A Phase II Randomized, Double-blind Study to Evaluate the Safety, Neutralizing Activity and Efficacy of AZD3152 for Pre-exposure Prophylaxis of COVID-19 in Participants Having an Increased Risk for Inadequate Response to Active Immunization (NOVELLA)
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Cli nic al St u d y Pr ot oc ol
St u d y I nter ve nti o n
A Z D 3 1 5 2
St u d y C o de
A Z -R U - 0 0 0 0 2
Ve rsi o n
3. 0
Date
0 2 A u g 2 0 2 3
A P h ase II R a n d o mize d , D o u ble-bli n d St u d y t o E v al u ate t he S afet y , Ne utr alizi n g 
Acti vit y a n d Effic ac y of A Z D 3 1 5 2 f or P re- e x p os ure Pr o p h yl a xis of C O VI D-1 9 i n 
P artici p a nts h a vi n g a n I ncre ase d Ris k f or In a de q u ate Res p o nse t o Acti ve I m m u niz ati o n
(N O V E L L A)
S p o ns or  N a me: Astr a Ze nec a P h ar m ace utic als L L C
Le gal Re gistere d A d dress: B uil di n g 1, 2 1, First Kras n o g var de ys ki y la ne, fl o or 3 0, r o o ms 1 3 
a n d 1 4, M osc o w, R ussia n Fe deratio n
T his C li 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 blic l 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 b al P olic y o n Bi o e t 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.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 of 9 4
P r ot oc ol N u m ber: A Z -R U - 0 0 0 0 2
A me n d me nt N u m ber: 3. 0
St u d y  Int er ve nt i on: A Z D 3 1 5 2 , a n o vel m o n ocl o n al  ant i b o d y (m A b ) a gai nst S A R S -C o V - 2 or 
p lace b o 
St u d y  P hase: II
Title: A P h ase II Ra n d o mize d, D o u ble -bli n d St u d y  t o E val uate t he Safet y, Ne utralizi n g Acti vit y 
a n d Ef ficac y of  A Z D 3 1 5 2 f or Pre -e x p os ure Pr o p h yla xis of  CO VI D - 1 9 i n Parti ci pa nts ha vi n g 
a n I ncrease d Ris k f or I na de q uate Res p o nse t o Acti ve I m m u nizat i on
A c r o n y m: N O V E L L A
St u d y P h ysici a n / C o or di n ati n g I n vesti g at or / Pri nci p al I n vesti g at ors N a me a n d C o nt act 
I nf or m ati o n will be pro vi de d se p ar atel y
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 of 9 4
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
C S P Versi o n 3. 0
1 7- J ul- 2 0 2 3
C S P Versi o n 2. 0
1 4- J u n- 2 0 2 3
O ver all R ati o n ale f or t he M o dific ati o n:
T he pr ot oc ol  has bee n a me n de d pri maril y t o c ha n ge t he c o mparat or fr o m (acti ve) A Z D 7 4 4 2
( E V U S H E L D) t o place b o. T hi s c ha n ge was i nitiate d t o b ri n g t he desi g n of  the l ocal st u d y in 
li ne wi t h the rece nt c ha n ges i n t he Mai n 
C o h ort of  on g oi n g P hase I/III gl o bal st u d y 
( S U P E R N O VA, N C T 0 5 6 4 8 1 1 0). C o m parati ve e val uat i on wi t h place b o is t he m ost i nf or mati ve 
a n d a p pr o priate o pti o n at t he c urre nt sta ge of c li nical de velo p me nt pr o gra m .
A s u m mar y of c ha n ges is prese nte d bel o w. W here a p plica ble, t he c ha n ges were als o a p plie d t o 
t he s y n o psis.
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Secti o n N u m ber a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
ra n d o mizati o n) s ho ul d be re p orte d as a n 
A E
9. 4. 3 Safet y
N ote d t hat t he m ost rece nt versi o n of 
Me d D R A
will o nl y be use d w h ere p ossi ble
C o nti n ge nc y, as i t ma y n ot al wa ys be 
p ossi ble t o use t he latest versi o n
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 of 9 4
T A B L E O F C O N T E N T S
1
P R O T O C O L  S U M M A RY ................................................................................1 0
1. 1
S y n o psis ...........................................................................................................1 0
1. 2
Sc he ma .............................................................................................................1 4
1. 3
Sc he d ule of Act i vities .......................................................................................1 4
1. 3. 1
Scree ni n g, Treat me nt a n d F o ll ow- u p Act i vities.................................................1 6
2
I N T R O D U C TI O N ............................................................................................1 9
2. 1
St u d y  Ratio nale ................................................................................................1 9
2. 2
Bac k gr o u n d ......................................................................................................2 0
2. 2. 1
Se vere Ac ute Res pirat or y S y n dr o me C or o na vir us 2 I nfect i on a n d Disease ........2 0
2. 2. 2
A Z D 5 1 5 6, A Z D 3 1 5 2 a n d E V U S H E L D ............................................................2 1
2. 3
Be nefit/ Ris k Assess me nt ...................................................................................2 5
2. 3. 1
Ris k Assess me nt ...............................................................................................2 5
2. 3. 2
Be nefit Assess me nt ...........................................................................................2 6
2. 3. 3
O verall Be nefit: Ris k C o ncl usi o n ......................................................................2 6
3
O BJ E C TI V E S A N D E N D P O I N T S ...................................................................2 7
4
S T U D Y  D E SI G N .............................................................................................3 0
4. 1
O verall Desi g n ..................................................................................................3 0
4. 2
S ci e nt ific Rati o nale f or St u d y Desi g n ...............................................................3 1
4. 2. 1
Rati o nale f or St u d y  P o p ulat i on .........................................................................3 2
4. 3
J ustificati o n f or D ose........................................................................................3 3
4. 3. 1
J ustificati o n f or A Z D 3 1 5 2 D ose ........................................................................3 3
4. 3. 2
J ustificati o n f or Place b o....................................................................................3 3
4. 4
E n d of St u d y  Defi niti on ....................................................................................3 3
5
S T U D Y  P O P U L ATI O N ....................................................................................3 4
5. 1
I ncl usi on Cri t eria ..............................................................................................3 4
5. 2
E xcl usi o n Cri t eria .............................................................................................3 6
5. 3
Li festyle C o nsi derat i ons ...................................................................................3 7
5. 4
Scree n Fail ures ................................................................................................. 3 7
6
S T U D Y  I N T E RV E N TI O N ...............................................................................3 7
6. 1
St u d y  I nter ve nti on(s) A d mi nistere d ...................................................................3 7
6. 1. 1
I n vesti gati onal Pr o d ucts ....................................................................................3 7
6. 2
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...................................................3 9
6. 3
Meas ures t o Mi ni mise Bias: Ra n d o mizati o n a n d Bli n di n g ................................4 0
6. 3. 1
Ra n d o mizati o n ..................................................................................................4 0
6. 3. 2
Bli n di n g ............................................................................................................4 0
6. 3. 3
Pr oce d ures f or U n bli n di n g ................................................................................4 1
6. 4
St u d y  I nter ve nti on C o m plia nce .........................................................................4 1
6. 5
C o nc o mita nt T hera p y ........................................................................................4 1
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
6. 6
D ose M o dificat i on ............................................................................................4 3
6. 7
I nter ve nti o n After t he E n d of t he St u d y.............................................................4 3
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 3
7. 1
Di sc o nti n uatio n of  St u d y I nter ve nti on ...............................................................4 3
7. 2
P arti cipa nt W ith dra wal fr om t he St u d y..............................................................4 4
7. 2. 1
St o p pi n g R ules ..................................................................................................4 5
7. 3
L ost t o F oll o w u p ..............................................................................................4 5
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 5
8. 1
Ef ficac y Assess me nts........................................................................................4 6
8. 1. 1
S A R S -C o V -2 Ne utralizi n g A nt i b o d y Assess me nts ............................................4 6
8. 1. 2
P arti cipa nt -re p orte d C O VI D-1 9 S y m pt o ms .......................................................4 6
8. 2
S af et y Assess me nts ...........................................................................................4 7
8. 2. 1
P h ysical E xa mi nat i ons ......................................................................................4 7
8. 2. 2
Vit al Sig ns........................................................................................................ 4 7
8. 2. 3
Electr ocar di o gra m .............................................................................................4 7
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts............................................................4 8
8. 2. 5
Ot her Safet y As sess me nts .................................................................................4 9
8. 2. 5. 1
I mme diate A d verse E ve nts ................................................................................4 9
8. 2. 5. 2
I njecti on Si te Reactio ns .................................................................................... 4 9
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................................5 0
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 ................5 0
8. 3. 2
F o ll ow- u p of  A Es a n d S A Es .............................................................................5 0
8. 3. 3
Ca usalit y C o llecti on ..........................................................................................5 1
8. 3. 4
A d verse E ve nts of S pecial I nterest ....................................................................5 1
8. 3. 5
Me dicall y  Atte n de d A d verse E ve nts..................................................................5 2
8. 3. 6
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ................................................5 2
8. 3. 7
A d verse E ve nts Base d o n E xa mi nat i ons a n d T ests ............................................5 2
8. 3. 8
H y ’s La w ..........................................................................................................5 3
8. 3. 9
Re p orti n g of Seri o us A d verse E ve nts ................................................................5 3
8. 3. 1 0
Pre g na nc y .........................................................................................................5 4
8. 3. 1 0. 1
Mater nal E x p os ure ............................................................................................5 4
8. 3. 1 1
Me dicat i on Err or , Dr u g A b u se, a n d Dr u g Mis use ..............................................5 4
8. 3. 1 1. 1
Ti meli nes ..........................................................................................................5 4
8. 3. 1 1. 2
M e dicat i on Err or ...............................................................................................5 5
8. 3. 1 1. 3
Dr u g A b use .......................................................................................................5 5
8. 3. 1 1. 4
Dr u g Mi s use .....................................................................................................5 5
8. 4
O ver d ose ..........................................................................................................5 5
8. 5
H u m a n Biol o g ical Sa m ples...............................................................................5 6
8. 5. 1
S A R S -C o V -2 Ser ol o g y  Assess me nts................................................................. 5 6
8. 5. 2
S A R S -C o V -2 Ne utralizi n g A nt i b o dies ..............................................................5 6
8. 5. 3
E x pl or at or y  a nal ysis ser u m sa m ple ...................................................................5 6
8. 5. 4
P har mac o d y na mics ...........................................................................................5 6
8. 5. 5
Vir ol o gic Assess me nts ......................................................................................5 6
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
8. 6
O pti o nal  Ge n o mics I nit iati ve Sa m ple................................................................5 7
8. 7
Me dical Res o urce Utilizat i on a n d Healt h Ec o n o mics ........................................5 7
9
S T A T I S TI C A L C O N SI D E RA T I O N S................................................................5 7
9. 1
Stati stical H y p ot heses.......................................................................................5 7
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 9
9. 4. 2
E n d p oi nts ..........................................................................................................5 9
9. 4. 2. 1
Pri mar y E n d p o i nt..............................................................................................5 9
9. 4. 2. 2
Sec o n dar y  E n d p oi nt(s)......................................................................................5 9
9. 4. 2. 3
E x pl or at or y  E n d p oi nt(s)....................................................................................6 0
9. 4. 3
S af et y ...............................................................................................................6 1
9. 5
I nteri m A nalyses ...............................................................................................6 2
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 3
1 1
R E F E R E N C E S ................................................................................................. 9 1
LI S T O F FI G U R E S
Fi g ure 1
St u d y  Desi g n...........................................................................................1 4
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of Act i vities..............................................................................1 6
Ta ble 2 
Assess me nt of a nt i viral acti vity of  cil ga vi ma b, ti xa ge vi ma b, A Z D 3 1 5 2, 
A Z D 5 1 5 6 a n d E V U S H E L D i n a pse u d o vir us ne utralizat i on assa y ...........2 3
Ta ble 3 
List of c o m plete d, o n g oi n g a n d pla n ne d cli nical trials ..............................2 4
Ta ble 4
O bject i ves a n d E n d p oi nts.........................................................................2 7
Ta ble 5                I n vesti gati o nal Pr o d ucts ...........................................................................3 8
Ta ble 6
Per mi tte d, Restricte d, a n d Pr o hi bite d Me dicat i ons ...................................4 2
Ta ble 7
La b orat or y  S afet y Varia bles .....................................................................4 8
Ta ble 8
P o p ul at i ons f or A nal ysis ..........................................................................5 8
Ta ble 9 
A n A p pr oac h t o Ma na ge me nt of A na p h ylact ic, H y perse nsitivit y, a n d 
P os t-i njecti on React i ons ...........................................................................8 3
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 4
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 6
A p pe n di x D
Act i ons Re q uire 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 ...........................................................................7 8
A p pe n di x E
A na p h yla xis .............................................................................................8 3
A p pe n d i x F
A b bre viat i ons ..........................................................................................8 6
A p pe n di x G
F or ms of Earl y  S af et y Data Re vie w ( E S D R) D ecisi o n b y t he Safet y 
Assess me nt C o m mittee i n t he S U P E R N O V A St u d y ................................8 9
A p pe n di x H
Pr ot oc ol  Versio n Hist or y .........................................................................9 0
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
E n d p oi nts:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P o p ul ati o n:
E n d p oi nt:
 
 
 
 
 
I nterc urre nt e ve nts:
 
 
 
 
 
 
 
 
 
S u m m ar y me as ure:
 
 
A E = a d verse e ve nt; A E SI = a d verse e ve nt of s pecial i nterest; CI = c o nfi de nce i nter val; G M F R = ge o metric mea n 
f ol d rise; G M T = ge o metric mea n titer; g S D = ge o metric sta n dar d de viati o n; I M P = i n vesti gati o nal me dici nal 
pr o d uct; M A A E = me dicall y atte n de d a d verse e ve nt; n A b = ne utralizi n g a nti b o d y; R T -P C R = re verse tra nscri pti o n 
p ol y merase c hai n reacti o n; S A E = seri o us a d verse e ve nt; S A R S -C o V - 2 = se vere ac ute res pirat or y sy n dr o me 
c or o na vir us 2; W H O = W orl d Healt h Or ga nizati o n
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 of 9 4
O ver all Desi g n
T his is a P hase II st u d y t hat will be c o n d ucte d i n a p pr o xi matel y 1 1 6 part ici pa nts t o e val uate t he 
safety, ne utralizi n g act i vity a n d efficac y of  A Z D 3 1 5 2 . 
P arti cipa nts will be ra n d o mize d i n a 3 : 1 r atio t o recei ve A Z D 3 1 5 2 ( 3 0 0 m g , 2 mL) or place b o 
( 2 m L) a d mi nistere d I M i n t he a nter olateral t hi g h.
St u d y  i nter ve nti on w ill be ha n dle d b y a n u n bli n de d p har macist ( or desi g nee, i n acc or da nce with 
i nstituti o nal  re g ulat i ons) at t he st u d y site w h o will be i n de pe n de nt of  safet y e val uat i ons a n d 
ot her tri al e v alu ati o ns.
If, fol l owi n g st u d y  i nter ve nti on a d mi nistrati o n, a s u bject de vel o ps C O VI D -1 9, acc or di n g t o t he 
Pr o visi o nal rec om me n dat i ons o n t he met h o ds f or pre ve nt i on, dia g n osis a n d treat m e nt of no vel 
c or o na vir us i nfecti o n ( C O VI D -1 9), iss ue d b y t he Mi nistr y o f Health of t he R ussia n Fe derati o n, 
versi o n 1 7 date d Dece m ber 1 4 , 2 0 2 2 ( Pr o visio n al rec o m me n datio ns 2 0 2 2) (s) he m u st call “ 1 2 2” 
t o be visite d b y a healt hcare pr ofessi o nal w h o, a m o n g ot her pr oce d ures, will perf or m a C O VI D -
1 9 test. O nce a visit b y a healt hcare pr ofessi o nal has bee n re q ueste d, t he s u bject m u st n otif y t he 
st u d y d oct orof  the date s y m pt o ms occ urre d a n d t he date a healt hcare p r ofessio n al visit has bee n 
re q ueste d, as s o o n as p ossi ble. Als o, o nce a test res ult is a vaila ble, t he parti ci pa nt m ust re p ort 
wi t hi n 3 da ys t he d at e of  t est a nd its res ult t o t he I n vesti gat or. If t he test res ult is p osi ti ve, t he 
I n vesti gat or ( or his/ her de le gate, acc or di n g t o t he l ocal re g ulat i ons a n d i nstituti o n g ui deli nes) 
will ma ke tele p h o ne calls every t hree d ays t o c ollect safety data u ntil t he s u bject i nf or ms a b o ut 
his/ her rec o ver y .
Discl os ur e St ate me nt :
T his is a parallel gr o u p, safet y, ne utralizi n g acti vit y a n d efficac y e val uat i on st u d y.
N u m ber of P artici p a nts:
I n t otal, a p pr o xi matel y 8 7 parti cipa nts will be e x p ose d t o a si n gle d os e of  A Z D 3 1 5 2 ( 3 0 0 m g , 
2 m L) I M, a n d 2 9 partici pa nts will be e x p ose d t o a si n gle d ose of pl ace b o ( 2 mL) I M.
I nter ve nti o n Gr o u ps a n d D ur ati o n :
Si n gle d ose of A Z D 3 1 5 2 ( 3 0 0 m g , 2 m L) I M or place b o ( 2 m L) I M.
T he d urati o n of  eac h parti ci pa nt ’s i n v ol ve me nt i n t he st u d y will be a p pr o xi matel y 6 m o nt hs 
fr om w he n t he st u d y  int er ve ntio n is a d mi nistere d.
St atistic al M et h o ds
Cate g orical varia bles will be prese nte d as fre q ue ncies a n d pr o p orti o ns i n perce nt val ues.  
C o nti n u o us varia bles will be prese nte d as mea n s, ge o metric mea ns ( w here a p plica ble), sta n dar d 
de viat i ons , ge o metri c sta n dar d de viat i ons
( w here a p plica ble), me dia n s, mi ni m u m 
a n d 
ma xi m u m, a n d q uartiles ( w here a p plica ble), wit h n u m ber of  obser vati o ns.
 
 All 
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U -0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 of 9 4
t he varia bles will be descri pt i vel y c om pare d bet wee n treat me nt ar ms.
A n i nteri m a nal ysis is pla n ne d after 1 1 6 partici pa nts ha ve c o m plete d visit 4 ( D a y 2 9 ) t o e val uate 
earl y s af et y a n d efficac y d at a at  Da y 2 9 . 
T his i nteri m a nal ysis will i ncl u de pri mar y e n d p oi nt varia bles: all A Es, S A Es, M A A Es, a n d 
A E SIs
a n d sec o n dar y efficac y e n d p o i nts: n A b res p o nses t o t he S A R S -C o V -2 e mer gi n g 
d o mi na nt varia nt(s) a n d i nci de nce of  sy m pt o matic C O VI D -1 9 cases ( o nl y if at le ast o n e case 
will be re p orte d at time of  data c ut -off ). T hi s i nteri m a nal ysis will be pr o vi de d b y  u n bli n de d
tea m. All t he para meters, al o n g wi t h ot her res ults (di s p ositio n , d e m o gra p hic data etc.) will b e 
pr o vi de d b y  treat me nt ar ms. T he c o m par is o ns bet wee n treat me nt ar ms will be p erf or m e d 
descri pt i vel y.
T he fi nal a nal ysis will be p erf or m e d o n ce all part ici pa nts c o mplete Vi sit 6 ( D a y 18 1) or earl y 
wi t hdra wal  fr o m t he st u d y. 
 
I nteri m a n d fi nal a nal yses will be descri be d i n detail i n t he Stati stical A nal ysis Pla n.
1. 2
Sc he m a
T he st u d y  gr o u ps a n d o verall st u d y desi g n are descri be d i n Fi g ure 1.
Fi g ure 1
St u d y D esi g n
N ote: A n i nteri m a nal ysis is pla n ne d after 1 1 6 partici pa nts ha ve c o m plete d Visit 4 ( Da y 2 9 ). A fi nal a nal ysis will 
occ ur after all partici pa nts ha ve c o m plete d Visit 6 ( Da y 18 1) or ha ve wit h dra w n fro m t he st u d y. T he st u d y will 
mai ntai n a d o u ble -bli n de d (i. e., bli n d f or partici pa nts, I n vesti gat ors/site staff, a n d Astra Ze neca) u ntil t he pri mary 
a nal ysis
1. 3
Sc he d ule of Acti vities
T he st u d y  will c o nsist of 2 peri o ds: a scree ni n g peri o d of u p t o 7 da ys ( Da y -7 t hr o u g h Da y  -1), 
a n d a treat me nt a n d f oll ow- u p p eri o d lasti n g 6 m o nt hs aft er t he a d mi nistratio n  of st u d y 
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 5 of 9 4
i nter ve nt i on (Ta ble 1) .
F or partici pa nts wit h q ualif yi n g s y m pt o ms of  CO VI D -1 9, a d dit i onal t ele p h o ne c o ntacts 
perf or m e d e ver y 3 da ys sh o ul d be i nc or p orate d i n t he sc he d ule.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
1. 3. 1
Scree ni n g, Tre at m e nt a n d F oll o w-u p Acti vities
Ta ble 1
Sc he d ule of Acti vities
Pr oce d ure
Scree ni n g
Tre at me nt a n d F oll o w -u p Peri o d
Visit
Scree ni n g
1
2 
3 
4 
5 
6
E D V
D a y
-7 t o - 1
1
8 
1 5 
2 9 
9 1 
1 8 1
N A
Wi n d o w ( d a ys)
N A
N A
± 3
± 3 
+ 3
± 5 
± 1 4
N A
Writte n i nf or me d c o nse nt
X
Verif y eli gi bilit y criteria
X
X ( pre d ose)
Ra n d o mizati o n
X ( pre d ose)
Me dical hist or y a n d 
de m o gra p hics (i ncl u di n g 
C O VI D - 1 9 vacci ne stat us 
a n d pre vi o us C O VI D - 1 9 
i nfecti o n)
X
F ull p h ysical 
e xa mi nati o n, i ncl u di n g 
hei g ht a n d wei g ht
X
X
Tar gete d p h ysical 
e xa mi nati o n base d o n 
me dical hist or y
X ( pre d ose)
Vital si g ns
X
X a
X
X
X
Ser u m c he mistr y, 
he mat ol o g y, c oa g ulati o n 
(l ocal la b orat or y)
X
X
X
X
Tr o p o ni n , hi g h -se nsiti vit y
test (l ocal la b orat or y)
Х b
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 of 9 4
Pr oce d ure
Scree ni n g
Tre at me nt a n d F oll o w -u p Peri o d
Visit
Scree ni n g
1
2 
3 
4 
5 
6
E D V
D a y
-7 t o - 1
1
8 
1 5 
2 9 
9 1 
1 8 1
N A
Wi n d o w ( d a ys)
N A
N A
± 3
± 3 
+ 3
± 5 
± 1 4
N A
F ollicle sti m ulati n g 
h or m o ne c
Х
HI V test
X
Electr ocar di o gra m 
(si n gle, t o be perf or me d 
l ocall y if feasi ble) d
X
Uri ne pre g na nc y test or 
ser u m β- h C G ( W O C B P 
o nl y)
X
X e
Ra pi d a nti ge n test f or 
S A R S -C o V -2 ( perf or me d 
l ocall y)
X
f 
Wee kl y 
tele p h o ne/e mail/te xt 
c o ntacts-m o nit ori n g f or 
safet y a n d C O VI D- 1 9 
q ualif yi n g s y mpt o m
−−−−−−−−−−−−−−−−X −−−−−−−−−−−−−−−−
Assess me nt of A Es
X
X
Assess me nt of S A Es,
M A A E s, a n d A E SIs
X ( S A Es)
X ( o n g oi n g o bser vati o n a n d q uesti o ni n g)
X
C o nc o mita nt me dicati o ns
X
X ( o n g oi n g o bser vati o n a n d q uesti o ni n g)
X
 
X ( pre d ose)
X  
X  
X
X
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 of 9 4
Pr oce d ure
Scree ni n g
Tre at me nt a n d F oll o w -u p Peri o d
Visit
Scree ni n g
1
2 
3 
4 
5 
6
E D V
D a y
-7 t o - 1
1
8 
1 5 
2 9 
9 1 
1 8 1
N A
Wi n d o w ( d a ys)
N A
N A
± 3
± 3 
+ 3
± 5 
± 1 4
N A
S A R S -C o V -2 n A b ser u m 
sa mple h
X ( pre d ose)
X  
X  
X  
X  
X
X
 
X ( pre d ose)
X  
X  
X
X
St u d y i nter ve nti o n 
a d mi nistrati o n
X
I njecti o n site reacti o n 
m o nit ori n g
X j
X
I m me diate A Еs k
X
a O n d osi n g da y, vital si g ns will be perf or me d pre d ose a n d a gai n a p pr o xi matel y 1 0 t o 1 5 mi n utes after i njecti o n. A n y a b n or mal vital si g ns m ust be re peate d after 
t he partici pa nt has bee n at rest f or at least 5 mi n utes.
b It is acce pta ble f or t his t o be perf or me d o n Da y 1 ( pre d ose) . Test res ults m ust be a vaila ble pr i or t o d osi n g.
c If a p plica ble, f or fe male partici pa nts a ge d < 5 0 years a n d ha ve bee n a me n orr h oeic f or 1 2 m o nt hs a n d c o nsi dere d p ost me n o pa usal f ollicle sti m ulati n g h or m o ne 
test s h o ul d be d o ne bef ore d osi n g .
d - T he I n vesti gat or ma y a d d e xtra 1 2 lea d re sti n g E C G safet y assess me nts if t here are a n y a b n or mal fi n di n gs or if t he I n vesti gat or c o nsi ders it is re q uire d f or a n y 
ot her safet y reas o n.
e Sa m ple uri ne or  ser u m β- h C G pre g na nc y test m ust ret ur n a ne gati ve res ult bef ore d osi n g.
f Sites will be pr o vi de d wit h ra pi d a nti ge n tests t o be d o ne i n partici pa nts at sites bef ore st u d y i nter ve nti o n a d mi nistrati o n at Visit 1. 
h I n eac h ti me p oi nt s h o ul d be c ollecte d 2 ali q u ots eac h 3 m L ( А a n d B), acc or di n g t o I n vesti gati o nal pr o d uct ha n dli n g ma n ual.
i 
.
j Perf or m i m me diatel y, 3 0 mi n utes ( + 1 0 mi n utes) a n d 1 h o ur after i njecti o n, a n d pri or t o partici pa nt release.
k I m me diate A Es will be c ollecte d f or a 1-h o ur o bser vati o n peri o d after st u d y i nter ve nti o n a d mi nistrati o n. 
A E = a d verse e ve nt; A E SI = a d verse e ve nt of s pecial i nterest; E D V = Earl y Disc o nti n uati o n Visit; M A A E = me dicall y atte n de d a d verse e ve nt; N A = n ot a p plica ble; 
n A b = ne utralizi n g a nti b o d y; S A E = seri o us a d verse e ve nt; S A R S-C o V -2 = se vere ac ute res pirat o r y s yn dr o me c or o na vir us 2; W O C B P = w o me n of c hil d beari n g 
p ote ntial ; β-h C G = beta h u ma n c h ori o nic g o na d otr o pi n .
C CI
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
2. 2
B ac k gr o u n d
2. 2. 1
Se vere Ac ute Res pir at or y S y n dr o me C or o n a vir us 2 I nfecti o n a n d 
Dise ase 
C or o na vir us S A R S -C o V - 2 is t he ca usat i ve a ge nt of t he o n g oi n g C O VI D - 1 9 pa n de mic t hat, as 
of  Ma y 3 1 , 2 0 2 3 , has ca use d o ver 7 6 7 milli o n c o nfir me d c as es of C O VI D-1 9, i ncl u di n g m o r e 
t ha n 6. 8 milli o n deat hs, re p orte d t o t he W H O ( W H O 2 0 2 3 ). T he maj orit y o f c or o navir uses ca use 
mil d di sease i n h u ma ns a n d a ni mals; h o we ver, S A R S -C o V -2 ca n re plicate i n t he l ower 
res pir at or y tract t o ca use ac ute res pirat or y distress s y n dr ome a n d fatal p ne u m o nia. 
I n Dece m ber 2 0 2 0, a gl o bal vacci nat i on ca m pai g n was i nitiate d t o pr otect agai nst serio us 
di sease ass o ciate d wit h C O VI D -1 9. Des pite t he r oll o ut of  effecti ve vacci nes, w hic h ha ve 
sig nifica nt l y re d uce d t he m or bi dity a n d m ortalit y ass ociate d wit h S A R S-C o V -2 i nfect i on, t here 
still re mai ns a n u n met me d ical nee d f or t he a p pr o xi matel y 2 % t o 3 % of  the p o p ulati o n w h o  
r e mai n at ris k of  se vere a n d fatal CO VI D -1 9 d ue t o decrease d res p o nse t o c o m p lete acti ve 
i m m u nizati on beca use o f c o n ditio ns/c o m o r bi dities t hat i m pair t he i m m u ne s yste m, res ult i n g i n 
re d uce d i m m u ne f u ncti on ( Al h u mai d et al 2 0 2 1, Har paz et al 2 0 1 6, Maltez o u et al 2 0 2 2, Par ker 
et al 2 0 2 2) or f or w h o m vacci nat i on is n ot s uita ble. S A R S -C o V - 2 m ut at i ons ma y ca use a 
re d uctio n i n efficac y of  curre nt l y a vaila ble m o n ocl o n al ant i b o dies ( mA bs), w hic h is w h y  it is 
parti c ularl y rele va nt t o de vel o p ne w m A bs f or C O VI D - 1 9 pr o p h yla xis f or t he p o p ul at i on of  
hi g h -ris k disease pr o gressi o n t o se vere gra des, d ue t o t he prese nce of c o n diti ons/c o m o r bi dities 
res ultin g i n wea ke ne d i m m u nit y.
Ne utralizi n g m A bs were de vel o pe d a n d de pl o ye d t o pr otect t h ose w h o ha ve a re d uce d i m m u ne 
res p o nse d ue t o c o n dit i ons / c o mor bi di ties affecti n g t he i m m u ne s yste m an d t hose at ris k of  
i na de q uate i m m u ne res p o nse t o vacci nati o n, wi t h de velo p me nt of  se vere C O VI D -1 9. S uc h 
a nt i b o dies act b y i n hi biti n g t he a bilit y of S A R S -C o V - 2 t o e nter h ost cells. C or o na vi r us e ntr y 
i nto h ost cells is me diate d b y t he S A R S -C o V -2 s pik e pr otei n, w hic h f or ms h o m o tri mers 
pr otr u di n g fr om t he vir al surf ace ( H off ma n n et al 2 0 2 0, Wa lls et al 2 0 1 7). T he S A R S -C o V -2 
s pik e pr otei n c o m pr ises 2 f unct i onal s ub u nits res p o nsi ble f or bi n di n g t o t he h ost cell rece pt or 
( S 1 s u b u nit) a n d f usi on of t he viral a n d cell ular me m bra nes ( S 2 s u b u nit). T he distal S 1 s u b u nit  
c o mprises t he R B D a n d c o ntri b utes t o sta bilizati o n of  the pref usi o n state of  the me m br a ne 
a nc h ore d S 2 su b u nit, w hic h c o ntai ns t he f usi on mac hi ner y ( B osc h et al 20 0 3, Li  20 1 6). T h e 
S A R S -C o V -2 s pi ke pr otei n is t he s o le viral me m bra ne pr otei n res p o nsi ble f or cell e ntr y. It bi n ds 
t o t he cell ular rece pt or h u ma n a n gi ote nsi n-c o n verti n g e nz y me 2 o n t he tar get cell a n d me diates 
vir us -cell fusi o n , allo wi n g t he viral ge n o me t o e nter a n d re plicate i n t he cell. T he S A R S -C o V -
2 s pike pr otei n is s urface-e x p ose d a n d n A bs act t hr o u g h di rect tar geti n g of  the s pi ke pr otei n. 
Cli nical st u di es ha ve s h o w n t hat m A bs t hat ne utralize t he s pi ke pr otei n are efficacio us i n b ot h 
t he pr o p h yla xis a n d treat me nt setti n gs (see secti o ns a b o ve f or m o re details) . S uc h class of 
c o mp o u n ds m a y be use d as a s u p ple me nt t o vacci nati o n or ot her met h o ds of pr o p h yla xis.
E ve n wi t h curre nt l y a vaila ble m A bs,
t here is a c o nt i n ue d nee d f or a d ditio nal t o ols t o c o m bat  
C O VI D -1 9 d ue t o t he e mer ge nce of ne w S A R S -C o V -2 varia nts wit h s pi ke pr otei ns c o ntai ni n g 
a mi n o aci d s u bstituti o ns t hat ha ve re d uce d t he ne utralizi n g p ote nc y  of t he m A bs. T his has 
necessitate d c o nti n ue d de vel o p m e nt of  no v el  ant i b o dies t hat retai n ne utralizi n g f u ncti onalit y 
a gai nst V O Cs.
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 2 of 9 4
c o ncer n.
A Z D 3 1 5 2 efficac y f or pre -e x p os ure pr o p h yla xis of C O VI D - 1 9 is s u p p orte d b y t he f oll owi n g 
e vi de nce:

T he mec ha nis m of  act i on a n d P K  of A Z D 3 1 5 2 are si milar t o t hose of  AZ D 7 4 4 2
(E V U S H E L D ).
 
 
 
 
Re p ort o n A Z D 3 1 5 2 p har mac o ki net ics i n tra ns ge nic mice e x pressi n g 
h Fc R n as of J u ne 1 4, 2 0 2 2). B ot h a g e nts bi n d t o t he e pit o p es of R B D o n t h e s pik e 
pr otei n, bl oc ki n g its attac h me nt t o t he h u ma n A C E 2 rece pt or a n d pre ve nt i n g S A R S-
C o V -2 e ntr y, res ult i n g i n its effecti ve ne utralizati on. 

T he n o ncli nical viral ne utralizat i on data a gai nst O micr o n varia nts B A. 1, B A. 1. 1, 
B A. 4/ 5 , B Q. 1, B Q. 1. 1, B F. 7, X B B, a n d X B B. 1 f or A Z D3 1 5 2 are s u perior t o t h ose 
of  E V U S H E L D
(see Ta ble 2). C urre ntl y t he X B B. 1 S A R S -C o V - 2 varia nt is 
pre d o mi na nt i n t he R ussia n Fe derat i on.

E V U S H E L D has d e m o n strate d efficac y i n re d uci n g t he i nci de nce of s y m pt o mat ic 
C O VI D - 1 9 
c o mpare d 
wi t h 
place b o 
i n 
t he 
P R O V E N T 
( D 8 8 5 0 C 0 0 0 0 2/ N C T 0 4 6 2 5 7 2 5) st u d y (Le vi n et al 20 2 2) , wit h 
r elat i ve ris k 
re d uctio n of  7 6. 7 3, 9 5 % CI 4 6. 0 5, 8 9. 9 6, р < 0. 0 0 1, a n d is a p pr o ve d as E V U S H E L D 
f or t he pre-e x p os ure pr o p h yla xis o f C O VI D -1 9, a n d f or treat me nt of C O VI D -1 9 i n 
t he R ussia n Fe derati o n, t he E U a n d Ja pa n. 
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Ta ble 2  
A ssess me nt of a nti vir al acti vit y of cil g a vi m a b, ti x a ge vi m a b, A Z D 3 1 5 2, 
A Z D 5 1 5 6 a n d E V U S H E L D i n a pse u d o vir us ne utr aliz ati o n ass a y
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N otes : I C5 0 val ues were calc ulate d base d o n mea n res ults i n at least t w o i n de pe n de nt e x peri me nts, eac h of w hic h 
was c o n d ucte d i n t hree re petiti ve r u ns.
A Z D 1 0 6 1 ( cil ga vi ma b, E V U S H E L D c o m p o ne nt wit h a hi g her ne utralizi n g acti vit y a gai nst O micr o n c o m pare d t o 
ti xa ge vi ma b)
I C 5 0, Half ma xi mal i n hi bit or y c o nce ntrati o n ; m A b, m o n ocl o nal a nti b o d y .
S o urce : St u d y E VI 5 1 5 6- 0 0 0 5.
S u bjects bel o n gi n g t o pri ori tize d p o p ul at i ons (see Pr o vi sio n al rec o m me n dat i ons 2 0 2 2), wit h 
hi g h ris k of  se vere C O VI D - 1 9 (e g, i n di vi d uals wit h i m m u n oc o m pr omisi n g c o n ditio n s or 
c o mor bi di ties,
i ncl u di n g t hose ta ki n g i m m u n os u p pressi ve me dicat i ons) or f or w h o m 
vacci nati o n is n ot s uita ble, will be nefit m o st fr o m A Z D 3 1 5 2 a d mi nistratio n f or C O VI D - 1 9 
pr o p h yla xis . It is n ote w ort h y  that c urre ntl y X B B. 1 is t he pre d o mi na nt varia nt i n t he R ussia n 
Fe derat i on, a n d t he i n vesti gati onal pr o d uct has hi g her ne utralizi n g p ote nti al a gai nst it, as 
c o mpare d t o E V U S H E L D (see T a ble 2).
T he A Z D 3 1 5 2 cli nical trial pr o gra m is prese nte d bel o w .
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Ta ble 3
List of c o m plete d, o n g oi n g a n d pl a n ne d cli nic al tri als 
Pr ot oc ol
St at us
Be gi n ni n g
E n d
P h ase
E x pecte d 
n u m ber of 
s u bjects
C o n d ucte d 
i n t he 
R ussi a n 
Fe der ati o n 
S U P E R N O V A 
D 7 0 0 0 C 0 0 0 0 1
O n g oi n g 
Dece m ber 
2 0 2 2
Fe br uar y  
2 0 2 5
I/III
3 2 5 6
n o
Little Di p per 
D 7 0 0 0 C 0 0 0 0 4
Pla n ne d
A pril 
2 0 2 3
Ja n uar y
2 0 2 5
I 
4 8
n o
D 7 0 0 0 C 0 0 0 0 7
Pla n ne d
A pril 
2 0 2 3
A u g ust
2 0 2 5
I 
4 0
n o
N O V E L L A 
A Z -R U - 0 0 0 0 2
Pla n ne d
J u ne 2 0 2 3
A pril 2 0 2 4
II
1 1 6
yes
N o w S U P E R N O V A ( N C T 0 5 6 4 8 11 0) P hase I/III gl o bal  st u d y is o n g oi n g t o e valuate t he saf et y 
a n d ne utralizi n g act i vity of  AZ D 3 1 5 2 i n c o m p aris o n wi t h place b o a n d E V U S H E L D
f or 
pre‑e x p os ure pr o p h yla xis of  CO VI D - 1 9 i n a d ults a n d a d olesce nts 1 2 years of  age or ol d er 
w ei g hi n g at least 4 0 k g. Parti ci pa nts of  the S U P E R N O VA st u d y recei ve I M i njecti ons of  
A Z D 5 1 5 6 (c o m bi nati on of  A Z D 1 0 6 1 [cil ga vi ma b] a n d A Z D 3 1 5 2 ) or place b o i n t he Se nt i nel 
S af et y C o h orts, A Z D 3 1 5 2 or place b o i n t he Mai n 
C o h ort,
a n d A Z D 3 1 5 2 or E V U S H E L D 
(A Z D 7 4 4 2 ) i n t he S u b-st u d y ( will be c o nsi dere d as p hase II ). At t he be gi n ni n g o f A ug ust, 2 0 2 3, 
1 0 5 4 s u bjects ha ve bee n e nr o lle d, i.e. e nr ol me nt i nto t he se nti nel safety c o h ort ( healt h y 
v o l unt eers, N = 5 7) is c o mplete a n d e nr ol me nt i nt o t he ma i n c o h ort (i m m u n oc o m pr omise d 
pati e nts) is o n g oi n g.
. N o safety c o ncer ns were n ote d base d o n re vie w of  the safety data fr o m the Se nt i nel Safet y
C o h ort ( Da y 2 9) after st u d y i nter ve nt i on d ose. O verall, t his safet y a nal ys is of data fr o m health y
parti ci pa nts i n t he Se nti nel Safet y  Co h ort s u p p orts m o vi n g f or war d i nt o t he Mai n C o h ort of
i m m u n oc o mpr o mise d parti ci pa nts i n t he S U P E R N O VA st u d y.I n t he l ocal st u d y, A Z D 3 1 5 2 is 
bei n g e val uate d f or t he pre -e x p os ure pr o p h yla xis of C O VI D -1 9 i n a d ults wit h i ncrease d ris k of 
i na de q uate i m m u ne res p o nse aft er vacci nat i on ( d ue t o i m m u n oc o m pr omisi n g 
c o n ditio ns 
i ncl u di n g c om o r bidi ties t hat ma y c o ntri b ute t o wea ke ne d i m m u nit y) , res ultin g i n a hi g h ris k of 
se vere C O VI D-1 9. 
T he res ults of  this st u d y will pr o vi de cli nical data o n safety a n d ne utralizi n g act i vity of  an 
i n n ovat i on dr u g i n t he ne w re gi o n (t he R ussia n Fe derati o n) will bec o me a n a d dit i on al  s o urce of 
e vi de nce s u p p orti n g A Z D 3 1 5 2 mar ket i n g a ut h orizati o n i n t he R ussia n Fe derat i on a n d will 
e x pa n d strate gies f or C O VI D -1 9 pr o p h yla xis i n a setti n g of c o nti n u o us vir us e v o l uti on.
A
m o r e detaile d descri pt i on of  the c he mistr y, p har mac o l og y, a n d n o ncli nical st u dies of  
A Z D 5 1 5 6
a n d A Z D 3 1 5 2
is pr o vi de d i n t he I n vesti gat or’s Br oc h ure
f or A Z D 5 1 5 6 a n d 
A Z D 3 1 5 2.
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
O bjecti ves
Esti m a n d Descri pti o ns/ E n d p oi nts
 
 
 
 
 
 
 
 
 
A E = a d verse e ve nt; A E SI = a d verse e ve nt of s pecial i nterest; CI = c o nfi de nce i nter val; G M F R = ge o metric mea n 
f ol d rise; G M T = ge o metric mea n titer; g S D = ge o metric sta n dar d de viati o n; I M P = i n vesti gati o nal me dici nal 
pr o d uct; M A A E = me dicall y atte n de d a d verse e ve nt; n A b = ne utralizi n g a nti b o d y; R T -P C R = re verse tra nscri pti o n 
p ol y merase c hai n reacti o n; S A E = seri o us a d verse e ve nt; S A R S -C o V - 2 = se vere ac ute res pirat or y sy n dr o me 
c or o na vir us 2; W H O = W orl d Healt h Or ga nizati o n
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
4
S T U D Y D E SI G N
4. 1
O ver all Desi g n
T his is a P hase II st u d y t hat will be c o n d ucte d t o e val uate t he safety, ne utralizi n g act i vity a n d 
efficac y of  AZ D 3 1 5 2. T he st u d y will e nr ol a p pr o xi matel y 1 1 6 a d ults w h o ha ve a re d uce d 
i m m u ne res p o nse d ue t o a disease/c o n ditio n affecti n g t he i m m u ne s yste m an d w h o are at ris k 
of  de vel o pi n g a n u n der de vel o pe d i m m u ne res p o nse t o vacci nati on a n d de vel o pi n g se vere f or ms 
of  C O VI D- 1 9.
P arti cipa nts will be ra n d omize d 3: 1 t o recei ve A Z D 3 1 5 2 ( 3 0 0 m g , 2 m L) or place b o ( 2 m L)
a d mi nistere d I M i n t he a nter olateral t hi g h o n Da y 1. A prere q ui sit e for i ncl usi o n  i n t his st u d y is 
t hat partici pa nts ha ve i m m u n oc o m pr omise d c o n ditio ns, i ncl u di n g c o mor bi di ties t hat ma y 
c o ntri b ute t o re duce d i m m u nity,  whic h i n t ur n i ncreases t heir ris k of  pr o gressio n  to se vere 
di sease. 
A Z D 3 1 5 2 or pl ace b o will be a d mi nistere d as a si n gle I M i njecti on i n t he a nter olateral t hi g h.
S t u d y i nter ve nti on w ill be ha n dle d b y a n u n bli n de d p har macist ( or desi g nee, in acc or da nce wit h 
l ocal a n d i nstit uti o nal re g ulat i ons) at t he st u d y sit e w h o will be i n de pe n de nt of  safet y 
e val uat i ons a n d ot her trial e val uati o ns.
T he st u d y  will be c o n d ucte d at a p pr o xi matel y 1 0 sites i n t he R ussia n Fe derati o n.
A d verse e ve nts , S A Es, M A A Es , a n d A E SIs will be c ollecte d t hr o u g h o ut t he st u d y. I m me diate 
A Es will  be c o llecte d f or a n 1-h o ur o bser vati o n p eri o d af t er st u d y int er ve nt i on a d mi nistratio n. 
T he d urati o n of  eac h parti ci pa nt ’s i n v ol ve me nt i n t he st u d y will be a p pr o xi matel y 6 mo n t hs 
fr om w he n t he st u d y  int er ve ntio n is a d mi nistere d.
If, f oll owi n g st u d y  i nter ve nti on a d mi nistrati o n, a s u bject de vel o ps C O VI D -1 9, acc or di n g t o t he 
Pr o visi o nal rec om me n dat i ons o n t he met h o ds f or pre ve nt i on, dia g n osis a n d treat m e nt of no vel 
c or o na vir us i nfecti o n ( C O VI D- 1 9), iss ue d b y t he Mi nistr y o f Health of t he R ussia n Fe derati o n, 
versi o n 1 7 date d Dece m ber 1 4 , 2 0 2 2 ( Pr o visio n al rec o m me n datio ns 2 0 2 2) (s) he m ust call “1 2 2 ” 
t o be visite d b y a healt hcare pr ofessi o nal w h o, a m o n g ot her pr oce d ures, will perf or m a C O VI D -
1 9 t est. O nce a visit b y a healt hcare pr ofessi o nal has bee n re q ueste d, t he s u bject m ust n otif y t he 
st u d y d oct or of  the date s y m pt o ms occ urre d a n d t he date a healt hcare pr ofessi o nal visit has bee n 
re q ueste d, as s o o n as p ossi ble. Als o, o nce a test res ult is a vai la ble, t he parti ci pa nt m u st re p ort 
wi t hi n 3 da ys t he d at e of  t est a n d its res ult t o t he I n vestig at or. If t he test res ult is p osi tive, t he 
I n vesti gat or ( or his/ her dele gate, acc or di n g t o t he l ocal re g ulat i ons a n d i nstituti o n g ui deli nes) 
will ma ke tele p h o ne calls every t hree d ays t o c ollect safety data u ntil t he s u bject i nf or ms a b o ut 
his/ her rec o ver y.
P arti cipa nts ca n recei ve S A R S- C o V -2 vacci nes after t he Da y  2 9 assess me nts.
O verall st u d y  desi g n is descri be d i n Fi g ure 1.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T his st u d y  fol l ows t h e d esi g n of  e xpl or at or y  p hase II t hera pe utic trials. I n acc or da nce wit h t he 
B oar d of  E urasia n Ec o n o mic C om missi o n Rec o m me n dat i ons , s uc h st u dies ma y i ncl u de parallel 
c o ntr ols a n d c o mparis o n wi t h baseli ne val ues, w hic h a p plies t o t he desig n of  t his cli nical trial. 
I n acc or da nce wi t h the B oar d of  Eurasi a n Ec o n o mic C o m missi o n Rec o m me n dat i ons s uc h 
e x pl orat or y st u dies are of  relat i vel y s hort d urati o n a n d are c o n d ucte d wi t h a small gr o u p of  
pati e nts usi n g s urr o gate or p har mac o l ogi c al en d p oi nts or cli nical i n dicat ors. I n t his st u d y, t he 
o bser vat i on per i od a n d sa m ple size are c o nsiste nt wi t h s uc h para meters. I n a d diti on t o assessi n g 
t he safety of  IP,  the stu d y als o assesses its ne utrali z i n g acti vit y a gai nst rele va nt varia nts of 
c or o na vir uses, w hic h is t he sta n dar d s urr o gate p oi nt f or assessi n g efficac y  in t his class of dr u g 
f or t his i n dicati o n.
E val uat i on of  s afet y a n d efficac y c o m p ar e d t o pla ce b o is a ge nerall y acce pte d a p pr oac h i n t h e 
earl y sta ges of  cli nical de vel o p m e nt of  mo n o cl o nal a nt i b o dies (Decisi o n of  Co u ncil  of t he 
E urasi a n Ec o n o mic C o m missi o n N o ve m ber 3, 2 0 1 6 №8 9 « R ules f or c o n d ucti n g researc h o n 
bi o l ogical  me dici nes i n t he E urasia n Ec o n o mic U ni o n » ). T his a p pr oac h pr o vi des o pti mal 
c o mparat i ve data f or s u bse q ue nt i nter pretati o n, is et hicall y j ustifie d a n d d oes n ot carr y an y 
a d ditio nal ris ks i n t he c o n dit i ons o f a fa v o ura ble c ha n ge i n t he e pi de mic sit uati o n i n t he R ussia n 
Fe derat i on (i n 2 0 2 2, R os p otre b na dz or lifte d r estrictio ns i m p ose d i n c o n nect i on wi t h the 
pa n de mic) . I n a d ditio n , u ne ve n i ncl usi on i n t he st u d y gr o u ps is pla n ne d – fewer parti ci pa nts
will recei ve a pl ace b o. All part ici pa nts will be a ble t o recei ve S A R S -C o V - 2 vacci nes aft er t h e 
D a y  2 9 assess me nts.
T he o verall st u d y desi g n is si milar t o t he E V U S H E L D (A Z D 7 4 4 2 ) P hase III efficac y st u d y 
( D 8 8 5 0 C 0 0 0 0 2/ P R O V E N T) as well as ot h er stu d y desi g ns e val uat i n g S A R S -C o V - 2 m A bs 
( Le vi n et al 2 0 2 2, Fact S heet E U A Be btelo vi ma b 2 0 2 2, G u pta et a l 2 0 2 1, Wei nreic h et al 2 0 2 1). 
T he 
ma i n differe nce fr om 
ot her st u d y desi g ns is t he ra n d omi zat i on r atio. U ne q ua l 
ra n d omizat i on r atio will c o ver t he nee d f or a d ditio nal  safet y i nf or mati on of  A Z D 3 1 5 2. Als o,
base d o n t he a vaila ble efficac y data, it is a ntici pate d t hat partici pa nts i n t he A Z D 3 1 5 2 ar m will
be nefit m ore t ha n p arti ci pa nts i n t he place b o ar m. A Z D 3 1 5 2 is de vel o pi n g s peciall y t o pre pare 
f or f ut ure resista nt m ut atio ns t h at ma y de vel o p as t h e S A R S -C o V -2 vir us c o nti n ues t o e v ol ve. 
T he data o btai ne d i n p re vi o us st u dies s u g gests t hat t he 6- m o nt h peri o d f oll owi n g a si n gle 
A Z D 3 1 5 2 i njecti on is a de q uate t o meet t he st u d y o bject i ves. T he str uct ural si milarity bet wee n 
A Z D 3 1 5 2 a n d t he c o m p o ne nts of  the E V U S H E L D dr u g s u g gests a si milar safety pr ofile of  
A Z D 3 1 5 2 t o t hat of E V U S H E L D; m o dificat i ons ma de i n t he de vel o p me nt of A Z D 3 1 5 2 are n ot 
e x pecte d t o affect t he safet y of  t he dr u g, w hic h was c o nfir me d i n t he se nti nel c o h ort of cli nical 
st u d y S U P E R N O VA ( D 7 0 0 0 C 0 0 0 0 1).  At  the t i me of assess me nt o n da y 2 9 , n o ne w safet y data 
were i de ntifie d, all o wi n g f urt her e nr ol me nt of patie nts i n p hase III. T he pri mar y e n d p oi nts are 
sta n dar d safety assess me nts.
Alt h o u g h t he pri mar y  e nd p oi nt of t he st u d y  is ai me d at assessi n g safet y, t he st u d y als o ai ms t o 
i n vesti gate t he ne utral izi n g act i vity a gai nst e mer gi n g d o mi na nt varia nts of  SA R S -C o V - 2 a n d 
t he efficac y of  the dr u g. T his st u d y will hel p t o i de ntif y a gr o u p of  pat ient s at hi g h ris k of  
de vel o pi n g se vere C O VI D -1 9 w h o m a y be nefit m ost fr o m t he dr u g a d mi nistrati o n. 
T he c o m bi nat i on of o bject i ves of t his st u d y is t heref ore c o nsiste nt wit h t he ai m: t o esta blis h t he 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
safety of  an i m m u n o bi ol ogical  me dici nal pr o d uct a n d its pre ve nt i ve efficac y f or i n di vi d uals 
wi t h certai n c o n diti ons or diseases t hat c o nfer hi g h ris k of de vel o pi n g se vere f or ms of C O VI D-
1 9.
4. 2. 1
R ati o n ale f or St u d y P o p ul ati o n
T his st u d y  will i n v ol ve a d ults 1 8 years of a ge or ol der w h o ha ve c o n di tio ns/ c o m or bi di ties t h at 
ma y c o ntri b ute t o re d uce d i m m u nit y,  w hic h i n t ur n i ncreases t heir ris k of pr o gressi o n t o se vere 
f or ms of disease. D u e t o t h e ris k of d e v elo pi n g a n i na de q uate res p o nse t o f ull vacci nat i on d u e 
t o i m m u ne s yste m dys f u ncti on d ue t o e xist i n g c o n ditio ns/c o m o r bi dities, a d mi nistrati o n of 
ne utralizi n g m A b is als o rec o m me n de d f or s uc h i n di vi d uals ( Pr o visio n al rec o m me n dati o ns,
versi o n 1 7 date d 2 4 Dece m ber 2 0 2 2; C D C 2 0 2 0).
A ge, 
co m or bi dit ies 
a n d 
i m m u n os u p pressi ve 
c o n dit i ons, 
i ncl u di n g 
t he 
use 
of  
i m m u n os u p pressi ve t hera p y, are ass ociate d wit h 
t he i na de q uate i m m u ne res p o nse t o 
vacci nati o n.
I mm u n o l ogi c al agi n g is a n a ge-relate d d y sre g ulatio n of  the i m m u ne s yste m, a n a ge-r elat e d 
c ha n ge i n t he c o mp o n e nts of  t he i n nate a n d a da pti ve i m m u ne s yste m i n t he el derl y, lea di n g t o 
i m paire d f or mat i on of  pr otecti ve i m m u nity f oll owi n g i m m u nizati on or i nfecti on ( P ola n d et al 
2 0 1 8, Wa g ner a n d Wei n ber ger 2 0 2 0, Zi m mer ma n n a n d C urtis 2 0 1 9).
O besit y has bee n s h o w n t o c orrelate wit h a wea ker i m m u ne res p o nse t o vacci nes, w hic h ca n 
als o be c o nsi dere d a mar ker or stat e of  im m u n os u p pressi o n. F or e xa m ple, o bese p e o pl e ha ve 
re d uce d C D 8 + T- cell act i vati on c o m p ar e d t o healt h y  pe o ple of  nor m al wei g ht ( P ola n d et al 
2 0 1 8, Wa g ner a n d Wei n ber ger 2 0 2 0, Zi m mer ma n n a n d C urtis 2 0 1 9).
P ati e nts wit h c hr o nic ki d ne y disease are a pri ori t y gr o u p f or vacci nat i on, b ut t he a de q uac y of 
t he i m m u n o l ogi c al res p o nse i n t his cate g or y of patie nts m a y n ot be hig h e n o u g h, a n d t heref ore 
b o oster vacci nati o n is nee de d, as well as t he use of pr ol o n ge d viral ne utralizi n g a nt i b o dies b ot h 
as pre- e x p os ure pr o p h yla xis a n d as treat me nt ( Pr o visio n al rec o m me n dat i ons, versi o n  1 7 of  2 4
Dece m ber 2 0 2 2).
Hi p pisle y -C o x, et al. c o n d ucte d a lar ge -scale st u d y o n 6, 9 5 2, 4 4 0 vacci nate d patie nts t o de vel o p 
a n d test ris k pre dict i on al g orit h ms f or C O VI D - 1 9-r elate d mortali t y a n d h os pi talizatio n i n a d ult 
pati e nts aft er o ne or t wo d oses of  CO VI D - 1 9 vacci ne. M ortali t y fr om C O VI D - 1 9 has bee n 
s h o w n t o be 1. 2 t o 2 ti mes hi g her i n vacci nate d patie nts w h o ha d c hr o nic o bstr ucti ve p ul m onar y 
di sease ( C O P D) a n d/ or car di o vasc ular disease (c or o nar y heart disease, str o ke, atrial fi brillat i on,  
heart fail ure, t hr o m b oe m b o lis m, peri p heral vasc ular disease) ( Hi p pisle y -C o x, et al 2 0 2 1). T h us, 
pati e nts wi t h these c o mor bi di ties als o re q uire t he use of  lo n g- act i n g dr u gs c o ntai ni n g vira l 
ne utralizi n g a nt i b o dies as pre-e x p os ure pr o p h yla xis
T he st u d y po p ul at i on m o st li kel y t o be nefit fr om receipt of  IM P . T he i ncl usi on crit eria are 
desi g ne d t o select s uc h i n di vi d uals (f or list of c o n diti ons, see Secti o n  5. 1 ).
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
5
S T U D Y P O P U L A TI O N
Pr os pecti ve a p pr o val of pr ot oc ol de viat i ons t o recr uit me nt a n d e nr ol me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e 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 of t h e fol l owi n g criteria a p pl y:
1.
P arti cip a nt m ust be 1 8 y ears of a ge or older at t he ti me of si g ni n g t he i nf or me d c o nse nt.
2.
Wr itte n i nf or me d c o nse nt o btai ne d fr om t he partici pa nt pri or t o perf or mi n g a n y pr ot oc ol-
r elate d pr oce d ures, i ncl u di n g scree ni n g e v al u ati o ns.
3.
Ne gati ve ra pi d a nt i ge n test S A R S -C o V - 2 at  Visit 1.
4.
Wei g ht ≥ 4 5 k g at Visit 1.
5.
A d ult parti ci pa nts at i ncrease d ris k of  pr o gressi o n t o se vere f or ms of  disease d ue t o 
i m m u n os u p pressi ve diseases/c o n dit i ons ( F urer et al 20 2 0, P ola n d et al 2 0 1 8, Wa g n er a n d 
Wei n ber ger 2 0 2 0, Zi m mer ma n n a n d C urt is 2 0 1 9), ha vi n g at least 1 of  the f oll owi n g ris k 
fact ors:

O bese, i e, B MI ≥ 3 0

C o n gest i ve heart fail ure

C hr o nic o bstr ucti ve p ul m o nar y  disease

C hr o nic ki d ne y  disease, ie, G F R < 3 0 m L/ mi n/ 1. 7 3 m2 ( La m b et al 2 0 1 3)

I nt olera nt of  vacci ne. Defi ne d as pre vi o us hist or y of  se vere a d verse e ve nt or 
serio us a d verse e ve nt after recei vi n g a n y  a p pr o ve d vacci ne.

I mm u n oc o m pr o mise d state ( m ust satisf y at l e ast 1 of t h e fol l owi n g ris k fact ors at 
e nr o ll me nt)
a)
Ha ve ca ncer (e g, acti ve s oli d t u mors a n d he mat ol o gi c mali g na ncies) e xce pt  
f or a de q uatel y treate d:

N o n -me la n oma s ki n ca ncer or le nt i g o mali g na

Uteri ne cer vical carci n o ma i n sit u

L ocal  pr ostate carci n oma
b)
Ha ve s o li d or ga n tra ns pla nt or a he mat o p oietic ste m cell tra ns pla nt ( wit hi n 2 
years o f tra ns pla ntati o n, are ta ki n g i m m u n os u p pressi o n t hera p y or w h o ha ve 
c hr o nic graft -vers us -h ost di sease)
c)
Are 
act i vel y ta ki n g i m m u n os u p pressi ve me di ci nes (e g, are usi n g 
c ortic oster oids [ie, ≥ 2 0 m g 
pre d nis o ne or e q ui vale nt per da y w h e n 
a d mi nistere d f or ≥ 2 wee ks], hi g h -d ose alk ylat i n g a ge nts, a nt i meta b olites, 
tra ns pla nt -r elate d i m m u n os u p pressi ve dr u gs, ca ncer c he m ot hera pe ut ic 
a ge nts classifie d as se verel y i m m u n os u p pressi ve [e g, Br ut o n’s t yr osi ne 
ki nase i n hi bit ors], t u mor -necr osis bl oc kers, or ot h er i m m un os u p pressi ve or 
i m m u n om o d ulat or y  biol o gi c a ge nts f or r he u mat ic diseases)
d)
Recei ve d c hi meric a nt i ge n rece pt or T-cell t hera p y
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
e)
Wit hi n 1 year of  recei vi n g B- cell de pleti n g t hera pies (e g, rit u xi ma b, 
ocreliz u ma b, ofat u m u ma b, ale mt uz u ma b)
f)
Ha ve a m o derate or se vere pri mar y  im m u n o deficie nc y 
(e g, Di Ge or ge 
s y n dr ome, Wis k ott -Al dr ic h s y n dr ome, se vere c o m bi ne d i m m u n o deficie nc y, 
c o m m o n vari a ble i m m u ne deficie nc y, a ga m ma gl o b uli ne mia)
6.
Me dicall y  sta ble defi ne d as disease n ot re q uiri n g si g nifica nt c ha n ge i n t hera p y or 
h os pi t alizati o n f or w orse ni n g disease d uri n g t he 1 m ont h pri or t o e nr oll me nt, wit h n o ac ute 
c ha n ge i n c o n ditio n at t he ti me of  st u d y enr o ll ment  as j u d ge d b y t he I n vesti gat or a n d n o 
e x pecte d c ha n ges at t he ti me of t he e nr o ll me nt.
7.
W O C B P m ust n ot be pre g na nt or lact ati n g a n d m ust still be usi n g a hi g hl y effecti ve met h o d 
of  co ntrace pti o n or a bst i ne nce u nt il at least 6 m o nt hs aft er st u d y i nter ve nt i on a d mi nistrati o n.
N O T E:

W o me n n ot of c hil d beari n g p ote ntial are defi ne d as fe males w h o are eit her per ma ne nt l y 
sterilize 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 m e n o pa usal. Fe males 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 f or 1 2 m o nt hs pri or t o t he pl a n ne d date of  ra n d o mizat i on wi t ho ut a n 
alter nati ve me dical c a use. T he f o ll owi n g a ge -s pecific re q uire me nts a p pl y:
o
Fe males < 5 0 years ol d w o ul d 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 f or 1 2 m o nt hs or m o re f oll owi n g cessat i on of  ex o ge n o us h or m o n al 
treat me nt a n d f ollicle st i m ulati n g h or m o ne le vels i n t he p ost me n o pa usal ra n ge.
o
Fe males ≥ 5 0 ye ars ol d w o ul d be c o nsi dere d p os t me n o pa usal if t he y ha ve bee n 
a me n orr h oeic f or 1 2 m o nt hs or m or e f oll owi n g cessat i on of  all e x o ge n o us h or mo n al 
treat me nt. 

All fe male parti ci pa nts of  chil d beari n g p ote nti al must ha ve a ne gat i ve uri ne pre g na nc y 
test res ult at scree ni n g.

Fe male part ici pa nts of c hil d beari n g p ote ntial m ust use o ne hi g hl y effecti ve f or m of birt h 
c o ntr ol. A hi g hl y effecti ve met h o d of c o ntrace pti o n is defi ne d as o ne t hat ca n ac hie ve a 
fail ure rate of  les s t ha n 1 % per ye ar w he n use d c o nsiste nt l y a n d c orrectl y. Fe males of  
c hil d beari n g p ote nti al w h o are se x uall y act i ve wi t h a no n -sterilize d male part ner m u st 
a gree t o use o ne hi g hl y effecti ve met h o d of  birt h c o ntr ol, as defi ne d b el o w, fr om 
e nr o ll me nt t hr o u g h out t he st u d y an d u nt il at least 6 m o nt hs aft er last d ose of  st u d y 
i nter ve nt i on. Cessat i on of  co ntrace pti o n aft er t his p oi nt s h o uld be disc usse d wi t h a 
res p o nsi ble p h ysicia n. 

Hi g hl y  effecti ve birt h c o ntr ol met h o ds i ncl u de: T otal se x ual a bsti ne nce is a n acce pta ble 
met h o d pr o vi de d it is t he us ual lifestyle of  the parti ci pa nt ( defi ne d as refrai ni n g fr om 
heter ose x ual i nterc o urse d uri n g t he e nt ire p eri o d of  ris k ass ociate d wit h t he st u d y 
treat me nts) [( peri o dic a bsti ne nce e g, cale n dar, o v ulat i on, s y m pt ot her mal, p os t-o v ul at i on 
met h o ds), declarat i on of  absti ne nce f or t he d urati o n of  ex p os ure t o stu d y i nter ve nt i on,  
a n d wi t hdra wal are n ot acce pta ble met h o ds of  co ntrace pti o n], a vasect o mize d part ner, 
I mpla n o n ® , bilateral  tu bal o c cl usi o n , i ntra uteri ne de vice/le v o n or gest rel i ntra uteri ne 
s yste m, D e p o-Pr o vera ™ i njecti ons, or al  co ntrace pti ve, a n d E vra Patc h ™, X ula ne ™, or 
N u va Ri n g ® or t hei r e q ui vale nts.

T he f oll owi n g 
are n ot acce pta ble met h o ds 
of c o nt race pti o n: p eri o di c a bst i ne nce 
(cale n dar, s y m pt ot her mal, p ost -o v ul at i on met h o ds), wit h dra wal ( c oit us i nterr u pt us), 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
s per mici des o nl y, a n d lactati o nal a me n orr hea. Fe male c o n d o m a n d male c o n d o m s h o ul d 
n ot be use d t o get her. 
8.
A ble t o u n dersta n d a n d c o mpl y  with all st u d y re q uire me nts/ pr oce d ures, base d o n t he 
assess me nt of t he I n vesti gat or.
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:
1
W o me n w h o are pre g na nt, lactati n g, or of  chil d beari n g p ote nti al a n d n ot usi n g a hi g hl y 
effect i ve met h o d of  co ntrace pti o n or a bst i ne nce fr om at least 4 w ee ks pri or t o st u d y 
i nter ve nt i on a d mi nistrati o n a n d u nt il at least 6 m o nt hs aft er st u d y int er ve nti o n 
a d mi nistrati o n.
2
K n o w n h y perse nsit i vity t o a n y  c o mp o ne nt of t he st u d y  int er ve nt i on.
3
Pre vi o us h y perse nsit i vity or se vere a d verse react i on f oll owi n g a d mi nistr atio n of  a m A b.
4
Ac ute (ti me- li mite d) or febr ile (t e mperat ure ≥ 3 8. 0° C) ill ness/i nfecti on o n d a y  prior t o or 
d a y  of pl a n ne d d osi n g; part ici pa nts e xcl u de d f or tra nsie nt ac ute ill ness ma y be d ose d if 
ill ness res ol ves a n d ma y be rescree ne d f or e nr oll me nt o nce.
5
Bl o o d dra w n i n e xcess of a t otal of 4 5 0 m L f or a n y reas o n wit hi n 3 0 da ys pri or t o Visit 1.
6
Cli nicall y si g nifica nt blee di n g dis or der (e g, fact or deficie nc y, c oa g ulo p at h y , or platelet 
di s or der), or pri or hist or y  of si g nifica nt blee di n g or br uisi n g f oll o wi n g I M i njecti o ns or 
ve ni p u nct ure.
7
Has HI V i nfecti o n.
8
Recei pt of c o n valesce nt C O VI D -1 9 plas ma treat me nt wit hi n 6 m o nt hs pri or t o Visit 1.
9
Pre vi o us recei pt of a m A b a gai nst S A R S -C o V -2 wit hi n 6 m o nt hs pri or t o Visit 1.
1 0
Recei pt of a C O VI D -1 9 vacci ne wit hi n 6 m o n t hs prior t o Visit 1.
1 1
Recei pt of a C O VI D -1 9 a nti viral f or pr o p h yla xis wit hi n at least 2 wee ks pri or t o Visit 1.
1 2
C O VI D - 1 9 wi t hi n 6 m o nt hs pri or t o Visit 1 (c o nfir me d eit her b y la b orat or y testi n g or a 
r a pid test [i ncl u di n g at -h o me testi n g]).
1 3
Recei pt of a n y I M P i n t he prece di n g 9 0 da ys or e x pecte d recei pt of  I M P d uri n g t he perio d 
of  st u d y fol l ow- u p. C o nc urre nt partici pat i on i n a n ot her i nter ve nt i onal st u d y where t he 
parti ci pa nt cease d I M P treat me nt > 9 0 da ys w h o is i n t he f oll ow- u p peri o d of  t he st u d y a n d 
n ot e x pecte d t o recei ve f urt her I M P, is per mitte d f or i ncl usi o n.
1 4
Alc o h o l or s u bsta nce a b use t hat, i n t he o pi ni on of t he I n vest i gat or, mi g ht i nterfere with t he 
trial c o n d uct or c o mplet i on. 
1 5
De pri ve d of  free d om b y a n a d mi nistrati ve or c o urt or der, or i n e mer ge nc y setti n g, or 
h os pi talize d i n v olu ntaril y.
1 6
A n y 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, mi g ht c o m pr omise part ici pa nt safety 
or i nterfere wi t h e val uati on of  t he st u d y int er ve nt i o n or i nter pretati o n of partici pa nt safet y 
or st u d y  res ults.
1 7
E m pl o y ees of  Astra Ze neca i n v ol ve d i n pla n ni n g, e xec uti n g, s u per visi n g, or re vie wi n g t he 
A Z D 5 1 5 6/ A Z D 5 1 3 2 pr o gra m , cli nical st u d y site staff, or a n y ot h er i n di vi d uals i n v ol ve d 
wi t h t he c o n d uct of t he st u d y, or fa mil y me m bers of s uc h i n di vi d uals.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
5. 3
Lifest yle C o nsi der ati o ns

P arti cipa nts m ust f ol l ow t he c o ntrace pti o n re q uire me nts o utli ne d i n a b o ve Secti o ns.

Restricti o ns relat i n g t o c o nc o mita nt me dicati ons are descri be d i n Sect i on  6. 5 .
5. 4
Scree n F ail ures
Scree n fail ures are defi ne d as parti ci pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y but 
are n ot s u bse q ue ntl y ra n d o ml y assi g ne d t o st u d y int er ve nt i on. A mi ni mal set o f 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 part ici pa nts t o meet t he 
C O N S O R T p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr om re g ulat or y aut h ori ties. 
Mi ni mal i nf or mati on i ncl u des d e m o gra p h y, scree n fail ure details, eli gi bilit y crit eria, a n d a n y 
S A E.
I n di vi d uals w h o d o n ot me et t h e criteria f or partici pat i on i n t his st u d y (scree n fail ure) ma y b e 
rescree ne d if t he parti ci pa nt has n ot met  the e li gi bilit y crit eria wi t hi n the scree ni n g p eri o d a n d/ or 
t he reas o n f or scree n fail ure was tra nsie nt (i ncl u di n g b ut n ot li mite d t o st u d y e q ui p me nt fail ure, 
u nf oresee n pers o nal e ve nts t hat ma n date misse d scree ni n g visi t). O nl y a si n gle rescree ni n g is 
all o we d i n t he st u d y a n d m ust be starte d wit hi n 2 wee ks of t he i nit ial scree ni n g. W he n p ossi ble, 
t he I n vesti gat or s h o ul d c o ns ult t he St u d y  Ph ysicia n pri or t o rescree ni n g. Rescree ne d 
parti ci pa nts s h o uld be assi g ne d t he sa me partici pa nt n u m ber as f or t he i nit ial scree ni n g.
6
S T U D Y I N T E R V E N TI O N
St u d y  int er ve nt i on is defi ne d as a n y in vest i 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 or me d ical de vice(s) ut ilise d b y 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
A S T R A Z E N E C A A B w ill s u p ply L L C Astra Ze neca P har mace ut icals A Z D 3 1 5 2, s ol uti on f or 
i ntr a musc ular i njecti on, at a d osa ge of 1 5 0 m g / ml, 2 ml i n a vial, as i n vesti gati onal dr u g i n a 
sta n dar d pac ka ge "I N B U L K".
F urt her sec o n dar y  pac ka gi n g, labelli n g a n d release of  I M P, will be carrie d o ut o n territ or y  of 
t he R ussia n Fe derati o n b y Ma n ufact uri n g site a n d b y S p o ns or,
i n acc or da nce wit h a p plica ble 
re g ulat i on s.
Pl ace b o 
P arti cipa nts will be ra n d o mize d t o recei ve A Z D 3 1 5 2 or place b o ( 3: 1 ratio). T here i s n o ca p f or 
ra n d omiz at i on i n eac h gr o u p t o be i m ple me nte d o n sit e le vel of  eac h i n vesti gati onal pr o d uct , 
beca use it will i ncrease o vera ge of I M P f or trial c o n d ucti o n. Details of t hese st u d y i nter ve nt i ons 
are prese nte d i n Ta ble 5 a n d are descri be d bel o w. 
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
P ac k a gi n g a n d 
l a belli n g
I M P will b e  pr o vi de d i n glass vials. 
Eac h glass vial will be la belle d as per 
c o u ntr y re q uire me nt.
 
 
 
 
I M = i ntra m usc ular; 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; w/ v 
= wei g ht per v ol u me.
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

I M P vials /a m p o ules are st ore d at 2° C t o 8° C a n d m ust n ot be fr oze n.

T he 
I n vesti gat or, or 
a n a p pr o ve d desi g nate d 
re prese ntati ve ( e g, 
p har macist), will e ns ure t hat all st u d y int er ve ntio n is st ore d i n a sec ure d 
area, i n r efrigerate d t e mperat ures ( 2° C t o 8° C) a n d i n accor da nce wi t h 
a p plica ble re g ulat or y re q uire me nts.

A te m perat ure l o g will be use d t o m o nit or t he st ora ge c o n diti ons of I M P i n 
t he st ora ge area. Te m perat ure e xc ursi o ns o utsi d e t he per missi ble ra n ge 
liste d i n t he cli nical s u p pl y pac ka gi n g will be re p orte d t o the m o nit or u p o n 
detecti o n. A cali brate d t e mperat ure m o nit ori n g de vice will be use d t o 
rec or d t he t e mperat ure c o n dit i ons i n t he dr u g st ora ge facility
or 
r efrig er at or . St ora ge c o n dit i ons state d i n t he I n vestigat or’s Br oc h ure ma y 
be s u perse de d b y t he la bel st ora ge.

St u d y  int er ve nti o n m u st be ke pt i n ori gi nal  pac ka gi n g u nt il t he ti me of 
pre parati o n t o pre ve nt pr ol o n ge d li g ht e x p os ure.

T he I n vesti gat or or desi g nee m ust 
c o nfir m a p pr o priate t e mperat ure 
c o n ditio ns 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 discre pa ncies are re p orte d. Use of st u d y i nter ve ntio n f or 
w hic h a t e mperat ure de viat i on has bee n i de ntified will n ot be per mitte d 
pri or t o Astra Ze neca's n otificat i on.

O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve st u d y int er ve nt i on a n d 
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 int er ve ntio n m ust be st ore d i n a sec ure, e n vir o n m e ntall y c o ntr olle d, 
a n d m o nit ore d ( m a n ual or a ut o mate d) area i n acc or da nce wit h t he la belle d 
st ora ge c o n dit i ons wi t h access li mite d t o t he I n vestig at or a n d a ut h orise d 
site staff.

T he I n vest i gat or, inst itut i on, or t h e h e a d of  t he me di cal i nstituti o n ( w here 
a p plica ble) 
is res p o nsi ble 
f or stu d y 
i nter ve nt i on 
acc o u nta bilit y,  
rec o nciliati on, a n d rec or d ma i nte na nce (ie, receipt, rec o nciliati on, a n d fi na l 
di s p ositio n rec or ds).
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

F urt her g ui da nce a n d i nf or mat i on f or t he fi nal dis p ositi on of u n use d st u d y 
i nter ve nt i ons, detaile d d ose pre parati o n, ha n dli n g, a n d a d mi nistrati o n 
i nf or mat i on will be pr o vi de d i n t he I n vesti gati o nal Pr o d uct Ha n dli n g 
Ma n ual.
T he d oses of A Z D 3 1 5 2 a n d place b o f or a d mi nistrati o n m ust be pre pare d b y t he U n bli n de d staff 
me m bers dele gate d b y t he I n vesti gat or ( or a n a p pr o priate desi g nee trai ne d i n st u d y dr u g 
pre parati o n), usi n g ase pt ic tec h ni q ue a n d f oll owi n g
l ocal re g ulat i ons a n d sit e re q uire me nts. 
To t al time bet wee n retrie v al of  t he dr u g fr o m t he vial/a m p o ule i nto t he s y rin ge a n d t he start of 
a d mi nistrati o n m ust n ot e xcee d:

2 4 h o urs at 2° C t o 8° C

4 h o urs at r o o m te m perat ure.
If t he fi nal pr o d uct is st ore d at b ot h refri gerate d a n d a m bie nt te m perat ures, t he t otal  time m ust  
n ot e xcee d 2 4 h o urs, ot her wise a ne w d ose m ust be pre pare d fr o m ne w vials/ a m p o ules (t hat is, 
t he i n di vi d ual st ora ge ti me li mits are n ot a d dit i ve). A Z D 3 1 5 2 a n d pl ace b o d o n ot c o nt ai n 
preser vat i ves; a n y u n use d p orti o n of t he vial/a m p o ule m ust be discar de d i m me diatel y after use.
6. 3
Me as ures t o Mi ni mise Bi as: R a n d o miz ati o n a n d Bli n di n g
6. 3. 1
R a n d o miz ati o n
T he parti ci pa nts will be ra n d o mize d t o recei ve A Z D 3 1 5 2 or place b o ( 3: 1 rati o). 
All part ici pa nts will be ce ntrall y assi g ne d t o ra n d o mize d st u d y int er ve nt i on usi n g a n I W R S. 
Bef ore t he st u d y  is ini tiate d, I W R S access a n d i nstr uctio n will be pr o vi de d t o eac h si t e. St u d y 
i nter ve nt i on will be a d mi nistere d at t he V isit 1.
T he I W R S will pr o vi de t o t he I n vest i gator(s) or p har macists t he kit i de nt ificati on n u m ber t o be 
all ocate d t o t he partici pa nt at  the di s pe nsi n g visit . R o uti nes f or t his will  be descri be d i n t h e 
I W R S user ma n ual t hat will be pr o vi de d t o eac h ce nter.
6. 3. 2
Bli n di n g
N ei t her t he partici pa nt n or a n y of  the I n vesti gat ors or S p o ns or staff w h o are i n v ol ve d i n t he 
treat me nt or cli nical e val uat i on a n d m o nit ori n g of  the parti ci pa nts will be a ware of  the st u d y 
i nter ve nt i on recei ve d. Si nce A Z D 3 1 5 2 a n d place b o are vis uall y dist i nct pri or t o d ose 
pre parati o n ( d ue t o differe nces i n a p peara nce), st u d y int er ve nt i on will be ha n dle d b y a n 
u n bli n de d p har macist ( or desi g nee, i n acc or da nce wit h l ocal a n d i nst ituti o nal  re g ulati o ns) at t he 
st u d y site w h o will be i n de pe n de nt of safet y e val uatio ns a n d ot her trial e val uat i ons. Per s o n nel 
pre pari n g a n d a d mi nisteri n g st u d y int er ve nt i on m a y  be t he sa me i n di vi d ual. S y rin ge ma s ki n g 
will be re q uire d i n or der t o ma i ntai n t he bli n d. T he I n vesti gat or res p o nsi ble f or safet y 
assess me nt will n ot atte n d t he st u d y i nter ve nti o n a d mi nistrati o n sess i on b ut will be a vaila ble i n 
case of e mer ge nc y (e g, a na p h ylact ic s h oc k). 
T he f oll owi n g pers o n nel will ha ve access t o t he ra n d omizat i on list d uri n g t he st u d y, pri or t o 
D B L:
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical S t u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

T h ose carr yi n g o ut t he pac ka gi n g a n d la belli n g of I M P

T h ose ge nerat i n g t he ra n d o mizatio n list a n d I W R S s yst e m

T he Astra Ze neca Allia nce Tea m me m bers res p o nsi ble f or s u p pl y c hai n 

U n bli n de d Astra Ze neca desi g nees (if a p plica ble)

U n bli n de d p har macist

Staff of bi oa nal yt ic la b orat or y

T he u n bli n de d tea m (s) (t o be s pecifie d i n t he St u d y  I nt e grity Pl a n) f or
i nteri m a nal ysis at Astra Ze neca a n d/ or its dele gate.
T he ra n d omizat i on c o de s h o uld n ot be br o ke n e xce pt i n me d ical emer 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 o mizat i on,  
or i n t he i nsta nce a part ici pa nt wi s hes t o be c o nsi dere d f or a S A R S -C o V - 2 vacci n e. T h e 
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, wi t ho 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 M P a n d t hat p ote ntiall y re q uir e e x pe dite d re p ortin g t o re g ulat or y 
a ut h orities. Ra n d o mizat i on c o des will n ot be br o ke n f or t he pla n ne d a nal yses of  dat a u ntil all 
decisi o ns o n t he e val ua bilit y of  t he data fr o m eac h i n di vi d ual parti ci pa nt ha ve bee n ma d e a n d 
d oc u m e nte d.
6. 3. 3
Pr oce d ures f or U n bli n di n g
T he I W R S will be pr o gra m me d wi t h bli n d-brea ki n g f unct i on. U n bli n di n g s h o uld o nl y  occ ur 
wi t hi n t he I W R S s yste m. I n case of  an e mer ge nc y, i n w hic h t he k n o wle d ge of  the s pecific 
bli n de d st u d y  int er ve nt i on 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 t hera p y ca n be u n bli n de d b y 4 1 a ut h orize d re prese ntatives of  th e 
st u d y site. P arti ci pa nt safety m ust 
alwa ys be t he first c o nsi derati o n i n ma ki n g 
s uc h a 
deter m i nati on. If a part ici pa nt’s i nter ve ntio n assi g n me nt is u n bli n de d, t he S p o ns or m ust b e 
n otifie d wi t hi n 2 4 h o urs aft er brea ki n g t he bli n d. T he I n vestig at or d oc u me nts a n d re p orts t he 
e ve nt t o Astra Ze neca, wi t ho ut re veali n g t he treat me nt gi ve n t o partici pa nt to t h e Astra Ze neca 
staff.
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 sit e, t he y will recei ve st u d y int er ve nt i on di rectl y fr om t he 
u n bli n de d p har macist or desi g nee. T he date, a n d ti me if a p plica ble, 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.
6. 5
C o nc o mit a nt T her a p y
A n y me dicat i on o r vacci ne (i ncl u di n g C O VI D-1 9 vacci nes a n d o ver -t he- c o u nter or prescri pt i on 
me dici nes) t hat t he partici pa nt is recei vi n g at t he ti me of e nr ol me nt or recei v es d uri n g t he st u d y 
m ust be rec or de d o n t he C o nc o mita nt Me dicat i on e C R F al o n g wit h: 

Reas o n f or use
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

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
T he St u d y  Ph ys icia n s h o uld be c o ntacte d if t here are a n y q uest i ons re gar di n g c o nc o mit a nt or 
pri or t hera p y. 
Ta ble 6 lists t he per mitte d a n d restricte d, me dicati o ns d uri n g t he st u d y.
Ta ble 6
Per mitte d, Restricte d, a n d Pr o hi bite d Me dic ati o ns
Use C ate g or y
T y pe of me dic ati o n/tre at me nt
Ti meli ne/i nstr ucti o ns
Per mitte d
R o uti ne vacci nes e xce pt S A R S -
C o V -2 vacci nes
All ot her vacci nes e xce pt S A R S -C o V -2 
vac ci nes (see t h e ‘Restricte d’ 
s ecti o n 
bel o w) ar e per mitte d; h o we ver, t he y s h o ul d 
n ot be gi ve n wit hi n 1 4 da ys bef ore or after 
a d mi nistrati o n of st u d y i nter ve nti o n.
Aller ge n i m m u n ot hera p y
All o we d if partici pa nt has bee n r ecei vi n g 
sta ble dese nsitizati o n t hera p y f or aller gies 
f or at least 3 0 da ys pri or t o scree ni n g a n d 
t here is n o a ntici pate d c ha n ge d uri n g t he 
treat me nt peri o d. Aller ge n i m m u n ot hera p y 
s h o ul d n ot be a d mi nistere d o n t he sa me da y 
as st u d y i nter ve nti o n. N o n -pr e scri pti o n 
o ver -t he-c o u nter treat ments f or aller gies 
s uc h as a nti hista mi nes, dec o n gesta nts, a n d 
nasal ster oi ds ar e per mitte d 
f or s uc h 
partici pa nts.
C o m mer cia l 
bi ol o gics, 
pre d nis o ne, 
i m m u n os u p pressi ve 
me dicati o ns 
(e g, 
azat hi o pri ne, 
tacr oli m us, 
c ycl os p ori ne, 
met h otre xate, 
or 
c yt ot o xic 
c he m ot h era p y)
All o we d. 
If p ossi ble, a d mi nistrati o n of 
bi ol o gics (e g, a dali m u ma b) s h o ul d be 
a v oi de d o n 
t he sa me da y 
as st u d y 
i nter ve nti o n.
I ntra ve n o us 
i m m u n o gl o b uli n 
i nf usi o n f or partici pa nts 
wit h 
c o m m o n 
varia ble 
i m m u ne 
deficie nc y
All o we d. 
If p ossi ble, a d mi nistrati o n of 
i m m u n o gl o b uli n s h o ul d b e  a v oi de d o n t he 
sa me da y as st u d y i nter ve nti o n.
Partici pa nts ma y ta ke c o nc o mita nt me dicati o ns prescri be d b y t heir healt hcare 
pr o vi der f or ma na ge me nt of c hr o nic me dical c o n diti o ns a n d/ or f or healt h 
ma i nte na nce. H e alt hcare pr o vi der or, w here a p pr o priate, I n vesti gat ors s h o ul d 
prescri be a p pr o priate c o nc o mita nt me dicati o ns or treat me nts dee me d necessar y 
t o pr o vi de f ull s u p p orti ve care a n d c o mf ort d uri n g t he st u d y. Partici pa nts w h o 
de vel o p C O VI D - 1 9 after r ecei vi n g st ud y i nter ve nti o n s h o ul d be treate d 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Use C ate g or y
T y pe of me dic ati o n/tre at me nt
Ti meli ne/i nstr ucti o ns
acc or di n g t o l ocal sta n dar d of care ( w hic h will be rec or de d as c o nc o mita nt 
me dicati o n), i ncl u di n g i n vesti gati o nal a ge nts o utsi de a cli nical trial setti n g.
Pr o hi bite d  
N o ne
N o ne
Restricte d
Bl o o d/ plas ma d o nati o n
Partici pa nts m ust a bstai n fr o m d o nati n g 
bl o o d or plas ma fr o m t he ti me of i nf or me d 
c o nse nt a n d f or 5 half -li ves after st u d y 
i nter ve nti o n a d mi nistrati o n, ie, 1 5 m o nt hs.
S A R S -C o V -2 vacci nes
S A R S -C o V -2 vacci nes s h o ul d n ot be gi ve n 
wit hi n 
6 m o nt hs 
pri or t o Vi sit 1 (see 
Secti o n 5 ). S A R S -C o V - 2 vacci nes s h o ul d 
als o n ot be gi ve n d uri n g t he st u d y u ntil 
after t he Da y 2 9 assess me nts.
C O VI D -1 9 a nti virals
C O VI D- 1 9 
a nti virals 
f or 
pr o p h yla xis 
s h o ul d n ot be gi ve n wit hi n at least 2 wee ks 
pri or t o Visit 1 as well as d uri n g t he st u d y 
u ntil after t he Da y 2 9 assess me nts.  If t he 
partici pa nt de vel o ps C O VI D -1 9, sta n dar d 
of care treat me nt is all o we d.
E V U S H E L D
E V U S H E L D s h o ul d n ot b e  gi ve n wit hi n 
6 m o nt hs pri or t o Visit 1 a n d u ntil 6 m o nt hs 
after t he d ose of I M P .
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
6. 6
D ose M o dific ati o n
D ose m o dificat i ons will n ot be per mitte d d uri n g t he st u d y.
6. 7
I nter ve nti o n After the E n d of t he St u d y
T here i s n o i nter ve nti on after t he e n d of t he st u d y  (see Sectio n  4. 4 ).
7
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N/ WI T H D R A W A L
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
Eac h parti ci pa nt will recei ve a si n gle d ose of  st u d y int er ve nt i on ( AZ D 3 1 5 2 or place b o). If a 
parti ci pa nt e x perie nces a n i m me diate h y perse nsit i vity reacti o n after recei pt of t he I M i nject i on,  
t he partici pa nt s h o ul d re mai n i n t he st u d y t o be e val uate d.
N ote t hat disc o nt i n uati on fr om st u d y int er ve nt i on is N O T t he sa me as a wi t hdra wal fr om t he 
st u d y.
T he st u d y ma y be st o p pe d if, i n t he j u d g me nt of  Astra Ze neca, trial part ici pa nts are place d at 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
u n necessar y  ris k beca use of cli nicall y si g nifica nt fi n di n gs t hat:
1.
meet i n di vi d ual st o p pi n g criteria or are ot her wise c o nsi dere d si g nifica nt 
2.
are assesse d as ca usall y relate d t o st u d y dr u g, 
3.
are n ot c o nsi dere d t o be c o nsiste nt wit h c o nt i n uati o n of t he st u d y
Re gar dless of  the reas o n f or ter mi nati on, all d at a a vaila ble f or t he partici pa nt s at t he ti me of  
di sc o nti n uati on of  fol l ow- u p m ust be rec or de d i n t he e C R F. All reas o ns f or disc o nt i n uati on of 
treat me nt must be d oc u m e nte d.
I n ter mi nati n g t he st u d y, t he S p o ns or will e ns ure t hat a de q uate c o nsi derati o n is gi ve n t o t he 
pr otec tio n of  t he partici pa nt s’ i nterests.
See t he S o A  for d at a t o b e c oll e ct e d at  t he ti me of i nter ve nti o n disc o nti n uati o n a n d f oll ow- u p 
a n d f or a n y furt her e val uat i ons t hat nee d t o be c o m plete d ( Secti o n  1. 3 ).
7. 2
P artici p a nt Wit h dr a w al fr o m t he St u d y
A part ici pa nt ma y wi t hdra w fr om t he st u d y at a n y time at his/ her o w n re q uest or ma y b e 
wi t hdra w n at a n y ti me at t he discreti o n of  the I n vesti gat or f or safety,  beha vi oral, c o mplia nce, 
or a d mi nistrati ve reas o ns. T his is e x pecte d t o be u nc o m m o n.
A part ici pa nt w h o c o nsid ers wi t hdra wi n g fr om t he st u d y must be i nf or me d b y t he I n vestig at or 
a b o ut m o difie d f oll ow- u p f or mat (e g, tele p h o ne c o ntact, a c o nt act wit h a relati ve or treati n g 
p h ysicia n, or i nf or mat i on fr o m me dical rec or ds).
At  the ti me of  
with dra wal fr om 
t he stu d y, if p ossi ble, a n Earl y  St u d y Int er ve nt i on 
Di sc o nti n uatio n visit s h o uld be c o n d ucte d, as s h o w n i n t he S o A. See S o A f or data t o be c ollecte d 
at t he ti me of  st u d y with dra wal a n d f oll ow- u p a n d f or a n y f urt her e val uat i ons t hat nee d t o be 
c o mplete d ( Secti o n  1. 3 ).
A parti ci pa nt w h o c o nsi ders wi t hdra wi n g fr om t he st u d y sh o ul d alwa ys be as ke d a b o ut t he 
reas o ns a n d t he prese nce of a n y A E. T he i n vesti gat or will f oll o w u p A Es o utsi de of t he cli nical 
st u d y.
If the partici pa nt wit h dra ws c o nse nt f or discl o s 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 nue 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 o m t he st u d y, it sh 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 wi t h the ori gi nal  co nse nt. If he/s he re q uests wit h dra wal of  co 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 
wi t h what was state d i n t he i nf or me d c o nse nt a n d l ocal re g ulat i on. T he I n vesti gat or m ust  
d oc u m e nt t he decisi o n o n use of  exist i n g sa m ples i n t he sit e st u d y rec or ds a n d i nf or m t h e 
S p o ns or .
If t he partici pa nt wit h dra ws fr o m t he st u d y, t he n his/ her e nr oll me nt/ra n d omizat i on c o de ca n n ot 
be re use d. W ith dra wal s u bjects will n ot be re place d.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
If a n y of t he st o p pin g crit eria detaile d i n Secti o n 7. 2. 1 are met , pri or a p pr o v al  of a su bsta nt ial 
pr ot oc ol  ame n d me nt s u m marizi n g t he e mer gi n g data a n d rati o nale f or restart will be re q uire d 
t o s u p p ort st u d y restart.
7. 2. 1
St o p pi n g R ules
T he st u d y will be p ut o n t e mp orar y  hol d ( defi ne d as a pa use i n e nr ol me nt of  t he parti ci pa nts) 
pe n di n g f urt her safety data a nal ysis if a n y S AE or ot her safet y  fi n di n g is assesse d as relate d t o 
t he st u d y i nter ve nt i on t hat, i n t he o pi ni o n o f Astra Ze neca, warra nts s us pe nsi on o f f urt her d osi n g 
of  p artici pa nts u nt il t he safety fi n di n g is f ull y assesse d.
7. 3
L ost t o F oll o w u p
A part ici pa nt will be c o nsi dere d l ost t o f oll 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 oll owi n g act i ons m ust be ta ke n if a parti ci pa nt fails t o r et ur n t o t he cli nic f or a re q uire d 
st u d y visit:

T he si t e must atte m pt t o c o ntact t he parti ci 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 parti ci pa nt o n t he i m p orta nce of  
mai ntai ni n g t he assi g ne d visi t sc he d ule a n d ascertai n w het her or n ot t he 
parti ci 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 oll ow u p, t he I n vesti 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 parti ci 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 
parti ci pa nt’s last k n o w n ma ili n g a d dress or l ocal eq ui vale nt met h o ds). 
T hese c o ntact atte m pts s h o ul d be d oc u m e nte d i n t he part ici 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 
b e 
c o nsi dere d t o ha ve wit h dra w n fr o m t he st u d y. 

Si t e pers o n nel, or a n i n de pe n de nt t hir d part y , will att e mpt t o c ollect t he 
vit al stat us of  the parti ci pa nt wit hi n le gal a n d et hical b o u n daries f or all 
parti ci pa nts ra n d o mize d, i ncl u di n g t hose w h o di d n ot get i n vesti gati o nal 
pr o d uct. P u blic s o urces ma y be searc he d f or vit al stat us i nf or mati o n. If 
vit al stat us is deter mi ne d as decease d, t his will be d oc u me nte d, a n d t he 
parti ci pa nt will n ot be c o nsi der e d l ost t o f oll ow- u p. S p o ns or pers o n nel will 
n ot be i n v o l ve d i n a n y atte m pts t o c ollect vital stat us i nf or mati on.
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.
8
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A. Pr ot oc ol wai vers or e xe m pti o ns 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
are n ot all o we d.
I mme diate safet y c o ncer ns s h o ul d be disc usse d wi t h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nt i n ue st u d y int er ve nt i on.
A d here nce t o t h e stu d y desi g n re q uire me nts, i ncl u di n g t hose 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.
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial part ici pa nts 
meet all eli gi bilit y crit eria. T he I n vesti gat or will mai ntai n a scree ni n g l og 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 bility or rec or d reas o ns f or scree ni n g fail ure, as 
a p plica ble.
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  the I C F ma y be utilize 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 wit hi n t he t i me 
fra me defi ne d i n t he S o A.
Re peat or u nsc he d ule d sa m ples ma y be ta ke n f or safet y reas o ns or f or tec h nical iss ues with t he 
sa m ples a n d m ust be ca pt ure d i n t he E D C s yste m. T h is ma y i ncl u de res ults fr om e xter nal 
la b orat ories w here partici pa nts ha ve teste d p ositi ve f or C O VI D- 1 9.
8. 1
Effic ac y Assess me nts
8. 1. 1
S A R S -C o V- 2 Ne utr alizi n g A nti b o d y Assess me nts
S er u m  sa mples t o meas ure S A R S -C o V - 2 n A b le vels will be c ollecte d fr o m parti ci pa nts 
accor di n g t o visi ts s pecifie d i n t he S o A (Ta ble 1 ). A ut h ori ze d la b orat or y will meas ure n A bs t o 
t he S A R S -C o V -2 e mer gi n g d o mi na nt varia nt(s) circ ulat i n g d urin g t he c o urse of t he st u d y, usi n g 
vali date d li ve vir us ne utralizat i on assa ys.
8. 1. 2
P artici p a nt- re p orte d C O VI D -1 9 S y m pt o ms 
To  det er mi ne t he i nci de nce of  infect i on, st u d y sites will c o ntact all part ici pa nts wee kl y 
(t ele p h o ne/e mail/te xt) t o c hec k f or a n y C O VI D -1 9 s y m pt o ms e x perie nce d si nce t he last c o ntact 
a n d wit h re mi n ders t o m o nit or a n d re p ort a n y C O VI D -1 9 s y m pt o ms.
D uri n g t hese c o ntacts, t he I n vesti gat or will assess w het her t he parti ci pa nts meet t he cli nical 
criteria f or S A R S -C o V - 2 i nfecti on (a da pte d fr o m t he W H O 
C O VI D - 1 9 case defi nit i on as 
defi ne d b y W H O 2 0 2 2 i n Cli nical ma na ge me nt of C O VI D -1 9: li vi n g g ui deli ne ) fr om t he past 
wee k.
T he f oll owi n g criteria a da pte d fr o m t he W H O C O VI D -1 9 case defi nit i on c li nical crit eria ( WH O 
2 0 2 2):

A n y t w o of  the f oll owi n g: fe ver (s u bjecti ve defi nit i on t o be use d f or fever) , c o u g h, 
p osi tive C O VI D -1 9 test (ra pi d a nt i ge n test or RT- P C R)
O R

Ac ute o nset of  AN Y T H R E E O R M O R E of  the f oll owi n g si g ns or s y m pt o ms: fever
(s u bjecti ve defi niti on t o be use d f or fe ver) , c o u g h, ge neral wea k ness/fat i g ue, hea dac he, 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
m yal gia, s ore t hr oat, c or yza, d ys p nea, na usea/ diarr hea/a n ore xia, c o nj u nct i vitis, p ositi ve 
C O VI D -1 9 test, s y m pt o m as j u d ge d b y t he I n vesti gat or t o be relate d t o C O VI D - 1 9.
If, f oll owi n g st u d y  i nter ve nti on a d mi nistrati o n, a s u bject de vel o ps C O VI D -1 9, acc or di n g t o t he 
Pr o visi o nal rec om me n dat i ons o n t he met h o ds f or pre ve nt i on, dia g n osis a n d treat m e nt of no vel 
c or o na vir us i nfecti o n ( C O VI D -1 9), iss ue d b y t he Mi nistr y o f Health of t he R ussia n Fe derati o n, 
versi o n 1 7 date d Dece m ber 1 4 , 2 0 2 2 ( Pr o visio n al rec o m me n datio ns 2 0 2 2) (s) he m ust call “ 1 2 2” 
t o be visite d b y a healt hcare pr ofessi o nal w h o, a m o n g ot her pr oce d ures, will perf or m a C O VI D -
1 9 a nti ge n test or R T -P C R . O nce a visit b y a h ealt hcare pr ofessi o nal has bee n re q ueste d, t he 
s u bject m ust n otif y t he st u d y do c t or of  the date s y m pt o ms occ urre d a n d t he date a healt hcare 
pr of essi o nal visit has bee n re q ueste d, as s o o n as p ossi ble. Als o, o nce a test res ult is a vaila ble, 
t he partici pa nt m ust re p ort wit hi n 3 da ys t he date of test a n d its res ult t o t he I n vesti gat or . If t he 
test res ult is p ositi ve, t he I n vesti gat or ( or his/ her dele gate, acc or di n g t o t he l o cal re g ulati ons a n d 
i nstituti o n g ui deli nes) will ma ke tele p h o ne calls every t hree d ays to c ollect safet y data u ntil t he 
s u bject i nf or ms a b o ut his/ her rec o ver y.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 ( Sectio n  1. 3 ).
8. 2. 1
P h ysic al E x a mi n ati o ns
F ull a n d tar gete d p h ysical e xa mi nat i ons will be perf or me d at t he visit s as s pecifie d i n t he S o As 
( Sectio n  1. 3 ).

A f ull p h ysical e xa mi nati on will i ncl u de, b ut is n ot li mi te d t o, assess m e nt of 
hei g ht, wei g ht, ge neral  a p peara nce, hea d, ears, e yes, n ose, t hr oat, nec k, s ki n, 
as well as car di o vasc ular, res pirat or y, a b d omi nal, a n d ner v o us s yste ms. Eac h 
cli nicall y si g nifica nt a b n or mal fi n di n g at scree ni n g will be rec or de d i n t he 
me dical hist or y  in t he e C R F.

A tar gete d p h ysical e xa mi nat i on will i ncl u de, b ut is n ot li mite d t o, areas 
s u g geste d b y t he me dical hist or y . W he n 
t here are n o ne w c o mplai nts or 
fi n di n gs, t his s h o uld be d oc u m e nte d. Eac h cli nicall y si g nifica nt a b n or ma l 
fi n di n g fr om t he ti me of st u d y int er ve nti o n a d mi nistrati o n s h o uld be re p orte d 
as a n A E per Secti o n  8. 3 .
8. 2. 2
Vit al Si g ns
Vit al si g ns, i ncl u di n g p ulse rate, res pirat or y r at e, blo o d press ure ( o n a n o n -d o mi na nt ar m  aft er 
a 1 0- mi n ute rest i n a sitti n g p osi tio n), a n d b o d y  te mperat ure will be assesse d at t he vis its as 
s pecifie d i n t he S o As ( Secti on  1. 3 ). O n t he visit 1 d a y  1, vit al sig ns will be assesse d pre -d ose 
a n d a gai n a p pr o xi matel y 1 0 t o 1 5 mi n utes af t er t he sec o n d i nject i on is gi ve n.
Si t u atio ns i n w hic h vital si g n res ults s h o ul d be re p orte d as A Es are descri be d i n Sect i on  8. 3. 7 .
8. 2. 3
Electr oc ar di o gr a m
1 2-lea d electr ocar di o gra m will be perf or me d at ti meli nes as s pecifie d i n t he S o A  ( Sectio n  1. 3 ). 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A 1 2- lea d E C G will be o btai ne d aft er 5 mi n utes ’ s u pi ne rest, usi n g t he sit e’s o w n E C G 
mac hi nes.
T he I n vesti gat or will j u d ge t he o verall i nter pretatio n as n or mal , b or derli ne, or a b n or mal. If 
a b n or mal, it will be d oc u me nte d as t o w het her or n ot t he a b n or mality is cli nicall y si g nifica nt b y 
t he I n vest i gat or. F or all a b n or malities (re gar dless of cli nical si g nifica nce), t he s pecific t y pe a n d 
nat ure of  the a b n or malit y will be d o c u m e nte d. Cli nicall y si g nifica nt fi n di n gs s h o uld als o be
d oc u m e nte d o n t he A E pa ge of t he e C R F .
T he I n vesti gat or ma y a d d e xtra 1 2- lea d resti n g E C G safety assess me nts if t here are a n y 
a b n or mal fi n di n gs or if t he I n vestig at or c o nsi ders it is re q uire d 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 u nsc he d ule d assess me nts.
8. 2. 4
Cli nic al S afet y L a b or at or y Assess me nts
T he ser u m che mistr y, hae mat ol o g y, a n d c oa g ulatio n  anal yses will be p erf or m e d at a l ocal 
la b orat or y at or near t o t he st u d y site (see Sectio n  1. 3. 1 ). Bl o o d s h o ul d be ta ke n i n t he m or ni n g 
o n a n e m pt y st o mac h, after 8-1 4 h o urs of o ver ni g ht fast.
S a m ple t u bes a n d sa mple sizes ma y var y  de pe n di n g o n lab orat or y  met h o d use d a n d r o uti ne 
prac tice at t he sit e.
A d dit i onal safety sa mples ma y be c ollecte d if cli nicall y in dicate d at t he di screti on of  the 
I n vesti gat or. T he date, ti me of  collect i on, a n d res ults ( val ues, u nits, a n d refere nce ra n ges) will 
be rec or de d o n t he a p pr o priate e C R F.
T he l a b orat or y varia bles t hat will be meas ure d are liste d i n Ta ble 7.
Ta ble 7
L a b or at or y S afet y V a r i a bles
He m at ol o g y
W hite bl o o d cell ( W B C) c o u nt 
Ne utr o p hils a bs ol ute c o u nt
Re d bl o o d cell ( R B C) c o u nt 
L y m p h oc ytes a bs ol ute c o u nt 
He m o gl o bi n ( H b) 
M o n oc ytes a bs ol ute c o u nt 
He mat ocrit ( H C T) 
E osi n o p hils a bs ol ute c o u nt 
Mea n c or p usc ular v ol u me ( M C V) 
Bas o p hils a bs ol ute c o u nt 
Mea n c or p usc ular he m o gl o bi n ( M C H) 
Platelets 
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
( M C H C)
Ser u m  C he mistr y 
S o di u m 
Al kali ne p h os p hatase ( A L P)
P otassi u m
Ala ni ne a mi n otra nsferase ( A L T)
Ur ea
As partate a mi n otra nsferase ( A S T)
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Creati ni ne (a n d esti mate d gl o mer ular filtrati o n 
rate [e G F R])
Ga m ma gl uta m yl tra ns pe pti dase ( G G T)
Al b u mi n
T otal bilir u bi n ( T B L) 
Calci u m 
C o nj u gate d bilir u bi n 
P h os p hate
Tr o p o ni n, hi g h -se nsiti vit y test (scree ni n g o nl y)
Gl uc ose (ra n d o m)
C o a g ul ati o n
Act i vate d partial t hr o m b o plasti n ti me (a P T T) 
Pr ot hr o m bi n ti me ( P T) ( or i nter nati o nal
n or ma lize d rati o)
Ot her
HI V test (all s u bjects)
Ot her ( w o me n of c hil d be ari n g p ote nti al o nl y)
Uri ne or ser u m ( β -h C G) pre g na nc y test
F ollicle sti m ulati n g h or m o ne а
a
F or fe male partici pa nts a ge d < 5 0 years w h o are c o nsi dere d p ost me n o pa usal, will be perf or me d at 
scree ni n g if t he y ha ve bee n a me n orr h oeic f or 1 2 m ont hs o r m ore f oll o wi n g cessati on o f e x o ge n o us h or m onal
treat me nt.
I n case a partici pa nt s ho ws a n A S T or A L T ≥ 3 × U L N t o get her wit h t otal bilir u bi n ≥ 2 × U L N please refer t o 
A p pe n di x D f or f urt her i nstr ucti o ns. 
β- h C G = beta h u ma n c h ori o nic g o na d otr o pi n; U L N = u p per li mit of n or mal
F or W O C B P o nl y , a uri ne or ser u m  β-h C G pre g na nc y test will b e p erf or m e d l ocall y at Visit 1. 
T he test m u st be ne gat i ve bef ore d osi n g. A ser u m pre g na nc y t est ma y be p erf or me d if a uri ne 
pre g na nc y test is n ot p ossi ble.
8. 2. 5
Ot her S afet y Assess me nts
8. 2. 5. 1
I m me di ate A d verse E ve nts 
P arti cipa nts will  be ke pt u n der o bser vat i on f or 1 h o ur after st u d y i nter ve nti o n a d mi nistrati o n t o 
e ns ure t heir safet y.  An y A E t hat occ urs d uri n g t his peri o d will be n ote d o n t he s o urce d oc u me nt  
a n d i n t he e C R F.
As wi t h a n y bi o l ogic pr o d uct, h y perse nsit i vity reactio ns (incl u di n g a na p h yla xis) a n d i njecti on 
sit e reactio ns are p ossi ble. T heref ore, a p pr o priate dr u gs a n d me dical e q ui p me nt t o tr e at t hese 
reactio ns m ust be i m me diatel y  a vaila ble, a n d st u d y pers o n nel m ust be traine d t o rec o g nize a n d 
treat a na p h yla xis. Ma na ge me nt of  ana p h yla xis a n d h y perse nsit i vity s h o uld be p erf or m e d i n 
acc or da nce wit h c urre nt sta n dar d of care a n d cli nical g ui deli nes.
A n y A Es s h o ul d be re p orte d as descri be d i n Sect i on  8. 3 .
8. 2. 5. 2
I njecti o n Site Re acti o ns 
I njecti on sit e reacti o ns ma y be o bser ve d a n d ma y ma nifest as l ocal infla m mati o n, re d ness, 
itc hi n g, pai n, s welli n g, br uisi n g, a n d p ossi ble blee di n g or i nfecti on at t he sit e of  inject i on.  
Di a meters of a n y re d ness/s welli n g will be rec or de d.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
I njecti on sit e reacti o ns will be m o nit ore d as s pecifie d i n t he S o As ( Sectio n 1. 3 ). O n stu d y da y 
w here st u d y int er ve nt i on is a d mi nistere d, t he i njecti on sit e m o nit ori n g will be p erf or m e d
i m me diatel y aft er, 3 0 mi n utes ( + 1 0 mi n utes) , a n d 1 h o ur aft er b ot h i nject i ons are c o m plete a n d 
als o prior t o p arti ci pa nt release. I njectio n site reactio n s will als o be m o nit or e d o n Vis it 2 ( D a y 
8).
A n y A Es s h o ul d be re p orte d as descri be d i n Sect i on  8. 3 .
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t hat all st aff i n v ol ve d i n t he st u d y ar e 
fa miliar with t he c o nte nt of t his sect i on. 
T he defi ni tio n s 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 ogate, or t he partici pa nt ’s le gall y a ut h orize d re prese ntati ve or e q ui vale nt re prese ntati ve as 
l ocall y defi ne d).
T he I n vestig at or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u m e 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.
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, M A A E, A E SI will be c o llecte d fr o m t he ti me of  st u d y int er ve ntio n a d mi nistratio n 
t hr o u g h o ut t he st u d y, u p t o a n d i ncl u di n g t he last visit.
S A Es will be rec or de d fr o m t he ti me of  si gni n g of  the I C F t hr o u g h o ut t he stu d y, u p t o a n d 
i ncl u di n g t he last visit. 
A n y A E SIs will be s pecifie d i n t he e C R F b y I n vesti gat or a n d will be assesse d fr o m t he ti me of 
st u d y int er ve ntio n (see Sect i on 8. 3. 4) .
If t he I n vesti gat or bec o mes a ware of  an A E/ S A E wit h a s us pecte d ca usal relatio ns hi p t o t he 
st u d y int er ve nt i on t hat occ urs after t he data c ollectio n  p erio d s pecifie d i n t he pr ot oc ol, or aft er 
t he e n d of t he cli nical st u d y i n a partici pa nt treate d b y hi m or her, t he I n vest i gat or s hall, wit h o ut
u n d ue dela y, b ut n ot late t ha n 2 4 h o urs, re p ort t he seri o us a d verse e ve nt 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 ol ve d at t he parti ci pa nt ’s last A E assess me nt i n t he st u d y are f oll owe d 
u p b y t he I n vesti gat or f or as l on g as me d icall 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 rig ht t o re q uest a d ditio nal i nf or mati on f or a n y part ici pa nt wi t 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 varia bles will be c ollecte d f or eac h A E:

A E ( ver bat i m)
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

T he date a n d ti me w he n t he A E starte d a n d st o p pe d

Se verit y gra de/ ma xi m u m se verit y gra de/c ha n ges i n se verit y gra de

W het her t he A E is seri o us or n ot

I n vesti gat or ca usality rati n g a gai nst t he I n vesti gati o nal Pr o d uct(s) ( yes or n o)

Act i on ta ke n wit h re gar d t o I n vesti gat i onal Pr o d uct(s)

If t he A E ca use d partici pa nt’s wit h dra wal fr om st u d y ( yes or n o)

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 s erio us d ue t o

Date of h os pi talizatio n

Date of disc har ge

Pr o ba ble ca use of deat h

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 t o ot her me dicat i on

Descri pt i on
Se verit y rati n gs will be use d, a da pte d fr o m  t he C T C A E v 5. 0 ( NI H 2 0 1 7), a n d are descri be d i n 
A p pe n di x B .
8. 3. 3
C a us alit y C ollecti o n
T he I n vest i gat or s h o ul d assess ca usal relati ons 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 uest i on ‘D o y o u c o nsi der t hat t here is a reas o na ble p ossi bil ity t hat t he e ve nt ma y 
ha ve bee n ca use d b y t he i n vest i gati onal pr o d uct? ’
F or S A Es, ca usal relati ons hi p s h o uld als o be assesse d f or ot her me 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 usa l 
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.
8. 3. 4
A d verse E ve nts of S peci al I nterest
A d verse e ve nts of s pecial i nterest will be A E SIs will be s pecifie d i n t he e C R F b y I n vesti gat or 
a n d will be assesse d fr o m t he ti me of st u d y int er ve nt i on.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A n A E SI is a n e v e nt of scie ntific a n d me dical i nterest, s pecific t o t he f urt her u n dersta n di n g of 
t he safet y pr ofile of  the st u d y int er ve nti o n a n d re q uires close m o nit ori n g a n d r a pid 
c o m m u nicat i on b y t he I n vest i gat ors t o Astra Ze neca. A n A E SI ca n be seri o us or n o n -seri o us.
T he A E SIs f or A Z D 3 1 5 2 are:

 
8. 3. 5
Me dic all y Atte n de d A d verse E ve nts
Me dicall y  atte n de d a d verse e ve nts will be c o llecte d acc or di n g t o t he ti me p oi nts s pecifie d i n t he 
S o As ( Secti o n 1. 3 ).
Me dicall y  atte n de d a d verse e ve nts are defi ne d as A Es lea d i n g t o me dicall y-atte n de d visit s t hat 
were n ot r o uti ne visits f or p h ysical e xa mi nat i on or vacci nati o n, s uc h as a n e mer ge nc y r o o m 
visit, or a n ot her wise u nsc he d ule d visit t o or fr o m me dical pers o n nel  ( me dical d oct or) f or a n y 
reas o n. A d verse e ve nts, i ncl u di ng a b n or mal vital si g ns, i de ntifie d o n a r o utine st u d y visit will 
n ot be c o nsi dere d M A A Es.
8. 3. 6
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 parti ci pa nt or care pr o vi der 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 site staff: ‘Ha ve y o u ha d a n y healt h pr o bl e 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 vat i on will be c ollecte d a n d rec or de d 
i n t he e C R F. W he n c o llecti n g A Es, t he rec or din g of  dia g n oses is pr ef erre d ( w he n p ossi ble) t o 
rec or di n g a list of  si gns 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 osi s a n d eac h si g n or 
s y m pt o m will be rec or de d se paratel y.
Di a g n oses of  sus pecte d or c o nfir me d C O VI D -1 9, c o nfir me d as y m pt o mat ic S A R S -C o V -2 
i nfecti on, a n d/ or rec urre nce of  CO VI D - 1 9 ( or of  SA R S -C o V - 2 rei nfecti on) will be c ollecte d 
a n d rec or de d i n t he e C R F as a n A E.
8. 3. 7
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 om t he C S P ma n date d lab orat or y  t ests a n d vital si g ns will be s u m marise d i n t h e 
C S R. 
Deteri or ati o n as c o mpare d t o baseli ne i n pr ot oc ol -ma n date d lab orat or y  val ues, vit al 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 ulfi l a n y of the S A E criteria, are t he reas o n f or 
di sc o nti n uati on of  treat me nt wit h t he i n vesti gati on al  pr o d uct or are c o nsi dere d t o be cli nicall y 
r ele va nt as j u d ge d b y t he I n vesti gat or ( w hic h ma y i ncl u de b ut n ot li mite d t o c o nsi derat i on as t o 
w het her treat me n t or n o n-pla n ne d visit s were re q uire d or ot her acti o n was ta ke n wit h t he st u d y 
i nter ve nt i on, e g, d ose a dj ust me nt  or dr u g i nterr u pti o n).
If d et eri or ati o n i n a la b orat or y val ue/ vit al sig n is ass ociat e d wit h cli nical sig ns a n d s y m pt o m s, 
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 lab orat or y  res ult/ vital 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 ter m (e g, a nae mia vers us l o w hae m o gl o bi n val ue) . I n t he 
a bse nce of  cli nical si g ns or s y m pt o ms, cli nicall y rele va nt deteri orati o ns i n n o n- ma n date d 
para m eters s h o uld be re p orte d as A E(s).
A n y ne w or a g gra vate d cli nicall y rele va nt a b n or mal me dical fi n di n g at a p h ysical e xa mi nat i on 
as c o mpare d wi t h the bas eli ne assess me nt will be re p orte d as a n A E u nless u ne q ui v ocall y relate d 
t o t he disease u n der st u d y.
8. 3. 8
H y’s L a w
Cases w here a partici pa nt s h o ws ele vat i ons i n li ver bi oc he mistr y ma y re q uire f urt her e val uat i on 
a n d occ urre nces of  A S T or A L T ≥3 × U L N t o get her wi t h total  bilir u bi n ≥2 × U L N ma y nee d 
t o be re p orte d as S A Es.
W here A S T or A L T ≥ 3 × U L N t o get her wit h T B L  ≥ 2 × U L N occ urs, w here n o ot her reas o n, 
ot her t ha n t he st u d y int er ve nt i on, ca n be f ou n d t o e x plai n t he c o m bi nat i on of  increases, e g, 
ele vate d alkali ne p h os p hatase i n dicati n g c h o lestasis, viral he pati tis, a n ot her dr u g s h o ul d b e 
e val uate d. T he ele vat i on i n tra nsa mi nases m ust prece de or be c oi nci d e nt wi t h (ie, o n t h e s a m e 
d a y ) t he ele vat i on i n T B L, b ut t here is n o s pecified ti mefra me wi t 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 .
Pl ease r efer t o A p pe n di x D f or f urt her i nstr ucti o n o n cases of  increases i n li ver bi oc he mistr y 
a n d e val uatio n of  H L.
8. 3. 9
Re p orti n g of Seri o us A d verse E ve nts
All S A Es m ust 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 M P. All S A Es will 
be rec or de d i n t he e C R F.
If a n y S A E occ urs i n t he c o urs e of t he st u d y, I n v estigat ors or ot her sit e pers o n nel will i nf orm 
t he a p pr o priate Astra Ze neca re prese ntati ves wi t hi n o ne d a y  ie, i m me diatel y b ut n o l ater th a n 
2 4 h o urs of  w he n he or s he bec omes 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 vest i gat or t o e ns ure t hat all t he 
necessar y  inf or mat i on is pr o vi de d t o t he Astra Ze neca Patie nt Safet y  d at a e ntr y sit e wit hi n o ne
c ale n d ar d a y of  i nitial recei pt f or fatal a n d life-t hreate ni n g eve nts a n d wit hi n 5 c ale n d ar d a ys 
of  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 mati 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 sit e pers o n nel will i nf orm
Astra Ze neca re prese ntati ves of a n y f o ll 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 wit hi n 
o ne cale n dar da y, ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs of  w he n he or s he bec ome s a ware 
of  it.
O nce t he I n vest i gat ors or ot her site pers o n nel in dicate a n A E is 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. 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 S A E 
t o t he a p pr o priate Astra Ze neca re prese ntati ve b y tele 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.
F or f urt her g ui da nce o n t he defi nit i on of a S A E, see  A p pe n di x B.
T he r efere nce d o c u m e nt f or defi nit i on of  ex pecte d ness/liste d ness is t he A Z D 3 1 5 2 / A Z D 5 1 5 6
I n vesti gat or’s Br oc h ure.
8. 3. 1 0
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:

If t he pre g na nc y is disc o vere d bef ore t he stu 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 ncies i n t he part ner of male partici pa nts
8. 3. 1 0. 1
M ater n al E x p os ure
T he I M P s h o ul d n ot be gi ve n t o pre g na nt w o me n.
Pre g na nc y itself is n ot re gar de d as a n a d verse e ve nt u nless t here is a s us picio n  that t he 
i n vesti gati onal pr o d uct u n der stu d y ma y 
ha ve i nterfere d wi t h the effecti ve ness of  a 
c o ntrace pti ve me d icatio n. 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. El ect i ve a b ortio ns wi t ho ut c o m p licati ons s h o uld n ot 
be ha n dle d as A Es. T he o utc o m e of  all pre g na ncies (s p o nta ne o us miscarria ge, 
elect i ve 
ter mi nati o n, e ct o pic pre g na nc y, n or m al birt h or c o n ge nital a n o ma l y/ birt h defect) s h o ul d b e 
f oll owe d u p a n d d oc u me nte d e ve n if t he partici p a nt was disc o nti n ue d fr om 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 vest i 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 ome s a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wi t h the I n vesti gat or t o e ns ure t hat all 
r ele va nt i nf or mati on is pr o vi de d t o t he Astra Ze neca Pati e nt S af et y data e ntr y sit e wit hi n 1 o r  
5 c ale n d ar d a ys f or S A Es (see Secti o n 8. 3. 9 ) 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 P R E G R E P m o d ul e i n t he e C R F is use d t o re p ort t he pre g na nc y  an d t he pa per -base d 
P R E G O U T m o d ule is use d t o re p ort t he o utc o me of t he pre g na nc y .
8. 3. 1 1
Me dic ati o n Err or, Dr u g A b use, a n d Dr u g Mis use
8. 3. 1 1. 1
Ti meli nes
If a n e ve nt of  me dicat i on err or, dr u g a b use, o r dr u g mis use occ urs d uri n g t he st u d y, t he n t h e 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 c ale n d ar  d a 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 t he y bec o me a ware of it.
T he desi g nate d Astra Z e neca re prese ntati ve w or ks wi t h the I n vesti gat or t o e ns ure t hat all 
r ele va nt i nf or mati on is c o m p lete d wit hi n 1
(I nitial Fatal / Life-T hreate ni n g or f oll ow u p 
Fatal / Life-T hreate ni n g) or  5 ( ot her seri o us i nitial a n d f oll ow u p) c ale n d ar da ys if t here is a n 
S A E ass ociate d wit h t he e ve nt of  me dicat i on err or, dr u g a b use, or mis use (see Secti o n 8. 3. 9 ) 
a n d wit hi n 3 0 d a ys f or all ot her me dicati on err ors.
8. 3. 1 1. 2
Me dic a ti 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 nte n de d fail ure or mista ke i n 
t he treat me nt pr ocess f or a n I M P or Astra Ze neca NI M P t hat eit her ca uses har m t o t he partici pa nt  
or has t he p ote ntial t o ca use har m t o t he partici pa nt .
T he f ull defi nit i on a n d e xa m ples ca n be f o u n d i n  A p pe n di x B B 4.
8. 3. 1 1. 3
Dr u g A b use
Dr u g a b use is t he persi ste nt or s p ora dic i nte nti o n al, n o n- t hera pe utic e xcessi ve use of  IM P or 
Astra Ze neca NI M P f or a percei ve d re war d or desire d n o n -t hera pe utic effect.
T he f ull d efi nitio n  a n d e xa m ples ca n be f o u n d i n A p pe n di x B B 4.
8. 3. 1 1. 4
Dr u g Mis use
Dr u g mis use is t he i nte nti o n al a n d i na p pr o priate use ( b y a st u d y partici pa nt) of  IM P 
or 
Astra Ze neca NI M P f or me dici nal p ur p oses o utsi de of t he a ut h orize d pr o d uct i nf or mat i on, or f or 
u na ut h ori ze d I M Ps or Astra Ze neca NI M Ps, o utsi d e t he i nte n de d use as s pecifie d i n t he pr ot oc o l 
a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y  t he wr o n g r o ute.
T he f ull defi nit i on a n d e xa m ples ca n be f o u n d i n  A p pe n di x B B 4.
I n t his st u d y partici pa nts will recei ve i n vesti gatio nal  pr o d ucts a d mi nistere d I M i n t he 
a nter olat er al t hig h o n Da y 1. All p arti ci pa nts will be d ose d at t h e sit e, t he y will recei ve st u d y 
i nter ve nt i on di rectl y fr om t he u n bli n de d p har macist or desi g nee, u n der me dical s u per visi on.  
T he c ha nce f or dr u g a b use a n d dr u g mis use b y partici pa nt is rare.
8. 4
O ver d ose
F or t his st u d y, a n y d ose of  st u d y int er ve nt i on ( or d osi n g fre q ue nc y) greater t ha n w hat is 
s pecifie d i n t his pr ot oc ol will be c o nsi dere d a n o ver d ose (see  Ta ble 5 ).

A n o ver d ose wi t h ass ociate d A Es is rec or de d as t he A E dia g n osi s/s y m pt o ms o n t he 
r ele va nt A E mo d ul es 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 int er ve ntio n occ urs i n t he c o urse of  the st u d y, t he 
I n vesti gat or or ot her 
sit e pers o n nel 
i nf or m a p pr o priate Astra Ze neca 
re prese ntativ es 
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical S t u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
assa y pr oce d ure will be carrie d o ut acc or di n g t o t he i nstr uctio ns e nclos e d i n t he c o m mercial 
r a pid test ki t.
8. 6
O pti o n al Ge n o mics I niti ati ve S a m ple
O pti o nal  Ge n o mics I nitiat i ve researc h is n ot a p plica ble i n t his st u d y.
8. 7
Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics
Me dical Res o urce Utilizat i on a n d Healt h Ec o n o mics para meters are n ot e val uate d i n t his st u d y .
9
S T A TI S TI C A L C O N SI D E R A TI O N S
9. 1
St atistic al H y p ot heses
T he pri mar y o bject i ve of the st u d y  is t o e val uate t he safety of  AZ D 3 1 5 2 c o m pare d wi t h place b o . 
N o f or mal statistical h y p ot hesis was pr o p ose d, a n d t he d ata prese ntati o n a n d a nal ysis will  be 
descri pt i ve i n its nat ure.
9. 2
S a m ple Size Deter mi n ati o n
T he pri mar y o bject i ve of the st u d y  is t o e val uate t he safety o f A ZD 3 1 5 2 c o m pare d wi t h place b o . 
C orres p o n di n g pri mar y e n d p oi nts t o be e xa mi ne d:

Occ urre nce of A Es c o llecte d t hr o u g h o ut t he st u d y

Occ urre nce of S A Es c ollecte d t hr o u g h o ut t he st u d y

Occ urre nce of M A A Es c ollecte d t hr o u g h o ut t he st u d y

Occ urre nce of A E SIs c ollecte d t hr o u g h o ut t he st u d y
S a m ple size deter mi nat i on is base d o n t he pr o ba bilit y -base d a p pr oac h f or a si n gle e ve nt. T he 
pr o ba bilit y o f a d verse e ve nt is p , t heref ore, t he pr o ba bility of  n o a d verse e ve nt is ( 1 – p) .
T he pr o ba bilit y o f n o o bser vat i ons i n n o bser vat i ons = ( 1 – p)^ n , a n d t his pr o ba bility is e q ual t o 
( 1 - p o w er) . We nee d t o s ol ve a n e q uati o n: ( 1 – p)^ n = ( 1 – p o w er) w hic h is e q ual t o n *l o g 1 0( 1 
– p) = l o g 1 0 ( 1 – p o w er) . 
S ol vi n g f or n, we get: n = l o g 1 0 ( 1 – p o w er) / l o g 1 0( 1 – p)
T he c h o ice of  the
 t hres h ol d of A E r ates was base d o n t he data fr o m P R O V E N T st u d y 
( D 8 8 5 0 C 0 0 0 0 2/ N C T 0 4 6 2 5 7 2 5). T he st u d y was perf or me d i n si milar p o p ul at i on. Safet y 
i nf or mat i on use d f or t he calc ulat i on was c o llecte d d uri n g a mi ni m u m of 5-m o nt h safet y f oll ow-
u p i n all p artici pa nts a n d a me d ia n d urat i on of  fol l o w-u p was a p pr o xi matel y 6 m o nt hs, w hic h 
is e q ual t o t he pla n ne d o bser vati on peri o d i n t he c urre nt st u d y, a d ditio nal safet y data (c ollecte d 
f or t he l o n ger f oll ow -u p peri o d) i n t he fi nal st u d y re p ort f or P R O V E N T st u d y was q uite si milar 
t o w hat is c o llecte d at  5-m o nt h safety f oll ow- u p. I n P R O V E N T st u d y t he fre q ue ncies of  S A E
were l ow: 
i n m A b
(E V U S H E L D ) gr o u p a n d 
 i n pl ace b o gr o u p. Perce nta ges of  
s u bjects e x perie nce d at least o ne A E SI (a na p h yla xis a n d ot her se vere h y perse nsiti vity r eact io ns 
C CI
C CI
C CI
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 9 of 9 4
9. 4. 1
Ge ner al C o nsi der ati o ns
Cate g orical varia bles will be prese nte d as fre q ue ncies a n d pr o p ortio ns i n perce nt.  C o nti n u o us 
varia bles will be prese nte d as mea ns, ge o metric mea ns ( w here a p plica ble), sta n dar d de viati ons, 
ge o m etric sta n dar d de viat i ons ( w here a p plica ble), me d ia ns, mi ni m u m a n d ma xi m u m, a n d 
q uartiles ( w here a p plica ble), wi t h nu m ber of  obser vat i ons. W he n 
necessar y, mea ns 
a n d 
ge o m etric mea ns will be pr o vi de d wi t h tw o -si de d 9 5 % c o nfi de nce i nter vals ( CI). Treat me nt  
ar ms will be descri pt i vel y c o mpare d b y c orres p o n di n g varia bles .
T he data a n d res ults of  t he a nal yses will be prese nte d i n t he f or m of ta bles as well  as listi n gs, 
s orte d b y treat me nt ar ms a n d part ici pa nt n u m bers. Met h o ds of a nal ysis will be o utli ne d i n detail 
i n t he Statistical A nal ysis Pla n.
Vali date d S A S s oft ware versi o n 9. 4 or R stati stical pac ka ge versi o n 4. 2 or hi g her will be use d 
f or st atistical a nal ysis a n d re p orti n g of  t he st u d y d at a. T h e r es ults of  t he a na l ysis prese nte d i n 
t he cli nical st u d y re p ort will be vali date d acc or di n g t o t he c o mpa n y's sta n dar d o perati n g 
pr oce d ures.
9. 4. 2
E n d p oi nts
9. 4. 2. 1
Pri m ar y E n d p oi nt 
Pri mar y safet y e n d p o i nt i ncl u des A Es a n d S A Es, M A A Es, a n d A E SIs c ollecte d t hr o u g h o ut t he 
st u d y. A d verse e ve nt s a n d S A Es will be c o de d usi n g t he m o st rece nt versi o n of  Me d D R A a nd 
will be s u m mari ze d b y s yste m or ga n class a n d preferre d ter m a n d b y se veri t y a nd r el ati o ns hi p 
t o st u d y int er ve nt i on as j u d ge d b y t he I n vest i gat or.
I nterc urre nt e ve nts: treat me nt p olic y will  be a p plie d, i.e., all e ve nts c ollecte d will be i ncl u de d 
i n t he a nal ysis.
S af et y a nal ysis set will be use d f or t he a nal ysis of t his e n d p o i nt. 
N u m ber a n d pr o p orti o n of  partici pa nts wit h A Es , S A Es, M A A Es, 
a n d A E SIs
( occ urri n g 
t hr o u g h o ut t he st u d y peri o d after st u d y i nter ve nti on a d mi nistrati o n) se paratel y will be pr o vi de d 
f or eac h ar m, a n d will be descri pti vel y c o m pare d bet wee n ar ms.
9. 4. 2. 2
Sec o n d ar y E n d p oi nt(s) 
Sec o n d ar y e n d p oi n t: Titer f or S A R S -C o V -2 e mer gi n g d o mi n a nt v ari a nt(s) n A bs .
C orres p o n di n g e n d p o i nts are G M T s a n d G M F T s f or S A R S -C o V -2 e mer gi n g d o mi na nt  
varia nt(s) n A bs.
I nterc urre nt e ve nts: P arti ci pa nts w h o e x perie nce a pr ot oc ol de viati on t hat ca n i nterfere wit h a n 
a nt i b o d y res p o nse or vi olate a d here nce t o t he assi g ne d d ose, bec ome i nfecte d, recei ve C O VI D -
1 9 treat me nt or vacci nat i on t hat ca n alt er n A b levels will ha ve data c ollecte d aft er t he 
i nterc urre nt e ve nt set t o missi n g f or a nal ysis of t his e n d p oi nt (i.e., w hile-o n -treat me nt strate g y 
is a p plie d).
S A R S -C o V -2 n e utralizi n g a nt i b o d y a nal ysis set will be use d f or t he a nal ysis o f t his e n d p oi nt.
R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
9. 5
I nteri m A n al yses
I nteri m a n al ysis (u n bli n de d)
A n i nteri m a nal ysis is pla n ne d after 1 1 6 partici pa nts ha ve c o m plete d Visit 4 visit 4 ( Da y 2 9) ( or 
earl y wi t hdr a w al  fr om
t he st u d y) t o e val uate earl y safety at Da y  29 . Efficac y d at a ma y b e 
prese nte d as a p pr o priate at  i nteri m a nal ysis if a de q uate data all o ws.
T his i nteri m a nal ysis will i ncl u de pri mar y e n d p oi nt varia bles: all A Es, S A Es, M A A Es, a n d 
A E SIs a n d n A b res p o nses t o t he S A R S -C o V -2 e mer gi n g d o mi na nt varia nt (s).
T his i nteri m a nal ysis will be u n bli n de d a n d will be perf or me d b y a se parate u n bli n de d tea m . All 
t he para meters, alo n g wi t h ot her res ults (di s p ositio n, de m o gra p hic data etc. – t o be s pecifie d i n 
t he S A P ) will be pr o vi de d b y treat me nt ar ms. Treat me nt ar ms will  be descri pti vel y c o m pare d 
b y c orres p o n di n g varia bles.
Fi n al a n al ysis ( u n bli n de d)
T he fi nal a nal ysis will  be p erf or m e d o nce all s u bjects c o mplete Visit 6 ( Da y 18 1) or earl y 
wi t hdra wal  fr o m t he st u d y. 
Res ults of  ex pl orat or y  en d p o i nt eval uat i on ma y be prese nte d i n a cli nical st u d y re p ort or i n a 
se parate re p ort.
T he Stati stical A nal ysis Pla n will descri be b ot h pla n ne d a nal yses i n m ore detail.
T he st u d y will mai ntai n a d o u ble -bli n de d ( i.e. , bli n d f or partici pa nts a n d I n vesti gat ors/site staff) 
u nt il the fi nal a nal ysis. To  mai ntai n t he i nte grit y o f the st u d y t o all o w f or ri g or o us e val uat i on o f 
safety a n d efficac y t hr o u g h t he e n d of t he st u d y, t he site pers o n nel a n d partici pa nts will re mai n 
bli n de d t o t he treat me nt assi g n me nt u ntil t he e n d of  the st u d y a n d fi nal rea d o ut. T he i nteri m 
a nal ysis will be c arrie d o ut b y a n u n bli n de d a nal ysis tea m at Astra Ze neca or i ts dele gates, a n d 
t he pr oce d ure will be detaile d i n a St u d y I nte grit y P la n. Parti ci pa nt -level u n bli n di n g i nf or mat i on 
will be ke pt strictl y c o nfi de n tial, a n d t he ratio nale f or a n y  u n bli n di n g will be d oc u me nte d.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 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
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 wit h t he pr ot oc ol a n d wit h t he 
f oll owi n g:
o
C o nse ns us et hical pri nci ples deri ve d fr om 
i nter nat i onal g ui deli nes i ncl u di n g t h e 
Declarati o n of  Helsi n ki an d C o u ncil f or I nter nati o nal Or ga nizat i ons o f Me dical Scie nces 
( CI O M S) I nter nati o nal Et hical G ui deli nes
o
A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli nes
o
A p plica ble la ws a n d re g ulati o ns

T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vest i gat or Br oc h ure, a n d ot her 
r ele va nt d oc u me nts (e g, a d vertise 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 vest i gat or a n d revie 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  Aut 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 desig 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 or o btai ni n g t he re q uire d a ut h orisat i ons 
t o c o n d uct t he st u d y fr o m the 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 
wi t 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  the st u d y at t he sit e a n d a d here nce t o re q uire me nts of  IC H g ui deli nes, 
t he I R B/I E C, a n d all ot her a p plica ble l ocal re g ulat i o ns
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es

Pr o m pt n 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 gal obli gat i ons a n d et hic al res p o nsi bilit ies t o war ds t he safety of 
parti ci pa nts a n d t he safety of  a st u d y int er ve nt i on u n der cli nical 
i n vesti gati on are met.

T he S p o ns or has a le gal res p o nsi bilit y to n otif y b ot h t he l ocal re g ulat or y 
a ut h orit y an d ot h er re g ulat or y a ge ncies a b o ut t he safety of  a st u d y 
i nter ve nt i on u n der cli nical i n vesti gati on. T he S p o ns or will c o m p l y wi t h 
c o u ntr y-s pecific re g ulat or y re q uire me nts relat i n g t o safet y re p orti n g t o t he 
re g ulat or y aut h ori t y, I nstituti o nal Re vie w 
B oar ds 
(I R B)/I n de pe n de nt 
Et hics C o m mit tees (I E C), a n d I n vesti gat ors.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

F or all st u dies e xce pt t hose ut ilizi n g me dical de vices, I n vesti 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 
reactio ns ( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d 
S p o ns or p olic y a n d f or war de d t o I n vest i gat ors as necessar y.
o
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 lo c al  re g ulati ons

A n I n vesti gat or w h o recei ves a n I n vestig at or safet y re p ort descri bi n g a 
S A E or ot her s pecific safet y i nf or mat i on (e g, s u m mar y or list i n g of SA Es) 
fr om t he S p o ns or will re vie w a n d t he n file it al o n g wit h t he [I n v est i gat or’s 
Br oc h ure or stat e ot her d oc u me nts] 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.
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us Bre ac hes

Pr o m pt n otificati o n b y t he I n vestig at or t o Astra Ze neca of  an y ( p ote ntial) 
serio us breac h of  t he pr ot oc ol  or r e g ul atio ns is esse nt ial s o t hat le gal a n d 
et hical o blig ati o ns are m et.
o
A ‘seri o us breac h’ mea ns a breac h li kel y t o affect t o a si g nifica nt de gree t he safety a n d 
rig hts of  a partici pa nt or t he relia bility a n d r o b ust ness of  t he data ge nerate d i n t he cli nical 
st u d y.

If a n y (p ote nti al) serio us breac h occ urs i n t he c o urse of  the st u d y, 
I n vesti gat ors or ot her site pers o n nel will  inf or m  the a p pr o priate 
Astra Ze neca re prese ntati ves i m me diatel y after he or s he bec o me s a ware of 
it.

I n certai n r e gio n s/c o u ntries, Astra Ze neca has a le gal res p o nsi bility t o 
n otif y b ot h t he l ocal re g ulat or y aut h ori t y an d ot her re g ulat or y age ncies 
a b o ut s uc h breac hes.
o
Astra Ze neca will c o m p l y with c o u ntr y-s pecific re g ulat or y re q uire me nts relati n g t o 
serio us br eac h re p ortin g t o t h e r e g ulat or y aut h ori t y, I R B/I E C, a n d I n vesti gat ors. If E U 
Cli nical Trials Re g ulat i on 5 3 6/ 2 0 1 4 a p plies, Astra Ze neca is re q uire d t o e nter details of 
serio us breac hes i nt o t he E ur o pea n Me dici nes A ge nc y C TI S. It is i m p orta nt t o n ote t hat 
r edacte d versi o ns o f serio us breac h re p orts will be a vaila ble t o t he p u blic via C TI S

T he I n vesti gat or s h o ul d ha ve a pr ocess i n place t o e ns ure t hat:
o
T he sit e staff or ser vice pr o vi ders d el e gate d b y t he I n vesti gat or/i nstit uti o n are a ble t o 
i de ntif y t he occ urre nce of a ( p ote ntial) seri o us breac h
A ( p ote ntial) serio us breac h is pr o m pt l y re p orte d t o Astra Ze neca or dele gate d part y , t hr o u g h 
t he c o ntacts (e mail a d dress or tele p h o ne n u m ber) pr o vi de d b y Astra Ze neca.
A 2
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-I n vestig a t 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 mplete a n d acc urate fi na ncial 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
certificati o n or discl o s ure state me nts t o t he a p pr o priate re g ulat or y a ut h orit ies. I n vesti gat ors are 
r es 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 an d 
f or 1 ye ar after c o mplet i on of t he st u d y.
A 3
I nfor me d C o nse nt Pr ocess

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of  the 
st u d y to t he parti ci pa nt or his/ her le gall y a ut h orise d re prese ntative a n d 
a ns wer all q uest i ons re gar di n g t he st u d y .

P arti cipa nts m ust be i nf or me d t hat t heir partici pati on is v o l unt ar y, a n d t he y 
are free t o ref use t o partici pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me 
a n d f o r a n y reas o n d uri n g t he st u d y. 

T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt 
was o btai ne d bef ore t he parti ci pa nt was e nr olle d i n t he st u d y a n d t he date 
t he wri tte n c o nse nt was o btai ne d. T he a ut h orise d pers o n o b tai ni n g t he 
i nf orme 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 he I C F(s) 
d uri n g t heir partici pat i on i n t he st u d y.

A c o p y  of the I C F(s) m ust be pr o vi de d t o t he parti ci pa nt or t he parti ci pa nt’s 
le gall y a ut h orise d re prese ntative.
A partici pa nt w h o i s rescree ne d is n ot re q uire d t o si g n a n ot her I C F.
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 o f 
a n y ma n dat or y  an d/ or o pti o nal  hu ma n bi o l ogical  sa m ples. T he I n vesti gat or or a ut h orise d 
desi g nee will e x plai n t o eac h partici pa nt t he o bject i 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 pot e nti al fut ure use. Parti ci pa nts will be t old t hat t h e y are free t o ref use t o p artici pate 
i n a n y o pti o nal  sa m ples or t h e f ut ure use a n d ma y wi t hdra w t heir c o nse nt at  an y time a n d f or 
a n y reas o n d uri n g t he rete nti o n peri o d.
A 4
D at a Pr otecti o n

P arti cipa nts will be assi g ne d a u ni q ue i de ntifier b y t he S p o ns or. A n y 
parti ci 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 ntifier o nl y; parti ci pa nt na mes or a n y i nf or mati on w hic h 
w o ul d ma ke t he parti cip a nt i de nt ifia ble will n ot be tra nsferre d.

T he parti ci pa nt m u st 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 i n acc or da nce wi t h lo c al  dat a pr otecti o n la w. 
T he level of discl os ure a n d use of t hei r d at a must als o be e x plai ne d t o t he 
parti ci 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/ her me dical rec or ds ma y b e 
e xa mi ne d b y Cli nical Q uali t y Ass ura nce a u dit ors or ot h er a ut h orise d 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
pers o n nel a p p oi 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 ins pect ors fr o m  re g ulat or y a ut h orities.
A 5
Disse mi n ati o n of Cli nic al St u d y D at a
A 
descri pt i on 
of  
this 
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 an d htt p:// w w w.cli nicaltrials. g o v as will  th e 
s u m mar y of  the st u d y res ults w he n t he y are a vaila ble. T he cli nical st u d y an d/ or s u m mar y of  
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 ulati ons of  the 
c o u ntries i n w hic h t he st u d y is c o n d ucte d.
A 6
D at a Q u alit y Ass ur a nce

All part ici pa nt data relati n g t o t he stu 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 si g ni n g t he e C R F.

T he I n vest i gat or must m ai ntai n acc urate d oc u me ntatio n (s o urce data) t hat 
s u p p orts t he i nf or mati on e ntere d i n t he e C R F.

T he I n vesti gat or m u st per mit st u d y-relate d m o nit ori n g, a u dits, I R B/IE C 
re vie w, a n d re g ulat or y age nc y  ins pect i ons a n d pr o vi de di rect access t o 
s o urce data d oc u me nts.

Q T Ls will be pre defi ne d t o i de ntif y s yste matic iss ues t hat ca n i m pact 
parti ci pa nt safety a n d/ or relia bility of  st u d y res ults. T hese pre defi ne d 
para m eters will be m o nit ore d d uri n g t he st u d y, a n d i m p orta nt de viat i ons 
fr om t he Q T Ls a n d re me dial act i ons ta ke n will be s u m marize d i n t he C S R.

M o ni t ori n g details descri bi n g strate g y (e g, ris k-base d i nitiati ves i n 
o perati o ns a n d q ualit y s uc h as Ris k Ma na ge me nt a n d Mit i gati on Strate gies 
a n d A nal y tical Ris k-Base d M o ni t ori n g), met h o ds, res p o nsi bilities a n d 
re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m p lia nce iss ues a n d m onit ori n g 
tec h ni q ues (ce ntral, r e mot e, or o n -sit e m o nit ori n 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  this 
st u d y incl u di n g q ualit y c hec ki n g of t he data.

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 o ntract Researc h Or ga nizati ons).

St u d y  mo ni t ors will p erf or m  on g o in 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 sit e pers o n nel are acc urate, 
c o mplete, a n d verifia ble fr o m 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 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
i n acc or da nce wi t h the c urre nt l y a p pr o ve d pr ot oc ol  an d a n y ot h er 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  this st u d y must be retai ne d b y t he I nvest i gat or f or a mi ni m u m of  
2 5 years aft er st u d y arc hi vi n g or as re q uire d b y l o cal re g ulat i ons, acc or di n g 
t o t he Astra Ze neca Gl o b al Rete nt i on a n d Dis p osal Sc he d ule. N o rec or ds 
ma 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 writte n a p pr o val 
of Ast ra Ze neca. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y 
wi t ho ut wri tte n n otificati on t o Astra Ze neca .
A 7
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 vest i 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 wit h t he s o urce d oc u me nts or t he discre pa ncies m u st be 
e x plai ne d. T he I n vest i gat or ma y nee d t o re q uest pre vi o 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 of  
what c o nstit utes s ource data ca n be f ou n d i n St u d y 
M o ni t ori n g Pla n.
A 8
St u d y a n d Site St art a n d Cl os ure
T he st u d y st art 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 uit me nt of 
parti ci pa nts.
T he first act of recr uit me nt is t he first partici pa nt scree ne d 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 site or ter mi nate t he st u d y at a n y ti me 
f or a n y reas o n at t he s ole discret i on of  the 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 sit e is c o nsi dere d close d w he n all re q uire d d o c u m e nts a n d st u d y su 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 ini tiat e st u d y-sit e clos ure at a n y  time, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.
Reas o ns f or t he earl y cl o s ure of a st u d y site b y t he S p o ns or or I n vestigat or m a y i ncl u de b ut are 
n ot li mite d t o:
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

Fail ure of  the I n vesti gat or t o c o mpl y wi t h the pr ot oc ol , t he re q uire me nts 
of  the I R B/I E C or l ocal he alt h aut h ori ties, t he S p o ns or's pr oce d ures, or 
G C P g ui deli nes

I na de q uate recr uitme nt  of partici pa nts 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 pr e m at 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 pt l y i nf or m th e 
I n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orit ies, a n d a n y co 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 nat i 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 o mptl y i nf or m t he partici pa nt a n d 
s h o uld ass ure a p pr o pri ate partici pa nt t hera p y a n d/ or f oll ow- u p.
P arti cipa nt s fr o m ter mi nate d sites will ha ve t he o p p ort u ni t y t o be tra nsferre d t o a n ot her sit e t o 
c o nti n ue t he st u d y.
A 9
P u blic ati o n P olic y

T he res ults of  this st u d y ma y be p u blis he d or prese nte d at scie ntific 
meet i n gs. If this is f oresee n, t he I n vesti gat or a grees t o s ub 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 mat i on 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 wi t h the re q uire me nts f or p u blicati o n of  st u d y 
res ults. I n acc or da nce wi t h sta n dar d e dit orial a n d et hical pract ice, t he 
S p o ns or will ge nerall y  su p p ort p u blicat i on of  multi ce ntre st u dies o nl y i n 
t heir e nt iret y an d n ot as i n di vi d ual sit e 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 w ill be deter mi ne d b y m ut ual  agree me nt a n d i n li ne wi t h 
I nter nati o nal C o m mittee 
of  
Me dical 
J o ur nal 
Edi t ors a ut h ors hi p 
re q uire me nts.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 verse E ve nts
A n a d verse e ve nt 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 nica l 
st u d y part ici 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 hi s treat me nt. A n A E ca n t heref ore be a n y u nfa v o ura ble a n d u ni nte n de d si g n 
(e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na usea, c hest pai n), or disease 
t e mp orall y  ass o ciat 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 relate 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 orati o n 
of  a pre-e xist i n g me dical occ urre nce. A n A E ma y occ ur at a n y ti me, i ncl u di n g r u n -i n or was h o ut 
p eri 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 Seri o us A d verse E ve nts
A S A E is a n A E occ urri n g d uri n g a n y st u d y phase (ie, r u n-i n, treat me nt, was h o ut, f oll ow- u p), 
t hat f ulfils o ne or m ore of t he f o ll owi n g cri teria:

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 pitaliz at i on or pr ol o n gat i on of  exist i n g 
h os pi talizatio n 

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 d ical e ve nt t hat ma 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 of t he o utc o mes liste d a b o ve.
A d verse E ve nts f or m ali g n a nt t u m o urs re p orte d d uri n g a st u d y s ho ul d ge nerall y be assesse d 
as S A Es . If no ot h er s eri o us ness cri t eria a p pl y, t he ‘I mp orta nt Me di cal E ve nt ’ crit erio n s h o ul d 
be use d. I n certai n sit uat i ons, 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. For e xa m ple, if t he t u mo ur is i ncl u de d as me d ical hist or y  a nd pr o gressi o n occ urs 
d uri n g t he st u d y, b ut t he pr o gressi o n d oes n ot c ha n ge treat me nt a n d/ or pr o g n osis of  the 
mali g na nt t u mo ur , t he A E ma y n ot f ulfil t he attri b utes f or bei n g assesse d as serio us, alt ho u g h 
re p orti n g of t he pr o gressio n of  t he ma li g na nt t u mo ur as a n A E is vali d a n d s h o uld occ ur . Als o, 
s o me t ypes of  mali g na nt t u mo urs, w hic h d o n ot s prea d re m otel y aft er a r o uti ne treat me nt t hat 
d oes n ot re q uire h os pi talizati on, ma y be assesse d as n o n- serio us; e xa mples i n a d ults i ncl u de 
Sta ge 1 basal cell carci n o ma a n d S ta ge 1 A 1 cer vical ca ncer re m o ve d via c o ne bi o ps y.
Life -t hre ate ni n g
‘Life -t hreate ni n g’ mea ns t hat t h e parti ci pa nt was at im me diate ris k of  deat h fr om t he A E as it 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
occ urre d, or it is s us pecte d t hat use or c o nt i n ue d use of  the 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 with o ut he patic fail ure).
H os pit aliz ati o n
O ut pati e nt treat me nt i n a n e mer ge nc y r o o m is n ot i n itself a serio us A E , alt ho 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 o e d e m a). H os pi t al ad missi o ns a n d/ or s ur gical 
o perati o ns pla n ne d b ef or e or d uri n g a st u d y are n ot c o nsi dere d A Es if t he ill ness or 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 vi de d t hat it di d 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 uld be e xercise d i n deci di n g w het her a case is serio us i n 
sit u atio ns w here i m p orta nt me dical e ve nts ma y n ot be i m me diatel y life t hreate ni n g or res ult i n 
deat h, h os pitaliz atio n, di sa bilit y or i nca pacity b ut ma y je o par dise t he partici pa nt or ma y re q uire 
me dical tr e at me nt t o pre ve nt o ne or m o re o utc o mes liste d i n t he defi ni tio n of  serio 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 m ea n t hat it is a n i m p orta nt me dical e ve nt; me d ical 
j u d ge me nt m ust be use d.

A n gi oe de ma n ot se vere e n o u g h t o re q uire i ntu 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 ol  (aceta mi n o p he n) 
o ver d ose 
re q uirin g treat m e nt wit h N-acet ylc ystei ne

I nte nsi ve treat me nt i n a n e mer ge nc y ro 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 pi talizatio n

De vel o p me nt of dr u g de pe n de nc y or dr u g a b use
Se verit y R ati n g Sc ale:
T he f o ll owi n g se verit y rati n gs will be use d, a da pte d fr o m t he C T C A E v 5. 0 ( NI H 2 0 1 7):

Gra de 1: A n e ve nt of  mil d i nte nsit y that is us uall y tra nsie nt a n d ma y 
re q uire o nl y cli nical or dia g n ostic o bser vat i ons. T he e ve nt d oes n ot 
ge nerall y i nterfere wit h us ual act i vities of dail y li vi n g.

Gra de 2: A n e ve nt of  mo dera t e i nte nsit y t h at is us uall y alle viate d wi t h 
a d ditio nal , s pecific t hera pe ut ic i nter ve ntio n, w hic h is mi ni mal, l ocal, or 
n o n- i n vasi ve. T he e ve nt i nterferes wi t h us ual acti vities of  dail y li vi n g, 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
ca usi n g disc o mf ort, b ut p oses n o si g nifica nt or per ma ne nt ri s k of  har m t o 
t he partici pa nt

Gra de 3: A se vere e ve nt t hat re q uires i nte nsi ve t hera pe utic i nter ve nti o n b ut 
is n ot i m me diatel y life-t hreate ni n g. T he e ve nt i nterr u pts us ual acti vities of 
dail y  li vi n g, or sig nifica nt l y affects t he cli nical stat us of t he particip a nt.

Gra de 4: A n e ve nt, a n d/ or its i m me diate se q uelae, t hat is ass ociate d wit h 
a n i m mi ne nt ris k of deat h a n d ur ge nt i nter ve nti on is i n dicate d.

Gra de 5: Deat h, as res ult of a n e ve nt.
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 usality c o nsi der t he f o ll owi n g fact 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 m a 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 part ici 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 t e mp oral 
r elat i ons hi p t o t he a d mi nistrati o n of t he s us pect dr u g?

C o nsiste nc y wi t h kn o w n dr u g pr ofile. Was 
t he A E c o nsiste nt wit h t he 
pre vi o us k n o wle d ge of t he s us pect dr u g ( p har mac ol o g 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 cla ss? Or c o ul d t he A E be a ntici pate d 
fr om it s p har mac o l ogi c al pr o perties ?

De -c halle n ge e x p erie 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 alt er nat i 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 
aetiol o g y  suc h as t he u n derl yi n g di sease, ot her dr u gs, ot her h ost or 
e n vir o n me ntal fact ors.

Re -c halle n ge e x perie nce. Di d 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 m all y 
rec o m me n d or s u p p ort a re-challe 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 relat 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  ‘r elate d’ is ma de if f oll o wi n g a re vie w of t he rele va nt data, t here is e vi de nce f or a 
‘reas o na ble p ossi bili t y’ of  a ca usal relat i ons hi p f or t he i n di vi d ual case. T he e x pressi o n 
‘reas o na ble p ossi bili t y’ of  a ca usal relati ons hi p is mea nt t o c o n ve y, i n ge neral, t hat t here are 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical S t u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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 ma ke a n i nf or me d j u d g me nt. Wit h n o a vaila ble facts or ar g u me nts t o s u g gest a ca usal 
r elat i ons hi p, t he e ve nt(s) will be assesse d as ‘n ot rel ate d’.
Ca usal relati o ns hi p i n cases w here t he disease u n der st u d y has deteri orate d d ue t o lac 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 o r, Dr u g A b use, a n d Dr u g Mis use
Me dic ati o n Err or
F or t he p ur p oses of t his cli nical st u d y  a me dicatio n err or i s a n u ni nte n de d fail ure or mista ke i n 
t he treat me nt pr ocess f or a n 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.
A me dicati o n err or is n ot lac k of  efficac y of  the 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 ut circ u msta nces were rec o g nise d t hat c o ul d ha ve le d t o a n 
err or.
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors:

Dr u g na me c o nf usi o n.

Di s pe nsi n g err or e g, me d icati on 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 nistratio 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 it sh o ul d 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 W R S 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 W R S 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 dies:
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

Err ors relate d t o or res ulti n g fr om I W R S - i ncl u di n g t hose 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 dicat i on 
err or.

P arti cipa nt acci de ntall y misse d dr u g d ose(s) e g, f or g ot t o ta ke me dicat i on.

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.
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  th e 
me dicat i on err or.
Dr u g A b use
F or t he p ur p ose of  this st u d y, dr u g a b use is defi ne d as t he persiste nt or s p ora dic i nte nt i onal, 
n o n- t hera pe ut ic e xcessi ve use of I M P or Astra Ze neca NI M P f or a percei ve d re war d or desir e d 
n o n- t hera pe ut ic effect.
A n y e ve nts of dr u g a b use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ure d a n d f or war de d t o 
t he D E S usi n g t he Dr u g A b use Re p ort F or m . T his for m  s ho ul d be use d b ot h if t he dr u g a b use 
ha p pe ne d i n a st u d y  p artici pa nt or if t he dr u g a b use i n v ol ves a pers o n n ot e nr olle d i n t he st u d y 
(s uc h as a relati ve of t he st u d y p artici pa nt) .
E xa m ples of dr u g a b use i ncl u de b ut are n ot li mite d t o:

T he dr u g is use d wit h t he i nte nt of getti n g a pe rcei ve d re war d ( b y t he st u d y 
parti ci pa nt or a pers o n n ot e nr olle d i n t he st u d y)
I n t his st u d y partici pa nts will recei ve i n vesti gatio nal  pr o d ucts a d mi nistere d I M i n t he 
a nter olat er al t hig h o n Da y 1. All p arti ci pa nts will be d ose d at t h e sit e, t he y will r e c ei ve st u d y 
i nter ve nt i on di rectl y fr om t he u n bli n de d p har macist or desi g nee, u n der me dical s u per visi on.  
T he c ha nce f or dr u g a b use a n d dr u g mis use.
Dr u g Mis use
Dr u g mis use is t he i nte nt i onal a n d i na p pr o priate use ( b y a st u d y partici pa nt) of  IM P 
or 
Astra Ze neca NI M P f or me dici nal p ur p oses o utsi de of t he a ut h orize d pr o d uct i nf or mat i on, or f or 
u na ut h ori ze d I M Ps or Astra Ze neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he pr ot oc o l 
a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y  t he wr o n g r o ute.
E ve nt s of dr u g mis use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ure d a n d f or war de d t o t he 
D E S usi n g t he Dr u g Mi s use Re p ort F or m . T his f or m sh o ul d be use d b ot h if t he dr u g mis use 
ha p pe ne d i n a st u d y  p artici pa nt or if t he dr u g mis use re gar ds a pers o n n ot e nr olle d i n t he st u d y 
(s uc h as a relati ve of t he st u d y p artici pa nt) .
E xa m ples of dr u g mis use i ncl u de b ut are n ot li mite d t o:

T he dr u g is use d wit h t he i nte nt i on t o ca use a n effect i n a n ot her pers o n
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

T he dr u g is s o l d t o ot her pe o ple f or recreati o nal p ur p oses

T h e dr u g is use d t o facilitate assa ult i n a n ot her pers o n

T he dr u g is deli beratel y a d mi nistere d b y t he wr o n g r o ute

T he dr u g is s plit i n half beca use it is easier t o s wall o w, w he n it is state d i n 
t he pr ot oc ol t hat it m ust be s wall o we d w h o le

O nl y half t he d ose is ta ke n beca use t he st u d y participa nt feels t hat he/s he 
is feeli n g better w he n n ot ta ki n g t he w h ole d ose

S o m e o ne w h o is n ot e nr olle d i n t he st u d y int e nt i onall y  ta kes t he dr u g.
I n t his st u d y partici pa nts will recei ve i n vesti gatio nal  pr o d ucts a d mi nistere d I M i n t he 
a nter olat er al t hig h o n Da y 1. All p arti ci pa nts will be d ose d at t h e sit e, t he y will recei ve st u d y 
i nter ve nt i on di rectl y fr om t he u n bli n de d p har macist or desi g nee, u n der me dical s u per visi on.  
T he c ha nce f or dr u g a b use a n d dr u g mis use b y partici pa nt is rare.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 6 of 9 4
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 O F C U S T 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 bility of  c ollecte d biol o gical sa m ples fr om t h e 
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 bility of t he sa m ples 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  the e nt ire life c ycle t hr o u g h 
i nter nal pr oce d ures, m o nit ori n g of  st u d y sites, a u ditin 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 bi o ba n ks or ot h er 
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 Te a m duri n g f or 
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 r e mai ni n g bi o l ogi c al sa m ples are ret ur ne d t o t he sit e 
acc or di ng t o l o c al  re g ulatio 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 ol o gical sa m ples are ret ur ne d t o t he s o urce or destr o y e d at t h e e n d 
of  a s pecifie d perio 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 ogi cal sa m ples, t he sa m ples will be 
di s p ose d of/ destr o ye d/re patriate d, a n d t he act i on 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  co nse nt f or bi o l ogi cal sa m ples, f urt her st u d y partici pat i on s h o uld 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 vesti gat or:

E ns ures partici pa nt’s wit h dra wal o f i nf or me d c o nse nt t o t he use of d o nate d 
sa m ples is hi g hli g hte d i m me diatel y t o Astra Ze neca or dele gate.

E ns ures t hat r ele va nt h u ma n bi o l ogical sa m ples fr o m that partici pa nt, if 
st ore d at  the st u d y site, are i m me diatel y i de ntifie d, di s p ose d of  as 
a p pr o priate, a n d t he acti o n d oc u me nte d.

E ns ures t hat t he parti ci pa nt a n d Astra Ze neca are i nf or me d a b o ut t he 
sa m ple dis p osal.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Astra Ze neca e ns ures t he or ga nizat i on(s) h o l di n g t he sa mples is/are i nf or me d a b o ut t he 
wi t hdra w n c o nse nt i m me diate l y a n d t hat sa mples are di s 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 u i d a n c e 
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 oci at i 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 orm t hat, w he n e x p os ure t o 
it occ urs, is ca pa ble of  ca usi n g p er m a ne nt disa bilit y,  life-t hreate ni n g or fatal disease i n 
ot her wi se 
healt h y 
h u ma ns 
or 
a ni mals. 
C ate g or y A  Pat h o ge ns are, e g, E b ol a, Lassa fe ver vir us. I nfecti 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 nfecti 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 nfecti ous S u bsta nces t hat d o n ot me et t h e 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 o ll owi 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 nt ai n i nfecti o us s u bsta nces or s u bsta nces w hic h ar e 
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 ons u nless t he y 
meet t he criteria f or i ncl usi o n i n a n ot her class.

Cli nical st u d y sa m ples will fall i nto Cate g or y  B or e xe m pt u n der I A T A 
re g ulat i 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 
t e mperat ure 
i n 
I AT A  
65 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 dit i onal da n ger o us 
g o o ds s pecificati o n f or t he dr y -ice c o nte nt
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A p pe n di x D
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
D 1
I ntr o d ucti o n
T his A p pe n di x descri bes t he p r ocess t o be f oll o we d i n or der t o i de ntif y a n d a p pr o priatel y re p ort 
P H L  cases a n d H L cases. It is n ot i nte n de d t o be a c o mpre he nsi ve g ui de t o t he m a na ge me nt of 
ele vate d li ver bi oc he mistries. 
D uri n g t he c o urse of  the st u d y the I n vesti gat or will re mai n vi gi la 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 parti ci pa nt me ets 
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 eve nts; t his 
i ncl u des sa m ples ta ke n at sc he d ule d st u d y visits a n d ot her visits incl u di n g ce ntral a n d all l oc al 
la b orat or y eval uat i ons e ve n if c o llecte d o utsi de of t he st u d y visits; f or e xa m ple, P H L  crit eri a 
c o uld be met  by a n ele vate d A LT fr o m a ce ntral la borat or y  a n d/ or ele vate d T B L fr o m a lo c al  
la b orat or y. 
T he I n vestig at or will als o re vie w A d verse E ve nt d at a (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 vesti gat or partici pates, t o get her wi t h AstraZe neca cli nical pr oj ect re prese ntatives, i n 
re vie 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 crit eria ar e met. H L 
criteria are met  if t here is n o alter nati ve e x pla nati o n f or t he ele vat i 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 vesti 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 m e of  the re vie w a n d assess me nt i n li ne wi t h sta n dar d 
safety re p orti n g pr ocesses.
D 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 Al kali ne P h os p hatase ( A L P).
H y’s L a w
A S T or A LT ≥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 ou n d t o e x plai n t he c o m bi nat i on of  increases, 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 v atio n i n tra nsa mi nases m ust prece de or be c oi nci de nt wi t h (ie, o n t h e 
sa me da y) t he ele vati o 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 vati o ns 
i n tra nsa mi nases a n d T B L must occ ur .
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
D 3
I de ntific ati o n of P ote nti al H y’s L a w C ases
I n or der t o i de ntif y cases of  PH L  it is i m p orta nt t o perf or m a c o mpre he nsi ve re vie w of  lab orat or y 
data f or a n y  p artici pa nt w h o meets a n y of t he foll o wi n g i de ntificati on criteria i n is olati o n 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
L oc al L a b or at ories Bei n g Use d:
T he I n vest i gat or will wi t ho ut d el a y re vie w eac h ne w lab orat or y re p ort a n d if t he i de ntificati on 
criteria are met will:

N otif y  t he Astra Ze neca re prese ntati ve

Deter mi ne w het her t he parti ci pa nt meets 
P H L criteria (see Sect i on D 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
D 4
F oll o w -u p
D 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 vestigat or will:

I nf or m t he Astra Ze neca re prese ntati ve t hat t he partici pa nt has n ot met P H L criteria.

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 C S P.
D 4. 2
P ote nti al H y’s L a w Criteri a met
If t he partici pa nt does m eet P H L crit eria t he I n vesti gat or will:

I nf or m t he Astra Ze neca re prese ntati ve t hat t he partici pa nt has met P H L criteria.

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  PH L crit eria bei n g met , t he I n vestig at or will re p ort t he 
case as a n S A E of P ote ntial H y’s La w; seri o us criteria ‘I m p orta nt me dical 
e ve nt’ a n d ca usalit y 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 partici pa nts t hat met  PH L criteria pri or t o starti n g I M P, the I n vesti gat or 
is n ot re q uire d t o s u b mit a P H L S A E u nless t here is a sig nifica nt c ha n ge #
i n t he partici pa nt’s c o n diti on
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

T he St u d y  Ph 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 partici pa nts’ f oll o w - u p (incl 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:
o
M o ni t or t he parti ci pa nt u ntil li ver bi oc he mistr y para meters a n d a p pr o priate cli nical 
s y m pt o ms a n d si g ns ret ur n t o n or mal or base li ne le vels, or as l o n g as me dicall y i n dicate d. 
C o m pletes f oll o w -u p S A E F or m as re q uire d.
o
I n vesti gate t he etiol o g y  of t he e ve nt a n d perf or m  dia g n ostic i n vesti gati ons as disc usse d 
wi t h t he St u d y P h ysicia n. 
o
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 m es 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 diti o n refers t o a cli nicall y rele va nt c ha n ge 
i n a n y of t he i n di vi d ual li ver bi oc he mistr y  para meters ( A LT,  AS 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 nat i on of  
w he t her t here has bee n a si g nifica nt c ha n ge will be at t he discreti o n o f the I n vest i gat or, t his may 
be i n c o ns ultati o n with t he St u d y  P h ysicia n if t here is a n y u ncertai nty.
D 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 aft er t he bi oc he mistr y a b n or malit y was i nitiall 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 alt er nat i ve e x pla nat i 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 healt h a ut h orities wi t hi n 1 5 cale n dar da ys fr om d at e 
P H L  crit eria was met. T he St u d y S afet y P h ysicia n will als o be i n v ol ve d i n t his re vie w t o get her 
wi t 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 m e of  the re vie w a n d assess me nt, t he I n vesti gat or will f oll o w t he 
i nstr uctio ns bel o w.
W her e t h e re is a n a g r ee 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 on s, a 
deter mi nat i on of  whet her t he alter nati ve e x pla nati o n is a n A E will be ma de a n d s u bse q ue ntl y 
w het her t he A E meets t he criteria f or a S A E:

If t he alter nati ve e x pla nat i on is n ot
a n A E, rec or d t he alter nati ve 
e x pla nat i on o n t he a p pr o priate e C R F

If t he alter nat i ve e x pla nat i 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 nti al Hy’s La w S A E a n d A E e C R Fs acc or di n gl y with t he 
ne w i nf or mat i on (reassessi n g e ve nt ter m; ca usalit y a n d serio us ness 
criteria) 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 L T o r A S T a n d T B L  ele vati ons 
ot her t ha n t he I M P:
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4

Se n d u p date d S A E (re p ort t er 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 mp orta nt’ serio us crit erio n s h o uld be use d if n o ot her serio us 
criteria a p pl y

As t here is n o alter nati ve e x pla nat i on f or t he H L case, a ca usalit y assess me nt of  
‘relate d’ s h o ul d be assi g ne d.
If there is a n u na v o i 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 nati ve e x pla nati on u nt il 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 f urt her u p date t o t he pre vi o usl y s u b mitt e d S A E of Pote nti al 
H y’s 
La w, (re p ort t er m no w ‘ H y’s La w case’) e ns uri n g ca usalit y 
assess me nt is r elate d t o I M P a n d seri o us ness criteria 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 oll ow- u p a n d re vie w acc or di n g t o a gree d pl a n. O nce t he 
necessar y  su p ple m e nt ar 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 w het her H L criteria are still met. U p date t he 
pre vi o usl y s u b mitt e 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, acc or di n g t o t he o utc o m e of  the re vie w a n d a me n di n g t he
re p orte d t er m if a n alter nati ve e x pla nat i on f or t he li ver bi oc he mistr y 
ele vat i ons is deter mi ne d.
D 6
L a b or at or y Tests
T he list bel o w re prese nts t he sta n dar d, c o m pre he nsi ve 
list of  fol l ow- u p tests w hic h are 
rec o m me n de d b ut n ot ma n dat or y. T he list ma y be m o difi e d base d o n cli nical j u d g me nt. A n y 
test res ults nee d t o be rec or de d.
H y’s L a w L a b Kit f or 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
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
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
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
C D -tra nsferri n
A ut oi m m u ne he patitis
A N A
A nti -L K M
A S M A
Meta b olic diseases
Al p ha - 1-a ntitr y psi n
Cer ul o plas mi n
Ir o n
Ferriti n
Tra nsferri n
Tra nsferri n sat urati o n
a H B V D N A is o nl y rec o m me n de d w he n I g G a nti -H Bc is p ositi ve.
b H C V R N A is o nl y rec o m me n de d w he n I g G a nti -H C V is p ositi ve or i nc o ncl usi ve. 
A b = a nti b o d y; A N A = a nti n uclear a nti b o d y; A S M A = a nti -s m o ot h m uscle a nti b o d y; C D = car b o h y drate 
deficie nt; C M V = c yt o me gal o vir us; E B V = E pstei n – Barr vir us; G G T = ga m ma gl uta m yl tra ns pe pti dase; H A V = 
he patitis A vir us; H Bc = he patitis B c ore a nti b o d y; H B V = he patitis B vir us; H Bs A g = he patitis B s urface 
a nti ge n; H C V = he patitis C vir us; H E V = he patitis E vir us; H S V = her pes si m ple x vir us; I g = i m m u n o gl o b uli n; 
I N R = i nter nati o nal n or malize d rati o; L D H = lactate de h y dr o ge nase; L K M = li ver/ ki d ne y micr os o mal
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A p pe n di x E
A n a p h yl a xis
T he NI AI D a n d F A A N cli nical crit eria f or dia g n osi n g a na p h yla xis are as f oll ows ( S a m ps o n et 
al 2 0 0 6):
A n a p h yl a xis is hi g hl y li kel y w he n a n y o ne of t he f oll o wi n g t hree criteri a is f ulfille d
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 ol ve me nt of t he s ki n, m uc osal 
tiss ue, or b ot h (e g, ge neralize d urti c aria, itc hi n g or fl us hi n g, s w olle n li ps-t o n g ue-u v ula) 
A N D A T L E A S T O N E O F T H E F O L L O WI N G:
(a) Res pirat or y  co m pr o mise (e g, d ys p nea, w heeze -br o nc h os pas m, strid or, re d uce d P E F, 
h y p o xe mia)
( b) Re d uce d bl o o d press ure or ass ociate d s y m pt o ms of  en d -or ga n d ysf u nct i on (e g, 
h y p ot o ni a [c olla pse], s y nc o pe, i nc o nt i ne nce)
2
T w o or m ore of t he f oll o wi 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 
pati e nt ( mi n utes t o se veral h o urs)
(a) I n v ol ve me nt of  the s ki n-m uc osa l tiss ue (e g, ge neralize d urti caria, itc h-fl us h, s w olle n 
li ps-t o ng ue- u v ula)
( b) Res pirat or y  co m pr o mise (e g, d ys p nea, w heeze -br o nc h os pas m, strid or, re d uce d P E F, 
h y p o xe mia)
(c) Re d uce d bl o o d press ure or ass ociate d s y m pt o ms (e g, h y p ot o nia [c olla pse], s y nc o pe, 
i nc o ntine 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) O R
3
Re d uce d bl o o d press ure aft er e x p os ure t o k n o w n aller ge n f or t hat patie nt ( mi n utes t o 
se veral h o urs)
(a) A d ults: s yst olic bl o o d press ure of  less t ha n 9 0 m m H g or greater t ha n 3 0 % decrease 
fr om t hat pers o n’s baseli ne 
To  assist wit h t he miti gatio n of  t hese A Es, see Ta ble 9 , w hic h cate g orizes react i ons b y se verit y 
of  s y m pt o ms a n d pr o p oses se verity- s pecific treat me nt a n d of fers g ui da nce o n ma na ge me nt of 
st u d y i nter ve nti on. Fi nal treat me nt is at t he discret i o n of  t he I n vest i gat or a n d s h o ul d reflect l ocal 
sta n dar d of care.
Ta ble 9
A n A p pr o ac h t o M a n a ge me nt 
of A n a p h yl actic, H y perse nsiti vit y , a n d 
P ost -i njecti o n Re acti o ns
Se verit y of S y m pt o ms
Tre at me nt
St u d y I nter ve nti o n
Mil d l oc al re acti o ns ( D u ri n g a n d 
p ost i njecti o n a n d 
h y perse nsiti vit y) 
Mil d i njecti o n site reacti o ns s uc h 
as re d ness, mil d s welli n g, pai n at 
t he i njecti o n site or hea dac he, 
na usea, n o n -pr ur itic ras h, or mil d 
h y perse nsiti vit y reacti o ns 
i ncl u di n g l ocalize d at t he i njecti o n 
E val uate partici pa nt, i ncl u di n g cl ose 
m o nit ori n g of vital si g ns. 
At t he discreti o n of t he I n v esti gat or, 
treat partici pa nt, f or e xa m ple, wit h: 
L ocalize d c ol d pac k or heat t o t he 
i njecti o n site. 
If m ore ge neralize d reacti o n: 
Pa use or h ol d a d diti o nal st u d y 
i nter ve nti on i njecti o n 
i m me diatel y.
At t he discreti o n of t he 
I n vesti gat or, res u me c urre nt 
st u d y i nter ve nti o n 
a dmi nistrati o n u n der 
o bser vati o n.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Se verit y of S y m pt o ms
Tre at me nt
St u d y I nter ve nti o n
site or ge neralize d c uta ne o us 
reacti o ns s uc h as mil d pr urit us, 
fl us hi n g, ras h, dizzi ness, 
hea dac he, ≤ 2 0 m m H g c ha n ge i n 
s yst olic B P fr o m pre-
a d mi nistrati o n meas ure me nt.

Di p he n h y dra mi ne 5 0 m g P O or 
e q ui vale nt a n d/ or 

Aceta mi n o p he n 5 0 0 t o 6 5 0 m g 
or  e q ui vale nt d ose of 
paraceta m ol a n d/ or 

T o pical a nti hista mi nes a n d/ or 
l o w-p ote nc y  t o pical 
c ortic oster oi d pre parati o ns 
a n d/ or 

A nti- na usea me dicati o n, as 
nee de d.
M o der ate re acti o ns ( d uri n g or 
i m me di atel y p ost i njecti o n) 
I njecti o n site reacti o n s uc h as 
t h ose liste d a b o ve u n der mil d 
reacti o ns b ut e xcl u di n g m o derate 
h y perse nsiti vit y reacti o ns (see 
bel o w).
E val uate partici pa nt, i ncl u di n g cl ose 
m o nit ori n g of vital si g ns.
Treat partici pa nt, f or e xa m ple, wit h: 

N or mal sali ne ( ~ 5 0 0 t o 
1 0 0 0 m L/ h o ur I V) a n d/ or

Di p he n h y dra mi ne 5 0 m g I V or 
e q ui vale nt a n d/ or 

Aceta mi n o p he n 5 0 0 t o 6 5 0 m g 
or  e q ui vale nt d ose of 
paraceta m ol a n d/ or 

A nti- na use a a n d/ or a ntiemetic 
i ntra m usc ular, as nee de d.
St o p or h ol d a d diti o nal st u d y 
i nter ve nti on a d mi nistrati o n 
i m me diatel y.
At t he discreti o n of t he 
I n vesti gat or, res u me c urre nt 
st u d y i nter ve nti o n 
a d mi nistrati o n u n der 
o bser vati o n.
M o der ate h y perse nsiti vit y 
re acti o ns
Reacti o ns w hic h ma y i ncl u de 
ge neralize d ras h or urticaria, 
pal pitati o ns, c hest disc o mf ort, 
s h ort ness of breat h, h y p o- or  
h y perte nsi o n w it h > 2 0 m m H g 
c ha n ge i n s yst olic B P fr o m pre -
i nf usi o n meas ure me nt.
E val uate partici pa nt, i ncl u di n g cl ose 
m o nit ori n g of vital si g ns.
Treat partici pa nt, f or e xa m ple, wit h:

N or mal sali ne ( ~ 5 0 0 t o 
1 0 0 0 m L/ h o ur I V) a n d/ or

Di p he n h y dra mi ne 5 0 m g I V or 
e q ui vale nt a n d/ or

Aceta mi n o p he n 5 0 0 t o 6 5 0 m g 
or  e q ui vale nt d ose of 
paraceta m ol a n d/ or

I V c ortic oster oi ds, s uc h as 
h y dr oc ortis o n e 1 0 0 m g or 
met h y l pre d nis ol o ne 2 0 t o 
4 0 m g.
St o p st u d y i nter ve nti o n 
a d mi nistrati o n i m me diatel y
Se vere
A b o ve pl us fe ver wit h ri g ors, 
h y p o- or  h yperte nsi o n wit h 
E val uate partici pa nt, i ncl u di n g cl ose 
m o nit ori n g of vital si g ns.
St o p st u d y i nter ve nti o n 
a d mi n istrati o n i m me diatel y. D o 
n ot res u me c urre nt d osi n g. 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
Se verit y of S y m pt o ms
Tre at me nt
St u d y I nter ve nti o n
≥4 0 m m H g c ha n ge i n s yst olic 
B P, si g ns of e n d -or ga n 
d y sf u ncti o n (e g, s y m pt o matic 
h y p ote nsi o n s uc h as h y p ot o nia, 
s ync o pe,
i nc o nti ne nce, seiz ure) fr o m 
pr e -i nf usi o n meas ure me nt, or 
w h eezi n g, a n gi oe de ma, or stri d or
O R
Life -t hre ate ni n g
Defi ne d as a reacti o n t hat is 
life-t hreate ni n g a n d re q uires 
press or a n d/ or ve ntilat or s u p p ort 
or  s h oc k ass ociate d wit h aci de mia 
a n d i m pairi n g vital or ga n f u ncti o n 
d ue t o tiss ue h y p o perf usi o n
Mai ntai n air wa y, o x y ge n if 
a vaila ble.
Treat partici pa nt i m me diatel y, f or 
e xa m ple wit h:
•
N or mal sali ne ( ~ 5 0 0 t o 
1 0 0 0 m L/ h o ur I V)
•
E pi ne p hri ne f or 
br o nc h os pas m, h y p ote nsi o n 
u nres p o nsi ve t o I V fl ui ds, or 
a n gi oe de ma. D ose a n d r o ute as per 
l ocal S O C, e xa m ple, e pi ne p hri ne 
1: 1 0 0 0, 0. 5 t o 1. 0 m L a d mi nistere d 
S C f or mil d cases a n d i ntra m usc ular 
f or m ore se vere cases
•
I V c ortic oster oi ds, s uc h as 
h y dr oc ortis o ne 1 0 0 m g or 
met h y l pre d nis ol o ne 2 0 t o 4 0 m g
•
Di p he n h y dra mi ne 5 0 m g I V 
or  e q ui vale nt
•
Aceta mi n o p he n 5 0 0 t o 
6 5 0 m g o r e q ui vale nt d ose of 
paraceta m ol
Call e mer ge nc y me dical tra ns p ort 
f or tra ns p ort t o e mer ge nc y h os pital 
base d o n j u d g me nt of t he 
I n vesti gat or.
Gra de 3 w heezi n g, h y p ote nsi o n or 
a n gi oe de ma is u nres p o nsi ve t o 
si n gle d ose of e pi ne p hri ne
Gra de 4 e ve nt
At t he discreti o n of t he 
I n vesti gat or
Per ma ne ntl y disc o nti n ue st u d y 
i nter ve nti on a d mi nistrati o n.
C o nsi der nee d f or a d diti o nal 
or al a nti hista mi ne 
a d mi nistrati o n or oral 
c ortic oster oi d a d mi nistrati o n t o 
pre ve nt re occ urre nce of 
s ym pt o ms o ver s u bse q ue nt 2 t o 
3 da y s.
B P = bl o o d press ure; I V  = i ntra ve n o us; P O = per os ( oral); S C = s u bc uta ne o usl y; S O C = sta n dar d of care.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 6 of 9 4
A p pe n di x F
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 D E
A nti b o d y de pe n de nt e n ha nce me nt
A E
A d verse e ve nt
A E SI
A d verse e ve nt of s pecial i nterest
A L P
Al kali ne p h os p hatase
A L T
Ala ni ne a mi n otra nsferase
A S T
As partate a mi n otra nsferase
C 1 q
C o m ple me nt c o m p o ne nt 1 q
CI
C o nfi de nce i nter val
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C 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 T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C TI S
Cli nical Trial I nf or mati o n S yste m
D B L
Data base l oc k
D E S
Data e ntr y site
DI LI
Dr u g -i n d uce d li ver i nj ur y
E C G
Electr ocar di o gra m
E C M O 
E xtrac or p oreal me m bra ne o x y ge nati o n
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 U
E ur o pea n u ni o n
E U A
E mer ge nc y use a ut h orizati o n
F A A N
F o o d aller g y a n d a na p h yla xis net w or k
F A S
F ull a nal ysis set
Fc
Fracti o n cr ystalliza ble
Fc R n
Ne o natal Fc rece pt or
G C P
G o o d cli nical practice
G M F R
Ge o metric mea n f ol d rise ( G M T rati o of p ost -treat me nt titer t o baseli ne titer)
G M T
Ge o metric mea n titer
g S D
Ge o metric sta n dar d de viati o n
HI V
H u ma n i m m u n o deficie nc y vir us
H L
H y’s la w
I CX X
C o nce ntrati o n re q uire d f or X X % i n hi biti o n
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
I C F
I nf or me d c o nse nt f or m
I C H
I nter nati o nal c o u ncil f or har m o nisati o n
I E C
I n de pe n de nt et hics c o m mittee
I g
I m m u n o gl o b uli n
I L- D
Ill ness da y
I M
I ntra m usc ular
I M P
I n vesti gati o nal me dici nal pr o d uct
I R B
I nstit uti onal re vie w b oar d
I W R S
I nteracti ve we b res p o nse s yste m
M A A E
Me dicall y atte n de d a d verse e ve nt
m A b
M o n ocl o nal a nti b o d y
Me d D R A
Me dical dicti o nar y f or re g ulat or y acti vities
n A b
Ne utralizi n g a nti b o d y
NI AI D
Nati o nal i nstit ute of aller g y a n d i nfecti o us disease
NI M P
N o n -i n vesti gati o nal me dici nal pr o d uct
NI V
N o n -i n vasi ve ve ntilati o n
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 K
P har mac o ki netics
Q T L
Q ualit y  t olera nce li mit
R B D
Rece pt or -bi n di n g d o mai n
R N A
Ri b o n ucleic aci d
R T -P C R
Re verse tra nscri pti o n p ol y merase c hai n reacti o n
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 o A
Sc he d ule of acti vities
S p O 2
O x y ge n sat urati o n
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
T B L
T otal bilir u bi n
T M
L 2 3 4f/l 2 3 5e/ p 3 3 1s s u bstit uti o ns i n t he i m m u n o gl o b uli n hea v y c hai n t o re d uce fc 
rece pt or a n d c 1 q bi n di n g
U L N
U p per li mit of n or mal
U S
U n ite d states of A merica
V O C
Varia nt of c o ncer n
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
W H O
W orl d healt h or ga nizati o n
W O C B P
W o ma n of c hil d beari n g p ote ntial
Y T E
M 2 5 2 Y/ S 2 5 4 T/ T 2 5 6 E s u bstit uti o ns i n t he i m m u n o gl o b uli n hea v y c hai n t o 
i ncrease Fc R n affi nit y t hat res ults i n t he i ncrease d half-life of a n a nti b o d y
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical S t u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A p pe n di x G
F or ms of E arl y S afet y D at a Re vie w ( E S D R) D ecisi o n b y t he 
S afet y Assess me nt C o m mittee i n t he S U P E R N O V A St u d y
T hese f or ms are a p pe n de d as se parate d oc u me nts.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
A p pe n di x H
Pr ot oc ol Versi o n Hist or y
T he S u m mar y  of C ha n ges Ta ble f or t he c urre nt re visi o n is l ocate d directl y bef ore t he T a ble of 
C o nte nts.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
1 1
R E F E R E N C E S
Al h u m ai d et al 2 0 2 1
Al h u mai d S, Al M ut ai r A, Al Ala wi  Z, Ra baa n A A, Tir u pat hi R, Al o mari 
M A, 
et al.  
A na p h ylactic a n d n o na na p h ylact ic reacti ons t o S A R S -C o V -2 vacci nes: a s yste mat ic re vie w a n d 
meta -a nal ysis. Aller g y Ast h ma Cli n I m m u n o l 2 0 2 1; 1 7( 1): 1 0 9.
B osc h et al 2 0 0 3
B osc h BJ, va n der Zee R, de Haa n C A M, R ottier PJ M. T he c or o na vir us s pi ke pr otei n is a class 
I vir us f usio n  pr otei n: Str uct ural a n d f uncti o n al  c h ar a ct erizat i on of  t he f usi on c ore c o mple x. J 
Vir ol . 2 0 0 3; 7 7: 8 8 0 1 – 1 1.
C ase et al 2 0 2 2
Case J B, Mac ki n S, Erri c o J, C ho n g Z, Ma d de n E A, W hite ner B, et al . Resilie nce of S 3 0 9 a n d 
A Z D 7 4 4 2 m o n ocl o nal a nt i b o d y treat me nts a gai nst i nfect i on b y S A R S -C o V -2 O micr o n li nea ge 
strai ns. Nat C o m m u n. 2 0 2 2; 1 3( 1): 3 8 2 4.
C D C 2 0 2 1
C D C ( Ce nters f or Dise ase C o ntr ol a n d Pre ve nti o n). Ge ner al Best Pr actice G ui deli nes f o r 
I m m u niz ati o n: 
Altere d 
I m m u n oc o m pete nce. 
A v ail a ble 
fr o m: 
htt ps:// w w w.c dc. g o v/ v acci nes/ hc p/ aci p -recs/ ge ner al-recs/i m m u n oc o m pete nce. ht ml. 
Accesse d 2 3 M a y 2 0 2 2. D all’ Ac q u a et al 2 0 0 6
Dall ’Ac q ua W F , Kie ner PA, Wu  H. Pr o perti es of h u ma n I g G 1s e n gi neere d f or e n ha nce d bi n di n g 
t o t he ne o natal Fc rece pt or ( Fc R n). J Bi ol C he m 2 0 0 6; 2 8 1( 3): 2 3 5 1 4 - 2 4.
F act S heet E U A Be btel o vi m a b 2 0 2 2
U S F o o d a n d Dr u g A d mi nistrati o n. Fact S heet F or Heal t hcare Pr o vi ders: E m er ge nc y Us e 
A ut h ori zat i on 
f or 
Be btel o vi ma b,
Marc h 
2 0 2 2. 
Av aila ble 
at: 
ht t ps:// w w w.fda. g o v/ me dia/ 1 5 6 1 5 2/ d o w nl oa d. Accesse d 2 3 Ma y 2 0 2 2 .
F urer et al 2 0 2 0
F urer V, R o n daa n C, Heijste k M W, A g m on- Le vi n N, va n Asse n S , Bijl M et al. 2 0 1 9 u p date of 
E U L A R rec o m me n dati o ns f or vacci nat i on i n a d ult pat ient s wi t h aut oi m m u ne i nfla m mat or y 
r he u matic diseases. A n n R he u m Dis. 2 0 2 0; 7 9( 1): 3 9- 5 2.
G u pt a et al 2 0 2 1
G u pta A, G o nzalez -R o jas Y,  J uarez E, Cres p o Casal M, M o ya J, Falci D R, et al. Earl y Treat me nt  
f or C o vi d - 1 9 wi t h 
Sars-C o v -2 Ne utralizi n g 
A nt i b o d y 
Sotr o vi ma b. N 
E n gl 
J M e d 
2 0 2 1; 3 8 5: 1 9 4 1 - 5 0.
H ar p az et al 2 0 1 6
Har paz R, Da hl R M, D o oli n g K L. Pre vale nce of I m m u n os u p pressi o n A m o n g U S A d ults, 2 0 1 3. 
J A M A 2 0 1 6; 3 1 6( 2 3): 2 5 4 7- 8.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
H off m a n n et al 2 0 2 0
H of f ma n n M, Klei ne-We ber H, Sc hr oe der S, Kr ü ger N, Herrler T,  Eric hse n S, et al. S A R S C o V-
2 cell e ntr y de pe n ds o n A C E 2 a n d T M P R S S 2 a n d is bl oc ke d b y a cli nicall y pr o ve n pr otease 
i n hi bit or. Cell 2 0 2 0; 1 8 1: 2 7 1 – 8 0.
L a m b et al 2 0 1 3
La m b EJ, Le ve y A S , Ste ve ns P E. T he Ki d ne y Disease I mpr o vi n g Gl o bal  Out c o m es ( K DI G O) 
g ui deli ne u p date f or c hr o nic ki d ne y disease: e v o l uti on n ot re v ol uti on. Cli n 
C he m. 
2 0 1 3; 5 9( 3): 4 6 2 - 5.
Le vi n et al 2 0 2 2
Le vi n MJ, Usti a n o ws ki A, De Wit  S, La u na y O, Av ila M, Te m p let o n A et al. I ntra musc ular 
A Z D 7 4 4 2 
( Ti xa ge vi ma b-Cil ga vi ma b) 
f or Pre ve nt i on 
of  
Co vi d- 1 9. 
N 
E n gl  J 
Me d 
2 0 2 2; 3 8 6( 2 3): 2 1 8 8 - 2 2 0 0.
Li 2 0 1 6
Li  F. Str uct ure, f u ncti o n, a n d e v o l uti on of  cor o na vir us s pi ke pr otei ns. A n n u Re v Vir ol . 
2 0 1 6; 3: 2 3 7 – 6 1.
L o o et al 2 0 2 2
L o o Y M, Mc T a m ne y P M, Are n ds R M, A bra m  ME, A ks y u k A A, Diall o S, et al. T h e S A R S -
C o V - 2 m o n ocl o nal  ant i b o d y co m bi nat i on, A Z D 7 4 4 2, is pr otecti ve i n n o n h u ma n pri mates a n d 
has a n e xte n de d half -life i n h u ma ns. Sci Tra nsl Me d 2 0 2 2; 1 4( 6 3 5):ea bl 8 1 2 4.
L us v ar g hi et al 2 0 2 2
L us var g hi S, P ollett S D, Neer u k o n da S N, Wa n g W,  Wa n g R, Va ssell R, et al. S A R S -C o V -2 
B A. 1 v ari a nt is ne utralize d b y vacci ne b o oster -elicite d ser u m, b ut e va des m o st c o n valesce nt  
ser u m a n d t hera pe utic a nt i b o dies. Sci Tra nsl Me d 2 0 2 2; 1 4( 6 4 5):ea b n 8 5 4 3.
M altez o u et al 2 0 2 2
Mal t e z o u H C, A nastass o p o ul o u C, Hatzia nt o ni o u S, P ola n d G A, T sa kris A. A na p h yla xis rates 
ass ociate d wi t h CO VI D - 1 9 vacci nes are c o mpara ble t o t hose of  ot her vacci nes. Va cci ne 
2 0 2 2; 4 0( 2): 1 8 3 - 6.
NI H 2 0 1 7
NI H. C o m m o n Te r mi n ol og y  Criteria f or A d verse E ve nts ( C T C A E) Ve rsio n 5. 0. Availa ble at: 
ht t ps://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati ons/ctc. ht m #ctc _ 5 0. 
P u blis he d 2 0 1 7. Accesse d 2 3 Ma y  2 0 2 2.
O g a nes y a n et al 2 0 0 8
O ga nes ya n V,  Ga o C, S hiri nia n L, Wu  H, Dall ’Ac q ua W F . Str uct ural c haracterizat i on of  a 
h u ma n Fc fra g me nt e n gi neere d f or lac k of  effect or f unct i ons. Acta Cr y stallo gr D Bi ol  
Cr y stallo gr. 2 0 0 8; 6 4( Pt 6): 7 0 0- 4.
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
P ar ker et al 2 0 2 2
Par ker E K, Desai S, Marti M, N o h y ne k H, Kasl o w D C, K oc h har S, et al. Res p o nse t o a d dit i ona l 
C o vi d -1 9 vacci ne d oses i n pe o pl e w h o are i m m u n oc o mpr o mise d: A r a pid re vie w. La ncet Glo b 
Heal t h 2 0 2 2; 1 0( 3):e 3 2 6-e 2 8.
P ol a n d et al 2 0 1 8
P ol a n d G A, O vs ya n ni k o va I G, Ke n ne d y R B. Pers o nalize d vacci n o l og y: A re vie w. Va cci ne. 
2 0 1 8; 3 6( 3 6): 5 3 5 0 -7.
S a m ps o n et al 2 0 0 6
S a m ps o n H A, M u ñ o z- F url o n g A, Ca m p bell R L, A d ki ns o n N F Jr, B oc k S A, Bra n u m 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  ana p h yla xis: s u m mar y re p ort-- Sec o n d 
Nati o nal  Inst itute of  Aller g y a n d I nfecti ous Di sease/ 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 um.  J Aller g y Cli n I m m u n ol. 2 0 0 6; 1 1 7( 2): 3 9 1- 7.
T ue k pr a k h o n et al 2 0 2 2
T ue k pra k h o n A, N utal ai R, Dij o kaite -G urali uc A, Z h o u D, Gi n n H M, Sel varaj M, 
et al.  
A nt i b o d y esca pe of S A R S-C o V -2 O micr o n B A. 4 a n d B A. 5 fr o m vacci ne a n d B A. 1 ser u m. Cell. 
2 0 2 2; 1 8 5( 1 4): 2 4 2 2- 3 3
W a g ner a n d Wei n ber ger 2 0 2 0
Wa g ner A, We i n ber ger B. Va cci nes t o Pre ve nt I nfecti ous Di seases i n t he Ol der P o p ul at i on: 
I mm u n o l ogi c al C halle n ges a n d F ut ure Pers pecti ves. Fr o nt I m m u n ol. 2 0 2 0; 11 7 1 7.
W alls et al 2 0 1 7
Wa lls A C, Tort ori ci M A, S nij der J, Xi o n g X, B osc h BJ, Re y F A, et al. T ect o nic c o nf or mati o nal 
c ha n ges of  a cor o na vir us s pi ke gl yc o pr otei n pr o m ot e me m bra ne f usi on. Pr oc Natl Aca d Sci 
U. S. A. 2 0 1 7; 1 1 4: 1 1 1 5 7 – 6 2.
Wei nreic h et al 2 0 2 1
We i nreic h D M, Si va palasi n ga m S, N ort o n T,  Ali S, Ga o H, B h ore R, et  al. Re g n-C o v 2, a 
Ne utralizi n g A nt i b o d y C oc ktail, i n O ut patie nts wit h C o vi d-1 9. N E n gl J Me d 2 0 2 1; 3 8 4: 2 3 8 - 5 1.
W H O 2 0 2 0
Wo rld Heal t h Or ga nizati on. W H O C O VI D - 1 9 Case defi nit i on, Dece m ber 2 0 2 0. Availa ble at: 
ht t ps://a p ps. w h o.i nt/iris/rest/ bitstrea ms/ 1 3 2 2 7 9 0/retrie ve. Accesse d 2 2 Se pte m ber 2 0 2 2.
W H O 2 0 2 3
W H O 
C or o na vir us disease ( C O VI D-1 9) das h b oar d. Av aila ble at: htt ps://c o vi d 1 9. w h o.i nt. 
Accesse d 0 5 J u ne 2 0 2 3.
W H O W or ki n g Gr o u p 2 0 2 0
W H O 
Wo r ki n g Gr o u p o n t he Cli nical C haracteri sati on a n d Ma na ge me nt 
of  CO VI D -1 9 
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y Pr ot oc ol - 3. 0
Astra Ze neca
A Z D 3 1 5 2 - A Z -R U - 0 0 0 0 2
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 4
i nfecti on. A mi ni mal c o m m o n o ut c o m e meas ure set f or C O VI D - 1 9 cli nical researc h. La ncet  
I nfect Dis. 2 0 2 0; 2 0( 8):e 1 9 2- 7.
Zi m mer m a n n a n d C urtis 2 0 1 9
Zi m mer ma n n P,  Curti s N. Fact ors T hat I nfl ue nce t he I m m u ne Res p o nse t o Va cci nat i on. Cli n 
Micr o bi ol  Re v. 2 0 1 9; 3 2(2).
R e d a ct e d f or P u bli c Di s cl o s ur e