Clinical trial NCT04788641
Conditions: Hyperkalaemia
Keywords: Pharmacokinetics Sodium Zirconium Cyclosilicate Tacrolimus Cyclosporin Drug-drug interaction study
Sponsor: AstraZeneca
Start date: 2021-03-30; Completion date: 2021-09-16
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be an open-label, randomised sequence, 2-period, 2-cohort, 2-treatment in each cohort, cross-over study in healthy subjects (males and females of non-childbearing potential), performed at a single study centre.

Detailed description:
The study will comprise:

* A screening period of maximum 28 days;
* Two treatment periods:

  * Treatment Period 1 starts with admission to the Clinical Unit on Day -1, followed by dosing on Day 1 with the assigned treatment (A, B, C, or D) as per assigned cohort and treatment sequence, followed by a washout period of at least 14 days.
  * Treatment Period 2 starts with admission to Clinical Unit on Day -1, followed by dosing on Day 1 with cross-over treatment as per assigned cohort, followed by a follow-up period of 7 to 10 days.
* A follow-up visit/early termination visit at 7 to 10 days after the last investigation medicinal product (IMP) administration.

Subjects will be assigned to either Cohort 1 (tacrolimus) or to Cohort 2 (cyclosporin). Each cohort will have 2 treatment periods. Subjects in each cohort will be randomly assigned to one of 2 treatment sequences (AB\|BA or CD\|DC) where,

* Treatment A: Tacrolimus
* Treatment B: Tacrolimus + SZC
* Treatment C: Cyclosporin
* Treatment D: Cyclosporin + SZC

Arms: arm 1: Subjects in Cohort 1 will be randomised in a 1:1 ratio to receive one of the 2 treatment sequences and then cross-over to the other: tacrolimus alone (treatment A) followed by the combination treatment of tacrolimus and SZC (treatment B) or vice versa. arm 2: Subjects in Cohort 2 will be randomised in a 1:1 ratio to receive one of the 2 treatment sequences and then cross-over to the other: cyclosporin alone (treatment C) followed by the combination treatment of cyclosporin and SZC (treatment D) or vice versa.
Interventions: intervention 1: Tacrolimus intervention 2: Cyclosporin intervention 3: Sodium Zirconium Cyclosilicate
Intervention descriptions: intervention 1: Each subject in this cohort will receive a single dose of oral capsules of tacrolimus on 2 occasions, once alone and once in combination with oral suspension of SZC. Drug administrations will occur after a 12 hour overnight fast. intervention 2: Each subject will receive a single dose of oral capsules of cyclosporin on 2 occasions, once alone and once in combination with oral suspension of SZC. Drug administrations will occur after a 12 hour overnight fast. intervention 3: Each subject will receive single oral doses of SZC with tacrolimus (cohort 1) or cyclosporin (cohort 2) under fasted conditions. The doses will be administered after an overnight fast of at least 12 hours.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Report Appendices 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
09 Feb 2022 
CONFIDENTIAL AND PROPRIETARY 
16.1 
STUDY INFORMATION 
16.1.1 
Protocol, Protocol Amendments 
16.1.1.1 
Protocol 
Document included: 
•
Clinical Study Protocol, Version 1.0, dated 28 Sep 2020
16.1.1.2 
Protocol Amendments 
Not Applicable 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
1 of 8 5  
Cli nic al St u d y Pr ot oc ol  
A T w o -C o h ort, R a n d o mi se d Se q ue nce, Cr oss -o ver, O pe n -l a bel 
S t u d y t o A ssess t h e E ffe ct of a Si n gl e D ose of S o di u m Zirc o ni u m 
C ycl osilic ate ( S Z C) o n t he P h ar m a c o ki netics of T acr oli m us a n d 
C ycl os p ori n i n He alt h y S u bjects 
P are xel  St u d y N o .: 
 
S p o ns or St u d y C o de:  
D 9 4 8 0 C 0 0 0 1 2  
E u dr a C T N o .: 
2 0 2 0 -0 0 0 5 1 5 -6 8  
St u d y T y pe  
Dr u g -dr u g i nteracti o n ( D DI) st u d y 
Test Pr o d uct:  
S o di u m zirc o ni u m c ycl osilicate / S Z C 
I nter acti o n Pr o d uct s: 
Tacr oli m us  a n d c ycl os p ori n 
T her a pe utic I n dic ati o n:  
H y per kalae mia  
P h ar m ac ol o gic al Cl ass:  
N o n -p ol y mer, i n or ga nic cati o n -e xc ha n ger 
De vel o p m e nt P h ase:  
P hase I 
S p o ns or:  
Astra Ze neca A B  
1 5 1 8 5 S ö dertälje  
S we de n  
St u d y Ce ntr e: 
Pare xel I nter nati o nal G m b H  
  
 
 
1 4 0 5 0 Berli n  
Ger ma n y  
D ate of Pr ot oc ol:  
Fi nal  1. 0, 2 8  Se pte m ber  2 0 2 0  
 
T his cli nical st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m plia nce wit h G o o d Cli nical 
Practice, wit h t he Declarati o n of Helsi n ki a n d wit h ot her a p plica ble re g ulat or y re q uire me nts. 
C o nfi de ntialit y State me nt 
T his c o nfi de ntial d oc u me nt is t he pr o pert y of Astra Ze neca. N o u n p u blis he d i nf or mati o n c o ntai ne d 
herei n ma y be discl ose d wit h o ut pri or writte n a p pr o val fr o m Astra Ze neca. Access t o t his d oc u me nt 
m ust be restricte d t o rele va nt parties . 
C CI
P P D


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
2 of 8 5  
P R O T O C O L S Y N O P SI S  
Title of t he St u d y  
A T w o - C o h ort, Ra n d o mise d Se q ue nce, Cr oss - o ver, O pe n-la b el St u d y t o Assess t he Effect of a 
Si n gle D ose of S o di u m Zirc o ni u m C ycl osilicate ( S Z C) o n t he P har mac o ki n etics of 
Tacr oli m us a n d C ycl os p ori n i n Healt h y S u bjects 
 
Pri nci p al I n vesti g at or 
Dr . T h o mas K oer nic ke 
 
St u d y Ce ntr e 
T his st u d y will be c o n d ucte d at a si n gle st u d y ce ntre: 
Pare xel I nter nati o nal G m b H 
  
 
1 4 0 5 0 Berli n 
Ger ma n y  
 
St u d y R ati o n ale 
S o di u m zirc o ni u m c ycl osilicate  ( S Z C), is a n oral, n o n- p ol y mer i n or ga nic cati o n-e xc ha n g er 
t hat has bee n a p pr o ve d as a n o vel t hera p y f or t he treat me nt of h y p er kalae mia. It s electi vel y 
ca pt ures p otassi u m i o ns i n e xc ha n g e f or s o di u m a n d h y dr o ge n i o ns i n t he gastr oi ntesti nal 
l u me n, t here b y r e d uci n g ser u m p otassi u m c o nce ntrati o n a n d re m o vi n g p otassi u m fr o m t he 
b o d y t hr o u g h i ncreas e d f aecal e xcr eti o n. S o di u m zirc o ni u m c ycl osilicate  e xerts its effect 
l ocall y a n d is n ot a bs or be d s yste micall y. D ue t o its i ns ol u ble, i n or ga nic, a n d  cr ystalli ne 
pr o perties, S Z C is n ot a bs or be d or meta b olise d b y t he b o d y a n d t heref ore n o meta b olic or 
tra ns p orter-b ase d dr u g - dr u g i nteracti o ns (D DIs ) are a ntici pate d i n ass o ciati o n wit h S Z C 
treat me nt. H o we v er, S Z C ca n bi n d t o h y dr o ge n i o ns w hic h ma y res ult i n i ncreas e d p H i n 
aci dic e nvir o n me nts s uc h as t he st o mac h. I n ge n eral, a n i ncrease i n gastri c p H ca n alter t he 
s ol u bilit y of dr u gs wit h p H- de pe n d e nt s ol u bilit y a n d ma y res ult i n a n altere d a bs or pti o n 
pr ofile  of t he dr u gs. Res ults fr o m a P hase 1 st u d y perf or me d i n h ealt h y s u bjects t o e xa mi ne 
t he p ote ntial f or D DIs b et wee n S Z C a n d a set of 9 c o m p o u n ds s h o we d t hat c o- a d mi nistrati o n 
of S Z C affect e d t he p har mac o ki netics ( P K ), pri m aril y t he C ma x val ues, of 5 c o m p o u n ds 
teste d (St u d y Z S- 0 0 9). 
 
T his st u d y will i n vesti gate if t he P K of tacr oli m us a n d c ycl os p ori n ma y b e altere d b y t he 
i ncreas e d gastric p H res ulti n g fr o m S Z C c o-a d mi nistrati o n . 
 
N u m ber of S u bjects Pl a n ne d  
A t otal of 6 0 s u bjects will be ra n d o mis e d ( 3 0 per c o h ort) t o e ns ure at least 5 6  e val ua ble 
s u bjects ( 2 8 s u bjects per c o h ort) at t he e n d of t he l ast treat me nt peri o d . 
 
St u d y Peri o d  
Esti mate d date of first s u bject e nr olle d:  Dece m ber  2 0 2 0 (si g ni n g of i nf or me d c o nse nt). 
Esti mate d date of last s u bject c o m plete d:  Marc h  2 0 2 1. 
P P D


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
3 of 8 5  
St u d y O bjecti ves  
Pri m ary O bjective:  
•  
T o assess t h e effect of c o -a d mi nistere d S Z C o n t he P K of tacr oli m us a n d c ycl os p ori n i n 
healt h y s u bjects as des cri be d b y C ma x a n d A U C i nf. 
Sec o n d ary O bjectives : 
•  
T o assess t he effect of c o -a d mi nistere d S Z C o n t he P K of tacr oli m us a n d c ycl os p ori n i n 
healt h y s u bjects, as des cri be d b y A U C last, t ½λ z, a n d t ma x. 
•  
T o e xa mi ne t he safet y a n d t olera bilit y of c o-a d mi nistrati o n of S Z C a n d 
tacr oli m us/c ycl os p ori n as c o m pare d t o tacr oli m us/c ycl os p ori n al o ne i n healt h y 
v ol u nteers. 
 
St u d y Desi g n  
T his st u d y will be a n o pe n-la bel, ra n d o mis e d s e q u e nce, 2- p eri o d, 2-c o h ort, 2-treat me nts i n 
eac h c o h ort , cr oss- o ver st u d y i n healt h y s u bjects ( males a n d fe m ales of n o n-c hil d beari n g 
p ote ntial), perf or me d at a si n gle st u d y ce ntre. 
 
T he st u d y will c o m prise: 
•  
A scree ni n g peri o d of ma xi m u m 2 8 da ys; 
•  
T w o t reat me nt peri o ds: 
− 
Treat me nt Peri o d  1 starts wit h a d missi o n t o t he Cli nical U nit o n Da y  - 1, f oll o we d b y 
d osi n g o n Da y 1 wit h t he assi g ne d treat me nt ( A, B, C, or D) as per assi g ne d c o h ort 
a n d treat me nt se q u e nce, f oll o we d b y a was h o ut peri o d of at least 1 4  da ys. S u bjects 
will be disc har ge d fr o m t he Cli nical U nit after t he last P K sa m ple was c ollecte d  f or 
t his treat me nt peri o d (D a y  4). 
− 
Treat me nt Peri o d  2 starts wit h a d missi o n t o Cli nical U nit o n Da y  - 1, f oll o w e d b y 
d osi n g o n Da y 1 wit h cr oss- o ver treat me nt as per assi g ne d c o h ort, f oll o we d b y a 
f oll o w- u p peri o d of 7 t o 1 0 da ys. S u bjects will be disc har ge d fr o m t he Cli nical U nit 
after t he l ast P K sa m ple was c ollecte d f or t his treat me nt peri o d ( D a y 4). 
•  
A f oll o w- u p visit/earl y ter mi nati o n visit  at 7 t o 1 0 da ys after t h e last I M P a d mi nistrati o n.  
 
S u bjects will be assi g ne d t o eit her C o h ort 1 (tacr oli m us) or t o C o h ort 2 (c ycl os p ori n). Eac h 
c o h ort will ha ve 2 treat me nt peri o ds. S u bjects i n eac h c o h ort will be ra n d o ml y assi g ne d t o o ne 
of 2  treat me nt se q u e nces ( A B| B A or C D| D C) w here, 
•  
Treat me nt A: Tacr oli m us   
. 
•  
Treat me nt B: Tacr oli m us 
 + S Z C  
. 
•  
Treat me nt C: C ycl os p ori n   
. 
•  
Treat me nt D: C ycl os p ori n  
 + S Z C  
. 
 
S u bjects w h o ha ve r ecei v e d Treat me nt A i n Treat me nt Peri o d  1 of C o h ort 1 will recei ve 
Treat me nt B i n Treat me nt Peri o d  2 a n d vice versa. S u bjects w h o ha ve recei ve d Treat me nt  C 
C CI
C CI
C CI
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
4 of 8 5  
i n Treat me nt Peri o d  1 of C o h ort  2 wi ll recei ve Treat me nt D i n Treat me nt P eri o d  2 a n d vice 
versa . 
 
Eac h s u bject will recei ve a si n gle d ose of oral  ca ps ules of tacr oli m us  
/c ycl os p ori n 
 o n 2 occasi o ns, o nce al o ne a n d o nce i n c o m bi nati o n wit h oral s us pe nsi o n of S Z C  
. All dr u g a d mi nistrati o ns will occ ur after a 1 2  h o ur o ver ni g ht fast. 
 
E x pecte d D ur ati o n of t he St u d y  
T he e x pecte d t otal st u d y d urati o n, i ncl u di n g t he scree ni n g peri o d, f or eac h s u bject will be at 
least 5 8 da ys ( 8 w ee ks) . 
 
T ar gete d St u d y P o p ul ati o n 
T his st u d y will be c o n d ucte d i n healt h y  male a n d fe male  s u bjects of n o n-c hil d beari n g 
p ote ntial, 1 8 t o 5 0 years of a ge . 
 
I n vesti g ati o n al Me dici n al Pr o d ucts 
I n vesti g ati o n al Me dici n al 
Pr o d uct N a m e  
S o di u m Zirc o ni u m 
C ycl osilic ate  
T acr oli m us  
C ycl os p ori n  
Tra de Na me : 
L o kel ma ™ 
Pr o graf  
Sa n di m m u n 
Ne oral / O pt oral 
Ma n ufact urer : 
Astra Ze neca  
Astellas P har ma  
N o vartis  
F or m ulati o n:  
P o w der f or oral s us pe nsi o n 
Har d ca ps ules  
S oft ca ps ules  
Stre n gt h/c o nce ntrati o n:  
 sac het 
 
 
D ose:  
 
 
 
R o ute of a d mi nistrati o n:  
Oral  
Oral  
Oral  
S pecific de vice f or dr u g 
a d mi nistrati o n, if a p plica ble: 
N ot a p plica ble  
N ot a p plica ble  
N ot a p plica ble  
Re gi me n:  
Si n gle d ose  of  
 c o nsisti n g 
of 3  sac hets s us pe n de d i n 
4 5  m L of water  
Si n gle d ose of  
 
Si n gle d ose of 
 
S pecial ha n dli n g re q uire me nts:  
N ot a p plica ble  
N ot a p plica ble  
N ot a p plica ble  
 
 
O utc o m e E n d p oi nts  
 
P h ar m ac o ki netic E n d p oi nts: 
W here p ossi ble, P K p ara meters will be assesse d f or tacr oli m us a n d c y cl os p ori n o n w h ole 
bl o o d sa m ples. 
•  
Pri mar y P K para meters: C ma x, A U C i nf 
− 
A U C i nf a n d C ma x meas ure d f or eac h s u bj ect  a n d eac h visit o n w hic h P K data are 
c ollecte d. 
•  
Sec o n dar y P K para meters: A U C last, t ½ λz, t ma x 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Clinical Study Protocol 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
CONFIDENTIAL AND PROPRIETARY 
5 of 85 
− 
AUClast, t½λz, and tmax measured for each subject and each visit on which PK data 
are collected. 
 
Additional PK parameters may be determined where appropriate. 
 
Safety and Tolerability Endpoints: 
Safety and tolerability variables will include 
• 
Adverse events, vital signs (systolic and diastolic BP, pulse, and tympanic temperature), 
12-lead ECGs, laboratory assessments (haematology, clinical chemistry, and urinalysis). 
 
Statistical Methods 
 
Presentation and Analysis of Pharmacokinetic Data: 
All PK concentration, parameter summaries and statistical analyses will be presented for the 
PK analysis set, unless otherwise specified. The PK concentration and parameter listings will 
be presented for the safety analysis set and will include all reportable individual PK results. 
Individual PK concentration and parameter data for any subjects not included in the PK 
statistical analyses will be included in the listings and flagged with an appropriate footnote. 
 
A listing of PK blood sample collection times, as well as derived sampling time deviations 
and concentrations at each protocol scheduled time point will be provided. Whole blood 
concentrations will be summarised by treatment and nominal time points descriptively. The 
PK parameters will be summarised by treatment using appropriate descriptive statistics. 
 
Individual concentrations with time deviations of ≥ ±10% from the protocol scheduled time, 
will be used in the PK analysis but will be flagged for exclusion from the summary tables and 
corresponding figures. 
 
Protocol scheduled times will be used to present the PK concentration summary tables and 
corresponding gmean concentration-time figures. 
 
Presentation and Analysis of Safety and Eligibility Data: 
All safety data (scheduled and unscheduled) will be presented in the data listings. Continuous 
variables will be summarised using descriptive statistics (n, mean, SD, minimum, median, 
maximum). Categorical variables will be summarised in frequency tables (frequency and 
proportion). The analysis of the safety variables will be based on the safety analysis set. 
 
Adverse events will be summarised by system organ class (SOC) and preferred term (PT) 
using MedDRA vocabulary. Furthermore, listings of SAEs and AEs that led to withdrawal 
will be made and the number of subjects who had any AE, SAEs, AEs that led to withdrawal, 
and AEs with severe intensity will be summarised. Serious adverse events that occur before 
dosing will be reported separately. 
 
Tabulations and listings of data for vital signs, clinical laboratory tests and ECGs will be 
presented. Any new or aggravated clinically relevant abnormal medical physical examination 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
6 of 8 5  
fi n di n g c o m pare d t o t he baseli ne assess me nt will be re p ort e d as a n A E. Data will be 
s u m marise d f or t he o bser ve d val ues at eac h s c he d ule d assess me nt, t o get her wit h t he 
c orres p o n di n g c ha n ges  (a n d/ or perce nta ge c ha n ge) fr o m t he baseli ne w h e n baseli ne val ue 
e xists. Cli nical la b orat or y data will be re p orte d i n S ystè me I nter nati o nal u nits i n t he C S R.  
 
O ut - of-r a n ge val u es f or s afet y la b orat or y will be fl a g ge d i n i n di vi d ual listi n gs as well as 
s u m marise d descri pti vel y usi n g a gree d sta n d ar d refere nce ra n g es a n d/ or e xte n de d refere nce 
ra n ges ( e g, A Z pr o gra m, or la b orat or y ra n ges). 
 
S a m ple Size  Deter mi n ati o n  
 
 
 
 
 
 
 
 
C CI


Clinical Study Protocol 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
CONFIDENTIAL AND PROPRIETARY 
7 of 85 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 7 
List of Tables ........................................................................................................................... 10 
List of Figures .......................................................................................................................... 10 
List of Appendices ................................................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 12 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .............................. 15 
1. 
INTRODUCTION ................................................................................................ 18 
1.1. 
Background ........................................................................................................... 18 
1.1.1. 
Background to COVID-19 .................................................................................... 18 
1.2. 
Rationale for Conducting this Study .................................................................... 19 
2. 
STUDY OBJECTIVES ........................................................................................ 20 
2.1. 
Primary Objective ................................................................................................. 20 
2.2. 
Secondary Objective ............................................................................................. 20 
3. 
STUDY DESIGN ................................................................................................. 21 
3.1. 
Overall Study Design and Flow Chart .................................................................. 21 
3.1.1. 
Order of Assessments ........................................................................................... 26 
3.1.2. 
End of Study ......................................................................................................... 26 
3.1.3. 
Expected Duration of the Study ............................................................................ 26 
3.2. 
Rationales for Study Design and Dose Selection ................................................. 26 
3.2.1. 
Rationale for Study Design ................................................................................... 26 
3.2.2. 
Dose Rationale ...................................................................................................... 27 
3.3. 
Risk-benefit Assessment ....................................................................................... 27 
3.3.1. 
Risks ..................................................................................................................... 27 
3.3.1.1. 
Risks Associated with SZC .................................................................................. 27 
3.3.1.2. 
Risks Associated with Tacrolimus........................................................................ 28 
3.3.1.3. 
Risks Associated with Cyclosporin ...................................................................... 28 
3.3.2. 
Benefits ................................................................................................................. 29 
3.3.3. 
Risk Assessment for COVID-19 Pandemic .......................................................... 29 
4. 
STUDY POPULATION ....................................................................................... 31 
4.1. 
Selection of Study Population .............................................................................. 31 
4.1.1. 
Inclusion Criteria .................................................................................................. 31 
4.1.2. 
Exclusion Criteria ................................................................................................. 31 
4.2. 
Restrictions During the Study ............................................................................... 34 
4.2.1. 
Reproductive Restrictions ..................................................................................... 35 
4.2.1.1. 
Women of Non-childbearing Potential ................................................................. 35 
4.2.1.2. 
Male Subjects........................................................................................................ 35 
4.3. 
Replacement of Subjects....................................................................................... 37 


Clinical Study Protocol 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
CONFIDENTIAL AND PROPRIETARY 
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5. 
STUDY CONDUCT ............................................................................................. 38 
5.1. 
Subject Enrolment and Randomisation ................................................................ 38 
5.1.1. 
Procedures for Randomisation .............................................................................. 38 
5.2. 
Procedures for Handling Incorrectly Enrolled Subjects ....................................... 39 
5.3. 
Blinding ................................................................................................................ 39 
5.4. 
Treatments ............................................................................................................ 39 
5.4.1. 
Identity of the Investigational Medicinal Product ................................................ 39 
5.4.2. 
Supply of Investigational Medicinal Product ....................................................... 40 
5.4.3. 
Dose and Treatment Regimens ............................................................................. 40 
5.4.4. 
Labelling ............................................................................................................... 40 
5.4.5. 
Storage and Handling Procedures ......................................................................... 41 
5.5. 
Concomitant and Post-study Treatment(s) ........................................................... 41 
5.6. 
Treatment Compliance.......................................................................................... 41 
5.6.1. 
Drug Accountability, Dispensing and Destruction ............................................... 41 
5.7. 
Discontinuation of Investigational Product and Withdrawal from Study ............ 42 
5.7.1. 
Procedures for Withdrawal of a Subject from the Study ...................................... 43 
5.7.2. 
Procedures for Lost to Follow-up ......................................................................... 43 
5.8. 
Premature Termination of the Study..................................................................... 43 
6. 
COLLECTION OF STUDY VARIABLES ......................................................... 45 
6.1. 
Recording of Data ................................................................................................. 45 
6.2. 
Enrolment and Screening Procedures ................................................................... 45 
6.3. 
Safety and Eligibility Measurements .................................................................... 45 
6.3.1. 
Adverse Events ..................................................................................................... 45 
6.3.1.1. 
Definition of Adverse Events ............................................................................... 45 
6.3.1.2. 
Definitions of Serious Adverse Event .................................................................. 46 
6.3.1.3. 
Other Significant Adverse Events ........................................................................ 46 
6.3.1.4. 
Recording of Adverse Events ............................................................................... 47 
6.3.1.5. 
Reporting of Serious Adverse Events ................................................................... 50 
6.3.1.6. 
Regulatory Reporting Requirements for SAEs..................................................... 50 
6.3.2. 
Clinical Laboratory Assessments ......................................................................... 51 
6.3.2.1. 
Haematology ......................................................................................................... 51 
6.3.2.2. 
Serum Clinical Chemistry..................................................................................... 51 
6.3.2.3. 
Urinalysis .............................................................................................................. 51 
6.3.2.4. 
Viral Serology and SARS-CoV-2 Virology ......................................................... 52 
6.3.2.5. 
Drugs of Abuse, Alcohol and Cotinine................................................................. 52 
6.3.3. 
Physical Examination ........................................................................................... 52 
6.3.4. 
Resting 12-lead Electrocardiogram ...................................................................... 52 
6.3.5. 
Vital Signs ............................................................................................................ 53 
6.4. 
Pharmacokinetics .................................................................................................. 53 
6.4.1. 
Collection of Pharmacokinetic Samples ............................................................... 53 
6.4.2. 
Pharmacokinetic Drug Assays .............................................................................. 53 
7. 
BIOLOGICAL SAMPLES PROCEDURES ........................................................ 54 
7.1. 
Total Blood Volume ............................................................................................. 54 


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7.2. 
Handling, Storage and Destruction of Biological Samples .................................. 54 
7.2.1. 
Pharmacokinetic Samples ..................................................................................... 54 
7.3. 
Labelling and Shipment of Biohazard Samples.................................................... 55 
7.4. 
Chain of Custody of Biological Samples.............................................................. 55 
7.5. 
Withdrawal of Informed Consent for Donated Biological Samples ..................... 55 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 56 
8.1. 
Ethical Conduct of the Study ................................................................................ 56 
8.2. 
Subject Data Protection ........................................................................................ 56 
8.3. 
Ethics and Regulatory Review.............................................................................. 56 
8.4. 
Insurance ............................................................................................................... 56 
8.5. 
Informed Consent ................................................................................................. 57 
8.6. 
Changes to the Protocol and Informed Consent Form.......................................... 57 
9. 
DATA QUALITY ASSURANCE AND DATA MANAGEMENT .................... 58 
9.1. 
Quality Control and Source Data Verification ..................................................... 58 
9.2. 
Audit/Inspections .................................................................................................. 58 
9.3. 
Study Monitoring .................................................................................................. 58 
9.4. 
Data Collection ..................................................................................................... 58 
9.4.1. 
Case Report Forms and Source Documents ......................................................... 59 
9.4.2. 
Access to Source Documents................................................................................ 59 
9.5. 
Data Management ................................................................................................. 59 
10. 
EVALUATION AND CALCULATION OF VARIABLES ................................ 61 
10.1. 
Safety Variables .................................................................................................... 61 
10.1.1. 
Adverse Events ..................................................................................................... 61 
10.1.2. 
Laboratory Assessments ....................................................................................... 62 
10.1.3. 
Physical Examination ........................................................................................... 63 
10.1.4. 
Resting 12-lead Electrocardiogram ...................................................................... 63 
10.1.5. 
Vital Signs ............................................................................................................ 64 
10.2. 
Pharmacokinetics .................................................................................................. 64 
10.2.1. 
Whole Blood Pharmacokinetic Parameters .......................................................... 64 
10.2.2. 
Calculation or Derivation of Pharmacokinetic Parameters .................................. 65 
11. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........... 67 
11.1. 
Description of the Analysis Sets ........................................................................... 67 
11.1.1. 
Safety Analysis Set ............................................................................................... 67 
11.1.2. 
Pharmacokinetic Analysis Set .............................................................................. 67 
11.1.3. 
Randomised Set .................................................................................................... 67 
11.2. 
Methods of Statistical Analyses............................................................................ 67 
11.2.1. 
General Principles ................................................................................................. 67 
11.2.2. 
Missing Data ......................................................................................................... 69 
11.2.3. 
Subject Disposition ............................................................................................... 69 
11.2.3.1. 
Demographic and Baseline Data .......................................................................... 69 
11.2.4. 
Prior and Concomitant Medication and Drug Administration ............................. 70 


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11.2.4.1. 
Prior and Concomitant Medication ....................................................................... 70 
11.2.4.2. 
Drug Administration ............................................................................................. 70 
11.2.5. 
Safety and Tolerability ......................................................................................... 70 
11.2.6. 
Pharmacokinetics .................................................................................................. 71 
11.2.6.1. 
Graphical Presentation of Pharmacokinetic Data ................................................. 71 
11.2.6.2. 
Statistical Analysis of Pharmacokinetic Data ....................................................... 72 
11.3. 
Protocol Deviations .............................................................................................. 72 
11.4. 
Determination of Sample Size .............................................................................. 73 
12. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................. 74 
12.1. 
Medical Emergencies and AstraZeneca Contacts................................................. 74 
12.2. 
Pregnancy ............................................................................................................. 74 
12.2.1. 
Paternal Exposure ................................................................................................. 75 
13. 
LEGAL AND ADMINISTRATIVE ASPECTS .................................................. 76 
13.1. 
Archiving of Study Documents ............................................................................ 76 
13.2. 
Publication of Study Results ................................................................................. 76 
13.3. 
Clinical Study Report ........................................................................................... 76 
14. 
REFERENCE LIST .............................................................................................. 77 
15. 
APPENDICES ...................................................................................................... 78 
 
List of Tables 
Table 1 
Primary Objective and Outcome Measures ................................................. 20 
Table 2 
Secondary Objective and Outcome Measures ............................................. 20 
Table 3 
Schedule of Assessments ............................................................................ 24 
Table 4 
Expected Duration of Each Study Part ........................................................ 26 
Table 5 
Identity of the Investigational Medicinal Product ....................................... 39 
Table 6 
Total Blood Volume .................................................................................... 54 
 
List of Figures 
Figure 3-1 
Study Flow Chart ........................................................................................ 23 
Figure 3-2 
Overall Graphical Representation of the Study .......................................... 23 
 
 
 


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List of Appendices 
Appendix A 
Additional Safety Information .................................................................... 78 
Appendix B 
International Airline Transportation Association 6. 2 Guidance 
Document .................................................................................................... 80 
Appendix C 
Actions Required in Cases of Combined Increase of Aminotransferase 
and Total Bilirubin - Hy’s Law ................................................................... 81 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Please note that definitions of abbreviations for pharmacokinetic variables are also presented 
in Section 10.2.1 of this protocol. 
Abbreviation or 
special term 
Explanation 
AE(s) 
Adverse event(s) (see definition in Section 6.3.1.1) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs 
and Medical Devices) 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
CI 
Confidence interval  
ClinBase™ 
Parexel's electronic source data capturing and information management system 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CRO 
Contract research organisation 
CRP 
C-reactive protein 
CSP 
Clinical study protocol 
CSR 
Clinical study report  
CV 
Coefficient of variation 
DCF 
Data clarification form 
DDI 
Drug-drug interaction 
DILI 
Drug induced liver injury 
DMP 
Data management plan 
DNA 
Deoxyribonucleic acid 
DVS 
Data validation specification 
ECG 
Electrocardiogram 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 


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Abbreviation or 
special term 
Explanation 
GCP 
Good Clinical Practice 
gCV 
Geometric mean of CV 
gmean 
geometric mean  
GMP 
Good Manufacturing Practice 
h 
hour(s) 
Hb 
Haemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCT 
Haematocrit 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
IATA 
International Airline Transportation Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMPs 
Investigational medicinal products 
IRB 
Institutional Review Board 
LLOQ 
Lower limit of quantification 
LSM 
Least-squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
OAE 
Other significant adverse events 
OTC 
Over-the-counter 
PD 
Pharmacodynamics 
PDF 
Portable Document Format 
PHL 
Potential Hy’s Law 
PK 
Pharmacokinetics 
PT  
Preferred term 
qd 
Once daily 
QRS 
ECG interval measured from the onset of the QRS complex to the J point 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T 
wave 
QTcB 
QT interval corrected for heart rate using Bazett's formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R&D 
Research and Development 
RR 
The time between corresponding points on 2 consecutive R waves on ECG 


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Abbreviation or 
special term 
Explanation 
SAE 
Serious adverse event (see definition in Section 6.3.1.2).  
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of assessments 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SUSAR 
Serious unsuspected serious adverse reaction 
SZC 
Sodium zirconium cyclosilicate  
TBL 
Total bilirubin 
UK 
United Kingdom 
ULN 
Upper limit of normal 
US/USA 
United States of America 
WAD 
Windows Allowance Document 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
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 8 5  
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E  
S p o ns or:  
Astra Ze neca A B  
1 5 1 8 5 S ö dertälje  
S we de n  
S p o ns or’s Lea d P h ysicia n:  
 
Astra Ze neca P har mace uticals  
 
4 3 1 5 3 M öl n dal  
S we de n  
Tel: 
 
M o bile: 
 
S p o ns or’s Bi ostatisticia n:  
 
Astra Ze neca R & D G ot he n b ur g  
 
4 3 1 5 3 M öl n dal  
S we de n  
Tel: 
 
M o bile: 
 
Pri nci pal I n vesti gat or:  
Dr. T h o mas K oer nic ke  
Pare xel  Earl y P hase Cli nical U nit Berli n  
 
 
1 4 0 5 0 Berli n  
Ger ma n y  
Tel: 
 
De p ut y Pri nci pal I n vesti gat or : 
 
Pare xel Earl y P hase Cli nical U nit Berli n  
 
 
1 4 0 5 0 Berli n  
Ger ma n y  
Tel: 
 
C o ntract R esearc h O r ga nisati o n: 
Pare xel  Earl y P hase Cli nical U nit Berli n  
 
 
1 4 0 5 0 Berli n  
Ger ma n y  
Tel: 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
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 8 5  
Cli nical La b orat or y:  
S y nla b Cli nical Trial G m b H  
 
1 0 5 5 9 Berli n  
Ger ma n y  
C o ntact:  
 
Tel: 
 
Fa x: 
 
E- mail: 
 
Pare xel Cli nical La b orat or y : 
 
La b orat or y Ma na ger  
Pare xel Earl y P hase Cli nical U nit Berli n  
 
 
1 4 0 5 0 Berli n  
Ger ma n y  
Tel: 
 
Fa x: 
 
P har mac y : 
H u bert us A p ot he ke a m Salz ufer  
 
1 0 5 8 7 Berli n  
Ger ma n y  
C o ntact pers o ns: 
 
Tel:  
 
E mail:  
 
  
 
 
A nal ytical La b orat or y:  
( p har mac o ki netic sa m ple a nal ysis) 
Bi oa nal ytical C he mistr y  
C o va nce La b orat ories, I nc . 
 
 Wisc o nsi n 5 3 7 0 4 
U S A  
C o ntact:  
 
Bi oa nal ytical Part ners hi p Pr o gra m Ma na ger  
C o va nce La b orat ories I nc . 
Tel: 
 
Fa x: 
 
e-mail: 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
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 8 5  
A d verse E ve nt Re p orti n g:  
Astra Ze neca Patie nt Safet y Data E ntr y Site  
Tata C o ns ulta nc y Ser vices  
Fa x: 
 
E- mail: 
 
 
A list a n d c o ntact details of I n vesti gat ors a n d ot her ke y st u d y tea m me m bers are pr o vi de d i n 
t he Pr oject Pla n i n t he electr o nic I n v esti gat or’s Site File. A list of all partici pati n g 
I n v esti gat ors will be pr o vi de d i n t he C S R. 
P P D
P P D


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1. 
INTRODUCTION 
1.1. 
Background 
Despite the association of hyperkalaemia with morbidity and mortality; and its high 
prevalence in common diseases, such as diabetes, chronic kidney disease, heart failure, and in 
patients on renin angiotensin aldosterone system (RAAS) inhibitor therapy, the treatment 
options available are limited and associated with significant safety and tolerability issues. 
Sodium zirconium cyclosilicate (SZC) is an oral, non-polymer, inorganic cation-exchanger 
that has been approved as a novel therapy for the treatment of hyperkalaemia. It selectively 
captures potassium ions in exchange for sodium and hydrogen ions in the gastrointestinal 
tract, thereby reducing serum potassium concentration and removing potassium from the body 
through increased faecal excretion. Sodium zirconium cyclosilicate exerts its effect locally 
and it is not absorbed systemically. Clinical use is therefore not associated with systemic 
toxicity. The formulation developed for therapeutic use is an insoluble, odourless, tasteless, 
white, powder for oral suspension. 
The efficacy of SZC in correcting hyperkalaemia and maintaining normokalaemia long term, 
irrespective of underlying morbidity, and its favourable safety profile have been well 
documented in the clinical programme. Sodium zirconium cyclosilicate has a rapid onset of 
effect and it maintains normokalaemia for up to 12 months. Unlike other oral drugs for 
hyperkalaemia (eg, resins and Patiromer), SZC is highly selective for potassium ions and its 
use is not associated with any clinically significant changes in the concentrations of other 
electrolytes such as calcium or magnesium. 
All in all, SZC fulfils an unmet medical need; and provides an efficacious and safe therapeutic 
option for patients with hyperkalaemia. 
1.1.1. 
Background to COVID-19 
There is currently an outbreak of respiratory disease (COVID-19) caused by the novel SARS 
CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new virus 
has rapidly spread across the globe causing the WHO to declare a pandemic situation on 
11 March 2020. The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new 
clinical studies. As the threat of pandemic burden, including new outbreaks locally or 
globally, will impact the further conduct of clinical studies, appropriate risk assessments and 
mitigation measures will need to be taken into consideration in all clinical studies to protect 
subjects, site staff and society as a whole. 
Both the EMA (EMA 28 April 2020) and the FDA (FDA 16 April 2020), as well as national 
health authorities in Europe, have issued new guidelines that aim to provide recommendations 


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for actions for conduct of clinical studies of medical products during the COVID-19 
pandemic. Since the pandemic situation is evolving, guidelines, recommendations, national 
laws and local restrictions may change at a high pace. Given the circumstances of a potentially 
relapsing pandemic or epidemic situations with regard to the spread of COVID-19, special 
attention will be paid to protect subjects participating in the study and site staff involved in the 
investigations against infection with SARS-CoV-2 as requested by the newly issued EMA 
guideline. 
1.2. 
Rationale for Conducting this Study 
Sodium zirconium cyclosilicate being an inorganic and crystalline compound, is not absorbed 
or metabolised by the body and therefore no metabolic or transporter-based drug-drug 
interactions are anticipated in association with SZC treatment. However, SZC can bind 
hydrogen ions which may result in increased pH in acidic environments such as the stomach. 
In general, an increase in gastric pH can alter the solubility of drugs with pH-dependent 
solubility and may result in an altered absorption profile of the drugs. Results from a Phase 1 
study performed in healthy subjects to examine the potential for drug-drug interactions 
between SZC and a set of 9 compounds showed that co-administration of SZC affected the 
PK, primarily the Cmax values, of 5 compounds tested (Study ZS-009). 
In general, other oral medications should be administered at least 2 hours before or 2 hours 
after SZC. Sodium zirconium cyclosilicate is not expected to impact systemic exposure of 
drugs that do not exhibit pH-dependent solubility and so spacing is not needed if it has been 
determined that the concomitant medication does not exhibit pH-dependent solubility. 
Tacrolimus and cyclosporin are considered narrow therapeutic drugs and important to protect 
from graft rejection. Both tacrolimus and cyclosporin may cause hyperkalaemia and thus 
spacing is considered a complication in this patient population when there is a requirement to 
co-administer tacrolimus/cyclosporin with SZC for treatment of hyperkalaemia. 
This study will investigate if the PK of tacrolimus and cyclosporin may be altered by the 
increased gastric pH resulting from SZC co-administration. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
Table 1 
Primary Objective and Outcome Measures 
Primary Objectives 
Outcome Measures 
To assess the effect of co-administered SZC on the PK 
of tacrolimus and cyclosporin in healthy subjects as 
described by Cmax and AUCinf. 
AUCinf and Cmax measured for each subject and each 
visit on which PK data are collected. 
Abbreviations: AUCinf = area under concentration-time curve from time zero to infinity; Cmax = maximum 
observed concentration; PK = pharmacokinetics; SZC = sodium zirconium cyclosilicate. 
 
2.2. 
Secondary Objective 
Table 2 
Secondary Objective and Outcome Measures 
Secondary Objectives 
Outcome Measures 
To assess the effect of co-administered SZC on the PK 
of tacrolimus and cyclosporin in healthy subjects, as 
described by AUClast, t½λz, and tmax. 
AUClast, t½λz, and tmax measured for each subject 
and each visit on which PK data are collected. 
To examine the safety and tolerability of 
co-administration of SZC and tacrolimus/cyclosporin 
as compared to tacrolimus/cyclosporin alone. 
AEs, vital signs (systolic and diastolic BP, pulse, and 
tympanic temperature), 12-lead ECGs, laboratory 
assessments (haematology, clinical chemistry and 
urinalysis). 
Abbreviations: AEs = adverse events; AUClast = area under the concentration-time curve from time zero to time 
of last quantifiable concentration; BP = blood pressure; ECGs = electrocardiograms; PK = pharmacokinetics; 
SZC = sodium zirconium cyclosilicate; t½λz = half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve; tmax = time to reach maximum observed concentration. 
 
For details, please refer to Section 10.2.1 on PK variables and Section 6.3 on safety variables. 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
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2 1  of 8 5  
3.  
S T U D Y D E SI G N  
3. 1.  
O ver all St u d y Desi g n a n d Fl o w C h art  
T his st u d y will be a n o pe n-la bel, ra n d o mis e d s e q u e nce, 2 - p eri o d, 2-c o h ort, 2-treat me nt i n 
eac h c o h ort , cr oss- o ver st u d y i n healt h y s u bjects ( males a n d fe m ales of n o n-c hil d beari n g 
p ote ntial), perf or me d at a si n gle st u d y ce nt re. 
T he st u d y will c o m prise: 
•  
A scree ni n g peri o d of ma xi m u m 2 8 da ys; 
•  
T w o treat me nt peri o ds: 
− 
Treat me nt Peri o d  1 starts wit h a d missi o n t o t he Cli nica l U nit o n Da y - 1, f oll o we d b y 
d osi n g o n Da y 1 wit h t he assi g ne d treat me nt ( A, B, C, or D) as per assi g ne d c o h ort 
a n d treat me nt se q u e nce, f oll o we d b y a was h o ut peri o d of at least 1 4 da ys. S u bjects 
will be disc har ge d fr o m t he Cli nical U nit after t he last P K sa m ple was c ollecte d f or 
t his treat me nt peri o d ( D a y 4).  
− 
Treat me nt Peri o d  2 starts wit h a d missi o n t o Cli nical U nit o n Da y  - 1, f oll o w e d b y 
d osi n g o n Da y 1 wit h cr oss- o ver treat me nt as per assi g ne d c o h ort, f oll o we d b y a 
f oll o w- u p peri o d of 7 t o 1 0 da ys. S u bjects will be disc har ge d fr o m t he Cli nical U nit 
after t he l ast P K sa m ple was c ollecte d f or t his treat me nt peri o d ( D a y  4).  
•  
A f oll o w- u p visit/earl y ter mi nati o n visit at 7 t o 1 0  da ys after t h e last I M P a d mi nistrati o n.  
 
S u bjects will be assi g ne d t o eit her C o h ort 1 (tacr oli m us) or t o C o h ort 2 (c ycl os p ori n). Eac h 
c o h ort will ha ve 2 treat me nt peri o ds. S u bjects i n eac h c o h ort will be ra n d o ml y assi g ne d t o o ne 
of 2 treat me nt se q u e nces ( A B| B A or C D| D C) w here,  
•  
Treat me nt A: Tacr oli m us   
. 
•  
Treat me nt B: Tacr oli m us 
 + S Z C 
. 
•  
Treat me nt C: C ycl os p ori n  
. 
•  
Treat me nt D: C ycl os p ori n  
 + S Z C  
. 
 
S u bjects w h o ha ve r ecei v e d Treat me nt A i n Treat me nt Peri o d  1 of C o h ort 1 will recei ve 
Treat me nt B i n Treat me nt Peri o d  2 a n d vice versa. S u bjects w h o ha ve recei ve d Treat me nt  C 
i n Treat me nt Peri o d 1 of C o h ort 2 will recei ve Treat me nt D i n Treat me nt P eri o d  2 a n d vice 
versa.  
Eac h s u bject will recei ve a si n gle d ose of oral ca ps ules of tacr oli m us 
/c ycl os p ori n 
 o n 2 occasi o ns, o nce al o ne a n d o nce i n c o m bi nati o n wit h oral s us pe nsi o n of S Z C 
. All dr u g a d mi nistrati o ns will occ ur after a 1 2  h o ur o ver ni g ht fast. 
Details o n I M Ps a d mi nistrati o n is pr o vi de d i n Secti o n 5. 4. 3 . 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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The Study Flow-Chart is presented in Figure 3-1 and the Overall Graphical Representation of 
the study scheme is illustrated in Figure 3-2. 
The Schedule of Assessments displaying assessments/tasks and time points is presented in 
Table 3. 
The study design is deemed appropriate for conduct in healthy volunteers during the 
COVID-19 pandemic (Section 3.3.3). 


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Figure 3-1 
Study Flow Chart 
 
Figure 3-2 
Overall Graphical Representation of the Study 
 
Abbreviations: IMPs = investigational medicinal products; SZC = sodium zirconium cyclosilicate. 
Single doses of all IMPs on indicated days: SZC: 
, tacrolimus: 
, cyclosporin: 
. 
CCI
CCI
CCI


Clinical Study Protocol 
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24 of 85 
Table 3 
Schedule of Assessments 
Visit Number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Study Period 
Screening 
Treatment Period 1 a 
Treatment Period 
2 
Follow-
up/Early 
Termination 
Visit 
Study Days 
-28 to -2 
-1 
1 to 4 
-1 
1 to 4 
At 7-10 days 
after last IMP 
administration 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
X (only weight) 
Medical and surgical 
history 
X 
 
 
 
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
Urinary drug/alcohol, 
cotinine screen 
X 
X 
 
X 
 
 
Viral serology 
X 
 
 
 
 
 
FSH testing b 
X 
 
 
 
 
 
Residence at Clinical Unit 
c 
 
X 
X 
X 
X  
 
Non-residential visit 
X 
 
 
 
 
X 
Investigational Medicinal Product Administration 
Tacrolimus/cyclosporin d 
 
 
X (Day 1, 0 h) 
 
X (Day 1, 
0 h) 
 
SZC 
 
 
X (Day 1, 0 h) 
e 
 
X (Day 1, 
0 h) f 
 
Pharmacokinetics 
Blood sample for PK 
analysis of 
tacrolimus/cyclosporin g 
 
 
X 
 
X 
X 
Safety and Tolerability 
Physical examination 
X 
X 
(brief) 
 
X 
(brief) 
 
X 
12-Lead ECG 
X 
X 
X h 
X 
X h 
X 
Vital signs 
X 
X 
X i 
X 
X i 
X 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 5  of 8 5  
Visit N u m ber  
Visit 1  
Visit 2  
Visit 3  
Visit 4  
St u d y Peri o d  
Scree ni n g  
Tre at m e nt Peri o d 1  a 
Tre at m e nt Peri o d 
2 
F oll o w -
u p/ E arl y 
Ter mi n ati o n 
Visit  
St u d y D a ys  
-2 8  t o - 2 
- 1 
1 t o 4  
- 1 
1 t o 4  
At 7- 1 0 d a ys 
after l ast I M P 
a d mi nistr ati o n  
Cli nical la b orat or y 
assess me nts  
X 
X 
X j 
X 
X j 
X 
Ser u m p otassi u m  
 
 
X k 
 
X k 
 
Uri nal ysis  
X 
X 
X j 
X 
X j 
X 
A d verse e ve nts q uesti o ni n g 
a n d m o nit ori n g 
O nl y 
S A Es  
O nl y 
S A Es  
X 
X 
X 
X 
C O VI D -1 9 Assess m e nts  
T y m pa nic te m perat ure  
X 
X 
X l 
X 
X l 
X 
Pre -visit p h o ne call m  
X 
X 
 
X 
 
X 
S A R S -C o V -2 R T -P C R n 
 
X 
 
X 
 
 
S A R S -C o V -2 a nti b o d y 
testi n g 
X 
 
 
 
 
 
a 
D osi n g o n Da y  1 of Treat me nt Peri o d  1 is f oll o we d b y a was h o ut peri o d of  at least 1 4  da ys.  
b 
Fe male s u bjects o nl y . 
c 
Resi de ntial peri o d s start o n  Da y  - 1 a n d e n d at 7 2  ho urs  after d osi n g o n Da y  1 of eac h  treat me nt peri o d. 
S u bjects s h o ul d c o me t o t he  Cli nical U nit i n t he m or ni n g of Da y - 1 of eac h  treat me nt peri o d t o ha ve  fasti n g 
safet y la b orat or y sa m ples c ollecte d a n d ha vi n g res ults a vaila ble i n t he after n o o n t o deci de o n t he s u bject’s 
eli gi bilit y /c o nti n uati o n. 
d 
S i n gle d oses of tacr oli m us 
 or c ycl os p ori n 
 will be a d mi nistere d per assi g ne d c o h ort a n d 
treat me nt se q ue nce o n Da y  1 of eac h treat me nt peri o d, after a n o ver ni g ht fast of 1 2 h o urs.  
e 
F or s u bjects assi g ne d t o B A or D C treat me nt se q ue nce. 
f 
F or s u bjects assi g ne d t o A B or C D treat me nt se q ue nce. 
g 
Bl o o d sa m ples f or tacr oli m us/c ycl os p ori n P K a nal ysis t o be c ollecte d at pre -d ose, 0 .2 5, 0 .5, 0 .7 5, 1,  1.2 5, 
1. 5,  1.7 5, 2,  2.2 5, 2 .5, 3, 4, 6, 8, 1 0, 1 2, 1 6, 2 4, 3 6, 4 8, a n d 7 2 h o urs  p ost -d ose . 
h 
1 2 -Lea d E C Gs  t o be ta ke n at pre -d ose, 4, 2 4 , 4 8, a n d 7 2  ho urs  p ost -d ose . 
i 
Vitals si g ns ( B P , p ulse ; s u pi ne) t o be perf or me d at pre -d ose, 4, 2 4, 4 8, a n d 7 2 h o urs  p ost -d ose . 
j 
Cli nical la b orat or y assess me nts a n d uri nal ysis t o be perf or me d 4 8  ho urs  p ost -d ose.  
k 
Bl o o d sa m ples f or ser u m p otassi u m le vels t o be ta ke n at pre -d ose  a n d at 4, a n d 7 2 h o urs  p ost -d ose.  
l 
T y m pa nic te m perat ure will be perf or me d dail y; pre -d ose o n Da y  1.  
m  
P h o ne calls will be ma de 1  da y pri or t o eac h res pecti ve visit t o rec or d si g ns a n d s y m pt o ms of C O VI D -1 9 or 
a n y c o ntact wit h pers o ns ha vi n g c o nfir me d S A R S -C o V -2 i nfecti o n. I n case of si g ns or s y m pt o ms or 
c o ntact, t he visit will be ca ncelle d a n d reas o n f or ca ncellati o n will be a p pr o priatel y d oc u me nte d.  
n 
T he res ult of t he S A R S -C o V -2 R T -P C R testi n g m ust be a vaila ble pri or t o d osi n g o n Da y  1 of eac h 
treat me nt peri o d. 
 
A b bre viati o ns: B P = bl o o d press ure; C O VI D -1 9 = c or o na vir us disease 2 0 1 9; E C G = electr ocar di o gra m;  
F S H  = f ollicle sti m ulati n g h or m o ne; P K = p har mac o ki netics; R T -P C R = re verse tra nscri ptase p ol y merase c hai n 
reacti o n; S A E = seri o us a d verse e ve nts; S A R S -C o V -2 = se vere ac ute res pirat or y s y n dr o me c or o na vir us  2; 
S Z C  = s o di u m zirc o ni u m c ycl osilicate. 
 
C CI
C CI


Clinical Study Protocol 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
CONFIDENTIAL AND PROPRIETARY 
26 of 85 
3.1.1. 
Order of Assessments 
It is important that PK sampling occurs as close as possible to scheduled time. In order to 
achieve this, other assessments scheduled at the same time may be initiated prior to the time 
point. The sequence at a particular time point is: 
1 
Electrocardiograms 
2 
Vital signs (systolic and diastolic BP, pulse, and tympanic temperature) 
3 
Pharmacokinetic blood sampling (will be drawn at the specified time points) 
4 
Safety blood sampling for clinical laboratory examinations 
 
Details of acceptable tolerance windows for safety PK assessments will be included in a WAD 
which will be agreed upon and signed off before the start of the study. 
3.1.2. 
End of Study 
The end of study is defined as the last subject’s last visit/contact to the Clinical Unit. 
3.1.3. 
Expected Duration of the Study 
The expected total study duration, including the screening period, for each subject will be at 
least 58 days (8 weeks). 
Table 4 
Expected Duration of Each Study Part 
Screening 
Between 1 to 27 days before dosing (Day -28 to Day -2). 
Treatment Period 1 
Five days during which subjects will be resident at the Clinical Unit from the day 
before dosing (Day -1) with discharge on Day 4 after the last PK sample. 
Washout Period 
At least 14 days between the 2 treatment periods, starting the day after the IMP 
administration in Treatment Period 1. 
Treatment Period 2 
Five days during which subjects will be resident at the Clinical Unit from the day 
before next IMP dosing with discharge on Day 4 after the last PK sample. 
Follow-up Visit 
7 to 10 days after the last IMP administration. 
Total Duration 
Approximately 58 days (8 weeks). 
Abbreviations: IMP = investigational medicinal product; PK = pharmacokinetics. 
 
3.2. 
Rationales for Study Design and Dose Selection 
3.2.1. 
Rationale for Study Design 
The present study will be an open-label, randomised sequence, 2-period, 2-cohort, 
2 treatments in each cohort, cross-over study in healthy subjects to investigate if the PK of 
tacrolimus and cyclosporin may be altered by SZC co-administration. 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 7  of 8 5  
T he U S F D A rec o m me n dati o ns of cli nical dr u g i nteracti o n st u dies a d v ocates t he use of 
cr oss- o ver desi g n o ver p arallel desi g ns f or p ot e ntial D DI st u dies t o re d u ce t he i nter-s u bject 
varia bilit y . 
T he c h oice of healt h y v ol u nteers as t he s u bject p o p ulati o n f or t his dr u g i nteracti o n st u d y is 
als o j ustifie d b y rec o m m e n dati o ns pr o vi de d b y re g ulat or y a ut h orities, wit h t he p ossi bilit y of 
fi n di n gs i n t his st u d y t o be use d t o pre dict t he fi n di n gs i n i nte n de d patie nt p o p ulati o n. 
All t he P K e n d p oi nts selecte d f or t his st u d y are als o i n li ne wit h t he P K assess me nts t hat ca n 
be use d f or i nter pretati o n of dr u g i nteracti o ns as rec o m me n de d b y t he re g ulat or y a ut h orities. 
3. 2. 2.  
D ose R ati o n ale 
T he d oses of t he I M Ps us e d i n dr u g i nteracti o n st u dies s h o ul d ma xi mise t he p ossi bilit y of 
i de ntif yi n g a dr u g- dr u g i nteracti o n, a n d t he us e of ma xi m u m d ose a n d t he s h ortest d osi n g 
i nter val of t he I M Ps u n der t he i nte n de d c o n diti o ns of use or as la b elle d is str o n gl y a d v ocate d. 
L o n g- term mai nte na n ce treat me nt wit h S Z C of u p t o 1 2  m o nt hs was e val uat e d i n 
h y per kalae mic patie nts i n 2 o pe n- la bel st u dies ( Z S- 0 0 4 E a n d Z S- 0 0 5) utilisi n g a d ose titrati o n 
sc he me wit h a starti n g d ose of 
 q d or  
 q d, titrate d t o a ma xi m u m of  
 q d or a 
mi ni m u m of  
 o nce e ver y ot her d a y. T he d ose of 
 was s h o w n t o be s afe a n d t olera ble i n 
b ot h t he st u dies (I B, S Z C  2 0 1 9). Base d o n t his data, t he d ose of  
 S Z C t o be e val uat e d i n 
t he c urr e nt st u d y p o p ulati o n of healt h y v ol u nteers is c o nsi dere d t o be safe. 
T he d ose s selecte d f or t acr oli m us ( 
) a n d c y cl os p ori n (
) are t he t y pical starti n g 
d oses i n or ga n tra ns pla nt e d patie nts a n d t heref ore is dee me d t o be safe i n t he c urre nt st u d y 
p o p ulati o n of healt h y v ol u nteers (Pr o graf S m P C , C ycl os p ori n S m P C ). 
3. 3.  
Ris k -be nefit Assess me nt  
3. 3. 1.  
Ris ks 
3. 3. 1. 1.  
Ris ks A ss oci ate d wit h S Z C  
T he safet y of S Z C has bee n e val uat e d i n cli nical trials f or t he re d u cti o n of h y per kalae mia 
i n v ol vi n g o ver 2 6 0 0 patie nts. T he m ost c o m m o nl y re p orte d A D Rs were oe de ma-relate d 
e ve nts, w hic h w ere 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  
,  
,  
, a n d place b o, res pecti vel y. Of t he oe de ma-rel ate d 
e ve nts, 5 3 % were ma n a g e 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. H y p o kalae mia ( d efi ne d as s er u m p otassi u m 
le vels < 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 treat e d wi t h S Z C. T hese e ve nts w ere 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. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C C
I
C CI
C CI


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 8  of 8 5  
T o  date, 3 cli nical trials were c o n d ucte d wit h S Z C i n healt h y v ol u nteers at d oses of  
 a n d 
 (
), a n d n o e ve nts of h y p o kalae mia i n were re p orte d 
i n a n y of these 3 st u dies. 
M ore det aile d i nf or mati o n a b o ut t he k n o w n ris ks a n d reas o n a bl y e x pecte d a d verse e ve nts of 
S Z C ma y be f o u n d i n t he I B (I B, S Z C  2 0 1 9). 
3. 3. 1. 2.  
Ris ks A ss oci ate d wit h T acr oli m us  
T he m ost c o m m o nl y re p orte d A Es ass oci ate d wit h t he use of tacr oli m us i ncl u de i ncrease d ris k 
of viral, bact erial, f u n g al, a n d pr ot oz oal i nfecti o ns, E pstei n Barr Vir us -ass ociate d 
l y m p h o pr oliferati ve dis or ders a n d s ki n mali g na n cies, bl o o d a n d l y m p hatic s yste m dis or ders 
li ke a nae mia, le u k o p e nia, t hr o m b oc yt o pe nia, le uc o c yt osis, re d bl o od cell a n al yses a b n or mal, 
aller gic a n d a na p h ylact oi d reacti o ns, meta b olis m a n d n utriti o n dis or ders li ke h y per gl ycae mic 
c o n diti o ns, dia betes mellit us, a n d h y per kalae mia, ps yc hiatric dis or ders li ke i ns o m nia, ner v o us 
s yste m dis or ders li ke tre m or a n d hea d ac he, e ye dis or ders li ke visi o n bl urre d a n d p h ot o p h o bia, 
ear dis or ders li ke ti n nit us, car diac dis or ders li ke is c hae mic c or o nar y arter y dis or ders a n d 
tac h ycar dia, vas c ular dis or ders li ke h y perte nsi o n, res pirat or y dis or d ers li ke d ys p n oea, 
pare nc h y m al l u n g dis or ders, ple ural eff usi o n, p har y n gitis, c o u g h, nasal c o n gesti o n a n d 
i nfla m mati o ns, gastr oi ntesti nal dis or ders li ke diarr h oea a n d n a usea, h e pat o biliar y dis or ders 
li ke c h olestasis a n d ja u n dice, he pat o cell ular da m a ge a n d h e patitis, a n d c h ola n gitis, s ki n 
dis or ders li ke pr urit us, ras h, al o pecia, ac ne, a n d s weati n g i ncrease d, m usc ul os keletal dis or ders 
li ke art hral gia, m uscle s p as ms, pai n i n e xtre mit y, a n d bac k p ai n, ki d ne y pr o ble ms li ke re nal 
i m pair me nt, a n d ot hers li ke ast he nic c o n diti o ns, fe brile dis or ders, oe d e ma, pai n a n d 
disc o mf ort, b o d y te m per at ure perce pti o n dist ur be d, he patic e n z y mes a n d f u ncti o n 
a b n or malities, bl o o d al kali ne p h os p hatase i ncrease d, a n d wei g ht i ncrease d. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n ris ks a n d reas o n a bl y e x pecte d a d verse e ve nts of 
tacr oli m us ma y be f o u n d i n S m P C (Pr o graf  S m P C ). 
3. 3. 1. 3.  
Ris ks A ss oci ate d wit h C ycl os p ori n 
T he pri nci pal A Es o bser ve d i n cli nical trials a n d ass ociate d wit h t he a d mi nistrati o n of 
c ycl os p ori n i ncl u de r e nal d ysf u ncti o n, tre m or, hirs utis m, h y perte nsi o n, diarr h oea, a n ore xia, 
na usea a n d v o miti n g. Le u k o pe nia, h y perli pi dae mi a, hea d ac he, di arr h o ea, gi n gi val h y per plasia, 
pe ptic ulcer, a b d o mi nal disc o mf ort, a b n or mal he p atic f u ncti o n, m yal gia a n d m uscle cra m ps, 
p yre xia, a n d fati g ue are als o a m o n g t he c o m m o nl y re p orte d A Es ass ociate d  wit h t he use of 
c ycl os p ori n i n cli nical tri als . 
M ore detaile d i nf or mati o n a b o ut t he k n o w n ris ks a n d reas o n a bl y e x pecte d a d verse e ve nts of 
c ycl os pori n ma y be f o u n d i n S m P C (C ycl os p ori n S m P C ). 
C CI
C CI
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Clinical Study Protocol 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
CONFIDENTIAL AND PROPRIETARY 
29 of 85 
3.3.2. 
Benefits 
This study will not provide any direct medical benefits to healthy subjects who participate in 
this clinical study. Subjects will be monitored under supervision in a Clinical Unit, where 
management of any AEs can take place. The chosen doses for all the 3 IMPs have been well 
tolerated in other populations that have been studied. 
The identified risks with all the 3 IMPs are manageable with proper monitoring, precautionary 
measures and mitigation. Overall, the benefit/risk assessment supports the administration of 
these IMPs to patients with respective indications, and thus the administration of single doses 
to healthy volunteers in the current study. 
3.3.3. 
Risk Assessment for COVID-19 Pandemic 
The study drug, SZC is an oral, non-polymer inorganic cation-exchanger that has been 
approved as a novel therapy for the treatment of hyperkalaemia. It selectively captures 
potassium ions in exchange for sodium and hydrogen ions in the gastrointestinal lumen, 
thereby reducing serum potassium concentration and removing potassium from the body 
through increased faecal excretion. As SZC exerts its effect locally and is not absorbed 
systemically or metabolised by the body, no metabolic or transporter-based drug-drug 
interactions are anticipated in association with SZC treatment (IB, SZC 2019). 
Cyclosporin is a potent immunosuppressive agent and is used to prevent graft rejection 
following solid organ transplantation. Although the mode of action is not fully understood, all 
available evidence suggests that cyclosporin acts specifically and reversibly on lymphocytes. 
Cyclosporin has been reported to inhibit the replication of diverse coronaviruses in vitro but 
this effect is not confirmed for the SARS-CoV-2. Cyclosporin may be beneficial in severe 
stages of COVID-19 based on inhibition on pro-inflammatory interleukin-2 (IL-2) 
(Cyclosporin SmPC). 
Tacrolimus is an immunosuppressive drug used mainly after allogeneic organ transplant to 
lower the risk of organ rejection. Tacrolimus side effects would not pose risks in healthy 
volunteers who does not have pre-existing risk factors (Prograf SmPC). 
It appears to be unlikely, that SZC, tacrolimus, or cyclosporin will worsen COVID-19 in case 
the subject acquires SARS-CoV-2. Only healthy subjects who are currently not infected with 
SARS CoV-2 under the specific precaution will be enrolled. Thus, the study is deemed 
feasible in the appropriate study population and no impact of the COVID-19 pandemic is 
expected in this healthy volunteer study. 
For subjects in this study, the risk to be exposed to SARS-CoV-2 or to suffer from COVID-19 
will be similar to the general population. However, the risk of exposure to infected people 
cannot be completely excluded as the subjects may need to expose themselves to public areas 


Clinical Study Protocol 
AstraZeneca 
Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
CONFIDENTIAL AND PROPRIETARY 
30 of 85 
(eg, commute to the site) and have additional human contact (eg, with site staff and other 
participants of the clinical study). 
Measures to mitigate the additional risks caused by COVID-19 include: 
• 
This study is going to restart enrolling only when the Sponsor and Parexel in 
collaboration deem it is safe to start the study. In addition, the study will not start until the 
local confinement measures or other safety restrictions linked to the COVID-19 pandemic 
are lifted by the local authorities. 
• 
Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to. 
• 
Subjects will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnoea, sore throat, fatigue, and loss of taste or smell throughout the 
study. Once clinical signs of infection are reported by subjects, the Investigator needs to 
determine whether samples can be collected, and safety data can be recorded on site. If 
not, AEs and concomitant medications will be obtained via phone calls. Daily body 
temperature measurements during in-house confinement and outpatient visits will be 
implemented. 
• 
The IMP will not be administered to subjects upon identification of any signs of 
COVID-19 infection. 
• 
Confirmation of COVID-19 infection will be made by mandatory testing at screening 
(serology) and at admission (RT-PCR) to mitigate risk for infection at the site and for the 
participants. 
• 
The probability of virus transmission will be controlled as much as possible by: 
− 
Advice for subject to adhere to local requirements for reduction of the public 
exposure while ambulatory. 
− 
All subjects are contacted by phone 1 day prior to every visit for assessing 
COVID-19 symptoms and signs and are asked not to attend the site in case of 
suspected reports. In addition, subjects are asked for any contact with a person who 
has tested positive for SARS-CoV-2. If applicable, subjects will be referred to the 
local health care system for further follow-up and treatment. 
− 
Physical distancing and person-to-person contact restrictions will be applied during 
site visits and in-house confinement. 
− 
Where physical distancing is not possible, personal protective equipment will be used 
by subject (face mask, gloves) and staff (for example but not limited to face masks, 
gloves, protectors, medical suits) if deemed appropriate by the Investigator and site 
staff and guided by local requirements. 
− 
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing. 
 


Clinical Study Protocol 
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Sodium zirconium cyclosilicate - D9480C00012 
28 September 2020 
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4. 
STUDY POPULATION 
4.1. 
Selection of Study Population 
The Investigator should keep a subject screening log of all potential subjects who consented 
and were subjected to screening procedures. 
Subjects who fail to meet the inclusion criteria or meet any exclusion criterion should not, 
under any circumstances, be randomised in the study. There can be no exceptions to this rule. 
This study will be conducted in male and female subjects. The study may not necessarily be 
balanced regarding gender. The study was not formally powered to detect differences between 
genders for the primary endpoint. It is not planned to perform sub-analyses on gender. 
4.1.1. 
Inclusion Criteria 
For inclusion in the study, subjects should fulfil the following criteria: 
1 
Provision of signed and dated, written informed consent prior to any study specific 
procedures. 
2 
Healthy male and female subjects aged 18 to 50 years (both inclusive) with suitable veins 
for cannulation or repeated venipuncture. 
3 
Females must be of non-childbearing potential, confirmed at screening and fulfil the 
criteria detailed in Section 4.2.1.1 by fulfilling 1 of the following criteria. 
(i) Postmenopausal defined as amenorrhea for at least 12 months or more following 
cessation of all exogenous hormonal treatments and FSH levels in the 
postmenopausal range. 
(ii) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation. 
4 
Male subject must adhere to the contraception methods details in Section 4.2.1.2. 
5 
Have a BMI between 18.5 and 30 kg/m2 inclusive and weigh at least 50 kg and no more 
than 100 kg inclusive. 
6 
Subject is able to understand and communicate in German. 
7 
Willing and able to comply with all required study procedures. 
 
4.1.2. 
Exclusion Criteria 
Subjects will not enter the study if any of the following exclusion criteria are fulfilled. For 
values deviating from the reference or specified range, 1 retest is allowed. 


Clinical Study Protocol 
AstraZeneca 
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1 
History of any clinically significant disease or disorder which, in the opinion of the 
Investigator, may either put the volunteer at risk because of participation in the study, or 
influence the results or the volunteer’s ability to participate in the study. 
2 
History or presence of gastrointestinal, hepatic or renal disease, or any other condition 
known to interfere with absorption, distribution, metabolism, or excretion of drugs. 
3 
Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks 
prior to screening. 
4 
Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis 
results, at screening visit and/or admission to the Clinical Unit as judged by the 
Investigator. 
5 
Abnormal vital signs, after 5 minutes rest in supine position, at screening visit and/or 
admission to the Clinical Unit, defined as any of the following: 
− 
Systolic BP > 140 mmHg. 
− 
Diastolic BP > 90 mmHg. 
− 
Pulse < 50 or > 90 bpm. 
6 
Any clinically important abnormalities in rhythm, conduction or morphology of the 
12-lead safety ECG, at screening visit and/or admission to the Clinical Unit, defined as 
any of the following: 
− 
Prolonged QTcF > 450 ms or family history of long QT syndrome. 
- 
PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if 
there is no evidence of ventricular pre-excitation). 
- 
PR (PQ) interval prolongation (> 220 ms) intermittent second (Wenckebach block 
while asleep is not exclusive) or third-degree AV block, or AV dissociation. 
- 
Persistent or intermittent complete bundle branch block (BBB), incomplete bundle 
branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS 
> 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no 
evidence of ventricular hypertrophy or pre-excitation. 
7 
Any positive result on screening visit for serum hepatitis B surface antigen or 
anti-hepatitis B core antigen antibody, hepatitis C antibody, and HIV testing. 
8 
Positive screen for drugs of abuse, alcohol, or cotinine at screening visit or on each 
admission to the Clinical Unit. 
9 
Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as 
judged by the Investigator. Excessive intake of alcohol defined as the regular 
consumption of more than 24 g of alcohol per day for men or 12 g of alcohol per day for 
women. 
10 Current smokers or those who have smoked or used nicotine products (including 
e-cigarettes) within the 3 months prior to screening visit. 


Clinical Study Protocol 
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11 Has received another new chemical entity (defined as a compound which has not been 
approved for marketing) within 3 months of the first administration of IMP in this study. 
The period of exclusion begins 3 months after the final dose or 1 month after the last visit 
whichever is the longest. 
Note: subjects consented and screened, but not randomised in this study or a previous 
phase I study, are not excluded. 
12 Plasma donation within 1 month of screening visit or any blood donation/loss more than 
500 mL during the 3 months prior to screening visit. 
13 History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged 
by the Investigator or history of hypersensitivity to drugs with a similar chemical 
structure or class to SZC, tacrolimus, or cyclosporin. 
14 Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks 
prior to screening. 
Use of any prescribed or non-prescribed medication including antacids, analgesics (other 
than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 
600 times the recommended daily dose) and minerals during the 2 weeks prior to the first 
administration of IMP or longer if the medication has a long half-life. 
15 Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as 
judged by the Investigator. Excessive intake of caffeine defined as the regular 
consumption of more than 600 mg of caffeine per day (eg, > 5 cups of coffee) or would 
likely be unable to refrain from the use of caffeine-containing beverages during 
confinement at the investigational site. 
16 Involvement of any AstraZeneca, Parexel, or study site employee or their close relatives. 
17 Subjects who have previously received SZC. 
18 Judgment by the Investigator that the subject should not participate in the study if they 
have any ongoing or recent (ie, during the screening period) minor medical complaints 
that may interfere with the interpretation of study data or are considered unlikely to 
comply with study procedures, restrictions, and requirements. 
19 Subjects with any special dietary restrictions such as subjects who are lactose intolerant or 
are vegetarians/vegans. 
20 Subjects who cannot communicate reliably with the Investigator. 
21 Vulnerable subjects, eg, those who are kept in detention, protected adults under 
guardianship, trusteeship, or committed to an institution by governmental or juridical 
order. 
22 Subject has a positive RT-PCR test for SARS-CoV-2 on admission. 
23 Subject has clinical signs and symptoms consistent with SARS-CoV-2 infection, eg, 
fever, dry cough, dyspnoea, sore throat, fatigue, loss of taste or smell or a positive 
SARS-CoV-2 test result within the last 4 weeks prior to screening or on admission. 


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24 Subject who had a severe course of COVID-19 (extracorporeal membrane oxygenation, 
mechanically ventilated). 
25 Recent (within previous 14 days) exposure to someone who has COVID-19 symptoms or 
positive test result. 
26 Recent (within previous 14 days) visit to a healthcare facility where COVID-19 patients 
are being treated. 
27 Subjects who are regularly exposed to COVID-19 as part of their daily life (eg, health 
care professionals working in COVID-19 wards or at emergency departments). 
 
4.2. 
Restrictions During the Study 
The following restrictions apply for the specified times during the study period: 
1 
On Day 1 of each treatment period, subjects will be fasted for 12 hours prior to dosing 
until 4 hours after dosing. No fluids will be allowed apart from water which can be given 
until 1 hour prior to dosing and then from 2 hours after dosing (excluding water used in 
conjunction with IMP administration; see Section 5.4.3). 
2 
Subjects should not lie fully supine (unless specified for certain assessments) for 4 hours 
after dosing. 
3 
Subjects should not engage in any strenuous activity from 72 hours prior to check-in until 
after their final follow-up visit. 
4 
Prior to each treatment period, subjects should abstain from alcohol for 72 hours prior to 
check-in until after their last PK sampling visit. Subjects should also abstain from alcohol 
for 72 hours before their final follow-up visit. 
5 
Prior to each treatment period, subjects should abstain from caffeine-containing foods and 
beverages for 24 hours prior to check-in until discharge from the Clinical Unit. 
6 
Subjects should abstain from grapefruit or grapefruit juice, Seville oranges, quinine (eg, 
tonic water) from 7 days prior to check-in on Day -1 until after their follow-up visit. 
7 
During in-house stay, subjects will receive a standard diet, which excludes all alcohol and 
grapefruit-containing products. No additional food or beverages must be consumed while 
in the Clinical Unit. 
8 
During the subjects’ outpatient periods, subjects should abstain from consuming high 
energy drinks (eg, Red Bull®), and food containing poppy seeds and any OTC medication 
or herbal preparations until after their final follow-up visit has been completed. Subjects 
should also limit their caffeine intake to equivalent of 3 servings of coffee per day 
(1 serving = 330 mL cola, 180 mL coffee, or 240 mL tea). Subjects should consume no 
more than 2 units of alcohol per day and completely abstain from alcohol from 72 hours 
prior to their next check-in. 


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9 
Subjects will be required to abstain from blood or plasma donation until 3 months after 
the final medical examination at the follow-up visit. 
10 Subjects should avoid any vaccination from screening until 14 days after the final dose of 
IMP. 
11 Subjects should avoid excess unprotected sun exposure and should not receive 
concomitant ultraviolet B irradiation or psoralen and ultraviolet A photochemotherapy 
from screening until the final medical examination at the follow-up visit. 
12 For medication restrictions, please refer to Section 5.6. 
13 Subjects will be advised to adhere to local requirements for reduction of the public 
SARS-CoV-2 exposure while ambulatory. All subjects will be contacted by phone to 
assess COVID-19 symptoms and signs 1 day prior to each respective visit and will be 
asked not to attend the site in case of suspected infection. In addition, subjects will be 
asked for details of any contact with a person who has confirmed infection. If applicable, 
subjects will be referred to the local health care system. Physical distancing and 
person-to-person contact restrictions will be applied and explained to subjects while 
staying at the study site. Where physical distancing is not possible, subjects will be asked 
to use face masks and/or gloves if deemed appropriate by the Investigator and site staff 
and guided by local requirements. 
 
4.2.1. 
Reproductive Restrictions 
4.2.1.1. 
Women of Non-childbearing Potential 
Women of non-childbearing potential are defined as female subjects who are permanently 
surgically sterilised or postmenopausal. 
Permanent sterilisation includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy at least 6 weeks before screening but excludes bilateral tubal ligation. Bilateral 
oophorectomy alone is acceptable only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment. 
Females are considered postmenopausal if they have had amenorrhea for at least 12 months or 
more following cessation of all exogenous hormonal treatments and without an alternative 
medical cause and the FSH level is in the postmenopausal range. 
4.2.1.2. 
Male Subjects 
Restrictions for Male Subjects 
There is limited or no information about effects that SZC, cyclosporin, or tacrolimus could 
have on the development of the foetus in humans. Therefore, it is important that woman of 
childbearing potential, who are the partners of male subjects, do not become pregnant during 
the study and for a total period of 3 months after the male subject has attended the study 
follow-up visit. 


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Male subjects who have been sterilised are required to use one barrier method of 
contraception (condom) from the time of IMP administration until after the follow-up visit. 
The subject must have received medical assessment of the surgical success. 
As a precaution, all non-sterilised male subjects should avoid fathering a child by either true 
abstinence1 or use a condom and their female partner/spouse has to be either of 
non-childbearing potential or has to use a highly effective contraception form of birth control, 
starting from the time of IMP administration until 3 months after the study follow-up visit. 
The female partner/spouse should be stable on their chosen method of birth control for at least 
3 months after the first IMP dosing. 
Highly effective contraception form of birth control, ie, a form of birth control with a failure 
rate of less than 1% per year when used consistently and correctly, are: 
• 
Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− 
Oral 
− 
Intravaginal 
− 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− 
Oral 
− 
Injectable 
− 
Implantable 
• 
Intrauterine device 
• 
Intrauterine system 
• 
Bilateral tubal occlusion of female partner 
 
Sperm Donation 
Male subjects should not donate sperm for the duration of the study and for at least 3 months 
after the study follow-up visit. 
Pregnancy 
Subjects will be instructed that if their partner becomes pregnant during the study, this should 
be reported to the Investigator. The Investigator should also be notified of pregnancy 
occurring during the study but confirmed after completion of the study. In the event that a 
subject’s partner is subsequently found to be pregnant after the volunteer is included in the 
 
1 Sexual abstinence is defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. It is only acceptable if preferred and usual lifestyle of the subject. 


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study, then consent will be sought from the partner and if granted, any pregnancy will be 
followed and the status of mother and/or child will be reported to the Sponsor after delivery. 
A pregnancy notification form and follow-up will be completed. 
4.3. 
Replacement of Subjects 
As there is a goal of meeting a particular sample size in this study, the subjects who are 
withdrawn from the study due to AEs or changes in safety parameters will not be replaced 
unless required to meet the specific sample size for statistical purposes and if the Sponsor’s 
responsible physician and the Investigator agree it is safe to do so. Subjects who withdraw or 
are withdrawn from the study for other reasons may be replaced following discussion with the 
Sponsor. 


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5. 
STUDY CONDUCT 
5.1. 
Subject Enrolment and Randomisation 
The Investigator will ensure: 
• 
Signed informed consent is obtained from each potential subject before any study specific 
procedures are performed. 
• 
Each potential subject is assigned a unique enrolment number at screening upon signing 
the informed consent. 
• 
The eligibility of each subject is in accordance with the inclusion and exclusion criteria. 
• 
Each eligible subject is assigned a unique randomisation code. 
 
Randomisation can be done on the evening prior to the day of first IMP dosing. 
Randomisation codes will be assigned strictly sequentially as subjects become eligible for 
enrolment (codes to be used without leading zero[s]). 
When using unique enrolment number, the specific format must be followed (ie, reduced 
enrolment number “01001” in ClinBase™ and on labels, full enrolment number “E0001001” 
for outputs). 
If a subject withdraws his/her participation in the study, then his/her randomisation code 
cannot be reused. If a replacement is mandated, replacement subjects will receive a new 
randomisation number and will be allocated to the same treatment sequence as the replaced 
subject. 
5.1.1. 
Procedures for Randomisation 
Upon completion of the randomisation requirements specifications form, the randomisation 
will be produced by Parexel according to the AstraZeneca randomisation system (AZRand). 
Subjects will be enrolled into Cohort 1 and Cohort 2 sequentially. 
Subjects in Cohort 1 and Cohort 2 will be randomised in a 1:1 ratio to receive one of the 
2 treatment sequences and then cross-over to the other: Tacrolimus alone (treatment A) 
followed by the combination treatment of tacrolimus and SZC (treatment B) or vice versa in 
Cohort 1 and cyclosporin alone (treatment C) followed by the combination treatment of 
cyclosporin and SZC (treatment D) or vice versa in Cohort 2. 
The randomisation will be completed for each cohort using consecutive randomisation codes. 
The number of subject identifiers generated for the study will account for the number of 
enrolment subjects per the sample size calculation (N = 60 total, as N = 30 for each of the 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 9  of 8 5  
2 c o h orts a n d N = 1 5 f or eac h of t h e 4 treat me nt se q ue nce) as w ell as pr o vi di n g s ufficie nt 
ra n d o misati o n n u m bers f or re place me nts. F or t his st u d y, a t otal of 1 2 0 s u bject i de ntifiers will 
be ra n d o ml y assi g ne d t o t he treat me nt se q u e nce(s): A B| B A  a n d C D |D C . 
5. 2.  
Pr oce d ures f or H a n dli n g I nc orrectl y E nr olle d  S u bjects  
S u bjects w h o fail t o meet t he i ncl usi o n  criteria or meet a n y e x cl usi o n criteri o n s h o ul d n ot, 
u n der a n y circ u msta nces, be ra n d o mis e d i nt o t he st u d y. T here ca n be n o e x ce pti o ns t o t his 
r ule. W here a s u bject, w h o d oes n ot meet t he selecti o n criteria, is ra n d o mise d i n err or a n d t his 
is i de ntifie d bef ore d osi n g, t he s u bject s h o ul d be wit h dra w n fr o m t he st u d y. If a s u bject is 
wit h dra w n pri or t o d osi n g t he y will be re place d. If a s u bject, w h o d o es n ot meet t he selecti o n 
criteria a n d has bee n d os e d bef or e t he err or is i de ntifie d, t he s u bject s h o ul d be wit h dra w n a n d 
a d vise d t o c o nti n ue saf et y assess me nts t o e ns ure t heir safet y . T h e I n vesti gat or will i nf or m t he 
Astra Ze neca L ea d P h ysicia n of t he err or a n d a j oi nt decisi o n ma de as t o w h et her t he s u bject 
s h o ul d be re place d. 
5. 3.  
Bli n di n g  
T his is a n o pe n-la bel st u d y a n d bli n di n g is n ot a p plica ble. 
5. 4.  
Tre at me nts 
5. 4. 1.  
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d uct 
Details o n t he i de ntit y of t he I M P are prese nte d i n  Ta ble 5 . 
T a ble 5 
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d uct 
I n vesti g ati o n al Me dici n al 
Pr o d uct N a m e  
S o di u m Zirc o ni u m 
C ycl osilic ate  
T acr oli m us  
C ycl os p ori n  
Tra de Na me : 
L o kel ma ™ 
Pr o graf  
Sa n di m m u n 
Ne oral / Opt oral  
Ma n ufact urer : 
Astra Ze neca  
Astellas P har ma  
N o vartis  
F or m ulati o n:  
P o w der f or oral s us pe nsi o n 
Har d ca ps ules  
S oft ca ps ules  
Stre n gt h/c o nce ntrati o n:  
 Sac het 
 
 
D ose:  
 
 
 
R o ute of a d mi nistrati o n:  
Oral  
Oral  
Oral  
S pecific de vice f or dr u g 
a d mi nistrati o n, if a p plica ble: 
N ot a p plica ble  
N ot a p plica ble  
N ot a p plica ble  
Re gi me n:  
Si n gle d ose of  
 c o nsisti n g 
of 3  sac hets s us pe n de d i n 
4 5  m L of water  
Si n gle d ose of  
 
Si n gle d ose of 
 
S pecial ha n dli n g re q uire me nts:  
N ot a p plica ble  
N ot a p plica ble  
N ot a p plica ble  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 0  of 8 5  
Details of t he batc h n u m bers will be i ncl u de d i n t he trial master file a n d t he fi nal  C S R . 
5. 4. 2.  
S u p pl y of I n vesti g ati o n al Me dici n al Pr o d uct 
T he I M P , S Z C  will be s u p plie d b y Astra Ze neca i n sac hets  pac ke d i n cart o ns. 
T he I M Ps, t acr oli m us a n d c ycl os p ori n will be s o urce d b y Pare xel. 
A tec h nical a gree me nt bet wee n t he I n v esti gat or a n d Astra Ze neca will be i n place t o c o v er all 
p har mac y relate d acti vities, detail i n g r oles a n d res p o nsi bilities pri or t o recei pt of t he I M Ps at 
t he Cli nical U nit. 
A releas e d oc u me nt si g n e d b y a le gall y a ut h oris e d Q ualifie d Pers o n will be place d i n t he 
a p pr o priate s ecti o n of t he Trial Master File t o d oc u me nt la belli n g a n d dis pe nsi n g of t he I M Ps 
t o t he s u bject. 
5. 4. 3.  
D ose a n d Tre at m e nt Re gi m e ns 
Eac h s u bject will recei ve si n gle oral d oses of S Z C  a n d/ or tacr oli m us/c ycl os p ori n u n der fast e d  
c o n diti o ns. T he d oses will be a d mi nistere d aft er a n o ver ni g ht fast of at least 1 2 h o urs. 
S o di u m zirc o ni u m c ycl osilicate will be a d mi nistere d orall y as s us pe nsi o n, c o ntai ni n g  
 of 
I M P diss ol ve d i n 4 5 m L of water . T acr oli m us a n d c ycl os p ori n will be a d mi nistere d as oral 
ca ps ules f or s wall o wi n g wit h 2 0 0 m L of n o n- car b o nate d water at r o o m te m perat ure . 
O n da ys of I M P c o- a d mi nistrati o n, S Z C will be a d mi nistere d i m me diatel y f oll o we d b y 
tacr oli m us/c ycl os p ori n. 
S u bjects will be all o we d t o dri n k water t o pre v e nt de h y drati o n u ntil 1 h o ur bef ore d osi n g. 
Water will be all o we d a d li bit u m fr o m 2 h o urs after d osi n g a n d a sta n d ar d meal will be gi ve n 
4 h o urs after d osi n g. 
After d osi n g, s u bjects will re mai n se mi -s u pi ne o n t heir be d or sitti n g (e xce pt w he n necessar y 
f or st u d y pr oce d ures) u ntil 4 h o urs after d osi n g. 
Ot her restri cti o ns, i ncl u di n g p ost ure c o ntr ol are descri be d i n Secti o n  4. 2 . D ata of s u bjects ma y 
be e xcl u de d fr o m t he P K a nal ysis set as descri be d i n Secti o n  1 1. 1. 2 . 
5. 4. 4.  
L a belli n g 
La bels will be pre p are d i n  acc or d a nce wit h G M P a n d l ocal re g ul at or y g ui d eli nes. 
T he la bels will f ulfil G M P A n ne x 1 3 re q uire m e nts f or la belli n g. 
C CI


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5.4.5. 
Storage and Handling Procedures 
All IMPs will be stored in a secure facility, details of storage conditions will be provided on 
the label of the IMPs. 
The AstraZeneca staff will be permitted upon request to audit the supplies, storage, dispensing 
procedures, and records. 
5.5. 
Concomitant and Post-study Treatment(s) 
Apart from paracetamol/acetaminophen, no concomitant medication or therapy will be 
allowed. 
The subjects should be instructed that no other medication is allowed, including herbal 
remedies, vitamin supplements and OTC products, without the consent of the Investigator. 
Medication, which is considered necessary for the subject’s safety and well-being, may be 
given at the discretion of the Investigator during the in-house period. Such instances will be 
registered as important protocol deviations unless the medication is 
paracetamol/acetaminophen. 
When any medication is required, it should be prescribed by the Investigator. Following 
consultation with AstraZeneca Lead Physician, the Investigator should determine whether or 
not the subject should continue in the study. Administration of concomitant medications may 
be documented as a protocol deviation after consultation of the Investigator with AstraZeneca 
Lead Physician. 
5.6. 
Treatment Compliance 
Dosing will take place at the Parexel Early Phase Clinical Unit. 
The administration of all IMPs will be recorded in ClinBase™. 
Compliance will be assured by direct supervision. After IMP administration, a check of the 
subject’s mouth and hands will be performed. 
5.6.1. 
Drug Accountability, Dispensing and Destruction 
The IMPs provided for this clinical study will be used only as directed in this CSP. 
In accordance with GCP, the investigational site will account for all supplies of SZC, 
tacrolimus and cyclosporin. Details of receipt, storage, assembly/dispensing and return will be 
recorded. 
All unused supplies of all IMPs will either be destroyed by Parexel or returned at the end of 
the study in accordance with instruction by the Sponsor. 


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5.7. 
Discontinuation of Investigational Product and Withdrawal from 
Study 
Individual subjects may be discontinued from IMPs in the following situations: 
• 
Severe non-compliance to study protocol. 
 
Individual subjects will be discontinued from IMPs in the following situations: 
• 
Healthy subject decision. The healthy subject is at any time free to discontinue treatment, 
without prejudice to further treatment. 
• 
Adverse events which in the opinion of the Investigator warrant discontinuation of the 
subject from treatment for his/her well-being, including (but not limited to): 
− 
A serious adverse reaction (ie, a SAE considered at least possibly related to IMP 
administration). 
− 
A severe non-serious adverse reaction (ie, a severe non-serious AE considered at 
least possibly related to IMP administration). 
• 
Any significant and clinically relevant changes in the safety parameters (eg, ECG, BP, 
pulse, laboratory assessments, and AE) making the continuation of IMP administration 
unjustified, including: 
− 
Any case of Potential Hy’s Law (PHL) or Hy’s Law (HL) according to threshold 
values listed in Appendix C. 
− 
QTc prolongation defined as QTcF > 500 ms, or a prolongation from baseline of 
> 60 ms, confirmed on a repeat 12-lead ECG. 
− 
Hypertension defined as an increase in resting supine systolic BP > 40 mmHg to 
above 180 mmHg and persisting for at least 10 minutes. 
− 
Tachycardia defined as resting supine heart rate > 125 bpm persisting for at least 
10 minutes. 
− 
Symptomatic bradycardia defined as resting supine heart rate < 45 bpm or 
asymptomatic bradycardia defined as resting heart rate < 40 bpm while awake 
persisting for at least 10 minutes. 
− 
Severe hypokalaemia defined as serum potassium < 3.0 mmol/L (confirmed by repeat 
measurement). 
• 
Any suspected or confirmed COVID-19 case in the judgment of the Investigator or 
Sponsor to protect the safety of the subject, other study participants or study site staff. 
 
The appropriate AE form in the CRF must be completed. 


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5.7.1. 
Procedures for Withdrawal of a Subject from the Study 
If a subject withdraws or is withdrawn from the study, the subject will be encouraged to 
continue with safety assessments in the respective treatment period and return to the Clinical 
Unit for an Early Termination Visit to ensure the subject’s safety. 
5.7.2. 
Procedures for Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• 
Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods) until the end of study. These contact attempts should be documented in the 
subject’s medical record. 
• 
Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study. Site personnel, or an independent third party, will attempt to 
collect the vital status of the subject within legal and ethical boundaries for all subjects 
randomised, including those who did not get IMP. 
 
5.8. 
Premature Termination of the Study 
The study will be terminated prematurely if: 
• 
The Investigator and the Sponsor assess that the number and/or severity of AEs justify 
discontinuation of the study in accordance with stopping rules listed in the Guideline on 
strategies to identify and mitigate risks for first-in-human and early clinical trials with 
investigational medicinal products (EMEA/CHMP/SWP/28367/07 Rev.1), ie,: 
− 
A ‘serious’ adverse reaction (ie, an SAE considered at least possibly related to the 
IMP administration) in 1 subject. 
− 
‘Severe’ non-serious adverse reactions (ie, severe non-serious AEs considered at least 
possibly related to the IMP administration) in 2 subjects, independent of within or not 
within the same SOC. 
• 
The Sponsor considers the applied doses of the IMPs to be no longer relevant. 
• 
The Sponsor decides to discontinue the study. 


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• 
New data become available and raise concern about the safety of IMPs so that 
continuation would pose potential risks to the subjects. 
• 
New data become available regarding COVID-19, which raise concern for the safe study 
conduct so that continuation would pose potential risks to the subjects or the study site 
staff. 
 
Premature termination of the study must be mutually agreed upon by the Investigator and the 
Sponsor and must be documented. However, study results will be reported according to the 
requirements outlined in this CSP as far as applicable. 


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6. 
COLLECTION OF STUDY VARIABLES 
6.1. 
Recording of Data 
Standard measures to assess PK, safety and tolerability apply during the study. For the single 
doses of IMPs planned to be given during this study, no safety issues are expected. 
For timing of assessments refer to Table 3. 
6.2. 
Enrolment and Screening Procedures 
Viral serology for assessment for hepatitis and HIV, and tests for use/abuse of drugs of abuse, 
alcohol, and smoking (cotinine) will be carried out, and subjects who have positive results for 
any of these will be excluded from the study. In addition, SARS-CoV-2 serology at screening 
and SARS-CoV-2 RT-PCR on admission will be assessed for eligibility. Follicle stimulating 
hormone (females only) and use of concomitant medication will also be assessed and reported. 
Phone calls will be made 1 day prior to each respective visit to record signs and symptoms of 
COVID-19 or any contact with persons having confirmed SARS-CoV-2 infection. In case of 
signs or symptoms or contact, the visit will be cancelled and reason for cancellation will be 
appropriately documented. 
6.3. 
Safety and Eligibility Measurements 
Safety and tolerability variables will include: 
• 
Adverse events 
• 
Clinical laboratory assessments (haematology, clinical chemistry, and urinalysis). 
• 
Physical examination 
• 
12-Lead ECGs 
• 
Vital signs (systolic and diastolic BP, pulse, and tympanic temperature) 
 
6.3.1. 
Adverse Events 
6.3.1.1. 
Definition of Adverse Events 
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 


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The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
washout period, even if no IMP has been administered. 
6.3.1.2. 
Definitions of Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, screening, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above 
 
For further guidance on the definition of an SAE, see Appendix A of this CSP. 
Adverse events for malignant tumours reported during a study should generally be assessed as 
SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a 
non-serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
6.3.1.3. 
Other Significant Adverse Events 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or where relevant AEs leading to 
discontinuation of IMP and withdrawal from the study. Based on the expert’s judgment, 
significant AEs of particular clinical importance may, after consultation with the Global 
Safety Physician, be considered OAEs and reported as such in the CSR. A similar review of 
other data from laboratory tests, vital signs, ECGs and other safety assessments will be 
performed for identification of OAEs. 


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Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
6.3.1.4. 
Recording of Adverse Events 
Time Period for Collection of Adverse Events 
Non-serious AEs will be collected from administration of IMP in Treatment Period 1 
throughout the treatment period and including the Follow-up Visit. 
Serious AEs will be recorded from the time of informed consent. 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in ClinBase™. 
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Variables 
The following variables will be collected for each AE: 
• 
AE diagnosis/description. 
• 
The date and time (if known) when the AE started and stopped. 
• 
Maximum intensity. 
• 
Whether the AE is serious or not. 
• 
Investigator causality rating against the IMPs (yes or no). 
• 
Action taken with regard to IMP. 
• 
Outcome. 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE. 
• 
Date Investigator became aware of SAE. 
• 
AE is serious due to. 
• 
Date of hospitalisation. 
• 
Date of discharge. 
• 
Probable cause of death. 
• 
Date of death. 


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• 
Autopsy performed. 
• 
Causality assessment in relation to study procedure(s). 
• 
Causality assessment to other medication. 
 
The following intensity ratings will be used: 
1 
Mild (awareness of sign or symptom, but easily tolerated). 
2 
Moderate (discomfort sufficient to cause interference with normal activities). 
3 
Severe (incapacitating, with inability to perform normal activities). 
It is important to distinguish between serious and severe AEs: 
• 
Severity is a measure of intensity whereas seriousness is defined by the criteria in 
Section 6.3.1.2. 
• 
An AE of severe intensity need not necessarily be considered serious. For example, 
nausea that persists for several hours may be considered severe nausea, but not an SAE. 
On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be an SAE. 
 
Causality Collection 
The Investigator will assess causal relationship between IMPs and each AE, and answer “yes” 
or “no” to the question “Do you consider that there is a reasonable possibility that the event 
may have been caused by the IMP?” 
For SAEs, causal relationship will also be assessed for other medication, any additional drug 
and study procedures. Note that for SAEs that could be associated with any study procedure 
the causal relationship is implied as “yes”. 
A guide to the interpretation of the causality question is found in Appendix A of this CSP. 
Adverse Events Based on Sign and Symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: “Have you had any health problems since you were last asked?” or 
revealed by observation will be collected and recorded in ClinBase™. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 


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Adverse Events Based on Examinations and Tests 
The results from protocol-mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarised in the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, 
ECGs and other safety assessments should therefore only be reported as AEs if they fulfil any 
of the SAE criteria or are the reason for discontinuation of treatment with the IMPs. 
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information. 
Wherever possible the reporting Investigator should use the clinical, rather than the laboratory 
term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-protocol-mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Hy's Law 
Cases where the subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 x ULN together with total bilirubin ≥ 2 x ULN may need 
to be reported as SAEs. Please refer to Appendix C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 
COVID-19 
Adverse event questioning will include specific questions regarding signs and symptoms of 
COVID-19, including fever, dry cough, dyspnoea, sore throat, fatigue, and loss of taste or 
smell as well as potential recent (within previous 14 days) exposure to someone who has 
COVID-19 symptoms or positive test result. 
Suspected and confirmed SARS-CoV-2 infection and COVID-19 will be recorded as AEs. 


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6.3.1.5. 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the IMPs, or to the 
study procedure(s). All SAEs will be recorded in ClinBase™. 
If any SAE occurs in the course of the study, then Investigators or other site personnel will 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. 
Investigators or other site personnel will inform AstraZeneca representatives of any follow-up 
information on a previously reported SAE immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
The reference document for definition of expectedness/listedness is the IB for SZC, and 
respective SmPCs for tacrolimus and cyclosporin. 
6.3.1.6. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of the IMP 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the IMP under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and Investigators. 
For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB or and will notify the IRB/IEC, if appropriate according to local 
requirements. 


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6.3.2. 
Clinical Laboratory Assessments 
6.3.2.1. 
Haematology 
White blood cell (WBC) count 
Neutrophils absolute count  
Red blood cell (RBC) count 
Lymphocytes absolute count  
Haemoglobin (Hb) 
Monocytes absolute count  
Haematocrit (HCT) 
Eosinophils absolute count  
Mean corpuscular volume (MCV) 
Basophils absolute count  
Mean corpuscular haemoglobin (MCH) 
Platelets 
Mean corpuscular haemoglobin concentration 
(MCHC) 
Reticulocytes absolute count  
 
6.3.2.2. 
Serum Clinical Chemistry 
Sodium 
Alkaline phosphatase (ALP) 
Potassium 
Alanine aminotransferase (ALT) 
Urea 
Aspartate aminotransferase (AST) 
Creatinine 
Gamma glutamyl transpeptidase (GGT) 
Albumin 
Total Bilirubin 
Calcium 
Unconjugated bilirubin 
Phosphate 
 
Glucose(fasting) 
 
C-reactive protein (CRP) 
 
T4 a 
Follicle stimulating hormone (FSH) a, b 
TSH a 
 
a 
Screening only. 
b 
Female subjects only. 
 
6.3.2.3. 
Urinalysis 
Glucose 
 
Protein 
 
Blood 
 
Upon a positive urine test from leucocytes, blood, nitrite or protein, the Investigator may require further urine 
analysis, such as flow cytometry. Results of additional urine analyses will be included in the database. If the 
flow cytometry examination shows a different result than the urine sticks, the urine will be investigated by 
fully automated digital imaging where leukocytes, erythrocytes, casts in urine will be analysed. 
 


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6.3.2.4. 
Viral Serology and SARS-CoV-2 Virology 
Hepatitis B surface antigen (HBsAg) 
Hepatitis B core antibody 
Hepatitis C antibody 
SARS-CoV-2 antibody testing 
Human immunodeficiency virus (HIV) I and II testing 
SARS-CoV-2 by RT-PCR (specimen may be collected by oropharyngeal and/or nasopharyngeal swabs) 
Additional investigations may be performed as judged by the Investigator, in collaboration 
with the Sponsor. 
6.3.2.5. 
Drugs of Abuse, Alcohol and Cotinine 
Amphetamine / Ecstasy 
Benzodiazepines 
Ethanol 
Methadone Metabolites 
Cannabinoids 
Barbiturates 
Cocaine 
Phencyclidine 
Opiates  
Urine Creatinine 
Cotinine 
 
Tricyclic antidepressants (TCA) 
 
 
6.3.3. 
Physical Examination 
Full 
The complete physical examinations will include an assessment of the general appearance, 
respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, musculoskeletal and neurological systems. 
Brief (Abbreviated) 
The brief physical examinations will include an assessment of the general appearance, skin, 
abdomen, cardiovascular system and respiratory. 
6.3.4. 
Resting 12-lead Electrocardiogram 
At the time points specified in the SoA (Table 3), a 10-second 12-lead safety ECG, including 
QTcF, PR, QRS QT interval, and HR will be obtained after 10 minutes supine rest, using the 
site’s own ECG machines. 
The Investigator will judge the overall interpretation as normal or abnormal and this 
evaluation will be reported in ClinBase™. If abnormal, it will be further documented as to 
whether or not the abnormality is clinically significant by the Investigator. For all 
abnormalities (regardless of clinical significance) the specific type and nature of the 
abnormality will be documented in ClinBase™. Clinically significant findings should also be 
documented on the AE page of the CRF if applicable. 


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The Investigator may add extra 12-lead resting ECG safety assessments if there are any 
abnormal findings or if the Investigator considers it is required for any other safety reason. 
These assessments should be entered as an unscheduled assessment. 
All subjects who have QTc prolongation defined as QTcF > 500 ms, or a prolongation from 
baseline of > 60 ms on repeat 12-lead ECG, should immediately have serum potassium 
assessed, if not already done within 1 hour of performing the ECG. 
All ECG readings will be digitally stored as source documents. 
6.3.5. 
Vital Signs 
The following variables will be collected after the subject has rested in the supine position for 
at least 5 minutes: 
• 
Systolic BP (mmHg) 
• 
Diastolic BP (mmHg) 
• 
Pulse (bpm) 
• 
Tympanic temperature (°C) 
 
The measurement of vital signs will be carried out according to the relevant Parexel SOPs. 
6.4. 
Pharmacokinetics 
6.4.1. 
Collection of Pharmacokinetic Samples 
Whole blood samples for the determination of concentrations of tacrolimus/cyclosporin will 
be collected for each treatment period as specified in the SoA (Table 3). 
Samples will be collected, handled, labelled, stored and shipped as detailed in the Laboratory 
Manual. 
6.4.2. 
Pharmacokinetic Drug Assays 
The PK samples will be analysed by Covance on behalf of AstraZeneca, using validated 
assays. 
Full details of the analytical method and analyses performed will be described in a separate 
bioanalytical report. 


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7. 
BIOLOGICAL SAMPLES PROCEDURES 
All biological samples will be performed by trained staff and in accordance with the Clinical 
Unit’s SOPs. 
7.1. 
Total Blood Volume 
The approximate total amount of blood to be collected from each subject in this study, 
excluding repeat samples, is summarised in Table 6. 
Table 6 
Total Blood Volume 
 
Volume per Sample 
Number of Samples 
Total 
Haematology 
2.7 mL 
6 
16.2 mL 
Clinical chemistry a 
7.5 mL 
6 
45 mL 
Serum potassium 
2.6 mL 
6 
15.6 mL 
PK assessments for 
tacrolimus/cyclosporin 
1 mL 
45 
45 mL 
SARS-CoV-2 antibody testing 
(ELISA) 
2.6 mL 
1 
2.6 mL 
Total 
124.4 mL 
a 
Viral serology testing and follicle stimulating hormone testing (for female subjects) will be performed using 
the clinical chemistry sample collected at the screening visit. 
 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; PK = pharmacokinetics; SARS-CoV-2 = severe 
acute respiratory syndrome coronavirus 2. 
 
Repeat blood samples may be collected for safety reasons. The maximum volume to be drawn 
from each subject must not exceed 500 mL. 
7.2. 
Handling, Storage and Destruction of Biological Samples 
Samples will be disposed of, on instruction from AstraZeneca, after the CSR has been 
finalised, unless samples are retained for additional or future analyses. 
7.2.1. 
Pharmacokinetic Samples 
Pharmacokinetic samples will be disposed of after the bioanalytical report finalisation or 
6 months after issuance of the draft bioanalytical report (whichever is earlier), unless 
requested for future analyses. 
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional analyses 
may be conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from the CSR. 


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Incurred sample reproducibility analysis or additional assay development work, if any, will be 
performed alongside the bioanalysis of the test samples. The results from the evaluation, if 
performed, will be reported in a separate Bioanalytical Report. 
7.3. 
Labelling and Shipment of Biohazard Samples 
Samples will be labelled and shipped in accordance with the Laboratory Manual and the 
Biological Substance, Category B regulations (materials containing or suspected to contain 
infectious substances that do not meet Category A criteria), see Appendix B of this CSP 
‘IATA 6. 2 Guidance Document’. 
Any samples identified as Infectious Category A materials will not be shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
7.4. 
Chain of Custody of Biological Samples 
A full chain of custody will be maintained for all samples throughout their lifecycle. 
The Investigator will ensure full traceability of collected biological samples from the subjects 
while in storage at the centre until shipment and will keep documentation of receipt of arrival. 
The sample receiver will keep full traceability of samples while in storage and during use, 
until used, disposed of, or until further shipment or disposal (where appropriate) and will keep 
documentation of receipt of arrival. 
7.5. 
Withdrawal of Informed Consent for Donated Biological Samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed if not already analysed and the action documented. 
As collection of donated biological samples is an integral part of the study, the subject is 
withdrawn from further study participation. 
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action 
documented, and the signed document returned to the Clinical Unit. 


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8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH-GCP and the AstraZeneca policy on 
Bioethics and Human Biological Samples. 
8.2. 
Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
All clinical study findings and documents will be regarded as confidential. The Investigator 
and members of his/her research team must not disclose such information without prior 
written approval from the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be specified in 
outputs and other documents containing subject data by their subject number, not by name. 
Documents that identify the subject (eg, signed ICF) will be maintained in confidence by the 
Investigator. 
Study data will be stored in accordance with local and global data protection laws. 
8.3. 
Ethics and Regulatory Review 
The study will be submitted to the national regulatory agency, BfArM, for review and 
approval, by Parexel in accordance with local regulatory procedures. 
The study will be submitted to IEC for ethical review and approval by the Investigator in 
accordance with local procedures. 
Parexel will provide the IEC and Investigator with safety updates/reports according to local 
requirements, including SUSARs, where relevant. 
AstraZeneca will provide the regulatory authority with safety updates/reports according to 
local requirements, including SUSARs, where relevant. 
Compensation will be reasonable and related to the nature and degree of inconvenience and 
discomfort as a result of participation in the study. Information on how subjects will be 
compensated is contained in the ICF. 
8.4. 
Insurance 
The Sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements. The name and address of the relevant insurance company, 


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the certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's Site File. 
8.5. 
Informed Consent 
The subjects shall be informed of the nature, significance, implications and risks of this 
clinical study, and informed consent will be freely given and evidenced in writing, dated and 
signed, or otherwise marked, by the subject as evidence to indicate his/her free informed 
consent, prior to the start of the study. 
The nature of the informed consent will comply with the Declaration of Helsinki, the current 
requirements of GCP (EMA/CHMP/ICH/135/1995) and local regulation which ever offers the 
greater subject protection. 
8.6. 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the Investigator and 
AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol. 
If a protocol amendment requires a change to the ICF, the IEC should approve the revised ICF 
before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by the IEC. 


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9. 
DATA QUALITY ASSURANCE AND DATA MANAGEMENT 
9.1. 
Quality Control and Source Data Verification 
Source data verification will be conducted with due regard to subject confidentiality. 
The Clinical Unit will allow the study monitor and Sponsor representative direct access to all 
study documents, medical files and source documents to enable verification of the study data, 
while maintaining the anonymity of the subject and confidentiality of the data. 
Internal quality control will be performed at all stages of the study by the Clinical Unit. 
9.2. 
Audit/Inspections 
The Clinical Unit facilities and all study data/documentation may be audited/inspected by 
independent auditor/inspector/any representatives of regulatory authorities. The Investigator 
must allow the applicable persons access to all relevant facilities and data/documents. The 
Investigator must be available to discuss any findings/issues. 
If an audit was performed, the audit certificate will be included in the CSR. 
9.3. 
Study Monitoring 
The conduct of the study will be monitored by an independent Parexel monitor to ensure 
compliance with applicable regulatory requirements and GCP. The summary of the 
documentation of the monitoring visits will form part of the study documentation and will be 
archived as such. 
Monitoring visits at site will be limited to a minimum required as deemed appropriate during 
COVID-19 pandemic. 
9.4. 
Data Collection 
The ClinBase™ system is an electronic source data capturing and information management 
system. The system combines all aspects of source data capturing with process control and 
clinical study management. All clinical and laboratory data, except those which are 
paper-based or provided by external vendor, will be collected in ClinBase™. Only 
paper-based data will be subject to data entry. For electronic source data, no data entry will be 
performed. 
The responsible study monitor will check data at the monitoring visits to the Clinical Unit. 
The Investigator will ensure that the data collected are accurate, complete and legible. Data 
will be monitored within ClinBase™ by the study monitor before being exported. Any 
changes made during monitoring will be documented with a full audit trail within ClinBase™. 


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9.4.1. 
Case Report Forms and Source Documents 
All data obtained using paper collection methods during the clinical study will be recorded in 
ClinBase™. All source documents from which ClinBase™ entries are derived should be 
placed in the subject’s personal records. 
The original ClinBase™ entries for each subject will be checked against source documents by 
the study monitor. Instances of missing or uninterpretable data will be discussed with the 
Investigator for resolution. 
9.4.2. 
Access to Source Documents 
During the course of the clinical study, a study monitor will make Clinical Unit visits to 
review protocol compliance, compare ClinBase™ entries and individual subject’s personal 
records, assess IMP accountability and ensure that the clinical study is being conducted 
according to pertinent regulatory requirements. ClinBase™ entries will be verified against 
source documents. The review of medical records will be handled confidentially to ensure 
subject anonymity. 
Checking of the ClinBase™ entries for completeness and clarity and verifying with source 
documents will be required to monitor the clinical study for compliance with GCP and other 
regulations. Moreover, regulatory authorities of certain countries, IRBs/IECs may wish to 
carry out source data inspections on-site, and the Sponsor’s clinical quality assurance group 
may wish to carry out audits. Direct access to source data will be required for these 
inspections and audits; they will be carried out giving due consideration to data protection and 
subject confidentiality. The Investigator assures the Sponsor of the necessary support at all 
times. 
9.5. 
Data Management 
Parexel will utilise standardized and validated procedures and systems to collect, process and 
file the clinical data of this study. Any system used will be compliant with FDA 21 Code of 
Federal Regulations Part 11 requirements. 
A DMP will be prepared to describe the processes and data flow within the clinical study. 
Timelines, versions for the computer systems and the coding will be defined in the DMP, and 
if applicable, sponsor specific requests will also be documented within. The DMP will be 
finalised before first dose where possible, but before database lock. 
A DVS will be created to outline the validation checks to be performed during the study. The 
DVS must be finalised before data validation. 
After the data has been monitored by the responsible study monitor all data received will be 
reviewed, logged and filed. 


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The raw data intended for further processing will be checked by standard routines or 
according to the DVS and queries will be generated and sent to the Investigator for review and 
resolution. Corrections resulting from these queries will be confirmed on the data clarification 
forms. This process will be repeated until no further discrepancies are found. The data will 
then be declared as clean. Applicable documentation will be stored in the study files. 
Only trained study staff will have access to the clinical database and every change in data will 
have a full audit trail. 


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10. 
EVALUATION AND CALCULATION OF VARIABLES 
10.1. 
Safety Variables 
10.1.1. 
Adverse Events 
All AEs will be coded using the latest version of the MedDRA vocabulary and will be listed 
for each subject. 
Adverse events will be assigned to a treatment based on the start date/time of the AE in 
relation to dosing in that period; for tabulation purposes the AE will then be assigned to the 
treatment received in the respective treatment period as follows: 
• 
Treatment Period 1: AEs with start date/time at the time of or after dosing in Treatment 
Period 1 until the time of dosing in Treatment Period 2. 
• 
Treatment Period 2: AEs with start date/time at the time of or after dosing in Treatment 
Period 2 until the Follow-up Visit. 
 
For assigning AEs to a specific treatment/dose, the following guidelines should be followed: 
• 
Adverse events with start date/time at the time of or after dosing (for each specific 
treatment) until the next treatment/dose or until Follow-Up Visit will be assigned to the 
specific treatment/dose (including washout period). 
• 
Adverse events with unknown start times, but with start date known, will be imputed with 
a time of 00:00, unless the start date corresponds to any given dosing date. In this case the 
start time will be imputed with the time of dosing. If this results in a start date/time after 
end date/time of the AE, then the time will also be imputed with 00:00. 
• 
Adverse events with completely unknown start dates will be imputed with the date and 
time of dosing, unless the end date is known and prior to dosing; in that case the start date 
will be imputed as the date of Screening and a time of 00:00. 
• 
Adverse events with partially known start dates/times will be treated as follows: 
− 
If only the day is missing, then the day will be imputed with the first day of the 
month, unless the month and year in which the AE started is a month and year in 
which IMP was administered, then the day will be imputed with the first day on 
which IMP was administered in that month. If this results in a start date after the end 
date, then the day will be imputed with the first day of the month. 
− 
If only the month is missing and the year is a year in which IMP was administered, 
then the month will be imputed with the first month in which IMP was administered. 
If this results in a start date after the end date of the AE, then the month will be 
imputed with JAN. If the known year part is not a year in which IMP was 
administered, then the month will also be imputed with JAN. 
− 
If both the day and month is missing and the year is a year in which IMP was 
administered, then the day and month will be imputed with the day and month of 


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dosing. If this results in a start date after end date, then the day and month will be 
imputed with 01JAN. If the year is not a year in which IMP was administered, then 
the day and month will also be imputed with 01JAN. 
− 
If only the year is missing, then the year will be imputed with the year of dosing. 
 
Adverse events with onset (start date/time) after dosing in Treatment Period 1 will be 
summarised by treatment and overall for all subjects, including tabulations by causality and 
severity (mild, moderate and severe). All tabulations will be presented by SOC and PT. 
Furthermore, separate listings of SAEs, AEs that led to discontinuation and AEs that led to 
death will be presented. 
The following information will be included in the listings: verbatim term, SOC, PT and lowest 
level term, start date/time, end date/time, time from last dose, causality, action taken, whether 
the AE was classified as serious and the outcome. 
All tabulations will include the number and percentage of subjects. In addition, a separate 
tabulation will be presented showing the number of events by treatment and PT. 
Finally, an overview of all AEs will be presented, separately for the number and percentage of 
subjects. This will include categories for any AE, AEs leading to discontinuation, AEs with 
outcome of death and SAEs. 
10.1.2. 
Laboratory Assessments 
Haematology and clinical chemistry values will be listed by subject and time point including 
changes from baseline and repeat/unscheduled measurements. Summary tabulations including 
absolute value and changes from baseline will be presented by treatment and time point for the 
safety analysis set. The baseline for the measurements will be the last measurement prior to 
dosing in the respective treatment periods. When a value is not available prior to treatment, 
the screening value will be taken as baseline. Changes from baseline will be calculated and 
presented for all post-baseline time points including the Follow-up Visit. Shift tables will also 
be presented for certain parameters. 
A summary of the key subject information on the laboratory changes outside the predefined 
criteria will also be presented. 
Any laboratory parameters with results from the laboratory given as “< xx” or “>xx” in the 
database will be imputed with the absolute value of the number without the sign (eg, < 2.2 will 
be imputed as 2.2) for the descriptive statistics and changes from baseline. 
The listings will include the following information: test name, date of measurement, reference 
range, result and flags for any measurements that are outside the reference range (eg, 


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AstraZeneca, program, or laboratory ranges). Clinical laboratory data will be reported in 
System International units in the CSR. 
Additional listings will be presented for the following: 
• 
Urinalysis (macroscopic and microscopic, if applicable). 
• 
FSH. 
 
The results of viral serology (including SARS-CoV-2 serology), SARS-CoV-2 RT PCR, and 
the drugs of abuse and alcohol screen will not be listed in the CSR. 
Lastly, a summary describing subjects with potential Hy’s Law results will be presented by 
subject and time point. Parameters might include ALT, AST, total bilirubin and ALP. 
10.1.3. 
Physical Examination 
The baseline/screening results of the physical examination will be documented in medical 
history for each subject. 
Any new or aggravated clinically relevant abnormal medical physical examination finding 
compared to the baseline assessment will be reported as an AE. 
10.1.4. 
Resting 12-lead Electrocardiogram 
Results of the safety ECGs (normal/abnormal assessments and specific findings) will be listed 
for each subject. 
Electrocardiogram parameter results will also be listed by treatment for each subject and time 
point of PR, RR, QRS, QT interval and the derived values of QTcF and HR. All parameters 
will have changes from baseline derived and presented. 
The following ECG parameters will be derived: 
• 
QTcF will be calculated as QTcF = QT*RR-1/3 where the QT interval is in milliseconds 
and the RR interval is in seconds 
• 
HR will be calculated, based on the RR interval as HR = 60/RR interval, where the RR 
interval is in seconds 
 
Descriptive statistics will be presented by treatment and time-point for the original and 
changes from baseline values of PR, RR, QRS, QT; derived values and changes from baseline 
for QTcF and HR will also be included. The baseline for the ECG measurements will be the 
pre-dose assessment on Day 1. 


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Outliers with respect to QTcF will also be tabulated for the following categories: 
• 
Absolute value > 450 ms and ≤ 480 ms. 
• 
Absolute value > 480 ms and ≤ 500 ms. 
• 
Absolute value > 500 ms. 
• 
Increase from baseline > 30 ms and ≤ 60 ms. 
• 
Increase from baseline > 60 ms. 
 
All calculations of ECG parameters and reporting described in this section will be performed 
by Parexel. 
10.1.5. 
Vital Signs 
The results of the vital signs measurements will be listed by subject and time point including 
the date/time of the assessment, changes from baseline and repeat/unscheduled measurements. 
The baseline for vital signs measurements will be last measurement prior to dosing in the 
respective treatment periods. Descriptive statistics will be presented by treatment and time 
point for both observed values and changes from baseline. 
10.2. 
Pharmacokinetics 
10.2.1. 
Whole Blood Pharmacokinetic Parameters 
The following PK parameters will be determined where possible from the whole blood 
concentrations of tacrolimus/cyclosporin. 
Primary PK parameters 
AUCinf 
Area under concentration-time curve from time zero to infinity 
AUClast 
Area under the concentration-time curve from time zero to time of last quantifiable 
concentration 
Cmax 
Maximum observed concentration 
 
Secondary PK parameters 
tmax 
Time to reach maximum observed concentration following drug administration 
t½λz 
Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-
time curve 
CL/F 
Apparent total body clearance of drug after extravascular administration 
Vz/F 
Apparent volume of distribution during the terminal phase after extravascular 
administration 
 


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The following diagnostic parameters will also be determined: 
λz 
Terminal elimination rate constant 
λz lower 
Lower (earlier) t used for λz determination 
λz upper 
Upper (later) t used for λz determination 
λz, N 
Number of data points used for λz determination 
λz span ratio 
Time period over which λz was determined as ratio of t½λz 
Rsq adj 
Statistical measure of fit for the regression used for λz determination adjusted for 
the number of used data points (n obs) 
AUCextr 
Extrapolated area under the curve from tlast to infinity, expressed as percentage of 
AUCinf 
 
Additional PK parameters may be determined where appropriate. 
10.2.2. 
Calculation or Derivation of Pharmacokinetic Parameters 
The PK analyses of the whole blood concentration data for tacrolimus/cyclosporin will be 
performed by Covance, on behalf of AstraZeneca, according to the AstraZeneca standards 
(LDMS_001_00201968 dated 13 July 2020). 
PK parameters will be derived using non-compartmental methods with Phoenix® WinNonlin® 
Version 8.1, or higher. 
Pharmacokinetic analysis will, where possible, be carried out using actual times recorded in 
the raw data. If actual times are missing, nominal times will be used. 
Concentration data will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with the amount and concentration units, 
will be presented as they are received from the analytical laboratory unless otherwise specified 
on the PK order form. 
The Cmax and tmax will be derived directly from the plasma concentration-time profiles. For 
multiples peaks the highest post-dose concentration will be reported as Cmax. In the case that 
the multiple peaks are of equal magnitude, the earliest tmax will be reported. 
Plasma concentrations which are BLQ prior to the administration of the first dose and up to 
the quantifiable concentration will be set to a value of zero with the following exceptions: 
• 
After the first quantifiable concentration, any BLQ concentrations will be set to missing 
for all concentration profiles. 
• 
Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and therefore any further quantifiable concentrations 


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will be set to missing for the calculation of the PK parameters unless it is considered to be 
a true characteristic of the profile of the drug. 
• 
Any embedded BLQ value (between 2 quantifiable concentrations) will be set to missing 
for the purposes of PK analysis. 
• 
If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
 
Terminal elimination half-life, calculated as (ln2)/λz, will be estimated by log-linear 
least-squares regression of the terminal part of the concentration-time curve. For the 
determination of λz, the start of the terminal elimination phase for each subject will be defined 
by visual inspection and will be the first point observed after Cmax at which there is no 
systematic deviation from the log-linear decline in plasma concentrations. A minimum of 
3 data points will be used in calculating λz, and the duration of time over which λz is 
recommended to be at least 3 times the subsequently estimated terminal half-life. Where an 
elimination half-life is estimated over less than 3 times the subsequently estimated terminal 
half-life, the robustness of the data will be discussed in the study report. The adjusted 
correlation coefficient (Rsq_adj) should be ≥ 0. 80. Where Rsq_adj < 0. 8 t½λz and related 
parameters will be listed, flagged and excluded from descriptive and inferential statistics. 
AUCinf is estimated by AUClast + Clast/λz where Clast is the observed last quantifiable drug 
concentration. 
AUCs (including AUCinf and AUClast) will be calculated using the linear trapezoidal method 
when concentrations are increasing and the logarithmic trapezoidal method when 
concentrations are decreasing (linear up log down). 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive plasma concentrations above the LLOQ, with at least 1 of these concentrations 
following Cmax. 
If AUCinf cannot be determined for all subjects or all dose levels, an alternative AUC 
measure, such as AUC to a fixed time point, may be used in the evaluation of DDI. 
If the concentration at the time of dosing is missing, then this will be set to 0. 
Pharmacokinetic parameters associated with positive pre-dose value(s) of greater than 5% 
Cmax may be excluded from the summary statistics of PK tables and statistical analysis at the 
discretion of the pharmacokineticist. 


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11. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
11.1. 
Description of the Analysis Sets 
11.1.1. 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of tacrolimus 
(Cohort 1) or cyclosporin (Cohort 2) and for whom any safety post-dose data are available. 
Unless otherwise stated, the randomised set will be used for the presentation of all 
demographic and disposition data, and the safety analysis set will be used for all safety 
analyses. Exposure to IMP will also be presented using the safety analysis set. 
11.1.2. 
Pharmacokinetic Analysis Set 
The PK analysis set will consist of all subjects in the safety analysis set and who received at 
least one quantifiable whole blood concentration post-dose tacrolimus (Cohort 1) or for 
cyclosporin (Cohort 2) with no important protocol deviations or AEs thought to impact the 
analysis of the PK data. A subject may be excluded if vomiting occurs at or before 2x the 
median tmax for the dose group and treatment. Data from subjects for whom the pre-dose 
concentration is > 5% of Cmax may be excluded for that treatment period. 
The exclusion of any subjects or time points from the calculation of the PK parameters will be 
documented by the PK Scientist including the reason(s) for exclusion. 
The available concentration data and PK parameter data for any subjects excluded from the 
PK analysis set will be listed only. Concentration data for subjects excluded from the PK 
analysis set will be presented in the individual figures of concentration versus time plots. 
11.1.3. 
Randomised Set 
The randomised set will consist of all subjects randomised into the study. 
11.2. 
Methods of Statistical Analyses 
11.2.1. 
General Principles 
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned. 
If circumstances should arise during the study rendering the analysis inappropriate, or if in the 
meantime improved methods of analysis should come to light, different analyses may be 
performed. A separate SAP will not be written for the study. Any deviations from the 
statistical methodology defined in this protocol, reasons for such deviations and all 
alternative/additional statistical analyses that may be performed will be described in the CSR. 


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Such changes to analyses may be written into an abbreviated SAP, if appropriate. The 
verification and review of all statistical modelling assumptions will be documented 
appropriately. 
All analyses discussed below will be replicated for both of the cohorts. 
Data listings will be based upon the safety analysis set. All original and derived PK 
parameters will be summarised using the PK set. Demographic and disposition data will be 
summarised, using the safety set. Safety data will be summarised using the safety set. 
All summaries done "by treatment" will be performed by actual treatment, rather than 
treatment to which a subject was randomised. 
For each cohort, demographic and baseline data will be summarised for all subjects in the 
randomised, by sequence and overall. Pharmacokinetic data will be summarised by treatment, 
or treatment and time point, as appropriate. Adverse events will be presented by treatment and 
overall. Safety data collected at multiple occasions within the same period will be presented 
by treatment, time point and overall. 
Frequency counts (number of subjects [n] and percentages) will be made for categorical 
variables. Descriptive statistics (n, mean, SD, median, minimum and maximum) will be 
calculated for continuous variables. Descriptive statistics will only be presented if n ≥ 3. If no 
subjects have data at a given time point, then only n = 0 will be presented. If n < 3, only the n, 
minimum and maximum will be presented. The other descriptive statistics will be left blank. 
The following rules will apply to any repeated safety assessments occurring within each 
treatment period: 
• 
If the repeated measurement of a specific parameter occurs prior to IMP administration 
(Day 1), then the last obtained value prior to dosing will be used (as baseline) in the 
descriptive statistics and in the calculation of changes from baseline; 
• 
If the repeated measurement of a specific parameter occurs after IMP administration 
(Day 1), then the first (non-missing) value after dosing will be used in descriptive 
statistics and in the calculation of changes from baseline. 
 
The planned sequence for measurement of multiple assessments at the same time point is 
described in Section 3.1.1. 
For safety assessments performed at screening and the follow-up, the following rules will 
apply for any repeated assessments: 
• 
If the repeated assessment occurs at screening the last available value will be used in the 
summary statistics; 


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• 
If the repeated assessment occurs at the Follow-up Visit the first non-missing assessment 
will be used in the summary statistics. 
 
All statistical analyses and production of tables, figures and listings will be performed using 
SAS® version 9.4 or later. 
11.2.2. 
Missing Data 
Missing dates and times in the AE data will be handled as described in Section 10.1.1. 
Concentrations that are non-quantifiable in the PK data will be handled as described in 
Section 10.2.2. 
There will be no imputations of other missing data. All subjects will be included in the safety 
analyses as far as the data permit. 
11.2.3. 
Subject Disposition 
A randomisation listing will be presented and include the following: each subject’s 
randomisation number, the subject’s full enrolment number, the treatment to which the subject 
has been randomised and the country where the study centre is located. 
Subjects and/or data excluded from the PK analysis set will be listed including the reason for 
exclusion. Subject disposition will be listed and summarised, and the summary will include 
the following information: number of subjects randomised and dosed, number and percentage 
of subjects dosed in the study, number and subjects completing study and number and 
percentage of subjects who were withdrawn (including reasons for withdrawal). Disposition 
data will be presented based on all subjects randomised. 
Subject discontinuations will be listed including the date of study exit, sequence, period, 
treatment received, date/time discontinuation, and treatment/study discontinuation (including 
reason for discontinuation) information. 
11.2.3.1. 
Demographic and Baseline Data 
Demographic variables (age, gender, race, ethnicity, height, weight and BMI) will be listed by 
subject. Demographic characteristics (age, gender, race and ethnicity) and subject 
characteristics (height, weight and BMI) will be summarised separately for all randomised 
subjects. The denominator for percentages will be the number of randomised subjects. 
Medical history data will be listed by subject including visit, description of the 
disease/procedure, MedDRA SOC, MedDRA PT, start date and stop date (or ongoing if 
applicable). 


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11.2.4. 
Prior and Concomitant Medication and Drug Administration 
11.2.4.1. 
Prior and Concomitant Medication 
Prior medications are those that started and stopped prior to the first dose of IMP; all 
medications taken after first dosing are considered as concomitant (including medications that 
started prior to dosing and continued after). Prior medication started within 3 months prior to 
the first dose of IMP will be recorded also in the concomitant medication module of 
ClinBase™. Prior medications that were started before 3 months of first dose of IMP will not 
be recorded. 
Prior and concomitant medication will be listed by subject and will include the following 
information: reported name, PT, the route of administration, dose, frequency, start date/time, 
duration, stop date/time and indication. Prior and concomitant medication will be coded 
according to the Sponsor’s drug dictionary. 
The duration will be calculated as: 
• 
Duration = end date/time – start date/time (+1 day, if time is not available) 
 
The duration may be presented in hours or days in the listing depending on the applicability to 
the emerging data. For medications with partial or completely missing start date/times and/or 
end date/times, the duration will not be calculated. 
Medications with missing or partial start date/time and/or end date/time such that it is not 
possible to classify as prior or concomitant will be considered as concomitant in the listings. 
11.2.4.2. 
Drug Administration 
Drug administration dates and times will be listed for each subject. 
11.2.5. 
Safety and Tolerability 
All safety data (scheduled and unscheduled) will be presented in the data listings. Continuous 
variables will be summarised using descriptive statistics (n, mean, SD, minimum, median, 
maximum). Categorical variables will be summarised in frequency tables (frequency and 
proportion). The analysis of the safety variables will be based on the safety analysis set. 
Safety measurement with start date/time at the time of or after dosing (for each specific 
treatment) until the next treatment/dose or until Follow-Up Visit will be assigned to the 
specific treatment/dose (including washout period). 
Adverse events will be summarised by SOC and PT using MedDRA vocabulary. Furthermore, 
listings of SAEs and AEs that led to withdrawal will be made and the number of subjects who 
had any AE, SAEs, AEs that led to withdrawal, and AEs that led to death will be summarised. 
Serious adverse events that occur before dosing will be reported separately. 


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Tabulations and listings of data for vital signs, clinical laboratory tests and ECGs will be 
presented. Any new or aggravated clinically relevant abnormal medical physical examination 
finding compared to the baseline assessment will be reported as an AE. Data will be 
summarised for the observed values at each scheduled assessment, together with the 
corresponding changes (and/or percentage change) from the baseline when baseline value 
exists, by treatment. Clinical laboratory data will be reported in Système International units in 
the CSR. 
Out-of-range values for safety laboratory will be flagged in individual listings as well as 
summarised descriptively using agreed standard reference ranges and/or extended reference 
ranges (eg, AZ, program, or laboratory ranges). 
11.2.6. 
Pharmacokinetics 
All PK concentration, parameter summaries and statistical analyses will be presented for the 
PK analysis set, unless otherwise specified. The PK concentration and parameter listings will 
be presented for the safety analysis set and will include all reportable individual PK results. 
Any PK concentration and parameter data not included in the PK statistical analyses will be 
included in the listings and flagged with an appropriate footnote. 
A listing of PK blood sample collection times, as well as derived sampling time deviations 
and concentrations at each protocol scheduled time point will be provided. Whole blood 
concentrations will be summarised by treatment and nominal time points descriptively. The 
PK parameters will be summarised by treatment using appropriate descriptive statistics. 
The listings, summaries and figures will be presented in accordance with the most recent 
version of the AstraZeneca Corporate CSRHLD Standards and the Final version of the 
TFL shells for this study. This include the applicable descriptive statistics, handling of 
individual concentrations below the LLOQ for listings, descriptive statistics and figures, and 
precision and rounding rules for concentrations and PK parameter data. 
Individual concentrations with time deviations of ≥ ±10% from the protocol scheduled time, 
will be used in the PK analysis but will be flagged for exclusion from the summary tables and 
corresponding figures. 
Protocol scheduled times will be used to present the PK concentration summary tables and 
corresponding gmean concentration-time figures. 
11.2.6.1. 
Graphical Presentation of Pharmacokinetic Data 
Individual, combined individual, and gmean plots will be presented. All gmean plots or 
combined individual plots showing all subjects by treatment will be based on the PK analysis 
set. Separate plots for each Cohort will be provided. Individual plots by subject will be based 
on the safety analysis set. 


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For consistency, the plasma concentration values used in the gmean data graphs will be those 
given in the descriptive statistics summary table for each time point. 
Individual plasma concentrations versus actual elapsed time after dose will be plotted on both 
the linear and semi-logarithmic scale with both treatments overlaid on the same plot and 
separate plots for each subject, and separate plots for each cohort. 
Combined individual plasma concentration versus actual times will be plotted on both the 
linear and semi-logarithmic scale. Plots will be grouped by treatment and separate plots for 
each cohort. 
The gmean plasma concentration (-/+gSD) versus nominal sampling time will be plotted on 
both the linear and semi-logarithmic scale with treatments overlaid on the same figure, and 
separate plots for each cohort. 
11.2.6.2. 
Statistical Analysis of Pharmacokinetic Data 
The below analyses will be performed for each of the 2 cohorts. 
The difference in mean PK parameters (Cmax, AUCinf) for the 2 cohorts will be analysed 
using a mixed effects model following a natural logarithmic transformation of the individual 
PK parameters, with period, treatment and sequence as fixed effects, and subject nested within 
sequence as random effects. Least-squares means (LSM) for each treatment, the difference 
thereof, and the corresponding 2-sided 90% confidence intervals (CIs) for the log-transformed 
values will be presented. The corresponding geometric LSM for each treatment, the ratio 
thereof, and the 2-sided 90% CI will be estimated and presented as well. 
The limits for the 90% CIs for the geometric mean ratio will be compared to the pre-specified 
interval (0.8000% to 1.2500%) for conclusion of no DDI (ie, if the CI lies entirely within the 
predetermined 0.8 and to 1.25 range, it will be concluded that SZC has no meaningful effect 
on the PK for tacrolimus/cyclosporin). 
Statistical analysis will be done by using PK analysis set. 
This mixed effects statistical model will be repeated for the secondary PK variables of 
AUClast, t½λz, and tmax, for both cohorts. 
11.3. 
Protocol Deviations 
Protocol deviations are considered any deviation from the CSP relating to a subject, and 
include the following: 
• 
Inclusion/exclusion criteria deviations 


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 3  of 8 5  
•  
D osi n g de viati o ns (e g, i nc orrect treat me nt recei ve d, s u bject was n ot faste d as per t he 
pr ot oc ol re q uire m e nts pri or t o a n d after d osi n g) 
•  
Ti me wi n d o w de viati o ns f or saf et y a n d/ or P K assess me nts 
•  
S u bjects recei vi n g pr o hi bite d c o nc o mita nt me di cati o ns 
•  
Ot her pr oce d ural a n d st u d y c o n d uct de viati o ns rec or de d b y t he Cli nical U nit o n a pr ot oc ol 
de viati o n l o g 
 
T he criteri a f or t he assess me nt a n d re p orti n g of pr ot oc ol de viati o ns will be sti p ulate d i n a 
se parat e st u d y s pecific pr ot oc ol de viati o n s pecificati o n d oc u me nt. T his will i ncl u de a W A D  
w hic h sti p ulates t olera nce wi n d o ws f or safet y a n d P K assess me nts. Meas ure me nts perf or me d 
wit hi n t hese t olera nce wi n d o ws will n ot be c o nsi dere d as pr ot oc ol de viati o ns a n d will n ot be 
re p orte d. 
All pr ot oc ol de viati o ns will be disc usse d at t he dat a re vie w m eeti n g pri or t o data base h ar d 
l oc k i n or der t o defi n e t he a nal ysis sets f or t he st u d y. 
I m p ort a nt pr ot oc ol de viati o ns will be liste d b y s u bject. Pr ot oc ol de viati o ns ( missi n g 
assess me nts/ visits) relate d t o C O VI D -1 9 will be liste d se parat el y.  
Pr ot oc ol de viati o ns will be ha n dle d i n acc or d a nce wit h Pare xel S O Ps. 
F or ha n dli n g of pr ot oc ol a me n d me nts, see Secti o n  8. 6 . 
1 1. 4.  
Deter mi n ati o n of S a m ple Size  
 
 
 
 
 
 
 
 
C CI


Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 4  of 8 5  
1 2.  
I M P O R T A N T M E DI C A L P R O C E D U R E S T O B E F O L L O W E D 
B Y T H E I N V E S TI G A T O R  
1 2. 1.  
Me dic al E mer ge ncies a n d Astr a Ze nec a C o nt acts  
I n case of me dical e mer g e nc y, t he pri mar y c o ntact is t he Pri nci pal I n v esti gat or, w h o ma y 
c o ntact t he S p o ns or’s Lea d P h ysicia n. If t he Pri nci pal I n v esti gat or  ca n n ot b e reac he d, t he 
site’s staff will c o ntact t h e De p ut y Pri nci pal I n v esti gat or or desi g nee or ma y c o ntact S p o ns or’s 
Lea d P h ysicia n . 
N a m e  
R ole i n t he St u d y  
C o nt act Det ails  
T h o mas K oer nic ke  
Pri nci pal I n vesti gat or  
Pare xel Earl y P hase Cli nical U nit Berli n  
 
 
1 4 0 5 0 Berli n  
Ger ma n y  
Tel: 
 
Fre dri k T h oré n  
S p o ns or’s Lea d P h ysicia n  
Astra Ze neca P har mace uticals  
 
 
S we de n  
Tel: 
 
M o bile: 
 
 
1 2. 2.  
Pre g n a nc y  
All pre g na ncies a n d o utc o mes of pre g n a nc y s h o ul d be re p ort e d t o Astra Ze neca e xce pt: 
•  
If t he pre g n a nc y is disc o vere d bef ore t h e st u d y patie nt has recei ve d a n y I M P. 
 
If a pr e g na nc y is r e p orte d, t he I n v esti gat or s h o ul d i nf or m t he S p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pr e g na n c y. 
A b n or mal pre g n a nc y o ut c o mes (e g, s p o nta n e o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g n a nc y) are c o nsi dere d S A Es . 
Please ref er t o Secti o n  4. 2. 1. 2  f or f urt her details. 
P P D
P P D
P P D
P P D
P P D


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12.2.1. Paternal Exposure 
Male subjects should refrain from fathering a child during the study and for 3 months 
following the last dose. 
In case of pregnancy of the partner of a male patient, the partner’s pregnancy should be 
reported on the pregnancy form (consent from the partner must be obtained before the 
pregnancy form is completed) following the same timeframe and routing as described for any 
subject’s pregnancy. Pregnancy of the patient’s partner is not considered to be an AE. These 
pregnancies will also be followed up, and the outcome of the pregnancy (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should, if possible, be obtained and documented. 
Please refer to Section 4.2.1.2 for further details. 


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13. 
LEGAL AND ADMINISTRATIVE ASPECTS 
13.1. 
Archiving of Study Documents 
All source documents generated in connection with the study will be retained in the limited 
access file storage area, respecting the privacy and confidentiality of all records that could 
identify the subjects. Direct access is allowed only for authorized people for monitoring and 
auditing purposes. Source documents will be handled, stored and archived according to 
in-house procedures. 
The Investigator’s Site File will be archived by the contract research organisation for at least 
15 years after completion of the study. 
13.2. 
Publication of Study Results 
All of the study information and data collected during the study are confidential and the 
property of AstraZeneca. After completion of the study, AstraZeneca may prepare a joint 
publication with the Investigator. The Investigator must undertake not to submit any data from 
this CSP for publication without prior consent of AstraZeneca at a mutually agreed time. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
13.3. 
Clinical Study Report 
An integrated CSR will be prepared in accordance with the standards of the ICH guideline for 
structure and content of clinical study reports (ICH E3). Copies of the CSR will be provided to 
the IRB/IEC and the national regulatory authority in accordance with regulatory requirements 
and Parexel SOPs. In the event of premature termination of the study or other conditions 
specified in ICH E3, an abbreviated CSR may be prepared. 


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14. 
REFERENCE LIST 
Cyclosporin SmPC 
Summary of product characteristics, Sandimmun (Cyclosporin) 
EMA 28 April 2020 
European Medicines Agency. Guidance on the Management of clinical trials during the 
COVID-19 (Coronavirus) pandemic, Version 3, dated 28 April 2020. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
FDA 16 April 2020 
Food and Drug Administration; FDA Guidance on conduct of clinical trials of medical 
products during COVID-19 public health emergency, dated March 2020, updated on 
16 April 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-
public-health-emergency 
IB, SZC 2019 
Investigator’s Brochure, LOKELMA™ (also known as sodium zirconium cyclosilicate), 
Edition Number 9.0, 21 September 2019. 
Prograf SmPC 
Summary of product characteristics, Prograf® (Tacrolimus). 


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15. 
APPENDICES 
Appendix A Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event 
Life-threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
Important Medical Event or Medical Intervention 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the subject or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
Examples of such events are: 
• 
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment. 
• 
Hepatotoxicity caused by paracetamol/acetaminophen overdose requiring treatment with 
N-acetyl cysteine. 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion) or convulsions 
that do not result in hospitalisation. 
• 
Development of drug dependency or drug abuse. 
 


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A Guide to Interpreting the Causality Question 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the IMP. 
• 
Time course / Exposure to suspect drug: 
Has the subject actually received the suspect drug? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect drug? 
• 
Consistency with known drug profile: 
Was the AE consistent with the previous knowledge of the suspect drug (pharmacology and 
toxicology) or drugs of the same pharmacological class? OR, could the AE be anticipated 
from its pharmacological properties? 
• 
Dechallenge experience: 
Did the AE resolve or improve on stopping or reducing the dose of the suspect drug? 
• 
No alternative cause: 
The AE cannot be reasonably explained by other aetiology such as the underlying disease, 
other drugs, other host or environmental factors. 
• 
Rechallenge experience: 
Did the AE reoccur if the suspected drug was reintroduced after having been stopped? 
Note: AstraZeneca would not normally recommend or support a rechallenge. 
• 
Laboratory tests: 
A specific laboratory investigation (if performed) has confirmed the relationship? 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. The causality assessment is 
performed based on the available data including enough information to make an informed 
judgment. With limited or insufficient information in the case, it is likely that the event(s) will 
be assessed as ‘not related’. Causal relationship in cases where the disease under study has 
deteriorated due to lack of effect should be classified as no reasonable possibility. 


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Appendix B International Airline Transportation Association 6. 2 
Guidance Document 
Labelling and Shipment of Biohazard Samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories (http://www. iata. org/whatwedo/cargo/dangerous_goods/infectious_substances. 
htm). For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt. There is 
no direct relationship between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are for example, Ebola and Lassa 
Fever viruses. Category A pathogens: 
Are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are for example, hepatitis A, B, C, D and E 
viruses, and human immunodeficiency virus (HIV) types 1 and 2. They are assigned the 
following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
Are to be packed in accordance with UN3373 and IATA Instruction 650. 
 
Exempt refers to all other materials with minimal risk of containing pathogens. 
• 
Clinical trial samples will fall into Category B or Exempt under IATA regulations. 
• 
Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging.   
(http://www. iata. org/whatwedo/cargo/dangerous_goods/infectious_substances. htm) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry ice content. 
• 
International Airline Transportation Association compliant courier and packaging 
materials should be used for packing and transportation. Packing should be done by an 
IATA certified person, as applicable. 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and packaging / 
containment materials at all times. The IATA 650 biological sample containment 
standards are encouraged wherever possible when road or rail transport is used. 


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Appendix C Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law 
C 1 
Introduction 
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also AE data (eg, for AEs that may indicate elevations in liver 
biochemistry) for possible PHL events. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than DILI caused by the IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
C 2 
Definitions 
Potential Hy’s Law 
Aspartate aminotransferase or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN at any point 
during the study following the start of IMPs irrespective of an increase in ALP. 
Hy’s Law 
Aspartate aminotransferase or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN, where no 
other reason, other than the IMP, can be found to explain the combination of increases, eg, 
elevated ALP indicating cholestasis, viral hepatitis, another drug. 


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For PHL and HL the elevation in transaminases must precede or be coincident with (i. e. , on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
C 3 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
• 
AST ≥ 3 x ULN. 
• 
ALT ≥ 3 x ULN. 
• 
TBL ≥ 2 x ULN. 
 
If local laboratories are being used: 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative. 
• 
Determine whether the subject meets PHL criteria (see Section 2 within this appendix for 
definition) by reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory CRF module(s). 
 
C 4 
Follow-Up 
C 4.1 
Potential Hy’s Law Criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the subject has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP. 
 
C 4.2 
Potential Hy’s Law Criteria met 
If the subject does meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team. 
• 
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting. 


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• 
For subjects that met PHL criteria prior to starting IMP, the Investigator is not required to 
submit a PHL SAE unless there is a significant change2 in the subject’s condition. 
• 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data. 
− 
Subsequent to this contact the Investigator will: 
o 
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
o 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests 
available in the HL laboratory kit should be used (if applicable). 
o 
Complete the 3 liver CRF modules as information becomes available. 
 
C 5 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date the PHL criteria were met. The AstraZeneca Global Clinical Lead or equivalent 
and Global Safety Physician will also be involved in this review together with other subject 
matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the AST or ALT and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets any criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF module(s). 
 
2 A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms. The determination of whether there has been a significant change will 
be at the discretion of the Investigator, this may be in consultation with the Study Physician if there is any 
uncertainty. 


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• 
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRF entries accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the AST or ALT and TBL 
elevations other than the IMP: 
• 
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes: 
− 
The ‘Medically Important’ seriousness criterion should be used if no other 
seriousness criteria apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for HL, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of PHL (report term now 
‘Hy’s Law case’), ensuring causality assessment is ‘related to IMP’ and seriousness 
criterion is ‘medically important’, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
C 6 
Laboratory Tests 
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgment. Any test results need to be 
recorded. 


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Hy’s Law laboratory kit for central laboratories (18 December 2018) 
Additional standard biochemistry and 
coagulation tests 
GGT (Gamma glutamyl transferase) 
LDH (Lactate dehydrogenase) 
Prothrombin time 
INR (International normalised ratio) 
Viral hepatitis 
IgM anti-HAV  
IgG anti-HCV 
IgM and IgG anti-HBc 
HCV RNA* 
HBsAg 
IgM anti-HEV 
HBV DNA 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-transferrin) 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
* HCV RNA is only tested when anti-HCV is positive or inconclusive. 
 
REFERENCES 
Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in 
drug‐induced liver injury. Clinical Pharmacology & Therapeutics 2011;89(6):806–15. 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. 


Cli nical St u d y Pr ot oc ol  – Ger ma n y A d de n d u m  
Astra Ze neca  
S o di u m zirc o ni u m c ycl osilicate  - D 9 4 8 0 C 0 0 0 1 2  
2 8  Se pte m ber  2 0 2 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
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Cli nic al St u d y Pr ot oc ol  – Ger m a n y A d de n d u m  
A T w o -C o h ort, R a n d o mi se d Se q ue nce, Cr oss -o ver, O pe n -l a bel 
S t u d y t o A ssess t h e E ffe ct of a Si n gl e D ose of S o di u m Zirc o ni u m 
C ycl osilic ate ( S Z C) o n t he P h ar m a c o ki netics of T acr oli m us a n d 
C ycl os p ori n i n He alt h y S u bjects 
P are xel  St u d y N o .: 
 
S p o ns or St u d y C o de:  
D 9 4 8 0 C 0 0 0 1 2  
E u dr a C T N o .: 
2 0 2 0 -0 0 0 5 1 5 -6 8  
St u d y T y pe  
Dr u g -dr u g i nteracti o n ( D DI) st u d y 
Test Pr o d uct:  
S o di u m zirc o ni u m c ycl osilicate / S Z C 
I nter acti o n Pr o d uct s: 
Tacr oli m us  a n d c yclos p ori n  
T her a pe utic I n dic ati o n:  
H y per kalae mia  
P h ar m ac ol o gic al Cl ass:  
N o n -p ol y mer, i n or ga nic cati o n -e xc han ger  
De vel o p m e nt P h ase:  
P hase I 
S p o ns or:  
Astra Ze neca A B  
1 5 1 8 5 S ö der tälje 
S we de n  
St u d y Ce ntr e: 
Pare xel I nter nati o nal G m b H  
 
 
1 4 0 5 0 B erli n 
Ger ma n y  
D ate of Pr ot oc ol:  
Fi nal  1. 0, 2 8  Se pt e m ber 2 0 2 0  
T his cli nical st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m plia nce wit h G o o d 
Cli nical Practice, wit h t he Declarati o n of Helsi n ki a n d wit h ot her a p plica ble re g ulat or y 
re q uire me nts. 
C o nfi de ntialit y State me nt 
T his c o nfi de ntial d oc u me nt is t he pr o pert y of Astra Ze neca. N o u n p u blis he d i nf or mati o n c o ntai ne d 
herei n ma y be discl ose d wit h o ut pri or writte n a p pr o val fr o m Astra Ze neca. Access t o t his d oc u me nt 
m ust be restricte d t o rele va nt parties . 
P P D
P P D


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ASTRAZENECA SIGNATURES 
 


Cli ni c al St u d y Pr ot o c ol - G er m a n y A d d e n d u m 
A str a Z e n e c a
S o di u m zir c o ni u m c y cl o sili e at e - D 9 4 8 0 C 0 0 0 1 2 
2 8 S e pt e m b er 2 0 2 0
D e cl ar ati o n  of S p o n s or or R e s p o n si bl e M e di c al E x p ert ( P h y si ci a n)
Pr ot o c ol Titl e: A T w o- C o h ort, R a n d o mi s e d S e q u e n c e, Cr o s s- o v er, O p e n-l a b el St u d y t o
A s s e s st h e Eff e ct of a Si n gl e D o s e of S o di u m Zir c o ni u m C y cl o sili c at e ( S Z C) o n t h e
P h ar m a c o ki n eti c s of T a cr oli m u s a n d C y ol o s p ori n  i n H e alt h y S u bj e ct s
Pr ot o c ol V er si o n: Fi n al 1. 0, 2 8 S e pt e m b er 2 0 2 0
T hi s cli ni c al st u d y pr ot o c ol w a s  s u bj e ct e d t o criti c al r e vi e w.  T h e i nf or m ati o n it c o nt ai n s i s
c o n si st s nt wit h c urr e nt k n o wl e d g e  of t h e ri s k s a n d b e n efit s of t h e i n v e sti g ati o n al  m e di ci n al
pr o d u ct s, a s w ell a s wit h t h e m or al, et hi c al a n d s ci e ntifi c pri n ci pl e s g o v er ni n g cli ni c al
r e s e ar c h a s s et o ut i n t h e D e cl ar ati o n of H el si n ki a n d t h e g ui d eli n e s o n G o o d Cli ni c al
Pr a cti c e a p pli c a bl e t o t hi s cli ni s al st u d y.
S p o n s or Si g n at or yl R e s p o n si bl e M e di c al E x p ert
Si g n at ur e
D at e of si g n at ur e
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 5
P P D
P P D
P P D


P P D
P P D
P P D


Cli nical St u d y Pr ot oc ol - Ger ma n y A d de n d u m 
S o di u m zirc o ni u m c ycl osilicate - D 9 4 8 0 C 0 0 0 1 2 
Astra Ze neca 
2 8 Se pte m ber 2 0 2 0 
P P D
P P D
P P D


P P D
P P D


P P D
P P D
P P D