Clinical trial NCT04986202
Conditions: Heart Failure With Preserved Ejection Fraction
Keywords: Heart failure Heart failure with preserved ejection fraction HFpEF
Sponsor: AstraZeneca
Start date: 2021-06-30; Completion date: 2024-03-27
Enrollment: 711 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomised, double-blind, placebo-controlled, multi-center sequential phase 2b and Phase 3 study to evaluate the efficacy and safety of AZD4831 administered for up to 48 Weeks in participants with heart failure with left ventricular ejection fraction \> 40%. The study will consist of 2 separate parts, Part A and Part B, approximately 660 participants will be randomised in Part A, 820 in Part B.

Detailed description:

Arms: arm 1: AZD4831 2.5 mg arm 2: AZD4831 5 mg arm 3: Placebo arm 4: AZD4831 Dose based on Part A arm 5: Placebo
Interventions: intervention 1: AZD4831 intervention 2: Placebo
Intervention descriptions: intervention 1: AZD4831 intervention 2: Placebo

Protocol documents:
SAP_003.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1  of 9 2  
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
St u d y C o de  
D 6 5 8 0 C 0 0 0 1 0  
 
E diti o n N u m ber  
4 . 0 
 
Date  
0 8 -Mar -2 0 2 4  
 
 
 
 
 
 
 
 
 
 
A R a n d o mise d, D o u ble -bli n d, Pl ace b o -c o ntr olle d, M ulti -ce nter 
Se q ue nti al P h ase 2 b a n d P h ase 3 St u d y t o E v al u ate t he Effic ac y 
a n d S afet y of A Z D 4 8 3 1 A d mi nistere d f or u p t o 4 8 Wee ks i n 
P artici p a nts wit h He art F ail ure Wit h Left Ve ntric ul ar Ejecti o n 
Fr acti o n > 4 0 %  
 
 
 
R e d a ct e d f or P u bli c Di s cl o s ur e


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2  of 9 2  
 
T A B L E O F C O N T E N T S  
1  
I N T R O D U C TI O N ....................................................................................... 2 6  
2  
C H A N G E S T O P R O T O C O L P L A N N E D A N A L Y S E S  ............................ 2 6  
3  
D A T A A N A L Y SI S C O N SI D E R A TI O N S  .................................................. 2 6  
3. 1  
Ti mi n g of A nal yses ...................................................................................... 2 6  
3. 2  
A nal ysis P o p ulati o ns  ................................................................................... 2 6  
3. 3  
Ge neral C o nsi derati o ns  ................................................................................ 2 6  
3. 3. 1  
Ge neral St u d y Le vel Defi niti o ns  ................................................................. 2 6  
3. 3. 1. 1  
Baseli ne ........................................................................................................ 2 6  
3. 3. 1. 2  
Ha n dli n g of i nc o m plete dates  ...................................................................... 2 7  
3. 3. 1. 3  
La b orat or y data pri nci ples  ........................................................................... 2 9  
3. 3. 1. 4  
St u d y Da y  .................................................................................................... 2 9  
3. 3. 1. 5  
St u d y peri o ds  ............................................................................................... 2 9  
3. 3. 1. 6  
S u bject ter mi n ol o g y c o n ve nti o n  .................................................................. 3 0  
3. 3. 1. 7  
S u m mar y statistics  ....................................................................................... 3 0  
3. 3. 1. 8  
Ti me at ris k a n d ce ns ori n g  ........................................................................... 3 1  
3. 3. 1. 9  
U nit c o n ve nti o ns  .......................................................................................... 3 1  
3. 3. 2  
Visit Wi n d o w  ............................................................................................... 3 1  
3. 3. 3  
Ha n dli n g of Sc he d ule d a n d U nsc he d ule d Visits  ......................................... 3 2  
3. 3. 4  
M ulti plicit y/ M ulti ple C o m paris o ns  ............................................................. 3 3  
3. 3. 5  
Ha n dli n g of Pr ot oc ol De viati o ns i n St u d y A nal ysis  .................................... 3 4  
3. 3. 5. 1  
C o vi d -1 9  ...................................................................................................... 3 4  
4  
S T A TI S TI C A L A N A L Y SI S  ....................................................................... 3 5  
4. 1  
St u d y P o p ulati o n  .......................................................................................... 3 5  
4. 1. 1  
S u bject Dis p ositi o n a n d C o m pleti o n Stat us  ................................................ 3 5  
4. 1. 1. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 3 5  
4. 1. 1. 2  
Prese ntati o n .................................................................................................. 3 6  
4. 1. 2  
A nal ysis Sets  ................................................................................................ 3 6  
4. 1. 2. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 3 6  
4. 1. 2. 2  
Prese ntati o n .................................................................................................. 3 7  
4. 1. 3  
St u d y Recr uit me nt  ....................................................................................... 3 7  
4. 1. 3. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 3 7  
4. 1. 3. 2  
Prese ntati o n .................................................................................................. 3 8  
4. 1. 4  
Stratificati o n fact ors  ..................................................................................... 3 8  
4. 1. 4. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 3 8  
4. 1. 4. 2  
Prese ntati o n .................................................................................................. 3 8  
4. 1. 5  
Pr ot oc ol De viati o ns  ..................................................................................... 3 8  
4. 1. 5. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 3 8  
4. 1. 5. 2  
Prese ntati o n .................................................................................................. 3 9  
4. 1. 6  
De m o gra p hics  .............................................................................................. 3 9  
4. 1. 6. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 3 9  
4. 1. 6. 2  
Prese ntati o n .................................................................................................. 4 0  
4. 1. 7  
Baseli ne C haracteristics  ............................................................................... 4 0  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3  of 9 2  
4. 1. 7. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 4 0  
4. 1. 7. 2  
Prese ntati o n .................................................................................................. 4 0  
4. 1. 8  
Alc o h ol a n d nic oti ne use at baseli ne  ........................................................... 4 0  
4. 1. 8. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 4 0  
4. 1. 8. 2  
Prese ntati o n .................................................................................................. 4 1  
4. 1. 9  
Baseli ne Disease C haracteristics  ................................................................. 4 1  
4. 1. 9. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 4 1  
4. 1. 9. 2  
Prese ntati o n .................................................................................................. 4 2  
4. 1. 1 0  
Me dical Hist or y a n d C o nc o mita nt Disease  ................................................. 4 2  
4. 1. 1 0. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 4 2  
4. 1. 1 0. 2  
Prese ntati o n .................................................................................................. 4 2  
4. 1. 1 1  
Pri or a n d C o nc o mita nt Me dicati o ns  ............................................................ 4 2  
4. 1. 1 1. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 4 2  
4. 1. 1 1. 2  
Prese ntati o n .................................................................................................. 4 3  
4. 1. 1 2  
St u d y Dr u g C o m plia nce  .............................................................................. 4 3  
4. 1. 1 2. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 4 3  
4. 1. 1 2. 2  
Prese ntati o n .................................................................................................. 4 3  
4. 2  
E n d p oi nt A nal yses  ....................................................................................... 4 4  
4. 2. 1  
Pri mar y E n d p oi nt –  K C C Q -T S S c ha n ge fr o m baseli ne at 1 6 wee ks  .......... 5 6  
4. 2. 1. 1  
Defi niti o n  ..................................................................................................... 5 6  
4. 2. 1. 2  
Deri vati o ns  ................................................................................................... 5 6  
4. 2. 1. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 5 7  
4. 2. 1. 4  
Pri mar y A nal ysis of Pri mar y E n d p oi nt ........................................................ 5 7  
4. 2. 1. 5  
Se nsiti vit y A nal yses of t he Pri mar y E n d p oi nt  ............................................. 5 8  
4. 2. 1. 6  
S u p ple me ntar y A nal yses of t he Pri mar y E n d p oi nt  ...................................... 5 8  
4. 2. 1. 7  
S u b gr o u p A nal yses  ...................................................................................... 6 0  
4. 2. 2  
Pri mar y E n d p oi nt –  6 M W D c ha n ge fr o m baseli ne at 1 6 wee ks  ................. 6 2  
4. 2. 2. 1  
Defi niti o n  ..................................................................................................... 6 2  
4. 2. 2. 2  
Deri vati o ns  ................................................................................................... 6 2  
4. 2. 2. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 2  
4. 2. 2. 4  
Pri mar y A nal ysis of Pri mar y E n d p oi nt ........................................................ 6 2  
4. 2. 2. 5  
Se nsiti vit y A nal yses of t he Pri mar y E n d p oi nt  ............................................. 6 2  
4. 2. 2. 6  
S u p ple me ntar y A nal yses of t he Pri mar y E n d p oi nt  ...................................... 6 2  
4. 2. 2. 7  
S u b gr o u p A nal yses  ...................................................................................... 6 2  
4. 2. 3  
Sec o n dar y E n d p oi nts –  K C C Q -T S S c ha n ge fr o m baseli ne at 2 4 a n d 4 8 
wee ks  ........................................................................................................... 6 2  
4. 2. 3. 1  
Defi niti o n  ..................................................................................................... 6 2  
4. 2. 3. 2  
Deri vati o ns  ................................................................................................... 6 2  
4. 2. 3. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 3  
4. 2. 3. 4  
Pri mar y A nal ysis of Sec o n dar y E n d p oi nt .................................................... 6 3  
4. 2. 4  
Sec o n dar y E n d p oi nt –  6 M W D c ha n ge fr o m baseli ne at 2 4 a n d 4 8 wee ks  .. 6 3  
4. 2. 4. 1  
Defi niti o n  ..................................................................................................... 6 3  
4. 2. 4. 2  
Deri vati o ns  ................................................................................................... 6 3  
4. 2. 4. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 3  
4. 2. 4. 4  
Pri mar y A nal ysis of Sec o n dar y E n d p oi nt .................................................... 6 3  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4  of 9 2  
 
4. 2. 5  
Sec o n dar y E n d p oi nts –  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -
pr o B N P at 1 6, 2 4 a n d 4 8 wee ks ................................................................... 6 3  
4. 2. 5. 1  
Defi niti o n  ..................................................................................................... 6 3  
4. 2. 5. 2  
Deri vati o ns  ................................................................................................... 6 3  
4. 2. 5. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 4  
4. 2. 5. 4  
Pri mar y A nal ysis of Sec o n dar y E n d p oi nt .................................................... 6 4  
4. 2. 5. 5  
S u p ple me ntar y A nal yses of t he Sec o n dar y E n d p oi nt  .................................. 6 4  
4. 2. 5. 6  
S u b gr o u p A nal ysis  ....................................................................................... 6 4  
4. 2. 6  
Sec o n dar y E n d p oi nts –  Ec h ocar di o gra p hic para meters c ha n ge fr o m baseli ne 
at 1 6 a n d 2 4 wee ks  ....................................................................................... 6 4  
4. 2. 6. 1  
Defi niti o n  ..................................................................................................... 6 4  
4. 2. 6. 2  
Deri vati o ns  ................................................................................................... 6 4  
4. 2. 6. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 5  
4. 2. 6. 4  
Pri mar y A nal ysis of Sec o n dar y E n d p oi nt .................................................... 6 5  
4. 2. 6. 5  
S u p ple me ntar y A nal yses of t he Sec o n dar y E n d p oi nt  .................................. 6 5  
4. 2. 6. 6  
S u b gr o u p A nal ysis  ....................................................................................... 6 5  
4. 2. 7  
Sec o n dar y E n d p oi nt –  Plas ma C o nce ntrati o ns of A Z D 4 8 3 1 b y ti me p oi nt  . 6 5  
4. 2. 7. 1  
Defi niti o n  ..................................................................................................... 6 5  
4. 2. 7. 2  
Deri vati o ns  ................................................................................................... 6 5  
4. 2. 7. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 5  
4. 2. 7. 4  
Pri mar y A nal ysis of Sec o n dar y E n d p oi nt .................................................... 6 5  
4. 2. 8  
Sec o n dar y E n d p oi nt –  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d 
i nfla m mat or y bi o mar kers at 1 6, 2 4 a n d 4 8 wee ks ....................................... 6 5  
4. 2. 8. 1  
Defi niti o n  ..................................................................................................... 6 5  
4. 2. 8. 2  
Deri vati o ns  ................................................................................................... 6 6  
4. 2. 8. 3  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ..................................................... 6 6  
4. 2. 8. 4  
Pri mar y A nal ysis of Sec o n dar y E n d p oi nt .................................................... 6 6  
4. 2. 8. 5  
S u p ple me ntar y A nal yses of t he Sec o n dar y E n d p oi nt  .................................. 6 6  
4. 2. 8. 6  
S u b gr o u p A nal ysis  ....................................................................................... 6 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5  of 9 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6  of 9 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 3  
P har mac o d y na mic E n d p oi nt(s)  .................................................................... 7 8  
4. 4  
P har mac o ki netics  ......................................................................................... 7 8  
4. 5  
I m m u n o ge nicit y ........................................................................................... 7 8  
4. 6  
Safet y A nal yses  ........................................................................................... 7 8  
4. 6. 1  
E x p os ure  ...................................................................................................... 8 0  
4. 6. 1. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 8 0  
4. 6. 1. 2  
Prese ntati o n .................................................................................................. 8 1  
4. 6. 2  
A d verse E ve nts  ............................................................................................ 8 1  
4. 6. 2. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 8 1  
4. 6. 2. 2  
Prese ntati o n .................................................................................................. 8 3  
4. 6. 3  
Cli nical La b orat or y, Bl o o d Sa m ple  ............................................................. 8 5  
4. 6. 3. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 8 5  
4. 6. 3. 2  
Prese ntati o ns  ................................................................................................ 8 6  
4. 6. 4  
Cli nical La b orat or y, Uri nal ysis  ................................................................... 8 7  
4. 6. 4. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 8 7  
4. 6. 4. 2  
Prese ntati o ns  ................................................................................................ 8 7  
4. 6. 5  
Ot her La b orat or y E val uati o ns  ...................................................................... 8 8  
4. 6. 5. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 8 8  
4. 6. 5. 2  
Prese ntati o ns  ................................................................................................ 8 8  
4. 6. 6  
Vital Si g ns  ................................................................................................... 8 8  
4. 6. 6. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 8 8  
4. 6. 6. 2  
Prese ntati o ns  ................................................................................................ 8 9  
4. 6. 7  
Electr ocar di o gra m  ........................................................................................ 9 0  
4. 6. 7. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 9 0  
4. 6. 7. 2  
Prese ntati o ns  ................................................................................................ 9 0  
4. 6. 8  
Ot her Safet y Assess me nts  ............................................................................ 9 0  
4. 6. 8. 1  
Defi niti o ns a n d Deri vati o ns  ......................................................................... 9 0  
4. 6. 8. 2  
Prese ntati o ns  ................................................................................................ 9 1  
5  
I N T E RI M A N A L Y SI S ................................................................................ 9 2  
6  
R E F E R E N C E S  ............................................................................................ 9 2  
 
 
 
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7  of 9 2  
 
LI S T O F A B B R E VI A TI O N S  
List a b bre viati o ns a n d defi niti o ns of s pecialise d or u n us ual ter ms, meas ure me nts, or u nits. 
E xa m ples are pr o vi de d bel o w. T hese ca n be m o difie d at st u d y le vel.  
A b bre vi ati o n or 
S peci alise d 
Ter m  
Defi niti o n  
6 M W D  
6 -mi n ute wal k dista nce  
6 M W T  
6 -mi n ute wal k test  
A E  
A d verse e ve nt  
A E o SI  
A d verse e ve nt of s pecial i nterest  
A L T  
Ala ni ne -A mi n otra nsferase  
A N C O V A  
A nal ysis of c o varia nce  
A R [ 1]  
A ut ore gressi ve or der 1  
A R H [ 1]  
Heter o ge ne o us a ut ore gressi ve or der 1  
A S T  
As partate -A mi n otra nsa mi nase  
A T C  
A nat o mical T hera pe utic C he mical  
B MI  
B o d y mass i n de x  
B P  
Bl o o d press ure  
CI  
C o nfi de nce I nter val  
C K D -E PI  
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n  
C R F  
Case Re p ort F or m  
C S R  
Cli nical St u d y Re p ort  
 
 
C S P  
Cli nical st u d y Pr ot oc ol  
C V  
C oefficie nt of Variati o n  
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  
D A E  
A d verse e ve nts lea di n g t o disc o nti n uati o n of st u d y me dicati o n  
D R C  
De vel o p me nt Re vie w C o m mittee  
 
 
E C G  
Electr ocar di o gra m  
e C D F 
E m pirical c u m ulati ve distri b uti o n f u ncti o n  
e C R F 
Electr o nic case re p ort f or m  
e G F R 
Esti mate d Gl o mer ular Filtrati o n Rate  
F A S  
F ull a nal ysis set  
H b A 1c  
Hae m o gl o bi n A 1c  
H F  
Heart Fail ure  
C CI
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8  of 9 2  
 
H R  
Hazar d Rati o  
hs C R P  
Hi g h -se nsiti vit y C-reacti ve pr otei n 
 
 
I C F 
I nf or me d c o nse nt f or m 
I L-6  
I nterle u ki n 6 
I P 
I n vesti gati o nal Pr o d uct 
I P D 
I m p orta nt Pr ot oc ol De viati o n 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y 
K C C Q  
Ka nsas cit y car di o m y o pat h y q uesti o n naire  
K C C Q -T S S  
Ka nsas cit y car di o m y o pat h y q uesti o n naire –  T otal S y m pt o m Sc ore  
K C C Q -O S S  
Ka nsas cit y  car di o m y o pat h y q uesti o n naire –  O verall S u m mar y Sc ore  
K M  
Ka pla n -Meier  
L A VI  
Left atrial v ol u me i n de x  
L L N  
L o wer Li mit N or mal  
L L o Q  
L o wer li mit of q ua ntificati o n  
L V E F  
Left ve ntric ular ejecti o n fracti o n  
L V -G L S  
Left ve ntric ular gl o bal l o n git u di nal strai n  
L V MI  
Left ve ntric ular mass i n de x  
Me d D R A  
Me dical dicti o nar y f or re g ulat or y acti vities  
MI  
M y ocar dial i nfarcti o n  
M M R M  
Mi xe d m o del re peate d meas ures  
M P O  
M yel o per o xi dase  
N T -pr o B N P  
N -ter mi nal pr o b-t y pe natri uretic pe pti de 
N Y H A  
Ne w Y or k heart ass ociati o n  
P D F  
Pr o ba bilit y distri b uti o n f u ncti o n  
 
 
 
 
 
 
 
P R O  
Patie nt -re p orte d o utc o me 
P T  
Preferre d ter m  
Q 1  
First Q uartile  
Q 3  
T hir d Q uartile  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S A S  
Safet y a nal ysis set  
C CI
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9  of 9 2  
 
S D  
Sta n dar d De viati o n  
S E  
Sta n dar d Err or  
S O C  
S yste m Or ga n Class  
T 2 D M  
T y pe -2 Dia betes Mellit us  
T 4  
T h yr o xi ne  
T A  
T hera pe utic Area  
T B  
T otal bilir u bi n  
TI B C  
T otal ir o n bi n di n g ca pacit y  
T S H  
T h yr oi d sti m ulati n g h or m o ne  
U A C R  
Uri nar y al b u mi n -t o-creati ni ne rati o  
U L N  
U p per Li mit N or mal  
U L o Q  
U p per li mit of q ua ntificati o n  
U R C  
U n bli n de d re vie w c o m mittee  
U N  
U nstr uct ure d  
W H O D D  
W H O Dr u g Dicti o nar y  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0  of 9 2  
A M E N D M E N T HI S T O R Y  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1  of 9 2  
 
C A T E G O R Y  
C h a n ge 
refers t o: 
D ate  
Descri pti o n of c h a n ge  
I n li ne wit h 
C S P ?  
R ati o n ale  
Versi o n 1  
N/ A  
6/ 2 3/ 2 0 2 1  
I nitial a p pr o ve d S A P 
N/ A  
N/ A  
Versi o n 2  
Ge neral  
1 0/ 1 9/ 2 0 2 2  
Re m o val of all te xt 
descri bi n g statistical 
a nal ysis f or Part B of 
st u d y. 
 
Re m o val of te xt i n 
I ntr o d ucti o n secti o n 
descri bi n g St u d y desi g n, 
Ra n d o misati o n a n d 
N u m ber of s u bjects.  
 
Britis h E n glis h use d 
t hr o u g h o ut.  
N/ A  
A gree me nt t o ha ve se parate S A P f or 
Part B of st u d y.  
 
 
 
A v oi d d u plicate i nf or mati o n. T he 
S A P s h o ul d n ot be rea d i n is olati o n 
b ut i n c o nj u ncti o n wit h t he C S P.  
 
 
 
C o nsiste nc y.  
Ti mi n g of 
a nal ysis 
1 0/ 1 9/ 2 0 2 2  
Re w or di n g.  
Yes  
T o ali g n wit h u p date d versi o n of 
C S P ( v 5).  
M ulti ple 
testi n g 
pr oce d ure  
1 0/ 1 9/ 2 0 2 2  
M o vi n g of secti o n, n o w 
descri be d i n Secti o n 
3. 3. 4 . Details gi ve n h o w 
al p ha distri b ute d a n d 
a d diti o n of testi n g or der. 
Defi niti o n of pri mar y 
c o m paris o n ( A Z D 4 8 3 1 
T otal vs place b o).  
Yes  
Ali g n wit h S A P te m plate.  
Clarificati o n.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2  of 9 2  
 
Ge neral st u d y 
le vel 
defi niti o ns  
  
1 0/ 1 9/ 2 0 2 2  
Re w or di n g a n d a d diti o n 
of defi niti o ns f or St u d y 
peri o ds, Ti me at ris k a n d 
ce ns ori n g, a n d U nit 
c o n ve nti o ns.  
B aseli ne:  
A d diti o n t o c o nsi der 
ti me p oi nt of assess me nt 
w he n data all o ws.  
H a n dli n g of i nc o m plete 
c ases: 
Re m o val of e n d -of -st u d y 
defi niti o n. Ce ns ori n g 
descri be d i n ne w Ti me at 
ris k a n d ce ns ori n g 
secti o n (3. 3. 1. 8 ).  
St u d y d a y:  
Re na mi n g fr o m 
Ra n d o misati o n start date 
a n d st u d y da y t o St u d y 
da y .  
Yes  
Clarificati o n. Ali g n wit h C S P.  
Visit wi n d o w  
1 0/ 1 9/ 2 0 2 2  
Re m o val of baseli ne a n d 
 fr o m 
Ta ble 1 . A nal ysis visit 
wi n d o ws f or t hese 
cate g ories are descri be d 
i n Secti o ns 3. 3. 1. 1 , 
4. 2. 9. 4  a n d 4. 2. 1 8. 1 .  
Yes  
Clarificati o n.  
Ha n dli n g of 
sc he d ule d a n d 
u nsc he d ule d 
visits  
1 0/ 1 9/ 2 0 2 2  
Re w or di n g. C ha n ge t o 
all o w u nsc he d ule d visit 
t o re place sc he d ule d visit 
if cl oser t o tar get da y.  
Yes  
T o ali g n wit h u p date d versi o n of 
C S P ( v 5).  
Ha n dli n g of 
pr ot oc ol 
de viati o ns i n 
st u d y a nal ysis 
1 0/ 1 9/ 2 0 2 2  
Re m o val of referral t o 
A p pe n di x O  
Yes  
A p pe n di x O is re m o ve d.  
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 3  of 9 2  
 
St u d y 
p o p ulati o n  
1 0/ 1 9/ 2 0 2 2  
C ha n ge of w hic h 
cate g ories are defi ne d 
here a n d a d diti o n of t he 
c orres p o n di n g 
defi niti o ns. Re w or di n g 
of prese ntati o n parts.  
 
U p date of defi niti o n of 
F ull a nal ysis set.  
Yes  
Ali g n wit h St u d y p o p ulati o n T F L 
sta n dar ds a n d wit h w hic h data are 
c ollecte d i n st u d y. Clarificati o n.  
 
 
 
 
Ali g n wit h defi niti o n of F A S t o be 
use d i n Part B of t he st u d y.  
E n d p oi nt 
a nal yses 
1 0/ 1 9/ 2 0 2 2  
C ha n ges i n Ta ble 2 . 
A d de d details o n 
I nterc urre nt e ve nt 
strate gies a n d P o p ulati o n 
le vel s u m maries.  
 
Di visi o n of secti o ns f or 
eac h varia ble ( or gr o u p 
of varia bles) t o be 
a nal yse d.  
 
Re w or di n g.  
 
A d diti o n of m o del 
s pecificati o ns. 
 
Yes  
Ali g n wit h a nal yses bei n g 
perf or me d.  
 
 
 
 
 
Ali g n wit h St u d y o bjecti ve a n d S A P 
te m plate i nstr ucti o ns. 
 
 
Clarificati o n.  
 
Clarificati o n.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4  of 9 2  
 
Statistical 
a nal ysis f or 
pri mar y 
e n d p oi nts 
1 0/ 1 9/ 2 0 2 2  
Se nsiti vit y a nal ysis of 
pri mar y e n d p oi nts 
c ha n ge d t o a 
s u p ple me ntar y a nal ysis. 
Ne w se nsiti vit y a nal ysis 
defi ne d. Ne w a d diti o nal 
s u p ple me ntar y a nal yses 
defi ne d.  
 
Esti ma n ds f or ne w 
s u p ple me ntar y a nal yses 
defi ne d.  
 
Clarificati o n of 
esti ma n ds, s pecificati o n 
of i nterc urre nt e ve nts a n d 
ha n dli n g of t hese, 
disti ncti o n ma de bet wee n 
i nterc urre nt e ve nts a n d 
missi n g data.  
 
A d diti o n of se veral 
bi o mar kers t o s u b gr o u p 
a nal yses. 
Yes  
Pla n ne d se nsiti vit y a nal ysis was 
a d dressi n g a differe nt esti ma n d t ha n 
t he pri mar y a nal ysis, he nce c ha n ge d 
i nt o a s u p ple me ntar y a nal ysis. 
 
 
 
 
 
Ali g n t o esti ma n d fra me w or k a n d 
S A P te m plate.  
 
 
Ali g n t o esti ma n d fra me w or k a n d 
S A P te m plate.  
 
 
 
 
 
F urt her e x pl orat or y a nal ysis t o be 
ma de.  
Statistical 
a nal ysis f or 
sec o n dar y 
e n d p oi nts 
1 0/ 1 9/ 2 0 2 2  
 
 
 
 
 
   
 
Re w or di n g of l o g -
tra nsf or me d varia bles 
a n d t he c orres p o n di n g 
a nal yses.  
 
 
 
 
  
Yes  
Ali g n wit h u p date d versi o n of C S P 
( v 5).  
 
 
 
 
 
Clarificati o n.  
 
 
 
 
  
C CI
C CI
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 5  of 9 2  
 
Statistical 
a nal ysis f or 
e x pl orat or y 
e n d p oi nts 
1 0/ 1 9/ 2 0 2 2  
 
  
 
 
 
 
  
 
 
  
Yes  
 
 
 
 
  
 
 
 
 
 
 
C CI
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 6  of 9 2  
 
Safet y 
a nal yses 
1 0/ 1 9/ 2 0 2 2  
E x p os ure:  
F or prese ntati o n: T otal 
year of e x p os ure a d de d, 
E x p os ure o ver ti me 
c ur ve a d de d, c u m ulati ve 
cate g ories a d de d.  
 
Ge ner al s afet y  
Re m o val of A E o bjecti ve 
te xt i n Secti o n 4. 6. 2 , 
i nstea d Ta ble 4  a d de d. 
Defi niti o n of Safet y 
esti ma n d a d de d. 
Defi niti o n of a nal yses f or 
O n -treat me nt a n d O n-
st u d y peri o ds a d de d (see 
ne w St u d y peri o ds 
Secti o n 3. 3. 1. 5 ). 
 
A d verse e ve nts  
Re w or di n g of cate g ories. 
Re w or di n g a n d 
restr uct uri n g of A E o SI 
cate g ories.  
C ha n ge of a nal ysis a n d 
prese ntati o n of A Es fr o m 
e ve nt rates t o ti me -t o-
e ve nt a nal ysis ( K M %, 
K M % differe nce a n d 
H R)  
 
Cli nic al l a b or at or y, 
Bl o o d s a m ple:  
Re m o val of referral t o 
Uri nal ysis i n t his secti o n. 
Re w or di n g a n d 
restr uct uri n g.  
 
Cli nic al l a b or at or y, 
Uri n al ysis:  
Re w or di n g a n d 
restr uct uri n g. 
 
Vit al si g ns:  
Yes  
Clarificati o n.  
 
 
 
 
 
 
Clarificati o n. C o m ple me ntar y 
a nal ysis a p pr oac hes a d de d.  
 
 
 
 
 
 
 
 
 
Clarificati o n. Ali g n wit h T F L 
sta n dar ds. C ha n ge of esti mat ors.  
 
 
 
 
 
 
 
 
Clarificati o n. Ali g n wit h T F L 
sta n dar ds. 
 
 
 
 
Clarificati o n. Ali g n wit h T F L 
sta n dar ds.  
  
 
 
Clarificati o n. Ali g n wit h T F L 
sta n dar ds.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 7  of 9 2  
 
Re w or di n g a n d 
restr uct uri n g. 
 
E C G:  
C ha n ge of o ut p uts a n d 
prese ntati o n  
 
A d diti o n of Ort h ostatic 
bl o o d press ure test t o 
Ot her S afet y 
Assess me nts  secti o n.  
 
 
 
Ali g n wit h data c ollecte d.  
 
 
 
Ali g n wit h C S P.  
 
 
I nteri m 
a nal ysis 
1 0/ 1 9/ 2 0 2 2  
Re w or di n g of ti mi n g of 
i nteri m a nal ysis. 
Refere nce t o U R C 
C harter a d de d.  
Yes  
Ali g n wit h u p date d versi o n of C S P 
( v 5). 
Refere nces  
1 0/ 1 9/ 2 0 2 2  
Re m o val of bi bli o gra p h y 
ite ms.   
Yes  
Ite ms are n ot use d d ue t o re m o val of 
Part B a nal yses a n d a p pe n dices.  
A p pe n dices  
1 0/ 1 9/ 2 0 2 2  
Re m o val of a p pe n dices. 
Esse ntial i nf or mati o n 
m o ve d t o mai n secti o ns 
w here s uita ble.   
Yes  
Clarificati o n a n d si m plificati o n of 
S A P. O nl y esse ntial i nf or mati o n 
ke pt i n S A P.  
Versi o n 3  
C ha n ges t o 
pr ot oc ol 
pla n ne d 
a nal yses 
0 3/ 2 3 / 2 0 2 3 
Clarificati o n of ass u me d 
sta n dar d de viati o n f or 
K C C Q -T S S i n sa m ple 
size calc ulati o ns.  
N o  
C orrecti o n.  
Ge neral st u d y 
le vel 
defi niti o ns  
0 3/ 2 3/ 2 0 2 3  
A d diti o n of c o nsi deri n g 
ra n d o misati o n w he n 
i m p uti n g missi n g da y 
val ue of a d verse e ve nt 
dates.  
 
Re m o val of 
c o nsi derati o n ta ke n t o 
ti me p oi nt of first I P d ose 
w he n deri vi n g st u d y 
peri o ds.  
Yes  
Ali g n wit h h o w ot her cases of 
i nc o m plete a d verse e ve nt dates are 
i m p ute d.  
 
 
 
Si m plificati o n  
St u d y peri o ds  
0 3/ 2 3/ 2 0 2 3  
Re w or di n g of defi niti o ns 
of st u d y peri o ds a d 
ce ns ori n g f or ti me -t o-
e ve nt a nal yses , efficac y 
a n d safet y .  
Yes  
Clarificati o n  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 8  of 9 2  
 
C o vi d -1 9  
0 3/ 2 3/ 2 0 2 3  
Re w or di n g of data 
c ollecti o n of C o vi d -1 9 
i m pact o n st u d y. 
Re m o val of referral t o 
listi n g of s u bjects wit h 
re p orte d iss ues i n t he 
C T M S d ue t o C o vi d -1 9.  
Yes  
Ali g n wit h data c ollecti o n  
St u d y 
p o p ulati o n  
0 3/ 2 3/ 2 0 2 3  
Defi niti o n of  s u bjects 
c o m plete d treat me nt 
e x pa n de d t o i ncl u de 
s u bjects w h o die d d uri n g 
f oll o w-u p.  
 
Ar ge nti na re m o ve d as 
c o u ntr y. 
 
Re m o val of ta b ulati o n of 
resc ue me dicati o n relate d 
t o ras h 
 
Yes  
T o all o w n u m ber of s u bjects starte d 
treat me nt t o e q ual n u m ber  of 
s u bjects w h o disc o nti n ue d or 
c o m plete d treat me nt . 
 
 
Ali g n wit h c o u ntries i ncl u de d i n 
st u d y. 
 
Ali g n wit h latest versi o n of C S P . 
Statistical 
a nal ysis f or 
pri mar y 
e n d p oi nts 
0 3/ 2 3/ 2 0 2 3  
‘ U nit’ re m o ve d after S-
C ystati n C  
Yes  
C orrecti o n of t y p o, u nit n ot 
prese nte d f or s u b gr o u ps defi ne d b y 
me dia n.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 9  of 9 2  
 
Statistical 
a nal ysis f or 
sec o n dar y 
e n d p oi nts 
0 3/ 2 3/ 2 0 2 3  
P o p ulati o n -le vel 
s u m mar y f or pri mar y a n d 
t hir d s u p ple me ntar y 
esti ma n d u p date d t o 
i ncl u de a dj uste d 
ge o metric mea n f or t he 
l o g-tra nsf or me d 
varia bles.  
 
P o p ulati o n -le vel 
s u m mar y i n esti man d 
ta ble f or s u b gr o u p 
a nal ysis of l o g -
tra nsf or me d varia bles 
u p date d.  
 
R ule a d de d f or w hic h I L -
6 la b c o de t o use i n 
a nal ysis if a s u bject ha ve 
t w o re p orte d la b c o des 
o n sa me visit.  
 
T w o s u p ple me ntar y 
a nal yses a d de d f or I L -6  
 
A d diti o n t hat P K 
a nal ysis is perf or me d o n 
F A S  
Yes  
Clarificati o n  
 
 
 
 
 
 
 
C orrecti o n of t y p os.  
 
 
 
 
 
 
T o ha n dle a d diti o n of hs -I L-6 la b  
c o des i n a nal ysis.  
 
 
 
 
T o e val uate i m pact of t w o differe nt 
la b orat or y a nal ysis met h o ds  use d.  
 
 
Clarificati o n  
Statistical 
a nal ysis f or 
e x pl orat or y 
e n d p oi nts 
0 3/ 2 3/ 2 0 2 3  
 
 
 
 
 
 
 
 
 
 
 
Yes  
Clarificati o n  
 
 
 
 
Clarificati o n  
E x p os ure  
0 3/ 2 3/ 2 0 2 3  
A d diti o n t o prese ntati o n 
of K M % pl ots of I P 
disc o nti n ui n g e ve nt.  
Yes  
I m pr o ve d o ver vie w a n d 
i nter pretati o n of data.  
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 0  of 9 2  
 
Safet y 
a nal yses 
0 3/ 2 3/ 2 0 2 3  
A d verse e ve nts  
A d diti o n of K M % pl ots 
of A E o SIs.  
 
Ma xi m u m i nte nsit y a n d 
C T C A E gra de cate g ories 
c ha n ge d t o be 
c u m ulati ve. 
 
Cli nic al l a b or at or y, 
bl o o d s a m ple  
Treat me nt e mer ge n t 
a b n or malit y criteria 
c o m prisi n g c o m bi nati o ns 
of para meters are fla g ge d 
w he n met o n sa me visit,  
 
A N C A  
Ma p pi n g of ne gati ve a n d 
p ositi ve res ults a d de d . 
 
Vit al si g ns  
> c ha n ge d t o ≥ a n d 6 0 
c ha n ge d t o 5 0 f or P ulse 
rate s hift fr o m baseli ne 
cate g orisati o ns.  
 
I m pr o ve d o ver vie w a n d 
i nter pretati o n of data. 
 
 
I m pr o ve d o ver vie w a n d 
i nter pretati o n of data. 
 
 
 
Clarificati o n  
 
 
 
 
 
 
 
Clarificati o n  
 
 
 
C orrecti o n of t y p os.  
 
Versi o n 4  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 1  of 9 2  
 
Ge neral st u d y 
defi niti o ns  
0 3 /0 8 / 2 0 24  
Re m o ve me nti o ni n g of 
ti me w he n defi ni n g 
baseli ne. O nl y date will 
be c o nsi dere d.  
 
U p date d defi niti o n of 
baseli ne f or K C C Q t o 
use first assess me nt if 
t w o assess me nts q ualif y  
as baseli ne o n t he sa me 
da y.  
 
Re place 'ti me' b y ' date'  
f or deri vi n g st u d y 
peri o ds . Re m o val of 
se nte nce w he n ti me p oi nt 
is missi n g.  
 
U p date t o use 
ra n d o misati o n f or 
deri vati o n of t he Pla n ne d 
treat me nt peri o d.  
 
T y p o i n s u bsecti o n title . 
 
 
Clarificati o n  
 
 
 
 
Clarificati o n re gar di n g t he ha n di n g 
of a n of a n a d diti o nal sce nari o  
 
 
 
 
Clarificati o n t o a v oi d 
misi nter preti n g ti me as ti me p oi nt 
w he n deri vi n g st u d y peri o ds  a n d 
c orrecti o n of t y p o ( u ni nte nti o nal 
left o ver fr o m t he last S A P u p date 
w he n ti me p oi nts were re m o ve d ).  
 
C orrecti o n  
 
 
 
C orrecti o n  
Visit wi n d o w  
0 3/ 0 8/ 2 0 2 4  
P ost -d ose vital si g ns (i n 
V S 7 f or m) c ollecte d at 
da y of ra n d o mizati o n are 
i ncl u de d i n visit 4 
a nal ysis wi n d o w. 
 
Clarificati o n  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 2  of 9 2  
 
St u d y 
p o p ulati o n  
0 3/ 0 8/ 2 0 2 4  
I P de viati o ns a d de d as 
I P D cate g or y t o matc h 
Pr ot oc ol De viati o n P la n 
cate g ories. 
 
Ti me fr o m dia g n osis of 
H F e nr ol me nt' cate g or y 
re m o ve d fr o m baseli ne 
disease c haracteristics 
cate g ories.  
 
U nit f or ne utr o p hil 
u p date d  
 
Ne utr o p hil c o u nt 
cate g or y a d de d t o 
baseli ne disease 
c haracteristics cate g ories.  
 
 
C orrecti o n t o matc h Pr ot oc ol 
De viati o n Pla n cate g ories.  
 
 
 
C orrecti o n  
 
 
 
 
C orrecti o n  
 
 
C orrecti o n  
Ti mefra me 
f or start of 
me dicati o n t o 
be c o nsi dere d 
a c o nc o mita nt 
me dicati o n is 
e xte n de d t o 
matc h o n -
treat me nt 
peri o d.  
 
0 3/ 0 8/ 2 0 2 4  
Ti mefra me f or start of 
me dicati o n t o be 
c o nsi dere d a c o nc o mita nt 
me dicati o n is e xte n de d . 
 
Resc ue me dicati o ns 
re m o ve d fr o m 
prese ntati o n  as part of 
c o nc o mita nt me dicati o ns . 
 
 
 
C orrecti o n t o matc h defi niti o n of o n -
treat me nt peri o d. 
 
 
 
C orrecti o n, t here is n o resc ue 
me dicati o n defi niti o n i n t he st u d y.  
E n d p oi nt 
a nal yses 
0 3/ 0 8/ 2 0 2 4  
Resc ue me dicati o ns 
re m o ve d as a p ote ntial 
i nterc urre nt e ve nt i n t he 
esti ma n d descri pti o n 
si nce we d o n ot ha ve a 
resc ue me dicati o n 
defi niti o n i n t he st u d y.  
 
U p date d w or di n g i n 
re gar di n g c o nc o mita nt 
me dicati o n  i n defi niti o n 
of esti ma n ds f or pri mar y 
a n d s u p ple me ntar y 
esti ma n ds. 
 
C orrecti o n, t here is n o resc ue 
me dicati o n defi niti o n i n t he st u d y.  
 
 
 
 
 
 
Ali g n me nt wit h Safet y esti ma n d 
w or di n g.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 3  of 9 2  
 
Statistical 
a nal ysis f or 
pri mar y 
e n d p oi nts 
 
0 3/ 0 8/ 2 0 2 4  
U p date d t hres h ol d f or 
H b A 1 C s u b gr o u p 
cate g ories. 
 
S u b gr o u p a nal ysis: 
De n o mi nat or f or 5 %  
( w he n se parate m o dels 
will be fitte d f or eac h 
s u b gr o u p cate g or y) 
c ha n ge d fr o m 
ra n d o mise d s u bjects t o 
F A S.  
 
 
 
C orrecti o n of t y p o  
 
 
 
C orrecti o n  
Statistical 
a nal ysis f or 
sec o n dar y 
e n d p oi nts 
 
0 3/ 0 8/ 2 0 2 4  
I L-6 o bser vati o ns 
re p orte d as L L o Q will be 
i m p ute d as descri be d i n 
Secti o n 3. 3. 1. 3.  
 
Descri pti o n of I L -6 
cate g ories f or first 
s u p ple me ntar y a nal ysis 
(l o gistic re gressi o n) 
u p date d .  
 
U p date of sec o n d 
s u p ple me ntar y a nal ysis 
( A N C O V A) t o i ncl u de 
all s u bjects wit h a 
matc he d pair of la b 
a nal ysis met h o d f or I L -6. 
Met h o d a d de d as 
c o variate i n t he m o del.  
 
 
Clarificati o n  
 
 
 
 
C orrecti o n of t y p o  
 
 
 
 
C orrecti o n  
 
 
 
 
 
 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 4  of 9 2  
 
Statistical 
a nal ysis f or 
e x pl orat or y 
e n d p oi nts 
 
0 3/ 0 8/ 2 0 2 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
Ti me -t o-C V e ve nt  
Resc ue me dicati o ns 
re m o ve d as a p ote ntial 
i nterc urre nt e ve nt i n t he 
esti ma n d descri pti o n  f or 
ti me-t o-e ve nt a nal ysis .  
 
W or di n g of 'a dj u dicate d' 
u p date d t o 're p orte d' f or 
C V e ve nts.  
 
Ti me -t o-e ve nt a nal ysis is 
stratifie d b y ne utr o p hil 
c o u nt. 
 
 
 
 
 
 
  
 
 
 
 
Clarificati o n a n d a li g n me nt of 
wi n d o ws f or b ot h a nal yses 
( descri pti ve a n d wit hi n-s u bject 
a nal ysis). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C orrecti o n, t here is n o resc ue 
me dicati o n defi niti o n i n t he st u d y.  
 
 
 
C orrecti o n of t y p o , t here is no 
a dj u dicati o n i n t he st u d y. 
 
 
 
Clarificati o n  
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 5  of 9 2  
 
 
 
 
 
 
 
 
 
 
Safet y 
a nal ysis 
0 3/ 0 8/ 2 0 2 4  
Data fr o m t he p ost -d ose 
vital si g ns e C R F f or m 
V S 7 will n ot be 
c o nsi dere d as baseli ne.  
 
T he or der f or selecti n g 
data fr o m e C R F f or ms 
f or baseli ne vital si g ns 
will als o be a p plie d f or 
p ost -ra n d o misati o n visit. 
 
O ver d ose listi n g a d de d.  
 
 
 
Clarificati o n  
 
 
 
 
Clarificati o n  
 
 
 
 
C orrecti o n  
 
C CI
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 6  of 9 2  
 
1  
I N T R O D U C TI O N 
T he p ur p ose of t his d oc u me nt is t o gi ve details f or t he statistical a nal ysis of st u d y D 6 5 8 0 C 0 0 0 1 0 
Part A s u p p orti n g t he cli nical st u d y re p ort. T he rea der is referre d t o t he C S P a n d t he C R F f or 
details of st u d y c o n d uct a n d data c ollecti o n.  
2  
C H A N G E S T O P R O T O C O L P L A N N E D A N A L Y S E S  
A sta n dar d de viati o n of 2 0 p oi nts was ass u me d f or K C C Q -T S S f or t he sa m ple size calc ulati o ns. 
N o ot her c ha n ges t o pla n ne d a nal yses.  
3  
D A T A A N A L Y SI S C O N SI D E R A TI O N S  
3. 1  
Ti mi n g of A n al yses  
At least t w o, b ut p ossi bl y se veral, i nteri m a nal yses will be perf or me d b y a n i nter nal st u d y-
i n de pe n de nt U n bli n de d Re vie w C o m mittee ( U R C), wit h t he p ur p ose of i nf or mi n g f urt her 
de vel o p me nt of t he cli nical pr o gra m me, i ncl u di n g b ut n ot li mite d t o d ose selecti o n t o start Part 
B. T he first i nteri m a nal ysis will be perf or me d  w he n at least 1 5 0 ra n d o mise d s u bjects ha ve ha d 
t he p ossi bilit y t o reac h t he 1 6 wee ks visit. O ne of t he i nteri m a nal yses will be perf or me d w he n 
all s u bjects i n Part A ha ve c o m plete d t he last p r ot oc ol-s pecifie d visit/assess me nt. If Part B were 
n ot t o start or pr o gress, t he n t he last i nteri m a nal ysis of Part A w o ul d be re gar de d as t he fi nal 
a nal ysis a n d t his will be use d t o write t he C S R.  
I n a d diti o n, a Data Re vie w C o m mittee ( D R C) will perf or m peri o dic a nal yses wit h f oc us o n s ki n 
reacti o ns a n d ras hes, a n d ge neral safet y. T hese a nal yses are n ot i n sc o pe f or t his d oc u me nt a n d 
are descri be d i n a se parate D R C c harter.  
3. 2  
A n al ysis P o p ul ati o ns  
See Secti o ns 4. 2 , 4. 6  a n d 4. 2. 1 6. 1  f or defi niti o ns of esti ma n d p o p ulati o ns. 
3. 3  
Ge ner al C o nsi der ati o ns  
3. 3. 1  
Ge ner al St u d y Le vel Defi niti o ns  
3. 3. 1. 1  
B aseli ne  
F or t he F ull a nal ysis set ( F A S, see Secti o n 4. 1. 2. 1 ), baseli ne is defi ne d as t he last n o n-missi n g 
val ue pri or t o or o n t he da y of ra n d o misati o n, i ncl u di n g u nsc he d ule d assess me nts t hat occ ur pri or 
t o t he ra n d o misati o n visit, f or eac h s u bject a n d e n d p oi nt. If a d mi nistrati o n of t he first d ose of 
i n vesti gati o nal pr o d uct s h o ul d ha p pe n t o occ ur pri or t o ra n d o misati o n, baseli ne will be defi ne d 
as t he last n o n -missi n g val ue o n or bef ore t he da y of t he first d ose.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 7  of 9 2  
 
F or t he Safet y a nal ysis set ( S A S, see Secti o n  4. 1. 2. 1 ), baseli ne is defi ne d as t he last n o n-missi n g 
val ue pri or t o or o n t he da y of first a d mi nistrati o n of I P, i ncl u di n g u nsc he d ule d assess me nts t hat 
occ ur pri or t o t he first d ose visit, f or eac h s u bject a n d e n d p oi nt.  
If t w o assess me nts ta ke n at t he sa me da y q ualifie as baseli ne, t he f oll o wi n g will  a p pl y : 
•  If t he varia ble is q ualitati ve, t he n t he w orst val ue fr o m a cli nical pers pecti ve will be use d 
as t he baseli ne val ue.  
•  F or K C C Q, t he first assess me nt ( val ue)  will be use d as baseli ne.  
•  F or ha n dli n g of cases w he n m ore t ha n o ne val ue c o ul d q ualif y as baseli ne f or a n y ot her 
reas o n, see Secti o n 3. 3. 3 . 
3. 3. 1. 2  
H a n dli n g of i nc o m plete d ates  
T he f oll o wi n g i m p ute d dates will o nl y be use d f or a nal ysis p ur p oses a n d will re mai n as re p orte d 
( partiall y or c o m pletel y missi n g) i n s u bject listi n gs. 
I nc o m plete I P st o p d ates 
Partiall y missi n g I P st o p dates will be i m p ute d as f oll o ws:  
•  If t he da y val ue of last d ose is missi n g, t he first da y of t he m o nt h will be use d; u nless t his 
occ urs i n t he sa me m o nt h a n d year as t he date of a k n o w n a d mi nistrati o n of I P, t he n t his 
date will be use d.  
I nc o m plete a dverse eve nt d ates 
Partiall y or c o m pletel y missi n g a d verse e ve nt ( A E) o nset dates will be i m p ute d as f oll o ws:  
•  If o nl y t he da y val ue of t he a d verse e ve nt o nset date is missi n g, t he first da y of t he m o nt h 
will be use d; u nless t his occ urs i n t he sa me m o nt h a n d year as t he latest of ra n d o misati o n 
a n d date of first d ose of I P, t he n t he latest of ra n d o misati o n a n d t he d ate of first d ose of 
I P will be use d. 
•  If t he da y a n d m o nt h val ues of t he a d verse e ve nt o nset date are missi n g, Ja n uar y 1 will be 
use d; u nless t his occ urs i n t he sa me year as t he latest of ra n d o misati o n a n d t he date of 
first d ose of I P, t he n t he latest of ra n d o misati o n a n d t he date of first d ose of I P will be 
use d.  
•  If t he a d verse e ve nt o nset date is c o m pletel y missi n g, t he latest of ra n d o misati o n a n d t he 
date of first d ose of I P will be use d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 8  of 9 2  
 
I nc o m plete de at h d ates 
Partiall y or c o m pletel y missi n g deat h dates will be i m p ute d as f oll o ws:  
•  If o nl y t he da y val ue of t he deat h date is missi n g, t he first da y of t he m o nt h will be use d; 
u nless t his occ urs i n t he sa me m o nt h a n d year as last visit date, t he last visit date will be 
use d.  
•  If t he da y a n d m o nt h val ues of t he deat h date are missi n g, Ja n uar y 1 will be use d; u nless 
t his occ urs i n t he sa me year as last visit date, t he n last visit date will be use d.   
•  If t he deat h date is c o m pletel y missi n g, last visit date will be use d. 
I nc o m plete effic acy eve nt d ates 
Partiall y or c o m pletel y missi n g e ve nt o nset dates will be i m p ute d as f oll o ws:  
•  If o nl y t he da y val ue of t he e ve nt o nset date is missi n g, t he first da y of t he m o nt h will be 
use d; u nless t his occ urs i n t he sa me m o nt h a n d year as ra n d o misati o n, t he n t he date of 
ra n d o misati o n will be use d. 
•  If t he da y a n d m o nt h val ues of t he e ve nt o nset date are missi n g, Ja n uar y 1 will be use d; 
u nless t his occ urs i n t he sa me year as ra n d o misati o n, t he n t he date of ra n d o misati o n will 
be use d.  
•  If t he e ve nt o nset date is c o m pletel y missi n g, t he date of ra n d o misati o n will be use d. 
I nc o m plete c o nc o mit a nt me dic ati o n d ates 
F or me dicati o ns t hat starte d pri or t o st u d y start, start da y will n ot be i m p ute d. Partiall y or 
c o m pletel y missi n g c o nc o mita nt me dicati o n ( C M) start dates will be i m p ute d as f oll o ws:  
•  If o nl y t he da y val ue of t he C M start date is missi n g, t he first da y of t he m o nt h will be 
use d; u nless t his occ urs i n t he sa me m o nt h a n d year as t he date of ra n d o misati o n, t he n t he 
date ra n d o misati o n will be use d  
•  If t he da y a n d m o nt h val ues of t he C M start date are missi n g, Ja n uar y 1 will be use d; 
u nless t his occ urs i n t he sa me year as t he date of ra n d o misati o n, t he n t he date 
ra n d o misati o n will be use d. 
•  If t he C M start date is c o m pletel y missi n g, t he date of ra n d o misati o n will be use d. 
If me dicati o n is mar ke d as ‘ Treat me nt c o nti n ues’ t he st o p date will n ot be i m p ute d. Partiall y or 
c o m pletel y missi n g C M st o p dates ( w here a p plica ble) will be i m p ute d as f oll o ws:  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 9  of 9 2  
 
•  If o nl y t he da y val ue of t he C M st o p date is missi n g, t he last da y of t he m o nt h will be 
use d; u nless t his occ urs i n t he sa me m o nt h a n d year as t he last visit, t he n t he date of t he 
last visit will be use d.  
•  If t he da y a n d m o nt h val ues of t he C M st o p date are missi n g, Dece m ber 3 1 will be use d; 
u nless t his occ urs i n t he sa me year as t he last visit, t he n t he date of t he last visit will be 
use d.  
•  If t he C M st o p date is c o m pletel y missi n g, t he date of t he last visit will be use d. 
3. 3. 1. 3  
L a b or at or y d at a pri nci ples  
Assesse d val ues of t he f or m ‘ < x’ ( bel o w t he l o wer li mit of q ua ntificati o n [ L L o Q]) or ‘ > x’ (a b o ve 
t he u p per li mit of q ua ntificati o n [ U L o Q]) will be i m p ute d as ‘ x/ 2’ f or ' < x' a n d ' x' f or ' > x' i n t he 
calc ulati o ns of s u m mar y statistics b ut dis pla ye d as ‘ < x’ or  ‘ > x’ i n listi n gs. T he n u m ber of 
i m p utati o ns will be s u m marise d. Missi n g safet y la b orat or y data will n ot be i m p ute d.  
3. 3. 1. 4  
St u d y D a y  
St u d y Da y will be calc ulate d fr o m t he ra n d o misati o n date a n d will be use d t o s h o w start/st o p da y 
of assess me nts a n d e ve nts. Da y 1 is t he da y of ra n d o misati o n, Da y -1 is t he da y pri or t o t he date 
of ra n d o misati o n, t here is n o Da y 0.  
•  If t he date of t he e ve nt is o n or after t he ra n d o misati o n date, t he n:  
o  St u d y Da y = date of e ve nt –  date of ra n d o misati o n + 1.  
•  If t he date of t he e ve nt is pri or t o t he ra n d o misati o n date, t he n: 
o  St u d y Da y = date of e ve nt –  date of ra n d o misati o n.  
3. 3. 1. 5  
St u d y peri o ds  
St u d y peri o ds f or F ull A n al ysis Set ( F A S)  
Scree ni n g peri o d  
T he scree ni n g peri o d starts at t he date of si g ne d i nf or me d c o nse nt a n d e n ds at t he da y bef ore 
ra n d o misati o n. F or s u bjects e nr olle d b ut n ot ra n d o mise d, t he e nr ol me nt peri o d e n ds at last visit. 
Pl a n ne d tre at me nt peri o d  
T he f oll o w -u p ti me f or t he Pla n ne d treat me nt peri o d will be calc ulate d fr o m ra n d o misati o n a n d 
t o t he earliest of da y of visit 1 1  (if s u bject atte n de d visit 1 1, ot her wise da y 3 4 3  will be use d) , 
date of wit h dra wal of c o nse nt or date of deat h. If wit h dra wal of c o nse nt or deat h di d n ot occ ur, it 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 0  of 9 2  
 
will be calc ulate d fr o m ra n d o misati o n a n d t o t he earliest of da y of visit 1 1 (if s u bject atte n de d 
visit 1 1, ot her wise da y 3 4 3 will be use d) or t he last st u d y visit.   
St u d y peri o ds f or S afet y A n al ysis Set ( S A S)  
Pre -tre at me nt peri o d 
T he pre -treat me nt peri o d starts at t he date of si g ne d i nf or me d c o nse nt a n d e n ds bef ore t he date 
a n d ti me p oi nt of first d ose of I P.  
O n -tre at me nt peri o d 
T he f oll o w -u p ti me f or t he O n -treat me nt peri o d will be calc ulate d fr o m t he date of t he first d ose 
of I P a n d t o t he earliest of 1 4 da ys after last d ose, date of wit h dra wal of c o nse nt or date of deat h. 
If wit h dra wal of c o nse nt or deat h di d n ot occ ur, it will be calc ulate d fr o m t he date of t he first 
d ose of I P a n d t o t he earliest of 1 4 da ys after last d ose of st u d y dr u g or t he last st u d y visit..  
O n -st u dy peri o d 
T he f oll o w -u p ti me f or t he O n -st u d y peri o d will be calc ulate d fr o m t he date of t he first d ose of 
I P a n d t o t he earliest date of wit h dra wal of c o nse nt or  date of deat h. If wit h dra wal of c o nse nt or 
deat h di d n ot occ ur, it will be calc ulate d fr o m t he date of t he first d ose of I P a n d t o t he last st u d y 
visit.  
3. 3. 1. 6  
S u bject ter mi n ol o g y c o n ve nti o n  
T he ter m “ Partici pa nt” is ge nerall y use d t o refer t o la n g ua ge base d o n t he C S P, ve n d or 
tec h n ol o g y, patie nt-re p orte d o utc o mes ( P R Os), a n d p u blicati o n titles. T he w or d “s u bject” is 
m ore c o m m o nl y e nc o u ntere d i n t he statistical secti o ns of t his S A P f or c o nsist e nc y wit h sta n dar d 
statistical ter mi n ol o g y. Partici pa nt, patie nt, a n d s u bject are use d i nterc ha n gea bl y. 
3. 3. 1. 7  
S u m m ar y st atistics  
Q ua ntitati ve data will be s u m marise d b y descri pti ve statistics i ncl u di n g n u m ber of s u bjects i n 
cate g or y ( n), mea n, sta n dar d de viati o n ( S D), mi ni m u m, first q uartile ( Q 1), me dia n, t hir d q uartile 
( Q 3), a n d ma xi m u m. Ge o metric mea n a n d c oefficie nt of variati o n ( C V) will be calc ulate d i n 
a d diti o n t o arit h metic me a n a n d S D, if a p pr o priate.  
Cate g orical data will be s u m marise d as t he n u m ber a n d perce nta ge of s u bjects i n eac h treat me nt 
gr o u p f or eac h cate g or y. W he n a p pr o priate, n u m ber of missi n g o bser vati o ns will be prese nte d, 
a n d t hese will n ot be i ncl u de d i n t he de n o mi nat or w he n calc ulati n g perce nta ges.  
A ge neral r ule is t o prese nt descri pti ve s u m mar y statistics ( mea n, S D, me dia n, Q 1, Q 3) t o 1 m ore 
deci mal place t ha n t he i n di vi d ual val ues. T he mi ni m u m a n d ma xi m u m val ues will be re p orte d t o 
t he sa me n u m ber of deci mal places as t he i n di vi d ual val ues. 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 1  of 9 2  
 
A bs ol ute c ha n ge fr o m baseli ne will be prese nte d i n a d diti o n t o a bs ol ute val ues. It will be 
s u m marise d b y descri pti ve statistics at t he sa me ti me p oi nts as a bs ol ute val ues, e xce pt f or 
baseli ne itself.  
All c o nfi de nce i nter vals ( CIs) will be 9 5 %.  
3. 3. 1. 8  
Ti me at ris k a n d ce ns ori n g  
If a s u bject has a n e ve nt wit h o nset da y d uri n g t he st u d y peri o d bei n g a nal yse d (see Secti o n 
3. 3. 1. 5 ), it will be i ncl u de d i n t he a nal ysis. F or s u bjects wit h a n e ve nt, t he ti me at ris k will be 
deri ve d as  
•  𝐸𝑣𝑒𝑛𝑡 𝑜𝑛𝑠𝑒𝑡 𝑑𝑎𝑡𝑒−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑠𝑎𝑡𝑖𝑜𝑛+ 1  f or F A S 
•  𝐸𝑣𝑒𝑛𝑡 𝑜𝑛𝑠𝑒𝑡 𝑑𝑎𝑡𝑒−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑡𝑒 𝑜𝑓 𝐼𝑃+ 1  f or S A S 
F or e ve nt -free s u bjects, t he ti me at ris k will be deri ve d base d o n t he st u d y peri o d bei n g a nal yse d, 
see t he defi niti o n i n Secti o n 3. 3. 1. 5 . E ve nt-free s u bjects are ce ns ore d o n t he last da y of t he st u d y 
peri o d.  
3. 3. 1. 9  
U nit c o n ve nti o ns  
•  1 year is defi ne d as 3 6 5. 2 5 da ys  
•  1 m o nt h is defi ne d as 3 6 5. 2 5/ 1 2 = 3 0. 4 3 7 5 da ys  
3. 3. 2  
Visit Wi n d o w  
Visit wi n d o ws will be use d f or a nal ysi n g visit -base d data a n d are base d o n t he tar get da y f or a 
sc he d ule d visit, see Sc he d ule of Acti vities i n t he C S P. T he ra n ge of t he wi n d o ws f or sc he d ule d 
o n -site assess me nts are s h o w n i n  
Ta ble 1 .  
T he visit cl osest t o t he tar get da y a n d wit hi n t he visit wi n d o w is assi g ne d. T his ca n be a 
sc he d ule d or u nsc he d ule d assess me nt.  
T a ble 1  Visit wi n d o ws f or o n -site assess me nts 
Sc he d ule d 
assess me nt  
Visit  
T ar get D a y  
Visit wi n d o w ( d a ys)  
All e n d p oi nts  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 2  of 9 2  
 
Wee k 4  
4  
2 9  
[ 21, 5 7] 
Wee k 1 2  
6  
8 5  
[ 5 8, 9 9]  
Wee k 1 6  
8  
1 1 3  
[ 1 0 0, 1 4 1]  
Wee k 2 4  
9  
1 6 9  
[ 1 4 2, 2 1 1] 
Wee k 3 6  
1 0  
2 5 3  
[ 2 1 2, 2 9 4] 
Wee k 4 8  
1 1  
3 3 6  
[ 2 9 5, 3 5 0] 
Wee k 5 2  
1 2  
3 6 5  
> 3 5 0  
1. T he Wee k 4 visit wi n d o w als o i ncl u des p ost -d ose  vital si g ns assess me nts  (V S 7)  ta ke n o n t he da y of 
ra n d o misati o n, b ut after t he baseli ne assess me nt.  
T he a nal ysis visit wi n d o w as defi ne d i n Ta ble 1  will n ot be use d f or t he Ort h ostatic bl o o d 
press ure test at 1 2 wee ks. I nstea d, t he n o mi nal visit n u m ber will be use d f or t his assess me nt.  
A nal ysis visit wi n d o ws f or
 will be descri be d i n Secti o ns 4. 2. 9. 4  a n d 4. 2. 1 8. 1 . 
Baseli ne is defi ne d i n Secti o n 3. 3. 1. 1 . 
3. 3. 3  
H a n dli n g of Sc he d ule d a n d U nsc he d ule d Visits  
U nsc he d ule d visits ca n be assi g ne d t o a visit wi n d o w if cl oser t o t he tar get da y t ha n t he 
sc he d ule d visit or if t here is n o meas ure me nt fr o m a sc he d ule d visit i n t he wi n d o w. If a patie nt 
has perf or me d m ore t ha n o ne u nsc he d ule d visit wit hi n a wi n d o w, t he assess me nt cl osest t o t he 
tar get da y will be use d. 
I n case of ties bet wee n sc he d ule d or u nsc he d ule d visits l ocate d o n differe nt si des of t he tar get 
da y, t he earlier assess me nt will be use d. I n case of ties l ocate d o n t he sa me si de of t he tar get da y 
(i.e., m ore t ha n o ne val ue f or t he sa me da y b ut differe nt ti me), t he val ue wit h t he earlier e ntr y 
ti me will be use d.   
I n case of t w o or m ore sc he d ule d or u nsc he d ule d  visits f or assess me nts wit h t he sa me p ur p ose 
a n d wit h i de ntical dates a n d ti mes (i ncl u di n g p ossi bl y missi n g ti mes), t he a vera ge val ue will be 
deri ve d, a n d i n case t hat t he rec or d is assi g ne d f or its res pecti ve a nal ysis visit, t he a vera ge val ue 
will be use d f or a nal ysis. T his will be d o ne b ot h f or cases wit h m ulti ple baseli ne val ues or wit h 
m ulti ple p ost -baseli ne val ues wit h t he sa me date a n d ti me.  
I n s o me i nsta nces, se veral assess me nts of a vital si g n varia ble are sc he d ule d at t he sa me visit f or 
differe nt p ur p oses, e. g., s yst olic bl o o d press ure at Visit 3. I n t his sit uati o n, t he meas ure me nt fr o m 
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 3  of 9 2  
 
t he assess me nt f or o nl y vital si g ns p ur p oses w o ul d be use d, u nless t his is missi n g. If it is missi n g, 
t he n t he s u pi ne B P pre-ort h ostatic test meas ure me nt or t he s u pi ne B P pre -6 M W T w o ul d be use d 
f or t he a nal ysis (i n t hat or der). 
3. 3. 4  
M ulti plicit y/ M ulti ple C o m p aris o ns  
T he f or mal h y p ot heses tests will a d dress t he treat me nt effect of A Z D 4 8 3 1 vers us place b o o n t he 
d ual pri mar y e n d p oi nts K C C Q T otal s y m pt o m sc ore ( T S S) c ha n ge fr o m baseli ne at 1 6 wee ks  
a n d 6 -mi n ute wal k dista nce ( 6 M W D) c ha n ge fr o m baseli ne at 1 6 wee ks . M ulti plicit y acr oss 
pri mar y a n d sec o n dar y e n d p oi nts d ue t o m ulti ple tests will be acc o u nte d f or acc or di n g t o a 
gate kee pi n g test strate g y f or al p ha rec ycli n g. T he strate g y is a p plie d t o c o ntr ol t he fa mil y -wise 
t y pe I err or rate of 5 % of a n err o ne o us rejecti o n of  t he n ull h y p ot hesis ( B ur ma n, 2 0 0 9) ( F D A, 
2 0 1 7) . 
T he c o m paris o n bet wee n p o ole d d oses of A Z D 4 8 3 1 a n d place b o is f or mall y teste d, u nless t he 
ra n d o misati o n t o t he A Z D 4 8 3 1 5 m g treat me nt gr o u p is st o p pe d d uri n g t he st u d y, i n w hic h case 
t he c o m paris o n of A Z D 4 8 3 1 2. 5 m g a n d place b o will be f or mall y teste d. 
First, b ot h d ual pri mar y e n d p oi nts are teste d wit h H ol m met h o d. T he p -val ues f or K C C Q -T S S 
a n d 6 M W D are s orte d fr o m l o west t o hi g hest, if t he l o west p -val ue is rejecte d at  α / 2 = 0 .0 2 5 , 
t he n t he ot her e n d p oi nt is teste d at f ull α = 0 .0 5 . If b ot h d ual pri mar y e n d p oi nts are rejecte d, 
t he n t he f ull testi n g mass of 0. 0 5 will be passe d o n t o testi n g i n t he sec o n dar y e n d p oi nt fa mil y. 
T he sec o n dar y e n d p oi nt fa mil y will be teste d wit hi n a fi xe d se q ue nce i n t he or der liste d bel o w:  
1.  K C C Q -T S S c ha n ge fr o m baseli ne at 2 4 wee ks  
2.  K C C Q -T S S c ha n ge fr o m baseli ne at 4 8 wee ks  
3.  6 M W D c ha n ge fr o m baseli ne at 2 4 wee ks  
4.  6 M W D c ha n ge fr o m baseli ne at 4 8 wee ks  
5.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -pr o B N P at 1 6 wee ks  
6.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -pr o B N P at 2 4 wee ks  
7.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -pr o B N P at 4 8 wee ks  
8.  L V -G L S c ha n ge fr o m baseli ne at 1 6 wee ks  
9.  L V -G L S c ha n ge fr o m baseli ne at 2 4 wee ks  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 4  of 9 2  
 
1 0.  L A VI c ha n ge fr o m baseli ne at 1 6 wee ks  
1 1.  L A VI c ha n ge fr o m baseli ne at 2 4 wee ks  
1 2.  L V MI c ha n ge fr o m baseli ne at 1 6 wee ks  
1 3.  L V MI c ha n ge fr o m baseli ne at 2 4 wee ks  
1 4.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d hs C R P at 1 6 wee ks  
1 5.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d hs C R P at 2 4 wee ks  
1 6.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d hs C R P at 4 8 wee ks  
1 7.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d I L-6 at 1 6 wee ks  
1 8.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d I L-6 at 2 4 wee ks  
1 9.  C ha n ge fr o m baseli ne i n l o g -tra nsf or me d I L-6 at 4 8 wee ks  
B y t his a p pr oac h, f ull al p ha is passe d o nt o t he ne xt h y p ot hesis i n t he se q ue nce u ntil a test fails t o 
reject t he n ull h y p ot hesis or u ntil all t he liste d n ull h y p ot heses are rejecte d. P-val ues fr o m all 
e n d p oi nts i n t he hierarc h y bel o w t he first n o n -rejecte d sec o n dar y e n d p oi nt a n d e x pl orati ve 
e n d p oi nts are n ot a dj uste d, t h us will be n o mi nal a n d c o nsi dere d e x pl orati ve.  
3. 3. 5  
H a n dli n g of Pr ot oc ol De vi ati o ns i n St u d y A n al ysis  
T he defi niti o n a n d ha n dli n g of i m p orta nt pr ot oc ol de viati o ns (I P Ds)  are prese nte d i n a se parate 
Pr ot oc ol De viati o n Pla n. Defi niti o n a n d prese ntati o n of pr ot oc ol de viati o ns are descri be d i n 
Secti o n 4. 1. 5 . 
3. 3. 5. 1  
C o vi d -1 9  
T he i m pact of t he C o vi d -1 9 pa n de mic is ca pt ure d i n e x p os ure, dis p ositi o n a n d visit data case 
re p ort f or m pa ges as a ge neral q uesti o n o n w het her a d mi nistrati o n/s u bject’s stat us/ visit was 
i m pacte d b y a n y gl o bal/c o u ntr y sit uati o n. S u bjects affecte d b y t he C O VI D -1 9 pa n de mic, s uc h as 
efficac y a n d safet y assess me nts n ot per C S P, will be rec or de d as pr ot oc ol de viati o ns. Listi n gs of 
C O VI D -1 9 st u d y disr u pti o ns a n d n u m ber of s u bject dis p ositi o ns d ue t o C O VI D -1 9 wi ll be 
prese nte d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 5  of 9 2  
 
4  
S T A TI S TI C A L A N A L Y SI S  
4. 1  
St u d y P o p ul ati o n  
T he d o mai n st u d y p o p ulati o n c o vers s u bject dis p ositi o n, a nal ysis sets, pr ot oc ol de viati o ns, 
de m o gra p hics, baseli ne c haracteristics, me dical a n d s ur gical hist or y, use of pri or a n d 
c o nc o mita nt me dicati o n, a n d st u d y dr u g c o m plia nce.  
T he ta bles will be prese nte d b y A Z D 4 8 3 1 2. 5 m g, A Z D 4 8 3 1 5 m g, A Z D 4 8 3 1 T otal ( p o ole d 
treat me nt gr o u ps A Z D 4 8 3 1 2. 5 m g a n d 5 m g), place b o a n d T otal.  
4. 1. 1  
S u bject Dis p ositi o n a n d C o m pleti o n St at us  
4. 1. 1. 1  
Defi niti o ns a n d Deri v ati o ns  
Scree ne d s u bjects  
E nr olle d s u bjects w h o ha ve si g ne d t he i nf or me d c o nse nt f or m (I C F) of t he st u d y.  
R a n d o mise d s u bjects  
S u bjects w h o ha ve bee n ra n d o mise d t o o ne of t he treat me nt gr o u ps.  
S u bjects w h o st arte d tre at me nt  
S u bjects w h o ha ve recei ve d at least o ne d ose of I P. 
S u bjects w h o c o m plete d tre at me nt  
S u bjects w h o ha ve a n assess me nt o n or after Wee k 4 8 wit h o ut disc o nti n ui n g st u d y me dicati o n 
pri or t o t he visit.  A s u bject w h o dies d uri n g t he st u d y wit h o ut ha vi n g per ma ne ntl y disc o nti n ue d 
I P pri or t o date of deat h, is c o nsi dere d t o ha ve c o m plete d treat me nt. 
S u bjects w h o disc o nti n ue d tre at me nt  
S u bjects w h o ha ve per ma ne ntl y pre mat urel y disc o nti n ue d I P.  
S u bjects w h o c o m plete d st u dy  
S u bjects w h o ha ve c o m plete d t he last pr ot oc ol s pecifie d visit/assess me nt (i ncl u di n g tele p h o ne 
c o ntact) re gar dless of t he n u m ber of d oses of st u d y me dicati o n t he y ha ve recei ve d.  
S u bjects wit h dr a w n fr o m st u dy  
S u bjects w h o ha ve wit h dra w n c o nse nt or bee n l ost t o f oll o w -u p.  
S u bjects w h o disc o nti n ue d tre at me nt d ue t o gl o b al/c o u ntry sit u ati o n  
S u bjects w h o ha ve per ma ne ntl y pre mat urel y disc o nti n ue d I P  d ue t o gl o bal/c o u ntr y sit uati o n(s).  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 6  of 9 2  
 
S u bjects w h o wit h dr a w fr o m st u dy d ue t o gl o b al/c o u ntry sit u ati o n  
S u bjects w h o ha ve wit h dra w n c o nse nt, bee n l ost t o f oll o w -u p, or die d, d ue t o gl o bal/c o u ntr y 
sit uati o n(s). 
4. 1. 1. 2  
Prese nt ati o n  
Dis p ositi o n of all s u bjects will be prese nte d, fr o m scree ni n g t o st u d y c o m pleti o n. T he n u m ber of 
e nr olle d a n d scree n -faile d s u bjects (a n d reas o n) will be s u m marise d. T he n u m ber a n d perce nta ge 
of s u bjects will be prese nte d b y treat me nt gr o u p a n d i n t otal f or all s u bjects i n t he f oll o wi n g 
cate g ories:  
•  scree ne d, 
•  scree n fail ures b y reas o n, 
•  ra n d o mise d,  
•  di d n ot recei ve I P b y reas o n,  
•  starte d treat me nt,  
•  c o m plete d treat me nt,  
•  disc o nti n ue d treat me nt (a n d reas o n),  
•  c o m plete d st u d y ( wit h s u bcate g ories ali ve a n d dea d),  
•  wit h dra w n fr o m st u d y b y reas o n,  
I n a d diti o n, n u m ber a n d perce nta ge of s u bjects w h o disc o nti n ue d treat me nt d ue t o gl o bal/c o u ntr y 
sit uati o n a n d s u bjects w h o wit h dra w fr o m st u d y d ue t o gl o bal/c o u ntr y sit uati o n will be ta b ulate d 
se paratel y. 
Listi n gs  
A listi n g of scree n fail ures a n d s u bjects disc o nti n ue d fr o m st u d y will be prese nte d.  
4. 1. 2  
A n al ysis Sets  
4. 1. 2. 1  
Defi niti o ns a n d Deri v ati o ns  
F ull a n alysis set  
All s u bjects w h o ha ve bee n ra n d o mise d t o st u d y treat me nt a n d w h o ha ve recei ve d at least o ne 
d ose of i n vesti gati o nal pr o d uct will be i ncl u de d i n F A S irres pecti ve of t heir pr ot oc ol a d here nce 
a n d c o nti n ue d partici pati o n i n t he st u d y. S u bjects will be a nal yse d  acc or di n g t o t heir ra n d o mise d 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 7  of 9 2  
 
st u d y me dicati o n assi g n me nt, irres pecti ve of t he treat me nt act uall y recei ve d. F A S is c o nsi dere d 
t he pri mar y a nal ysis set f or t he pri mar y a n d sec o n dar y efficac y varia bles as well as f or t he 
e x pl orat or y efficac y varia bles.  
S afety a n alysis set  
S A S c o nsists of all s u bjects w h o ha ve recei ve d at least o ne d ose of I P. Err o ne o usl y treate d 
s u bjects (e. g., t h ose ra n d o mise d t o treat me nt A b ut act uall y gi ve n treat me nt B) are acc o u nte d f or 
i n t he treat me nt gr o u p of t he treat me nt t he y act uall y recei ve d. A s u bject w h o has recei ve d a n y 
d ose of t he acti ve I P will be classifie d as i n t he acti ve I P treat me nt gr o u p. A s u bject w h o has 
recei ve d b ot h d oses of acti ve I P will be classifie d as i n t he hi g hest d ose treat me nt gr o u p. S A S is 
use d f or all safet y a nal yses.  
4. 1. 2. 2  
Prese nt ati o n  
A nal ysis sets will be prese nte d b y n u m ber of s u bjects i n eac h set f or all ra n d o mise d s u bjects, b y 
treat me nt gr o u p a n d t otal n u m ber of s u bjects. T he reas o n f or e xcl usi o n fr o m a n a nal ysis set will 
be prese nte d.  
Listi n gs  
A listi n g of s u bjects e xcl u de d fr o m a n a nal ysis set will be prese nte d al o n g wit h reas o ns f or 
e xcl usi o n.  
4. 1. 3  
St u d y Recr uit me nt  
4. 1. 3. 1  
Defi niti o ns a n d Deri v ati o ns  
T he re gi o ns are defi ne d as E ur o pe, w here Wester n E ur o pe a n d Easter n E ur o pe are s u bsets, N ort h 
A merica, S o ut h A merica, A ustralia a n d Asia, eac h re gi o n i ncl u di n g t he f oll o wi n g c o u ntries:  
•  E ur o pe: Bel gi u m, B ul garia, Czec h Re p u blic, De n mar k, Fra nce, H u n gar y, Net herla n ds, 
P ola n d, R ussia, Sl o va kia, S we de n, T ur ke y.  
o  West E ur o pe: Bel gi u m, De n mar k, Fra nce, Net herla n ds, S we de n.  
o  East E ur o pe: B ul garia, Czec h Re p u blic, H u n gar y, P ola n d, R ussia, Sl o va kia, 
T ur ke y  
•  N ort h A merica: Ca na da, U S A.  
•  S o ut h A merica: Brazil.  
•  Asia a n d A ustralia: A ustralia, Ja pa n, Tai wa n.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 8  of 9 2  
 
4. 1. 3. 2  
Prese nt ati o n  
T he n u m ber of s u bjects recr uite d b y re gi o n, c o u ntr y a n d site will be prese nte d, b y treat me nt 
gr o u p a n d t otal n u m ber of s u bjects f or eac h a nal ysis set a n d scree ne d s u bjects.  
4. 1. 4  
Str atific ati o n f act ors  
4. 1. 4. 1  
Defi niti o ns a n d Deri v ati o ns  
T he ra n d o misati o n will be stratifie d b y Ne utr o p hil c o u nt as  
•  > 4 × 1 0 6/ m L 
•  ≤4 × 1 0 6/ m L. 
4. 1. 4. 2  
Prese nt ati o n  
T he n u m ber a n d perce nta ge of s u bject i n eac h strat u m will be prese nte d b y treat me nt gr o u p f or 
F A S, as rec or de d i n t he I nteracti ve res p o nse tec h n ol o g y (I R T).  
4. 1. 5  
Pr ot oc ol De vi ati o ns  
4. 1. 5. 1  
Defi niti o ns a n d Deri v ati o ns  
I m p orta nt pr ot oc ol de viati o ns (I P D) are defi ne d as pr ot oc ol de viati o ns w hic h ma y si g nifica ntl y 
affect t he c o m plete ness, acc urac y a n d/ or relia bilit y of t he st u d y data, or w hic h ma y si g nifica ntl y 
affect a s u bject’s ri g hts, safet y, or well -bei n g. T he I P Ds are relate d t o  
•  I ncl usi o n criteria 
•  E xcl usi o n criteria  
•  Disc o nti n uati o n criteria f or st u d y pr o d uct met b ut s u bject n ot wit h dra w n fr o m st u d y 
treat me nt 
•  Disc o nti n uati o n criteria f or o verall st u d y wit h dra wal met b ut s u bject n ot wit h dra w n fr o m 
st u d y 
•  I P de viati o ns 
•  E xcl u de d me dicati o n ta ke n  
•  De viati o ns relate d t o st u d y pr oce d ure  
•  Ot her i m p orta nt de viati o ns.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
3 9  of 9 2  
 
All I P Ds e xce pt f or d osi n g err or will be i de ntifie d a n d d oc u me nte d b y t he st u d y tea m pri or t o 
u n bli n di n g of t he trial. Details o n t he ha n dli n g of I P Ds are s pecifie d i n t he Pr ot oc ol de viati o n 
pla n.  
Listi n gs  
A listi n g of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns will be prese nte d.  
4. 1. 5. 2  
Prese nt ati o n  
T he n u m ber a n d perce nta ge of s u bjects wit h at least o ne I P D cate g or y as well as t he n u m ber a n d 
perce nta ge of s u bjects meeti n g eac h I P D cate g or y will be pr o vi de d b y treat me nt gr o u p a n d i n 
t otal. S u bjects meeti n g a n I P D cate g or y m ore t ha n o nce will be c o u nte d o nce f or t he 
c orres p o n di n g I P D cate g or y. A n y s u bject w h o has m ore t ha n o ne I P D cate g or y will be c o u nte d 
o nce i n t he o verall s u m mar y. I P Ds will n ot be use d t o e xcl u de a n y s u bject fr o m a n y a nal ysis set, 
n or t o e xcl u de a n y data fr o m s u bjects i ncl u de d i n a n a nal ysis set. S u bjects ha vi n g I P Ds will be 
s u m marise d f or t he F A S p o p ulati o n b y treat me nt gr o u p a n d i n t otal. 
4. 1. 6  
De m o gr a p hics  
4. 1. 6. 1  
Defi niti o ns a n d Deri v ati o ns  
De m o gra p hic c haracteristics i ncl u des  
•  A ge ( years)   
•  A ge gr o u p ( < 6 5; 6 5 -7 5; > 7 5 years)  
•  Se x ( male, fe male)  
•  Race ( Blac k or Africa n A merica n, Nati ve Ha waiia n or ot her Pacific Isla n der, A merica n 
I n dia n or Alas ka Nati ve, Asia n, W hite, Ot her)  
•  Et h nicit y  
o  His pa nic  
o  N ot His pa nic  
•  Et h nic Asia n s u b gr o u p (tri g gere d b y ‘ Asia n’ i n t he R S G fiel d f or et h nic ori gi n i n t he 
C R F):  
o  Asia n, n ot s pecifie d  
o  C hi nese  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 0  of 9 2  
 
o  Ja pa nese 
o  Tai wa nese  
o  K orea n  
o  Viet na mese  
o  Ot her  
4. 1. 6. 2  
Prese nt ati o n  
De m o gra p hic c haracteristics will be s u m marise d f or t he F A S p o p ulati o n b y treat me nt gr o u p a n d 
i n t otal. 
Listi n gs  
A listi n g of de m o gra p hics a n d baseli ne c haracteristics f or ra n d o mise d s u bjects will be prese nte d.  
4. 1. 7  
B aseli ne C h ar acteristics  
4. 1. 7. 1  
Defi niti o ns a n d Deri v ati o ns  
Baseli ne s u bject c haracteristics i ncl u des  
•  Hei g ht (c m)  
•  Wei g ht ( k g)  
•  B o d y mass i n de x, calc ulate d usi n g wei g ht a n d hei g ht varia bles at baseli ne ( k g/ m 2) 
•  Cate g orical b o d y mass i n de x ( < 3 0, ≥3 0 a n d < 4 0, ≥4 0) ( k g/ m 2) 
4. 1. 7. 2  
Prese nt ati o n  
Baseli ne s u bject c haracteristics will be s u m marise d f or t he F A S p o p ulati o n b y treat me nt gr o u p 
a n d i n t otal . 
4. 1. 8  
Alc o h ol a n d nic oti ne use at b aseli ne  
4. 1. 8. 1  
Defi niti o ns a n d Deri v ati o ns  
Alc o h ol use a n d Nic oti ne use are cate g orise d as  
•  Ne ver  
•  F or mer  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 1  of 9 2  
 
•  C urre nt  
4. 1. 8. 2  
Prese nt ati o n  
Alc o h ol use a n d Nic oti ne use will be prese nte d b y n u m ber of s u bjects i n eac h cate g or y f or t he 
F A S p o p ulati o n b y treat me nt gr o u p a n d i n t otal.  
4. 1. 9  
B aseli ne Dise ase C h ar acteristics  
4. 1. 9. 1  
Defi niti o ns a n d Deri v ati o ns  
T he f oll o wi n g disease c haracteristics will be prese nte d at baseli ne:  
•  K C C Q -T S S ( p oi nts)  
•  Cate g orical K C C Q -T S S ( ≤8 0, > 8 0 ) ( p oi nts) 
•  K C C Q O verall s u m mar y sc ore ( O S S) ( p oi nts)  
•  Cate g orical K C C Q -O S S ( ≤8 0, > 8 0 a n d ≤9 0, > 9 0 ) ( p oi nts) 
•  6 M W D ( meters)  
•  Cate g orical 6 M W D (≤3 5 0, > 3 5 0 a n d ≤4 0 0,  > 4 0 0)  ( meters)  
•  H os pitalise d f or H F pri or t o ra n d o misati o n ( Yes/ N o)  
•  Ti me fr o m pri or h os pitalisati o n f or H F t o ra n d o misati o n ( m o nt hs) (f or s u bjects wit h pri or 
h os pitalisati o n)  
•  N Y H A classificati o n (II, III, I V)  
•  L V E F ( %)  
•  Cate g orical L V E F ( %) (< 5 0, ≥5 0)  
•  Hist or y of atrial fi brillati o n ( Yes/ N o)  
•  Hist or y of atrial fl utter ( Yes/ N o)  
•  Hist or y of h y perte nsi o n ( Yes/ N o)  
•  N T -pr o B N P ( p g/ m L)  
•  Ne utr o p hil c o u nt ( 1 0 9/ L) 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 2  of 9 2  
 
•   Ne utr o p hil c o u nt cate g or y ( 1 0 9/ L) (≤4, > 4)  
•  e G F R, calc ulate d acc or di n g t o C K D -E PI S -Creati ni ne e q uati o n ( m L/ mi n/ 1. 7 3 m 2) 
•  Cate g orical e G F R, calc ulate d acc or di n g t o C K D -E PI e q uati o n 6 0, > 6 0) ( m L/ mi n/ 1. 7 3 m 2) 
F or baseli ne e G F R, a ge at scree ni n g is use d.  
4. 1. 9. 2  
Prese nt ati o n  
Baseli ne disease c haracteristics will be s u m marise d f or t he F A S p o p ulati o n b y treat me nt gr o u p 
a n d i n t otal . 
4. 1. 1 0  
Me dic al Hist or y a n d C o nc o mit a nt Dise ase  
4. 1. 1 0. 1  
Defi niti o ns a n d Deri v ati o ns  
Disease relate d me dical hist or y a n d s ur gical/ pr oce d ure hist or y will be c o de d acc or di n g t o 
Me d D R A.  
4. 1. 1 0. 2  
Prese nt ati o n  
Me dical hist or y a n d c o nc o mita nt disease will be prese nte d f or F A S, b y treat me nt gr o u p a n d i n 
t otal, classifie d b y S yste m or ga n class ( S O C) a n d Preferre d ter m ( P T). Perce nta ges will be 
calc ulate d wit h n u m ber of s u bjects i n F A S as de n o mi nat or. S u bjects wit h m ulti ple e ve nts i n t he 
sa me S O C/ P T will be c o u nte d o nl y o nce i n t hat S O C/ P T. S u bjects wit h e ve nts i n m ore t ha n o ne 
S O C/ P T will be c o u nte d o nce i n eac h of t hat S O C/ P T. Rele va nt me dical a n d s ur gical/ pr oce d ure 
hist or y will be s orte d b y i nter nati o nal or der of S O C a n d al p ha beticall y b y P T.  
4. 1. 1 1  
Pri or a n d C o nc o mit a nt Me dic ati o ns  
4. 1. 1 1. 1  
Defi niti o ns a n d Deri v ati o ns  
Pri or me dicati o n is defi ne d as a n y me dicati o n ta ke n b y t he s u bject bef ore t he first d ose of st u d y 
me dicati o n. If t he e n d date is bef ore or o n t he da y of first d ose of st u d y me dicati o n, it will be 
defi ne d as a pri or me dicati o n.  
C o nc o mita nt t hera p y is defi ne d as a n y me dicati o n or vacci ne ta ke n c o nc urre ntl y wit h st u d y 
me dicati o n re gar dless of t he start date of t he me dicati o n. If a me dicati o n starts o n or pri or t o last 
d ose  + 1 4 da ys,  it is c o nsi dere d t o be ta ke n c o nc o mita ntl y. If t he e n d date of t he me dicati o n is 
pri or t o or o n t he da y of first d ose t he me dicati o n will n ot be c o nsi dere d t o be ta ke n 
c o nc o mita ntl y.  
All o we d a n d pr o hi bite d a n d/ or restricte d c o nc o mita nt me dicati o ns will be prese nte d res pecti vel y. 
Secti o n 6. 5 of t he C S P lists me dicati o ns a n d treat me nts w hic h are pr o hi bite d a n d/ or restricte d.  
All ot her c o nc o mita nt me dicati o ns are classifie d as all o we d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 3  of 9 2  
 
All me dicati o ns will be re p orte d b y A T C classificati o n a n d ge neric dr u g na me a n d are c o de d 
usi n g t he latest versi o n of W H O Dr u g Dicti o nar y ( W H O D D).  
4. 1. 1 1. 2  
Prese nt ati o n  
N u m ber of s u bjects t hat ha ve ta ke n pri or a n d c o nc o mita nt me dicati o ns will be prese nte d f or 
F A S, b y treat me nt gr o u p a n d i n t otal, classifie d b y A T C classificati o n a n d ge neric dr u g na me, 
a n d are c o de d usi n g t he latest versi o n of W H O Dr u g Dicti o nar y ( W H O D D) . Perce nta ges will be 
calc ulate d wit h n u m ber of s u bjects i n F A S as de n o mi nat or. S u bjects are o nl y c o u nte d o nce per 
A T C classificati o n a n d ge neric dr u g na me re gar dless of t he n u m ber of me dicati o ns wit hi n eac h 
cate g or y. Ge neric dr u g na me will be prese nte d ne ste d wit hi n t he rele va nt A T C classificati o n a n d 
s orte d al p ha beticall y b y A T C classificati o n a n d t he n ge neric dr u g na me. 
Pri or me dicati o ns, disall o we d c o nc o mita nt me dicati o ns  a n d all o we d c o nc o mita nt me dicati o ns 
will be prese nte d se paratel y.  
Listi n gs  
A listi n g of a n y c o nc o mita nt me dicati o n f or ra n d o mise d s u bjects will be prese nte d.  
4. 1. 1 2  
St u d y Dr u g C o m pli a nce  
4. 1. 1 2. 1  
Defi niti o ns a n d Deri v ati o ns  
C o m plia nce wit h st u d y me dicati o n is defi ne d as t he n u m ber of recei ve d d oses, di vi de d b y t he 
n u m ber of e x pecte d d oses, m ulti plie d b y 1 0 0, e x presse d as a perce nta ge. T he n u m ber of recei ve d 
d oses is defi ne d as t he pill c o u nt differe nce bet wee n pills dis pe nse d a n d pills ret ur ne d.  
T he n u m ber of e x pecte d d oses is defi ne d as t he n u m ber of e x pecte d d oses bet wee n first d ose a n d 
ti me of last d ose acc or di n g t o C S P or t he ti me w he n st u d y me dicati o n is pre mat urel y 
per ma ne ntl y disc o nti n ue d.  If t he n u m ber of ta blets dis pe nse d or t he n u m ber of ta blets ret ur ne d is 
missi n g f or at least 1 o bser vati o n, c o m plia nce is n ot calc ulate d f or t hat s u bject.  
T he le vel of c o m plia nce of I P per s u bject will be cate g orise d as  
•  < 8 0 %,  
•  8 0 % -1 2 0 %, a n d  
•  > 1 2 0 %.  
4. 1. 1 2. 2  
Prese nt ati o n  
St u d y dr u g c o m plia nce will be prese nte d descri pti vel y, i ncl u di n g mea n, S D, me dia n, Q 1, Q 3, 
mi ni m u m, ma xi m u m, a n d 5 % a n d 9 5 % perce ntiles a n d cate g oricall y b y c o m plia nce gr o u p 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 4  of 9 2  
 
( < 8 0 %, 8 0 %-1 2 0 %, > 1 2 0 %)  f or S A S b y treat me nt gr o u p a n d i n t otal. N u m ber of s u bjects wit h 
missi n g c o m plia nce will be prese nte d.  
Listi n gs  
A listi n g of a d mi nistrati o n a n d c o m plia nce of I P will be prese nte d.  
4. 2  
E n d p oi nt A n al yses  
T his secti o n c o vers details relate d t o t he e n d p oi nt a nal yses s uc h as pri mar y, sec o n dar y, a n d 
e x pl orat or y e n d p oi nts i ncl u di n g se nsiti vit y a n d s u p p orti ve a nal yses.  
Pri m ary esti m a n d  
T he pri mar y esti ma n d is defi ne d b y t he f oll o wi n g attri b utes:  
•  E n d p oi nt: C ha n ge fr o m baseli ne i n varia ble at a nal ysis ti me p oi nt.  
•  Tre at me nt: Ra n d o mise d treat me nt gr o u p (re gar dless of act ual recei ve d treat me nt), 
A Z D 4 8 3 1 2. 5 m g/ 5 m g or place b o , a d mi nistere d i n a d diti o n t o o pti mal bac k gr o u n d 
t hera p y f or c o-m or bi dities.  
•  P o p ul ati o n:  S u bjects a ge d ≥ 4 0 years wit h a n esta blis he d dia g n osis of H F wit h L V E F  > 
4 0 % , a n d at least o ne or m ore of str uct ural  heart disease, si g ns of i ncrease d left 
ve ntric ular filli n g  press ure, si g ns of si g nifica nt diast olic  d ysf u ncti o n, or a rece nt 
h os pitalisati o n f or dec o m pe nsate d H F  a n d ali ve. T his is i m ple me nte d o n e val ua ble 
s u bjects defi ne d b y a s u bset of F A S (see Ta ble 2 ) w hic h ha ve a vaila ble meas ure me nts of 
t he efficac y e n d p oi nts at baseli ne a n d a nal ysis ti me p oi nt. 
•  P o p ul ati o n -le vel s u m m ar y: Differe nce i n a dj uste d mea n c ha n ge fr o m baseli ne t o 
a nal ysis ti me p oi nt  or a dj uste d ge o metric mea n rati o .  
•  H a n dli n g of i nterc urre nt e ve nts: Treat me nt p olic y strate g y c o m bi ne d wit h pri nci pal 
strat u m strate g y 
o  I nitiati o n or c ha n ge of c o nc o mita nt me dicati o n  a n d per ma ne nt pre mat ure 
disc o nti n uati o ns of I P will be ha n dle d b y a treat me nt p olic y strate g y, i.e., i g n ori n g 
t hese i nterc urre nt e ve nts, i m ple me nte d b y i ncl u di n g all a vaila ble data.  
o  S u bjects wit h i nterc urre nt e ve nts res ulti n g i n missi n g assess me nts of t he pri mar y 
e n d p oi nts, e. g., ter mi nal e ve nts or wit h dra wal fr o m t he st u d y, are e x pecte d t o be 
ver y fe w a n d will be e xcl u de d fr o m t he a nal ysis ( pri nci pal strat u m strate g y).  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 5  of 9 2  
 
S u p ple me nt ary esti m a n ds  
S u p ple me ntar y a nal yses of t he pri mar y o bjecti ves will be c o n d ucte d usi n g f o ur differe nt  
s u p ple me ntar y esti ma n ds. T he treat me nt attri b ute f or t he s u p ple me ntar y esti ma n ds is t he sa me as 
f or t he pri mar y esti ma n d.  
F or t he first s u p ple me ntar y esti ma n d, t he ot her attri b utes are t he f oll o wi n g:  
•  E n d p oi nt:  C ha n ge fr o m baseli ne i n varia ble at a nal ysis ti me p oi nt.  
•  P o p ul ati o n:  S u bjects a ge d ≥ 4 0 years wit h a n esta blis he d dia g n osis of H F wit h L V E F  > 
4 0 % , a n d at least o ne or m ore of str uct ural  heart disease, si g ns of i ncrease d left 
ve ntric ular filli n g  press ure, si g ns of si g nifica nt diast olic  d ysf u ncti o n, or a rece nt 
h os pitalisati o n f or dec o m pe nsate d H F . I m ple me nte d b y F A S. 
•  P o p ul ati o n -le vel s u m m ar y: Differe nce i n a dj uste d mea n c ha n ge fr o m baseli ne t o 
a nal ysis ti me p oi nt.  
•  H a n dli n g of i nterc urre nt e ve nts: Treat me nt p olic y strate g y c o m bi ne d wit h h y p ot hetical 
strate g y 
o  I nitiati o n or c ha n ge of c o nc o mita nt me dicati o n a n d per ma ne nt pre mat ure 
disc o nti n uati o ns of I P will be ha n dle d b y a treat me nt p olic y strate g y, i.e., i g n ori n g 
t hese i nterc urre nt e ve nts, i m ple me nte d b y i ncl u di n g all a vaila ble data.  
o  Deat hs will be ha n dle d b y a h y p ot hetical strate g y f or t he h y p ot hetical sce nari o 
w here deat h ca n n ot occ ur. U n der t he ass u m pti o n t hat deat h is a n o n -i nf or mati ve 
e ve nt, t his is i m ple me nte d b y i ncl u di n g all a vaila ble data u p t o ti me of deat h.  
F or t he sec o n d s u p ple me ntar y esti ma n d, t he ot her attri b utes are t he f oll o wi n g:  
•  E n d p oi nt:  C ha n ge fr o m baseli ne i n varia ble at a nal ysis ti me p oi nt wit h deat h c o nsi dere d 
w orst p ossi ble o utc o me.  
•  P o p ul ati o n:  S u bjects a ge d ≥ 4 0 years wit h a n esta blis he d dia g n osis of H F wit h L V E F  > 
4 0 % , a n d at least o ne or m ore of str uct ural  heart disease, si g ns of i ncrease d left 
ve ntric ular filli n g  press ure, si g ns of si g nifica nt diast olic  d ysf u ncti o n, or a rece nt 
h os pitalisati o n f or dec o m pe nsate d H F . I m ple me nte d b y F A S. 
•  P o p ul ati o n -le vel s u m m ar y: Differe nce i n a dj uste d me dia n c ha n ge fr o m baseli ne t o 
a nal ysis ti me p oi nt.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 6  of 9 2  
 
•  H a n dli n g of i nterc urre nt e ve nts: Treat me nt p olic y strate g y c o m bi ne d wit h c o m p osite 
varia ble strate g y.  
o  I nitiati o n or c ha n ge of c o nc o mita nt me dicati o n a n d per ma ne nt pre mat ure 
disc o nti n uati o ns of I P will be ha n dle d b y a treat me nt p olic y strate g y, i.e., i g n ori n g 
t hese i nterc urre nt e ve nts, i m ple me nte d b y i ncl u di n g all a vaila ble data.  
o  Deat h is ha n dle d b y i nc or p orati n g t his i nterc urre nt e ve nt i n t he e n d p oi nt a n d 
c o nsi der it as w orst p ossi ble o utc o me (c o m p osite varia ble strate g y).  
o  S u bjects wit h i nterc urre nt e ve nts res ulti n g i n missi n g assess me nts of t he pri mar y 
e n d p oi nts ot her t ha n deat h are e x pecte d t o be ver y fe w a n d will be e xcl u de d fr o m 
t he a nal ysis ( pri nci pal strat u m strate g y).  
F or t he t hir d s u p ple me ntar y esti ma n d, t he ot her attri b utes are t he f oll o wi n g:  
•  E n d p oi nt:  C ha n ge fr o m baseli ne i n varia ble at a nal ysis ti me p oi nt.  
•  P o p ul ati o n:  S u bjects a ge d ≥ 4 0 years wit h a n esta blis he d dia g n osis of H F wit h L V E F  > 
4 0 % , a n d at least o ne or m ore of str uct ural  heart disease, si g ns of i ncrease d left 
ve ntric ular filli n g  press ure, si g ns of si g nifica nt diast olic  d ysf u ncti o n, or a rece nt 
h os pitalisati o n f or dec o m pe nsate d H F  w h o are ali ve a n d ha ve n ot per ma ne ntl y 
pre mat urel y disc o nti n ue d I P. T his is i m ple me nte d o n e val ua ble s u bjects defi ne d b y a 
s u bset of F A S w hic h ha ve n ot disc o nti n ue d I P a n d ha ve a vaila ble meas ure me nts of t he 
efficac y e n d p oi nts at baseli ne a n d a nal ysis ti me p oi nt . 
•  P o p ul ati o n -le vel s u m m ar y: Differe nce i n a dj uste d mea n c ha n ge fr o m baseli ne t o 
a nal ysis ti me p oi nt  or a dj uste d ge o metric mea n rati o .  
•  H a n dli n g of i nterc urre nt e ve nts: Treat me nt p olic y strate g y c o m bi ne d wit h pri nci pal 
strat u m strate g y.  
o  I nitiati o n or c ha n ge of c o nc o mita nt me dicati o n will be ha n dle d b y a treat me nt 
p olic y strate g y, i.e., i g n ori n g t hese i nterc urre nt e ve nts. I m ple me nte d b y i ncl u di n g 
all a vaila ble data.  
o  S u bjects wit h i nterc urre nt e ve nts res ulti n g i n missi n g assess me nts of t he pri mar y 
e n d p oi nts, e. g., ter mi nal e ve nts or wit h dra wal fr o m t he st u d y, are e x pecte d t o be 
ver y fe w a n d will be e xcl u de d fr o m t he a nal ysis ( pri nci pal strat u m strate g y).  






















S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 7  of 9 2  
 
Eac h res p o nse t o a K C C Q q uesti o n is assi g ne d a n or di nal val ue.  
F or S y m pt o ms fre q ue nc y, t he res p o nse will be assi g ne d a val ue starti n g fr o m 1 ( m ost fre q ue nt) 
t o 5 or 7 (least fre q ue nt), de pe n di n g o n t he n u m ber of o pti o ns. T he sc ore f or eac h q uesti o n will 
be deri ve d as  
(sc or e fr o m q u esti o n  − 1 )/ (n u m b er  of  u ni q u e  or di n al  v al u e  o pti o ns  − 1 ).  
If res p o nses t o at least t w o of t he S y m pt o ms fre q ue nc y q uesti o ns are n ot missi n g, t he S y m pt o ms 
fre q ue nc y sc ore is calc ulate d as  
1 0 0 ∗m e a n (sc or es f or all  S y m pt o ms  fr e q u e nc y q u esti o ns ).  
F or S y m pt o ms b ur de n, t he res p o nse will be assi g ne d a sc ore starti n g fr o m 1 ( m ost b ot hers o me) 
t o 5 ( n ot b ot hers o me). If res p o nse t o at least o ne of t he S y m pt o ms b ur de n q uesti o ns are n ot 
missi n g, t he S y m pt o ms b ur de n sc ore is calc ulate d as  
1 0 0 ∗ (m e a n  of  sc or es f or all  S y m pt o ms  b ur d e n  q u esti o ns  act u all y  a ns w er e d −1 )/ 4.  
K C C Q -T S S is deri ve d as t he mea n of t he S y m pt o ms fre q ue nc y sc ore a n d S y m pt o ms b ur de n 
sc ore.  
T he a bs ol ute c ha n ge fr o m baseli ne at 1 6 wee ks will be deri ve d.  
4. 2. 1. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
F or t he pri mar y a n d s u p ple me ntar y a nal yses usi n g A N C O V A as esti mat or, missi n g data will n ot 
be i m p ute d. S u bjects wit h missi n g baseli ne data of a n y varia bles w hic h are use d as c o variates i n 
t he a nal ysis will be e xcl u de d fr o m t hese a nal yses. F or t he s u p ple me ntar y a nal ysis usi n g M M R M 
as esti mat or all a vaila ble data will be i ncl u de d.  
4. 2. 1. 4  
Pri m ar y A n al ysis of Pri m ar y E n d p oi nt  
T he K C C Q -T S S c ha n ge fr o m baseli ne at 1 6 wee ks e n d p oi nt is a nal yse d u n der t he pri mar y 
esti ma n d usi n g A N C O V A as pri mar y esti mat or, c o m pari n g A Z D 4 8 3 1 T otal vers us place b o. T he 
i n di vi d ual d oses will als o be c o m pare d se paratel y wit h place b o b ut are n ot part of t he f or mal 
testi n g se q ue nce. 
Treat me nt gr o u p a n d ne utr o p hil c o u nt strat u m are i ncl u de d as cate g orical c o variates a n d baseli ne 
val ue of res pecti ve e n d p oi nt as c o nti n u o us c o variate. S u bjects wit h a vaila ble data at t he 1 6 
wee ks a nal ysis ti me p oi nt will be i ncl u de d i n t he a nal ysis.   
T he differe nce i n mea n c ha n ge fr o m baseli ne f or t he pri mar y efficac y e n d p oi nts will be 
e val uate d t o test t he f oll o wi n g h y p ot heses:  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 8  of 9 2  
 
H 0: μ( A Z D 4 8 3 1 T otal) - μ( place b o) = 0, vers us t he alter nati ve h y p ot hesis:  
H 1: μ( A Z D 4 8 3 1 T otal) - μ( place b o) ≠ 0, w here μ( x) is tr ue mea n c ha n ge fr o m baseli ne f or 
treat me nt x. 
T he strate g y t o c o ntr ol f or m ulti plicit y is defi ne d i n Secti o n 3. 3. 4 : 
Prese nt ati o n  
Least s q uares mea n esti mates f or eac h treat me nt gr o u p a n d t he differe nce i n least s q uares mea ns 
bet wee n acti ve treat me nt gr o u ps a n d place b o wit h 9 5 % CIs a n d p -val ues will be prese nte d.  
Distri b uti o ns of e n d p oi nt data will be prese nte d b y s u m mar y statistics o ver ti me, pr o ba bilit y 
de nsit y f u ncti o n ( P D F) c ur ves a n d e m pirical c u m ulati ve distri b uti o n f u ncti o n (e C D F) c ur ves, b y 
treat me nt gr o u p. 
4. 2. 1. 5  
Se nsiti vit y A n al yses of t he Pri m ar y E n d p oi nt  
As a se nsiti vit y a nal ysis t he pri mar y e n d p oi nt will be a nal yse d usi n g a n A N C O V A wit h 
treat me nt gr o u p i ncl u de d as cate g orical c o variate a n d ne utr o p hil c o u nt a n d baseli ne val ue as 
c o nti n u o us c o variates. T he a nal ysis is e val uate d u n der t he pri mar y esti ma n d defi ne d i n Secti o n 
4. 2 .  
Prese nt ati o n  
See Secti o n 4. 2. 1. 4 . N o mi nal p-val ue will be prese nte d.  
4. 2. 1. 6  
S u p ple me nt ar y A n al yses of t he Pri m ar y E n d p oi nt  
A mi xe d m o del re peate d meas ures ( M M R M) m o del is use d as o ne of t he s u p ple me ntar y 
esti mat ors f or t he K C C Q -T S S c ha n ge fr o m baseli ne at 1 6 wee ks e n d p oi nt, c o m pari n g A Z D 4 8 3 1 
vers us place b o. T his a nal ysis is e val uate d u n der t he first s u p ple me ntar y esti ma n d defi ne d i n 
Secti o n 4. 2 . 
Treat me nt gr o u p, ne utr o p hil c o u nt strat u m, visit a n d treat me nt -b y -visit i nteracti o n ter m are 
i ncl u de d as fi xe d effects a n d c o nti n u o us baseli ne val ue of res pecti ve e n d p oi nt as c o variate. T he 
c o varia nce str uct ure use d is u nstr uct ure d ( U N). If t he m o del d oes n ot c o n ver ge wit h U N, t he n 
a ut ore gressi ve or der 1 ( A R [ 1]) a n d heter o ge ne o us a ut ore gressi ve or der 1 ( A R H [ 1]) str uct ures 
will be trie d i n t his or der. T he fi nal c o varia nce str uct ure will  be deci de d base d o n m o del 
c o n ver ge nce stat us.   
A sec o n d s u p ple me ntar y a nal ysis will be e val uate d u n der t he sec o n d s u p ple me ntar y esti ma n d 
defi ne d i n Secti o n 4. 2 . T he ra n ke d c ha n ge fr o m baseli ne f or K C C Q -T S S at 1 6 wee ks will be 
assesse d. F or t his esti ma n d, t here are t w o esti mat ors: a stratifie d ra n k A N C O V A a n d H o d ges 
Le h ma n n l ocati o n -s hift esti mates.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 9  of 9 2  
 
A t w o -si de d n o mi nal p-val ue will be deri ve d fr o m a stratifie d ra n k A N C O V A, testi n g t he 
e q ualit y of distri b uti o ns of ra n ke d o utc o mes bet wee n A Z D 4 8 3 1 T otal a n d place b o. First t he 
c ha n ge fr o m baseli ne at wee k 1 6 i n eac h of t he pri mar y efficac y e n d p oi nts as we ll as val ues of 
t he baseli ne c o variate will be tra nsf or me d t o sta n dar dise d ra n ks wit hi n eac h ne utr o p hil c o u nt 
ra n d o misati o n strat u m, usi n g fracti o nal ra n ks ( di vi di n g b y t he de n o mi nat or n + 1) a n d t he mea n 
met h o d f or ties. Wit hi n eac h strat u m, disease d s u bjec ts are ra n ke d w orse t ha n a n y ali ve s u bject. 
Wit hi n t he gr o u p of disease d s u bjects f or eac h strat u m, s u bjects are ra n ke d base d o n t heir last 
e n d p oi nt val ue w hile ali ve. Se parate A N C O V A m o dels will be fitte d t o t he ra n ke d data f or eac h 
ra n d o misati o n strat u m usi n g a re gressi o n m o del wit h t he ra n ke d c o m p osite e n d p oi nt as t he 
de pe n de nt varia ble, a dj usti n g f or t he ra n ke d baseli ne as a c o variate. Resi d uals fr o m t his 
re gressi o n m o del will be ca pt ure d f or testi n g of differe nces bet wee n treat me nt gr o u ps. T he 
C oc hra n -Ma ntel -Hae nszel ( C M H) test, stratifie d b y ne utr o p hil c o u nt ra n d o misati o n strat u m, 
usi n g t he val ues of t he resi d uals as sc ores will be use d t o c o m pare treat me nt gr o u ps.  
H o d ges -Le h ma n n esti mates will be use d t o esti mate t he treat me nt effect i n ter ms of l ocati o n -
s hift, i.e., t he differe nce i n p o p ulati o n me dia ns bet wee n acti ve a n d place b o ar m.  
A t hir d s u p ple me ntar y a nal ysis will be e val uate d u n der t he t hir d s u p ple me ntar y esti ma n d defi ne d 
i n Secti o n 4. 2  usi n g A N C O V A as pri mar y esti mat or, c o m pari n g A Z D 4 8 3 1 vers us place b o. 
Treat me nt gr o u p a n d ne utr o p hil c o u nt strat u m are i ncl u de d as cate g orical c o variates a n d baseli ne 
val ue of res pecti ve e n d p oi nt as c o nti n u o us c o variate. S u bjects wit h a vaila ble data a n d w h o ha ve 
n ot disc o nti n ue d I P at t he 1 6 wee ks a nal ysis ti me p oi nt will be i ncl u de d i n t he a nal ysis.  
A f o urt h s u p ple me ntar y a nal ysis will be e val uate d u n der t he f o urt h s u p ple me ntar y esti ma n d 
defi ne d i n Secti o n 4. 2  usi n g A N C O V A as pri mar y esti mat or, c o m pari n g A Z D 4 8 3 1 vers us 
place b o. Treat me nt gr o u p a n d ne utr o p hil c o u nt strat u m are i ncl u de d as cate g orical c o variates, t he 
baseli ne val ue of res pecti ve e n d p oi nt as c o nti n u o us c o variate a n d a ter m f or baseli ne -b y -
treat me nt i nteracti o n. S u bjects wit h a vaila ble data at baseli ne a n d a nal ysis ti me p oi nt or w h o ha ve 
die d pri or t o t he a nal ysis ti me p oi nt will be i ncl u de d i n t he a nal ysis.  
Prese nt ati o n  
F or t he M M R M a nal ysis, see prese ntati o n part of Secti o n 4. 2. 1. 4 . N o mi nal p-val ues will be 
prese nte d.  
F or t he ra n k A N C O V A a n d H o d ges Le h ma n n a nal ysis, me dia n esti mates f or eac h treat me nt 
gr o u p a n d t he differe nce i n me dia ns bet wee n acti ve treat me nt gr o u ps a n d place b o wit h 9 5 % CIs 
a n d n o mi nal p -val ues will be prese nte d.  
F or t he t hir d s u p ple me ntar y a nal ysis, see prese ntati o n part of Secti o n 4. 2. 1. 4 . N o mi nal p-val ues 
will be prese nte d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 0  of 9 2  
 
 
F or t he f o urt h s u p ple me ntar y a nal ysis of K C C Q -T S S, least s q uares mea n esti mates are e val uate d 
at a baseli ne val ue of 6 0 p oi nts. Least s q uares mea n esti mates f or eac h treat me nt gr o u p a n d t he 
differe nce i n least s q uares mea ns bet wee n acti ve treat me nt gr o u ps a n d place b o wit h 9 5 % CIs a n d 
n o mi nal p -val ues will be prese nte d. I n a d diti o n, para meter esti mates fr o m t he A N C O V A m o del 
will be ta b ulate d wit h sta n dar d err ors a n d n o mi nal p -val ue a n d t he differe nce bet wee n t he t w o 
re gressi o n li nes vers us t he baseli ne val ues will be prese nte d i n a fi g ure.  
4. 2. 1. 7  
S u b gr o u p A n al yses  
A s u b gr o u p a nal ysis will be c o n d ucte d f or t his e n d p oi nt u n der t he pri mar y esti ma n d defi ne d i n 
Secti o n 4. 2 . F or eac h of t he pre-s pecifie d s u b gr o u p varia bles, a se parate A N C O V A m o del will 
be fitte d usi n g t he sa me ter ms as use d i n t he pri mar y a nal ysis i n Secti o n 4. 2. 1. 4  a n d a d diti o nall y 
i ncl u di n g t he s u b gr o u p varia ble a n d t he i nteracti o n ter m f or s u b gr o u p-b y -treat me nt i nteracti o n.  
S u b gr o u ps  
T he s u b gr o u p a nal yses will be perf or me d f or t he f oll o wi n g baseli ne a n d de m o gra p hic varia bles 
a n d cate g orisati o ns. T he c ut -off val ues are base d o n baseli ne val ues.  
•  A ge ( < 6 5; 6 5 -7 5; > 7 5 years)  
•  Se x ( Male, Fe male)  
•  
Race ( Blac k or Africa n A merica n, Nati ve Ha waiia n or ot her Pacific Isla n der, A merica n 
I n dia n or Alas ka Nati ve, Asia n, W hite, Ot her)  
•  
His pa nic/ Lati n o ( Yes/ N o)  
•  Ge o gra p hic re gi o n ( E ur o pe, N ort h A merica, S o ut h A merica, Asia a n d A ustralia) wit h re gi o ns 
defi ne d as i n Secti o n 4. 1. 3 . 
•  B MI ( < 3 0, ≥3 0)  
•  Alc o h ol c o ns u m pti o n ( Ne ver, F or mer, C urre nt)  
•  Nic oti ne c o ns u m pti o n ( Ne ver, F or mer, C urre nt)  
•  K C C Q -T S S ( p oi nts) ( ≤8 0, > 8 0 ) 
•  6 M W D ( meters) ( ≤3 5 0, > 3 5 0)  
•  H os pitalize d f or H F pri or t o ra n d o misati o n ( Yes/ N o) 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 1  of 9 2  
 
•  N Y H A f u ncti o nal classificati o n (II, III, I V)  
•  L V E F ( %) (< 5 0, ≥5 0)  
•  Hist or y of atrial fi brillati o n ( Yes/ N o)  
•  Hist or y of atrial fl utter ( Yes/ N o)  
•  Hist or y of h y perte nsi o n ( Yes/ N o)  
•  N T -pr o B N P  ( ≤M e dia n, >M e dia n) 
•  Ne utr o p hil c o u nt ( ≤4 × 1 0 9/ L, >4 × 1 0 9/ L) 
•  H b A 1 C ( %) ( < 6. 5 , ≥6. 5 ) 
•  e G F R, calc ulate d acc or di n g t o C K D -E PI S -Creati ni ne e q uati o n ( m L/ mi n/ 1. 7 3 m 2) (≤6 0, > 6 0)    
•  S -C ystati n C ( ≤Me dia n, > Me dia n ) 
•  M P O le vels  (≤Me dia n, > Me dia n ) 
•  Uri nar y al b u mi n -t o-creati ni ne rati o  ( U A C R) (≤Me dia n, > Me dia n ) 
•  Cer ul o plas mi n ( ≤Me dia n, > Me dia n ) 
•  Ir o n deficie nc y deter mi ne d b y Ser u m Ferriti n i n c o m bi nati o n wit h Tra nsferri n sat urati o n  
( Ser u m Ferriti n < 1 0 0 n g/ m L O R Ser u m Ferriti n 1 0 0-2 9 9 n g/ m L wit h Tra nsferri n sat urati o n 
< 2 0 %) ( Yes/ N o)  
•  Re d cell distri b uti o n wi dt h ( %) ( ≤1 4, > 1 4)  
•  He pci di n ( ≤Me dia n, > Me dia n ) 
•  hs C R P  (≤Me dia n, > Me dia n ) 
Tra nsferri n sat urati o n is deri ve d as S -Ir o n/ TI B C ∗1 0 0 . See Secti o n 4. 2. 1 7. 2  f or deri vati o n of 
U A C R.  
Prese nt ati o n  
See prese ntati o n part of Secti o n 4. 2. 1. 4 , h o we ver t he p-val ue f or eac h s u b gr o u p will be e xcl u de d. 
I n a d diti o n, p-val ue of i nteracti o n will be prese nte d f or eac h s u b gr o u p. A f orest pl ot will be 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 2  of 9 2  
 
prese nte d f or differe nce i n least s q uares mea ns wit h 9 5 % CIs. If a n y cate g or y of a s u b gr o u p 
varia ble c o ntai ns less t ha n 5 % of t he s u bjects i n t he f ull a nal ysis set , se parate A N C O V A m o dels 
si milar t o t he o verall a nal ysis will i nstea d be fitte d t o s u bjects i n eac h se parate cate g or y, t h us n o 
p -val ue of i nteracti o n will be prese nte d.  
4. 2. 2  
Pri m ar y E n d p oi nt –  6 M W D c h a n ge fr o m b aseli ne at 1 6 wee ks  
4. 2. 2. 1  
Defi niti o n  
T he ot her d ual pri mar y efficac y e n d p oi nt is 6 M W D c ha n ge fr o m baseli ne at 1 6 wee ks. F or t his 
e n d p oi nt, t he sa me esti ma n ds will be use d as f or t he a nal ysis of K C C Q -T S S c ha n ge fr o m 
baseli ne at 1 6 wee ks descri be d i n Secti o ns 4. 2  a n d 4. 2. 1 . 
4. 2. 2. 2  
Deri v ati o ns  
T he a bs ol ute c ha n ge fr o m baseli ne at 1 6 wee ks will be deri ve d.  
4. 2. 2. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
See  Secti o n  4. 2. 1. 3  f or details.   
4. 2. 2. 4  
Pri m ar y A n al ysis of Pri m ar y E n d p oi nt  
See secti o n 4. 2. 1. 4  f or details.  
4. 2. 2. 5  
Se nsiti vit y A n al yses of t he Pri m ar y E n d p oi nt  
See Secti o n 4. 2. 1. 5  f or details. 
4. 2. 2. 6  
S u p ple me nt ar y A n al yses of t he Pri m ar y E n d p oi nt  
See Secti o n 4. 2. 1. 6  f or details. F or t he f o urt h s u p ple me ntar y a nal ysis, t he A N C O V A m o del will 
i ncl u de treat me nt gr o u p a n d ne utr o p hil c o u nt strat u m as cate g orical c o variates, a n d t he baseli ne 
val ue as c o nti n u o us c o variate. T he fi g ure descri be d f or t he K C C Q -T S S f o urt h s u p ple me ntar y 
a nal ysis i n Secti o n 4. 2. 1. 6  will n ot be prese nte d f or t his a nal ysis.  
4. 2. 2. 7  
S u b gr o u p A n al yses  
See Secti o n 4. 2. 1. 7  f or details. 
4. 2. 3  
Sec o n d ar y E n d p oi nts –  K C C Q -T S S c h a n ge fr o m b aseli ne at 2 4 a n d 4 8 
wee ks  
4. 2. 3. 1  
Defi niti o n  
K C C Q -T S S c ha n ge fr o m baseli ne at 2 4 a n d 4 8 wee ks res pecti vel y are sec o n dar y e n d p oi nts.  
4. 2. 3. 2  
Deri v ati o ns  
T he a bs ol ute c ha n ge fr o m baseli ne at 2 4 a n d 4 8 wee ks res pecti vel y will be deri ve d. See Secti o n 
4. 2. 1. 2  f or deri vati o n of K C C Q-T S S.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 3  of 9 2  
 
4. 2. 3. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
See  Secti o n  4. 2. 1. 3  descri bi n g  ha n dli n g  of  missi n g  data  f or t he A N C O V A  esti mat or  f or details.   
4. 2. 3. 4  
Pri m ar y A n al ysis of Sec o n d ar y E n d p oi nt  
See part of Secti o n 4. 2. 1. 4  f or details o n t he statistical i nfere nce. I n a d diti o n, distri b uti o n of 
K C C Q -T S S at baseli ne, 1 2, 1 6, 2 4 a n d 4 8 wee ks res pecti vel y will be prese nte d as s u m mar y 
statistics. 
T he sa me h y p ot hesis as i n secti o n 4. 2. 1. 4  will be teste d. See Secti o n 3. 3. 4  f or details o n t he 
hierarc hical testi n g se q ue nce.  
4. 2. 4  
Sec o n d ar y E n d p oi nt –  6 M W D c h a n ge fr o m b aseli ne at 2 4 a n d 4 8 wee ks  
4. 2. 4. 1  
Defi niti o n  
6 M W D c ha n ge fr o m baseli ne at 2 4 a n d 4 8 wee ks res pecti vel y are sec o n dar y e n d p oi nts.  
4. 2. 4. 2  
Deri v ati o ns  
T he a bs ol ute c ha n ge fr o m baseli ne at 2 4 a n d 4 8 wee ks res pecti vel y will be deri ve d.  
4. 2. 4. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
See  part  of  Secti o n  4. 2. 1. 3  descri bi n g  ha n dli n g  of  missi n g  data  f or t he A N C O V A  esti mat or  f or 
details.  
4. 2. 4. 4  
Pri m ar y A n al ysis of Sec o n d ar y E n d p oi nt  
See part of Secti o n 4. 2. 1. 4  f or details o n t he statistical i nfere nce. I n a d diti o n, s u m mar y statistics 
will be s h o w n, as descri be d i n Secti o n 4. 2. 2. 4 . 
T he sa me h y p ot hesis as i n secti o n 4. 2. 1. 4  will be teste d. See Secti o n 3. 3. 4  f or details o n t he 
hierarc hical testi n g se q ue nce.  
4. 2. 5  
Sec o n d ar y E n d p oi nts –  C h a n ge fr o m b aseli ne i n l o g -tr a nsf or me d N T -
pr o B N P at 1 6, 2 4 a n d 4 8 wee ks  
4. 2. 5. 1  
Defi niti o n  
C ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -pr o B N P at 1 6, 2 4 a n d 4 8 wee ks res pecti vel y  are 
sec o n dar y e n d p oi nts.  
4. 2. 5. 2  
Deri v ati o ns  
T he c ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -pr o B N P  at 1 6, 2 4 a n d 4 8 wee ks res pecti vel y 
will be deri ve d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 4  of 9 2  
 
4. 2. 5. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
See  part  of  Secti o n  4. 2. 1. 3  descri bi n g  ha n dli n g  of  missi n g  data  f or t he A N C O V A  esti mat or  f or 
details.  
4. 2. 5. 4  
Pri m ar y A n al ysis of Sec o n d ar y E n d p oi nt  
T he a nal ysis is e val uate d u n der t he pri mar y esti ma n d defi ne d i n Secti o n 4. 2 , usi n g A N C O V A as 
esti mat or, c o m pari n g A Z D 4 8 3 1 T otal vers us place b o.  
T he c ha n ge fr o m baseli ne i n l o g -tra nsf or me d N T -pr o B N P  is t he res p o nse varia ble i n t he 
A N C O V A m o del wit h t he sa me c o variate m o del s pecificati o n as i n Secti o n 4. 2. 1. 4 , b ut wit h a 
l o g-tra nsf or me d baseli ne val ue. T he e n d p oi nt will be a nal yse d o n a nat ural l o garit h mic scale a n d 
t he n bac k tra nsf or me d t o t he ori gi nal scale res ulti n g i n ge o metric mea ns. 
T he c ha n ge fr o m baseli ne i n l o g -tra nsf or me d  N T -pr o B N P  is teste d i n t he h y p ot hesis testi n g 
pr oce d ure. See Secti o n 3. 3. 4  f or details o n t he hierarc hical testi n g se q ue nce. 
Ge o metric mea n esti mates f or eac h treat me nt gr o u p, ge o metric mea n rati os bet wee n treat me nt 
gr o u ps, 9 5 % CIs a n d p -val ue will be prese nte d. I n a d diti o n, distri b uti o n of N T -pr o B N P at 
baseli ne, 1 6, 2 4 a n d 4 8 wee ks  res pecti vel y will be prese nte d as s u m mar y statistics i ncl u di n g 
ge o metric mea n, ge o metric C V, a n d ge o metric mea n rati o.  
4. 2. 5. 5  
S u p ple me nt ar y A n al yses of t he Sec o n d ar y E n d p oi nt  
T he s u p ple me ntar y a nal ysis f or t his e n d p oi nt will be e val uate d u n der t he t hir d s u p ple me ntar y 
esti ma n d defi ne d i n Secti o n 4. 2  usi n g A N C O V A. See Secti o n 4. 2. 5. 4  f or details. 
4. 2. 5. 6  
S u b gr o u p A n al ysis  
A s u b gr o u p a nal ysis will be perf or me d f or t he 1 6 wee ks a nal ysis ti me p oi nt. See Secti o n 4. 2. 1. 7  
f or details. T he f oll o wi n g varia bles liste d f or pri mar y e n d p oi nts will n ot be i ncl u de d: Alc o h ol 
c o ns u m pti o n, Nic oti ne c o ns u m pti o n, S -C ystati n -C a n d Cer ul o plas mi n.  
4. 2. 6  
Sec o n d ar y E n d p oi nts –  Ec h oc ar di o gr a p hic p ar a meters c h a n ge fr o m 
b aseli ne at 1 6 a n d 2 4 wee ks  
4. 2. 6. 1  
Defi niti o n  
L V -G L S, L A VI a n d L V MI c ha n ge fr o m baseli ne at 1 6 a n d 2 4 wee ks res pecti vel y are sec o n dar y 
e n d p oi nts.  
4. 2. 6. 2  
Deri v ati o ns  
T he a bs ol ute c ha n ge fr o m baseli ne at 1 6 a n d 2 4 wee ks res pecti vel y will be deri ve d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 5  of 9 2  
 
4. 2. 6. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
See  part  of  Secti o n  4. 2. 1. 3  descri bi n g  ha n dli n g  of  missi n g  data  f or t he A N C O V A  esti mat or  f or 
details.  
4. 2. 6. 4  
Pri m ar y A n al ysis of Sec o n d ar y E n d p oi nt  
See part of Secti o n 4. 2. 1. 4  f or details o n t he statistical i nfere nce. T he sa me h y p ot hesis as i n 
secti o n 4. 2. 1. 4  will be teste d. See Secti o n 3. 3. 4  f or details o n t he hierarc hical testi n g se q ue nce. In 
a d diti o n, s u m mar y statistics will be s h o w n, as descri be d i n Secti o n 4. 2. 3. 4 . 
4. 2. 6. 5  
S u p ple me nt ar y A n al yses of t he Sec o n d ar y E n d p oi nt  
S u p ple me ntar y a nal yses of L V -G L S, L A VI a n d L V MI c ha n ge fr o m baseli ne at 1 6 wee ks will be 
e val uate d u n der t he t hir d s u p ple me ntar y esti ma n d defi ne d i n Secti o n 4. 2  usi n g A N C O V A. See 
Secti o n 4. 2. 1. 6  f or details. 
4. 2. 6. 6  
S u b gr o u p A n al ysis  
S u b gr o u p a nal yses will be perf or me d f or t he 1 6 wee ks a nal ysis ti me p oi nt. See Secti o n 4. 2. 1. 7  f or 
details. T he f oll o wi n g varia bles liste d f or pri mar y e n d p oi nts will n ot be i ncl u de d: Alc o h ol 
c o ns u m pti o n, Nic oti ne c o ns u m pti o n, S -C ystati n -C a n d Cer ul o plas mi n.  
4. 2. 7  
Sec o n d ar y E n d p oi nt –  Pl as m a C o nce ntr ati o ns of A Z D 4 8 3 1 b y ti me p oi nt  
4. 2. 7. 1  
Defi niti o n  
T he e n d p oi nt is plas ma c o nce ntrati o n.  
4. 2. 7. 2  
Deri v ati o ns  
Plas ma c o nce ntrati o ns of A Z D 4 8 3 1 b y assess me nt ti me p oi nt will be deri ve d. T he n u m ber of 
o bser vati o ns bel o w L L o Q will be prese nte d a n d will be i m p ute d t o L L o Q/ 2 i n t he a nal yses.  
4. 2. 7. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
A n y missi n g data will n ot be i m p ute d.  
4. 2. 7. 4  
Pri m ar y A n al ysis of Sec o n d ar y E n d p oi nt  
Plas ma A Z D 4 8 3 1 c o nce ntrati o ns will be s u m marise d b y descri pti ve statistics f or t he f ull a nal ysis 
set, b y assess me nt ti me p oi nts a n d d ose le vel.  
4. 2. 8  
Sec o n d ar y E n d p oi nt –  C h a n ge fr o m b aseli ne i n l o g -tr a nsf or me d 
i nfl a m m at or y bi o m ar kers at 1 6, 2 4 a n d 4 8 wee ks 
4. 2. 8. 1  
Defi niti o n  
C ha n ge fr o m baseli ne i n l o g -tra nsf or me d hs C R P a n d I L-6 at 1 6, 2 4 a n d 4 8 wee ks res pecti vel y  
are sec o n dar y e n d p oi nts.   


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 6  of 9 2  
 
4. 2. 8. 2  
Deri v ati o ns  
C ha n ge fr o m baseli ne i n l o g -tra nsf or me d hs C R P a n d I L-6 at 1 6, 2 4 a n d 4 8 wee ks res pecti vel y  
will be deri ve d.  
If a n I L-6 o bser vati o n is  re p orte d wit h hi g hl y se nsiti ve  ( hs) I L-6 la b c o de, t his data will  be 
i ncl u de d i n a nal ysis. Ot her wise, t he n o n-hs I L -6 la b c o de will be use d .  
O bser vati o ns  re p orte d as L L o Q will be i m p ute d as descri be d i n S ecti o n 3. 3. 1. 3 . 
T he dic h ot o m o us res p o nse varia ble f or t he l o gistics re gressi o n f or I L -6 at 1 6, 2 4 a n d 4 8 wee ks 
res pecti vel y is cate g orise d as  
•  < 3. 1 6  
•  ≥3. 1 6  
w here  3. 1 6 is t he  L L o Q  re p orte d f or t he n o n -hs a nal ysis met h o d  first use d.  
4. 2. 8. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
See  part  of  Secti o n  4. 2. 1. 3  descri bi n g  ha n dli n g  of  missi n g  data  f or t he A N C O V A  esti mat or  f or 
details.  
4. 2. 8. 4  
Pri m ar y A n al ysis of Sec o n d ar y E n d p oi nt  
See Secti o n 4. 2. 5. 4  f or details o n t he statistical i nfere nce, h y p ot hesis testi n g a n d prese ntati o n.  
4. 2. 8. 5  
S u p ple me nt ar y A n al yses of t he Sec o n d ar y E n d p oi nt  
A s u p ple me ntar y a nal ysis f or c ha n ge fr o m baseli ne i n l o g -tra nsf or me d I L-6 at 1 6 wee ks will be 
e val uate d u n der t he t hir d s u p ple me ntar y esti ma n d defi ne d i n Secti o n 4. 2  usi n g A N C O V A. See 
Secti o n 4. 2. 5. 4  f or details. 
I n a d diti o n, t he f oll o wi n g t w o e x pl orat or y a nal yses will be perf or me d t o i n vesti gate i m pact of 
L L o Q fre q ue nc y o n I L -6 a nal yses : 
•  A  l o gistic re gressi o n m o del wit h t he dic h ot o m o us res p o nse varia ble deri ve d i n Secti o n 
4. 2. 8. 2  a n d treat me nt gr o u p, ne utr o p hil c o u nt strat u m a n d baseli ne I L -6 val ue as 
c o variates will be use d t o c o m pare t he acti ve treat me nt gr o u ps wit h place b o. T he 
o bser v e d n u m ber a n d pr o p orti o n of s u bjects i n t he bel o w or  e q ual t o a n d o ver L L o Q f or 
I L-6 res pecti vel y, a n d o d ds rati os c o m pari n g acti ve treat me nt gr o u ps a gai nst place b o 
al o n g wit h 2-si de d 9 5 % c o nfi de nce i nter vals a n d p-val ue will be prese nte d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 7  of 9 2  
 
•  A n a nal ysis usi n g A N C O V A as s pecifie d i n usi n g o nl y s u bjects wit h eit her hsI L -6 data  
( usi n g hs la b test or refle x test f or hi g h val ues ) at b ot h baseli ne or 1 6 wee ks, or I L -6 
( usi n g sta n dar d la b test) at b ot h baseli ne or 1 6 wee ks will be perf or me d wit h m o del 
s pecificati o n a n d prese ntati o n as descri be d i n Secti o n 4. 2. 5. 4 , wit h t he a d diti o n of a 
bi nar y la b test c o variate t o t he m o del . 
4. 2. 8. 6  
S u b gr o u p A n al ysis  
S u b gr o u p a nal yses will be perf or me d f or t he 1 6 wee ks a nal ysis ti me p oi nt. See Secti o n 4. 2. 1. 7  f or 
details. T he f oll o wi n g varia bles liste d f or pri mar y e n d p oi nts will n ot be i ncl u de d: Alc o h ol 
c o ns u m pti o n, Nic oti ne c o ns u m pti o n, S -C ystati n -C a n d Cer ul o plas mi n  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
  
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S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 8  of 9 2  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
  
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 9  of 9 2  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
 
  
 
 
  
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 0  of 9 2  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
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S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 1  of 9 2  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
4. 2. 1 6  
E x pl or at or y E n d p oi nt –  Ti me t o c ar di o v asc ul ar e ve nt  
4. 2. 1 6. 1  
Defi niti o n  
Esti m a n ds  
T he f oll o wi n g attri b utes defi ne t he esti ma n d use d t o e val uate t he pri mar y a nal ysis of t his 
e n d p oi nt.  
C CI


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 2  of 9 2  
 
•  E n d p oi nt:  Ti me t o t he first occ urre nce of a n y e ve nt i n t he c o m p osite e ve nt varia ble 
c o nsisti n g of H F h os pitalisati o n, ur ge nt H F visits wit h re q uire me nt f or a d diti o nal l o o p 
di uretic treat me nt, MI, car di o vasc ular deat hs, a n d all -ca use m ortalit y.  
•  Tre at me nt: Ra n d o mise d treat me nt gr o u p (re gar dless of act ual recei ve d treat me nt), 
A Z D 4 8 3 1 2. 5 m g/ 5 m g or place b o.  
•  P o p ul ati o n:  S u bjects a ge d ≥ 4 0 years wit h a n esta blis he d dia g n osis of H F wit h L V E F  > 
4 0 % , a n d at least o ne or m ore of str uct ural  heart disease, si g ns of i ncrease d left 
ve ntric ular filli n g  press ure, si g ns of si g nifica nt diast olic  d ysf u ncti o n, or a rece nt 
h os pitalisati o n f or dec o m pe nsate d H F . I m ple me nte d b y F A S. 
•  P o p ul ati o n -le vel s u m m ar y: Ka pla n -Meier ( K M) esti mate b y treat me nt gr o u p, differe nce 
i n K M esti mate bet wee n treat me nt gr o u ps a n d hazar d rati o ( H R) bet wee n treat me nt 
gr o u ps.  
•  H a n dli n g of i nterc urre nt e ve nts: Treat me nt p olic y strate g y c o m bi ne d wit h c o m p osite 
varia ble strate g y.  
o  I nitiati o n or c ha n ge of c o nc o mita nt me dicati o n a n d per ma ne nt pre mat ure 
disc o nti n uati o ns will be ha n dle d b y a treat me nt p olic y strate g y, i.e., i g n ori n g 
t hese i nterc urre nt e ve nts, i m ple me nte d b y i ncl u di n g all a vaila ble data.   
4. 2. 1 6. 2  
Deri v ati o ns  
Ti me (i n da ys) fr o m ra n d o misati o n t o first e ve nt i n c o m p osite varia ble will be deri ve d. I n 
a d diti o n, ti me (i n da ys) fr o m ra n d o misati o n t o first e ve nt f or eac h i n di vi d ual c o m p o ne nt is 
deri ve d.  
T he Pla n ne d treat me nt peri o d will be use d. See Secti o n 3. 3. 1. 8  f or ce ns ori n g r ule.  
Deat hs re p orte d as ‘ca use u n deter mi ne d’ will be i ncl u de d  as n o n-C V deat h s i n t he a nal ysis.  
4. 2. 1 6. 3  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
A n y missi n g data will n ot be i m p ute d. See Secti o n 3. 3. 1. 8  f or details o n ti me-at-ris k a n d 
ce ns ori n g.  
4. 2. 1 6. 4  
Pri m ar y A n al ysis of E x pl or at or y E n d p oi nt  
T he ris k f or a n e ve nt at 4 8 wee ks will be e val uate d u n der t he esti ma n d defi ne d i n Secti o n 
4. 2. 1 6. 1  a n d esti mate d usi n g K M % esti mates. A Z D 4 8 3 1 T otal a n d place b o will be c o m pare d 
usi n g a C o x re gressi o n m o del wit h fact ors f or treat me nt gr o u p a n d  stratifie d b y ne utr o p hil c o u nt. 
T he Efr o n met h o d f or ties a n d p -val ue base d o n t he sc ore statistic will be use d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 3  of 9 2  
 
T he c o m p osite e ve nt a n d i n di vi d ual c o m p o ne nts will be a nal yse d se paratel y usi n g t he sa me 
m o del a n d t he c o ntri b uti o n of eac h c o m p o ne nt of t he pri mar y c o m p osite e n d p oi nt t o t he o verall 
treat me nt effect will be prese nte d. F or t he i n di vi d ual c o m p o ne nt a nal yses, all first e ve nts of t he 
gi ve n t y pe will be i ncl u de d irres pecti ve of a n y prece di n g n o n -fatal c o m p osite e ve nt of a differe nt 
t y pe.  
F or t he i nteri m a nal ysis/es, t he ris k f or a n e ve nt at 1 6 wee ks will be esti mate d.  
Prese nt ati o n  
T he n u m ber of e ve nts, Ka pla n -Meier %, H R wit h 9 5 % CI a n d p -val ue will be prese nte d. K M % 
esti mates of t he c u m ulati ve distri b uti o n f u ncti o n  of s u bjects wit h t he c o m p osite e ve nt as well as 
t he i n di vi d ual c o m p o ne nt will be pl otte d c o m pari n g all treat me nt gr o u ps.  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
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S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 4  of 9 2  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
C CI




S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 6  of 9 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
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S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 7  of 9 2  
 
 
 
  
 
 
  
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
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S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
7 8  of 9 2  
 
 
 
 
 
 
 
 
4. 3  
P h ar m ac o d y n a mic E n d p oi nt(s)  
I nfla m mat or y bi o mar kers will be a nal yse d as descri be d i n Secti o ns 4. 2. 8  a n d 4. 2. 1 4 .    
4. 4  
P h ar m ac o ki netics  
Plas ma c o nce ntrati o ns of A Z D 4 8 3 1 will be prese nte d as descri be d i n Secti o n 4. 2. 7 .  
4. 5  
I m m u n o ge nicit y  
N ot a p plica ble.  
4. 6  
 S afet y A n al yses  
T he d o mai n safet y c o vers e x p os ure, a d verse e ve nts, cli nical la b orat or y, vital si g ns, a n d 
electr ocar di o gra m ( E C G).  
Ta bles, fi g ures, a n d listi n gs are pr o vi de d f or S A S u nless ot her wise state d. All ta b ulati o ns of 
safet y data ( A Es, la b orat or y para meters, vital si g ns, a n d E C G) will be base d o n b ot h t he O n -
treat me nt peri o d a n d O n-st u d y peri o d res pecti vel y u nless ot her wise state d.  
T he a nal yses will be prese nte d f or A Z D 4 8 3 1 2. 5 m g, A Z D 4 8 3 1 5 m g, A Z D 4 8 3 1 T otal ( p o ole d 
treat me nt gr o u ps A Z D 4 8 3 1 2. 5 m g a n d 5 m g) a n d place b o, u nless ot her wise state d.  
S afety esti m a n d defi niti o n  
T he ai m wit h t he a nal yses of safet y data is t o assess t he ge neral safet y o bjecti ve; t his will be 
d o ne f or a h y p ot hetical sce nari o w here st u d y treat me nt is n ot pre mat urel y disc o nti n ue d . T w o 
differe nt ha n dli n g of i nterc urre nt e ve nt strate gies are c o nsi dere d c o m ple me ntar y t o assess t his 
h y p ot hetical sce nari o f or all safet y e n d p oi nts:  
•  
O n -treat me nt; u n biase d u n der t he ass u m pti o n t hat ce ns ori n g f oll o wi n g pre mat ure 
treat me nt disc o nti n uati o n is n o n-i nf or mati ve. N ote t hat t his a p pr oac h c o ul d als o be 
descri be d as ha n dli n g pre mat ure treat me nt disc o nti n uati o n wit h a h y p ot hetical strate g y.  
•  O n -st u d y; u n biase d u n der t he ass u m pti o n t hat t he ris k f or a n e ve nt is i n de pe n de nt of 
c o nti n ue d treat me nt. N ote t hat t his a p pr oac h c o ul d als o be descri be d as ha n dli n g 
pre mat ure treat me nt disc o nti n uati o n wit h a treat me nt p olic y strate g y.  
C CI






S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 1  of 9 2  
 
D ose i nterr u pti o ns will n ot be ta ke n i nt o c o nsi derati o n f or calc ulati o n of d urati o n of e x p os ure.  
T otal ti me of e x p os ure (s u bjects -years) is calc ulate d as  
𝐸𝑣𝑒𝑛𝑡 𝑜𝑛𝑠𝑒 𝑡𝑑 𝑎𝑡𝑒𝑑𝑎𝑡𝑒𝑜= 𝑓𝑟𝑎(𝑛𝑑𝑜𝑚𝑖𝑠𝑎𝑡 𝑖𝑜 𝑛𝐸𝑣𝑒𝑛𝑡𝑜𝑛 𝑠𝑒𝑡 𝑑𝑎𝑡ℎ 𝑒𝑑𝑎𝑡𝑒𝑜𝑓)  ÷ 3 6 5 .2 5   
4. 6. 1. 2  
Prese nt ati o n  
D urati o n of e x p os ure a n d T otal ti me of e x p os ure will be prese nte d descri pti vel y b y treat me nt 
gr o u p a n d i n t otal.  
T otal e x p os ure will be prese nte d cate g oricall y b y c u m ulati ve cate g ories b y e ver y 2 8 t h da y fr o m 
Da y 1 t o Da y 3 3 7. T hese cate g ories are c u m ulati ve, a n d s u bjects will be i ncl u de d i n all 
cate g ories t hat a p pl y t o t he m.  
A fi g ure of e x p os ure o ver ti me will be prese nte d, wit h o ne li ne f or eac h treat me nt gr o u p, a n d 
perce nta ge of s u bjects still e x p ose d o n t he y -a xis a n d ti me fr o m first d ose o n t he x -a xis. At a 
gi ve n ti me t, t he c ur ve will s h o w t he perce nta ge of s u bjects wit h e x p os ure ti me >t.  
I n a d diti o n, K M % esti mates of t he c u m ulati ve distri b uti o n f u ncti o n of s u bjects w h o ha ve 
disc o nti n ue d I P will be pl otte d c o m pari n g all treat me nt gr o u ps , a p plie d o n t he pla n ne d treat me nt 
peri o d . 
Listi n gs  
S u bjects w h o recei ve I P w hic h is n ot c o nsiste nt wit h t he treat me nt he or s he was ra n d o mise d t o 
recei ve will be liste d.  
4. 6. 2  
A d verse E ve nts  
4. 6. 2. 1  
Defi niti o ns a n d Deri v ati o ns  
A d verse e ve nt will be assi g ne d t o t he a nal ysis peri o d base d o n t he o nset date, as defi ne d i n 
Secti o n 3. 3. 1. 5 .  
A d verse e ve nts will be classifie d b y S O C a n d P T a n d  c o de d usi n g Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A).  
Ris k f or a n e ve nt will be esti mate d usi n g K M % esti mates. C o m paris o ns of ris k f or a n e ve nt 
bet wee n t he treat me nt gr o u ps will be esti mate d b y H Rs wit h 9 5 % CIs base d o n a C o x re gressi o n 
m o del wit h a fact or f or treat me nt gr o u p, a n d differe nce i n K M %. A s u bject s first e ve nt t hat 
occ urs d uri n g t he O n -treat me nt or O n-st u d y peri o d, res pecti vel y, will be i ncl u de d i n t he a nal ysis. 
All s u bjects w h o are e ve nt free f or t he gi ve n A E ( or A E cate g or y) will be ce ns ore d acc or di n g t o 
t he defi niti o ns i n Secti o ns 3. 3. 1. 5  a n d 3. 3. 1. 8 .  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 2  of 9 2  
 
A ny A E  
Defi ne d as a n A E re p orte d wit h a n o nset date wit hi n t he defi ne d peri o d.  
A ny S A E  
Defi ne d as a n A E re p orte d as seri o us, irres pecti ve of o utc o me.  
S A Es wit h o utc o me de at h  
Defi ne d as a n A E wit h re p orte d o utc o me as ‘ Fatal’, t here ma y be m ore t ha n o ne A E wit h 
o utc o me deat h f or a s u bject. T he o nset date of t he A E deter mi nes t he a nal ysis peri o d, 
irres pecti ve of date of deat h. 
A Es le a di n g t o disc o nti n u ati o n of I P  
Defi ne d as a n A E wit h acti o n ta ke n I P re p orte d as dr u g per ma ne ntl y disc o nti n ue d. T he o nset 
date of t he A E deter mi nes t he a nal ysis peri o d, irres pecti ve of date of disc o nti n uati o n of I P.  
A Es p ossi bly rel ate d t o I P  
Defi ne d as a n A E t hat is re p orte d as “reas o na ble p ossi bilit y A E ca use d b y I P”. If t his e val uati o n 
is missi n g, it will be c o u nte d as a n A E p ossi bl y relate d t o I P. 
A Es by m a xi m u m i nte nsity  
A Es will be classifie d b y t he re p orte d ma xi m u m i nte nsit y, “ Mil d”, “ M o derate” a n d “ Se vere”. If 
t his ma xi m u m i nte nsit y e val uati o n is missi n g, it will be c o u nte d as “ Se vere”. 
A dverse eve nts of s peci al i nterest  
T he f oll o wi n g t w o gr o u ps of a d verse e ve nts are A d verse e ve nts of s pecial i nterest ( A E o SI):  
•  I nfecti o ns: will be i de ntifie d b y t he S O C “I nfecti o ns a n d i nfestati o ns”.  
o  T he pat h o ge n s pecific Hi g h le vel gr o u p ter m ( H L G T) " F u n gal i nfecti o us 
dis or ders".  
•  S ki n reacti o ns, i ncl u di n g mac ul o pa p ular ras h:  
o  S ki n reacti o ns/ras hes c o nsi dere d mac ul o pa p ular ( descri be d as mac ules/ pa p ules 
u n der t he m or p h ol o g y/a p peara nce q uesti o n).  
o  S ki n reacti o ns/ras hes n ot c o nsi dere d mac ul o pa p ular ( n ot descri be d as 
mac ules/ pa p ules u n der t he m or p h ol o g y/a p peara nce q uesti o n).  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 3  of 9 2  
 
4. 6. 2. 2  
Prese nt ati o n  
F or all A E ta bles, u nless ot her wise state d, t he n u m ber a n d perce nta ge of s u bjects e x perie nci n g a n 
e ve nt al o n g wit h Ka pla n -Meier perce nta ges at 1 6 a n d 4 8 wee ks will be prese nte d f or all 
treat me nt gr o u ps. I n a d diti o n, K M % differe nces a n d H R t o get her wit h 9 5 % c o nfi de nce i nter vals 
will be prese nte d f or t he c o m paris o ns of eac h acti ve treat me nt gr o u p t o plac e b o. Perce nta ges will 
be calc ulate d wit h n u m ber of s u bjects i n S A S as de n o mi nat or, a n d s u bjects will o nl y be c o u nte d 
o nce per cate g or y , re gar dless of t he n u m ber of A Es satisf yi n g eac h c o n diti o n.  
Ta bles w here A Es are prese nte d b y S O C a n d P T will be s orte d b y i nter nati o nal or der f or S O C 
a n d al p ha betical or der f or P T.   
I n a d diti o n, K M % esti m ates of t he c u m ul ati ve distri b uti o n f u ncti o n  of s u bjects wit h A E o SIs 
will be pl otte d c o m p ari n g all tre at me nt gr o u ps.  Over all  s u m m ary of A Es  
T he f oll o wi n g cate g ories will be prese nte d i n t he o verall s u m mar y:  
•  a n y A E,  
•  a n y S A E,  
•  a n y S A E wit h o utc o me deat h,  
•  a n y A E lea di n g t o disc o nti n uati o n of I P, a n d  
•  a n y A E p ossi bl y relate d t o I P (as assesse d b y i n vesti gat or).  
A n y A E lea di n g t o disc o nti n uati o n of I P cate g or y will o nl y be a nal yse d f or t he O n -treat me nt 
peri o d.  
By S O C a n d P T  
Se parate A E ta bles b y S O C a n d P T will be prese nte d f or t he f oll o wi n g cate g ories:  
•  a n y A E,  
•  A Es p ossi bl y relate d t o I P,  
•  A Es lea di n g t o disc o nti n uati o n of I P,  
•  A Es b y c u m ulati ve ma xi m u m i nte nsit y (a n y, m o derate or se vere, se vere),  
•  a n y S A E,  
•  S A E wit h o utc o me deat h, a n d  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 4  of 9 2  
 
•  A Es of s pecial i nterest.  
M ost c o m m o n A Es  
A ta ble of t he n u m ber a n d perce nta ge, a n d K M % at 1 6 a n d 4 8 wee ks of t he m ost c o m m o n 
a d verse e ve nts b y P T (fre q ue nc y of > 5 %). T his ta ble will be s orte d b y decreasi n g fre q ue nc y i n 
A Z D 4 8 3 1 5 m g ar m.  
M ost c o m m o n n o n -seri o us A Es  
A ta ble of n o n -seri o us A Es occ urri n g i n m ore t ha n 5 % of s u bjects i n a n y treat me nt gr o u p will be 
prese nte d , b y S O C a n d P T.  
A Es of s peci al i nterest  
A ma p pi n g of t he A E o SIs t o Preferre d ter ms will be prese nte d.  
F or eac h of t he S O C I nfecti o ns a n d i nfestati o ns a n d t he H L G T F u n gal i nfecti o us dis or ders, a n 
o verall s u m mar y, a n d a n y A E a n d S A E b y P T will be prese nte d. I n t he o verall s u m maries, A Es 
b y c u m ulati ve ma xi m u m i nte nsit y (a n y, m o derate or se vere, se vere ) will be prese nte d i n a d diti o n 
t o cate g ories descri be d u n der O verall s u m mar y of A Es.  
S ki n reacti o ns will be prese nte d b y a  s u m mar y of t he f oll o wi n g cate g ories of s ki n reacti o ns: 
•  a n y s ki n reacti o n/ras h  
•  a n y mac ul o pa p ular s ki n reacti o n/ras h lea di n g t o per ma ne nt pre mat ure I P disc o nti n uati o n 
b y c u m ulati ve ma xi m u m C T C A E gra de (a n y, 2 or 3, 3), a n d  
•  a n y n o n -mac ul o pa p ular s ki n reacti o n/ras h lea di n g t o per ma ne nt pre mat ure I P 
disc o nti n uati o n ( S A Es a n d ge neralise d s ki n reacti o n/ras h)  
F or mac ul o pa p ular s ki n reacti o n/ras h a n o verall s u m mar y, mac ul o pa p ular A Es b y P T a n d 
mac ul o pa p ular S A Es b y P T will be prese nte d. I n t he o verall s u m mar y, A Es b y c u m ulati ve 
ma xi m u m i nte nsit y ( a n y, m o derate or se vere, se vere ) a n d A Es b y c u m ulati ve ma xi m u m C T C A E 
gra de ( a n y, 2 or 3, 3 ) will be prese nte d i n a d diti o n t o cate g ories descri be d u n der O verall 
s u m mar y of A Es. 
I n a d diti o n, mac ul o pa p ular A Es a n d S A Es will be prese nte d b y c u m ulati ve  ma xi m u m C T C A E 
gra de ( a n y, 2 or 3, 3 1, 2, 3), o n P T le vel.  
F or ot her s ki n reacti o ns/ras hes (e xcl u di n g mac ul o pa p ular s ki n reacti o ns/ras hes) a n o verall 
s u m mar y, A Es b y P T a n d S A Es b y P T will be prese nte d. I n t he o verall s u m maries, A Es b y 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 5  of 9 2  
 
c u m ulati ve  ma xi m u m i nte nsit y ( a n y, m o derate or se vere, se vere ) will be prese nte d i n a d diti o n t o 
cate g ories descri be d u n der O verall s u m mar y of A Es.  
Key s u bject i nf or m ati o n  
Ke y s u bject i nf or mati o n will be prese nte d f or s u bjects wit h  
•  S A Es wit h o utc o me deat h,  
•  a n y S A Es, a n d  
•  A Es lea di n g t o disc o nti n uati o n of I P f or t he f ull st u d y peri o d.  
Listi n gs  
A d verse e ve nts listi n gs will be prese nte d f or  
•  eac h i n di vi d ual A E,  
•  s u bjects wit h A E o SIs relate d t o s ki n reacti o ns (i ncl u di n g mac ul o pa p ular ras h), a n d  
•  A Es re p orte d f or s u bjects w h o recei ve d t he i nc orrect I P, i.e., n ot t he ra n d o mise d I P.  
N arr atives  
Narrati ves will be ge nerate d f or all deat hs, A Es lea di n g t o disc o nti n uati o n of I P, A Es of s pecial 
i nterest a n d S A Es. 
4. 6. 3  
Cli nic al L a b or at or y, Bl o o d S a m ple  
4. 6. 3. 1  
Defi niti o ns a n d Deri v ati o ns  
Bl o o d sa m ples f or deter mi nati o n of cli nical c he mistr y a n d hae mat ol o g y will be c ollecte d 
acc or di n g t o t he sc he d ule of acti vities i n Secti o n 1. 3 of t he C S P. Cli nical Safet y La b orat or y 
Assess me nts are liste d i n Secti o n 8. 2. 4 of t he C S P.  
Tre at me nt e mer ge nt a b n or m alities  
Treat me nt e mer ge nt a b n or malities i n selecte d para meters f or hae mat ol o g y a n d c he mistr y 
la b orat or y meas ure me nts are defi ne d as p ost -baseli ne meas ure me nts meeti n g t he pre -defi ne d 
criteria f or a b n or malit y bel o w a n d is m ore e xtre me t ha n t he n o n -missi n g baseli ne val ue f or a 
s u bject. T h us, if t he baseli ne val ue met t he criteria f or mar ke d a b n or malit y a n d t he p ost-baseli ne 
val ue is e q ual t o or less e xtre me t ha n t he baseli ne val ue, t his is n ot c o nsi dere d a treat me nt 
e mer ge nt a b n or malit y. L o w a n d hi g h ra n ges are deri ve d base d o n refere nce ra n ge s pr o vi de d b y 
t he ce ntral la b orat or y, if a vaila ble.  
•  Hae mat ol o g y:  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 6  of 9 2  
 
o  E osi n o p hils ≥ 0. 7 x 1 0 9/ L; ≥1. 5 x 1 09/ L  
o  Hae m o gl o bi n < 1 0 0 g/ L; < 8 0 g/ L  
o  Ne utr o p hils < 1. 5 x 1 0 9/ L; < 1. 0 x 1 09/ L  
o  W hite bl o o d cell c o u nt < 3. 0 x 1 0
9/ L; < 2. 0 x 1 09/ L 
•  C he mistr y:  
o  Creati ni ne: ≥ 1. 5 x baseli ne creati ni ne a n d ≥ 2 x baseli ne creati ne  
o  A L P > 1. 5 x U L N;  > 3 x U p per li mit n or mal ( U L N)  
o  A L T > 3 x U L N; > 5 x U L N; > 1 0 x  U L N  
o  A S T > 3 x U L N; > 5 x U L N; > 1 0 x  U L N  
o  T B > 1. 5 x U L N; > 2 x U L N  
o  A S T or A L T > 3 x U L N  
o  A S T or A L T > 3 x U L N a n d T B > 2 x U L N  
o  T S H > 6 mI U/ L; ≥1 0 mI U/ L  
o  T S H > 6 mI U/ L a n d free T 4 < L o wer li mit n or mal ( L L N); ≥1 0 mI U/ L a n d free T 4 < 
L L N  
F or criteria c o m prisi n g c o m bi nati o ns of para meters, t he treat me nt e mer ge nt a b n or malit y is 
fla g ge d w he n b ot h  para meter s meet t heir i n di vi d ual criteria  o n sa me visit.  
4. 6. 3. 2  
Prese nt ati o ns  
Cli nical la b orat or y para meters will be prese nte d f or S A S b y treat me nt gr o u p, a n d sc he d ule d 
visit, se paratel y f or hae mat ol o g y a n d c he mistr y para meters, a n d t he para meters will be prese nte d 
i n al p ha betical or der.  
Val ues a n d a bs ol ute c ha n ge fr o m baseli ne will be prese nte d f or c o nti n u o us varia bles usi n g 
descri pti ve statistics f or all sc he d ule d assess me nts after baseli ne.  
Ma xi m u m o n -treat me nt/ o n-st u d y A L T a n d A S T vers us ma xi m u m o n-treat me nt/ o n-st u d y t otal 
bilir u bi n will be prese nte d, b y treat me nt gr o u p  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 7  of 9 2  
 
Tre at me nt e mer ge nt a b n or m alities  
T he n u m ber of s u bjects wit h o bser vati o ns meeti n g t he pre -s pecifie d a b n or malit y la b orat or y 
criteria i n Secti o n 4. 6. 3. 1  f or eac h para meter will be prese nte d, f or S A S.  
Key s u bject i nf or m ati o n  
Ke y s u bject i nf or mati o n will be prese nte d f or s u bjects wit h treat me nt e mer ge nt a b n or malities as 
defi ne d a n d liste d i n Secti o n 4. 6. 3. 1 . 
S u bjects meeti n g  p ote ntial H y's la ws criteria will be prese nte d as ke y s u bject i nf or mati o n, wit h 
treat me nt gr o u p prese nte d b y pa ge.  
Listi n gs  
A listi n g of i n di vi d ual la b orat or y meas ure me nts, i ncl u di n g refere nce ra n ge i n dicat or will be 
prese nte d.  
4. 6. 4  
Cli nic al L a b or at or y, Uri n al ysis  
4. 6. 4. 1  
Defi niti o ns a n d Deri v ati o ns  
Cli nical la b orat or y para meters f or uri nal ysis c ollecte d acc or di n g t o t he sc he d ule of acti vities 
acc or di n g t o Secti o n 1. 3 of t he C S P. Cli nical Safet y La b orat or y Assess me nts are liste d i n Secti o n 
8. 2. 4 of t he C S P.  
Tre at me nt e mer ge nt a b n or m alities  
S u bjects wit h treat me nt e mer ge nt uri nal ysis para meter a b n or malities i n q ua ntitati ve para meters  
will be defi ne d acc or di n g t o t he n o n -m ut uall y e xcl usi ve t hres h ol ds base d o n ce ntral la b orat or y 
ra n ges ( w he n a p plica ble): < L L N, > U L N.  
4. 6. 4. 2  
Prese nt ati o ns  
Cli nical la b orat or y para meters f or uri nal ysis will be prese nte d f or S A S b y treat me nt gr o u p, a n d 
t he para meters will be prese nte d i n al p ha betical or der.   
C ha n ge fr o m baseli ne t o ma xi m u m a n d mi ni m u m assess me nt o n -treat me nt a n d o n-st u d y 
res pecti vel y will be prese nte d i n s hift ta bles. 
Tre at me nt e mer ge nt a b n or m alities  
T he n u m ber of s u bjects wit h o bser vati o ns meeti n g t he pre -s pecifie d a b n or malit y la b orat or y 
criteria i n Secti o n 4. 6. 4. 1 , f or eac h para meter will be prese nte d, f or S A S.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 8  of 9 2  
 
4. 6. 5  
Ot her L a b or at or y E v al u ati o ns  
4. 6. 5. 1  
Defi niti o ns a n d Deri v ati o ns  
Tre at me nt e mer ge nt a b n or m alities  
Treat me nt e mer ge nt A N C A p ositi vit y is defi ne d as s hifts fr o m ne gati ve at baseli ne t o p ositi ve 
p ost -treat me nt. 
‘ Ne gati ve’ res ults will be ma p pe d t o ne gati ve cate g or y. Res ults n ot re p orte d as ‘ Ne g ati ve’ will 
be ma p pe d t o p ositi ve cate g or y.  
4. 6. 5. 2  
Prese nt ati o ns  
Tre at me nt e mer ge nt a b n or m alities  
T he n u m ber of s u bjects wit h treat me nt e mer ge nt A N C A p ositi vit y will be prese nte d i n a s hift 
ta ble wit h t he cate g ories p ositi ve a n d ne gati ve, b y treat me nt gr o u p. 
4. 6. 6  
Vit al Si g ns  
4. 6. 6. 1  
Defi niti o ns a n d Deri v ati o ns  
Vital si g ns (s u pi ne bl o o d press ure ( B P), p ulse rate a n d b o d y te m perat ure) will be perf or me d at 
ti me p oi nts acc or di n g t o t he sc he d ule of acti vities i n Secti o n 1. 3 of t he C S P. 
F or baseli ne vital si g ns assess me nts, t he f oll o wi n g or der of e C R F f or ms s h o ul d be use d.  
•  
V S 4 (if n ot missi n g),  
•  V S 3 (if V S 4 is missi n g),  
•  V S 5 (if b ot h V S 4 a n d V S 3 are missi n g),  
If all a b o ve are missi n g, earlier assess me nts s h o ul d be use d. 
O bser vati o ns fr o m V S 7 will n ot  be c o nsi dere d as baseli ne si nce t his is c o m plete d p ost first d ose 
of I P  as per t he e C R F i nstr ucti o ns . 
T he sa me l o gic a p plies t o all p ost -ra n d o misati o n visits.  
Vital si g ns s hift fr o m baseli ne will be defi ne d base d o n t he f oll o wi n g cate g orisati o n:  
•  S yst olic B P: Hi g h if ≥1 4 0; N or mal if < 1 4 0 a n d ≥9 0; L o w if < 9 0  
•  Diast olic B P: Hi g h if ≥9 0; N or mal if < 9 0 a n d ≥6 0; L o w if < 6 0  
•  P ulse rate: Hi g h if ≥1 0 0; N or mal if < 1 0 0 a n d ≥5 0; L o w if < 5 0.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 9  of 9 2  
 
Tre at me nt e mer ge nt a b n or m alities  
Vital si g n treat me nt e mer ge nt a b n or malities are deter mi ne d as f oll o ws:  
•  S yst olic B P ( m m H g):  
o  O bser ve d val ue ≥ 1 4 0 a n d a bs ol ute i ncrease of ≥ 2 0 fr o m baseli ne f or hi g h le vel.  
o  O bser ve d val ue < 9 0 a n d a bs ol ute decrease of ≥ 2 0 fr o m baseli ne f or l o w le vel.  
•  Diast olic B P ( m m H g):  
o  O bser ve d val ue ≥ 9 0 a n d a bs ol ute i ncrease of ≥ 1 0 fr o m baseli ne f or hi g h le vel.  
o  O bser ve d val ue < 6 0 a n d a bs ol ute decrease of ≥ 1 0 fr o m baseli ne f or l o w le vel.  
•  P ulse rate ( beats/ mi n):  
o  O bser ve d val ue ≥ 1 0 0 a n d a bs ol ute i ncrease of ≥ 2 0 fr o m baseli ne f or hi g h le vel.  
o  O bser ve d val ue < 5 0 a n d a bs ol ute decrease of ≥ 2 0 fr o m baseli ne f or l o w le vel.  
4. 6. 6. 2  
Prese nt ati o ns  
Val ues a n d a bs ol ute c ha n ge fr o m baseli ne will be prese nte d base d o n S A S b y visit f or 
c o nti n u o us varia bles usi n g descri pti ve statistics f or all sc he d ule d assess me nts after baseli ne, b y 
treat me nt gr o u p.  
Vital si g n s hift fr o m baseli ne t o ma xi m u m/ mi ni m u m o n -treat me nt/ o n-st u d y val ue will be 
prese nte d.  
Tre at me nt e mer ge nt a b n or m alities  
T he n u m ber a n d perce nta ge of s u bjects wit h vital si g ns treat me nt e mer ge nt a b n or malities will be 
prese nte d b y treat me nt gr o u p.  
Key s u bject i nf or m ati o n  
Ke y s u bject i nf or mati o n will be prese nte d f or s u bjects wit h treat me nt e mer ge nt a b n or malities as 
defi ne d i n Secti o n 4. 6. 6. 1 . 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 0  of 9 2  
 
4. 6. 7  
Electr oc ar di o gr a m  
4. 6. 7. 1  
Defi niti o ns a n d Deri v ati o ns  
Si n gle 1 2 -lea d E C G (sta n dar d E C G wit h a pa per s pee d of 2 5-5 0 m m/sec o n d c o veri n g at least 6 
se q ue ntial beats) will be o btai ne d acc or di n g t o t he sc he d ule of acti vities i n Secti o n 1. 3 of t he 
C S P.  
Tre at me nt e mer ge nt a b n or m alities  
E C G treat me nt e mer ge nt a b n or malities are defi ne d as s u bjects wit h a b n or mal cli nicall y 
si g nifica nt res ults t hat were n ot prese nt at baseli ne.  
4. 6. 7. 2  
Prese nt ati o ns  
S u m mar y statistics will be s h o w n f or t he f oll o wi n g cate g ories f or S A S b y treat me nt gr o u p:  
•  Heart r h yt h m cate g or y  
•  O verall E C G e val uati o n  
•  Was t he E C G cli nicall y si g nifica nt?  
S hifts fr o m baseli ne t o last o bser vati o n i n E C G o verall e val uati o n will be a nal yse d i n ter ms of 
n or malit y a n d cli nical si g nifica nce.  
Tre at me nt e mer ge nt a b n or m alities  
T he n u m ber a n d perce nta ge of s u bjects wit h E C G treat me nt e mer ge nt a b n or malities  will be 
prese nte d b y treat me nt gr o u p  f or S A S, w here t he perce nta ge is base d o n n u m ber of s u bjects per 
treat me nt gr o u p wit h a baseli ne val ue a n d at least o ne p ost-baseli ne val ue.  
Key s u bject i nf or m ati o n  
Ke y s u bject i nf or mati o n will be prese nte d f or s u bjects wit h treat me nt e mer ge nt a b n or malities . 
Listi n gs  
A listi n g f or all s u bjects will prese nt date of E C G perf or ma nce, cate g ories liste d a b o ve a n d 
reas o ns if c o n d ucti o n was a b n or mal. 
4. 6. 8  
Ot her S afet y Assess me nts  
4. 6. 8. 1  
Defi niti o ns a n d Deri v ati o ns  
Ort h ost atic bl o o d press ure test  
Ort h ostatic h y p ote nsi o n relate d meas ures are deri ve d fr o m t he ort h ostatic B P meas ure me nts. T he 
ort h ostatic h y p ote nsi o n test is descri be d i n secti o n 8. 2. 2 i n t he C S P. It was c o m m u nicate d t o sites 
o n 1 2 A u g ust 2 0 2 2 t o st o p perf or mi n g t he p ost -d ose assess me nt  at t he da y of ra n d o misati o n. 


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 1  of 9 2  
 
T heref ore, o nl y s u bjects ra n d o mise d pri or t o 1 2 A u g ust 2 0 2 2 will be at ris k i n t he a nal ysis 
prese nti n g res ults f or t he p ost -d ose test at t he da y of ra n d o misati o n. All o bser vati o ns will be 
prese nte d i n t he listi n g re gar dless of w he n t he test was perf or me d.  
T he f oll o wi n g defi niti o ns will be a p plie d:  
•  B P decrease: a decrease ≥ 2 0 m m H g i n s yst olic bl o o d press ure or ≥ 1 0 m m H g i n diast olic 
bl o o d press ure.  
•  B P decrease re p orte d as A E: a B P decrease a n d a re p orte d A E of Ort h ostatic H y p ote nsi o n 
t he sa me da y p ost-first d ose or wit hi n t he sa me da y of t he 1 2 wee ks meas ure me nt. 
•  S y m pt o matic B P decrease: B P decrease w hic h t he i n vesti gat or j u d ge t hat t here were 
s y m pt o ms t hat were relate d t o t he ort h ostatic bl o o d press ure meas ure me nt. 
•  As y m pt o matic B P decrease: B P decrease w hic h t he i n vesti gat or j u d ge t hat t here were n o 
s y m pt o ms t hat were relate d t o t he ort h ostatic bl o o d press ure meas ure me nt. 
T hese cate g ories will be prese nte d at t hree ti me p oi nts  
•  p ost -first d ose irres pecti ve of baseli ne stat us, 
•  o nl y p ost -first d ose (i ncl u di n g o nl y s u bjects wit h n o o bser ve d B P decrease pre-first 
d ose), a n d  
•  at 1 2 wee ks.  
4. 6. 8. 2  
Prese nt ati o ns  
Ort h ost atic bl o o d press ure test  
Meas ure me nts relate d t o t he Ort h ostatic h y p ote nsi o n test will be s u m marise d f or eac h of t he 
t hree ti me p oi nts descri be d i n Secti o n 4. 6. 8. 1  b y n u m ber a n d perce nta ge of s u bjects wit h a n e ve nt 
a n d t otal n u m ber of e ve nts base d o n t he safet y a nal ysis set, b y treat me nt gr o u p.   
Listi n gs  
A listi n g of all s u bjects wit h at least o ne test se q ue nce s u g gesti ve of Ort h ostatic  h y p ote nsi o n will 
be prese nte d.  
A listi n g of A Es, S A Es a n d D A Es b y S O C/ P T f or s u bjects wit h at least o ne test se q ue nce 
s u g gesti ve of Ort h ostatic h y p ote nsi o n will be prese nte d. A d verse e ve nts occ urri n g wit hi n 3 h o urs 
after first d ose of I P f or t he baseli ne visit or t he 1 2 wee ks meas ure me nt will be fla g ge d.  


S T A TI S TI C A L A N A L Y SI S P L A N  
Astra Ze neca  
D 6 5 8 0 C 0 0 0 1 0  –  e d. 4. 0  
0 8 -Mar -2 0 2 4  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 2  of 9 2  
 
5  
I N T E RI M A N A L Y SI S 
At least o ne, b ut p ossi bl y se veral, i nteri m A nal yses f or Part A wit h t he p ur p ose of i nf or mi n g 
f urt her de vel o p me nt of t he cli nical pr o gra m me will be c o n d ucte d, i ncl u di n g b ut n ot li mite d t o 
d ose selecti o n f or Part B. T he first i nteri m a nal ysis will be perf or me d  w he n at least 1 5 0 
ra n d o mise d s u bjects ha ve ha d t he p ossi bilit y t o reac h t he 1 6 wee ks visit. T he last i nteri m 
a nal ysis will be perf or me d w he n all partici pa nts i n Part A ha ve c o m plete d t he last pr ot oc ol -
s pecifie d visit/assess me nt (t he last Wee k 5 2 visit [i ncl u di n g tele p h o ne c o ntact]). A n U n bli n de d 
Re vie w C o m mittee ( U R C) will re vie w eac h of t he i nteri m a nal yses. If Part B were n ot t o start or 
pr o gress, t he n t he last i nteri m w o ul d n ot be re gar de d as a n i nteri m b ut w o ul d bec o me t he fi nal 
a nal ysis. 
F urt her details of t he i nteri m a nal ysis, e. g., me m bers of t he U R C, sc o pe of a nal ysis, G o/ N o g o 
criteria f or f urt her cli nical de vel o p me nt a n d descri pti o ns of u n bli n di n g pr oce d ures a n d meeti n gs, 
are prese nte d i n a se parate U R C C harter.  
6  
R E F E R E N C E S  
B ur ma n, C. -F. S. ( 2 0 0 9). A rec ycli n g fra me w or k f or t he c o nstr ucti o n of B o nferr o ni -base d 
m ulti ple tests. St atistics i n Me dici ne, 2 8 , 7 3 9-7 6 1.  
F D A. ( 2 0 1 7). M ulti ple E n d p oi nts i n Cli nic al Tri als G ui d a nce f or I n d ustry.  Ce nter f or Dr u g 
E val uati o n a n d Researc h. U. S. f o o d a n d Dr u g A d mi nistrati o n.  
Gas par ya n, S. F. ( 2 0 2 0). A dj uste d wi n rati o wit h stratificati o n: Calc ulati o n met h o ds a n d 
i nter pretati o n. St atistic al Met h o ds i n Me dic al Rese arc h, 3 0 , 5 8 0-6 1 1.  
Mc Gra w, K. W. ( 1 9 9 6). F or mi n g i nfere nces a b o ut s o me i ntraclass c orrelati o n c oefficie nts. 
Psyc h ol o gic al Met h o ds, 1 , 3 0-4 6.  
 

Prot_000.pdf: 
Clinical Study Protocol – Version 5.0 (Amendment Number 4.0)
AstraZeneca
AZD4831 - D6580C00010
CONFIDENTIAL AND PROPRIETARY
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Clinical Study Protocol 
Study Intervention
AZD4831
Study Code
D6580C00010
Version
5.0 (Amendment Number 4.0)
Date
23 September 2022
A Randomised, Double-blind, Placebo-controlled, Multi-center
Sequential Phase 2b and Phase 3 Study to Evaluate the Efficacy 
and Safety of AZD4831 Administered for up to 48 Weeks in 
Participants with Heart Failure With Left Ventricular Ejection 
Fraction > 40%
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Local Sponsor (Part A of study): AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-
0011, Japan
Regulatory Agency Identifier Number(s): EudraCT 2020-005844-4 ; IND 134026
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results ar  
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D6580C00010
Amendment Number: 4
Redacted for Pu
ted
mised, Doub
d f
mised, Doub
Phase 2b and
d fo
Phase 2b and
f AZD4831 A
for
f AZD4831 A
Heart Failu
or P
Heart Failu
Fractio
r P
Fractio
Public Disclosure
51 85 Södertälj
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51 85 Södertälj
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and in


Clinical Study Protocol – Version 5.0 (Amendment Number 4.0) 
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CONFIDENTIAL AND PROPRIETARY 
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Study Intervention: AZD4831 
Study Phase: 2b/3 
Short Title:  A Sequential Phase 2b and Phase 3 Study to Evaluate the Efficacy and Safety of 
AZD4831 in Participants with Heart Failure with Left Ventricular Ejection Fraction > 40% 
Acronym: ENDEAVOR (Efficacy aNd safety of AZD4831 aDministEred for up to 48 weeks 
in pArticipants with heart failure with left Ventricular ejection fractiOn > foRty%) 
Study Physician Name and Contact Information will be provided separately 
International co-ordinating investigator 
 
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Version 5 (Amendment 4) 
23 September 2022 
Version 4 (Amendment 3) 
09 February 2022 
Version 3 (Amendment 2) 
01 November 2021 
Version 2 (Amendment 1) 
25 May 2021 
Version 1 (Original Protocol) 
18 February 2021 
 
Amendment 4 (23 September 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment 
To change the Part B study design regarding the duration of the treatment, number of 
participants and their allocation to treatment groups. All changes and the rationale are listed 
below, except for the minor changes that are introduced throughout the document to meet the 
standards of sponsor housestyle.  
Section Number and Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 1.1 Synopsis, Objective 
and Endpoints Table, Part B 
Changed text to improve 
clarity. Assessment of 
Pharmacokinetics as a 
Secondary objective has 
been removed. 
Clarification of the 
Section 3. 
Assessment of 
Pharmacokinetics has 
been moved to Tertiary 
objectives to reflect the 
changes in the study 
design for Part B. 
Non-substantial 
Section 1.1 Synopsis, Overall 
Design 
Added text 
The text has been 
added since it was 
missing in the version 
4 of the CSP 
Non-substantial 
Section 1.1 Synopsis, Number 
of Participants Table 
Changed text for Part B 
regarding the number of 
enrolled, randomised and 
participants with complete 
safety data data. 
To reflect changes in 
study design for Part B 
Substantial 


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Section Number and Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 1.1 Synopsis, 
Intervention Groups and 
Duration 
Changed text regarding 
Part B (allocation 1:1, 
flexible treatment 
duration). 
Clarification 
To reflect changes in 
study design for Part B 
Substantial 
Section 1.1 Synopsis, Data 
Monitoring Committee 
Changed text: When all 
participants in Part A have 
completed Week 52, the 
Part A will be analysed as 
final interim analysis. 
 
Clarification 
Non-substantial 
Section 1.1 Synopsis, Statistical 
Methods 
Changed text regarding 
Part B. 
To reflect changes in 
study design for Part B 
Substantial 
Section 1.2 Schema, Figure 2, 
Study Design – Part B 
New Figure 
Additional footnotes 
To reflect changes in 
study design for Part B 
(remote visits have 
been removed). 
Substantial 
Section 1.3 Schedule of 
Activities, Table 1, Part A 
In footnote ‘e’ the sentence 
‘At baseline orthostatic BP 
will also be measured 1-2 
hours post dose’ has been 
removed. 
To reflect changes in 
study design for Part 
A. 
Non-substantial 
Section 1.3 Schedule of 
Activities, Table 2, Part B 
New Figure 
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 2.3.1 Risk Assessment, 
Table 3 
Added/removed and edited 
text 
Potential risk of clinical 
significance: Ovarian 
interstitial gland 
vacuolation in rats has 
been removed. Renal 
toxicity has been added. 
To reflect the most 
recent data presented 
in IB. 
Substantial 
Section 3.1 Part A 
New text (KCCQ 
comparison of remote and 
on-site results). 
Clarification 
Non-substantial 
Section 3 Objective and 
Endpoints, 3.2 Part B, Table 5 
Changed text to improve 
clarity. 
 
 
 
 
 
 
, 
Clarification 
Changes in the study 
design for Part B. 
Non-Substantial 
CCI


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Section Number and Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
 
 
. 
Section 4.1 Overall Design 
Changed text regarding 
Part B (allocation, flexible 
treatment duration, number 
of participants). 
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 4.2 Scientific rationale 
for study design 
Changed text in the first 
paragraph. 
To reflect changes in 
Inclusion criteria for 
both Part A and Part B 
Non-substantial 
Section 4.4 End of Study 
Definition 
Added text (third 
paragraph) regarding Part 
B. 
Added text regarding 
Clinical Trial 
Transparency (CTT). 
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 5 Study Population, 
5.1.1 Inclusion criteria - Part A 
Inclusion criterion 9. 
Changed text   
Clarification 
Non-substantial 
Section 5.1 Inclusion Criteria 
Additional sections (5.1.1 
and 5.1.2) have been 
created to present inclusion 
criteria for Part A and Part 
B separately. 
To improve readability 
of the document 
considering differences 
in inclusion criteria for 
Part A and Part B. 
Substantial 
Section 5.2.1 Exclusion criteria 
– Part A 
Text has been added/edited 
to clarify exclusion criteria 
10, 11, 13, 15, 19, 20, 23 
and 25. 
Clarification 
Non-substantial 
Section 5.2 Exclusion criteria  
Additional sections (5.2.1 
and 5.2.2) have been 
created to present 
exclusion criteria for Part 
A and Part B separately . 
To improve readability 
of the document 
considering differences 
in exclusion criteria for 
Part A and Part B.  
Substantial 
Section 5.4 Screen Failures 
Text regarding individuals 
who do not meet the eGFR 
and NT-proBNP 
inclusion/exclusion criteria 
has been changed and 
shortened.   
Clarification and 
simplification 
Non-substantial 
Section 6.1.1 Investigational 
Products Table 6 
Added text on labelling of 
bottles for Part B. 
Additional information 
to aid the conduction 
of the study. 
Non-substantial 
CCI


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Section Number and Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 6.1.1 Investigational 
Products 
 
Added text on taking study 
intervention.  
Additional information 
to aid the conduction 
of the study. 
 
Non-substantial 
Section 6.3 Measures to 
Minimise Bias: Randomisation 
and Blinding 
Text regarding allocation 
of participants in Part B 
has been changed. 
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 6.3 Measures to 
Minimise Bias: Randomisation 
and Blinding 
New text: A maximum of 
25% of the participants can 
have 6MWD ≥ 350 and 
≤400 meters at 
randomisation visit. 
 
Clarification 
Non-substantial 
Section 6.5 Concomitant 
therapy 
Silymarin has been added 
to the list of treatments that 
are prohibited and/or 
restricted. 
Additional information 
to aid the conduction 
of the study. 
Non-substantial 
Section 6.5.1 Rescue Medicine 
Section 6.5.1 has been 
removed. The text in this 
section has been added to 
section 8.2.5. 
To improve readability 
of the document. 
Non-substantial 
Section 7.1 Discontinuation of 
Study Intervention 
Added text (Pregnancy) 
Clarification 
Non-substantial 
Section 7.2 Participant 
Withdrawal from the Study 
Deleted text ‘safety’ 
Clarification 
Non-substantial 
Section 8 Study Assessments 
and Procedures 
Changed text regarding 
maximum amount of blood 
to be collected for Part B 
(approximately 300 mL). 
Clarification 
Non-substantial 
Section 8.1.1 Patient Reported 
Outcomes 
The text regarding the 
remote visits for Part B has 
been removed/edited.  
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 8.1.1 Patient Reported 
Outcomes 
Added text (with the 
exception of the 
 which is to 
be competed before the 
6MWT). 
 
Clarification 
Non-substantial 
Section 8.1.1 Patient Reported 
Outcomes 
Added text for additional 
PROs to be used in Part B 
. 
To reflect changes in 
study design for Part 
B. 
Substantial 
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Section Number and Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 8.1.1.2 Patient Global 
Impression of Severity in Heart 
Failure Symptoms (Part A only) 
 
Removed text (‘Part A 
only’, ‘and is used to 
 
 
 
). 
To reflect changes in 
study design for Part 
B. 
Non-substantial 
Section 8.1.1.3 Patient Global 
Impression of Severity in 
Walking Difficulties (Part A 
only) 
Removed text (‘Part A 
only’, ‘and will be used to 
 
 
 
 
To reflect changes in 
study design for Part 
B.  
Non-substantial 
Section 8.1.4 Echocardiography 
Heading changed to 
Echocardiogram. 
Subsections (8.1.4.1 and 
8.1.4.2) created to present 
Part A-specific and Part-B-
specific text separately  
Minor changes in Part A-
specific section. 
To align the 
terminology 
throughout the 
document. 
To reflect changes in 
study design for Part 
B.  
Non-substantial 
Section 8.2.1 Physical 
Examination 
Text regarding full 
physical examinations for 
Part B has been edited. 
To reflect changes in 
study design for Part 
B.  
Non-substantial 
Section 8.2.2 Vital signs 
Subsection created for Part 
A-specific text (8.2.2.1). 
Removed text that is not 
applicable anymore. 
To improve readibility 
Non-substantial 
Section 8.2.4 Clinical Safety 
Laboratory Assessments, Table 
8 
Edited text regarding 
centrally and locally 
performed analyses. 
Added footnote ‘b’ to 
Table 8. 
Clarification 
Non-substantial 
Section 8.2.5 Skin Reactions, 
Including Maculopapular Rash 
Text from the removed 
section 6.5.1 has been 
placed in 8.2.5. 
To improve readability 
of the document. 
Non-substantial 
Section 8.3.1 Time Period and 
Frequency for Collecting AE 
and SAE Information 
Final follow up visit for 
Part B changed to Visit 8. 
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 8.3.9 Medication Error 
New subsections with an 
additional text have been 
created (8.3.9.1 and 
8.3.9.2). 
To introduce revised 
language regarding 
Drug misuse/Drug 
Non-substantial 
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Section Number and Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
abuse from the new 
CSP Template 
Section 8.5.1 Pharmacokinetics 
Text regarding visits at 
which the last dose is taken 
in Part B has been 
changed.  
To reflect changes in 
study design for Part 
B. 
Substantial 
Section 8.5.2. 
Pharmacodynamics 
Text added regarding 
optinional NT-proBNP 
sampling. 
To aid the enrolment 
of potential 
participants. 
Non-substantial 
Section 8.6.1 Collection of 
Blood Samples for MPO 
Quantification 
Text removed (or serum) 
To clarify that the 
measurement of MPO 
is to be performed 
exclusively in plasma.  
Non-substantial 
Section 8.6.2 Collection of 
Mandatory Samples for 
Exploratory Biomarker Analysis 
Heading has been edited 
(added ‘and Metabolite’). 
Text added regarding Part 
B. 
To reflect changes in 
study design for Part 
B. 
Non-substantial 
Section 8.6.3 Collection of 
Mandatory Sample for Genetic 
Analysis 
Text regarding sampling 
for Part B has been added. 
To reflect changes in 
study design for Part 
B. 
Non-substantial 
Section 9 Statistical 
Considerations 
Text regarding statistical 
consideration for Part B 
has been rewritten. 
To reflect changes in 
study design for Part 
B. 
Substantial 
Appendix A1 
Text regarding serious 
Breach has been 
introduced under heading 
‘Regulatory Reporting 
Requirements for Serious 
Breach’. 
To introduce revised 
language from the new 
CSP Template 
Non-substantial 
Appendix A7 
Retention of documents 
changed to ’25 years’. 
To reflect the change 
in regulatory 
requirements 
Non-substantial 
Appendix B4 
Text regarding Drug 
Misuse/Drug Abuse has 
been introduced. 
To introduce revised 
language regarding 
Drug Misuse/Drug 
Abuse from the new 
CSP Template 
Non-substantial 
Appendix O, COVID-19 
Specifics 
Text has been edited. 
Clarification 
To reflect current 
recommendations 
regarding COVID-19. 
Non-substantial 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE...................................... 3 
TABLE OF CONTENTS .......................................................................................................... 9 
1 
PROTOCOL SUMMARY ................................................................................... 14 
1.1 
Synopsis ................................................................................................................ 14 
1.2 
Schema .................................................................................................................. 20 
1.3 
Schedule of Activities ........................................................................................... 23 
2 
INTRODUCTION ................................................................................................ 34 
2.1 
Study Rationale ..................................................................................................... 34 
2.2 
Background ........................................................................................................... 34 
2.3 
Benefit/Risk Assessment ...................................................................................... 36 
2.3.1 
Risk Assessment ................................................................................................... 36 
2.3.2 
Benefit Assessment ............................................................................................... 39 
2.3.3 
Conclusion ............................................................................................................ 39 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 39 
3.1 
Part A .................................................................................................................... 39 
3.2 
Part B .................................................................................................................... 43 
4 
STUDY DESIGN ................................................................................................. 45 
4.1 
Overall Design ...................................................................................................... 45 
4.2 
Scientific Rationale for Study Design .................................................................. 46 
4.3 
Justification for Dose ............................................................................................ 47 
4.4 
End of Study Definition ........................................................................................ 48 
5 
STUDY POPULATION ....................................................................................... 48 
5.1 
Inclusion Criteria .................................................................................................. 49 
5.1.1 
Inclusion Criteria – Part A .................................................................................... 49 
5.1.2 
Inclusion Criteria – Part B .................................................................................... 51 
5.2 
Exclusion Criteria ................................................................................................. 53 
5.2.1 
Exclusion Criteria – Part A ................................................................................... 53 
5.2.2 
Exclusion Criteria - Part B .................................................................................... 55 
5.3 
Lifestyle Considerations ....................................................................................... 57 
5.3.1 
Meals and Dietary Restrictions ............................................................................. 57 
5.4 
Screen Failures ..................................................................................................... 57 
6 
STUDY INTERVENTION .................................................................................. 58 
6.1 
Study Intervention(s) Administered ..................................................................... 58 
6.1.1 
Investigational Products ....................................................................................... 58 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 59 
6.3 
Measures to Minimise Bias: Randomisation and Blinding .................................. 60 


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6.4 
Study Intervention Compliance ............................................................................ 62 
6.5 
Concomitant Therapy ........................................................................................... 62 
6.6 
Dose Modification ................................................................................................ 63 
6.7 
Intervention After the End of the Study ............................................................... 63 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................ 63 
7.1 
Discontinuation of Study Intervention ................................................................. 63 
7.1.1 
Temporary Discontinuation .................................................................................. 64 
7.1.2 
Rechallenge .......................................................................................................... 65 
7.2 
Participant Withdrawal from the Study ................................................................ 65 
7.3 
Lost to Follow up .................................................................................................. 66 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 66 
8.1 
Efficacy Assessments ........................................................................................... 67 
8.1.1 
Patient Reported Outcomes .................................................................................. 67 
8.1.1.1 
Kansas City Cardiomyopathy Questionnaire ....................................................... 69 
8.1.1.2 
Patient Global Impression of Severity in Heart Failure Symptoms ..................... 69 
8.1.1.3 
Patient Global Impression of Severity in Walking Difficulties ............................ 69 
8.1.1.4 
Patient Rating of Dyspnoea, Acute Version ......................................................... 69 
8.1.1.5 
EuroQol Five-dimensional Five-level Questionnaire (Part B only) ..................... 69 
8.1.2 
New York Heart Association Class ...................................................................... 69 
8.1.3 
6 Minute Walk Test .............................................................................................. 69 
8.1.4 
Echocardiogram .................................................................................................... 70 
8.1.4.1 
Echocardiogarm – Part A ..................................................................................... 70 
8.1.4.2 
Echocardiogram – Part B ...................................................................................... 71 
8.1.5 
Assessment of CV Events ..................................................................................... 71 
8.1.6 
Study Participant Feedback Questionnaire (Part A only) ..................................... 71 
8.2 
Safety Assessments ............................................................................................... 72 
8.2.1 
Physical Examinations .......................................................................................... 72 
8.2.2 
Vital Signs ............................................................................................................ 72 
8.2.2.1 
Vital Signs - Part A only ....................................................................................... 72 
8.2.3 
Electrocardiograms ............................................................................................... 74 
8.2.4 
Clinical Safety Laboratory Assessments .............................................................. 74 
8.2.5 
Skin Reactions, Including Maculopapular Rash ................................................... 75 
8.2.6 
Infection ................................................................................................................ 76 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 76 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 77 
8.3.2 
Follow-up of AEs and SAEs ................................................................................ 77 
8.3.3 
Causality Collection ............................................................................................. 78 
8.3.4 
Adverse Events Based on Signs and Symptoms .................................................. 78 
8.3.5 
Adverse Events Based on Examinations and Tests .............................................. 78 
8.3.6 
Hy’s Law .............................................................................................................. 79 
8.3.7 
Reporting of Serious Adverse Events ................................................................... 79 
8.3.8 
Pregnancy ............................................................................................................. 80 
8.3.8.1 
Maternal Exposure ................................................................................................ 80 


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8.3.8.2 
Paternal Exposure ................................................................................................. 81 
8.3.9 
Medication Error ................................................................................................... 81 
8.3.9.1 
Drug Abuse ........................................................................................................... 81 
8.3.9.2 
Drug Misuse ......................................................................................................... 81 
8.4 
Overdose ............................................................................................................... 82 
8.5 
Human Biological Samples .................................................................................. 82 
8.5.1 
Pharmacokinetics .................................................................................................. 82 
8.5.1.1 
Determination of Drug Concentration .................................................................. 83 
8.5.2 
Pharmacodynamics ............................................................................................... 83 
8.5.2.1 
Collection of Samples ........................................................................................... 83 
8.6 
Human Biological Sample Biomarkers ................................................................ 84 
8.6.1 
Collection of Blood Samples for MPO Quantification ........................................ 84 
8.6.2 
Collection of Mandatory Samples for Exploratory Biomarker and Metabolite 
Analysis ................................................................................................................ 84 
8.6.3 
Collection of Mandatory Sample for Genetic Analysis ........................................ 85 
8.6.4 
Collection of Mandatory Samples for Potential Diagnostic Assay Development 85 
8.6.5 
Collection of Optional Samples for Future Biomarker Research ......................... 86 
8.7 
Optional Genomics Initiative Sample ................................................................... 86 
8.8 
Medical Resource Utilisation and Health Economics .......................................... 86 
9 
STATISTICAL CONSIDERATIONS ................................................................. 87 
9.1 
Statistical Hypotheses ........................................................................................... 87 
9.2 
Sample Size Determination .................................................................................. 87 
9.3 
Populations for Analyses ...................................................................................... 89 
9.4 
Statistical Analyses ............................................................................................... 90 
9.4.1 
General Considerations ......................................................................................... 90 
9.4.2 
Efficacy ................................................................................................................. 90 
9.4.2.1 
Primary Endpoint(s) ............................................................................................. 90 
9.4.2.2 
Secondary Endpoint(s) ......................................................................................... 93 
9.4.2.3 
Tertiary/Exploratory Endpoint(s) ......................................................................... 93 
9.4.3 
Safety .................................................................................................................... 93 
9.4.4 
Other Analyses ..................................................................................................... 96 
9.5 
Interim Analyses ................................................................................................... 96 
9.6 
Data Monitoring Committee ................................................................................. 96 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 96 
11 
REFERENCES ................................................................................................... 168 
 
 
LIST OF FIGURES 
Figure 1 
Study Design – Part A ................................................................................. 20 


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Figure 2 
Study Design – Part B ................................................................................. 21 
 
LIST OF TABLES 
Table 1 
Schedule of Activities – Part A ................................................................... 23 
Table 2 
Schedule of Activities – Part B ................................................................... 29 
Table 3 
Risk Assessment .......................................................................................... 36 
Table 4 
Objectives and Endpoints – Part A ............................................................. 40 
Table 5 
Objectives and Endpoints – Part B .............................................................. 43 
Table 6 
Investigational Products .............................................................................. 58 
Table 7 
Orthostatic Blood Pressure Criteria and Management ................................ 73 
Table 8 
Laboratory Safety Variables ....................................................................... 74 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 97 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................... 103 
Appendix C 
Handling of Human Biological Samples ................................................... 113 
Appendix D 
Optional Genomics Initiative Sample ....................................................... 115 
Appendix E 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 118 
Appendix F 
 ............ 123 
Appendix G 
Typical Symptoms and Signs of Heart Failure ......................................... 124 
Appendix H 
Kansas City Cardiomyopathy Questionnaire ............................................ 125 
Appendix I 
 .......... 129 
Appendix J 
 ................ 130 
Appendix K 
 ................................ 131 
Appendix L 
 ............................................ 132 
Appendix M 
Clinical Data Interchange Standards Consortium Definition for 
Hospitalisation for Heart Failure and Urgent Heart Failure Visit ............. 135 
Appendix N 
Study Participant Feedback Questionnaire ............................................... 137 
Appendix O 
COVID-19 Specifics ................................................................................. 144 
Appendix P 
Abbreviations ............................................................................................ 147 
Appendix Q 
Protocol Amendment History ................................................................... 150 
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Number of Participants:
 
Part A 
Part B 
Enrolled 
Estimated 1100 participants 
Estimated 1350 participants 
Randomised 
Estimated 660 participants 
Estimated 820 participants 
Participants with complete 
safety data 
Estimated 600 participants 
Estimated 745 participants 
 
Note: “Enrolled” means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are enrolled for the purpose of determining eligibility for the study, 
but are not randomised in the study, are considered “screen failures”, unless otherwise 
specified by the protocol.  
The study will be conducted in approximately 180 sites and approximately 15 countries. 
Intervention Groups and Duration: 
In Part A, participants will undergo a screening period of up to 4 weeks, followed by 
randomisation across 3 different treatment arms. Eligible participants will be randomised at a 
1:1:1 ratio and dosed orally once daily. The planned treatment arms are AZD4831 2.5 mg, 
AZD4831 5 mg, and placebo. Participants will receive either AZD4831 or placebo for 16 
weeks and then continue into a safety extension, during which they will receive an additional 
32 weeks of the intervention (AZD4831 or placebo, as per their assigned arm during 
randomisation). A final follow-up visit (end of study visit) will occur at 52 weeks from 
randomisation. In the event that randomisation to the AZD4831 5 mg treatment arm is stopped 
during the study in either the whole study or in a country or specific ethnic population due to 
safety, the remaining participants in that cohort would be randomised at a 2:1 ratio to 
AZD4831 2.5 mg or matching placebo. 
In Part B, participants will undergo a screening period of up to 2 weeks, followed by 
randomisation across 2 treatment arms. Eligible participants will be randomised at a 1:1 
(AZD4831:placebo) ratio and dosed orally once daily. The planned treatment groups are 
AZD4831 at the dose selected based on Part A, and placebo. Participants will be treated for 
24, 36 or 48 weeks, depending on when in time they were enrolled. The date of the last 
participant randomised in the study will determine the treatment period for patients who are 
still in the study. When the last patient is randomised, the end of the 24 week treatment period 
will be known; therefore the end of treatment date for all other ongoing participants will be 
scheduled in advance to occur  at 24, 36 or 48 weeks. Consequently, earlier enrolment will 
allow a longer treatment period, whereas later enrolment will restrict the treatment period to 
24 weeks. Participants will be treated for a minimum of 24 weeks to allow sufficient time for 


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efficacy evaluation, and a maximum of 48 weeks to assess longer-term safety and effect of the 
IP. A final end of study visit will occur 4 weeks after the final dose.  
Participants can be randomised only once in the study; therefore, participants who were 
randomised into Part A cannot be included in Part B. 
Data Monitoring Committee: Yes 
Data Review Committee: For Part A, an unblinded DRC consisting of AZ personnel, an 
external dermatologist, and an external cardiologist will be set up for ongoing, periodic safety 
monitoring, with a focus on skin reactions. Additional details will be contained in the DRC 
charter. 
Unblinded Review Committee: A URC consisting of a limited number of AZ personnel will 
be formed to review data from Part A from at least one, but possibly several, interim analyses, 
with the purpose of informing further development of the clinical programme, including but 
not limited to dose selection for Part B. The URC will review the risk/benefit profile and make 
recommendations on the dose for Part B and, based on safety, on the continuation of the 
program. When all participants in Part A have completed Week 52,the Part A data will be 
analysed as final interim analysis. 
External Data Monitoring Committee:  For Part B, an independent DMC, including a 
dermatologist, will be responsible for monitoring the safety of the study participants and 
making appropriate recommendations based on the available data. The DMC will have access 
to the unblinded data. The committee will operate in accordance with a DMC Charter. 
Statistical Methods 
The primary and key secondary endpoints (variables will be change from baseline) will be 
analysed using ANCOVA for Part A and Part B. The analyses will use baseline as covariate 
(for the relevant endpoint) and will be adjusted for the stratification factor for neutrophil count 
for Part A and Part B. In Part B, a treatment-by-baseline interaction term will be included as 
an independent variable in the model for KCCQ-TSS.  
Sample size estimation for Part A: 
Approximately 660 participants randomised, of which we estimate approximately 600 will 
have complete safety data, and 1:1:1 allocation is chosen to have enough participants exposed 
to AZD4831 at the therapeutic dose to fulfil the minimum requirement in the ICH E1 
guideline on population exposure, taken together with Part B of this study, as well as a second 
function and symptom study with a similar design as Part B, and Phase 1 studies completed 
ahead of submission. 
With 85% power at a significance level of α = 0.05, 200 participants per arm 
(220 randomised) will allow detection of a difference of 6.0 points in mean change from 


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baseline between active and placebo in KCCQ-TSS comparing each active arm with placebo. 
The critical value for statistical significance is 3.9 points. The corresponding number for 
6MWD is 21 meters and 14 meters. Calculations of detectable differences and critical values 
are based on ANCOVA, which will also be used for the analysis.  
Sample size estimation for Part B: 
Approximately 820 participants will be randomised in 1:1 allocation, of which we estimate 
approximately 745 will have complete safety data. The sample size is chosen to have enough 
participants exposed to AZD4831 at the therapeutic dose to fulfil the minimum requirement in 
the ICH E1 guideline on population exposure, taken together with Part A of this study as well 
as a second function and symptom study with a similar design as Part B, and Phase 1 studies 
completed ahead of submission.  
The power to assess the two primary efficacy objectives will, given the assumed effect, 
exceed 90% at an alpha of 0.025. 






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g 
V7 will occur only for participants treated for 48 weeks. 
h 
Measurement not needed to be performed if historical Echo (<12m) is available. 
 
6MWT, 6-minute walk test; EDV, early discontinuation visit; Echo, echocardiogram; EoS, End of Study; HF, heart failure; hsCRP, high-sensitivity C-reactive 
protein; IL-6, interleukin 6; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; NA, Not applicable; NT-proBNP, 
N-terminal natriuretic peptide;
, R, randomisation; S, screening; V, visit; w, week.  
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1.3 
Schedule of Activities 
Table 1 
Schedule of Activities – Part A 
Procedure 
Screening 
16-week treatment 
32-week extension 
Follow 
up 
Details in 
CSP Section 
or Appendix 
Visit 
1 
2a 
3b 
4 
5a 
6 
7a 
8 
9 
10 
11/EDV 
12 
 
Weeks from randomisation 
Up to -4  
-1 
0 
4 
8 
12 
15 
16 
24 
36 
48 
52 
 
Study Day 
Up to -28 
-7 
1 
29 
57 
85 
106 
113 
169 
253 
336 
365 
 
Visit Window 
 
± 2 
days 
 
± 3 
days 
± 5 
days 
± 3 
days 
± 2 
days 
± 3 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Informed consent for Genetic 
sampling (optional), future 
use blood and urine samples 
(optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Inclusion and exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
Sections 5.1 
and 5.2 
Medical history of alcohol, 
drugs of abuse, and nicotine 
use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication  
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Section 6.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KCCQ c 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
Section 
8.1.1.1 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1 
Schedule of Activities – Part A 
Procedure 
Screening 
16-week treatment 
32-week extension 
Follow 
up 
Details in 
CSP Section 
or Appendix 
Visit 
1 
2a 
3b 
4 
5a 
6 
7a 
8 
9 
10 
11/EDV 
12 
 
Weeks from randomisation 
Up to -4  
-1 
0 
4 
8 
12 
15 
16 
24 
36 
48 
52 
 
Study Day 
Up to -28 
-7 
1 
29 
57 
85 
106 
113 
169 
253 
336 
365 
 
Visit Window 
 
± 2 
days 
 
± 3 
days 
± 5 
days 
± 3 
days 
± 2 
days 
± 3 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Section 
8.2.1 
Skin examination 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
Section 
8.2.1 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.1 
Weight 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
Section 
8.2.1 
Vital signs d 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Section 
8.2.2 
Orthostatic Test e 
 
 
X 
 
 
X 
 
 
 
 
 
 
Section 
8.2.2 
12-lead ECG 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
Section 
8.2.3 
6MWT f 
Section 
8.1.3 
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Table 1 
Schedule of Activities – Part A 
Procedure 
Screening 
16-week treatment 
32-week extension 
Follow 
up 
Details in 
CSP Section 
or Appendix 
Visit 
1 
2a 
3b 
4 
5a 
6 
7a 
8 
9 
10 
11/EDV 
12 
 
Weeks from randomisation 
Up to -4  
-1 
0 
4 
8 
12 
15 
16 
24 
36 
48 
52 
 
Study Day 
Up to -28 
-7 
1 
29 
57 
85 
106 
113 
169 
253 
336 
365 
 
Visit Window 
 
± 2 
days 
 
± 3 
days 
± 5 
days 
± 3 
days 
± 2 
days 
± 3 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
 
Urinalysis 
X 
 
X 
 
 
 
 
X 
X 
 
X 
X 
Sections 
8.2.4 and 
8.6.2 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.4 
Clinical safety laboratory 
assessments  
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Section 
8.2.4 
ANCA testing 
 
 
X 
 
 
 
 
 
 
 
X 
 
Section 
8.2.4 
NT-proBNP 
Section 
8.5.2.1 
PK blood sampling for 
AZD4831 g 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Section 
8.5.1 
hsCRP and IL-6  
Section 
8.5.2.1 
Blood sample for MPO 
Quantification 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
Section 
8.6.1 
Blood sample for genetic 
analysis 
 
 
X 
 
 
 
 
 
 
 
 
 
Section 
8.6.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1 
Schedule of Activities – Part A 
Procedure 
Screening 
16-week treatment 
32-week extension 
Follow 
up 
Details in 
CSP Section 
or Appendix 
Visit 
1 
2a 
3b 
4 
5a 
6 
7a 
8 
9 
10 
11/EDV 
12 
 
Weeks from randomisation 
Up to -4  
-1 
0 
4 
8 
12 
15 
16 
24 
36 
48 
52 
 
Study Day 
Up to -28 
-7 
1 
29 
57 
85 
106 
113 
169 
253 
336 
365 
 
Visit Window 
 
± 2 
days 
 
± 3 
days 
± 5 
days 
± 3 
days 
± 2 
days 
± 3 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for potential 
diagnostic assay development 
X 
 
X 
 
 
 
 
 
 
 
 
 
Section 
8.6.4 
Echocardiography  k 
X  
 
 
 
 
 
 
X 
X 
 
 
 
Section 
8.1.4 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
Section 6.3 
Optional genomics initiative 
exploratory genetic sample 
 
 
X 
 
 
 
 
 
 
 
 
 
Section 8.7 
and 
Appendix D 
Optional future use blood and 
urine samples 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Section 
8.6.5 
Study intervention dispensed 
(daily dosing l) 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Section 6.2 
Study intervention return and 
accountability check 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Sections 6.2 
and 6.4 
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Table 1 
Schedule of Activities – Part A 
Procedure 
Screening 
16-week treatment 
32-week extension 
Follow 
up 
Details in 
CSP Section 
or Appendix 
Visit 
1 
2a 
3b 
4 
5a 
6 
7a 
8 
9 
10 
11/EDV 
12 
 
Weeks from randomisation 
Up to -4  
-1 
0 
4 
8 
12 
15 
16 
24 
36 
48 
52 
 
Study Day 
Up to -28 
-7 
1 
29 
57 
85 
106 
113 
169 
253 
336 
365 
 
Visit Window 
 
± 2 
days 
 
± 3 
days 
± 5 
days 
± 3 
days 
± 2 
days 
± 3 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
 
Assessment of AEs and SAEs 
m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.3 
Assessment of CV events 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Section 
8.1.5 
Optional Study participant 
feedback questionnaire 
 
 
 
X 
 
 
 
 
X 
 
 
X 
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a 
Remote completion of KCCQ at Visit 2 and Visit 7 by participant (and telephone contact by the site to remind the participant of the first completion) 
and telephone contact by site with participant at Visit 5. 
b 
Assessments and blood draws taken pre-dose at Visit 3.  
c 
To avoid bias in participant responses, KCCQ will be completed prior to any other study procedures, following informed consent. KCCQ will also be 
completed by the participant at home on a provisioned tablet during 3 consecutive days on Week -1 and Week 15.  
d 
Vital Signs: supine BP (average of 3 measurements), pulse rate, and body temperature will be measured. 
e 
Orthostatic BP will be measured at baseline visit and at Visit 6 (Week 12) prior to any required blood draw and study intervention. Orthostatic BP will 
be measured 1 and 3 minutes after the participant stands.  
f 
The 6MWT consists of a suite of assessments that are carried out before and after the 6MWT itself: 
 
  
g 
One PK sample will be collected pre-dose from all participants. In a subset of participants (approximately 20%), 3 additional post-dose samples will be 
collected at Visit 6. Visit 6 sample collection times are: pre-dose, and 0.5 to 1.5 h, 1.5 to 3 h and > 3 h post-dose, with a minimum of 1 hour between 
the post-dose sampling occasions. Once approximately 20% of participants have been tested, no further participants would need this additional post 
dose sampling. For participants who are discontinued from investigational product due to rash, a PK sample should be collected at the discontinuation 
visit. 
h 
 
 
i 
 
j 
Only for participants who discontinue investigational product due to rash or skin reaction: blood and urine sample for exploratory metabolite analysis 
should also be collected at the EDV. 
k 
Screening echocardiogram can be performed on a different day if it is not possible to be done on the screening visit day due to scheduling purposes but 
must be as soon after the screening visit as possible ie, within 1-2 days in order to allow for results to be back prior to randomisation. For the 
echocardiogram at Visit 8 and Visit 9, if due to scheduling purposes the echocardiogram cannot be performed on the same day as the clinic visit, the 
echocardiogram should be performed at the earliest opportunity and within 7 days of the scheduled visit. 
l 
The first dose of study intervention will be administered in clinic on the day of randomisation after completing all pre-dose procedures. Participants 
will receive study intervention at the site on visit days and at home between visits for a total of 48 weeks. 
m 
AEs will be collected from the first dose (the only exception is related to the pre-dose orthostatic test at Visit 3: if orthostatic hypotension is confirmed, 
it should be reported as an AE, and symptoms related to the measurement of orthostatic vitals if present should also be reported as an AE). SAEs will 
be collected from signing of the ICF. 
6MWT, 6-minute walk test; AEs, adverse events; ANCA, anti-neutrophil cytoplasmic antibodies; BP, blood pressure; CSP, clinical study protocol; ECG, 
electrocardiogram; EDV, early discontinuation visit; EoS, End of Study; FSH, follicle stimulating hormone; HF, heart failure; hsCRP, high-sensitivity C-
reactive protein; ICF, informed consent form; IL-6, interleukin 6; KCCQ, Kansas City Cardiomyopathy Questionnaire; MPO, myeloperoxidase; 
NT-proBNP, N-terminal pro-brain natriuretic peptide; 
 
PK, pharmacokinetics; 
; SAE, serious adverse event; UACR, urinary albumin-to-creatinine ratio; 
. 
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Table 2 
Schedule of Activities – Part B 
Procedure 
S 
R 
Variable Treatment Period; 24, 36 or 48 weeksa, 
b 
EDVc 
EoS visitb, d 
Details in CSP 
Section or 
Appendix 
Visit 
1 
2 
3 
4 
5 
6e  
7f 
NA 
8 
 
Weeks from randomisation 
-2 to 0 
0 
4 
16 
24 
36 
48 
Variable 
28/40/52 
 
Study Day 
-14 to 0 
1 
29 
113 
169 
253 
337 
Variable 
197/281/365 
 
Visit window 
 
Within 14 days 
from enrolment ± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
 
± 7 days 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
Section 5.1 
Enrolment in IRT/RTSM 
X 
 
 
 
 
 
 
 
 
Section 6.3 
Randomisation 
 
X 
 
 
 
 
 
 
 
Section 6.3 
Informed consent for genetic 
sampling (optional) and future 
use blood and urine samples 
(optional) 
X 
 
 
 
 
 
 
 
 
Section 5.1 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Sections 5.1 and 
5.2 
Medical history of alcohol, 
drugs of abuse and nicotine 
use 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical & surgical history  
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.5 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2 
Schedule of Activities – Part B 
Procedure 
S 
R 
Variable Treatment Period; 24, 36 or 48 weeksa, 
b 
EDVc 
EoS visitb, d 
Details in CSP 
Section or 
Appendix 
Visit 
1 
2 
3 
4 
5 
6e  
7f 
NA 
8 
 
Weeks from randomisation 
-2 to 0 
0 
4 
16 
24 
36 
48 
Variable 
28/40/52 
 
Study Day 
-14 to 0 
1 
29 
113 
169 
253 
337 
Variable 
197/281/365 
 
Visit window 
 
Within 14 days 
from enrolment ± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
 
± 7 days 
 
KCCQ g 
X 
X 
 
X 
X 
X 
X 
X 
 
Section 8.1.1.1 
PGIS-HF 
X 
X 
 
X 
X 
X 
X 
X 
 
Section 8.1.1.2 
PGIS-WD 
X 
X 
 
X 
X 
X 
X 
X 
 
Section 8.1.1.3 
 
 
 
 
 
 
 
 
 
 
 
Physical examination h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.1 
Height 
X 
 
 
 
 
 
 
 
 
Section 8.2.1 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.1 
Vital signs i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.2 
12-lead ECG 
X 
X 
X 
 
X 
  
X 
X 
X 
Section 8.2.3 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
Section 8.2.4 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
Section 8.2.4 
Clinical safety laboratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.4 
ANCA testing 
 
X 
 
 
 
 
 
 
 
Section 8.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2 
Schedule of Activities – Part B 
Procedure 
S 
R 
Variable Treatment Period; 24, 36 or 48 weeksa, 
b 
EDVc 
EoS visitb, d 
Details in CSP 
Section or 
Appendix 
Visit 
1 
2 
3 
4 
5 
6e  
7f 
NA 
8 
 
Weeks from randomisation 
-2 to 0 
0 
4 
16 
24 
36 
48 
Variable 
28/40/52 
 
Study Day 
-14 to 0 
1 
29 
113 
169 
253 
337 
Variable 
197/281/365 
 
Visit window 
 
Within 14 days 
from enrolment ± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
 
± 7 days 
 
NT-proBNP j 
X 
X 
 
X 
X 
X 
X 
X 
 
Section 8.5.2.1 
Blood sample for genetic 
analysis 
 
X 
 
 
 
 
 
 
 
Section 8.6.3 
hsCRP and IL-6 
 
X 
 
X 
X 
X 
X 
X 
 
Section 8.5.2.1 
 
 
 
 
 
 
 
 
 
 
 
 
6MWTk 
X 
X 
 
X 
X 
X 
X 
X 
 
Section 8.1.3 
Echocardiogram l 
X 
 
 
 
 
 
 
 
 
Section 8.1.4 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for potential 
diagnostic assay development 
X 
X 
 
 
 
 
 
 
 
Section 8.6.4 
Optional future use blood and 
urine sampling 
 
X 
 
 
X 
 
 
 
 
Section 8.6.5 
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Table 2 
Schedule of Activities – Part B 
Procedure 
S 
R 
Variable Treatment Period; 24, 36 or 48 weeksa, 
b 
EDVc 
EoS visitb, d 
Details in CSP 
Section or 
Appendix 
Visit 
1 
2 
3 
4 
5 
6e  
7f 
NA 
8 
 
Weeks from randomisation 
-2 to 0 
0 
4 
16 
24 
36 
48 
Variable 
28/40/52 
 
Study Day 
-14 to 0 
1 
29 
113 
169 
253 
337 
Variable 
197/281/365 
 
Visit window 
 
Within 14 days 
from enrolment ± 7 days 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
 
± 7 days 
 
Optional genomics initiative, 
exploratory genetic sample 
 
X 
 
 
 
 
 
 
 
Section 8.7 and 
Appendix D 
Study intervention dispensed 
(daily dosing n) 
 
X 
X 
X 
X 
X 
 
 
 
Section 6.2 
Study intervention return and 
accountability check 
 
 
X 
X 
X 
X 
X 
X 
 
Sections 6.2 and 
6.4 
Assessment of AEs and SAEs 
o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.3 
Assessment of CV events  
 
 
X 
X 
X 
X 
X 
X 
X 
Section 8.1.5 
 
a 
Participants will be treated for 24, 36 or 48 weeks, depending on when in time they were randomised in the study. 
b 
If study intervention is permanently discontinued, the participant should remain in the study, ie, continue to participate in scheduled study visits and 
evaluations.  
c 
EDV will occur only for patients who are permanently discontinued from study intervention. 
d 
EoS visit will take place 4 weeks after final dose, which may occur after 24, 36 or 48 weeks of treatment. For participants who are discontinued from the 
study intervention, and later decide to withdraw from the study before scheduled EoS visit, the EoS visit should be performed at the time of withdrawal.  
e 
V6 will occur only for participants treated for at least 36 weeks. 
f 
V7 will occur only for participants treated for 48 weeks. 
g 
To avoid bias in participant responses, KCCQ will be completed prior to any other study procedures, following informed consent. 
h 
At Visits 1 and EoS/EDV, a full physical examination is performed. 


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i 
Vital Signs: supine BP (average of 3 measurements), pulse rate, and body temperature will be measured. 
j 
An additional, local NT-proBNP test can be performed as pre-screening at the site. Participants must sign the specific Pre-Screening Informed Consent 
before collection of a blood sample for this procedure. This test can be done within 30 days preceding the Screening (Visit 1), and latest on the day of 
the Screening (Visit 1). The central lab result will be used to determine if the participant is eligible for the study. 
k 
 
 
l 
Screening echocardiogram can be performed on a different day if it is not possible to be done on the screening visit day due to scheduling purposes but 
must be performed as soon after the screening visit as possible in order to allow for results to be available prior to randomisation. Screening 
echocardiogram is not needed if there is an available echocardiogram performed up to 12 months before screening. 
m 
To be sampled at Visit 2 and either Visit 5, Visit 6 or Visit 7, for participants treated for either 24, 36 or 48 weeks, resepectively. 
n 
The first dose of study intervention will be administered in clinic on the day of randomisation after completing all pre-dose procedures. Participants will 
receive study intervention at the site on visit days and at home between visits for a total of 24, 36 or 48 weeks 
o 
AEs will be collected from the first dose. SAEs will be collected from signing of the ICF 
 
6MWT, 6-minute walk test; AEs, adverse events; ANCA, anti-neutrophil cytoplasmic antibodies; BP, blood pressure; CSP, clinical study protocol; ECG, 
electrocardiogram; EDV, early discontinuation visit; EoS, End of Study; FSH, follicle stimulating hormone; HF, heart failure; hsCRP, high-sensitivity C-
reactive protein; ICF, informed consent form; IL-6, interleukin 6; KCCQ, Kansas City Cardiomyopathy Questionnaire; MPO, myeloperoxidase; 
NT-proBNP, N-terminal pro-brain natriuretic peptide; 
; 
; 
PK, pharmacokinetics; 
; R, randomisation; S, screening; SAE, serious adverse event; UACR, urinary albumin-to-creatinine 
ratio; 
. 
 
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2 
INTRODUCTION 
AZD4831 is a highly potent MPOi that is being developed for the management of 
cardiovascular disease, engaging both macro- and microvascular structure and function. 
2.1 
Study Rationale 
This study aims to evaluate the effect of AZD4831 on functional improvement and reduction 
of symptoms in participants with heart failure with left ventricular ejection fraction > 40%. 
Additionally, the PK and overall safety profile of AZD4831 will be evaluated. 
2.2 
Background 
Chronic HF continues to be a major cause of mortality, hospitalisations, and suboptimal 
quality of life. Even with the best possible treatment, the 5-year survival rate for HF patients is 
worse than for most cancers (Braunwald 2015). Heart failure affects 2% of the Western 
population, increases to 10% over the age of 65 years, and up to 20% over the age of 75 years 
(Go et al 2014). The proportion of the Western population over the age of 65 years is expected 
to increase to over 30% by year 2050 and the costs of HF to society are expected to triple 
between years 2010 and 2030. Heart failure is currently broadly divided into three categories 
based on the systolic function of the left ventricle: (1) HFrEF (LVEF < 40%), (2) HFmrEF 
(LVEF 40-49%), and (3) HFpEF (LVEF ≥ 50%). Together, HFmrEF and HFpEF account for 
55% of HF cases; HFpEF and HFrEF are distinct clinical phenotypes with differing 
underlying pathophysiology, while HFmrEF appears to share some features of both HFrEF 
and HFpEF whilst remaining a possible independent category. Over recent years, there has 
been a drive to include HFmrEF patients into future HF studies in order to learn more about 
this category while evaluating new therapies for the treatment of either HFpEF or HFrEF. To 
further increase knowledge about this condition, patients with HFmrEF will be included in the 
current study.  
Heart failure with preserved ejection fraction is overrepresented in elderly and in women. 
Mortality in the community approaches 25% at one year. In a comparison of trial populations, 
the prognosis in HFpEF is 50-75 deaths and 40-75 HF hospitalisations per 1000 patient-years, 
whereas in stable coronary disease it is 10-30 deaths and 5-10 hospitalisations per 1000 
patient-years and has improved further with modern therapy. Thus, novel interventions for 
coronary artery disease have little potential, whereas for HFpEF, novel treatment is both a 
critical unmet need and of great public health impact, if successful (Butler et al 2014, 
McMurray et al 2012).  
A novel paradigm for HFpEF pathophysiology states that co-morbidities (renal disease, 
hypertension, obesity, and diabetes) lead to a global inflammatory state, leading to immune 
cell recruitment and endothelial and coronary microvascular dysfunction, with distinct 


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pathophysiology different from macrovascular coronary disease (Paulus and Tschope 2013). 
This, in turn, can lead to both extracellular fibrosis and myocardial stiffness and reduced 
myocardial nitric oxide bioavailability and cyclic guanosine monophosphate content and 
impaired myocyte relaxation. Numerous clinical data support this hypothesis.  
Coronary endothelial dysfunction is associated with diastolic dysfunction and with worse 
outcomes in HFpEF. Exercise studies implicate vascular stiffness and impaired exercise 
vasodilation and suggest that impaired diastolic reserve may be related to endothelial and 
microvascular dysfunction. Angina and false positive stress tests are common in HFpEF. 
Further, recent autopsy studies have provided convincing evidence of coronary microvascular 
rarefaction in HFpEF (Mohammed et al 2015). Using transthoracic Doppler echocardiography 
- coronary flow velocity reserve approach, Shah et al (2018) was the first to provide robust 
evidence that coronary microvascular dysfunction is highly prevalent in HFpEF, as diagnosed 
according to guidelines.   
Myeloperoxidase is a highly abundant protein mainly present in azurophilic granules of 
neutrophils, constituting 5% of the dry weight of the cells. In addition to neutrophils, there are 
also data suggesting the presence of MPO in monocytes and macrophages. MPO can be 
secreted, and is unique in its ability to generate reactive chlorinating species such as 
hypochlorous acid, the active component of bleach, which possesses potent bactericidal and 
viricidal activities. In addition, hypochlorous acid reacts with electron-rich moieties of a large 
range of biomolecules (Nicholls and Hazen 2005).  
Multiple lines of evidence suggest that MPO may play a role in atherogenesis in humans 
(Baldus et al 2003, Brennan et al 2003, Zhang et al 2001) and MPO plasma levels predict 
outcome of cardiovascular disease. In chronic HF, plasma levels of MPO are elevated and also 
associated with more advanced HF (Tang et al 2006). Additionally, elevated plasma MPO 
levels can predict increased adverse clinical outcomes in HF patients (Tang et al 
2007). Individuals with inherited low MPO activity were protected from leukocyte activation 
induced deterioration of vascular function (Rudolph et al 2012). Direct MPO administration in 
anaesthetised pigs increased the tone of conductance and resistance vessels and adversely 
affected myocardial blood flow, thereby strengthening the concept that MPO indeed acts as a 
modulator of vascular tone in vivo and identifying MPO as a systemic regulator of 
vasomotion in humans and thus a potential therapeutic target (Rudolph et al 2012). MPO is 
also involved in structural remodelling of the myocardium, leading to an increased 
vulnerability to atrial fibrillation (Rudolph et al 2010).  
Overall, recent evidence suggests that MPO may provide a mechanistic link between 
inflammation, oxidative stress, vascular dysfunction and impaired cardiac remodelling. It is 
thus hypothesised that the MPO inhibitor AZD4831 will improve coronary microvascular 


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status as well as systemic endothelial function, leading to improved diastolic function and 
overall status of HFpEF patients.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD4831 is 
provided in the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
Potential risks of AZD4831 and mitigation strategy are shown in Table 3. More detailed 
information about the known and expected benefits and potential risks of AZD4831 may be 
found in the Investigator’s Brochure. 
2.3.1 
Risk Assessment 
All study activities are considered routine clinical practice and judged not to expose 
participants to any additional risks. 
Table 3 
Risk Assessment 
Identified risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
AZD4831 
Maculopapular rash  
 
 
 
Generalized maculopapular rash has been observed in 
healthy volunteers in completed global SAD/MAD 
studies at single doses of 45 mg and above and at 
repeated doses of 15 mg and above, at 7-10 days post 
dose. In the Phase IIa study in participants with HFpEF, 
1 of 27 participants had generalized maculopapular rash 
CTCAE Grade 3 at AZD4831 5 mg occurring 5 days 
after up-titration from 2.5 to 5 mg. In a single-blind 
multiple-ascending dose study in healthy Japanese and 
Chinese participants, maculopapular rash CTCAE 
Grade 1 was reported in 1 of 6 Japanese participants on 
AZD4831 5 mg, and maculopapular rash Grade 2 was 
reported in 1 of 6 Chinese participants on AZD4831 5 
mg and in 3 of 6 Japanese participants on AZD4831 10 
mg. See IB Section 6.3 for further information. 
Exclusion criteria 5. 
Specific discontinuation 
criteria. AEoSI with 
special data 
collection/eCRF. DRC 
oversight in Part A and 
DMC in Part B, both 
including dermatologist 
representation. Protocol 
measures for Part A to 
stop randomisation to the 
AZD4831 5 mg treatment 
arm or in specific 
countries or ethnic 
populations in response 
to emerging safety 
information. Dose 
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Table 3 
Risk Assessment 
Identified risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
AZD4831 
Host-defence 
impairment 
(infections, including 
pneumonia) 
The MPO in neutrophils generate ROS to fight infecting 
microorganisms; therefore, there is a theoretical risk 
that treatment with an MPO inhibitor could impair host-
defence mechanisms. Humans with total or partial MPO 
deficiency generally do not have an increased 
susceptibility to infections but the incidence of Candida 
infections may be increased. An increased incidence of 
infection has not been seen in participants in clinical 
studies with AZD4831. See IB Section 6.2 for further 
information. 
AEoSI. AE monitoring 
for infections and 
relevant labs (CBC, 
hsCRP). 
 
 
 
 
 
In the nonclinical safety studies in rats and dogs, 
inhibition of 
 caused reversible 
 
 
. These effects have also been observed in 
nonclinical and clinical studies with other compounds 
of the same class and the magnitude of this effect is 
related to the degree of selectivity 
 
. Clinically relevant changes in 
 
 have not been seen in limited clinical 
data with AZD4831. See IB Section 6.2 for further 
information. 
Monitoring 
 
 
 
. 
Specific discontinuation 
criteria. 
 
 
There is a 
 
 in the AZD4831 
molecule, since it is known that 
 
. In completed 
nonclinical studies 
 
 
 has not been seen in 
participants in clinical studies with AZD4831. See IB 
Section 6.2 for further information. 
Monitoring WBC 
differential 
 
reduction and 
 
 increase 
In secondary pharmacology studies, AZD4831 was 
shown to be an inhibitor of 
. 
Inhibition of this receptor is known to decrease 
 
. Clinically relevant changes in 
 have not been seen in participants in clinical 
studies with AZD4831. See IB Section 6.2 for further 
information. 
Monitoring 
 
 
 
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Table 3 
Risk Assessment 
Identified risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
AZD4831 
Anaemia and 
inflammation 
One high-dose 
 dog developed severe 
clinical symptoms on 
 of dosing and did not 
recover sufficiently to allow further dosing. The dog 
was euthanised on 
 showed 
ation. The cause of these findings 
is unknown. No other dogs in any studies with 
AZD4831 showed similar symptoms or 
 
. Clinically relevant 
 
have not been seen in participants in clinical studies 
with AZD4831. See IB Section 6.2 for further 
information. 
Routine 
 
monitoring. 
 
 has been shown in transgenic 
 
mice in the 
 dose range finding study. 
 findings included increased 
 
. Pathology showed 
, increased 
 showed 
 
 
 
No 
 were observed at 
 
 
Clinically relevant changes in kidney function have not 
been seen in participants in clinical studies with 
AZD4831. See IB Section 6.2 for further information. 
Exclusion criterion of 
eGFR < 
30mL/min/1.73m2 (See 
exclusion criterion 1). 
Routine monitoring of 
renal function 
(creatinine) 
Other 
COVID-19 pandemic 
risks 
While there is a theoretical risk that treatment with an 
MPO inhibitor could impair host-defence mechanisms, 
an increased incidence of infection with SARS-CoV-2 
has not been seen in limited clinical data with 
AZD4831; therefore, the risk to participants exposed to 
SARS-CoV-2 or to those who suffer from COVID-19 is 
expected to be similar to the background population 
with the same co-morbidities as those in the study, in 
particular HF. The risk of exposure to infected people 
cannot be completely excluded as the participants may 
need to expose themselves to public areas (eg, commute 
to the site) and have additional human contact (eg, with 
site staff and other participants of the clinical study). 
Participants with signs or 
confirmation of infection 
may be excluded from 
the study (See exclusion 
criterion 23). Further risk 
mitigation measures are 
detailed in Appendix O 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Table 3 
Risk Assessment 
Identified risk of 
clinical significance 
Summary of data/rationale for risk  
Mitigation strategy 
 
AEoSI, adverse event of special interest; BP, blood pressure; CBC complete blood count; COVID-19, 
coronavirus disease 2019; CTCAE, Common Terminology Criteria for Adverse Events; DMC, Data 
Monitoring Committee; DRC, Data Review Committee; eCRF, electronic case report form; HF, heart failure; 
; HR, heart rate; hsCRP, high-sensitivity C-reactive 
protein; IB, Investigator’s Brochure; MPO, myeloperoxidase; 
; SAE, serious 
adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; T3, triiodothyronine; T4, 
thyroxine; 
; WHO, World 
Health Organisation. 
2.3.2 Benefit Assessment 
All participants in the study are expected to be optimally treated according to local guidelines, 
including treatments to control co-morbidities, and the study intervention may be used in 
conjunction with standard of care for any comorbidities. Participants involved in the proposed 
study may benefit from the given treatment.  
All participants of clinical trials irrespective of whether treated with active treatment or not, 
generally receive closer medical attention than those in ordinary clinical practice which may 
be to their advantage.  
Heart failure with LVEF > 40% is a common condition with rising prevalence associated with 
poor quality of life and adverse prognosis for which there are no approved therapies; 
therefore, information acquired from this study could be of benefit to patients in the future. 
2.3.3 Conclusion 
Taking into account the measures taken to minimise risk to participants participating in this 
study, the potential risks identified in association with AZD4831 are justified by the 
anticipated benefits that may be afforded to participants with HF with LVEF > 40%. 
3 
OBJECTIVES AND ENDPOINTS 
3.1 
Part A 
The following information in Table 4 relates to the objectives of Part A of the study. The dose 
in Part B will be the dose with optimal risk-benefit profile based on the data in Part A. 
CCI
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Table 4 
Objectives and Endpoints – Part A 
Objectives 
Endpoints/Variables 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To evaluate the effect of AZD4831 on 
CV events  
Composite of HF hospitalisation, urgent HF 
visits with requirement for additional loop 
diuretic treatment, MI, CV deaths, and all-cause 
mortality from baseline to end of study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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4 
STUDY DESIGN 
4.1 
Overall Design 
This is a randomised, double-blind, placebo-controlled, multi-centre sequential Phase 2b and 
Phase 3 study to evaluate the efficacy and safety of AZD4831 in participants with HF with 
LVEF > 40%. The study will consist of 2 separate parts; see the study flow charts in Figure 1 
and Figure 2.  
Part A will evaluate the efficacy and safety of once-daily oral dosing of AZD4831 2.5 mg or 
5 mg compared to placebo, administered in addition to optimal background therapy for co-
morbidities for 16 weeks in participants with HF with LVEF > 40%. Approximately 660 
participants will be randomised in a 1:1:1 allocation, of which we estimate approximately 600 
will have complete safety data to establish efficacy as well as the safety and tolerability 
profile, and identify and select a dose for the pivotal part of the study (Part B). Randomisation 
will be stratified by neutrophil count. Participants in Part A will continue into a safety 
extension, during which they will receive an additional 32 weeks of the intervention 
(AZD4831 or placebo, as per their assigned arm during randomisation). The primary and 
secondary endpoints will be evaluated at 16, 24, and 48 weeks (echocardiography parameters 
will be evaluated at 16 and 24 weeks only). 
An unblinded review will be performed of at least one, but possibly several, interim analyses 
by an internal Unblinded Review Committee, with the purpose of informing further 
development of the clinical programme, including but not limited to dose selection to start 
Part B. One of the interim analyses will be performed when all participants in Part A have 
completed the last protocol-specified visit/assessment. If Part B were not to start or progress, 
then the last interim analysis of Part A would be regarded as the final analysis. 
Part B will evaluate the efficacy and safety of once-daily oral dosing of AZD4831, 
administered in addition to optimal background therapy for co-morbidities for 24, 36 or 48 
weeks to a new cohort of participants with HF with LVEF > 40%. Approximately 820 
participants will be randomised, of which we estimate approximately 745 will have complete 
safety data. Analysis of Part B will be based on participants in Part B only. Randomisation 
will be stratified by neutrophil count. Participants will receive once-daily oral doses of the 
selected dose of AZD4831 or placebo in a 1:1 allocation. The primary and secondary 
endpoints will be evaluated at 24 weeks. 
The efficacy, safety, and tolerability data from Part A will be evaluated by an internal URC at 
at least one, but possibly several, interim analyses (see Appendix A 5). Based on this data, the 
dose for Part B of the study will be selected. The analysis of Part A will be performed by 
study-independent sponsor personnel. 


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Oversight from an unblinded DRC focusing on skin reactions for part A and external DMC for 
part B will be included for this study; see Appendix A 5 for more details.  
4.2 
Scientific Rationale for Study Design 
This is a randomised, multi-centre, double-blind, placebo-controlled study. Randomisation 
and double-blinding will minimise potential bias. The target population includes both male 
and female participants aged ≥ 40 years with an established diagnosis of HF with LVEF > 
40% and evidence of structural heart disease (ie, left ventricular hypertrophy or left atrial 
enlargement). Detailed characteristics of the target population can be seen in inclusion criteria 
(see Section 5.1). These requirements in combination with elevated natriuretic peptides aims 
to support the diagnosis of HF, since other common co-morbidities may cause overlapping 
symptoms. 
The control group will receive matching placebo; there are no approved pharmacological 
treatments for HF with LVEF > 40% that could be used as a comparator. All participants will 
be treated according to local guidelines on standard of care treatment, focusing on treatment of 
HF symptoms (eg, diuretics) and co-morbidities (including treatment for hypertension, 
ischaemic heart disease, and atrial fibrillation/flutter). 
The study is designed to evaluate the efficacy and safety of AZD4831 in HF subjects with 
LVEF > 40% and is made up of 2 separate parts: Part A is intended to establish efficacy as 
well as the safety and tolerability profile of AZD4831 and identify and select a dose for the 
pivotal study Part B. Part B is intended to confirm the efficacy and safety of the selected dose.  
The primary endpoints in Part A are change from baseline in KCCQ-TSS and 6MWD at 
16 weeks compared with placebo. The primary endpoints in Part B are change from baseline 
in KCCQ-TSS and 6MWD at 24 weeks compared with placebo.  
The rationale for using change in 6MWD is that the 6MWT (the test used to determine the 
6MWD) can act as a surrogate of normal daily activity. The 6MWT is a standard method for 
measuring exercise response (American Thoracic Society 2002, Holland et al 2014) to 
medical interventions in patients with moderate to severe heart or lung disease, having already 
been used to give pre-treatment and post-treatment comparisons for patients with HF (De 
Bock et al 1994, O'Keeffe et al 1998). 
Patients with HF experience debilitating symptoms that substantially impact daily 
functioning, physical capacity, and quality of life. For these reasons, it is important to measure 
the impact of new HF therapies on the HF patients’ symptoms and functioning (Zannad et al 
2013). The KCCQ instrument quantifies both the frequency of four cardinal HF-symptoms 
(fatigue, peripheral oedema, dyspnoea, and orthopnoea) and how bothersome three of the 
cardinal HF-symptoms (fatigue, peripheral oedema and dyspnoea) are to patients, as well as 
HF-related physical limitations, social limitations, self-efficacy, and health-related quality of 


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life. First developed in 1996 (Greene et al 2018, Spertus et al 2005), over the following two 
decades, the experience with the KCCQ has grown in industry-sponsored and academic 
studies, and it is now the most common disease PRO instrument collected in HF studies.  
The study will evaluate general safety and tolerability with special focus in the incidence of 
AEoSIs related to skin reactions (including maculopapular rash) and infection, vital signs, 
clinical laboratory parameters, and ECG. 
4.3 
Justification for Dose 
To date, 4 Phase 1 clinical studies have been completed in which a total of 36 HVs have been 
exposed to AZD4831 at doses 5 to 405 mg as single doses and 53 HVs at doses 2.5 to 45 mg 
as multiple doses. In the HV, AZD4831 was generally well tolerated with the exception of 
generalised maculopapular rash seen around 7-10 days after the first dose: in the single 
ascending dose study (D6580C00001), 1 HV out of 6 receiving 45 mg, 1 HV out of 6 
receiving 135 mg and 2 HVs out of 6 receiving 405 mg; in the MAD study (D6580C00004), 
2 HVs out of 8 receiving 15 mg and 2 HVs out of 5 receiving 45 mg. 
In a single-blind MAD study in Japanese and Chinese HVs (Study D6580C00008), 
maculopapular rash was reported in 5 of 24 Japanese and Chinese HVs who received 
AZD4831. Maculopapular rash CTCAE Grade 1 was reported in one of 6 Japanese HVs on 
5 mg AZD4831 and maculopapular rash Grade 2 was reported in one of 6 Chinese participants 
on 5 mg AZD4831 and in 3 of 6 Japanese HVs on 10 mg AZD4831.  
A Phase 2a study intended to assess target engagement, safety, and tolerability of AZD4831 in 
participants with HFpEF was prematurely terminated during the COVID-19 pandemic after 
meeting pre-defined target engagement, safety, and tolerability criteria (Study D6580C00003). 
One participant out of 27 receiving 5 mg AZD4831 was discontinued from study treatment 
due to Grade 3 generalised maculopapular rash. 
The dose selection for Part A is based on target engagement (MPO inhibition) data from the 
Phase 1 MAD study (HV), the Phase 2a study (HFpEF), and data from the MAD study in 
Japanese and Chinese healthy participants. Two dose levels are being proposed (2.5 and 5 mg) 
based on expected efficacy (lower dose) and safety (upper dose). The 2.5 mg dose is predicted 
to be the lowest clinically relevant dose (predicted to result in approximately 50% MPO 
inhibition) and 5 mg is the upper safety dose since no rash was observed at doses below 15 mg 
AZD4831 in the Phase 1 MAD study (HV), in 1 of 27 participants at 5 mg AZD4831 in the 
Phase 2a study (HFpEF), and in 2 of 12 HVs on 5 mg AZD4831 in the Japanese and Chinese 
MAD study. The dose selection for Part B will be based on totality of data in Part A, ie, safety 
and effect on symptoms and functions as well as effects on other biomarkers/efficacy 
endpoints, in order to select the dose with the predicted optimal risk/benefit ratio. The dose 
selection for Part B will be done by a firewalled URC (to maintain blinding) at an interim 


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analysis conducted when it is assessed there is a sufficient number of participants randomised 
and data accrued. 
4.4 
End of Study Definition 
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements: 
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity. 
Food and Drug Administration requirements defines two completion dates: 
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes. 
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated. 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last protocol specified visit/assessment (including telephone contact) 
regardless of the number of doses of study medication they have received.  
The end of the study is defined as the date of the last protocol specified visit/assessment 
(including telephone contact) of the last participant in the study. This would be the last 
participant in Part B, or Part A (the last Week 52 visit [including telephone contact] for Part 
A) in the event that Part B is never started. 
In Part B, the EoS visit will take place 4 weeks after the final dose, which may occur upon 
completion of either 24, 36 or 48 weeks of treatment (see study design in Section 4).  
Participants who are discontinued from the IP will be encouraged to attend all the scheduled 
visits, including the EoS visit, which will occur 4 weeks after the initially planned final dose. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 


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5.1 
Inclusion Criteria  
5.1.1 
Inclusion Criteria – Part A 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1 
Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics  
2 
Documented stable symptomatic HF (New York Heart Association Class II-IV) for at 
least 1 month at Screening (Visit 1) (transient HF in the setting of an MI does not 
qualify), with a medical history of typical signs and symptoms of HF and receiving 
optimal therapy for HF as determined by the health-care physician. Symptoms and signs  
are defined in Appendix G. 
3 
LVEF > 40% at Screening (Visit 1). All participants will undergo a local echocardiogram 
at the Screening (Visit 1) with central reading to confirm the LVEF > 40% eligibility 
criteria before randomisation. 
4 
6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 3). 
Difference in 6MWD between Screening and Randomisation must be < 50 meters. 
5 
KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 3).  
6 
NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at 
Screening (Visit 1) for patients with BMI ≤ 30 kg/m2.  
NT-proBNP ≥ 200 pg/mL (sinus rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at 
Screening (Visit 1) for patients with BMI > 30 kg/m2.  
The ECG performed at Screening should be used for heart rhythm evaluation. 
7 
At least one of the following: 
(a) Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the 
echocardiogram performed at Screening (Visit 1). Left atrial enlargement is defined 
by at least 1 of the following: LA width (diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, 
or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34 mL/m2. Left ventricular 
hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or 
LVMI > 95 g/m2 in women and > 115 g/m2 in men. 
(b) Spectral tissue Doppler echocardiography - E/e’ ratio (average of septal and lateral) 
≥ 13 at rest at the echocardiogram performed at Screening (Visit 1). 
(c) Indirectly estimated elevation of PASP by TRmax velocity > 2.8 m/s (280 cm/s) 
(PASP > 35 mmHg) at the echocardiogram performed at Screening (Visit 1) OR 
directly measured pulmonary capillary wedge pressure > 15 mmHg at rest within the 
past 12 months or > 25 mmHg at exercise documented by right heart catheterisation 
within 12 months prior to Screening (Visit 1). 


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(d) HF decompensation within 6 months before Randomisation (Visit 3), defined as 
hospitalisation for HF or IV diuretic treatment for HF during an urgent, unscheduled 
visit without hospitalisation. 
Weight 
8 
Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2 (without rounding the values). 
Sex 
9 
 Male or female of non-childbearing potential. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Male participants: 
Male participants must be surgically sterile or using an acceptable method of contraception 
(defined as barrier methods in conjunction with spermicides, except in countries where 
spermicides are not approved) during treatment and until the end of relevant systemic 
exposure, plus a further 90-day period. Study participants must not donate or bank sperm 
during this same time period.  
For a female partner (non-pregnant and of childbearing potential) of a male study participant, 
contraception recommendations should also be considered. Acceptable methods of 
contraception include birth control pills, injections, implants, or patches, intrauterine devices, 
and tubal ligation/occlusion. A barrier method is not necessary if the female partner is 
sterilised 
Female participants: 
Female participants must not be lactating and must be of nonchild-bearing potential. Women 
not of childbearing potential are defined as women who are either permanently sterilised 
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy [but not tubal ligation]), or 
who are postmenopausal. Women will be considered postmenopausal if they have been 
amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative 
medical cause. The following age-specific requirements apply: 
• 
Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone levels in the postmenopausal range. 
• 
Women ≥ 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment. 


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Informed Consent 
10 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
11 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports the 
Genomic Initiative.  
12 Provision of signed and dated written informed consent prior to collection of samples for 
optional future use blood and urine samples. 
 
5.1.2 
Inclusion Criteria – Part B 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1 
Participant must be ≥ 40 to ≤ 85 years of age, at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2 
Documented diagnosis of symptomatic HF (NYHA class II-IV) at Screening (Visit 1), 
and a medical history of typical symptoms/signs of heart failure ≥6 weeks before 
Screening (Visit 1), and receiving optimal therapy for HF as determined by the health-
care physician, with at least intermittent need for diuretic treatment. Symptoms and signs 
are defined in Appendix G.  
3 
LVEF >40% and evidence of structural heart disease (ie, left ventricular hypertrophy or 
left atrial enlargement [1]) documented by the most recent echocardiogram, or cardiac 
magnetic resonance imaging within the last 12 months prior to Screening (Visit 1). If no 
echocardiogram is available, it can be performed at Screening (Visit 1). 
[1] Structural heart disease, ie, LA enlargement and/or left ventricular hypertrophy at the echocardiogram 
performed at Screening (Visit 1). Left atrial enlargement is defined by at least 1 of the following: LA width 
(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm, or LA area ≥ 20 cm2 or LA volume ≥ 55 mL or LAVI > 34 
mL/m2. Left ventricular hypertrophy is defined by septal thickness or posterior wall thickness ≥ 1.1 cm or 
LVMI > 95 g/m2 in women and > 115 g/m2 in men. 
4 
6MWD ≥ 30 meters and ≤ 400 meters at Screening (Visit 1) and Randomisation (Visit 2). 
Difference in 6MWD between Screening and Randomisation must be < 50 meters. 
5 
KCCQ-TSS ≤ 90 points at Screening (Visit 1) and Randomisation (Visit 2).  
6 
NT-proBNP ≥ 250 pg/mL (sinus rhythm) or ≥ 500 pg/mL (atrial fibrillation/flutter) at 
Screening (Visit 1) for patients with BMI ≤ 30 kg/m2. NT-proBNP ≥ 200 pg/mL (sinus   
rhythm) or ≥ 400 pg/mL (atrial fibrillation/flutter) at Screening (Visit 1) for patients with 
BMI > 30 kg/m2. The ECG performed at Screening should be used for heart rhythm 
evaluation. 


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Weight 
7 
Body mass index ≥ 18.0 kg/m2 and ≤ 45.0 kg/m2 (without rounding the values). 
Sex 
8 
Male or female of non-childbearing potential. 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Male participants: 
Male participants must be surgically sterile or using an acceptable method of contraception 
(defined as barrier methods in conjunction with spermicides, except in countries where 
spermicides are not approved) during treatment and until the end of relevant systemic 
exposure, plus a further 90-day period. Study participants must not donate or bank sperm 
during this same time period.  
For a female partner (non-pregnant and of childbearing potential) of a male study participant, 
contraception recommendations should also be considered. Acceptable methods of 
contraception include birth control pills, injections, implants, or patches, intrauterine devices, 
and tubal ligation/occlusion. A barrier method is not necessary if the female partner is 
sterilised. 
Female participants: 
Female participants must not be lactating and must be of nonchild-bearing potential. Women 
not of childbearing potential are defined as women who are either permanently sterilised 
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy [but not tubal ligation]), or 
who are postmenopausal. Women will be considered postmenopausal if they have been 
amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative 
medical cause. The following age-specific requirements apply: 
Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic 
for 12 months or more following cessation of exogenous hormonal treatment and follicle 
stimulating hormone levels in the postmenopausal range. 
Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic 
for 12 months or more following cessation of all exogenous hormonal treatment. 
Informed Consent 
9 
Capable of  giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 


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10 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports the 
Genomic Initiative. 
11 Provision of signed and dated written informed consent prior to collection of samples for 
optional future use blood and urine samples. 
 
5.2 
Exclusion Criteria  
5.2.1 
Exclusion Criteria – Part A 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
eGFR < 30 mL/min/1.73m2 by Chronic Kidney Disease-Epidemiology Collaboration 
formula at Screening (Visit 1). 
2 
Systolic blood pressure < 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3 BP 
lowering medications or ≥ 180 mmHg irrespective of treatments at Randomisation 
(Visit 3) 
3 
Heart rate > 110 bpm or < 50 bpm at Randomisation (Visit 3). 
4 
Life expectancy < 3 years due to other reasons than cardiovascular disease. 
5 
History or ongoing allergy/hypersensitivity reactions to drugs (including but not limited 
to rash, angioedema, acute urticaria). 
6 
Presence of any disease or condition rather than HF constituting the main reason for 
limiting the ability to exercise/reduced exercise capacity.  
7 
Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1) 
8 
Documented history of ejection fraction ≤ 40%, i.e. HF with recovered ejection fraction. 
Transient ejection fraction decrease e.g. in the setting of an MI does not apply. 
9 
Any planned cardiovascular procedure (eg, coronary revascularisation, ablation of atrial 
fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery, etc). 
10 Any cardiac event (eg, myocardial infarction, unstable angina), coronary revascularisation 
(percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial 
fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation 
therapy device within 12 weeks prior to Screening (Visit 1) or between Screening and 
Randomisation (Visit 3). Patients who underwent a successful atrial fibrillation/flutter 
cardioversion, can be enrolled in the study after 4 weeks. 
11 Medical history of aborted sudden cardiac death unless protected by an implantable 
cardioverter-defibrillator or sustained ventricular tachycardia with haemodynamic 
compromise in the past 6 months. 


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12 Any primary cardiomyopathy (eg, genetic hypertrophic cardiomyopathy, obstructive 
hypertrophic, arrhythmogenic right ventricular cardiomyopathy/dysplasia), 
cardiomyopathies related to current toxic or infective conditions (eg, ongoing 
chemotherapy, myocarditis, septic cardiomyopathy), cardiomyopathies due to infiltrative 
diseases (eg, amyloidosis, sarcoidosis), peripartum cardiomyopathy, as well as HF due to 
pericardial disease, congenital heart disease or clinically significant uncorrected primary 
cardiac valvular disease.  
13 Any past or planned organ transplantation (including cardiac), with the exception of skin 
transplantation. 
14 Hb < 110 g/L (male) and < 100 g/L (female) or iron-deficiency with/without anaemia 
requiring ongoing or planned IV iron treatment. 
15 Participants with hyperthyroidism, uncontrolled hypothyroidism (including but not 
limited to TSH ≥10 mIU/mL), or any clinically significant thyroid disease as judged by the 
investigator. 
16 Active malignancy requiring treatment (with the exception of basal cell or squamous cell 
carcinomas of the skin). 
17 Acute or chronic primary liver disease with severe impairment of liver function (eg, 
ascites, oesophageal varices, coagulopathy). Any known and ongoing hepatitis B or C. 
18 ALT or AST ≥ 2 × ULN at Screening (Visit 1). 
19 Pulmonary arterial hypertension, chronic pulmonary embolism, severe pulmonary disease 
including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic oral 
steroid therapy, or hospitalization for exacerbation of COPD requiring ventilatory support 
within 12 months prior to Screening (Visit 1). 
20 Any active infection requiring oral, intravenous, or intramuscular treatment at Screening 
(Visit 1) and/or at Randomisation (Visit 3). 
21 Prior history of drug or alcohol abuse likely to impact participant safety or compliance 
with study procedures as judged by the investigator or ongoing drug or alcohol abuse. 
22 History of any clinically significant disease or disorder other than HF that, in the opinion 
of the investigator, may either put the patient at risk of participation in the study or 
influence the results or the patient’s ability to participate in the study. 
23 Any signs or confirmation of COVID-19 infection: 
• Suspected (as judged by PI) or confirmed COVID-19 within the last 2 weeks prior 
to Screening (Visit 1) or at Randomisation (Visit 3). 
• Hospitalisation for COVID-19 within the last 12 weeks prior to Screening (Visit 
1). 


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Prior/Concomitant Therapy 
24 Any concomitant medications known to be a potent CYP3A4 inducers or inhibitors, eg, 
itraconazole, rifampicin, clarithromycin, or propylthiouracil (refer to Section 6.5 for a list 
of prohibited and/or restricted medications and treatments). 
Prior/Concurrent Clinical Study Experience 
25 Participation in another clinical study with an Investigational Product administered in the 
last month prior to Screening (Visit 1) (or 5 half-lives), whichever is longer. 
26 Participants with a known hypersensitivity to AZD4831 or any of the excipients of the 
product. 
Other Exclusions 
27 Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or 
staff at the study site) 
28 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements, 
especially completing ePRO assessments; therefore participants who are unable to read 
(eg, are blind or are illiterate) should be excluded from participating in this trial. 
29 Previous enrolment and randomisation in the present study. (Participants who where 
screened and screen failed and not randomised in Part A can be screened for possible 
entry to Part B). 
 
5.2.2 
Exclusion Criteria - Part B 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 eGFR < 30 mL/min/1.73m2 by Chronic Kidney Disease-Epidemiology Collaboration 
formula at Screening (Visit 1). 
2 Systolic blood pressure < 90 mmHg or ≥ 160 mmHg if not on treatment with ≥ 3 BP 
lowering medications or ≥ 180 mmHg irrespective of treatments at Randomisation 
(Visit 2). 
3 Heart rate > 110 bpm or < 50 bpm at Randomisation (Visit 2). 
4 Life expectancy < 2 years due to other reasons than cardiovascular disease. 
5 History or ongoing allergy/hypersensitivity reactions to drugs (including but not limited to 
rash, angioedema, acute urticaria). 
6 Presence of any disease or condition rather than HF constituting the main reason for 
limiting the ability to exercise/reduced exercise capacity.  
7 Current decompensated HF and/or NT-proBNP > 5000 pg/mL at Screening (Visit 1). 


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8 Documented history of ejection fraction ≤ 40% (ie, HF with recovered ejection fraction). 
Transient ejection fraction decrease (eg, in the setting of an MI does not apply). 
9 Any planned cardiovascular procedure (eg, coronary revascularisation, ablation of atrial 
fibrillation/flutter, valve repair/replacement, aortic aneurysm surgery etc). 
10 Any cardiac event (eg, myocardial infarction, unstable angina), coronary revascularisation 
(percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial 
fibrillation/flutter, valve repair/replacement, implantation of a cardiac resynchronisation 
therapy device within 12 weeks prior to Screening (Visit 1) or between Screening (Visit 
1) and Randomisation (Visit 2). Patients who underwent a successful atrial 
fibrillation/flutter cardioversion, can be enrolled in the study after 4 weeks. 
11 HF due to any of the following: known infiltrative cardiomyopathy (eg, amyloid, sarcoid, 
lymphoma, endomyocardial fibrosis), active myocarditis, constrictive pericarditis, cardiac 
tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic 
cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), 
or uncorrected primary valvular disease. 
12 Any past or planned organ transplantation (including cardiac), with the exception of skin 
transplantation. 
13 Hb < 110 g/L (male) and < 100 g/L (female) or iron-deficiency with/without anaemia 
requiring ongoing or planned IV iron treatment. 
14 Participants with hyperthyroidism, uncontrolled hypothyroidism (including but not limited 
to TSH ≥10 mIU/mL), or any clinically significant thyroid disease as judged by the 
investigator. 
15 Active malignancy requiring treatment (with the exception of basal cell or squamous cell 
carcinomas of the skin). 
16 Acute or chronic primary liver disease with severe impairment of liver function (eg, 
ascites, oesophageal varices, coagulopathy). Any known and ongoing hepatitis B or C. 
17 ALT or AST ≥ 2 × ULN at Screening (Visit 1). 
18 Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease 
including COPD (ie, requiring home oxygen, chronic nebulizer therapy or chronic oral 
steroid therapy, or hospitalization for exacerbation of COPD requiring ventilatory support 
within 12 months prior to Screening [Visit 1]). 
19 Any active infection requiring oral, intravenous, or intramuscular treatment at Screening 
(Visit 1) and/or at Randomisation (Visit 2). 
20 Prior history of drug or alcohol abuse likely to impact participant safety or compliance 
with study procedures as judged by the investigator or ongoing drug or alcohol abuse. 
21 History of any clinically significant disease or disorder other than HF that, in the opinion 
of the investigator, may either put the patient at risk of participation in the study or 
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22 Any of the following related to COVID-19: 
• Suspected (as judged by PI) or confirmed COVID-19 within the last 2 weeks prior 
to Screening (Visit 1) or at Randomisation (Visit 2). 
• Hospitalisation for COVID-19 within the last 12 weeks prior to Screening (Visit 
1). 
Prior/Concomitant Therapy 
23 Any concomitant medications known to be a potent CYP3A4 inducers or inhibitors, eg, 
itraconazole, rifampicin, clarithromycin, or propylthiouracil (refer to Section 6.5 for a list 
of prohibited and/or restricted medications and treatments). 
Prior/Concurrent Clinical Study Experience 
24 Participation in another clinical study with an IP or device during the last month prior to 
enrolment. 
25 Participants with a known hypersensitivity to AZD4831 or any of the excipients of the 
product. 
Other Exclusions  
26 Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or 
staff at the study site). 
27 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements, 
especially completing ePRO assessments; therefore participants who are unable to read 
(eg, are blind or are illiterate) should be excluded from participating in this trial. 
28 Previous enrolment and randomisation in the present study. (Participants who where 
screened and screen failed and not randomised in Part A can be screened for possible 
entry to Part B). 
 
5.3 
Lifestyle Considerations 
No restrictions on lifestyle are required. 
5.3.1 
Meals and Dietary Restrictions 
Refrain from consumption of grapefruit juice from the start of study intervention until the 
final dose. Study intervention can be taken with or without food. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomised to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 


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respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who narrowly miss (by not more than 10%) the inclusion/exclusion criteria for 
eGFR and NT-proBNP may be re-tested once within 14 days.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened one time within the same study part if, in the opinion of the investigator, there is a 
reason to believe they may be eligible/fulfil the inclusion/exclusion criteria then. Participants 
that previously withdrew from the study are not allowed for rescreening. Rescreened 
participants should be assigned the same participant number as for the initial screening, and all 
enrolment assessments and procedures, including signing of the informed consent form, 
should be performed again. 
6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to or medical device(s) utilised by a study participant 
according to the study protocol. 
6.1 
Study Intervention(s) Administered 
6.1.1 
Investigational Products 
Table 6 
Investigational Products 
Intervention name 
Part A 
Part B 
AZD4831 
Placebo 
AZD4831 
Placebo 
Type  
Drug 
Drug 
Drug 
Drug 
Dose formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Unit dose 
strength(s) 
2.5 mg; 5 mg 
Not applicable 
2.5 mg or 5 mg  
Not applicable 
Dosage level(s) 
2.5 mg; 5 mg; once 
daily a 
Once daily a 
2.5 mg or 5 mg;  
once daily 
Once daily 
Route of 
administration 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Placebo- 
comparator 
Experimental 
Placebo- 
comparator 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally 
by AstraZeneca 
Provided centrally 
by AstraZeneca 
Provided centrally 
by AstraZeneca 
Provided centrally 
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Table 6 
Investigational Products 
Intervention name 
Part A 
Part B 
AZD4831 
Placebo 
AZD4831 
Placebo 
Packaging and 
labelling 
Study drug will be 
provided in bottles. 
Labels of bottle 
with AZD4831 2.5 
mg will have white 
background and 
black description. 
Labels of bottle 
with AZD4831 5 
mg will have green 
background and 
black description. 
Each bottle will be 
labelled in 
accordance with 
GMP Annex 13 
and per country 
regulatory 
requirement. 
Study drug will be 
provided in bottles. 
Labels of bottle 
with AZD4831 
PTM 2.5 mg will 
have white 
background and 
black description. 
Labels of bottle 
with AZD4831 
PTM 5 mg will 
have green 
background and 
black description. 
Each bottle will be 
labelled in 
accordance with 
GMP Annex 13 
and per country 
regulatory 
requirement. 
Study drug will be 
provided in bottles. 
Labels of bottle 
with AZD4831 
(dose to be decided 
based on Part A 
data) will have 
orange background 
and black 
description. Each 
bottle will be 
labelled in 
accordance with 
GMP Annex 13 
and per country 
regulatory 
requirement. 
Study drug will be 
provided in bottles. 
Labels of bottle 
with AZD4831 
PTM (dose to be 
decided based on 
Part A data) will 
have orange 
background and 
black description. 
Each bottle will be 
labelled in 
accordance with 
GMP Annex 13 
and per country 
regulatory 
requirement. 
a 
To ensure blinding to study intervention, each participant will take one tablet once daily of each type 
(AZD4831 2.5 mg or AZD4831 PTM 2.5 mg and AZD4831 5 mg or AZD4831 PTM 5 mg). 
GMP, Good Manufacturing Practice; IMP, investigational medicinal product; NIMP, Non-investigational 
medicinal product; PTM, Placebo to Match. 
For Part A, to ensure blinding to study intervention, participants will take study intervention 
from two bottles (one tablet from one bottle with white label and one tablet from one bottle 
with green label) once daily. Each bottle contains 35 tablets, and the participant will receive 
enough bottles to last until the next visit. 
For Part B, participants will take study intervention from one bottle (one tablet from one bottle 
with orange label) once daily, for 24, 36 or 48 weeks.  
The tablets are sensitive to moisture and should remain in original packaging (with desiccant) 
until administration. The tablets must not be chewed, crushed or divided but should be 
swallowed whole with water. 
6.2 
Preparation/Handling/Storage/Accountability 
1 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 


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2 
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
3 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4 
For Part A: Study medication will be dispensed to participants in bottles. Participants will 
be instructed to take one tablet per day from two bottles (one tablet from one bottle with 
white label and one tablet from one bottle with green label). Each bottle contains 35 
tablets and the participant will receive enough bottles to last until the next visit.  
5 
For Part B: Study medication will be dispensed to participants in a bottle with the dose 
selected on data from Part A. Participants will be instructed to take one tablet per day 
from the bottle. Each bottle contains 35 tablets, and the participant will receive enough 
bottles to last until the next visit.  
6 
Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual.  
 
6.3 
Measures to Minimise Bias: Randomisation and Blinding 
All participants will be centrally assigned to randomised study intervention using an 
IRT/RTSM. This computerised randomisation procedure will ascertain allocation concealment 
and will assign the participants 1:1:1 to two dose levels of AZD4831 or matching placebo in 
Part A and 1:1 to AZD4831 or matching placebo in Part B. For Part A, in the event that 
randomisation to the AZD4831 5 mg treatment arm is stopped during the study due to safety 
in either the whole study or in specific countries or ethnic populations, the remaining 
participants in that cohort will be randomised at a 2:1 ratio to 2.5 mg AZD4831 or matching 
placebo. 
The randomised study population will be capped by neutrophil count, 6MWD and KCCQ-TSS 
in both Part A and Part B. The capping will consist of:  
• 
The proportion of participants having neutrophil count > 4 × 106/mL at Screening will be 
60%-80% 
• 
A maximum of 25% of the participants can have 6MWD ≥ 350 and ≤ 400 meters at 
randomisation visit. 
• 
A maximum of 30% of the participants can have KCCQ-TSS > 80 and ≤ 90 at 
randomisation visit. 
 


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LVEF value at screening and atrial fibrillation/flutter status on ECG at Screening (Visit 1) 
may also be capped in the IRT/RTSM to avoid over- or under-representation of these 
participant subgroups. 
The randomisation will be stratified by neutrophil count in both Part A and Part B. 
The study will be blinded to both participants and Investigators/site staff as well as to the 
sponsor (designated sponsor personnel will be unblinded as part of DRC and URC in Part A 
as described in Appendix A 5). The IRT/RTSM will provide to the Investigator(s) the kit 
identification number to be allocated to the participant at the dispensation visit. Study 
intervention will be dispensed at the study visits summarised in the SoA (See Section 1.3). 
Routines for this will be described in the IRT/RTSM user manual that will be provided to each 
centre. 
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The investigator documents and reports the action to AZ, without revealing the treatment 
given to participant to the AZ staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to the investigational product and that potentially require 
expedited reporting to regulatory authorities. Randomisation codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented. Data in Part A will be analysed and reviewed by 
a URC as described in Section 9.5.  
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention will affect the 
immediate management of the participant’s condition (eg, antidote available), the investigator 
has the sole responsibility for determining if unblinding of a participant’s intervention 
assignment is warranted. Participant safety must always be the first consideration in making 
such a determination. If a participant’s intervention assignment is unblinded, the sponsor must 
be notified within 24 hours after breaking the blind. The investigator documents and reports 
the action to AZ, without revealing the treatment given to the participant to the AZ staff. 
Pharmacokinetic samples will be analysed by the bioanalytical laboratory performing the 
bioanalyses only for participants on active treatment, as referenced in Section 8.5.1.1. To 
allow for the appropriate selection of samples, the bioanalytical laboratory will, therefore, 
have access to the treatment codes but will not share the codes with the sponsor or others 
involved in the study until the blinding is broken for the study. 


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6.4 
Study Intervention Compliance 
The first dose of study intervention will be administered in clinic on the day of randomisation. 
Participants will receive study intervention at the site on visit days and at home between visits. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision, after checking treatment was not taken at 
home before coming to the study site. The date, and time if applicable, of dose administered in 
the clinic will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning 
and counting returned tablets during the site visits and documented in the source documents 
and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
Participants will be provided with a dosing card to record the date and time of last dose taken 
the day before the clinic visit for the purposes of PK evaluation. 
A record of the number of AZD4831/placebo tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays will also be 
recorded in the eCRF. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrolment or 
receives during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
COVID-19 vaccines received during the study and prior to study entry are to be recorded; the 
type of vaccine is also to be recorded. 
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The following medications and treatments are prohibited and/or restricted: 
• 
Strong inhibitors of CYP3A4, including grapefruit juice 


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• 
Strong inducers of CYP3A4 such as nevirapine, rifampicin, carbamazepine, fosphenytoin, 
pentobarbital, phenobarbital, phenytoin, primidone, rifapentine, enzalutamide, lumacaftor, 
St. John's Wort, mitotane, apalutamide, quinine, rimexolone, rifaximin, rifamycin, 
topiramate, qsymia, oxcarbazepine, midostaurin 
• 
Cyclosporin or Tacrolimus 
• 
Protease inhibitors such as ritonavir, indinavir, nelfinavir, saquinavir, atazanavir, 
darunavir, lopinavir, tipranavir 
• 
Macrolide antibiotics: clarithromycin, telithromycin 
• 
Chloramphenicol (antibiotic) 
• 
Azole antifungals, ie, ketoconazole, itraconazole, posaconazole, voriconazole 
• 
Nefazodone (antidepressant) 
• 
Cobicistat 
• 
Propylthiouracil 
• 
Silymarin 
 
6.6 
Dose Modification 
No dose modifications are allowed during the study. 
6.7 
Intervention After the End of the Study 
There is no planned intervention following the end of the study. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant should 
remain in the study, ie, continue to participate in scheduled study visits and evaluations.  
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. For procedures in the case of withdrawal from the study, see Section 7.2. 
At each visit, participants will be instructed to contact the investigator immediately, if rash or 
skin reaction has developed. If maculopapular rash grade 1, 2, or 3 has developed, participant 
must be permanently discontinued from the study intervention and AZ medical staff should be 
informed. 
• 
Grade 1: Macules/papules covering < 10% Body Surface Area with or without symptoms 
(eg, pruritus, burning, tightness). 


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• 
Grade 2: Macules/papules covering 10 - 30% Body Surface Area, with or without 
symptoms (eg, pruritus, burning, tightness); limiting Instrumental ADL (refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc); rash 
covering > 30% Body Surface Area with or without mild symptoms. 
• 
Grade 3: Macules/papules covering > 30% Body Surface Area, with moderate or severe 
symptoms; limiting Self-care ADL (refer to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden). 
 
If the participant develops a rash or skin reaction that is not considered a maculopapular rash, 
but is a generalised rash/skin reaction or is considered to be an SAE, the participant must be 
permanently discontinued from the study intervention and AZ medical staff should be 
informed. 
For further information and skin reaction evaluation guidance, see Appendix B 5. 
Study participants also may be discontinued from study intervention in the following 
situations: 
• 
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. 
• 
Adverse Event or other safety reasons as judged by the Investigator and/or sponsor where 
continued treatment may put the participant at undue risk.  
• 
Development of uncontrolled and clinical significant 
 as judged by the 
Investigator.  
• 
Severe non-compliance with the CSP. 
• 
Pregnancy 
 
At the time of permanent discontinuation of study intervention, an Early Discontinuation visit 
should be conducted. See the SoA (See Section 1.3) for data to be collected at the time of 
intervention discontinuation and follow-up and for any further evaluations that need to be 
completed. 
7.1.1 
Temporary Discontinuation 
Every attempt should be made to maintain participants on the study intervention during the 
course of the study. If the study intervention has been interrupted, it should be re-introduced 
as soon as, in the opinion of the Investigator, the participant is able to re-start study treatment. 
Note related to AEoSI skin reactions (including maculopapular rash): In the occurrence of 
maculopapular rash CTCAE Grade 1, 2, or 3, or any other generalised rash/skin reaction or 
serious rash/skin reaction, study intervention should be permanently discontinued. At each 
visit, participants will be instructed to stop the study intervention and contact the investigator 
immediately if rash or skin reaction has developed. After the participant has been seen by the 
study doctor or designee and the skin reaction is not considered a maculopapular rash CTCAE 
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Grade 1, 2, or 3, or any other generalised rash/skin reaction or serious rash/skin reaction, the 
study treatment can be restarted. 
7.1.2 
Rechallenge 
Participants who have temporarily discontinued study intervention can resume treatment as 
soon as, in the opinion of the Investigator, the participant is able to re-start study treatment 
and the participant wishes to resume. No minimum time period is necessary before treatment 
can resume. 
If a participant develops maculopapular rash CTCAE Grades 1, 2, or 3 or any other 
generalised rash/skin reaction or serious rash/skin reaction, study intervention should be 
permanently discontinued. 
7.2 
Participant Withdrawal from the Study 
A participant may withdraw from the study (eg, withdraw consent) at any time (study 
intervention and assessments) at his/her own request, without prejudice to further treatment, or 
may be withdrawn at any time at the discretion of the investigator for behavioural, 
compliance, or administrative reasons. This is expected to be uncommon. 
A participant who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records). 
At the time of withdrawal from the study, if possible, an EDV should be conducted, as shown 
in the SoA (See Section 1.3). If the participant is discontinued from study intervention, and 
later decides to withdraw from the study before scheduled EoS visit, the EoS visit should be 
performed at the time of withdrawal. See the SoA (See Section 1.3) for data to be collected at 
the EDV and EoS visit. For procedures in the case of discontinuation from study intervention, 
see Section 7.1. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be carried 
out in line with what was stated in the informed consent and local regulation The investigator 
must document the decision on use of existing samples in the site study records and inform the 
Global Study Team. 
 


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7.3 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site and vital status not found in 
publicly available sources at the end of the study. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised in the SoA. Protocol waivers or exemptions 
are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 318 mL (Part A) and 
approximately 300 mL (Part B). Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples. 
8.1 
Efficacy Assessments 
8.1.1 
Patient Reported Outcomes 
Participants will perform the PRO assessments using an electronic tablet during clinic visits  
) at the timepoints indicated in the SoA (See Section 1.3). 
 
. All questionnaires, except the PRD-acute version for the 
6MWT, must be completed using the electronic tablet (or the web-based backup, in case of 
technical failure or if the participant forgets to bring the device to the clinic). The PRD-acute 
version will be recorded by site staff in the eCRF. Each site must allocate the responsibility 
for the administration of the PROs to a specific site personnel and, if possible, assign a back-
up person to cover if that individual is absent. A key aspect of study success is to have high 
PRO compliance. Therefore, it is essential that site personnel follow the SoA (See Section 1.3) 
and ensure that the device is charged and set up properly before the participant comes for the 
visit.  
If participants have any medical problems, they should discuss them with their doctor or 
research nurse separately from the PRO assessment.  
The research nurse or appointed site staff must remind participants there are no right or wrong 
answers and that the value and relevance of PRO data is to hear directly from participants, 
without interpretation from health care professionals or others, how they function and feel. 
Site staff must administer questionnaires available in the language that the participant speaks 
and understands. Questions should not be read in an available language and translated into 
another language for the participant. 
The following best practice guidelines should be followed: 
• 
The PRO questionnaires must be completed after signed consent but before any other 
study procedures are conducted, including being seen by the doctor, with the exception of 
the PRD-acute version which is to be completed before the 6MWT. 
• 
The appointed site personnel must show participants how to use the electronic PRO 
device, in accordance with the instructions provided. 
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• 
To avoid bias participants must not receive help from relatives, friends or site staff to 
answer or to clarify the PRO questionnaires.  
• 
The PRO questionnaires must be completed by the participant in privacy. 
• 
The participant should be given enough time to complete the PRO questionnaires at his or 
her own speed.  
On completion of the questionnaires during clinic visits, the tablet should be handed back to 
the designated responsible person, who should check that all questionnaires, relevant for the 
specific visit (See Section 1.3), were completed. If any PRO questionnaire was not completed 
the site personnel must document the reason why a participant could not complete assessments 
in the eCRF. 
• 
The appointed site personnel should also stress that the information is confidential. 
Therefore, if the participant has any medical problems, he or she should discuss them 
with the doctor or study nurse separately from the PRO assessment. 
 
The following PROs will be used in this study: 
Part A 
• 
KCCQ 
• 
 
 
 
 
 
 
Part B 
• 
KCCQ 
• 
PGIS-HF 
• 
PGIS-WD 
• 
PRD-acute version 
• 
 
 
Baseline PROs will be collected at the Randomisation visit (Visit 3 and Visit 2 for Part A and 
Part B, respectively). 
 
 
 
 
 
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8.1.1.1 
Kansas City Cardiomyopathy Questionnaire 
The KCCQ is a psychometrically validated questionnaire developed for patients with 
congestive HF (Green et al 2000). It is a 23-item, self-administered health status measure that 
quantifies physical limitations, symptoms, social interference, self-efficacy, and quality of life. 
Results for each domain are summarised and transformed to a score of 0 to 100; higher scores 
indicate better health status. Total symptom score will be calculated to assess the frequency 
and burden of clinical symptoms. The KCCQ English US Master version is enclosed in 
Appendix H. 
8.1.1.2 
Patient Global Impression of Severity in Heart Failure Symptoms  
The PGIS-HF (Appendix I) item assesses how a participant perceives his or her overall 
severity of HF symptoms over the past two weeks. Participants will choose from 6 response 
options ranging from ‘no symptoms’ to ‘very severe’. 
8.1.1.3 
Patient Global Impression of Severity in Walking Difficulties  
The PGIS-WD (Appendix J) item assesses how a participant perceives his or her current 
overall limitation in walking ability. Participants will choose from 6 response options ranging 
from ‘no limitations’ to ‘very severe limitations’.  
8.1.1.4 
Patient Rating of Dyspnoea, Acute Version  
The PRD-acute version (Appendix K) is a single question item asking the participant to rate 
his or her shortness of breath right now on a scale from 0 to 10, where 0 indicates ´No 
shortness of breath´ and 10 ‘As bad as you can imagine’.   
This item will be collected as part of the 6MWT and recorded by site staff in the eCRF. 
8.1.1.5 
 
 
 
 
  
8.1.2 
 
 
 
8.1.3 
6 Minute Walk Test 
The 6MWT will be conducted based on the ATS guidelines at the timepoints specified in the 
SoA (See Section 1.3). The clinical research staff will receive appropriate training on how to 
perform the test. As far as possible, for each participant, the test should be performed in the 
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same location, by the same study personnel, and at the same time of day (in the morning, if 
possible) in order to minimise within- participant variability.  
 
 
 
 
After completing the PRD-acute version, the participant will walk as far as he or she can in 
6 minutes. The 6MWD will be assessed under standard test conditions, in accordance with the 
ATS guidelines. 
 
 
 
 
 
When the oxygen saturation is measured immediately before and after the test, it is important 
to keep the finger at heart level (IC4) for standardised measurement. 
If the participant uses oxygen therapy for a HF condition, its use during the test should be 
recorded (including the volume/min) and be kept consistent during each 6MWT. If the 
participant is wearing a face mask, eg, due to COVID-19, it should also be recorded and 
should be used consistently thereafter for each test.  
8.1.4 
Echocardiogram 
8.1.4.1 
Echocardiogarm – Part A 
Transthoracic echocardiographic images will be obtained at the timepoints specified in the 
SoA (See Section 1.3). Transthoracic echocardiography examination will be performed with 
participants at rest in the best position for optimal image acquisition. Standard adult clinical 
cardiac transducers will be used for 2D, M-mode, colour Doppler, and tissue Doppler 
imaging, as detailed in the echocardiography imaging manual that will be supplied to all study 
sites. Doppler and tissue Doppler echocardiography will be performed to obtain indices 
necessary for comprehensive assessment of LV systolic and diastolic function and non-
invasive haemodynamic measurements. Finally, 2D images of the LV will be obtained and 
optimised (with frame rate 50-80 frames per second) for off-line 2D speckle tracking analysis. 
Imaging personnel and equipment will be undergo certification by a separate, blinded to study 
treatment, independent core laboratory. 
Baseline echocardiogram will be performed at screening for all participants to confirm 
eligibility. Images will be sent to the core laboratory for analysis and interpretation. If for any 
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reason an echocardiogram image is deemed uninterpretable for any planned measurements by 
the core laboratory, then echocardiography may be repeated at the discretion of the 
investigator, participant, and Medical Monitor. The repeat echocardiogram should be obtained 
within 7 days of the previous test whenever possible apart from the screening echocardiogram, 
where should a repeat be needed, this can be obtained more than 7 days after the first 
screening echocardiogram, however, this must be performed so that the results are available to 
assess study eligibility prior to randomisation (Visit 3).  If Visit 8 or Visit 9 echocardiogram 
cannot be repeated within 7 days, the repeat echocardiogram can be performed if it occurs 
within 28 days of initial echocardiogram and no later than study Day 141 (Visit 8) or Day 211 
(Visit 9). 
Planned measurements include but are not limited to: 
• 
LV-GLS: left ventricular global longitudinal strain 
• 
LAVI: left atrial volume index 
• 
LVEF: left ventricular ejection fraction 
• 
LVMI: left ventricle mass index 
• 
 
 
The complete list of parameters is described in the echocardiogram imaging manual/charter. 
The de-identified echocardiographic images may be transferred to the sponsor at the end of 
the study or before for potential future scientific health-related research. 
8.1.4.2 
Echocardiogram – Part B 
Echocardiogram will be performed at Screening (Visit 1) unless there is an available 
echocardiogram or cardiac magnetic resonance imaging performed up to 12 months before 
Screening (Visit 1). Echocardiogram will be performed according to local procedures, without 
central reading. 
8.1.5 
Assessment of CV Events 
To evaluate the effect of AZD4831 vs placebo on CV events, the following will be collected 
in Part A and Part B: HF hospitalisation, urgent HF visits with requirement for additional loop 
diuretic treatment, MI, CV deaths, and all-cause mortality. Unstable angina, urgent coronary 
revascularization, and cerebrovascular events are not considered endpoints of this study, but 
will also be collected in the specific eCRF. See Appendix M for definitions of HF 
hospitalization and urgent HF visit. 
8.1.6 
Study Participant Feedback Questionnaire (Part A only) 
This study will include an option for participants to complete an anonymised questionnaire, 
‘Study Participant Feedback Questionnaire’ (Appendix N) for participants to provide feedback 
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on their clinical trial experience. Individual participant level responses will not be reviewed by 
investigators. Responses would be used by the sponsor to understand where improvements can 
be made in the clinical trial process. This questionnaire does not collect data about the 
participant's disease, symptoms, treatment effect, or AEs and, therefore, would not be study 
data. The questionnaire is completed at the timepoints specified in the SoA (See Section 1.3). 
8.2 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (See Section 1.3) 
8.2.1 
Physical Examinations 
A full physical examination, performed at Visits 1, 8, and 11/EDV in Part A and at Visits 1 
and EoS visit/EDV in Part B, will include assessments of the following; general appearance, 
respiratory, cardiovascular, skin, head and neck (including ears, eyes, nose, and throat), lymph 
nodes, thyroid, abdomen (liver and spleen) including waist circumference, musculoskeletal 
(including spine and extremities) and neurological systems. On other occasions as specified in 
the SoA, either a skin examination only, or a brief physical examination will be conducted and 
will include, at a minimum, assessments of the following: general appearance, skin, abdomen 
(liver and spleen), and musculoskeletal, cardiovascular, and respiratory systems. 
Physical examination as well as assessments of height and weight will be performed at 
timepoints as specified in the SoA (See Section 1.3). Body mass index will be calculated at 
Visit 1: BMI = weight/(height)2, where weight is measured in kg, and height in metres. 
8.2.2 
Vital Signs 
Vital signs (supine BP [average of 3 measurements], pulse rate, and body temperature) will be 
performed at timepoints as specified in the SoA (See Section 1.3).  
The measurements should be done before any blood sampling or the exercise testing. The 
measurements should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions. 
8.2.2.1 
Vital Signs - Part A only 
At Visit 3 and Visit 6 for Part A, the vital signs BP measurements can be used for the pre-dose 
supine measurements for the orthostatic test, if taken after being supine for at least 10 minutes 
and as long as the standing BP measurements are taken after these supine measurements at the 
time intervals described below for the orthostatic blood pressure measurement. 
Orthostatic Blood Pressure Measurements and Follow-up of Confirmed Orthostatic 
Hypotension (Part A only) 
For participants in Part A, orthostatic BP measurements will be obtained at baseline (Visit 3) 
and at Week 12 (Visit 6) during the treatment period using a standard sphygmomanometer and 


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taken after scheduled supine measurements (1 and 3 minutes after the participant stands) and 
prior to any required blood draw or study intervention (to be measured pre dose at Day 1 
[Visit 3] and pre dose at Week 12 [Visit 6]).  
To minimise chances of orthostatic hypotension related to volume depletion, participants 
should be well hydrated when they come to the clinic for study visits. Supine BP measures 
will be collected after participants have been lying down for at least 10 minutes. To ensure 
that a stable supine BP is obtained, at least 2 systolic and 2 diastolic BP measurements will be 
obtained. If the replicate measurements differ by no more than 10 mmHg and 5 mmHg, 
respectively, the supine BP will be considered stable. The mean value of each replicate (mean 
systolic and mean diastolic value) will represent the baseline BP for that visit. After stable BP 
is achieved, the participant will stand and a BP measurement will be taken at 1 and 3 minutes 
after the participant stands. If the BP measurements do not meet the criteria for orthostatic 
hypotension, no additional measurement is needed. If the BP measurement meets the criteria 
shown in Table 7, investigators will repeat the supine and standing measurements up to 2 
additional times.The exception is for participants with orthostatic hypotension symptoms: in 
this situation, the orthostatic hypotension AE should be reported based on a single orthostatic 
test sequence.  
When evaluating orthostatic vitals, record any symptoms of dizziness or light headedness. 
Record on the AE page in the eCRF.  
Table 7 
Orthostatic Blood Pressure Criteria and Management 
Decrease in BP indicative of 
orthostatic hypotension  
Actions 
≥ 20 mmHg systolic or  
≥ 10 mmHg diastolic  
Repeat the BP measurements (supine and standing) up to 2 additional 
times, unless orthostatic hypotension is present in association with 
symptoms related to the measurement of orthostatic vitals: in such a case 
the test doesn't need to be repeated and the orthostatic hypotension AE and 
symptoms related to the measurement of orthostatic vitals AE should be 
reported based on a single sequence. 
• 
If either the 1 minute or 3 minute standing BP meets the orthostatic 
(postural) hypotension criteria, then the sequence is considered 
indicative of orthostatic hypotension.  
• 
If 2 of 2 or 2 of 3 sequences are positive, then orthostatic hypotension 
is confirmed and an AE of orthostatic hypotension will be reported.  
 
For participants with orthostatic hypotension, individualised treatment should be prescribed at 
the investigator’s discretion following local guidelines, including pharmacological (eg, down 
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8.2.3 
Electrocardiograms 
Single 12-lead ECG (standard ECG with a paper speed of 25-50 mm/second covering at least 
6 sequential beats) will be obtained after the participant has been resting in a supine position 
for at least 5 minutes, at the visits outlined in the SoA (See Section 1.3). A digital ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals will be used. Interpretation of the clinical safety digital ECG findings will be 
reviewed and confirmed by the Investigator and recorded in the eCRF. 
8.2.4 
Clinical Safety Laboratory Assessments 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the visits indicated in the SoA (See Section 1.3). 
Additional safety samples, including ANCA samples, may be collected if clinically indicated 
at the discretion of the investigator. The date, time of collection, and type of sample will be 
recorded on the appropriate eCRF. 
The clinical chemistry and, haematology, will be performed at a central laboratory. Dipstick 
urinalysis will be performed locally. 
The following laboratory variables will be measured:  
Table 8 
Laboratory Safety Variables 
Haematology/Haemostasis (whole blood) 
B-Hb 
B-Leukocyte differential count (absolute count and 
percent differential) 
B-Leukocyte count 
B-Platelet count 
haematocrit 
MCV 
MCHC 
MCH 
RDW 
reticulocyte  
Clinical Chemistry (serum or plasma) 
S-Creatinine 
S-Albumin 
S-Bilirubin, total 
S-Potassium 
S-Bilirubin, direct 
 
S-Bilirubin, unconjugated, ie, indirect (total – direct) 
S-Calcium, total 
S-ALP 
S-Sodium 
S-AST 
S-Creatine kinase 
S-ALT 
Glucose 
Free T4 and total T4 
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Table 8 
Laboratory Safety Variables 
TSH 
Phosphorus 
Magnesium 
S-Uric Acid a 
Urinalysis (dipstick) 
U-Hb/Erythrocytes/Blood 
U-Glucose 
U-Protein/Albumin 
 
Immunology 
c-ANCAb 
p-ANCA 
Other assessments 
FSH (females only, at screening) 
 
a 
Serum samples sent to the central laboratory for serum uric acid safety assessment will also be used as 
part of the exploratory biomarker assessment at Visit 3, Visit 8, and Visit 11/EDV (Part A). 
b 
The ANCA sample collected at baseline is only to be tested upon requirement ie, appearance of 
maculopapular rash, based on investigator discretion. An additional sample should be collected if 
clinically indicated. 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, whole blood; 
c-ANCA, cytoplasmic staining anti-neutrophil cytoplasmic antibodies; FSH, follicle-stimulating hormone; Hb, 
haemoglobin; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; 
MCV, mean corpuscular volume; p-ANCA, perinuclear-anti-neutrophil cytoplasmic antibodies; RDW, red cell 
distribution width; S, serum; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; U, urine. 
 
Note: In case a participant shows an AST or ALT ≥ 3 × ULN together with total bilirubin 
≥ 2 × ULN please refer to Appendix E. Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law, for further instructions.  
Blood samples for the determination of c-ANCA and p-ANCA will be assayed by 
bioanalytical test sites operated by or on behalf of AZ, using appropriately validated 
bioanalytical methods.  
Analysis of c-ANCA and p-ANCA will be performed by an indirect immunofluorescent assay. 
For samples that test positive, titres of the specific ANCA will subsequently be evaluated. In 
addition, positive samples will also be tested using MPO and proteinase 3 fluorescent 
microparticle immunoassays. These analyses will be performed at a central laboratory. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.2.5 
Skin Reactions, Including Maculopapular Rash 
Skin reactions, including maculopapular rash, will be considered AEs of special interest in this 
study. To ensure that data are collected systematically, any skin reaction will be recorded on a 
special eCRF page. All skin reactions should be recorded in the eCRF as an AE or SAE. If the 
rash is considered maculopapular, it will be evaluated using CTCAE grades 1-3 for rash 
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mild/moderate/severe, along with data element components generally used for CTCAE 
grading of other skin reactions, given that CTCAE grading is specific to the particular type of 
skin lesion. For all rashes, various aspects of the rash will be documented, including start/end 
date, morphology of lesions (maculopapular vs other morphologies), body surface area 
impacted, anatomical site(s), symptoms, signs, effect on participant (including ADL 
impacted), concomitant medications, medication administered, and specific rash diagnosis, if 
available. Photos (overview and detailed) should be taken.  
Please refer to Appendix B 5 for further guidance in rash assessment and reporting. 
At all visits, participants will be instructed to contact the investigator immediately if rash or 
skin reaction has developed at any time point during the study. Participants will be 
recommended to make an acceptable quality self-photo of skin affected with rash/skin 
reaction. 
If any study participant develops a confirmed generalised maculopapular rash CTCAE grade 
1-3, throat tightness or angioedema at any time during the study, the investigator should 
immediately stop the study drug and arrange for the participant to receive the appropriate 
medical treatment relevant to this situation. 
Participants who develop skin reactions, including rash, will be asked to return to the clinic for 
an additional visit that will include a full physical exam and collection of blood samples for 
safety, hsCRP, and PK. If a participant is discontinued from investigational product and 
proceeds to the EDV, an exploratory biomarker sample and blood and urine samples for 
exploratory metabolite analysis will also be collected. The mandatory genetic sample per 
Section 8.6.3 should also be collected at the EDV if not previously collected from the 
participant. It is suggested to start the treatment with a topical steroid and/or oral 
antihistamine. The treatment should be individualised per participant and based on PI 
discretion. Upon PI discretion, a clinical dermatologist can be consulted and a skin biopsy 
considered. The participant can be provided with a treatment for the skin rash, according to 
clinical management standard. Blood samples should be drawn prior to treatment, if possible, 
and without delaying treatment. 
8.2.6 
Infection 
Infections will be considered AE of special interest in this study. Local laboratory testing for 
microorganisms per local guidelines is requested for serious infections (those that meet SAE 
criteria) and results documented.  
8.3 
Adverse Events and Serious Adverse Events 
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
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The definitions of an AE or SAE can be found in Appendix B. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
Adverse events will be collected from the time of the first dose throughout the treatment 
period and including the follow-up period (final follow up is Visit 12 for Part A and Visit 8 
for Part B). The only exception is related to the pre-dose orthostatic test at Visit 3: if 
orthostatic hypotension is confirmed, it should be reported as an AE, and symptoms related to 
the measurement of orthostatic vitals if present should also be reported as an AE. 
SAEs will be recorded from the time of signing of the informed consent form. 
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
sponsor. 
8.3.2 
Follow-up of AEs and SAEs 
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse event variables 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
Maximum intensity 
• 
Maximum CTCAE grade for rash maculopapular 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the Investigational Product(s) (yes or no) 
• 
Action taken with regard to Investigational Product(s) 
• 
AE caused participant’s withdrawal from study (yes or no) 
• 
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In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
In case of fatality: 
− 
Probable cause of death 
− 
Date of death 
− 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 
8.3.3 Causality Collection 
The investigator should assess causal relationship between Investigational Product and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
8.3.4 Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
8.3.5 Adverse Events Based on Examinations and Tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR.  


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Deterioration as compared to baseline in protocol-mandated measurements should therefore 
only be reported as AEs if they fulfil any of the SAE criteria, are the reason for 
discontinuation of treatment with the investigational product or are considered to be clinically 
relevant as judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin 
≥ 2 × ULN may need to be reported as SAEs. Please refer to Appendix E for further 
instruction on cases of increases in liver biochemistry and evaluation of Hy’s Law. 
8.3.7 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AZ representatives within one day ie, immediately but no later than 24 hours 
of when he or she becomes aware of it. 
The designated AZ representative will work with the investigator to ensure that all the 
necessary information is provided to the AZ Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AZ representatives of any follow-up information on a previously reported SAE within one 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware of 
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Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AZ representative. If the EDC system is not 
available, then the investigator or other study site staff reports a SAE to the appropriate AZ 
representative by telephone. The AZ representative will advise the investigator/study site staff 
how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol. 
The reference document for definition of expectedness/listedness is the IB for the AZ drug.  
8.3.8 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AZ except for: 
• If the pregnancy is discovered before the study participant has received any study 
intervention 
8.3.8.1 
Maternal Exposure 
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to AZ. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital anomalies/birth defects and spontaneous miscarriages 
should be reported and handled as SAEs. Elective abortions without complications should not 
be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital anomaly) should be followed up 
and documented even if the participant was discontinued from the study. 
If any pregnancy occurs in the course of the study and is discovered after the first dose, then 
the investigator or other site personnel informs the appropriate AZ representatives within 1 
day, ie, immediately but no later than 24 hours of when he or she becomes aware of it. 
The designated AZ representative works with the investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site within 1 or 5 calendar days 
for SAEs (see Section 8.3.7) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy. 


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8.3.8.2 
Paternal Exposure  
Male participants should refrain from fathering a child or donating sperm during the study 
until 3 months after the final Follow-up Visit. 
In case of pregnancy in the partner of a male participant, the partner’s pregnancy should be 
reported on the pregnancy form (consent from the partner must be obtained before the 
pregnancy form is completed) following the same timeframe and routing as described for any 
participant’s pregnancy. Pregnancy of the participants’s partner is not considered to be an AE. 
These pregnancies will also be followed up, and the outcome of the pregnancy (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital anomaly) 
should, if possible, be obtained and documented. 
8.3.9 
Medication Error 
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AZ representatives within 1 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware 
of it. 
The designated AZ representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (other serious initial and follow up) calendar days if there is an SAE 
associated with the medication error (see Section 8.3.7) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B 4.   
8.3.9.1 
Drug Abuse 
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B 4.   
8.3.9.2 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix B 4.   


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8.4 
Overdose 
For this study, any dose of investigational product greater than those specified in this protocol 
within the same day will be considered an overdose. 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• An overdose without associated symptoms is only reported on the Overdose eCRF 
module 
 
If an overdose on an AZ study intervention occurs in the course of the study, the investigator 
or other site personnel inform appropriate AZ representatives immediately, but no later than 
24 hours of when he or she becomes aware of it. 
The designated AZ representative works with the investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site within one or 5 calendar 
days for overdoses associated with an SAE (see Section 8.3.7) and within 30 days for all 
other overdoses. 
8.5 
Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix C. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  
• 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses.  
− 
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled or individual pharmacokinetic 
samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR. 
 
8.5.1 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of AZD4831 as 
specified in the SoA (See Section 1.3). Pharmacokinetic Samples will be collected pre-dose; 
thus, participants should be reminded not to take their study medication at home on the day of 
their clinic visit as they will receive study medication in clinic on these days. Therefore, the 
last dose of study medication at Visit 11 for Part A, and either Visit 5, Visit 6 or Visit 7 for 


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Part B will be in clinic. For Part A, in a subset of participants where sites are able, additional 
post-dose PK samples will be collected at Visit 6 at the timepoints specified in the SoA. For 
participants who are discontinued from investigational product due to rash, a PK sample 
should be collected at the discontinuation visit. Samples may be collected at additional 
timepoints during the study if warranted and agreed upon between the investigator and the 
sponsor, eg, for safety reasons. The timing of sampling may be altered during the course of the 
study based on newly available data (eg, to obtain data closer to the time of peak or trough 
matrix concentrations) to ensure appropriate monitoring.  
Plasma samples will be used to analyse the PK of AZD4831. Samples collected for analyses 
of AZD4831 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.5.1.1 
Determination of Drug Concentration 
Samples for determination of drug concentration in plasma will be assayed by bioanalytical 
test sites operated by or on behalf of AZ, using an appropriately validated bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
report. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 
Placebo samples will not be analysed unless there is a need to confirm that correct treatment 
has been given to study participants. 
8.5.2 
Pharmacodynamics 
8.5.2.1 
Collection of Samples 
Blood samples will be collected for measurement of NT-proBNP, hsCRP, and IL-6 as 
specified in the SoA (See Section 1.3).  
An additional 5 mL blood sample may be collected for a NT-proBNP quick test to be 
performed on-site for pre-screening purposes; this test will be analysed locally and will not be 
sent to the central laboratory. The test must be recorded by site staff on the Pre-screening Log 
with a date and note of potential eligibility per Inclusion Criterion 6 (See Section 5.1) as Y/N 
based on the test result.  The pre-screening test does not replace the NT-proBNP sampling at 
the Screening (Visit 1) (See Section 1.3), which will be sent to the central laboratory.  


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Samples will be collected, handled, labelled, stored, and shipped as detailed in the Laboratory 
Manual. 
For storage, re-use, and destruction of pharmacodynamic samples, see Section 8.5 and 
Appendix C.  
8.6 
Human Biological Sample Biomarkers 
8.6.1 
Collection of Blood Samples for 
 
Blood samples for exploratory quantification of 
 are required and 
will be collected from participants in Part A and B of this study as specified in the SoA (See 
Section 1.3). 
Samples will be collected, handled, labelled, stored, and shipped as detailed in the Laboratory 
Manual. For storage, re-use and destruction of samples see Section 8.5 and Appendix C. 
8.6.2 
Collection of Mandatory Samples for Exploratory Biomarker and 
Metabolite Analysis 
By consenting to participate in the study the participant consents to the mandatory research 
components of the study.  
Blood samples for exploratory biomarker research are required and will be collected from all 
participants in this study as specified in the SoA (See Section 1.3). Plasma and serum samples 
will be collected for the analysis of biomarkers that may respond to treatment of AZD4831 
and/or that may predict response to treatment with AZD4831, including but not limited to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Part A, exploratory analysis of 
 
 will be performed at the timepoints specified in the SoA (See Section 1.3). Exploratory 
analysis of AZD4831 metabolites in plasma will also be performed at the timepoints specified 
in the SoA (See Section 1.3). 
CCI
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Where 
 is part of the parameters measured from blood samples collected for safety 
assessment and analysed at the central laboratory, the parameter from the sample collected for 
the safety assessment will be used for the exploratory biomarker analysis. 
 will be analysed through local laboratory and entered in the appropriate 
eCRF page. 
For Part A, for participants who discontinue investigational product due to rash or skin 
reaction, blood and urine will be collected at the EDV for exploratory biomarker analysis in 
blood and analysis of AZD4831 metabolites in urine and plasma. For Part B, only blood 
(plasma) will be collected for analysis of AZD4831 metabolites.  
Samples will be collected, handled, labelled, stored, and shipped as detailed in the Laboratory 
Manual. For storage, re-use and destruction of exploratory samples, see Section 8.5 and 
Appendix C. 
8.6.3 
Collection of Mandatory Sample for Genetic Analysis 
A blood sample will be collected for mandatory genetic analysis by AZ or designated 
organisation(s). This sample will be used to prepare DNA to assess the genotype of certain 
genes that may be related to how the investigational drug is metabolised by the participant's 
body and/or to the development of skin reactions. Genotyping will include, but will not be 
limited to, an assessment of the human leukocyte antigen genes. The genetic research may 
involve the genotyping of selected genes or the analysis of the whole genome sequence.  The 
sample will only be used for these purposes as outlined. 
The blood sample for genetic research will be obtained from the participants at Visit 3 and 
Visit 2 for Part A and Part B, respectively. 
If for any reason the sample is not drawn at these visits, it may be taken at any visit until the 
last study visit. Samples will be collected, labelled, stored, and shipped as detailed in the 
Laboratory Manual. 
8.6.4 
Collection of Mandatory Samples for Potential Diagnostic Assay 
Development 
Plasma and serum samples for potential diagnostic development are required and will be 
collected from all participants in Part A and B of this study as specified in the SoA (See 
Section 1.3). The intention of these samples is to provide additional samples for assessment of 
the variability in levels of candidate biomarkers that show potential to predict response to 
treatment with AZD4831 and to bridge from a Research Use Only assay to a diagnostic assay. 
The samples may be used for commercial diagnostic assay development. 
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Plasma and serum samples will be collected, handled, labelled, stored, and shipped as detailed 
in the Laboratory Manual. For storage, re-use and destruction of samples, see Section 8.5 and 
Appendix C. 
8.6.5 
Collection of Optional Samples for Future Biomarker Research 
Collection of plasma, serum and urine samples for future biomarker research is also part of 
this study for both Part A and B as specified in the SoA (See Section 1.3) and is subject to 
agreement to optional consent.  
Plasma, serum and urine samples will be collected for the future exploratory analysis of 
biomarkers that may respond to treatment with AZD4831 or that predict response to treatment 
with AZD4831. Distinct from the mandatory collection of exploratory samples, these samples 
may be used to analyse exploratory biomarkers not defined in the CSP and may include 
multiplex analysis using biomarker panels.  
Samples will be collected, handled, labelled, stored, and shipped as detailed in the Laboratory 
Manual. For storage, re-use and destruction of exploratory samples, see Section 8.5 and 
Appendix C. 
8.7 
Optional Genomics Initiative Sample 
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA (See Section 1.3) and is subject to agreement in the ICF addendum.  
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual.  
For storage and destruction of genetic samples see Appendix D.  
8.8 
Medical Resource Utilisation and Health Economics 
Medical Resource Utilisation and Health Economics parameters are not evaluated in this 
study. 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
Part A – 6MWD and KCCQ-TSS change from baseline at 16 weeks: 
The primary statistical test has the null hypothesis that there will be no difference between 
AZD4831 and placebo regarding mean change from baseline for the primary efficacy 
variables at 16 weeks.  
H0: μ(AZD4831) - μ(placebo) = 0, versus the alternative hypothesis: 
H1: μ(AZD4831) - μ(placebo) ≠ 0, where μ(x) is true mean change from baseline for 
treatment x. 
Part B – 6MWD change from baseline at 24 weeks: 
The primary statistical test has the null hypothesis that there will be no difference between 
AZD4831 and placebo regarding mean change from baseline for the primary efficacy  
variables at 24 weeks. 
H0: μ(AZD4831) - μ(placebo) = 0, versus the alternative hypothesis: 
H1: μ(AZD4831) - μ(placebo) ≠ 0, where μ(x) is true mean change from baseline for 
treatment x. 
Part B - KCCQ-TSS change from baseline at 24 weeks: 
The null hypothesis will be that neither the treatment group nor treatment-by-baseline 
interaction terms explain the expected change from baseline in KCCQ-TSS, ie: 
H0: β3=β4 = 0, versus the alternative hypothesis: 
H1: β3≠0 or β4≠0 or both. 
Where β3 is the coefficient for treatment group and β4 is the coefficient for the treatment-by-
baseline interaction term. See Section 9.4.2.1 for model specification details.  
9.2 
Sample Size Determination 
 
Part A 
Part B 
Enrolled 
Estimated 1100 participants 
Estimated 1350 participants 
Randomised 
Estimated 660 participants 
Estimated 820 participants 
Participants with complete safety 
data 
Estimated 600 participants 
Estimated 745 participants 
 


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Part A 
The sample size selection was based on the following assumptions: 
• 
Change from baseline in 6MWD is approximately normally distributed with a standard 
deviation of 70 meters (Nassif et al 2019). 
• 
Change from baseline in KCCQ-TSS is approximately normally distributed with a 
standard deviation of 18 points. 
 
Approximately 660 participants randomised, of which we estimate approximately 600 will 
have complete safety data, and 1:1:1 allocation, is chosen to have enough participants exposed 
to AZD4831 at the therapeutic dose to fulfil the minimum requirement in the ICH E1 
guideline on population exposure, taken together with Part B of this study, as well as a second 
function and symptom study with a similar design as Part B, and Phase 1 studies completed 
ahead of submission. 
With 85% power at a significance level of α = 0.05, 200 participants per arm will allow 
detection of a difference of 6.0 points in mean change from baseline between active and 
placebo in KCCQ-TSS comparing each active arm with placebo. The critical value for 
statistical significance is 3.9 points. The corresponding numbers for 6MWD are 21 meters and 
14 meters. Calculations of detectable differences and critical values are based on ANCOVA, 
which will also be used for the analysis. 
The potential effect of informative censoring, including all-cause mortality, will be considered 
during the analysis of the data and interpretation of the results, but not taken into account in 
the sample size calculations for Part A.  
Part B  
For part B, we assume that the type 1 error is controlled using Bonferroni adjustment (this is 
not necessarily the choice of method for type 1 error control in the analysis phase). 
For KCCQ-TSS, we assume that:  
• 
Change from baseline in KCCQ-TSS is approximately normally distributed with an 
expected value dependent on the baseline score, treatment group and treatment-by-
baseline interaction, and with a residual error of 18.  
• 
For KCCQ-TSS, due to the assumed treatment-by-baseline interaction, the power was 
assessed through simulation of normally distributed values truncated to the range [0, 100]. 
Simulated studies are analysed with ANCOVA with an interaction effect between 
treatment group and baseline KCCQ-TSS. The global null hypothesis of no impact of 
treatment group on the expected change from baseline is assessed by a likelihood-ratio 
test comparing this model to a model with no treatment effects.  
 


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Approximately 820 participants will be randomised in 1:1 allocation, of which we estimate 
approximately 745 will have complete safety data. The sample size is chosen to have enough 
participants exposed to AZD4831 at the therapeutic dose to fulfil the minimum requirement in 
the ICH E1 guideline on population exposure, taken together with Part A of this study as well 
as a second function and symptom study with a similar design as Part B, and Phase 1 studies 
completed ahead of submission. 
With the proposed number of participants, and under the alternative hypothesis for the 
treatment effect represented by the line y = 18.2 - 0.112*BASEKCCQ-TSS for the difference in 
expected change from baseline with AZD4831 compared to placebo as a function of the 
baseline score, the global null hypothesis can be rejected in more than 99% of simulations. 
For 6MWD, change from baseline in 6MWD is assumed to be approximately normally 
distributed with a standard deviation of 70 meters. Power calculations are based on a two-
sample t-test with shared variance. Assuming a true difference in mean change from baseline 
of 19 meters, the power to reject the null hypothesis is 95% with the proposed number of 
participants. The critical value is 11. 
9.3 
Populations for Analyses 
Part A 
Full Analysis Set: 
All participants who have been randomised to study treatment and who have received at least 
one dose of investigational product will be included in the Full Analysis Set irrespective of 
their protocol adherence and continued participation in the study. Participants will be analysed 
according to their randomised study medication assignment, irrespective of the treatment 
actually received. 
Safety Analysis Set: 
The Safety Analysis Set consists of all participants who have received at least one dose of 
investigational product. Erroneously treated participants (eg, those randomised to treatment A 
but actually given treatment B) are accounted for in the treatment group of the treatment they 
actually received. A participant who has received any dose of the experimental IP will be 
classified as in the experimental IP treatment group.  
Part B 
Full Analysis Set: 
All participants who have been randomised to study treatment and who have received at least 
one dose of investigational product will be included in the Full Analysis Set irrespective of 
their protocol adherence and continued participation in the study. Participants will be analysed 
according to their randomised study medication assignment, irrespective of the treatment 
actually received.  


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Efficacy and safety analyses in Part B will be done on the Full Analysis Set. 
9.4 
Statistical Analyses 
The Statistical analysis plans will be finalised prior to database lock and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. 
9.4.1 
General Considerations 
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violations have been identified and documented. The only exception are study 
independent personnel who are involved in the interim analyses in Part A. Analyses will be 
performed by AZ or its representatives. 
Nominal significance levels will be 0.05 and all tests performed will be two-sided. All 
confidence intervals will be 95%. 
For Part A, baseline will be defined as the last non-missing value on or before the day of first 
dose and on or before the day of randomisation (whatever occurs first), individually for each 
participant and endpoint. The baseline value for safety analyses is the last non-missing value 
prior to administration of the first dose of IP. 
In Part B, for subjects who receive first administration of IP on the day of randomisation, the 
baseline value for statistical analysis of safety parameters is the last non-missing value prior to 
the administration of the first dose of IP. For subjects where the first administration of IP takes 
place after the day of randomisation, the baseline is defined as relative to the day and 
timepoint of randomisation instead of actual day of first administration of IP. 
9.4.2 
Efficacy  
9.4.2.1 
Primary Endpoint(s) 
The primary efficacy endpoints are KCCQ-TSS and 6MWD and the primary efficacy 
variables are change from baseline in KCCQ-TSS and 6MWD at 16 weeks for Part A and at 
24 weeks for Part B. 
All primary variables will be analysed using ANCOVA with baseline and treatment group as 
covariate, and will be adjusted for the stratification factor for neutrophil count (Part A and 
Part B), comparing the AZD4831 doses versus placebo. For Part A, both single doses alone, 
and both doses pooled, will be compared with placebo. In Part B, a term for treatment by-
baseline interaction will be included as independent variable in the model for KCCQ-TSS. 


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Model summary in Part A: 
• 6MWD change from baseline at 16 Weeks: 
𝐸[𝐶𝐻𝐺6𝑀𝑊𝐷|𝐵𝐴𝑆𝐸6𝑀𝑊𝐷, 𝑇𝑅𝑇] 
= 𝛽0  + 𝛽1 ∗𝐵𝐴𝑆𝐸6𝑀𝑊𝐷 + 𝛽2 ∗𝑆𝑇𝑅𝐴𝑇𝐴 + 𝛽3 ∗𝑇𝑅𝑇 
• KCCQ-TSS change from baseline at 16 Weeks:  
𝐸[𝐶𝐻𝐺𝐾𝐶𝐶𝑄−𝑇𝑆𝑆 |𝐵𝐴𝑆𝐸𝐾𝐶𝐶𝑄−𝑇𝑆𝑆, 𝑇𝑅𝑇] 
= 𝛽0  + 𝛽1 ∗𝐵𝐴𝑆𝐸𝐾𝐶𝐶𝑄−𝑇𝑆𝑆+ 𝛽2 ∗𝑆𝑇𝑅𝐴𝑇𝐴 + 𝛽3 ∗𝑇𝑅𝑇 
Model summary in Part B 
• 6MWD change from baseline at 24 Weeks: 
𝐸[𝐶𝐻𝐺6𝑀𝑊𝐷|𝐵𝐴𝑆𝐸6𝑀𝑊𝐷, 𝑇𝑅𝑇] 
= 𝛽0  + 𝛽1 ∗𝐵𝐴𝑆𝐸6𝑀𝑊𝐷 + 𝛽2 ∗𝑆𝑇𝑅𝐴𝑇𝐴 + 𝛽3 ∗𝑇𝑅𝑇 
• KCCQ-TSS change from baseline at 24 Weeks:  
𝐸[𝐶𝐻𝐺𝐾𝐶𝐶𝑄−𝑇𝑆𝑆|𝐵𝐴𝑆𝐸𝐾𝐶𝐶𝑄−𝑇𝑆𝑆, 𝑇𝑅𝑇] 
= 𝛽0  + 𝛽1 ∗𝐵𝐴𝑆𝐸𝐾𝐶𝐶𝑄−𝑇𝑆𝑆+ 𝛽2 ∗𝑆𝑇𝑅𝐴𝑇𝐴 + 𝛽3 ∗𝑇𝑅𝑇 + 𝛽4
∗ 𝐵𝐴𝑆𝐸𝐾𝐶𝐶𝑄−𝑇𝑆𝑆∗𝑇𝑅𝑇 
Where TRT indicates randomized treatment group; STRATA indicates neutrophil baseline 
strata; BASE6MWD and CHG6MWD indicates baseline and change from baseline in 6MWD, 
respectively; and BASEKCCQ-TSS and CHGKCCQ-TSS indicates baseline and change from baseline 
in KCCQ-TSS, respectively. 
Subgroup analyses will be performed for both primary endpoints. 
Primary Efficacy Objectives Related Estimands: 
Part A: 
Treatment: Treatment with 2.5 mg or 5 mg AZD4831 compared to placebo, administered in 
addition to optimal back-ground therapy for co-morbidities. 
Population: Patients that fulfill all of the inclusion criteria, none of the exclusion criteria and 
have available measurements of the efficacy endpoint at baseline and 16 weeks. 
Endpoint: Change from baseline to 16 weeks in KCCQ-TSS and 6MWD. 
Intercurrent events: Patients with intercurrent events resulting in missing assessments of the 
primary endpoints, eg, terminal events or withdrawal from the study, is expected to be very 
few and will be excluded from the analysis (principal stratum strategy). Other intercurrent 


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events, eg, premature discontinuation of study treatment, will be ignored (treatment policy 
strategy).  
Population-level summary: Difference in adjusted mean change from baseline between 
groups. 
Missing data will not be imputed. 
Part B: 
Treatment: Treatment with either 2.5 mg or 5 mg AZD4831 compared to placebo, 
administered in addition to optimal back-ground therapy for co-morbidities. 
Population: Patients that fulfill all of the inclusion and none of the exclusion criteria. 
Endpoint: Change from baseline to 24 weeks in KCCQ-TSS and 6MWD. 
Intercurrent events:  
• 
Deaths will be handled by a While-alive strategy, implemented by using the change from 
baseline to 24 weeks or last measurement prior to death (if earlier than 24 weeks). 
• 
Intercurrent events other than deaths will be handled by a Treatment-policy strategy, ie, 
measurements will be collected and used in the statistical analysis regardless of the 
occurrence of the event 
 
Population-level summary: Between group difference in mean change from baseline at 24 
weeks or prior to death, if earlier. For KCCQ-TSS, this will be a function of baseline values.  
For patients with missing measurements for reasons other than death, a multiple imputation 
scheme will be employed, which differentiates between monotonous and non-monotonous 
missing data. Monotonous missing data are where observations are consistently missing after 
a point in time whereas non-monotonous missing data are missing observations followed by at 
least one recorded observation. For monotonous missing data, retrieved dropouts (patients 
remaining in the study despite same intercurrent events as drop-outs) will be used to impute 
missing values or, if there are too few retrieved dropouts, a Jump-to-reference approach 
utilizing placebo patients will be applied.  
As a supplementary approach, analyses where deaths are combined with the outcome 
variables in a Composite strategy will be conducted, and will be described in the SAP for Part 
B. 
Methods for multiplicity control, both Part A and Part B: 
The endpoints will be tested using an overall 2-sided alpha level of 0.05. Multiplicity across 
primary and secondary endpoints will be accounted for by utilising a pre-specified testing 


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procedure of the primary and secondary endpoints (and potentially among doses in Part A) 
and alpha recycling will be considered using a weighted group sequential recycling procedure 
following the approach of Burman et al (2009), (Ye et al 2013). Details will be described in 
the SAPs. 
9.4.2.2 
Secondary Endpoint(s) 
The secondary efficacy endpoints for Part A are 6MWD and KCCQ-TSS (at 24 and 48 
weeks), NT-proBNP, IL-6, and hsCRP (at 16, 24, and 48 weeks), LV-GLS, LAVI, and LVMI 
(at 16 and 24 weeks), and pharmacokinetic concentrations. The secondary efficacy endpoints 
for Part B are NT-proBNP, IL-6, and hsCRP (at 24 weeks). The secondary efficacy variables 
will be change from baseline in 6MWD, LV-GLS, LAVI, and LVMI for Part A and NT-
proBNP, IL-6, and hsCRP for Parts A and B, and will be analysed in the same manner as for 
the primary endpointof 6MWD. The secondary efficacy variable of KCCQ-TSS will be 
analysed in the same manner as for the primary endpoint of KCCQ-TSS. NT-proBNP, IL-6, 
and hsCRP will be analysed by applying log scale. 
Plasma concentrations of AZD4831 will be summarised by timepoints and dose level. If PK 
data permit, PK parameters, eg, AUC and Cmax, will be derived but also a population PK 
model will be developed, possibly with the support of PK data from other studies, using 
nonlinear mixed effects regression analysis in NONMEM. Furthermore, if data allows, the 
population PK model may be coupled with separate PD models. All PK/PD modelling will be 
described in a separate data analysis plan. Moreover, the derived PK parameters and the 
results of any such modelling will be provided in a separate PK and population PK/PD report 
(as an appendix to the CSR or as a stand-alone report). 
9.4.2.3 
Tertiary/Exploratory Endpoint(s) 
Tertiary/exploratory endpoints will be described in the SAPs. 
9.4.3 
Safety  
Safety and tolerability will be evaluated in terms of AEs, Vital signs, Clinical laboratory 
variables, and ECG . In addition, extra evaluation will be done for the following Adverse 
Events of Special Interest (AEoSI): skin reactions, including maculopapular rash, and 
infections (see Section 8.2). Exposure to study treatment will be described. 
Safety analyses will be performed using the safety analysis set in Part A, and using the full 
analysis set in Part B. Safety data will be presented using descriptive statistics unless 
otherwise specified. 
Safety analyses will be performed for two different study periods: on-study and on-treatment. 
These periods are defined in the Part A SAP and Part B SAP, respectively.  


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Safety Estimand Definition 
The aim with the analyses of safety data is to assess the general safety objective, evaluated in 
a scenario where study treatment is not prematurely discontinued. Two analysis approaches 
are considered complementary to assess this hypothetical scenario for all safety endpoints: 
• 
On-treatment; unbiased under the assumption that censoring following premature 
treatment discontinuation is non-informative. 
• 
On-study; unbiased under the assumption that the risk for an event is independent of 
continued treatment. Note that this approach could also be described as handling 
premature treatment discontinuation with a treatment policy approach. 
 
Hence, the general safety objective will be assessed through an estimand defined by the 
following attributes: 
Population: Patients that fulfill all of the inclusion and none of the exclusion criteria.. 
Treatment: Treatment with either 2.5 mg or 5 mg of AZD4831 compared to placebo, 
administered in addition to optimal back-ground therapy for co-morbidities. 
Intercurrent events: 
• 
Premature study treatment discontinuation: All analyses will be provided using two 
complementary approaches. 
o 
Hypothetical as premature study treatment discontinuation cannot occur, 
implemented by excluding/censoring data after premature study treatment 
discontinuation + 14 days.  
o 
Treatment policy by ignoring study treatment discontinuation, implemented by 
including all available data. 
• 
Initiation or change of concomitant medication, including rescue medication: Will be 
ignored, that is, handled using a treatment policy approach. 
• 
Death: With the exception of assessment of mortality, will be handled hypothetically as it 
cannot occur, implemented by censoring time to event data at death and not imputing any 
data after death.  
 
Population level summaries: Distribution of endpoints by treatment group, Kaplan-Meier 
estimate for endpoints by treatment group, difference in Kaplan-Meier estimates between 
treatment groups and treatment hazard ratios. 
This estimand requires that to the extent possible, randomised subjects are followed up 
regardless of study intervention compliance and adherence to the study protocol. 


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Adverse Events 
All AEs will be classified by system organ class, high level group term, high level term, and 
preferred term according to MedDRA. 
AEs will be presented for each treatment group by SOC and/or PT, covering number and 
percentage of subjects reporting at least one event. An overview of AEs will present for each 
treatment group the number and percentage of subjects with any AE, AEs with outcome of 
death, serious AEs, and AEs leading to discontinuation of IP. Separate AE tables will be 
provided taking into consideration seriousness, death, and events leading to discontinuation of 
IP. An additional table will present number and percentage of subjects with most common 
AEs. Most common (eg, frequency of >x%, ≥x%) will be defined in the SAP. In accordance 
with the requirements of the FDA, a separate table will present non-serious AEs occurring in 
more than 5% of subjects in any treatment group. Key subject information will be presented 
for subjects with AEs with outcome of death, serious AEs, and AEs leading to discontinuation 
of IP. An AE listing for the safety analysis set will cover details for each individual AE. 
AEoSIs related to skin reactions, including maculopapular rash, and infection will be 
presented. Full details of AE analyses will be provided in the SAP. 
All safety analyses are descriptive; hence no p-values will be presented for any safety 
analyses, and confidence intervals are provided as an illustration of precision of the estimate. 
Hazard ratio between treatment groups will be based on a Cox proportional hazards regression 
model with a factor for treatment group. 
Treatment emergent  
For Part A, the definition for treatment emergent events will be provided in the SAP. 
For Part B, the following AEs are considered treatment emergent: AEs with an onset date on 
or after baseline or a worsening of pre-existing AEs on or after baseline. A treatment emergent 
abnormality is defined as a switch in a safety parameter from not-abnormal at baseline to 
abnormal at post-baseline assessments accordingly to predefined criteria specified in the SAP. 
Vital signs  
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, Min, Q1, median, Q3, and Max. For each scheduled 
post-baseline visit, descriptive statistics for all vital sign parameters will be presented for 
observed values and change from baseline. Details of vital sign analyses will be provided in 
the SAP. 
In Part B, time to first treatment emergent abnormality will also be presented.  


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Laboratory 
Laboratory parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, Min, Q1, median, Q3, and Max. For each scheduled 
post-baseline visit, descriptive statistics for all clinical chemistry and haematology parameters 
will be presented for observed values and change from baseline. A frequency table presents 
number of subjects reporting at least one treatment emergent change in selected laboratory 
parameters. Details of laboratory analyses will be provided in the SAP. 
In Part B, time to first treatment emergent abnormality will also be presented. 
Electrocardiogram  
Electrocardiogram evaluation will be summarised and presented by treatment group for 
baseline and for each scheduled post-baseline assessment. More details of ECG analyses will 
be provided in the SAP. 
9.4.4 
Other Analyses  
For any digital devices used in the study, summaries of the related variables will be made and 
comparisons between treatment arms will be assessed descriptively. 
9.5 
Interim Analyses  
The Sponsor will conduct at least one, but possibly several, interim Analyses for Part A with 
the purpose of informing further development of the clinical programme, including but not 
limited to dose selection for Part B. The last interim analysis will be performed when all 
participants in Part A have completed the last protocol-specified visit/assessment (the last 
Week 52 visit [including telephone contact]). A URC will review each of the interim analyses. 
If Part B were not to start or progress, then the last interim would not be regarded as an 
interim but would become the final analysis.  
The SAP will describe the planned interim analyses in greater detail. 
9.6 
Data Monitoring Committee 
For details on Data Review Committee, Unblinded Review Committee, and Data Monitoring 
Committee, refer to Appendix A 5 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 


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Appendix A Regulatory, Ethical, and Study Oversight Considerations 
A 1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AZ. 
• 
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 
 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
For all studies except those utilising medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
− 
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [Investigator’s Brochure or state other documents] and will 
notify the IRB/IEC, if appropriate according to local requirements. 


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Regulatory Reporting Requirements for Serious Breaches 
• 
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
− 
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
− 
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency (EMA) Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS. 
• 
The investigator should have a process in place to ensure that: 
o 
The site staff or service providers delegated by the investigator/institution are 
able to identify the occurrence of a (potential) serious breach 
− 
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca. 
A 2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
A 3 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 


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Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study centre. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 
 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
A 5 
Committees Structure 
Data Review Committee:  For part A, an unblinded DRC will be set up for ongoing, periodic 
safety monitoring, with a focus on skin reactions. The DRC consists of internal sponsor 
expertise, an external dermatologist, and an external cardiologist. More information on roles, 
responsibilities, and procedures will be contained in the DRC charter. 
Unblinded Review Committee:  A URC consisting of a limited number of sponsor personnel 
will be formed to review data from Part A for at least one, but possibly several, interim 
analyses, with the purpose of informing further development of the clinical programme, 
including but not limited to dose selection for Part B. The URC will review the risk/benefit 


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profile and make recommendations on the dose for Part B and, based on safety, on the 
continuation of the program. When all participants in Part A have completed Week 52, the 
URC will review data for the last interim analysis to help inform further clinical development. 
External Data Monitoring Committee:  For Part B, an independent DMC, including a 
dermatologist, will be appointed and will report to the sponsor. The DMC will be responsible 
for safeguarding the interests of the participants by assessing the safety of the study treatment 
during the study and making appropriate recommendations based on the available data. The 
DMC will have access to the individual treatment codes and be able to merge these with the 
collected study data while the study is ongoing. A DMC charter will be prepared to detail 
precise roles and responsibilities and procedures to ensure maintenance of the blinding and 
integrity of the study in the review of accumulating data and interactions with the sponsor. 
A 6 
Dissemination of Clinical Study Data 
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted. 
A 7 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organisations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 


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the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
A 8 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
• 
Definition of what constitutes source data can be found in source data verification plan. 
 
A 9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. Part B will start following analysis of Part A. The sponsor will inform sites when 
Part B can be started. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or Good Clinical Practice guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 


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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study. 
A 10 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 


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Appendix B Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
B 1 
Definition of Adverse Events 
An adverse event is the development of any untoward medical occurrence in a participant or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
B 2 
Definition of Serious Adverse Events 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-participant hospitalisation or prolongation of existing hospitalisation  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a non-serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
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Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself an serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 
Intensity Rating Scale: 
• 
Mild (awareness of sign or symptom, but easily tolerated) 
• 
Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Severe (incapacitating, with inability to perform normal activities) 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 


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several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2. 
B 3 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


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B 4 
Medication Error, Drug Abuse, and Drug Misuse 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AZ study intervention that either causes harm to the participant or 
has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.  
• 
Occurred 
• 
Was identified and intercepted before the participant received the drug 
• 
Did not occur, but circumstances were recognised that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature  
• 
Wrong participant received the medication (excluding IRT/RTSM errors) 
• 
Wrong drug administered to participant (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
• 
Participant accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product  
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used 
both if the drug abuse happened in a study participant or if the drug abuse involves a person 
not enrolled in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
• The drug is used with the intent of getting a perceived reward (by the study participant 
or a person not enrolled in the study) 
• The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high  
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant). 
Examples of drug misuse include but are not limited to: 
• The drug is used with the intention to cause an effect in another person 
• The drug is sold to other people for recreational purposes  
• The drug is used to facilitate assault in another person 
• The drug is deliberately administered by the wrong route 
• The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 


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• Only half the dose is taken because the study participant feels that he/she is feeling 
better when not taking the whole dose 
• Someone who is not enrolled in the study intentionally takes the drug 
B 5 
Guide to skin reaction assessment 
This Appendix describes the process to be followed to appropriately identify, assess and 
report cases of skin reactions. Skin reactions, including maculopapular rash, will be 
considered AEs of special interest in this study. To ensure that data are collected 
systematically, any skin reaction will be recorded on a special eCRF page. All skin reactions 
should be recorded and reported as AEs or SAEs. 
If the rash is considered maculopapular, it will be evaluated using CTCAE grades 1-3 for rash 
maculopapular; if not considered maculopapular, severity will be captured as 
mild/moderate/severe, along with data element components generally used for CTCAE 
grading of other skin reactions, given that CTCAE grading is specific to the particular type of 
skin lesion. For all rashes, various aspects of the rash will be documented, including start/end 
date, morphology of lesions (maculopapular vs other morphologies), body surface area 
impacted, anatomical site(s), symptoms, signs, effect on participant (including ADL 
impacted), concomitant medications, medication administered, and specific rash diagnosis, if 
available.  
If maculopapular rash Grade 1, 2, or 3 has developed, participant must be permanently 
discontinued from IP, and AZ medical staff should be informed.  
If the participant develops a rash or skin reaction that is not considered a maculopapular rash, 
the participant must permanently discontinue if the rash/skin reaction is considered an SAE or 
is a generalised rash/skin reaction. AstraZeneca medical staff should be informed. 
At all visits, participants will be instructed to contact the investigator immediately if rash has 
developed at any time point during the study. Participants will be recommended to make an 
acceptable quality self-photo of skin affected with rash. 
Participants who develop skin reactions, including rash, will be asked to return to the clinic for 
an additional visit that will include a full physical examination and blood samples for safety, 
hsCRP, and PK. If a participant is discontinued from investigational product and proceeds to 
the EDV, exploratory biomarker sample and blood and urine samples for exploratory 
metabolite analysis will also be collected. The mandatory genetic sample per Section 8.6.3 
should also be collected at the EDV if not previously collected from the participant. Initiation 
of treatment with a topical steroid and/or oral antihistamine is suggested. The treatment should 
be individualised per participant and based on Investigator discretion. Upon Investigator 
discretion, a clinical dermatologist can be consulted and a skin biopsy considered. The 


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participant can be provided with a treatment for the skin rash, according to clinical 
management standard. Blood samples should be drawn prior to treatment, if possible, and 
without delaying treatment.  
Investigator should make quality photo(s) of participant’s skin affected with rash, that will 
allow the evaluation of rash according to the guidance given in this section.  
The Common Terminology Criteria for AEs is a descriptive terminology that can be used for 
AE reporting. 
In general, CTCAE Guideline describes the Grades of AE severity from 1 to 5:  
Grade 1:   
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
Grade 2:   
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*  
Grade 3:   
Severe or medically significant, but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self-care ADL**  
Grade 4:   
Life-threatening consequences; urgent intervention indicated 
Grade 5:  
Death related to AE 
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
**Self-care Activities of Daily Living (ADL) refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 


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Note: for Maculo-Papular rash, only 3 CTC Grades exist: 
Maculo-Papular Rash 
Definition: A disorder characterised by the presence of macules (flat) and papules (elevated). Also 
known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently 
affecting the upper trunk, spreading centripetally and associated with pruritis. 
Grade 1 
Macules/papules covering < 10% Body Surface Area with or without symptoms (eg, pruritus, 
burning, tightness) 
Grade 2 
Macules/papules covering 10 - 30% Body Surface Area, with or without symptoms (eg, pruritus, 
burning, tightness); limiting Instrumental Activities of Daily Living*; rash covering > 30% Body 
Surface Area with or without mild symptoms 
Grade 3 
Macules/papules covering > 30% Body Surface Area, with moderate or severe symptoms; limiting 
Self-care Activities of Daily Living ** 
 
Ref: (NCI 2017) 
 
To assess the Body Surface Area (BSA) affected by rash, please follow the algorithm 
described below: 
Area 
Number of palms 
Percent area 
Whole body 
100 
100% 
Head and Neck 
10 
10% 
Upper extremities 
20 
20% 
Trunk 
30 
30% 
Lower extremities 
40 
40% 
 
The participant’s palm is defined as ”1”, representing 1% of total Body Surface Area 
(BSA).  
Total BSA = 100% (100 palms).  
 


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Appendix C Handling of Human Biological Samples 
C 1 
Chain of Custody 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers 
Samples retained for further use will be stored in the AZ-assigned biobanks or other sample 
archive facilities and will be tracked by the appropriate AZ Team for the remainder of the 
sample life cycle. 
 
C 2 
Withdrawal of Informed Consent for Donated Biological Samples  
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AZ is not obliged to destroy the results of this research. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AZ or delegate. 
• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures that the participant and AZ are informed about the sample disposal. 
 
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified. 


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C 3 
International Airline Transportation Association 6.2 Guidance 
Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN 3373 and IATA 650 
 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf). 
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content 


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Appendix D Optional Genomics Initiative Sample 
D 1 
Use/Analysis of DNA 
• 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants. 
• 
This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome.  
• 
The results of genetic analyses may be reported in a separate study summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
 
D 2 
Genetic Research Plan and Procedures 
Selection of Genetic Research Population 
• 
All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study. 
 
Inclusion Criteria 
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent for 
the Genomics Initiative sampling and analyses. 
Exclusion Criteria 
• 
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following: 
− 
Previous allogeneic bone marrow transplant 
− 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection 
 
Withdrawal of Consent for Genetic Research 
• 
Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main Clinical Study Protocol. 
 


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Collection of Samples for Genetic Research 
• 
The 6 mL K2 EDTA blood sample for this genetic research will be obtained from the 
participants at Visit 3 and Visit 2 in Part A and Part B, respectively Although DNA is 
stable, early sample collection is preferred to avoid introducing bias through excluding 
participants who may withdraw due to an AE. If for any reason the sample is not drawn at 
Visit 3, it may be taken at any visit until the last study visit. Only one sample should be 
collected per participant for genetics during the study. 
 
Coding and Storage of DNA Samples 
• 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached. 
• 
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AZ genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AZ employee or designated organisations working with the DNA). 
• 
The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at AZ or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory 
audit, and permit tracing of samples for destruction in the case of withdrawal of consent. 
 
Ethical and Regulatory Requirements 
• The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A. 
 
Informed Consent 
• 
The genetic component of this study is optional and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study centre. The Principal investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time. 
 


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Participant Data Protection 
• 
AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law. 
• 
Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AZ Physician or an investigator 
might know a participant’s identity and also have access to his or her genetic data. 
Regulatory authorities may require access to the relevant files, though the participant’s 
medical information and the genetic files would remain physically separate. 
 
Data management 
• 
Any genetic data generated in this study will be stored at a secure system at AZ and/or 
designated organisations to analyse the samples. 
• 
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers.  
• 
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database. 
 


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


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
E 3 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 × ULN 
• 
AST ≥ 3 × ULN 
• 
TBL ≥ 2 × ULN 
 
Central Laboratories Being Used: 
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to AZ 
representative).  
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will: 
• 
Notify the AZ representative 
• 
Request a repeat of the test (new blood draw) by the central laboratory without 
delay 
• 
Complete the appropriate unscheduled laboratory eCRF module(s) with the 
original local laboratory test result 
 
When the identification criteria are met from central or local laboratory results the investigator 
will without delay: 
• 
Determine whether the participant meets PHL criteria (see Section E 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results) 
E 4 
Follow-up 
E 4.1 
Potential Hy’s Law Criteria not met 
If the participant does not meet PHL criteria the investigator will: 
• 
Inform the AZ representative that the participant has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 


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E 4.2 
Potential Hy’s Law Criteria met 
If the participant does meet PHL criteria the investigator will: 
• 
Notify the AZ representative who will then inform the central Study Team. 
• 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting. 
• 
For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition. 
• 
The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data. 
• 
Subsequent to this contact the investigator will: 
− 
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
− 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which tests available in 
the Hy’s law lab kit should be used.  
− 
Complete the three Liver eCRF Modules as information becomes available.  
 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. The 
determination of whether there has been a significant change will be at the discretion of the 
investigator, this may be in consultation with the Study Physician if there is any uncertainty. 
E 5 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AZ Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review together with other subject matter experts as 
appropriate.  


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According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
• 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Send updated SAE (report term ‘Hy’s Law’) according to AZ standard processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 


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E 6 
Laboratory Tests 
Hy’s Law Lab Kit for Central Laboratories  
Additional standard chemistry and coagulation 
tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
HBsAg 
IgM and IgG anti-HBc 
 
HBV DNA a 
IgG anti-HCV 
HCV RNA b 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-
transferrin) c 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin c 
Transferrin saturation 
aHBV DNA is only recommended when IgG anti-HBc is positive 
bHCV RNA is only recommended when IgG anti-HCV is positive or inconclusive  
cCD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly 
 
E 7 
References 
FDA Guidance for Industry, July 2009 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation 


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CCI


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Appendix G Typical Symptoms and Signs of Heart Failure 
Symptoms 
• 
Breathlessness 
• 
Orthopnoea 
• 
Paroxysmal nocturnal dyspnoea 
• 
Reduced exercise tolerance 
• 
Fatigue, tiredness 
• 
Increased time to recover after exercise. 
 
Signs 
More specific:  
• 
Elevated jugular venous pressure (JVP) 
• 
Hepatojugular reflex 
• 
Third heart sound (gallop rhythm) 
• 
Laterally displaced apical impulse. 
 
Less specific: 
• 
Weight gain (>2 kg/week) 
• 
Weight loss (in advanced HF) 
• 
Tissue wasting (cachexia) 
• 
Cardiac murmur 
• 
Peripheral oedema (ankle, sacral, scrotal) 
• 
Pulmonary crepitations 
• 
Reduced air entry and dullness to percussion at lung bases (pleural effusion) 
• 
Tachycardia, irregular pulse 
• 
Tachypnoea, Cheyne Stokes respiration 
• 
Hepatomegaly 
• 
Ascites 
• 
Cold extremities 
• 
Oliguria 
• 
Narrow pulse pressure. 


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Appendix H Kansas City Cardiomyopathy Questionnaire 
 


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Appendix I 
Patient Global Impression of Severity in Heart Failure 
Symptoms 
 
Patient Global Impression of Severity for Heart Failure Symptoms 
Overall, how would you rate the severity of your heart failure symptoms over the past 
2 weeks? 
 No symptoms 
 Very mild 
 Mild 
 Moderate 
 Severe 
 Very Severe 


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Appendix J 
Patient Global Impression of Severity in Walking Difficulties 
 
Patient Global Impression of Severity in Walking Difficulties 
 
Overall, how would you rate your walking ability today? 
 No limitations 
 Very mild limitations 
 Mild limitations 
 Moderate limitations 
 Severe limitations 
 Very Severe limitations 
 


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Appendix K Patient Rating of Dyspnoea (PRD) – Acute Version 
 
 


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Appendix L EuroQol 5-dimension 5-level Questionnaire 
 


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Appendix M Clinical Data Interchange Standards Consortium Definition 
for Hospitalisation for Heart Failure and Urgent Heart 
Failure Visit 
An HF Event includes hospitalisation for HF and may include urgent outpatient visits. Heart 
Failure hospitalisations should remain delineated from urgent visits. If urgent visits are 
included in the HF event endpoint, the number of urgent visits needs to be explicitly presented 
separately from the hospitalisations. 
Heart Failure Hospitalisation is defined as an event that meets ALL of the following 
criteria: 
1 
The patient is admitted to the hospital with a primary diagnosis of HF 
2 
The patient's length-of-stay in hospital extends for at least 24 hours (or a change in 
calendar date if the hospital admission and discharge times are unavailable) 
3 
The patient exhibits documented new or worsening symptoms due to HF on presentation, 
including at least ONE of the following: 
(a) Dyspnoea (dyspnoea with exertion, dyspnoea at rest, orthopnea, paroxysmal 
nocturnal dyspnoea) 
(b) Decreased exercise tolerance 
(c) Fatigue 
4 
The patient has objective evidence of new or worsening HF, consisting of at least TWO 
physical examination findings OR one physical examination finding and at least ONE 
laboratory criterion), including: 
(a) Physical examination findings considered to be due to HF, including new or 
worsened: 
o 
Peripheral oedema 
o 
Increasing abdominal distention or ascites (in the absence of primary hepatic 
disease) 
o 
Pulmonary rales/crackles/crepitations 
o 
Increased jugular venous pressure and/or hepatojugular reflux 
o 
S3 gallop 
o 
Clinically significant or rapid weight gain thought to be related to fluid retention 
(b) Laboratory evidence of new or worsening HF, if obtained within 24 hours of 
presentation, including: 
o 
Increased BNP/NT-proBNP concentrations consistent with decompensation of 
HF (such as BNP > 500 pg/mL or NT-proBNP > 2,000 pg/mL).  In patients with 
chronically elevated natriuretic peptides, a significant increase should be noted 
above baseline. 


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o 
Radiological evidence of pulmonary congestion. 
o 
Non-invasive diagnostic evidence of clinically significant elevated left- or right-
sided ventricular filling pressure or low cardiac output. For example, 
echocardiographic criteria could include: E/e’ > 15 or D-dominant pulmonary 
venous inflow pattern, plethoric inferior vena cava with minimal collapse on 
inspiration, or decreased left ventricular outflow tract minute stroke distance 
(time velocity integral). 
OR 
o 
Invasive diagnostic evidence with right heart catheterisation showing a 
pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) 
≥ 18 mmHg, central venous pressure ≥ 12 mmHg, or a cardiac index < 2.2 
L/min/m2  
Note: All results from diagnostic tests should be reported, if available, even if they do not 
meet the above criteria, because they provide important information for the 
adjudication of these events. 
5 
The patient receives initiation or intensification of treatment specifically for HF, 
including at least ONE of the following: 
(a) Augmentation in oral diuretic therapy 
(b) Intravenous diuretic or vasoactive agent (eg, inotrope, vasopressor, or vasodilator) 
(c) Mechanical or surgical intervention, including: 
o 
Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist 
device, extracorporeal membrane oxygenation, total artificial heart) 
o 
Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis) 
 
An Urgent HF Visit is defined as an event that meets all of the following: 
6 
The patient has an urgent, unscheduled office/practice or emergency department visit for 
a primary diagnosis of HF, but not meeting the criteria for a HF hospitalisation. 
7 
All signs and symptoms for HF hospitalisation (ie, symptoms and physical examination 
findings/laboratory evidence of new or worsening HF, as indicated above) must be met. 
8 
The patient receives initiation or intensification of treatment specifically for HF, as 
detailed in the above section with the exception of oral diuretic therapy, which will not be 
sufficient. 


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Appendix N Study Participant Feedback Questionnaire 


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Appendix O COVID-19 Specifics 
O 1 
Introduction 
The COVID-19 pandemic has had a striking impact on health care, as well as on ongoing and 
prospective clinical studies. Both EMA and FDA as well as national health authorities in 
Europe have issued new guidelines that aim to provide recommendations for actions for 
conduct of clinical studies of medical products during COVID-19 pandemic. As the threat of 
pandemic burden including new outbreaks, locally or globally, may impact the further conduct 
of clinical studies, appropriate risk assessments and mitigation measures will need to be taken 
into consideration in all clinical studies to protect subjects, site staff, and society as a whole.   
O 2 
Risk Assessment for COVID-19 Pandemic 
While there is a theoretical risk that treatment with an MPO inhibitor could impair host-
defense mechanisms, an increased incidence of infection has not been seen in limited clinical 
data with AZD4831; therefore, the risk to participants exposed to SARS-CoV-2 or to those 
who suffer from COVID-19 is expected to be similar to the background population with the 
same co-morbidities as those in the study, in particular HF. The risk of exposure to infected 
people cannot be completely excluded as the participants may need to expose themselves to 
public areas (eg, commute to the site) and have additional human contact (eg, with site staff 
and other participants of the clinical study). 
AstraZeneca has no data on the co-administration of AZD4831 and COVID-19 vaccines being 
approved. Potential AZD4831 vaccine interactions affecting patient safety or IMP and vaccine 
efficacy are therefore unclear. 
O 3 
Measures to Mitigate the Risks Associated with COVID-19 
National laws and local recommendations regarding the pandemic will be strictly adhered to. 
The probability of virus transmission will be controlled as much as possible by considering: 
• 
Advice for participant to adhere to local requirements for reduction of the public 
exposure while ambulatory. 
• 
Confirmation of COVID-19 by optional laboratory assessment will be conducted 
based on availability (test capacity and turnaround time) of approved tests and on 
Investigator’s discretion. 
• 
Requesting all participants to be contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs, including fever, dry cough, dyspnoea, 
sore throat, and fatigue and are asked not to attend the site in case of suspected 
reports. In addition, participants are asked for any contact with a person who has 
tested positive for SARS-CoV-2. If applicable, participants will be referred to the 
local health care system for further follow-up and treatment. 


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• 
Physical distancing and person-to-person contact restrictions will be applied during 
site visits.  
• 
Where physical distancing is not possible, personal protective equipment will be used 
by study participants (surgical face mask, gloves) and staff (for example but not 
limited to masks, gloves, protectors, medical suits) if deemed appropriate by the 
Investigators and site staff and guided by local requirements. 
• 
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing. 
O 4 
Suspected or Confirmed COVID-19 
O 4.1 
Prior to Enrolment 
Prior to Screening (Visit 1), participants should be called to confirm they are not experiencing 
any signs and symptoms of COVID-19, including fever, dry cough, dyspnoea, sore throat and 
fatigue. The participants with suspected ongoing (as judged by PI) or not completely resolved 
COVID-19 at Screening (Visit 1) will not be enrolled in the study. If the participant has a 
positive SARS-CoV-2 reverse transcription-polymerase chain reaction test result within 2 
weeks before Screening (Visit 1), the participant will not be enrolled in the study. 
Furthermore, the participants who have previously been hospitalised with SARS-CoV-2 
infection within the last 12 weeks, will not be enrolled in the study. Excluded participants will 
be treated according to standard of care. 
O 4.2 
At Randomisation 
The participants with suspected ongoing (as judged by PI) or confirmed COVID-19 at 
Randomisation (Visit 3 and Visit 2 for Part A and Part B, respectively), will be excluded from 
the study, and treated according to standard of care. 
O 4.3 
After Randomisation 
If the participant becomes symptomatic after screening, and has suspected (as judged by PI) or 
confirmed COVID-19, regardless of severity of the symptoms and potential hospitalisation, 
the participant may temporarily or permanently discontinue study intervention at the 
discretion of the site investigator. 
O 5 
References 
Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) 
pandemic, EMA, Version 3 (28/04/2020). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 


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FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020, Updated on June 03, 2020 https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-
products-during-covid-19-public-health-emergency 


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Appendix P Abbreviations 
Abbreviation or special 
term 
Explanation 
 6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
ADL 
Activities of Daily Living 
AE 
adverse event 
AEoSI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase/transaminase 
ANCA 
anti-neutrophil cytoplasmic antibody 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase/transaminase 
ATS 
American Thoracic Society 
AZ 
AstraZeneca 
BP 
blood pressure 
BMI  
body mass index 
BNP 
brain natriuretic peptide 
C-ANCA 
cytoplasmic staining anti-neutrophil cytoplasmic antibody 
CFR 
Code of Federal Regulations 
COVID-19 
coronavirus disease 2019 
CSP 
clinical study protocol 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
CYP3A4 
cytochrome P450 3A4 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DRC 
Data Review Committee 
E/e’ 
Ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity 
ECG 
electrocardiogram 
Echo 
echocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 


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Abbreviation or special 
term 
Explanation 
EQ-5D-5L 
EuroQol Five-dimensional Five-level Questionnaire 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
Hb 
haemoglobin 
HF 
heart failure 
HFmrEF 
heart failure with mid-range ejection fraction 
HFpEF 
heart failure with preserved ejection fraction 
HFrEF 
heart failure with reduced ejection fraction 
HL 
Hy’s Law 
HLT 
High-Level Terms 
hsCRP 
high-sensitivity C-reactive protein 
HV 
healthy volunteer(s) 
HV 
healthy volunteer 
IB 
Investigator’s Brochure 
IATA 
International Airline Transportation Associations 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IL-6 
interleukin 6 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
left atrial 
LAVI 
left atrial volume index 
LV 
left ventricle 
LVEF 
left ventricle ejection fraction 
LV-GLS 
left ventricular global longitudinal strain 
LVM 
left ventricular mass 
LVMI 
left ventricular mass index 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 


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Abbreviation or special 
term 
Explanation 
MPO 
myeloperoxidase 
MPOi 
MPO inhibitor 
NIMP 
Non Investigational Medicinal Product 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
p-ANCA 
perinuclear-anti-neutrophil cytoplasmic antibody 
PASP 
pulmonary artery systolic pressure 
PCWP 
pulmonary capillary wedge pressure 
PD 
pharmacodynamics 
PGIS-HF 
Patient Global Impression of Severity in Heart Failure 
PGIS-WD 
Patient Global Impression of Severity in Walking Difficulties 
PHL 
Potential Hy’s Law 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PRD 
Patient Rating of Dyspnoea 
PRO 
patient reported outcome 
PT 
Preferred Terms 
RNA 
ribonucleic acid 
RTSM 
Randomisation and Trial Supply Management 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
TBL 
total bilirubin 
TSS 
total symptom score 
UACR 
urinary albumin to creatinine ratio 
ULN 
upper limit of normal 
URC 
Unblinded Review Committee 
 


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Appendix Q Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the Table of Contents. 
Amendment 3 (09 February 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment 
To broaden entry criteria for KCCQ-TSS, modify entry criteria for NT-ProBNP. Some 
clarification to text is also included. All changes and the rationale are listed below. 
Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 1.1 Synopsis, 
Section 4.1 Overall Design, 
Section 4.3 Justification for 
Dose, Section 6.3 Measures 
to Minimise Bias: 
Randomisation and 
Blinding, Section 8.1.1 
Patient Reported Outcomes, 
Section 9.5 Interim 
analysis, Appendix A5 
Committees Structure 
Wording on interim analysis 
updated to add possibility for 
further interim analyses for 
Part A 
To allow for further 
interim analyses during 
Part A 
Substantial 
Section 1.1 Synopsis, , 
Section 9.2 Sample Size 
Determination 
Part A change from baseline 
clarified as mean change 
Clarification 
Non-substantial 
Section  1.2 Schema 
Figure 1 updated to clarify 
safety follow-up is double 
blind and to updated interim 
analysis timing 
Clarification 
Non-substantial 
Section 1.3 Schedule of 
Activities, Table 1, Part A. 
Footnote G 
Revised text:  Once 
approximately 20% of 
participants have been tested, 
no further participants would 
not need this additional post 
dose sampling 
Correction 
Non-substantial 
Section 1.3 Schedule of 
Activities, Table 1, Part A. 
Footnote H 
Wording updated to separate 
the calculation of UACR 
from central laboratory. 
UACR not calculated by 
central laboratory, 
calculation done by 
sponsor 
Non-substantial 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 1.3 Schedule of 
Activities, Table 1, Part A. 
Footnote K 
Included in the footnote for 
Echo that for Visit 8 and 
Visit 9 the Echo can be done 
at the earliest opportunity and 
within 7 days of the clinic 
visit if it cannot be performed 
on the same day as the clinic 
visit due to Echo scheduling. 
To add flexibility for 
participant scheduling 
Non-substantial 
Section 1.3 Schedule of 
Activities, Table 1, Part A. 
Footnote M, Section 8.3.1 
Time Period and Frequency 
for Collecting AE and SAE 
Information 
Added for pre-dose 
orthostatic test at Visit 3: if 
orthostatic hypotension is 
confirmed, it should be 
reported as AE, and 
symptoms related to the 
measurement of orthostatic 
vitals if present should also 
be reported as an AE 
To clarify that if 
orthostatic hypotension is 
confirmed on the pre-dose 
orthostatic test that this 
still be reported as AE 
even though before IMP 
to be consistent with 
wording in Section 8.2.2 
vital signs and for clearer 
identification and 
assessment of cases of 
orthostatic hypotension. 
Non-substantial  
Section 5.1 Inclusion 
Criteria (Inclusion criterion 
2) and Appendix G 
Heart failure criterion revised 
Simplification of the 
criteria 
Non-substantial 
Section 5.1 Inclusion 
Criteria (Inclusion criterion 
5) 
KCCQ-TSS points at 
Screening (Visit 1) and 
Randomisation (Visit 3) 
changed from ≤ 80 to ≤ 90 
Due to high screen failure 
rate this inclusion criterion 
has been broadened.  
However, a maximum of 
30% of the participants 
can have KCCQ-TSS > 80 
and ≤ 90 at randomisation 
visit. This cap has been 
added to Section 6.3. 
Substantial 
Section 5.1 Inclusion 
Criteria (Inclusion criterion 
6) 
Wording added that the ECG 
performed at Screening 
should be used for heart 
rhythm evaluation for this 
Inclusion criterion.  
Clarification 
Non -Substantial 
Section 5.1 Inclusion 
Criteria (Inclusion criterion 
6) 
Added that adjustment for 
NT-proBNP is now made for 
BMI. 
To accommodate the 
lower levels of NT-
proBNP that can be 
observed in obese patients 
Non-substantial 
Section 5.1 Inclusion 
Criteria (Inclusion criterion 
7c) 
Added alternative TRmax 
velocity units. 
To align with the unit that 
appears on the central core 
laboratory report. 
Non-substantial 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 5.2 Exclusion 
Criteria (Exclusion criterion 
8) 
Clarified that patients should 
be excluded if they have HF 
with recovered ejection 
fraction. Transient ejection 
fraction decrease eg, in the 
setting of an MI does not 
apply. 
Clarification 
Non-substantial 
Section 5.2 Exclusion 
Criteria (Exclusion criterion 
20) 
Added that exclusion is for 
active infection requiring 
oral, intravenous or 
intramuscular treatment  
Clarification 
Non-substantial 
Section 5.2 Exclusion 
Criteria (Exclusion criterion 
24) 
Any concomitant medications 
known to be associated with 
Torsades de Pointes: wording 
associated with Torsades de 
Pointes removed.  
QTc exposure/response 
modelling confirming no 
QTc prolongation after 
administration of 
AZD4831 at predicted and 
supra therapeutic exposure 
levels. 
Non-substantial 
Section 5.4 Screen Failures 
Added that NT-proBNP can 
also be re-tested once if 
Inclusion criterion 6 is not 
met, providing the result is 
not lower than 10% below 
the inclusion cut off 
To allow for re-test of NT-
proBNP on the low end 
value. Re-test of NT-
proBNP is already 
allowed on the high end 
value in Exclusion criteria 
7 
Non-substantial  
Requirement for rescreen to 
be after at least 30 days 
removed 
Restriction is not needed 
and this adds flexibility 
Non-substantial 
Section 6.3 Measures to 
Minimise Bias: 
Randomisation and 
Blinding 
Added that the study will also 
be capped for KCCQ-TSS 
With the change to the 
inclusion criteria for 
KCCQ-TSS to ≤90, a cap 
has been added that a 
maximum of 30% of the 
participants can have 
KCCQ-TSS > 80 and ≤ 90 
at randomisation visit in 
order that participants 
entering on the higher 
range are not over 
represented. 
Non-substantial  
Section 6.3 Measures to 
Minimise Bias: 
Randomisation and 
Blinding 
Cap on neutrophil count 
adjusted for > 4 × 106/mL 
from 70% to 60%-80% 
To add flexibility for 
recruitment without 
compromising the 
scientific intent. 
Non-substantial  


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 8.1.4 
Echocardiography 
Clarified that the independent 
core laboratory will be 
blinded to study treatment 
Clarification 
Non-substantial 
Section 8.2.2 Vital Signs 
Included “Visit 6” in the text 
that for Part A the repeated 
supine blood pressure 
measurement can also be 
used as the pre-dose supine 
measurement for the 
orthostatic test as long as the 
required conditions are met. 
To reduce the number of 
repeated blood pressure 
measurements at Visit 6 
Non-substantial 
Added that at Visit 3, if 
orthostatic hypotension is 
confirmed pre-dose and post-
dose, the orthostatic 
hypotension AE should be 
reported twice (pre-dose and 
post-dose) 
Clarification 
Non-substantial 
Added guidance related to 
reporting of symptoms 
related to the measurement of 
orthostatic vitals 
Clarification 
Non-substantial 
Section 9.4.2.1 Primary 
Endpoint(s) 
Wording “stratified by” 
corrected to “adjusted for” 
neutrophil count 
To allow for other 
methods of accounting for 
the randomisation 
stratification variable. 
Non-substantial 
AE, adverse event; BMI, body mass index; ECG, electrocardiogram; Echo, echocardiogram; HF, heart failure; 
IMP, Investigational Medicinal Product; KCCQ, Kansas City Cardiomyopathy Questionnaire; MI, myocardial 
infarction; NT-proBNP, N-terminal pro-brain natriuretic peptide; QT, ECG interal measured from the beginning 
of the QRS complx to the end of the T wave; QTc, corrected QT interval; SAE, serious adverse event; TSS, total 
symptom score; UACR, urinary albumin to creatinine ratio. 
 
Amendment 2 (01 November 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the EU 
because it neither significantly impacts the safety or physical/mental integrity of participants 
nor the scientific value of the study. 
Overall Rationale for the Amendment 
To reduce the complexity of the study by removing some exploratory assessments and 
optional assessments to reduce the burden to both participants and sites. Some clarification to 
text is also included. All changes and the rationale are listed below. 


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 1.1 
(Synopsis: Objectives 
and Endpoints) 
Observed value and absolute change 
from baseline values over time for 
ECG measurements removed and 
replaced with investigator evaluation. 
Correction as 
observed values are 
not being collected 
only investigator 
evaluation 
Non-substantial 
Section 1.1 
(Synopsis: Data 
Monitoring 
Committee) 
Addition of a further external member 
Request of French 
regulatory authority 
Non-substantial 
Section 1.2 
(Schema: Figure 1 
Study Design - Part A) 
Removal of 1MSTST, activity monitor, 
Holter Patch, retinal scans, and CPET  
Simplification of the 
CSP 
Non-substantial 
Section 1.2 
(Schema: Figure 2 
Study Design - Part B) 
Removal of Visit “8” as no longer 
applicable due to removal of activity 
monitor – subsequent visit numbers (9, 
10 and 11) changed to 8, 9, and 10 
Simplification of the 
CSP 
Non-substantial 
Section 1.2 
(Schema: Figure 2 
Study Design - Part B) 
Footnotes a and b included 
To align with 
presentation in the 
Schema for Part A 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A) 
Removal of optional informed consent 
collection for retinal scan 
Retinal scans are no 
longer being 
performed in this 
study. 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, and 
associated footnote) 
Removal of 1MSTST with oximeter 
Simplification of the 
CSP 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A) 
Removal of ANCA samples at Week 4, 
Week 12, Week 16, Week 24, 
Week 36, and Week 52 Follow-up 
Simplification of the 
CSP 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A) 
Removal of complement samples 
Simplification of the 
CSP 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, and 
associated footnote) 
Removal of activity monitor  
Simplification of the 
CSP 
Non-substantial  
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, and 
associated footnote) 
Removal of placement of Holter patch 
Simplification of the 
CSP 
Non-substantial  


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, and 
associated footnotes) 
Removal of CPET 
Simplification of the 
CSP 
Non-substantial  
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, and 
associated footnote) 
Removal of collection of digital retinal 
photographs 
Simplification of the 
CSP 
Non-substantial  
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A) 
Removal of optional Paxgene blood 
sample for RNA analysis 
Simplification of the 
CSP 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A) 
Additional AE/SAE assessments 
introduced at Visits 2 and 7 
To align assessments 
with the timing of 
telephone contact by 
site  
Non-substantial  
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, 
footnote a) 
Text added to indicate that telephone 
contact will be made by the site at 
Visits 2 and 7 to remind participants of 
the need to complete remote KCCQ 
To assist participant 
with management of 
the electronic PRO 
assessment device at 
home 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 1 – Part A, 
footnote h) 
Text added to indicate creatinine and 
albumin will also be collected at 
Visits 3, 8, and 11 along with 
calculation of UACR 
Sample added as a 
biomarker of 
endothelial 
dysfunction for 
prognostic evaluation 
in the study 
population 
Non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 2 – Part B) 
Removal of Visit “8” as no longer 
applicable due to removal of the 
activity monitor – subsequent visit 
numbers (9, 10, and 11) changed to 8, 
9, and 10  
Simplification of the 
CSP 
Non-substantial  
Removal of ANCA samples at Week 4, 
Week 12, and Week 28 Follow-up 
Removal of complement samples 
Section 1.3  
(Schedule of Activities: 
Table 2 – Part B, and 
associated footnote) 
Removal of activity monitor dispense 
and collection 
Simplification of the 
CSP 
Non-substantial  


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name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 1.3  
(Schedule of Activities: 
Table 2 – Part B) 
Additional AE/SAE assessments 
introduced at Visits 2, 6 and 7 
To align assessments 
with the timing of 
telephone contact by 
site 
Non-substantial  
Section 1.3  
(Schedule of Activities: 
Table 2 – Part B 
footnote a) 
Text added to indicate that telephone 
contact will be made by the site at 
indicated visits to remind participants 
of the need to complete remote KCCQ 
To assist participant 
with management of 
the electronic PRO 
assessment device at 
home 
Non-substantial 
Section 2.3.1 
(Risk Assessment) 
Updates to number of participants with 
events of maculopapular rash 
Updated in line with 
latest data for 
completed Phase 1 
studies 
Non-substantial 
Section 3.1 
(Objectives and 
Endpoints: Part A 
Table 4: Objectives and 
Endpoints - Safety) 
Observed value and absolute change 
from baseline values over time for 
ECG measurements removed and 
replaced with investigator evaluation 
Correction as 
observed values are 
not being collected 
only investigator 
evaluation 
Non-substantial 
Section 3.1 
(Objectives and 
Endpoints: Part A 
Table 4: Objectives and 
Endpoints - Tertiary/ 
Exploratory)  
Removal of objectives and endpoints 
related to: 
• 
pVO2 
• 
Activity monitor 
• 
Holter patch 
• 
1MSTST  
• 
Collection of pulse oximeter data 
Simplification of the 
CSP 
Non-substantial  
Section 3.1 
(Objectives and 
Endpoints: Part A 
Table 4: Objectives and 
Endpoints - Tertiary/ 
Exploratory) 
Addition of urine to objective wording 
for exploratory analysis of biomarkers 
To align with update 
to endpoints 
Non-substantial 
Section 3.1 
(Objectives and 
Endpoints: Part A 
Table 4: Objectives and 
Endpoints - Tertiary/ 
Exploratory) 
Removal of insulin from endpoints for 
exploratory analysis of biomarkers 
Simplification of the 
CSP 
Non-substantial 


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 3.1 
(Objectives and 
Endpoints: Part A 
Table 4: Objectives and 
Endpoints - Tertiary/ 
Exploratory) 
Addition of UACR to endpoints for 
exploratory analysis of biomarkers 
Addition of UACR as 
a biomarker of 
endothelial 
dysfunction for 
prognostic evaluation 
in the study 
population 
Non-substantial 
Section 3.2 
(Objectives and 
Endpoints: Part B 
Table 5: Objectives and 
Endpoints - Safety) 
Observed value and absolute change 
from baseline values over time for 
ECG measurements removed and 
replaced with investigator evaluation. 
Correction as 
observed values are 
not being collected 
only investigator 
evaluation 
Non-substantial 
Section 3.2 
(Objectives and 
Endpoints: Part B 
Table 5: Objectives and 
Endpoints - Tertiary/ 
Exploratory) 
Removal of objective and endpoint 
related to activity monitor 
Simplification of the 
CSP 
Non-substantial  
Section 4.3 
(Justification for Dose) 
Updates to exposure in Phase 1 studies 
and number of participants with events 
of maculopapular rash 
Updated in line with 
latest data for 
completed Phase 1 
studies 
Non-substantial 
Section 5.1 
(Inclusion Criterion 2) 
Rewording of text in relation of signs 
and symptoms of HF to align with 
Appendix G. 
Text related to signs 
of symptoms of HF 
clarified to align with 
Appendix G. 
Non-substantial 
Section 5.1 
(Inclusion Criterion 2) 
Removal of text relating to participant 
use of an oral diuretic prior to study 
entry 
For the removal of 
text related to use of 
oral diuretic. Site 
clinicians to make the 
clinical diagnosis of 
HF. The degree of 
congestion and/or 
diuretic use does not 
impact the scientific 
rationale for the 
study, nor the 
anticipated effect of 
AZD4831 
Non-substantial 


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 5.1 
(Inclusion Criterion 3) 
Removal of text in relation to 
documenting LVEF > 40% within 
12 months prior to Screening and 
added LVEF should be > 40% at 
Screening Visit 1 
Simplification of the 
CSP as the LVEF is 
confirmed on the 
echocardiogram 
performed at the 
screening visit and 
read through central 
imaging core 
laboratory this 
historical 
confirmation is 
deemed as not 
necessary 
Non-substantial 
Section 5.1 
(Inclusion Criterion 13) 
Removal of optional informed consent 
collection for retinal scan 
Retinal scans are no 
longer being 
performed in this 
study 
Non-substantial 
Section 5.1 
(Inclusion Criterion 14) 
Removal of optional informed consent 
collection for Paxgene RNA analysis 
Paxgene RNA 
analysis is no longer 
being performed in 
this study 
Non-substantial 
Section 5.2 
(Exclusion Criterion 6) 
Removal of method of assessment sub 
bullets  
To improve clarity 
the additional sub 
bullets were removed 
as these do not assist 
with the assessment 
of exercise capacity. 
Non-substantial  
Section 5.2 
(Exclusion Criterion 8) 
Change of text from cardiac to 
cardiovascular and expansion of text to 
include aortic aneurysm surgery, etc 
Typographical update 
from cardiac to 
cardiovascular, and 
for clarity further 
examples of planned 
cardiovascular 
procedures given 
Non-substantial  


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 5.2 
(Exclusion 
Criterion 23) 
Removal of bullet related to signs and 
symptoms consistent with COVID-19  
Bullet removed as the 
examples for signs 
and symptoms cover 
conditions other than 
COVID-19 which are 
not always 
exclusionary 
therefore this added 
bullet is not deemed 
necessary and is 
covered in the first 
line of the exclusion. 
Non-substantial  
Section 6.1.2 
(Medical Devices) 
Section removed  
DMS MyPatch, 
Masimo MightySat 
and Actigraph 
Centrepoint Insight 
Watch no longer 
being used due to 
simplification of the 
protocol. Section 
therefore no longer 
applicable 
Non-substantial 
Section 8 
(Study Assessments 
and Procedures) 
Total blood volumes collected on study 
revised to: 
• 
318 mL (from 420 mL) for Part A 
• 
194 mL (from 250 mL) for Part B 
In line with reduction 
and removal of 
samples 
Non-substantial 
Section 8.1.1 
(Patient Reported 
Outcomes) 
Wording added that PRO assessments 
completed at home could be removed 
for Part B if not supported from the 
Part A Week 16 interim analysis. 
To allow for removal 
of the remote 
collection of KCCQ 
for Part B 
Non-substantial 
Removed reference to 1MSTST 
1MSTST removed at 
this amendment, 
therefore no longer 
applicable 
Language added to permit the omission 
of the at home collection of the KCCQ. 
Participant inability to use the 
electronic device at home for specified 
reasons will not preclude their 
participation in the study 
To allow for 
instances where 
participants find they 
are not able, or 
comfortable, to use 
the electrical device 
at home 


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Text added to indicate that telephone 
contact will be made by the site to 
remind participants of the need to 
complete remote KCCQ 
To assist participant 
with management of 
the electronic PRO 
assessment device at 
home 
Non-substantial 
Section 8.1.1.3 
(Patient Global 
Impression of Severity 
in Walking Difficulties 
[Part A only]) 
Removed reference to 1MSTST 
1MSTST removed at 
this amendment, 
therefore no longer 
applicable 
Non-substantial 
Section 8.1.1.4 
(Patient Rating of 
Dyspnoea, Acute 
Version) 
Removed reference to 1MSTST 
1MSTST removed at 
this amendment, 
therefore no longer 
applicable 
Non-substantial 
Section 8.1.3 
(6-Minute Walk Test) 
Reference to 1MSTST being done after 
6MWT removed 
1MSTST removed at 
this amendment, 
therefore no longer 
applicable 
Non-substantial 
Section 8.1.4 
(Echocardiography) 
Text added to permit > 7 days for a 
repeat echocardiogram assessment 
following the screening 
echocardiogram. Repeat assessment to 
be completed prior to randomisation 
(Visit 3)  
To allow greater 
flexibility with repeat 
echocardiogram 
scheduling at 
Screening  
Non-substantial 
Section 8.1.5 
(Peak VO2 
Cardiopulmonary 
Exercise Test [Part A 
only]) 
Section removed  
Simplification of the 
CSP 
Non-substantial 
Section 8.1.7  
(Activity Monitoring) 
Section removed  
Simplification of the 
CSP 
Non-substantial 
Section 8.1.8 
(1-Minute Sit-to-stand 
Test [Part A only])  
Section removed 
Simplification of the 
CSP 
Non-substantial 
Section 8.1.9  
(Holter Patch [Part A 
only]) 
Section removed 
Simplification of the 
CSP 
Non-substantial 
Section 8.1.10 
(Retinal Scan [Part A 
only]) 
Section removed 
Simplification of the 
CSP 
Non-substantial 


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 8.2.1 
(Physical 
Examinations) 
Part B Visit 10 changed to Visit 9  
Visit 8 removed from 
CSP (collection of 
activity monitor) – 
visit numbers updated 
accordingly  
Non-substantial 
BMI calculation included 
For clarity 
Section 8.2.2 
(Vital Signs) 
Clarified that for Part A, the repeated 
supine blood pressure measurement at 
Visit 3 can also be used as the pre-dose 
supine measurement for the orthostatic 
test as long as the required conditions 
are met 
To reduce the number 
of repeated blood 
pressure 
measurements at 
Visit 3 
Non-substantial 
Section 8.2.4 
(Clinical Safety 
Laboratory 
Assessments) 
Indicated that ANCA samples may be 
collected if clinically indicated 
For clarification 
Non-substantial 
Section 8.2.4 
(Clinical Safety 
Laboratory 
Assessments) 
Removal of complement sample 
collection from Table 8 
Simplification of the 
CSP 
Non-substantial 
Text relating to blood sample 
collection and measurement for ANCA 
and complement (taken at Week 4, 
Week 12, Week 24, Week 36, Week 52 
Follow-up for Part A and Week 4 and 
Week 28 Follow-up for Part B) 
removed as these samples are no longer 
being taken 
Section 8.3.1  
(Time Period and 
Frequency for 
Collecting AE and 
SAE Information)  
Part B Visit 11 changed to Visit 10  
Visit 8 removed from 
CSP (collection of 
activity monitor) – 
visit numbers updated 
accordingly 
Non-substantial  
Section 8.3.10  
(Medical Device 
Deficiencies) 
Section removed 
Medical devices no 
longer being used in 
the study. Section no 
longer applicable 
Non-substantial. 
Section 8.5.1 
(Pharmacokinetics)  
Part B Visit 10 changed to Visit 9 
Visit 8 removed from 
CSP (collection of 
activity monitor) – 
visit numbers updated 
accordingly 
Non-substantial  


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Section number and 
name 
Description of changes 
Brief rationale 
Substantial/ 
non-substantial 
Section 8.6.2 
(Collection of 
Mandatory Samples for 
Exploratory Biomarker 
Analysis) 
Removal of insulin from endpoints for 
exploratory analysis of biomarkers 
Simplification of the 
CSP 
Non-substantial 
Section 8.6.2 
(Collection of 
Mandatory Samples for 
Exploratory Biomarker 
Analysis) 
Addition of UACR to endpoints for 
exploratory analysis of biomarkers 
Addition of UACR as 
a biomarker of 
endothelial 
dysfunction for 
prognostic evaluation 
in the study 
population 
Non-substantial 
Section 8.6.6 
(Optional Collection of 
Paxgene Blood Sample 
for RNA Analysis [Part 
A only]) 
Section removed 
Paxgene RNA 
analysis is no longer 
being performed in 
this study 
Non-substantial 
Section 9.4.3 (Safety; 
Electrocardiograms) 
Section updated as ECG data will be 
investigator evaluation rather than 
individual ECG values   
Correction as 
observed values are 
not being collected 
only investigator 
evaluation 
Non-substantial 
Appendix A 5 
Committees Structure 
Addition of a further external member 
Request of French 
regulatory authority 
Non-substantial 
Appendix Q 
(Protocol Amendment 
History) 
Details of Amendment 1 moved to this 
section 
Change in line with 
CSP template 
requirements 
Non-substantial 
1MSTST, 1-minute sit-to-stand test; 6MWT, 6-minute walk test; AE, adverse event; ANCA, anti-neutrophil 
cytoplasmic antibody; BMI, body mass index; COVID-19, coronavirus disease 2019; CPET, cardiopulmonary 
exercise test; CSP, clinical study protocol; ECG, electrocardiogram; HF, heart failure; LVEF, left ventricle 
ejection fraction; KCCQ, Kansas City Cardiomyopathy Questionnaire; PRO, patient reported outcome; pVO2, 
peak volume of oxygen consumption; RNA, ribonucleic acid; SAE, serious adverse event; UACR, urinary 
albumin-to-creatinine ratio. 
 
Amendment 1 (25 May 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for the Amendment 
To provide clarifications on various points, to remove unnecessary tests, and include 
additional safety testing based on regulatory feedback. 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Urine sample for biomarker 
analysis line added for sample that 
is sent to central laboratory. 
To add clarity to 
distinguish between 
urine sample tested at 
site and sample tested by 
central laboratory for 
uric acid. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A and 
Table 1 Part B) 
Pregnancy testing removed. 
As women of 
childbearing potential are 
excluded from the study 
pregnancy testing is not 
considered necessary. 
Substantial 
Section 1.2 
(Study Design Part A) 
Section 1.3 
(Schedule of Activities 
Table 1 Part A and 
related footnotes a and 
g) 
Removal of remote 1MSTST 
measurement. 
Reduce complexity of 
study. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
As Visit 5 now only covers a 
telephone call to check for AEs, 
timing been changed from 
11 weeks post-randomisation to 8 
weeks post-randomisation. 
To check AEs midway 
between Visit 4 and 6. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Removal of assessment of AEs at 
Visit 2 and Visit 7. 
In line with removal of 
1MSTST, site no longer 
contacting the participant 
at this visit. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Footnote e related to orthostatic 
hypotension updated to include 
measurement 1-2 hours after the 
first dose of AZD4831. 
Added in line with 
recommendations from 
FDA. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Footnote g updated to remove 
reference to site reminding 
participant to wear activity monitor 
whilst doing the 1MSTST at home. 
Text removed as not 
applicable. 
Non-substantial 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Footnote h updated to modify the 
timepoints from 0.5-1 hours and 
1-3 hours to 0.5-1.5 hours and 1.5-3 
hours post dose timepoints for PK 
at Visit 6 and to clarify that when 
approximately 20% of the 
participants having this assessment 
have been reached no further 
participants need undergo the extra 
PK sampling. 
To modify the timepoints 
and reduce participant 
burden by limiting the 
number of participants 
undergoing extra PK 
assessments post dose. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Footnote i updated to clarify that 
urine sample at Visit 3, Visit 8 and 
Visit 11 is sent to central 
laboratory. 
To distinguish between 
urine sample tested at 
site and sample tested by 
central laboratory for 
uric acid. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Footnote j text added specifying 
that Met-haemoglobin is performed 
at sites that have the facility to 
conduct this test. 
To clarify as not all sites 
have the facilities to 
conduct this test. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A and 
Table 1 Part B) 
Footnote l added to clarify that 
screening echocardiogram can be 
performed on a different day to 
Screening Visit 1 if not possible to 
schedule on the same day but must 
be done as soon as possible after 
Screening Visit 1 ie, within 1-2 
days. 
To accommodate for 
potential scheduling 
difficulties. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part A) 
Footnote n updated to clarify that 
the patch be placed on participant 
after the echocardiogram. 
As the patch will 
interfere with conducting 
the echocardiogram the 
patch should be placed 
on the participant after 
the echocardiogram. 
Non-substantial 
Section 1.3 
(Schedule of Activities 
Table 1 Part B) 
AE check added at Visit 8. 
Participant would be 
coming to clinic at this 
visit, so AE check added. 
Non-substantial 
Section 3 
(Objectives and 
Endpoints Part A, 
Table 4) 
Text regarding remote 1MSTST 
removed. 
In line with removal of 
remote 1MSTST. 
Non-substantial 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 3 
(Objectives and 
Endpoints Part A, 
Table 4 and Part B, 
Table 5) 
Specified comparison with placebo 
for tertiary/exploratory objective on 
NHYA class. 
For clarity. 
Non-substantial 
Section 5.1 
(Inclusion Criteria)  
Section on informed consent 
updated to include optional 
collection of paxgene blood sample 
for RNA analysis. 
Updated as collection of 
paxgene blood sample 
for RNA analysis is also 
an optional consent. 
Non-substantial 
Section 5.2 
(Exclusion Criteria) 
Exclusion Criterion 12 updated to 
clarify cardiomyopathies. 
To add clarity to criteria 
of cardiomyopathies. 
Non-substantial 
Section 5.2 
(Exclusion Criteria) 
Exclusion Criterion 17 updated to 
include any known and ongoing 
Hepatitis B or C. 
To add clarity to the 
exclusion of chronic 
infectious liver disease. 
Non-substantial 
Section 5.2 
(Exclusion Criteria) 
Exclusion Criterion 21 updated to 
prior history of drug or alcohol 
abuse to be abuse likely to impact 
participant safety or compliance 
with study procedures as judged by 
the investigator. 
To add clarity to the 
criteria of prior history. 
Non-substantial 
Section 5.3.1 
(Meals and Dietary 
Restrictions) 
Text added that study intervention 
can be taken with or without food. 
To clarify that study 
intervention can be taken 
with or without food. 
Non-substantial 
Section 8.1.1.4 
(Patient Rating of 
Dyspnoea, Acute 
Version) 
Reference at home removed. 
In line with removal of 
remote 1MSTST. 
Non-substantial 
Section 8.1.8 
(1-Minute Sit-to-Stand 
Test Part A only) 
Text removed regarding assessment 
at home. 
In line with removal of 
remote 1MSTST to 
reduce complexity of the 
study. 
Non-substantial 
Section 8.2.2 
(Vital Signs) 
Assessment of orthostatic vitals at 
1-2 hours after the first dose of 
AZD4831 added. 
Added in line with 
recommendations from 
FDA. 
Non-substantial 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 8.2.2 
(Vital Signs) 
Cut-offs for change in systolic and 
diastolic blood pressure to diagnose 
orthostatic hypotension based on 
baseline systolic blood pressure 
updated to be definition of 
orthostatic hypotension a drop of 
≥ 20 mmHg of systolic blood 
pressure or ≥ 10 mmHg 
independent of the baseline blood 
pressure. 
Added in line with 
recommendations from 
FDA. 
Non-substantial 
Section 8.2.2 
(Vital Signs) 
Text added regarding participants 
with orthostatic hypotension. 
Added in line with 
recommendations from 
FDA. 
Non-substantial 
Section 8.2.2 
(Vital Signs) 
Instructions added regarding 
recording of symptoms of dizziness 
or light headedness. 
Added in line with 
recommendations from 
FDA. 
Non-substantial 
Section 8.2.4 
(Clinical Safety 
Laboratory 
Assessments [Table 8]) 
Table updated to remove reference 
to uric acid sample as this has now 
been added to Schedule of 
Activities table. 
 
Reference to pregnancy testing 
removed in table. 
To add clarity to 
distinguish between 
urine sample tested at 
site and sample tested by 
central laboratory. 
 
To reflect update of 
removal or pregnancy 
testing. 
Non-substantial 
Section 8.2.4 
(Clinical Safety 
Laboratory 
Assessments) 
Text added to clarify that the blood 
samples for ANCA and 
complement taken at Week 4, Week 
12, Week 24, Week 36, Week 52 
follow-up for Part A and Week 4 
and Week 28 Follow-up for Part B 
will be collected and only be 
measured if the resulting analyses 
are deemed to be useful to further 
evaluation of AZD4831 based on 
emerging study data. 
To add clarity samples 
will be collected at the 
highlighted timepoints 
but not measured unless 
deemed to be useful for 
further evaluation of 
AZD4831. These 
samples are still useful to 
be collected if needed 
based on emerging safety 
data. 
Non-substantial 
Section 8.3.8.1 
(Maternal Exposure) 
Congenital abnormality changed to 
congenital anomaly. 
To meet regulatory 
requirements on good 
pharmacovigilance 
practices. 
Non-substantial 
Section 8.3.8.1 
(Maternal Exposure) 
Wording “When the eCRF module 
is used include the following” 
removed. 
Text not required as 
authoring instruction. 
Non-substantial 


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Section Number and 
Name 
Description of Changes 
Brief rationale 
Substantial/ 
Non-substantial 
Section 9.4.2.1 
(Primary Endpoint(s)) 
Text updated regarding primary 
objectives related estimands. 
To be more specific. 
Non-substantial 
Section 3 
Minor edits to statistics wording 
To correct typographical 
errors. 
Non-substantial 
Appendix O 
(Covid-19 specifics) 
Wording added that study 
intervention may be delivered direct 
to participant if appropriate and via 
Sponsor approved courier service. 
Added as potential 
mitigation for Covid-19. 
Non-substantial 
1MSTST, 1-minute sit-to-stand test; AE, adverse event; ANCA, anti-neutrophil cytoplasmic antibody; Covid-
19, coronavirus disease 2019; eCRF, electronic case report form; FDA, Food and Drug Administration; 
PK, pharmacokinetics. 
 
 


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11 
REFERENCES 
American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J 
Respir Crit Care Med. 2002;166(1):111-7. 
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