Clinical trial NCT04625725
Conditions: COVID-19
Keywords: Pre-exposure Prophylaxis of COVID-19
Sponsor: AstraZeneca
Start date: 2020-11-21; Completion date: 2023-12-08
Enrollment: 5197 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety and efficacy of a single dose of AZD7442(× 2 IM injections) compared to placebo for the prevention of COVID-19.

Detailed description:
SARS-CoV-2 is the causative agent of the ongoing COVID-19 pandemic that, as of 29 September 2020, has resulted in a high death toll to date. Unlike the majority of coronaviruses that cause mild disease in humans and animals, SARS-CoV-2 can replicate in the lower respiratory tract to cause acute respiratory distress syndrome and fatal pneumonia. Effective interventions to prevent or treat COVID-19 remain limited in number and clinical experience is limited. Clinical management is limited to supportive care, consequently overwhelming resources of healthcare systems around the world. As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 S protein. The SARS-CoV-2 spike protein contains the virus's RBD, which enables the virus to bind to receptors on human cells. By targeting this region of the virus's spike protein, antibodies can block the virus's attachment to human cells, and, therefore, is expected to block infection. Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector function in order to decrease the potential risk of antibody-dependent enhancement of disease. AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated for administration to prevent and/or treat COVID-19. There is currently one completed and 2 ongoing Phase I studies with AZD7442.

-The Provent repeat dose open-label sub-study is initiated to assess the safety, PK and immunogenicity of repeat doses of AZD7442 in participants currently enrolled in the Provent study who may benefit from repeat dose of AZD7442.

Arms: arm 1: Approximately 5150 participants will be randomized in a 2:1 ratio

• Arm 1 (n=approximately 3433) will receive a single dose (× 2IM injections) of 300 mg of AZD7442 arm 2: Approximately 5150 participants will be randomized in a 2:1 ratio

• Arm 2 (n=approximately 1717) will receive saline placebo arm 3: Approximately 500 participants will receive AZD7442 in the repeat dose sub-study.

-Sub-study Arm 1 (\~ 12 month repeat dose interval): Participants who received AZD7442 300 mg IM on Day 1 of the parent study will receive a second dose of AZD7442 300mg IM on sub-study Day 1. arm 4: Approximately 500 participants will receive AZD7442 in the repeat dose sub-study.

-Sub-study Arm 2(\~ 6 month repeat dose interval): Participants who received placebo on Day 1 of the parent study will receive their first dose of AZD7442 300mg IM on sub-study Day1 followed by a second dose on sub-study Day 183. arm 5: A subset of Arm 1 and Arm 2 participants who will receive additional doses of AZD7442, 600mg, at Day 183 and Day 366 of the sub-study.
Interventions: intervention 1: AZD7442 intervention 2: Placebo
Intervention descriptions: intervention 1: * Single dose (× 2IM injections) of 300 mg of AZD7442 on parent study Day 1.
* Single dose (× 2IM injections) of 300 mg of AZD7442 on sub-study Day 1.
* Single dose (× 2IM injections) of 300 mg of AZD7442 on sub-study Day 183.
* Single dose (x 2IM injections) of 600mg of AZD7442 on sub-study Day 183 and Day 366 intervention 2: Single dose (× 2IM injections) of saline placebo on parent study Day 1.

Protocol documents:
Prot_004.pdf: 
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
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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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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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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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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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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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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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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
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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
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
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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
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
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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
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
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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
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
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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
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
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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
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
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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
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
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 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.


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Astra Ze neca
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 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.


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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.


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C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 6 of 9 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
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 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
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 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 


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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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.


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
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7 6 of 9 6
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 


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 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
8 8 of 9 6
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.


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
8 9 of 9 6
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.


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
9 0 of 9 6
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.


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
9 1 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
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. 


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
9 2 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
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
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
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.


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
9 4 of 9 6
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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C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 5 of 9 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
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
9 6 of 9 6
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.

SAP_005.pdf: 
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29-Jul-2021
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STATISTICAL ANALYSIS PLAN
Study Code
D8850C00002
Edition Number
V4.0
Date
29-Jul-2021
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
Study Statistician:
Global Product Statistician:
PPD
PPD


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MODIFICATION HISTORY
Unique 
Identifier for 
this Version
Date of the 
Document 
Version
Author
Significant Changes from 
Previous Version
1.0
09Dec2020
Not Applicable – first version based on CSP v3
2.0
14Apr2021
Updates reflect CSP changes in versions 4, 5, 
6, and 7. Key changes include:
Addition of unblinding for proper consideration 
of COVID-19 vaccine as an intercurrent event,
revised definitions for intercurrent events, 
primary endpoint definition, changes in
primary estimand, timing of the primary 
analysis, removal of the interim analysis, added 
subgroups, increase of sample size for clonal 
material, last visit of Day 457 added, addition 
of key supportive analysis, removal of BSSR, 
proportions of cohorts to be recruited, removal 
of strata caps within cohorts, simplification of 
supplementary analyses, removal of select lab 
summaries, removal of IQVIA as Analysis & 
Reporting vendor.
3.0
30Jun2021
Updates reflect CSP changes in version 8. Key 
changes include:
Additional estimand of the primary endpoint
and inclusion in the multiple testing hierarchy. 
Day 366 endpoint changed from Key 
Secondary to Exploratory, and nucleocapsid 
antibodies endpoint from Secondary to Key 
Secondary. Other updates include: Addition of
imputation rules for partial COVID-19 
vaccination dates. Removal of Symptomatic 
COVID-19 Analysis Set. Revision of  analysis 
method to be used if convergence cannot be 
achieved using primary analysis method. 
4.0
23Jul2021
Updates reflect CSP changes in version 9. 
Editorial changes are not listed. Key changes 
PPD
PPD
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PPD


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include:
Removal of “to properly consider vaccination 
for COVID-19” with respect to unblinded 
intercurrent event language. Addition of 
Morbidity Adjudication Committee. Removal 
of vaccine efficacy censor estimand. Addition 
of key supportive estimand including death due 
to any cause. Revision of multiple testing 
hierarchy. Change from age at randomization 
to age at informed consent. Removal of 
“severe” requirement for COVID-19 
hospitalizations to be included in primary 
endpoint. Revision to sensitivity analysis 
approach. Addition of descriptive statistics for 
Day 366 exploratory endpoint. 


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TABLE OF CONTENTS
1.
INTRODUCTION ...........................................................................................................9
2.
STUDY OBJECTIVES AND ESTIMANDS ..................................................................9
2.1.
Primary Objectives ...................................................................................................................................9
2.2.
Secondary Objectives................................................................................................................................9
2.3.
Exploratory Objectives........................................................................................................................... 10
2.4.
Estimands................................................................................................................................................ 11
3.
STUDY DESIGN ...........................................................................................................23
3.1.
General Description ................................................................................................................................ 23
3.2.
Schedule of Events .................................................................................................................................. 24
3.3.
Changes to Analyses from Protocol ........................................................................................................ 24
4.
PLANNED ANALYSES................................................................................................24
4.1.
Data and Safety Monitoring Board (DSMB).......................................................................................... 24
4.2.
Morbidity Adjudication Committee ....................................................................................................... 25
4.3.
Interim Analysis...................................................................................................................................... 25
4.4.
Primary Analysis..................................................................................................................................... 25
4.5.
Final Analysis.......................................................................................................................................... 26
5.
ANALYSIS SETS..........................................................................................................26
5.1.
All Participants Analysis Set................................................................................................................... 26
5.2.
Full Analysis Set...................................................................................................................................... 26
5.3.
Full Pre-Exposure Analysis Set............................................................................................................... 26
5.4.
Safety Analysis Set.................................................................................................................................. 27
5.5.
Pharmacokinetic Analysis Set................................................................................................................. 27
5.6.
ADA Evaluable Analysis Set................................................................................................................... 27
5.7.
nAb Evaluable Analysis Set.................................................................................................................... 27


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6.
GENERAL CONSIDERATIONS.................................................................................28
6.1.
Reference Start Date and Study Day...................................................................................................... 28
6.2.
Baseline ................................................................................................................................................... 28
6.3.
Unscheduled Visits, Retests, and Early Termination Data..................................................................... 29
6.4.
Windowing Conventions......................................................................................................................... 29
6.5.
Common Calculations............................................................................................................................. 31
7.
STATISTICAL CONSIDERATIONS..........................................................................32
7.1.
Sample Size Calculation.......................................................................................................................... 32
7.2.
Missing data............................................................................................................................................ 33
7.3.
Statistical Tests........................................................................................................................................ 33
7.4.
Multiple Comparisons/ Multiplicity ....................................................................................................... 33
7.5.
Multicenter Studies................................................................................................................................. 34
7.6.
Adjustments for Covariates and Factors to be Included in Analyses .................................................... 34
7.7.
Examination of Subgroups...................................................................................................................... 34
7.8.
Software Version..................................................................................................................................... 35
8.
OUTPUT PRESENTATIONS ......................................................................................35
9.
DISPOSITION AND WITHDRAWALS......................................................................36
9.1.
Disposition............................................................................................................................................... 36
9.2.
Protocol Deviations ................................................................................................................................. 36
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.......................36
10.1.
Derivations .......................................................................................................................................... 37
11.
MEDICAL HISTORY...................................................................................................37
12.
CONCOMITANT ILLNESSES....................................................................................38
13.
MEDICATIONS............................................................................................................38


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14.
EXPOSURE TO STUDY INTERVENTION ...............................................................39
15.
COMPLIANCE WITH STUDY INTERVENTION ....................................................39
16.
EFFICACY ENDPOINTS.............................................................................................39
16.1.
Primary Efficacy................................................................................................................................. 39
16.1.1.
Primary Efficacy Endpoint................................................................................................................. 39
16.1.2.
Missing Data Imputation Method for Primary Efficacy Endpoint........................................................ 40
16.1.3.
Primary Estimand.............................................................................................................................. 41
16.1.4.
Primary Analysis of Primary Efficacy Endpoint................................................................................. 41
16.1.5.
Sensitivity Analyses for Primary Efficacy Endpoint........................................................................... 43
16.1.6.
Supplementary Analyses for Primary Efficacy Endpoint .................................................................... 44
16.1.7.
Subgroup Analyses for Primary Efficacy Endpoint............................................................................. 44
16.1.8.
Additional Estimands for Primary Efficacy Endpoint ......................................................................... 45
16.1.8.1.
Hypothetical Estimand............................................................................................................... 49
16.1.9.
Key Supportive Analyses of Primary Efficacy Endpoint..................................................................... 50
16.2.
Secondary Efficacy.............................................................................................................................. 52
16.2.1.
Key Secondary Efficacy Endpoint...................................................................................................... 52
16.2.2.
Estimands for Key Secondary Efficacy .............................................................................................. 52
16.2.3.
Other Secondary Efficacy Endpoints.................................................................................................. 53
16.2.3.1.
The Incidence of SARS-CoV-2 RT-PCR-Positive Severe or Critical Symptomatic Illness 
Occurring Post Dose ..................................................................................................................................... 53
16.2.3.2.
The Incidence of COVID-19-Related Emergency Department Visits Occurring After Dosing with 
IMP
53
16.2.4.
Missing Data Imputation Method for Secondary Efficacy Endpoints .................................................. 54
16.2.5.
Analysis of Secondary Efficacy Endpoints......................................................................................... 54
16.2.6.
Sensitivity Analyses for Secondary Efficacy Endpoints...................................................................... 54
16.2.7.
Supplementary Analyses for Secondary Efficacy Endpoints ............................................................... 54
16.2.8.
SUBGROUP ANALYSES FOR SECONDARY EFFICACY ENDPOINTS....................................... 54
16.3.
Exploratory Efficacy........................................................................................................................... 54
16.3.1.
Exploratory Efficacy Endpoints......................................................................................................... 55
16.3.1.1.
The Incidence of the First Case of SARS-CoV-2 RT-PCR-Positive Symptomatic Illness Occurring 
after Dosing with IMP through Day 366........................................................................................................ 55
16.3.1.2.
Viral Genome Copies in NP Swabs Collected at Illness Visits as Determined by qRT-PCR......... 55
16.3.1.3.
Duration of SARS-CoV-2 Shedding in Saliva Over Time (Illness Visits only) ............................ 56
16.3.1.4.
Genotypic Analysis and Biochemical and/or Susceptibility Analysis of SARS-CoV-2 Variants to 
AZD7442 (Illness Visits Only)...................................................................................................................... 57
16.3.1.5.
Biophysical Parameters, Including But Not Limited to Serial Measurements of Skin Temperature, 
Heart Rate, Respiratory Rate, Blood Oxygen Saturation, and Physical Activity, Recorded Using a Biosensor 
From Illness Visits Day 1 Through Day 28.................................................................................................... 57
16.3.1.6.
Symptoms recorded by participants in an Illness e-Diary from Illness Visits Day 2 through Day 28
57
16.3.2.
Missing Data Imputation Method for Exploratory Efficacy Endpoints ................................................ 57
16.3.3.
Sensitivity Analyses for Exploratory Efficacy Endpoints.................................................................... 57
16.3.4.
Supplementary Analyses for Exploratory Efficacy Endpoints............................................................. 57
17.
PHARMACOKINETIC, PHARMACODYNAMIC, AND ADA ENDPOINTS .........58
17.1.
Analysis of PK, PD, and ADA Endpoints ........................................................................................... 58


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17.1.1.
Serum AZD7442 Concentrations ....................................................................................................... 58
17.1.2.
The Incidence of ADA to AZD7442 in Serum.................................................................................... 59
17.1.2.1.
ADA Variables.......................................................................................................................... 59
17.1.2.2.
ADA Analysis ........................................................................................................................... 59
17.1.3.
AZD7442 Nasal Fluid Concentrations................................................................................................ 60
17.1.4.
Neutralizing Antibody Geometric Mean Titers and Geometric Mean Fold Rise .................................. 60
17.1.5.
Missing Data Imputation Method for PK, PD, and ADA Endpoints.................................................... 60
17.1.6.
Sensitivity Analyses for PK, PD, and ADA Endpoints........................................................................ 61
17.1.7.
Supplementary Analyses for PK, PD, and ADA Endpoints................................................................. 61
18.
SAFETY ENDPOINTS .................................................................................................61
18.1.
Adverse Events.................................................................................................................................... 62
18.1.1.
Adverse Events and Serious Adverse Events...................................................................................... 63
18.1.1.1.
Severity for AEs ........................................................................................................................ 64
18.1.1.2.
Relationship to IMP/Other Medication/Study Procedure............................................................. 64
18.1.2.
AEs Leading to Discontinuation of IMP............................................................................................. 64
18.1.3.
AEs Leading to Discontinuation of Study........................................................................................... 64
18.1.4.
AEs with Outcome of Death .............................................................................................................. 64
18.1.5.
Medically Attended Adverse Events .................................................................................................. 64
18.1.6.
Adverse Events of Special Interest..................................................................................................... 65
18.2.
Deaths.................................................................................................................................................. 65
18.3.
Laboratory Evaluations ...................................................................................................................... 65
18.3.1.
CTCAE Toxicity Grades ................................................................................................................... 66
18.3.2.
Laboratory Normal Ranges................................................................................................................ 66
18.4.
Vital Signs............................................................................................................................................ 67
18.5.
ECG Evaluations................................................................................................................................. 67
18.5.1.
ECG Markedly Abnormal Criteria ..................................................................................................... 68
18.6.
Physical Examination.......................................................................................................................... 69
19.
OTHER DATA COLLECTED.....................................................................................69
20.
REFERENCES..............................................................................................................70
APPENDIX 1.
PARTIAL DATE CONVENTIONS............................................................71
Algorithm for Prior / Concomitant Medications ............................................................................................... 71
APPENDIX 2.
PROGRAMMING CONVENTIONS FOR OUTPUTS .............................73
Dates & Times .................................................................................................................................................... 73
Spelling Format.................................................................................................................................................. 73
Paper Size, Orientation, and Margins................................................................................................................ 73


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Fonts ................................................................................................................................................................... 73
Presentation of Treatment Groups .................................................................................................................... 73
Presentation of Nominal Visits........................................................................................................................... 74
Descriptive Statistics........................................................................................................................................... 75
Percentages......................................................................................................................................................... 75
p-values............................................................................................................................................................... 75
Listings ............................................................................................................................................................... 75
APPENDIX 3.
LABORATORY ASSESSMENTS..............................................................76
APPENDIX 4.
CTCAE TOXICITY GRADE, VERSION 5.0 ............................................78
APPENDIX 5.
CLINICAL ABNORMALITIES: VITAL SIGNS......................................83
APPENDIX 6.
HIGH RISK OF SEVERE COVID-19 AT BASELINE .............................84
APPENDIX 7.
LIST OF ABBREVIATIONS......................................................................86


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1. INTRODUCTION
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for protocol D8850C00002. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed. 
This SAP is based on protocol version 9.0, dated 26Jul2021.
The term IMP (investigational medicinal product) is used throughout this SAP to include both treatment groups 
(AZD7442 and placebo). AZD7442 is specified when referring only to those who received active intervention.
2. STUDY OBJECTIVES AND ESTIMANDS
2.1.
PRIMARY OBJECTIVES
The primary objectives are:
!
To estimate the efficacy of a single intramuscular (IM) dose of AZD7442 compared to placebo for the 
prevention of COVID-19 prior to Day 183
!
To assess the safety and tolerability of a single IM dose of AZD7442 compared to placebo
2.2.
SECONDARY OBJECTIVES
The key secondary objective is:
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of SARS-
CoV-2 infection
The other secondary objectives are:
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of severe or 
critical symptomatic COVID-19
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of COVID-
19-related Emergency Department visits
!
To assess the pharmacokinetics (PK) of AZD7442 administered as a single dose of 300 mg IM
!
To evaluate anti-drug antibody (ADA) responses to AZD7442 in serum


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2.3.
EXPLORATORY OBJECTIVES
The exploratory objectives are:
!
To estimate the efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of COVID-19 
through Day 366
!
To evaluate the single dose pharmacokinetic concentrations of AZD7442 in nasal fluid
!
To determine anti-SARS-CoV-2 neutralizing antibody (nAb) levels in serum following a single IM dose of 
AZD7442 or placebo
!
To quantify SARS-CoV-2 viral loads in infected participants treated with a single IM dose of AZD7442 or 
placebo (Illness Visits)
!
To quantify duration of viral shedding in participants with symptomatic COVID-19 treated with a single IM 
dose of AZD7442 or placebo (Illness Visits)
!
To characterize resistance to AZD7442 (Illness Visits) – not covered by this SAP
!
To assess the biometric profiles associated with COVID-19 using a biosensor in participants treated with a 
single IM dose of AZD7442 or placebo (Illness Visits)
!
To assess symptoms associated with COVID-19 using an e-Diary in participants treated with a single IM dose 
of AZD7442 or placebo (Illness Visits only)
!
To assess additional immune responses following a single IM dose of AZD7442 or placebo – not covered by 
this SAP


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2.4.
ESTIMANDS
Table A:
List of Estimands – Primary
Label
Attributes
Definition Population
Treatment Condition
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
Primary 
Efficacy 
Estimand –
The efficacy 
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
prevention 
of COVID-
19 prior to
Day 183
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, and 
did not have a prior SARS-CoV-2 RT-PCR-
positive confirmed COVID-19 infection. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
A binary 
response, 
whereby a 
participant is 
defined as a 
COVID-19 
case if their 
first case of 
SARS-CoV-
2 RT-PCR-
positive 
symptomatic 
illness 
occurs post 
dose of IMP
prior to Day 
183.
Participants who become 
unblinded to treatment 
assignment and/or take 
COVID-19 vaccine or 
other COVID-19 
preventive product, in 
both cases prior to having 
met the criteria for the 
primary efficacy 
endpoint, will be censored 
at the date of 
unblinding/receipt of first 
dose of COVID-19 
preventive product, 
whichever is earlier (i.e., 
intercurrent events will be 
handled using a while on 
treatment strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
Primary 
Safety 
Safety analysis set, defined as all participants 
who received at least one of the planned 
Single dose of 
AZD7442 (× 2 IM 
Incidence of 
adverse 
Not Applicable
Descriptive 
statistics, including 


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Label
Attributes
Definition Population
Treatment Condition
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
Estimand –
The safety 
and 
tolerability 
of a single 
IM dose of 
AZD7442 
compared to 
placebo
injections of IMP. Targeted participants will 
have the following characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
injections, 1 for each 
mAb component) or 
placebo
events, 
serious 
adverse 
events, 
medically 
attended 
adverse 
events, and 
adverse 
events of 
special 
interest post 
dose of IMP
number and 
percentages of 
participants who 
have the incidence; 
Number of the 
events.
Table B:
List of Estimands – Key Secondary
Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
Key 
Secondary 
Estimand –
The efficacy 
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, and 
did not have a prior SARS-CoV-2 RT-PCR-
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
The 
incidence of 
participants 
who have a 
Participants who become 
unblinded to treatment 
assignment and/or take 
COVID-19 vaccine or 
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
prevention 
of SARS-
CoV-2 
infection
positive confirmed COVID-19 infection. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
placebo
post-
treatment 
response 
(negative at 
baseline to 
positive at 
any time 
post-
baseline) for 
SARS-CoV-
2 
nucleocapsi
d antibodies.
other COVID-19 
preventive product, in 
both cases prior to having 
met the criteria for the 
key secondary efficacy 
endpoint, will be censored 
at the date of 
unblinding/receipt of first 
dose of COVID-19 
preventive product, 
whichever is earlier (i.e., 
intercurrent events will be 
handled using a while on 
treatment strategy).
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.)
Table C:
List of Estimands – Other Secondary
Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The efficacy 
of a single 
IM dose of 
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least of the planned injections of IMP, and did 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
The incidence 
of SARS-
CoV-2 RT-
Participants who 
become unblinded to 
treatment assignment 
Prophylactic 
efficacy, calculated 
as 1-relative risk. 


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
AZD7442 
compared to 
placebo for 
the 
prevention 
of severe or 
critical 
symptomatic 
COVID-19
not have a prior SARS-CoV-2 RT-PCR-positive 
confirmed COVID-19 infection. Targeted 
participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
mAb component) or 
placebo
PCR-positive 
severe or 
critical 
symptomatic 
illness 
occurring after 
dosing with 
IMP.
and/or take COVID-19 
vaccine or other 
COVID-19 preventive 
product, in both cases 
prior to having met the 
criteria for this 
secondary efficacy 
endpoint, will be 
censored at the date of 
unblinding/receipt of 
first dose of COVID-19 
preventive product, 
whichever is earlier 
(i.e., intercurrent events 
will be handled using a 
while on treatment 
strategy).
(Relative risk is the 
incidence of severe 
or critical 
symptomatic 
infection in the 
AZD7442 group 
relative to the 
incidence of severe 
or critical 
symptomatic 
infection in the 
control group.)
The efficacy 
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, and 
did not have a prior SARS-CoV-2 RT-PCR-
positive confirmed COVID-19 infection. 
Targeted participants will have the following 
characteristics:
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
The incidence 
of COVID-19-
related 
Emergency 
Department 
visits 
occurring after 
Participants who 
become unblinded to 
treatment assignment 
and/or take COVID-19 
vaccine or other 
COVID-19 preventive 
product, in both cases 
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
COVID-19-related 
emergency 


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
prevention 
of COVID-
19-related 
Emergency 
Department 
visits
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
dosing with 
IMP.
prior to having met the 
criteria for this 
secondary efficacy 
endpoint, will be 
censored at the date of 
unblinding/receipt of 
first dose of COVID-19 
preventive product, 
whichever is earlier 
(i.e., intercurrent events 
will be handled using a 
while on treatment 
strategy).
department visits in 
the AZD7442 group 
relative to the 
incidence of 
COVID-19-related 
emergency 
department visits in 
the control group.)
The 
pharmacoki
netics of 
AZD7442 
administered 
as a single 
dose of 300 
mg IM
Pharmacokinetic analysis set, defined as all 
participants who receive at least one of the 
planned injections of AZD7442, from whom PK 
blood samples are assumed not to be affected by 
factors such as protocol violations, and who had 
at least one quantifiable serum PK observation 
post dose. Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component)
Serum 
AZD7442 
concentrations.
PK parameters 
if data permit.
Not Applicable
Individual 
AZD7442 
(AZD8895 and 
AZD1061) serum 
concentration data 
descriptive 
statistics; 
Pharmacokinetic 
exposure (i.e., 
AUCs) and other 
PK parameters may 


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
be estimated using 
non compartmental 
analysis, if data 
permit.
ADA 
responses to 
AZD7442 in 
serum
ADA analysis set, defined as all participants 
who received at least one of the planned 
injections of IMP and who have a non-missing 
baseline AZD7442 ADA result and at least one 
non-missing post-baseline AZD7442 ADA 
result. Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
Incidence of 
ADA to 
AZD7442 in 
serum.
Not Applicable
Descriptive 
statistics, including 
number and 
percentage of 
participants who 
developed ADAs to 
AZD7442.


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
and COVID-19.
Table D:
List of Estimands – Exploratory
Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The efficacy 
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
prevention 
of COVID-
19 through 
Day 366
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, and 
did not have a prior SARS-CoV-2 RT-PCR-
positive confirmed COVID-19 infection. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
The 
incidence of 
the first case 
of SARS-
CoV-2 RT 
PCR 
positive 
symptomatic 
illness 
occurring 
after dosing 
with IMP 
through Day 
366.
Participants who become 
unblinded to treatment 
assignment and/or take 
COVID-19 vaccine or 
other COVID-19 
preventive product, in 
both cases prior to having 
met the criteria for this 
exploratory efficacy 
endpoint, will be censored 
at the date of 
unblinding/receipt of first 
dose of COVID-19 
preventive product, 
whichever is earlier (i.e., 
intercurrent events will be 
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.)


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
and COVID-19.
handled using a while on 
treatment strategy).
The single 
dose 
pharmacoki
netic 
concentratio
ns of 
AZD7442 in 
nasal fluid
A subset of the pharmacokinetic analysis set, per 
available data, defined as all participants who 
receive at least one of the planned injections of 
AZD7442, from whom PK blood samples are 
assumed not to be affected by factors such as 
protocol violations, and who had at least one 
quantifiable serum PK observation post dose. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component)
AZD7442 
nasal 
concentratio
ns.
Not Applicable
Individual 
concentration data 
with descriptive 
statistics
Anti-SARS-
CoV-2 nAb 
The nAb analysis set, defined as all participants 
who received at least one of the planned 
Single dose of 
AZD7442 (× 2 IM 
Post-
treatment 
Not Applicable
GMT and GMFR 
with descriptive 


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
levels in 
serum 
following a 
single IM 
dose of 
AZD7442 or 
placebo
injections of IMP, from whom blood samples 
are assumed not to be affected by factors such as 
protocol violations, and who had at least one 
quantifiable serum titer observation post dose. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
injections, 1 for each 
mAb component) or 
placebo
GMTs and 
GMFRs 
from 
baseline 
value 
through Day 
457 after 
single IM 
dose in 
SARS-CoV-
2 
neutralizing 
antibodies 
(wild-type 
assay or 
pseudo 
neutralizatio
n assay).
statistics
SARS-CoV-
2 viral loads 
in infected 
participants 
treated with 
a single IM 
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, did 
not have a prior SARS-CoV-2 RT-PCR-positive 
confirmed COVID-19 infection, and who met 
the criteria for symptomatic COVID-19 and 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
Viral 
genome 
copies in NP 
swabs 
collected at 
Illness Visits 
Not Applicable
Observed and 
change from 
baseline descriptive 
statistics


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
dose of 
AZD7442 or 
placebo 
(Illness 
Visits)
began Illness Visits following confirmed SARS-
CoV-2 infection. Targeted participants will have 
the following characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
as 
determined 
by qRT-
PCR.
Duration of 
viral 
shedding in 
participants 
with 
symptomatic 
COVID-19 
treated with 
a single IM 
dose of 
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, did 
not have a prior SARS-CoV-2 RT-PCR-positive 
confirmed COVID-19 infection, and who met 
the criteria for symptomatic COVID-19 and 
began Illness Visits following confirmed SARS-
CoV-2 infection. Targeted participants will have 
the following characteristics:
Adults ≥ 18 years of age who are candidates for 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
Duration of 
SARS-CoV-
2 shedding 
in saliva 
over time.
Not Applicable
Descriptive statistics 
on number of days
of shedding


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
AZD7442 or 
placebo 
(Illness 
Visits)
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
Symptoms 
associated 
with 
COVID-19 
using an e-
Diary in 
participants 
treated with 
a single IM 
dose of 
AZD7442 or 
placebo 
(Illness 
Visits only)
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, did 
not have a prior SARS-CoV-2 RT-PCR-positive 
confirmed COVID-19 infection, and who met 
the criteria for symptomatic COVID-19 and 
began Illness Visits following confirmed SARS-
CoV-2 infection. Targeted participants will have 
the following characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
Symptoms 
recorded by 
participants 
in an Illness 
e-Diary 
from Illness 
Visits Day 2 
through Day 
28.
Not Applicable
Descriptive 
statistics, including 
number and 
percentage of 
participants with 
symptoms.


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.


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3. STUDY DESIGN
3.1.
GENERAL DESCRIPTION
This is a Phase III, randomized, double-blind, placebo-controlled, multi-country, multi-center study assessing the 
safety and efficacy of a single dose of AZD7442 (× 2 IM injections) compared to placebo for the prevention of 
COVID-19. 
Participants will be adults ≥ 18 years of age who are candidates for benefit from passive immunization with 
antibodies, defined as having increased risk for inadequate response to active immunization (predicted poor 
responders to vaccines OR intolerant of vaccine), OR having increased risk for SARS-CoV-2 infection, defined as 
those whose locations or circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19, 
based on available risk assessment at time of enrollment. Participants will be enrolled into one of two cohorts:
!
Cohort 1: Adults ≥ 60 years of age. All participants will be considered as being at increased risk for inadequate 
response to active immunization on the basis of age (presumed immunosenescence). Cohort 1 will be capped, 
not to exceed 80% of total participants randomized. Within this cohort, randomization will be stratified by 
residence in a long-term care facility or not.
!
Cohort 2: Adults < 60 years of age. Cohort 2 will be capped, not to exceed 80% of total participants 
randomized. Within this cohort, randomization will be stratified by risk of exposure to infection with SARS-
CoV-2.
Approximately 5150 participants will be randomized in a 2:1 ratio to receive a single dose (× 2 IM injections) of 
either 300 mg of AZD7442 (n = approximately 3433) or saline placebo (n = approximately 1717) on Day 1. 
Enrollment will occur in two stages, which is contingent upon evaluation of 7-day safety data of Stage 1 enrollment 
by an independent DSMB and its recommendation to proceed with Stage 2:
!
Stage 1 (N = 300 [at least 150 from Cohort 1]: 200 to AZD7442, 100 to placebo). The first 15 participants 
(Sentinel Cohort), will undergo safety monitoring for 4 hours post IMP administration before dosing the rest of 
the participants in Stage 1. The remaining 285 participants will undergo safety monitoring for 2 hours post IMP 
administration.
!
Stage 2 (N = 4850: 3233 to AZD7442, 1617 to placebo). Stage 2 will start only after an independent Data 
Safety Monitoring Board (DSMB) has confirmed it is appropriate to proceed. The DSMB will evaluate 7-day 
safety data from participants dosed in Stage 1. If hypersensitivity reactions are observed during Stage 1, safety 
monitoring for 2 hours post IMP administration will be implemented for Stage 2; otherwise the minimum safety 
monitoring time will be 1 hour.
To allow for the assessment of clonal material, 150 participants in the US will receive the clonal material or placebo 
in a 2:1 ratio. The participants will be recruited according to the current inclusion and exclusion criteria and will be 
followed as per the schedule of activities. A PK analysis will be performed of pooled versus clonal material.


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Following a screening period of ≤7 days, participants will receive a single dose (× 2 IM injections) of IMP. After 
administration of the dose of IMP on Day 1, participants will undergo follow-up for 15 months (until Day 457). 
Figure A: Study Design
Following screening (-7 to 0 days), randomization will occur in 2 stages and is contingent on safety. The planned 
primary analysis will occur after approximately 24 primary endpoint events have occurred or 30% of study 
participants have become unblinded, whichever occurs first. A final analysis is planned when all participants 
complete the study (Day 457).
DSMB, Data Safety Monitoring Board
3.2.
SCHEDULE OF EVENTS
Schedule of events can be found in Section 1.3 of the protocol.
3.3.
CHANGES TO ANALYSES FROM PROTOCOL
There are no changes to the analyses planned in the protocol.
4. PLANNED ANALYSES
4.1.
DATA AND SAFETY MONITORING BOARD (DSMB)
An independent DSMB will provide oversight, to ensure safe and ethical conduct of the study.
The DSMB will meet monthly and make any necessary recommendations to the Sponsor based on their evaluations 
of emerging data. In particular, the evaluation of 7-day safety data from participants dosed in Stage 1 will be 
performed by the DSMB, who will advise the sponsor on whether it is appropriate to proceed into Stage 2 of the 
study. The DSMB will also review study progress and monitor for evidence of harm resulting from AZD7442. If 
required, the DSMB will recommend temporarily stopping or termination of the study. There is no formal efficacy 
look by the DSMB with the potential for early stopping due to efficacy planned for this study.


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Figure B:
Study Dose Exposure Expansion
Further details, composition, and operation of the independent DSMB will be described in a DSMB Charter.
4.2.
MORBIDITY ADJUDICATION COMMITTEE
An independent Morbidity Adjudication Committee (MAC) will be constituted to provide an independent, external, 
systematic, and unbiased assessment of blinded data to evaluate whether the causes of death for participants are 
considered COVID-19 associated. Only adjudicated deaths will be included in efficacy endpoints. All fatal events 
will be further assessed as part of safety evaluation. Further details of this adjudication will be provided in a separate 
Morbidity Adjudication Committee Charter. 
4.3.
INTERIM ANALYSIS
No interim analysis is planned.
4.4.
PRIMARY ANALYSIS
The primary analysis will occur after approximately 24 primary endpoint events have been confirmed across the 
active and control groups or 30% of study participants have become unblinded (at which point the ability to observe 
primary endpoint events is expected to have diminished), whichever occurs earlier. All primary endpoint events 
accrued up until the data cut-off (DCO) will be included in the primary analysis. The date for the DCO for this 
analysis will be the date that the 24th primary endpoint event is confirmed or the date that 30% of study participants 
have become unblinded, whichever occurs earlier.
All planned primary analyses are detailed in this SAP and will be performed by AstraZeneca or its delegates
following Sponsor authorization of this SAP, Sponsor authorization of the analysis sets, database lock (DBL), and 
Day 1
Day 8
Day 10
Stage 1
AZD7442 dose n = 300
Stage 2
AZD7442 dose
n = 4850
Safety observation
Review/Analysis


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analysis team unblinding. The primary analysis will be carried out by an unblinded analysis team, and the procedure 
will be detailed in an unblinding plan; participant level unblinding information will be kept strictly confidential, and 
rationale for any unblinding will be documented.
4.5.
FINAL ANALYSIS 
The final analysis will be conducted at the end of the study, i.e., after the last participant dosed has completed the 
Day 457 visit. 
All final, planned analyses are detailed in this SAP and will be performed by AstraZeneca or its delegates following
Sponsor authorization of this SAP, Sponsor authorization of the analysis sets, DBL, and general study unblinding.
5. ANALYSIS SETS
5.1.
ALL PARTICIPANTS ANALYSIS SET
The all participants analysis set (PAS) will contain all participants screened for the study. All participants analysis 
set is to be used for reporting disposition and screening failures.
All participants screened are those who provide informed consent.
5.2.
FULL ANALYSIS SET
The Full Analysis Set (FAS) will contain all participants in the PAS who were randomized and received at least one 
of the planned injections of IMP, irrespective of their protocol adherence and continued participation in the study.
Per the protocol a dose is two injections, but any participant receiving at least one injection will be included in the 
FAS based on intent-to-treat (ITT) principle. Participants will be analyzed according to their randomized treatment 
irrespective of whether they have prematurely discontinued, according to the ITT principle. Participants who 
withdraw consent to participate in the study will be included up to the date of their study termination.
For analyses and displays based on the FAS, participants will be classified according to randomized treatment 
regardless of what treatment they actually received.
5.3.
FULL PRE-EXPOSURE ANALYSIS SET
The Full Pre-Exposure Analysis Set (FPAS) will contain all participants in the FAS who did not have a prior SARS-
CoV-2 RT-PCR-positive confirmed COVID-19 infection. 
For analyses and displays based on the FPAS, participants will be classified according to randomized treatment 
regardless of what treatment they actually received.


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5.4.
SAFETY ANALYSIS SET
The safety analysis set (SAF) will contain all participants in the PAS who received at least one of the planned 
injections of IMP. Per the protocol a dose is two injections, but any participant receiving at least one injection will 
be included in the SAF to account for safety in all participants receiving any injection.   
For analyses and displays based on SAF, participants will be classified according to the actual treatment received.
Erroneously-treated participants (e.g., those randomized to treatment A, but were actually given treatment B) are 
accounted for in this analysis set by assigning them to the treatment they actually received. A participant who has 
once or on several occasions received active IMP is classified as active.
5.5.
PHARMACOKINETIC ANALYSIS SET
The PK analysis set will contain all participants in the PAS who received at least one injection of AZD7442 
components and from whom PK blood samples are assumed not to be affected by factors such as protocol violations 
and who had at least one quantifiable serum PK observation post dose. Per the protocol a dose is two injections, but 
any participant receiving one injection will be accounted for in the corresponding individual mAb component.   
For analyses and displays based on PK analysis set, participants will be included according to the actual treatment 
received. Participants who received placebo will not be included. Participants should be excluded from the PK 
analysis set if they were randomized to AZD7442 and instead received placebo, were randomized to placebo and 
instead received AZD7442, or received two injections of the same mAb component. Summaries will be displayed by 
the individual mAb components, AZD8895 and AZD1061. Participants who received only one mAb component 
should be excluded from both the AZD7442 total summary and the summary of the mAb component they did not 
receive.
5.6.
ADA EVALUABLE ANALYSIS SET
The ADA evaluable analysis set will contain all participants in the SAF who have a non-missing baseline AZD7442 
ADA result and at least one non-missing post-baseline AZD7442 ADA result. This analysis set is not defined in the 
protocol but is required for the analyses.
5.7.
NAB EVALUABLE ANALYSIS SET
The SARS-CoV-2 nAb evaluable analysis set will contain all participants in the SAF from whom blood samples are 
assumed not to be affected by factors such as protocol violations, and who had at least one quantifiable serum titer 
observation post dose. Participants should be excluded from the SARS-CoV-2 nAb evaluable analysis set if they 
were randomized to AZD7442 and instead received placebo, were randomized to placebo and instead received 
AZD7442, received two injections of the same mAb component, or received only one mAb component. This 
analysis set is not defined in the protocol but is required for the analyses.


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6. GENERAL CONSIDERATIONS
6.1.
REFERENCE START DATE AND STUDY DAY
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. Reference start date is defined as the day of the dose of IMP i.e., Day 1.
Study Day will be computed as follows:
!
Study Day = (Date of event – Date of dose of IMP) + 1 if the date of the event is on or after the date of the dose 
of IMP;
!
Study Day = (Date of event – Date of dose of IMP) if the date of the event is prior to the date of dose of IMP.
In the situation where the event date is partial or missing, Study Day and any corresponding durations will be 
displayed as missing in the listings.
For illness visits, an illness study day will be calculated. The reference start date is defined as the day of first illness 
assessment, i.e., illness visit Day 1. This will be calculated separately for each illness episode.
Illness Study Day will be computed as follows:
!
Illness Study Day = (Date of event – Date of illness visit Day 1) + 1.
Partial dates
Partial dates for unblinding and COVID-19 vaccination/COVID-19 preventative product in which the month and/or 
year are missing are not expected. However, imputation rules are specified as follows: in cases where the day is 
missing, then day will be imputed as the first of the month. In cases where the month is missing, then month will be 
imputed as the later of January or month of IMP administration. If the date is completely missing, the date will be 
imputed as the day after IMP administration.
6.2.
BASELINE
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the dose of IMP. 
In the case where the last non-missing measurement and the date and time of the dose of IMP coincide or where 
time is missing, that measurement will be considered baseline, but adverse events (AEs) and medications 
commencing on the date and time of the dose of IMP will be considered post-baseline.
Illness Visit baseline is defined as the first non-missing measurement taken on Illness Visit Day 1. If there is no non-
missing measurement available on Illness Visit Day 1, Illness Visit baseline is considered as missing. For instances 
where Illness Visit Day 1 occurs on the same day as a main study Visit, and Illness Visit Day 1 measurements are 
missing, then the measurements from the main study Visit will be used as Illness Visit baseline. Otherwise if there is 
still no available measurement for Illness Visit Day 1, Illness Visit baseline is considered as missing.    


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6.3.
UNSCHEDULED VISITS, RETESTS, AND EARLY TERMINATION 
DATA
For by-visit summaries, data recorded at the nominal visit will be presented. That is, unscheduled, retest (same visit 
number assigned), and early termination measurements will not be included in by-visit summaries but might
contribute to the baseline timepoint and/or maximum value, where required (e.g. shift table). Visits for human 
biological samples data will follow a windowing convention as described in Section 6.4.
Listings will include scheduled, unscheduled, retest and early discontinuation data.
6.4.
WINDOWING CONVENTIONS 
A windowing convention will be used to determine the analysis value for a given study visit for human biological 
samples data analyses. The window definitions as following will be used for the following assessments:
!
Main study: serum sample for SARS-CoV-2 serology (anti-nucleocapsid testing)
!
Main study: serum sample for AZD7442 pharmacokinetic assessment (PK)
!
Main study: serum sample for AZD7442 ADA assessment (ADA)
!
Main study: serum sample for SARS-CoV-2 nAbs assessment (pharmacodynamic [PD])
!
Main study: serum sample exploratory biomarkers 
!
Main study: participant subset only: nasal adsorption for exploratory assessments (PK)
!
Illness visits schedule: saliva sample for viral shedding
!
Illness visits schedule: serum sample for AZD7442 pharmacokinetic assessment (PK)
!
Illness visits schedule: serum sample for SARS-CoV-2 nAbs assessment (PD)
!
Illness visits schedule: nasal adsorption for SARS-CoV-2 mucosal responses and exploratory assessments (PK)
!
Illness visits schedule: serum sample for exploratory assessments
The window for the visits following baseline will be constructed in such a way that the upper limit of the interval 
falls halfway between the two visits (the lower limit of the first post-baseline visit will be Day 2). If an even number 
of days exists between two consecutive visits, then the upper limit will be taken as the midpoint value minus 1 day.
Table E:
Analysis windows for serum sample for SARS-CoV-2 serology testing and serum 
sample exploratory biomarkers by Visit 
Visit
Day Relative to Dose 
Visit Window (Study Day)
Day 1
≤ 1
≤ 1


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Day 8
8
2 - 18
Day 29
29
19 - 43
Day 58
58
44 - 74
Day 92
92
75 - 137
Day 183
183
138 - 274
Day 366
366
≥ 275
Table F:
Analysis windows for serum sample for AZD7442 PK assessment and serum sample 
for SARS-CoV-2 nAbs assessment (PD)
Visit
Day Relative to Dose 
Visit Window (Study Day)
Day 1
≤ 1
≤ 1
Day 8
8
2 - 18
Day 29
29
19 - 43
Day 58
58
44 - 74
Day 92
92
75 - 137
Day 183
183
138 - 274
Day 366
366
275 - 411
Day 457
457
≥ 412
Table G:
Analysis windows for serum sample for AZD7442 ADA assessment by Visit 
Visit
Day Relative to Dose 
Visit Window (Study Day)
Day 1
≤ 1
≤ 1
Day 29
29
2 - 43
Day 58
58
44 - 120
Day 183
183
120 - 274
Day 366
366
275 - 411
Day 457
457
≥ 412
Table H:
Analysis windows for nasal adsorption for exploratory assessments by Visit 
Visit
Day Relative to Dose 
Visit Window (Study Day)
Day 1
≤ 1
≤ 1
Day 8
8
2 - 49
Day 92
92
50 - 137
Day 183
183
138 - 274
Day 366
366
≥ 275
Table I:
Analysis windows for serum sample for AZD7442 PK, serum sample for SARS-CoV-
2 nAbs assessment (PD), and serum sample for exploratory assessments by Visit (Illness Visit 
Schedule)
Visit
Day Relative to Illness
Visit Window (Illness Day)
Illness Day 1
≤ 1
≤ 1


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Illness Day 14  
14
8 - 17
Illness Day 21
21
18 - 24
Illness Day 28
28
25 - 35
Table J:
Analysis windows for Viral Shedding by Visit (Illness Visit Schedule)
Visit
Day Relative to Illness
Visit Window (Illness Day)
Illness Day 1
≤ 1
≤ 1
Illness Day 3
3
2 - 3
Illness Day 5
5
4 - 6
Illness Day 8
8
7 - 9
Illness Day 11
11
10 - 12
Illness Day 14  
14
13 - 17
Illness Day 21
21
18 - 24
Illness Day 28
28
25 - 35
Table K:
Analysis windows for nasal adsorption for exploratory assessments by Visit (Illness 
Visit Schedule)
Visit
Day Relative to Illness
Visit Window (Illness Day)
Illness Day 1
≤ 1
≤ 1
Illness Day 14  
14
8 - 20
Illness Day 28
28
21 - 35
For assessments occurring during the Illness Visit Schedule, windows are applied only to illness episodes with 
laboratory confirmed positive RT-PCR test results. One or more results for a particular human biological samples
variable may be obtained in the same visit window. In such an event, the result with the date closest to the expected 
visit date will be used in the analysis. In the event that two observations are equidistant from the expected visit date, 
the later observation will be used in the analysis.
6.5.
COMMON CALCULATIONS
Change from baseline will be calculated as:
!
Change from baseline = Test value at post-baseline visit – Baseline value
Percent change from baseline will be calculated as:
!
Percent change from baseline (%) = (Change from baseline at post-baseline visit / Baseline value) * 100%
Change from baseline for Illness Visits will be calculated as:


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!
Change from baseline at Illness Visit Day 1 = Test value at Illness Visit Day 1 – Baseline value
!
Change from baseline at Illness Visits after Illness Visit Day 1 = Test value at post Illness Visit  – Illness Visit 
baseline value
Percent change from baseline at Illness Visits will be calculated as:
!
Percent change from baseline Illness Visit Day 1 (%) = (Change from baseline at Illness Visit Day 1/ Baseline 
value) * 100%
!
Percent change from baseline at Illness Visits after Illness Visit Day 1 (%) = (Change from baseline at post-
baseline Illness Visit / Illness Visit baseline value) * 100%
If baseline is not available, the change from baseline and percent change from baseline will not be calculated and 
will remain missing.  
7. STATISTICAL CONSIDERATIONS
For continuous data, descriptive statistics (i.e., n [number of participants with available data], mean, standard 
deviation [SD], median, minimum, maximum, and quartile values) will be presented by treatment group and visit, 
when applicable. For concentration data and log-transformed data, descriptive statistics (i.e., n [number of 
participants with available data], n < lower limit of quantification (LLOQ) [number of participants with results 
below the limit of quantification], geometric mean, arithmetic mean, SD, co-efficient of variation, median, min and 
max) will be presented by treatment group and visit, when applicable.
For categorical data, the number and percentages of participants in each category will be presented by treatment 
group and visit, when applicable. The denominator for percentage calculation is the underlying analysis set 
population unless otherwise stated.
7.1.
SAMPLE SIZE CALCULATION
Approximately 5150 participants will be randomized in a 2:1 ratio to receive a single IM dose of AZD7442 (divided 
in 2 sequential injections, one for each mAb component) (the active group, n = approximately 3433) or saline 
placebo (the control group, n = approximately 1717) on Day 1. 
The sample size calculations are based on the primary efficacy endpoint and were derived following a modified 
Poisson regression approach (Zou 2004). All participants will be followed for the entire duration of the study.
With at least 18 observed events, assuming 80% true efficacy, the study will have approximately 90% power to 
demonstrate that the lower bound of the 2-sided 95% CI for efficacy is greater than 0 (see Table L:).


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Table L:
Simulated Power by Number of Observed Events
	


Observed Events
Simulated Power
0.0074
0.0015
18
89%
0.0082
0.0016
20
96%
0.0090
0.0018
22
97%
0.0098
0.0020
24
98%
Simulated power is based upon 10000 simulations of trials assuming 80% efficacy 1 − 	


, 
using Poisson regression model with robust variance, with no participants lost follow-up. Power is the proportion of 
trials with p-value < 0.05.
The sample size necessary to achieve the power for the primary endpoint is calculated based on the assumed attack 
rate in the placebo group and the 80% efficacy assumption, using Poisson regression model with robust variance. 
7.2.
MISSING DATA
Missing efficacy data will be handled as described in Sections 16.1.2, 16.2.4, and 16.3.2 of this analysis plan. 
Partially or completely missing medication dates will be handled as described in APPENDIX 1.
7.3.
STATISTICAL TESTS
Statistical tests will be conducted at the two-sided 5% significance level. Confidence Intervals (CIs) will be two-
sided with 95% coverage.
The null hypothesis for the primary endpoint is: efficacy of AZD7442 compared to placebo in preventing COVID-
19 is equal to 0. Whereas, the alternative hypothesis is: efficacy of AZD7442 compared to placebo in preventing 
COVID-19 is not equal to 0. That is:
H0: efficacy = 0
HA: efficacy ≠ 0
Primary efficacy will be presented with a 2-sided 95% CI, and statistical significance will be achieved if the lower 
bound of the 2-sided 95% CI is > 0. The success criterion for the study will be statistical significance.
If the statistical significance of the primary efficacy endpoint is demonstrated at two-sided alpha of 0.05, formal 
assessments of the key supportive estimands and key secondary estimand will be conducted at the primary analysis.
7.4.
MULTIPLE COMPARISONS/ MULTIPLICITY
A hierarchical approach will be used to control for multiplicity of the primary, key supportive, and key secondary 
analyses. That is, the null hypotheses for these efficacy analyses will be tested in a hierarchical order, and the 


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subsequent null hypothesis will be tested at a significance level of 0.05 (two-sided) only if the prior null hypothesis 
is rejected (i.e., the treatment effect on the efficacy endpoint is demonstrated at the significance level of two-sided 
0.05). The hierarchical approach will include the below analyses as ordered:
1.
The primary efficacy endpoint will be assessed at the primary analysis, using the primary estimand, after 
approximately 24 primary endpoint events have been confirmed or 30% of study participants have become 
unblinded, whichever occurs earlier. All primary endpoint events accrued up until data cut-off will be 
included in the primary analysis.
2.
If the statistical significance of the primary efficacy endpoint is demonstrated at 2-sided alpha of 0.05, a 
formal assessment of the primary endpoint using the first key supportive estimand (treatment policy 
strategy) will be conducted also at the primary analysis. 
3.
If the statistical significance of the first key supportive analysis of the primary endpoint is demonstrated at 
2-sided alpha of 0.05, a formal assessment of the primary endpoint using the second key supportive 
estimand (including death due to any cause) will be conducted also at the primary analysis.
4.
If the statistical significance of the second key supportive analysis of the primary endpoint is demonstrated 
at 2-sided alpha of 0.05, a formal assessment of the key secondary efficacy endpoint will be conducted also 
at the primary analysis. 
Only nominal p-values will be provided for the other secondary and exploratory efficacy endpoints.  No statistical 
testing will be performed for the safety endpoints.
7.5.
MULTICENTER STUDIES
This study will be conducted by multiple investigators at multiple centers internationally.  Data from all centers will 
be pooled together in the analyses and there are no plans to perform an analysis of homogeneity of the results across 
centers.
7.6.
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES
The analyses will be adjusted for the following covariates and factors. For details of their inclusion in the models, 
refer the Sections 16.1.3 and 16.2.5.
!
Categorical age (years) at randomization from the Electronic Data Capture (EDC) system (≥60 and < 60).
7.7.
EXAMINATION OF SUBGROUPS
Subgroup analyses will be conducted as stated in Section 16.1.7. It should be noted that the study was not designed 
to detect treatment differences with high statistical power within subgroups.


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The list of subgroups includes but may not be limited to:
!
Categorical age (years) at informed consent (3 groupings 1: ≥60 years and <60 years, 2: ≥65 years and <65 
years, 3: ≥75 years and <75 years);
!
Residence in long-term care facility (yes and no);
!
Increased risk of exposure to infection with SARS-CoV-2 (yes and no);
!
Increased risk for inadequate response to active immunization (yes and no);
!
Sex (male and female);
!
Region (North America, United Kingdom, and European Union);
!
Country (United States, United Kingdom, Belgium, France, Spain);
!
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific 
Islanders, White);
!
Ethnicity (Hispanic or Latino, Not Hispanic or Latino);
!
COVID-19 co-morbidities at baseline (at least one co-morbidity, no co-morbidity);
!
High Risk for severe COVID-19 at baseline (History of Obesity, Obese (baseline BMI≥30), Morbid Obesity
(baseline BMI≥40), Chronic kidney disease (CKD), Diabetes, Immunosuppressive disease, Immunosuppressive 
treatment, Cardiovascular disease (CV disease), Chronic obstructive pulmonary disease (COPD), Chronic liver 
disease, Hypertension, Asthma, Cancer, Smoking, Sickle cell disease) (yes/no; refer to APPENDIX 1 for 
description of each condition).
If models of subgroup analysis do not converge due to sparse data, changes to planned subgroup analysis will be 
described in the CSR.
Subgroup data will be obtained from the EDC system for items collected in both EDC and Interactive Response 
Technology (IRT).
7.8.
SOFTWARE VERSION
All analyses will be conducted using SAS version 9.4 or higher. 
8. OUTPUT PRESENTATIONS
APPENDIX 2 shows conventions for presentation of data in outputs. 
The templates provided with this SAP describe the presentations for this study and therefore, the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics.


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9. DISPOSITION AND WITHDRAWALS
All participants who provide informed consent will be accounted for in this study. 
9.1.
DISPOSITION
Number of participants screened will be presented overall for the PAS. Number and percentage of participants with 
screen failure and reason for screen failure will also be presented overall based on the PAS. Number of participants 
randomized will be presented overall and by treatment group for the PAS.
Number and percentages of participants dosed, discontinued early from IMP (including reason for not receiving both 
injections), ongoing in study (for primary analysis only), who discontinued early from the study (including reason 
for withdrawal), and who became unblinded to received treatment (including reason for unblinding) will be provided 
overall and by planned treatment group based on the FAS.
The number of participants included and excluded from each analysis set (including reason for exclusion) will be 
summarized overall and by planned treatment group based on the FAS. A listing showing inclusion and exclusion of 
each participant from each analysis set, including reason for exclusion, will be provided.
9.2.
PROTOCOL DEVIATIONS
Number and percentage of participants with important protocol deviations, as identified by the study team in a 
blinded fashion before the DBL, will be provided overall and by planned treatment group based on the FAS for each 
category of protocol deviations specified in the Protocol Deviations Management Plan.
A listing of protocol deviations identified by the study team (important or not) will be provided.
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
The following demographic and other baseline characteristics will be reported for this study:
!
Age (years) – collected at informed consent
!
Age groups (≥18 to <60 years, ≥60 to <70 years, ≥70 to <80 years, and ≥80 years; ≥60 years, ≥65 years, and 
≥75 years)
!
Sex (refer to Section 7.7)
!
Race (refer to Section 7.7)
!
Ethnicity (refer to Section 7.7)
!
Weight (kg)


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!
Height (cm)
!
Body Mass Index (BMI) (kg/m2)
!
BMI group (kg/m2) (<18.5, ≥18.5 - <25, ≥25 - <30, ≥30 - <40, and ≥40)
!
Screening result from NP swab for SARS-CoV-2 RT-PCR (positive, negative)
!
Smoking status (current, former, never)
!
ECOG performance status (0, 1, and >1)
!
Home or other confinement status (yes/no)
!
Country (refer to Section 7.7)
!
High Risk for severe COVID-19 at baseline (History of Obesity, Obese (baseline BMI≥30), Morbid Obesity
(baseline BMI≥40), CKD, Diabetes, Immunosuppressive disease, Immunosuppressive treatment, CV Disease, 
COPD, chronic liver disease, Hypertension, Asthma, Cancer, Smoking, Sickle cell disease) (yes/no)
!
COVID-19 risk assessment data as collected on the eCRF
!
Subgroups specified in Section 7.7 and not previously listed above
Continuous demographic and other baseline characteristics will be summarized using descriptive statistics overall 
and by planned treatment group based on the FAS and FPAS.  For categorical demographic and other baseline 
characteristics, number and percentage of participants in each category will be provided overall and by planned
treatment group based on the FAS and FPAS. If there are major differences between the FAS and the SAF, the 
summaries will be repeated and presented by actual treatment group for the SAF. No statistical testing will be 
carried out for demographic or other baseline characteristics.
All demographic and risk assessment data will be listed.
10.1. DERIVATIONS
BMI, in kg/m2, will be calculated as follows: 
!
BMI (kg/ m2) = weight (kg)/ [height (m)2]
11.
MEDICAL HISTORY
Medical history is defined as any medical conditions/diseases that started and stopped before the first dose of IMP. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.1 or 
higher, and will be summarized by System Organ Class (SOC) and Preferred Term (PT) overall and by planned 
treatment group based on the FAS. A participant having more than one medical condition/disease within the same 


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SOC/PT will be counted only once for that SOC or PT.
COVID co-morbidities are collected on the Medical history page of the eCRF. The number and percentage of 
participants with each co-morbidity and also with any co-morbidities will be summarized overall and by planned 
treatment group based on the FAS.
All medical history will be listed.
12.
CONCOMITANT ILLNESSES
Concomitant conditions/illnesses are defined as any medical conditions/illnesses that started before the first dose of
IMP AND were ongoing at the time of the dose of IMP or ended on date of dose.
Concomitant conditions/illnesses will be coded using the MedDRA, version 23.1 or higher, and will be summarized 
by SOC and PT overall and by planned treatment group based on the FAS.  A participant having more than one 
medical condition/illness within the same SOC or PT will be counted only once for that SOC or PT.
All concomitant conditions/illnesses will be listed.
13.
MEDICATIONS
Prior medications are defined as any medication that started and stopped prior to the dose of IMP.
Concomitant medications are defined as:
!
Any medication that started before the dose of IMP AND was ongoing at the time of the dose of IMP or ended 
on the date of dose of IMP;
!
Any medication that started on or after the dose of IMP.
Partially or completely missing medication start and stop dates will be handled as described in APPENDIX 1.
All medications will be coded using the World Health Organization (WHO) Drug Global dictionary, version B3 
March 2020, or a more recent version.
Prior and concomitant medications will be summarized by Anatomical Therapeutic Class (ATC) level 2 and 
preferred drug name overall and by planned treatment group based on the FAS. A participant having more than one 
medication within the same ATC Level 2 or preferred drug name will be counted only once for that ATC Level 2 or 
preferred drug name.
All collected prior and concomitant medications will be listed.


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14.
EXPOSURE TO STUDY INTERVENTION
Due to the simplicity of dosing for this study, exposure is summarized in the participant disposition table. All 
exposure data will be listed.
15.
COMPLIANCE WITH STUDY INTERVENTION
Compliance will not be calculated since participants receive a single dose (2 IM injections) within clinic.
16.
EFFICACY ENDPOINTS
Unless otherwise indicated, all efficacy summaries and figures will be presented based on the FPAS.
16.1. PRIMARY EFFICACY
16.1.1.
PRIMARY EFFICACY ENDPOINT
The primary endpoint is the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose of 
IMP and prior to Day 183. The primary efficacy endpoint is to be to be assessed after approximately 24 primary 
endpoint events have been confirmed or 30% of study participants have become unblinded, whichever occurs 
earlier. 
Participants will be included as an event in the primary endpoint if they have RT-PCR-confirmed SARS-CoV-2
prior to Day 183 and present with at least one of the qualifying symptoms in Table M:. The onset of symptoms will 
commonly occur between 2 and 8 days of infection with detectable virus typically up to 15 days. To maintain the 
relationship between the RT-PCR sample and symptoms the sample should be collected on or close to the symptom 
assessment but must be collected within 5 days prior or 10 days following the assessment of qualifying symptoms. 
This duration will allow participants time to assess and confirm symptoms under medical supervision after the onset 
of symptoms, which will typically, but not always, occur at Illness Visit Day 1. A positive SARS-CoV-2 RT-PCR
will be defined based on the central laboratory result whenever both central and local laboratory results are available
for nasopharyngeal (NP) swabs, or if only a central lab NP swab result is available. If only a local NP swab 
laboratory result is available, then the local laboratory result will be used. If neither central nor local NP swab 
laboratory results are available, a saliva sample taken within window during Illness Visits will be used to determine
the RT-PCR result. If no SARS-CoV-2 RT-PCR results are available, the participant will be considered as not 
having met the primary endpoint. Data from the eCRF will be used to determine if the participant met the qualifying 
symptoms. If a participant’s first case of SARS-CoV-2 RT-PCR positive symptomatic illness occurs on or after Day 
183, the participant will be considered as not having met the primary endpoint.


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Table M:
COVID-19 Qualifying Symptoms
Duration
Symptom
No minimum duration
Fever
Shortness of breath
Difficulty breathing
New onset confusion (only for participants ≥60 years old)
Appetite loss or decrease food intake (only for participants ≥60 years old)
Increased supplemental oxygen requirement (only for participants ≥60 years 
old on baseline supplemental oxygen)
Must be present for ≥2 days
Chills
Cough
Fatigue
Muscle aches
Body aches
Headache
New loss of taste
New loss of smell
Sore throat
Congestion
Runny nose
Nausea
Vomiting
Diarrhea
Adapted from (CDC, 2020) 
CDC, Centers for Disease Control and Prevention
16.1.2.
MISSING DATA IMPUTATION METHOD FOR PRIMARY EFFICACY ENDPOINT
No missing data imputation method will be used for primary efficacy analysis. For participants who withdraw from 
the study prior to having met the criteria for the primary efficacy endpoint. Participants will be censored (considered 
as not having the event) at the time of last observation.
Sensitivity analyses will be explored to assess the robustness of treatment effects for the primary efficacy endpoint, 
where different missing data mechanisms will be explored using multiple imputation approaches. Full details of the 
sensitivity analyses are specified in Section 16.1.5.


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16.1.3.
PRIMARY ESTIMAND 
The treatment condition of interest is single dose of AZD7442 (two IM injections, one for each mAb component, 
AZD8895 and AZD1061). The alternative treatment condition to which comparison will be made is a placebo.
The population of participants targeted in the primary estimand includes adults at least 18 years of age who have not 
had a prior SARS-CoV-2 RT-PCR-positive confirmed COVID-19 infection and who are candidates for benefit from 
passive immunization with antibodies, defined as having increased risk for inadequate response to active 
immunization (predicted poor responders to vaccines OR intolerant of vaccine), OR having increased risk for 
SARS-CoV-2 infection, defined as those whose locations or circumstances put them at appreciable risk of exposure 
to SARS-CoV-2 and COVID-19.
The primary endpoint (variable) to be obtained is a binary response, whereby a participant is defined as a COVID-19 
case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurs post dose of IMP prior to Day 
183.
The primary estimand uses a while on treatment strategy. Data for participants who become unblinded to treatment 
assignment and/or take COVID-19 vaccine or other COVID-19 preventive product, in both cases prior to having met 
the criteria for the primary efficacy endpoint, are censored at the date of unblinding/receipt of first dose of COVID-
19 preventive product, whichever is earlier.
The population-level summary measure is prophylactic efficacy, calculated as 1 −relative risk (RR). (RR is the 
incidence of infection in the AZD7442 group relative to the incidence of infection in the control group.)
16.1.4.
PRIMARY ANALYSIS OF PRIMARY EFFICACY ENDPOINT
The primary efficacy analysis of the primary endpoint will be performed on the FPAS. Participants who withdraw 
from the study prior to having met the criteria for the primary efficacy endpoint will be censored (considered as not 
having the event) at the time of last observation. Participants with deaths that are caused by SARS-CoV-2 (death 
related to COVID marked on the death eCRF page) will be considered as having the event, even if no other 
qualifying symptoms are met. Participants with hospitalizations due to COVID-19 will also be considered as having 
the event.
A Poisson regression model with robust variance (Zou, 2004) adjusting for follow-up time, will be used as the 
primary efficacy analysis model to estimate the RR on the incidence of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring post dose of IMP between the AZD7442 and the placebo groups. The model contains 
the planned treatment group and age group at the time of informed consent (i.e., ≥ 60 years and < 60 years, see 
Section 7.6) as a covariate. The logarithm of the participant’s corresponding follow-up time at risk starting from 
dose up to the study day 183 visit will be used as an offset variable in the model to adjust for participants having 
different exposure times during which the events occur. Participants who withdraw or have a non-COVID-19 related 
death prior to meeting the primary endpoint will not be counted as having the event. The follow up time for those 
participants will be at that time relative to dose. Calculation of follow-up time is detailed as following: 


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!
For participants who meet the primary endpoint before Day 183, the follow-up time will be calculated as (Date 
of Onset of Primary Endpoint) – (Date of Dosing) + 1. Date of Onset of Primary Endpoint is defined as the 
assessment date of qualifying COVID symptoms, if associated with a positive SARS-CoV-2 RT-PCR lab test
from a sample collected within the 5 days prior to symptom assessment through 10 days after symptom 
assessment. In the case of death due to COVID-19 or hospitalization due to COVID-19, the Date of Onset of 
Primary Endpoint is the earliest date of death/date of hospital admission when a qualifying symptom assessment 
is not observed.
!
For participants who do not experience a primary endpoint before Day 183, the efficacy follow-up time will be
considered censored and determined based on the following: 
o
If an end of study date occurs prior to Day 183, the efficacy follow-up time will be calculated as (Date 
of End of Study or Date of Last Assessment, whichever is later) – (Date of Dosing) + 1. 
o
If an end of study date occurs after Day 183, the efficacy follow-up will be censored at Day 183.
For participants who continue to participate in the study at the time of the primary analysis, the DCO date will be 
used as their last assessment date. For participants with no post-baseline visit data available, the date of IMP 
administration will be used i.e. follow-up will be 1 day.
Efficacy is the incidence of infection in the AZD7442 group relative to the incidence of infection in the placebo
group, expressed as a percentage. Efficacy will be calculated as relative risk reduction (RRR) = 100% x (1 - relative 
risk).
RRR and its corresponding 2-sided 95% CI will be estimated from the Poisson regression model with robust 
variance. In addition, the 2-sided p-value testing null hypothesis that there is no difference in efficacy between 
AZD7442 and placebo (i.e. the efficacy is equal to 0) will be obtained from the model. Statistical significance will 
be achieved if the lower bound of the 95% CI for efficacy is > 0, which corresponds to an observed two-sided p-
value < 0.05. For the final analysis nominal 95% CI’s will be presented.
The Poisson regression with robust variance analysis will be implemented by using the SAS PROC GENMOD 
procedure with the REPEATED statement for participant ID and logarithm link as well as OFFSET option. The 
estimated parameter [i.e., log(RR)], 2-sided 95% confidence interval (CI) for , and the 2-sided p-value will be 
obtained from the SAS outputs. The estimated RR and corresponding CI for the RR is given by exponentiating 
and its confidence limits. Therefore, the percent of RRR is given by [(1 – exp()) * 100%]. The CI for the percent of 
RRR is given by ([1 – exp(upper confidence limit for ) * 100%], [1 – exp(lower confidence limit for ) * 100%]).
If convergence cannot be achieved with the Poisson regression analysis model with robust variance, the Cochran-
Mantel-Haenszel (CMH) will be used as the primary analysis model to test the treatment effect on SARS-CoV-2 
RT-PCR-positive symptomatic illness between AZD7442 and placebo groups. The CMH test will be stratified by 
age group at the time of informed consent (i.e., ≥ 60 years and < 60 years, see Section 7.6). The RR of AZD7442
over placebo for the incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose and the 
95% CI will be obtained. The percent of RRR and the 95% CI will be reported following the relationship of RRR 


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(%) = (1- RR) * 100%. A Breslow-Day test will be conducted, and p-value presented, to evaluate homogeneity of 
the RRR across strata. 
A listing will be provided for all COVID-19 symptom assessments and NP swabs assessed by RT-PCR (both local 
laboratory and central laboratory samples) regardless of RT-PCR result.
16.1.5.
SENSITIVITY ANALYSES FOR PRIMARY EFFICACY ENDPOINT
As a sensitivity analysis to the handling of missing data in the analysis of the primary efficacy endpoint, the primary 
analysis of the primary efficacy endpoint (Section 16.1.4) will be repeated with multiple imputation for intercurrent 
events. For participants who are in FPAS but (1) do not have a SARS-CoV-2 RT-PCR-positive symptomatic illness 
status occurring post dose of IMP and withdraw from the study prior to the time of analysis, or (2) were unblinded to 
treatment assignment prior to having met the criteria for the primary efficacy endpoint, or (3) received COVID-19 
vaccine or other preventive product prior to having met the criteria for the primary efficacy endpoint, their event 
status will be imputed assuming the observed event rate per treatment group conditional on stratification factors 
using multiple imputation techniques as described in the following paragraphs. 
The primary analysis using Poisson regression with robust variance requires a participant-level dataset. A repeated 
imputation approach is introduced to impute the status of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring post dose of IMP for missing observations at the participant level for the model fitting. By incorporating 
the between-imputation variance, a reliable statistical inference in both hypothesis testing and CI estimation of the 
treatment effect is expected through the repeated imputation (Little and Rubin, 2002). In the primary analysis the 
missing outcome for participants who drop out (e.g., withdrawal, lost to follow-up, death not caused by SARS-CoV-
2, etc.) prior to reaching cut-off time for analysis without a SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring post dose of IMP will be imputed per stratum determined by the stratification factor using observed event 
rate per treatment group. The imputation and subsequent analysis may be carried out using SAS PROC MI 
(Monotone Logistic Regression Method) and SAS PROC MIANALYZE. The detailed imputation steps are 
described as follows. 
!
Step 1: Missing events in both arms will be imputed with the observed event rate per treatment group. The 
imputation may be executed using SAS PROC MI (logistic regression method with the recoded treatment term 
and stratification factor), or random sampling from an appropriate distribution. The random seed is 10021.
!
Step 2: A complete dataset comprises the imputed SARS-CoV-2 RT-PCR-positive symptomatic illness status 
and observed SARS-CoV-2 RT-PCR-positive symptomatic illness status.
!
Step 3: Analyze the complete dataset using a Poisson regression model with robust variance to estimate the RR 
on the incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness between AZD7442 and placebo, with 
the term of treatment group and the stratification factor. The point estimate of log-transformed RR and its 
variance will be extracted from the model. 
!
Steps 1-3 will be repeated 20 times. SAS procedure PROC MIANALYZE will be used to combine inferences 
from the 20 completed datasets, that will result in a combined point estimate of log-transformed RR and the 


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variance. 
A sensitivity analysis of the primary endpoint, in which participants who were seropositive by any test for SARS-
CoV-2 pre-dose of IMP are excluded, may be performed.
16.1.6.
SUPPLEMENTARY ANALYSES FOR PRIMARY EFFICACY ENDPOINT
As a supplementary analysis, the primary analysis of the primary efficacy endpoint (refer to Section 16.1.4) will be 
repeated including region (Section 7.7) as an additional covariate to assess the robustness of the efficacy results, if 
data permit.
To support the primary analysis, time to event (i.e., the duration in days from dose to first event or censoring) 
analyses will be performed as follows. A Cox proportional hazard (PH) model, stratified by age group at informed 
consent (Section 7.6) with treatment group as the only covariate, will be fitted to the data, and the Efron method will 
be used to control for ties. The hazard ratio and corresponding 95% CI from the Cox PH model will be presented. 
Kaplan-Meier curves with log-rank test p-value will also be presented by treatment arm.. Corresponding descriptive 
statistics for the active and control groups will also be produced.
In addition, the absolute risk reduction of AZD7442 over placebo in preventing the incidence of the SARS-CoV-2 
RT-PCR positive symptomatic illness prior to Day 183 will be presented, along with the 2-sided 95% CI using the 
Miettinen and Nurminen’s score method (Miettinen and Nurminen, 1985). The absolute risk reduction (ARR) will 
be implemented using the SAS PROC FREQ procedure.
16.1.7.
SUBGROUP ANALYSES FOR PRIMARY EFFICACY ENDPOINT
Subgroup analysis will be performed for the primary efficacy endpoint, SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring post dose of IMP and prior to Day 183. For subgroup analysis, FPAS will be used. 
Treatment-by-subgroup interaction will be tested using the Poisson regression with robust variance model adjusting 
for follow-up time with the terms of planned treatment, age group (Section 7.6), subgroup, and treatment-by-
subgroup interaction, which will be implemented using PROC GENMOD procedure. If this full model does not 
achieve convergence, a reduced model of planned treatment, subgroup, and treatment-by-subgroup interaction will 
be considered. Within each level of a subgroup, the RRR and its corresponding 95% CI will be estimated using a 
Poisson regression model with robust variance with the term of treatment. A forest plot of the RRR and the 95% CI 
will be presented. If the CMH model is used for primary analysis (e.g. if the Poisson regression model fails to
converge), a CMH model will also be used for subgroup analyses to generate the RRR and the corresponding 95% 
CI.
The subgroup analysis will be conducted for the subgroups in Section 7.7 on the FPAS population.
For subgroups corresponding to one of the factor levels included in the analysis model, the corresponding factor will 
not be included in the model.  For example, the age group factor will not be included in the model for the analysis of 
participants < 60 years old at the time of informed consent subgroup and analysis of participants ≥ 60 years old at 


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the time of informed consent subgroup.
No adjustment to the significance level for testing of all these subgroup analyses will be made since all these 
analyses will be considered supportive of the primary analysis.
16.1.8.
ADDITIONAL ESTIMANDS FOR PRIMARY EFFICACY ENDPOINT
Additional estimands will also be used for the primary efficacy as shown in Table N:. 


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Table N:
List of Additional Estimands for Primary Efficacy 
Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
The efficacy 
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
prevention 
of COVID-
19 prior to
Day 183 –
Hypothetical 
Estimand
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, and 
did not have a prior SARS-CoV-2 RT-PCR-
positive confirmed COVID-19 infection. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
A binary 
response, 
whereby a 
participant is 
defined as a 
COVID-19 
case if their 
first case of 
SARS-CoV-
2 RT-PCR-
positive 
symptomatic 
illness 
occurs post 
dose of IMP
and prior to 
Day 183.
For participants who 
become unblinded to 
treatment assignment
and/or take COVID-19 
vaccine or other COVID-
19 preventive product, in 
both cases prior to having 
met the criteria for the 
primary efficacy 
endpoint, only data prior 
to the intercurrent event
(i.e., up to the date of 
unblinding/receipt of first 
dose of COVID-19 
preventive product, 
whichever is earlier) will 
be considered and data 
after the intercurrent 
event will be imputed
(i.e., intercurrent events 
will be handled using 
hypothetical strategy).
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
See Section 16.1.8.1.
The efficacy 
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
prevention 
of COVID-
19 prior to
Day 183 –
Principal 
Stratum 
Estimand
Full pre-exposure analysis set, defined as all 
participants who were randomized, received at 
least one of the planned injections of IMP, and 
did not have a prior SARS-CoV-2 RT-PCR-
positive confirmed COVID-19 infection. 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
Single dose of 
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
A binary 
response, 
whereby a 
participant is 
defined as a 
COVID-19 
case if their 
first case of 
SARS-CoV-
2 RT-PCR-
positive 
symptomatic 
illness 
occurs post 
dose of IMP
and prior to 
Day 183.
Participants who become 
unblinded to treatment 
assignment and/or take 
COVID-19 vaccine or 
other COVID-19 
preventive product, in 
both cases prior to having 
met the criteria for the 
primary efficacy 
endpoint, will be excluded 
from analysis (i.e., 
intercurrent events will be 
handled using principal 
stratum strategy). The 
principal stratum is the 
stratum of participants 
who did not experience an 
intercurrent event
independent of 
randomized treatment 
assignment.
Prophylactic 
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 
The efficacy 
A subset of the full pre-exposure analysis set, 
Single dose of 
A binary 
Participants who become 
Prophylactic 


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Label
Attributes
Definition Population
Treatment Condition 
of Interest
Variable/
Endpoint
Intercurrent event 
handling strategy
Population-level 
summary measure
of a single 
IM dose of 
AZD7442 
compared to 
placebo for 
the 
prevention 
of COVID-
19 prior to
Day 183 –
Per Protocol 
Estimand
defined as all participants who were 
randomized, received a full dose of IMP, who
did not have a prior SARS-CoV-2 RT-PCR-
positive confirmed COVID-19 infection, and 
who have no significant deviations from the 
protocol prior to Day 183 or meeting the 
primary endpoint (whichever occurs first). 
Targeted participants will have the following 
characteristics:
Adults ≥ 18 years of age who are candidates for 
benefit from passive immunization with 
antibodies, defined as having increased risk for 
inadequate response to active immunization 
(predicted poor responders to vaccines OR 
intolerant of vaccine), OR having increased risk 
for SARS-CoV-2 infection, defined as those 
whose locations or circumstances put them at 
appreciable risk of exposure to SARS-CoV-2 
and COVID-19.
AZD7442 (× 2 IM 
injections, 1 for each 
mAb component) or 
placebo
response, 
whereby a 
participant is 
defined as a 
COVID-19 
case if their 
first case of 
SARS-CoV-
2 RT-PCR-
positive 
symptomatic 
illness 
occurs post 
dose of IMP
and prior to 
Day 183.
unblinded to treatment 
assignment and/or take 
COVID-19 vaccine or 
other COVID-19 
preventive product, in 
both cases prior to having 
met the criteria for the 
primary efficacy 
endpoint, will be censored 
at the date of 
unblinding/receipt of first 
dose of COVID-19 
preventive product, 
whichever is earlier (i.e., 
intercurrent events will be 
handled using a while on 
treatment strategy).
efficacy, calculated 
as 1-relative risk. 
(Relative risk is the 
incidence of 
infection in the 
AZD7442 group 
relative to the 
incidence of 
infection in the 
control group.) 


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16.1.8.1.
Hypothetical Estimand  
The treatment condition of interest is single dose of AZD7442 (two IM injections, one for each mAb component, 
AZD8895 and AZD1061). The alternative treatment condition to which comparison will be made is a placebo.
The population of participants targeted in the primary estimand includes adults at least 18 years of age who have not 
had a prior SARS-CoV-2 RT-PCR-positive confirmed COVID-19 infection and who are candidates for benefit from 
passive immunization with antibodies, defined as having increased risk for inadequate response to active 
immunization (predicted poor responders to vaccines OR intolerant of vaccine), OR having increased risk for 
SARS-CoV-2 infection, defined as those whose locations or circumstances put them at appreciable risk of exposure 
to SARS-CoV-2 and COVID-19.
The primary endpoint (variable) to be obtained is a binary response, whereby a participant is defined as a COVID-19 
case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurs post dose of IMP prior to Day 
183.
The population-level summary measure is prophylactic efficacy, calculated as 1 −relative risk (RR). (RR is the 
incidence of infection in the AZD7442 group relative to the incidence of infection in the control group.)
For participants who become unblinded to treatment assignment and/or take COVID-19 vaccine or other COVID-19 
preventive product, in both cases prior to having met the criteria for endpoint, only data prior to the intercurrent 
event (i.e., up to the date of unblinding/receipt of first dose of COVID-19 preventive product, whichever is earlier) 
will be considered and data after the intercurrent event will be imputed (i.e., intercurrent events will be handled 
using hypothetical strategy). A single imputation from the Bernoulli distribution will be used, where the probability 
that the participant experiences the primary endpoint is the event rate observed in the subset of participants who did 
not have an intercurrent event in the same arm. The detailed imputation steps are described as follows. 
!
If the participant experiences a primary endpoint event then no imputation is required, and data is considered up 
to the Date of Onset of Primary Endpoint (Section 16.1.4).
!
If the participant does not experience a primary endpoint event and also has no intercurrent event, then no 
imputation is performed, and data is considered up to Date of End of Study or Date of Last Assessment, 
whichever is later. If an end of study date or date of last assessment occurs after Day 183, the efficacy follow-up 
will be censored at Day 183. For participants who continue to participate in the study at the time of the primary 
analysis, the DCO date will be used as their last assessment date. For participants with no post-baseline visit 
data available, the date of IMP administration will be used i.e. follow-up will be 1 day.
!
If the participant has an intercurrent event before Day 183 and before a primary endpoint event: 
o
Step 1: The missing event status will then be imputed using a single imputation from the Bernoulli 
distribution, where the probability that the participant experiences the primary endpoint is the event 
rate observed in the subset of participants who did not have an intercurrent event in the same arm and 
age group. For participants in the placebo group:  =
"#$%&'(),+) ,-
.#$%&'(),+) ,- , where: / ,0 1" is the 


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number of participants in the placebo arm who experience a primary endpoint event and did not 
experience an intercurrent event; 2 ,0 1" is the number of participants in the placebo arm who 
did not experience an intercurrent event. The value of  will be calculated separately for each 
age group within the placebo arm. For participants in the AZD7442 group: 3456778 =
"9:;<==>,+) ,-
.9:;<==>,+) ,- , 
where: /3456778,0 1" is the number of participants in the AZD7442 arm who experience a primary 
endpoint event and did not experience an intercurrent event; 23456778,0 1" is the number of 
participants in the AZD7442 arm who did not experience an intercurrent event. The value of 3456778
will be calculated separately for each age group within the AZD7442 arm. If there are zero events 
observed in a given age group in a given arm, then the event rate used for imputation will be the arm-
specific event rate (pooled across both age groups). The random seed is 23456.
o
Step 2: The follow-up time will be calculated as described in Section 16.1.4. For participants who 
previously had an intercurrent event prior to meeting the primary endpoint and now have an imputed 
primary endpoint event, the Date of Onset of Primary Endpoint will be the date of the first intercurrent 
event.
o
Step 3: Analyze the complete hypothetical estimand dataset using a Poisson regression model with 
robust variance as described in Section 16.1.4. Participants with an observed event or an imputed event 
are both included as events, and participants without an observed event or without an imputed event 
are no included as primary endpoint events.
o
Step 4: Repeat steps 1 through 3 above 100 times. The reported effect size will be the average of the 
results from the 100 analyses using the imputed datasets.
16.1.9.
KEY SUPPORTIVE ANALYSES OF PRIMARY EFFICACY ENDPOINT
As key supportive analyses, the primary analysis of the efficacy endpoint (refer to Section 16.1.4) will be repeated 
using two key supportive estimands: one, which utilizes a treatment policy strategy for intercurrent events , and a 
second, which includes death due to any cause in the primary endpoint. These analyses are included in the multiple
testing hierarchy described in Section 7.4. The attributes of the key supportive estimands are described in Table O:
and Table P:.
Table O:
List of First Key Supportive Estimand Attributes
Label
The efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of 
COVID-19 prior to Day 183 – Treatment Policy Estimand
Definition 
Population
Full pre-exposure analysis set, defined as all participants who were randomized, received 
at least one of the planned injections of IMP, and did not have a prior SARS-CoV-2 RT-
PCR-positive confirmed COVID-19 infection. Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age who are candidates for benefit from passive immunization with 
antibodies, defined as having increased risk for inadequate response to active 
immunization (predicted poor responders to vaccines OR intolerant of vaccine), OR 


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having increased risk for SARS-CoV-2 infection, defined as those whose locations or 
circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19.
Treatment 
Condition of 
Interest
Single dose of AZD7442 (× 2 IM injections, 1 for each mAb component) or placebo
Variable/Endpoint
A binary response, whereby a participant is defined as a COVID-19 case if their first case 
of SARS-CoV-2 RT-PCR-positive symptomatic illness occurs post dose of IMP and prior 
to Day 183.
Intercurrent event 
handling strategy
Participants who become unblinded to treatment assignment and/or take COVID-19 
vaccine or other COVID-19 preventive product, in both cases prior to having met the 
criteria for the primary efficacy endpoint, will be included and analyzed regardless (i.e., 
intercurrent events will be handled using a treatment policy strategy).
Population-level 
summary measure
Prophylactic efficacy, calculated as 1-relative risk. (Relative risk is the incidence of 
infection in the AZD7442 group relative to the incidence of infection in the control 
group.)
Table P:
List of Second Key Supportive Estimand Attributes
Label
The efficacy of a single IM dose of AZD7442 compared to placebo for the prevention of 
COVID-19 prior to Day 183 – All-Cause Mortality Estimand
Definition 
Population
Full pre-exposure analysis set, defined as all participants who were randomized, received 
at least one of the planned injections of IMP, and did not have a prior SARS-CoV-2 RT-
PCR-positive confirmed COVID-19 infection. Targeted participants will have the 
following characteristics:
Adults ≥ 18 years of age who are candidates for benefit from passive immunization with 
antibodies, defined as having increased risk for inadequate response to active 
immunization (predicted poor responders to vaccines OR intolerant of vaccine), OR 
having increased risk for SARS-CoV-2 infection, defined as those whose locations or 
circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19.
Treatment 
Condition of 
Interest
Single dose of AZD7442 (× 2 IM injections, 1 for each mAb component) or placebo
Variable/Endpoint
A binary response, whereby a participant is defined as a COVID-19 case if their first case 
of SARS-CoV-2 RT-PCR-positive symptomatic illness or death from any cause occurs 


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post dose of IMP and prior to Day 183.
Intercurrent event 
handling strategy
Participants who become unblinded to treatment assignment and/or take COVID-19 
vaccine or other COVID-19 preventive product, in both cases prior to having met the 
criteria for the primary efficacy endpoint, will be censored at the date of 
unblinding/receipt of first dose of COVID-19 preventive product, whichever is earlier 
(i.e., intercurrent events will be handled using a while on treatment strategy).
Population-level 
summary measure
Prophylactic efficacy, calculated as 1-relative risk. (Relative risk is the incidence of 
infection in the AZD7442 group relative to the incidence of infection in the control 
group.)
16.2. SECONDARY EFFICACY
The key secondary efficacy endpoint is:
!
The incidence of participants who have a post-treatment response (negative at baseline to positive at any time 
post-baseline) for SARS-CoV-2 nucleocapsid antibodies
The other secondary efficacy endpoints are:
!
The incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic illness occurring post dose of 
IMP
!
The incidence of COVID-19-related Emergency Department visits occurring after dosing with IMP
Please refer to Section 17 for other secondary endpoints related to PK and ADA data.
16.2.1.
KEY SECONDARY EFFICACY ENDPOINT
The key secondary endpoint is the incidence of participants who have a post-treatment response (negative at 
baseline to positive at any time post-baseline) for SARS-CoV-2 nucleocapsid antibodies. 
The primary and the key secondary efficacy hypotheses will be assessed by a hierarchical order. More details on 
multiplicity are provided in Section 7.4.
16.2.2.
ESTIMANDS FOR KEY SECONDARY EFFICACY
The treatment condition of interest is single dose of AZD7442 (two IM injections, one for each mAb component, 
AZD8895 and AZD1061). The alternative treatment condition to which comparison will be made is a placebo.
The population of participants targeted in the key secondary estimand includes adults at 18 years of age who have 
not had a prior SARS-CoV-2 RT-PCR-positive confirmed COVID-19 infection and who are candidates for benefit 


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from passive immunization with antibodies, defined as having increased risk for inadequate response to active 
immunization (predicted poor responders to vaccines OR intolerant of vaccine), OR having increased risk for 
SARS-CoV-2 infection, defined as those whose locations or circumstances put them at appreciable risk of exposure 
to SARS-CoV-2 and COVID-19.
The key secondary endpoint (variable) to be obtained is a binary response, whereby a participant is defined as post-
baseline positive if the participant has a positive serology test result for SARS-CoV-2 nucleocapsid antibodies from 
the validated assay performed at the central laboratory.
The estimand for the key secondary efficacy endpoint uses a while on treatment strategy. Data for participants who 
become unblinded to treatment assignment and/or take COVID-19 vaccine or other COVID-19 preventive product,
in both cases prior to having met the criteria for the key secondary efficacy endpoint, are censored at the date of 
unblinding/receipt of first dose of COVID-19 preventive product, whichever is earlier.
The population-level summary measure is prophylactic efficacy, calculated as 1 −relative risk. (Relative risk is the 
incidence of infection in the AZD7442 group relative to the incidence of infection in the control group.)
16.2.3.
OTHER SECONDARY EFFICACY ENDPOINTS
The following endpoints will be presented along with 95% CIs and p-values. These will be nominal, as they are not 
controlled for multiplicity.
16.2.3.1.
The Incidence of SARS-CoV-2 RT-PCR-Positive Severe or Critical Symptomatic 
Illness Occurring Post Dose 
The severity of COVID-19 will be evaluated in participants who test positive for SARS-CoV-2 by RT-PCR. A 
diagnosis of severe or critical COVID-19 will include laboratory-confirmed COVID-19 (SARS-CoV-2 RT-PCR-
positive symptomatic illness) plus meeting the severity criteria. The calculation of the follow up time (included as 
offset in model) will be calculated by using date symptoms become severe as the reference date.
Severe COVID-19 is characterized by a minimum of either pneumonia (fever, cough, tachypnea, OR dyspnea, AND
lung infiltrates) or hypoxemia (SpO2 < 90% in room air and/or severe respiratory distress) and a WHO Clinical 
Progression Scale score of 5 or higher. Data from the eCRF will be used to determine if the participant met the 
qualifying severe symptoms.
All COVID-19 severity data will be listed.
16.2.3.2.
The Incidence of COVID-19-Related Emergency Department Visits Occurring After 
Dosing with IMP
Incidence of COVID-19-related Emergency Department visits is collected on the Emergency Room visit eCRF 
form. If there is any record with hospitalization status as ER with primary reason for ER visit selected as ‘COVID-
19 related symptoms’, it is considered that the participant has an incidence of COVID-19-related emergency 


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department visit. The calculation of the follow-up time (included as offset in model) will be calculated by using the 
earliest start date of ER visit.
All Emergency Department visit data will be listed, regardless of primary reason for ER visit.
16.2.4.
MISSING DATA IMPUTATION METHOD FOR SECONDARY EFFICACY ENDPOINTS
No imputation method will be used for the main analysis of the key secondary efficacy endpoint or for any analysis 
of other secondary efficacy endpoints.
16.2.5.
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS
The key secondary efficacy endpoint will be analyzed as described in Section 16.2.1.
All other secondary efficacy endpoints described in Section 16.2.3 above will be analyzed in the same manner as the 
primary analysis of the primary efficacy endpoint (refer to Section 16.1.4), prior to Day 183. These analyses will be 
repeated for these endpoints through Day 183 and through Day 366.
The key secondary efficacy endpoint will be assessed by a hierarchical order. More details on multiplicity control 
are described in Section 7.4. For the other secondary efficacy endpoints, the 95% CIs and p-values will be nominal 
as they are not controlled for multiplicity.
16.2.6.
SENSITIVITY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS
No sensitivity analysis will be performed for any secondary efficacy endpoints.
16.2.7.
SUPPLEMENTARY ANALYSES FOR SECONDARY EFFICACY ENDPOINTS
For all secondary efficacy endpoints (Section 16.2.3), the incidence of each endpoint will be presented graphically 
using Kaplan-Meier curves with log-rank test p-value.
16.2.8.
SUBGROUP ANALYSES FOR SECONDARY EFFICACY ENDPOINTS
Subgroup analyses for secondary endpoints will be conducted if their sample is sufficient. The same methodology 
for the primary endpoint will be employed (refer to Section 16.1.7).  If the model will not converge because the 
sample is too small, then only descriptive statistics such as counts and percentages and where applicable continuous 
summary statistics will be presented.
16.3. EXPLORATORY EFFICACY
The exploratory efficacy endpoints are:


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!
The incidence of the first case of SARS CoV-2 RT-PCR-positive symptomatic illness occurring after dosing
with IMP through Day 366
!
Viral genome copies in NP swabs collected at Illness Visits as determined by qRT-PCR (Illness Visits only)
!
Duration of SARS-CoV-2 shedding in saliva over time (Illness Visits only)
!
Genotypic analysis and biochemical and/or susceptibility analysis of SARS-CoV-2 variants to AZD7442 
(Illness Visits only)
!
Biophysical parameters, including, but not limited to serial measurements of skin temperature, heart rate, 
respiratory rate, blood oxygen saturation, and physical activity, recorded using a biosensor from Illness Visits 
Day 1 through Day 28
!
Symptoms recorded by participants in an Illness e-Diary from Illness Visits Day 2 through Day 28.
Only nominal p-values will be provided for exploratory efficacy endpoints (see Section 7.4). Please refer to Section 
17 for exploratory endpoints related to PK and PD data.
16.3.1.
EXPLORATORY EFFICACY ENDPOINTS
16.3.1.1.
The Incidence of the First Case of SARS-CoV-2 RT-PCR-Positive Symptomatic 
Illness Occurring after Dosing with IMP through Day 366
An exploratory endpoint is the incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness 
occurring after dosing with IMP through Day 366. The criteria for determining this endpoint is the same as those for 
the primary efficacy endpoint (see Section 16.1.1) except that the endpoint will only be evaluated within the 
specified efficacy evaluation period, through Day 366. The analysis will be performed on the full pre-exposure 
analysis set. This endpoint will be analyzed as described in Section 16.2.1.
To assess the durability of efficacy analyses for the incidence of the first case of SARS-CoV-2 RT-PCR-positive 
symptomatic illness occurring after dosing with IMP through Day 366, single-arm descriptive summaries over the
Day 366 follow-up period for participants who received AZD7442 with no censoring for unblinding intercurrent 
events will be presented. However, if a participant receives a COVID-19 vaccine or COVID-19 preventive product, 
their follow-up will be censored at the date of first administration of that product. 
16.3.1.2.
Viral Genome Copies in NP Swabs Collected at Illness Visits as Determined by 
qRT-PCR 
An exploratory efficacy endpoint is the viral genome copies in NP swabs which will be collected via SARS-CoV-2 
RT-PCR test at central laboratory at Illness Visits as described in protocol section 1.3. The analysis will be 
performed on the full pre-exposure analysis set. Observed and change from baseline for Illness Visits (as defined in 
Section 6.5) in viral load will be summarized by planned treatment group and time points for the Illness Visits. A 


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logistic regression analysis of the proportion of participants with viral load >104 copies/mL may be performed. In 
addition, the number of weeks of high viral load (>104 copies/mL) among participants may be performed using a 
Stratified Wilcoxon rank sum test.
A listing will be provided for all viral genome copy data, regardless of RT-PCR result. Indicators will be included in 
listings of illness visits to distinguish those with positive RT-PCR results from those with negative RT-PCR results.
16.3.1.3.
Duration of SARS-CoV-2 Shedding in Saliva Over Time (Illness Visits only)
!
Viral Shedding
An exploratory efficacy endpoint is the duration of SARS-CoV-2 shedding in saliva over time. The analysis will be 
performed on the full pre-exposure analysis set. Saliva samples for viral shedding will be collected at Illness Visits 
as described in protocol section 1.3. The number and proportion of participants shedding on Illness Visits planned in 
the protocol Schedule of Assessments will be summarized. Exact 95% CIs using Clopper-Pearson method for 
binomial proportions will be computed.
The duration of SARS-CoV-2 shedding in saliva will be calculated as following:
Duration (days) = (Date of Illness Visit when viral shedding first tested as persistently negative or date of last Illness 
Visit when test was positive, if no negative test is available) – Date of first positive + 1.
The number of days of shedding will be summarized by descriptive statistics. 
A listing will be provided for all viral shedding data, regardless of RT-PCR result. Indicators will be included in 
listings of illness visits to distinguish those with positive RT-PCR results from those with negative RT-PCR results.
!
Viral Quantitation
For values reported as lower than the lower limit of quantification (LLOQ), a value equal to half of the limit of 
quantification will be imputed in viral quantitation summaries. Missing values will not be imputed in viral 
quantitation summaries. 
For the subset of participants who shed, viral quantities as measured by qRT-PCR will be summarized for Illness 
Visits planned in the protocol Schedule of Assessments. Summary statistics will be presented describing the mean, 
standard deviation, median, minimum and maximum of Log10 (viral copies/mL) at Illness Visit baseline (Date of 
first positive) and each post-baseline time-points. 
Change and percent change from Illness Visit baseline at each post-baseline time point will also be summarized. 
Time weighted change from Illness Visit baseline to each post-baseline time-point is derived on a by-participant
basis using the linear trapezoidal rule with all available data from baseline to that specific time-point minus the 
baseline value. This is defined as (Area Under the Curve [AUC])/number of days – Illness Visit baseline value, 
between Illness Visit baseline to that specific post-baseline time-point. AUC from Illness Visit baseline to each post-
baseline time-point will be reported as well. 


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Figures such as Log10 (viral copies/mL) over time (mean ± SD), AUC and time weighted change from Illness Visit 
baseline of Log10 (viral copies/mL) over time (box plots) will be provided.
16.3.1.4.
Genotypic Analysis and Biochemical and/or Susceptibility Analysis of SARS-CoV-2 
Variants to AZD7442 (Illness Visits Only)
An exploratory efficacy endpoint is the Genotypic analysis and biochemical and/or susceptibility analysis of SARS-
CoV-2 from NP swabs collected at Illness Visit baseline. This analysis will not be covered in this SAP.
16.3.1.5.
Biophysical Parameters, Including But Not Limited to Serial Measurements of Skin 
Temperature, Heart Rate, Respiratory Rate, Blood Oxygen Saturation, and Physical Activity, 
Recorded Using a Biosensor From Illness Visits Day 1 Through Day 28
A group of efficacy endpoints are biophysical parameters collected from Current Health wearable device. The 
analysis of these exploratory endpoints results is not covered in this SAP.
16.3.1.6.
Symptoms recorded by participants in an Illness e-Diary from Illness Visits Day 2 
through Day 28
A group of exploratory endpoints are symptoms collected by participants in an illness e-Diary. Symptoms from the 
first SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post dose will be summarized. The number and 
percentage of participants with these symptoms, onset study day of these symptoms, and the duration days will be 
summarized by treatment group. The analysis will be based on participants in the full pre-exposure analysis set.
All symptoms from each illness visit will be listed, regardless of RT-PCR result. Indicators will be included in 
listings of illness visits to distinguish those with positive RT-PCR results from those with negative RT-PCR results.
16.3.2.
MISSING DATA IMPUTATION METHOD FOR EXPLORATORY EFFICACY ENDPOINTS
No imputation method will be used for exploratory efficacy endpoints.
16.3.3.
SENSITIVITY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No sensitivity analysis will be performed for the exploratory efficacy endpoints.
16.3.4.
SUPPLEMENTARY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No supportive analysis will be performed for the exploratory efficacy endpoints.


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17.
PHARMACOKINETIC, PHARMACODYNAMIC, AND ADA
ENDPOINTS
The PK and ADA secondary endpoints are:
!
Serum AZD7442 concentrations
!
PK parameters, if data permit
!
The incidence of ADA to AZD7442 in serum
The exploratory PK and PD endpoints are:
!
AZD7442 nasal fluid concentrations
!
Post-treatment geometric mean titers (GMTs) and geometric mean fold rises (GMFRs) for neutralizing 
antibodies (nAbs) to SARS-COV-2 from baseline value through Day 366 after single IM dose in SARS-CoV-2 
nAb (wild-type assay or pseudo neutralization assay)
Other exploratory assays for humoral, mucosal and cellular immune responses may be performed based upon 
emerging safety, efficacy, and PD data.
17.1. ANALYSIS OF PK, PD, AND ADA ENDPOINTS
17.1.1.
SERUM AZD7442 CONCENTRATIONS
Individual AZD7442 (AZD8895 and AZD1061) serum concentration data will be listed and tabulated by mAb 
component, along with descriptive statistics for the PK analysis set. A figure of serum concentrations by mAb 
component will also be presented.
Pharmacokinetic exposure (i.e., AUCs) and other PK parameters may be estimated using non-compartmental 
analysis; this will be optional if data permit. Potential correlation between PK exposure and efficacy/safety response 
may optionally be explored. Population PK analysis may be performed by the Sponsor and reported in a separate 
report. The analysis is not covered in this SAP.
To demonstrate that there is no difference between the clonal material and the pooled material, a bioequivalence 
comparison will be conducted. All participants included in the pharmacokinetic analysis set will be used to evaluate 
comparability between the clonal and pooled material. This analysis is not covered in this SAP.


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17.1.2.
THE INCIDENCE OF ADA TO AZD7442 IN SERUM
17.1.2.1.
ADA Variables
Serum samples for ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer), and ADA 
data will be collected at scheduled visits shown in protocol section 1.3. ADA result from each sample will be 
reported as either positive or negative. If the sample is positive, the ADA titer will be reported as well. In addition, 
the presence of nAb will be tested for all ADA-positive samples. The nAb results will be reported as positive or 
negative. A participant is defined as being ADA-positive if a positive ADA result is available at any time, including 
baseline and all post-baseline measurements; otherwise the participant is defined as ADA negative.
The number and percentage of ADA-evaluable participants in the following ADA categories in each treatment group 
will be determined. The number of ADA-evaluable participants in the treatment group will be used as the 
denominator for percentage calculation.
!
ADA positive at any visit (at baseline and/or post-baseline). The percentage of these participants in a population 
is known as ADA prevalence.
!
Treatment-induced ADA positive (positive post-baseline and not detected at baseline).
!
Treatment-boosted ADA positive (baseline ADA titer that was boosted by ≥4-fold following drug 
administration).
!
Treatment-emergent ADA positive (either treatment-induced ADA positive or treatment-boosted ADA 
positive). The percentage of these participants in a population is known as ADA incidence.
!
ADA positive post-baseline and positive at baseline.
!
ADA positive at baseline and not detected post-baseline.
!
Treatment-emergent ADA (TE-ADA) persistently positive, defined as treatment-emergent ADA positive
participants having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) 
between the first and last positive measurement, or an ADA positive result at the last available assessment.
!
Treatment-emergent ADA (TE-ADA) transiently positive, defined as treatment-emergent ADA positive 
participants having at least one post-baseline ADA positive measurement and not fulfilling the conditions for 
TE-ADA persistently positive.
!
nAb (to AZD7442) positive at any visit (at baseline and/or post-baseline).
17.1.2.2.
ADA Analysis
A summary of the number and percentage of participants who developed detectable ADA to AZD7442 (ADA 
results to AZD8895 and AZD1061 will be reported separately) by ADA categories (Section 17.1.2.1) in different 
treatment arms will be presented based on the ADA evaluable analysis set. Descriptive statistics of the maximum 


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titer will also be presented by ADA category. ADA results and titers will be summarized by visit and treatment 
group. ADA results will be listed for all participants in the safety analysis set regardless of ADA-evaluable status. 
ADA titer and nAb data will be presented for samples confirmed positive for the presence of ADA to AZD7442. 
AEs in ADA positive participants by ADA positive category will be listed.
The effect of ADA on PK, safety, and efficacy will be examined by descriptive summaries if data permits.
17.1.3.
AZD7442 NASAL FLUID CONCENTRATIONS
Individual AZD7442 (AZD8895 and AZD1061) nasal fluid concentration data will be listed and tabulated by mAb 
component, along with descriptive statistics for the participants in the PK analysis set who have at least one 
quantifiable nasal fluid PK observation post-dose.
17.1.4.
NEUTRALIZING ANTIBODY GEOMETRIC MEAN TITERS AND GEOMETRIC MEAN 
FOLD RISE
Geometric mean titers (GMTs) and geometric mean fold rises (GMFRs) for nAbs will be calculated for the active 
and control groups and will be summarized at each scheduled visit as per protocol section 1.3. GMT and GMFR 
summaries will be based on the nAb evaluable analysis set.
Descriptive statistics for GMTs and GMFRs will include number of participants, geometric mean, geometric 
standard deviation (GSD), 95% CI, minimum and maximum. 
The GMT will be calculated as the antilogarithm of Σ(log2 transformed titer/n), i.e. as the antilogarithm 
transformation of the mean of the log-transformed titer, where n is the number of participants with titer information. 
The GSD for GMT will be calculated as the antilogarithm transformation of the standard deviation of the log-
transformed titer. The 95% CI will be calculated as the anti-logarithm transformation of the upper and lower limits 
for a two-sided CI for the mean of the log-transformed titers.
The fold rise is calculated as the ratio of the post-dose titer level to the pre-dose titer level. GMFR will be calculated 
as anti-logarithm of Σ (log2 transformed (post-dose titer/ pre-dose titer)/n). The GSD and 95% CIs for GMFR will be 
calculated similarly to those for GMT.
All nAb data will be listed.
17.1.5.
MISSING DATA IMPUTATION METHOD FOR PK, PD, AND ADA ENDPOINTS
The PK descriptive analyses of serum AZD7442 concentrations (Section 17.1.1) and AZD7442 nasal fluid 
concentrations (Section 17.1.3) will use the following imputation methods: Individual concentrations below the 
LLOQ of the bioanalytical assay will be reported as Not Quantifiable (NQ) in the listings with the LLOQ defined in 
the footnotes of the relevant tables, figures, and listings (TFLs). Individual plasma concentrations that are Not 
Reportable (NR) will be reported as NR and those that are missing will be reported as No Sample (NS) in the 
listings. Plasma concentrations that are NQ, NR, or NS will be handled as follows for the provision of descriptive 


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statistics:
!
Any values reported as NR or NS will be excluded from the summary tables and corresponding figures.
!
At a time point where less than or equal to 50% of the concentration values are NQ, all NQ values will be set to 
the LLOQ, and all descriptive statistics will be calculated accordingly.
!
At a time point where more than 50% (but not all) of the values are NQ, the geometric mean, geometric mean ± 
GSD and geometric coefficient of variation (gCV%) will be set to Not Computed (NC). The maximum value 
will be reported from the individual data, and the minimum and median will be set to NQ.
!
If all concentrations are NQ at a time point, no descriptive statistics will be calculated for that time point. The 
geometric mean, minimum, median, and maximum will be reported as NQ and the gCV% and geometric mean 
± GSD as NC.
!
The number of values below LLOQ (n < LLOQ) will be reported for each time point together with the total 
number of collected values (n).
Three observations > LLOQ are required as a minimum for a plasma concentration or PK parameter (e.g. Cmax, 
Cmin, Clast) to be summarized. Two observations > LLOQ are presented as minimum and maximum with the other 
summary statistics as NC.
The analysis for the incidence of ADA to AZD7442 in serum (Section 17.1.2) will use the following imputation 
method: ADA titers values below the limit of detection (LOD) are negative results, hence they are not imputed and 
are excluded from calculation of summary statistics. Titer values of positive ADA samples reported as ≤ LOD are 
imputed as LOD in the calculation of summary statistics on ADA titer.
The analysis of neutralizing antibody geometric mean titers and geometric mean fold rise (Section 17.1.4) will use 
the following imputation method: a titer value measured below the LLOQ will be imputed to a value that is half of 
the LLOQ in summaries and analyses, but will be listed as reported in the raw data. Titer values measured as above 
the upper limit of quantification (ULOQ) will be imputed at the ULOQ value.
17.1.6.
SENSITIVITY ANALYSES FOR PK, PD, AND ADA ENDPOINTS
No sensitivity analysis will be performed for the PK, PD, and ADA endpoints.
17.1.7.
SUPPLEMENTARY ANALYSES FOR PK, PD, AND ADA ENDPOINTS
No supportive analysis will be performed for the PK, PD, and ADA endpoints.
18.
SAFETY ENDPOINTS
The safety of AZD7442 will primarily be assessed by:


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!
Incidence of AEs
!
Incidence of SAEs
!
Incidence of medically attended adverse events (MAAEs, defined in Protocol Section 8.3.5)
!
Incidence of adverse events of special interest (AESIs, defined in Protocol Section 8.3.4)
There are also other safety endpoints, including:
!
Deaths
!
Laboratory evaluations
!
Vital signs
!
ECG evaluations
!
Physical examinations
All safety summaries will be presented by actual treatment group based on the SAF and may be summarized by 
cohort and/or comorbidities. Additional summaries may be presented by whether participants receive COVID-19 
vaccination or other COVID-19 preventive product (Yes/No) during study and unblinding status (Yes/No) during 
study. Data will be presented using all the available data up to 15 months (Day 457) following the dose of IMP to 
the last assessment unless stated otherwise. There will be no statistical comparisons between the treatment groups 
for safety data.
18.1. ADVERSE EVENTS
All AEs will be coded using the MedDRA dictionary, version 23.1 or higher.
Unless specified, event summary refers to the summary of number of participants with the corresponding adverse 
event.
Overall summaries of number and percentage of participants with AE in the following categories will be provided 
by treatment group based on the SAF.
!
AEs
!
SAEs 
!
Related SAEs
!
AEs leading to IMP discontinuation
!
Related AEs leading to IMP discontinuation
!
AEs leading to study discontinuation


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!
Related AEs leading to study discontinuation
!
MAAEs
!
Related MAAEs
!
AEs with outcome of death
!
AESIs
!
Related AESIs
Should a participant experience multiple events within a category, the participant will be counted only once for that 
category.
An overall summary of number and percentage of participants, including exposure adjusted rates, and number of 
events within categories of all SAEs, related SAEs, AEs leading to study discontinuation, related AEs leading to 
study discontinuation, MAAEs, AEs with outcome of death, and AESIs during the entire period of study will be 
provided by actual treatment group. Exposure adjusted rate is calculated as number of participants with AEs in 
categories above divided by total participant-year exposure to investigational study intervention. Participant years is 
determined by summing the total number of follow-up days of each participant, and then dividing by 365.25. The 
exposure period is calculated from time of dose to end of study.
An overall summary of number of AEs within each of the categories will also be provided by actual treatment 
group.
18.1.1.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
AEs will be recorded from the time of IMP administration throughout the study up to and including the last visit.  
Serious adverse events (SAEs) are those events recorded as “Serious” on the AE page of the eCRF. SAEs will be 
recorded from the time of signing of the informed consent form.
Adverse events and serious adverse events post the dose of IMP will be summarized by SOC and PT by actual 
treatment group. Specific AEs will be counted once for each participant for calculating percentages. 
Summary of AEs and SAEs post the dose of IMP will be broken down further by maximum severity and 
relationship to study intervention. If the same AE occurs multiple times for a particular participant, the highest/worst
severity (i.e. from highest to lowest: severe, moderate and mild) and level of relationship to study intervention
observed will be reported.
Listings of AEs and SAEs will be provided. SAEs prior to the dose of IMP and AEs and SAEs starting after Day 
457 will only be presented in the listings. For SAEs with partial dates, if the known part of the date indicates that 
SAE stopped before the dose of IMP, it will be considered as SAE prior to the dose of IMP. Otherwise, it will be 
considered as SAE post dose of IMP. 


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18.1.1.1.
Severity for AEs
Severity will be classified as mild, moderate, severe, potentially life-threatening, or fatal (increasing severity) by
using grading for AEs. Severity for AEs will be collected on “Adverse Events” form of the eCRF. Should a 
participant experience multiple events within a SOC or PT, only the participant’s worst severity grade will be 
counted for that SOC or PT.
18.1.1.2.
Relationship to IMP/Other Medication/Study Procedure
Relationship to IMP/other medication/study procedure, as indicated by the Investigator, will be classified as not 
related or related.
Should a participant experience multiple events within a SOC or PT, the participant will be counted as related for 
that SOC or PT if one of those is related.
18.1.2. AES LEADING TO DISCONTINUATION OF IMP
AEs leading to permanent discontinuation of IMP are not expected due to this being a single dose study. Given the 
single dose is comprised of 2 sequential injections, the AE would need to occur immediately after the 1st injection
and lead to discontinuation of the 2nd injection—this scenario is expected to be rare. Therefore, no summary will be 
prepared.
A listing of all AEs leading to discontinuation of IMP will be provided, if data permit.
18.1.3. AES LEADING TO DISCONTINUATION OF STUDY
A summary of AEs during the study leading to permanent discontinuation of study by SOC and PT will be prepared. 
A summary of related AEs leading to permanent discontinuation of study by SOC and PT will also be prepared. 
A listing of all AEs leading to permanent discontinuation of study will be provided.
18.1.4. AES WITH OUTCOME OF DEATH
AEs with outcome of death are those AEs with “Fatal” outcome recorded on the “Adverse Events” form of the 
eCRF. A summary of AEs with outcome of death by SOC and PT will be prepared. A summary of related AEs with 
outcome of death by SOC and PT will also be prepared.
18.1.5.
MEDICALLY ATTENDED ADVERSE EVENTS
Medically attended adverse events (MAAEs) are AEs leading to medically-attended visits that were not routine 
visits for physical examination or dosing, such as an emergency room visit, or an otherwise unscheduled visit to or 
from medical personnel (medical doctor) for any reason. AEs, including abnormal vital signs, identified on a routine 


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study visit or during the scheduled Illness Visits will not be considered MAAEs. MAAEs will be recorded from Day 
1, post dose, through the last participant contact.
A summary of MAAEs by SOC and PT by actual treatment group will be prepared.  Should a participant experience 
multiple events within a SOC or PT, the participant will be counted only once for that SOC or PT. A summary of 
related MAAEs by SOC and PT will also be prepared.
A listing of all MAAEs will be provided.
18.1.6.
ADVERSE EVENTS OF SPECIAL INTEREST
AEs of special interest (AESIs) are:
!
Anaphylaxis and other serious hypersensitivity reactions including immune complex disease
!
Injection site reactions
AESIs are indicated on the eCRF and will be recorded from Day 1, post dose, through the last participant contact. A 
summary of AESIs by SOC and PT by actual treatment group will be prepared.  Should a participant experience 
multiple events within a SOC or PT, the participant will be counted only once for that SOC or PT. A summary of 
related AESIs by SOC and PT will also be prepared.
A listing of all AESIs will be provided.
18.2. DEATHS
If any participants die during the study as recorded on the “Death Details” page of the eCRF, the number and 
percentage of participants with death related to COVID-19 and those with other deaths will be summarized by actual 
treatment group based on the SAF. The number and percentage of participants with death related to COVID-19 as 
adjudicated by the MAC will also be summarized by actual treatment group based on the SAF.
A listing of all deaths will be provided.
18.3. LABORATORY EVALUATIONS
A urine pregnancy test will be performed at screening and per the schedule of events (refer to protocol, Section 1.3).
If urine tests positive or indeterminate, a serum test will be performed for confirmation. Chemistry, hematology,
coagulation, and urinalysis will be performed as per the schedule of events (refer to protocol, Section 1.3).  A list of 
laboratory parameters to be included in the outputs is included in APPENDIX 3.
Quantitative laboratory parameters reported as “< X”, i.e. below the lower limit of quantification (BLQ) or “> X”, 
i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative summaries, 
but will be presented as recorded, i.e. as “< X” or “> X” in the listings


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The following summaries will be provided by actual treatment group based on the SAF for each of chemistry,
hematology, coagulation, and urinalysis laboratory parameter:
!
Observed and change from baseline in Standard International (SI) units by visit (for quantitative parameters);
!
Observed and change from baseline for Illness Visits as defined in Section 6.5 (for coagulation parameters) in 
SI units by Illness Visit (the Illness Visits corresponding to positive RT-PCR test will be used in the summary);
!
Number and percentage of participants in each laboratory parameter category by visit (for categorical 
parameters);
!
Shift from baseline to the worst post-baseline observed value according to the Common Terminology Criteria 
for Adverse Events (CTCAE) toxicity grades (for quantitative parameters with available CTCAE toxicity 
grades; refer to Section 18.3.1)
!
Shifts from baseline to the maximum/minimum post-baseline observed value according to normal range criteria 
(for quantitative parameters without CTCAE toxicity grades; refer to Section 18.3.2);
!
Maximum post-baseline ALT/AST observed value categorized as < 3 x upper limit of normal (ULN), ≥3 to < 5 
x ULN, ≥5 to < 10 x ULN or ≥10 ULN by maximum post-baseline total bilirubin  (TBL) observed value 
categorized as < 2 x ULN or ≥2 x ULN
All laboratory evaluations will be listed.
18.3.1.
CTCAE TOXICITY GRADES
Quantitative laboratory parameters with available CTCAE toxicity grades will be categorized as follows where 
higher grades representing a more severe toxicity (refer to APPENDIX 4 for each parameter toxicity grade criteria): 
!
Grade 1 (i.e., mild);
!
Grade 2 (i.e., moderate);
!
Grade 3 (i.e., severe)
!
Grade 4 (i.e., life-threatening)
!
Grade 5 (i.e., death)
Although not defined in the CTCAE toxicity grading system, version 5, non-missing laboratory parameter results 
not meeting any of the 5 grades defined in the CTCAE toxicity grading system will be categorized as ‘No Event’ for 
the purpose of the shift from baseline summaries.
18.3.2.
LABORATORY NORMAL RANGES
Quantitative laboratory parameters will be compared with the relevant central laboratory normal ranges in SI units 


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and categorized as:
!
Low: Below the lower limit of the laboratory normal range. 
!
Normal: Within the laboratory normal range (upper and lower limit included).
!
High: Above the upper limit of the laboratory normal range.
18.4. VITAL SIGNS
The following vital sign parameters will be collected for this study as per the schedule of events (refer to protocol, 
Section 1.3):
!
Systolic blood pressure (SBP) (mmHg)
!
Diastolic blood pressure (DBP) (mmHg)
!
Heart rate (beats per minute [bpm])
!
Oxygen saturation (%)
!
Respiratory rate (breaths/min)
!
Body temperature (⁰C)
For severity grades of abnormal Vital Signs refer to APPENDIX 5. 
The following summaries will be provided by actual treatment group based on the SAF for each vital sign
parameter:
!
Observed and change from baseline by visit;
!
Observed and change from baseline for Illness Visits (as defined in Section 6.5), by Illness Visit (the first illness 
episode with positive RT-PCR test result will be used for the summary);
!
Number and percentages of participants with at least one abnormal post-baseline observed value (refer to 
APPENDIX 5);
All vital sign data will be listed. Indicators will be included for illness visits to distinguish those with positive RT-
PCR results from those with negative RT-PCR results.
18.5. ECG EVALUATIONS
The following electrocardiogram (ECG) parameters will be measured for this study as per the schedule of events 
(refer to protocol, Section 1.3):
!
Heart rate (bpm);


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!
PR interval (msec);
!
RR interval (msec);
!
QRS interval (msec);
!
QT interval (msec);
!
QTc interval (msec);
!
QTcF interval (msec);
!
QTcB interval (msec);
!
Overall ECG interpretation (Investigator’s judgment):
o
Normal;
o
Abnormal, not clinically significant (NCS);
o
Abnormal, clinically significant (CS)
Since triplicate ECGs will be performed for this study, the mean of the 3 measurements collected on a visit will be 
used in the by-visit summaries for that visit, but the worst of the 3 measurements collected on a visit will be used for 
the shift from baseline summaries for that visit.  Should one or two of the triplicate measurements be missing at a 
specific visit, the mean of the available measurements will be used in the by-visit summaries for that visit.  All 
individual measurements will be listed.
The following summaries will be provided by actual treatment group for each ECG parameter:
!
Observed and change from baseline by visit (for quantitative parameters);
!
Number and percentages of participants with at least one markedly abnormal post-baseline observed 
value/change from baseline (for quantitative parameters; refer to Section 18.5.1);
All ECG data will be listed.
18.5.1.
ECG MARKEDLY ABNORMAL CRITERIA
Markedly abnormal quantitative ECG parameters will be identified in accordance with the following predefined 
markedly abnormal criteria:
!
Observed values for QTc, QTcF, and QTcB intervals will be classified as:
o
> 450 msec;
o
> 480 msec;


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o
> 500 msec
!
Change from baseline for QTc, QTcF, and QTcB intervals will be classified as:
o
>30 msec increase from baseline
o
>60 msec increase from baseline
It is to be noted that the previous categories are not mutually exclusive, but cumulative.  For example, if a 
participant’s worst post-baseline QTc post-baseline observed value is 490 mmHg, then this participant will be 
reported once under QTc > 450 msec and once under QTc > 480 msec.
18.6. PHYSICAL EXAMINATION
Physical examinations will be conducted as per the schedule of events (refer to protocol Section 1.3).  Clinically 
significant findings at screening will be recorded on the “Medical History” form of the eCRF while clinically 
significant changes from screening will be recorded on the “Adverse Events” form of the eCRF for the post-
screening visits.  Hence, clinically significant findings/changes will be summarized through the Medical history 
summary (refer to Section 11) or AE summaries (refer to Section 18.1), as appropriate.  That is, no summaries will 
be specifically provided for the general physical examination.
19.
OTHER DATA COLLECTED
The following data collected on the eCRF will be summarized in listings only:
!
Exposure
!
Pregnancy test and report
!
Overdose Report
!
Medication Error
!
Virology: Hepatitis B surface antigen, hepatitis C virus antibody; HIV-I and HIV-II
!
Rapid point of care SARS-CoV-2 serology
!
Related procedures
!
PBMCs for B and T cell responses
!
Nasal adsorption for SARS-CoV-2 mucosal responses
!
Pharmacogenetics


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20.
REFERENCES 
CDC. (Centers for Disease Control and Prevention). Coronavirus Disease 2019 (COVID-19), Symptoms of 
Coronavirus. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Published 2020. 
Accessed 01 July 2020.
Little, R. J. A. and Rubin, D. B. Statistical Analysis with Missing Data, 2nd Edition, Hoboken, NJ: John Wiley & 
Sons 2002; 257.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213-26.
Zou, G. A Modified Poisson Regression Approach to Prospective Studies with Binary Data. Am J Epidemiol 2004; 
159:702–706.


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APPENDIX 1.
PARTIAL DATE CONVENTIONS
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS
START DATE
STOP DATE
ACTION
Known
Known or 
ongoing
If medication stop date < date of dose of IMP, assign as prior;
If medication start date < date of dose of IMP and medication stop date ≥
date of dose of IMP, assign as concomitant;
If date of dose of IMP ≤medication start date, assign as concomitant.
Partial
If known components of medication stop date show that medication stopped 
before date of dose of IMP, assign as prior;
If medication start date < date of dose of IMP and (known components of 
medication stop date show that medication stopped on or after date of dose 
of IMP), assign as concomitant;
If date of dose of IMP ≤medication start date, assign as concomitant.
Missing, not 
ongoing
If medication stop date is missing, then it can never be assigned as prior 
only;
If medication start date < date of dose of IMP, assign as concomitant;
If date of dose of IMP ≤medication start date, assign as concomitant.
Partial
Known or 
ongoing
If medication stop date < date of dose of IMP, assign as prior;
If (known components of medication start date show that medication started 
before date of dose of IMP) and (medication stop date ≥date of dose of 
IMP), assign as concomitant;
If known components of medication start date show that medication started 
on or after date of dose of IMP, assign as concomitant.


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START DATE
STOP DATE
ACTION
Partial
If known components of medication stop date show that medication stopped 
before date of dose of IMP, assign as prior;
If (known components of medication start date show that medication started 
before date of dose of IMP) and (known components of medication stop date 
show that medication stopped on or after date of dose of IMP), assign as 
concomitant;
If known components of medication start date show that medication started 
on or after date of dose of IMP, assign as concomitant.
Missing, not 
ongoing
Cannot be assigned as prior only;
If known components of medication start date show that medication started 
before study drug start date, assign as concomitant;
If known components of medication start date show that medication started 
on or after date of dose of IMP, assign as concomitant.
Missing
Known or
ongoing
If medication stop date < date of dose of IMP, assign as prior;
If medication stop date >= date of dose of IMP, assign as concomitant.
Partial
If known components of medication stop date show that medication stopped 
before date of dose of IMP, assign as prior;
If known components of medication stop date show that medication stopped 
on or after date of dose of IMP, assign as concomitant.
Missing, not 
ongoing
Assign as concomitant.


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APPENDIX 2.
PROGRAMMING CONVENTIONS FOR OUTPUTS
DATES & TIMES
Depending on data available, dates and times will take the form yyyy-mm-dd hh:mm:ss.
SPELLING FORMAT
English US. 
PAPER SIZE, ORIENTATION, AND MARGINS
The size of paper will be letter and the page orientation will be landscape. Margins will provide at least 1 inch (2.54 
centimeters) of white space all around the page.
FONTS
The font type ‘Courier New’ will be used, with a font size of 8.  The font color will be black with no bolding, 
underlining, italics or subscripting.
PRESENTATION OF TREATMENT GROUPS
For outputs, treatment groups will be represented as follows and in the given order:
Treatment Group
Tables and Graphs
Listings
AZD7442
1
1
Placebo
2
2
Total [1]
5
n/a
Randomized, Not Dosed
n/a
3
Screen Failure
n/a
4
[1] Not applicable for efficacy tables, safety tables and graphs.
PK analyses will be conducted for participants who receive AZD7442 only. Groups will be represented as follows 
and in the given order:


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Treatment Group
Tables and Graphs
Listings
AZD8895
1
1
AZD1061
2
2
AZD7442
3
3
PRESENTATION OF NOMINAL VISITS
For outputs, analysis visits will be represented as follows and in that order:
Long Name (default)
Short Name 
Screening
Scrn
Rescreening
RScrn
Day 1
D1
Day 8
D8
Day 29
D29
Day 58
D58
Day 92
D92
Day 183
D183
Day 366
D366
Day 457
D457
For outputs, analysis visits regarding Illness Visit will be represented as follows and in that order:
Long Name (default)
Short Name 
Episode 1 Illness Visit Day X, 
X=1,3,5,8,11,14,21,28
1IL-DXX,
X=1,3,5,8,11,14,21,28
Episode 2 Illness Visit Day X, 
2IL-DXX,


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Long Name (default)
Short Name 
X=1,3,5,8,11,14,21,28
X=1,3,5,8,11,14,21,28
Episode Y Illness Visit Day X, 
X=1,3,5,8,11,14,21,28
Y = 1, 2, 3, and so on, as applicable
YIL-DXX,
X=1,3,5,8,11,14,21,28
Y = 1, 2, 3, …
DESCRIPTIVE STATISTICS
If the original data has N decimal places, then the summary statistics will have the following decimal places:
!
Minimum and maximum: N;
!
Mean, median, Q1, Q3, lower and upper bounds of two-sided 95% CI: N + 1;
!
SD and SE: N + 2
PERCENTAGES
Percentages will be reported to one decimal place.  Rounding will be applied, except for percentages < 0.1 but > 0.0 
which will be presented as ‘< 0.1’ and percentages < 100.0 but >99.9 which will be presented as ‘>99.9’.
Where counts are zero, no percentages will appear in the output.
P-VALUES
p-values will be reported to four decimal places.  Rounding will be applied, except for the p-values < 0.0001 which 
will be presented as ‘< 0.0001’ and p-values < 1.000 but > 0.9999 which will be presented as ‘> 0.9999’.
LISTINGS
All listings will be ordered by the following (unless otherwise indicated in the output template):
!
Randomized treatment group (or treatment received if it’s a safety output);
!
Participant ID;
!
Parameter, when applicable;
!
Date/Time, when applicable;
!
Timepoint, when applicable


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APPENDIX 3.
LABORATORY ASSESSMENTS
Chemistry (SI unit)
!
Alkaline phosphatase (ALP) (U/L)
!
Creatinine (μmol/L)
!
Alanine transaminase (ALT) (U/L)
!
Glucose (mmol/L)
!
Aspartate transaminase (AST) (U/L)
!
Creatine kinase (CK) (U/L)
!
Total bilirubin (μmol/L)
!
Sodium (mmol/L)
!
Conjugated bilirubin (μmol/L)
!
Potassium (mmol/L)
!
Gamma glutamyl transferase (GGT) (U/L)
!
Calcium (mmol/L)
!
C-Reactive protein (CRP) (nmol/L)
!
Phosphate (mmol/L)
!
Albumin (g/L)
!
Urea (mmol/L)
Hematology (SI unit)
!
Hemoglobin (g/L)
!
Absolute neutrophils count (x10E9/L)
!
Hematocrit
!
Absolute lymphocyte count (x10E9/L)
!
Mean corpuscular volume (MCV) (fL)
!
Absolute monocyte count (x10E9/L)
!
Red blood cells (RBC) count total (x10E12/L)
!
Absolute eosinophils count (x10E9/L)
!
White blood cell (WBC) count total (x10E9/L)
!
Absolute basophils count (x10E9/L)
!
Mean corpuscular hemoglobin (MCH) (pg)
!
Absolute reticulocyte count (x10E9/L)
!
Mean corpuscular hemoglobin concentration 
(MCHC) (g/L)
!
Platelet count (x10E9/L)


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Coagulation (SI unit)
!
International normalized ratio (INR)
!
Prothrombin time (PT) (s)
!
Activated partial thrombin time (aPTT) (s)
Urinalysis (SI unit)
Dip stick
Microscopy
!
Blood
!
White blood cells
!
Protein
!
Red blood cells
!
Glucose
!
Casts


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APPENDIX 4.
CTCAE TOXICITY GRADE, VERSION 5.0
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (accessed on 22-Apr-2020)
CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Anemia
Hemoglobin (g/L)
≥ LLN
≥ 100 g/L -
< LLN
≥ 80 -
< 100 g/L
< 80 g/L
n/a
n/a
Hemoglobin increased
Hemoglobin (g/L)
No increase 
from baseline
Increase from 
baseline > 0 - ≤ 
20 g/L
Increase from 
baseline > 20 -
≤ 40 g/L
Increase from 
baseline 
> 40 g/L
n/a
n/a
Platelet count decreased
Platelet count 
(x10E9/L)
≥ LLN
≥75 x 10E9/L 
– < LLN
≥50 -
< 75 x 10E9/L
≥25 -
< 50 x 10E9/L
< 25 x 10E9/L
n/a
White blood cell (WBC) 
decreased
WBC (x 10E9/L)
≥ LLN
≥3.0 x 10E9/L 
– < LLN
≥2.0 -
< 3.0 x 10E9/L
≥1.0 - < 2.0 x 
10E9/L
< 1.0 x 10E9/L
n/a
Leukocytosis
WBC (x 10E9/L)
≤ 100 x 
10E9/L
n/a
n/a
> 100 x 10E9/L
n/a
n/a
Absolute neutrophils 
count decreased
Absolute neutrophils 
count (x 10E9/L)
≥ LLN
≥1.5 x 10E9/L 
– < LLN
≥1.0 -
< 1.5 x 10E9/L
≥0.5 - < 1.0 x 
10E9/L
< 0.5 x 10E9/L
n/a
Absolute lymphocytes 
count decreased
Absolute lymphocytes 
count (x 10E9/L)
≥ LLN
≥0.8 x 10E9/L 
– < LLN
≥0.5 -
< 0.8 x 10E9/L
≥0.2 -
< 0.5 x 10E9/L
< 0.2 x 10E9/L
n/a
Absolute lymphocytes 
count increased
Absolute lymphocytes 
count (x 10E9/L)
≤ 4 x 10E9/L
n/a
> 4 –
≤20 x 10E9/L
> 20 x 10E9/L
n/a
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Eosinophilia
Absolute eosinophils
≤ ULN or
≤ Baseline
> ULN and
> Baseline
n/a
n/a
n/a
n/a
Hypernatremia
Sodium (mmol/L)
≤ ULN
> ULN – ≤150 
mmol/L
> 150 –
≤155 mmol/L
> 155 –
≤160 mmol/L
> 160 mmol/L
n/a
Hyponatremia
Sodium (mmol/L)
≥ LLN
≥130 mmol/L 
– < LLN
≥125 -
< 130 mmol/L
≥120 -
< 125 mmol/L
< 120 mmol/L
n/a
Hyperkalemia
Potassium (mmol/L)
≤ ULN
> ULN –
≤5.5 mmol/L
> 5.5 –
≤6.0 mmol/L
> 6.0 –
≤7.0 mmol/L
> 7.0 mmol/L
n/a
Hypokalemia
Potassium (mmol/L)
≥ LLN
≥3.0 mmol/L –
< LLN
n/a
≥2.5 -
< 3.0 mmol/L
< 2.5 mmol/L
n/a
Hypercalcemia
Ionized calcium 
(mmol/L)
≤ ULN
> ULN –
≤1.5 mmol/L
> 1.5 –
≤1.6 mmol/L
> 1.6 –
≤1.8 mmol/L
> 1.8 mmol/L
n/a
Hypocalcemia
Ionized calcium 
(mmol/L)
≥ LLN
≥1.0 mmol/L –
< LLN
≥0.9 -
< 1.0 mmol/L
≥0.8 -
< 0.9 mmol/L
< 0.8 mmol/L
n/a
Hypermagnesemia
Magnesium (mmol/L)
≤ ULN
> ULN –
≤1.23 mmol/L
n/a
> 1.23 –
≤3.30 mmol/L
> 3.30 mmol/L
n/a
Hypomagnesemia
Magnesium (mmol/L)
≥ LLN
≥0.5 mmol/L –
< LLN
≥0.4 -
< 0.5 mmol/L
≥0.3 -
< 0.4 mmol/L
< 0.3 mmol/L
n/a
Hypoglycemia
Glucose (mmol/L)
≥ LLN
≥3.0 mmol/L –
< LLN
≥2.2 -
< 3.0 mmol/L
≥1.7 -
< 2.2 mmol/L
< 1.7 mmol/L
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Creatinine increased
Creatinine (μmol/L)
≤ ULN
> ULN –
≤1.5 x ULN
> 1.5 –
≤3.0 x ULN 
or
> 1.5 – ≤3.0 x 
baseline
> 3.0 –
≤6.0 x ULN 
or
> 3.0 x baseline
> 6.0 x ULN
n/a
Alkaline phosphatase 
(ALP) increased
ALP (U/L)
≤ ULN if 
baseline 
normal; 
≤ 2.0 x 
baseline if 
baseline 
abnormal
> ULN –
≤2.5 x ULN if 
baseline 
normal; 
> 2.0 -
≤2.5 x baseline 
if baseline 
abnormal
> 2.5 –
≤5.0 x ULN if 
baseline 
normal;
> 2.5 –
≤5.0 x baseline 
if baseline 
abnormal
> 5.0 –
≤20.0 x ULN if 
baseline 
normal;
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal;
> 20.0 x 
baseline if 
baseline 
abnormal
n/a
Alanine transaminase 
(ALT) increased
ALT (U/L)
≤ ULN if 
baseline 
normal; 
≤ 1.5 x 
baseline if 
baseline 
abnormal
> ULN –
≤3.0 x ULN if 
baseline 
normal; 
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal
> 3.0 –
≤5.0 x ULN if 
baseline 
normal;
> 3.0 – ≤ 5.0 x 
baseline if 
baseline 
abnormal
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal;
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal;
> 20.0 x 
baseline if 
baseline 
abnormal
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Aspartate transaminase 
(AST) increased
AST (U/L)
≤ ULN if 
baseline 
normal; 
≤ 1.5 x 
baseline if 
baseline 
abnormal
> ULN –
≤3.0 x ULN if 
baseline 
normal; 
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal
> 3.0 –
≤5.0 x ULN if 
baseline 
normal;
> 3.0 – ≤ 5.0 x 
baseline if 
baseline 
abnormal
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal;
> 5.0 – ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal;
> 20.0 x 
baseline if 
baseline 
abnormal
n/a
Blood bilirubin 
increased
Total bilirubin
(μmol/L)
≤ ULN if 
baseline 
normal; 
≤ baseline if 
baseline 
abnormal
> ULN –
≤1.5 x ULN if 
baseline 
normal; 
> baseline - ≤ 
1.5 x baseline 
if baseline 
abnormal
> 1.5 –
≤3.0 x ULN if 
baseline 
normal; 
> 1.5 - ≤ 3.0 x 
baseline if 
baseline 
abnormal
> 3.0 – ≤ 10.0 x 
ULN if baseline 
normal; 
> 3.0 - ≤ 10.0 x 
baseline if 
baseline 
abnormal
> 10.0 x ULN if 
baseline 
normal; 
> 10.0 x 
baseline if 
baseline 
abnormal
n/a
Gamma glutamyl 
transferase (GGT) 
increased
GGT (U/L)
≤ ULN if 
baseline 
normal; 
≤ 2.0 x 
baseline if 
baseline 
abnormal
> ULN –
≤2.5x ULN if 
baseline 
normal; 
> 2.0 -
≤2.5 x baseline 
if baseline 
abnormal
> 2.5 –
≤5.0 x ULN if 
baseline 
normal; 
> 2.5 -
≤5.0 x baseline 
if baseline 
abnormal
> 5.0 – ≤ 20.0 x 
ULN if baseline 
normal; 
> 5.0 - ≤ 20.0 x 
baseline if 
baseline 
abnormal
> 20.0 x ULN if 
baseline 
normal; 
> 20.0 x 
baseline if 
baseline 
abnormal
n/a


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CTCAE Term
Laboratory Test
No Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Hypoalbuminemia
Albumin (g/L)
≥ LLN
≥ 30 g/L - < 
LLN
≥ 20 - < 30 g/L
< 20 g/L
n/a
n/a
CPK increased
Creatine kinase (U/L)
≤ ULN
> ULN –
≤2.5 x ULN
> 2.5 –
≤5 x ULN
> 5 –
≤10 x ULN
> 10 x ULN
n/a
International normalized 
ratio (INR) increased
INR
≤ 1.2 if not on 
anticoagulant;
≤ baseline if 
on 
anticoagulant
> 1.2 – ≤1.5 if 
not on 
anticoagulant;
> baseline -
≤1.5 x baseline 
if on 
anticoagulant
> 1.5 – ≤2.5 if 
not on 
anticoagulant;
> 1.5 - ≤ 2.5 x 
baseline if on 
anticoagulant
> 2.5 if not on 
anticoagulant;
> 2.5 x baseline 
if on 
anticoagulant
n/a
n/a


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APPENDIX 5.
CLINICAL ABNORMALITIES: VITAL SIGNS
Vital Signs a
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Fever (℃) b
(℉) b
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
ER visit or 
hospitalization for 
arrhythmia
Bradycardia 
(beats/minute) c
50-54
45-49
< 45
ER visit or 
hospitalization for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
ER visit or 
hospitalization for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
ER visit or 
hospitalization for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
ER visit or 
hospitalization for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Note: Record vital signs as adverse events only if clinically relevant and changed from baseline.
a
Participant should be at rest for vital signs measurements.
a
No recent hot or cold beverages or smoking.
b
Use clinical judgment when characterizing bradycardia among some healthy participant populations, for 
example, conditioned athletes.
ER = emergency room; Hg = mercury.


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APPENDIX 6.
HIGH RISK OF SEVERE COVID-19 AT BASELINE
High Risk of Severe 
COVID-19 Condition
Description
History of Obesity: 
(eCRF)
COVID Co-Morbidities eCRF: “Does the subject have a history of Obesity --
those with a BMI greater than 30”
Programming example: MHDIAGYN4 = “Y”
Obese: BMI ≥30 (derived)
Derived from the participant’s reported height and weight at baseline
Morbid Obesity: BMI ≥40 
(derived)
Derived from the participant’s reported height and weight at baseline
CKD
COVID Co-Morbidities eCRF: “Does the subject have a history of Chronic 
kidney disease?”
Programming example: MHDIAGYN1 = “Y”
Diabetes
COVID Co-Morbidities eCRF: “Does the subject have a history of Type 1 
diabetes?”
“Does the subject have a history of Type 2 diabetes?”
Programming example: MHDIAGYN15 = “Y” or MHDIAGYN7 = “Y”
Immunosuppressive 
disease
From reported Medical History Term
Programming example: SOC_NAME = “IMMUNE SYSTEM DISORDERS” and 
HLGT different than 'ALLERGIC CONDITIONS'
Immunosuppressive 
treatment
From reported Concomitant medications identified as prior and ongoing with 
ATC2 is 'L01' or 'L04'.
CV disease
COVID Co-Morbidities eCRF: “Does the subject have a history of Serious heart 
conditions like heart failure and coronary artery disease”
Programming example: MHDIAGYN5 = “Y”
COPD
COVID Co-Morbidities eCRF: “Does the subject have a history of Chronic 
obstructive pulmonary disease (COPD), like emphysema?”
Programming example: MHDIAGYN2 = “Y”
Chronic liver disease
COVID Co-Morbidities eCRF: “Does the subject have a history of Liver 
disease?”
Programming example: MHDIAGYN13 = “Y”
Hypertension
COVID Co-Morbidities eCRF: “Does the subject have a history of High blood 
pressure?”
Programming example: MHDIAGYN12 = “Y”
Asthma
COVID Co-Morbidities eCRF: “Does the subject have a history of Asthma?”
Programming example: MHDIAGYN8 = “Y”
Cancer
From ongoing Medical History terms where SOC NAME='NEOPLASMS 
BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)' 
and PT name different than 'UTERINE LEIOMYOMA'
Smoking
COVID Co-Morbidities eCRF: “What is the subject’s smoking history?”
MHDIAGYN17 = “1” (“Current smoker”)


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High Risk of Severe 
COVID-19 Condition
Description
Sickle cell disease
COVID Co-Morbidities eCRF: “Does the subject have a history of Sickle cell 
disease?”
Programming example: MHDIAGYN6 = “Y”
Note: Final programming logic may differ to address the specific data elements such as additional fields, 
different field name, or levels.


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APPENDIX 7.
LIST OF ABBREVIATIONS
Abbreviation or special term
Explanation
ADA
anti-drug antibody 
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AST
aspartate aminotransferase/transaminase
ATC
Anatomical Therapeutic Class
AUC
area under the plasma concentration-time curve
BMI
body mass index
BLQ
below the lower limit of quantification
BSSR
blinded sample size re-estimation
CI
confidence interval
COVID-19
coronavirus disease 2019
CDC
Centers for Disease Control and Prevention
CMH
Cochran-Mantel-Haenszel
CS
clinically significant
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DBL
database lock
DBP
diastolic blood pressure
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
FAS
full analysis set
FPAS
full pre-exposure analysis set
gCV%
geometric coefficient of variation
GMT
geometric mean titers
GMFR
geometric mean fold rise
GSD
geometric standard deviation
IA
interim analysis
IM
intramuscular
IMP
Investigational Medicinal Product
IRT
Interactive Response Technology


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Abbreviation or special term
Explanation
ITT
intent-to-treat
LLOQ
lower limit of quantification
LOD
limit of detection
MAAE
medically attended adverse event
mAbs
monoclonal antibodies
MAC
Morbidity Adjudication Committee
MedDRA
Medical Dictionary for Regulatory Activities
nAb
neutralizing antibody
NCS
not clinically significant
NP
nasopharyngeal
NQ
not quantifiable 
NR
not reportable
NS
no sample
PAS
all participants analysis set
PD
pharmacodynamic
PH
proportional hazard
PK
pharmacokinetic(s)
PT
preferred term
RR
relative risk
RRR
relative risk reduction
RT-PCR
reverse transcriptase polymerase chain reaction
SAE
serious adverse event 
SAF
safety analysis set
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome-coronavirus 2
SBP
systolic blood pressure
SD
standard deviation
SI
Standard International
SOC
system organ class
TBL
total bilirubin level
TE-ADA
treatment-emergent ADA
TFLs
tables, figures, and listings
TMA
Therapeutic Medical Advisor
ULN
upper limit of normal
ULOQ
upper limit of quantification


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Abbreviation or special term
Explanation
ULQ
above the upper limit of quantification
WHO
World Health Organization


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