Conditions: Hyperlipidaemia
Keywords: AZD8233 Efficacy PK PD Safety Tolerability
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 411
Healthy volunteers: no

Brief summary:
AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study aims to evaluate safety, efficacy and tolerability of AZD8233.

Detailed description:
This is a randomized parallel, double-blind, placebo-controlled Phase 2b study in approximately 376 participants with hyperlipidaemia. The primary objective of the study is to assess the safety and tolerability of AZD8233 as compared with placebo, and the effect of AZD8233 versus placebo on relative change in LDL-C. The study will be conducted at up to 100 sites in up to 8 countries.

The screening period starts up to 28 days before the randomization visit and ends on Day -1. Eligible participants will attend 1 enrollment visit and 15 visits during the treatment period and 2 additional visits during the safety follow up period.

Arms:
arm 1: AZD8233 for subcutaneous use arm 2: Placebo solution for subcutaneous injection

Interventions: intervention 1: AZD8233 intervention 2: Placebo
Intervention descriptions: intervention 1: PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. intervention 2: Placebo solution

Protocol document:
Prot_000.pdf: 
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
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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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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
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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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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
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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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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
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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T A 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
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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
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
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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
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 


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
4 6 of 9 8
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


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 7 of 9 8

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)


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 8 of 9 8
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.


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 9 of 9 8
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
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 0 of 9 8
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
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 1 of 9 8
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
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 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 


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 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
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 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
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 9 of 9 8

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.


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
7 0 of 9 8
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


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 1 of 9 8
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

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Code
D7990C00004
Edition Number
4.0
Date
8-Jul-2022
A Randomized, Parallel, Double-Blind, Placebo-Controlled 
Phase 2b Study to Assess the Safety, Tolerability and Efficacy of 
AZD8233 Treatment in Participants with Hyperlipidaemia 
(SOLANO)


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TABLE OF CONTENTS
1
INTRODUCTION ............................................................................................12
1.1
Study Design ....................................................................................................12
1.2
Randomization..................................................................................................13
1.3
Number of subjects ...........................................................................................13
2
CHANGES TO PROTOCOL PLANNED ANALYSES....................................14
3
DATA ANALYSIS CONSIDERATIONS ........................................................14
3.1
Timing of Analyses...........................................................................................14
3.2
General Considerations.....................................................................................14
3.2.1
General Study Level Definitions .......................................................................14
3.2.2
Visit Window....................................................................................................18
3.2.3
Multiplicity/Multiple Comparisons ...................................................................19
3.2.4
Covid-19...........................................................................................................20
4
STATISTICAL ANALYSIS.............................................................................21
4.1
Study Population...............................................................................................21
4.1.1
Subject Disposition and Completion Status.......................................................21
4.1.2
Analysis Sets ....................................................................................................22
4.1.3
Study Recruitment ............................................................................................22
4.1.4
Protocol Deviations...........................................................................................23
4.1.5
Demographics...................................................................................................23
4.1.6
Baseline Characteristics ....................................................................................24
4.1.7
Baseline Disease Characteristics .......................................................................24
4.1.8
Medical History and Concomitant Disease........................................................25
4.1.9
Prior and Concomitant Medications ..................................................................26
4.1.10
Study Drug Compliance....................................................................................27
4.2
Efficacy Analyses .............................................................................................27
4.2.1
Primary Endpoint..............................................................................................31
4.2.2
Secondary Endpoint..........................................................................................35
4.2.3
Tertiary Endpoint..............................................................................................36
4.3
Pharmacodynamic Endpoint(s)..........................................................................37
4.4
Pharmacokinetics..............................................................................................38
4.5
Immunogenicity................................................................................................38
4.6
Safety Analyses ................................................................................................39
4.6.1
Exposure...........................................................................................................40
4.6.2
Adverse Events.................................................................................................41
4.6.3
Clinical Laboratory, Blood Sample ...................................................................46
4.6.4
Clinical Laboratory, Urinalysis .........................................................................48
4.6.5
Vital Signs ........................................................................................................49
4.6.6
Electrocardiogram.............................................................................................49
4.6.7
Other Safety Assessments .................................................................................50


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5
INTERIM ANALYSIS .....................................................................................50
6
REFERENCES .................................................................................................50
7
APPENDIX ......................................................................................................51
7.1
Missing data handling: MI-RD and placebo-washout imputation sensitivity 
analysis.............................................................................................................51
7.2
Laboratory Safety Variables..............................................................................52


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized 
Term
Definition
ADA
Anti-drug antibodies
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Apo A1
Apolipoprotein A1
Apo B
Apolipoprotein B
AST
Aspartate aminotransferase
ASO
Antisense oligonucleotide
BMI
Body mass index
Cmax
Maximum concentration 
CI
Confidence Interval
CM
Concomitant medication
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CV
Cardiovascular
 
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FAS
Full analysis set
GST
Global Study Team
HDL-C
High-density lipoprotein cholesterol
ICE
Intercurrent event
IP
Investigational Product
IPD
Important Protocol Deviation
IRT
Interactive response technology
iSMC
Internal Safety Monitoring Committee
ISR
Injection site reaction
ITT
Intention-To-Treat
LSMD
Least Squares Mean Difference
CCI


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Abbreviation or 
Specialized 
Term
Definition
LDL-C
Low-density lipoprotein cholesterol
LLN
Lower Limit Normal
Lp(a)
Lipoprotein(a)
LTFU
Lost to follow-up
MACE
Major adverse cardiovascular events
MAR
Missing at random
MCMC
Markov chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
Min
Minimum
MI-RD
Multiple imputation retrieved dropouts
MMRM
Mixed model repeated measures
MNAR
Missing not at random
PCSK9
Proprotein convertase subtilisin/kexin type-9
PD
Pharmacodynamic
PE
Pulmonary embolism
PK
Pharmacokinetics
PT
Preferred term 
PUC
Preparative ultracentrifugation 
Q1
First Quartile
Q3
Third Quartile
Q4W
Every 4 weeks
RTSM
Randomisation and Trial Supply Management
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SMQ
Standardised MedDRA Queries
SoA
Schedule of Activities
SOC
System Organ Class
TC
Total cholesterol
TP
Treatment Policy


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Abbreviation or 
Specialized 
Term
Definition
ULN
Upper Limit Normal
VLDL-C
Very low-density lipoprotein cholesterol
WHO
World Health Organisation
WOC
Withdrawal of consent
AMENDMENT HISTORY
CATEGORY*
Change refers 
to:
Date
Description of change
In
line 
with 
CSP?
Rationale
N/A
02 Jul 2021
Initial approved SAP
N/A
N/A
Derivation of 
primary 
endpoint(s)
05 Jan 2022
Clarified situation when LDL-C 
value is obtained with PUC.
Yes
Clarified in CSP 
Version 2.0.
Statistical 
analysis method 
for the primary 
endpoint.
05 Jan 2022
Added details to primary 
analysis missing data handling 
algorithm.
Yes
To facilitate 
reproduction of 
results. 
Statistical 
analysis method 
for the primary 
endpoint.
05 Jan 2022
Added supplementary analysis 
of relative change in LDL-C to 
end of week 16.
Yes
Relevant analysis, in 
particular for 
Interim analysis. 
Statistical 
analysis method 
for the primary 
endpoint.
05 Jan 2022
Added details to subgroup 
analysis of primary endpoint.
Yes
To facilitate 
reproduction of 
results. 
Statistical 
analysis method 
for the primary 
endpoint.
05 Jan 2022
Added comparative 
measurements based on time to 
event analysis, Kaplan-Meier 
estimates and Hazard ratios, to 
AE analyses 
Yes
To align estimator 
with Safety 
estimand. 
Data presentation
05 Jan 2022
Renamed IPD categories.
Yes
To align with data 
collection and 
company standards.
Data presentation
05 Jan 2022
Added HLGT and HLT levels to 
AE by SOC and PT tables
Yes
As suggested in 
FDA interaction. 


STATISTICAL ANALYSIS PLAN
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CATEGORY*
Change refers 
to:
Date
Description of change
In
line 
with 
CSP?
Rationale
Data presentation
05 Jan 2022
Added that all SOC, HLGT, 
HLT, and PT tables will be 
presented for both On-study and 
On-treatment period.
Yes
To align with Safety 
estimand and 
Overall summary 
tables. 
 
 
Data presentation
05 Jan 2022
Added “On-study period” 
definition to safety periods to 
denote period used for treatment 
emergent safety events. 
Yes
No defined study 
period for treatment 
emergent safety 
events.
Data presentation
05 Jan 2022
Changed presentation of relative 
change by removing “100*”
Yes
Discrepancy 
between Section 3 
and 4.
Data presentation
05 Jan 2022
Added PK set to Analysis set 
presentations.
Yes
Align with company 
standard outputs.
Data presentation
05 Jan 2022
Removed baseline eGFR labels.
Yes
Not clinically 
relevant labels. 
Data presentation
05 Jan 2022
Clarified that Statin and 
Ezetimibe therapy at baseline I 
defined as ongoing use at 
randomisation.
Yes
Clarification of 
definition.
Data presentation
05 Jan 2022
Added details on outputs from 
primary analysis model.
Yes
To facilitate 
reproduction of 
results. 
Data presentation
05 Jan 2022
Changed name of LDL-C 
“Enzymatic approach” to “Direct 
approach”
Yes
Clarification of 
definition.
Data presentation
05 Jan 2022
Added geometric mean and CV 
to Tertiary endpoint descriptive 
statistics
Yes
Relevant estimates 
for skewed 
distributed 
endpoints. 
Data presentation
05 Jan 2022
Added definition of ADA 
positive subjects and figures of 
individual ADA response over 
time.
Yes
Clarification and 
addition of figures to 
facilitate 
interpretation. 
CCI


STATISTICAL ANALYSIS PLAN
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CATEGORY*
Change refers 
to:
Date
Description of change
In
line 
with 
CSP?
Rationale
Data presentation
05 Jan 2022
Added Kaplan-Meier estimates 
of cumulative proportion of IP 
discontinuation.
Yes
To facilitate 
interpretation.
Data presentation
05 Jan 2022
Changed categorisation of AEs 
by maximum intensity.
Yes
To facilitate 
interpretation.
Data presentation
05 Jan 2022
Added definitions of clinical 
laboratory parameter 
abnormalities and shift table 
categories, as well as clarified 
language in section.  
Yes
To facilitate 
reproduction of 
results. 
Data presentation
05 Jan 2022
Added figures of empirical 
distribution function and 
individual values over time for 
platelet count.
Yes
To facilitate 
interpretation.
Data presentation
05 Jan 2022
Added Potential Hy’s law key 
subject information table.
Yes
Required company 
standard table. 
Data presentation
05 Jan 2022
Added cross table of baseline 
versus each scheduled visit for 
coagulation parameters. 
Yes
To facilitate 
interpretation.
Data presentation
05 Jan 2022
Added figures of individual 
Complement activation panel 
parameter values over time.
Yes
To facilitate 
interpretation.
Other
05 Jan 2022
Fixed typos, missing 
abbreviations, and other 
language-related issues.
Yes
Correction of errors.
Other
05 Jan 2022
Clarified that death and 
withdrawal of consent will be 
considered a study visit in the 
period derivation context.
Yes
Clarification for 
scenarios not 
previously handled.  
Other
05 Jan 2022
Visit window definitions 
updated to avoid overlapping.
Yes
To facilitate 
interpretation.
Other
05 Jan 2022
Replaced first database lock with 
interim analysis, specified 
interim analysis section.
Yes
Changed in CSP 
Version 2.0.
Other
05 Jan 2022
Added that baseline definition 
will disregard time of day.
Yes
Clarification for 
scenarios not 
previously handled.  


STATISTICAL ANALYSIS PLAN
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CATEGORY*
Change refers 
to:
Date
Description of change
In
line 
with 
CSP?
Rationale
Other
05 Jan 2022
Added that multiple measures of 
qualitative variables on same 
day will use clinically worse 
value in summary statistics.
Yes
Clarification for 
scenarios not 
previously handled.  
Other
05 Jan 2022
Changed 1 year definition from 
360 to 365 days, and removed 1 
month definition (not used). 
Yes
To facilitate 
interpretation.
Other
05 Jan 2022
Changed in concomitant 
medication use and total 
exposure definitions to be based 
on IP + 45 days instead of IP 
+ 30 days. 
Yes
Align with On-
treatment period 
definition.
Other
05 Jan 2022
Changed Safety objective 
intercurrent event strategy in 
Table 2 to “Hypothetical 
scenario” and moved to 4.2 
Safety Analysis
Yes
Correction to 
intercurrent event 
strategy and align 
table content with 
correct section. 
Other
05 Jan 2022
Changed to definition of 
Bleeding AEs to include 
laboratory terms.
Yes
As suggested in 
FDA interaction. 
Other
05 Jan 2022
Added that confirmation with 
consecutive HbA1C value is 
required for definition of new 
onset of diabetes.
Yes
Changed in CSP 
Version 2.0.
Other
05 Jan 2022
Added summary of AEs by 
ADA response.
Yes
To facilitate 
interpretation.
Other
05 Jan 2022
Changed category of eGFR in 
Laboratory Safety Variables 
Table from Urine renal safety 
biomarkers to Clinical chemistry
Yes
Error, fixed in CSP 
Version 2.0.
Statistical 
analysis method 
for the primary or 
secondary 
endpoints
28 Apr 2022
Clarified details on multiple 
imputation methods.
Yes
To facilitate 
interpretation.
Data presentation
28 Apr 2022
Updated the presentation of 
MMRM model, removed the 
redundant information and added 
details on figures. 
Yes
To facilitate 
interpretation.


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CATEGORY*
Change refers 
to:
Date
Description of change
In
line 
with 
CSP?
Rationale
Data presentation
28 Apr 2022
Corrected the data included in 
the key subject information for 
subjects with haematogy
abnormalities, chemistry 
abnormalities, or potential Hy’s 
law. 
Yes
Fixed the error.
Data presentation
28 Apr 2022
Updated rule 2b in visit window 
to include case of multiple 
assessments for qualitative 
variables.  
Yes
To facilitate 
interpretation.
Data presentation
28 Apr 2022
Added Hypersensitivity to pre-
defined AE categories.
Yes
To facilitate 
interpretation.
Data presentation
28 Apr 2022
Efficacy endpoint estimates to 
be presented as % by 
multiplying estimates by 100, 
including the eCDF figure. 
Yes
To facilitate 
interpretation. 
Data presentation
28 Apr 2022
Clarified the AEs with CK 
elevations.
Yes
To align with FDA 
comment.
Other
28 Apr 2022
Updated the narratives to include 
pre-specified AEs. 
Yes
To facilitate 
interpretation. 
Other
28 Apr 2022
MACE: Clarified the assumed 
order of occurrence of events 
when multiple events occur on 
the same date, and corrected 
typo. 
Yes
To fix typo and 
facilitate 
interpretation. 
Other
28 Apr 2022
Added how the missing values 
are treated when plotting the 
empirical cumulative 
distribution function.
Yes
To facilitate 
interpretation.
Other
28 Apr 2022
Clarified the references. 
Yes
To present more 
consistently. 
Other
28 Apr 2022
Adjusted the on-study period for 
discontinuation/interruption as 
patients are not at risk for these 
events after discontinuation. 
Yes
To facilitate 
interpretation. 
Other
28 Apr 2022
Updated the figure of study 
design to fix a typo and used the 
term “clinical data lock”.
Yes
To align with CSP.


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CATEGORY*
Change refers 
to:
Date
Description of change
In
line 
with 
CSP?
Rationale
Other
28 Apr 2022
Updated the definition of 
baseline diabetes.
Yes
To align with CSP.
Other
28 Apr 2022
Removed the section 5 of 
interim analysis and related 
contents on interim analysis. 
Yes
To align with CSP.
Other
28 Apr 2022
Updated the definition of 
exposure.
Yes
To align with study 
period. 
Other
28 Apr 2022
Clarified the global/country 
situation.
Yes
To clarify.
Other
28 Apr 2022
Added a non-breaking space 
before and after mathematical 
symbols.
Yes
To follow AZ 
authoring style 
guidance.
Statistical 
analysis method 
for the primary or 
secondary 
endpoints
8 Jul 2022
Updated methodology for MI-
RD and provided details for 
placebo washout and updated 
subgroup analysis interaction 
test pooling to be based on 
Rubin’s rules. 
Yes
To update to the 
more robust 
predictive mean 
matching model and 
to facilitate 
interpretation. 
Statistical 
analysis method 
for the primary or 
secondary 
endpoints
8 Jul 2022
Clarified the sensitivity analysis 
without imputing data.
Yes
To clarify. 
Other
8 Jul 2022
Included MCMC, MNAR, ICE 
and ITT into the abbreviation 
list. 
Yes
To clarify.
Other
8 Jul 2022
Updated the title of this SAP.
Yes
To align with CSP.
Other
8 Jul 2022
Clarified the definition of “Only 
baseline ADA positive”. 
Yes
To clarify.
Other
8 Jul 2022
Updated the boxplots to show 
the relative change of LDL-C 
and PCSK9 by ADA response 
instead of LDL-C and PCSK9 
raw values.
Yes
To facilitate 
interpretation. 
* Pre-specified categories are Primary or secondary endpoints; Statistical analysis method for the primary or 
secondary endpoints; Derivation of primary or secondary endpoints; Multiple Testing Procedure; Data presentations;
Other.




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1.2
Randomization
All subjects will be centrally assigned to randomised study intervention using an Interactive 
Response Technology/Randomisation and Trial Supply Management (IRT/RTSM). 
Eligible subjects will be randomly assigned to AZD8233 60 mg or matching placebo in a 1:1 
ratio. Subjects will be treated with AZD8233 or placebo SC Q4W for 28 weeks. 
1.3
Number of subjects
Approximately 530 subjects will be enrolled to achieve 376 subjects randomly assigned to study 
intervention. Subjects will be randomly assigned at a 1:1 ratio to one of the 2 treatment groups 
listed below:
!
AZD8233 
, SC Q4W, approximately 188 subjects randomly assigned
!
Placebo matching dose, SC Q4W, approximately 188 subjects randomly assigned
CCI
CCI


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2
CHANGES TO PROTOCOL PLANNED ANALYSES
There are no changes to protocol planned analyses.
3
DATA ANALYSIS CONSIDERATIONS
3.1
Timing of Analyses
The study is divided into a screening period of up to 28 days, a planned treatment period of 
28 weeks followed by a safety follow-up period of 12 weeks. The final clinical data lock for 
writing the CSR will occur once all subjects have completed their full study participation or 
withdrawn from study.
There will be iSMC meetings scheduled approximately every 2 months after first dosing in the 
study. The iSMC works independent of the GST and will review unblinded study safety data and 
make a recommendation to GST.
3.2
General Considerations
3.2.1
General Study Level Definitions
3.2.1.1
Baseline
For analyses on the full analysis set (FAS), baseline is defined as the last non-missing value prior 
to or on the date of randomisation including unscheduled assessments that occurs prior to the 
randomisation visit.
For analyses on the safety analysis set, baseline is defined as the last non-missing value prior to 
or on the date of first administration of IP including unscheduled assessments.
Baseline definition will only consider date, and disregard time of day of data collection, unless 
pre- and post-dose assessments are collected in which case the pre-dose assessment will be used 
as baseline. If more than one value qualifies for baseline for any other reason, the scheduled 
assessment will be taken as the baseline value. If the scheduled assessment is not one of these, 
then the average of the non-missing values will be taken as the baseline value, unless the variable 
is qualitative then the clinically worse value will be taken as the baseline value.
3.2.1.2
Study periods
Study periods on the full analysis set
Enrolment period
The enrolment period starts at the date of signed informed consent and ends at the day before 
randomisation. For subjects enrolled but not randomised, the enrolment period ends at last visit.


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Planned treatment period
The follow-up time during the planned treatment period will be calculated from the day of 
randomisation and to the day of end of planned treatment period visit, irrespective of if the 
subject has discontinued IP prior to this visit. 
If the end of planned treatment period visit is missing or has occurred outside of the visit 
window, for the purpose of defining the planned treatment period, it will be replaced by the 
earliest of: 

the upper end of the visit window of the end of planned treatment period visit (Day 200),

the date of withdrawal of consent,

the date of death,

the date of the last study visit, 
where the date of death and withdrawal of consent will be considered a study visit in this context. 
Full study period
The follow-up time for the full study period will be calculated from the day of randomisation and 
to the earliest of date of death, withdrawal of consent and last study visit (the date of death and 
withdrawal of consent will be considered a study visit in this context). 
Study periods on the safety analysis set
Pre-treatment period
The pre-treatment period starts at the date of signed informed consent and ends at the day before 
the date of first dose of IP. 
On-study period
The follow-up time for the on-study period will be calculated from the day of first dose of IP and 
to the earliest of date of death, withdrawal of consent and last study visit (the date of death and 
withdrawal of consent will be considered a study visit in this context). 
On-treatment period 
The follow-up time for the on-treatment period will be calculated from the day of first dose of IP 
and to the earliest of 45 days after last dose of IP, at date of death, withdrawal of consent or last 
study visit (the date of death and withdrawal of consent will be considered a study visit in this 
context).


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3.2.1.3
Time at risk and subjects with an event included in the analysis
If a subject has an event with onset day during the study period being analysed (see Section 
3.2.1.2), it will be included in the analysis. For subjects with an event, the time at risk will be 
derived as 

 	
  − 	 	
	 + 1 for the FAS, 

 	
  −
 	
 	  + 1 for the safety analysis set
For event-free subjects, the time at risk will be derived based on the study period being analysed, 
see the definition in Section 3.2.1.2. Event free subjects are censored on the last day of the study 
period.
3.2.1.4
Study Day
Study Day will be calculated from the randomisation date. Day 1 is the day of randomisation, 
Day -1 is the day prior to the date of randomisation, there is no Day 0.

If the date of the event is on or after the randomisation date then:
Study Day = date of event – date of randomisation + 1 day.

If the date of the event is prior to the randomisation date then:
Study Day = date of event – date of randomisation.
When converting the number of days to other units, the following conversion factor will be used: 
1 year = 365 days.
3.2.1.5
Imputation of incomplete dates
The following imputed dates will only be used for analysis purposes and will remain as reported 
(partially or completely missing) in subject listings.
Incomplete death dates
Partially or completely missing death dates will be imputed as follows:
If only the day value of the death date is missing, the first day of the month will be used; unless 
this occurs in the same month and year as the date of last visit, then the date of last visit will be 
used.
If the day and month values of the death date are missing, January 1 will be used; unless this 
occurs in the same year as the date of last visit, then the date of last visit will be used.
If the death date is completely missing, the date of last visit will be used.


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Incomplete concomitant medication dates
For medications that started prior to study start, start day will not be imputed. Partially or 
completely missing concomitant medication (CM) start dates will be imputed as follows:
If only the day value of the CM start date is missing, the first day of the month will be used; 
unless this occurs in the same month and year as the date of randomisation, then the date of 
randomisation will be used. If the day and month values of the CM start date are missing, 
January 1 will be used; unless this occurs in the same year as the date of randomisation, then the 
date of randomisation will be used.
If the CM start date is completely missing, the date of randomisation will be used.
If medication is marked as ‘Treatment continues’ the stop date will not be imputed. Partially or 
completely missing CM stop dates (where applicable) will be imputed as follows:
If only the day value of the CM stop date is missing, the last day of the month will be used; 
unless this occurs in the same month and year as the last visit, then the date of the last visit will 
be used. If the day and month values of the CM stop date are missing, December 31 will be used; 
unless this occurs in the same year as the last visit, then the date of the last visit will be used.
If the CM stop date is completely missing, the date of the last visit will be used.
3.2.1.6
Descriptive statistics
Summary data will be presented by treatment group and analysis visit when applicable. 
Quantitative data will be summarised by descriptive statistics, unless otherwise stated, including 
n, mean, standard deviation (SD), minimum, Q1, median, Q3 and maximum. Geometric mean 
and CV will be calculated in addition to arithmetic mean and SD, if appropriate. Categorical data 
will be summarised as the number and percentage of subjects in each treatment group for each 
category. When appropriate, number of missing observations will be presented, and these will 
not be included in the denominator when calculating percentages.
A general rule is to present descriptive summary statistics (mean, SD, median, Q1, Q3) to 1 more 
decimal place than the individual values. The minimum and maximum values should be reported 
to the same number of decimal places as the individual values.
Change from baseline will be presented similarly to summary data, with the absolute change 
from baseline and relative change from baseline summarised by descriptive statistics at the same 
timepoints, with the exception of baseline itself, in addition to the absolute values. Relative 
change from baseline at each timepoint will be calculated as: 
( −)

,


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where  is the value at timepoint , and  is the value at baseline.
All CIs will be 95%.
3.2.1.7
Subject convention
The term “Participant” is generally used to refer to language based on the CSP, vendor 
technology, patient-reported outcomes and publication titles. The word “subject” is more 
commonly encountered in the statistical sections of this SAP for consistency. Participant, patient 
and subject are used interchangeably.
3.2.2
Visit Window
For the purposes of analysing visit based data, analysis visit windows will be used and are based 
on the target date for the planned visit. The analysis visit windows are constructed based on the 
scheduled assessment timepoint (see Schedule of Activities in the CSP), and the range of the 
windows for scheduled assessments are shown in Table 1. Parameters are handled differently 
depending on the sampling frequency.
For each visit window, consider all assessments within the window and assign the visit 
assessment based on the following rules:
1. If the scheduled assessment is within the visit widow, then it is assigned.
2. If the scheduled assessment is not within the visit window, the closest assessment to the 
target date is assigned.
a.
If multiple assessments are equally close to the target date, the earliest is assigned.
b. If there are multiple closest assessments on the same date, the mean of these 
assessments will be assigned for quantitative variables and the clinically worst value 
will be assigned for qualitative variables.
3. If there are no assessments within the visit window, then it remains missing.
Table 1 Visit windows
Scheduled assessment
Target day
Analysis visit window 
(days)
Platelet counts and Liver function tests
Visit 3
15
- 13 to + 7
Visit 16
197
- 6 to + 14
Visit 17, 18
225, 281
- 13 to + 14


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All other visits
See SoA
- 6 to + 7
All other parameters with a Visit 3 assessment
Visit 3
15
- 13 to + 7
Visit 4
29
- 6 to + 14
All other visits
See SoA
- 13 to + 14
PK Plasma sample
Visit 15
183
- 13 to + 7
Visit 16
197
- 6 to + 14
All other visits
See SoA
- 13 to + 14
All other parameters
All visits
See SoA
- 13 to + 14
Data that are mapped to a scheduled visit will be counted in the study period (see Section 
3.2.1.2) that the scheduled visit belongs, not necessarily the assessment collection date. 
For summaries of extreme data at a subject level, all observations will be included regardless of 
whether it is included in the by-visit data presentation, e.g. when deriving a statistic such as the 
maximum.
3.2.3
Multiplicity/Multiple Comparisons
The formal hypotheses tests will focus on the treatment effect of AZD8233 versus placebo on the 
efficacy endpoints related to LDL-C and PCSK9. To maintain a family-wise Type I error rate of 
5%, the hypotheses will be evaluated in a hierarchical sequence by a two-sided test at a 5% 
significance level until a test fails to reject the null hypothesis or until all the listed null 
hypotheses are rejected. Any subsequent test will be considered exploratory. Statistical tests will 
be done in the order as listed in Table 2.


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Table 2 Endpoint hierarchy
Order
Null hypothesis
Alternative hypothesis
1
µ(LDL-C, A) = µ(LDL-C, P)
µ(LDL-C, A) ≠ µ(LDL-C, P)
2
µ(PCSK9, A) = µ(PCSK9, P)
µ(PCSK9, A) ≠ µ(PCSK9, P)
P: Placebo; A: AZD8233. 
The hypotheses are formalised using µ(biomarker, treatment group) to denote the mean relative reduction of 
biomarker in treatment group at the end of Week 28. For example, the mean relative reduction in concentrations of 
LDL-C in plasma for AZD8233 after 28 weeks is denoted with µ(LDL-C, A) and similarly for placebo with µ(LDL-
C, P).
Endpoints that are not listed in Table 2 are of an exploratory nature, and no adjustment will be 
made for multiple testing of these endpoints.
3.2.4
Covid-19
The impact of the COVID-19 pandemic is captured in exposure, disposition and visit data case 
report form pages as a general question on whether administration/subject’s status/visit was 
impacted by global/country situation and is discussed in Appendix H, COVID-19 Specifics, in 
the CSP.
Subjects affected by the COVID-19 pandemic, such as efficacy and safety assessments not per 
CSP, will be recorded as protocol deviations and listed. Summaries of COVID-19 study 
disruptions and number of subject dispositions due to COVID-19 will be presented.


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4
STATISTICAL ANALYSIS
This section provides information on definitions, derivation and analysis/data presentation per 
domain.
4.1
Study Population
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics, medical history, prior and concomitant medication and 
study drug compliance. 
4.1.1
Subject Disposition and Completion Status
4.1.1.1
Definitions and Derivations

Enrolled will be defined as a subject who signed the informed consent of the study. 

Randomised will be defined as a subject who has been randomised to a treatment group. 

Received treatment will be defined as a subject who has received at least one dose of IP. 

Completed treatment will be defined as a subject who has not permanently prematurely 
discontinued IP during the study. A subject who dies during follow-up without having 
permanently discontinued IP prior to date of death, will be considered to have completed 
treatment.

Subjects who discontinued treatment is defined as subjects who have permanently 
prematurely discontinued IP, the reasons for discontinuation as collected on the DOSDISC 
eCRF will be presented. For reason collected as other, the specify field will be presented in 
listings but not in the disposition table.

Completed study will be defined as a subject who has completed the end of planned 
treatment visit, or a later visit.

Completed safety follow-up will be defined as a subject who has completed the final safety 
follow-up visit.

Subjects who discontinued the study is defined as subjects who have withdrawn consent, 
have been lost to follow-up or died, the numbers for each of these categories will be 
presented.

Subjects who discontinued treatment due to global/country situation, if applicable.

Subjects who withdraw from study due to global/country situation, if applicable.
4.1.1.2
Presentation
Subject disposition and completion status will be described by treatment group and total number 
of subjects, for all subjects who have signed ICF for the study. 


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Number of subjects in each category will be presented, when applicable, percentages will also be 
presented. 
4.1.2
Analysis Sets
4.1.2.1
Definitions and Derivations
Full Analysis Set
All subjects who were randomly assigned to study intervention. Subjects will be analysed 
according to their randomised study medication assignment, irrespective of the treatment actually 
received. 
Safety Analysis Set
The safety analysis set consists of all subjects who have received at least one dose of 
investigational product. Erroneously treated subjects (e.g., those randomised to treatment A but 
actually given treatment B) are accounted for in the treatment group of the treatment they 
actually received. A subject who has on one or several occasions received active IP is classified 
as active and is accounted for the active IP treatment group.
PK Analysis Set
The PK analysis set will consist of all subjects who receive at least 1 dose of AZD8233, for 
whom at least 1 post-dose PK concentration assessment is available as determined at the final 
protocol deviations meeting prior to unblinding of this study. Subjects will be presented in 
accordance to the actual treatment received.
4.1.2.2
Presentation
Analysis sets will be presented by number of subjects in each analysis set for all randomised 
subjects, by treatment group and total number of subjects. The reason for exclusion from an 
analysis set will be presented. 
4.1.3
Study Recruitment
4.1.3.1
Definitions and Derivations
Region will be categorised by US and Europe. 
4.1.3.2
Presentation
Patient recruitment by region, country and site will be summarised for all enrolled subjects, the 
safety analysis set, the FAS and the PK set by treatment group and total number of subjects.


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4.1.4
Protocol Deviations
4.1.4.1
Definitions and Derivations
Important protocol deviations (IPDs) are defined as protocol deviations which may significantly 
affect the completeness, accuracy and/or reliability of the study data, or which may significantly 
affect a patient’s rights, safety or well-being. They will include (but are not limited to):

Inclusion Criteria Deviations. 

Exclusion Criteria Deviations. 

Discontinuation Criteria for study product met but patient not withdrawn from study 
treatment. 

Discontinuation Criteria for overall study withdrawal met but patient not withdrawn from 
study. 

Investigational Product (IP) Deviation. 

Excluded Medications taken.

Deviations to study procedure. 

Other Important Deviations. 
All IPDs except for dosing error will be identified and documented by the study team prior to 
unblinding of the trial. Subjects meeting an IPD category more than once will be counted once 
for the corresponding IPD category. Any subject who have more than one IPD category will be 
counted once in the overall summary. IPDs will not be used to exclude any subject from any 
analysis set, nor to exclude any data from patients included in an analysis set. 
IPD handling depends on detection method and are verified with site and entered/reconciled with 
Clinical trial management system. Further details will be described in the protocol deviation 
plan. 
4.1.4.2
Presentation
Important protocol deviations (IPDs) will be summarised and listed for the FAS by randomised 
treatment group and total number of subjects. The number and percentage of patients with at 
least one IPD category as well as the number and percentage of patients meeting each IPD 
category will be provided by treatment group and in total.
4.1.5
Demographics
4.1.5.1
Definitions and Derivations
Demographic based on the FAS characteristics includes 

Age (years) 

Age group (< 65, ≥65 years) 


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
Sex (male, female)

Race (Black or African American, Native Hawaiian or other Pacific Islander, American 
Indian or Alaska Native, Asian, White, Other) 

Ethnicity (Hispanic/Latino, not Hispanic/Latino) 
4.1.5.2
Presentation
Demographics will be presented for the FAS, by treatment group and total number of subjects. 
Age will be presented as a continuous variable with descriptive statistics and categorically by age 
group. Sex, race and ethnicity will be presented as categorical variables. 
4.1.6
Baseline Characteristics
4.1.6.1
Definitions and Derivations
Baseline patient characteristics includes 

Weight (kg) 

Height (cm) 

BMI (kg/m2)

BMI group:
o
underweight (< 18.5 kg/m2), 
o
normal weight (≥ 18.5 kg/m2 and < 25 kg/m2),
o
overweight (≥ 25 kg/m2 and < 30 kg/m2) and 
o
obese (≥ 30kg/m2).
BMI will be calculated based on weight and height of the subject at baseline.
4.1.6.2
Presentation
Baseline patient characteristics will be presented descriptively by randomised treatment group 
and overall and will be based on FAS. Height, weight and BMI will be presented as continuous 
variables with descriptive statistics. BMI will also be presented categorically by BMI group.
4.1.7
Baseline Disease Characteristics
4.1.7.1
Definitions and Derivations
The following disease characteristics will be presented at baseline:

Baseline diabetes is defined according to the below criteria:
a)
Medical history of diabetes (type 1 or type 2), defined by SMQ Hyperglycemia/new 
onset diabetes mellitus (narrow), or


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b)
Measurement of HbA1c ≥ 6.5% (48 mmol/mol) confirmed by a consecutive 
HbA1c ≥6.5% (48 mmol/mol) or a fasting serum glucose ≥ 126 mg/dL (7.0 mmol/L) on 
or before the date of first dose of IP.

Baseline HbA1c, grouped by < 6.5%, ≥6.5% 

Baseline fasting serum glucose, grouped by < 126 mg/dL, ≥ 126 mg/dL

Baseline eGFR calculated according to CKD-EPI formula, grouped by 
o
< 15 mL/min/1.73m2, 
o
≥15 and < 30 mL/min/1.73m2, 
o
≥ 30 and < 60 mL/min/1.73m2, 

≥30 and < 45 mL/min/1.73m2, 

≥45 and < 60 mL/min/1.73m2, 
o
≥ 60 and < 90 mL/min/1.73m2, 
o
≥ 90 mL/min/1.73m2. 

Baseline PCSK9

Baseline LDL-C

Baseline lipoprotein(a)

Baseline triglycerides, grouped by < 200 mg/dL, ≥200 mg/dL

Statin therapy ongoing use at randomisation: 
o
high intensity statin therapy (defined as atorvastatin ≥40 mg, or rosuvastatin ≥20 mg)
o
medium or low intensity statin therapy
o
no statins

Ezetimibe therapy ongoing use at randomisation (Yes, No)
4.1.7.2
Presentation
Disease characteristics will be presented for the FAS, by treatment group and total number of 
subjects. 
Baseline HbA1c and eGFR will be presented as continuous variables with descriptive statistics 
and categorically by group. Baseline PCSK9, LDL-C and Lp(a) will be presented as a continuous 
variable with descriptive statistics. All other variables will be presented categorically only.
4.1.8
Medical History and Concomitant Disease
4.1.8.1
Definitions and Derivations
Medical history as well as surgical history will be coded according to MedDRA and will be 
summarized by system organ class (SOC) and preferred term (PT) for the FAS.  


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4.1.8.2
Presentation
Medical and surgical history will be presented descriptively for the FAS, by treatment group and 
total number of subjects. Percentages will be calculated with number of subjects in the FAS as 
denominator. Subjects are only counted once per SOC and PT regardless of the number of 
occurrences within each category. PT will be presented nested within the relevant SOC and 
sorted by international order of SOC and alphabetically by PT.
4.1.9
Prior and Concomitant Medications
4.1.9.1
Definitions and Derivations
Prior medication is defined as any medication taken by the subject before the first dose of IP. If 
the end date is the day of first dose of IP, it will be defined as a prior medication.
Concomitant medication is defined as any medication taken concurrently with IP regardless of 
the start date of the medication. If the end date of the medication is prior to or on the day of first 
dose or start date of the medication is on or more than 45 days after last IP injection, the 
medication will not be considered to be taken concomitantly.
Disallowed concomitant medication are defined in Section 5.2, Exclusion Criteria and Section 
6.5, Concomitant Therapy of the CSP. All other concomitant medications are classified as 
allowed.
Prior and concomitant medications will be reported by ATC classification and generic drug name 
(according to WHODrug).
4.1.9.2
Presentation
Prior and concomitant medications will be presented descriptively.
Prior and concomitant medications will be presented for the FAS, by treatment group and total 
number of subjects. Percentages will be calculated with number of subjects in the FAS as 
denominator. Subjects are only counted once per ATC classification and generic drug name 
regardless of the number of medications within each category. Generic drug name will be 
presented nested within the relevant ATC classification and sorted alphabetically by ATC 
classification and then generic drug name.
Prior medications, disallowed concomitant medications, and allowed concomitant medications 
will be presented separately. 


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4.1.10
Study Drug Compliance
4.1.10.1
Definitions and Derivations
Compliance to IP is defined by how many of the planned doses the subject has received. This 
will be expressed in percentage with the following formula 
Number of injections taken
Number of expected injections × 100.
Where number of expected injections is defined as the number of expected injections between 
first dose and time of completed planned treatment period or the time when IP is prematurely 
permanently discontinued, irrespective of temporary discontinuation of IP. Number of injections 
taken are defined as the number of injections taken according to the EX eCRF, for missing data 
see below.
The data will also be categorised in three different groups, these are

< 80%

≥80% to < 120%

≥120%.
If the information on whether the planned dose has been administered is missing, it will be 
counted as if the injection was not taken irrespective of the drug was dispensed or not. Number 
of injections taken will be based on EX eCRF only.
4.1.10.2
Presentation
Compliance will be presented for the FAS by treatment group and total number of subjects. 
Compliance will be presented as a continuous variable with descriptive statistics and 
categorically by compliance group. Number of subjects with missing compliance will be 
presented.
4.2
Efficacy Analyses
This section covers details related to the efficacy endpoint analyses such as primary, secondary, 
other endpoints including sensitivity and supportive analyses.










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
Intercurrent events: Non-terminal intercurrent events will be handled using a treatment 
policy strategy, i.e. the variable of interest is aimed to be collected and used irrespective of 
intercurrent events. Terminal events are expected to be few without substantial impact on the 
efficacy estimates and handled in the framework for missing data.

Population-level summary: difference in variable means between treatments.
This estimand requires that to the extent possible, randomised subjects are followed up 
regardless of study intervention compliance.
4.2.1.2
Derivations
The dependent variable is the relative change in LDL-C, that is 
(456 −)

,
where  and 456 denotes the LDL-C measurements at baseline and at the end of Week 28 
(Day 197).
The LDL-C value obtained using PUC will be used in the analysis of LDL-C through reflex 
testing when the LDL-C is < 40 mg/dL (by the Friedewald method) or if the triglycerides are 
≥400 mg/dL. If there is no measurement taken using PUC, the calculated LDL-C value obtained 
using the Friedewald formula will be used [Friedewald 1972]. If neither LDL-C measured with 
PUC or calculated using the Friedewald formula is available, the measurement will be 
considered as missing. 
4.2.1.3
Handling of Dropouts and Missing Data
For cases when baseline values are missing, the baseline values will be imputed by the mean 
value of non-missing baseline from other subjects. For post-baseline missing LDL-C values, a 
distinction in the imputation will be made between non-monotone and monotone missing data. 
Monotone missing data are defined as missing data which constitute the end of patient follow-up, 
while non-monotone missing data means that there are observations made after the missing time 
point. Any non-monotone missing data will be replaced using PROC MI MCMC while 
monotone missing data will use PROC MI with a predictive mean matching model. The 
imputation model will include treatment group, baseline LDL-C and post-baseline LDL-C 
assessments at all scheduled timepoints in chronological order.
If there are sufficient retrieved dropouts per missingness-pattern by treatment group 
combination, pattern mixture imputation will be based on multiple imputation with retrieved 
dropouts (MI-RD), otherwise placebo-washout imputation will be used. Further details shown in 
Appendix 7.1. 


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4.2.1.4
Primary Analysis of Primary Endpoint
The main estimator is an ANCOVA for the relative change from baseline to the end of Week 28, 
including all subjects in the FAS. The model will include treatment group as a fixed categorical 
factor and baseline value as a continuous covariate. In this model, the dependent variable will be 
the relative change in LDL-C from baseline to the end of Week 28.
Available observations at baseline and the end of Week 28 will be used in the model, missing 
data will be imputed according to the principles outlined in Section 4.2.1.3. In addition, 
descriptive statistics will be presented and the distribution of missing data, number and 
proportions, according to each missing data pattern will be summarised per treatment arm. 
Least square mean estimates for each treatment group and the difference between treatment 
groups, 95% CIs and p-value will be presented. In presentations, estimates based on relative 
change will be expressed in percent by multiplying by 100.
4.2.1.5
Sensitivity Analyses of the Primary Endpoint
The following sensitivity analyses will be conducted:

The same approach as in Section 4.2.1.4 for the primary analysis but without imputing 
missing data, (i.e., subjects with missing data at baseline or end of Week 28 will be 
excluded). 

The same approach as in Section 4.2.1.4 for the primary analysis but LDL-C is derived from 
the Martin/Hopkins approach [Martin 2013].

The same approach as in Section 4.2.1.4 for the primary analysis but LDL-C is derived from 
the Direct approach (direct fast determination in 24h) [Martin 2018].

Analysis of relative reduction of LDL-C from baseline to end of Week 28 with MMRM as 
discussed in Section 4.2.3.1.
4.2.1.6
Supplementary Analyses of the Primary Endpoint
The following supplementary analyses will be conducted:

Analysis of relative reduction of LDL-C from baseline to the end of Week 16, including all 
subjects in the FAS, using ANCOVA as estimator as described in 4.2.1.4. 

Analysis of relative reduction of LDL-C from baseline to last observation on-treatment, 
using ANCOVA as estimator. To assess the robustness of the main analysis of primary 
endpoint to the choice of intercurrent event strategy. Same approach as the primary analysis 
but instead of handling intercurrent events using the treatment-policy strategy, a while-on-
treatment approach will be used. The last observation while-on-treatment is carried forward 
(LOCF) for the endpoint measurement and data after intercurrent event, i.e. last dose + 45 


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days, WOC, LTFU. Note that the treatment allocation with more intercurrent events may 
appear to have higher efficacy.

The empirical cumulative distribution function (eCDF) within each treatment group of the 
endpoint variable, relative change in LDL-C from baseline to the end of Week 28, without 
imputing missing data, will be presented in a figure. The figure will present the cumulative 
probability on the y-axis and the endpoint variable on the x-axis. The x-axis will be 
multiplied by 100 to show relative change in percentage. Both treatment groups will be 
presented in the same figure. 
4.2.1.7
Subgroup Analyses of the Primary Endpoint
The following baseline and demographic variables are defined for the purpose of efficacy 
subgroup analysis to assess consistency of effect:

Baseline age (< 65, ≥65 years)

Sex (male, female)

Geographic region (US, Europe)

Race (Black or African American, Native Hawaiian or other Pacific Islander, American 
Indian or Alaska Native, Asian, White, Other) 

Ethnicity (Hispanic/Latino, not Hispanic/Latino) 

Categorical calculated baseline BMI:
o
underweight (< 18.5 kg/m2), 
o
normal weight (≥ 18.5 kg/m2 and < 25 kg/m2),
o
overweight (≥ 25 kg/m2 and < 30 kg/m2) and 
o
obese (≥ 30kg/m2).

Baseline diabetes (Yes/No)

Baseline categorical HbA1c (< 6.5%, ≥6.5%) 

Baseline fasting serum glucose (< 126 mg/dL, ≥ 126 mg/dL)

Baseline eGFR calculated according to CKD-EPI formula ([≥30,< 60], [≥60,< 90], [≥90] 
ml/min/1.73m2)

Baseline PCSK9 (< median, ≥median)

Baseline LDL-C (< Q1, ≥Q1 - < median, ≥median – < Q3, ≥Q3)

Baseline lipoprotein(a) (< median, ≥median)

Baseline Triglycerides (< 200 mg/dl, ≥200 mg/dl)

High intensity statin ongoing use at randomisation (Yes/No)


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For each of the pre-specified subgroup variables, a separate ANCOVA model will be fitted using 
the same terms as used in the primary analysis in Section 4.2.1.4 but additionally including the 
subgroup variable and the interaction term for subgroup-by-treatment interaction. Missing values 
in LDL-C will be handled in the same way as in the overall analysis. Subjects with missing 
values in the subgroup variables is expected to be minimal, and will not be imputed but excluded 
before analysis. When applicable, the p-value for interaction will be derived by combining 
interaction test statistics from each multiple imputation ANCOVA result using Rubin’s rules. 
Least square mean estimates for each treatment group and the difference between treatment 
groups per subgroup, 95% CIs and the p-value for the interaction term will be presented. Least 
square mean estimates for each treatment group and the differences will also be presented in a 
forest plot. 
If any category of a subgroup variable contains less than 5% of the randomised subjects, separate 
ANCOVA models similar to the overall analysis will instead be fitted to subjects in each 
separate category, thus no p-value of interaction will be presented. 
4.2.2
Secondary Endpoint
4.2.2.1
Relative change from baseline in concentrations of PCSK9
The secondary endpoint is relative change from baseline in concentrations of PCSK9 at the end 
of Week 28. This endpoint will be analysed with an ANCOVA model, including all subjects in 
the FAS, as described in Section 4.2.1.4.
4.2.2.2
PK Parameters
Evaluating the PK of AZD8233 is a secondary objective. If data permit, a population PK model 
will be developed, possibly with the support of PK data from studies such as D7990C00001, 
D7990C00002, D7990C00003 and potentially other studies, using nonlinear mixed effects 
modelling in NONMEM. The population PK model may be coupled with separate PD models for 
PCSK9 and LDL-C. All PK/PD modelling will be described in a separate data analysis plan and 
the results of any such modelling will be provided in a separate population PK/PD report.
AZD8233 full length ASO concentrations in plasma will be summarised by descriptive statistics 
by sampling time point and listed on individual level based on the PK analysis set. 
Concentrations will be analysed on a natural logarithmic scale and then back-transformed to the 
original scale. 


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4.2.3
Tertiary Endpoint
4.2.3.1
Absolute values, absolute and relative changes compared with baseline, in 
serum LDL-C over time
For this exploratory endpoint an MMRM will be the estimator for each of the relative and 
absolute change in LDL-C from baseline over time. The observed relative (or absolute) change 
from baseline at each scheduled post baseline assessment in the planned treatment period is the 
dependent variable. The model will include LDL-C at baseline as the fixed effect covariate, and 
treatment group, visit and treatment-by-visit interaction as fixed effect categorical factors.
The covariance structure used is unstructured (UN). If the model does not converge with UN, 
then Toeplitz, first-order autoregressive or compound symmetric covariance structure will be 
tried and the covariance structure will be decided based on model convergence status.
MMRM model assumes MAR for patients with missing data, missing data for participants who 
have discontinued IP are treated the same way as the observed measurements from participants 
who have not discontinued IP in the same treatment group.
Least square mean estimates from the MMRM for each treatment group and the difference 
between treatment groups and 95% CIs will be provided at each scheduled post baseline 
assessment in the planned treatment period. Figures showing absolute and relative change, 
respectively, from baseline to each scheduled assessment together with 95% CI in the full study 
period will be presented for serum LDL-C.
Descriptive statistics including n, arithmetic mean and standard deviation (SD), geometric mean 
and CV, minimum, Q1, median, Q3 and maximum, will be presented for the observed values, 
absolute and relative change from baseline for each scheduled assessment in the full study period 
will be presented. 
In presentations, estimates based on relative change will be expressed in percent by multiplying 
by 100.
4.2.3.2
Absolute values, absolute and relative changes compared with baseline, in 
plasma PCSK9 over time
This exploratory efficacy variable is change in PCSK9 and will be analysed as described in 
Section 4.2.3.1. Descriptive statistics will also be presented in a similar way.
4.2.3.3
Cardiovascular outcomes: MACE and thromboembolic event
These exploratory endpoints are:

Time to the first occurrence of any component of the 3-point MACE composite defined as 
CV death, myocardial infarction, ischaemic stroke.

Time to first thromboembolic event defined as the first occurrence of DVT or PE.


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The number of events and number of subjects with events in the MACE composite (CV death, 
MI, ischaemic stroke), and in the composite of thromboembolic events (DVT and PE) will be 
presented by treatment group. If there are at least 10 events in the MACE composite and 
thromboembolic events composite, respectively, the time to first event will also be analysed 
using survival analysis. Components in those endpoints are identified based on PTs for the 
investigator reported AEs. If there are multiple MACE with the same onset date, they will be 
assumed to occur in the following order: MI onset prior to stroke onset, and death onset occurs 
last. If there are multiple thromboembolic events, they will be assumed to occur in the following 
order: DVT onset prior to PE onset. 
These composite endpoints will be analysed under a treatment policy intercurrent event strategy. 
The subjects’ first event in the composite, that occurs during the planned treatment period will be 
included in the analysis. All subjects who are event free for the given endpoint will be censored 
according to the definition of planned treatment period in Section 3.2.1.3, i.e. events are included 
regardless of discontinuation of study medication. WOC and non-CV death which are censoring 
events.
In each composite endpoint, relative risk reduction between treatment groups will be compared 
using a Cox proportional hazards model with a factor for treatment group. The Efron method for 
ties will be used, and the HR, and 95% CI will be reported.  Kaplan-Meier estimates of the 
cumulative proportion of patients with the composite event will be plotted and the estimate at 
Day 197 will be presented in tables.
The number of subjects with events for each component of the composites will be presented. If 
there are at least 10 events reported, HR with 95% CI and Kaplan-Meier estimates at Day 197 
will be presented.
4.2.3.4
Change in cholesterol, triglycerides, apolipoproteins, lipoprotein
For Apo A1, Apo B, TC, HDL-C, Non-HDL-C, VLDL-C, remnant cholesterol, triglycerides and 
Lp(a), descriptive statistics including n, arithmetic mean and standard deviation (SD), geometric 
mean and CV, minimum, Q1, median, Q3 and maximum will be presented for observed values, 
absolute and relative change from baseline at each scheduled visit in the full study period.  
These endpoints will be analysed with an ANCOVA model at the end of Week 28, including all 
subjects in the FAS, as described in Section 4.2.1.4 and descriptive statistics will be presented.
4.3
Pharmacodynamic Endpoint(s) 
Details for these endpoints are described in Section 4.2.


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4.4
Pharmacokinetics 
Details are provided in Section 4.2.2.2.
4.5
Immunogenicity 
Immunogenicity parameters are immunogenicity titre tested in an external laboratory. A 
validated screening assay will be used to determine ADA positive samples. Any positive samples 
will be tested in a confirmatory assay whereby the specificity of the ADA response will be 
confirmed as either positive or negative with respect to AZD8233. Titre evaluation are 
performed on samples that are ADA positive. 
Immunogenicity results are calculated for all subjects included in the Safety analysis set. The 
following ADA response categories will be used to categorise subjects:

ADA positive: baseline result or ≥1 post-baseline result positive,

Treatment emergent ADA positive: ≥1 post-baseline result positive,

Treatment induced ADA positive: baseline result negative and ≥1 post-baseline result
positive,

Treatment boosted ADA positive: baseline result positive and ≥1 post-baseline result 
positive with ≥4-fold titre increase from baseline,

Baseline and post-baseline ADA positive: baseline result and ≥1 post-baseline result 
positive,

Only baseline ADA positive: baseline result positive and no post-baseline result positive,

ADA persistently positive: baseline result negative and ≥2 Positive with ≥16 weeks between 
first and last positive sample, or last post-baseline result positive,

ADA transiently positive: baseline result negative and ≥1 positive but not ADA persistently 
positive,

Treatment emergent ADA positive with maximum titre > median of maximum titres: ≥1 post 
baseline result positive with maximum titre > median of maximum titres in all ADA positive 
subjects within treatment group.
Number and percentage of subjects in each ADA response category will be tabulated by 
treatment group and in total, with corresponding summary statistics (minimum, Q1, median, Q3, 
maximum) for ADA titre when applicable. Number of ADA positive subject and summary 
statistics for ADA titres will be tabulated by treatment group and visit. If a subject has more than 
one non-missing titre which qualifies for a category, the maximum titre is used in summary 
statistics calculations.
A figure of proportion of subjects with positive ADA response over time will be presented, with 
one line for each treatment group, and percentage of subjects with positive ADA response on the 




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!
Treatment: Actual treatment group, AZD8233 
Q4W SC injections compared to 
placebo on a background of a stable dose of maximally tolerated statin and/or ezetimibe 
treatment.
!
Population: Safety analysis set (see Section 4.1.2.1)
!
Variable: 
o
Treatment emergent adverse event variables defined as

Events with an onset date on or after first dose of IP,

Worsening of pre-existing events on or after first dose of IP.
o
Treatment emergent vital sign, ECG, or clinical laboratory evaluation results defined as

Results at post-dose assessments on date of first dose of IP or at any assessments 
after the date of first dose of IP.
!
Intercurrent events (ICEs): the risk of a safety event will in the analyses be evaluated under a 
hypothetical scenario where premature discontinuation of study treatment or study visits or 
loss to follow-up cannot happen.
4.6.1
Exposure
4.6.1.1
Definitions and Derivations
Exposure is calculated for all subjects included in the safety analysis set.
Total exposure
Total exposure (days) is calculated as the minimum of the date of last IP administration plus 45 
days and last study visit minus date of first IP administration plus one, i.e.
Total exposure (days) = min(Last administered IP + 45, Last study visit)
−First administered IP + 1
Last IP administered will be extracted from the DOSDISC form, while the first dose 
administration are derived from the earliest administered dose collected on the EX form.
Total treatment time will be expressed in years in data presentations, defined as the sum of days 
of total exposure for a given treatment group divided by 365 days.
Time to permanent IP discontinuation will be analysed using survival analysis. Subjects who did 
not permanently discontinue IP are censored at the earliest of WOC, death, Day 172, and last 
dose. Kaplan-Meier estimates of the cumulative proportion of patients who discontinue IP will 
be calculated for each treatment group.
CCI


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4.6.1.2
Presentation
Exposure will be presented by treatment group, summary statistics of total exposure will be 
presented, as well as total treatment time. 
A figure of exposure over time will be presented, with one line for each treatment group, and 
percentage of subjects still exposed on the y-axis and time from first dose on the x-axis. At a 
given time t, the curve will show the percentage of subjects with exposure time > t.
Total exposure will also be presented categorically with cumulative categories: ≥4 weeks, ≥12 
weeks, ≥20 weeks, ≥28 weeks. These categories are cumulative, and subjects will be included 
in all categories that apply to them.
Number of administrated doses will be presented for the given study duration by descriptive 
statistics and categorised based on number of injections: ≥1, ≥3, ≥5, ≥7. These categories are 
cumulative, and subjects will be included in all categories that apply to them.
A figure of Kaplan-Meier estimates of the cumulative proportion of subjects discontinuing IP 
will be plotted by treatment group.
4.6.2
Adverse Events
Safety analyses will be performed using the safety analysis set. Safety data will be presented 
using descriptive statistics unless otherwise specified.
4.6.2.1
Definitions and Derivations
Each AE will be assigned to the following periods, defined in Section 3.2.1.2 based on onset 
date:

Pre-treatment

On-study

On-treatment
For on-study the assumption is that the risk for an event is independent of continued exposure to 
study drug, while for on-treatment the assumption is that the ICE’s are non-informative. On-
study and on-treatment approaches are complementary estimands.
All AEs will be classified by SOC, HLGT, HLT and PT according to a MedDRA version not 
more than one older than the latest version available at the time of database lock.
Comparative measurements between treatment groups based on time to the first occurrence of 
any component within an AE category will be calculated using survival analysis. The subjects’ 
first event in the composite, that occurs during the on-study or on-treatment period, respectively, 


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will be included in the analysis. All subjects who are event free for the given endpoint will be 
censored according to the definitions of study periods in Section 3.2.1.3. For on-study Kaplan-
Meier estimates with patients censored at the end of study is an appropriate estimator 
(corresponds to ITT analysis), for analyses on-treatment Kaplan-Meier estimates with patients 
censored at last dose + 45 days is the estimator. For time-to-event analysis of AEs leading to 
discontinuation or interruption of IP, in both on-study and on-treatment analyses event-free 
subjects that did not complete treatment are censored 14 days following the date of last dose of 
IP and event-free subjects who did not die and completed treatment are censored on the date of 
last dose of IP.
For each AE category, relative risk reduction between treatment groups will be compared using a 
Cox proportional hazards model with a factor for treatment group. The Efron method for ties will 
be used. The absolute difference and 95% CIs in Kaplan-Meier estimates at the end of the 
planned treatment period (Day 197) between treatment groups will be calculated. 
The following definitions and principles are to be followed: 
Any AE
Defined as subjects with at least one reported AE with an onset date within the defined period.
AEs with outcome death
Defined as an AE with reported outcome as ‘Fatal’, there may be more than one AE with 
outcome death for a subject. The onset date of the AE determines the analysis period, 
irrespective of date of death.
AEs leading to discontinuation of IP
Defined as an AE with action taken IP reported as drug permanently discontinued. The onset 
date of the AE determines the analysis period, irrespective of date of discontinuation of IP.
 
. 
AEs leading to interruption of IP and the subject subsequently discontinues IP 
Defined as an AE with action taken IP reported as drug interrupted and where drug has been 
permanently discontinued with a DOSDISC form IP discontinuation date after the date of the AE 
onset with action reported as drug interrupted. The onset date of the AE determines the analysis 
period, irrespective of date of IP discontinuation.
SAEs 
Defined as an AE reported as serious, irrespective of outcome.
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AEs possibly related to IP
Defined as an AE that is reported as “reasonable possibility AE caused by IP”. If this causality 
evaluation is missing, it will be counted as an AE possibly related to IP.
AEs by maximum intensity
AEs will be classified by the reported maximum intensity (mild, moderate, and severe) and 
categorised in presentations as “Any”, “Moderate or Severe” and “Severe”. If this maximum 
intensity evaluation is missing, it will be counted as “Severe”.
Pre-specified AE categories
For AZD8233 there is a set of pre-specified AE categories for which separate outputs will be 
produced. The following AE categories are pre-defined: 

Bleedings: will be identified by MedDRA Haemorrhage SMQ (broad) 

New onset or worsening of diabetes: See below. 

Injection site reactions: will be collected on specific forms where the symptoms of each 
reaction is collected and presented by MedDRA HLT Injection site reactions.

AEs of thrombocytopenia: will be identified by PT/SOC (PTs: Thrombocytopenia, Immune 
thrombocytopenia, Platelet count abnormal, Platelet count decreased and Platelet disorder). 
In addition, tables based on platelet counts will be presented (see details in Section 4.6.3).

Outcome of neurological examinations will be presented.

AEs of hypersensitivity: will be identified by MedDRA Hypersensitivity SMQ (narrow). 
New onset of diabetes
New onset of diabetes mellitus during the study is identified programmatically among patients 
without diabetes mellitus at baseline (for definition, see Section 4.1.7.1).
In the subset of patients without diabetes at baseline, new onset diabetes should be defined to 
have occurred with any of the following:
a) A post-baseline HbA1C ≥6.5%, confirmed by a consecutive HbA1C ≥6.5% (48 
mmol/mol) or a fasting serum glucose ≥126 mg/dL (7.0 mmol/L) with both tests after 
date of first dose of IP, or
b) two consecutive values of fasting serum glucose ≥126 mg/dL (7.0 mmol/L) after date of 
first dose of IP, or
c) addition of a new medication for control of serum glucose after date of first dose of IP, or
d) diabetic treatment emergent adverse events identified by SMQ search 
(Hyperglycemia/new onset of diabetes mellitus).
If more than one of the above criteria are met, the earliest date will be considered as the onset 
date of the event of new onset of diabetes mellitus.  


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Worsening of diabetes
Worsening of diabetes mellitus during the study is identified programmatically among patients 
with diabetes mellitus at baseline (for definition, see Section 4.1.7.1).
a) Absolute increase in HbA1c from baseline of > 0.5% (5.5 mmol/mol) after first dose of 
IP, and/or
b) addition of a new antidiabetic medication or an increase in dose of current antidiabetic 
therapy after first dose of IP, and/or
c) diabetic treatment emergent adverse events identified by SMQ search 
(Hyperglycemia/new onset of diabetes mellitus).
4.6.2.2
Presentation
The number and percentage of subjects with AEs,  the Kaplan-Meier estimate at Day 197, 
difference in Kaplan-Meier estimate at Day 197 between treatment groups and 95% CIs, and 
HRs ad 95% CIs will be tabulated. Unless otherwise specified, summaries of AEs will be 
presented for subjects in the safety analysis set, by actual treatment group, for both the on-study 
and on-treatment period. Percentages will be calculated with number of subjects in the analysis 
set as denominator, and subjects will only be counted once per category, regardless of the 
number of AEs satisfying each condition. Tables where AEs are presented by SOC, HLGT, HLT 
and PT, will be sorted by international order for SOC and alphabetical order for HLGT, HLT, 
and PT.
The following summaries will be presented: 
Overall summary of AEs 
Number of subjects with any AE, any AE with outcome of death, any serious AE, any AE 
leading to discontinuation of IP, any AE leading to interruption of IP, any AEs leading to 
interruption of IP and the subject subsequently discontinues IP, any AE possibly related to IP. 
Number and percentage of subjects by treatment group, and comparative measurements based on 
survival analysis will be presented. 
For each pre-specified AE category, an overall summary of AEs will be presented for the on-
study period and the on-treatment period.
An overall summary of AEs by ADA response (positive/negative) as defined in Section 4.5 will 
be presented.


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By SOC, HLGT, HLT and PT
Separate AE tables by SOC, HLGT, HLT and PT will be provided for: Any AE, possibly related 
AEs, AEs by maximum intensity, SAE with outcome death, Any SAE, AEs leading to 
discontinuation of IP, AEs leading to interruption of IP and the subject subsequently discontinues 
IP and pre-specified AE categories as relevant. New onset or worsening of diabetes will be 
presented by criteria, including by SOC, HLGT, HLT and PT for the AE criteria. 
For each treatment group the number, percentage of subjects, and comparative measurements 
based on survival analysis. 
Most common AEs
A table of number and percentage of subjects with most common AEs (≥ 2%) by PT will be 
presented.
Most common non-serious AEs 
A table of non-serious AEs occurring in more than 5% of subjects in any treatment group will be 
presented.
Key subject information
Key subject information will be presented for subjects with AEs with outcome of death, SAEs, 
and AEs leading to discontinuation of IP.
Summary of injection site reactions
A table presenting number of subjects with Any, 1, 2, 3, 4, 5, and > 5 ISR AEs, symptoms and 
location of ISR and maximum diameter will be presented.
Listings
An AE listing will cover details for each individual AE, a separate listing will be presented for 
ISRs. 
A listing of outcomes of neurological examinations for subjects with at least one abnormal 
outcome during the on-study period will be presented. 
An AE listing for all randomised subjects who received at least one dose of incorrect IP will be 
presented, the listing will include AE onset date and date of treatment switch. 
An AE listing for each individual AE in ADA positive subjects as defined in Section 4.5 will be 
presented. An AE listing for each individual AE in subjects with elevated complement activation 
panel factors (defined as C5a or Bb > ULN) at any time during the on-study period will be 
presented. 


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Narratives
Narratives will be produced for all deaths, SAEs and AEs leading to permanent discontinuation 
of IP. In addition, narrative will be produced for patients with ALT > 3 x ULN and AEs of 
bleedings, thrombocytopenia and injection site reactions of moderate or severe intensity. 
4.6.3
Clinical Laboratory, Blood Sample
4.6.3.1
Definitions and Derivations
Blood samples for determination of clinical chemistry, haematology and coagulation will be 
collected according to the schedule of activities according to Section 1.3 of the CSP. Clinical 
Safety Laboratory Assessments are listed in Appendix 7.2 of the SAP. 
Subjects with clinical chemistry, haematology and coagulation parameters abnormalities will be 
defined according to non-mutually exclusive thresholds based on reference ranges from the 
central lab, where applicable. In addition, the following definitions of laboratory abnormalities 
will be used for specific parameters:

Platelet count will be categorised by the following, non-mutually exclusive thresholds: 
< 50, < 75, < 100, < 150 x 109/L, and > 30% decrease from baseline

Creatine kinase (CK) elevations will be categorised by the following, non-mutually 
exclusive, thresholds: > 5 x ULN, > 10 x ULN and > 20 x ULN.

Hepatic safety laboratory parameter elevations will be categorised by the following, non-
mutually exclusive, thresholds:
o
ALT: > 1 x ULN, > 3 x ULN, > 5 x ULN, > 10 x ULN, > 20 x ULN
o
AST: > 1 x ULN, > 3 x ULN, > 5 x ULN, > 10 x ULN, > 20 x ULN
o
Alkaline Phosphatase: > 2 x ULN, > 3 x ULN
o
Total Bilirubin (TBL): > 2 x ULN, > 5 x ULN, > 8 x ULN
o
Direct Bilirubin: > 2 x ULN, > 5 x ULN

International normalised ratio (INR) will be categorised by the following, non-mutually 
exclusive, thresholds: > 1.5 x ULN, > 3 x ULN, > 5 x ULN.

Renal safety laboratory parameter worsening will be assessed for eGFR and Creatinine. 
Percent change from baseline in eGFR will be categorised by the following, non-
mutually exclusive, thresholds: ≥25% decrease, ≥50% decrease and ≥75% decrease. 


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Creatinine will be categorised by the following, non-mutually exclusive thresholds: ≥1.5 
x baseline, ≥2 x baseline and ≥3 x baseline. 
The risk difference B = CD −CE is defined as the difference in proportions between AZD8233 
treatment group CD and placebo group CF. The 95% CI for the risk difference is given by 
CD −CF ± H ⋅JCD ⋅(1 −CD)
D
+ CF ⋅(1 −CF)
F
where D, F represent the number of subjects in AZD8233 and placebo group, respectively, and 
z is the 1 −
K
5 quantile of the standard normal distribution where L = 0.05.
In shift tables, all parameters will be categorized according to the following mutually exclusive 
categories based on central laboratory ranges (when applicable): Low (< LLN), Normal (≥LLN 
and ≤ULN), High (> ULN). In addition, platelet count will be categorised according to 
categories : < 50, ≥50 and < 75,  ≥75 and < 100, ≥100 and < 150, and ≥150 x 109/L. 
Potential Hy’s law is defined as AST ≥3 x ULN or ALT ≥3 x ULN and Total 
bilirubin ≥2 x ULN, where at least one time Total bilirubin ≥2 x ULN occurred on or after the 
date of the first occurrence of ALT ≥3 x ULN or AST ≥3 x ULN and on or after the date of first 
administration of IP.
Assessed values of the form ‘<x’ (below the lower limit of quantification) or ‘>x’ (above the 
upper limit of quantification will be imputed as ‘x’ in the calculations of summary statistics but 
displayed as ‘<x’ or ‘>x’ in listings. 
4.6.3.2
Presentations
All laboratory data will be presented during the on-study period, for the safety analysis set and in 
SI or conventional units.
Clinical laboratory parameters will be presented by treatment group and scheduled visit, 
separately for haematology, chemistry and coagulation parameters. All parameters will be 
presented as continuous variables with descriptive statistics for all visits at which an assessment 
is scheduled. Observed value, absolute change and relative change from baseline will be 
presented using descriptive statistics for all scheduled assessments after baseline. 
The number of subjects with treatment-emergent laboratory parameter abnormalities will be 
presented categorically by treatment group, alongside risk differences with 95% CIs for each 
category of elevation, according to the categories defined in Section 4.6.3.1. Safety laboratory 


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parameter abnormality categories are cumulative and subjects will be included in all categories 
for which they have a qualifying assessment during the on-study period. 
Key subject information will be presented for subjects with haematology abnormalities, 
chemistry abnormalities, or potential Hy’s law in separate tables. 
Shift tables from baseline to maximum and minimum value during the on-treatment period will 
be presented, by treatment group, according to the mutually exclusive categories defined in 
Section 4.6.3.1.
The empirical cumulative distribution function within each treatment group of change from 
baseline to the minimum platelet count measurement after first dose of IP will be presented in a 
figure. Time course of recovery of platelet counts after thrombocytopenia will be displayed by 
spaghetti plots showing platelet count by visit for subjects with <150 x 109/L or with decrease 
from baseline >30% at any time during the on-study period.
Subjects with CK elevations will be presented categorically by treatment group. For subjects 
meeting the criteria for CK elevations, an AE listing for each individual AE will be produced and 
CK values over time will be presented in a Spaghetti plot.
For subjects with eGFR worsening, the eGFR values over time will be presented in a Spaghetti 
plot.
A descriptive table for maximum on-treatment ALT and AST versus maximum on-treatment 
bilirubin for each treatment group in the safety analysis set will be shown. 
Coagulation parameter results will further be presented as a cross table with number and 
percentages in categories Low (< LLN), Normal (≥LLN and ≤ULN), High (> ULN), by 
treatment group for baseline versus each scheduled post-baseline visit. 
A listing including variables, such as assessment date and value, change from baseline, LLN, 
ULN, reference range indicator will be created. Percentages will be calculated with number of 
subjects with available assessment at each visit as denominator.
Parameters will be presented in alphabetical order.
4.6.4
Clinical Laboratory, Urinalysis
4.6.4.1
Definitions and Derivations
Urinalysis (dipstick), urinalysis (positive dipstick) and urine renal safety biomarkers will be 
taken according to the schedule of activities according to Section 1.3 of the CSP. Clinical Safety 
Laboratory Assessments are listed in Appendix 7.2. 


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Subjects with treatment emergent urinalysis parameter abnormalities in quantitative parameters 
will be defined according to the non-mutually exclusive thresholds based on central laboratory 
ranges (when applicable): < LLN, > ULN. 
Assessed values of the form ‘<x’ (below the lower limit of quantification) or ‘>x’ (above the 
upper limit of quantification will be imputed as ‘x’ in the calculations of summary statistics but 
displayed as ‘<x’ or ‘>x’ in listings. 
4.6.4.2
Presentations
Clinical laboratory parameters for urinalysis will be presented for the safety analysis set by 
treatment group and scheduled visit, separately for urinalysis parameters and urine renal safety 
biomarkers parameters. All parameters will be presented with descriptive statistics for all visits at 
which an assessment is scheduled. Absolute change from baseline will be presented for 
continuous variables using descriptive statistics for all scheduled assessments after baseline. 
Shift tables from baseline to maximum and minimum value during the on-treatment period will 
also be presented.
Parameters will be presented in alphabetical order.
4.6.5
Vital Signs
4.6.5.1
Definitions and Derivations
Vital signs (weight, height, systolic and diastolic blood pressure, pulse and temperature) will be 
performed at the time points specified in the SoA in the CSP.
4.6.5.2
Presentations
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will be 
presented for observed values and change from baseline.
4.6.6
Electrocardiogram
4.6.6.1
Definitions and Derivations
ECG assessment is limited to overall ECG evaluation, i.e. normal, abnormal not clinically 
significant and abnormal clinically significant.
4.6.6.2
Presentations
ECG results will be presented as a cross table with number and percentages, by treatment group 
for baseline versus each scheduled post-baseline visit. Frequency tables will show the 
interpretation of the ECG reading (normal, abnormal - clinically not significant, abnormal -
clinically significant) at each timepoint. Change from baseline to last on-treatment value will be 
presented in shift tables for the overall ECG evaluation.


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4.6.7
Other Safety Assessments
4.6.7.1
Definitions and Derivations
Other laboratory measurements are composed of complement activation panel (Bb, C5a), high-
sensitivity C-reactive protein (hs-CRP).
4.6.7.2
Presentations
Measurements will be presented in the same way as blood samples in Section 4.6.3.2.
Results will further be presented as a cross table with number and percentages in categories Low 
(< LLN), Normal (≥LLN and ≤ULN), High (> ULN), by treatment group for baseline versus 
each scheduled post-baseline visit when applicable.
For subjects with C5a elevations, the C5a and Bb values over time will be presented in a 
Spaghetti plot. For subjects with Bb elevations, the Bb values over time will be presented in a 
Spaghetti plot.
5
INTERIM ANALYSIS
Interim Analysis is not planned for this study.
6
REFERENCES
[Crooke 2017] The Effects of 2'-O-Methoxyethyl Containing Antisense Oligonucleotides on 
Platelets in Human Clinical Trials. Nucleic Acid Ther. 2017; 27:121-129. 
[Friedewald 1972] Estimation of the concentration of low-density lipoprotein cholesterol in 
plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499-502. 
[Martin 2013] Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-
Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile. JAMA. 2013; 19:2061-
2068.
[Martin 2018] Comparison of Low-Density Lipoprotein Cholesterol Assessment by 
Martin/Hopkins Estimation, Friedewald Estimation, and Preparative Ultracentrifugation. JAMA 
cardiology. 2018; 8: 749-753.


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7
APPENDIX
7.1
Missing data handling: MI-RD and placebo-washout imputation 
sensitivity analysis
For cases when baseline values are missing, the baseline values will be imputed by the mean 
value of baseline. For post-baseline missing LDL-C values, a distinction in the imputation will 
be made between non-monotone and monotone missing data. Monotone missing data are defined 
on a subject level as missing data that constitutes the end of subject follow-up, while non-
monotone missing data means that observations exist after the time point with the missing data. 
The steps of the imputation algorithm is described in Table 5.
Table 5 ANCOVA missing data imputation algorithm
Step
Description 
Step 1
Impute non-monotone missing 
data
Impute all non-monotone missing data using the Markov chain 
Monte Carlo (MCMC) method assuming missing data are missing 
at random (MAR). This is performed using PROC MI in SAS, 
stratified by treatment group, with the IMPUTE=MONOTONE and 
CHAIN=MULTIPLE options in the MCMC statement. The 
imputation model will include baseline LDL-C and all scheduled 
post-baseline LDL-C assessments in chronological order. In this 
step, 1000 imputation datasets will be generated using the seed 
674752, each of which will now solely contain missing data of the 
same monotone pattern.
Step 2
Impute monotone missing data
For each of the 1000 imputed datasets, impute all monotone missing 
LDL-C data sequentially using the pattern mixture model assuming 
missing data are missing not at random (MNAR) with the seed 
6747521. The preferred method of imputation will be to use MI-
RD, where imputation of missing data will be performed after 
stratifying for each combination of treatment group and on-
treatment status. To impute missing data at Time t, subjects are 
categorised as either as on-treatment (= subject for whom Time t is 
during the on-treatment period), or as treatment discontinuers (= 
subject for whom Time t is outside the on-treatment period).  
The pattern mixture model imputation with a predictive mean 
matching model is preformed using PROC MI in SAS with the 
MONOTONE statement set to the REGPMM option. The statement 
is repeated sequentially for each measured timepoint, including 
baseline value and all previous timepoints. Subjects who had 


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missing data imputed at previous timepoints will contribute to the 
imputation for the current timepoint.
Step 3
Fit ANCOVA models
Fit the pre-specified ANCOVA model to each imputed dataset, each 
now without any missing data, using PROC MIXED and store the 
1000 resulting least square mean estimates for each treatment group 
and the difference between treatment groups, and corresponding 
standard errors for each model.
Step 4
Pool ANCOVA model estimates
Pool results using Rubin’s rules in PROC MIANALYZE in SAS to 
provide the final least square mean estimates, 95% CIs, and p-value 
for the difference between treatment groups.
This MI-RD approach described in Step 2 in Table 5 will be used as long as the number of 
retrieved dropouts for each combination of treatment group and on-treatment status is sufficient 
to construct imputation models. The distribution of missing data, number and proportions, 
according to each missing data pattern will be summarised per treatment group.  
If MI-RD cannot be used due to an insufficient number of retrieved dropouts, missing data at the 
end of Week 28 in the placebo group will be replaced based on subjects in the same group using 
standard MI and assuming missing at random, including baseline value and observations 
between baseline and the end of Week 28 in the imputation model. Missing values in the active 
treatment group will be replaced by washout multiple imputation. In washout multiple 
imputation, the end of Week 28 data are imputed based on observed values in the placebo group 
only, including baseline value in the imputation model but not accounting for any observations 
after baseline. A total of 1000 datasets will be imputed. The seed for imputing non-monotone 
missing data will be the same as in the MI-RD analysis (i.e., 674752). For the imputation of 
monotone missing data, seed 101010 will be used for the placebo group and seed 201010 will be 
used for the AZD8233 group.
7.2
Laboratory Safety Variables
Laboratory measurements according to Section 8 of the CSP:
Table 6 Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
White blood cell (WBC) count
Sodium
Red blood cell (RBC) count
Potassium
Haemoglobin (Hb) 
Blood urea nitrogen (BUN)
Haematocrit (HCT)
Creatinine
Mean-corpuscular volume (MCV)
Calcium


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Mean corpuscular haemoglobin concentration (MCHC)
Phosphate
Neutrophils absolute count
Creatine kinase (CK)
Lymphocytes absolute count
Direct bilirubin
Monocytes absolute count
Alkaline phosphatase (ALP)
Eosinophils absolute count
Alanine aminotransferase (ALT)
Basophils absolute count
Aspartate aminotransferase (AST)
Platelets absolute count
Gamma glutamyl transpeptidase (GGT)
Reticulocytes absolute count
Total bilirubin (TBL)
Glutamate dehydrogenase (GLDH)
Urinalysis (dipstick)
Bicarbonate
Urinalysis (positive dipstick)
Uric acid
pH
Follicle stimulating hormone (FSH[women only])
Specific gravity
Luteinising hormone (LH) (women only)
Glucose
haemoglobin A1c, glycated haemoglobin  
(HbA1c)
Blood
p-glucose
Colour
Estimated glomerular filtration rate (eGFR) by 
CKD-EPI formula)
Protein
Clarity/Appearance
Coagulation
Nitrites
Prothrombin time 
Ketones
Activated partial thromboplastin time (aPTT)
Leukocytes
International normalised ratio (INR)
Microscopic analysis (if positive for blood, nitrites or 
protein)
Urobilinogen
Urine renal safety biomarkers
Albumin
Other Laboratory Assessments
Total protein
Complement activation panel (Bb, C5a)
Creatinine
High-sensitivity C-reactive protein (hs-CRP)
Urine protein to creatinine ratio (UPCR)
Urine albumin to creatinine ratio (UACR)


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