Clinical trial NCT04676646
Conditions: Hyperkalaemia Heart Failure With Reduced Ejection Fraction
Sponsor: AstraZeneca
Start date: 2021-03-08; Completion date: 2024-07-15
Enrollment: 366 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to evaluate the efficacy of SZC as compared with placebo in keeping potassium levels within the normal range (3.5-5.0 mEq/L) while on spironolactone ≥25 mg daily without assistance of rescue therapy for hyperkalaemia (HK).

Detailed description:
REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study that includes the following 3 phases: screening, 4-6 week open-label run-in phase where sodium zirconium cyclosilicate (SZC) and spironolactone will be optimized, followed by a 6-month double-blind, placebo-controlled, randomized withdrawal treatment phase.

Patients meeting the following criteria will enter the 4-6 week open-label run-in phase: symptomatic heart failure with reduced ejection fraction (HFrEF); receiving an angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-Neprilysin inhibitor (ARNi); receiving no spironolactone or eplerenone, or receiving low-dose spironolactone (\<25 mg daily); receiving a beta-blocker unless contraindicated; AND with hyperkalemia (sK+ 5.1-5.9 mEq/L) and an eGFR \>/= 30 mL/min/1.73m2, OR normokalemic (sK+ 3.5-5.0 mEq/L) and 'at risk' of developing hyperkalemia (ie, history of hyperkalemia within the past 36 months and eGFR \>/= 30 mL/min/1.73m2, or sK+ 4.5-5.0 mEq/L and eGFR 30-60 mL/min/1.73m2 and/or age \>75 years).

Patients who are normokalemic on SZC and receiving spironolactone \>/= 25 mg daily at the end of the open-label run-in phase will enter the 6-month double-blind, placebo-controlled, randomized withdrawal treatment phase. Eligible patients will be randomized 1:1, stratified by run-in phase sK+ cohort.

Arms: arm 1: Cohort 1 (4 weeks duration): Patients who are hyperkalemic at study entry will begin SZC 10 g TID for up to 48 hours followed by SZC 10 g once daily to achieve and maintain normokalemia. The SZC dose will be adjusted as needed to maintain normokalemia (dose range = 5 g every other day, to 5-15 g once daily).

Cohort 2 (up to 6 weeks duration): Patients who develop hyperkalemia during the uptitration of spironolactone will receive SZC 10 g TID for up to 48 hours followed by SZC 10 g once daily to achieve and maintain normokalemia. The SZC dose will be adjusted as needed to maintain normokalemia (dose range = 5 g every other day, to 5-15 g once daily). arm 2: SZC arm and Placebo arm: Patients will continue on the SZC dose they were receiving at the end of the run-in phase.

The SZC / Placebo dose will be adjusted as needed to maintain normokalemia (dose range = 5 g every other day, to 5-15 g once daily).
Interventions: intervention 1: Sodium zirconium cyclosilicate intervention 2: Placebo intervention 3: Spironolactone
Intervention descriptions: intervention 1: Investigational medicinal product intervention 2: Placebo comparator intervention 3: Background intervention.

During the run-in phase, spironolactone will be initiated/uptitrated up to a maximum of 50 mg per day. During the randomized withdrawal phase the spironolactone dose at the end of the run-in phase will be maintained.

Protocol documents:
Prot_000.pdf: 
Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 of 1 3 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 
( S Z C)
St u d y C o de
D 9 4 8 0 C 0 0 0 1 8
Ve rsi o n
4 . 0
Date
0 9 N o v 2 0 2 3
P h ase I V , D o u ble-Bli n d, Pl ace b o -C o ntr olle d, R a n d o mize d -
Wi t h dr a w al Tri al E v al u ati n g S o di u m Zirc o ni u m C ycl osilic ate 
( S Z C) f or t he M a n a ge me nt of H y per kal a e mi a i n P atie nts wit h 
S y m pt o m atic He art F ail ure wit h Re d uce d Ejecti o n Fr acti o n a n d 
Recei vi n g S pir o n ol act o ne ( R E A LI Z E -K)
S p o ns or  N a me: Astra Ze neca A B
Le g al Re gister e 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): 
T his Cli nical St u d y  Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
Sta n dar d pr oce d ures. T he Cli nical St u d y  Pr ot oc ol is p u blicl y re gistere d a n d t he res ults are 
di s close d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o mplia nce wi t h pre vaili n g la ws a n d re g ulati ons.
Pr ot oc ol N u m ber: 4 . 0
A me n d me nt N u m ber: 3 . 0
E u dr a C T n u m ber: 2 0 2 0 ‐ 0 0 3 3 1 2‐ 2 7
St u d y I nter ve nti o n: S o di u m Zirc o ni u m C ycl o silicate ( S Z C)
St u d y P h ase: 4
Acr o n y m: R E A LI Z E - K
 Pri nci p al I n vesti g at or: Mi k hail K osi b or o d 
P P D
R e d a ct e d f or P u bli c Di s cl o s ur e


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 of 1 3 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 3
0 9- N o v - 2 0 2 3
A me n d me nt 2
0 3- A u g- 2 0 2 2
A me n d me nt 1
2 9- J u n- 2 0 2 1
Ori gi nal Pr ot oc ol
2 9- Se p - 2 0 2 0
A me n d me nt 3, 0 9 N o ve m ber 2 0 2 3
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he 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.
O ver all R ati o n ale f or t he A me n d me nt 3:
T he o verall rati o nale ( o ne pri mar y dri ver) f or t he c ha n ges i m ple me nte d i n t he pr ot oc ol a me n d me nt is
t he u p date d defi niti o n of pri mar y e n d p oi nt t o i ncl u de a d diti o nal data p oi nts d uri n g t he mai nte na nce 
p hase. T his will lea d t o a re d ucti o n i n sa m ple size.
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
1. 1 S y n o psis
3 O bjecti ves a n d E n d p oi nts
9. 4. 3. 1 Pri mar y E n d p oi nt
9. 4. 3. 2 Sec o n dar y E n d p oi nts
A d de d “ T he m o nt hl y visits 
ar e use d f or res p o nse 
assess me nt fr o m m o nt h 1 t o 
m o nt h 6 ” t o pri mar y a n d 
sec o n dar y e n d p oi nts a n d 
delete d “at t he e n d of 
treat me nt ( E O T) visit 
(a p pr o xi matel y 6 m o nt hs 
p ost -ra n d o misati o n)”.
Defi niti o n f or 
pri m ar y e n d p oi nt 
a me n de d t o a 
l o n git u di nal a nal ysis 
w hic h i ncreases t he 
p o wer of st u d y a n d 
all o ws f or a re d uce d 
s a mple size.
S u bsta ntial
1. 1 S y n o psis
3 O bjecti ves a n d E n d p oi nts
9. 4. 3. 1 Pri mar y E n d p oi nt
9. 4. 3. 2 Sec o n dar y E n d p oi nts
A d de d (a) “ Res p o nse a n d 
N o n -r es p o nse defi niti o ns” 
( b) “ eac h assess me nt visits” 
i nstea d of “ E O T visits” f or 
patie nts w h o ar e l ost t o 
f oll o w- u p at t he visit, 
i ncl u di n g d ue t o deat h.
(a) U p date d f or 
clarit y 
( b) U p date d n o n -
r es p o nse i m p utati o n 
r ule f or re visi o n of 
pri m ar y a n d 
sec o n dar y e n d p oi nt 
defi niti o ns.
S u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 of 1 3 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
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Fe ma le partici pa nts s h o ul d 
be willi n g t o re mai n o n t he 
birt h c o ntr ol “ 7 d a ys ” i nstea d 
of 4 wee ks after t he last d ose
U p date d t o ali g n 
wit h F oll o w u p 
peri o d .
N o n -
s u bsta ntial
1. 1 S y n o psis
9. 2 Sa m ple Size 
Det er mi nati o n
Decrease i n n u m ber of 
partici pa nts w h o will be 
ra n d o mise d a n d e nter t he 6-
m o nt h ra n d o mise d p hase of 
t he trial, fr o m 2 6 0 t o 1 6 6 
patie nts .
U p date d t o ali g n 
wit h t he u p date d 
pri m ar y e n d p oi nt.
S u bsta ntial
1. 1 S y n o psis
9. 2 Sa m ple Size 
Det er mi nati o n
T he e x pecte d c orrelati o n of 
r es p o nse bet wee n sc he d ule d 
visits was i ncl u de d t o be 
0. 5 5.
U p date d t o ali g n 
wit h t he c ha n ge i n 
t he sa m ple size 
esti mati o n 
calc ulati o n met h o d 
f or t he re vise d 
pri m ar y e n d p oi nt.
S u bsta ntial
1. 1 S y n o psis
9. 2 Sa m ple Size 
Det er mi nati o n
9. 4. 3. 1 Pri mar y E n d p oi nt
9. 4. 3. 2 Sec o n dar y E n d p oi nts
(a) G E E m o del f or pri mar y
e n d p oi nt a nal yses a n d 
sec o n dar y efficac y e n d p oi nt 
a nal yses wer e a d ded. ( b) T he 
l o gistic re gressi o n m o del was 
delete d.
Det er mi ne d t o be t he 
a p pr o priate statistical 
met h o d f or 
esti mati n g res p o nses 
at eac h ti me p oi nt 
a n d fi xe d treat me nt 
effect.
S u bsta ntial
1. 1 S y n o psis
3 O bjecti ves a n d E n d p oi nts
9. 4. 3. 1 Pri mar y E n d p oi nt
9. 4. 3. 2 Sec o n dar y E n d p oi nts
A d de d “ T he treat me nt effect 
c o ncer ns t he o verall O d ds 
Rati o” .
U p date d f or clarit y
d ue t o a ne w pri mar y 
e n d p oi nt .
S u bsta ntial
1. 1 S y n o psis
3 O bjecti ves a n d E n d p oi nts
9. 4. 3. 2 Sec o n dar y E n d p oi nts
A d de d “ S Z C c o m pare d wit h 
place b o usi n g H R” a n d 
delete d “f or patie nts o n S Z C 
c o m pare d t o place b o d uri n g 
t he ra n d o mise d-wit h dra wal 
p hase” .
U p date d f or clarit y
d ue t o a ne w pri mar y 
e n d p oi nt .
S u bsta ntial
1. 1 S y n o psis
3 O bjecti ves a n d E n d p oi nts
9. 4. 3. 2 Sec o n dar y E n d p oi nts
A d de d “ S Z C c o m pare d wit h 
place b o usi n g differe nce i n 
mea n” a n d delete d “f or 
U p date d f or clarit y
d ue t o a ne w pri mar y 
e n d p oi nt .
S u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 of 1 3 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
patie nts o n S Z C c o m pare d t o 
place b o” .
1. 3 Sc he d ule of 
Act i vities
U n der “ p h ysical 
e xa mi nati o n” pr oce d ure: 
delete d visit 6 a n d o pti o nal 
visits ( 6a a n d 6 b) f or 
c o h ort 1; delete d visit 6, 6. 1, 
6. 2, a n d o pti o nal visits ( 6a 
a n d 6 b) f or c o h ort 2 .
Clarif yi n g e dit .
N o n -
s u bsta ntial
1. 3 Sc he d ule of 
Act i vities
U n der “ tar gete d p h ysical 
e xa mi nati o n, i ncl u di n g f or 
oe de ma ” pr oce d ure: delete d 
visit n u m ber 1 ( Scree ni n g) 
f or C o h orts 1 a n d 2.
Clarif yi n g e dit .
N o n -
s u bsta ntial
1. 3 Sc he d ule of 
Act i vities
F oll o w -u p peri o d was 
u p date d t o 2 6 wee ks i n 
Ra n d o mise d, D o u ble -Bli n d, 
Wit h dra wal P hase a n d P ost -
E O T F oll o w - up ta ble.
Clarif yi n g e dit .
N o n -
s u bsta ntial
1. 3 Sc he d ule of 
Act i vities
E C G at visit 1 5 was a d de d i n 
Ra n d o mise d, D o u ble -Bli n d, 
Wit h dra wal P hase a n d P ost -
E O T F oll o w -u p ta ble.
Clarif yi n g e dit .
N o n -
s u bsta ntial
1. 3 Sc he d ule of 
Act i vities
A d de d citati o n details f or 
St u d y I nter ve nti o n 
A d mi nistrati o n i n S o A .
Clarif yi n g e dit .
N o n -
s u bsta ntial
8. 1 A d mi nistrati ve 
Pr oce d ures
A d de d Secti o n 8. 1 hea der 
t hat was u ni nte nti o nall y 
o mitte d fr o m pre vi o us C S P .
F or matti n g err or .
N o n -
s u bsta ntial
8. 2. 2 Patie nt -R e p orte d 
O utc o mes ( P R Os)
A d de d t he use of pa per P R Os 
i n a d diti o n t o t he electr o nic 
P R Os .
Clarif yi n g e dit .
N o n -
s u bsta ntial
8. 4. 8 Me dicati o n Err or, Dr u g 
A b use, a n d Dr u g Mis use
(a) Secti o n na me has bee n 
u p date d t o “ Me dicati o n 
Err or, Dr u g A b use, a n d Dr u g 
Mis use”
( b) Ne w secti o ns ha ve bee n 
a d de d as f oll o ws “ 8. 4. 8. 1 
U p date d t o ali g n 
wit h i n d ustr y 
sta n dar ds.
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 of 1 3 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
Ti meli nes, 8. 4. 8. 2
Me dicati o n Err or, 8. 4. 8. 3 
Dr u g A b use a n d 8. 4. 8. 4 Dr u g 
Mis use”.
9. 1. Statistical H y p ot heses
A d de d t he details of t he 
pri m ar y h y p ot hesis teste d.
U p date d f or clarit y 
d ue t o a ne w p ri mar y 
e n d p oi nt .
S u bsta ntial
9. 2 Sa m ple Size 
Det er mi nati o n
A ne w state me nt “ T hese 
ass u me d effect sizes f or t he 
ori gi nal pri mar y e n d p oi nt 
will be retai ne d f or t he 
re vise d pri mar y e n d p oi nt 
w hic h will e val uate 
r es p o nses o bser ve d fr o m 
wee ks 5 -2 5” has bee n a d de d.
T he ori gi nal ass u me d 
effect size f or S Z C 
has bee n retai ne d b ut 
a p plie d t o t he ne w 
e n d p oi nt defi niti o n t o 
i ncrease t he p o wer of 
t he st u d y all o wi n g 
f or a re d uce d sa m ple 
size.
N o n -
s u bsta ntial
9. 4. 3. 1 Pri m ar y E n d p oi nts
A ne w state me nt “ A 
s u p ple me ntar y a nal ysis will 
be c o n d ucte d i ncl u di n g a n 
i nteracti o n ter m bet wee n 
treat me nt a n d a ti me 
de pe n de nt c o variate of d ose 
r ecei ve d ( 5 g e ver y ot her da y, 
5 g dail y, 1 0 g dail y, 1 5 g 
dail y) t o all o w f or t he effect 
of d os e t o be assesse d” has 
bee n a d de d
U p date d t o a d d a 
s u p ple me ntar y 
a nal ysis f or eac h 
d ose o pti o n.
N o n -
s u bsta ntial
9. 4. 3. 3 E x pl orat or y 
E n d p oi nts
A ne w state me nt “•
Patie nts w h o be gi n 
t he d o u ble-bli n d i nter ve nti o n 
peri o d recei vi n g 5 g e ver y 
ot her da y, 5 g dail y, or 1 0 g 
dail y” has bee n a d de d
U p date d t o a d d a 
s u pple me ntar y 
a nal ysis f or eac h 
d ose o pti o n.
N o n -
s u bsta ntial
A p pe n di x A 1: Re g ulat or y 
a n d Et hical C o nsi derati o ns
“ Re g ulat or y Re p orti n g 
Re q uir e me nts f or Seri o us 
Breac hes” ha ve bee n a d de d .
Clarif yi n g e dit .
N o n -
s u bsta ntial
A p pe n di x A 6: Disse mi nati o n 
of Cli nical St u d y Data
A state me nt i n dicati n g t hat 
“a n y res ults b ot h tec h nical 
a n d la y s u m maries f or t his 
Clarif yi n g e dit .
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 of 1 3 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
trial, will be s u b mitte d t o E U 
C TI S wit hi n a year fr o m 
gl o bal E n d of Trial Date i n 
all partici pati n g c o u ntries” 
has bee n a d de d .
A p pe n di x A 7: Data Q ualit y 
Ass ura nce
(a) A state me nt i n dicati n g 
t hat “ Astra Ze neca or 
desi g nee is res p o nsi ble f or 
me dical o versi g ht t hr o u g h o ut 
t he c o n d uct of t he st u d y” has 
bee n a d de d ( b) Rec or ds a n d 
d oc u me nts rete nti o n has bee n 
u p date d t o “ 2 5 years” i nstea d 
of 1 5 years .
Clarif yi n g e dit .
N o n -
s u bsta ntial
A p pe n di x B 4: Me dicati o n 
Err or, Dr u g A b use, a n d Dr u g 
Mis use
(a) Secti o n na me has bee n 
u p date d t o “ Me dicati o n 
Err or, Dr u g A b use, a n d Dr u g 
Mis use”
( b) Ne w secti o ns ha ve bee n 
a d de d as f oll o ws “ Dr u g 
A b use, a n d Dr u g Mis use”.
Clarif yi n g e dit .
N o n -
s u bsta ntial
A p pe n di x A 8: S o urce 
D oc u me nts
Defi niti o n of t he s o urce 
d oc u me nts has bee n pr o vi de d
Clarif yi n g e dit .
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 - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 of 1 3 2
T A B L E O F C O N T E N T S
P R O T O C O L  A M E N D M E N T SU 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 ......................................................................................................7
1
P R O T O C O L  S U M M A RY ................................................................................ 1 1
1. 1
S y n o psis ........................................................................................................... 1 1
1. 2
Sc he ma .............................................................................................................2 2
1. 3
Sc he d ule of Ac tivit ies .......................................................................................2 3
1. 4
S y n o psis Refere nces .........................................................................................3 2
2
I N T R O D U C TI O N ............................................................................................3 3
2. 1
St u d y  Ratio nale ................................................................................................3 3
2. 2
Bac k gr o u n d ......................................................................................................3 3
2. 3
Be nefit/ Ris k Assess me nt ...................................................................................3 4
2. 3. 1
Ris k Assess me nt ...............................................................................................3 6
2. 3. 2
Be nefit Assess me nt ...........................................................................................3 6
2. 3. 3
O verall Be nefit: Ris k C o ncl usi o n ......................................................................3 6
3
O BJ E C TI V E S A N D E N D P O I N T S ...................................................................3 8
4
S T U D Y  D E SI G N .............................................................................................4 1
4. 1
O verall De si g n ..................................................................................................4 1
4. 2
S ci e nt ific Rati o nale f or St u d y Desi g n ...............................................................4 3
4. 3
J ustificati o n f or D ose........................................................................................4 3
4. 4
E n d of St u d y  Defi niti on ....................................................................................4 3
5
S T U D Y  P O P U L ATI O N ....................................................................................4 4
5. 1
I ncl usi on Cri t eria ..............................................................................................4 4
5. 2
E x cl usio n  Crit eria .............................................................................................4 5
5. 3
Lifest yle C o nsi derat i ons ...................................................................................4 7
5. 3. 1
Meals a n d Dietar y  Restrict i ons .........................................................................4 7
5. 4
Scree n Fail ures ................................................................................................. 4 7
6
S T U D Y  I N T E RV E N TI O N ...............................................................................4 8
6. 1
St u d y  I nter ve nti ons A d mi nistere d .....................................................................4 8
6. 1. 1
I n vesti gati onal Pr o d ucts ....................................................................................4 8
6. 2
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...................................................4 9
6. 3
Meas ures t o Mi ni mise Bias: Ra n d o misat i on a n d Bli n di n g ................................. 5 0
6. 4
St u d y  I nter ve nti on C o m plia nce .........................................................................5 0
6. 5
C o nc o mita nt T hera p y ........................................................................................5 1
6. 5. 1
Resc ue Me dici ne ...............................................................................................5 2
6. 6
D ose M o dificat i on ............................................................................................5 2
6. 6. 1
O pe n -la bel R u n-i n P hase: .................................................................................5 2
6. 6. 2
D o u bl e- bli n d, Place b o -c o ntr olle d, Ra n d o mise d -wit h dra wal  P hase....................5 6


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 of 1 3 2
6. 7
I nter ve nti o n after t he E n d of t he St u d y..............................................................5 8
7
DI S C O N TI N U A TI O N O F S T U D Y  IN T E R V E N TI O N A N D P A R T I CI PA N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ...........................................................5 8
7. 1
Di sc o nti n uatio n of  St u d y I nter ve nti on ...............................................................5 8
7. 1. 1
Te m p orar y  Disc o nti n uati o n...............................................................................5 9
7. 2
P arti cipa nt W ith dra wal fr o m t he St u d y..............................................................5 9
7. 3
L ost t o F oll o w - u p .............................................................................................5 9
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 ..............................................6 0
8. 1
A d mi nistrati ve Pr oce d ures ................................................................................6 0
8. 2
Ef ficac y Assess me nts........................................................................................6 1
8. 2. 1
P otassi u m .........................................................................................................6 1
8. 2. 2
P ati e nt -Re p orte d O utc o mes ( P R Os) ..................................................................6 1
8. 2. 2. 1
Ka nsas Cit y Car di o m y o p at h y  Q u estio n nai re ( K C C Q).......................................6 2
8. 2. 2. 2
P ati e nt Glo b al  I mpressi o n  of Se verit y ( P GI S)...................................................6 2
8. 2. 3
Ne w Y or k Heart Ass ociat i on ( N Y H A) Class .....................................................6 2
8. 2. 4
E n d p oi nt re p orti n g o ver vie w .............................................................................6 3
8. 2. 4. 1
Cl assificat i on of Deat h ......................................................................................6 3
8. 2. 4. 2
Heart Fail ure E ve nts .........................................................................................6 3
8. 2. 5
Uri ne A nal ysis ..................................................................................................6 3
8. 3
S af et y Assess me nts ...........................................................................................6 4
8. 3. 1
P h ysical E xa mi nat i ons ......................................................................................6 4
8. 3. 2
Vit al Sig ns........................................................................................................ 6 4
8. 3. 3
Electr ocar di o gra ms ( E C Gs) ..............................................................................6 5
8. 3. 4
Cli nical Safet y  La b orat or y Assess me nts............................................................6 5
8. 4
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................................6 7
8. 4. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollect i n g A E a n d S A E I nf or mati on ................6 7
8. 4. 2
F o ll ow- u p of  A Es a n d S A Es .............................................................................6 8
8. 4. 3
Ca usalit y C o llecti on ..........................................................................................6 8
8. 4. 4
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ................................................6 9
8. 4. 5
A d verse E ve nts Base d o n E xa mi nat i ons a n d T ests ............................................6 9
8. 4. 6
Re p orti n g of Seri o us A d verse E ve nts ................................................................6 9
8. 4. 7
Pre g na nc y .........................................................................................................7 0
8. 4. 7. 1
Mate r nal E x p os ure............................................................................................7 0
8. 4. 7. 2
Pater nal  E x p os ure.............................................................................................7 1
8. 4. 8
Me dicat i on Err or , Dr u g A b u se, a n d Dr u g Mis use ..............................................7 1
8. 4. 8. 1
Ti meli nes ..........................................................................................................7 1
8. 4. 8. 2
Me dicat i on Err or ...............................................................................................7 1
8. 4. 8. 3
Dr u g A b use .......................................................................................................7 1
8. 4. 8. 4
Dr u g Mi s use .....................................................................................................7 2
8. 5
O ver d ose ..........................................................................................................7 2
8. 6
H u m a n Biol o gi c al  Sa m ples...............................................................................7 2
8. 6. 1
P har mac o ki net ics..............................................................................................7 2
8. 6. 2
I mm u n o ge nicit y Assess me nts ...........................................................................7 3
8. 6. 3
P har mac o d y na mics ...........................................................................................7 3


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 of 1 3 2
8. 7
H u m a n Biol o gi c al  Sa m ple Bio m ar kers .............................................................7 3
8. 8
O pti o nal  Ge n o mics I nitiat i ve Sa m ple................................................................7 3
8. 9
Heal t h Ec o n o mics.............................................................................................7 4
9
S T A T I S TI C A L C O N SI D E RA T I O N S................................................................7 4
9. 1
Stati stical H y p ot heses.......................................................................................7 4
9. 2
S a m ple Si ze Deter mi nat i on ...............................................................................7 4
9. 3
P o p ul at i ons f or A nal yses ...................................................................................7 5
9. 4
Stati stical A nal yses ...........................................................................................7 6
9. 4. 1
Ge neral C o nsi derati o ns .....................................................................................7 6
9. 4. 2
C O VI D -1 9 C o nsi derat i ons ................................................................................7 7
9. 4. 3
Ef ficac y ............................................................................................................7 7
9. 4. 3. 1
Pri mar y E n d p o i nt..............................................................................................7 7
9. 4. 3. 2
Sec o n dar y  E n d p oi nts ........................................................................................7 8
9. 4. 3. 3
E x pl or at or y  E n d p oi nts ......................................................................................7 9
9. 4. 4
S af et y ...............................................................................................................8 2
9. 5
I nteri m A nal yses ...............................................................................................8 2
9. 6
I n de pe n de nt Data M o nit ori n g C om mittee .........................................................8 3
1 0
S U P P O R TI N G 
D O C U M E N T A TI O N 
A N D 
O P E R A TI O N A L
C O N SI D E R A TI O N S ........................................................................................8 3
1 1
R E F E R E N C E S ...............................................................................................1 3 1
LI S T O F FI G U R E S
Fi g ure 1
St u d y  desi g n............................................................................................2 2
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of Act i vities ( S o A)....................................................................2 3
Ta ble 2
Ris k Assess me nt ......................................................................................3 6
Ta bl e 3
O bject i ves a n d E n d p oi nts.........................................................................3 8
Ta ble 4
I n vesti gati onal Pr o d ucts ...........................................................................4 8
Ta ble 5
Restricte d Me dicat i ons .............................................................................5 1
Ta ble 6
D osi n g a n d Titrati o n Sc he ma: O pe n- La bel  R u n-i n P hase ( 4 -6 Wee ks a)....5 3
Ta ble 7
S pi r o n olact o ne D ose Ti tratio n D uri n g t he 4 - t o 6-Wee k
a, O pe n-lab el , 
R u n -i n P hase ...........................................................................................5 4
Ta ble 8
S Z C a n d S pir o n o lact o ne D osi n g Base d o n Ser u m P otassi u m  (s K +), 
S er u m  Creati ni ne (s Cr), a n d S yst olic Bl o o d Press ure Stat us D uri n g t he 
O pe n -la bel, R u n-i n P hase ........................................................................5 5


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
Ta ble 9
S Z C/ Pl ace b o a n d S pir o n olact o ne D osi n g Base d o n Ser u m P otassi u m 
(s K +) Le vels D uri n g t he 6-M o nt h D o u ble -bli n d, Place b o -c o ntr olle d, 
Ra n d o mise d -wi t hdra wal  P hase ................................................................5 7
Ta ble 1 0
La b orat or y  S afet y Varia bles .....................................................................6 6
Ta ble 1 1
P o p ul at i ons f or A nal ysis ..........................................................................7 5
Ta ble 1 2
A nal ysis Peri o ds ......................................................................................7 6
LI S T O F A P P E N DI C E S
A p pe n di x A
Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsid er ati o ns .........................8 4
A p pe n di x B
A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or Rec or di n g, E val uati n g, 
F o ll ow- u p, a n d Re p orti n g ........................................................................9 0
A p pe n di x C
Ha n dli n g of H u ma n Bi o l ogical  Sa m ples ..................................................9 5
A p pe n di x D
O pti o nal  Ge n o mics I nitiat i ve Sa m ple.......................................................9 7
A p pe n di x E
Ma na ge me nt of St u d y  Pr oce d ures D uri n g t he C O VI D-1 9 Pa n de mic ......1 0 0
A p pe n di x F
Ka nsas Cit y Car di o m y o p at h y  Q u estio n nai re ( K C C Q)............................1 0 3
A p pe n di x G
P ati e nt Glo b al  I mpressi o n  of Se verit y for Heart Fail ure S y m pt o ms ........1 0 7
A p pe n di x H
Ne w Y or k Heart Ass ociat i on ( N Y H A) F u ncti onal Cl assificat i on ...........1 0 8
A p pe n di x I
E n d p oi nt Defi nit i ons ..............................................................................1 0 9
A p pe n di x J
A b bre viat i ons ........................................................................................1 1 5
A p pe n di x K
O pe n -La bel  Visit Flo w Di a gra ms ..........................................................1 1 8
A p pe n di x L
Pr ot oc ol  A me n d me nt Hist or y................................................................. 1 2 0








Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 of 1 3 2
i.
C o h ort 1 ( 4 wee ks): P atie nts w h o are H K at st u d y e ntr y:

H K C orrecti o n P hase: Pati e nts will start S Z C o n Da y 1 at a d ose 
of  1 0 g t hree ti mes dail y f or u p t o 4 8 h o urs u ntil s K + 3 . 5-
5. 0 m E q/ L ( N K). N O T E : Pati e nts w h o d o n ot ac hie ve N K 
d uri n g t he 4 8 -h o ur c orrecti o n p hase will be disc o nti n ue d fr o m 
t he st u d y.

s K + Mai nte na nce P hase: Patie nts w h o ac hie ve N K will c o nti n ue 
o n S Z C 1 0 g o nce dail y a n d t he n titrate bet wee n 5 g e ver y  ot her 
da y a n d 5 t o 1 5 g dail y t o mai ntai n s K + 3. 5 -5. 0 m E q/ L per 
pr ot oc ol  instr ucti o ns. 

S pi r o n olact o ne: Patie nts will ini tiate or u p-titrate s pir o n olact o ne 
be gi n ni n g o n Da y  2 or 3 w he n t he y bec o me N K o n S Z C . 
S pi r o n olact o ne will be s yste mat icall y u p-titrate d t o a tar get d ose 
of  5 0 mg dail y , as t olerate d per pr ot oc ol instr ucti o ns. N O T E: 
P ati e nts w h o de vel o p H K o n s pir o n o lact o ne 5 0 mg dail y w hile 
recei vi n g ma xi m u m d ose S Z C ( 1 5 g) b ut were N K o n 
s pir o n olact o ne 2 5 mg dail y  ma y re mai n i n t he o pe n-la bel, r u n-i n 
p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o 
s pir o n olact o ne 2 5 mg a n d bec o m e N K a gai n.
ii.
C o h ort 2 ( 4 -6 wee ks): P atie nts w h o are N K at st u d y e ntr y:

S pi r o n olact o ne: Patie nts will ini tiate or u p-titrate s pir o n olact o ne 
be gi n ni n g o n Da y  1. S pir o n olact o ne will be s yste mat icall y u p-
titrate d t o a tar get d ose of 5 0 m g dail y, as t olerate d per pr ot oc ol 
i nstr uctio ns.

H K C orrecti o n P hase: Pati e nts w h o de vel o p H K d uri n g t he first 
4 wee ks of t he r u n -i n p hase will be gi n S Z C 1 0 g t hree ti mes 
dail y  for u p t o 4 8 h o urs u ntil s K + 3. 5-5. 0 m E q/ L. N O T E : 
P ati e nts w h o d o n ot ac hie ve N K d uri n g t he 4 8 -h o ur c orrecti o n 
p hase will be disc o nt i n ue d fr o m t he st u d y.

s K + Mai nte na nce P hase: Patie nts w h o ac hie ve N K will c o nti n ue 
o n S Z C 1 0 g dail y  a n d t he n titrate bet wee n 5 g e ver y ot her da y 
a nd 5 t o 1 5 g dail y  t o mai ntai n s K + 3. 5 -5. 0 m E q/ L per pr ot oc ol  
i nstr uctio ns.
iii.
N O T E : 

P ati e nts i n C o h ort 2 w h o d o n o t de velo p H K d uri n g t he first 
4 wee ks (a n d as a res ult d o n ot meet t he re q uire me nt t o recei ve 
S Z C) will be disc o nt i n ue d fr om t he st u d y d uri n g t he r u n-i n p hase.

P ati e nts w h o de vel o p H K o n s pir o n o lact o ne 5 0 mg dail y w hile 
recei vi n g ma xi m u m d ose S Z C ( 1 5 g), b ut were N K o n 
s pir o n olact o ne 2 5 mg dail y  ma y re mai n i n t he o pe n-la bel, r u n-i n 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 3 2
p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o 
s pir o n olact o ne 2 5 mg a n d bec o m e N K a gai n.
b.
D o u bl e- bli n d, place b o -c o ntr olle d, ra n d o mise d -wi t hdra wal p hase ( 6 m o nt hs):
i. P ati e nts w h o are N K o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y at 
t he e n d of t he r u n-i n p hase will be ra n d omise d 1: 1 t o S Z C or place b o
stratifie d acc or di n g t o t he prese nce of H K/ N K ( o pe n la bel C o h ort 1 vs. 
C o h ort 2) at st u d y  e ntr y, c o nti n ui n g o n t he d ose t he y were bei n g 
a d mi nistere d at t he e n d of t he r u n- i n p hase.

I nstr uctio ns o n h o w t o ma na ge pat ient s w h o d o n ot q ualif y f or 
ra n d omisat i on d ue t o h y per kalae mia are detaile d i n Secti o n  6. 6. 1 .

C o m plete i nf or m at i on re gar di n g S Z C a n d s pir o n o lact o ne d osi n g is 
pr o vi de d i n Sect i on  6. 6 .
3.
F o ll ow- u p peri o d ( 1 wee k) after t he E O T visit: s K + will be c hec ke d 7 da ys after last d ose 
of  st u d y dr u g ( S Z C or place b o).
Discl os ure St ate me nt: T hi s is a parallel-gr o u p treat m e nt st u d y wit h 2 ar ms t hat is partici pa nt -
a n d i n vest i gat or-bli n de d.
N u m ber of P artici p a nts:
A p pr o xi matel y  4 0 0 p atie nts meet i n g t he i ncl usi on criteria will e nter t he o pe n-label p hase, a n d 
a p pr o xi matel y 1 6 6 of  t hese patie nts w h o are N K ( 3. 5 -5. 0 m E q/ L) o n S Z C a n d recei vi n g 
s pir o n olact o ne ≥2 5 m g dail y at t he e n d of t he 4 - t o 6-wee k r u n -i n p hase will be ra n d omise d 
a n d e nter t he 6- m o nt h ra n d o mise d p hase of t he trial.
M ai n I ncl usi o n Criteri a:

A d ults a ge d ≥1 8 ye ars

P otassi u m  a n d esti mate d gl omer ular filtrat i on rate (e G F R):

C o h ort 1: sK + 5. 1 -5. 9 m E q/ L at scree ni n g/st u d y  e nr ol me nt a n d 
e G F R ≥3 0 m L/ mi n/ 1. 7 3 m 2; o r

C o h ort 2: N or m o kalae mic (s K + 3. 5 -5. 0 m E q/ L) at scree ni n g a n d ‘at ris k’ of 
de vel o pi n g H K defi ne d as a n y of t he f oll o wi n g :
Ha ve a hist or y  of H K (sK + > 5. 0 m E q/ L) wi t hi n t he prior 3 6 m o nt hs a n d 
e G F R ≥3 0 m L/ mi n/ 1. 7 3 m 2; o r
s K + 4. 5-5. 0 m E q/ L a n d e G F R 3 0 t o 6 0 m L/ mi n/ 1. 7 3 m 2 ; o r
s K + 4. 5-5. 0 m E q/ L a n d a ge > 7 5 y ears

D oc u m e nte d dia g n osis of s y m pt o mat ic H Fr E F (Ne w Y o r k Heart Ass ociati o n [N Y H A ]
class II -I V), w hic h has bee n prese nt f or at least 3 m ont hs

Left ve ntric ular eject i on fracti on ( L V E F) ≤4 0 % (a n y  meas ure me nt ma de wit hi n t he 
past 2 4 m o nt hs usi n g ec h ocar di o gra p h y, m ult i ple gate ac q uisiti on sca n, c o m p uter 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 3 2
t o mo gra p h y sca n ni n g, ma g net ic res o na nce i ma gi n g, or ve ntric ular a n gi o gra p h y is 
acce pta ble, pr o vi de d n o s u bse q ue nt meas ure me nt a b o ve 4 0 %)

Recei vi n g a n gi ote nsi n -c o n verti n g e nz y me i n hi bit or ( A C Ei), a n giote nsi n II rece pt or 
bl oc ker ( A R B), or a n gi ote nsi n rece pt or-Ne pril ysi n i n hi bit or ( A R Ni; e g, E ntrest o ®
[sac u bitril/ valsarta n])

N ot o n, or o n l o w- d ose s pir o n olact o ne or e plere n o ne ( < 2 5 mg dail y).  

Recei vi n g beta - bl oc ker u nless c o ntrai n dicate d.
I ncl usi o n Criteri a f or Pr ocee di n g t o t he 6-m o nt h R a n d o m ised- Wit h dr a w al Tre at me nt 
P h ase:

N K ( 3. 5 -5. 0 m E q/ L) o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y at t he e n d of 
t he r u n-i n p hase.
Se x

F e male:

Fe male partici pa nts of c hil d beari n g p ote ntial m ust ha ve a ne gat i ve pre g na nc y 
test (ser u m).

Fe male partici pa nts m us t be 1 year p ost -me n o pa usal, s ur gicall y sterile, or usi n g 
o ne hi g hl y effect i ve f or m of birt h c o ntr ol ( defi 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 nt l y a n d c orrectl y). 
T he y  s ho 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 o f 4 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 nt il 7 da ys after t he last d ose.
I nf or me d C o nse nt

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 mplia nce wi t h t he re q uir e me nts a n d restrict i ons liste d i n t he i nf or me d c o nse nt f or m 
(I C F) a n d i n t his C S P

P r o visi on of si g ne d a n d date d writte n O pti o nal Ge net ic Researc h I nf or mati on 
i nf or me d c o nse nt prior t o c ollect i on of sa m ples f or o pti o nal ge net ic researc h t hat 
s u p p orts Ge n o mic I nitiati ve.
M ai n E xcl usi o n Criteri a:

Heart fail ure ( H F) d ue t o restrict i ve car di om y o pat h y , acti ve m yo c ar di tis, c o nstrict i ve 
p eri car ditis, h y pertr o p hic ( o bstr ucti ve) car di om y o pat h y , or se vere ste n otic val ve 
di sease as a pri mar y c a us e of H F

C urre nt i n pat ient  h os pit alisatio n wi t h u nsta ble H F , defi ne d as a n y of t he f o ll owi n g:
a.
S B P < 9 5 m m H g d uri n g t he 6 h o urs prior t o scree ni n g.
b.
I ntra ve n o us di uret ic t hera p y d uri n g t he 1 2 h o urs pri or t o scree ni n g.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 of 1 3 2
c.
Use of i ntra ve n o us i n otr o pic dr u gs d uri n g t he 2 4 h o urs pri or t o scree ni n g.
d.
Recei ve d mec ha nical circ ulat or y  s u p p ort d uri n g t he 4 8 h o urs pri or t o 
scree ni n g.

T y pe 1 m y ocar dial  infarcti o n ( MI), u nsta ble a n gi na, or str o ke wit hi n 1 2 wee ks pri or t o 
e nr o l me nt

C or o nar y  re vasc ularisatio n ( perc uta ne o us c or o nar y i nter ve nt i on [ P CI] or c or o nar y  
arter y b y pass grafti n g [ C A B G]) or val v ular re pair/re place me nt wit hin 1 2 wee ks pri or 
t o e nr ol me nt or pla n ne d t o u n der g o a n y of t hese pr oce d ures

I mpla ntati o n of  a Car diac Res y nc hr o n isatio n T hera p y  ( C R T) de vice withi n 1 2 wee ks 
pri or t o e nr ol me nt or i nte nt t o perf or m atrial fi brillati o n a blat i on or t o i m pla nt a C R T 
de vice

Pre vi o us car diac tra ns pla ntati o n or i m pla ntati o n of a ve ntric ular assista nce de vice 
( V A D) or si milar de vice, or tra ns pla ntati o n or i m pla ntati o n e x pecte d after 
ra n d om isatio n

S y m pt o m atic or u nc o ntr olle d atrial fi brillat i on des pi te treat me nt, or as y m pt o mat ic 
s ustai ne d ve ntric ular tac h ycar dia. S u bjects wit h atrial fi brillat i on c o ntr olle d b y  
me dicat i on are per mitte d.

Cli nicall y si g nifica nt bra d y car dia, as per i n vest i gat or’s j u d ge me nt, or sec o n d- or 
t hir d-de gree heart bl oc k wit h o ut a pace ma ker

Q Tc(f) > 5 5 0 msec

Hi st or y of Q T pr olo n gat i on ass oci ate d wit h ot her me dicati ons t hat re q uire d 
di sc o nti n uati on of t hat me dicati o n

C o n ge nital l o n g Q T s y n dr o me

S y m pt o m atic h y p ote nsi o n or s y st olic bl o o d press ure ( S B P) < 9 0 m m H g o n 
3 c o nsec uti ve meas ure me nts

Recei vi n g dial ysis or a n tici pate d b y t he i n vesti gat or t o re q uire dial ysis t hera p y withi n 
3 m o nt hs

> 3 0 % decli ne i n e G F R wit hi n t he past 3 0 da y s; if la b orat or y res ults are n ot a vaila ble, 
t he n e xcl u de if ac ute ki d ne y inj ur y  ( A KI) wit hi n past 3 0 da ys base d o n me dical hist or y 
or me d ical rec or ds

Cli nicall y si g nifica nt h y p o natr ae mia i n t he o pi ni o n of t he i n vest i gat or

Hi st or y of g y nec o mastia d ue t o s pir o n olact o ne t hera p y re q uirin g d o w n -titratio n or 
di sc o nti n uati on of s pir o n o lact o ne, or s witc h t o a differe nt M R A

A d dis o n’s disease 

Ele vate d p otassi u m d ue t o m eas ure me nt i n hae m o l yse d sa m ple ( m ust re peat bl o o d 
dra w)


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 of 1 3 2

A n y c o n dit i on o utsi de t he car di o vasc ular ( C V) a n d re nal disease area, s uc h as, b ut n ot 
li mite d t o, mali g na nc y with a life e x pecta nc y o f less t ha n 1 year base d o n 
i n vesti gat or’s cli nical j u d ge me nt.
Pri or/c o nc o mit a nt t her a p y:

T he f o ll owi n g p otassi u m -r elate d prior/c o nc o mita nt t hera p y :

Treat me nt wit h p otassi u m -s pari n g diuret ics ot her t ha n s pir o n olact o ne or 
e plere n o ne (e g, tria mtere ne, a milori de) wi t hi n 7 da ys pri or t o e nr ol me nt

P ot assi u m-bi n di n g resi ns s uc h as s o di u m p ol yst yr e ne s ulf o nate ( S P S; e g, 
Ka ye xalate ® ) or calci u m p ol ystyr e ne s ulf o nate ( C P S; e g, Res o ni u m ® ), t he 
catio n e xc ha n ge p ol y mer, patir o mer s or bite x calci u m ( Veltassa ® ), or S Z C 
wi t hi n 7 da ys pri or t o e nr ol me nt

P otassi u m  s u p ple me nts wit hi n 7 da ys prior t o e nr ol me nt.  
C o nc urre nt Cli nic al St u d y E x perie nce

P arti cip ati o n i n a n ot her cli nical st u d y  wit h a n i n vestigat i onal pr o d uct (I P) a d mi nistere d 
i n t he last m o nt h.1
Ot her E xcl usi o ns

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 sit e).

J u d ge me nt b y t he i n vestigat 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 mpl y wit h st u d y  pr oce d ures, restricti o ns a nd 
re q uire me nts.

Pre vi o us e nr ol me nt i n t he prese nt st u d y . 

F or w o m e n o nl y - breast -fee di n g or pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y.

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) wi t hi n 2 
wee ks pri or t o e nr ol me nt (see  A p pe n di x E ), t he partici pa nt ca n n ot be e nr olle d i n t he 
st u d y.
I nter ve nti o n Gr o u ps a n d D ur ati o n:
T ot al  d uratio n of  st u d y p artici pat i on for eac h pati e nt will be a p pr o xi matel y 8 m o nt hs. T he 
brea k d o w n of d urati o n b y peri o d/ p hase ca n be f o u n d i n t he O verall Desi g n , Sectio n 4. 1 , alo n g 
wi t h d osi n g at eac h p hase.
D at a M o nit ori n g C o m mittee ( D M C): Y es. 
T he r ol e of t he i n de pe n de nt D M C (i D M C) i n t his trial is t o e val uate partici pa nt safety 
t hr o u g h o ut t he st u d y a n d t o e ns ure t he i nte grity,  vali dity,  a n d scie ntific merit of t he st u d y. T he 
                                               
1 P artici 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 - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 of 1 3 2
r oles a n d res p o nsi bilit ies of t he i D M C are o utli ne d i n t he res pecti ve C harter .
St atistic al Met h o ds:
A nal yses will be f urt her detaile d i n t he Statist ical A nal ysis Pla n ( S A P), w hic h will be fi nalise d 
pri or t o t he u n bli n di n g a n d l oc ki n g o f t he cli nical data base.
Pri mar y E n d p o i nt
Per vi sit, res p o nse is defi ne d b y 

Ha vi n g p otassi u m (s K +) wit hi n 3. 5 -5. 0 m E q/ L as assesse d b y  ce ntral la b orat or y AN D

Bei n g o n s pir o n o lact o ne ≥2 5 m g dail y A N D

N ot usi n g resc ue t hera p y for H K d uri n g t he last m o nt h
Res p o nse mea ns all t hree b ullet p oi nts h o l d. N o n-res p o nse is i n dicate d if at least o ne b ullet 
p oi nt d oes n ot h ol d.
A d dit i onall y , for eac h assess me nt visit, n o n -res p o nse is i n dicate d f or patie nts w h o are l ost t o 
f oll ow- u p at t he visit, i ncl u di n g d ue t o deat h. T he m o nt hl y  visits are use d f or res p o nse 
assess me nt fr o m m o nt h 1 t o m o nt h 6 .

T he treat me nt effect c o ncer ns t he o verall O d ds Rati o a n d will be a nal yse d usi n g a 
Ge neralize d Est i mati n g E q uati o n (G E E ) m o d el , with a n esti mate of res p o nse f or eac h 
ti me p oi nt a n d fi xe d treat me nt effect, usi n g a bi n omial distri b ut i on wi t h e xc ha n gea ble 
c orrelat i on mat rix a n d teste d usi n g a t w o -si de d al p ha = 0. 0 5. T he o d ds rati o will be 
deri ve d t o get her wit h t w o -si de d 9 5 % c o nfi de nce i nter vals. Se nsiti vity a nal yses will be 
pre -s pecifie d i n t he S A P a n d will deter mi ne t he i m pact of treati n g deat hs a n d l ost t o 
f oll ow- u p as a missi n g res p o nse. As a mi ni m u m, t hese will use t he P P S p o p ulat i on 
a n d will treat patie nts l ost t o f o ll ow- u p a n d deat h s as a missi n g res p o nse.
Sec o n dar y  Efficac y E n d p oi nts 
Stati stical a nal yses of t he sec o n dar y e n d p oi nts will i ncl u de str o n g c o ntr ols f or m ulti plicity. 
T he details o f t his a p pr oac h will be detaile d i n t he S A P.
1. Per vi sit, res p o nse is defi ne d b y 

H avi n g p ot assi u m (s K +) wit hi n 3. 5 -5. 0 m E q/ L as assesse d by ce ntr al l a b or at ory A N D

Bei n g o n t he s a me s pir o n ol act o ne d ose as t hey w ere at r a n d o mi sati o n A N D

N ot usi n g resc ue t her a py f or H K d uri n g t he l ast m o nt h
Res p o nse mea ns all t hree b ullet p oi nts h o l d. N o n-res po nse is i n dicate d if at least o ne b ullet 
p oi nt d oes n ot h ol d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 0 of 1 3 2
A d dit i onall y , for eac h assess me nt visit, n o n -res p o nse is i n dicate d f or patie nts w h o are l ost t o 
f oll ow- u p at t he visit, i ncl u di n g d ue t o deat h. T he m o nt hl y  visits are use d f or res p o nse 
assess me nt fr o m mo nt h 1 t o m o nt h 6 .
T he treat me nt effect c o ncer ns t he o verall O d ds Rati o a n d will be a nal yse d usi n g a G E E 
m o d el , wit h a n esti mate of res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt effect, usi n g a 
bi n o mial distri b ut i on wi t h e xc ha n gea ble c orrelat i on matri x. Pati e nts w h o are lost t o f oll o w -u p, 
i ncl u di n g d ue t o deat h, pri or t o a n y s pecific assess me nt visits will be treate d as n o n-res p o nse 
f or t h ose assess me nt visits. T he c o m m o n o d ds rati o will be deri ve d t o get her wit h t w o -si de d 
9 5 % c o nfi de nce i nter vals.
2.
Per vi sit, res p o nse is defi ne d b y 

Bei n g o n s pir o n o lact o ne ≥2 5 m g dail y
Res p o nse mea ns b ullet p oi nt h ol ds . N o n-res p o nse i n dicates b ullet p oi nt d oes n ot h ol d.
A d dit i onall y , for eac h assess me nt visit, 
n o n- res p o nse is i n dicate d f or patie nts w h o are l ost t o f oll ow- u p at t he visit, i ncl u di n g d ue t o 
deat h.
T he m o nt hl y  visits are use d f or res p o nse assess me nt fr o m mo nt h 1 t o m o nt h 6. 
3.
T he treat me nt effect c o ncer ns t he o verall O d ds Rati o a n d will be a nal yse d usi n g a G E E 
m o d el , wit h a n esti mate of res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt effect, usi n g a 
bi n o mial distri b ut i on wi t h e xc ha n gea ble c orrelat i on matri x. Pati e nts w h o are lost t o 
f oll ow- u p, i ncl u di n g d ue t o deat h, pri or t o a n y  s pecific assess me nt visits will be treate d as 
n o n-res p o nse f or t h ose assess me nt visits. T he c o m m o n o d ds rati o will be deri ve d t o get her 
wi t h t w o-si de d 9 5 % c o nfi de nce i nter vals.
4.
Ti me t o first H K e pis o de w it h H K defi ne d as s K + > 5. 0 m E q/ L as assesse d by ce ntr al 
l a b or at ory S Z C c o m pare d wi t h place b o usi n g H R a n d will be a nal yse d usi n g a 
ca use-s pecific pr o p ortio nal  hazar ds mo d el  wit h deat h treate d as a c o m peti n g ris k, 
ra n d omise d treat me nt as a n i n de pe n de nt fact or, a n d o pe n-lab el  p hase c o h ort as a 
stratificati on fact or. T he hazar d rati o a n d t w o-si de d 9 5 % c o nfi de nce i nter val will be 
prese nte d. Gra p hicall y , t he treat me nt differe nce will be dis pla ye d usi n g c u m ulat i ve 
i nci de nce c o m peti n g ris k c ur ves.
5.
Ti me t o fir st i nst a nce of decre ase or disc o nti n u ati o n of s pir o n ol act o ne d ose d ue t o H K
S Z C c o m pare d wit h pl ace b o usi n g H R a n d will be a nal yse d usi n g a ca use-s pecific 
pr o p orti o nal hazar ds re gressi on m o d el  wit h deat h treate d as a c o m peti n g ris k, ra n d omise d 
treat me nt as a n i n de pe n de nt fact or, a n d o pe n-label p hase c o h ort as a stratificat i on fact or. 
T he hazar d rati o a n d t w o -side d 9 5 % c o nfi de nce i nter val will be prese nte d. Gra p hicall y , 
t he treat me nt differe nce will be dis pla ye d usi n g c u m ulat i ve i nci de nce c om peti n g ris k 
c ur ves.
6.
C h a n ge i n K C C Q -C S S at t he E O T visit ( a p pr oxi m ately 6 m o nt hs p ost -r a n d o mis ati o n) 
fr o m r a n d o mis ati o n S Z C c o m pare d wit h place b o usi n g differe nce i n mea n a n d will  be 
a nal yse d wit h re peate d meas ures a nal ysis of c o varia nce ( A N C O V A) m o dels wit h fi xe d 
t er ms f or treat me nt, K C C Q-C S S at ra n d o misat i on , o pe n-lab el  p hase c o h ort, visit, a n d 
treat me nt b y visit int eractio n.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 1 of 1 3 2
S af et y E n d p o i nts
S af et y e n d p o i nts will be a nal yse d usi n g descri pti ve met h o ds.
S a m ple Size:
S a m ple size deter mi nat i on is base d o n t he pri mar y  o bjective, ie, To  e val uate t he efficac y of 
S Z C as c o m pare d wit h place b o i n kee pi n g p otassi u m le vels wit hi n t he n or mal ra n ge 
( 3. 5-5. 0 m E q/ L) w hile o n s pir o n o lact o ne ≥2 5 m g dail y wit h o ut assista nce of resc ue t hera p y 
f or H K. Ass u mi n g t hat t he pr o ba bilit y of  res p o nse is 0. 7 i n t he S Z C gr o u p a n d 0. 5 i n t he 
pl ace b o gr o u p, a n d a c orrelati o n of 0. 5 5 bet wee n sc he d ule d visit s, t he n a G E E m o del, wit h a n 
esti mate of res p o nse f or eac h ti me p o i nt a n d fi xe d treat me nt effect, usi n g a bi n omial 
di stri b uti on wi t h e xc ha n gea ble c orrelati o n matri x wi t h a 5 % t w o-si de d si g nifica nce le vel a n d 
9 0 % p o wer will re q uire 1 5 8 patie nts t o be ra n d o m ised. Cli n ical data s u g gests a deat h rate of 
1 0 per 1 0 0 pers o n y ears; t heref ore, a p pr o xi matel y 8 deat hs are e x pecte d. To e ns ure n = 1 5 8 i n 
t he mai n se nsit i vity a nal ysis f or t he pri mar y e n d p oi nt, t he sa mple size will be i ncrease d t o 
a p pr o xi matel y 1 6 6 ra n d o mise d patie nts.
A n al ysis P o p ul ati o ns:

Scree ne d Set: all pat ient s w h o were scree ne d f or i ncl usi o n i nt o t he st u d y.

S afet y Set O pe n ( S S O): all patie nts w h o e nter t he o pe n-lab el  p hase a n d recei ve at least 
o ne d ose of S Z C .

S afet y Set R a n d o m ised ( S S R): all ra n d o mised p ati e nts w h o receive d at l east o ne d ose of 
eit her S Z C or place b o. Safet y a nal yses will be a nal yse d usi n g t he S S O a n d S S R 
p o p ul at i ons .

F ull A n al ysis Set ( F A S): all ra n d o m ised pat ient s, irres pecti ve of treat me nt a n d a n y 
pr ot oc ol  de viati ons, w h o ha ve o ne or m ore p ost ra n d o m isatio n ce ntral  la b orat or y s K + 
meas ure me nts a vaila ble. T he F A S will be use d as t he pri mar y p o p ulat i on f or t he pri mar y 
a n d sec o n dar y efficac y e n d p oi nts.

Per Pr ot oc ol Set ( P P S): F A S patie nts wit h o ut a n y i m p orta nt pr ot oc ol de viat i ons lea di n g 
t o e xcl usi o n fr om t he P P S.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 2 of 1 3 2
1. 2
Sc he m a
Fi g ure 1
St u d y desi g n
a
C o h ort assi g n me nt is base d o n l ocal la b s K + o n Visit 1.
b
Patie nts w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w h ile recei vi n g ma xi m u m d ose S Z C ( 1 5 g) ,b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y 
re mai n i n t he o pe n-la bel, r u n-i n p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K a gai n. 
c
S Z C 1 0 g t hree ti mes dail y f or u p t o 4 8 h, t he n S Z C 1 0 g o nce dail y, titrate if nee de d per pr ot oc ol t o mai ntai n s K + 3. 5 -5. 0 m E q/ L (ra n ge: 5 g e ver y ot her da y  
t o 1 5 g dail y.
A b bre viati o ns: e G F R = esti mate d gl o mer ular filtrati o n rate; H K = h y per kalae mia; s K + = ser u m p otassi u m; S Z C = s o di u m zirc o ni u m c ycl osilic ate; 
W N L
= wit hi n n or mal li mits.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 1 3 2
1. 3
Sc he d ule of Acti vities
Ta ble 1
Sc he d ule of Acti vities ( S o A)
Scr ee ni n g a n d O pe n -L a bel R u n -i n P h ase – C o h ort 1
Pr oce d ure
Scree ni n g
O pe n -L a bel I nter ve nti o n Peri o d ( 4 wee ks)
Det ails i n 
C S P secti o n
Visit a
1 
2
2. 1
( o pti o n al)b
2. 2 c
3  
4  
5 
6 h
6 a
( o pti o n al)i
6 b
( o pti o n al)i
Wee k
-2 t o 1
1 
1 
1 
2 
3 
4 
5
6
7
Tre at me nt D a y ( Visit Wi n d o w)
-1 4 t o 1
1 
2 
3
7 
( ± 2)
1 4 ( ± 3) 
2 1 ( ± 2) 
2 8 ( ± 3)
3 5 ( ± 3) 
4 2 ( ± 3)
I nf or me d c o nse nt
X
Secti o n  5. 1
I ncl usi o n a n d e xcl usi o n criteria
X
X  
X
X
Secti o ns  5. 1
a n d 5. 2
R o uti ne Cli nic al Pr oce d ures
De m o gra p h y
X
P h ysical e xa mi nati o n
X
Secti o n  8. 3. 1
Tar gete d p h ysical e xa mi nati o n, i ncl u di n g 
f or oe de ma
X  
X
X
Secti o n  8. 3. 1
Me dical hist or y a n d c o m or bi dities
X
Secti o n  5. 2
C o nc o mita nt me dicati o n (i ncl u di n g di uretic 
use)
X  
X  
X  
X  
X  
X  
X  
X
X
X
Secti o n  6. 5
Vital si g ns (i ncl u di n g B P)
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Secti o n  8. 3. 2
Hei g ht 
X
Secti o n  8. 3. 1
Wei g ht
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Secti o n  8. 3. 1
E C G i ncl u di n g Q Tc(f)
X
X  
X
X
Secti o n  8. 3. 3
R o uti ne S afet y Me as ure me nts
A d verse e ve nts ( A Es)
X  
X  
X  
X  
X  
X  
X  
X
X
Secti o n  8. 4


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 1 3 2
A b bre viati o ns: B P = bl o o d press ure; C S P = cli nical st u d y pr ot oc ol; E C G = electr ocar di o gra m; H K = h y per kalae mia; K C C Q = Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire; N K = n or m o kalae mic ; 
P GI S = Patie nt Gl o bal I m pressi o n of Se verit y; s Cr = ser u m creati ni ne; s K + = ser u m p otassi u m ( 3. 5 -5. 0 m E q/ L ); S Z C = s o di u m zirc o ni u m c ycl osilicate; W O C B P = w o me n of c hil d beari n g p ote ntial.
a
U nsc he d ule d visits ca n occ ur f or patie nts w h o ha ve a s p o nta ne o us A E re p ort, are n ot feeli n g well f or a n y reas o n, or if t he y ha ve h y p o- or h y per kalae mia t hat re q uires f oll o w -u p pri or t o t he ne xt 
sc he d ule d visit.
b
Visit 2. 1 is o pti o nal f or i n vesti gat or’s w h o w o ul d li ke t o c hec k t he patie nt’s ser u m K + le vel 2 4 h o urs after st arti n g S Z C 1 0 g TI D c orrecti ve d osi n g.  
c
F or patie nts w h o c o m plete t he o pti o nal 2. 1 visit, o nl y t h ose patie nts w h o are h y per kal a e mic at t his visit ha ve t o ret ur n f or visit 2. 2 t o ha ve t heir ser u m K + le vel rec hec ke d.
d
L ocal la b orat or y f or C he m 7 pa nel (e g, s Cr a n d s K+; c o h ort assi g n me nt is base d o n l ocal la b s K + o n Visit 1) , a n d uri nal ysis ( di pstic k) ; c e ntral la b orat or y f or c he mistr y, meta b olic, re nal pa nels , a n d 
bi o mar kers f or t he data a nal yses.
Ser u m pre g na nc y test ( W O C B P o nl y)
X
Secti o n  5. 1
Uri ne pre g na nc y test ( pre -d ose)
X
Secti o n  8. 3. 4
Cli nical safet y la b orat or y assess me nts 
(i ncl u di n g s K + a n d s Cr)d
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Secti o n  8. 3. 4
Bi o m ar ker A n al yses
Bi o mar ker bl o o d a n d uri ne c ollecti o n
X
X  
X
X
Secti o n  8. 7
First m or ni n g s p ot uri ne ( 3 c o nsec uti ve 
da ys) e
X
X
X
X
Secti o n  8. 2. 5
Ge n o mics I niti ati ve o pti o n al, e x pl or at or y ge netic s a m ple
Bl o o d sa m ple
X
Secti o n  8. 8
St u d y S pecific Assess me nts f
K C C Q
X
X  
X
X
Secti o n  8. 2. 2
P GI S
X
X  
X
X
Secti o n  8. 2. 2
St u d y I nter ve nti o n A d mi nistr ati o n
St u d y  i nter ve nti o n dis pe nsati o n ( o pe n-la bel 
S Z C) g
X
X  
X  
X
X
Secti o n  6. 6. 1
S pir o n olact o ne h
X
X  
X
X  
X  
X  
X
X
X
Secti o ns 
6. 6. 1 a n d 
6. 6. 2
Ra n d o misati o n ( 1: 1 S Z C or place b o) j
X
X
X
Secti o n 6. 6. 2
St u d y  i nter ve nti o n dis pe nsati o n ( d o u ble-
bli n d S Z C or place b o)
X
X
X
Secti o n  6. 6. 2


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 5 of 1 3 2
e
Uri ne c ollecti o n kits will be ha n de d o ut at t he visit bef ore t he visit w he n uri ne is t o be c ollecte d t o all o w t he s u bject t o c ollect uri ne o n t he 3 c o nsec uti ve m o r ni n gs i m me diatel y prece di n g t he visit. 
I n t he e ve nt t hat a s u bject f or gets t o c ollect a n y of t he 3 first m or ni n g v oi ds, t he sa m ples ca n i nstea d be c ollecte d o n t he c o nsec uti ve 3 m or ni n gs i m me diatel y f oll o wi n g t he visit, a n d deli vere d t o 
t he st u d y site.
f
B ot h K C C Q a n d P GI S will be a d mi nistere d i n pa per or usi n g a site -base d electr o nic de vice. It is preferre d t hat patie nt -re p orte d o utc o me (P R O ) q uesti o n naires are c o m plete d pri or t o a n y ot her 
st ud y pr oce d ures a n d bef ore disc ussi o n of disease pr o gressi o n t o a v oi d biasi n g t he patie nt’s res p o nses t o t he q uesti o ns.
g
H K C orrecti o n P hase : Start o n Da y 1, S Z C 1 0 g t hree ti mes dail y f or u p t o 4 8 h o urs u ntil N K. 
Mai nte na nce P hase : Patie nts c o nti n ue o n S Z C 1 0 g dail y a n d t he n titrate bet wee n 5 g e ver y ot her da y a n d 5-1 5 g dail y t o mai ntai n N K. 
h
T he assess me nts u ni q ue t o Visit 6 ( na mel y t he tar gete d p h ysical e xa ms, bi o mar ker a nal yses, a n d t he K C C Q & P GI S ) will o nl y occ ur o nce i n de pe n de ntl y if t he patie nt atte n ds all o pti o nal visits ( 6a 
a n d 6 b).
i
Patie nts will i nitiate or u p -titrate s pir o n olact o ne be gi n ni n g o n Da y 2 or 3 w he n t he y bec o me N K. S pir o n olact o ne will be s yste maticall y u p -titrate d t o a tar get d ose of 5 0 m g dail y as detaile d i n 
Secti o n  6. 6. 1 . Patie nts w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile recei vi n g ma xi m u m d ose S Z C ( 1 5 g) , b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n-la bel, r u n-
i n p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K a gai n.
j
At e n d of r u n -i n p hase, patie nts w h o are N K o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y will be ra n d o mise d 1: 1 t o S Z C or place b o o n d o se t he y were ta ki n g at e n d of r u n-i n p hase.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 6 of 1 3 2
Scr ee ni n g a n d O pe n -L a bel R u n -i n P h ase – C o h ort 2
Pr oce d ure
Scree ni n g
O pe n -L a bel I nter ve nti o n Peri o d ( 4 -6 we e ks)
Det ails i n C S P 
secti o n
Visit a
1 
2 
3
3. 1 b
o pti o n al
3. 2
4
4. 1 b
o pti o n al
4. 2
5
5. 1 b
o pti o n al
5. 2
6 j, k
6. 1 j, k
6. 2 j, k
6 a
( o pti o n al)i
6 b
( o pti o n al)i
W e e k
-2 t o 1
1 
2 
2 
2
3 
3 
3
4 
4 
4
5 
6 
7 
8
9
Tre at me nt D a y ( Visit 
Wi n d o w )
-1 4 t o 1
1
7 
( ± 2)
8 
9
1 4
( ± 3)
1 5 
1 6
2 1
( ± 2)
2 2 
2 3
2 8 
( ± 3)
3 5 
(± 3)
4 2 
(± 3)
4 9
( ± 3)
5 6
( ± 3)
I nf or me d c o nse nt
X
Secti o n  5. 1
I ncl usi o n a n d e xcl usi o n 
criteria
X
X  
X  
X
X
X
Secti o ns  5. 1 a n d 
5. 2
R o uti ne Cli nic al Pr oce d ures
De m o gra p h y
X
P h ysical e xa mi nati o n
X
Secti o n  8. 3. 1
Tar gete d p h ysical 
e xa mi nati o n, i ncl u di n g f or 
oe de ma
X  
X  
X
X
X 
Secti o n  8. 3. 1
Me dical hist or y a n d 
c o m or bi dities
X
Secti o n  5. 2
C o nc o mita nt me dicati o n 
(i ncl u di n g di uretic use)
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X 
Secti o n  6. 5
Vital si g ns (i ncl u di n g B P)
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X 
Secti o n  8. 3. 2
Hei g ht
X
Secti o n  8. 3. 1
Wei g ht
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X 
Secti o n  8. 3. 1
E C G i ncl u di n g Q Tc(f)
X
X  
X  
X
X
X 
Secti o n  8. 3. 3
R o uti ne S afet y Me as ure me nts
A d verse e ve nts ( A Es)
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X 
Secti o n  8. 4


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 7 of 1 3 2
Ser u m pre g na nc y test 
( W O C B P o nl y)
X
Secti o n  5. 1
Pr oce d ure
Scree ni n g
O pe n -L a bel I nter ve nti o n Peri o d ( 4 -6 we e ks)
Det ails i n C S P 
secti o n
Visit a
1 
2 
3
3. 1 b
o pti o n al
3. 2
4
4. 1 b
o pti o n al
4. 2
5
5. 1 b
o pti o n al
5. 2
6 j, k
6. 1 j, k
6. 2 j, k
6 a
( o pti o n al)i
6 b
( o pti o n al)i
W e e k
-2 t o 1
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
6 
7 
8
9
Tre at me nt D a y ( Visit 
Wi n d o w )
-1 4 t o 1
1
7 
( ± 2)
8 
9
1 4 
( ± 3)
1 5 
1 6
2 1 
( ± 2)
2 2 
2 3
2 8 
( ± 3)
3 5 
(± 3)
4 2 
(± 3)
4 9
( ± 3)
5 6
( ± 3)
Uri ne pre g na nc y test 
( pre-d ose)
X
Secti o n  8. 3. 4
Cli nical safet y la b orat or y 
assess me nts (i ncl u di n g 
s K + a n d s Cr) c
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X 
Secti o n  8. 3. 4
Bi o m ar ker A n al yses
Bi o mar ker bl o o d a n d 
uri ne sa m ple c ollecti o n
X
X  
X  
X
X
X 
Secti o n  8. 7
First m or ni n g s p ot uri ne 
( 3 c o nsec uti ve da ys)d
X
X  
X  
X
X
X 
Secti o n  8. 2. 5
Ge n o mics I niti ati ve o pti o n al, e x pl or at or y ge netic s a m ple
Bl o o d sa m ple
X
Secti o n  8. 8
St u d y S pecific Assess me nts e
K C C Q
X
X  
X  
X
X
X 
Secti o n  8. 2. 2
P GI S
X
X  
X  
X
X
X 
Secti o n  8. 2. 2
St u d y I nter ve nti o n A d mi nistr ati o n
St u d y i nter ve nti o n 
dis pe nsati o n ( o pe n -la bel 
S Z C) f, g
X f
X f
X f
X f
X  
X
X
Secti o n  6. 6. 1
S pir o n olact o ne h
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
Secti o n s 6. 6. 1
a n d 6. 6. 2
Ra n d o misati o n ( 1: 1 S Z C 
or place b o) i
X
j
X j
X j
X i
X j
Secti o n  6. 6. 2


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
St u d y i nter ve nti o n 
dis pe nsati o n ( d o u ble -bli n d 
S Z C or place b o)
X  
X  
X
X
X
Secti o n  6. 6. 2
A b bre viati o ns: B P = bl o o d press ure; C S P = cli nical st u d y pr ot oc ol; E C G = electr ocar di o gra m; H K = h y per kalae mia; K C C Q = Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire; N K = n or m o kalae mic; 
P GI S = Patie nt Gl o bal I m pressi o n of Se verit y; s Cr = ser u m creati ni ne; s K + = ser u m p otassi u m ( 3. 5 -5. 0 m E q/ L); S Z C = s o di u m zirc o ni u m c ycl osilicate; W O C B P = w o me n of c hil d beari n g p ote ntial.
a
U nsc he d ule d visits ca n occ ur f or patie nts w h o ha ve a s p o nta ne o us A E re p ort, are n ot feeli n g well f or a n y reas o n, or if t he y ha ve h y p o- or h y per kalae mia t hat re q uires f oll o w -u p pri or t o t he ne xt 
sc he d ule d visit.
b
F or patie nts w h o bec o me h y per kalae mic a n d start S Z C 1 0 g TI D c orrecti ve t hera p y f or u p t o 4 8 h o urs, Visit X. 1 ( e g, Visit 3. 1, 4. 1 or 5. 1) is o pti o nal f or i n vesti gat ors w h o w o ul d li ke t o c hec k t he 
patie nt’s ser u m K + le vel 2 4 h o urs after starti n g S Z C. F or patie nts w h o c o m plete t he o pti o nal visit, o nl y t h ose w h o are h y per kalae mic at t his visit ha ve t o ret ur n f or visit X. 2 (e g, Visit 3. 2, 4. 2 or 
5. 2) t o ha ve t heir ser u m K + le vel rec hec ke d.
c
L ocal la b orat or y f or C he m 7 pa nel (e g, s Cr a n d s K +) , a n d uri nal ysis ( di pstic k); ce ntral la b orat or y f or c he mistr y, meta b olic, re nal pa nels, a n d bi o mar kers f or t he data a nal yses.
d
Ur i ne c ollecti o n kits will be ha n de d o ut at t he visit bef ore t he visit w he n uri ne is t o be c ollecte d t o all o w t he s u bject t o c ollect uri ne o n t he 3 c o nsec uti ve m or ni n gs i m me diatel y prece di n g t he visit.
I n t he e ve nt t hat a s u bject f or gets t o c ollect a n y of t he 3 first m or ni n g v oi ds, t he sa m ples ca n i nstea d be c ollecte d o n t he c o nsec uti ve 3 m or ni n gs i m me diatel y f oll o wi n g t he visit, a n d deli vere d t o 
t he st u d y site.
e
B ot h K C C Q a n d P GI S will be a d mi nistere d i n pa per or us i n g a site-base d electr o nic de vice. It is preferre d t hat patie nt -re p orte d o utc o me ( P R O) q uesti o n naires are c o m plete d pri or t o a n y ot her 
st ud y pr oce d ures a n d bef ore disc ussi o n of disease pr o gressi o n t o a v oi d biasi n g t he patie nt’s res p o nses t o t he q uesti o ns.
f
S Z C dis pe nsati o n if patie nt beca me H K.
g
H K C orrecti o n P hase : Patie nts w h o de vel o p H K d uri n g t he first 4 wee ks will be gi n S Z C 1 0 g t hree ti mes dail y f or u p t o 4 8 h o urs u ntil N K. 
Mai nte na nce P hase ( b ot h c o h orts) : Patie nts c o nti n ue o n S Z C 1 0 g dail y a n d t he n titrate bet wee n 5 g e ver y ot her da y an d 5 -1 5 g dail y t o mai ntai n N K.
h
I nitiate or u p-titrate s pir o n olact o ne be gi n ni n g o n Da y 1. U p-titrate s pir o n olact o ne t o ma x d ose of 5 0 m g dail y as detaile d i n Secti o n 6. 6. 1 . Patie nts w h o d o n ot de vel o p H K b y Visit 5 will be 
disc o nti n ue d fr o m t he st u d y d uri n g t he r u n -i n p hase.
i
Patie nts i n C o h ort 2 s h o ul d recei ve at least 3 wee ks of S Z C bef ore t he y ca n be c o nsi dere d f or ra n d o misati o n.Patie nts w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile recei vi n g ma xi m u m 
d ose S Z C ( 1 5 g) , b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n-la bel, r u n-i n p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K 
a gai n.
j
At e n d of r u n -i n p hase, patie nts w h o are N K o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y will be ra n d o mise d 1: 1 t o S Z C or place b o o n d o se t he y were ta ki n g at e n d of r u n-i n p hase.
k
T he assess me nts u ni q ue t o Visit 6 ( or 6. 1, 6. 2) ( na mel y t he t ar g et e d p h ysical e xa ms, bi o mar ker a nal yses, a n d t he K C C Q & P GI S ) will o nl y occ ur o nce i n de pe n de ntl y if t he patie nt atte n ds all 
o pti o nal visits ( 6a a n d 6 b). Refer t o  A p pe n di x K f or t he sce nari o w he n ra n d o misati o n ca n ha p pe n f or C o h ort 2.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Z irc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
R a n d o m ised, D o u ble -Bli n d, Wit h dr a w al P h ase a n d P ost -E O T F oll o w -U p
Pr oce d ure
D o u ble -Bli n d I nter ve nti o n Peri o d ( 6 m o nt hs)
F oll o w -u p 
Peri o d
Det ails i n 
C S P 
secti o n
Visit a
7
8
9  
1 0 
1 1 
1 2 
1 3
E O T b
1 4
1 5
Wee k
1
2
5 
9 
1 3 
1 7 
2 1 
2 5 
2 6
Tre at me nt D a y ( Visit Wi n d o w)
3 d a ys p ost - R
( ± 2)
7 d a ys p ost -R 
( ± 3)
1 m o p ost -R 
( ± 7)
2 m o p ost -R 
( ± 7)
3 m o p ost -R 
( ± 7)
4 m o p ost -R 
( ± 7)
5 m o p ost -R 
( ± 7)
6 m o p ost -R 
( ± 7)
7 d a ys 
p ost -E O T( ± 3)
Tar gete d p h ysical e xa mi nati o n, 
i ncl u di n g f or oe de ma
X
X
X
Secti o n 
8. 3. 1
C o nc o mita nt me dicati o n 
(i ncl u di n g di uretic use)
X
X
X  
X  
X  
X  
X  
X
X
Secti o n 
6. 5
Vital si g ns (i ncl u di n g B P)
X
X
X  
X  
X  
X  
X  
X
X
Secti o n 
8. 3. 2
Wei g ht
X
X
X  
X  
X  
X  
X  
X
X
Secti o n 
8. 3. 1
E C G i ncl u di n g Q Tc(f)
X
X
Secti o n 
8. 3. 3

R o uti ne S afet y Me as ure me nts
A d verse e ve nts ( A Es)
X
X
X  
X  
X  
X  
X  
X
X
Secti o n 
8. 4
Cli nical safet y la b orat or y 
assess me nts (i ncl u di n g s K + a n d 
s Cr)
X
X
X  
X  
X  
X  
X  
X
X
Secti o n 
8. 3. 4
Bi o m ar ker A n al yses
Bi o mar ker bl o o d a n d uri ne 
sa m ple c ollecti o n
X
X c
X
Secti o n 
8. 7
First m or ni n g s p ot uri ne ( 3 
c o nsec uti ve da ys) d
X
X
Secti o n 
8. 2. 5


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 0 of 1 3 2
Pr oce d ure
D o u ble -Bli n d I nter ve nti o n Peri o d ( 6 m o nt hs)
F oll o w -u p 
Peri o d
Det ails i n 
C S P 
secti o n
Visit a
7
8
9  
1 0 
1 1 
1 2 
1 3
E O T b
1 4
1 5
Wee k
1
2
5 
9 
1 3 
1 7 
2 1 
2 5 
2 6
Tre at me nt D a y ( Visit Wi n d o w)
3 d a ys p ost - R
( ± 2)
7 d a ys p ost -R 
( ± 3)
1 m o p ost -R 
( ± 7)
2 m o p ost -R 
( ± 7)
3 m o p ost -R 
( ± 7)
4 m o p ost -R 
( ± 7)
5 m o p ost -R 
( ± 7)
6 m o p ost -R 
( ± 7)
7 d a ys 
p ost -E O T( ± 3)
St u d y S pecific Assess me nt
C V e ve nts ( C V deat h a n d H F 
w orse ni n g)
X
X
X  
X  
X  
X  
X  
X
Secti o ns 
8. 2. 4. 1
a n d 
8. 2. 4. 2
K C C Q e
X
Secti o n 
8. 2. 2
P GI S e
X
Secti o n 
8. 2. 2
St u d y I nter ve nti o n A d mi nistr ati o n
St u d y  i nter ve nti o n dis pe nsati o n 
( d o u ble-bli n d S Z C or place b o )f
X  
X  
X  
X  
X
Secti o n 
6. 6. 2
S pir o n olact o ne g
X
X
X  
X  
X  
X  
X  
X
X
Secti o n 
6. 6. 2
A b bre viati o ns: B P = bl o o d press ure; C S P = cli nical st u d y pr ot oc ol; C V = car di o vasc ular; E C G = electr ocar di o gra m; E O T = e n d of treat me nt; H F = heart fail ure; K C C Q = Ka nsas Cit y Car di o m y o pat h y
Q uesti o n naire; N K = n or m o kalae mic; P GI S = Patie nt Gl o bal I m pressi o n of Se verit y; R = ra n d o misati o n; s Cr = ser u m creati ni ne; s K + = ser u m p otassi u m; S Z C = s o di u m zirc o ni u m c ycl osilicate.
a
U nsc he d ule d visits ca n occ ur f or patie nts w h o ha ve a s p o nta ne o us A E re p ort, are n ot feeli n g well f or a n y reas o n, or if t he y ha ve h y p o- or h y per kalae mia t hat re q uires f oll o w-u p pri or t o t he ne xt 
sc he d ule d visit, or f or a d diti o nal dr u g dis pe nsati o n i n case of d ose titrati o n.
b
Patie nts w h o pre mat urel y disc o nti n ue fr o m t he st ud y d uri n g t he ra n d o mis e d p hase, i ncl u di n g patie nts w h o pre mat urel y disc o nti n ue st u d y i nter ve nti o n a n d ref use t o c o nti n ue st u d y visits f or 
t he d urati o n of t he ra n d o mise d p hase, s h o ul d recei ve all E O T assess me nts at t heir last st u d y visit.
c  
O nl y N-ter mi nal pr o- B-t y pe natri uretic pe pti de (N T -pr o B N P ) is c ollecte d at 4 m o nt hs p ost-r a n d o misati o n.
d
Uri ne c ollecti o n kits will be ha n de d o ut at t he visit bef ore t he visit w he n uri ne is t o be c ollecte d t o all o w t he s u bject t o c ollect uri ne o n t he 3 c o nsec u ti ve m or ni n gs i m me diatel y prece di n g t he 
visit. I n t he e ve nt t hat a s u bject f or gets t o c ollect a n y of t he 3 first m or ni n g v oi ds, t he sa m ples ca n i nstea d be c ollecte d o n t he c o nsec uti ve 3 m or ni n gs i m me diatel y f oll o wi n g t he visit, a n d 
deli vere d t o t he st u d y s it e.
e
B ot h K C C Q a n d P GI S will be a d mi nistere d i n pa per or us i n g a site-base d electr o nic de vice. It is preferre d t hat patie nt -re p orte d o utc o me (P R O ) q uesti o n naires are c o m plete d pri or t o a n y 
ot her st u d y pr oce d ures a n d bef ore disc ussi o n of disease pr o gressi o n t o a v oi d biasi n g t he patie nt’s res p o nses t o t he q uesti o ns.
f
I nitial S Z C/ place b o d ose at ra n d o misati o n will c o nti n ue wit h t he sa me d ose of S Z C a d mi nistere d at e n d of r u n-i n. S Z C/ place b o d ose will t he n be a dj uste d bet wee n 5 g e ver y ot her da y a n d 5-
1 5 g dail y t o mai ntai n N K.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 1 of 1 3 2
g
I nitial s pir o n olact o ne d ose at ra n d o misati o n will c o nti n ue wit h t he sa me d ose a d mi nistere d at e n d of r u n-i n. S pir o n olact o ne d ose will t he n be a dj uste d, if nee de d, as detaile d i n S ecti o n 6. 6. 2
a n d T a bl e 9. S pir o n olact o ne d ose will be a dj uste d , if nee de d, f oll o wi n g st u d y c o m pleti o n as detaile d i n  Secti o n 6. 7 .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 2 of 1 3 2
1. 4
S y n o psis Refere nces
1.
E pstei n M, et al. E val uat i on of t he treat me nt ga p bet wee n cli nical g ui deli nes a n d t he 
utilizat i on of re ni n -a n giote nsi n -al d oster o ne s yste m i n hi bit ors. A m J M a n a g C are . 
2 0 1 5; 2 1( S u p pl 1 1): S 2 1 2 – S 2 2 0.
2.
T h o mse n R W, et al. Ele vate d p otassi u m le vels i n patie nts wit h c o n gest i ve heart fail ure: 
occ urre nce, ris k fact ors, a n d cli nical o utc o mes. A Da nis h p o p ulat i on- base d c o h ort st u d y . 
J A m He art Ass oc . 2 0 1 8; 7:e 0 0 8 9 1 2.
3.
L O K E L M A ® (s o diu m zi rc o ni u m c yclosilicate) f or oral  s us pe nsio n . U nite d States 
Prescri bi n g I nf or mat i on ( U S PI). Astra Ze neca P har mace ut icals L P, Wil mi n gt o n, D E. 
A pril 2 0 2 0 .
4.
L o kel ma p o w der f or oral s us pe nsi o n. S u m mar y of  Pr o d uct C haracteristics ( S mP C) . 
ht t ps:// w w w.e ma.e ur o pa.e u/e n/ d oc u me nts/ pr o d uct-i nf or mati on/ l okel ma -e par -pr o d uct -
i nf or mat i on _e n. p df. Accesse d 6 Fe b 2 0 2 0.
5.
L O K E L M A ® (s o diu m zi rc o ni u m c yclosilicate) p o w der f or oral  s us pe nsio n . Pr o d uct 
M o n o gra p h
( P M). Astra Ze neca Ca na da, I nc. A u g ust 2 0 2 0 .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 3 of 1 3 2
2
I N T R O D U C TI O N
S o di u m  zirc o ni u m c y closilicate ( S Z C) i s 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 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 ( E U), Ca na da, Ja pa n, 
C hi na , a n d Brazil.
2. 1
St u d y R ati o n ale
T he p ur p ose of R E A LI Z E -K, a p hase I V , d o u ble-bli n d, pl ace b o -c o ntr olle d, ra n d o mised-
wi t hdra wal  trial, is t o e valuate t he l o n g- t er m efficac y a n d safet y of  S Z C c o mpare d wi t h 
pl ace b o i n kee pi n g p otassi u m le vels wit hi n t he n or mal ra n ge ( 3. 5 -5. 0 m E q/ L) i n pati e nts wit h 
heart fail ure wit h re d uce d eject i on fracti on ( H Fr E F) w hile o n s pir o n o lact o ne ≥2 5 m g dail y 
wi t ho ut assista nce of resc ue t hera p y  for H K .  
Data fr o m R E A LI Z E -K will pr o vi de 6 m o nt hs of d o u ble -bli n d, place b o -c o ntr olle d, 
ra n d om ised- wi t hdra wal  s af et y a n d efficac y data as well as mi neral oc ortic o i d rece pt or 
a nta g o nist ( M R A ) persi ste nce data i n t he H Fr E F p o p ulat i on.   

I n Z S-0 0 3, Z S -0 0 4, a n d Z S - 0 0 5, o nl y  1 0% t o 1 5 % of pat ient s ha d H F as defi ne d b y 
Astra Ze neca base d o n vali date d a n d sta n dar d ised lists of preferre d ter m s i n t he 
Me dical Dict i onar y f or Re g ulat or y  Acti vit ies (Me d D R A ) narr o w sta n dar dise d 
Me d D R A  q ueries (S M Qs ) (U S PI 2 0 2 0 ; Data o n file) .

I n Z S-0 0 4 E, o nl y  1 3. 2 % of patie nts ha d H F ( R o ger et al . 2 0 1 9). A d diti o nall y , w hile t he 
st u d y pr o vides 1 1 -m o nt hs efficac y a n d safet y data, t he o pe n -label si n gle -ar m st u d y 
desi g n si g nifica nt l y li mits i nter pretati o n of t he data, es peciall y t he safet y data.

I n Z S - 0 0 5, o nl y  1 5 % of patient s ha d H F (S pi n o wi tz et al. 2 0 1 9). A d dit i onall y, w hile 
t he st u d y pr o vides 1 2 m o nt hs of  efficac y a n d safet y d at a, as well as re ni n -a n giote nsi n -
ald oster o ne s yste m  in hi bit or ( R A A Si) persiste nce data, t he o pe n-label, si n gle -ar m 
st u d y desi g n si g nifica ntl y li mits i nter pretati o n of t he data, es peciall y t he safety data.

W hile P RI O RI TI Z E -H F will pr o vi de safet y a n d efficac y, as well as R A A Si 
o pti m isatio n data i n H Fr E F patie nts, t he st u d y  d ur atio n is o nl y 3 m o nt hs ( Astra Ze neca 
2 0 2 0) . Cli nicia ns are re q uiri n g l o n ger ter m data f or S Z C d ue t o its s o di u m c o nte nt a n d 
p ote nti al ris k of oe de m a, es peciall y i n t his patient  p o p ulat i on t hat i s pr o ne t o fl ui d 
o verl oa d.
2. 2
B ac k gr o u n d
T he A merica n C olle ge of Car di o l og y  F o u n dati on ( A C C F), A merica n Heart 
Ass oci at i on ( A H A), a n d E ur o pea n S ociet y of  Car diol o g y  ( E S C) Heart Fail ure ( H F) g ui deli nes 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
rec o m me n d R A A Si, i ncl u di n g M R A t hera p y, as a Class I rec o m me n dat i on f or t he treat me nt of 
s y m pt o mat ic H Fr E F (level o f e vi de nce A). S pecificall y, t he A C C F/ A H A practice g ui deli nes 
rec o m me n d M R A in all pat ient s wit h c hr o nic H Fr E F (left ve ntric ular eject i on fracti on [ LV E F] 
≤3 5 %) a n d Ne w Yor k Heart Ass ociat i on ( N Y H A) class II – I V s y m pt o ms i n t he a bse nce of 
c o ntrai n dica tio ns (Ya nc y et al. 2 0 1 3). T he E S C H F g ui deli nes si milarl y rec o m me n d M R A  
t hera p y in pat ient s wit h HFr E F w h o re mai n s y m pt o mat ic des pite treat me nt wit h a n 
a n gi ote nsi n-c o n vert i n g e nz y me i n hi bit or ( A C Ei)/a n gi ote nsi n II rece pt or bl oc ker 
( A R B)/a n gi ote nsi n rece pt or-Ne pril ysi n i n hi bit or ( A R Ni) a n d a β- bl oc ker t o re d uce t he ris k of 
H F h os pital isatio n a n d deat h (P o ni k o ws ki et al. 2 0 1 6 ).
W hile R A A Si is a Class I rec o m me n dat i on i n patient s wit h H Fr E F, t hese patie nts ofte n 
e x perie nce H K as a n a d verse e ve nt ( A E), res ulti n g i n d o w n-titr atio n or di sc o nti n uati on of 
t hera p y (E pstei n et al. 2 0 1 5 ). H y per kalae mia a n d s u bse q ue nt s u b o pti mal R A A Si treat me nt is 
ass ociat e d wit h increase d m or bi dit y a n d mortali t y in t hese pat ient s (E pstei n et al. 2 0 1 5 ; 
T h o mse n et al. 2 0 1 8 ). 
T he 2 0 2 2 A H A/ A C C/ H F S A  H F G ui deli ne rec o m me n ds ( Class 2 b) pat iro m er or S Z C f or t he 
ma na ge me nt of h y per kalae mia (ser u m K+ ≥5. 5 m E q/ L) i n patie nts wit h heart fail ure, b ut 
states t hat t he effecti ve ness of t hese me dicat i ons t o i m pr o ve o utc o mes b y facilitat i n g 
c o nti n uat i on of R A A Si t hera p y is u ncertai n (Hei de nreic h, et al . 2 0 2 2). W hile, n ot gi ve n a 
gra de d rec o m me n dati o n, t he 2 0 2 1 E S C H F g ui deli ne states t hat t he a d mi nistrati o n of t he K + -
l oweri n g a ge nts, patir o mer or S Z C, ca n be c o nsi dere d f or t he ma na ge me n t of h y per kalae mia 
t o p ote ntiall y all o w t he i nitiati o n or u ptitrati o n of R A A Si (Mc D o na g h et al. 2 0 2 1 ).
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 otassiu m  in 
e xc ha n ge f or h ydr o ge n a n d s o diu m. S Z C is a p pr o ve d i n t he U S, E U, Ca na da , Ja pa n, C hi na ,
a n d Brazil f or t he treat me nt of H K i n a d ult patient s ( U nite d States Prescri bi n g [ U S PI] 2 0 2 0; 
S u m mar y  of Pr o d uct C haracteristics [ S m P C] 2 0 2 0; Pr o d uct M o n o gra p h [ P M] 2 0 2 0 ).
A detaile d descri pti o n o f t he c he mistr y, p har ma c ol o g y, efficac y, a n d safety of  S Z C is pr o vide 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 his st u d y  will r e cr uit s u bjects w h o eit her ha ve mil d-t o-m o derate H K or are at hi g h ris k of 
de vel o pi n g H K d uri n g M R A treat me nt . All s u bjects will recei ve s pir o n olact o ne w hic h has t he 
p ote nti al t o i ncrease ser u m p ot assiu m (s K +), p utti n g t he m at ris k of de velo pi n g H K .  
A d dit i onall y , t here is a ris k of  H K i n t h ose s u bjects w h o are ra n d o mised t o pl ace b o i n t he 
treat me nt wit hdra wal p hase. He nce , H K is t he maj or me dical ris k f or s u bjects partici pati n g i n 
t his trial. A d ditio n all y, u p-titr atio n of  s pir o n olact o ne d uri n g t he r u n-i n p hase ma y res ult i n 
decrease d re nal f u nct i on, as assesse d b y ser u m creati ni ne (s Cr). T he f oll owi n g st u d y  desi g n 
feat ures were i ncl u de d t o mi ni mise t he ris k t o s u bjects:


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2

L ocal  la bor at ori es will be use d b y sites t o all o w d ose a dj ust me nts t o occ ur ra pi dl y at 
eac h visit b y pr o vi di n g i n vestigat ors wi t h u p-t o-date s K + a n d creati ni ne 
meas ure me nts.

S Z C a n d s pir o n o lact o ne d ose ti tratio n a n d st o p pi n g r ules base d o n l o c al  la borat or y
sK + m o nit ori n g is i ncl u de d i n t his C S P to mi ni m ise t he ris k of H K d ue t o 
s pir o n olact o ne.

T he ri s k of H K u p o n ra n d o m isatio n t o p lace b o will be miti gate d wit h i nte nsi ve 
m o nit ori n g of s K + at t he be gi n ni n g of t he ra n d o m ised- wi t hdra wal treat me nt p hase.

T he ri s k of H K after t he e n d of treat me nt (E O T ) visit will be mit i gate d b y c ar eful 
m o nit ori n g of s K + 7 da y s after t he last st u d y treat me nt d ose.

H y p o k al ae mia has bee n re p orte d wit h S Z C. S Z C d ose titrati o n a n d st o p pi n g r ules 
base d o n l o c al  la borat or y sK + m o nit ori n g is i ncl u de d i n t his C S P t o mi ni mise t he ris k 
of  h y p o kalae mia i n s u bjects recei vi n g S Z C. 

S pi r o n olact o ne d ose titr atio n a n d st o p pi n g r ules base d o n l ocal la b or at or y s Cr 
m o nit ori n g is i ncl u de d i n t his C S P t o mi ni mise t he ris k of decrease d re nal f u ncti on d ue 
t o s pir o n olact o ne.

Oe de ma -r elate d e ve nts ( gr o u pe d ter ms i nclu de preferre d ter m s of o e d e m a, oe de m a
p eri p heral , ge neralised o e d e m a, fl ui d rete ntio n, h y per v ol e mia, lo c al ised oe de m a, a n d 
p eri p heral  s welli n g) ha ve bee n re p orte d b y patient s treate d wit h S Z C, i n partic ular at 
hi g her d oses. Patie nts wit h H F ha ve a hi g h li keli h o o d of e x perie nci n g o e d e m a. 
P h ysical e xa mi nat i ons t o assess oe de m a will  be perf or me d a n d t he s u bject will be 
w ei g he d at pre s pecifie d visits t o e ns ure de vel o p me nt of o e d e m a will be detecte d earl y 
a n d a p pr o priatel y ma na ge d (see Secti on  8. 3. 1 ).

Si mila r t o P RI O RI TI Z E-H F , t here is a ris k t hat i n vesti gat ors will n ot a d here t o t he 
pr ot oc oli se d u p-titr atio n of  s pir o n olact o ne d uri n g t he r u n -i n p hase. To mi tigate t hi s 
ris k, si milar t o P RI O RI TI Z E-H F , all i n vesti gat ors will be re q uire d t o d oc u me nt w h y 
s pir o n olact o ne was n ot i ncrease d w he n para meters s uc h as bl o o d press ure a n d 
p otassi u m  were n or mal a n d re nal fu nct i on was sta ble.   
M ore detaile d i nf or mat i on 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 nti al 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 o t oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 6 of 1 3 2
2. 3. 1
Ris k Assess me nt
Ta ble 2
Ris k Assess me nt
P ote nti al Ris k of Cli nic al 
Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or 
Ris k
Miti g ati o n Str ate g y
St u d y I nter ve nti o n
C o m m o n ( ≥1/ 1 0 0 t o < 1/ 1 0) 
a d verse dr u g reacti o n ( A D R )
o bser ve d i n S Z C cli nical st u dies: 
oe de ma -relate d e ve nts
Oe de ma -relate d e ve nts ha ve o nl y 
bee n o bser ve d i n t he mai nte na nce 
p hase of S Z C cli nical st u dies; t he y 
were re p orte d b y 5. 7 % of S Z C 
s u bjects; 2. 7 %, 5. 2 %, 1 4. 3 %, a n d 
1. 7 % of s u bjects ra n d o mise d t o 
S Z C 5 g, 1 0 g, 1 5 g, a n d place b o, 
res pecti vel y. Gr o u pe d ter ms 
i ncl u de preferre d ter ms of 
Oe de ma, Oe de ma peri p heral, 
Ge neralize d oe de ma, Fl ui d 
rete nti o n, H y per v ole mia, 
L ocalise d oe de ma, a n d Peri p heral 
s welli n g. ( Refer t o I B Secti o n 5. 4-
5. 5 a n d 6. 4.)
Of t he oe de m a -relate d e ve nts, 
5 3 % were ma na ge d wit h i nitiati n g 
di uretic treat me nt or a dj usti n g t he 
di uretic d ose, w hile t he re mai n der 
di d n ot re q uire treat me nt.
C o m m o n ( ≥1/ 1 0 0 t o < 1/ 1 0) A D R 
o bser ve d i n S Z C cli nical st u dies: 
H y p o kalae mia
H y p o kalae mia ( s K +
< 3. 5 m m ol/ L), a res ult of t he 
p har mac ol o gical acti o n of t he 
dr u g, was o bser ve d i n 4. 1 % of 
s u bjects treate d wit h S Z C.
Res ol ve d wit h d ose a dj ust me nt or 
disc o nti n uati o n of S Z C treat me nt.
2. 3. 2
Be nefit Assess me nt
Cli nical st u dies i n patie nts wit h H K ha ve de m o nstrate d t h e efficac y o f S Z C i n t he c orrecti o n 
of  H K a n d mai nte na nce of n or m o kalae mia ( N K).
2. 3. 3
O ver all Be nefit: Ris k C o ncl usi o n
Ta ki n g i nt o acc o u nt t he meas ures ta ke n t o mi ni m ise ris k t o partici pa nts partici pati n g i n t his 
st u d y, t he p ote ntial ris ks ide nt ifie d i n ass ociati on wi t h S Z C are just ifie d b y t he a ntici pate d 
be nefits t hat ma y be aff or de d t o partici pa nts wit h H K .
S Z C has pr o ve n t o effect i vel y c orrect H K t o t he n or mal s K+ ra n ge a n d mai ntai n N K f or u p t o 
1 2 m o nt hs i n a br oa d pati e nt p o p ulat i on wi t h H K , i ncl u di n g t h ose o n hae m o dial ysis. 
U nfa v o ura ble effects were li mite d, a n d t he a d verse dr u g reacti o ns ( A D Rs ) of  o e d e ma- relate d 
e ve nts a n d h y p o kalae mia were ge nerall y mil d a n d easil y ma na ge d. D ose titrati o n d uri n g 
mai nte na nce treat me nt all o ws i n di vi d ual ised treat me nt t o m ai ntai n N K . Base d o n t he a vaila ble 
cli nical data, t he be nefit -ris k assess me nt is fa v o ura ble f or c orrecti o n of H K wi t h S Z C 1 0 g 
t hree ti mes dail y f or u p t o 2 da ys, a nd f or m ai nte na nce treat me nt of patie nts wit h H K acr oss 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 7 of 1 3 2
t he d ose ra n ge 5 g e ver y ot her da y t o 5 t o 1 5 g o nce dail y. Data fr o m t hese st u dies 
d e m o nstrate t hat t he m ajori t y of s u bjects ca n be a de q uatel y mai ntai ne d o n t he 5 g dail y or 
1 0 g dail y d ose.






Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 0 of 1 3 2
O bjecti ve
E n d p oi nt ( O utc o me V ari a ble)

T o e x pl ore t he p ote ntial occ urre nce of 
car di o vasc ular ( C V ) deat h, w or se ni n g of H F 
( defi ne d as H F H os pitalisati ons or Ur ge nt H F 
visits re gar dless of i ntra ve n o us [I V] l o o p di uretic 
use), a n d t he i n di vi d ual c o m p o ne nts i n t he S Z C 
a n d place b o ar ms d uri n g t he ra n d o m ised p hase

Ti me t o first e ve nt of C V deat h or w orse ni n g H F 
( defi ne d as H F H os pitalisati ons or Ur ge nt H F 
visits re gar dless of I V l o o p di uretic use), a n d t he 
i n di vi d ual c o m p o ne nts d uri n g t he ra n d o mised 
p hase: 
o
C V Deat h
o
W orse ni n g H F ( H F h os pital isati ons or 
ur ge nt H F visits re gar dless of I V l o o p 
di uretic use )
o
H F H os pital isati o ns
o
Ur ge nt H F Visits

T o e x pl ore t he p ote ntial c ha n ge i n mea n ur i ne 
al b u mi n-t o-creati ni ne rati o ( U A C R ) i n t he S Z C 
a n d place b o ar ms 

C ha n ge i n mea n U A C R i n S Z C gr o u p c o m pare d 
wit h place b o gr o u p at:  
o
Scree ni n g c o m pare d t o E O T
o
Ra n d o m isati on c o m pare d t o E O T
o
Scree ni n g c o m pare d t o ra n d o m isati o n 

T o e x pl ore t he c ha n ge fr o m ra n d o misati o n i n 
K C C Q T otal S y m pt o m Sc ore ( T S S ) a n d K C C Q 
O verall S y m pt o m Sc ore ( O S S) a n d ot her K C C Q 
s u b-d o mai ns (i ncl u di n g K C C Q p h ysical 
li mitati o n sc ore) bet wee n t he S Z C a n d place b o
ar ms

C ha n ge i n K C C Q-T S S , K C C Q-O S S a n d ot her 
K C C Q s u b -d o mai ns (i ncl u di n g K C C Q p h ysical 
li mitati o n sc ore) at E O T (a p pr o xi matel y 6
m o nt hs p ost ra n d o m isati on) c o m pare d wit h 
ra n d o misati on 

T o e x pl ore t he relati o ns hi p bet wee n 
al d oster o ne le vels a n d P GI C a n d K C C Q 
sc ores, wit h partic ular atte nti o n t o 
i ntra patie nt c o nsiste nc y, bet wee n t he S Z C 
a n d place b o ar ms at t he E O T visit c o m pare d 
t o ra n d o misati o n

C ha n ge i n P GI C a n d K C C Q sc ores wit h 
al d oster o ne le vels at E O T c o m pare d wit h 
ra n d o misati o n

T o e x pl ore t he p ote ntial differe nce i n N- ter mi nal 
pr o - B-t yp e n a tri uretic pe pti de (N T -pr o B N P )
bet wee n S Z C a n d place b o ar ms ( mea n differe nce 
as c o m pare d t o ra n d o misati o n, as well as t he 
li keli h o o d of a n i ncrease, decrease, a n d sta bilit y)

C ha n ge i n N T -pr o B N P meas ure me nts at E O T
(a p pr o xi matel y 6 m o nt hs p ost ra n d o m isati on)
c o m pare d wit h ra n d o m isati on 

T o e val uate t he efficac y of S Z C as c o m pare d t o 
place b o i n a v oi di n g t he re q uire me nt of resc ue 
t hera p y use f or H K

Ti me t o first i nsta nce of use of resc ue t hera p y f or 
H K d uri n g t he ra n d o m ised- wit h dra wal p hase


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 1 of 1 3 2
4
S T U D Y D E SI G N
4. 1
O ver all Desi g n
T his st u d y  is a parallel-gr o u p, pl ace b o -c o ntr olle d, m ult i-ce ntre st u d y wit h a n o pe n-la bel r u n-i n 
p hase. T he p o p ulat i on bei n g st u die d is pat ient s wit h s y m pt o mat ic H Fr E F w h o are ta ki n g n o or 
l ow- d ose s pi r o n olact o ne or e pl ere n o ne ( < 2 5 mg dail y ) at scree ni n g. St u d y  sites will be locate d 
i n N ort h a n d S o ut h A merica a n d E ur o pe.
To t al d uratio n of  st u d y p artici pat i on f or eac h patient  will be a p pr o xi matel y 8 m o nt hs. T he 
st u d y c o nsists of 3 perio ds: 1) scree ni n g peri o d, 2) t reat me nt peri o d c o m prise d of a n o pe n-
la bel r u n-i n p hase a n d a ra n d omi se d d o u ble-bli n d wi t hdra wal  p hase, a n d 3) f ollo w -u p peri o d.
1.
Scree ni n g peri o d ( u p t o 2 wee ks)
a)
P atie nts recei vi n g l o w-d ose e plere n o ne will  be s witc he d t o s pir o n olact o ne 1 2. 5 m g 
dail y d uri n g t he scree ni n g peri o d .
b)
C o h ort assi g n me nt is base d o n l ocal la b s K + o n V isit 1
c)
I n patie nts wit h h y per kalae mia ( C o h ort 1), Visit 2 ma y occ ur at t he sa me ti me as, or 
s h ortl y after Visit 1 ( Scree ni n g), s o t hat treat me nt wit h S Z C ca n be i nitiate d as s oo n as 
p ossi ble, as per i n vest i gat or’s g uida nce .
2.
Treat me nt peri o d ( a p pr o xi matel y 8 m o nt hs) 
a.
O pe n -la bel, r u n-i n p hase ( 4-6 wee ks) 
i. C o h ort 1 ( 4 wee ks): Patie nts w h o are H K at st u d y e ntr y:

H K C orrecti o n P hase: Pati e nts will start S Z C o n Da y 1 at a d ose of 
1 0 g t hree ti mes dail y f or u p t o 4 8 h o urs u ntil s K + 3. 5-5. 0 m E q/ L 
( N K). N O T E: Patie nts w h o d o n ot ac hie ve N K d uri n g t he 4 8- h o ur 
c orrectio n p hase will be disc o nt i n ue d fr om t he st u d y.

s K + Mai nte na nce P hase: Patie nts w h o ac hie ve N K will c o nt i n ue o n 
S Z C 1 0 g dail y a n d t he n t itrate bet wee n 5 g e ver y ot her da y a n d 5 t o
1 5 g dail y t o mai ntai n s K + 3. 5 -5. 0 m E q/ L per pr ot oc ol i nstr ucti o ns.

S pi r o n olact o ne: Patie nts will ini tiate or u p-titrate s pir o n olact o ne 
be gi n ni n g o n Da y  2 or 3 w he n t he y bec o me N K o n S Z C . 
S pi r o n olact o ne will be s yste mat icall y u p-titrate d t o a tar get d ose of 
5 0 m g dail y , as t olerate d per pr ot oc ol i nstr ucti o ns. N O T E: Pati e nts 
w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile recei vi n g 
ma xi m u m d ose S Z C ( 1 5 g ) b ut were N K o n s pir o n olact o ne 2 5 m g 
dail y  ma y re mai n i n t he o pe n-label, r u n -i n p hase f or u p t o 2 
a d ditio nal  wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d 
bec o me N K a gai n.
ii. C o h ort 2 ( 4-6 wee ks) : Patie nts w h o are N K at st u d y e ntr y:


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 2 of 1 3 2

S pi r o n olact o ne: Patie nts will ini tiate or u p-titrate s pir o n olact o ne 
be gi n ni n g o n Da y  1. S pir o n olact o ne will be s yste mat icall y u p-
titrate d t o a tar get d ose of 5 0 m g dail y, as t olerate d per pr ot oc ol 
i nstr uctio ns.

H K C orrecti o n P hase: Pati e nts w h o de vel o p H K d uri n g t he first 
4 wee ks of t he r u n-i n p hase will be gi n S Z C 1 0 g t hree ti mes dail y 
f or u p t o 4 8 h o urs u ntil s K + 3. 5-5. 0 m E q/ L. N O T E: Patie nts w h o 
d o n ot ac hie ve N K d uri n g t he 4 8 -h o ur c orrecti o n p hase will be 
di sc o nti n ue d fr om t he st u d y.

s K + Mai nte na nce P hase: Patie nts w h o ac hie ve N K will c o nt i n ue o n 
S Z C 1 0 g dail y a n d t he n t itrate bet wee n 5 g e ver y ot her da y a n d 5 t o
1 5 g dail y t o mai ntai n s K + 3. 5 -5. 0 m E q/ L per pr ot oc ol i ns tr u ctio ns. 
iii. N O T E : 

P ati e nts i n C o h ort 2 w h o d o n ot de vel o p H K d uri n g t he first 
4 wee ks (a n d as a res ult d o n ot meet t he re q uire me nt t o recei ve 
S Z C) will be disc o nt i n ue d fr om t he st u d y d uri n g t he r u n-i n p hase.

P ati e nts w h o de vel o p H K o n s pir o n o lact o ne 5 0 m g  dail y w hile 
recei vi n g ma xi m u m d ose S Z C ( 1 5 g), b ut were N K o n 
s pir o n olact o ne 2 5 mg dail y  ma y re mai n i n t he o pe n -la bel, r u n-i n 
p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o 
s pir o n olact o ne 2 5 mg a n d bec o m e N K a gai n.
b.
D o u bl e- bli n d, place b o -c o ntr olle d, ra n d o m ised- wi t hdra wal p hase ( 6 m o nt hs): 

P ati e nts w h o are N K o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y at t he 
e n d of t he r u n-i n p hase will be ra n d om ised 1: 1 t o S Z C or place b o stratifie d 
acc or di n g t o t he prese nce o f H K /N K ( o pe n la bel C o h ort 1 vs. Co h ort 2) at 
st u d y e ntr y, c o nti n ui n g o n t he d ose t he y were bei n g a d mi nistere d at t he e n d of 
t he r u n-i n p hase.

I nstr uctio ns o n h o w t o ma na ge pat ient s w h o d o n ot q ualif y f or ra n d o misati o n 
d ue t o h y per kalae mia are details i n Sect i on  6. 6. 1 .

C o m plete i nf or m at io n re gar di n g S Z C a n d s pir o n o lact o ne d osi n g is pr o vi de d i n 
Secti o n  6. 6 .
3.
F o ll ow- u p peri o d ( 1 wee k) after t he E O T visit: s K + will be c hec ke d 7 da ys after last 
d ose of st u d y  dr u g ( S Z C or place b o). Patie nts w h o are disc o nti n ue d fr o m t he st u d y  
d uri n g t he r u n -i n p hase d ue t o h yper kalea mia:
o
Ret ur n s pir o n olact o ne t o t he d ose t he patie nt was recei vi n g (ie, n o, or l o w -
d ose) pri or t o st u d y  e nr ol me nt. If t he patie nt’s d ose was st o p pe d d uri n g t he 
r u n-i n p hase, d o n ot restart it. 
o
Use cli nical j u d ge me nt t o deter mi ne if t he pat ient  s h o uld/ca n be c o nti n ue d o n 
c o m merciall y a vaila ble S Z C t o ma na ge t heir h y per kalae mia. 


Cli ni cal St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 3 of 1 3 2
o
Refer t he patie nt t o t heir H F treati n g cli nicia n wi t hi n 1 wee k of st u d y disc har ge 
f or fol l ow- u p a n d t o deter mi ne t heir c o urse of treat me nt m o vi n g f or war d.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T he st u d y  was desi g ne d wit h 2 c o h orts of patie nts i n t he o pe n-la bel peri o d (o ne wi t h H K 
pati e nts at scree ni n g a n d o ne wit h N K patie nts at scree ni n g) t o i ncrease t he n u m ber o f eli gi ble 
pati e nts a n d pr o vide m o re cli nicall y rele va nt data.
I ncl usi on cri t erio n # 2 : B y  not ca p pi n g t he all o wa bl e e G F R b ut i nstea d ma ki n g it 
3 0 m L/ mi n/ 1. 7 3 m 2 or greater, t he n u m ber of eli gi bl e pat ient s will i ncrease as it ca pt ures 
pati e nts wit h H F a n d c o mor bi d c o n di tio ns ot her t ha n sta ge 3 c hr o nic ki d ne y disease ( C K D )
t hat i ncrease t he ris k of H K.
E xcl usi o n Cri t erio n # 2: All o ws f or t he i ncl usi o n of he m o d y na micall y  sta ble patie nts w h o are 
eit her c urre nt l y or rece ntl y h os pitalise d. T hese patie nts are ofte n recei vi n g s u b o pti mal M R A 
a n d ha ve c halle n gi n g H K iss ues.
4. 3
J ustific ati o n f or D ose
Cli nical st u dies i n s u bjects wit h H K c o nsiste nt l y de m o nstrate d t hat i nitial treat me nt wit h S Z C 
1 0 g t hree ti mes dail y f or 2 4 h o urs u p t o 7 2 h o urs res ulte d i n cli nicall y mea ni n gf ul s K + 
re d uctio n wi t h a majori t y of s u bjects ac hie vi n g N K wi t hi n 2 4 t o 4 8 h o urs. M ore o ver, s u bjects 
wi t h hi g her baseli ne s K + le vels ha d greater re d ucti o ns i n s K + le vels. O nset of efficac y was 
r a pid wi t h s K + re d ucti on o bser ve d as earl y as 1 h o ur after d ose i nta ke.
After c orrecti o n of H K , c o nti n ue d mai nte na nce treat me nt for 2 8 da y s wit h S Z C 
5 g, 1 0 g, or 1 5 g dail y res ulte d i n c o nt i n ue d effecti ve c o ntr ol of s K + wit hi n t he N K ra n ge. 
T he pr o p orti o n of  s u bjects w h o re mai ne d N K at t he E O T wit h S Z C 5 g, 1 0 g, a n d 1 5 g dail y  
i ncrease d d ose-de pe n de nt l y (ra n ge: 7 1 % t o 8 5 %) a n d was s u peri or t o place b o. I n a d diti on, 
l on g -t er m mai nte na nce treat me nt of u p t o 1 2 m o nt hs wit h S Z C utilisi n g a d ose titrati o n
sc he me wit h t he starti n g d ose of 5 g dail y or 1 0 g dail y, titrate d t o a ma xi m u m of 1 5 g dail y or 
a mi ni m u m of 5 g e ver y ot h er d a y was effecti ve i n mai ntai ni n g N K i n t he maj ority of  s u bjects.
4. 4
E n d of St u d y Defi niti o n
A partici pa nt i s c o nsidere d t o ha ve c o m plete d t he st u d y  if he/s he has c o m p lete d all p hases of 
t he st u d y incl u di n g t he last visit.
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t h e last partici pa nt i n t he st u d y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 4 of 1 3 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 o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o l 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
P arti cipa 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 o f t he fol l owi n g criteri a a p pl y:
A ge
1
P arti cip a 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
P otassi u m  a n d esti mate d gl omer ular filtrat i on rate (e G F R):
(a) C o h ort 1: sK + 5. 1 -5. 9 m E q/ L at scree ni n g/st u d y  e nr ol me nt a n d e G F R ≥3 0 
m L/ mi n/ 1. 7 3 m 2; o r
( b) C o h ort 2: N or m o kalae mic (s K + 3. 5-5. 0 m E q/ L) at scree ni n g a n d ‘ at ris k’ of 
de vel o pi n g H K defi ne d as a n y of t he f oll o wi n g :
i.
Ha ve a hist or y  of H K (sK + > 5. 0 m E q/ L) wi t hi n t he prior 3 6 m o nt hs a n d e G F R 
≥3 0 m L/ mi n/ 1. 7 3 m 2; o r
ii.
s K + 4. 5 -5. 0 m E q/ L a n d e G F R 3 0 t o 6 0 m L/ mi n/ 1. 7 3 m 2 ;o r
iii.
s K + 4. 5 -5. 0 m E q/ L , a n d a ge > 7 5 years
3
D oc u m e nte d dia g n osis of s y m pt o mat ic H Fr E F ( N Y H A class II-I V), w hic h has bee n 
prese nt f or at least 3 m o nt hs
4
Left ve ntric ular eject i on fracti on ( L V E F) ≤4 0 % (a n y  meas ure me nt ma de wit hi n t he past 
2 4 m o nt hs usi n g ec h ocar di o gra p h y, m ult i ple gate ac q uisiti on sca n, c o m p uter t o m o gra p h y  
sca n ni n g, ma g net ic res o na nce i ma gi n g, or ve ntric ular a n gi o gra p h y is acce pta ble, pr o vide d 
n o s u bse q ue nt meas ure me nt a b o ve 4 0 %)
5
Recei vi n g A C Ei, A R B, or A R Ni ( e g, E ntrest o ® [sac u bitril/ valsarta n]) 
6
N ot o n or o n l o w -d ose s pi r o n olact o ne or e plere n o ne, ( < 2 5 m g dail y)  
7
Recei vi n g beta - bl oc ker u nless c o ntrai n dicate d.
I ncl usi o n Criteri a f or Pr ocee di n g t o t he 6- m o nt h R a n d o m ised- Wit h dr a w al Tre at me nt 
P h ase:
8
N K ( 3. 5 -5. 0 m E q/ L) o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y at t he e n d of t he 
r u n-i n p hase.
Se x
9
I ncl usi on Cri t eria for t he F e male s:
(a) Fe male partici pa nts of c hil d beari n g p ote ntial m ust ha ve a n e gat i ve pre g na nc y test 
(ser u m).


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 5 of 1 3 2
( b) Fe male partici pa nts m ust be 1 y ear p ost -me n o pa usal, s ur gicall y sterile, or usi n g o ne 
hi g hl y  effecti ve f or m of birt h c o ntr ol ( defi 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 nt l y a n d c orrectl y). T he y s ho 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 4 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 7 da ys after t he last 
d ose.
I nf or me d C o nse nt
1 0
Ca pa ble of gi vi n g si g ne d i nf or m e 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 mplia nce wi t h t he re q uir e me nts a n d restrict i ons 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 C S P
1 1
Pr o visi o n of si g ne d a n d date d writte n O pti o nal Ge net ic Researc h I nf or mati on i nf or me d 
c o nse nt pri or t o c ollecti o n o f sa m ples f or o pti o nal ge netic researc h t hat s u p p orts Ge n o mic 
I nitiati ve.
5. 2
E xcl usi o n Criteri a 
P arti cipa nts are e xcl u de d fr o m t he st u d y if a n y of t he f o ll owi n g cri t eria a p pl y:
Me dic al C o n diti o ns
1
H F d ue t o restrict i ve car di om y o p at h y , acti ve m yo c ar di tis, c o nstrict i ve pericar ditis, 
h y pertr o p hic ( o bstr ucti ve) car di o m y o pat h y , or se vere ste n otic val ve disease as a pri mar y
ca use of H F.
2
C urre nt i n pat ient  h os pit alisatio n wi t h u nsta ble H F , defi ne d as a n y of t he f oll o wi n g:
(a) S B P < 9 5 m m H g d uri n g t he 6 h o urs pri or t o scree ni n g .
( b) I ntra ve n o us di uret ic t hera p y d uri n g t he 1 2 h o urs pri or t o scree ni n g .
(c) Use of i ntra ve n o us i n otr o pic dr u gs d uri n g t he 2 4 h o urs pri or t o scree ni n g .
( d) Recei ve d mec ha nical circ ulat or y  s u p p ort d uri n g t he 4 8 h o urs pri or t o scree ni n g.
3
T y pe 1 m y ocar dial  infarcti o n ( MI), u nsta ble a n gi na, or str o ke wit hi n 1 2 wee ks pri or t o 
e nr o l me nt
4
C or o nar y  re vasc ularisati on ( perc uta ne o us c or o nar y i nter ve nt i on [ P CI] or c or o nar y  arter y 
b y pass graft i n g [ C A B G]) or val v ular re pair/re place me nt wit hi n 1 2 wee ks pri or t o 
e nr o l me nt or pla n ne d t o u n der g o a n y of t hese pr oced ures
5
I mpla ntati o n of  a Car diac Res y nc hr o nisat i on T hera p y  ( C R T) de vice withi n 1 2 wee ks 
pri or t o e nr ol me nt or i nte nt t o perf or m atrial fi brillati o n a blat i on or t o i m pla nt a C R T 
de vice
6
Pre vi o us car diac tra ns pla ntati o n or i m pla ntati o n of a ve ntric ular assista nce de vice ( V A D) 
or si milar de vice, or tra ns pla ntati o n or i m pla ntati o n e x pecte d after ra n d o misat i on


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o n i u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 6 of 1 3 2
7
S y m pt o m atic or u nc o ntr olle d atrial fi brillat i on des pi te treat me nt, or as y m pt o mat ic 
s ustai ne d ve ntric ular tac h ycar dia. S u bjects wit h atrial fi brillat i on c o ntr olle d b y  
me dicat i on are per mitte d.
8
Cli nicall y si g nifica nt bra d y car dia, as per i n vesti gat or’s j u d ge me nt, or sec o n d- or t hi r d-
de gree heart bl oc k wit h o ut a pace ma ker 
9
Q Tc(f) > 5 5 0 msec
1 0
Hi st or y of Q T pr olo n gat i on ass oci ate d wit h ot her me dicati ons t hat re q uire d 
di sc o nti n uati on of t hat me dicati o n
1 1
C o n ge nital l o n g Q T s y n dr o me
1 2
S y m pt o m atic h y p ote nsi o n or s y st olic bl o o d press ure ( S B P) < 9 0 m m H g o n 3 c o nsec ut i ve 
meas ure me nts
1 3
Recei vi n g dial ysis or a nt ici pate d b y t he i n vesti gat or t o re q uire dial ysis t hera p y withi n 3 
m o nt hs
1 4
> 3 0 % decli ne i n e G F R wit hi n t he past 3 0 da y s; if la b orat or y res ults are n ot a vaila ble, t he n 
e xcl u de if ac ute ki d ne y i nj ur y ( A KI) wit hi n past 3 0 da y s base d o n me dical hist or y or 
me dical rec or ds
1 5
Cli nicall y si g nifica nt h y p o natrae mia i n t he o pi ni o n of t he i n vest i gat or
1 6
Hi st or y of g y nec o mastia d ue t o s pir o n olact o ne t hera p y re q uirin g d o w n -titratio n or 
di sc o nti n uati on of s pir o n olact o ne, or s witc h t o a differe nt M R A.
1 7
A d dis o n’s disease 
1 8
Ele vate d p otassi u m d ue t o meas ure me nt i n hae m o l yse d sa m ple ( m ust re peat bl o o d dra w)
1 9
A n y c o n dit i on o utsi de t he car di o vasc ular ( C V) a n d re nal disease area, s uc h as, b ut n ot 
li mite d t o, mali g na nc y with a life e x pecta nc y o f less t ha n 1 year base d o n i n vest i gat or’s 
cli nical j u d ge me nt
2 0
P arti cip a nts wi t h a k n o w n h y perse nsiti vity t o S Z C or a n y  of t he e xci pie nts of t he pr o d uct.
Pri or/ C o nc o mit a nt T her a p y
2 1
T he f o ll owi n g p otassi u m -r elat e d prior/c o nc o mita nt t hera p y :
(a) Treat me nt wit h p otassi u m -s pari n g diuret ics ot her t ha n s pir o n olact o ne or e plere n o ne 
(e g, tria mtere ne, a milori de) wi t hi n 7 da ys pri or t o e nr ol me nt
( b) P otassi u m -bi n di n g resi ns s uc h as s o di u m p ol yst yr e ne s ulf o nate ( S P S; e g, 
Ka ye xalate ®) or calci u m p o l ystyr e ne s ulf o nate ( C P S; e g, Res o ni u m ®), t he cati o n 
e xc ha n ge p ol y mer, patir o mer s or bite x calci u m ( Veltassa ®), or S Z C wit hi n 7 da ys 
pri or t o e nr ol me nt.
(c) P otassi u m  s u p ple me nts wit hi n 7 da ys prior t o e nr ol me nt.  


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 7 of 1 3 2
Pri or/ C o nc ur re nt Cli nic al St u d y E x perie nce
2 2
P arti cip ati o n i n a n ot her cli nical st u d y  wit h a n i n vestigat i onal pr o d uct (I P) a d mi nistere d i n 
t he last m o nt h. 2
Ot her E xcl usi o ns
2 3
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 4
J u d ge me nt b y t he i n vestigat 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 
parti ci pa nt is u nli kel y t o c o mpl y  wit h st u d y pr oce d ures, restricti ons a n d re q uire me nts.
2 5
Pre vi o us e nr ol me nt i n t he prese nt st u d y . 
2 6
F or w o m e n o nl y - breast -fee di n g or pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y.
2 7
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) wi t hi n 2 wee ks 
pri or t o e nr ol me nt (see  A p pe n di x E ), t he partici pa nt ca n n ot be e nr olle d i n t he st u d y.
5. 3
Lifest yle C o nsi der ati o ns
N o a d di tio n al  lifestyle restrict i ons are re q uire d b y  t his st u d y. St u d y sites are e nc o ura ge d t o 
i nstr uct partici pa nts t o a d here t o a n y lifestyle restricti o ns t hat a p pl y f or si milar patie nts n ot 
parti ci pat i n g i n a trial.
5. 3. 1
Me als a n d Diet ar y R estricti o ns
N o a d di tio n al  di et ar y restrict i ons are re q uire d b y  t his st u d y. St u d y sites are e nc o ura ge d t o 
i nstr uct partici pa nts t o a d here t o a n y diet ar y restrictio ns t hat a p pl y f or si milar patie nts n ot 
parti ci pat i n g i n a trial.
5. 4
Scree n F ail ures
Scree n fail ures are defi ne d as part ici 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 nt l y ra n d o ml y assi g ne d t o st u d y in ter ve nti on . A mi ni mal set of scree n fail ure 
i nf or mat i on 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 RT) 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 bility cri t eria, a n d a n y s erio us a d verse e ve nt ( S A E).
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 b e 
rescree ne d t wice if: 

Scree n fail ure is d ue t o n ot meet i n g s K + or M R A d ose i ncl usi o n criteria at baseli ne, 
                                               
2 P artici 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 - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 8 of 1 3 2

Scree ni n g pr oce d ures ca n n ot be c o m plete d wit hi n t he 2 -wee k peri o d, 

Tec h nical iss ues e nc o u ntere d at e nr ol me nt site visit
P ati e nts w h o are rescree ne d 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 nit ial 
scree ni n g.
T hese s u bjects s h o ul d ha ve t he reas o n f or scree n fail ure rec or de d i n t he electr o nic Case 
Re p ort F or m  (e C R F).
6
S T U D Y I N T E R V E N TI O N
St u d y  i nter ve nt i on is defi ne d as a ny i n vesti gati onal i nter ve nt i on (s), mar kete d pr o d uct(s), or 
pl ace b o i nte n de d t o be a d mi nistere d t o or m e dical de vice(s) utilised 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 ns A d mi nistere d
6. 1. 1
I n vesti g ati o n al Pr o d ucts
Ta ble 4
I n vesti g ati o n al Pro d ucts
I nter ve nti o n N a me
S Z C
Place b o
S pir o n olact o ne
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 
or al s us pe nsi o n i n 5 g 
a n d 1 0 g sac hets
P o w der f or oral 
s us pe nsi o n i n a sac het
C o m merciall y a vaila ble ta blet: 
2 5 m g a n d 5 0 m g ta blets
D os a ge Le vel(s)
1 0 g t hree ti mes dail y; 
t he n titrate bet wee n 5 g 
e ver y ot her da y a n d 5 g 
dail y  t o 1 5 g dail y
Titrate bet wee n 5 g 
e ver y ot her da y a n d 5 g 
dail y  t o 1 5 g dail y

Patie nts n ot o n 
s pir o n olact o ne at 
scree ni n g: 1 2. 5 t o 5 0 m g
dail y  d uri n g t he r u n-i n 
p hase (start at 1 2. 5 m g 
dail y  a n d titrate t o 2 5 m g 
dail y  at Wee k 2, t he n 5 0 
m g dail y at Wee k 3 *).

Patie nts o n l o w -d ose 
s pir o n olact o ne at 
scree ni n g: 2 5 t o 5 0 m g 
dail y  d uri n g t he r u n-i n 
p hase (i ncrease t o 2 5 m g 
dail y  at Wee k 1, i ncrease t o 
5 0 m g dail y at Wee k 2, a n d 
c o nti n ue at 5 0 m g at 
Wee k
3 *). 

Patie nts o n l o w -d ose 
e plere n one at scree ni n g: 
s witc h t o spir o n olact o ne 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 9 of 1 3 2
1 2. 5 m g dail y d uri n g 
scree ni n g a n d t he n f oll o w 
titrati o n i nstr ucti o ns f or t he 
l o w-d ose s pir o n olact o ne 
gr o u p.
* D oses s h o ul d be titrate d as 
t olerate d per pr ot oc ol 
i nstr ucti ons. S pir o n olact o ne 
ma xi m u m dail y d ose is 5 0 m g.
R o ute of 
A d mi nistr ati o n
or al
or al
o r al
Use
I n vesti gati o nal pr o d uct
Place b o c o m parat or
Bac k gr o u n d i nter ve nti o n
I M P a n d NI M P
I M P 
I M P
NI M P
S o urci n g
Pr o vi de d ce ntrall y b y 
t he s p o ns or
Pr o vi de d ce ntrall y b y 
t he s p o ns or
C o m merciall y a vaila ble 
pr o d uct
P ac k a gi n g a n d 
L a belli n g
St u d y i nt er 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.
Place b o 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.
C o m merciall y a vaila ble 
pr o d uct
A b bre viati o ns: I M P = i n vesti gati o nal me dici nal pr o d uct; G M P = G o o d Ma n ufact uri n g Practice; 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. 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 vest i 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 ons ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  int er ve nt i on 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 int er ve nt i on.
2
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y int er ve nt i on a n d o nl y a ut h orise d 
site staff ma y s u p pl y or a d mi nister st u d y int er ve nt i o n. All st u d y int er ve nt i on m u st 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 ( m a 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 dit i ons wi t 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 vest i gat or, i nstit uti o n, or t he hea d of t he me dical i nstituti o n ( w here a p plica ble) is 
res p o nsibl e f or s t u d y int er ve ntio n acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte na nce 
(ie, receipt, rec o nciliat i on, a n d fi nal dis p osit i on 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 osit i on of u n use d st u d y  int er ve ntio ns 
will de pe n d o n l ocal re g ulat i ons i n a gi ve n st u d y c o u ntr y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 0 of 1 3 2
6. 3
Me as ures t o Mi ni m ise Bi as: R a n d o m is ati o n a n d Bli n di n g
T his st u d y  be gi ns with a n o pe n -label r u n -i n p hase, f oll owe d b y a d o u ble -bli n d, ra n d o m ised 
treat me nt perio d. 
All partici pa nts e nteri n g t he d o u ble -bli n d, ra n d o mise d treat me nt perio d will be ce ntrall y 
assi g ne d t o ra n d o mise d st u d y int er ve nt i on usi n g a n I nteracti ve Res p o nse 
Te c h n o l og y / Ra n d o misati on a n d Trial S u p pl y Ma na ge me nt (I RT/ R T S M) . Ra n d o misati o n will 
be stratifie d b y  t he s K + c o h ort deter mi ne d b y ce ntral la b orat or y at t he start of t he o pe n-label 
p hase ( Da y  1). 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 ons f or t he 
I RT a n d/ or t he l o g i n i nf or mat i on a n d direct i ons f or t he RT S M will be pr o vi de d t o eac h site.
St u d y  int er ve nt i on will be dis pe n se d at t he st u d y visits s u m marise d i n t he Sc he d ule o f 
Act i vities (S o A , Ta ble 1 ).
Ret ur ne d st u d y  int er ve nt i on s h o ul d n ot be re -dis pe nse d t o t he partici pa nts.
T he I R T/ R T S M will pr o vi de t o t he i n vest i gat or(s) or p har macists t he kit i de ntificati on n u m ber 
t o be all ocate d t o t he partici pa nt at t he dis pe nsi n g visit.
R o uti nes f or t his will be descri be d i n t he I RT/ R T S M user m a n ual t hat will be pr o vid e d t o eac h 
ce ntre.
T he I R T/ R T S M will be pr o gra m me d wit h bli n d -br ea ki n g i nstr ucti o ns. I n case of a n 
e mer ge nc y, i n w hic h t he k n o wle d ge of t he s pecific bli n de d st u d y int er ve ntio n will  affect t he 
i m me diate ma na ge me nt of t he partici pa nt’s c o n ditio n (e . g., a nti d ote a vaila ble), t he 
i n vesti gat or has t he s ole res p o nsi bility f or deter mi ni n g if u n bli n di n g of a partici pa nts’ 
i nter ve nt i on assi g n me nt is warra nte d. Partici pa nt safet y m u st alwa ys be t he first c o nsi derat i on 
i n ma ki n g s uc h a deter mi nat i on. If a partici pa nt ’s i nter ve nt i on assi g n me nt is u n bli n de d, t he 
s p o ns or must be n otifie d wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he i n vesti gat or d oc u me nts 
a n d re p orts t he acti o n t o Astra Ze neca, wit h o ut re veali n g t he treat me nt gi ve n t o partici pa nt t o 
t he Astra Ze neca staff .
Astra Ze neca retai ns t he ri g ht t o brea k t he c o de f or S A Es t hat are u ne x pecte d a n d are 
s us pecte d t o be ca usall y relate d t o a n I P a n d t hat p ote ntiall y re q uire e x pe dite d re p orti n g t o 
re g ulat or y a ut h orities. Ra n d omisat i on c o des will n ot be br o ke n f or t he pla n ne d a nal yses of 
data u ntil all decisi o ns o n t he e val ua bilit y of  t he data fr o m eac h i n di vi d ual partici pa nt ha ve 
bee n ma de a n d d oc u me nte d.
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, t he y  will recei ve st u d y int er ve nt i on di rectl y fr o m t he 
i n vesti gat or or desi g nee, u n der me dical s u per visi on . 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 eC R F .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 1 of 1 3 2
T he d ose of st u d y  int er ve nt i on a n d st u d y  p artici pa nt ide nt ificat i on 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 sit e st aff ot her t ha n t he pers o n a d mi nisteri n g t he 
st u d y int er ve ntio n .
W he n partici pa nts self -a d mi nister st u d y int er ve nti o n(s) at h o me, c o m plia nce wit h st u d y  
i nter ve nt i on will be assess e d at eac h visit. C o m plia nce will be assesse d b y direct q uesti o ni n g 
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 on(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.
A rec or d of t he n u m ber of sac hets di s 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  int er ve nt i on a n d c o m p lia nce rec or ds. I nter ve nti on start 
a n d st o p dates, i ncl u di n g dates f or i nter ve nt i on 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 e C R F.
6. 5
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne (i ncl u di n g o ver -t he- c o u nter or prescri pt i on 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 o l me nt or recei ves d uri ng t he st u d y  must 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.
T he st u d y ph ysicia n s h o uld be c o ntacte d if t here are a n y  q u estio ns re gar di n g c o nc o mit a nt or 
pri o r t hera p y.
Ta ble 5
Restricte d Me dic ati o ns
Use C ate g or y 
T y pe of M e dic ati o n/ T re at me nt
Ti meli ne/I nstr ucti o ns
Pr o hi bite d
P otassi u m -s pari n g di uretics
ot her t ha n s pir o n olact o ne a n d 
e plere n on e (e g, tria mtere ne, 
a mil ori de)
N ot per mitte d
Restricte d
P otassi u m bi n ders i ncl u di n g so di u m 
p ol y st yre ne s ulf o nate ( S P S), calci u m 
p ol y st yre ne s ulf o nate ( C P S), 
Patir o mer S or bite x Calci u m 
( Veltassa® ) 
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 E q/ L) after I M P has 
bee n disc o nti n ue d
P otassi u m 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 E q/ L) acc or di n g t o me dical 
j u d ge me nt 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 2 of 1 3 2
Use C ate g or y 
T y pe of M e dic ati o n/ T re at me nt
Ti meli ne/I nstr ucti o ns
Dr u gs wit h p H -de pe n de nt a bs or pti o n
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 ur s bef ore or 2 h o urs 
after oral me dicati o ns wit h cli nicall y mea ni n gf ul 
gastric p H de pe n de nt bi oa vaila bilit y s uc h as az ole 
a ntif u n gals ( ket oc o naz ole, itrac o naz ole, a n d 
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 , a n d ril pi viri ne), t yr osi ne 
ki nase i n hi bit ors (erl oti ni b, dasati ni b , a n d 
nil oti ni b) , a n d tacr oli m us. S Z C ca n be c o-
a d mi nistere d wit h o ut s paci n g of d osi n g ti mes 
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 (L O K E L M A C D S, 
2 0 2 2) .
N o nster oi dal a nti -i nfla m mat or y dr u gs 
( N S AI Ds)
N ot per mitte d u nless t here is a c o m pelli n g 
me dical reas o n
Per mitte d
Dail y  m ulti vita mi ns
P otassi u m c o nte nt is n ot si g nifica nt ( ~ 1 0 0 m g)
S o di u m -gl uc ose tra ns p ort pr otei n 2 
i n hi bit or ( S G L T 2i) t hera p y
L o w d ose acet ylsalic ylic aci d ( A S A)
6. 5. 1
Resc ue Me dici ne
Resc ue t hera p y  is defi ne d as a n y t hera pe utic i nter ve nt i on c o nsi dere d necessar y  in acc or da nce 
t o lo c al  practice patter ns t o re d uce s K + i n t he setti n g of se vere H K . T his ma y incl u de 
i ns uli n/ gl uc ose, beta a dre ner gic a g o nists, s o di u m bicar b o nate, p otassi u m bi n ders, as well as 
di al ysis or ot her f or ms of re nal re place me nt treat me nts gi ve n wit h t he g oal of c o ntr olli n g t he 
H K . Resc ue t hera p y s h o uld be f o ll owe d b y a st u d y dr u g 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.
6. 6
D ose M o dific ati o n
6. 6. 1
O pe n- l a bel R u n-i n P h ase:
O pe n -la bel visit fl o w dia gra ms are pr o vi de d f or refere nce i n Ta ble 6.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 3 of 1 3 2
Ta ble 6
D osi n g a n d Titr ati o n Sc he m a: O pe n -L a bel R u n -i n P h ase ( 4-6 Wee ks a)
H K, h y per kalae mic; N K, n or m o kalae mic; s K +, ser u m p otassi u m; S Z C, s o di u m zirc o ni u m c ycl osilicate.
a Patie nts i n eit her C o h ort w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w h ile recei vi n g ma xi m u m d ose S Z C 
( 1 5 g), b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n-la bel, r u n-i n p hase f or u p t o 2 
a d diti o nal wee ks i n or der t o r et ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K a gai n.
bPatie nts i n C o h ort 2 c o ul d p ote ntiall y de vel o p h y per kalae mia at Wee k 2 ( Visit 3), Wee k 3 ( Visit 4), or Wee k 4 
( Visit 5). If a n d whe n t he y  de vel o p h yper kalae mia, t he y will be gi n S Z C. Patie nts i n C o h ort 2 w h o d o n ot de vel o p 
h y per kalae mia b y Wee k 4 will be disc o nti n ue d fr o m t he st u d y.  
P atie nts Recei vi n g l o w - d ose E plere n o ne at Scree ni n g:

S wi tc h patie nts recei vi n g l o w-d ose e pl ere n o ne at scree ni n g t o s pir o n o lact o ne 1 2. 5 m g 
dail y .
S pir o n ol act o ne D osi n g:

D uri n g t he r u n-i n p hase, s pir o n olact o ne will be s yste maticall y i nitiate d a n d/ or u p-
titrate d, as t olerate d, base d o n d ose at scree ni n g (e. g., n o or l o w-d ose), as well as 
p otassi u m  le v el, s Cr lev el , a n d S B P as detaile d i n  Ta ble 7 a n d Ta ble 8.

P ati e nts i n C o h ort 1 ( H K at  st u d y e ntr y) will i nitiate or u p-titrate s pir o n olact o ne w he n 
N K is ac hie ve d with S Z C 1 0 g t hree ti mes dail y c orrecti o n treat me nt (st u d y Da y 2 or 
3). 

P ati e nts i n C o h ort 2 ( N K at  st u d y e ntr y) will i nitiate or u p-titrate s pir o n olact o ne o n 
D a y  1. P atie nts w h o de vel o p H K o n s pir o n o lact o ne will start S Z C 1 0 g t hree ti mes 
dail y  for u p t o 4 8 h o urs a n d sta y o n t heir c urre nt d ose of s pir o n o lact o ne (at t he ti me 
t he y de velo p H K). Pati e nts w h o d o n ot de vel o p H K d uri n g t he first 4 wee ks of t he r u n -
i n p hase will be disc o nti n ue d fr om t he st u d y.

P ati e nts i n eit her C o h ort w h o de vel o p H K o n s pir o n olact o ne 5 0 m g a n d ma xi mal d ose 
S Z C ( 1 5 g), b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n -la bel, 




Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 5 of 1 3 2

P ati e nts i n C o h ort 1 a n d C o h ort 2 w h o ac hie ve d N K d uri n g t he c orrecti o n p hase will 
t he n recei ve S Z C 1 0 g dail y t o mai ntai n s K + bet wee n 3. 5 -5. 0 m E q/ L. T he S Z C d ose 
will be a dj uste d bet wee n 5 g e ver y  ot her da y a n d 5 t o 1 5 g dail y d uri n g t he re mai n der 
of  t he r u n-i n p hase t o mai ntai n N K as descri be d i n  Ta ble 8 . S Z C d osi n g i nstr uctio ns 
f or p atie nts wit h s K + < 3. 5 m E q/ L or ≥6. 0 m E q/ L are als o detaile d i n  Ta ble 8.

P ati e nts i n eit her c o h ort w h o de vel o p H K o n s pir o n o lact o ne 5 0 m g dail y a n d 
ma xi m u m d ose S Z C ( 1 5 g dail y), b ut were N K o n s pir o n o lact o ne 2 5 m g dail y ma y 
r e mai n i n t he o pe n-label, r u n -i n p hase f or u p t o 2 a d ditio n al wee ks i n or der t o ret ur n t o 
s pir o n olact o ne 2 5 mg a n d bec o m e N K a gai n.
Ta ble 8
S Z C a n d S pir o n ol act o ne D osi n g B ase d o n Ser u m P ot assi u m (s K +), 
Ser u m C r e ati ni ne (s Cr), a n d S yst olic Bl o o d Press ur e St at us D uri n g th e 
O pe n -l a bel, R u n-i n P h ase


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 6 of 1 3 2
Di sc o nti n uatio n f r o m t he st u d y d uri n g t he o pe n -label p hase :

P atie nts w h o are disc o nti n ue d fr o m t he st u d y d uri n g t he r u n -i n p h ase d ue t o 
h y per k al ae mi a :
o
Ret ur n s pir o n olact o ne t o t he d ose t he patie nt was recei vi n g (ie, n o, or l o w -
d ose) pri or t o st u d y  e nr ol me nt. If t he patie nt’s d ose was st o p pe d d uri n g t he 
r u n-i n p hase, d o n ot restart it. 
o
Use cli nical j u d ge me nt t o deter mi ne if t he pat ient  s h o uld/ca n be c o nt i n ue d o n 
c o m merciall y a vaila ble S Z C t o ma na ge t heir h y per kalae mia. 
o
Refer t he patie nt t o t heir H F treati n g cli nicia n wi t hi n 1 wee k of st u d y disc har ge 
f or fol l ow- u p a n d t o deter mi ne t heir c o urse of treat me nt m o vi n g f or war d.  

P atie nts i n C o h ort 2 w h o are di sc o nti n ue d fr o m t he st u d y d uri n g t he r u n-i n p h ase 
bec a use t he y di d n ot de vel o p H K o n s pir o n ol act o ne:
o
T he i n vest i gat or s h o ul d refer t he patie nt t o t heir car di ol o gist wit hi n 1 wee k of 
st u d y disc har ge t o deter mi ne w het her or n ot t o c o nti n ue s pir o n olact o ne 
t hera p y. If s pir o n olact o ne is c o nti n ue d t he pat ient  s h o ul d be m o nit ore d b y t heir 
cli nicia n as per sta n dar d of care.

P atie nts w h o q u alif y f or r a n d o mi sati o n b ut deci de t o disc o nti n ue fr o m t he st u d y 
d uri n g t he r u n -i n p h ase a n d d o n ot c o nti n ue o n c o m merci all y a v ail a ble S Z C
s h o uld ha ve t hei r s pir o n olact o ne ret ur ne d t o t he d ose t he y were recei vi n g pri or t o 
st u d y enr o l me nt (e g, n o s pir o n olact o ne or < 2 5 m g/ da y) a n d be ma na ge d as per 
sta n dar d of care.
6. 6. 2
D o u ble -bli n d, Pl ace b o -c o ntr olle d, R a n d o mis ed- wit h dr a w al P h ase
As state d pre vi o usl y , p atie nts w h o mai ntai n N K w hile recei vi n g s pir o n o lact o ne ≥2 5 m g dail y 
a n d S Z C at t he e n d of t he o pe n-label, r u n -i n p hase will be ra n d om ised 1: 1 t o recei ve eit her 
S Z C or place b o i n t he 6- m o nt h, d o u bl e- bli n d, pl ace b o -c o ntr olle d, ra n d o mised- wi t hdra wal 
p hase. Ra n d o m isatio n will be stratifie d acc or di n g t o t he prese nce of H K/ N K at st u d y  e ntr y.
M o nit ori n g of Ser u m P ot assi u m F oll o wi n g R a n d o m is ati o n t o S Z C or Pl ace b o 
( Disc o nti n u ati o n of S Z C):
sK + levels will be m o nit ore d as descri be d i n Sect i o n 8. 2 to q ui c kl y ide nt if y patient s w h o ma y 
de vel o p H K f oll owi n g ra n d o m isatio n t o place b o ( disc o nti n uati on of S Z C). 
S Z C/ Pl ace b o D osi n g:
I n t his st u d y p hase, S Z C/pl ace b o will c o nt i n ue with t he sa me d ose of S Z C a d mi nistere d at t he 
e n d of t he o p e n-label, r u n -i n p hase. D ose titrati o n i nstr ucti o ns t o mai ntai n N K (s K + 3. 5 -5. 0 
m E q/ L) are detaile d i n Ta ble 8.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 7 of 1 3 2
If S Z C/place b o is te m p oraril y hel d d ue t o s K + 3. 0 t o < 3. 5 m E q/ L, i t ma y be restarte d as 
detaile d i n  Ta ble 9.
S Z C/ place b o s h o uld be per m a ne nt l y disc o nti n ue d if s K + < 3. 0 m E q/ L (s K + c o nfir me d b y a 
sec o n d rea di n g).
S pir o n ol act o ne D osi n g:
S pi r o n olact o ne d ose at  t he e n d of t he o pe n-label r u n -i n p hase s h o ul d be mai ntai ne d i n t he 6-
m o nt h ra n d o m ised- wi t hdra wal p hase. S pi r o n olact o ne d ose s h o ul d n ot be i ncrease d f urt her
h o we ver, it ’s all owe d t o be decrease d i n patie nts wit h H K as detaile d i n Ta ble 9 . T he d ose of 
s pir o n olact o ne ma y als o be decrease d d ue t o ot her A E s s uc h as h y p ote nsi o n, ele vate d s Cr, a n d 
g y na ec o mast ia.
Ta ble 9
S Z C/ Pl ace b o a n d S pir o n ol act o ne D osi n g B ase d o n Ser u m P ot assi u m 
(s K +) Le vels D uri n g t he 6- M o nt h 
D o u ble -bli n d, Pl ace b o -c o ntroll e d, 
R a n d o m ised- wit h dr a w al P h ase
Resc ue T her a p y:
P ati e nts wit h s K + ≥6. 0 m E q/ L  will be ma na ge d wit h resc ue t hera p y base d o n t he 
i n vesti gat or’s cli nical j u d ge me nt, e m pl oyi n g l o c al  sta n dar d of care a n d m o nit ore d m ore 
i nte nsel y u nt il l ocal la b-K has bee n c o nfir me d t o be bet wee n 3. 5 a n d 5. 5 m E q/ L  incl usi ve. 
Resc ue t hera p y  is defi ne d as treat me nts w hic h re d uce s K +, s uc h as i ns uli n/ gl uc ose, beta -
a dre ner gic a g o nists, s o di u m bicar b o nate, p otassi u m bi n ders, a n d dial ysis or ot her f or ms of  


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 8 of 1 3 2
re nal re place me nt treat me nts gi ve n wit h t he g oal of c o ntr olli n g t he H K. Resc ue t hera p y d oes 
n ot i ncl u de re d ucti o n i n s pir o n o lact o ne d ose or disc o nti n uati on of s pir o n olact o ne t hera p y, n or 
d ose re d ucti o n or disc o nt i n uati on of c o nc o mit a nt me dicat i ons t hat are k n o w n t o ele vate s K + 
(incl u di n g, b ut n ot li mite d t o, A C E i, A R B, A R Ni, beta-bl oc kers, N S AI D, tri met h o pri m).  
A d dit i onal st u d y visits ma y occ ur at a n y ti me at t he i n vesti gat or’s discreti o n t o e ns ure safety 
a n d pr ot oc ol a d here nce.
P ati e nts wit h lo c al  la b orat or y s K + < 3. 0 mE q/ L  will b e ma na ge d wit h resc ue t hera p y base d o n 
t he i n vest i gat or’s cli nical j u d ge me nt, e m pl oyi n g l o c al  sta n dar d of care s h o ul d be treate d 
acc or di n g t o t he i n vest i gat or’s me dical j u d ge me nt usi n g sta n dar d of care a n d m o nit ore d m ore 
i nte nsel y u nt il l ocal la b-K has bee n c o nfir me d t o be bet wee n 3. 5 a n d 5. 5 m E q/ L  incl usi ve. 
P otassi u m  s u p ple me nts ma y be a d mi nistere d at t he i n vest i gat or’s discreti o n a n d as me dicall y 
a p pr o priate. A d dit i onal st u d y visits ma y occ ur at a n y time at t he i n vesti gat o r’s discreti on t o 
e ns ure safet y a n d pr ot oc ol a d here nce.
6. 7
I nter ve nti o n after t he E n d of t he St u d y
U p o n st u d y  c o mplet i on, pati e nts w h o will not c o nti n ue o n c o m merciall y  a vaila ble S Z C after 
st u d y c o mplet i on, s h o ul d be ret ur ne d t o t heir ori gi nal s pir o n olact o ne d ose pri or t o st u d y  
e nr o l me nt a n d ma na ge d b y t heir p h ysicia n per sta n dar d of care. I n i nsta nces i n w hic h t he 
i n vesti gat or ha d d o w n-titrate d or st o p pe d s pir o n olact o ne, t he patie nt s h o ul d n ot be ret ur ne d t o 
t heir origi nal  d ose a n d s h o uld be gi ve n t he l o west s pir o n olact o ne d ose a d mi nistere d d uri n g t he 
ra n d omise d -wi t hdra wal  p erio d.
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 for a parti ci pa nt t o per ma ne nt l y disc o nti n ue ( defi nitive disc o nti n uati o n) 
st u d y int er ve ntio n. If  st u d y int er ve nt i on is per ma ne ntl y disc o nti n ue d, t he partici pa nt will 
r e mai n i n t he st u d y a n d will be e xcl u de d fr o m t he P P S p o p ulat i on . 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 nt i n uati on of st u d y int er ve nt i on a n d f o ll ow- 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.
F or pati e nts disc o nti n ui n g fr om t he st u d y d uri n g t he r u n-i n p hase, please refer t o Secti o n 
6. 6. 1 , for g ui da nce o n treat m e nt ma na ge me nt.
P ati e nts w h o disc o nt i n ue t he st u d y earl y duri n g t he ra n d o mise d p hase s h o ul d ha ve t hei r E O T 
visit as s o o n as p ossi ble after t heir last d ose of st u d y dr u g (ass u mi n g t he y disc o nt i n ue t he dr u g 
w hile at h o me a n d n ot at a st u d y  visit).
N ote t hat disc o nti n uati o n fr o m st u d y i nter ve nt i on is N O T t he sa me t hi n g as a wit h dra wal fr om 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
t he st u d y.
See t he S o A  for data t o be c ollecte d at t he ti me o f i nter ve nt i on disc o nti n uati o n a n d f o ll ow- u p 
a n d f or a n y furt her e val uat i ons t hat nee d t o be c o m plete d
F or di sc o nti n uati on pertai ni n g t o C O VI D -1 9, plea se see A p pe n di x E.
7. 1. 1
Te m p or ar y Disc o nti n u ati o n
Pl ease r efer t o Ta ble 9.
7. 2
P artici p a nt Wit h dr a w al fr o m t he St u d y

A parti ci pa nt ma y wi t hdra w fr o m  t he st u d y at a n y time at hi s/ her o w n re q uest, or ma y be 
wi t hdra w n at a n y  ti me at t he discretio n of  t he i n vestig at or f or safety,  be ha vi o ural ,
c o mplia 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 parti ci pa nt w h o c o nsi ders wit h dra wi n g fr o m t he st u d y must be i nf or me d b y  t he 
i n vesti gat or a b o ut m o difie d f o ll ow- u p o pti o ns (e g, tele p h o ne c o ntact, a c o ntact wit h a 
r elat i ve or treati n g p h ysicia n, or i nf or mati o n fr om me dical rec or ds).

At  t he ti me of wi t hdr a w al  fr om t he st u d y, if p ossi ble, a n E arl y St u d y  I nter ve nti on 
Di sc o nti n uatio n visit s h o ul d be c o n d ucte d, as s h o w n i n t he S o A (Ta ble 1) . See t he S o A 
f or data t o be c ollecte d at t he ti me of st u d y wi t hdra wal  a n d f o ll ow- u p a n d f or a n y f urt her 
e val uat i ons t hat nee d t o be c o m plete d.

T he parti ci pa nt will disc o nt i n ue t he st u d y int er 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 parti ci pa nt wi t hdra ws c o nse nt f or discl osur e of  fut ure i nf or m at i on, t he s p o ns or m a y 
retai n a n d c o nt i 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 .

If a partici pa nt wit h dra ws fr om t he st u d y, it s h o uld be c o nfir me d if he/s he st ill a grees f or 
e xist i 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 ulat i on. T he 
i n vesti gat or m ust d oc u me nt t he decisi on o n use of e xist i n g sa m ples i n t he sit e st u d y 
rec or ds a n d i nf or m t he Gl o bal St u d y T e a 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 o ll ow- 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 sit e.
T he f o ll owi n g acti o ns m ust be ta ke n if a parti ci 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:


Cli nical S t u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2

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 nc e 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 parti cipa 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 fol l ow u p, t he i n vest i 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 l ocal 
e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he parti ci pa nt ’s 
me dical rec or d .

Eff orts t o reac h t he s u bject s h o ul d c o nt i n ue u ntil t he e n d of t he st u d y. S h o ul d t he s u bject 
be u nreac ha ble at t he e n d of t he st u d y  t he s u bject s h o ul d be c o nsi dere d t o be l ost t o 
f oll ow u p wi t h u n k n o w n vital stat us at e n d of st u d y.
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h o le 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
8. 1
A d mi nistr ati ve Pr oce d ures

St u d y  pr oce d ures a n d t heir ti mi n g are s u m marised i n t he S o A (Ta ble 1) . Pr ot oc ol wai vers 
or e xe m pt i ons are n ot all o we d.

I mme diate safety c o ncer ns s h o uld 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 ntio 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, is 
esse nt ial a n d re q uire d f or st u d y c o n d uct.

All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote nti al 
parti ci pa nt s meet all eli gi bilit y cri t eria. T he i n vest i gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nt s 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.

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 util ised f or scree ni n g 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 
wi t hi n t he ti me fra me defi ne d i n t he S o A.

F or m a 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, please see 
A p pe n di x E.

A n o pe n -la bel visit fl o wc hart is pr o vi de d f or refere nce i n A p pe n di x K . 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
8. 2
Effic ac y Assess me nts
8. 2. 1
P ot assi u m
S er u m  sa m ples will be a nal yse d l ocall y usi n g local la b orat or y t o ge nerate lo c al  la b-K f or t he 
p ur p oses of st u d y  incl usi o n a n d m o nit ori n g. S a m ples dra w n at t he sa me t i me p oi nts will be 
pre pare d a n d s hi p pe d t o t he ce ntral la b orat or y for a nal ysis of s K + f or use i n a nal ysis of 
a p plica ble efficac y e n d p o i nts.
All ser u m sa m ples s h o uld be e xa mi ne d a n d a n y  o vertl y hae mol y se 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 o f bl o o d sa m ples.
8. 2. 2
P atie nt - Re p orte d O utc o mes ( P R Os)
P R Os is a n u m brella ter m referri n g t o all o utc o mes a n d s y m pt o ms t hat are direct l y re p orte d b y 
t he patie 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.
P ati e nts will eit her c o mplete t he P R O assess me nts i n pa per or usi n g a n electr o nic ta blet d uri n g 
cli nic visits at t he ti me p oi nts i n dicate d i n t he S o A (Ta ble 1 ). Patie nts will ha ve t he o pti o n t o 
deci de if t he y prefer t o use pa per or t he electr o nic de vice t o pr o vide a ns wer s. 
If t he s u bject is u na ble to rea d t he q uesti o n naire (e g, is bli n d or illiterate), t he s u bject will be 
e xe m pte d fr o m c o m p leti n g t he P R O q uesti on naires a n d ma y  still participate i n t he 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 nistratio n of  t he P R Os t o a s pecific site 
pers o n nel 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 sit e 
pers o n nel f o ll ow t he S o A (Ta ble 1 ) a n d e ns ure t hat t he pa per P R O q uesti o n naires are 
a vaila ble a n d/ or t he de vice is c har ge d a n d set u p pr o perl y bef ore t he first patie nt c o mes f or 
P R O visit s (baseli ne [ D a y 1 of o pe n-la bel p hase], ra n d o m isatio n v isit, a nd E O T visi t), i n or der 
t o mi ni mise missi n g data.  
If patient s ha ve a n y me dical pr o ble ms, t he y s h o uld disc uss t he m wit h t heir d oct or or researc h 
n urse se paratel y fr o m t he P R O assess me nt.  
T he researc h n u rse or a p p oi nte d site staff m ust re mi n d patie nts t here are n o ri g ht or wr o n g 
a ns wers a n d t hat t he val ue a n d rele va nce of P R O data is t o hear direct l y fr om patie nts, wi t ho ut 
i nter pretatio n f r o m healt h care pr ofessi onals or ot hers, h o w t he y  fu nct i on a n d feel . 
T he f o ll owi n g best practice g ui deli nes s h o ul d be f oll o we d: 

T he P R O q uesti o n naires m ust be c o 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.  


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2

T he a p p oi nte d site pers o n nel m ust s h o w patie nts h o w t o use t he electr o nic P R O de vice
(if a p plica ble) , i n acc or da nce wit h t he i nstr ucti o ns pr o vi de d. 

T o a v oi d bias pat ient s must n ot recei ve hel p fr o m relat i ves, frie n ds, or si te staff t o 
a ns wer or t o clarif y t he P R O q uesti o n naires. 

T he P R O q uesti o n naires m ust be c o m p lete d b y t he patie nt i n pri vac y. 

T he patie nt s h o ul d be gi ve n e n o u g h ti me t o c o m plete t he P R O q uesti o n naires at his or 
her o w n s pee d. 

O n c o m p leti on of t he q uesti o n naires t he pa per/ 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 (Ta ble 1 ), were c o mpl ete d. If a n y P R O q uestio n naire was n ot 
c o mplete d t he site pers o n nel m ust d oc u me nt t he reas o n w h y a patie nt c o ul d n ot 
c o mplete assess me nts i n t he R E V P R DI m o d ule i n t he e C R F. 
T he f o ll owi n g P R Os will be use d i n t his st u d y : K C C Q a n d P GI S .
8. 2. 2. 1
K a ns as Cit y C ar di o m y o p at h y Q uesti o n n aire ( K C C Q)
P ati e nts wit h H F e x perie nce de bilitat i n g s y m pt o ms t hat s u bsta ntiall y i m pact dail y fu nct i oni n g, 
p h ysical ca pacit y a n d q ualit y of life. F or t hese reas o ns, it is i m p orta nt t o meas ure t he i m pact 
of  ne w H F t hera pies o n t he H F patie nt’s s y m pt o ms a n d f u ncti oni n g (Za n na d et al. 2 0 1 3 ).  
T he K C C Q i nstr u me nt q ua ntifies b ot h t he fre q ue nc y  of 4 car di nal H F-s y m pt o ms (fat i g ue, 
p eri p heral  oe de ma , d y s p n oea, a n d ort h o p n oea ) a n d h o w b ot hers o me 3 of  t he car di nal H F 
s y m pt o ms (fati g ue, peri p heral o e d e m a, a n d d ys p n o ea) are t o patie nts, as well as H F-r elate d 
p h ysical li mitat i ons, s ocial li mitati o ns, self -efficac y, a n d healt h-r elate d q ualit y of life. First 
de vel o pe d i n 1 9 9 6 (Gree n et al . 2 0 0 0; S pert us et al. 2 0 0 5) o ver t he f o ll owi n g 2 deca des t he 
e x perie nce wit h t he K C C Q has gr o w n i n i n d ustr y -s p o ns ore d a n d aca de mic st u dies a n d it is 
n o w t he m ost c o m m o n disease P R O i nstr u me nt c ollecte d i n H F st u dies.  
T he K C C Q c o nsists of 2 3 ite ms meas uri n g, fr o m t he pat ient s’ pers pect i ves, t heir H F-relate d 
s y m pt o ms, p h ysical li mitati ons, s oci al li mit atio ns, self -efficac y, a n d healt h-r elate d q ualit y of 
life o ver t he pri or 2 wee ks (see A p pe n di x F ).
8. 2. 2. 2
P atie nt Gl o b al I m pressi o n of Se verit y ( P GI S) 
T he P GI S is a 1- ite m q uesti on assessi n g patie nt perce pti o n of his or her se verit y of  H F
s y m pt o ms t he last 2 wee ks. T he ite m is use d t o e na ble a nc h or -base d assess me nts of wit hi n -
pati e nt cli nicall y mea ni n gf ul c ha n ge. Patie nts will c h o ose fr o m 6 res p o nse o pti o ns, ra n gi n g 
fr om ‘ n o s y m pt o ms’ t o ‘ ver y se vere’ (see A p pe n di x G ).
8. 2. 3
Ne w Y or k He art Ass oci ati o n ( N Y H A) Cl ass
T he i n vest i gat or will e val uate N Y H A  class acc or di n g t o t he N Y H A  F u nctio n al  Classificati on 
as i ncl u de d i n A p pe n di x H. A ssess me nt will be rec or de d i n t he eC R F .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
8. 2. 4
E n d p oi nt re p orti n g o ver vie w
T he f o ll owi n g p ote nti al e n d p oi nts will be re p orte d a n d s o urce d oc u me nts s u b mitte d f or ce ntral 
a dju dicat i on b y t he Cli nical E v e nts C o m mittee ( C E C) d uri n g t he ra n d o mise d p hase at eac h 
st u d y visit, i ncl u di n g a n y a d diti onal u nsc he d ule d visit s:

All deat hs

All H F e ve nts ( h os pital isatio ns f or H F or ur ge nt H F visits).
8. 2. 4. 1
Cl assific ati o n of De at h
All A E s wit h a fat al o ut c o me s h o uld be re c or de d as S A E s a n d o n a se parate pa ge i n t he e C R F; 
all deat hs will be s u b mitte d t o t he C E C f or a dj u dicati o n. T he C E C me m bers will a dj u dicate 
a n d classif y all deat hs base d o n defi nit i ons descri be d i n  A p pe n di x I. T he i n vest i gat or will 
rec or d t he classificati o n of deat h as C V, no n -C V , or u n deter mi ne d ca use of deat h i n t he e C R F. 
B ot h t he i n vest i gat or a n d C E C will assess t he e ve nts, b ut o nl y C V deat hs that occ ur d uri n g t he 
ra n d omise d -wi t hdra wal  p hase t hat are C E C-a dju dicate d will be i ncl u de d i n t he efficac y 
a nal ysis. 
8. 2. 4. 2
He art F ail ure E ve nts
Wo rse ni n g H F e ve nts (ie, h os pitalisati ons defi ne d as H F h os pital isatio ns or ur ge nt H F visit s 
re gar dless of i ntra ve n o us [I V] l o o p di uretic use) that occ ur d uri n g t he ra n d o mise d -wi t hdra wal  
p hase will be i ncl u de d i n t he efficac y a nal ysis a n d s h o ul d be rec or de d i n t he eC R F . All 
w orse ni n g H F e ve nts t hat meet S A E / A E crit eria s ho ul d be rec or de d as a n S A E / AE a n d as 
p ote nti al C V e n d p oi nts. All w orse ni n g H F e ve nts will be s u b mitte d t o t he C E C f or 
a dju dicat i on base d o n t he defi nit i ons s pecifie d i n  A p pe n di x I. T he defi niti on of Heart fail ure 
e ve nt is acc or di n g t o C DI S C defi niti on ( Hi c ks et al. 2 0 15 ) w hic h is c urre ntl y t he latest 
versi o n. C DI S C m a y be u p date d d urin g t he c o urse of t he st u d y. 
8. 2. 5
Uri ne A n al ysis
T hree c o nsec ut i ve first m or ni n g v oi d s p ot uri ne sa m ples will be c ollecte d at t he ti me p oi nts 
i n dicate d i n t he S o A (Ta ble 1 ). Uri nar y alb u mi n a n d creatini ne will be meas ure d at t he ce ntral 
la b orat or y a n d re p orte d, a n d mea n uri ne al b u mi n -t o-creati ni ne rati o ( U A C R ) will be 
calc ulate d base d o n t he meas ure d uri nar y alb u mi n a n d creat i ni ne a n d re p orte d.
Uri ne c ollecti o n kits will be ha n de d o ut at t he visi t before t he visi t w he n uri ne is t o be 
c ollecte d t o all o w t he s u bject t o c ollect uri ne o n t he 3 c o nsec ut i ve m o r ni n gs i m me diatel y 
prece di n g t he visit. He nce, 3 uri ne sa m ples will be c ollecte d f or eac h ti me p oi nt. 
I n t he e ve nt t hat a s u bject f or gets t o c ollect a n y o f t he 3 first mor ni n g v o i ds, t he sa mples ca n 
i nstea d be c ollecte d o n t he c o nsec ut i ve 3 m o r ni n gs i m me diatel y f oll owi n g t he visi t, a n d 
deli vere d t o t he st u d y  sit e.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
8. 3
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A (Ta ble 1) .
8. 3. 1
P h ysic al E x a mi n ati o ns
A c o m p lete p h ysical e xa mi nati on will be perf or me d at scree ni n g as i n dicate d i n t he S o A  
(Ta ble 1 ) a n d will i ncl u de a n assess me nt of ge neral a p peara nce, res pirat or y  s yste m, C V
s yste m (i ncl u di n g si g ns of fl ui d o verl oa d), a b d o me n, s ki n, hea d a n d nec k (i ncl u di n g ears, 
e yes, n ose, a n d t hr oat), l y m p h n o des, t h yr oid gl a n d, musc ul o- s keletal s yste m (i ncl u di n g s pi ne 
a n d e xtre mit ies), a n d ne ur o l ogi cal s yst e m.
A tar gete d p h ysical e xa mi nati on, i ncl u di n g oe de ma assess me nt, will be perf or me d at t he ti me 
p oi nts i n dicate d i n t he S o A a n d will i ncl u de a n assess me nt of ge neral a p peara nce a n d t he 
m usc ul o -s keletal s yste m (lo wer e xtre mit ies), res pirat or y s yste m, C V s yste m, a n d a b d ome n.
Ta r gete d oe de m a assess me nts will occ ur at scree ni n g, ra n d o misatio n, 1- m o nt h p ost -
ra n d om isatio n, 4 m o nt hs p ost -ra n d o misatio n, a n d E O T . N- ter mi nal pr o-B- t ype natri uretic 
pe pti de ( N T -pr o B N P ) levels , b o d y w eig ht , a n d di ur etic use ( yes/ n o; if yes, d ose) will als o be 
c ollecte d at t he sa me ti me o e d e m a assess me nts are c o n d uc te d.
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o u n derl yi n g me dical 
c o n ditio ns (i ncl u di n g H F, re nal i m pair me nt, sig ns of  fl ui d o verl oa d, a n d dia betes). Patie nts 
ca n be assesse d as nee de d t hr o u g h o ut t he st u d y if t he y s h o w sig ns o f w orse ni n g H F or re p ort 
t he y ar e feeli n g u n well. Ne w or w orse ni n g a b n or malit ies ma y q ualif y as A E s, see Secti o n 8. 4
f or details.
H ei g ht will be assesse d at scree ni n g usi n g l ocall y  a vaila ble t o ols wit ho ut t he s u bject weari n g 
s h oes, a n d rec or de d i n t he eC R F .
We i g ht will be assesse d usi n g t he sa me scale, pr o perl y mai ntai ne d a n d cali brate d at eac h visit, 
a n d wit h t he s u bject weari n g si m ilar a mo u nt of  clot h es (e g, u n der wear o nl y or li g ht i n d o or 
clot hi n g o nl y) at eac h visit.
8. 3. 2
Vit al Si g ns
Vit al si g ns 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) .
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d wit h a c o m pletel y a ut o mate d de vice. 
Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d de vice is n ot a vaila ble.
Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece de d b y  at least 5 mi n utes of rest f or 
t he s u bject i n a q uiet setti n g wit h o ut distracti o ns (eg, tel e visio n , cell p h o nes).
S y st olic a n d diast olic bl o o d press ure will be meas ure d b y a n a de q uatel y trai ne d healt h care 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
pr of essi o nal. Meas ure me nts wit h a cali brate d s p h y g m o ma n o met er are preferre d. If n ot 
a vaila ble, a n ot her de vice cali brate d caref ull y i n pr o p orti o n t o a merc ur y s p h y g m o ma n o met er 
is preferre d. Use of a ner oi d ma n omet ers s h o ul d be a v o i de d. A p pr o priate c uff size m ust be 
use d t o e ns ure acc urate meas ure me nt.
T he disa p peara nce of s o u n d ( K or ot k o v p hase V) s h o ul d be use d f or t he diast olic rea di n g. 
T hree ( 3) rea di n gs se parate d b y  2 mi n utes s h o uld be a vera ge d, a n d t he a vera ge res ult will be 
rec or de d i n t he e C R F. If t he first 2 rea di n gs of s ystolic bl o o d press ure ( S B P) differ b y m ore 
t ha n 5 m m H g, a d dit i onal rea di n gs s h o ul d be o btai ne d.
Bl o o d press ure s h o ul d b e m eas ure d i n eit her t he s u pi ne or sitti n g p ositi o n. N o s hift fr o m o ne 
p osi tio n t o a n ot her s h o ul d be ma de d uri n g t he st u d y. S u pi ne or sitti n g p ost ure s h o ul d be 
a d o pte d f or at least 5 mi n utes bef ore meas ure me nt. T he s u bject s h o ul d be rela xe d a n d wit h t he 
ar m o utstretc he d a n d s u p p orte d.
Bl o o d press ure s h o ul d b e m eas ure d u n der sta n dar d ised c o n di tio ns, as nearl y as p ossi ble at t he 
sa me ti me eac h visit, o n t he sa me ar m ( prefera bl y t he d o mi na nt ar m), b y t he sa me pers o n nel, 
a n d wit h t he sa me a p parat us.
8. 3. 3
Electr oc ar di o gr a ms ( E C Gs)
A n E C G will be perf or me d at scree ni n g, ra n d o m isatio n, e n d of tr e at me nt, a n d f o ll ow- u p (as 
s pecifie d i n t he S o A [Ta ble 1] ), a n d acc or di n g t o cli nical j u d ge me nt i n c o n nect i on wi t h se vere 
h y p o kal ae mia (s K + < 3. 0 mE q/ L), se vere H K (s K + > 6. 0), or a n y  s ym pt o ms or cli nical e ve nts 
s u g gesti n g car diac arr h yth mia.
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 uld be rea d m a n uall y a n d be rec or de d i n t he 
e C R F.

If n ot f ulfilli n g t he i ncl usi on/e xcl u sio n crit eria or f ulfilli n g t he disc o nti n uati o n criteria, 
pace ma ker patie nts s h o ul d be ma na ge d as rec o m me n de d b y pr ot oc ol ( wit h o ut 
e xce pti o ns) .
8. 3. 4
Cli nic al S afet y L a b or at or y Assess me nts
Ta ble 1 0 lists t he cli nical safety la b orat or y tests t o be perf or me d a n d t he S o A  (Ta ble 1 ) 
i ncl u des t he ti mi n g a n d fre q ue nc y. All pr ot oc ol-r e q uir e d la b orat or y assess me nts, as defi ne d i n 
t he ta ble, must be c o n d ucte d i n acc or da nce wit h t he l a b orat or y ma n ual a n d t he S o A.
T he r o uti ne cli nical c he mistr y  a n d hae mat olo g y  will be perf or me d at a ce ntral la b orat or y, wit h 
t he e xce pt i on of p otassi u m a n d creati ni ne meas ure me nts perf or me d b ot h l ocall y usi n g l ocal 
la b orat or y a n d at t he ce ntral la b orat or y at eac h visit, a n d pre g na nc y tests perf or me d o nl y 
l ocall y. Uri nal ysis ( dipsti c k) will be a nal yse d at t he lo c al  la b orat or y. Sa mpl es f or s K + a n d 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
creati ni ne a nal ysis usi n g l ocal la b orat ories s h o ul d be c o llecte d acc or di n g t o sa m ple c ollecti on 
a n d pr ocessi n g re q uire me nts f or t hese para meters. P otassi u m a n d creat i ni ne meas ure d l ocall y 
will be use d f or s u bject m a na ge me nt a n d f or st u d y i ncl usi on a n d will be re p orte d i n t he e C R F, 
b ut sa m ples c o llecte d at t he sa me ti me a n d a nal yse d at t he ce ntral la b orat or y will be use d f or 
t he mai n statist ical a nal yses.
Si tes are e nc o ura ge d t o use l ocal lab orat ori es t hat ca n pr o vi d e p otassiu m  a nd creati ni ne res ults 
as r a pidl y  as p ossi ble. If t he site ca n o btai n t he res ults i n a reas o na ble ti me (as deter mi ne d b y 
t he in vest i gat or a n d t he s u bject), t he sa mples f or t he l ocal lab orat ori es ca n be dra w n at t he 
be gi n ni n g of eac h visit, a n d t he n t he patie nt me dicatio ns t itrate d a n d/ or I P dis pe nse d bef ore 
t he patie nt lea ves t he cli nic.
T he m a xi m u m a mo u nt of  ti me bet wee n l ocal la b orat or y sa m ple c ollecti o n a n d o btai n me nt of 
data res ults s h o ul d be 1 d a y. If blo o d sa m pl es f or l ocal  la b orat or y testi n g are ta ke n at t he st u d y 
visit a n d t he res ults are n ot k n o w n pri or t o t he s u bject lea vi n g t he visit, t he i n vest i gat or ma y 
call t he s u bjects or bri n g t he m bac k t he f o ll owi n g da y  for i nstr ucti o ns re gar di n g c o nc o mita nt 
me dicat i on ti tr atio n a n d I P d osi n g. Al ter nati vel y, if mor e feasi ble f or t he s u bject a n d 
in vesti g at or , bl o o d sa m ples f or t he l ocal la b orat or y tests ma y be c ollecte d 1 d a y  bef ore st u d y 
pr oce d ure i n cases w he n t he l ocal la b orat or y sa m ple a nal ysis ti me is e x pecte d t o be l o n ger 
t ha n t he d urati o n of t he s u bject ’s cli nic visit.
T he res ults of p otassi u m a n d creati ni ne le vels perf or m e d locall y usi n g l o c al  la b orat ories will 
be pr o vi de d t o t he i n vest i gat or t he sa me da y a n d a nal ys e d bef ore assess me nt a gai nst t he 
i ncl usi on cri t eria a n d ra n d o m isatio n. It i s rec o m me n de d t o perf or m t he l ocal la b orat or y 
assess me nt of creati ni ne a n d p otassi u m bef ore ot her assess me nts, wit h t he e xce pt i on of t he 
K C C Q q uest i on naire, as t he l ocal la b orat or y assess me nt is li kel y t o tri g ger t he m o st scree ni n g 
fail ures.
A d dit i onal safety sa m ples ma y be c ollecte d (‘u nsc he d ule d ’) if cli nicall y i n dicate d at t he 
di scretio n of  t h e in vest i gat or. T he date, ti me of c ollecti on, 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 eC R F . If a d ditio nal  s af et y a nal yses of  
p otassi u m  or creati ni ne are c o n d ucte d ( wit h or wit h o ut s u bse q ue nt calc ulati on of e G F R), t he n 
l ocal la b orat ories s h o uld be use d t o perf or m t he a nal ysis o f t he a d ditio nal safet y sa m ples.
Esti mate d gl o mer ular filtrati o n rate (e G F R) will be calc ulate d usi n g t he n o n- race-base d
c hr o nic ki d ne y disease e pi de mi o l og y  (C K D -E PI ) c o lla b orati o n e q uatio n f or mula f or eac h ti me 
p oi nt w he n creati ni ne is a nal yse d.
Ta ble 1 0
L a b or at or y S afet y V a r i a bles
H ae m at ol o g y/ H ae m o st asis ( w h ole bl o o d)
Cli nic al C he mistr y (ser u m)
B- Hae m o gl o bi n ( H b)
S- S o di u m ( Na +)


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
B- Le u k oc y te c o u nt
S- P otassi u m ( K +)
B- Le u k oc y te differe ntial c o u nt (a bs ol ute c o u nt)
S- Bicar b o nate ( T otal C O 2)
B- Platelet c o u nt
S- C hl ori de ( Cl -)
B- Hae mat ocrit ( Hct)
S- Gl uc ose
S- Creati ni ne
S- Bl o o d Urea Nitr o ge n ( B U N)
Ur ea ( B U N)/ Creati ni ne Rati o
Esti mate d g l o mer ular filtrati o n rate (e G F R) usi n g 
t he n o n- race-base d C K D -E PI f or m ula
Uri n al ysis ( di pstic k)
A ni o n ga p
U- H b/ Er y t hr oc ytes/ Bl o o d 
S- Al b u mi n
U- Pr otei n/ Al b u mi n 
S- T otal Pr otei n
U- Gl uc ose 
S- Calci u m ( Ca + +)
S- Ma g nesi u m ( M g + +)
S- P h os p hate ( P O 4)
S- Bilir u bi n, t otal
S- Al kali ne p h os p hatase ( A L P)
S- Ala ni ne a mi n o tra nsferase ( A L T)
S- As partate a mi n o tra nsferase ( A S T)
8. 4
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he Pri nci pal In vest i 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 with t he c o nte nt of t his sect i on.
T he defi nit i ons of a n A E or S A E ca n be f o u n d i n A p p e n di x B .
A E s 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 
parti ci pa nt 's le gall y a ut h or ised re prese ntati ve) . 
T he i n vest i 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 nit i on of a n A E.
8. 4. 1
Ti m e 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 Es will be c o llecte d fr om the start of t he o pe n -label r u n -i n p hase, t hr o u g h o ut t he treat me nt 
p eri o d, a n d d uri n g t he f oll o w -u p peri o d .
S A Es will be rec or de d fr o m t he ti me of si g ni n g of I C F.
If t he i n vesti gat or bec o mes a ware of an S A E wi t h a s us pecte d ca usal relati ons hi p t o t he 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
i n vesti gati onal 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 parti ci pa nt
treate d b y hi m or her, t he i n vesti gat or s hall, with 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. 4. 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 o l ve d at t he f o ll ow- u p visit i n t he st u d y ar e fol l owe 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 mat i on f or a n y part ici 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 ju d ge d necessar y.
A d verse e ve nt v ari a bles
T he f o ll owi n g varia bles will be c ollecte d f or eac h A E ;

A E ( ver bat i m)

T he date w he n t he A E starte d a n d st o p pe d

M a 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 usality rati n g a gai nst t he st u d y i nter ve nt i on ( yes or n o)

Act i on ta ke n wit h re gar d t o I P

O utc o m e.
I n a d diti on, t he f o ll owi n g vari a bles will be c ollecte d f or S A Es:

Date A E m et crit eria for S A E

Date i n vesti gat or beca me a ware of S A E

A E i s s erio us d ue t o

Date of h os pitalisat i on

Date of disc har ge

Pr o ba ble ca use of deat h

Date of deat h

A ut o ps y  p erfor m e d

Ca usalit y assess me nt i n relat i on t o st u d y pr oce d ure(s)

Ca usalit y assess me nt t o ot her me dicat i on.
8. 4. 3
C a us alit y C ollecti o n
T he i n vesti gat or will assess ca usal relat i ons hi p bet wee n I P 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  


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
ha ve bee n ca use d b y t he I P?’
F or S A Es, ca usal relat i ons hi p s h o uld als o be assesse d f or ot her me dicat i on a n d st u d y  
pr oce d ures . 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 
r elat i ons 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 usali t y q uesti o n is f o u n d i n A p pe n di x B.
8. 4. 4
A d verse E ve nts B ase d o n Si g ns a n d S y m pt o ms
All A Es s p o nta ne o usl y re p orte d b y t he parti ci 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 om t he st u d y site staff: ‘Ha ve y o u ha d a n y heal t h pr o ble ms si nce t he pre vi o us visit/ yo u were 
last as ke d?’, or re veale d b y o bser vati on will  be c ollecte d a n d rec or de d i n t he eC R F . W he n 
c ollect i n g A Es, t he rec ordi 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 
sig 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 
r ec or de d se paratel y.
8. 4. 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 Cli nical St u d y  Pr ot oc ol ( C S P) ma n date d la b orat or y  tests a n d vit al si g ns 
will be s u m marise d i n t he Cli nical St u d y  Re p ort (C S R ). 
Deteri or ati o n as c o m pare d t o scree ni n g i n C S P -ma n date d lab orat or y  val ues a n d vit al si g ns 
s h o uld t heref ore o nl y  be re p orte d as A Es if t he y f ulfil a n y o f t he S A E criteria, are t he reas o n 
f or disc o nti n uati on of treat me nt wit h t he I P 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-pl a 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 nt i on , e g, d ose a dj ust me nt  or dr u g i nterr u pti o n).
If deteriorati o n i n a la b orat or y  va l 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 sig 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/ vit al si g n 
will be c o nsi dere d as a d dit i onal i nf or mat i on . 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 t er 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).
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 on 
as c o mpare d wi t h t he scree ni n g assess me nt will be re p orte d as a n A E u nless u ne q ui v ocall y 
r elate d t o t he disease u n der st u d y.
8. 4. 6
Re p orti n g of Seri o us A d verse E ve nts
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he I P, or t o t he 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 3 2
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 bec o mes a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve will w or k wi t 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 p r o vide d t o t he Astra Ze neca Pat ient  Safety data e ntr y  sit e wit hi n 
1 c ale n d ar d a y of  init ial 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  init ial 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 on is missi n g, acti ve 
f oll ow- u p will be u n derta ke n i m me diatel y. In vest i 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  foll o w -u p i nf or mat i on o n a pre vi o usl y  re p orte d S A E 
wi t hi n 1 cale n dar d a y, ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs of  w he n he or s he bec o mes 
a ware of it.
F or f urt her g ui da nce o n t he defi nit i on of a n S A E, see  A p pe n di x B.
8. 4. 7
Pre g n a nc y
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 parti ci pa nt has recei ve d a n y st u d y 
i nter ve nt i on.

Pre g na ncies i n t he part ner of male partici pa nt
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, 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 but n o l ater 
t ha n 2 4 h o urs of w he n he or s he bec o mes a ware of it .
8. 4. 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 (see Secti o n  5. 1 ). S h o ul d a pre g na nc y still occ ur, t he I P
s h o uld be disc o nt i n ue d i m me diatel y, a n d t he pre g na nc y re p orte d t o Astra Ze neca
Pre g na nc y itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t he I P u n der st u d y 
ma y ha ve i nterfere d wit h t he effect i ve ness of a c o ntrace pti ve me dicati on . C o n ge nital 
a b n or malities/ 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 . Electi ve a b orti o ns wit h o ut c o m plicat i ons 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 on, 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 uld be f ol l owe d u p a n d d oc u me nte d e ve n if t he parti ci pa nt


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 1 of 1 3 2
was disc o nt i n ue d fr o m t he st u d y.
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, 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 ome s 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 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n 1 or 5 
cale n dar da ys for S A Es (see Secti o n  8. 4. 7 ) a n d wit hi n 3 0 da 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 mat i o n is a vaila ble.
T he P R E G R E P m o d ule i n t he e C R F is use d t o re p ort t he pre g na nc y a n d t he pa per -base d 
P R E G O U T m o d ule is use d t o re p ort t he o utc o me of t he pre g na nc y .
8. 4. 7. 2
P ater n al E x p os ure
T here i s n o restrict i on 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.
8. 4. 8
Me dic ati o n E rr or, Dr u g A b use, a n d Dr u g Mis use
8. 4. 8. 1
Ti meli nes
If a me dicati on err or , dr u g a b use, or dr u g mis use 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 da y, i.e. , 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 me s 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 
r ele va nt i nf or mat i on is c om p lete 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 u s i nitial a n d f oll ow u p) cal e n dar da ys if t here is a n 
S A E ass ociate d wit h t he me dicat i on err or , dr u g a b use, or mis use (see Secti o n s 8. 4. 8. 2 , 8. 4. 8. 3 , 
a n d 8. 4. 8. 4 ) a n d wit hi n 3 0 da ys f or all ot her e ve nts.
T he defi nit i on of a me dicat i on e rr or ca n be f ou n d i n  A p pe n di x B .
8. 4. 8. 2
Me dic ati o n Err or
F or t he p ur p oses of t his cli nical st u d y  a me dicat i on 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  int er ve nt i on t hat eit her causes har m t o t he 
parti ci pa nt or has t he p ote ntial t o ca use har m t o t he partici pa nt.
T he f ull defi ni tio n  a n d e xa m ples of  me dicat i on err or ca n be f o u n d i n A p pe n di x  B 4.
8. 4. 8. 3
Dr u g A b use
Dr u g a b use is t he persiste nt or s p ora dic i nte nti o n al, n o n-t hera pe utic e xcessi ve use of I M P or 
Astra Ze neca NI M P f or a percei ve d re war d or desire d n o n -t hera pe utic effect.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 2 of 1 3 2
T he f ull defi nit i on a n d e xa m ples o f dr u g a b use ca n be f o u n d i n A p pe n di x  B 4.
8. 4. 8. 4
Dr u g Mis use
Dr u g mis use is t he i nte nti o n al a n d i na p pr o priate use ( b y a st u d y partici pa nt) of I M P or 
Astra Ze neca NI M P f or me dici nal p ur p oses o utsi de of t he a ut h orise d pr o d uct i nf or mat i on, or 
f or u na ut h orise d I M Ps or Astra Ze neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol  a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute.
T he f ull defi nit i on a n d e xa m ples o f dr u g mis use ca n be f o u n d i n A p pe n di x  B 4.
8. 5
O ver d ose
D uri n g t he H K c orrectio n p hase a n y S Z C d ose greater t ha n 3 0 g wit hi n 1 d a y , or c o nti n uati on 
of  t he c orrecti o n d ose ( 1 0 g t hree ti mes dail y) for m ore t ha n 7 2 h o urs will be c o nsi dere d a n 
o ver d ose.
D uri n g t he m ai nte na nce peri o d, a d ose hi g her t ha n 1 5 g per da y  will be c o nsidere d a n 
o ver d ose.

A n o ver d ose wi t h ass ociate d A Es is rec or de d as t he A E di a g n osis/s y m pt o ms o n t he 
r ele va nt A E m o d ul es 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 ntio 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 ome s a ware of it.
T h e 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 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n 1 or 5 
cale n dar da ys for o v er d os es ass ociate d wit h a n S A E (see S ecti o n 8. 4. 6 ) a n d wit hi n 3 0 da ys f or 
all ot her o ver d oses.
8. 6
H u m a n  Bi ol o gic al S a m ples
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bi o l o gica l sa m ples will be pr o vi de d i n t he 
st u d y-s pecific la b orat or y ma n ual. Sa mples s h o ul d be st ore d i n a sec ure st ora ge s pace wit h 
a de q uate meas ures t o pr otect c o nfi de nt iality.  F or f urt her details o n Ha n dli n g of H u ma n 
Bi ol o gi cal Sa m ples, see A p pe n di x C.
8. 6. 1
P h ar m ac o ki netics
P K para meters are n ot e val uate d i n t his st u d y .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 3 of 1 3 2
8. 6. 2
I m m u n o ge nicit y Assess me nts
I mm u n o ge nicit y will  not be assesse d i n t his st u d y.
8. 6. 3
P h ar m ac o d y n a mics
P har mac o d y na mics are n ot e val uate d i n t his st u d y .
8. 7
H u m a n  Bi ol o gic al S a m ple Bi o m ar kers
Bl o o d sa m pl es f or t he f o ll owi n g C V a n d re nal bi o mar kers will be c o llecte d t o e val uate h o w 
t he y are affecte d b y t he a d ditio n  of S Z C a n d o pti mal d oses of s piro n ol act o ne: 

Pl as ma/ser u m: N T-pr o -B N P , ser u m ald oster o ne * 
* Pati e nts nee d t o be eit her sta n di n g or seate d u pri g ht f or at least 2 h o urs bef ore 
sa m ple c ollecti on f or ald oster o ne. 
I n a d diti on, bl o o d a n d uri ne sa m ples will be c ollecte d a n d a nal ysis ma y be p erf or m e d o n 
a d ditio nal  bio m ar kers t h o u g ht t o pla y a r ole i n H F, C K D , or p otassiu m  ho m e ostasis t o 
e val uate t heir ass ociat i on wi t h o bser ve d cli nical res p o nses t o S Z C or t he effect of S Z C o n t he 
bi o mar kers. S a m ples ma y  als o be use d f or researc h t o de vel o p met ho ds, assa ys, pr o g n ostics 
a n d/ or c o m pa ni o n dia g n ostics relate d t o S Z C, H F, C K D , H K , a n d/ or ot her diseases.
S a m ples will  be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he Last S u bject ’s Last 
Vis it, after w hic h t he y will be destr o ye d. T he res ults of t his bio m ar ker researc h will be 
re p orte d eit her i n t he C S R itself or as a n a d de n d u m, or se paratel y i n a scie ntific re p ort or 
p u blicat i on. T he res ults of t his bi o mar ker researc h ma y be p o ole d wit h bi o mar ker data fr o m 
ot her st u di es wit h t he st u d y dr u g t o ge nerate h yp ot heses t o be teste d i n f ut ure researc h.
8. 8
O pti o n al Ge n o mics I niti ati ve S a m ple
A p pr o xi matel y  6 m L bl o o d sa m pl e f or de o x y rib o n ucl eic aci d ( D N A) is olati on will be 
c ollecte d fr o m parti ci pa nts w h o ha ve c o nse nte d t o partici pate i n t he ge net ic a nal ysis 
c o m p o ne nt of t he st u d y . Partici pat i on is o pti o nal. Parti ci pa nts w h o d o n ot wis h t o partici pate 
i n t he ge netic researc h ma y still partici pate i n t he st u d y.
I n t he e ve nt of D N A e xtractio n f ail ure, a re place me nt ge net ic bl o o d sa m ple ma y be re q ueste d 
fr om t he s u bject. Si g ne d i nf or me d c o nse nt will be re q uire d t o o btai n a re place me nt sa m ple 
u nless it was i ncl u de d i n t he ori gi nal c o nse nt.
See  A p pe n di x D f or inf or m at i on re gar di n g Ge n o mics I nit iati ve ge netic sa m ple. Details o n 
pr ocesses f or c ollect i on a n d s hi p me nt a n d destr ucti o n of t hese sa m ples ca n be f o u n d eit her i n 
t he a p pe n di x or i n t he Lab orat or y  Ma n ual.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 4 of 1 3 2
T he pr ocesses a d o pte d f or t he c o di n g a n d st ora ge of sa m ples f or ge net ic a nal ysis are 
i m p orta nt t o mai ntai n s u bject c o nfi de ntiality.  Sa m ples ma y be st ore d f or a ma xi m u m of 1 5 
years or as per l ocal re g ulat i ons fr om t he date of t he Last S u bject ’s Last Visit, after w hic h t he y 
will be destr o y e d. D N A is a fi nite res o urce t hat ma y be use d u p d uri n g a nal yses. T he res ults of 
a n y f urt her a nal yses will be re p orte d se paratel y in a sci e nt ific re p ort or p u blicati o n.
N o pers o nal details i de ntif yi n g t he i n di vi d ual will be a vaila ble t o Astra Ze neca or desi g nate d 
or ga n isatio ns w or ki n g wi t h t he D N A .
F or st ora ge a n d destr ucti o n of ge netic sa m ples, see  A p pe n di x D.
8. 9
He alt h Ec o n o mi cs
Heal t h ec o n o mics para meters are 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
P ati e nts assi g ne d t o t he S Z C are e x pecte d t o ha ve a lar ger li keli h o o d of bei n g N K, recei vi n g 
s pir o n olact o ne ≥2 5 m g dail y a n d n ot ha vi n g recei ve d resc ue t hera p y  for H K c o m pare d t o 
pati e nts recei vi n g place b o .
T he pri mar y  h y p ot hesis teste d is t hat of n o differe nce bet wee n S Z C a n d Place b o 
H 0: O R = 1 
vs 
H 1: O R ≠ 1
Ass u mi n g t hat t he O R is c o nsta nt o ver t he mai nte na nce peri o d fr o m m ont h 1 t o m o nt h 6.
9. 2
S a m ple Size Deter mi n ati o n
S a m ple size deter mi nat i on is base d o n t he pri mar y  o bject i ve, ie,
To  e val uate t he efficac y of S Z C as c o m pare d with pl ace b o i n kee pi n g p otassi u m le vels wit hi n 
t he n or m al ra n ge ( 3. 5 -5. 0 m E q/ L) w hile o n s pir o n olact o ne ≥2 5 m g dail y wit h o ut assista nce of 
resc ue t hera p y for h y p er k al ae mia ( H K) . 
Ass u mi n g t hat t he pr o ba bilit y of  res p o nse is 0. 7 i n t he S Z C gr o u p a n d 0. 5 i n t he place b o 
gr o u p , a n d a c orrelat i on of 0. 5 5 bet wee n sc he d ule d visits, t he n a G E E m o d el , wit h a n esti mate 
of  res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt effect, usi n g a bi n omial distri b ut i on wi t h 
e xc ha n gea ble c orrelat i on matri x wi t h a 5 % t w o-side d si g nifica nce le vel a n d 9 0 % p o wer will 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 5 of 1 3 2
re q uire 1 5 8 pati e nts t o be ra n d o mised. Cli nical data s u g gests t hat t he rate of deat h i n t his 
pati e nt p o p ulatio n is a p pr o xi matel y 1 0 deat hs per 1 0 0 pers o n -years. Wit h 7 9 pati e nt -years of 
o bser vat i on ( 1 5 8 * 6 / 1 2), a p pr o xi matel y 8 deat hs are a nt ici pate d (7 9 * 1 0/ 1 0 0) d uri n g t he 6-
m o nt h ra n d o m ised p hase. T heref ore, t he sa m ple size will be i ncrease d t o a p pr o xi matel y1 6 6
ra n d om ised pat ient s t o e ns ure n =1 5 8 i n t he mai n se nsiti vity a nal ysis f or t he pri mar y  e n d p oi nt. 
P ati e nts will be e ntere d i nt o t he o pe n-label p hase u nt il t he re q uire d n u m ber of ra n d o m ised 
pati e nts is reac he d, at w hic h p oi nt t he recr uit me nt  will st o p. Te ntati vel y, it is e x pecte d t hat 
a p pr o xi matel y 4 0 0 p atie nts will e nter t he o pe n la bel p hase i n or der t o ac hie ve t he g oal of 1 6 6 
ra n d om ised pat ient s.
U n der t he ori gi nal pri mar y e n d p o i nt w hic h was t o be e val uate d at E O T, r es ults fr o m t he 
DI A M O N D st u d y  s u g gest t hat a si milar effect size bet wee n S Z C a n d place b o s h o ul d be 
o bser ve d if t he d urati o n of t he d o u ble - bli n d ra n d o mise d p hase is re d uce d fr o m 8 m o nt hs t o 6 
m o nt hs d ue t o t he earl y se parati o n of Ka pla n - Meier c ur ves bet wee n place b o a n d acti ve 
treat me nt. I n t he DI A M O N D st u d y, at 2 5 a n d 3 3 wee ks, t he K M fail ure esti mate f or first H K 
e ve nt (ser u m K + > 5. 5 m E q/ L) are a p pr o xi matel y 0. 1 8 a n d 0. 2 2 i n t he place b o ar m c o m pare d 
t o 0. 1 2 a nd 0. 1 5 5 i n t he acti ve ar m. If it’s ass u me d a pr o ba bilit y of  res p o nse of 0. 7 5 i n t he 
S Z C gr o u p a n d 0. 5 6 i n t he place b o gr o u p t he n a t w o gr o u p c hi -s q uare test wit h a 5 % 
t wo- si de d si g nifica nce le vel a n d 1 2 4 patie nts per treat me nt gr o u p wi ll ha ve a p o wer of 
8 7. 9 3 %. If it’s ass u med a pr o ba bilit y of res p o nse of 0. 7 5 i n t he S Z C gr o u p a n d 0. 5 8 i n t he 
pl ace b o gr o u p t he n a t w o gr o u p c hi-s q uare test wit h a 5 % t w o-si de d si g nifica nce le vel a n d 
1 2 4 pati e nts per treat me nt gr o u p will ha ve a p o wer of 8 1. 3 4 %. T hese ass u me d effect sizes f or 
t he origi nal pri mar y  e n d p oi nt will be retai ne d f or t he re vise d pri mar y e n d p o i nt w hic h will 
e val uate res p o nses o bser ve d fr o m wee ks 5 - 2 5.
9. 3
P o p ul ati o ns f or A n al yses
Ta ble 11
P o p ul ati o ns f or  An al ys is
P o p ul ati o n/ A n al ysis S et
Descri pti o n
Tre at me nt Assi g n me nt
Scree ne d Set
All patie nts w h o were scree ne d f or i ncl usi o n 
i nt o t he st u d y.
N ot a p plica ble
Safet y Set O pe n ( S S O)
All patie nts w h o e nter t he o pe n -la bel p hase 
a n d recei ve at least o ne d ose of S Z C.
N ot a p plica ble
Safet y Set Ra n d o m ised ( S S R)
All ra n d o m ised patie nts w h o recei ve d at least 
1 d ose of eit her S Z C or place b o. Safet y 
a nal yses will be a nal yse d usi n g t he S S O a n d 
S S R p o p ulati o ns.
Acc or di n g t o treat me nt 
act uall y recei ve d


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 6 of 1 3 2
P o p ul ati o n/ A n al ysis S et
Descri pti o n
Tre at me nt Assi g n me nt
F ull A nal y sis Set ( F A S)
All ra n d o m ised patie nts, irres pecti ve of 
treat me nt a n d a n y pr ot oc ol de viati o ns, w h o 
ha ve 1 or m ore p ost ra n d o m isati o n ce ntral 
la b orat or y s K + meas ure me nts a vaila ble. T he 
F A S will be use d as t he pri mar y p o p ulati o n 
f or t he pr i mar y, sec o n dar y, a n d e x pl orat or y
efficac y e n d p oi nts.
Acc or di n g t o ra n d o m ised 
treat me nt
Per Pr ot oc ol Set ( P P S)
F A S patie nts wit h o ut a n y i m p orta nt pr ot oc ol 
de viati o ns lea di n g t o e xcl usi o n fr o m t he P P S .
Acc or di n g t o ra n d o m ised 
treat me nt
T he n u m ber of pat ient 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 dit i on, t he f o ll owi n g peri o ds will  b e 
defi ne d f or t he p ur p ose of re p orti n g.
Ta ble 1 2
A n al ysis Peri o ds
Peri o d
Descri pti o n
Scree ni n g
Scree ni n g refers t o t he peri o d fr o m i nf or me d c o nse nt t o t he first d ose of 
o pe n -la bel st u d y i nter ve nti on or  scree n fail ure.
O pe n -la bel
T he o pe n -la bel peri o d refers t o t he peri o d fr o m t he date of first d ose of o pe n-
la bel st u d y i nter ve nti on t o t he earliest date of ra n d o misati o n, wit h dra wal of 
c o nse nt, last c o ntact wit h t he patie nt , or deat h.
Ra n d o m ised- wit h dra wal
T he ra n d o m ised- wit h dra wal peri o d refers t o t he peri o d fr o m t he date of 
ra n d o misati on t o t he earliest date of last assess me nt d uri n g t he f oll o w - u p 
p eri o d, wit h dra wal of c o nse nt, last c o ntact wit h t he patie nt , or deat h.
9. 4
St atistic al A n al yses
T he stati stical a nal ysis pla n ( S A P) will be fi nalise d pri or t o t he u n bli n di n g a n d l oc ki n g of t he 
cli nical data base a n d it will i ncl u de a m ore tec h nical a n d detaile d descri pt i on of t he statist ical 
a nal yses descri be d i n t his sect i on. T his sect i on is a s u m mar y of t he pla n ne d statistical a nal yses 
of  t h e most i m p orta nt e n d p oi nts i ncl u di n g pri mar y  a n d ke y sec o n dar y e n d p oi nts.
9. 4. 1
Ge ner al C o nsi der ati o ns
I nterc urre nt e vent s, s uc h as deat h, are ha n dle d as o utli ne d wit hi n eac h sect i on f or t he pri mar y 
a n d sec o n dar y e n d p oi nts bel o w. Scree ni n g baseli ne is defi ne d as t he last a vaila ble assess me nt 
pri or t o t he date of first d ose of o pe n -label treat me nt. Meas ure me nts ma de o n t he sa me date as 
t he first d ose of o pe n-label treat me nt will n ot be c o nsi dere d u nless t he meas ure me nt is 
c o nfir me d t o be pre -d ose b y t he ti mes t he meas ure me nt a n d d ose are rec or de d. Ra n d o m isatio n 
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 m isatio n 
visit f or all pat ient s, u nless ot her wise s pecifie d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 7 of 1 3 2
C o nti n u o us data will be s u m mar ised b y  tr e at me nt gr o u p usi n g t he n u m ber of o bser vat i ons 
a vaila ble ( n), mea n, sta n dar d de viat i on ( S D), mi ni m u m, q uartile 1, me dia n, q uartile 3, a n d
ma xi m u m. Cate g orical data will be s u m mar ised b y treat m e nt gr o u p usi n g t he c o u nt of patie nts 
a n d perce nta ge.
I n ge neral, descri pti ve statistics of q ua ntitati ve efficac y a n d safet y para meters b y  sc he d ule d 
visit s will be pr o vi de d o n o bser ve d cases (ie, i ncl u di n g o nl y patient s w h o ha ve n o n-missi n g 
assess me nts at a gi ve n visit).
T he o pe n -label p hase c o h ort ( C o h ort 1 or 2) is use d as a stratificati on fact or f or t his st u d y. I n 
t he e ve nt of a differe nce bet wee n t he stratifie d gr o u p a n d t he c ollecte d eC R F val ue at 
ra n d om isatio n, t he stratifie d gr o u p use d t o ra n d o m ise t he patie nt will be i ncl u de d i n statist ical 
m o delli n g, u nless ot her wise s pecifie d.
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 onal se nsit i vity a n d s u p ple me ntar y a nal yses will be re q ui re 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 o i nts. Pla n ne d 
se nsiti vity a nal yses will dist i 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 nsit i vity a nal yses. F or insta nce, i n t he pre -pl a n ne d 
tip pi n g p oi nt se nsit i vity a nal ysis f or t he pri mar y e n d p oi nt, tip pi n g p o i nt ass u m pti ons o n 
res p o nse will var y for C V-r elate d deat hs a n d l oss t o f oll o w -u p b ut sta n dar d missi n g at ra n d o m
a p pr oac hes s uc h as m ult i ple i m p utat i on will  be use d f or C O VI D - 1 9-relate d deat hs or l oss t o 
f oll ow- u p. ( See Secti o n  E 4, M o difie d Visits , i n A p pe n di x E .)
9. 4. 3
Effic ac y 
All pri mar y  a n d sec o n dar y efficac y e nd p oi nts a n d e x pl orat or y e n d p o i nts will be a nal yse d 
usi n g t he FA S.
9. 4. 3. 1
Pri m ar y E n d p oi nt
Per visit, res p o nse is defi ne d by 

Ha vi n g p otassi u m (s K +) wit hi n 3. 5 -5. 0 m E q/ L as assesse d b y  ce ntral la b orat or y AN D

Bei n g o n s pir o n o lact o ne ≥2 5 m g dail y A N D

N ot usi n g resc ue t hera p y  for H K d uri n g t he last m o nt h
Res p o nse me a ns all t hree b ullet p oi nts h ol d. N o n -res p o nse is i n dic ate d if at le ast o ne b ullet 
p oi nt d oes n ot h ol d.
A d diti o n ally, f or e ac h assess me nt visit, n o n -res p o nse is i n dic ate d f or p atie nts wh o are l ost t o 
f oll o w-u p at t he visit, i ncl u di n g d ue t o de at h.
T he m o nt hl y  visits are use d f or res p o nse assess me nt fr o m m o nt h 1 t o m o nt h 6. 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 8 of 1 3 2

T he treat me nt effect c o ncer ns t he o verall O d ds Rati o a n d will be a nal yse d usi n g a G E E 
m o d el , wit h a n esti mate of res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt effect, usi n g a 
bi n o mial distri b ut i on wi t h e xc ha n gea ble c orrelat i on matri x a n d teste d usi n g a t w o-side d 
alp ha = 0. 0 5. T he c o m plete m o del, i ncl u di n g t he c o m plete list of c o variate a dj ust me nt s 
will be descri be d i n t he S A P. P atie nts w h o are lost t o f oll ow- u p , i ncl u di n g d ue t o de at h,
pri or t o a n y s pecific assess me nt visits will be treate d as n o n-res p o nse f or t h ose 
assess me nt visits f or t he p ur p ose of t he pri mar y a nal ysis. T he c o m mo n  o d ds ratio will be
deri ve d t o get her wit h t w o -si de d 9 5 % c o nfi de nce i nter vals. Se nsiti vity a nal yses will be 
pres pecifie d i n f ull i n t he S A P a n d will deter mi ne t he i m pact of treati n g deat hs a n d 
pati e nts lost t o f oll ow- u p as a n o n -res p o nse. As a mi ni m u m, t hese will use t he P P S 
p o p ul at i on a n d will treat deat hs as a missi n g o bser vat i on. A s u p ple me ntar y  a nal ysis will 
be c o n d ucte d i ncl u di n g a n i nteracti o n ter m bet wee n treat me nt a n d a ti me de pe n de nt 
c o variat e of d ose recei ve d (5 g e ver y  ot her da y, 5 g dail y, 1 0 g dail y, 1 5 g dail y) t o all ow f or 
t he effect of d ose t o be assesse d.
9. 4. 3. 2
Sec o n d ar y E n d p oi nts
Stati stical a nal yses of t he sec o n dar y e n d p oi nts will i ncl u de str o n g c o ntr ols f or m ulti plicity. 
T he details o f t his a p pr oac h will be detaile d i n t he S A P.
1. Per visit, res p o nse is defi ne d b y

Ha vi n g p otassi u m  (s K +) wit hi n 3. 5-5. 0 m E q/ L as assesse d b y  ce ntral la b orat or y AN D

Bei n g o n t he sa me s pir o n o lact o ne d ose as t he y were at ra n d o misatio n A N D

N ot usi n g resc ue t hera p y  for H K d uri n g t he last m o nt h
Res p o nse mea ns all t hree b ullet p oi nts h o l d. N o n -res p o nse is i n dicate d if at least o ne b ullet 
p oi nt d oes n ot h ol d.
A d dit i onall y , for eac h assess me nt visit, n o n -res p o nse is i n dicate d f or patie nts w h o are l ost t o 
f oll ow- u p at t he visit, i ncl u di n g d ue t o deat h.
T he m o nt hl y  visits are use d f or res p o nse assess me nt fr o m mo nt h 1 t o m o nt h 6.
T he treat me nt effect c o ncer ns t he o verall O d ds Rati o a n d will be a nal yse d usi n g a G E E 
m o d el , wit h a n esti mate of res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt effect, usi n g a 
bi n o mial distri b ut i on wi t h e xc ha n gea ble c orrelat i on matri x. Pati e nts w h o are lost t o f oll o w - u p,
i ncl u di n g d ue t o de at h, pri or t o a n y s pecific assess me nt visits will be treate d as n o n -res p o nse 
f or t h ose assess me nt visits. T he c o m m o n o d ds rati o will be deri ve d t o get her wit h t w o -si de d 
9 5 % c o nfi de nce i nter vals.
2.
Per vi sit, res p o nse is defi ne d b y 

Bei n g o n s pir o n o lact o ne ≥2 5 m g dail y
Res p o nse mea ns b ullet p oi nt h ol ds. N o n -res p o nse i n dicates b ullet p oi nt d oes n ot h ol d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 9 of 1 3 2
A d dit i onall y , for eac h assess me nt visit, 
n o n- res p o nse is i n dicate d f or patie nts w h o are l ost t o f oll ow- u p at t he visit, i ncl u di n g d ue t o 
deat h.
T he m o nt hl y  visits are use d f or res p o nse assess me nt fr o m m o nt h 1 t o mo nt h 6. 
T he treat me nt effect c o ncer ns t he o verall O d ds Rati o a n d will be a nal yse d usi n g a G E E 
m o d el , wit h a n esti mate of res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt effect, usi n g a 
bi n o mial distri b ut i on wi t h e xc ha n gea ble c orrelat i on matri x. Pati e nts w h o are lost t o f oll o w - u p, 
i ncl u di n g d ue t o de at h, pri or t o a n y s pecific assess me nt visits will be treate d as n o n-res p o nse 
f or t h ose assess me nt visits. T he c o m m o n o d ds rati o will be deri ve d t o get her wit h t w o -si de d 
9 5 % c o nfi de nce i nter vals.
3.
Ti me t o first H K e pis o de wit h H K defi ne d as s K + > 5. 0 m E q/ L as assesse d by ce ntr al 
l a b or at ory. S Z C c o m pare d wit h pl ace b o usi n g H R a n d will be a nal yse d usi n g a ca use-
s pecific pr o p orti o nal hazar d m o del wit h deat h treate d as a c o m pet i n g ris k, ra n d om ised 
treat me nt as a n i n de pe n de nt fact or a n d o pe n-la bel p hase c o h ort as a stratificati on fact or. 
T he hazar d rati o a n d t w o -side d 9 5 % c o nfi de nce i nter val will be prese nte d. Gra p hicall y , 
t he treat me nt differe nce will be dis pla ye d usi n g c u m ulat i ve i nci de nce c om peti n g ris k 
c ur ves.
4.
Ti me t o first i nst a nce of decre ase or disc o nti n u ati o n of  s pir o n ol act o ne d ose d ue t o H K
S Z C c o m pare d wit h pl ace b o usi n g H R a n d will be a nal yse d usi n g a ca use-s pecific 
pr o p orti o nal hazar d m o d el  wit h deat h treate d as a c o m peti n g ris k, ra n d o mised treat m e nt as 
a n i n de pe n de nt fact or, a n d o pe n-la bel p hase c o h ort as a stratificati on fact or. T he hazar d 
r atio a n d t w o -side d 9 5 % c o nfi de nce i nter val will be prese nte d. Gra p hicall y, t he treat me nt 
differe nce will be dis pla ye d usi n g c u m ulat i ve i nci de nce f u ncti on c o m pet i n g ris k c ur ves.
5.
C h a n ge i n K C C Q -C S S at E O T visit ( a p pr oxi m ately 6 m o nt hs p ost -r a n d o mis ati o n) fr o m 
r a n d o mis ati o n. S Z C c o m pare d wit h place b o usi n g differe nce i n mea n a n d will  be a nal yse d 
wi t h re peate d meas ures a nal ysis o f c o varia nce ( A N C O V A) mo d el s wit h fi xe d t er ms for 
treat me nt, K C C Q-C S S at ra n d o misati o n, o pe n-lab el  p hase c o h ort, visit, a n d treat me nt b y 
visit i nteracti o n.
9. 4. 3. 3
E x pl or at or y E n d p oi nts
All e x plor at or y  e n d p oi nts will be a nal yse d usi n g t he FA S.
He art F ail ur e

Ke y Car di o vasc ular E x pl or at or y  E n d p oi nt:

Ti me t o first e ve nt of C V deat h or w orse ni n g H F ( defi ne d as H F H os pitalisatio ns or 
Ur ge nt H F visits re gar dless o f I V lo o p di ureti c use), a n d t he i n di vi d ual c o m p o ne nts 
d uri n g t he ra n d o m ised p hase: 
o
C V Deat h
o
W o rse ni n g H F ( H F h os pitalisatio ns or ur ge nt H F visit s re gar dless of I V lo o p 
di uretic use )

Ot her C V E x pl orat or y  E n d p oi nts/ pre-s pecifie d a nal yses:


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl os ilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 0 of 1 3 2

T ot al  e ve nts of C V deat h a n d w orse ni n g H F (as defi ne d a b o ve) d uri n g t he 
ra n d om ised p hase

Mea n dail y f ur ose mi de e q ui vale nt l o o p di uret ic d ose o ver ti me i n t he S Z C gr ou p 
c o mpare d wi t h t he place b o gr o u p d uri n g t he ra n d o mised p hase

C ha n ge i n N T-pr o B N P at t he E O T visit c o m pare d t o ra n d o m isatio n i n t he S Z C a n d 
pl ace b o ar ms.
P atie nt -Re p orte d O utc o mes

To  e x pl ore t he differe nce i n K C C Q- T S S, K C C Q-O S S, a n d ot her K C C Q s u b d o mai ns 
(incl u di n g K C C Q p h ysical li mitat i on sc ore) bet wee n t he S Z C a n d place b o ar ms at t he 
E O T visit c o m pare d t o ra n d o misati o n. 

To  e x pl ore t he relati ons hi p bet wee n al d oster o ne le vels a n d P GI C a n d K C C Q sc ores, 
wi t h p artic ular atte ntio n t o i ntra pati e nt c o nsiste nc y, bet wee n t he S Z C a n d place b o 
ar ms at t he E O T visit c o m pare d t o ra n d o misat i on.
Re n al

Ke y Re nal E x pl orat or y  E n d p oi nt:

C ha n ge i n mea n U A C R * i n t he S Z C gr o u p c o m pare d wi t h place b o gr o u p at :  
o
Scree ni n g c o mpare d t o E O T
o
Ra n d o m isatio n c o m pare d t o E O T
o
Scree ni n g c o mpare d t o ra n d o m isatio n 

Ot her Re nal E x pl or at or y  E n d p oi nts/ pre-s pecifie d a nal yses:

C ha n ge i n mea n U A C R i n S Z C gr o u p c o m pare d wit h pl ace b o gr o u p (as a b o ve), 
a nal yse d b y U A C R strata at  scree ni n g ( < 3 0 mg/ g; 3 1 – 3 0 0 m g/ g; > 3 0 0 m g/ g)

A bs ol ute c ha n ge i n e G F R fr o m ra n d om isatio n t o E O T i n S Z C gr o u p c o m pare d wit h 
pl ace b o gr o u p

C ha n ge i n e G F R sl o pe i n S Z C gr o u p c o m pare d wit h place b o gr o u p ( ac ute [ scree ni n g 
t o ra n d o misatio n], c hr o nic [ra n d o m isatio n t o E O T] , a n d t otal [ scree ni n g t o E O T] 
e G F R sl o pe)

Natri uretic res p o nse o ver ti me i n S Z C vs place b o gr o u ps:  
o
Fract i onal e xcreti o n of Na + ( bl o o d t o uri ne [sa me uri ne sa m ple as f or U A C R; 
m ust c ollect uri ne sa m ple pri or t o l o o p di uret ic d ose])
o
M o ni t or at scree ni n g; at ra n d o misati o n; 1-m o nt h p ost -ra n d o misatio n; E O T
*  U A C R meas ure d as t he mea n o f 3 c o nsec uti ve 1 st m o r ni n g s p ot uri ne c ollecti ons .
Ot her  E x pl or at or y E n d p oi nts:


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 1 of 1 3 2

A d here nce t o st u d y  dr u g ( descri pti ve)

S Z C/ place b o d ose assi g ne d at eac h visit d uri n g t he st u d y  (e g, 5 g e ver y ot her da y; 5, 1 0, 
1 5 g dail y)

S pi r o n olact o ne d ose assig ne d at eac h visit d uri n g t he st u d y  in t he S Z C a n d place b o ar ms 
(e g, 0 m g/ da y; 1 2. 5 m g/ da y or 2 5 mg e ver y ot her da y; 2 5 m g/ da y; 5 0 m g/ da y )
H K -relate d e n d p oi nts:

Ti me t o f irst i nsta nce of use of resc ue t hera p y for H K d uri n g t he ra n d o m ised- wi t hdra wal 
p hase

# of H K e pis o des per treat me nt gr o u p d uri n g t he ra n d omise d -wi t hdra wal  p hase

% of patie nts per treat me nt gr o u p wit h a s K + val ue i n t he f o ll owi n g ra n ges d uri n g t he 6-
m o nt h ra n d omi se d p hase: s K+ 5. 1 -5. 4 m E q/ L; 5. 5 -5. 9 m E q/ L; 6. 0 -6. 4 m E q/ L; 
≥6. 5 m E q/ L

# of e mer ge nc y de part me nt visits f or H K i n t he S Z C a n d place b o ar ms 

# of h os pital isatio ns wi t h dia g n osis c o de f or H K i n t he S Z C a n d place b o ar ms.
O pe n -la bel R u n-i n P hase Descripti ve A nal yses:

% of patie nts t hat are N K a n d recei vi n g s pir o n o lact o ne ≥2 5 m g dail y  at t he e n d of t he 
o pe n -label r u n -i n p hase (e g, % of patient s recei vi n g 2 5 m g, % recei vi n g 5 0 m g)

% of patie nts disc o nt i n ue d fr o m st u d y d uri n g t he o pe n-la bel r u n-i n p hase d ue t o reas o ns 
ot her t ha n H K: 

% of patie nts wit h w orse ne d re nal f u nct i on

% of patie nts wit h h y p ote nsi o n

% ot her
S u b gr o u p a nal yses:

D e m o gra p hics (c o u ntr y , c o mor bi d c o n di tio ns, N T pr o B N P, etc)

P ati e nts wit h H K vs N K at scree ni n g (a nal ysis f or b ot h st u d y p hases)

P ati e nts wit h/ wit ho ut di a betes 

P ati e nts o n s o diu m -gl uc ose tra ns p ort pr otei n 2 i n hi bit or ( S G L T 2i)

P ati e nt o n n o vs l o w-d ose M R A at scree ni n g (a nal ysis f or b ot h p hases)

P ati e nts o n A C Ei/ AR B/ A R Ni; d osi n g/ persiste nce t hr o u g h o ut st u d y  in b ot h treat me nt 
ar ms

P ati e nts e nr olle d d uri n g h os pitalisat i on

P ati e nts wit h rece nt h os pit alisatio n


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 2 of 1 3 2

P ati e nts w h o be gi n t he d o u ble -bli n d i nter ve nt i on peri o d recei vi n g 5 g e ver y  ot her da y, 5 g 
dail y , or 1 0 g dail y .
Ge net ic Researc h

T o c ollect a n d st ore sa m ples of plas ma a n d ser u m f or f ut ure e x pl orat or y  bio m ar ker a n d 
( o ptio nal ) ge netic researc h. Res ults t o be re p orte d o utsi de of t he C S R .
9. 4. 4
S afet y
S af et y will be assesse d i n ter ms o f A Es, S A Es, A Es lea di n g t o treat me nt disc o nt i n uati on, 
la b orat or y data, vit al si g ns, E C G, a n d p h ysical e xa mi nat i ons d uri n g b ot h t he r u n -i n a n d 
ra n d om ised- wi t hdra wal  st u d y p hases. T hese assess me nts will be c ollecte d f or all patient s.
A p pr o priate s u m maries of t hese data will be prese nte d b y  tr e at me nt gr o u p. A Es will be 
classifie d usi n g t he Me d D R A s yste m of n o me nclat ure s yst e m or ga n class ( S O C) a n d preferre d 
t er m ( P T).
A treat me nt -e mer ge nt A E ( T E A E) w ill be 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. Si milarl y, t he n u m ber 
of  p atie nts e x perie nci n g 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 
treat me nt -relate d A Es, a n d n u m ber of s uc h e ve nts, will be s u m marised b y  tr e at me nt gr o u p.
A n o ver vie w of oe de ma- r elate d A Es a n d i nsta nces of sK + < 3. 5 will  be prese nte d.
T he i de nt ifie d ris k of h y p o kalae mia is defi ne d b y la b orat or y val ues a n d n ot b y s pecific 
Me d D R A ter ms.
All A E data will be liste d f or all pat ient s. I n a d ditio 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 (i ncl u di n g s K + a n d sCr) will  be s u m marise d a n d liste d. 
S hift ta bles wi ll be pr o vi de d f or select tests, w here s hift fr o m scree ni n g t o t he w orst val ue 
wi t 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 utside t he 
refere nce ra n ges will be i n dicate d i n all listi n gs.
All safety a nal yses will be perf or me d o n t he Safet y Sets. 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 a n d se paratel y f or t he o pe n-la bel a n d ra n d omise d -
wi t hdra wal  p hases. F ull details o n safety 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 o i nt eri m a nal ysis is pla n ne d f or t his st u d y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 3 of 1 3 2
9. 6
I n de pe n de nt D at a M o nit ori n g C o m mittee
A n i D M C t hat is i n de pe n de nt o f t he s p o ns or will be utilise d for t hi s st u d y. A p pe n di x A , 
Secti o n  A 5, pr o vi des m ore details o n t he rati o nale f or a n d t he re mit of  t he c o m mittee.
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


Cl i nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 4 of 1 3 2
A p pe n di x A
Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
A 1
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h t he f o ll owi n g:

C o n se 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 n isatio ns of Me dical 
S ci e nces ( CI O M S) I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui de li 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 vert ise me nts) m ust be s u b mitte d t o a n I nstituti o nal Re vie w B oar d/I n de pe n de nt Et hics 
C o m mittee ( I R B/I E C) b y t he i n vest i gat or a n d re vie we d an d a p pr o ve d b y t he I R B/I E C
bef ore t he st u d y  is i nitiate d.

A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a n d a p plica ble Re g ulat or y 
A ut h ori t y a p pr o val before 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 p artici pa nts.

Astra Ze neca will be res p o nsi ble f or o btai ni n g t he re q uire d a ut h orisati o ns t o c o n d uct t he 
st u d y fr o m t he c o ncer ne d Re g ulat or y Aut h ori t y. T his res p o nsi bility ma y be dele gate d t o a 
c o ntract researc h or ga nisat i on ( C R O ) b ut t he acc o u nta bilit y re mai ns wit h AstraZe neca.

T he i n vest i 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 F R, I C H g ui deli nes, t he I R B/I E C, 
E ur o pea n Re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), E ur o pea n M e dic al 
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 ulat i ons.
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 otificat i on b y t he i n vest i gat or t o t he s p o ns or of a S A E is esse ntial s o t hat le g al 
o bli gat i ons a n d et hical res p o nsi bilit ies t o war ds t he safety of  partici pa nts a n d t he safet y of  
a st u d y int er ve nt i on u n der cli nical i n vest i gati on are m et.

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 lo c al  re g ulat or y a ut h orit y a n d 
ot her re g ul at or y a ge ncies a b o ut t he safety of  a st u d y int er ve nt i on u n der cli nical 
i n vesti gati on. T he s p o ns or will c o m p l y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts 
r elat i n g t o safety re p orti n g t o t he re g ulat or y a ut h ority,  I R B/I E C, a n d i n vesti gat ors.

F or all st u die s e xce pt t h ose utilizi n g me dical de vices, i n vesti gat or safety 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) acc or di n g t o l ocal 
re g ulat or y r e 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 ulat i on 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 ulat i ons


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 5 of 1 3 2

A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safety i nf or mati on ( e g, s u m mar y or list i n g of S A Es) fr om 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.
Re g ul at or y Re p orti n g Re q uir e me nts f or Seri o us Bre ac hes

Pr o m pt n otificat i on b y t he i n vest i gat or t o Astra Ze neca of a n y ( p ote ntial) seri o us breac h of 
t he pr ot oc ol or re g ulati o ns is esse ntial s o t hat le gal a n d et hical o bli gat i ons are met.

A ‘seri o us breac h’ mea ns a breac h li kel y t o affect t o a si g nifica nt de gree t he safet y 
a n d rig hts of  a partici pa nt o r t he relia bility a n d r o b ust ness o f t he data ge nerate d i n t he 
cli nical st u d y.

If a n y ( p ote ntial) seri o us breac h occ urs i n t he c o urse of t he st u d y, i n vestigat 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 i m me diatel y after 
he or s he bec o me s a ware of it.

I n certai n re gi o ns/c o u ntries, Astra Ze neca has a le gal res p o nsi bility 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 s uc h breac hes.

Astra Ze neca 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 relat i n g t o 
serio us breac h 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. If 
E U Cli nical Trials Re g ulati o n 5 3 6/ 2 0 1 4 a p plies, Astra Ze neca is re q uire d t o e nter 
details o f serio us breac hes i nt o t he E ur o pea n Me dici nes A ge nc y  (E M A) Cli nical 
Tri al I nf or matio n S yste m  ( C TI S). It is i m p orta nt t o n ote t hat re dacte d versi o ns of 
serio us breac h re p orts will be a vaila ble t o t he p u blic via C TI S.

T he i n vest i gat or s h o ul d ha ve a pr ocess i n place t o e ns ure t hat:

T he site staff or ser vice pr o v i ders dele gate d b y t he i n vesti gat or/i nstituti o n are a ble t o 
i de ntif y t he occ urre nce of a ( p ote ntial) seri o us breac h

A ( p ote ntial) seri o us breac h is pr o m pt l y re p orte d t o Astra Ze neca or dele gate d part y, 
t hr o u g h t he c o ntacts (e mail a d dress or tele p h o ne n u m ber) pr o vide d b y Astra Ze neca.
A 2
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i n 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 mat i on 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 vestigat 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 mpleti o n of  t he st u d y.
A 3
I nfor me d C o nse nt Pr ocess


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 6 of 1 3 2

T he i n vest i 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 
parti ci pa nt or his/ her le gall y a ut h orised re prese ntati ve a n d a ns wer all q uest i ons re gar di n g 
t he st u d y.

P arti cipa nts m ust be i nf or m e d t hat t heir partici pat i o n is v ol unt ar y a n d t he y are free t o 
ref use t o partici pate a n d ma y with dra w t heir c o nse nt at a n y  ti me a n d f or a n y reas o n 
d uri n g t he st u d y . Participa nts or t hei r le gall y a ut h orised re prese ntati ve will be re q uire d t o 
sig n a state m e nt of inf or m e d c o nse nt t hat meets t he re q uire me nts of  2 1 C F R 5 0, lo c al  
re g ulat i ons, 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 IR B/I E C or st u d y  ce ntre.

T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o bta i 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 or ised pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.

P arti cipa 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 u ri n g t heir 
parti ci pat i on i n t he st u d y.

A c o p y  of t he I C F(s) must 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 or ised re prese ntati ve.
P arti cipa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F .
T he I C F will c o ntai n a se parate secti o n t hat a d dresses a n d d oc u me nts t he c ollect i on a n d use of 
a n y ma n dat or y a n d/ or o ptio nal h u ma n bi o l ogical  s a mples. T he i n vest i gat or or a ut h orised 
desi g nee will e x plai n t o eac h partici pa nt t he o bjecti ves of t he a nal ysis t o be d o ne o n t he 
sa m ples a n d a n y p ote ntial f ut ure use. Partici pa nts will be t ol d t hat t he y are free t o ref use t o 
parti ci pate i n a n y o pti o nal sa m ples or t he f ut ure use a n d ma y wit h dra w t heir c o nse nt at a n y  
ti me a n d f or a n y reas o n d uri n g t he rete nti o n peri o d. 
A 4
D at a Pr otecti o n

P arti cipa nts will be assig ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y part ici 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 nt ifier o nl y; partici pa nt 
na mes or a n y  inf or m at i on w hic h w o ul d ma ke t he partici pa nt i de nt ifia ble will n ot be 
tra nsferre d.

T he parti ci pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-r elate d data will be use d b y 
t he s p o ns or in acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl o s ure a n d use 
of  t h eir data m ust als o b e 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 parti ci pa nt m ust be i nf or me d t hat his/ h er me dical rec or ds ma y be e xa mi ne d b y 
Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h or ised pers o n nel a p p oi nte d b y  t he 
s p o ns or, b y a p pr o 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


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zir c o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 7 of 1 3 2
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 has bee n 
esta blis he d f or t he S Z C de vel o p me nt pr o gra m me i n H F . See t he Steeri n g C o m mittee me m ber 
c o ntracts a n d/ or c harter f or details. T he Steeri n g C o m mittee desi g ne d si g nifica nt as pects of 
t his st u d y pr ot oc ol.
T he safet y of  all Astra Ze neca cli nical st u dies is cl osel y mo ni t ore d o n a n o n-g oi n g basis b y  
Astra Ze neca re prese ntati ves i n c o ns ultat i on wi t h t he Patie nt Safety f unct i on at Astra Ze neca. 
Iss ues i de ntifie d will  be a d dresse d , e g, b y a me n di n g t he C S P a n d letters t o I n vesti gat ors.
A data m o ni t orin g c o m mittee will be esta blis he d t o re vie w e mer gi n g safet y data at pre defi ne d 
i nter vals. T he c o m mit tee will incl u de me m ber(s) i n de pe n de nt of t he s p o ns or . See t he 
i n de pe n de nt data m o nit ori n g c o m mittee (i D M C) c harter f or details o n t he sc o pe a n d 
me m bers hi p. T he i D M C ma y re q uest u n bli n de d data if nee de d t o assess a n y e mer gi n g safet y 
c o ncer ns. T he i D M C ca n rec o m me n d t he st u d y t o be a me n de d if necessar y f or t he pr otectio n 
of  t he s u bjects partici pati n g i n t he trial.
A 6
Disse mi n ati o n of Cli nic al St u d y D at a
A n y res ults b ot h tec h nical a n d la y  s u m maries f or t his trial, will be s u b mitte d t o E U C TI S 
wi t hi n a year fr o m glo bal E n d of Trial Date i n all partici pat i n g c o u ntries, d ue t o scie nt ific 
reas o ns, as ot her wise statistical a nal ysis is n ot rele va nt.
A descri pt i on of t his cli nical st u d y will  be a vaila ble o n 
ht t 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 
s u m mar y of t he mai n st u d y res ults w hen 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 mai n 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 ulat i ons of t he c o u ntries i n w hic h t he mai n 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 relat i n g to t he st u d y  will be rec or de d o n eC 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 
sig ni n g t he eC R F.

T he i n vest i 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 mat i on e ntere d i n t he eC R F.

T he i n vest i gat or m ust per mit st u d y-r elat e d mo ni t 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 pectio ns a n d pr o vi de di rect access t o s o urce data d oc u me nts.

M o ni t ori n g details descri bi n g strate g y, i ncl u di n g defi niti on o f st u d y-critical d at a it e ms 
a n d pr ocesses (e g, ris k-base d i nit iati ves i n o perati o ns a n d q uality s uc h as Ris k 
Ma na ge me nt a n d Mit i gati on Strate gies a n d A nal yt ical 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 om p lia nce iss ues a n d 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 8 of 1 3 2
m o nit ori n g tec h ni q ues (ce n tr al, re mote, or o n -site mo ni t ori n g) are pr o vide d i n t he 
M o ni t ori n g Pla n.

Astra Ze neca or desi g nee is res p o nsi ble f or me dical o versi g ht t hr o u g h o ut t he c o n d uct of 
t he st u d y w hic h i ncl u des cli nical re vie ws of st u d y data i n acc or da nce wit h t he c urre ntl y 
a p pr o ve d pr ot oc ol. M o nit ori n g details descri bi n g cli nical re vie ws of st u d y  data fr o m a 
me dical pers pect i ve are i ncl u de d i n m ore detail i n t he M o nit ori n g Pla n.

Astra Ze neca 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  incl u di n g 
q ualit y c hec ki n g of  t he data.

Astra Ze neca ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals ( e g,
C o ntract Researc h Or ga n isatio ns).

St u d y  mo ni t ors will perf or m o n g oi n g s o urce data verificati o n as per t he M o nit ori n g Pl a n
t o c o nfir m t hat data e ntere d i nt o t he eC R F b y a ut h or ised si te pers o n nel are acc urate, 
c o mplete, 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 rig hts of  partici pa nts 
are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d i n acc or 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 ulator y  r e 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 vest i gat or f or 2 5 y ears after st u d y arc hi vi n g or as re q uire d b y 
local re g ulati o ns, acc or di n g t o t he Astra Ze neca Gl o bal rete nti o n a n d Dis p osal ( G R A D) 
Sc he d ule. 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 
wi t ho ut wri tte n n otificati on 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. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.

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 
wi t 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 dical 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 n t me dical rec or ds m ust be a vaila ble.

Defi nit i on o f w hat c o nstit utes s o urce data ca n be f o u n d i n t he Trial Master File a n d 
I n vesti gat or Site File. All i nf or mati on i n ori gi nal rec or ds a n d certifie d c o pies of ori gi nal  
rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a cli nical st u d y necessar y 
f or t he rec o nstr ucti o n a n d e val uati on of t he st u d y  are defi ne d as s o urce d oc u me nts. 
S o urce data are c o ntai ne d i n s o urce d oc u me nts ( ori gi nal rec or ds or certifie d c o pies).
A 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 uitme nt  of 
parti ci pa nts. T he st u d y start date f or t his st u d y will be Dece m ber 2 0 2 0.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 9 of 1 3 2
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 on of t he s p o ns or . St u d y sites will be close d u p o n st u d y  
c o mplet i on. A st u d y site is c o nsi dere d close 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 o llecte d a n d a st u d y-sit e clos ure visi t has bee n perf or me d.
T he i n vest i gat or ma y i nitiate st u d y-sit e clos ure at a n y  time, pr o vi de d t here i s 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 nat i on.
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 may i ncl u de b ut are 
n ot li mite d t o:

Fail ure of t he i n vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  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 uitme nt  of p artici pa nts b y t he i n vestigat or

D isc o nti n uati o n o f f urt her st u d y int er ve nt i on de vel o p m e 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 IR Bs /IE C s, t he re g ulat or y a ut h orities, a n d a n y c o ntract researc h 
or ga n isatio n(s) use d i n t he st u d y of t he reas o n f or ter mi nati on or s us pe nsi o n, as s pecifie d b y 
t he a p plica ble re g ulat or y r e q uire me nts. T he i n vesti gat or s hall pr om ptl y i nf or m t he parti ci pa nt 
a n d s h o ul d ass ure a p pr o priate parti ci pa nt t hera p y a n d/ or f ollo w - u p.
P arti cipa nts fr o m  t ermi 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 nt ific meet i 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  inf or mati o n a n d t o 
pr o vi de c o m me nts.

T he s p o ns or will c o m p l y with t he re q uire me nts f or p u blicati o n o f st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit o rial a n d et hic al pr a ctice, t he s p o ns or will ge nerall y s u p p ort 
p u blicat i on of m ult ice ntre st u dies o nl y in t hei r 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 de ter mi ne d b y mut u al  a gree me nt a n d i n li ne with I nter nat i onal 
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 - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 0 of 1 3 2
A p pe n di x B
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
B 1
Defi niti o n of a d verse e ve nts
A n a d verse e ve nt ( A E) 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 pat ient  or 
cli nical st u d y parti ci 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 relat i ons 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 ur a 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 (e g, na usea, c hest pai n), or 
di sease te mp orall y ass oci at e 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 
r elate d t o t he me dici nal pr o d uct . 
T he ter m  A E is use d t o i ncl ude b ot h seri o us a n d n o n -serio us A Es a n d ca n i ncl u de a 
deteri or ati o n of  a pre-e xist i n g me d ical 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 int er ve nt i on has bee n a d mi nistere d.
B 2
Defi niti o n of S eri o us A d verse E ve nts
A serio us a d verse e ve nt i s 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 ulfils o ne or m ore of t he f o ll owi n g cri t eria:

Res ults i n deat h

Is i m me diatel y life-t hreate ni n g

Re q ui res i n-partici pa nt h os pitalisat i on or pr ol o n gati o n of e xist i n g h os pitalisati on 

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca paci t y. 

Is a c o n ge nital a n o ma l y or bi rt 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 m a 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.
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 i t 
occ urre d or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d uct w o ul d res ult i n t he 
parti ci pa nt ’s deat h. ‘Life -t hreate ni n g’ d oes n ot m ea 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 patit is t hat res ol ve d with o ut he patic fail ure).
H os pit alis ati o n
O ut pati e nt treat me nt i n a n e mer ge nc y r o o m is n ot i n itself a serio us A E, alt h o u g h t he reas o ns 
f or it ma y be ( e g, br o nc h os pas m, lar y n geal oe de ma) . H o s 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 nsidere d A Es if t he ill ness or disease 
e xiste d bef ore t he parti ci pa nt was e nr o lle d i n t he st u d y, pr o vide d t hat i t did 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.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 1 of 1 3 2
I m p ort a nt me dic al e ve nt or me dic al tre 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 u atio ns w here i m p or ta nt me dical e ve nts ma y not be i m me diatel y life t hreate ni n g or res ult i n 
deat h, h os pi talisati on, di sa bilit y or i nca pacit y but ma y je o par d ise t he parti ci pa nt or ma y  
re q uir e me dical treat me nt t o pre ve nt o ne or m ore o utc o mes liste d i n t he defi nit i on of seri o u s. 
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 V h y dr oc ortis o ne 
treat me nt

He pat ot o xicit y ca use d b y paraceta m o l (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 y scrasias (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, etc.) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisat i on

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 sc 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 ( di s c o mfort s ufficie nt t o ca use i n t erfere nce wit h n or mal a cti vities)

se vere (i nca pacitati n g, wit h i na bility t o perf or m n or m al 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 serio 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 
se veral h o urs ma y be c o nsi dere d se vere na usea, b ut n ot a S A E u nless it meets t he criteria 
s h o w n i n A p pe n di x B 2 . 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 
di sa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a S A E w he n it satisfies t he criteria 
s h o w n i n A p pe n di x B 2.
B 3
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n
W he n ma ki n g a n assess me nt of ca usalit y c o nsider t he f oll o wi n g f act 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 m a 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 ble te m p oral relat i ons hi p t o t he a d mi nistrati o n of t he 
s us pect dr u g?


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 2 of 1 3 2

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 wl e dge of t he s us pect dr u g ( p har mac ol o g y  a n d t o xic o l og y ) or dr u gs of t he sa me 
p har mac o l ogi cal class? Or c o ul d t he A E be a nt ici pate d fr o m its p har mac ol ogi cal 
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 al ter 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 o l og 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 nt r 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  t ests. A s pecific la b orat or y i n vest i gati on (if perf or me d) has c o nfir me d t he 
r elat i ons 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 d e if f o ll 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 bility ’ of  a ca usal r el atio 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 ons hi p.
T he ca usalit y assess me nt is perf or me d base d o n t he a vaila ble da ta i ncl u di n g e n o u g h 
i nf or mat i on t o m a ke a n i nf or me d j u d ge 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 relat i ons hi p, t he e ve nt(s) will be assesse d as ‘n ot rel ate d’.
Ca usal relat i ons hi p i n cases w here t he disease u n der st u d y  has deterior at e d d ue t o lac k of 
effect s h o uld be classifie d as n o reas o na ble p ossi bilit y.
B 4
Me dic ati o n Err or , Dr u g A b use, a n d Dr u g Mis use
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 dicat i on 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 for a n Astra Ze neca st u d y  i nter ve nt i on t hat eit her ca uses har m t o t he 
parti ci pa nt or has t he p ote ntial t o ca use har m t o t he partici pa nt . 
A me dicat i on 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 ocess-r elate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y sit e st aff or parti ci pa nt.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 3 of 1 3 2
Me dicat i on err or i ncl u des sit uat i ons 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 uld 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

Di s 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 nister e 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 o l 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 dicat i on (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 dicati on err ors i n cli nical st u dies:

Err ors relate d t o or res u lti n g fr om I R T/ R T S M - i ncl u di n g t h ose w hic h lea d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha ve bee n a me dicati o n err or 

P arti cip a nt a c ci 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)

P arti cip a nt f aile d t o ret ur n u n use d me dicat i on 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 dicat i on, or sta n dar d of care me dicat i on i n 
o pe n l a bel st u dies, e ve n if a n Astra Ze neca pr o d uct 
Me dicat i on 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 dicat i on err or.
Dr u g A b use
F or t he p ur p ose of t his st u d y , dr u g a b use is defi ne d as t he persiste nt or s p ora dic i nte nti onal, 
n o n- t hera pe ut ic e xcessi ve use of I n vesti gati onal M e di ci nal Pr o d uct ( I M P) or Astra Ze neca 
N o n -I M P (NI M P ) f or a percei ve d re war d or desire d n o n-t hera pe utic effect.
A n y e ve nts of dr u g a b use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ure d a n d f or war de d t o 
t he Data E ntr y Site ( D E S) usi n g t he Dr u g A b u se Re p ort F or m. T his f or m s h o ul d be use d b ot h 


Cli nical St u d y Pr ot o c ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 4 of 1 3 2
if t he dr u g a b use ha p pe ne d i n a st u d y partici pa nt or if t he dr u g a b use i n v o l ves a pers o n n ot 
e nr o lle d i n t he st u d y (s uc h as a relati ve of t he st u d y p artici pa nt).
E xa m ples of dr u g a b use i ncl u de b ut are n ot li mite d t o:

T he dr u g is use d wit h t he i nte nt of get ti n g a percei ve d re war d ( b y t he st u d y partici pa nt 
or a pers o n n ot e nr olle d i n t he st u d y )

T he dr u g i n t he f or m o f a ta blet is cr us he d a n d i njecte d or s n orte d wit h t he i nte nt of 
getti n g hi g h
Dr u g Mis use
Dr u g mis use is t he i nte nt i onal a n d i na p pr o priate use ( b y a st u d y partici pa nt) of I M P or 
Astra Ze neca NI M P f or me dici nal p ur p oses o utsi de of t he a ut h orise d pr o d uct i nf or mat i on, or 
f or u na ut h orise d I M Ps or Astra Ze neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol  a n d i ncl u des deli berate a d mi nistratio n of  t he pr o d uct b y t he wr o n g r o ute.
E ve nts of dr u g mis use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ure d a n d f or war de d t o 
t he D E S usi n g t he Dr u g Mis use Re p ort F or m. T his f or m s h o ul d be use d b ot h if t he dr u g 
mis use ha p pe ne d i n a st u d y  p artici pa nt or if t he dr u g mis use re gar ds a pers o n n ot e nr olle d i n 
t he st u d y (s uc h as a relat i ve of t he st u d y partici pa nt).
E xa m ples of dr u g mis use i ncl u de b ut are n ot li mite d t o:

T he dr u g is use d wit h t he i nte nt i on t o ca use a n effect i n a n ot her pers o n

T he dr u g is s o ld t o ot her pe o ple f or recreati o nal p ur p oses 

T he dr u g is use d t o facilitate assa ult i n a n ot her pers o n

T he dr u g is deli beratel y a d mi nistere d b y t he wr o n g r o ute

T he dr u g is s plit i n half beca use it is easier t o s wall o w, w he n it is state d i n t he pr ot oc ol 
t hat it must be s wall o we d w h ole

O nl y half t he d ose is ta ke n beca use t he st u d y  participa nt feels t hat he/s he is feeli n g 
better w he n n ot ta ki n g t he w h ole d ose

S o m e o ne w h o is n ot e nr olle d i n t he st u d y int e nt i onall y  ta kes t he dr u g


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 5 of 1 3 2
A p pe n di x C
H a n dli n g of H u m a n Bi ol o gic al S a m ples
C 1
C h ai n of c ust o d y
A f ull c hai n of c ust o d y is mai ntai ne d f or all sa m ples t hr o u g h o ut t heir lifec ycle.
T he i n vest i gat or at eac h ce ntre kee ps f ull tracea bilit y of c ollecte d bi ol ogi cal sa mpl es f r o m t he 
parti ci pa nts w hile i n st ora ge at t he ce ntre u ntil s h i p me nt or dis p osal ( w here a p pr o priate) a n d 
rec or ds rele va nt pr ocessi n g i nf or mati o n relate d t o t he sa m ples w hilst at site.
T he sa m ple recei ver kee ps f ull tracea bilit y of  t he sa mples w hile i n st ora ge a n d d uri n g use u nt il 
use d or dis p ose d of or u ntil f urt her s hi p me nt a n d kee ps rec or d of recei pt of arri val a n d o n war d 
s hi p me nt or dis p osal.
Astra Ze neca or dele gate d re prese ntati ves will kee p o versi g ht of t he e nt ire life c ycle t hr o u g h 
i nter nal pr oce d ures, mo ni t orin g of st u d y  sites, a u diti n g or pr ocess c hec ks, a n d co ntract ual  
re q uire me nts of e xter nal la b orat or y pr o viders
S a m ples retai ne d f or f urt her use will be st ore d i n t he Astra Ze neca -assi g ne d bio b a n ks or ot her 
sa m ple arc hi ve facilities a n d will be trac ke d b y t he a p pr o priate Astra Ze neca T ea m d uri n g f or 
t he re mai n der of t he sa mple life c ycle.
If re q uire d, Astra Ze neca will e ns ure t hat re mai ni n g bi ol ogi c al s a mples are ret ur ne d t o t he site 
acc or di n g t o l ocal re g ulati o ns or at t he e n d of t he rete nti o n peri o d, w hic he ver is t he s o o ner.
C 2
Wit h dr a w al of I nf or me d C o nse nt f or d o n ate d bi ol o gic al s a m ples 
Astra Ze neca e ns ures t hat bi o l ogi cal sa m ples are ret ur ne d t o t he s o urce or destr o ye d at t he e n d 
of  a s pecifie d peri o d as descri be d i n t he i nf or me d c o nse nt.
If a partici pa nt wit h dra ws c o nse nt t o t he use of d o nate d bi ol ogical  sa m ples, t he sa m ples will 
be dis p ose d of/ destr o y e d/re patriate d, a n d t he acti o n d oc u me nte d. If sa m ples are alrea d y  
a nal yse d , Astra Ze neca is n ot o bli ge d t o destr o y  t he res ults of t his researc h.
F o ll owi n g wi t hdra wal  of c o nse nt f or bi ol ogi c al sa m ples, f urt her st u d y particip ati o n s h o ul d be 
c o nsi dere d i n relat i on t o t he wi t hdra wal  pr ocesses o utli ne d i n t he i nf or me d c o nse nt.
T he i n vest i gat or:

E ns ures partici pa nt ’s wit hdra wal of i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
hi g hli g hte d i m me diatel y t o Astra Ze neca or dele gate.

E ns ures t hat rele va nt h u ma n bi o l ogical sa m ples fr o m  t hat partici pa nt, if st ore d at t he 
st u d y site, are i m me diatel y ide nt ifie d, dis p ose d of as a p pr o priate, a n d t he acti o n 
d oc u m e nte d


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 6 of 1 3 2

E ns ures t hat t he partici pa nt a n d Astra Ze neca are i nf or me d a b o ut t he sa m ple di s p osal.
Astra Ze neca e ns ures t he or ga n isatio n(s) h ol di n g t he sa m ples is/are i nf or m e d a b o ut t he 
wi t hdra w n c o nse nt i m me diatel y a n d t hat sa m ples are dis p ose d of or re patriate d as a p pr o priate, 
a n d t he acti o n is d o c u m e nte d a n d st u d y sit e is n otifie d.
C 3
I nter n ati o n al Airli ne Tr a ns p ort ati o n Ass oci ati o n 6. 2 G ui d a nce 
D oc u me nt
L A B E L LI N G A N D S HI P M E N T O F BI O H A Z A R D S A M P L E S
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati on (I AT A)  
(htt ps:// w w w .i at a. or g/ w h at we d o/c ar g o/ d gr/ P a ges/ d o w nl o a d. as p x) classifies i nfecti ous 
s u bsta nces i nt o 3 cate g ories: Cate g or y A, Cate g or y B or E xe m pt
C ate g or y A I nfecti o us S u bst a nces are i nfect i ous s u bsta nces i n a f or m t hat, w he n e x p os ure t o 
it occ urs, is ca pa ble of ca usi n g per ma ne nt disa bilit y,  life-t hreate ni n g or fatal disease i n 
ot her wi se health y h u ma ns or a ni mals. 
C ate g or y A p at h o ge ns are e g, E b ola, Lassa fe ver vir us. I nfecti o us s u bsta nces meet i n g t hese 
criteria w hic h ca use disease i n h u ma ns or b ot h i n h u ma ns a n d a ni mals m ust be assi g ne d t o U N 
2 8 1 4. I nfecti o us s u bsta nces w hic h c a use disease o nl y in a ni mals m ust be assi g ne d t o U N 
2 9 0 0:
C ate g or y B I nfecti o us S u bst a nces are i nfect i ous S u bsta nces t hat d o n ot meet t he criteria f or 
i ncl usi on i n Cate g or y  A. Cate g or y B pat h o ge ns are e g, He patitis A, C, D, a n d E vir uses. T he y 
are assi g ne d t he f o ll owi n g U N n u m ber a n d pr o per s hi p pi n g na me

U N 3 3 7 3 – Bi o l ogi cal S u bsta nce, Cate g or y B

Are t o be pac ke d i n acc or da nce wit h U N 3 3 7 3 a n d I A T A 6 5 0 .
E xe m pt - S u bsta nces w hic h d o n ot c o ntai n i nfect i o us s u bsta nces or s u bsta nces w hic h are 
u nli kel y  t o ca use disease i n h u ma ns or a ni mals are n ot s u bject t o t hese Re g ulati o ns u nless t he y 
meet t he criteria f or i ncl usi o n i n a n ot her class.

Cli nical st u d y sa m ples will fall i nt o Cate g or y  B or e xe m pt u n der I A T A re g ulati ons

Cli nical st u d y  sa m ples will r o uti nel y b e pac ke d a n d tra ns p orte d at a m bie nt te m perat ure i n 
I A T A 6 5 0 c o m plia nt pac ka gi n g 
( htt ps:// w w w.iata. or g/ w hat we d o/car g o/ d gr/ D oc u me nts/ D G R- 6 0-E N -PI 6 5 0. p df).

Bi ol o gi cal sa m ples tra ns p orte d i n dr y ice re q uire a d ditio nal  da n ger o us g o o ds s pecificati on 
f or t he dr y-ice c o nte nt .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilica te ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 7 of 1 3 2
A p pe n di x D
O pti o n al Ge n o mics I niti ati ve S a m ple 
D 1
Use/ A n al ysis of D N A

Astra Ze neca i nte n ds t o c ollect a n d st ore D N A f or ge net ic researc h t o e x pl ore h o w ge netic 
variat i ons ma y affect cli nical para meters, ris k a n d pr o g n osis o f di seases, a n d t he res p o nse 
t o me d icati ons. T his ge netic researc h ma y lea d t o better u n dersta n di n g of diseases, better 
di a g n osis of diseases or ot her i m pr o ve me nts i n healt h care a n d t o t he disc o ver y o f ne w 
di a g n ostics, treat me nts or me dicat i ons. T heref ore, w here l ocal re g ulat i ons a n d I R B/I E C 
all o w, a bl o o d sa m ple will be c ollecte d f or D N A a nal ysis fr o m c o nse nt i n g partici pa nts.

T his o pti o nal ge net ic researc h ma y c o nsist of t he a nal ysis of t he str uct ure of t he 
parti ci pa nt ’s D N A, ie, t he e ntire ge n o me. 

T he res ults of ge net ic a nal yses ma y be re p orte d i n a se parate st u d y s u m mar y.

T he s p o ns or will st ore t he D N A sa m ples i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de nt iality.
D 2
Ge netic R ese arc h P l a n a n d P r oce d ures
Selecti o n of Ge netic R ese arc h Po p ul ati o n

All p arti ci pa nt s will be as ke d t o parti cipate i n t his ge net ic researc h. Parti ci pat i on is 
v o l unt ar y a n d if a parti ci pa nt decli nes t o partici pate t here will be n o pe nalt y or l oss of 
be nefit . T he parti ci pa nt will n ot be e xcl u de d fr o m a n y as pect of t he mai n st u d y.
I ncl usi o n Crite ri a
F or i ncl usi o n i n t his ge netic researc h, parti ci pa nt s m ust f ulfil all of t he i ncl usi on cri teria 
descri be d i n t he mai n b o d y  of t he C S P a n d p r o vide i nf or me d c o nse nt f or t he Ge n o mics 
I nitiati ve sa m pli n g a n d a nal yses.
E xcl usi o n Cr iteri a

E xcl usi o n fr om t his ge net ic researc h ma y be f or a n y of t he e xclusi o n  crit eria s pecifie d i n 
t he mai n st u d y or a n y of t h e fol l owi n g:

Pre vi o us all o ge neic b o ne marr o w tra ns pla nt

N o n -le u k oc yte de plete d w h ole bl o o d tra nsf usi on i n 1 2 0 da ys of ge netic sa m ple 
c ollect i on

Heal t h y V olu nt eers a n d pae diatric pat ient  sa mples will  not be c oll ecte d f or t he 
Ge n o mics I nit iati ve.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 8 of 1 3 2
Wit h dr a w al of C o nse nt f or G e netic R ese arc h

P arti cipa nts ma y  wit hdra w fr o m  t his ge netic researc h at a n y ti me, i n de pe n de nt of a n y 
decisi o n c o ncer ni n g partici pati o n i n ot h er as pects of t he mai n st u d y. V ol u ntar y  
wi t hdra wal  will n ot preju dice f urt her treat me nt . Pr oce d ures f or wit h dra wal are o utli ne d i n 
S ectio n  7. 2 of  t he p r ot oc ol.
C ollecti o n of S a m ples f or Ge netic R ese arc h

T he bl o o d sa m ple f or t his ge netic researc h will be o btai ne d fr o m t he parti ci pa nt s at st u d y 
e ntr y. Alt h o u g h D N A is sta ble, earl y sa m ple c ollecti o n is preferre d t o a v oi d i ntr o d uci n g 
bias t hr o u g h e xcl u di n g parti ci pa nt s w h o ma y wit h dra w d ue t o a n a d verse e ve nt ( A E). If 
f or a n y reas o n t he sa m ple is n ot dra w n at st u d y e ntr y, it ma y be ta ke n at a n y visit u ntil t he 
last st u d y visit. O nl y o ne sa m ple s h o ul d be c ollecte d per partici pa nt f or ge netics d uri n g 
t he st u d y.
C o di n g a n d S t or a ge of D N A S a m ples

T he pr ocesses a d o pte d f or t he c o di n g a n d st ora ge of sa m ples f or ge net ic a nal ysis are 
i m p orta nt t o mai ntai n parti ci pa nt c o nfi de nt iality . S a mples will be st ore d f or a ma xi m u m 
of  1 5 years, fr o m t he date of last partici pa nt last visit, after w hic h t he y will be destr o ye d. 
D N A is a fi nite res o urce t hat is use d u p d uri n g a nal yses . S a mples will  be st ore d a n d use d 
u nt il n o f urt her a nal yses are p ossi ble or t he ma xi m u m st ora ge ti me has bee n reac he d.

A n a d dit i on al  sec o n d c o de will be assi g ne d t o t he sa m ple either bef ore or at t he ti me of 
D N A e xtracti o n re placi n g t he i nf or mat i on o n t he sa m ple t u be. T hereafter, t he sa m ple will 
be i de ntifia ble o nl y b y t he sec o n d, u ni q ue n u m ber . T hi s n u m ber is use d t o ide ntif y  t he 
sa m ple a n d c orres p o n di n g data at t he Astra Ze neca ge net ics la b orat ories, or at t he 
desi g nate d or ga nisati o n . N o pers o nal details i de nt if yi n g t he i n di vi d ual will be a vaila ble t o 
a n y pers o n ( Astra Ze neca e m pl o yee or desi g nate d or ga ni sati ons w or ki n g wit h t he D N A).

T he li n k bet wee n t he parti ci pa nt e nr ol me nt/ra n d o misat i on c o de a n d t he sec o n d n u m ber 
will be mai ntai ne d a n d st ore d i n a sec ure e n vir o n me nt, wit h restricte d access at 
Astra Ze neca or desi g nate d or ga nisat i o ns. T he li n k will be use d t o i de ntif y  t h e r ele va nt 
D N A sa m ples f or a nal ysis, facilitate c orrelat i on of ge n ot y pic res ul ts wit h cli nical data, 
all o w re g ulat or y a u dit, a n d per mit traci n g of sa m ples f or destr ucti o n i n t he case of 
wi t hdra wal  of c o nse nt.
Et hic al a n d R e g ul at or y R e q uire me nts

T he pri nci ples f or et hical a n d re g ulat or y  re q uire me nts f or t he st u d y, i nclu di n g t his 
ge net ics researc h c o m p o ne nt, are o utli ne d i n A p pe n di x A.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 9 of 1 3 2
I nf or me d Co nse nt

T he i nf or me d c o nse nt f or t he o pti o nal ge n o mic s ini tiat i ve sa m ple will be o btai ne d at 
V isit 1.

T he ge netic c o m p o ne nt of t his st u d y  is o ptio nal a n d t he parti ci pa nt ma y part ici pate i n 
ot her c o m p o ne nts o f t he mai n st u d y wit ho ut parti ci pati n g i n t his ge net ic c o m p o ne nt. T o 
parti ci pate i n t he ge net ic c o m p o ne nt of t he st u d y t he partici pa nt m ust si g n a n d date b ot h 
t he c o nse nt f or m f or t he mai n st u d y a n d t he a d de n d u m for t he Ge n o mics I nit iati ve 
c o mp o ne nt of t he st u d y. C o pies of b ot h sig ne d a n d date d c o nse nt f or ms m ust be gi ve n t o 
t he partici pa nt a n d t he ori gi nal file d at t he st u d y ce ntre. T he Pri nci pal i n vesti gat or(s) is 
res p o nsi ble f or e ns uri n g t hat c o nse nt is gi ve n freel y a n d t hat t he partici pa nt u n dersta n ds 
that t he y ma y freel y wit h dra wal fr o m t he ge netic as pect of t he st u d y at a n y time.
P artici p a nt D at a P r otecti o n

Astra Ze neca will n ot pr o vi de i n di vi d ual ge n ot y pe res ul ts t o partici pa nt s, a n y ins ura nce 
c o mpa n y, a n y e m pl o yer, t hei r fa mil y me m bers, ge neral p h ysicia n u nless re q uire d t o d o s o 
b y la w.

E xtra preca uti o ns are ta ke n t o preser ve c o nfi de nt iality a n d pre ve nt ge netic data bei n g 
li n ke d t o t he i de ntity of  t he parti ci pa nt . I n e xce pti onal circ u msta nces, h o we ver, certai n 
i n di vi d uals mi g ht see b ot h t he ge netic data a n d t he pers o nal i de ntifiers of a parti ci pa nt . 
F or e xa m ple, i n t he case of a me dical e mer ge nc y , a n Astra Ze neca P h ysicia n or a n 
i n vesti gat or mi g ht k n o w a partici pa nt ’s i de ntity a n d als o ha ve access t o his or her ge netic 
data . Re g ul at or y a ut h orities ma y re q uire access t o t he rele va nt files, t h o u g h t he 
parti ci pa nt ’s me d ical inf or m at i on a n d t he ge net ic files w o ul d re mai n p h ysicall y se parate.
D at a M a n a ge me nt

A n y ge net ic data ge nerate d i n t his st u d y will be st ore d at a sec ure s yste m at Astra Ze neca 
a n d/ or desi g nate d or ga n isatio ns t o a nal yse t he sa m ples.

Astra Ze neca a n d its desi g nate d or ga nisat i ons ma y s hare s u m mar y res ults (s uc h as ge net ic 
differe nces fr o m gr o u ps of i n di vi d uals wit h a disease) fr o m t his ge netic researc h wit h 
ot her researc hers, s uc h as h os p itals, aca de mic or ga nisati o ns or healt h i ns ura nce 
c o mpa nies . T his ca n be d o ne b y placi n g t he res ults i n scie ntific data bases, w here t he y ca n 
be c o m bi ne d wit h t he res ults of si milar st u dies t o lear n e ve n m ore a b o ut healt h a n d 
di sease. T he researc hers ca n o n l y use t his i nf or matio n  for healt h -relate d researc h 
p ur p oses . Researc hers ma y see s u m mar y res ult s b ut t he y will not be a ble t o see i n di vi d ual 
parti ci pa nt data or a n y pers o nal i de nt ifiers. 

S o m e or all of t he cli nical datasets fr o m t he mai n st u d y ma y be mer ge d wi t h t he ge netic 
data i n a s uita ble sec ure e n vir o n me nt se parate fr o m t he cli nical data base.

Ge net ic data will be re p orte d se paratel y fr om t he cli nical st u d y re p ort.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 0 of 1 3 2
A p pe n di x E
M a n a ge me nt of S t u d y Pr oce d ures D uri n g t he C O VI D - 1 9 
P a n de mic
E 1
I ntr o d ucti o n
S af e 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 o f 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 oin g C O VI D -1 9 o ut brea k. 
Ma na ge me nt descri be d i n t his a p pe n di x relat e d t o st u d y visits a n d S A R S-C O V -2 testi n g 
s h o uld be i m ple me nte d o nl y  d uri n g t he C O VI D-1 9 pa n de mic a n d will a p pl y u nt il f urt her 
n oti ce, as c o m m u nicate d b y t he s p o ns or. C ha n ges t o st u d y visits d ue t o partici pa nts n ot 
wi s hi n g t o or bei n g u na ble t o visit sites s h o uld o nl y  be i m ple me nte d if all o wa ble b y 
l ocal/re gio n al g ui deli nes a n d f ollo wi n g a gree me nt fr o m  t he s p o ns or. 
C ha n ges t hat ma y affect t he st u d y partici pa nts ’ parti ci pat i on i n t he st u d y s h o uld be 
c o m m u nicate d t o t he partici pa nt. It is t he Pri nci pal I n vestigat or ’s res p o nsi bility t o i nf or m t he 
st u d y partici pa nts of a n y c ha n ge i n t he st u d y c o n d uct t hat ma y be i m ple me nte d. T he 
parti ci pa nts’ asse nt a n d/ or c o nse nt t o a n y s uc h c ha n ge i n st u d y c o n d uct s h o uld als o be 
d oc u m e nte d. 
E 2
Ris k Assess me nt f or C O VI D -1 9 P a n de mic 
S Z C is a p otassi u m 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 ditio nal  ris k fr o m C O VI D-1 9 i s e x pecte d d ue t o S Z C. H o we ver, t he ris k o f 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 pat i on 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 dit i onal 
h u ma n c o ntact (e g, wit h site staff). 
Me as ur es 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 dee ms it is a p pr o priate. 
I n a d diti on, t he e nr ol me nt at a site le vel will o nl y  start or res u me w he n l ocal re g ulati ons 
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 dat i ons re gar di n g t he pa n de mic will be strict l y a d here d 
t o. 

Si te is e nc o ura ge d t o c o ntact t he particip a nt wi t hi n 1 da y pri or t o a st u d y  visit, see ne xt 
secti on. St u d y  visits m a y b e mo difie d w here a p pr o pri ate a n d per mitte d b y lo c al  practice, 
see Secti o n E 4.
E 3
C O VI D -1 9 Assess me nt
I n or der t o li mit p ote ntial i nfecti on at t he site, t he site is e nc o ura ge d t o c o ntact t he partici pa nt 
wi t hi n o ne da y pri or t o a n y 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. 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 1 of 1 3 2
C O VI D -1 9 s y m pt o m s i nclu de, b ut are n ot li mit e d t o: fe ver or c hills, c o u g h, s h ort ness of 
breat h or diffic ult y breat hi n g, fat i g ue, m uscle or b o d y ac hes, hea dac he, ne w l oss of taste or 
s mell, s ore t hr oat, c o n gesti o n or r u n n y nose, na usea or v o mit i n g, a n d di arr h oea.
Rec o m me n de d q uest i ons t o deter mi ne ris k o f C O VI D -1 9 are i n cl u de d bel o w f or i nf or m at i on: 
1
Ha ve y o u e x perie nce d u ne x plai ne d fe ver, c o u g h, s h ort ness of breat h, c hills, m uscle pai n, 
hea dac he, s ore t hr oat, a n d/ or ne w l oss of taste or s mell wit hi n t h e past 1 4 da ys ?
2
Ha ve y o u bee n i n c o ntact wit h a n y o ne w h o is sic k or wit h s y m pt o ms i n t he last 1 4 da ys?
3
N ote t o site: pr o be o n t he sa me s y m pt o ms as Q 1
4
Ha ve y o u bee n e x p ose d t o s o me o ne dia g n ose d wit h C O VI D -1 9 i n t he l ast 1 4 da ys?
5
Ha ve y o u bee n practici n g s oc ial dista nci n g o ver t he last 1 4 da ys? 
6
N ote t o site: please refer t o re gi o n/cit y/c o u ntr y  re g ulat i ons
7
Ha ve y o u tra velle d i n t he last 1 4 da ys, if s o w here? 
8
N ote t o site: rece nt tra vel i ncl u di n g t o c o u ntries/re gi o ns wit h Ce nters f or Disease C o ntr ol 
a n d Pre ve nt i on ( C D C ) Le vel 2 or hi g her tra vel war ni n g or e q ui vale nt or k n o w n C O VI D -
1 9 h ot s p ots .
9
Ha ve y o u bee n i n is o lati on or q uara nti ne f or a n y  reas o n i n t he past 1 4 da ys ?
1 0
Ha ve y o u bee n dia g n ose d wit h C O VI D -1 9 at a n y  ti me, if s o w here a n d w he n?
T he parti ci pa nt is als o e nc o ura ge d t o c o ntact t he st u d y site i n case he/s he de vel o ps a n y 
s y m pt o ms of or has a c o nfir me d C O VI D-1 9 dia g n osis.
C O VI D -1 9 pri or  t o e nrol me nt
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 on are n ot t o be e nr o lle 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 
wi t hi n 2 wee ks prior t o e nr ol me nt (e g, a p osit i ve C O VI D-1 9 test or a cli n ical 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 e nr o lle d a n d will be treate d acc or di n g 
t o sta n dar d of care. 
S us pecte d C O VI D- 1 9 after  e n rol me nt
P artici p a nt is sever ely ill or h os pit alise d .
If t he partici pa nt bec ome s s y m pt o matic after e nr ol me nt, 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 ul ts t hat ma y be a vaila ble), a n d is se verel y ill a n d/ or 
h os pi t alised t he parti ci pa nt will per ma ne ntl y disc o nt i n ue st u d y int er ve nt i on . 
If p ossi ble, t he partici pa nt is e nco 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 e ve n 
if off tr e at me nt. Visits ma y be mo difie d per g ui da nce i n Secti o n  E 4 a n d per l o c al  re g ulati ons 
a n d g ui deli nes relate d t o C O VI D- 1 9.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 2 of 1 3 2
P artici p a nt is N O T sever ely ill or h os pit alise d .
If t he partici pa nt bec ome s s y m pt o matic after e nr o l me nt, 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 ul ts are a vaila ble or n ot), a n d is N O T se verel y 
ill a n d/ or h os pitalise d t he i n vesti gat or s h o ul d deter mi ne if c o nti n uati o n of treat me nt wit h I P is 
i n t he best i nterest of t he patie nt.
Re gar dless if I P is c o nt i 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. Visits ma y be mo difie d per g ui da nce i n Secti o n  E 4 a n d per l ocal 
re g ulat i ons a n d g ui deli nes relate d t o C O VI D - 1 9.
E 4
M o difie d Visits
As a ge neral r ule, t he s p o ns or’s e x pectati o n is t hat as l o n g as c o n diti ons per mit, t he partici pa nt 
s h o uld re mai n i n t he st u d y  a n d c o mplete visits as per t he sc he d ule. Of n ote, w he n direct l y 
i nteract i n g wit h a partici pa nt wit hi n t he b o u n daries set b y t his g ui da nce d oc u me nt (e g, st u d y 
vi sit of a n y ki n d) it is e x pecte d a n d ass u me d b y t he s p o ns or t hat it is d o ne i n acc or da nce with 
‘s o cial dista nci n g ’ a n d pr otectio n re q ui re me nts as set b y lo c al  or ders t o ma na ge t he C O VI D -
1 9 pa n de mic. T he s pecifics of s uc h c o n d uct are n ot part of t he sc o pe of t his d oc u me nt. 
Vis its ma y be mo difie d if nee de d d ue t o t he C O VI D -1 9 pa n de mic, if a n o n -site visit is n ot 
p ossi ble d ue t o partici pa nts n ot wis hi n g t o or bei n g u na ble t o visit sites. M o difie d visits ca n 
o nl y  re place a site visit if all o we d b y l ocal/re gi o na l g ui deli nes a n d re g ul at i ons. F urt her, 
m o difie d visit s s h o ul d als o be a gree d wit h t he s p o ns or. 
T he s p o ns or s h o uld be n otifie d of a n y de viat i on fr o m t he re g ular sc he d ule d visits a n d pla n ne d 
st u d y pr oce d ures, a n d of t he alter nati ve pla n t he site will i m ple me nt. A n y de viat i on fr o m t he 
pr ot oc ol  s h o uld be d oc u m e nte d i n t he partici pa nt file wit h a c o m me nt e x plai ni n g t he relat i on 
t o C O VI D-1 9. A m o difie d visit ma y f or e xa m ple be a h o me visit. Re gar dless o f t he mo difie d 
visit a p pr oac h, e ver y  eff ort s h o uld be ma de t o c o m pl ete t he f ull sc o pe of t he st u d y visit 
acti vit ies a n d pr oce d ures (see Sc he d ule of Act i vities [S o A ], Ta ble 1 ). If t his is n ot p ossi ble, t he 
mi ni m u m safet y meas ure me nts s h o ul d al wa ys i ncl u de s K + meas ure me nts a n d, w here 
i n dicate d, a n E C G, i n a d diti on t o c ollect i on of a d verse e ve nts a n d c o nc o mit a nt me dicat i on.
If a n i n-pers o n visit wit h t he partici pa nt is n ot p ossi ble, t he site ma y  c o nsi der ha vi n g a 
t ele me dici ne visit. T he ter m tele me dici ne visit refers t o re m ote c o ntact wit h t he partici pa nts 
usi n g tel ec o m m u nicat i ons tec h n o l og y  s uc h as p h o ne calls, virt ual or vi de o visits, a n d mo bile 
healt h de vices. Ha vi n g a tele me dici ne c o ntact wit h t he pa rtici pa nt will all o w a d verse e ve nts, 
c o nc o mita nt me dicat i on a n d p ote ntiall y re vie w of t he d osi n g car d a n d diar y  t o be re p orte d a n d 
d oc u m e nte d. At  t he earliest p ossi bility,  t he mi ni m u m s af et y meas ure me nts i ncl u di n g s K +
meas ure me nts a n d, w here i n dicate d, a n E C G, m ust be d o ne.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 3 of 1 3 2
A p pe n di x F
K a ns as Cit y C ar di o m y o p at h y Q uesti o n n aire ( K C C Q)


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


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 5 of 1 3 2


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 6 of 1 3 2


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 7 of 1 3 2
A p pe n di x G
P atie nt Gl o b al I m pressi o n of Se verit y f or He art F ail ure 
S y m pt o ms
O verall, h o w w o ul d y o u rate t he se verit y of  yo ur heart fail ure s y m pt o ms o ver t he past 2 
wee ks?
N o s y m pt o ms
Ve r y mil d
Mil d
M o derate
Se vere
Ve r y Se vere


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 8 of 1 3 2
A p pe n di x H
Ne w Y or k He art Ass oci ati o n ( N Y H A) F u ncti o n al 
Cl assific ati o n
Cl ass
P atie nt s y m pt o ms
I
N o li mitati o n of p h ysical acti vit y. 
Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue 
fati g ue, pal pitati o n, d ys p nea (s h ort ness of 
breat h).
II
Sli g ht li mitati o n of p h ysical acti vit y.
C o mf orta ble at rest. Or di nar y p h ysical acti vit y 
r es ults i n fati g ue, pal pitati o n, d ys p nea (s h ort ness 
of breat h).
III
Mar ke d li mitati o n of p h ysical acti vit y.
C o mf orta ble at rest. Less t ha n or di nar y acti vit y 
ca uses fati g ue, pal pitati o n, or d ys p nea.
I V
U na ble t o carr y o n a n y p h ysical acti vit y wit h o ut 
disc o mf ort. S y m pt o ms of heart fail ure at rest. If 
a n y p h ysical acti vit y is u n derta ke n, disc o mf ort 
i ncreases.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 9 of 1 3 2
A p pe n di x I
E n d p oi nt Defi niti o ns
All car dio vasc ular e n d p oi nt defi nit i ons are m o dificati o ns base d o n t he draft Sta n dar dize d 
Defi nit i ons f or Car di o vasc ular a n d Str o ke E n d p oi nt E ve nts i n Cli nical Trials f or C DI S C
( Hic ks et al. 2 0 1 5).
I 1
Cl assific ati o n of De at h
C ar di ov asc ul ar De at h
Car di o vasc ular deat h i ncl u des t he f o ll owi n g cate g ori es:
1
De at h d ue t o Ac ute M y oc ar di al I nf arcti o n ( MI): refers t o a deat h wit hi n 3 0 da ys after a 
m y ocar dial  infarct i on ( MI) relate d t o c o nse q ue nces see n i m me diatel y after t he m y ocar dial 
i nfarcti o n, s uc h as pr o gressi ve c o n gesti ve heart fail ure ( C H F), i na de q uate car diac o ut p ut, 
or refract or y arr h yth mia. If t hese e ve nts occ ur after a “ brea k” (e g, a C H F a n d arr h yt h mia 
free perio d), t he y  s h o uld be desi g nate d b y  t he i m me diate ca use. T he ac ute MI s h o ul d be 
verifie d b y t he dia g n ostic criteria o utli ne d f or ac ute MI (i ncl u di n g a ut o ps y  fi n din gs 
s h o wi n g rece nt MI or rece nt c or o nar y t hr o mb us) a n d t here s h o ul d be n o c o ncl usi ve 
e vi de nce of a n ot her ca use of deat h.
S u d de n, u ne x pecte d car diac deat h, i n v o l vi n g car diac arrest, ofte n wit h s y m pt o ms 
s u g gesti ve of m y ocar dial isc he mia, a n d acc om pa nie d b y p res u ma bl y ne w S T 
ele vat i on, or ne w L B B B a n d/ or e vi de nce of fres h t hr o m b us b y c or o nar y a n gi o gra p h y 
a n d/ or at a ut o ps y, b ut deat h occ urri n g bef ore bl o o d sa m ples c o ul d be o btai ne d, or at a 
ti me bef ore t he a p peara nce of car diac bi omar kers i n t he bl o o d s h o ul d be c o nsidere d 
deat h d ue t o ac ute m y ocar dial  infarcti o n.
Deat h res ult i n g fr o m a pr oce d ure t o treat m y ocar dial isc he mia or t o treat a 
c o mplicat i on res ult i n g fr om m y o car dial infarcti o n s h o ul d als o be c o nsi dere d deat h d ue 
t o ac ute MI.
If deat h occ urs bef ore bi oche mical c o nfir mat i on of m y o car dial necr osis ca n be 
o btai ne d, a dj u dicat i on s h o ul d be base d o n cli nical prese ntati o n a n d E C G e vi de nce.
Deat h d ue t o a m y ocar dial  infarcti o n t hat occ urs as a direct c o nse q ue nce of a 
car dio vasc ular i n vesti gati on/ pr oce d ure/ o perati o n will be classifie d as deat h d ue t o 
ot her car di o vasc ular ca use.
2
S u d de n C ar di ac De at h: refers t o deat h t hat occ urs u ne x pecte dl y a n d i ncl u des t he 
f oll owi n g deat hs:
a.
Deat h wi t nesse d a n d i nsta nta ne o us wit h o ut ne w or w orse ni n g s y m pt o ms
b.
Deat h wi t nesse d wit hi n 6 0 mi n utes of t he o nset of ne w or w orse ni n g car diac 
s y m pt o ms


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 0 of 1 3 2
c.
Deat h wi t nesse d a n d attri b ute d t o a n ide nt ifie d arr h yth mia (e g, ca pt ure d o n a n 
electr ocar dio gra p hic ( E C G) rec or di n g or wit nesse d o n a m o nit or b y  eit her a 
me dic or para me dic, or u n wit nesse d b ut f o u n d o n i m pla nta ble car di o verter -
defi brillat or re vie w) 
d.
Deat h after u ns uccessf ul res uscitat i on fr o m car diac arrest or s uccessf ull y 
res uscitate d fr om car diac arrest b ut w h o die wit hi n 2 4 h o urs wit h o ut 
i de ntificati on of a n o n -car diac etiol o g y  
e.
Deat h > 2 4 h o urs aft er a patie nt has bee n s uccessf ull y res uscitate d fr o m car diac 
arrest a n d wit h o ut i de ntificat i on of a n o n -car dio v asc ular etiol o g y
f.
U n wit nesse d deat h i n a s u bject see n ali ve a n d cli nicall y sta ble ≤2 4 h o urs pri or 
t o bei n g f o un d dea d wit h o ut a n y  e vi de nce s u p p orti n g a s pecific n o n-
car dio vasc ular ca use of deat h (i nf or mat i on re gar di n g t he patie nt’s cli nical 
stat us prece di n g deat h s h o ul d be pr o vi de d, if a vaila ble.
3
De at h d ue t o He art F ail ure or C ar di o ge nic S h oc k: r efers t o deat h occ urri n g i n t he 
c o nte xt of cli nicall y w orse ni n g s y m pt o ms a n d/ or si g ns of heart fail ure n ot i n t he c o nte xt 
of  a n ac ute MI a n d wit h o ut e vi de nce of a n ot her ca use of deat h. Ne w or w orse ni n g si g ns 
a n d/ or s y m pt o ms of c o n gest i ve heart fail ure ( C H F) i ncl u de a n y o f the f oll owi n g:
a.
Ne w or i ncreasi n g s y m pt o ms a n d/ or si g ns of heart fail ure re q uiri n g t he 
i nitiati on of, or a n i ncrease i n, treat me nt directe d at heart fail ure or occ urri n g i n 
a patie nt alrea d y recei vi n g ma xi mal t hera p y for heart fail ure.
b.
Heart fail ure s y m pt o ms or si g ns re q ui rin g c o nt i n u o us i ntra ve n o us dr u g t hera p y 
or o x y ge n a d mi nistrati o n
c.
C o nfi ne me nt t o be d pre d o mi na nt l y d ue t o heart fail ure s y m pt o ms
d.
P ul m o nar y  e de ma s ufficie nt t o ca use tac h yp nea a n d distress n ot occ urri n g i n 
t he c o nte xt of a n ac ute m y ocar dial infarct i on or as t he c o nse q ue nce of a n 
arr h yt h mia occ urri n g i n t he a bse nce of w orse ni n g heart fail ure
e.
Car di o ge nic s h oc k n ot occ urri n g i n t he c o nte xt of a n ac ute MI or as t he 
c o nse q ue nce o f a n arr h yt h mia occ urri n g i n t he a bse nce of w orse ni n g heart 
fail ure.
C ar dio ge nic s h oc k i s defi ne d as s yst olic bl o o d press ure ( S B P) < 9 0 m m H g f or 
greater t ha n 1 h o ur, n ot res p o nsi ve t o fl ui d res uscit atio n a n d/ or heart rate 
c orrectio n, a n d felt t o be sec o n dar y  t o car diac d ysf u nct i on a n d ass ociate d wit h 
at least o ne of t he f o llo wi n g si g ns of h y p o perf usi o n:

C o ol , cla m m y s ki n or

Oli g uria ( uri ne o ut p ut < 3 0 m L/ h o ur) or

Alt ere d se ns oriu m  or

Car di ac i n de x < 2. 2 L/ mi n/ m 2


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 1 of 1 3 2
Car di o ge nic s h oc k ca n als o be defi ne d as S B P ≥9 0 m m H g as a res ult of 
p osi tive i n otr o pic or vas o press or a ge nts al o ne a n d/ or wit h mec ha nical s u p p ort 
i n less t ha n 1 h o ur.
T his cate g or y  will incl u de s u d de n deat h occ urri n g d uri n g a n a d missi o n f or 
w orse ni n g heart fail ure.
4
De at h d ue t o Str o ke: r efers t o cere br o vasc ular e ve nt t he se q uelae of w hic h lea d t o deat h, 
ge nerall y wit hi n 3 0 da ys. T he cere br o vasc ular e ve nt s h o ul d be verifie d b y  t he dia g n ostic 
criteria o utli ne d f or cere br o vasc ular e ve nts (i ncl u di n g a ut o ps y fi n di n gs) a n d t here s h o ul d 
be n o c o ncl usi ve e vi de nce of a n ot her ca use of deat h.
5
De at h d ue t o C ar di o v asc ul ar Pr oce d ures : r efers t o deat h ca use d b y t he i m me diate 
c o mplicat i ons o f a car diac pr oce d ure.
6
De at h d ue t o C ar di o v asc ul ar H ae m orr h a ge: refers t o deat h relate d t o hae m orr ha ge 
s uc h as a n o n-str o ke i ntracra nial hae m orr ha ge, n o n-pr oce d ural or n o n -tra u matic vasc ular 
r u pt ure (e g, a ortic a ne ur ys m), or hae m orr ha ge ca usi n g car diac ta m p o na de
7
De at h d ue t o Ot her C ar di o v asc ul ar C a uses: refers t o a C V deat h n ot i ncl u de d i n t he 
a b o ve cate g ories b ut wit h a s pecific, k n o w n ca use (e g, p ul m o nar y  e m b olis m or perip heral  
arteria disease).
N o n -C ar di ov asc ul ar De at h
N o n -car dio vasc ular deat h is defi ne d as a n y deat h n ot c o vere d b y  car dio vasc ular deat h a n d 
falli n g i nt o o ne of t he f oll owi n g cate g ori es:

P ul m o nar y  fail ure

Re nal *

Gastr oi ntesti nal ca uses

He pat o biliar y

Pa ncreat ic

I nfecti o n (i ncl u des sepsis)

I nfla m mat or y (e g, S yste mic I nfla m mat or y Res p o nse S y n dr o me ( SI R S) / I m m u ne 
(incl u di n g a ut oi m m u ne) ( ma y i ncl u de a na p h yla xis fr o m e n vir o n me ntal (e g, f o o d) 
aller gies)

Hae m orr ha ge t hat i s neit her C V blee di n g or str o ke

N o n -C V pr oce d ure or s ur ger y

Tra u m a

S u ici de

N o n -prescri pt i on dr u g reacti o n or o ver d ose


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 2 of 1 3 2

Prescri pt i on dr u g reacti o n or o ver d ose

Ne ur ol o gi cal ( n o n-car dio v asc ular)

Mali g na nc y

Ot her, pl ease s pecif y.
* Re nal deat h is defi ne d as deat h d ue t o E S R D b ut dial ysis treat me nt was deli beratel y wit h hel d 
( dial ysis was n ot starte d or disc o nti n ue d) f or a n y reas o n, e g, patie nt ref uses dial ysis, treati n g 
p h ysicia n c o nsi ders t he dial ysis f ut ile, or dial ysis is n ot a vaila ble. If deat h is relate d t o ot her 
ca uses t ha n E S R D, t he deat h will N O T be a dj u dicate d as re nal ca u se of deat h. Re nal deat h 
will be classifie d as a n o n -C V deat h.
U n deter mi ne d C a use of De at h
U n deter mi ne d Ca use of Deat h refers t o a deat h n ot attri b uta ble t o o ne of t he a b o ve cate g ories 
of  C V deat h or t o a n o n-C V ca use. I na bilit y t o cl assif y t he ca use of deat h ma y  be d ue t o lac k 
of  inf or m at i on (e g, t he o nl y  a vaila ble i nf or mati o n is “pat ient  die d”) or w he n t here is 
i ns ufficie nt s u p p orti n g i nf or mati on or detail t o assi g n t he ca use of deat h. I n ge neral, m ost 
deat hs s h o ul d be classifia ble as C V or n o n -C V , a n d t he use of t his cate g or y of deat h, t heref ore, 
s h o uld be disc o ura ge d a n d s h o ul d a p pl y t o fe w patie nts i n well -r u n cli nical trials.
I 2
H os pit aliz ati o n f or He art F ail ure
A Heart Fail ure H os pitalizat i on is defi ne d as a n e ve nt t hat meets A L L  of t h e foll o wi n g 
crit eria:
1
T he patie nt is a d mitte d t o t he h os pital wit h a pri mar y  dia g n osis of H F
2
T he patie nt’s le n gt h -of -st a y in h os pi t al e xte n ds f or at least 2 4 h o urs ( or a c ha n ge i n 
cale n dar date if t he h os pital a d missi o n a n d disc har ge ti mes are u na vaila ble)
3
T he patie nt e x hi bits d oc u me nte d ne w or w orse ni n g s y m pt o ms d ue t o H F o n prese ntati o n, 
i ncl u di n g at least O N E of t he f oll owi n g:
a.
D ys p nea ( d ys p nea wit h e xert i on, d y s p nea at rest, ort h o p nea, par o x ys mal 
n oct ur nal  d ys p nea)
b.
Decrease d e xercise t olera nce
c.
Fat i g ue
d.
Ot her s y m pt o m s of  w orse ne d e n d-or ga n perf usi o n or v ol u me o verl oa d (as 
deter mi ne d b y t he me dical j u d ge me nt of t he i n vesti gat or)
4
T he patie nt has o bject i ve e vi de nce of ne w or w orse ni n g H F, c o nsisti n g of at least T W O 
p h ysical e xa mi nat i on fi n di n gs O R o ne p h ysical e xa mi nati on fi n di n g a n d at least O N E 
la b orat or y crit erio n, i ncl u di n g:


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 3 of 1 3 2
a.
P h ysical e xa mi nat i on fi n di n gs c o nsi dere d t o be d ue t o heart fail ure, i ncl u di n g 
ne w or w orse ne d:
i.
P eri p heral  e de ma
ii.
I ncreasi n g a b d omi nal diste nti o n or ascites (i n t he a bse nce of pri mar y 
he pat ic disease)
iii.
P ul m o nar y  rales/crac kles/cre pitati ons
i v.
I ncrease d j u g ular ve n o us press ure a n d/ or he pat oj u g ular refl u x
v.
S 3 gall o p
vi.
Cli nicall y si g nifica nt or ra pi d wei g ht gai n t h o u g ht t o be relate d t o fl ui d 
rete ntio n
b.
La b orat or y  e vi de nce of ne w or w orse ni n g H F, if o btai ne d withi n 2 4 h o urs of 
prese ntati o n, i ncl u di n g:
i.
I ncrease d B-t ype natri uret ic pe pti de ( B N P)/ N-ter mi nal pr o-B N P 
( N T-pr o B N P) c o nce ntrati o ns c o nsiste nt wit h dec o m pe nsati o n o f heart 
fail ure (s uc h as B N P > 5 0 0 p g/ m L or N T -pr o B N P > 2, 0 0 0 p g/ m L). I n 
pati e nts wit h c hr o nica ll y ele vate d natri uretic pe pti des, a si g nifica nt 
i ncrease s h o ul d be n ote d a b o ve scree ni n g baseli ne.
ii.
Ra di ol o gi c al e vi de nce of p ul m onar y  c o n gesti on
iii.
N o n -i n vasi ve dia g n ostic e vi de nce of cli nicall y si g nifica nt ele vate d left -
or ri g ht- side d ve ntri c ular filli n g press ure or lo w car di ac o ut p ut. F or 
e xa m ple, ec h ocar dio gra p hic cri teria c o uld i ncl u de: E/e’ > 1 5 or D -
d o mi na nt p ul m o nar y  ve n o us i nflo w patter n, pl et h oric i nferior ve na ca va 
wi t h mi ni mal c olla pse o n i ns pirati on, or decrease d left ve ntric ular 
o utfl o w tract ( L V O T) mi n ute str o ke dista nce (ti me vel ocit y i nte gral 
( T VI))
O R
i v.
I n vasi ve dia g n ostic e vi de nce with ri g ht heart cat heterizat i on s h o wi n g a 
p ul m o nar y  ca pillar y we d ge press ure ( p ul m o nar y art er y occlusi o n  
press ure) ≥1 8 m m H g, ce ntral ve n o us press ure ≥1 2 m m H g, or a c ar diac 
i n de x < 2. 2 L/ mi n/ m 2
N ote: All res ults fr o m di a g n ost ic tests s h o ul d be re p orte d, if a vaila ble, e ve n if t he y d o n ot 
meet t he a b o ve criteria, beca use t he y  pr o vide i m p orta nt i nf or m at i on f or t he a dju dicat i on of 
t hese e ve nts.
5
T he patie nt recei ves i nitiati on or i nte nsificat i on of treat m e nt s pecificall y for H F, 
i ncl u di n g at least O N E of t he f oll owi n g:
a.
A u g me ntati o n i n oral di uret ic t hera p y


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o n i u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 4 of 1 3 2
b.
I ntra ve n o us di uret ic or vas oacti ve a ge nt (eg, i n otr o pe, vas o press or, or 
vas o dilat or)
c.
Mec ha nical or s ur gical i nter ve nt i on, i ncl u di n g:
i.
Mec ha nical circ ulat or y  s u p p ort (e g, i ntra-a o rtic ballo o n p u m p, 
ve ntri c ular assist de vice, e xtrac or p oreal me m bra ne o x yg e n ati o n, t otal  
artificial heart)
ii.
Mec ha nical fl ui d re m o val (e g, ultrafiltrati o n, he m o filtrati on, di al ysis) .
A n Ur ge nt He art F ail ur e Visit is defi ne d as a n e ve nt t hat meets all of t he f oll owi n g:
1 
T he patie nt has a n ur ge nt, u nsc he d ule d office/ practice or e mer ge nc y de part me nt visit f or 
a pri mar y di a g n osis of H F, b ut n ot meet i n g t he criteria f or a H F h os pitalizati on.
2
All si g ns a n d s y m pt o ms f or H F h os pitalizati on (i e, 3) s y m pt o ms, 4) p h ysical e xa mi nati on 
fi n di n gs/la b orat or y e vi de nce of ne w or w orse ni n g H F, as i n dicate d a b o ve).
3
T he patie nt recei ves i nit iati on or i nte nsificat i on of treat m e nt s pecificall y for H F, as 
detai le d i n t he a b o ve secti on wi t h t he e xce pti on of oral  diuret ic t hera p y, w hic h will n ot be 
s ufficie nt.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 5 of 1 3 2
A p pe n di x J
A b bre vi ati o ns 
A b bre vi ati o n 
E x pl a n ati o n
A C C F
A merica n C olle ge of Car di ol o g y F o u n dati o n
A C E i
a n gi ote nsi n -c o n verti n g e nz y me i n hi bit or
A D R
a d verse dr u g reacti o n
A E
a d verse e ve nt
A H A
A merica n Heart Ass ociati o n
A KI
ac ute ki d ne y i nj ur y
A N C O V A
a nal ysis of c o varia nce
A R B
a n gi ote nsi n II rece pt or bl oc ker
A R Ni
a n gi ote nsi n rece pt or -Ne pril ysi n i n hi bit or
B N P
B- t ype natri uretic pe pti de
C A B G
c or o nar y arter y b y pass grafti n g
C E C
Cli nical E ve nts C o m mittee
C K D
c hr o nic ki d ne y disease
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C O VI D - 1 9
C or o na vir us disease 2 0 1 9
C P S
calci u m p ol yst yre ne s ulf o nate
C R O
C o ntract Researc h Or ga nisati o n
C R T
Car diac Res y nc hr o nisati o n T hera p y
C S P
Cli nical St u d y Pr ot oc ol
C S R
Cli nical St u d y Re p ort
C TI S
Cli nical Trial I nf or mati o n S yste m
C V
car di o vasc ular
D E S
Data E ntr y Site
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d 
E C G
electr ocar di o gra m
e C R F
electr o nic Case Re p ort F or m
e G F R
esti mate d gl o mer ular filtrati o n rate
E M A
E ur o pea n Me dici nes A ge nc y
E O T
e n d of treat me nt
E S C
E ur o pea n S ociet y of Car di ol o g y
F A S
F ull A nal y sis Set
G C P
G o o d Cli nical Practice
G E E
Ge neralize d Esti mati n g E q uati o n


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 6 of 1 3 2
A b bre vi ati o n 
E x pl a n ati o n
G M P
G o o d Ma n ufact uri n g Practice
G R A D
Gl o bal rete nti o n a n d Dis p osal
H F
heart fail ure
H Fr E F
heart fail ure wit h re d uce d ejecti o n fracti o n
H K
h y per kalae mia or  h yper kalae mic
H R
hazar d rati o
I B
I n vesti gat or’s Br oc h ure
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
i D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I M P/ NI M P
I n vesti gati o nal Me dici nal Pr o d uct/ N o n-I M P
I P
i n vesti gati o nal pr o d uct
I R B/I E C
I nstit uti onal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee
I R T/ R T S M
I nteracti ve Res p o nse Tec h n ol o g y/ Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt
I V
i ntra ve n o us
K C C Q -C S S
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire Cli nical S u m mar y Sc ore
K C C Q -O S S
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire O verall S y m pt o m Sc ore
K C C Q -T S S
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire T otal S y m pt o m Sc ore
L V E F
Left ve ntric ular ejecti o n fracti o n
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
MI
m y ocar dial i nfarcti o n
M R A
mi neral oc ortic oi d rece pt or a nta g o nist
N K
n or m o kalae mia or n or m o kalae mic
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u g
N T -pr o B N P
N- ter mi nal pr o- B-t ype natri uretic pe pti de
N Y H A
Ne w Y or k Heart Ass ociati o n
P CI
perc uta ne o us c or o nar y i nter ve nti o n
P GI S
Patie nt Gl o bal I m pressi o n of Se verit y
P P S
Per Pr ot oc ol Set
P R O
patie nt re p orte d o utc o me
R A A Si
r eni n -a n gi ote nsi n -al d oster o ne s yste m i n hi bit or
S A E
Seri o us A d verse E ve nt 
S A P
Statistical A nal ysis Pla n
S B P
s yst olic bl o o d press ure
s Cr
ser u m creati ni ne
s K +
ser u m p otassi u m


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 7 of 1 3 2
A b bre vi ati o n 
E x pl a n ati o n
S m P C
S u m mar y of Pr o d uct C haracteristics
S M Q
sta n dar dise d Me d D R A q ueries
S o A
Sc he d ule of Acti vities
S O C
Sta n dar d of Care
S P S
s o di u m p ol yst yre ne s ulf o nate
S S O
Safet y Set O pe n
S S R
Safet y Set Ra n d o mise d
S Z C
s o di u m zirc o ni u m cycl osilicate
U A C R
uri ne al b u mi n -t o-creati ni ne rati o
U S PI
U n ite d States Prescri bi n g I nf or mati o n
V A D
ve ntric ular assista nce de vice


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 8 of 1 3 2
A p pe n di x K
O pe n -L a bel Visit Fl o w Di a gr a ms
C o h ort 1 - P atie nt H K at St u d y E ntr y a, b
C o h ort 2 - P atie nt N K at St u d y E ntr y; Bec o mes H K at Wee k 2 a , c, d
a Patie nts i n eit her c o h ort w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile recei vi n g ma xi m u m d ose S Z C ( 1 5 g) , b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n 
t he o pe n-la bel, r u n-i n p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K a gai n.
b F or C o h ort 1, t he ra n d o misati o n will occ ur at Visit 6 or at o ne of t he o pti o nal Visits 6a or 6 b ( de pe n di n g o n w he n t he patie nt bec o mes N K).
C Patie nts i n C o h ort 2 s h o ul d recei ve at least 3 wee ks of S Z C bef ore t he y ca n be c o nsi dere d f or ra n d o misati o n. 
d T he ra n d o misati o n will occ ur at Visit 6, Visit 6. 1, Visit 6. 2 or at o ne of t he o pti o nal Visits 6a or 6 b ( de pe n di n g o n w he n t he patie nt bec o mes N K).


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 9 of 1 3 2
C o h ort 2 - P atie nt N K at St u d y E ntr y; Bec o mes H K at Wee k 3 a , b, c
C o h ort 2 - P atie nt N K at St u d y E ntr y; Bec o mes H K at Wee k 4 a , b, d
a Patie nts i n eit her c o h ort w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile recei vi n g ma xi m u m d ose S Z C ( 1 5 g) , b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n 
t he o pe n-la bel, r u n-i n p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K a gai n.
b Patie nts i n C o h ort 2 s h o ul d recei ve at least 3 wee ks of S Z C bef ore t he y ca n be c o nsi dere d f or ra n d o misati o n.
c T he ra n d o misati o n will occ ur at Visits 6. 1, 6. 2 or at o pti o nal Visit s 6a or 6 b ( de pe n di n g o n w he n t he patie nt bec o mes N K).
d T he ra n d o misati o n will occ ur at Visit 6. 2 or at o ne of t he o pti o nal Visits 6a or 6 b ( de pe n di n g o n w he n t he patie nt bec o mes N K).


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 0 of 1 3 2
A p pe n di x L
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 
di rectl y bef ore t he T a ble of C o nte nts.
A me n d me nt 2, 0 3 A u g ust 2 0 2 2
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) of 
Direc ti 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.
O ver all R ati o n ale f or t he A me n d me nt 2:
T he o verall rati o nale ( o ne pri mar y dri ver) f or t he c ha n ges i m ple me nte d i n pr ot oc ol a me n d me nt 2 is t he 
s h orte ni n g of t he ra n d o mise d, d o u ble -bli n d, wit h dra wal p hase fr o m 8 t o 6 m o nt hs. Base d o n rece nt 
r es ults fr o m a si milar st u d y (DI A M O N D st u d y ), s h orte ni n g t he d urati o n b y 2 m o nt hs will n ot i m pact 
t he res ults a n d ma y alle viate t he b ur de n t o t he patie nts.
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
1. 1 S y n o psis
1. 3 Sc he d ule of Acti vities 
(ra n d o mise d, d o u ble-bli n d 
wit h dra wal p hase)
2. 1 St u d y Rati o nale
3. O bjecti ves a n d E n d p oi nts
4. 1 O verall Desi g n
5. 1 I ncl usi o n Criteria
6. 6. 2 D o u ble -bli n d, Place b o -
c o ntr olle d, Ra n d o mise d -
wit h dra wal P hase
9. 1 Statistical H y p ot heses
9. 2 Sa m ple Size Deter mi nati o n
9. 4. 3. 1 Pri mar y E n d p oi nt
9. 4. 3. 2 Sec o n dar y E n d p oi nts
Decrease of t he ra n d o mise d, 
d o u ble -bli n d, wit h dra wal p hase 
fr o m 8 t o 6 m o nt hs 
Ease patie nt visit
b ur de n
N o n -
s u bsta ntial
1. 1 S y n o psis
4. 1 O verall Desi g n
Patie nts fr o m C o h orts 1 a n d 2 i n 
t he H K C orrecti o n P hase w h o 
d o n ot ac hie ve N K wit hi n 4 8
h o urs will be disc o nti n ue d fr o m 
t he st u d y
Clarif y i n g e dit
N ot 
s u bsta ntial
1. 1 S y n o psis
4. 2 Scie ntific Rati o nale f or 
St u d y Desi g n
5. 2 E xcl usi o n Criteria
Criteri o n # 2: Clarif y t hat 
patie nts c urre ntl y h os pitalise d 
d ue t o heart fail ure ( H F) ca n be 
e nr olle d if H F is 
he m o d y na micall y sta ble.
E na ble patie nts wit h 
rece nt H F w orse ni n g t o 
be e nr olle d as t hese 
patie nts ofte n ha ve H K 
a n d/ or are o n n o or 
l o w- d ose 
S u bsta ntial


Cli nical St u d y P r ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 of 1 3 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
mi neral oc ortic oi d 
rece pt or a nta g o nist 
( M R A)
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Criteri o n # 2 ( b): a d de d 
c o m ple me ntar y defi niti o n of ‘at 
ris k of de vel o pi n g
h y per kalae mia ( H K) ’ f or 
C o h ort 2.
Clarif y i n g e dit
N o n -
s u bsta ntial
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Criteri o n # 2 ( b): Ti mefra me 
use d t o defi ne hist or y of H K has 
bee n e xte n de d fr o m 2 4 t o 3 6 
m o nt hs.
D uri n g t he C O VI D - 1 9 
pa n de mic, n ot all 
patie nts ha ve 
la b orat or y val ues 
rec or de d i n t he past 2 
years. E xte n di n g t he 
ti me fra me b y 1 year 
( pr e-pa n de mic) ma y 
hel p ca pt ure t hese 
patie nts.
S u bsta ntial
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Criteri o n # 4: Ti mefra me use d t o 
defi ne left ve ntric ular ejecti o n 
fracti o n has bee n e xte n de d fr o m 
1 2 t o 2 4 m o nt hs.
D ur i n g t he C O VI D- 1 9 
pa n de mic, s o me 
patie nts were hesita nt 
t o g o t o i n-pers o n visits 
f or H F assess me nts, 
s uc h as 
ec h ocar di o gra ms. 
E xte n di n g t he ti me 
fra me b y 1 year ma y 
hel p ca pt ure t hese 
patie nts wit h less 
fre q ue nt assess me nts.
S u bsta ntial
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Criteri o n # 5: Re m o ve d 
restricti o n o n sta ble d ose 
d urati o n f or a n gi ote nsi n -
c o n verti n g e nz y me i n hi bit or 
( A C Ei), a n gi ote nsi n II rece pt or 
bl oc ker ( A R B), or a n gi ote nsi n 
rece pt or-Ne pril ysi n i n hi bit or 
( A R Ni).
E na ble patie nts wit h 
rece nt R A A Si d ose 
c ha n ges t o be e nr olle d
S u bsta ntial
1. 1 S y n o psis
4. 1 O verall Desi g n
5. 1 I ncl usi o n Criteria
5. 2 E xcl usi o n Criteria
Criteri o n # 6: Patie nts o n l o w -
d ose ( < 2 5 m g dail y) of
e plere n one are n o w all o we d t o 
partici pate i n t he st u d y. T he y 
E na ble patie nts o n l o w -
d ose e plere n o ne t o 
s witc h t o l o w-d ose 
s pir o n olact o ne s o t he y 
S u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 2 of 1 3 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
6. 1. 1 I n vesti gati o nal Pr o d ucts
6. 5 C o nc o mita nt t hera p y
6. 6. 1 O pe n -la bel R u n-i n P hase
will be s witc he d t o 
s pir o n olact o ne 1 2. 5 m g dail y 
( 1: 1 d ose c o n versi o n) at st u d y 
scree ni n g o nce it’s c o nfir me d 
t he y meet t he criteria f or st u d y 
e ntr y.
m a y  be e nr olle d, as 
t hese patie nts are o n 
l o w-d ose M R A d ue t o 
H K. 
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Criteri o n # 7: Re m o ve d 
restricti o n o n sta ble d ose 
d urati o n f or beta -bl oc kers.
E na ble patie nts wit h 
rece nt beta-bl oc ker 
d ose c ha n ges t o be 
e nr olle d
S u bsta ntial
1. 1 S y n o psis
5. 1 I ncl usi o n Criteria
Criteria # 9 a p plies o nl y f or 
fe males
Criteri o n # 9 ( b): ti me fra me 
defi ne d f or birt h c o ntr ol use 
bef ore e nteri n g t he st u d y has 
bee n a dj uste d fr o m 3 t o 4 
m o nt hs, a n d fr o m 1 2 t o 4 wee ks 
after t he st u d y’s last d ose. 
Clarif y i n g e dit t o ali g n 
t o P S S R versi o n 8
N o n -
s u bsta ntial
1. 1 S y n o psis
5. 2 E xcl usi o n Criteria
Criteri o n # 4: clarificati o n o n 
c or o nar y re vasc ularizati o n or
v al v ul ar re p air/re pl ace me nt
pr oce d ure
Clarif y i n g e dit
N o n -
s u bsta ntial
1. 1 S y n o psis
5. 2 E xcl usi o n Criteria
Criteri o n # 1 6: clarificati o n o n 
hist or y  of g ynec o mastia
Clarif y i n g e dit
N o n -
s u bsta ntial
1. 1 S y n o psis
1. 2 Sc he ma
1. 3 Sc he d ule of Acti vities
4. 1 O verall Desi g n
Clarif y  t hat c o h ort assi g n me nt is 
base d o n l ocal la b orat or y ser u m 
p otassi u m (s K +) o n Visit 1.
Clarif y i n g e dit
N o n -
s u bsta ntial
1. 1 S y n o psis
1. 3 Sc he d ule of Acti vities 
( F oll o w- u p)
2. 3 Be nefit/ Ris k Assess me nt
4. 1 O verall Desi g n
C ha n ge t he d urati o n of t he 
f oll o w-u p peri o d fr o m 3 wee ks 
t o 1 wee k after e n d of treat me nt 
( E O T)
F oll o w -u p peri o d after t he E O T 
visit: s K + will n o w be c hec ke d 
7 da y s after last d ose of st u d y 
dr u g i nstea d of 2 a n d 2 1 da ys.
Ease patie nt visit 
b ur de n
N o n -
s u bsta ntial
1. 1 S y n o psis
1. 2 Sc he d ule of Acti vities, 
C o h orts 1 a n d 2
4. 1 O verall Desi g n
O pe n -la bel r u n-i n p hase ca n be 
e xte n de d b y 2 wee ks.
Patie nts w h o de vel o p 
H K o n s pir o n olact o ne 
5 0 m g dail y, b ut were 
N K o n s pir o n olact o ne 
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 3 of 1 3 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
6. 6. 1. O pe n -la bel R u n-i n P hase
A p pe n di x K
2 5 m g dail y are n o w 
all o we d t o re mai n i n 
the o pe n -la bel, r u n-i n 
p hase f or u p t o 2 
a d diti o nal wee ks i n 
or der t o ret ur n t o 
s pir o n olact o ne 2 5 m g 
a n d bec o me N K a gai n 
a n d t h us q ualif y f or 
ra n d o misati o n.
1. 1 S y n o psis
4. 1 O verall Desi g n
I n C o h ort 1, Visit 2 ma y occ ur 
at t he sa me ti me as, or s h ortl y 
after Visit 1 ( Scree ni n g), f or 
patie nts wit h h y per kalae mia.
T o e x pe dite treat me nt 
wit h S Z C
N o n -
s u bsta ntial
1. 2 Sc he ma
Fi g ure 1 has bee n u p date d t o 
reflect t he ne w n u m ber of 
patie nts i n t he o pe n -la bel c o h ort 
( N = 2 6 0)
T he te xt was u p date d as 
C o h ort 2 s ho ul d recei ve at least 
3 wee ks of S Z C bef ore t he y ca n 
be c o nsi dere d f or 
ra n d o misati o n.
Clarif yi n g e dit
N o n -
s u bsta ntial
1. 3 Sc he d ule of Acti vities
Clarificati o n has bee n a d de d f or 
uri ne c ollecti o n.
Clarif yi n g e dit
N o n -
s u bsta ntial
1. 3 Sc he d ule of Acti vities
F or C o h o rt 1, t he 2 4 -h o ur visit 
( Visit 2. 1) has bee n u p date d as 
o pti o nal d uri n g t he S Z C 1 0 g 
TI D d osi n g p hase. 
Ease patie nt visit 
b ur de n
N o n -
s u bsta ntial
1. 3 Sc he d ule of Acti vities
F or C o h o rt 2, t he 2 4 -h o ur visits 
( Visits 3. 1, 4. 1 a n d 5. 1) ha ve 
bee n u p date d as o pti o nal d uri n g 
t he S Z C 1 0 g TI D d osi n g 
p hase. 
Ease patie nt visit 
b ur de n
N o n -
s u bsta ntial
1. 3 Sc he d ule of Acti vities
A d de d o pti o nal 2 visits ( 6a a n d 
6 b) f or C o h orts 1 a n d 2 t o be 
ali g ne d wit h t he f o ot n ote a d de d 
i n S o A (Patie nts w h o de vel o p 
H K o n s pir o n olact o ne 5 0 m g 
dail y w h ile recei vi n g ma xi m u m 
d ose S Z C ( 1 5 g) , b ut were N K 
o n s pir o n olact o ne 2 5 m g dail y 
m a y  re mai n i n t he o pe n-la bel, 
T o e na ble patie nts w h o 
ca n mai ntai n 
n or m o kalae mia o n 
s pir o n olact o ne 2 5 m g 
dail y  t o re mai n on 
g ui deli ne -directe d 
me dical t hera p y a n d 
sta y i n t he st u d y
S u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 4 of 1 3 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
r un -i n p hase f or u p t o 2 
a d diti o nal wee ks i n or der t o 
ret ur n t o s pir o n olact o ne 2 5 m g 
a n d bec o me N K a gai n).
1. 3 Sc he d ule of Acti vities
A d diti o nal i nf or mati o n was 
a d de d t o e ns ure t hat f or b ot h 
c o h orts t he assess me nts u ni q ue 
t o Visit 6 ( or 6. 1, 6. 2) ( na mel y 
t he p h ysical e xa ms, bi o mar ker 
a nal yses, a n d t he K C C Q & 
P GI S) will o nl y occ ur o nce 
i n de pe n de ntl y if t he patie nt 
atte n ds all o pti o nal visits ( 6a 
a n d 6 b).
Clarif y i n g e dit
N o n -
s u bsta ntial
1. 3 Sc he d ule of Acti vities
8. 2. 4 Cli nical Safet y 
La b orat o r y Assess me nts
L ocal la b orat or y t o be use d 
i nstea d of ce ntral la b orat or y f or 
uri nal y sis ( di pstic k).
Clarif y i n g e dit
N o n -
s u bsta ntial
2. 2 Bac k gr o u n d
A d diti o nal i nf or mati o n pr o vi de d 
i n t he bac k gr o u n d.
U p date d bac k gr o u n d 
secti o n wit h ne w 2 0 2 1 
a n d 2 0 2 2 H F 
G ui deli nes
N o n -
s u bsta ntial
2. 3 Be nefit/ Ris k 
Assess me nt
Re m o ve d fl ui d o verl oa d a m o n g 
oe de ma -relate d e ve nts 
Fl ui d o verl oa d has 
bee n de m ote d t o L L T 
a n d is i ncl u de d wit h P T 
h y per v olae mia 
(acc or di n g t o Me d D R A 
u p date versi o n 2 4. 1)
N o n -
s u bsta ntial
4. 1 O verall Desi g n
Re m o ve d te xt a b o ut t he 
p ossi bilit y of a re gistr y f or a 
real-w or d o bser vati o n of t he H F 
ma na ge me nt of patie nts w h o 
c o m plete d t he st u d y
N o l o n ger a p plica ble
N o n -
s u bsta ntial
5. 4 Scree n Fail ures
C o n diti o ns u n der w hi c h 
rescree ni n g is all o we d have
bee n a d de d. Als o clarifie d t hat 
rescree ni n g ca n ha p pe n t wice.
I n crease t he n u m ber of 
patie nts eli gi ble f or 
e nr ol me nt
N o n -
s u bsta ntial
6. 6. 2 D o u ble -bli n d, Place b o -
c o ntr olle d, Ra n d o mise d -
wit h dra wal P hase
S pir o n olact o ne d oses are 
all o we d t o be decrease d i n 
patie nts wit h H K d uri n g t he 
ra n d o mise d wit h dra wal p hase
Clarif y i n g e dit
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 5 of 1 3 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
6. 5 C o nc o mita nt T hera p y
D DIs ha ve bee n u p date d 
acc or di n g t o t he C D S
Clarif y i n g e dit t o be 
ali g ne d t o C D S 2 0 2 2
N o n -
s u bsta ntial
6. 5 C o nc o mita nt T hera p y
A d diti o nal restricte d me dicati o n 
(tacr oli m us) was a d de d.
Ne w data a vaila ble 
s h o wi n g t he nee d t o 
se parate tacr oli m us 
fr o m S Z C 
a d mi nistrati o n b y 
2 h o urs
N o n -
s u bsta ntial
6. 5 C o nc o mita nt T hera p y
A d diti o nal per mitte d me dicati o n 
was a d de d (l o w d ose 
acet ylsalic ylic aci d).
Clarif y i n g e dit t o a v oi d 
c o nf usi o n wit h t he 
N S AI D restricti o n
N o n -
s u bsta ntial
6. 6. 1 O pe n -la bel R u n-i n P hase
Ta ble 8 was re place d b y t he 
c orres p o n di n g ta ble fr o m
A p pe n di x K a n d A p pe n di x K
was delete d. Ta ble 8 was 
m o difie d f or clarificati o n a b o ut 
t he rec o m me n dati o n f or 
s pir o n olact o ne w he n 
s K+ < 3. 0 m E q/ L s h o ul d be t he 
sa me as f or patie nts wit h s K+
< 3. 5 – 5 m E q/ L.
E na bles patie nts wit h 
l o w p otassi u m t o 
re mai n o n 
s pir o n olact o ne a n d 
re mai n o n 
g ui deli ne -directe d 
me dical t hera p y
N o n -
s u bsta ntial
6. 6. 1 O pe n -la bel R u n-i n P hase
Te xt was a d de d f or clarificati o n 
a b o ut st u d y disc o nti n uati o n 
d uri n g t he o pe n -la bel p hase.
Clarif y i n g e dit
N o n -
s u bsta ntial
6. 6. 2 D o u ble -bli n d, Place b o -
c o ntr olle d, Ra n d o mise d -
wit h dra wal P hase
Ta ble 9 was re place d b y t he 
c orres p o n di n g ta ble fr o m 
A p pe n di x L a n d A p pe n di x L
was delete d. Te xt was a d de d i n 
Ta ble 9 f or clarificati o n a b o ut 
t he rec o m me n dati o n t o mai ntai n 
s pir o n olact o ne w he n 
s K+ < 3. 0 m E q/ L.
E na bles patie nts wit h 
l o w p otassi u m t o 
re mai n o n 
s pir o n olact o ne a n d 
re mai n o n 
g ui deli ne -directe d 
me dical t hera p y
N o n -
s u bsta ntial
8. 2. 4 Cli nical Safet y La b orat or y 
Assess me nts
C o m ple me ntar y i nf or mati o n 
re gar di n g t he C K D-E PI f or m ula 
t o be use d was a d de d.
Clarif y i n g e dit
N o n -
s u bsta ntial
8. 3. 7. 2 Pater nal E x p os ure
Te xt a b o ut t he d oc u me ntati o n of 
pre g na nc y of t he partici pa nt’s 
part ner has bee n re m o ve d t o be 
ali g ne d t o L o kel ma P S S R.
Clarif y i n g e dit. A Z is 
n ot c ollecti n g data o n 
pre g na nt part ners t o 
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 6 of 1 3 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
males w h o p artici pate 
i n L o kel ma st u dies
9. 4. 3. 3 E x pl orat or y E n d p oi nts
‘ Patie nts e nr olle d d uri n g 
h os pitalisati o n’ a d de d as a 
s u b-gr o u p a nal y sis.
H os pitalise d patie nts t o 
be a nal yze d as a 
s u b gr o u p t o kee p t he 
c o nsiste nc y of res ults 
acr oss patie nt t ypes
N o n -
s u bsta ntial
A p pe n di x K
T he fl o wc harts were u p date d t o 
clarif y t hat:
I n C o h ort 1 t he ra n d o misati o n
occ urs at Visit 6 or at o ne of t he 
o pti o nal Visits 6a or 6 b 
( de pe n di n g o n w he n t he patie nt 
bec o mes N K).
I n C o h ort 2, s u bjects s h o ul d be 
recei vi n g S Z C f or a mi ni m u m 
of 3 wee ks pri or t o 
ra n d o misati o n.
C o h ort 2 starts S Z C at Visit 3 
a n d t he ra n d o misati o n will 
occ ur at Visit 6, Visit 6. 1, 
Visit 6. 2, or at o ne of t he 
o pti o nal Visits 6a or 6 b 
( de pe n di n g o n w he n t he patie nt 
bec o mes N K).
C o h ort 2 starts S Z C at Visit 4 
a n d t he ra n d o misati o n will 
occ ur at Visit 6. 1, Visit 6. 2 or at 
o ne of t he o pti o nal Visits 6a or 
6 b ( de pe n di n g o n w he n t he 
patie nt bec o mes N K).
C o h ort 2 starts S Z C at Visit 5 
a n d t he ra n d o misati o n will 
occ ur at Visit 6. 2 or at o ne of 
t he o pti o nal Visits 6a or 6 b 
( de pe n di n g o n w he n t he patie nt 
bec o mes N K).
Clarif y i n g e dit
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 7 of 1 3 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
1 1 Refere nces 
A d de d C D S 2 0 2 2 as a refere nce 
as t he S m P C has n ot yet bee n 
a p pr o ve d b y t he E M A.
A d de d Hei de nreic h P A, B oz k urt 
B, A g uilar D, et al. 2 0 2 2 
A H A/ A C C/ H F S A g ui deli ne f or 
t he ma na ge me nt of heart fail ure: 
a re p ort of t he A merica n 
C olle ge of 
Car di ol o g y/ A merica n Heart 
Ass ociati o n j oi nt c o m mittee o n 
cli nical practice g ui deli nes [i n 
press -c orrecte d pr o of; p oste d 
o nli ne A pril 1, 2 0 2 2]. J A m C oll 
Car di ol. 2 0 2 2. 
d o i: 1 0. 1 0 1 6/j.jacc. 2 0 2 1. 1 2. 0 1 2.
A d de d Mc D o na g h T A, Metra 
M, A da m o M, et al. 2 0 2 1 E S C 
g ui deli nes f or t he dia g n osis a n d 
treat me nt of ac ute a n d c hr o nic 
heart fail ure. E ur Heart J. 
2 0 2 1; 4 2: 3 5 9 9 -3 7 2 6.
Clarif y i n g e dit
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
A me n d me nt 1, 2 9 J u ne 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 1:
T he o verall rati o nale ( o ne pri mar y dri ver) f or t he c ha n ges i m ple me nte d i n t he pr ot oc ol a me n d me nt 
was mi n or clarificati o ns a n d f urt her descri pti o ns , bel o w (e. g., c ha n ges t o i n di vi d ual 
i ncl usi o n/e xcl usi o n criteria). 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 8 of 1 3 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 n ti al/
N o n -
s u bst a nti al
1. 1 S y n o psis -
O bjecti ves a n d 
E n d p oi nts; 
Statistical Met h o ds; 
3 O bjecti ves a n d 
E n d p oi nts; 
9. 4. 3 Efficac y
C ha n ge of t he w or d “ pr o p orti o n” t o “ occ urre nce” 
( yes/ n o) at all i nsta nces i n t he ta ble
Sec o n dar y e n d p oi nt se nte nce was c ha n ge d as 
f oll o wi n g – “ Patie nts w h o are l ost t o f oll o w -u p, 
i ncl u di n g d ue t o deat h, pri or t o t he E O T visit will 
be treate d as n o n -res p o nse”
C ha n ge i n K C C Q fr o m T otal S y m pt o m Sc ore 
( T S S) t o Cli nical S u m mar y Sc ore ( C S S)
Clarit y  of 
a nal ysis
N o n -
s u bsta ntial
3 O bjecti ves a n d 
E n d p oi nts
Sec o n dar y O bjecti ve a n d E n d p oi nt - C h a n ge i n 
K C C Q fr o m T S S t o C S S
E x pl o rat or y O bjecti ve a n d E n d p oi nt - C ha n ge i n 
K C C Q fr o m C S S t o T S S
C ha n ge o n 
e m p hasis of 
partici pa nts’ 
p h y sical 
li mitati o n ( C S S) 
rat her t ha n 
s ym pt o m 
fre q ue nc y a n d 
s ym pt o m b ur de n 
d o mai ns ( T S S)
N o n -
s u bsta ntial
1. 1 S y n o psis –
O verall Desi g n; 
1. 1 Sc he ma;
4. 1 O verall Desi g n; 
6. 6 D ose 
M o dificati o n
Treat me nt Peri o d - C o h ort 2 – H K C orrecti o n 
P hase - c h a n ge i n st u d y assess me nt / m o nit ori n g 
da y s of H K f or 4 wee ks i nstea d of 3 wee ks.
F oll o w -u p peri o d after t he E O T visit: s K + will 
n o w be c hec ke d 2 a n d 2 1 da ys after last d ose of 
st u d y dr u g i nstea d of 7 a n d 2 1 da ys. 
Decrease d t he 
ti me t o m o nit or 
f or c ha n ges i n 
s K + f oll o wi n g 
E O T visit 
N o n -
s u bsta ntial
1. 3 Sc he d ule of 
Acti vities ( S o A), 
Ta ble 1
C ha n ges were ma de t o reflect t he c ha n ges i n t he 
te xt of t he pr ot oc ol a n d t he Scree ni n g a n d 
O pe n -La bel R u n -i n P hase Ta ble was s plit i nt o t w o 
– F or C o h ort 1 a n d f or C o h ort 2.
T he S o A was 
u p date d f or 
clarit y p ur p ose 
N o n -
s u bsta ntial
4. 1 O verall Desi g n; 
6. 6. 1 4 - t o 6-Wee k 
O pe n -la bel R u n-i n 
P hase
Te xt was a d de d: patie nts w h o d o n ot q ualif y f or 
ra n d o misati o n d ue t o h y per kalae mia s h o ul d ha ve a 
f oll o w-u p visit 2 da ys after t heir last d ose of st u d y 
dr u g.
Clarif y  f or 
patie nt safet y 
t hat patie nts n ot 
bei n g 
ra n d o mise d t o 
d o u ble -bli n d d ue 
t o H K are t o 
ha ve a f oll o w - u p 
visit wit hi n 
2 da y s.  
N o n -
s u bsta ntial
5. 2 E xcl usi o n 
Criteria
Criteria # 2 2 a d de d as a f o ot n ote a b o ut C O VI D - 1 9 
vacci nate d patie nts t o be i ncl u de d i n t he st u d y
C O VI D vacci nes 
are n ot a p pr o ve d 
– b ut will be 
all o we d d ue t o 
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 9 of 1 3 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 n ti al/
N o n -
s u bst a nti al
t he C O VI D-1 9 
pa n de mic
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
Ra n d o misati o n c o de bli n d -br ea ki n g i nstr ucti o ns 
were detaile d.
Clarit y  o n 
ra n d o misati o n
c o de bli n d-
br ea ki n g 
i nstr ucti ons
N o n -
s u bsta ntial
6. 6. 1 4 - t o 6-Wee k 
O pe n -la bel R u n-i n 
P hase
Se nte nce a b o ut o pe n -la bel titrati o n g ui de as 
refere nce d i n A p pe n di x K was a d de d.
A ne w Ta ble 6 was a d de d o n d osi n g a n d titrati o n.
Ta ble 8 – If recei vi n g S Z C 1 5 g dail y  – se nte nce 
f or “ m o nit ori n g of s K + i n 7 ( ± 2) da ys if S Z C or 
s pir o n olact o ne d ose c ha n ge d” was delete d 
Clarit y  o n 
titrati o n 
g ui da nce a n d 
patie nt safet y
N o n -
s u bsta ntial
6. 6. 2 8 -M o nt h 
D o u ble -bli n d, 
Place b o -c o ntr olle d, 
Ra n d o mise d -
wit h dra wal P hase
Se nte nc e a b o ut o pe n -la bel titrati o n g ui de as 
refere nce d i n A p pe n di x L was a d de d.
Ta ble 9 – If recei vi n g S Z C/ place b o 1 5 g dail y –
se nte nce f or “ m o nit ori n g of s K + i n 7 ( ± 2) da ys if 
S Z C/ place b o or s pir o n olact o ne d ose c ha n ge d” was 
delete d. A f o ot n ote was a d de d o n t he S Z C/ Place b o 
a n d S pir o n olact o ne D ose A dj ust me nt – “ M o nit or 
s K + i n 7 +/-2 da ys if S Z C/ place b o or 
s pir o n olact o ne d ose c ha n ge d”
Clarit y  o n 
titrati o n 
g ui da nce a n d 
patie nt safet y
N o n -
s u bsta ntial
7. 1 Disc o nti n uati o n 
of St u d y 
I nter ve nti o n
T he f oll o wi n g se nte nce was a d de d – “ Patie nts w h o 
disc o nti n ue t he st u d y earl y d uri n g t he ra n d o mi se d 
p hase s h o ul d ha ve t heir E O T visit as s o o n as 
p ossi ble after t heir last d ose of st u d y dr u g 
(ass u mi n g t he y disc o nti n ue t he dr u g w hile at h o me 
a n d n ot at a st u d y visit).”
Clarit y  t hat
disc o nti n ue d 
patie nts s h o ul d 
ha ve a n E O T 
visit as s o o n as 
p ossi ble
N o n -
s u bsta ntial
8 St u d y  
Assess me nts a n d 
Pr oce d ures
T he f oll o wi n g b ullet p oi nt was a d de d – “ A n 
o pe n -la bel visit fl o wc hart is pr o vi de d f or refere nce 
i n A p pe n di x M”
Refere nce t o ne w 
A p pe n di x M
N o n -
s u bsta ntial
8. 6 H u ma n 
Bi ol o gical Sa m ple 
Bi o mar kers
Ur i ne sa m ple was delete d fr o m C V a n d re nal 
bi o mar kers i ncl u di n g plas ma re ni n acti vit y 
( P R A) *, t otal re ni n, a n gi ote nsi n o ge n, atrial 
natri uretic pe pti de ( A N P), hi g h se nsiti vit y tr o p o ni n 
I, Uri ne: a n gi ote nsi n o ge n, t otal re ni n, A C E, 
A C E 2.
T he w or ds “ bl o o d a n d uri ne sa m ples” were a d de d 
t o a d diti onal bi o mar kers.
Re m o ve d 
s pecific bl o o d 
a n d uri ne 
para meters at 
t his ti me b ut 
retai ni n g t he 
sa m ples f or 
p ote ntial f ut ure 
a nal yses.
N o n -
s u bsta ntial
8. 3. 7 Pre g na nc y; 
1 0. A p pe n di x B - 2
T he w or d “a b n or malit y” was c ha n ge d t o 
“a n o mal y”
Better clarit y
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 0 of 1 3 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 n ti al/
N o n -
s u bst a nti al
3 O bjecti ves a n d 
E n d p oi nts;
9. 4. 3. 3 E x pl orat or y 
E n d p oi nts
E n d p oi nt re gar di n g relati o ns hi p bet wee n 
al d oster o ne le vels a n d P GI C a n d K C C Q sc ores
was a d de d
T o c o nfer a n y 
ass ociati o n 
bet wee n 
al d oster o ne 
le vels a n d t he 
patie nt ‘feeli n g 
better’ a n d 
e x pl ori n g 
p ote ntial reas o ns 
f or t he 
i m pr o ve me nt i n 
P GI C a n d K C C Q 
sc ores.
N o n -
s u bsta ntial
1 0. A p pe n di x A –
A 7 Data Q ualit y 
Ass ura nce
Rec or ds a n d d oc u me nts rete nti on ti me was 
c ha n ge d t o 1 5 years
T o har m o nize 
bet wee n I C F a n d 
sa m ple st ora ge
N o n -
s u bsta ntial
1 0. A p pe n di x K 
O pe n -la bel r u n-i n p hase titrati o n g ui da nce a d de d
G ui da nce a d de d 
t o clarif y d osi n g 
g ui da nce d uri n g 
t he o pe n-la bel 
r un- i n p hase
N o n -
s u bsta ntial
1 0. A p pe n di x L 
D o u ble -bli n d titrati o n g ui da nce a d de d 
G ui da nce a d de d 
t o clarif y d osi n g 
g ui da nce d uri n g 
t he d o u ble-bli n d 
p hase
N o n -
s u bsta ntial
1 0. A p pe n di x M
O pe n -la bel fl o w dia gra ms were a d de d f or 
C o h orts 1 a n d 2 
Patie nt fl o w 
dia gra ms a d de d 
t o clarif y t he 
patie nts’ 
pr o gressi o n 
t hr o u g h t he st u d y
N o n -
s u bsta ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 1 of 1 3 2
1 1  
R E F E R E N C E S
Astra Ze neca. P otassi u m re d ucti o n i nit iati ve t o o pti mize R A A S i n hi biti on t hera p y  wit h s o diu m  
zirc o ni u m c yclosilicate i n heart fail ure ( P RI O RI TI Z E H F). Cli nical Trials. g o v we bsite. 
ht t ps://cli nicaltrials. g o v/ct 2/s h o w/ N C T 0 3 5 3 2 0 0 9. Accesse d Marc h 5, 2 0 2 0.
Data o n file, R E F -3 4 7 5 6, Astra Ze neca P har mace uticals L P .
E pstei n M, et al. E val uat i on of t he treat me nt ga p bet wee n cli nical g ui deli nes a n d t he 
utilizat i on of re ni n -a n giote nsi n- al d oster o ne s yste m i n hi bit ors. A m J M a n a g C ar e. 
2 0 1 5; 2 1( S u p pl 1 1): S 2 1 2 – S 2 2 0.
Gree n C P , P orter C B, Bres na ha n D R, S pert us J A. De vel o p me nt a n d e val uati on of t he Ka nsas 
Ci t y Car dio m y o p at h y  Q u estio n nai re: a ne w healt h stat us meas ure f or heart fail ure. 
J A m C o ll C ardi ol . 2 0 0 0; 3 5( 5): 1 2 4 5- 1 25 5.
H ei de nreic h PA, B oz k urt B, A g uilar D, et al.  2 0 2 2 A H A/ A C C/ H F S A  g uideli ne f or t he 
ma na ge me nt of heart fail ure: a re p ort of t he A merica n C o lle ge of 
Car di ol o g y / A merica n Heart Ass ociat i on j oi nt c o m mittee o n cli nical practice g ui deli nes 
[in press -c orrecte d pr o of; p oste d o nli ne A pril 1, 2 0 2 2]. J A m C o ll Car di ol. 2 0 2 2. 
d oi : 1 0. 1 0 1 6/j.jacc. 2 0 2 1. 1 2. 0 1 2.
Hi c ks K A, Tc he n g J E, B oz k urt B, et al. 2 0 1 4 A C C/ A H A  ke y data ele me nts a n d defi niti ons f or 
car dio vasc ular e n d p o i nt e ve nts i n cli nical trials: a re p ort of t he A merica n C o lle ge of 
Car di ol o g y / A merica n Heart Ass ociat i on Tas k F orce o n Cli nical Data Sta n dar ds 
( writin g c o m mit tee t o de velo p car di o vasc ular e n d p oi nts data sta n dar ds) [ p u blis he d 
c orrectio n a p pears i n J A m C oll C ardi ol . 2 0 1 5; 6 6( 8):9 8 2]. J A m C oll C ardi ol . 
2 0 1 5; 6 6( 4): 4 0 3 - 4 6 9.
L O K E L M A  p o wer f or oral s us pe nsio n , 5 g a n d 1 0 g. C ore Data S heet. Astra Ze neca 
P har mace ut icals L P , Wil mi n gt o n, D E. Marc h 2 0 2 2.
L O K E L M A ® (s o diu m zi rc o ni u m c yclosilicate) f or oral  s us pe nsio n . U nite d States Prescri b i n g 
I nf or mat i on ( U S PI). Astra Ze neca P har mace ut icals L P , Wil mi n gt o n, D E. A pril 2 0 2 0 .
L o kel ma p o w der f or oral s us pe nsi o n. S u m mar y  of Pr o d uct C haracteristics 
( S mP C). htt ps:// w w w .e ma.e ur o pa.e u/e n/ d oc u me nts/ pr o d uct -i nf or mati on/ l okel ma -e par-
pr o d uct -i nf or mati o n _e n. p df. Accesse d 6 Fe b 2 0 2 0
L O K E L M A ® (s o diu m zi rc o ni u m c yclosilicate) p o w der f or oral  s us pe nsio n . Pr o d uct 
M o n o gra p h
( P M). Astra Ze neca Ca na da, I nc. A u g ust 2 0 2 0.
Mc D o na g h T A, Metra M, A da m o M, et al.  2 0 2 1 E S C g ui deli nes f or t he dia g n osis a n d 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
S o di u m Zirc o ni u m C ycl osilicate ( S Z C) - D 9 4 8 0 C 0 0 0 1 8
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 2 of 1 3 2
treat me nt of ac ute a n d c hr o nic heart fail ure. E ur Heart J. 2 0 2 1; 4 2: 3 5 9 9 - 3 7 2 6.
P o ni k o ws ki  P, et al. 2 0 1 6 E S C G ui deli nes f or t he dia g n osis a n d treat me nt of ac ute a n d c hr o nic 
heart fail ure. E ur J He art F ail . 2 0 1 6; 1 8: 8 9 1– 9 7 5.
R o ger S D, et al. Efficac y a n d safet y of  s o diu m zi r c o niu m  c y closilicate f or treat m e nt of 
h y per kale mia: a n 1 1 -m o nt h o pe n -label e xte nsi o n of H A R M O NI Z E. A m J Ne p hr ol . 
2 0 1 9; 5 0: 4 7 3 – 4 8 0. 
S pert us J, Peters o n E, C o nar d M W , et al. Car di o v asc ular O utc o mes Researc h C o ns orti u m. 
M o ni t ori n g cli nical c ha n ges i n patient s wit h heart fail ure: a c o m paris o n of met h o ds. 
A m He art J . 2 0 0 5; 1 5 0( 4): 7 0 7- 7 1 5.
S pi n o wi tz B S, et al. S o diu m  zirc o ni u m c y closilicate a m o n g i n di vi d uals wit h h y per kale mia: a 
1 2- m o nt h p hase 3 st u d y  [ article a n d s u p ple me ntal material]. Cli n J A m S oc Ne p hr ol . 
2 0 1 9; 1 4: 7 9 8 - 8 0 9.
T h o mse n R W , et al. Ele vate d p otassiu m  le vels i n patie nts wit h c o n gest i ve heart fail ure: 
occ urre nce, ris k fact ors, a n d cli nical o utc o mes. A Da nis h p o p ulat i on- base d c o h ort 
st u d y. J A m He art Ass oc . 2 0 1 8; 7:e 0 0 8 9 1 2.
Ya nc y C W, et al. 2 0 1 3 A C C F/ A H A  G ui deli ne f or t he ma na ge me nt of heart fail ure. J A m C oll 
C ar di ol . 2 0 1 3; 6 2( 1 6):e 1 4 7- 2 3 9.
Za n na d F , Garcia A A, A n ker S D, et al. Cli nical o utc o me e n d p o i nts i n heart fail ure trials: a 
E ur o pea n S ociet y of  Car diol o g y  Heart Fail ure Ass ociati on c o nse ns us d oc u me nt. E ur J 
He art F ail . 2 01 3; 1 5: 1 0 8 2 – 1 0 9 4.


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 8-cs p- v 4-a me n d me nt- 3
D oc u me nt Title:
D 9 4 8 0 C 0 0 0 1 8 Cli nical St u d y Pr ot oc ol versi o n 4 A me n d me nt
3
D oc u me nt I D:
D oc I D- 0 0 4 3 2 5 6 2 1
Versi o n L a bel:
7. 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
1 3- Dec- 2 0 2 3 1 3: 5 3 U T C
C o nte nt A p pr o val
1 3- Dec- 2 0 2 3 1 2: 0 0 U T C
Ma na ge me 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 A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
 
St atistic al A n al ysis Pl a n  
 
St u d y C o de  
D 9 4 8 0 C 0 0 0 1 8  
 
E diti o n N u m ber  
E xter nal 5. 0  
 
Date  
0 6 /A U G / 2 0 24  
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ase I V, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, R a n d o mize d -
Wit h dr a w al Tri al E v al u ati n g S o di u m Zirc o ni u m C ycl osilic ate 
( S Z C) f or t he M a n a ge me nt of H y p er k al ae mi a i n P atie nts wit h 
S y m pt o m atic He art F ail ure wit h Re d uce d Ejecti o n Fr acti o n a n d 
Recei vi n g S pir o n ol act o ne ( R E A LI Z E -K)  
 
 
 
 
 
 
 
 
 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 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  
T A B L E O F C O N T E N T S  .......................................................................................................... 2  
LI S T O F A B B R E VI A TI O N S  ................................................................................................... 5  
A M E N D M E N T HI S T O R Y  ....................................................................................................... 7  
1  
S T U D Y D E T AI L S  ............................................................................................... 1 4  
1. 1  
St u d y o bjecti ves  .................................................................................................... 1 4  
1. 2  
St u d y desi g n  ......................................................................................................... 1 8  
1. 2. 1  
Ra n d o misati o n  ...................................................................................................... 2 0  
1. 3  
N u m ber of partici pa nts  ......................................................................................... 2 1  
2  
A N A L Y SI S S E T S  ................................................................................................ 2 1  
2. 1  
Defi niti o n of a nal ysis sets  ..................................................................................... 2 1  
2. 2  
Vi olati o ns a n d de viati o ns  ..................................................................................... 2 3  
2. 3  
A nal ysis Peri o ds  ................................................................................................... 2 4  
3  
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S  ................................................. 2 4  
3. 1  
Ti me p oi nts a n d Visit Wi n d o ws  ........................................................................... 2 4  
3. 2  
Partici pa nt Dis p ositi o n .......................................................................................... 2 6  
3. 3  
Efficac y Varia bles  ................................................................................................ 2 7  
3. 3. 1  
Deat h Classificati o n  .............................................................................................. 2 7  
3. 3. 2  
Heart Fail ure E v e nts  ............................................................................................. 2 7  
3. 3. 3  
P otassi u m  .............................................................................................................. 2 7  
3. 3. 4  
Patie nt Re p orte d O utc o m es ( P R Os)  ..................................................................... 2 7  
3. 3. 4. 1  
C ollecti o n of P R Os  ............................................................................................... 2 7  
3. 3. 4. 2  
K C C Q  ................................................................................................................... 2 8  
3. 3. 4. 3  
P GI S -H F  ............................................................................................................... 2 9  
3. 3. 5  
N Y H A Class  ......................................................................................................... 2 9  
3. 3. 6  
Uri ne A nal ysis  ...................................................................................................... 2 9  
3. 3. 7  
Plas ma a nal ysis  ..................................................................................................... 2 9  
3. 3. 8  
F ur ose mi de E q ui val e nt L o o p Di uretic D ose  ........................................................ 2 9  
3. 4  
Safet y Vari a bles  .................................................................................................... 3 0  
3. 4. 1  
E x p os ure a n d d ose i nterr u pti o ns  ........................................................................... 3 0  
3. 4. 2  
A d verse E v e nts  ..................................................................................................... 3 0  
3. 4. 3  
La b orat or y Data  .................................................................................................... 3 1  
3. 4. 4  
Vital Si g ns  ............................................................................................................ 3 2  
3. 4. 5  
Electr ocar di o gra ms  ............................................................................................... 3 3  
4  
A N A L Y SI S M E T H O D S  ...................................................................................... 3 3  
4. 1  
Ge neral pri nci ples  ................................................................................................. 3 3  
4. 1. 1  
Ha n dli n g of missi n g dates  .................................................................................... 3 4  
4. 1. 1. 1  
Partial start dates  ................................................................................................... 3 4  
4. 1. 1. 2  
Partial e n d dates  .................................................................................................... 3 5  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
4. 1. 2  
Ha n dli n g of Missi n g Efficac y Data  ...................................................................... 3 5  
4. 1. 3  
Ha n dli n g of Missi n g Safet y Data  ......................................................................... 3 5  
4. 2  
A nal ysis met h o ds  .................................................................................................. 3 5  
4. 2. 1  
S u bject Dis p ositi o n a n d A nal ysis Sets A nal yze d  ................................................. 3 5  
4. 2. 2  
Pr ot oc ol De viati o ns  .............................................................................................. 3 6  
4. 2. 3  
De m o gra p hics a n d Ot her Baseli ne C haracteristics ............................................... 3 6  
4. 2. 4  
Me dical Hist or y  .................................................................................................... 3 9  
4. 2. 5  
Pre vi o us a n d C o nc o mita nt Me dicati o ns  ............................................................... 3 9  
4. 2. 6  
Meas ure me nts of St u d y Treat me nt C o m plia nce ................................................... 4 0  
4. 2. 7  
Efficac y  ................................................................................................................. 4 2  
4. 2. 7. 1  
Pri mar y Efficac y A nal ysis  .................................................................................... 4 2  
4. 2. 7. 2  
Sec o n dar y Efficac y A nal yses  ............................................................................... 4 6  
4. 2. 7. 3  
S u b gr o u p A nal ysis  ................................................................................................ 5 4  
4. 2. 7. 4  
E x pl orat or y Effi cac y A nal yses  ............................................................................. 5 5  
4. 2. 8  
Safet y  .................................................................................................................... 6 4  
4. 2. 8. 1  
A d verse E v e nts  ..................................................................................................... 6 4  
4. 2. 8. 2  
Deat hs  ................................................................................................................... 6 6  
4. 2. 8. 3  
La b orat or y Data  .................................................................................................... 6 6  
4. 2. 8. 4  
Vital Si g ns  ............................................................................................................ 6 7  
4. 2. 8. 5  
Electr ocar di o gra ms  ............................................................................................... 6 7  
4. 2. 8. 6  
P h ysical E xa mi nati o n  ........................................................................................... 6 8  
4. 2. 8. 7  
Heart Fail ure E v e nts  ............................................................................................. 6 8  
4. 2. 8. 8  
Oe de ma Ass ess me nt  ............................................................................................. 6 8  
4. 2. 8. 9  
E x p os ure  ............................................................................................................... 6 8  
4. 2. 8. 1 0  
Pre g na nc y T est ...................................................................................................... 6 9  
4. 2. 9  
Bi o mar ker Sa m ple C ollecti o n ............................................................................... 6 9  
5  
I N T E RI M A N A L Y S E S ........................................................................................ 6 9  
6  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L  .............................................. 7 0  
7  
R E F E R E N C E S  ..................................................................................................... 7 1  
A P P E N DI X A: T F L S H E L L S P R E S E N T E D T O D M C  ........................................................ 7 2  
 
LI S T O F T A B L E S  
Ta ble 1 Defi niti o n of visit wi n d o ws f or o pe n -la bel peri o d ..................................................... 2 5  
Ta ble 2 Defi niti o n of visit wi n d o ws f or ra n d o mise d -wit h dra wal a n d f oll o w -u p peri o d ......... 2 6  
Ta ble 3: L o o p di uretic d ose c o n versi o n  .................................................................................. 3 0  
Ta ble 4: La b orat or y Safet y Varia bles  ...................................................................................... 3 2  
 
LI S T O F FI G U R E S  
Fi g ure 1: St u d y Desi g n  ............................................................................................................ 2 0  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
A C Ei  
A n gi ote nsi n -C o n verti n g E nz y me i n hi bit or  
A E  
A d verse E ve nt  
A N C O V A  
A Nal ysis of C O V Aria nce  
A R B  
A n gi ote nsi n II Rece pt or Bl oc ker  
A R Ni  
A n gi ote nsi n Rece pt or -Ne pril ysi n I n hi bit or  
B P  
Bl o o d Press ure  
C E C  
Cli nical E ve nts C o m mittee  
C R O  
C o ntract Researc h Or ga nisati o n  
C S A  
Cli nical St u d y A gree me nt  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C S P  
Cli nical St u d y Pr ot oc ol  
C S R  
Cli nical St u d y Re p ort  
C T  
Cli nical Trial  
C V  
Car di o vasc ular  
D B L  
Data Base L oc k  
D C O  
Data C ut Off  
D N A  
de o x yri b o n ucleic aci d  
E C G  
Electr ocar di o gra m  
e C R F  
electr o nic Case Re p ort F or m  
e G F R  
Esti mate d Gl o mer ular Filtrati o n Rate  
E O T  
E n d Of Treat me nt  
F A S  
F ull A n al ysis Set  
F D A  
U. S. F o o d a n d Dr u g A d mi nistrati o n  
F SI  
First S u bject I n  
G C P  
G o o d Cli nical Practice  
G E E  
Ge n erali se d Esti mati n g E q uati o n  
H F  
Heart Fail ure  
H Fr E F  
Heart Fail ure Wit h Re d uce d Ejecti o n Fracti o n  
H K  
H y per kalae mia  
I B 
I n vesti gat or’s Br oc h ure 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
K C C Q  
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire  
K C C Q -C S S  
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire Cli nical S u m mar y Sc ore  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
K C C Q -O S S  
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire O verall S y m pt o m Sc ore  
K C C Q -T S S  
Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire T otal S y m pt o m Sc ore  
L S L V  
Last S u bject Last Visit  
L T F U  
L ost T o F oll o w -U p  
MI D  
Mi ni mall y I m p orta nt Differe nce  
N K  
N or m o kalae mia or N or m o kalae mic  
N T -pr o B N P  
N -ter mi nal pr o-B -t y pe natri uretic pe pti de 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
P GI S  
Patie nt Gl o bal I m pressi o n of Se verit y  
PI  
Pri n ci pal I n vesti gat or  
P P S  
Per Pr ot oc ol Set  
P R O  
Patie nt Re p orte d O utc o me  
P S S R  
Pr oject S pecific Safet y Re q uire me nts  
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 ors  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S m P C  
S u m mar y of Pr o d uct C haracteristics  
S o A  
Sc he d ule of Acti vities  
S O C  
Sta n dar d of Care  
S S O  
Safet y Set O pe n  
S S R  
Safet y Set Ra n d o mi se d  
S Z C  
S o di u m Zirc o ni u m C ycl osilicate  
T A  
T hera p e utic Area  
U A C R  
Uri ne Al b u mi n -t o-Creati ni ne Rati o  
W B D C  
We b Base d Data Ca pt ure  
 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
A M E N D M E N T HI S T O R Y  
C ate g or y *:  
C h a n ge refers t o  
D ate  
Descri pti o n of c h a n ge  
I n li ne wit h t he 
C S P ?  
R ati o n ale  
Ot her  
0 6 -A u g ust -2 0 2 4  
A d de d a d diti o nal 
a nal ysis p o p ulati o n of 
safet y set e x pl orat or y f or 
prese ntati o n of a d diti o nal 
e x pl orat or y a nal yses  
N o  
T o all o w a d diti o nal e x pl orat or y 
a n al ysis prese ntati o n  
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
Se nsiti vit y a nal yses f or 
alter nati ve defi niti o ns of 
res p o n ders a d de d  
N o  
A d diti o nal se nsiti vit y a n al ysis 
a d de d 
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
S u b gr o u p a nal ysis f or 
p artici pa nts wit h L V E F > 
me dia n a n d ≤me dia n at 
scree ni n g 
N o  
C orrecti o n, as it was a mista ke t o 
ha v e > < E F 4 0 %  
Ot her  
0 6 -A u g ust -2 0 2 4  
A me n de d descri pti o n of 
a n e x pl orat or y e n d p oi nt 
( o utc o me varia ble) t o 
refer t o d o mai ns a n d 
s u b d o mai ns 
N o  
Clarificati o n  
Ot her  
0 6 -A u g ust -2 0 2 4  
A me n de d 1. 3 N u m ber of 
partici pa nts t o clarif y t he 
n u m ber refers t o a 
mi ni m u m of 1 6 6  
N o  
Clarificati o n  
Ot her  
0 6 -A u g ust -2 0 2 4  
Cli nical c haracteristics 
a d de d t o t he list of 
s u m maries t o be 
prese nte d f or Scree ne d 
Set  
Yes  
T o ali g n wit h t he prese ntati o ns  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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  of 7 2  
 
 
Ot her  
0 6 -A u g ust -2 0 2 4  
S u m mar y of ma xi m u m 
d ose of s pir o n olact o ne 
ac hie ve d i n c o h ort 2 
a m o n g s u bjects w h o d o 
n ot bec o me 
h y per kalae mic a d de d  
Yes  
T o ali g n wit h t he st u d y o bjecti ves  
Ot her  
0 6 -A u g ust -2 0 2 4  
E fficac y of S Z C i n 
ac hie vi n g 
n or m o kal ae mia, a n d 
mai ntai ni n g 
n or m o kal ae mia d uri n g 
t he r u n-i n p hase a d de d t o 
t he list of s u m maries t o 
be prese nte d f or Safet y 
Set  
Yes  
T o ali g n wit h t he st u d y o bjecti ves  
Ot her  
0 6 -A u g ust -2 0 2 4  
Secti o n 3. 3. 8 re vise d t o 
refer t o l o o p di uretics; 
d ose c o n versi o n 
f or m ulas a d de d 
Yes  
Clarificati o n  
Ot her  
0 6 -A u g ust -2 0 2 4  
Secti o n 4. 1 re vise d t o 
i ncl u de o nl y a ge neric 
state me nt o n t he 
pr o gra m mi n g vali dati o n 
pr ocess; C o va nce 
re place d wit h F ortrea 
N/ A  
Clarificati o n  
Ot her  
0 6 -A u g ust -2 0 2 4  
S u m mar y of c ha n ge i n 
mea n dail y f ur ose mi de 
e q ui vale nt l o o p di uretic 
d ose d uri n g ra n d o mise d -
wit h dra wal peri o d  a d de d 
Yes  
T o s u p p ort t he s u m maries of t he 
f ur ose mi de e q ui vale nt l o o p di uretic 
d ose  o ver ti me  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9  of 7 2  
 
 
Ot her  
0 6 -A u g ust -2 0 2 4  
S u m mar y of s u bjects 
ac hie vi n g 
n or m o kalae mia, a n d 
mai ntai ni n g 
n or m o kalae mia d uri n g 
t he r u n-i n peri o d a d de d  
t o 4. 2. 7. 4. 6 
Yes  
T o s u p p ort s u m maries of s u bject 
stat us d uri n g a n d at t he e n d of t he 
o pe n -la bel r u n-i n peri o d 
Ot her  
0 6 -A u g ust -2 0 2 4  
Re vise d defi niti o n of 
safet y set o pe n i n secti o n 
2. 1, descri pti o n of  
c ha n ge fr o m pr ot oc ol 
a d de d t o secti o n 6.  
N o  
Safet y s u m maries i n o pe n -la bel 
peri o d s h o ul d i ncl u de s u bjects 
e x p ose d t o S Z C or  s pir o n olact o ne. 
Ot her  
0 6 -A u g ust -2 0 2 4  
Re vise d defi niti o n of 
o pe n -la bel peri o d f or 
s u bjects i n c o h ort 2 i n 
secti o ns 2. 3 a n d 3. 2. 
N o  
S u bjects i n c o h ort 2 d o n ot 
i m me diatel y recei ve S Z C b ut 
peri o d is meas ure d fr o m visit 2.  
Ot her  
0 6 -A u g ust -2 0 2 4  
A me n de d baseli ne 
defi niti o n f or s u bjects i n 
c o h ort 2 i n li ne wit h 
c ha n ges t o o pe n -la bel 
peri o d i n secti o ns 3. 1 a n d 
4. 1.  
N o  
S u bjects i n c o h ort 2 s h o ul d ha ve 
baseli ne c o m para ble t o c o h ort 1 
rat her t ha n date of first d ose of 
S Z C.  
Ot her  
0 6 -A u g ust -2 0 2 4  
Missi n g dates i m p utati o n 
u p date d i n secti o n 4. 1. 1 
f or c o h ort 2 s u bjects. 
N o  
Missi n g dates i m p utati o n altere d i n 
li ne wit h c h a n ge i n defi niti o n of 
o pe n -la bel peri o d i n c o h ort 2. 
Ot her  
0 6 -A u g ust -2 0 2 4  
A nal ysis of baseli ne 
heart fail ure me dicati o ns 
a n d di uretics a d de d t o 
secti o n 4. 2. 5. 
N o  
T hese me dicati o ns are of cli nical 
i nterest t o descri be. 
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
S u p ple me ntar y a nal ysis 
met h o d u p date d i n 
secti o n 4. 2. 7. 1. 3 t o 
N o  
Ti me -de p e n de nt c o variates acte d as 
c o nf o u n der a n d me diat or s o 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
re m o ve ti me-de pe n de nt 
d ose fr o m statistical 
m o del. Descri pti o n of 
c ha n ge fr o m pr ot oc ol 
a d de d t o secti o n 6.  
re m o ve d fr o m a n al ysis as i n d uce d 
bias i n treat me nt effect esti mate.  
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
A d diti o n of calc ulati o n 
of me dia n perce nta ge 
a n d c orres p o n di n g 
m o delle d perce nta ge 
descri be d i n secti o n 
4. 2. 7. 1 . 
N o  
I ncl u de d t o gi ve i n dicati o n of 
o verall p o p ulati o n wit h res p o nse.  
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
T w o a d diti o nal 
s u p ple me ntar y a nal yses 
f or pri mar y e n d p oi nt 
a d de d i n secti o n 4. 2. 7. 1. 3  
e xcl u di n g partici pa nts 
wit h 1 5 g dail y 
S Z C/ place b o at 
ra n d o misati o n a n d wit h 
a n alter nate defi niti o n of 
h y per kalae mia.  
N o  
I ncl u de d t o pr o vi de f urt her 
s u p ple me ntar y a n al yses of t he 
pri mar y e n d p oi nt.  
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
A d diti o nal se nsiti vit y 
a nal yses a d de d i n secti o n 
4. 2. 7. 2  f or sec o n dar y 
e n d p oi nts e x pl ori n g a n 
alter nate defi niti o n of 
h y per kalae mia.  
N o  
I ncl u de d t o pr o vi de f urt her 
s u p ple me ntar y a n al yses of t he 
sec o n dar y e n d p oi nt. 
Statistical a n al ysis met h o d f or t he 
pri mar y or sec o n dar y e n d p oi nts  
0 6 -A u g ust -2 0 2 4  
A d de d l o g -ra n k test t o 
Ka pla n -Meier fi g ure i n 
secti o ns 4. 2. 7. 2, 4. 2. 7. 3, 
4. 2. 7. 4. 2 a n d 4. 2. 7. 4. 5.  
N o  
I ncl u de d as part of Ka pla n-Meier 
pl ots i n Astra Ze n eca sta n dar ds.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
Ot her  
0 6 -A u g ust -2 0 2 4  
S pecifie d l o g -
tra nsf or mati o n f or N T-
pr o B N P a n d al d oster o ne 
i n statistical met h o ds i n 
secti o n 4. 2. 7. 4. 2 
N o  
B ot h para meters o bser ve d t o be n o n 
n or mall y distri b ute d s o 
tra nsf or mati o n will i m pr o ve m o del 
fit. 
Ot her  
0 6 -A u g ust -2 0 2 4  
S pecifie d bac k war d 
selecti o n a p pr oac h f or 
varia ble selecti o n i n 
secti o n 4. 2. 7. 4. 2. 
N o  
M o del was o ver -fitte d a n d ter ms 
nee de d t o be re d uce d.  
Ot her  
0 6 -A u g ust -2 0 2 4  
Re vise d cate g ories f or 
prese ntati o n of R A A Si 
persiste nce i n secti o n 
4. 2. 7. 4. 5.  
N o  
Re vise d base d o n cli nical fee d bac k.  
Ot her  
0 6 -A u g ust -2 0 2 4  
E x p os ure calc ulati o n 
u p date d i n secti o n 
4. 2. 8. 8. 9.  
N o  
Clarifie d e x p os ure i nf or mati o n t o 
use f or e x p os ure calc ulati o n base d 
o n latest e x p os ure rec or d i n relati o n 
t o st u d y visit date.  
Pri mar y a n d sec o n dar y e n d p oi nts  
2 1 -Dec -2 0 2 3  
A d de d “ T he m o nt hl y 
visits are use d f or 
res p o nse assess me nt 
fr o m m o nt h 1 t o m o nt h 
6” t o pri mar y a n d 
sec o n dar y e n d p oi nts a n d 
delete d “at t he e n d of 
treat me nt ( E O T) visit 
(a p pr o xi matel y 6 m o nt hs 
p ost -ra n d o misati o n)”. 
U p date d res p o nse a n d 
n o n -res p o nse defi niti o ns 
a n d t he n o n -res p o nse 
i m p utati o n r ules d ue t o 
Yes, v 4. 0  
Defi niti o n f or pri mar y e n d p oi nt 
a me n de d t o a l o n git u di nal a nal ysis 
w hic h i ncreases t he p o wer of st u d y 
a n d all o ws f or a re d uce d sa m ple 
size. 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
t he c ha n ge i n e n d p oi nt 
defi niti o n.  
Statistical a n al ysis met h o d f or t he 
pri mar y a n d sec o n dar y e n d p oi nts  
2 1 -Dec -2 0 2 3  
G E E m o del f or pri mar y 
e n d p oi nt a n d sec o n dar y 
efficac y e n d p oi nt 
a nal yses were a d de d, t he 
l o gistic re gressi o n m o del 
was delete d.  
Yes, v 4. 0  
Deter mi ne d t o be a p pr o priate 
statistical met h o d f or esti mati n g 
res p o nses at eac h ti me p oi nt a n d 
fi xe d treat me nt effect. 
Ot her  
2 1 -Dec -2 0 2 3  
Re vise d sa m ple size 
calc ulati o n f or ne w 
pri mar y e n d p oi nt 
defi niti o n. Decrease i n 
n u m ber of partici pa nts 
w h o will be ra n d o mise d 
a n d e nter t he 6 m o nt h 
ra n d o mise d p hase of t he 
trial, fr o m 2 6 0 t o 1 6 6 
partici pa nts.  
Yes, v 4. 0  
Sa m ple size calc ulati o n u p date d t o 
ali g n wit h t he u p date d pri mar y 
e n d p oi nt d efi niti o n.  
Ot her  
2 1 -Dec -2 0 2 3  
Clarifie d selecti o n r ules 
f or t he use of pa per 
P R Os vers us electr o nic 
P R Os w he n b ot h are 
a vaila ble or m ulti ple 
P R Os ha ve bee n 
rec or de d. 
Yes, v 4. 0  
Clarificati o n base d o n t he rec or di n g 
of P R Os d uri n g t he st u d y.  
Ot her  
2 1 -Dec -2 0 2 3  
Clarifie d selecti o n r ules 
f or t he use of pa per 
P R Os vers us electr o nic 
P R Os w he n b ot h are 
a vaila ble or m ulti ple 
P R Os ha ve bee n 
rec or de d. 
Yes, v 4. 0  
Clarificati o n base d o n t he rec or di n g 
of P R Os d uri n g t he st u d y.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
Ot her  
2 1 -Dec -2 0 2 3  
U p date d C K D -E PI 
f or m ula t o n o n-race 
base d C K D -E PI 
Creati ni ne E q uati o n 
2 0 2 1.  
Yes, v 3. 0  
C S P a me n d me nt v 3. 0, clarifie d 
C K D -E PI f or m ula t o be use d.  
Ot her  
0 8 -J ul-2 0 2 2  
A me n de d visit 
wi n d o wi n g, restricte d 
c o nc o mita nt t hera p y 
defi niti o n, a d diti o nal 
s u b gr o u p a nal ysis 
Yes, v 3. 0  
S A P a me n de d t o reflect c ha n ges t o 
trial desi g n ma d e i n pr ot oc ol v 3. 0. 
Data prese ntati o ns  
1 1 -Mar -2 0 2 2  
A d de d details of a nal ysis 
f or peri p heral e de ma a n d 
heart fail ure e ve nts. 
C orrecte d ot her errata.  
Yes, v 2. 0  
Details of a n al ysis were missi n g 
fr o m S A P te xt a n d T F L s hells. 
* Pre -s pecifie d cate g ories are  
Pri mar y or sec o n dar y e n d p oi nts; Statistical a n al ysis met h o d f or t he pri mar y or sec o n dar y e n d p oi nts; Deri vati o n of pri mar y or sec o n dar y e n d p oi nts; M ulti ple 
Testi n g Pr o ce d ure; Data prese ntati o ns; Ot her  
 




Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
O bjecti ve  
E n d p oi nt ( O utc o me V ari a ble) 
Res p o nse mea ns all t hree b ullet p oi nts 
h ol d. N o n -res p o nse is i n dicate d if at least 
o ne b ullet p oi nt d oes n ot h ol d.  
A d diti o nall y, f or eac h assess me nt visit, 
n o n -res p o nse is i n dicate d f or partici pa nt s 
w h o are l ost t o f oll o w -u p at t he visit, 
i ncl u di n g d ue t o deat h. 
T he m o nt hl y visits are use d f or res p o nse 
assess me nt fr o m m o nt h 1 t o m o nt h 6  
( Visits 9-1 4 d uri n g t he Ra n d o mi se d 
Wit h dra wal P hase, Pr ot o c ol Ta ble 1).  
T he treat me nt effect c o ncer ns t he o v erall 
o d ds rati o.  
•  T o c o m pare t h e S Z C a n d place b o ar ms 
wit h res pect t o s pir o n olact o ne d ose  
•  R es p o nse ( yes/ n o), defi n e d b y:  
o  Bei n g o n s pir o n olact o ne ≥2 5 m g 
dail y  
Res p o nse mea ns t he b ull et p oi nt h ol ds. 
N o n -res p o nse i n dicates b ullet p oi nt d oes 
n ot h ol d.  
A d diti o nall y, f or eac h assess me nt visit, 
n o n -res p o nse is i n dicate d f or partici pa nt s 
w h o are l ost t o f oll o w -u p at t he visit, 
i ncl u di n g d ue t o deat h. 
T he m o nt hl y visits are use d f or res p o nse 
assess me nt fr o m m o nt h 1 t o m o nt h 6  
( Visits 9-1 4 d uri n g t he Ra n d o mi se d 
Wit h dra wal P hase, Pr ot o c ol Ta ble 1) . 
T he treat me nt effect c o ncer ns t he o v erall 
o d ds rati o.  
•  T o e val uate t he effi cac y of S Z C as 
c o m pare d t o place b o i n k ee pi n g 
p otassi u m le vels ≤5. 0 m E q/ L  
•  Ti me t o first H K e pis o de f or partici pa nt s 
o n S Z C c o m pare d t o place b o d uri n g t he 
ra n d o mise d-wit h dra wal peri o d, wit h H K 
defi ne d as s K + > 5. 0 m E q/ L as assesse d 
b y ce ntral la b orat or y  
•  T o c o m pare t h e S Z C a n d place b o ar ms 
wit h res pect t o a bilit y t o pre ve nt 
decreases i n s pir o n olact o ne d ose  
•  Ti me t o first i nsta nce of decrease or 
disc o nti n uati o n of s pir o n olact o ne d ose 
d ue t o H K f or p artici pa nt s o n S Z C 
c o m pare d t o place b o d uri n g t he 
ra n d o mise d-wit h dra wal peri o d  




Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7  of 7 2  
 
 
O bjecti ve  
E n d p oi nt ( O utc o me V ari a ble) 
o  H F H os pitalizati o ns  
o  Ur ge nt H F Visits  
•  T o e x pl ore t he p ote ntial c ha n ge i n mea n 
uri ne al b u mi n -t o-creati ni ne ( U A C R) i n 
t he S Z C a n d Place b o ar ms  
•  C ha n ge i n mea n U A C R i n S Z C gr o u p 
c o m pare d wit h place b o gr o u p at:   
o  Scree ni n g c o m pare d t o E O T  
o  Ra n d o mis ati o n c o m pare d t o E O T  
•  C ha n ge i n mea n U A C R at:  
o  Scree ni n g c o m pare d t o 
ra n d o misati o n  
•  T o e x pl ore t he c ha n ge fr o m baseli ne i n 
K C C Q T otal S y m pt o m Sc ore ( T S S) a n d 
K C C Q O verall S y m pt o m Sc ore ( O S S) 
a n d ot her K C C Q s u b -d o mai ns 
(i ncl u di n g K C C Q p h ysical li mitati o n 
sc ore) bet wee n t h e S Z C a n d Place b o 
ar ms 
•  C ha n ge i n K C C Q -T S S, K C C Q -O S S a n d 
ot her K C C Q s u b -d o mai ns (i ncl u di n g 
K C C Q p h ysical li mitati o n sc ore) at E O T 
(a p pr o xi matel y 6 m o nt hs p ost 
ra n d o misati o n) c o m pare d wit h 
ra n d o misati o n baseli ne  
•  T o e x pl ore t he relati o ns hi p bet wee n 
al d oster o ne le v el a n d P GI S a n d K C C Q 
sc ores, wit h partic ul ar att e nti o n t o 
i ntra patie nt c o nsiste nc y, bet wee n t he 
S Z C a n d place b o ar ms at t he E O T visit 
c o m pare d t o r a n d o misati o n.  
•  C ha n ge i n P GI S a n d K C C Q sc ores 
(acr oss d o mai ns a n d s u b d o mai ns ) fr o m 
scree ni n g t o t he e n d of o pe n-la bel, 
scree ni n g t o t he E O T a n d ra n d o misati o n 
t o E O T a dj uste d f or c h a n ge i n 
al d oster o ne le vels d uri n g t he sa me peri o d  
•  T o e x pl ore t he p ote ntial differe n ce i n N -
ter mi nal pr o-B -t y pe natri uretic pe pti de 
( N T pr o-B N P) bet w ee n S Z C a n d 
Place b o ar ms ( me a n differe nce as 
c o m pare d t o bas eli ne, as well as t he 
li keli h o o d of a n i ncrease, decrease a n d 
sta bilit y) 
•  C ha n ge i n N T pr o -B N P meas ure me nts at 
E O T (a p pr o xi mat el y 6 m o nt hs p ost 
ra n d o misati o n) c o m pare d wit h 
ra n d o misati o n baseli ne  
•  T o e val uate t he effi cac y of S Z C as 
c o m pare d t o place b o i n a v oi di n g t he 
re q uire me nt of resc u e t hera p y use f or 
H K  
•  Ti me t o first i nsta nce of use of res c ue 
t hera p y f or H K d uri n g t h e ra n d o mise d-
wit h dra wal peri o d  
•  T o e val uate t he p ot e ntial c ha n ge i n 
p otassi u m le vels after t he E O T i n t he 
S Z C a n d Place b o ar ms  
•  C ha n ge i n s K + at 7 da ys p ost E O T 
c o m pare d wit h E O T  
•  T o e val uate t he effi cac y of S Z C as 
c o m pare d wit h place b o i n kee pi n g 
•  Res p o nse  ( yes/ n o) of p artici pa nt s o n S Z C 
c o m pare d t o place b o w h o, at t he e n d of 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 8  of 7 2  
 
 
O bjecti ve  
E n d p oi nt ( O utc o me V ari a ble) 
p otassi u m le vels wit hi n t he n or mal 
ra n ge ( 3. 5-5. 0 m E q/ L) w hile o n 
s pir o n olact o ne ≥2 5 m g dail y wit h o ut 
assista nce of resc u e t hera p y f or 
h y per kala e mia ( H K)  
treat me nt ( E O T) visit (a p pr o xi matel y 6 
m o nt hs p ost -ra n d o misati o n), ha ve ser u m 
p otassi u m (s K +) wit hi n 3. 5 -5. 0 m E q/ L as 
assesse d b y ce ntral la b orat or y, are o n 
s pir o n olact o ne ≥2 5 m g dail y, a n d di d n ot 
use resc u e t hera p y f or H K at a n y p oi nt 
d uri n g t he ra n d o mis e d-wit h dra wal p hase. 
Partici pa nt s w h o are l ost t o f oll o w-u p, 
i ncl u di n g d ue t o deat h, pri or t o t he E O T 
visit will be treate d as n o n -res p o nse. 
1. 2  
St u d y desi g n  
T his st u d y is a parallel -gr o u p, place b o -c o ntr olle d, m ulti -ce ntre st u d y wit h a n o pe n -la bel r u n-i n 
peri o d. T he p o p ulati o n st u die d will be partici pa nt s wit h s y m pt o matic heart fail ure wit h 
re d uce d ejecti o n fracti o n ( H Fr E F) w h o are ta ki n g n o s pir o n olact o ne or l o w-d ose 
s pir o n olact o ne  or e pl ere n o ne ( < 2 5 m g dail y) at baseli ne. D uri n g t he o p e n -la bel 4- t o 6-wee k 
r u n-i n peri o d, ser u m p otassi u m (s K +) will be n or mal ise d wit h s o di u m zirc o ni u m c ycl osilicate 
( S Z C) as nee d e d a n d s pir o n olact o ne will be i nitiate d/ u p-titrated t o a ma xi m u m d ose of 5 0 m g 
dail y. Partici pa nt s w h o are n or m o kalae mic ( N K; 3. 5 ≤s K + ≤5. 0 m E q/ L) a n d recei vi n g 
s pir o n olact o ne ≥2 5 m g dail y at t he e n d of t he o pe n-la bel r u n-i n peri o d will be ra n d o mise d t o 
S Z C or place b o d uri n g t h e d o u ble -bli n d ra n d o m ise d-wit h dra wal p eri o d wit h ra n d o misati o n 
stratifie d acc or di n g t o t he prese n ce of H K/ N K at st u d y e ntr y. St u d y sites will be l ocate d i n 
N ort h a n d S o ut h A merica a n d E ur o p e. T otal d urati o n of st u d y partici pati o n f or eac h 
partici pa nt  will be a p pr o xi matel y 8 m o nt hs, i nc l u di n g 7 m o nt hs o n treat me nt. T he st u d y 
c o nsists of 3 peri o ds:  
1.  Scree ni n g peri o d ( u p t o 2 wee ks)  
a.  Partici pa nt s recei vi n g l o w-d ose e plere n o n e will be s witc he d t o s pir o n olact o ne 1 2. 5 m g 
dail y d uri n g t he scree ni n g peri o d.  
b.  C o h ort assi g n me nt is base d o n l ocal la b s K + o n Visit 1.  
c. I n p artici pa nt s wit h h y per kalae mia ( C o h ort 1), Visit 2 ma y occ ur at t he sa me ti me as, 
or s h ortl y after Visit 1 ( Scree ni n g), s o t hat treat me nt wit h S Z C ca n be i nitiate d as s o o n 
as p ossi ble, as per i n vesti gat or’s g ui da nce.  
2.  Treat me nt peri o d ( a p pr o xi matel y 8  m o nt hs)  
a. O pe n -la bel, r u n-i n peri o d ( 4-6 wee ks)  
1. C o h ort 1 ( 4 wee ks): P artici p a nt s w h o are H K at st u d y e ntr y: 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  H K C orrecti o n Peri o d: Partici pa nt s will start S Z C o n Da y 1 at a 
d ose of 1 0 g t hree ti mes dail y f or u p t o 4 8 h o urs u ntil s K + 3. 5 -5. 0 
m E q/ L ( N K). N O T E:  Partici pa nt s w h o d o n ot ac hie ve N K d uri n g 
t he 4 8-h o ur c orrecti o n p hase will be disc o nti n ue d fr o m t he st u d y.  
•  s K + Mai nte na n ce Peri o d: Partici pa nt s w h o ac hie ve N K will 
c o nti n ue o n S Z C 1 0 g dail y a n d t he n titrate bet wee n 5 g e ver y ot h er 
da y a n d  
5 t o 1 5 g dail y t o mai ntai n s K + 3. 5 -5. 0 m E q/ L per pr ot oc ol 
i nstr ucti o ns. 
•  S pir o n olact o ne: Partici pa nt s will i nitiate or u p-titrate s pir o n olact o ne 
be gi n ni n g o n Da y 2 or 3 w he n t he y bec o me N K o n S Z C. 
S pir o n olact o ne will be s yste maticall y u ptitrate d t o a tar get d ose of 
5 0 m g dail y, as t olerate d per pr ot oc ol i nstr ucti o ns. N O T E:  
Partici pa nt s w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile 
recei vi n g ma xi m u m d ose S Z C ( 1 5 g), b ut were N K o n 
s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n-la bel, r u n-i n 
p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o 
s pir o n olact o ne 2 5 m g a n d bec ome N K a gai n.  
2. C o h ort 2 ( 4 -6 w ee ks): P artici p a nt s w h o are N K at st u d y e ntr y: 
•  S pir o n olact o ne: Partici pa nt s will i nitiate or u p-titrate s pir o n olact o ne 
be gi n ni n g o n Da y 1. S pir o n olact o ne will be s yste maticall y 
u ptitrate d t o a tar get d ose of 5 0 m g dail y, as t olerate d per pr ot oc ol 
i nstr ucti o ns. 
•  H K C orrecti o n Peri o d: Partici pa nt s w h o de v el o p H K d uri n g t he first 
4  wee ks of t he r u n -i n peri o d will be gi n S Z C 1 0 g t hree ti mes dail y 
f or u p t o 4 8 h o urs u ntil s K + 3. 5-5. 0 m E q/ L. N O T E:  Partici pa nt s 
w h o d o n ot ac hie ve N K d uri n g t he 4 8 -h o ur c orrecti o n p hase will be 
disc o nti n ue d fr o m t he st u d y.  
•  s K + Mai nte na n ce Peri o d:  Partici pa nt s will c o nti n ue o n S Z C 1 0 g 
dail y a n d t he n titrate bet wee n 5 g e v er y ot her da y a n d 5 - 1 5 g dail y 
t o mai ntai n s K + 3. 5-5. 0 m E q/ L per pr ot oc ol i nstr ucti o ns.  
3. N O T E:  
•  Partici pa nt s i n C o h ort 2 w h o d o n ot de vel o p H K d uri n g t he first 3 
wee ks ( a n d as a res ult d o n ot meet t he re q uir e me nts t o recei ve S Z C) 
will be disc o nti n ue d fr o m t he st u d y d uri n g t he r u n -i n peri o d. 
•  Partici pa nt s w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile 
recei vi n g ma xi m u m d ose S Z C ( 1 5 g), b ut were N K o n 
s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n-la bel, r u n-i n 
p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o 
s pir o n olact o ne 2 5 m g a n d bec o me N K a gai n. 
b.  D o u ble -bli n d, place b o -c o ntr olle d, ra n d o m ise d-wit h dra wal peri o d ( 6 m o nt hs):  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
1. Partici pa nt s w h o are N K o n S Z C a n d recei vi n g s pir o n olact o ne ≥2 5 m g dail y 
at t he e n d of t he r u n -i n p eri o d will be ra n d o mise d 1: 1 t o S Z C or place b o 
stratifie d acc or di n g t o t he prese n ce of H K/ N K ( o pe n la bel c o h ort 1 vs. c o h ort 
2) at st u d y e ntr y, c o nti n ui n g o n t he d ose t he y were bei n g a d mi nistere d at t he 
e n d of t he r u n -i n p hase. 
2. I nstr u cti o ns o n h o w t o ma na ge p artici pa nt s w h o d o n ot q ualif y f or 
ra n d o misati o n d ue t o h y per kalae mia  are detaile d i n t he C S P, secti o n 6. 6. 1.  
3. C o m plete i nf or mati o n re gar di n g S Z C a n d s pir o n olact o ne d osi n g is pr o vi de d 
i n t he C S P, secti o n 6. 6. 
3.  F oll o w -u p peri o d ( 1 wee k) after t h e E O T visit: s K + will be c hec ke d 7 da ys after last 
d ose of st u d y dr u g ( S Z C or place b o). Partici pa nt s w h o d o n ot q ualif y f or 
ra n d o misati o n d ue t o h y per kalae mia s h o ul d ha ve a f oll o w -u p visit 2 da ys after t heir 
last d ose of st u d y dr u g.  
T he st u d y sc he ma is dis pla ye d i n Fi g ure 1.  
Fi g ure 1 : St u d y Desi g n 
 
1. 2. 1  
R a n d o mis ati o n  
Partici pa nt s w h o are n or m o kalae mic ( N K; 3. 5 ≤s K + ≤5. 0 m E q/ L) a n d recei vi n g s pir o n olact o ne 
≥2 5 m g dail y at t he e n d of t he o pe n -la bel r u n-i n peri o d will be ra n d o mise d 1: 1 t o eit her S Z C 
or place b o, c o nti n ui n g o n S Z C d ose fr o m e n d of 4 -6 wee k o pe n -la bel r u n-i n peri o d. 
Ra n d o mis ati o n will be stratifie d acc or di n g t o t he prese nce of h y per kalae mia ( C o h ort 
1)/ n or m o kalae mia ( C o h ort 2) at st u d y e ntr y. Ra n d o mis ati o n will be perf or me d usi n g 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
ra n d o ml y per m ute d bl oc ks. T he ra n d o misati o n c o des will be c o m p uter ge n erate d a n d l oa de d 
i nt o t he I x R S data bas e. 
Dr u g is dis pe nse d b y t he I R T s yste m f or Visit 2: O pe n -La b el R u n -I n a n d Ra n d o mis ati o n. 
F urt her m ore, dr u g ma y b e dis pe nse d at Visit 3: O pe n -La b el Wee k 2, Visit 4: O pe n -La b el 
Wee k 3, Visit 5: O pe n -L a bel Wee k 4, Visit 6: O pe n -La b el Wee k 5, Visit 6. 1: O pe n -La b el 
Wee k 6 a n d Visit 9 D o u ble Bli n d Wee k 5, Visit 1 0, D o u ble -Bli n d Wee k 9, Visit 1 1: D o u ble -
Bli n d Wee k 1 3, Visit 1 2: D o u ble -Bli n d Wee k 1 7, Visit 1 3: D o u ble -Bli n d Wee k 2 1, Visit 1 4: 
D o u ble -Bli n d Wee k 2 5, Visit 1 5: D o u ble -Bli n d Wee k 2 9.  
1. 3  
N u m ber of p artici p a nt s 
T he sa m ple size calc ulati o n is base d o n t he pri mar y o bjecti ve, i.e. T o ev al u ate t he effic acy of 
S Z C as c o m p are d wit h pl ace b o i n kee pi n g p ot assi u m levels wit hi n t he n or m al r a n ge ( 3. 5 –  5. 0 
m E q/ L as assesse d by ce ntr al l a b or at ory) w hile o n s pir o n ol act o ne ≥2 5 m g d aily wit h o ut 
assist a nce of resc ue t her a py f or hy perk al ae mi a . 
Ass u mi n g t hat t he pr o ba bilit y of res p o nse is 0. 7 i n t he S Z C gr o u p a n d 0. 5 i n t he place b o 
gr o u p,  a n d a c orrel ati o n of 0. 5 5 bet wee n sc he d ule d visits, t he n a ge neral ise d esti mati n g 
e q uati o n (G E E ) m o d el, wit h a n esti mate of res p o nse f or eac h ti me p oi nt a n d fi xe d treat me nt 
effect, usi n g a bi n o mial distri b uti o n wit h e xc ha n gea ble c orrelati o n matri x wit h a 5 % t w o -
si de d si g nifica nce le v el a n d 9 0 % p o wer will r e q uire 1 5 8 partici p a nt s t o be ra n d o mise d. 
Cli nical data s u g gests t hat t he rate of d eat h i n t his partici pa nt  p o p ulati o n is a p pr o xi matel y 1 0 
deat hs per 1 0 0 p ers o n -y ears. Wit h 7 9 partici pa nt -years of o bs er vati o n ( 1 5 8 * 6/ 1 2), 
a p pr o xi matel y 8 deat hs are a ntici pate d ( 7 9 * 1 0/ 1 0 0) d uri n g t he 6 -m o nt h ra n d o mise d p hase. 
T heref ore, t he s a m ple siz e will be i ncrease d t o a mi ni m u m of  1 6 6 ra n d o mise d partici pa nt s t o 
e ns ure n = 1 5 8 i n t he m ai n se nsiti vit y a nal ysis f or t he pri mar y e n d p oi nt. Partici pa nt s will be 
e ntere d i nt o t he o pe n -la b el p hase u ntil t he re q uir e d n u m ber of ra n d o mise d partici pa nt s is 
reac h e d, at w hic h p oi nt t he recr uit ment will st o p. Te ntati vel y, it is e x pecte d t hat 
a p pr o xi matel y 4 0 0 partici pa nt s will e nter t he o pe n la bel p hase i n or d er t o ac hie ve t he g oal of 
at least 1 6 6  ra n d o mise d p artici pa nt s. 
2  
A N A L Y SI S S E T S  
2. 1  
Defi niti o n of a n al ysis sets  
Scree ne d Set  
All partici pa nt s w h o were scree ne d f or i ncl usi o n i n t he o pe n-la bel r u n-i n p eri o d of t he st u d y. 
T his a nal ysis set will be use d t o descri be t he de m o gra p hics a n d cli nical c haract eristics of 
partici pa nt s c o nsi dere d f or i ncl usi o n i n t he st u d y. T he assi g n me nt of partici pa nt s t o a 
treat me nt gr o u p f or a nal ysis is n ot a p plica ble.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
S afet y Set O pe n  
All partici pa nt s w h o meet i ncl usi o n/e xcl usi o n criteria a n d e nter t he o pe n-la bel peri o d of t he 
st u d y a n d recei ve at least o ne d ose of S Z C or S pir o n olact o ne . T he Safet y Set O pe n ( S S O) 
a nal ysis set will be use d t o descri be t he s afet y c haracteristics of S Z C .. T he assi g n me nt of 
partici pa nt s t o a treat me nt gr o u p f or a n al ysis is n ot a p plica ble. 
S afet y Set R a n d o m ise d 
All ra n d o m ise d partici pa nt s w h o recei v e d at least o ne d ose of eit her S Z C or place b o d uri n g 
t he ra n d o mise d-wit h dr a wal peri o d of t he st u d y. T he Safet y Set Ra n d o m ise d ( S S R) a nal ysis set 
will be use d t o descri be t he safet y c haracteristics of S Z C or place b o d uri n g t he ra n d o m ise d-
wit h dra wal peri o d. Partici pa nt s will be a nal yze d acc or di n g t o t he treat me nt act uall y recei ve d 
d uri n g t he ra n d o m ise d-wit h dra wal p hase.  
S afet y Set E x pl or at or y  
All partici pa nts w h o meet i ncl usi o n/e xcl usi o n criteria a n d e nter t he o pe n -la bel peri o d of t he 
st u d y a n d recei ve at least o ne d ose of S Z C. T he S afet y Set E x pl orat or y ( S SE ) a nal ysis set will 
be use d t o descri be t he efficac y of S Z C i n ac hie vi n g n or m o kalae mia, mai ntai ni n g 
n or m o kal ae mia a n d ac hi e vi n g at least 2 5 m g of s pir o n olact o ne d uri n g t he o pe n -la bel r u n-i n 
peri o d. . T he assi g n me nt of partici pa nts t o a tr eat me nt gr o u p f or a n al ysis is n ot a p plica ble. 
F ull A n al ysis Set  
All ra n d o m ise d partici pa nt s, irres pecti ve of treat m e nt a n d a n y pr ot oc ol d e viati o ns, w h o ha ve 
o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nts a vail a ble. T he F ull 
A nal ysis Set ( F A S) will be use d at t he pri mar y p o p ulati o n f or t he pri mar y a n d sec o n dar y 
effic ac y o bje cti ves. Partici pa nt s will be a nal yze d acc or di n g t o t he ra n d o mise d treat me nt, 
re gar dl ess of t he treat me nt act uall y recei ve d. 
Per Pr ot oc ol Set  
T he Per Pr ot oc ol Set ( P P S) is defi ne d as partici pa nt s i n t he F A S w h o d o n ot ha ve a n y 
i m p orta nt pr ot oc ol de viati o ns c o nsi dere d t o ha ve a maj or effect o n efficac y. T he P P S will be 
use d as a se nsiti vit y a nal ysis f or t he pri mar y a n d s ec o n dar y e n d p oi nts.  
Pr ot oc ol de viati o ns are d efi ne d as a n y c ha n g e, di v er ge nce, or de part ure fr o m t he st u d y desi g n 
of pr oce d ures defi ne d i n t he st u d y pr ot oc ol. I m p orta nt pr ot oc ol de viati o ns are a s u bset of 
pr ot oc ol de viati o ns a n d ma y si g nifica ntl y i m pact t he c orrect ness, acc ur ac y, a n d/ or relia bilit y 
of t he st u d y data or t hat ma y si g nifica ntl y affect a partici pa nt ’s ri g hts, safet y, or well-bei n g.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
2. 2  
Vi ol ati o ns a n d de vi ati o ns  
Partici pa nt s will be assesse d b y c o m paris o n of t heir e C R F data wit h t he criteria bel o w; 
pr ot oc ol wai vers will n ot be ta ke n i nt o c o nsi derati o n (e. g. if a p artici pa nt  y o u n ger t ha n 1 8 
e nters t he st u d y o n a pr ot oc ol wai ver, t he p artici pa nt  w o ul d still be e xcl u de d fr o m t he P P S).  
I m p ort a nt pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m t he P P S will be defi ne d b y t he 
S p o ns or bef ore d ata bas e l oc k b y j u d gi n g t he i m p orta nce of t he de viati o ns u p o n t he pri mar y 
effic ac y e n d p oi nt. T he f oll o wi n g criteria ma y be c o nsi dere d as i m p orta nt pr ot oc ol de viati o ns 
w hic h ma y ha ve a maj or effect o n efficac y or t hat c o ul d p ote ntiall y affect t he i nter pret a bilit y 
of t he st u d y res ults.  
•  Partici pa nt s w h o faile d a n y of t he i ncl usi o n or e xcl usi o n criteria of t he st u d y. 
•  All pr o hi bite d me dicati o ns w hic h are a d mi nistere d d uri n g t he st u d y. Pr o hi bite d 
me dicati o ns i ncl u de a n y p otassi u m s pari n g di uretics ot her t ha n s pir o n olact o ne (e. g. 
e plere n o n e, tria mtere ne, a mil ori de)  
•  All restricte d me dicati o ns w hic h are a d mi nistere d d uri n g t he st u d y w he n us e d f or a 
p ur p ose ot her t ha n t h ose i nstr ucte d i n secti o n 6. 5 of t he C S P.  
•  Err ors i n treat me nt all ocati o n. A n y partici pa nt  w h o recei v e d i nc orrect st u d y treat me nt 
c o m pare d wit h r a n d o m ise d st u d y treat me nt at a n y ti me d uri n g t he st u d y 
•  A n y partici pa nt  u n bli n de d i n err or, i.e. n ot d ue t o e mer ge n c y u n bli n di n g f or safet y 
c o ncer ns, d uri n g t he st u d y  
•  Start of d o u ble -bli n d st u d y me dicati o n pri or t o ra n d o misati o n date  
•  Partici pa nt  wit h first d ose date pri or t o b aseli ne e val uati o ns  
I n a d diti o n, pr ot oc ol de vi ati o ns will be defi ne d b y t he S p o ns or bef ore d ata base l oc k as 
C O VI D -1 9 pa n d e mic rel ate d or n ot b y j u d gi n g t he r o ot ca us e of t he pr ot o c ol de viati o n, i n li ne 
wit h F D A g ui da nce ( F D A G ui da nce o n C o n d u ct of Cli nical Trials of Me dical P r o d ucts d uri n g 
C O VI D -1 9 P u blic Healt h E mer ge nc y; Marc h 2 0 2 0). T he f oll o wi n g criteria ma y be c o nsi dere d 
as i n dicati ve of a pr ot oc ol de viati o n relate d t o t he C O VI D -1 9 pa n d e mic.  
•  Misse d i n -pers o n visit d ue t o C O VI D -1 9 ill ness a n d/ or C O VI D -1 9 p u blic h ealt h 
c o ntr ol meas ures  
•  St u d y visit o ut of wi n d o w d ue t o C O VI D -1 9 ill ness a n d/ or C O VI D -1 9 p u blic healt h 
c o ntr ol meas ures  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  Misse d d oses d ue t o C O VI D -1 9 ill ness a n d/ or C O VI D -1 9 p u blic h ealt h c o ntr ol 
meas ures  
•  Misse d s K + meas ur e me nts d ue t o C O VI D -1 9 ill ness a n d/ or C O VI D -1 9 p u blic healt h 
c o ntr ol meas ures  
2. 3  
A n al ysis Peri o ds  
Scree ni n g Peri o d  
T he scree ni n g peri o d is d efi ne d fr o m i nf or me d c o nse nt t o t he first d ose of o pe n -la bel st u d y or 
scree n fail ure. 
O pe n -l a bel peri o d 
I n c o h ort 1, the o pe n -la b el peri o d refers t o t he peri o d fr o m t he date of first d ose of o pe n -l a bel 
st u d y treat me nt ( S Z C) t o t he earliest date of ra n d o misati o n, wit h dra wal of c o nse nt, last 
c o ntact wit h t he partici p a nt  or deat h.  I n c o h ort 2, t he o pe n-la bel peri o d r efers t o t he peri o d 
fr o m t he date of t h e visit 2 st u d y visit t o t he earliest date of ra n d o misati o n, wit h dra wal of 
c o nse nt, last c o ntact wit h t he partici pa nt  or deat h.  
R a n d o m ise d-wit h dr a w al peri o d  
T he ra n d o m ise d-wit h dra wal peri o d r efers t o t he peri o d fr o m t he dat e of ra n d o misati o n t o t he 
earliest date of disc o nti n uati o n of st u d y treat me nt  ( S Z C/ Place b o), wit h dra wal of c o nse nt, last 
c o ntact wit h t he partici p a nt , or deat h. 
F oll o w -u p peri o d  
T he f oll o w -u p peri o d refers t o t he peri o d fr o m t he date of st u d y treat me nt disc o nti n uati o n 
( S Z C/ Place b o) t o t he earlier date of l ast assess me nt d uri n g f oll o w-u p (sc he d ule d t o be 7 da ys 
after t he E O T visit), wit h dra wal of c o nse nt, last c o ntact wit h t he partici pa nt , or deat h.  
3  
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S  
3. 1  
Ti me p oi nts a n d Visit Wi n d o ws  
F or all p o p ulati o ns, assess me nts will be assi g ne d t o visits a n d a nal ysis peri o ds f or cate g orical 
s u m maries as f oll o ws: 
•  
Assess me nts wit h missi n g data a n d ass ess me nts mar ke d “ N ot D o ne” will be c o nsi dere d 
as pr o vi di n g a missi n g res p o nse a n d are n ot per mitte d t o be assi g ne d t o a visit wi n d o w.  
•  
T he w orst val ue (e. g. o ut of refere n ce ra n ge preferre d t o wit hi n ra n ge; a b n or mal preferre d 
t o n or mal) will be use d i n eac h wi n d o w. If m ulti ple assess me nts fall wit hi n t he sa me 
wi n d o w wit h e q ual val ue t he n t he first n o n -missi n g will be use d f or t he s u m mar y.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  
I n t he T F L s h ells, “ Ti me P oi nt” is use d i nterc ha n g ea bl y wit h “ Visit” as m ulti ple 
o bser vati o ns are n ot ma d e at t he sa me visit.  
 
Sc he d ule d da y a n d visit wi n d o w d uri n g t he o pe n -la bel peri o d i n Ta ble 1  are i n c o h ort 1 wit h 
res pect t o t he first d ose of o pe n-la bel st u d y treat m e nt a n d i n c o h ort 2 wit h res pect t o t he date 
of t he st u d y 2 visit . 
T a ble 1  Defi niti o n of visit wi n d o ws f or o pe n -l a bel peri o d 
Visit  
Sc he d ule d  
D a y  
of Visit  
A n al ysis 
Peri o d  
E x pecte d ?  
Pr ot oc ol Visit 
Wi n d o w  
A n al ysis Visit 
Wi n d o w  
Visit 1  
-1 4 t o 1  
Scree ni n g  
Yes  
Da ys -1 4 t o 1  
Da ys -1 4 t o 1  
Visit 2  
1  
O pe n -La bel  
Yes  
Da y 1  
Da y 1  
Visit 2. 1 i 
2  
O pe n -La bel  
O pti o nal if C o h ort 1  
Da y 2  
Da y 2  
Visit 2. 2 i 
3  
O pe n -La bel  
All C o h ort 1 e xce pt t h ose N K at 
visit 2. 1  
Da y 3  
Da y 3  
Visit 3  
7 ( ± 2)  
O pe n -La bel  
Yes  
Da ys 5 t o 9  
Da ys 4 t o 9  
Visit 3. 1  
8  
O pe n -La bel  
O pti o nal if C o h ort 2  
Da y 8  
Da y 8  
Visit 3. 2  
9  
O pe n -La bel  
All C o h ort 2 e xce pt t h ose N K at 
visit 3. 1  
Da y 9  
Da y 9  
Visit 4  
1 4 ( ± 3)  
O pe n -La bel  
Yes  
Da ys 1 1 t o 1 7  
Da ys 1 0 t o 1 7  
Visit 4. 1  
1 5  
O pe n -La bel  
O pti o nal if C o h ort 2  
Da y 1 5  
Da y 1 5  
Visit 4. 2  
1 6  
O pe n -La bel  
All C o h ort 2 e xce pt t h ose N K at 
visit 4. 1  
Da y 1 6  
Da y 1 6  
Visit 5  
2 1 ( ± 2)  
O pe n -La bel  
Yes  
Da ys 1 9 t o 2 3  
Da ys 1 8 t o 2 3  
Visit 5. 1  
2 2  
O pe n -La bel  
O pti o nal if C o h ort 2  
Da y 2 2  
Da y 2 2  
Visit 5. 2  
2 3  
O pe n -La bel  
All C o h ort 2 e xce pt t h ose N K at 
visit 5. 1  
Da y 2 3  
Da y 2 3  
Visit 6  
2 8 ( ± 3)  
O pe n -La bel  
Yes  
Da ys 2 5 t o 3 1  
Da ys 2 4 t o 3 1  
Visit 6. 1  
3 5 ( ± 3)  
O pe n -La bel  
If n ot ra n d o mise d a n d C o h ort 2 
Da ys 3 2 t o 3 8  
Da ys 3 2 t o 3 8  
Visit 6. 2  
4 2 ( ± 3)  
O pe n -La bel  
If n ot ra n d o mise d a n d C o h ort 2 
Da ys 3 9 t o 4 5  
Da ys 3 9 t o 4 5  
Visit 6a ii 
3 5 ( ± 3)  
O pe n -La bel  
If n ot ra n d o mise d a n d C o h ort 1 
Da ys 3 2 t o 3 8  
Da ys 3 2 t o 3 8  
Visit 6 b ii 
4 2 ( ± 3)  
O pe n -La bel  
If n ot ra n d o mise d a n d C o h ort 1 
Da ys 3 9 t o 4 5  
Da ys 3 9 t o 4 5  
Visit 6a  
4 9 ( ± 3)  
O pe n -La bel  
If n ot ra n d o mise d a n d C o h ort 2 
Da ys 4 6 t o 5 2  
Da ys 4 6 t o 5 2  
Visit 6 b  
5 6 ( ± 3)  
O pe n -La bel  
If n ot ra n d o mise d a n d C o h ort 2 
Da ys 5 3 t o 5 9  
Da ys 5 3 t o 5 9  
i Visits 2. 1 a n d 2. 2 will o nl y be assi g ne d if visit 2 has alrea d y ha d a v al ue all ocate d.  
ii Partici pa nt s w h o de vel o p H K o n s pir o n olact o ne 5 0 m g dail y w hile recei vi n g ma xi m u m d ose 
S Z C ( 1 5 g), b ut were N K o n s pir o n olact o ne 2 5 m g dail y ma y re mai n i n t he o pe n -la bel, r u n-i n 
p hase f or u p t o 2 a d diti o nal wee ks i n or der t o ret ur n t o s pir o n olact o ne 2 5 m g a n d bec o me N K 
agai n.  
T he da y of ra n d o misati o n is varia ble de p e n di n g u p o n t he ti me re q uire d t o ac hie ve N K. I n 
C o h ort 1 t he ra n d o misati o n will occ ur at visit 6 b ut ca n occ ur at visit 6, 6a or 6 b. F or 
partici pa nt s i n C o h ort 2, t he o pe n-la bel p eri o d c o nti n ues f or u p t o 8 wee ks. Sc he d ule d da y a n d 
visit wi n d o w d uri n g t he ra n d o m ise d-wit h dra wal peri o d i n Ta ble 2  are wit h res pect t o t he date 
of ra n d o misati o n. I n s u m mar y ta bles, val ues fr o m t he da y of ra n d o misati o n will be dis pla ye d 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
a Ra n d o mis ati o n ( Visit 6) re gar dless of t he s u b visit w here ra n d o misati o n occ urs. W h e n a visit 
c o ul d fall i n t he a nal ysis visit wi n d o w f or b ot h visits 1 4 a n d visit 1 5 t he visit will be assi g ne d 
base d o n treat me nt stat us (if visit date > treat me nt e n d date t he n assi g n t o visit 1 5).  
T a ble 2  Defi niti o n of visit wi n d o ws f or r a n d o m ise d-wit h dr a w al a n d f oll o w -u p peri o d  
Visit  
Sc he d ule d 
D a y of 
Visit i  
A n al ysis Peri o d  
Pr ot oc ol Visit 
Wi n d o w *  
A n al ysis Visit 
Wi n d o w  
Visit 7  
3  ( ± 2) 
Ra n d o m ise d-wit h dra wal  
Da ys 2 t o 4  
Da ys 2 t o 4  
Visit 8  
7  ( ± 3) 
Ra n d o m ise d-wit h dra wal  
Da ys 5 t o 9  
Da ys 5 t o 1 4  
Visit 9  
3 0  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 2 3 t o 3 7  
Da ys 1 5 t o 4 5  
Visit 1 0  
6 1  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 5 4 t o 6 8  
Da ys 4 6 t o 7 5  
Visit 1 1  
9 1  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 8 4 t o 9 8  
Da ys 7 6 t o 1 0 5  
Visit 1 2  
1 2 1 ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 1 1 4 t o 1 2 8  
Da ys 1 0 6 t o 1 3 5  
Visit 1 3  
1 5 2  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 1 4 5 t o 1 5 9  
Da ys 1 3 6 t o 1 6 5  
Visit 1 4 
( E O T) 
1 8 2  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 1 7 5 t o 1 8 9  
Da ys 1 6 6 t o 1 9 5  
Visit 1 4a ii 
2 1 2  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 2 0 5 t o 2 1 9  
Da ys 1 9 6 t o 2 2 5  
Visit 1 4 b ii  
2 4 3  ( ± 7) 
Ra n d o m ise d-wit h dra wal  
Da ys 2 3 6 t o 2 5 0  
Da ys 2 2 6 t o 2 5 5  
Visit 1 5 iii 
7 da ys p ost 
E O T  ( ± 3) 
F oll o w -U p  
7 da ys p ost E O T 
± 3 da ys  
7 da ys p ost E O T ± 
7 da ys  
Visit 1 5a iii 
2 1 da ys 
p ost E O T  
( ± 7) 
F oll o w -U p  
2 1 da ys p ost E O T 
± 7 da ys  
2 1 da ys p ost E O T ± 
7 da ys  
i Sc he d ule d da y a n d visit wi n d o w are wit h res pect t o t he date of ra n d o misati o n 
ii Visits 1 4a a n d 1 4 b d uri n g t he ra n d o m ise d-wit h dra wal peri o d occ urre d f or partici pa nt s 
e nr olle d pri or t o versi o n 3 of t he pr ot oc ol a n d were la belle d as Visits 1 5 a n d 1 6 res pecti vel y  
iii F or partici pa nt s e nr olle d pri or t o versi o n 3 of t he pr ot oc ol t here were t w o f oll o w-u p peri o d 
visits at 2 da ys p ost E O T ± 7 da ys a n d 2 1 da ys p ost E O T ± 7 da ys la belle d as visits 1 7 a n d 1 8 
res pecti vel y. T h e Visit 1 5 a nal ysis visit wi n d o w i ncl u des t he first sc he d ul e d visit d uri n g 
f oll o w-u p f or all partici pa nt s a n d visit 1 5a s h o ul d o nl y occ ur i n partici p a nt s e nr olle d pri or t o 
versi o n 3 of t he pr ot oc ol.  
3. 2  
P artici p a nt  Dis p ositi o n  
Scree n fail ures are defi ne d as partici pa nt s w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
w h o are n ot s u bse q u e ntl y ra n d o ml y assi g ne d t o st u d y i nter ve nti o n. I n di vi d uals w h o d o n ot 
meet t he criteri a f or p arti ci pati o n i n t his st u d y (scree n fail ure) ma y b e res cree ne d t wice if:  
•  Scree n fail ure is d ue t o n ot meeti n g s K + or M R A d ose i ncl usi o n criteria at baseli ne,  
•  Scree ni n g pr o ce d ures ca n n ot be c o m plete d wit hi n t he 2 -wee k p eri o d,  
•  Tec h nical iss ues e nc o u nt ere d at e nr ol me nt site visit.  
 
Partici pa nt s w h o are rescree ne d s h o ul d b e assi g ne d t he sa me partici p a nt  n u m ber as f or t h e 
i nitial scree ni n g. Rescree ne d partici pa nt s i nf or m e d c o nse nt date will be prese nte d as t he 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
rescree ne d i nf or me d c o nse nt date. Rescree n e d partici pa nt s will a p pear o nce i n dis p ositi o n 
s u m maries. 
3. 3  
Effic ac y V ari a bles  
3. 3. 1  
De at h Cl assific ati o n  
T he Cli nical E ve nts C o m mittee ( C E C) will a dj u dicate a n d classif y all deat hs base d o n 
defi niti o ns descri be d i n t he C E C c h arter. T he C E C c harter will b e s pecifi e d se p aratel y t o t he 
S A P. F or t he p ur p oses of t he efficac y a nal ysis, deat hs will be s u b classifie d  b y car di o vasc ular 
( C V), n o n-C V, or u n deter mi ne d ca use of d eat h. T he i n vesti gat or will rec or d t he classificati o n 
of deat h as C V, n o n -C V or u n deter mi ne d i n t he e C R F. F or t he p ur p oses of t his a nal ysis t he 
C E C a dj u dicate d decisi o n will be use d.   
3. 3. 2  
He art F ail ure E ve nts  
All p ote ntial heart fail ure ( H F) e n d p oi nt e ve nts ( h os pitalizati o n f or H F or ur ge nt H F visits) 
will be rec or de d as a n A E a n d als o o n a se p arat e pa ge i n t he e C R F. P ote ntial H F e n d p oi nt 
e ve nts will be a dj u dicate d b y t he C E C as s pecifie d i n t he C E C c harter. T h e defi niti o n of a H F 
e ve nt will be acc or di n g t o t he latest C DI S C defi niti o n ( Hic ks et al 2 0 1 4), b ut will e xcl u de t he 
fift h re q uire m e nt of treat me nt s pecificall y f or H F s uc h as a I V l o o p di uretic, a n d ma y be 
u p date d d uri n g t he c o urse of t his st u d y.  
3. 3. 3  
P ot assi u m  
Ser u m sa m ples will be a nal yse d usi n g l ocal la b orat or y t o ge nerate l ocal la b p otassi u m ( K) 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. Sa m ples dra w n at t he sa m e ti me p oi nts will 
be pre pare d a n d s hi p pe d t o t he ce ntral la b orat or y f or t he a nal ysis of s er u m p otassi u m (s K). All 
statistical a nal yses will use ce ntr al la b orat or y s K val ues. N or m o kalae mia is defi ne d as 
3. 5 ≤s K ≤5. 0 a n d h y per kal ae mia is defi ne d as s K > 5. 0.  
3. 3. 4  
P atie nt Re p orte d O ut c o m es ( P R Os)  
T w o P R Os are use d i n t his st u d y: T he Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire ( K C C Q) 
a n d S u bject Gl o bal I m pr essi o n of Se verit y ( P GI S -H F) q uesti o n naire.  
3. 3. 4. 1  
C ollecti o n of P R Os  
Partici pa nt s will eit her c o m plete t he P R O assess me nt  o n pa per or usi n g a n electr o nic ta bl e 
d uri n g cli nic visits at t he ti me p oi nts i n dicate d i n t he C S P. W here P R Os are a vaila ble as b ot h 
pa per a n d electr o nic rec or ds at a st u d y visit, t he electr o nic ass ess me nt will be use d. 
F urt her m ore, if P R O assess me nts are  a v aila ble f or m ore t ha n o ne visit of visit 6, 6a a n d 6 b 
t he n t he earliest visit w here a n ass ess me nt are a vaila ble will be use d f or t he ra n d o misati o n 
visit i n a nal yses descri be d i n secti o ns 4. 2. 7. 4. 3 . 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
3. 3. 4. 2  
K C C Q  
T he K C C Q i nstr u me nt q ua ntifies b ot h t he fre q u e nc y of f o ur car di n al H F -s y m pt o ms (fati g ue, 
peri p heral e de ma, d ys p n oea, a n d ort h o p n o ea) a n d h o w b ot hers o me t hree of t he car di nal H F -
s y m pt o ms (fati g ue, peri p heral e d e ma a n d d ys p n o ea) are t o partici pa nt s, as well as H F-rel ate d 
p h ysical li mitati o ns, s ocial li mitati o ns, self -efficac y, a n d healt h -relate d q u alit y of life. T he 
K C C Q c o nsists of 2 3 ite ms meas uri n g, fr o m t he partici pa nt s’ pers pecti ves, t heir H F-relate d 
s y m pt o ms, p h ysical li mitati o ns, s ocial li mitati o ns, self-efficac y, a n d healt h -relate d q ualit y of 
life o ver t he pri or 2 wee ks. All ite ms are meas ure d o n a Li kert scal e wit h 5-7 res p o nse 
o pti o ns. T he K C C Q will be sc ore d as f oll o ws:  
•  P h ysical Li mitati o n Sc ore ( q uesti o n 1a -f) 
•  S y m pt o m Sta bilit y Sc ore ( q uesti o n 2)  
•  S y m pt o m Fre q ue nc y Sc ore ( q uesti o ns 3, 5, 7 a n d 9)  
•  S y m pt o m B ur de n Sc ore ( q uesti o ns 4, 6 a n d 8)  
•  Self Efficac y Sc ore ( q uesti o ns 1 0 a n d 1 1)  
•  Q ualit y of Life ( Q o L) Sc ore ( q uesti o ns 1 2, 1 3 a n d 1 4)  
•  S ocial Li mitati o n Sc ore ( q uesti o n 1 5a -d)  
T he K C C Q is sc ore d b y assi g ni n g eac h res p o nse a n or di nal val ue, be gi n ni n g wit h 1 f or t he 
res p o nse t hat i m plies t he l o west le vel of f u ncti o ni n g a n d 5-7 f or t h e hi g hest le vel of 
f u ncti o ni n g. T o calc ulate a sc ore, t h e res p o ns es are s u m me d wit hi n eac h d o mai n an d t he 
a vera g e is ta ke n. Missi n g val ues wit hi n eac h d o mai n are assi g ne d t he a vera ge of t he a ns w ere d 
ite ms wit hi n t hat d o mai n. Scale sc ores are tra nsf or me d t o a 0 t o 1 0 0 ra n ge b y s u btracti n g t he 
l o west p ossi ble scale sc ore, di vi di n g b y t he ra n ge of t he scale a n d m ulti pl yi n g b y 1 0 0. Sc ores 
f or a d o mai n are o nl y c alc ulate d f or a partici p a nt  if m ore t ha n 5 0 % of res p o nses are a vaila ble 
at a visit. 
T hree s u m mar y s c ores will be calc ulate d:  
•  T otal S y m pt o m Sc ore ( K C C Q -T S S): A vera ge of S y m pt o m Fre q ue nc y a n d S y m pt o m 
B ur de n Sc ores  
•  Cli nical S u m mar y Sc ore ( K C C Q -C S S): A vera ge of P h ysical Li mitati o n Sc ore a n d 
T otal S y m pt o m Sc ore  
•  O verall S u m mar y Sc ore ( K C C Q -O S S): A vera g e of P h ysical Li mitati o n Sc ore, T otal 
S y m pt o m Sc ore, Q o L Sc ore, S ocial Li mitati o n Sc ore  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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3. 3. 4. 3  
P GI S -H F  
T he P GI S -H F is a o n e ite m q uesti o n w hic h assess es a partici p a nt ’s perce pti o n of his/ her 
se verit y of H F s y m pt o ms i n t he last 2 wee ks. T his ite m will be use d t o e na ble a nc h or -base d 
assess me nts of wit hi n -partici pa nt  cli nicall y mea ni n gf ul c ha n ge f or t he K C C Q -T S S. T he 
or di nal res p o nses t o P GI S -H F will be assi g ne d t h e f oll o wi n g n u meric val u es:  
•  1 (“ n o s y m pt o ms”)  
•  2 (“ ver y mil d”)  
•  3 (“ mil d”)  
•  4 (“ m o derate”)  
•  5 (“se vere”)  
•  6 (“ ver y s e vere”)  
3. 3. 5  
N Y H A Cl ass  
T he defi niti o n of Ne w Y or k Healt h Ass oci ati o n ( N Y H A) class is s pecifie d i n A p pe n di x H of 
t he C S P. T his will be assesse d acc or di n g t o t he S o A a n d t he res p o ns e as rec or de d i n t he C R F 
will be a nal y se d.  
3. 3. 6  
Uri ne A n al ysis  
Uri nar y al b u mi n a n d creati ni ne will be c ollecte d as s pecifie d i n t he S o A of t he C S P. Uri nar y 
al b u mi n, creati ne a n d uri nar y al b u mi n creati ne rati o ( U A C R, defi ne d as uri nar y 
al b u m in/ uri nar y creati ni ne) will be assess e d at eac h visit of c ollecti o n. U A C R will be 
meas ure d as t he mea n of t hree c o ns ec uti ve first m or ni n g s p ot uri ne c ollecti o ns. T he fracti o nal 
e xcreti o n of s o di u m ( Na +) will be meas ure d as t h e mea n of t he t hree c o nsec uti ve first 
m or ni n g s p ot uri ne c ollecti o ns.  
3. 3. 7  
Pl as m a a n al ysis  
N T -pr o -B N P, ser u m al d oster o ne, plas ma re ni n acti vit y, t otal re ni n, a n gi ote nsi n o ge n, atrial 
natri uretic pe pti de a n d hi g h se nsiti vit y tr o p o ni n I will be c ollecte d as s p ecifie d i n t he S o A of 
t he C S P. 
3. 3. 8  
F ur ose mi de E q ui v ale nt L o o p Di uretic D ose  
F ur ose mi de E q ui val e nt L o o p Di uretics  D ose  will be i de ntifie d usi n g t he c o nc o mita nt 
me dicati o ns e C R F w here t he W H O Dr u g Dicti o nar y ge neri c ter m e q uals “ F ur ose mi de”. T he 
c u m ulati ve d ose will be c ollecte d as:  




Statistical A nal ysis Pla n  
Astra Ze n eca  
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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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t he date of first d ose of st u d y treat me nt ( S Z C) w h ose se verit y w ors e ns o n or after t h e date of 
first d ose d uri n g t he o pe n-la bel peri o d. 
T E A Es will be f urt her cate g or ise d as eit her (i) occ urri n g d uri n g t he o pe n -l a bel peri o d, if t he 
start date is o n or aft er t h e first d ose date d uri n g t he o pe n-la bel peri o d a n d pri or t o t he date of 
ra n d o misati o n, (ii) occ urri n g d uri n g t he ra n d o m is e d peri o d if t he start date is o n or after t he 
date of ra n d o misati o n a n d pri or t o t he date of st u d y treat me nt disc o nti n uati o n + 1 4.  
T he Me dical Di cti o nar y f or Re g ulat or y Acti vities ( Me d D R A) ( usi n g t he lat est or c urre nt 
Me d D R A versi o n) will b e use d t o classif y A Es s yste m or ga n class ( S O C) a n d preferre d t er m 
( P T). 
E ver y eff ort s h o ul d be m a de t o c ollect t he ma xi m u m i nte nsit y a n d relati o ns hi p t o treat me nt 
f or all A Es. H o we ver, if t he ma xi m u m i nte nsit y is missi n g f or a T E A E t he n it will be 
c o nsi dere d as se vere o nl y i n t he o verall cat e g or y i n t he s u m mar y ta bles. If t he relati o ns hi p t o 
treat me nt is missi n g t he n t he A E will be c o nsi dere d as p ossi bl y relate d t o treat me nt. 
Ot her si g nific a nt a d verse e ve nts  
Tar gete d o e de ma assess me nts will occ ur at scree ni n g, ra n d o misati o n, 1 -m o nt h p ost 
ra n d o misati o n, 4 m o nt hs p ost-ra n d o misati o n, a n d E O T. N-ter mi nal pr o-B -t y pe natri uretic 
pe pti de ( N T -pr o B N P) le vels, b o d y wei g ht, a n d di uretic use yes/ n o; if yes, d ose) will als o be 
c ollecte d at t he s a me ti me oe de ma assess me nts are c o n d ucte d.  Oe de m a -relate d a d verse e v e nts 
( O A Es) will be c ollecte d as ot her si g nifica nt A Es. 
De at hs  
All a d verse e ve nts lea di n g t o deat h will be c ollect e d u ntil t he e n d of t he st u d y.  
3. 4. 3  
L a b or at or y D at a  
A bs ol ute c ha n ge fr o m baseli ne i n hae mat ol o g y, cli nical c he mistr y a n d uri n al ysis varia bles 
will be calc ulate d f or eac h p ost -d ose visit. A bs ol ute val ues will be c o m pare d t o t he l ocal 
la b orat or y refere nce ra n g e a n d classifie d as l o w ( bel o w ra n ge), n or mal ( withi n ra n ge or o n 
li mits of ra n ge) a n d hi g h (a b o ve ra n ge). All val ues classifie d as hi g h or l o w will be fla g ge d o n 
t he listi n gs. 
Bl o o d a n d uri ne sa m ples f or deter mi nati o n of h ae mat ol o g y/ hae m ostatis, cli nical c he mistr y 
a n d uri nal ysis will be ta ke n as per Sc he d ule of Acti vities ( S o A) Ta bles 1 of t he C S P f or t he 
ti mi n g a n d fre q ue nc y. Prese ntati o ns a n d s u m mari es will use ce ntral la b orat or y res ults.  
La b orat or y p ara m eters i n cl u de:  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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T a ble 4 : L a b or at or y S afet y V a ri 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)  
B -Hae m o gl o bi n ( H b)  
S -S o di u m ( Na +)  
B -Le u k oc yte c o u nt  
S -P otassi u m ( K +)  
B -Le u k oc yte differe ntial c o u nt (a bs ol ute c o u nt)  
S -Bicar b o nate T otal ( T otal C O 2) 
B -Platelet c o u nt  
S -Gl uc ose  
B -He m at ocrit ( Hct)  
S -Creati ni ne  
 
S -Bl o o d Urea Nitr o ge n ( B U N)  
Uri n al ysis  ( di pstic k) 
Urea ( B U N)/ Creati ni ne Rati o  
U -H b/ Er yt hr oc ytes/ Bl o o d  
Esti mate d gl o mer ular filtrati o n rate (e G F R) usi n g t he n o n -
race-base d C K D -E PI f or m ula  
U -Pr otei n/ Al b u mi n  
A ni o n ga p  
U -Gl uc ose  
S -Al b u mi n  
 
S -T otal Pr otei n  
M or ni n g v oi d uri ne  
S -Calci u m ( Ca + +)  
Uri nar y al b u mi n  
S -Ma g nesi u m ( M g + +) 
Uri nar y creati ni ne  
S -P h os p hate ( P O 4) 
 
S -Bilir u bi n, t otal  
 
S -Al kali ne p h os p hatase ( A L P)  
 
S -Ala ni ne a mi n o tra nsferase ( A L T)  
 
S -As partate a mi n o tra nsferase  ( A S T) 
 
Esti mate d e G F R will be calc ulate d usi n g t he C K D -E PI (c hr o nic ki d ne y disease e pi d e mi ol o g y 
c olla b orati o n e q uati o n) 2 0 2 1 f or m ula f or eac h ti m e-p oi nt a n d will be a nal yse d as e ntere d o n 
t he e C R F: 
e G F R ( C K D -E PI) =  1 4 2  x mi n( S Cr / κ, 1)α x ma x( S Cr  / κ, 1)-1. 2 0 0 x 0. 9 9 3 8 A ge  x 1. 0 1 2  [if fe male] 
W here S Cr  (sta n d ar dise d ser u m creati ni ne) = m g/ d L,  κ = 0. 7 (fe males) or 0. 9 ( males), α = -
0. 2 4 1  (fe males) or -0. 3 0 2  ( males), mi n( S Cr / κ, 1) = i n dicates t he mi ni m u m of S Cr / κ or 1, 
ma x( S Cr  / κ, 1) = i n dicates t he ma xi m u m of S Cr / κ or 1 a n d a ge = years. 
3. 4. 4  
Vit al Si g ns  
Vital si g ns will be e val uate d a n d assesse d at scree ni n g, t he start of t he o pe n -la bel peri o d, at 
ra n d o misati o n a n d all f urt her st u d y visits acc or di n g t o t he S o A, Ta bles 1 of t he C S P. Vital 
si g ns i ncl u de hei g ht (c m, visit 1 o nl y), wei g ht ( k g), p ulse rate ( b eats per mi n ute), s yst olic 
bl o o d press ure ( m m H g) a n d diast olic bl o o d press ure ( m m H g). A bs ol ute c ha n ge fr o m b aseli ne 
will be calc ulate d f or eac h p ost -d ose visit.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
3. 4. 5  
Electr oc ar di o gr a ms  
Electr ocar di o gra m ( E C G) assess me nts will be perf or me d at scree ni n g, ra n d o misati o n, E O T, 
a n d f oll o w-u p (as s pecifi e d i n t he S o A), a n d acc or di n g t o cli nical j u d ge me nt i n c o n necti o n 
wit h se vere h y p o k alae mi a (s K + < 3. 0 m E q/ L), se v ere h y per kal ae mia (s K + > 6. 0) or a n y 
s y m pt o ms or cli nical e ve nts s u g gesti n g car diac arr h yt h mia. E C G para meters will i ncl u de heart 
rate ( b eats/ mi n), P R i nter val ( msec), R R i nter val ( msec), Q R S d urati o n ( ms ec), Q T i nter val 
( msec) a n d Q Tc F i nter val ( msec). T he a bs ol ute c h a nge fr o m b aseli ne w ill be calc ul ate d f or 
eac h p ost -d os e visit. T he baseli ne meas ure me nt f or eac h E C G para meter will be calc ulate d 
base d o n t he a v era g e of all rec or de d m eas ure me nts ma de at t he bas eli ne visit.  
4  
A N A L Y SI S M E T H O D S  
4. 1  
Ge ner al pri nci ples  
T he pri nci pal a n al yses o utli ne d i n t his statistical a nal ysis pla n will be c o n d ucte d b y F ortrea , i n 
acc or da nce wit h t he c o ntract wit h Astra Z e neca A B a n d f oll o wi n g t he E xcelle nce i n Me dical 
Part ners hi p f or O uts o urce d W orl d wi de E vi d e nce Researc h ( E M P O W E R) descri pti o n of 
ser vices. E xter nal v ali dati o n of e n d p oi nts will be c o n d ucte d b y Sai nt L u ke’s H os pital of 
Ka nsas Cit y , a n d ma y i ncl u de  f ull y i n de pe n de nt pr o gra m mi n g.  
T he bel o w me nti o ne d ge neral pri nci ples will be f oll o we d f or a n al yses:  
Descri pti ve statistics will be use d f or all varia bles, as a p pr o priat e. C o nti n u o us varia bles will 
be s u m marise d b y t he n u m ber of o bser vati o ns, mea n, sta n dar d de viati o n, me dia n, Q 1, Q 3, 
mi ni m u m a n d ma xi m u m. F or l o g tra nsf or me d data it is m ore a p pr o priate t o prese nt ge o metri c 
mea n, c oefficie nt of v ari ati o n ( C V), me dia n, mi ni m u m a n d ma xi m u m. Cate g orical varia bles 
will be s u m mar ise d b y fre q ue nc y c o u nts a n d perce nta ges f or eac h cat e g or y.  
U nless ot her wise state d, perce nt a ges will be calc ulate d o ut of t he a nal ysis s et t otal f or t he 
treat me nt gr o u p. 
F or c o nti n u o us data, t h e mea n a n d me dia n will be r o u n de d t o 1 a d diti o nal deci mal place 
c o m pare d t o t he ori gi nal data. T he sta n d ar d de viati o n will be r o u n de d t o 2 a d diti o nal deci mal 
places c o m pare d t o t he ori gi nal data. Mi ni m u m a n d ma xi m u m will be dis pla ye d wit h t he sa me 
acc urac y as t he ori gi nal d ata. 
F or cate g oric al data, p erce nta ges will be r o u n d e d t o 1 deci mal place.  
S A S ® versi o n 9. 3 or hi g her will be use d f or all a n al yses  
It is acce pt a ble t o pres e nt lar ge n u meri cal val ues i n m ore a p pr o priate u nits. F or e x a m ple, a n 
A U C val ue of 1 2 3, 0 0 0 n g h/ m L ma y be re p orte d as 1 2 3 µ g h/ m L i nstea d. It is h o we v er, 


Statistical A nal ysis Pla n  
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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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i m p orta nt t o kee p t he u nits c o nsiste nt wit hi n t he re p ort a n d t he precisi o n c o nsiste nt wit h t hat 
pri or t o c o n versi o n.  
I n c o h ort 1, f or all e n d p oi nts, t he last o bser vati o n bef ore t h e first d ose of st u d y treat me nt i n 
t he o pe n-la bel p eri o d will be c o nsi dere d t h e baseli ne meas ure me nt, u nless ot her wise s pecifie d. 
I n c o h ort 2, f or all e n d p oi nts, t he last o bser vati o n bef ore t h e date of t h e visit 2 st u d y visit will 
be c o nsi dere d t he baseli n e meas ur e me nt, u nless ot her wise s pecifie d. I n c o h ort 1, f or 
assess me nts o n t he da y of first d ose  or i n c o h ort 2 , f or assess me nts o n t he d a y of t he visit 2 
st u d y visit, w here ti me is n ot ca pt ure d , a n o mi nal pre-d ose i n dicat or, if a v aila ble, will ser ve as 
s ufficie nt e vi de n ce t hat t he assess me nt occ urre d pri or t o first d ose. A n y o bser vati o n ma de 
after t he first d ose of st u d y treat me nt will be c o nsi dere d p ost -bas eli ne.  
Assess me nts o n t he da y of t he first d ose  (c o h ort 1)/ visit 2 st u d y visit (c o h ort 2) w he n neit her 
ti me n or a n o mi nal pre-d ose i n dicat or are ca pt ure d will be c o nsi dere d pri or t o t he first d ose if 
s uc h pr oce d ures are re q uire d b y t he pr ot oc ol t o be c o n d ucte d bef ore first d ose.  
I n all q ua ntitati ve s u m maries fr o m baseli ne, v aria bles will be calc ulate d as t he p ost-treat me nt 
val ue mi n us t he val ue at baseli ne. T he p erce nta ge c ha n ge fr o m baseli ne will be calc ulate d as 
( p ost-baseli ne val u e –  baseli ne val ue) / bas eli ne v al ue x 1 0 0.  
Safet y a n d treat me nt e x p os ure data will be s u m marise d base d u p o n t he S S O a n d S S R a nal ysis 
sets se parat el y. A nal yses usi n g t he S S O a nal ysis set will be restricte d t o visits w hic h occ ur 
d uri n g t he o pe n -la b el a nal ysis peri o d. St u d y p o p ulati o n, de m o gra p h y data will als o be 
s u m marise d usi n g t he S S O a n d S S R a nal ysis sets.  
4. 1. 1  
H a n dli n g of missi n g d ates  
I n c o m plete dates ( partial or missi n g dates w here a f ull date is per missi ble) will be prese nte d i n 
t he data listi n gs as rec or de d o n t he e C R F. H o we ver, f or use i n calc ulati o ns (f or i nsta nce i n 
calc ulati o n of t he d urati o n of a n A E or m e dicati o n use), dates wi ll be esti m ate d as f oll o ws: 
4. 1. 1. 1  
P arti al st art d at es  
If t he year is u n k n o w n, t he n: 
•  
T he date will n ot be i m p ute d, a n d will be assi g ne d a missi n g val ue  
If t he m o nt h is u n k n o w n, t he n: 
•  
If t he year matc h es t he y ear of t h e first d ose dat e i n t he o pe n-la bel p eri o d  (c o h ort 1) or t he 
date of t he visit 2 st u d y visit (c o h ort 2) , t he n i m p ute t he m o nt h a n d da y of t he first d ose 
date  or visit 2 st u d y visit date . 
•  
Ot her wise, assi g n t he m o nt h as Ja n uar y  
If t he da y is u n k n o w n, t h e n: 


Statistical A nal ysis Pla n  
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•  
If t he m o nt h a n d year matc h t he m o nt h a n d year of t he first d ose date i n t he o pe n-la bel 
peri o d  (c o h ort 1) or t he d ate of t he visit 2 st u d y visit (c o h ort 2), t he n i m p ute t he da y of t he 
first d ose date or visit 2 st u d y visit date . 
•  
Ot her wise, assi g n t he d a y as 1 st of t he m o nt h.  
4. 1. 1. 2  
P arti al e n d d ates  
If t he year is u n k n o w n, t he n t he date will n ot be i m p ute d a n d will be assi g ne d a missi n g val ue. 
If t he m o nt h is u n k n o w n, t he n assi g n Dece m ber. 
If t he da y is u n k n o w n, t h e n assi g n t he last da y of t he m o nt h. 
If t he a b o v e r ules f or e n d dates res ult i n ill o gical date wit h re gar ds t o t he dates t he partici pa nt  
was i n t he st u d y, t he n t he e n d date will be re place d wit h t he partici pa nt ’s date of 
c o m pleti o n/ disc o nti n uati o n.  
4. 1. 2  
H a n dli n g of Missi n g Effic ac y D at a  
Partici pa nt s wit h missi n g data f or efficac y a nal yses will be treate d as d escri be d u n der eac h 
e n d p oi nt’s esti ma n d defi niti o n. E x pl orat or y efficac y a nal yses usi n g a n A N C O V A m o del will 
use c o m plete cases o nl y, s o partici pa nt s wit h o ut a meas ure me nt at a s pecific visit will be 
e xcl u de d fr o m t he a nal ysis. E x pl orat or y effi cac y a nal yses usi n g mi xe d -effect m o dels 
re peat e d-me as ures will ass u me t hat missi n g o utc o mes are missi n g at ra n d o m ( M A R).  
4. 1. 3  
H a n dli n g of Missi n g S afet y D at a  
I n g e neral, missi n g cli nical la b orat or y d ata, vital si g ns, a n d E C G data will n ot be i m p ute d. 
A d verse e ve nt i m p utati o ns f or missi n g se verit y or relati o ns hi p are pr o vi de d i n secti o n 3. 4. 2 . 
U n k n o w n or partial me di cati o n a n d A E dat e i m p utati o ns are gi ve n a b o ve a n d are t o be us e d 
o nl y f or t he assess me nt of pri or/c o nc o mita nt stat us f or me dicati o ns a n d tr eat me nt -e mer g e nt 
stat us f or A Es. 
4. 2  
A n al ysis met h o ds  
4. 2. 1  
S u bject Dis p ositi o n a n d A n al ysis Sets A n al yse d  
S u bject dis p ositi o n will be liste d a n d s u m mar ise d b y treat me nt gr o u p a n d o verall. T he n u m ber 
a n d perce nta ges of partici pa nt s i n t he f oll o wi n g cate g ories will be s u m marise d f or partici pa nt s 
i n t he scree n e d set: 
•  Scree ne d;  
•  Di d n ot e nter o pe n -l a bel peri o d ( Scree ni n g fail ures) a n d ass ociat e d reas o ns; 
•  E ntere d t he o p e n -la bel p eri o d a n d recei v e d treat m e nt 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  E ntere d t he o p e n -la bel p eri o d a n d di d n ot recei ve treat me nt 
•  Ra n d o m ise d; 
•  N ot ra n d o m ise d ( O p e n-la bel peri o d fail ure) a n d ass ociate d reas o ns; 
•  Ra n d o m ise d s u bjects w h o recei v e d treat me nt; 
•  Ra n d o m ise d s u bjects w h o di d n ot recei ve treat me nt a n d ass ociate d reas o ns; 
•  S u bjects w h o c o m plete d t he st u d y;  
•  Disc o nti n ue d treat me nt a n d ass ociate d reas o ns;  
•  Ter mi nate d st u d y a n d ass ociate d reas o ns;  
T he de n o mi nat or use d f or perce nta ges will be calc ulate d as f oll o ws. T he d e n o mi nat or f or 
s u bjects w h o are scree ne d or w h o di d n ot e nter t h e o pe n-la bel peri o d ( a n d ass ociate d reas o ns) 
will be calc ulate d usi n g t he n u m ber of scree ne d s u bjects. T he de n o mi nat or f or s u bjects w h o 
e ntere d t he o p e n -la b el peri o d a n d recei ve d treat me nt, w h o e ntere d t he o pe n-la bel peri o d a n d 
di d n ot recei ve treat me nt (a n d ass ociat e d reas o ns), ra n d o m ise d a n d n ot ra n d o m ise d (a n d 
ass ociate d reas o ns) will be calc ul ate d usi n g t he n u m ber of s u bjects w h o e ntere d t he o pe n -la bel 
peri o d. T he re mai ni n g s u bject dis p ositi o n cate g ories will use t he n u m ber of s u bjects w h o were 
ra n d o mise d f or t he d e n o mi nat or. 
T he n u m ber of s u bjects i n eac h of t h e a nal ysis sets a n d t he reas o ns f or e x cl usi o n fr o m eac h 
will be s u m mar ise d f or all scree n e d s u bjects b y treat me nt gr o u p a n d o verall. 
4. 2. 2  
Pr ot oc ol De vi ati o ns  
All i m p orta nt pr ot oc ol de viati o ns, defi ne d acc or di n g t o secti o n 2. 2 , lea di n g t o e xcl usi o n fr o m 
t he P P S will be liste d a n d s u m marise d b y treat me nt gr o u p a n d o verall f or t he F A S. I m p orta nt 
pr ot oc ol de viati o ns will be f urt her classifie d as eit her pa n de mic -relat e d or e xcl u di n g pa n de mic 
relate d i m p orta nt pr ot oc ol de viati o ns. 
4. 2. 3  
De m o gr a p hics a n d Ot her B aseli ne C h a r acte ristics  
De m o gra p hic a n d baseli n e c haracteristics will be liste d a n d s u m mar ise d b y o pe n -la bel c o h ort 
a n d t otal f or t he S S O a n d treat me nt gr o u p a n d t otal f or t he S S R a n d F A S. T he de m o gra p hic 
a n d baseli ne c h aracteristi cs i ncl u de t he f oll o wi n g:  
•  A ge ( Years);  
•  A ge gr o u ps ( 1 8 -6 4, 6 5 -8 4 a n d o ver 8 5 years);  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  Se x ( Male, fe m ale);  
•  Race cate g or y ( W hite, Blac k or Africa n A merica n, Asia n, Nati ve Ha waiia n or Ot her 
Pacific Isla n der, A meri ca n I n dia n or Alas k a n Nati ve, Ot her); 
•  Et h nicit y ( His pa nic or Lati n o, N ot His pa nic or Lati n o);  
•  C o u ntr y;  
N o f or mal tests of statistical si g nifica nce will be p erf or me d o n t h e de m o gr a p hic a n d baseli ne 
data.  
A se parate ta ble will s u m marize t he s u bject c haracteristics at baseli ne a n d will be liste d a n d 
s u m marise d b y o pe n -la b el c o h ort a n d t otal f or t h e S S O a n d treat me nt gr o u p a n d t otal f or t he 
S S R a n d F A S. T he y will i ncl u de:  
•  Baseli ne hei g ht (c m);  
•  Baseli ne wei g ht ( k g);  
•  Baseli ne b o d y mass i n de x ( k g/ m 2) [calc ulate d as ( baseli ne wei g ht/ baseli ne hei g ht2 
w here wei g ht is i n k g a n d hei g ht is i n m ]; 
A se parate ta ble will s u m marize t he s u bject c haracteristics at baseli ne relate d t o heart fail ure 
a n d will be liste d a n d s u m mar ise d b y o pe n -la bel c o h ort a n d t otal f or t he S S O a n d treat me nt 
gr o u p a n d t otal f or t he S S R a n d F A S. T he y will i ncl u de:  
•  Ti me fr o m dia g n osis of H F t o e nr ol me nt ( 0 -3 m o nt hs, > 3 -6 m o nt hs, > 6 -1 2 m o nt hs, > 1 -
2 years, > 2 -5 years, > 5 y ears)  
•  H F h os pitalizati o n pri or t o ra n d o misati o n ( N o/ Yes)  
•  Ti me fr o m last H F h os pit alizati o n t o ra n d o misati o n (, > 3-6 m o nt hs, > 6 -1 2 m o nt hs, > 1 -
2 years, > 2 -5 years, > 5 y ears, N o pri or H F h os pitalizati o n)  
•  N Y H A class at e nr ol me nt (II,III,I V)  
•  L V E F ( %)  
•  L V E F gr o u ps ( ≤2 5, 2 6 -3 0, 3 1 -3 5, 3 6 -4 0)  
•  Mai n eti ol o g y of H F (Isc hae mic, N o n -Isc hae mic, Val v ular, Arr yt h mia, U n k n o w n, 
Ot her)  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  Hist or y of Atrial Fi brillati o n/ Fl utter ( Yes, C hr o nicit y: Par o x ys mal, Persiste nt, 
Per ma ne nt)  
•  Q R S D urati o n, a g gre g ate at e nr ol me nt E C G ( msec)  
•  Q R S d urati o n ( ≥1 5 0 msec, ≥1 3 0 msec)  
•  N T -pr o B N P at e nr ol me nt ( p g/ m L)  
•  N T -pr o B N P ( p g/ m L) at e nr ol me nt i n partici pa nt s wit h Atrial Fi brillati o n/ Fl utter at 
e nr ol me nt  
•  N T -pr o B N P ( p g/ m L) at e nr ol me nt i n partici pa nt s wit h o ut Atrial Fi brillati o n/ Fl utter at 
e nr ol me nt  
•  Car diac Pace ma ker I nserti o n ( Yes)  
•  Pace ma ker t y pe ( C o n ve nti o nal pace ma ker, C R T-P, C R T -D, Pace ma ker t y pe n ot 
rec or de d) 
•  C R T -D or C R T -P ( Yes)  
•  P ulse rate ( Beats/ mi n)  
•  P ulse rate ( Beats/ mi n) i n Partici pa nt s wit h Atrial Fi brillati o n/ Fl utter at e nr ol me nt 
•  P ulse rate ( Beats/ mi n) i n Partici pa nt s wit h o ut Atrial Fi brillati o n/ Fl utter at e nr ol me nt 
•  S yst olic bl o o d press ure ( m m H g)  
•  S yst olic bl o o d press ure ( m m H g) cate g or y ( ≥1 4 0, ≥1 3 0)  
•  Diast olic bl o o d press ure ( m m H g)  
•  e G F R (ml/ mi n ) 
•  Ser u m p otassi u m ( m E q/ L ) 
All baseli ne meas ur e me nts, s uc h as vital si g ns a n d E C G res ults, will als o be re p orte d wit h 
p ost -baseli ne meas ur e me nts.  Cate g ories f or s u bjects wit h re p orte d baseli ne c haracteristics 
w hic h are c o ntrar y t o t he i ncl usi o n/e xcl usi o n criteria f or t he st u d y will be mar ke d wit h a 
f o ot n ote. 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
4. 2. 4  
Me dic al Hist or y  
Me dical hist or y will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A) [ Versi o n 2 3. 0 ( or a later versi o n if u p date d d uri n g t he st u d y)]. All me dical hist or y 
will be liste d, a n d t he n u m ber a n d perce nt a ge of s u bjects wit h a n y me dical hi st or y will be 
s u m marise d b y s yste m or ga n class ( S O C) a n d preferre d t er m f or t he o p e n -l a bel c o h ort a n d 
t otal f or t he S S O a n d treat me nt gr o u p a n d t otal f or t he S S R a n d F A S 
4. 2. 5  
Pre vi o us a n d C o nc o mit a nt Me di c ati o ns  
Me dicati o ns recei ve d pri or t o or c o nc o mita ntl y wit h st u d y treat me nt will be c o de d usi n g t he 
W H O Dr u g Dicti o nar y [ Versi o n Marc h 2 0 2 0 ( or a later versi o n if u p date d d uri n g t he st u d y)], 
A nat o mical T hera pe utic C he mical ( A T C) Classificati o n c o des.  
Pri or me dicati o ns a n d c o nc o mita nt me dicati o ns are defi ne d as f oll o ws:  
Pri or me dicati o ns are t h ose ta ke n wit h a st o p date pri or t o t he first d ose dat e of st u d y 
treat me nt d uri n g t he o pe n-la bel peri o d. 
C o nc o mita nt me dicati o ns d uri n g t he o pe n -la bel p eri o d are t h ose wit h a st o p date pri or t o t he 
first d ose of st u d y treat m e nt d uri n g t he ra n d o mise d-wit h dra wal p eri o d a n d eit her a start d ate 
o n or after t h e first d ose date of st u d y treat me nt d uri n g t he o pe n -la bel peri o d, or t h ose wit h a 
start date bef ore, a n d a st o p date o n or after t he first d ose date of st u d y treat me nt d uri n g t he 
o pe n -la bel peri o d. 
C o nc o mita nt me dicati o ns d uri n g t he ra n d o m ise d-wit h dra wal peri o d are t h ose wit h a start date 
o n or after t h e first d ose date of st u d y treat me nt d uri n g t he ra n d o m ise d-wit h dra wal peri o d, or 
t h ose wit h a start date bef ore, a n d a st o p date o n or after t h e first d ose dat e of st u d y treat me nt 
d uri n g t he ra n d o m ise d-wit h dra wal peri o d.  
If a me dicati o n ca n n ot be classifie d as “ pri or” or “c o nc o mita nt d uri n g t he o pe n-la bel peri o d” 
or “c o nc o mita nt d uri n g t he ra n d o m ise d-wit h dra wal peri o d” after a p pl yi n g i m p utati o n r ules f or 
missi n g/i nc o m plete dates, it will be classifie d as c o nc o mita nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d.  
C o nc o mita nt me dicati o ns d uri n g t he o pe n -la bel a n d ra n d o mise d-wit h dra wal peri o ds will be 
f urt her cate g orise d b y t h ose all o we d a n d disall o we d. Disall o we d c o n c o mita nt me dicati o ns are 
defi ne d i n t he C S P Secti o n 6. 5 as p otassi u m s pari n g di uretics ot her t ha n s pir o n olact o ne a n d 
e plere n o n e (tria mtere ne a n d a mil ori de). F urt h er m ore, se veral me dicati o ns are descri b e d as 
restricte d, s uc h as p otassi u m bi n ders, p otassi u m s u p ple me nts, dr u gs wit h p H -de pe n d e nt 
a bs or pti o n a n d n o nster oi dal a nti -i nfla m mat or y dr u gs, a n d will als o be i ncl u de d as disall o we d 
c o nc o mita nt me dicati o ns.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
Pri or me dicati o ns, all o we d/ disall o we d c o nc o mita nt me dicati o ns d uri n g t he o pe n -la bel peri o d 
a n d all o we d/ disall o we d c o nc o mita nt me dicati o ns d uri n g t he ra n d o m ise d-wit h dra wal peri o d 
will be liste d t o get her. All o we d/ disall o we d c o nc o mita nt me dicati o ns d uri n g t he o pe n -la bel 
peri o d will be s u m mar ise d se parat el y b y o pe n-la bel c o h ort a n d o verall usi n g t he S S O a n d 
prese nte d i n t otal. All o w e d/ disall o we d c o nc o mita nt me dicati o ns d uri n g t he ra n d o m ise d-
wit h dra wal peri o d will be s u m mar ise d se paratel y b y treat me nt gr o u p a n d o verall usi n g t he 
S S R.  
T he n u m ber a n d p erce nta ges of s u bjects usi n g eac h me dicati o n will be dis pla ye d t o get her wit h 
t he n u m ber a n d perce nta ge of s u bjects usi n g at least o ne me dicati o n wit hi n eac h t hera pe utic 
class ( A T C -L e vel 2), c h e mical s u b gr o u p ( A T C -Le vel 4), a n d ge n eric ter m.  
A se parate s u m mar y will prese nt pri or me di cati o n relate d t o heart fail ure or di uretics f or t he 
S S O a n d S S R. T his s u m mar y will prese nt t he n u m ber  a n d perce nt a ge of s u bjects b y c o h ort 
( S S O) a n d ra n d o mise d tr eat me nt gr o u p ( S S R) w h o were recei vi n g A C E i n hi bit or t hera p y at 
scree ni n g (i d e ntifie d fr o m e C R F “ Heart Fail ure Stat us” a n d q uesti o n “Is t h e s u bject ta ki n g 
A C E i n hi bit or” ), A R B t hera p y at s cree ni n g (i de ntifie d fr o m e C R F “ Heart Fail ure Stat us” a n d 
q uesti o n “Is t he s u bject t a ki n g A R B ( A n gi ote nsi n Rece pt or Bl o c kers”) , A R Ni t hera p y at 
scree ni n g (i d e ntifie d fr o m e C R F “ Heart Fail ure Stat us” a n d q uesti o n “Is t h e s u bject ta ki n g 
Ne pril ysi n i n hi bit or/ A R B ( A R NI)”) , A C E i n hi bit or t h era p y or A R B t hera p y at scree ni n g, beta 
bl oc kers at scree ni n g  (i d e ntifie d fr o m e C R F “ Heart Fail ure Stat us” a n d q uesti o n “Is t he 
s u bject ta ki n g beta bl oc k ers”), l o w-d ose M R A at scree ni n g,  (i d e ntifie d fr o m e C R F “ Heart 
Fail ure Stat us” a n d q uesti o n “ Mi neral oc ortic oi d/ Al d o ster o ne A nta g o nist Treat me nt?”), 
S G L T 2i at scree ni n g  (i d e ntifie d fr o m pri or/c o nc o mita nt me dicati o n e C R F pa ge usi n g A T C 
c o de A 1 0 B K w h ere pri or me dicati o n defi niti o n is f ulfille d) , l o o p di uretics at scree ni n g  
(i de ntifie d fr o m pri or/ c o nc o mita nt me dicati o n e C R F pa ge usi n g th e ter ms “ F ur ose mi de” , 
“B u meta ni de ”, “T orse mi de ”, “A z ose mi de ” an d  “Et hacr y nic aci d ” w here pri or me dicati o n 
defi niti o n is f ulfille d ) a n d all di uretics at scree ni n g  (i de ntifie d fr o m pri or/ c o nc o mita nt 
me dicati o n e C R F pa g e a n d A T C c o des “ C 0 3” e xcl u di n g “ C 0 3 D”) . 
4. 2. 6  
Me as ure m e nts of St u d y Tre at m e nt C o m pli a nce  
T he perce nta g e c o m plia n ce f or S Z C a n d place b o is calc ulate d as:  
1 0 0 *act ual sac h ets ta ke n/ e x pecte d s ac hets ta k e n  
, w here: 
Act ual sac h et ta ke n is defi ne d as: 
S u m of t he sac hets ta ke n t hr o u g h o ut t he res pecti ve a nal ysis peri o d  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
A n d t he e x pecte d sac h ets ta ke n t hr o u g h o ut t he res pecti ve a n al ysis peri o d is deri ve d usi n g t he 
st u d y i nter ve nti o n a n d dr u g dis pe nsati o n rec or ds t o calc ulate t he n u m b er of sac hets e x p ecte d 
acc o u nti n g f or c ha n g es t o t he prescri b e d d osa ge l e vel (fr o m 1 0 g t hree  ti mes dail y t o 5 g e ver y 
ot her da y) a n d t he u nit d ose stre n gt h dis pe nse d ( 5 g a n d 1 0 g sac h ets). T he s u m of t he sac hets 
ta ke n d uri n g t he o pe n-la bel peri o d is calc ul ate d as: n u m ber of sac h ets dis pe nse d-n u m ber of 
sac hets ret ur ne d w h ere d ates are bef ore ra n d o misati o n. T he n u m ber of sac hets ta ke n d uri n g 
t he ra n d o mise d-wit h dr a wal peri o d is cal c ulate d as: n u m ber of sac h ets dis pe nse d -n u m ber of 
sac hets ret ur ne d w h ere d ates are after ra n d o misati o n. T he n u m ber of sac hets ta ke n is 
calc ulate d b ase d u p o n t h e d ose a n d fre q ue nc y of S Z C or place b o pres cri be d:  
D ose a n d fre q ue nc y  
N u m ber of s ac hets e x pecte d  
5 g e ver y ot her da y  
N u m ber of da ys b et wee n visits/ 2  
5 g dail y  
N u m ber of da ys b et wee n visits  
1 0 g dail y  
N u m ber of da ys b et wee n visits  
1 0 g t hree ti mes per da y ( O pe n -la bel) 
3 * N u m ber of da ys b et wee n visits  
1 5 g dail y  
2 * N u m ber of da ys b et wee n visits  
 
T he perce nta g e c o m plia n ce f or S Z C a n d place b o will be calc ulate d s e paratel y f or t he o pe n-
la bel a n d ra n d o mise d-wit h dra wal peri o ds a n d will be s u m mar ise d descri pti vel y b y o pe n -la bel 
c o h ort usi n g t he S S O a n d treat me nt gr o u p (i ncl u di n g o verall) usi n g t he S S R res pecti vel y.  
T he perce nta g e c o m plia n ce f or s pir o n ol act o ne is calc ulate d as:  
1 0 0 *act ual ta bles ta k e n/e x pecte d ta blets ta k e n  
, w here: 
Act ual ta blets ta ke n is defi ne d as:  
S u m of t he ta blets ta ke n t hr o u g h o ut t he res pecti ve a nal ysis peri o d  
A n d t he e x pecte d ta blets ta ke n t hr o u g h o ut t he res p ecti ve a n al ysis peri o d is deri ve d usi n g t he 
st u d y i nter ve nti o n a n d dr u g dis pe nsati o n rec or ds t o calc ulate t he n u m b er of ta blets e x pecte d 
acc o u nti n g f or c ha n g es t o t he prescri b e d d osa ge l e vel (fr o m 1 2. 5 g d ai l y t o 5 0 g dail y) a n d t he 
u nit d ose stre n gt h dis pe nse d ( 2 5 m g a n d 5 0 m g ta bl ets). T he perce nt a ge c o m plia nce f or 
s pir o n olact o ne will be calc ulate d se paratel y f or t h e o pe n-la bel a n d ra n d o mise d-wit h dra wal 
peri o ds a n d will be s u m mar ise d descri pti vel y b y o pe n -la bel c o h ort usi n g t he S S O a n d b y 
treat me nt gr o u p (i ncl u di n g o verall) usi n g t he S S R res pecti vel y. 
F urt her m ore, f or b ot h S Z C/ place b o a n d s pir o n olact o ne t he n u m ber a n d p erce nta ge c o m plia nce 
will be prese nte d se p aratel y f or t he o pe n -la bel a n d ra n d o mise d-wit h dra wal peri o ds usi n g t he 
S S O a n d S S R res pecti vel y wit h t he f oll o wi n g c o m plia nce cate g ories:  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  < 5 0 %  
•  ≥5 0 % t o < 8 0 %  
•  ≥8 0 % t o < 1 2 0 %  
•  ≥1 2 0 %  
4. 2. 7  
Effic ac y  
T o c o ntr ol f or t y pe I err or, a hierarc hical testi n g pr oce d ure will be f oll o we d w he n f or mall y 
testi n g pri mar y a n d sec o n dar y efficac y a nal ysis e n d p oi nts. T he hierarc hical testi n g pr oce d ure 
will f oll o w a ste p wise al g orit h m w here eac h e n d p oi nt is o nl y f or mall y  testi n g if t he prece di n g 
n ull h y p ot heses is rejecte d ( p < 0. 0 5). T h e first sec o n dar y e n d p oi nt will o nl y be f or mall y teste d 
if t he n ull h y p ot hesis f or t he pri mar y e n d p oi nt is r ejecte d at p < 0. 0 5. T he c urre nt or der f or 
testi n g t he s u bse q ue nt sec o n dar y e n d p oi nts is t he or der prese nte d b el o w b ut ma y be a me n de d 
pri or t o data base l o c k.  
4. 2. 7. 1  
Pri m ar y Effic ac y A n al ysis  
T he pri mar y effic ac y e n d p oi nt is res p o nse ( yes/ n o) of partici pa nt s o n S Z C c o m pare d t o 
place b o w h o, d uri n g t he mai nte na nce p h ase ( ≥ m o nt h 1 a n d ≤6 m o nt hs), ha ve s K + wit hi n 3. 5 -
5. 0 m E q/ L as assesse d b y ce ntral la b orat or y, are o n s pir o n olact o ne ≥2 5 m g dail y, a n d di d n ot 
use resc u e t hera p y f or H K at a n y p oi nt d uri n g t he ra n d o mise d -wit h dra wal p hase . A res p o nse  
is defi ne d b y (i)  ha v i n g s K + wit hi n 3. 5-5. 0 m E q/ L  as assesse d b y ce ntral la b orat or y A N D (ii)  
bei n g o n s pir o n olact o ne ≥ 2 5 m g dail y  A N D (iii)  n ot us i n g resc ue t hera p y f or h y per kalae mia at 
a n y p oi nt d uri n g t he last m o nt h. Res p o nse mea ns all t hree re q uire me nts are met. N o n -res p o nse 
is i n dicate d if at least o ne re q uire me nt is n ot met. A d diti o nall y, f or eac h assess me nt visit, n o n-
res p o nse is i n dicate d f or partici pa nt s w h o are l ost t o f oll o w-u p at t he visit, i ncl u di n g d ue t o 
deat h. T he m o nt hl y visits are use d f or res p o nse ass ess me nt fr o m m o nt h 1 t o m o nt h 6  ( Visits 9-
1 4 d uri n g t he Ra n d o m ise d Wit h dra wal P hase, Pr ot oc ol Ta ble 1) .. 
T he n u m ber a n d p erce nta ge of s u bjects w h o ac hie ve d a res p o ns e ( Yes, N o, Missi n g) f or eac h 
m o nt hl y visit will be s u m mar ise d b y ra n d o m ise d tr eat me nt gr o u p i n t he F A S. 
T he treat me nt effect c o n cer ns t he o v erall O d ds R ati o a n d will be a nal yse d usi n g a G E E 
m o del, wit h a bi n o mial distri b uti o n  fa mil y a n d a l o git li n k wit h e xc ha n gea ble c orrelati o n 
matri x  a n d teste d usi n g a t w o -si de d al p ha = 0. 0 5. T he de pe n d e nt varia bl e will be res p o nse at 
eac h visit. Fi xe d treat me nt effects will i ncl u de ra n d o m ise d treat me nt, s u bject recr uit me nt 
c o u ntr y, a per visit i n dicat or varia ble (e. g. visit 7, 8, 9, 1 0, 1 1, 1 2, 1 3 a n d 1 4 ) a n d o pe n-l a bel 
peri o d c o h ort. T he c o m m o n o d ds rati o will be deri ve d t o get her wit h t w o-si de d 9 5 % 
c o nfi de nce i nter vals.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
Fr o m t he perce nt a ge of res p o n ders per visit, i n t he place b o gr o u p, t he me dia n perce nta ge of 
res p o n ders f or place b o a n d S Z C will be calc ulate d a n d prese nt e d. T he me dia n perce nta ge of 
res p o n ders f or place b o will als o be prese nte d as t h e c orres p o n di n g m o delle d perce nt a ge f or 
place b o. Fr o m t his val ue, o d ds f or place b o  =( me di a n pr o ba bilit y of res p o n d ers f or 
place b o)/( 1 -me dia n pr o b a bilit y of res p o n ders f or place b o). T h e m o delle d o d ds f or S Z C will be 
calc ulate d as t he ra w o d ds f or place b o ( deri v e d a b o ve) × c o m m o n o d ds rati o fr o m t he G E E 
m o del. T he m o delle d o d ds will t he n be use d t o calc ulate t he c orres p o n di n g m o delle d 
perce nt a ge f or S Z C as ( m o delle d o d ds f or S Z C)/( 1 + m o delle d o d ds f or S Z C). T he 
c orres p o n di n g m o delle d perce nt a ge f or S Z C will be prese nt e d.  
Esti ma n d Attri b utes  
I n li ne wit h 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 b ee n s pecifie d t o tra nslat e t he pri mar y a n d ke y 
sec o n dar y effi cac y o bj ecti ves i nt o treat me nt effects t hat are t o be esti mate d (esti ma n ds). 
E n d p oi nt:  
•  H y per kala e mia res p o nse at eac h visit, defi n e d as a n o bser ve d s K + wit hi n 3. 5 -5. 0 
m E q/ L A N D bei n g o n s pir o n olact o ne ≥ 2 5 m g dail y A N D (iii) n ot usi n g res c ue t hera p y 
f or h y per kalae mia at a n y p oi nt d uri n g t he last m o nt h. 
P o p ulati o n:  
•  Partici pa nt s wit h s y m pt o matic H Fr E F w h o meet i ncl usi o n/e xcl usi o n criteri a. 
Partici pa nt s ha ve eit her h y per kalae mia (s K + 5. 1-5. 9 m E q/ L) or n or m o kalae mia (s K + 
3. 5 -5. 0 m E q/ L) w h o bec o me h y per kalae mic d uri n g t he first 4  wee ks of t he o pe n -la bel 
peri o d, a n d w h o mai ntai n s K + 3. 5 -5. 0 w he n d os e d wit h S Z C, w h o are ra n d o m ise d a n d 
ha ve o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nt a vaila ble  
Treat me nt:  
•  S Z C or Place b o a d mi nistere d dail y wit h s pir o n olact o ne. Partici pa nt s wit h s K + ≥ 6. 0 
m E q/ L will be ma na ge d wit h resc ue t hera p y e m pl o yi n g l ocal sta n dar d of care.  
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 
•  Disc o nti n uati o n of s pir o n olact o ne ≥2 5 m g dail y pri or t o t he E O T visit ( C o m p osite 
varia ble strat e g y i.e. c o nsi dere d t o be n o n -res p o ns e). 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( C o m p osite varia ble strat e g y, i.e. c o nsi dere d t o be n o n -res p o nse). 
•  Deat h pri or t o t he E O T visit ( C o m p osite varia ble strate g y, i.e. c o nsi dere d t o be n o n -
res p o nse). 
•  Partici pa nt  l ost t o f oll o w-u p f or a n y reas o n pri or t o t he E O T visit C o m p osite varia ble 
strate g y, i.e. c o nsi dere d t o be n o n-res p o ns e). 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
P o p ulati o n Le vel S u m mar y:  
•  T he c o m m o n o d ds rati o of t he occ urre n ce ( yes/ n o) of res p o ns e i n t he S Z C treat me nt 
gr o u p c o m pare d t o t he place b o gr o u p.  
4. 2. 7. 1. 1  
Pri m ar y Effic ac y A n al ysis –  Se nsiti vit y A n al yses –  P P S  
T w o se nsiti vit y a nal yses will be c o n d ucte d usi n g t he P P S.  
i. 
A nal yses will be c o n d uct e d as descri be d a b o v e f or t he pri mar y efficac y e n d p oi nt.  
ii. 
Deat hs pri or t o t he E O T will be treate d as missi n g res p o nse. A n al yses will be 
c o n d ucte d as d escri be d a b o ve usi n g t he F A S as f or t he pri mar y efficac y e n d p oi nt. 
4. 2. 7. 1. 2  
Pri m ar y Effic ac y A n al ysis –  Se nsiti vit y A n al yses –  C O VI D -1 9 i nterc urre nt e ve nts  
As a se nsiti vit y a nal ysis, t he i nterc urre nt e ve nt strate g y will be altere d t o descri be t he 
treat me nt effect i n a C O VI D-1 9 pa n d e mic -free w orl d. 
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt d uri n g t he last m o nt h n ot relate d t o t he C O VI D -1 9 
pa n de mic ( Treat me nt p olic y strate g y, i.e. re gar dl ess of t he i nterc urre nt e ve nt) 
•  Disc o nti n uati o n of treat me nt d uri n g t he last m o nt h relate d t o t he C O VI D-1 9 pa n de mic 
( H y p ot hetical strate g y, i. e. ass u me res p o ns e is missi n g). 
•  Disc o nti n uati o n of s pir o n olact o ne ≥2 5 m g dail y d uri n g t he last m o nt h  n ot relate d t o t he 
C O VI D -1 9 pa n d e mic ( C o m p osite varia ble strate g y i.e. c o nsi dere d t o b e n o n -res p o nse). 
•  Disc o nti n uati o n of s pir o n olact o ne ≥2 5 m g dail y d uri n g t he last m o nt h  relate d t o t he 
C O VI D -1 9 pa n d e mic ( H y p ot hetical strate g y, i.e. ass u me res p o nse is missi n g).  
•  Use of resc ue t hera p y f or h y per kalae mia d uri n g t h e last m o nt h  ( C o m p osite varia ble 
strate g y, i.e. c o nsi dere d t o be n o n-res p o ns e). 
•  Deat h d uri n g t he last m o nt h  n ot relate d t o t he C O VI D -1 9 pa n d e mic ( C o m p osite 
varia ble strat e g y, i.e. c o nsi dere d t o be n o n -res p o nse). 
•  Deat h d uri n g t he last m o nt h  relate d t o t he C O VI D-1 9 pa n de mic ( H y p ot hetical 
strate g y, i.e. ass u me res p o nse is missi n g). 
•  Partici pa nt  l ost t o f oll o w-u p pri or d uri n g t he last m o nt h  irres pecti ve of rel ati o ns hi p t o 
C O VI D -1 9 pa n d e mic ( C o m p osite  strate g y, i.e. c o nsi dere d t o be n o n -res p o nse). 
4. 2. 7. 1. 3  
Pri m ar y Effic ac y A n al ysis –  S u p ple me nt ar y A n al ys es 
A s u p ple me ntar y a n al ysis will be c o n d ucte d wit h t he sa me a nal ysis met h o d as t he pri mar y 
a nal ysis b ut wit h t he a d diti o n of a n i nteracti o n ter m bet wee n treat me nt recei ve d a n d d ose 
recei v e d at r a n d o misati o n ( 5 g e ver y ot h er da y, 5 g dail y, 1 0 g dail y, 1 5 g dail y) t o all o w f or t he 
effect of d ose t o be assesse d.  
A n a d diti o nal s u p ple me ntar y a nal ysis will be c o n d ucte d wit h t he sa me a n al ysis met h o d as t he 
pri mar y a nal ysis b ut e xcl u di n g partici pa nts w h o recei ve d 1 5 g dail y at r a n d o misati o n.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
A n a d diti o nal s u p ple me ntar y a nal ysis will be c o n d ucte d wit h t he sa me a n al ysis met h o d as t he 
pri mar y a nal ysis b ut wit h res p o nse  ( yes/ n o) defi n e d as t he n u m ber of p artici pa nt s o n S Z C 
c o m pare d t o place b o w h o, d uri n g t he mai nte na nce p hase ( ≥ m o nt h 1 a n d ≤6 m o nt hs), ha ve 
s K + wit hi n 3. 5-5. 5  m E q/ L as assesse d b y ce ntr al la b orat or y, are o n s pir o n olact o ne ≥2 5 m g 
dail y, a n d di d n ot use res c ue t hera p y f or H K at a n y p oi nt d uri n g t he ra n d o mise d -wit h dra wal 
p hase . 
 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
4. 2. 7. 2  
Sec o n d ar y Effic ac y A n al yses  
1. T he first sec o n d ary effic acy e n d p oi nt is res p o ns e (yes/ n o) of p artici p a nt s o n S Z C c o m p are d 
t o pl ace b o w h o, d uri n g t he m ai nte n a nce p h as e ( ≥m o nt h 1 a n d < 6 m o nt hs), h ave s K + wit hi n 
3. 5 -5. 0 m E q/ L as assesse d by ce ntr al l a b or at ory, are o n t he s a me s pir o n ol act o ne d ose as t hey 
were at r a n d o misati o n a n d di d n ot use resc ue t her a py f or hy perk al ae mi a at a ny p oi nt d uri n g 
t he r a n d o mise d-wit h dr a w al  p h ase.  
Res p o nse  is defi ne d b y (i) ha vi n g s K + wit hi n 3. 5 -5. 0 m E q/ L as assesse d b y ce ntral la b orat or y 
A N D (ii) bei n g o n t he s a me s pir o n olact o ne d ose as t he y were at ra n d o misati o n A N D (iii) n ot 
usi n g resc ue t hera p y f or h y per kala e mia at a n y p oi nt d uri n g t he last m o nt h. Res p o nse  mea ns all 
t hree re q uire me nts are m et. N o n-res p o ns e is i n dicate d if at least o ne re q uir e me nt is n ot met. 
A d diti o nall y, f or eac h assess me nt visit, n o n -res p o nse is i n dicate d f or p artici pa nt s w h o are l ost 
t o f oll o w-u p at t he visit, i ncl u di n g d ue t o  deat h. T he m o nt hl y visits are use d f or res p o ns e 
assess me nt fr o m m o nt h 1 t o m o nt h 6  ( Visits 9-1 4 d uri n g t he Ra n d o m ise d Wit h dra wal P hase, 
Pr ot oc ol Ta ble 1) . 
T he n u m ber a n d p erce nta ge of s u bjects w h o ac hie ve d a res p o ns e ( Yes, N o, Missi n g) f or eac h 
m o nt hl y visit will be s u m mar ise d b y ra n d o m ise d tr eat me nt gr o u p i n t he F A S. 
T he treat me nt effect c o n cer ns t he o v erall O d ds R ati o a n d will be a nal yse d usi n g a G E E 
m o del, wit h  a bi n o mial distri b uti o n fa mil y a n d a l o git li n k wit h a n e xc ha n g ea ble c orrel ati o n 
matri x  a n d teste d usi n g a t w o -si de d al p ha = 0. 0 5. Fi xe d treat me nt effects will i ncl u de 
ra n d o mise d treat me nt, s u bject recr uit me nt c o u ntr y, a per visit i n dicat or varia ble (e. g. visit 7, 8, 
9, 1 0, 1 1, 1 2, 1 3 a n d 1 4)  a n d o pe n-la bel peri o d c o h ort. T he c o m m o n o d ds rati o will be deri ve d 
t o get her wit h t w o-si de d 9 5 % c o nfi de n ce i nter vals. 
Esti ma n d Attri b utes  
E n d p oi nt:  
•  H y per kala e mia res p o nse at eac h visit, defi n e d as a n o bser ve d s K + wit hi n 3. 5 -5. 0 
m E q/ L A N D bei n g o n t he sa me s pir o n olact o n e d ose as t he y were at ra n d o misati o n 
A N D (iii) n ot usi n g resc u e t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he last 
m o nt h.  
P o p ulati o n:  
•  Partici pa nt s wit h s y m pt o matic H Fr E F w h o meet i ncl usi o n/e xcl usi o n criteri a. 
Partici pa nt s ha ve eit her h y per kalae mia (s K + 5. 1-5. 9 m E q/ L) or n or m o kalae mia (s K + 
3. 5 -5. 0 m E q/ L) w h o bec o me h y per kalae mic d uri n g t he first 3 wee ks of t he o pe n -la bel 
peri o d, a n d w h o mai ntai n s K + 3. 5 -5. 0 w he n d os e d wit h S Z C, w h o are ra n d o m ise d a n d 
ha ve o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nt a vaila ble.  
Treat me nt:  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  S Z C or Place b o a d mi nistere d dail y wit h s pir o n olact o ne. Partici pa nt s wit h s K + ≥ 6. 0 
m E q/ L will be ma na ge d wit h resc ue t hera p y e m pl o yi n g l ocal sta n dar d of care. 
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 
•  C ha n ge i n d ose of s pir o n olact o ne pri or t o t he E O T visit ( C o m p osite varia ble strate g y 
e. g. c o nsi dere d t o be n o n -res p o nse). 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( C o m p osite varia ble strat e g y, e. g. c o nsi dere d t o be n o n -res p o nse). 
•  Deat h pri or t o t he E O T visit ( C o m p osite varia ble strate g y, e. g. c o nsi dere d t o be n o n -
res p o nse). 
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( C o m p osite varia ble strate g y, 
c o nsi dere d t o be n o n -res p o nse). 
P o p ulati o n Le vel S u m mar y:  
•  T he c o m m o n o d ds rati o of t he occ urre n ce ( yes/ n o) of res p o ns e i n t he S Z C treat me nt 
gr o u p c o m pare d t o t he place b o gr o u p.  
Sec o n d ar y Effic ac y E n d p oi nt A n al ysis –  Se nsiti vit y A n al ysis  
As a s u p ple me ntar y a nal ysis t he a nal ysis of t his sec o n dar y e n d p oi nt will be re peate d b ut wit h 
res p o nse defi ne d as (i) ha vi n g s K + wit hi n 3. 5-5. 5 m E q/ L as assesse d b y ce ntral la b orat or y 
A N D (ii) bei n g o n t he s a me s pir o n olact o ne d ose as t he y were at ra n d o misa ti o n A N D (iii) n ot 
usi n g resc ue t hera p y f or h y per kala e mia at a n y p oi nt d uri n g t he last m o nt h.  
2. T he sec o n d sec o n d ar y effic acy e n d p oi nt is res p o nse (yes/ n o) of p artici p a nt s o n S Z C 
c o m p are d t o pl ace b o w h o, d uri n g t he m ai nte n a nce p h ase ( ≥m o nt h 1 a n d < 6 m o nt hs), are o n 
s pir o n ol act o ne ≥2 5 m g d aily. 
A res p o nse  (y es ) is defi n e d b y (i) bei n g o n s pir o n olact o ne ≥2 5 m g dail y. Res p o nse mea ns t hat 
t his re q uire me nt is met. N o n-res p o nse ( n o) i n dicates t his re q uire me nt is n ot met. A d diti o nall y, 
f or eac h assess me nt visit, n o n-res p o nse ( n o) is i n dicate d f or partici pa nt s w h o are l ost t o 
f oll o w-u p at t he visit, i ncl u di n g d ue t o deat h. T he m o nt hl y visits are use d f or res p o nse 
assess me nt fr o m m o nt h 1 t o m o nt h 6  ( Visits 9-1 4 d uri n g t he Ra n d o m ise d Wit h dra wal P hase, 
Pr ot oc ol Ta ble 1) . 
T he n u m ber a n d p erce nta ge of s u bjects w h o ac hie ve d a res p o ns e ( Yes, N o, Missi n g) f or eac h 
m o nt hl y visit will be s u m mar ise d b y ra n d o m ise d tr eat me nt gr o u p i n t he F A S. 
T he treat me nt effect c o n cer ns t he o v erall O d ds R ati o a n d will be a nal yse d usi n g a G E E 
m o del, wit h a bi n o mial distri b uti o n fa mil y a n d a l o git li n k a n d a n e xc ha n g ea ble c orrel ati o n 
matri x  a n d teste d usi n g a t w o -si de d al p ha = 0. 0 5. T he de pe n d e nt varia bl e will be res p o nse 
( yes/ n o) at e ac h visit. Fi xe d treat me nt effects will i ncl u de ra n d o m ise d tr eat me nt, s u bject 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
recr uit me nt c o u ntr y, a p er visit i n dicat or varia ble (e. g. visit 7, 8, 9, 1 0, 1 1, 1 2, 1 3 a n d 1 4) a n d 
o pe n -la bel peri o d c o h ort. T he c o m m o n o d ds rati o will be deri ve d t o get her wit h t w o -si de d 
9 5 % c o nfi de n ce i nter vals.  
Esti ma n d Attri b utes  
E n d p oi nt:  
•  Bei n g o n s pir o n olact o ne ≥ 2 5 m g dail y at eac h visit  
P o p ulati o n:  
•  Partici pa nt s wit h s y m pt o matic H Fr E F w h o meet i ncl usi o n/e xcl usi o n criteri a. 
Partici pa nt s ha ve eit her h y per kalae mia (s K + 5. 1-5. 9 m E q/ L) or n or m o kalae mia (s K + 
3. 5 -5. 0 m E q/ L) w h o bec o me h y per kalae mic d uri n g t he first 3 wee ks of t he o pe n -la bel 
peri o d, a n d w h o mai ntai n s K + 3. 5 -5. 0 w he n d os e d wit h S Z C, w h o are ra n d o m ise d a n d 
ha ve o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nt a vaila ble  
Treat me nt:  
•  S Z C or Place b o a d mi nistere d dail y wit h s pir o n olact o ne. Partici pa nt s wit h s K + ≥ 6. 0 
m E q/ L will be ma na ge d wit h resc ue t hera p y e m pl o yi n g l ocal sta n dar d of care.  
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( Treat me nt p olic y strate g y, i.e. re gar dl ess of t he i nterc urre nt e ve nt).  
•  Deat h pri or t o t he E O T visit ( C o m p osite varia ble strate g y, e. g. c o nsi dere d t o be n o n -
res p o nse). 
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( C o m p osite varia ble strate g y, e. g. 
c o nsi dere d t o be n o n -res p o nse). 
P o p ulati o n Le vel S u m mar y:  
•  C o m m o n o d ds rati o of t he occ urre n ce of res p o nse i n t he S Z C treat me nt gr o u p 
c o m pare d t o t he pla ce b o gr o u p.  
3. Ti me t o first hy perk al ae mi a e pis o de f or s u bjects o n S Z C c o m p are d t o pl ace b o d uri n g t he 
r a n d o mise d-wit h dr a w al peri o d, wit h hy perk al ae mi a defi ne d as s K + > 5. 0 m E q/ L as assesse d 
by ce ntr al l a b or at ory.  
T his will be a nal yse d usi n g a ca use -s pecific pr o p orti o nal hazar d m o del wit h deat h a n d t he use 
of resc u e t hera p y treat e d as c o m peti n g ris k e ve nts, ra n d o mise d treat me nt a n d s u bject 
recr uit me nt c o u ntr y as i n de pe n de nt f act ors a n d o p e n-la bel peri o d c o h ort as a stratificati o n 
fact or i n t he FA S. I n practice, t he use of t he ca use -s pecific pr o p orti o nal hazar d m o del will 
treat s u bjects wit h a c o m peti n g e ve nt as ce ns ore d. Partici pa nt s wit h o ut h y per kalae mia will be 
ce ns ore d at t he date of t he last a vaila ble ce ntral la b orat or y meas ure me nt of s K +. T he ti me t o 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
first h y per kala e mia e pis o de will be calc ulat e d as ( date of ser u m p otassi u m meas ure me nt –  
date of ra n d o misati o n + 1). 
T o assess f or t he pr o p orti o nalit y of hazar ds t he l o g( -l o g(esti mate d s ur vi val f u ncti o n)) will be 
pl otte d c o m pare d t o l o g( da ys) f or eac h ra n d o m ise d treat me nt gr o u p a n d vis uall y i ns pecte d t o 
deter mi ne if t he c ur ves are a p pr o xi matel y parallel. T o assess f or t he i m pact of ce ns ori n g, a n d 
t he d urati o n of f oll o w-u p, a re verse Ka pla n -Mei er fi g ure will be pr o d uce d w here t he st at us 
i n dicat ors are re v erse d s u ch t hat t he ce ns or bec o m es t he e ve nt a n d t h e c o m p osite e ve nt of 
i nterest as t he ce ns or. T h ese will be pres e nte d b y ra n d o m ise d treat me nt gr o u p, t o get her wit h a 
s u m mar y of ass ociate d st atistics ( me dia n ti me a n d ass ociate d 9 5 % CIs).  
T he hazar d rati o ( S Z C ar m/ place b o ar m), a dj uste d f or t he stratificati o n fact or ( H K vs N K at 
st u d y e ntr y) a n d its t w o-si de d 9 5 % c o nfi de n ce i nter val will be esti mate d usi n g t he C o x 
re gressi o n m o del. K a pla n-Meier s ur vi v al c ur ves ( pr o d uct -li mit esti mates) of ti me t o first 
h y per kala e mia e pis o de will be prese nte d b y ra n d o m ise d treat me nt gr o u p, t o get her wit h a 
s u m mar y of ass ociate d st atistics ( me dia n ti me t o fail ure wit h t he 2 5 t h a n d 7 5 t h perce ntiles a n d 
ass ociate d 9 5 % CIs).  T he Ka pla n -Mei er fi g ur es will i ncl u de t he p -val ue fr o m a l o g -ra n k test 
b y ra n d o mise d treat me nt gr o u p.  
I n a d diti o n, c u m ulati ve i nci de nce s ur vi val c ur v es will be prese nte d b y ra n d o mise d treat me nt 
gr o u p wit h t he esti mate d rate s u bjects de v el o p h y p er kalae mia at da ys 4 4, 8 8, 1 3 2 a n d 1 7 5 
after t he d ate of ra n d o misati o n. 
Esti ma n d Attri b utes  
E n d p oi nt:  
•  Ti me of first h y per kalae mia e pis o de wit h h y per kalae mia defi ne d as s K + > 5. 0 m E q/ L 
as assesse d b y ce ntral la b orat or y.  
P o p ulati o n:  
•  Partici pa nt s wit h s y m pt o matic H Fr E F w h o meet i ncl usi o n/e xcl usi o n criteri a. 
Partici pa nt s ha ve eit her h y per kalae mia (s K + 5. 1-5. 9 m E q/ L) or n or m o kalae mia (s K + 
3. 5 -5. 0 m E q/ L) w h o bec o me h y per kalae mic d uri n g t he first 3 wee ks of t he o pe n -la bel 
peri o d, a n d w h o mai ntai n s K + 3. 5 -5. 0 w he n d os e d wit h S Z C, w h o are ra n d o m ise d a n d 
ha ve o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nt a vaila ble  
Treat me nt:  
•  S Z C or Place b o a d mi nistere d dail y wit h s pir o n olact o ne. Partici pa nt s wit h s K + ≥ 6. 0 
m E q/ L will be ma na ge d wit h resc ue t hera p y e m pl o yi n g l ocal sta n dar d of care.  
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( H y p ot hetical strate g y, e. g. c o nsi dere d t o be ce ns ore d).  
•  Deat h pri or t o t he E O T visit ( H y p ot hetical strate g y, e. g. c o nsi dere d t o be ce ns ore d).  
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( H y p ot hetical strate g y, e. g. 
c o nsi dere d t o be ce ns or e d  at t he date of t he l ast a vaila ble ce ntr al la b orat or y 
meas ure me nt of s K + d uri n g t he ra n d o mise d -wit h dra wal peri o d ). 
P o p ulati o n Le vel S u m mar y:  
•  Ka pla n -Mei er esti mates of t he me dia n ti me t o first h y per kalae mia e pis o de i n t he S Z C 
treat me nt gr o u p c o m p are d t o t he place b o gr o u p. 
Sec o n d ar y Effic ac y E n d p oi nt A n al ysis –  Se nsiti vit y A n al ysis  
As a se nsiti vit y a nal ysis a C o x re gressi o n m o del will be use d wit h t he sa me a nal ysis a p pr oac h 
w here c o m peti n g e ve nts i n t he pre vi o us m o del are treate d as h y p er kal ae mia e ve nts. T he 
f oll o wi n g i nterc urre nt e v e nt strate g y will be use d wit h all ot her c o m p o ne nts of t he esti ma n d as 
defi ne d i n t he mai n a n al ysis  
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( C o m p osite varia ble strat e g y, e. g. c o nsi dere d t o be e ve nt).  
•  Deat h pri or t o t he E O T visit ( C o m p osite varia ble strate g y, e. g. c o nsi dere d t o be e ve nt).  
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( H y p ot hetical strate g y, e. g. 
c o nsi dere d t o be ce ns or e d  at t he date of t he l ast a vaila ble ce ntr al la b orat or y 
meas ure me nt of s K + d uri n g t he ra n d o mise d -wit h dra wal peri o d ). 
As a n a d diti o nal se nsiti vit y a nal ysis, s u bjects will be a d mi nistrati vel y ce ns ore d at t he earliest 
date of t heir visit 1 4 visit or last visit d uri n g t he ra n d o mise d -wit h dra wal peri o d t o i n vesti gate 
t he i m pact of l o n ger d urati o n i n t he st u d y f or s u bjects e nr olle d pri or t o versi o n 3 of t he C S P. 
A f urt her s e nsiti vit y a nal ysis will use t he sa me a n al ysis a p pr oac h as t he mai n a nal ysis f or t his 
sec o n dar y e n d p oi nt b ut will defi ne ti me of first h y per kalae mia e pis o de usi n g a defi niti o n f or  
h y per kala e mia as s K + > 5. 5  m E q/ L as assesse d b y ce ntral la b orat or y.  
4.  Ti me t o first i nst a nce of decre ase of s pir o n ol act o ne d ose d ue t o hy perk al a e mi a f or 
s u bjects o n S Z C c o m p are d t o pl ace b o d uri n g t he r a n d o mise d-wit h dr a w al peri o d.  
T his will be a nal yse d usi n g a ca use -s pecific pr o p orti o nal hazar d m o del wit h deat h treat e d as a 
c o m peti n g ris k e ve nt, ra n d o mise d treat me nt a n d s u bject recr uit me nt c o u ntr y as i n de pe n de nt 
fact ors a n d o p e n-la b el peri o d c o h ort as a str atificati o n fact or i n t he F A S. I n practice, t h e use of 
the ca use -s pecifi c pr o p orti o nal hazar d m o del will treat s u bjects wit h a c o m peti n g e ve nt as 
ce ns ore d. Partici pa nt s wit h o ut a decrease of s pir o n olact o ne d ose d ue t o h y per kalae mia will be 
ce ns ore d at t he date of t heir last visit d uri n g t he ra n d o mise d -wit h dra wal peri o d . T o clarif y, f or 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
s u bjects w h o are e nr olle d i n versi o n 1. 0 or 2. 0 of t he C S P t his will be t he date of visit 1 4 b a n d 
f or all ot her s u bjects t his will be t he date of visit 1 4. If t hese visits are n ot a vaila ble, 
partici pa nts will be ce ns ore d at  t he last a v aila ble visit d uri n g t he ra n d o mise d-wit h dra wal 
peri o d.  
T o assess f or t he pr o p orti o nalit y of hazar ds t he l o g( -l o g(esti mate d s ur vi val f u ncti o n)) will be 
pl otte d c o m pare d t o l o g( da ys) f or eac h ra n d o m ise d treat me nt gr o u p a n d vis uall y i ns pecte d t o 
deter mi ne if t he c ur ves are a p pr o xi matel y parallel. T o assess f or t he i m pact of ce ns ori n g, a n d 
t he d urati o n of f oll o w-u p, a re verse Ka pla n -Mei er fi g ure will be pr o d uce d w here t he st at us 
i n dicat ors are re v erse d s u ch t hat t he ce ns or bec o m es t he e ve nt a n d t h e c o m p osite e ve nt of 
i nterest as t he ce ns or. T h ese will be pres e nte d b y ra n d o m ise d treat me nt gr o u p, t o get her wit h a 
s u m mar y of ass ociate d st atistics ( me dia n ti me a n d ass ociate d 9 5 % CIs).  
T he hazar d rati o ( S Z C ar m/ place b o ar m), a dj uste d f or t he stratificati o n fact or ( H K vs N K at 
st u d y e ntr y) a n d its t w o-si de d 9 5 % c o nfi de n ce i nter val will be esti mate d usi n g t he C o x 
re gressi o n m o del. K a pla n-Meier s ur vi v al c ur ves ( pr o d uct -li mit esti mates) of ti me t o first 
h y per kala e mia e pis o de will be prese nte d b y ra n d o m ise d treat me nt gr o u p, t o get her wit h a 
s u m mar y of ass ociate d st atistics ( me dia n ti me t o fail ure wit h t he 2 5 t h a n d 7 5 t h perce ntiles a n d 
ass ociate d 9 5 % CIs).  T he Ka pla n -Mei er fi g ur es will i ncl u de t he p -val ue fr o m a l o g -ra n k test 
b y ra n d o mise d treat me nt gr o u p.  
I n a d diti o n, c u m ulati ve i nci de nce s ur vi val c ur v es will be prese nte d b y ra n d o mise d treat me nt 
gr o u p wit h t he esti mate d rate s u bjects first d ecreas e s pir o n olact o ne d ose at da y 4 4, 8 8, 1 3 2 
a n d 1 7 5 after t he date of ra n d o misati o n. 
Esti ma n d Attri b utes  
E n d p oi nt:  
•  Ti me t o first i nsta nce of decrease of s pir o n olact o n e d ose d ue t o h y per kalae mia d uri n g 
t he ra n d o mise d-wit h dr a wal peri o d.  
P o p ulati o n:  
•  Partici pa nt s wit h s y m pt o matic H Fr E F w h o meet i ncl usi o n/e xcl usi o n criteri a. 
Partici pa nt s ha ve eit her h y per kalae mia (s K + 5. 1-5. 9 m E q/ L) or n or m o kalae mia (s K + 
3. 5 -5. 0 m E q/ L) w h o bec o me h y per kalae mic d uri n g t he first 3 wee ks of t he o pe n -la bel 
peri o d, a n d w h o mai ntai n s K + 3. 5 -5. 0 w he n d os e d wit h S Z C, w h o are ra n d o m ise d a n d 
ha ve o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nt a vaila ble.  
Treat me nt:  
•  S Z C or Place b o a d mi nistere d dail y wit h s pir o n olact o ne. Partici pa nt s wit h s K + ≥ 6. 0 
m E q/ L will be ma na ge d wit h resc ue t hera p y e m pl o yi n g l ocal sta n dar d of care.  
I nterc urre nt E ve nt Strat e g y: 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( H y p ot hetical strate g y, e. g. c o nsi dere d t o be ce ns ore d).  
•  Deat h pri or t o t he E O T visit ( H y p ot hetical strate g y, e. g. c o nsi dere d t o be ce ns ore d).  
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( H y p ot hetical strate g y, e. g. 
c o nsi dere d t o be ce ns or e d  at t he date of t heir last visit d uri n g t he ra n d o mise d -
wit h dra wal peri o d ). 
P o p ulati o n Le vel S u m mar y:  
•  Ka pla n -Mei er esti mates of t he me dia n ti me t o first h y per kalae mia e pis o de i n t he S Z C 
treat me nt gr o u p c o m p are d t o t he place b o gr o u p. 
Sec o n d ar y Effic ac y E n d p oi nt A n al ysis –  Se nsiti vit y A n al ysis  
As a se nsiti vit y a nal ysis a C o x re gressi o n m o del will be use d wit h t he sa me a nal ysis a p pr oac h 
w here c o m peti n g e ve nts i n t he pre vi o us m o del are treate d as s pir o n ol act o ne d ose decrease 
e ve nts. T he f oll o wi n g i nterc urre nt e ve nt strate g y will be use d wit h all o t her c o m p o ne nts of t he 
esti ma n d as defi ne d i n t h e mai n a nal ysis  
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( C o m p osite varia ble strat e g y, e. g. c o nsi dere d t o be e ve nt).  
•  Deat h pri or t o t he E O T visit ( C o m p osite varia ble strate g y, e. g. c o nsi dere d t o be e ve nt).  
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( H y p ot hetical strate g y, e. g. 
c o nsi dere d t o be ce ns or e d  at t he date of t heir last visit d uri n g t he ra n d o mise d -
wit h dra wal peri o d ). 
As a n a d diti o nal se nsiti vit y a nal ysis, s u bjects will be a d mi nistrati vel y ce ns ore d at t he dat e of 
t heir visit 1 4 visit t o i n vesti gate t he i m pact of l o n ger d urati o n i n t he st u d y f or s u bjects e nr olle d 
pri or t o versi o n 3 of t he C S P.  
5. C h a n ge i n K C C Q -C S S at E O T visit ( a p pr oxi m ately 6 m o nt hs p ost -r a n d o mis ati o n) fr o m 
r a n d o mis ati o n b aseli ne f or s u bjects o n S Z C c o m p are d t o pl ace b o. 
T he K C C Q -C S S will be s u m mar ise d a n d liste d i n t he F A S usi n g t he visits of Visit 2 
( Baseli ne), Visit 6 (Ra n d o mis ati o n) a n d Visit 1 4 ( E O T). Visit 1 4 res ults will i ncl u de val ues 
fr o m Visit 1 4 b w here res ults fr o m Visit 1 4 are n ot a vaila ble. T he a bs ol ute val ues a n d c h a n ge 
fr o m baseli ne a n d ra n d o misati o n i n K C C Q -C S S will be s u m mar ise d at eac h sc he d ule d 
ti me p oi nt b y ra n d o mise d treat me nt gr o u p. F urt her m ore, t he c ha n g e fr o m b aseli ne a n d 
ra n d o misati o n will be cat e g or ise d as: < -5. -5 t o + 5, > 5 - 1 0, > 1 0 t o 2 0, > 2 0  a n d as: > = 5, > = 1 0, 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
> = 1 5 a n d > = 2 0 (res p o n d er a nal ysis) a n d s u m mar ise d at eac h visit b y ra n d o m ise d treat me nt 
gr o u p usi n g t he F A S.  
T he c ha n g e i n K C C Q -C S S will  be a nal yse d wit h re peat e d meas ures a n al ysis of c o varia n ce 
( A N C O V A) m o d els w here t he de p e n de nt varia ble is p ost ra n d o misati o n K C C Q -C S S a n d wit h 
fi xe d ter ms f or ra n d o mise d treat me nt gr o u p, K C C Q-C S S sc ore at ra n d o misati o n, stratificati o n 
fact or ( H K vs N K at st u d y e ntr y) a n d s u bject recr uit me nt c o u ntr y. T he statistical m o del will 
be use d t o calc ul ate t he l east s q uares m ea n ( L S M ea n) treat me nt esti mates, treat me nt 
differe n ce ( S Z C –  place b o) a n d 9 5 % CI at E O T o nl y. T he p -val ue fr o m t he statistical m o del 
f or th e co m p ariso n  o f ra n d o mise d treat me nt gr o u p will be prese nte d. 
D oc u me ntati o n will be pr o vi de d o n t he u n derl yi n g ass u m pti o ns f or t he A N C O V A m o del. T his 
will i ncl u de a c hec k t hat t he resi d uals are a p pr o xi matel y n or mall y distri b ute d b y pl otti n g a 
hist o gra m of t he resi d uals f or t he m o del as well as a S ha pir o -Wil k test w hi c h will reject t he 
n ull h y p ot hesis t hat t he resi d uals are n or mall y distri b ute d if p < 0. 0 5. Sec o n dl y, t he 
h o m o ge neit y of varia n ce will be vis uall y c hec ke d t hr o u g h a n i ns pecti o n of a pl ot of resi d uals 
vers us pre dict e d val ues fr o m t he m o del. Fi nall y, t he h o m o g e neit y of sl o pes will be deter mi ne d 
b y c o n d ucti n g a n A N C O V A a nal ysis w here t he de pe n de nt varia ble is E O T K C C Q -C S S a n d 
t he i n de pe n de nt varia bles are ra n d o mise d treat me nt gr o u p, baseli ne K C C Q-C S S a n d a n 
i nteracti o n ter m bet w ee n ra n d o mise d treat me nt gr o u p a n d baseli ne K C C Q-C S S. If p > 0. 0 5 f or 
t he i nteracti o n ter m, t he n we will acce pt t he h o m o ge neit y of t he treat me nt sl o pes. 
Esti ma n d Attri b utes  
E n d p oi nt:  
•  C ha n ge i n K C C Q -C S S at E O T visit fr o m ra n d o misati o n baseli ne  
P o p ulati o n:  
•  Partici pa nt s wit h s y m pt o matic H Fr E F w h o meet i ncl usi o n/e xcl usi o n criteri a. 
Partici pa nt s ha ve eit her h y per kalae mia (s K + 5. 1-5. 9 m E q/ L) or n or m o kalae mia (s K + 
3. 5 -5. 0 m E q/ L) w h o bec o me h y per kalae mic d uri n g t he first 3 wee ks of t he o pe n -la bel 
peri o d, a n d w h o mai ntai n s K + 3. 5 -5. 0 w he n d os e d wit h S Z C, w h o are ra n d o m ise d a n d 
ha ve o ne or m ore p ost ra n d o misati o n ce ntral la b orat or y s K + meas ure me nt a vaila ble  
Treat me nt:  
•  S Z C or Place b o a d mi nistere d dail y wit h s pir o n olact o ne. Partici pa nt s wit h s K + ≥ 6. 0 
m E q/ L will be ma na ge d wit h resc ue t hera p y e m pl o yi n g l ocal sta n dar d of care.  
I nterc urre nt E ve nt Strat e g y: 
•  Disc o nti n uati o n of treat me nt ( Treat me nt p olic y strate g y, i.e. re gar dless of t he 
i nterc urre nt e ve nt) 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  Use of resc ue t hera p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d ( Treat me nt p olic y strate g y, i.e. re gar dl ess of t he i nterc urre nt e ve nt).  
•  Deat h pri or t o t he E O T visit ( W hile o n treat me nt strate g y, i.e. t he e n d p oi nt is o nl y 
e val ua ble i n s u bjects w h o re mai n ali ve a n d c o m plete t he K C C Q at E O T visit).  
•  Partici pa nt  l ost t o f oll o w-u p pri or t o t he E O T visit ( W hile o n treat me nt strate g y, i.e. 
t he e n d p oi nt is o nl y e val ua ble i n s u bjects w h o c o m plete t he K C C Q at E O T visit). 
P o p ulati o n Le vel S u m mar y:  
•  Least s q uares mea n esti mate i n t he S Z C treat me nt gr o u p c o m pare d t o t he place b o 
gr o u p.  
Sec o n d ar y Effic ac y E n d p oi nt A n al ysis –  Se nsiti vit y A n al ysis  
As a se nsiti vit y a nal ysis, s u bjects will be a d mi nistrati vel y ce ns ore d at t he d ate of t heir visit 1 4 
visit t o i n vesti gate t he i m pact of l o n ger d urati o n i n t he st u d y f or s u bjects e nr olle d pri or t o 
versi o n 3 of t he C S P.  
Sec o n d ar y Effic ac y E n d p oi nt A n al ysis –  S u p ple me nt ar y A n al ysis  
Usi n g t he re peate d meas ures A N C O V A m o d el a n d A N C O V A h o m o ge neit y of sl o pes tests 
descri be d f or t he ‘c ha n ge i n K C C Q -C S S at E O T visit fr o m ra n d o misati o n baseli ne’ t he 
‘c ha n ge i n K C C Q-C S S at E O T visit fr o m scree ni n g baseli ne’ will als o be a nal yse d wit h a 
fi xe d ter m f or K C C Q-C S S sc ore at scree ni n g bas eli ne re placi n g t he fi xe d ter m f or K C C Q -
C S S sc ore at ra n d o misati o n i n t he m o dels.  
4. 2. 7. 3  
S u b gr o u p A n al ysis  
E x pl orat or y a nal ys es of t he pri mar y e n d p oi nt will be perf or me d f or t h e f oll o wi n g s u b gr o u ps. 
I n t he cas e of a l o w n u m ber of s u bjects wit hi n a s u b gr o u p le vel ( < 5 s u bjects), le vels will be 
p o ole d w he n mea ni n gf ul. If a s u b gr o u p a nal ysis is prese nte d b y a varia bl e use d i n t he 
statistical m o del t he n t his ter m will be re m o ve d fr o m t he m o del. 
•  
Partici pa nt  recr uit me nt re gi o n ( N ort h A merica, S o ut h A merica, E ur o p e) 
•  
Partici pa nt  stratificati o n fact or ( H K vs N K at st u d y e ntr y) 
•  
Partici pa nt  a ge ( < me dia n, ≥me dia n)  
•  
Partici pa nt  a ge ( < 7 5, ≥7 5)  
•  
Partici pa nt  se x ( Male, Fe male) 
•  
Partici pa nt  race ( W hite, Blac k or Afri ca n A merica n, Ot her: Asia n, Nati ve Ha waiia n or 
Ot her Pacific Isla n der, A merica n I n di a n or Alas k a Nati ve, Ot her)  
•  
Partici pa nt s wit h a n d wit h o ut dia betes at scree ni n g  
•  
Partici pa nt s wit h a n d wit h o ut atrial fi brillati o n at scree ni n g 
•  
Partici pa nts wit h L V E F > me dia n a n d ≤me dia n at scree ni n g  
•  
Partici pa nt s wit h N T-pr o B N P > me dia n a n d ≤me dia n at scree ni n g  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  
Partici pa nt s wit h e G F R < 4 5, ≥4 5 ml/ mi n at scree ni n g 
•  
Partici pa nt s wit h s K + > me dia n a n d ≤ me dia n at scree ni n g 
•  
Partici pa nt s c urre ntl y recei vi n g or n ot recei vi n g s o di u m-gl uc ose c otra ns p ort er 2 i n hi bit or 
( S G L T 2i) t hera p y at scree ni n g 
•  
Partici pa nt s c urre ntl y recei vi n g or n ot recei vi n g l o w-d ose mi neral oc ortic oi d rece pt or 
a nta g o nist ( M R A) at scree ni n g  
•  
Partici pa nt s c urre ntl y recei vi n g A C E i n hi bit or t hera p y at scree ni n g  
•  
Partici pa nt s c urre ntl y recei vi n g A R B t hera p y at scree ni n g 
•  
Partici pa nt s c urre ntl y recei vi n g A R Ni t hera p y at s cree ni n g 
•  
Partici pa nts c urre ntl y recei vi n g A C E  i n hi bit or or  A R B  t hera p y at scree ni n g 
•  
Partici pa nt s wit h a n d wit h o ut rece nt h os pitalisati o n f or heart fail ure pr i or t o 
ra n d o misati o n (rece nt h os pitalisati o n defi ne d as a s u bject a d mitte d t o t he h os pital wit h a 
le n gt h-of -sta y i n h os pital e xcee di n g at least 2 4 h o urs d uri n g t he 1 2 m o nt hs pri or t o 
baseli ne).  
4. 2. 7. 4  
E x pl or at or y Effic ac y A n al yses  
4. 2. 7. 4. 1  
E x pl or at or y E x p os ure A n al yses  
•  S Z C/ place b o d ose assi g ne d at eac h visit d uri n g t he st u d y (e. g. 5 g e v er y ot her da y; 5, 
1 0, 1 5 g o nce dail y).  
•  T he s pir o n olact o ne d os e assi g ne d at eac h visit d uri n g t he st u d y  
F urt her m ore, at e ac h st u d y visit d uri n g t he o pe n -la bel a n d ra n d o mise d-wit h dra wal peri o ds 
t here will be a cate g ori cal s u m mar y of t he n u m ber a n d perce nta ge of s u bjects assi g ne d t o 
eac h d ose of S Z C/ place b o (e. g. 5 g e ver y ot her da y, 5 g dail y, 1 0 g dail y, 1 5 g dail y) a n d 
s pir o n olact o ne (e. g. 1 2. 5 m g dail y, 2 5 m g dail y, 5 0 m g dail y) wit h o ut a n y i nfere ntial test 
statistics. 
4. 2. 7. 4. 2  
E x pl or at or y C ar di o v asc ul ar A n al yses  
•  Ti me t o first eve nt of c ar di ov asc ul ar ( C V) de at h or w orse ni n g H F ( defi ne d as H F 
H os pit alis ati o ns or Ur ge nt H F visits re g ar dless of I V l o o p di uretic use), a n d t he 
i n divi d u al c o m p o ne nts d uri n g t he r a n d o mise d-wit h dr a w al peri o d:  
o  C V De at h  
o  W orse ni n g H F ( H F h os pit alis ati o ns or ur ge nt H F visits re g ar dless of I V l o o p 
di uretic use ) 
•  T ot al eve nts of C V de at h a n d w orse ni n g H F d uri n g t he r a n d o mise d peri o d  
All deat hs re p orte d p ost-ra n d o misati o n, e xce pt f or s u bjects w h o wit h dra w c o nse nt, 
will be a dj u dicate d b y t h e Cli nical E ve nts C o m mittee. Deat hs will be s u b -classifie d b y 
t he C E C as eit her C V, n o n-C V pri mar y ca use or a n u n deter mi ne d ca use of deat h. 
Partici pa nt s wit h o ut a date of deat h or w orse ni n g H F will be ce ns ore d at t heir e n d of 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
treat me nt date. T o clarif y, f or s u bjects w h o are e nr olle d i n versi o n 1. 0 or 2. 0 of t he 
C S P t his will be t he date of visit 1 4 b a n d f or all ot her s u bjects t his will be t he date of 
visit 1 4. If t hese visits are n ot a vaila ble, partici pa nts will be ce ns ore d at t h e last 
a vaila ble visit d uri n g t he ra n d o mise d -wit h dra wal peri o d . T he ti me t o first 
car di o vas c ular e v e nt ( da ys) will be defi ne d as ( Date of deat h/ w orse ni n g H F/last 
f oll o w-u p visit –  date of ra n d o misati o n + 1). T he ti me t o first car di o vasc ul ar e ve nt, 
ti me to C V deat h a n d ti me t o w orse ni n g H F will be prese nt e d gra p hicall y usi n g 
Ka pla n -Mei er c ur ves f or eac h tr eat me nt gr o u p usi n g t he F A S. A d diti o nall y, ta b ular 
s u m maries will be pr o vi de d of Ka pla n-Meier s ur vi val pr o ba bilities wit h 9 5 % CIs at 
da y 4 4, 8 8, 1 3 2 a n d 1 7 5 after t he after t he date of ra n d o misati o n, detaili n g t he 
c u m ulati ve c o u nts of s u bjects at ris k, wit h e ve nts, a n d ce ns ore d. F urt her m ore, t he 
esti mate d me dia n ti me t o eac h e ve nt a n d 9 5 % CI will be prese nte d f or eac h treat me nt 
gr o u p.  T he Ka pl a n -Meier fi g u res will i ncl u de t he p-val ue fr o m a l o g -ra n k t est b y 
ra n d o mise d treat me nt gr o u p. 
T o assess f or t he pr o p orti o nalit y of hazar ds t he – l o g(-l o g(esti mate d s ur vi val f u ncti o n)) 
will be pl otte d c o m pare d t o l o g( da ys) f or eac h ra n d o m ise d treat me nt gr o u p a n d 
vis uall y i ns pecte d t o deter mi ne if t he c ur ves are a p pr o xi matel y parallel. T o assess f or 
t he i m pact of ce ns ori n g, a n d t he d urati o n of f oll o w-u p, a re verse Ka pla n -Meier fi g ure 
will be pr o d uce d w h ere t he stat us i n dicat ors are re verse d s uc h t h at t he ce ns or bec o mes 
t he e ve nt a n d t he c o m p osite e ve nt of i nterest as t he ce ns or. T h ese will be prese nte d b y 
ra n d o mise d treat me nt gr o u p, t o get her wit h a s u m mar y of ass oci ate d statistics ( me dia n 
ti me, 2 5t h a n d 7 5 t h perce ntiles a n d ass ociate d 9 5 % CIs).  
•  Me a n d aily f ur ose mi de e q uiv ale nt l o o p di uretic d ose over ti me i n t he S Z C gr o u p 
c o m p are d wit h t he pl ace b o gr o u p d uri n g t he r a n d o mise d -wit h dr a w al peri o d.  
T he mea n dail y f ur ose mi de e q ui vale nt l o o p di uretic d ose per s u bject d uri n g t he 
ra n d o mise d-wit h dra wal peri o d is defi ne d as t h e t otal c u m ulati ve d ose of dail y 
f ur ose mi de e q ui val e nt l o o p di uretic d ose d uri n g t he ra n d o mise d-wit h dra wal peri o d 
di vi de d b y t he n u m ber of da ys of f oll o w -u p d uri n g t he ra n d o m ise d-wit h dr a wal peri o d. 
T he mea n dail y f ur ose mi de e q ui vale nt l o o p di uretic d ose will be s u m mar ise d b y 
treat me nt gr o u p usi n g descri pti ve c o nti n u o us statistics i n t he F A S wit h o ut a n y 
i nfere ntial test statistics. C ha n ge i n mea n dail y f ur ose mi de e q ui vale nt l o o p di uretic 
d ose d uri n g t he ra n d o mis e d-wit h dra wal peri o d  will be s u m marise d b y treat me nt gr o u p 
usi n g descri pti ve c o nti n u o us statistics i n t he F A S wit h o ut a n y i nfere ntial test statistics . 
T he c ha n g e dail y f ur os e mi de e q ui vale nt l o o p di uretic d ose d uri n g t he ra n d o mise d-
wit h dra wal peri o d will be a nal yse d usi n g a n A N C O V A a nal ysis wit h de pe n de nt 
varia ble of d ail y f ur ose mi de e q ui vale nt l o o p di uretic d ose at E O T visit a n d 
i n de pe n de nt vari a bles of ra n d o mise d treat me nt gr o u p a n d ra n d o misati o n b aseli ne 
val ue of dail y f ur os e mi de e q ui vale nt l o o p di uretic d ose . T he statistical m o del will be 
use d t o calc ulate t h e L S Mea n treat me nt esti mates, treat me nt differe nce ( S Z C –  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
place b o) a n d 9 5 % CI at E O T o nl y. T he p -val u e fr o m t he statistical m o del f or 
ra n d o mise d treat me nt gr o u p will be prese nte d. 
•  Differe nce i n N T -pr o B N P at t he E O T visit c o m p are d t o r a n d o mis ati o n i n t he S Z C a n d 
pl ace b o ar ms  
N T -pr o B N P will be s u m mar ise d usi n g t he visits of: Ra n d o mis ati o n, Visit 9, Visit 1 2 
a n d Visit 1 4. Visit 1 4 res ults will i ncl u de val ues fr o m Visit 1 4 b w here Visit 1 4 res ults 
are n ot a v aila ble. A bs ol ute val ues, c ha n g e fr o m ra n d o misati o n a n d c ha n ge fr o m 
ra n d o misati o n i n nat ural l o g -tra nsf or me d N T-pr o B N P will be s u m mar ise d b y 
treat me nt gr o u p as c o nti n u o us data usi n g t he F A S. T he c ha n g e i n l o g -tra nsf or me d 
N T pr o B N P d uri n g t he ra n d o mise d -wit h dra wal peri o d will be a nal yse d  usi n g a n 
A N C O V A a n al ysis wit h de pe n de nt varia ble of N T pr o B N P at E O T visit a n d 
i n de pe n de nt vari a bles of ra n d o mise d treat me nt gr o u p a n d ra n d o misati o n b aseli ne 
val ue of N T pr o B N P. T he statistical m o del will be use d t o calc ulate t h e L S Mea n 
treat me nt esti mates, treat me nt differe n ce ( S Z C –  place b o) a n d 9 5 % CI at E O T o nl y. 
T he p -val ue fr o m t he statistical m o del f or ra n d o mise d treat me nt gr o u p will be 
prese nte d.  
 
D oc u me ntati o n will be pr o vi de d o n t he u n derl yi n g ass u m pti o ns f or t he A N C O V A 
m o del. T his will i ncl u de a c hec k t hat t he resi d u als are a p pr o xi matel y n or m all y 
distri b ute d b y pl otti n g a hist o gra m of t he resi d uals f or t he m o del as well as a S ha pir o -
Wil k test w hi c h will reje ct t he n ull h y p ot hesis t hat t he resi d uals are n or mall y 
distri b ute d if p < 0. 0 5. Sec o n dl y, t he h o m o ge neit y of varia n ce will be vis uall y c hec k e d 
t hr o u g h a n i ns pecti o n of a pl ot of resi d uals vers us pre dicte d val u es fr o m t he m o del. 
Fi nall y, t he h o m o g e neit y of sl o pes will be deter mi ne d b y c o n d ucti n g a n A N C O V A 
a nal ysis w here t he de pe n de nt varia ble is E O T n at ural l o g -tra nsf or me d N T -pr o B N P 
a n d t he i n de pe n d e nt vari a bles are ra n d o m ise d tr eat me nt gr o u p, nat ural l o g -tra nsf or me d 
ra n d o misati o n N T-pr o B N P a n d a n i nteracti o n ter m bet wee n ra n d o m ise d tr eat me nt 
gr o u p a n d nat ur al l o g -tra nsf or me d ra n d o misati o n N T-pr o B N P. If p > 0. 0 5 f or t he 
i nteracti o n ter m, t he n w e will acce pt t he h o m o ge neit y of t he treat me nt sl o p es.  
 
4. 2. 7. 4. 3  
E x pl or at or y S u bject -Re p orte d O utc o me A n al yses  
•  T o ex pl ore t he differe nce i n K C C Q -T S S, K C C Q -O S S, a n d ot her K C C Q s u b d o m ai ns 
(i ncl u di n g K C C Q p hysic al li mit ati o n sc ore) bet wee n t he S Z C a n d pl ace b o ar ms at t he 
E O T visit c o m p are d t o b aseli ne  
T he f oll o wi n g K C C Q d o mai ns will be s u m mar ise d usi n g t he visits of Baseli ne ( Visit 2), 
Ra n d o mis ati o n ( Visit 6) a n d Visit 1 4: Visit 1 4 res ults will i ncl u de val ues fr o m Visit 1 4 b 
w here res ults fr o m Visit 1 4 are n ot a vaila ble. P h ysical Li mitati o n Sc ore, S y m pt o m Sta bilit y 
Sc ore, S y m pt o m Fre q ue n c y Sc ore, S y m pt o m B ur de n Sc ore, Self Efficac y Sc ore, Q ualit y  of 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
Life Sc ore, S ocial Li mitati o n Sc ore, K C C Q -T S S a n d K C C Q -O S S. T he a bs ol ute val ues a n d 
c ha n ge fr o m baseli ne a n d ra n d o misati o n will be s u m mar ise d b y ra n d o m ise d treat me nt gr o u ps 
as c o nti n u o us data usi n g t he F A S wit h o ut a n y i nfere ntial test statistics . F urt her m ore, t he 
c ha n ge fr o m baseli ne will be cate g or is e d as: <-5. -5 t o + 5, > 5 - 1 0, > 1 0 t o 2 0, > 2 0 a n d as: 
> = 5, > = 1 0, > = 1 5 a n d > = 2 0 (res p o n der a nal ysis) s u m marise d at eac h visit b y ra n d o m ise d 
treat me nt gr o u p usi n g t he F A S. 
 
•  A n a nc h or -b ase d assess me nt t o deter mi ne t he mi ni m ally i m p ort a nt differe nce ( MI D)  
T he P GI S will be use d as a n a nc h or t o d eter mi ne t he MI D f or t h e c ha n g e i n K C C Q -
C S S fr o m ra n d o misati o n t o Visit 1 4. Visit 1 4 res ults will i ncl u de val ues fr o m Visit 1 4 b 
w here res ults fr o m Visit 1 4 are n ot a vaila ble. T he P GI S will be c o d e d wit h 1 
re pres e nti n g “ n o s y m pt o ms” a n d 6 “ ver y se vere” a n d a li near re gressi o n a p pr oac h 
[ A n gst et al 2 0 1 7] will be use d. T he c ha n ge i n P GI S fr o m ra n d o misati o n t o E O T will 
be calc ul ate d, val ues of 0 will be c o de d as “ N o c h a n ge” = 0, val ues of + 1 will be 
c o de d as “s m all ne gati v e c ha n ge” = 1 a n d v al ues of -1 will be c o de d as “s m all p ositi ve 
c ha n ge” = 1. T w o s e parate li near re gressi o n m o dels will be fitte d f or i m pr o vi n g or 
deteri orati n g sc ores. T he o utc o me varia ble will be K C C Q -C S S a n d t he c o variate t he 
bi nar y a nc h or varia bl e. T he r es ulti n g βs (i.e. t he sl o pe para m eter of t h e m o del) 
c orres p o n d t o t he MI D f or i m pr o ve me nt a n d det eri orati o n res pecti vel y.  
•  C h a n ge i n P GI S a n d K C C Q sc ores fr o m scree ni n g t o t he e n d of o pe n -l a bel, scree ni n g 
t o t he E O T a n d r a n d o misati o n t o E O T a dj uste d f or c h a n ge i n  al d oster o ne levels 
d uri n g t he s a me peri o d.  
T he c ha n g e i n al d oster o ne fr o m scree ni n g t o t he e n d of o pe n -la bel will be s u m marise d 
a n d t he c ha n g e i n al d oster o ne fr o m, scree ni n g t o visit 1 4, a n d ra n d o misati o n t o visit 1 4 
will be s u m mar ise d b y ra n d o m ise d treat me nt gr o u p as c o nti n u o us data usi n g t he F A S. 
Visit 1 4 res ults will i ncl u de val ues fr o m Visit 1 4 b w here res ults fr o m Visit 1 4 are n ot 
a vaila ble. T he c ha n g e fr o m scree ni n g t o t he e n d of o pe n -la bel, c ha n ge fr o m scree ni n g 
t o visit 1 4, a n d c ha n ge fr o m ra n d o misati o n t o visit 1 4 i n K C C Q -T S S, K C C Q -C S S, 
K C C Q -O S S a n d P GI S will be a nal yse d usi n g li near re gressi o n m o dels i n t he F A S wit h 
t he sc ore at visit 1 4 as t he de pe n d e nt varia ble a n d t he i n de pe n de nt varia bles of c ha n ge 
i n nat ural l o g al d oster o ne o ver t he sa me peri o d, baseli ne K C C Q/ P GI S sc ore, baseli ne 
nat ural l o g al d oster o ne, ra n d o m ise d treat me nt gr o u p (e xcl u di n g c ha n g e fr o m scree ni n g 
t o t he e n d of o pe n-l a bel), stratificati o n gr o u p a n d i nteracti o n ter ms bet w ee n nat ural l o g 
al d oster o ne c h a n ge a n d b aseli ne K C C Q/ P GI S sc ore, baseli ne nat ural l o g al d oster o ne 
a n d ra n d o mise d treat me nt gr o u p. Baseli ne will i n dicate eit her scree ni n g val ue or val ue 
at ra n d o misati o n de pe n di n g u p o n t he peri o d bei n g a nal yse d. C ha n ge i n n at ural l o g 
al d oster o ne, bas eli ne K C C Q/ P GI S sc ore a n d bas eli ne nat ural l o g al d oster o ne will be 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
i ncl u de d i n t he m o del usi n g 3-k n ot nat ural s pli nes , w here k n ots are e q uall y s pace d 
bet wee n t he e xtre me of t he data,  t o all o w f or a n o n-li near ass o ciati o n wit h E O T 
K C C Q/ P GI S sc ore. T o a v oi d o ver -fitti n g a bac k war d selecti o n met h o d will be use d t o 
select a parsi m o ni o us set of i n de pe n de nt varia bles w here f or eac h m o del fit t he hi g hest 
p -val ue greater t h a n 0. 0 5 is re m o ve d .  
As a n e xa m ple, t he c ha n ge i n K C C Q -T S S fr o m scree ni n g b aseli ne t o t he visit 1 4 will 
be a nal yse d wit h de p e n d e nt varia bles of: n at ural l o g al d oster o ne c h a n ge fr o m 
scree ni n g t o t he visit 1 4, scree ni n g K C C Q-T S S, s cree ni n g n at ural l o g al d oster o ne, 
ra n d o mise d treat me nt gr o u p, al d oster o ne c h a n ge fr o m scree ni n g t o visit 1 4 *scree ni n g 
K C C Q -T S S, nat ural l o g al d oster o ne c h a n ge fr o m scree ni n g t o visit 1 4 *scree ni n g 
nat ural l o g al d oster o ne a n d nat ural l o g al d oster o ne c ha n g e fr o m scree ni n g t o visit 
1 4 *ra n d o m ise d treat me nt gr o u p. 
4. 2. 7. 4. 4  
E x pl or at or y Re n al A n al yses  
•  C h a n ge i n me a n U A C R  
U A C R will be s u m mar ise d usi n g t he visits of Scree ni n g ( Visit 1), Ra n d o mis ati o n 
( Visit 6), Visit 9 a n d visit 1 4 ( E O T). Visit 1 4 res ults will i ncl u de val ues fr o m Visit 1 4 b 
w here res ults fr o m Visit 1 4 are n ot a vaila ble. T he a bs ol ute val ue a n d c ha n g e fr o m 
scree ni n g b aseli ne a n d ra n d o misati o n baseli ne will be s u m mar ise d b y ra n d o m ise d 
treat me nt gr o u ps as c o nti n u o us data usi n g t he F A S wit h o ut a n y i nfere ntial test 
statistics. I n a d diti o n, a s u b gr o u p a nal ysis will be c o n d ucte d usi n g t he sa m e met h o d 
wit h baseli ne U A C R strata ( < 3 0 m g/ g; 3 1 – 3 0 0 m g/ g; > 3 0 0 m g/ g ). 
•  C h a n ge i n e G F R  
e G F R will be s u m mar ise d usi n g t he visits of Scree ni n g ( Visit 1), Visit 2, Visit 3, Visit 
4, Visit 5, Visit 6, Ra n d o mis ati o n ( Visit 7), Visit 8, Visit 9, Visit 1 0, Visit 1 1, Visit 1 2, 
Visit 1 3, Visit 1 4, Visit 1 4a, Visit 1 4 b, Visit 1 5 a n d Visit 1 5a. T he a bs ol ute val ue a n d 
c ha n ge fr o m scree ni n g b aseli ne ( Visit 1) a n d ra n d o misati o n baseli ne ( Visit 6) will be 
s u m marise d b y ra n d o m ise d treat me nt gr o u p as c o nti n u o us data usi n g t he F A S. 
T hree mi xe d effect m o dels will be calc ulate d usi n g t he F A S t o deter mi ne t he i m pact of 
S Z C o n e G F R:  
o  T he de pe n d e nt varia bl e will be e G F R d uri n g t he o pe n -la bel peri o d. T he 
i n de pe n de nt fi xe d effect varia bles will i ncl u de da ys fr o m scree ni n g assess me nt, 
e G F R at scree ni n g, stratificati o n fact or, s u bject r ecr uit me nt c o u ntr y a n d a n 
i nteracti o n bet wee n ra n d o mise d treat me nt gr o u p a n d da ys fr o m scree ni n g. 
o  T he de pe n d e nt varia bl e will be e G F R d uri n g t he ra n d o m ise d-wit h dra wal 
peri o d. T he i n de p e n de nt fi xe d effect varia bles will i ncl u de ra n d o m ise d 
treat me nt gr o u p, da ys fr o m scree ni n g ass ess me nt, e G F R at ra n d o misati o n, 
stratificati o n fact or, s u bject recr uit me nt c o u ntr y a n d a n i nteracti o n bet w ee n 
ra n d o mise d treat me nt gr o u p a n d da ys fr o m scree ni n g. 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
o  T he de pe n d e nt varia bl e will be e G F R d uri n g t he o pe n -la bel a n d ra n d o mis e d-
wit h dra wal peri o ds. T he i n de pe n de nt fi xe d effect varia bles will i ncl u de 
ra n d o mise d treat me nt gr o u p, da ys fr o m scree ni n g assess me nt, e G F R at 
scree ni n g, str atificati o n fact or, s u bject r ecr uit me nt c o u ntr y a n d a n i nteracti o n 
bet wee n ra n d o m ise d treat me nt gr o u p a n d da ys fr o m scree ni n g. 
P ost m o del para meter esti mates f or t he e G F R sl o pe f or eac h tr eat me nt gr o u p, 9 5 % CI 
a n d p-val ue f or t he i nteracti o n ter m will be re p orte d fr o m eac h m o del.  T he esti mate f or 
t he differe nce i n e G F R b et wee n tr eat me nt gr o u ps, 9 5 % CI a n d p-val u e will be 
prese nte d f or eac h m o del.  
•  C h a n ge i n N atri uretic res p o nse  
Natri uretic res p o nse will be a nal yse d usi n g t he fracti o nal e xcreti o n of Na + usi n g t he 
visits of Scree ni n g ( Visit 1), Ra n d o mis ati o n ( Visit 6), Visit 9 a n d Visit 1 4 ( E O T). Visit 
1 4 ( E O T) res ults will i ncl u de val ues fr o m Visit 1 4 b w here res ults fr o m Visit 1 4 ( E O T) 
are n ot a v aila ble. T he a bs ol ute val ue a n d c h a n ge fr o m scree ni n g b aseli ne ( Visit 1) a n d 
ra n d o misati o n baseli ne ( Visit 6) will be s u m mar ise d b y ra n d o m ise d treat me nt gr o u p as 
c o nti n u o us data usi n g t he F A S wit h o ut a n y i nfere ntial test statistics.  
4. 2. 7. 4. 5  
E x pl or at or y H y per k al ae mi a A n al yses  
•  
Ti me t o first i nst a nce of use of resc ue t her a p y f or hy perk al ae mi a d uri n g t h e r a n d o mise d 
wit h dr a w al peri o d  
T he ti me ( da ys) t o t he first use of resc u e f or h y p er kalae mia d uri n g t he ra n d o m ise d-
wit h dra wal peri o d is defi ne d as t he date of first us e of res c ue t hera p y –  dat e of 
ra n d o misati o n + 1. Partici pa nt s w h o d o n ot re q uire resc ue t h era p y will be ce ns ore d at the  
date of t heir last visit d uri n g t he ra n d o mise d -wit h dra wal peri o d . T o clarif y, f or s u bjects 
w h o are e nr olle d  i n versi o n  1. 0  or  2. 0  of  t he C S P  t his will  be  t he date  of  visit  1 4 b  a n d f or 
all ot her  s u bjects t his will  be  t he date  of  visit  1 4 . If t hese visits are n ot a vaila ble, 
partici pa nts will be ce ns ore d at t he last a v aila ble visit d uri n g t h e ra n d o mise d -wit h dra wal 
peri o d.  T he ti me t o first use of res c ue t hera p y f or h y per kalae mia will be prese nte d 
gra p hicall y usi n g Ka pla n -Meier c ur ves f or eac h tr eat me nt gr o u p usi n g t he F A S. 
A d diti o nall y, ta b ular s u m maries will be pr o vi de d of Ka pla n -M eier s ur vi v al pr o ba bilities 
wit h 9 5 % CIs a t d a ys 4 4, 8 8, 1 3 2 a n d 1 7 5 after t he date of ra n d o misati o n, detaili n g t he 
c u m ulati ve c o u nts of s u bjects at ris k, wit h e ve nts, a n d ce ns ore d. F urt her m ore, t he 
esti mate d me dia n ti me t o eac h e ve nt a n d 9 5 % CI will be prese nte d f o r eac h treat me nt 
gr o u p.  T he Ka pl a n -Meier fi g ures will i ncl u de t he p -val ue fr o m a l o g -ra n k t est b y 
ra n d o mise d treat me nt gr o u p. 
T o assess f or t he pr o p orti o nalit y of hazar ds t he – l o g(-l o g(esti mate d s ur vi val f u ncti o n)) 
will be pl otte d c o m pare d t o l o g( da ys) f or eac h ra n d o m ise d treat me nt gr o u p a n d vis uall y 
i ns pecte d t o deter mi ne if t he c ur ves are a p pr o xi matel y parallel. T o ass ess f or t he i m pact 
of ce ns ori n g, a n d t he d urati o n of f oll o w -u p, a re verse Ka pla n -Meier fi g ure will be 
pr o d uce d w h ere t h e stat us i n dicat ors are re verse d s uc h t hat t he ce ns or bec o mes t he e ve nt 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
a n d t he c o m p osite e ve nt of i nterest as t he ce ns or. T hese will be pres e nte d b y ra n d o m ise d 
treat me nt gr o u p, t o get her wit h a s u m mar y of ass ociate d statistics ( me dia n ti me, 2 5t h a n d 
7 5 t h perce ntiles a n d ass ociate d 9 5 % CIs).  
•  
N u m ber of hy perk al ae mi a e pis o des per tre at me nt gr o u p  
T he o verall n u m ber of h y per kalae mia e pis o des d uri n g t he o pe n -la bel peri o d, ra n d o mise d-
wit h dra wal peri o d a n d o verall, i ncl u di n g s u bjects wit h o ne or m ore i nsta nce of 
h y per kala e mia a n d m ulti ple i nsta nces of h y per kal ae mia per s u bj ect will be s u m mar ise d 
b y treat me nt gr o u p usi n g t he F A S wit h o ut a n y i nfere ntial test statistics.  
•  W orst s K + d uri n g r a n d o m ise d-wit h dr a w al p h ase  
T he w orst ( hi g hest) s K + d uri n g t he ra n d o m ise d-wit h dra wal per s u bject will be prese nt e d 
wit h t he n u m ber a n d perce nta ge of s u bjects i n t he f oll o wi n g ra n ges per ra n d o m ise d 
treat me nt gr o u p usi n g t he F A S wit h o ut a n y i nfere ntial test statistics: 5. 1-5. 4 m E q/ L; 5. 5 -
5. 9 m E q/ L, 6. 0 -6. 4 m E q/ L, ≥6. 5 m E q/ L  
•  
N u m ber of e mer ge n cy d e p art me nt visits f or hy perk al ae mi a i n t he S Z C a n d pl ace b o ar ms  
T he o verall n u m ber of e mer ge nc y d e part me nt visits d uri n g t he o pe n -la bel peri o d, 
ra n d o mise d wit h dra w al peri o d a n d o verall, i ncl u di n g s u bjects wit h o ne or m ore 
e mer ge n c y de part me nt visits a n d m ulti ple e mer ge nc y de part me nt visits per s u bject will be 
s u m marise d b y treat me nt gr o u p usi n g t he F A S wit h o ut a n y i nfere ntial test statistics.  
•  
N u m ber of h os pit aliz ati o ns  wit h di a g n osis c o de f or hy perk al ae mi a i n t he S Z C a n d 
pl ace b o ar ms  
T he o verall n u m ber of h os pitalizati o ns d uri n g t he o pe n -la bel peri o d, ra n d o mise d 
wit h dra wal peri o d a n d o verall, i ncl u di n g s u bjects wit h o ne or m ore e m er ge nc y 
de part me nt visits a n d m ulti ple e mer ge nc y d e part m e nt visits per s u bject will be 
s u m marise d b y treat me nt gr o u p usi n g t he F A S wit h o ut a n y i nfere ntial test statistics.  
•  Persiste nce of R A A Si me dic ati o n  
Base d o n t he ori gi nal R A A Si ( A C Ei/ A R B/ A R N i) bei n g recei ve d at e nr ol me nt i n t he o pe n-
la bel peri o d t he f oll o wi n g n u m ber a n d perce nt a ge of s u bjects will be prese nte d wit h o ut 
a n y i nfere ntial test statistics:  
o  Re mai ni n g o n ori gi nal d ose fr o m ra n d o misati o n  
o  Wit h d ose decrease  fr o m ra n d o misati o n 
o  Wit h d ose i ncrease  fr o m ra n d o misati o n 
o  Disc o nti n ue d ori gi nal R A A Si  fr o m ra n d o misati o n 
o  Missi n g  
•  I niti ati o n of A R Ni 
Partici pa nts w h o are classifie d as n ot recei vi n g A R Ni at e nr ol me nt at ra n d o misati o n will 
ha ve t he n u m ber a n d perce nta ge of s u bjects w h o i nitiate A R Ni d uri n g t he ra n d o mise d 
wit h dra wal peri o d prese nte d b y treat me nt gr o u p.  
•  C h a n ge i n s K + at 7 d ays p ost E O T c o m p are d wit h E O T  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
s K + will be s u m marise d usi n g t he visits of E O T, Visit 1 5 ( 7 da ys p ost E O T) a n d Visit 
1 5a ( 2 1 da ys p ost E O T). T he a bs ol ute val ue a n d c ha n ge fr o m E O T will be s u m mar ise d 
b y ra n d o m ise d treat me nt gr o u p as c o nti n u o us data usi n g t he F A S. 
A mi xe d effect m o dels will be calc ulate d usi n g t he F A S t o deter mi ne t he i m pact of 
S Z C o n s K + p ost E O T:  
o  T he de pe n d e nt varia bl e will be s K + d uri n g t he f oll o w -u p peri o d. T he 
i n de pe n de nt fi xe d effect varia bles will i ncl u de da ys fr o m E O T, s K + at E O T, 
stratificati o n fact or, s u bject recr uit me nt c o u ntr y a n d a n i nteracti o n bet w ee n 
ra n d o mise d treat me nt gr o u p a n d da ys fr o m E O T. 
P ost m o del para meter esti mates f or t he e G F R sl o pe f or eac h tr eat me nt gr o u p, 9 5 % CI 
a n d p-val ue f or t he i nteracti o n ter m will be re p orte d fr o m t he m o del.  
•  Res p o nse  (yes/ n o) of s u bjects o n S Z C c o m p are d t o pl ace b o w h o, at t he e arliest visit of 
eit her E O T or visit 1 4 ( a p pr oxi m ately 6 m o nt hs p ost -r a n d o misati o n), h ave s K + wit hi n 
3. 5 -5. 0 m E q/ L, are o n s pir o n ol act o ne ≥2 5 m g d aily, a n d di d n ot use resc ue t her a py f or 
hy perk al ae mi a at a ny p oi nt d uri n g t he r a n d o misati o n -wit h dr a w al peri o d  
Res p o nse  ( yes/ n o) will b e c o m pare d bet wee n treat me nt gr o u ps i n t he F A S usi n g a 
l o gistic re gressi o n m o del i ncl u di n g res p o nse as t h e de pe n d e nt varia ble, ra n d o mise d 
treat me nt a n d s u bject recr uit me nt c o u ntr y as i n de pe n de nt fact ors a n d o pe n-la bel peri o d 
c o h ort as a str atificati o n fact or, a n d will be test e d usi n g a t w o -si de d al p ha = 0. 0 5. 
S u bjects w h o ha ve n ot re mai ne d o n s pir o n olact o n e ≥2 5 m g dail y at E O T visit or w h o 
ha ve use d resc ue t h era p y f or h y per kalae mia at a n y p oi nt d uri n g t he ra n d o m ise d-
wit h dra wal peri o d a re treate d as n o n-res p o nse. S u bjects w h o are l ost t o f oll o w-u p pri or 
t o t he E O T visit will ha ve res p o nse treate d as missi n g. S u bjects w h o die pri or t o t he 
E O T visit will be treate d as n o n -res p o ns e f or t he p ur p ose of t he pri mar y a n al ysis. F or 
s u bjects w h o are assi g ne d a n o n-res p o ns e val ue, a s u b ta ble will be pr o vi de d t o 
s u m marize t he i nterc urre nt e ve nts w hic h le d t o t his assi g n me nt b y treat me nt gr o u p. 
T he n u m ber a n d p erce nta ge of s u bjects w h o ac hie ve d a res p o ns e ( Yes, N o, Missi n g) 
will be s u m mar ise d b y ra n d o m ise d treat me nt gr o u p i n t he F A S. T he c o m m o n o d ds 
rati o will be deri ve d t o get her wit h t he t w o-si de d 9 5 % c o nfi de n ce i nter val. 
4. 2. 7. 4. 6  
E x pl or at or y O pe n -l a bel Peri o d A n al yses 
•  
N u m ber a n d perce nt a g e of s u bjects t h at are n or m ok al ae mic ( N K) a n d receivi n g 
s pir o n ol act o ne ≥2 5 m g d aily at t he e n d of t he o pe n-l a bel r u n-i n peri o d 
T he o verall n u m ber a n d perce nt a ge of s u bjects wit h 3. 5 ≤ s K + ≤5. 0 m E q/ L i n t he S S O at 
t he date of ra n d o misati o n will be s u m mar ise d b y t he d ose of s pir o n olact o ne recei ve d at 
t he date of ra n d o misati o n (e. g. 1 2. 5 m g dail y, 2 5 m g dail y, 5 0 m g dail y) wit h o ut a n y 
i nfere ntial test statistics. 
•  
N u m ber a n d perce nt a g e of s u bjects disc o nti n ue d fr o m st u dy d uri n g t he o pe n -l a bel r u n-i n 
peri o d d ue t o re as o ns ot her t h a n H K  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
T he o verall n u m ber a n d perce nt a ge of s u bjects i n t he S S O w h o disc o nti n ue d treat me nt 
d uri n g t he o pe n -la b el peri o d will be s u m marise d, wit h o ut a n y i nfere ntial test statistics, 
i ncl u di n g reas o ns f or dis c o nti n uati o n w hic h will i ncl u de: 
− 
W orse ne d re nal f u ncti o n  
− 
H y p ote nsi o n  
− 
Ot her  
T he o verall n u m ber a n d perce nt a ge of s u bjects w h o e ntere d t he o pe n la bel peri o d a n d 
disc o nti n ue d  fr o m st u d y d uri n g t he o pe n-la bel r u n-i n f or t he f oll o wi n g reas o ns: 
− 
D eat hs  
− 
A Es lea di n g t o treat me nt disc o nti n uati o n  
− 
S u bjects  i n C o h ort 1 ( h y per kalae mic at e ntr y) w h o re mai ne d h y per kalae mic at e n d of 
o pe n -la bel p has e 
− 
S u bjects  i n C o h ort 2 ( n or m o kalae mic at e ntr y) w h o ne ver beca me h y per kalae mic  
− 
S u bjects i n C o h ort 2 ( n or m o kalae mic at e ntr y) w h o beca me h y per kal ae mic a n d 
re mai ne d h y per kala e mic at t he e n d of t he o pe n-la bel p hase 
− 
S u bjects wit h i m p orta nt pr ot oc ol de viati o n  i n dicati n g t he y were i nc orrectl y e nr olle d 
after scree ni n g  
− 
S u bject w h o wit h dre w fr o m t he st u d y  
S u bjects s h o ul d be re p ort e d i n a hierarc hical fas hi o n b y t he first cate g or y w hic h a p plies i n 
t he or der prese nte d a b o v e.  
•  
S pir o n ol act o ne d ose a m o n g C o h ort 2 s u bjects w h o  never bec a me h y per k al ae mic  
T he ma xi m u m d ose of s pir o n olact o ne ac hie ve d a m o n g c o h ort 2 s u bjects i n t he S S E w h o 
ne ver beca me h y p er kalae mic will be s u m marise d cate g oricall y b y d ose a n d  s u m marise d 
as c o nti n u o us data.  
•  
N u m ber a n d pr o p orti o n of s u bjects ac hievi n g n or m ok al ae mi a d uri n g t he first 4 8 h o urs of 
t he o pe n -l a bel r u n-i n c orrecti o n peri o d   
T he o verall n u m ber a n d perce nt a ge of s u bjects wit h 3. 5 ≤ s K + ≤5. 0 m E q/ L i n t he S SE  
d uri n g t he first 4 8 h o urs of t he o pe n -la bel r u n-i n c orrecti o n peri o d will be s u m marise d 
wit h o ut a n y i nfere ntial test statistics.  
•  
N u m ber a n d pr o p orti o n of s u bjects w h o are n or m ok al ae mic by t h eir l ast visit d uri n g t he 
o pe n -l a bel r u n-i n peri o d   
T he o verall n u m ber a n d perce nt a ge of s u bjects wit h 3. 5 ≤ s K + ≤5. 0 m E q/ L i n t he S SE  at 
t he date of ra n d o misati o n will be s u m marise d wit h o ut a n y i nfere ntial test st atistics. 
•  
N u m ber a n d pr o p orti o n of s u bjects w h o d o n ot h ave a n e pis o de of hy p erk al ae mi a  d uri n g 
t he o pe n-l a bel r u n-i n peri o d   
T he o verall n u m ber a n d perce nt a ge of s u bjects i n t he S S E  w h o d i d n ot ha ve a n e pis o de of 
hy perk al ae mi a  d uri n g t he o pe n -la bel r u n-i n peri o d will be s u m marise d  wit h o ut a n y 
i nfere ntial test statistics. 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  
N u m ber a n d pr o p orti o n of s u bjects w h o ac hieve at le ast 2 5 m g of s pir o n ol act o ne d uri n g 
o pe n -l a bel r u n-i n peri o d  
T he o verall n u m ber a n d perce nt a ge of s u bjects i n t he S S E  w h o ac hie ve at l east 2 5 m g of 
s pir o n olact o ne d uri n g t he o pe n-la bel r u n-i n peri o d will be s u m marise d  wit h o ut a n y 
i nfere ntial test statistics. 
 
4. 2. 7. 4. 7  
Ot her E x pl or at or y A n al yses  
C ha n ge i n ser u m bicar b o nate  
Ser u m bicar b o nat e will be s u m mar ise d usi n g t he visits of Scree ni n g ( Visit 1), Ra n d o mis ati o n 
( Visit 6), a n d Visit 1 4. Visit 1 4 ( E O T) res ults will i ncl u de val ues fr o m Visit 1 4 b w here res ults 
fr o m Visit 1 4 ( E O T) are n ot a vaila ble. T he a bs ol ute val ue a n d c ha n ge fr o m scree ni n g b aseli ne 
a n d ra n d o misati o n baseli ne will be s u m mar ise d b y ra n d o m ise d treat me nt gr o u ps as c o nti n u o us 
data usi n g t he F A S wit h o ut a n y i nfere ntial test statistics . 
 
4. 2. 7. 4. 8  
Ge n o mics I niti ati ve  
O pti o nal ge netic sa m ple c ollecti o n will be liste d o nl y usi n g t he S S O. A n y f urt her a n al yses of 
ge n o mic sa m ples will be pr o vi de d i n a se parate a n al ysis pla n.  
4. 2. 8  
S afet y  
4. 2. 8. 1  
A d verse E ve nts  
A n o verall s u m mar y ta bl e of t he n u m ber of s u bjects e x perie nci n g eac h cate g or y of A Es will 
be pr o d uce d usi n g t he S S O a n d S S R. A nal yses usi n g t he S S O will be restricte d t o A Es w hic h 
occ urre d d uri n g t he o pe n -la bel peri o d a n d will be prese nte d b y o pe n-la bel c oh ort a n d o verall. 
A nal yses usi n g t he S S R will i ncl u de all A Es a n d will be prese nte d b y treat me nt gr o u p 
recei v e d d uri n g t he ra n d o mise d-wit h dra wal peri o d a n d o verall.  
A n y A E occ urri n g wit hi n 1 4 da y s of t he disc o nti n uati o n of i n vesti gati o nal pr o d uct will be 
i ncl u de d i n t he A E s u m maries. Treat me nt e mer ge nt a d verse e ve nts ( T E A Es) occ urri n g pri or 
t o first d ose of i n vesti gati o nal pr o d uct (i.e. b ef ore st u d y da y 1) w hic h s u bse q ue ntl y w orse n i n 
se verit y f ollo wi n g d osi n g will be prese nte d i n t he s u m mar y ta bles. All ot her A Es occ urri n g 
pri or t o first d ose of i n vesti gati o nal pr o d uct (i.e. b ef ore st u d y da y 1) or m ore t ha n 1 5  da ys 
after t he disc o nti n uati o n of i n vesti gati o nal pr o d uct will be liste d se paratel y, b ut n ot i ncl u de d 
i n t he s u m maries. 
A n o ver vie w t a ble will s u m marize t he n u m ber a n d perce nt a ge of s u bjects wit h at least o ne of 
t he f oll o wi n g A Es, w here partici pa nt s wit h m ore t ha n o ne A E i n a partic ular cate g or y are 
c o u nte d o nl y o nce i n t hat cate g or y, as well as t he a bs ol ute c o u nts of n u m ber of A Es. F or t he 
o verall s u m mar y of s u bjects wit h a n y A Es  a n d S A Es , i n t he safet y set ra n d o mise d a nal ysis 
gr o u p, t he e ve nt r ate will be dis pla ye d. T his will be calc ul ate d as t he N u m b er of s u bjects wit h 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
A Es di vi de d b y t he t otal n u m ber of da ys at ris k f or A Es acr oss all s u bjects i n gi ve n gr o u p, 
m ulti plie d b y 3 6 5. 2 5 m ulti plie d b y 1 0 0.  
•  
A n y A Es  
•  
A n y A Es assesse d b y i n v esti gat or as p ossi bl y relat e d t o treat me nt  
•  
A n y A Es wit h o utc o me of deat h  
•  
A n y S A Es (i ncl u di n g e v e nts wit h o utc o me of deat h)  
•  
A n y S A Es lea di n g t o treat me nt disc o nti n uati o n  
•  
A n y A Es lea di n g t o treat me nt disc o nti n uati o n  
•  
A n y A Es lea di n g t o d ose re d ucti o n of st u d y treat me nt  
•  
A n y A Es lea di n g t o d ose i nterr u pti o n of st u d y treat me nt  
 
T he n u m ber a n d p erce nta ge of s u bjects re p orti n g eac h A E a n d t h e a bs ol ute c o u nt of A Es will 
be s u m mar ise d b y s yste m or ga n class ( S O C) a n d preferre d t er m ( P T). Ta bles will be s orte d b y 
i nter nati o nal or der f or S O C a n d P Ts will be s orte d al p ha beticall y. T he f oll o wi n g s u m maries 
will be pr o d uce d usi n g t h e S S O a n d S S R:  
•  
A Es b y S O C a n d P T;  
•  
M ost c o m m o n A Es ( > 5 % i n a n y treat me nt gr o u p) b y S O C a n d P T;  
•  
A Es assesse d b y i n vesti g at or as p ossi bl y relate d t o treat me nt, b y S O C a n d P T;  
•  
A Es b y relati o ns hi p t o treat me nt, b y S O C a n d P T;  
•  
A Es b y ma xi m u m i nte nsit y, b y S O C a n d P T;  
•  
A Es assesse d b y i n vesti g at or as p ossi bl y relate d t o treat me nt b y ma xi m u m i nte nsit y, b y 
S O C a n d P T;  
•  
A Es lea di n g t o treat me nt disc o nti n uati o n, b y S O C a n d P T;  
•  
A Es assesse d b y i n vesti g at or as p ossi bl y relate d t o treat me nt lea di n g t o treat me nt 
disc o nti n uati o n, b y S O C a n d P T;  
•  
A Es assesse d b y i n vesti g at or as p ossi bl y relate d t o treat me nt lea di n g t o treat me nt 
i nterr u pti o n, b y S O C a n d P T; 
•  
A Es lea di n g t o d ose re d u cti o n, b y S O C a n d P T;  
•  
A Es assesse d b y i n vesti g at or as p ossi bl y relate d t o treat me nt lea di n g t o d os e re d ucti o n, b y 
S O C a n d P T;  
•  
S A Es, b y S O C a n d P T;  
•  
S A Es relate d t o treat me nt, b y S O C a n d P T;  
•  
A Es lea di n g t o deat h, b y S O C a n d P T;  
•  
Oe de ma relate d e ve nts, b y P T;  
•  
Heart fail ure e v e nts ( Heart fail ure e v e nts as classifie d b y t he ce ntr al a dj u dicati o n 
c o m mittee), b y P T  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
 
All A E data will be liste d a p pr o priatel y f or all s u bjects i ncl u di n g i nf or mati o n o n A E d urati o n, 
i nte nsit y, seri o us ness, acti o n ta ke n, o utc o me, rel ati o ns hi p as assesse d b y i n v esti gat or, ti mi n g 
of o nset of A E i n r elati o n t o t he first d ose of st u d y treat me nt i n t he o pe n-la bel peri o d, st u d y 
treat me nt at t he ti me of e ve nt. 
I n a d diti o n, details c ollecte d o n t he peri p heral oe de ma a n d heart fail ure e v e nt e C R F pa ges will 
be s u m marise d usi n g t he S S O a n d S S R. A nal yses usi n g t he S S O will be restricte d t o 
peri p heral oe de ma a n d h eart fail ure e v e nts w hic h occ urre d d uri n g t he o pe n -la bel peri o d a n d 
will be prese nte d b y o p e n -la bel c o h ort a n d o verall. A nal yses usi n g t he S S R will i ncl u de all 
i ncide nces of p eri p heral oe de ma a n d h eart fail ure e ve nts a n d will be prese nte d b y treat me nt 
gr o u p recei ve d d uri n g t h e ra n d o m ise d-wit h dra wal peri o d a n d o verall. T he first i nsta nce of 
peri p heral oe de ma or heart fail ure e v e nt per s u bject i n t he S S O a n d S S R a nal ysis peri o ds will 
be re p ort e d.  
4. 2. 8. 2  
De at hs  
A s u m mar y of deat hs will be pr o vi de d wit h n u m ber a n d perce nta ge of s u bj ects cate g or ise d as:  
•  
Car di o vasc ular/ N o n -car di o vasc ular/ U n det er mi ne d ca use of deat h  
•  
Pri mar y ca use of car di o vasc ular d eat hs  
•  
Pri mar y ca use of n o n -car di o vasc ular deat hs  
•  
N u m ber of s u bjects wit h a n y A E wit h o utc o me = deat h  
All deat hs will be liste d.  
4. 2. 8. 3  
L a b or at or y D at a  
La b orat or y d ata (cli nical c he mistr y, hae mat ol o g y a n d uri nal ysis) will be s u m mar ise d a n d 
liste d. La b orat or y dat a o utsi de t he refere n ce ra n g es will be i n dicate d i n t he listi n gs. If a 
s u bject has m ulti ple res ults f or a partic ul ar test at a partic ular ti me p oi nt, t he first n o n -missi n g 
sc he d ule d val ue will be use d f or t he s u m mar y. S yste m i nter nati o nal ( SI) u nits will be re p orte d 
f or all a nal ytes. 
La b orat or y d ata a bs ol ute a n d c ha n g e fr o m bas eli ne val ues f or c o nti n u o us c he mistr y, 
hae mat ol o g y a n d uri nal ysis para meters will be s u m mar ise d at eac h sc he d ule d assess me nt 
ti me. Se parate ta bles will be pr o vi de d f or t he S S O, restricte d t o visits d uri n g t he o pe n-la bel 
peri o d a n d prese nte d b y o pe n -la bel c o h ort a n d f or t he S S R w hic h will i ncl u de all visits a n d be 
prese nte d b y treat me nt r ecei ve d d uri n g t he ra n d o m ise d-wit h dra wal peri o d.  
S hift ta bles will be pr o vi de d f or select tests, w here s hift fr o m baseli ne t o t he ma xi m u m val ue 
will be s u m mar ise d. T hese will be pr o vi de d se paratel y f or t he S S O w hic h will be li mite d t o 
visits d uri n g t he o pe n -la bel peri o d a n d t he S S R w hic h will s u m marize t he w orst o verall val ue 
acr oss all visits. S hift ta bles f or la b orat or y val ues b y w orst c o m m o n t o xicit y criteria ( C T C) 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
gra de will be pr o d u ce d f or all para m eters wit h gr a di n g. T hese will be pr o vi de d se paratel y f or 
t he S S O w hic h will be li mite d t o visits d uri n g t he o pe n-la bel peri o d a n d prese nte d b y o pe n-
la bel c o h ort a n d t he S S R w hic h will s u m marize t h e w orst C T C gra de acr oss all visits a n d be 
prese nte d b y treat me nt r ecei ve d d uri n g t he ra n d o m ise d-wit h dra wal peri o d.  
T he t otal n u m ber of s u bj ects wit h e ve nts of h y p o k alae mia ( < 3. 5, < 3. 0 a n d < 2. 5 m E q/ L) a n d 
h y per kala e mia ( > 5. 0, > 5. 5, > 6. 0 a n d > 6. 5 m E q/ L) will be s u m mar ise d, as w ell as t he 
c u m ulati ve c o u nt f or eac h cate g or y. Se p arat e ta bl es will be pr o vi de d f or t h e S S O, restricte d t o 
visits d uri n g t he o pe n -la bel peri o d a n d prese nte d b y o pe n-la bel c o h ort a n d f or t he S S R w hic h 
will i ncl u de all visits a n d be prese nt e d b y treat m e nt recei ve d d uri n g t he ra n d o m ise d-
wit h dra wal peri o d.  
I n a d diti o n, t he n u m ber a n d perce nt a ge of s u bjects wit h mar ke dl y a b n or mal cli nical la b orat or y 
val ues will be s u m mar ise d f or eac h para meter b y ti me p oi nt. T hese will be pr o vi de d se paratel y 
f or t he S S O, w hic h will be li mite d t o visits d uri n g t he o pe n-la bel p eri o d a n d be prese nt e d b y 
o pe n -la bel c o h ort, a n d t h e S S R, w hic h will s u m marize a b n or mal cli nical la b orat or y val ues 
acr oss all visits a n d be prese nte d b y treat me nt recei ve d d uri n g t he ra n d o m is e d-wit h dra wal 
peri o d.  
4. 2. 8. 4  
Vit al Si g ns  
Vital si g n val ues will be s u m mar ise d a n d liste d. Vital si g n data a bs ol ute a n d c ha n ge fr o m 
baseli ne will be s u m mar ise d at eac h sc he d ul e d ti me p oi nt. T he c o nti n u o us vital si g n 
para meters will be s u m mar ise d wit h descri pti ve statistics. If a s u bject has m ulti ple res ults f or a 
partic ular test at a partic ular ti me p oi nt, t he first n o n -missi n g sc he d ule d val u e will be use d f or 
t he s u m mar y. T hese will be pr o vi de d f or t he S S O, li mite d t o visits d uri n g t he o pe n-la bel 
peri o d a n d prese nte d b y o pe n -la bel c o h ort, a n d t h e SS R w hic h will i ncl u de all visits wit h 
sc he d ule d vital si g n assess me nt a n d be pres e nte d b y treat me nt recei ve d d uri n g t he 
ra n d o mise d-wit h dra wal peri o d.  
4. 2. 8. 5  
Electr oc a r di o gr a ms  
E C G data will be s u m mar ise d a n d liste d. A bs ol ute a n d c ha n g e fr o m bas eli ne i n E C G 
para meters will be s u m mar ise d at e ac h sc h e d ule d ti me p oi nt. T he c o nti n u o us E C G para meters 
will be s u m mar ise d wit h descri pti ve statistics. If a s u bject has m ulti ple res ults f or a partic ul ar 
test at a partic ular ti me p oi nt, t he first n o n-missi n g sc he d ule d val ue will be use d f or t he 
s u m mar y. T hese will be pr o vi de d f or t he S S O, li mite d t o visits d uri n g t he o pe n -la bel peri o d 
a n d prese nt e d b y o pe n -la bel c o h ort, a n d t he S S R w hic h will i ncl u de all visits wit h E C G 
assess me nts a n d be prese nte d b y treat me nt r ecei ve d d uri n g t he ra n d o m ise d-wit h dra wal peri o d.  
T he n u m ber a n d p erce nta ge of s u bjects wit h Q Tc F res ults e xcee di n g I C H b o u n daries ( > 4 5 0, 
> 4 8 0, > 5 0 0) a n d wit h i ncreases fr o m baseli ne > 3 0, > 6 0, > 9 0 will be pres e nt e d f or t he S S O, 
li mite d t o visits d uri n g t he o pe n-la bel peri o d a n d prese nte d b y o pe n-la bel c o hort, a n d t he S S R 
w hic h will i ncl u de all visits wit h sc he d ule d E C G assess me nt a n d be prese nt e d b y treat me nt 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
recei v e d d uri n g t he ra n d o mise d-wit h dra wal peri o d. Partici pa nt s are i ncl u d e d base d o n 
ma xi m u m Q Tc F val ue a n d are c o u nt e d i n all a p plica ble cate g ories (e. g. a s u bject wit h a Q Tc F 
val ue of 5 1 0 ms w o ul d be i ncl u de d i n 4 5 0, 4 8 0 a n d 5 0 0 r o ws).  
4. 2. 8. 6  
P h ysic al E x a mi n ati o n  
P h ysical e xa mi nati o n assess me nts w here a ne w or w orse ni n g a b n or m alit y is o bser ve d will be 
re p orte d as a n A E.  
Hei g ht ( Scree ni n g visit o nl y), wei g ht a n d B MI will be s u m mar ise d o ver ti m e b y o pe n -la bel 
c o h ort f or t he S S O, restri cte d t o visits d uri n g t he o pe n -la bel peri o d, a n d b y treat me nt recei ve d 
d uri n g t he ra n d o m ise d-wit h dra wal peri o d usi n g t h e S S R.  
4. 2. 8. 7  
He art F ail ure E ve nts  
F or s u bjects w h o e x peri e nce a h eart fail ure e v e nt, re p orte d as a n A E, t he f oll o wi n g 
i nf or mati o n will be liste d: st u d y da y of A E, treat m e nt gr o u p, I P d ose at A E o nset, a ge, ge n d er, 
ca usalit y assess me nt, N Y H A class at bas eli ne, N Y H A class at A E assess me nt, L V E F % at 
baseli ne, e G F R at A E ass ess me nt, Me d D R A dicti o nar y -deri ve d a n d re p orte d ter m f or t he 
heart fail ure a d v erse e ve nt, se verit y of H F e ve nt ( h os pital ise d/ ur ge nt visit), acti o n ta ke n wit h 
I P ( d os e n ot c ha n g e d, d ose i ncrease d, d ose re d uce d, d ose i nterr u pte d, dr u g per ma ne ntl y 
disc o nti n ue d), a d diti o nal acti o n ta ke n (a d diti o nal/i ncreas e i n I V di uretic t hera p y, I V 
vas oacti ve t hera p y, i nitiati o n of a u g me ntati o n of oral di uretic t hera p y) a n d a d verse e ve nt 
o utc o me (rec o vere d/res ol ve d, rec o v eri n g/res ol vi n g, rec o v ere d/r es ol ve d wit h se q uelae, n ot 
rec o vere d/ n ot res ol v e d, fatal). 
4. 2. 8. 8  
Oe de m a Assess m e nt  
Oe de ma assess me nts w h ere a n e w or w orse ni n g a b n or malit y is o bser ve d will be re p orte d as 
a n A E. F or s u bjects w h o e x perie n ce oe d e ma, re p orte d as a n A E, t he f oll o wi n g i nf or mati o n 
will be liste d: st u d y da y of A E, treat me nt gr o u p, I P d ose at A E o nset, ca us alit y  assess me nt, 
bl o o d press ure (s yst olic/ diast olic)  at last a vaila ble meas ure me nt pri or t o A E o nset , e G F R, 
descri pti o n of oe de m a (l ocati o n & se verit y), acti o n ta ke n wit h I P ( d ose n ot c ha n ge d, d os e 
i ncreas e d, d ose re d uce d, d ose i nterr u pte d, dr u g p er ma ne ntl y disc o nti n ue d), di uretic d ose 
c ha n ge ( d os e n ot c ha n g e d, d ose i ncrease d, d ose re d uce d, d ose i nterr u pte d, dr u g per ma n e ntl y 
disc o nti n ue d),  a n d a d v erse e ve nt o utc o me (rec o vere d/res ol ve d, rec o v eri n g/res ol vi n g, 
rec o vere d/r es ol ve d wit h se q uelae, n ot r ec o v ere d/ n ot res ol ve d, fatal).  
4. 2. 8. 9  
E x p os ure  
E x p os ure (i n da ys) t o i n v esti gati o nal pr o d uct i.e. t otal a m o u nt of st u d y dr u g will be 
s u m marise d b y o pe n -la b el c o h ort f or t he S S O a n d treat me nt gr o u p f or t he S S R. 
Act ual a n d t otal e x p os ure ( da ys) will be s u m mar ise d b y t he f oll o wi n g: mea n, sta n dar d 
de viati o n, mi ni m u m, ma xi m u m, me dia n a n d n u m ber of o bser vati o ns.  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
T he d osa ge ( g/ d a y) will be calc ul ate d f or t he o pe n -la bel peri o d a n d ra n d o mise d-wit h dra wal 
peri o d res pecti vel y:  
T he t otal c u m ulati ve d ose recei ve d ( g)/ N u m ber of da ys recei vi n g st u d y dr u g (i.e. e xcl u di n g 
d ose i nterr u pti o ns)  
S Z C/ Place b o a n d S pir o n olact o ne d osa ge ( g/ da y a n d m g/ da y, res pecti vel y) will be s u m marise d 
b y t he f oll o wi n g: ra n ge, mea n, ra n g e of mea n d oses, me dia n d ose, i nter q uartile ra n ge of d os e. 
T otal c u m ulati ve d ose recei ve d ( g a n d m g, res pecti vel y) will be s u m mar ise d b y mea n a n d 
ra n ge. T h e ra n g e of t he ma xi m u m d ose recei v e d ( g/ da y a n d m g/ da y, res pecti vel y) will be 
s u m marise d. 
F or eac h st u d y visit peri o d (e. g. fr o m visit 1 t o visit 2, visit 2 t o visit 3) t he t otal n u m ber ( %) 
of s u bjects w h o recei ve d d ose will be prese nte d a n d t he prescri b e d dail y d ose. I n or der t o 
deter mi ne t he d ose at st u d y visit x, t he latest e x p os ure rec or d w h ere t he st art date of 
a d mi nistrati o n is less t ha n or e q ual t o t he st u d y visit date will be selecte d. If m ulti ple e x p os ure 
rec or ds e xist f or t he sa m e da y, t he rec or d wit h t he hi g hest d ose will be selecte d. F or 
S Z C/ Place b o t he I P d ose at visit e C R F fiel d wi ll be prese nt e d a n d f or S pir o n olact o ne t he 
prescri be d d os e will be prese nte d.  
F or t he ra n d o m ise d-wit h dra wal peri o d t he t otal n u m ber of s u bjects wit h I P u p -titrate d at a n y 
ti me p oi nt, d o w n-titrate d at a n y p oi nt a n d wit h n o re gistere d c ha n ge will be s u m marize b y 
treat me nt gr o u p f or t he S S R. 
4. 2. 8. 1 0  
Pre g n a nc y Test  
Ser u m pre g na n c y a n d uri ne pre g na n c y test res ults will be liste d o nl y usi n g t he S S O a nal ysis 
set. 
4. 2. 9  
Bi o m ar ker S a m ple C ollecti o n  
T he c ollecti o n of bi o mar ker sa m ples ( N T -pr o B N P a n d ser u m al d oster o ne) will be liste d usi n g 
t he S S O a nal ysis set. 
5  
I N T E RI M A N A L Y S E S 
T his st u d y i ncl u des a D M C, u n bli n de d t o st u d y treat me nt, w h o are res p o nsi ble f or 
safe g uar di n g t he i nterests of st u d y s u bjects, assessi n g safet y of t he i nter ve nti o ns d uri n g t he 
trial, a n d f or m o nit ori n g t he o verall c o n d u ct of t he cli nical trial.  T he D M C will be res p o nsi ble 
f or rec o m me n di n g w het h er t o c o nti n ue or ter mi nate t he trial, a n d f or rec o m me n di n g w het her 
a me n d me nts t o t he pr ot o c ol or c ha n g es i n st u d y c o n d uct are re q uire d.  
D M C meeti n gs are e nr ol me nt dri ve n a n d are t o occ ur at a p pr o xi matel y:  


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
•  1 0 % s u bjects ra n d o m ise d 
•  2 5 % s u bjects ra n d o m ise d 
•  5 0 % s u bjects ra n d o m ise d 
•  7 5 % s u bjects ra n d o m ise d  
 
D M C meeti n g will be hel d at least e ver y si x m o nt hs. F ull details of t he c o m p ositi o n a n d 
res p o nsi bilities of t he c o m mittee are descri be d i n t he D M C c harter. 
T he D M C c o m mittee will n ot e val uate t he efficac y res ults as part of t heir re mit t o safe g uar d 
t he safet y of tri al s u bjects. S o me efficac y ta bles ma y be i ncl u de d i n t he re p orts f or D M C data 
re vie w me eti n gs t o all o w c o nsi derati o n of p ote ntial be nefits i n t he assess me nt of safet y ris ks. 
A s u bset of ta bles, listi n gs a n d fi g ures t o be pre pare d f or eac h D M C r e vie w is i n dicate d i n 
A p pe n di x A. N o f or m al i nteri m a nal yses are pla n ne d f or t his st u d y a n d n o a dj ust me nt is 
re q uire d f or t he t y pe I err or rate. 
6  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L  
T he defi niti o n of t he safet y set o pe n was re vise d. T he pr o t oc ol states t hat t he S S O is defi ne d 
as “ All partici pa nt s w h o e nter t he o pe n-la bel p h ase a n d recei ve at least o ne d ose of S Z C” T his 
was re vise d t o “ All partici pa nt s w h o meet i ncl usi o n/e xcl usi o n criteria a n d e nter t he o pe n-l a bel 
peri o d of t he st u d y a n d recei ve at least o ne d os e of S Z C or S pir o n olact o ne.”  
T he defi niti o n of t he per pr ot oc ol set was re vise d. T he pr ot oc ol states t hat t he P P S is defi ne d 
as “ F A S partici pa nt s wit h o ut a n y i m p orta nt pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m t he 
P P S”. T he P P S is use d f or se nsiti vit y a nal yses of efficac y e n d p oi nts o nl y s o was re vise d t o 
“partici pa nt s i n t he F A S w h o d o n ot ha ve a n y i m p orta nt pr ot oc ol de viati o ns c o nsi dere d t o 
ha ve a maj or effect o n efficac y. ”  
T he pr ot oc ol s u g gests t hat a “ pre-pla n ne d ti p pi n g p oi nt se nsiti vit y a nal ysis” will be use d f or 
t he pri mar y e n d p oi nt a n d t hat “ti p pi n g p oi nt ass u m pti o ns o n res p o nse will var y f or C V-relat e d 
deat hs a n d l oss t o f oll o w -u p b ut sta n dar d missi n g at ra n d o m a p pr o ac h es s uc h as m ulti ple 
i m p utati o n will be use d f or C O VI D-1 9 -relat e d deat hs or l oss t o f oll o w-u p.” M ulti ple 
i m p utati o n is n ot bei n g a p plie d f or t he pri mar y e n d p oi nt a n d a n alter nat e i nterc urre nt e ve nt 
strate g y has bee n descri be d t o e val uate t he i m pact of t he C O VI D -1 9 p a n de mic o n t he pri mar y 
esti ma n d. 
T he pr ot oc ol states t hat a “s u p ple me ntar y a nal ysis will be c o n d ucte d i ncl u di n g a n i nteracti o n 
ter m bet wee n treat me nt a n d a ti me de pe n de nt c o variate of d ose recei ve d ( 5 g e ver y ot her da y, 
5 g dail y, 1 0 g dail y, 1 5 g dail y) t o all o w f or t he effect of d ose t o be assess e d.” Per pr ot oc ol, a n 
i ncreas e i n ser u m p otassi u m s h o ul d lea d t o i ncreas es i n t he d ose of S Z C a n d place b o. As s uc h, 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
ti me-de pe n de nt d ose acts as a me diat or a n d c o nf o u n der a n d will lea d t o biase d esti mates of 
treat me nt effect. T his a n al ysis has bee n u p date d t o i ncl u de d ose recei ve d at baseli ne. 
T he pr ot oc ol states t hat C ha n ge i n P GI C a n d K C C Q sc ores wit h al d oster o ne le vels at E O T 
c o m pare d wit h ra n d o misati o n will be a nal yse d. P GI S is c ollecte d i n t his st u d y s o will be 
i n vesti gate d i nstea d. 
T he a d diti o n of e x pl orat or y e n d p oi nt C ha n ge i n s K + at 7  da ys p ost E O T c o m pare d wit h E O T 
was a d de d t o t he S A P a n d is n ot refere nce d i n t he pr ot oc ol.  
7  
R E F E R E N C E S  
A n gst F, Aesc hli ma n n A, A n gst J. T he mi ni mal cli nicall y i m p orta nt differe nce rais e d t he 
si g nifica nce of o ut c o me effects a b o ve t he st atistical le vel, wit h met h o d ol o gical i m plicati o ns 
f or f ut ure st u dies. J Cli n E pi de mi ol 2 0 1 7; 8 2: 1 2 8– 3 6. 1 0. 1 0 1 6/j.jcli ne pi. 2 0 1 6. 1 1. 0 1 6.  
F D A. F D A G ui d a nce o n C o n d uct of Cli nical Trials of Me dical Pr o d ucts d uri n g C O VI D -1 9 
Pa n de mic: G ui da nce f or I n d ustr y, I n vesti gat ors, a n d I nstit uti o nal Re vie w B oar ds. 
htt ps:// w w w.f da. g o v/ me dia/ 1 3 6 2 3 8/ d o w nl oa d. Accesse d 1 8 N o v 2 0 2 0.  
Hic ks, K. A., Ma haffe y, K. W., Me hra n, R., Nisse n, S. E., Wi vi ott, S. D., D u n n, B., S ol o m o n, 
S. D., Marler, J. R., Teerli n k, J. R., Far b, A. a n d M orr o w, D. A., 2 0 1 8. 2 0 1 7 Car di o vasc ular a n d 
str o ke e n d p oi nt defi niti o ns f or cli nical trials.  J o ur n al of t he A meric a n C olle ge of 
C ar di ol o gy , 7 1 ( 9), p p. 1 0 2 1-1 0 3 4. P oc oc k, S.J., Ariti, C. A., C ollier, T.J. a n d Wa n g, D., 2 0 1 2. 
T he wi n rati o: a ne w a p pr oac h t o t he a n al ysis of c o m p osite e n d p oi nts i n cli nical trials base d 
o n cli nical pri orities. E ur o pea n heart j o ur nal, 3 3( 2), p p. 1 7 6 -1 8 2.  
 
 


Statistical A nal ysis Pla n  
Astra Ze n eca  
D 9 4 8 0 C 0 0 0 1 8  - E xter nal 5. 0  
0 6/ A U G/ 2 0 2 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 7 2  
 
 
A P P E N DI X A: T F L S H E L L S  P R E S E N T E D T O D M C  
T F L N u m ber, Title ( A n al ysis P o p ul ati o n)  
D M C  
T a bl e 1 4. 3. 2. 1: N u m b er of s u bj ects wit h a dv ers e ev e nts i n a n y c at e g ory ( S af et y S et O p e n)  
Y  
T a bl e 1 4. 3. 2. 2: N u m b er of s u bj ects wit h a dv ers e ev e nts i n a n y c at e g ory ( S af et y S et 
R a n d o mis e d)  
Y  
T a bl e 1 4. 3. 2. 5: N u m b er of s u bj ects wit h a dv ers e ev e nts, m ost c o m m o n (fr e q u e nc y of > 5 %), 
by s yst e m or g a n cl ass a n d pr ef err e d t er m ( S af et y S et O p e n)  
Y  
T a bl e 1 4. 3. 2. 6: N u m b er of s u bj ects wit h a dv ers e ev e nts, m ost c o m m o n (fr e q u e nc y of > 5 %), 
by s yst e m or g a n cl ass a n d pr ef err e d t er m ( S af et y S et R a n d o mis e d)  
Y  
T a bl e 1 4. 3. 2. 1 9: N u m b er of s eri o us a d v ers e e v e nts, b y s yst e m or g a n cl ass a n d pr ef err e d 
t er m ( S af et y S et O p e n) 
Y  
T a bl e 1 4. 3. 2. 2 0: N u m b er of s eri o us a d v ers e e v e nts, b y s yst e m or g a n cl ass a n d pr ef err e d 
t er m ( S af et y S et R a n d o mis e d) 
Y  
A p p e n dix 1 6. 2. 4. 1: D e m o gr a p hic a n d b as eli n e c h ar act eristics, S af ety S et O p e n  
Y  
A p p e n dix 1 6. 2. 4. 2: D e m o gr a p hic a n d b as eli n e c h ar act eristics, S af ety S et R a n d o mis e d  
Y  
A p p e n dix 1 6. 2. 4. 4: C o nc o mit a nt m e dic ati o n o n e ntry a n d d uri n g t h e st u dy, S af et y S et O p e n  
Y  
A p p e n dix 1 6. 2. 5. 1: A d mi nistr ati o n of i nv esti g ati o n al pr o d uct, S af et y S et R a n d o mis e d  
Y  
A p p e n dix 1 6. 2. 7. 1: A dv ers e e v e nts pri or t o first d os e of i nv esti g ati o n al pr o d uct, Scr e e n e d 
S et  
Y  
A p p e n dix 1 6. 2. 7. 2: A dv ers e e v e nts aft er disc o nti n u ati o n of i nv esti g ati o n al pr o d uct, 
Scr e e n e d S et  
Y  
A p p e n dix 1 6. 2. 7. 3: A dv ers e e v e nts, Scr e e n e d S et  
Y  
A p p e n dix 1 6. 2. 7. 4: H e art F ail ur e A dv ers e Ev e nts, Scr e e n e d S et  
Y  
A p p e n dix 1 6. 2. 7. 5: O e d e m a -r el at e d A dv ers e Ev e nts, Scr e e n e d S et 
Y  
A p p e n dix 1 6. 2. 8. 1: I n di vi d u al l a b or at or y m e as ur e m e nt, S af ety S et O p e n  
Y  
A p p e n dix 1 6. 2. 9. 1: I n di vi d u al vit al si g ns d at a, S af ety S et O p e n  
Y  
A p p e n dix 1 6. 2. 1 0. 1: El ectr oc ar di o gr a m d at a, S af et y S et O p e n  
Y  
A p p e n dix 1 6. 2. 1 0. 2: A b n or m aliti es i n el ectr oc ar di o gr a m, S af et y S et O p e n  
Y  
D M C T a bl e 1 4. 3. 2. 2. 2: N u m b er of s u bj ects wit h a dv ers e ev e nts i n a ny c at e g ory, pr es e nt e d 
by tr e at m e nt a n d o p e n -l a b el c o h ort gr o u ps ( S af ety S et R a n d o mis e d)  
Y  
D M C T a bl e 1 4. 3. 2. 6. 2: N u m b er of s u bj ects wit h a dv ers e ev e nts, m ost c o m m o n (fr e q u e nc y of 
> 5 %), by s yst e m or g a n cl ass a n d pr ef err e d t er m, pr es e nt e d b y tr e at m e nt a n d o p e n -l a b el 
c o h ort gr o u ps ( S af ety S et R a n d o mis e d)  
Y  
D M C T a bl e 1 4. 3. 2. 2 0. 2: N u m b er of s eri o us a d v ers e e v e nts, by s yst e m or g a n cl ass a n d 
pr ef err e d t er m, pr es e nt e d by tr e at m e nt a n d o p e n -l a b el c o h ort gr o u ps ( S af ety S et 
R a n d o mis e d)  
Y  
D M C T a bl e 1 4. 3. 7. 1. 2. 2: H a e m at ol o gy a n d cli nic al c h e mistry l a b or at or y v ari a bl es o v er ti m e, 
pr es e nt e d by tr e at m e nt a n d o p e n -l a b el c o h ort gr o u ps ( S af ety S et R a n d o mis e d) 
Y  
D M C T a bl e 1 4. 3. 8. 1. 4. 2: E C G v ari a bl es o v er ti m e, pr es e nt e d b y tr e at m e nt a n d o p e n -l a b el 
c o h ort gr o u ps ( S af ety S et R a n d o mis e d)  
Y