A Randomised, Parallel, Double-Blind, Placebo-Controlled Phase 2b Study to Assess the Safety, Tolerability and Efficacy of AZD8233 Treatment in Participants With Hyperlipidaemia
Phase: PHASE2
Conditions: Hyperlipidaemia
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 of 9 8
Cli nic al St u d y Pr ot oc ol 
St u d y I nter ve nti o n
A Z D 8 2 3 3
St u d y C o de
D 7 9 9 0 C 0 0 0 0 4
A me n d me nt N u m ber 
1
Date
0 8 Fe b 2 0 2 2
A R a n d o mise d, P ar allel, D o u ble -Bli n d, Pl ace b o -C o ntr olle d 
P h ase 2 b St u d y t o Assess t he S afet y , Toler a bilit y a n d Effic ac y of 
A Z D 8 2 3 3 T re at me nt i n P artici p a nts wit h H y perli pi d ae mi a 
( S O L A N O)
S p o ns or  N a me: Astra Ze neca A B
Le g al Re gister e d A d dress: 1 5 1 8 5 S ö dertälje, S we de n
Re g ul at or y A ge nc y I de ntifier  N u m ber(s): E u dra C T n u m ber, 2 0 2 0 - 0 0 5 8 4 5-1 8; I N D n u m ber, 
1 3 8 3 4 8
T his Cli nical St u d y  Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
Sta n dar d pr oce d ures. T he Cli nical St u d y Pr ot oc ol  is p u blicl y re gistere d a n d t he res ults are 
di s close d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o mplia nce wi t h pre vaili n g la ws a n d re g ulati ons.
P r ot oc ol N u m ber: D 7 9 9 0 C 0 0 0 0 4
A me n d me nt N u m ber: 1. 0
St u d y I nter ve n ti o n: A Z D 8 2 3 3
St u d y P h ase: P hase 2 b
S h ort Title: A P hase 2 b St u d y  t o Assess t he Safet y , Tol era bilit y a n d Efficac y of A Z D 8 2 3 3 
Treat me nt i n Partici pa nts wit h H y perli pi dae mia.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 of 9 8
St u d y N a me : S O L A N O
St u d y P h ysici a n n a me a n d c o nt act i nf or m ati o n will be pr o vi de d se p ar atel y.
I nter n ati o n al c o-o r di n ati n g i n vesti g at ors:
  
 
P P D
P P D
P P D
P P D

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 of 9 8
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
A me n d me nt 1
0 8 -Fe b - 2 0 2 2
Ori gi nal Pr ot oc ol
2 1 -A pr - 2 0 2 1
A me n d me nt 1 0 8 Fe br u ar y 2 0 2 2
T his a me n d me nt is c o nsidere d t o be n o n -s u bsta ntial base d o n t he criteria set f ort h i n Art icle 
1 0(a) of Direct i ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n 
U ni o n.
O ver all R ati o n ale f or t he A me n d me nt:
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brie f R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
Title p a ge, 1. 1 
S y n o psis ( m ulti ple 
pl aces). 4. 1 O ver all 
desi g n
T olera bilit y a n d efficac y 
w or ds or der c ha n ge d i n 
m ulti ple places acr oss t he 
d oc u me nt
T o kee p c o nsiste nc y acr oss 
t he d oc u me nt
N o n -s u bsta ntial
Fi g ure 1 f o ot n ote, 
O bjecti ves a n d 
e n d p oi nts t a ble 
f o ot n ote
L o w -de nsit y  li pi d 
c h olester ol c ha n ge d t o 
l o w-de nsit y  li p o pr otei n 
c h olester ol
T o kee p c o nsiste nc y acr oss 
t he d oc u me nt
N o n -s u bsta ntial
T a ble 1 (f o ot n ote i)
Visit 1 c ha n ge d t o visit 2 i n 
f o ot n ote i S o A
T o ali g n wit h descri pti o n of 
visits a n d g ui da nce
N o n -s u bsta ntial
T a ble 1 (f o ot n ote 
j), 
8 St u d y 
Assess me nts a n d 
Pr oce d ures 
“ ± 1 5 mi n utes” a d de d t o 
p ost -d ose sa m ple 
c ollecti o n i n f o ot n ote j
T o ali g n g ui da nce t o sites 
a n d t o defi ne P D
N o n -s u bsta ntial
T a ble 1 
e x pl a n ati o ns
I P, i n vesti gati o nal pr o d uct 
re m o ve d fro m e x pla nati o ns 
T o kee p c o nsiste nc y, I P is 
n ot use d i n t he ta ble
N o n -s u bsta ntial
5. 1 I ncl usi o n 
criteri a 
“ At scree ni n g” w or di n g 
a d de d t o i ncl usi o n criteria 
4
T o clarif y start of 
me dicati o n ti mefra me
N o n -s u bsta ntial
T a ble 4
W or di n g c ha n ge d fr o m “ … 
t o be pr o vi de d b y Cli nical 
Site” t o “ … t o be pr o vi de d 
b y La bc or p ce ntral 
la b orat or y”
T o be c o nsiste nt wit h 
pr ocess
N o n -s u bsta ntial

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 of 9 8
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brie f R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
6. 3 Me as ures t o 
Mi ni mise Bi as: 
R a n d o mis ati o n 
a n d Bli n di n g
Secti o n “ Ha n dli n g of 
data base l oc ks” re m o ve d
Se q ue ntial cli nical data 
l oc ks re place d b y si n gle 
fi nal l oc k at e n d of st u d y
N o n -s u bsta ntial
6. 5 C o nc o mit a nt 
T her a p y
“ Patie nts w h o are 
c o m pletel y i nt olera nt t o 
stati n t hera p y will be 
all o we d t o partici pate as 
t he ma xi m u m t olerate d 
d ose is n o ne.” a d de d t o 
me dical restricti o ns
T o clarif y i ncl usi o n criteria 
f or patie nts i nt olera nt t o 
stati n t hera p y
N o n -s u bsta ntial
7. 1 Disc o nti n u ati o n 
of St u d y 
I nter ve nti o n
Disc o nti n uati o n of st u d y 
i nter ve nti on c riteria 
u p date d
T o clarif y t he pr ocess
N o n -s u bsta ntial
7. 1 Disc o nti n u ati o n 
of St u d y 
I nter ve nti o n
F oll o w -u p f or partici pa nts 
w h o ha ve disc o nti n ue d 
I M P secti o n ha d bee n 
u p date d. Na me of secti o n: 
“ M o difie d f oll o w-u p f or 
partici pa nts w h o ha ve 
disc o nti n ue d I M P” ha d 
bee n re m o ve d
T o clarif y f oll o w -u p pr ocess 
f or patie nts w h o ha ve 
disc o nti n ue d I M P
N o n -s u bsta ntial
8 St u d y 
Assess me nts a n d 
Pr oce d ures
Ne ur ol o gic e xa m a n d I M P 
I S R assess me nt a d de d t o 
list of assess me nts
T o clarif y t he pr ocess
N o n -s u bsta ntial
8 St u d y 
Assess me nts a n d 
Pr oce d ures
Ne ur ol o gical e xa mi nati o n 
a d de d t o visit 2 a n d f oll o w-
u p visits assess me nts 
descri pti o n
T o clarif y t he pr ocess
N o n -s u bsta ntial
8 St u d y 
Assess me nts a n d 
Pr oce d ures
W or di n g f or visit 1 6 
c ha n ge d
T o be c o nsiste nt wit h S o A
N o n -s u bsta ntial
8. 2. 3 Assess me nts 
f or A Es, i ncl u di n g 
ne w 
o nset/ w orse ni n g of 
di a betes A Es
Assess me nts f or 
h y per gl yce mia -relate d A Es 
w or di n g ha d bee n u p date d
T o clarif y criteria basi n g o n 
F D A rec o m me n dati o n
N o n -s u bsta ntial
8. 2. 6 Cli nic al 
S afet y L a b or at or y 
Assess me nts
Ce ntral La b orat or y na me 
c ha n ge d fr o m C O V A N C E 
t o La bc or p
T o kee p c o nsiste nc y as 
ve n d or le gal na me c ha n ge d 
d uri n g c o urse of t he st u d y
N o n -s u bsta ntial
T a ble 5
e G F R m o ve d t o Cli nical 
c he mistr y c ol u m n
T o be c o nsiste nt wit h t he 
pr ocess
N o n -s u bsta ntial

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 of 9 8
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brie f R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
8 . 3. 2 F oll o w-u p of 
A Es a n d S A Es
W or d “ti me” re m o ve d 
fr o m A E varia bles
T o be c o nsiste nt wit h t he 
pr ocess
N o n -s u bsta ntial
8. 3. 5 A d verse 
E ve nts B ase d o n 
E x a mi n ati o n a n d 
Tests
W or di n g a b o ut p h ysical 
e xa mi nati o n e val uati o n 
a d de d
T o clarif y pr ocess re gar di n g 
p h y sical 
e xa mi nati o n/ ne ur ol o gical 
e xa mi nati o n
N o n -s u bsta ntial
8. 3. 8 Pre g n a nc y
“ A E” c ha n ge d t o “a d verse 
e ve nt”
T o ali g n C S P te m plate 6. 0
N o n -s u bsta ntial
8. 3. 8 Pre g n a nc y
“a b n or malities” c ha n ge d t o 
“a n o malies”
T o ali g n C S P te m plate 6. 0
N o n -s u bsta ntial
8 . 3. 1 0 I M P 
I njecti o n Site 
Re acti o ns
Secti o n re na me d b y a d di n g 
“I M P” t o t he na me a n d t o 
t he secti o n w or di n g 
T o be c o nsiste nt acr oss t he 
d oc u me nt
N o n -s u bsta ntial
8. 5. 2 
I m m u n o ge nicit y 
Assess me nts
A D A p ositi ve partici pa nts 
f oll o w-u p w or di n g ha d 
bee n a dj uste d 
T o clarif y t he A D A p ositi ve 
patie nts f oll o w -u p pr ocess
N o n -s u bsta ntial
T a ble 6
W or d “ d ose” re m o ve d 
fr o m a f o ot n ote
T o be c o nsiste nt acr oss t he 
d oc u me nt
N o n -s u bsta ntial
T a ble 7
P K A nal y sis set a d de d
T o be c o nsiste nt wit h S A P
N o n -s u bsta ntial
9 . 4. 1 Ge ner al 
C o nsi der ati o ns
W or di n g a b o ut usi n g of 
P U C ha d bee n a d de d
T o clarif y t he pr ocess
N o n -s u bsta ntial
9. 4. 2. 1 Pri m ar y 
E n d p oi nts
W or di n g c ha n ge d
T o be c o nsiste nt wit h S A P
N o n -s u bsta ntial
A p pe n di x I 
A b bre vi ati o ns
A D A a n d L D L -C 
e x pla nati on c ha n ge d
T o be c o nsiste nt acr oss t he 
d oc u me nt
N o n -s u bsta ntial
M ulti ple pl aces
T y p o gra p hical err o rs were 
c orrecte d i n m ulti ple 
places i n t he pr ot oc ol
T o be c o nsiste nt acr oss t he 
d oc u me nt
N o n -s u bsta ntial

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 of 9 8
T A B L E O F C O N T E N T S
TI T L E P A G E ........................................................................................................................1
T A B L E O F C O N T E N T S ......................................................................................................6
1
P R O T O C O L  S U M M AR Y ................................................................................1 0
1. 1
S y n o psis ...........................................................................................................1 0
1. 2
Sc he ma .............................................................................................................1 3
1. 3
Sc he d ule of Act i vities .......................................................................................1 4
2
I N T R O D U C TI O N ............................................................................................2 0
2. 1
St u d y  Ratio nale ................................................................................................2 0
2. 2
Bac k gr o u n d ......................................................................................................2 0
2. 3
Be nefit/ Ris k Assess me nt ...................................................................................2 1
2. 3. 1
Ris k Assess me nt ...............................................................................................2 2
2. 3. 2
Be nefit Assess me nt ...........................................................................................2 5
2. 3. 3
O verall Be nefit: Ris k C o ncl usi o n ......................................................................2 5
3
O BJ E C TI V E S A N D E N D P O I N T S ...................................................................2 6
4
S T U D Y  D E SI G N .............................................................................................2 8
4. 1
O verall Desi g n ..................................................................................................2 8
4. 2
S ci e nt ific Rati o nale f or St u d y Desi g n ...............................................................2 8
4. 3
J ustificati o n f or D ose........................................................................................2 9
4. 4
E n d of St u d y  Defi niti on ....................................................................................2 9
5
S T U D Y  P O P U L ATI O N ....................................................................................2 9
5. 1
I ncl usi on Cri t eria ..............................................................................................2 9
5. 2
E xcl usi o n Cri t eria .............................................................................................3 1
5. 3
Lifest yle C o nsi derat i ons ...................................................................................3 3
5. 3. 1
Meals a n d Dietar y  Restrict i ons .........................................................................3 3
5. 3. 2
Caffei ne, Alc o h ol, a n d T o bacc o .........................................................................3 4
5. 3. 3
Re pr o d ucti ve restrict i ons ..................................................................................3 4
5. 3. 4
Bl o o d d o nati o n ................................................................................................. 3 4
5. 4
Scree n Fail ures ................................................................................................. 3 5
6
S T U D Y  I N T E RV E N TI O N ...............................................................................3 5
6. 1
St u d y  I nter ve nti on(s) A d mi nistere d ...................................................................3 5
6. 1. 1
I n vesti gati onal Pr o d ucts ....................................................................................3 5
6. 2
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...................................................3 6
6. 3
Meas ures t o Mi ni mise Bias: Ra n d o misat i on a n d Bli n di n g ................................. 3 7
6. 4
St u d y  I nter ve nti on C o m plia nce .........................................................................3 8
6. 5
C o nc o mita nt T hera p y ........................................................................................3 8
6. 5. 1
Resc ue Me dici ne ...............................................................................................3 9
6. 6
D ose M o dificat i on ............................................................................................4 0

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 of 9 8
6. 7
I nter ve ntio n After t he E n d of t he St u d y .............................................................4 0
7
DI S C O N TI N U A TI O N O F S T U D Y  IN T E R V E N TI O N A N D P A R T I CI PA N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L ...........................................................4 0
7. 1
Di sc o nti n uatio n of  St u d y I nter ve nti on ...............................................................4 0
7. 1. 1
Te m p orar y  Disc o nti n uati o n...............................................................................4 1
7. 2
P arti cipa nt W ith dra wal fr o m t he St u d y..............................................................4 1
7. 3
L ost t o F oll o w u p ..............................................................................................4 2
8
S T U D Y  A S S E S S M E N T S A N D P R O C E D U R E S ..............................................4 2
Ge neral Descri pt i on of St u d y  Visits ....................................................................................4 3
8. 1
Ef ficac y Assess me nts........................................................................................4 5
8. 2
S af et y Assess me nts ...........................................................................................4 5
8. 2. 1
P h ysical E xa mi nat i on ........................................................................................4 5
8. 2. 2
Ne ur ol o gi cal E xa mi natio n ................................................................................4 5
8. 2. 3
Assess me nts f or A Es, i ncl u di n g ne w o nset/ w orse ni n g of dia betes A Es ..............4 5
8. 2. 4
Vit al Sig ns........................................................................................................ 4 6
8. 2. 5
Electr ocar di o gra ms ...........................................................................................4 6
8. 2. 6
Cli nical Safet y  La b orat or y Assess me nts............................................................4 7
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................................4 8
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollect i n g A E a n d S A E I nf or mati on ................4 9
8. 3. 2
F o ll ow- u p of  A Es a n d S A Es .............................................................................4 9
8. 3. 3
Ca usalit y C o llecti on ..........................................................................................5 0
8. 3. 4
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ................................................5 0
8. 3. 5
A d verse E ve nts Base d o n E xa mi nat i ons a n d T ests ............................................5 0
8. 3. 6
H y ’s La w ..........................................................................................................5 1
8. 3. 7
Re p orti n g of Seri o us A d verse E ve nts ................................................................5 1
8. 3. 8
Pre g na nc y .........................................................................................................5 1
8. 3. 8. 1
Pater nal  E x p os ure.............................................................................................5 2
8. 3. 9
Me dicat i on Err or ...............................................................................................5 2
8. 3. 1 0
I njecti on Si te Reactio ns .................................................................................... 5 3
8. 4
O ver d ose ..........................................................................................................5 3
8. 5
H u m a n Biol o gi c al  Sa m ples...............................................................................5 3
8. 5. 1
P har mac o ki net ics..............................................................................................5 4
8. 5. 1. 1
Deter mi nat i on of Dr u g C o nce ntrati o n ...............................................................5 4
8. 5. 2
I mm u n o ge nicit y Assess me nts ...........................................................................5 4
8. 5. 3
P har mac o d y na mics ...........................................................................................5 5
8. 5. 3. 1
C ollect i on of Sa m ples .......................................................................................5 5
8. 6
H u m a n Biol o gi c al  Sa m ple Bio m ar kers .............................................................5 6
8. 6. 1
C ollect i on of ma n dat or y  sa m ples f or bi omar ker a nal ysis ...................................5 6
8. 7
8. 8
Heal t h Ec o n o mics.............................................................................................5 6
9
S T A T I S TI C A L C O N SI D E RA T I O N S................................................................5 6
9. 1
Stati stical H y p ot heses.......................................................................................5 6
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 of 9 8
9. 2
S a m ple Si ze Deter mi nat i on ...............................................................................5 7
9. 3
P o p ul at i ons f or A nal yses ...................................................................................5 8
9. 4
Stati stical A nal yses ...........................................................................................5 8
9. 4. 1
Ge neral C o nsi derati o ns .....................................................................................5 8
9. 4. 2
Ef ficac y ............................................................................................................5 9
9. 4. 2. 1
Pri mar y E n d p o i nt(s)..........................................................................................5 9
9. 4. 2. 2
Sec o n dar y  E n d p oi nt(s)......................................................................................6 0
9. 4. 2. 3
Te rtiar y E n d p oi nt(s)..........................................................................................6 1
9. 4. 3
S af et y ...............................................................................................................6 1
9. 4. 3. 1
Pri mar y E n d p o i nt(s)..........................................................................................6 1
9. 4. 4
Ot her A nal yses ..................................................................................................6 3
9. 5
I nteri m A nal yses ...............................................................................................6 4
9. 6
Data M o nit ori n g C o m mittee .............................................................................6 4
1 0
S U P P O R TI N G 
D O C U M E N T A TI O N 
A N D 
O P E R A TI O N A L
C O N SI D E R A TI O N S ........................................................................................6 4
1 1
R E F E R E N C E S ................................................................................................. 9 6
LI S T O F FI G U R E S
Fi g ure 1
St u d y  Desi g n...........................................................................................1 3
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of Act i vities..............................................................................1 4
Ta ble 2
Ris k assess me nt .......................................................................................2 2
Ta ble 3
O bject i ves a n d E n d p oi nts.........................................................................2 6
Ta ble 4
I n vesti gati onal Me dici nal Pr o d ucts ..........................................................3 6
Ta ble 5
La b orat or y  S afet y Varia bles .....................................................................4 7
Ta ble 6
Hi erarc hical Or der f or Statist ical Testi n g.................................................5 7
Ta ble 7
P o p ul at i ons f or A nal ysis ..........................................................................5 8

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 of 9 8
LI S T O F A P P E N DI C E S
A p pe n di x A
Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsid er ati o ns .........................6 5
A p pe n di x B
A d verse E ve nts: Defi nit i ons a n d Pr oce d ures f or Rec or di n g, E val uati n g, 
F o ll ow- u p, a n d Re p orti n g ........................................................................7 0
A p pe n di x C
Ha n dli n g of H u ma n Bi o l ogical  Sa m ples ..................................................7 4
A p pe n di x D
......................................................7 6
A p pe n di x E
Act i ons Re q uire d i n Cases of 
 a n d 
E val uat i on of H y’s La w ...........................................................................7 9
A p pe n di x F
Act i ons i n Case of De vel o p me nt of 
 or 
U ni nter preta ble  
C o u nts After A d mi nistrati o n of 
................8 4
A p pe n di x G
G ui da nce f or Defi nit i on of A na p h ylactic/ H y perse nsit i vity React i ons a n d 
C hec klist f or t he i n vest i gat or ...................................................................8 7
A p pe n di x H
C O VI D -1 9 S pecifics ................................................................................9 0
A p pe n di x I
A b bre viat i ons ..........................................................................................9 3
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 2 of 9 8
t o partici pate i n a cli nical st u d y fol l owi n g c o m plet i o n of t he i nf or me d c o nse nt pr ocess. 
P ote nti al p artici pa nts w h o are scree ne d f or t he p ur p ose of deter mi ni n g eli g i bility f or t he st u d y, 
b ut are n ot ra n d o ml y assi g ne d/assi g ne d i n t he st u d y, are c o nsi dere d “scree n fail ures”, u nless 
ot her wi se s pecifie d b y t he pr ot oc ol. 
I nter ve nti o n Gr o u ps a n d D ur ati o n:
It is pla n ne d t o ha ve 2 i nter ve nti on gr o u ps: a n A Z D 8 2 3 3 gr o u p a n d a
 gr o u p. 
T here will be a n i nit ial scree ni n g peri o d starti n g u p t o
 prior t o ra n d o misat i on. T he 
st u d y is di vi de d i nt o a pla n ne d treat me nt peri o d of  
 f oll owe d b y a safet y f oll ow- u p of  
 O verall, t his ma kes a t otal st u d y parti ci patio n ti me of  
 o nce partici pa nts 
are ra n d o ml y assi g ne d i nt o t he trial.
D at a M o nit ori n g C o m mittee:
A n i nter nal Safet y M o nit orin g C o m mittee will be use d f or m o nit ori n g of u n bli n de d safety data 
i n t he o n g oi n g st u d y. 
St atistic al Met h o ds:
T he pri mar y  s afet y o bject i ve is t o assess t he safet y a n d t olera bility of  A Z D 8 2 3 3 as c om pare d 
wi t h 
i n participa nts wi t h h y perli pi dae mia. T his will be e val uate d i n ter ms of A Es, 
vit al si g ns, E C G, a n d cli nical la b orat or y e val uati ons, i ncl u di n g 
 Safet y a nal yses 
will be perf or me d usi n g t he safet y  a nal ysis set a n d will be prese nte d usi n g descri pti ve 
statistics u nless ot her wise s pecifie d.
Pri mar y a n d sec o n dar y efficac y varia bles (c ha n ge fr o m baseli ne i n L D L -C, P C S K 9) will be 
assesse d t hr o u g h a Treat me nt P olic y Esti ma n d. T his a p pr oac h will assess t he effect of t he 
treat me nt p olic y of A Z D 8 2 3 3 a n d c o m parat ors, re gar dless of disc o nt i n uati on of st u d y  
me dicat i on. T he mai n esti mat or is a n 
f or t he relati ve c ha n ge fr o m baseli ne t o t he 
e n d of 
 i ncl u di n g all partici pa nts i n t he FA S. T he m o del will i ncl u de treat me nt gr o u p 
as a fi xe d cate g orical fact or a n d baseli ne val ue as a c o nti n u o us c o variate. 
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 6 of 9 8
Ta ble 1
Sc he d ule of Acti vities
Pr oce d ure
Scree ni n g
Pl a n ne d Tre at me nt Peri o d a
S afet y F oll o w -u p 
E nr ol me nt
R a n d o mis ati o n
P ost First 
D ose 
assess me nt 
Visit
D osi n g Visits
S afet y 
M o nit ori n g 
Visits b
E n d of 
Pl a n ne d 
Tre at me nt 
Peri o d Visit 
First 
S afet y 
F oll o w -
u p Visit
Fi n al S afet y 
F oll o w -u p 
Visit
Vital si g ns h ( bl o o d press ure, p ulse 
a n d te m perat ure)
X
X
X
X
X  
X
X
E C G i
X
X
X ( Visits 8 a n d 
1 4)
X
X
Ser u m c he mistr y
X
X
X
X
X  
X
X
Hae mat ol o g y
X
X
X
X
X  
X
X
C oa g ulati o n para meters j
X
X
X
X  
X
X
 
X
X
X
X
X
X  
X
X
Li ver f u ncti o n tests l
X
hs -C R P
X
X
X
X
X  
X
X
C o m ple me nt acti vati o n pa nel j 
X
X
Ur i nal ysis
X
X
X
X
X  
X
X
e G F R, U A C R, U P C R
X
X
X
X
X  
X
X
Ur i ne re nal safet y bi o mar kers: 
al b u mi n, creati ni ne, t otal pr otei n
X
X
X
X
X  
X
X
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 of 9 8
k
c o u nt res ults m ust be a vaila ble wit hi n 
 pri or t o all s u bse q ue nt d osi n g f oll o wi n g 
l
A S T, A L T, T B L, direct bilir u bi n, G G T, A L P 
m
Sa m ples t o be c ollecte d pre -d ose w here a p plica ble, i n a faste d state.
n
Li p o pr otei n pr ofile. Ot her li pi d para meters i ncl u de c h olester ol ( T C, H D L -C, n o n- H D L -C, V L D L -C, re m na nts c h olester ol), A p o B, A p o A 1, a n d L p(a).
o
Sa m ples t o be c ollecte d pre -d ose i n a faste d state wit h a n a d diti o nal sa m ple 2 h o urs p ost-d ose at  
.
A E, a d verse e ve nt; A L P, al kali ne p h os p hatase; A L T, ala ni ne a mi n otra nsferase; A p o A 1, a p oli p o pr otei n A 1; A p o B, A p oli p o pr otei n B; A S T, as partate 
a mi n otra nsferase; E C G, electr ocar di o gra m; D, Da y; e G F R, esti mate d gl o mer ular filtrati o n rate; F S H, f ollicle sti m ulati n g h or m o ne; G G T, ga m ma gl uta m yl 
tra nsferase; H b A 1c, hae m o gl o bi n A 1c; H D L-C, hi g h -de nsit y li p o pr otei n c h olester ol; L D L -C, l o w -de nsit y  li p o pr otei n c h olester ol; L p(a), li p o pr otei n(a); hs-C R P , 
hi g h se nsiti vit y C -reacti ve pr otei n; I M P, i n vesti gati o nal me dici nal pr o d uct; 
; I V R S/I W R S, i nteracti ve v oice res p o nse
s yste m/i nteracti ve we b res p o nse s yste m; L D L-C, l o w -de nsit y  li p o pr otei n c h olester ol; L H, l utei nisi n g h or m o ne; P C S K 9, pr o pr otei n c o n vertase s u btilisi n/ ke xi n 
t ype 9; P K, p har mac o ki netic; S A E, seri o us a d verse e ve nt; T B L, t otal bilir u bi n; T C, t otal c h olester ol; U A C R, uri ne al b u mi n t o cr eati ni ne rati o; U P C R, uri ne 
pr otei n t o creati ni ne rati o; V L D L -C, ver y  l o w-de nsit y  li p o pr otei n c h olester ol
N ote: Partici pa nts are re q uire d t o fast f or at least 8 h o urs o ver ni g ht pri or t o 
 a n d 
. Partici pa nts are per mitte d t o dri n k water 
d uri n g t his peri o d of fasti n g. O n da ys w here partici pa nts atte n d t he cli nic i n a faste d state, bl o o d a n d uri ne sa m ples s h o ul d be o btai ne d pri or t o a d mi nistrati o n of 
I M P.
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 0 of 9 8
2
I ntr o d ucti o n
2. 1
St u d y R ati o n ale
A Z D 8 2 3 3 is a 
 T his is a 
safety a n d t olera bilit y st u d y wit h t he ai m of creati n g a safety data base c o veri n g e x p os ure 
f oll owi n g treat m e nt wit h A Z D 8 2 3 3 f or 
, t o i n vesti gate w het her a n y si g nals 
r elate d t o 
 or ot her safety para meters are prese nt t hat c o u l d p ote ntiall y lea d 
t o restricti on of partici pa nt p o p ulat i ons d ue t o safet y. Efficac y of A Z D 8 2 3 3 will als o be 
e val uate d t hr o u g h its a bilit y t o re d uce L D L-C.
2. 2
B ac k gr o u n d
Ele vate d plas ma L D L -C, i s a mai n ris k fact or f or car di o vasc ular disease a n d is t ypicall y
ca use d b y a c o m bi nati on of e n vir o n me ntal a n d ge netic fact ors. Stati n t hera p y is t he sta n dar d 
li pi d lo weri n g m e dicatio n f or b ot h pri mar y  a n d sec o n dar y pre ve nti on of car di o vasc ular 
di sease. Re d ucti on of L D L -C b y stati ns lea ds t o a si g nifica nt re d ucti o n i n c ar dio vasc ular 
e ve nts (C olli ns et al 2 0 1 6 ). Stati ns re d uce L D L-C b y  in hi bi tin g H M G C o A re d uctase, t he rate-
li miti n g e nz y me of he patic c h olester ol s y nthesis. H o we ver, des pite t he s u bsta nt ial be nefits o f 
stati n t hera p y, m a n y patient s d o not reac h L D L -C tar get g oals.
Ge net ic st u dies ha ve i de ntifie d P C S K 9 as a n i m p orta nt H M G-C o A -i n de pe n de nt circulat i n g 
re g ulat or of L D L- C (C o he n et al  2 0 0 5, 2 0 0 6) . Circ ulati n g P C S K 9 is deri ve d mai nl y fr om t he 
li ver a n d i ncreases L D L-C b y pr o m oti n g de gr a dati o n of he pat ic L D L rece pt ors. Gai n of 
f u ncti on m ut atio ns i n P C S K 9 ca use fa milial d o mi na nt h y perc h olester ole mia; l oss of f u ncti o n 
is ass ociate d wit h l o w circ ulati n g le vels of L D L -C a n d a re d uce d ri s k of maj or vasc ular 
e ve nts.
T w o  
 (
) ha ve bee n s uccessf ull y de vel o pe d t o 
p har mac o l ogi call y i n hi bit P C S K 9. 
 of t hese c om p o u n ds l o wers L D L -C 
le vels b y a p pr o xi matel y 6 0 %, e ve n i n patient s alr e a d y recei vi n g ma xi m u m d ose stati n t hera p y 
(Sa bat i ne et al 2 0 1 7). F urt her m ore, 
w as f o u n d t o l o wer P C S K 9 ( 6 9. 1 %) a n d L D L ( 5 2. 6 %) 
le vels i n patie nts at hi g h car di o vasc ular ris k w h o ha d ele vate d L D L-C l e vels (Ra y  et al 2 0 1 7).
Base d o n t he si g nifica nt cli nical be nefit of P C S K 9 i n hi bit i on, Astra Ze neca is de vel o pi n g a 
 
t hat s pecificall y 
 e x pressi on 
i n t he li ver (Pra kas h et al 2 0 1 4 ). P ote ntial ris ks for A Z D 8 2 3 3 base d o n
 class ha ve bee n 
i de ntifie d (see Ta ble 2 ) a n d will be e val uate d i n t his st u d y. A Z D 8 2 3 3 ma y  pr o vi de n o vel 
treat me nt o ptio ns f or pati e nts wit h h y perli pi dae mia. 
I n t he o n g oi n g S A D ( St u d y D 7 9 9 0 C 0 0 0 0 1), gl o bal M A D ( St u d y D 7 9 9 0 C 0 0 0 0 2), Ja pa nese 
M A D ( D 7 9 9 0 C 0 0 0 0 6 [ H A Y A T E]), a n d gl o bal d ose ra n gi n g ( St u d y  D 7 9 9 0 C 0 0 0 0 3 
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 1 of 9 8
[ E T E SI A N]) st u dies, > 1 2 0 participa nts ha ve bee n e x p ose d t o m ult i ple d oses of 
 
a d mi nistrati o n of A Z D 8 2 3 3.
T he m ajori t y of t he A Es re p orte d ha ve bee n mil d or m o derate. I S Rs ha ve bee n re p orte d i n 
s o me partici pa nts, of w hic h o ne was disc o nti n ue d fr o m treat me nt. 
A t otal o f si x partici pa nts prese nte d treat me nt-e mer ge nt A L T i ncreases bet wee n 3 × U L N a n d 
< 6 × U L N ( ma x = 2 6 8 U/ L). N o i ncrease i n t otal bilir u bi n has bee n o bser ve d i n a n y of t hese 
parti ci pa nts, a n d n o cli nical si g ns or s y m pt o ms ha ve bee n ass ociate d. I n all 6 partic i pa nts, t he 
ele vat i on i n A L T was tra nsie nt, a n d all part ici pa nts rec o vere d w hile still i n t he st u d y ( 3 o n 
c o nti n ue d treat me nt, a n d 3 t hat ha d disc o nt i n ue d). 
E xce pt f or t hese fi n di n gs, t here ha ve bee n n o i n dicati o ns o f A S O -relate d plat f or m ris ks, 
i ncl u di n g t hr o m b oc yt o p e nia ( plat elet c o u nts ha ve re mai ne d sta ble i n all partici pa nts), re nal 
i nj ur y, i m paire d blo o d c oa g ul at i on, c o m ple me nt acti vat i on, h y perse nsit i vity/a na p h ylactic 
reactio n, a n d fl u -li ke reacti o ns. Res ults o n A D A fr o m o n g oi n g st u dies are n ot yet availa ble. 
O verall, A Z D 8 2 3 3 has bee n ge nerall y well t olerate d at all d oses st u die d wit h n o si g nifica nt 
safety fi n di n gs o n vital si g ns, E C G, b o d y t e mperat ure, hae m at olo gi cal, or cli nical c he mistr y 
safety la b para meters.
Preli mi nar y data fr o m St u d y  D 7 9 9 0 C 0 0 0 01 s h o we d t hat A Z D 8 2 3 3 d oses of
 re d uce d 
P C S K 9 b y  ≥ 9 0 % a n d L D L-C b y as m uc h as 7 0 %. 
A detaile d descri pti o n o f t he c he mistr y, p har ma c ol o g y, efficac y, a n d safety of  A Z D 8 2 3 3 is 
pr o vi de d i n t he c urre nt I B.
2. 3
Be nefit/ Ris k Assess me nt
P ote nti al ris ks of A Z D8 2 3 3 a n d mit i gati on strate g y  are s h o w n i n Ta ble 2 . M ore detaile d 
i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefit s a n d p ote ntial ris ks of A Z D 8 2 3 3 ca n be 
f ou n d i n t he c urre nt I B.
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Cl i nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 9 8
Ta ble 2
Ris k Assess me nt
P ote nti al ris k of cli nic al 
si g nific a nce
S u m m ar y of d at a/r ati o n ale 
f or ris k 
Miti g ati o n str ate g y
St u d y i nter ve nti o n ( A Z D 8 2 3 3)
 
I njecti o n Site Re acti o ns
I S Rs ma y occ ur f oll o wi n g 
s u bc uta ne o us a d mi nistrati o n of 
A S Os a n d ot her bi ol o gics a n d is 
re gar de d as a class effect. M ost ofte n 
t he y ar e mil d wit h o nl y sli g ht 
er yt he ma a n d are ra pi dl y re versi ble 
a n d t olerate d b y patie nts. T he y are 
als o d ose-de pe n de nt. T here ha ve 
bee n re p orts i n s o me A S O pr o gra ms 
of a fe w cases of se vere I S Rs wit h a 
hi g h i nci de nce of disc o mf ort t o t he 
patie nt t hat ha ve le d t o wit h dra wal 
fr o m treat me nt.
I n t he o n g oi n g cli nical pr o gra m me 
f or A Z D 8 2 3 3, mil d I S Rs ha ve bee n 
o bser ve d i n a fe w partici pa nts (see 
Secti o n  2. 2 for  details). 
M o nit ori n g f or I S Rs.
C o m ple me nt Acti v ati o n
T his is a k n o w n class effect of 
oli g o n ucle oti des a n d a p pears t o be 
directl y plas ma c o nce ntrati o n ( C ma x ) 
dri ve n. M o n ke ys are c o nsi dere d 
m ore se nsiti ve t o c o m ple me nt 
acti vati on t ha n h u ma ns (Cr o o ke et al 
2 0 1 6) . I n t he 9-m o nt h m o n ke y 
st u d y, mi ni mal t o mil d hi g her 
c o m ple me nt B b was o bser ve d at ≥ 6 
m g/ k g/ occasi o n at t he e n d of t he 
st u d y a n d c orrelate d micr osc o picall y 
wit h m o n o n uclear cell 
( pre d o mi na ntl y l y m p h oc ytic) 
i nfiltrati on/ i nfla m mati o n o bser ve d i n 
m ulti ple tiss ues, i ncl u di n g t he 
a d mi nistrati o n site.
Assess me nt of c o m ple me nt 
acti vati on ar o u n d C ma x ( C 5a, B b).
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 9 8
Ta ble 2
Ris k Assess me nt
P ote nti al ris k of cli nic al 
si g nific a nce
S u m m ar y of d at a/r ati o n ale 
f or ris k 
Miti g ati o n str ate g y
St u d y i nter ve nti o n ( A Z D 8 2 3 3)
I n hi biti o n of I ntri nsic 
C o a g ul ati o n P at h w a y
I n creases i n a P T T, i n t he a bse nce of 
cli nical or pat h ol o gical se q uelae, 
ha ve bee n o bser ve d wit h A S Os
(B urel et al 2 0 1 3 , He nr y et al 1 9 9 7 ). 
Mec ha nisticall y, i nteracti o n of 
A S Os wit h t he i ntri nsic te nase 
c o m ple x a n d t hr o m bi n res ults i n a 
selecti ve i n hi biti o n of t he i ntri nsic 
cl otti n g casca de a n d he nce i ncreases 
i n a P T T (He nr y et al 2 0 1 7 , S h ee ha n 
a n d La n 1 9 9 8, S h ee ha n a n d P ha n 
2 0 0 1) . C ha n ges i n acti vit y of t he 
i ntri nsic cl otti n g pat h wa y re verse 
w h e n A S Os are cleare d fr o m 
plas ma. Tra nsie n t pr ol o n gati o n of 
a P T T has bee n descri be d i n ma n a n d 
was o bser ve d t o c orrelate i n a li near 
ma n ner wit h t he C ma x at t he e n d of 
i nf usi o n (Se well et al 2 0 0 2 ). T here 
were n o treat me nt relate d c ha n ges i n 
a n y c oa g ulati o n para meters i n t he 
n o ncli nical t o xic ol o g y st u dies.
Assess me nt of a P T T a n d 
Pr ot hr o m bi n Ti me ar o u n d C ma x
C ollecti o n of A Es relate d t o 
blee di n g. 
H y perse nsiti vit y a n d 
A n a p h yl actic Re acti o n
Si milar t o a n y f orei g n bi ol o gical 
a ge nt, a d mi nistrati o n of A Z D 8 2 3 3 
m a y  i n d uce h yperse nsiti vit y  
reacti o ns. T hese ac ute reacti o ns are 
i m p orta nt beca use t he y ma y be 
se vere b ut are c o nsi dere d rare.
M o nit ori n g f or i m m u n o ge nicit y 
effects (se vere aller g y a n d 
h y perse nsiti vit y reacti o ns a n d 
A D A), see A p pe n di x G.
Fl u -li ke Re acti o ns
Fl u -li ke s y m pt o ms (c hills, m yal gia, 
art hral gia, feeli n g h ot, a n d b o d y 
te m perat ure i ncrease) are rat her 
c o m m o n f or s o me A S Os . N o 
i n dicati o ns of s yste mic 
i nfla m mat or y effects i n d uce d b y 
A Z D 8 2 3 3 ha ve bee n see n i n t he 
t o xic ol o g y st u dies.
M o nit ori n g f or a n y fl u -li ke 
reacti o ns a n d assess me nt of 
hs -C R P.
St u d y pr oce d ures
Pai n near t he i njecti o n site (f or 1 or 
2 da y s) is t he m ost c o m m o n 
c o m plicati o n 
Sl o w 
 of A Z D 8 2 3 3 usi n g 
ge ntle press ure (at least 5 sec o n ds 
d urati o n is rec o m me n de d) a n d 
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Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 8 of 9 8
4
St u d y Desi g n
4. 1
O ver all Desi g n
F or a n o ver vie w of t he st u d y  desi g n, see Fi g ure 1 . F or details o n treat me nt gi ve n d uri n g t he 
st u d y, see Sectio n  6. 1 .
T his is a ra n d o mise d paralle l, d o u ble bli n d, place b o c o ntr olle d P hase 2 b st u d y t o e valuate t he 
safety,  t olera bilit y a n d efficac y of A Z D 8 2 3 3 as c o m pare d wit h place b o. T he st u d y is pla n ne d 
t o be carrie d o ut acr oss a p pr o xi matel y 1 0 0 cli nical sites i n ar o u n d 8 c o u ntries.
A p pr o xi matel y 3 7 6 partici pa nts wit h h y perli pi dae mia will be ra n d o ml y assi g ne d t o 
A Z D 8 2 3 3  
 or matc hi n g place b o i n a 1: 1 rati o. Partici pa nts will be treate d wi t h 
A Z D 8 2 3 3 or place b o S C, Q 4 W  for 2 8 wee ks, t o pr o vi de data t o g ui de pl atelet mo ni t ori n g f or 
f ut ure pr o gra ms. T he ai m is t hat, of t he partici pa nts ra n d omise d t o A Z D 8 2 3 3 d oses, at least 
1 5 0 s h o ul d c o m plete t he 2 8 wee ks of pl a n ne d treat me nt.
T he effect of A Z D 8 2 3 3 
 a d mi nistere d S C, Q 4 W for 2 8 wee ks, o n c o nce ntrati o ns of 
L D L -C i n ser u m  will als o be e val uate d. 
T here will be a n i nit ial scree ni n g peri o d starti n g u p t o 2 8 da ys bef ore a n d e n di n g o n t he da y 
bef ore t he ra n d o misat i on visit (ie, Da y  -1). T he st u d y  is di vi de d i nt o a pla n ne d treat me nt 
p eri o d of  2 8 wee ks f oll owe d b y a safet y f oll ow- u p of  1 2 wee ks. O verall, t his ma kes a t otal 
st u d y partici patio n ti me of 4 0 wee ks o nce partici pa nts are ra n d o ml y  assig ne d i nt o t he trial. 
A n i SM C will be use d f or re g ular re vie w of u n bli n de d safet y data d uri n g t he st u d y  (see 
A p pe n di x  A 5 ). T he re mit of t he i S M C will be detaile d i n t he i S M C c harter. 
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
Ele vate d plas ma L D L -C, i s a mai n ris k fact or f or C V D a n d is ca use d b y a c o m bi nat i on of 
e n vir o n me ntal a n d ge net ic fact ors. Stati n t hera p y is t he sta n dar d li pi d l o weri n g me dicati on 
f or b ot h sec o n dar y a n d pri mar y pre ve ntio n of  C V D, as a n a dju nct t o di et. Re d uctio n of  
L D L -C b y  st atins l ea ds t o a sig nifica nt re d ucti o n i n car di o vasc ular e ve nts (C olli ns et al 
2 0 1 6) . Stati ns re d uce L D L-C b y  in hi bi tin g H M G -C o A  re d uctase, t he rate- li miti n g e nz y me of 
he pat ic c h olester ol s y nthesis. H o we ver, des pite t he s u bsta nt ial be nefits of stati n t hera p y, 
ma n y pat ient s d o n ot reac h L D L-C tar get g oals a n d s o me c o nti n ue t o be at resi d ual ris k 
des pite ma xi m u m d oses.
Ge net ic st u dies ha ve i de ntifie d P C S K 9 as a n i m p orta nt, H M G-C o A -i n de pe n de nt, circ ulati n g 
re g ulat or of L D L- C (C o he n et al  2 0 0 5, 2 0 0 6) . Gai n of f u ncti on varia nts i n P C S K 9 ca use 
fa milial a ut os o mal h y perc h olester ole mia; l oss of f u ncti on is ass ociate d wit h l o w circ ulati n g 
le vels of L D L -C a n d a re d uce d ri s k of maj or vasc ular e ve nts. Circ ulati n g P C S K 9 is deri ve d 
mai nl y  fr o m t he li ver a n d i ncreases L D L-C b y  pr o moti n g de gra dati o n of he pat ic L D L 
rece pt ors. 
Base d o n t he si g nifica nt cli nical be nefit of P C S K 9 i n hi bit i on, Astra Ze neca is de vel o pi n g a 
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 9 of 9 8
P C S K 9 -tar gete d, Gal N Ac -c o nj u gate d A S O t hat s pecificall y i n hi bits i ntracell ular P C S K 9 
e x pressi o n i n t he li ver (Pra kas h et al 2 0 1 4 ). Se vere, re versi ble t hr o m b oc yt o p e nia has bee n 
o bser ve d i n s o m e A S O pr o gra ms i n cli nical trials, b ut it is n ot k n o w n w het her all me m bers of 
t he class ha ve t his c haracteristic (Cr o o ke et al  2 0 1 7). T his st u d y will e val uate platelet c o u nt, 
o ver ti me, i n A Z D 8 2 3 3 -treate d partici pa nts wit h h y perli pi dae mia, recei vi n g ma xi mall y 
t oler ate d stati n a n d/ or ezeti mi be t hera p y, c o mpare d wi t h place b o. T he ai m of t he st u d y is t o 
see if a n y t hr o m b oc yt o pe nia si g nal is o bser ve d, a n d w het her it is feasi ble t o re d uce platelet 
m o nit ori n g fre q ue nc y  a n d mai ntai n patient  safety.  
4. 3
J ustific ati o n f or D ose
T he t hera pe utic g oal of A Z D 8 2 3 3 is t o l o wer L D L -C b y  7 0 % d uri n g t he e ntire d osi n g 
i nter val. P C S K 9 re d uctio n ca uses L D L -C re d ucti o n b y a well -k n o w n a n d pre vi o usl y  
q ua nt ifie d mec ha nis m, a n d l o weri n g P C S K 9 b y 9 0 % has bee n s h o w n t o re d uce L D L-C b y  
7 0 % (Gi b bs et al 2 0 1 7 , Kat h ma n et al 2 0 1 8 , S o k ol o v et al 2 0 1 9 ).
 
 
 
 
 
 
 
 
 
 
 
4. 4
E n d of St u d y Defi niti o n
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t h e last partici pa nt i n t he st u d y.
5
St u d y P o p ul ati o n
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr ol me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
5. 1
I ncl usi o n Criteri a
P arti cipa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all o f t he fol l owi n g criteria a p pl y:
A ge
1
P arti cipa nts m ust be 1 8 t o 7 5 ye ars of a ge i ncl usi ve, at  t he ti me of si g ni n g t he 
i nf or me d c o nse nt f or m.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2
P arti cipa nts w h o ha ve a fast i n g L D L-C ≥ 7 0 m g/ d L ( 1. 8 m m ol / L) b ut < 1 9 0 mg/ d L 
( 4. 9 m m ol/L) at scree ni n g.
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 0 of 9 8
3
P arti cipa nts w h o ha ve fast i n g tri gl yceri des < 4 0 0 m g/ d L ( < 4. 5 2 m m o l/ L) at 
scree ni n g.
4
P arti cipa nts are recei vi n g a sta ble d ose ( ≥ 3 m o nt hs) of ma xi mall y  t olerate d stati n
a n d/ or ezeti mi be t hera p y as defi ne d b y t he i n vestigat or f or t hat partici pa nt at 
scree ni n g.
Se x
5
Mal e or fe male of n o n- c hil d beari n g p ote ntial.
C o ntrace pti ve use b y me n s h o ul d be c o nsiste nt wit h l ocal re g ulat i ons re gar di n g t he met h o ds 
of  c o ntrace ptio n f or t h ose parti ci pat i n g i n cli nical st u dies. 

Male parti ci pa nts:
Males m ust be s ur gicall y sterile or usi n g, i n c o nj u ncti o n wit h t heir fe male p art ner, a 
hi g hl y  effecti ve met h o d of c o ntrace pti o n f or t he d urati o n of t he st u d y (fr o m t he ti me 
t he y si g n c o nse nt) a n d f or 3 m o nt hs after t he fi nal f oll ow u p visit t o pre ve nt pre g na nc y 
i n a part ner. Acce pta ble met h o ds of c o ntrace pti o n i ncl u de birt h c o ntr ol pills, i nject i ons, 
i m pla nts, or patc hes, i ntra uteri ne de vices (I U Ds), t u bal li gati o n/ occl usi on a n d 
vasect o m y . T hese met h o ds of c o ntrace pti o n s h o ul d be c o m bi ne d wit h a barrier met h o d 
e xce pt f or w he n t he fe male part ner is sterilize d. Male st u d y partici pa nts m u st n ot d o nate 
or ba n k s per m d uri n g t his sa me ti me peri o d.

Fe male partici pa nts:
W o me n m ust n ot be of c hil dreari n g p ote ntial a n d m ust n ot be lactati n g a n d m ust ha ve a 
ne gat i ve pre g na nc y test at scree ni n g. W ome n n ot of c hil d beari n g p ote ntial are defi ne d 
as w o m e n w h o are eit her per ma ne nt l y sterilise d ( h ysterect o m y, bilateral o o p h orect o m y, 
or bilateral sal pi n gect o m y), or w h o are p ost me n o pa usal. W o me n will be c o nsi dere d 
p ost m e n o pa usal if t he y ha ve bee n a me n orr h oeic for 1 2 m o nt hs pri or t o t he pl a n ne d date 
of  r an d o misat i on wi t ho ut a n al ter nati ve me dical ca use. T he f oll o wi n g a ge -s pecific 
re q uire me nts a p pl y:
o
W o me n < 5 0 y e ars old w o ul d be c o nsi dere d p ost me n o pa usal if t he y  ha ve bee n 
a me n orr h oeic for 1 2 m o nt hs or m ore f o ll owi n g cessati o n o f e x o ge n o us 
h or m o nal  tr e at me nt a n d f ollicle sti m ulati n g h or m o ne le vels i n t he 
p ost m e n o pa usal ra n ge.
o
W o me n ≥ 5 0 y e ars old w o ul d be c o nsi dere d p ost me n o pa usal if t he y  ha ve bee n 
a me n orr h oeic for 1 2 m o nt hs or m ore f o ll owi n g cessati o n o f all e x o ge n o us 
h or m o nal  tr e at me nt .
I nf or me d C o nse nt
6
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n  A p pe n di x A w hic h 
i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he IC F a n d i n 
t his pr ot oc ol.
7
Pr o visi o n of si g ne d a n d date d, writte n I C F pri or t o a n y ma n dat or y  st u d y s pecific 
pr oce d ures, sa m pli n g, a n d a nal yses. Partici pa nts w h o c o nse nt o nl y t o t he mai n st u d y  

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 1 of 9 8
ma y partici pate i n ot her c o m p o ne nts of t he mai n st u d y  wit ho ut part ici pati n g i n t he 
o pti o nal  c o mp o ne nt of t he st u d y . H o we ver, t o partici pate i n t he o pti o nal c om p o ne nt 
of  t he st u d y, t he partici p a nt must si g n a n d date b ot h t he c o nse nt f or ms f or t he mai n 
st u d y a n d o ptio nal c o m p o ne nt of t he st u d y . If a partici pa nt decli nes t o partici pate i n 
t he o ptio nal  c o mp o ne nt of t he st u d y , t here will be n o pe nalty or l oss of be nefi t t o t he 
parti ci pa nt. T he partici pa nt will n ot be e xcl u de d fr o m ot her as pects of t he st u d y 
descri be d i n t his pr ot oc ol.
8
 
 
 
5. 2
E xcl usi o n Criteri a 
P arti cipa nts are e xcl u de d fr o m  t he st u d y if a n y of t he f o ll owi n g cri t eria a p pl y:
Me dic al C o n diti o ns
1
As j u d ge d b y  t he i n vesti gat or, a n y e vide nce of a c o n di tio n, w hic h i n t he 
i n vesti gat or's o pi ni on, m a kes it u n desir a bl e for t he parti ci pa nt t o partici pate i n t he 
st u d y.
2
e G F R < 4 0 m L/ mi n/ 1. 7 3 m 2 usi n g t he C K D -E PI.
3
Hi st or y or prese nce of gastr oi ntesti nal, he patic or re nal disease or a n y ot her 
c o n ditio ns k n o w n t o i nterfere wit h a bs or pti o n, distri b uti o n, meta b o lism or e xcreti o n 
of  dr u gs, per t he i n vesti gat or’s j u d ge me nt.
4
A n y u nc o ntr olle d or seri o us disease, or a n y  me dical (e g, k n o w n major acti ve 
i nfecti on or maj or hae mat ol o gical, re nal, meta b o lic, gastr oi ntesti nal or e n d ocri ne 
d y sf u ncti on) or s ur gical c o n dit i on t hat, i n t he o pi ni o n of t he i n vest i gat or, ma y either 
i nterfere wit h p artici pat i on i n t he cli nical st u d y a n d/ or p ut t he partici pa nt at 
sig nifica nt ris k (acc or di n g t o t he i n vest i gat or’s j u d g me nt) if he/s he partici pates i n 
t he cli nical st u d y.
5
P o orl y c o ntr olle d T 2 D M, defi ne d as H b A 1c > 1 0 %.
6
Ac ute i sc hae mic car di o vasc ular e ve nt, i ncl u di n g str o ke, wit hi n 3 0 da ys, or heart 
fail ure wit h Ne w Y or k Heart Ass ociati on ( N Y H A) Class III t o I V.
7
Bl o o d d y scrasias with i ncrease d ris k of blee di n g i ncl u di n g i di o pat hic 
t hr o mb oc y t o pe nic p ur p ura a n d t hr o m b otic t hr o m b oc y t o p e nic p ur p ura or s y m pt o ms 
of  increase d ris k o f blee di n g (fre q ue nt blee di n g g u ms or n ose blee ds).
8
Hi g h -ris k of blee di n g diat hesis or a n y a nti-platel et t hera p y ot her t ha n lo w d ose 
as pirin ( ≤ 1 0 0 m g/ da y ).
9
Mali g na nc y  (e xce pt no n -mela n o ma s ki n ca ncers, cer vical i n sit u carci n o ma, breast 
d uctal  carci n oma i n sit u, or Sta ge 1 pr ostate carci n o ma) wit hi n t he last 1 0 years.
1 0
Reci pie nt of a n y maj or or ga n tra ns pla nt, e g, l u n g, li ver, heart, b o ne marr o w, re nal.
1 1
L D L or pl as ma a p heresis wit hi n 1 2 m o nt hs pri or t o ra n d o misat i on.
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 2 of 9 8
1 2
U nc o ntr olle d h y perte nsi o n defi ne d as a vera ge sitti n g S B P > 1 6 0 m m H g or D B P > 
9 0 m m H g.
1 3
Heart rate after 1 0 mi n utes sitti n g rest < 5 0 or > 1 0 0 b p m.
1 4
A n y la b orat or y  val ues wit h t he f o ll owi n g de viat i ons at t he Scree ni n g Visi t; test ma y 
be re peate d at t he discret i on of t he i n vest i gat or if a b n or mal:

A n y p osi tive res ult o n scree ni n g f or ser u m he pat itis B s urface a nti ge n, he patitis 
C a nt i b o d y, a n d h u ma n i m m u n o deficie nc y vir us ( HI V)

A L T > 1. 5 × U L N

A S T > 1. 5 × U L N

T B L > U L N

A L P > 1. 5 × U L N

W B C < l o wer li mit of n or mal ( L L N).

Hae m o gl o bi n < 1 2 g/ d L i n m ales or < 1 1 g/ d L i n fe males

Pl at elet c o u nt ≤ L L N

a P T T > U L N or Pr ot hr o m bi n Ti me > U L N

U A C R > 1 1 m g/ m m o l ( 1 0 0 mg/ g)

U P C R > 3 0 0 m g/ g
1 5
A n y cli nicall y  i m p orta nt a b n or malities i n r h yt h m, c o n d ucti o n or m or p h ol o g y of t he 
resti n g E C G a n d a n y cli nicall y i m p orta nt a b n or malities i n t he 1 2-lea d E C G as 
j u d ge d b y t he i n vesti gat or.
1 6
Q Tc F > 4 7 0 ms; hi g h de gree atri o ve ntric ular ( A V) -bl oc k gra de II -III a n d si n us n o de 
d y sf u ncti on wi t h si g nifica nt si n us pa use u ntreate d wi t h pace ma ker; a n d car diac 
tac h yarr h yt hmias.
1 7
K n o w n or s us pecte d hist or y  of dr u g a b use or a p ositi ve scree n f or dr u gs of a b use at 
t he Scree ni n g Visit, li kel y t o i m pact partici pa nt safet y or c o mplia nce wi t h st u d y 
pr oce d ures, at t he discret i on of t he I n vest i gat or.
1 8
Hi st or y of alc o h ol a b use or e xcessi ve i nta ke of alc o h ol as j u d ge d b y t he i n vesti gat or.
Pri or/ C o nc o mit a nt T her a p y
1 9
Use of warfari n, direct a n d i n direct t hr o m bi n i n hi bit ors or fact or Xa i n hi bit ors
2 0
Mi p o m erse n, or lo m ita pid e wi t hi n 1 2 m o nt hs pri or t o ra n d o misat i on. 
2 1
A n y fi brate t hera p y  ot her t ha n fe n ofi brate; if t he partici pa nt is o n fe n ofi brate 
t hera p y, t he d ose s h o ul d be sta ble f or at least 6 wee ks pri or t o ra n d o misat i on.
2 2
Pre vi o us a d mi nistrati o n of A Z D 8 2 3 3/ A Z D 6 6 1 5 or i nclisira n ( L E Q VI O ® , N o vartis).
2 3
Use of e v ol oc u ma b ( R E P A T H A ® , A m ge n) a n d alir oc u ma b ( P R A L U E N T® , 
Re ge ner o n) wit hi n 3 m o nt hs of scree ni n g.
2 4
Hi st or y of se vere aller g y/ h y perse nsitivi t y or o n g oi n g cli nicall y i m p orta nt 
aller g y/ h y perse nsit i vity, as ju d ge d b y  t he i n vesti gat or, or hist or y of h y perse nsiti vity 
t o dr u gs wit h a si milar c he mical str uct ure or Gal N Ac -c o nj u gate d A S Os.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 3 of 9 8
2 5
A n y cli nicall y  i m p orta nt ill ness, me dical/s ur gical pr oce d ure or tra u ma wit hi n 
4 wee ks of t he first a d mi nistrati o n of I M P. Hi st or y or e vide nce of a n y ot her 
cli nicall y si g nifica nt dis or der (e g, c o g nit i ve i m pair me nt), c o n diti o n or disease ot her 
t ha n t h ose o utli ne d a b o ve t hat, i n t he o pi ni o n o f t he i n vest i gat or or Astra Ze neca 
p h ysicia n, if c o ns ulte d, ma y c o m pr o mise t he a bilit y of  the partici pa nt t o gi ve writte n 
i nf or me d c o nse nt, w o uld p ose a ris k t o partici pa nt safet y,  or int erfere wit h t he st u d y 
e val uat i on, pr oce d ures or c o m plet i on.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 6
Recei ve d a n ot her ne w c he mical e nt ity ( defi ne d as a c o mp o u n d w hic h has n ot bee n 
a p pr o ve d f or mar ket i n g) wit hi n 3 0 da ys of last fol l o w-u p t o first a d mi nistrati o n o f 
t he I M P of t his st u d y or 5 half-li ves fr om la st d ose t o first a d mi nistrati o n of I M P, 
w hic he ver i s t he l o n gest.
2 7
P arti cip a nts wi t h a k n o w n h y perse nsiti vity t o A Z D 8 2 3 3 or a n y of t he e xci pie nts of 
t he pr o d uct.
2 8
Use of ot her I M P or i n vesti gati o nal de vices d uri n g t he c o urse of t he st u d y .
Ot her E xcl usi o ns
2 9
I n v ol ve me nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o b ot h 
Astra Ze neca staff a n d/ or staff at t he st u d y sit e).
3 0
J u d g me nt b y t he i n vesti gat or t hat t he partici pa nt s h o ul d n ot partici pate i n t he st u d y if 
t he partici pa nt is u nli kel y t o c o mpl y wit h st u d y  pr oce d ures, restricti o ns, a n d 
re q uire me nts.
3 1
Pre vi o us ra n d o misati o n i nt o t he prese nt st u d y .
3 2
P arti cip a n ts w h o ca n n ot c o m m u nicate relia bl y with t he i n vesti gat or.
3 3
P arti cipa nts (e g, ke pt i n dete nti o n, pr otecte d a d ults u n der g uar dia ns hi p, tr ustees hi p, 
or c o m mitte d t o a n i nst itut i on b y g o ver n me ntal or j uri dical or der).
3 4
Pl as ma d o nat i on wi t hi n 1 mo nt h of t he visit at t he cli nic or a n y blo o d d o n ati o n/ bl o o d 
l oss > 5 0 0 m L d uri n g t he 3 m o nt hs pri or t o scree ni n g visit.
 
3 5
3 6
 
5. 3
Lifest yle C o nsi der ati o ns
5. 3. 1
Me als a n d Diet ar y Restricti o ns
P arti cipa nts are re q ui re d t o fast f or at least 8 h o urs o ver ni g ht pri or t o V isits 1, 2, 4, 6, 8, 1 0, 
1 2, 1 4, 1 6, a n d 1 8. Parti ci pa nts are per mitte d t o dri n k water d uri n g t his peri o d of fast i n g. O n 
da ys w here partici pa nts atte n d t he cli nic i n a faste d state, bl o o d a n d uri ne sa m ples s h o ul d be 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 4 of 9 8
o btai ne d pri or t o a d mi nistrati o n of  I M P.
5. 3. 2
C affei ne, Alc o h ol, a n d T o b acc o
P arti cip a nts wi t h k n o w n or s us pecte d hist or y of alc o h ol a b use, as ju d ge d b y  t he i n vesti gat or, 
are n ot all o we d t o partici pate i n t he st u d y.
5. 3. 3
Re pr o d ucti ve restricti o ns
W o me n of N o n -C hil d Be ari n g P ote nti a l
Wo me n of n o n -c hil d beari n g p ote ntial are defi ne d as fe male partici pa nts w h o are 
p er m a ne nt l y s ur gicall y sterilize d or p ost me n o pa usal (see i ncl usi o n cri t eria, Sectio n  5. 1 ).
Restricti o n f or M ale P artici p a nts
T here i s n o i nf or mati o n a b o ut a n y p ot e ntial effect of A Z D 8 2 3 3 o n de vel o p me nt of t he f oet us 
i n h u ma ns. T heref ore, it is i m p orta nt t hat w o me n of c hil d beari n g p ote ntial w h o are t he 
part ners of male partici pa nts d o n ot  bec o me pre g na nt d uri n g t he st u d y a n d for a t otal  p erio d 
of  3 m o nt hs after t he male partici pa nt has atte n de d t he fi nal f o ll o w-u p visit.
As a preca uti o n, all male partici pa nts s h o ul d a v oi d fat heri n g a c hil d b y eit her tr ue a bsti ne nce 
or b y  usi n g (t o get her wit h t heir fe male part ner/s p o use) a hi g hl y effecti ve c o ntrace pti o n f or m 
of  birt h c o ntr ol in c o m bi nati o n wit h a barrier met h o d, starti n g fr o m t he ti me of st u d y 
i nter ve nt i on a d mi nistrati o n u nt il 3 m o nt hs after t he fi nal f o ll ow- u p visit. Acce pta ble met h o ds 
o f pre ve nt i n g pre g na nc y i ncl u de birt h c o ntr ol pills, i njecti o ns, i m pla nts, or patc hes, I U Ds, 
t u bal li gati on/ occl usi o n , a n d vasect o m y.
Male parti ci pa nts w h o ha ve bee n sterilize d are re q uire d t o use 1 barri er met h o d of 
c o ntrace pti o n (c o n d o m) fr o m t he ti me of st u d y int er ve nt i on a d mi nistrati o n u ntil after t he fi nal 
f oll ow- u p visit. A barri er met h o d is n ot necessar y if t he fe male part ner is sterilize d.
S per m D o n ati o n
Male parti ci pa nts s h o uld n ot d o nate s per m  for t he d urati o n of  t he st u d y a n d for at l east 
3 m o nt hs after t he st u d y fi nal f oll ow- u p visi t.
Pre g n a nc y
Male parti ci pa nts will be i nstr ucte d t hat if t heir part ner bec o mes pre g na nt d uri n g t he st u d y  
t his s h o uld be re p orte d t o t he i n vest i gat or. T he i n vesti gat or s h o ul d als o be n otifie d of 
pre g na nc y occ urri n g d uri n g t he st u d y  b ut c o nfir me d after c o m pleti o n of t he st u d y. I n t he 
e ve nt t hat a partici pa nt ’s part ner is s u bse q ue ntl y f ou n d t o be pre g na nt after t he partici pa nt is 
i ncl u de d i n t he st u d y, t he n c o nse nt will be s o u g ht fr o m t he part ner ( via t he partici pa nt’s 
re quest t hat t heir part ner c o ntact t he st u d y  site) a n d, if gra nte d, a n y pre g na nc y will be 
f oll owe d, a n d t he stat us of m ot her a n d/ or c hil d will be re p orte d t o t he S p o ns or after deli ver y .
5. 3. 4
Bl o o d d o n ati o n
P arti cipa nts s h o ul d r ef rai n fr om bl o o d d o nati o n t hr o u g h o ut t he st u d y, i ncl u di n g t he f oll o w- u p 
p eri o d.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 5 of 9 8
5. 4
Scree n F ail ures
Scree n fail ures are defi ne d as part ici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
are n ot s u bse q ue nt l y ra n d omise d t o st u d y  int er ve nti o n. A mi ni mal set of scree n fail ure 
i nf or mat i on is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure partici pa nts t o meet 
t he C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C O N S O RT) p u blis hi n g re q uire me nts a n d t o 
res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, 
scree n fail ure details, eli gi bility cri t eria, a n d a n y S A E.
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y b e 
rescree ne d. At  t he i n vesti gat or’s discreti on, partici pa nts ma y be rescree ne d o nce d uri n g t he 
recr uit me nt perio d. Parti ci pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F a n d 
s h o uld be assi g ne d t he sa m e part ici pa nt n u m ber as per t heir i nitial scree ni n g visit.
6
St u d y I nter ve nti o n
St u d y  int er ve nt i on is defi ne d as a n y i n vesti gati onal i nter ve nt i on(s) , mar kete d pr o d uct(s) or 
pl ace b o i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he st u d y pr ot oc ol.
6. 1
St u d y I nter ve nti o n(s) A d mi nistere d
6. 1. 1
I n vesti g ati o n al Pr o d ucts
Details o f t he ide nt ity of  t he i n vesti gati onal pr o d ucts are prese nte d i n  Ta ble 4 a n d i n t he st u d y 
s pecific I M P ha n dli n g i nstr ucti o ns. 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 6 of 9 8
Ta ble 4 
I n vesti g ati o n al Me dici n al Pr o d ucts
Ar m n a me
C o h ort 1 
C o h ort 2
I nter ve nti o n n a me
A Z D 8 2 3 3
Pl ace b o 
D ose f or m ul ati o n
A Z D 8 2 3 3 s ol uti o n f or i njecti o n
Matc hi n g place b o s ol uti o n f or i njecti o n
U nit d ose stre n gt h(s) a
Place b o, 
 
D os a ge le vel(s) b
 Q 4 W
Place b o, 
 
Re gi me n
A Z D 8 2 3 3/ Place b o, Da ys 1, 2 9, 5 7, 8 5, 1 1 3, 1 4 1, 1 6 9
R o ute of 
a d mi nistr ati o n
S C i njecti o n
Tre at me nt 
A d mi nistr ati o n 
G ui deli nes
S C i njecti o n i n eit her a b d o mi nal re gi o n (a v oi d a 5 c m ra di us ar o u n d 
u m bilic us) , ar m, t hi g h or b utt oc k is t o be use d . Sl o w i njecti o n of st u d y 
i nter ve nti on usi n g ge ntle press ure (at least 5 sec o n ds d urati o n is 
rec o m me n de d) a n d r otati o n of i njecti o n sites. T he a nat o mical l ocati o n of 
eac h i njecti o n site s h o ul d be d oc u me nte d i n t he e C R F.
S pecific de vice f or dr u g 
a d m i nistr ati o n
S y ri n ges a n d nee dles f or i njecti o n t o be pr o vi de d b y La bc or p ce ntral 
la b orat or y
Use
E x peri me ntal
Place b o
I M P a n d NI M P
I M P 
S o urci n g
Vials pr o vi de d ce ntrall y b y t he S p o ns or
P ac k a gi n g a n d 
l a belli n g
 
 
S peci al H a n dli n g 
Re q uire me nts 
Re q uire me nts will be pr o vi de d i n a se parate d oc u me nt.
A v ail a bilit y of I M P
Will be s hi p pe d w he n
a p pr o vals are i n place
a
A Z D 8 2 3 3 is als o a vaila ble as a 5 5 m g/ m L s ol uti o n t o gi ve fle xi bilit y s h o ul d a l o wer stre n gt h be nee de d. 
T he re q uire d i njecti o n v ol u mes are descri be d i n t he st u d y s pecific ha n dli n g i nstr ucti o ns.
b
Pla n ne d d ose
e C R F, electr o nic case r e p ort f or m; I M P, i n vesti gati o nal me dici nal pr o d uct; NI M P, n o n -i n vesti gati o nal 
me dici nal pr o d uct; Q 4 W, e ver y 4 wee ks; S C, s u bc uta ne o us
6. 2
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
1
T he i n vest i gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti ons ha ve 
bee n mai ntai ne d d uri n g tra nsit f or all st u d y  int er ve nt i on recei ve d a n d a n y 
di scre pa ncies are re p orte d a n d res ol ve d bef ore use of t he st u d y int er ve nt i on.
2
O nl y partici pa nts ra n d o mise d i nt o t he st u d y ma y recei ve st u d y i nter ve nt i on a n d o nl y 
w he n a n assess me nt of platelet c o u nt has bee n ma de. All partici pa nts m ust meet 
i ncl usi on cri t eria for pl at el et c o u nt base d o n la b orat or y val ues fr o m Visit 1 i n or der 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 7 of 9 8
t o be d ose d at ra n d o misati on ( Vi sit 2); after ra n d o misati on, parti ci pa nts must ha ve 
pl at elet c o u nt assess e d wit hi n 1 4 ( +/-3) da y s of eac h s u bse q ue nt d ose a d mi nistrati o n.
3
O nl y a ut h orise d site staff ma y  s u p pl y or a d mi nister st u d y int er ve nt i on. All st u d y  
i nter ve nt i on m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d 
( ma n ual or a ut o mate d) area in acc or da nce wit h t he la belle d st ora ge c o n dit i ons wit h 
access li mite d t o t he i n vest i gat or a n d a ut h orise d site staff.
4
T he i n vest i gat or, i nstit uti o n, or t he hea d of t he me dical i nstituti o n ( w here a p plica ble) 
is res p o nsi ble f or st u d y int er ve nt i on acc o u nta b ility, rec o nciliat i on, a n d rec or d 
mai nte na nce (ie, recei pt, rec o nciliat i on, a n d fi nal dis p osit i on rec or ds).
5
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p osit i on of u n use d st u d y  
i nter ve nt i ons are pr o vi de d i n t he st u d y s pecific ha n dli n g i nstr ucti o ns.
6. 3
Me as ures t o Mi ni mise Bi as: R a n d o mis ati o n a n d Bli n di n g
All partici pa nts will be ce ntrall y assi g ne d t o ra n d o mise d st u d y i nter ve nti o n usi n g a n 
I nteracti ve Res p o nse Tec h n o l og y / Ra n d omisati o n a n d Trial S u p pl y Ma na ge me nt 
(I RT/ R T S M). Bef ore t he st u d y is i nit iate d, t he lo g i n i nf or mati o n & direct i ons f or t he 
I RT/ R T S M will be pr o vi de d t o eac h site.
Eli gi ble partici pa nts will be ra n d o ml y assi g ne d t o A Z D 8 2 3 3  
 or matc hi n g place b o i n a 
1: 1 rati o. P arti cipa nts will be treate d wit h A Z D 8 2 3 3 or place b o S C Q 4 W  for 2 8 wee ks. 
St u d y  int er ve nt i on will be dis pe nse d at t he st u d y  visits s u m marise d i n t he S o A. Ret ur ne d 
st u d y int er ve ntio n s h o ul d n ot be re -dis pe nse d t o t he partici pa nts.
T he I R T/ R T S M will pr o vi de t o t he i n vest i gat or(s) or p har macists t he kit i de ntificati on 
n u m ber t o be all ocate d t o t he partici pa nt at t he dis pe nsi n g visit. R o uti nes f or t his will be 
descri be d i n t he I R T/ R T S M user ma n ual t hat will be pr o vi de d t o eac h ce ntre.
T he ra n d o misat i on c o de s h o ul d n ot be br o ke n e xce pt i n me dical e mer ge ncies w he n t he 
a p pr o priate ma na ge me nt of t he partici pa nt re q uires k n o wle d ge of t he treat me nt 
ra n d omisat i on. T he i n vest i gat or d oc u me nts a n d re p orts t he acti o n t o Astra Ze neca, wit h o ut 
re veali n g t he treat me nt gi ve n t o partici pa nt t o t he Astra Ze neca staff.
Astra Ze neca retai ns t he ri g ht t o brea k t he c o de f or S A Es t hat are u ne x pecte d a n d are 
s us pecte d t o be ca usall y relate d t o a n i n vesti gati on al  pr o d uct a n d t hat p ote ntiall y re q uire 
e x pe dite d re p orti n g t o re g ulat or y a ut h orities. Ra n d o misat i on c o des will n ot be br o ke n f or t he 
pl a n ne d a nal yses of data u ntil all decisi ons o n t he e val ua bilit y of  t he data fr o m eac h 
i n di vi d ual partici pa nt ha ve bee n ma de a n d d oc u me nte d.
T he R T S M will  be pr o gra m me d wit h bli n d -brea ki n g i nstr ucti o ns. I n case of a n e mer ge nc y, i n 
w hic h t he k n o wle d ge of t he s pecific bli n de d st u d y  treat me nt will affect t he i m me diate 
ma na ge me nt of t he partici pa nt ’s c o n ditio n  (e g, a nti d ote a vaila ble), t he i n vesti gat or has t he 
s ole res p o nsi bility f or deter mi ni n g if u n bli n di n g of a partici pa nts’ i nter ve ntio n assi g n me nt is 
warra nte d. Partic i pa nt safety m ust al wa ys be t he first c o nsi derat i on i n ma ki n g s uc h a 
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 8 of 9 8
deter mi nat i on. If a partici pa nt ’s i nter ve nti on assi g n me nt is u n bli n de d, t he s p o ns or m ust be 
n otifie d wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he i n vesti gat or d oc u me nts a n d re p orts t he 
actio n t o Astra Ze neca, wit h o ut re veali n g t he treat me nt gi ve n t o partici pa nt t o t he Astra Ze neca 
staff.
Data f or t he p har mac o d y na mic para meters i n t he li pi d pa nel liste d i n Secti o n  8. 5. 3 are 
c o nsi dere d p ote ntial u n bli n di n g i nf or mat i on. T heref ore, a n y s uc h res ults ta ke n p ost 
ra n d omisat i on will be ke pt c o nfi de nt ial a n d bli n de d t o site staff as s p o ns or pers o n nel. T he 
e xce pti o ns are la b orat or y ve n d or a n d data ma na ge me nt pers o n nel assi g ne d i n u n bli n de d r ole
T he l a b orat or y ve n d or pers o n nel perf or mi n g t he bi oa nal yses of t he plas ma sa m ples will ha ve 
access t o t he ra n d o misat i on list. T he la b orat or y ve n d or will recei ve i nstr ucti o ns o n bli n di n g 
of  s pecific p har mac o d y na mic bi omar kers, s uc h as L D L-C, t o l a b orat or y res ults accesse d b y 
sites a n d s p o ns or. A d dit i onall y, g uida nce will be pr o vi de d t o i n vest i gat ors t o a d vise 
parti ci pa nts a n d t heir cli nicia ns t o a d here t o rec o m me n de d g ui deli nes f or li pi d m o nit ori n g 
a n d a v o i d a d diti onal assess me nt  w he n n ot cli nicall y i n dicate d.
6. 4
St u d y I nter ve nti o n C o m pli a nce
W he n partici pa nts are d ose d at t he site, t he y  will recei ve st u d y int er ve nt i on di rectl y fr o m t he 
i n vesti gat or or desi g nee, u n der me dical s u per visi on. T he date, a n d ti me, of d ose a d mi nistere d 
i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he e C R F. T he d ose of 
st u d y int er ve ntio n a n d st u d y  p artici p a nt ide nt ificati o n will be c o nfir me d at t he ti me of d osi n g 
b y a me m ber of t he st u d y site staff ot her t ha n t he pers o n a d mi nisterin g t he st u d y  int er ve nt i on. 
S af et y m o nit ori n g visits ma y be u n derta ke n at t he partici pa nt’ s h ome or a n y  ot her a p pr o priate 
l ocat i on usi n g h o me n ursi n g ca pa bilit y.  Ot her visits ma y als o be u n derta ke n at t he 
parti ci pa nt ’s h ome or a n y  ot her a p pr o priate l ocati on if dee me d a p plica ble, f oll o wi n g 
c o ns ultati o n wit h t he s p o ns or . O nce t he h o me visit is c o m p lete, t he har d c o p y of t he s o urce 
d oc u m e nt will be sec urel y maile d t o t he site f or data e ntr y int o t he e C R F.
6. 5
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne, i ncl u di n g a n y a p pr o ve d or e mer ge nc y use a ut h orise d C O VI D - 1 9 
vacci nes, o ver -t he- c o u nter or prescri pt i on me d ici nes, vita mi ns, a n d/ or her bal s u p ple me nts 
t hat t he partici pa nt is recei vi n g at t he ti me of e nr o l me nt or recei ves d uri n g t he st u d y must be 
rec or de d al o n g wi t h:

Reas o n f or use

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates

D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y
S pecific g ui da nce f or C O VI D -1 9 vacci nat i on ca n be f o u n d i n  A p pe n di x H . 
I n vesti gat ors ma y prescri be c o nc o mita nt me dicati ons or treat me nts dee me d necessar y t o 
pr o vi de a de q uate care f or partici pa nts e xce pt f or t h ose me dicat i ons e xcl u de d bel o w or liste d 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 9 of 9 8
i n t he e xcl usi on cri teria. S pecificall y, partic i pa nts s h o ul d recei ve f ull s u p p orti ve care d uri n g 
t he st u d y as dee me d a p pr o priate, a n d i n acc or da nce wit h l ocal g ui deli nes. 
T he f o ll owi n g m e dical restrict i ons a p pl y:

Me dicat i ons/t hera pies s pecifie d i n t he e xcl usi o n criteria are pr o hi bite d fr o m use f or t he
d urati o n of  t he participa nt’s i n v ol ve me nt i n t he st u d y . 

P arti cipa nts s h o ul d be recei vi n g a sta ble d ose ( ≥ 3 m o nt hs) of ma xi mall y t olerate d stati n 
a n d/ or ezeti mi be t hera p y as defi ne d b y t he i n vesti gat or f or t hat partici pa nt. Beca use t he 
t hera pe utic wi n d o w of  stati n t hera p y ma y var y bet wee n patient  i n acc or da nce t o k n o w n 
or p ote ntial ris ks f or si de effects, t he ma xi m u m t olerate d d ose of stati n t hera p y will be 
defi ne d b y t he i n vest i gat or f or eac h patie nt base d o n cli nical j u d ge me nt. Patie nts w h o are 
c o mplete l y i ntol era nt t o stati n t hera p y will be allo w e d t o partici pate as t he ma xi m u m 
t olerate d d ose is n o ne .

F or parti ci pa nts o n fe n o fi brate t hera p y, t he d ose m ust be sta ble f or at least 6 wee ks pri or 
t o ra n d o misati o n at a d ose t hat is a p pr o priate f or t he d urati on of t he st u d y  in t he 
j u d ge me nt of t he i n vesti gat or. Ot her fi brate t hera p y (a n d deri vati ves) are pr o hi bite d.

Use of ic osa pe nt et h yl ( Vasce pa), be m pe d o ic aci d ( Ne xlet ol), bile aci d se q uestra nts a n d 
nic oti nic aci d are per mitte d; h o we ver, partici pa nts s h o ul d be recei vi n g a sta ble d ose ( ≥ 3 
m o nt hs) pri or t o ra n d o misati o n. I nit iati n g t hese me dicati ons after a partici pa nt is e nr o lle d 
is n ot per mitte d.

P arti cipa nts s h o ul d n ot be o n a n y a nti- pl at elet t hera p y ot her t ha n lo w -d ose as pi rin 
( ≤1 0 0 m g/ da y).

P arti cipa nts m u st a bstai n fr om ma k i n g d ose c ha n ges a n d ta ki n g ne w prescri pti on or n o n -
prescri pt i on dr u gs wit h o ut c o ns ultat i on wi t h t he i n vestigat or (i ncl u di n g vita mi ns a n d 
di et ar y or her bal s u p ple me nts) wit hi n 7 da ys ( or 1 4 da ys if t he dr u g is a p ote ntial e nz y me 
i n d ucer) or 5 half-li ves ( w hic he ver is l o n ger) bef ore t he start of st u d y i nter ve nti o n u ntil 
c o mplet i on of t he f o ll ow- u p visit.

Paraceta m o l/aceta mi n o p he n, at d oses of 2 g/ da y , is per mitte d f or use a n y ti me d uri n g 
t he st u d y. Ot her c o nc o mita nt me dicati on ma y be c o nsi dere d o n a case - b y-case basis b y 
t he i n vesti gat or i n c o ns ultati on wi t h t he St u d y  P h ysicia n if re q uire d.

T he St u d y  P h ysicia n s h o uld be c o ntacte d if t here are a n y  q uestio ns re gar di n g 
c o nc o mita nt or pri or t hera p y.
6. 5. 1
R esc ue Me dici ne
T he st u d y  will not s u p pl y a n y  s pecific resc ue me dicatio n. 
T he date a n d ti me of a n y resc ue me dicat i on a d mi nistrati o n or res pecti ve d ose c ha n ge m ust be 
rec or de d i ncl u di n g:

N a m e of me dicat i on;

Reas o n f or use or c ha n ge;

Cli ni cal St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 0 of 9 8

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates;

A n d d osa ge i nf or mat i on i ncl u di n g d ose a n d fre q ue nc y.
6. 6
D ose M o dific ati o n
N o d ose m o dificat i on is all owe d. 
6. 7
I nter ve nti o n After t he E n d of t he St u d y
T here i s n o pla n ne d i nter ve nt i on f oll owi n g t he e n d of t he st u d y . H o we ver, s h o uld a 
parti ci pa nt de vel o p t hr o m b oc yt o pe nia d uri n g t he safety f oll ow- u p t hat re m ai ns u nres ol ve d 
after t he st u d y e n ds, f urt her e val uati on ma y be necessar y as o utli ne d i n A p pe n di x F. 
7
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h ole are ha n dle d as part of A p pe n di x A.
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
A n i n di vi d ual partici pa nt will n ot recei ve f urt her I M P if a n y of t he f o ll owi n g occ ur i n t he 
parti ci pa nt i n q uest i on:

P arti cipa nt decisi o n . T he partici pa nt is free at a n y ti me t o disc o nti n ue I M P treat me nt, 
wi t ho ut prej u dice t o f urt her treat me nt

A E precl u di n g f urt her t hera p y  ( w here t he i n vesti gat or t hi n ks c o nti n ue d treat me nt ma y 
p ut t he patie nt at u n d ue ris k, re gar dless o f w het her t he A E is t h o u g ht t o be relate d t o 
I M P)

I n vesti gat or’s decisi on, i ncl u di n g b ut n ot li mite d t o t hese e xa m ples:

I nc orrectl y ra n d o mise d patie nt i n w h o m t he i ncl usi o n/e xcl usi o n criteria vi o lati on 
w o ul d p ut t he pati e nt at u n d ue ris k

Se vere n o n -c o mplia nce t o Cli nical St u d y  Pr ot oc ol

Pre g na nc y

Pl at elet c o u nt < 7 5 × 1 09/ L, c o nfir me d b y ta ki n g a sec o n d meas ure me nt (A p pe n di x F)

H y’s La w defi ne d as ‘a n i ncrease i n A S T or A L T ≥ 3 × U L N t o get her wit h T B L ≥ 2 × 
U L N, w here n o ot her reas o n, ot her t ha n t he I M P, ca n be f o u n d t o e x plai n t he 
c o m bi nat i on of i ncreases’, a s defi ne d i n A p pe n di x E.

C o nfir me d: 

A L T or A S T > 8 × U L N

A L T or A S T > 5 × U L N f or > 2 wee ks

A L T or A S T > 3 × U L N a n d T B L > 2 × U L N or I N R > 1. 5

A L T or A S T > 3 × U L N wit h t he a p peara nce of fati g ue, na usea, v o mit i n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 1 of 9 8

C o nfir me d b y re peat testi n g i ncrease i n ser u m creati ni ne of 0. 3 m g/ d L fr o m baseli ne at 
t he discret i on of t he i n vest i gat or

C o nfir me d b y re peat testi n g 2 5 % decli ne i n e G F R fr o m baseli ne at t he discreti o n of t he 
i n vesti gat or

C o nfir me d b y re peat testi n g ne w o nset hae mat uria of u n k n o w n et i ol og y , al b u mi n uria 
( uri ne al b u mi n/creati ni ne rati o [ U A C R] ≥ 3 0 0 m g/ g), or pr otei n uria ( uri ne 
pr otei n/creati ni ne [ U P C R] ≥ 5 0 0 m g/ g) at t he di scretio n of  t he i n vestig at or

A na p h ylactic reacti o n or se vere h y perse nsit i vity reacti o n s us pecte d t o be relate d t o st u d y  
i nter ve nt i on.
F oll o w -u p f or  p artici p a nts w h o h a ve disc o nti n ue d I M P
P arti cipa nts w h o are pr e mat urel y a n d per ma ne nt l y di sc o nti n ue d fr om recei vi n g I M P will be 
e nc o ura ge d t o c o nti n ue t heir st u d y partici patio n b y f oll o wi n g t he ori gi nal  visit sc he d ule, 
wi t ho ut ta ki n g I M P, wit h t he e xce ptio n of  t he safet y mo ni t orin g visit s d uri n g t he treat me nt 
p eri o d .
If t he partici pa nt is u n willi n g t o c o m pl y wit h t he visit sc he d ule, a m o difie d f oll ow- u p 
sc he d ule ca n be offere d, w hic h s h o ul d at a mi ni m u m i ncl u de t he f oll owi n g visi ts: 

T he ne xt sc he d ule d visit, usi n g t he ori gi nal visit sc he d ule.

Vi sit 8 (if t he partici pa nt disc o nti n ues pri or t o Visit 8) a n d Visit 1 6 (e n d of pla n ne d 
treat me nt perio d) per t he S o A.

S af et y f oll ow- u p visits (t o i ncl u de S o A pr oce d ures f or Visit 1 7 a n d Visit 1 8), a dj uste d t o 
occ ur 8 a n d 1 6 wee ks after last d ose, res pecti vel y .
N ote t hat disc o nti n uati o n f r o m st u d y int er ve nt i on is N O T t he sa me t hi n g as a wit h dra wal 
fr om t he st u d y.
7. 1. 1
Te m p or ar y Disc o nti n u ati o n
If a partici pa nt te m p oraril y disc o nti n ues I M P f or a n y reas o n, t he partici pa nt ma y restart t he 
me dicat i on at a n y t i me d uri n g t he d osi n g peri o d i n acc or da nce wit h t he d osi n g sc he d ule , b ut 
o nl y  w he n a n assess me nt of platelet c o u nt has bee n ma de wit hi n 1 4 ( +/-3) da y s of pla n ne d 
a d mi nistrati o n a n d re -assess me nt of t he partici pa nts cli nical stat us. N o a d dit i onal d oses will 
be a d mi nistere d t o ma ke u p f or misse d d oses. T he reas o n f or a n y te m p orar y I M P i nterr u pti o n 
will be c o llecte d i n t he e C R F.
7. 2
P artici p a nt Wit h dr a w al fr o m  t he St u d y

A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y time at hi s/ her o w n re q uest wit h o ut 
pr ej u dice t o f urt her treat me nt. I n e xce pt i onal circ u msta nces, t he partici pa nt ma y be 
wi t hdra w n at a n y  ti me at t he discretio n of  t he i n vestigat or f or safety,  be ha vi o ural, 
c o mplia nce, or a d mi nistrati ve reas o ns .

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 2 of 9 8

A partici pa nt w h o c o nsi ders wit h dra wi n g fr o m t he st u d y must be i nf or me d b y  t he 
i n vesti gat or a b o ut mo difie d f oll o w -u p o pti o ns (tel e p h o ne c o ntact, c o ntact wit h a relat i ve 
or t he treati n g p h ysicia n, i nf or mat i on fr o m me dical rec or ds or m o dificat i on of t he S o A as 
descri be d i n Secti o n  7. 1 ).

If t he partici pa nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati on, t he s p o ns or 
ma y retai n a n d c o nt i n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.

If a partici pa nt wit h dra ws fr om t he st u d y, it s h o ul d be c o nfir me d if he/s he still a grees f or 
e xist i n g sa m ples t o be use d i n li ne wit h t he ori gi nal c o nse nt. If he/s he re q uests 
wi t hdra wal  of c o nse nt f or use of sa m ples, destr ucti o n of a n y sa m ples ta ke n a n d n ot 
teste d s h o ul d be carrie d o ut i n li ne with w hat w as state d i n t he i nf or me d c o nse nt a n d 
l ocal re g ulati o ns. T he i n vestig at or m ust i nf or m t he Gl o bal St u d y  T e a m im me diatel y a n d 
d oc u m e nt t he decisi o n o n use of e xist i n g sa m ples i n t he site st u d y rec or ds.
7. 3
L ost t o F oll o w u p
A partici pa nt will be c o nsi dere d l ost t o f o ll ow- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e.
T he f o ll owi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he partici pa nt o n t he i m p orta nce o f ma i ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he partici pa nt wis hes t o a n d/ or s h o ul d c o nti n ue i n 
t he st u d y.

Bef ore a partici pa nt is dee me d l ost t o f o ll ow u p, t he i n vest i gat or or desi g nee m ust ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne calls a n d, 
if necessar y , a certifie d letter t o t he partic i pa nt’s last k n o w n maili n g a d dress or l ocal 
e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s 
me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wi t hdra w n fr o m  t he st u d y.
8
St u d y Assess me nts a n d Pr oce d ures
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marise d i n t he S o A. Pr ot oc ol wai vers or 
e xe m pt i ons are n ot all o we d.

All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote ntial 
parti ci pa nts meet all eli gi bilit y cri t eria. T he i n vest i gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble.

Pl at elet c o u nt res ults must be a vaila ble wit hi n 1 4 da ys ( +/ -3) pri or t o all s u bse q ue nt 
d osi n g f o ll owi n g Visi t 2

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 3 of 9 8

Assess me nts sc he d ule d at t he sa me t i me ma y be i nitiate d base d o n t he se q ue nce bel o w 
( w here a p plica ble):
1 
E C G 
2
Vi t al si g ns ( S B P, D B P, p ulse rate, a n d te m perat ure), a n d p h ysical e xa m, i ncl u di n g 
ne ur o l ogi c e xa m a n d A E re vie w i ncl u di n g I M P I S R assess me nt
3
P K, P D a n d safet y bl o o d a n d uri ne sa m pli n g
4
D ose a d mi nistrati o n. Pre -d ose assess me nts ma y be perf or me d u p t o 6 0 mi n utes pri or 
t o d osi n g
5
W here a p plica ble, 2 -h o ur ( 1 5 mi n utes) p ost -d ose assess me nts, i ncl u di n g 
c o mple me nt acti vat i on pr ofile, c oa g ulat i on para meters a n d P K ( Visit 1 2)

I mme diate safet y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or u p o n occ urre nce or 
a ware ness t o deter mi ne w het her t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nt i on.

A d he re nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse nt ial a n d re q uire d f or st u d y c o n d uct.

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, bl o o d 
c o u nt) a n d o btai ne d bef ore si g ni n g of t he I CF ma y be utilise d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d 
wi t hi n t he ti me fra me defi ne d i n t he S o A.
T he st u d y  is di vi de d i nt o a scree ni n g peri o d of 2 8 da ys, a pla n ne d treat me nt perio d of  
2 8 wee ks f oll o we d b y a safet y f oll ow- u p peri o d of  1 2 wee ks, wit h t he first visit i n t he safety 
f oll ow- u p peri o d occ urri n g 8 wee ks after t he last d ose of I M P is a d mi nistere d. O n t he 
scree ni n g visit ( Visit 1), partici pa nts are c hec ke d f or eli gi bilit y, e nr o lle d i nt o t he st u d y, a n d 
e xa mi nat i ons a n d sa m ples ta ke n acc or di n g t o t he S o A. At  Visit 2, after st u d y assess me nts a n d 
a d ditio nal  blo o d a n d uri ne sa m ples are ta ke n, partici pa nts are ra n d o ml y assi g ne d t o A Z D 8 2 3 3 
or m atc hi n g place b o in a 1: 1 rati o . T he first d ose will be a d mi nistere d at ra n d o misat i on 
Vis it 2. Parti ci pa nts will t he n recei ve a f urt her d ose e ver y 4 wee ks o n 6 m ore occasio ns. T he 
e n d of t he pla n ne d treat me nt peri o d Visit will occ ur o n Vis it 1 6 f oll owe d b y t he fi rst s afet y 
f oll ow- u p Visit 4 wee ks later . T he fi nal safety f oll ow- u p visit ta kes place 8 wee ks after t he 
first safet y fol l ow- u p visi t.
Ge ner al Descri pti o n of St u d y Visits
Vi sit 1 (e nrol me nt): At  Visit 1, partici pa nts will be as ke d t o si g n t he i nf or me d c o nse nt. 
P arti cipa nts are re q ui re d t o be fasti n g f or at least 8 h o urs o ver ni g ht pri or t o t he visit. 
P arti cipa nt eli gi bili t y crit eria will be re vie we d a n d de m o gra p hics, me dical hist or y, i ncl u di n g, 
dr u g a n d alc o h o l c o ns u m pt i on hist or y, as well as c o nc o mita nt me dicat i on re vie w will be 
rec or de d i n t he e C R F. A c o mplete p h ysical e xa mi nati o n m ust be perf or me d. V ital si g ns, 
hei g ht, wei g ht ,a n d E C G will be c hec ke d, as well as bl o o d a n d uri ne sa m ple c ollecti o n, per 
t he S o A. Ser u m pre g na nc y, F S H, a n d L H tests will be ta ke n f or fe male partici pa nts. All 
la b orat or y tests perf or me d at Visit 1 s h o uld be re vie we d f or eli gi bilit y pri or t o t he parti ci pa nt 
ret ur ni n g f or Visit 2. E nr ol me nt will be perf or me d i n I RT/ R T S M. 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 4 of 9 8
Vi sit 2 (r a n d o mis ati o n): At  Visit 2, partic i pa nts are re q uire d t o be fasti n g f or at least 8 h o urs 
o ver ni g ht pri or t o t he visit ; partici pa nts are per mitte d t o dri n k water d uri n g t his peri o d u ntil 
1 h o ur bef ore bl o o d sa m pli n g. Eli gi bilit y cri t eria m ust be verifie d b y c hec ki n g scree ni n g 
la b orat or y assess me nts a n d i ncl usi o n/e xcl usi o n criteri a. 
 
 A c o mplete p h ysical e xa mi nat i on, ne ur o l ogic 
e xa mi nat i on a n d vital si g n assess me nts will be perf or me d. Bl o o d sa m ples, i ncl u di n g t h ose 
nee de d f or ef ficac y a n d p har mac o d y na mics, A D A  a n d uri ne sa mples will be o btai ne d i n 
acc or da nce wit h t he S o A. E C G will be c hec ke d. If t he partici pa nt f ulfils all i ncl usi o n cri teria 
a n d n o ne of t he e xcl usi o n cri t eria, t he partici pa nt will be ra n d o mise d i n I RT/ R T S M a n d I M P 
will be a d mi nistere d as a S C i nject i on. P ost -d ose assess me nts (c o m ple me nt acti vati o n pr ofile 
a n d c oa g ulat i on para meters) will ta ke place 2 -h o urs after d osi n g of I M P.
Vi sit 3: At  Visit 3, c o nc o mit a nt me dicat i ons, A Es, a n d a n assess me nt f or I S Rs will be 
re vie we d, as well as a n a b bre viate d p h ysical e xa m a n d assess me nt of vital si g ns. Bl o o d a n d 
uri ne sa m ples, a n d platelet c o u nt, will be o btai ne d i n acc or da nce t o t he S o A. 
D osi n g Visits ( Visits 4, 6, 8, 1 0, 1 2, 1 4): At d osi n g visits, partici pa nts are re q uire d t o be 
fasti n g f or at least 8 h o urs o ver ni g ht pri or t o t he visit; partici pa nts are per mitte d t o dri n k 
water d uri n g t his peri o d u ntil 1 h o ur bef ore bl o o d sa m pli n g. C o nc o mita nt me dicat i ons, A Es 
a n d a n assess me nt f o r I S Rs will be re vie we d. A n a b bre viate d p h ysical e xa m a ne ur o l ogi c 
e xa mi nat i on a n d assess me nt of vital si g ns will be perf or me d. Re vie w of t he m ost rece nt 
pl at elet c o u nt wit hi n 1 4 ( +/-3 da y s) prior t o t he visi t. E C G, blo o d sa m ples, i ncl u di n g t h ose 
nee de d f o r efficac y a n d p har mac o d y na mics, a n d uri ne sa m ples will be c ollecte d i n 
acc or da nce wit h t he S o A. Bl o o d sa m ples f or A D A  will be c ollecte d. P K sa m ples will be 
c ollecte d pre-d ose o n Visits 4, 8, a n d 1 2. St u d y int er ve nt i on will t he n be a d mi nistere d. P ost -
d ose assess me nts (c oa g ulat i on pa nel a n d c o m ple me nt acti vat i on pr ofile; P K at Visit 1 2) will 
be o btai ne d 2 h o urs after d osi n g of I M P.  
S afet y M o nit ori n g V isits ( Visits 5, 7, 9, 11, 1 3, 1 5):   At safet y visits, c o nc o mit a nt 
me dicat i ons, A Es a n d a n assess me nt f or I S Rs will be re vie we d. Platelet c o u nt a n d li ver 
f u ncti on tests will be o btai ne d. A P K  sa m ple will be o btai ne d o n Visit 1 5. Partici pa nts d o n ot 
ha ve t o be fast i n g f or t his visit. W here a p plica ble, t he safety m o nit ori n g visit ma y be 
perf or m e d via h o me visits.
E n d of Pl a n ne d T re at me nt Peri o d V isit ( Visit 1 6): At  t he e n d of treat me nt visit, t he 
parti ci pa nts are re q uire d t o be fasti n g f or at least 8 h o urs o ver ni g ht pri or t o t he visit. 
C o nc o mita nt me dicat i ons, A Es a n d a n assess me nt f or I S Rs will be re vie we d. A n a b bre viate d 
p h ysical e xa m, a ne ur o l ogi c e xa mi nat i on a n d assess me nt of vital si g ns will be perf or me d. 
Bl o o d sa m ples, i ncl u di n g t h ose nee de d f or efficac y  a nd p har mac o d y na mics, P K a n d A D A, as 
well as uri ne sa m ples, will be c o llecte d. C oa g ulati o n para meters will als o be assesse d.
S afet y F oll o w -u p V isits ( Visit 1 7, 1 8): At  t he safet y fol l ow- u p visit s, partici pa nts are 
re q uire d t o be fasti n g f or at least 8 h o urs o ver ni g ht pri or t o Visit 1 8 ( n ot necessar y for 
Vis it 1 7). C o nc o mita nt me dicat i ons a n d A Es will be re vie w e d. A n a b bre viate d p h ysical 
e xa mi nat i on a n d assess me nt of vital si g ns will be perf or me d o n V isit 1 7 a n d a c o m plete 
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 5 of 9 8
p h ysical e xa mi nat i on, a ne ur o l ogic e xa mi nat i on a n d assess me nt of vital si g ns o n V isit 1 8. 
A d dit i onall y, E C G will be o btai ne d. Blo o d a n d uri ne sa m ples, i ncl u di n g A D A, will be 
c ollecte d i n acc or da nce wit h t he S o A. F or partici pa nts w h o ha ve pre mat urel y disc o nt i n ue d 
I M P, t hese visits will be a dj uste d t o occ ur 8 a n d 1 6 wee ks after t he last d ose of I M P, as 
descri be d i n Secti o n  7. 1 .  
8. 1
Effic ac y Assess me nts
Pl ease see Sect i on  8. 5. 3 f or t he p har mac o d y na mic assess me nts, w hic h will be use d f or 
pri mar y  a n d ke y sec o n dar y efficac y a nal yses. Pri mar y efficac y will be deter mi ne d b y relati ve 
c ha n ge fr o m baseli ne i n L D L-C at t he e n d of  Wee k 2 8. Sec o n dar y efficac y will be 
deter mi ne d b y relat i ve c ha n ge fr o m baseli ne i n P C S K 9 at t he e n d of Wee k 2 8.
8. 2
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A. T he safet y f oll ow- u p 
p eri o d will be defi ne d as t he ti me fr o m t he e n d of treat me nt Visit t o t he fi nal safety f oll ow- u p 
Vis it.
8. 2. 1
P h ysic al E x a mi n ati o n

A c o m p lete p h ysical e xa mi nati on will i ncl u de assess me nts of t he f o ll owi n g; ge neral  
a p peara nce, res pirat or y, car dio vasc ular, a b d o m e n, s ki n, hea d a n d nec k (i nc l u di n g ears, 
e yes, n ose a n d t hr oat), l y m p h n o des, t h yr oid, m us c ul os keletal  (i ncl u di n g s pi ne a n d 
e xtre mit ies), a n d ne ur ol o gical s yste ms. 

A n a b bre viate d p h ysical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he 
s ki n, l u n gs, car di o vasc ular s yste m, a n d a b d o me n (li ver a n d s plee n). D uri n g h o me visit s, 
t he a b bre viate d p h ysical e xa m ca n be c o n d ucte d via s y m pt o m le d assess me nt. 

B o d y  wei g ht s h o uld be meas ure d i n li g ht i n d o or cl ot hes wit h o ut s h oes, after a pri or visit 
t o t he bat hr o o m
P h ysical e xa mi nat i on will be perf or me d at ti me p oi nts as s pecifie d i n t he S o A. 
8. 2. 2
Ne ur ol o gic al E x a mi n ati o n

A c o m p lete ne ur ol o gical e xa mi nat i on will i ncl u de peri p heral se ns or y  a n d mot or 
e val uat i on, as well as a n assess me nt of gait, pai n, p osit i on, stre n gt h a n d refle xes. 
A p pr o priate trai ni n g t o be gi ve n at t he i n vest i gat ors’ Meeti n g.

Ne ur ol o gi cal e xa mi nat i on will be perf or me d at ti me p oi nts as s pecifie d i n t he S o A.
8. 2. 3
Assess me nts f or A Es, i ncl u di n g ne w o nset/ w orse ni n g of di a betes A Es
A n assess me nt of A Es will be perf or me d at t he ti me p oi nts s pecifie d i n t he S o A. T hese A Es 
will als o i ncl u de a n y w orse ni n g of pre vi o usl y  d oc u me nted m e dical c o n dit i ons as deter mi ne d 
b y t he i n vesti gat or . 
A d dit i onall y, assess me nts f or h yper gl yce mia -relate d A Es s h o ul d be i ncl u de d wit h t he 

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assess me nt f or c o nc o mita nt me dicat i ons a n d A Es. T his s h o ul d i ncl u de:
A n y re p ort of ‘Ne w o nset of di a betes’ i n w hic h parti ci pa nts wit h n o me dical hist or y of 
di a betes are f o u n d t o ha ve a n y of t he f o ll owi n g:

a p ost -baseli ne H b A 1 C ≥6. 5 %, c o nfir me d b y  a c o nsec uti ve H b A 1 C val ue ≥6. 5 % ( 4 8 
m m o l/ m ol) or a fasti n g plas ma gl uc ose ≥1 2 6 m g/ d L ( 7. 0 m m ol / L), or

t wo c o nsec uti ve val ues of  fasti n g plas ma gl uc ose ≥ 1 2 6 m g/ d L ( 7. 0 m m o l/L), or

a d ditio n of  a ne w c o nc omit a nt me dicat i on f or c o ntr ol of plas ma gluc ose (if a d dit i onal 
i nf or mat i on pr o vi de d t o t he i n vest i gat or s u p p orts t he dia g n osis), or

a d verse e ve nts s u g gesti ve of  dia betes (e. g. t ypical  dia betes ma nifestatio ns, si g ns, 
s y m pt o ms, c o m plicati ons).
A n y re p ort of ‘ W orse ni n g of t he gl yce mic c o ntr ol’ or ‘ dia betic c o m plicat i ons’ i n w hic h
parti ci pa nts wit h a me dical hist or y of dia betes are f o u n d t o ha ve:

A bs ol ute i ncrease i n H b A 1c f r o m baseli ne of  > 0. 5 % ( 5. 5 m m ol/ m ol), a n d/ or

A ne w c o nc o mit a nt a ntidia bet ic me dicat i on or a n i ncrease i n d ose of c urre nt a nti dia bet ic 
t hera p y in res p o nse t o u nc o ntr olle d dia betes, or a n y  c o nfir matio n of  u nc o ntr olle d 
di a betes/ w orse ni n g gl yce mic c o ntr ol fr o m  cli nical data c ollecte d b y t he i n vesti gat or 
8. 2. 4
Vit al Si g ns
Vit al si g ns ( bl o o d press ure, p ulse a n d te m perat ure) will be perf or me d at t he ti me p oi nts 
s pecifie d i n t he S o A.

Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n a sitti n g p osit i on wi t h a 
c o mpletel y a ut o m ate d de vice. Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d 
de vice is n ot a vaila ble

B P a n d p ulse meas ure me nts s h o ul d be prece de d b y at least 5 mi n utes of rest f or t he 
parti ci pa nt i n a q uiet setti n g wit h o ut distracti o ns (e g, tele visi o n, cell p h o nes)
Vit al si g ns (t o be ta ke n bef ore bl o o d c ollecti on f or la b orat or y tests) will c o nsist of 1 p ulse a n d 
3 B P meas ure me nts ( 3 c o nsec ut i ve B P rea di n gs will be rec or de d at i nter vals of at least 
1 mi n ute). T he a vera ge of t he 3 B P rea di n gs will be rec or de d o n t he e C R F.
8. 2. 5
Electr oc ar di o gr a ms
E C G will be perf or me d pre -d ose w here a p plica ble, at ti me p o i nts s pecifie d i n t he S o A.

At  ra n d o misati on ( Vi sit 2), t he baseli ne 1 2-lea d E C G will be o btai ne d o n t hree 
c o nsec ut i ve occasi o ns after t he partici pa nt has reste d i n s u pi ne p ositi on f or at least 
1 0 mi n utes

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
D uri n g t he treat me nt peri o d a n d safet y f oll ow- u p, a si n gle 1 2 -lea d E C G will be o btai ne d 
after t he partici pa nt has reste d i n s u pi ne p ositi o n f or at least 1 0 mi n utes

T he sa me rec or der s h o ul d be use d f or eac h parti ci pa nt at eac h ti me p oi nt, if p ossi ble
T he i n vest i gat or ( or q ualifie d desi g nee) will ma ke a n o verall e val uati on of t he E C G as 
n or m al or a b n or mal. If a b n or mal, it will be deci de d w het her t he a b n or malit y is cli nicall y 
sig nifica nt or n ot cli nicall y si g n ifica nt, a n d t he reas o n f or t he cli nicall y si g nifica nt 
a b n or malit y will be rec or de d o n t he e C R F.
A b n or m al val ues s hall not be rec or de d as A Es u nless dee me d cli nicall y si g nifica nt. T he 
pri nt o ut of t he E C G is t o be si g ne d, date d, a n d file d i n t he i n vest i gative site file al o n g wit h a 
sig ne d a n d date d c o p y  (if t he pri nt o uts are n ot o n arc hi ve-q uali t y pa per).
T he i n vest i gat or ma y perf or m a d diti onal 1 2 -lea d E C G assess me nts i n case of a n y a b n or mal 
fi n di n gs or if c o nsi dere d re q uire d b y t he i n vesti gat or f or a n y ot her safety reas o n. T hese 
assess me nts s h o ul d be e ntere d as a n u nsc he d ule d assess me nt.
8. 2. 6
Cli nic al S afet y L a b or at or y Assess me nts
La b orat or y  varia bles will be a nal yse d at La bc or p  ce ntral la b orat or y. A n y l ocal la b orat or y  
varia bles, perf or me d f or safet y assess me nt, s uc h as platelet c o u nt, m ust be c o nfir me d b y 
ce ntral la b orat or y assess me nt. Sa m ples will be c o llecte d, ha n dle d, la belle d, st ore d a n d 
s hi p pe d as detaile d i n t he la b orat or y ma n ual. 
T he f o ll owi n g la b orat or y  varia bles will be meas ure d.
Ta ble 5
L a b or at or y S afet y V a r i a bles
H ae m at ol o g y/ H ae m ost asis ( w h ole bl o o d)
Cli nic al C he mistr y (ser u m or pl as m a)
W hite bl o o d cell ( W B C) c o u nt
S o di u m
Re d bl o o d cell ( R B C) c o u nt
P otassi u m
Hae m o gl o bi n ( H b) 
Bl o o d urea nitr o ge n ( B U N)
Hae mat ocrit ( H C T)
Creati ni ne
Mea n -c or p usc ular v ol u me ( M C V)
Calci u m
Mea n c or p usc ular hae m o gl o bi n c o nce ntrati o n ( M C H C)
P h os p hate
Ne utr o p hils a bs ol ute c o u nt
Creati ne ki nase ( C K)
L y m p h oc y tes a bs ol ute c o u nt
Direct bilir u bi n
M o n oc ytes a bs ol ute c o u nt
Al kali ne p h os p hatase ( A L P)
E osi n o p hils a bs ol ute c o u nt
Ala ni ne a mi n otra nsferase ( A L T)
Bas o p hils a bs ol ute c o u nt
As partate a mi n otra nsferase ( A S T)
Platelets a bs ol ute c o u nt
Ga m ma gl uta m yl tra ns pe pti dase ( G G T)
Retic ul oc ytes a bs ol ute c o u nt
T otal bilir u bi n ( T B L)

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Ta ble 5
L a b or at or y S afet y V a r i a bles
Gl uta mate de h y dr o ge nase ( G L D H)
Uri n al ysis ( di pstic k)
Bicar b o nate
Uri n al ysis ( p ositi ve di pstic k)
Ur ic aci d
p H
F ollicle sti m ulati n g h or m o ne ( F S H[ w o me n 
o nl y ])
S pecific gra vit y
L utei nisi n g h or m o ne ( L H) ( w o me n o nl y)
Gl uc ose
H ae m o gl o be A 1c , gl ycate d hae m o gl o bi n   
( H b A 1c)
Bl o o d
G l uc ose
C ol o ur
Esti mate d gl o mer ular filtrati o n rate (e G F R) b y 
C K D -E PI f or m ula)
Pr otei n
Clarit y / A p peara nce
C o a g ul ati o n
Nitrites
Pr ot hr o m bi n ti me 
Ket o nes
Acti vate d partial t hr o m b o plasti n ti me (a P T T)
Le u k oc ytes
I nter nati o nal n or malise d rati o (I N R)
Micr osc o pic a nal ysis (if p ositi ve f or bl o o d, nitrites or 
pr otei n)
Ur o bili n o ge n
Uri ne re n al s afet y bi o m ar kers
Al b u mi n
T otal pr otei n
Ot her L a b or at or y Assess me nts
Creati ni ne
C o m ple me nt acti vati o n pa nel ( B b, C 5a)
Ur i ne pr otei n t o creati ni ne rati o ( U P C R)
Hi g h -se nsiti vit y C-reacti ve pr otei n ( hs-C R P)
Ur i ne al b u mi n t o creati ni ne rati o ( U A C R)
N B. If a partici pa nt s h o ws a n A S T or A L T ≥3 × U L N t o get her wit h T B L ≥2 × U L N pl ease 
refer t o A p pe n di x E . Actio ns re q ui re d i n cases of i ncreases i n li ver bi oc he mistr y a n d 
e val uat i on of H y’s La w, f or f urt her i nstr ucti o ns. 
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he PI is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are fa miliar wit h t he 
c o nte nt of t his sect i on.
T he defi nit i ons of a n A E or S A E ca n be f o u n d i n  A p pe n di x B.
A d verse e ve nts will be re p orte d b y  t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, 
s urr o gate, or t he partici pa nt's le gall y a ut h orise d re prese ntati ve). 
T he i n vest i gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nt i n g, a n d rec or di n g 
e ve nts t hat meet t he defi nit i on of a n A E. Care will be ta ke n n ot t o i ntr o d uce bias w he n 
detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d n o n-lea di n g ver bal q uesti oni n g o f t he 
parti ci pa nt is t he preferr e d met h o d f or deter mi ni n g t he occ urre nce of A Es.

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8. 3. 1
Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
A Es will be c o llecte d fr om ra n d omisat i on, ( V isit 2) a n d S A Es fr o m si g ni n g t he I C F ( Visit 1). 
B ot h A Es a n d S A Es will c o nt i n ue t o be c ollecte d t hr o u g h o ut t he treat me nt peri o d a n d 
i ncl u di n g t he f oll o w-u p peri o d ( Visit 1 8).
If t he i n vesti gat or bec o mes a ware of a n seri o us a d verse e ve nt wit h a s us pecte d ca usal 
r elat i ons hi p t o t he I M P t hat occ urs after t he e n d of t he cli nical st u d y i n a partici pa nt trea te d 
b y hi m or her, t he i n vest i gat or s hall, wit h o ut u n d ue dela y, re p ort t he S A E t o t he s p o ns or.
8. 3. 2
F oll o w- u p of A Es a n d S A Es
A n y A Es t hat are u nres o l ve d at t he partici pa nt’s last A E assess me nt i n t he st u d y are f o ll owe d 
u p b y  t he i n vesti gat or f or as l o n g as me dicall y i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he 
e C R F. Astra Ze neca retai ns t he ri g ht t o re q uest a d diti o nal i nf or mati o n f or a n y  p artici pa nt wit h 
o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if ju d ge d necessar y.
A d verse e ve nt v ari a bles
T he f o ll owi n g v aria bles will be c ollecte d f or eac h A E:

A E ( ver bat i m)

T he date w he n t he A E starte d a n d st o p pe d

Ma xi m u m i nte nsit y ( mil d, mo derate, se vere)

W het her t he A E is seri o us or n ot

W het her t he A E re q uire d treat me nt 

W het her t he A E was assesse d as a n I S R

I n vesti gat or ca usalit y rati n g a gai nst t he I M P(s) ( yes or n o)

Act i on ta ke n wit h re gar d t o I M P(s)

O utc o m e
I n a d diti on, t he f o ll owi n g vari a bles will be c ollecte d f or S A Es:

Date A E m et crit eria for S A E

Date i n vest i gat or beca me a ware of S A E

A E i s serio us d ue t o

Date of h os pi talisati on

Date of disc har ge

Pr o ba ble ca use of deat h if a p plica ble

Date of deat h

A ut o ps y  p erfor m e d

Ca usalit y assess me nt i n relat i on t o st u d y  pr oce d ure(s)

Ca usalit y assess me nt i n relat i on t o ot her me dicat i on

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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8. 3. 3
C a us alit y C ollecti o n
T he i n vest i gat or s h o uld assess ca usal relati o ns hi p bet wee n I M P a n d eac h A E a n d a ns wer 
‘yes ’ or ‘n o ’ t o t he q uesti o n ‘D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y t hat t he 
e ve nt ma y ha ve bee n ca use d b y t he I M P?’
F or S A Es ca usal relati o ns hi p s h o ul d als o be assesse d f or ot her m e dicat i on a n d st u d y  
pr oce d ures. N ote t hat f or S A Es t hat c o ul d be ass ociate d wit h a n y st u d y  pr oce d ure t he ca usal 
r elat i ons hi p is i m plie d as ‘yes ’.
A g ui de t o t he i nter pretati o n of t he ca usalit y q uesti o n is f o u n d i n  A p pe n di x B t o t he Cli nical 
St u d y  Pr ot oc ol.
8. 3. 4
A d verse E ve nts B ase d o n Si g ns a n d S y m pt o ms
All A Es s p o nta ne o usl y re p orte d b y t he partici pa nt or re p orte d i n res p o nse t o t he o pe n 
q uesti o n fr o m t he st u d y sit e st aff: Ha ve y o u ha d a n y  h e alt h pr o ble ms si nce t he pre vi o us 
visit/ y o u were last as ke d? , or re veale d b y o bser vati o n, will be c ollecte d a n d rec o r de d i n t he 
e C R F. W he n c ollecti n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n p ossi ble) t o 
rec or di n g a list of si g ns a n d s y m pt o ms. H o we ver, if a dia g n osis is k n o w n a n d t here are ot her 
sig ns or s y m pt o m s t hat are n ot ge nerall y p art of t he dia g n osis, t he dia g n osis a n d eac h si g n or 
s y m pt o m will be rec or de d se paratel y.
8. 3. 5
A d verse E ve nts B ase d o n E x a mi n ati o ns a n d Tests
T he res ults fr o m t he C S P ma n date d la b orat or y tests a n d vital si g ns will be s u m marise d i n t he 
C S R. 
Deteri or ati o n as c o m pare d t o baseli ne i n pr ot o c ol -ma n date d lab orat or y  val ues a n d vital si g ns 
s h o uld t heref ore o nl y  be re p orte d as A Es if t he y f ulfil a n y o f t he S A E criteria, are t he reas o n 
f or disc o nti n uati on of treat me nt wit h t he i n vest i gati onal pr o d uct or are c o nsi dere d t o be 
cli nicall y rele va nt as j u d ge d b y t he i n vest i gat or ( w hic h ma y i ncl u de b ut n ot li mite d t o 
c o nsi derati o n as t o w het her treat me nt or n o n -pl a n ne d visits were re q uire d or ot her acti o n was 
ta ke n wit h t he st u d y int er ve nt i on, e g, d ose a dj ust me nt or dr u g i nterr u pti o n).
If deteriorati o n i n a la b orat or y val ue/ vit al si g n is ass ociate d wit h cli nical si g ns a n d s y m pt o ms, 
t he sig n or s y m pt o m  will be re p orte d as a n A E a n d t he ass ociate d la b orat or y  res ult/ vit al si g n 
will be c o nsi dere d as a d dit i onal i nf or mat i on. W here ver p ossi ble t he re p orti n g i n vest i gat or 
uses t he cli nical, rat her t ha n t he la b orat or y  t er m (e g, a nae mia vers us l o w hae m o gl obi n val ue). 
I n t he a bse nce of cli nical si g ns or s y m pt o ms, cli nicall y rele va nt deteri orati o ns i n n o n-
ma n date d para meters s h o ul d be re p orte d as A E(s).
A n y fi n di n g fr om p h ysical e xa mi nat i on (i ncl u di n g ne ur ol o gi cal e xa mi natio n) s h o ul d be 
e val uate d as n or mal/a b n or mal. If t he a b n or mal p h ysical fi n di n g (i ncl u di n g ne ur o l ogi cal 
e xa mi nat i on) starte d pri or t o e nr ol me nt, it m ust be rec or de d as me dical hist or y. If t he 
a b n or mal p h ysical  fi n di n g (i ncl u di n g ne ur ol o gical e xa mi nati on) starte d or w orse ne d after 

Cli nical St u d y Pr ot oc o l – A me n d me nt N u m ber 1
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e nr o l me nt, it m ust be rec or de d as a n A d verse E ve nt.
8. 3. 6
H y’s L a w
Cases w here a partici pa nt s h o ws ele vati o ns i n li ver bi oc he mistr y  ma y re q uir e furt her 
e val uat i on a n d occ urre nces o f A S T or A L T ≥3 × U L N t o get her wit h T B L  ≥2 × U L N ma y 
nee d t o be re p orte d as S A Es. Please refer t o  A p pe n di x E f or furt her i nstr ucti o n o n cases of 
i ncreases i n li ver bi oc he mistr y a n d e val uati on of H y ’s La w
8. 3. 7
Re p orti n g of Seri o us A d verse E ve nts
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he 
i n vesti gati onal pr o d uct, or t o t he st u d y  pr oce d ure(s). All S A Es will be rec or de d i n t he e C R F .
If a n y S A E occ urs i n t he c o urse of t he st u d y, i n vestigat ors or ot her site pers o n nel will i nf or m 
t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n o ne da y  ie, i m me diatel y b ut n o l ater  t h a n 
2 4 h o urs of  w he n he or s he bec o mes a ware of it .
T he desi g nate d Astra Ze neca re prese ntati ve will w or k wit h t he i n vesti gat or t o e ns ure t hat all 
t he necessar y i nf or mati o n is pr o vi de d t o t he Astra Ze neca Pat ient  Safety data e ntr y  sit e wit hi n 
o ne c ale n d ar d a y of  init ial recei pt for f at al a n d life-t hreate ni n g e ve nts a n d wit hi n 
fi ve c ale n d ar d a ys of  init ial recei pt f or all ot her S A Es.
F or fatal  or life-t hreate ni n g A Es w here i m p orta nt or rele va nt i nf or mat i on is missi n g, acti ve 
f oll ow- u p will be u n derta ke n i m me diatel y . I n vesti gat ors or ot her site pers o n nel will i nf or m 
Astra Ze neca re prese ntati ves of a n y  foll o w -u p i nf or mat i on o n a pre vi o usl y  re p orte d S A E 
wi t hi n o ne cale n dar da y, ie, i m me diatel y but n o l ater  t h a n 2 4 h o urs of  w he n he or s he 
bec o me s a ware of it.
O nce t he i n vest i gat ors or ot her site pers o n nel i n dicate a n A E i s serio us i n t he E D C s yste m , a n 
a ut o mat e d e mail alert is se nt t o t he desi g nate d Astra Ze neca re prese ntati ve.
If t he E D C s yste m is n ot a vaila ble, t he n t he i n vesti gat or or ot her st u d y sit e st aff re p orts a n 
S A E t o t he a p pr o p riate Astra Ze neca re prese ntati ve b y  t ele p h o ne.
T he Astra Ze neca re prese ntati ve will a d vise t he i n vesti gat or/st u d y site staff h o w t o pr ocee d. 
I n vesti gat ors or ot her site pers o n nel se n d rele va nt C R F m o d ules b y fa x (
) or 
e mail (
t o Astra Ze neca Pat ient  Safety Data 
E ntr y  Site, Tata C o ns ulta nc y Ser vices.
T he refere nce d oc u me nt f or defi nit i on o f e x pecte d ness/liste d ness is t he I B for A Z D 8 2 3 3. 
8. 3. 8
Pre g n a nc y
All pre g na ncies a n d o utc o mes of pre g na nc y s h o ul d be re p orte d t o Astra Ze neca e xce pt f or:
P P D
P P D

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 2 of 9 8

If t he pre g na nc y is disc o vere d bef ore t he st u d y partici pa nt has recei ve d a n y st u d y 
i nter ve nt i on
Pre g na nc y itself is n ot re gar de d as a n a d verse e v e nt u nless t here is a s us pici o n t hat t he 
i n vesti gati onal pr o d uct u n der st u d y  ma y ha ve i nterfere d wit h t he effect i ve ness of a 
c o ntrace pti ve me dicat i on. C o n ge nital a n o ma lies/ birt h defects a n d s p o nta ne o us miscarria ges 
s h o uld be re p orte d a n d ha n dle d as S A Es. E lecti ve a b orti o ns wit h o ut c o m plicati ons s h o ul d n ot 
be ha n dle d as A Es. T he o utc o me o f all pre g na ncies (s p o nta ne o us miscarria ge, electi ve 
ter mi nati o n, ect o pic pre g na nc y, n or mal birt h or c o n ge nit al a n o mal y) s h o uld be f ol l owe d u p 
a n d d oc u me nte d e ve n if t he par tici pa nt was disc o nti n ue d fr o m t he st u d y.
If a n y pre g na nc y occ urs i n t he c o urse of t he st u d y, t he n t he i n vesti gat or or ot her site 
pers o n nel i nf or ms t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n o ne d a y , ie, 
i m me diatel y b ut n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec o me s a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n o ne 
or  fi ve c ale n d ar d a ys f or S A Es (see Secti o n 8. 3. 7 ) a n d wit hi n 3 0 d a ys f or all ot her 
pre g na ncies.
T he sa me ti meli nes a p pl y w he n o utc o me i nf or mat i o n is a vaila ble.
T he pre g na nc y re p ort m o d ule i n t he e C R F is use d t o re p ort t he pre g na nc y a n d t he pa per -
base d pre g na nc y  o ut c o me mo d ul e i s use d t o re p ort t he o utc o me of t he pre g na nc y.
8. 3. 8. 1
P ater n al E x p os ure 
Male parti ci pa nts s h o uld r ef rai n fr o m fat heri n g a c hil d d uri n g t he st u d y a n d for 3 m o nt hs 
f oll owi n g t he fi nal f o ll ow- u p visit (see als o Secti o n  5. 3. 3 ).
I n case of pre g na nc y of t he part ner of a male partici pa nts, t he part ner ’s pre gna nc y s h o ul d be 
re p orte d o n t he pre g na nc y f or m (c o nse nt fr om t he part ner must be o btai ne d bef ore t he 
pre g na nc y f or m is c o m plete d) f o ll owi n g t he sa me ti mefra me a n d r o uti n g as descri be d f or a n y  
parti ci pa nt ’s pre g na nc y. Pre g na nc y of t he partici pa nt's part ner is n ot c o nsi dere d t o be a n A E. 
T hese pre g na ncies will als o be f o ll owe d u p, a n d t he o utc o me of t he pre g na nc y (s p o nta ne o us 
miscarri a ge, electi ve ter mi nat i on, ect o pic pre g na nc y, n or mal birt h or c o n ge nital a n o mal y) 
s h o uld, if p ossi ble, be o btai ne d a n d d oc u me nt e d.
8. 3. 9
Me dic ati o n Err or
If a me dicati on err or occ urs i n t he c o urse of t he st u d y, t he n t he i n vesti gat or or ot her site 
pers o n nel i nf or ms t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n 1 d a y , ie, i m me diatel y 
b ut n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec o mes a ware of it, a n d rec or ds t he err or o n 
t he Me dicat i on err or e C R F m o d ule.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is c om p lete d wit hi n o ne (I nitial F at al/ Life-T hreate ni n g or f o ll ow u p 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 3 of 9 8
Fa t al/ Life-T hreate ni n g) o r  fi ve ( ot her seri o us i nitial a n d f o ll ow u p) c ale n d ar d a ys if t here is 
a n S A E ass ociate d wit h t he me dicat i on err or (see Secti o n  8. 3. 7 ) a n d wit hi n 3 0 d a ys f or all 
ot her m e dicatio n err ors.
T he defi nit i on of a Me dicat i on Err or ca n be f o u n d i n A p pe n di x  B 4 . 
8. 3. 1 0
I M P I njecti o n Site Re acti o ns
A n y react i ons at t he I M P i nject i on site(s) (ie, I S Rs) will be c ollecte d as A Es a n d detaile d 
i nf or mat i on re gar di n g s y m pt o ms etc, will be c o llecte d o n a s pecific CR F .
8. 4
O ver d ose
F or t hi s st u d y, a n y d ose of A Z D 8 2 3 3 greater t ha n t he pla n ne d d ose will be c o nsi dere d a n 
o ver d ose.

A n o ver d ose wit h ass ociate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
r ele va nt A E mo d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule

A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y  re p orte d o n t he O ver d ose e C R F 
m o d ule
If a n o ver d ose o n a n Astra Ze neca st u d y i nter ve nti o n occ urs i n t he c o urse of t he st u d y, t he 
i n vesti gat or or ot her site pers o n nel i nf or m a p pr o priate Astra Ze neca re prese ntat i ves 
i m me diatel y, b ut n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec ome s a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he i n vest i gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n o ne 
or  5 c ale n d ar d a ys f or o ver d oses ass ociate d wit h a n S A E (see secti o n 8. 3. 7 ) a n d wit hi n 
3 0 d a ys f or all ot her o ver d oses.
8. 5
H u m a n Bi ol o gic al S a m ples
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bi o l o gical sa m ples will be pr o vi de d i n t he 
st u d y s pecific la b orat or y ma n ual. Sa m ples s h o uld be st ore d i n a sec ure st ora ge s pace wit h 
a de q uate meas ures t o pr otect c o nfi de nt iality.  For f urt her details o n Ha n dli n g o f H u m a n 
Bi ol o gi cal Sa m ples see A p pe n di x C.
S a m ples will  be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he iss ue of t he C S R i n 
li ne wit h c o nse nt a n d lo c al  r e q uire me nts, after w hic h t he y will be destr o ye d/re patriate d. 

P K sa m ples (assessi n g A Z D 8 2 3 3 t otal f ull le n gt h A S Os) will be dis p ose d of after 
Bi oa nal y tic al Re p ort fi nalizati on or 6 m o nt hs after iss ua nce of t he draft Bi oa nal y tical 
Re p ort ( w hic he ver is earlier), u nless c o nse nt is o btai ne d f or f ut ure a nal yses. 

P K sa m ples ma y be dis p ose d of or a n o n y mise d b y p o oli n g. A d dit i onal a nal yses ma y 
be c o n d ucte d o n t he a n o n y mise d, p o ole d p har mac o ki net ic sa m ples t o f urt her 
e val uate a n d vali date t he a nal ytical met h o d. A n y r es ults fr o m s uc h a nal yses ma y be 
re p orte d se paratel y fr o m t he Cli nical St u d y Re p ort ( C S R).

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 4 of 9 8

Re mai ni n g A D A sa m ple ali q u ots will be retai ne d at Astra Ze neca or its desi g nee f or a 
ma xi m u m o f 1 5 y ears f o ll owi n g iss ue of t he C S R. A d dit i onal use i ncl u des b ut is n ot 
li mite d t o f urt her c haracterizati on of a n y A D As, c o nfir mat i on a n d/ or re q ualificat i on of 
t he assa y as well as a d dit i onal assa y  d e v elo p me nt w or k. T he res ults fr o m f ut ure a nal ysis 
will n ot be re p orte d i n t he C S R.
8. 5. 1
P h ar m ac o ki netics
Pl as ma sa mples will be c ollecte d f or meas ure me nt of c o nce ntrati o n of A Z D 8 2 3 3 (t otal f ull 
le n gt h A S Os) as s pecifie d i n t he S o A.
S a m ples ma y  be c ollecte d at a d ditio n al  time p oi nts d uri n g t he st u d y  if warra nte d a n d a gree d 
u p o n bet wee n t he i n v estigat or a n d t he s p o ns or, e g, f or safet y reas o ns. T he ti mi n g of sa m pli n g 
ma y be altere d d uri n g t he c o urse of t he st u d y  base d o n ne wl y a vaila ble data (e g, t o o bt ain 
data cl oser t o t he ti me o f pea k or tr o u g h matri x c o nce ntrati o ns) t o e ns ure a p pr o priate 
m o ni t ori n g. 
Pl as ma s a mples will be use d t o a nal yse t he P K of A Z D 8 2 3 3. T he sa m ples c ollecte d ma y als o 
be use d t o e val uate safet y or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or after t he 
st u d y.
S a m ples will  be c ollecte d, la belle d, st ore d, a n d s hi p pe d as detaile d i n t he La b orat or y Ma n ual.
8. 5. 1. 1
Deter mi n ati o n of Dr u g C o nce ntr ati o n
S a m ples f or deter mi nati o n of dr u g c o nce ntrati o n ( A Z D 8 2 3 3 t otal f ull le n gt h A S Os) i n plas ma 
will be assa ye d at bi oa nal y tical test sites o perate d b y or o n be half of Astra Ze neca, usi n g a n 
a p pr o priatel y vali date d bio a n al y tical met h o d. F ull details of t he a nal ytical met h o d use d will 
be descri be d i n a se parate bi oa nal yt ical re p ort.
Pl ace b o sa mples will n ot be a nal yse d, u nless t here is a nee d t o c o nfir m t hat c orrect treat me nt 
has bee n gi ve n t o st u d y participa nts.
Dr u g c o nce ntrati o n i nf or mat i on t hat w o ul d u n bli n d t he st u d y  will not be re p orte d t o 
i n vesti gati ve sites or bli n de d pers o n nel u ntil t he st u d y has bee n u n bli n de d.
I nc urre d sa m ple re pr o d uci bility a nal ysis or a d dit i onal assa y  d e v elo p m e n t/ vali datio n w or k, if 
a n y, will be perf or me d alo n gsi de t he bi oa nal ysis of t he test sa m ples. T he res ults fr o m t he 
e val uat i on, if perf or me d, will be re p orte d i n a se parate Bi oa nal yt ical Re p ort.
8. 5. 2
I m m u n o ge nicit y Assess me nts
Bl o o d sa m pl es f or i m m u n o ge nicit y assess me nts ( A D A) i n plas ma will be c ollecte d acc or di n g 
t o t he S o A (Ta ble 1 ).
T he prese nce or a bse nce of A D As will be deter mi ne d i n t he plas ma sa m ples usi n g a vali date d
bi oa nal yt ical met h o d. A tiere d testi n g sc he me will be e m pl o ye d, wi t h t he first ste p bei n g 
scree ni n g. Sa m ples f o u n d p osit i ve i n t he scree ni n g ste p will be teste d i n t he c o nfir mat or y 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 5 of 9 8
ste p. Sa m ples c o nfir me d p ositi ve f or A D A  in t he c o nfir mat or y  ste p will u n der g o e n d p oi nt 
titre deter mi nati on. F ull details of t he a nal yt ical met h o d a n d a nal yses perf or me d will be 
descri be d i n a se parate bi oa nal yt ical re p ort.
A D A  sa m ples ma y als o be f urt her teste d f or c haracterisati on of t he A D A res p o nse. St u d y 
res ults ma y be re p o rte d i n de pe n de ntl y t o A D A  fol l o w-u p.
S a m ples will  be c ollecte d, la belle d, st ore d, a n d s hi p pe d as detaile d i n t he La b orat or y Ma n ual.
P arti cip a nts wi t h treat me nt -e mer gi n g A D A-p osi tive ti tres at  t he last st u d y visit, a n d t hat has a 
tit er of at least 8 0 0 t hat is > 2 dil uti o n ste ps hi g her t ha n at baseli ne, ma y be as ke d t o ret ur n t o 
pr o vi de a n ot her sa m ple i n t he ti me fra me a p pr o xi matel y 3- 6 m o nt hs after t he last st u d y visit.
8. 5. 3
P h ar m ac o d y n a mics
8. 5. 3. 1
C ollecti o n of S a m ples
Bl o o d sa m ples will be c ollecte d f or meas ure me nt of L D L - C a n d ot her li pi ds, w hic h will be 
meas ure d i n ser u m usi n g a vali date d a nal y tical met h o d. Plas ma P C S K 9 le vels will be 
meas ure d usi n g a vali date d a nal y tical met h o d.
P har mac o d y na mic la b orat or y  assess me nts i ncl u de:

L D L - C

P C S K 9

Tri gl yceri des

Li p o pr otei n pr ofile ( parti cle size a n d n u m ber)

Bi o m ar ker a nal yses
A n d ot her li pi d para meters: 

T ot al  c h olester ol

H D L - C

N o n -H D L -C ( Cal c ulate d)

V L D L - C

Re m na nts c h o lester ol (calc ulate d)

A p o B

A p o A 1

L p(a)

L D L -C/ A p o B
F or st ora ge, re -use a n d destr ucti o n of p har mac o d y na mic sa m ples see Secti o n  8. 5 a n d 
A p pe n di x C.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 6 of 9 8
8. 6
H u m a n Bi ol o gic al S a m ple Bi o m ar kers
8. 6. 1
C ollecti o n of m a n d at or y s a m ples f or bi o m ar ker a n al ysis
B y  c o nse nti n g t o ta ke part i n t he st u d y, t he partici pa nt c o nse nts t o ta ke part i n t he ma n dat or y 
researc h c o m p o ne nts of t he st u d y. 

S a m ples f or bi o m ar ker researc h are re q uire d a n d will be c o llecte d fr om all part ici pa nts i n 
t his st u d y as s pecifie d i n t he S o A (Ta ble 1 ). 

 

Bi o m ar kers t o be ta ke n:

Bl o o d (f or pl as ma a n d ser u m) a n d uri ne sa m ple a nal yses

Pl as ma a n d/ or uri ne sa m ples will be c o llecte d f or tar gete d a n d u n biase d -o mics 
a p pr oac hes, P D bi o mar kers a n d bi o mar ker researc h relat i ve t o safety,  t olera bilit y 
a n d P K pr ofiles, t o e val uate t heir ass ociati o n wit h t he o bser ve d cli nical res p o nses t o 
A Z D 8 2 3 3 treat me nt.
8. 7
 
 
 
 
 
 
8. 8
He alt h Ec o n o mics
Heal t h Ec o n o mics/ Me dical Res o urce Utilizati o n a n d Health Ec o n o mics para meters are n ot 
e val uate d i n t his st u d y.
9
St atistic al C o nsi der ati o ns
9. 1
St atistic al H y p ot heses
T he f or mal h y p ot heses tests will f oc us o n t he treat me nt effect of A Z D 8 2 3 3 vers us place b o o n 
t he efficac y e n d p oi nts relate d t o L D L-C a n d P C S K 9 (Ta ble 6 ). To m ai ntai n a fa mil y-wise 
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 7 of 9 8
T y p e I err or rate of 5 %, t he h y p ot heses will  be e val uate d i n a hierarc hical se q ue nce b y a t w o -
side d test at a 5 % si g nifica nce l e v el 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. A n y s u bse q ue nt test will be c o nsi dere d e x pl orat or y .
Stati stical tests will be d o ne i n t he or der as liste d i n Ta ble 6.
Ta ble 6
Hier arc hic al Or der  f or St atistic al Testi n g
Or der
N ull h y p ot hesis
Alter nati ve h y p ot hesis
1
µ( L D L -C, A) = µ( L D L -C, P)
µ( L D L -C, A) ≠
µ( L D L -C, P)
2
µ( P C S K 9, A) = µ( P C S K 9, P)
µ( P C S K 9, A) ≠
µ( P C S K 9, P)
L D L -C, l o w-de nsit y  li p o pr otei n c h olester ol; P C S K 9, pr o pr otei n c o n vertase s u btilisi n/ ke xi n t y pe-9; P, Place b o; 
A, A Z D 8 2 3 3
T he h y p ot heses are f or malise d usi n g µ( bi o m arker, tre at me nt gr o u p ) t o de n ote t he mea n relati ve re d ucti o n of 
bi o m arker i n treat me nt gr o u p at t he e n d of Wee k 2 8. F or e xa m ple, t he mea n relati ve re d ucti o n i n c o nce ntrati o ns 
of L D L -C i n plas ma f or A Z D 8 2 3 3 after 2 8 wee ks is de n ote d wit h µ( L D L -C, A) a n d si milarl y f or place b o wit h 
µ( L D L -C, P).
E n d p oi nts t hat are n ot liste d i n  Ta ble 6 are of a n e x pl orat or y nat ure, a n d n o a dj ust me nt  will 
be ma de f or m ult i ple testi n g of t hese e n d p oi nts.
9. 2
S a m ple Size Deter mi n ati o n
A p pr o xi matel y 5 3 0 parti ci pa nts will be e nr olle d t o ac hie ve 3 7 6 parti ci pa nts ra n d o ml y 
assi g ne d t o st u d y int er ve ntio n . P arti ci pa nts will be ra n d o ml y assi g ne d at a 1: 1 rati o t o o ne of 
t he 2 treat me nt ar ms liste d bel o w:

A Z D 8 2 3 3  
,  
 a p pr o xi matel y 1 8 8 partici pa nts ra n d o ml y assi g ne d

Pl ace b o matc hi n g d ose,  
, a p pr o xi matel y 1 8 8 partici pa nts ra n d o ml y assi g ne d
 
 
. 
 
 
 
 
N ote : “E nr o lle d” me a ns a partici pa nt ’s, or t heir le gall y acce pta ble re prese ntati ve’s, 
a gree me nt t o partici pate i n a cli nical st u d y f oll owi n g c o m p leti o n of t he i nf or me d c o nse nt 
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 8 of 9 8
pr ocess. P ote ntial part ici pa nts w h o are scree ne d f or t he p ur p ose of deter mi ni n g eli gi bility f or 
t he st u d y, b ut are n ot ra n d o ml y assi g ne d/assi g ne d i n t he st u d y, are c o nsidere d ” scree n 
fail ures”, u nless ot her wise s pecifie d b y t he pr ot oc ol. 
9. 3
P o p ul ati o ns f or A n al yses
F or p ur p oses of a nal ysis, t he f oll o wi n g p o p ulat i ons are defi ne d:
Ta ble 7 
P o p ul ati o ns f or  An al ysis
P o p ul ati o n/ A n al ysis set
Descri pti o n
E nr olle d 
All partici pa nts w h o si g n t he I C F
F ull A nal y sis Set ( F A S)
All partici pa nts w h o were ra n d o ml y assi g ne d t o st u d y i nter ve nti o n. Data 
fr o m partici pa nts will be a nal yse d acc or di n g t o t he treat me nt t o w hic h t he y 
were ra n d o ml y assi g ne d. 
Safet y a nal ysis set ( S A S)
T he Safet y a nal ysis set c o nsists of all partici pa nts w h o ha ve recei ve d at 
least one d ose of i n vesti gati o nal pr o d uct. 
Err o ne o usl y treate d partici pa nts (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 ou p of t he 
treat me nt t he y act uall y recei ve d. 
A partici pa nt w h o has o n o ne or se veral occasi o ns recei ve d acti ve I M P is 
classifie d as acti ve a n d is acc o u nte d f or t he acti ve I M P treat me nt gr o u p.
P K A nal y sis Set
T he P K a nal ysis set will c o nsist of all s u bjects w h o recei ve at least 1 d ose 
of A Z D 8 2 3 3, f or w h o m at least 1 p ost -d ose P K c o nce ntrati o n assess me nt is 
a vaila ble as deter mi ne d at t he fi nal pr ot oc ol de viati o ns meeti n g pri or t o 
u n bli n di n g of t his st u d y. S u bjects will be prese nte d i n acc or da nce t o t h e 
act ual treat me nt recei ve d.
9. 4
St atistic al A n al yses
T he stati stical a nal ysis pla n will be fi nalise d pri or t o u n bli n di n g a n d it will i ncl u de a mor e 
tec h nical a n d detaile d descri pti o n of t he statistical a nal yses descri be d i n t his secti on. T his 
secti on is a su m mar y  of t he pla n ne d statistical a nal yses of t he m ost i m p orta nt e n d p oi nts 
i ncl u di n g pri mar y a n d sec o n dar y e n d p oi nts.
9. 4. 1
Ge ner al C o nsi der ati o ns
H a n dli n g of m ulti ple met h o ds f or  me as uri n g L D L- C
T he L D L -C val ue o btai ne d usi n g P U C will be use d i n t he a nal ysis o f L D L -C t hr o u g h refle x 
testi n g w he n t he L D L-C is < 4 0 m g/ d L ( b y t he Frie de wal d met h o d) or if t he tri gl yceri des are 
≥4 0 0 m g/ d L. If t here is n o meas ure me nt ta ke n usi n g P U C, t he calc ulate d L D L - C val ue 
o btai ne d usi n g t he Frie de wal d f or m ula will be use d 
). If neither L D L -C 
meas ure d wit h P U C or calc ulate d usi n g t he Frie de wal d f or m ula is a vaila ble, t he me as ure me nt 
will be c o nsi dere d as missi n g. F urt her details or a n y a d dit i on al  meas ure me nt met h o ds will be 
descri be d i n t he S A P.
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 0 of 9 8
p oi nt.
A n y n o n -m o n ot o ne missi n g data will be re place d usi n g t he pr oce d ure, P R O C MI i n t he S A S 
S of t ware, wit h t he Mar k o v C hai n M o nte Carl o me t ho d. T he i m p utati o n m o del will i ncl u de 
ti me p oi nt, baseli ne val ue a n d treat me nt gr o u p.
F or m o n ot o ne missi n g data, patter n mi xt ure m o dels will be use d, ass u mi n g missi n g data are 
n ot missi n g at ra n d o m. I m p utati o n of m o n ot o ne missi n g data will be d o ne se pa ratel y f or eac h 
treat me nt ar m.
T he preferre d met h o d of i m p utati o n f or m o n ot o ne missi n g data will be t o use MI -R D f or 
eac h disti nct patter n. Missi n g data patter ns at t he e n d of 
 are defi ne d as:

Missi n g data wit h o ut disc o nt i n uati on of treat me nt (i ncl u di n g deat hs as disc o nt i n uati on of 
treat me nt) prior t o t he e n d of 

Missi n g data after disc o nt i n ue d treat me nt pri or t o t he e n d of 
F or b ot h of t hese missi n g data patter ns, m o n ot o ne missi n g val ues will be i m p ute d 
se q ue ntiall y b y visit; for patt er n a) base d o n c o m pleters (ie, ha d f o ll ow- u p u nt il t he e n d of 
) i n t he sa me treat me nt ar m w h o ha d n ot disc o nti n ue d treat me nt, a n d f or patter n b) 
base d o n c o m pleters i n t he sa me treat me nt ar m w h o ha d disc o nti n ue d treat me nt. T he baseli ne 
val ue will b e i ncl u de d i n t he i m p utati o n m o dels a n d data u p t o eac h missi n g visit will be 
acc o u nte d f or. T his MI-R D a p pr oac h will be use d as l o n g as t he n u m ber of retrie ve d dr o p o uts 
f or eac h c om bi nat i on of treat me nt ar m a n d missi n g data patter n is s ufficie nt t o c o nstr uct 
i m p utatio n m o dels. T he distri b uti o n o f missi n g data, n u m ber a n d pr o p orti o ns, acc or di n g t o 
eac h missi n g data patter n will be s u m marise d per treat me nt ar m.
T he A N C O V A m o d el  descri be d a b o ve will be use d t o pr o vi de least-s q uares mea ns, least-
s q uares mea n differe nces a n d c orres p o n di n g sta n dar d err ors f or eac h of t he m ult i ple i m p ute d 
datasets. T hese res ults are t he n p o ole d acc or di n g t o R u bi n ’s r ules i n P R O C MI A N A LY Z E i n 
S A S t o pr o vi de t he fi nal est i mates as well as p-val ue. 
If MI-R D ca n n ot be use d d ue t o a n i ns ufficie nt n u m ber of retrie ve d dr o p o uts, missi n g data at 
t he e n d of 
 i n t he place b o ar m will be re place d base d o n partici pa nts i n t he sa me ar m 
usi n g sta n dar d MI a n d ass u mi n g missi n g at ra n d o m, i ncl u di n g baseli ne val ue a n d 
o bser vat i ons bet wee n bas eli ne a n d t he e n d of 
 i n t he i m p utati o n m o del. Missi n g 
val ues i n t he acti ve treat me nt ar m will be re place d b y was h o ut m ult i ple i m p utati o n. I n 
was h o ut m ult i ple i m p utati o n, t he e n d of 
 data are i m p ute d base d o n o bser ve d val ues 
i n t he place b o gro u p o nl y, i ncl u di n g baseli ne val ue i n t he i m p utati o n m o del b ut n ot 
acc o u nti n g f or a n y o bs er v atio ns after baseli ne.
9. 4. 2. 2
Sec o n d ar y E n d p oi nt(s)
Relati ve c ha n ge fr o m baseli ne i n c o nce ntrati o ns of P C S K 9 i n plas ma at t he e n d of 
, 
will be a nal yse d si milar t o t he a nal ysis o f t he pri mar y e n d p oi nt as o utli ne d i n Secti on  9. 4. 2. 1 . 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 1 of 9 8
9. 4. 2. 3
Terti ar y E n d p oi nt(s)
 
 
9. 4. 3
S afet y
S af et y a nal yses will be perf or me d usi n g t he safet y a nal ysis set. Safety data will be prese nte d 
usi n g descri pt i ve statistics u nless ot her wise s pecifie d.
9. 4. 3. 1
Pri m ar y E n d p oi nt(s)
A d verse E ve nts
S af et y varia bles will be s u m marise d b y treat me nt gr o u p a n d visit usi n g descri pti ve statist ics 
( n, mea n, S D, me dia n, mi ni m u m a n d ma xi m u m [a n d ge o metric me a n a n d c oefficie nt of 
variat i on, if a p plica ble]) f or c o nti n u o us data a n d a bs o l ute a n d relati ve fre q ue ncies f or 
cate g orical data.
Cli nical la b orat or y  data a n d E C G para meters will be s u m marise d b y tr e at me nt gr o u p a n d 
visit.
A d verse e ve nts will be s u m marise d b y P T a n d S O C usi n g Me d D R A voca b ular y. A d verse 
e ve nts t hat le d t o disc o nt i n uati on of I M P, S A Es, A Es b y  se verit y a n d ca usall y relate d A Es 
will als o be prese nte d. All A E s u m maries will be d o ne b y treat me nt gr o u p. A d verse e ve nts 
will be c o de d usi n g t he m ost r ece nt versi o n of Me d D R A t hat will ha ve bee n release d f or 
e xec uti o n at A Z.
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 2 of 9 8
A Es will be prese nte d f or eac h treat me nt gr o u p b y  S O C, P T c o veri n g n u m ber a n d perce nta ge 
of  p artici pa nts re p orti n g at least o ne e ve nt a n d n u m ber of e ve nts w here a p pr o priate.
A n o ver v ie w of A Es will prese nt f or eac h treat me nt gr o u p t he n u m ber a n d perce nta ge of 
parti ci pa nts wit h a n y A E, A Es wit h o utc o me of deat h, seri o us A Es, a n d A Es lea di n g t o 
di sc o nti n uati on of I M P, as well as A Es lea di n g t o I M P i nterr u pti o ns. 
A Es of I S Rs will be s u m marise d se paratel y . 
Se parate A E ta bles will be pr o vi de d ta ki n g i nt o c o nsi derati o n relati o ns hi p t o I M P as assesse d 
b y t he i n vesti gat or, seri o us ness, deat h a n d e ve nts lea di n g t o disc o nti n uati o n o f I M P a n d ot her 
sig nifica nt a d verse e ve nts a n d ti mi n g of e ve nt s. 
A n a d dit i on al  ta ble will prese nt n u m ber a n d perce nta ge of partici pa nts wit h m ost c o m m o n 
A Es. M ost c o m m o n (e g, fre q ue nc y ≥ x % ) will be defi ne d i n t he S A P.
I n acc or da nce wit h t he re q uire me nts of t he F D A, a se parate ta ble will prese nt n o n-serio us 
A Es occ u rri n g i n m ore t ha n 5 % of partici pa nts i n a n y treat me nt gr o u p. 
Ke y partici pa nt i nf or mat i on will be prese nte d f or partici pa nts wit h A Es wit h o utc o me o f 
deat h, seri o us A Es, a n d A Es lea di n g t o disc o nt i n uati o n of I M P.
A n A E listi n g f or t he safety a nal ysis set will c o ver details f or eac h i n di vi d ual A E; a n A E 
listi n g f or partici pa nts w h o were n ot e x p ose d t o I M P is prese nte d se paratel y.
F ull details o f A E a nal yses will be pr o vi de d i n t he S A P.
A Es occ urri n g pri or t o start of I M P a n d treat me nt e mer ge nt A Es will be p rese nte d se paratel y.
Tre at me nt e mer ge nt
T he f o ll owi n g e ve nts are c o nsi dere d treat me nt e mer ge nt:

A d verse e ve nts wit h a n o nset date o n or after first d ose of I M P

W o rse ni n g of pre-e xist i n g e ve nts o n or after first d ose of I M P
Vi t al si g ns
Vit al si g n para meter s will be prese nte d f or eac h treat me nt gr o u p. S u m mar y statistics f or 
c o nti n u o us varia bles c o ver n, mea n, S D, Mi n, Q 1, me dia n, Q 3, a n d Ma x. Fre q ue nc y ta bles 
a n d s hift ta bles c o ver n u m ber a n d perce nta ge of partici pa nts i n t he res pect i ve cate g or y.
F or eac h sc he d ule d p ost -baseli ne visit, descri pt i ve statistics f or all vit al si g n para meters will 
be prese nte d f or o bser ve d val ues a n d c ha n ge fr o m baseli ne.
Details o f vit al si g n a nal yses will be pr o vi de d i n t he S A P.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 3 of 9 8
T hr o m b oc yt o pe ni a
A nal yses relate d t o platelet c o u nts will i ncl u de s u m maries of t he f o ll owi n g, b y treat me nt 
gr o u p:

A bs ol ute platelet c o u nts 

Perce nta ge decli ne of t he platelet c o u nt fr o m baseli ne ( mea n, me dia n, ra n ge, a n d 
meas ures of varia nce)

Ti me c o urse of rec o ver y  of pl at elet c o u nts f o ll owi n g a n e ve nt  of t hr o m b oc yt o pe nia.
I n a d diti on, se parate s u m maries of A Es relate d t o t hr o m b oc yt o pe nia s uc h as blee di n g e ve nts, 
br uisi n g, a n d petec hiae will be pr o vi de d.
L a b or at or y
La b orat or y  para meters will be prese nte d f or eac h treat me nt gr o u p. S u m mar y statistics for 
c o nti n u o us varia bles c o ver n, mea n, S D, Mi n, Q 1, me dia n, Q 3, a n d Ma x. Fre q ue nc y ta bles 
a n d s hift ta bles c o ver n u m ber a n d perce nta ge of partici pa nts i n t he res pect i ve cate g or y.
F or eac h sc he d ule d p ost -baseli ne visit, descri pt i ve statistics f or all s er u m c he mistr y, 
hae mat ol o g y, c oa g ulat i on, pl at elet, uri nal ysis, uri ne re nal safet y bio m ar ker, a n d ot her 
la b orat or y assess me nts (see Ta ble 5 ) as well as platelet c o u nt will be prese nte d f or o bser ve d 
val ues as well as c ha n ge fr o m baseli ne. 
Ele vat i on i n li ver para meters f or assess me nt of H y’s La w will be d o ne a n d re p orte d 
a p pr o priatel y if p ot e ntial cases are ide nt ifie d d uri n g t he c o urse of t he st u d y.
Electr oc ar di o gr a m
Electr ocar di o gra m para meters will be prese nte d f or eac h treat me nt gr o u p. Fre q ue nc y ta bles 
will s h o w t he i nter pretati o n of t he E C G rea di n g ( n or mal, a b n or mal - cli nicall y n ot si g nifica nt, 
a b n or mal - cli nicall y si g nifica nt) at eac h ti me p oi nt. S hift ta bles (c o m pare d t o baseli ne) ma y 
als o be ge nerate d. 
9. 4. 4
Ot her A n al yses
P K e n d p oi nts
T his is sec o n dar y  e nd p oi nt. If data per mit, a p o p ulati o n P K m o del will be de vel o pe d, 
p ossi bl y  wit h t he s u p p ort of P K data fr o m st u dies D 7 9 9 0 C 0 0 0 0 1, D 7 9 9 0 C 0 0 0 0 2, 
D 7 9 9 0 C 0 0 0 0 3, usi n g n o nli near mi xe d effects m o deli n g i n N O N M E M. F urt her m ore, if data 
all o w, t he p o p ulat i on P K m o d el  ma y be c o u ple d wit h se parate P D mo d el s for P C S K 9 a n d 
L D L -C. 
All P K/ P D m o delli n g will be descri be d i n a se parate data a nal ysis pla n. M ore o ver, t he res ults 
of  a n y s uc h m o delli n g will be pr o vi de d i n a se parate p o p ulati o n P K/ P D re p ort (as a n 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 4 of 9 8
a p pe n di x t o t he C S R or as a sta n d -alo ne re p ort).
Pl as ma c o nce ntrati o n data of A Z D 8 2 3 3 will als o be s u m marise d b y descri pti ve statist ics per 
sa m pli n g ti me p oi nt i n t he C S R.
9. 5
I nteri m A n al yses
I nteri m A nal ysis is n ot pla n ne d f or t his st u d y.
9. 6
D at a M o nit ori n g C o m mittee
A n i SM C will be use d f or m o nit ori n g of u n bli n de d safet y data i n t he o n g oi n g st u d y. F or 
details o n t he iS M C t o be use d i n t his st u d y , please refer t o A p pe n di x  A 5.
1 0
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al 
C o nsi der ati o ns

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 5 of 9 8
A p pe n di x A
Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
A 1
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce with t he pr ot oc ol a n d wit h t he f oll owi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizat i ons of Me dical 
S ci e nces I nter nat i onal Et hical G ui deli nes

A p plica ble I C H G C P G ui deli nes

A p plica ble la ws a n d re g ulati o ns

T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts (e g, 
a d vert ise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d re vie we d a n d 
a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d.

A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a n d a p plica ble Re g ulat or y 
A ut h ori t y a p pr o val before i m ple me ntati o n of  c ha n ges ma de t o t he st u d y desi g n, e xce pt 
f or c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o st u d y p artici pa nts.

Astra Ze neca will be res p o nsi ble f o r o btai ni n g t he re q uire d a ut h orisati o ns t o c o n d uct t he 
st u d y fr o m t he c o ncer ne d Re g ulat or y Aut h ori t y. T his res p o nsi bility ma y be dele gate d t o 
a C R O b ut t he acc o u nta bilit y re mai ns wit h Astra Ze neca.

T he i n vest i gat or will be res p o nsi ble f or pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at 
t he site a n d a d here nce t o re q uire me nts of 2 1 C F R, I C H g ui deli nes, t he I R B/I E C, 
E ur o pea n Re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), E ur o pea n Me dical 
De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice researc h (if a p plica ble), a n d all ot her 
a p plica ble l ocal re g ulat i ons
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es

Pr o m pt n otificat i on b y t he i n vest i gat or t o t he s p o ns or of a S A E is esse ntial s o t hat le g al 
o bli gat i ons a n d et hical res p o nsi bilit ies t o war ds t he safety of  partici pa nts a n d t he safet y of  
a st u d y int er ve nt i on u n der cli nical i n vest i gati on are m et.

T he s p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he lo c al  re g ulat or y a ut h orit y a n d 
ot her re g ulat or y  a ge ncies a b o ut t he safety of  a st u d y int er ve nt i on u n der cli nic al 
i n vesti gati on. T he s p o ns or will c o m p l y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts 
r elat i n g t o safety re p orti n g t o t he re g ulat or y a ut h ority,  I R B/I E C, a n d i n vesti gat ors.

F or all st u dies e xce pt t h ose utilizi n g me dical de vices, i n vest i gat or safety re p orts m ust be 
pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A R) acc or di n g t o l ocal 
re g ulat or y r e q uire me nts a n d s p o ns or p olic y a n d f or war de d t o i n vesti gat ors as necessar y.

E ur o pea n Me dical De vice Re g ulat i on 2 0 1 7/ 7 4 5 f or cli nical de vice researc h (if 
a p plica ble), a n d all ot her a p plica ble l ocal re g ulat i ons

A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safety i nf or mati on (e g, s u m mar y or list i n g of S A Es) fr om t he s p o ns or will 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 6 of 9 8
re vie w a n d t he n file it alo n g wi t h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate 
acc or di n g t o l ocal re q uire me nts.
A 2
Fi n a nci al Discl os ure
i n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 year after c o mpleti o n of  t he st u d y. 
A 3
I nfor me d C o nse nt Pr ocess

T he i n vest i gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he 
parti ci pa nt or his/ her le gall y a ut h orise d re prese ntati ve a n d a ns wer all q uesti ons re gar di n g 
t he st u d y.

P arti cipa nts m ust be i nf or m e d t hat t heir partici pat i o n is v ol unt ar y a n d t he y ar e free t o 
ref use t o partici pate a n d ma y with dra w t heir c o nse nt at a n y  ti me a n d f or a n y reas o n 
d uri n g t he st u d y . Particip a nts will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt 
t hat meet s t he re q uire me nts of 2 1 C F R 5 0, l o c al  r e g ulat i ons, I C H g ui deli nes, Healt h 
I ns ura nce P orta bility a n d Acc o u nta bilit y Act re q uire me nts, w here a p plica ble, a n d t he 
I R B/I E C or st u d y ce ntre.

T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt  was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h orise d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.

P arti cipa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t h e I C F(s) d uri n g t heir 
parti ci pat i on i n t he st u d y.

A c o p y  of t he I C F(s) must be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y  
a ut h orise d re prese ntati ve.

P arti cipa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F a n d s h o ul d be assi g ne d 
t he sa me participa nt n u m ber as per t hei r i nitial scree ni n g visit.

T he I C F will c o ntai n a se parate secti o n t hat a d dresses a n d d oc u me nts t he c ollect i on a n d 
use of a n y ma n dat or y  a n d/ or o ptio nal h u ma n bi o l ogi cal sa m ples. T he i n vest i gat or or 
a ut h orise d desi g nee will e x plai n t o eac h partici pa nt t he o bjecti ves of t he a nal ysis t o be 
d o ne o n t he sa m ples a n d a n y p ote ntial f ut ure use. Partici pa nts will be t ol d t hat t he y  are 
free t o ref use t o partici pate i n a n y o ptio nal  sa m ples or t he f ut ure use a n d ma y with dra w 
t heir c o nse nt at a n y ti me a n d f or a n y reas o n d uri n g t he rete ntio n peri o d.
A 4
D at a Pr otecti o n

P arti cipa nts will be assi g ne d a u ni q ue i de nt ifier b y t he s p o ns or. A n y partici pa nt rec or ds 
or datasets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de nt ifier o nl y; partici pa nt 

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C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 7 of 9 8
na mes or a n y  inf or m at i on w hic h w o ul d ma ke t he partici pa nt i de nt ifia ble will n ot be 
tra nsferre d.

T he parti ci pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-r elate d data will be use d b y 
t he s p o ns or in acc or da nce wit h l ocal data pr otecti o n la w. T he l e vel of discl o s ure a n d use 
of  t h eir data must al s o be e x plai ne d t o t he partici pa nt i n t he i nf or me d c o nse nt 

T he parti ci pa nt m ust be i nf or me d t hat his/ h er me dical rec or ds ma y be e xa mi ne d b y 
Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h orise d pers o n nel a p p o i nte d b y t he 
s p o ns or, b y a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut h orities.
A 5
I nter n al S afet y M o nit ori n g C o m mittee
A n i SM C will be esta blis he d f or t his st u d y . T he iS M C s hares res p o nsi bilit y wi t h G S T f or 
m o nit ori n g s u bject safet y a n d e ns uri n g t hat st u d y s u bjects are n ot e x p ose d t o u n d ue ris k. T he 
i S M C is res p o nsi ble f or peri o dicall y assessi n g u n bli n de d st u d y safety data acc or di n g t o a n 
a gree d u p o n sc he d ule (as well as o n a n a d -h oc basis) a n d ma ki n g a rec o m me n dati o n t o G S T. 
A n i SM C c harter i s i n place a n d gi ves details of precise r oles a n d res p o nsi bilit ies a n d 
pr oce d ures t o e ns ure mai nte na nce of t he bli n di n g a n d i nte grit y of  t he st u d y in t he re vie w of 
acc u m ulat i n g data a n d i nteracti o ns with t he st u d y  t e a m.  
A 6
Disse mi n ati o n of Cli nic al St u d y D at a
A descri pt i on of t his cli nical st u d y  will be a vaila ble o n 
ht t p://astraze neca gr o u ptrials. p har mac m.c o m a n d htt p:// w w w.cli nicaltrials. g o v as will t he 
s u m mar y of t he mai n st u d y res ults w he n t he y are a vaila ble. T he cli nical st u d y a n d/ or 
s u m mar y of mai n st u d y  res ults ma y als o be a vaila ble o n ot her we bsites acc or di n g t o t he 
re g ulat i ons of t he c o u ntries i n w hic h t he st u d y  is c o n d ucte d.
A 7
D at a Q u alit y Ass ur a nce

All partici pa nt data relat i n g t o t he st u d y will be rec or de d o n e C R F u nless tra ns mitte d t o 
t he s p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he i n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y electr o nicall y 
sig ni n g t he e C R F.

T he i n vest i gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he e C R F.

T he i n vest i gat or m ust per mit st u d y-r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pectio ns a n d pr o vi de di rect access t o s o urce data d oc u me nts.

M o ni t ori n g details descri bi n g strate g y (e g, ris k-base d i nit iati ves i n o perati o ns a n d q uality 
s uc h as Ris k Ma na ge me nt a n d Miti gati on Strate gies a n d A nal yt ical Ris k -Base d 
M o ni t ori n g), met h o ds, res p o nsi bilit ies a n d re q uire me nts, i ncl u di n g ha n dli n g of 
n o nc o m p lia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntral, r e mot e , or o n-sit e mo ni t orin g) 
are pr o vi de d i n t he M o ni t ori n g Pla n. T he s p o ns or or desi g nee is res p o nsi ble f or t he data 
ma na ge me nt of t his st u d y  incl u di n g q ualit y c hec ki n g of t he data.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
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6 8 of 9 8

T he s p o ns or ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals (e g, 
C R Os).

St u d y  mo ni t ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he e C R F b y a ut h orise d site pers o n nel are acc urate, c o m plete, a n d verifia ble 
fr om s o urce d oc u me nts; t hat t he safet y a n d rig hts of  partici pa nts are bei n g pr otecte d; a n d 
t hat t he st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre nt l y a p pr o ve d pr ot oc ol a n d 
a n y ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts.

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he i n vest i gat or f or 1 5 years after st u d y  c o mplet i on u nless l ocal 
re g ulat i ons or i nst ituti o nal  p olicies re q uir e a lo n ger rete nti o n peri o d. N o rec or ds m a y be 
destr o y e d d uri n g t he rete nti o n peri o d wit h o ut t he wri tte n a p pr o val of t he s p o ns or. N o 
rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y wit ho ut wri tte n n otificati on t o t he 
s p o ns or.
A 8
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate 
t he i nte grit y of  t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.

Data e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts m ust be c o nsiste nt 
wi t h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he i n vesti gat or ma y 
ne e d t o re q uest pre vio us m e dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y . 
Als o, c urre nt me dical rec or ds m ust be a vaila ble.

Defi nit i on o f w hat c o nstit utes s o urce data ca n be f o u n d i n t he M o nit ori n g Pla n .
A 9
St u d y a n d Site St art a n d Cl os ure
T he st u d y start date is t he date o n w hic h t he cli nical st u d y will be o pe n f or recr uitme nt  of 
parti ci pa nts.
T he first act of recr uit me nt is t he first site o pe n a n d will be t he st u d y start date.
T he s p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y  sit e or t er mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti on of t he s p o ns or . St u d y sites will be close d u p o n st u d y  
c o mplet i on. A st u d y site is c o nsi dere d close d w he n all  re q uire d d oc u me nts a n d st u d y s u p plies 
ha ve bee n c o llecte d a n d a st u d y-sit e clos ure visi t has bee n perf or me d.
T he i n vest i gat or ma y i nitiate st u d y-sit e clos ure at a n y  time, pr o vi de d t here i s reas o na ble 
ca use a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.
Reas o ns f or t he earl y cl os ure of a st u d y  site b y t he s p ons or or i n vesti gat or ma y i ncl u de b ut 
are n ot li mit e d t o:

Fail ure of t he i n vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  healt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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
I na de q uate recr uitme nt  of p artici pa nt s b y t he i n vestigat or

Di sc o nti n uatio n of  furt her st u d y  int er ve nt i on de vel o p m e nt
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y c o ntract researc h 
or ga nizat i on(s) use d i n t he st u d y  of t he reas o n f or ter mi nati on or s us pe nsi o n, as s pecifie d b y 
t he a p plica ble re g ulat or y r e q uire me nts. T he i n vesti gat or s hall pr om ptl y i nf or m t he partici pa nt 
a n d s h o ul d ass ure a p pr o priate partici pa nt t hera p y a n d/ or f ollo w - u p.
P arti cipa nts fr o m  ter mi nate d sites will ha ve t he o p p ort u nit y t o be tra nsferre d t o a n ot her site t o 
c o nti n ue t he st u d y.
A 1 0
P u blic ati o n P olic y

T he res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie nt ific meet i n gs. If t his is 
f oresee n, t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or 
bef ore s u b missi o n. T his all o ws t he s p o ns or t o pr otect pr o prietar y  inf or mati o n a n d t o 
pr o vi de c o m me nts.

T he s p o ns or will c o m p l y with t he re q uire me nts f or p u blicati o n o f st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hic al pr a ctice, t he s p o ns or will ge nerall y 
s u p p ort p u blicati o n of m ult ice ntre st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site 
data. I n t his case, a c o or di nat i n g i n vesti gat or will be desi g nate d b y m ut ual a gree me nt.

A ut h ors hi p will be deter mi ne d b y  mut u al  a gree me nt a n d i n li ne with I nter nat i onal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.

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A p pe n di x B
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
B 1
Defi niti o n of A d v erse E ve nts
A n A E is t he de vel o p me nt of a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y 
parti ci pa nt a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal 
r elat i ons hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u n fa v o ura ble a n d u ni nte n de d 
sig n (e g, a n a b n or m al la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na usea, c hest pai n), or 
di sease te mp orall y ass oci at e d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d 
r elate d t o t he me dici nal pr o d uct. 
T he ter m  A E is use d t o i ncl u de b ot h seri o us a n d n o n -serio us A Es a n d ca n i ncl u de a 
deteri or ati o n of  a pre-e xist i n g me d ical occ urre nce. A n A E ma y occ ur at a n y  ti me, i ncl u di n g 
 or  
peri o ds, e ve n if n o st u d y int er ve nt i on has bee n a d mi nistere d.
B 2
Defi niti o n of Ser i o us A d verse E ve nts
A serio us a d verse e ve nt i s a n A E occ urri n g d uri n g a n y st u d y p hase (ie,
, treat me nt, 
, f oll o w-u p), t hat f ulfils o ne or m ore of t he f o ll owi n g cri t eria:

Res ults i n deat h

Is i m me diatel y life-t hreate ni n g

Re q ui res i n-partici p a nt h os pitalisat i on or pr ol o n gati o n of e xist i n g h os pitalisati on 

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca paci t y. 

Is a c o n ge nital a n oma l y or birt h defect

Is a n i m p orta nt me dical e ve nt t hat ma y je o par dise t he partici pa nt or ma y re q uire me dical 
treat me nt t o pre ve nt o ne of t he o utc o mes liste d a b o ve.
A Es f or m ali g n a nt t u m o urs
re p orte d d uri n g a st u d y s h o uld ge nerall y be assesse d as Seri o us 
A Es . If no ot her seri o us ness criteria a p pl y, t he ‘I mp orta nt Me dical E ve nt ’ crit erio n s h o ul d be 
use d. I n certai n sit uati o ns, h o we ver, me dical j u d ge me nt o n a n i n di vi d ual e ve nt basis s h o ul d 
be a p plie d t o clarif y t hat t he mali g na nt t u m o ur e ve nt s h o ul d be assesse d a n d re p orte d as a 
n o n -seri o us A E . F or e xa m ple, if t he t u mo ur is i ncl u de d as m e dical hist or y a n d pr o gressio n 
occ urs d uri n g t he st u d y, b ut t he pr o gressi o n d oes n ot c ha n ge treat me nt a n d/ or pr o g n osis of 
t he mali g na nt t u m o ur, t he A E m a y n ot f ulfil t he attri b utes f or bei n g assesse d as seri o us, 
alt ho u g h re p orti n g of t he pr o gressi o n of t he mali g na nt t u m o ur as a n A E is vali d a n d s h o ul d 
occ ur .Als o, s o me t y pes o f ma li g na nt t u m o urs, w hic h d o n ot s prea d re m otel y after a r o uti ne 
treat me nt t hat d oes n ot re q uire h os pitalizat i on, m a y be assesse d as n o n-serio us; e xa m p les i n 
a d ults i ncl u de Sta ge 1 basal cell carci n oma a n d S ta ge 1 A 1 cer vical ca ncer re m o ve d via c o ne 
bi o ps y.
Life -t hre ate ni n g
‘Life -t hreate ni n g’ mea ns t hat t he partici pa nt was at i m me diate ris k of deat h fr o m t he A E as i t 
C CI
C CI
C CI
C CI

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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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occ urre d or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d uct w o ul d res ult i n t he 
parti ci pa nt ’s deat h. ‘Life -t hreate ni n g’ d oes n ot m ea n t hat ha d a n A E occ urre d i n a m ore 
se vere f or m it mi g ht ha ve ca use d deat h (e g, he patitis t hat res ol ve d wit h o ut he pat ic fail ure).
H os pit alis ati o n
O ut pat ient  treat me nt i n a n e mer ge nc y r o o m is n ot i n itself a seri o us A E, alt h o u g h t he reas o ns 
f or it ma y be (e g, br o nc h os pas m, lar y n geal oe de ma). H os pital a d missi o ns a n d/ or s ur gical 
o perati o ns pla n ne d bef ore or d uri n g a st u d y  are n ot c o nsidere d A Es if t he ill nes s or disease 
e xiste d bef ore t he partici pa nt was e nr olle d i n t he st u d y, pr o vide d t hat i t did n ot deteri orate i n 
a n u ne x pecte d wa y d uri n g t he st u d y.
I m p ort a nt Me dic al E ve nt or Me dic al Tre at me nt
Me dical a n d scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g
w het her a case is seri o us i n 
sit u atio ns w here i m p orta nt m e dical e ve nts ma y not be i m me diatel y life t hreate ni n g or res ult 
i n deat h, h os pitalisati on, disa bilit y or i nca pacit y b ut m a y je o par dise t he partici pa nt or ma y 
re q uir e me dical treat me nt t o pre ve nt o ne or m ore o utc o m es liste d i n t he defi nit i on of seri o us. 
T hese s h o ul d us uall y be c o nsi dere d as seri o us.
Si m pl y st o p pi n g t he s us pect dr u g d oes n ot mea n t hat it is a n i m p orta nt me dical e ve nt; 
me dical j u d ge me nt m ust be use d.

A n gi oe de ma n ot se vere e n o u g h t o re q u ire i nt u bati o n b ut re q uiri n g i v h y dr oc ortis o ne 
treat me nt

He pat ot o xicit y ca use d b y paraceta m o l (aceta mi n o p he n) o ver d ose re q uiri n g treat me nt 
wi t h N-acet ylc ystei ne

I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m

Bl o o d d y scrasias (e g, ne utr o pe nia or a nae mia re q uiri n g bl o o d tra nsf usi o n, etc.) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisat i on

De vel o p me nt of dr u g de pe n de nc y or dr u g a b use
I nte nsit y R ati n g Sc ale:

Mil d (a ware ness of si g n or s y m pt o m, b ut easil y t olerate d)

M o derate ( di sc omf o rt s ufficie nt t o ca use i nterfere nce wit h n or mal acti vities)

Se vere (i nca pacitat i n g, wit h i na bility t o perf or m n or mal acti vities)
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d se vere A Es. Se verity is a meas ure of 
i nte nsit y w hereas serio us ness is defi ne d b y t he criteria i n A p pe n di x  B 2 . A n A E of se vere 
i nte nsit y nee d n ot necessaril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or 
se veral h o urs ma y be c o nsidere d se vere na usea, b ut n ot a S A E u nless it meets t he criteria 
s h o w n i n A p pe n di x B 2 . O n t he ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of 
di sa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a S A E w he n it satisfies t he criteria 
s h o w n i n A p pe n di x B 2 .

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 2 of 9 8
B 3
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n
W he n ma ki n g a n assess me nt of ca usalit y c o nsider t he f oll o wi n g f act ors w he n deci di n g if 
t here is a ‘reas o na ble p ossi bilit y’ t hat a n A E ma y ha ve bee n ca use d b y t he dr u g.

Ti me C o urse. E x p os ure t o s us pect dr u g. Has t he partici pa nt act uall y recei ve d t he s us pect 
dr u g?  Di d t he A E occ ur i n a reas o na ble te m p oral relat i ons hi p t o t he a d mi nistrati o n of 
t he s uspect dr u g?

C o nsiste nc y wit h k n o w n dr u g pr ofile. Was t he A E c o nsiste nt wit h t he pre vi o us 
k n o wl e d ge of t he s us pect dr u g ( p har mac o l og y  a n d t o xic o l og y ) or dr u gs of t he sa me 
p har mac o l ogi cal class? Or c o ul d t he A E be a nt ici pate d fr o m its p har mac ol ogi cal 
pr o perti es ?

De -c halle n ge e x perie nce. Di d t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he 
d ose of t he s us pect dr u g?

N o al ter nati ve ca use. T he A E ca n n ot be reas o na bl y e x plai ne d b y a n ot her aeti ol og y  s uc h 
as t he u n derl yi n g disease, ot her dr u gs, ot her h ost or e n v ir o n me ntal fact ors.

Re -c halle n ge e x perie n c e. Did t he A E re occ ur if t he s us pecte d dr u g was rei ntr o d uce d 
after ha vi n g bee n st o p pe d? Astra Ze neca w o ul d n ot n or mall y rec o m me n d or s u p p ort a re-
c halle n ge.

La b orat or y  tests. A s pecific la b orat or y in vest i gati on (if p erf or m e d) has c o nfir me d t he 
r elat i ons hi p .
I n diffic ult cases, ot her fact ors c o ul d be c o nsi dere d s uc h as:

Is t his a rec o g nise d feat ure of o ver d ose of t he dr u g?

Is t here a k n o w n mec ha nis m?
Ca usalit y of  ‘relate d’ is ma d e if f o ll o wi n g a re vie w of t he r ele va nt data, t here is e vi de nce f or 
a ‘reas o na ble p ossi bilit y’ of  a ca usal relati ons hi p f or t he i n di vi d ual case. T he e x pressi on 
‘reas o na ble p ossi bility ’ of  a ca usal r el atio ns hi p is mea nt t o c o n ve y, i n ge neral, t hat t here are 
facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati ons hi p.
T he ca usalit y assess me nt is perf or me d base d o n t he a vaila ble data i ncl u di n g e n o u g h 
i nf or mat i on t o m a ke a n i nf or me d j u d g me nt. With n o a vaila ble facts or ar g u me nts t o s u g gest a 
ca usal relat i ons hi p, t he e ve nt(s) will be asses se d as ‘n ot rel ate d’.
Ca usal relat i ons hi p i n cases w here t he disease u n der st u d y  has deteriorate d d ue t o l ac k of 
effect s h o uld be classifie d as n o reas o na ble p ossi bilit y.
B 4
Me dic ati o n Err or
F or t he p ur p oses of t his cli nical st u d y  a me dicat i on err or is a n u ni nt e n de d fail ure or mista ke 
i n t he treat me nt pr ocess f or a n Astra Ze neca st u d y  int er ve nt i on t hat eit her ca uses har m t o t he 
parti ci pa nt or has t he p ote ntial t o ca use har m t o t he partici pa nt. 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 3 of 9 8
A me dicat i on err or is n ot lac k of efficac y of t he dr u g, b ut rat her a h u ma n or pr ocess relate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y sit e st aff or parti ci pa nt.
Me dicat i on err or i ncl u des sit uat i ons w here a n err or. 

Occ urre d

Was i de nt ifie d a n d i nterce pte d bef ore t he partici pa nt recei ve d t he dr u g

Di d n ot occ ur, b u t circ u msta nces were rec o g nise d t hat c o ul d ha ve le d t o a n err or
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors:

Dr u g na me c o nf usi o n

Di s pe nsi n g err or e g, me dicati o n pre pare d i nc orrectl y, e ve n if it was n ot act uall y gi ve n t o 
t he partici pa nt

Dr u g n ot a d mi nistere d as i n dicate d, f or e xa m ple, wr o n g r o ute or wr o n g site of 
a d mi nistrati o n

Dr u g n ot ta ke n as i n dicate d e g, ta blet diss o l ve d i n water w he n it s h o ul d be ta ke n as a 
s oli d ta blet 

Dr u g n ot st ore d as i nstr ucte d e g, ke pt i n t he fri d ge w he n i t s h o uld be at r o o m  t e mperat ure 

Wr o n g partici pa nt recei ve d t he me dicat i on (e xcl u di n g I R T/ R T S M err ors)

Wr o n g dr u g a d mi nistere d t o partici pa nt (e xcl u di n g I R T/ R T S M err ors)
E xa m ples of e ve nts t hat d o n ot re q uire re p orti n g as me dicati on err ors i n cli nical st u di es:

Err ors relate d t o or res ulti n g fr o m I R T/ R T S M - i ncl u di n g t h ose w hic h lea d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha ve bee n a me dicati o n err or 

P arti cip a nt a c ci de ntall y  misse d dr u g d ose(s) e g, f or g ot t o ta ke me dicati o n

Acci de ntal  o ver d ose ( will be ca pt ure d as a n o ver d ose)

P arti cip a nt f aile d t o ret ur n u n use d me dicat i on or e m pt y pac ka gi n g

Err ors relate d t o bac k gr o u n d a n d resc ue me dicat i on, or sta n dar d of care me dicat i on i n 
o pe n l a bel st u dies, e ve n if a n Astra Ze neca pr o d uct 
Me dicat i on err ors are n ot re gar de d as A Es b ut A Es ma y occ ur as a c o nse q ue nce of t he 
me dicat i on err or.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 4 of 9 8
A p pe n di x C
H a n dli n g of H u m a n Bi ol o gic al S a m ples
C 1
C h ai n of C ust o d y
A f ull c hai n of c ust o d y is mai ntai ne d f or all sa m ples t hr o u g h o ut t heir lifec ycle.
T he i n vest i gat or at eac h ce ntre kee ps f ull tracea bilit y of c ollecte d bi ol ogi cal sa mpl es f r o m t he 
parti ci pa nts w hile i n st ora ge at t he ce ntre u ntil s hi p me nt or dis p osal ( w here a p pr o priate) a n d 
rec or ds rele va nt pr ocessi n g i nf or mati o n relate d t o t he sa m ples w hilst at site.
T he sa m ple recei ver kee ps f ull tracea bilit y of  t he sa mples w hile i n st ora ge a n d d uri n g use 
u nt il use d or dis p ose d of or u ntil f urt her s hi p me nt a n d kee ps rec or d of recei pt of arri val a n d 
o n war d s hi p me nt or dis p osal.
Astra Ze neca or dele gate d re prese ntati ves will kee p o versi g ht of t he e nt ire life c ycle t hr o u g h 
i nter nal pr oce d ures, mo ni t orin g of st u d y  sites, a u diti n g or pr ocess c hec ks, a n d c o ntract ual 
re q uire me nts of e xter nal la b orat or y pr o viders
S a m ples retai ne d f or f urt her use will be st ore d i n t he Astra Ze neca -assi g ne d bio b a n ks or ot her 
sa m ple arc hi ve facilities a n d will be trac ke d b y t he a p pr o priate Astra Ze neca T ea m d uri n g for 
t he re mai n der of t he sa mple life c ycle.
If re q uire d, Astra Ze neca will e ns ure t hat re mai ni n g bi ol ogi c al s a mples are ret ur ne d t o t he site 
acc or di n g t o l ocal re g ulati o ns or at t he e n d of t he rete nti o n peri o d, w hic he ver is t he s o o ner.
C 2
Wit h dr a w al of I nf or me d
C o nse nt f or D o n ate d Bi ol o gic al S a m ples 
Astra Ze neca e ns ures t hat bi o l ogi cal sa m ples are ret ur ne d t o t he s o urce or destr o ye d at t he e n d 
of  a s pecifie d peri o d as descri be d i n t he i nf or me d c o nse nt.
If a partici pa nt wit h dra ws c o nse nt t o t he use of d o nate d bi ol ogical  sa m ples, t he sa mples will 
be dis p ose d of/ destr o y e d/re patriate d, a n d t he acti o n d oc u me nte d. If sa m ples are alrea d y  
a nal yse d , Astra Ze neca is n ot o bli ge d t o destr o y  t he res ults of t his researc h.
F o ll owi n g wi t hdra wal  of c o nse nt f or bi ol ogi c al sa m ples, f urt her st u d y particip ati o n s h o ul d be 
c o nsi dere d i n relat i on t o t he wi t hdra wal  pr ocesses o utli ne d i n t he i nf or me d c o nse nt.
T he i n vest i gat or:

E ns ures partici pa nt’s wit h dra wal of i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
hi g hli g hte d i m me diatel y t o As tra Ze neca or dele gate.

E ns ures t hat rele va nt h u ma n bi o l ogical sa m ples fr o m  t hat partici pa nt, if st ore d at t he 
st u d y site, are i m me diatel y ide nt ifie d, dis p ose d of as a p pr o priate, a n d t he acti o n 
d oc u m e nte d.

E ns ures t hat t he partici pa nt a n d Astra Ze neca are i n f or me d a b o ut t he sa m ple dis p osal.
Astra Ze neca e ns ures t he or ga nizat i on(s) h o l di n g t he sa m ples is/are i nf or me d a b o ut t he 

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

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 7 of 9 8






C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 8 of 9 8





C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 9 of 9 8
A p pe n di x E
Acti o ns Re q uire d i n C ases of I ncre ases i n Li ver 
Bi oc he mistr y a n d E v al u ati o n of H y’s L a w
E 1
I ntr o d ucti o n
T his A p pe n di x descri bes t he pr ocess t o be f o ll owe d i n or der t o i de nt if y a n d a p pr o priatel y 
re p ort P H L cases a n d H L cases. It is n ot i nte n de d t o be a c o m pre he nsi ve g ui de t o t he 
ma na ge me nt of ele vate d li ver bi oc he mistries. 
D uri n g t he c o urse of t he st u d y  t he i n vesti gat or will re mai n vi gila nt f or i ncreases i n li ver 
bi oc he mistr y. T he i n vesti gat or is res p o nsi ble f or deter mi ni n g w het her a partici pa nt meets 
p ote nti al P H L crit eria at a n y p oi nt d uri n g t he st u d y.
All s o urces of la b orat or y data are a p pr o priate f or t he deter mi nat i on of P H L  a n d H L e ve nts; 
t his i ncl u des sa m ples ta ke n at sc he d uled st u d y  visits a n d ot her visits i ncl u di n g ce ntral a n d all 
l ocal la b orat or y e val uati ons e ve n if c o llecte d o utsi de of t he st u d y visits; for e xa m ple, P H L  
criteria c o uld b e m et b y a n ele vate d A L T fr om a ce ntral la b orat or y a n d/ or ele vate d T B L fr o m 
a lo c al  la b or at or y. 
T he i n vest i gat or will als o re vie w A d verse E ve nt data (f or e xa m ple, f or A Es t hat ma y i n dicate 
ele vat i ons i n li ver bi oc he mistr y ) for p ossi ble P H L  e ve nts.
T he i n vest i gat or partici pates, t o get her wit h Astra Ze neca cli nical pr oject re prese ntati ves, i n 
r evie w a n d assess me nt of cases meet i n g P H L crit eria t o a gree w het her H L criteria are met. 
H L  crit eria are met if t here is n o alter nat i ve e x pla nati o n f or t he ele vati ons i n li ver 
bi oc he mistr y  ot her t ha n DI LI ca use d b y t he I M P. 
T he i n vest i gat or is res p o nsi ble f or rec or di n g data pertai ni n g t o P H L/ H L cases a n d f or 
re p orti n g S A Es a n d A Es acc or di n g t o t he o utc o me of t he re vie w a n d assess me nt i n li ne wit h 
sta n dar d safety re p orti n g pr ocesses.
E 2
Defi niti o ns
P ote nti al H y’s L a w
A S T or A L T ≥3 × U L N t o get her wit h T B L  ≥2 × U L N at a n y  p oi nt d uri n g t he st u d y 
f oll owi n g t he start of st u d y  me dicat i on irres pecti ve of a n i ncrease i n A L P.
H y’s L a w
A S T or A L T ≥3 × U L N t o get her wit h T B L  ≥2 × U L N, w here n o ot her reas o n, ot her t ha n t he 
I M P, ca n be f o u n d t o e x plai n t he c om bi nat i on of i n creases, e g, ele vate d A L P i n dicati n g 
c h o lestasis, viral he patitis, a n ot her dr u g. 
F or P H L  a n d H L t he ele vat i on i n tra nsa mi nases m ust prece de or be c oi nci de nt wit h (ie, o n t he 
sa me da y) t he ele v atio n i n T B L, b ut t here is n o s pecifie d ti mefra me wit hi n w hic h t he 
ele vat i ons i n tra nsa mi nases a n d T B L  must occ ur .

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 0 of 9 8
E 3
I de ntific ati o n of P ote nti al H y’s L a w C ases
I n or der t o ide ntif y  cases of P H L it is i m p orta nt t o perf or m a c o m pre he nsi ve re vie w of 
la b orat or y data f or a n y p artici pa nt w h o meets a n y of t he f o ll owi n g i de ntif icati on cri t eria i n 
is olati on or i n c o m bi nat i on:

A L T ≥3 × U L N

A S T ≥3 × U L N

T B L ≥2 × U L N
I de ntificati o n of P H L cases ma y be t hr o u g h ce ntral la b orat ories a n d/ or l ocal la b orat ories.
Ce ntr al L a b or at ories Bei n g Use d:
W he n a partici pa nt meets a n y of t he P H L  ide nt ificati o n criteria, i n is olati on or i n 
c o m bi nat i on, t he ce ntral la b orat or y  will i m me diatel y se n d a n alert t o t he i n vest i gat or (als o 
se nt t o Astra Ze neca re prese ntati ve). 
T he i n vest i gat or will als o re mai n vi gila nt for a n y  l o c al la b orat or y re p orts w here t he P H L 
i de ntificati on cri teria are met, w here t his is t he case t he i n vesti gat or will:

N otif y  t he Astra Ze neca re prese ntati ve 

Re q uest a re peat of t he test ( ne w bl o o d dra w) b y  t he ce ntral la b orat or y wi t ho ut 
d el a y

C o m plete t he a p pr o pri ate u nsc he d ule d la b orat or y e C R F mo d ule(s) wi t h t he 
ori gi nal  local la b orat or y  test res ult
W he n t he i de ntificat i on cri t eria are met fr o m ce ntral or lo c al  la b orat or y res ults t he 
i n vesti gat or will with o ut dela y:

Deter mi ne w het her t he partici pa nt meets P H L criteria (see Secti o n  E 2 f or 
defi nit i on) b y  re vie wi n g la b orat or y re p orts fr o m all pre vio us visi ts (i ncl u di n g 
b ot h ce ntral a n d l ocal la b orat or y  res ults)
L oc al L a b or at ories Bei n g Use d:
T he i n vest i gat or will with o ut dela y  re vie w eac h ne w la b orat or y re p ort a n d if t he 
i de ntificati on cri teria are met will:

N otif y  t he Astra Ze neca re prese ntati ve 

Deter mi ne w het her t he partici pa nt meets P H L criteria (see Secti o n  E 2 f or 
defi nit i on) b y  re vie wi n g la b orat or y re p orts fr o m all pre vio us visi ts

Pr o m pt l y e nter t he la b orat or y data i nt o t he la b orat or y e C R F

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 1 of 9 8
E 4
F oll o w -u p
E 4. 1
P ote nti al H y’s L a w Criteri a n ot met
If t he partici pa nt d oes n ot meet P H L crit eria t he i n vesti gat or will:

Perf or m  fol l ow- u p o n s u bse q ue nt la b orat or y  res ults acc or di n g t o t he g ui da nce 
pr o vi de d i n t he Cli nical St u d y  Pr ot oc ol.
E 4. 2
P ote nti al H y’s L a w Criteri a met
If t he partici pa nt d oes meet P H L crit eria t he i n vesti gat or will:

Deter mi ne w het her P H L criteria were met at a n y  st u d y visit prior t o starti n g st u d y  
i nter ve nt i on (see A p pe n di x  E 6)

N otif y  t he Astra Ze neca re prese ntati ve w h o will t he n i nf or m t he ce ntral St u d y T e a m 

Wit hi n 1 da y of P H L criteria bei n g met, t he i n vest i gat or will re p ort t he case as a n S A E of 
P ote nti al H y’s La w; seri o us criteria ‘I m p orta nt me dical e ve nt’ a n d ca usality assess me nt 
‘ yes/relate d’ acc or di n g t o C S P pr ocess f or S A E re p orti n g.

F or parti ci pa nts t hat met P H L criteria pri or t o starti n g I M P, t he i n vest i gat or is n ot 
re q uire d t o s u b mit a P H L S A E u nless t here is a si g nifica nt c ha n ge# i n t he partici pa nt’s 
c o n ditio n

T he St u d y  P h ysicia n c o ntacts t he i n vesti gat or, t o pr o vi de g ui da nce, disc uss a n d a gree a n 
a p pr oac h f or t he st u d y p artici pa nts’ f o ll ow -u p (i ncl u di n g a n y f urt her la b orat or y  testi n g) 
a n d t he c o nti n u o us re vie w of data

S u bse q ue nt t o t his c o ntact t he i n vest i gat or will:

M o ni t or t he partici pa nt u ntil li ver bi o c he mistr y p ar a meters a n d a p pr o priate cli nical 
s y m pt o ms a n d si g ns ret ur n t o n or mal or baseli ne le vels, or as l o n g as me dicall y 
i n dicate d. C o m pletes f oll ow- u p S A E F or m as re q uire d.

I n vesti gate t he aeti ol o g y of t he e ve nt a n d perf or m dia g n ostic i n vesti gat i ons as 
di sc usse d wit h t he St u d y P h ysicia n. < < F or st u dies usi n g a ce ntral la b orat or y a d d: 
T his i ncl u des deci di n g w hic h t he tests a vaila ble i n t he H y ’s la w la b ki t s h o uld be 
use d > > 

C o m plete t he t hree Li ver e C R F M o d ules as i nf or mati o n bec o mes a vaila ble 
#A ‘si g nific a nt’ c h a n ge i n t he partici pa nt’s c o n ditio n refers t o a cli nicall y rele va nt c ha n ge i n 
a n y of t he i n di vi d ual li ver bi oc he mistr y para meters ( A LT,  A S T or T B L) i n is olati on or i n 
c o m bi nat i on, or a cli nicall y  rele va nt c ha n ge i n ass ociate d s y m pt o ms. T he deter mi nati o n of 
w he t her t here has bee n a si g nifica nt c ha n ge will be at t he discret i on of t he i n vesti gat or, t his 
ma y be i n c o ns ultat i on wi t h t he St u d y P h ysicia n if t here is a n y u ncertai nty.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 2 of 9 8
E 5
Re vie w a n d Assess me nt of P ote nti al H y’s L a w C ases
T he i nstr ucti o ns i n t his Secti o n s h o ul d be f ol l owe d f or all cases w here P H L  crit eria are met.
As s o o n as p ossi ble after t he bi oc he mistr y  a b n or mality was i ni tiall y detecte d, t he St u d y 
P h ysicia n c o ntacts t he i n vest i gat or i n or der t o re vie w a vaila ble data a n d a gree o n w het her 
t here is a n alter nat i ve e x pla nati on f or meet i n g P H L crit eria ot her t ha n DI LI ca use d b y t he 
I M P, t o e ns ure ti mel y a nal ysis a n d re p orti n g t o health a ut h orit ies withi n 1 5 cale n dar da ys 
fr om date P H L  crit eria was met. T he Astra Ze neca Gl o bal Cli nical Lea d or e q ui vale nt a n d 
Gl o ba l Safety P h ysicia n will als o be i n v o l ve d i n t his re vie w t o get her wit h ot her s u bject 
matter e x perts as a p pr o priate. 
Acc or di n g t o t he o utc o me of t he re vie w a n d assess me nt, t he i n vest i gat or will f oll o w t he 
i nstr uctio ns bel o w.
W her e t h e re is a n a gree d alter n ati ve e x pl a n ati o n f or t he A L T or A S T a n d T B L ele vat i ons, 
a deter mi nati o n of w het her t he alter nat i ve e x pla nati on is a n A E will be ma de a n d 
s u bse q ue ntl y w het her t he A E m eets t he crit eria for a S A E:

If t he alter nati ve e x pla nati on is n ot a n A E, rec or d t he alter nati ve e x pla natio n o n t he 
a p pr o priate e C R F

If t he alter nati ve e x pla nati on is a n A E/ S A E: u p date t he pre vi o usl y s u b mitte d P ote ntial 
H y’s La w S A E a n d A E e C R Fs acc or di n gl y wit h t he ne w i nf or mat i on (reassessi n g e ve nt 
ter m; ca usality a n d serio us ness cri t eria) f oll owi n g t he Astra Ze neca sta n dar d pr ocesses.
If it is a gree d t hat t here is n o e x pla nat i on t hat w o ul d e x plai n t he A LT or A S T a n d T B L  
ele vat i ons ot her t ha n t he I M P:

Se n d u p date d S A E (re p ort ter m ‘ H y’s La w’) acc or di n g t o Astra Ze neca sta n dar d 
pr ocesses.

T he ‘ Me dicall y  I m p orta nt’ serio us cri t erio n s h o ul d be use d if n o ot her seri o us 
criteria a p pl y

As t here is n o alter nat i ve e x pla nati o n f or t he H L case, a ca usality assess me nt of 
‘relate d’ s h o ul d be assi g ne d.
If, t here is a n u na v oi da ble dela y, of o ver 1 5 cale n dar da ys i n o btai ni n g t he i nf or mati on 
necessar y  t o assess w het her or n ot t he case meets t he criteria f or H L, t he n it is ass u me d t hat 
t here is n o alter nat i ve e x pla nati o n u ntil s uc h ti me as a n i nf or me d decisi on ca n be ma de:

Pr o vi des a n y  furt her u p date t o t he pre vi o usl y s u b mitte d S A E of P ote ntial H y’s La w, 
(re p ort ter m n o w ‘ H y’s La w case’) e ns uri n g ca usality assess me nt is relate d t o I M P a n d 
serio us ness cri t eria is me dicall y i m p orta nt, acc or di n g t o C S P pr ocess f or S A E re p orti n g.

C o nti n ue f o ll ow- u p a n d re vie w acc or di n g t o a gree d pla n. O nce t he necessar y  
s u p ple me ntar y inf or mat i on is o btai ne d, re peat t he re vie w a n d assess me nt t o deter mi ne 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 3 of 9 8
w het her H L criteria are still met. U p date t he pre vi o usl y s u b mitte d P H L S A E re p ort 
f oll owi n g C S P pr ocess f or S A E re p orti n g, a cc or di n g t o t he o utc o me of t he re vie w a n d 
a me n di n g t he re p orte d ter m if a n alter nat i ve e x pla nati on f or t he li ver bi oc he mistr y 
ele vat i ons is deter mi ne d.
E 6
L a b or at or y Tests
H y’s L a w L a b Kit f or Ce ntr al L a b or at ories 
A d diti o nal sta n dar d c he mistr y a n d c oa g ulati o n tests
G G T
L D H
Pr ot hr o m bi n ti me
I N R
Viral he patitis
I g M a nti-H A V 
H Bs A g
I g M a n d I g G a nti-H Bc
H B V D N A
a
I g G a nti-H C V
H C V R N A b
I g M a nti-H E V
H E V R N A
Ot her viral i nfecti o ns
I g M & I g G a nti-C M V
I g M & I g G a nti-H S V
I g M & I g G a nti-E B V
Alc o h olic he patitis
Car b o h y drate deficie nt tra nsferri n ( C D -tra nsferri n) c
A ut oi m m u ne he patitis
A nti n uclear a nti b o d y ( A N A)
A nti- Li ver/ Ki d ne y Micr os o mal A b ( A nti -L K M)
A nti- S m o ot h M uscle A b ( A S M A)
Meta b olic diseases
al p ha - 1-a ntitr ypsi n
Cer ul o plas mi n
Ir on
Ferriti n
Tra nsferri n c
Tra nsferri n sat urati o n
aH B V D N A is o nl y rec o m me n de d w he n I g G a nti -H Bc is p ositi ve
bH C V R N A is o nl y rec o m me n de d w he n I g G a nti -H C V is p ositi ve or i nc o ncl usi ve 
cC D -tra nsferri n a n d Tra nsferri n are n ot a vaila ble i n C hi na. St u d y tea ms s h o ul d a me n d t his list acc or di n gl y

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 4 of 9 8
A p pe n di x F
Acti o ns i n C ase of De vel o p me nt of T hr o m b oc yt o pe ni a or 
U n i nter pret a ble Pl atelet C o u nts After A d mi nistr ati o n of 
A S Os
Rec o m me n de d act i ons i ncl u de reassess me nt of platelet c o u nt, a dj ustme nt  of m o nit ori n g 
fre q ue nc y ( pl at elet c o u nt < 1 0 0, 0 0 0/ µ L), assess me nt of a d dit i on al  la b orat or y para meters 
( plat elet c o u nt < 7 5, 0 0 0/ µ L), referral t o a hae mat ol o gist ( platelet c o u nt ≤ 5 0, 0 0 0/ µ L) a n d 
start of s u p p orti ve treat me nt wit h c ortic oster oi ds ( platelet c o u nt ≤ 3 0, 0 0 0/ µ L). Dr u g 
disc o nti n u ati o n acc or di n g t o t he defi ne d st o p pi n g criteri a is esse nti al i n p artici p a nts 
wit h s us pecte d t hr o m b oc yt o pe ni a.
F 1
Acti o ns i n c ase of u ni nter pret a ble pl atel et c o u nt res ults
P artici p a nts wit h u ni nter pr et a ble pl atelet l a b or at or y res ults d ue t o cl u m pi n g, 
h ae m ol ysis or  q u a ntit y n ot s ufficie nt m ust be re assesse d wit hi n 2 d a ys. D o si n g is n ot 
all o we d t o pr ocee d u ntil t he i n vest i gat or has deter mi ne d t hat t he res ults are wit hi n acce pta ble 
ra n ge acc or di n g t o t he defi ne d st o p pi n g criteria. 
I n a cli nical st u d y wit h t he A S O i n oterse n, dia g n osis a n d treat me nt of se vere 
t hr o mb oc y t o pe nia were dela ye d i n s o me partici pa nts beca use of u ni nter preta ble platelet 
c o u nts d ue t o cl u mpi n g of platel ets i n t he test t u be. Platelet cl u m pi n g i n t he test t u be was 
m o st lik el y  ca use d b y a c o m bi nati on of A S O -i n d uce d a nti platelet i m m u n o glo b uli n G (I g G) 
a nt i b o dies a n d t he a ntic oa g ula nt E D TA. If t here is s us pici o n of E D TA- me diate d platelet 
clu m pi n g, a re peat pl at elet c o u nt usi n g a differe nt a nt ic oa g ula nt, e g, s o diu m  citrate or 
he pari n, s h o ul d be d o ne as s o o n as p ossi ble a n d al wa ys bef ore a ne w d ose is gi ve n.
T hr o m b oc yte M o nit ori n g Fr e q ue nc y
Pl atelet C o u nt ( per µ L)
M o nit ori n g Fre q ue nc y
> 1 0 0, 0 0 0
E ver y 2 wee ks
≥7 5, 0 0 0 t o < 1 0 0, 0 0 0 or m ore t ha n 5 0 % re d ucti o n 
fr o m baseli ne
E ver y wee k
< 7 5, 0 0 0
I nte nsifie d m o nit ori n g; t wice wee kl y t o dail y 
m o nit ori n g de pe n de nt of platelet c o u nt a n d rate of 
decli ne

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 5 of 9 8
A d diti o n al L a b or at or y Assess me nts ( Pl atelet C o u nt < 7 5, 0 0 0/ μ L)
Peri p heral s mear 
Fi bri n o ge n s plit pr o d ucts or D -di mer o n fres h bl o o d 
Citrate d sa m ple f or platelets
C oa g ulati o n pa nel ( Pr ot hr o m bi n Ti me/I N R, a P T T)
C B C wit h retic ul oc ytes a n d mea n platelet v ol u me ( M P V)
Ser u m B 1 2 a n d f olate
Fi bri n o ge n
v o n Wille bra n d fact or
T ot al gl o b uli ns, t otal I g A, I g G, a n d I g M
C o m ple me nt: t otal C 3, t otal C 4, B b, C 5a 
hs -C R P
Ser ol o g y f or:
H B V , H C V, HI V (if n ot d o ne f or scree ni n g)
R u bella
C M V
E B V
Par v o B 1 9
Helic o bacter p yl ori (I g G ser u m test)
A ut o-a nti b o d y scree n:
A nti p h os p h oli pi d
R h e u mat oi d fact or
A nti- ds D N A
A nti- t h yr oi d
T o be perf or me d at s pecialt y la b(s):
A nti platelet a nti b o dies a n d A nti -P F 4 assa y
A nti- dr u g a nti b o d y 
F 2
Referr al t o E x pert H ae m at ol o gist C are
P arti cipa nts t hat de vel o p t hr o m b oc y t o p e nia wit h platelet c o u nts ≤ 5 0, 0 0 0/ µ L s h o uld be 
referre d t o a H ae m at ol o gist f or dia g n ost ic a n d t hera pe utic ma na ge me nt. T his ma y i ncl u de 
t he a d ditio n al  la b orat or y tests descri be d i n t he ta ble a b o ve. A d dit i onal b o ne marr o w 
as pirati on a n d bi o ps y  s ho ul d be c o nsi dere d.
S u p p orti ve T re at me nt wit h C ortic osteroi ds
Treat me nt of se vere t hr o m b oc yt o pe nia re q uires cl ose c o m m u nicat i on a m o n g c o ns ult i n g 
s pecialists. F or maj or or life-t hreate ni n g blee di n g, platelet tra nsf usi ons s h o ul d be 
a d mi nistere d wit h o ut dela y. Beca use A S Os ha ve bee n ass ociate d wit h i m m u ne -me diate d 
t hr o mb oc y t o pe nia it is str o n gl y rec o m me n de d t hat partici pa nts wit h platelet c o u nts 
≤3 0, 0 0 0/ µ L recei ve gl uc oc ortic oi d t hera p y ( u nless c o ntrai n dicate d). Hi g h d ose ster oi ds ha ve 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 7 of 9 8
A p pe n di x G
G u i d a nce f or Defi niti o n of A n a p h yl actic/ H y perse nsiti vit y 
Re acti o ns a n d C hec klist f or t he i n vesti g at or
T he Nati o nal I nst itute of Aller g y a n d I nfect i ous Disease a n d F o o d Aller g y a n d A na p h yla xis 
Net w or k G ui da nce f or A na p h yla xis Dia g n osis defi ne a na p h yla xis as a seri o u s aller gic 
reactio n t hat i s ra pi d i n o nset a n d ma y ca use deat h. T he y rec o g nize 3 cate g ories of 
a na p h yla xis, wit h cri teria desi g nate d t o ca pt ure fr o m 8 0 % of cases (cate g or y 1) t o > 9 5 % of 
all cases of a na p h yla xis (f or all 3 cate g ories). Refer t o  
.
1.
Ac ute o nset of a n ill ness ( mi n utes t o se veral h o urs) wit h i n v o l ve me nt of t he s ki n, 
m uc osal t iss ue, or b ot h (e g, ge neralise d hi ves, pr urit us or fl us hi n g, s w olle n li ps-t o ng ue-
u v ula) a n d at le ast o ne of t he f oll o wi n g :
(a) Res pirat or y  c o mpr o mise (e g, d ys p n oea, w heeze- br o nc h os pas m, stri d or, re d uce d 
P E F, h y p o xae mia)
( b) Re d uce d B P or ass ociate d s y m pt o ms of e n d -or ga n d y sf u ncti on (e g, h y p ot o ni a 
[c olla pse], s y nc o pe, i nc o nti ne nce).
2.
T w o or m ore of t he f o ll owi n g t hat occ ur ra pi dl y  after e x p os ure t o a li kel y aller ge n f or 
t hat partici pa nt ( mi n utes t o se veral h o urs):
(a) I n v ol ve me nt of t he s ki n-m uc osal t iss ue (e g, ge neralise d hi ves, itc h-fl us h, s w olle n 
li ps-t o ng ue- u v ul a)
( b) Res pirat or y  c o mpr o mise (e g, d ys p n oea, w heeze -br o nc h os pas m, stri d or, re d uce d 
P E F, h y p o xe mia)
(c) Re d uce d B P or ass ociate d s y m pt o ms (e g, h y p ot o nia [c oll a pse], s y nc o pe, 
i nc o nti ne nce)
( d) Persi ste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o mi nal pai n, v o mitin g)
3.
Re d uce d B P after e x p os ure t o k n o w n aller ge n f or t hat partici pa nt ( mi n utes t o se veral 
h o urs):
(a) I nfa nts a n d c hil dre n: l o w S B P (a ge s pecific) or greater t ha n 3 0 % decrease i n S B P.
( b) A d ults: S B P of less t ha n 9 0 m m H g or greater t ha n 3 0 % decrease fr o m t hat pers o n’s 
baseli ne.
P P D

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 8 of 9 8
H y perse nsiti vit y Re acti o ns – C hec klist f or T he i n vesti g at or 
At  least t he f oll owi n g s h o ul d be c hec ke d. If “Ye s” t he dia g n osis ( prefera bl y n ot s y m pt o ms) 
s h o uld be rec or de d as A E.
Y es
N o
S ki n a n d S C e ve nts 
Ur ticaria 
Er y t he ma 
Pr urit us 
Face oe de ma 
E ye oe de ma 
T o n g ue s welli n g 
A n gi oe de ma 
Res pir at or y c o m pr o mise 
Br o nc h os pas m 
D y s p n oea 
C o u g h 
C h o ki n g 
Stri d or 
Res pirat or y  arrest 
C ar di o v asc ul ar e ve nts 
Car diac arrest 
Car di o vasc ular i ns ufficie nc y 
H y p ote nsi o n

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 9 of 9 8
A d diti o n al S a m ples t o be C ollecte d i n C ase of a n A n a p h yl actic -li ke Re acti o n
I n case of a na p h ylactic-li ke reacti on, t he bl o o d sa m ples f or tr y ptase assess me nts s h o ul d be 
ta ke n 3 0, 6 0, a n d 1 2 0 mi n utes after t he o nset of e ve nt, if feasi ble.
I n a d diti on, sa m ples f or a nal ysis o f A DA s h o uld be ta ke n at t he da y  of t he a na p h ylactic-li ke 
reactio n, if feasi ble.
G 1
Refere nce
S a m ps o n et al 2 0 0 6
S a m ps o n H A et al. Sec o n d s y m p osi u m o n t he defi nit i on a n d ma na ge me nt of a na p h yla xi s: 
S u m mar y  re p ort - Sec o n d Nati o nal I nst itute of Aller g y  a n d I nfecti ous Disease/ F o o d Aller g y 
a n d A na p h yla xis Net w or k s y m p osi u m. J Aller g y Cli n I m m u n o l. 2 0 0 6; 1 1 7: 3 9 1- 3 9 7.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 0 of 9 8
A p pe n di x H
C O VI D -1 9 S pecifics
H 1
B ac k gr o u n d t o C O VI D - 1 9
T here i s c urre ntl y a n o ut brea k of res pir at or y disease ( C O VI D-1 9) ca use d b y a n o vel 
S A R S -C o V -2 t hat was first detecte d i n Wu ha n Ci t y, H u bei Pr o vi nce, C hi na i n 2 0 1 9. T his ne w 
vir us has ra pi dl y s prea d acr oss t he gl o be ca usi n g t he W H O t o declare a pa n de mic sit uat i on o n 
1 2 Marc h
2 0 2 0. T he c o u nt er meas ures i nit iate d b y nat i onal a n d l ocal g o ver n me nts w orl d wi de 
a n d t he rec o m me n dat i ons i ss ue d b y t he healt h a ut h orities ha ve i m pacte d c urre nt a n d ne w 
cli nical st u dies. As t he t hreat of pa n de mic b ur de n i ncl u di n g ne w o ut brea ks, l ocall y or 
gl o ball y, will i mpact t he f urt her c o n d uct of cli nical st u dies, a p pr o priate ris k assess me nts a n d 
mit i gati on meas ures will nee d t o be ta ke n i nt o c o nsi derati o n i n all cli nical st u dies t o pr otect 
parti ci pa nts, site staff, a n d s ociety as a w h ole.
B ot h E M A  a n d F D A as well as nati onal heal t h a ut h orities i n E ur o pe ha ve iss ue d ne w 
g ui deli nes t hat ai m t o pr o vi de rec o m me n dati o ns f or acti o ns f or c o n d uct of cli nical st u dies of 
me dical pr o d ucts d uri n g C O VI D -1 9 pa n de mic. Si nce t he pa n de mic sit uati o n is e v o l vi n g, 
g ui deli nes, rec o m me n dati o n s, nati onal la ws, a n d l ocal restricti o ns ma y c ha n ge at hi g h pace. 
Gi ve n t he circ u msta nces o f p ote nti all y rela psi n g pa n de mic or e pi de mic sit uati on wi t h re gar d 
t o t he s prea d of C O VI D-1 9 i n f ut ure, s pecial atte nti o n will be pai d t o pr otect partici pa nts 
parti c i pati n g i n t he st u d y a n d site staff i n v ol ve d i n t he i n vesti gati ons a gai nst i nfect i on wi t h 
S A R S -C o V -2 as re q ueste d b y  t he ne wl y iss ue d E M A g uideli ne o n t he m a na ge me nt of cli nical 
trials d uri n g t he C O VI D -1 9 (c or o na vir us) pa n de mic v 4.
H 2
A Z D 8 2 3 3 a n d C O VI D -1 9 v ac ci n ati o ns  
H 2. 1
M o de of Acti o n
A Z D 8 2 3 3 is a n A S O t hat i n hi bits t he pr o d ucti o n of P C S K 9 i n t he li ver . A Z D 8 2 3 3 is directe d 
t o t he li ver b y e n ha nce d u pta ke me diate d b y t he A S G P-rece pt or prese nt o n he pat oc ytes. 
Ci rc ulati n g P C S K 9 is mai nl y pr o d uce d i n t he li ver a n d re g ulates circ ulati n g levels of L D L -C 
b y i nterferi n g wit h L D L-R rec y cli n g i n he pat oc ytes. here are t w o a p pr o ve d P C S K 9 
m o n ocl o nal a nti b o d y  in hi bi t ors a p pr o ve d f or li pi d l o weri n g as well as a n P C S K 9 si R N A 
i n hi bit or, all b ot h wit h g o o d efficac y a n d safet y profiles. T he A S O plat f or m has bee n 
ass ociat e d wit h a mil d pr o-i nfla m mat or y effect i n s o me partici pa nts, i ncl u di n g I S Rs a n d fl u-
li ke s y m pt o ms.
H 2. 2
P ote nti al i nterfere nce wit h C O VI D -1 9 v acci nes
T here i s n o biol o gi cal ratio nale t hat i n hi bit i on of P C S K 9 w o ul d re d uc e i m m u ne res p o nse t o 
vacci nes.
H 2. 3
De gree of p ote nti al i m p act (l o w, m e di u m, hi g h)
A Z D 8 2 3 3 is pre dicte d t o ha ve a l o w ris k of i nfl ue nci n g C O VI D -1 9 vacci ne effect i ve ness, 
a n d n o a d dit i onal safet y c o ncer ns are i de nt ifie d at t his earl y sta ge i n de vel o p me nt.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 1 of 9 8
H 2. 4
Rec o m me n d ati o n
P arti cipa nts e nr olle d i n st u dies wit h A Z D 8 2 3 3 ca n ta ke part i n vacci nat i on pr o gra m s for 
C O VI D -1 9. A d mi nistrati o n of C O VI D -1 9 vacci nes s h o ul d be i n acc or da nce wit h t he la bel f or 
t he vacci ne a n d l ocal g ui deli nes f or a d mi nistrati o n s h o ul d be f o ll owe d. C O VI D - 1 9 
vacci nati o n s h o ul d be rec or de d i n t he e C R F as c o nc o mita nt me dicat i on. If C O VI D - 1 9 
vacci nati o n is pla n ne d pri or t o e nteri n g a st u d y, t he first d ose of A Z D 8 2 3 3 s h o ul d be gi ve n at 
least 3 0 da ys after t he last d ose of vacci ne. I n partici pa nts alrea d y u n der g oi n g d osi n g with 
A Z D 8 2 3 3, vacci nat i on s h o ul d be se parate d fr o m  AZ D 8 2 3 3 d osi n g b y at least 7 da y s w he n 
p ossi ble. A d verse E ve nts ( A E) re p orti n g i n t he st u d y  s h o uld use sta n dar d re p orti n g.
I 3
Ris k Assess me nt f or C O VI D -1 9 P a n de mic
Meas ures t o mi tigate t he a d di tio nal ris ks ca use d b y C O VI D -1 9 are:

T his st u d y  will start e nr olli n g o nl y w he n t he S p o ns or a n d C R O, i n c o lla b orati o n, dee m it 
is safe t o start t he st u d y. I n a d ditio n, t he st u d y  will not start u ntil t he l ocal c o nfi ne me nt 
meas ures or ot her saf et y restrictio ns li n ke d t o t he C O VI D -1 9 pa n de mic i m p ose d b y t he 
l ocal a ut h orities are c o mpat i ble wit h safe c o n d uct of t he st u d y

C urre nt nati o nal la ws a n d l ocal rec o m me n dat i ons f or pre ve nt i on of pa n de mic will be 
strict l y a d here d t o

P arti cipa nts will be cl os el y mo ni t or e d for a n y  si g ns a n d s y m pt o ms of C O VI D-1 9, 
i ncl u di n g fe ver, dr y c o u g h, d ys p n oea, s ore t hr oat a n d fati g ue t hr o u g h o ut t he st u d y d uri n g 
t he pa n de mic. O nce cli nical si g ns of i nfect i on are re p orte d b y part ici pa nts, t he 
i n vesti gat or nee ds t o deter mi ne w het her sa m ples ca n be c ollecte d, a n d safet y data ca n be 
rec or de d o n site. If n ot, A Es a n d c o nc o mita nt me dicati o ns will be o btai ne d via p h o ne 
calls. T he decisi o n t o c o nti n ue wit h t he st u d y  int er ve nt i ons i n t he e ve nt of partici pa nts 
s h o wi n g s y m pt o ms of C O V I D-1 9 i nfect i on will  be per t he i n vest i gat or’s discreti o n

T he pr o ba bilit y of  vir us tra ns missi o n will be c o ntr olle d as m uc h as p ossi ble b y:

A d vice f or partici pa nt t o a d here t o l ocal re q uire me nts f or re d ucti o n of t he p u blic 
e x p os ure w hile a m b ulat or y

C o nfir ma tio n of  C O VI D-1 9 i nfect i on b y o pti o nal la b orat or y  assess me nt will be 
c o n d ucte d base d o n a vaila bilit y (test ca pacit y a n d t ur nar o u n d ti me) of a p pr o ve d tests 
a n d o n i n vesti gat or’s discret i on

Re q uest i n g all partici pa nts are c o ntacte d b y p h o ne 1 d a y  prior t o e v er y visit for 
assessi n g C O VI D -1 9 s y m pt o ms a n d si g ns a n d are as ke d n ot t o atte n d t he site i n case 
of  s us pecte d re p orts. I n a d diti on, parti cipa nts are as ke d f or details of a n y c o ntact 
wi t h a pers o n w h o has teste d p ositi ve f or S A R S-C o V - 2. If a p plica ble, partici pa nts 
will be referre d t o t he l ocal healt h care s yste m f or f urt her f o ll ow- u p a n d treat m e nt

P h ysical dista nci n g a n d pers o n- t o-pers o n c o ntact restrict i ons will be a p plie d d uri n g 
site visits a n d i n-h o use c o nfi ne me nt

W here p h ysical dista nci n g is n ot p ossi ble , P P E will be use d b y st u d y partici pa nts 
(s ur gical fa c e mas k, glo ves) a n d staff (f or e xa m ple b ut n ot li mite d t o mas ks, gl o ves, 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 2 of 9 8
pr otect ors, me dical s uits) if dee me d a p pr o priate b y t he i n vesti gat ors a n d site staff 
a n d g ui de d b y l ocal re q uire me nts

L o gist ical i m pr o ve me nts of t he site a n d str uct ural meas ures of t he st u d y site b uil di n g 
will be i m ple me nte d t o f urt her i m pr o ve p h ysical dista nci n g
H 3
Restricti o ns Rel ate d t o C O VI D- 1 9
D uri n g t he C O VI D- 1 9 pa n de mic, partici pa nts are a d vise d t o a d here t o l ocal re q uire me nts f or 
re d uctio n of  t he p u blic S A R S-C o V -2 e x p os ure w hile a m b ulat or y. If a p plica ble, prior t o 
Scree ni n g Visit 1, p ote nti al partici pa nts s h o uld be calle d t o c o nfir m t he y are n ot e x perie nci n g 
a n y C O VI D-1 9 s y m pt o ms a n d si g ns a n d are as ke d n ot t o atte n d t he site i n case of s us pecte d 
i nfecti on. If a p pr o priate, partici pa nts will be referre d t o t he l ocal healt h care s yste m. P h ysical 
di sta nci n g a n d pers o n-t o-pers o n c o ntact restricti o ns will be a p plie d a n d e x plai ne d t o 
parti ci pa nts w hile sta yi n g at t he st u d y site. W here p h ysical dista nci n g is n ot p ossi ble, st u d y  
parti ci pa nts will be as ke d t o use s ur gical face mas ks a n d/ or gl o ves if dee me d a p pr o priate b y  
t he i n vest i gat or a n d site staff a n d g ui de d b y l ocal re q uire me nts.
H 4
D at a Q u alit y Ass ur a nce Rel ate d t o C O VI D - 1 9
M o ni t ori n g visit s at site, w he n necessar y, will be li mite d t o a mi ni m u m re q uire d as dee me d 
a p pr o priate d uri n g C O VI D -1 9 pa n de mic, per l ocal re g ulat i ons.
I n a d diti on, w here p ossi ble, ot her meas ures f or carr yi n g o ut pr ot oc ol relate d acti vit ies, s uc h 
as b ut n ot li mit e d t o h o me n ursi n g, ma y be e mpl o ye d as re q ui re d a n d a n y a dj ust me nts nee de d 
i n res p o nse t o t he C O VI D-1 9 pa n de mic will be d oc u me nte d as s uc h. 
H 5
Refere nces
1.
G ui da nce o n t he Ma na ge me nt of Cli nical Trials d uri n g t he C O VI D 1 9 ( C or o na vir us) 
pa n de mic, E M A, Versio n  3 ( 28/ 0 4/ 2 0 2 0). 
ht t ps://ec.e ur o pa.e u/ health/sites/ healt h/files/files/e u drale x/ v o l-
1 0/ g ui da ncecli nicaltri als _c o vid 1 9 _e n. p df
2.
F D A  G ui da nce on C o n d uct of Cli nical Trials of Me dical Pr o d ucts d uri n g C O VI D - 1 9 
P u blic Healt h E mer ge nc y, Marc h 2 0 2 0, U p date d o n A pril 1 6, 2 0 2 0 
ht t ps:// w w w.fda. g o v/re g ulat or y -i nf or mati on/searc h -f da-g ui da nce -d oc u m e nts/f da-
g ui da nce -c o n d uct -cli nical-trials-me dical -pr o d ucts -d uri n g -c o vid- 1 9- p u blic -heal t h-
e mer ge nc y

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 3 of 9 8
A p pe n di x I
A b bre vi ati o ns
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
A N C O V A
a nal ysis of c o varia nce
A p o A 1
a p oli p o pr otei n A 1
A p o B
a p oli p o pr otei n B
A D A
a nti -dr u g a nti b o dies
A E
a d verse e ve nt
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase/tra nsa mi nase
a P T T
acti vate d partial t hr o m b o plasti n ti me
A S O
a ntise nse oli g o n ucle oti de
A S G P - R
asial o gl yc o pr otei n rece pt or
A S T
as partate a mi n otra nsferase/tra nsa mi nase
B P
bl o o d press ure
C ma x
ma xi m u m c o nce ntrati o n 
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 O VI D - 1 9
c or o na vir us disease 2 0 1 9
C R O
c o ntract researc h or ga nisati o n
C S P
cli nical st u d y pr ot oc ol
C S R
cli nical st u d y re p ort
C V
car di o vasc ular
C V D
car di o vasc ular disease
DI LI
dr u g i n d uce d li ver i nj ur y
D N A
de o x yri b o n ucleic aci d 
D B P
diast olic bl o o d press ure
D V T
dee p vei n t hr o m b osis
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
E D T A
et h yle ne dia mi netetraacetic Aci d
e G F R
esti mate d gl o mer ular filtrati o n rate
E M A
E ur o pea n Me dici nes A ge nc y
F A S
f ull a nal ysis set
F D A
U n ite d States F o o d a n d Dr u g A d mi nistrati o n
F S H 
f ollicle sti m ulati n g h or m o ne
Gal N Ac
N- acet yl galact osa mi ne
G C P
g o o d cli nical practice
G G T
ga m ma gl uta m yl tra nsferase 

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 4 of 9 8
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
H b A 1c
hae m o gl o bi n A 1c, gl ycate d hae m o gl o bi n
H D L - C
hi g h -de nsit y li p o pr otei n c h olester ol
H L
H y’s La w
H M G -C o A
3- h y dr o x y - 3-met h y l-gl utar y lc oe nz yme A
I B
I n vesti gat or’s Br oc h ure
I A T A
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati o n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or
P har mace uticals f or H u ma n Use
I E C
i n de pe n de nt et hics c o m mittee
I M P
i n vesti gati o nal me dici nal pr o d uct
I N R
i nter nati onal n o r malise d rati o
I R B
i nstit uti o nal re vie w b oar d
I R T
i nteracti ve res p o nse tec h n ol o g y
i S M C
i nter nal Safet y M o nit ori n g C o m mittee
L D L
l o w-de nsit y  li pi d
L D L - C
l o w-de nsit y  li p o pr otei n c h olester ol
L H
l utei nisi n g h or m o ne
L p(a)
li p o pr otei n(a)
M A C E
maj or a d verse car di o vasc ular e ve nts
M A D
m ulti ple asce n di n g d ose
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
MI -R D
m ulti ple i m p utati o n retrie ve d dr o p o uts
NI M P
n o n- i n vesti gati o nal me dici nal pr o d uct
P D
p har mac o d y na mic(s)
P E
p ul m o n ar y  e m b olis m
P E F
pea k e x pirat or y fl o w
P H L
p ote ntial H y’s La w
P C S K 9
pr o pr otei n c o n vertase s u btilisi n/ ke xi n t y pe - 9
PI
pri nci pal i n vesti gat or 
P K
p har mac o ki netic(s)
P R E G O U T
pre g na nc y o utc o me
P R E G R E P
pre g na nc y re p ort
P T
preferre d ter m 
P U C
pre parati ve ultrace ntrif u gati o n 
Q 4 W
e ver y 4 wee ks
R T S M
ra n d o misati o n a n d trial s u p pl y ma na ge me nt

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 5 of 9 8
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
S A D
si n gle asce n di n g d ose
S A E
seri o us a d verse e ve nt 
S A P
statistical a nal ysis pla n
S A R S -C o V - 2
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2
S B P
s yst olic bl o o d press ure
S C
s u bc uta ne o us
S o A
sc he d ule of acti vities
S O C
s yste m or ga n class
T B L
t otal bilir u bi n
T C
t otal c h olester ol
U A C R
uri nar y  al b u mi n creati ni ne rati o 
U L N
u p per li mit of n or mal
U P C R
uri nar y  pr otei n creati ni ne rati o
U R C
u n bli n de d re vie w c o m mittee
V L D L - C
ver y l o w-de nsit y  li p o pr otei n c h olester ol
W B C
w h ite bl o o d cell c o u nt
W H O
W orl d Healt h Or ga nizati o n

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 6 of 9 8
1 1
Refere nces
B ur dic k et al 2 0 1 4
B ur di c k A D, Scia b o la S, Ma nte na S R, H olli n gs hea d B D, Sta nt o n R, War ne ke J A et al. 
Se q ue nce m otifs ass ociate d wit h he pat ot o xicit y of  loc ke d n ucleic aci d --m o difie d a nt ise nse 
oli g o n ucle oti des. N ucleic Aci ds Res. 2 0 1 4; 4 2( 8): 4 8 8 2 - 9 1.
B urel et al 2 0 1 3
B urel  S A, Ha n S R, Lee H S, N orris D A, Lee B S, Mac he mer T et al. Precli nical e val uati on of 
t he t o xic ol o gical effects of a n o vel c o nstrai ne d et h yl m o difie d a ntise nse c o m p o u n d tar geti n g 
sig n al  tra ns d ucer a n d acti vat or of tra nscri pti o n 3 i n mice a n d c y n om o l g us m on ke ys. N ucleic 
Aci d T her . 2 0 1 3; 2 3( 3): 2 1 3- 2 7.
C o he n et al 2 0 0 5
C o he n J, Pertse mli dis A, K ot o ws ki I K, Gra ha m R, Garcia C K, H o b bs H H. L o w L D L  
c h o lester ol in i n di vi d uals of Africa n desce nt res ulti n g fr om fre q ue nt n o nse nse m utatio ns i n 
P C S K 9. Nat Ge net. 2 0 0 5; 3 7( 2): 1 6 1 -5.
C o he n et al 2 0 0 6
C o he n J C, B oer wi n kle E, M osle y T H, Jr ., H o b bs H H. Se q ue nce variati ons i n P C S K 9, l o w 
L D L, a n d pr otecti o n a gai nst c or o nar y  heart disease. N E n gl J Me d. 2 0 0 6; 3 5 4( 1 2): 1 2 6 4- 7 2.
C olli ns et al 2 0 1 6
C olli ns R, Reit h C, E m bers o n J, Ar mita ge J, Bai ge nt C, Blac k well L  et al. I nter pretatio n of  
t he e vi de nce f or t he efficac y a n d safet y of  stati n t hera p y. La ncet. 2 0 1 6; 3 8 8( 1 0 0 5 9): 2 5 3 2- 6 1.
Cr o o ke et al 2 0 1 6
Cr o o ke S T , Ba ker B F, K w o h TJ, C he n g W, Sc h ulz DJ, Xi a S et al. I nte grate d Safety 
Assess me nt of 2' - O-Met h o x yet h yl C hi meric A nt ise nse Oli g o n ucle oti des i n N o n H u ma n 
Pri mates a n d Healt h y H u ma n Vol u nteers. M ol  T her. 2 0 1 6; 2 4( 1 0): 1 7 7 1-8 2.
Cr o o ke et al 2 0 1 7
Cr o o ke S T , Ba ker B F, Witzt u m J L, K w o h TJ, P ha m N C, Sal ga do N et al . T he Effects of 2'- O-
Met h o x yet h yl C o ntai ni n g A nt ise nse Oli g o n ucle oti des o n Platelets i n H u ma n Cli nical Trials. 
N ucl eic Aci d T her. 2 0 1 7; 2 7( 3): 1 2 1- 9.
Frie de w al d 1 9 7 2
Fr ie de wal d. Esti mati on of t he C o nce ntrati o n o f L o w -De nsit y Li p o pr otei n C h o lester ol 
Pl as ma, With o ut Use of t he Pre parati ve Ultrace ntrif u ge. J o ur nal of Cli nical C he mistr y. 
1 9 7 2; 1 8 4 9 9 - 5 0 2.
Gi b bs et al 2 0 1 7 
Gi b bs J P , D os hi S, K uc hi ma nc hi M, Gr o ver A, E mer y  M G, D o d ds M G et al. I m pact of 
Ta r get-Me diate d Eli mi nat i on o n t he D ose a n d Re gi me n of E v o l oc u ma b, a H u ma n 
M o n ocl o nal  A nti b o d y A gai nst Pr o pr otei n C o n vertase S u btilisi n/ Ke xi n T y pe 9 ( P C S K 9). J 
Cli n P har mac ol. 2 0 1 7; 5 7( 5): 6 1 6 - 2 6.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 7 of 9 8
H a ge d or n et al 2 0 1 3
Ha ge d or n P H, Y a ki m o v V, Ott ose n S, Ka m mler S, Nielse n N F, H o g A M et al. He pat ot o xic 
p ote nti al of t hera pe utic oli g o n ucle oti des ca n be pre dicte d fr o m t heir se q ue nce a n d 
m o dificati o n patter n. N ucl eic Aci d T her. 2 0 1 3; 2 3( 5): 3 0 2- 1 0.
He nr y et al 1 9 9 7
He nr y  S P, N o v ot n y W, Lee ds J, A u letta C, K or n br ust DJ. I n hi biti on of c oa g ulati o n b y a 
p h os p h or ot hi oate oli g o n u cl e oti de. A nt ise nse N ucleic Aci d Dr u g De v. 1 9 9 7; 7( 5): 5 0 3- 1 0.
He nr y et al 2 0 1 7
He nr y  S P, Nara ya na n P, S he n L, B ha n ot S, Yo u ni s H S, B urel S A. Assess me nt of t he Effects 
of  2'-Met h o x yet h yl A nt ise nse Oli g o n ucle oti des o n Platelet C o u nt i n C y n o m o l g us N o n h u ma n 
Pr i mates. N ucleic Aci d T her. 2 0 1 7; 2 7( 4): 1 9 7- 2 0 8.
Hil de br a n dt -Eri kse n et al 2 0 1 2
Hil de bra n dt -Eri kse n E S, Aar u p V , Perss o n R, Ha nse n H F, M u n k M E, Or u m H. A l oc ke d 
n ucleic aci d oli g o n ucle oti de tar geti n g micr o R N A 1 2 2 is well-t olerate d i n c y n o m o l g us 
m o n ke ys. N ucleic Aci d T her . 2 0 1 2; 2 2( 3): 1 5 2- 6 1.
H u n g et al 2 0 1 3
H u n g G, Xi a o X, Peralta R, B hattac harjee G, M urra y S, N orris D et al. C haracteriz atio n of  
tar get m R N A re d uctio n t hr o u g h i n sit u R N A h y bri dizat i on i n m ult i ple or ga n s yste ms 
f oll owi n g s yste mic a ntise nse t reat me nt i n a ni mals. N ucleic Aci d T her. 2 0 1 3; 2 3( 6): 3 6 9- 7 8.
K at h m a n et al 2 0 1 8
Kat h ma n S, Belli bas S E, Kalle n d D G, Ra y  K K, W heeler J, Wij n gaar d P. P o p ulat i on d ose -
res p o nse m o deli n g of i nclisira n, a n o vel si R N A in hi bi t or t o P C S K 9, i n patient s at hi g h 
car dio v asc ular ris k wit h ele vate d L D L c h olester ol. Cli n P har mac ol T her. 2 0 1 8; 1 0 3: S 7 2.
Pr a k as h et al 2 0 1 4
Pra kas h T P, Gra ha m MJ, Yu J, Cart y  R, L o w A, C ha p pell A  et al. Tar gete d deli ver y of 
a nt ise nse o li g o n ucle oti des t o he pat oc ytes usi n g tria nte n nar y N-acet yl gal act osa mi ne 
i m pr o ves p ote nc y 1 0-f ol d i n mice. N ucl eic Aci ds Res. 2 0 1 4; 4 2( 1 3): 8 7 9 6 - 8 0 7.
R a y et al 2 0 1 7
Ra y  K K, La n d messer U, Leiter L A, Kalle n d D, D uf o ur R, Kara kas M et al. I nclisira n i n 
P ati e nts at Hig h Car di o v asc ular Ris k wit h Ele vate d L D L C h olester ol. N E n gl  J Me d. 
2 0 1 7; 3 7 6( 1 5): 1 4 3 0 - 4 0.
S a b ati ne 2 0 1 7
Sa bat i ne M S, Gi u glia n o R P, Keec h A C, H o nar p o ur N, W i vi ott S D, M ur p h y S A et al. 
E v ol oc u ma b a n d Cli nical O utc o mes i n Pat ient s wit h Car dio v asc ular Disease. N E n gl J Me d. 
2 0 1 7; 3 7 6( 1 8): 1 7 1 3 - 2 2.

Cli nical St u d y Pr ot oc ol – A me n d me nt N u m ber 1
Astra Ze neca
A Z D 8 2 3 3 - D 7 9 9 0 C 0 0 0 0 4
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 8 of 9 8
Se well et al 2 0 0 2
Se well K L, Gear y  R S, Ba ker B F, Glo ver J M, Ma nt T G, Yu R Z et al. P hase I trial of I SI S 
1 0 4 8 3 8, a 2' -met h o x yet h yl m o difie d a nt ise nse oli g o n ucle oti de tar geti n g t u m or necr osis 
fact or-al p ha. J P har mac o l E x p T her . 2 0 0 2; 3 0 3( 3): 1 3 3 4- 4 3.
S hee h a n et al 1 9 9 8
S hee ha n J P, La n H C. P h os p h or ot hi oate oli g o n ucle oti des i n hi bit t he i ntri nsic te nase c o m ple x. 
Bl o o d. 1 9 9 8; 9 2( 5): 1 6 1 7 -2 5.
S hee h a n et al 2 0 0 1
S hee ha n J P , P ha n T M. P h os p h or ot hi oate oli g o n ucle oti des i n hi bit t he i ntri nsic te nase c om p le x 
b y a n all o steric mec ha nis m. Bioc he mistr y . 2 0 0 1; 4 0( 1 6): 4 9 8 0-9.
S o k ol o v 2 0 1 9
S o k ol o v V, Hel mli n ger G, Nilss o n C, Z h u de n k o v K, S krtic S, Ha mre n B et al. C o m parati ve 
q ua nt itati ve s yste ms p har mac o l og y  mo deli n g of a nti -P C S K 9 t hera pe ut ic m o dalit ies i n 
h y perc h o lester ole mia. J Li pi d Res. 2 0 1 9; 6 0( 9) : 1 6 1 0- 2 1.
v a n Meer et al 2 0 1 7
va n Meer L, va n D o n ge n M, M oerla n d M, de Ka m M, C o he n A, B ur g graaf J. N o vel S G LT 2 
i n hi bit or: first-i n-ma n st u di es of a ntise nse c o mp o u n d is ass ociate d wit h u ne x pecte d re nal 
effects. P har mac ol Res Pers pect. 2 0 1 7; 5( 1):e 0 0 2 9 2.
v a n P oel geest et al 2 0 1 3
va n P oel geest E P, S wart R M, Betjes M G, M oerla n d M, Wee ni n g JJ, Tessier Y et al. Ac ute 
ki d ne y i nj ur y  d uri n g t hera p y wit h a n a ntise nse o li go n ucl e otide di recte d a gai nst P C S K 9. 
A merica n j o ur nal of ki d ne y diseases : t he official j o ur nal of t he Natio nal Ki d ne y  Fo u n dat i on. 
2 0 1 3; 6 2( 4): 7 9 6 - 8 0 0.
v a n P oel geest et al 2 0 1 5
va n P oel geest E P, H o d ges M R, M oerla n d M, Tessier Y, Le vi n A A, Perss o n R et al. A ntise nse-
me diate d re d ucti o n of pr o pr otei n c o n vertase s u btilisi n/ ke xi n t y pe 9 ( P C S K 9): a first -i n-
h u ma n ra n d o mize d, place b o -c o ntr olle d trial. Br J Cli n P har mac ol. 2 0 1 5; 8 0( 6): 1 3 5 0 - 6 1.

SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 7 9 9 0c 0 0 0 0 4-cs p-a me n d me nt- 1
D oc u me nt Title:
D 7 9 9 0 C 0 0 0 0 4 Cli nical St u d y Pr ot oc ol A me n d me nt 1
D oc u me nt I D:
Versi o n L a bel:
5. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
1 4- Fe b- 2 0 2 2 1 4: 2 2 U T C
C o nte nt A p pr o val
0 9- Fe b- 2 0 2 2 1 3: 4 1 U T C
C o nte nt A p pr o val
0 9- Fe b- 2 0 2 2 1 3: 2 4 U T C
A ut h or A p pr o val
1 0- Fe b- 2 0 2 2 1 5: 0 0 U T C
C o nte nt A p pr o val
N otes: ( 1) 
.
P P D
P P D
P P D
P P D
P P D
P P D