A Phase III Randomized, Double-blind, Placebo-controlled, Multi-center Study in Adults to Determine the Safety and Efficacy of AZD7442, a Combination Product of Two Monoclonal Antibodies (AZD8895 and AZD1061), for Pre-exposure Prophylaxis of COVID-19.
Phase: PHASE3
Conditions: COVID-19
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
A Z D 7 4 4 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
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Cli nic al St u d y Pr ot oc ol A d de n d u m
I M P
A Z D 7 4 4 2
St u d y C o de
D 8 8 5 0 C 0 0 0 0 2
S u b -st u d y C o de
D 8 8 5 0 C 0 0 2 A 0 1
Ve rsi o n
A me n d me nt 2. 0 U S A
Date
1 3 J u ne 2 0 2 2
A P h ase III M ulti -ce nter, O pe n-l a bel S u b-st u d y i n A d ults t o Assess t he 
S afet y , P K, a n d I m m u n o ge nicit y of Re pe at D oses of A Z D 7 4 4 2, a 
C o m bi n ati o n Pr o d uct of T w o M o n ocl o n al A nti b o dies ( A Z D 8 8 9 5 a n d 
A Z D 1 0 6 1) ( T he P R O V E N T Re pe at D ose S u b -st u d y)
S p o ns or  N a me:
Astra Ze neca A B
Le g al Re gister e d A d dress:
Re g ul at or y A ge nc y I de ntifier  N u m ber(s): 
I N D N u m ber: 1 5 0 7 1 2
E u dra C T N u m ber: 2 0 2 0- 0 0 4 3 5 6- 1 6
T his Cli nical St u d y  Pr ot oc ol A d de n d u m has bee n s u bject t o a peer re vie w acc or di n g t o 
Astra Ze neca Sta n dar d pr oce d ures. T he Cli nical St u d y Pr ot oc ol  is p u blicl y re gistere d, a n d t he 
res ults are discl ose d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P o lic y o n 
Bi o et hi cs a n d i n c o mplia nce wi t h pre vaili n g la ws a n d re g ulati ons.
P P 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 A d de n d u m - A me n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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of  6 0 0 m g I M. T hi s a p pr oac h will mai ntai n a bala nce d sa m ple acr oss t he 3 gr o u ps t o 
s u p p ort descri pti ve a nal ysis f or P K a n d safety at eac h d ose sc he d ule. I m m u n os u p presse d 
parti ci pa nts will be pri orit ize d t o be e nr olle d i nt o t he ne w 6 0 0 m g I M d osi n g st u d y gr o u p. 
T his is i n li ne with t he i n dicat i on f or w hic h t he pr o d uct is c urre ntl y a ut h orize d f or 
e mer ge nc y use i n t he U S A.
S pecific c ha n ges of t he s u b-st u d y C S P a d de n d u m are as f oll ows:
Secti o n 1 . 1 ( S y n o psis)
T he s u b -secti ons were u p date d t o i ncl u de t he ne w 6 0 0 m g re peat d ose partici pa nt st u d y  
ar m, e xte n de d st u d y d uratio n, a n d i nteri m a nal yses. I n a d dit i on t he Car di o vasc ular E ve nt 
A d ju dicat i on C o m mittee was a d de d t o ali g n wit h ot her A Z D 7 4 4 2 st u dies.
Secti o n 1 . 2 ( Sc he m atic)
T he sc he mat ic has bee n u p date d t o i ncl u de t he a d dit i onal re peat d ose partici pa nt ar m a n d 
e xte n de d st u d y d uratio n.
Secti o n 1 . 3 ( Sc he d ule of Acti vities)
A ne w Sc he d ule of  Acti vity ta ble has bee n i ncl u de d f or e xte n de d s u b-st u d y treat me nt a n d 
f oll ow -u p peri o ds of t he a d dit i onal re peat d ose partici pa nt gr o u ps. I n a d dit i on t he 
C O VI D -1 9 m o ni t orin g sc he d ule f or all gr o u ps were ali g ne d.
Secti o n 2 . 3. 1 ( Ris k Assess me nt)
T he ta bl e was u p date d t o ali g n wit h t he c urre nt I n vesti gat or Br oc h ure a n d S A E occ urre nce 
u p date d
Secti o n 3 ( O bjecti ves a n d E n d p oi nts)
T he sect i on has bee n u p date d t o i ncl u de t he a d dit i o nal re peat d ose partici pa nt ar m.
Secti o n 4 . 1 ( O ver all St u d y Desi g n)
T he sect i on has bee n u p date d t o i ncl u de t he a d dit i o nal re peat d ose partici pa nt ar m a n d 
e xte n de d st u d y d uratio n.
Secti o n 4 . 2 ( Scie ntific R ati o n al f or t he St u d y Desi g n)
T he sect i on has bee n u p date d t o i ncl u de t he rati o nal f or t he a d dit i onal re peat d ose 
parti ci pa nt ar m a n d e xte n de d st u d y d ur atio n.
Secti o n 4 . 3 ( J ustific ati o n f or D ose) 
T he sect i on has bee n u p date d t o i ncl u de t he j ust ificati o n of t he 6 0 0 m g d ose.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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Secti o n 6 ( St u d y I nter ve nti o n)
T his sect i on was e dite d t o u p date stat us of t he A Z D 7 4 4 2 pr o d uct s.
Secti o n 6 . 1 (I M Ps A d mi nistere d) 
T he sect i on has bee n u p date d t o i ncl u de t he a d dit i o nal re peat d ose partici pa nt d ose, 
e xte n de d st u d y d uratio n, a n d t he ne w I M P d ose use d. 
Secti o n 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)
T he sect i on has bee n u p date d t o i ncl u de ne w d ose use d. 
Secti o n 6 . 3 ( Me as ure t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g)
T he sect i on has bee n u p date d t o i ncl u de ne w d ose use d. 
Secti o n 6 . 5 ( C o nc o mit a nt T her a p y)
Ta ble 1 0 ( Per mitte d, Restricte d a n d Pr o hi bite d Me dicati ons) u p date d t o ali g n wit h ot her 
A Z D 7 4 4 2 st u dies. 
Secti o n 8 . 1 ( Effic ac y Assess me nts)
T he Secti o n 8 . 1. 1 ( M o nit ori n g C O VI D-1 9 S y m pt o ms) has bee n u p date d t o i ncl u de t he 
a d ditio nal  re peat d ose partici pa nt ar m sc he d ule of acti vit ies f or mo ni t ori n g C O VI D-1 9 
s y m pt o ms. I n a d diti on, la n g ua ge i n Sect i on 8 . 1. 3 (Ill ness Visits) was a d de d f or clarificati o n.
Secti o n 8 . 4 ( O ver d ose)
T he sect i on has bee n u p date d t o i ncl u de ne w d ose use d. 
Secti o n 8 . 5. 2 ( I m m u n o ge nicit y Assess me nts) 
Secti o n 8 . 5. 2. 5 ( A d diti onal Ser u m I m m u n o ge nicit y) u p date d t o reflect w hat is i n S o A . I n 
a d ditio n ser ol o gical  assess me nts mo ve d i nt o Secti o n 8 . 5. 3 P har mac o d y na mics.
Secti o n 9 . 1 ( St atistic al H y p ot hesis)
T he sect i on has bee n u p date d t o i ncl u de ne w d ose use d. 
Secti o n 9 . 2 ( S a m ple Size Deter mi n ati o n)
Para gra p h a d de d t o j ust if y partici pa nt n u m bers c h ose n f or t he gr o u ps wit hi n t his 
a me n d me nt .
9. 4. 2 ( Sec o n d ar y E n d p oi nts)
Para gra p h a d de d t o acc o u nt f or ne w C O VI D -1 9 treat me nts a vaila ble .

Cli nical St u d y Pr ot oc ol A d de n d u m - Ame n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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Secti o n 9 . 7 ( A dj u dic ati o n C o m mittees)
T his sect i on was s plit i nt o 2 s u b -secti ons ( M or bi dit y  A dj u dicati on C o m mittee a n d ne wl y 
a d de d Car di o vasc ular E ve nt A d j u dicati o n C om mit tee ) f or 2 c o m mittees t o ali g n with ot her 
A Z D 7 4 4 2 st u dies.
A 5
Details o n D S M B str uct ure were
V ari o us secti o ns
Cl arificat i ons ha ve bee n ma de w here a p pr o priate as well as ot her mi n or e dit orial a n d 
d oc u m e nt for m atti n g re visi o ns t hro u g h o ut .

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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T A B L E O F C O N T E N T S
TI T L E P A G E ........................................................................................................................1
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E ....................................2
T A B L E O F C O N T E N T S ......................................................................................................6
1
P R O T O C O L A D D E N D U M S U M M A R Y .........................................................1 0
1. 1
S y n o psis ...........................................................................................................1 0
1. 2
Sc he mat ic .........................................................................................................1 3
1. 3
Sc he d ule o f Act i vities.......................................................................................1 3
2
I N T R O D U C TI O N ............................................................................................3 1
2. 1
St u d y  Ratio nale ................................................................................................3 1
2. 2
Bac k gr o u n d ......................................................................................................3 1
2. 3
Be nefit/ Ris k Assess me nt ...................................................................................3 1
2. 3. 1
Ris k Assess me nt ...............................................................................................3 1
2. 3. 2
Be nefit Assess me nt ...........................................................................................3 2
2. 3. 3
O verall Be nefit: Ris k C o ncl usi o n ......................................................................3 2
3
O BJ E C TI V E S A N D E N D P O I N T S...................................................................3 2
4
S T U D Y D E SI G N .............................................................................................3 3
4. 1
O verall De si g n ..................................................................................................3 3
4. 2
S ci e nt ific Rati o nale f or St u d y Desi g n ...............................................................3 5
4. 3
J ustificati o n f or D ose........................................................................................3 6
4. 4
J ustificati o n f or St u d y P o p ulati o n .....................................................................3 6
4. 5
E n d of St u d y  Defi niti on ....................................................................................3 7
5 
S T U D Y P O P U L A TI O N ...................................................................................3 7
5. 1
I ncl usi on Cri t eria ..............................................................................................3 7
5. 2
E x cl usio n  Crit eria .............................................................................................3 9
5. 3
Lifest yle C o nsi derat i ons ...................................................................................3 9
5. 4
Scree n Fail ures ................................................................................................. 4 0
6
S T U D Y I N T E R V E N TI O N...............................................................................4 0
6. 1
I M P(s) A d mi nistere d ........................................................................................4 0
6. 1. 1
I M P ..................................................................................................................4 0
6. 2
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y ...................................................4 1
6. 2. 1
D ose Pre parati o n a n d A d mi nistrati o n I nstr ucti o ns .............................................4 2
6. 2. 1. 1
I n vesti gati onal Pr o d uct I ns pect i on ....................................................................4 2
6. 2. 1. 2
D ose Cal c ulat i on ...............................................................................................4 2
6. 2. 1. 3
D ose Pre parati o n Ste ps .....................................................................................4 2
6. 3
Meas ures t o Mi ni mize Bias: Ra n d o mizat i on a n d Bli n di n g ................................4 3
6. 4
I M P C o mplia nce ...............................................................................................4 3
6. 5
C o nc o mita nt T hera p y ........................................................................................4 3

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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6. 5. 1
C O VI D -1 9 Vacci nes .........................................................................................4 5
6. 6
D ose M o dificat i on ............................................................................................4 6
6. 7
I nter ve nti o n After t he E n d of t he St u d y.............................................................4 6
7  
DI S C O N TI N U A TI O N O F I M P 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 ..........................................................4 6
7. 1
Di sc o nti n uatio n of  St u d y I M P...........................................................................4 6
7. 2
P arti cip a nt Wi t hdra wal fr o m  t he St u d y .............................................................4 6
7. 3
L ost t o F oll o w - u p .............................................................................................4 7
7. 4
St u d y  S us pe nsi on/ Earl y Ter mi nat i on ................................................................4 7
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 8
8. 1
Efficac y Assess me nts ........................................................................................4 8
8. 1. 1
M o ni t ori n g C O VI D- 1 9 S y m pt o ms ....................................................................4 8
8. 1. 2
Se vere or Critical Criteria .................................................................................5 0
8. 1. 3
Ill ness Visits .....................................................................................................5 0
8. 1. 4
S A R S -C o V -2 Testi n g a n d Ot her Vir ol o g y  Assess me nts....................................5 1
8. 2
S af et y Assess me nts ...........................................................................................5 1
8. 2. 1
P h ysical E xa mi nat i ons ......................................................................................5 1
8. 2. 2
Vi t al Sig ns........................................................................................................ 5 2
8. 2. 3
Electr ocar di o gra ms ...........................................................................................5 2
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts............................................................5 2
8. 2. 4. 1
Fe males O nl y ....................................................................................................5 4
8. 2. 5
I njecti on Si te I ns pecti on ....................................................................................5 4
8. 2. 5. 1
M o ni t ori n g After I M P A d mi nistrati o n...............................................................5 4
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................................5 4
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  for C ollect i n g A E a n d S A E I nf or mat i on ................5 5
8. 3. 2
F o ll ow -u p of  A Es a n d S A Es.............................................................................5 5
8. 3. 3
Ca usalit y C o llecti on ..........................................................................................5 7
8. 3. 4
A d verse E ve nts of S pecial I nterest ....................................................................5 7
8. 3. 5
Me dicall y  Atte n de d A d verse E ve nts ................................................................. 5 7
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 7
8. 3. 7
A d verse E ve nts Base d o n E xa mi nat i ons a n d Tests ............................................5 8
8. 3. 8
H y’s La w ..........................................................................................................5 8
8. 3. 9
Re p orti n g of Seri o us A d verse E ve nts ................................................................5 9
8. 3. 1 0
Pre g na nc y .........................................................................................................5 9
8. 3. 1 0. 1
Mat er nal E x p os ure ............................................................................................5 9
8. 3. 1 0. 2
Pater nal  E x p os ure.............................................................................................6 0
8. 3. 1 1
Me dicat i on Err or ...............................................................................................6 0
8. 4
O ver d ose ..........................................................................................................6 1
8. 5
H u m a n Biol o g ical Sa m ples...............................................................................6 1
8. 5. 1
P har mac o ki net ics Assess me nts .........................................................................6 2
8. 5. 1. 1
Deter mi nat i on of Dr u g C o nce ntrati o n ...............................................................6 2
8. 5. 2
I mm u n o ge nicit y Assess me nts ...........................................................................6 2
8. 5. 2. 1
A nt i dr u g A nti b o d y Assess me nts.......................................................................6 3

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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LI S T O F T A B L E S
Ta ble 1
O bject i ves a n d E n d p oi nts for t he Re peat D ose S u b -St u d y ........................1 0
Ta ble 2
Sc he d ule of Act i vities: S u b-St u d y  Treat me nt a n d F o ll ow- u p Peri o d f or 
Gr o u p 1 ( A Z D 7 4 4 2 Partici pa nts fr o m t he P R O V E N T Pare nt St u d y )........1 5
Ta ble 3
Sc he d ule of Act i vities: S u b-St u d y  Treat me nt a n d F o ll ow- u p Peri o d f or 
Gr o u p 2 ( Place b o Partici pa nts fr o m P R O V E N T Pare nt St u d y ).................2 0
Ta ble 4
Sc he d ule of Act i vities: E xte n de d S u b-St u d y  Treat me nt a n d F oll o w- u p 
P eri o d f or Gr o u p 3 ( A Z D 7 4 4 2 a n d Place b o Partici pa nts fr o m t he 
P R O V E N T Pare nt St u d y ) ........................................................................2 6
Ta ble 5
Sc he d ule of Act i vities: Ill ness Visits ( Partici pa nts wit h Q ualif yi n g 
Cli nical S y m pt o ms) .................................................................................2 9
Ta ble 6
Ris k Assess me nt f or A Z D 7 4 4 2 ................................................................3 1
Ta ble 7
O bject i ves a n d E n d p oi nts for Re peat D ose S u b -St u d y .............................3 3
Ta ble 8
Hi g hl y  Effecti ve Met h o ds of C o ntrace pti o n.............................................3 9
Ta ble 9
I n vesti gati onal Pr o d uct ............................................................................4 1
Ta ble 1 0
Per mi tte d, Restricte d, a n d Pr o hi bite d Me dicat i ons ...................................4 4
Ta ble 1 1
C O VI D -1 9 Q ualif yi n g S y m pt o ms ............................................................4 9
Ta ble 1 2
W H O Cli nical Pr o gressi o n Scale
.............................................................5 0
Ta ble 1 3
I njecti on Si te I ns pect i on ..........................................................................5 4
Ta ble 1 4
P o p ul at i ons f or A nal ysis ..........................................................................6 6
Ta ble 1 5
A n A p pr oac h t o Ma na ge me nt of A na p h ylact ic, H y perse nsiti vity, a n d 
P os t-i njecti on React i ons ...........................................................................9 1
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 .........................7 1
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 7
A p pe n di x C
Ha n dli n g of H u ma n Bi o l ogical  Sa m ples ..................................................8 2
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 ...........................................................................8 4
A p pe n di x E
A na p h yla xis .............................................................................................9 0
A p pe n di x F
A b bre viat i ons ..........................................................................................9 4

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
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1
P R O T O C O L A D D E N D U M S U M M A R Y
1. 1
S y n o psis
S u b -st u d y Title: A P h ase III, M ulti-ce nter, O pe n-la bel S u b-st u d y in A d ults t o Assess t he 
S af et y, P har mac o ki netics ( P K), a n d I m m u n o ge nicit y of Re peat D oses of A Z D 7 4 4 2, a 
C o m bi nat i on Pr o d uct of T w o M o n ocl o nal A nt i b o dies ( A Z D 8 8 9 5 a n d A Z D 1 0 6 1) ( T he 
P R O V E N T Re peat D ose S u b -st u dy) . 
R ati o n ale : A Z D 7 4 4 2 is bei n g e val uate d f or t he pre ve nt i on a n d treat me nt of C or o na vir us 
Di sease 2 0 1 9 ( C O VI D-1 9). P R O V E N T is a n o n g oi n g P hase III ra n d o mize d, d o u ble -bli n d, 
pl ace b o -c o ntr olle d, m ult i-ce nter st u d y in a d ults t o assess t he safet y a n d efficac y of  a si n gle 
d ose of A Z D 7 4 4 2 f or pre -e x p os ure pr o p h yla xis of C O VI D -1 9 ( P R O V E N T pare nt st u d y). T his 
P R O V E N T s u b -st u d y will assess t he safety,  P K, a n d i m m u n o ge nicity of re peat d oses of 
A Z D 7 4 4 2 i n partici pa nts c urre nt l y e nr olle d i n t he P R O V E N T st u d y w h o ma y be nefit fr o m a 
re peat d ose of A Z D 7 4 4 2. T his s u b-st u d y will i n vestigate w het her a d dit i onal d oses of 
A Z D 7 4 4 2 ha ve a n a p pr o priate safet y pr ofile i n t his v ul nera ble p o p ulat i on. P har mac o ki net ic 
data will als o be ge nerate d t o e val uate w het her re peat d osi n g ca n ma i ntai n ser u m 
c o nce ntrati o ns of A Z D 7 4 4 2 le vels ass ociate d wit h pr otecti o n a gai nst C O VI D-1 9. 
O bjecti ves a n d E n d p oi nts:
Ta ble 1 prese nts t he o bject i ves a nd e n d p o i nts for t he re peat d ose s u b -st u d y.
Ta ble 1
O bjecti ves a n d E n d p oi nts f or  t he Re pe at D ose S u b-St u d y
O bjecti ve
E n d p oi nt
Pri m ar y
T o e val uate t he safet y a n d t olera bilit y of re peat d oses of 
A Z D 7 4 4 2 3 0 0 a n d 6 0 0 m g I M
A Es, S A Es, M A A Es, a n d A E SIs p ost re peat d ose of I M P
Sec o n d ar y
T o e val uate t he P K of re peat d oses of A Z D 7 4 4 2 3 0 0 
a n d 6 0 0 m g I M
Ser u m A Z D 7 4 4 2 c o nce ntrati o ns after re peat d osi n g
P K para meters if data per mit after re peat d osi n g
T o e val uate A D A res p o nses t o re peat d oses of 
A Z D 7 4 4 2 3 0 0 a n d 6 0 0 m g I M i n ser u m
I nci de nce of A D A t o re peat d oses of A Z D 7 4 4 2 i n ser u m
T o deter mi ne a nti -S A R S -C o V -2 n A b le vels i n ser u m 
f oll o wi n g re peat d oses of A Z D 7 4 4 2 3 0 0 a n d 6 0 0 m g I M
P ost d ose G M Ts a n d G M F Rs fr o m baseli ne val ues after a 
re peat I M d ose i n S A R S-C o V -2 n A bs ( wil d -t ype assa y  or 
pse u d o -ne utralizati o n assa y)
A D A, a nti dr u g a nti b o d y; A E, a d verse e ve nt; A E SI, a d verse e ve nt of s pecial i nterest; G M T, ge o metric mea n titer; 
G M F R, ge o metric mea n f ol d rise; I M, i ntra m usc ular; 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; P K, p har mac o ki netic; 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 s y n dr o me -c or o na vir us 2.
F or E x pl orat or y  o bject i ves, see Secti o n 3 .

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 of 9 6
O ver all Desi g n:
T his is a P hase III, m ult i-c o u ntr y, m ulti-ce nter, o pe n-la bel, s u b-st u d y assessi n g t he safety,  P K, 
a n d i m m u n o ge nicit y ( AD A) of re peat d oses of A Z D 7 4 4 2. Partici pa nts at a s u b set of  acti ve 
P R O V E N T pare nt st u d y  sites i n partici pati n g c o u ntries will be i n vite d t o e nr oll i n t his 
s u b-st u d y.
P arti cipa nts will be a d ults w h o ha ve bee n ra n d o mize d a n d are acti vel y partici pati n g i n t he 
P R O V E N T pare n t st u d y a n d w h o ma y be nefit fr o m a re peat d ose of A Z D 7 4 4 2. T here is n o 
scree ni n g peri o d i n t he s u b-st u d y a n d partici pa nts will retai n t heir s u bject i de ntificati o n 
n u m ber fr o m t he pare nt st u d y.
P arti cipa nts will be eli gi ble f or i ncl usi o n i n t he s u b-st u d y o nce t he y ha ve reac he d 
1 2 ± 2 m o nt hs p ost d ose of I M P i n t he d o u ble -bli n d pare nt st u d y. Eli gi ble partici pa nts w h o 
ha ve alrea d y c o m p lete d t heir Da y 3 6 6 Vis it in t he pare nt st u d y  will be u n bli n de d, assi g ne d t o 
a s u b-st u d y gr o u p, a n d t he n u n der g o t he s u b-st u d y Da y 1 ( S S -D 1) assess me nts. F or 
parti ci pa nts w h o ha ve n ot yet c o mplete d t hei r D a y 3 6 6 Visit i n t he pare nt st u d y, t he S S-D 1 
visit will i ncl u de t he Da y 3 6 6 assess me nts. Pre -d ose Da y 3 6 6 assess me nts will ser ve as 
baseli ne assess me nts f or t he s u b -st u d y.
All par tici pa nts will recei ve A Z D 7 4 4 2 i n t he re peat d ose s u b -st u d y. I nitiall y, participa nts will 
be assi g ne d t o o ne of t w o d osi n g i nter val gr o u ps, base d o n t heir d o u ble -bli n d I M P assi g n me nt 
i n t he pare nt st u d y, as f oll ows:

Gr o u p 1 ( ~ 1 2- m o nt h re peat d ose i nter val): Partici pa nts w h o recei ve d A Z D 7 4 4 2 3 0 0 m g 
I M o n Da y 1 of  t he pare nt st u d y will recei ve a sec o n d d ose of A Z D 7 4 4 2 3 0 0 m g I M o n 
S S -D 1.

Gr o u p 2 ( ~ 6- m o nt h re peat d ose i nter val): Partici pa nts w h o recei ve d place b o o n Da y 1 of  
t he pare nt st u d y  will recei ve t heir first d ose of A Z D 7 4 4 2 3 0 0 m g I M o n S S -D 1 f o ll owe d 
b y a sec o n d d ose o n S S-D 1 8 3.
At  6 mo nt hs ( S S -D 1 8 3), a s u bset of partici pa nts fr o m U S A  sites i n Gr o u p 1 a n d Gr o u p 2
(e ve nl y bala nce d bet wee n gr o u ps), w h o c o nse nt t o recei ve a ddi tio nal A Z D 7 4 4 2 6 0 0 m g d oses 
a p pr o xi matel y e v er y 6 mo nt hs will  be assi g ne d t o a ne w ar m - Gr o u p 3 . All ot her partici pa nts 
will c o nt i n ue i n t he s u b-st u d y acc or di n g t o t heir ori gi nall y assi g ne d d osi n g i nter val gr o u p 
sc he d ule. T he a d dit i on of Gr o u p 3 will cr eate 4 p ossi ble d osi n g c o h orts , base d o n t he h o w 
ma n y d oses of 3 0 0 m g A Z D 7 4 4 2 recei ve d pri or t o e nteri n g Gr o u p 3 a n d w het her or n ot t his 
was f o ll owe d b y a f urt her t w o d oses of 6 0 0 m g A Z D 7 4 4 2 :
Gr o u p 1 

C o h ort 1: A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g
Gr o u p 2

Cli nical St u d y Pr o t oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6

C o h ort 2: Pl ace b o, A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g
Gr o u p 3

C o h ort 3 (fr o m Gr o u p 1): A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g, 6 0 0 m g, 6 0 0 m g

C o h ort 4 ( Fr o m Gr o u p 2): Place b o, A Z D 7 4 4 2 3 0 0 m g, 6 0 0 m g, 6 0 0 m g
Gr o u p lev el  recr uit me nt ca ps ma y be place d t o e ns ure 5 0 or m ore parti ci pa nts c o mplete t he 
st u d y wit h t h eir assi g ne d d ose a n d vali d sa m ples.
Gr o u p 1 a n d Gr o u p 2 will u n der g o safet y f oll ow- u p f or 4 5 6 da y s after t he last d ose of 
A Z D 7 4 4 2, a n d Gr o u p 3 will u n der g o safet y f oll ow- u p f or 1 8 3 da y s after t he last d ose of 
A Z D 7 4 4 2 (Fi g ure 1 ).
Discl os ur e St ate me nt: T hi s is a safety/ P K /i m m u n o ge nicit y st u d y wit h t hree ar ms (all 
A Z D 7 4 4 2 b ut wit h differe nt d oses, d osi n g i nter vals a n d/ or st u d y d urati o ns) t hat is n ot 
bli n de d.
N u m ber  of P artici p a nts: A p pr o xi matel y 5 0 0 partici pa nts will be e nr o lle d fr o m t he pare nt 
P R O V E N T st u d y i nt o t he s u b -st u d y a n d recei ve A Z D 7 4 4 2. T he ai m is t o a p pr o xi matel y 
bala nce t he pr o p orti o n of partici pa nts deri ve d fr o m eac h of t he A Z D 7 4 4 2 a n d place b o ar m s 
fr om t he d o u ble-bli n d pare nt st u d y. If a n i m bala nce bet wee n t he ar ms is o bser ve d, a ca p ma y 
be i ntr o d uce d. 
To  in vest i gate re peat d osi n g wit h 6 0 0 m g I M, partici pa nts i n t he U S A  sites will b e of fere d t he 
o pti o n t o be e nr olle d t o recei ve re peat d oses of 6 0 0 m g i n Gr o u p 3 fr o m S S- D 1 8 3 o n war ds.
I nter ve nti o n Gro u ps a n d D ur ati o n: All part ici pa nts will recei ve a re peat d ose of A Z D 7 4 4 2. 
T he pl a n ne d d urat i on of t he s u b -st u d y is 4 5 7 da ys f or Gr o u p 1, 6 3 9 da ys f or Gr o u p 2, a n d 5 4 8
da ys f or Gr o u p 3.
D at a S afet y M o n it ori n g B o ar d: T he i n de pe n de nt D S M B m o nit ori n g t he P R O V E N T pare nt 
st u d y will pr o vi de safety o versi g ht, t o e ns ure safe a n d et hical c o n d uct of t he s u b -st u d y.
St atistic al Met h o ds
Pri m ar y E n d p oi nt: T he safet y a n d t olera bilit y of A Z D 7 4 4 2 will pri maril y be asses se d b y t he 
i nci de nce of A Es, S A Es, M A A Es, a n d A E SIs.
I nteri m a n al ysis: A n i nitial i nteri m a nal ysis is pla n ne d after a mi ni m u m o f 5 0 parti ci pa nts at 
t he first sta ge of e nr o ll me nt of Gr o u p 1, w h o recei ve d A Z D 7 4 4 2 o n Da y 1 of  t he pare nt 
P R O V E N T st u d y ha ve rec ei ve d a re peat d ose of A Z D 7 4 4 2 o n S S -D 1 a n d f o ll owe d u nt il S S-
D 2 9 (i e, for 2 8 da y s after t heir sec o n d d ose of A Z D 7 4 4 2). T his i nteri m a nal ysis will assess t he 
pri mar y  safety e n d p o i nt a n d a vaila ble sec o n dar y e n d p oi nts. T he first Data Re vie w Meeti n g b y 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
t he D S M B will occ ur i n c o nj u nct i on wi t h t he i nteri m a nal ysis. A d dit i on al  int eri m a nal yses 
ma y be c o n d ucte d as re q uire d f or a n y  fut ure re g ulat or y  c o m mitme nts.
M or bi dit y A dj u dic ati o n C o m mittee: A n i n de pe n de nt M or bi dity A d j u dicati on C o m mittee 
will assess bli n de d data t o e val uate w het her t he ca uses of deat h f or partici pa nts are c o nsi dere d 
C O VI D -1 9 ass oci ate d.
C ar di o v asc ul ar  E ve nt A dj u dic ati o n C o m mittee: A n i n de pe n de nt Car di o vasc ular E ve nt 
A d j u dicati on C o m mittee will pr o vi de a n i n de pe n de nt, e xter nal, s yste mat ic, a n d u n biase d 
assess me nt of de -i de ntifie d bli n de d data t o s yste maticall y e val uate car di o vasc ular e ve nts.
1. 2
Sc he m atic
Fi g ure 1
P R O V E N T Re pe at D ose S u b -st u d y Desi g n
a
Partici pa nts fr o m P R O V E N T pare nt st u d y w h o ma y be nefit fr o m a re peat d ose of A Z D 7 4 4 2. 
b
Base d o n ra n d o mizati o n i n t he pare nt st u d y.
c
Partici pa nts will be eli gi ble f or t he s u b -st u d y o nce t he y ha ve reac he d 1 2 ± 2 m o nt hs p ost d ose i n t he 
d o u ble -bli n d pare nt st u d y. T heref ore, i n t he A Z D 7 4 4 2 gr o u p, t he d osi n g i nter val bet wee n D ose 1 ( pare nt 
st u d y) a n d D ose 2 ( S S-D 1) will be a p pr o xi matel y 1 2 m o nt hs.
d
F or partici pa nts w h o ha ve n ot u n der g o ne a Da y 3 6 6 visit i n t he pare nt st u d y, t he Da y 3 6 6 assess me nts will 
be perf or me d at S S -D 1.
e
Partici pa nts i n Gr o u p 3 are t h ose w h o c o nse nte d t o recei ve e xte n de d A Z D 7 4 4 2 d oses a n d c o m prise t h ose 
fr o m U S A sites Gr o u p 1 a n d Gr o u p 2 ( a p pr o xi matel y e ve nl y distri b ute d bet wee n gr o u ps) wh o alrea d y 
recei ve d D ose 2 a n d D ose 1 of A Z D 7 4 4 2 o n S S-D 1 , res pecti vel y. Partici pa nts i n Gr o u p 3 will n o w recei ve 
a d diti o nal A Z D 7 4 4 2 d oses a p pr o xi matel y e ver y 6 m o nt hs a n d will be f oll o we d f or a p pr o xi matel y 6 m o nt hs 
after recei vi n g t heir last d ose at S S - D 3 6 6.
M, m o nt h; S S -D, s u b -st u d y da y.
1. 3
Sc he d ule of Acti vitie s
Ta ble 2 , Ta ble 3 , a n d Ta ble 4 s u m marize t he sc he d ule of acti vities f or t he P R O V E N T re peat 
d ose s u b -st u d y for Gr o u p 1 ( partici pa nts ra n d o mize d t o A Z D 7 4 4 2 i n t he pare nt st u d y), 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Gr o u p 2 ( partici pa nts ra n d o mize d t o place b o i n t he pare nt st u d y), a n d Gr o u p 3 ( partici pa nt s 
fr om Gr o u p 1 or Gr o u p 2 w h o will recei ve a d dit i onal A Z D 7 4 4 4 2 re peat d oses) res pecti vel y . 
O n d osi n g da ys, all assess me nts are t o be o btai ne d pre -d ose u nless ot her wise s pecifie d. F or 
parti ci pa nts w h o ha ve n ot u n der g o ne a Da y 3 6 6 visi t in t he pare nt st u d y, t he Da y 3 6 6
assess me nts liste d i n t he ta bles s h o ul d be perf or me d at S S -D 1. F or partici pa nts w h o ha ve 
alrea d y u n der g o ne t he Da y 3 6 6 visit i n t he pare nt st u d y, o nl y t he S S-D 1 assess me nts nee d t o 
be perf or m e d.
P arti cipa nts w h o prese nt wi t h or re p ort a C O VI D-1 9 q ualif yi n g s y m pt o m(s) after S S -D 1 will 
be i nstr ucte d t o i nitiate Ill ness Visits a n d will be teste d l ocall y f or S A R S-C o V -2 (Ta ble 5 ). If 
ne gat i ve at I ll ness Visit Da y 1 , t he partici pa nt will be i nstr ucte d t o st o p Ill ness Visits a n d 
c o nti n ue wit h t he s u b -st u d y sc he d ule d assess me nts i n Ta ble 2 , Ta ble 3 , or Ta ble 4 . If p ositive, 
t he partici pa nt will be i nstr ucte d t o c o nti n ue wi t h all Ill ness Visits a n d will ha ve a d diti onal 
assess me nts per  Ta ble 5 . 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 2
Sc he d ule of Acti vities: S u b -St u d y Tr e at me nt a n d F oll o w -u p Peri o d f or Gr o u p 1 ( A Z D 7 4 4 2 P artici p a nts fr o m t he 
P R O V E N T P ar e nt St u d y)
Pr oce d ure
P are nt st u d y
S u b -st u d y Tre at me nt a n d F oll o w-u p Peri o d
E arl y 
Disc o nti n u ati o n 
Visit
F or 
det ails, 
see 
Secti o n:
D a y a
D a y 3 6 6 b
S S -D 1 b
S S -D 2 9
S S -D 9 2
S S -D 1 8 3
S S -
D 2 7 5
S S -D 3 6 6 
S S -D 4 5 7
Wi n d o w ( d a ys)
± 6 1
N A
± 3 
± 5
± 1 0 
± 1 5 
± 1 5 
± 1 5
I nf or me d c o nse nt 
(s u b-st u d y)
X ( pre -
d ose)
A 3
Verif y  eli gi bilit y criteria
X ( pre -
d ose)
5. 1 , 5. 2
Tar gete d p h ysical 
e xa mi nati o n
X  
X  
X  
X
X  
X  
X
X
8. 2. 1
Wei g ht
X
8. 2. 1
Vital si g ns (i ncl u di n g p ulse 
o xi metr y )
X ( pre -d ose)
X ( p ost -
d ose c) 
X  
X
X  
X  
X
X
8. 2. 2
Tri plicate 1 2 -lea d E C G 
X ( pre -d ose)
X
X
X
X
8. 2. 3
Ser u m c he mistr y
X ( pre -d ose)
X  
X
X  
X  
X
X
8. 2. 4
He mat ol o g y
X ( pre -d ose)
X  
X
X  
X  
X
X
8. 2. 4
C oa g ulati o n
X ( pre -
d ose)
X  
X
X  
X  
X
X
8. 2. 4
Ur i nal ysis
X ( pre -d ose)
X  
X
X  
X  
X
X
8. 2. 4
Car diac bi o mar kers
X ( pre -
d ose)
X
X
X
X
8. 2. 4
Tr o p o ni n T/l
X ( pre -
d ose)
8. 2. 4

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 2
Sc he d ule of Acti vities: S u b -St u d y Tr e at me nt a n d F oll o w -u p Peri o d f or Gr o u p 1 ( A Z D 7 4 4 2 P artici p a nts fr o m t he 
P R O V E N T P ar e nt St u d y)
Pr oce d ure
P are nt st u d y
S u b -st u d y Tre at me nt a n d F oll o w-u p Peri o d
E arl y 
Disc o nti n u ati o n 
Visit
F or 
det ails, 
see 
Secti o n:
D a y a
D a y 3 6 6 b
S S -D 1 b
S S -D 2 9
S S -D 9 2
S S -D 1 8 3
S S -
D 2 7 5
S S -D 3 6 6 
S S -D 4 5 7
Wi n d o w ( d a ys)
± 6 1
N A
± 3 
± 5
± 1 0 
± 1 5 
± 1 5 
± 1 5
D oc u me nte d S A R S -C o V - 2 
R T -P C R test ta ke n ≤ 3 da ys 
bef ore S S -D 1 g O R
Ra pi d S A R S -C o V - 2 
a nti ge n test (f or scree ni n g 
criteria)
X ( pre -
d ose) h
8. 6. 1. 1
N P s wa b f or S A R S -C o V - 2 
R T -P C R (ce ntral 
la b orat or y)
X ( pre -
d ose) i
8. 6. 1. 1
Ser u m sa m ple f or S A R S -
C o V -2 ser ol o g y (a nti -
n ucle oca psi d) testi n g k
X
X  
X
X  
X  
X
X
8. 5. 2. 2
P h ar m ac o ki netics, p h ar m ac o d y n a mics, a n d A D A assess me nts
Ser u m sa m ple f or 
A Z D 7 4 4 2 p har mac o ki netic 
assess me nt
X
X  
X
X  
X  
X
X
8. 5. 1
Ser u m sa m ple f or 
A Z D 7 4 4 2 A D A assess me nt
X
X  
X
X  
X  
X
X
8. 5. 2. 1
Ser u m sa m ple f or S A R S -
C o V - 2 n A bs assess me nt
X
X  
X
X  
X  
X
X
8. 5. 3. 1

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 of 9 6
e
F S H will be a nal yze d at S S -D 1 t o c o nfir m p ost me n o pa usal stat us o nl y i n w o me n < 5 0 years of a ge w h o ha ve bee n a me n orr h oeic f or ≥1 2 m o nt hs. U ntil 
F S H is d oc u me nte d t o be wit hi n me n o pa usal ra n ge, t he partici pa nt is t o be c o nsi dere d of c hil d beari n g p ote ntial. F or w o me n a ge d ≥5 0 years, 
p ost me n o pa usal is defi ne d as ha vi n g a hist or y of ≥1 2 m o nt hs’ a me n orr hea pri or t o S S -D 1, wit h o ut a n alter nati ve ca use, f oll o wi n g cessati o n of e x o ge n o us 
se x-h or m o nal treat me nt.
f
Wee kl y c o ntact u p t o S S -D 1 8 3 wit h partici pa nts t o re mi n d t he m t o prese nt t o t he st u d y site f or S A R S -C o V -2 testi n g if t he y ha ve q ualif yi n g s y m pt o ms. T he 
I n vesti gat or will e n q uire a b o ut a n y C O VI D-1 9 s y m pt o ms fr o m t he past 7 da ys a n d ot her a d verse e ve nts.
M o nt hl y  c o ntact wit h partici pa nts fr o m S S-D 1 8 3 t o E O S, t o assess o verall safet y. T he I n vesti gat or will as k a b o ut a n y C O VI D -1 9 q ualif yi n g s y m pt o ms a n d 
car diac e ve nts fr o m t he past m o nt h a n d ot her A Es. Partici pa nts s h o ul d be re mi n de d t o prese nt t o t he st u d y site f or S A R S -C o V -2 testi n g if t he y ha ve 
q ualif y i n g s ym pt o ms a n d t o c o ntact t he site s h o ul d t he y de vel o p q ualif yi n g s y m pt o ms be t wee n eac h m o nt hl y c o ntact.
g
T his test is n ot perf or me d as part of t he cli nical st u d y b ut m ust be a vaila ble pri or t o e nr oll me nt.
h
If a d oc u me nte d S A R S-C o V -2 R T -P C R test is n ot a vaila ble at scree ni n g, a ra pi d S A R S -C o V -2 a nti ge n test will be perf or me d. Eit her test m ust be ne gati ve 
bef ore d osi n g (see i ncl usi o n criteria i n Secti o n  5. 1 ) 
i
Baseli ne sa m ple, n ot a scree ni n g sa m ple; res ults n ot nee de d pri or t o d osi n g.
j
W he n test s u p plies are a vaila ble, sa m pli n g s h o ul d be perf or me d.
k
Perf or m i m me diatel y, 3 0 mi n utes ( ± 1 0 mi n utes) after b ot h i njecti o ns are c o m plete, a n d pri or t o partici pa nt release ( 1 h o ur after I M P a d mi nistrati o n).
l
After I M P a d mi nistrati o n, partici pa nts will be cl osel y m o nit o re d f or on e h o ur bef ore t he y ca n lea ve t he site.
m
A Es, S A Es, M A A Es, a n d A E SIs will be assesse d via a p h o ne call at S S - D 4 5 7.
O n d osi n g da ys, all assess me nts are t o be c o n d ucte d pre -d ose u nless ot her wise s pecifie d.
A D A, a nti dr u g a nti b o d y; A E, a d verse e ve nt; A E SI, a d verse e ve nt of s pecial i nterest; β -h C G, be t a-h u ma n c h ori o nic g o na d otr o pi n; C O VI D -1 9, c or o na vir us 
disease 2 0 1 9; E C G, electr ocar di o gra m; E O S, e n d of st u d y; F S H, f ollicle-sti m ulati n g h or m o ne; 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, n ot a p plica ble; n A b, ne utralizi n g a nti b o d y; N P, nas o p har y n geal; R T-P C R, re verse tra nscri ptase 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 s y n dr o me -c or o na vir us-2; S S -D, s u b -st u d y da y; W O C B P, w o me n of c hil d beari n g p ote ntial.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 3
Sc he d ule of Acti vities: S u b -St u d y T re at me nt a n d F oll o w -u p Peri o d f or G ro u p 2 ( Pl ace b o P artici p a nts fr om 
P R O V E N T P ar e nt St u d y)
Pr oce d ure
P are nt 
St u d y
S u b -st u d y Tre at me nt a n d F oll o w-u p Peri o d
E arl y 
Disc o n -
ti n u ati o n 
Visit
F or 
det ails, 
see 
Secti o n
D a y a
D a y 3 6
6 b
S S -
D 1 b
S S -
D 2 9
S S -
D 9 2
S S -
D 1 8 3
S S -
D 2 1 1
S S -
D 2 7 5
S S -
D 3 6 6 
S S -
D 4 5 7
S S -
D 5 4 8
S S -
D 6 3 9
Wi n d o w ( d a ys)
± 6 1
N A
± 3 
± 5
± 1 0
± 3 
± 5
± 1 5
± 1 5 
± 1 5 
± 1 5
I nf or me d c o nse nt (s u b-
st u d y)
X ( pre -
d ose)
A 3
Verif y  eli gi bilit y 
criteria
X ( pre-
d ose)
5. 1 , 5. 2
Tar gete d p h ysical 
e xa mi nati o n
X  
X  
X  
X
X ( pre-
d ose)
X  
X  
X  
X  
X
X
8. 2. 1
Wei g ht
X
8. 2. 1
Vital si g ns (i ncl u di n g 
p ulse o xi metr y)
X ( pre -
d ose)
X 
( p ost-
d ose c)
X  
X
X ( pre-
a n d 
p ost -
d ose c)
X  
X  
X  
X  
X
X
8. 2. 2
Tri plicate 1 2 -lea d E C G
X ( pre -
d ose)
X
X ( pre -
d ose)
X
X
X
X
8. 2. 3
Ser u m c he mistr y
X ( pre -
d ose)
X  
X
X ( pre-
d ose)
X  
X  
X  
X  
X
X
8. 2. 4
He mat ol o g y
X ( pre -
d ose)
X  
X
X ( pre-
d ose)
X  
X  
X  
X  
X
X
8. 2. 4
C oa g ulati o n
X ( pre -
d ose)
X  
X
X ( pre-
d ose)
X  
X  
X  
X  
X
X
8. 2. 4
Ur i nal ysis
X ( pre -
d ose)
X  
X
X ( pre-
d ose)
X  
X  
X  
X  
X
X
8. 2. 4

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 3
Sc he d ule of Acti vities: S u b -St u d y T re at me nt a n d F oll o w -u p Peri o d f or G ro u p 2 ( Pl ace b o P artici p a nts fr om 
P R O V E N T P ar e nt St u d y)
Pr oce d ure
P are nt 
St u d y
S u b -st u d y Tre at me nt a n d F oll o w-u p Peri o d
E arl y 
Disc o n -
ti n u ati o n 
Visit
F or 
det ails, 
see 
Secti o n
D a y a
D a y 3 6
6 b
S S -
D 1 b
S S -
D 2 9
S S -
D 9 2
S S -
D 1 8 3
S S -
D 2 1 1
S S -
D 2 7 5
S S -
D 3 6 6 
S S -
D 4 5 7
S S -
D 5 4 8
S S -
D 6 3 9
Wi n d o w ( d a ys)
± 6 1
N A
± 3 
± 5
± 1 0
± 3 
± 5
± 1 5
± 1 5 
± 1 5 
± 1 5
Ot her assess me nts
Ser u m sa m ple 
e x pl orat or y bi o mar kers
X ( pre -
d ose)
X  
X
X ( pre-
d ose)
X  
X  
X  
X  
X
X
8. 5. 2. 5
a
T o disti n g uis h bet wee n s u b -st u d y visits a n d pare nt st u d y visits, t he s u b-st u d y visits will be la bele d as f oll o ws: t he first s u b-st u d y visit Da y 1 = S S -D 1, s u b -
st u d y visit Da y 2 9 = S S- D 2 9, a n d s o o n as a p plica ble.
b
F or partici pa nts w h o ha ve n ot u n der g o ne a Da y 3 6 6 visit i n t he pare nt st u d y, t he Da y 3 6 6 assess me nts liste d a b o ve s h o ul d be perf or me d at S S -D 1. F or 
partici pa nts w h o ha ve alrea d y u n der g o ne t he Da y 3 6 6 visit i n t he pare nt st u d y,  o nl y t he S S-D 1 assess me nts nee d t o be perf or me d. Da y 3 6 6 assess me nts i n 
t he pare nt st u d y will be use d as baseli ne i n t he s u b-st u d y. 
c
Perf or m 1 5 mi n utes ( ± 5 mi n utes) after b ot h i njecti o ns are c o m plete.
d
If t he uri ne pre g na nc y test is p ositi ve or i n deter mi nate, a q ua ntitati ve ser u m β-h C G will be perf or me d b y t he ce ntral la b orat or y f or c o nfir mati o n. At visits 
S S -D 1 a n d S S -D 1 8 3, a ne gati ve pre g na nc y test is re q uire d bef ore t he partici pa nt recei ves I M P.
e
F S H will be a nal yze d at S S -D 1 t o c o nfir m p ost me n o pa usal stat us o nl y i n w o me n < 5 0 years of a ge w h o ha ve bee n a me n orr h oeic f or ≥1 2 m o nt hs. U ntil 
F S H is d oc u me nte d t o be wit hi n me n o pa usal ra n ge, t he partici pa nt is t o be c o nsi dere d of c hil d beari n g p ote ntial. F or w o me n a ge d ≥5 0 years, 
p ost me n o pa usal is defi ne d as ha vi n g a hist or y of ≥1 2 m o nt hs’ a me n orr hea pri or t o S S -D 1, wit h o ut a n alter nati ve ca use, f oll o wi n g cessati o n of e x o ge n o us 
se x-h or m o nal treat me nt.
f
Wee kl y c o ntact u p t o S S -D 1 8 3 wit h partici pa nts t o re mi n d t he m t o prese nt t o t he st u d y site f or S A R S -C o V -2 testi n g if t he y ha ve q ualif yi n g s y m pt o ms. T he 
I n vesti gat or will e n q uire a b o ut a n y C O VI D-1 9 s y m pt o ms fr o m t he past 7 da ys a n d ot her a d verse e ve nts.
M o nt hl y  c o ntact wit h partici pa nts fr o m S S-D 1 8 3 t o E O S, t o assess o verall safet y. T he I n vesti gat or will as k a b o ut a n y C O VI D-1 9 q ualif yi n g s y m pt o ms a n d 
car diac e ve nts fr o m t he past m o nt h a n d ot her A Es. Partici pa nts s h o ul d be re mi n de d t o prese nt t o t he st u d y site f or S A R S -C o V -2 testi n g if t he y ha ve 
q ualif y i n g s ym pt o ms a n d t o c o ntact t he site s h o ul d t he y de vel o p q ualif yi n g s y m pt o ms bet wee n eac h m o nt hl y c o ntact .
g
T his test is n ot perf or me d as part of t he cli nical st u d y b ut m ust be a vaila ble pri or t o e nr oll me nt.
h
If a d oc u me nte d S A R S-C o V -2 R T -P C R test is n ot a vaila ble at scree ni n g, a ra pi d S A R S -C o V -2 a nti ge n test will be perf or me d. Eit her test m ust be ne gati ve 
bef ore d osi n g (see i ncl usi o n criteria i n Secti o n  5. 1 ) 
i
Baseli ne sa m ple, n ot a scree ni n g sa m ple; res ults n ot nee de d pri or t o d osi n g.
j
W he n test s u p plies are a vaila ble, sa m pli n g s h o ul d be perf or me d.
k
Perf or m i m me diatel y, 3 0 mi n utes ( ± 1 0 mi n utes) after b ot h i njecti o ns are c o m plete, a n d pri or t o partici pa nt release ( 1 h o ur after I M P a d mi nistrati o n).
l
After I M P a d mi nistrati o n, partici pa nts will be cl osel y m o nit o re d f or on e h o ur bef ore t he y ca n lea ve t he site.
m
A Es, S A Es, M A A Rs, a n d A E SIs will be assesse d via a p h o ne call at S S -D 6 3 9 .

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 5 of 9 6
T he Da y 3 6 6 Visit assess me nts i n t he pare nt st u d y = baseli ne i n t he s u b -st u d y (ie, sa m ples d o n ot nee d t o be c ollecte d t wice).
O n d osi n g da ys, all assess me nts are t o be c o n d ucte d pre -d ose u nless ot her wise s pecifie d.
A D A, a nti dr u g a nti b o d y ; A E, a d verse e ve nt; A E SI, a d verse e ve nt of s pecial i nterest; β-h C G, beta -h u ma n c h ori o nic g o na d otr o pi n; C O VI D -1 9, c or o na vir us 
disease 2 0 1 9; E C G, electr ocar di o gra m; E O S, e n d of st u d y; F S H, f ollicle-sti m ulati n g h or m o ne; 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, n ot a p plica ble; n A b, ne utralizi n g a nti b o d y; N P, nas o p har y n geal; R T -P C R, re verse tra nscri ptase 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 s y n dr o me -c or o na vir us- 2; S S -D, s u b -st u d y da y; W O C B P, w o me n of c hil d beari n g p ote ntial.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 8 of 9 6
d
M o nt hl y  c o ntact wit h partici pa nts t o E O S t o assess o verall safet y. T he I n vesti gat or will as k a b o ut a n y C O VI D-1 9 q ualif yi n g s y m pt o ms a n d car diac e ve nts 
fr o m t he past m o nt h a n d ot her A Es. Partici pa nts s h o ul d be re mi n de d t o pr ese nt t o t he st u d y site f or S A R S -C o V -2 testi n g if t he y ha ve q ualif yi n g s y m pt o ms 
a n d t o c o ntact t he site s h o ul d t he y de vel o p q ualif yi n g s y m pt o ms bet wee n eac h m o nt hl y c o ntact.
e
W he n test s u p plies are a vaila ble, sa m pli n g s h o ul d be perf or me d.
f
Perf or m i m me diat el y, 3 0 mi n utes (± 1 0 mi n utes) after b ot h i njecti o ns are c o m plete, a n d pri or t o partici pa nt release ( 1 h o ur after I M P a d mi nistrati o n).
g
After I M P a d mi nistrati o n, partici pa nts will be cl osel y m o nit o re d f or on e h o ur bef ore t he y ca n lea ve t he site.
A D A, a nti dr u g a nti b o d y; A E, a d verse e ve nt; A E SI, a d verse e ve nt of s pecial i nterest; β -h C G, beta -h u ma n c h ori o nic g o na d otr o pi n; C O VI D -1 9, c or o na vir us 
disease 2 0 1 9; E/ D, earl y disc o nti n uati o n visit; E C G, electr ocar di o gra m; E O S, e n d of st u d y; I M P, i n vesti gati o nal me dici n al 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; S S -D, s u b -st u d y da 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 or y s y n 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.

Cli nic al St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 5
Sc he d ule of Acti vities: Ill ness V isits ( P artici p a nts wit h Q u alif yi n g Cli nic al S y m pt o ms)
Pr oce d ure a
Site Visit
H o me C ollecti o n b y P artici p a nt
Site Visit f or S A R S -C o V -2 P ositi ve 
P artici p a nts O nl y c
F or 
det ails, see 
Secti o n:
D a y b
I L-D 1
I L-D 3
I L-D 5
I L-D 8
I L-D 1 1
I L-D 1 4
I L-D 2 1
I L-D 2 8
Wi n d o w ( d a ys)
N A
± 1 
± 1 
± 2 
± 2 
± 2 
± 2 
± 2
Me dical hist or y 
X
X
X  
X
Br ief p h ysical e xa mi nati o n
X
X
X  
X
8. 2. 1
Vital si g ns (i ncl u di n g p ulse 
o xi metr y )
X
X
X  
X
8. 2. 2
Tri plicate 1 2 -lea d E C G 
X
8. 2. 3
C o nc o mita nt me dicati o n
6. 5
Effic ac y assess me nts
Sali va sa m ple f or viral s he d di n g d
X
X 
X  
X  
X
X
X  
X
8. 6. 1. 2
N as o p h ar y n ge al s w a b
S A R S -C o V -2 R T -P C R (l ocal 
la b orat or y)e
X
8. 6. 1. 1
S A R S -C o V -2 R T -P C R (ce ntral 
la b orat or y), se q ue nci n g, 
res pirat or y pa nel
X
X
X  
X
8. 6. 1. 1
I m m u n o ge nicit y, P h ar m ac o d y n a mics, a n d P h ar m ac o ki netics
P B M Cs f or B -cell a n d T-cell 
res p o nsese
X
X
8. 5. 2. 4
Ser u m sa m ple f or A Z D 7 4 4 2 
p har mac o ki netic assess me nt
X
X
X  
X
8. 5. 1
Ser u m sa m ple f or S A R S -C o V - 2 
n A bs assess me nt
X
X
X  
X
8. 5. 3. 1

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 5
Sc he d ule of Acti vities: Ill ness V isits ( P artici p a nts wit h Q u alif yi n g Cli nic al S y m pt o ms)
Pr oce d ure a
Site Visit
H o me C ollecti o n b y P artici p a nt
Site Visit f or S A R S -C o V -2 P ositi ve 
P artici p a nts O nl y c
F or 
det ails, see 
Secti o n:
D a y b
I L-D 1
I L-D 3
I L-D 5
I L-D 8
I L-D 1 1
I L-D 1 4
I L-D 2 1
I L-D 2 8
Wi n d o w ( d a ys)
N A
± 1 
± 1 
± 2 
± 2 
± 2 
± 2 
± 2
Nasal a ds or pti o n f or S A R S -
C o V -2 m uc osal res p o nses a n d 
e x pl orat or y assess me nts f
X
X
X
8. 5. 2. 3
Ser u m sa m ple f or e x pl orat or y 
assess me nts
X
X
X  
X
8. 5. 2. 5
S afet y assess me nts
S A Es, M A A Es, a n d A E SIs
8. 3
Tele p h o ne c o ntact f or safet y 
m o nit ori n g
X
X
C oa g ulati o n
X
X
X  
X
8. 2. 4
a
F oll o wi n g a vaila bilit y of t he S A R S -C o V -2 R T -P C R res ults, o nl y partici pa nts w h o test p ositi ve at I L D -1 will c o nti n ue wit h t he Ill ness Visits (i e, f ull visit 
series starti n g fr o m I L-D 1 a n d lea di n g u p t o I L -D 2 8), i ncl u di n g a n y h o me c ollecti o n re q uire me nts. Partici pa nts w h o test ne gati ve f or S A R S -C o V -2 at I L -
D 1 will be i nstr ucte d t o st o p all Ill ness Visit assess me nts. 
b
T o disti n g uis h bet wee n ill ness e pis o des t he visits will be la bele d as f oll o ws. F or t he first e pis o de Ill ness Visit Da y 1 = 1I L -D 1, Ill ness Visit Da y 3 = 1I L -D 3 
etc, a n d f or t he sec o n d e pis o de 2I L -D 1, 2I L -D 3, a n d s o o n as a p plica ble.
c
W here s u p p orte d, h o me or m o bile visits b y st u d y staff m a y s u bstit ute f or site visits
d
T o be c ollecte d w he n o perati o nall y via ble.
e
A l ocal test is re q uire d. If a n i m me diate test res ult is n ot a vaila ble, t he partici pa nt s h o ul d c o nti n ue wit h t he Ill ness Visi t sc he d ule u ntil t heir res ult has bee n 
c o nfir me d. O nl y if t he l ocal la b orat or y res ult is u na vaila ble s h o ul d t he ce ntral la b orat or y res ult be use d t o assess c o nti n uati o n i n Ill ness Visit sc he d ule. I n all 
i nsta nces b ot h tests are re q uire d.
f
W he n test s u p plies are a vaila ble, sa m pli n g s h o ul d be perf or me d.
N ote: T he Ill ness Visit sc he d ule is t o be perf or me d i n a d diti o n t o t he sc he d ule d visits i n t he mai n s u b-st u d y peri o d (Ta ble 2 , Ta ble 3 , or Ta ble 4 ). W here visits 
c oi nci de, all assess me nts fr o m t he sc he d ule d visit i n  Ta ble 2, Ta ble 3 , or  Ta ble 4 a n d t he Ill ness Visit s h o ul d be perf or me d.
A E SI, a d verse e ve nts of s pecial i nterest; D, da y; E C G, electr ocar di o gra m; I L, ill ness 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; P B M C, peri p heral bl o o d m o n o n uclear cell; R T -P C R, re verse tra nscri ptase 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 s y n dr o me-c or o na vir us-2.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
2
I N T R O D U C TI O N
See Secti o n 2 of  t he P R O V E N T C S P f or t he pare nt st u d y a n d t he A Z D 7 4 4 2 I B.
2. 1
St u d y R ati o n ale
A Z D 7 4 4 2, a c o mbi nat i on of 2 m A bs ( A Z D 8 8 9 5 a n d A Z D 1 0 6 1), is bei n g e val uate d f or t he 
pre ve nt i on or treat me nt of C O VI D -1 9. P R O V E N T is a n o n g oi n g P hase III, ra n d o mize d, 
d o u bl e- bli n d, place b o -c o ntr olle d, m ult i-ce nter st u d y i n a d ults t o assess t he safet y a n d efficac y 
of  a si n gle d ose of A Z D 7 4 4 2 f or pre -e x p os ure pr o p h yla xis o f C O VI D -1 9 ( P R O V E N T pare nt 
st u d y). T his P R O V E N T s u b-st u d y will assess t he safety,  P K, a n d i m m u n o ge nicity of  re peat 
d oses of A Z D 7 4 4 2 i n partici pa nts c urre nt l y e nr olle d i n t he P R O V E N T st u d y w h o ma y be nefit 
fr om a re peat d ose of A Z D 7 4 4 2. T his st u d y will i n vesti gate w het her a d dit i onal d oses of 
A Z D 7 4 4 2 ha ve a n a p pr o priate safet y pr ofile i n t his v ul nera ble p o p ulat i on. P har mac o ki net ic 
data will als o be ge nerate d t o e val uate w het her re peat d osi n g ca n mai ntai n se r u m 
c o nce ntrati o ns of A Z D 7 4 4 2 ass o ciate d wit h pr otectio n a gai nst C O VI D - 1 9.
2. 2
B ac k gr o u n d
See Secti o n 2. 2 of  t he P R O V E N T C S P f or t he pare nt st u d y.
2. 3
Be nefit/ Ris k Assess me nt
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d p ote ntial ris ks of 
A Z D 7 4 4 2 ca n be f o u n d i n t he A Z D 7 4 4 2 I B.
2. 3. 1
Ris k Assess me nt 
Base d o n all a vaila ble cli nical st u d y  data wit h a c ut-of f date of 2 0 A u g ust 2 0 2 1, t here were n o 
i de ntifie d ris ks ass ociate d wit h A Z D 7 4 4 2. T he c urre nt ris k assess me nt f or A Z D 7 4 4 2 is 
s u m marize d i n Ta ble 6 . 
Ta ble 6
Ris k Assess me nt f or  AZ D 7 4 4 2
I m p orta nt I de ntifie d Ris ks
N o ne
I de ntifie d Ris ks
N o ne
I m p orta nt P ote ntial Ris ks
N o ne
P ote ntial Ris ks
P ote ntial ris ks i ncl u de i njecti o n -relate d reacti o ns, A D E disease, seri o us 
h y perse nsiti vit y i ncl u di n g a na p h yla xis, a n d car diac a n d t hr o m b oe m b olic 
e ve nts.
Refere nce Safet y 
I nf or mati o n 
F or A Z D 7 4 4 2, n o S A Rs ha ve bee n i de ntifie d. A n y S A E t hat is dee me d t o be 
relate d t o t he I P b y t he I n vesti gat or or t he S p o ns or will be treate d as a 
s us pecte d u ne x pecte d seri o us a d verse reacti o n a n d a p pr o priatel y e x pe dite d.
Base d o n a data c ut -off of 2 0 A u g ust 2 0 2 1.
A D E, a nti b o d y -de pe n de nt e n ha nce me nt of di sease; I P, i n vesti gati o nal pr o d uct; S A E, seri o us a d verse e ve nt; 
S A R, seri o us a d verse reacti o n.

Cli nical St u d y Pr ot oc ol A d de n d u m - A m e n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
I n t he P R O V E N T pare nt st u d y, A Z D 7 4 4 2 was ge nerall y well t olerate d a n d preli mi nar y 
a nal yses s h o we d t hat o verall A Es were bala nce d bet wee n t he place b o a n d A Z D 7 4 4 2 gr o u ps. A 
s mall n u m ber of car di o vasc ular seri o us a d verse e ve nts ( m yocar dial  infarcti o n a n d car diac 
fail ure) ha ve bee n re p orte d i n t he P R O V E N T pare nt st u d y at a hi g her rate i n partici pa nts w h o 
recei ve d A Z D 7 4 4 2 c o mpare d t o pl ace b o. All part ici pa nts w h o e x perie nce d car diac S A Es were 
at hi g h ris k f or car diac e ve nts, ma n y o f w h o m ha d a pri or hist or y  of car dio v asc ular disease at 
baseli ne. T here was n o clear te m p oral patter n a n d a ca usal relat i ons hi p bet wee n A Z D 7 4 4 2 a n d 
t hese e ve nts has n ot bee n esta blis he d. T here was n o si g nal f or car diac t o xicit y or t hr o m b oti c 
e ve nts i de nt ifie d i n t he n o ncli nical st u dies. M o nit ori n g of car di o vasc ular e ve nts will occ ur i n 
t his s u b-st u d y. T here were n o cases of se vere C O VI D-1 9 or C O VI D - 1 9-relate d deat hs i n t h ose 
treate d wit h A Z D 7 4 42. I n t he place b o ar m, t here were 3 cases of se vere C O VI D -1 9, w hi c h 
i ncl u de d 2 deat hs.
I n a se parate P hase III A Z D 7 4 4 2 st u d y S T O R M C H A S E R ( N = 1 1 2 1), w hic h e nr olle d a 
y o u n ger p o p ul at i on wi t h fe wer baseli ne car diac ris k fact ors t ha n P R O V E N T a n d n o relate d 
car diac S A Es at t he ti me of pri mar y a nal ysis.
2. 3. 2
Be nefit Assess me nt
T he P R O V E N T pri mar y a nal ysis s h o we d t hat A Z D 7 4 4 2 ac hie ve d a statist icall y si g nifica nt 
re d uctio n i n t he i nci de nce of s y m pt o matic C O VI D -1 9, t he st u d y's pri mar y e n d p o i nt. 
A Z D 7 4 4 2 re d uce d t he ris k of  de vel o pi n g s y m pt o matic C O VI D-1 9 b y 7 7 % ( 9 5 % CI: 4 6, 9 0), 
c o mpare d t o pl ace b o. T he st u d y accr ue d 2 5 cases of s y m pt o matic C O VI D-1 9 at t he pri mar y  
a nal ysis.
T he parti ci pa nts i ncl u de d i n t his P R O V E N T s u b-st u d y are t h ose most li kel y  t o be nefit fr o m 
re peat doses of A Z D 7 4 4 2 f or o n g oi n g pr otecti o n a gai nst C O VI D -1 9.
2. 3. 3
O ver all Be nefit: Ris k C o ncl usi o n
Ta ki n g i nt o acc o u nt t he meas ures ta ke n t o mi ni mize ris k t o partici pa nts i n t his s u b -st u d y, t he 
p ote nti al ris ks ide nt ifie d i n ass ociati on wi t h A Z D 7 4 4 2 are j ustifie d b y t he a nticipate d be nefits 
t hat ma y be aff or de d t o partici pa nts at ris k of C O VI D- 1 9.
3
O B J E C TI V E S A N D E N D P O I N T S
Ta ble 7 lists t he o bjecti ves a n d e n d p oi nts for t he P R O V E N T re peat d ose s u b -st u d y.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 3 of 9 6
Ta ble 7
O bjecti ves a n d E n d p oi nts f or  Re pe at D ose S u b-St u d y
O bjecti ve
E n d p oi nt
Pri m ar y
T o e val uate t he safet y a n d t olera bilit y of 
re peat d oses of A Z D 7 4 4 2 3 0 0 m g a n d 
6 0 0 m g I M
A Es, S A Es, M A A Es, a n d A E SIs p ost re peat d ose of I M P
Sec o n d ar y
T o e val uate t he p har mac o ki netics of 
re peat d oses of A Z D 7 4 4 2 3 0 0 m g a n d 
6 0 0 m g I M
Ser u m A Z D 7 4 4 2 c o nce ntrati o ns f oll o wi n g re peat d osi n g.
P K para meters if data per mit f oll o wi n g re peat d osi n g
T o e val uate A D A res p o nses t o re peat 
d oses of A Z D 7 4 4 2 3 0 0 m g a n d 6 0 0 m g 
I M i n ser u m
I nci de nce of A D A t o re peat d oses of A Z D 7 4 4 2 i n ser u m
T o deter mi ne a nti -S A R S -C o V -2 n A b 
le vels i n ser u m f oll o wi n g re peat d oses of 
A Z D 7 4 4 2 3 0 0 m g a n d 6 0 0 m g I M
P ost -treat me nt G M Ts a n d G M F Rs fr om baseli ne val ues after a re peat I M 
d ose i n S A R S -C o V -2 n A bs ( wil d -t ype assa y  or pse u d o-ne utralizati o n 
assa y)
E x pl or at or y
 
 
 
 
 
 
 
 
 
 
 
A D A, a nti dr u g a nti b o d y; A E, a d verse e ve nt; A E SI, a d verse e ve nt of s pecial i nterest; C O VI D-1 9, c or o na vir us 
disease 2 0 1 9; G M T, ge o metric mea n titers; G M F R, ge o metric mea n f ol d rise; I M, i ntra m usc ular; 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; P K, 
p har mac o ki netic; R T- P C R, re verse tra nscri ptase 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 s y n dr o me -c or o na vir us 2.
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 III, m ult i-c o u ntr y, m ulti-ce nter, o pe n-la bel, P R O V E N T s u b-st u d y assessi n g t he 
safety,  P K, a n d i m m u n o ge nicity ( AD A) of re peat d oses of A Z D 7 4 4 2. Partici pa nts at a s u b set
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
of  acti ve P R O V E N T pare nt st u d y sites i n partici pati n g c o u ntries will be i n vite d t o e nr oll i n 
t his s u b-st u d y. 
P arti cipa nts will be a d ults w h o ha ve bee n ra n d o mize d a n d are acti vel y partici pati n g i n t he 
P R O V E N T pare nt st u d y  w h o ma y be nefit fr o m a re peat d ose of A Z D 7 4 4 2. T he ai m is t o 
a p pr o xi matel y bala nce t he pr o p ortio n of  partici pa nts deri ve d fr o m eac h of t he A Z D 7 4 4 2 a n d 
pl ace b o ar ms fr o m t he d o u ble- bli n d par e nt st u d y. If a n i m bala nce bet wee n t he ar ms is 
o bser ve d, a ca p ma y be i ntr o d uce d .
T here i s n o scree ni n g peri o d i n t he s u b-st u d y a n d partici pa nts will retai n t heir s u bject 
i de ntificati on n u m ber fr o m t he pare nt st u d y. 
P arti cipa nts will be eli gi ble f or i ncl u sio n  in t he s u b -st u d y o nce t he y ha ve reac he d 
1 2 ± 2 m o nt hs p ost d ose of I M P i n t he d o u ble -bli n d pare nt st u d y. Eli gi ble partici pa nts w h o 
ha ve alrea d y c o m p lete d t heir Da y 3 6 6 Vis it in t he pare nt st u d y  will be u n bli n de d, assi g ne d t o 
a s u b-st u d y gr o u p, a n d t hen u n der g o t he S S -D 1 assess me nts. F or partici pa nts w h o ha ve n ot 
yet c o m plete d t hei r D a y 3 6 6 Visit i n t he pare nt st u d y, t he S S-D 1 visit will i ncl u de t he Da y 3 6 6
assess me nts. Pre -d ose Da y 3 6 6 assess me nts will ser ve as baseli ne assess me nts f or t he s u b-
st u d y.
A ll partici pa nts will recei ve a d dit i onal d oses of A Z D 7 4 4 2 i n t he re peat d ose s u b -st u d y 
(Fi g ure 1 ). I nitiall y, p artici pa nts will be assi g ne d t o o ne of t w o d osi n g i nter val gr o u ps as 
f oll ows:

Gr o u p 1 ( ~ 1 2-m o nt h re peat d ose i nter val): Partici pa nts w h o recei ve d A Z D 7 4 4 2 3 0 0 m g 
I M o n Da y 1 of  t he pare nt st u d y will recei ve t heir sec o n d d ose of A Z D 7 4 4 2 3 0 0 m g I M 
o n S S -D 1. 

Gr o u p 2 ( ~ 6-m o nt h re peat d ose i nter val): Parti ci pa nts w h o recei ve d place b o o n Da y 1 i n 
t he pare nt st u d y will recei ve t heir first d ose of A Z D 7 4 4 2 3 0 0 m g I M o n S S -D 1 f o ll owe d 
b y a sec o n d d ose o n S S-D 1 8 3. 
A t 6 m o nt hs ( S S -D 1 8 3), a s u bset of partici pa nts fr o m U S A  sites i n Gr o u p 1 a n d Gr o u p 2 w h o 
c o nse nt t o recei ve a d dit i onal A Z D 7 4 4 2 6 0 0 m g d oses ( a p pr o xi matel y e ve nl y distri b ute d 
bet wee n gr o u ps) a p pr o xi matel y e ver y  6 mo nt hs a n d will be assi g ne d t o a ne w ar m - Gr o u p 3. 
All ot her partici pa nts will c o nt i n ue i n t he s u b-st u d y acc or di n g t o t heir origi nall y assig ne d 
d osi n g i nter val gr o u p sc he d ule. T he a d dit i on of Gr o u p 3 will create 4 p ossi ble d osi n g c o h orts , 
base d o n t he h o w ma n y d oses of 3 0 0 m g A Z D 7 4 4 2 recei ve d pri or t o e nteri n g Gr o u p 3 a n d 
w het her or n ot t his was f o ll owe d b y a f urt her t w o d oses of 6 0 0 m g A Z D 7 4 4 2 :
Gr o u p 1 

C o h ort 1: A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Gr o u p 2

C o h ort 2: Pl ace b o, A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g
Gr o u p 3

C o h ort 3 (fr o m Gr o u p 1): A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g, 6 0 0 m g, 6 0 0 m g

C o h ort 4 ( Fr o m Gr o u p 2): Place b o, A Z D 7 4 4 2 3 0 0 m g, 6 0 0 m g, 6 0 0 m g
G r o u p le v el recr uit me nt ca ps ma y be place d t o e ns ure 5 0 or m or e partici pa nts c o m plete t he 
st u d y wit h t h eir assi g ne d d ose a n d vali d sa m ples.
Gr o u p 1 a n d Gr o u p 2 will u n der g o safet y f oll ow- u p f or 4 5 6 da y s after t he last d ose of 
A Z D 7 4 4 2, a n d Gr o u p 3 will u n der g o safet y f oll ow- u p f or 1 8 3 da y s after t he last d ose of 
A Z D 7 4 4 2. T he t otal d urati o n of t he s u b -st u d y will be 4 5 7 da ys f or Gr o u p 1, 6 3 9 da ys for 
Gr o u p 2, a n d 5 4 8 d a y s for Gr o u p 3.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T his s u b -st u d y of t he o n g oi n g P R O V E N T pare nt st u d y was desi g ne d t o ra pi dl y o btai n cli nical 
safety,  P K, a n d i m m u n o ge nicity data after re peat A Z D 7 4 4 2 d osi n g i n i n di vi d uals w h o ca n n ot 
recei ve a C O VI D-1 9 vacci ne or are n ot e x pecte d t o be a de q uatel y  pr otecte d b y a vacci ne (ie, 
t he tar get p o p ulat i on f or re peat d osi n g). T his s u b-st u d y will ai m t o e nric h t he P R O V E N T 
st u d y p o p ulat i on wi t h in di vi d uals w h o ma y  be nefit fr o m a re peat d ose of A Z D 7 4 4 2 b y 
tar geti n g a p pr o priate partici pa nt gr o u ps e nr olle d i n t he pare nt st u d y (see Secti o n 5. 1 ).
T he d osi n g i nter vals of a p pr o xi matel y  6 mo nt hs a n d 1 2 m o nt hs t o be e val uate d i n t his st u d y  
are base d u p o n t he e xte n de d half- life of A Z D 7 4 4 2 a n d e x pecte d nee d f or re peat d osi n g i n 
cli nical practice. 
To  ge nerate re peat d ose data as ra pi dl y as p ossi ble, part ici pa nts ra n d omize d t o t he P R O V E N T 
pare nt st u d y  w h o meet t he s u b-st u d y incl usi o n cri t eria will be offere d partici pat i on i n t he s u b-
st u d y w he n it is i nitiate d. T his will res ult i n s o me partici pa nts recei vi n g a re peat d ose as earl y 
as 1 0 mo nt hs after t he fir st d ose i n t he pare nt st u d y. 

P arti cipa nts assi g ne d t o t he 1 2 -m o nt h d osi n g i nter val ( Gr o u p 1 ) will be deri ve d fr om t he 
A Z D 7 4 4 2 ar m i n t he pare nt st u d y . T hese partici pa nts will e nter t he s u b-st u d y a n d recei ve 
t heir sec o n d d ose 1 2 ± 2 m o nt hs after recei vi n g t heir first d ose i n t he pare nt st u d y, (see 
Fi g ure 1 ). A n i nteri m a nal ysis will ta ke place w he n a mi ni m u m of 5 0 partici pa nts ha ve 
bee n f o ll owe d u nt il Da y 2 9.

P arti cipa nts assi g ne d t o t he 6 -m o nt h d osi n g i nter val ( Gr o u p 2 ) will be deri ve d fr om t he 
pl ace b o ar m in t he pare nt st u d y . T his gr o u p will recei ve t heir first d ose of A Z D 7 4 4 2 u p o n 
e nteri n g t he s u b-st u d y fol l owe d b y  a re peat d ose at a p pr o xi matel y 6 m o nt hs (see 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Fi g ure 1 ). T his gr o u p will ge nerate data s u p p orti n g assess me nt of a s h orter re peat d osi n g 
ti me i nter val of t he l o n g-act i n g A Z D 7 4 4 2 f or m ulati o n.

P articipa nts assi g ne d t o t he 1 8- m o nt h d osi n g sc he d ule ( Gr o u p 3 ) will be deri ve d fr om a 
s u bset of partici pa nts at t he U S A sites i n Gr o u p 1 a n d Gr o u p 2 i n t he s u b-st u d y 
(a p pr o xi matel y e ve nl y distri b ute d bet wee n gr o u ps). T his gr o u p will recei ve 2 d oses of 
6 0 0 m g I M A Z D 7 4 4 2 at a p pr o xi matel y 6 m o nt h i nter vals starti n g at S S -D 1 8 3, f o ll owi n g 
c o nse nt t o t he a me n de d s u b-st u d y (see Fi g ure 1) , t o ali g n t he d osi n g sc he d ule per t he 
F D A Fact s heet . T his gr o u p will ge nerate a d diti on al  safety,  P K, a n d i m m u n o ge nicity data 
f or lo n ger -t er m re peat d osi n g ti me i nter vals of t he l on g -act i n g A Z D 7 4 4 2 f or m ulati o n.
E val uat i on of t he safet y,  P K, a n d A D A i m m u n o ge nicit y of re peat d osi ng wi t h A Z D 7 4 4 2 will 
i nf or m t h e fol l owi n g:

W het her re peat d osi n g at differe nt d osi n g i nter vals will mai ntai n t he ser u m c o nce ntratio ns 
of  A Z D 7 4 4 2 ass ociate d wit h pr otecti o n a gai nst s y m pt o mat ic disease i n t he pare nt st u d y.

W het her t he safet y pr ofile a n d i m m u n o ge nici t y ( A D A) pr ofile after a re peat A Z D 7 4 4 2 
d ose are c o m para ble t o t he safet y pr ofile a n d i m m u n o ge nicit y pr ofile o bser ve d after a 
si n gle A Z D 7 4 4 2 d ose. 
To  pr o vi de safety data o n A Z D 7 4 4 2 f or 5 half -li ves, safety e n d p oi nts will be c ollecte d f or 
4 5 6 d a y s after t he last d ose of I M P i n Gr o u p 1 a n d Gr o u p 2 . 
4. 3
J u stific ati o n f or D ose
T he d ose le vel, 3 0 0 m g I M, selecte d f or t his s u b -st u d y is base d o n t he d ose a d mi nistere d i n 
t he P R O V E N T pare nt st u d y w hic h de m o nstrate d a fa v ora ble safet y a n d efficac y pr ofile i n t he 
pri mar y  a nal ysis a n d is t he pr o p ose d d ose t o be mar kete d (see Secti o n 2. 3 ). F or f urt her details 
o n t he d ose j ustificat i on, pl ease refer t o t he A Z D 7 4 4 2 I B. 
T he 6 0 0 m g I M d ose selecte d f or t his s u b-st u d y e xte nsio n is base d o n t he 6 0 0 m g d ose 
a d mi nistere d i n t he TA C K L E st u d y , a n d 6 0 0 m g A Z D 7 4 4 2 is a ut h orize d f or e mer ge nc y use i n 
t he U S A si nce 2 4 Fe br uar y 2 0 2 2; b ot h of w hic h were c o nsi dere d ge nerall y  safe a n d well-
t olerate d.
4. 4
J u stific ati o n f or St u d y P o p ul ati o n
I n t he P R O V E N T pare nt st u d y, more t ha n 7 5 % of partici pa nts ha ve c o -m o r bi dities, w hic h 
i ncl u des t h ose wit h a re d uce d i m m u ne res p o nse t o vacci nati o n. T he pri mar y a nal ysis s h o we d 
t hat A Z D 7 4 4 2 was well t olerate d, a n d A Es were bal a nce d bet wee n t he place b o a n d A Z D 7 4 4 2 
gr o u ps.
T he P R O V E N T s u b -st u d y tar gets t he st u d y p o p ulatio n m ost li kel y  t o be nefit fr o m recei pt of a 
re peat d ose of A Z D 7 4 4 2. Partici pa nts will be eli gi ble t o e nter t he s u b -st u d y a n d t he a d ditio nal 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Gr o u p 3 , if t he y f ulfill at least o ne of t he f o ll owi n g cri t eria: (a) i m m u n oc o m pr o mise d a n d/ or 
ma y be at i ncrease d ris k f or a n i na de q uate res p o nse t o a C O VI D -1 9 vacci nat i on; ( b), i n t he 
o pi ni o n of t he I n vest i gat or, are at i ncrease d ris k of se vere C O VI D-1 9 (i ncl u di n g partici pa nts
w h o ha ve n ot recei ve d a C O VI D -1 9 vacci ne) (see Secti o n  5. 1 ). 
4. 5
E n d of St u d y Defi niti o n
A partici pa nt i s c o nsidere d t o ha ve c o m plete d t he s u b -st u d y if t he y c o mplete d all  p hases of t he 
st u d y, i ncl u di n g t he last sc he d ule d pr oce d ure s h o w n i n t he S o A (see Sectio n 1. 3 ).
T he e n d o f t he s u b-st u d y is defi ne d as t he date of t he last sc he d ule d pr oce d ure s h o w n i n t he 
S o A  (see Sectio n  1. 3 ) for t he l ast partici pa nt i n t he st u d y glo b all y. 
5
S T U D Y P O P U L A TI O N
Pl a n ne d pr ot oc ol de viat i ons are n ot c o nsi dere d acce pta ble. A pr ot oc ol de viati on t hat i s 
s us pecte d or k n o w n t o ha ve t he p ote ntial t o si g nifica nt l y i m pact a partici pa nt’s safet y, 
p h ysical or me ntal i nte grit y,  or scie nt ific v al ue will be classifie d as a seri o us breac h.
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 s u b -st u d y if all t he f o ll owi n g cri t eria a p pl y:
1
T he parti ci pa nt has bee n ra n d o mize d, d ose d, a n d is o n g oi n g i n t he P R O V E N T pare nt 
st u d y a n d is 1 2 ± 2 m o nt hs p ost first d ose of bli n de d I M P.
2
If o ne or more of t he f o ll owi n g a p pl y :
(a) I mm u n oc o m pr o mise d a n d/ or m a y be at i ncrease d ris k f or a n i na de q uate i m m u ne 
res p o nse t o a C O VI D-1 9 vacci ne, i ncl u di n g: 
o
El derl y, i e, ≥6 0 y e ars old
o
O bese, i e, Bo d y  Mass I n de x≥3 0
o
C o n gest i ve heart fail ure
o
C hr o nic l u n g disease
o
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)
o
C hr o nic li ver disease
o
I mm u n oc o m pr o mise d state fr o m s oli d or ga n tra ns pla nt, bl o o d or b o ne marr o w 
tra ns pla nt, i m m u ne deficie ncies, h u ma n i m m u n o deficie nc y vir us, use of 
c ortic oster oids, or use o f ot her i m m u n os u p pressi ve me dici nes
o
I nt olera nt of vacci ne. Defi ne d as pre vi o us hist or y of se vere A E or S A E after 
recei vi n g a n y a p pr o ve d vacci ne.
( b) I n t he o pi ni o n of t he I n vest i gat or, are at i ncrease d ris k a n d w o ul d be nefit fr o m a 
re peat d ose of A Z D 7 4 4 2 (e g, partici pa nts w h o ha ve a c hr o nic c o n dit i on t hat i ncreases 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 8 of 9 6
t heir ris k of se vere C O VI D-1 9 or t h ose w h o ha ve n ot bee n vacci nate d a gai nst 
C O VI D - 1 9).
3
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 talizatio n f or w orse ni n g disease d uri n g t he o ne m o nt h pri or t o e nr oll me nt t o t he s u b-
st u d y, wit h no ac ute c ha n ge i n c o n dit i on at t he ti me of s u b -st u d y e nr oll me nt as ju d ge d b y  
t he I n vest i gat or. T his i ncl u des c o n diti ons ne wl y dia g n ose d si nce t he partici pa nt e ntere d 
t he pare nt st u d y.
4
D oc u m e nte d ne gat i ve S A R S-C o V -2 R T -P C R test c ollecte d ≤3 da y s prior t o S S -D 1 or a 
ne gat i ve ra pi d S A R S-C o V -2 a nti ge n test at scree ni n g. 
Re pr o d ucti o n
5
C o ntrace pti ve use b y me n or w o me n:
(a) Male Parti ci pa nts: C o ntrace pti o n f or male partici pa nts is n ot re q uire d, h o we ver, t o 
a v o i d t he tra nsfer of a n y fl ui ds, all male partici pa nts must use a c o n d o m  fr o m S S-D 1 
a n d a gree t o c o nti n ue t hr o u g h 3 6 5 da ys f o ll owi n g a d mi nistrati o n of t he I M P. 
( b) Fe male Par tici pa nts:

W o me n n ot of c hil d beari n g p ote ntial are defi ne d as w o me n w h o are eit her 
p er m a 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 me n o pa usal. Wo m e n will be c o nsi dere d 
p ost m e n o pa usal if t he y ha ve bee n a me n orr h oeic for 1 2 m o nt hs pri or t o t he 
pl a n ne d date of ra n d o mizati o n wit h o ut a n alter nat i ve me dical ca use. T he 
f oll owi n g a ge -s pecific re q uire me nts a p pl y:
o
W o me n < 5 0 y e ars old w o ul d be c o nsi dere d p ost me n o pa usal if t he y  ha ve 
bee n a me n orr h oeic f or 1 2 m o nt hs or m or e f ol l owi n g cessat i on of e x o ge n o us 
h or m o nal  tr e at me nt a n d F S H le vels i n t he p ost me n o pa usal ra n ge.
o
W o me n ≥ 5 0 y e ars old w o ul d be c o nsi dere d p ost me n o pa usal if t he y  ha ve 
bee n a me n orr h oeic f or 1 2 m o nt hs or m ore f o ll owi n g cessat i on of all 
e x o ge n o us h or m o nal treat me nt.

Fe male partici pa nts of c hil d beari n g p ote ntial m ust use o ne hi g hl y effect i 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 less t ha n 1 % per y ear w he n use d c o nsiste nt l y a n d 
c orrectl y. Wo m e n of c hil d beari n g p ote ntial w h o are se x uall y act i ve with a n o n -
sterilize d male part ner m ust 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 bel o w, fr o m S S-D 1 a n d a gree t o c o nti n ue t hr o u g h 3 6 5 da y s 
f oll owi n g a d mi nis tr atio n of  t he I M P. Cessati o n of c o ntrace pti o n after t his p oi nt 
s h o uld be disc usse d wit h a res p o nsi ble p h ysicia n. Peri o dic 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), 
s per mici des o nl y, a n d lactati o nal a me norr hea m et h o d are n ot acce pta ble met h o ds 
of  c o ntrace ptio n. Fe male c o n d o m  a n d male c o n d o m s ho ul d n ot be use d t o get her. 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
All w o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y test 
res ult b efore d osi n g at Visit S S -D 1 a n d at S S -D 1 8 3 as i n dica te d i n t he S o A (see 
Secti o n  1. 3 ).
E xa m ples of hi g hl y  effecti ve birt h c o ntr ol met h o ds are liste d i n Ta ble 8.
Ta ble 8
Hi g hl y Effecti ve Met h o ds of C o ntr ace pti o n
B arrier Met h o ds
H or m o n al Met h o ds
•
I ntra uteri ne de vice
•
I ntra uteri ne h or m o ne-releasi n g s yste m 
(I U S) a
•
Bilateral t u bal occl usi o n
•
Vasect o mize d part ner b
•
Se x ual a bsti ne nce c
•
C o m bi ne d (estr o ge n - a n d pr o gest o ge n -c o ntai ni n g 
h or m o nal c o ntrace pti o n) ass ociate d wit h i n hi biti o n of 
o v ulati o n

Oral (c o m bi ne d pill)

I ntra va gi nal

I njecta ble

Tra ns der mal ( patc h)
•
Pr o gest o ge n -o nl y  h or m o nal co ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n

Oral 

I njecta ble

I m pla nta ble
a
T his is als o c o nsi dere d a h or m o nal met h o d.
b
Pr o vi de d t he part ner is t he s ole se x ual part ner of t he w o ma n of c hil d beari n g p ote ntial st u d y partici pa nt 
a n d t hat t he vasect o mize d part ner has recei ve d me dical assess me nt of t he s ur gical s uccess. 
c
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if defi ne d as refrai ni n g fr o m heter ose x ual 
i nterc o urse d uri n g t he e ntire peri o d of t he st u d y a n d if it is t he preferre d a n d us ual lifest yle of t he 
partici pa nt.
5. 2
E xcl usi o n Criteri a 
P arti cipa nts are t o be e xcl u de d fr o m t he st u d y  if a n y of t h e fol l owi n g criteria a p pl y:
1
Ha ve recei ve d a C O VI D -1 9 vacci nat i on ≤1 4 da ys bef ore S S -D 1 or pla n t o recei ve a 
C O VI D -1 9 vacci nat i on ≤1 4 da y s after S S-D 1. ( S uc h partici pa nts ca n s u bse q ue ntl y be 
i ncl u de d i n t he st u d y o nce t he y ha ve reac he d 1 4 da ys after t heir last d ose of  vacci ne).
2
Ha ve 2 o r more u ntreate d car diac ris k fact ors or s us pecte d u nsta ble car diac disease.
3
J u d g me nt b y t he I n vesti gat or t hat t he partici pa nt s h o ul d n ot partici pate i n t he st u d y if t he 
parti ci pa nt is u nli kel y t o c o mpl y  wit h st u d y pr oce d ures, restrictio ns, a n d re q ui re me nts.
5. 3
Lifest yle C o nsi der ati o ns
Lifest yle c o nsi derat i ons f or t he s u b-st u d y are c o nsiste nt wit h t h ose i n t he pare nt st u d y. See 
Secti o n 5. 3 i n t he P R O V E N T C S P f or details.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
5. 4
Scree n F ail ures
N ot a p plica ble. See Secti o n 5. 2 f or g uida nce o n C O VI D -1 9 vacci nat i ons.
6
S T U D Y I N T E R V E N TI O N
T he I M P is defi ne d as a n y i n vest i gati onal i nter ve nti o n(s) or a ut h orize d pr o d uct(s) i nte n de d t o 
be a d mi nistere d t o or me dical de vice(s) utilize 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
I M P(s) A d mi nistere d
6. 1. 1
I M P
T he m ajori t y of p artici pa nts will recei ve at least o ne d ose of 3 0 0 m g d ose of A Z D 7 4 4 2 
( di vide d i n 2 se q ue ntial i njecti ons, o ne f or eac h m A b c o m p o ne nt) a d mi nistere d I M (Ta ble 9 ). 
P arti cipa nts w h o were ra n d o mize d t o A Z D 7 4 4 2 i n t he pare nt st u d y ( Gr o u p 1 ) recei ve d t heir 
first d ose of A Z D 7 4 4 2 o n Day 1 of  t he pare nt st u d y a nd will  recei ve t heir sec o n d d ose o n S S-
D 1 i n t he s u b -st u d y. Partici pa nts w h o were ra n d o mize d t o place b o i n t he pare nt st u d y 
( Gr o u p 2) will recei ve t heir first a n d sec o n d A Z D 7 4 4 2 d oses o n S S -D 1 a n d S S -D 1 8 3 of t he 
s u b-st u d y, res pecti vel y.
P arti cipa nts c o nse nt i n g t o t he s u b-st u d y e xte nsi on a me n d me nt ( Gr o u p 3) will recei ve 2 re peat 
d oses of 6 0 0 m g I M A Z D 7 4 4 2 at 6 m o nt h i nter vals. 
A 3 0 0 m g a n d 6 0 0 m g d ose of A Z D 7 4 4 2 c o nsists of 2 I M i njecti ons ( o ne i n eac h gl uteal 
r e gio n). If a parti cipa nt e x peri e nces a n i m me diate h y perse nsit i vity react i on after recei pt of t he 
first I M i njecti on i n t he s u b-st u d y, b ut bef ore t he s u bse q ue nt I M i njecti ons, f urt her I M P s h o ul d 
n ot be gi ve n. F or details o n t he treat me nt of a na p h ylact ic reacti ons after I M P I M i njecti ons see 
A p pe n di x E . F or f urt her details o n I M P disc o nti n uati o n, see Secti o n 7. 1 . 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 9
I n vesti g ati o n al Pro d uct
I nter ve nti o n 
n a me
3 0 0 m g A Z D 7 4 4 2 ( A Z D 8 8 9 5 + A Z D 1 0 6 1)
6 0 0 m g A Z D 7 4 4 2 ( A Z D 8 8 9 5 + A Z D 1 0 6 1)
D ose 
f or m ul ati o n
Li q ui d Pr o d uct
A Z D 7 4 4 2 will be s u p plie d as se parate vials 
of A Z D 8 8 9 5 a n d A Z D 1 0 6 1 as 1 5 0 m g 
c ol or less t o sli g htl y yell o w, clear t o 
o palesce nt s ol uti o ns f or i njecti o n. T he 
s ol uti o ns c o ntai n 1 0 0 m g/ m L of acti ve 
i n gre die nt ( A Z D 8 8 9 5 or A Z D 1 0 6 1) i n 
2 0 m M L -his ti di ne/ L- histi di ne 
h y dr oc hl ori de, 2 4 0 m M s ucr ose, a n d 0. 0 4 % 
( w/ v) p ol ys or bate 8 0, at p H 6. 0. T he la bel-
clai m v ol u me is 1. 5 m L.
Li q ui d Pr o d uct
A Z D 7 4 4 2 will be s u p plie d as se parate vials 
of A Z D 8 8 9 5 a n d A Z D 1 0 6 1 as 3 0 0 m g 
c ol or less t o sli g htl y yell o w, clear t o 
o palesce nt s ol uti o ns f or i njecti o n. T he 
s ol uti o ns c o ntai n 1 0 0 m g/ m L of acti ve 
i n gre die nt ( A Z D 8 8 9 5 or A Z D 1 0 6 1) i n 
2 0 m M L -his ti di ne/ L-histi di ne 
h y dr oc hl ori de, 2 4 0 m M s ucr ose, a n d 0. 0 4 % 
( w/ v) p ol ys or bate 8 0, at p H 6. 0. T he la bel-
clai m v ol u me is 3. 0 m L. 
U nit d ose 
stren gt h(s)
3 0 0 m g A Z D 7 4 4 2 c o nsisti n g of 1 5 0 m g 
eac h of A Z D 8 8 9 5 a n d A Z D 1 0 6 1 at 
1 0 0 m g/ m L 
6 0 0 m g A Z D 7 4 4 2 c o nsisti n g of 3 0 0 m g 
A Z D 8 8 9 5 a n d 3 0 0 m g A Z D 1 0 6 1 eac h at 
1 0 0 m g/ m L
D os a ge le vel(s)
3 0 0 m g si n gle d ose of A Z D 7 4 4 2
( 1 5 0 m g of A Z D 8 8 9 5 a n d 1 5 0 m g of 
A Z D 1 0 6 1)
6 0 0 m g si n gle d ose of A Z D 7 4 4 2
( 3 0 0 m g of A Z D 8 8 9 5 a n d 3 0 0 m g of 
A Z D 1 0 6 1)
R o ute of 
a d mi nistr ati o n
T w o I M i njecti o ns of 1. 5 m L eac h ( o ne i n 
eac h gl uteal re gi o n)
T w o I M i njecti o ns of 3 m L eac h ( o ne i n 
eac h gl uteal re gi o n)
Use
E x peri me ntal
E x peri me ntal
S o urci n g
A Z D 7 4 4 2 ( A Z D 8 8 9 5 + A Z D 1 0 6 1): 
Astra Ze neca.
A Z D 7 4 4 2 ( A Z D 8 8 9 5 + A Z D 1 0 6 1): 
Astra Ze neca
P ac k a gi n g a n d 
l a beli n g
I M P will be pr o vi de d i n glass vials. Eac h 
glass vial will be la bele d as re q uire d per 
c o u ntr y re q uire me nt.
I M P will be pr o vi de d i n glass vials. Eac h 
glass vial will be la bele d as re q uire d 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; 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

T he I n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te mperat ure c o n di tio ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all I M P recei ve d, a n d a n y discre pa ncies are re p orte d a n d 
res ol ve d bef ore use of t he I M P.

O nl y partici pa nts e nr o lle d i n t he s u b-st u d y ma y recei ve I M P a n d o nl y a ut h orize d site staff 
m a y s u p pl y or a d mi nister I M P. All I M P m ust be st ore d i n a sec ure, e n vir o n me ntall y 
c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce wit h t he la bele d 
st ora ge c o n diti ons, wit h access li mite d t o t he I n vesti gat or a n d a ut h orize d site staff.

T he I n vestigat or, i nst ituti o n, or t he hea d of t he me dical i nst ituti o n ( w here a p plica ble) is 
res p o nsi ble f or I M P acc o u nta bility,  rec o nciliati on, a n d rec or d mai nte na nce (ie, recei pt, 
rec o nciliati on, a n d fi nal dis p osit i on rec or ds).

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi on of u n use d I M Ps are pr o vi de d i n 
t he P har mac y Ma n ual or s pecifie d ha n dli n g i nstr ucti o ns. 
6. 2. 1
D ose Pre p ar ati o n a n d A d mi nistr ati o n I nstr ucti o ns 
Eac h vial selecte d f or d ose pre parati o n s h o ul d be i ns pecte d. If t here are a n y  d efects n oted wi t h 
t he I M P, t he I n vesti gat or a n d site m o nit or s h o ul d be n otifie d i m me diatel y.
6. 2. 1. 1
I n vesti g ati o n al Pr o d uct I ns pecti o n
A Z D 7 4 4 2 I M P is c o m pr ise d of 2 se parate dr u g pr o d ucts, A Z D 8 8 9 5 a n d A Z D 1 0 6 1, t o be 
a d mi nistere d se q ue ntiall y. O ne kit is re q uir e d for t he 3 0 0 m g d ose a n d 2 k its are re q uire d f or 
t he 6 0 0 m g d ose.
Dr u g Pr o d uct
T he A Z D 8 8 9 5 a n d A Z D 1 0 6 1 D Ps are eac h s u p plie d as sterile clear t o o palesce nt, c ol orless t o 
sli g htl y ye ll ow s ol ut i ons, wi t h a la bel-clai m of 1 5 0 mg at 1 0 0 m g/ m L  per vial. 
6. 2. 1. 2
D ose C alc ul ati o n
F or A Z D 7 4 4 2 ( A Z D 8 8 9 5 a n d A Z D 1 0 6 1), t he d oses will be pre pare d direct l y fr om t he 
A Z D 8 8 9 5 a n d A Z D 1 0 6 1 D P vials. A Z D 8 8 9 5 a n d A Z D 1 0 6 1 will be a d mi nistere d i n di vi d uall y , 
usi n g se parate c o m p o ne nts. 
6. 2. 1. 3
D ose Pre p ar ati o n Ste ps
T he 2 D Ps A Z D 8 8 9 5 a n d A Z D 1 0 6 1 (c o m prisi n g A Z D 7 4 4 2), m ust b ot h be a d mi nistere d 
se paratel y t o t he partici pa nt i n se q ue ntial or der, wit h n o partici pa nt recei vi n g d oses of 
A Z D 8 8 9 5 wit h o ut als o recei vi n g t he matc hi n g d ose of A Z D 1 0 6 1. T he d ose of A Z D 8 8 9 5 m ust 
be a d mi nistere d first. T he d ose of A Z D 8 8 9 5 a n d A Z D 1 0 6 1 f or a d mi nistrati o n m ust be 
pre pare d b y  t he I M P Ma na ger or ot her q ualifie d pr ofessi onal usi n g ase pt ic tec h ni q ue, a n d w h o 
s h o uld o nl y  r e mo v e t he re q uire d D P vials f or partici pa nt d osi n g fr om st ora ge. N o 
i nc om pat i bilities ha ve bee n o bser ve d bet wee n A Z D 7 4 4 2 a n d dis p osa ble p o l y pr o p yle ne or 
p ol ycar b o nate s y rin ges use d f or I M a d mi nistrati o n.
D ose Pre p ar ati o n a n d A d mi nistr ati o n f or A Z D 7 4 4 2 ( A Z D 8 8 9 5/ A Z D 1 0 6 1) 
T he d ose of A Z D 7 4 4 2 ( A Z D 8 8 9 5 a n d A Z D 1 0 6 1) f or a d mi nistrati o n m ust be pre pare d b y t he 
I n vesti gat or’s or site’s desi g nate d I M P Ma na ger usi n g ase ptic tec h ni q ue. Total  ti me fr om 
nee dle p u nct ure of t he vial t o 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 ( 3 6 ° F t o 4 6 ° F)

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 ti me 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. Eac h A Z D 8 8 9 5 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
a n d A Z D 1 0 6 1 vial m ust be use d o nl y o nce t o pre pare a si n gle d ose. A Z D 7 4 4 2 ( A Z D 8 8 9 5 a n d 
A Z D 1 0 6 1) d oes n ot c o n tai n preser vati ves, a n d a n y u n use d p orti o n m ust be discar de d.
A se parate dis p osa ble s yri n ge wit h a 2 2 t o 2 5 ga u ge a n d 1 t o 1. 5 i n ( 2 5 t o 3 8 m m) le n gt h 
nee dle s h o ul d be use d f or eac h A Z D 8 8 9 5 a n d A Z D 1 0 6 1 D P i nject i on. Eac h D P s h o ul d be 
a d mi nistere d a s a se parate si n gle i njecti on a n d a d mi nistere d se q ue nt iall y. I ntra musc ular d oses 
s h o uld be pre pare d b y  acc uratel y wit hdra wi n g 1. 5 m L  vol u me of D P f or Gr o u p 1 a n d Gr o u p 2
a n d 3. 0 mL of  D P for Gr o u p 3 i nto a n a p pr o priatel y size d late x-free dis p osa ble p ol y pr o p yle ne 
or p ol ycar b o nate s y rin ge. A Z D 8 8 9 5 a n d A Z D 1 0 6 1 s h o ul d be a d mi nistere d acc or di n g t o 
sta n dar d practice pr oce d ures f or I M i njecti ons, wit h o ne i nject i on i n eac h gl uteal re gi o n. T he 
I M P d oes n ot c o ntai n preser vati ves a n d a n y u n use d p orti o n m ust be di scar de d.
6. 3
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
T his is a n o pe n -la bel st u d y in w hic h all partici pa nts recei ve A Z D 7 4 4 2 3 0 0 m g f oll owe d b y 
eit her a 3 0 0 m g or 6 0 0 m g I M d ose(s). W here a partici pa nt d oes n ot meet all t he eli gi bilit y 
criteria b ut i nc orrectl y  recei ve d I M P, t he I n vesti gat or s h o ul d i nf or m t he St u d y P h ysicia n 
i m me diatel y, a n d a disc ussi on s h o ul d occ ur bet wee n t he St u d y  P h ysicia n a n d t he I n vesti gat or 
re gar di n g w het her t o c o nti n ue or disc o nti n ue t he partici pa nt.
6. 4
I M P C o m pli a nce
D osi n g will  t a k e place u n der t he g uida nce of st u d y pers o n nel, ma y  occ ur at st u d y sit es, mo bile 
u nits, or wit hi n l o n g -t er m care facilities, a n d will be rec or de d i n t he e C R F.
L o n g -t er m care facilities i ncl u de: s kille d n ursi n g facilities, assiste d li vi n g facilities, a n d 
i n de pe n de nt li vi n g facilities f or se ni or a d ults.
C o m plia nce will be ass ure d b y di rect s u per visio n  a n d wit nessi n g of t he I M P a d mi nistrati o n. If 
a pr o ble m occ urs d uri n g d osi n g, s uc h as nee dle brea k, n o re d osi n g is per mitte d.
6. 5
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne (i ncl u di n g C O VI D -1 9 vacci nes, o ver -t he- c o u nter, or prescri pt i on 
me dici nes, vita mi ns, a n d/ or her bal s u p ple me nts) t hat t he partici pa nt is recei vi n g at t he ti me of 
e nr o ll me nt or recei ves d uri n g t he st u d y m ust be rec or de d i n t he e C R F, alo n g wit h:

Reas o n f or use

Dates of a d mi nistrati o n, i ncl u di n g start a n d e n d dates

D osa ge i nf or 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  P h ysicia n s h o uld be c o ntacte d if t here are a n y  q uestio ns re gar di n g c o nc o mita nt or 
pri or t hera p y.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 1 0 lists t he per mitte d, restricte d, a n d pr o hi bite d me dicati ons d uri n g t he s u b- st u d y.
Ta ble 1 0
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
Lice nse d i nfl ue nza vacci nes are per mitte d at 
a n y ti me.
All ot her r o uti ne vacci nes are per mitte d 
pr o vi de d t he r o uti ne vacci ne is recei ve d 
> 3 0 da ys pr i or t o, or f oll o wi n g a n I M P d ose.
C O VI D -1 9 Vacci nes
Vacci nes f or t he pre ve nti o n of S A R S -C o V -2 or 
C O VI D -1 9 are per mitte d pr o vi de d t he vacci ne 
is recei ve d ≥ 1 4 da y s pri or t o I M P 
a d mi nistrati o n or f oll o wi n g recei pt of I M P 
a d mi nistrati o n (see Secti o n  6. 5. 1 ).
Aller ge n i m m u n ot hera p y 
All o we d if partici pa nt has bee n recei 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 Visit 1 i n t he pare nt st u d y 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 
I M P. N o n-pr escri pti o n o ver -t he-c o u nter 
treat me nts 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 are per mitte d 
f or s uc h partici pa nts. 
C o m mercial 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 hera p y)
•
All o we d, pr o vi de d t he partici pa nt is
sta ble o n mai nte na nce d ose (at stea d y 
state) pri or t o Visit 1 i n t he pare nt st u d y. 
•
Recei pt of a p pr o ve d/lice nse d treat me nts 
f or t he pre ve nti o n of C O VI D-1 9 are 
per mitte d d uri n g t he f oll o w -u p peri o d 
(starti n g ≥ 3 m o nt hs after t he last d ose of 
A Z D 7 4 4 2) as pe r l ocal 
g ui deli nes/sta n dar d of care a n d s h o ul d be 
d oc u me nte d as c o nc o mita nt me dicati o n.

T re at me nt of C O VI D -1 9 wit h 
ot her m o n ocl o n al a nti b o dies will 
re q uire t h at t he p artici p a nt n ot 
recei ve a n y f urt her A Z D 7 4 4 2 
d oses as p art of t he st u d y, b ut 
s h o ul d re m ai n in st u d y f or l o n g -
ter m s afet y f oll o w-u p.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Ta ble 1 0
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
Partici pa nts ma y ta ke c o nc o mita nt me dicati o ns prescri be d b y t heir pri mar y care 
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 
mai nte na nce. Pri mar y care pr o vi ders 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 n c 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 recei vi n g I M P s h o ul d be treate d acc or di n g t o l ocal 
sta n dar d of care, 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. 
Restricte d
•
Pr o d ucts i n dicate d f or t he 
pre ve nti o n of 
S A R S -C o V -2 or 
C O VI D -1 9 (i ncl u di n g 
t h ose u n der i n vesti gati o n 
or  a ut h orize d u n der earl y 
access pr o visi o ns)
•
H y dr o x yc hl or o q ui ne
•
C hl or o q ui ne
•
I ver mecti n
•
HI V pr otease i n hi bit ors
•
C o n valesce nt C O VI D - 1 9 
plas ma a n d sera
•
H y peri m m u ne gl o b uli n
•
N ote: F or partici pa nts w h o de vel o p 
S A R S -C o V -2 i nfecti o n or bec o me 
h os pitalize d wit h C O VI D -1 9, recei pt of 
a p pr o ve d/lice nse d treat me nt o pti o ns are 
per mitte d a n d partici pa nts s h o ul d be 
treate d acc or di n g t o l ocal sta n dar d of 
care, i ncl u di n g i n vesti gati o nal a ge nts 
u n der E mer ge nc y Use A ut h orizati o n or 
e q ui vale nt re g ulati o ns.
•
Use of h y dr o x yc hl or o q ui ne is acce pta ble 
if use d c hr o nicall y f or a ut oi m m u ne 
disease, a n d t he d ose is sta ble pri or t o 
Da y 1 a n d u p t o Da y 2 9.
•
Use of c hl or o q ui ne if use d t o treat a 
parasitic i nfecti o n
•
Use of i ver mecti n is acce pta ble if use d t o 
treat a parasitic i nfecti o n
•
HI V pr otease i n hi bit ors are acce pta ble if 
use d c hr o nicall y f or HI V i nfecti o n, a n d 
t he d ose is sta ble pri or to Da y 1 a n d u p t o 
Da y 2 9.
C o ntrace pti ve met h o ds
See Secti o n 5. 1 i n t he pare nt st u d y pr ot oc ol.
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 d ose of st u d y dr u g; ie, 
o ne year.
C O VI D -1 9, c or o na vir us disease 2 0 1 9 ; HI V, H u ma n i m m u n o deficie nc y vir us; I M P, i n vesti gati o nal me dici nal 
pr o d uct; 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. 5. 1
C O VI D- 1 9 V acci nes
P arti cipa nts w h o ha ve recei ve d a pre vi o us d ose or d oses of a C O VI D -1 9 vacci ne are per mitte d 
t o be i ncl u de d i n t he s u b-st u d y; h o we ver, partici pa nts e nr o lli n g i n t he re peat d ose s u b-st u d y 
m ust n ot ha ve recei ve d a d ose of a C O VI D -1 9 vacci ne ≤1 4 da ys bef ore r ecei vi n g a d ose of 
I M P or pla n t o recei ve a C O VI D-1 9 vacci nat i on ≤1 4 da y s after recei vi n g a d ose of I M P. S uc h 
parti ci pa nts ca n s u bse q ue nt l y be i ncl u de d i n t he s u b-st u d y o nce t he y ha ve reac he d 1 4 da ys 
after t he last d ose of vacci ne. Ot her wise, partici pa n ts ca n elect t o recei ve a C O VI D- 1 9 
vacci nati o n at a n y  time d uri n g t he s u b -st u d y.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
6. 6
D ose M o dific ati o n
T he I M P will be a d mi nistere d as descri be d i n Sect i o n 6. 1. 1 . D ose m o dificati on is n ot 
per mitte d. 
6. 7
I nter ve nti o n After t he E n d of t he St u d y
T here i s n o i nter ve nti on after t he e n d of t he st u d y  (see defi niti on i n Secti on  4. 5 ).
7
DI S C O N TI N U A TI O N O F I M P 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 M P
It ma y be necessar y for a parti ci pa nt t o per ma ne nt l y disc o nti n ue ( defi niti ve disc o nti n uati o n) 
I M P. If I M P is per ma ne ntl y disc o nti n ue d, t he partici pa nt s h o ul d r e m ai n i n t he st u d y t o be 
e val uate d. See t he S o A (see Secti o n 1. 3 ) for data t o be c ollecte d at t he ti me of disc o nt i n uati on 
of  I M P a n d f o ll ow -u p, a n d f or a n y  furt her e val uati o ns t hat nee d t o be c o m plete d.
N ote t hat disc o nti n uati o n fr o m I M P is N O T t he sa me t hi n g as a with dra wal fr o m t he st u d y.
See t he S o A  for data t o be c ollecte d at t he ti me o f i nter ve nt i on disc o nti n uati o n a n d f o ll 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.
7. 2
P artici p a nt Wit h dr a w al fr o m t he St u d y

A partici pa nt ma y wit h dra w fr o m t he s u b-st u d y at a n y ti me at his/ her o w n re q uest, or ma y 
be wit h dra w n at a n y t i me at t he discreti on of t he I n vesti gat or f or safety,  be ha 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 partici pa nt w h o c o nsi ders wit h dra wi n g fr o m t he st u d y must be i nf or me d b y  t he 
I n vesti gat or a b o ut m o difie d f oll ow- u p o pti o ns (e g, tele p h o ne c o ntact, a c o n tact wit h a 
r elat i ve or treati n g p h ysicia n, or i nf or mati o n fr om me dical rec or ds).

At  t he ti me of wit h dra wal fr om t he st u d y, if p ossi ble, a n Earl y Disc o nti n uati on 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 Secti o n  1. 3 ). See S o A f or data t o be 
c ollecte d at t he ti me of st u d y wit hdra wal a n d f oll o w- 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.

If t he partici pa nt wit h dra ws c o nse nt f or disclos ur e of  fut ure i nf or m at i on, t he S p o ns or ma y 
retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.

If a partici pa nt wit h dra ws fr om t he st u d y, it s h o uld be c o nfir me d if he/s he st ill a grees f or 
e xist i n g sa m ples t o be use d i n li ne wi t h t he origi nal  c o nse nt at t he ti me of wit h dra wal. If 
he/s he re q uests wit h dra wal o f c o nse nt f or use of sa m ples, destr ucti o n of a n y sa m ples 
ta ke n a n d n ot teste d s h o ul d be carrie d o ut i n li ne with w hat was state d i n t he i nf or me d 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
c o nse nt a n d l ocal re g ulat io n. T he I n vesti gat or m ust d oc u me nt t he decisi o n o n use of 
e xist i n g sa m ples i n t he site st u d y rec or ds a n d i nf or m t he Gl obal St u d y  T e a m.
7. 3
L ost t o F oll o w -u p
A partici pa nt will be c o nsi dere d l ost t o f o ll ow- u p if t he partici pa nt 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 site. O nce a partici pa nt has 
bee n d oc u me nt as l ost t o f oll o w -u p, t he y  ca n n ot rej oi n t he st u d y.
T he f o ll owi n g actio ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit:

T he st u d y  sit e must atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as 
s o o n as p ossi ble, a n d c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he partici pa nt wis hes t o a n d/ or 
s h o uld c o nt i n ue i n t he st u d y.

Bef ore a partici pa nt is dee me d l ost t o f o ll ow- u p, t he I n vest i gat or or desi g nee m ust ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne calls a n d, 
if necessar y , a certifie d letter t o t he partici pa nt’s last k n o w n maili n g a d dress or l ocal 
e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s 
me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wi t hdra w n fr o m  t he st u d y. 

Si te 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 vital stat us of t he 
parti ci pa nt wit hi n le gal a n d et hical b o u n daries f or all partici pa nts, i ncl u di n g t h ose w h o 
di d n ot recei ve I M P. P u blic s o urces ma y be searc he d f or vital stat us i nf or mat i on. If vital 
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 partici pa nt will n ot be 
c o nsi dere d l ost t o f o ll ow- u p. S p o ns or per s on 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 o n.
Di sc o nti n uatio n of  s pecific sites or of t he st u d y as a w h ole are ha n dle d as part of A p pe n di x A.
7. 4
St u d y S us pe nsi o n/ E arl y Ter mi n ati o n
T he S p o ns or reser ves t he ri g ht t o te m p oraril y s us pe n d or per ma ne nt l y ter mi nate t his st u d y or a 
c o mp o ne nt of t he st u d y  at a n y ti me. T he reas o ns f or te m p oraril y s us pe n di n g t he st u d y ma y 
i ncl u de, b ut are n ot li mite d t o, t he f o ll owi n g:

A n y deat h, S A E, or ot her safet y fi n di n g assesse d as relate d t o I M P t hat, i n t he o pi ni on of 
t he S p o ns or, ma y precl u de f urt her a d mi nistrati o n of I M P.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6

If o ne or more parti ci pa nt e x perie nces a gra de I V h y perse nsit i vity r eact i on or 
h y perse nsit i vity react i on classifie d as a n S A E.

If 2 or m ore parti ci pa nts, wit hi n t he first 5 0 partici pa nts e x perie nce a gra de III or hi g her 
h y perse nsit i vity react i on.

If 2 or m ore parti ci pa nts, wit hi n t he first 5 0 partici pa nts recei vi n g t he seco n d d ose 
e x perie nce a gra de III or hi g her i nject i on site reacti o n.
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 pt i ons 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 w ith 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 nti n ue 
I M P.

A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse nt ial a n d re q uire d f or st u d y c o n d uct.

All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote ntial 
parti ci pa nts meet all eli gi bilit y cri t eria. T he I n vest i gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d re as 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 t he 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 m et t he pr ot oc ol-s pecifie d criteria a n d were perf or me d 
wi t hi n t he ti mefra me defi ne d i n t he S o A.
8. 1
Effic ac y Assess me nts
T his pri mar y  o bjecti ve of t his s u b-st u d y is safety a n d t olera bilit y. Efficac y assess me nts 
descri be d i n t his sect i on are e x pl orat or y.
8. 1. 1
M o nit ori n g C O VI D -1 9 S y m pt o ms
To  deter mi ne t he i nci de nce of i nfecti o n, st u d y sites will c o ntact partici pa nts wee kl y 
(t ele p h o ne/e mail/te xt) t hr o u g h t o t he S S-D 1 8 3 a n d t he n m o nt hl y t o t he e n d of t he st u d y , wit h 
re mi n ders t o m o nit or f or C O VI D-1 9 s y m pt o ms a n d c ar diac e ve nts. D uri n g t hese c o ntacts t he 
I n vesti gat or will e n q uire a b o ut a n y C O VI D-1 9 s y m pt o m s (see Ta ble 1 1 ) a n d car diac e ve nts 
fr om t he past 7 da ys or m o nt h res pect i vel y a n d will nee d t o i nit iate Ill ness Visit s wit hi n 3 da ys 
if s uc h s y m pt o ms are re p orte d. Partici pa nts w h o prese nt wit h at least o ne of t he C O VI D- 1 9 
q ualif yi n g s y m pt o ms liste d i n  Ta ble 1 1 , must c o ntact t he st u d y  sit e. 

Cli nical St u d y Pr ot oc o l A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
P arti cipa nts w h o prese nt wi t h a C O VI D-1 9 q ualif yi n g s y m pt o m(s) after S S -D 1 will be 
i nstr ucte d t o i nitiate Ill ness Visits a n d will be teste d l ocall y f or S A R S-C o V -2 (see Secti o n
8. 6. 1. 1 ). If ne gati ve at Ill ness Visit D 1, t he partici pa nt will be i nstr ucte d t o st o p Ill ness Visits 
a n d c o nt i n ue wit h t he wit h t he s u b-st u d y sc he d ule d assess me nts (ie, Ta ble 2 , Ta ble 3 , or 
Ta ble 4 ). If p ositi ve, t he partic i pa nt will be i nstr ucte d t o c o nti n ue t o c o m plete all Ill ness Visits 
a n d will ha ve a d dit i onal assess me nts per  Ta ble 5 . C O VI D-1 9 q ualif yi n g s y m pt o m(s), S A R S -
C o V -2 p osit i ve test res ults, a n d/ or C O VI D-1 9 di a g n osis 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.
Ta ble 11
C O VI D -1 9 Q u alif yi n g S y m pt o ms
P artici p a nt m ust prese nt wit h at le ast o ne of t he f oll o wi n g s y m pt o ms:
D ur ati o n
S y m pt o m
N o mi ni m u m d urati o n
Fe ver
S h ort ness of breat h
Diffic ult y breat hi n g
Ne w o nset c o nf usi o n ( o nl y f or partici pa nts ≥6 0 y o)
A p petite l oss or decrease f o o d i nta ke ( o nl y f or 
partici pa nts ≥6 0 y o)
I n crease d s u p ple me ntal o x y ge n re q uire me nt ( o nl y f or 
partici pa nts ≥6 0 y o o n baseli ne s u p ple me ntal 
o x y ge n)
M ust be prese nt f or ≥2 da ys
C hills
C o u g h
Fati g ue
M uscle ac hes
B o d y ac hes
Hea dac he
Ne w l oss of taste
Ne w l oss of s mell
S ore t hr oat
C o n gesti o n
R u n n y n ose
Na usea
V o miti n g
Diarr hea
A da pte d f r om  C D C 2 0 2 1
C D C, Ce nters f or Disease C o ntr ol a n d Pre ve nti o n; y o, years ol d. 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
8. 1. 2
Se vere or Critic al Criteri a
Se vere C O VI D -1 9 i s c haracterize d b y a mi ni m u m of eit her p ne u mo nia (fe ver, c o u g h, 
tac h yp nea or d ys p nea, a n d l u n g i nfiltrates) or h y p o xe mia ( o x y ge n sat urati o n < 9 0 % i n r o o m 
air a n d/ or se vere res pirat or y distress) a n d a W H O Cli nical Pr o gressi o n Scale sc ore of 5 or 
hi g her (Ta ble 1 2 ). C o nfir me d p ositi ve cases of C O VI D-1 9 m ust ha ve a W H O Cli nical 
Pr o gressi o n sc ore rec or de d i n t he e C R F .
Ta bl e 1 2  
W H O Cli nic al Pro gressi o n Sc ale
P atie nt St ate
Descri pt or
Sc ore
U n i nfecte d
U n i nfecte d, n o viral R N A detecte d
0
A m b ulat or y mil d disease
As y m pt o matic; viral R N A detecte d
1
S y m pt o matic; i n de pe n de nt
2
S y m pt o matic; assista nce nee de d
3
H os pitalize d: m o derate disease
H os pitalize d; n o o x y ge n t hera p y a
4
H os pitalize d; o x y ge n b y mas k or nasal 
pr o n gs
5
H os pitalize d: Se vere Disease
H os pitalize d; o x y ge n b y NI V or hi g h 
fl o w
6
I nt u bati on a n d mec ha nical ve ntilati o n, 
p O 2/ Fi O2 ≥1 5 0 or S p O 2/ Fi O2 ≥2 0 0
7
Mec ha nical ve ntilati o n p O
2/ Fi O2 < 1 5 0 
( S p O2/ Fi O2 < 2 0 0) or vas o press ors 
8
Mec ha nical ve ntilati o n p O
2/ Fi O2 < 1 5 0 
a n d vas o press ors, dial ysis, or E C M O 
9
Dea d
Deat h
1 0
a
If h os pitalize d f or is olati o n o n l y, rec or d stat us as f or a m b ulat ory patie nt.
E C M O, e xtrac or p oreal me m bra ne o x y ge nati o n; Fi O 2, fracti o n of i ns pire d o x y ge n; NI V, n o n-i n vasi ve ve ntilati o n; 
R N A, ri b o n ucleic aci d; p O 2, partial press ure of o x y ge n; S p O2, o x y ge n sat urati o n.
Mars hall et al 2 0 2 0 .
8. 1. 3
Ill ness Visits
S y m pt o m atic partici pa nts (as defi ne d i n Secti o n  8. 1. 1 ) will be i nstr ucte d t o visit t he st u d y sit e 
f or i nitiatio n of  ill ness assess me nts (Ta ble 5) ; w here s u p p orte d, h o me or m o bile visits ma y be 
s u bstitut e d f or t he site visits. S y m pt o matic partici pa nts will c o m p lete t he I L-D 1 a n d will be 
i nstr ucte d t o c o nti n ue with t he h o me c ollecti o n re q uire me nts. Res ults of S A R S -C o V -2 RT -
P C R test will be a vaila bl e d uri n g t he h o me c o llecti o n peri o d a n d partici pa nts will be i nf or me d 
of  t h eir stat us. T he res ults of t he C O VI D-1 9 RT- P C R testi n g s h o ul d als o be re p orte d t o t he 
parti ci pa nts’ pri mar y  care pr o viders. S y m pt o matic partici pa nts will c o nt i n ue wit h t he Ill ness 
V isits u ntil a la b orat or y res ult is a vaila ble. O nl y p artici pa nts w h o test p osit i ve b y t he l ocal 
la b orat or y res ults ( or ce ntral la b orat or y res ults, if l o c al not a vaila ble) will be i nstr ucte d t o 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
c o nti n ue wit h t he Ill ness Visits a n d c o m p lete t he e ntire Ill ness Vis it series, i ncl u di n g h o me 
c ollect i on re q uire me nts. All h o me la b kits s h o ul d be br o u g ht t o all s u bse q ue nt Ill ness Visits. 
P arti cipa nts w h o test ne gati ve f or S A R S -C o V -2 at I L -D 1 will be i nstr ucte d t o st o p all Ill ness 
Vis it assess me nts a n d ret ur n t he h o me la b kits. Partici pa nts will c o nti n ue with f oll ow- u p visits 
per  Ta ble 2 or  Ta ble 3 or  Ta ble 4 .
T he Ill ness V isit sc he d ule is t o be perf or me d i n a d diti on t o t he sc he d ule d visit i n  Ta ble 2 , 
Ta ble 3 or  Ta ble 4 . W here visits c oi nci de, all assess me nts fr o m t he sc he d ule d visit a n d Ill ness 
Vis it s h o uld be perf or m e d.
To  disti n g uis h bet wee n t he sc he d ule d visits f or t he treat me nt a n d f oll ow -u p peri o d (Ta ble 2,
Ta ble 3 or  Ta ble 4 ) a n d t he Ill ness Visits (Ta ble 5 ), a n d t o disti n g uis h bet wee n ill ness e pis o des 
t he visits will be la bele d as f o ll ows: f or t he first e pis o de Ill ness V isit Da y 1 = 1I L -D 1, Ill ness 
Vis it D a y 3 = 1I L -D 3 etc, a n d f or t he sec o n d e pis o de 2I L -D 1, 2I L -D 3, a n d s o o n as 
a p plica ble.
8. 1. 4
S A R S -C o V- 2 Testi n g a n d Ot her Vir ol o g y Assess m e nts
At  t he I L-D 1, N P s wa bs will be c ollecte d f or l ocal a n d ce ntral la b orat ories a n d teste d f or 
S A R S -C o V -2 b y  a ut h orize d RT- P C R assa ys (see Secti o n  8. 6. 1. 1 ).
Resista nce m o nit ori n g as perf or me d b y ge n ot y pic a n d p he n ot y pic c haracterizati o n o f vir us 
is olate d fr o m Ill ness Visits ma y be c o n d ucte d per t he S o A (see Secti o n  1. 3 a n d Secti o n 
8. 6. 1. 1 ). A d dit i onall y, a res pir at or y pa nel t o i n vestigate t he prese nce of a d dit i onal viral 
pat h o ge ns ma y be carrie d o ut at ti me p oi nts per t he S o A, a n d as o utli ne d i n Sect i on  8. 6. 1. 1 .
Sali va ma y  be c ollecte d d uri n g site Ill ness Visits a n d b y self-c o llecti on at h o m e t hr o u g h o ut t he 
Ill ness Visits t o q ua ntif y d urati o n of viral s he d di n g (see Secti o n  8. 6. 1. 2 ). 
8. 2
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A.
8. 2. 1
P h ysic al E x a mi n ati o ns
Ta r gete d p h ysical e xa mi nati ons will be perf or me d as s pecifie d i n t he S o A (see Sectio n  1. 3 ).

A tar gete d p h ysical e xa mi nat i on will  incl u de areas s u g geste d b y  c ha n ges t o t he me dical 
hist or y , v ul nera ble me dical c o n ditio n s, a n d re p orte d cli nical c o m plai nts d uri n g t he st u d y 
visit. Eac h cli nicall y si g nifica nt a b n or mal fi n di n g f oll o wi n g vacci nat i on will be rec or de d 
as a n A E.

Wei g ht will be rec or de d at t he first s u b -st u d y visit.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
All p h ysical e xa mi nat i ons will be perf or me d b y a lice nse d healt hcare pr o vi der i ncl u di n g, b ut 
n ot li mite d t o, p h y sicia n, p h ysicia n assista nt, or lice nse d n urse practit i oner.
8. 2. 2
Vit al Si g ns
Vit al si g ns, i ncl u di n g heart rate, res pirat or y rate, p ulse o xi metr y, blo o d press ure, a n d b o d y  
t e mperat ure, will be perf or me d as s pecifie d i n t he S o A (see Sectio n  1. 3 ). T he partici pa nt 
s h o uld be rest i n g pri or t o t he c ollecti on of vital si g ns.
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 ms
Tri p licate 1 2-lea d E C Gs will be perf or me d at ti me p oi nts s pecifie d i n t he S o A (see 
Secti o n 1. 3 ). A 1 2- lea d safet y E C G will be o btai ne d after 5 mi n utes ’ s u pi ne rest, usi n g t he 
sites 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 pretati o n as n or mal or a b n or m al. 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 malit y is cli nicall y si g nifica nt b y t he 
I n vesti 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 ype a n d 
nat ure of t he a b n or malit y will  be d oc u me nte d. C li nicall y si g nifica nt fi n di n gs s h o ul d 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 , if a p plica ble.
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 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. 
T hese assess me nts s h o ul d be e ntere d as a n u nsc he d ule d assess me nt.
All E C G rea di n gs will be di gitall y st ore d as s o urce d oc u me nts.
8. 2. 4
Cli nic al S afet y L a b or at or y Assess me nts
Bl o o d a n d uri ne sa m ples f or deter mi nat i on of cli nical c he mistr y, he mat olo g y, c oa g ulat i on, 
uri nal ysis, a n d car diac bi o mar kers will be ta ke n at t he visits i n dicate d i n t he S o A  (see 
Secti o n 1. 3 ).
A d dit i ona l safety sa m ples ma y be c ollecte d if cli nicall y i n dicate d, at t he discreti o n of t he 
I n vesti gat or. T he date, ti me of c ollect 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 cli nical c he mistr y , he mat olo g y, c oa g ulat i on, uri nal ysis, car diac/t hr o m b osis bi o mar kers, 
ser u m β-h C G, a n d F S H will be perf or me d at a ce ntral la b orat or y. Sa mple t u bes a n d sa m ple 
sizes ma y var y de pe n di n g o n la b orat or y met h o d use d a n d r o uti ne practice at t he site. 
I nstr uctio n f or t he c ollect i on a n d ha n dli n g of t he sa m ples will be pr o vi de d i n t he st u d y  
s pecific La b orat or y Ma n ual.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
T he f o ll owi n g la b orat or y  varia bles will be meas ure d.
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 y tes 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)
Retic ul oc ytes a bs ol ute c o u nt 
Ser u m Cli nic al 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)
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
Calci u m
C o nj u gate d bilir u bi n
P h os p hate
Creati ne Ki nase
Gl uc ose
C- reacti ve pr otei n ( C R P)
Uri n al ysis
Gl uc ose
Bl o o d
Pr otei n
Micr osc o p y (if p ositi ve f or pr otei n or bl o o d): R B C, 
W B C, Casts ( Cell ular, Gra n ular, H yali ne)
C o a g ul ati o n
I nter nati o nal n or malize d rati o (I N R)
Pr ot hr o m bi n Ti me ( P T)
Acti vate d partial t hr o m bi n ti me (a P T T)
N ote: I n case a partici pa nt s h o ws a n A S T or A L T ≥3 × U L N t o get her wit h T B L ≥2 × U L N please refer t o 
A p pe n di x D . Acti o ns re q uire d i n cases of i ncreases i n li ver bi oc he mistr y a n d e val uati o n of H y’s La w, f or f urt her 
i nstr ucti ons.
C ar di ac/ T hr o m b osis Bi o m ar kers
D- di mer
Ser u m- L D L c h olester ol
P- selecti n
Ser u m- H D L c h olester ol
T hr o m bi n
hs -C R P a
Fact or VIII le vels
T otal ser u m c h olester ol
Tr o p o ni n T/l b
a
Hi g h -se nsiti vit y C-reacti ve pr otei n ( hs-C R P)
b
O nl y t o be c ollecte d o n s u b -st u d y Da y 1.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
8. 2. 4. 1
Fe m ales O nl y
Pre g n a nc y test ( w o me n of c hil d be ari n g p ote nti al o nl y)
Ur i ne h u ma n beta c h ori o nic g o na d otr o p hi n ( β-h C G) 
( pr e-d ose)
Ser u m β -h C G a
S us pecte d p ost me n o p a us al w o me n < 5 0 ye ars o nl y)
F ollicle -sti m ulati n g h or m o ne ( F S H) b
a
If uri ne tests p ositi ve or i n deter mi nate, a q ua ntitati ve ser u m β-h C G will be perf or me d f or c o nfir mati o n.
b
F S H will be a nal yze d at t he scree ni n g visit t o c o nfir m p ost me n o pa usal stat us o nl y i n w o me n < 5 0 years of 
a ge w h o ha ve bee n a me n orr h oeic f or ≥ 1 2 m o nt hs. U ntil F S H is d oc u me nte d t o be wit hi n me n o pa usal 
ra n ge, t he partici pa nt is t o be c o nsi dere d of c hil d beari n g p ote ntial. F or w o me n a ge d ≥ 5 0 years, 
p ost me n o pa usal is defi ne d as ha vi n g a hist or y of ≥ 1 2 m o nt hs’ a me n orr hea pri or t o ra n d o mizati o n, wit h o ut 
a n alter nati ve ca use, f oll o wi n g cessati o n of e x o ge n o us se x -h or m o nal treat me nt.
8. 2. 5
I njecti o n Site I ns pecti o n
A n i njecti on site i ns pecti o n will be perf or me d after a d mi nistrati o n of I M P acc or di n g t o 
Ta ble 1 3 (see Secti o n 1. 3 ).
Ta ble 1 3
I njecti o n Site I ns pecti o n
Pr oce d ure/ Ti me after b ot h i njecti o ns h a ve bee n 
a d mi nistere d
I m me di atel y 
after I M P 
a d mi nistr ati o n
3 0 mi n utes 
( ± 1 0 
mi n utes)
I m me di atel y 
pri or t o 
p artici p a nt 
rele ase
Vis ual i ns pecti o n of site
X
X
X
Pal pati o n of site
X
X
X
Partici pa nt will be as ke d
Are y o u e x perie nci n g a n y disc o mf ort?
X
X
X
If yes, has t he feeli n g of disc o mf ort 
c ha n ge d si nce y o u recei ve d t he i njecti o n
X
X
I M P, i n vesti gati o nal me dici nal pr o d uct
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. 1
M o nit ori n g After I M P A d mi nistr ati o n
I n a d diti on t o t h e i njecti o n site i ns pect i on, safet y m o nit ori n g will be perf or me d after I M P 
a d mi nistrati o n. Partici pa nts will be cl osel y m o nit ore d f or o ne h o ur p ost I M P a d mi nistrati o n. 
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v o l ve d i n t he st u d y are fa miliar 
wi t h t he c o nte nt of t his secti on.
T he defi nit i ons of a n A E or S A E ca n be f o u n d i n  A p pe n di x B.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
A d ve rse e ve nts will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, 
s urr o gate, or t he partici pa nt’s le gall y a ut h 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 vesti gat or a n d a n y desi g nees are res p o nsi ble f o r detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi 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
All A Es a n d S A Es will be c ollecte d fr o m t he ti me of I M P a d mi nistrati o 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 eri o us a d verse e ve nts will be rec or de d fr o m t he ti me of si g ni n g of t he s u b -st u d y I C F.
If t he I n vesti gat or bec o mes a ware of a n S A E wit h a s us pecte d ca usal relati ons hi p t o t he I M P 
t hat occ urs after t he e n d of t he cli nical st u d y in a p arti ci pa nt treate d b y hi m or her, t he 
I n vesti gat or s hall, with o ut u n d ue dela y, re p ort t he S A E t o t he S p o ns or.
8. 3. 2
F oll o w- u p of A Es a n d S A Es
A n y A Es t hat are u nres o l ve d at t he partici pa nt’s last A E assess me nt i n t he st u d y are f o ll owe d 
u p b y  t he I n vesti gat or f or as lo n g as m e dicall y i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he 
e C R F. Astra Ze neca retai ns t he ri g ht t o re q uest a d diti o nal i nf or mati o n f or a n y  p artici pa nt wit h 
o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if ju d ge d necessar y. Me dical rec or ds ass ociate d 
wi t h S A Es s h o uld be c ollecte d a n d re dacte d c o pies pr o vi de d t o t he C R O/ S p o ns or, w he n 
re q ueste d.
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)

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 s e v erit y gra de/c ha n ges i n se verity 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 M P(s) ( yes or n o)

Act i on ta ke n wit h re gar d t o I M P

If t he A E ca use d partici pa nt’s wit h dra wal fr om t he st u d y ( yes or n o)

O utc o m e
I n a d ditio n, 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

Cl i nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 6 of 9 6

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 pitalizati o n

Date of disc har ge

Pr o ba ble ca use of deat h

Ca use of deat h relate d t o C O VI D -1 9 ( y es/ no/ u n k n o w n)

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
T he f o ll owi n g se verit y rati n gs will be use d, a da pte d fr om 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 nsity t hat is us uall y tra nsie nt a n d ma y re q uire o nl y cli nical 
or di a g n ostic o bser vati o ns. T he e ve nt d oes n ot ge nerall y  int erfere wit h us ual a cti vities of 
dail y  li vi n g. 

Gra de 2 : A n e ve nt of m o derate i nte nsity t hat i s us uall y alle viate d wit h a d ditio n al , s pecific 
t hera pe utic i nter ve nt i on 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 a cti vities of dail y li vi n g, ca usi n g disc o mf ort, b ut p oses n o si g nifica nt or 
p er m a ne nt ris 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 on b ut i s 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 partici pa 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 o n is i n dicate d.

Gra de 5 : Deat h, as res ult of a n e ve nt.
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d se vere A Es:

Se verit y is a meas ure of i nte nsity, w hereas seri o us ness is defi ne d b y  t he crit eria i n 
A p pe n di x  B 2.

A n A E of se vere i nte nsit y nee d n ot necessaril y be c o nsi dere d seri o us. F or e xa m ple, 
na usea t hat persists f or se veral h o urs m a y be c o nsi dere d se vere na usea, b ut n ot a n S A E. 
O n t he ot her ha n d, a str o ke t hat res ul ts i n o nl y a li mite d de gree of disa bility ma y be 
c o nsi dere d a mil d str o ke b ut w o ul d be a n S A E.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
8. 3. 3
C a us alit y C ollecti o n
T he I n vesti gat or s h o ul d assess ca usal relat i 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 uesti o n ‘D o y o u c o nsi der t ha t t here is a reas o na ble p ossi bility t hat t he 
e ve nt ma y ha ve bee n ca use d b y t he I M P?’
F or S A Es, ca usal relat i ons hi p s h o ul d als o be assesse d f or ot her me dicat i on(s) a n d st u d y  
pr oce d ures. N ote t hat f or S A Es t hat c o ul d be ass ociate d wit h a n y st u d y  pr oce d ure t he ca usal 
r elat i ons hi p is i m plie d as ‘yes ’.
A g ui de t o t he i nter pretati o n of t he ca usalit y q uesti o n is f o u n d i n  A p pe n di x B.
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 c ollecte d acc or di n g t o t he ti me p oi nts s pecifie d i n 
t he S o A (see Sectio n  1. 3 ).
A d verse e ve nts of s pecial i nterest are e ve nts of scie nt ific 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 I M P safety pr ofile, a n d re q uire cl ose 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 t he S p o ns or. A n A E SI ca n be seri o us or n o n -serio us. 
All A E SIs will be rec or de d i n t he e C R F . Serio us A E SIs will be rec or de d a n d re p orte d as per 
Secti o n  8. 3. 9 . See als o t he A Z D 7 4 4 2 I B, f or a d dit i o nal i nf or mati on o n A E SIs.
A E SIs f or A Z D 7 4 4 2 are liste d bel o w . T he y incl u de:

A na p h yla xis a n d ot her seri o us h y perse nsit i vity reactio ns ( A p pe n di x E ).

I njecti on site reacti o ns.

Car di ac isc he mia, car diac fail ure, a n d t hr o m b otic e ve nts.
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 ollecte d acc or di n g t o t he ti me p oi nts s pecifie d i n 
t he S o A (see Sectio n 1. 3 ).
Me dicall y  atte n de d a d verse e ve nts are defi ne d as A Es lea di n g t o me dicall y atte n de d visit s t hat 
were n ot r o uti ne visit s for p h y sical e xa mi nati 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 n g a b n or mal v ital si g ns, ide ntifie d o n a r o uti ne st u d y  visit or 
d uri n g t he sc he d ule d Ill ness V isits 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 partici 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 heal t h pr o ble ms si nce t he 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 8 of 9 6
pre vi o us visit/ y o u w er e l ast as ke d?’, or re veale d b y o bser vat i on, will be c o llecte d a n d 
rec or de d i n t he e C R F. W he n c ollecti n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n 
p ossi ble) t o rec or di n g a list of si g ns a n d s y m pt o ms. H o we ver, if a dia g n osis is k n o w n a n d 
t here are ot her si g ns or s y m pt o ms t hat are n ot ge nerall y part of t he dia g n osis, t he dia g n osis 
a n d eac h si g n or s y m pt o m will be rec or de d se paratel y. S y m pt o ms of  C O VI D-1 9, c o nfir me d 
S A R S -C o V -2 i nfecti o n, a n d/ or dia g n osis o f C O VI D -1 9 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 o m t he pr ot oc ol -ma n date d la b orat or y tests, vital si g ns, E C G, a n d ot her safet y 
assess me nts will be s u m marize d i n t he C S R. 
Deteri or ati o n, as c o m pare d t o baseli ne i n pr ot oc ol -ma n date d safet y assess me nts, s h o uld 
t heref ore o nl y be re p orte d as A Es if t he y f ulfill a n y of t he S A E criteria, are t he reas o n f or 
di sc o nti n uati on of t reat me nt wit h t he I M P, or are c o nsi dere d t o be cli nicall y rele va nt as j u d ge d 
b y t he I n vest i gat or ( w hic h ma y i ncl u de, b ut n ot li mite d t o, c o nsi derati on as t o w het her 
treat me nt or n o n-pl a n ne d visits were re q uire d or ot her acti o n was ta ke n wit h t he I M P, e g, dose 
a djust m e nt or dr u g i nterr u pti o n).
If deteriorati o n i n a la b orat or y  val ue/ vit al si g n is ass ociate d wit h cli nical si g ns a n d s y m pt o ms, 
t he sig n or s y m pt o m  will be re p orte d as a n A E a n d t he ass ociate d la b orat or y  res ult/ vit al si g n 
will be c o nsi dere d as a d d iti onal i nf or mat i on. W here ver p ossi ble, t he re p orti n g I n vest i gat or 
uses t he cli nical, rat her t ha n t he la b orat or y  t er m (e g, a ne mia vers us l o w he 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 m pare d wit h t he baseli 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 vati o ns i n li ver bi oc he mistr y  ma y re q uir e furt her 
e val uat i on. A n y occ urre nces of A S T or A L T ≥ 3 × U L N, t o get her wit h T B L  ≥ 2 × U L N a n d 
c o nfir me d as a H L case s h o uld be re p orte d as a n S A E.
A S T or A L T ≥ 3 × U L N t o get her wit h T B L  ≥ 2 × U L N, w here n o ot her reas o n, ot her t ha n t he 
I M P, ca n be f o u n d t o e x plai n t he c om bi nat i on of i ncreases, 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 s h o ul d be e val uate d. T he ele vati on i n tra nsa mi nases 
m ust prece de or be c oi nci de nt wit h (ie, o n t he sa me da y ) t he ele vat i on i n T B L, b ut t here is n o 
s pecifie d ti mefra me withi n w hic h t he ele vat i ons i n tra nsa mi nases a n d T B L must occ ur .

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
Pl ease refer t o  A p pe n di x D f or furt her i nstr ucti o n o n cases of i ncreases i n li ver bi oc he mistr y  
a n d e val uat i on 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 ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y r elate d t o t he I M P or t o t he 
st u d y pr oce d ure(s). All S A Es will be rec or de d i n t he e C R F .
If a n y S A E occ urs i n t he c o urse of t he st u d y, I n vestigat ors or ot her site pers o n nel will i nf or m 
t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n o ne da y , ie, i m me diate l 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 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 i nf or mati o n is pr o vi de d t o t he Astra Ze neca Pat ient  Safety data e ntr y  sit e wit hi n 
o ne c ale n d ar d a y of  init ial recei pt f or fatal a n d life-t hreate ni n g e ve 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 mat i on is missi n g, acti ve 
f oll ow- u p will be u n d erta ke n i m me diatel y. I n vesti gat ors or ot her site pers o n nel will i nf or m 
Astra Ze neca re prese ntati ves of a n y  foll o w -u p i nf or mat i on o n a pre vi o usl y  re p orte d S A E 
wi t hi n o ne cale n dar da y, ie, i m me diatel y but n o l ater  t h a n 2 4 h o urs of  w he n he or s he 
bec o me s a ware of  it.
O nce t he I n vest i gat ors or ot her site pers o n nel i n dicate a n A E i s serio us i n t he E D C s yste m , a n 
a ut o mat e d e mail alert is se nt t o t he desi g nate d Astra Ze neca re prese ntati ve.
If t he E D C s yste m is n ot a vaila ble, t he n t he I n vesti gat or or ot her st u d y sit e st aff re p orts a n 
S A E t o t he a p pr o priate Astra Ze neca re prese ntati ve via pa per f or m t o a gl o bal safet y mail b o x.
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 n S A E, se e A p pe n di x B.
T he refere nce d oc u me nt f or defi nit i on o f e x pecte d ness/liste d ness is t he I B f or t he Astra Ze neca 
dr u g. 
8. 3. 1 0
Pre g n a nc y
All pre g na ncies a n d o u t co m es of pre g na nc y s ho ul d be re p orte d t o Astra Ze neca.
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 E u nless t here is a s us pici o n t hat t he I M P u n der st u d y 
ma y ha ve i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve me dicati on. C o n ge nital 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 0 of 9 6
a b n or malities/ birt h defects a n d s p o nta ne o us miscarria ges s h o ul d be re p orte d a n d ha n dle d as 
S A Es. Electi ve a b orti o ns wit h o ut c o m plicat i ons s h o ul d n ot be ha n dle d as A Es. T he o utc o me 
of  all pre g na ncies (s p o nta ne o us miscarria ge, electi ve ter mi nati on, ect o pic pre g na nc y, n or mal 
birt h, or c o n ge nital a b n or malit y)  s h o uld be f ol l owe d u p a n d d oc u m e nte d e ve n if t he 
parti ci pa nt was disc o nt i 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 hen 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 o ne d a y , ie, i m me diatel y, b ut n o 
l ater t h a n 2 4 h o urs of  w he n he or s he bec o mes a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he I n vest i gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n o ne 
or  5 c ale n d ar d a ys f or 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 ule i n t he e C R F is use d t o re p ort t he pre g na nc y a n d t he pa per-base d 
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 0. 2
P ater n al E x p os ure 
Male parti ci pa nts s h o uld r ef rai n fr o m fat heri n g a c hil d d uri n g t he st u d y a n d for 3 6 5 da y s 
f oll owi n g eac h d ose of A Z D 7 4 4 2.
I n case of pre g na nc y of t he par t ner of a male partici pa nt, t he part ner’ s pre g na nc y s ho ul d be 
re p orte d o n t he pre g na nc y f or m (c o nse nt fr om t he part ner must be o btai ne d bef ore t he 
pre g na nc y f or m is c o m plete d) f o ll owi n g t he sa me ti mefra me a n d r o uti n g as descri be d f or a n y  
parti ci pa nt ’s pre gna nc y. Pre g na nc y of t he partici pa nt’s part ner is n ot c o nsi dere d t o be a n A E. 
T hese pre g na ncies will als o be f o ll owe d u p, a n d t he o utc o me of t he pre g na nc y (s p o nta ne o us 
miscarri a ge, electi ve ter mi nat i on, ect o pic pre g na nc y, n or mal birt h, or c o n ge nit al a b n or ma lity)  
s h o uld, if p ossi ble, be o btai ne d a n d d oc u me nte d.
Pl ease refer t o Secti o n 8. 3. 1 0 f or furt her details.
8. 3. 1 1
Me dic ati o n Err or
If a me dicati on err or o cc urs i n t he c o urse of t he st u d y, t he n t he I n vesti gat or or ot her site 
pers o n nel i nf or ms t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n o ne d a y , ie, 
i m me diatel y but n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec ome s a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is c om p lete d wit hi n o ne (I nitial F at al/ Life-T hreate ni n g or f o ll ow- u p 
Fatal / Life-T hreate ni n g) o r  5 ( ot her seri o us i nitial a n d f oll ow- u p) c ale n d ar d a y(s) if t here is 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 1 of 9 6
a n S A E ass ociat e d wit h t he me dicati on err or (see Secti o n  8. 3. 9 ) a n d wit hi n 3 0 d a ys f or all 
ot her m e dicatio n err ors.
T he defi nit i on of a Me dicat i on Err or ca n be f o u n d i n A p pe n di x  B 4 . 
8. 4
O ver d ose
F or t hi s st u d y, a n y d ose of A Z D 7 4 4 2 > 1 5 0 m g of eit her i n di vi d ual m A b f or t he 3 0 0 m g d ose 
or > 3 0 0 m g of  eit her i n di vi d ual m A b f or t he 6 0 0 m g d ose or a n a d dit i onal d ose gi ve n b y 
mista ke o utsi de t he st u d y  sc he d ule will be c o nsi dere d a n o ver d ose.
Astra Ze neca d oes n ot rec o m me n d a s pecific treat me nt f or a n o ver d ose. S y m pt o ms of o ver d ose 
s h o uld be treate d as per cli nical j u d g me nt.

A n o ver d ose wit h ass ociate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
r ele va nt A E mo d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule.

A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y  re p orte d o n t he O ver d ose e C R F 
m o d ule.
If a n o ver d ose of a n Astra Ze neca st u d y dr u g occ urs i n t he c o urse of t he st u d y, t he n t he 
I n vesti gat or or ot her site pers o n nel i nf or m a p pr o priate Astra Ze neca re prese ntati ves 
i m me diatel y, b ut n o l ater  t h a n 2 4 h o urs of  w he n he or s he bec o me s a ware of it.
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all 
r ele va nt i nf or mat i on is pr o vi de d t o t he Astra Ze neca Pati e nt Safet y data e ntr y  sit e wit hi n 
1 or 5 da ys f or S A Es, a n d wit hi n 3 0 da ys f or ot her o ver d o ses.
8. 5
H u m a n  Bi ol o gic al S a m ples
I nstr uctio ns f or t he c ollect i on a n d ha n dli n g of bi o l o gical sa m ples will be pr o vi de d i n t he st u d y 
s pecific La b orat or y Ma n ual. Sa mples s h o ul d be st ore d i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de nt iality.  F or f urt her details o n Ha n dlin g of  H u ma n Biol o gical 
S a m ples, see  A p pe n di x C.
S a m ples will  be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he iss ue of t he C S R i n 
li ne wit h co nse nt a n d l o c al  r e q uire me nts, after w hic h t he y will be destr o ye d/re patriate d. 

P har mac o ki net ic sa m ples will be dis p ose d of after t he Bi oa nal ytical Re p ort fi nalizati on or 
6 m o nt hs after iss ua nce of t he draft Bi oa nal y tical Re p ort ( w hic he ver is earlier), u nless 
c o nse nte d f or f ut ure a nal yses. 

P har mac o ki net ic sa m ples ma y be dis p ose d of or a n o n y mize d b y p o oli n g. A d diti onal 
a nal yses ma y be c o n d ucte d o n t he a n o n y mize d, p o ole d P K sa m ples t o f urt her 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
e val uate a n d vali date t he a nal yt ical met h o d. A n y r es ults fr o m s uc h a nal yses ma y be 
re p orte d se paratel y fr o m t he C S R.

Re mai ni n g A D A sa m ple ali q u ots will be retai ne d at Astra Ze neca or its desi g nee f or a 
ma xi m u m o f 1 5 y ears f o ll owi n g iss ue of t he C S R. A d dit i onal use i ncl u des, b ut is n ot 
li mite d t o, f urt her c haracterizati on of  a n y AD As, c o nfi r mat i on a n d/ or re q ualificat i on of 
t he assa y, as well as a d dit i onal assa y de vel o p me nt w or k. T he res ults fr o m f ut ure a nal ysis 
will n ot be re p orte d i n t he C S R.
8. 5. 1
P h ar m ac o ki netics Assess me nts

S er u m  sa m ples will be c ollecte d f or meas ure me nt of ser u m c o nce ntrati o ns of A Z D 7 4 4 2 
( A Z D 8 8 9 5 a n d A Z D 1 0 6 1), as s pecifie d i n Ta ble 2 , Ta ble 3 , a n d Ta ble 4.

S a m ples ma y  be c ollecte d at a d ditio n al  time p oi nts d uri n g t he st u d y  if warra nte d a n d 
a gree d u p o n bet wee n t he I n vest i gat or a n d t he S p o ns or, e g, f or safet y reas o ns. 

S a m ples c o llecte d f or a nalyses of A Z D 7 4 4 2 ser u m c o nce ntrati o n ma y be use d t o e val uate 
safety or efficac y  as pects.

S a m ples will  be c ollecte d, la bele d, st ore d, a n d s hi p pe d, as detaile d i n t he La b orat or y 
Ma n ual.

Ser u m A Z D 8 8 9 5 a n d A Z D 1 0 6 1 c o nce ntrati o ns will be s u m marize d descri pt i vely b y t i me 
p oi nt a n d P K para meters (e g, A U C, t 1/ 2) will be deri ve d if data all o w. T he A Z D 8 8 9 5 a n d 
A Z D 1 0 6 1 data will be f urt her a nal yze d wi t h p o p ulatio n P K met h o ds t o c haracterize t he 
m ult i ple d ose P K f or differe nt d osi n g i nter vals.
8. 5. 1. 1
Deter mi n ati o n of Dr u g C o nce ntr ati o n
S a m ples f or deter mi nati o n of dr u g c o nce ntrati o n i n ser u m will be assa ye d b y bi oa nal y tical t est 
sites o perate d o n be half of Astra Ze neca, usi n g a n a p pr o priatel y vali date d bi oa nal y tical 
met h o d. F ull details o f t he a nal ytical met h o d use d will be de scri be d i n a se parate Bi oa nal ytical 
Re p ort.
I nc urre d Sa m ple Rea nal ysis (I S R), if a n y, will be perf or me d alo n gsi de t he bi oa nal ysis of t he 
test sa m ples. T he res ults fr o m t he e val uati on, if perf or me d, will be re p orte d i n a se parate 
Bi oa nal y tic al Re p ort.
8. 5. 2
I m m u no ge nicit y Assess me nts
S er u m  sa m ples f or A D A  im m u n o ge nicit y assess me nts will be c o llecte d acc or di n g t o Ta ble 2 ,
Ta ble 3 , or Ta ble 4 . S a mples will  be c ollecte d, la bele d, st ore d, a n d s hi p pe d as detaile d i n t he 
La b or at or y  Ma n ual.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
8. 5. 2. 1
A nti dr u g A nti b o d y Assess me nts
S er u m  sa m ples f or deter mi nati on of A D A will be c o n d ucte d o n be half of Astra Ze neca, usi n g a 
vali date d assa y. S er u m sa m ples f or deter mi nati on of A D As will be c o llecte d as s pecifie d i n 
t he S o A (see Sectio n  1. 3 ). U nsc he d ule d sa m ples f or A D A  a nal ysis s h o ul d be c ollecte d i n 
res p o nse t o s us pecte d i m m u ne-relate d A Es.
T he prese nce or a bse nce of A D A  will be deter mi ne d i n t he ser u m sa m ples usi n g a vali date d 
bi oa nal yt ical met h o d. A tiere d testi n g sc he me will be e m pl o ye d, wi t h t he first ste p bei n g 
scree ni n g. Sa m ples f o u n d p osit i ve i n t he scree ni n g ste p will be teste d i n t he c o nfir mat or y ste p. 
S a m ples c o nfi r me d p ositive f or A D A  in t he c o nfir mat or y  ste p will u n der g o e n d p oi nt titer 
deter mi nat i on.
F ull details o f t he a nal ytical met h o d a n d a nal yses perf or me d will be descri be d i n a se parate 
Bi oa nal y tic al R e p ort.
8. 5. 2. 2
S A R S -C o V -2 Ser ol o g y Assess me nts
S er u m  sa m ples will be c ollecte d t o assess S A R S -C o V -2 a nti ge n -s pecific a nti b o d y le vels fr o m 
all partici pa nts acc or di n g t o t he S o A (see Secti o n 1. 3 ). Baseli ne ser ostat us a n d t he rate of
S A R S -C o V -2 i nfecti o n i n part ici pa nts i n t his s u b-st u d y will be deter mi ne d b y ser oc o n versio n  
( ne gati ve t o p ositi ve) i n a vali date d S A R S-C o V -2 N assa y o perate d b y  a n a ut h orize d 
la b orat or y. 
 
 
 
 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
8. 5. 3
P h ar m ac o d y n a mics
8. 5. 3. 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 m ples t o meas ure S A R S -C o V -2 n A b l e vels will be c ollecte d fr o m partici pa nts 
acc or di n g t o t he ti me p o i nts s pecifie d i n t he S o A (see Sectio n  1. 3 ). A ut h orize d la b orat ories 
ma y meas ure n A bs t o S A R S -C o V -2 usi n g vali date d li ve vir us ne utralizati o n assa ys or 
pse u d o -ne utralizat i on assa ys. 
S er ol o gic assess me nt t o seas o nal c or o na vir us a nti ge ns m a y als o be assesse d q ua nt itati vel y 
usi n g a q ualifie d m ult i ple xe d mes o scale disc o ver y ( M S D) i m m u n oassa y. E x plor at or y  sera 
sa m ples ma y be ut ilize d t o i n vesti gate a d diti onal h u m or al  a n d cell ular i m m u ne res p o nses, as 
well as p ote ntial c orrelates of pr otec tio n as deter mi ne d b y  t he S p o ns or base d u p o n e mer gi n g 
safety,  efficac y, a n d i m m u n o ge nicity data.
8. 6
H u m a n  Bi ol o gic al S a m ple f or Bi o m ar kers
8. 6. 1
C ollecti o n of M a n d at or y S a m ples f or Bi o m ar ker A n al ysis
B y  c o nse nti n g t o partici pate i n t he s u b-st u d y, t he partici pa nt c o nse nts t o t he ma n dat or y  
researc h c o m p o ne nts of t he st u d y. 
S a m ples f or bi o m ar ker researc h are re q uire d a n d will be c o llecte d fr om parti ci pa nts, as 
s pecifie d i n t he S o As (see Sect i on  1. 3 ). Nas o p har y n geal s wa bs will be c ollecte d f or vir ol ogic 
assess me nts. Sali va sa m ples ma y be c ollecte d at site Ill ness Visits a n d b y t he partici pa nts 
d uri n g t he h o me c ollect i on peri o d. T hese bi o mar ker m eas ure me nts will su p p ort u n dersta n di n g 
of  p ote ntial c orrelates of pr otectio n, d urati o n of  im m u ne res p o nses, a n d c orrelat i ons bet wee n 
p har mac o d y na mics a n d A D A i m m u n o ge nicit y. Details f or sa mple c ollect i on, pr ocessi n g, a n d 
testi n g will be pr o vi de d i n t he La b orat or y Ma n ual.
A n y res ults fr o m s uc h a nal yses ma y be re p orte d se paratel y fr om t he s u b-st u d y C S R.
8. 6. 1. 1
Vir ol o gic Assess me nts
P arti cipa nts w h o ha ve n ot recei ve d a ne gat i ve S A R S-C o V -2 RT -P C R test res ult ≤3 da y s 
bef ore st u d y  e ntr y will re q uire a ne gati ve res ult fr o m a S A R S-C o V -2 r a pi d a nt i ge n test o n 
S S -D 1 t o be i ncl u de d i nt o t he s u b -st u d y. 
Nas o p har y n geal s wa bs will als o be assesse d b y a ut h orize d R T -P C R assa ys f or t he detecti o n of 
S A R S -C o V -2 b y  t he ce ntral la b orat ories acc or di n g t o t he ti me p o i nts s pecifie d i n t he S o A 
( Sectio n 1. 3 ). I nstr ucti o ns f or o btai ni n g a n d pr ocessi n g N P s wa b sa m ples are pr o vi de d i n t he 
La b orat or y  Ma n ual. T he f ull-le n gt h S ge ne ( A A 1-1 2 7 4) fr o m S A R S -C o V - 2-p osi tive nasal 
sa m ples ma y be a m plifie d usi n g a sta n dar d, si n gle t u be p o p ulati o n -base d RT -P C R m et h o d a n d 
se q ue nce d b y ne xt -ge nerat i on se q ue nci n g ( N G S) at I L -D 1, I L -D 1 4, I L -D 2 1, a n d I L -D 2 8. 
A mi n o aci d variat i on acr oss t he f ull -le n gt h S pr otei n se q ue nce ma y be deter mi ne d a n d 
re p orte d se paratel y fr o m t he C S R. A mi n o aci d c ha n ges i de nt ifie d b y ge n ot ypic a nal yses of t he 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
S tri mer pr otei n ect o d o mai n ( A A  2 0-1 2 1 3) ca n be e val uate d b y eit her a s pi ke tri mer bi n di n g 
affi nity assa y a n d/ or a rec o m bi na nt S A R S -C o V -2 S pi ke- pse u d o vir us ne utralizati o n assa y. 
A d dit i onal details o n cli nical vir o l og y  a nal yses, i nclu di n g m ol ec ular s ur veilla nce of t he S 
pr otei n i n gl o bal circ ulat i on will be pr o vi de d i n t he V irol o g y  A nal ysis Pla n.
L ocal  a n d ce ntral assess me nts s h o ul d be c ollecte d per t he sc he d ule of act i vities; w here b ot h 
l ocal a n d ce ntral assess me nts are liste d b ot h are re q uire d a n d s h o ul d be c ollecte d. 
A d dit i onall y, a vali date d mul tiple xe d res pi r at or y pa nel ma y be utilize d t o assess f or t he 
prese nce of ot her res pirat or y  pat h o ge ns i n N P s wa bs i n a ce ntral la b orat or y o perate d o n be half 
of  t he S p o ns or at I L-D 1.
 
 
 
 
 
 
 
 
 
 
8. 7
O pti o n al Ge n o mics I niti ati ve S a m ple
Ge n o mics sa m pli n g is n ot a p plica ble i n t his s u b -st u d y. 
8. 8
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 mic s are n ot a p plica ble i n t his s u b-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 bjecti ve of t his s u b-st u d y is t o assess t he safet y a n d t olera bility of  re peat d oses 
of  AZ D 7 4 4 2 3 0 0 m g a n d 6 0 0 m g I M. N o h y p ot heses will be teste d.
9. 2
S a m ple Size Deter mi n ati o n
A p pr o xi matel y  5 0 0 partici pa nts will be e nr olle d i n t he s u b-st u d y t o recei ve re peat d oses of 
A Z D 7 4 4 2. If t he tr ue a d verse e ve nt rate is 1 %, t he pr o ba bilit y o f o bser vi n g at least o ne A E i n 
P P D
P P D
P P D
P P D

Cli nical S t u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
5 0 0 partici pa nts is > 9 9 %. T he i nci de nce of 1 % is t he lo wer li mi t of t he cate g or y of c o m m on 
A Es ( bet wee n i nfre q ue nt a n d fre q ue nt A Es) b y t he C o u ncil f or I nter nati o nal Or ga nizat i ons of 
Me dical Scie nces ( CI O M S) W or ki n g Gr o u p (CI O M S 1 9 9 9 ).
P arti cipa nts i n t he s u b -st u d y will recei ve d re peat d osi n g of A Z D 7 4 4 2 as o utli ne d i n Fi g ure 1 . 
G r o u p le v el recr uit me nt ca ps ma y be place d t o e ns ure at least 5 0 s u bjects c o m plete t he st u d y  
wi t h t h eir assig ne d d ose a n d vali d sa m ples f or a nal ysis. A st u d y sa m ple of 5 0 or m or e 
parti ci pa nts will ha ve greater t ha n a 9 0 % pr o ba bilit y t o esti mate a 9 5 % c o nfi de nce i nter val 
wi t hi n 6 0 % t o 1 4 0 % of t he ass u me d tr ue ge o metric mea n f or p har mac o ki netic para meters. 
T his calc ulat i on ass u mes a c o nser vati ve est i mate d sta n dar d de viati on of 2 5, tr ue ge o metric 
mea n of 2 0 a n d a half wi dt h c o nfi de nce i nter val o f 8. T he c urre nt n u m ber of partici pa nts i n 
t he s u b-st u d y ( 5 03 ) will pr o vi de a s ufficie nt sa m ple ass u mi n g partici pa nts are e ve nl y 
di stri b ute d acr oss t he 3 gr o u ps. T he a d dit i on of Gr o u p 3 will create 4 p ossi ble d osi n g c o h orts , 
base d o n t he h o w ma n y d oses of 3 0 0 m g A Z D 7 4 4 2 re cei ve d pri or t o e nteri n g Gr o u p 3 a n d 
w het her or n ot t his was f o ll owe d b y a f urt her t w o d oses of 6 0 0 m g A Z D 7 4 4 2 :
Gr o u p 1 

C o h ort 1: A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g
Gr o u p 2

C o h ort 2: Pl ace b o, A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g
Gr o u p 3

C o h ort 3 (fr o m Gr o u p 1): A Z D 7 4 4 2 3 0 0 m g, 3 0 0 m g, 6 0 0 m g, 6 0 0 m g

C o h ort 4 ( Fr o m Gr o u p 2): Place b o, A Z D 7 4 4 2 3 0 0 m g, 6 0 0 m g, 6 0 0 m g
9. 3
P o p ul ati o ns f or A n al yses
T he f o ll owi n g p o p ul at i ons are defi ne d i n  Ta ble 1 4.
Ta ble 1 4
P o p ul ati o ns f or  An al ysis
P o p ul ati o n/ A n al ysis set
Descri pti o n
Safet y a nal ysis set
T he safet y a nal ysis set c o nsists of all partici pa nts w h o ha ve recei ve d at least
o ne d ose of I M P i n t he s u b -st u d y.
Safet y pre -e x p os ure a nal ysis 
set
T he safet y pre -e x p os ure a nal ysis set will i ncl u de all partici pa nts i n t he 
safet y a nal ysis set w h o were n ot S A R S-C o V -2 R T -P C R -p ositi ve at baseli ne 
i n t he pare nt st u d y.
P har mac o ki neti c a nal ysis set
All partici pa nts i n t he safet y a nal ysis set w h o recei ve d A Z D 7 4 4 2 a n d fr o m 
w h o m P K bl o o d sa m ples are ass u me d n ot t o be affecte d b y fact ors s uc h as 
pr ot oc ol vi olati o ns a n d w h o ha d at least o ne q ua ntifia ble ser u m P K 
o bser vati o n p ost d ose will b e i ncl u de d i n t he P K a nal ysis dataset.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
I M P, i n vesti gati o nal me dici nal pr o d uct; P K, p har mac o ki netic; R T-P C R, re verse tra nscri ptase p ol y merase c hai n 
reacti o 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.
9. 4
St atistic al A n al yses
All res ults will be s u m marize d wit h descri pt i ve st atistics b y c o h ort. Cate g orical varia bles will 
be s u m marize d usi n g fre q ue nc y a n d perce nta ges, w here t he de n o mi nat or f or calc ulati o n is t he 
u n derl yi n g a nal ysis set p o p ulat i on, u nless ot her wise state d. C o nti n u o us vari a bles will be 
s u m marize d with descri pti ve statist ics of n u m ber of a vaila ble o bser vati o ns, mea n, sta n dar d 
de viat i on, m e dia n, mi ni m u m a n d ma xi m u m, a n d q uartiles w here m ore a p pr o priate.
9. 4. 1
S afet y: Pri m ar y E n d p oi nt
9. 4. 1. 1
Pri m ar y E n d p oi nt(s)
T he safet y of  A Z D 7 4 4 2 will pri maril y be assesse d b y:

I nci de nce of A Es

I nci de nce of S A Es

I nci de nce of M A A Es

I nci de nce of A E SIs
T he A E se verit y will be gra de d acc or di n g t o  A p pe n di x B a n d c o de d usi n g t he m ost rece nt 
versi o n of t he Me dical Dict i onar y  for Re g ul at or y Acti vities. A d verse e ve nts will be prese nte d 
f or eac h d osi n g i nter val gr o u p b y s yste m or ga n class a n d preferre d ter m. S u m maries will 
i ncl u de t he n u m ber a nd perce nta ge of partici pa nts re p orti n g at least o ne e ve nt, n u m ber of 
e ve nts, a n d e x p os ure a dj uste d rates, w here a p pr o priate.
A n o ver vie w of A Es will be prese nte d f or eac h gr o u p, i ncl u di n g t he n u m ber a n d perce nta ge of 
parti ci pa nts wit h a n y A E a n d S A Es. S u m maries will prese nt t he relatio ns hi p t o I M P as 
assesse d b y t he I n vesti gat or, ma xi m u m int e nsit y, s erio us ness, a n d deat h.
A listi n g will c o ver details f or eac h i n di vi d ual A E.
9. 4. 1. 2
Ot her S afet y E n d p oi nt(s)

La b orat or y  para meters ( he mat olo g y , cli nical c he mistr y, c oa gulat i on, uri nal ysis, a n d 
car diac bio m ar kers)

1 2- lea d safety E C G

Vi t al si g ns ( bl o o d press ure, p ulse rate, oral te m perat ure, a n d res pirat or y rate)

P h ysical e xa mi nat i on

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
La b orat or y  assess me nts will be perf or me d f or he mat ol o g y, cli nical c he mistr y, c oa g ulatio n,
uri nal ysis, a n d car diac bi o mar kers para meters. La b orat or y para meters will be gra de d usi n g t he 
m o st rece nt versi o n of t he C T C A E. 
A d dit i onall y, per t he S o A ( Sectio n  1. 3 ), all partici pa nts will be e val uate d via E C G, vital si g ns, 
a n d a tar gete d p h ysical e xa mi nati on. All para meters fr o m la b orat or y , E C G, vit al sig ns, a n d 
p h ysical e xa mi nat i on assess me nts will be s u m marize d wit h descri pti ve statist ics base d o n data 
t ype (c o nti n u o us, cate g orical, etc). N o h y p ot hesis testi n g or CIs will be perf or me d or 
calc ulate d, u nless ot her wise s pecifie d. 
9. 4. 2
Sec o n d ar y E n d p oi nts
9. 4. 2. 1
P h ar m ac o ki netic
I n di vi d ual A Z D 7 4 4 2 ( A Z D 8 8 9 5 a n d A Z D 1 0 6 1) ser u m  c o nce ntratio n data will be liste d a n d 
ta b ulate d, alo n g wi t h descri pti ve statistics. P har mac o ki netic para meters (e g, A U C, t 1/ 2) ma y be 
esti mate d usi n g n o n- c o m part me ntal a nal ysis if data per mit. P ote ntial c orrelat i on bet wee n P K 
e x p os ure a n d efficac y/safet y res p o nse ma y be e x pl ore d. T he ser u m AZ D 8 8 9 5 a n d A Z D 1 0 1 6 
c o nce ntrati o n data will be a nal yze d usi n g a p o p ulati o n P K a nal ysis a p pr oac h t o c haracterize 
t he P K f or t he differe nt d osi n g i nter vals a n d will be re p orte d i n a se parate re p ort.
9. 4. 2. 2
A nti dr u g A nti b o dies
T he i nci de nce of A D A  t o A Z D 7 4 4 2 will be assesse d a n d s u m marize d b y n u m ber a n d 
perce nta ge of partici pa nts w h o are A D A  p ositi ve b y d osi n g i nter val gr o u p. T he A D A  titer will 
be liste d b y partici pa nt at differe nt ti me p oi nts. T he i m pact of A D A o n P K, p har mac o dy na mic, 
efficac y, a n d ass ociat i on wi t h A Es a n d S A Es, will be assesse d. 
P arti cipa nts w h o recei ve a n a differe nt C O VI D m o n ocl o nal a nt i b o d y t ha n A Z D 7 4 4 2, 3 0 da ys 
pri or t o e nteri n g t he s u b -st u d y will be e xcl u de d fr o m t his a nal ysis set. I n a d dit i on, sa m ples 
c ollecte d after a partici pa nt recei ves a n ot her C O VI D m o n ocl o nal a nt i b o d y ma y be e xcl u de d.
9. 4. 2. 3
Ne utr alizi n g A nti b o dies
Descri pt i ve statistics f or G M Ts a n d G M F R will  in cl u de n u m ber of parti ci pa nts, ge o metric 
mea n, G S D, 9 5 % CI, mi ni m u m, a n d ma xi m u m. 
T he G M T will be calc ulate d as t he a nt il og ari t h m of Σ( l og 2 tra nsf or me d titer/ n), ie, as t he 
a nt il og ari t h m tra nsf or mat i on of t he mea n of t he l o g -tra nsf or me d titer, w here n is t he n u m ber 
of  p artici pa nts wit h titer i nf or mat i on. T he G S D f or G M T will be calc ulate d as t he 
a nt il og ari t h m tra nsf or mat i on of t he sta n dar d de viati o n of t he l o g -tra nsf or me d titer. T he 9 5 % 
CI will be calc ulate d as t he a nti l og ari t hm tra nsf or mati on of t h e u p per a n d l o wer li mits f or a 
t wo -si de d CI f or t he mea n of t he l o g-tra nsf or me d titers.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
m o nit or f or e vi de nce of har m res ult i n g fr om A Z D 7 4 4 2. If re q uire d, t he D S M B will 
rec o m me n d te m p oraril y st o p pin g or ter mi nat i on of t he s u b -st u d y.
F or details o n t he D S M B, refer t o A p pe n di x  A 5 . F urt her details, c o m p ositi on, a n d o perati o n 
of  t he i n de pe n de nt D S M B will be descri be d i n a D S M B C harter.
9. 7
A dj u dic ati o n C o m mittees
9. 7. 1
M or bi dit y A dj u dic ati o n C o m mittee
A n i n de pe n de nt M or bi dity A d j u dicati on C o m mit tee will pr o vi de a n i n de pe n de nt, e xter nal, 
s yste mat ic, a n d u n biase d assess me nt of bli n de d data t o e val uate w het her t he ca uses of deat h 
f or p articipa nts are c o nsi dere d C O VI D -1 9 ass oci ate d. All fatal e ve nts will be f urt her assesse d 
as part of safet y e val uat i on. F urt her details o f t his a dju dicat i on will be pr o vi de d i n a se parate 
M or bi di t y A dj u dicati on C o m mittee C harter .
9. 7. 2
C ar di o v asc ul ar E ve nt A d j u dic ati o n C o m mittee
A n i n de pe n de nt Car dio vasc ular E ve nt A d j u dicati on C o m mit tee will pr o vi de a n i n de pe n de nt, 
e xter nal, s yste mat ic, a n d u n biase d assess me nt of de-i de ntifie d data t o s yst e mat icall y e val uate 
car dio vasc ular e ve nts. T he a dj u dicate d car di o vasc ular e ve nts will be i ncl u de d i n descr i pti ve 
a nal yses o f safety data. F urt her details of t he Car di o vasc ular E ve nt A d j u dicati o n C om mittee 
c o mp osi tio n, o perati o n, a n d list i n gs of preferre d ter ms t o i de ntif y e ve nts are pr o vi de d i n a 
se parate Car di o vasc ular E ve nt A d j u dicati on C o m mittee C harter .
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

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

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6

A n I n vest i gat or w h o recei ves a n I n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safety i nf or mati on (e g, s u m mar y or list i n g of S A Es) fr om t he S p o ns or will 
re vie w a n d t he n file it al o n g with t he I n ves tigat or’s Br oc h ure a n d will n otif y  t he I R B/I E C, 
if a p pr o priate acc or di n g t o l ocal re q uire me nts.
A 2
Fi n a nci al Discl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on, as re q ueste d, t o all o w t he S p o ns or t o s u b mit c o m p lete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or o ne 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 t he s u b -st u d y t o t he 
parti ci pa nt or his/ her 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 a nd a ns wer all  q u estio ns re gar di n g t he s u b -st u d y.

P arti cipa nts m ust be i nf or m e d t hat t heir partici pat i o n is v ol unt ar y, a n d t he y ar e free t o 
ref use t o partici pate a n d ma y with dra w t heir c o nse nt at a n y  ti me a n d f or a n y reas o n 
d uri n g t he st u d y . Participa nts or t heir 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 will  be re q uire d t o sig n a state m e nt of i nf or me d c o nse nt 
t hat meets t he re q uire me nts of 2 1 C F R 5 0, l o c al  r e g ulat i ons, I C H g ui deli nes, Healt h 
I ns ura nce P orta bility a n d Acc o u nta bilit y Act ( HI P A A) re q uire me nts, w here a p plica ble, 
a n d t he I R B/I E C or st u d y ce nter.

T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he s u b- st u d y a nd t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf o r me d c o nse nt m ust als o si g n t he I C F.

P arti cipa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
parti ci pat i on i n t he s u b-st u d y.

A c o p y  of t he I C F(s) must be pr o vi de d t o t he partici pa nt or t he parti ci 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 C F will c o ntai n a se parate secti o n t hat a d dresses a n d d oc u me nts t he c ollect i on a n d use of 
a n y ma n dat or y a n d/ or o ptio nal h u ma n bi o l ogical  s a mples. T he I n vest i gat or or a ut h orize d 
desi g nee will e x plai n t o eac h partici pa nt t he o bjecti ves of t he a nal ysis t o be d o ne o n t he 
sa m ples a n d a n y p ote ntial f ut ure use.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
P arti cipa nts will be t ol d t hat t he y  ar e free t o ref use t o partici pate i n a ny o pti o nal sa m ples or 
t he f ut ure use a n d ma y wit h dra w t heir c o nse nt at a n y t i me a n d f or a n y reas o n d uri n g t he 
rete ntio n peri o d.
A 4
D at a Pr otecti o n
P arti cipa nts will be assi g ne d a u ni q ue i de nt ifier b y t he S p o ns or. A n y partici pa nt rec or ds or 
datasets t hat are t ra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; partici pa nt na mes 
or a n y  inf or mat i on t hat w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d.

T he parti ci pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y-r elate d data will be use d b y
t he S p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl o s ure a n d use 
of  t h eir data must al s o be e x plai ne d t o t he partici pa nt i n t he i nf or me d c o nse nt. 

T he parti ci pa nt m ust be i nf or me d t hat his/ h er me dical rec or ds ma y be e xa mi ne d b y 
Cl i nical Q uality Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p o i nte d b y t he 
S p o ns or, b y  a p pr o priate I R B/I E C me m bers, a n d b y ins pect ors fr o m  re g ulat or y a ut h orities.
A 5
C o m mittees Str uct ure
T he safet y of  all S p o ns or cli nical st u dies is cl osel y m o nit ore d on a n o n g o i n g basis b y S p o ns or 
re prese ntati ves i n c o ns ultati on wi t h P atie nt Safet y.  Iss ues i de ntifie d will be a d dresse d; f or 
i nsta nce, t his c o ul d i n v ol ve a me n d me nts t o t he C S P a n d letters t o I n vesti gat ors.
D at a a n d S afet y M o nit ori n g B o ar d ( D S M B)
T he sa me e x ter nal D S M B fr o m t he P R O V E N T pare nt st u d y will mo ni t or a n d pr otect t he 
safety of  t he partici pa nts t hr o u g h o ut t he s u b-st u d y. T he D S M B me m bers were selecte d f or 
t heir e x pertise. T he v oti n g me m bers o f t he D S M B are e xter nal t o Astra Ze neca, i ncl u di n g t he 
D S M B c h ai r. S u m maries of data will be pre pare d a n d pr o vi de d t o t he D S M B. To mi ni mize t he 
p ote nti al int r o d u cti o n of bias, D S M B me m bers will not ha ve di rect c o ntact wit h t he st u d y sit e 
pers o n nel or partici pa nts . T he data f or re vie w will be o utli ne d i n t he D S M B C harter a n d will 
be a gree d t o i n a d va nce b y t he D S M B me m bers. T he first Data Re vie w Meeti n g will occ ur i n 
c o nju nct i on wi t h t he i nteri m a nal ysis. S u bse q ue nt Data Re vie w Meet i n gs will be hel d i n li ne 
wi t h t he D S M B C harter . A d h oc meet i n gs will be i m ple me nte d if re q uire d. T he D S M B will 
re vie w safety data o n a re g ular basis as set o ut i n t he D S M B C harter . Partici pa nt e nr oll me nt 
ca n c o nt i n ue d uri n g D S M B re vie w of safety data. T he a vaila ble safet y data f or t he partici pa nts
will be e val uate d b y t he D S M B. Safet y  s u m maries will be pre pare d pri or t o eac h Data Re vie w 
Meet i n g. D uri n g t he st u d y, t he be nefit/ris k assess me nt will be c o nti n u o usl y mo ni t or e d b y t he 
D S M B t o e ns ure t hat t he bala nce re mai ns fa v ora ble. 
T he D S M B ca n rec o m me n d m o dificat i ons of t he s u b -st u d y pr ot oc ol t o e n ha nce parti ci pa nt 
safety a n d t o rec o m me n d te m p oraril y st o p pi n g t he st u d y or earl y ter mi nati on of t he st u d y  if 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
t here is str o n g e vi de nce t hat A Z D 7 4 4 2 or c o nti n uati o n of t he st u d y p oses a safet y c o ncer n t o 
parti ci pa nts.
T he i n de pe n de nt D S M B m o nit ori n g t he P R O V E N T pare nt st u d y will pr o vi de o versi g ht, t o 
e ns ure safe a n d et hical c o n d uct of t he s u b-st u d y. 
T he D S M B will ma ke a n y  necessar y rec o m me n datio n s t o t he S p o ns or base d o n t heir 
e val uat i ons of e mer gi n g data. T he first Da ta Re vie w Meeti n g will occ ur i n c o nj u ncti on wi t h 
t he first i nteri m a nal ysis as s pecifie d i n Secti o n 9. 5 . S u bse q ue nt Data Re vie w Meeti n gs will 
be hel d i n li ne with t he D S M B C harter . T he D S M B will als o re vie w s u b-st u d y pr o gress a n d 
m o nit or f or e vi de nce of har m res ult i n g fr om A Z D 7 4 4 2. If re q uire d, t he D S M B will 
rec o m me n d te m p oraril y st o p pin g or ter mi nat i on of t he s u b -st u d y.
F or details o n t he D S M B, refer t o A p pe n di x  A 5 . F urt her details, c o m p ositi on, a n d o perati o n 
of  t he i n de pe n de nt D S M B will be descri be d i n a D S M B C harter.
M or bi dit y A dj u dic ati o n C o m mi ttee
See Secti o n  9. 7. 1
C ar di o v asc ul ar E ve nt A dj u dic ati o n C o m mittee
See Secti o n  9. 7. 2 .
A 6
Disse mi n ati o n of Cli nic al St u d y D at a
A descri pt i on of t his cli nical st u d y  will be a vaila ble o n 
ht t p://astraze neca gr o u ptrials. p har mac m.c o m a n d htt p:// w w w.cli nicaltrials. g o v as will t he 
s u m mary of t he st u d y  res ults w he n t he y are a vaila ble. T he cli nical st u d y a n d/ or s u m mar y of 
st u d y res ults m a 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 o ns of t he 
c o u ntries i n w hic h t he st u d y is c o n d ucte d.
A 7
D at a Q u alit y Ass ur a nce

All partici pa nt data relat i n g t o t he st u d y will be rec or de d i n t he e C R F, u nless tra ns mitte d 
t o t he S p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he I n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y electr o nicall y 
sig ni n g t he e C R F.

T he I n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he e C R F.

T he I n vesti gat or m ust per mit st u d y -r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pectio ns, a n d pr o vi de di rect access t o s o urce data d oc u me nts.

M o ni t ori n g details descri bi n g strate g y (e g, ris k-base d i nit iati ves i n o perati o ns a n d q uality,  
s uc h as Ris k Ma na ge me nt a n d Miti gati on Strate gies a n d A nal yt ical Ris k -Base d 

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M o ni t ori n g), met h o ds, res p o nsi bilit ies a n d re qui re me nts, i ncl u di n g ha n dli n g of 
n o nc o m p lia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n-sit e mo ni t orin g) 
are pr o vi de d i n t he rele va nt st u d y pla ns.

T he S p o ns or or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his s u b -st u d y 
i ncl u di n g, qualit 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 R Os).

St u d y  mo ni t ors will perf or m o n g oi n g s o urce data re vie w 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 orize d site pers o n nel are acc urate, a n d c o mplete; 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 s u b -st u d y is bei n g c o n d ucte d i n 
acc or da nce wit h t he c urre nt l y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y a gree me nts, I C H 
G C P, a n d all a p plica ble re g ulat or y  re q uire me nts. 

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his 
s u b-st u d y must be retai ne d b y  t he I n vesti gat or f or 1 5 years after st u d y c o mplet i on, u nless 
l ocal re g ulatio ns or i nst itut i onal p o licies re q uire a l o n ger rete nti o n peri o d. N o rec or ds 
ma y be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he S p o ns or. 
N o rec or ds ma y be t ra nsferre d t o a n ot her l ocati o n or part y wit ho ut wri tte n n otificati on t o 
t he S p o ns or.
A 8
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate 
t he i nte grit y of  t he data c ollecte d. S o urce d oc u me nts are file d at t he I n vesti gat or’s site.

Data e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts m ust be c o nsiste nt 
wi t h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he I n vesti gat or ma y 
nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer re c o r ds, de pe n di n g o n t he st u d y. 
Als o, c urre nt me dical rec or ds m ust be a vaila ble.

Defi nit i on o f w hat c o nstit utes s o urce data ca n be f o u n d i n t he st u d y  mo ni t ori n g pla n. 
A 9
St u d y a n d Site St art a n d Cl os ure
T he first act of recr uit me nt is t he first partici pa nt s cree ne d i n t he P R O V E N T pare nt st u d y 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 time f or a n y reas o n at t he s ole discreti on of t he S p o ns or . St u d y sites 
will be cl ose d u p o n s t u d y c o mpleti o n. A st u d y site is c o nsi dere d close d w he n all re q uire d 
d oc u m e nts a n d st u d y s u p plies ha ve bee n c ollecte d a n d a st u d y sit e clos ure visit has bee n 
perf or m e d.

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T he I n vesti gat or ma y  ini tiate st u d y sit e clos ure at a n y  time, pr o vi de d t here i s reas o nable ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.
Reas o ns f or t he earl y cl os ure of a st u d y  site b y t he S p o ns or or I n vesti gat or ma y i ncl u de, b ut 
are n ot li mit e d t o:

Fail ure of t he I n vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes

I na de q uate recr uitme nt  of p artici pa nts b y t he I n vestigat or

Di sc o nti n uatio n of  furt her I M P de vel o p me nt
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or s hall pr o m pt l y i nf or m t he 
I n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y C R O(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  
re q uire me nts. T he I n vesti gat or s hall pro m pt l y i nf or m t he partici pa nt a n d s h o uld ass ure 
a p pr o priate partici pa nt t hera p y a n d/ or f ollo w - u p.
P arti cipa nts fr o m  ter mi nate d sites will ha ve t he o p p ort u nit y t o be tra nsferre d t o a n ot her site t o 
c o nti n ue t he st u d y.
A 1 0
P u blic ati o n P olic y

T he res ults of t his s u b -st u d y ma y be p u blis he d or prese nte d at scie nt ific meeti n gs. If t his 
is f oresee n, t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or 
bef ore s u b missi o n. T his all o ws t he S p o ns or t o pr otect pr o prietar y  inf or mati o n a n d t o 
pr o vi de c o m me nts.

T he S p o ns or will c o m p l y wit h t he re q uire me nts f or p u blicati on of st u d y  res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort 
p u blicat i on of m ult i-ce nter st u dies o nl y in t hei r e ntiret y a n d n ot as i ndi vi d ual si te data. I n 
t his case, a c o or di nat i n g I n vesti gat or will be desi g nate d b y m ut ual a gree me nt.

A ut h ors hi p will be deter mi ne d b y  mut u al  a gree me nt a n d i n li ne with I nter nat i onal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.

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A p pe n di x B
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
B 1
Defi niti o n of A d verse E ve nts
A n A E is t he de vel o p me nt of a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y 
parti ci pa nt a d mi nistere d a n I M P a n d w hic h d oes n o t necessaril y ha ve a ca usal relati ons hi p 
wi t h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora 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 (e g, na usea, c hest pai n), or disease te m p orall y 
ass ociat e d wit h t he use of a n I M P, w het her or n ot c o nsi dere d relate d t o t he I M P. 
T he ter m  A E is use d t o i ncl u de b ot h seri o us a n d n o n-serio us A Es a n d ca n i ncl u de a 
deteri or ati o n of  a pre-e xist i n g me d ical occ urre nce. A n A E ma y occ ur at a n y  ti me, i ncl u di n g 
r u n-i n or was h o ut peri o ds, e ve n if n o I M P 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 i s a n A E occ urri n g d uri n g a n y st u d y p hase (ie, r u n-i n, treat me nt, was h o ut, f oll ow- u p), 
t hat f ulfills o ne or m ore of t he f o ll owi n g criteria:

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 pa nt h os pi talizatio n or pr ol o n g ati o n of  e xisti n g h os pitalizati on 

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca paci t y 

Is a c o n ge nital a b n or mality or bi rt h defect

Is a n i m p orta nt me dical e ve nt t hat ma y je o par dize t he partici pa nt or ma y re q uire me dical 
treat me nt t o pre ve nt o ne of t he o utc o mes liste d a b o ve
A d verse e ve nts f or m ali g n a nt t u m ors re p orte d d uri n g a st u d y s h o uld ge nerall y be assesse d as 
S A Es . If n o ot her seri o us ness criteria a p pl y, t he ‘I m p orta nt Me dical E ve nt’ crit erio n s h o ul d be 
use d. I n certai n sit uati o ns, h o we ver, me dical j u d g 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 or e ve nt s h o ul d be assesse d a n d re p orte d as a n o n -
seri o us A E . F or e xa mple, if t he t u m or i s i ncl u de d as me dical hist or y  a n d pr o gressi o n occ urs 
d uri n g t he st u d y, b ut t he pr o gressi o n d oes n ot c ha n ge treat me nt a n d/ or pr o g n osis of t he 
mali g na nt t u m or, t he A E m a y not f ulfill  t he attri b utes f or bei n g assesse d as seri o us, alt h o u g h 
re p orti n g of t he pr o gressi o n of t he malig na nt t u m or as a n A E is vali d a n d s h o ul d occ ur . Als o, 
s o me t yp es of  mali g na nt t u mors, w hic h d o n ot s prea d re m otel y after a r o uti ne treat me nt t hat 
d oes n ot re q uire h os pitalizat i on, m a y be assesse d as n o n-serio us; e xa m ples i n a d ult s i ncl u de 
Sta ge 1 basal cel l carci n oma a n d Sta ge 1 A 1 cer vical ca ncer re m o ve d via c o ne bi o ps y .

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Life -t hre ate ni n g
‘Life -t hreate ni n g’ mea ns t hat t he partici pa nt was at i m me diate ris k of deat h fr o m t he A E as i t 
occ urre d or it is s us pecte d t hat use or c o nti n ue d use of t he I M P w o ul d res ult i n t he 
parti ci pa nt ’s deat h. ‘Life -t hreate ni n g’ d oes n ot m ea n t hat, ha d a n A E occ urre d i n a m ore 
se vere f or m, it mi g ht ha ve ca use d deat h (e g, he patitis t hat res ol ve d wit h o ut he 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 n S A E, alt h o u g h t he reas o ns f or it 
ma y be (e g, br o nc h os pas m, lar y n geal e de ma). H os pital a d missi o ns a n d/ or s ur gical o perati o ns 
pl a n ne d bef ore or d uri n g a st u d y are n ot c o nsidere d A Es if t he ill ness or disease e xiste d bef ore 
t he partici pa nt was enr o lle d i n t he st u d y, pr o vide d t hat i t did n ot deteri orate i n a n u ne x pecte d 
w a 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 g me nt s h o ul d be e xercise d i n deci di n g w het her a case is seri o us i n 
sit u atio ns w here i m p orta nt m e dical e ve nts ma y not be i m me diatel y life- t hreate ni n g or res ult i n 
deat h, h os pi talizati on, disa bilit y or i nca paci t y but ma y je o par dize t he parti cipa nt or m a y 
re q uir e me dical treat me nt t o pre ve nt o ne or m ore o utc o mes liste d i n t he defi nit i on of seri o us. 
T hese s h o ul d us uall y be c o nsi dere d as seri o us.
Si m pl y st o p pi n g t he s us pect dr u g d oes n ot mea n t hat it is a n i m p orta nt me dical e ve nt; me dical 
j u d g me nt m ust be use d.

A n gi oe de ma n ot se vere e n o u g h t o re q uire i nt u bati o n b ut re q uiri n g I V h y dr oc ortis o ne 
tr e at me nt

He pat ot o xicit y ca use d b y paraceta m o l (aceta mi n o p he n) o ver d ose re q uiri n g treat me nt wit h 
N- acet ylc ystei ne

I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m

Bl o o d d y scrasias (e g, ne utr o pe nia or a ne mia re q uiri n g bl o o d tra nsf usi on, etc) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizat i on

De vel o p me nt of dr u g de pe n de nc y or dr u g a b use
Se verit y R ati n g Sc ale ( A d a pte d fr o m C T C A E v 5. 0):

Gra de 1 : A n e ve nt of mil d i nte nsity t hat is us uall y tra nsie nt a n d ma y re q uire o nl y cli nical 
or di ag n ostic o bser vati o ns. T he e ve nt d oes n ot ge nerall y  int erfere wit h us ual a cti vities of 
dail y  li vi n g.

Gra de 2 : A n e ve nt of m o derate i nte nsity t hat i s us uall y alle viate d wit h a d ditio n al , s pecific 
t hera pe utic i nter ve nt i on w hic h is mi ni mal, l ocal or n o n -i n vasi ve. T he e ve nt i nterferes 

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wi t h us ual a cti vities of dail y li vi n g, ca usi n g disc o mf ort b ut p oses n o si g nifica nt or 
p er m a ne nt ris 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 on b ut i s 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 partici pa 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 o n is i n dicate d.

Gra de 5 : Deat h, as res ult of a n e ve nt
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d se vere A Es. Se verity is a meas ure of 
i nte nsit y, w hereas serio us ness is defi ne d b y  t he crit eria i n A p pe n di x B 2 . A n A E of se vere 
i nte nsit y nee d n ot necessaril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or 
se veral h o urs ma y be c o nsidere d se vere na usea, b ut n ot a n S A E u nless it meets t he criteria 
s h o w n i n A p pe n di x B 2 . O n t he ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of 
di sa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a n S A E w he n it satisfies t he criteria 
s h ow n i n A p pe n di x  B 2.
B 3
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n
W he n ma ki n g a n assess me nt of ca usalit y,  c o nsi der t he f oll o wi 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 ma y ha ve bee n ca use d b y t he dr u g.

Ti me C o urse. E x p os ure t o s us pect dr u g. Has t he partici pa nt act uall y recei ve d t he s us pect 
dr u g? Di d t he A E occ ur i n a reas o na ble te m p oral relat i ons hi p t o t he a d mi nistrat i on of t he 
s us pect dr u g?

C o nsiste nc y wit h k n o w n dr u g pr ofile. Was t he A E c o nsiste nt wit h t he pre vi o us 
k n o wl e d ge of t he s us pect dr u g ( p har mac o l og y  a n d t o xic o l og y ) or dr u gs of t he sa me 
p har mac o l ogi cal class? Or c o ul d t he A E be a nt ici pate d fr o m its p har mac ol ogi cal 
pr o perties?

De -c halle n ge e x perie nce. Di d t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he d ose 
of  t he s us pect dr u g?

N o al ter nati ve ca use. T he A E ca n n ot be reas o na bl y e x plai ne d b y a n ot her eti ol og y , s uc h as 
t he u n derl yi n g disease, ot her dr u gs, ot h er h ost, or e n vir o n me ntal fact ors.

Re -c halle n ge e x perie n c e. Did t he A E re occ ur if t he s us pecte d dr u g was rei ntr o d uce d after 
ha vi n g bee n st o p pe d? Astra Ze neca w o ul d n ot n or mall y rec o m me n d or s u p p ort a 
r e-c halle n ge.

La b orat or y  tests. A s pecific la b orat or y in v est i gati on (if perf or me d) has c o nfir me d t he 
r elat i ons hi p .

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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 nize d feat ure of o ver d ose of t he dr u g?

Is t here a k n o w n mec ha nis m?
Ca usalit y of  ‘relate d’ is ma d e if, f o ll owi 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 bilit y’ of  a ca usal relati ons hi p f or t he i n di vi d ual case. T he e x pressi on 
‘reas o na ble p ossi bility ’ of  a ca usal r el atio ns hi p is mea nt t o c o n ve y, i n ge neral, t hat t here are 
facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati ons hi p.
T he ca usalit y assess me nt is perf or me d base d o n t he a vaila ble data, i ncl u di n g e n o u g h 
i nf or mat i on t o m a ke a n i nf or me d j u d g me nt. With li mite d or n o a vaila ble facts or ar g u me nts t o 
s u g gest a ca usal relati ons hi p, t he e ve nt(s) will be assesse d as ‘n ot rel ate d’.
Ca usal relat i ons hi p i n cases w here t he disease u n der st u d y  has deteriorate d d ue t o l ac k of 
effect s h o uld be classifie d as n o reas o na ble p ossi bilit y.
B 4
Me dic ati o n Err or
F or t he p ur p oses of t his cli nical st u d y , a me d icati 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 Astra Ze neca I 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. 
A me dicat i on err or is n ot lac k of efficac y of t he dr u g, b ut rat her a h u ma n or pr ocess -r elate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y 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 ci rc u msta nces were rec o g nize d t hat c o ul d ha ve le d t o a n err or
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors:

Dr u g na me c o nf usi o n

Di s pe nsi n g err or, e g, me dicati 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, e g, wr o n g r o ute or wr o n g site of a d mi nistrati o n

Dr u g n ot ta ke n as i n dicate d, e g, ta blet diss 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 h e frid ge w he n i t s h o uld be at r o o m  t e mperat ure 

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8 1 of 9 6

Wr o n g partici pa nt recei ve d t he me dicat i on (e xcl u di n g I R T/ R T S M err ors)

Wr o n g dr u g a d mi nistere d t o partici pa nt (e xcl u di n g I R T/ R T S M err ors)
E xa m ples of e ve nts t hat d o n ot re q uire re p orti n g as me dicati on err ors i n cli nical st u dies:

Err ors relate d t o or res ulti n g fr o m I R T/ R T S M - i ncl u di n g t h ose t hat le d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha ve bee n a me dicati o n err or 

P arti cip a nt a c ci de ntall y  misse d dr u g d ose(s), e g, f or g ot t o ta ke me dicati o n

Ac ci d e nt al o ver d ose ( will be ca pt ure d as a n o ver d ose)

P arti cip a nt f aile d t o ret ur n u n use d me dicat i on or e m pt y pac ka gi n g

Err ors relate d t o bac k gr o u n d a n d resc ue me dicat i on, or sta n dar d of care me dicat i on i n 
o pe n -label st u dies, e ve n if a n Astra Ze neca pr o d uct 
Me dicat i on err ors are n ot re gar de d as A Es, b ut A Es ma y occ ur as a c o nse q ue nce of t he 
me dicat i on err or.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
A p pe n di x C
H a n dli n g of H u m a n Bi ol o gic al S a m ples
C 1
C h ai n of C ust o d y
A f ull c hai n of c ust o d y is mai ntai ne d f or all sa m ples t hr o u g h o ut t heir lifec ycle.
T he I n vestigat or at eac h ce nter kee ps f ull tracea bilit y  of c ollecte d biol o gi cal sa mpl es f r o m t he 
parti ci pa nts w hile i n st ora ge at t he ce nter 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 hile at t he sit e.
T he sa m ple recei ver kee ps f ull tracea bilit y of  t he sa mples w hile i n st ora ge a n d d uri n g use u nt il 
use d or dis p ose d of or u ntil f urt her s hi p me nt, a n d kee ps rec or d of recei pt of arri val a n d 
o n war d s hi p me nt or dis p osal.
Astra Ze neca or dele gate d r e prese ntati ves will kee p o versi g ht of t he e nt ire life-c ycle t hr o u g h 
i nter nal pr oce d ures, mo ni t orin g of st u d y  sites, a u diti n g or pr ocess c hec ks, a n d c o ntract ual 
re q uire me nts of e xter nal la b orat or y pr o viders.
S a m ples retai ne d f or f urt her use will be st ore d i n t he Astra Ze neca -assi g ne d bio b a n ks or ot her 
sa m ple arc hi ve facilities a n d will be trac ke d b y t he a p pr o priate Astra Ze neca T ea m for t he 
r e mai n der of t he sa m ple lifec ycle.
If re q uire d, Astra Ze neca will e ns ure t hat re mai ni n g bi ol ogi c al s a mples are ret ur ne d t o t he sit e 
acc or di n g t o l ocal re g ulati o ns or at t he e n d of t he rete nti o n peri o d, w hic he ver is earlier.
C 2
Wit h dr a w al of I nf or me d C o nse nt f or D o n ate d Bi ol o gic al S a m ples 
Astra Ze neca e ns ures t hat bi o l ogi cal sa m ples are ret ur ne d t o t he s o urce or destr o ye d at t he e n d 
of  a s pecifie d peri o d, as descri be d i n t he i nf or me d c o nse nt.
If a partici pa nt wit h dra ws c o nse nt t o t he use of d o nate d bi ol ogical  sa m ples, t he sa mples will 
be dis p ose d of/ destr o y e d/re patriate d, a n d t he acti o n d oc u me nte d. If sa m ples are alrea d y  
a nal yze d, Astra Ze neca is n ot o bli ge d t o destr o y  t he res ults of t his researc h.
F o ll owi n g wi t hdra wal  of c o nse nt f or bi ol ogi c al sa m ples, f urt her st u d y particip ati o n s h o ul d be 
c o nsi dere d i n relat i on t o t he wi t hdra wal  pr ocesses o utli ne d i n t he i nf or me d c o nse nt.
T he I n vestig at or:

E ns ures partici pa nt’s wit h dra wal of i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
hi g hli g hte d i m me diatel y t o Astra Ze neca or dele gate.

E ns ures t hat rele va nt h u ma n bi o l ogical sa m ples fr o m  t hat partici pa nt, if st ore d at t he 
st u d y sit e, ar e im me diatel y i de nt ifie d, dis p ose d of as a p pr o priate, a n d t he acti o n 
d oc u m e nte d.

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

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
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 pr ocess t o be f o ll owe d i n or der t o i de nt if y a n d a p pr o priatel y 
re p ort P H L cases a n d H L cases. It is n ot i nte n de d t o be a c o m pre he nsi ve g ui de t o t he 
ma na ge me nt of ele vate d li ver bi oc he mistries. 
D uri n g t he c o urse of t he st u d y , t he I n vesti gat or will re mai n vi gila nt f or i ncreases i n li ver 
bi oc he mistr y. T he I n vesti gat or is res p o nsi ble f or deter mi ni n g w het her a partici pa nt meets P H L 
criteria at a n y p oi nt d uri n g t he st u d y.
All s o urces of la b orat or y data are a p pr o priate f or t he deter mi na tio n of  P H L a n d H L  e ve nts; 
t his i ncl u des sa m ples ta ke n at sc he d ule d st u d y visits a n d ot her visits, i ncl u di n g ce ntral a n d all 
l ocal la b orat or y e val uati ons e ve n if c o llecte d o utsi de of t he st u d y visits; e g, P H L crit eria c o uld 
be met b y a n ele vate d A L T fr o m a ce ntral la b orat or y a n d/ or ele vate d T B L fr o m a lo c al  
la b orat or y. 
T he I n vesti gat or will als o re vie w A E data (e g, 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 wit h Astra Ze neca c li nical pr oject re prese ntati ves, i n 
re vie w a n d assess me nt of cases meeti n g P H L crit eria t o a gree w het her H L criteria are 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 vati ons i n li ver bi oc he mistr y  
ot her t ha n DI LI ca use d b y  t he I M P. 
T he I n 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 me of t he re vie w a n d assess me nt i n li ne wit h 
sta n dar d safety re p orti n g pr ocesses.
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 A L P.
H y’s L a w
A S T or A L T ≥3 × U L N t o get her wit h T B L  ≥2 × U L N, w here n o ot her reas o n, ot her t ha n t he 
I M P, ca n be f ou n d t o e x plai n t he c o m bi nat i on of i ncreases, 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. 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
F or P H L  a n d H L , t he ele vat i on i n tra nsa mi nases m ust prece de or be c oi nci de nt wit h (ie, o n t he 
sa me da y) t he ele v atio n i n T B L, b ut t here is n o s pecifie d ti mefra me wit hi n w hic h t he 
ele vat i ons i n tra nsa mi nases a n d T B L  must occ ur .
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 ide ntif y  cases of P H L, it is i m p orta nt t o perf or m a c o m pre he nsi ve re vie w of 
la b orat or y data f or a n y p artici pa nt  w h o meets a n y of t he f o ll owi n g i de ntificat i on cri t eria i n 
is olati on or i n c o m bi nat i on:

A L T ≥3 × U L N

A S T ≥3 × U L N

T B L ≥2 × U L N
If Ce ntr al L a b or at ories are Bei n g Use d:
W he n a partici pa nt meets a n y of t he P H L  ide nt ificati o n criteria, i n is olati on or i n c o m bi nat i on, 
t he ce ntral la b orat or y will i m me diatel y se n d a n alert t o t he I n vesti gat or (als o se nt t o 
Astra Ze neca re prese ntati ve). 
T he I n vesti gat or will als o re mai n vi gila nt f or a n y  l o c al la b orat or y re p orts w here t he P H L 
i de ntificati on cri teria are met; w here t his is t he case, t he I n vest i gat or will:

Re q uest a re peat of t he test ( ne w bl o o d dra w) b y  t he ce ntral la b orat or y wi t ho ut dela y

C o m plete t he a p pr o pri ate u nsc he d ule d la b orat or y e C R F mo d ule(s) wi t h t he origi nal  local 
la b orat or y test res ult
W he n t he i de nt ificati on cri t eria are met fr o m ce ntral or lo c al  la b orat or y res ults, t he 
I n vesti gat or, will with o ut dela y :

Deter mi ne w het her t he partici pa nt meets P H L criteria (see Secti o n  D 2 f or defi niti on) b y 
re vie wi n g la b orat or y re p orts fr o m all pre vio us visits (i ncl u di n g b ot h ce ntral  a n d lo c al  
la b orat or y res ults)
If L oc al L a b or at ories are Bei n g Use d:
T he I n vesti gat or , will with o ut del a y, re vie w eac h ne w la b orat or y re p ort a n d if t he 
i de ntificati on cri teria are met will:

Deter mi ne w het her t he partici pa nt meets P H L criteria (see Secti o n  D 2 f or defi niti on) b y
re vie wi n g la b orat or y re p orts fr o m all pre vio us visits

Pr o m pt l y e nter t he la b orat or y data i nt o t he la b orat or y e C R F

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
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 d oes meet P H L crit eria t he I n vesti gat or wil l:

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 o ne da y  of P H L crit eria bei n g met, t he I n vestigat or will re p ort t he case as a n S A E 
of  P H L; serio us cri teria ‘I mp orta nt m e dical e ve nt’ a n d ca usality assess me nt ‘ y es/relate d’ 
acc or di n g t o C S P pr ocess f or S A E re p orti n g

F or parti ci pa nts t hat met P H L criteria pri or t o starti n g I M P, t he I n vest i gat or is n ot 
re q uire d t o s u b mit a P H L S A E u nless t here is a si g nifica nt c ha n ge i n t he partici pa nt’s 
c o n ditio n

T he St u d y  P h ysicia n c o ntacts t he I n vest i gat or, t o pr o vi de g ui da nce, disc uss a n d a gree a n 
a p pr oac h f or t he st u d y p artici pa nts’ f o ll ow- u p (i ncl u di n g a n y f urt her la b orat or y  testi n g) 
a n d t he c o nti n u o us re vie w of data

S u bse q ue nt t o t his c o ntact t he I n vest i gat or will:

M o ni t or t he partici pa nt u ntil li ver bi o c he mistr y p ar a meters a n d a p pr o priate cli nical 
s y m pt o ms a n d si g ns ret ur n t o n or mal or baseli ne le vels, or as l o n g as me dicall y 
i n dicate d. C o m pletes f oll ow- u p S A E F or m as re q uire d.

I n vesti gate t he eti ol og y  of t he e ve nt a n d perf or m dia g n ostic i n vesti gati ons as 
di sc usse d wit h t he St u d y P h ysicia n. 

C o m plete t he 3 Li ver e C R F M o d ules as i nf or mat i on bec o mes a vaila ble. 
A ‘si g nific a nt’ c h a n ge i n t he partici pa nt’s c o n 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,  A S T or T B L) i n is olati on or i n 
c o m bi nat i on, or a cli nicall y  rele va nt c ha n ge i n ass ociate d s y m pt o ms. T he deter mi nati o n of 
w het her t here has bee n a si g nifica nt c ha n ge will be at t he discret i on of t he I n vest i gat or, t his 
ma y be i n c o ns ultat i on wi t h t he St u d y P h ysicia n if t here is a n y u ncertai nty.
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 o ll owe d f or all cases w here P H L  crit eria are met.

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
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 6
As s o o n as p ossi ble after t he bi oc he mistr y  a b n or mality was i ni tiall y detecte d, t he St u d y 
P h ysicia n c o ntacts t he I n vest i gat or i n or der t o re vie w a vaila ble data a n d a gree o n w het her 
t here is a n alter nat i ve e x pla nati on f or meet i n g P H L crit eria ot her t ha n DI LI ca use d b y t he 
I M P, t o e ns ure ti mel y a nal ysis a n d re p orti n g t o health a ut h orit ies withi n 1 5 cale n dar da ys fr o m 
date P H L  crit eria w as met. T he Astra Ze neca Gl o bal Cli nical Lea d or e q ui vale nt a n d Gl o bal 
S af et y P h ysicia n will als o be i n v o l ve d i n t his re vie w t o get her wit h ot her s u bject matter e x perts 
as a p pr o priate. 
Acc or di n g t o t he o utc o me of t he re vie w a n d assess me nt, t he I n vest i gat or will f oll ow t he 
i nstr uctio ns bel o w.
W her e t h e re is a n a gree d alter n ati ve e x pl a n ati o n f or t he A L T or A S T a n d T B L  ele vat i ons, a 
deter mi nat i on of w het her t he alter nat i ve e x pla nati on is a n A E will be ma de a n d s u bse q ue nt l y 
w het her t he A E meets t he criteria f or a n S A E:

If t he alter nati ve e x pla nati on is n ot a n A E, rec or d t he alter nati ve e x pla nati o n o n t he 
a p pr o priate e C R F

If the alter nat i ve e x pla nati on is a n A E/ S A E: u p date t he pre vi o usl y s u b mitte d P H L S A E 
a n d A E e C R Fs acc or di n gl y wit h t he ne w i nf or mat i o n (reassessi n g e ve nt ter m; ca usality 
a n d seri o us ness criteria) f o ll owi n g t he Astra Ze neca sta n dar d pr ocesses.
If it is a gree d that t here is n o e x pla nat i on t hat w o ul d e x plai n t he A LT or A S T a n d T B L  
ele vat i ons ot her t ha n t he I M P:

Se n d u p date d S A E (re p ort ter m ‘ H y’s La w’) acc or di n g t o Astra Ze neca sta n dar d 
pr ocesses. 

T he ‘ Me dicall y  I m p orta nt’ serio us cri t erio n s h o ul d be use d if n o ot her seri o us criteria 
a p pl y

As t here is n o alter nat i ve e x pla nati o n f or t he H L case, a ca usality assess me nt of 
‘relate d’ s h o ul d be assi g ne d.
If t here is a n u na v oi da ble dela y of o ver 1 5 cal e n dar da ys i n o btai ni n g t he i nf or mat i on 
necessar y  t o assess w het her or n ot t he case meets t he criteria f or H L, t he n it is ass u me d t hat 
t here is n o alter nat i ve e x pla nati o n u ntil s uc h ti me as a n i nf or me d decisi on ca n be ma de:

Pr o vi des a n y  furt her u p date t o t he pre vi o usl y s u b mitte d S A E of P H L, (re p ort ter m n o w 
‘ H y’s La w case’) e ns uri n g ca usality assess me nt is 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 o ll ow- u p a n d re vie w acc or di n g t o a gree d pla n. O nce t he necessar y  
s u p ple me ntar y inf or mat i on is o btai ne d, re peat t he re vie w a n d assess me nt t o deter mi ne 

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
D 8 8 5 0 C 0 0 0 0 2 - D 8 8 5 0 C 0 0 2 A 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y
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w het her H L criteria are still met. U p date t he pre vi o usl y s u b mitte d P H L S A E re p ort 
f oll owi n g C S P pr ocess f or S A E re p orti n g, acc or di n g t o t he o utc o me of t he re vie w a n d 
a me n di n g t he re p orte d ter m if a n alter nat i 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 f o ll ow- u p tests w hic h are 
rec o m me n de d b ut n ot ma n dat or y w he n usi n g a ce ntral la b orat or y. F or st u dies usi n g a l ocal 
la b orat or y, t he list ma y be mo difie 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 Ce ntr al L a b or at ories 
A d diti o nal sta n dar d c he mistr y a n d c oa g ulati o n 
tests
G G T ( Ga m ma gl uta m yl tra ns pe pti dase)
L D H
Pr ot hr o m bi n ti me
I N R
Viral he patitis
I g M (i m m u n o gl o b uli n M) a nti-H A V
H Bs A g
I g M a n d I g G (i m m u n o gl o b uli n G) a nti-H Bc
H B V D N A
a
I g G a nti-H C V
H C V R N A b
I g M a nti-H E V
H E V R N A
Ot her viral i nfecti o ns
I g M & I g G a nti-C M V
I g M & I g G a nti-H S V
I g M & I g G a nti-E B V
Alc o h olic he patitis
Car b o h y drate deficie nt tra nsferri n 
( C D-tra nsferri n) c
A ut oi m m u ne he patitis
A nti n uclear a nti b o d y ( A N A)
A nti -Li ver/ Ki d ne y Micr os o mal a nti b o d y ( A nti -
L K M)
A nti -S m o ot h M uscle a nti b o d y ( 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.

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b
H C V R N A is o nl y rec o m me n de d w he n I g G a nti -H C V is p ositi ve or i nc o ncl usi ve. 
c
C D -tra nsferri n a n d Tra nsferri n are n ot a vaila ble i n C hi na. St u d y tea ms s h o ul d a me n d t his list acc or di n gl y.

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A p pe n di x E
A n a p h yl a xis
I n a d ults, a na p h yla xis is hi g hl y li kel y w he n a n y o ne of  t he f oll owi n g 3 cri t eria 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 o l ve me nt of t he s ki n, m uc osal 
tiss ue, or b ot h (e g, ge neralize d hi ves, pr urit us or fl us hi n g, s w olle n li ps, t o n g ue a n d/ or 
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:

Res pirat or y  c o mpr o mise (e g, d ys p nea, w heeze- br o nc h os pas m, stri d or, re d uce d pea k 
e x pirat or y fl ow, h y p o xe mia)

Re d uce d B P (see n u m ber 3 bel o w f or defi nit i on) or ass ociate d s y m pt o ms of e n d -
or ga n d ysf u ncti o n (e g, h y p ot o nia [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 o ll owi n g t hat occ ur ra pi dl y after e x p os ure t o a li kel y aller ge n f or t hat 
parti ci pa nt ( mi n utes t o se veral h o urs):

I n v ol ve me nt of  t he s ki n-m uc osal t iss ue (e g, ge neralize d hi ves, itc h, fl us h, s w olle n 
li ps, t o n g ue a n d/ or u v ula)

Res pirat or y  c o mpr o mise (e g, d ys p nea, w heeze- br o nc h os pas m, stri d or, re d uce d pea k 
e x pirat or y fl ow, h y p o xe mia)

Re d uce d B P (see n u m ber 3 bel o w f or defi nit i on) or ass ociate d s y m pt o ms (e g, 
h y p ot o ni a [c olla pse], s y nc o pe, i nc o nt i ne nce)

Persi ste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o mi nal pai n, v o mitin g)
3
Re d uce d B P after e x p os ure t o k n o w n aller ge n f or t hat partici pa nt ( mi n utes t o se veral 
h o urs); f or a d ults a s y stolic B P of less t ha n 9 0 m m H g or greater t ha n 3 0 % decrease fr o m 
t hat pers o n’s baseli ne B P (ta ke n at or i m me diatel y pri or t o start of t he I M P 
a d mi nistrati o n), w hic he ver B P is l o wer.
T he f o ll owi n g defi nit i ons are pr o vi de d f or t he p ur p oses of t his st u d y :
H y pe rse nsiti vit y re acti o n: A n ac ute o nset of a n ill ness wit h i n v o l ve me nt of t he s ki n, m uc osal 
tiss ue, or b ot h aft er i njecti o n of  I M P ( b ut d oes n ot meet t he defi niti on of a na p h yla xis 
descri be d a b o ve).
To  assist wit h t he miti gati on of t hese A Es, see  Ta ble 1 5 , w hic h cate g orizes react i ons b y 
se verity of  s y m pt o ms a n d pr o p oses se verity- s pecific treat me nt a n d offers g ui da nce o n 
ma na ge me nt of I M P . Fi nal treat me nt is at t he discretio n of  t he I n vesti gat or a n d s h o ul d reflect 
l ocal sta n dar d of care.

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Ta ble 1 5
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
I n vesti g ati o n al pr o d uct
Mil d l oc al re acti o ns ( D uri 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 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 
pr e -a d mi nistrati 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.
At t he discreti o n of t he I n vesti 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: 
•
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.
Pa use or h ol d a d diti o nal I M P i njecti o n 
i m me diatel y.
At t he discreti o n of t he I n vesti gat or, r es u me 
c urre nt I M P a d mi nistrati o n u n der o bser vati o n. 
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 usea a n d/ or a ntie metic 
i ntra m usc ular, as nee de d.
St o p or h ol d a d diti o nal I M P 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 I M P a d mi nistrati o n u n der o bser vati o n. 

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Ta ble 1 5
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
I n vesti g ati o n al pr o d uct
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 yperte nsi o n wit 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 ne 
1 0 0 m g o r meth y l pre d nis ol o ne 2 0 t o 
4 0 m g.
St o p I M P a d mi nistrati o n i m me diatel y.

Cli nic al St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 3 of 9 6
Ta ble 1 5
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
I n vesti g ati o n al pr o d uct
Se vere
A b o ve pl us fe ver wit h ri g ors, h y p o - or  h yp ert e nsi o n 
wit h ≥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 ysf 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 y nc o pe, 
i nc onti n e nce, seiz ure) fr o m pre -i nf usi o n 
meas ure me nt, or w heezi 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
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.
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 n c 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 o r met h yl 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 or 
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 d e 3 w h eezi 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
St o p I M P a d mi nistrati o n i m me diatel y. D o n ot 
res u me c urre nt d osi n g. Per ma ne ntl y 
disc o nti n ue I M P a d mi nistrati o n.
C o nsi de r nee d f or a d diti o nal oral 
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 y m pt o ms o ver s u bse q ue nt 2 
t o 3 da ys.
B P, bl o o d press ure; I M P, i n vesti gati o nal me dici nal pr o d uct; I V, i ntra ve n o usl y; P O, per os ( b y m o ut h); S C, s u bc uta ne o usl y; S O C, sta n dar d of care.

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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 A
a nti dr u g a nti b o d y
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/tra nsa mi nase
A S T
as partate a mi n otra nsferase/tra nsa mi nase
A U C
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve
β- h C G
beta -h u ma n c h ori o nic g o na d otr o pi n
B P
Bl o o d press ure
CI
c o nfi de nce i nter val
C O VI D - 1 9
c or o na vir us disease 2 0 1 9
C R O
C o ntract Researc h Or ga nizati o n
C S P
Cli nical St u d y Pr ot oc ol
C S R
Cli nical St u d y Re p ort
C 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
DI LI
Dr u g I n d uce d Li ver I nj ur y
D N A
de o x yri b o n ucleic aci d
D P
dr u g pr o d uct
D S M B
Data Safet y M o nit ori n g B oar d
E C G
electr ocar di o gra m
E D C
electr o nic data ca pt ure
e C R F
electr o nic Case Re p ort F or m
E U A
E mer ge nc y Use A ut h orizati o n
F S H
F ollicle -sti m ulati n g h or m o ne
F D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice
G F R
gl o mer ular filtrati o n rate
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
H L
H y’s La w
I B
I n vesti gat or’s Br oc h ure
I A T A
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati o n

Cli nical St u d y Pr ot oc ol A d de n d u m - A me n d me nt 2. 0 U S A
Astra Ze neca
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9 5 of 9 6
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 G
i m m u n o gl o b uli n G
I g M
i m m u n o gl o b uli n M
I 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 R T
I nteracti ve Res p o nse Tec h n ol o g y
I V
i ntra ve n o us
M A A E
me dicall y atte n de d a d verse e ve nt
m A bs
m o n ocl o nal a nti b o dies
n A b
ne utralizi n g a nti b o d y
N P
nas o p har y n geal
P H L
P ote ntial H y’s La w
P B M C
peri p heral bl o o d m o n o n uclear cell
P K
p har mac o ki netic(s)
R N A
ri b o n ucleic aci d
R T -P C R
re verse tra nscri ptase p ol y merase c hai n reacti o n
R T S M
Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt
S A E
seri o us a d verse e ve nt
S A 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 S - D
s u b-st u d y d a y
T B L
t otal bilir u bi n le vel
U S A
U n ite d States of A merica
U L N
u p per li mit of n or mal
W H O
W orl d Healt h Or ga nizati o n

Cli nical St u d y Pr ot oc ol A d de n d u m - A m e n d me nt 2. 0 U S A
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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1 1
R E F E R E N C E S
C D C 2 0 2 1
C D C. ( Ce nters f or Disease C o ntr ol a n d Pre ve nt i on). C or o na vir us Disease 2 0 1 9 ( C O VI D -1 9), 
S y m pt o m s of C or o na vir us. htt ps:// w w w.c dc. g o v/c or o na vir us/ 2 0 1 9-nc o v/s y m pt o m s-
testi n g/s y m pt o ms. html. P u blis he d 2 2 Fe br uar y  2 0 2 1. Accesse d 0 3 N o ve m ber 2 0 2 1.
CI O M S 1 9 9 9
C o u ncil f or I nter nati o nal Or ga nizat i ons of Me dical Scie nces ( CI O M S). “ 5. H o w? – G o o d 
S af et y I nf or mat i on Practisi n g ”. G ui deli nes F or Pre pari n g C ore Cli nical- Safet y I nf or mat i on o n 
Dr u gs Sec o n d E dit i on: Re p ort of CI O M S W or ki n g Gr o u p III a n d V. Ge ne va, S witzerla n d: 
CI O M S, 1 9 9 9, p. 3 6.
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 m pr o vi n g Gl o bal O utc 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 oluti o n  n ot re v olut i on. Cl i n C he m. 
2 0 1 3; 5 9( 3): 4 6 2 - 5.
M ars h all et al 2 0 2 0
Mars hall J C, M urt h y  S, Diaz J, A d hi kari N K, A n g us D C, Ara bi Y M et al. W H O W or ki n g 
Gr o u p o n t he Cli nical C haracterisat i on a n d Ma na ge me nt of C O VI D- 1 9 i nfect i on . A mi ni mal 
c o m m o n o utc 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.
NI H 2 0 1 7
NI H. ( Nati o nal  I nstitutes of Healt h) Nat i onal I nst itute of Aller g y a n d I nfecti o us Diseases, 
Di visi o n of AI D S. Di visi o n of AI D S ( D AI D S) T a ble f or Gra di n g t he Se verity of  A d ult a n d 
P e di atric A d verse E ve nts, C orrecte d Versio n 2. 1 [J ul y  2 0 1 7]. 
ht t ps://rsc. niai d. ni h. g o v/sites/ defa ult/files/ dai ds gra di n gc orrecte d v 2 1. p df. P u blis he d 2 0 1 7. 
Accesse d 1 3 N o ve m ber 2 0 2 0.