A Multicentre, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety of Zibotentan/Dapagliflozin in Combination Compared to Zibotentan Monotherapy, Zibotentan/Dapagliflozin and Zibotentan Monotherapy Compared to Placebo in Participants With Cirrhosis
Phase: PHASE2
Conditions: Liver Cirrhosis
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1  of 1 4 3
Cli nic al St u d y  P r ot oc ol 
St u d y 
I nter ve nti o n 
Zi b ote nta n a n d Da p a glifl ozi n  
St u d y C o de  
D 4 3 2 6 C 0 0 0 0 4  
Versi o n
3 . 0 E U
Date  
0 9  Se pte m ber  2 0 2 4  
E U C T N u m ber  2 0 2 3 -5 0 6 8 9 3 -1 1  
A M ultice ntre, R a n d o mis ed, D o u bl e -bli n d, Pl ace b o -c o ntr olle d, 
P h ase II b St u d y t o E v al u ate t he S afet y of Zi b ote nt a n/ D a p a glifl ozi n 
i n C o m bi n ati o n C o m p are d t o Zi b ote nt a n M o n ot her a p y as well as 
Zi b ote nt a n/ D a p a glifl ozi n a n d Zi b ote nt a n M o n ot her a p y C o m p are d 
t o Pl ace b o i n P artici p a nts with Cirr h osis   
S p o ns or N a me: Astra Z e neca A B  
Le g al Re gistere d A d dress:  
Astra Ze neca A B, 1 5 1 8 5 S ö dertälje, S we de n  
Re g ul at or y A g e nc y I de ntifier N u m ber:  
E U C T N u m ber  2 0 2 3 -5 0 6 8 9 3 -1 1  
T his pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze n eca Sta n dar d 
pr oce d ures. T he pr ot oc ol is p u blicl y re gistere d, a n d t he res ults are discl os e d a n d/ or p u blis he d 
acc or di n g t o t he Astra Z e neca Gl o b al Sta n dar d - Bi oet hics a n d i n c o m plia nce wit h pre v aili n g 
la ws a n d re g ul ati o ns. 
Versi o n Sc o pe: Re gi o nal - E U  
Pr ot oc ol N u m ber: D 4 3 2 6 C 0 0 0 0 4  
St u d y I nter ve nti o n:  Zi b ote nta n a n d Da p a glifl ozi n  
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b o te nta n a n d Da p a glifl ozi n - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2  of 1 4 3
Brief Title: A P hase II b St u d y t o E val uate t he Safet y of Zi b ote nta n/ Da p a glifl ozi n i n 
Partici pa nts wit h Cirr h osis -Z E A L -U N L O C K  
St u d y P h ase: P hase II b  
St u d y Cli nic al Le a d N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y.  
C o or di n ati n g I n vesti g at or:  
, H ull U ni versit y Teac hi n g H os pitals, H ull, 
U nite d K i n g d o m. 
 
 
P P D

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3  of 1 4 3
S U M M A R Y O F C H A N G E S T A B L E   
D O C U M E N T HI S T O R Y  
D oc u m e nt  
D ate of Iss ue  
C S P versi o n 3 . 0 / C S P versi o n 3 . 0 E U 
0 9 -Se pte m ber -2 0 2 4  
C S P versi o n 3. 0  
0 9 -Se pte m ber -2 0 2 4  
C S P versi o n 2. 0 / C S P versi o n 2. 0 E U  
1 6 -Ma y -2 0 2 4  
C S P versi o n 2. 0  
1 6 -Ma y -2 0 2 4  
C S P versi o n 1. 0 / C S P versi o n 1. 0 E U  
0 6 -Marc h -2 0 2 4  
C S P versi o n 1. 0  
1 1 -Oct o ber -2 0 2 3  
 
C S P Versi o n 3. 0 E U ( E E A re gi o n al m o dific ati o n) 0 9 -Se pte m ber -2 0 2 4  
T his m o dificati o n t o C S P versi o n 2. 0 E U is c o nsi d ere d t o be n o n -s u bsta ntial base d o n t he 
criteria set f ort h i n Articl e 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he 
C o u ncil of t he E U a n d i n t he E U Cli nical Trial Re g ulati o n Article 2, 2 ( 1 3) beca use it neit her 
si g nifica ntl y i m pacts t he safet y or p h ysical/ me ntal i nte grit y of partici pa nts n or t he scie ntific 
val ue of t he st u d y.  
O ver all R ati o n ale f or t he M o dific ati o n:  
T he p ur p ose of t his a me n d me nt is t o per mit t he use of pa per P R Os w he n t h e pr o visi o ne d 
ha n d hel d electr o nic de vi ces ca n n ot b e use d t o rec or d t he P R O res p o nses a n d t o i ncl u de 
a d diti o nal la b orat or y tests t o be c o n d ucte d b y t he ce ntral la b orat ories w h e n a partici pa nt meets 
a n y of t he P H L i de ntificati o n criteria.  
S u m m ar y of C h a n ges:  
List of N o n -S u bst a nti al M o dific ati o ns  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
S u m mar y of C ha n ges Ta ble  
Secti o n u p date d t o reflect t he c ha n ges 
ma d e t o C S P v 2. 0 E U t o pr o d uce 
v 3. 0  E U.  
T o gi ve details of c ha n ges ma de t o 
t he pre vi o us versi o n of t he C S P. 
Secti o n 3 O bjecti ves, 
E n d p oi nts, a n d Esti ma n ds  
E n d p oi nts relati n g t o t he e x pl orat or y 
o bjecti ve, ‘ T o e val uate t he effect of 
zi b ote nta n/ da pa glifl ozi n a n d 
zi b ote nta n m o n ot hera p y ver s us 
place b o o n fati g ue, a b d o mi nal 
s y m pt o ms, p h ysical f u ncti o ni n g a n d 
healt h -relate d q ualit y of life’ ha ve bee n 
s plit i nt o 2 b ullet p oi nts, a n d ‘at 
baseli ne a n d Wee k  6’ was a d de d t o t he 
P GI S –  Li ver Disease q uesti o n naire  
•  
T o se parate t he P GI S –  Li ver 
Disease q uesti o n naire fr o m t he 
ot her q uesti o n naires f or clarit y 
beca use it will n ot be e val uate d 
as a c ha n ge fr o m baseli ne t o 
Wee k  6  
•  
T o clarif y t hat t he P GI S –  Li ver 
Disease q uesti o n naire will be 
e val uate d at baseli ne a n d 
Wee k  6  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4  of 1 4 3
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Secti o n  6. 1. 2 Me dical 
De vices I ncl u di n g 
C o m bi nati o n Pr o d ucts wit h 
a De vice C o nstit ue nt  
Di gital d e vices s u b -b ullets a me n de d t o 
b ullets of e q ual hierarc h y  
C orrecti o n of hierarc h y  
Secti o n  8. 2. 2. 4 
Patie nt -re p orte d O utc o mes 
Te xt a me n de d t o i n dicate t h at t he 
preferre d met h o d of rec or di n g P R O 
data is via t he pr o visi o ne d ha n d hel d 
electr o nic de vice b ut t hat pa per 
q uesti o n naires ma y be use d if a 
pr o visi o ne d ha n d hel d electr o nic de vice 
is n ot a vaila ble, or t he partici pa nt is 
u na ble t o use o ne.  
T o per mit t he u se of pa per 
q uesti o n naires w he n nee de d.  
A p pe n di x A 4  
•  
A me n de d ‘ Re g ultai o n’ t o 
‘ Re g ulati o n’ 
•  
A me n de d as f oll o ws: ‘ … 
re prese ntati ve will pr o vi de will 
pr o vi de  Astra Ze neca wit h …’  
C orrecti o n of mi n or s pelli n g err ors 
a n d t y p o gra p hical err ors  
A p pe n di x B 1  
Deleti o n of re peate d ‘relate d t o t he 
me dici nal pr o d uct’  
C orrecti o n of t y p o gra p hical err or  
A p pe n di x E 7 La b orat or y 
Tests  
I g G a nti-H S V, a n d H S V 1/ 2 I g M 
testi n g or H S V 1/ 2 P C R testi n g 
( de p e n di n g o n t he re gi o n) were a d de d 
t o t he list of la b orat or y tests t o be 
c o n d ucte d at t he ce ntral la b orat or y 
w he n a partici pa nt meets P H L criteria  
U p date d t o reflect u p date d tests 
s u p p orti n g ac ute H S V i nfecti o n 
dia g n osis i n s o me re gi o ns  
A p pe n di x F  
A p pe n di x u p date d wit h t he list of e dits 
t hat were ma de t o pr o d uce t he pre vi o us 
m o dificati o n ( v 2. 0 E U) fr o m v 1. 0 E U.  
T o ca pt ure t he hist or y of 
m o dificati o ns t o t he E U C S P  
C S P  =  cli nical st u d y pr ot oc ol; E U  =  E ur o pea n U ni o n; H S V  =  her pes si m ple x vir us; I g G  =  i m m u n o gl o b uli n G; 
I g M =  i m m u n o gl o b uli n M; P C R  =  p ol y merase c hai n reacti o n; P GI S  =  Patie nt Gl o bal I m pressi o n of Se verit y; 
P H L  =  p ote ntial H y’s La w; P R O  =  patie nt -re p orte d o utc o me 
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5  of 1 4 3
T A B L E  O F C O N T E N T S  
S U M M A R Y O F C H A N G E S T A B L E  ....................................................................................... 3  
T A B L E O F C O N T E N T S  ........................................................................................................... 5  
LI S T O F FI G U R E S  ................................................................................................................... 8  
LI S T O F T A B L E S  ..................................................................................................................... 8  
LI S T O F A P P E N DI C E S  ............................................................................................................ 9  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  .......................................... 1 0  
1  
P R O T O C O L S U M M A R Y  .................................................................................... 1 3  
1. 1  
S y n o psis  ................................................................................................................ 1 3  
1. 2  
Sc he ma  .................................................................................................................. 1 9  
1. 3  
Sc he d ule of Acti vities  ........................................................................................... 2 0  
2  
I N T R O D U C TI O N ................................................................................................ 2 7  
2. 1  
St u d y Rati o nale  ..................................................................................................... 2 7  
2. 2  
Disease Bac k gr o u n d  ............................................................................................. 2 8  
2. 2. 1  
Cirr h osis wit h Feat ures of P ortal H y perte nsi o n .................................................... 2 8  
2. 2. 2  
C urre nt Treat me nt O pti o ns f or Patie nts wit h Cirr h osis wit h Feat ures of P ortal 
H y perte nsi o n  ......................................................................................................... 2 9  
2. 3  
Be nefit/ Ris k Assess me nt  ...................................................................................... 2 9  
2. 3. 1  
Zi b ote nta n  ............................................................................................................. 2 9  
2. 3. 2  
Da pa glifl ozi n  ........................................................................................................ 2 9  
2. 3. 3  
Ris k Assess me nt  ................................................................................................... 3 0  
2. 3. 4  
Be nefit Assess me nt  ............................................................................................... 3 3  
2. 3. 4. 1  
E vi de nce f or t h e R ole of E n d ot heli n A nta g o nists i n Cirr h osis wit h Feat ures of 
P ortal H y perte nsi o n  .............................................................................................. 3 3  
2. 3. 4. 2  
E vi de nce f or t he R ole of S G L T 2  i n hi bit ors i n Cirr h osis a n d Feat ur es of P ortal 
H y perte nsi o n  ......................................................................................................... 3 4  
2. 3. 4. 3  
P ossi ble C o m ple me ntar y Acti o ns of Zi b ote nta n a n d Da pa glifl ozi n ..................... 3 4  
2. 3. 5  
O verall Be nefit/ Ris k C o ncl usi o n  .......................................................................... 3 4  
3  
O BJ E C TI V E S, E N D P OI N T S, A N D E S TI M A N D S  ............................................ 3 5  
4  
S T U D Y D E SI G N  ................................................................................................. 3 8  
4. 1  
O verall De si g n ...................................................................................................... 3 8  
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  .................................................................. 3 9  
4. 3  
J ustificati o n f or D ose ............................................................................................ 3 9  
4. 4  
E n d -of -st u d y Defi niti o n ........................................................................................ 4 0  
5  
S T U D Y P O P U L A TI O N  ....................................................................................... 4 0  
5. 1  
I ncl usi o n Criteria .................................................................................................. 4 0  
5. 2  
E xcl usi o n Criteria  ................................................................................................. 4 2  
5. 3  
Li fest yle C o nsi derati o ns ....................................................................................... 4 4  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6  of 1 4 3
5. 3. 1  
Meals a n d Dietar y Restri cti o ns  ............................................................................. 4 4  
5. 3. 2  
Caffei ne, Alc o h ol, a n d To bacc o  ............................................................................ 4 5  
5. 3. 3  
Acti vit y  ................................................................................................................. 4 5  
5. 3. 4  
Re pr o d uc ti ve Restricti o ns ..................................................................................... 4 5  
5. 3. 5  
S per m D o nati o n  .................................................................................................... 4 6  
5. 3. 6  
Pre g na nc y  ............................................................................................................. 4 6  
5. 3. 7  
Ot her Restricti o ns  ................................................................................................. 4 6  
5. 4  
Scree n Fail ures ...................................................................................................... 4 7  
5. 5  
Criteria f or Te m p oraril y Dela yi n g E nr ol me nt/ Ra n d o misati o n/ A d mi nistrati o n of 
St u d y I nter ve nti o n  ................................................................................................ 4 7  
6  
S T U D Y I N T E R V E N TI O N S A N D C O N C O MI T A N T T H E R A P Y  ...................... 4 7  
6. 1  
St u d y I nter ve nti o ns A d mi nistere d  ........................................................................ 4 7  
6. 1. 1  
St u d y I nter ve nti o n  ................................................................................................ 4 7  
6. 1. 2  
Me dical De vi ces I ncl u di n g C o m bi nati o n Pr o d ucts wit h a De vice C o nstit ue nt  ... 4 8  
6. 2  
Pre parati o n, H a n dli n g, St ora ge, a n d Acc o u nta bilit y  ............................................ 4 9  
6. 3  
Assi g n me nt t o St u d y I nter ve nti o n  ........................................................................ 4 9  
6. 4  
Bli n di n g  ................................................................................................................ 4 9  
6. 5  
St u d y I nter ve nti o n C o m plia nce  ............................................................................ 5 0  
6. 6  
D ose M o dificati o n  ................................................................................................ 5 1  
6. 7  
C o nti n ue d Access t o St u d y I nter ve nti o n After t he E n d of t he St u d y ................... 5 1  
6. 8  
Treat me nt of O ver d ose  ......................................................................................... 5 1  
6. 9  
Pri or a n d C o nc o mita nt T hera p y  ............................................................................ 5 1  
6. 9. 1  
Pr o hi bite d Me dicati o ns  ......................................................................................... 5 2  
6. 9. 2  
Per mitte d Pr oce d ures a n d Me dicati o ns  ................................................................ 5 3  
6. 9. 2. 1  
Parace nt esis ........................................................................................................... 5 3  
6. 9. 2. 2  
Me dicati o ns I n d uci n g H y p o gl ycae mia  ................................................................. 5 3  
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ............................................................. 5 3  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n  ................................................................. 5 3  
7. 1. 1  
Dia betic Ket o aci d osis  ........................................................................................... 5 5  
7. 1. 2  
Ma na ge me nt of Treat m e nt -e mer ge nt A b n or malities i n Li ver F u ncti o n Tests 
( L F Ts) ................................................................................................................... 5 5  
7. 2  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ...................................... 5 9  
7. 3  
L ost t o F oll o w -u p  ................................................................................................. 5 9  
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ................................................ 6 0  
8. 1  
A d mi nistrati ve a n d G e neral/ Baseli ne Pr oce d ures  ................................................ 6 1  
8. 2  
Efficac y Assess me nts  ............................................................................................ 6 1  
8. 2. 1  
Ke y Varia bles  ........................................................................................................ 6 1  
8. 2. 1. 1  
Fl ui d Rete nti o n  ..................................................................................................... 6 1  
8. 2. 1. 2  
Electr o nic Scale M eas ure me nt of B o d y Wei g ht  ................................................... 6 1  
8. 2. 1. 3  
Bi oi m pe da nce S pectr osc o p y  ................................................................................. 6 2  
8. 2. 2  
E x pl orat or y Varia bles  ........................................................................................... 6 2  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7  of 1 4 3
8. 2. 2. 1  
 ........................................................ 6 2  
8. 2. 2. 2  
Ser u m A nal ysis of Creati ni ne a n d C ystati n C (e G F R)  ......................................... 6 2  
8. 2. 2. 3  
La b orat or y Assess me nts f or E x pl orat or y A nal yses  .............................................. 6 3  
8. 2. 2. 4  
Patie nt -re p orte d O ut c o mes ................................................................................... 6 4  
8. 3  
Safet y Assess me nts  ............................................................................................... 6 6  
8. 3. 1  
P h ysical E xa mi nati o ns  .......................................................................................... 6 6  
8. 3. 2  
Vital Si g ns  ............................................................................................................. 6 6  
8. 3. 3  
Electr ocar di o gra ms  ............................................................................................... 6 7  
8. 3. 4  
Ec h ocar di o gra m  .................................................................................................... 6 8  
8. 3. 5  
Cli nical Safet y La b orat or y Assess me nts  .............................................................. 6 8  
8. 3. 6  
Ot her Safet y Assess me nts  ..................................................................................... 7 0  
8. 3. 6. 1  
Self -M o nit ore d Gl uc ose a n d H y p o gl ycae mic E ve nts ........................................... 7 0  
8. 3. 6. 2  
Alc o h ol  Use Dis or ders  I de ntificati o n Test Q uesti o n naire .................................... 7 0  
8. 4  
A d verse E v e nts, S A Es, a n d Ot her Safet y Re p orti n g  ............................................ 7 1  
8. 4. 1  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E I nf or mati o n  ................. 7 2  
8. 4. 2  
F oll o w -u p of A Es a n d S A Es  ................................................................................. 7 2  
8. 4. 3  
Ca usalit y C ollecti o n .............................................................................................. 7 2  
8. 4. 4  
A Es Base d o n E xa mi nati o ns a n d Tests  ................................................................. 7 2  
8. 4. 5  
A Es Base d o n Si g ns a n d S y m pt o ms  ..................................................................... 7 3  
8. 4. 6  
A d verse E v e nts of S peci al I nterest  ....................................................................... 7 3  
8. 4. 7  
H y’s La w  ............................................................................................................... 7 4  
8. 4. 8  
Re p orti n g of S A Es  ................................................................................................ 7 4  
8. 4. 9  
Pre g na nc y  ............................................................................................................. 7 5  
8. 4. 9. 1  
Mater nal E x p os ur e  ................................................................................................ 7 5  
8. 4. 9. 2  
Pater nal E x p os ure  ................................................................................................. 7 6  
8. 4. 1 0  
Me dicati o n Err or, Dr u g A b use, a n d Dr u g Mis use  ................................................ 7 6  
8. 4. 1 0. 1  
Ti meli nes  .............................................................................................................. 7 6  
8. 4. 1 0. 2  
Me dicati o n Err or  ................................................................................................... 7 7  
8. 4. 1 0. 3  
Dr u g A b us e  ........................................................................................................... 7 7  
8. 4. 1 0. 4  
Dr u g Mis use .......................................................................................................... 7 7  
8. 4. 1 1  
Re p orti n g of O ver d os e  .......................................................................................... 7 7  
8. 4. 1 2  
Me dical De vic e Deficie n cies  ................................................................................ 7 8  
8. 5  
P har mac o ki netics  .................................................................................................. 7 8  
8. 5. 1  
C o llecti o n of Sa m ples f or P har mac o ki netics ........................................................ 7 9  
8. 5. 2  
Deter mi nati o n of Dr u g C o nce ntrati o n  .................................................................. 7 9  
8. 6  
P har mac o d y na mics  ............................................................................................... 7 9  
8. 6. 1  
C ollecti o n of Sa m ples f or P har mac o d y n a mics  ..................................................... 7 9  
8. 7  
O pti o nal Ge n o mics I nitiati ve  ................................................................................ 7 9  
8. 8  
Bi o mar kers  ............................................................................................................ 8 0  
8. 8. 1  
Ma n dat or y Bi o mar ker Sa m ple C ollecti o n  ............................................................ 8 0  
8. 9  
I m m u n o ge nicit y Assess me nts ............................................................................... 8 0  
8. 1 0  
Me dical Res o urce Utilisati o n a n d Healt h Ec o n o mi cs  .......................................... 8 0  
8. 1 1  
St u d y Partici pa nt Fee d bac k Q uesti o n naire  ........................................................... 8 0  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................... 8 0  
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8  of 1 4 3
9. 1  
Statistical H y p ot heses  ........................................................................................... 8 1  
9. 2  
Sa m ple Size Deter mi nati o n  .................................................................................. 8 1  
9. 3  
P o p ulati o ns f or A nal yses  ...................................................................................... 8 1  
9. 4  
Statistical A nal yses  ............................................................................................... 8 1  
9. 4. 1  
Ge neral C o nsi derati o ns  ......................................................................................... 8 1  
9. 4. 2  
Ke y E n d p oi nts  ...................................................................................................... 8 2  
9. 4. 3  
Safet y  .................................................................................................................... 8 3  
9. 4. 3. 1  
A d verse E v e nts  ..................................................................................................... 8 3  
9. 4. 3. 2  
Vital Si g ns  ............................................................................................................. 8 4  
9. 4. 3. 3  
La b orat or y Assess me nts  ....................................................................................... 8 4  
9. 4. 3. 4  
Electr ocar di o gra ms  ............................................................................................... 8 4  
9. 4. 4  
E x pl orat or y e n d p oi nts  ........................................................................................... 8 5  
9. 4. 4. 1  
E x pl orat or y P har mac o ki netic E n d p oi nts  .............................................................. 8 5  
9. 4. 4. 2  
E x pl orat or y P har mac o d y na mic a n d Bi o mar ker E n d p oi nts  .................................. 8 5  
9. 4. 4. 3  
E x pl orat or y P R O E n d p oi nts  ................................................................................. 8 5  
9. 4. 4. 4  
Ot her E x pl orat or y E n d p oi nts  ................................................................................ 8 5  
9. 4. 4. 5  
E x pl orat or y Researc h a n d O pti o nal Ge netic Researc h  ......................................... 8 5  
9. 5  
I nteri m A nal ys es ................................................................................................... 8 6  
9. 6  
Data M o nit ori n g C o m mittee  ................................................................................. 8 6  
1 0  
S U P P O R TI N G  
D O C U M E N T A TI O N  
A N D  
O P E R A TI O N A L 
C O N SI D E R A TI O N S  ............................................................................................ 8 7  
1 1  
R E F E R E N C E S  ................................................................................................... 1 4 1  
 
LI S T O F FI G U R E S   
Fi g ure 1  
 ............................................................................................... 1 9  
 
LI S T O F T A B L E S   
Ta ble  1  
Sc he d ule of A cti vities  ................................................................................. 2 0  
Ta ble  2  
Ris k Assess me nt  .......................................................................................... 3 1  
Ta ble  3  
O bjecti ves a n d E n d p oi nts  ............................................................................ 3 5  
Ta ble  4  
St u d y I nter v e nti o n  ....................................................................................... 4 7  
Ta ble  5  
 .................................................... 5 3  
Ta ble  6  
C hil d -P u g h Sc ore  ........................................................................................ 6 4  
Ta ble  7  
La b orat or y Safet y Varia bles  ....................................................................... 6 9  
Ta ble  8  
P o p ulati o ns f or A nal ysis  ............................................................................. 8 1  
 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9  of 1 4 3
LI S T O F A P P E N DI C E S   
A p pe n di x  A  
Re g ulat or y, Et hical, a n d St u d y O versi g ht C o nsi derati o ns  .......................... 8 8  
A p pe n di x  B  
A Es: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w -u p, 
a n d Re p orti n g  ............................................................................................ 1 1 0  
A p pe n di x  C  
Ha n dli n g of H u ma n Bi ol o gical Sa m ples  ................................................... 1 1 6  
A p pe n di x  D  
O pti o nal Ge n o mics I nitiati ve Sa m ple  ....................................................... 1 1 8  
A p pe n di x  E  
Acti o ns Re q uire d i n Cases of I ncreas es i n Li ver Bi oc he mistr y a n d 
E val uati o n of H y’s La w  ............................................................................ 1 2 2  
A p pe n di x  F  
Pr ot oc ol A me n d me nt Hist or y  ................................................................... 1 3 3  
 

C li nical St u d y Pr ot oc ol - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0  of 1 4 3
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S   
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
A B V  
Alc o h ol b y v ol u me  
A C E  
A n gi ote nsi n -c o n verti n g e nz y me  
A E  
A d verse E ve nt  
A E SI  
A d verse e v e nts of s pecial i nterest 
A L P  
Al kali ne P h os p hatase  
A L T  
Ala ni ne A mi n otra nsferase/ Tra nsa mi nase  
A S T  
As partate A mi n otra nsferase/ Tra nsa mi nase  
A U DI T  
Alc o h ol Use Dis or ders I de ntificati o n Test  
A x M P  
A u xiliar y Me dici nal Pr o d uct  
BI S  
Bi oi m pe d a nce s pectr osc o p y  
B N P  
B -t y pe natri uretic pe pti de  
B U N  
B l o o d urea nitr o ge n 
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
C o nfi de n ce i nter val  
C K D  
C hr o nic ki d ne y disease  
C L D Q  
C hr o nic li ver disease q uesti o n naire  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O VI D -1 9  
C or o na Vir us Disease 2 0 1 9  
C R F  
Case Re p ort F or m  
C R O  
C o ntract Researc h Or ga nisati o n  
C R P C  
Castrati o n resista nt Pr ostate Ca ncer  
C S P  
Cli nical St u d y Pr ot oc ol  
C S P H  
C li nicall y si g nifica nt p ortal h y perte nsi o n 
C S R  
Cli nical St u d y Re p ort  
C T C  
C o m m o n Ter mi n ol o g y Criteria  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C TI S  
Cli nical Trial I nf or mati o n S yste m  
C T pr o E T 1  
C -Ter mi nal -Pr o -E n d ot heli n -1  
D E S  
Data E ntr y Site  
DI LI  
Dr u g I n d uce d Li ver I nj ur y  
D K A  
Dia b etic Ket oaci d osis  
D M C  
Data M o nit ori n g C o m mittee  
D U S  
Disease U n der St u d y  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1  of 1 4 3
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
E/ D  
Earl y St u d y I nter ve nti o n Disc o nti n uati o n  
E C H O  
Ec h ocar di o gra p h y  
e C R F  
E lectr o nic Case Re p ort F or m 
E D C  
Electr o nic data ca pt ure  
E E A  
E ur o pea n Ec o n o mic Area  
e G F R  
E sti mate d gl o mer ular filtrati o n rate  
E R A  
E n d ot heli n rece pt or a nta g o nist  
E T  
E n d ot heli n  
E U  
E ur o pea n U ni o n  
E U C T  
E U Cli nical Trial  
E u dra C T  
E U Dr u g Re g ulati n g A ut h orities Cli nical Trials Data base  
F A S  
F ull A n al ysis Set  
FI B -4  
F i br osis-4  
F O C B P  
Fe male(s) of c hil d beari n g p ote ntial  
F S H  
F ollicle -sti m ulati n g h or m o ne 
G C P  
G o o d Cli nical Practice  
H b  
Hae m o gl o bi n  
H B V  
He p atitis B Vir us  
H C V  
He p atitis C Vir us  
H F  
Heart Fail ure  
H R  
Heart rate  
H V P G  
H e p atic ve n o us press ure gra die nt  
I A T A 
T he I nter nati o nal Air Tra ns p ort Ass ociati o n  
I B 
I n vesti gat or’s Br oc h ure 
I C5 0 
H alf ma xi mal i n hi bit or y c o nce ntrati o n  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
I n de p e n de nt Et hics C o m mittee 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct  
I N D 
I n vesti gati o nal Ne w Dr u g 
I N R 
I nter nati o nal n or malise d rati o 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y 
L F Ts  
Li ver F u ncti o n Tests  
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2  of 1 4 3
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
M E L D  
M o del f or e n d -sta ge-li ver disease 
M M R M  
M i xe d m o del re peate d meas ures  
N/ A  
N ot a p plica ble  
N A F L D  
N o nalc o h olic fatt y li ver disease  
N A S H  
N o nalc o h olic steat o he patitis  
NI M P  
N o n -i n vesti gati o nal Me dici nal Pr o d uct  
N T -pr o B N P  
N -ter mi nal pr o h or m o ne of brai n natri uretic pe pti de  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
P D  
P har mac o d y na mic(s)  
P GI S  
Patie nt Gl o bal I m pressi o n of Se verit y  
P H L  
P ote ntial H y’s La w  
P K  
P har mac o ki netic(s)  
P K S  
P har mac o ki netic A nal ysis Set  
P R O  
Patie nt -re p orte d o utc o me 
R T S M  
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S A S  
Scree ne d a nal ysis set  
S D  
Sta n dar d de viati o n  
S G L T 2  
S o di u m gl uc ose c otra ns p orter 2  
S o A  
Sc he d ule of Acti vities  
S P F Q  
St u d y Partici pa nt Fee d bac k Q uesti o n naire  
S U  
S ulf o n yl urea  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns  
T 1 D M  
T y pe 1 dia betes mellit us  
T 2 D M  
T y pe 2 dia betes mellit us  
T B L  
T otal Bilir u bi n  
TI P S  
Tra nsj u g ular i ntra he patic p ort os yste mic s h u nt  
U L N  
U p per Li mit of N or mal  
 
 
 
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3  of 1 4 3
1  
P R O T O C O L S U M M A R Y   
1. 1  
S y n o psis   
Pr ot oc ol Title: A M ultic e ntre, Ra n d o mise d, D o u ble -bli n d, Place b o -c o ntr oll e d, P hase IIb 
St u d y t o E val uate t he Safet y of Zi b ote nta n/ Da p a glifl ozi n i n C o m bi nati o n C o m pare d t o 
Zi b ote nta n M o n ot hera p y as well as Zi b ote nta n/ Da pa glifl ozi n a n d Zi b ote nta n M o n ot hera p y 
C o m pare d t o Place b o i n Partici pa nts wit h Cirr h osis  
Brief Title: A P hase IIb St u d y t o E val uate t he Safet y of Zi b ote nta n/ Da p a glifl ozi n i n 
Partici pa nts wit h Cirr h osis -Z E A L -U N L O C K  
Re g ul at or y A ge nc y I de ntifier N u m bers:  
I N D n u m ber 1 5 6 9 0 1 
E U C T N u m ber 2 0 2 3 -5 0 6 8 9 3 -1 1  
R ati o n ale:  
Cirr h osis is t he e n d -sta ge res ult of c hr o nic li ver i nj ur y/ disease a n d is c h aracterise d b y 
a d va nce d fi br osis a n d, ulti matel y, he patic fail ure. Cirr h osis ma y be c o m pe nsate d i n w hic h n o 
cli nical c o m plicati o ns t hat affect o utc o me (ie, variceal hae m orr ha g e, asc ites, he patic 
e nce p h al o pat h y, he pat oc ell ular ca n cer) ha ve o cc urre d, or d ec o m pe ns ate d, i n w hic h patie nts 
ha ve ha d at least o ne of t hese cli nical c o m plicati o ns. T he aeti ol o g y of cirr h osis varies wit h 
viral he patitis ( he patitis  B a n d C), alc o h olic li ver disea se, a n d n o n-alc o h oli c steat o he patitis 
( N A S H) bei n g t he le a di n g ca uses of cirr h osis gl o b all y, wit h less c o m m o n ca uses i ncl u di n g 
a ut oi m m u ne he patitis, pri mar y scler osi n g c h ola n gitis, pri mar y biliar y c h ola n gitis, 
hae m oc hr o mat osis, a n d Wils o n’s disease. Cirr h o sis is a seri o us c o n diti o n w hic h lea ds t o 
si g nifica nt m or bi dit y, res o urce i nte nsi ve c o m plicati o ns, he pat ocell ular carci n o ma, a n d, i n t he 
a bse nce of li ver tra ns pla ntati o n, deat h. I n 2 0 1 7 , o ver 1. 3 2 milli o n cirr h osis relate d deat hs were 
re p orte d gl o ball y, w h ic h was a p pr o xi matel y 2. 4 % of all deat hs w orl d wi de. I n 2 0 1 9, cirr h osis 
ca use d 1. 4 8 milli o n deat hs, a n i ncrease of 8. 1 % c o m pare d t o 2 0 1 7, a n d its disa bilit y -a dj uste d 
life-years ra n k e d 1 6t h a m o n g all diseases. T he gl o bal b ur de n of cirr h osis d ue t o he patitis B 
vir us a n d he patitis C vir us i nfecti o n is decreasi n g, w hile t he b ur de n of cirr h osis d ue t o alc o h ol 
a n d n o n-alc o h olic fatt y li ver disease is i ncreasi n g ra pi dl y. 
P ortal h y perte nsi o n is t he maj or ca use of c o m plicati o ns i n li ver cirr h osis. T he pri mar y ca use 
o f p ortal h y perte nsi o n i n cirr h osis is a c o m bi nati o n of str uct ural c ha n ges i n t he li ver 
ass ociate d wit h fi br osis a n d i ncreas e d vasc ular t o n e i n t he he patic micr ocirc ulati o n b ot h 
lea di n g t o a n i ncrease i n i ntra he patic vas c ular resista nce. As p ortal h y pert e nsi o n de vel o ps, 
s pla nc h nic vas o dilati o n pr o gresses, w hi c h res ults i n i ncreas e d bl o o d fl o w t o t he p ortal 
circ ulati o n t hat f urt her i ncreas es p ortal pr ess ure. C o nse q ue ntl y, a h y per d y na mic circ ulati o n 
de vel o ps, c ollateral vessels are f or m e d a n d t here is a n i ncre ase d ris k f or dec o m pe nsati o n 
e ve nts.  
T he mec ha nis ms of acti o n of zi b ote nta n a n d d a pa glifl ozi n o n li ver cirr h osis a n d ass ociate d 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4  of 1 4 3
c o m plicati o ns are differe nt a n d t he o utc o me of c o m bi ne d treat me nt is e x pecte d t o be 
c o m ple me ntar y. T he mai n bi ol o gical effects o f zi b ote nta n are e x pecte d fr o m bl oc ki n g 
e n d ot heli n -1 dri ve n i ncrease i n i ntra he p atic vasc ul ar resista nce (i ncl u di n g ele me nts of p ortal 
vei n a n d si n us oi dal vas oc o nstricti o n). F urt her m ore, zi b ote nta n is e x pecte d t o decrease 
vasc ular stiff ness, i m pr o ve e n d ot helial f u ncti o n, re d uce h e patic i nfla m mati o n a n d, i n t he 
l o n gter m, p ote ntiall y re d uce fi br osis. 
Se paratel y, da pa glifl ozi n is e x pecte d t o ha v e be neficial effects o n meta b olic d ysf u ncti o n, 
re d uce h e pat oc yt e i nj ur y a n d s o di u m a n d water o v erl oa d w hilst a v oi di n g h y p o natrae mia a n d 
h y per kala e mia. A re d uce d nee d f or di uretics ma y als o re d uce t he ris k f or p ot e ntial ac ute 
ki d ne y i nj ur y or ot her c o m plicati o ns s uc h as e nce p hal o pat h y. I n a pil ot st u d y, 3  cases of 
cirr h osis wit h ascites a n d t y pe 2 dia betes mellit us ( T 2 D M) were tr eate d wit h a s o di u m -gl uc ose 
c otra ns p orter 2 ( S G L T 2) i n hi bit or. I n t hese patie nts, S G L T 2  i n hi biti o n res ulte d i n wei g ht l oss 
a n d re d uce d as cites or peri p heral oe de ma. 
A partic ularl y i m p orta nt li mitati o n of e n d ot heli n rece pt or a nta g o nists, w hic h i ncl u des 
zi b ote nta n, is t he i ncreas e d ris k f or fl ui d rete nti o n. A p pr o xi matel y 4 0 % of patie nts treate d 
wit h zi b ote nta n ( d oses r a n gi n g fr o m 5 t o 2 2. 5  m g, wit h t he maj orit y of patie nts recei vi n g t he 
1 0  m g o nce dail y d ose) fr o m t he P hase I -III o nc ol o g y st u dies re p orte d peri p heral oe de ma. 
Als o, i n patie nts wit h p ort o p ul m o nar y h y perte nsi o n wit h or wit h o ut li ve r cirr h osis e n d ot heli n 
rece pt or a nta g o nists ha ve bee n s h o w n t o i ncrease ris k f or fl ui d rete nti o n. A d verse e v e nts of 
fl ui d rete nti o n were re p orte d i n 2 6 % of patie nts wit h p ort o p ul m o nar y h y perte nsi o n wit h or 
wit h o ut cirr h osis recei vi n g macite nta n a n d 3 9 % of patie nts wit h p ort o p ul m o nar y h y pert e nsi o n 
wit h cirr h osis recei vi n g a m brise nta n . Da pa glifl ozi n’s effect i n c orrecti n g s o di u m a n d water 
o verl oa d is e x pecte d t o miti gate t his fl ui d rete nti o n safet y c o ncer n i n t he li ver cirr h osis 
p o p ulati o n wit h or wit h o ut a h ist or y of dec o m pe nsati o n. A p ost-h oc a nal ysis of t he S O N A R 
trial, i n patie nts wit h t y pe 2 dia betes a n d c hr o nic ki d ne y disease, has d e m o nstrate d a re d uce d 
b o d y wei g ht gai n w he n atrase nta n was c o m bi ne d wit h a n S G L T 2 i n hi bit or as c o m pare d t o a 
c o ntr ol gr o u p t reat e d wit h atrase nta n, wit h o ut a n S G L T 2 i n hi bit or (-0. 7  k g, 9 5 % CI -1. 6 t o 
0. 3  k g vs 0. 6  k g, 9 5 % CI 0. 0 t o 1. 1  k g), f or a b et w ee n -gr o u p  differe nce of 1. 2  k g ( 9 5 % CI, 0. 1 
t o 2. 3 k g, p = 0. 0 2 8).  
T he st u d y is desi g ne d t o e val uate t he s afet y of zi b ote nta n/ da p a glifl ozi n i n c o m bi nati o n as 
c o m pare d t o zi b ote nt a n m o n ot hera p y as w ell as zi b ote nta n/ da pa glifl ozi n i n c o m bi nati o n a n d 
zi b ote nta n m o n ot hera p y as c o m pare d t o place b o i n patie nts wit h cirr h osis wit h or wit h o ut a 
hist or y of dec o m pe nsati o n.  
 
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 5  of 1 4 3
O bjecti ves a n d E n d p oi nts : 
O bjecti ves  
E n d p oi nts  
Ke y O bjecti ve s 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n a 
c o m p osite e n d p oi nt of fl ui d rete nti o n . 
Occ urre nce of a n y of t he f oll o wi n g c o m p o ne nts of t his 
c o m p osite e n d p oi nt fr o m baseli ne t o Wee k  6 : 
•  
> 2 k g i ncrease i n b o d y wei g ht ( office -base d)  
•  
> 2  L i ncrease i n t otal b o d y water  
•  
I ncrease i n 2 or m ore l o o p-di uretic e q ui vale nts  a 
•  
Fl ui d rete nti o n a d verse e ve nt ( A E)  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n a 
c o m p osite e n d p oi nt of fl ui d rete nti o n . 
Occ urre nce of a n y of t he f oll o wi n g c o m p o ne nts of t his 
c o m p osite e n d p oi nt fr o m baseli ne t o Wee k  6 : 
•  
> 2 k g i ncrease i n b o d y wei g ht  
•  
> 2  L i ncrease i n t otal b o d y water  
•  
I ncrease i n 2 or m ore l o o p-di uretic e q ui vale nts a 
•  
Fl ui d rete nti o n A Es  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n 
b o d y wei g ht , b o d y water v ol u me s a n d b o d y fat mass . 
•  
C ha n ge i n b o d y wei g ht ( k g)  o ver ti me c o urse of 
st u d y ( h o me-base d m o nit ori n g).  
•  
C ha n ge fr o m baseli ne i n b o d y wei g ht , t otal b o d y 
water , e xtracell ular a n d i ntracell ular water 
v ol u mes , a n d b o d y fat mass  at Wee k  6 ( office -
base d m o nit ori n g).  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n b o d y 
wei g ht , b o d y water v ol u me s a n d b o d y fat mass . 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n 
t otal l o o p-di uretic e q ui vale nts use a. 
C ha n ge i n t otal d osa ge of l o o p -di uretic e q ui vale nts use 
fr o m baseli ne t o Wee k 6  a. 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n t otal 
l o o p-di uretic e q ui vale nts use a. 
T o e v al uate t he effects of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n t he 
c o m p osite of t ot al b o d y water a n d t otal d osa ge of 
l o o p-di uretic e q ui vale nts a 
Occ urre nce of eit her of t he t w o c o m p o ne nts of t his 
c o m p osite:  
1  
> 3 L i ncrease i n t otal b o d y water v ol u me fr o m 
baseli ne t o Wee k  6 . 
2  
I ncrease i n 3 or m ore l o o p-di uretic e q ui vale nts use 
fr o m baseli ne t o Wee k 6 a. 
T o e v al uate t he effects of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n t he 
c o m p osite of t otal b o d y water a n d t otal d osa ge of 
l o o p-di uretic e q ui vale nts a 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n 
office -base d s yst olic a n d diast olic bl o o d press ure.  
A bs ol ute c ha n ge i n s yst olic a n d diast olic bl o o d press ure 
fr o m baseli ne t o Wee k 6.  
T o e v al uate t he effect of zi b ote nta n/ da pa glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n 
office -base d s yst olic a n d diast olic bl o o d press ure.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 6  of 1 4 3
O bjecti ves  
E n d p oi nts  
S afet y O bjecti ves  
T o assess t he safet y a n d t olera bilit y of 
zi b ote nta n / da p a glifl o zi n a n d zi b ote nta n vers us 
place b o.  
•  
A Es, S A Es, a n d D A Es  
•  
A E SIs 
 
 
) 
•  
Vital si g ns  
•  
Safet y la b orat or y tests 
•  
E C G assess me nts  
a 
O ne l o o p -di uretic e q ui vale nt = 4 0  m g f ur ose mi de  =  1  m g b u meta ni de  =  2 0  m g t orse mi de  =  5 0  m g 
et hacr y nic aci d.  I n Ja p a n, o ne l o o p-di uretic e q ui vale nt = 4 0 m g f ur ose mi de = 8 m g t orse mi de = 6 0 m g 
az ose mi de.  
A E  =  a d verse e v e nt; A E SI  =  a d verse e v e nt of s pecial i nterest;
; A L T  =  ala ni ne 
a mi n otra nsferase; A S T  =  as partate a mi n otra nsferase; B U N = Bl o o d urea nitr o ge n; D A E  =  disc o nti n uati o n d ue t o 
a d verse e ve nt; E C G  =  electr ocar di o gra m; e G F R  =  esti mate d gl o mer ular filtrati o n rate; 
H b A 1c  =  hae m o gl o bi n  A 1c; M E L D  =  m o del f or e n d sta ge li ver disease; P D  =  p har mac o d y na mic; P GI S = Patie nt 
Gl o bal I m pressi o n of Se verit y; P K  =  p har mac o ki netic; S A E  =  seri o us a d verse e ve nt; 
 
 
 
F or ex pl orat or y o bj ecti ves a n d esti ma n ds descri pti o ns/e n d p oi nts, see Secti o n  3  of t he pr ot oc ol.  
O ver all Desi g n S y n o psis:  
T his is a P hase IIb m ultice ntre, ra n d o mi se d, d o u ble -bli n d, parallel -gr o u p, place b o -c o ntr olle d 
st u d y t o e val uate t he safet y of zi b ote nta n/ da pa glifl ozi n i n c o m bi nati o n as c o m pare d t o 
zi b ote nta n m o n ot hera p y as well as zi b ote nta n/ d a p a glifl ozi n a n d zi b ote nta n m o n ot hera p y as 
c o m pare d t o place b o i n p artici p a nts wit h cirr h osis . Eli gi ble partici pa nts c o ul d ha ve a hist or y 
of dec o m pe ns ati o n e ve nts or ha ve c o m p e nsate d cirr h osis. If c o m pe ns ate d cirr h osis, t he 
eli gi ble partici pa nts m ust ha ve feat ures of p ortal h y perte nsi o n defi ne d as si g ns a n d meas ures 
t hat w o ul d in dicate t hat t he partici pa nt has cli nicall y si g nifica nt p ortal h y perte nsi o n ( C S P H) 
a n d i ncl u de, b ut n ot li mite d t o, prese n ce of gastr o -oes o p ha geal v arices at e n d osc o p y or 
c ollaterals at i ma gi n g ( eit her o ne wit hi n 1 2 m o nt hs pri or t o scree ni n g), a n d/ or 
 
 k Pa, or of 
 k Pa a n d 
 (at ti me of scree ni n g). 
All partici pa nts s h o ul d ha ve a M E L D s c ore <  1 5 a n d be classifie d as C hil d -P u g h A or B . 
Brief S u m m ar y:  
T his st u d y will c o nsist of t he f oll o wi n g peri o ds:  
Sc ree ni n g Peri o d of u p t o 3 wee ks: T he Scree ni n g Visit ( Visit 1) will ta ke place bet w ee n 7 t o 
2 1 da ys bef ore t he Ra n d o misati o n Visit ( Visit  2) t o c o nfir m partici pa nt eli gi bilit y a n d c ollect 
baseli ne data . T here m ust be at least 7 da ys b et wee n Visit 1 a n d Visit  2 t o all o w s ufficie nt ti me 
f or la b orat or y res ults t o be e xa mi ne d. At t he Ra n d o misati o n Visit ( Visit 2), eli gi bilit y criteria 
will be reassess e d, safet y la b orat or y dat a re v erifie d, a n d partici pa nts will b e pr o vi de d di gital 
de vices t o meas ur e t heir b o d y wei g ht starti n g t he first da y after t he Ra n d o misati o n Visit a n d 
e ver y da y at h o me.  
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nt a n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 7  of 1 4 3
Tre at me nt Peri o d of 6  wee ks: D uri n g t he Treat me nt Peri o d, partici pa nts will visit t he st u d y 
ce ntre 5  ti mes. At Visit 2, partici pa nts will be ra n d o mise d a n d will recei v e t h e first d ose of t he 
st u d y i nter ve nti o n. At eac h st u d y visit d uri n g t he treat me nt peri o d (fr o m Visit  3 till Visit  6) 
partici pa nts will recei ve t he o nce d ail y d ose at t he st u d y ce ntre a n d will pr o vi de a pre -d ose 
bl o o d sa m ple f or P K a nal ysis a n d ot her la b sa m ples bef ore t he i nta ke of st u d y i nter ve nti o n. 
W he n n ot visiti n g t he st u d y ce ntre t he patie nts will ta ke t he o nce d ail y d ose of st u d y 
i nter ve nti o n at h o me. 
F oll o w -u p Peri o d  of  2  wee ks : Partici pa nts will ret ur n t o t he st u d y ce ntre f or f oll o w -u p 
assess me nts a p pr o xi matel y 2 wee ks aft er t heir  pla n ne d last d ose of st u d y i nter ve nti o n 
( pla n ne d last d ose is at Visit 6). 
Discl os ure St ate me nt : T his is a parallel -gr o u p, pl ace b o -c o ntr olle d st u d y t o e val uate t he 
safet y of zi b ote nt a n a n d zi b ote nta n/ da pa glifl ozi n ; t he st u d y is bli n de d t o t he partici pa nts, 
i n vesti gat ors, a n d S p o ns or. 
N u m ber of P artici p a nts:  
A p pr o xi matel y 2 2 eli gi ble partici pa nts are pla n ne d t o be ra n d o mi se d t o eac h of t he 
3  treat me nt gr o u ps, f or a t otal of u p t o 6 6  partici pa nts . 
N ote : “ E nr olle d ” mea ns a partici pa nt’s a gree me nt t o partici pate i n a cli nical st u d y f oll o wi n g 
c o m pleti o n of t he i nf or m e d c o nse nt pr o cess. P ote ntial partici pa nts w h o are scree n e d f or t h e 
p ur p ose of det er mi ni n g eli gi bilit y f or t he st u d y b ut are n ot ra n d o ml y assi g n e d/assi g ne d i n t he 
st u d y, are c o nsi dere d “scree n fail ures” u nl ess ot her wise s pecifi e d b y t he pr ot oc ol.  
St u d y Ar ms a n d D ur ati o n:  
Partici pa nts w h o meet t h e eli gi bilit y criteria a n d a gree t o partici pate will be ra n d o mise d t o o ne 
of t he f oll o wi n g treat me nt gr o u ps ( 2 2 partici pa nts per gr o u p).  All partici pa nts will recei ve 
1  ca ps ule (zi b ote nta n or matc hi n g place b o) a n d 1  ta blet ( da pa glifl ozi n or m atc hi n g place b o) at 
e ver y d osi n g.  
•  
Treat me nt Gr o u p  1 : place b o matc hi n g zi b ote nta n ca ps ule + place b o mat c hi n g 
da pa glifl ozi n ta blet.  
•  
Treat me nt Gr o u p  2 : zi b ote nta n ca ps ule m g + place b o matc hi n g da pa glifl ozi n ta blet.  
•  
Treat me nt Gr o u p  3 : zi b ote nta n ca ps ule m g + da p a glifl ozi n ta blet 1 0  m g.  
 
D at a M o nit ori n g/ Ot her C o m mittee:  
A Data M o nit ori n g C o m mitte e ( D M C) will m o nit or o n g oi n g safet y/t olera bilit y data a n d ma y 
rec o m me n d st o p pi n g f urt her recr uit me nt a n d/ or tr eat me nt of partici pa nts i n a treat me nt gr o u p 
at a n y ti me. T he D M C will c o n d uct pre -s pecifie d meeti n gs a n d a d h oc meeti n gs as nee de d.  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 8  of 1 4 3
T he r ole a n d  res p o nsi bilities of t he D M C, a n d st o p pi n g criteria f or t he st u d y, will be descri be d 
i n t he D M C c harter. 
St atistic al Met h o ds : 
F or fl ui d rete nti o n c o m p osite e n d p oi nts defi ne d as : 
•  
occ urre nce of a n y of t he f oll o wi n g e ve nts: ( 1)  >  2  k g i ncreas e i n b o d y wei g ht,  ( 2) >  2  L 
i ncreas e i n t otal b o d y water, ( 3) i ncreas e i n 2 or m ore l o o p-di uretic e q ui val e nts , or 
( 4) fl ui d rete nti o n A Es, fr o m baseli ne t o Wee k 6  
•  
occ urre nce of eit her ( 1) > 3  L i ncreas e i n t otal b o d y water v ol u me fr o m bas eli ne t o 
Wee k  6 ; or ( 2) i ncrease i n 3 or m ore l o o p-di uretic e q ui vale nts use fr o m b aseli ne t o 
Wee k  6  
 
E xact 9 0 % (t w o-si de d) CIs f or pr o p orti o ns of p atie nts wit h t he c o m p osite of fl ui d rete nti o n i n 
treat me nt gr o u ps will be calc ulate d usi n g t he Cl o p per -Pears o n met h o d.  T he e xact 
u nc o n diti o nal 9 0 % (t w o-si de d) CIs f or differe nce i n pr o p orti o ns bet wee n 2  treat me nt gr o u ps 
will be c o m p ute d base d o n sc ore statistic  (C ha n a n d Z ha n g 1 9 9 9 ). 
T he c ha n g e i n b o d y wei g ht, t otal d osa ge of l o o p -di uretic e q ui vale nts, b o d y water v ol u mes, 
b o d y fat mass a n d bl o o d press ure fr o m baseli ne t o Wee k  6 will be a nal yse d usi n g mi xe d 
m o del re p eat e d meas ur es ( M M R M) met h o d ol o g y f or pair wise c o m paris o ns bet wee n tr eat me nt 
gr o u ps. T he a n al ytic m o del will i ncl u de t he 
 of 
, 
, a n d 
, a n d 
 of t he 
 
 A n 
 will be use d f or t he 
 
 
S a m ple Size C alc ul ati o n : 
A p pr o xi matel y 2 2 partici pa nts are pla n ne d t o be ra n d o mi se d t o eac h of t he 3  treat me nt gr o u ps . 
T he sa m ple size is n ot deter mi ne d base d o n a f or m al statistical h y p ot hesis testi n g f or t his 
P hase IIb st u d y. Wit h 
 e v al ua ble partici p a nts per gr o u p, a n o bser ve d differe nce of 
% (
%) i n pr o p orti o n of patie nts wit h t he c o m p osite of fl ui d rete nti o n bet wee n a 
zi b ote nta n/ da pa glifl ozi n gr o u p  a n d a n o bser ve d 
% c o m p osite of fl ui d ret e nti o n i n t he 
c orres p o n di n g zi b ote nta n gr o u p, t he l o wer li mit of a t w o-si de d 9 0 % CI f or t he differe nce will 
be
%.  
C CI
C CI
C CI
C CI
C CI
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 9  of 1 4 3
1. 2  
Sc he m a   
Fi g ure 1  
  
 
E O T  =  e n d of trial; F/ U  =  f oll o w-u p; R  =  ra n d o misati o n. 
 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 0  of 1 4 3
1. 3  
Sc he d ule of Acti vities   
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g 
peri o d  
Tre at me nt peri o d  
F oll o w -u p  
Secti o n i n t he C S P  
 
R a n d o mis ati o n  
Visits  
Visit n u m ber  
1  
2  
3  
4  
5  
6 n 
7  
 
Wee k  
-3  
0  
1  
2  
3  
6  
8  
 
St u d y d a y  
-2 1  t o -7  a 
1  
8  
1 5  
2 2  
4 3  
5 7  
 
Visit wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 5  
± 3  
 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
A p pe n di x  A  3  
I ncl usi o n/e xcl usi o n 
criteria 
X  
X  
 
 
 
 
 
Secti o n  5. 1  a n d 
Secti o n  5. 2  
Alc o h ol breat h test  
X  
X  
 
 
 
X  
 
Secti o n  5. 2  
Scree n f or dr u gs of 
a b use 
X  
 
 
 
 
 
 
Secti o n  8. 3. 5  
A U DI T q uesti o n naire  
X  
 
 
 
 
 
 
Secti o n 8. 3. 6. 2  
E nr ol me nt i n 
I R T/ R T S M 
X  
 
 
 
 
 
 
Secti o n  6. 3  
Ra n d o misati o n i n 
I R T/ R T S M 
 
X  
 
 
 
 
 
Secti o n  6. 3  
R o uti ne cli nic al pr oce d ures  
De m o gra p h y a n d 
baseli ne c haracteristics 
(i n cl u di n g s m o ki n g 
hist or y a n d alc o h ol 
c o ns u m pti o n) 
X  
 
 
 
 
 
 
Secti o n  5. 3. 2  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 1  of 1 4 3
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g 
peri o d  
Tre at me nt peri o d  
F oll o w -u p  
Secti o n i n t he C S P  
 
R a n d o mis ati o n  
Visits  
Visit n u m ber  
1  
2  
3  
4  
5  
6 n 
7  
 
Wee k  
-3  
0  
1  
2  
3  
6  
8  
 
St u d y d a y  
-2 1  t o -7  a 
1  
8  
1 5  
2 2  
4 3  
5 7  
 
Visit wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 5  
± 3  
 
Me dical/s ur gical hist or y  
X  
 
 
 
 
 
 
 
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
X  
X  
Secti o n  6. 9  
B o d y wei g ht  
X  
X  
X  
X  
X  
X  
X  
Secti o n 8. 2. 1. 2  
Hei g ht, B MI calc ulati o n  
X  
 
 
 
 
 
 
Secti o n  8. 3. 1  
E C H O  
X c 
 
 
 
 
 
 
Secti o n  8. 3. 4  
HI V ser ol o g y 
X  
 
 
 
 
 
 
Secti o n  8. 3. 5  
F S H (fe males o nl y)  
X d 
 
 
 
 
 
 
Secti o n  8. 3. 5  
Pre g na nc y tests 
(fe males o nl y; ser u m) 
X  
 
 
 
 
 
 
Secti o n  8. 3. 5  
St u d y i nter ve nti o n  
St u d y i nter ve nti o n 
dis pe nse d  
 
X  
 
 
X  
 
 
Secti o n  6  
St u d y i nter ve nti o n 
acc o u nta bilit y (c o u nti n g 
re mai ni n g ta blets a n d 
ca ps ules)  
 
 
X  
X  
X  
X  
 
Secti o n  6. 2  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 2  of 1 4 3
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g 
peri o d  
Tre at me nt peri o d  
F oll o w -u p  
Secti o n i n t he C S P  
 
R a n d o mis ati o n  
Visits  
Visit n u m ber  
1  
2  
3  
4  
5  
6 n 
7  
 
Wee k  
-3  
0  
1  
2  
3  
6  
8  
 
St u d y d a y  
-2 1  t o -7  a 
1  
8  
1 5  
2 2  
4 3  
5 7  
 
Visit wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 5  
± 3  
 
St u d y i nter ve nti o n 
i nta ke e 
 
X  
X  
X  
X  
X  
 
Secti o n  6  
Ke y assess me nts  
Dail y di gital b o d y 
wei g ht meas ure me nt  
 
Dail y h o me meas ure me nt usi n g a di gital de vice s h o ul d be gi n at Visit 2  (ra n d o misati o n ) t o e n d of 
f oll o w-u p  q. 
Secti o n 8. 2. 1. 2  
Bi oi m pe da nce 
s pectr osc o p y r 
X  
X  
X  
X  
X  
X  
X  
Secti o n 8. 2. 1. 3  
S afet y assess me nts  
A E re vie w h 
X  
S A Es o nl y  
X  
X  
X  
X  
X  
X  
Secti o n  8. 4. 2  
P h ysical e xa mi n ati o n  
X  
X  
X b 
X b 
X b 
X b 
X  
Secti o n  8. 3. 1  
E C G ce ntral 
m o nit ori n g  p 
X  
X ( pre -d ose)  
X  
X  
X  
X  
X  
Secti o n  8. 3. 3  
X ( 2  h o urs 
p ost -d ose)  
Vital si g ns ( s u pi ne a n d 
sta n di n g bl o o d press ure 
a n d p ulse) 
X  
X ( pre -d ose)  
X  
X  
X  
X  
X  
Secti o n  8. 3. 2  
X ( 6 0, 1 2 0, 1 8 0 
mi n utes)  
B o d y te m perat ure  
X  
X  
X  
X  
X  
X  
X  
Secti o n  8. 3. 2  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 3  of 1 4 3
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g 
peri o d  
Tre at me nt peri o d  
F oll o w -u p  
Secti o n i n t he C S P  
 
R a n d o mis ati o n  
Visits  
Visit n u m ber  
1  
2  
3  
4  
5  
6 n 
7  
 
Wee k  
-3  
0  
1  
2  
3  
6  
8  
 
St u d y d a y  
-2 1  t o -7  a 
1  
8  
1 5  
2 2  
4 3  
5 7  
 
Visit wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 5  
± 3  
 
Cli nical safet y 
la b orat or y tests 
( hae mat ol o g y, cli nical 
c he mistr y, c oa g ulati o n , 
electr ol ytes, ser u m 
os m olalit y, a n d N T -pr o 
B N P  
X  
X i 
X i 
X i 
X i 
X i 
X  
Secti o n  8. 3. 5  
P K assess me nts  
Pre -d ose P K plas ma 
sa m ple (all 
partici p a nts)  j 
 
 
X  i 
X  i 
X  i 
 
 
Secti o n  8. 5  
P K pr ofile (Ja pa nese)  
 
 
 
 
X k, l 
 
 
Secti o n  8. 5  
P ost -d ose sa m ple 
( N o n-Ja pa nese) 
 
 
 
 
X m  
 
 
Secti o n  8. 5  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 4  of 1 4 3
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g 
peri o d  
Tre at me nt peri o d  
F oll o w -u p  
Secti o n i n t he C S P  
 
R a n d o mis ati o n  
Visits  
Visit n u m ber  
1  
2  
3  
4  
5  
6 n 
7  
 
Wee k  
-3  
0  
1  
2  
3  
6  
8  
 
St u d y d a y  
-2 1  t o -7  a 
1  
8  
1 5  
2 2  
4 3  
5 7  
 
Visit wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 5  
± 3  
 
E x pl o r at or y assess me nt s 
 
X g 
 
 
 
 
X f, g 
 
Secti o n 8. 2. 2. 1  
e G F R c alc ulati o n s 
X  
X  
X  
X  
X  
X  
X  
Secti o n 8. 2. 2. 2  
M E L D sc ore calc ulati o n  
X  
X  
X  
X  
X  
X  
X  
Secti o n 8. 2. 2. 3  
C hil d -P u g h sc ore  
X  
X  
X  
X  
X  
X  
X  
N o n -fasti n g 
plas ma/ser u m 
bi o mar kers  
 
X i 
 
 
X i 
X i 
 
H b A 1c  
X i 
X i 
 
 
X i 
X i 
 
P R Os: C L D Q, P GI S - 
Li ver Disease, a n d S F -
3 6 v 2 ac ute  
 
X o 
 
 
 
X  
 
Secti o n 8. 2. 2. 4  
C ollect a n d st ore ser u m 
a n d plas ma sa m ples f or 
e x pl orat or y assess me nt 
of bi o mar kers  
 
X i 
 
 
 
X i 
 
Secti o n  8. 8. 1  
C CI

Cli ni cal St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 5  of 1 4 3
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g 
peri o d  
Tre at me nt peri o d  
F oll o w -u p  
Secti o n i n t he C S P  
 
R a n d o mis ati o n  
Visits  
Visit n u m ber  
1  
2  
3  
4  
5  
6 n 
7  
 
Wee k  
-3  
0  
1  
2  
3  
6  
8  
 
St u d y d a y  
-2 1  t o -7  a 
1  
8  
1 5  
2 2  
4 3  
5 7  
 
Visit wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 5  
± 3  
 
C ollect a n d st ore uri n e 
sa m ples f or e x pl orat or y 
assess me nt of 
bi o mar kers  
 
X  i 
 
 
 
X  i 
 
Secti o n  8. 8. 1  
O pti o nal Ge n o mics 
I nitiati ve, e x pl orat or y 
ge n o mics , a n d m ulti -
o mics sa m ples  
 
X  
 
 
 
 
 
Secti o n  8. 7  a n d 
A p pe n di x  D  
a. 
Scree ni n g visit ca n ta ke place fr o m 2 1 da ys u p t o 7 da ys bef ore ra n d o misati o n visit ( Visit  2 ). It m ust be at least 7 da ys bet wee n Visit 1  a n d Visit 2 t o all o w 
ti me f or la b orat or y res ults t o be e x a mi ne d. 
b.  Brief p h ysical e x a mi nati o n.  
c. 
O nl y i n t h ose partici pa nts wit h hist or y of H eart F ail ure  a n d if hist orical data fr o m E C H O or car diac M RI i n t he pri or 1 2 m o nt hs is n ot a vaila ble. 
d.  Res ults nee d t o be a v aila ble bef ore t he  ra n d o misati o n visit ( Visit  2 ). 
e. 
St u d y i nter ve nti o n i nta ke will ta k e place at t he st u d y ce ntre a n d at h o me w he n n ot visiti n g t he st u d y ce ntre.  
f. 
 t o be assesse d ≥ 3  h o urs after st u d y i nter ve nti o n a d mi nistrati o n at Visit  6 . A 
 
assess me nt of 
s a n d/ or 
 s h o ul d o nl y be d o ne if 
 t o c o m plete a n acc urate 
 a n d/ or 
 
meas ure me nt. 
 s h o ul d o nl y be d o ne if 
 is a vaila ble. 
g.  
m ust n ot ta ke place earlier t ha n at least 3 h o urs after a li g ht meal , s uc h as brea kfast. If t he partici pa nt 
is o n a n o n-selecti ve beta-bl oc ker, t he m or ni n g d ose s h o ul d n ot be ta ke n, b ut ta ke n directl y after t he 
. 
h.  If a SA E occ urs wit hi n 4 8  h o urs after t he last d ose, a P K sa m ple will be ta ke n if p ossi ble. T he e xact ti me of last d osi n g a n d of bl o o d sa m pli n g will be  
rec or de d. 
i. 
Pre -d ose sa m ple i n all partici pa nts ( b ot h Ja pa nese a n d n o n -Ja pa nese). 
j. 
Pre -d ose sa m ple a n d  d osi n g at t he st u d y ce ntre at e ver y visit.  P har mac o ki n etics  sa m ple t o be d o ne at earl y ter mi nati o n visit as well. If n o d osi n g ta kes place, 
sa m ple at a n y ti me d uri n g t he st u d y ce ntre visit a n d d oc u me nt e xact date a n d ti me.  
C CI
C CI
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 6  of 1 4 3
k.  
P har mac o ki n etics  pr ofile o nl y f or Ja p a n ese patie nts. Sa m ples f or P K pr ofile c ollecte d o ver 5  h o urs at t he st u d y ce ntre. Sa m pli n g ti mes: pre -d ose, 0. 5 t o 1. 0, 
1. 5 t o 2. 0, 2. 5 t o 3. 0, 3. 5 t o 4. 0, 4. 5 t o 5. 5  h o urs p ost -d ose; e xact cl oc k ti mes nee d t o be d oc u me nte d. See Secti o n  5. 3. 1  f or f urt her details o n meal 
restricti o ns. 
l. 
P har mac o ki n etics  pr ofile ca n be d o ne at Visit  4 if n ot p ossi ble at Visit  5. At t he da y selecte d f or t he P K pr ofile, t he st u d y i nter ve nti o n m ust b e a d mi nistere d at 
t he st u d y ce ntre s o t hat P K sa m pli n g acc or di n g t o sc he d ule is p ossi ble. 
m.  A p ost -d ose sa m ple is ta ke n as late as p ossi ble after d osi n g o n t he d ose da y (at least 1 h after d osi n g); t he e x act act ual sa m pli n g t i me nee ds t o be rec or de d. 
n.  Visit  6  is p la n ne d E n d of Treat me nt ( E o T) visit. If partici pa nt  ter mi nates earl y fr o m t he st u d y (ie Wit h dra w c o nse nt), please perf or m e x a mi nati o ns as Visit  6 . 
o.  Baseli ne P R O Q uesti o n naires t o be c o m plete d bef ore treat me nt i nitiati o n.  
p.  Di gital E C Gs will be ce ntrall y rea d. T he pre d ose E C G rea d o ut fr o m Visit  2 is t o be re vie we d b y t he i n vesti gat or bef ore ra n d o misati o n as ce ntral re p ort will 
n ot b e a vaila ble o n t he da y. All E C Gs will be rec or de d i n tri plicate after a 1 0 -mi n ute s u pi ne rest peri o d wit h n o m ore t ha n a b o ut 2 mi n utes bet wee n 
i n di vi d ual E C Gs, c o m pleti n g all 3 E C Gs wit hi n a ma xi m u m of a b o ut 5 mi n utes. E C Gs s h o ul d be c ollecte d pri or t o vital si g ns, P K sa m ple c ollecti o n, or ot her 
assess me nts as t hese ma y alter a ut o n o mic t o ne. U nsc he d ule d E C Gs ma y be a d d e d if cli nicall y i n dicate d . 
q.  Partici pa nts s h o ul d als o perf or m first wei g ht meas ure me nt at t he st u d y site o n m o bile a p plicati o n  at Visit 2  ( w hic h is w he n it will b e distri b ute d t o t he 
partici pa nt).  
r. 
Partici pa nts are rec o m me n de d t o n ot e n ga ge i n eati n g a lar ge  meal bef ore meas ure me nt c ollecti o n. C ollecti o n of fasti n g ti me pri or t o meas ure me nt is 
re q uire d. 
s. 
e G F R 1 is at e v er y visit a n d e G F R 2 is at Visits 2, 5, a n d 6.  
A b bre viati o ns: A E = A d verse e ve nt ; A U DI T =  Alc o h ol Use Dis or ders I d e ntificati o n Test; B MI  =  b o d y m ass i n de x; C L D Q = C hr o nic Li ver Disease Q uesti o n naire ; C S P =  Cli nical 
st u d y pr ot o c ol; E C G =  electr o car di o gra p h y ; e G F R =  esti mate d gl o mer ular filtrati o n rate; E C H O = ec h ocar di o gra p h y ; E o T = E n d of Treat me nt; E T = Earl y Ter mi n ati o n visit; 
F S H  =  f ollicle-sti m ulati n g h or m o ne; h = h o ur; H b A 1c =  hae m o gl o bi n  A 1c; HI V  =  H u ma n i m m u n o deficie nc y vir us; I R T =  I nteracti ve Res p o nse Tec h n ol o g y; M E L D =  M o del f or 
E n d -sta ge Li ver D isease; N T-pr o B N P  =  N -ter mi nal pr o h or m o ne of brai n natri uretic pe pti d e; P GI S = Patie nt Gl o bal I m pressi o n of Se verit y; P K = p har mac o ki n etics; 
P R O  =  patie nt -re p orte d o utc o me; R T S M =  Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt; S A E  =  seri o us a d verse e ve nt; S F-3 6 v 2  = S h ort f or m 3 6 healt h y s ur ve y q uesti o n na ire, 
versi o n 2 ; 
. 
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 7  of 1 4 3
2  
I N T R O D U C TI O N  
Zi b ote nta n is a selecti ve e n d ot heli n ( E T A ) rece pt or a nta g o nist, ori gi nall y i n vesti gate d f or 
car di o vas c ular a n d o n c ol o g y i n dicati o ns. Zi b ote nta n is c urre ntl y bei n g i n vesti gate d as a 
treat me nt f or C K D i n c o m bi nati o n wit h da pa glifl ozi n. Zi b ote nta n is a vaila ble f or oral 
a d mi nistrati o n a n d re q uir es o nc e dail y d osi n g.  
Da pa glifl ozi n is a hi g hl y p ote nt, selecti ve, a n d re v ersi ble i n hi bit or of S G L T 2 t hat i m pr o ves 
gl ycae mic c o ntr ol i n pati e nts wit h dia betes mellit us a n d pr o vi des car di ore nal be nefits i n 
patie nts wit h a n d wit h o ut T 2 D M. Da pa glifl ozi n is a vaila bl e f or oral a d mi nistrati o n a n d 
re q uires o nce dail y d osi n g. 
2. 1  
St u d y R ati o n ale   
T he mec ha nis ms of acti o n of zi b ote nta n a n d d a pa glifl ozi n o n li ver cirr h osis a n d ass ociate d 
c o m plicati o ns  are differe nt , a n d t he o utc o me of c o m bi ne d treat me nt is e x pecte d t o be 
c o m ple me ntar y. T he mai n bi ol o gical effects of zi b ote nta n are e x pecte d fr o m bl oc ki n g 
e n d ot heli n -1 dri ve n i ncrease i n i ntra he p atic resista nce (i ncl u di n g ele m e nts of p ortal vei n a n d 
si n usoi dal vas oc o nstricti o n). F urt her m ore, zi b ote nta n is e x pecte d t o decrease vasc ul ar 
stiff ness, i m pr o ve e n d ot h elial f u ncti o n, re d u ce he p atic i nfla m mati o n, a n d, i n t he l o n g -ter m, 
p ote ntiall y re d uce fi br osis ( Zi b ote nta n I n vesti gat or’s Br oc h ure ). 
Se paratel y, da pa glifl ozi n is e x pecte d t o ha v e be neficial effects o n meta b olic d ysf u ncti o n, 
re d uce h e pat oc yt e i nj ur y, a n d s o di u m a n d water o verl oa d w hil st a v oi di n g h y p o natrae mia a n d 
h y per kala e mia ( D a pa glifl ozi n I n vesti gat or’s Br oc h ure ). A re d uce d nee d f or di uretics ma y als o 
re d uce t h e ris k f or p ote ntial A KI  or ot her c o m plicati o ns s uc h as e nce p hal o pat h y. I n a pil ot 
st u d y, 3  cases of N A S H cirr h osis wit h T 2 D M a n d ascites were treate d wit h a n S G L T 2 
i n hi bit or. I n t hese patie nts, S G L T 2 i n hi biti o n res ulte d i n wei g ht l oss a n d re d uce d ascites or 
peri p heral oe de ma ( M o ntal v o -G or d o n  et al 2 0 2 0 ). 
A partic ularl y i m p orta nt  li mitati o n of e n d ot heli n rece pt or a nta g o nists, w hic h i ncl u des 
zi b ote nta n, is t he i ncreas e d ris k f or fl ui d rete nti o n. A p pr o xi matel y 4 0 % of patie nts treate d 
wit h zi b ote nta n ( d oses r a n gi n g fr o m 5 t o 2 2. 5  m g, wit h t he maj orit y of patie nts recei vi n g a 
d ose of 1 0  m g o nce d ail y)  fr o m P hase I t o III o nc ol o g y st u dies re p orte d peri p heral oe de ma. 
Als o, i n patie nts wit h p ort o p ul m o nar y h y perte nsi o n wit h or wit h o ut li ver cirr h osis , e n d ot heli n 
rece pt or a nta g o nists ha ve bee n s h o w n t o i ncrease ris k f or fl ui d rete nti o n. A d verse e v e nts of 
fl ui d rete nti o n were re p orte d i n 2 6 % of patie nts wit h p ort o p ul m o nar y h y perte nsi o n wit h or 
wit h o ut cirr h osis recei vi n g macite nta n ( Sit b o n et al 2 0 1 9 ) a n d 3 9 % of patie nts wit h 
p ort o p ul m o nar y h y perte nsi o n wit h cirr h osis recei vi n g a m brise nta n ( Prest o n et al 2 0 2 0 ). 
Da pa glifl ozi n’s effect i n re d uci n g s o di u m a n d wat er o verl o a d is e x pect e d t o miti gate t his fl ui d 
rete nti o n safet y c o ncer n i n t he p o p ulati o n of patie nt wit h li ver cirr h osis wit h feat ur es of p ortal 
h y perte nsi o n . A p ost -h oc a nal ysis of t he S O N A R trial, i n patie nts wit h T 2 D M a n d C K D, has 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 8  of 1 4 3
de m o nstrate d a re d uce d b o d y wei g ht gai n w he n atrase nta n was c o m bi ne d wit h a n S G L T 2 
i n hi bit or as c o m pare d t o a c o ntr ol gr o u p treate d wit h atrase nta n, wit h o ut a n S G LT 2 i n hi bit or 
(-0. 7  k g, 9 5 % CI -1. 6 t o 0. 3  k g vs 0. 6  k g, 9 5 % CI 0. 0 t o 1. 1  k g) ( Heers pi n k et al 2 0 2 0 ). 
T he st u d y is desi g ne d t o e val uate t he s afet y of zi b ote nta n/ da pa glifl ozi n i n c o m bi nati o n as 
c o m pare d t o zi b ote nt a n m o n ot hera p y as w ell as zi b ote nta n/ da pa glifl ozi n i n c o m bi nati o n a n d 
zi b ote nt a n m o n ot hera p y as c o m pare d t o place b o i n patie nts wit h cirr h osis wit h or wit h o ut a 
hist or y of dec o m pe nsati o n.  
2. 2  
Dise ase B ac k gr o u n d   
Patie nts wit h c o m pe nsate d cirr h osis wit h si g ns of  cli nicall y si g nifica nt p ortal h y perte nsi o n a n d 
patie nts wit h dec o m pe ns ate d cirr h osis ha v e li mite d p har mac ol o gical treat m e nt o pti o ns a n d 
si g nifica nt ris k of dec o m pe nsati o n a n d deat h. 
2. 2. 1  
Cirr h osis wit h Fe at ur es of P ort al H y pert e nsi o n   
Cirr h osis is t he e n d -sta ge res ult of c hr o nic li ver i nj ur y/ disease a n d is c h aracterise d b y 
a d va nce d fi br osis a n d, ulti matel y, he patic fail ure. Cirr h osis ma y be c o m pe nsate d , i n w hic h 
case n o cli nic al c o m plicati o ns t hat affect o utc o m e ha ve occ urre d (ie, variceal hae m orr h a ge, 
ascites, he patic e nce p h al o pat h y, he pat ocell ular ca ncer), or dec o m p e nsate d, i n w hic h case 
patie nts ha ve ha d at least o ne of t hese cli nical c o m plicati o ns ( Ts oc hatzis et al 2 0 1 4 ). T he 
aeti ol o g y of cirr h osis varies , wit h viral he patitis ( he patitis  B a n d C), alc o h olic li ver disease, 
a n d N A S H bei n g t he le a di n g ca uses of cirr h osis gl o ball y, a n d less c o m m o n ca uses i ncl u di n g 
a ut oi m m u ne he patitis, pri mar y scler osi n g c h ola n gitis, pri mar y biliar y c h ola n gitis, 
hae m oc hr o mat osi s, a n d Wils o n’s disease (R o ma nelli a n d Stasi 2 0 1 6 ). Cirr h osis is a seri o us 
c o n diti o n w hic h lea ds t o si g nifica nt m or bi dit y, res o urce i nte nsi ve c o m plicat i o ns, 
he pat ocell ular carci n o ma, a n d, i n t he a bse nce of li ver tra ns pla ntati o n, deat h. T he Gl o bal 
B ur de n of Diseas e st u d y i n 2 0 1 7 re p orte d o ver 1. 3 2 milli o n cirr h osis relate d deat hs gl o ball y, 
w hic h was a p pr o xi matel y 2. 4 % of all deat hs w orl d wi de ( G B D 2 0 1 7 ). I n 2 0 1 9, cirr h osis 
ca use d 1. 4 8 milli o n deat hs, a n i ncrease of 8. 1 % c o m pare d t o 2 0 1 7, a n d its disa bilit y -a dj uste d 
life-years ra n k e d 1 6t h a m o n g all disea ses. T he gl o bal b ur de n of cirr h osis d ue t o he patitis B 
vir us a n d he patitis C vir us i nfecti o n is decreasi n g, w hile t he b ur de n of cirr h osis d ue t o alc o h ol 
a n d n o n-alc o h olic fatt y li ver disease is i ncreasi n g ra pi dl y ( Li u  et al 2 0 2 2 ). 
P ortal h y perte nsi o n is t he maj or ca use of c o m plicati o ns i n li ver cirr h osis. T he pri mar y ca use 
of p ortal h y perte nsi o n i n cirr h osis is a c o m bi nati o n of str uct ural c ha n ges ass ociate d wit h 
fi br osis a n d i ncrease d vasc ular t o ne i n t he he p atic micr ocirc ulati o n b ot h lea di n g t o a n i ncrease 
i n i ntra he patic vas c ular resista nce. As p ortal h y perte nsi o n de vel o ps, s pla nc h nic vas o dilati o n 
pr o gresses, w hi c h res ults i n i ncrease d bl o o d fl o w  t o t he p ortal circ ul ati o n t hat f urt her 
i ncreas es p ortal press ure (I wa kiri 2 0 1 4). C o nse q u e ntl y , a h y per d y na mic cir c ulati o n de vel o ps, 
c ollateral vess els  are f or me d a n d t here is a n i ncrease d ris k f or dec o m pe ns ati o n e ve nts 
(P o or da d 2 0 1 5 ). 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 9  of 1 4 3
2. 2. 2  
C urre nt T re at m e nt O pti o ns f or P atie nts wit h Cirr h osis wit h Fe at ur es 
of P ort al H y perte nsi o n   
Sta n dar d treat me nt f or patie nts wit h c hr o nic li ver disease ce ntres u p o n treat me nt of t he 
u n derl yi n g ca use of li ver disease, e g, a bsti ne nce fr o m alc o h ol, a nti -viral a ge nts f or viral 
he patitis, a n d treat me nt of u n derl yi n g meta b olic disease i n N A S H. Alt h o u g h H C V ca n n o w be 
era dic ate d, gi ve n t he c o nti n ue d e mer ge n ce of fatt y li ver diseases, diseas e m o dif yi n g t hera pies 
are i n ge n eral e x pecte d t o ha ve ma r gi n al i m pact o n t he o utc o me i n patie nts wit h 
dec o m pe nsate d cirr h osis or c o m pe nsate d cirr h osis wit h si g ns of cli nicall y si g nifica nt p ortal 
h y perte nsi o n. A cc or di n gl y, t here is a si g nifica nt cli nical u n met nee d f or ne w treat me nts i n 
patie nts wit h cirr h osis. C urre nt g ui deli nes s u p p ort t he use of n o n -sel ecti ve beta bl oc kers, 
di uretics a n d vas oacti ve dr u gs ( G u narat h ne  et al 2 0 2 0 ). I n patie nts de vel o pi n g variceal 
hae m orr h a ge, i nter ve nti o n wit h TI P S ma y be use d t o re d uce p ortal h y perte nsi o n ( García -
Pa gá n  et al 2 0 2 0 ). 
2. 3  
Be nefit/ Ris k Assess me nt   
2. 3. 1  
Zi b ote nt a n   
Zi b ote nta n, Z D 4 0 5 4, is a n E T A  a nta g o nist wit h t he hi g hest le vel of selecti vit y o ver E T B  
c urre ntl y k n o w n ( E T A  I C5 0 = 1 3  n M, n o effect at t he E T B  u p t o 5 0  m M) ( M orris  et al 2 0 0 5 ). 
Zi b o te nta n 1 0 a n d 1 5 m g was i nitiall y de vel o pe d f or treat me nt of p atie nts wit h castrati o n -
resista nt pr ostate ca ncer. It di d n ot ac hie ve its efficac y e n d p oi nt i n P hase III (s ur vi val rate), 
h o we ver, it was d e m o nstrate d t o ha ve a n acce pt a ble safet y pr ofile i n t his p o p ulati o n 
(Nels o n  et al 2 0 1 2 ). Zi b ote nta n is c o nsi dere d s afe t o use i n cli nical testi n g ( n o n-cli nical safet y 
pac ka g e c o m plete d) wit h a k n o w n safet y pr ofile fr o m o nc ol o g y st u dies ( Zi b ote nta n 
I n vesti gat or’s Br oc h ure). C urre ntl y, t here are st u dies o n g oi n g wit h zi b ote nta n a n d 
da pa glifl ozi n i n c o m bi nati o n i n patie nts wit h cirr h osis wit h p ortal h y perte nsi o n ( Z E A L st u d y, 
D 4 3 2 6 C 0 0 0 0 3 a n d c hr o ni c ki d ne y disease ( Z E NI T H -C K D, D 4 3 2 5 C 0 0 0 0 1), as well as  a n 
i n vesti gat or-s p o ns ore d st u d y wit h zi b ote nta n i n micr o vasc ular a n gi na ( P RI Z E , 
N C T 0 4 0 9 7 3 1 4) (
 m g, 8  wee ks; n  =  3 5 6 ). F urt h er m ore, a P hase II st u d y i n patie nts wit h 
s yste mic scler o der m a (C K D -Z E B R A , N C T 0 2 0 4 7 7 0 8) (
 m g ; 5 2 wee ks; n  =  2 3)  has bee n 
c o m plete d. 
A  detaile d descri pti o n of t he c he mistr y, p har mac ol o g y, efficac y, a n d safet y of zi b ote nta n is 
pr o vi de d i n t he  Zi b ote nta n I n vesti gat or’s Br oc h ure  
2. 3. 2  
D a p a glifl ozi n   
Da pa glifl ozi n is a sele cti ve S G L T 2 i n hi bit or (I C 5 0 = 3. 7 5  n M). It was ori gi nall y de vel o pe d a n d 
a p pro ve d as a n a dj u nct gl uc ose l o weri n g t hera p y i n T 2 D M. S u bse q ue ntl y , it has bee n 
a p pr o ve d t o treat heart fail ure wit h re d uce d ejecti o n fracti o n i n b ot h T 2 D M a n d n o n -dia betic 
patie nts a n d i n C K D i n patie nts wit h a n d wit h o ut T 2 D M. Da pa glifl ozi n has als o bee n 
d e m o nstrate d t o re d u ce ris k i n patie nts wit h heart fail ure wit h preser ve d ejecti o n fracti o n a n d 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 0  of 1 4 3
has bee n i n vesti gate d i n h os pitalise d patie nts wit h C O VI D -1 9 ( K osi b or o d  et al 2 0 2 1 ). 
A  detaile d descri pti o n of t he c he mistr y, p har mac ol o g y, efficac y, a n d safet y of da pa glifl ozi n is 
pr o vi de d i n t he  Da pa glifl ozi n I n vesti gat or’s Br oc h ure  
2. 3. 3  
Ris k Assess m e nt   
Da pa glifl ozi n a d mi nistrati o n is well t olerate d wit h a well -esta blis he d  s afet y pr ofile. T he 
p ote ntial a n d i de ntifie d ris ks of da pa glifl ozi n treat me nt ha ve bee n well c h aracterise d t hr o u g h 
t he da pa glifl ozi n cli nical de vel o p me nt pr o gra m a n d fr o m p ost-mar keti n g  data. I n cli nical 
st u dies, c o m m o nl y re p orte d A Es i ncl u de U TIs, ge nital i nfecti o ns, p ol y uria, a n d 
h y p o gl ycae mia w h e n c o m bi ne d wit h i ns uli n or a s ulf o n yl urea. I n a d diti o n, D K A was 
c o m m o nl y see n i n cli nical trials i n patie nts wit h T 1 D M treate d wit h da p a glifl ozi n b ut was rare 
i n cli nical trials i n patie nts wit h T 2 D M.  See Ta ble  2  f or f urt her details. 
T he a d verse cli nical effects of zi b ote nta n o bser ve d i n hea lt h y v ol u nteers a n d o nc ol o g y 
p o p ulati o ns were lar gel y d ue t o its p har mac ol o gicall y -me diate d effects o n E T A  rece pt or 
a nta g o nis m res ulti n g i n vas o dilati o n , w hic h are h ea dac h e, h y p ote nsi o n, nasal c o n gesti o n, 
peri p heral oe de ma, c o nj u ncti val re d de ni n g, dizzi ness, fl us hi n g, mi n or decreases i n s yste mic 
vasc ular resista nce, mi n or i ncreases i n car diac o ut p ut, a n d effects d ue t o hae m o dil uti o n w hic h 
lea d t o a re d u cti o n i n H b c o nce ntr ati o n, hae mat ocrit  a n d a nae mia. Re d u cti o n i n H b te n ds t o 
de vel o p wi t hi n a m o nt h of c o m me nci n g t he dr u g a n d is mil d i n m ost patie nts ( C T C 
Gra de  1/ 2), n o n pr o gressi ve a n d te n ds t o re v erse o n st o p pi n g t he dr u g. H o we ver, s o me p atie nts 
i n o nc ol o g y st u dies ha ve de vel o pe d cli nical a nae mia. T he a d v erse cli nical effect of heart 
fail ure has b ee n o bser ve d, bei n g m ore c o m m o nl y r e p orte d i n C R P C patie nts recei vi n g 
zi b ote nta n t ha n i n t h ose recei vi n g place b o. T he fre q ue nc y of re p orts i n patie nts recei vi n g 
zi b ote nta n has bee n less t ha n 1 0 % a n d m ost cas es ha ve res p o n d e d t o sta n dar d heart fai l ure 
treat me nt. See Ta ble  2  f or f urt her details. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d p ote ntial be nefits a n d ris ks of zi b ote nta n a n d 
da pa glifl ozi n ma y be f o u n d i n res pecti ve I n vesti gat or’s Br oc h ures  (Zi b ote nta n I n vesti gat or’s 
Br oc h ure  i ncl u di n g t he F D C de vel o p me nt, a n d Da pa glifl ozi n I n vesti gat or’s Br oc h ure ). 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 1  of 1 4 3
Ta ble  2  
Ris k Assess me nt   
P ote nti al ris k of 
cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or ris k  
Miti g ati o n str ate g y  
D a p a glifl o zi n  
Dia betic 
ket o aci d osis 
i n cl u di n g e ve nts 
wit h at y pical 
prese ntati o n  
Dia betic ket o aci d osis  (D K A ) has bee n i d e ntifie d as 
a n i m p orta nt i de ntifie d ris k f or da pa glifl ozi n i n 
patie nts wit h dia betes . Dia betic ket o aci d osis was 
o nl y o bser ve d i n patie nts wit h dia betes mellit us:  
Ty pe 2 dia betes mellit us:  
I n t h e car di o vasc ular o utc o me st u d y D E C L A R E 
TI MI -5 8 i n p atie nts wit h T 2 D M, 8 5 7 4 patie nts 
recei v e d da pa glifl o zi n 1 0 m g a n d 8 5 6 9 patie nts 
recei v e d place b o, f or a me dia n e x p os ure ti me of 
4 8  m o nt hs. E ve nts of D K A were re p orte d i n 2 7 
patie nts i n t he da pa glifl o zi n 1 0 m g gr o u p a n d 1 2 
patie nts i n t he place b o gr o u p. T h e e ve nts o cc urre d 
e ve nl y distri b ute d o ver t h e st u d y peri o d. Of t he 2 7 
patie nts wit h D K A e ve nts i n t he da pa glifl o zi n gr o u p, 
2 2 ha d c o nc o mita nt i ns uli n treat me nt at t h e ti me of 
t h e e ve nt. Preci pitati n g fact ors f or D K A were as 
e x pecte d i n a T 2 D M p o p u lati o n. 
I n cli nical trials i n patie nts wit h heart fail ure 
( D A P A-H F) or C K D  ( D A P A-C K D) wit h a n d 
wit h o ut T 2 D M, e ve nts of ket o aci d osis were o nl y 
o bser ve d i n patie nts wit h T 2 D M. I n t h e D A P A -H F 
st u d y, e ve nts of D K A were re p orte d i n 3 patie nts 
wit h T 2 D M i n t he d a pa glifl ozi n gr o u p a n d n o ne i n 
t h e place b o gr o u p. I n t he D A P A-C K D st u d y, e ve nts 
of D K A were n ot re p orte d i n a n y patie nt i n t he 
da pa glifl ozi n gr o u p a n d i n 2 patie nts wit h T 2 D M i n 
t h e place b o gr o u p. 
I n a d diti o n, t h ere ha ve bee n p ost mar keti n g re p orts of 
ket o a ci d osis, i n cl u di n g D K A , i n patie nts wit h 
T 1 D M a n d T 2 D M ta ki n g da pa glifl o zi n or ot h er 
S G L T 2  i n hi bit ors. 
Partici p a nts wit h T 1 D M are e xcl u de d fr o m 
t h e st u d y (see e xcl usi o n criteria). D K A  
i n cl u di n g e u gl y ce mic D K A ha ve bee n 
re p orte d wit h use of da pa glifl ozi n.  
If D K A is s us pecte d , te m p orar y i nterr u pti o n 
of st u d y treat me nt s h o ul d be c o nsi d ere d a n d  
the partici pa nt s h o ul d be pr o m ptl y 
e val u ate d. If D K A  is c o nfir me d, st u d y 
i nter ve nti o n s h o ul d be disc o nti n ue d 
per ma ne ntl y. If D K A  is n ot c o nfir me d, re-
start of st u d y i nter ve nti o n s h o ul d be 
c o nsi dere d (see Secti o n  7. 1 ). 
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 2  of 1 4 3
Ta ble  2  
Ris k Assess me nt  
P ote nti al ris k of 
cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or ris k 
Miti g ati o n str ate g y  
Zi b ote nt a n (i n c o nte xt of d a p a glifl o zi n c o m bi n ati o n tre at m e nt)  
Fl ui d rete nti o n  
Fl ui d rete nti o n is a class effect of e n d ot heli n 
rece pt or a nta g o nists. 
Peri p heral oe de ma has b ee n ver y c o m m o nl y 
re p orte d i n o nc ol o g y patie nts recei vi n g zi b ote nta n 
a n d te n de d t o de vel o p wit hi n a m o nt h of 
c o m me nci n g t h e dr u g. M ost cases are mil d ( C T C 
Gra de  1 / 2) a n d te n d t o res ol v e wit h c o nti n ue d 
d osi n g.  
T h e p ote ntial fl ui d rete nti o n ris k fr o m 
zi b ote nta n is e x pecte d t o be miti gate d b y t h e 
di uretic a n d natri uretic effects of 
da pa glifl ozi n. 
 f or 
 
 of 
 is 
 will be 
 (see Secti o n 
).
 
t h er t h a n 
 
 (see bel o w) t hat are 
 fr o m t h e 
(see criteria i n 
M o nit ori n g of 
, a n d 
 
 acc or di n g t o t h e S o A will be 
perf or me d.  
Heart fail ure  
E n d ot h eli n rece pt or a nta g o nists ha ve t h e p ote ntial t o 
i n crease fl ui d rete nti o n a n d pr o m ote fl ui d o verl oa d 
w hic h ma y lea d t o heart fail ure i n s usce pti ble 
patie nts, es peciall y t h ose wit h a k n o w n hist or y of 
car diac d ysf u ncti o n.  
T h e cli nical A Es of n o n -a dj u dicate d car diac fail ure 
ha ve bee n o bser ve d, bei n g m ore c o m m o nl y re p orte d  
i n C R P C patie nts recei vi n g zi b ote nta n t ha n i n t h ose 
recei vi n g place b o. T he fre q ue nc y of re p orts i n 
patie nts recei vi n g zi b ote nta n has b ee n less t h a n 1 0 % 
a n d m ost cases h a ve res p o n de d t o sta n dar d heart 
fail ure treat me nt. 
Partici p a nts wit h m o derate t o se vere  H F 
( N Y H A class III or I V) will be e xcl u de d 
fr o m t h e st u d y. 
T h e p ote ntial ris k of H F fr o m zi b ote nta n is 
e x pecte d t o be miti gate d b y t he di uretic a n d 
natri uretic effects of da pa glifl o zi n.  
(see Secti o n 
(see criteria i n Secti o n 
. 
M o nit ori n g of 
, a n d 
 will be perf or me d.  
H y p ote nsi o n  
T h e a d verse cli nical effect of h y p ote nsi o n is lar gel y 
d ue t o zi b ote nta n’s  p har mac ol o gicall y me diate d  
effects of E T A rece pt or a nta g o nis m res ulti n g i n 
vas o dilati o n. S mall re d ucti o ns i n s yst olic a n d 
diast olic bl o o d press ure of a p pr o xi matel y 5 m m H g 
has b ee n re p orte d wit h zi b ote nta n b ut t his has 
us uall y bee n as y m pt o matic . Da pa glifl o zi n ca uses 
os m otic di uresis, w hic h ma y lea d t o a s mall 
re d ucti o n i n bl o o d press ure. 
 acc or di n g t o 
t h e S o A. Partici p a nts wit h ort h ostatic 
h y p ote nsi o n or h y p ote nsi o n are e xcl u de d 
fr o m t h e st u d y ( Secti o n 5. 2 ). 
(see 
criteria i n Secti o n  
. 
 will be re p orte d as 
a n 
 (see Secti o n 
). 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 3  of 1 4 3
Ta ble  2  
Ris k Assess me nt   
P ote nti al ris k of 
cli nic al 
si g nific a nce 
S u m m ar y of d at a/r ati o n ale f or ris k  
Miti g ati o n str ate g y  
Terat o ge nicit y  
E x p os ure d uri n g gestati o n t o E R As, i n cl u di n g 
zi b ote nta n, is ass ociate d wit h maj or e m br y o -f oetal 
har m. E R As h a ve bee n de m o nstrate d t o i n d uce 
terat o ge nic effects i n a ni mals w he n d ose d d uri n g 
or ga n o ge nesis, earl y i n pre g na nc y. W he n 
a d mi nistere d  t o pre g na nt ra b bits d uri n g t h e peri o d of 
maj or e m br y o nic or ga n o ge nesis, zi b ote nta n ca use d 
f oetal cra ni ofacial a n d car diac malf or mati o ns at d ose 
le vels of 
 a n d a b o ve, c o nsiste nt wit h 
E R As (zi b ote nta n I B). D ue t o t h e esta blis he d 
terat o ge nic effect, pre g na nt w o me n m ust n ot recei v e 
zi b ote nta n. W o C B P are n ot eli gi ble f or partici pati o n 
i n t his st u d y. T h ere is a n e xtre mel y hi g h ris k of 
e m br y o -f oetal har m, if pre g na nc y occ urs w hile 
bei n g e x p ose d t o zi b ote nta n i n a n y a m o u nt, e ve n f or 
s h ort peri o ds of ti me. P ote ntiall y, a n y f oet us 
e x p ose d d uri n g pre g na nc y ca n be affecte d.  
 
Per t h e prescri bi n g i nf or mati o n, da pa glifl o zi n m ust 
n ot be use d i n t h e sec o n d a n d t hir d tri mesters of 
pre g na nc y d ue t o t h e i n crease d i nci d e nce a n d/ or 
se verit y of re nal pel vic a n d t u b ular dilatati o ns i n 
pr o ge n y. W he n pre g na nc y is detecte d, da pa glifl o zi n 
s h o ul d be disc o nti n ue d. H o we ver, si nce zi b ote nta n is 
terat o ge nic earl y i n pre g na nc y, t he m ore restricti v e 
g ui da nce f or zi b ote nta n m ust be f oll o we d.  
W O C B P m ust  n ot be i n cl u de d i n t h e st u d y 
(see i n cl usi o n criteri o n i n Secti o n 5. 1 ). 
F or re pr o d ucti ve restricti o ns f or male 
partici p a nts, see i n cl usi o n criteri o n i n 
Secti o ns  5. 1  a n d details i n Secti o n  5. 3 .4 . 
Partici p a nts m ust n ot d o nate or ba n k bl o o d 
( b ot h male a n d fe males) or s per m, see 
Secti o n  5. 3. 5  a n d Secti o n  5. 3. 7 . 
Ne gati ve pre g na nc y test will be c ollecte d as 
per t h e S o A . 
If a fe male p artici p a nt or t h e fe male p art n er 
of a male p artici p a nt bec o mes pre g na nt 
d uri n g t h e c o urse of t he st u d y, st u d y 
i nter ve nti o n m ust  be disc o nti n ue d 
i m me diatel y, see disc o nti n uati o n criteri o n i n 
Secti o n  7. 1 . 
T h e i n vesti g at or is re q uire d t o i nf or m 
partici p a nts f ull y a n d tra ns pare ntl y  of t h e 
terat o ge nic ris k. 
As part of t he I C F, i nf or mati o n will be 
pr o vi d e d o n restricti o ns f or male 
partici p a nts .  
A E = a d verse e ve nt; A E SI = a d verse e v e nt of s pecial i nterest; C K D = c hr o nic ki d ne y disease; 
C R P C  =  castrati o n -resista nt pr ostate ca ncer; C T C = C o m m o n Ter mi n ol o g y Criteria; D K A =  dia betic ket oaci d osis; 
E C G  =  electr ocar di o gra m; E R A = E n d ot heli n rece pt or a nta g o nist; H F  =  heart fail ure; N Y H A = Ne w Y or k Heart 
Ass ociati o n; S G L T 2  =  s o di u m-gl uc ose c otra ns p orter 2; T 1 D M  =  t y pe 1 dia betes mellit us; T 2 D M =  t y pe 2 
dia betes mellit us; W O C B P = w o me n of c hil d -beari n g p ote ntial . 
 
2. 3. 4  Be nefit Assess m e nt   
2. 3. 4. 1  
E vi de nce f or t he R ole of E n d ot heli n A nt a g o nists i n Cirr h osis wit h Fe at ures of 
P ort al H y perte nsi o n   
E n d ot heli n -1 pr o d ucti o n has be e n f o u n d t o b e i ncrease d i n patie nts wit h li ver i nj ur y a n d i n 
cirr h osis a n d is i m plicate d i n he patic vas oc o nstricti o n dri vi n g i ncrease d p ortal ve n o us 
press ure. A d diti o nall y, precli nical st u dies ha ve i n dicate d t hat t he e n d ot heli n pat h wa y is 
i n v ol ve d i n t he de vel o p me nt of li ver fi br osis ( O ka m ot o  et al 2 0 1 6 ; R oc ke y a n d C h u n g  1 9 9 6 ). 
Cli nicall y, plas ma e n d ot heli n le vels are i ncrease d i n patie nts w it h cirr h osis a n d c orrelate wit h 
t he se verit y of li ver dise ase a n d p ortal h y perte nsi o n. I n a st u d y usi n g t he selecti ve E T A  
rece pt or a nta g o nist B Q 1 2 3 i n patie nts wit h cirr h osis, l ocal he patic art er y i nf usi o n of B Q 1 2 3 
res ulte d i n a decrease i n H V P G wit h n o effect o n s yste mic hae m o d y na mic para meters 
(Zi p pric h  et al 2 0 2 1 ). T h e sa me re p ort de m o nstrat e d t hat t he effect of a si n gle oral d ose of 
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 4  of 1 4 3
a m brise nta n res ult e d i n a si g nifica nt decrease i n H V P G. I n t his st u d y, 4 0 % of partici pa nts ha d 
a > 1 0 % d ecrease i n H V P G or a decreas e bel o w 1 2  m m H g.  
2. 3. 4. 2  
E vi de nce f or t he R ole of S G L T 2  i n hi bit ors i n Cirr h osis a n d Fe at ures of 
P ort al H y perte nsi o n   
Se veral st u dies ha ve e val uate d t he i m pact of S G L T 2 i n hi bit ors o n li ver bi o mar kers i n patie nts 
wit h T 2 D M, N A S H , a n d N A F L D. A re vi e w of res ults fr o m 7  st u dies a n d 1 1 c o h ort st u dies 
de m o nstrate d c o nsiste nt decreases i n li ver a mi n otra nsferase le vels, li ver fat, a n d FI B -4 i n de x 
after treat me nt wit h a n S G L T 2  i n hi bit or (Hsia n g  et al 2 0 2 0 ). A  pil ot st u d y i n dicate d t hat 
7 2  wee ks of treat me nt wit h a n S G L T 2 i n hi bit or re d uce d li ver fi br osis i n patie nts wit h N A F L D 
a n d dia betes (Ta ka h as hi  et al 2 0 2 1 ). N o st u dies i n m ore a d va n ce d cirr h osis patie nts ha ve bee n 
re p orte d t o dat e. A s mall pil ot st u d y e val uate d t he effect of S G L T 2 i n hi bit ors o n b o d y wei g ht 
i n patie nts wit h cirr h osis, T 2 D M a n d ascites (M o ntal v o -G or d o n  et al 2 0 2 0 ). All 3 patie nts 
s h o we d a decrease i n b o d y wei g ht ra n gi n g fr o m 4. 9 k g ( 7. 8 %) t o 1 1. 2  k g ( 1 3. 8 %) acr oss 
6  m o nt hs ass oci ate d wit h decrease d ascites a n d fl ui d o verl oa d , w hilst h y p o natrae mia was 
c orrecte d or s o di u m le vels were u n c ha n ge d , a n d n o h y per kalae mia was o bs er ve d. S G L T 2  
in hi bit ors  ha ve als o bee n s h o w n t o i m pr o ve e n d ot helial f u ncti o n a n d decrease vasc ular 
stiff ness w hic h ma y bri n g a d diti o nal be nefit t o patie nts wit h cirr h osis a n d p ortal h y perte nsi o n.  
2. 3. 4. 3  
P ossi ble C o m ple me nt ar y Acti o ns of Zi b ote nt a n a n d D a p a glifl ozi n   
T he c o m bi nati o n of zi b ot e nta n a n d da p a glifl ozi n is e x pecte d t o tar get 2  d isti nct feat ur es of 
cirr h otic diseas e , t hat is, p ortal h y perte nsi o n a n d fl ui d rete nti o n. Gi ve n re d ucti o n i n p ortal 
ve n o us pre ss ur e is esta blis he d t o i m pr o ve o utc o mes i n t his p o p ulati o n, it is a ntici pate d t hat t he 
c o m bi nati o n will re d uce t he ris k of variceal hae m orr ha ge, ascites , a n d p er ha ps deat h. Fl ui d 
rete nti o n is a class effect of e n d ot heli n rece pt or a nta g o nists w hic h ma y li mit t heir p ote ntial 
use as m o n ot hera p y i n cirr h osis. T he re d ucti o n i n p ortal h y perte nsi o n aff or de d b y zi b ote nta n  
has t he p ote ntial t o miti gate re ni n -a n gi ote nsi n -al d oster o ne s yste m acti vati o n, p ote ntiall y 
re d uci n g as cites f or mati o n. I n a d diti o n, it is a nticipate d t hat p ote ntial fl ui d rete nti o n ris k fr o m 
zi b ote nta n will be miti gate d b y t he os m otic di uretic effects of d a pa glifl ozi n.  
2. 3. 5  O ver all Be nefit /Ris k C o ncl usi o n   
T he o verall cli nical e vi de nce s u g gests t hat t he c o m bi nati o n of zi b ote nta n a n d da pa glifl ozi n 
s h o ul d ha ve cli nical be n efit, a n d a n acce pta bl e safet y pr ofile i n patie nts wit h cirr h osis , 
j ustif yi n g f urt her dr u g de vel o p me nt wit h a p pr o pri ate ris k miti gati o n strate gies f or p ote ntial 
ris ks relate d t o h y p ote nsi o n, fl ui d rete nti o n, a n d heart fail ure. 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 5  of 1 4 3
3  
O B J E C TI V E S, E N D P OI N T S, A N D E S TI M A N D S   
Ta ble  3  
O bjecti ves a n d E n d p oi nts   
O bjecti ves  
E n d p oi nts  
Ke y O bjecti ve s 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n a 
c o m p osite e n d p oi nt of fl ui d rete nti o n . 
Occ urre nce of a n y of t he f oll o wi n g c o m p o ne nts of t his 
c o m p osite e n d p oi nt fr o m baseli ne t o Wee k  6 : 
•  
> 2 k g i ncrease i n b o d y wei g ht ( office-base d)  
•  
> 2  L i ncrease i n t otal b o d y water  
•  
I ncrease i n 2 or m ore l o o p-di uretic e q ui vale nts  a 
•  
Fl ui d rete nti o n A Es  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n a 
c o m p osite e n d p oi nt of fl ui d rete nti o n. 
Occ urre nce of a n y of t he f oll o wi n g c o m p o ne nts of t his 
c o m p osite e n d p oi nt fr o m baseli ne t o Wee k  6 : 
•  
> 2 k g i ncrease i n b o d y wei g ht  
•  
> 2  L i ncrease i n t otal b o d y water  
•  
I ncrease i n 2 or m ore l o o p-di uretic e q ui vale nts  a 
•  
Fl ui d rete nti o n A Es  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n 
b o d y wei g ht , b o d y water v ol u mes, a n d b o d y fat 
mass . 
•  
C ha n ge  i n b o d y wei g ht ( k g) o ver ti me c o urse of 
st u d y ( h o me-base d m o nit ori n g).  
•  
C ha n ge fr o m baseli ne i n b o d y wei g ht, t otal b o d y  
water , e xtracell ular  a n d i ntracell ular water 
v ol u mes , b o d y fat mass at Wee k  6 ( office -base d 
m o nit ori n g).  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n b o d y 
wei g ht , b o d y water v ol u mes, a n d b o d y fat mass . 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n 
t otal l o o p-di uretic e q ui vale nts us e. a 
C ha n ge i n t otal d osa ge of l o o p -di uretic e q ui vale nts use 
fr o m baseli ne t o Wee k 6  a. 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n t otal 
l o o p-di uretic e q ui vale nts use . a 
T o e v al uate t he effects of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n t he 
c o m p osite of t otal b o d y water a n d t otal d osa ge of 
l o o p-di uretic e q ui vale nts . a 
Occ urre nce of eit her of t he t w o c o m p o ne nts of t his 
c o m p osite:  
1  
>  3  L  i ncrease i n t otal b o d y water v ol u me fr o m 
baseli ne t o Wee k  6 . 
2  
I ncrease i n 3 or m ore l o o p-di uretics e q ui vale nts 
use fr o m baseli ne t o Wee k  6  a. 
T o e v al uate t he effects of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n t he 
c o m p osite of  t otal b o d y water a n d t otal d osa ge of 
l o o p-di uretic e q ui vale nts . a 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us c orres p o n di n g zi b ote nta n m o n ot hera p y o n 
office -base d s yst olic a n d diast olic bl o o d press ure.  
A bs ol ute c ha n ge i n s yst olic a n d diast olic bl o o d press ure 
fr o m baseli ne t o Wee k 6.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 6  of 1 4 3
Ta ble  3  
O bjecti ves a n d E n d p oi nts  
O bjecti ves 
E n d p oi nts  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n 
office -base d s yst olic a n d diast olic bl o o d press ure.  
E x pl or at or y O bjecti ves  
T o c h aracterise t he plas ma e x p os ure t o zi b ote nta n 
a n d da pa glifl o zi n.  
Plas ma c o nce ntrati o ns of zi b ote nta n a n d da pa glifl ozi n 
per treat me nt, visit , a n d ti me p oi nt.  
T o e v al uate t he effect of zi b ote nta n /da p a glifl ozi n i n 
c o m bi nati o n a n d zi b ote nta n m o n ot hera p y vers us 
place b o o n 
 a n d/ or 
 as 
meas ure d wit h 
. b 
Perce nta ge a n d a bs ol ute c ha n ge i n
a n d/ or 
 fr o m baseli ne t o Wee k 6.  
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n li ver 
healt h a n d p ortal h y perte nsi o n bi o mar kers.
•
Perce nta ge a n d a bs ol ute c ha n ge i n A S T a n d A L T
fr o m baseli ne t o Wee k 6 .
•
A bs ol ute c ha n ge i n M E L D sc ore fr o m baseli ne t o
Wee k  6 .
T o assess t he effect of zi b ote nta n /da p a glifl ozi n i n 
c o m bi nati o n a n d zi b ote nta n m o n ot hera p y vers us 
place b o o n plas ma/ser u m le vels of
 a n d 
. 
E val uati o n  of c ha n ges i n bl o o d bi o mar kers acr oss ti me 
fr o m baseli ne t o Wee k 6 . 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
vers us zi b ote nta n m o n ot hera p y a n d place b o o n  
e G F R.  
C ha n ge i n e G F R fr o m baseli ne t o Wee k  6 . 
T o e v al uate t he effect of zi b ote nta n/ da p a glifl ozi n 
a n d zi b ote nta n m o n ot hera p y vers us place b o o n 
fati g ue, a b d o mi nal s y m pt o ms, p h ysical f u ncti o ni n g 
a n d healt h -relate d q ualit y of life 
•
C ha n ge fr o m baseli ne t o Wee k  6  i n C L D Q
Fati g ue a n d A b d o mi nal S y m pt o ms sc ores,
S F -3 6 v 2 P h ysical F u ncti o ni n g sc ore, T otal C L D Q
sc ore, S F-3 6 v 2 P h ysical C o m p o ne nt S u m mar y
sc ore, S F -3 6 v 2 Me ntal C o m p o ne nt S u m mar y
sc ore
•
Patie nt Gl o bal I m pressi o n of Se verit y –  Li ver
Disease at baseli ne a n d Wee k  6
T o c ollect a n d st ore plas ma, ser u m a n d uri ne 
sa m ples f or e x pl orat or y researc h ai me d at e x pl ori n g 
bi o mar kers i n v ol ve d i n P K, P D, safet y a n d 
t olera bilit y relate d t o zi b ote nta n a n d da p a glifl ozi n i n 
c o m bi nati o n vers us place b o or 
 t o  
 
E val uati o n of c ha n ges i n bl o o d a n d uri ne bi o mar kers  
Res ults of t his f ut ure a nal ysis are t o be re p orte d 
se paratel y fr o m t he C S R. 
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 7  of 1 4 3
Ta ble  3  
O bjecti ves a n d E n d p oi nts  
O bjecti ves 
E n d p oi nts  
S afet y O bjecti ves  
T o assess t he safet y a n d t olera bilit y of 
zi b ote nta n/ da p a glifl o zi n a n d zi b ote nta n vers us 
place b o.  
•
A Es, S A Es, a n d D A Es
•
A E SIs
•
Vital si g ns
•
Safet y la b orat or y tests
•
E C G assess me nts
a)
O ne l o o p -di uretic e q ui vale nt = 4 0  m g f ur ose mi de  =  1  m g b u meta ni de  =  2 0  m g t orse mi de  =  5 0  m g
et hacr y nic aci d.  I n Ja p a n, o ne l o o p-di uretic e q ui vale nt = 4 0 m g f ur ose mi de = 8 m g t orse mi de = 6 0 m g
az ose mi de.
b)
assess me nt of 
 a n d/ or 
 s h o ul d o nl y be d o ne if 
 t o c o m plete a n acc urate  
 a n d/ or 
 meas ure me nt. 
 s h o ul d o nl y be 
d o ne if 
 is a v aila ble. 
A E  =  a d verse e v e nt; A E SI  =  a d verse e v e nt of s pecial i nterest; 
; A L T  =  ala ni ne 
a mi n otra nsferase; A S T  =  as partate a mi n otra nsferase; 
; D A E  =  disc o nti n uati o n d ue t o 
a d verse e ve nt; E C G  =  electr ocar di o gra m; e G F R  =  esti mate d gl o mer ular filtrati o n rate; 
H b A 1c  =  hae m o gl o bi n  A 1c; M E L D  =  m o del f or e n d -sta ge li ver disease; P GI S = Patie nt Gl o bal I m pressi o n of 
Se verit y; P K  =  p har m ac o ki netic; S A E  =  seri o us a d verse e ve nt; 
. 
C CI
C CI
C CI
C CI
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 8  of 1 4 3
4  
S T U D Y D E SI G N   
4. 1  
O ver all Desi g n   
T his is a P hase II b m ultice ntre, ra n d o mise d, d o u ble -bli n d, parallel -gr o u p, place b o -c o ntr olle d 
st u d y t o e val uate t he safet y of zi b ote nta n/ da pa glifl ozi n i n c o m bi nati o n as c o m pare d t o 
zi b ote nta n m o n ot hera p y  as well as zi b ote nta n/ d a p a glifl ozi n a n d zi b ote nta n m o n ot hera p y as 
c o m pare d t o place b o i n p atie nts wit h cirr h osis. Eli gi ble partici pa nts s h o ul d ha ve a hist or y of 
dec o m pe nsati o n e v e nts or c o m pe nsate d cirr h osis wit h si g ns of C S P H. If c o m pe nsate d 
cirr h osis, t he eli gi ble partici pa nt m ust ha ve si g ns a n d meas ures t hat w o ul d i n dicate t hat t he 
partici pa nt has C S P H a n d i ncl u des, b ut n ot li mite d t o, prese nce of gastr o -o es o p ha geal v arices 
at e n d osc o p y or c ollaterals at i ma gi n g (eit her o ne wit hi n 1 2 m o nt hs pri or t o scr ee ni n g), a n d/ or 
 k Pa, or of 
 k Pa wit h 
 (at ti me of 
scree ni n g). Partici pa nts s h o ul d ha ve a M E L D s c ore < 1 5 a n d s h o ul d be classifie d as 
C hil d -P u g h A or B (Ta ble  6 ). 
It is pla n ne d t hat a p pr o xi matel y 2 2 eli gi ble partici pa nts will be ra n d o mise d t o eac h of t he 
3  treat me nt gr o u ps, f or a t otal of u p t o 6 6 partici pa nts (see Fi g ure 1 ). F or details of t he st u d y 
assess me nts, please s ee S o A (Ta ble  1 ). 
T his st u d y will c o n sist of t he f oll o wi n g peri o ds: 
Scree ni n g Peri o d  of u p t o 3 wee ks: T he Scree ni n g Visit ( Visit 1) will ta ke place bet w ee n 7 t o 
2 1 da ys bef ore t he Ra n d o mi sati o n Visit ( Visit  2 ) t o c o nfir m partici pa nt eli gi bilit y a n d c ollect 
baseli ne data . T here m ust be at least 7 da ys b et wee n Visit 1  a n d Visit  2  t o all o w s ufficie nt ti me 
f or la b orat or y res ults t o be e xa mi ne d. At t he Ra n d o misati o n Visit (Visit  2 ), eli gi bilit y criteria 
will be reassess e d, safet y la b orat or y dat a re v erifie d , a n d partici pa nts will b e pr o vi de d di gital 
de vices t o meas ur e t heir b o d y wei g ht starti n g t he first da y after t he Ra n d o misati o n Visit a n d 
e ver y da y at h o me.  
Tre at me nt Peri o d  of 6  wee ks : D uri n g t he Treat me nt Peri o d, partici pa nts will visit t he st u d y 
ce ntre 5  ti mes. At Visit 2 , partici pa nts will be ra n d o mise d a n d will recei v e t he first d ose of t he 
st u d y i nter ve nti o n. At eac h st u d y visit d uri n g t he treat me nt peri o d (fr o m Visit  2  till Visit 6) 
partici pa nts will recei ve t he o nce d ail y d ose at t he st u d y ce ntre a n d  will pr o vi de a pre -d ose 
bl o o d sa m ple f or P K a nal ysis a n d ot her la b sa m ples bef ore t he i nta ke of st u d y i nter ve nti o n. 
W he n n ot visiti n g t he st u d y ce ntre t he patie nts will ta ke t he o nce d ail y d ose of st u d y 
i nter ve nti o n at h o me. 
F oll o w -u p Peri o d  of  2  wee ks : P artici pa nts will ret ur n t o t he st u d y ce ntre f or f oll o w -u p 
assess me nts a p pr o xi matel y 2 wee ks aft er t heir pla n ne d last d ose of st u d y i nter ve nti o n 
( pla n ne d last d ose is at Visit 6). 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 9  of 1 4 3
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n  
T he mec ha nis ms of acti o n of zi b ote nta n a n d d a pa glifl ozi n are differe nt a n d t he o utc o me of 
c o m bi ne d treat me nt is e x pecte d t o be c o m ple me ntar y. Fl ui d rete nti o n is a class effect of 
e n d ot heli n rece pt or a nta g o n ists w hic h ma y li mit t heir p ote ntial use as m o n ot hera p y i n 
cirr h osis. It is a ntici pate d t hat p ote ntial fl ui d rete nti o n ris k fr o m zi b ote nta n will be miti gate d 
b y t he os m otic di uretic effects of da p a glifl ozi n wit h o ut i ncreasi n g t he ris k f or h y p o - or 
h y per kal ae mia, h y p o natr ae mia, or h y p o v ol ae mia. B y i n vesti gati n g t he effects of zi b ote nta n 
m o n ot hera p y as c o m p are d t o t he c o m bi nati o n of zi b ote nta n a n d da pa glifl ozi n a n d  place b o t he 
i m p orta nce of da pa glifl o zi n t o re d uce t h e ris k f or fl ui d rete nti o n ca use d b y zi b otenta n will be 
e val uate d.  A p lace b o ar m is i ncl u de d t o assess  t he effect of zi b ote nt a n m o n ot hera p y. 
4. 3  
J ustific ati o n f or D ose  
Partici pa nts w h o meet t h e eli gi bilit y criteria a n d a gree t o partici pate will be ra n d o mise d t o o ne 
of t he f oll o wi n g treat me nt gr o u ps ( 2 2  partici pa nts per treat me nt gr o u p).  All pa rtici pa nts will 
recei v e 1 ca ps ul e zi b ote nta n or matc hi n g place b o) a n d 1  ta blet ( da p a glifl ozi n or matc hi n g 
place b o) at e ver y d osi n g.  
•
Treat me nt Gr o u p  1 : place b o matc hi n g zi b ote nta n ca ps ule + place b o mat c hi n g
da pa glifl ozi n ta blet.
•
Treat me nt Gr o u p  2 : zi b ote ntan ca ps ule
m g + place b o matc hi n g da pa glifl ozi n ta blet.  
•
Treat me nt Gr o u p  3 : zi b ote nta n ca ps ule
m g + da p a glifl ozi n ta blet 1 0  m g . 
I n t he pre vi o us P hase III pr o gra m me i n o nc ol o g y, zi b ote nta n 1 0 m g was us e d a n d e xte nsi ve 
safet y data are a vaila ble f or t his d ose. T his  st u d y will i ncl u de partici pa nts wit h mil d or 
m o derate he p atic i m pair me nt (C hil d -P u g h  A a n d B ) a n d wit h n or mal re n al f u ncti o n or mil d 
re nal i m pair me nt ( M E L D sc ore < 1 5 a n d e G F R  >  6 0  m L/ mi n/ 1. 7 3  m 2). C o nc urre nt m o derate 
he patic a n d m o derate re n al i m pair me nt has bee n f o u n d t o i ncrease zi b ote nt a n e x p os ure 
a p pr o xi matel y t w o -f ol d (St u d y D 4 3 2 6 C 0 0 0 0 1 ); t his ma xi mal e x p os ure i ncrease has b ee n 
ta ke n i nt o acc o u nt b y t he 
 i n t his st u d y 
m g) bei n g 
 of t he 
 m g).  
Da pa glifl ozi n 1 0  m g has bee n e xte nsi vel y st u die d as m o n ot hera p y. A hi g her e x p os ure of 
da pa glifl ozi n is e x pecte d i n partici pa nts wit h re nal a n d/ or he patic i m pair me nt c o m pare d t o 
healt h y partici pa nts b ut d oes n ot re q uire d os e a dj ust me nt g i ve n t he safet y a n d t olera bilit y 
pr ofile of da p a glifl ozi n. Da pa glifl ozi n 1 0 m g o nce dail y di d n ot lea d t o a n y u ni q ue safet y or 
t olera bilit y si g nals i n partici pa nts wit h re nal i m pair me nt i n b ot h c hr o nic ki d ne y disease 
( ≥ 2 5  m L/ mi n/ 1. 7 3  m 2; D A P A-C K D o utc o mes  st u d y) a n d heart fail ure p o p ulati o ns 
( D A P A-H F o utc o mes st u d y). A d mi nistrati o n  of da pa glifl ozi n d oses of u p t o 1 0 0  m g f or 
1 4  da ys t o healt h y v ol u nteers ha v e bee n s h o w n t o be t olera ble. Da pa glifl ozi n 1 0  m g o nce 
dail y has t heref ore als o bee n sele cte d f or t h e pla n ne d cli nical pr o gra m me i n cirr h osis. 
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 0  of 1 4 3
4. 4  
E n d -of -st u d y Defi niti o n 
A partici pa nt is c o nsi dere d t o ha ve c o m plete d t he st u d y if t he y ha ve c o m plet e d all p hases of 
t he st u d y, i ncl udi n g t he foll o w -u p v isit as s h o w n i n t he S o A (Ta ble  1 ). 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last partici pa nt i n t he st u d y. 
F or t he p ur p ose of Cli nical Trial Tra ns pare nc y , the defi niti o n of t he e n d of t he st u d y di ffers 
u n der F D A a n d E U re g ulat or y re q uir e me nts:  
•
E U  re q uire m e nts defi ne st u d y c o m pleti o n as t he last visit of t he last s u bject f or a n y
pr ot oc ol -relat e d acti vit y.
T he F D A re q uire me nts d efi ne 2  co m pleti o n dates:  
•
Pri mar y C o m pleti o n Date –  t he date t hat t he fi nal partici pa nt is e xa mi ne d or recei ves a n
i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y o utc o me meas ure,
w het her t he cli nical st u d y c o ncl u de d acc or di n g t o t he pre -s pecifie d pr ot o c ol or was
ter mi nate d. I n t he case of cli nical st u dies wit h m ore t ha n o ne pri mar y o utc o me meas ure
wit h differe nt c o m pleti o n dates, t his ter m refers t o t he date o n w hic h data c ollecti o n is
c o m plete d f or all of t he pri mar y o utc o mes.
•
St u d y C o m pleti o n Date –  t he date t he fi nal p artici pa nt is e xa mi ne d or recei ves a n
i nter ve nti o n f or p ur p oses of fi nal c ollecti o n of d ata f or t he pri mar y a n d sec o n dar y
o utc o me meas ur es a n d A Es (f or e x a m ple, last partici pa nt’s last visit), w het her t he cli nical
st u d y c o ncl u des acc or di n g t o t he pre-s pecifie d pr ot oc ol or is ter mi nate d.
5  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d. All st u d y  i ncl usi o n/e xcl usi o n criteria a n d 
partici pa nt re q uir e me nts i n t his secti o n a p pl y t o all partici pa nts , e xce pt w here e x pressl y n ote d.  
5. 1  
I ncl usi o n Criteri a 
A ge  
1  
Partici pa nt m ust be a ge d ≥ 1 8  years  a n d ≤ 8 0 y ears of a ge at t he ti me of si g ni n g t he 
i nf or me d c o nse nt. 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 1  of 1 4 3
T y pe of P artici p a nt a n d Dise ase C h ar acteristi cs  
2  
Partici pa nts w h o ha ve t h e f oll o wi n g:  
a)
Cli nical a n d/ or hist ol o gical dia g n osis of cirr h osis
N ote:  Eit her hist or y of d ec o m pe nsati o n or c o m pe nsate d cirr h osis wit h si g ns of C S P H ,
i ncl u di n g varices at e n d osc o p y or c ollaterals at i ma gi n g (eit her o ne wit hi n 1 2 m o nt hs
pri or t o scree ni n g), a n d/ or 
 of 
 k Pa, or of 
k Pa 
 (at ti me of scree ni n g)
b)
M o del f or e n d  sta g e li ver disease sc ore ( M E L D) < 1 5.
c)
C hil d -P u g h sc ore <  1 0.
d)
N o ascites or ascites u p t o  a n d i ncl u di n g  gra de  2 wit h o ut c ha n ge i n di ureti c treat me nt
wit hi n t he last m o nt h pri or t o first d ose of st u d y i nter ve nti o n a n d n o parace ntesis
wit hi n t he last m o nt h.
e)
N o e vi de nce of w ors e ni n g of he patic f u ncti o n (e g, n o cli nicall y si g nifica nt c ha n ge i n
si g ns, s y m pt o ms, or la b orat or y para meters of he p atic disease stat us) wit hi n t he last
m o nt h pri or t o d osi n g, as deter mi ne d b y t he i n vesti gat or or us ual practiti o ner.
Me dic al Tre at me nt  
3  
N o c urre nt or pri or ( wit hi n 1 m o nt h of e nr ol me nt) me dical treat me nt wit h a n S G L T 2 
i n hi bit or or e n d ot heli n rece pt or a nta g o nist. 
4  
O n n o or a sta ble d os e of beta bl oc kers, wit h n o m aj or d ose c h a n ges wit hi n 1  m o nt h pri or 
t o t he first d ose of st u d y i nter ve nti o n. 
Se x a n d C o ntr ace pti ve/ B arrier R e q uire me nts  
5  
Males  or fe m ales of n o n -c hil d beari n g p ote ntial . 
−
M ale p artici p a nts  m ust be s ur gicall y sterile, a bsti ne nt , or m ust use i n c o nj u ncti o n
wit h t heir fe male p art ner a hi g hl y effecti ve met h o d of c o ntrace pti o n fr o m t he ti me
t he y si g n t he i nf or me d c o nse nt d oc u me nt a n d f or 3 m o nt hs after t he last d os e of st u d y
i nter ve nti o n t o pre ve nt pr e g na nc y i n a part ner. I n a d diti o n, t he male partici pa nt
s h o ul d use a c o n d o m f or t he d urati o n of t he st u d y a n d f or 3 m o nt hs after t he last d ose
of st u d y i nter ve nti o n. Male partici pa nts m ust n ot d o nate or ba n k s p er m d uri n g t he
sa me peri o d See s ecti o n s 5. 3. 5  a n d 8. 4. 9. 2 .
Hi g hl y effecti ve birt h c o ntr ol met h o ds are defi ne d as t h ose  t hat ca n ac hie ve a fail ure
rate of less t ha n 1 % per year w h e n use d c o nsiste ntl y a n d c orrectl y. F or details, refer
t o Secti o n 5. 3. 4 .
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 2  of 1 4 3
− 
F e m ale p artici p a nts  m ust be of n o n -c hil d be ari n g p ote nti al  c o nfir me d at scree ni n g 
b y f ulfilli n g o ne of t he f oll o wi n g criteria:  
o  
P ost -me n o pa usal: defi ne d as a me n orr h oea f or at l east 1 2 m o nt hs o r m ore 
f oll o wi n g cessati o n of all e x o ge n o us h or m o nal treat me nts; a n d als o F S H le vels 
i n t he p ost-me n o pa usal r a n ge b y ce ntral la b orat or y ( N ote: T he p ost -me n o pa usal  
ra n ge m ust be c h ec k e d a gai nst t he s pecific F S H assa y use d). I n t he a bse nce of 
1 2  m o nt hs of a m e n orr ho ea , a si n gle F S H meas ure me nt is i ns ufficie nt t o defi ne 
p ost -me n o pa usal  criteria. I n case of peri me n o p a us e or i nfre q u e nt peri o ds wit h 
varia ble le v els of F S H, w o me n s h o ul d be c o nsi dere d of c hil d beari n g p ote ntial 
a n d, t heref ore, n ot eli gi bl e f or partici pati o n i n t his st u d y.  
o  
D oc u me ntati o n of irre versi ble s ur gical sterilisati o n b y h ysterect o m y, bilateral 
o o p h orect o m y , or bilateral sal pi n gect o m y b ut n ot t u bal li gati o n.  
− 
Fe male p artici pa nts m ust ha ve a n e gati ve pre g na n c y test at scree ni n g a n d m ust n ot be 
lactati n g. 
 
I nf or me d C o nse nt 
6  
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as d es cri be d i n A p pe n di x A , w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restri cti o ns liste d i n t he I C F a n d i n t his pr ot oc ol.  
7  
Pr o visi o n of si g ne d a n d date d, writte n I C F pri or t o a n y ma n dat or y st u d y -s p ecific 
pr oce d ures, sa m pli n g, a n d a nal yses.  
8  
Pr o visi o n of si g ne d a n d date d writte n O pti o nal Ge n o mic s I nitiati ve Researc h I nf or mati o n 
a n d C o nse nt  F or m  pri or t o c ollecti o n of sa m ples f or o pti o nal ge n o mics i nitiati ve researc h 
t hat s u p p orts Ge n o mic I nitiati ve. 
 
5. 2  
E xcl usi o n Criteri a   
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
Me dic al C o n diti o ns  
1  
A n y e vi de nce of a cli nicall y si g nifica nt disease , w hic h i n t he i n vesti gat or’s  o pi ni o n ma kes 
it u n desira ble f or t he p artici pa nt t o partici pate i n t he st u d y. 
2  
Ala ni ne a mi n otra nsf eras e/tra nsa mi nase or A S T ≥ 1 5 0  U/ L a n d/ or t otal bilir u bi n 
≥ 3  ×  U L N.  
3  
I nter nati o nal n or malise d rati o > 1. 7.  
4  
Ser u m/ plas ma le vels of al b u mi n ≤ 2 8  g/ L.  
5  
Platelet c o u nt <  5 0  ×  1 0 9L.  
6  
Ac ute ki d ne y i nj ur y  ( A KI) wit hi n 3  m o nt hs of scree ni n g.  
7  
Hist or y of e nce p hal o pat h y of West Ha v e n Gra de  2 or hi g her.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 3  of 1 4 3
8  
Hist or y of variceal ha e m orr ha ge wit hi n 6  m o nt hs pri or t o scree ni n g.  
9  
A n y hist or y of he pat oc ell ular carci n o ma.  
1 0  A n y hist or y of p ortal ve n o us t hr o m b osis.  
1 1  Li ver tra ns pla nt or e x pecte d li ver tra ns pla ntati o n wit hi n 6  m o nt hs of scree ni n g.  
1 2  Hist or y of TI P S or a pla n ne d TI P S wit hi n 6  m o nt hs fr o m e nr ol me nt i nt o t he st u d y.  
1 3  P ositi ve alc o h ol breat h test or scree n f or  dr u gs of a b use (e xcl u di n g dr u gs prescri be d b y 
t he partici pa nts’ us ual p h ysicia n ) at scree ni n g. 
1 4  O n g oi n g or hist or y of si g nifica nt use of al c o h ol e x pecte d t o precl u de c orrect a d here n ce t o 
st u d y pr oce d ures ( F or details, refer t o Secti o n 5. 3. 2 ). 
1 5  Acti ve treat me nt f or H C V wit hi n t he last 1  year or H B V a nti -viral  t hera p y f or less t ha n 
1  year.  
1 6  Acti ve uri nar y tract i nfecti o n or ge nital i nfecti o n . 
1 7  U nc o ntr olle d dia betes m ellit us ( H b A 1c > 8. 5 % or >  6 9  m m ol/ m ol wit hi n t he last m o nt h).  
1 8  Partici pa nts wit h T 1 D M.  
1 9  Re nal tra ns pla nt or c hr o nic re nal r e place me nt t hera p y or s h ort -ter m dial ysis wit hi n t he 
pre vi o us 6  m o nt hs.  
2 0  e G F R < 6 0  m L/ mi n/ 1. 7 3 m 2 (e G F Rcr[ A S]). 
2 1  A c ute c or o nar y s y n dr o m e e ve nts wit hi n 3 m o nt hs pri or t o scree ni n g.  
2 2  Ort h ostatic h y p ote nsi o n or h y p ote nsi o n (s yst olic bl o o d press ure < 9 5 m m H g or diast olic 
bl o o d press ure < 6 0 m m H g) . 
2 3  Ne w Y or k Heart Ass ociati o n f u ncti o nal heart fail ure Class III or I V or p atie nts wit h 
u nsta ble heart fail ure re q uiri n g h os pitalisati o n f or o pti misati o n of heart fail ure treat me nt 
a n d w h o are n ot yet sta bl e o n heart fail ure t hera p y wit hi n 6 m o nt hs pri or t o scree ni n g.  
2 4  Heart fail ure d ue t o car di o m y o pat hies t hat w o ul d pri maril y re q uire  s p ecific ot her 
treat me nt. 
2 5  Hi g h o ut p ut heart fail ure (e g , d ue t o h y pert h yr oi dis m or Pa get’s disease).  
2 6  Heart fail ure d ue t o pri mar y car diac v al v ular disease/ d ysf u ncti o n, se vere f u ncti o nal mitral 
or tric us pi d val ve i ns uffi cie nc y, or pla n ne d car diac val ve re p air/re place me nt.  
2 7  Partici pa nts treate d wit h 
 or 
wit hi n 
 of st u d y i nter ve nti o n a d mi nistrati o n; t his 
2 8  Hist or y or o n g oi n g aller g y/ h y perse nsiti vit y, as j u d ge d b y t he i n vesti gat or, t o S G L T 2 
i n hi bit ors (e g, da pa glifl o zi n, ca na glifl ozi n, e m pa glifl ozi n), zi b ote nta n, dr u gs wit h a 
si milar c he mical str uct ur e t o zi b ote nta n, or a n y of t he e xci pie nts of t he pr o d ucts . 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 4  of 1 4 3
2 9  A n y cli nicall y si g nifica nt c hr o nic diseas e or dis or d er (e g , car di o v asc ular, g astr oi ntesti nal, 
li ver, re nal, n e ur ol o gical, m usc ul os keletal, e n d ocri ne, meta b olic, ps yc hiatri c, maj or 
p h ysical i m pair me nt) w hic h, as j u d ge d b y t he i n vesti gat or, mi g ht p ut t he partici pa nt at 
ris k beca use of partici pati o n i n t he st u d y, or pr o ba ble alter nati ve pri mar y reas on f or 
partici pa nt’s s y m pt o ms i n j u d g me nt of i n vesti gat or.  
3 0  Ac ute li ver i nj ur y ca use d b y dr u g t o xicit y or b y a n i nfecti o n.  
 
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce  
3 1  Partici pati o n i n a n ot her cli nical st u d y wit h a st u d y i nter ve nti o n  a d mi nistere d i n t he last 3 
m o nt hs pri or t o ra n d o misati o n.  
 
Ot her E xcl usi o ns  
3 2  I m pla nte d car diac el ectr o nic de vice s uc h as pace m a ker or i m pla nta bl e car di o verter 
defi brillat or.  
3 3  I n v ol ve m e nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o b ot h Astra Ze neca 
staff a n d/ or staff at t he st u d y ce ntre ). 
3 4  J u d g me nt b y t he i n vesti gat or t hat t he partici pa nt s h o ul d n ot partici pate i n t he st u d y if t he 
partici pa nt is u nli kel y t o c o m pl y wit h st u d y pr oce d ures, restricti o ns, a n d re q uire me nts.  
3 5  Male partici pa nt i n a s e x uall y acti ve rel ati o n wit h pre g na nt or breastf ee di n g part ner.  
3 6  V ul nera ble p artici pa nts, e g, ke pt i n dete nti o n, pr otecte d a d ults u n der g uar dia ns hi p, 
tr ustees hi p, or c o m mitte d t o a n i nstit uti o n b y g o ver n me ntal or j uri dical or d er. 
 
E xcl usi o n Criteri a f or P artici p a nts C o nse nti n g t o O pti o n al Ge netic S a m pli n g  
T he f oll o wi n g partici pa nts are n ot eli gi ble t o c o nse nt t o t he o pti o nal ge netic sa m pli n g:  
3 7  Pre vi o us all o ge neic b o ne marr o w tra ns pl a nt . 
3 8  N o n -le u k oc yte d e plete d w h ole bl o o d tra nsf usi o n i n 1 2 0 da ys of ge netic s a m ple c ollecti o n. 
 
5. 3  Lifest yle C o nsi der ati o ns   
5. 3. 1  
Me als a n d Diet ar y Restricti o ns   
Partici pa nts will be a d vise d t o a d here t o diet as per rec o m me n d ati o ns b y t heir us ual 
p h ysicia n/ me dical tea m.  
St u d y i nter ve nti o n s h o ul d be ta ke n bet w ee n a p pr o xi matel y 0 8: 0 0 t o 1 0: 0 0 eac h m or ni n g. If 
st u d y i nter ve nti o n is n ot ta ke n bef ore n o o n ( 1 2: 0 0 p m ), it is rec o m me n de d t o ta ke t he ne xt 
d ose i n t he m or ni n g t he ne xt da y. O n t he da y of ra n d o misati o n, st u d y i nter ve nti o n ca n be 
ta ke n after n o o n, wit h o ut affecti n g t he ne xt da y’s d ose. 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 5  of 1 4 3
O n t he da ys of 
 ass ess me nts, meas ure me nts will be perf or me d at t he 
ti me p oi nts s pecifie d i n t he S o A (Ta ble  1 ) after a n o ver-ni g ht fast or at least 3 h o urs after a 
meal. A d diti o nall y, f or Visit 6, 
 s h o ul d be perf or m e d ≥ 3 h o urs after st u d y 
i nter ve nti o n is gi ve n. 
O n t he da y of t he P K pr ofile (t his a p plies t o Ja pa n ese patie nts o nl y), partici pa nts will be as ke d 
t o a v oi d hi g h-fat, hi g h-cal oric meals ( ma xi m u m a p pr o xi matel y 6 0 0  kcal) i n t he m or ni n g 
bef ore a n d f or 2  h o urs aft er st u d y i nter ve nti o n a d mi nistrati o n.  
Partici pa nts s h o ul d refrai n 
 a n d 
 d uri n g t he 
c o urse of t he st u d y.  
5. 3. 2  
C affei ne, Alc o h ol, a n d T o b acc o  
Partici pa nts will be re q uire d t o li mit t heir alc o h ol c o ns u m pti o n t o <  2  u nits per da y. F or 
refere nce, t he f oll o wi n g re prese nt 1 u nit of al c o h ol: 7 6  m L of 1 3 % A B V wi ne; 2 5  m L of 4 0 % 
A B V s pirit (e g, w his k y); 2 5 0  m L of 4 % A B V beer/la ger; 2 1 8  m L of 4. 5 % A B V ci der , or 
2 5 0  m L of 4 % A B V alc o p o p.  
5. 3. 3  
Acti vit y  
Partici pa nts s h o ul d tr y t o mai ntai n t heir n or mal acti vit y, i ncl u di n g me dicall y prescri be d l e vel 
of e xercise acti vities d uri n g t he st u d y.  
5. 3. 4  
Re pr o d ucti ve Restricti o ns  
Fe m ale p artici p a nts:  
Wo me n of c hil d beari n g p ote ntial are n ot eli gi ble f or partici pati o n i n t his st u d y (f or defi niti o n 
of W O C B P, see Secti o n 5. 1 ). 
M ale p artici p a nts:  
It is i m p orta nt t hat w o me n of c hil d beari n g p ote nti al, w h o are t h e part n ers of male partici pa nts, 
d o n ot bec o me pre g n a nt d uri n g t he st u d y a n d f or a t otal peri o d of 3  m o nt hs after t he mal e 
st u d y partici pa nt has recei ve d his last d ose of st ud y i nter ve nti o n.  
−
All male partici pa nts s h o ul d a v oi d fat heri n g a c hil d b y eit her tr ue a bsti ne nce (see
defi niti o n bel o w) or use t o get her wit h t heir fe male part ner a hi g hl y effecti v e met h o d of
c o ntrace pti o n, starti n g fr o m t he ti me t he y si g n i nf or me d c o nse nt u ntil 3  m o nt hs after t he
last d ose of st u d y i nter ve nti o n. I n a d diti o n, t he male partici pa nt s h o ul d use a c o n d o m f or
t he d urati o n of t he st u d y a n d f or 3 m o nt hs after t he last d ose of st u d y i nter ve nti o n.
Hi g hl y effecti ve birt h c o ntr ol met h o ds are defi ne d as t h ose t hat ca n ac hie ve a fail ure rat e
of less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y, a n d i ncl u de:
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 6  of 1 4 3
a)  Per ma ne nt sterilisati o n: male vasect o m y or fe mal e h ysterect o m y, bilateral 
o o p h orect o m y, or bilateral t u bal occl usi o n/sal pi n gect o m y.  
b)  C o m bi ne d ( oestr o ge n a n d pr o gester o n e c o ntai ni n g) h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, i ntra va gi nal, tra ns der m al) ; 
pr o gester o ne -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
( oral, i njecta ble, i m pla nt a ble); i ntrauteri n e de vice ; i ntra uteri ne h or m o ne-releasi n g 
s yste m. 
c)  T otal se x ual a bsti ne nce (tr ue a bsti ne nce i n li ne wit h t he preferre d a n d us ual 
lifest yle c h oice of t h e partici pa nt). 
Tr ue a bsti ne nce refers t o: w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yl e of t he 
partici pa nt. Peri o dic a bsti ne nce (e g, cal e n dar, o v ulati o n, s y m pt o -t her mal, p ost-o v ulati o n 
met h o ds), declarati o n of a bsti ne nce f or t he d urati o n of a st u d y, a n d wit h dra wal are n ot 
acce pta ble met h o ds of c o ntrace pti o n.  
If t he partici p a nt or male partici pa nt’s part ner bec o mes pre g na nt d uri n g t he c o urse of t he 
st u d y, st u d y i nter ve nti o n m ust  be disc o nti n ue d i m me diatel y, a n d a n Astra Z e neca 
re pres e ntati ve n otifie d. 
5. 3. 5  
S per m D o n ati o n   
Male partici pa nts s h o ul d n ot d o nate or ba n k s per m f or t he d urati o n of t h e st u d y a n d f or at least 
3  m o nt hs after t he last d ose of st u d y i nter ve nti o n.  
5. 3. 6  
Pre g n a nc y   
Wo me n of c hil d bear i n g p ote ntial are n ot eli gi ble f or partici pati o n  i n t his st u d y. 
Male partici pa nts will be i nstr ucte d t hat if t heir part ner bec o mes pre g na nt d uri n g t he st u d y, or 
wit hi n t hree m o nt hs after last d ose of t he st u d y i nter ve nti o n, t his s h o ul d be re p orte d t o t he 
in vesti gat or, a n d t he st u d y i nter ve nti o n s h o ul d be disc o nti n ue d. I n t he e ve nt t hat a 
partici pa nt’s part ner is s u bse q ue ntl y f o u n d t o be pre g na nt after t he st u d y partici pa nt is 
i ncl u de d i n t he st u d y, t he n c o nse nt will be s o u g ht fr o m t he part ner a n d if gra nte d t he 
pre g na nc y will be f oll o w e d a n d t he stat us of m ot h er a n d/ or c hil d will be re p orte d t o t he 
s p o ns or after deli ver y. 
A pre g na nc y n otificati o n f or m a n d f oll o w -u p will be c o m plete d.  
5. 3. 7  
Ot her Rest ricti o ns   
Partici pa nts s h o ul d n ot d o nate bl o o d d uri n g t he st u d y a n d f or 1 m o nt h f oll o wi n g 
disc o nti n uati o n of t he st u d y i nter ve nti o n beca us e of t he p ote ntial ris k t o t he f oet us of a 
pre g na nt tra nsf usi o n reci pie nt.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d D a p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 7  of 1 4 3
5. 4  
Scree n F ail ures   
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cl i nical st u d y b ut 
are n ot s u bse q u e ntl y assi g ne d t o st u d y i nter ve nti o n. A mi ni mal set of scree n fail ure 
i nf or mati o n is re q uire d t o e ns ure tra ns p are nt re p orti n g of scree n fail ure partici pa nts t o meet 
t he C O N S O R T p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m r e g ulat or y a ut h orities. 
Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure det ails, eli gi bilit y criteria, a n d a n y 
S A E.  
I n di vi d uals w h o d o n ot meet bl o o d a nal ysis criteria f or partici pati o n i n t his st u d y (scree n 
fail ure) ma y h a ve t hes e p ara meters ret este d u p t o 2 ti mes d uri n g t he scree ni n g peri o d. 
Partici pa nts ma y be res cree ne d o n ce, at t he discreti o n of t he i n vesti gat or, if t he y ha ve reas o n 
t o belie ve t he y ma y be eli gi ble. 
Rescree n e d partici pa nts s h o ul d be assi g ne d t he sa me partici pa nt n u m ber a s f or t he i nitial 
scree ni n g. Partici p a nts w h o are rescree n e d are re q uire d t o si g n a ne w I C F.  
5. 5  
Criteri a f or Te m p or aril y Del a yi n g  
E nr ol me nt/ R a n d o mis ati o n/ A d mi nistr ati o n of St u d y I nter ve nti o n   
N ot a p plica ble.  
6  
S T U D Y I N T E R V E N TI O N S A N D C O N C O MI T A N T T H E R A P Y   
St u d y i nter ve nti o ns are all pre -s pecifie d, I M Ps a n d NI M Ps, di gital de vices , a n d ot her 
i nter ve nti o ns (e g, s ur gic al a n d be ha vi oral ) i nte n de d t o be a d mi nistere d t o t he st u d y 
partici pa nts d uri n g t he st u d y c o n d uct.  
6. 1  
St u d y I nter ve nti o ns A d mi nistere d   
6. 1. 1  
St u d y I nter ve nti o n   
All partici pa nts will recei ve 1  ca ps ule (zi b ote nta n or matc hi n g place b o ) a n d 1  ta blet 
(da pa glifl ozi n or mat c hi n g place b o ), o n ce dail y i n t he m or ni n g.  
Ta ble  4  
St u d y I nter ve nti o n   
Ar m n a m e  
Tre at m e nt gr o u p  1  
Tre at m e nt gr o u p  2  
Tre at m e nt gr o u p  3  
I nter v e nti o n 
n a m e  
Place b o  
Zi b ote nta n  +   
place b o  
Zi b ote nta n + 
da pa glifl ozi n  
T y pe  
Place b o  
Dr u g/ place b o  
Dr u g  
D ose 
f or m ul ati o n 
Place b o ca ps ule ( matc hi n g 
zi b ote nta n ca ps ule)  a n d  p lace b o 
ta blet ( matc hi n g da pa glifl ozi n 
ta blet) 
Zi b ote nta n ca ps ule a n d 
place b o ta blet ( matc hi n g 
da pa glifl ozi n ta blet)  
 
Zi b ote nta n ca ps ule  
a n d da pa glifl ozi n 
ta blet 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 8  of 1 4 3
Ta ble  4  
St u d y I nter ve nti o n  
Ar m n a m e  
Tre at m e nt gr o u p  1  
Tre at m e nt gr o u p  2  
Tre at m e nt gr o u p  3  
U nit d ose 
stre n gt h(s) 
N A  
m g zi b ote nta n  
m g zi b ote nta n  
1 0  m g da pa glifl o zi n  
D os a ge le vel(s)  
O ne matc hi n g ta blet a n d ca ps ule 
o nce dail y  
O ne ca ps ule a n d o ne ta blet 
o nce dail y  
O ne ta blet a n d o ne 
ca ps ule o nce dail y  
R o ute of 
a d mi nistr ati o n  
Oral  
Oral  
Oral  
Use  
E x peri me ntal  
E x peri me ntal  
E x peri me ntal  
I M P or 
NI M P/ A x M P  
I M P 
I M P 
I M P 
S o urci n g  
Zi b ote nta n, da p a glifl ozi n, a n d t heir res pecti ve matc hi n g place b o treat me nts will be 
s u p plie d ce ntrall y b y Astra Ze neca.  
P ac k a gi n g a n d 
l a belli n g 
F or eac h stre n gt h, zi b ote nta n a n d matc hi n g place b o will be s u p plie d i n H D P E b ottles.  
Da p a glifl ozi n a n d matc hi n g place b o will be s u p plie d i n H D P E b ottles.  
All b ottles will be la belle d as per c o u ntr y re q uire me nt.  
A x M P =  a u xiliar y  me dici nal pr o d uct; H D P E  =  hi g h -de nsit y p ol yet h yle ne; I M P  =  i n vesti gati o nal me dici nal 
pr o d uct; N A = n ot a p plica ble; NI M P  =  N o n -i n vesti gati o nal me dici nal pr o d uct. 
N ote: St u d y i nter ve nti o n refers t o b ot h zi b ote nta n a n d da pa glifl ozi n. N a me of t he st u d y dr u g 
is s pecifie d if it is zi b ote nta n or da pa glifl ozi n al o ne. 
6. 1. 2  
Me dic al De vices I ncl u di n g C o m bi n ati o n Pr o d ucts wit h a De vice 
C o nstit ue nt   
N o Astra Z e neca ma n ufact ure d me dical de vi ces ( or me dical de vices m a n ufact ure d f or 
Astra Ze neca b y a t hir d -p art y) will be pr o vi de d f or use i n t his st u d y.  
Di gital de vices ( n ot ma n ufact ur e d b y or f or Astra Ze neca) pr o vi de d f or use i n t his st u d y are: 
•
H o me -base d b o d y wei g ht di gital scales a n d ass oci ate d ha n d hel d d e vice .
•
 (f or partici pa nts  wit h 
 a n d/or 
•
Gl uc o meter ( p artici pa nts wit h T 2 D M a n d treate d wit h i ns uli n or s ulf o n yl urea o nl y).
I nstr ucti o ns f or di gital de vice use will be pr o vi de d t o eac h partici pa nt. All d e vices pr o vi de d 
f or t he st u d y will be ret ur ne d b y t he partici pa nt o n or bef ore t he fi nal safet y foll o w -u p v isit. 
All di gital de vice deficie ncies (i ncl u di n g malf u ncti o n, use err o r, a n d i na de q uate la belli n g) 
s hall be d oc u me nte d a n d re p orte d b y t he i n v esti gat or t hr o u g h o ut t he cli nical i n vesti gati o n a n d 
a p pr o priatel y ma n a ge d b y t he s p o ns or. I n t his st u d y, a n y deficie nc y o bs er ve d wit h a t hir d -
part y di gital de vice will be c ollecte d a n d  re p orte d t o t he ma n ufact ur er. A di gital de vice 
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 9  of 1 4 3
deficie nc y is a n i na de q u ac y of a di gital de vice wit h res pect t o its i de ntit y, q ualit y, d ura bilit y, 
relia bilit y, safet y, or perf or ma nce. Di gital de vi ce deficie nci es i ncl u de malf u ncti o ns, use err ors, 
a n d i nf or m ati o n s u p plie d b y t he ma n ufact urer. T h e ma n ufact urer's di gital d e vice c o m plai nt 
re p ort will be use d t o c ollect t he defici e nc y. 
6. 2  
Pre p ar ati o n, H a n dli n g, St or a ge, a n d Acc o u nt a bilit y   
•  
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei v e d a n d a n y dis cre p a ncies are 
re p orte d a n d res ol ve d b ef ore use of t he st u d y i nter ve nti o n. 
•  
O nl y partici pa nts ra n d o mi se d i n t he st u d y ma y recei ve st u d y i nter ve nti o n a n d o nl y 
a ut h orise d st u d y ce ntr e staff ma y s u p pl y , pre pare, or a d mi nister st u d y i nter ve nti o n. All 
st u d y i nter ve nti o n m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d , a n d m o nit ore d 
( ma n ual or a ut o mat e d) area i n acc or da n ce wit h t he la belle d st ora ge c o n diti o ns wit h access 
li mite d t o t he i n vesti gat or a n d a ut h orise d st u d y ce ntre staff. 
•  
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nterve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(ie, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 
•  
F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o ns 
are pr o vi d e d i n t he P har mac y Ma n ual.  
 
6. 3  
Assi g n me nt t o St u d y I nter ve nti o n   
All partici pa nts will be ce ntrall y assi g ne d t o ra n d o mise d, bli n de d st u d y i nter ve nti o n usi n g a n 
I R T/ R T S M. Bef ore t he st u d y is i nitiate d, directi o ns f or l o g i n will be pr o vi de d t o eac h st u d y 
ce ntre. T he I R T/ R T S M will pr o vi de t o t he i n vesti gat ors or p har m acists t he kit i de ntificati o n 
n u m ber t o be all ocat e d t o t he partici pa nt at t he d osi n g visit. R o uti nes f or t his will be descri be d 
i n t he I R T/ R T S M user ma nual t hat will be pr o vi de d t o eac h st u d y ce ntre.  
A se parate ra n d o mi sati o n list will be pr o vi de d f or Ja pa n sites.  
I n t his st u d y, eli gi ble partici pa nts will be ra n d o mise d t o Treat me nt Gr o u ps 1  t o 3  wit h e q ual 
all ocati o n ( 1: 1: 1). Ja pa n will ha ve u p t o  5  partici p a nts  per ar m ( o ut of 2 2 ). 
Partici pa nts will be 
 t o t he 
 of 
 at t he ti me 
of ra n d o misati o n, t o e ns ure a n a p pr o xi mate bala nce bet wee n treat me nt gr o u ps wit hi n eac h 
s u b-p o p ulati o n. T here will be n o  
 f or Ja pa nese p artici pa nts as it ma y lea d t o 
 f or t he st u d y. 
6. 4  
Bli n di n g   
T he ra n d o misati o n c o de s h o ul d n ot be br o ke n e xce pt i n me dical e mer ge nci es w he n t he 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 0  of 1 4 3
ap pr o priate m a na ge me nt of t he partici pa nt re q uires k n o wle d ge of t he tr eat me nt assi g n me nt. 
T he i n vesti gat or d oc u me nts a n d re p orts t he acti o n t o Astra Ze n eca, wit h o ut re veali n g t he 
treat me nt gi ve n t o partici pa nt t o t he Astra Z e neca staff. 
T he f oll o wi n g pers o n nel will be u n bli n de d as t o t he e xact c o nte nt of st u d y i nter ve nti o n 
treat me nts (ie, t he ra n d o misati o n c o de): 
•
Pers o n nel carr yi n g o ut t he pac k a gi n g a n d la belli n g of st u d y i nter ve nti o n treat me nt.
•
Pers o n nel ge nerati n g t he ra n d o misati o n list.
•
Pers o n nel a nal ysi n g t he P K sa m ples.
•
T he D M C.
Astra Ze neca retai ns t he ri g ht t o brea k t he c o de f or S A Es t hat are u ne x p ecte d a n d are 
s us pecte d t o be ca usall y relate d t o st u d y i nter ve nti o n a n d t hat p ote ntiall y re q uire e x pe dite d 
re p orti n g t o re g ulat or y a ut h orities. Ra n d o misati o n c o des will n ot be br o ke n f or t he pla n ne d 
a nal yses of dat a u ntil all decisi o ns o n t he e val ua bilit y of t he data fr o m eac h i n di vi d ual 
partici pa nt ha ve b ee n ma de a n d d oc u me nt e d.  
T he I R T/ R T S M will be pr o gra m me d wit h bli n d brea ki n g i nstr ucti o n s. I n cas e of a n e m er g e nc y, 
i n w hic h t he k n o wle d ge of t he s pecific bli n de d st u d y i nter ve nti o n will affect t he i m me diate 
ma na ge me nt of t he p artici pa nt’s c o n diti o n (e g, a nti d ote a vaila ble), t h e i n vesti gat or has t he 
res p o nsi bilit y f or deter mi ni n g if u n bli n di ng of a partici pa nt ’s i nter ve nti o n assi g n me nt is 
warra nte d. Partici pa nt safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s uc h a 
deter mi nati o n. If a p artici pa nt’s i nter ve nti o n assi g n me nt is u n bli n de d, t he s p o ns or m ust be 
n otifie d wit hi n 2 4 h o urs after  brea ki n g t he bli n d.  T he i n vesti gat or d oc u me nts a n d re p orts t he 
acti o n t o Astra Z e neca, wit h o ut re veali n g t he treat me nt gi ve n t o t he partici pa nt t o t he 
Astra Ze neca staff.  
6. 5  
St u d y I nter ve nti o n C o m pli a nce  
At t he visits s pecifie d i n  t he S o A (Ta ble  1 ), partici pa nts will recei ve st u d y i nter ve nti o n at t he 
st u d y ce ntre or will ta ke t he st u d y i nter ve nti o n at h o me. W he n p artici pa nts are d ose d at t he 
site, t he y will recei ve st u d y i nter ve nti o ns directl y fr o m t he i n vesti gat or or d esi g nee, u n der 
me dical s u per visi o n. T he date a n d ti me of t he d os e a d mi nistere d o n t he visit da y, as well as 
t he date a n d ti me of t he d ose ta ke n t he da y b ef ore eac h visit t o t he st u d y ce ntre, will be 
rec or de d i n t he s o urce d o c u me nts a n d rec or de d i n t he e C R F. T he d ose of st u d y i nter ve nti o n 
a n d st u d y partici pa nt i de ntificati o n will be c o nfir me d at t he ti me of d osi n g b y a me m ber of t h e 
st u d y ce ntre staff ot her t h a n t he pers o n a d mi nisteri n g t he st u d y i nter ve nti o n.  
A rec or d of t h e n u m ber of st u d y i nter ve nti o n s (ca ps ules a n d ta blets ) dis pe ns e d t o a n d 
a d mi nistere d b y eac h partici pa nt m ust be mai ntai ne d a n d rec o ncile d wit h st u d y i nter ve nti o n 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 1  of 1 4 3
a n d c o m plia nce rec or ds. I nter ve nti o n start a n d st o p dates, i ncl u di n g dates f or i nter ve nti o n 
dela ys will als o be rec or de d i n t he e C R F.  
6. 6  
D ose M o dific ati o n   
D ose m o dificati o n of st u d y i nter ve nti o n is n ot per mitte d. All partici pa nts will recei ve t he 
assi g ne d d osa ge of st u d y i nter ve nti o n t o be ta ke n i n t he m or ni n g. If a partici pa nt f or gets t o 
ta ke a st u d y i nter ve nti o n d ose i n t he m or ni n g a n d t he ti me has past n o o n ( 1 2:0 0  P M ), t he ne xt 
d ose m ust be ta ke n t he n e xt da y. W he n ta ki n g t he ne xt d ose after a misse d d ose, p artici pa nts 
s h o ul d n ot ta ke a d o u ble d ose t o ma ke u p f or t he misse d d ose. 
6. 7  
C o nti n ue d Access t o St u d y I nter ve nti o n After t he E n d of t he 
St u d y   
After t he e n d of t he st u d y ( foll o w -u p v isit), partici pa nts will n o l o n ger recei ve zi b ote nta n 
a n d/ or da pa glifl ozi n. Partici pa nts s h o ul d mai ntai n t heir ot her pres cri be d tr eat me nts at t he 
discreti o n of t he i n vesti g at or.  
6. 8  
Tre at me nt of O ver d ose   
F or t his st u d y, a n o ver d ose will be defi ne d as t he use of t he st u d y i nter ve nti o n i n d oses i n 
e xcess of t hat s p ecifie d i n t he pr ot oc ol. F or i nf or mati o n re gar di n g re p orti n g of o ver d ose, s ee 
Secti o n 8. 4. 1 1 . 
If a n o ver d ose is s us pect e d, m o nit ori n g of vital f u ncti o ns as well as treat me nt s h o ul d be 
perf or me d as a p pr o priate.  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d: 
•  
E val uate t he partici pa nt t o deter mi ne, i n c o ns ultati o n wit h t he St u d y Cli nical Lea d, if 
p ossi ble, w het her st u d y i nter ve nti o n s h o ul d be i nterr u pte d or w het her t he d ose s h o ul d be 
re d uce d. 
•  
Cl osel y m o nit or t he partici pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities as 
me dicall y a p pr o pri ate a n d at least u ntil t he ne xt sc he d ule d f oll o w -u p . Refer t o 
Secti o n  8. 4. 1 1  f or details of A E/ S A E re p orti n g relate d t o o ver d ose. 
•  
O btai n a plas ma sa m ple f or P K a nal ysis as s o o n as p ossi ble fr o m t he date of t he last d ose 
of st u d y i nter ve nti o n , if re q ueste d b y t he St u d y Cli nical Lea d ( deter mi ne d o n a 
case-b y -cas e basis).  
•  
D oc u me nt t he q ua ntit y of t he e xcess d ose as w ell as t he d urati o n of t he o ver d ose.  
 
6. 9  
Pri or a n d C o nc o mit a nt T her a p y   
As E T -1 has a p ote ntial r ole i n t he mai nte na nce of bl o o d press ure, h y p ote nsi o n ma y be 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 2  of 1 4 3
e nc o u ntere d f oll o wi n g E T rece pt or bl oc ka d e. Alt h o u g h o nl y mi n or re d ucti o ns i n bl o o d 
press ure w ere see n st u dies wit h zi b ote nta n i n o nc ol o g y patie nts, it is p ossi ble t hat more 
mar ke d c h a n ges mi g ht occ ur i n h y perte nsi ve pati e nts , es peciall y t h ose ta ki n g h y p ote nsi ve 
t hera p y s uc h as A C E i n hi bit ors, calci u m a nta g o nists, or al p ha bl oc kers. If s y m pt o matic 
h y p ote nsi o n occ urs, partici pa nts s h o ul d re mai n s u pi ne u ntil res ol uti o n of s y m pt o ms. 
I ntra ve n o us fl ui d s u p p ort s h o ul d be c o nsi dere d f or cases c o nsi dere d s e vere b y t he i n vesti gat or. 
A n y me dicati o n (i ncl u di n g o ver -t he-c o u nter or prescri pti o n me dici nes, vita mi ns, a n d/ or her bal 
s u p ple me nts) or vacci ne t hat t he partici pa nt is recei vi n g at t he ti me of e nr ol me nt or recei ves 
d uri n g t he st u d y m ust be rec or de d al o n g wit h:  
•
Reas o n f or use
•
Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates
•
D osa ge i nf or m ati o n i ncl u di n g d ose a n d fre q ue nc y
As zi b ote nta n has bee n ass ociate d wit h a n i ncreas e d ris k of hea dac h e i n pr e vi o us cli nical 
st u dies, paraceta m ol/acet a mi n o p he n ma y be a d mi nistere d t o t he st u d y parti ci pa nts as nee d e d , 
pr o vi de d it is prescri be d i n acc or da nce wit h t he la bel a n d ta ki n g i nt o acc o u nt t he partici pa nt’s 
de gree of he p atic i m pair me nt; d osi n g a n d ti me of a d mi nistrati o n will be d oc u me nte d. Ot her 
c o nc o mita nt me dicati o n ma y be c o nsi dere d o n a case -b y -case b asis b y t he i n vesti gat or, i n 
c o ns ultati o n wit h t he st u d y p h ysicia n, if re q uir e d.  
T he precli nical a n d cli nic al data i n dicate d n o dr u g -dr u g i nteracti o n ris k bet wee n zi b ote nt a n 
a n d paraceta m ol/aceta mi n o p he n ( Zi b ote nta n I n v esti gat or’s Br oc h ure ).  
T he st u d y p h ysicia n s h o ul d be c o ntacte d if t h ere are a n y q uesti o ns re g ar di n g c o nc o mita nt or 
pri or t hera p y.  
6. 9. 1  Pr o hi bite d Me dic ati o ns  
T he me dicati o ns a n d s u p ple me nts liste d bel o w are pr o hi bite d fr o m t he ti me of i nf or me d 
c o nse nt a n d f or t he d urati o n of t he st u d y.  
•
Ot her S G L T 2 i n hi bit ors.
•
Ot her E n d ot heli n rece pt or a nta g o nists.
D ose c ha n g es of bet a bl oc kers s h o ul d i deall y be k e pt t o a mi ni m u m d uri n g t he treat me nt 
peri o d b ut are p er mitte d, if re q uire d f or safet y.  
Ot her pr o hi bite d me dicati o ns 
 a n d 
 of 
, i ncl u di n g 
, wit hi n 
 pri or t o d ose of zi b ote nta n (Ta ble  5 ) a n d d uri n g t he c o urse of t he st u d y. A ntaci ds are 
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 3  of 1 4 3
pr o hi bite d fr o m 2  h o urs bef ore d osi n g u ntil disc h ar ge o n all da ys w here d osi n g ta kes place 
a n d P K or P D meas ur e me nts are ta ke n ( Da ys  8, 1 5, a n d 2 2).  
Ta ble  5  
List of 
Me dic ati o n  
R ati o n ale  
N ote: T h is list is n ot i nte n de d 
, a n d t he 
 s h o ul d 
 t o 
 t hat are 
6. 9. 2  
Per mitte d Pr oce d ur es a n d Me dic ati o ns   
6. 9. 2. 1  
P ar ace ntesis   
Parace nt esis is per mitte d d uri n g t he st u d y if re q uir e d f or safet y.  
6. 9. 2. 2  
Me dic ati o ns I n d uci n g H y p o gl yc ae mi a   
Partici pa nts usi n g me dicati o ns t hat ca n ca us e h y p o gl ycae mia i n T 2 D M p artici pa nts, i ncl u di n g 
i ns uli n or s ulf o n yl urea, ma y be re q uir e d t o re d u ce i ns uli n b y 1 0 % t o 2 0 % (t otal dail y d ose) 
a n d s ulf o n yl urea b y 2 5 % t o 5 0 %. I n a d diti o n, partici pa nts o n a n y of t hese dr u g classes will be 
pr o vi de d wit h a h o me -b ase d gl uc o meter t o m o nit or t heir bl o o d gl uc ose (if t he y d o n ot alrea d y 
ha ve a gl uc o m eter at h o me) , si nce m ore fre q u e nt bl o o d gl uc ose m o nit ori n g s h o ul d be 
c o nsi dere d i n partici pa nts recei vi n g i ns uli n a n d/ or s ulf o n yl urea, es p eciall y wit h H b A 1c ≤ 7 % 
at ra n d o mi sati o n. Als o, k et o nes, e g, plas ma le vels of beta -h y dr o x y b ut yrate, s h o ul d be 
c o nsi dere d t o be m o nit ore d m ore fre q ue ntl y - if i ns uli n d osi n g is re d uce d (see Secti o n  7. 1. 1  f or 
details a b o ut dia betic ket oaci d osis a n d Secti o n  8. 3. 6. 1  f or details a b o ut h y p o gl ycae mia). 
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N/ WI T H D R A W A L   
Disc o nti n uati o n of s pecific sites or of t he st u d y as a w h ole are ha n dle d as p art of A p pe n di x  A . 
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
It ma y be necessar y f or a partici pa nt t o per ma ne ntl y disc o nti n ue ( defi niti ve disc o nti n uati o n) 
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 4  of 1 4 3
st u d y i nter ve nti o n. 
A n i n di vi d ual partici pa nt ma y be disc o nti n ue d fr o m st u d y i nter ve nti o n i n t he f oll o wi n g 
sit uati o ns: 
•
; Secti o n 
. 
•
Ne w dia g n osis of 
 of t he 
. 
•
Ne w or w orse ni n g of s y m pt o ms of 
 ot her t ha n 
 t hat is n ot 
res p o nsi ve t o 
 d oses of 
. 
•
O vert e nce p hal o pat h y ( Gra de  2 or hi g h er), v ariceal ha e m orr ha g e, or  he p at o cell ular
ca ncer.
•
Seri o us/se vere 
. 
•
Seri o us/se vere 
. 
•
Dia betic ket oa ci d osis  i ncl u di n g e u gl ycae mic D K A ha ve bee n re p orte d wit h use of
da pa glifl ozi n. C o nsi der t e m p orar y i nterr u pti o n of st u d y i nter ve nti o n if D K A is s us pecte d.
T he partici pa nt s h o ul d be pr o m ptl y e val uate d. If D K A is c o nfir me d, st u d y i nter ve nti o n
s h o ul d be disc o nti n ue d per ma ne ntl y (see Secti o n 7. 1. 1  f or details). If D K A is n ot
c o nfir me d, re -start of st u d y i nter ve nti o n s h o ul d be c o nsi dere d.
•
W he n DI LI is s us pecte d a n d re -start of t he st u d y i nter ve nti o n is n ot per mitte d base d o n
t he al g orit h m o utli ne d i n Secti o n 7. 1. 2 .
•
eG F R < 4 5  m L/ mi n/ 1. 7 3  m 2 c o nfir me d u p o n re peat testi n g.
•
De vel o p me nt of 
 or ot her ca uses of 
•
Li ver tra ns pla ntati o n.
•
Tra nsj u g ular i ntra h e patic p ort os yste mic s h u nt.
•
Partici pa nt decisi o n. T he partici pa nt is at a n y ti me free t o disc o nti n ue tr eat me nt, wit h o ut
prej u dice t o f urt h er treat me nt.
•
A n A E t hat, i n t he o pi ni o n of t he i n vesti gat or or Astra Ze neca, warra nts disc o nti n uati o n
fr o m f urt her d osi n g.
•
Se vere n o n -c o m plia nce wit h t he C S P.
•
Pre g na nc y: if a fe male p artici pa nt or t he fe m ale part ner of a m ale partici pa nt bec o mes
pre g na nt d uri n g t he c o urse of t he st u d y, st u d y i nter ve nti o n s h o ul d be disc o nti n ue d
i m me diatel y, a n d a n Astr a Ze neca re pres e ntati ve n otifie d.
•
Safet y reas o ns as j u d ge d b y t he i n vesti gat or a n d/ or s p o ns or w here c o nti n ue d treat me nt
ma y p ut partici pa nt at u n d ue ris k.
N ote t hat disc o nti n uati o n fr o m st u d y i nter ve nti o n is N O T t he sa me t h i n g as a wit h dra wal fr o m 
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 5  of 1 4 3
t he st u d y ( Secti o n 7. 2 ). 
Partici pa nts w h o pre mat urel y disc o nti n ue st u d y i nter ve nti o n s h o ul d re mai n , i n t he st u d y a n d 
atte nd all pla n ne d st u d y visits i ncl u di n g t he F oll o w -u p Visit  as per S o A (Ta ble  1 ). 
7. 1. 1  
Di a betic Ket o aci d osis  
Pre dis p osi n g fact ors t o k et oaci d osis i ncl u de a l o w beta -cell f u ncti o n reser ve res ulti n g f r o m 
pa ncreatic dis or ders (e g, T 1 D M, hist or y of pa ncreatitis or pa ncreatic s ur ger y), i ns uli n d ose 
re d ucti o n, re d u ce d cal ori c i nta ke or i ncreas e d i ns uli n re q uire me nts d ue t o i nfecti o ns, ill ness or 
s ur ger y, a n d al c o h ol a b us e. Da pa glifl ozi n s h o ul d b e use d wit h  ca uti o n i n t hese partici p a nts.  
Partici pa nts o n st u d y i nter ve nti o n w h o pres e nt wit h si g ns a n d s y m pt o ms c o nsiste nt wit h 
ket oaci d osis, i ncl u di n g na usea, v o miti n g, a b d o mi nal pai n, malaise, a n d s h ort ness of breat h 
s h o ul d be assesse d f or ket oaci d osis, e ve n if bl o o d gl uc ose le vels are bel o w 1 4 m m ol/ L 
( 2 5 0 m g/ d L). If ket oa ci d osis is s us pecte d, disc o nti n uati o n or te m p orar y i nt err u pti o n of st u d y 
i nterve nti o n  s h o ul d be c o nsi dere d, a n d t he partici p a nt s h o ul d be pr o m ptl y e val uate d.  
7. 1. 2  
M a n a ge m e nt of T re at m e nt -e m er ge nt A b n o r m alities i n Li ver F u n cti o n 
Tests ( L F Ts)   
I n or der t o i de ntif y cases of s us pecte d DI LI, t he f oll o wi n g al g orit h ms m ust be f oll o we d (see 
A p pe n di x  E  f or acti o ns r e q uire d f or e val uati o n of m o difie d H y’s La w). T h e DI LI al g orit h ms 
acc o u nt f or 
 of t he 
 val u e ( defi ne d as t he 
 of t h e 
 d uri n g 
t he 
 peri o d 
 visit val ues) or a 
 val ue, 
w hic he ver c o mes first, a n d n ot s olel y o n 
 of t he 
. T h e al g orit h ms als o acc o u nt 
f or t he stat us of t he partici pa nt at 
 as 
 a n d 
ta ke i nt o c o nsi derati o n n or mal or a b n or mal b aseli ne 
f or partici pa nts wit h 
 It is i m p orta nt t o perf or m a c o m pre h e nsi ve re vie w of la b orat or y d ata f or a n y 
partici pa nt w h o meets a n y of t he criteri a.  
*I n t his st u d y, a n d f or t he p ur p ose of t he DI LI al g orit h m, 
 is defi ne d 
as 
 wit h prese nce at b aseli ne of 
 or hist or y of 
 or hist or y of 
.
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 6  of 1 4 3
M a n a ge me nt g ui deli nes f or p artici p a nts wit h 
 at b aseli ne, a n d n or m al b aseli ne 
 at 
b aseli ne)  
 a n d a b o ve 
 
If 
 or 
 ( w hic he v er c o mes first) A N D  t here 
is 
 a n d a b o ve 
O R  
O R  
 a n d a b o ve 
 
O R  
O R  
 a n d a b o ve 
 wit h 
 a n d 
 o ver baseli ne  
O R  
O R  
A n y i ncrease i n 
 fr o m baseli ne of 
 a n d a b o ve 
 
De v el o p me nt of 
 or 
, or 
 j u d ge d t o be cli nic all y si g nific a nt  b y t he i n vesti gat or  
 at least 
If 
 criteria a p pl y  
, assess f or 
 i ncl u di n g disease 
u n der st u d y, 
 or p ossi bilit y of 
. 
 ( w he n st u d y i nter ve nti o n has bee n 
 as a ca use of c ha n ges i n
 or 
) ma y be per mitte d after s ufficie nt 
 bac k t o 
, a n d after disc ussi o n bet wee n t he i n vesti gat or a n d t he me dical m o nit or. 
 will ge n erall y re q uire a n 
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 7  of 1 4 3
M a n a ge me nt g ui deli nes f or p artici p a nts wit h 
 at b aseli ne, wit h a b n or m al b aseli ne 
 
 at b aseli ne)  
 b ut 
 a n d 
, 
 is 
 or 
 ( w hic he ver c o mes first) 
A N D  
A N D A T L E A S T 
 O F T H E F O L L O WI N G  
•
 (if n or mal at 
) or 
 (if a b n or mal 
at 
), A N D  
•
 if n or mal at 
 ( wit h 
) O R  
 if 
, 
•
, A N D  
•
 o ver baseli ne , 
•
 (if n or mal at 
 or 
 (if 
 
was 
•
) O R i ncrease d b y 
 was 
O R  
 ( w hic he v er c o mes first) 
O R  
 a n d 
 o ver baseli ne  
O R  
De v el o p me nt of 
 or 
, or 
 j u d ge d t o be cli nic all y si g nific a nt  b y t he i n vesti gat or.  
dr u g, 
 st u d y i nter ve nti o n, assess f or 
 i ncl u di n g disease 
u n der st u d y, a d diti o nal 
 or p ossi bilit y of 
. 
 ( w he n st u d y i nter ve nti o n has bee n  
 as a ca use of c ha n ges i n 
 or
) ma y be per mitte d after s ufficie nt 
 bac k t o 
, a n d after disc ussi o n bet wee n t he i n vesti gat or a n d t he me dical m o nit or. 
 will ge n erall y re q uire a n 
. 
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 8  of 1 4 3
M a n a ge me nt g ui deli nes f or p artici p a nts wit h 
 at b aseli ne, wit h eit her n or m al or a b n or m al b aseli ne 
 
 (a n d 
) or
, w hic he ver c o mes first; or 
 ×  p ost -baseli ne o n -treat me nt 
 val ues  
O R  
 wit h 
 of t he t otal, or a n y i ncrease i n 
 o ver baseli ne  
O R  
 ×  baseli ne  
O R  
 (if n or mal 
 at baseli ne) or a n y i ncrease of 
 if baseli ne
O R  
 i ncrease d b y 
 o ver baseli ne (if 
 at baseli ne) or b y 
 o ver baseli ne (if 
 at baseli ne)  
O R  
De v el o p me nt of ne w 
 or 
 of 
 or 
j u d ge d t o be cli nic all y si g nific a nt  b y t he i n vesti gat or.  
 st u d y i nter ve nti o n, assess f or ca use of 
 i ncl u di n g disease u n der st u d y, 
 or p ossi bilit y  of 
. 
D ue t o varia bilit y i n 
 patie nts wit h 
 meeti n g re q uire me nt f or h ol d of st u d y dr u g base d s olel y o n 
 c h a n ge, a n d n ot meeti n g a n y 
ot her criteria f or dr u g h ol d, ma y ha v e o ne 
 re-test wit h 1-2 da ys at t he discreti o n of t he i n vesti gat or t o deter mi ne w het her t he 
 c h a n ge is s ustai ne d.  
 ( w he n st u d y i nter ve nti o n has bee n 
 as a ca use of c ha n ges i n 
 or 
) ma y be per mitte d after s ufficie nt 
 bac k t o 
 ×  baseli ne, a n d after disc ussi o n bet wee n t he i n vesti gat or a n d t he me dical m o nit or. 
 wil l g e n erall y re q uire a n 
a
 is defi ne d as 
 wit h prese nce at baseli ne of 
 or 
 or 
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 9  of 1 4 3  
7. 2  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y  
Disc o nti n uati o n of t he partici pa nt fr o m t he st u d y b y t he i n vesti gat or:  
•
A partici pa nt ma y be dis c o nti n ue d fr o m t he st u d y at a n y ti me at t he discreti o n of t he
i n vesti gat or f or be h a vi o ural, or c o m plia nce reas o ns.
Vol u ntar y wit h dra w al fr o m t he st u d y b y t he partici pa nt:  
•
A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me at t he partici pa nt’s o w n re q uest
f or a n y reas o n ( or wit h o ut pr o vi di n g a n y reas o n).
•
A partici pa nt w h o c o nsi d ers wit h dra wi n g fr o m t he st u d y m ust be i nf or me d b y t he
i n vesti gat or a b o ut m o difie d f oll o w-u p o p ti o ns (e g, tele p h o ne c o ntact, a c o nt act wit h a
relati ve or tr eati n g p h ysicia n, or i nf or mati o n fr o m me dical rec or ds).
•
At t he ti me of wit h dra wal fr o m t he st u d y, if p ossi ble, a n Earl y Ter mi nati o n Visit s h o ul d
be c o n d ucte d, t h at will c o m prise of t he sa me asses s me nts as f or Visit  6 , as per  t he S o A
(Ta ble  1 ).
−
T he partici pa nt will disc o nti n ue t he st u d y i nter ve nti o n a n d be wit h dra w n fr o m t he
st u d y at t hat ti me.
•
If t he partici p a nt wit h dra ws c o nse nt f or discl os ur e of f ut ure i nf or mati o n, Astra Ze neca
ma y retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s u c h a wit h dr a wal of c o nse nt.
•
If a partici pa nt wit h dra ws fr o m t he st u d y, it s h o ul d be c o nfir me d if h e/s he still a grees f or
e xisti n g sa m ples t o be use d i n li ne wit h t he ori gi nal c o nse nt. If he/s he re q u ests wit h dra wal
of c o nse nt f or us e of sa m ples, destr ucti o n of a n y s a m ples ta ke n a n d n ot test e d s h o ul d be
carri e d o ut i n li ne wit h w hat was state d i n t he i nf or me d c o nse nt a n d l o cal r e g ulati o n t he
i n vesti gat or m ust d oc u me nt t he decisi o n o n use of e xisti n g sa m ples i n t he st u d y ce ntre
rec or ds a n d i nf or m t he Gl o bal St u d y Tea m.
7. 3  
L ost t o F oll o w -u p  
A partici pa nt  will be c o nsi dere d l ost t o f oll o w -u p if t he partici pa nt re peat e dl y fails t o ret ur n 
f or sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y ce ntre. 
T he f oll o wi n g acti o ns m ust be ta ke n if a p artici pa nt fails t o ret ur n t o t he st u d y ce ntre f or a 
re q uire d st u d y visit: 
•
T he st u d y ce ntre m ust att e m pt t o c o ntact t he partici pa nt a n d resc h e d ule t he misse d visit as
s o o n as p ossi ble. T he partici pa nt s h o ul d be c o unselle d o n t he i m p orta nce of mai ntai ni n g
t he assi g ne d visit sc he d ule. At t his ti me ascertai n w het her t he partici pa nt wis hes t o a n d/ or
s h o ul d c o nti n ue i n t he st u d y.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 0  of 1 4 3  
•
Bef ore a p artici pa nt is dee me d l ost t o f oll o w -u p, t he i n vesti gat or or desi g n ee m ust ma ke
e ver y eff ort t o r e gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne calls a n d,
if necessar y, a certifie d l etter t o t he partici pa nt’s last k n o w n maili n g a d dress or l ocal
e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he p arti ci pa nt’s
me dical rec or d.
•
S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, t he partici pa nt will be c o nsi dere d l ost
t o f oll o w-u p .
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
•
St u d y pr oce d ures a n d t heir ti mi n g are s u m marise d i n t he S o A  (Ta ble  1 ). Pr ot oc ol wai vers
or e xe m pti o ns are n ot all o we d.
•
I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h Astra Ze ne nca  i m me diatel y u p o n
occ urre nce or a w are ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue
st u d y i nter ve nti o n.
•
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A
(Ta ble  1 ), is ess e ntial a n d re q uire d f or st u d y c o n d uct.
•
All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial
partici pa nts meet all eli gi bilit y c riteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o
rec or d details of all parti ci pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or
scree ni n g f ail ure, as a p plica ble.
•
Pr oce d ures s u c h as E C H O (t o e xcl u de val v ular disease a n d/ or si g nifica n t car di o m y o pat h y
as defi ne d i n Secti o n  5. 2 ), cli nical c he mistr y, a n d hae mat ol o g y c o n d uct e d as part of t he
partici pa nt’s r o uti ne cli nical ma na g e me nt a n d o btai ne d bef ore si g ni n g of t he I C F ma y be
utilise d f or scree ni n g p ur p oses , pr o vi de d t he pr o ce d ures met t he pr ot oc ol -s p ecifie d
criteria a n d were perf or m e d wit hi n t he ti me fr a me defi ne d i n t he S o A  (Ta bl e  1 ).
•
T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m eac h partici pa nt o ver t h e d urati o n of t he
st u d y, i ncl u di n g a n y e xtra assess me nts t hat ma y b e re q uir e d, will n ot e xcee d 1 6 5  m L.
Re peat or u nsc h e d ule d sa m ples ma y be c ollecte d f or safet y r eas o ns or f or tec h nical iss ues
wit h t he sa m ples  a n d ma y be teste d at t he l ocal la b orat or y.
•
A m o bile s oft ware a p plicati o n, a n d ass ociate d we bsite s yste m, will pr o vi de di gital
s u p p ort t o partici pa nts fr o m ra n d o misati o n t hr o u g h t o, a n d i ncl u di n g, F oll o w-u p.
Astra Ze neca will pr o vi de a ha n d hel d de vi ce t o access t he m o bile s oft ware a p plicati o n.
T he s yste m will pr o vi de partici pa nts a n d site st u d y staff wit h i nf or mati o n a n d t o ols
rele va nt t o t he c o n d u ct of t he st u d y i n acc or da nce wit h t his pr ot oc ol. T his will c o m prise
of st u d y i nter ve nti o n re mi n ders, cli nical visit re mi n ders, P R O  q uesti o n nair es, a n d
e d ucati o nal c o nte nt relati n g t o t he dis ease a n d me dicati o n. Astra Ze n eca ( or t h ose acti n g
o n be half of Astr a Ze n eca) will set  u p cli nical sites a n d i n vite site staff t o use t he di gital

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 1  of 1 4 3  
 
platf or m b y pr o visi o ne d e mail b ut will n ot ha ve t he a bilit y t o vie w a n y patie nt le vel 
s yste m data d uri n g t he trial. A n y data c ollecte d will o nl y be use d f or f u ncti o nalit y of t he 
di gital healt h platf or m a n d is n ot c o nsi dere d t o be cli nical trial data. Astra Z e neca will 
o w n a n y s yste m data c oll ecte d w hic h m a y be use d after t he tri al t o ma ke i m pr o ve me nts t o 
di gital heal t h platf or m a n d t he ass ociate d data c oll ecte d will be retai ne d f or a peri o d of 1 0 
years after trial cl os ure. T he use of t he p artici pa nt m o bile  s oft ware a p plicati o n is 
ma n dat or y f or t he p atie nt a n d ca pt ur e d i n t he I C F. T he m o bile s oft ware a p plicati o n is t he  
pri mar y i n p ut t o ca pt ure t he P R Os a n d t he dail y h o me -base d wei g ht meas ure me nts i n t he 
pr ot oc ol.  
 
8. 1  
A d mi nistr ati ve a n d Ge ner al/ B aseli ne Pr oce d ures   
N o ne.  
8. 2  
Effic ac y Assess me nts   
T here are n o effi cac y ass ess me nts i n t his st u d y. Pla n ne d ti me p oi nts f or ke y a n d e x pl orat or y 
assess me nts carrie d o ut i n t his st u d y are pr o vi de d i n t he S o A (Ta ble  1 ). 
8. 2. 1  
Ke y  V ari a ble s  
8. 2. 1. 1  
Fl ui d Rete nti o n   
T he f l ui d rete nti o n c o m p osite varia bles  are defi ne d as : 
•  
Occ urre nce of a n y of t he f oll o wi n g e ve nts fr o m baseli ne t o Wee k 6 :  
( 1) >  2  k g i ncreas e i n b o d y wei g ht,  
( 2) >  2  L i ncreas e i n t otal b o d y water,  
( 3) i ncrease i n 2 or m or e l o o p-di uretic e q ui vale nts  or  
( 4) fl ui d rete nti o n A Es. 
•  
Occ urre nce of eit her :  
( 1) > 3  L i ncrease i n t otal b o d y water v ol u me fr o m baseli ne t o Wee k  6 , or  
( 2) i ncreas e i n 3 or m ore l o o p-di uretic e q ui val e nts use fr o m baseli ne t o Wee k  6 . 
 
8. 2. 1. 2  
Electr o nic Sc ale Me as ure me nt of B o d y Wei g ht   
B o d y wei g ht will be meas ure d at t he st u d y ce ntre at st u d y visits. T here will be safet y 
m o nit ori n g of b o d y wei g ht fr o m t he h o me -bas e d m o nit ori n g de vices, or as a n alter nati ve, 
pa per diaries ca n b e use d f or ca pt uri n g t he i nf or m ati o n. A b o d y wei g ht c ha n ge of 
k g p er 
 is re g ar de d as a 
 wei g ht c ha n g e a n d nee ds t o be f oll o we d u p b y t he 
in vesti gat or.  
T he in vesti gat or will ha v e direct a ccess t o t he o nli ne data f or t heir partici pa nts usi n g di gital 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a g lifl ozi n - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 2  of 1 4 3  
de vices. If t h ere is a si g nifica nt wei g ht gai n, t he i n vesti gat or will c o ntact t he partici pa nt 
i m me diatel y a n d arra n ge a cli nic visit t o assess healt h stat us. Partici pa nts wit h pa per diaries 
will be i nstr ucte d t o c o ntact t he st u d y staff if t h ere is a si g nifica nt wei g ht gai n.  
Partici pa nts will als o be a d vise d t o self -m o nit or a n d c o ntact t he i n vesti gat or wit h a n y 
c o ncer ns.  
8. 2. 1. 3  
Bi oi m pe d a nce S pectr osc o p y   
Bi oi m pe da nce s pectr os c o p y will be perf or me d at t he st u d y ce ntre at t he ti me p oi nts s pecifie d 
i n t he S o A (Ta ble  1 ) t o m o nit or b o d y fl ui d v ol u mes. T his n o n-i n vasi ve pr oce d ure uses s ki n 
electr o des t o p ass a l o w -l e vel alter n ati n g c urre nt t hr o u g h t he b o d y a n d meas ures t he 
i m pe da nce t o t he fl o w of t his c urre nt. Tiss ues s uc h as fat a n d b o ne act as i ns ulat ors , w hereas 
electr ol yte b o d y fl ui ds c o n d uct electrical c urre nt . As  t he fl ui d i ncreas es, i m pe da nce t o c urre nt 
fl o w decreases (ie, c h a n g es i n i m pe da nce are i n v ersel y pr o p orti o nal t o t he v ol u me of t he 
e xtracell ular fl ui d i n t he b o d y). At l o w fre q ue n cies, cell me m bra nes are n o n -c o n d ucti ve a n d 
c urre nt p asses o nl y t hr o u g h t he e xtracell ular fl ui d, w hile at hi g h fre q u e ncies, t he c urre nt 
passes t hr o u g h cell me m bra nes i n a d diti o n t o t he e xtra -a n d i ntracell ular fl ui ds.  
8. 2. 2  
E x pl or at o r y V ari a bles  
8. 2. 2. 1  
 will be perf or me d at t he ti me p oi nts 
s pecifie d i n t he S o A (Ta ble  1 ), at least 3 h o urs after a meal , as well as ≥ 3  h o urs after st u d y 
i nter ve nti o n a d mi nistrati o n at V isit 6 . If t he partici pa nt is ta ki n g a n o n-selecti ve beta-bl oc ker, 
t he d ose s h o ul d n ot be ta ke n i n t he m or ni n g bef ore  
 b ut ri g ht after t he 
assess me nt. 
 a n d/ or 
 is assesse d as a n e x pl orat or y e n d p oi nt t o 
i n vesti gate t o w hat e xte nt it ma y be use d as a 
f or 
. 
will be meas ure d o nl y if 
 is a vaila ble. T he meas ure m e nt s h o ul d 
prefera bl y be d o n e b y t he sa me e xa mi ner o n all occasi o ns.  
 assess me nt of 
 or  
s h o ul d o nl y be d o ne if 
 a n d its use is u p t o t he 
 of t he i n vesti gat or 
at t he st u d y ce ntre.  
8. 2. 2. 2  
Ser u m A n al ysis of Cre ati ni ne a n d C yst ati n C (e G F R)   
T he partici pa nt’s e G F R will be calc ulate d at t he ti me p oi nts s pecifie d i n t he S o A (Ta ble  1 ) 
acc or di n g t o t he 2 0 2 1  C K D -E PI e q u ati o n, base d o n ser u m creati ni ne c o nce ntrati o n al o ne 
(I n ker et al 2 0 2 1 ) f or eli gi bilit y a n d safet y, referre d t o bel o w as e G F R 1. T his f or m ula is use d 
f or safet y m o nit ori n g as well as f or e x pl orat or y assess me nt. A d diti o nall y, e G F R f or 
e x pl orat or y ass ess me nt will be calc ulate d base d o n b ot h ser u m creati ni ne a n d  ser u m c ystati n 
C c o nce ntrati o ns ( I n ker et al 2 0 2 1 ), referre d t o bel o w as e G F R 2. 
C CI
C CI
C CI
C CI
C CI
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 3  of 1 4 3  
Esti mate d G F R usi n g ser u m creati ni ne al o n e or t o get her wit h ser u m c yst ati n C is calc ulate d as 
f oll o ws: 
e G F R 1 = 1 4 2 × mi n( S cr/κ, 1)  −0. 2 4 1 ( if fe male)/ −0. 3 0 2 (if male) × ma x( S cr/κ, 1) −1. 2 0 0 × 0. 9 9 3 8 A ge  × 1. 0 1 2 
[if fe male] 
e G F R 2 = 1 3 5 × mi n( S cr/κ, 1)  −0. 2 1 9 ( if fe male)/ −0. 1 4 4 (if male) × ma x( S cr/κ, 1) −0. 5 4 4 × mi n( S c ys/0. 8, 
1) −0. 3 2 3 × ma x( S c ys/0. 8, 1) −0. 7 7 8 × 0. 9 9 6 A ge  × 0. 9 6 3 [if fe male]  
W here:  
S cr = ser u m creati ni ne ( m g/ d L)  
S c ys = ser u m c ystati n C ( m g/ L)  
κ = 0. 7 f or fe males; a n d 0. 9 f or males 
mi n = mi ni m u m of S cr/κ or 1  
ma x = ma xi m u m of S cr/κ or 1  
Base d o n t he S o A  (Ta ble  1 ), e G F R 1 calc ulati o ns will be at e ver y visit, w hile e G F R 2 
calc ulati o ns will be at Visits  2, 5 a n d 6.  
8. 2. 2. 3  
L a b or at or y Assess m e nts f or E x pl or at or y A n al yses   
Bl o o d sa m ples will be c ollecte d at t he ti me p oi nts s pecifie d i n t he S o A (Ta bl e  1 ) t o meas ure 
le vels of t he f oll o wi n g bi o mar kers f or a nal ysis of e x pl orat or y varia bles: 
•
Plas ma/ser u m A S T, A L T  are deri ve d fr o m safet y varia bles ( T a ble  7 ).
•
M o del f or e n d  sta g e li ver disease sc ore ( M E L D = 3. 7 8 ×  l n[ser u m bilir u bi n
( m g/ d L)] +  1 1. 2 ×l n[I N R] + 9. 5 7  ×  l n[ser u m creati ni ne ( m g/ d L)] + 6. 4 3) cal c ulate d at
e ver y visit.  If bilir u bi n, I N R a n d/ or creati ni ne val ues are l ess t ha n 1. 0, t he val ue is set as
1. 0.
•
Plas ma/ser u m
, a n d 
 are t he n o n -fasti n g plas ma 
bi o mar ker s i n t he S o A. 
All bl o o d sa m ples f or e x pl orat or y a nal yses will be ha n dle d b y t he ce ntral l a b orat or y.  
C hil d -P u g h sc ore, calc ul ate d as per Ta ble  6 . 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 4  of 1 4 3  
 
Ta ble  6  
C hil d -P u g h Sc ore   
Cli nic al a n d l a b or at or y criteri a  
P oi nts  
1  
2  
3  
E nce p hal o pat h y  
N o ne  
Mil d t o m o derate 
( West Ha ve n 
gra de  1 or 2)  
Se vere ( West Ha ve n 
gra de  3 or 4)  
Ascites  
N o ne  
Mil d t o m o derate 
( di uretic res p o nsi ve) 
Se vere ( di uretic 
refract or y) 
Bilir u bi n ( m g/ d L)  
<  2  
2 - 3  
>  3  
Al b u mi n ( g/ d L)  
>  3. 5  
2. 8 –  3. 5  
<  2. 8  
Pr ot hr o m bi n ti me  
 
 
 
Sec o n ds pr ol o n ge d  
<  4  
4 - 6  
>  6  
I N R 
<  1. 7  
1. 7 –  2. 3  
>  2. 3  
C hil d -T urc otte -P u g h cl ass o bt ai ne d b y a d di n g sc ore f or e ac h p ar a m eter (t ot al p oi nts)  
Class A = 5 t o 6 p oi nts (least se vere li ver disease)  
Class B = 7 t o 9 p oi nts ( m o deratel y se v ere li ver disease) 
Class C = 1 0 t o 1 5 p oi nts ( m ost se vere li ver disease)  
A b bre viati o ns: I N R  =  I nter nati o nal N or malise d Rati o. 
 
8. 2. 2. 4  
P atie nt -r e p orte d O utc o mes   
Patie nt -re p orte d o utc o m es ( P R Os) refer t o all s y m pt o ms, i m pacts, a n d o utc o mes t hat are 
directl y re p ort e d b y t he p artici pa nt. P R Os ha ve bec o me i m p orta nt e n d p oi nts f or re g ulat or y 
a n d rei m b urse me nt a ut h orities w he n e val u ati n g efficac y or safet y of treat me nt i n cli nical 
trials. 
T he f oll o wi n g P R Os will be a d mi nistere d i n t his st u d y at t he ti me p oi nts s pecifie d i n t he S o A 
(Ta ble  1 ): 
•  
C hr o nic Li ver Diseas e Q uesti o n naire ( C L D Q)  
•  
S F -3 6 v 2 ac ut e  
•  
Patie nt Gl o bal I m pr essi o n of Se verit y - Li ver Disease ( P GI S - Li ver Dise ase)  
 
P artici pa nts will be as ke d t o c o m plete t he q uesti o n naires o n a pr o visi o ne d ha n d hel d electr o nic 
de vice. Pa per q uesti o n naires ma y be use d i f a pr o visi o ne d ha n d hel d electr o nic de vice is n ot 
a vaila ble or t he p artici pa nt is u na ble t o use o ne.   
T he ha n d hel d de vi ce has bee n pr o gra m me d t o all o w fle xi bilit y f or partici pa nts t o c o m plete 
P R O q uesti o n naires pri or t o t he Visit 6 i n -cli nic visit. I n case t he P R O q uesti o n naires are n ot 
c o m plete d bef ore t he i n -cli nic Visit 6, t he partici pa nt s h o ul d c o m plete P R Os at t he site pri or t o 
ot her Visit 6 st u d y  pr oce d ures.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 5  of 1 4 3  
 
T he f oll o wi n g best practice g ui deli nes s h o ul d be f oll o we d:  
•  
P R O q uesti o n naires s h o ul d be c o m plete d bef ore a n y ot her st u d y pr oce d ures d uri n g 
Visit  6, t o a v oi d bias w he n res p o n di n g t o q uesti o ns.  
•  
S ite pers o n nel m ust s h o w partici pa nts h o w t o use t he electr o nic P R O de vi ce, i n 
acc or da nce wit h t he i nstr ucti o ns pr o vi de d.  
•  
Partici pa nts m ust n ot recei ve hel p fr o m r elati ves, frie n ds, or site staff t o a ns wer or t o 
clarif y P R O q uesti o ns.  
•  
If partici pa nts h a ve a n y me dical pr o ble ms, t he y s h o ul d disc uss t he m wit h t heir d oct or or 
researc h n urs e se paratel y fr o m t he P R O assess me nt. 
•  
Site staff m ust re mi n d partici pa nts t here are n o ri g ht or wr o n g a ns w ers, a n d t hat t he val ue 
a n d rele v a nce of P R O data are t o hear directl y fr o m partici pa nts, wit h o ut i nter pretati o n 
fr o m a ny o ne else, h o w t h e y f u ncti o n a n d feel.  
 
C L D Q:  
T he C L D Q is a diseas e -s pecific P R O i nstr u me nt, assessi n g s y m pt o ms a n d healt h-rel ate d 
q ualit y of life, rele v a nt f or patie nts wit h li ver dise ase. T he C L D Q i ncl u des 2 9 ite ms wit h a 
recall peri o d of t he past 2  wee ks. T h e C L D Q i ncl u des 6 d o mai ns: A b d o mi nal s y m pt o ms ( 3 
ite ms), Fati g ue ( 5 ite ms), S yste mic s y m pt o ms ( 5 ite ms), Acti vit y ( 3 ite ms), E m oti o nal 
f u ncti o n ( 8 ite ms), Worr y ( 5 ite ms). Sc ori n g of t his i nstr u me nt pr o d uces a gl o bal sc ore, as well 
as sc ores f or eac h of t h e d o mai ns.  
S F -3 6 v 2:  
T he S F -3 6 v 2 is a vali date d ge neri c P R O i nstr u me nt f or assessi n g healt h -relate d q ualit y of life. 
T he ac ute v ersi o n of S F -3 6 v 2 as ks a b o ut t he past wee k a n d t h e partici pa nt’s c urre nt 
e x perie n ce. T h e S F -3 6 v 2 c o nsists of 3 6 ite ms c o m bi ne d i nt o d o mai ns, a n d 2 a g gre gat e d 
s u m mar y sc ores: Me ntal C o m p o ne nt S u m mar y a n d P h ysical C o m p o ne nt S u m mar y. T he 8 
d o mai ns are: P h ysical F u ncti o ni n g, R ole -P h ysical (r ole li mitati o ns ca use d b y p h ysical healt h 
pr o ble ms), B o dil y Pai n, Ge neral Healt h, Vita lit y, R ole-E m oti o nal (r ole li mitati o ns ca use d b y 
e m oti o nal pr o ble ms), S ocial F u ncti o ni n g a n d Me ntal Healt h. Res p o nses t o 3 5 of t he 3 6 ite ms 
are use d t o c o m p ute a n 8 -d o mai n pr ofile of f u n cti o nal healt h a n d well bei n g sc ores. T h e 
re mai ni n g ite m, referre d t o as t he “ Healt h Tra nsiti o n” ite m, as ks partici pa nts t o rate h o w t heir 
c urre nt state of healt h c o m pares t o t heir state of healt h 1 year a g o a n d is n ot use d t o calc ulate 
d o mai n sc ores.  
P atie nt Gl o b al I m pressi o n of Se verit y - Li ver Dise ase ( P GI S - Li ver Dise ase ): 
T he P GI S meas ures t h e p artici pa nt’s o verall perce pti o ns of t heir li ver disease -relat e d 
s y m pt o ms. T he P GI S is a static, si n gle-ite m meas ure of t he se v erit y of li ver disease s y m pt o ms 
d uri n g t he last 2  wee ks. T he P GI S has 4 res p o nse o pti o ns: " n o s y m pt o ms,"  " mil d," 
" m o derate," a n d "se v ere." P GI S is usef ul f or deter mi ni n g t he mea ni n gf ul c ha n ge val ues of 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b o te nta n a n d Da p a glifl ozi n - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 6  of 1 4 3  
 
ot her P R O meas ures s uc h as C L D Q.  
8. 3  
S afet y Assess me nts   
Pla n ne d ti me p oi nts f or all s afet y assess me nts are pr o vi de d i n t he S o A (Ta ble  1 ). 
8. 3. 1  
P h ysic al E x a mi n ati o ns   
P h ysical e xa mi nati o n, a n d meas ure me nt of wei g ht a n d hei g ht will be c o n d u cte d at t he 
ti me poi nts o utli ne d i n t he S o A  (Ta ble  1 ). 
•  
A f ull p h ysical e xa mi nati o n will i ncl u de assess me nts of ge neral a p peara n ce, res pirat or y 
(res pirat or y rate a n d breat h s o u n ds), car di o vas c ular ( H R, j u g ular ve n o us press ure, 
s o u n ds), a b d o me n (li ver a n d s plee n t o detect a n y i ncreas e as w ell as cli nical ascites 
gra de), s ki n (c ol o ur, t ur g or), hea d a n d nec k (i ncl u di n g ears, e y es, n ose, a n d t hr oat), l y m p h 
n o des, t h yr oi d, m us c ul os keletal (i ncl u di n g s pi ne a n d e xtre mities) , a n d ne ur ol o gical 
s yste ms a n d a n assess me nt of t he prese n ce a n d e xte nt of peri p heral (a n kl e/le g) oe de m a.  
•  
A brief p h ysical e xa mi nati o n will i ncl u de assess me nt of s ki n (c ol o ur, t ur g or), res pir at or y 
(res pirat or y rate a n d breat h s o u n ds), car di o vas c ular s yste m ( H R, j u g ular ve n o us press ure, 
s o u n ds), a n d a b d o me n (li ver a n d s plee n t o detect a n y i ncreas e as well as cli nical ascites 
gra de) a n d a n assess me nt of t he prese n ce a n d e xte nt of peri p heral (a n kle/le g ) oe de ma. 
 
F or i nf or mati o n o n h o w A Es base d o n p h ysical e xa mi nati o n fi n di n gs s h o ul d be rec or de d a n d 
re p orte d, see Secti o n 8. 4. 4 . 
I n a d diti o n, b o d y wei g ht will be m o nit ore d at h o me usi n g a n electr o nic scal e t hr o u g h o ut t he 
i nter ve nti o nal peri o d as p art of t he ke y  m eas ure me nts  (Ta ble  1 ); Secti o n  8. 2. 1. 2 ). F or 
meas ure me nt, t he p artici pa nt s h o ul d wear i n d o or, da yti me cl ot hi n g wit h n o s h oes a n d n o 
c oats/jac kets a n d re m o val of hea v y o bject s fr o m p oc kets. 
8. 3. 2  
Vit al Si g ns   
Vital si g ns  assess me nts  will be perf or me d at ti me p oi nt as s pecifie d i n t he S o A (Ta ble  1 ). 
Vital si g ns will i ncl u de s u pi ne a n d sta n di n g bl o o d press ure, p ulse, a n d b o d y te m perat ur e 
meas ure me nts.  
R o uti ne bl o o d press ure, p ulse, a n d b o d y te m perat ure will be assess e d at t he st u d y ce ntre, as 
o utli ne d i n t he S o A (Ta ble  1 ), pri or t o bl o o d c ollecti o n for la b orat or y tests wit h t he partici pa nt 
resti n g i n a s u pi ne p ositi o n usi n g a c o m pletel y a ut o mate d de vice. Ma n u al tec h ni q ues will be 
use d o nl y if a n a ut o mate d de vice is n ot a vaila ble.  
Partici pa nt s w h o s uffer fr o m 
 a n d/ or 
 of 
 
d uri n g t he c o urse of t he st u d y , will be pr o vi de d  wit h 
 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 7  of 1 4 3  
( Secti o ns 6. 1. 2  a n d 8. 4. 6 ). 
Vital si g n meas ure me nts i n a s u pi ne p ositi o n s h o ul d be prece de d b y at le ast 5 mi n utes of rest 
f or t he partici p a nt i n a q uiet setti n g wit h o ut distracti o ns (e g, tele visi o n, cell p h o nes) a n d will 
c o nsist of o ne p ulse, o ne  b o d y te m perat ur e, a n d 3  bl o o d press ure meas ure m e nts 
(3  c o nsec uti ve bl o o d pr ess ure rea di n gs will be rec or de d at i nter v als of at least 1 mi n ute). T he 
a vera g e of t he 3 bl o o d pr ess ure rea di n gs will be rec or de d o n t he e C R F. I n a d diti o n, 
 s h o ul d be 
 in t he 
. 
T hese assess me nts s h o ul d prefera bl y be d o ne i n t he m or ni n g. If 
 is 
c o nfir me d d uri n g t he test, it s h o ul d be re p orte d as a n A E SI i ncl u di n g s y m pt o ms relate d t o t he 
meas ure me nt of 
 if prese nt ( Secti o n 8. 4. 6 ). 
F or i nf or mati o n o n h o w A Es base d o n vital si g n res ults s h o ul d be rec or de d a n d re p ort e d, see 
Secti o n 8. 4. 4 . 
B o d y wei g ht will be meas ure d at t he st u d y ce ntre at st u d y visits. T here will be safet y 
m o nit ori n g of b o d y wei g ht fr o m t he h o me -bas e d m o nit ori n g de vices, or as a n alter nati ve,  
pa per diaries ca n b e use d f or ca pt uri n g t he i nf or m ati o n. A b o d y wei g ht c ha n ge of 
 k g p er 
 is re g ar de d as a 
 wei g ht c ha n g e a n d nee ds t o be f oll o we d u p b y t he 
i n vesti gat or. 
T he i n vesti gat or will ha v e direct a ccess t o t he o nli ne data f or t heir partici pa nts usi n g di gital 
de vices. If t h ere is a si g nifica nt wei g ht gai n, t he i n vesti gat or will c o ntact t he partici pa nt 
i m me diatel y a n d arra n ge a cli nic visit t o assess healt h stat us. Partici pa nts wit h pa per diaries 
will be i nstr ucte d t o c o ntact t he  st u d y staff if t h ere is a si g nifica nt wei g ht gai n. 
Partici pa nts will als o be a d vise d t o self -m o nit or a n d c o ntact t he i n vesti gat or wit h a n y 
c o ncer ns.  
8. 3. 3  
Electr oc ar di o gr a ms  
E C Gs will  be rec or de d at t he sites usi n g 1 2 -lea d E C G rec or ders i n t he s u pi ne p ositi o n after t he 
partici pa nt has bee n resti n g f or at least 1 0 mi n utes, at t he ti me p oi nts s pecifie d i n  t he S o A 
(Ta ble  1 ). T he i n vesti gat or ma y a d d e xtr a 1 2-lea d E C G safet y assess me nts if t here are a n y 
a b n or mal fi n di n gs or if t he i n vesti gat or c o nsi ders it is re q uire d f or a n y ot h er safet y r eas o n.  
Di gital E C Gs will be rec or de d i n tri plicate o n sta n dar dise d st u d y E C G mac hi nes a n d assesse d 
ce ntrall y. 
Sta n dar dise d 1 2 -lea d di gital E C G e q ui p me nt a n d all re q uisite h o o k u p s u p plies will be 
pr o vi de d. E C Gs will be u pl oa de d via a sec ure p ort al f or hi g h -res ol uti o n meas ure me nt of t he 
car diac i nter vals a n d m or p h ol o gical assess me nt b y a ce ntr al car di ol o gist bli n de d t o t he st u d y 
treat me nt. W h ere di gital tra ns missi o n is n ot p ossi ble, a pr ocess f or recei pt a n d a nal ysis of 
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 8  of 1 4 3  
 
sca n ne d or pa per E C Gs is als o esta blis he d. C onfir me d E C Gs will be a vaila ble o n a st u d y 
p ortal wit hi n t he c o ntract e d t ur nar o u n d ti me.  
O n -scree n meas ure me nts of t he R R, P R, Q R S, a n d Q T i nter val d ur ati o ns will be perf or me d,  
a n d varia bles f or Q Tc F, Q Tc B, a n d heart rat e will be calc ul ate d. Eac h fi d u cial p oi nt ( o nset of  
P wa ve, o nset of Q wa v e, offset of S wa v e, a n d offset of T wa v e) will be electr o nicall y  
mar ke d. T h e ori gi nal E C G wa vef or m a n d s uc h a n n otati o ns will be sa ve d se parat el y i n X M L  
f or mat f or i n de p e n de nt r e vie w. 
T he i n vesti gat or or a ut h ori se d delegat e will ma ke a n i nitial assess me nt of w het her t he E C G 
fi n di n gs are n or mal or a b n or mal a n d if a b n or m al, cli nicall y si g nifica nt or n ot. I n t he case of a 
discre pa n c y bet wee n t he i n vesti gat or’s i nitial assess me nt a n d t he ce ntr al E C G rea di n g, t he  
ce ntral r ea d i n g will ta ke prece d e nce. 
If a site re q uires e x p e dite d re p orti n g f or E C Gs d u e t o s us pecte d E C G a b n or malities or f or 
ur ge nt decisi o n ma ki n g, t he site s h o ul d c o ntact t he E C G pr o vi der per i nstr ucti o ns t o re q uest  
e x pe dite d E C G pr ocessi n g.  
I n case of a n E C G d e vice malf u ncti o n, t he site s h o ul d f oll o w t he ste ps rec o m me n de d wit hi n 
t he Car diac Safet y St u d y Ma n ual i n or der t o ha v e t he E C G a nal yse d i n a ti mel y ma n ner.  
F or i nf or mati o n o n h o w A Es base d o n E C G res ults s h o ul d be rec or de d a n d re p orte d, see 
Secti o n 8. 4. 4 . 
8. 3. 4  
Ec h oc ar di o gr a m   
I n partici pa nts wit h a k n o w n hist or y of H F  fr o m a n y aeti ol o g y, a n d n o hist orical E C H O  or 
car diac M RI a vaila ble wit hi n 1 2 m o nt hs pri or t o V isit 1 , a baseli ne E C H O  s h o ul d be o btai ne d 
d uri n g t he scree ni n g peri o d a n d pri or t o ra n d o mi sati o n. 
8. 3. 5  
Cli nic al S afet y L a b or at or y Assess m e nts   
Bl o o d a n d uri ne sa m ples f or deter mi nati o n of cli nical c he mistr y, electr ol yte, c oa g ulati o n , a n d 
hae mat ol o g y f or safet y a nal ysis will be ta ke n at t he ti me p oi nts s pecifie d i n t he So A (Ta ble  1 ). 
S o me of t he la b orat or y v aria bles are als o c ollecte d f or assess me nts f or e x pl orat or y e n d p oi nts, 
as descri be d i n Secti o n 8. 2. 2. 3 . 
A d diti o nal safet y sa m ples ma y be c ollecte d if cli nicall y i n dicate d at t he dis creti o n of t he 
i n vesti gat or. T he date, ti me of c ollecti o n a n d res ults ( val ues, u nits, a n d refere nce ra n ges) will 
be rec or de d o n t he a p pr o priate e C R F.  
T he la b orat or y assess me nts f or cli nical c he mistr y  a n d hae mat ol o g y will be perf or me d at a 
ce ntral la b orat or y.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 9  of 1 4 3  
T he f oll o wi n g la b orat or y varia bles will be meas ure d  (Ta ble  7 ). 
Ta ble  7  
L a b or at or y S afet y Va ri a bles   
H ae m at ol o g y a n d differe nti al p a nel  
W hite bl o o d cell c o u nt  
L y m p h oc ytes a bs ol ute c o u nt  
Re d bl o o d cell c o u nt  
M o n oc ytes a bs ol ute c o u nt  
Hae m o gl o bi n 
E osi n o p hils a bs ol ute c o u nt  
Hae mat ocrit 
Bas o p hils a bs ol ute c o u nt  
Ne utr o p hils a bs ol ute c o u nt  
Platelet a bs ol ute c o u nt  
C he mistr y p a nel  
B U N  
Ala ni ne a mi n otra nsferase 
Creati ni ne a n d calc ulate d e G F R ( C K D -E PI)  
As partate a mi n otra nsferase 
T otal bilir u bi n a n d direct bilir u bi n  
Al kali ne p h os p hatase 
Al b u mi n  
Creati ne ki nase 
Calci u m  
Ser u m gl uc ose  
P h os p hate  
Ga m ma -gl uta m yl tra nsferase 
Ot her  
Ser u m Os m olalit y  
N T -pr o B N P  
C o a g ul ati o n gr o u ps (fr oze n s a m ples)  
I nter nati o nal n or malise d rati o 
Pr ot hr o m bi n ti me 
Partial t hr o m b o plasti n ti me 
Electr ol yte p a nel  
Bicar b o nate ( H C O 3-) 
S o di u m  
C hl ori de ( Cl -) 
P otassi u m  
Ma g nesi u m ( M g
+ ) 
Uri ne scree n f or dr u gs of a b use ( Scree ni n g o nl y)  
A m p heta mi ne/ M D M A  
O piates  
A nti de pressa nts  
Met ha d o ne  
Bar bit urates  
P he nc ycli di ne 
Be n z o diaze pi nes  
Pr o p o x y p he ne  
Ca n na bi n oi ds  
C ocai ne  
HI V ser ol o g y  
H u ma n I m m u n o deficie n c y Vir us l oa d 
Re pr o d ucti ve scree ni n g  
F S H (fe males o nl y)  
Pre g na nc y test (fe males o nl y; ser u m)  
N ote:  Refer t o A p pe n di x  E  f or acti o ns re q uire d i n cases of i ncreases i n li ver bi oc he mistr y a n d 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 0  of 1 4 3  
 
e val uati o n of m o difie d H y’s La w.  
I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g of t he sa m ples will be pr o vi de d i n t he 
st u d y-s pecific La b orat or y Ma n ual. 
8. 3. 6  
Ot her S afet y Assess m e nts   
8. 3. 6. 1  
Self -M o nit ore d Gl uc ose a n d H y p o gl yc ae mic E ve nts   
T he partici pa nts wit h T 2 D M a n d o n c o nc o mita nt treat me nt wit h i ns uli n or s ulf o n yl urea will 
be as ke d t o c h ec k t heir bl o o d gl uc ose re g ularl y a n d , if t he y de vel o p s y m pt o ms s u g gesti ve of 
h y p o gl ycae mia , t o rec or d s pecific s y m pt o ms. Partici pa nts o n i ns uli n or s ulf o n yl urea will be 
pr o vi de d wit h a h o me -b ase d gl uc o meter t o m o nit or t heir bl o o d gl uc ose if t h e y d o n ot alrea d y 
ha ve a gl uc o m eter at h o me ( Secti o n 6. 1. 2 ). Partici pa nts will be i nstr ucte d t o rec or d a n y 
h y p o gl ycae mic e v e nt a n d t o c o ntact t he i n vesti gat or.  
D uri n g t he visits  s pecifie d i n t he S o A (Ta ble  1 ), t he i n vesti gat or is res p o nsi ble f or re vi e wi n g 
a n y bl o o d gl uc ose data c ollecte d fr o m t he partici p a nt a n d q uesti o ni n g t he partici pa nt a b o ut all 
s y m pt o ms re p orte d a n d f or deter mi ni n g if t he y meet t he cli nical defi niti o n of h y p o gl ycae mia. 
O nl y s y m pt o ms a n d/ or bl o o d gl uc ose val ues t hat meet t he f oll o wi n g criteri a s h o ul d be 
re p orte d o n t he d e dicat e d h y p o gl ycae mia e C R F pa ges: 
•  
A gl uc ose le vel of <  3. 0  m m ol/ L ( <  5 4  m g/ d L).  
•  
Se vere h y p o gl yc ae mia, as defi ne d b y se v ere c o g niti ve i m pair me nt re q uiri n g e xter nal 
assista nce f or rec o ver y.  
 
I n all partici pa nts, h y p o gl ycae mic e v e nts sh o ul d be re p ort e d o n t he A E e C R F pa ge if f ulfilli n g 
t he A E defi niti o n (see A p pe n di x B ). 
8. 3. 6. 2  
Alc o h ol  Use Dis or ders  Ide ntific ati o n Test Q uesti o n n aire   
T he A U DI T q u esti o n nair e t o assess alc o h ol use h a bits will be c o m plete d at scree ni n g o nl y  
(Ta ble  1 ). T he self-assess me nt versi o n of t he q uesti o n naire will be c o m plete d b y t he 
partici pa nt. T he res ults will be use d f or deter mi ni n g partici pa nt eli gi bilit y. A sc ore of 8 or 
m ore is ass ociate d w it h h ar mf ul or hazar d o us dri n ki n g, a sc ore of 1 3 or m ore i n w o me n, a n d 
1 5 or m ore i n me n, is li kel y t o i n dicate alc o h ol de pe n de nce.  
Defi niti o n of a St a n d ar d Dri n k : 
I n t he A U DI T q u esti o ns 2 a n d 3, it is ass u me d t hat a sta n dar d dri n k e q ui v ale nt is 1 0 gra ms of 
alc o h ol. T he al c o h ol c o nt e nt of a dri n k de p e n ds o n t he stre n gt h of t he be v era ge a n d t he 
v ol u me of t he c o ntai ner. T he partici pa nt s h o ul d be i nstr ucte d t o esti mate t he n u m ber of dri n ks 
i n t he res p o nse cate g ories f or t hese q uesti o ns i n or der t o fit t he m ost c o m m o n dri n k sizes a n d 
alc o h ol stre n gt h i n t heir c o u ntr y.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
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8. 4  
A d verse E ve nts, S A Es, a n d Ot her S afet y Re p orti n g   
T he pri nci pal i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are 
fa miliar wit h t he c o nte nt of t his secti o n. 
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x  B . 
A d verse e ve nts will be re p orte d b y t he partici p a nt ( or, w he n a p pr o priat e, b y a care gi ver, 
s urr o gate, or t h e partici p a nt’s le gall y a ut h orise d re prese nt ati ve); t hese m ust t he n be assesse d 
b y t he i n vesti gat or a n d if c o nsi dere d a n A E it will be re p ort e d b y t he i n vesti gat or . 
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi niti o n of a n A E.  
A d verse E ve nt V a ri a bles  
T he f oll o wi n g varia bles will be c ollecte d f or eac h A E: 
•  
A d verse e ve nt ( ver bati m)  
•  
T he date w h e n t he A E st arte d a n d st o p pe d  
•  
Ma xi m u m i nte nsit y  
•  
W het her t he A E is seri o us or n ot  
•  
I n v esti gat or ca us alit y assess me nt a gai nst t he st u d y i nter ve nti o n ( yes or n o) 
•  
Acti o n ta ke n wit h re g ar d t o st u d y i nter ve nti o n  
•  
O utc o me  
 
I n a d diti o n, t he f oll o wi n g varia bles will be c ollecte d f or S A Es: 
•  
Date A E met criteria f or S A E  
•  
Date i n vesti gat or beca me a ware of S A E  
•  
A d verse e ve nt des cri pti o n  
•  
A d verse e ve nt is seri o us d ue t o  
•  
Date of h os pitalisati o n  
•  
Date of disc h ar ge  
•  
Pr o ba ble ca us e of deat h  
•  
Date of deat h  
•  
A ut o ps y perf or me d  
•  
Ca usalit y assess me nt i n relati o n t o st u d y pr oce d ure(s)  
•  
Ca usalit y assess me nt t o ot her me dicati o n  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 2  of 1 4 3  
 
 
8. 4. 1  
Ti m e Peri o d a n d Fre q ue nc y f o r C ollecti n g A E a n d S A E I nf or m ati o n   
Seri o us A Es will be rec or de d fr o m t he ti me of si g ni n g of t he I C F.  
All A Es  will be c ollecte d after t he p artici pa nt has recei v e d t he first d ose of t he st u d y 
i nter ve nti o n t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w-u p p eri o d.  
If t he i n vesti gat or bec o m es a ware of a n S A E wit h a s us pecte d ca usal r elati o ns hi p t o t he 
i n vesti gati o nal me dici nal pr o d uct t hat occ urs after t he e n d of t he cli nical st u d y i n a partici pa nt 
treate d b y hi m or her, t he i n vesti gat or s hall, wit h o ut u n d ue dela y, re p ort t he S A E t o t he 
s p o ns or. 
8. 4. 2  
F oll o w -u p of A Es a n d S A Es   
A n y A Es t hat are u nres ol ve d at t he partici p a nt’s last A E assess me nt or ot her assess me nt/ visit 
as a p pr o priat e i n t he st u d y, are f oll o we d u p b y t he i n vesti gat or f or as l o n g as me dicall y 
i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he e C R F. Astra Ze n eca retai ns t h e ri g ht t o re q uest 
a d diti o nal i nf or mati o n f or a n y partici p a nt wit h o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, 
if j u d ge d necess ar y. 
8. 4. 3  C a us alit y C ollecti o n   
T he i n vesti gat or s h o ul d assess ca usal r elati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h A E, 
a n d a ns wer ‘ yes’ or ‘ n o’ t o t he q uesti o n ‘ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y 
t hat t he e ve nt ma y ha v e bee n ca use d b y t he st ud y i nter ve nti o n?’ . 
F or S A Es, ca usal rel ati o ns hi p s h o ul d als o be assesse d f or ot her m e dicati o n s a n d st u d y 
pr oce d ures. N ote t hat f or S A Es t hat c o ul d be ass o ciate d wit h a n y st u d y pr oce d ure t h e ca us al 
relati o ns hi p is i m plie d as ‘ yes’. 
A g ui de t o t he i nter pretati o n of t he ca usalit y q uesti o n is f o u n d i n A p pe n di x  B . 
8. 4. 4  A Es B ase d o n E x a mi n ati o ns a n d Tests   
Deteri or ati o n as c o m pare d t o baseli ne i n pr ot oc ol -ma n date d la b orat or y val u es, vital si g ns, a n d 
E C Gs s h o ul d o nl y be re p orte d as A Es if t he y meet a n y of t he f oll o wi n g:  
•  
f ulfil a n y of t he S A E crit eria 
•  
are t he reas o n f or disc o nti n uati o n of t he I M P  
•  
are cli nic all y rele va nt as j u d ge d b y t he i n vesti gat or ( w hic h ma y i ncl u d e , b ut is n ot li mite d 
t o, c o nsi derati o n as t o w het her i nter ve nti o n or n o n-pla n ne d visits were re q uire d or ot her 
acti o n was ta ke n wit h t he I M P, e g, dr u g i nterr u pti o n).  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 3  of 1 4 3  
If deteri orati o n i n a la b orat or y val ue/ vital si g n is ass ociate d wit h cli nical sig ns a n d s y m pt o ms, 
t he si g n or s y m pt o m will be re p ort e d as a n A E a n d t he ass ociate d la b orat or y res ult/ vital si g n 
will be c o nsi dere d as a d diti o nal i nf or mati o n. W here ver p ossi ble , t he re p orti n g i n vesti gat or 
uses t he cli nical, rat h er t ha n t he la b orat or y ter m ( e g, a nae mia vs l o w hae m o gl o bi n val ue). I n 
t he a bse nce of cli nical si g ns or s y m pt o ms, cli nicall y rele va nt deteri orati o ns i n n o n-ma n date d 
para meters s h o ul d be re p orte d as A Es ( Secti o n 8. 4 ). 
A n y ne w or a g gra v ate d cli nicall y rele va nt a b n or m al me dical fi n di n g at a p h ysical e xa mi nati o n 
as c o m pare d wit h t he bas eli ne assess me nt will be re p orte d as a n A E.  
T he res ults fr o m t he pr ot oc ol -ma n date d la b orat or y tests a n d vital si g ns will be s u m marise d i n 
t he C S R. 
8. 4. 5  A Es B ase d o n Si g ns a n d S y m pt o ms  
All A Es s p o nta ne o usl y re p orte d b y t he partici p a nt ( or care pr o vid er) or re p orte d i n res p o nse t o 
t he o pe n q uesti o n fr o m t he st u d y ce ntre staff: ‘ Ha ve y o u ha d a n y h ealt h pr o ble ms si nce t he 
pre vi o us visit/ y o u were l ast as ke d?’ , or re v eale d b y o bser vati o n will be c oll ecte d a n d rec or de d 
i n t he e C R F. W he n c ollecti n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n p ossi ble) t o 
rec or di n g a list of si g ns a n d s y m pt o ms. H o we ver, if a dia g n osis is k n o w n a n d t here are ot her 
si g ns or s y m pt o ms t hat are n ot ge nerall y part of t h e dia g n osis, t he dia g n osis a n d eac h si g n or 
s y m pt o m will be rec or de d se parat el y.  
8. 4. 6  
A d verse E ve nts of S p eci al I nterest  
A d diti o nal m o nit ori n g a n d data c ollecti o n will be perf or me d d uri n g t he st u d y f or t he 
f oll o wi n g safet y e ve nts classifie d as A E SI, base d o n t he
 i de ntifie d f or 
zi b ote nta n i n o nc ol o g y cli nical st u dies c o n d ucte d pre vi o usl y, as 
 of b ot h 
zi b ote nta n a n d da p a glifl ozi n (e g, 
), a n d 
ass ociate d wit h t he use of da pa glifl ozi n: 
•
Ne w dia g n osis of  
 or  
of t he e xisti n g  
 c o n diti o n. A n y 
 s u g gesti ve of  
 s h o ul d be pr o perl y assesse d b y t he i n vesti gat or, t o e ns ure 
ti mel y a n d pr o per ma n a g e me nt of t he partici pa nt’s c o n diti o n. 
•
 or w orse ni n g of 
 (e g, 
 of a n y 
, etc). 
•
 defi ne d as a  
 of 
 m m H g i n 
 or a 
 of 
 m m H g i n
 wit hi n
. 
Partici pa nts will be e d ucate d a b o ut t he s y m pt o ms of 
a n d partici pa nts wit h 
 or 
 will be 
pr o vi de d wit h a
 a n d as ke d t o c o ntact t he i n vesti gat or 
if s y m pt o ms occ ur or if t heir 
 is 
 m m H g.  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C li nical St u d y Pr ot oc ol - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 4  of 1 4 3  
•
. I n t he e ve nt of s y m pt o ms of 
, a  
 
 s h o ul d be perf or me d. 
•
. 
•
, i ncl u di n g t he f oll o wi n g: i ncrease i n 
 b y 
m g/ d L 
(
 μ m ol/ L) wit hi n 4 8  h o urs ; or i ncrease i n 
 t o 
 w hic h is 
k n o w n or pres u me d t o h a ve occ urre d w it hi n t he pri or 7 da ys ( or usi n g t he last a vaila ble 
val ue of o ut patie nt 
 wit hi n 3 m o nt hs as t he baseli ne val u e); or  
 
 m L/ k g/ h f or 6  h o urs.  
8. 4. 7  H y’s L a w  
Cases w here a partici pa nt s h o ws ele vati o ns i n L F Ts or rele va nt cli nical ma nifestati o ns as 
defi ne d i n A p p e n di x  E  2  a n d i de ntifie d i n A p pe n di x  E  3  ma y re q uire f urt her e val uati o n a n d 
ma y nee d t o be re p orte d as S A Es. Please refer t o A p pe n di x  E  f or f urt her i nstr ucti o n o n cases 
of i ncreases i n li ver  bi oc he mistr y a n d e val uati o n of m o difie d H y’s La w.  
8. 4. 8  
Re p orti n g of S A Es  
All S A Es m ust be re p orte d, w het her or n ot c o nsi d ere d ca usall y rel ate d t o t he I M P. All S A Es 
will be rec or de d i n t he e C R F.  
If a n y S A E occ urs d uri n g t he st u d y, i n vesti gat ors or ot her site pers o n nel will i nf or m t he 
a p pr o priate Astra Ze neca re pres e ntati ves wit hi n o ne da y, ie, i m me diatel y b ut n o l ater t h a n 
2 4  h o urs of w he n he or s he bec o mes a ware of it.  
T he desi g nate d Astra Z e n eca re prese ntati ve will w or k wit h t he i n vesti gat or t o e ns ure t hat all 
t he necess ar y i nf or mati o n is pr o vi de d t o t he Astra Ze neca Patie nt Safet y dat a e ntr y site wit hi n 
o ne  c ale n d ar d a y  of i nitial recei pt f or fatal a n d life -t hreate ni n g eve nts a n d wit hi n 5  c ale n d ar 
d a ys of i nitial recei pt f or all ot her S A Es.  
F or fatal or life -t hreate ni n g A Es w here i m p orta nt or rele va nt i nf or mati o n is missi n g, acti ve 
f oll o w-u p will be u n derta ke n i m me diatel y. I n vesti gat ors or ot her site pers o n nel will i nf or m  
Astra Ze neca re prese ntati ves of a n y f oll o w -u p i nf or mati o n o n a pre vi o usl y r e p orte d S A E 
wit hi n o ne cale n dar da y, ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n he or s he 
bec o mes a w are of it.  
O nce t he i n vesti gat ors or ot her st u d y ce ntre p ers o n nel i n dicat e a n A E is seri o us i n t he E D C 
s yste m, a n a ut o mate d e m ail alert is se nt t o t he desi g nate d Astra Ze n eca re prese ntati ve.  
If t he E D C s yste m is n ot a vaila ble, t he n t he i n vesti gat or or ot her st u d y ce ntr e staff re p orts a 
S A E t o t he a p pr o priate Astra Ze neca re pres e n tati ve b y tele p h o ne, e mail or as per l ocal 
a p pr o ve d pr ocess.  W he n t he E D C is te m p oraril y n ot accessi ble, t he Astra Ze neca St u d y 
C CI
C CI
C CI
C CI
C CI
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 5  of 1 4 3  
Re prese ntati ve s h o ul d c o nfir m t hat t he i n vesti gat or/site staff e nters t he S A E i n t he 
Astra Ze neca E D C w he n access res u mes.  
T he Ast ra Ze neca re prese ntati ve will a d vise t he i n vesti gat or/st u d y ce ntre st aff h o w t o pr ocee d. 
I n t he E U, t he S p o ns or will c o m pl y wit h safet y re p orti n g re q uire me nts a n d pr oce d ures as 
descri be d i n t he E ur o pea n Cli nical Trials Re g ulati o n ( E U) N o 5 3 6/ 2 0 1 4. All S us pe cte d 
U ne x pect e d Seri o us A d v erse Reacti o ns ( S U S A Rs) t o i n vesti gati o nal me dici nal pr o d uct will 
be re p ort e d t o t he E u dra Vi gila nce data base wit hi n t he re q uire d re g ulat or y ti meli nes.  
F or f urt her g ui da n ce o n t he defi niti o n of a S A E, s ee A p pe n di x  B . 
T he refere nce d o c u me nt f or defi niti o n of e x p ecte d ness/liste d ness is t he Da pa glifl ozi n 
I n vesti gat or’s Br oc h ure a n d Zi b ote nta n I n vesti gat or’s Br oc h ure . 
8. 4. 9  
Pre g n a nc y  
All pre g na ncies a n d o utc o mes of pre g n a nc y s h o ul d be re p ort e d t o Astra Ze n eca e xce pt if t he 
pre g na nc y is disc o v ere d bef ore t h e st u d y partici pa nt has recei ve d a n y st u d y i nter ve nti o n.  
8. 4. 9. 1  
M ater n al E x p os ure   
E x p os ure d uri n g gestati o n t o E R As, i ncl u di n g zi b ote nta n, is ass ociate d wit h maj or 
e m br y o-f oet al har m. E R As ha ve bee n de m o nstrat e d t o i n d uce terat o ge nic effects i n a ni mals 
w he n d ose d d uri n g or ga n o ge nesis, earl y i n pre g na nc y. W he n a d mi nistere d t o pre g na nt r a b bits 
d uri n g t he peri o d of maj or e m br y o nic or g a n o ge n esis, zi b ote nta n ca use d f oet al cra ni of acial a n d 
car diac malf or mati o ns at 
 a n d a b o v e, c o nsiste nt wit h E R As 
(zi b ote nta n I B). T h ere is a n e xtre mel y hi g h ris k of e m br y o-f oet al har m if pre g na nc y o cc urs 
w hile bei n g e x p ose d t o zi b ote nta n i n a n y a m o u nt, e ve n f or s h ort peri o ds of ti me. P ote ntiall y, 
a n y f oet us e x p os e d d uri n g pre g na nc y ca n b e affecte d. Wo me n of c hil d bear i n g p ote ntial are n ot 
all o we d t o be i ncl u de d i n t his st u d y  (f or defi niti o n see i ncl usi o n criteri a, Secti o n 5. 1 ).  
Da pa glifl ozi n m ust n ot be use d i n t he sec o n d a n d t hir d tri mesters of pre g n a nc y (refer t o 
Da pa glifl ozi n I n v esti gat or’s Br oc h ure  f or d etails). 
Pre g na nc y itself is n ot re gar de d as a n A E , u nless t here is a s us pici o n t hat t h e st u d y 
i nter ve nti o n ma y ha ve i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve me dicati o n. 
C o n ge nital a n o mal y/ birt h defects a n d s p o nta ne o us miscarria ges s h o ul d be re p orte d a n d 
ha n dle d as S A Es. Electi v e a b orti o ns wit h o ut c o m plicati o ns s h o ul d n ot be ha n dle d as A Es. T h e 
o utc o me of all pre g n a nci es (s p o nta ne o us miscarri a ge, electi ve ter mi nati o n, ect o pic pre g n a nc y, 
n or mal birt h , or c o n ge nit al a n o mal y/ birt h defect) s h o ul d be f oll o we d u p a n d d oc u me nte d e v e n 
if t he partici pa nt w as disc o nti n ue d fr o m t he st u d y.  
If a n y pre g na nc y occ urs d uri n g t he st u d y , t he n t he i n vesti gat or or ot her st u d y ce ntre p ers o n nel 
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 6  of 1 4 3  
 
i nf or ms t he a p pr o priat e Astra Ze neca re prese ntati ves wit hi n 1 d a y , ie, i m me diatel y b ut n o 
l ater t h a n 2 4 h o urs of w he n he or s he  b ec o mes a ware of it.  
T he desi g nate d Astra Z e n eca re prese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or m ati o n is pr o vi de d t o t he Astra Z e neca Patie nt Safet y data e ntr y site wit hi n o ne 
or 5  c ale n d ar d a ys  f or S A Es (see Secti o n 8. 4. 8 ) a n d wit hi n 3 0 d a ys  f or all ot her pre g n a ncies. 
T he sa me ti meli nes a p pl y w he n o utc o me i nf or m ati o n is a vaila ble.  
T he P R E G R E P m o d ule i n t he e C R F is use d t o re p ort t he pre g na n c y a n d t he pa per -b ase d 
P R E G O U T m o d ule is use d t o re p ort t he o utc o m e of t he pre g n a nc y.  
8. 4. 9. 2  
P ater n al E x p os ure   
To pre ve nt p ote ntial e x p os ure via se me n, me n recei vi n g zi b ote nta n w h o are se x uall y acti ve 
wit h a w o ma n of c hil d beari n g p ote ntial s h o ul d e m pl o y t he use of c o n d o ms t o get her wit h o t her 
hi g hl y effecti ve met h o ds of c o ntrace pti o n d uri n g t he st u d y a n d f or a t otal peri o d of 3  m o nt hs 
after t he m ale st u d y parti ci pa nt has recei ve d his last d ose of st u d y i nter ve nti o n.  
Hi g hl y effecti ve birt h c o ntr ol met h o ds are defi ne d as t h ose t hat ca n ac hie v e a fail ure rat e of 
less t ha n 1 % per year w h e n use d c o nsiste ntl y a n d c orrectl y. F or details refer t o Secti o n 5. 3. 4 . 
Male partici pa nts s h o ul d n ot d o nate or ba n k s per m f or t he d urati o n of t h e st u d y a n d f or at least 
3  m o nt hs after t he last d ose of st u d y i nter ve nti o n. 
Male partici pa nts will be i nstr ucte d t hat  if t heir part ner bec o mes pre g na nt d uri n g t he st u d y, or 
wit hi n 3 m o nt hs after last d ose of t he st u d y i nter ve nti o n, t his s h o ul d be re p orte d t o t he 
i n vesti gat or, a n d t he st u d y i nter ve nti o n m ust  be disc o nti n ue d i m me diatel y. T he i n vesti gat or or 
ot her st u d y ce n tre p ers o n nel s h o ul d i nf or m t he a p pr o priate Astra Z e neca re prese ntati ves a b o ut 
t he pre g na n c y wit hi n t he ti meli nes s pecifie d i n secti o n 8. 4. 9. 1 .  
Pre g na nc y of t h e partici p a nt’s part ners is n ot c o nsi dere d t o be a n A E. H o we ver, t he o utc o me 
of all pre g na n cies (s p o nt a ne o us miscarria ge, electi ve ter mi nati o n, ect o pic pre g na nc y, n or mal 
birt h , or c o n ge nital a n o m al y/ birt h defect), o cc urri n g d uri n g t he st u d y or wit hi n 3 m o nt hs after 
last d ose of t he st u d y i nter ve nti o n s h o ul d, if p ossi ble, be f oll o we d u p a n d d o c u me nte d i n t he 
Pre g na nc y Re p ort F or m. C o nse nt fr o m t he part ner m ust be o btai ne d bef or e t he Pre g na nc y 
Re p ort F or m is c o m plete d.  
8. 4. 1 0  
Me dic ati o n Err or, Dr u g A b us e, a n d Dr u g Mis use   
8. 4. 1 0. 1  
Ti m eli nes   
If an e v e nt of me dicati o n err or , dr u g a b use, o r  dr u g mis use  occ urs d uri n g t he st u d y, t he n t he 
i n vesti gat or or ot her site pers o n nel i nf or ms t he a p pr o priate Astra Z e neca re prese ntati ves wit hi n 
o ne c ale n d ar d a y , ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs  of w he n t he y bec o me a ware of 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 7  of 1 4 3  
it. 
T he desi g nate d Astra Z e n eca re prese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or m ati o n is c o m plete d wit hi n o ne  (i nitial fatal/life-t hreate ni n g or f oll o w-u p 
fatal/life-t hreate ni n g) or 5  ( ot her seri o us i nitial a n d f oll o w-u p) c ale n d ar d a ys  if t here is a n 
S A E ass ociate d wit h t he e ve nt of me dicati o n err or, dr u g a b use, or mis use (see Secti o n 8. 4. 8 ) 
a n d wit hi n 3 0 d a ys  f or all ot her e ve nts . 
8. 4. 1 0. 2  
Me dic ati o n Err or   
F or t he p ur p oses of t his cli nical st u d y , a me dicati o n err or is a n u ni nte n de d  fail ure or mista ke 
i n t he treat me nt pr ocess f or a n I M P or Astra Z e neca NI M P t hat eit her ca uses har m t o t he 
partici pa nt or has t he p ot e ntial t o ca use har m t o t he partici pa nt.  
T he f ull defi niti o n a n d e x a m ples of me dicati o n  err or ca n be f o u n d i n A p pe n di x B  4 . 
8. 4. 1 0. 3  
Dr u g A b use   
Dr u g a b use is t he p er siste nt or s p ora dic i nte nti o n al, n o n-t hera pe utic e xcessi ve use of I M P or 
Astra Ze neca NI M P f or a percei v e d re war d or desir e d n o n -t hera pe utic effect. 
T he f ull defi niti o n a n d e x a m ples of dr u g a b us e ca n be f o u n d i n A p pe n di x B  4 . 
8. 4. 1 0. 4  
Dr u g Mis use   
Dr u g mis use is t he i nte nti o n al a n d i na p pr o priate use ( b y a st u d y partici p a nt) of I M P or 
Astra Ze neca NI M P f or m e dici nal p ur p oses o utsi de of t he a ut h orise d pr o d u ct i nf or mati o n, or 
f or u na ut h orise d I M Ps or Astra Z e neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol a n d i ncl u d es deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute.  
T he f ull defi niti o n a n d e x a m ples of dr u g mis use ca n be f o u n d i n A p pe n di x B  4 . 
8. 4. 1 1  
Re p ort i n g of O ver d os e 
Da pa glifl ozi n has b ee n w ell t olerate d at d oses u p t o 5 0 0  m g/ da y i n si n gle d ose testi n g i n 
healt h y partici pa nts a n d u p t o 1 0 0  m g/ da y i n re peat d ose testi n g f or 1 4 da ys i n healt h y 
partici pa nts a n d patie nts wit h T 2 D M.  
If a n o ver d ose is s us pect e d, m o nit ori n g of vital f u ncti o ns as well as treat me nt s h o ul d be 
perf or me d as a p pr o priate.  
T he ma xi m u m well  t olerate d dail y d ose of zi b ote nta n i n o nc ol o g y patie nts was c o nsi dere d t o 
be
 m g; h o we ver, pres e ntl y t here is li mite d i nf or mati o n re gar di n g o v er d ose of zi b ote nta n i n 
c o m bi nati o n wit h da pa glifl ozi n  i n patie nts wit h li ver cirr h osis.  
F or t he p ur p oses of t his st u d y, a n o ver d ose will be defi ne d as t he us e of t he st u d y  i nter ve nti o n 
i n d oses i n e xcess of t hat s pecifie d i n t he pr ot oc ol. 
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 8  of 1 4 3  
 
•  
A n o ver d ose wit h ass o ciate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
rele va nt A E m o d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule. 
•  
A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y re p orte d o n t he O ver d ose e C R F 
m o d ule.  
 
If a n o ver d ose o n a n Astr a Ze neca st u d y i nter ve nti o n occ urs i n t he c o urse of t he st u d y, t he 
i n vesti gat or or ot her st u d y ce ntre p ers o n nel i nf or m a p pr o priate Astra Z e neca re prese nt ati ves 
i m me diatel y, b ut n o l ater t h a n 2 4 h o urs  of w he n he or s he bec o mes a ware of it.  
T he desi g nate d Astra Z e n eca re prese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or m ati o n is pr o vi de d t o t he Astra Z e neca Patie nt Safet y data e ntr y site wit hi n o ne 
or 5  c ale n d ar d a ys  f or o ver d oses ass o ciate d wit h a n S A E (see s ecti o n 8. 4. 8 ) a n d wit hi n 
3 0  d a ys  f or all ot her o ver d oses. 
8. 4. 1 2  
Me dic al De vice Defici e ncies   
N o Astra Z e neca ma n ufact ure d me dical de vi ces ( or me dical de vices m a n ufact ure d f or 
Astra Ze neca b y a t hir d -p art y) will be pr o vi de d f or use i n t his st u d y. F or details  o n di gital 
de vices use d i n t his st u d y a n d n ot ma n ufact ure d b y or f or Astra Z e neca , refer t o Secti o n 6. 1. 2 . 
8. 5  
P h ar m ac o ki netics   
Plas ma sa m ples will be c ollecte d f or meas ure m e nt of plas ma  c o nce ntrati o ns of st u d y 
i nter ve nti o n as s pecifi e d i n t he S o A (Ta ble  1 ). 
Sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts d uri n g t he st u d y if warra nte d a n d a gree d 
u p o n bet wee n t he i n v esti gat or a n d t he s p o ns or, e g, f or safet y reas o ns s u c h as a n S A E; t hese 
sa m ples ma y be re p orte d o utsi de t he C S R.  
T he ti mi n g of sa m pli n g ma y be altere d d uri n g t he st u d y base d o n ne wl y a v aila ble data (e g, t o 
o btai n data cl oser t o t he ti me of pea k or tr o u g h m atri x c o nce ntr ati o ns) t o e ns ure a p pr o priate 
m o nit ori n g.  
•  
Plas ma sa m ples will be use d t o a nal yse t he P K of st u d y i nter ve nti o ns. Sa m ples c ollecte d 
f or a nal yses of st u d y i nter ve nti o n plas ma c o nce ntr ati o n ma y als o be use d t o e val uate 
safet y or effic ac y as p ects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.  
 
Sa m ples will be c oll ecte d, la belle d, st ore d, a n d s hi p pe d as detaile d i n t he La b orat or y Ma n ual.  
•  
F or st ora g e, re -use, a n d d estr ucti o n of sa m ples f or P K see A p pe n di x  C . 
•  
P K sa m ples will be dis p ose d of after t he Bi oa nal ytical Re p ort fi nalisati o n or 6 m o nt hs 
after iss ua n ce of t he draft Bi oa nal ytical Re p ort ( w hic he ver is earlier).  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 9  of 1 4 3  
 
•  
A d diti o nal a nal yses ma y be c o n d ucte d o n t h e a n o n y mise d, p o ole d, or i n di vi d ual P K 
sa m ples t o f urt her e v al uate a n d vali date t he a nal ytical met h o d. A n y res ults fr o m s uc h 
a nal yses ma y be re p ort e d se parat el y fr o m t he C S R . 
 
8. 5. 1  
C ollecti o n of S a m ples f or P h ar m ac o ki netics   
Plas ma sa m ples will be c ollecte d f or meas ure m e nt of c o nce ntrati o ns of zi b ote nta n a n d 
da pa glifl ozi n at t he ti me p oi nts  s pecifie d i n t he S o A (Ta ble  1 ). 
8. 5. 2  
Deter mi n ati o n of Dr u g C o nce nt r ati o n   
Sa m ples f or deter mi nati o n of dr u g c o nce ntrati o n i n plas ma will be assa ye d b y bi oa nal ytical 
test sites o perate d b y La b C or p o n be half of Astra Z eneca, usi n g a n a p pr o priatel y vali date d 
bi oa nal ytical met h o d. F ull details of t he a nal ytical met h o d use d will be des cri be d i n a se p arat e 
Bi oa nal ytical Re p ort.  
Dr u g c o nce ntrati o n i nf or mati o n t hat w o ul d u n bli n d t he st u d y will n ot be re p orte d t o 
i n vesti gati ve st u d y ce ntres or bli n de d pers o n nel u ntil t he st u d y has bee n u n bli n de d.  O nl y 
sa m ples fr o m partici pa nts o n acti ve treat me nt will be a nal yse d, u nless t here is a nee d t o 
c o nfir m t hat c orrect treat me nt has bee n gi ve n t o st u d y partici pa nts.  
I nc urre d sa m ple re pr od u ci bilit y a nal ysis, if a n y, will be perf or me d al o n gsi de t he bi oa nal ysis 
of t he test sa m ples. T he res ults fr o m t he e val uati o n, if perf or m e d, ma y be re p orte d i n a 
se parat e Bi oa nal ytical Re p ort. 
8. 6  
P h ar m ac o d y n a mics   
D uri n g t he st u d y plas ma/ser u m sa m ples will be c ollecte d f or t he e val uati o n of t he e x pl orat or y 
e n d p oi nts. Para meters will be assesse d fr o m t he bl o o d sa m ples c ollecte d f or safet y a n al yses at 
a ce ntr al c ore la b orat or y (see Secti o n  8. 3. 5 ). 
8. 6. 1  
C ollecti o n of S a m ples f or P h ar m ac o d y n a mics   
Sa m ples will be c ollecte d, la belle d, st ore d, a n d s hi p pe d as detaile d i n t he L a b orat or y Ma n ual. 
D uri n g t he st u d y bl o o d sa m ples will be c ollecte d as descri be d i n t he S o A  (Ta ble  1 ) a n d 
a nal yse d b y a ce ntr al la b orat or y.  
F or st ora ge, re -use , a n d d estr ucti o n of P D sa m ples, see A p pe n di x C . 
8. 7  
O pti o n al Ge n o mics I niti ati ve   
C ollecti o n of o pti o nal sa m ples f or Ge n o mics I niti ati ve researc h is als o part of t his st u d y as 
s pecifie d i n t he S o A (Ta ble  1 ) a n d is s u bject t o a gree me nt i n t he o pti o nal G e n o mics I nitiati ve 
researc h i nf or m ati o n I C F. 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 0  of 1 4 3  
 
Bl o o d sa m ple f or D N A is olati o n will be c ollecte d fr o m partici pa nts w h o ha v e c o nse nte d t o 
partici pate  i n t he ge n etic a n d m ulti-o mics a nal ysis c o m p o ne nt of t he st u d y. Partici pa nts w h o 
d o n ot wis h t o partici pate i n t he ge netic a n d m ulti -o mics researc h ma y still partici pate i n t he 
st u d y. 
See A p pe n di x D  f or i nf or mati o n re gar di n g t he Ge n o mics I nitiati ve ge n o mi c a n d m ulti -o mics 
sa m ples. Details o n pr ocesses f or c ollecti o n a n d s hi p me nt a n d destr ucti o n of t hese sa m ples 
ca n be f o u n d eit her i n t he a p pe n dices or i n t he La b orat or y Ma n u al.  
T he bl o o d sa m ple f or e x pl orat or y ge netic researc h will be o btai ne d fr o m t he part ici pa nts at 
Visit  2  or after ra n d o mi sati o n. 
8. 8  
Bi o m ar kers   
8. 8. 1  
M a n d at or y Bi o m ar ke r S a m ple C ollecti o n   
B y c o nse nti n g t o partici pate i n t he st u d y , t he partici pa nt c o nse nts t o t he ma n dat or y researc h 
c o m p o ne nts of t he st u d y. Ma n dat or y c ollecti o n of sa m ples f or bi o mar ker researc h is part of 
t his st u d y. 
T he f oll o wi n g sa m ples f or bi o mar ker researc h are re q uir e d a n d will be c ollecte d fr o m all 
partici pa nts i n t his st u d y a t t he ti me p oi nt s pecifie d i n t he S o A (Ta ble  1 ): 
•  
Plas ma /ser u m a n d uri ne sa m ples are c ollecte d f or e x pl orat or y a n al yses t o assess t he effect 
of zi b ote nta n a n d d a pa glifl ozi n o n li ver diseases a n d dr u g mec ha nis m -relat e d bi o mar kers 
at a ce ntr al la b orat or y.  
 
F or st ora ge, re -use, a n d d estr ucti o n of bi o mar ker sa m ples see A p pe n di x  C . 
8. 9  
I m m u n o ge nicit y Assess me nts  
I m m u n o ge nicit y a nal ysis will n ot be d o ne i n t his st u d y. 
8. 1 0  
Me dic al Res o urce Utilis ati o n a n d He alt h Ec o n o mics   
Me dical res o urce utilisati o n a n d healt h ec o n o mics are n ot e val uate d i n t his st u d y.  
8. 1 1  
St u d y P artici p a nt Fee d b ac k Q uesti o n n aire   
N ot a p plica ble.  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S   
T he S A P will be fi nalise d wit hi n 9 0 cale n da r da ys after First Partici pa nt I n a n d it will i ncl u de 
a m ore tec h ni cal a n d d etaile d descri pti o n of t he pla n ne d statistical a nal yses. T his secti o n is a 
s u m mar y of t he pla n ne d statistical a nal yses of t he m ost i m p orta nt or ke y  e n d p oi nts.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nt a n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 1  of 1 4 3  
9. 1  
St atistic al H y p ot heses  
As t his is a n earl y -p has e safet y st u d y, n o f or mal statistical h y p ot hesis tests or m ulti plicit y 
a dj ust me nt will be perf or me d . 
9. 2  
S a m ple Size Deter mi n ati o n  
A p pr o xi matel y 2 2 partici pa nts are pla n ne d t o be ra n d o mi se d t o eac h of t he 3 treat me nt gr o u ps . 
T he sa m ple size is n ot deter mi ne d base d o n a f or m al statistical h y p ot h esis testi n g f or t his 
P hase II b st u d y. Wit h  
 e val u a ble partici p a nts per treat me nt gr o u p, a n o bser ve d 
differe nce of 
%  
%) i n pr o p orti o n of partici pa nts wit h t he c o m p osite of fl ui d rete nti o n 
bet wee n 2  treat me nt gr o u ps a n d a n o bser ve d 
% c o m p osite of fl ui d rete nti o n i n t he 
c orres p o n di n g zi b ote nta n gr o u p, t he l o wer li mit of a t w o -si de d 9 0 % CI f or t he differe nce will 
be
%.  
9. 3  
P o p ul ati o ns f or A n al yses  
T he f oll o wi n g p o p ulati o ns are defi ne d:  
Ta ble  8  
P o p ul ati o ns f or A n al ysis  
P o p ul ati o n/ a n al ysis set  
Descri pti o n  
Scree ne d a nal ysis set 
All p artici pa nts w h o si g ne d t he I C F. 
U nless ot her wise state d, t he e nr olle d set will be use d f or t he prese ntati o n of 
dis p ositi o n data.  
F A S  
All p artici pa nts w h o are ra n d o mise d a n d recei ve a n y st u d y i nter ve nti o n.  
Partici pa nts are e val uate d acc or di n g t o t he treat me nt assi g ne d at 
ra n d o misatio n.  
T he F A S will be t he a nal ysis s et f or all e n d p oi nt a nal yses  wit h t he e xce pti o n 
of t he P K a nal yses . 
P K S  
All p artici pa nts i n t he F A S w h o ha ve at least o ne detecta ble zi b ote nta n or 
da p a glifl ozi n plas ma c o nce ntrati o n meas ure me nt p ost -treat me nt. 
P har mac o ki n etic sa m ples c ollecte d after V isit 5  ma y be e xcl u de d fr o m t he 
P K S  a n d ma y be re p orte d o utsi de t he C S R.  
T he P K S will be use d f or all P K a nal yses.  
A b bre viati o ns: F A S: F ull A n al ysis Set; I C F: I nf or me d c o nse nt f or m; P K S: P har mac o ki netic A nal ysis Set; P K: 
P har mac o ki netics . 
9. 4  
St atistic al A n al yses   
9. 4. 1  
Ge ner al C o nsi de r ati o ns  
All res ults will be prese nte d b y trea t me nt gr o u p a n d o verall , as a p pr o priate , wit h descri pti ve 
statistics a p pr o priate t o t he nat ure of t he vari a bles. 
De m o gra p hic a n d baseli n e c haracteristics as well as pri or a n d c o n c o mita nt me dicati o n will be 
prese nte d. F or c o nti n u o us varia bles, t he n u m ber of n o n -missi n g o bser vati o ns, mea n, S D, 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 2  of 1 4 3  
 
me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d. F or cate g orical varia bles: c o u nts ( n) a n d 
perce nt a ges ( %) ( w h ere s pecifie d) will be prese nt e d. T hese s u m maries will be pr o vi de d b y 
ti me p oi nt of assess me nt, as a p pr o priat e. 
W he n c h a n ge fr o m baseli ne is descri be d, t he baseli ne val ue will be, i n ge n eral, t he last 
n o n -missi n g val ue pri or t o or o n t he sa me dat e as a d mi nistrati o n of t he first d ose. F urt her 
details will be descri be d i n t he S A P.  
I n ge neral, t here will be no i m p utati o n of missi n g data f or t he s afet y a nal yses. A d diti o nal 
details will be pr o vi de d i n t he S A P.  
De viati o ns fr o m t he pr ot oc ol will be assesse d as “i m p orta nt” or “ n ot -i m p orta nt”. I m p orta nt 
de viati o ns fr o m t he pr ot o c ol ma y lea d t o t he e x cl usi o n of parti ci pa nts fr o m a n y of t he st u d y 
a nal ysis sets. De viati o ns will be defi ne d bef ore cli nical data l oc k. I m p orta nt de viati o ns will 
i ncl u de t he f oll o wi n g: 
•  
Vi olati o n of i ncl usi o n a n d/ or e xcl usi o n criteri a  
•  
A d mi nistrati o n of pr o hi bite d c o nc o mita nt me dicati o ns t hat a re e x p ecte d t o i nfl ue nce t he 
meas ure me nt of t h e ke y e n d p oi nt s. 
 
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 cli nical data l oc k 
i n or der t o defi ne t h e a nal ysis sets f or t he st u d y. All t he i m p orta nt pr ot oc ol de viati o ns will be 
liste d b y partici pa nts. F urt her details will be descri be d i n t he S A P. 
9. 4. 2  
Ke y  E n d p oi nts   
T he a nal ysis of all ke y e n d p oi nts will be perf or m e d o n t he F A S. T he n o n -ter mi nal i nterc urre nt 
e ve nts (e g, tr eat me nt disc o nti n uati o ns d ue t o a n y reas o n, use of pr o hi bite d me dicati o n) will be 
ha n dle d b y a treat me nt p olic y strate g y. F or ter mi nal i nterc urre nt e ve nts (i e, deat h), a 
w hile -ali ve strate g y will be a p plie d. T he d etaile d esti ma n d attri b utes will be pr o vi de d i n S A P.  
F or fl ui d rete nti o n, t he c o m p osite e n d p oi nts  are d efi ne d as: 
•  
occ urre nce of a n y of t he f oll o wi n g e ve nts: ( 1)  >  2  k g i ncreas e i n b o d y wei g ht , ( 2) >  2  L 
i ncreas e i n t otal b o d y water, ( 3) i ncreas e i n 2 or m ore l o o p-di uretic e q ui val e nts , or 
( 4) fl ui d rete nti o n A Es, fr o m baseli ne t o Wee k 6  
•  
occ urre nce of eit her ( 1) > 3  L i ncreas e i n t otal b o d y water v ol u me fr o m bas eli ne t o 
Wee k  6 ; or ( 2) i ncrease i n 3 or m ore l o o p-di uretic e q ui vale nts use fr o m b aseli ne t o 
Wee k  6  
 
E xact 9 0 % (t w o -si de d) CIs f or pr o p orti o ns of p arti ci pa nt s wit h t he c o m p osite of fl ui d 
rete nti o n i n treat me nt gr o u ps will be calc ulate d usi n g t he Cl o p per -Pears o n met h o d. T he e xact 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 3  of 1 4 3  
u nc o n diti o nal 9 0 % (t w o -si de d) CIs f or differe nce i n pr o p orti o ns bet wee n 2  treat me nt gr o u ps 
will be c o m p ute d base d o n sc ore statistic ( C ha n a n d Z ha n g 1 9 9 9 ). 
T he c ha n g e i n b o d y wei g ht, b o d y water v ol u mes, t otal d osa ge of l o o p-di ur etic e q ui vale nts, 
b o d y fat mass , a n d bl o o d press ure fr o m baseli ne t o Wee k  6  will be a nal yse d usi n g M M R M 
met h o d ol o g y  f or pair wis e c o m paris o ns bet w ee n tr eat me nt gr o u ps. T he a nal ytic m o del will 
i ncl u de t he 
 of
, a n d 
, a n d 
 of t h e 
. A n 
 will be use d f or t h e 
F urt her d etails will be descri be d i n t he S A P.  
9. 4. 3  
S afet y  
Safet y a nal yses will be perf or me d usi n g t he F A S. Safet y data will be prese nte d usi n g 
descri pti ve statistics u nless ot her wise s pecifi e d. I n ge neral, t he b aseli ne v al ue f or statistical 
a nal ysis is t he last n o n missi n g val ue pri or t o a d mi nistrati o n of t he first d ose of st u d y 
i nter ve nti o n. Details will be descri b e d i n t he S A P. 
9. 4. 3. 1  
A d verse E ve nts   
A d verse e ve nts will be c o de d usi n g t he m ost  rece nt versi o n of t he Me d D R A t hat will ha ve 
bee n rel ease d f or e x ec uti o n at Astra Z e neca or desi g nee.  
A d verse e ve nts will be prese nte d f or eac h treat me nt gr o u p b y s yste m or ga n class a n d/ or 
preferre d t er m c o veri n g n u m ber a n d perce nt a ge of partici pa nts re p ort i n g at least o ne  e ve nt.  
O nl y A Es occ urri n g wit h a n o nset date, or w orse ni n g, o n or after first d ose of st u d y 
i nter ve nti o n, t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w-u p peri o d will be 
prese nte d i n s u m mar y ta bles. S A Es occ urri n g pri or t o start  of st u d y i nter ve nti o n will be 
i ncl u de d i n data listi n gs. 
A n o ver vie w of A Es will be prese nt e d f or eac h tr eat me nt gr o u p; t he n u m ber a n d perce nta ge of 
partici pa nts wit h a n y A E, A Es wit h o utc o me of d eat h, S A Es, A Es lea di n g t o disc o nti n uati o n 
of st u d y i nter venti o n , A Es lea di n g t o st u d y i nter ve nti o n d ose i nterr u pti o ns , a n d A E SIs.  
Se parate A E ta bles will be pr o vi de d ta ki n g i nt o c o nsi derati o n relati o ns hi p as assesse d b y t he 
i n vesti gat or a n d ma xi m u m i nte nsit y, seri o us ness, deat h, a n d A Es lea di n g t o disc o nti n uati o n of 
st u d y i nter ve nti o n, as well as acti o n ta ke n wit h res pect t o t he st u d y i nter ve nti o n, a n d ot her 
si g nifica nt A Es. 
Ke y partici pa nt i nf or mati o n will be prese nte d f or partici pa nts wit h A Es wit h o utc o me of 
deat h, S A Es, a n d A Es lea di n g t o disc o nti n uati o n of st u d y i nter ve nti o n. A n A E listi n g f or t he 
F A S will c o ver details f or eac h i n di vi d ual A E; a n A E listi n g f or partici pa n ts w h o were n ot 
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 4  of 1 4 3  
e x p ose d t o st u d y i nter ve nti o n is prese nte d se parat el y. 
F ull details of A E a nal ys es will be pr o vi de d i n t he S A P.  
9. 4. 3. 2  
Vit al Si g ns   
Vital si g n para meters ( s u pi ne a n d sta ndi n g  bl o o d press ure, p ulse, a n d b o d y te m perat ur e) will 
be prese nt e d f or eac h tr eat me nt gr o u p.  
F or eac h sc h e d ule d p ost -baseli ne visit, descri pti ve statistics f or all vital si g n para meters will 
be prese nt e d f or o bs er ve d val ues a n d c h a n ge fr o m baseli ne.  
S u p p o rti ve vital si g n listi n gs c o ver o bser ve d val u es a n d c ha n ges fr o m bas eli ne as well as 
a b n or malities.  
Details of vital si g n a nal yses i ncl u di n g defi niti o n of a b n or malit y criteria (e g, defi niti o n of l o w, 
n or mal, hi g h) a n d pr oje ct -s pecific pre defi ne d criteria for treat me nt -e m er ge nt c ha n ges i n 
rele va nt vital si g n para meters (e g, s yst olic a n d di ast olic bl o o d press ure) will be pr o vi de d i n 
t he S A P. 
9. 4. 3. 3  
L a b or at or y Assess m e nts   
La b orat or y p ara m et ers will be prese nte d f or eac h treat me nt gr o u p.  
F or eac h sc h e d ule d p ost -baseli ne visit, descri pti ve statistics f or all cli nical c he mistr y, 
electr ol yte, c o a g ulati o n , a n d hae mat ol o g y para meters will be prese nt e d f or o bser ve d val u es 
a n d c ha n g e fr o m bas eli ne.  
Ele vati o n i n li ver para m eters f or ass ess me nt of H y’s la w (see  A p pe n di x E ) will be d o ne a n d 
re p orte d a p pr o priat el y if p ote ntial cases ha v e bee n i de ntifie d d uri n g t he c o urse of t he st u d y. 
Ke y partici pa nt i nf or mati o n will be prese nte d f or partici pa n ts wit h treat me nt-e mer g e nt 
c ha n ges i n la b orat or y para meters o utsi de of pre defi ne d criteria.  
S u p p orti ve la b orat or y listi n gs will c o ver o bser ve d val ues a n d c h a n ges fr o m baseli ne f or eac h 
i n di vi d ual partici pa nt as well as a b n or malities. 
Details of la b orat or y a nal yses i ncl u di n g defi niti o n of a b n or malit y criteria (e g, defi niti o n of 
l o w, n or mal, hi g h) a n d st u d y-s pecific pre defi ne d criteria f or tr eat me nt -e mer ge nt c ha n ges i n 
rele va nt la b orat or y para meters will be pr o vi de d i n t he S A P. 
9. 4. 3. 4  
Electr oc a r di o gr a ms   
Electr ocar di o gra m fi n di n gs will be liste d f or eac h partici pa nt a n d will i ncl u de t he E C G 
para meters ( w h ere a p plica ble) a n d c ha n ges fr o m b aseli ne, assess me nt b y t h e i n vesti gat or 
( n or mal/a b n or mal n ot cli nicall y si g nifica nt/a b n or mal cli nicall y si g nifica nt) a n d details of a n y 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 5  of 1 4 3  
 
a b n or malities. E C G para meters will be s u m marise d b y ti me -p oi nt i ncl u di n g c ha n ges fr o m 
baseli ne. T he b aseli ne f or t he safet y E C G para m eters will be t he res ults o bt ai ne d pre -d ose o n 
Da y  1.  
E C G para meters t o be ta b ulate d will be pr o vi de d i n t he S A P.  
9. 4. 4  
E x pl or at o r y e n d p oi nts   
9. 4. 4. 1  
E x pl or at or y P h ar m ac o ki netic E n d p oi nts   
Plas ma c o nce ntr ati o ns of zi b ote nta n a n d da p a glifl ozi n will be s u m marise d b y treat me nt gr o u p, 
visit, a n d ti me -p oi nt  base d o n t he P K S.  
A d diti o nal P K a nal yses ma y be c o n d uct e d as ap pr o priate b ut  will be re p orte d o utsi de t he 
C S R.  
F urt her details of t his will be pr o vi de d i n t he S A P.  
9. 4. 4. 2  
E x pl or at or y P h ar m ac o d y n a mic a n d Bi o m ar ker E n d p oi nts   
T he e x pl orat or y P D a n d b i o mar ker e n d p oi nts des cri be d i n Secti o n 8. 2. 2. 3  will be s u m marise d 
b y treat me nt gr o u p a n d ti me -p oi nt  base d o n t he F A S . 
F urt her details o n t his will be pr o vi de d i n t he S A P.  
9. 4. 4. 3  
E x pl or at or y P R O E n d p oi nts   
Res ults f or p atie nt-re p orte d o utc o mes will be s u m marize d b y tr eat me nt gr o u p f or F A S. 
F urt her details o n t his will be pr o vi de d i n t he S A P.  
9. 4. 4. 4  
Ot her E x pl or at or y E n d p oi nts   
Perce nta g e a n d a bs ol ute c ha n ge i n  
 a n d/ or 
 assesse d usi n g 
 at Wee k 6, c ha n ge i n e G F R at Wee k  1, Wee k  6, a n d e v al uati o n of c ha n ges i n 
bl o o d bi o mar kers acr oss ti me c o urse of t he st u d y will be a nal yse d acc or di n g t o treat me nt 
gr o u p. F or details o n e x pl orat or y o bjecti ves a n d e n d p oi nts, see Secti o n  3 . 
F urt her details a b o ut a nal yses of e x pl orat or y e n d p oi nts will be pr o vi de d i n t he S A P.  
9. 4. 4. 5  
E x pl or at or y Rese a rc h a n d O pti o n al Ge netic Rese arc h   
T he f oll o wi n g a nal yses will n ot be part of t he C S R:  
•  
E val uati o n of c ha n g es i n ot her bl o o d a n d uri ne bi o mar kers, n ot o utli ne d i n t his pr ot oc ol, 
b ut rele va nt t o li ver diseases a n d dr u g -relate d mec ha nis ms o ver t he ti me c o urse of t he 
st u d y. 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 6  of 1 4 3  
•
O pti o nal e x pl orat or y researc h i nt o ge nes/ g e netic v ariati o n t hat ma y i nfl ue nce res p o ns e t o
treat me nt.
A nal yses f or t hes e e x pl or at or y o bjecti ves will be d escri be d i n a s e parate a n al ysis pla n a n d 
results will be prese nte d se parat el y fr o m t he mai n C S R.  
9. 5  
I nteri m A n al yses 
N ot a p plica bl e.  
9. 6  
D at a M o nit ori n g C o m mittee  
A D M C will m o nit or o n g oi n g safet y/t olera bilit y data (i ncl u di n g m o nit ori n g of m o difie d  
 
 a n d  
 i ncl u di n g 
) a n d ha ve t he a ut h orit y 
t o u n bli n d a partici pa nt’s i nter ve nti o n assi g n me nt d ue t o safet y c o ncer ns if warra nte d. T he 
D M C will be as ke d t o meet at re g ul ar i nter val s a n d ma y als o meet m ore oft e n if t he y t hi n k it 
is nee de d fr o m a safet y pers pecti ve. T he D M C ma y rec o m me n d sto p pi n g  f urt her recr uit me nt 
a n d/ or treat me nt of p artici pa nts i n a treat me nt gr o u p at a n y ti me after a c o m pre he nsi ve 
assess me nt of safet y data. T he rec o m me n dati o n will be e val uate d b y a n u n bli n de d se ni or 
ma na ger w h o will pr o vi de a decisi o n base d o n t he D M C r ec o m me n dati o n t o t he st u d y tea m. 
F urt her details will be pr o vi de d i n a  se parate D M C c harter. 
F or details o n t he D M C, refer t o A p pe n di x A  5 . 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 7  of 1 4 3  
 
1 0  
S U P P O R T I N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S   
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 8  of 1 4 3  
 
A p pe n di x  A  Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns   
A  1  
Re g ul at or y a n d Et hic al C o nsi der ati o ns   
•  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi n g:  
− 
C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes  
− 
A p plica ble I C H G C P G ui de li nes 
− 
A p plica ble la ws a n d re g ulati o ns  
•  
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vesti gat or's Br oc h ure, a n d ot h er rel e va nt 
d oc u me nts (e g, a d v ertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d 
re vie we d a n d a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d. 
•  
A n y re vise d pr ot o c ol will re q uire I R B/I E C a n d a p plica ble Re g ulat or y A ut h orit y a p pr o val 
bef ore i m ple me nt ati o n of c ha n ges ma d e t o t he st u d y desi g n, e xce pt f or c ha n ges necess ar y 
t o eli mi nate a n i m me diate hazar d t o st u d y partici p a nts. 
•  
Astr a Ze neca will be res p o nsi ble f or o btai ni n g t he re q uire d a ut h orisati o ns t o c o n d uct t he 
st u d y fr o m t he c o ncer ne d Re g ulat or y A ut h orit y. T his res p o nsi bilit y ma y be dele gate d t o a 
C R O, b ut t he acc o u nta bilit y re mai ns wit h Astra Ze neca.  
•  
T he i n vesti gat or will be res p o nsi ble f or pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at 
t he site a n d a d here nce t o re q uire me nts of 2 1 C F R 3 1 2. 1 2 0 , I C H g ui deli nes, t he I R B/I E C, 
E ur o pea n Re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), E ur o pea n Me dical 
De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vi ce researc h (if a p plica ble), a n d all ot her 
a p plica ble l ocal re g ulati o ns . 
 
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es  
•  
Pr o m pt n otificati o n b y t he i n vesti gat or t o Astra Ze neca  of a n S A E is esse nti al s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of 
a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
•  
Astra Ze neca  h as a le g al r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he sa fet y of a st u d y i nter ve nti o n u n der cli nical 
i n vesti gati o n. Astra Ze neca  will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts 
relati n g t o safet y r e p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors.  
•  
I n t he E U, t he S p o ns or will c o m pl y wit h safet y re p orti n g re q uire me nts a n d pr oce d ures as 
descri be d i n t he E ur o pea n Cli nical Trials Re g ulati o n ( E U) N o 5 3 6/ 2 0 1 4. All S U S A Rs t o 
i n vesti gati o nal me dici nal pr o d uct will be re p ort e d t o t he E u dra Vi gila nce data base wit hi n 
t he re q uire d re g ulat or y ti meli nes. 

Cli ni cal St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 9  of 1 4 3  
 
•  
F or all st u dies e xce pt t h ose utilisi n g  me dical de vices, i n vesti gat or safet y re p orts m ust be 
pre pare d f or S U S A Rs, acc or di n g t o l ocal re g ul at or y re q uire me nts a n d s p o ns or p olic y a n d 
f or war de d t o i n vesti gat ors as necess ar y. 
− 
E ur o pea n Me dical De vi ce Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice res earc h (if 
a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns  
•  
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A Es) fr o m Astra Ze n eca  will 
re vie w a n d t h e n file it al o n g wit h t he I n v esti gat or's Br oc h ure a n d will n otif y t he I R B/I E C, 
if a p pr o priate acc or di n g t o l ocal re q uir e me nts. 
 
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us Bre ac hes of Pr ot oc ol or G C P  
Pr o m pt n otificati o n b y t he I n vesti gat or t o Astra Ze neca of a n y ( p ote ntial) s eri o us breac h of t he 
pr ot oc ol or re g ulati o ns is esse ntial s o t hat le gal a n d et hical o bli gati o ns are met.  
A “seri o us breac h” me a ns a breac h li kel y t o affect t o a si g nifica nt de gree t h e safet y 
a n d ri g hts of a p artici pa nt or t he relia bilit y a n d r o b ust ness of t he data ge n erate d i n t he 
cli nical st u d y.  
Astra Ze neca will c o m pl y wit h c o u ntr y -s pecifi c re g ulat or y re q uire m e nts rel ati n g t o seri o us 
breac h re p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d in vesti gat ors.  
W h ere t h e E U Cli nical Trials Re g ulati o n 5 3 6/ 2 0 1 4 a p plies, Astra Z e neca h as i n place 
pr ocesses t o e nt er details of seri o us breac hes i nt o t he E ur o pea n Me dici nes A ge nc y 
C TI S. It is i m p orta nt t o n ote t hat re dacte d versi o ns of seri o us breac h re p orts will be 
a vailable t o t he p u blic vi a C TI S.  
If a n y ( p ote ntial) seri o us breac h o cc urs i n t he c o urse of t he st u d y, I n vesti gat ors or ot her site 
pers o n nel will i nf or m t he a p pr o priate Astra Ze neca re pres e ntati ves i m me diatel y.  
I n cert ai n re gi o ns/c o u ntri es, Astra Ze neca has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal 
re g ulat or y a ut h orit y a n d ot her re g ulat or y a ge n cies a b o ut s uc h breac hes. 
T he i n vesti gat or s h o ul d ha ve a pr ocess i n place t o e ns ure t hat:  
•  
T he site staff or s er vice pr o vi ders dele gate d b y t he i n vesti gat or/i nstit uti o n are a ble t o 
i de ntif y t he occ urre nce of a ( p ote ntial) s eri o us breac h 
•  
A ( p ote ntial) seri o us breac h is pr o m ptl y re p orte d t o Astra Ze neca or dele gate d part y, 
t hr o u g h t he c o ntacts ( e mail a d dress or tel e p h o ne n u m ber) pr o vi de d b y Astra Ze neca. 
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 0  of 1 4 3  
 
A  2  
Fi n a nci al Discl os ure   
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de Astra Ze neca wit h s uffi cie nt, acc urate 
fi na ncial i nf or mati o n as re q ueste d t o all o w Astra Z e neca t o s u b mit c o m plete a n d acc urate 
fi na ncial certificati o n or discl os ure state me nts t o t he a p pr o pri ate re g ul at or y a ut h orities. 
I n v esti gat ors are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he st u d y 
a n d f or o ne y ear after c o m pleti o n of t he st u d y.  
A  3  
I nf or me d C onse nt Pr ocess   
•  
T he i n vesti gat or or t heir re pres e ntati ve will e x plai n t he nat ure of t h e st u d y t o t he 
partici pa nt a n d a ns wer all q uesti o ns re gar di n g t he st u d y.  
•  
Partici pa nts m ust be i n f or me d t hat t heir partici p ati o n is v ol u ntar y, a n d t he y are free t o 
ref use t o partici pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me a n d f or a n y reas o n 
d uri n g t he st u d y. Partici pa nts will be re q uire d t o si g n a state me nt of i nf or m e d c o nse nt t hat 
meets t he re q uir e me nts of 2 1  C F R  5 0, l ocal re g ul ati o ns, I C H g ui deli nes, pri vac y a n d d ata 
pr otecti o n re q uir e me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y ce ntr e.  
•  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d 
bef ore t h e parti ci pa nt w as e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h orise d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.  
•  
If ne w i nf or mati o n re q uir es c ha n ges t o t he I C F, c o nsi der if partici pa nts m ust be 
re-c o ns e nte d a n d i f s o, t his m ust be t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y.  
•  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt . 
 
Partici pa nts w h o are rescree ne d are re q uir e d t o si g n a ne w I C F.  
T he I C F will c o ntai n a se parate  s ecti o n t hat a d dresses a n d d oc u me nts t he c ollecti o n a n d use of 
a n y ma n dat or y a n d/ or o pti o nal H u ma n Bi ol o gical Sa m ples. T he i n vesti gat or or a ut h orise d 
desi g nee will e x plai n t o e ac h partici p a nt t he o bjecti ves of t he a nal ysis t o be d o ne o n t he 
sa m ples a n d a ny p ote ntial f ut ure use. Partici pa nts will be t ol d t hat t he y are free t o r ef use t o 
partici pate i n a n y o pti o nal sa m ples or f ut ure use, a n d ma y wit h dra w t heir c o nse nt at a n y ti me 
a n d f or a n y reas o n d uri n g t he rete nti o n peri o d.  
A  4  
D at a Pr otecti o n   
•  
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y Astra Ze neca. A n y parti ci pa nt rec or ds 
or datasets t hat are tra nsferre d t o Astra Ze n eca will c o ntai n t he i de ntifier o nl y; parti ci pa nt 
na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be 
tra nsferre d. 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 1  of 1 4 3  
 
•  
T he partici pa nt m ust be i nf or me d t hat t heir pers o nal st u d y -relate d d ata will be use d b y 
Astra Ze neca i n a cc or da n ce wit h l ocal data pr otecti o n la w. T he le v el of discl os ure a n d use 
of t heir data m ust als o be e x plai ne d t o t he partici p a nt i n t he i nf or me d c o nse nt.  
•  
T he partici pa nt m ust be i nf or me d t hat t heir me dical rec or ds ma y be e x a mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orise d pers o n nel a p p oi nte d b y Astr a Ze neca, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.  
•  
T he partici pa nt m ust be i nf or me d t hat data will be c ollecte d o nl y f or t h e b usi ness nee ds. 
We will o nl y c ollect a n d use t he mi ni m u m a m o u nt of pers o nal d ata t o s u p p ort o ur 
b usi ness acti vities a n d will n ot ma ke pers o nal data a vaila ble t o a n y o n e (i ncl u di n g i nter nal 
staff) w h o is n ot a ut h oris e d or d oes n ot ha v e a b usi ness nee d t o k n o w t he i nf or mati o n.  
•  
T he partici pa nt m ust be i nf or me d t hat i n s o me cas es t heir data ma y be pse u d o n y mise d. 
T he Ge neral dat a Pr otecti o n Re g ul ati o n ( G D P R) defi nes pse u d o n y misati o n as t he 
pr ocessi n g of pers o nal data i n s uc h a wa y t hat t he pers o nal data ca n n o l o n g er be 
attri b ute d t o a s pecific i n di vi d ual wit h o ut t he use of a d diti o nal i nf or mat i o n, pr o vi de d t hat 
s uc h a d diti o nal i nf or mati o n is ke pt se paratel y a n d pr otecte d b y tec h nical a n d 
or ga nisati o nal meas ur es t o e ns ure t hat t he pers o nal data are n ot attri b ute d t o a n i de ntifie d 
or i de ntifia ble nat ur al pers o n.  
 
Pers o n al D at a Bre a c hes  
A ‘ pers o nal data breac h’ mea ns a breac h of sec urit y lea di n g t o t he acci de ntal or u nla wf ul 
destr ucti o n, l oss, alterati o n, u na ut h orise d discl os ure of, or access t o, pers o nal data tra ns mitte d, 
st ore d or ot her wis e pr ocesse d. 
•  
I n c o m plia nce wit h a p pli ca ble la ws, the Data C o ntr oller f or t he pr o cessi n g acti vit y w here 
t he pers o nal dat a breac h occ urre d ( Astr a Ze n eca or res pecti vel y t he site), will n otif y t he 
data pr otecti o n a ut h orities wit h o ut u n d ue dela y wit hi n t he le gal ter ms pr o vi de d f or s uc h 
n otificati o n a n d wit hi n t he prescri be d f or m a n d c o nte nt. 
•  
W hilst Astra Ze neca has pr ocesses i n place t o deal wit h pers o nal data breac hes it is 
i m p orta nt t hat i n vesti gat ors t hat w or k wit h Astra Ze neca ha ve c o ntr ols i n place t o pr otect 
patie nt data pri vac y.  
 
T he in vesti gat or s h o ul d ha ve a pr ocess i n place t o e ns ure t hat:  
•  
T he y all o w site staff or ser vice pr o vi ders del e gate d b y t he i n vesti gat or/i nstit uti o n t o 
i de ntif y t he occ urre nce of a ( p ote ntial) p ers o nal d ata breac hes. 
•  
A n y ( p ote ntial) pers o n al data breac h is pr o m ptl y re p orte d t o Astr a Z e neca or dele gate d 
part y, t hr o u g h t he c o nta cts (e -mail a d dress or tele p h o ne n u m ber) pr o vi de d b y 
Astra Ze neca.  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 2  of 1 4 3  
 
Astra Ze neca a n d t he site m ust de m o nstrate t hat t he y:  
•  
H a ve ta k e n all necessar y ste ps t o a v oi d pers o nal d ata breac hes a n d  
•  
H a ve u n derta ke n me as ur e s t o pre ve nt s uc h breac h es fr o m occ urri n g i n t he first place a n d 
t o miti gate t he i m pact of occ urre d data breac hes (e g, a p pl yi n g e ncr y pti o n, mai ntai ni n g 
a n d kee pi n g s yste ms a n d I T s ec urit y meas ures u p -t o-date, re g ular re vie ws a n d testi n g, 
re g ular tr ai ni n g of e m pl o yees, a n d de v el o pe d sec urit y p olicies a n d sta n dar ds). 
•  
W here p ossi ble, h a ve de vel o pe d a n i nter nal data breac h re p orti n g a n d i n v esti gati o n 
pr ocess a n d i nter nal pr ot oc ols wit h g ui da nce o n h o w t o res p o n d s wiftl y a n d dili ge ntl y t o 
t he occ urre nce of a p ers o nal data breac h. 
•  
W here it has n ot b ee n p ossi ble t o de vel o p a n i nter nal data breac h re p orti n g a n d 
i n vesti gati o n pr ocess, t he site f oll o ws Astra Ze neca’s i nstr ucti o ns. 
 
N otificati o n of pers o n al Data Breac h t o partici p a nts:  
•  
N otificati o n t o partici pa nts is d o ne b y t he site f or t he data breac h es t hat occ urre d wit hi n 
t he pr ocessi n g acti vities f or w hic h t he site is t he Data C o ntr oller a n d f or dat a breac hes 
occ urre d wit hi n t he pr ocessi n g acti vities of Astra Ze neca as t he Data C o ntr oller, t he 
n otificati o n is d o ne i n  c olla b orati o n wit h t he site a n d is perf or me d b y t he site a n d/ or 
Pri nci pal I n v esti gat or, acti n g o n be half of Astra Z e neca, s o t hat Astra Ze n eca has n o access 
t o t he i de ntif yi n g pers o nal i nf or mati o n of t he partici pa nts. T he site a n d/ or Pri nci pal 
I n v esti gat or s hall c o n d uct t he n otificati o n b y c o ntacti n g t he partici pa nts usi n g t he 
i nf or mati o n t hat t he y ga v e f or c o m m u nicati o n p ur p oses i n cli nical researc h. 
•  
If a pers o nal data breac h occ urs i n a pr ocess or’s s yste ms, e n ga ge d b y Astra Ze neca, t he 
pr ocess or u n d er c o ntr act ual o bli gati o ns wit h Astra Ze neca pr o m ptl y a n d i n d ue c o urse 
after disc o v eri n g t he breac h n otifies Astra Ze n eca a n d pr o vi des f ull c o o perati o n wit h t he 
i n vesti gati o n. I n t hese cases, t o t he e xte nt Astra Z e neca is t he Data C o ntr oller f or t he 
pr ocessi n g acti v it y w here t he breac h occ urre d, it will be res p o nsi ble f or t he n otificati o n t o 
data pr otecti o n a ut h orities a n d, if a p plica ble, t o p artici pa nts. If t he pers o nal data breac h 
nee ds t o be n otifie d t o t h e partici pa nts, t he n otificati o n t o partici pa nts is d o ne i n  
c olla b orati o n wit h t he site a n d is perf or me d b y t he site a n d/ or Pri nci pal I n v esti gat or, 
acti n g o n be half of t he S p o ns or, s o t hat Astra Ze n eca h as n o access t o t he i de ntif yi n g 
pers o nal i nf or mati o n of t he partici pa nts.  
•  
If a pers o nal data breac h i n v ol vi n g a n Astra Ze neca's re prese ntati ve de vice ( ie, St u d y 
M o nit or la pt o p), Astra Ze neca re prese ntati ve will pr o vi de Astra Z e neca wit h all of t he 
i nf or mati o n nee de d f or n otificati o n of t he breac h, wit h o ut discl osi n g data t hat all o ws 
Astra Ze neca dir ectl y or i n directl y t o  i de ntif y t he partici pa nts. T he n otificati o n will be 
d o ne b y Astra Z e neca s olel y wit h t he i nf or mati o n pr o vi de d b y t he St u d y M o nit or a n d i n 
n o e ve nt wit h access t o i nf or mati o n t hat c o ul d e nt ail a ris k of re -i de ntificati o n of t he 
partici pa nts. If t he d ata bre ac h m ust be n otifie d t o t he data s u bjects, t he n otificati o n will 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 3  of 1 4 3  
 
be d o ne directl y b y t he St u d y M o nit or i n c olla b orati o n wit h t he site a n d/ or Pri nci pal 
I n v esti gat or, acti n g o n be half of t he S p o ns or, s o t h at Astra Ze n eca h as n o access t o t he 
i de ntif yi n g pers onal i nf or mati o n of t he partici pa nts. T he c o ntract bet wee n Astra Ze neca 
a n d t he St u d y M o nit or s hall e x pressl y s pecif y t h es e c o n diti o ns.  
•  
T he c o ntract bet wee n t he site a n d Astra Ze n eca f or perf or mi n g t he cli nical r esearc h 
i ncl u des t he pr o visi o ns a n d r ules re gar di n g w h o is res p o nsi ble f or c o or di nati n g a n d 
directi n g t he acti o ns i n relati o n t o t he breac h es a n d perf or mi n g t he ma n dat or y 
n otificati o ns t o a ut h orities a n d partici pa nts, w here a p plica ble.  
 
A  5  
C o m mittees Str uct ure   
A D M C will be set  u p f or t his st u d y i n acc or da nce wit h t he Astra Z e neca c h arter f or data 
re vie w c o m mittees. 
T he safet y of all Astr a Ze neca cli nical st u dies is cl osel y m o nit ore d o n a n o n g oi n g basis b y 
Astra Ze neca re prese n tati ves i n c o ns ultati o n wit h Patie nt Safet y. Iss ues i de ntifie d will be 
a d dresse d; f or i nsta nce, t his c o ul d i n v ol ve a me n d me nts t o t he pr ot oc ol a n d letters t o 
i n vesti gat ors. 
A  6  
Disse mi n ati o n of Cli nic al St u d y D at a   
A n y res ults b ot h tec h nical a n d la y s u m maries f or t his trial, will be  s u b mitte d t o E U C TI S wit hi n 
a year fr o m gl o bal E n d of Trial Dat e i n all  partici pati n g c o u ntries, d ue t o s cie ntific reas o ns, as 
ot her wise statistical a nal ysis is n ot rele va nt. 
A descri pti o n of t his cli nical st u d y will be a vaila ble o n w w w. astraze necacli nicaltrials.c o m 
[ htt p:// w w w.cli nicaltrials. g o v] a n d htt ps://e ucli nicaltrials.e u/ as will t he s u m mar y of t he mai n 
st u d y res ults w he n t he y are availa bl e. T he cli nical st u d y a n d/ or s u m mar y of mai n st u d y res ults 
ma y als o be a vaila bl e o n ot her we bsites acc or di n g t o t he re g ulati o ns of t h e c o u ntries i n w hic h 
t he mai n st u d y is c o n d ucte d. Descri be s p o ns or -s p ecific p olic y o n pr o visi o n of st u d y res ults. 
A  7  
D at a Q u alit y Ass ur a nce   
•  
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n e C R F u nless tr a ns mitte d t o 
Astra Ze neca or desi g nee electr o nicall y (e g, la b orat or y data). T he i n v esti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y electr o nicall y 
si g ni n g t he e C R F. 
•  
T he i n vesti gat or m ust mai ntai n acc urate d oc u me nt ati o n (s o urce d ata) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e e C R F. 
•  
T he i n vesti gat or  m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a g e nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. 
•  
M o nit ori n g details descri bi n g strate g y, i ncl u di n g defi niti o n of st u d y -critical data ite ms 
a n d pr ocess es (e g , ris k-b ase d i nitiati ves i n o perati o ns a n d q ualit y s uc h as Ris k 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 4  of 1 4 3  
 
Ma na ge me nt a n d Miti gati o n Strate gies a n d A nal ytical Ris k -base d M o nit ori n g), met h o ds, 
res p o nsi bilities a n d re q uire me nts, i ncl u di n g ha n dli n g of n o n-c o m plia nce  iss ues a n d 
m o nit ori n g tec h ni q ues (c e ntral, re m ote, or o n -site m o nit ori n g) are i ncl u de d i n t he 
M o nit ori n g Pla n  
•  
Astra Ze neca or desi g nee is res p o nsi ble f or me dical o versi g ht t hr o u g h o ut t he c o n d uct of 
t he st u d y w hic h i ncl u des cli nical re vie ws of st u d y data i n acc or da n ce wit h t he c urre ntl y 
a p pr ove d pr ot o c ol. M o nit ori n g details descri bi n g cli nical re vie ws of st u d y data fr o m a 
me dical pers p ecti ve are i ncl u de d i n m ore detail i n t he Me dical O versi g ht Pla n.  
•  
Astra Ze neca or desi g nee is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y i ncl u di n g 
q ualit y c hec ki n g of t he d ata.  
•  
Astra Ze neca ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals (e g, 
C R Os).  
•  
St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n as p er t he 
M o nit ori n g  Pla n(s) t o c o nfir m t hat data e ntere d i nt o t he e C R F b y a ut h ori se d site 
pers o n nel are acc urate, c o m plete, a n d verifi a ble fr o m s o urce d oc u me nts; t h at t he safet y 
a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d i n 
acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her st u d y a g ree me nts, I C H 
G C P, a n d all a p plica ble re g ulat or y re q uir e me nts.  
•  
Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he i n vesti gat or f or 1 5  years after st u d y c o m pleti o n u nless l ocal 
re g ulati o ns or i nstituti o nal p olicies re q uire a l o n g er ret e nti o n peri o d. N o rec or ds ma y be 
destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t h e s p o ns or. N o 
rec or ds ma y b e tra nsferre d t o a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o t he 
s p o ns or. 
 
A  8  
S o urce D oc u me nts   
•  
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he p artici pa nt a n d s u bsta ntiate 
t he i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he i n v esti gat or’s site. 
•  
Data e ntere d i n t he e C R F t hat are tr a nscri be d fr o m s o urce d oc u m e nts m ust be c o nsiste nt 
wit h t he s o urce d oc u m e nts or t he discre pa n cies m ust be e x plai ne d. T he i n v esti gat or ma y 
nee d t o re q u est pre vi o us me dical rec or ds or tr a nsfer rec o r ds, de p e n di n g o n t he st u d y. 
Als o, c urre nt me dic al rec or ds m ust be a vaila ble.  
•  
Defi niti o n of w hat c o nstit utes s o urce data a n d its ori gi n ca n be f o u n d i n s o urce dat a 
ac k n o wle d g me nt or m o nit ori n g g ui deli nes.  
 
A  9  
St u d y a n d Site St art a n d Cl os ure   
T he st u d y start date is t he date o n w hic h t h e cli nical st u d y will be o pe n f or recr uit me nt of 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 5  of 1 4 3  
 
partici pa nts.  
T he first act of recr uit me nt is t he first partici pa nt scree n e d a n d i nc l u d e d i n t he st u d y (ie, w h o 
si g ne d c o nse nt) a n d will be t he st u d y start date. 
Astra Ze neca d esi g nee res er ves t he ri g ht t o cl ose t h e st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti o n of Astra Z e neca. St u d y sites will be cl osed u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl os e d w he n all re q uire d d o c u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d a n d a st u d y  site cl os ure visit has bee n perf or m e d. 
T he i n vesti gat or ma y i nitiate st u d y  site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y Astra Ze neca or t h e i n vesti gat or ma y i ncl u de 
b ut are n ot li mite d t o:  
•  
Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr o t oc ol, t he re q uir e me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, Astra Ze neca’s pr oce d ures, or G C P g ui deli nes  
•  
I n a de q uat e recr uit me nt of partici pa nts b y t he i n vesti gat or 
•  
Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt  
 
If t he st u d y is pre mat urely ter mi nate d or s us pe n de d, Astra Z e neca s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he I R Bs/I E Cs, t he re g ulat or y a ut h orities, a n d a n y C R Os use d i n t he st u d y of t he 
reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y re q uire m e nts. 
T he i n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt a n d s h o ul d ass ure a p pr o priate 
partici pa nt t hera p y a n d/ or f oll o w -u p.  
A  1 0  
P u blic ati o n P olic y   
•  
T he res ults of t his st u d y ma y be p u bl is he d or pres e nte d at scie ntific meeti n gs. If t his is 
f oresee n, t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o Astra Ze neca 
bef ore s u b missi o n. T his all o ws Astra Ze n eca t o pr otect pr o prietar y i nf or mati o n a n d t o 
pr o vi de c o m me nts.  
•  
Astra Ze neca  will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical pr actice, Astra Ze n eca will ge nerall y 
s u p p ort p u blicati o n of m ultice ntre st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site 
data. I n t his case, a c o or di nati n g i n vesti gat or will be desi g nate d b y m ut ual a gree m e nt.  
•  
A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nt er nati o nal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 6  of 1 4 3  
 
A  1 1  
St u d y P artici p a nt Fee d b ac k Q uesti o n n aire   
N ot a p plica ble.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 7  of 1 4 3  
A  1 2  
Cli nic al O utc o me Assess me nt /P atie nt -re p orte d O utc o me 
Q uesti o n n aire s 
C hr o nic Li ver Dise ase Q uesti o n n aire ( C L D Q)  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: C L D Q w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 8  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: C L D Q w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 9  of 1 4 3  
 
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: C L D Q w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 0  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: C L D Q w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 1  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: C L D Q w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 2  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: C L D Q w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 3  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 4  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 5  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 6  of 1 4 3  
 
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 7  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 8  of 1 4 3  
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0 9  of 1 4 3  
 
P atie nt Gl o b al I m pressi o n of Se verit y - Li ver Dise ase ( P GI S - Li ver Dise ase) 
Q uesti o n n aire   
P ati e nt R e p ort e d O ut c o m e Q u e sti o n n air e: P GI S w a s r e m o v e d d u e t o c o p yri g ht s.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 0  of 1 4 3  
 
A p pe n di x  B  A Es: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E v al u ati n g, 
F oll o w -u p, a n d Re p orti n g   
B  1  
Defi niti o n of A Es   
A n A E  is t he de v el o p me nt of a n y u nt o war d me di cal occ urre n ce i n a p atie nt or cli nical st u d y 
partici pa nt a d mi nistere d a me dici nal pr o d uct, a n d w hic h d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v o ura ble a n d uni nte n de d si g n 
(e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na us ea, c hest pai n), or diseas e 
te m p orall y ass ociate d wit h t he use of a me di ci nal pr o d uct, w het her or n ot r elate d t o t he 
me dici nal pr o d uct.  
T he ter m A E is use d t o i ncl u de b ot h seri o u s a n d n o n-seri o us A Es a n d a d eteri orati o n of a pre -
e xisti n g me dical occ urre nce. A n A E ma y occ ur at a n y ti me, i ncl u di n g r u n -i n or was h o ut 
peri o ds, e ve n if n o st u d y i nter ve nti o n has bee n a d mi nistere d.  
B  2  
Defi niti o n of S A Es   
A n S A E is a n A E occ urri n g d uri n g a n y st u d y P hase (ie, r u n -i n, treat me nt, w as h o ut, 
f oll o w-u p), t hat f ulfils o n e or m ore of t h e f oll o wi n g criteria:  
•  
Res ults i n deat h.  
•  
Is i m me diatel y life-t hreate ni n g. 
•  
Re q uires i n-patie nt h os pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalisati o n.  
•  
Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y.  
•  
Is a c o n ge nital a n o mal y or birt h defect. 
•  
Is a n i m p orta nt me dical e ve nt t hat ma y je o par dise t he partici pa nt or ma y re q uire me dical 
treat me nt t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
 
A d verse E v e nts f or m ali g n a nt t u m o urs  re p orte d d uri n g a st u d y s h o ul d ge nerall y be ass esse d 
as S A Es . If n o ot her seri o us ness criteria a p pl y, t he ‘I m p orta nt Me di cal E v e nt’ criteri o n s h o uld 
be use d. I n certai n sit uati o ns, h o we ver, me di cal j u d ge me nt o n a n i n di vi d ual e ve nt basis s h o ul d 
be a p plie d t o clarif y t hat t he mali g na nt t u m o ur e ve nt s h o ul d be assesse d a n d re p orte d as a 
n o n -S A E . F or e xa m ple, if t he t u m o ur is i ncl u de d as me dical hist or y an d pr o gressi o n occ urs 
d uri n g t he st u d y, b ut t he pr o gressi o n d oes n ot c h a n ge treat me nt a n d/ or pr o g n osis of t he 
mali g na nt t u m o ur, t he A E ma y n ot f ulfil t he attri b utes f or bei n g ass esse d as seri o us, alt h o u g h 
re p orti n g of t he pr o gressi o n of t he mali g na nt t u m o ur as a n A E is vali d a n d s h o ul d occ ur. Als o, 
s o me t y pes of mali g na nt t u m o urs, w hic h d o n ot s prea d re m otel y after a r o uti ne treat me nt t hat 
d oes n ot re q uire h os pitalisati o n, ma y be assesse d as n o n -seri o us; e xa m ples i n a d ults i ncl u de 
Sta ge 1 basal cell carci n o ma a n d S ta ge 1 A 1 cer vical ca ncer re m o ve d via c o ne bi o ps y. 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d D a p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 1  of 1 4 3  
 
Life -t hre ate ni n g 
‘ Life-t hr eate ni n g’ mea ns t hat t he partici pa nt was at i m me diate ris k of deat h fr o m t he A E as it 
occ urre d, or it is s us pecte d t hat use or c o nti n ue d use of t he me dici nal pr o d u ct w o ul d res ult i n 
t he partici pa nt’s deat h. ‘ Life-t hreate ni n g’ d oes n ot mea n t hat ha d a n A E occ urre d i n a m ore 
se vere f or m it mi g ht ha ve ca use d d eat h ( e g, he p atitis t hat res ol ve d wit h o ut he patic fail ure).  
H os pit alis ati o n  
O ut patie nt treat me nt i n a n e mer ge n c y r o o m is  n ot i n itself a S A E, alt h o u g h t he reas o ns f or it 
ma y be (e g, br o nc h os pas m, lar y n geal oe de ma). H os pital a d missi o ns a n d/ or s ur gical o perati o ns 
pla n ne d bef ore or d uri n g a st u d y are n ot c o nsi dere d A Es if t he ill ness or dis ease e xiste d b ef ore 
t he partici pa nt was e nr oll e d i n t he st u d y, pr o vi de d t hat it di d n ot deteri orate i n a n u ne x pect e d 
wa y d uri n g t he st u d y.  
I m p ort a nt Me dic al E ve nt or Me dic al Tre at me nt 
Me dical a n d sci e ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her a case is seri o us i n 
sit uati o ns w here i m p orta nt me dical e ve nts ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n 
deat h, h os pitalisati o n, disa bilit y or i nca pacit y b ut ma y je o par dise t he partici pa nt or ma y 
re q uire me di cal treat me nt t o pre ve nt o ne or m or e o utc o mes liste d i n t he defi niti o n of seri o us. 
T hese s h o ul d us uall y be c o nsi dere d as seri o us.  
Si m pl y st o p pi n g t he s us pect dr u g d oes n ot mea n t hat it is a n i m p orta nt me dical e ve nt; me dical 
j u d ge me nt m ust be use d. 
•  
A n gi oe de ma n ot se vere e n o u g h t o re q uire i nt u bati o n b ut re q uiri n g i v h y dr oc ortis o n e 
treat me nt 
•  
He pat ot o xicit y ca use d b y paraceta m ol (aceta mi n o p he n) o ver d ose re q uiri n g treat me nt wit h 
N --acet ylc ystei ne  
•  
I nte nsi v e treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m 
•  
Bl o o d d yscrasias (e g, n e utr o pe nia or a n ae mia re q uiri n g bl o o d tra nsf usi o n, etc) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisati o n  
•  
De vel o p me nt of dr u g d e pe n de nc y or dr u g a b us e  
 
I nte nsit y R ati n g Sc ale: 
•  
Mil d (a ware n ess of si g n or s y m pt o m, b ut easil y t olerate d)  
•  
M o derate ( dis c o mf ort s ufficie nt t o ca use i nterfere n ce wit h n or mal acti vities) 
•  
Se vere (i n ca pacitati n g, wit h i na bilit y t o perf or m n or mal acti vities)  
 
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d s e vere A Es. Se v erit y is a meas ure of 
i nte nsit y w hereas seri o us ness is defi ne d b y t he criteria i n Ap p e n di x B  2 . A n A E of se vere 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 2  of 1 4 3  
 
i nte nsit y nee d n ot necess aril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or 
se veral h o urs m a y be c o nsi dere d se vere n a usea, b ut n ot a n S A E u nless it meets t he criteria 
s h o w n i n A p pe n di x B  2 . O n t he ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of 
disa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a n S A E w he n it satisfies t he criteria 
s h o w n i n A p pe n di x B  2 . 
B  3  
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n   
W he n assessi n g c a usalit y c o nsi der t he f oll o wi n g fact ors w he n d eci di n g if t here is a 
‘reas o n a ble p ossi bilit y’ t hat a n A E m a y ha ve b ee n ca use d b y t he me di ci nal pr o d uct. 
•  
Ti me C o urse. E x p os ure t o s us pect dr u g. Has t he p artici pa nt recei ve d t he s us pect dr u g? 
Di d t he A E occ ur i n a reas o na ble te m p oral r elati o ns hi p t o t he a d mi nistrati o n of t he 
s us pect dr u g? 
•  
C o nsiste nc y wit h k n o w n dr u g pr ofile. Was t he A E c o nsiste nt wit h t he pre vi o us 
k n o wle d ge of t he s us p ect dr u g ( p har mac o l o g y a n d t o xic ol o g y) or dr u gs of t he sa me 
p har mac ol o gical class? Or c o ul d t he A E b e a ntici pate d fr o m its p har mac ol o gical 
pr o perties?  
•  
De -c h alle n ge e x p erie n ce. Di d t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he d ose 
of t he s us pect dr u g ?  
•  
N o alter nati ve ca use. T h e A E ca n n ot be reas o n a bl y e x plai ne d b y a n ot her aeti ol o g y s uc h 
as t he u n derl yi n g diseas e, ot her dr u gs, ot her h ost, or e n vir o n me ntal fact ors.  
•  
Re -c halle n g e e x perie nce. Di d t he A E re o cc ur if t h e s us pecte d dr u g was rei ntr o d uce d after 
ha vi n g bee n st o p pe d? Astra Ze neca w o ul d n ot n or mall y rec o m me n d or s u p p ort a 
re-c h alle n ge. 
•  
La b orat or y tests. A s p ecific la b orat or y i n v esti gati o n (if perf or me d) has c o nfir me d t he 
relati o ns hi p. 
 
I n diffic ult cas es, ot her fact ors c o ul d be c o nsi dere d s uc h as: 
•  
Is t his a rec o g nise d feat ure of o ver d ose of t h e dr u g? 
•  
Is t here a k n o w n mec h a nis m? 
 
Ca usalit y of ‘relate d’ is ma de if f oll o wi n g a re vie w of t he rel e va nt data, t h ere is e vi de n ce f or a 
‘reas o n a ble p ossi bilit y’ of a ca us al relati o ns hi p f or t he i n di vi d ual case. T he e x pressi o n 
‘reas o n a ble p ossi bilit y’ of a ca us al relati o ns hi p is mea nt t o c o n ve y, i n ge neral,  t hat t here are 
facts (e vi d e nce ) or ar g u m e nts t o s u g gest a ca usal r elati o ns hi p . 
T he ca us alit y assess me nt is perf or me d b ase d o n t h e a vaila ble data i ncl u di n g e n o u g h 
i nf or mati o n t o ma ke a n i nf or me d j u d g me nt. Wit h n o a vaila ble facts or ar g u me nts t o s u g gest a 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 3  of 1 4 3  
ca usal r elati o ns hi p, t he e ve nt(s) will be assess e d as ‘ n ot relate d’.  
Ca usal relati o ns hi p i n cases w here t he D U S has d eteri orat e d d ue t o lac k of effect s h o ul d be 
classifie d as ‘ n o reas o n a ble p ossi bilit y’.  
B  4  
Me dic ati o n Err or, Dr u g A b use, a n d Dr u g Mis use  
Me dic ati o n Err or  
F or t he p ur p oses of t his cli nical st u d y a me dicati o n err or is a n u ni nte n d e d fail ure or mista ke i n 
t he treat me nt pr ocess f or a n I M P or Astra Ze n eca NI M P t hat eit her ca uses har m t o t he 
partici pa nt or has t he p ot e ntial t o ca use har m t o t he partici pa nt. 
A me dicati o n err or is n ot lac k of efficac y of t h e dr u g, b ut rat her a h u m a n or pr ocess r elate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y site staff or p artici pa nt. 
Me dicati o n err or i ncl u des sit uati o ns w here a n err or:  
•
Occ urre d
•
W as i d e ntifie d a n d  i nterce pte d bef ore t h e partici p a nt recei ve d t he dr u g
•
Di d n ot occ ur, b ut circ u msta nces were rec o g nise d t hat c o ul d ha ve le d t o a n err or
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors:  
•
Dr u g na me c o nf usi o n
•
Dis pe nsi n g e rr or, e g, me dicati o n pre pare d i nc orrectl y, e ve n if it was n ot act uall y gi ve n t o
t he partici pa nt
•
Dr u g n ot a d mi nistere d as i n dicate d, e g, wr o n g r o ute or wr o n g site of a d mi nistrati o n
•
Dr u g n ot ta ke n as i n dicate d, e g, ta blet diss ol ve d i n water w he n it s h o ul d be  ta ke n as a
s oli d ta blet
•
Dr u g n ot st ore d as i nstr u cte d, e g, ke pt i n t he refri d gerat or w h e n it s h o ul d be at r o o m
te m perat ur e
•
Wr o n g partici p a nt recei v e d t he me dicati o n (e xcl u di n g I R T/ R T S M err ors)
•
Wr o n g dr u g a d mi nistere d t o partici pa nt (e x cl u di n g I R T/ R T S M err ors)
E xa m ples of e ve nts t hat d o n ot  re q uire re p orti n g as me dicati o n err ors i n cli nical st u dies: 
•
Err ors r elate d t o or res ulti n g fr o m I R T/ R T S M - i ncl u di n g t h ose w hic h le d t o o ne of t he
a b o ve liste d e ve nts t hat w o ul d ot her wise ha v e bee n a me dicati o n err or
•
Pa rtici pa nt acci d e ntall y misse d dr u g d ose(s), e g, f or g ot t o ta ke me dicati o n
•
Acci de ntal o v er d ose ( will be ca pt ure d as a n o v er d ose)

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 4  of 1 4 3  
 
•  
Partici pa nt faile d t o ret ur n u n use d me dicati o n or e m pt y pac ka gi n g  
 
Me dicati o n err ors are n ot re gar de d as A Es b ut A Es ma y occ ur as a c o ns e q ue nce of t he 
me dicati o n err or.  
Dr u g A b use  
F or t he p ur p ose of t his st u d y, dr u g a b use is defi ne d as t he persiste nt or s p ora dic i nte nti o nal, 
n o n -t hera p e utic e xcessi ve use of I M P or Astra Ze n eca NI M P f or a percei ve d re war d or desir e d 
n o nt hera pe utic effect.  
A n y e ve nts of dr u g a b use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ur e d a n d f or war de d t o 
t he Data E ntr y Site ( D E S) usi n g t he Dr u g A b us e Re p ort F or m. T his f or m s h o ul d be use d b ot h 
if t he dr u g a b use h a p pe n e d i n a st u d y partici pa nt or if t he dr u g a b us e i n v ol ves a pers o n n ot 
e nr olle d i n t he st u d y (s uc h as a rel ati ve of t he st u d y partici pa nt).  
E xa m ples of dr u g a b us e i ncl u de b ut are n ot li mite d t o:  
•  
T he dr u g is use d wit h t he i nte nt of getti n g a percei ve d re war d ( b y t h e st u d y partici pa nt or 
a pers o n n ot e nr olle d i n t he st u d y)  
•  
T he dr u g i n t he f or m of a ta blet is cr us he d a n d i njecte d or s n orte d wit h t he i nte nt of 
getti n g hi g h  
 
Dr u g Mis use  
Dr u g mis use is t he i nte nti o nal a n d i na p pr o priat e use ( b y a st u d y partici p a nt) of I M P or 
Astra Ze neca NI M P f or m e dici nal p ur p oses o utsi de of t he a ut h orise d pr o d u ct i nf or mati o n, or 
f or u na ut h orise d I M Ps or Astra Z e neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute.  
E ve nts of dr u g mis use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ur e d a n d f or war de d t o 
t he D E S usi n g t he Dr u g Mis use Re p ort F or m. T his f or m s h o ul d be use d b ot h if t he dr u g 
m is use ha p pe ne d i n a st u d y partici pa nt or if t he dr u g mis use re gar ds a pers o n n ot e nr olle d i n 
t he st u d y (s uc h as a relati ve of t he st u d y partici pa nt). 
E xa m ples of dr u g mis use i ncl u de b ut are n ot li mite d t o:  
•  
T he dr u g is use d wit h t he i nte nti o n t o ca use a n ef fect i n a n ot her p ers o n 
•  
T he dr u g is s ol d t o ot her pe o ple f or recreati o nal p ur p oses  
•  
T he dr u g is use d t o facilitate assa ult i n a n ot her p ers o n  
•  
T he dr u g is deli beratel y a d mi nistere d b y t he wr o n g r o ute  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 5  of 1 4 3  
 
•  
T he dr u g is s plit i n half beca use it is e asier t o s wall o w, w he n it is state d i n t he pr ot oc ol 
t hat it m ust be s wall o we d w h ole 
•  
O nl y half t he d ose is ta ke n beca use t h e st u d y parti ci pa nt feels t hat h e/s he is feeli n g better 
w he n n ot ta ki n g t he w h ol e d ose  
•  
S o me o ne w h o is n ot e nr olle d i n t he st u d y i nte nti o nall y t a kes t he dr u g  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 6  of 1 4 3  
 
A p pe n di x  C  H a n dli n g of H u m a n Bi ol o gic al S a m ples   
C  1  
C h ai n of C ust o d y   
A f ull c hai n of c ust o d y is mai nta i ne d f or all sa m pl es t hr o u g h o ut t heir lifec y cle. 
T he i n vesti gat or kee ps f ull tracea bilit y of c ollect e d bi ol o gical sa m ples fr o m t he partici pa nts 
w hile i n st ora ge at t he ce ntre u ntil s hi p me nt or dis p osal ( w here a p pr o priate) a n d rec or ds 
rele va nt pr o cessi n g i nf or mati o n relate d t o t he sa m ples w hilst at t he site. 
T he sa m ple recei ver kee ps f ull tracea bilit y of t he sa m ples w hile i n st ora ge a n d d uri n g use u ntil 
use d or dis p ose d of or u ntil f urt her s hi p me nt, a n d kee ps rec or d of recei pt of arri val a n d 
o n war d s hi p me nt or dis p osal.  
Astra Ze neca or dele g ate d re pres e ntati ves will kee p o versi g ht of t he e ntire life c ycle t hr o u g h 
i nter nal pr oce d ures, m o nit ori n g of st u d y sites, a u diti n g or pr ocess c hec ks, a n d c o ntract ual 
re q uire me nts of e xter n al la b orat or y pr o vi ders 
Sa m ples ret ai ne d f or f urt her use will be st ore d i n t he Astra Ze neca -assi g ne d bi o ba n ks or ot her 
sa m ple arc hi v e facilities a n d will be trac k e d b y t he a p pr o pri ate Astra Ze n eca tea m f or t h e 
re mai n der of t he sa m ple life c ycle. 
C  2  
Wit h dr a w al of I nf or me d C o nse nt f or D o n ate d Bi ol o gic al S a m ples   
Astra Ze neca e ns ures t hat bi ol o gical sa m ples are ret ur ne d t o t he s o urce or destr o ye d at t he e n d 
of a s pecifi e d peri o d as descri be d i n t he i nf or me d c o nse nt.  
If a partici pa nt wit h dra ws c o nse nt t o t he use of d o nate d bi ol o gical sa m ples, t he sa m ples will 
be dis p ose d of/ destr o ye d/re patriat e d, a n d t he acti o n d oc u me nte d. If s a m ples are alr ea d y 
a nal yse d, Astra Ze n eca is n ot o bli ge d t o destr o y t he res ults of t his researc h.  
F oll o w i n g wit h dra wal of c o nse nt f or bi ol o gical sa m ples, f urt her st u d y parti ci pati o n s h o ul d be 
c o nsi dere d i n r elati o n t o t he wit h dra wal pr ocess es o utli ne d i n t he i nf or me d c o nse nt.  
T he i n vesti gat or:  
•  
E ns ures t he partici pa nt’s wit h dra wal of i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
hi g hli g hte d i m me diatel y t o Astra Ze neca or dele gate.  
•  
E ns ures t hat rele v a nt h u ma n bi ol o gical sa m ples fr o m t hat partici pa nt, if st ore d at t he 
st u d y site, are i m me diatel y i de ntifie d, dis p ose d of as a p pr o priat e, a n d t he acti o n 
d oc u me nte d.  
•  
E ns ures t hat t he partici p a nt a n d Astra Ze n eca are i nf or me d a b o ut t he sa m pl e dis p osal.  
 
Astra Ze neca e ns ures t he or ga nisati o n(s) h ol di n g t he sa m ples is/are i nf or me d a b o ut t he 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 7  of 1 4 3  
 
wit h dra w n c o nse nt i m me diatel y a n d t hat sa m ples are dis p ose d of or re p atri ate d as a p pr o priate, 
a n d t he acti o n is d oc u me nte d, a n d st u d y site is n otifie d.  
C  3  
I nter n ati o n al Air Tr a ns p ort Ass oci ati o n G ui d a nce D oc u me nt 6 2 n d  
e diti o n   
L A B E L LI N G A N D S HI P M E N T O F BI O H A Z A R D S A M P L E S  
T he I nter nati o nal Air Tra ns p ort Ass ociati o n (I A T A) 
(htt ps:// w w w.i at a. or g/ w h at we d o/c ar g o/ d gr/ P a ges/ d o w nl o a d. as p x ) classifies i nfecti o us 
s u bsta nces i nt o 3 cate g ories: Cate g or y A, Cate g or y B, or E xe m pt 
C ate g or y A I nfecti o us S u bst a nces are i nfecti o us s u bsta nces i n a f or m t hat, w he n e x p os ure t o 
it occ urs, is ca pa bl e of ca usi n g per ma ne nt disa bilit y, life-t hreate ni n g or fatal disease i n 
ot her w ise healt h y h u ma ns or a ni mals.  
C ate g or y A P at h o ge ns  are, e g, E b ola, Lassa fe ver vir us. I nfecti o us s u bsta nces meeti n g t hese 
criteria w hi c h ca us e dise ase i n h u ma ns or b ot h i n h u ma ns a n d a ni mals m ust be assi g ne d t o 
U N  2 8 1 4. I nfecti o us s u bsta nces w hic h ca use dise ase o nl y i n a ni mals m ust be assi g ne d t o 
U N  2 9 0 0.  
C ate g or y B I nfecti o us S u bst a nces are i nfecti o us s u bsta nces t hat d o n ot meet t he criteria f or 
i ncl usi o n i n Cate g or y A. Cate g or y B pat h o ge ns are, e g, He p atitis A, C, D, a n d E vir uses. T he y 
are assi g ne d t h e  f oll o wi n g U N n u m ber a n d pr o per s hi p pi n g na me: 
•  
U N 3 3 7 3 –  Bi ol o gical S u bsta nce, Cate g or y B  
•  
Are t o be pac ke d i n a cc or da nce wit h U N  3 3 7 3 a n d I A T A 6 5 0  
 
E xe m pt  S u bst a nces  are s u bsta nces w hic h d o n ot c o ntai n i nfecti o us s u bsta nces, or s u bsta nces 
w hic h are u nli kel y t o ca use disease i n h u ma ns or a ni mals, are n ot s u bject t o t hese re g ulati o ns 
u nless t he y meet t he criteria f or i ncl usi o n i n a n ot h er class.  
•  
Cli nical st u d y sa m ples wi ll fall i nt o Cate g or y B or e xe m pt u n der I A T A re g ulati o ns. 
•  
Cli nical st u d y sa m ples will r o uti nel y be pac ke d a n d tra ns p orte d at a m bie nt t e m perat ur e i n 
I A T A 6 5 0 c o m plia nt pac ka gi n g 
( htt ps:// w w w.iata. or g/c o nte ntassets/ b 0 8 0 4 0a 1 3 8 dc 4 4 4 2a 4f 0 6 6e 6f b 9 9fe 2a/ d gr-6 2 -e n -
pi 6 5 0. p df).  
•  
Bi ol o gical sa m ples tra ns p orte d i n dr y ice re q uire a d diti o nal da n ger o us g o o ds s pecificati o n 
f or t he dr y ic e c o nte nt. 
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 8  of 1 4 3  
 
A p pe n di x  D  O pti o n al Ge n o mics I niti ati ve S a m ple   
D  1  
Use/ A n al ysis of D N A   
•  
Astra Ze neca i nte n ds t o c ollect a n d st ore D N A a n d bl o o d deri vati ves (s uc h as plas ma a n d 
ser u m) f or g e n o mic a n d c o m pre he nsi ve o mics c h aract erisati o n res earc h (s uc h as pr otei n, 
n ucle oti des a n d ot her e ntities i n circ ulati o n), w hic h ma y i ncl u de meta b ol o mic, pr ote o mic 
a n d li pi d o mic a nal ysis, t o e x pl ore h o w ge n o mic a n d ti me -p oi nt o mics variati o ns ma y 
affect cli nical para meters, ris k a n d pr o g n osis of diseases, a n d t h e re s p o nse t o me dici nal 
pr o d uct.  
•  
T his ge n o mic a n d m ulti -o mics researc h ma y lea d t o better u n dersta n di n g of diseases, 
better dia g n osis of diseas es or ot her i m pr o ve m e nts i n healt h care, a n d t o t he disc o ver y of 
ne w dia g n ostics, treat me nts, or me dicati o ns. T heref o re, w here l ocal r e g ulati o ns a n d 
I R B/I E C all o w, a bl o o d s a m ple will be c ollecte d f or D N A a n d m ulti-o mics a nal ysis fr o m 
c o nse nti n g partici pa nts.  
•  
T his o pti o nal ge n o mic a n d m ulti -o mics researc h m a y c o nsist of t he a nal ysis of t he 
str uct ure of t he p artici pa nt’s D N A, ie, t he e ntire g e n o me.  
•  
T he res ults of t hese g e netic a nal yses ma y be re p orte d i n a se parate st u d y s u m mar y.  
•  
Astra Ze neca will st ore t h e D N A sa m ples i n a s ec ure st ora ge s p ace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y.  
 
D  2  
M ulti -o mics Rese arc h Pl a n a n d Pr oce d ures   
Selecti o n of M ulti -o mics Rese arc h P o p ul ati o n  
All partici pa nts will be as ke d t o partici pate i n t his ge n o mic a n d m ulti -o mics researc h. 
Partici pati o n is v ol u ntar y a n d if a partici pa nt decli nes t o partici pate t here will be n o pe nalt y or 
l oss of be nefit. T he p artici pa nt will n ot be e xcl u de d fr o m a n y as p ect of t he mai n st u d y. 
I ncl usi o n Criteri a 
F or i ncl usi o n i n t his ge n o mic a n d m ulti -o mics researc h, partici pa nts m ust  f ulfil all of t he 
i ncl usi o n criteria des cri b e d i n t he mai n b o d y of t he pr ot oc ol a n d: Pr o vi de i nf or me d c o ns e nt 
f or t he Ge n o mics I nitiati ve sa m pli n g a n d a nal yses. 
E xcl usi o n Criteri a  
E xcl usi o n fr o m t his ge n o mic a n d m ulti -o mics researc h ma y be f or a n y of t h e e xcl usi o n 
criteria s pecifie d i n t he m ai n st u d y or a n y of t he f oll o wi n g:  
•  
Pre vi o us all o ge neic b o ne marr o w tra ns pl a nt  
•  
N o n -le u k oc yte d e plete d w h ole bl o o d tra nsf usi o n i n 1 2 0 da ys of ge netic s a m ple c ollecti o n 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1 9  of 1 4 3  
 
 
Wit h dr a w al of C o nse nt f or M ulti -o mics Rese a rc h  
•  
Parti ci pa nts ma y wit h dra w fr o m t his ge n o mic a n d m ulti -o mics researc h at a n y ti me, 
i n de pe n de nt of a n y d ecisi o n c o ncer ni n g partici pati o n i n ot her as pects of t h e mai n st u d y. 
V ol u ntar y wit h dra w al will n ot prej u dice f urt her treat me nt. Pr oce d ures f or wit h dra wal are 
o utli ne d i n Secti o n 7. 2  of t he mai n pr ot oc ol.  
 
C ollecti o n of S a m ples f or M ulti -o mics Rese arc h  
•  
T he bl o o d sa m ple f or t his ge n o mic a n d m ulti -o mics researc h will be o btai ne d fr o m t he 
partici pa nts at Visit  2 ra n d o misati o n. Alt h o u g h D N A is sta ble, earl y sa m ple c ollecti o n is 
preferre d t o a v oi d i ntr o d uci n g bias t hr o u g h e xcl u di n g partici pa nts w h o ma y wit h dra w d ue 
t o a n A E. If f or a n y reas o n t he sa m ple is n ot dra w n at Visit 2, it ma y be ta ke n at a n y visit 
u ntil t he last st u d y visit. O nl y o ne sa m ple s h o ul d be c ollecte d per partici pa nt f or ge netics 
researc h d uri n g t he st u d y. 
 
C o di n g a n d St or a ge of D N A S a m ples a n d M ulti -o mics S a m ples  
•  
T he pr ocesses a d o pte d f or t he c o di n g a n d st ora g e of sa m ples f or g e n o mic a n d m ulti -
o mics a nal ysis are i m p orta nt t o mai ntai n partici pa nt c o nfi de ntialit y. Sa m ples will be 
st ore d f or a m a xi m u m of 1 5 years fr o m t he date of last s u bject last visit, after w hic h t he y 
will be des tr o ye d. D N A a n d bl o o d deri vati ves are a fi nite res o urce t hat will be use d u p 
d uri n g a nal yses. Sa m ples will be st ore d a n d use d u ntil n o f urt her a nal yses are p ossi ble or 
t he ma xi m u m st ora ge ti me has bee n reac he d. 
•  
A n a d diti o nal sec o n d c o d e will be assi g ne d t o  t he sa m ples eit her bef ore or at t he ti me of 
sa m ple pr ocessi n g, re pla ci n g t he i nf or mati o n o n t he sa m ple t u be. T hereaft er, t he sa m ple 
will be i de ntifia ble o nl y b y t he sec o n d, u ni q ue n u m ber. T his n u m ber is use d t o i de ntif y 
t he sa m ple a n d c orres p o n di n g data at t he Astra Z e n eca g e netics la b orat ories, or at t he 
desi g nate d or ga nisati o n. N o pers o nal det ails i de ntif yi n g t he i n di vi d ual will be a vaila ble t o 
a n y pers o n ( Astra Ze n eca e m pl o yee or desi g n ate d or ga nisati o ns w or ki n g wit h t he D N A or 
bl o o d deri vati ves).  
•  
T he li n k bet wee n t he p artici pa nt e nr ol me nt/ra n d o misati o n c o de a n d t he sec o n d n u m ber 
will be mai ntai ne d a n d st ore d i n a sec ure e n vir o n me nt, wit h restricte d access at 
Astra Ze neca or desi g nate d or ga nisati o ns. T he li n k will be use d t o i de ntif y t he rele va nt 
sa m ples f or a n al ysis, facilitate c orrelati o n of g e n ot y pic, or m ulti-o mics res ults wit h 
cli nical data, all o w re g ul at or y a u dit, a n d per mit traci n g of sa m ples f or destr ucti o n i n t he 
case of wit h dra wal of c o nse nt.  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 0  of 1 4 3  
 
Et hic al a n d Re g ul at or y Re q uire me nts  
•  
T he pri nci ples f or et hical a n d re g ulat or y re q uir e me nts f or t he st u d y, i ncl u di n g t his 
ge n o mics a n d m ulti -o mics researc h c o m p o n e nt, are o utli ne d i n A p pe n di x  A . 
 
I nf or me d C o nse nt 
•  
T he ge n o mic c o m p o ne nt of t his st u d y are o pti o nal a n d t he partici pa nt ma y partici pate i n 
ot her c o m p o ne nts of t he mai n st u d y wit h o ut partici pati n g i n t his ge netic c o m p o ne nt. T o 
partici pate i n t he ge n o mi c a n d m ulti -o mics c o m p o ne nt of t he st u d y t he partici pa nt m ust 
si g n a n d date b ot h t he c o nse nt f or m f or t he mai n st u d y a n d t he o pti o nal ge netic researc h 
i nf or mati o n I C F. C o pies of b ot h si g ne d a n d date d c o nse nt f or ms m ust be gi ve n t o t he 
partici pa nt a n d t he ori gi nals file d at t he st u d y ce ntre. T he Pri nci pal I n vesti gat or(s) is 
res p o nsi ble f or e ns uri n g t hat c o nse nt is gi ve n freel y, a n d t hat t he partici pa nt u n dersta n ds 
t hat t he y ma y freel y wit h dra w fr o m t he ge netic as pect of t he st u d y at a n y ti me. 
 
P artici p a nt D at a Pr otecti o n  
•  
Astra Ze neca wi ll n ot pr o vi de i n di vi d ual se q ue nci n g, ge n ot y pe, or m ulti-o mics res ults t o 
partici pa nts, a n y i ns ura n ce c o m pa n y, a n y e m pl o y er, t heir fa mil y me m bers, or ge neral 
p h ysicia n u nless re q uire d t o d o s o b y la w.  
•  
E xtra preca uti o ns are ta k e n t o preser ve c o nfi de ntialit y  a n d pre ve nt ge n o mi c a n d m ulti -
o mics data bei n g li n ke d t o t he i de ntit y of t he partici pa nt. I n e xce pti o nal circ u msta nces, 
h o we ver, cert ai n i n di vi d uals mi g ht see b ot h t he ge netic data a n d t he pers o nal i de ntifiers 
of a partici p a nt. F or e xa m ple, i n t he case of  a me dical e mer ge nc y, a n Astra Ze neca 
P h ysicia n or a n i n vesti gat or mi g ht k n o w a partici p a nt’s i de ntit y a n d als o ha ve access t o 
his or her ge n o mic dat a. Re g ulat or y a ut h orities ma y re q uir e access t o t he rele va nt files, 
t h o u g h t he partici pa nt’s me dical i nf or mati o n a n d t he ge n o mic files w o ul d re mai n 
p h ysicall y se parat e.  
 
D at a m a n a ge me nt  
•  
Data will be re p orte d se p aratel y fr o m t he C S R.  
•  
A n y ge n o mic or m ulti -o mics data ge nerate d i n t his st u d y will be st ore d at a sec ure s yste m 
at Astra Ze n eca a n d/ or desi g nate d or ga nisa ti o ns t o a nal yse t he sa m ples. 
•  
Astra Ze neca a n d its desi g nate d or ga nisati o ns ma y s hare s u m mar y res ults (s uc h as ge netic 
differe n ces fr o m gr o u ps of i n di vi d uals wit h a disease) fr o m t his ge netic a n d m ulti -o mics 
researc h wit h ot her researc hers, s u c h as h os pitals, aca d e mic or ga nisati o ns, or dr u g- or 
healt h -rel ate d c o m pa nies. T his ca n be d o ne b y pl aci n g t he res ults i n scie ntific data bas es, 
w here t he y ca n b e c o m bi ne d wit h t he res ults of si milar st u dies t o lear n e ve n m ore a b o ut 
healt h a n d diseas e. T he researc hers ca n o nl y use t his i nf or mati o n f or healt h -relate d 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 1  of 1 4 3  
 
researc h p ur p os es. Researc hers ma y s ee s u m mar y res ults, b ut t he y will n ot be a ble t o see 
i n di vi d ual partici pa nt data or a n y pers o nal i de ntifi ers. 
•  
S o me or all of t he cli nical datasets fr o m t he mai n st u d y ma y be  mer ge d wit h t he ge netic 
data i n a s uita ble sec ure e n vir o n me nt se parate fr o m t he cli nical data bas e.  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 2  of 1 4 3  
A p pe n di x  E  Acti o ns Re q uire d i n C ases of I ncre ases i n Li ver Bi oc he mistr y 
a n d E v al u ati o n of H y’s L a w  
E  1  
I ntr o d ucti o n 
T his a p pe n di x descri b es t he pr ocess t o b e f oll o we d i n or der t o i de ntif y a n d a p pr o priatel y 
re p ort P ote ntial H y’s La w ( P H L) cases a n d H y’s La w cas es as defi ne d i n t his st u d y i n v ol vi n g 
patie nts wit h cirr h osis. It is n ot i nte n de d t o be a c o m pre he nsi ve g ui de t o t he ma na ge me nt of 
ele vate d li ver bi o c he mistries. Gi ve n t he partici pa nt p o p ulati o n, a n d t he li kel y pre vale nce of 
a b n or mal a n d fl u ct uati n g L F Ts, t he cr iteria use d t o deter mi ne w het h er a case meets P H L a n d 
H L re p orti n g criteria are  
 t o t his  
 a n d defi ne d bel o w.  
S pecific g ui da nce o n ma na gi n g li ver a n o malies ca n be f o u n d i n Secti o n 7. 1. 2  Ma na ge me nt of 
Treat me nt -e mer ge nt a b n or malities i n L F Ts.  
D uri n g t he c o urs e of t he st u d y t he i n vesti gat or will re mai n vi gila nt f or i ncreases i n li ver 
bi oc he mistr y. T he i n vesti gat or is res p o nsi ble f or deter mi ni n g w het her a partici pa nt meets 
p ote ntial P H L criteria at a n y p oi nt d uri n g t he st u d y.  
All s o urces of la b orat or y data are a p pr o priate f or t he deter mi nati o n of P H L a n d H y’s La w 
e ve nts; t his i ncl u des sa m ples ta ke n at sc h e d ule d st u d y visits a n d ot her visits i ncl u di n g ce ntral 
a n d all l ocal la b orat or y e val uati o ns e ve n if c ollecte d o utsi de of t he st u d y visits; f or e xa m ple, 
P H L criteria c o ul d be met b y a n ele vate d A L T fr o m a ce ntral la b orat or y A N D/ O R ele vate d 
T B L fr o m a l ocal la b orat or y.  
T he i n vesti gat or will als o re vie w A E data (f or e xa m ple, f or A Es t hat ma y i n dicate ele vati o ns 
i n li ver bi oc he mistr y) f or p ossi ble P H L e ve nts. 
T he i n vesti gat or partici p ates, t o get her wit h Astra Ze neca cli nical pr oject re prese ntati ves, i n 
re vie w a n d assess me nt of cases me eti n g P H L criteria t o a gree w het h er H y’s La w criteria are 
met. H y’s La w criteria are met if t here is n o alter nati ve e x pla nati o n f or t he ele vati o ns i n li ver 
bi oc he mistr y ot her t ha n DI LI ca use d b y t he st u d y i nter ve nti o n.  
T he i n vesti gat or is res p o nsi ble f or rec or di n g data per tai ni n g t o P H L/ H y’s La w cas es a n d f or 
re p orti n g S A Es a n d A Es acc or di n g t o t he o utc o m e of t he re vie w a n d ass ess me nt i n li ne wit h 
sta n dar d safet y re p orti n g pr ocesses. 
E  2  
Defi niti o ns  
P ote nti al H y’s L a w   
Ele vati o n i n L F Ts or rele va nt cli nical ma nifestati o ns defi ne d i n Secti o n  E  3  fl o wc harts t hat 
lea d t o h ol d of t he st u d y i nter ve nti o n t o assess t he ca use of t h ese c h a n ges. 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 3  of 1 4 3  
 
H y’s L a w   
Ele vati o n i n L F Ts or rele va nt cli nical ma nifestati o ns defi ne d i n t he fl o wc h arts i n Secti o n  E  3  
t hat lea d t o h ol d of t he st u d y i nter ve nti o n a n d w he n t here n o ot her reas o n, ot her t ha n t he st ud y 
i nter ve nti o n, ca n be f o u n d t o e x plai n t he c o m bi nati o n of s uc h i ncreases i n L F Ts. 
E  3  
I de ntific ati o n of P ote nti al H y’s L a w C ases  
I n or der t o i de ntif y cases of P H L it is i m p orta nt to perf or m a c o m pre h e nsi ve re vie w of 
la b orat or y dat a f or a n y p artici pa nt w h o meets a n y of t he f oll o wi n g
: 
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 4  of 1 4 3  
M a n a ge me nt g ui deli nes f or p artici p a nts wit h 
 at b aseli ne, a n d n or m al b aseli ne 
 at 
b aseli ne)  
 a n d a b o ve 
 
If 
 or 
 ( w hic he v er c o mes first) A N D  t here 
is 
 a n d a b o ve 
O R  
O R  
 a n d a b o ve 
 
O R  
O R  
 a n d a b o ve  
 wit h 
 a n d 
 o ver baseli ne  
O R  
O R  
A n y i ncrease i n 
 fr o m baseli ne 
 a n d a b o ve 
 
De v el o p me nt of 
 or 
, or 
 j u d ge d t o be cli nic all y si g nific a nt  b y t he i n vesti gat or  
 at least 
If 
 criteria a p pl y  
, assess f or 
 i ncl u di n g disease 
u n der st u d y, 
 or p ossi bilit y of 
. 
 ( w he n st u d y i nter ve nti o n has bee n 
 as a ca use of c ha n ges i n 
 or 
) ma y be per mitte d after s ufficie nt 
 bac k t o 
, a n d after disc ussi o n bet wee n t he i n vesti gat or a n d t he me dical m o nit or. 
 will ge n erall y re q uire a n 
C CI
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 5  of 1 4 3  
M a n a ge me nt g ui deli nes f or p artici p a nts wit h 
 at b aseli ne, wit h a b n or m al b aseli ne  
 
) 
 b ut 
 a n d 
, 
 or 
 ( w hic he ver c o mes first) 
A N D  
A N D A T L E A S T 
 O F T H E F O L L O WI N G  
•
 (if n or mal at 
 or <  
 (if a b n or mal 
at 
 A N D  
•
 if n or mal at 
) O R  
 if 
a b n or mal at 
 
•
 o ver 
 A N D  
•
 o ver baseli ne , 
•
 (if n or mal at 
 or 
 of 
if 
 
was 
•
 (if 
 was 
) O R i ncrease d b y 
 (if 
 was 
O R  
 is 
 or 
 ( w hic he v er c o mes first) 
O R  
 a n d 
 o ver baseli ne  
O R  
De v el o p me nt of 
 or 
, or 
 j u d ge d t o be cli nic all y si g nific a nt  b y t he i n vesti gat or.  
 dr u g, 
 st u d y i nter ve nti o n, assess f or 
 i ncl u di n g disease 
u n der st u d y, a d diti o nal
 or p ossi bilit y of 
. 
 ( w he n st u d y i nter ve nti o n has bee n 
 as a ca use of c ha n ges i n 
 or 
) ma y be per mitte d after s ufficie nt 
 
 bac k t o 
, a n d after disc ussi o n bet wee n t he i n vesti gat or a n d t he me dical m o nit or. 
 will ge n erall y re q uire a n 
. 
C CI
C CI
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C CI
C CI
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C CI
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Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a g lifl ozi n - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 6  of 1 4 3  
M a n a ge me nt g ui deli nes f or p artici p a nts wit h 
 at b aseli ne, wit h eit her n or m al or a b n or m al b aseli ne 
 
a n d 
) or 
, w hic he ver c o mes first; or 
 ×  p ost -baseli ne o n -treat me nt 
 val ues  
O R  
 wit h 
 of t he t otal, or a n y i ncrease i n 
 o ver baseli ne  
O R  
 ×  baseli ne  
O R  
 (if n or mal 
 at baseli ne) or a n y i ncrease of 
 if baseli ne 
O R  
 i ncrease d b y 
 o ver baseli ne (if 
 at baseli ne) or b y 
 o ver baseli ne (if 
 at baseli ne)  
O R  
De v el o p me nt of ne w 
 or 
 of 
 or 
 j u d ge d t o be cli nic all y si g nific a nt  b y t he i n vesti gat or.  
 st u d y i nter ve nti o n, assess f or ca use of 
 i ncl u di n g disease u n der st u d y, 
 or p ossi bilit y  of 
. 
D ue t o varia bilit y i n 
 patie nts wit h 
 meeti n g re q uire me nt f or h ol d of st u d y dr u g base d s olel y o n 
 c h a n ge, a n d n ot meeti n g a n y 
ot her criteria f or dr u g h ol d, ma y ha v e o ne 
 at t he discreti o n of t he i n vesti gat or t o deter mi ne w het her t he 
 c h a n ge is s ustai ne d.  
 ( w he n st u d y i nter ve nti o n has bee n 
as a ca use of c ha n ges i n 
 or 
) ma y be per mitte d after s ufficie nt 
 bac k t o 
 ×  baseli ne, a n d after disc ussi o n bet wee n t he i n vesti gat or a n d t he me dical m o nit or. 
 wil l g e n erall y re q uire a n 
a
 is defi ne d as 
 wit h prese nce at baseli ne of 
 or 
 or 
C CI
C CI
C CI
C CI
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C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 7  of 1 4 3  
Ce ntr al L a b or at ories B ei n g Use d:  
W he n a p artici pa nt meets a n y of t he P H L i de ntificati o n criteria, t he ce ntr al la b orat or y will 
i m me diatel y se n d a n alert t o t he i n vesti gat or (als o se nt t o Astra Ze n eca re prese ntati ve). 
T he i n vesti gat or will als o re mai n vi gila nt f or a n y l a b orat or y re p orts w here t he P H L 
i de ntificati o n criteria are met, w here t his is t he cas e t he i n vesti gat or will: 
•
Re q uest a re p eat of t he t est ( ne w bl o o d dra w) b y t he ce ntr al la b orat or y  wit h o ut dela y.
•
C o m plete t he a p pr o priate u nsc he d ule d la b orat or y e C R F m o d ule(s) wit h t he ori gi nal
la b orat or y test res ult.
W he n t he i de ntificati o n criteria are met fr o m ce ntr al or l ocal la b orat or y res ults t he i n vesti gat or 
will wit h o ut dela y:  
•
Deter mi ne w h et her t he p artici pa nt meets P H L criteria (se e Secti o n E  2  f or defi niti o n a n d
Secti o n  E  3 ) b y re vie wi n g la b orat or y re p orts fr o m all pre vi o us visits (i ncl u di n g b ot h
ce ntral a n d l o cal la b orat or y res ults).
L oc al L a b or at ories Bei n g Use d:  
T he i n vesti gat or will wit h o ut dela y re vie w eac h n e w la b orat or y re p ort a n d if t he i de ntificati o n 
criteria are met will:  
•
Deter mi ne w h et her t he p artici pa nt meets P H L criteria (see Secti o n E  2  f or defi niti o n a n d
Secti o n  E  3 ) b y re vie wi n g la b orat or y re p orts fr o m all pre vi o us visits.
•
Pr o m ptl y e nter t he la b orat or y data i nt o t he la b orat or y e C R F.
E  4  
F oll o w -u p   
E  4. 1  
P ote nti al H y’s L a w C riteri a n ot m et   
If t he partici p a nt d oes n ot meet P H L criteria t h e i n vesti gat or will: 
•
Perf or m f oll o w -u p o n s u bse q ue nt la b orat or y res ults acc or di n g t o t he g ui da nce pr o vi de d i n
t he pr ot oc ol.
E  4. 2  
P ote nti al H y’s L a w C riteri a m et   
If t he partici p a nt d oes meet P H L criteria t he i n vesti gat or will:  
•
N otif y t he Astra Ze n eca re prese nt ati ve w h o will t he n i nf or m t he ce ntral st u d y tea m.

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 8  of 1 4 3  
 
•  
Wit hi n 1 da y of P H L crit eria bei n g met, t he i n vesti gat or will re p ort t he case as a n S A E of 
P H L; seri o us criteria “I m p orta nt me dical e ve nt” a n d ca usa lit y assess me nt “ yes/relate d ” 
acc or di n g t o pr ot o c ol pr o cess f or S A E re p orti n g.  
•  
F or partici pa nts t hat met P H L criteria pri or t o starti n g st u d y i nter ve nti o n, t he i n vesti gat or 
is n ot re q uire d t o s u b mit a P H L S A E u nless t here is a si g nifica nt c ha n ge# i n t he 
pa rtici pa nt’s c o n diti o n. 
•  
T he st u d y p h ysicia n c o nt acts t he i n vesti gat or, t o pr o vi de g ui da nce, dis c uss a n d a gree a n 
a p pr oac h f or t he st u d y partici pa nts’ f oll o w -u p (i ncl u di n g a n y f urt her la b orat or y testi n g) 
a n d t he c o nti n u o us re vie w of data.  
•  
S u bse q ue nt t o t his c o ntact t he i n vesti gat or will:  
− 
M o nit or t he partici pa nt u ntil li ver bi oc he mistr y para meters a n d a p pr o priate cli nical 
s y m pt o ms a n d si g ns ret ur n t o n or mal or baseli ne l e vels, or as l o n g as me di call y 
i n dicate d. C o m pletes f oll o w-u p S A E F or m a s re q uire d. 
− 
I n v esti gate t he aeti ol o g y of t he e ve nt a n d perf or m dia g n ostic i n vesti gati o ns as 
disc usse d wit h t he st u d y p h ysicia n.  
− 
C o m plete t he t hree Li ver e C R F M o d ules as i nf or mati o n bec o mes a vaila bl e.  
 
#A “si g nific a nt ” c h a n ge  i n t he partici pa nt’s c o n diti o n refers t o a cli nicall y rele va nt c ha n ge i n 
a n y of t he i n di vi d ual li ver bi oc he mistr y para meters i n is olati o n or i n c o m bi nati o n, or a 
cli nicall y rele va nt c ha n g e i n ass ociate d s y m pt o ms. T he deter mi nati o n of w het her t here has 
bee n a si g nifica nt c ha n g e fr o m bef o re starti n g st u d y i nter ve nti o n will be at t he discreti o n of 
t he i n vesti gat or, t his ma y be i n c o ns ultati o n wit h t he st u d y p h ysicia n if t here is a n y 
u ncertai nt y.  
E  5  
Re vie w a n d Assess me nt of P ote nti al H y’s L a w C ases   
T he i nstr ucti o ns i n t his secti o n s h o ul d be f oll o we d f or all cas es w here P H L criteri a are met.  
As s o o n as p ossi ble after t he bi oc he mistr y a b n or m alit y was i nitiall y detecte d, t he st u d y 
p h ysicia n c o ntacts t he i n vesti gat or i n or der t o re vie w a vaila bl e data a n d a gree o n w het h er 
t here is a n alter nati ve e x pla nati o n f or meeti n g P H L criteri a ot her t ha n DI LI ca use d b y t he 
st u d y i nter ve nti o n, t o e ns ure ti mel y a nal ysis a n d re p orti n g t o healt h a ut h orities wit hi n 
1 5  cale n dar da ys fr o m date  P H L criteri a was met.  
Acc or di n g t o t he o utc o m e of t he re vie w a n d assess me nt, t he i n vesti gat or will f oll o w t he 
i nstr ucti o ns bel o w. 
W here t here is  a n a gree d alter n ati ve e x pl a n ati o n  f or t he L F T ele vati o ns or cli nicall y 
rele va nt ma nif estati o n of si g nifica nt cha n ges i n he patic f u ncti o n, a det er mi nati o n of w het her 
t he alter nati ve e x pla nati o n is a n A E will be ma de a n d s u bse q ue ntl y w het her t he A E meets t he 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2 9  of 1 4 3  
 
criteria f or a S A E:  
•  
If t he alter nati ve e x pla n ati o n is n ot  a n A E, rec or d t he alter nati ve e x pla nati o n o n t he 
a ppr o priate e C R F.  
•  
If t he alter nati ve e x pla n ati o n is a n A E/ S A E: u p date t he pre vi o usl y s u b mitte d P H L S A E 
a n d A E e C R Fs acc or di n gl y wit h t he ne w i nf or mati o n (reass essi n g e ve nt ter m; ca usalit y 
a n d seri o us ness criteria) f oll o wi n g t he Astra Ze n eca sta n dar d pr o cess es . 
 
If it is a gree d t h at t here is n o e x pla nati o n f or t he L F T ele vati o ns or cli nicall y rele va nt 
ma nifestati o n of si g nifica nt c ha n ges i n he patic f u ncti o n, ot her t ha n t he st u d y i nter ve nti o n:  
•  
Se n d u p date d S A E (re p ort ter m ‘ H y’s L a w’) acc or di n g t o Astra Ze neca sta n dar d 
pr ocesses.  
− 
T he “ Me dic all y I m p orta nt” seri o us criteri o n s h o ul d be use d if n o ot her s eri o us 
criteria a p pl y.  
− 
As t here is n o alter nati ve e x pla nati o n f or t he H y’s La w cas e, a ca usalit y 
assess me nt of “relate d ” s h o ul d be assi g ne d.  
 
If, t here is a n u na v oi da bl e dela y, of o ver 1 5 cale n dar da ys i n o btai ni n g t he i nf or mati o n 
necessar y t o assess w h et her or n ot t he case meets t he criteria f or H y’s La w, t he n it is ass u me d 
t hat t here is n o alter nati ve e x pla nati o n u ntil s uc h ti me as a n i nf or me d decisi o n ca n be ma de:  
•  
Pr o vi des a n y f urt her u p date t o t he pre vi o usl y s u b mitte d S A E of P H L, (re p ort ter m n o w 
‘ H y’s La w cas e’) e ns uri n g ca usalit y assess me nt is relate d t o st u d y i nter ve nti o n a n d 
seri o us ness criteria is me dicall y i m p orta nt, acc or di n g t o pr ot oc ol pr ocess  f or S A E 
re p orti n g. 
•  
C o nti n ue f oll o w -u p a n d re vie w acc or di n g t o a gree d pla n. O nce t he necessar y 
s u p ple me ntar y i nf or mati o n is o btai ne d, re peat t he re vie w a n d assess me nt t o deter mi ne 
w het her H y’s La w criteri a are still met. U p date t h e pre vi o usl y s u b mitte d P H L  S A E re p ort 
f oll o wi n g pr ot oc ol pr ocess f or S A E re p orti n g, acc or di n g t o t he o utc o me of t he re vie w a n d 
a me n di n g t he re p orte d ter m if a n alter nati ve e x pla nati o n f or t he li ver bi oc h e mistr y 
ele vati o ns is deter mi ne d.  
 
E  6  
Acti o ns Re q uire d f or Re pe at E pis o des of P ote nti al H y’s L a w   
T his secti o n is a p plica ble w he n a partici pa nt meets P H L criteria o n st u d y i nt er ve nti o n a n d has 
alrea d y met P H L criteri a at a pre vi o us o n st u d y i nter ve nti o n visit, w h ere assess me nt of t he 
u n derl yi n g ca use of P H L was c o nsi dere d t o be u nli kel y t o relate t o t he st u d y i nter ve nti o n (see 
Secti o n  E  5 ). Re-c h alle n ges ( w he re a ca usal r elati o ns hi p of t he st u d y i nter ve nti o n c o ul d n ot be 
e xcl u de d) are n ot p er mitte d.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b o te nta n a n d Da p a glifl ozi n - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 0  of 1 4 3  
 
T he re q uir e me nt t o c o n d uct f oll o w -u p, re vie w a n d assess me nt of a re peat occ urre nce(s) of 
P H L is base d o n t he nat ure of t he alter nati ve ca us e i de ntifie d f or t he pre vi o us occ urre nce.  
T he i n vesti gat or s h o ul d deter mi ne t he ca use f or t h e pre vi o us occ urre nce of P H L criteria b ei n g 
met a n d a ns wer t he f oll o wi n g q uesti o n:  
Was t he alter nati ve ca use f or t he pre vi o us o cc urre nce of P H L criteria b ei n g met f o u n d t o be 
t he disease un der st u d y?  
If N o : f oll o w t he pr ocess descri be d i n Secti o n E  4. 2  f or re p orti n g P H L as a n S A E. 
If Yes : deter mi ne if t here has bee n a si g nifica nt c ha n ge i n t he partici p a nt’s c o n diti o n# 
c o m pare d wit h w h e n P H L criteri a were pre vi o usl y met.  
If t here is n o si g nifica nt c ha n ge n o acti o n is re q uire d. 
If t here is a si g nifica nt c h a n ge# f oll o w t he pr ocess descri be d i n Secti o n E  4. 2  f or re p orti n g 
P H L as a n S A E.  
# A ‘si g nific a nt’ c h a n ge  i n t he partici pa nt’s c o n diti o n refers t o a cli nicall y rele va nt c ha n ge i n 
a n y of t he i n di vi d ual li ver bi oc he mistr y para meters i n is olati o n or i n c o m bi nati o n, or a 
cli nicall y rele va nt c ha n g e i n ass ociate d s y m pt o ms. T he deter mi nati o n of  w het her t here has 
bee n a si g nifica nt c ha n g e will be at t he discreti o n of t he i n vesti gat or, i n c o ns ultati o n wit h t he 
st u d y p h ysicia n.  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 1  of 1 4 3  
 
E  7  
L a b or at or y Tests   
H y’s L a w L a b Kit f or Ce ntr al L a b or at ories  
A d diti o nal sta n dar d c he mistr y a n d c oa g ulati o n 
tests 
G G T  
L D H  
Pr ot hr o m bi n ti me  
I N R 
Viral he patitis  
I g M a nti-H A V  
H Bs A g  
I g M a n d I g G a nti-H Bc  
H B V D N A a) 
I g G a nti-H C V  
H C V R N A b) 
I g M a nti-H E V  
H E V R N A  
Ot her viral i nfecti o ns  
I g M a n d I g G a nti-C M V  
I g M a n d I g G a nti-H S V  
I g G a nti-H S V, a n d H S V 1/ 2 I g M testi n g or H S V 
1/ 2 P C R testi n g c) 
I g M a n d I g G a nti-E B V  
Alc o h olic he patitis  
C D -tra nsferri n 
A ut oi m m u ne he patitis  
A N A  
A nti -L K M A b  
A S M A A b  
Meta b olic diseases  
Al p ha -1 -a ntitr y psi n 
Cer ul o plas mi n  
Ir o n 
Ferriti n  
Tra nsferri n   
Tra nsferri n sat urati o n  
A N A  =  a nti n uclear a nti b o d y; A S M A A b  =  a nti-s m o ot h m uscle; C D -tra nsferri n =  car b o h y drate -deficie nt -
tra nsferri n; C M V =  c yt o me g al o vir us; D N A  =  de o x yri b o n ucleic aci d; E B V  =  E pstei n -Barr vir us; 
G G T  =  ga m ma -gl uta m yl tra nsferase; H A V  =  he patitis  A vir us; H Bc  =  hae m o gl o bi n  C; H Bs A g  =  he patitis  B 
s urface a nti ge n; H B V  =  he p atitis  B vir us; H C V  =  he patitis  C vir us; H E V  =  he patitis  E vir us; H S V  =  her pes 
si m ple x vir us; I g G =  i m m u n o gl o b uli n G; I g M  =  i m m u n o gl o b uli n M; I N R  =  I nter nati o nal N or malise d Rati o; 
L D H  =  lactate de h y dr o ge n ase; L K M =  li ver/ ki d ne y micr os o mal; P C R  =  p ol y merase c hai n reacti o n; 
R N A  =  ri b o n ucleic aci d. 
a) H B V D N A is o nl y rec o m me n de d w he n I g G a nti -H Bc is p ositi ve.  
b)  H C V R N A is o nl y rec o m me n de d w he n I g G a nti -H C V is p ositi ve or i nc o ncl usi ve.  
c) H S V 1/ 2 I g M testi n g or H S V 1/ 2 P C R testi n g de pe n di n g o n re gi o n.  
 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 2  of 1 4 3  
 
E  8  
Refere nces   
Ait h al et al 2 0 1 1   
Ait hal G P, Wat ki ns P B, A n dra de RJ, Larre y D, M ol o k hia M, Ta ki ka wa H, H u nt C M, et al. 
Case defi niti o n a n d p he n ot y pe sta n dar dizati o n i n dr u g -i n d uce d li ver i nj ur y. Cli n P har mac ol 
T her. 2 0 1 1;  8 9( 6): 8 0 6 -1 5.  
F D A G ui d a nce f or I n d ustr y, J ul y 2 0 0 9   
F D A G ui da nce f or I n d ustr y (iss ue d J ul y 2 0 0 9) ‘ Dr u g -i n d uce d li ver i nj ur y: Pre mar keti n g 
cli nical e val uati o n’. Availa ble fr o m; htt ps:// w w w.f da. g o v/re g ulat or y -i nf or m ati o n/searc h-f da-
g ui da nce -d o c u me nts/ dr u g -i n d uce d-li ver-i nj ur y-pre mar keti n g -cli nical-e v al uati o n . 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 3  of 1 4 3  
A p pe n di x  F  Pr ot oc ol A me n d me nt Hist or y  
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y bef ore t he Ta ble of C o nte nts.   
C S P Versi o n 2. 0 E U ( E E A re gi o n al m o dific ati o n) 1 6 M a y -2 0 2 4  
T his m o dificati o n is c o nsi dere d t o be s u bsta ntial b ase d o n t he criteria set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E U a n d i n t he E U 
Cli nical Trial Re g ulati o n Article 2, 2 ( 1 3) . 
O ver all R ati o n ale f or t he M o dific ati o n:  
T he C S P was m o difie d f or use i n E U/ E E A c o u ntries i n res p o nse t o t he c o n diti o n i m p ose d as 
part of t he a p pr o val of 2 0 2 3 -5 0 6 8 9 3 -1 1, recei v e d fr o m t he Re p orti n g Me m ber State, 
re q uesti n g re m o val of ‘le gall y a ut h orise d re prese ntati ve’ te xt fr o m t he i nf or me d c o nse nt 
pr ocess w or di n g. I n a d diti o n, mi n or c orrecti o ns, a d diti o ns, deleti o ns, a n d clarificati o ns ( n o ne 
of w hic h si g nifica ntl y i m pact t he safet y or p h ysical/ me ntal i nte grit y of partici pa nts n or t he 
scie ntific val ue of t h e st u d y) ha ve bee n ma de t o ali g n wit h t he gl o bal C S P versi o n 2. 0 t hat has 
bee n pr o d uce d i n parallel wit h t his re gi o nal a me n d me nt.  
S u m m ar y of C h a n ges:  
List of S u bst a nti al M o dific ati o ns  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
A p pe n di x A 3 I nf or me d 
C o nse nt Pr ocess  
State me nt i n b ol d re gar di n g le gall y 
a ut h orise d re prese ntati ve re m o ve d 
fr o m 3 places i n t his secti o n: 
“.. partici pa nt or t heir le g all y 
a ut h orise d re prese nt ati ve ..” 
T o a d dress a re g ulat or y a ge nc y 
re q uest s urr o u n di n g re m o val of 
‘le gall y a ut h orise d re prese ntative’ 
te xt fr o m t he i nf or me d c o nse nt 
pr ocess w or di n g  
List of N o n -S u bst a nti al M o dific ati o ns  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
S u m mar y of C ha n ges Ta ble  
Secti o n u p date d t o reflect t he c ha n ges 
ma d e t o C S P v 1. 0 ( E E A re gi o nal 
m o dificati o n) t o pr o d uce v 2. 0.  
T o gi ve details of c ha n ges ma de t o 
t he pre vi o us versi o n of t he E E A 
re gi o nal m o dificati o n. 
1. 1 S y n o psis, 3 O bjecti ves 
a n d E n d p oi nts 
I n O bjecti ves a n d E n d p oi nts ta ble, 
A E SI of  
’ e dite d t o 
’. 
T o pr o vi de clarificati o n  
1. 1 S y n o psis, 3 O bjecti ves 
a n d E n d p oi nts 
I n O bjecti ves a n d E n d p oi nts ta ble 
f o ot n ote, state me nt a d de d a b o ut Ja pa n 
o ne l o o p -di uretic e q ui vale nt.  
T o pr o vi de clarificati o n f or Ja p a n  
1. 1 S y n o psis  
O bjecti ves a n d E n d p oi nts t a ble 
f o ot n ote b re m o ve d. 
F o ot n ote n ot a p plica ble t o t his ta ble.  
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 4  of 1 4 3  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1 S y n o psis, 4. 1 O verall 
Desi g n, 5. 1 I ncl usi o n 
Criteria  
Re g ar di n g t he si g ns a n d meas ures of 
C S P H, t he te xt was e dite d t o 
“.. prese nce of gastr o -oes o p ha geal 
varices at e n d osc o p y or c ollaterals  at 
i ma gi n g (eit her o ne wit hi n 1 2 m o nt hs 
pri or t o scree ni n g) , a n d/ or 
 of 
 k Pa, or of 
 k Pa 
 (at ti me of scree ni n g).”. T he 
ne w w or di n g is sli g htl y differe nt i n 
Secti o n  5. 1 b ut c o n ve ys t he sa me 
mea ni n g.  
T o pr o vi de clarificati o n  
1. 1 S y n o psis, 4. 1 O verall 
Desi g n  
U n necessar y/c o nf usi n g w or di n g 
ar o u n d n ot ta ki n g st u d y i nter ve nti o n 
d uri n g t he 2 -wee k f oll o w -u p peri o d 
was re m o ve d a n d t he f oll o wi n g 
a d diti o nal w or di n g i n b ol d was a d de d 
“.. 2 wee ks after t heir  pl a n ne d  last d ose 
of st u d y i nter ve nti o n ( pl a n ne d l ast 
d ose is at Visit 6 )”. 
T o si m plif y a n d clarif y te xt  
1. 1 S y n o psis  
C ha n a n d Z ha n g 1 9 9 9 refere nce a d de d.  
T o pr o vi de a refere nce f or t he q u ote d 
statistical i nf or mati o n. 
1. 3 Sc he d ule of Acti vities, 
8. 2 Efficac y Assess me nts, 
8. 2. 2. 1 
, 
8. 3. 4 Ec h ocar di o gra m  
M ulti ple mi n or u p dates ma de t o Ta ble 
1: C S P secti o n cr oss -refere nces 
c orrecte d i n s o me i nsta nces (as well as 
i n f o ot n ote k); car diac M RI re m o ve d 
as a n o pti o n - o nl y E C H O will be use d 
(affects Secti o n 8. 3. 4 als o); ‘ Efficac y 
assess me nts’ c ha n ge d t o ‘ Ke y 
assess me nts’ (affects Secti o n 8. 2 als o); 
e G F R calc ulati o n a n d M E L D sc ore 
calc ulati o n r o ws s witc he d ar o u n d d ue 
t o differe nt C S P secti o n cr oss 
refere nces; a d diti o nal cr oss a d de d f or 
H b A 1c Visit 5; f o ot n ote g 
 ti mi n g m o difie d t o 
‘ or at least 3 h o urs’ fr o m ‘ or 3 t o 4 
h o urs’ (affects Secti o n 8. 2. 2. 1 als o) 
a n d refere nce t o a n o ver ni g ht fast 
re m o ve d; f o ot n ote o re m o ve d (‘if uri ne 
test is p ositive, partici pa nt s h o ul d 
u n der g o c o nfir mat or y ser u m test’) a n d 
s u bse q ue nt f o ot n otes re n u m bere d; ne w 
f o ot n ote p u p date d t o s pecif y ‘ di gital’ 
E C Gs a n d ‘ pre d ose’ E C Gs; ne w 
f o ot n ote q visit c orrecte d fr o m Visit 1 
M ulti ple mi n or u p dates t o c orrect 
i nc orrect i nf or mati o n or t o clarif y. 
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 5  of 1 4 3  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
t o Visit 2; f o ot n otes r a n d s a d de d 
(relati n g t o n ot eati n g a lar ge meal 
bef ore meas ure me nt c ollecti o n (r), a n d 
clarif yi n g t hat e G F R 1 is at e ver y visit 
a n d e G F R 2 at Visits 2, 5, a n d 6 (s).  
3 O bjecti ves a n d E n d p oi nts  
Ta ble 3: E n d p oi nt  of e x pl orat or y 
o bjecti ve relati n g t
 etc, was 
e dite d; “ E val uati o n of c ha n ges i n 
bl o o d a n d uri ne bi o mar kers acr oss ti me 
fr o m baseli ne t o Wee k 6” e dite d t o 
re m o ve refere nce t o uri ne bi o mar kers. 
Uri ne bi o mar kers wil l n ot be use d 
f or t his o bjecti ve 
3 O bjecti ves a n d E n d p oi nts  
E x pl orat or y P R O e n d p oi nt “ Patie nt 
Gl o bal I m pressi o n of Se verit y –  Li ver 
Disease se verit y le vel” a d de d t o P R O 
e n d p oi nts list.  
E n d p oi nt pre vi o usl y o mitte d fr o m 
ta ble i n err or. 
5. 2 E xcl usi o n Criteria  
Criteri o n 3 2 e dite d t o a d d t he w or ds i n 
b ol d: “I m pla nte d c ar di ac  electr o nic 
de vice s uc h as pace ma ker or 
i m pl a nt a ble c ar di o verter 
defi brill at or ” 
A d diti o nal details a d de d f or clarit y  
5. 3. 1 Meals a n d Dietar y 
Restricti o ns  
Re vise d te xt i n b ol d was a d de d: “ St u d y 
i nter ve nti o n s h o ul d be ta ke n bet wee n 
a p pr o xi matel y 0 8: 0 0 t o 1 0: 0 0 eac h 
m or ni n g. If st u d y i nter ve nti o n is n ot 
ta ke n bef ore n o o n ( 1 2: 0 0 p m), it is 
rec o m me n de d t o ta ke t he ne xt d ose i n 
t he m or ni n g t he ne xt da y. O n t he d a y 
of r a n d o mis ati o n, st u d y i nter ve nti o n 
c a n be t a k e n after n o o n, wit h o ut 
affecti n g t he ne xt d a y’s d ose.  O n t he 
da ys of 
 assess me nts, 
m e as ure m e nts will be perf or m e d at 
t he ti m e p oi nts s pecifie d i n t h e S o A 
( T a ble 1) after a n o ver-ni g ht f ast or 
at  le ast 3 h o urs after a m e al. 
A d diti o n all y, f or Visit 6, 
 s h o ul d be 
perf or m e d ≥ 3 h o urs after st u d y 
i nter ve nti o n is gi ve n.” 
F or practical p ur p oses, d ue t o t he 
n u m ber of acti vities o n t he da y of 
ra n d o misati o n (a p plies t o d osi n g 
ti mi n g), a n d t o pr o vi de clarificati o n 
re gar di n g 
assess me nt ti mi n g vers us d osi n g a n d 
fee di n g. 
6. 9. 1 Pr o hi bite d 
Me dicati o ns  
 re m o ve d as a pr o hi bite d 
me dicati o n i n Ta ble 5.  
 is n ot a bs or be d s o d oes 
n ot nee d t o be pr o hi bite d  
7. 1 Disc o nti n uati o n of 
St u d y I nter ve nti o n  
‘ Rec urre nt e nce p hal o pat h y’ was e dite d 
t o ‘ O vert e nce p hal o pat h y’ 
C orrecti o n of pre vi o us te xt  
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 6  of 1 4 3  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
7. 1. 2 Ma na g e me nt of 
Treat me nt -e mer ge nt 
A b n or malities i n L F Ts  
Te xt i n b ol d was a d de d: “ T he DI LI 
al g orit h ms acc o u nt f or 
 of t he 
 val ue ( defi ne d as t he  
 of 
t he 
 d uri n g t he 
 peri o d 
 visit v al ues).” 
T o pr o vi de clarificati o n  
7. 2 Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal 
fr o m t he St u d y 
Sec o n d b ullet re m o ve d: “ At t he ti me  of 
disc o nti n ui n g fr o m t he st u d y, if t he 
partici pa nt has n ot bee n disc o nti n ue d 
fr o m t he st u d y i nter ve nti o n, see 
Secti o n 7. 2”  
B ullet c o nsi dere d u n necessar y  
7. 3 L ost t o F oll o w -u p  
Fi nal b ullet a me n de d fr o m “ S h o ul d t he 
partici pa nt c o nti n ue t o be u nreac ha ble, 
t he partici pa nt will be c o nsi dere d 
wit h dr a w n fr o m st u d y “ t o “ S h o ul d 
t he partici pa nt c o nti n ue t o be 
u nreac h a ble, t he partici pa nt will be 
c o nsi dere d l ost t o f oll o w-u p ” 
C orrecti o n of pre vi o us te xt  
8. 2 Efficac y a n d 
E x pl orat or y Assess me nts  
“ T here are n o efficac y assess me nts i n 
t his st u d y” was a d de d. T he sec o n d 
se nte nce was u p date d t o sa y ‘k e y  a n d 
e x pl or at or y  e n d p oi nts’. 
T o ali g n wit h t he o bjecti ves a n d 
clarif y t hat t here are n o efficac y 
assess me nts  
8. 2. 2. 2 Ser u m A nal ysis of 
Creati ni ne a n d C ystati n C 
(e G FR)  
T y p o gra p hical err ors c orrecte d i n 
e G F R 1 a n d e G F R 2 f or m ulae, pl us t he 
f oll o wi n g te xt was a d de d at t he e n d of 
t his secti o n “ Base d o n t he S o A, e G F R 1 
calc ulati o ns will be at e ver y visit, 
w hile e G F R 2 calc ulati o ns will be at 
Visits 2, 5 a n d 6” a n d re m o ve d fr o m 
Secti o n  8. 2. 2. 3.  
T o c orrect t y p o gra p hical err ors a n d 
t o place te xt i n m ore a p pr o priate 
l ocati o n 
8. 2. 2. 3 La b orat or y 
Assess me nts f or 
E x pl orat or y A nal yses  
T he f oll o wi n g te xt was a d de d t o b ullet 
2: “If bilir u bi n, I N R, a n d/ or creati ni ne 
val ues are less t ha n 1. 0, t he val ue is set 
as 1. 0.” 
T o a d d clarificati o n  
8. 2. 2. 3 La b orat or y 
Assess me nts f or 
E x pl orat or y A nal yses  
“ Bl o o d a n d uri ne sa m ples” c ha n ge d t o 
“ Bl o o d sa m ples” t hr o u g h o ut t his 
secti o n 
Uri ne sa m ples will n ot be use d  
8. 2. 2. 3 La b orat or y 
Assess me nts f or 
E x p l orat or y A nal yses 
T he f oll o wi n g te xt was re m o ve d: 
“ N ote: E x pl orat or y a nal yses la b orat or y 
res ults c o ul d be c o nsi dere d p ote ntiall y 
u n bli n di n g a n d res ults f or t hese 
e x pl orat or y assess me nts will n ot be 
ma d e a v aila ble t o t he st u d y tea m u ntil 
after t he Last S u bject Last Visit.”  
T he state me nt was i nc orrect; o nl y 
P K data w o ul d be u n bli n di n g  
8. 2. 2. 4 Patie nt -re p orte d 
O utc o mes  
E ntire s u bsecti o n m o ve d fr o m 8. 3. 6. 3 
t o bec o me 8. 2. 2. 4. 
T he s u bsecti o n was i nc orrectl y 
i ncl u de d u n der safet y assess m e nts 
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  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 7  of 1 4 3  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
8. 2. 2. 4 Patie nt -re p orte d 
O utc o mes  
Te xt i n b ol d a d de d: “ P R O 
q uesti o n naires s h o ul d be c o m plete d 
bef ore a n y ot her st u d y pr oce d ures 
d uri n g Visit 6 , t o a v oi d bias w he n 
res p o n di n g t o q uesti o ns” 
T o pr o vi de clarificati o n of ti mi n g  
8. 4 A d verse E ve nts, S A Es, 
a n d Ot her Safet y Re p or ti n g 
Te xt i n b ol d a d de d: “ A d verse e ve nts 
will be re p orte d b y t he partici pa nt ( or, 
w he n a p pr o priate, b y a care gi ver, 
s urr o gate, or t he partici pa nt’s le gall y 
a ut h orise d re prese ntati ve); t hese m ust 
t he n be assesse d b y t he i n vesti g at or 
a n d if c o nsi dere d a n A E it will be 
re p orte d b y t he i n vesti g at or . 
T o pr o vi de a d diti o nal detail of t he 
re p orti n g pr ocess 
9. 1 Statistical H y p ot heses  
T he f oll o wi n g te xt i n b ol d was a d de d:  
“ As t his is a n e arl y -p h ase s afet y 
st u d y, n o f or mal statistical h y p ot hesis 
tests or m ulti plicit y  a dj ust m e nt  will 
be perf or me d.”  
T o clarif y t hat n o f or mal statistical 
h y p ot hesis testi n g or m ulti plicit y 
a dj ust me nt will be perf or me d d ue t o 
t his bei n g a n earl y-p hase safet y 
st u d y 
9. 1 Statistical H y p ot heses  
T he f oll o wi n g te xt was re m o ve d: “ T he 
a n al yses will b e descri pti ve usi n g a n 
esti mati o n a p pr oac h.  
T he a nal yses are descri be d i n m ore 
detail i n Secti o n 9. 4 a n d t his brief 
se nte nce i n 9. 2 c o ul d ha ve res ulte d 
i n mis u n dersta n di n g of t he pla n ne d 
a nal yses.  
9. 4. 2 Ke y E n d p oi nts  
Te xt e dite d fr o m “ All i nterc urre nt 
e v e nts will be ha n dle d b y a w hile -o n -
treat me nt strate g y. Treat me nt 
disc o nti n uati o ns d ue t o a n y reas o n 
(i ncl u di n g ter mi nal e ve nts, s uc h as 
deat h) are re gar de d as i nterc urre nt 
e v e nts. P ost -i nterc urre nt e ve nt 
meas ure me nts f or t he c o m p o ne nts of 
t he c o m p osite e n d p oi nts will n ot be 
i ncl u de d i n t he efficac y a nal ysis” t o 
“ T he n o n -ter mi nal i nterc urre nt e ve nts 
(e g, treat me nt disc o nti n uati o ns d ue t o 
a n y reas o n, use of pr o hi bite d 
me dicati o n) will be ha n dle d b y a 
treat me nt p olic y strate g y. F or ter mi nal 
i nterc urre nt e ve nts (ie, deat h), a 
w hile -ali ve strate g y will be a p plie d.”.  
T o better ali g n wit h safet y e n d p oi nt 
a nal ysis 
9. 4. 3. 1 A d verse E ve nts  
Te xt e dite d as A Es lea di n g t o 
wit h dra wal fr o m st u d y will n ot be 
i ncl u de d i n t he o ver vie w of A Es a n d 
se p arate A E ta bles f or ti mi n g of e ve nts 
will n ot be pr o vi de d  
A Es lea di n g t o wit h dra wal fr o m 
st u d y are n o l o n ger pr o vi de d as 
c o m pa n y sta n dar d, a n d re gar di n g 
se parate A E ta bles f or ti mi n g of 
e ve nts, t his was a c orrecti o n  

C li nical St u d y Pr ot oc ol - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 8  of 1 4 3  
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
9. 4. 3. 2 Vital Si g ns  
Te xt e dite d as details of t he de fi niti o n 
of cli nicall y si g nifica nt vital si g ns will 
n ot be pr o vi de d i n t he S A P  
C orrecti o n of pre vi o us te xt  
9. 4. 3. 3 La b orat or y 
Assess me nts  
Te xt e dite d as details of t he defi niti o n 
of cli nicall y si g nifica nt la b orat or y 
assess me nts will n ot be pr o vi de d i n t he  
S A P  
C orrecti o n of pre vi o us te xt  
9. 4. 4. 3 E x pl orat or y P R O 
E n d p oi nts  
Ne w ‘ E x pl orat or y P R O E n d p oi nts’ 
s u bsecti o n a d de d 
S u bsecti o n was missi n g pre vi o usl y  
9. 4. 4. 4 Ot her E x pl orat or y 
E n d p oi nts  
T his secti o n use d t o be 9. 4. 4. 1 a n d 
e ntitle d ‘ E x pl orat or y Efficac y 
E n d p oi nts’, b ut was m o ve d t o bec o me 
9. 4. 4. 4 s o t hat t he title c o ul d be 
c h a n ge d t o ‘ Ot her E x pl orat or y 
E n d p oi nts’  
T here are n o efficac y e n d p oi nts i n 
t his st u d y 
9. 4. 4. 4 Ot her E x pl orat or y 
E n d p oi nts  
B ol d te xt a d de d (a n d i nc orrect te xt 
re gar di n g uri ne bi o mar kers re m o ve d): 
“ Perce nta ge a n d a bs ol ute c ha n ge i n 
 a n d/ or 
 assesse d 
usi n g 
 at Wee k 6, 
c h a n ge i n e G F R at Wee k 1, Wee k 6, 
a n d e v al uati o n of c ha n ges i n bl o o d 
bi o mar kers acr oss ti me c o urse of t he 
st u d y will be a nal yse d acc or di n g t o 
tre at m e nt gr o u p ” 
T o pr o vi de clarificati o n, i ncl u di n g 
t he fact t hat uri ne bi o mar kers will 
n ot be use d  
9. 4. 4. 4 E x pl orat or y 
[secti o n delete d] 
Secti o n delete d  
 details are n o w 
a d de d t o Secti o n 9. 4. 4. 1.  
A p pe n di x A 1  
Te xt e dits t o c o m pl y wit h rece nt C S P 
te m plate c ha n ges, i ncl u di n g details of 
S U S A R re p orti n g re q uire me nts a n d 
re p orti n g i n t he case of a seri o us 
breac h  
T o c o m pl y wit h ne w C S P te m plate 
a n d re p orti n g re q uire me nts. 
A 4 Data Pr otecti o n  
Pers o nal data breac hes te xt a d de d  
T o c o m pl y wit h ne w C S P te m plate 
a n d data -pr otecti o n re q uire me nts.  
A 6 Disse mi nati o n of 
Cli nical St u d y Data  
We bsites o n w hic h t he cli nical st u d y 
descri pti o n will be a vaila ble was e dite d  
D ue t o a n u p date t o t he C S P 
te m plate 
D 2 M ulti -o mics Researc h 
Pla n a n d Pr o ce d ures  
Title a n d secti o n c o nte nt e dite d fr o m 
‘ ge n o mics’ t o m ulti-o mics’ t hr o u g h o ut  
D ue t o a n u p date t o t he C S P 
te m plate 
A p pe n di x F  
A p pe n di x a d de d t o kee p a rec or d of t he 
e dits t hat were ma de t o pr o d uce t he 
pre vi o us E E A re gi o nal m o dificati o n 
( v 1. 0) fr o m t he gl o bal C S P v 1. 0. 
T o ca pt ure t he hist or y of E E A 
re gi o nal m o dificati o ns t o t he gl o bal 
C S P  
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3 9  of 1 4 3  
 
Secti o n N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1 1 Refere n ces  
C ha n a n d Z ha n g 1 9 9 9 a d de d a n d all 
refere nces or dere d al p ha beticall y  
Refere nce ori gi nall y missi n g a n d 
refere nce list n ot i n al p ha betical 
or der  
 
C S P versi o n 1. 0 E U ( E E A re gi o n al m o dific ati o n) 0 6-M arc h -2 0 2 4  
T his m o dificati o n t o t he gl o bal C S P versi o n 1. 0 was c o nsi dere d t o b e n o n -s u bsta ntial base d o n 
t he criteria s et f ort h i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d 
t he C o u ncil of t he E U  a n d i n t he E U Cli nical Trial Re g ulati o n Article 2, 2 ( 1 3) beca us e it 
neit her si g nifica ntl y i m pacte d t he safet y or p h ysical/ me ntal i nte grit y of partic i pa nts n or t he 
scie ntific val ue of t h e st u d y. 
O ver all R ati o n ale f or t he A me n d me nt:  
T his a me n d me nt t o t he gl o bal C S P versi o n 1. 0 f oc use d o n u p dates a n d clarificati o ns i n 
res p o nse t o E U C T R c o m me nts. T he ke y u p dates c o nsiste d of clarif yi n g t h at statistical 
anal yses a p plie d t o c o m p ari n g all treat me nt gr o u ps, i ncl u di n g t he place b o gr o u p, a n d 
e x pa n di n g t he e x cl usi o n criteri o n a b o ut o n g oi n g aller g y/ h y perse nsiti vit y t o i ncl u de t he 
e xci pie nts of t he liste d pr o d ucts. A d diti o nall y, i nf or mati o n o n S U S A R re p orti n g was a d de d t o 
t he secti o n o n t he re p orti n g of S A Es. 
S u m m ar y of C h a n ges:  
List of N o n -S u bst a nti al M o dific ati o ns  
Secti o n 
N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1 S y n o psis  
U p date d te xt t o reflect c ha n ges ma de i n t he 
b o d y of t he C S P  
T o be c o nsiste nt wit h t he b o d y of t he C S P  
5. 2 E xcl usi o n 
Criteria ( # 2 8)  
A d de d “ or a n y of t he e xci pie nts of t he 
pr o d ucts” t o t he e x cl usi o n criteri o n o n 
hist or y or o n g oi n g aller g y/ h y perse nsiti vit y  
T o clarif y t hat a n y e xci pie nts of t he 
pr o d ucts are i ncl u de d i n t he e xcl usi o n 
criteri o n i n res p o nse t o E U C T R c o m me nts  
8. 4. 8 Re p orti n g 
of S A Es  
A d de d state me nt re g ar di n g t he S p o ns or 
c o m pl yi n g wit h E ur o pea n Cli nical Trials 
Re g ulati o n ( E U) N o 5 3 6/ 2 0 1 4 f or re p orti n g 
all S U S A Rs  
T o a d d i nf or mati o n i n res p o nse t o E U C T R 
c o m me nts 
9. 1 Statistical 
H y p ot heses  
Clarifie d t hat f or mal statistical h y p ot hesis 
testi n g or m ulti plicit y a dj ust me nt will n ot be 
perf or me d d ue t o t his bei n g a n earl y p hase 
safet y st u d y  
T o a d d j ustificati o n f or n ot perf or mi n g 
m ulti plicit y a dj ust me nt i n res p o nse t o E U 
C T R c o m me nts  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4 0  of 1 4 3  
Secti o n 
N u m ber a n d 
N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
9. 4. 2 Ke y 
E n d p oi nts  
Delete d “zi b ote nta n/ da pa glifl ozi n 
c o m bi nati o n a n d c orres p o n di n g zi b ote nta n 
m o n ot hera p y” fr o m t he te xt disc ussi n g t he 
calc ulati o n of 9 0 % CIs usi n g t he Cl o p per -
Pears o n met h o d  
A d de d “f or pair wise c o m paris o ns bet we e n 
treat me nt gr o u ps” t o te xt descri bi n g t he 
a n al ysis usi n g M M R M met h o d ol o g y  
T o clarif y t hat a nal ysis met h o ds a p pl y t o 
c o m pari n g all treat me nt gr o u ps, i ncl u di n g 
t he place b o gr o u p 

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4 1  of 1 4 3  
 
1 1  
R E F E R E N C E S   
C h a n a n d Z h a n g 1 9 9 9   
C ha n I, Z ha n g Z. Test -base d c o nfi de n ce i nter vals f or t he differe n ce of t w o bi n o mial 
pr o p orti o ns. Bi o metrics. 1 9 9 9; 5 5: 1 2 0 2 -9.  
D a p a glifl ozi n I n vesti g at or’s Br oc h ure   
Da pa glifl ozi n I n v esti gat or’s Br oc h ure, E diti o n 1 8.  
G arcí a -P a g á n  et al  2 0 2 0   
García -Pa gá n J C, Saff o S, Ma n d orfer M, Garcia -Tsa o G. W h ere d o es TI P S fit i n t he 
ma na ge me nt of p atie nts wit h cirr h osis? J H E P Re p. 2 0 2 0 Ma y 2 3; 2( 4): 1 0 0 1 2 2.  
G B D 2 0 1 7   
G B D 2 0 1 7 Cirr h osis C olla b orat ors. T h e gl o bal, re gi o nal, a n d nati o nal b ur d e n of cirr h osis b y 
ca use i n 1 9 5 c o u ntri es a n d territ ories, 1 9 9 0 -2 0 1 7: a s yste matic a nal ysis f or t he Gl o b al B ur de n 
of Disease St u d y 2 0 1 7. L a ncet G astr oe nter ol H e pat ol. 2 0 2 0; 5( 3): 2 4 5 -6 6.  
G u n ar at h ne  et al  2 0 2 0   
G u narat h ne L S, Raja pa ks ha H, S hac kel N, A n g us P W, Herat h C B. Cirr h otic p ort al 
h y perte nsi o n: Fr o m pat h o p h ysi ol o g y t o n o vel t hera pe utics. Worl d J Gastr o e nter ol. 
2 0 2 0; 2 8; 2 6( 4 0): 6 1 1 1 -4 0.  
Heers pi n k et al 2 0 2 0   
Heers pi n k HJ L, K o h a n D E, de Zee u w D. Ne w i nsi g hts  fr o m S O N A R i n dicate a d di n g s o di u m 
gl uc ose c o -tr a ns p orter 2 i n hi bit ors t o a n e n d ot heli n rece pt or a nta g o nist miti gates fl ui d 
rete nti o n a n d e n h a nces al b u mi n uria re d ucti o n. Ki d ne y I nt. 2 0 2 1; 9 9( 2): 3 4 6-4 9.  
Hsi a n g  et al  2 0 2 0   
Hsia n g J C, Wo n g V W. S G L T 2 i n hi bit ors i n li ver patie nts. Cli n Gastr oe nter ol He pat ol. 
2 0 2 0; 1 8( 1 0): 2 1 6 8 -7 2 . 
I n ker et al  2 0 2 1   
I n ker L A, E nea ny a N D, C ores h J, Ti g hi o uart H, Wa n g D, Sa n g Y, et al. Ne w creati ni ne - a n d 
c ystati n C – base d e q uati o ns t o esti mate G F R wit h o ut race. N E n gl J Me d. 2 0 2 1; 3 8 5: 1 7 3 7 -4 9.  
I w a kiri 2 0 1 4  
I wa kiri Y. Pat h o p h ysi ol o g y of p ortal h y perte nsi o n. Cli n Li ver Dis. 2 0 1 4; 1 8( 2): 2 8 1 -9 1.  
K osi b or o d  et al  2 0 2 1   
K osi b or o d M N, Esterli ne R, F urta d o R H M, Oscarss o n J, Gas par ya n S B, K oc h G G, et al. 
Da pa glifl ozi n i n patie nts wit h car di o meta b olic ris k fact ors h os pitalise d wit h C O VI D -1 9 
( D A R E-1 9): a ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d, p hase 3 trial. La ncet Dia betes 
E n d ocri n ol. 2 0 2 1; Se p; 9( 9): 5 8 6 -9 4.  

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4 2  of 1 4 3  
 
Li u  et al  2 0 2 2   
Li u Y B, C he n M K. E pi de mi ol o g y of li ver cirr h osis a n d ass ociate d c o m plicati o ns: C urre nt 
k n o wle d ge a n d f ut ure dir ecti o ns. Worl d J Gastr o e nter ol. 2 0 2 2 N o v 7; 2 8( 4 1): 5 9 1 0 -3 0.  
M o nt al v o -G or d o n  et al  2 0 2 0   
M o ntal v o -G or d o n I, C hi -Cer vera L A, García -Tsa o G. S o di u m -gl uc ose c otra ns p orter 2 
i n hi bit ors a meli orate ascites a n d peri p heral e de ma i n patie nts wit h cirr h osis a n d dia betes. 
He pat ol o g y 2 0 2 0; 7 2( 5): 1 8 8 0 -2.  
M orris  et al  2 0 0 5   
M orris C D, R ose A, C ur we n J, H u g hes A M, Wils o n DJ, We b b DJ. S pecifi c i n hi biti o n of t he 
e n d ot heli n A rece pt or wit h Z D 4 0 5 4: cli nical  a n d pre-cli nical e vi de nce. Br J Ca ncer. 
2 0 0 5; 9 2( 1 2): 2 1 4 8 -5 2.  
Nels o n  et al  2 0 1 2   
Nels o n J B, Fizazi K, Miller K, Hi ga n o C, M o ul J W, A kaza H, et al. P hase 3, ra n d o mize d, 
place b o -c o ntr olle d st u d y of zi b ote nta n ( Z D 4 0 5 4) i n patie nts wit h castrati o n-resista nt pr ostate 
ca ncer metastatic t o b o ne. Ca ncer. 2 0 1 2; 1 1 8( 2 2): 5 7 0 9 -1 8.  
O k a m ot o  et al  2 0 1 6   
O ka m ot o T, K o da M, Mi y os hi K, O n o ya ma T, Kis hi na M, Mat o n o T, et al. A ntifi br otic effects 
of a m brise nta n, a n e n d ot heli n -A rece pt or a nta g o nist, i n a n o n -alc o h olic steat o he patitis m o use 
m o del. Worl d J He p at ol. 2 0 1 6; 8( 2 2): 9 3 3 ‒ 4 1.  
P o or d a d 2 0 1 5   
P o or da d F F. Prese ntati o n a n d c o m plicati o ns ass ociate d wit h cirr h osis of t he li ver. C urr Me d 
Res O pi n. 2 0 1 5; 3 1( 5): 9 2 5 -3 7.  
Prest o n et al 2 0 2 0   
Prest o n I R, B ur ger C D, Bart ol o me S, Saf dar Z, Kr o w ka M, S o o d N, et al. A m brise nta n i n 
p ort o p ul m o nar y h y perte nsi o n: A m ultice nter, o pe n -la bel trial. J Heart L u n g Tra ns pla nt. 
2 0 2 0; 3 9( 5): 4 6 4 -4 7 2.  
R oc ke y a n d C h u n g  1 9 9 6   
R oc ke y D C, C h u n g JJ. E n d ot heli n a nta g o nis m i n e x peri me ntal he p atic fi br osis. I m plicati o ns 
f or e n d ot heli n i n t he pat h o ge nesis of w o u n d heali n g. J Cli n I n vest. 1 9 9 6; 9 8( 6): 1 3 8 1-8.  
R o m a nelli a n d St asi 2 0 1 6   
R o ma nelli R G, Stasi C. Rece nt a d va n ce me nts i n dia g n osis a n d t hera p y of li ver cirr h osis. C urr 
Dr u g Tar gets. 2 0 1 6; 1 7( 1 5): 1 8 0 4 -1 7.  
Sit b o n et al 2 0 1 9   
Sit b o n O, B osc h J, C ottreel E, Cs o n ka D, de Gr o ot e P, H oe per M M, et al. Macite nta n f or t he 
treat me nt of p ort o p ul m o nar y h y pert e nsi o n ( P O R TI C O): a m ultice ntre, ra n d o mise d, d o u ble-

Cli nical St u d y Pr ot oc ol  - 3. 0 E U  
Astra Ze n eca  
Zi b ote nta n a n d Da p a glifl ozi n  - D 4 3 2 6 C 0 0 0 0 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4 3  of 1 4 3  
bli n d, place b o -c o ntr olle d, p hase 4 trial. La n cet Res pir Me d. 2 0 1 9; 7( 7): 5 9 4 -6 0 4. 
T a k a h as hi  et al  2 0 2 1   
Ta ka has hi H, K ess o k u T, Ka wa n a ka M, N o n a ka M, H y o g o H, F ujii H, et al. I pra glifl ozi n 
i m pr o ves t he he patic o ut c o mes of patie nts wit h dia betes wit h N A F L D. He pat ol C o m m u n. 
2 0 2 2; 6( 1): 1 2 0 -3 2.  
Ts oc h atzis et al 2 0 1 4   
Ts oc hatzis E A, B osc h J, B urr o u g hs A K. Li ver cirr h osis. La ncet. 2 0 1 4; 3 8 3( 9 9 3 0): 1 7 4 9 -6 1.  
Zi b ote nt a n I n vesti g at or’s Br oc h ure   
Zi b ote nta n I n vesti gat or’s Br oc h ure, E diti o n 2 1. 2.  
Zi p pric h  et al  2 0 2 1  
Zi p pric h A, Gitti n ger F, Wi n kler M, D olli n ger M M, Ri p oll C. Effect of E T -A bl oc ka de o n 
p ortal press ur e a n d he p atic arteri al perf usi o n i n patie nts wit h cirr h osis: A pr o of of c o nce pt 
st u d y. Li ver I nt. 2 0 2 1; 4 1( 3): 5 5 4 -6 1.