa nt s is reac he d, at w hic h p oi nt t he recr uit me nt will st o p. 
A nal ysis p o p ulati o ns are as f oll o ws : All-partici pa nts a nal ysis set, H K treat me nt safet y a nal ysis 
set, full a nal ysis set ( F A S), a n d safet y a nal ysis set ( S A S).  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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  of 8 2  
I nfere nce c o ncer ni n g t he pri mar y a nal ysis will be perf or me d at t he 1-si de d 2. 5 % si g nifica nce 
le vel. All p oi nt esti mates will be prese nte d t o get her wit h c o nfi de nce i nter vals of 2-si de d 9 5 % 
c o vera ge, wit h g ui da nce i ncl u de d i n o ut p uts w here i nfere nce is base d u p o n 1 tail of t he 
i nter val. 
1. 2  
Sc he m a  
Fi g ure 1 
St u d y Desi g n  
  
A b bre viati o ns: H K = h y per kalae mia; K +  = p otassi u m; LI DI = l o n g i nter dial ytic - dial ysis i nter val; N = n u m ber of partici pa nts; 
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.  
N ote: O nl y partici pa nt s wit h S- K +  ≤5. 5 m m ol/ L o n 5 or 1 0 g S Z C at  e n d of H K Treat me nt P hase  will be ra n d o mi se d.  
 
1. 3  
Sc he d ule of Acti vities  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Ta ble  1 
Sc he d ule of Acti vities  
Pr oce d ure  
Scree ni n g/  
E nr oll me nt a 
H K Tre at me nt P h ase b  
Diet C o m p aris o n P h ase  
F oll o w- u p c 
E D d  
Det ails i n C li nic al 
St u d y Pr ot oc ol ( C S P)  
Secti o n or A p pe n di x  
M o nt h 1  
M o nt h 2  
M 3  
M 4  
M 5  
Visit e 
1  
2  
3  
4 f  
5f  
6g  
7  
8  
9  
1 0  
1 1  
1 2  
1 3 
Visit Wi n d o w ( Da ys)  
-7 t o - 1  
0  
± 1  
± 1  
± 1  
± 1  
± 1  
± 1  
± 1  
± 3  
± 3  
± 3  
  
  
 
Electr o nic i nf or me d 
c o nse nt h ( via e-de vice at 
site) 
X  
  
  
  
 
 
  
  
  
 
  
  
  
 
Secti o n  5. 1 
Eli gi bilit y criteria  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Secti o ns  5. 1  a n d 5. 2 
De m o gra p h y 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
P h ysical e xa mi nati o n i 
  
X  
  
  
  
X  
  
  
  
  
  
X  
  
X 
Secti o n  8. 2. 1   
Hei g ht 
  
X  
  
  
  
  
  
  
  
  
  
  
  
 
Secti o n  8. 2. 1   
Lea n wei g ht, trice ps s ki n -
f ol d t hic k nessi 
  
X  
  
  
  
X  
  
  
  
  
  
X  
  
X 
Secti o n  8. 2. 1  
Me dical hist or y j 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Ser u m pre g na nc y test 
( W O C B P o nl y) 
X  
  
  
  
 
 
  
  
  
 
  
  
  
 
Secti o n  8. 3. 7  
Ser u m K +  meas ure me nt i 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
Secti o n  8. 1. 1  
Cli nical safet y la b orat or y 
assess me nts i 
X  
  
  
  
  
X  
  
  
  
 
 
X 
 
X 
Secti o n  8. 2. 4  
E C G i 
X  
X  
  
  
  
X  
  
  
  
  
  
X  
X  
X 
Secti o n  8. 2. 3  
Vital si g ns d, i 
  
X  
  
  
  
X  
  
  
  
  
  
X  
X  
X 
Secti o n  8. 2. 2  
I D W Gk 
  
X  
  
  
  
X  
  
  
  
  
  
X  
  
X 
Secti o n  8. 2. 5. 3  
Dr u g dis pe nsati o n/ Dr u g 
acc o u nta bilit y 
 
X  
X  
X  
X  
X l  
Xl  
Xl  
Xl  
Xl  
Xl  
Xm   
 
X m  
Secti o ns  6. 1  a n d 6. 2  
A Es / S A Es 
X  
X  
X  
X  
X 
X 
X  
X  
X  
X  
X 
X 
X  
X  
S ecti o n 8. 3 
Pri or/ C o nc o mita nt 
me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
Secti o n  6. 5 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Pr oce d ure  
Scree ni n g/  
E nr oll me nt a 
H K Tre at me nt P h ase b  
Diet C o m p aris o n P h ase  
F oll o w- u p c 
E D d  
Det ails i n C li nic al 
St u d y Pr ot oc ol ( C S P)  
Secti o n or A p pe n di x  
M o nt h 1  
M o nt h 2  
M 3  
M 4  
M 5  
Visit e 
1  
2  
3  
4 f  
5f  
6g  
7  
8  
9  
1 0  
1 1  
1 2  
1 3 
Dial ysate K +  prescri pti o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
Secti o n  6. 5. 2  
Dial ysis prescri pti o n n 
X  
  
  
  
  
X  
X  
X  
X  
X  
X  
X  
  
 
Secti o n  8. 2. 5. 1  
Dial ysis a de q uac y o 
X  
  
  
  
  
  
  
  
  
  
  
X  
  
 
Secti o n  8. 2. 5. 2  
P R Os ( K D Q O L -3 6, E Q - 5 D-
5 L, T S Q M -9, P GI C) v ia e-
de vice at sitep 
  
X  
  
  
 
X 
  
  
  
  
  
X  
  
X 
Secti o n  8. 1. 2  
N o o m a p p q 
  
X  
  
  
  
  
  
  
  
  
  
  
  
 
Secti o ns  6. 1. 2, 6. 1. 3  a n d 
6. 1. 4 
Sta n dar d diet a d vice  
  
X  
X  
X  
X  
  
  
  
  
  
  
  
  
Xr 
Secti o n  6. 1. 2  
Sta n dar d diet a d vice ( S o C 
ar m i n Diet C o m paris o n 
P hase ) 
  
  
  
  
  
X  
X  
X  
X  
X  
X  
X  
  
 
Secti o n  6. 1. 2  
E n ha nce d diet a d vice ( S Z C 
ar m i n Diet C o m paris o n 
P hase ) 
  
  
  
  
  
X  
X  
X  
X  
X  
X  
X  
  
 
Secti o n  6. 1. 3  
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 = Earl y Disc o nti n uati o n; E Q -5 D -5 L = E ur o Q ol -5 Di me nsi o ns -5 Le vels;  H K = h y per kalae mia; I D W G = 
i nter dial ytic wei g ht gai n; K+  = p ot assi u m; K D Q O L -3 6 = Ki d ne y Disease a n d Q ualit y of Life -3 6 ite m; M = m o nt h; P GI C = Patie nts’ Gl o bal I m pressi o n of C ha n ge; P R O = p atie nt-
re p orte d o utc o me; S A E = seri o us a d verse e ve nt; 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; T S Q M -9 = A b bre viate d Treat me nt Satisfacti o n Q uesti o n naire f or 
Me dicati o n ( 9 ite ms); W O C B P = w o ma n of c hil d beari n g p ote ntial.  
 
a 
Scree ni n g P hase d urati o n: U p t o 7 da ys bef ore Da y 0.  
b 
H K Treat me nt P hase d urati o n: U p t o 1 m o nt h.  
c F oll o w- u p P hase d urati o n: 1 4 ± 3 da ys after pre vi o us visit . I ncl u des partici pa nts w h o ha ve bee n e nr olle d i nt o t he H K Treat me nt P hase  b ut n ot bee n ra n d o mi se d i nt o t he Diet 
C o m paris o n P hase . 
d 
A p plica ble f or E D pri or t o t he e n d of st u d y treat me nt.  
e 
Visits 1 t o 1 2 re q uire d t o be perf or me d at a l o n g i nter dial ytic-dial ysis i nter val  visit . 
f Visits 4 a n d 5 if nee de d; partici pa nt s wit h c o ntr olle d S- K +  le vels ca n be ra n d o mise d earlier. 
g  Ra n d o mis ati o n occ urs at Visit 6 . O nl y partici pa nt s wit h S- K +  ≤5. 5 m m o l/ L o n 5 or 1 0 g S Z C will be ra n d o mise d. 
h  I C F ca n be o btai ne d u p t o 7 da ys pri or t o st u d y s pecific assess me nts. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
i 
Pr oce d ure t o be perf or me d bef ore dial ysis.  
j C O VI D -1 9 vacci nati o n bef ore e nr ol me nt s h o ul d be ca pt ure d u n der “ me dical hist or y”  a n d u n der “ pri or me dicati o n”.  
k  C urre nt pre -dial ysis wei g ht mi n us pre vi o us p ost -dial ysis wei g ht ( meas ure d at i m me diate dial ysis sessi o n pri or t o t he st u d y visit) i n K g.  
l  Dr u g dis pe nsati o n i n S Z C ar m o nl y.  
m  O nl y dr u g acc o u nta bilit y at Visit 1 2 a n d at E D.  
n 
Bl o o d fl o w ( Q b, m L / mi n), ti me o n dial ysis ( mi n utes). 
o 
s p Kt/ V a n d/ or urea re d ucti o n rati o; rec or d t he m ost rece nt val ue b ut t his s h o ul d be n o ol der t ha n 5 wee ks.  
p 
P R Os are t o be c ollecte d bef ore treat me nt i nitiati o n o n Visits 2 a n d 6 . P GI C t o be c ollecte d at Visit 6 , 12, a n d E D visits o nl y.  
q 
Create t he N o o m acc o u nt a n d trai n t he partici pa nt s o n N o o m a p plicati o n. Partici pa nt s are e x pecte d t o trac k t heir dail y f o o d i nta ke via t he N o o m a p p u ntil Visit 1 2. 
r  I n case of earl y disc o nti n uati o n, all partici pa nt s will be pr o vi de d wit h sta n dar d diet a d vice. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 6  
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 a n o vel n o n- a bs or be d zirc o ni u m silicate t hat 
prefere ntiall y ca pt ures p otassi u m  ( K+ ) i n e xc ha n ge f or h y dr o ge n a n d s o di u m t hat is bei n g 
de vel o pe d f or t he treat me nt of h y per kalae mia ( H K) i n a d ult patie nts. S Z C ( bra n d na me 
L O K E L M A ® ) is a p pr o ve d i n t he U nite d States ( U S), E ur o pea n U ni o n, Ca na da, Ja pa n, C hi na, 
a n d Brazil. 
2. 1  
St u d y R ati o n ale  
Prescri bi n g S Z C  wit h e n ha nce d n utriti o nal a d vice t o partici pa nts wit h h y per kalae mia o n 
hae m o dial ysis will re d uce ser u m K +  ( S- K+ ) a n d e na ble t he c o ns u m pti o n of m ore fr uit a n d 
ve geta bles a n d m ore satisf yi n g diet. T he st u d y ai ms t o s h o w t hat partici pa nt s usi ng S Z C  
ac hie ve S- K +  re d ucti o n as well as partici pa nts o n S o C ( ot her t ha n K +  bi n ders), wit h o ut t he 
nee d f or restricti n g K +  i n t he diet. 
2. 2  
B ac k gr o u n d  
T here is gr o wi n g e vi de nce s u p p orti n g t he p ositi ve effects of pla nt- base d dietar y patter ns. 
Dietar y a d vice t hat e nc o ura ges i ncrease d fr uit a n d ve geta ble i nta ke c o ul d be a n effecti ve t o ol 
t o re d uce m or bi dit y a n d m ortalit y i n pe o ple wit h ki d ne y disease ( Wai et al. 2 0 1 7). T his st u d y 
ai ms t o s h o w t hat f or hae m o dial ysis patie nts wit h H K, treat me nt wit h S Z C t o get her wit h 
e n ha nce d n utriti o nal a d vice e nc o ura gi n g t he c o ns u m pti o n of fr uit a n d ve geta bles is as 
effecti ve as S o C, w hic h i ncl u des dietar y restricti o n of K + -c o ntai ni n g f o o ds, i n mai ntai ni n g 
S- K +  i n t he ra n ge 3. 5 – 5. 5 m m ol/ L.
Healt h y diet patter ns ha ve bee n wi del y li n ke d t o better healt h a n d healt h o utc o mes. 
Diets ric h i n ve geta bles a n d fr uits, w hile l o w i n fats, meats , a n d s weete ne d pr o d ucts, ha ve 
bee n i de ntifie d as heal t h y dietar y patter ns a n d ha ve s h o w n pr otecti ve ass ociati o ns wit h 
m or bi dit y a n d m ortalit y. S uc h diets ha ve bee n s h o w n t o l o wer bl o o d press ure i n 
pre h y perte nsi ve a n d h y perte nsi ve a d ults, a n d ha ve bee n ass ociate d wit h l o wer ris ks of 
car di o vasc ular a n d cere br o vasc ular disease i n o bser vati o nal st u dies (Li u et al. 2 0 1 7 ). 
A m o n g ki d ne y o utc o mes e xa mi ne d, a healt hier fr uit a n d ve geta ble ric h diet has bee n 
ass ociate d wit h sl o wer esti mate d gl o mer ular filtrati o n rate decli ne (Ki m et al. 2 0 1 9)  a n d wit h 
l o wer o d ds of i nci de nt c hr o nic ki d ne y disease (C K D ). I n a d diti o n, a n i nter ve nti o nal st u d y 
f o u n d t hat a dietar y patter n, ric h i n fr uits a n d ve geta bles, atte n uate d mar kers of ki d ne y i nj ur y 
a m o n g pers o ns wit h macr oal b u mi n uria (G ora ya et al. 2 0 1 9 ). 
T he mai n s o urce of re nal aci d l oa d c o mes fr o m diet, a n d t he mai n s o urce of dietar y bala nce is 
pr o vi de d b y K + -c o ntai ni n g a mi n o aci ds pri nci pall y f o u n d i n fr uits a n d ve geta bles 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 7  
(Sie ner  2 0 1 8). It has bee n s h o w n t hat fr uits a n d ve geta bles ha ve a si milar effect o n meta b olic 
aci d osis as  s o di u m bicar b o nate ta blets (G ora ya et al. 2 0 1 4 ). 
O ne of t he mai n wa ys of e xcreti n g K +  o nce t he ki d ne y is i m paire d is b y e xcreti o n i n t he st o ol. 
K +  e xcreti o n i n t he st o ol is pr o p orti o nal t o  t he a m o u nt of st o ol pr o d uce d (Ha yes et al. 1 9 6 7 ), 
a n d dial ysis patie nts wit h c o nsti pati o n ha ve si g nifica ntl y h i g her S- K +  t ha n t h ose wit h o ut 
c o nsti pati o n (El - S har ka w y et al. 2 0 0 9). 
A detaile d descri pti o n of t he c he mistr y, p har mac ol o g y, efficac y, a n d safet y of S Z C  is pr o vi de d 
i n t he I n vesti gat or’s Br oc h ure (I B). 
2. 3  
Be nefit/ Ris k Assess me nt  
T he pri mar y be nefit f or partici pa nts ra n d o mi se d t o S Z C treat me nt is e x pecte d t o be t he 
mai nte na nce of n or m o kalae mia d uri n g t he l o n g i nter dial ytic-dial ysis i nter val ( LI DI ), i n li ne 
wit h w hat was o bser ve d  i n t he DI A LI Z E st u d y. F urt her, s h o ul d t he st u d y h y p ot hesis pr o ve 
tr ue, partici pa nt s ta ki n g S Z C will be a ble t o c o ns u me a healt h y diet i ncl u di n g m ore fr uit a n d 
ve geta bles. S uc h dietar y c ha n ges are e x pecte d t o ha ve partici pa nt be nefits i ncl u di n g i m pr o ve d 
q u alit y of life a n d satisfacti o n wit h treat me nt.  
Partici pa nts treate d wit h S o C ma y n ot o btai n a n y be nefit i n ter ms of h y per kala e mia c orrecti o n 
a n d mai nte na nce b ut ma y be nefit fr o m a cl oser f oll o w-u p. Partici pa nts will recei ve alter nati ve 
t hera pies w he ne ver cli nicall y i n dicate d.  
A n esta blis he d d ose a dj ust me nt al g orit h m will be use d d uri n g t he st u d y t o titrate S Z C d oses t o 
e na ble partici pa nts t o ac hie ve a n d mai ntai n pre- dial ysis n or m o kala e mia after t he LI DI. I n 
acc or da nce wit h t he al g orit h m, t he d ose ma y be i n crease d, re d uce d , or ke pt u nc ha n ge d, 
de pe n di n g o n t he c urre nt K +  c o nce ntrati o n, a da pti n g t he d osi n g re gi me n t o eac h partici pa 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. 
T he ris ks i de ntifie d wit h S Z C treat me nt i ncl u de h y p o kalae mia a n d o e de ma-relate d e ve nts 
(i ncl u des fl ui d o verl oa d, fl ui d rete nti o n, ge neralise d oe de ma, h y per v ol ae mia, l ocali se d 
o e de ma, o e de ma, peri p heral o e de ma, peri p heral s welli n g). I n t his st u d y, t he ris k f or 
h y p o kala e mia is miti gate d b y peri o dic m o nit ori n g of S- K +  a n d a dj ust me nt of t he S Z C d ose as 
necessar y. Oe de ma ca n be ma na ge d b y c o nser vati ve meas ures i n li ne wit h sta n dar d cli nical 
practice. N o a d diti o nal safet y ris ks were i de ntifie d i n t he DI A LI Z E st u d y.  
I n c o ncl usi o n, t he fa v o ura ble be nefit-ris k rati o t hat has bee n esta blis he d f or S Z C i n t he 
cli nical de vel o p me nt pr o gra m re mai ns p ositi ve w he n S Z C is use d t o treat h y per kal ae mia i n 
partici pa nts o n c hr o nic hae m o dial ysis, as s h o w n i n t he DI A LI Z E st u d y. 
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 nefits 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. 






Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
3. 1  
Esti m a n ds f or Pri m ar y O bjecti ve  
I n li ne wit h t he I C H E 9 ( R 1) a d de n d u m, 5 attri b utes (treat me nt, p o p ulati o n, e n d p oi nt, 
i nterc urre nt e ve nts, a n d p o p ulati o n le vel s u m mar y) ha ve bee n s pecifie d t o tra nslate t he 
pri mar y a n d sec o n dar y efficac y o bjecti ves i nt o treat me nt effects t hat are t o be esti mate d 
(esti ma n ds). 
•  T he treat me nt c o n diti o n of i nte rest is: 
o  S Z C  d ose d as per l ocal la bel t o c o ntr ol H K a n d mai ntai n n or m o kalae mia i n 
a d diti o n t o S o C dietar y a d vice f or t he u p t o 1- m o nt h H K Treat me nt P hase  f oll o we d 
b y t he 4- m o nt h Diet C o m paris o n P hase  (S Z C  wit h e n ha nce d n utriti o n a d vice 
vers us S o C, i ncl u di n g sta n dar d dietar y a d vice) f or t he f ull 5 -m o nt h treat me nt 
d urati o n. 
•  T he treat me nt effect is assesse d b y t he pri mar y efficac y e n d p oi nt of c ha n ge fr o m 
baseli ne i n S- K +  le vels o ver t he M 3, M 4, a n d M 5 visits. 
•  T he p o p ulati o n of partici pa nt s tar gete d is a d ults wit h H K  as defi ne d b y t he 
i ncl usi o n/e xcl usi o n criteria w h o are a ble t o c o m plete t he H K Treat me nt P hase . 
•  I nterc urre nt e ve nts are ha n dle d t hr o u g h a c o m bi nati o n of a treat me nt p olic y strate g y a n d 
a c o m p osite strate g y. S pecificall y, t he f oll o wi n g e ve nts w hic h precl u de t he c ollecti o n of 
data f or t he pri mar y esti ma n d as defi ne d i n S ecti o n 9. 4. 3. 1 will be ha n dle d acc or di n g t o 
t he ta ble bel o w: 
I nterc urre nt e ve nt 
D at a c ollecti o n a n d a n al ysis  
Pre mat ure treat me nt 
disc o nti n uati o n d ue t o lac k of 
efficac y or p h ysicia n’s decisi o n  
S u bjects will be f oll o we d a n d data c ollecte d will be a nal yse d after 
t he i nterc urre nt e ve nt i n li ne wit h a treat me nt p olic y strate g y . 
I n t he case of missi n g data after treat me nt disc o nti n uati o n, val ues 
will be i m p ute d t hr o u g h a m ulti ple i m p utati o n ( MI) pr oce d ure.  
Pre mat ure treat me nt 
disc o nti n uati o n d ue t o reas o ns 
ot her t ha n lac k of efficac y or 
p h ysicia n’s decisi o n  
S u bjects will be f oll o we d a n d data c ollecte d after t he i nterc urre nt 
e ve nt i n li ne wit h a treat me nt p olic y strate g y. 
I n t he case of missi n g data after treat me nt disc o nti n uati o n, val ues 
will be i m p ute d t hr o u g h a MI pr oce d ure.  
I ntr o d ucti o n of resc ue t hera p y of a 
K +  bi n der f or H K  
S u bjects will be f oll o we d a n d data c ollecte d after t he i nterc urre nt 
e ve nt f or re p orti n g p ur p os es; h o we ver , t his data will n ot be use d f or 
t he pri mar y a nal ysis of t he pri mar y esti ma n d. 
All val ues after i ntr o d ucti o n of resc ue me dicati o n will be i m p ute d 
usi n g a c o m p osite p ol ic y t hr o u g h a MI pr oce d ure . 
•  T he treat me nt effect will be q ua ntifie d b y via re c o m bi nati o n of t he least s q uares ( L S) 
mea n of t he c ha n ge fr o m baseli ne i n S- K +  le vels acr oss t he M 3, M 4, a n d M 5 visits, 
o btai ne d fr o m a re peate d meas ures a nal ysis of c o varia nce ( A N C O V A ) perf or me d 
m ulti ple ti mes o n MI  data as o utli ne d i n Secti o n  9. 4. 3. 1. 
Details re gar di n g se nsiti vit y esti ma n ds f or t he pri mar y o bjecti ve a n d esti ma n ds f or t he 
sec o n dar y o bjecti ve will be i ncl u de d wit hi n t he S tatistical A nal ysis P la n ( S A P). 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 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 I V, ra n d o mi se d, c o ntr olle d, o pe n -la bel, parallel-gr o u p, m ultice nt re, 
pr os pecti ve st u d y t o e val uate t he effect of t he c o m bi nati o n of S Z C  a n d e n ha nce d n utriti o nal 
a d vice t o c o ns u me fr uit a n d ve geta bles as c o m pare d t o S o C i n re d uci n g S- K+  le vels i n 
partici pa nts wit h h y per kalae mia o n hae m o dial ysis . 
4. 1. 1  
St u d y C o n d uct Miti g ati o n D ur i n g St u d y Disr u pti o ns D ue t o 
C ases of Ci vil Crisis, N at ur al Dis aster, or P u blic He alt h Crisis  
T he g ui da nce gi ve n bel o w s u perse des i nstr ucti o ns pr o vi de d else w here i n t his Cli nical St u d y 
Pr ot oc ol ( C S P ) a n d s h o ul d be i m ple me nte d o nl y d uri n g cases 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 
restricti 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 me i nfecte d wit h 
C O VI D - 1 9 or si milar pa n de mic i nfecti o n) t hat w o ul d pre ve nt t he c o n d uct of st u d y- relate d 
acti vities at st u d y sites, t here b y c o m pr o misi n g t he st u d y site staff or t he partici pa nt’s a bilit y t o 
c o n d uct t he st u d y. T he i n vesti gat or or desi g nee s h o ul d c o ntact t he st u d y s p o ns or t o disc uss 
w het her t he miti gati o n pla ns bel o w s h o ul d be i m ple me nte d. 
To e ns ure c o nti n uit y of t he cli nical st u d y d uri n g a ci vil crisis, nat ural disaster, or p u blic healt h 
crisis, c ha n ges ma y be i m ple me nte d t o e ns ure t he safet y of st u d y partici pa nts, m ai ntai n 
c o m plia nce wit h G o o d Cli nical Practice ( G C P), a n d mi ni mi se ris ks t o st u d y i nte grit y.  
W here all o wa ble b y l ocal healt h a ut h orities, et hics c o m mittees, healt hcare pr o vi der ( H C P) 
g ui deli nes ( e g, h os pital p olicies) , or l ocal g o ver n me nt, t hese c ha n ges ma y i ncl u de t he 
f oll o wi n g o pti o ns: 
•  
O btai ni n g c o nse nt f or t he miti gati o n pr oce d ures a n d d oc u me nti n g t his i n t he s o urce data 
•  
Tele me dici ne visit: Re m ote c o ntact wit h t he 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. 
F or f urt her details o n st u d y c o n d uct d uri n g ci vil crisis, na t ural disaster, or p u blic healt h crisis, 
refer t o A p pe n di x D.  
4. 1. 2  
U p t o 1 -m o nt h H K Tre at me nt P h ase ( all p artici p a nt s) 
Partici pa nt s will f oll o w la belle d i nstr ucti o ns f or d osi n g dial ysis partici pa nt s, starti n g at 5 g o n 
n o n- dial ysis da ys. At wee kl y i nter vals partici pa nt s ca n be titrate d u p or d o w n i n 5-g ste ps t o a 
ma xi m u m of 1 5 g o n n o n- dial ysis da ys a n d a mi n i m u m of 5 g o n n o n- dial ysis da ys, t o kee p 
S- K +  i n t he ra n ge of 3. 5- 5. 5 m m ol/ L. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
K +  will be c orrecte d wit h S Z C  as per l ocal la bel. Partici pa nts will recei ve dietar y a d vice 
c o nsiste nt wit h S o C at t hat site , i ncl u di n g K+  restricti o n. Dietar y a d vice will be gi ve n b y 
dietitia ns at st u d y visits.  
4. 1. 3  
4- m o nt h Diet C o m p aris o n P h ase ( 2 ar ms)  
Ra n d o misati o n will occ ur at Visit 6 . O nl y partici pa nt s wit h S- K +  ≤5. 5 m m ol/ L o n 5 or 1 0 g 
S Z C will be ra n d o mis e d. Partici pa nt s o n 1 5 g S Z C will be c o nsi dere d as ra n d o misati o n 
fail ures. 
S Z C ar m:  Partici pa nt s will c o nti n ue ta ki n g S Z C, w hic h ca n be titrate d u p or d o w n as 
descri be d i n Secti o n  4. 1. 2 t o mai ntai n S- K +  i n t he ra n ge 3. 5- 5. 5 m m ol/ L; partici pa nt s will als o 
recei ve e n ha nce d n utriti o nal a d vice t o c o ns u me fr uit a n d ve geta bles. A d vice will be pr o vi de d 
b y dietitia ns at st u d y visits a n d b y N o o m a p p bet wee n visits. 
S o C ar m: S Z C will be wit h dra w n a n d partici pa nt s will recei ve S o C as per site practice, 
i ncl u di n g dietar y K+  restricti o n. Dietar y a d vice will be gi ve n b y dietitia ns at st u d y visits a n d 
b y N o o m a p p bet wee n st u d y visits. 
4. 1. 4  
F oll o w - up P h ase ( all p artici p a nt s) 
U p o n c o m pleti o n of t he st u d y, or earl y disc o nti n uati o n, all partici pa nts t hat ha ve recei ve d 
st u d y dr u g, i ncl u di n g t h ose w h o ha ve bee n e nr olle d i nt o t he H K Treat me nt P hase  b ut n ot bee n 
ra n d o mise d i nt o t he Diet C o m paris o n P hase , will pr ocee d t o t he p ost-treat me nt f oll o w- u p visit 
after 1 4± 3 da ys. After c o m pleti n g t he st u d y, or earl y disc o nti n uati o n, partici pa nt s will recei ve 
S o C a n d sta n dar d diet a d vice as deter mi ne d b y t heir treati n g p h ysicia n. 
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n  
F or t he p ur p oses of t his st u d y, t he acce pte d ra n ge f or n or m o kalae mia of 3. 5 – 5. 5 m m ol/ L has 
bee n selecte d f oll o wi n g a d vice fr o m t he steeri n g c o m mittee t o ali g n wit h ne p hr ol o gist 
perce pti o ns of H K i n dial ysis patie nts a n d t o cl osel y reflect t he ra n ge c o m m o nl y re gar de d as 
acce pta ble i n t hese patie nts.  
4. 3  
J ustific ati o n f or D ose 
F or patie nts o n dial ysis, S Z C s h o ul d o nl y be d ose d o n n o n- dial ysis da ys. T he rec o m me n de d 
starti n g d ose is 5 g o nce dail y. To esta blis h n or m o kalae mia (i n t he ra n ge c o m m o nl y re gar de d 
as acce pta ble i n t hese patie nts [ 3. 5 -5. 5 m m ol/ L]) , t he d ose ma y be titrate d u p or d o w n wee kl y 
base d o n t he pre- dial ysis S- K +  val ue after t he LI DI . T he d ose ca n be a dj uste d at i nter vals of 
1 wee k i n i ncre me nts of 5 g u p t o 1 5 g o nce dail y o n n o n- dial ysis da ys. It is rec o m me n de d t o 
m o nit or S- K +  wee kl y w hile t he d ose is a dj uste d; o nce n or m o kalae mia is esta blis he d, S- K +  
s h o ul d be m o nit ore d re g ularl y (e g, m o nt hl y, or m ore fre q ue ntl y base d o n cli nical j u d ge me nt 
i ncl u di n g c ha n ges i n dietar y K+  or me dicati o n affecti n g S- K+ ). 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
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 f oll o w- u p visit. 
T he e n d of t he st u d y is defi ne d as t he date of t he last visit of t he last partici pa nt i n t he st u d y.  
E n d of treat me nt is defi ne d as t he date of t he last visit i n t he Diet C o m paris o n P hase 
( Visit 1 2). 
5  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val 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 xe m pti o ns, is n ot per mitte d. 
5. 1  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be i ncl 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 criteri a a p pl y: 
A ge  
1  
Partici pa nt m ust be ≥1 8 years of a ge at t he ti me of si g ni n g t he i nf or me d c o nse nt. 
T y pe of P artici p a nt a n d Dise ase C h ar acteristics  
2  
Partici pa nts wit h pre vale nt H K ( S- K +  > 5. 5 m m ol/ L at t he e n d of LI DI) n ot re q uiri n g ac ute 
treat me nt. 
3  
Recei vi n g ha e m o dial ysis 3 ti mes a wee k wit h sta ble vasc ular access f or at least 3 m o nt hs 
bef ore scree ni n g visit.  
4  
Partici pa nts w h o ha ve a n d are a ble a n d willi n g t o use s mart p h o ne (a n dr oi d or i O S) 
n utriti o n a p p. 
Se x  
5  
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns re gar di n g 
t he met h o ds of c o ntrace pti o n f or t h ose partici pati n g i n cli nical st u dies. 
•  
F e male partici pa nts  of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y 
test (see Secti o n 8. 3. 7 ). 
•  
Fe male partici pa nts m ust be 1 year p ost - me n o pa usal, s ur gicall y sterile, or usi n g 
1 hi g hl y effecti ve f or m of birt h c o ntr ol ( de fi ne d as o ne t hat ca n ac hie ve a fail ure 
rate of less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y). T he y s h o ul d 
ha ve bee n sta ble o n t heir c h ose n met h o d of birt h c o ntr ol f or a mi ni m u m of 
3 m o nt hs bef ore e nteri n g t he st u d y a n d willi n g t o re mai n o n t he birt h c o ntr ol 
u ntil 1 2 wee ks after t he last d ose . 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
F or 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) i ncl u de d i n U nite d-
Ki n g d o m sites, hi g hl y effecti ve f or ms of birt h c o n tr ol are defi ne d as f oll o ws: 
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: ora l, i njecta ble, i m pla nta ble 
c) I ntra uteri ne de vice (I U D) 
d)  I ntra uteri ne h or m o ne-releasi n g s yste m (I U S) 
e) Bilateral t u bal occl usi o n  
f) 
Vasect o mise d part ner ( vasect 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 ner has recei ve d me dical 
assess me nt of t he s ur gical s uccess  
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 refrai 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.  
 
I nf or me d C o nse nt  
6  
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be 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 me nts a n d restricti o ns liste d i n t he I nf or me d C o nse nt For 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  
As j u d ge d b y t he i n vesti gat or or s p o ns or , a n y me dical c o n diti o n (i ncl u di n g acti ve, 
cli nicall y si g nifica nt i nfecti o n) t hat ma y p ose a safet y ris k t o t he partici pa nt i n t his st u d y, 
ma y c o nf o u n d safet y or efficac y assess me nts a n d je o par di se t he q ualit y of data, or ma y 
i nterfere wit h st u d y partici pati o n. 
2  
M y ocar dial i nfarcti o n, ac ute c or o nar y s y n dr o me ( S T -ele vati o n m y ocar dial i nfarcti o n , 
n o n- S T -ele vati o n m y ocar dial i nfarcti o n , or u nsta ble a n gi na), str o ke, seiz ure, 
t hr o m b otic/t hr o m b oe m b olic e ve nt (e g, dee p vei n t hr o m b osis or p ul m o nar y e m b olis m, b ut 
e xcl u di n g vasc ular access t hr o m b osis), perc uta ne o us tra nsl u mi nal c or o nar y a n gi o plast y, 
or c or o nar y arter y b y pass graft wit hi n 1 2 wee ks pri or t o scree ni n g visit. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
3  
Se vere le uc oc yt osis ( > 2 0 × 1 0 9/ L) or t hr o m b oc yt osis ( ≥4 5 0 × 1 09/ L) d uri n g scree ni n g. 
4  
P ol yc yt hae mia ( hae m o gl o bi n > 1 4 g/ d L) d uri n g scree ni n g. 
5  
Se vere c o nsti pati o n, b o wel o bstr ucti o n, p ost- o perati ve m otilit y dis or ders.  
6  
Sc he d ule d date f or li vi n g d o n or ki d ne y tra ns pla nt. 
7  
Partici pa nts wit h a life e x pecta nc y of less t ha n 6 m o nt hs.  
8  
Fe males of c hil d beari n g p ote ntial, u nless usi n g c o ntrace pti o n as detaile d i n t he pr ot oc ol 
or se x ual l y a bsti ne nt. 
9  
C urre ntl y pre g na nt (c o nfir me d wit h p ositi ve pre g na nc y test) or breast-fee di n g. 
1 0  Prese nce of car diac arr h yt h mias or c o n d ucti o n defects t hat re q uire i m me diate tre at me nt at 
H C P discreti o n . 
1 1  Hist or y of alc o h ol or dr u g a b use wit hi n 2 years pri or t o scree ni n g visit. 
1 2  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. 
1 3  C o n ge nital l o n g Q T s y n dr o me or Q T i nter val c orrecte d f or heart rate ( Q Tc) usi n g 
Fri dericia’s met h o d ( Q Tc F) > 5 5 0 ms. 
1 4  S y m pt o matic or u nc o ntr olle d atrial fi brillati o n des pite treat me nt, or as y m pt o matic 
s ustai ne d ve ntric ular tac h ycar dia. S u bjects wit h atrial fi brillati o n c o ntr olle d b y 
me dicati o n are per mitte d.  
1 5  If t he partici pa nt  has e vi de nce of C or o na vir us disease 2 0 1 9 ( C O VI D - 1 9) wit hi n 2 wee ks 
pri or t o scree ni n g (see  A p pe n di x D), t he partici pa nt ca n n ot be e nr olle d i n t he st u d y. 
 
Pri or/ C o nc o mit a nt T her a p y  
1 6  Partici pa nt s treate d wit h S Z C , s o di u m p ol yst yre ne s ulf o nate (S P S: Ka ye xalate ™; 
Res o ni u m ™ A), calci u m p ol yst yre ne s ulf o nate ( C P S: Calci u m Res o ni u m ™), or 
patir o mer ( Veltassa ™)
1 wit hi n 4 wee ks bef ore scree ni n g. 
1 7  Partici pa nts wit h a k n o w n h y perse nsiti vit y or pre vi o us a na p h yla xis t o S Z C or a n y of t he 
e xci pie nts of t he pr o d uct. 
1 8  Partici pa nt s u na ble t o ta ke oral S Z C . 
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce  
1 9  Partici pati o n i n a n ot her cli nical st u d y wit h a n in vesti gati o nal pr o d uct a d mi nistere d d uri n g 
t he m o nt h bef ore scree ni n g2.  
 
1  As a p pr o ve d a n d a vaila ble l ocall y  
2 Partici pa nts vacci nate d wit h C O VI D -1 9 vacci ne w hilst still u n der E mer ge nc y Use Utilisati o n will n ot be 
e xcl u de d fr o m t he st u d y  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
2 0  I n v ol ve me 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). 
2 1  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. 
2 2  Pre vi o us e nr ol me nt i n t he prese nt st u d y. 
5. 3  
Lifest yle C o nsi der ati o ns  
T here are n o pr oject -s pecific safet y re q uire me nts or restricti o ns f or S Z C . 
5. 4  
Scree n F ail ures  
Scree n fail 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 ue ntl y assi g ne d t o st u d y i nter ve nti o n . 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 pare nt re 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 ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o 
res p o n d t o q ueries 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 serio us a d verse e ve nt s ( S A Es). 
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y  be 
rescree ne d. O nl y 1 rescree ni n g is all o we d i n t he st u d y. Rescree ne d partici pa nts s h o ul d be 
assi g ne d t he sa me partici pa nt n u m ber as f or t he i nitial scree ni n g. 
At Visit 6, o nl y partici pa nt s wit h S- K +  ≤5. 5 m m ol/ L o n 5 or 1 0 g S Z C will be ra n d o mise d. 
Partici pa nt s o n 1 5 g S Z C are ra n d o misati o n fail ures.  
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 kete d pr o d uct(s), or 
place b o i nte n de d t o be 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 C S P . 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistere d  
6. 1. 1  
I n vesti g ati o n al Pr o d ucts 
Ta ble 3 
I n vesti g ati o n al Pr o d uct 
I nter ve nti o n N a me 
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 - a n d 1 0-g sac hets  
D os a ge Le vel(s)  
Partici pa nt s i n t he acti ve ar m will recei ve S Z C d ose d as per t he l ocal la bel t o 
c o ntr ol H K a n d mai ntai n n or m o kalae mia . A n y decisi o n t o disc o nti n ue S Z C 
will be u p t o t he treati n g p h ysicia n’s j u d ge me nt a n d as a d vise d b y t he la bel. 
Per t he la bel, S Z C s h o ul d o nl y be d ose d o n n o n -dial ysis da ys. T he 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
rec o m me n de d starti n g d ose is 5 g o nce dail y. T o esta blis h n or m o kalae mia (i n 
t he ra n ge c o m m o nl y re gar de d as acce pta ble i n t hese patie nts [ 3. 5-
5. 5  m m ol/ L]) , t he d ose ma y be titrate d u p or d o w n wee kl y base d o n t he 
pre -dial ysis S- K +  val ue after LI DI . T he d ose ca n be a dj uste d at i nter vals of 
1 wee k i n i ncre me nts of 5 g u p t o 1 5 g o nce dail y o n n o n -dial ysis da ys.  
R o ute of A d mi nistr ati o n  
O ral 
Use 
I n vesti gati o nal pr o d uct 
I M P a n d NI M P 
S o di u m zirc o ni u m c ycl osilicate   
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 belli n g  
St u d y i nter ve nti o n will be pr o vi de d i n sac hets pac ke d i n a b o x. Eac h sac het 
a n d b o x will be la belle d i n acc or da nce wit h G M P 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. 
A b bre viati o ns: G M P = G o o d Ma n ufact uri n g Practice; H K = h y per kalae mia; I M P = i n vesti gati o nal me dici nal 
pr o d uct; LI DI = l o n g i nter dial ytic -dial ysis i nter val; NI M P = n o n -I M P; S Z C = s o di u m zirc o ni u m c ycl osilicate. 
6. 1. 2  
S o C Diet ar y A d vice  
All partici pa nt s d uri n g t he H K Treat me nt P hase , a n d partici pa nts ra n d o mise d t o t he So C ar m 
of t he Diet C o m paris o n P hase  will recei ve sta n dar d dietar y a d vice i ncl u di n g K +  restricti o n. 
T his a d vice will be pr o vi de d b y dietitia ns at st u d y visits a n d will be c o nsiste nt wit h S o C at 
t hat site a n d will use a m o bile a p p ( N o o m, descri be d bel o w) t o trac k f o o d i nta ke o nl y. 
Partici pa nts will be e nc o ura ge d t o c o ns u me less t ha n 5 0 m m ol K +  per da y. 
6. 1. 3  
E n h a nce d D iet ar y A d vice  
U p o n ra n d o mis ati o n t o t he S Z C  ar m of t he Diet C o m paris o n P hase , partici pa nts will recei ve 
e n ha nce d dietar y a d vice i n a d diti o n t o ta ki n g S Z C . T his will i ncl u de a d vice fr o m dietit ia ns at 
st u d y visits t o c o ns u me fr uit a n d ve geta bles. Partici pa nt s will recei ve dietar y s u p p ort fr o m t he 
N o o m a p p bet wee n visits.  Partici pa nt s will be e nc o ura ge d t o c o ns u me u p t o 7 0 m m ol K +  per 
da y.  
6. 1. 4  
Diet M o bile A p p ( N o o m)  
I n or der t o trac k dietar y c ha n ges, partici pa nts i n b ot h ar ms will be s u p p orte d b y a m o bile a p p 
( N o o m) bet wee n st u d y visits. Partici pa nts will be re q uire d t o e nter i nf or mati o n dail y o n t heir 
f o o d i nta ke. T his a p p will (a) trac k f o o d i nta ke, i ncl u di n g K+ , fr uit a n d ve geta bles, a n d fi bre, 
( b) pr o vi de fee d bac k re gar di n g a n esti mate of dail y K+  c o ns u m pti o n, a n d (c) pr o vi de li ve 
g ui da nce o n f o o d c o ns u m pti o n b y h u ma n c oac hes. 
N o o m is a c o m merciall y a vaila ble m o bile a p p (a n dr oi d a n d i O S) t hat has bee n i n use f or o ver 
7 years a n d c urre ntl y has m ore t ha n 5 0 milli o n users w orl d wi de. T he a p p all o ws partici pa nt s 
t o e nter a n d trac k t heir f o o d i nta ke a n d has a 3. 7 milli o n -ite m pre dicti ve f o o d data base 
bac ke n d, w hic h i ncl u des f o o d ite m K +  c o nte nt. T here are 1 5 p u blis he d st u dies (i ncl u di n g 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Nat ure a n d B MJ) descri bi n g use of t he a p p, a n d N o o m has recei ve d 4 Nati o nal I nstit utes of 
Healt h ( NI H ) gra nts. 
6. 2  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y  
1)  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 f or all st u d y i nter ve nti o n recei ve d a n d a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y i nter ve nti o n. 
2)  O nl y partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n a n d o nl y a ut h or ised 
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 mate d) area i n 
acc or da nce 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. 
3)  T he i n vesti gat or, i nstit 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 nta 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). 
4)  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 
are pr o vi de d i n t he St u d y Refere nce Ma n ual . 
6. 3  
Me as ures t o Mi ni m ise Bi as: R a n d o mi sati 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 pecific 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 nteracti ve Res p o nse 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 S M). Bef ore t he st u d y is i nitiate d, t he tele p h o ne n u m ber a n 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 pa nt. T he site will rec or d t he i nter ve nti o n 
assi g n me nt o n t he a p plica ble electr o nic C ase Re p ort F or m ( e C R F), if re q uire d. P ote ntial bias 
will be re d uce d b y ce ntral ra n d o misati o n. 
6. 4  
St u d y I nter ve nti o n C o m pli a nce 
W he n partici pa nts are d ose d at t he site, w hic h will occ ur o n n o n- dial ysis da ys a n d s h o ul d be 
ke pt t o a mi ni m u m, t he y will recei ve st u d y i nter ve nti o n directl y fr o m t he i n vesti gat or or 
desi g nee, u n der me 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 cli nic 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 
st u d y i nter ve nti o n 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 ha 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 pa nts self -a d mi nister st u d y i nter ve nti o n(s) at h o me, c o m plia nce wit h st u d y 
i nter ve nti o n will be assesse d at eac h visit. C o m plia nce will be assesse d b y c o u nti n g ret ur ne d 
sachets d uri n g t he site visits a n d d oc u me nte d i n t he s o urce d oc 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 be rec or de d i n t he e C R F. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 8  of 8 2  
A rec or d of t he n u m ber of S Z C  sac hets dis pe nse d t o a n d ta ke n b y eac h partici pa nt m ust be 
mai ntai ne d  a n d rec 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 will als o be 
rec or de d i n t he eC R F.  
6. 5  
C o nc o mit a nt T her a p y  
S Z C  ca n tra nsie ntl y i ncrease gastric 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 ha 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 de 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 
oral me dicati o ns wit h ga stric p H-de pe n de nt bi oa vaila 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 bef ore or after S Z C  t o a v oi d p ossi ble raise d 
gastric p H dr u g i nteracti o n are liste d bel o w: 
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 -HI V 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  
S Z C  ca n be c o -a d mi nistere d wit h oral me dicati o ns t hat d o n ot e x hi bit p H - de pe n de nt 
bi oa vaila bilit y wit h o ut s paci n g of d osi n g ti mes. 
A n y me dicati o n or vacci ne (i ncl u di n g o ver- t he-c o u nter or prescri pti o n me dici nes, vita mi ns, 
a n d/ or her bal s u p ple me nts, or ot her s pecific cate g ories of i nterest) t hat t he partici 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 mati o n i ncl u di n g d ose a n d fre q ue nc y. 
H o we ver, if t he partici pa nt recei ve d o ne ( or m ore) C O VI D - 1 9 vacci nati 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 i n vesti gat or s h o ul d be c o ntacte d if t here 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. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 9  of 8 2  
Ta ble 4 
Restricte d Me dic ati o ns  
T y pe of Me dic ati o n/ Tre at me nt  
Ti meli ne/I nstr ucti o ns  
K +  bi n ders i ncl u di n g S P S, C P S, p atir o mer 
O nl y per mitte d t o be use d as resc ue t hera p y t o treat se vere 
H K ( S- K +  > 6. 0 m m ol/ L) after I M P has bee n disc o nti n ue d  
K +  s u p ple me nts or ot her dr u gs a d mi nistere d t o 
raise S- K +  (e g, p otassi u m c hl ori de)  
E xce pt if use d t o treat h y p o kalae mia ( S -K +  < 3. 5  m m ol/ L) 
acc or di n g t o me dical j u d ge me nt  
A b bre viati o ns: C P S = G o o d Ma n ufact uri n g Practice; H K = h y per kalae mia; I M P = i n vesti gati o nal me dici nal 
pr o d uct; S- K +  = ser u m p otassi u m; S P S = s o di u m p ol yst yre ne s ulf o nate.  
6. 5. 1  Resc ue Me dici ne  
F or b ot h ar ms, resc ue t hera p y is defi ne d as a n y t hera pe utic i nter ve nti o n c o nsi dere d necessar y 
i n acc or da nce wit h  l ocal practice patter ns t o re d uce S- K +  i n t he setti n g of se vere H K as 
defi ne d b y p h ysicia n a n d site. 
Treat me nts c o nsi dere d resc ue ma y i ncl u de : 
•  I ntra ve n o us i ns uli n/ gl uc ose or de xtr ose, beta a dre ner gic a g o nists, i ntra ve n o us s o di u m 
bicar b o nate, a n d a n y a d diti o nal dial ysis or ot her f or ms of re nal -re place me nt treat me nts 
w he n use d s pecificall y f or t he treat me nt of se vere H K as defi ne d l ocall y at site. 
•  I n a d diti o n, re d ucti o n i n t he dial ysate K+  c o nce ntrati o n t hat is prescri be d f or t he 
treat me nt of se vere H K d uri n g t he st u d y is als o c o nsi dere d resc ue t hera p y. 
I n vesti gat ors ma y c ha n ge dial ysate bat h as nee de d. 
•  Use of ot her K +  bi n ders i ncl u di n g S P S, C P S, a n d patir o mer. 
Resc ue t hera 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 if a p pr o priate a n d 
pr o per d oc u me ntati o n of t he e ve nt. Use of resc ue t hera p y will be treate d statisticall y a s 
descri be d i n t he S A P. 
See Statistical C o nsi derati o ns, Secti o n  9,  f or i m plicati o ns of t he use of resc ue 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. 5. 2  
Di al ys ate  P ot assi u m C o nce ntr ati o n Prescri pti o n  
T he dial ysate K +  c o nce ntrati o n prescri pti o n s h o ul d be rec or de d at t he ti mes i n dicate d i n t he 
Sc he d ule of Acti vities ( S o A ; see Ta ble  1). 
F or pre- dial ysis S- K +  c o nce ntrati o ns < 3. 5 m m ol/ L, s u bse q ue nt a dj ust me nts will be ma de i n 
acc or da nce t o l ocall y acce pte d cli nical practice patter ns a n d g ui de d b y t he i n vesti gat or’s 
cli nical j u d g me nt . 
F or ce ntres  t hat a d o pt t he cli nical practice of m o dif yi n g t he prescri be d dial ysate p otassi u m 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
c o nce ntrati o n w he n t he pre- dial ysis ser u m p otassi u m c o nce ntrati o n decreases, if pre -dial ysis 
S- K +  is bel o w 3. 5 m m ol/ L t he dial ysate K +  c o nce ntrati o n s h o ul d be i ncrease d b y 0. 5 or 
1 m m ol/ L acc or di n g t o S o C, e g, i ncrease dial ysate K+  fr o m 1 K+  t o 1. 5 or 2 K+ , fr o m 2 K+  t o 2. 5 
or 3 K + , or fr o m 3 K+  t o 3. 5 or 4 K+ . 
6. 6  
D ose M o dific ati o n  
T he rec o m me n de d starti n g d ose is 5 g o nce dail y o n n o n- dial ysis da ys. To esta blis h 
n or m o kalae mia (i n t he ra n ge c o m m o nl y re gar de d as acce pta ble i n t hese patie nts [ 3. 5-
5. 5 m m ol/ L]) , t he d ose ma y be titrate d u p or d o w n wee kl y base d o n t he pre- dial ysis S- K+  
val ue after t he LI DI . T he d ose c o ul d be a dj uste d at i nter vals of 1 wee k i n i ncre me nts of 5 g u p 
t o 1 5 g o nce dail y o n n o n- dial ysis da ys. 
6. 7  
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 
It ma y be necessar y f or a partici pa nt t o per ma ne 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 
re mai n i n t he st u d y a n d c o m plete all e n d- of-treat me nt pr oce d ures. See t he S o A (Ta ble  1) f or 
data t o be c ollecte 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 a n d 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. 
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 t hi n g as a wit h dra wal fr o m 
t he st u d y. 
To mi ni mi se ris k f or e ve nts relate d t o pr ol o n gati o n of Q Tc, t he f oll o wi n g disc o nti n uati o n 
criteria will be f oll o we d:  
•  
If a n a bs ol ute Q Tc F > 5 5 0 ms or a n i ncrease i n Q Tc F i nter val > 6 0 ms fr o m 
e nr ol me nt t o m ore t ha n 5 0 0 ms is reac he d , t he s u bject s h o ul d i m me diatel y 
recei ve a p pr o priate me dical i nter ve nti o n a n d be disc o nti n ue d fr o m t he st u d y 
dr u g treat me nt.  
•  
All partici pa nts meeti n g t he Q Tc F > 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 ormi n g t he E C G.  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 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 : T he 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 her treat me nt.  
•  
I nc orrectl y ra n d o mise d partici pa nt i n w h o m t he i ncl usi o n/e xcl usi o n criteria 
vi olati o n w o ul d p ut t he partici pa nt at u n d ue ris k. 
•  
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 nce wit h t he C S P . 
See t he S o A  (Ta ble  1) f or data t o be c ollecte d at t he ti me of i nter ve nti o n disc o nti n uati o n 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 be c o m plete d . 
7. 1. 1  
Te m p or ar y Disc o nti n u ati o n  
I n hae m o dial ysis  patie n ts, if S- K +  is < 3. 0 m m ol/ L o n a n y n o n- dial ysis da y or pre-dial ysis , 
S Z C  a d mi nistrati o n s h o ul d be wit h hel 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. T he  partici pa nt  s h o ul d be e val uate d f or a n y i nterc urre nt ill ness or c o m or bi dit y t hat 
ma y i ncrease t he ris k of h y p o kalae mia. S Z C  a d mi nistrati o n ca n be res u me d if i n dicate d  b ut 
o nl y after t he i nterc urre nt me dical c o n diti o n  t hat preci pitate d t he h y p o kalae mia has i m pr o ve d 
a nd S- K +  has ret ur ne d t o t he tar get ra n ge of n or mal le vels ( 3. 5 – 5. 5 m m ol/ L).  
If partici pa nt  te m p oraril y disc o nti n ue 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 pa nt c o n diti o n is sta bilis e 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 to ta ke treat me nt.  
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 dra 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 pecte d t o be u nc o m m o n. 
•  
A partici pa nt w h o c o nsi ders 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 ntact wit h a 
relati ve or treati 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 Earl y 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) f or data t o be c ollecte 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 be 
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 pa 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 use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
•  
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 he/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 nal c o nse nt. If he/s he re q uests wit h dra wal 
of c o nse nt f or use of sa m ples, destr ucti o n of a n y sa m ples ta ke n a n d n ot teste d s h o ul d be 
carrie 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 ocal 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 is u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic 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 ule 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 mai 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 partici pa 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 partici pa nt is dee me d l ost t o f oll o w - u p, t he i n vesti gat or or desi g nee m ust ma ke 
e ver y eff ort t o re 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 letter t o t he partici pa nt’s last k n o w n maili n g a d dress or as per 
l ocall y all o we d re g ulati o ns). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he 
partici pa nt’s me dical rec or d.  
•  
S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y. 
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 part 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 marise d i n t he S o A (Ta ble  1). Pr ot oc ol wai vers 
or e xe m pti o ns are n ot all o we d. 
•  
I m me diate safet 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 deter 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 nce t o t he st u d y desi 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. 
•  
A ll scree ni n g e val 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 nts 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 details of all partici 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 fail ure, as a p plica ble. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
•  
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 me nt (e g, bl o o d 
c o u nt) a n d o btai ne d bef ore si g ni n g of t he I C F ma y be utilise d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol- s pecifie d criteria a n d were perf or me 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  
P ot assi u m  
P otassi u m will be meas ure d after LI DI a n d after vital si g ns , E C G , a n d p h ysical e xa mi nati o n . 
Ser u m sa m ples will be a nal yse d usi n g l ocal la b orat or y f or t he p ur p oses of st u d y i ncl usi o n a n d 
m o nit ori n g.  
All ser u m 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.  
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 nal ysis of bl o o d sa m ples. 
8. 1. 2  
P atie nt -Re p orte d O utc o mes  ( P R Os) 
P R Os refer t o all o utc o mes a n d s y m pt o ms t hat are directl y re p orte d b y t he partici pa nt . P R Os 
ha ve bec o me i m p orta nt e n d p oi nts f or re g ulat or y a n d rei m b urse me nt a ut h orities w he n 
e val uati n g effecti ve ness of treat me nts i n cli nical trials.  
T he f oll o wi n g P R Os will be a d mi nistere d i n t he st u d y: K D Q O L - 3 6, E Q - 5 D- 5 L, T S Q M - 9, a n d 
P GI C  (refer t o A p pe n di x C ). Partici pa nts will be as ke d t o c o m plete t he q uesti o n naires i n a n 
electr o nic de vice at site visits s pecifie d i n t he S o A (Ta ble  1). 
8. 1. 2. 1  
K D Q O L ™- 3 6 
T he K D Q O L - 3 6 is a vali date d, self-re p orte d q uesti o n naire t hat c o m bi nes ge neric a n d 
disease -s pecific c o m p o ne nts f or assessi n g s y m pt o ms a n d healt h-relate d q ualit y of life 
( H R Q o L) of patie nts wit h C K D, see A p pe n di x  C 1 (Ricar d o et al . 2 0 1 3). T he K D Q O L- 3 6 
c o m prises a P C S (1 2 ite ms) , M C S (1 2 ite ms) , S y m pt o ms/ Pr o ble ms ( 1 2 ite ms) , B ur de n of 
Ki d ne y Disease ( 4 ite ms) , a n d Effects of Ki d ne y Disease ( 8 ite ms). Hi g her sc ores i n dicate 
better healt h/ H R Q ol. 
8. 1. 2. 2  
E Q - 5 D- 5 L 
T he E Q - 5 D-5 L is a self-re p orte d q uesti o n naire t hat is use d t o deri ve a sta n dar dise d meas ure of 
healt h stat us, als o referre d t o as a utilit y sc ore (refer t o A p pe n di x  C 2 [Her d ma n et al. 2 0 1 1 ]). 
E Q - 5 D-5 L utilit y sc ores are wi del y acce pte d b y rei m b urse me nt a ut h orities a n d will be use d t o 
s u p p ort healt h ec o n o mic e val uati o ns. 
8. 1. 2. 3  
T S Q M - 9 
T he T S Q M - 9 is a patie nt -re p orte d i nstr u me nt t o assess patie nts’ satisfacti o n wit h me dicati o n, 
pr o vi di n g sc ores o n 3 scales: effecti ve ness ( 3 ite ms), c o n ve nie nce ( 3 ite ms), a n d gl o bal 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 4  of 8 2  
satisfacti o n ( 3 ite ms) (see A p pe n di x C 3). T he T S Q M - 9 d o mai n sc ores ra n ge fr o m 0 t o 1 0 0 
wit h hi g her sc ores re prese nti n g hi g her satisfacti o n o n t hat d o mai n . T S Q M- 9 is a n a b bre viate d 
versi o n deri ve d fr o m t he T S Q M versi o n 1. 4 a n d has s h o w n g o o d ps yc h o metric pr o perties 
( B har mal et al. 2 0 0 9). 
8. 1. 2. 4  
P GI C  
T he P GI C will be i ncl u de d t o assess h o w a patie nt percei ves his/ her c ha n ge i n acti vit y 
li mitati o ns, s y m pt o ms, e m oti o ns, a n d o verall H R Q o L  si nce t he start of st u d y treat me nt (see 
A p pe n di x  C 4 ). 
8. 1. 2. 5  
A d mi nistr ati o n of Electr o nic P at ie nt-Re p orte d O utc o mes (e P R Os)  
T he f oll o wi n g best practice s h o ul d be f oll o we d: 
•  
All P R O q uesti o n naires m ust be c o m plete d b y partici pa nts at site usi n g a n electr o nic 
de vice; pa per q uesti o n naires are n ot all o we d i n t his st u d y. 
•  
Eac h site m ust all ocate t he res p o nsi bilit y f or t he a d mi nistrati o n of t he e P R Os t o a s pecific 
i n di vi d ual a n d, if p ossi ble, assi g n a bac k u p pers o n t o c o ver if t hat i n di vi d ual is a bse nt. 
•  
A ke y as pect of st u d y s uccess is t o ha ve hi g h P R O c o m plia nce. T heref ore, it is esse ntial 
t hat site pers on nel f oll o w t he S o A (Ta ble  1) a n d e ns ure t hat t he de vice is c har ge d a n d set 
u p pr o perl y bef ore t he first partici pa nt atte n ds visit 1, i n or der t o mi ni mise missi n g data. 
•  
It is rec o m me n de d t hat t he e P R O q uesti o n naires are co m plete d bef ore a n y ot her st u d y 
pr oce d ures are c o n d ucte d, i ncl u di n g bei n g see n b y t he i n vesti gat or. 
•  
T o a v oi d bias partici pa nts m ust n ot recei ve hel p fr o m relati ves, frie n ds , or site staff t o 
a ns wer or t o clarif y t he e P R O q uesti o n naires a n d m ust be c o m plete d b y t he partici pa nt i n 
pri vate.  
•  
T he a p p oi nte d site pers o n nel s h o ul d e x plai n t o partici pa nts t he val ue a n d rele va nce of 
e P R O assess me nts a n d i nf or m t hat t hese q uesti o ns are bei n g as ke d t o fi n d o ut, directl y 
fr o m partici pa nts, h o w he/s he feels. 
•  
T he a p p oi nte d site pers o n nel m ust s h o w partici pa nts h o w t o use t he e P R O de vice, i n 
acc or da nce wit h t he i nstr ucti o ns pr o vi de d.  
•  
If t he partici pa nt is u na ble t o rea d t he q uesti o n naire (e g, is bli n d or illiterate), t he 
partici pa nt is e xe m pte d fr o m c o m pleti n g t he e P R O q uesti o n naires b ut ma y still partici pate 
i n t he st u d y. Partici pa nt s e xe m pte d i n t his re gar d s h o ul d be fla g ge d a p pr o priatel y b y t he 
site staff i n t he s o urce d oc u me nts a n d i n e C R F. 
•  
If a partici pa nt uses vis ual ai ds (e g, s pectacles or c o ntact le nses) f or rea di n g a n d d oes n ot 
ha ve t he m at ha n d, t he partici pa nt will be e xe m pte d fr o m c o m pleti n g t he P R Os 
q uesti o n naires o n t hat visit. Partici pa nt s e xe m pte d i n t his re gar d s h o ul d be fla g ge d 
a p pr o priatel y b y site t he staff i n s o urce d oc u me nts a n d i n t he e C R F. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 5  of 8 2  
•  
T he researc h n urse or a p p oi nte d site staff s h o ul d stress t hat t he i nf or mati o n is n ot 
r o uti nel y s hare d wit h st u d y staff. T heref ore, if t he partici pa nt has a n y me dical pr o ble ms, 
t he y s h o ul d disc uss t he m wit h t he d oct or or researc h n urse se paratel y fr o m t he e P R O 
assess me nt. 
•  
Site staff m ust a d mi nister q uesti o n naires a vaila ble i n t he la n g ua ge t hat t he partici pa nt 
s pea ks a n d u n dersta n ds. Q uesti o ns s h o ul d n ot be rea d i n a n a vaila ble la n g ua ge a n d 
tra nslate d i nt o a n ot her la n g ua ge f or t he partici pa nt. 
•  
O n c o m pleti o n of t he q uesti o n naires, t he ta blet s h o ul d be ha n de d bac k t o t he desi g nate d 
res p o nsi ble pers o n w h o s h o ul d c hec k t hat all q uesti o n naires rele va nt f or t he s pecific visit 
were c o m plete d. If a n y P R O q uesti o n naire was n ot c o m plete d, t he site pers o n nel m ust 
d oc u me nt t h e reas o n w h y a partici pa nt c o ul d n ot c o m plete assess me nts i n s o urce 
d oc u me nts a n d t he R E V P R DI m o d ule i n t he e C R F. 
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 brief p h ysical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car di o vasc ular s yste m, a n d a b d o me n (li ver a n d s plee n).  Hei g ht, lea n wei g ht, a n d trice ps 
s ki n-f ol d t hic k ness assess me nts will als o be ma de at t he ti mes s pecifie d i n t he S o A (Ta ble  1). 
P h ysical e xa mi nati o n 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). 
8. 2. 2  
Vit al Si g ns  
Vital si g ns  ( bl o o d press ure, p ulse rate, a n d oral te m perat ure) 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), after 5 mi n of l yi n g or sitti n g d o w n wit h o ut a n y distracti o ns. 
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 s pecifie d i n t he S o A  (Ta ble  1). Q Tc( F) s h o ul d be 
rec or de d at eac h E C G meas ure me nt. E C G data a n d S- K +  val ues s h o ul d be c ollecte d a n d 
rec or de d i n t he e C R F i n c o n necti o n wit h re p orti n g A Es of S- K+  bel o w 3. 0 m m ol/ L . 
St u d y s u bjects wit h pace ma kers: 
•  
All E C G varia bles, i ncl u di n g Q T/ Q Tc( F), s h o ul d be rea d ma n uall y  a n d 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 ker partici pa nt s 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). 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
8. 2. 4  
Cli nic al S afet y L a b or at or y Assess me nts  
Bl o o d sa m ples f or deter mi nati o n of cli nical c he mistr y  a n d hae mat ol o g y will be ta ke n bef ore 
dial ysis at t he visits  i n dicate d i n t he S o A (Ta ble  1). 
A d diti o nal safet y sa m ples ma y be c ollecte d if cli nicall y i n dicate d at t he discreti o n of t he 
i n vesti gat or. T he date, ti me of c ollecti o n , a n d res ults ( val ues, u nits , a n d refere nce ra n ges) will  
be rec or de d o n t he a p pr o priate e C R F. 
T he cli nical c he mistr y  a n d hae mat ol o g y will be perf or me d at a l ocal la b orat or y at or near t o 
t he i n vesti gat or site. Sa m ple t u bes a n d sa m ple sizes ma y var y de pe n di n g o n la b orat or y 
met h o d use d a n d r o uti ne practice at t he site. 
T he f oll o wi n g la b orat or y varia bles will be meas ure d.  
Ta b le 5  
La b or at or y S afet y Vari a bles  
H ae m at ol o g y/ H ae m ost asis ( w h ole bl o o d)  
Cli nic al C he mistr y (ser u m or pl as m a)  
B- Hae m o gl o bi n ( H b)  
S/ P -Creati ni ne   
B- Le u k oc yte c o u nt  
Bl o o d urea nitr o ge n ( B U N)  
B- Le u k oc yte differe ntial c o u nt (a bs ol ute c o u nt)  
S/ P -Bilir u bi n, t otal  
B -Platelet c o u nt  
S/ P -Al kali ne p h os p hatase ( A L P) 
 
S/ P -As partate tra nsa mi nase ( A S T)  
 
S/ P Ga m ma -gl uta m yl tra nsferase ( G G T)  
 
S/ P -Al b u mi n  
 
S/ P- Lactate d e h y dr o ge nase  
 
S- K +  
 
S- calci u m  
 
S- ma g nesi u m  
 
S-s o di u m  
 
S -p h os p hate  
 
S- bicar b o nate  
 
S/ P- C hl ori de  
 
S/ P- Gl uc ose  
 
S/ P -Creati ne ki nase ( C K)  
 
S/ P- T otal pr otei n  
 
S- Pre g na nc y test (ser u m h C G)  
A b bre viati o ns: B = bl o o d; h C G = h u ma n c h ori o nic g o na d otr o pi n; P = plas ma; S = ser u m.  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
8. 2. 5  
Ot her Assess me nts  
8. 2. 5. 1  
Di al ysis Prescri pti o n  
Dial ysis prescri pti o n para meters i ncl u di n g bl o o d fl o w ( Q b, m L / mi n) a n d ti me o n dial ysis 
( mi n utes) s h o ul d be rec or de d at t he ti mes s pecifie d i n Ta ble  1. 
8. 2. 5. 2  
Di al ysis A de q u ac y  
Dial ysis a de q uac y i n dices i ncl u di n g s p Kt/ V a n d/ or urea re d ucti o n rati o ( U R R ) s h o ul d be 
rec or de d at t he ti mes s pecifie d i n Ta ble  1. I n vesti gat ors s h o ul d rec or d t he m ost rece nt val ues 
b ut t hese s h o ul d be n o ol der t ha n 5 wee ks. If n o val ues wit hi n 5 wee ks are a vaila ble, a ne w 
assess me nt of s p Kt/ V a n d/ or U R R s h o ul d be perf or me d o n t he ne xt wee kl y visit. Sites s h o ul d 
c o nsiste ntl y use eit her s p Kt/ V or U R R i n deter mi ni n g dial ysis a de q uac y. A c o m bi nati o n of 
b ot h is n ot acce pta ble.  
8. 2. 5. 3  
I nter di al ytic W ei g ht G ai n (I D W G) 
I D W G will be calc ulate d as t he differe nce bet wee n c urre nt pre - dial ysis wei g ht mi n us pre vi o us 
p ost- dial ysis wei g ht ( meas ure d at i m me diate dial ysis sessi o n pri or t o t he visit) i n kil o gra ms. 
I n or der t o o btai n all re q uire d meas ure me nts of I D W G t he i n vesti gat ors m ust ma ke s ure t hat a 
p ost- dial ysis wei g ht is a vaila ble f or t he i m me diate dial ysis sessi o n (as per us ual sc he d ule) 
pri or t o t he visit . 
8. 3  
A d verse E ve nts  a n d  Seri o us A d verse E ve nts  
T he pri 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 pa nt  ( or, w he n a p pr o priate, b y a care gi ver, 
s urr o gate, or t he partici pa nt 's le gall y a ut h orise d 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 . 
8. 3. 1  
Ti me Peri o d a n d Fre q ue nc y f or 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 t he first d ose of S Z C, t hr o u g h o ut t he st u d y, a n d d uri n g 
t he f oll o w- u p peri o d, descri be d earlier. 
S 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 mes 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 n vesti gati o nal me dici nal pr o d uct 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  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
treate 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 nres 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 partici 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 ve nt v ari a bles  
T he f oll o wi n g varia ble s will be c ollecte d f or eac h A E: 
•  
A E ( ver bati m)  
•  
T he date w he n t he A E starte 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 vesti gat or ca usalit y rati n g a gai nst t he i n vesti gati o nal pr o d uct ( yes or n o) 
•  
Acti o n ta ke n wit h re gar d t o i n vesti gati o nal pr o d uct 
•  
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 ware of S A E  
•  
A E is seri o us d ue t o  
o  
Res ults i n deat h  
o  
Is i m me diatel y life-t hreate ni n g 
o  
Re q uires i n -patie nt h os pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n  
o  
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y or s u bsta ntial disr u pti o n 
of t he a bilit y t o c o n d uct n or mal life f u ncti o ns  
o  
Is or res ults i n a c o n ge nital a n o mal y or birt h defect 
o  
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 i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
•  
Date of h os pitalisati o n  
•  
Date of disc har ge 
•  
Pr o ba ble ca use of deat h 
•  
Date of deat h  
•  
A ut o ps y perf or me d 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
•  
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  Collecti o n  
T he i n vesti gat or will  assess ca usal relati o ns hi p bet wee n i n vesti gati o nal pr o d uct a n d eac h A E , 
a n d a ns wer ‘ yes’ or ‘ n o’ t o t he 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 ve bee n ca use d b y t he i n vesti gati o nal pr o d uct?’ 
F or S A Es, ca usal relati o ns hi p s h o ul d als o be assesse d f or ot her me dicati o n a n d st u d y 
pr oce d ur es. N ote t hat f or S A Es t hat c o ul d be ass ociate 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 t o t he CS P. 
8. 3. 4  
A d verse E ve nts B ase d o n S i 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 pa nt  or 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: ‘ Ha ve y o u ha d a n y healt h pr o ble ms si nce t he pre vi o us visit/ y o u were 
last as ke d?’, 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 eC 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 he 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 paratel 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  
T he res ults fr o m t he C S P -ma n date d la b orat or y tests a n d vital si g ns will be s u m marise d i n t he 
Cli nical St u d y Re p ort . 
Deteri orati o n as c o m pare d t o baseli ne i n C S P - ma n date d la b orat or y val ues, vital si g ns , a n d 
E C Gs  s h o ul d t heref ore 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 he 
reas o n f or disc o nti n uati o n of treat me nt wit h t he i n vesti gati o nal pr o d uct, or are c o nsi dere d t o 
be cli nicall y rele va nt as j u d ge d b y t he i n vest i 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 ne d visits were re q uire d or ot her acti o n was 
ta ke n wit h t he st u d y i nter ve nti o n, 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 orat 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 m pt o m will be re p orte 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 her t ha n t he la b orat or y ter m ( e g, a nae mia vers us l o w hae m o gl o bi n val ue) . 
I n t he a bse nce of cli nical si g ns or s y m pt o ms, cli nicall y rele va nt deteri orati o ns i n 
n o n- ma n date d para meters s h o ul d be re p orte d as A E(s). 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Deteri orati o n of a la b orat 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 vate d cli nicall y rele va nt a b n or mal me dical fi n di n g at a p h ysical e xa mi nati o n 
as c o m pare d wit h t he baseli ne assess me nt will be re p orte d as a n A E u nless u ne q ui v ocall y 
relate d t o t he disease u n der st u d y. 
8. 3. 6  
Re p orti n g of S eri 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 relate d t o t he i n vesti gati o nal 
pr o d uct, or t o t he st u d y pr oce d ure(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 priate Astra Ze neca re prese 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 be c o mes a ware of it . 
T he desi g nate d Astra Ze neca re prese 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 necessar y i nf or mati o n is pr o vi de d t o t he Astra Ze neca Patie nt Safet y data e ntr y site wit hi n 
1  c ale n d ar d a y  of i nitial recei pt f or fatal a n d life-t hreate ni n g e ve 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 va 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 prese 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  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. 
O nce t he i n vesti gat ors or ot her site pers o n nel i n dicate a n A E is seri o us i n t he electr o nic 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 prese ntati ve. 
If t he 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 re p orts an 
S A E t o t he a p pr o priate Astra Ze neca re prese ntati ve b y tele p h o ne.  
T he Astra Ze neca re prese 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. 
F or f urt her g ui da nce o n t he defi niti o n of a S A E, see  A p pe n di x B of t he C S P . 
T he refere nce d oc u me nt f or defi niti o n of e x pecte d ness/liste d ness is t he I B f or t he Astra Ze neca 
dr u g. 
8. 3. 7  
Pre g n a nc y  
A ser u m pre g na nc y test i n dial ysis patie nts ca n res ult i n false p ositi ve or i n deter mi nate 
o utc o mes, li kel y d ue t o cleara nce of t he h or m o ne h u ma n c h ori o nic g o na d otr o pi n ( h C G ). I n a 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
real pre g na nc y, h C G le vels us ual d o u ble e ver y 2- 3 da ys. A re peat h C G test will be re q uire d 
± 1- 2 wee ks after t he 1 st assess me nt t o o bser ve t he tre n d. A false -p ositi ve 1 st res ult will yiel d 
si milar res ults i n t he 2 n d test. I n case of d o u bt a n ultras o u n d s h o ul d be c o nsi dere d t o e xcl u de 
a n y pre g na nc y, per t he discreti o n of t he i n vesti gat or. 
All pre g na ncies a n d o utc o mes of pre g na nc y s h o ul d be re p orte d t o Astra Ze neca e xce pt f or:  
•  If t he pre g na nc y is disc o vere d bef 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 ncies i n t he part ner of male partici pa nts . 
If a n y pre g na nc y occ urs i n t he c o urse of t he st u d y ( partici pa nt-re p orte d), 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 Ze neca re prese ntati ves wit hi n 1 da y, ie, 
i m me diatel y b ut n o later t ha n 2 4 h o urs of w he n he or s he bec o mes a ware of it. 
8. 3. 7. 1  
M ater n al E x p os ure  
Wo me n of c hil d beari n g p ote ntial are n ot all o we d t o be i ncl u de d i n t his st u d y u nless usi n g 
acce pta ble met h o ds of c o ntrace pti o n . S h o ul d a pre g na nc y still occ ur, t he i n vesti gati o nal 
pr o d uct s h o ul d be disc o nti n ue d i m me diatel y a n d t he pr e g na nc y re p orte d t o Astra Ze neca  
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 bec o mes a ware of 
it. 
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 he i n vesti gati o nal 
pr o d uct u n der st u d y ma y ha ve i nterfere 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 he 
o utc o me of all pre g na ncies (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 ve n if t he 
parti ci pa nt was disc o nti n ue d fr o m t he st u d y. 
T he desi g nate d Astra Ze neca re prese 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 pr o vi de d t o t he Astra Ze neca Patie nt Safet y data e ntr y site wit hi n 1 or 
5 c ale n d ar d a ys  f or S A Es (see Secti o n 8. 3. 6) a n d wit hi n 3 0 d a ys  f or all ot her pre g na ncies. 
T he sa me ti meli nes a p pl y w he n 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 is use d t o re p ort t he pre g na nc y a n d t he P R E G O U T m o d ule is use d t o 
re p ort t he o utc o me of t he pre g na nc y. 
8. 3. 7. 2  
P ater n al E x p os ure  
T here is n o restricti o n o n fat heri n g c hil dre n or d o nati n g s per m d uri n g t he st u d y. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
8. 3. 8  
Me dic ati o n E rr or 
F or t he p ur p oses of re p orti n g i n Astra Ze neca  cli nical st u dies, a me dicati o n err or  is a n 
u ni nte n de d de viati o n fr o m t he all o wa ble sc he d ule 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 uses har m t o t he partici pa nt or has t he p ote ntial t o ca use har m t o t he 
partici pa nt . 
If a me dicati o n err or 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 priate 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 bec o mes a ware of it.  
T he desi g nate d Astra Ze neca re prese 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 1  (I nitial 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 a n 
S A E ass ociate d wit h t he me dicati o n err or (see Secti o n  8. 3. 6 ) a n d wit hi n 3 0 d a ys  f or all ot her 
me dicati o n err ors.  
T he defi niti o n of a Me dicati o n Err or ca n be f o u n d i n A p pe n di x  B 4. 
8. 4  
O ver d ose  
F or t his st u d y, a n y d ose of S Z C greater t ha n 1 5 g per da y o n n o n- dial ysis da ys will be 
c o nsi dere d a n o ver d ose. Treat me nt wit h S Z C o n dial ysis da ys s h o ul d be j u d ge d as a 
me dicati o n err or a n d re p orte d i n t he e C R F.  
A n o ver d ose wit h ass ociate 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 ose e C R F m o d ule. 
If a n o ver d ose o n a n Astra 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 i nf or m a p pr o priate Astra Ze 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 Ze neca re prese 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 pr o vi de d t o t he Astra Ze neca Patie nt Safet y data e ntr y site wit hi n 1 or 
5 c ale n d ar d a ys  f or o ver d oses ass ociate d wit h a n S A E (see Secti o n 8. 3. 6) a n d wit hi n 3 0 d a ys  
f or all ot her o ver d oses. 
8. 5  
H u m a n Bi ol o gic al S a m ples  
P har mac o ki netic  a n d p har mac o d y na mic para meters are n ot e val uate d i n t his st u d y, n or is 
i m m u n o ge nicit y. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
8. 6  
H u m a n Bi ol o gic al S a m ple Bi o m ar kers  
Sa m ples f or bi o mar ker researc h are n ot re q uire 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. 
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 pri mar y statistical h y p ot hesis of t he st u d y is t hat prescri bi n g S Z C wit h e n ha nce d 
n utriti o nal a d vice t o partici pa nts wit h h y per kalae mia o n hae m o dial ysis  will s h o w a 
n o n- i nferi or differe nce i n t he c ha n ge fr o m baseli ne i n S- K +  ta ke n at LI DI visits M 3, M 4, a n d 
M 5 w he n c o m pare d t o partici pa nt s o n S o C ( ot her t ha n K +  bi n ders). 
9. 2  
S a m ple Size Deter mi n ati o n  
Sa m ple size deter mi nati o n is base d u p o n t he pri mar y o bjecti ve of t he pri mar y esti ma n d, ie, To 
ev al u ate t he effect of t he c o m bi n ati o n of S Z C a n d e n h a nce d n utriti o n al a dvice t o c o ns u me 
fr uit a n d ve get a bles as c o m p are d t o S o C i n re d uci n g S- K + . 
Wit h 8 0 % p o wer t o reject t he pri mar y h y p ot hesis, 8 1 ra n d o mise d partici pa nts per treat me nt 
ar m ( 1 6 2 i n t otal) w o ul d be re q uire d usi n g a 2- gr o u p t- test wit h e q ual n’s wit h a 1-si de d al p ha 
of 0. 0 2 5, ass u mi n g a c o m m o n sta n dar d de viati o n acr oss treat me nt gr o u ps of 0. 4 5 a n d a 
n o n- i nferi orit y mar gi n of 0. 2 ( defi ne d as cli nicall y mea ni n gf ul b y scie ntific c o m mittee). It is 
e x pecte d t hat 1 5 % of partici pa nt s w h o e nter t he H K Treat me nt P hase will n ot c o nti n ue t o t he 
Diet C o m paris o n P hase, a n d c o nse q ue ntl y it is a ntici pate d t hat a p pr o xi matel y 1 9 1 partici pa nt s 
will e nter t he H K Treat me nt P hase  i n or der t o ac hie ve 1 6 2 ra n d o mise d. F urt her, t he scree ni n g 
fail ure rate is esti mate d t o be 5 0 %, mea ni n g 3 8 2 partici pa nt s will be e nr olle d. 
Partici pa nt s will be ra n d o mise d i nt o t he 4- m o nt h Diet C o m paris o n P hase  u ntil t he re q uire d 
n u m ber of ra n d o mis e d partici pa nt s is reac he d, at w hic h p oi nt t he recr uit me nt will st o p. 
9. 3  
P o p ul ati o ns f or A n al yses  
T he a nal ysis of data will be base d o n differe nt a nal ysis sets acc or di n g t o t he p ur p o se of 
a nal ysis, i.e. f or efficac y a n d safet y.  
Ta ble 6 
P o p ul ati o ns f or A n al ysis  
P o p ul ati o n  
Descri pti o n  
All -partici pa nts a nal ysis set 
T he all -partici pa nts a nal ysis set will c o nsist of all partici pa nt s w h o are 
scree ne d f or t he st u d y. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
P o p ul ati o n  
Descri pti o n  
H K treat me nt safet y a nal ysis 
set ( H K S) 
T he H K S will i ncl u de all partici pa nt s w h o recei ve at least 1 d ose of S Z C 
d uri n g t he H K Treat me nt P hase . 
F ull a nal ysis set ( F A S)  
T he F A S, t he pri mar y efficac y a nal ysis set, will i ncl u de all ra n d o mi se d 
partici pa nt s, wit h partici pa nt s bei n g a nal yse d as ra n d o mise d, rat her t ha n as 
treate d. 
Safet y a nal ysis set ( S A S)  
T he S A S will i ncl u de all ra n d o mi se d partici pa nt s recei vi n g at least 1 d ose 
of st u d y treat me nt  d uri n g t he Diet C o m paris o n P hase , f or t he S Z C  ar m, a n d 
all ra n d o mise d partici pa nt s c o m pleti n g visit 5 f or t he So C ar m.  
A b bre viati o ns: H K = h y per 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.  
T he n u m ber of partici pa nt s i n eac h a nal ysis set, a n d t he n u m ber e xcl u de d a n d ass ociate d 
reas o ns will be s u m marise d b y treat me nt gr o u p a n d o verall. I n a d diti o n, t he f oll o wi n g peri o ds 
will be defi ne d f or t he p ur p ose of re p orti n g.  
Ta ble  7 
A n al ysis Peri o ds  
Peri o d  
Descri pti o n  
Scree ni n g  P hase  
Scree ni n g refers t o t he peri o d fr o m t he first st u d y s pecific assess me nt t o 
t he first d ose of S Z C d uri n g t he H K Treat me nt P hase or scree n fail ure , 
w hic he ver occ urs first  
H K Treat me nt P hase  
T he H K Treat me nt P hase ( o pe n -la bel peri o d) refers t o t he peri o d fr om t he 
date of first d ose of S Z C d uri n g t he H K Treat me nt P hase  u ntil t he date of 
ra n d o misati o n at t he start of t he Diet C o m paris o n P hase  
Diet C o m paris o n P hase  
T he Diet C o m paris o n P hase 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 
A b bre viati o ns: H K = h y per kalae mia; S Z C = s o di u m zirc o ni u m c ycl osilicate.  
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 urse of t he st u d y will be fi nalise d pri or t o Data 
Base L oc k . T he S A P will i ncl u de a m ore tec h nical a n d detaile d descri pti o n of t he stati stical 
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 he 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 ke y sec o n dar y e n d p oi nts. 
9. 4. 1  
Ge ner al C o nsi der ati o ns  
I nfere nce c o ncer ni n g t he pri mar y a nal ysis will be perf or me d at t he 1 -si de d 2. 5 % si g nifica nce 
le vel. All p oi nt esti mates will be prese nte d t o get her wit h c o nfi de nce i nter vals of 2-si de d 9 5 % 
c o vera ge, wit h g ui da nce i ncl u de d i n o ut p uts w here i nfere nce is base d u p o n 1 tail of t he 
i nter val. 
I nterc urre nt e ve nts are ha n dle d as o utli ne d wit hi n eac h secti o n f or t he pri mar y a n d sec o n dar y 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
e n d p oi nts bel o w. F or t he pri mar y e n d p oi nt, missi n g data will occ ur i n t he case w here 
partici pa nt s are l ost t o f oll o w- u p, pr o vi de i ns ufficie nt e val ua ble data, wit hdra w c o nse nt , or die 
d uri n g t he st u d y. T he pr o p orti o n of partici pa nt s missi n g data f or t he pri mar y e n d p oi nt will be 
prese nte d al o n gsi de t he n u m ber of res p o nses a n d n o n- res p o nses. 
Baseli ne is defi ne d as t he last a vaila ble assess me nt pri or t o or o n t he date of t he ra n d o mis ati o n 
visit f or all partici pa nts, u nless ot her wise s pecifie d.  
I n ge neral ter ms, t he f ull a nal ysis set (F A S ) will be use d f or t he efficac y a nal yses, w hile t he 
H K safet y a nal ysis set ( H K S ) a n d safet y a nal ysis set (S A S ) will be use d f or t he safet y 
re p orti n g. 
I n ge neral, all baseli ne c haracteristics a n d efficac y a n d safet y varia 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 mari se d b y 
descri pti ve statistics (i ncl u di n g n u m ber of partici pa nt s [ n], mea 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 orical varia bles will be s u m mari se d usi n g 
fre q ue ncies a n d perce nta ges, w here t he de n o mi nat or of calc ulati o n is t he u n derl yi n g a nal ysis 
set p o p ulati o n u nless state d. 
D escri pti ve statistics of q ua ntitati ve efficac y a n d safet y para meters b y sc he d ule d visits will be 
pr o vi de d o n o bser ve d cases (ie, i ncl u di n g o nl y partici pa nt s w h o ha ve n o n-missi n g 
assess me nts at a gi ve n visit).  
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 nal 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 pa 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 de mic a n d n o n- pa n de mic-relate d i nterc urre nt 
e ve nts i n ter ms of t he a p pr oac h ta ke n f or se nsiti vit y a nal yses. 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  
All efficac y e n d p oi nts will be a nal yse d usi n g t he F A S.  
9. 4. 3. 1  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt will be defi ne d as t he c ha n ge i n t he ser u m K +  ta ke n at LI DI visits M 3, 
M 4 , a n d M 5 c o m pare d t o t he ser u m K + ta ke n at baseli ne.  
T he pri mar y o bjecti ve will test t he n ull h y p ot hesis of [ S- K +  f or S Z C  partici pa nts] – [ S- K +  f or 
S o C partici pa nt s] > = 0. 2 m m ol/ L a gai nst t he alter nati ve h y p ot hesis t hat [ S- K +  f or S Z C  
partici pa nt s] – [ S- K +  f or So C partici pa nt s] < 0. 2 m m ol/ L at t he 1-si de d 0. 0 2 5 si g nifica nce 
le vel. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
T he pri mar y a nal ysis will acc o u nt f or missi n g val ues  a n d val ues rec or de d f or partici pa nt s after 
c o m me nce me nt of resc ue t hera p y of a K +  bi n der f or h y per kalae mia t hr o u g h a MI met h o d. A n y 
assess me nts perf or me d after t he i ntr o d ucti o n of resc ue t hera p y of a K + bi n der f or H K will n ot 
be use d as i n p uts f or t he MI  pr oce d ure. Precise details of t he MI pr ocess will be defi ne d 
wit hi n t he S A P.  
All sc he d ule d ass ess me nts d uri n g t he Diet C o m paris o n P hase  will be use d f or i m p utati o n a n d 
a nal ysis. I nter mitte nt o bser ve d val ues will be use d t o ge nerate a f ull set of i m p ute d val ues u p 
t o a n d i ncl u di n g M 5. 
A re peate d -meas ures  A N C O V A m o del will be use d f or eac h of t he c o m plete d datasets, wit h 
fi xe d ter ms f or t he treat me nt gr o u ps f or S Z C  a n d S oC, ti me p oi nt, baseli ne S- K +  as a c o variate, 
treat me nt b y ti me p oi nt as a n i nteracti o n. A d diti o nal m o del ter ms ma y be i ncl u de d, details of 
w hic h will be descri be d i n t he S A P. T he res ults fr o m eac h m o del will be rec o m bi ne d t o 
pr o vi de t he esti mate d c ha n ge fr o m baseli ne i n S- K +  f or eac h treat me nt gr o u p o ver t he peri o d 
of M 3 t o M 5, as well as t he bet wee n gr o u p differe nce a n d t he 9 5 % c o nfi de nce i nter val ( CI)  
f or t he bet wee n gr o u p differe nce. T he n ull h y p ot hesis will be rejecte d if t he u p per b o u n d of 
t he CI is bel o w 0. 2. 
9. 4. 3. 2  
Sec o n d ar y E n d p oi nts  
A m ulti plicit y c orrecti o n pr oce d ure t hat c o vers t he pri mar y a n d t he sec o n dar y e n d p oi nts will 
be a p plie d, wit h t he met h o d bei n g a fi xe d- se q ue nce hi erarc hical testi n g pr oce d ure w here  t he 
pri mar y h y p ot hesis is teste d first. If t he pri mar y e n d p oi nt or a n y of t he sec o n dar y e n d p oi nts 
liste d i n t he or der of i m p orta nce are ne gati ve, t he n all e n d p oi nts be neat h t he m i n t he hierarc h y 
are t he n re d uce d t o bei n g e x pl orat or y e n d p oi nts. T he or der of i m p orta nce f or t he sec o n dar y 
e n d p oi nts is as f oll o ws:  
•  Mai ntai ni n g S- K
+  le vels wit hi n a ra n ge of 3. 5 – 5. 5 m m ol/ L wit h o ut re q uiri n g resc ue 
t hera p y f or H K 
•  C o ns u m pti o n of fr uit a n d ve geta bles  
•  E Q - 5 D- 5 L sc ore 
•  K D Q O L - 3 6 P C S 
•  K D Q O L - 3 6 M C S 
•  T S Q M - 9 
•  P GI C . 
T he sec o n dar y e n d p oi nt of mai ntai ni n g S- K +  le vels wit hi n t he n or m o kalae mic ra n ge of 
3. 5- 5. 5 m m ol/ L wit h o ut re q uiri n g resc ue t hera p y f or H K will be assesse d as a bi nar y 
(res p o n der/ n o n-res p o n der) varia ble, wit h partici pa nt s bei n g dee me d res p o n ders if all of t he 
f oll o wi n g are tr ue: 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
1.  T he partici pa nt  pr o vi des 2 or m ore n o n-missi n g S- K +  assess me nts d uri n g t he peri o d fr o m 
M 3 t o M 5, i ncl usi ve. 
2.  A t least 6 6 % of t heir n o n -missi n g S- K +  assess me nts bet wee n t he M 3 a n d M 5 visits , 
i ncl usi ve, s h o w val ues wit hi n t he n or m o kalae mic ra n ge. 
3.  T he partici pa nt  d oes n ot recei ve resc ue t hera p y or a K +  bi n der f or H K  at a n y p oi nt 
bet wee n t he M 3 a n d M 5 visits , i ncl usi ve. 
Partici pa nt s will be dee me d n o n-res p o n ders if p oi nt 3 is n ot tr ue, or if p oi nt 1 is tr ue  a n d p oi nt 
2 is n ot tr ue. 
Partici pa nts will be e xcl u de d fr o m t he sec o n dar y a nal ysis if p oi nt 1 is n ot tr ue a n d p oi nt 3 is 
tr ue. 
T his sec o n dar y o bjecti ve will test t he n ull h y p ot hesis of [ Pr o p orti o n of S Z C res p o n ders] – 
[ Pr o p orti o n of So C res p o n ders] < - 0. 1 a gai nst t he alter nati ve h y p ot hesis t hat [ Pr o p orti o n of 
S Z C res p o n ders] – [ Pr o p orti o n of So C res p o n ders] ≥ - 0. 1 at t he 1-si de d 0. 0 2 5 si g nifica nce 
le vel. 
T he pr o p orti o ns of res p o n ders a n d n o n- res p o n ders will be calc ulate d f or eac h treat me nt ar m, 
a n d a differe nce i n pr o p orti o ns ( S Z C - S o C) c o nstr ucte d. A 9 5 % 2- si de d CI  f or t he differe nce 
will be create d, a n d t he n ull h y p ot hesis will be rejecte d if t he l o wer b o u n d of t he CI is greater 
or e q ual t o - 0. 1. 
A se nsiti vit y a nal yses will be perf or me d w here partici pa nt s w h o disc o nti n ue d st u d y pri or t o 
pr o vi di n g a res p o nse f or t his sec o n dar y e n d p oi nt will be treate d as n o n-res p o n ders. Details 
re gar di n g se nsiti vit y a nal yses will be i ncl u de d i n t he S A P. 
C o ns u m pti o n of fr uit a n d ve geta bles will be trac ke d wit hi n t he N o o m a p p. Details  re gar di n g 
t he a nal ysis a n d prese ntati o n of data fr o m t his s o urce, i ncl u di n g h o w missi n g/i nc o m plete data 
is t o be ha n dle d, will be descri be d i n t he S A P.  
T he a vera ge dail y fr uit a n d ve geta ble c o ns u m pti o n per 2 8 da ys will be a nal yse d usi n g a 
re peate d-meas ures A N C O V A m o del wit h fi xe d ter ms f or treat me nt, 2 8 - da y peri o d, baseli ne 
a vera ge dail y c o ns u m pti o n, a n d treat me nt b y 2 8- da y peri o d i nteracti o n. T he c o m paris o n 
bet wee n treat me nt gr o u ps will be assesse d base d u p o n t he p -val ue ass ociate d wit h t he 
treat me nt b y 2 8- da y peri o d i nteracti o n ter m at M 5, w hic h will be prese nte d al o n gsi de t he L S  
mea n of t he M 5 treat me nt differe nce a n d its ass ociate d 9 5 % CI . F urt her, descri pti ve statistics, 
L S mea n esti mates, 9 5 % CIs , a n d p- val ues will be pr o vi de d per eac h 2 8- da y peri o d. 
T he E Q - 5 D- 5 L q uesti o n naire sc ore c ha n ge fr o m st u d y baseli ne at M 2 a n d M 5 will be 
a nal yse d usi n g a re peate d-meas ures A N C O V A m o del wit h fi xe d ter ms f or treat me nt, visit, 
baseli ne E Q - 5 D- 5 L, a n d treat me nt b y visit i nteracti o n. T he c o m paris o n bet wee n treat me nt 
gr o u ps will be assesse d base d u p o n t he p- val ue ass ociate d wit h t he treat me nt b y visit 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
i nteracti o n ter m at t he M 5 visit, w hic h will be prese nte d al o n gsi de t he L S  mea n of t he o verall 
treat me nt differe nce a n d its ass ociate d 9 5 % CI . F urt her, descri pti ve statistics, L S mea n 
esti mates, 9 5 % CIs , a n d p- val ues will be pr o vi de d per visit. 
T he K D Q O L -3 6 sc ores f o r s y m pt o ms, P C S, a n d M C S will be a nal yse d a n d s u m marise d usi n g 
t he sa me A N C O V A a p pr oac h as f or t he E Q- 5 D-5 L.  
9. 4. 3. 3  
E x pl or at or y E n d p oi nts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 data, 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 treat me nt gr o u p. 
A Es will be classifie d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A)  
s yste m or ga n class ( S O C) a n d preferre d ter m ( P T). A treat me nt-e mer ge nt A E ( T E A E) is 
defi 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) 
1 4 da ys after t he last d ose date. O nl y T E A Es will be i ncl u de d i n ta ble s u m maries.  
T he n u m ber a n d perce nta ge of partici pa nts e x perie nci n g A Es, S A Es, A Es t hat le d t o 
wit h dra wal, A Es t hat le d t o deat h , a n d t he n u m ber of s uc h e ve nts, will be s u m marise d b y 
S O C, P T , a n d treat me nt gr o u p. T he n u m ber a n d perce nta ge of partici pa nts e x perie nci n g A Es 
will f urt her be s u m marise d b y i nte nsit y, a n d will be prese nte d wit h t he n u m ber of e ve nts at 
eac h le vel of i nte nsit y.  
A d diti o nall y, f or partici pa nt s i n t he S Z C  treat me nt ar m, t he n u m ber a n d perce nta ge of 
partici pa nt s wit h A Es lea di n g t o disc o nti n uati o n of S Z C  will be prese nte d b y S O C a n d P T, 
a n d t he n u m ber a n d perce nta ge of partici pa nt s wit h a n y A E will be prese nte d b y S O C, P T, 
a n d relati o ns hi p t o S Z C  as assesse d b y t he i n vesti gat or. Eac h of t hese S Z C  s u m maries will 
a d diti o nall y i ncl u de t he n u m ber of s uc h e ve nts.  
A n o ver vie w of I D W G a n d i nsta nces of S- K+  < 3. 5 will be prese nte d. 
C CI


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4
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 8 2
All A E data will be liste d f or all partici pa nt s. 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 deat 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 select 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 data o utsi de t he refere nce 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 Safet y Set. I n ge neral, safet y assess me nts will be 
re p orte d descri pti vel y b y treat me nt gr o u p. F ull details o n safet y a nal 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 ot a p plica ble. 
9. 6
D at a M o nit ori n g C o m mittee
N ot a p plica ble. 
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
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 nce 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 
Declarati 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 ( CI O M S) I nter nati o nal Et hical G ui deli nes
−
A p plica ble I C H 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 B, a n d ot her rele va nt d oc u me nts ( e g,
a d vertise 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 de pe n de nt 
Et hics C o m mittee ( IE C ) b y t he i n vesti gat or a n d re vie we 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 niti ate 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 ore 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 ges necessar y t o eli mi nate a n i m me diate hazar d t o st u d y partici pa nts.


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
•  
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 Researc h Or ga ni sati o n, b ut t he acc o u nta bilit y re mai ns wit h Astra Ze neca.  
•  
T he i n vesti gat or will be res 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 deral 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 (i f 
a p plica ble), E ur o pea n Me dical De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice researc h 
(if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns. 
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es  
•  
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 nical i n vesti gati o n are met.  
•  
T he s p o ns or has a le gal 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 ncies 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 re 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 pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A R s) 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 de d t o i n vesti gat ors as necessar y. 
− 
E ur o pea n Me dical De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice researc h (if 
a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns. 
•  
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 n 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 priate acc or di n g t o 
l ocal re q uire me nts. 
A 2  
Fi n a nci al Discl os ure  
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as re q ueste 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 ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y a ut h orities. I n vesti gat ors 
are res 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 ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
partici pa nt or his/ her  le gall y a ut h orise d re prese ntati ve a n d a ns wer 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  - 3. 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 1 4  
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 8 2  
•  
Partici pa nts m ust be i nf or me d t hat t heir partici pati 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 u ri n g t he st u d y. Partici pa nts or t heir le gall y a ut h orise d 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 
( HI P A A) re q uire me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y site. 
•  
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was 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 orise d 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. 
•  
T he first st u d y s pecific assess me nt has t o be perf or me d wit hi n 7 da ys after t he I C F has 
bee n si g ne d , all o wi n g t he scree ni n g p hase t o start at t he first st u d y s pecific assess me nt. 
•  
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 orise d re prese ntati ve.  
A partici pa nt w h o is rescree ne d is n ot re q uire d t o si g n a n ot her I C F if t he rescree ni n g occ urs 
wit hi n 7 da ys fr o m t he pre vi o us I C F si g nat ure date.  
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 are  tra nsferre 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 t hat w o ul d ma ke t he partici pa nt i de ntifia 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 data 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 otecti o n la w. T he le vel of discl os ure a n d use 
of t heir data m ust als o be e x plai ne d t o t he partici pa 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 orise d 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 priate 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 Steeri n g C o m mittee c o nsisti n g of me m bers i n de pe n de nt of Astra Ze neca will be e n ga ge d 
d uri n g t he de vel o p me nt a n d c o n d uct of t his st u d y t o pr o vi de scie ntific a d vice o n t he st u d y 
desi g n a n d o bjecti ves. 
A 6  
Disse mi n ati o n of Cli nic al St u d y D at a  
A descri pti o n of t his cli nical st u d y will be a vaila ble o n 
htt p://astraze neca gr o u ptrials. p har mac m .c o m a n d htt p:// w w w.cli nicaltrials. g o v  as will t he 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
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 ulati 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 relati n g t o t he st u d y will be rec or de d i n t he 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, la b orat or y data). T he i n vesti gat or is 
res p o nsi ble f or verif 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 ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he e C R F. 
•  
T he i n vest i 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 ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. 
•  
M o nit ori n g details descri bi n g strate g y ( e g, ris k- base 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-Base 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 de 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 data ma na ge me 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 data. 
•  
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, 
C o ntract Researc h Or ga ni sati o ns). 
•  
St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati 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 me nts; t hat t he safet y a n d ri g hts of partici pa nts are bei n g pr otecte d; an d t hat 
t he st u d y is bei n g c o n d ucte d i n acc or da 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 me nts. 
•  
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai 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 1 5 years after st u d y c o m pleti o n u nless l ocal 
re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec 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. 
A 8  
S o urce D oc u me nts  
•  
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate 
t he i nte grit y of t he data c ollecte d. So urce d oc u me nts are file d at t he i n vesti gat or’s site.  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 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 me nts m ust be c o nsiste nt 
wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he i n vesti gat or ma y 
nee d t o re q uest pre vi o us me d ical rec or ds or tra nsfer rec or ds, de pe 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.  
A 9  
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 he 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 i n 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 reser ves t he ri g ht t o cl ose t he 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 osed 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 ose d w he n all re q uire d d oc 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 me 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 nte 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: 
•  
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 
•  
I na de q uate recr uit me nt of partici pa nts b y t he i n vesti gat or 
•  
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 urel y ter mi nate d or s us pe n de 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 Co ntract R esearc h 
Or ga nisati o n(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 he 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 partici pa nt t hera 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.  
A 1 0  
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 prese 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. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
•  
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 da 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 nerall y s u p p o rt 
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 me nt a n d i n li ne wit h I nter 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.  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4
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 8 2
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 d verse e ve nt is t he de vel o p me nt of a n y u nt o war d me dical occ urre nce i n a pa tie nt or 
cli nical st u d y partici pa nt  a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y 
ha ve a ca usal relati 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 disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot 
c o nsi dere d relate 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, i ncl u di n g 
r u n-i n or was h o ut peri o ds, 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 n of Seri o us A d verse E ve nts
A seri o us a d verse e ve nt is a n A E occ urri n g d uri n g a n y st u d y p hase (ie, r u n-i n, treat me nt, 
was h o ut, f oll o w- u p) t hat f ulfil s 1 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 p italisati 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.
•
Res ults i n 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 ve nts ( A Es) f or m ali g n a nt t u m o urs  re p orte d d uri n g a st u d y s h o ul d ge nerall y be 
assesse d as Seri o us A Es . If n o ot her seri o us ness criteria a p pl y, t he ‘I m p orta nt Me dical E ve nt’ 
criteri o n s h o ul d be use d. I n certai n sit uati o ns, h o we ver, 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 assesse 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 oes n ot re q uire h os pitalisati o n, ma y be assesse d as n o n-s eri 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 ncer 
re m o ve d via c o ne bi o ps y. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Life -t hre ate 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 urre d or it is s us pect e d t hat use or c o nti n ue d use of t he pr o d uct w o ul d res ult i n t he 
partici pa nt’s deat h . ‘ Life-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 vere 
f or m it mi g ht ha ve ca use d deat h (e g, he 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 nc y r o o m is n ot i n itself a seri o us AE, 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 de 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 i f t he ill ness or disease 
e xiste d bef ore t he partici pa nt  was e nr olle 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 pecte 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 scie 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 d ise t he partici pa nt or ma y 
re q uire me dical treat me nt t o pre ve nt 1 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 ose re q uiri n g treat me nt wit h 
N- acet ylc ystei ne 
•  
I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m 
•  
Bl o o d d yscrasias ( e g, ne utr o pe nia or a nae mia re q uiri n g bl o o d tra nsf usi o n) 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 de pe n de nc y or dr u g a b use. 
I nte nsit y R ati n g S c ale: 
•  
Mil d (a ware ness of si g n or s y m pt o m, b ut easil y t olerate d)  
•  
M o derate ( disc o mf ort s ufficie nt t o ca use i nterfere nce wit h n or mal acti vities)  
•  
Se vere (i nca 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 se vere A Es. Se verit y is a meas ure of 
i nte nsit y w hereas seri o us ness is defi ne d b y t he criteria i n A p pe n di x B 2. A n A E of se vere 
i nte nsit y nee d n ot necessaril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
se veral h o urs ma y be c o nsi dere d se vere na usea, b ut n ot an 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.  O n t he ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of 
disa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a n 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 na ble p ossi bilit y’ t hat a n A E ma y ha ve bee n ca use d b y t he dr u g. 
•  
Ti me C o urse. E x p os ure t o s us pect dr u g. Has t he partici pa nt act uall y recei ve d t he s us pect 
dr u g? Di d t he A E occ ur i n a reas o na bl e 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 pect 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 he sa me 
p har mac ol o gical class? Or c o ul d  t he A E be a ntici pate d fr o m its p har mac ol o gical 
pr o perties? 
•  
De -c halle n ge  e x perie nce. 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 he A E ca n n ot be reas o na 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 disease, ot her dr u gs, ot her h ost, or e n vir o n me ntal fact ors.  
•  
Re -c halle n ge  e x perie nce. Di d t he A E re occ ur if t he 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 halle n ge. 
•  
La b orat or y tests. A s pecific la b orat or y i n vesti gati o n (if perf or me d) has c o nfir me d t he 
relati o ns hi p. 
I n diffic ult cases, ot her fact ors c o ul d be c o nsi dere d s uc h as: 
•  
Is t his a rec o g nise d feat ure of o ver d ose of t he dr u g? 
•  
Is t here a k n o w n mec ha 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 rele va nt data, t here is e vi de nce f or 
a ‘reas o na ble p ossi bilit y’ of a ca usal 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 na ble p ossi bilit y’ of a ca usal 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 de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p. 
T he ca usalit y assess me nt is perf or me d base d o n t he a vaila ble data 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 relati o ns hi p, t he e ve nt(s) will be assesse d as ‘ n ot r elate d’. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Ca usal relati o ns hi p i n cases w here t he disease u n der st u d y has deteri orate d d ue t o lac k of 
effect s h o ul d be classifie d as n o reas o na ble p ossi bilit y. 
B 4  
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 f or a n Astra Ze neca 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 ote 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 he dr u g, b ut rat her a h u ma n or pr o cess-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 partici pa nt. 
Me dicati o n err or i ncl u des sit uati o ns w here a n err or : 
•  
Occ urre d  
•  
Was i de ntifie d a n d i nterce pte d bef ore t he partici pa nt recei ve d t he dr u g 
•  
Di d n ot occ ur, b ut circ 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 dicate d , e g, ta blet diss ol ve d i n water w he 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 ucte d , e g, ke pt i n t he fri d ge w he n it s h o ul d be at r o o m te m perat ure  
•  
Wr o n g partici pa nt recei ve d t he me dicati o n (e xcl u di n g I R T/ R T S M err ors) 
•  
Wr o n g dr u g a d mi nistere d t o partici pa nt (e xcl u di n g I R T/ R T S M 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 dicatio n err ors i n cli nical st u dies:  
•  
Err ors relate d t o or res ulti n g fr o m I R T/ R T S M - i ncl u di n g t h ose w hic h lea d t o 1 of t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha ve bee n a me dicati o n err or  
•  
Partici pa nt acci de 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 ver d ose ( will be ca pt ure d as a n o ver 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 
•  
Err ors relate d t o bac k gr o u n d a n d resc ue me dicati o n, or S o C me dicati o n i n o pe n -la bel 
st u dies, e ve n if a n AstraZe neca pr o d uct . 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 9  of 8 2  
Me dicati o n err ors are n ot re gar de d as A Es , b ut A Es ma y occ ur as a c o nse q ue nce of t he 
me dicati o n err or.  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 0 of 8 2
Electr o nic P atie nt -Re p orte d O utc o mes
C 1
K D Q O L ™- 3 6


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 1  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 2  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 3  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 4  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 5  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 6  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 7  of 8 2  
 
 
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 8  of 8 2  
C 2  
E Q -5 D -5 L  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 9  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 0  of 8 2  
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
C 3  
T S M Q - 9 
T S Q M - 9 
A b bre vi ate d Tre at me nt S atisf acti o n Q uesti o n n aire f or Me dic ati o n  
 
I nstr ucti o ns: Please ta ke s o me ti me t o t hi n k a b o ut y o ur le vel of satisfacti o n or dissatisfacti o n 
wit h t he me dicati o n y o u are ta ki n g i n t his cli nical trial.  
We are i ntereste d i n y o ur e val uati o n of t he effecti ve nes s a n d c o n ve nie nce of t he me dicati o n 
over t he l ast t w o t o t hree weeks, or si nce y o u l ast use d it.   
F or eac h q uesti o n, please place a si n gle c hec k mar k ne xt t o t he res p o nse t hat m ost cl osel y 
c orres p o n ds t o y o ur o w n e x perie nces. 
1.  H o w s atisfie d or diss atisfie d are y o u wit h t he a bilit y of t he me dic ati o n t o pre ve nt 
or tre at y o ur c o n diti o n ? 
□1 E xtre mel y Dissatisfie d  
□2 Ver y Dissatisfie d  
□3 Dissatisfie d  
□4 S o me w hat Satisfie d  
□5 Satisfie d  
□6 Ver y Satisfie d  
□7 E xtre mel y Satisfie d  
 
2.  H o w s atisfie d or diss atisfie d ar e y o u wit h t he w a y t he me dic ati o n relie ves y o ur 
s y m pt o ms ? 
□1 E xtre mel y Dissatisfie d  
□2 Ver y Dissatisfie d  
□3 Dissatisfie d  
□4 S o me w hat Satisfie d  
□5 Satisfie d  
□6 Ver y Satisfie d  
□7 E xtre mel y Satisfie d  
 
 
 
 
C o p yri g ht © 2 0 0 7 Q ui ntiles. All Ri g hts Reser ve d  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
3.  H o w s atisfie d or diss atisfie d are y o u wit h t he a m o u nt of ti me it t a kes t he 
me dic ati o n t o st art w or ki n g ?  
□1 E xtre mel y Dissatisfie d  
□2 Ver y Dissatisfie d  
□3 Dissatisfie d  
□4 S o me w hat Satisfie d  
□5 Satisfie d  
□6 Ver y Satis fie d  
□7 E xtre mel y Satisfie d  
4.  H o w e as y or diffic ult is it t o use t he me dic ati o n i n its c urre nt f or m ?  
□1 E xtre mel y Diffic ult  
□2 Ver y Diffic ult  
□3 Diffic ult  
□4 S o me w hat Eas y  
□5 Eas y  
□6 Ver y Eas y  
□7 E xtre mel y Eas y  
5.  H o w e as y or diffic ult is it t o pl a n w he n y o u will use t he me dic ati o n e ac h ti me ?  
□1 E xtre mel y Diffic ult  
□2 Ver y Diffic ult  
□3 Diffic ult  
□4 S o me w hat Eas y  
□5 Eas y  
□6 Ver y Eas y  
□7 E xtre mel y Eas y  
6.  H o w c o n ve nie nt or i nc o n ve nie nt is it t o t a ke t he me dic ati o n as i nstr ucte d ?  
□1 E xtre mel y I nc o n ve nie nt  
□2 Ver y I nc o n ve nie nt 
□3 I nc o n ve nie nt 
□4 S o me w hat C o n ve nie nt 
□5 C o n ve nie nt 
□6 Ver y C o n ve nie nt 
□7 E xtre mel y C o n ve nie nt 
 
 
 
C o p yri g ht © 2 0 0 7 Q ui ntiles. All Ri g hts Reser ve d  


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
7.  O ver all, h o w c o nfi de nt are y o u t h at t a ki n g t his me dic ati o n is a g o o d t hi n g f or 
y o u ? 
□1 N ot at All C o nfi de nt  
□2 A Little C o nfi de nt  
□3 S o me w hat C o nfi de nt 
□4 Ver y C o nfi de nt 
□5 E xtre mel y C o nfi de nt 
8.  H o w cert ai n are y o u t h at t he g o o d t hi n gs a b o ut y o ur me dic ati o n o ut wei g h t he b a d 
t hi n gs ? 
□1 N ot at All Certai n  
□2 A Little Certai n  
□3 S o me w hat Certai n  
□4 Ver y Certai n  
□5 E xtre mel y Certai n  
9.  Ta ki n g all t hi n gs i nt o acc o u nt, h o w s atisfie d or diss atisfie d are y o u wit h t his 
me dic ati o n ?  
□1 E xtre mel y Dissatisfie d  
□2 Ver y Dissatisfie d  
□3 Dissatisfie d  
□4 S o me w hat Satisfie d  
□5 Satisfie d  
□6 Ver y Satisfie d  
□7 E xtre mel y Satisfie d  
 
 
 
C o p yri g ht © 2 0 0 7 Q ui ntiles. All Ri g hts Reser ve d   
 
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
C 4  
P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E - P GI C  
 
O verall, h o w w o ul d y o u rate t he c ha n ge i n y o ur acti vit y li mitati o ns ( e g, co o ki n g a n d eati n g, 
d oi n g h o use h ol d c h ores or cli m bi n g stairs) si nce starti n g t his st u d y?  
Please select o ne res p o nse o nl y  
  
M uc h better  
  
A little better  
   
A b o ut t he sa me 
  
A little w orse  
   
M uc h w orse 
 
O verall, h o w w o ul d y o u rate t he c ha n ge i n y o ur Ki d ne y Disease s y m pt o ms (e g, lac k of a p petite 
or feeli n g tire d) si nce starti n g t his st u d y?  
Please select o ne res p o nse o nl y  
  
M uc h better  
  
A little better  
   
A b o ut t he sa me 
  
A little w orse  
   
M uc h w orse  
 
 
 
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
O verall, h o w w o ul d y o u rate t he c ha n ge i n y o ur e m oti o ns ( e g, feeli n g o ver w hel me d or 
de presse d) si nce starti n g t his st u d y?  
Please select o ne res p o nse o nl y  
  
M uc h better  
  
A little better  
   
A b o ut t he sa me 
  
A little w orse  
   
M uc h w orse  
 
O verall, h o w w o ul d y o u rate t he c ha n ge i n y o ur o verall q ualit y of life ( e g, satisfacti o n wit h 
life, or se nse of well bei n g) si nce starti n g t his st u d y? 
Please select o ne res p o nse o nl y  
  
M uc h better  
  
A little better  
   
A b o ut t he sa me 
  
A little w orse 
   
M uc h w orse 
 
 
  
 
 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4
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 8 2
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
D 1
I ntr o d ucti o n
Safe g uar di n g t he healt 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 para 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 restricti 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 me i nfecte d wit h 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 ma 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 ges 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. 
D 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 ( S Z C) is a K +  bi n der acti n g i n t he gastr oi ntesti nal tract a n d is 
n ot a bs or be d. N o a d diti o nal r is 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 pe o ple ca n n ot be c o m pletel 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 ose t he msel ves t o p u blic areas (e g , c o m m ute 
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).
D 2. 1
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 he 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 vel will o nl y star t 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 rec o m me n dati o ns re gar 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. 
D 3
C O VI D -1 9 Pri or t o Scree ni n g
It is i m p orta nt t hat partici pa nts wit h p ossi ble o n g oi n g or n ot c o m pletel y res ol ve d C O VI D- 1 9 
i nfecti o n are n ot t o be e nr olle d i n t he st u d y. If t he partici pa nt has e vi de nce of C O VI D- 1 9 
wit hi n 2 wee ks pri o r t o scree ni n g (e g, a p ositi ve C O VI D -1 9 test or a cli nical ris k t hat has n ot 
bee n satisfact oril y e xcl u de d), t he partici pa nt ca n n ot be scree ne d a n d will be treate d acc or di n g 
t o S o C . 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
D 4  
S us pecte d C O VI D -1 9 After Scree ni n g  
D 4. 1  
P artici p a nt is Se verel y Ill or H os pit ali se d 
If t he partici pa 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 pitalis e d, t he partici pa nt ma y te m p oraril y or per ma ne ntl y disc o nti n ue st ud y i nter ve nti o n at 
t he discreti o n of t he site i n vesti gat or. 
D 4. 2  
P artici p a nt is N O T Se verel y Ill or H os pit ali se d 
If t he partici pa 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 het her a n y S A R S-C o V- 2 test res ults are a vaila ble o r 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 c o 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 partici 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 sc he d ule. 
D 5  
C O VI D -1 9 D uri n g t he St u d y  
D 5. 1  
Rec o nse nt of St u d y P artici 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 pa 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 the visits a n d assess me nts 
ma y be necessar y, e g , re m ote visits. Rec o nse nt s h o ul d be o btai ne d f or t he alter nati ve mea 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 ures 
descri be d i n t he S o A ( Secti o n 1. 3). L ocal 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 
rec 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 rec o nse nt s h o ul d be a v oi de d. 
D 5. 2  
Tele me 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 healt 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 nal 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 E s a n d c o nc o mita nt me dicati o n s t o be 
re p orte d a n d d oc u me nte d. 
D 5. 3  
D at a C a pt ure D uri n g Tele me dici ne Visits  
Data c ollecte d d uri n g tele me dici ne visits will be ca pt ure d b y t he q ualifie d H C P fr o m t he st u d y 
site. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4
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 8 2
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
ad verse eve nt
A N C O V A
a nal ysis of c o varia nce
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
C K D
c hr o nic ki d ne y disease
C P S
calci u m p ol yst yre ne s ulf o nate
C S P
C li nical S t u d y P r ot oc ol
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 C 
electr o nic data ca pt ure
e P R O
electr o nic patie nt -re p orte d o utc o mes
E Q- 5 D - 5 L  
E ur o Q ol -5 Di me nsi o ns -5 Le vels
F A S
f ull a nal ysis set
G C P
G o o d Cli nical Practice
H C P
healt hcare pr o vi der
H K
h y per kalae mia
H R Q o L
healt h -relate d q ualit y of life
I B
I n vesti gat or’s Br oc h ure
I C F
Inf 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 D W G
i nter dial ytic wei g ht gai n
I E C 
I n de pe n de nt Et hics C o m mittee
I R B
I nstit uti o nal Re vie w B oar d
I R T
I nteracti ve Res p o nse Tec h n ol o g y
K +
p otassi u m
K D Q O L -3 6 
Ki d ne y Disease a n d Q ualit y of Life -3 6 ite m
LI DI
l o n g i nter dial ytic-dial ysis i nter val
L S 
least s q uares
M 
M o nt h
M C S
Me ntal C o m p o ne nt S u m mar y
MI
m ulti ple i m p utati o n
P C S
P h ysical C o m p o ne nt S u m mar y
P GI C
Patie nts’ Gl o bal I m pressi o n of C ha n ge


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
P R O  
patie nt -re p orte d o utc o me 
P T  
preferre d ter m  
Q Tc 
Q T i nter val c orrecte d f or heart rate 
Q Tc F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s 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  
R T S M  
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt  
S A E  
seri o us ad verse eve nt  
S A P  
S tatistical A nal ysis P la n 
S- K +  
ser u m p otassi u m 
S o A  
S c he d ule of A cti vities  
S o C 
sta n dar d of care 
S O C  
s yste m or ga n class 
S P S  
s o di u m p ol yst yre ne s ulf o nate 
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 
T S Q M -9  
A b bre viate d Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n  (9 ite m s) 
U R R  
urea re d ucti o n rati o  
U S  
U nite d States  
V A S  
vis ual a nal o g ue scale  
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  - 3. 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 1 4
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 8 2
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 ore t he Ta ble of C o nte nts.
A me n d me nt 1 0 5- M a y- 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 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 beca use 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 scie ntific val ue of t he st u d y.
O ver all R ati o n ale f or t he A me n d me nt:
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al 
Secti o n 1. 3 
Sc he d ule of 
Acti vities a n d 
Secti o n 6. 5 
C o nc o mita nt 
T hera p y
C ollecti o n of 
i nf or mati o n o n 
C O VI D -1 9 vacci nati o n 
has bee n clarifie d
T o s pecif y t hat C O VI D -1 9 
vacci nati o n at a n y ti me pri or t o 
e nr ol me nt s h o ul d be rec or de d 
i n t he e C R F
N o n -S u bsta ntial
A p pe n di x C 4 
Patie nt Gl o bal 
I m pressi o n of 
C ha n ge - P GI C
Pre vi o us versi o n of t he 
q uesti o n naire was 
re place d b y a ne w o ne
P GI C q uesti o n naire has bee n 
u p date d
N o n -s u bsta ntial
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 
N o n -s u bsta ntial


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
1 1  
R E F E R E N C E S  
At ki ns o n MJ, Si n ha A, Hass S L, C ol ma n S S, K u mar R N, Br o d M, et al. Vali dati o n of a 
ge neral meas ure of treat me nt satisfacti o n, t he Treat me nt Satisfacti o n Q uesti o n naire f or 
Me dicati o n ( T S Q M), usi n g a nati o nal pa nel st u d y of c hr o nic disease. He alt h Q u al Life 
O utc o mes . 2 0 0 4; 2( 1): 1 2. 
B har mal  M, Pa y ne K, At ki ns o n MJ. Vali dati o n of a n a b bre viate d Treat me nt Satisfacti o n 
Q uesti o n naire f or Me dicati o n  ( T S Q M- 9) a m o n g patie nts o n a nti h y perte nsi ve me dicati o ns. 
He alt h Q u al Life O utc o mes . 2 0 0 9; 7: 3 6 
C o he n D E, Lee A, Si b bel S, Be n ner D, Br u nelli S M, Te nt ori F. Use of t he K D Q O L- 3 6 T M  f or 
assess me nt of healt h -relate d q ualit y of life a m o n g dial ysis patie nts i n t he U nite d States. B M C 
Ne p hr ol . 2 0 1 9; 2 0( 1): 1 1 2. 
El - S har ka w y M, K he dr E, A b del w ha b S, Ali M, El Sai d K. Pre vale nce of h y per kalae mia 
a m o n g hae m o dial ysis patie nts i n E g y pt. Re n F ail . 2 0 0 9; 3 1( 1 0): 8 9 1 – 8. 
G ora ya N, M u n oz- Mal d o na d o Y, Si m o ni J, Wess o n D E. Fr uit a n d ve geta ble treat me nt of 
c hr o nic ki d ne y disease- relate d meta b olic aci d osis re d uces car di o vasc ular ris k better t han 
s o di u m bicar b o nate. A m J Ne p hr ol . 2 0 1 9; 4 9( 6): 4 3 8 – 4 8. 
G ora ya N, Si m o ni J, J o C- H, Wess o n D E. Treat me nt of meta b olic aci d osis i n patie nts wit h 
sta ge 3 c hr o nic ki d ne y disease wit h fr uits a n d ve geta bles or oral bicar b o nate re d uces uri ne 
a n gi ote nsi n o ge n a n d p reser ves gl o mer ular filtrati o n rate. Ki d ney I nt . 2 0 1 4; 8 6( 5): 1 0 3 1 – 8. 
Ha yes C P, Mc Le o d M E, R o bi ns o n R R. A n e xtra ve nal mec ha nis m f or t he mai nte na nce of 
p otassi u m bala nce i n se vere c hr o nic re nal fail ure. Tr a ns Ass oc A m P hysici a ns . 1 9 6 7; 8 0: 2 0 7 –
1 6. 
Her d ma n M, G u de x C, Ll o y d A, Ja nsse n M F, Ki n d P, Par ki n D, et al. De vel o p me nt a n d 
preli mi nar y testi n g of t he ne w fi ve -le vel versi o n of E Q-5 D ( E Q - 5 D- 5 L). Q u al Life Res . 
2 0 1 1; 2 0( 1 0): 1 7 2 7 – 3 6. 
Ki m H, Ca ulfiel d L E, Garcia -Larse n V, Steffe n L M, Gra ms M E, C ores h J, et al. Pla nt -base d 
diets a n d i nci de nt C K D  a n d ki d ne y f u ncti o n. Cli n J A m S oc Ne p hr ol . 2 0 1 9; 1 4( 5): 6 8 2 –9 1.  
Li u Y, K ucz mars ki M F, Miller E R, Na va M B, Z o n der ma n A B, E va ns M K, et al. Dietar y 
ha bits a n d ris k of ki d ne y f u ncti o n decli ne i n a n ur ba n p o p ulati o n. J Re n N utr . 2 0 1 7; 2 7( 1): 1 6–
2 5. 


Cli nical St u d y Pr ot oc ol  - 3. 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 1 4  
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 8 2  
Ricar d o A, Hac ker H, L ora C, Ac kers o n L, De Sal v o K, G o A et al. Vali dati o n of t he Ki d ne y 
Disease Q ualit y of Life S h ort F or m 3 6 ( K D Q O L - 3 6) U S S pa nis h a n d E n glis h versi o ns i n a 
c o h ort of His pa nics wit h c hr o nic ki d ne y disease. Et h n Dis . 2 0 1 3; 2 3( 2): 2 0 2- 9. 
Sie ner R. Dietar y treat me nt of meta b olic aci d osis i n c hr o nic ki d ne y disease. N utrie nts . 
2 0 1 8; 1 0( 4): 5 1 2. 
S o di u m Zirc o ni u m C ycl osilicate ( L o kel maT M ) I n vesti gat or Br oc h ure E diti o n 9, date d 1 st 
N o ve m ber 2 0 1 9. 
Wai S N, Kell y J T, J o h ns o n D W, Ca m p bell K L. Dietar y patter ns a n d cli nical o utc o mes i n 
c hr o nic ki d ne y disease: t he C K D. Q L D N utriti o n St u d y. J Re n N utr . 2 0 1 7; 2 7( 3): 1 7 5 –8 2.  


SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 9 4 8 0c 0 0 0 1 4-cs p- v 3
D oc u me nt Title:
D 9 4 8 0 C 0 0 0 1 4 Cli nical St u d y Pr ot oc ol versi o n 3
D oc u me nt I D:
D oc I D- 0 0 4 5 1 8 6 0 4
Versi o n L a bel:
3. 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
C o nte nt A p pr o val
C o nte nt A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
P P D

SAP_001.pdf: 
Statistical analysis plan      
 AstraZeneca 
D9480C00014 
    15 Oct 2021 
1 of 42
Last updated: 10 April 2018
Parent SOP: AZDoc0083874
Statistical analysis plan
Study code
D9480C00014 
Version
1.0
Date 
15 Oct 2021 
An Open-Label, Randomised, Controlled, Parallel-Design, 
Multicentre, Phase IV Study of Sodium Zirconium Cyclosilicate 
and Enhanced Nutrition Advice Compared to Standard of Care in 
Dialysis Patients with Hyperkalaemia (GRAZE) 
Redacted for Public Disclosure
ted
en-Label, Ra
en-Label, Ra
Phase IV St
hase IV
utrition Adv
utrition A
atients with
atients with H
P


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
2of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874

 
 
An Open-Label, Randomised, Controlled, Parallel-Design, 
Multicentre, Phase IV Study of Sodium Zirconium Cyclosilicate 
and Enhanced Nutrition Advice Compared to Standard of Care in 
Dialysis Patients with Hyperkalaemia (GRAZE) 
 
 
AZ Study Statistician 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










 
PPD




Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
4of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
4.3.1.4
Electrocardiograms...........................................................................................................21
4.3.1.5
PhysicalExaminations......................................................................................................21
4.3.1.6
Pregnancy.........................................................................................................................21
4.3.1.7
InterdialyticWeightGain(IDWG).....................................................................................21
4.3.2
Other variables ......................................................................................................22
4.3.2.1
DialysisPrescription.........................................................................................................22
4.3.2.2
DialysisAdequacy.............................................................................................................22
5.
ANALYSIS METHODS ......................................................................................22
5.1
General principles .................................................................................................22
5.1.1
Handling of missing dates .....................................................................................23
5.1.1.1
Partialstartdates.............................................................................................................23
5.1.1.2
Partialenddates...............................................................................................................24
5.1.2
Handling of Missing Efficacy Data ......................................................................24
5.1.3
Handling of Missing Safety Data ..........................................................................24
5.1.4
COVID-19 Impact.................................................................................................24
5.2
Visit Windows.......................................................................................................25
5.3
Analysis methods ..................................................................................................26
5.3.1
Participant Disposition and Analysis Sets Analyzed ............................................26
5.3.2
Protocol Deviations ...............................................................................................27
5.3.3
Demographics and Other Baseline Characteristics ...............................................27
5.3.4
Medical History.....................................................................................................28
5.3.5
Previous and Concomitant Medications ...............................................................28
5.3.6
Measurements of Study Treatment Compliance ...................................................29
5.3.7
Efficacy .................................................................................................................29
5.3.7.1
PrimaryEfficacyAnalysis..................................................................................................30
5.3.7.2
PrimaryEfficacyAnalysis–SensitivityAnalyses...............................................................32
5.3.7.3
SecondaryEfficacyAnalyses.............................................................................................34
5.3.7.4
SecondaryEfficacyAnalyses–SensitivityAnalyses.........................................................37


5.3.8
Safety ....................................................................................................................38
5.3.8.1
AdverseEvents.................................................................................................................38
5.3.8.2
Deaths...............................................................................................................................39
5.3.8.3
LaboratoryData................................................................................................................39
5.3.8.4
VitalSigns.........................................................................................................................40
5.3.8.5
Electrocardiograms...........................................................................................................40
5.3.8.6
PhysicalExamination........................................................................................................40
5.3.8.7
Exposure...........................................................................................................................41
5.3.8.8
PregnancyTest.................................................................................................................41
5.3.8.9
DialysisPrescription.........................................................................................................41
5.3.8.10
DialysisAdequacy.............................................................................................................41
5.3.8.11
InterdialyticWeightGain(IDWG).....................................................................................41
6.
INTERIM ANALYSES ........................................................................................41
7.
REFERENCES......................................................................................................41

CCI


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
5of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or special 
term 
Explanation 
AE 
Adverse Event 
ANCOVA 
ANalysis of COVAriance 
BMI 
Body Mass Index 
CI  
Confidence Interval  
CKD  
Chronic Kidney Disease  
COVID-19 
Coronavirus Disease 2019 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CTC 
Common Toxicity Criteria 
DBL 
Data Base Lock 
DCO 
Data Cut Off 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ePRO
electronicPatientͲReportedOutcomes
EOT 
End Of Treatment 
EQͲ5DͲ5L
EuroQolͲ5DimensionsͲ5Levels
FAS 
Full Analysis Set 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
HCP 
Healthcare Provider 
HK 
Hyperkalaemia 
HKS 
Hyperkalaemia treatment Safety analysis set 
HRQoL 
Health-Related Quality of Life 
ICH 
International Council for Harmonisation 
 
 
IDWG  
Interdialytic Weight Gain  
K+  
Potassium  
KDQOL-36   
Kidney Disease and Quality of Life-36 item  
LIDI  
Long Interdialytic-Dialysis Interval  
LS  
Least Squares  
M  
Month  
MCMC 
Markov Chain Monte Carlo 
MCS  
Mental Component Summary  
MedDRA 
The Medical Dictionary for Regulatory Activities 
MI  
Multiple Imputation  
NK 
Normokalaemia 
CCI


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
6of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
Abbreviation or special 
term 
Explanation 
PCS  
Physical Component Summary  
PGIC  
Patients’ Global Impression of Change  
PRO 
Patient Reported Outcome 
PT  
Preferred Term  
QTc  
QT interval corrected for heart rate  
QTcF  
QT interval corrected for heart rate using Fridericia’s method  
RAASi 
Renin-Angiotensin-Aldosterone System Inhibitors 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
S-K+  
Serum Potassium  
SoA 
Schedule of Activities 
SoC  
Standard of Care  
SOC 
System Organ Class 
SZC  
Sodium Zirconium Cyclosilicate  
TEAE  
Treatment-Emergent Adverse Event  
TSQM-9  
Treatment Satisfaction Questionnaire for Medication (9 items)  
URR  
Urea Reduction Ratio  
VAS  
Visual Analogue Scale  




Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
7of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
AMENDMENT HISTORY 
Date 
Brief description of change 
15Oct2021 
Initial version 
 








Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
11of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
2. 
STUDY DESIGN AND SAMPLE SIZE 
2.1 
Overall Design  
This is a Phase IV, randomised, controlled, open-label, parallel-group, multicentre, 
prospective study to evaluate the effect of the combination of SZC and enhanced nutritional 
advice to consume fruit and vegetables as compared to SoC in reducing S-K+ levels in 
participants with hyperkalaemia on haemodialysis.  
2.1.1 
 Up to 1-month HK Treatment Phase (all participants)  
Participants will follow labelled instructions for dosing dialysis participants, starting at 5 g on 
non-dialysis days. At weekly intervals participants can be titrated up or down in 5 g steps to a 
maximum of 15 g on non-dialysis days and a minimum of 5 g on non-dialysis days, to keep 
S-K+ in the range of 3.5-5.5 mmol/L.  
K+ will be corrected with SZC as per local label. Participants will receive dietary advice 
consistent with SoC at that site, including K+ restriction. Dietary advice will be given by 
dietitians at study visits.  
2.1.2 
4-month Diet Comparison Phase (2 arms)  
Randomisation will occur at Visit 6. Only participants with S-K+ 5.5 mmol/L on 5 or 10 g 
SZC will be randomised. Participants on 15 g SZC will be considered as randomisation 
failures.  
SZC arm: Participants will continue taking SZC, which can be titrated up or down as 
described in Section 2.1.1 to maintain S-K+ in the range 3.5-5.5 mmol/L; participants will 
also receive enhanced nutritional advice to consume fruit and vegetables. Advice will be 
provided by dietitians at study visits and by Noom app between visits.  
SoC arm: SZC will be withdrawn and participants will receive SoC as per site practice, 
including dietary K+ restriction. Dietary advice will be given by dietitians at study visits and 
by Noom app between study visits.  
2.1.3 
 Follow-up Phase (all participants)  
Upon completion of the study, or early discontinuation, all participants that have received 
study drug, including those who have been enrolled into the HK Treatment Phase but not 
been randomised into the Diet Comparison Phase, will proceed to the post-treatment follow-
up visit after 14±3 days. After completing the study, or early discontinuation, participants 
will receive SoC and standard diet advice as determined by their treating physician. 
Figure1
Studydesign


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
12of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874

Abbreviations: HK = hyperkalaemia; K = potassium; LIDI = long interdialytic-dialysis interval; N = number of 
participants; NK = normokalaemia; SoC = standard of care; SZC = sodium zirconium cyclosilicate.  
Note: Only participants with S-K+ 5.5 mmol/L on 5 or 10 g SZC at end of HK Treatment Phase will be 
randomised.   
3. 
ANALYSIS SETS 
3.1 
Analysis sets 
All-Participants Analysis Set 
The all-participants analysis set will consist of all participants who are screened for the study. 
This analysis set will be used to describe the demographics of participants considered for 
inclusion in the study. The assignment of participants to a treatment group for analysis is not 
applicable. 
HK Treatment Safety Analysis Set (HKS) 
The HKS will include all participants who receive at least 1 dose of sodium zirconium 
cyclosilicate (SZC) during the hyperkalaemia (HK) Treatment Phase. The HKS will be used 
to describe the safety and exposure endpoints during the HK Treatment Phase and certain 
baseline and demographic characteristics. Summaries will combine all participants together 
within the SZC treatment group. 
Full Analysis Set (FAS) 
The FAS, the primary efficacy analysis set, will include all randomised participants, with 
participants being analysed as randomised, rather than as treated. The FAS will be the 
primary analysis set used for the primary, secondary and exploratory endpoints and baseline 
and demographic characteristics. Summaries and analysis will group participants according to 
their randomized treatment arm. 
Safety Analysis Set (SAS) 
The SAS will include all randomised participants receiving at least 1 dose of study treatment 
during the Diet Comparison Phase, for the SZC arm, and all randomised participants 
completing visit 5 for the standard of care (SoC) arm. The SAS will be the analysis set used 
for safety and exposure endpoints during the diet comparison phase. Summaries will group 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
13of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
participants according SZC if they received at least one dose of SZC during the Diet 
Comparison Phase, and to SoC if they were randomized to SoC. 
3.2 
Analysis Periods 
The following periods will be defined for the purpose of reporting. 
Screening Phase 
Screening refers to the period from the date of the first study specific assessment to the date 
and time of the first dose of SZC during the HK Treatment Phase or date of screen failure, 
whichever occurs first. 
HK Treatment Phase 
The HK Treatment Phase (open-label dosting period) refers to the period from the date and 
time of first dose of SZC during the HK Treatment Phase until randomisation at the start of 
the Diet Comparison Phase. 
Diet Comparison Phase 
The Diet Comparison Phase refers to the period from of randomisation until the earliest date 
of last assessment during the follow-up period, date of withdrawal of consent, date of last 
contact with the participant, or date of death. 
3.3 
Violations and deviations 
Important protocol deviations will be defined by the Sponsor before database lock by judging 
the importance of the deviations upon the primary efficacy endpoint. The following criteria 
may be considered as important protocol deviations which may have a major effect on 
efficacy or that could potentially affect the interpretability of the study results. 
x 
Incorrectly enrolled participant who failed any of the inclusion or exclusion criteria of 
the study as provided in sections 5.1 and 5.2 of the CSP respectively. 
x 
Inappropriate compliance with study treatment during the HK treatment phase and diet 
comparison phase of the study, e.g. treatment compliance of less than 80% or greater 
than 120% 
x 
All restricted medications which are administered during the study when used for a 
purpose other than those instructed, as detailed in section 6.5 of the CSP. 
x 
Any participant who received incorrect study treatment compared with randomized study 
treatment at any time during the diet comparison phase. This also includes any 
participant who received SZC instead of randomized SoC at any time during the diet 
comparison phase. 
x 
Participant with first dose date prior to baseline evaluations in the diet comparison phase. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
14of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
In addition, protocol deviations will be defined by the Sponsor before database lock as 
coronavirus disease 2019 (COVID-19) pandemic related or not by judging the root cause of 
the protocol deviation, in line with FDA guidance (FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency; March 2020). The 
following criteria may be considered as indicative of a protocol deviation related to the 
COVID-19 pandemic. 
x 
Missed in-person visit due to COVID-19 illness and/or COVID-19 public health control 
measures 
x 
Study visit out of window due to COVID-19 illness and/or COVID-19 public health 
control measures 
x 
Missed doses due to COVID-19 illness and/or COVID-19 public health control measures 
x 
Missed sK+ measurements due to COVID-19 illness and/or COVID-19 public health 
control measures 
4. 
EXPOSURE(S) AND OUTCOMES 
4.1 
Exposures 
4.1.1 
Investigational Product - SZC 
Participants in the active arm will receive SZC dosed as per the local label to control HK and 
maintain normokalaemia. Any decision to discontinue SZC will be up to the treating 
physician’s judgement and as advised by the label. Per the label, SZC should only be dosed 
on non-dialysis days. The recommended starting dose is 5 g once daily. To establish 
normokalaemia (in the range commonly regarded as acceptable in these participants [3.5-5.5 
mmol/L]), the dose may be titrated up or down weekly based on the pre-dialysis S-K+ value 
after LIDI. The dose can be adjusted at intervals of 1 week in increments of 5 g up to 15 g 
once daily on non-dialysis days. 
4.1.2 
SoC Dietary Advice 
All participants during the HK Treatment Phase, and participants randomised to the SoC arm 
of the Diet Comparison Phase will receive standard dietary advice including K+ restriction. 
This advice will be provided by dietitians at study visits and will be consistent with SoC at 
that site and will use a mobile app (Noom) to track food intake only.  
Participants will be encouraged to consume less than 50 mmol K+ per day.  
4.1.3 
Enhanced Dietary Advice 
Upon randomisation to the SZC arm of the Diet Comparison Phase, participants will receive 
enhanced dietary advice in addition to taking SZC. This will include advice from dietitians at 
study visits to consume fruit and vegetables. Participants will receive dietary support from the 
Noom app between visits. Participants will be encouraged to consume up to 70 mmol K+ per 
day.  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
15of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
4.1.4 
Diet Mobile App (Noom)  
In order to track dietary changes, participants in both arms will be supported by a mobile app 
(Noom) between study visits. Participants will be required to enter information daily on their 
food intake. This app will (a) track food intake, including K+, fruit and vegetables, and fibre, 
(b) provide feedback regarding an estimate of daily K+ consumption, and (c) provide live 
guidance on food consumption by human coaches.  
4.2 
Outcomes 
4.2.1 
Primary efficacy outcome - Potassium 
Serum potassium (S-K+) will be measured at each visit prior to dialysis, and the primary 
outcome will use assessments during the Diet Comparison Phase (including the baseline 
assessment for the Diet Compaison Phase as defined in Section 5.1). Serum samples will be 
analysed using local laboratory for the purposes of study inclusion and monitoring.  
Serum potassium results after the introduction of rescue theapy of K+ binder for HK will be 
collected but excluded from the primary analysis of the primary efficacy outcome. 
Rescue therapy is defined as any therapeutic intervention considered necessary in accordance 
with local practice patterns to reduce S-K+ in the setting of severe HK as defined by 
physician and site. 
Treatments considered rescue may include:  
x 
Intravenous insulin/glucose or dextrose, beta adrenergic agonists, intravenous sodium 
bicarbonate, and any additional dialysis or other forms of renal-replacement treatments 
when used specifically for the treatment of severe HK as defined locally at site.  
x 
In addition, reduction in the dialysate K+ concentration that is prescribed for the 
treatment of severe HK during the study is also considered rescue therapy. Investigators 
may change dialysate bath as needed. 
x 
Use of other K+ binders including SPS, CPS, and patiromer.  
Rescue medication will be identified using the concomitant medication eCRF page, using 
pre-specified drug codes. 
4.2.2 
Secondary outcome(s)  
4.2.2.1 
Maintaining S-K+ levels within a range of 3.5–5.5 mmol/L without requiring 
rescue therapy for HK  
The secondary endpoint of maintaining S-K+ levels within the normokalaemic range of 3.5-
5.5 mmol/L without requiring rescue therapy for HK will be assessed as a binary 
(responder/non-responder) variable, with participants being be deemed responders if all of the 
following are true:  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
16of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
1. The participant provides 2 or more non-missing S-K+ assessments during the period 
from M3 to M5, inclusive.  
2. At least 66% of their non-missing S-K+ assessments between the M3 and M5 visits, 
inclusive, show values within the normokalaemic range.  
3. The participant does not receive rescue therapy or a K+ binder for HK at any point 
between the M3 and M5 visits, inclusive.  
Participants will be deemed non-responders if point 3 is not true, or if point 1 is true and 
point 2 is not true.  
Participants will be excluded from the secondary analysis if point 1 is not true and point 3 is 
true.  
4.2.2.2 
KDQOL™-36 
The KDQOL-36 is a validated, self-reported questionnaire that combines generic and 
diseasespecific components for assessing symptoms and health-related quality of life 
(HRQoL) of participants with CKD, refer Appendix C1 of the CSP (Ricardo et al. 2013). The 
KDQOL-36 comprises a PCS (12 items), MCS (12 items), Symptoms/Problems (12 items), 
Burden of Kidney Disease (4 items), and Effects of Kidney Disease (8 items). Higher scores 
indicate better health/HRQoL.  
4.2.2.3 
EQ-5D-5L 
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility (refer Appendix C2 of the CSP). 
The EQ-5D-5L, developed by the EuroQol Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal. The EQ-5D-5L questionnaire comprises six questions that cover five dimensions of 
health (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). For each 
dimension, respondents select which statement best describes their health on that day from a 
possible five options of increasing levels of severity (no problems, slight problems, moderate 
problems, severe problems and unable to/ extreme problems). A unique EQ-5D health state, 
termed the EQ-5D-5L profile, is reported as a five-digit code with a possible 3,125 health 
states. For example, state 11111 indicates no problems on any of the five dimensions. 
Respondents also assess their health today using the EQ-VAS, which ranges from 0 (worst 
imaginable health) to 100 (best imaginable health). 
The EQ-5D profile will be converted into a weighted health state utility value, termed the 
EQ-5D index, by applying a country-specific equation to the EQ-5D-5L profile that 
represents the comparative value of health states. This equation is based on national valuation 
sets elicited from the general population and the base case will be the UK perspective. Where 




Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
18of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
CCI
CCI
CCI




Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
20of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
x 
an AE with a start date on or after the date of randomization in the diet comparison phase 
up to (and including) the follow-up visit (or 14 days after the last visit if no follow-up 
visit is performed) for participants either randomized to SoC or who do not enter the Diet 
Comparison Phase. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorised representative).   
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.  
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a 
participant treated by him or her, the investigator shall, without undue delay, should report 
the SAE to the sponsor.  
The Medical Dictionary for Regulatory Activities (MedDRA) (using the latest or current 
MedDRA version) will be used to classify AEs according to system organ class (SOC) and 
preferred term (PT).  
4.3.1.2 
Clinical Safety Laboratory Assessments 
Blood samples for determination of clinical chemistry and haematology will be taken before 
dialysis at the visits indicated in the protocol SoA. Additional safety samples may be 
collected if clinically indicated at the discretion of the investigator.  
The clinical chemistry and haematology will be performed at a local laboratory at or near to 
the investigator site. Sample tubes and sample sizes may vary depending on laboratory 
method used and routine practice at the site.  
The following laboratory variables will be measured (note that S-K+ will be summarized and 
analysed as part of the efficacy objectives).  
Table 2  
Laboratory Safety Variables  
Haematology/Haemostasis (whole blood)  
Clinical Chemistry (serum or plasma)  
B-Haemoglobin (Hb)  
S/P-Creatinine   
B-Leukocyte count  
Blood urea nitrogen (BUN)  
B-Leukocyte differential count (absolute count)  
S/P-Bilirubin, total  
B-Platelet count  
S/P-Alkaline phosphatase (ALP)  
  
S/P-Aspartate transaminase (AST)  
   
S/P Gamma-glutamyl transferase (GGT)  
 
S/P-Albumin  
  
S/P-Lactate dehydrogenase  
  
S-K+  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
21of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
  
S-Calcium  
  
S-Magnesium  
  
S-Sodium  
  
S-Phosphate  
  
S-Bicarbonate  
  
S/P-Chloride  
 
S/P-Glucose  
 
S/P-Creatine kinase (CK)  
  
S/P-Total protein  
  
S-Pregnancy test (serum hCG)  
Abbreviations: B = blood; hCG = human chorionic gonadotropin; P = plasma; S = serum.   
4.3.1.3 
Vital signs 
Vital signs (blood pressure, pulse rate, and oral temperature) will be collected at timepoints as 
specified in the protocol SoA, after 5 min of lying or sitting down without any distractions.  
4.3.1.4 
Electrocardiograms 
An ECG will be performed at timepoints specified in the protocol SoA. QTc(F) will be 
collected at each ECG measurement. ECG data and S-K+ values will be collected and 
recorded in the eCRF in connection with reporting AEs of S-K+ below 3.0 mmol/L.  
4.3.1.5 
Physical Examinations 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). Height, lean weight, and triceps skin-
fold thickness assessments will be also be collected before dialysis at timepoints as specified 
in the protocol SoA. 
4.3.1.6 
Pregnancy 
Women of childbearing potential will get a pregnancy test as described in protocol. 
All pregnancies and outcomes of pregnancy should be reported, except for:  
x 
If the pregnancy is discovered before the study participant has received any study 
intervention  
x 
Pregnancies in the partner of male participants.  
4.3.1.7 
Interdialytic Weight Gain (IDWG) 
IDWG will be calculated as the difference between current pre-dialysis weight minus 
previous post-dialysis weight (measured at immediate dialysis session prior to the visit) in 
kilograms.  
IDWG will be collected at the times specified in the protocol SoA. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
22of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
4.3.2 
Other variables 
4.3.2.1 
Dialysis Prescription 
Dialysis prescription parameters including blood flow (Qb, mL/min) and time on dialysis 
(minutes) will be collected at the times specified in the protocol SoA. 
4.3.2.2 
Dialysis Adequacy  
Dialysis adequacy indices including spKt/V and/or urea reduction ratio (URR) will be 
collected at the times specified in the protocol SoA.  
5. 
ANALYSIS METHODS 
5.1 
General principles 
The principal analyses outlined in this statistical analysis plan will be conducted by Labcorp 
Drug Development Inc., in accordance with the contract with AstraZeneca Pharmaceuticals 
LP and following the Excellence in Medical Partnership for Outsourced Worldwide Evidence 
Research (EMPOWER) description of services.  
The below mentioned general principles will be followed for analyses: 
In general, all baseline characteristics and efficacy and safety variables will be summarised 
using descriptive statistics as appropriate. Continuous variables will be summarised by 
descriptive statistics (including number of participants [n], mean, standard deviation, 
minimum, median, and maximum). Categorical variables will be summarised using 
frequencies and percentages, where the denominator of calculation is the underlying analysis 
set unless stated.  
Descriptive statistics of quantitative efficacy and safety parameters by scheduled visits will 
be provided on observed cases (ie, including only participants who have non-missing 
assessments at a given visit).  
For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional decimal 
places compared to the original data. Minimum and maximum will be displayed with the 
same accuracy as the original data. 
For categorical data, percentages will be rounded to 1 decimal place. 
SAS® version 9.3 or higher will be used for all analyses. 
The last observation before the first dose of study treatment in the HK treatment phase will be 
considered the baseline measurement for HK treatment phase, unless otherwise specified.  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
23of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
The last available assessment prior to or on the date of the randomisation visit for all 
participants in Diet Comparison phase will be considered the baseline measurement for Diet 
Comparison phase , unless otherwise specified. 
In all quantitative summaries from baseline, variables will be calculated as the post-treatment 
value minus the value at baseline. The percentage change from baseline will be calculated as 
(post-baseline value – baseline value) / baseline value x 100. 
The following treatment labels will be used for the analyses during the HK Treatment Phase 
and Diet Comparison Phase. 
x 
HK Treatment Phase: SZC 
x 
Diet Comparison Phase: SZC and SoC 
In general terms, the FAS will be used for the efficacy analyses, while the HKS and SAS will 
be used for the safety reporting. Study population, baseline and demography data will also be 
summarized using the FAS and selected summaries will be produced for the HKS. 
5.1.1 
Handling of missing dates 
Incomplete dates (partial or missing dates where a full date is permissible) will be presented 
in the data listings as recorded on the eCRF. However, for use in calculations (for instance in 
calculation of the duration of an AE or medication use), dates will be estimated as follows: 
5.1.1.1 
Partial start dates 
If the year is unknown, then: 
x 
The date will not be imputed, and will be assigned a missing value 
If the month is unknown, then: 
x 
If the year matches the year of the first dose date in the HK treatment phase then impute 
the month and day of the first dose date. 
x 
Otherwise, if the year matches the year of the first dose date in the Diet Comparison 
phase then impute the month and day of the first dose date. 
x 
Otherwise, assign the month as January 
If the day is unknown, then: 
x 
If the month and year match the month and year of the first dose date in the HK 
treatment phase, then impute the day of the first dose date. 
x 
Otherwise if the month and year match the month and year of the first dose date in the 
Diet Comparison phase, then impute the day of the first dose date. 
x 
Otherwise, assign the day as 1st of the month. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
24of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
5.1.1.2 
Partial end dates 
If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
If the month is unknown, then assign December. 
If the day is unknown, then assign the last day of the month. 
If the above rules for end dates result in an illogical date with regard to the dates the 
participant was in the study, then the end date will be replaced with the participant’s date of 
study completion/discontinuation. 
5.1.2 
Handling of Missing Efficacy Data 
Participants with missing data for efficacy analyses will be treated as described under each 
endpoint’s estimand definition. The primary analysis will need to account for missing values, 
and values recorded for participants after commencement of rescue therapy of a K+ binder for 
hyperkalaemia, through a multiple imputation (MI) method using the missing not at random 
framework separately for each treatment group. Any assessments performed after the 
introduction of rescue therapy will not be used as inputs for the MI procedure and will be 
treated as missing. Details of handling missing values for secondary efficacy analysis is 
detailed in section 5.3.7.4. 
5.1.3 
Handling of Missing Safety Data 
In general, missing clinical laboratory data, vital signs, and ECG data will not be imputed. 
Unknown or partial medication and AE date imputations are given above and are to be used 
only for the assessment of prior/concomitant status for medications and treatment-emergent 
status for AEs. 
5.1.4 
COVID-19 Impact 
A listing of all participants affected by the COVID-19 related study disruption along with the 
description of how the individual’s participation was altered will be produced. 
Depending on the extent of COVID-19 impact, summaries of AEs associated with new onset 
SARS-CoV-2 infection, discontinuation of study treatment, discontinuation of study, missed 
visits, COVID-19 related protocol deviations and other missing data will be generated. 
Additional sensitivity and supplementary analyses will be performed to determine the impact 
of the COVID-19 pandemic on this trial and its endpoints. Planned sensitivity analyses will 
distinguish between pandemic and non-pandemic-related intercurrent events in terms of the 
approach taken for sensitivity analyses. Further details will be included under each endpoint’s 
estimand definition. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
25of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
5.2 
 Visit Windows 
For all populations, assessments will be assigned to visits for non-categorical summaries as 
follows: 
x 
Only assessments recorded with a nominal visit number or recorded as an unscheduled 
visit will be considered for assignment to visits (i.e. results recorded on the end of 
treatment and end of study CRF forms will not be used). 
x 
Assessments will be assigned to baseline for the HK Treatment Phase and Diet 
Comparison Phase as defined in Section 5.1. 
x 
Assessments with missing data and assessments marked ‘Not Done’ will be considered 
as providing a missing response and are not permitted to be assigned to a visit window. 
x 
If the initial nominal visit, (defined hereafter as the earliest assessment for a given visit to 
be recorded as the nominal visit number via the eCRF), has a non-missing response, then 
that will be chosen for analysis. 
x 
If the initial nominal visit has a missing response, then the earliest of all subsequent 
assessments with a non-missing response which have either: 
 
been recorded as the same nominal visit, or 
 
been recorded as an unscheduled visit which is assigned to the given visit as per 
Table 1 
will be chosen for the analysis. 
x 
If a given visit has no initial nominal visit record, then the earliest of all unscheduled 
visits which are assigned to the given visit as per Table 1 will be chosen for the analysis. 
For all populations, assessments will be assigned to visits and analysis periods for categorical 
summaries as follows: 
x 
Assessments with missing data and assessments marked “Not Done” will be considered 
as providing a missing response and are not permitted to be assigned to a visit window. 
x 
The worst value (e.g. out of reference range preferred to within range; abnormal 
preferred to normal) will be used in each window. If multiple assessments fall within the 
same window with equal value then the first non-missing will be used for the summary. 
Scheduled Month and visit window during the HK Treatment Phase and Diet Comparison 
Phase is shown in  Table 1. The window for visits will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits, except in the case where the 
visit is the first in a phase, or immediately follows the first visit in a phase. 
Table 1 Definition of visit windows for HK Treatment Phase and Diet Comparison Phase 
Analysis Period 
Scheduled Month 
of Visit 
Visit 
Visit Windowa 
 
Screening 
 
Visit 1 
Up to and including HK 
Day -1 
HK Treatment Phase 
Month 1 
Visit 2 
HK Day 1 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
26of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
 
 
Visit 3 
HK Day 2 to 11 
 
 
Visit 4 
HK Day 12 to 18 
 
 
Visit 5 
HK Day 19 to DC Day -1 
Diet Comparison Phase 
Month 2 
Visit 6 
DC Day 1 
 
 
Visit 7 
DC Day 2 to 11 
 
 
Visit 8 
DC Day 12 to 18 
 
 
Visit 9 
DC Day 19 to DC Day 25 
 
Month 3 
Visit 10 
DC Day 26 to DC Day 44 
 
Month 4 
Visit 11 
DC Day 45 to DC Day 75 
 
Month 5 
Visit 12 
DC Day 76 to FU Visit 
a Visit window is assigned based upon study day and is calculated as as (date – start of phase date + 1). Date of 
the start of the phase according to the Analysis Periods in Section 3.2. For participants who do not proceed to 
the next phase and for whom the study day is after the lower limit of window of the last visit of the phase, the 
assessment will be assigned to the last visit of the phase. 
5.3 
Analysis methods 
5.3.1 
Participant Disposition and Analysis Sets Analyzed 
Participant disposition will be listed and summarized for SZC in the HK Treatment Phase and 
for SZC, SoC and overall for participants in the Diet Comparison Phase. The number of 
participants in the following categories will be summarized: 
x 
Screened; 
The number and percentages of participants in the following categories will be summarized: 
x 
Did not enter HK Treatment Phase (screening failures), and associated reasons 
x 
Entered the HK Treatment Phase and received treatment 
x 
Entered the HK Treatment Phase and did not receive treatment, and associated reasons 
x 
Randomized; 
x 
Not randomized (Diet Comparison Phase failure) and associated reasons; 
x 
Randomized participants who received treatment; 
x 
Randomized participants who did not receive treatment and associated reasons; 
x 
Participants who completed the study; 
x 
Discontinued treatment and associated reasons; 
x 
Terminated study and associated reasons; 
The denominator used for percentages will be calculated as follows. The denominator for 
participants who did not enter the HK Treatment Phase (and associated reasons) will be 
calculated using the All-participants analysis set. The denominator for participants who 
entered the HK Treatment Phase and received treatment, who entered the HK Treatment 
Phase and did not receive treatment (and associated reasons) will be calculated using the 
number of participants who entered the HK Treatment Phase; randomized and not 
randomized (and associated reasons) will be calculated using the number of participants who 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
27of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
entered the Diet Comparison Phase. The remaining participant disposition categories will use 
the number of participants who were FAS for the denominator. 
The number of participants in each of the analysis sets and the reasons for exclusion from 
each will be summarized for all screened participants by treatment group and overall. 
5.3.2 
Protocol Deviations 
All important protocol deviations, defined according to section 3.3, will be listed for the 
HKS, and summarized by SZC for the HKS and by SZC, SoC and overall for the FAS 
separately. COVID-19 related important protocol deviations will be listed for the HKS. Each 
listing of important protocol deviations will include the phase during which the deviation 
occurred. 
5.3.3 
Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by SZC for the HKS 
and by SZC, SoC and overall for the FAS. The demographic and baseline characteristics 
include the following: 
x 
Age (Years); 
x 
Age groups (18-64, 65-84 and over 85 years); 
x 
Sex (Male, Female); 
x 
Race category (White, Black or African American, Asian, Native Hawaiian or Other 
Pacific Islander, American Indian or Alaskan Native, Other, Not reported); 
x 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 
x 
Country 
No formal tests of statistical significance will be performed on the demographic and baseline 
data. 
A separate table will summarize the participant characteristics at baseline and will be listed 
and summarized by SZC for the HKS and by SZC, SoC and overall for the FAS. They will 
include: 
x 
Baseline height (cm); 
x 
Baseline weight (kg); 
x 
Baseline body mass index (BMI) (kg/m2) [calculated as (baseline weight/baseline height2 
where weight is in kg and height is in m]; 
x 
Prevalent HK (S-K+ : >5.5 mmol/L vs 5.5 mmol/L) at baseline  
x 
Dialysis status at baseline (Former / Current / No) 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
28of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
x 
Current dialysis (Times / Week) 
x 
Dialysis access type (Arteriovenous Fistula / Arteriovenous Graft / Tunneled Catheter / 
Other) 
Other baseline measurements, such as vital signs and ECG results, will be reported with post-
baseline measurements.  
5.3.4 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 24.0 (or a later version if updated during the study)]. All medical history 
will be listed, and the number and percentage of participants with any medical history will be 
summarized by SZC for the HKS and by SZC, SoC and overall for the FAS by SOC and PT. 
5.3.5 
Previous and Concomitant Medications 
 
Medications received prior to or concomitantly with study treatment will be coded using the 
WHO Drug Dictionary [Version March 2021 B3 (or a later version if updated during the 
study)], Anatomical Therapeutic Chemical (ATC) Classification codes. 
Prior medications and concomitant medications are as defined as follows: 
Prior medications are those taken with a stop date prior to the first dose date of study 
treatment during the HK Treatment Phase. 
Concomitant medications during the HK Treatment Phase are those with a start date anytime 
before the first dose date of study treatment during the Diet Comparison Phase for SZC 
randomized participants, or with a start date before the date of randomization for SoC 
randomized participants. 
Concomitant medications during the Diet Comparison Phase are those which are either 
ongoing at the end of the Diet Comparison Phase, or with a stop date anytime after the first 
dose date of the Diet Comparison Phase for SZC randomized participants, or with a stop date 
anytime after the date of randomization for SoC randomized participants. 
If a medication cannot be classified as “prior” or “concomitant during the HK Treatment 
Phase” or “concomitant during the Diet Comparison Phase” after applying imputation rules 
for missing/incomplete dates, it will be classified as concomitant during the Diet Comparison 
Phase. 
Prior and concomitant medications will be listed for HKS. Concomitant medications during 
the HK Treatment Phase will be summarized by SZC for the HKS. Concomitant medications 
during the Diet Comparison Phase will be summarized separately by SZC, SoC and overall 
for the SAS. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
29of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
For all summaries of medications, the number and percentages of participants using each 
medication will be displayed together with the number and percentage of participants using at 
least one medication within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-
Level 4), and generic term. 
5.3.6 
Measurements of Study Treatment Compliance 
The percentage compliance for SZC  is calculated for each analysis period as: 
100*actual sachets taken/expected sachets taken 
, where: 
Actual sachet taken is defined as: 
Sum of the sachets taken throughout the respective analysis period 
And the expected sachets taken throughout the respective analysis period is derived using the 
study intervention and drug dispensation records (planned study drug dosage) to calculate the 
number of sachets expected accounting for changes to the prescribed dosage level (5g up to 
15g once daily on non-dialysis days) and the unit dose strength dispensed (5g and 10g 
sachets).  
The percentage compliance for SZC will be calculated separately for the HK Treatment 
Phase and Diet Comparison Phase and will be summarized descriptively by SZC for the HKS 
and by SZC, SoC and overall for the SAS. 
Furthermore, for SZC the number and percentage compliance will be presented separately for 
the HK Treatment Phase and Diet Comparison Phase using the HKS and SAS respectively 
with the following compliance categories: 
x 
<50% 
x 
50% to <80% 
x 
80% to <120% 
x 
120% 
Furthermore, at each study visit during the HK Treatment Phase and Diet Comparison Phase 
there will be a categorical summary of the number and percentage of participants assigned to 
each dose of SZC (e.g. 5g every other day, 5g daily, 10g daily, 15g daily). 
5.3.7 
Efficacy 
The primary statistical hypothesis of the study is that prescribing SZC with enhanced 
nutritional advice to participants with hyperkalaemia on haemodialysis will show a non-


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
30of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
inferior difference in the change from baseline in S-K+ taken at LIDI visits M3, M4, and M5 
when compared to participants on SoC (other than K+ binders).  
All efficacy endpoints will be analysed using the FAS.  
5.3.7.1 
Primary Efficacy Analysis 
The primary endpoint will be defined as the change in the S-K+ taken at LIDI visits M3, M4, 
and M5 compared to the S-K+ taken at baseline.  
The primary objective will test the null hypothesis of [S-K+ for SZC participants] – [S-K+ for 
SoC participants] >= 0.2 mmol/L against the alternative hypothesis that [S-K+ for SZC 
participants] – [S-K+ for SoC participants] <0.2 mmol/L at the 1-sided 0.025 significance 
level.  
Estimand Attributes 
In line with the ICH E9 (R1) addendum, 5 attributes (treatment, population, endpoint, 
intercurrent events, and population level summary) have been specified to translate the 
primary and secondary efficacy objectives into treatment effects that are to be estimated 
(estimands).  
Endpoint: 
The treatment effect is assessed by the primary efficacy endpoint of change from baseline in 
S-K+ levels over the M3, M4, and M5 visits.  
Population: 
The population of participants targeted is adults with HK as defined by the 
inclusion/exclusion criteria who are able to complete the HK Treatment Phase.  
Treatment: 
SZC dosed as per local label to control HK and maintain normokalaemia in addition to SoC 
dietary advice for the up to 1-month HK Treatment Phase followed by the 4-month Diet 
Comparison Phase (SZC with enhanced nutrition advice versus SoC, including standard 
dietary advice) for the full 5-month treatment duration. 
Intercurrent Event Strategy: 
Intercurrent events are handled through a combination of a treatment policy strategy and a 
composite strategy (whereby the incidence of the intercurrent event is incorporated into the 
endpoint). Specifically, the following events which preclude the collection of data for the 
primary estimand will be handled according to the table below:  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
31of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
Intercurrent event  
Data collection and analysis  
Premature treatment 
discontinuation due to lack of 
efficacy or physician’s decision  
Participants will be followed and data collected will be 
analysed after the intercurrent event in line with a treatment 
policy strategy.  
In the case of missing data after treatment discontinuation, 
values will be imputed through a MI procedure.  
Premature treatment 
discontinuation due to reasons 
other than lack of efficacy or 
physician’s decision  
Participants will be followed and data collected after the 
intercurrent event in line with a treatment policy strategy.  
In the case of missing data after treatment discontinuation, 
values will be imputed through a MI procedure.  
Introduction of rescue therapy 
of a  
K+ binder for HK  
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for the primary analysis of the primary 
estimand.  
All values after introduction of rescue medication will be 
imputed using a composite policy through a MI procedure.  
Population Level Summary: 
The treatment effect will be quantified by via recombination average of the least squares (LS) 
mean of the change from baseline in S-K+ levels across the M3, M4, and M5 visits, obtained 
from a repeated measures ANCOVA performed multiple times on MI data as described 
below.  
All scheduled assessments during the Diet Comparison Phase (visits 6 to 12) will be used for 
imputation, and the visits during the LIDI will be used for analysis. Intermittent observed 
values will be used to generate a full set of imputed values up to and including M5.  
The primary analysis will need to account for missing values, and values recorded for 
participants after commencement of rescue therapy of a K+ binder for hyperkalaemia, through 
a MI method with 1000 imputations using the missing not at random framework separately 
for each treatment group. Any assessments performed after the introduction of rescue therapy 
will not be used as inputs for the MI procedure and will be treated as missing. 
Intermittent observed values will be used to generate a full set of imputed values up to and 
including M5. In case that a non-monotone missing data pattern exists at the intermediate 
visits, these data points will be first imputed separately 1000 times for each treatment group 
using the Markov Chain Monte Carlo (MCMC) method in order to achieve a monotone 
missing data pattern for all participants. The full set of endpoint values will be subsequently 
imputed from the multiple copies of the original dataset where each copy will have a 
monotone missing pattern; if the MCMC method was previously used, this will be done once 
per existing imputation, otherwise this will be done 1000 times on the existing data. 
The following types of missing data will be handled differently: 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
32of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
x 
Missing values at times where the participant remains on treatment, or after the 
participant discontinues treatment for reasons other than either the physician’s decision 
or lack of efficacy, will be imputed based on known values for the treatment group the 
participant was randomized to. 
x 
Missing values at times after discontinuation of treatment for reasons of physician’s 
decision or lack of efficacy, will be imputed based on known values for the treatment 
group the participant was randomized to, with a penalty of 10% applied to the values 
used for imputation. 
x 
Values at times whilst the participant remains on treatment and after commencement of 
rescue therapy of a K+ binder for hyperkalaemia will be imputed based on known values 
for the treatment group the participant was randomized to with a penalty of 10%.   
A repeated-measures ANCOVA model will be used for each of the 1000 imputed datasets, 
with fixed terms for the treatment groups for SZC and SoC, visit and baseline S-K+ for the 
Diet Comparison Phase as a covariate.. An unstructured variance-covariance matrix will be 
assumed. The analysis will be performed using post-baseline data from the Diet Comparison 
Phase ( Visit 10 to 12). The results from each model will be recombined using Rubin’s rule to 
provide the estimated change from baseline in S-K+ for each treatment group over the period 
of M3 to M5, as well as the  average of esitmated mean group differences over visit 10, 11 
and 12 and its  95% confidence interval (CI) . The null hypothesis will be rejected if the 
upper bound of the 95% CI is below 0.2. P-value will be generated as well. 
5.3.7.2 
Primary Efficacy Analysis – Sensitivity Analyses 
The following sensitivity analyses will be pre-specified to be conducted for the primary 
efficacy endpoint. Aside from the stated amended intercurrent event strategy in each case, the 
analysis and imputation will be performed in the same way as for the primary analysis. 
(i) 
The intercurrent event strategy will be altered to describe the treatment effect 
using while on-treatment strategy. 
 
Intercurrent Event Strategy: 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
33of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
Intercurrent event  
Data collection and analysis  
Premature treatment 
discontinuation due to lack of 
efficacy or physician’s decision  
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for this sensitivity analysis of the primary 
estimand. All values after treatment discontinuation will be 
imputed using a composite policy through a MI procedure. 
 
Premature treatment 
discontinuation due to reasons 
other than lack of efficacy or 
physician’s decision  
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for this sensitivity analysis of the primary 
estimand. All values after treatment discontinuation will be 
imputed using a composite policy through a MI procedure. 
 
Introduction of rescue therapy 
of a  
K+ binder for HK  
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for the primary analysis of the primary 
estimand.  
In the case of missing data whilst the participant is on-
treatment, values will be imputed through a MI procedure. 
(ii) 
The intercurrent event strategy will be altered to describe the treatment effect in a 
COVID-19 pandemic-free world. 
Intercurrent Event Strategy: 
Intercurrent event  
Data collection and analysis  
Premature treatment 
discontinuation not related to 
the COVID-19 pandemic 
Participants will be followed and data collected will be 
analysed after the intercurrent event in line with a treatment 
policy strategy.  
In the case of missing data after treatment discontinuation, 
values will be imputed through a MI procedure.  
Premature treatment 
discontinuation related to the 
COVID-19 pandemic 
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for this sensitivity analysis of the primary 
estimand.  
All values after diagnosis of COVID-19 will be imputed using 
a composite policy through a MI procedure. 
 
Introduction of rescue therapy 
of a  
K+ binder for HK  
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for this sensitivity analysis of the primary 
estimand.  
All values after introduction of rescue medication will be 
imputed using a composite policy through a MI procedure.  
(iii) 
Missing values at times after discontinuation of treatment or values at times whilst 
the participant remains on treatment and after commencement of rescue therapy of 
a K+ binder for hyperkalaemia will be imputed based on known values for the 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
34of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
treatment group the participant was randomized to, with a penalty of 15%.  The 
intercurrent event strategy will otherwise be the same as the primary analysis. 
5.3.7.3 
Secondary Efficacy Analyses 
A multiplicity correction procedure that covers the primary and the secondary endpoints will 
be applied, with the method being a fixed-sequence hierarchical testing procedure where the 
primary hypothesis is tested first. If the primary endpoint or any of the secondary endpoints 
listed in the order of importance are negative, then all endpoints beneath them in the 
hierarchy are then reduced to being exploratory endpoints. The order of importance for the 
secondary endpoints is as follows:  
x 
Maintaining S-K+ levels within a range of 3.5–5.5 mmol/L without requiring rescue 
therapy for HK  
x 
Consumption of fruit and vegetables  
x 
EQ-5D-5L score  
x 
KDQOL-36 PCS  
x 
KDQOL-36 MCS  
x 
TSQM-9  
x 
PGIC 
Maintaining S-K+ levels within a range of 3.5–5.5 mmol/L without requiring rescue 
therapy for HK  
The first secondary objective (Maintaining S-K+ levels within a range of 3.5–5.5 mmol/L 
without requiring rescue therapy for HK) will test the null hypothesis of [Proportion of SZC 
responders] – [Proportion of SoC responders] < -0.1 against the alternative hypothesis that 
[Proportion of SZC responders] – [Proportion of SoC responders]  - 0.1 at the 1-sided 0.025 
significance level.  
The proportions of responders and non-responders and 95% 2-sided Wilson CI for responders 
will be calculated for each treatment arm, and a difference in proportions (SZC - SoC) 
constructed. A 95% 2-sided Newcombe CI for the risk difference will be created, and the null 
hypothesis will be rejected if the lower bound of the CI is  -0.1. 
Estimand Attributes for the secondary endpoint of maintaining S-K+ levels within the 
normokalaemic range of 3.5-5.5 mmol/L without requiring rescue therapy for HK 
In line with the ICH E9 (R1) addendum, 5 attributes (treatment, population, endpoint, 
intercurrent events, and population level summary) have been specified to translate the 
primary and secondary efficacy objectives into treatment effects that are to be estimated 
(estimands).  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
35of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
Endpoint: 
The treatment effect is assessed by the secondary endpoint of maintaining S-K+ levels within 
the normokalaemic range of 3.5-5.5 mmol/L without requiring rescue therapy for HK will be 
assessed as a binary (responder/non-responder) variable, with participants being be deemed 
responders if all of the following are true:  
1. The participant provides 2 or more non-missing S-K+ assessments during the period 
from M3 to M5, inclusive.  
2. At least 66% of their non-missing S-K+ assessments between the M3 and M5 visits, 
inclusive, show values within the normokalaemic range.  
3. The participant does not receive rescue therapy or a K+ binder for HK at any point 
between the M3 and M5 visits, inclusive.  
Participants will be deemed non-responders if point 3 is not true, or if point 1 is true and 
point 2 is not true.  
Participants will be excluded from the secondary analysis if point 1 is not true and point 3 is 
true.  
Population: 
The population of participants targeted is adults with HK as defined by the 
inclusion/exclusion criteria who are able to complete the HK Treatment Phase.  
Treatment: 
SZC dosed as per local label to control HK and maintain normokalaemia in addition to SoC 
dietary advice for the up to 1-month HK Treatment Phase followed by the 4-month Diet 
Comparison Phase (SZC with enhanced nutrition advice versus SoC, including standard 
dietary advice) for the full 5-month treatment duration. 
Intercurrent Event Strategy: 
Intercurrent events are handled through a combination of a treatment policy strategy and a 
composite strategy. Specifically, the following events which preclude the collection of data 
for the secondary estimand will be handled according to the table below:  
Intercurrent event  
Data collection and analysis  
Premature treatment 
discontinuation due to lack of 
efficacy or physician’s decision  
Participants will be followed and data collected will be 
analysed after the intercurrent event in line with a treatment 
policy strategy. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
36of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
Intercurrent event  
Data collection and analysis  
Premature treatment 
discontinuation due to reasons 
other than lack of efficacy or 
physician’s decision  
Participants will be followed and data collected after the 
intercurrent event in line with a treatment policy strategy. 
Introduction of rescue therapy 
of a  
K+ binder for HK 
Participants will be followed and data collected after the 
intercurrent event for reporting purposes; however, this data 
will not be used for the secondary analysis and participant will 
be treated as non-responder in line with a composite strategy. 
Population Level Summary: 
The proportions of responders and non-responders will be calculated for each treatment arm, 
and a difference in proportions (SZC - SoC) constructed. A 95% 2-sided CI for the difference 
will be created, and the null hypothesis will be rejected if the lower bound of the CI is  -0.1. 
Consumption of fruit and vegetables  
The average daily fruit and vegetable consumption per 28 days during the Diet Comparison 
Phase will be analysed using a repeated-measures ANCOVA model with fixed terms for 
treatment, 28-day period, baseline average daily consumption, and treatment by 28-day 
period interaction. An unstructured variance-covariance matrix will be assumed.The baseline 
average daily fruit and vegetable consumption and the 28-day period consumption will be 
calculated as described in section 4.2.2.6.The comparison between treatment groups will be 
based upon the p-value associated with the treatment by 28-day period interaction term at 
M5, which will be presented alongside the LS mean of the M5 treatment difference and its 
associated 95% CI. Further, descriptive statistics, LS mean estimates, 95% CIs, and p-values 
will be provided per each 28-day period.  
EQ-5D-5L 
The EQ-5D-5L questionnaire score change from study baseline at M2 (visit 6) and M5 will 
be analysed using a  ANCOVA model with fixed terms for treatment,  and baseline EQ-5D-
5L . The comparison between treatment groups will be assessed based upon the p-value 
associated with the treatment at the M5 visit, which will be presented alongside the LS mean 
of the overall treatment difference and its associated 95% CI. Further, descriptive statistics, 
LS mean estimates, 95% CIs, and p-values will be provided at the M2 visit and overall.  
KDQOL-36 
The change from study baseline at M2 (visit 6) and M5 for KDQOL-36 scores for symptoms, 
PCS, and MCS will be analysed  using a ANCOVA model with fixed terms for treatment and 
baseline KDQOL-36. The comparison between treatment groups will be assessed based upon 
the p-value associated with the treatment at the M5 visit, which will be presented alongside 
the LS mean of the overall treatment difference and its associated 95% CI. Further, 






Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
39of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
x 
Any AEs leading to dose interruption of study treatment 
x 
Any AEs leading to study discontinuation 
The number and percentage of participants reporting each AE will be summarized by SOC 
and PT. Tables will be sorted by international order for SOC, and PTs will be sorted 
alphabetically. The following summaries will be produced using the HKS and SAS: 
x 
AEs by SOC and PT; 
x 
Most common AEs (>5% overall for HKS, >5% in any treatment group for SAS) by 
SOC and PT; 
x 
AEs assessed by investigator as possibly related to SZC treatment, by SOC and PT; 
x 
AEs by relationship to treatment, by SOC and PT; 
x 
AEs by maximum intensity, by SOC and PT; 
x 
AEs assessed by investigator as possibly related to SZC treatment, by maximum 
intensity, SOC and PT; 
x 
AEs leading to treatment discontinuation, by SOC and PT; 
x 
AEs assessed by investigator as possibly related to SZC treatment leading to treatment 
discontinuation, by SOC and PT; 
x 
SAEs, by SOC and PT; 
x 
SAEs related to SZC treatment, by SOC and PT; 
x 
AEs leading to death, by SOC and PT; 
All AE data will be listed appropriately for all participants including information on AE 
duration, intensity, seriousness, action taken, outcome, relationship as assessed by 
investigator, timing of onset of AE in relation to the first dose of study treatment in the both 
HK Treatment Phase and Diet Comparison Phase, study treatment at the time of event. 
5.3.8.2 
Deaths 
A summary of deaths will be provided with number and percentage of participants 
categorized as: 
x 
Number of participants with any AE with outcome = death 
x 
AEs with outcome of death only  
All deaths will be listed. 
5.3.8.3 
Laboratory Data 
Laboratory data (clinical chemistry and haematology) will be summarized and listed. 
Laboratory data outside the reference ranges will be indicated in the listings. If a participant 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
40of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
has multiple results for a particular test at a particular time point, the first non-missing 
scheduled value will be used for the summary. System international (SI) units will be 
reported for all analytes. 
Laboratory data absolute and change from baseline values for continuous chemistry and 
haematology parameters will be summarized at each scheduled assessment time during the 
Diet Comparison Phase using SAS.  
Shift tables will be provided for parameters with available reference range, where shift from 
baseline to the worst value with respect to the reference range will be summarized, where 
worst is defined to low or high in preference to normal categorization. Where a participant 
has both high and low responses, they will be summarized in both categories. This will be 
provided for the SAS, summarizing the worst overall value across all visits during the Diet 
Comparison Phase.  
5.3.8.4 
Vital Signs 
Vital sign values will be summarized and listed. Vital sign data absolute and change from 
baseline will be summarized at each scheduled timepoint. The continuous vital sign 
parameters will be summarized with descriptive statistics. If a participant has multiple results 
for a particular test at a particular time point, the first non-missing scheduled value will be 
used for the summary. These will be provided for the HKS which will be limited to visits 
during the HK Treatment Phase and be presented overall, and the SAS, which will include all 
visits  during the Diet Comparison Phase with scheduled vital sign assessment and be 
presented by treatment group. 
5.3.8.5 
Electrocardiograms 
ECG data will be summarized and listed. Absolute and change from baseline in ECG 
parameters will be summarized at each scheduled timepoint. The continuous ECG parameters 
will be summarized with descriptive statistics. If a participant has multiple results for a 
particular test at a particular time point, the first non-missing scheduled value will be used for 
the summary. These will be provided for the HKS, limited to visits during the HK Treatment 
Phase and presented overall, and the SAS which will include all visits  during the Diet 
Comparison Phase with ECG assessments and be presented by treatment group.  
5.3.8.6 
Physical Examination 
Physical examination assessments where a new or worsening abnormality is observed will be 
reported as an AE and included within the AE summaries detailed in section 5.3.8.1.  
Height (Visit 2 only), weight and BMI will be summarized overall for the HKS, restricted to 
visits during the HK Treatment Phase, and by treatment received during the Diet Comparison 
Phase using the SAS. 


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
41of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
5.3.8.7 
Exposure 
Exposure (in days) to IP i.e. total amount of study drug will be summarized overall for the 
HKS and by treatment group for the SAS. 
Actual and total exposure (days) will be summarized by the following: mean, standard 
deviation, minimum, maximum, median and number of observations. 
5.3.8.8 
Pregnancy Test 
Serum pregnancy test results will be listed only using the HKS. 
5.3.8.9 
Dialysis Prescription 
Dialysis prescription parameters including blood flow (Qb, mL/min) and time on dialysis 
(minutes) will be summarized and listed by treatment group for the SAS. 
5.3.8.10 
Dialysis Adequacy  
Dialysis adequacy indices including spKt/V and/or urea reduction ratio (URR) will be 
summarized and listed by treatment group for the SAS. 
5.3.8.11 
Interdialytic Weight Gain (IDWG) 
IDWG will be summarized overall for the HKS and by treatment group for the SAS. 
Change in IDWG from visit 2 to visit 6, and visit 6 to visit 12 will also be summarized by 
treatment group for the SAS. 
6. 
INTERIM ANALYSES  
No interim analysis is planned for this study. 
7. 
REFERENCES 
FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic: Guidance for Industry, Investigators, and Institutional Review Boards. 
https://www.fda.gov/media/136238/download. Accessed 25 May 2021. 
Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, et al. Validation of a 
general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for 
Medication (TSQM), using a national panel study of chronic disease. Health Qual Life 
Outcomes. 2004;2(1):12 
 
BharmalM,PayneK,AtkinsonMJ.ValidationofanabbreviatedTreatmentSatisfaction
QuestionnaireforMedication(TSQMͲ9)amongpatientsonantihypertensivemedications.
HealthQualLifeOutcomes.2009;7:36
Cohen DE, Lee A, Sibbel S, Benner D, Brunelli SM, Tentori F. Use of the KDQOL-36TM for 
assessment of health-related quality of life among dialysis patients in the United States. BMC 
Nephrol. 2019;20(1):112.  


Statistical analysis plan                                                                                                                        AstraZeneca  
1.0 
                                                                                                               15 Oct 2021 
 
42of42
Lastupdated:10April2018
ParentSOP:AZDoc0083874
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727–36.  
Newcombe, R. G. (1998). Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Statistics in Medicine. 17 (8): 857–872. 
Ricardo A, Hacker H, Lora C, Ackerson L, DeSalvo K, Go A et al. Validation of the Kidney 
Disease Quality of Life Short Form 36 (KDQOL-36) US Spanish and English versions in a 
cohort of Hispanics with chronic kidney disease. Ethn Dis. 2013;23(2):202-9. 
Wilson, E. B. (1927). Probable inference, the law of succession, and statistical inference. 
Journal of the American Statistical Association. 22 (158): 209–212.  























SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9480c00014-sap-v1
Document Title:
Statistical Analysis Plan Version 1
Document ID:
Doc ID-005000792
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
19-Oct-2022 16:54 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD