Clinical trial NCT03766399
Conditions: Asthma
Keywords: Inhaled JAK inhibitor
Sponsor: AstraZeneca
Start date: 2018-11-30; Completion date: 2021-06-24
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This will be a Phase I, first in human (FIH) study consisting of the following parts: Part 1a (SAD), Part 1b (IV Cohort), Part 2 (Multiple ascending dose (MAD), and Part 3 dry-powder inhalation (DPI)/ Proof of mechanism (PoM). Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study performed at a single study center. Part 1b, will be an open-label, single-dose, single-cohort study. It will follow a 2-stage design in the way that participants from Part 1a will be selected for the IV Cohort in Part 1b. Part 2 of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design and study performed at 3 study centers. Part 3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. The expected duration of each subject in Part 1a of the study is up to 36 days and up to 53 days for subjects participating in Part 1b. The expected duration of each participant in Part 2 is up to 52 days and Part 3 is up to 55 days.

Detailed description:
This will be a Phase I, consisting of the following parts: Part 1a, Part 1b, Part 2a/b, Part 3a/b. Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study performed at a single study center. Six inhaled dose levels of AZD0449 nebulized suspension are planned to be investigated in 6 cohorts. Depending on emerging safety and PK data, up to 3 additional inhaled dose levels (cohorts), within the pre-specified dose range, may be added at the discretion of the Sponsor. Within each cohort, 6 volunteers will be randomized to receive an inhaled dose of AZD0449 nebulized suspension and 2 volunteers will be randomized to receive inhaled placebo. Intravenous (IV) dosing in Part 1b of the study will be initiated after the completion of cohort 6 in Part 1a or (if Part 1a is completed with less than 6 cohorts) after completion of the last cohort in Part 1a. Part 1b, will be open-label and consist of 2 dose cohorts (IV 0.090 mg and 0.360 mg) and be conducted in 12 healthy volunteers. Six (6) volunteers will be selected for the first IV dose cohort in Part 1b following a 2-stage design. If Part 1b cannot be completed with 6 volunteers from Part 1a or if some of the data are considered not evaluable, up to 6 additional naïve volunteers may be enrolled. A second IV dose cohort in Part 1b will be initiated after the evaluation of the PK and safety results from all cohorts in Part 1a and completion of the first IV dose cohort in Part 1b. The second IV dose cohort will consist of 6 healthy volunteers who have not previously participated in the study (naïve volunteers). Part 2a/b of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design study performed at approximately 3 study centers. Part 2a will include cohorts 1 and 2, each comprising of 9 patients with mild asthma. Within each of these cohorts 6 patients will be randomized to receive AZD0449 nebulized suspension and 3 patients randomized to receive placebo. Additional cohorts with 9 patients could be added to study PK, PD and safety for doses lower than 1.2 mg or up to 5 mg. Part 2b will consist of 1 cohort of 8 healthy volunteers; 6 volunteers will be randomized to receive AZD0449 nebulized suspension and 2 volunteers will be randomized to receive placebo. Part 3a/b of the study will be initiated after the completion of Part 2b. Part 3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. Part 3 will be conducted in up to 36 patients with mild asthma (Part 3a) and 8 healthy volunteers (Part 3b, optional). Part 3a will consist of 36 patients, where 18 patients will be randomized to AZD0449 DPI and 18 patients to placebo. An Interim Analysis (IA) will be conducted when 9 patients on each arm have completed the study (50% Part 3a). Should new data on the variability of the FeNO measurements emerge at the IA, the sample size in Part 3a could be changed. If the optional Part 3b is conducted, it will comprise 8 healthy volunteers; 6 volunteers will be randomized to AZD0449 DPI and 2 volunteers to placebo.

Arms: arm 1: 6 participants will receive inhaled dose 1 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo. arm 2: 6 participants will receive inhaled dose 2 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo. arm 3: 6 participants will receive inhaled dose 3 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo. arm 4: 6 participants will receive inhaled dose 4 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo. arm 5: 6 participants will receive inhaled dose 5 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo. arm 6: 6 participants will receive inhaled dose 6 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo. arm 7: All 6 participants will receive single IV dose of AZD0449 solution. arm 8: 6 participants will receive inhaled dose 7 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo. arm 9: 6 participants will receive inhaled dose 8 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo. arm 10: 18 healthy volunteers will receive inhaled dose 9 of AZD0449 nebulized suspension and 12 healthy volunteers will receive inhaled placebo. arm 11: 18 participants will receive inhaled dose 10 of AZD0449 DPI and 6 participants will receive inhaled placebo. arm 12: 6 healthy volunteers will receive single IV dose of AZD0449 solution. arm 13: Part 3b is optional. 8 healthy volunteers; 6 volunteers will receive AZD0449 DPI and 2 volunteers will recieve placebo.
Interventions: intervention 1: AZD0449 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive single inhaled AZD0449 nebulizer suspension and single IV dose of AZD0449 solution. intervention 2: Participants will receive single dose of placebo for AZD0449 (nebulizer suspension).

Protocol documents:
Prot_000.pdf: 
A Si n gle- Bli n d, R a n d o mize d, Pl ace b o- C o ntr olle d 3- P art 
St u d y i n He alt h y V ol u nteers a n d P atie nts wit h Mil d Ast h m a 
t o I n vesti g ate t he S afet y, T oler a bilit y a n d P h ar m ac o ki netics 
of I n h ale d A Z D 0 4 4 9 F oll o wi n g Si n gle a n d M ulti ple 
Asce n di n g D oses a n d t o I n vesti g ate t he A nti-I nfl a m m at or y 
Effect of  I n h ale d A Z D 0 4 4 9 
Cli nic al Tri als. g o v I de ntifier: N C T 0 3 7 6 6 3 9 9 
Pr ot oc ol A me n d me nt 1 0: Fi n al, 0 4 Fe br u ar y 2 0 2 1 


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Cli nic al St u d y Pr ot oc ol
A Si n gle -bli n d, R a n d o mize d, Pl ace b o - Co ntr olle d 3 - Part St u d y i n He alt h y 
Vo l u nteers a n d P atie nts wit h Mil d Ast h m a t o I n vesti g ate t he S afet y , 
To ler a bilit y a n d P h ar m ac o ki netics of I n h ale d A Z D 0 4 4 9 F oll o wi n g Si n gle 
a n d M ulti ple Asce n di n g D oses a n d t o I n vesti g ate t he A nti -Infl a m m at or y 
Effect of I n h ale d A Z D 0 4 4 9
P are xel St u d y N o.:
S p o ns or St u d y C o de:
D 5 3 7 1 C 0 0 0 0 1
E u dr a C T N o.:
2 0 1 8- 0 0 3 4 6 9- 3 2
Test Pr o d uct:
A Z D 0 4 4 9
T her a pe utic I n dic ati o n:
Ast h ma
P h ar m ac ol o gic al Cl ass:
I n hale d J A K i n hi bit or
De vel o p me nt P h ase:
P hase I
S p o ns or:
Astra Ze neca A B
1 5 1 8 5 S ö dertälje
S we de n
D ate of Pr ot oc ol:
Fi nal 1. 0, 1 8 Se pte m ber 2 0 1 8
Pr ot oc ol A me n d me nt N o. 1
Fi nal 1. 0, 2 3 Oct o ber 2 0 1 8
Pr ot oc ol A me n d me nt N o. 2
Fi nal 1. 0, 0 4 Dece m ber 2 0 1 8
Pr ot oc ol A me n d me nt N o. 3
Fi nal 1. 0, 0 9 Ma y 2 0 1 9
Pr ot oc ol A me n d me nt N o. 4
Fi nal , 0 3 Dece m ber 2 0 1 9
Pr ot oc ol A me n d me nt N o. 5
Fi nal, 1 1 Fe br uar y 2 0 2 0
Pr ot oc ol A me n d me nt N o. 6
Fi nal, 2 7 Ma y
2 0 2 0
Pr ot oc ol A me n d me nt N o. 7
Fi nal, 2 6 J u ne 2 0 2 0
Pr ot oc ol A me n d me nt N o. 8
Fi nal, 1 1 Se pte m ber 2 0 2 0
Pr ot oc ol A me n d me nt N o. 9
Fi nal , 08 Dece m ber 2 0 2 0
Pr ot oc ol A me n d me nt N o. 1 0
Fi nal , 0 4 Fe br uar y 2 0 2 1
T his cli nical st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m plia nce wit h G o o d Cli nical 
Practice, wit h t he Declarati o n of Helsi n ki ( versi o n 1 9 9 6) a n d wit h ot her a p plica ble re g ulat or y 
re q uire me nts.
C o nfi de ntialit y State me nt
T his c o nfi de ntial d oc u me nt is t he pr o pert y of Astra Ze neca . N o u n p u blis he d i nf or mati o n c o ntai ne d 
her ei n ma y be discl ose d wit h o ut pri or writte n a p pr o val fr o m Astra Ze neca . Access t o t his d oc u me nt 
m ust be restricte d t o rele va nt parties.
C CI






Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
P R O T O C O L A M E N D M E N T S
Pr ot oc ol A me n d me nt N o . 1 0, d ate d 0 4 Fe br u ar y 2 0 2 1
Pr ot oc ol  A me n d me nt N o. 9, date d 0 8 Dece m ber 2 0 2 0 was a me n de d t o u p date t he ti mi n g t o 
c o n d uct t he i nteri m a nal ysis of Part 3a . Secti o ns t hat were u p date d were Secti o n 3. 1. 4 , 
Secti o n 1 0. 4. 1 a n d Pr ot oc ol S y n o psis .
Pr ot oc ol A me n d me nt N o. 9 , d ate d 0 8 Dece m ber 2 0 2 0
Pr ot oc ol  Ame n d me nt N o . 8, date d 1 1 Se pte m ber 2 0 2 0 was a me n de d t o c ha n ge t he C hie f
I n vesti gat or fr o m 
 t o 
Pr ot oc ol A me n d me nt N o. 8, d ate d 1 1 Se pte m ber 2 0 2 0
T he mai n c ha n ges ma de t o t he Pr ot oc ol A me n d me nt N o. 7 , date d 26 J u ne 2 0 2 0 are as f o ll ows:
1.
I n vesti g at ors a n d st u d y a d mi nistr ati ve str uct ure: C o ntact details f or t he S p o ns or ’s lea d 
p h ysicia n a n d t he S p o ns or’s bi o st atisticia n were u p date d t o reflect c ha n ge s i n t he st u d y 
tea m.
2.
T re at me nt s: I n res p o nse t o a re q uest fr om t he Ger ma n Fe der al Inst itute f or Dr u gs a n d 
Me dical De vices
(Bf A r M), i nf or mati on a b o ut t he dr y -p o w der i n haler ( D PI) t o be use d f or 
t he a d mi nistrati o n of  st u d y treat me nt d uri n g Part 3 was a d de d i n Secti o n 3. 5. 4. 1 ,
Secti o n 7. 1 , a n d Pr ot oc ol  S y n o psis. I n res p o nse t o a re q uest fr o m a n et hics c o m mitt ee, t he 
act ual d ose a d mini stere d i n Part 3 was a d de d i n Secti o n 4. 2. 5 a n d Secti o n 7. 6 f or clarit y.
3.
Deter mi n ati o n of s a m ple size: I n Sect i on 1 0. 4 a n d Pr ot oc ol  Sy n o psis , r efer e nce t o t he 
Stati stical A nal ysis Pl a n ( S A P) was r e mo ve d . If t he act ual esti mate of  baseli ne Fe N O 
sta n dar d de viat i on (S D ) e xcee ds 0. 5 5 d uri n g t he i nteri m a nal ysis (I A), t he n t he pr ot oc ol 
a me n d me nt pre pare d t o descri be f urt her a djust me nt s i n t he sa m ple size will  incl u de t he
criteria f or sa m ple size re-e val uat i on.
4.
A n al ysis of fr acti o n e x h ale d nitric o xi de ( Fe N O) i n P ar t 2 a a n d P art 3 a : Part 2a was 
r e mo ve d fr o m t he treat me nt c o m par is o ns bet wee n D PI A Z D 0 4 4 9 
 a n d place b o. It 
was pre vi o usl y i ncl u de d i n err or as Part 2a d oes n ot i ncl u de treat me nt wit h D PI A Z D 0 4 4 9 
 a n d pl ace b o.
5.
A d verse E ve nts B ase d o n E x a mi n ati o ns a n d Tests : I n res p o nse t o a re q uest fr o m BfA r M, 
Secti o n 1 1. 2. 6
i n dicates t hat c ha n ges i n Cli nical  St u d y Pr ot oc ol (C S P )-ma n date d
la b orat or y val ues, vit al si g ns, e lectr ocar di o gra ms ( E C Gs), a n d ot her safety assess me nts
will be re p orte d as a d verse e ve nts (A Es ) if c o nsidere d t o be cli nicall y rele va nt as j u d ge d 
b y t he i n ve stig at or .
P P D
P P D
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Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Pr ot oc ol A me n d me nt N o. 7, d ate d 2 6 J u ne 2 0 2 0
T he mai n c ha n ges ma de t o t he Pr ot oc ol A me n d me nt N o. 6, date d 2 7 Ma y
2 0 2 0 are as f o ll ows:
1.
E xte n de d S afet y M o nit ori n g Peri o d : T he safet y m o nit ori n g p eri o d f or St u d y  Part 2 b, 
Part 3a, a n d P art 3 b was e xte n de d t o 1 5 da ys aft er last d ose a d mi nistrati o n. T his was i n 
r es p o nse t o a Me dici nes a n d Heal t hcare Pr o d ucts Re g ulat or y Ag e n c y  ( M H R A) re q uest t o 
e xte n d safet y m o nit ori n g a n d o bser vati o n u nt il t he e n d of e x p os ure, at least 5 half-li ves or 
e n d of e x pecte d p har mac o l ogi cal acti vit y, w hic he ver is l on ger. First, 9 7 % of t he last d ose 
is esti mate d t o be eli mi nate d after 1 1 da ys, w hic h is e q ui vale nt t o t he 5 half-li ves-c o n ditio n. 
Sec o n d, t he d urati o n of t he p har mac o l ogi cal effect was c o nser vat i vel y esti mate d t o 1 5 da ys 
after t he last d ose. T his esti mate is base d o n p har mac o ki net ic (P K ) a n d fracti onal e x hale d 
nit ric o xi de (Fe N O ) data c o llecte d aft er re peate d d osi n g of  
 i n Part 2 a i n 
mil d ast h matics. T he l o n ger of t he 2 esti mates was use d t o deter mi ne t he safet y m o nit ori n g 
p eri o d. T his e xte n de d peri o d of safet y m o nit ori n g will c o nt i n ue u ntil Da y 2 7 ( 1 5 da ys after 
t he last d ose a d mi nistrati o n) a n d will a p pl y t o all patie nts a n d v o lu nteers i n Part 2 b, 3a, a n d 
3 b. T his pr oce d ure will be u n derta ke n o n a resi d e nti al basis at t he Cli nical U nit u ntil s uc h 
ti me as t he r ele v a nt Re g ul at or y Aut h ori t y is satisfie d t hat o ut pati e nt base d assess me nt is 
feasi ble a n d safe. C ha n ges ha ve bee n ma d e t o t he f oll owi n g secti ons: Pr ot oc ol  Sy n o psis, 
Secti o ns 3. 1. 3 , 3. 1. 4 , 3. 1. 6 , 3. 2. 2 , 3. 2. 4 , a n d 5. 1. 2. 1. 1.
2.
S afet y a n d P K assess me nts: D uri n g t his e xte n de d safety m o ni t ori n g p eri o d , a d ditio nal 
safety,  PK, a n d P D assess me nts/sa m pli n g will be d o ne. C ha n ges ha ve bee n ma de t o t he 
f oll owi n g sect i on: Secti o n 3. 2. 2 .
3.
Bl o o d v ol u mes: Mi n or u p dates t o bl o o d v ol u mes f or Part
1 b, Parts 2a a n d 2 b, a n d Parts 3a 
a n d 3 b t o reflect c o rrect sa mpli n g d uri n g t he st u d y. C ha n ges ha ve bee n ma de t o t he 
f oll owi n g s ect i ons: Secti o n 3. 2. 4 , Ta ble 3. 2 - 1 2, Ta ble 3. 2 -1 3 , a n d Ta ble 3. 2 -1 4 .
4.
E xcl usi o n criteri a: Mi n or 
c orrectio ns of  ty p o gra p hical err ors i n Part 1a/ b e xcl usi o n 
crit erio n n u m ber 7 , patie nts wit h mil d ast h ma Part 2a/ 3a e xcl usi o n crit erio n n u m ber 1 8 , 
a n d healt h y v o l un teers Part 2 b/ 3 b e xcl usi o n criteria n u m ber 7 a n d 8 . C ha n ges ha ve bee n 
ma de t o t he f o ll owi n g sect i ons: Secti o n 5. 1. 1. 2 , Secti o n 5. 1. 2. 2. 1 , a n d Secti o n 5. 1. 2. 2. 2 .
5.
Di git al E C G sc he d ule: Mi n or c orrecti o n of t y p o gra p hical err ors i n t he f o ot n otes f or d E C G 
sc he d ule f or Part 1 b a n d t he f oot n otes f or d E C G sc he d ule f or P art 2a. C ha n ges ha ve bee n 
ma de t o t he f o ll owi n g sect i on: Sect i on 3. 2. 2 , Ta ble 3. 2 - 9, an d Ta ble 3. 2 - 1 0.
6.
I nteri m a n al ysis: Mi n or c orrecti o n t o re m o ve d u plicat i on i n te xt. T he sec o n d para gra p h i n 
t he secti o n was delete d ( delete d te xt i n striket hr o u g h ).
“ As me nt i one d a b o ve, a n u n bli n de d I A will be perf or me d w he n 5 0 % of t he patie nts i n ha ve 
c o mplete d Part 3a. T he c ollecte d data will be use d t o i nf or m v ari o us decisi o ns or a cti o ns 
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Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
s uc h as assessi n g t he efficac y of  AZ D 0 4 4 9 i n a n u n bli n de d ma n ner a n d t o perf or m a n 
u n bli n de d sa m ple size re -esti mat i on. Base d o n t he res ults fr o m t he I A ( P K, P D [ Fe N O] a n d 
safety) , t he P o M c o h ort size will be deci de d. F urt her details will be i ncl u de d i n t he S A P 
f or Part 3. T he latter will d et ail t he nat ure a n d t he e xact crit eria of t he decisi o ns as well as 
ha n dli n g of t he data a n d act ual decisi o n ma kers.
I n Part 3a, a n u n bli n de d I A will be p erf or m e d w he n 5 0 % of  the pati e nts ha ve c o mplete d 
t he c o h ort. Base d o n t he res ults fr o m t he I A ( P K, P D [ Fe N O] a n d safet y), t he f or mulati o n 
c o h ort size will be deci de d. ”
C ha n ges ha ve bee n ma de t o t he f o ll owi n g sect i on: Secti o n 1 0. 4. 1 .
7.
Pr ot oc ol de vi ati o n: Mi n or clarificat i on i n descri bi n g Data Re vie w Meet i n g ( delete d te xt 
i n striket hr o u g h ). 
“ All pr ot oc ol  de viatio ns will be di sc usse d at t he Data Re vie w Meet i n g ( D R M) bef ore 
data base har d l oc k i n or der t o defi ne t he a nal ysis sets f or t he st u d y. T he precise reas o ns f or 
e xcl u di n g pat ient s fr om t he st u d y p o p ulat i ons will be f ull y defi ne d a gree d o n i n t he D R M 
re p ort”
C ha n ges ha ve bee n ma de t o t he f o ll owi n g sect i on: Secti o n 1 0. 5 .
8.
F ol l o w-u p: Mi n or cl arificat i ons t hr o u g h o ut of  “ F oll o w-u p Visi t ” t o “F o ll ow- u p Visi t/last 
d a y  of st u d y” or “last da y of st u d y” or “safety m o nit ori n g peri o d” w he n descri bi n g Part 2 b, 
3a, a n d 3 b. C ha n ges ha ve bee n ma de t o t he f oll o wi n g secti ons: Pr ot oc ol  Sy n o psi s, 
Secti o ns 2. 4 , 5. 2. 2 , 1 0. 2 , 1 0. 6. 4. 9 , 1 1. 1. 2 , 1 1. 2. 1 .
Pr ot oc ol A me n d me nt N o. 6, d ate d 2 7 M a y
2 0 2 0
T he ma i n c ha n ges ma de t o t he Pr ot oc ol A me n d me nt N o . 5, date d 1 1 Fe br uar y 2 0 2 0 are as 
f oll ows:
1.
C O VI D -1 9 sit u ati o n : T he first 2 m ulti p le asce n di n g d ose ( M A D) c o h orts wit h t he 
 
 d oses wit h t he ne b ulize d f or mulat i on ha ve bee n c o m p lete d i n mil d ast h matics. 
T he pri mar y  (safety a n d t olera bilit y) a n d sec o n dar y (P K a n d p har mac o d y na m ics [ P D]) 
o bj ect i ves of  Part 2 w ere e val uate d. T he r e mai ni n g ne b uli ze d 
 c o h ort i n mil d 
ast h matics r e mai ns o n h o l d d ue t o t he st u d y sites s us pe nsi on of  recr uit me nt of  mil d 
ast h matics r elat e d t o t h e C O VI D - 1 9 pa n de mic. As t he i nte nt i on is f or t he 
 ne b ulize d 
P K a n d safety data t o i nf or m t he sa me d ose a n d f or mulati o n t o s u p p ort a p ote ntial 
C O VI D - 1 9 st u d y, t he S p o ns or has deci de d t o re place t he fi nal mil d ast h mat ic c o h ort i n 
Part 2 of  the stu d y wi t h a co h ort of  he alt h y vol u nteers. T he sec o n dar y PD o bject ive “t o 
e val uate a nt i-i nfla m mat or y effect i n pati e nts wit h mil d ast h ma” via Fe N O has bee n 
r e mo ve d fr o m t he t hir d c o h ort i n Part 2 a n d a d de d t o Part 3a t o be perf or me d at a ti me w he n 
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Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
t he recr uitme nt  of mil d ast h matics bec o me s feasi ble. T he S p o ns or belie ves there is n o 
c ha n ge i n t he be nefit: ris k t o eit her healt h y v o l unteers or mil d ast h ma s u bjects base d o n 
t his a me n d me nt t o t he st u d y. T he pri mar y o bjecti ve a n d t he sec o n dar y o bjecti ve ( P K) ca n 
be st u die d i n healt h y v o l unt eers as well as mil d ast h mat ics. C ha n ge s ha ve bee n ma de t o t he 
f oll owi n g sect i ons: Pr ot o c ol  Sy n o psis, Secti o n s 1. 3 , 2. 1 , 2. 2 , 2. 3 , 2. 4 , 3. 1 , 3. 2 , 3. 5 , 3. 6 , 4. 1 , 
4. 2. 5 , 5. 1 , 6. 2 , 7. 6 , 7. 1 0. 1, 8. 2. 7 , 8. 5 , 8. 6 , 1 0. 4 , 1 0. 6. 5. 4 , 1 0. 6. 6 a n d 1 0. 6. 7 .
2.
S plit of P art 2 t o P art 2 a a n d P art 2 b: F or practical reas o ns Part 2 has bee n di vi de d t o 
Part 2a (Patie nts wi t h mil d ast h ma) a n d Part 2 b ( Healt h y v ol u nteers). Se parate o bj ecti ves
[Ta ble 2. 3 - 1 a n d Ta ble 2. 3 - 2], Sc he d ule of  Assess me nts [Ta ble 3. 2- 4 a n d Ta ble 3. 2 -5 ], a n d 
i ncl usi on a n d e xcl usio n crit eria ( Secti on 5. 1. 2 ) are a vaila ble i n t he a me n de d pr ot oc ol  for 
Part 2a a n d Part 2 b, res pecti vel y. C ha n ges ha ve bee n ma de t o t he f oll owi n g secti ons: 
Pr ot oc ol  S y n o psis, Secti o ns 1. 3 , 2. 3 , 3. 1. 3 , 3. 1. 6 , 3. 2. 1 , 3. 2. 3 , 3. 2. 4 , 3. 5. 3 , 3. 6 , 4. 1. 3 , 4. 2. 5 , 
5. 2. 2 , 5. 2. 3 , 6. 2 , 8. 5 , 8. 6 , 1 0. 4 , 1 0. 6. 3. 2 , 1 0. 6. 5 , 1 0. 6. 6 a n d 1 0. 6. 7 .
3.
S plit of P art 3 t o P art 3 a a n d P art 3 b: T he pri mar y  a n d sec o n dar y o bjecti ves of Part 3 is 
i de ntical to Part 2. I n a sit u atio n (ie, C O VI D - 1 9 pa n de mic) w he n t he S p o ns or ca n n ot recr uit 
mil d ast h mat ics to t he st u d y t he S p o ns or will ha ve t he o pti o n t o st u d y t he pri mar y o bject i ve 
a n d o n e of t he sec o n dar y o bject i ves ( P K) i n a n o ptio nal c o h ort i n healt h y v o l unt eers. T he 
decisi o n t o start t his c o h ort w o uld be ma de at a Sa fety R e vie w C o m mittee ( S R C) meet i n g 
w he n Part 2a/ b of  t he st u d y has bee n c o m p lete d.
F or practical reas o ns t he Part 3 has bee n di vi de d t o Part 3a ( Patie nts wit h mil d ast h ma ) a n d 
Part 3 b ( Healt h y v ol u nteers). Part 3 b, if c o n d ucte d, ma y be r u n i n parallel  or c o m p lete d 
a hea d of Part 3a. Se parate o bj ect i ves (Secti o n 2. 4 ), Sc he d ule of Assess me nts (Ta ble 3. 2 - 6
a n d Ta ble 3. 2 - 7), a n d i ncl usi on a n d e x clusi o n crit eria ( Sectio n 5. 1. 2 ) are a vaila ble i n t he 
a me n de d pr ot oc ol  for Part 3 a a n d Part 3 b, res pecti vel y. C ha n ges ha ve bee n ma de t o t he 
f oll owi n g secti ons: Pr ot o c ol  Sy n o psis, Secti o n s 1. 3 , 2. 3 , 3. 1. 4 , 3. 1. 6 , 3. 2. 1 , 3. 2. 3 , 3. 2. 4 , 
3. 5. 4 , 3. 6 , 4. 1. 4 , 4. 2. 5 , 4. 3. 1 , 5. 2. 2 , 5. 2. 3 , 7. 6. 4 , 7. 1 0. 1. 4 , 8. 5 , 8. 6 , 1 0. 4 , 1 0. 6. 4. 3 , 1 0. 6. 5 , 
1 0. 6. 6 a n d 1 0. 6. 7 .
4.
I ncl usi o n/e xcl usi o n criteri a: I n clusi o n /e xcl usi on criteria ha ve bee n u p date d t o reflect t he 
a b o ve pr o p ose d a me n d me nt f or healt h y v o l unt eers t o recei ve re peate d d osi n g. T he o n g oi n g 
assess me nt of  safet y is pr o vi de d a n d is ali g ne d t o t hat f or t he mil d ast h ma s u bjects. C ha n ges
ha ve bee n ma de t o t he Secti o n 5. 1 .
T he e xcl usi o n o f W ome n o f Chil d beari n g P ote ntial ( W O C B P) f or Part 1 b sec o n d I V c o h ort
has bee n r e-assesse d ta ki n g i nto c o nsi derat i on t he c urre nt pre dicte d A U C a n d C ma x f or 
i ntra ve n o us (I V) A Z D 0 4 4 9 
are pre dicte d t o be well b el o w t he safety e x p os ure 
li mits ( 6-f ol d l o wer f or ma xi m u m o bser ve d plas ma c o nce ntrati o n [ C ma x] a n d 9-f ol d l o wer 
f or area u n der t he c o nce ntrati o n -time c ur ve [ AU C]) a n d t his s h o uld mi ni mize p ote ntial 
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
re pr o d uctive ris ks. I n vie w of  the C li nical Tri al Facilitati o n Gr o u p ( C T F G) g ui da nce, 
a vaila ble data, a n d d ose f or mulat i on of  AZ D 0 4 4 9 i n t his st u d y, it was c o nclu de d t hat 
e xcl usi o n of  WO C B P fr o m Part 1 b sec o n d I V c o h ort is n ot necessar y, pr o vi de d hi g hl y 
effect i ve meas ures 
of  co nt race ptio n are i m ple me nte d a n d t hat pre g na nc y testi n g is 
perf or m e d d uri n g t he trial. C ha n ges ha ve bee n ma de t o Secti o n 5. 2. 3 .
5.
E nl ar ge me nt of s a m ple size f or t he D PI
c o h ort i n mil d ast h m atics ( P art 3): T he 
pr o of -of -mec ha nis m ( P o M) assess me nt has bee n m o ve d fr om t he ne b ulize d c o h ort 3 
( Part 2 b) t o t he D PI c o h ort ( Part 3a). As t he ne b ulize d c o h ort 3 will n o w be p erf or m e d i n 
healt h y v o l unt eers f or P K a n d safety,  t he sec o n dar y o bjecti ve of Fe N O ( P D) will be m o ve d 
t o Part 3a t o be c o n d ucte d i n a p o were d c o h ort of  mil d ast h matics once recr uit me nt  of these 
s u bjects bec o mes feasi ble. T he sa mple size of  the Part 3a c o h ort is i ncrease d i n or der t o 
p o wer t he c o h ort f or stat istical a nal ysis of  the P D, Fe N O o utc o m es. C ha n ges ha ve bee n 
ma de t o f oll owi n g secti ons: Pr ot oc ol  Sy n o psis, Secti o n s 1. 3 , 2. 3 , 2. 4 , 3. 1. 4 , 4. 1. 3 , 4. 1. 4 , 
8. 5. 1 , 1 0. 4 , a n d 1 0. 6. 6. 1 .
6.
Re d ucti o n of s a m ple size f or t he t hir d M A D c o h ort : As i n dicate d a b o ve, t he 
 M A D 
c o h ort ( Part 2 b) will be c o n d ucte d i n healt h y v o l unteers wit h t he pri mar y o bject i ve to st u d y 
safety a n d t olera bilit y a nd t he sec o n dar y o bject i ve t o stu d y P K. T heref ore, t he n u m ber of 
s u bjects nee de d t o st u d y t hese o bject i ves is t he sa me as use d i n t he Si n gle Asce n di n g D ose 
( S A D) c o h orts ( 6 recei vi n g A Z D 0 4 4 9 a n d 2 place b o). C ha n ges ha ve bee n ma de t o 
f oll owi n g sect i ons: Pr ot oc ol  Sy n o psis, Secti o n s 2. 3 , 3. 1. 3 , 4. 1. 3 , a n d 1 0. 4 .
7.
T wice d ail y o pti o n is re m o ve d : Base d o n a vaila ble data fr o m Part 1 a n d Part 2a it has 
bee n deci de d t o c o nti n ue t his st u d y wit h o nce dail y ( Q D) d osi n g. T heref ore t he t wice dail y 
( BI D) o ptio n h as bee n r e mo ve d fr o m t he pr ot oc ol . C ha n ges ha ve bee n ma de t o f oll owi n g 
secti ons : Pr ot oc ol  S y n o psis, Secti o n s 3. 1. 3 , 3. 1. 4 , 3. 1. 6 , 3. 2. 1 , 3. 2. 2 , a n d 1 0. 6. 5. 4 .
8.
Di a g n ostic testi n g f or C O VI D - 1 9: S u bjects will u n der g o ser ol o g y (as a vaila ble) a n d s wa b 
testi n g f or C O VI D -1 9 at scree ni n g aft er si g ne d i nf or me d c o nse nt a n d bef ore 
ra n d omizat i on. If a st u d y su bject s h o ws a n y s y m pt o m of a pote nti al CO VI D - 1 9 i nfecti on 
a n a d h o c nasal a n d/ or t hr oat-s wa b s peci me n f or t he i de ntificat i on o f a s us pecte d res pirat or y 
i nfecti on i ncl u di n g C O VI D - 1 9 will be ta ke n. S u bjects w h o test p osit i ve f or ha vi n g act i ve 
C O VI D - 1 9 i nfecti on will be disc o nt i n ue d fr o m t he st u d y an d f oll owe d u p u ntil t he fi nal 
o utc o m e of t he A E. C ha n ges ha ve bee n ma de t o Secti o ns 3. 2. 2 , 5. 2 , 6. 2 , a n d 8. 2. 7 .
Pr ot oc ol A me n d me nt N o. 5, d ate d 1 1 Fe br u ar y 2 0 2 0
T he ma i n c ha n ges ma de t o t he Pr ot oc ol A me n d me nt N o. 4, date d 0 3 Dece m ber 2 0 1 9 are as 
f oll ows:
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1.
Base d o n e mer gi n g data, a n a d ditio n al  co h ort wit h i ntra ve n o us (I V) a d mi nistrati o n was 
a d de d: t he sec o n d I V d ose c o h ort. T he rati o nale be hi n d a d di n g a n e xtra I V c o h ort was t o 
i m pr o ve t he p ossi bilit ies t o c haracterize t he eli mi nat i on ki net ics of  AZ D 0 4 4 9. F o ll owi n g 
a d mi nistrati o n of 
 t he eli mi nat i on ki net ics of A Z D 0 4 4 9 c o uld n ot be s ufficie ntl y 
descri be d. T he c o nce ntrati o ns i n plas ma decli ne d ra pi dl y wit h 2 -c o mpart me nt  ki netics a n d 
t he c o nce ntratio ns were q ua nt ifia ble o nl y 1 0 t o 1 2 h o urs aft er a d mi nistrati o n. Wit h t he 
sec o n d I V d ose c o h ort, it is pre dicte d t hat a 4 ti mes hi g her d ose 
 will res ult i n 
c o nce ntrati o ns i n plas ma t hat are q ua ntifia ble u p t o 2 4 h o urs aft er d osi n g a n d t hus i m pr o ve d 
p ossi bilit i es t o full y c haracterize t he eli mi nat i on ki net ics of A Z D 0 4 4 9 ( Secti o ns 2. 2 , 3. 1. 2
[incl u di n g ne w secti on 3. 1. 2. 2 a n d sc he d ule of  assess me nt ta ble f or t he sec o n d I V c o h ort 
Ta ble 3. 2 - 3], 3. 2 , 3. 5. 2 , 4. 1. 2 , 5. 1. 1 , 5. 2. 1 , 7. 6. 2 , 7. 1 0. 1. 2 ).
2.
Secti o ns 3. 5. 2. 1 a n d 4. 1. 2 w ere u p date d t o i ncl u de t he d ose strate g y a nd r atio nale f or t he 
hi g her d ose use d i n t he sec o n d I V c o h ort i n Part 1 b 
 A Z D 0 4 4 9). Res ults f or t he 
o bser ve d e x p os ure at  t he l owest d ose were a d de d (as pre dicte d, e x p os ure was well bel o w 
t he ma xi m u m allo w e d e x p os ure [ 1 % of  Cma x , 0. 3 % of  AU C]). T he pre dicte d e x p os ure at 
t he sec o n d d ose was a d de d (als o e x pecte d t o be well bel o w t he ma xi m u m all o we d e x p os ure 
[ 4. 4 % of Cma x , 1. 2 % of A U C]).
3.
T he pri mar y a n d sec o n dar y o bjecti ves f or Part 1 b (I V C o h orts) were u p date d t o state “ T o 
c haracterize t he bl o o d plas ma P K  of AZ D 0 4 4 9 f oll owi n g i ntra ve n o us a d mi nistrati o n of  a
2 si n gle d ose s t o healt h y s u bjects” ( ne w te xt i n b ol d , d elete d te xt i n striket hr o u g h ) i n t he
Pr ot oc ol  S y n o psis a n d Ta ble 2. 2 - 1.
4.
E x pl or at or y  o bjecti ves were a d de d t o Part 2 ( C o h ort 3): 
 
 
 a n d Part 3 
 
 
 (Pr ot oc ol  
Sy n o psis
a n d Ta ble 2 . 4-1 ).
C orres p o n di n g 
P K te xt was 
als o u p date d w here 
a p plica ble (Pr ot oc ol S y n o psis,
Secti o ns 8. 3. 1 , 8. 3. 2 , 1 0. 6. 5. 1 , 1 0. 6. 5. 2 , 1 0. 6. 5. 3 ).
5.
Base d o n e mer gi n g data, a n e xtra p har m ac o ki net ic s a mple was a d de d at 1 0 h f or C o h ort 3 
o n war ds i n Part 2 ( mul tiple asce n di n g d ose [ M A D]/ pr o of-of -mec ha nis m [ P o M]) – o nce 
dail y  (Q D) d osi n g [Ta ble 3. 2 - 4] a n d t wice dail y [ BI D] d osi n g [Ta ble 3. 2 -5 ]) a n d Part 3 
( Brid gi n g – Q D a n d BI D d osi n g [ Ta ble 3. 2 - 6 a n d Ta ble 3. 2 - 7].
6.
I n or d er t o pr o vi de f urt her data o n t he P K -P D r elatio ns hi p, t he st u d y desi g n was u p date d 
t o i ncl u de a n o pti o nal s u bset of u p t o 1 5 patie nts ( Part 2 [ M A D/ P o M]) or u p t o 1 2 patie nts 
( Part 3 [ Bri d gi n g]) w h o a gree t o re mai n i n-h o use fr o m  D a ys 1 4 t o 1 6, bei n g disc har ge d o n 
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
D a y 1 7 ( D a y 1 8 f or BI D d osi n g i n Part 3), t o all o w f or a d ditio nal  P K a nd Fe N O sa m ples 
t o be ta ke n (Pr ot oc ol S y n o psis,
Sect i ons 3. 1. 3 , 3. 1. 4 , 3. 1. 6
a n d 5. 1. 2. 1 , i ncl usi on 
crit erio n 3 ; sc he d ule of  assess me nt ta bles f or Part 2 [Ta ble 3. 2 -4 a n d Ta ble 3. 2 - 5] a n d 
Part 3 [ Ta ble 3. 2 -6 a n d Ta ble 3. 2 - 7]).
7.
T he bl o o d v ol u me ta bles were u p date d t o a d dress t he a b o ve c ha n ges t o assess me nts 
(Ta ble 3. 2 -1 1 , Ta ble 3. 2 -1 2 , Ta ble 3. 2 - 1 3, a n d Ta ble 3. 2 -1 4 ).
8.
A f o ot n ote was a d de d t o t he bl o o d v ol u me ta bles f or Part 2 ( M A D/ P o M; Ta ble 3. 2 -1 3 ) a n d
Part 3 ( Brid gi n g; T a ble 3. 2 -1 4 ), stati n g t hat f or all c o h orts, a n a d ditio nal 2. 5 m L sa m ple 
will be ta ke n f or i m u n o gl o b uli ns at Da y -1 o nl y. T his was a c orrecti o n w hic h was o mitte d 
i n t he pre vi o us A me n d me nt w hen t he Cli nical safet y  sa m pli n g was mo v e d fr o m D a y -1 t o 
D a y -2.
9.
Pr ot oc ol  Sy n o psis , Secti o ns 3. 2. 3 , 8. 6. 3 , a n d Ta ble 3. 2 - 5 ( Part 2 [ M A D/ P o M]) were 
re vise d t o state t hat s p ut u m sa m ples were t o be ta ke n at partici pati n g sites o nl y.
1 0. Assess me nt f or c ollecti o n of uri ne f or e x pl orat or y a nal yses of meta b o lites of A Z D 0 4 4 9 f or 
C o h ort 3 was a d ded t o t he sc he d ule of  assess me nt ta ble f or Part 2 ( M A D/ P o M) – Q D 
[Ta ble 3. 2 - 4] a n d BI D [Ta ble 3. 2 -5 ] d osi n g, a n d c orres p o n di n g te xt was a d de d i n 
Secti o n 8. 5. 2 .
1 1. Secti o n 3. 1. 4 a n d c orres p o n di n g Pr ot oc ol  S y n o psis te xt re vise d t o state “ Part 3 of t he st u d y 
will o nl y be i nitiate d after t he c o mpleti o n of  C o h ort 3 i n Part 2 ( M A D/ P o M) of t he st u d y 
a n d after a p pr o val of the s u bsta ntial a me n d me nt is recei ve d ” ( ne w te xt i n b ol d , delete d te xt 
i n striket hr o u g h ).
1 2. Part 2 a n d Part 3 i ncl usi o n crit erio n 7 i n Sect i on 5. 1. 2. 1 was clarifie d t o state t hat  lu n g 
f u ncti on ≥7 0 % pre dicte d f or F orce d E x pi rat or y V ol u m e i n 1 sec o n d ( F E V1) at t he 
Scree ni n g Visit A N D at t h e 1 2 h ti me p oi nt o n Da y - 1 is i n acc or da nce wit h t he A merica n 
T h oracic S ociet y ( A T S)/ E ur o pea n Res pirat or y S ociety ( E R S) crit eria.
1 3. T he p ul m o nar y  st o p pi n g criteria f or i n Secti o n 6. 2 were re vise d t o i ncl u de pat ient s w h o 
recei ve d A Z D 0 4 4 9 as well as s u bjects.
1 4. A Z D 0 4 4 9 Dr y -p o w der i n halati on ( D PI) a n d c orres p o n di n g pl ace b o were a d de d t o t he 
I n vesti gati onal Me dici nal Pr o d uct (I M P) ta ble i n t he Pr ot oc ol  S yn o psi s a n d i n Secti o n 7. 1 
(Ta ble 7. 1 - 1). As a res ult, refere nces t o t he C he mistr y , Ma n ufact uri n g, 
a n d C o ntr ols 
( C M C) d oc u me ntati o n s u p p orti ng t he D PI f or m ul ati o n were re m o ve d.
1 5.
 
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 6. T he i nteri m a nal ysis te xt i n Secti on 1 0. 4. 1 was u p date d t o i ncl u de t he perce nta ge of  patie nts 
re q uire d f or sa mple size r e-est i mati on f or t he Part 2 P o M a n d Part 3 i n halati on c o h orts.
Refere nce t o ‘a s pecial c harter (i nteri m a nal ysis pla n)’ was re m o ve d.
1 7. Te xt referri n g t o Pr ot oc ol A me n d me nt 5, i.e., “ …s u bsta nt ial a me n d me nt of  the pr ot oc o l 
will be s u b mitte d bef ore start of Part 3” was delete d t hr o u g h o ut.
1 8. Te xt was a d de d i n Sect i on 3. 3. 1. 4 t o descri be peri o dic m o nit ori n g a n d re g ular o versi g ht.
1 9. Cr oss refere nces t o sc he d ule of a ssess me nt ta bles were c orrecte d i n t he f oll owi n g secti o ns: 
3. 2 , 8. 2. 3. 1 , 8. 2. 3. 2 , a n d 8. 5. 7
(Ta ble 3. 2 - 5 li n k m o ve d t o Part 2, Ta ble 3. 2 - 6 a n d 
Ta ble 3. 2 - 7 a d de d t o Part 3); Secti o n 5. 2. 3. 1 (Ta ble 3. 2 - 5, Ta ble 3. 2 -6 , a n d Ta ble 3. 2 - 7
a d de d); Sectio n 8. 5. 4 (Ta ble 3. 2 - 4 a n d Ta ble 3. 2 - 5 a d de d t o Part 2 a n d li n k t o Ta ble 3. 2 - 6
c orrecte d); Secti o ns 8. 4. 2 , 8. 5. 5 , a n d 8. 5. 6 (Ta ble 3. 2 - 5 a d de d).
2 0. T he I n vesti gat or Br oc h ure E dit i on i n t he Refere nce List (Secti o n 1 4 ) was u p date d.
2 1. Mi n or f or m at a n d lan g ua ge c ha n ges were ma de t hr o u g h o ut t he d oc u me nt.
2 2. Pr ot oc ol  S y n o psis te xt was u p date d per t he a b o ve c ha n ges.
Pr ot oc ol A me n d me nt N o. 4, d ate d 0 3 Dece m ber 2 0 1 9
T he mai n c ha n ges ma de t o t he Pr ot oc ol A me n d me nt N o. 3, date d 0 9 Ma y
2 0 1 9 are as f o ll ows:
1.
T he e xclusi o n  of W o me n of  Chil d beari n g P ote nti al (W O C B P) 
i n t his st u d y has bee n 
r e-assesse d ta ki n g i nto c o nsi derat i on rec o m me n dati ons relate d t o c o nt race pti o n a n d 
pre g na nc y test i n g i n cli nical trials fr o m t he Cli nical Trial Facilitati on Gr o u p ( C T F G) of t he 
Hea ds o f Me di ci nes A ge ncies ( H M A), date d 0 9 Se pte m ber 2 0 1 5 [ 1 ]. Alt h o u g h t here ha ve 
bee n n o re pr o d ucti v e st u di es c o n d ucte d wit h AZ D 0 4 4 9 s o f ar, t he c urre nt e vi de nce base d 
o n p har mac ol o gical effects of  oral Ja n us ki nase (J A K) i n hi bit ors s u g gests p ote ntial t o xicit y, 
as descri be d i n t he A Z D 0 4 4 9 I n vest i gat or’s Br oc h ure [2 ]. S yste mic e x p os ures of A Z D 0 4 4 9 
u p t o t he 
 d ose level, i n hale d re peate dl y, are pre dicte d t o be well b el o w t he safet y 
e x p os ure li mits ( 6-f ol d l ower f or ma xi m u m o bser ve d plas ma c o nce ntratio n [ Cma x] a n d 9 -
f ol d l ower f or area u n der t he c o nce ntr atio n -ti me c ur ve [ A U C]) a n d t his s h o uld mi ni mize 
p ote nti al re pr o d ucti ve ris ks. I n vie w of  the C T F G g ui da nce, a vaila ble data, a n d d ose 
f or mulat i on of  AZ D 0 4 4 9 i n t his st u d y, it was c o ncl u de d t hat e xcl usi o n of  WO C B P fr om 
st u d y P art 2 ( m ul tiple asce n di n g d ose [ M A D]) a n d Part 3 ( pr o of -of -mec ha nis m [ P o M] ) is 
n ot necessar y, pr o vi de d hi g hl y  effecti ve meas ures of  co ntrace pti o n are i m ple me nte d a n d 
t hat pre g na nc y testi n g is p erf or m e d d uri n g t he trial. Pre g na nc y testi n g will be d o ne o n 
w o m e n parti ci pa nts at scree ni n g, pri or t o r a n d o mi z ati o n, a n d at t he F oll o w - u p Visi t. Use 
of  hi ghl y effect i ve met h o ds of  co ntrace pti o n as per t he a b o ve C T F G g ui da nce will be 
ma n dat or y  for W O C B P
part ici pa nts, ma le part ici pa nts, a n d W O C B P 
part ners of  male 
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
parti ci pa nts. Te xt c ha n ges d o ne t o reflect i ncl usi o n of  WO C B P i n t he st u d y Part 2 a n d 
Part 3 are as f o ll ows:
1. 1. Secti o n 3. 1. 3 , Part 2 ( M A D/ P o M) St u d y  Desig n, Secti o n 3. 1. 4 , Part 3 ( Brid gi n g) St u d y  
Desi g n, a n d Secti o n 4. 1. 3 , Rati o nale f or Desi g n of Part 2 ( M A D/ P o M): Te xt was u p date d t o 
clarif y t hat W O C B P will be recr uite d.
1. 2. T he f o ll owi n g select i on cri t eria were u p date d:

Secti o n 5. 1. 2. 1 , I ncl usi on Cri t eria, n u m ber 2 : T he re q uire me nt f or female patie nts 
t o be of n o n-c hil d beari n g p ote ntial has bee n re m o ve d.

Secti o n 5. 1. 2. 1 , I ncl usi o n Cri t eria, n u m ber 4 : Te xt has bee n a me n de d t o i n dicate 
fe male patie nts m ust n ot be pre g na nt.

Secti o n 5. 1. 2. 2 , E xcl usi o n Cri t eria, n u m ber 2 2 was a d de d t o e xcl u de female 
pati e nts w h o are pre g na nt, breastfee di n g, or pla n ni n g a pre g na nc y d uri n g t he st u d y 
p eri o d or wit hi n 1 m o nt h aft er t he last d ose of  in vesti gati o nal me dici nal pr o d uct 
(I M P).

Secti o n 5. 1. 2. 2 , E xcl usi o n Cri t eria, n u m ber 2 3 , was a d de d t o me nti on re pr o d ucti ve 
restrict i ons o n W O C B P patie nts a n d W O C B P part ners of male pat ient s.
1. 3. Te x t i n Sectio n 5. 2. 3 , Re pr o d ucti ve Restrict i ons, was u p date d as f o ll ows:

Secti o n 5. 2. 3. 1 , W o me n of C hil d beari n g P ote ntial, was a d de d t o descri be W O C B P 
a n d i nstr ucti o ns o n t he use of hi g hl y effecti ve met h o ds of c o ntrace pti o n.

Secti o n 5. 2. 3. 3 , Male S u bjects, was u p date d f or t ext  o n WO C B P part ners of  male 
pati e nts. Pre vi o us te xt was s u m marize d, a n d d u plicate i nf or mat i on was re m o ve d.
2.
I n t he o n g oi n g st u d y Part 2 a n d Part 3, patie nts wi t h mil d ast h ma will be e nr olle d.
T heref ore, electr ocar di o gra m ( E C G) c haracterist ics ha ve bee n a me n de d t o be fit for a 
pati e nt p o p ulatio n rat her t ha n healt h y v ol u nteers. I n t he a bse nce of a n y pre-cli nical si g nal 
i n v ol vi n g car diac c o n d uct i on s yste m, t he f oll owi n g m o dificat i ons of  the criteria were 
c o nsi dere d acce pta ble. A ri g ht -side d i ntra ve ntric ular c o n d ucti o n dela y or ri g ht i nc o m plete 
b u n dle bra nc h bl oc k (I B B B) res ultin g i n sli g htl y wi der Q R S c o mple x c o m pare d wi t h 
healt h y v o l u nteers is n ot u nc o m m o n i n ast h ma p ati e nts. T he Q R S d urati o n > 1 2 0 ms will 
be e xcl u de d si nce t his c o ul d be relate d t o a n u n derl yi n g, cli nicall y rele va nt a n d si g nifica nt 
car diac pat h o l og y . Fi rst de gree A V bl oc k ( pr ol o n ge d P R i nter val > 2 0 0 ms a n d < 2 4 0 ms) is 
acce pta ble i n t he a bse nce of  an y cli nical bra d y c ar dia wi t h sy m pt o m s s uc h as dizzi ness, 
pres y nc o pe/s y nc o pe, etc, as j u d ge d b y t he pri nci pal  in vest i gat or ( PI). Te xt c ha n ges ma de 
t o reflect t he c ha n ges i n t he E C G para meters were t he f oll owi n g:


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
2. 1. Secti o n 5. 1. 2. 2 , E xcl usi o n Cri t eria, n u m ber 1 0. 5 : P R ( P Q) i nter val pr ol o n g ati o n was 
c ha n ge d fr o m > 2 2 0 ms t o > 2 4 0 ms.
2. 2. Secti o n 5. 1. 2. 2 , E xcl usi on Criteria, n u m ber 1 0. 6 , was m o difie d t o i n dicate t hat patie nts wit h 
i ntra ve ntric ular c o n d uct i on dela y  (I V C D) a n d Q R S > 1 1 0 ms b ut < 1 2 0 ms ma y be selecte d.
3.
Ta ble 3. 2 1 0 , E C G sa mpli n g f or stu d y Part 2: T he o nce dail y  an d t wice dail y  dosi n g 
re gi me ns were prese nte d se paratel y i n 2 differe nt pa nels i n t he ta ble.
4.
T he 1 0 h o ur ti me p oi nt for E C G was eli mi nate d beca use t here is n o P K sa mpli n g at t his 
ti me p oi nt. C o nse q ue nt l y t he f oot n ote “ g” was delete d i n Ta ble 3. 2 1 0 , E C G sa mpli n g f or 
st u d y Part 2.
5.
I n t he o n g oi n g st u d y P art 2 a n d P art 3, p atie nts wit h mil d ast h ma will be e nr olle d. O n t he 
basis o f safety data fr o m t he Si n gle Asce n di n g D ose ( S A D) part of t his st u d y ( Part 1a) a n d 
c o nsi deri n g t he p h ysi o l ogical varia bilit y i n a p atie nt p o p ulat i on, t he per missi ble le vels f or 
ala ni ne a mi n otra nsferase ( A L T) a n d as part ate a mi n otra nsferase ( AS T) will n o w be u p t o 
1. 5 × u p per li mit of  nor m al (U L N).
T heref ore, u p dates were ma de i n Secti o n 5. 1. 2. 2 ,
E xcl usi o n Cri t eria, n u m ber 7 t o ma ke it ap pr o priate f or a patie nt p o p ul at i on rat her t ha n 
healt h y v o l unt eers.
6.
I n t he o n g oi n g st u d y Part 2 a n d Part 3, t he re q uire me nt f or t he ratio of  F E V1 t o f orce d vital 
ca pacit y ( F V C) t o be > 0. 7 is n o w eli mi nate d. Eli mi nat i n g t he s pecificati on of  FE V 1/ F V C 
r atio as a n i ncl usi on crit erio n w o ul d allo w pat ients wit h hi g h F V C i n r elat i on t o F E V 1
(c o nsiste nt wit h ast h ma patie nts) t o be i ncl u de d. N o c ha n ges were ma de t o t he sc he d ule of 
meas uri n g t he F E V 1/ F V C rati o; t hese assess me nts will be d o ne as ori gi nall y pla n ne d. Te xt 
has bee n a me n de d i n Secti o n 5. 1. 2. 1 , I ncl usi on Criteri o n, n u m ber 7 .
7.
F orce d E x pi rat or y Vol u me i n o ne sec o n d ( F E V1) a n d fracti onal e x hale d nit ric o xi de 
( Fe N O) assesse d at t he 1 2 h o ur ti me p oi nt on Da y −1 will be c o nsi dere d f or patie nt 
i ncl usi on; pre vi o usl y, t he ti me p oi nt ha d n ot bee n s pecifie d. C o nse q ue nt l y, te xt has bee n 
a me n de d i n Sectio n 5. 1. 2. 1 , I ncl usi on Cri t eria, n u m bers 7 a n d 8 .
8.
T he f o ll ow -u p peri o d was e xte n de d fr o m 6 ± 1 da ys after t he last d o se t o 1 0 ± 1 da ys after t he 
last d ose. T he s yste mic t otal co nce ntrati o ns of  AZ D 0 4 4 9 1 0 d a y s aft er t he last d ose are 
pre di cte d t o be b el o w t he r ele va nt s yste mic e x p os ures (a p pr o xi matel y 0. 1 n M). T his is 
base d o n m o deli n g of  int ra ve n o us a n d i n hale d d ose data fr o m the S A D part of  t his st u d y 
( Part 1a). T heref ore, Ta ble 3. 2 - 4, Ta ble 3. 2 - 5, Ta ble 3. 2 - 6, Ta ble 3. 2 - 7, Sc he d ules of 
Assess me nts were u p date d.
9.
I n t he o n g oi n g st u d y Part 2, t he starti n g d ose level f or Part 2 was c h ose n as 
 
A Z D 0 4 4 9 deli vere d d ose. T h is d ose le vel was c h ose n o n t he basis of Part 1a C o h ort 6 data.
T heref ore, Secti o n 3. 5. 3. 1 a n d Fi g ure 3 - 3 were u p date d.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 0. Cli nical c he mistr y tests d o ne o n D a y −2 ( n ot t he tests o n Da y −1) will be c o nsidere d f or 
assessi n g patie nt select i on. U p dates were ma d e i n Sect i on 5. 1. 2. 2 , E xcl usi o n Cri t eria, 
n u m bers 7 a n d 3. 1 0 f or clarificat i on.
1 1. Ta ble 3. 2 - 4, Ta ble 3. 2 -5 , Ta ble 3. 2 - 6, a n d Ta ble 3. 2 -7 , Sc he d ules of Assess me nts: F or t he 
c o mme nt “ P ost me n o pa usal fe males o nl y” a gai nst  fol licle sti m ulati n g h or m o ne testi n g, a 
cr oss-refere nce was a d de d t o t he defi nit i on of  “p ost me n o pa usal ” t hat is pr o vi de d i n 
Secti o n 5. 2. 3. 2 , for cl arificat i on.
1 2. Ta ble 3. 2 -4 a n d Ta ble 3. 2 - 5, Sc he d ules of  Assess me nts, were u p date d per Pr ot oc ol 
A me n d me nt 3, date d 0 9 Ma y 2 0 1 9 t hat 
 
 
T he ti me p oi nts are n o w liste d f or t hese 2 c o h orts, 
i n t he “ C om me nts” c o l um n i n t hese ta bles, f or clarificati on.
1 3. I n st u d y Part 1, p har mac o ki net ic ( P K) sa m pli n g ti me p oi nts ha d been a d de d o n t he basis of 
e mer gi n g data. T hi s is n o w i n dicate d i n t he f oll o wi n g secti ons:
1 3. 1. Ta ble 3. 2 -1 : F or Part 1a C o h ort 5, 1 a d dit i onal p har mac o ki net ic ( P K) bl o o d sa m ple w as 
ta ke n at 7 2 h o urs p ost -d ose o n St u d y  Da y 4. T hi s assess me nt was a d de d as per decisi o ns 
ta ke n at t he Safet y Re vie w Meet i n g hel d o n 2 4 Ma y  20 1 9 t o re vie w P K data f or Part 1a  
C o h ort 4.
1 3. 2. Ta ble 3. 2 - 1: F or Part 1a C o h ort 6, 3 a d dit i onal P K  bl oo d sa mples were ta ke n at 1 0 h o urs 
p ost -d ose, 7 2 h o urs p ost -d ose, a n d at t he F oll o w -u p Visi t. T hese assess me nt were a d de d as 
per decisi o ns ta ke n at t he Safet y Re vie w C o m mittee Meeti n g hel d o n 2 0 J u ne 2 0 1 9 t o re vie w 
P K data f or Part 1a C o h ort 5.
1 3. 3. Ta ble 3. 2 -2 : F or Part 1 b, 2 a d ditio nal P K  bl oo d sa mples were ta ke n at 1 4 h o urs a n d 
1 6 h o urs p ost -i nf usi on o n t he basis o f e mer gi n g data at t he re q uest of t he S p o ns or.
1 4. F or Part 1 b, i n Ta ble 3. 2 -2 , E C G sa mpli n g p oi n ts o n Da y 3 are n o w s pecifie d i n t he ta ble, 
f or clarificatio n.
1 5. Secti o n 1 4
Refere nces 
was 
u p date d wi t h ad diti o n of  the first 2 ne w refere nces.
C o nse q ue nt l y, t he n u m beri n g of t he pre vi o us refere nces i n t he list a n d t heir citati on i n -te xt 
were al s o u p date d.
1 6. Secti o n 1 5. 3 A p pe n di x, Act i ons Re q ui r e d i n Ca ses I ncreases i n Li ver Bi oc he mistr y  an d 
E val uat i on of H y’s La w, was u p date d wit h t he c urre nt sta n dar d te xt use d b y t he S p o ns or.
1 7. Mi n or f or mat a n d la n g ua ge c ha n ges (e g, re placi n g “s u bjects” wit h “ pat ient s” f or Part 2 a n d 
Part 3, a n d re placi n g “st u d y  dr u g” wit h “I M P”) were ma de t hr o u g h o ut t he d oc u me nt.
1 8. Pr ot oc ol  S y n o psis: T e xt for s t u d y Part 2 was u p date d per t he a b o ve c ha n ges.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Pr ot oc ol A me n d me nt N o. 3, d ate d 0 9 M a y 2 0 1 9
T he 
f oll owi n g 
c ha n ges 
were 
ma de 
t o t he 
Pr ot oc ol 
A me n d me nt 
N o. 
2, 
date d 
0 4 Dece m ber 2 0 1 8:
1.
T h e starti n g d ose has bee n u p date d t o 
2.
Part 1a of  the st u d y has bee n u p date d t o reflect ne w ti me p oi nts f or p ulse o xi metr y , vit al 
sig ns, p har mac o ki net ic ( P K) sa m pli n g, a n d bl o o d sa m ple c o llecti o n f or e x pl orat or y 
assess me nts.
3.
Part 1 b of t he st u d y  has bee n u p date d t o reflect ne w ti me p o i nts for P K bl o o d sa m pli n g.
4.
Part 1 b st u d y desi g n has bee n u p date d re gar di n g s u bjects t o be i ncl u de d i n t he c o h ort: 
healt h y s u bjects w h o ha ve partici pate d i n Part 1a a n d/ or naï ve s u bjects
5.
Part 2 st u d y desi g n has bee n u p date d re gar di n g treat me nt peri o d a n d d ose a d mi nistrati o n 
f or t wice dail y d osi n g.
6.
T he sc he d ule of  assess me nts ta ble f or Part 2 a n d Part 3 has bee n d u plicate d t o reflect 
ti me p oi nts f or o nce dail y d osi n g (Ta ble 3. 2 - 4 a n d Ta ble 3. 2 - 6) a n d t wice dail y d osi n g 
(Ta ble 3. 2 -5 a n d Ta ble 3. 2 - 7).
7.
T he sc he d ule of  assess me nts ta ble f or Part 2 of  the st u d y has bee n u p date d t o reflect 
di sc har ge fr o m t he Cli nical U ni t o n Da y 1 4, ne w ti me p oi nts f or s pir o metr y, Fe N O, 
 
 a n d bl o o d sa mple c ollect i on f or P K a n d 
8.
T he sc he d ule of  assess me nts ta ble f or Part 3 of  the st u d y has bee n u p date d t o reflect, 
di sc har ge fr om t he Cli nical U ni t o n Da y 1 4, t o re m ove 
 
 
 
9.
Part 2 a n d Part 3 of  t he st u d y ha ve bee n u p date d t o state s u bjects will be disc har ge d fr om 
t he Cli nical U ni t o n Da y 1 4, Ta ble 3. 2 - 4 a n d Ta ble 3. 2 - 6 ( Da y 1 5 f or t wice dail y d osi n g; 
Ta ble 3. 2 - 5 a n d Ta ble 3. 2 - 7).
1 0. Electr ocar di o gra m ( E C G) ti me p oi nts were u p date d i n Part 1a, Part 1 b a n d Part 2 of  the 
st u d y (Ta ble 3. 2 -8 , Ta ble 3. 2 -9 a n d Ta ble 3. 2 - 1 0).
1 1. T he bl o o d v ol u mes c o llecte d i n Part 2 a n d Part 3 of  the st u d y ha ve bee n u p date d, see 
Ta ble 3. 2 -1 3 a n d Ta ble 3. 2 - 1 4.
1 2. All st u d y fl ow c harts ha ve bee n u p date d.
1 3. Secti o n 1 0. 3. 2 was u p date d f or P K a nal ysis set.
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 4. T he deter mi nat i on of sa m ple size was f urt her detaile d i n Sect i on 1 0. 4 .
1 5. Secti o n 1 0. 6. 5 was re vise d f or P K a nal ysis.
1 6. A p pe n di x 1 5. 3 was u p date d i n li ne wit h t he ne w H y’s la w te m plate date d 1 0 Ja n uar y 2 0 1 9.
1 7. T y p o gra p hi c al err ors were c orrecte d t hr o u g h o ut t he d oc u me nt.
Pr ot oc ol A me n d me nt N o. 2, d ate d 0 4 Dece m ber 2 0 1 8
T he f o ll owi n g c ha n ges was ma de t o t he Pr ot oc ol A me n d me nt N o. 1, date d 2 3 Oct o ber 2 0 1 8.
1.
T he e x plor at or y  object i ve, 
 
2.
Part 1a of  the st u d y has bee n u p date d t o state t hat bl o o d sa mples f or t he assess me nt of 
 will o nl y be c ollecte d f or 
C o h ort 5 a n d o n war ds, see Ta ble 3. 2 - 1.
3.
Part 1 b of  the st u d y has bee n u p date d t o m o ve t he 3 0 mi n utes p ost -d ose s pir omet r y 
assess me nt o n Da y 1 t o 1 h o ur p ost -d ose, see Ta ble 3. 2 -2 .
4.
Part 1 b o f the st u d y has bee n u p date d, t o re m o ve bl o o d sa m ple c o llecti o n f or t he assess me nt 
 see Ta ble 3. 2 - 2.
5.
Part 2 of  the st u d y has bee n u p date d t o stat e t hat bl o o d sa m ples f or t he assess me nt of 
 will o nl y be c ollecte d f or 
C o h ort 3 a n d o n war ds, see Ta ble 3. 2 -4.
6.
T he ti me-p oi nts f or 1 2- lea d safety E C Gs were u p date d t o t he start of  eac h di gi t al-E C G 
e xtractio n wi n d o w, see Ta ble 3. 2 - 8, Ta ble 3. 2 - 9 a n d Ta ble 3. 2 - 1 0.
7.
T he bl o o d v ol u mes c o llecte d i n eac h part of t he st u d y ha ve bee n u p date d, see Ta ble 3. 2 -1 1 , 
Ta ble 3. 2 - 1 2, Ta ble 3. 2 -1 3 a n d Ta ble 3. 2 - 1 4.
8.
Details o n t he prese ntati o n of  
 res ults ha ve bee n a d de d, see 
Secti o n 1 0. 6. 7 . 6.
9.
T y p o gra p hi c al err ors were c orrecte d t hr o u g h o ut t he d oc u me nt.
Pr ot oc ol A me n d me nt N o. 1, d ate d 2 3 Oct o ber 2 0 1 8
T he f oll owi n g c ha n ges was ma de t o t he ori gi nal pr ot oc ol , fi nal 1. 0 date d 1 8 Se pte m ber 2 0 1 8 
as re q ueste d b y t he M H R A a n d t o c orrect i nc o nsiste ncies.
1.
T he defi nit i on of  tr ue se x ual a bst i ne nce was a d de d t o t he re pr o d ucti ve r estrict i ons as 
re q ueste d b y t he M H R A, see Secti o n 5. 2. 3. 3 .
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
2.
T he n u m ber of bl o o d sa m ples f or P K a nal yses i n Part 2 a n d Part 3 were c orrecte d a n d t he 
c orres p o n di n g bl o o d v o l ume u p date d, see Ta ble 3. 2 - 1 3 a n d Ta ble 3. 2 - 1 4.
3.
T y p o gra p hi c al err ors were c orrecte d t hr o u g h o ut t he d oc u me nt.


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
P R O T O C O L S Y N O P SI S
Title of t he St u d y
A Si n gle -bli n d, Ra n d o mize d, Place b o -C o ntr olle d 3- P art St u d y i n Healt h y  Vol u nteers a n d Patie nts wit h Mil d 
Ast h ma t o I n vesti gate t he Safet y , T olera bilit y a n d Phar mac o ki netics of I n hale d A Z D 0 4 4 9 F oll o wi n g Si n gle a n d 
M ulti ple As ce n di n g D oses a n d t o I n vesti gate t he A nti -Infla m mat or y  Effect of I n hale d A Z D 0 4 4 9
C hief I n vesti g at or
St u d y Ce nters
T his st u d y will be c o n d ucte d i n t he U nite d Ki n g d o m a n d Ger ma n y at a p pr o xi matel y 3 st u d y ce nters.
St u d y Desi g n, St u d y R ati o n ale a n d J ustific ati o n of St u d y Desi g n
T his will be a P hase I, first i n h u ma n ( FI H) st u d y c o nsisti n g of 3 st u d y parts.
P art 1 a ( Si n gle Asce n di n g D ose [ S A D])
A Z D 0 4 4 9 has n ot bee n st u die d i n ma n pre vi o usl y . T his FI H cli nical st u d y  will assess t he safet y a n d t olera bilit y 
as well as t he si n gle d ose p har mac o ki netics ( P K) of i n hale d A Z D 0 4 4 9 i n healt h y v ol u nteers .
Part 1a of t he st u d y  will be a ra n d o mize d, si n gle-bli n d, place b o -c o ntr olle d, S A D, se q ue ntial gr o u p desi g n st u d y 
perf or me d at a si n gle st u d y  ce nter. Si x i n hale d d ose le vels of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n are pla n ne d t o be 
i n vesti gate d i n 6 c o h orts of 8 healt h y  v ol u nteers, wit h 6 v ol u nteers ra n d o ml y assi g ne d t o i n hale d A Z D 0 4 4 9 a n d 
2 v ol u nteers ra n d o ml y assi g ne d t o i n hale d place b o i n eac h c o h ort. De pe n di n g o n e mer gi n g safet y a n d P K data, 
u p t o 3 a d diti o nal i n hale d d ose le vels (c o h orts) wit hi n t he pre -s pecifie d d ose ra n ge, ma y be a d de d at t he discreti o n 
of t he S p o ns or.
Healt h y  male v ol u nteers a n d healt h y  fe male v ol u nteers of n o n -c hil d beari n g p ote ntial wi ll be i ncl u de d t o mi ni mize 
i nterfere nce wit h ot her dr u gs or wit h disease pr ocesses.
Eac h c o h ort will be prece de d b y a se nti nel c o h ort of 2 v ol u nteers ( 1 will recei ve A Z D 0 4 4 9 a n d 1 will recei ve 
place b o) . T he re mai ni n g v ol u nteers of eac h c o h ort will o n l y be d ose d after t he 2 4- h o ur safet y data fro m t he 
se nti nel s u bjects h as  bee n re vie we d . Escalati o n t o t he ne xt d ose c o h ort will o nl y ta ke place after safet y a n d P K 
data fr o m t he pre vi o us c o h ort(s) ha ve bee n re vie we d.
T his st u d y part will c o m prise a Scree ni n g Visit wit hi n 2 8 da ys bef ore d osi n g, a treat me nt peri o d ( Da y -1 t o Da y 4) 
wit h a si n gle i n hale d d ose of A Z D 0 4 4 9 or c orres p o n di n g place b o o n Da y 1 a n d a F oll o w-u p Visit wit hi n 6 ± 1 da y s 
after d osi n g . Assess me nts will be perf or me d, a n d sa m ples c ollecte d fr o m bef o re d osi n g u ntil at least 3 6 h o urs 
p ost -d ose . Healt h y  v ol u nteers will be disc har ge d after all sa m ples ha ve bee n c ollecte d a n d assess me nts ha ve bee n 
perf or me d o n Da y 4. De pe n di n g o n t he e mer gi n g data, t he le n gt h of t he sta y at t he Cli nical U nit, ti mi n g a n d 
n u m ber of assess me nts a n d/ or bl o o d a n d uri ne sa m ples m a y  be a dj uste d a n d t he c ollecti o n peri o d ma y be e xte n de d 
t o 9 6 h o urs p ost -d ose.
P art 1 b ( Intr ave n o us [I V] C o h ort s)
I n Part 1 b, A Z D 0 4 4 9 will be a d mi nistere d as a si n gle I V d ose at 2 differe nt d ose le vels t o 2 c o h ort s of healt h y  
v ol u nteers i n or der t o c o m pare t he P K bet wee n I V a n d i n hale d a d mi nistrati o n, t o deter mi ne a bs ol ute 
bi oa vaila bilit y a n d t o c haracterize plas ma cleara nce. T his will ma ke it p ossi ble t o de d uce t he i m pact of l u n g 
a bs or pti o n after i n hal ati on. T he first (a n d l o west) I V d ose wa s c h ose n fr o m t he l o w e n d of t he Part 1a ( S A D) d ose 
ra n ge. T he sec o n d I V d ose was selecte d after c o m pleti o n of Part 1a a n d t he first I V c o h ort i n Part 1 b.
Healt h y  male v ol u nteers a n d healt h y  fe male v ol u nteers of eit h er n o n- c h il d beari n g or c hil d beari n g ( Part 1 b sec o n d 
I V c o h ort o nl y ) p ote ntial will be i ncl u de d . D osi n g i n Part 1 b of t he st u d y will be i nitiate d after t he c o m pleti o n of 
c o h ort 6 i n Part 1a ( S A D), or, if Part 1a is c o m plete d wit h fe wer t ha n 6 c o h orts, after c o m pleti o n of t he last c o h ort 
i n Part 1a.
Part 1 b will be o pe n -la bel a n d c o nsist of 2 d ose c o h ort s
Si x v ol u nteers will be selecte d 
f or t he first I V d ose c o h ort i n Part 1 b f oll o wi n g a 2- sta ge desi g n . If t he first I V c o h ort of Part 1 b ca n n ot be 
c o m plete d wit h 6 v ol u nteers fro m Part 1a or if s o me of t he data are c o nsi dere d n ot e val ua ble, u p t o 6 a d diti on al  
naï ve v ol u nteers ma y be e nr olle d . I n t he first I V c o h ort, th e r e will be a was h o ut peri o d of at least 2 wee ks f or t he 
v ol u nteers r ecei vi n g b ot h i n hale d d osi n g i n Part 1a a n d I V d osi n g i n Part 1 b . All 6 v ol u nteers i n t he first I V c o h ort 
will recei ve a si n gle I V d ose 
 of A Z D 0 4 4 9 s ol uti o n . T he first I V co h ort will be prece de d b y a se nti nel 
s u bject a n d t he re mai ni n g v ol u nteers w ill o nl y be d ose d after t he 2 4 -h o ur safet y  d at a fr om t he se nti nel v ol u nteer
ha ve bee n re vie we d . T he sec o n d I V d ose c o h ort will c o nsist of 6 v ol u nteers w h o ha ve n ot pre vi o usl y partici pate d 
P P D
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
i n t he st u d y. All 6 s u bjects will recei ve a si n gle I V d ose 
 of A Z D 0 4 4 9 s ol uti o n. D osi n g will als o start 
wit h 1 v ol u nteer i n a se nti nel c o h ort.
F or t he I V treat me nt peri o d s, v ol u nteers will be a d mitte d t o t he Cli nical U nit . O n  Da y 1, v ol u nteers will recei ve 
a si ngle I V d ose of t h e AZ D 0 4 4 9 s ol uti o n. Assess me nts will be perf or me d, a n d sa m ples c ollecte d fr o m bef ore 
d osi n g u ntil 4 8 h o urs p ost -d ose . V ol u nteers will be disc har ge d fr o m t he Cli nical U nit after all sa m ples ha ve bee n 
c ollecte d a n d assess me nts ha ve bee n perf or me d o n Da y 3.
V ol u nteers will ret ur n t o t he Cli nical U nit wit hi n 6 ± 1 da ys after t he last d ose of A Z D 0 4 4 9 f or a F oll o w -u p Visit.
P art 2 a/ b ( M ulti ple Asce n di n g D ose [ M A D])
Part 2a/ b of t he st u d y will be a ra n d o mize d, si n gle -bli n d, place b o -c o ntr olle d, M A D, se q ue ntial gr o u p desi g n 
st u d y perf or me d at a p pr o xi matel y 3 st u d y ce nters. S u bjects a ge d 1 8 t o 5 5 y ears will be i ncl u de d i n t his part of 
t he st u d y. U nli ke i n Part 1 a a n d Part 1 b first I V c o h ort , fe male s u bjects of c hil d beari n g p ote ntial ma y als o be 
e nr olle d. T his part of t he st u d y will recr uit u p t o 5 6 s ubjects. A t otal of 2 6 e val ua ble s u bjects are nee de d f or 
c o m pleti o n of Part 2 a/ b. P ote ntiall y, 3 0 e xtra s u bjects m a y be ra n d o mize d t o c o u nteract dr o p -o uts a n d all o w f or 
a n e xtra c o h ort if nee de d.
T hree d ose le vels of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n are pla n ne d t o be i n vesti gate d i n 3 c o h orts. T he c o h orts 
c o ul d c o m prise eit her patie nts wit h mil d ast h ma or healt h y v ol u nteers.
Part 2a will i ncl u de co h orts 1 a n d 2, eac h c o m prisi n g of 9 patie nts wit h mil d ast h ma. Wit hi n eac h of t hese 
c o h orts 6 patie nts will be ra n d o mize d t o recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi o n a n d 3 patie nts ra n d o mize d t o 
recei ve place b o. A d diti o nal c o h orts wit h 9 patie nts c o ul d be a d de d t o st u d y P K, P D a n d safet y f or d oses l o wer 
t ha n 
 Part 2 b will c o nsist of 1 c o h ort of 8 healt h y v ol u nteers; 6 v ol u nteers will be 
ra n d o mize d t o recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi o n a n d 2 v ol u nteers will be ra n d o mize d t o recei ve place b o.
D osi n g f or eac h asce n di n g d ose c o h ort will start wit h 2 s u bjects i n a se nti nel c o h ort, s uc h t hat 1 s u bject will be
ra n d o mize d t o recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi o n a n d 1 s u bject will be ra n d o mize d t o place b o.
Eac h s u bject will recei ve a si n gle d ose of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n at t he selecte d d ose le vel or place b o 
o n Da y 1 f oll o we d b y 1 0 dail y  d oses fr o m Da y 3 t o Da y 1 2.
F or t he treat me nt peri o d, s u bjects will be a d mitte d t o t he Cli nical U nit. T he first d ose will be a d mi nistere d o n 
Da y 1. F oll o wi n g t his first d ose, plas ma P K sa m ples will be c ollecte d u p t o 4 8 h o urs p ost -d ose f or t he first d ose 
( Da y 1) t o all o w f or c haracterizati o n of t he ter mi nal eli mi nati o n p hase. O nce dail y d osi n g will start o n Da y 3, 
4 8 h o urs p ost -Da y 1 d ose P K sa m pli n g a n d c o nti n ue u p t o Da y 1 2 wit h i nter vals of 2 4 h o urs bet wee n d oses.
Eac h s u bject will recei ve i n hale d d oses of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n at t he selecte d d ose le vel or place b o 
o n t he s pecifie d d osi n g da ys. Assess me nts will be perf or me d, a n d sa m ples c ollecte d fr o m bef ore d osi n g u ntil u p 
t o 2 4 0 h o urs after last d ose ( Part 2a ) a n d u ntil u p t o 3 6 0 h o urs after last d ose ( Part 2 b) . S ubjects will re mai n i n 
h o use f or t he d urati o n of t he treat me nt peri o d a n d will be disc har ge d fr o m t he Cli nical U nit o n Da y 1 4 , 2 da y s 
after t he last d ose a d mi nistrati o n ( Part 2a) a n d after a n e xte n de d safet y m o nit ori n g peri o d o n Da y 2 7, 1 5 da y s 
after t he last d ose a d mi nistrati o n ( Part 2 b) . If per mitte d b y l ocal rele va nt re g ulat or y a ut h orities a n d c o nsi dere d 
feasi ble a n d safe t o d o s o, t he e xte n de d safet y m o nit ori n g peri o d ma y be c o n d ucte d as n o n-resi de ntial visits.
F oll o wi n g re vie w of e mer gi n g data, t he S a fet y Re vie w C o m mittee ( S R C) ma y deci de t o a dj ust t he le n gt h of t he 
sta y at t he Cli nical U nit a n d t he ti mi n g a n d n u m ber of assess me nts a n d/ or bl o o d a n d uri ne sa m ples f or 
s u bse q ue nt c o h orts. T he ti me wi n d o w bet wee n t he si n gle d ose a n d start of re peate d d osi ng ma y  als o be a dj uste d 
a n y ti me d uri n g t he st u d y.
P art 3 a/ b (D PI/ P o M)
Part 3a/ b of t he st u d y will be i nitiate d after t he c o m pleti o n of Part 2 b.
Part 3a/ b will be a ra n d o mize d, si n gle -bli n d, place b o -c o ntr olle d, D PI/ P o M st u d y. Male a n d/ or fe male patie nts 
wit h mil d ast h ma ( Part 3a) or healt h y v ol u nteers ( Part 3 b), a ge d 1 8 t o 5 5 y ears will be i ncl u de d i n t his part of 
t he st u d y. T his part of t he st u d y will be c o n d ucte d i n u p t o 4 4 s u bjects di vi de d i nt o 2 parts; 3 6 patie nts wit h mil d 
ast h ma ( Part 3a) a n d 8 healt h y v ol u nteers ( Part 3 b o pti o nal).
Part 3a will c o nsist of 3 6 patie nts w here 1 8 patie nts will be ra n d o mize d t o recei ve A Z D 0 4 4 9 D PI a n d 
1 8 patie nts ra n d o mize d t o recei ve place b o. A n I nteri m A nal ysis will be c o n d ucte d w he n a p pr o xi matel y 5 0 % of 
t he patie nts ha ve c o m plete d Part 3a . S h o ul d ne w data o n t he varia bilit y of t he Fe N O meas ure me nts e mer ge at 
t he Int e ri m A nal ysis (I A), t he sa m ple size of Part 3a c o ul d be c ha n ge d.
If t he o pti o nal Part 3 b is c o n d ucte d, it will be c o m prise d of 8 healt h y  v ol u nteers, 6 v ol u nteers will be 
ra n d o mize d t o recei ve A Z D 0 4 4 9 D PI a n d 2 v ol u nteers ra n d o mize d t o recei ve place b o.
F or t he treat me nt peri o d, s u bjects will be a d mitte d t o t he Cli nical U nit. T he first d ose will be a d mi nistere d o n 
Da y 1. O nce dail y d osi n g will start o n Da y 3, 4 8 h o urs p ost -Da y 1 d ose P K sa m pli n g a n d c o nti n ue u p t o 
Da y 1 2. S u bjects will re mai n i n h o use f or t he d urati o n of t he treat me nt peri o d a n d u n der g o a n e xte n de d safet y 
m o nit ori n g peri o d u ntil bei n g disc har ge d fr o m t he Cli nical U nit o n Da y 2 7 , 1 5 da ys after t he last d ose 
C CI
C CI














Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
sc he d ule d ti mes a n d a p pr o priate descri pti ve statistics. I n di vi d ual a n d c o m bi ne d i n di vi d ual plas ma c o nce ntrati o ns 
vers us act ual ela pse d ti me after d ose will be pl otte d o n b ot h t he li near a n d se mi-l o garit h mic scale f or A Z D 0 4 4 9.
Ge o metric mea n ( ± g S D) plas ma c o nce ntrati o n vers us n o mi nal sa m pli n g ti me will be pl otte d o n b ot h t he li near 
a n d se mi -l o garit h mic scale f or eac h St u d y Part a n d St u d y D a y wit h all d ose le vels o verlai d o n t he sa me pl ot f or 
Part 1a Da y 1 a n d Part 2a/ b Da y 1 a n d Da y 1 2 , wit h Da y 1 a n d Da y 1 2 o verlai d o n t he sa me pl ot f or eac h d ose 
le vel f or Part 2a/ b a n d wit h St u d y Da y 1 a n d St u d y  D a y 1 2 o verlai d o n t he sa me pl ot f or Part 3a/ b . All pl ots will 
be base d o n t he P K a nal ysis set, wit h t he e xce pti o n of i n di vi d ual pl ots b y s u bject, w h ic h will be base d o n t he 
safet y a nal ysis set ( S A F).
D ose -pr o p orti o nalit y  will be assesse d f oll o wi n g a si n gle d ose a n d f oll o wi n g m ulti ple d osi n g via least s q uares 
li near re gressi o n of t he l o g-tra nsf or me d P K para meters vers us t he l o g-tra nsf or me d d ose, ie, l o g ( P K 
para meter) = α + βl o g( D ose) . A n esti mate of t he sl o pe a n d i nterce pt of t he re gressi o n li ne a n d t he c orres p o n di n g 
2- si de d 9 5 % c o nfi de nce i nter val ( CI) f or t he sl o pe will be o btai ne d a n d ta b ulate d f or A U C a n d Cma x .
T he p o wer m o del will be fitte d b y restricte d ma xi m u m li keli h o o d ( R E M L) usi n g S A S Pr oc Mi xe d . B ot h t he 
i nterce pt a n d sl o pe will be fitte d as fi xe d effects.
Scatter pl ots f or eac h of t he l o g -tra nsf or me d P K para meters Cma x , A U C( 0-t) a n d A U C vers us l o g -tra nsf or me d d ose 
will be pr ese nte d wit h t he re gressi o n li ne fro m t he a nal ysis o verlai d o n t he sa me pl ot f or Part 1a Da y 1, a n d 
Part 2a/ b Da y 1, Da y 1 2. I n a d diti o n, fi g ures of d ose n or malize d C ma x , A UC ( 0-t) a n d A U C vers us d ose, s h o wi n g 
i n di vi d ual val ues a n d ge o metric mea n will be prese nte d se paratel y f or eac h P K para meter f or Part 1a Da y 1 a n d 
f or Part 2a/ b Da y 1 a n d Da y 1 2 , t o vis uall y de m o nstrate d ose-pr o p orti o nalit y.
Prese nt ati o n a n d A n alysis of S afety a n d T oler a bility D at a
S u bject dis p os iti o n will be s u m marize d. All safet y data will be prese nte d i n t he data listi n gs . Use of c o nc o mita nt 
me dicati o n will be re p orte d.
A Es will be c o de d usi n g t he a p plica ble dicti o nar y a n d s u m marize d b y s yste m or ga n class ( S O C) a n d pr eferre d 
ter m. A d diti o nal s u m maries b y se verit y a n d ca usalit y will be prese nte d.
Vital si g ns meas ure me nts a n d la b orat or y res ults will be liste d a n d s u m marize d i ncl u di n g c ha n ges fr o m baseli ne .
A n y  o ut of ra n ge vital si g ns meas ure me nts a n d la b orat or y res ults will be fla g ge d i n t he i ndi vi d ual listi n gs.
Res ults of t he E C Gs, i ncl u di n g n or mal/a b n or mal a n d s pecific fi n di n gs will be liste d.
S pir o metr y val ues ( F or ce d E x pirat or y V ol u me i n 1 sec o n d [ F E V 1] a n d f orce d vital ca pacit y [ F V C]) will be liste d 
b y treat me nt ( d ose le vel of A Z D 0 4 4 9 a n d po ole d place b o), s u bject a n d ti me -p oi nt i ncl u di n g a bs ol ute val ues a n d 
perce nta ge c ha n ges fro m baseli ne . S u m mar y ta b ulati ons f or a bs ol ute val ues a n d c h a n ges fr o m baseli ne will be 
prese nte d b y treat me nt (eac h d ose le vel of A Z D 0 4 4 9, or p o ole d place b o, a n d p o ol e d A Z D 0 4 4 9) a n d ti me-p oi nt.
Peri p heral ca pillar y o x y ge n sat urati o n will be liste d a n d s u m marize d i ncl u di n g c ha n ges fro m baseli ne a n d 
perce nta ges c ha n ges fr o m baseli ne.
A n alysis of P h ar m ac o dy n a mic D at a
Fr acti o n al Ex h ale d Nitric Oxi de
T he c ha n ge fr o m baseli n e  i n 2 h o urs p ost -d ose Fe N O le vel t o 1 2 da ys ( Part 2a a n d Part 3a) will be a nal y se d base d 
o n a mi xe d effect m o del of re peate d meas ures ( M M R M) usi n g all p ost -baseli ne 2 h o urs p ost -d ose Fe N O 
assess me nts. A nal yses will be perf or me d o n t he l o g -tra nsf or me d Fe NO data t o n or malize t he s ke we d distri b uti o n 
of t his e n d p oi nt.
T he wit hi n -patie nt c orrelati o n will be m o dele d usi n g t he u nstr uct ure d c o varia nce matri x . T he -Ke n war d -R o ger 
a p pr o xi mati o n will be use d t o esti mate de n o mi nat or de grees of free d o m. T he a nal ysis will be perf or me d usi n g 
o nl y  the o bser ve d cases ( O C) wit h o ut i m p utati o n of missi n g val ues . If t he m o del d oes n ot c o n ver ge, t he n t he 
c o m p o u n d s y m metr y c o varia nce str uct ure will be use d . R E M L met h o d will be use d f or esti mati o n.
Treat me nt effect a n d treat me nt differe nces will be esti mate d usi n g c o ntrasts of t he Least -S q uare ( L S) mea ns o n 
t he c orres p o n de nt treat me nt- b y-d a y  int e racti o n, al o n g wit h t heir S E a n d 2- si de d 9 0 % CI, a n d t he p- val ue 
c orres p o n di n g t o t he bet wee n -treat me nt gr o u p differe nce.
T he sa me m o del will be use d t o e val uate treat me nt effect bet wee n t he gr o u ps .
I n a d diti o n, treat me nt effect of t he c ha n ge fr o m baseli ne i n 2 h o urs p ost -d ose Fe N O le vel at 1 2 da y s ( Part 2a a n d 
Part 3a) will be a nal y se d usi n g a nal ysis of c o varia nce ( A N C O V A) wit h treat me nt as a fi xe d effect, a n d baseli ne 
as a c o variate. T he last o bser vati o n carrie d f or war d ( L O C F) met h o d will be use d t o deal wit h missi n g val ues . N o 
m ulti plicit y a dj ust me nts will be a p plie d.
Fracti o nal e xhale d nitric o xi de will be liste d a n d s u m marize d i ncl u di ng c ha n ges fr o m baseli ne . I n a d diti o n, as 
se nsiti vit y a nal ysis, t he c ha n ge fr o m baseli ne i n Fe N O area u n der t he effect – ti me c ur ve t o Da y 1 2 ( A U C 0 -1 2) will 




Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T A B L E O F C O N T E N T S
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E...............................2
P R O T O C O L A M E N D M E N T S .............................................................................................4
Pr ot oc ol  A me n d me nt N o. 1 0, date d 0 4 Fe br uar y 2 0 2 1 .......................................................4
Pr ot oc ol  A me n d me nt N o. 9, date d 0 8 Dece m ber 2 0 2 0.......................................................4
Pr ot oc ol  A me n d me nt N o. 8, date d 1 1 Se pte m ber 2 0 2 0 ......................................................4
Pr ot oc ol  A me n d me nt N o. 7, date d 2 6 J u ne 2 0 2 0 ................................................................5
Pr ot oc ol  A me n d me nt N o. 6, date d 2 7 Ma y
2 0 2 0 ................................................................6
Pr ot oc ol  A me n d me nt N o. 5, date d 1 1 Fe br uar y 2 0 2 0.........................................................8
Pr ot oc ol  A me n d me nt N o. 4, date d 0 3 Dece m ber 2 0 1 9.....................................................1 1
Pr ot oc ol  A me n d me nt N o. 3, date d 0 9 Ma y 2 0 1 9..............................................................1 5
Pr ot oc ol  A me n d me nt N o. 2, date d 0 4 Dece m ber 2 0 1 8 .....................................................1 6
Pr ot oc ol  A me n d me nt N o. 1, date d 2 3 Oct o ber 2 0 1 8 ........................................................1 6
P R O T O C O L S Y N O P SI S ....................................................................................................1 8
T A B L E O F C O N T E N T S ....................................................................................................2 8
List of Ta bles ...................................................................................................................3 5
List of Fi g ures .................................................................................................................3 6
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ........................................3 7
1.
I N T R O D U C TI O N .......................................................................................................4 3
1. 1.
Di sease Bac k gr o u n d..............................................................................................4 3
1. 2.
I n vestigat i onal Me dici nal Pr o d uct I nf or mat i on ......................................................4 3
1. 2. 1.
Descri pt i on of M o de of Act i on .......................................................................4 4
1. 2. 2.
T o xic ol o g y  Pr e-cli nical Data ..........................................................................4 7
1. 2. 3.
Cli nical St u dies ..............................................................................................4 9
1. 3.
O verall Rat i onale f or C o n d ucti n g t his St u d y .........................................................4 9
2.
St u d y  O bjecti ves..........................................................................................................5 1
2. 1.
Part 1a O bject i ves ................................................................................................. 5 1
2. 2.
Part 1 b O bject i ves................................................................................................. 5 2
2. 3.
Part 2a/ b O bject i ves ..............................................................................................5 3
2. 4.
Part 3a/ b O bject i ves ..............................................................................................5 5


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3.
St u d y  Desi g n................................................................................................................5 8
3. 1.
O verall St u d y Desi g n ............................................................................................5 8
3. 1. 1.
Part 1a St u d y Desi g n ......................................................................................5 8
3. 1. 2.
Part 1 b St u d y Desi g n ......................................................................................5 9
3. 1. 3.
Part 2a/ b St u d y Desi g n ...................................................................................6 0
3. 1. 4.
Part 3a/ b St u d y Desi g n ...................................................................................6 1
3. 1. 5.
E n d of St u d y ..................................................................................................6 2
3. 1. 6.
E x pecte d D urati o n of t he St u d y ......................................................................6 3
3. 2.
St u d y  Fl ow C hart, Sc he d ules of  Assess me nts a n d Ti me Sc he d ules f or Di gital 
Electr ocar di o gra p h y ..............................................................................................6 3
3. 2. 1.
St u d y  Flo w C harts .........................................................................................6 4
3. 2. 2.
Sc he d ules of Assess me nts ..............................................................................6 7
3. 2. 3.
Or der of Assess me nts ................................................................................... 1 1 2
3. 2. 4.
T ot al  Blo o d V ol u me .................................................................................... 1 1 2
3. 3.
S af et y Re vie w C o m mit t e e................................................................................... 1 1 5
3. 3. 1.
Data Re vie we d b y Safet y  Re vie w C o m mittee f or D ose Escalati o n Decisi o n 1 1 6
3. 4.
O verall D ose Strate g y  Base d o n Re g ulat or y G ui da nce ........................................ 1 1 8
3. 4. 1.
S u m mar y  of D ose a n d E x p os ure Ra n ge........................................................ 1 1 8
3. 4. 2.
N O A E L -Base d Ma xi m u m Rec o m me n de d Starti n g D ose .............................. 1 1 9
3. 4. 3.
Mi ni m u m A nt ici pate d Bi ol ogi c al Effect Le vel D ose.................................... 1 1 9
3. 4. 4.
P har mac o l ogi call y Acti ve D ose ................................................................... 1 2 0
3. 4. 5.
Pr e di cte d H u ma n T hera pe utic D ose/ A nt ici pate d T hera pe utic D ose.............. 1 2 0
3. 4. 6.
Esti mate d H u ma n P har mac o d y na mic D ose Ra n ge ....................................... 1 2 0
3. 4. 7.
N O A E L -Base d Ma xi m u m All o we d D ose ..................................................... 1 2 1
3. 4. 8.
S y ste mic E x p os ure Li mit s............................................................................ 1 2 2
3. 5.
D ose Strate g y  in t he I n di vi d ual St u d y  P arts......................................................... 1 2 2
3. 5. 1.
D osi n g Part 1a ............................................................................................. 1 2 2
3. 5. 2.
D osi n g Part 1 b ............................................................................................. 1 2 4
3. 5. 3.
D osi n g Part 2a/ b .......................................................................................... 1 2 5
3. 5. 4.
D osi n g Part 3a/ b .......................................................................................... 1 2 7


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 6.
Pre di ctio ns of  E x p os ures a n d Mar gi ns f or Differe nt D ose Le vels........................ 1 2 8
3. 6. 1.
Met h o ds f or M o deli n g D oses a n d Esti mate d E x p os ure Le vels ...................... 1 2 8
4.
Rati o nale, U ncertai nt y a n d Ris ks ................................................................................ 1 3 0
4. 1.
St u d y  Desi g n Rati onale a n d J ust ificati o n............................................................. 1 3 0
4. 1. 1.
Rati o nale f or Desi g n of  Part 1a .................................................................... 1 3 0
4. 1. 2.
Rati o nale f or Desi g n of  Part 1 b .................................................................... 1 3 1
4. 1. 3.
Rati o nale f or Desi g n of  Part 2a/ b ................................................................. 1 3 3
4. 1. 4.
Rati o nale f or Desi g n of  Part 3a/ b ................................................................. 1 3 5
4. 2.
De gree of U ncertai nt y ......................................................................................... 1 3 6
4. 2. 1.
U ncertai nt y Ass ociate d wit h t he M o de of Act i on ......................................... 1 3 6
4. 2. 2.
U ncertai nt y Ass ociate d wit h Bi o mar kers ...................................................... 1 3 7
4. 2. 3.
U ncertai nt y Ass ociate d wit h t he Nat ure of t he Tar get ................................... 1 3 7
4. 2. 4.
U ncertai nt y Ass ociate d wit h N o n -cli nical Safet y Fi n di n gs ........................... 1 3 9
4. 2. 5.
U ncertai nt ies Ass ociat e d wit h t he D osi n g i n Part 3a/ b .................................. 1 3 9
4. 3.
Ris ks Ass ociate d wit h St u d y  Desi g n a n d Pr oce d ures........................................... 1 3 9
4. 3. 1.
Ris ks Deri vi n g fr o m t he C haracteristics of  t he St u d y P o p ulat i on .................. 1 3 9
4. 3. 2.
Ris k f or Dr u g -Dr u g I nteracti o ns ................................................................... 1 3 9
4. 3. 3.
Ris ks Deri vi n g fr o m St u d y  Pr oce d ures......................................................... 1 4 0
4. 4.
Ris k -Be nefi t Assess me nt..................................................................................... 1 4 0
4. 4. 1.
Mi tigat i on Pl a n for Rat L u n g Safet y  Fi n di n gs.............................................. 1 4 0
4. 4. 2.
Mi tigat i on Pl a n for Ri s ks Relate d t o I m m u ne S u p pressi on ........................... 1 4 0
4. 4. 3.
Be nefit of Treat me nt wit h I n hale d A Z D 0 4 4 9 ............................................... 1 4 0
4. 4. 4.
C o ncl usi o n  Ris k-Be nefi t Assess me nt........................................................... 1 4 1
5.
St u d y  P o p ulat i on a n d Restricti o ns .............................................................................. 1 4 2
5. 1.
S u bject Selecti o n Criteria .................................................................................... 1 4 2
5. 1. 1.
Part 1a/ b ....................................................................................................... 1 4 2
5. 1. 2.
Part 2a/ b a n d Part 3a/ b ................................................................................. 1 4 7
5. 2.
Restricti o ns D uri n g t he St u d y .............................................................................. 1 5 7
5. 2. 1.
Part 1a/ b ....................................................................................................... 1 5 7
5. 2. 2.
Part 2a/ b a n d Part 3a/ b ................................................................................. 1 5 8


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
5. 2. 3.
Re pr o d ucti ve Restrict i ons ............................................................................ 1 5 9
5. 3.
Re place me nt of S u bjects ..................................................................................... 1 6 3
6.
St u d y  St o p pi n g R ules................................................................................................. 1 6 4
6. 1.
St o p pi n g f or a n I n di vi d ual S u bject, at A n y Ti me i n t he St u d y ............................. 1 6 4
6. 2.
St o p pi n g R ules f or a W h o le C o h ort, D ose Escalati o n, Pr o gressi o n to Ne xt St u d y Part 
a n d Ter mi nat i on of St u d y .................................................................................... 1 6 4
7.
Treat me nts ................................................................................................................. 1 6 8
7. 1.
I de ntity of  t he I n vesti gati onal Me dici nal Pr o d ucts ............................................... 1 6 8
7. 2.
S u p pl y  of I n vestig ati o n al  Me dici nal Pr o d uct....................................................... 1 6 9
7. 3.
St ora ge a n d Ha n dli n g Pr oce d ures ........................................................................ 1 6 9
7. 4.
La beli n g .............................................................................................................. 1 6 9
7. 5.
Dr u g Acc o u nta bilit y, Dis pe nsi n g a n d Destr ucti o n ............................................... 1 6 9
7. 6.
D ose a n d Treat me nt Re gi me ns ............................................................................ 1 7 0
7. 6. 1.
Part 1a .......................................................................................................... 1 7 0
7. 6. 2.
Part 1 b ......................................................................................................... 1 7 0
7. 6. 3.
Part 2a/ b ....................................................................................................... 1 7 1
7. 6. 4.
Part 3a/ b ....................................................................................................... 1 7 1
7. 7.
C o nc o mita nt a n d P ost -st u d y Treat me nt(s) ........................................................... 1 7 1
7. 8.
Treat me nt C o m plia nce ........................................................................................ 1 7 1
7. 9.
R a n d o mizati o n .................................................................................................... 1 7 2
7. 9. 1.
S u bject E nr ol me nt a n d Ra n d o mizat i on ......................................................... 1 7 2
7. 9. 2.
Pr oce d ures f or Ra n d o mizat i on ..................................................................... 1 7 2
7. 9. 3.
Pr oce d ures f or Ha n dli n g I nc orrectl y Ra n d o mize d S u bjects .......................... 1 7 3
7. 1 0.
Bli n di n g a n d Pr oce d ures f or U n bli n di n g t he St u d y .............................................. 1 7 3
7. 1 0. 1.
Met h o ds f or E ns uri n g Bli n di n g .................................................................... 1 7 3
7. 1 0. 2.
Met h o ds f or U n bli n di n g t he St u d y ............................................................... 1 7 4
8.
Meas ure me nts a n d Met h o ds of Assess me nt ................................................................ 1 7 5
8. 1.
A p pr o priate ness of Meas ure me nts ....................................................................... 1 7 5
8. 2.
S af et y a n d Eli gi bilit y Meas ure me nts ................................................................... 1 7 5
8. 2. 1.
A d verse E ve nts ............................................................................................ 1 7 5


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
8. 2. 2.
Vi tal Sig ns................................................................................................... 1 7 5
8. 2. 3.
Electr ocar di o gra p h y ..................................................................................... 1 7 6
8. 2. 4.
P h ysical E xa mi nat i on ................................................................................... 1 7 8
8. 2. 5.
S pi r o metr y ................................................................................................... 1 7 8
8. 2. 6.
P ul se Oxi metr y ............................................................................................ 1 7 8
8. 2. 7.
La b orat or y  Assess me nts............................................................................... 1 7 8
8. 2. 8.
C o nc o mita nt Me dicati o n .............................................................................. 1 8 0
8. 3.
P har mac o ki net ics................................................................................................ 1 8 0
8. 3. 1.
S a m ple C ollect i on a n d Ha n dli n g .................................................................. 1 8 0
8. 3. 2.
P har mac o ki net ic Dr u g Assa ys...................................................................... 1 8 0
8. 5.
P har mac o d y na mic Assess me nts .......................................................................... 1 8 1
8. 5. 1.
Fract i onal E x hale d Nitric O xi de Part 2a a n d Part 3a ..................................... 1 8 1
8. 6.
E x pl or at or y  Assess me nts .................................................................................... 1 8 1
8. 7.
Pr oce d ures f or Ha n dli n g o f Bi ol o gi cal Sa m ples .................................................. 1 8 3
8. 7. 1.
St ora ge a n d Destr ucti o n of Bi o l ogical Sa m ples ............................................ 1 8 3
8. 7. 2.
La beli n g a n d S hi p me nt of Bi o hazar d Sa m ples .............................................. 1 8 4
8. 7. 3.
C hai n o f C ust o d y  of Biol o gical  Sa m ples...................................................... 1 8 5
8. 7. 4.
Wit h dra wal o f I nf or me d C o nse nt f or D o nate d Bi ol o gical Sa m ples............... 1 8 5
9.
Data Q ualit y Ass ura nce a n d Data Ma na ge me nt .......................................................... 1 8 6
9. 1.
Q ualit y C o ntr ol  a n d S o urce Data Verificati on ..................................................... 1 8 6
9. 2.
A u dit/I ns pect i ons ................................................................................................ 1 8 6
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
9. 3.
St u d y  M o nit ori n g................................................................................................ 1 8 6
9. 4.
Data C o llecti on ................................................................................................... 1 8 6
9. 4. 1. 
Case Re p ort F or ms a n d S o urce D oc u me nts .................................................. 1 8 7
9. 4. 2.
Access t o S o urce D oc u me nts ....................................................................... 1 8 7
9. 5.
Data Ma na ge me nt ............................................................................................... 1 8 7
1 0. Stati stical A nal yses .................................................................................................... 1 8 9
1 0. 1.
O ver vie w ............................................................................................................ 1 8 9
1 0. 2.
Ge neral Statist ical Met h o d ol o g y ......................................................................... 1 8 9
1 0. 2. 1.
Missi n g Data ................................................................................................ 1 9 0
1 0. 3.
St u d y  A nal yses Sets............................................................................................ 1 9 0
1 0. 3. 1.
S af et y A nal ysis Set ...................................................................................... 1 9 0
1 0. 3. 2.
P har mac o ki net ic A nal ysis Set ...................................................................... 1 9 1
1 0. 3. 3.
Ra n d o mize d Set ........................................................................................... 1 9 1
1 0. 3. 4.
E nr olle d A nal ysis Set ................................................................................... 1 9 1
1 0. 3. 5.
F ull A nal ysis Set .......................................................................................... 1 9 1
1 0. 3. 6.
Per Pr ot oc ol  Set ........................................................................................... 1 9 1
1 0. 4.
De ter mi nati on of Sa m ple Size ............................................................................. 1 9 1
1 0. 4. 1.
I nteri m A nal ysis........................................................................................... 1 9 2
1 0. 5.
Pr ot oc ol  De viati ons ............................................................................................. 1 9 3
1 0. 6.
Stati stical Met h o ds.............................................................................................. 1 9 3
1 0. 6. 1 .
S u bject Dis p osit i on ...................................................................................... 1 9 3
1 0. 6. 2.
D e m o gra p hic a n d Baseli ne Data .................................................................. 1 9 4
1 0. 6. 3.
Pri or a n d C o nc o mi ta nt Me dicati on a n d Dr u g A d mi nistrati o n ....................... 1 9 4
1 0. 6. 4.
A nal ysis of Safet y Data ................................................................................ 1 9 5
1 0. 6. 5.
P har mac o ki net ic A nal ysis ............................................................................ 2 0 0
1 0. 6. 6.
A nal ysis of P har mac o d y na mic Data ............................................................. 2 0 7
1 0. 6. 7.
A nal ysis of E x pl orat or y  Data....................................................................... 2 0 9
1 1. A d verse E ve nts .......................................................................................................... 2 1 0
1 1. 1.
Defi nit i ons .......................................................................................................... 2 1 0
1 1. 1. 1.
Defi nit i on o f A d verse E ve nts ....................................................................... 2 1 0


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 1. 1. 2.
Defi nit i ons of Seri o us A d verse E ve nt ........................................................... 2 1 0
1 1. 1. 3.
Ot her Si g nifica nt A d verse E ve nts ................................................................. 2 1 0
1 1. 2.
Rec or di n g of A d verse E ve nts .............................................................................. 2 1 1
1 1. 2. 1.
Ti me Peri o d f or C ollect i on of A d verse E ve nts ............................................. 2 1 1
1 1. 2. 2.
F o ll ow- u p of  U nres ol ve d A d verse E ve nts .................................................... 2 1 1
1 1. 2. 3.
V ari a bles ...................................................................................................... 2 1 1
1 1. 2. 4.
Ca usalit y C o llecti on ..................................................................................... 2 1 2
1 1. 2. 5.
A d verse E ve nts Base d o n S y m pt o ms a n d Si g ns ........................................... 2 1 2
1 1. 2. 6.
A d verse E ve nts Base d o n E xa mi nat i ons a n d Tests ....................................... 2 1 2
1 1. 3.
Re p orti n g of Seri o us A d verse E ve nts .................................................................. 2 1 3
1 2. Et hical a n d Re g ulat or y  Re q uir e me nts......................................................................... 2 1 5
1 2. 1.
Et hical C o n d uct of t he St u d y ............................................................................... 2 1 5
1 2. 2.
S u bject Data Pr otecti o n ....................................................................................... 2 1 5
1 2 . 3. Et hics a n d Re g ulat or y  Re vie w............................................................................. 2 1 5
1 2. 4.
I ns ura nce ............................................................................................................ 2 1 6
1 2. 5.
I nf or me d C o nse nt ................................................................................................ 2 1 6
1 2. 6.
C ha n ges t o t he Pr ot oc ol a n d I nf or me d C o nse nt D oc u me nt .................................. 2 1 6
1 3. Le gal a n d A d mi nistrati ve As pects .............................................................................. 2 1 7
1 3. 1.
Arc hi vi n g of St u d y  D o c u me nts ........................................................................... 2 1 7
1 3. 2.
P u blicat i on of St u d y  Res ults ............................................................................... 2 1 7
1 3. 3.
Cli nical St u d y  Re p ort.......................................................................................... 2 1 7
1 4. Refere nce List ............................................................................................................ 2 1 8
1 5. A p pe n dices ................................................................................................................ 2 2 0
1 5. 1.
A d dit i onal Safet y I nf or matio n ............................................................................. 2 2 0
1 5. 2.
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati on 6. 2 G ui da nce D oc u me nt ........... 2 2 2
1 5. 3.
Act i ons Re q ui re d i n Cases I ncreases i n Li ver Bi oc he mistr y  an d E val uat i on of  Hy’s 
La w ..................................................................................................................... 2 2 4
1 5. 3. 1.
I ntr o d ucti o n ................................................................................................. 2 2 4
1 5. 3. 2.
Defi nit i ons ................................................................................................... 2 2 4
1 5. 3. 3.
I de ntificati o n of P ote ntial H y’s La w Cases................................................... 2 2 5


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5. 3. 4.
F o ll ow- U p ................................................................................................... 2 2 5
1 5. 3. 5.
Re vie w a n d Assess me nt of P ote ntial H y’s La w Cases .................................. 2 2 6
1 5. 3. 6.
Act i ons Re q uire d f or Re peat E pis o des of P ote ntial H y’s La w ...................... 2 2 7
1 5. 3. 7.
La b orat or y  Tests.......................................................................................... 2 2 8
1 5. 4.
Taste Assess me nt ................................................................................................ 2 3 0
List of T a bles
Ta ble 2. 1 - 1
Part 1a O bject i ves a n d O utc o me Meas ures.....................................................5 1
Ta ble 2. 2 - 1
Part 1 b O bject i ves a n d O utc o me Meas ures.....................................................5 2
Ta ble 2. 3 - 1
Part 2a O bject i ves a n d O utc o me Meas ures i n Patient s wit h Mil d Ast h ma.......5 3
Ta ble 2. 3 - 2
Part 2 b O bject i ves a n d O utc o me Meas ures i n Healt h y V olu nteers ..................5 4
Ta ble 2. 4 - 1
Part 3a O bject i ves a n d O utc o me Meas ures i n Patient s wit h Mil d Ast h ma.......5 5
Ta ble 2. 4 - 2
Part 3 b O bject i ves a n d O utc o m e Meas ures 
i n Heal t h y V o l unt eers ( o ptio nal 
c o h ort) ...........................................................................................................5 6
Ta ble 3. 2 - 1
Sc he d ule of Assess me nts Part 1a ( S A D) ........................................................6 7
Ta ble 3. 2 - 2
Sc he d ule of Assess me nts Part 1 b ( First I V C o h ort) ........................................7 2
Ta ble 3. 2 - 3
Sc he d ule of Assess me nts Part 1 b ( Sec o n d I V C o h ort) ....................................7 5
Ta ble 3. 2 - 4
Sc he d ule of Assess me nts Part 2a i n patie nts wit h mil d ast h ma .......................7 9
Ta ble 3. 2 - 5
Sc he d ule of Assess me nts Part 2 b i n healt h y v o l unt eers ..................................8 5
Ta ble 3. 2 - 6
Sc he d ule of Assess me nts Part 3a i n patie nts wit h mil d ast h ma .......................9 2
Ta ble 3. 2 - 7
Sc he d ule of Assess me nts Part 3 b i n healt h y v o l unt eers ................................ 1 0 1
Ta ble 3. 2 - 8
Ti me Sc he d ule f or Di gital Electr ocar di o gra m Part 1a ( S A D) ........................ 1 0 8
Ta ble 3. 2 - 9
Ti me Sc he d ule f or Di gital Electr ocar di o gra m Part 1 b (I V C o h orts) .............. 1 0 9
Ta ble 3. 2 - 1 0 Ti me Sc he d ule f or Di gital Electr ocar di o gra m Part 2a/ b, Part 3a/ b ............... 1 1 1
Ta ble 3. 2 - 1 1 T ot al  Blo o d V ol u me Part 1a ......................................................................... 1 1 3
Ta ble 3. 2 - 1 2 T ot al  Blo o d V ol u me Part   1 b ........................................................................ 1 1 3
Ta ble 3. 2 - 1 3 T ot al  Blo o d V ol u me Part 2a/ b ...................................................................... 1 1 4
Ta ble 3. 2 -1 4 T ot al  Blo o d V ol u me Part 3a/ b ...................................................................... 1 1 5
Ta ble 3. 6 - 1
Pr e di cte d E x p os ures a n d Mar gi ns ................................................................. 1 2 9
Ta ble 7. 1 - 1
I de ntity of  t he I n vesti gati onal Me dici nal Pr o d ucts ........................................ 1 6 8
Ta ble 8. 2 - 1
H e m at olo g y ................................................................................................. 1 7 8
Ta ble 8. 2 - 2
Cli nical C he mistr y ....................................................................................... 1 7 9
Ta ble 8. 2 - 3
Uri nal ysis .................................................................................................... 1 7 9
Ta ble 8. 2 - 4
Pre g na nc y Testi n g ........................................................................................ 1 7 9
Ta ble 8. 2 - 5
S er ol o g y ...................................................................................................... 1 7 9


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Ta ble 8. 2 - 6
Dr u gs of A b use, Alc o h o l a n d C oti ni ne ......................................................... 1 7 9
Ta ble 8. 2 - 7
C O VI D -1 9 Testi n g ....................................................................................... 1 8 0
List of Fi g ures
Fi g ure 3- 1
Hi g h -Le vel O ver vie w of t he St u d y  Sc he me...................................................6 4
Fi g ure 3 - 2
D ose Escal atio n a n d Decisi o n P o i nts i n Part 1a/ b ...........................................6 5
Fi g ure 3 - 3
D ose Escal atio n a n d Decisi o n P o i nts i n Part 2a/ b a n d Part 3a/ b ......................6 6


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
A E
A d verse e ve nt (see defi nit i on i n Secti on 1 1. 1. 1 )
A L P
Al kali ne p h os p hatase
A L T
Ala ni ne a mi n otra nsferase
A N C O V A
A nal ysis of c o varia nce
A S T
As partate a mi n otra nsferase
A T D
A nt ici pate d T hera pe utic D ose (i n t his pr ot oc ol  use d s y n o n y m f or 
pre di cte d ( h u ma n) t hera pe utic d ose)
A T P
A de n osi ne tri p h os p hate
A T S
A merica n T h oracic S ociet y
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o i nfi nity
A U C ( 0-1 2)
Area u n der t he pl as ma c o nce ntrati o n-time c ur ve fr o m ti me zer o t o 
1 2 h o urs p ost -d ose
A U C ( 0-2 4)
Area u n der t he pl as ma c o nce ntrati o n-time c ur ve fr o m ti me zer o t o 
2 4 h o urs p ost -d ose
A U C/ D
D ose n or m alize d A U C
% A U Ce xtr
Perce nta ge of A U C e xtra p olate d
A U C ( 0-t)
Area u n der t he pl as ma c o nce ntratio n c ur ve fr o m time zer o t o t he ti me 
of  last q ua ntifia ble c o nce ntrati o n
A U C ( 0-t)/ D
D ose n or m alize d A U C( 0-t)
A V
At rio ve ntri c ular
A Z Ra n d
Astra Ze neca ra n d o mizat i on s yste m
B A L F
Br o nc h oal ve o lar la va ge fl ui d
B B B
B u n dle bra nc h bl oc k
Bf A r M
Fe deral I nsti t ut e f or Dr u gs a n d Me dical De vices ( B u n desi nstitut f ür 
Arz nei mittel u n d Me dizi n pr o d u kte )
BI D
Bis i n die (t wice dail y )
B L Q
Bel o w t he li mi t of q ua ntificati o n
B MI
B o d y  mass i n de x
B P
Bl o o d press ure
b p m
Beats per mi n ute
C C L 1 7
C he m o ki ne ( C -C m otif ) li ga n d 1 7
C D 2 8
Cl uster of differe nt iati on 2 8
c D C
C o n ve nti o nal de n drit ic cells
CI
C o nfi de nce i nter val
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
C L
T ot al  cleara nce of dr u g fr o m plas ma (I V a d mi nistrati o n)
C L/ F
A p pare nt 
t otal cleara nce of  dr u g fr om 
pl as ma ( E xtra vasc ular 
a d mi nistrati o n)
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
C ma x/ D
D ose n or m alize d C ma x
C M C
C he mistr y , Ma n ufact uri n g, a n d C o ntr ols
C O P D
C hr o nic o bstr ucti ve p ul m o nar y  disease
C O VI D - 1 9
C or o na vir us disease 2 0 1 9
C R F
Case re p ort f or m
C R O
C o ntract researc h or ga nizat i on
C R P
C- reacti ve pr otei 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 
D A E
A d verse e ve nt lea di n g t o t he disc o nt i n uati on of I M P
D C
De n drit ic cells
D C F
Data cl arificatio n f or m
d E C G
Di gi t al electr ocar dio gr a m
D E S
Data 
E n tr y Site –
w here 
serio us a d verse e ve nt re p orts fr o m 
Astra Ze neca Cli nical st u dies are e ntere d o nt o t he Astra Ze neca 
P ati e nt Safet y data base b y Tata C o ns ulta nc y  Ser vices
D G R
Da n ger o us G o o ds Re g ulati o ns
DI LI
Dr u g -I n d uce d Li ver I nj ur y
D M P
Data m a na ge me nt pla n
D N A
De o x y rib o n ucleic aci d
D PI
Dr y - po w der i n haler
D V S
Data vali dat i on s pecificat i on
E C G
Electr ocar di o gra m
E Cl ysis ©
User -i nteracti ve, m o d ul ar c o m p uter -base d s yste m f or d E C G data 
pr ocessi n g, a nal ysis a n d meas ure me nt of  EC G i nter vals a n d wa ve 
a mpli t u des, e x p orts a n d re p orts, use d b y t he Astra Ze neca E C G 
Ce nter 
E C M O
E xtrac or p oreal Me m bra ne O x y ge nat i on
E D
Effect i ve d ose
 
E M A
E ur o pea n Me dici nes A ge nc y
E N
E nr olle d a nal ysis set
e N O
E x hale d nitric o xi de
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 3 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
E P C U
Earl y P hase Cli nical U nit
E P O
Er y t hr o p oiet i n
E R S
E ur o pea n Res pirat or y  S o ciet y
E U
E ur o pea n U ni o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F E V
F orce d E x pirat or y  V olu me
F E V 1
F orce d E x pirat or y  V olu me i n o ne sec o n d
Fe N O
Fract i onal e x hale d nit ric o xide
FI H
Fi rst i n H u ma n
F S H
F o llicle-sti m ulati n g h or m o n e
F V C
F orce d vital ca pacit y
G C P
G o o d Cli nical Pract ice
g C V %
Ge o m etric c oefficie nt of variat i on
G G T
Ga m ma gl uta m yl tra ns pe pt i dase (tra nsferase)
GI N A
Gl o bal I nit iati ve f or Ast h ma
G L P
G o o d La b orat or y  Practice
G M -C S F
Gra n ul oc yte macr o p ha ge -c o l on y sti m ulati n g fact or
G M P
G o o d Ma n ufact uri n g Practi ce
g m ea n
Ge o m etric mea n
g S D
Ge o m etric sta n dar d de viati o n
H b
H e m o gl o bi n
H bs A g
He pati tis B s urface a nti ge n
H C T
H e m at o crit
H E D
H u m a n e q ui vale nt d ose
h E R G
H u m a n et her -a- g o-g o -relate d ge ne
HI V
H u m a n i m m u n o deficie nc y vir us
H L
H y’s La w
H O P
Hea d o ut pl et h ys mo gra p h y
H R
Heart rate
i.t.
I ntratrac heal
I A
I nteri m A nal ysis
I A T A
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati on
I B
I n vesti gat or’s Br oc h ure
I B B B
I nc om p lete b u n dle bra nc h bl oc k
I C5 0
Half ma xi mal i n hi bit or y  c o nce ntratio n
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
I C A M- 1
I ntercell ular A d hesi on M o lec ule 1
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 on 
I C S
I n hale d c ortic oster oi ds
I E C
I n de pe n de nt Et hics C o m mittee
I M P
I n vesti gati onal Me dici nal Pr o d uct
I P F
I dio pat hic p ul m o nar y  fi br osis
I S R B
I n vesti gati onal Me dici nes Safet y Re vie w B oar d
I V
I ntra ve n o us
I V C D
I ntra ve ntric ular c o n d ucti on dela y
J A K
Ja n us ki nase
λz
Ter mi nal eli mi nat i on rate c o nsta nt 
λz N
N u m ber of data p oi nts i n t he l o g- li near re gressi o n a nal ysis
L D D
L u n g -de p osi te d d ose
L L N
L o wer li mit of n or mal
L L O Q
L o wer li mit of q ua nt ificati on
L O C F
Last o bser vat i on carri e d for war d
L S
Least -S q uare
L S L V
Last S u bject Last Visit
M A B E L
Mi ni mal a nt ici pate d bi ol ogi c al effect le vel
ma x
Ma xi m u m
M A D
M ul tiple asce n di n g d ose
M C H
Mea n c or p usc ular he m o gl o bi n
M C H C
Mea n c or p usc ular he m o gl o bi n c o nce ntratio n
M C V
Mea n c or p usc ular v o l ume
Me d D R A
Me dical Dict i onar y f or Re g ulat or y  Acti vities
mi n
Mi ni m u m
M M R M
Mi xe d effect m o del of re peate d meas ures
M R S D
Ma xi m u m Rec o m me n de d Starti n g D ose
n
T ot al  n u m ber of i n di vi d ual data val ues
N
N u m ber of s u bjects
N A
N ot a p plica ble
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
N C
N ot cal c ulate d
N O( A) E L
N o -o bser ve d -(a d verse) -effect le vel
N Q
N ot Q ua nt ifia ble
N R
N ot re p orta ble
N S
N o sa m ple
O A E
Ot her si g nifica nt a d verse e ve nts
O T C
O ver t he c o u nter
O V A
O val b u mi n
P A D
P har mac o l ogi call y acti ve d ose
P B M C
P eri p heral  blo o d m o n o n uclear cells
P B P K
P h ysi o l og y Base d P har mac o ki net ic
P D
P har mac o d y na mics
P D F
P orta ble D oc u m e nt F or mat
P D S
Pr ot oc ol  de viati on s pecificat i on ( d oc u me nt)
p E C G
Pa per pri nt o ut E C G
P H L
P ote nti al H y’s La w
PI
Pri nci pal I n vest i gat or
P K
P har mac o ki net ics
P K S
P har mac o ki net ic a nal ysis set
P o M
Pr o of -of -mec ha nis m
P P
Per Pr ot oc ol  a nal ysis set
P V
P har mac o vi gila nce
Q D
Q ua q ue di e ( o nce dail y)
Q P
Q ualifie d Pers o n
Q R S
E C G i nter val meas ure d fr o m t he o ns et of t he Q R S c o mple x t o t he J 
p oi nt
Q T
E C G i nter val meas ure d fr o m t he o nset of  the Q R S c o mple x t o t he 
e n d of t he T wa ve
Q Tc F
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s f or m ula
R & D
Researc h a n d De vel o p me nt
R B C
Re d bl o o d cell
R E M L
Restricte d ma xi m u m li keli h o o d 
R R
T he ti me bet wee n c orres p o n di n g p oi nts o n 2 c o nsec ut i ve R wa ves 
o n E C G
R S
Ra n d o mize d Set
Rs q -a dj
Re gressi o n c oefficie nt a d j uste d f or λz, N, G o o d ness -of -fit st atistic 
f or c alc ulat i on of λz


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
S A B A
S h ort Acti n g Beta A g o nist
S A D
Si n gle asce n di n g d ose
S A E
S eri o us a d verse e ve nt (see defi nit i on i n Secti on 1 1. 1. 2 ).
S A F
S af et y A nal ysis Set 
S A P
Stati stical A nal ysis Pla n
S D
Sta n dar d de viat i on
S O C
S y st e m Or ga n Class
S O P
Sta n dar d o perati n g pr oce d ure
S p O 2
P eri p heral  ca pillar y o x y ge n sat uratio n
S R C
S af et y Re vie w C o m mit t e e
S U S A R
S us pecte d u ne x pecte d seri o us a d verse react i on
t1/ 2λz
Ter mi nal eli mi nat i on half -life
t lo wer
Start of e x p o ne nt ial fit of t he ter mi nal p hase
t u p per
E n d of e x p o ne ntial fit of ter mi nal p hase
T B
T u berc ul osis
T B L
T ot al  bilir u bi n
T C A
Tri c yclic a nt i de pressa nt
T C S
Tata C o ns ulta nc y Ser vices – a n Astra Ze neca part ner w h o c o n d uct 
data e ntr y  o nt o Sa p p hire
T h 2
T- hel per t y pe 2
tlast
Ti me o f last q ua ntifia ble c o nce ntrati o n
tma x
Ti me o f ma xi m u m o bser ve d c o nce ntrati o n (first occ urre nce)
T S H
T h y r oid- sti m ulati n g h or m o ne
T S L P
T h y mic str o mal l y m p h o p oiet i n
T Y K 2
T y r osi ne ki nase 2
U K
U nite d Ki n g d o m
U L N
U p per li mit of n or mal
Vz
A p pare nt v o l ume of  distri b uti on d uri n g t he ter mi nal p hase (I V 
a d mi nistrati o n)
Vz/ F
V ol u me of  distri b uti on d uri n g t he ter mi nal p hase (e xtra vasc ular 
a d mi nistrati o n)
W A D
Wi n d o ws All o wa nce D oc u me nt
W B C
W hite bl o o d cell
W H O D D
W o rld Heal t h Or ga nizati on dr u g dicti o nar y
W O C B P
W o me n of C hil d beari n g P ote nti al
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1.
I N T R O D U C TI O N
1. 1.
Dise ase B ac k gr o u n d
Ast h ma affects a n est i mate d 3 0 0 milli o n i n di vi d uals w orl d- wi de, a n d t his n u m ber ma y gr o w 
b y m o re t ha n 1 0 0 milli o n b y 2 0 2 5 [ 3 ]. U p t o 1 0 % of t he p o p ulati o n i n de vel o pe d c o u ntries ma y 
ha ve ast h ma, a n d of t hese, u p t o 1 0 % ha ve se vere disease, c haracterize d b y t he re q uire me nt f or 
hi g h d oses of  in hale d c ortic oster oids (IC S) a n d a n a d ditio nal br o nc h o dilat or me d icatio n [ 4 ].
Ar o u n d half of  all ast h ma is dri ve n b y T- hel per t ype 2 ( T h 2) cell i nfla m mat or y cyt o ki nes 
i ncl u di n g i nterle u ki n (I L)-4, I L-5, a n d I L-1 3 [5 ]. T his s u b gr o u p e xists acr oss t he s pectr u m of 
ast h ma se verity . C urre nt cli nical mar kers t o i de ntif y this s u bty pe i ncl u de p eri p heral a n d s p ut u m 
e osi n o p hils, e x hale d nit ric o xi de (e N O), as well as s er u m periosti n . A d dit i onal ast h ma s u bty p es 
ha ve bee n i de ntifie d base d o n i nfla m mat or y pr ocesses i ncl u di n g ne utr o p hilic, mi xe d a n d 
pa uci gra n ul o c y tic [ 4 ].
C urre nt ast h ma ma na ge me nt is directe d t o war ds c o ntr olli n g i nfla m mat i on, usi n g oral a n d I C S, 
as well as pr o vi di n g s h ort a n d l on g -t er m br o nc h o dilati on [6 ]. Alt h o u g h I C S a d dress m o st of  
t he pat h wa ys t hat dri ve ast h ma, n ot all p atie nts res p o n d t o t hese me d icati ons . I n t he setti n g of 
se vere e xacer bati ons, pat ient s re q uire oral gl uc oc ortic o ids f or di sease ma na ge me nt, a n d ma n y 
se vere ast h mat ics re q uire c hr o nic or al  gl uc oc ortic o i d use . I n hale d gl uc oc orti c o i ds ha ve 
p ote nti al side effects i ncl u di n g t hr us h a n d ha ve bee n s h o w n t o affect gr o wt h i n c hil dre n. Oral 
gl uc oc orti c o i ds ha ve a d ditio nal  side effects i ncl u di n g h y per gl yce mia, decrease d b o ne de nsit y 
a n d i ncrease d i nfect i on ri s k [8 ]. M ore rece ntl y, bi o l ogic t hera pi es directe d t o war ds t he dri vers 
of  t ype - 2 ast h ma ha ve bee n de vel o pe d . T hese me di cat i ons ca n re d uce or al  cortic oster oi d use 
a n d i m pr o ve l u n g f u nct i on i n se vere ast h mat ics, b ut are ofte n e x pe nsi ve, re q uire s pecialist care 
a n d ma y nee d t o be a d mi nistere d i n of fice setti n gs [9 ]. I n t his setti n g, t here is a nee d f or 
a d ditio nal  t o pical t ar g et e d t h er a pies di recte d s pecificall y t o war ds T h 2 ast h ma, b ut p ote ntiall y 
a p plica ble t o all pa tie nts.
1. 2.
I n vesti g ati o n al Me dici n al Pr o d uct I nf or m ati o n
A Z D 0 4 4 9 is a n i n hale d Ja n us ki nase (J A K) 1 i n hi bit or deri ve d fr o m a cell-base d plat f or m t hat 
bl oc ks p h os p h or ylat i on of  si g nal tra ns d ucer a n d acti vat or of  tra nscri pti on ( S T A T), i ncl u di n g 
S T A T 6, S T A T 5, S T A T 3, a n d S T A T 1 i n d uce d b y a ra n ge of  cyt o ki nes . T he J A K 1/ S T A T 6 
pat h wa y  is a partic ularl y attracti ve tar get f or ast h ma ma na ge me nt. I nterle u ki n (I L) -4 a n d I L -1 3 
acti vate J A K 1, w hic h i n t ur n p h os p h or ylates S T A T 6 lea di n g t o i nit iati on o f “ T 2” i nfla m mat or y 
pr ocesses i ncl u di n g e osi n o p hil recr uit me nt a n d acti vat i on, a nti b o d y class s witc hi n g t o 
i m m u n o glo b uli n E (I g E) pr o d ucti o n, g o blet cell h y per plasia a n d m uc us h y persecret i on a n d 
air wa y h y perreacti vity a n d re m o deli n g.


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1. 2. 1.
Descri pti o n of M o de of Acti o n
A Z D 0 4 4 9 is a n a de n osi ne tri p h os p hate ( A T P) c o m petit i ve t y pe I ki nase i n hi bit or t hat bi n ds t o 
t he acti ve J A K 1 c o nf or mat i on i n hi biti n g its ki nase acti vit y. It is a p ote nt a n d selecti ve J A K 1 
i n hi bit or wit h a bi oc he mical half ma xi mal i n hi bitor y  co nce ntrati o n (I C5 0) val ue of  0. 0 0 3 µ M 
f or J A K 1 i n t he prese nce of  5 m M A T P a n d n o si g nifica nt i n hi biti on o f JA K 2, J A K 3 or t yr osi ne 
ki nase 2 ( T Y K 2) at c o m p o u n d c o nce ntrati o ns as hi g h as 3 0 µ M.
1. 2. 1. 1.
Pri m ar y P h ar m ac o d y n a mics
P har mac o l ogi cal characterizat i on i n a ra n ge of  pre-cli nical i n vi tr o a n d i n vi v o m o dels 
i de ntifie d A Z D 0 4 4 9 as a p ote nt i n hi bit or of J A K 1 de pe n de nt bi ol ogi cal pr ocesses.
T he effect of  AZ D 0 4 4 9 o n I L-4/I L - 1 3 i n d uce d si g nali n g was st u die d i n se veral cell m o dels 
i ncl u di n g h u ma n l un g fi br o blasts, s mall airwa y  epi t helial cells
a n d p eri p h er al  bl oo d 
m o n o n uclear cells ( P B M C). I n t hese cells A Z D 0 4 4 9 i n hi bite d I L-4/I L - 1 3 i n d uce d e n d p oi nts 
i ncl u di n g S T A T 6 p h os p h or ylat i on, e ota xi n pr o d ucti o n, I ntercell ular A d hesi o n M o lec ule-1 
(I C A M-1) e x pressi o n a n d p eri osti n secretio n wi t h IC 5 0 val ue s i n t he ra n ge of  0. 0 1 1 t o 
0. 0 5 7 µ M .E x vi v o sti m ulati o n of  sp ut u m  cells o btai ne d fr o m a st h matic d on ors wi t h IL- 4/I L - 1 3 
le d t o i n d ucti on of  S T A T 6 p h os p h or ylati on i n t he l y m p h oc yte a n d m o n oc y t e p o p ulatio ns t hat 
was i n hi bite d b y A Z D 0 4 4 9 wit h I C 5 0 val ues of 0 . 0 1 3 µ M a n d 0. 0 3 2 µ M, res pecti vel y.
I n h u ma n pri mar y  T cells, A Z D 0 4 4 9 i n hi bite d I L- 2 i n d uce d S T A T 5 p h os p h or ylati o n a n d 
pr oliferat i on, I L- 2 1 i n d uce d S T A T 3 p h os p h or ylati o n a n d i nterfer o n al p ha (I F N- α) i n d uce d 
S T A T 1 p h os p h or ylat i on wi t h IC 5 0 val ues i n t he ra nge of  0. 0 1 7 t o 0. 0 4 4 µ M. A Z D 0 4 4 9 was 
sig nifica nt l y less act i ve o n J A K 2/T Y K 2 -de pe n de nt S T A T 4 p h os p h or ylat i on sti m ulate d b y 
I L- 1 2 (I C5 0 of  9. 0 3 μ M), or J A K 2-de pe n de nt er yt hr o p oieti n ( E P O)-i n d uce d c ult ure d h u ma n 
er yt hr oid prec urs or cell s ur vi val (I C5 0 of  1. 3 5 µ M), as e x pecte d fr o m a J A K 1 selecti ve 
i n hi bit or. A Z D 0 4 4 9 als o i n hi bite d t he mi xe d l y m p h oc yt e reactio n (I C5 0 val ue of  0. 0 2 2 µ M) 
wi t ho ut affecti n g t he n u m ber of  li ve cells i n t he reactio n (I C5 0 > 5 µ M, n = 2), i n dicati n g t hat 
A Z D 0 4 4 9 ca n s pecificall y bl oc k de n dri tic cell-dri ve n T- cell pr oliferati o n, wi t ho ut bei n g 
c yt ot o xic t o t he T- cells or t he de n drit ic cells. I n w h o le bl o o d, A Z D 0 4 4 9 c o uld i n hi bit I L- 2
i n d uce d S T A T 5 p h os p h or ylat i on wi t h an I C5 0 of 1. 7 4 µ M, w hic h was a b o ut 4 0- f ol d less 
p ote nc y  t ha n i n is olate d T- cells. T his is a 4 0- f ol d p ote nc y  dr o p-off as c o mpare d t o is olate d T 
cells, b ut it ca n be e x plai ne d b y t he str o n g bi n di n g of A Z D 0 4 4 9 t o plas ma pr otei ns. T he J A K 1 
selecti vity was mai ntai ne d 
i n w h o le bl o o d c o nfi g urati o n, as A Z D 0 4 4 9 di d n ot i n hi bit 
J A K 2-de p e n de nt gra n ul oc y t e-ma cr o p ha ge c o l on y sti m ulat i n g fact or (G M -C S F ) sig nali n g e ve n 
at t he hi g hest c o nce ntrati o n teste d ( 2 0 μ M). Fi nall y, R 2 5 6/ A Z D 0 4 4 9 di d n ot si gnifica nt l y 
i n hi bit p h os p h or ylat i on e ve nts d o w nstrea m  of t he T cell rece pt or as s h o we d b y mi ni ma l 


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
i n hi biti on of  T cell rece pt or/clust er of  differe ntiati o n 2 8 ( C D 28) i n d uce d I L- 2 pr o d ucti o n 
(I C5 0 > 4 µ M).
T h y mic str o mal l y m p h o p oiet i n ( T S L P) is e mer gi n g as ke y c yt o ki ne i n ast h ma as e vi de nce d b y 
t he cli nical efficac y of the a nt i-T S L P a nt i b o d y teze pel u ma b i n ast h ma pati e nts [2 1 ]. T h y mic 
str o mal l y m p h o p oieti n i n d uce d si g nali n g i n m o st c ell t ypes, i ncl u di n g de n dritic cells ( D C), is 
J A K 1 de pe n de nt a n d i n v ol ves p h os p h or ylat i on of  ST A T 5 . F or t his reas o n, t he i m pact of  
A Z D 0 4 4 9 o n T S L P i n d uce d D C res p o nses was st u die d. A Z D 0 4 4 9 
bl oc ke d si g nali n g 
d o w nstrea m of  the T S L P rece pt or i n h uma n c o n ve ntio nal de n dri tic cells (c D Cs) a n d m o n oc ytes 
as d e m o n strate d b y i n hi biti on of  TS L P -i n d uce d S T A T 5 p h os p h or ylat i on i n c D Cs. T h y mic 
str o mal ly m p h o p oi et i n-i n d uce d c he mo ki ne ( C-C m o tif) li ga n d 1 7 ( C C L 1 7) pr o d ucti o n i n 
m o n oc y tes was i n hi bite d with a n I C 5 0 val ue of 0. 0 6 6 µ M . T 2 s ke wi n g b y D Cs pre -treate d wit h 
A Z D 0 4 4 9 a n d s u bse q ue ntl y sti m ulate d wi t h TS L P was bl oc ke d as i n dicate d b y a l oss i n t he 
a bility of  these D Cs t o dri ve pr oliferat i on a n d pr o d ucti o n of  Th 2 c yt o ki nes i n naï ve a n d 
me m or y  C D 4 + T cells.
T o 
i nf or m 
f urt her 
c haracterizat i on 
of  
AZ D 0 4 4 9 
i n 
i n 
vi v o 
p har mac o ki net ic 
( P K)/ p har mac o d y na mic ( P D) m o dels a n d i n sec o n dar y P D a n d safety p har mac o l og y m o dels 
(see Secti o n 1. 2. 1. 2 ) t he cr oss-s pecies act i vity of A Z D 0 4 4 9 was deter mi ne d i n cell-base d 
m o dels. A Z D 0 4 4 9 s h o we d e q ui p ote nt i n hi bi tio n  of I L- 1 3 i n d uce d S T A T 6 p h os p h or ylati on i n 
h u ma n, m o use a n d rat pri mar y l un g fi br o blasts wit h I C5 0 val ues of  0. 0 3 5 µ M, 0. 0 2 6 µ M a n d 
0. 0 2 8 µ M, res pecti vel y . AZ D 0 4 4 9 als o s h o we d e q ui p ote nt i n hi bi tio n  of I L- 2 i n d uce d S T A T 5 
p h os p h or ylat i on i n h u ma n a n d d o g P B M Cs wi t h a n I C5 0 val ue of 0. 0 1 8 µ M i n b ot h s pecies.
T o de m o nstrate s uita bility of  AZ D 0 4 4 9 f or i n hale d deli ver y a n d t o g ui de d ose t o ma n 
pre di ct i on, A Z D 0 4 4 9 was c haracterize d i n s e v er al i n vi v o m o dels t o de m o nstrate t ar get 
e n ga ge me nt a n d effect o n aller gic air wa y infla m mat i on w he n d ose d b y i ntratrac heal (i.t.) 
i nstillati on as well as b y D PI . I n t hese st u dies, cli nicall y rele va nt f or mulat i ons of  AZ D 0 4 4 9 
(free base or f umarate salt) i n the cr ystal li ne state were a d mi nistere d via t he i.t. or i n hale d (D PI ) 
r o ut e. All state d d oses refer t o l un g -de p osi te d d ose ( L D D), w hic h aft er i.t. d osi n g e q uals t he 
deli vere d d ose ( d ose de p osite d di rectl y i nto t he air wa ys) a n d aft er D PI d osi n g is calc ulate d 
fr om P K m eas ure me nts ( nee de d beca use n ot all of t he n o mi nal d ose will reac h t he l u n g d ue t o 
rete ntio n of  s u bsta nce i n i n halati o n s yste m a n d/ or de p ositi o n i n t he u p per res pirat or y tract).
D ose d i.t. A Z D 0 4 4 9 (free base) d e m o nstrate d t ar get e n ga ge me nt i n vi v o b y i n hi biti n g I L-1 3 
i n d uce d S T A T 6 p h os p h or ylati on i n mice . Si g nifica nt i n hi bit i on ( 6 2 %) was o bser ve d at a L D D 
of  5 µ g/ k g wit h calc ulate d effecti ve d ose ( E D) 5 0 a n d E D 8 0 val ues of 1 a n d 4 μ g/ k g b o d y wei g ht, 
res pecti vel y.


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he d ose de pe n de nt effects o n aller gic ai r w a y i nfla m mati on of  AZ D 0 4 4 9 a d mi nistere d b y  i.t. 
i nstillati on were i n vest i gate d i n o val b u mi n ( O V A) c halle n ge d Br o w n N or wa y rats. As rea d -o ut 
of  efficac y, i n hi biti on of O V A c halle n ge i n d uce d e osi n o p hilia i n br o nc h oal ve o lar la va ge fl ui d 
( B A L F) was use d. A Z D 0 4 4 9 (fu marate sal t) als o d e mo nstrate d d ose de pe n de nt effects i n t his 
m o d el , wit h si g nifica nt i n hi biti on ( 3 8 %) of air wa y e osi n o p hilia o bser ve d at 3 μ g/ k g i ncreasi n g 
t o 6 2 % at 3 0 0 μ g/ k g . T he calc ulate d E D 8 0 val ue was 1 1 µ g/ k g b o d y wei g ht (c orres p o n di n g t o 
9. 1 µ g/ k g b o d y wei g ht of A Z D 0 4 4 9 free base).
T he sa me m o d el  was use d t o d eter mi ne t he effects of  AZ D 0 4 4 9 (fu marate salt) a d mi nistere d 
b y D PI . A gai n, d ose de pe n de nt i n hi biti on of  aller gic air wa y i nfla m mati on was o bser ve d . T he 
i n hi bit or y eff e ct of AZ D 0 4 4 9 o n l u n g e osi n o p hil i nfl u x reac he d si g nifica nce a n d a ma xi m u m 
( 5 8 % i n hi biti on) at a L D D of 7 3 µ g/ k g b o d y wei g ht . T he calc ulate d E D 8 0 val ue was 1 5 µ g/ k g 
f or t he A Z D 0 4 4 9 f umarate salt (c orres p o n di n g t o 1 2. 4 µ g/ k g b o d y wei g ht of  AZ D 0 4 4 9 free 
base) . T his val ue was use d f or scali n g t o a pre dicte d efficaci o us L D D i n ma n ( 7 0 k g) of  
a p pr o xi mat i vel y 1. 1 m g, c o rres p o n di n g t o 0. 9 1 m g A Z D 0 4 4 9 free base . Ass u mi n g a l un g -
de p osi te d fracti on of  80 %, t his d ose c orres p o n ds t o 1. 1 4 m g A Z D 0 4 4 9 free base deli vere d 
d ose.
1. 2. 1. 2.
Sec o n d ar y P h ar m ac o d y n a mics a n d S afet y P h ar m ac ol o g y
A di verse s et of i n vitr o ra di oli ga n d bi n di n g, e nz y me a n d f unct i onal a n d electr o p h ysi o l ogical 
assa ys i ncl u di n g car diac i on c ha n nels, di d n ot i de nt if y a n y off-tar get acti vit ies li kel y to be 
r ele va nt i n or near t he e x pecte d pl as ma e x p os ure ra n ge i n h u ma ns.
I n a hea d - o ut plet h ys m o gra p h y ( H O P) st u d y  in t he rat, i n halat i on a d mi nistrati o n of  A Z D 0 4 4 9 
at a t otal in hale d d ose l e v el of 2 6. 2 m g/ k g res ulte d i n decreases i n tidal v ol u me o f u p t o 3 0 t o 
4 0 %. T hese decreases c oi nci de d wi t h t he 3 0- mi n ute d osi n g peri o d a n d were prese nt f or u p t o 
1 h o ur p ost -d ose. T he decreases i n t i dal v o l ume were acc o m pa nie d b y  increases i n res pirat or y 
rate a n d a n o verall decrease i n mi n ute v ol u me. T here were n o effects o n f u ncti onal res pirat or y 
para m eters at t otal in hale d d ose levels of  0. 7 0 7 or 2. 7 2 m g/ k g. I n t he re peat d ose t o xicity 
st u dies, decreases i n tidal v o l ume were o bser ve d i n t he r at at  total  in hale d d ose le vels 
≥1 8. 1 m g/ k g/ da y, b ut t here were n o acc o m pa n yi n g c ha n ges i n res pir at or y rate or mi n ute
v o l ume, w hile n o effects were o bser ve d i n t he d o g (als o see Secti o n 1. 2. 2. 1 ).
A Z D 0 4 4 9 ha d n o effect o n car di o vasc ular para m eters assesse d i n c o nscio us tele metere d d o gs 
f oll owi n g si n gle i n hale d a d mi nistrati o n of a t otal i n hale d d ose of 2 m g/ k g/ da y . T hi rt y mi n utes 
f ollo wi n g s u p ple me ntar y ( b ol us) i ntra ve n o us (I V) d osi n g (a d mi nistere d 2 h o urs p ost i n halat i on 
d osi n g), a tra nsie nt decrease i n diast olic press ure ( 1 6 %) occ urre d aft er a d ose of  0. 2 m g/ k g; 
hi g her d oses ( 1 a n d 2 m g/ k g) tra nsie ntl y re d uce d s yst olic, diast olic a n d mea n arterial bl o o d 
press ure, wi t h re d uctio ns of  41 %, 3 6 % a n d 4 0 %, res pecti vel y, at 2 m g/ k g, w hile left ve ntri c ular 


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
c o ntractilit y para meters were als o decrease d (e g, d P/ dt ma x b y 4 3 % a n d 4 2 % after 1 a n d 2 m g/ k g 
I V, res pecti vel y), trac ki n g t he bl o o d press ur e c ha n ges. All t he car dio vasc ular para m eters ha d 
rec o vere d t o baseli ne wi t hi n 1 h o ur of  t he I V d osi n g . T he n o o bser va ble effect le vel (N O E L )
f or t he car di o vasc ular effects was c o nsi dere d t o be 2 m g/ k g (i n hale d) c o m bi ne d wit h 0. 2 m g/ k g 
I V. F urt her m ore, t her e was n o A Z D 0 4 4 9 relate d i n hi bit i on of t he h u ma n et her -à- g o-g o -relate d 
ge ne ( h E R G) e nc o de d p otassi u m c ha n nel.
I n t he c o nsci o us rat, a d mi nistrati o n of  AZ D 0 4 4 9 at a t otal in hale d d ose of  18. 7 m g/ k g, 
pr o d uce d re d ucti o ns i n p u pil dia meter w hic h were o bser ve d u p t o 2 h o urs p ost -d ose . T here was 
n o ot her c o nsiste nt be ha vi oral effect or a n y  effects o n b o d y t e mperat ure or l o c o m ot or acti vit y 
t hat were attri b uta ble t o A Z D 0 4 4 9 . T here were n o effects at i n hale d d ose levels of  0. 7 1 2 or  
4. 5 5 m g/ k g.
T he mar gi ns fr o m t he N O E L i n eac h of t he safet y p har mac o l og y  stu dies t o t he pre dicte d h u ma n 
C ma x pl as ma e x p os ure ass ociate d wit h a ma xi mal all o we d d ose of  5 m g ( 3 2. 9 n m o l/L/ 0. 0 3 3; 
t otal/free) are as f oll ows: ner v o us s yste m (> 4 -f ol d); h E R G ( > 6 5, 0 0 0-f ol d); car dio vasc ular 
s yste m (> 8- f ol d); res pir at or y syste m  (> 2 -f ol d; wi t h the N O E L d ose > 1 0 -f ol d hi g her t he 
ma xi m u m all o we d h u ma n d ose).
1. 2. 2.
T o xic ol o g y Pre -cli nic al D at a
A Z D 0 4 4 9 i n halat i on t o xi cit y st u dies i n t he rat ra n ge u p t o 6 m o nt hs i n d urati on, w hile st u dies 
u p t o 3 m o nt hs ha ve bee n c o m plete d i n t he d o g . F urt her i nf or mat i on o n pre -cli nical t o xic o l og y 
fi n di n gs is a vaila ble i n t he I n vestigat or’s Br oc h ure , b ut a s u m mar y of  the ke y fi n di n gs is 
prese nte d bel o w [2 ].
1. 2. 2. 1.
Res pir at or y Tr act Effects
I n halati on a d mi nistrati o n of  AZ D 0 4 4 9 t o rats a n d d o gs at  dose levels ≥3. 7 5 m g/ k g/ da y was 
ass ociat e d wit h pat h olo gi c al fi n di n gs i n t he res pirat or y tract.
I n t he rat, c ha n ges i n t he l u n g i ncl u de d p ol y p oi d lesi o ns i n t he br o nc hi/ br o nc hi o les, de p ositi o n 
of  e osi n o p hilic material/ pi g me nts i n t he al ve oli/ br o nc hi o les/ br o nc hi, h y pertr o p h y/ h y per plasia 
of  the br o nc hi o lar/ br o nc hial e pit heli u m an d al ve o lar macr o p ha ge 
a g gre gates at t he 
al ve o l obr o nc hi o lar j u ncti on. C ha n ges i n t he nasal t ur bi nates c o nsiste d of  atr o p h y/i nfla m mati on 
of  t he r es pir at or y/ olfact or y epi t heli u m a n d e osi n o p hilic material/ pi g me nts/i nfla m mat or y  cells 
i n the l u me n . F o ll owi n g p ol arize d li g ht e val uati o n, s pecial stai ni n g, i m m u n o hist oc he mistr y a n d 
mass s pectr o metr y ima gi n g, t he pi g me nts, see n e m be d de d i n t he e osi n o p hilic mat erial of t he 
l u n gs a n d nasal t ur bi nates, were c o nsi dere d t o be A Z D 0 4 4 9.
I n t he d o g, c ha n ges i n t he l un g c o nsiste d of  foa m y  al ve olar macr o p ha ges, w hic h were see n 
m o stl y i n t he pr o xi mit y of  ter mi nal br o nc hi o les a n d br o nc hi o l oal ve o lar j unct i ons . T hese 


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
c ha n ges were fre q ue ntl y ass ociate d wit h a mi ni mal le vel o f al ve olar ne utr o p hilic i nfla m mat or y 
cell i nfiltrate . T here were n o ot her res pirat or y  tract c ha n ges i n t he d o g.
T here were n o A Z D 0 4 4 9 relate d res pirat or y  tract pat h ol o gic fi n di n gs i n t he rat at t otal i n hale d 
d ose levels ≤1. 8 8 m g/ k g/ da y (teste d o ver 6 m o nt hs) or i n t he d o g at t otal in hale d d ose levels 
≤2. 0 1 m g/ k g/ da y (teste d o ver 3 m o nt hs, wi t h a s u p ple me ntar y 1 m g/ k g/ da y I V d os e).
F u nct i onal r es pir at or y assess me nts were 
perf or me d i n a sta n dal one res pirat or y safet y 
p har mac o l og y  st u d y in t he rat (see Secti o n 1. 2. 1. 2 ) a n d wi t hi n re peat d ose t o xi cit y st u dies of 
u p t o 3 m o nt hs i n d urati on. I n t he rat decreases i n ti dal v ol u me ( u p t o ca. 4 0 %) were o bser ve d 
at t otal in hale d d ose levels ≥1 8. 1 m g/ k g/ da y . T he decreases c o i nci de d wi t h the 3 0 -mi n ute 
d osi n g peri o d a n d w er e pr es e nt f or u p t o 1 -h o ur p ost -d ose . I n t he safety p har mac o l og y  st u d y, 
t he decreases c oi nci de d wit h a n increase i n res pirat or y rate a n d a n o verall decrease i n mi n ute 
v o l ume, h o we ver t hese c ha n ges were n ot o bser ve d i n t he re peat d ose t o xicit y st u dies. T here 
were n o c ha n ges i n t he rat at t otal i n hale d d ose le vels ≤3. 7 5 m g/ k g/ da y . T here were n o c ha n ges 
i n t he d o g at t he hi g hest d ose le vel teste d a n d assesse d f or f u ncti onal res pirat or y c ha n ges (t otal 
i n hale d d ose le vel of 2. 0 1 m g/ k g/ da y pl us a 1 m g/ k g/ da y  I V d ose).
T he res pirat or y tract pat h ol o g y  fi n di n gs are li kel y to be a c o nse q ue nce of  ad mi nistrati o n of  
hi g h i n hale d d oses of a l o w s ol u bilit y c o m p o u n d [ 2 ], w hile t he a bse nce of t he p ol y p oid l esi o n  
i n t he l u n g of t he d o g i n dicates t hat t his partic ular fi n di n g is p ossi bl y rat or r o de nt s pecific. T he 
ca use of  the f unct i onal res pirat or y cha n ges is n ot k n o w n . Ne vert heless, t here were n o 
pat h ol o gi cal or f unct i onal c ha n ges o b ser ve d at t he n o -o bser ve d -a d verse-effect le vels 
( N O A E L). T he ma xi m u m all o we d d ose has bee n calc ulate d b y a p pl yi n g a 1 0 -f ol d safety fact or 
o n t he N O A E L i n t he m ost se nsit i ve s pecies (rat); see Secti o n 3. 4. 7 .
1. 2. 2. 2.
S yste mic Effects
A d mi nistrati o n of  AZ D 0 4 4 9 t o rats a n d d o gs was well t olerate d, wit h n o A Z D 0 4 4 9 r elate d 
cli nical sig ns or pre mat ure deat hs . Ke y fi n di n gs are s u m marize d bel o w, h o we ver n o ne were 
c o nsi dere d t o be a d verse.
I n rats, l o wer t ha n c o ntr ol b o d y w eig ht gai n was o bser ve d (ca. 0. 8 -f ol d c o ntr ol at t otal i n hale d 
d oses ≥1. 8 8 m g/ k g/ da y o ver 6 m o nt hs) . T here were n o effects o n b o d y  wei g ht i n t he d o g.
I n t he rat, decreases i n w hi t e bl o o d cell c o u nts were o bser ve d, wi t h the m o st c o nsiste nt decrease 
rec or de d i n l y m p h oc ytes ( u p t o ca. 0. 7 -f ol d c o ntr ol); t hese c ha n ges were n ot o bser ve d i n t he 
d o g.
Retic ul oc y tes were als o decrease d ( pre d o mi natel y i n t he rat; u p t o ca. 0. 7-f ol d c o ntr ol), b ut t he 
effect was o nl y o bser ve d i n st u dies u p t o 1 mo nt h i n d urat i on a n d t here was n o effect o n t otal 
re d blo o d cell  c o u nts.


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 4 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Decrease d l y m p h oi d tiss ue (s plee n a n d t h y m us) wei g hts were rec or de d ( u p t o ca. 0. 6 -f ol d 
c o ntr ol in r at a n d u p t o ca. 0. 3 -f ol d c o ntr ol in t he d o g [ males o nl y ]); h o we ver, t hese c ha n ges 
were wit h o ut hist o pat h ol o gic c orrelates a n d n ot c o nsiste nt l y o bser ve d acr oss all t o xic o l og y 
st u dies.
T here were n o A Z D 0 4 4 9 relate d pat h ol o gi c c ha n ges, ot her t ha n t hose i n t he res pirat or y tr a ct 
(see Secti o n 1. 2. 2. 1 ).
1. 2. 2. 3.
I ntr a ve n o us A d mi nistr ati o n
F o ll owi n g I V a d mi nistrati o n o f the i nte n de d cli nical f or m ulat i on o f A Z D 0 4 4 9 t o ra b bits, t here 
were n o sig ns of  local irritat i on or micr osc o pic fi n di n gs at t he i njecti on sites t hat were 
c o nsi dere d t o be relate d t o A Z D 0 4 4 9.
F urt her m or e, a s us pe nsi on of  
AZ D 0 4 4 9 
was 
well 
t olerate d f oll owi n g 
o nce dail y 
I V a d mi nistrati o n t o d o gs at a d ose le vel o f 1 m g/ k g f or 3 m o nt hs.
A n i n vitr o bl o o d c o m pat i bility st u d y  was c o n d ucte d i n h u ma n bl o o d usi n g t he i nt e n de d cli nical 
f or mulat i on o f A Z D 0 4 4 9. T here was n o effect u p o n he m o l ysis, er yt hr o c yt e clu m pi n g or plas ma 
preci pi t atio n.
1. 2. 3.
Cli nic al St u dies
A Z D 0 4 4 9 has n ot bee n pre vi o usl y  e val uate d i n cli nical st u dies. T his is a first -i n-h u ma n ( FI H) 
cli nical st u d y.
1. 3.
O ver all R ati o n ale f or C o n d ucti n g t his St u d y
A Z D 0 4 4 9 has n ot bee n pre vi o usl y  st u die d i n h u ma ns. T his st u d y  will ha ve 3 parts:
Part 1 will i n vesti gate t he safety,  tol era bilit y an d p har mac o ki net ics ( P K) of  AZ D 0 4 4 9 aft er 
i n hale d si n gle asce n di n g d oses ( S A D) i n healt h y v ol u nteers ( Part 1a) a n d will i n vesti gate t wo 
I V-d ose c o h ort s t o deter mi ne a bs ol ute bi oa vaila bility ( Part 1 b).
Part 2a/ b will be c o n d ucte d i n patie nts wit h mil d ast h ma ( Part 2a) a n d healt h y v o l unt eers
( Part 2 b), i n vesti gati n g t he safety,  tol era bilit y an d P K of  AZ D 0 4 4 9 aft er m ulti p le asce n di n g 
d oses ( M A D) a n d st u d yi n g t he effect of A Z D 0 4 4 9 o n air wa y i nfla m mati on. Part 2a/ b will b e 
d o ne wi t h ne b ulize d f or m ulati on.
Part   3a/ b will be c o n d ucte d i n patie nts wit h mil d ast h ma ( Part 3a) a n d wit h a n o pti o nal  c o h ort 
of  heal t h y v o l unt eers ( Part 3 b) , i n vesti gati n g t he safety,  t olera bilit y a n d P K of A Z D 0 4 4 9 after 
re peate d d ose a n d st u d yi n g t he effect of  AZ D 0 4 4 9 o n air wa y i nfla m mati on t o s h o w t arget 
e n ga ge me nt a n d pr o of -of -mec ha nis m 
( P o M). Part 3a/ b will 
be d o ne wi t h dr y -p o w der 
i n halati on ( D PI) .


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 5 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Details o n desi g n a n d r atio nale f or t he differe nt st u d y parts are pr o vi de d i n Sect i on 3 a n d 
Secti o n 4 , res pecti vel y.
















Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 5 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3.
S T U D Y D E SI G N
3. 1.
O ver all St u d y Desi g n
T his will be a P hase I, FI H st u d y  c o nsisti n g of t he f o ll owi n g parts:

Part 1a – Secti o n 3. 1. 1

Part 1 b – Secti o n 3. 1. 2

Part 2a/ b – Secti o n 3. 1. 3

Part 3a/ b – Secti o n 3. 1. 4
3. 1. 1.
P art 1 a St u d y Desi g n
Part 1a of  the st u d y will be a ra n d o mize d, si n gle-bli n d, place b o -c o ntr olle d, S A D, se q ue ntial 
gr o u p desi g n st u d y  p erfor m e d at a si n gle st u d y ce nter. M ale a n d/ or fe male hea lth y v o l unt eers, 
a ge d 1 8 t o 5 5 years will be i ncl u de d i n t his part of  the st u d y. Fe male v o l unt eers m ust be of  
n o n- c hil d beari n g p ot e nti al. T his part of t he st u d y will be c o n d ucte d i n u p t o 7 2 v ol u nteers .
Si x i n hale d d ose levels of  AZ D 0 4 4 9 ne b ulize d s us pe nsio n  are pl a n ne d t o be i n vesti gate d i n 
6 c o h orts. De pe n di n g o n e mer gi n g safety a n d P K data, u p t o 3 a d dit i onal i n hale d d ose le vels 
(c o h orts), wit hi n t he pre -s pecifie d d ose ra n ge (see Secti o n 3. 5. 1 ), ma y be a d de d at  the 
di scretio n of  t he S p o ns or.
Wit hi n eac h c o h ort, 6 v ol u nteers will be ra n d o mize d t o recei ve a n i n hale d d ose of  AZ D 0 4 4 9 
ne b ulize d s us pe nsi o n a n d 2 v o l unt eers will be ra n d o mize d t o recei ve i nhale d pl ace b o . D o si n g 
f or eac h asce n di n g d ose c o h ort will st art wit h 2 v ol u nteers i n a se nti nel c o h ort, s uc h t hat 
1 v ol u nteer will be ra n d o mize d t o recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi o n a n d 1 v o l unt eer will 
be ra n d o mize d t o recei ve place b o (see Secti o n 3. 5. 1. 3 ).
I n eac h c o h ort, v ol u nteers will atte n d a Scree ni n g Visit wit hi n 2 8 da ys bef ore recei vi n g t he 
d ose of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n or c orres p o n di n g place b o.
F or t he treat me nt peri o d, v ol u nteers will be a d mitte d t o t he Cli nical U nit o n Da y - 1. O n Da y 1, 
v o l unt eers
will 
recei ve a si n gle i n hale d d ose of  
AZ D 0 4 4 9 ne b ulize d s us pe nsi on or 
c orres p o n di n g place b o . Assess me nts will be perf or m e d, a nd sa m ples c ollecte d fr om bef ore 
d osi n g u nt il at least 3 6 h o urs p ost -d ose . V o l unt eers will be di sc har ge d fr om t he Cli nical U ni t 
aft er all s a mples ha ve bee n c ollecte d a n d assess me nts ha ve bee n p erf or m e d o n Da y 4.
De pe n di n g o n t he e mer gi n g data i n co h ort 1, the c ollect i on per i od ma y be e xte n de d t o 9 6 h o urs 
p ost -d ose.
V ol u nteers will ret ur n t o t he Cli nical U ni t wi t hi n 6 ± 1 da ys aft er t he d ose of  AZ D 0 4 4 9 
ne b ulize d s us pe nsi o n or c orres p o n di n g place b o f or a F oll o w -u p Vi sit.


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 5 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
F o ll owi n g re vie w o f the st u d y data, t he S af et y Re vie w C o m mittee ( S R C) ma y deci de t o a dj ust 
t he len gt h of  the st a y at t he Cli nical U ni t a n d t he ti mi n g a n d n u m ber of  assess me nts a n d/ or 
bl o o d a n d uri ne sa m ples f or s u bse q ue nt c o h orts.
D osi n g, se nt i nel c o h orts, d ose escalat i on a n d st o p pi n g criteria a re descri be d i n Secti o n 3. 5. 1 .
3. 1. 2.
P art 1 b St u d y Desi g n
I ntra ve n o us (I V) dosi n g i n Part 1 b o f the st u d y will be i nit iate d after t he c o m plet i on o f co h ort 6 
i n Part 1a o r (if Part 1a is c o m p lete d wit h less t ha n 6 c o h orts) aft er c o m plet i on o f the last c o h ort 
i n Part 1a. Part 1 b, will be o pe n -label a n d c o nsist of  2 d ose c o h orts (I V
)
a n d be c o n d ucte d i n 1 2 heal t h y v olu nteer s.
3. 1. 2. 1.
First I V D ose C o h ort
Si x (6) v ol u nteers will be selecte d f or the first I V d ose co h ort i n Part 1 b f oll ow i n g a 2 -sta ge 
desi g n . If Part 1 b ca n n ot be c o m p lete d wit h 6 v o l unt eers fr om Part 1a or if s o me o f the data are 
c o nsi dere d n ot e val ua ble, u p t o 6 a d diti o nal naï ve v ol u nteers ma y be e nr olle d (f or rati o nale see 
Secti o n 4. 1. 2 ). T he i n hale d d ose f or naï ve v o l unt eers will be deci de d base d o n e mer gi n g data .
T he i n hale d d ose ca n n ot be hi g her t ha n t he hi g hest i n hale d d ose c o nsi dere d safe i n pre vi o us 
c o h orts.
All 6 v o l unt eers will recei ve a si n gle I V d ose 
 of  AZ D 0 4 4 9 s ol uti on. D os i n g will 
start wit h 1 healt h y v o l unt eer i n a se nti nel c o h ort (see Secti o n 3. 5. 2. 2 ).
T here will be a was h o ut peri o d of  at least 2 wee ks f or t he v ol u nt eers recei vi n g b ot h i n hale d 
d osi n g i n Part 1a a n d I V d osi n g i n Part 1 b. F or t he I V tr e at me nt peri o d, v o l unt eers will be 
a d mitte d t o t he Cli nical U ni t o n D a y - 1. O n Da y 1, v ol u nteers will recei ve a si n gle I V d ose 
of  t he A Z D 0 4 4 9 s ol uti on . Assess me nts will be p erf or m e d, a n d s a mples c o llecte d 
fr om bef ore d osi n g u nt il 4 8 h o urs p ost -d ose . V o l unt eers will be di sc har ge d fr o m t he Cli nical 
U nit after all sa m ples ha ve bee n c ollecte d a n d assess me nts ha ve bee n perf or me d o n Da y 3.
V ol u nteers will ret ur n t o t he Cli nical U nit wit hi n 6 ± 1 da ys after t he last d ose of A Z D 0 4 4 9 f or 
a F oll o w-u p Visi t.
D osi n g, se nt i nel c o h orts, d ose escalat i on a n d st o p pi n g criteria are descri be d i n Secti o n 3. 5. 2 .
3. 1. 2. 2.
Sec o n d I V D ose C o h ort
A sec o n d I V d ose c o h ort i n Part 1 b will be i nit iate d aft er t he e val uat i on of  t he P K a n d safety 
res ults fr o m all c o h orts i n Part 1a a n d c o m plet i on of t he first I V d ose c o h ort i n Part 1 b.
T he sec o n d I V d ose c o h ort will c o nsist of  6 heal t h y v o l unt eers w h o ha ve n ot pre vi o usl y 
parti ci pate d i n t he st u d y ( naï ve v o l unt eers).
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
All 6 v o l unt eers will recei ve a si n gle I V d ose 
 of  AZ D 0 4 4 9 s olut i on. D osi n g will 
start wit h 1 healt h y v o l unt eer i n a se nti nel c o h ort (see Secti o n 3. 5. 2. 2 ).
T he v o l unt eers will be a d mitte d t o t he Cli nical U nit . O n Da y 1, v ol u nteers will recei ve a si n gle 
I V d ose 
 of  the A Z D 0 4 4 9 s olut i on. Assess me nts will be perf or m e d, a n d sa m ples 
c ollecte d fr o m bef ore d osi n g u ntil 4 8 h o urs p ost -d ose . V o l unt eers will be disc har ge d fr o m t he 
Cli nical U ni t aft er all sa m ples ha ve bee n c o llecte d a n d assess me nts ha ve bee n p erf or m e d o n 
D a y  3.
V ol u nteers will ret ur n t o t he Cli nical U nit wit hi n 6 ± 1 da ys after t he last d ose of A Z D 0 4 4 9 f or 
a F oll o w-u p Visi t.
D osi n g, se nt i nel c o h orts, d ose escalat i on a n d st o p pi n g criteria are descri be d i n Secti o n 3. 5. 2 .
3. 1. 3.
P art 2 a/ b St u d y Desi g n
Part 2a/ b of  t he st u d y will be a ra n d omize d, si n gle-bli n d, place b o -c o ntr olle d , M A D, se q ue ntial 
gr o u p desi g n st u d y perf or me d at a p pr o xi matel y 3 st u d y ce nters. S u bjects a ge d 1 8 t o 5 5 years 
will be i ncl u de d i n t his p art of  t he stu d y. U nli ke i n Part 1 a or Part 1 b (Fir st I V D o se C o h ort) , 
fe male s u bjects of  chil d beari n g p ote nti al may a lso be e nr olle d. T his part of  the st u d y w ill recr uit 
u p t o 5 6 s u bjects. A t otal of 2 6 e val ua ble s u bjects are nee de d f or c o mpleti o n of  Part 2 a/ b. 
P ote nti all y, 3 0 e xtra s u bjects ma y be ra n d o mize d t o c o u nteract dr o p -o uts a n d all o w f or a n e xtra 
c o h ort if nee de d.
T hree d ose levels of  AZ D 0 4 4 9 ne b ulize d s us pe nsi on are pla n ne d t o be i n vesti gate d i n 
3 c o h orts. T he c o h orts c o ul d c o m prise eit her pati e nts wit h mil d ast h ma or heal t h y vol u nteers .
Part 2a will i ncl u de co h orts 1 a n d 2 , eac h c o mprisi n g of  9 patie nts wi t h mil d ast h ma. W ithi n 
eac h of t hese c o h orts 6 patie nts will be ra n d o mize d t o recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi o n 
a n d 3 pati e nts ra n d omize d t o recei ve pl ace b o. A d dit i onal c o h orts wit h 9 pati e nts c o uld be 
a d de d t o st u d y P K, P D a n d safet y for d oses l ower t ha n 
Part 2 b will c o nsist of  1 c o h ort of  8 he alt h y v o l unt eers; 6 v ol u nteers will be ra n d omize d t o 
recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi on a n d 2 v o l unt eers will be ra n d omize d t o recei ve 
pl ace b o.
D osi n g f or eac h asce n di n g d ose c o h ort will start wit h 2 s u bjects i n a se nti nel c o h ort, s uc h t hat 
1 s u bject will be ra n d o mize d t o recei ve A Z D 0 4 4 9 ne b ulize d s us pe nsi o n a n d 1 s u bject will be 
ra n d omize d t o place b o (see Secti o n 3. 5. 3. 2 ).
Eac h s u bject will recei ve a si n gle d ose of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n at t he selecte d d ose 
le vel or place b o o n Da y 1 f o ll owe d b y  1 0 dail y  d oses fr o m D a y 3 t o Da y 1 2.
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
F or t he treat me nt peri o d, s u bjects will be a d mitte d t o t he Cli nical U ni t. T he first d ose will be 
a d mi nistere d o n Da y 1. F oll o wi n g t his first d ose, pl as ma P K sa m ples will be c o llecte d u p t o 
4 8 h o urs p ost -d ose f or t he first d ose ( Da y 1) t o all o w f or c haracterizat i on of  the ter mi nal 
eli mi nat i on p hase. O nce dail y  d osi n g will start o n Da y 3, 4 8 h o urs p ost -Da y 1 d ose P K 
sa m pli n g a n d c o nti n ue u p t o Da y 1 2 wi t h int er vals of 2 4 h o urs bet wee n d oses.
Eac h s u bject will recei ve i n hale d d oses of A Z D 0 4 4 9 ne b ulize d s us pe nsi o n at t he selecte d d ose 
le vel or place b o o n t he s pecifie d d osi n g da ys. Assess me nts will be p erf or m e d, a n d sa m ples 
c ollecte d fr o m b ef or e d osi n g u nt il u p t o 2 4 0 h o urs aft er last d ose ( Part 2 a) a n d u nt il u p t o 
3 6 0 h o urs aft er last d ose ( Part 2 b) . S u bjects will re mai n i n h o use f or t he d urati o n of  the 
treat me nt perio d a n d will be disc har ge d fr o m t he Cli nical U nit o n Da y 1 4 , 2 da ys after t he last 
d ose a d mi nistrati o n ( P art 2a) a n d aft er a n e xte n de d safet y mo ni t orin g p eri o d o n Da y 2 7 , 1 5
da ys aft er t he last d ose a d mi nistrati o n ( Part 2 b). If per mitte d b y l ocal rele va nt re g ulat or y 
a ut h orities a n d c o nsi dere d feasi ble a n d safe t o d o s o, t he e xte n de d safety m o nit ori n g p eri o d 
ma y be c o n d ucte d as n o n -reside nt ial visits.
F o ll owi n g re vie w of e mer gi n g data, t he S R C ma y deci de t o a dj ust t he le n gt h of t he sta y  at t he 
C li nical U ni t a n d t he ti mi n g a n d n u m ber of  assess me nts a n d/ or bl o o d a n d uri ne sa mples f or 
s u bse q ue nt c o h orts. T he ti me wi n d o w bet wee n t he si n gle d ose a n d start of  re peate d d osi n g ma y 
als o be a dj uste d a n y t i me d uri n g t he st u d y.
D osi n g, se nt i nel c o h orts, d ose escalat i on a n d st o p pi n g criteria are descri be d i n Secti o n 3. 5. 3 .
3. 1. 4.
P art 3 a/ b St u d y Desi g n
Part 3a/ b of  t he st u d y will be i nitiate d after t he c o m plet i on of Part 2 b.
Part 3a/ b will be a ra n d omize d, si n gle-bli n d, pl ace b o -c o ntr olle d , D PI/ P o M st u d y. Part 3 will 
be c o n d ucte d i n u p t o 3 6 patie nts wi t h mil d ast h ma ( Part 3a) a n d 8 healt h y v o l unt eers ( Part 3 b,
o pti o nal ).
Part 3a will c o nsist of  36 patie n ts, a g e d 1 8 t o 5 5 years, w here 1 8 patie nts will be ra n d o mize d 
t o A Z D 0 4 4 9 D PI a n d 1 8 pat ient s t o place b o. A n I nteri m A nal ysis (I A) will be c o n d ucte d w he n 
a p pr o xi matel y 5 0 % of t he patie nts ha ve c om p lete d Part 3a . S h o ul d ne w data o n t he varia bilit y 
of  t he Fe N O meas ure me nts e mer ge at t he I A, t he sa mple size i n Part 3a c o ul d be c ha n ge d.
If t he o pti o nal Part 3 b is c o n d ucte d, it will c o mprise 8 healt h y v o l unt eers; 6 v o l unt eers will be 
ra n d omize d t o A Z D 0 4 4 9 D PI a n d 2 v ol u nteers t o place b o.
F or i nf or mat i on o n d os i n g i n Part 3 a/ b, please refer t o Sectio n 3. 5. 4 .
D osi n g a n d assess me nt ti me -p oi nts are prese nte d i n Ta ble 3. 2 -6 a n d Ta ble 3. 2 - 7. 


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Eac h s u bject will recei ve a si n gle d ose of A Z D 0 4 4 9 D PI at  t he select e d d os e le vel or place b o 
o n Da y 1 f o ll owe d b y  1 0 dail y  d os es fr o m D a y 3 t o D a y 1 2.
F or t he treat me nt peri o d, s u bjects will be a d mitte d t o t he Cli nical U ni t. T he first d ose will be 
a d mi nistere d o n D a y 1. O nce dail y d osi n g will  start o n Da y 3, 4 8 h o urs p ost -Da y 1 d ose P K 
sa m pli n g a n d c o nti n ue u p t o Da y 1 2.
Eac h s u bject will recei ve i n hale d d oses of A Z D 0 4 4 9 D PI at t he selecte d d ose le vel or place b o 
o n t he s pecifie d d osi n g da ys. Assess me nts will be p erf or m e d, a n d sa m ples c o llecte d fr o m 
bef ore d osi n g u nt il u p t o 3 6 0 h o urs aft er last d ose. S u bjects will re mai n i n h o use f or t he 
d urati o n of  t he treat me nt peri o d a n d u n der g o a n e xte n de d safet y m o nit ori n g peri o d u n til bei n g
di sc har ge d fr om t he Cli nical U ni t o n Da y 2 7 , 1 5 d a y s aft er t he last d ose a d mi nistrati o n. If 
per mitte d b y l ocal rele va nt re g ulat or y a ut h orities a n d c o nsi dere d feasi ble a n d safe t o d o s o, t he 
e xte n de d safet y m o nit ori n g peri o d m a y be c o n d ucte d as n o n-resi de ntial visit s.
F o ll owi n g re vie w of e mer gi n g data, t he S R C ma y deci de t o a dj ust t he le n gt h of t he sta y at t he 
Cli nical U ni t a n d t he ti mi n g a n d n u m ber of  assess me nts a n d/ or bl o o d a n d uri ne sa mples f or 
s u bse q ue nt c o h orts. T he ti me wi n d o w bet wee n t he si n gle d ose a n d start of  re peate d d osi n g ma y 
als o be a dj uste d a n y t i me d uri n g t he st u d y.
D osi n g a n d s t o p pi n g crit eria are descri be d i n Sect i o n 3. 5. 4 .
Details o f t he statistical a nal ys es are prese nte d i n Secti o n 1 0 .
3. 1. 5.
E n d of St u d y
St u d y  c o mplet i on is defi ne d as t he last visit of t he last s u bject f or a n y pr ot oc ol relate d acti vity 
( L S L V – Last S u bject Last Visit).


Astra Ze neca
Cli nical St u d y Pr ot oc o l
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 1. 6.
E x pecte d D ur ati o n of t he St u d y
Scree ni n g
Tre at me nt Peri o d *
S afet y 
M o nit ori n g * *
Peri o d
F oll o w -u p
T ot al 
D ur ati o n
P art 1 a 
2 8 da ys 
bef ore d ose
1 da y
3 da y s
6 ± 1 da ys after 
d ose
U p t o 
3 6 da ys
P art 1 b
( First 
I V C o h ort)
2 8 da ys 
bef ore d ose
1 da y
2 da y s
6 ± 1 da ys after 
d ose
U p t o 
5 3 da ys
P art 1 b
( Sec o n d 
I V C o h ort)
2 8 da ys 
bef ore d ose
1 da y
2 da y s
6 ± 1 da ys after 
I V d ose
U p t o 
3 6 da ys
P art 2 a
2 8 da ys 
bef ore first 
d ose
1 2 da ys
2 da y s
1 0 ± 1 da y s after 
last d ose
U p t o
5 2 da ys
P art 2 b
2 8 da ys 
bef ore first 
d ose
1 2 da ys
1 5 da ys
N ot a p plica ble
U p t o
5 5 da ys
P art 3 a a n d 
P art 3 b
2 8 da ys 
bef ore first 
d ose
1 2 da ys 
1 5 da ys
N ot a p plica ble
U p t o 
5 5 da ys
* T his is a 1 2 da y peri o d wit h d osi n g o n Da y 1 a n d Da y 3 t o 1 2
* * Peri o d of i n-h o use m o nit ori n g fr o m last d ose u ntil disc har ge fr o m t he u nit . If pe r mitte d b y l ocal rele va nt 
re g ulat or y a ut h orities a n d c o nsi dere d feasi ble a n d safe t o d o s o, t he safet y m o nit ori n g peri o d f or Part 2 b, 3a, a n d 
3 b ma y  be c o n d ucte d as n o n-resi de ntial visits.
3. 2.
St u d y Fl o w C h art, Sc he d ules of Assess me nts a n d Ti me Sc he d ules f or Di git al 
Electr oc ar di o gr a p h y
A hi g h -lev el  o ver vie w of the st u d y sc he me is prese nte d i n Fi g ure 3- 1 . O ver vie ws a n d decisi o n 
p oi nts of  the i n di vi d ual st u d y parts are prese nte d i n Fi g ure 3- 2 ( Part 1a a n d Part 1 b) a n d 
Fi g ure 3- 3 ( Part 2 a/ b a n d Part 3 a/ b).
T he Sc he d ule of  Assess me nts di s pla yi n g assess me nts/tas ks a n d ti me-p oi nts is prese nte d i n 
Ta ble 3. 2 - 1 ( Part 1a), Ta ble 3. 2 - 2 a n d Ta ble 3. 2 - 3 ( Part 1 b), Ta ble 3. 2 - 4 a n d Ta ble 3. 2 - 5
( Part 2 a/ b), Ta ble 3. 2 - 6, a n d Ta ble 3. 2 -7 ( Part 3 a/ b). T he ti me sc he d ule f or di gi t al EC Gs 
( d E C Gs) is prese nte d i n Ta ble 3. 2 - 8 ( Part 1a), Ta ble 3. 2 - 9 ( Part 1 b) a n d Ta ble 3. 2 - 1 0
(Part 2 a/ b a n d Part 3 a/ b).


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 2. 1. 
St u d y Fl o w C h arts
Fi g ure 3- 1
Hi g h - Le vel O ver vie w of t he St u d y Sc he me


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Fi g ure 3- 2
D ose Esc al ati o n a n d Decisi o n P oi nts i n P art 1 a/ b


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Fi g ure 3- 3
D ose Esc al ati o n a n d Decisi o n P oi nts i n P art 2 a/ b a n d P art 3 a/ b


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 2. 2.
Sc he d ules of Assess me nts
T a ble 3. 2 - 1
Sc he d ule of Assess me nts P art 1 a ( S A D)
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
Visit
C o m me nts
D a ys -2 8 
t o-- 2
D a y - 1
D a ys 1 
t o 3 a
D a y 4 a
( 6 ± 1 d a ys 
p ost -d ose )
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n criteria
X  
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d c oti ni ne scree n 
X  
X
Ser ol o g y
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g h or m o ne testi n g
X
P ost -me n o pa usal fe males o nl y (see Secti o n 5. 2. 3. 2 f or 
defi niti o n)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
At least 6 0 h p ost -d ose, ma y be e xte n de d u p t o 9 6 h 
p ost -d ose de pe n di n g o n e mer gi n g data
N o n -resi de ntial visit
X
X
I n vesti g ati o n al Me dici n al Pr o d uct 
A d mi nistr ati o n:
I n haler Ne b ulizer Trai ni n g
X
Ra n d o mizati o n
Da y 1
A Z D 0 4 4 9/ Place b o a d mi nistrati o n via 
ne b ulizer
Da y 1 
( 0 h) b
S afet y a n d T oler a bilit y:
A d verse e ve nt q uesti o ni n g
O nl y S A Es
O nl y S A Es
X  
X  
X


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 1
Sc he d ule of Assess me nts P art 1 a ( S A D)
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
Visit
C o m me nts
D a ys -2 8 
t o-- 2
D a y - 1
D a ys 1 
t o 3 a
D a y 4 a
( 6 ± 1 d a ys 
p ost -d ose )
S pir o metr y
X  
X  
X  
X  
X
Da y 1: Pr e -d ose a n d 3 0 mi n, 1. 5 h, 3 h, 6 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 4: 7 2 h p ost -d ose
P ulse o xi metr y
X  
X  
X  
X  
X
C o h orts 1- 4:
Da y 1: Pr e -d ose a n d 3 0 mi n, 1. 5 h, 3 h, 6 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose 
Da y 4: 7 2 h p ost -d ose
C o h orts 5- 6:
Da y 1: Pr e -d ose, 1 h, 1. 5 h, 3 h, 6 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose 
Da y 4: 7 2 h p ost -d ose
Bl o o d press ure, p ulse a n d res pirat or y 
rate (s u pi ne) a n d b o d y te m perat ure
X  
X  
X  
X  
X
C o h orts 1- 4:
Da y 1: Pr e -d ose a n d 3 0 mi n, 1 h, 1. 5 h, 2 h, 3 h, 4 h, 6 h, 8 h 
a n d 1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
Da y 4: 7 2 h p ost -d ose
C o h orts 5- 6:
Da y 1: Pr e -d ose a n d 1 h, 1. 5 h, 2 h, 3 h, 4 h, 6 h, 8 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost - dose
Da y 3: 4 8 h p ost -d ose
Da y 4: 7 2 h p ost -d ose
1 2 -lea d d E C G
X
See Ta ble 3. 2 - 8
1 2 -lea d safet y E C G
X  
X  
X
X
1 2- lea d safet y E C G will be c ollecte d at t he start of eac h 
d E C G e xtracti o n wi n d o w w he n ti me-p oi nts c oi nci de, see 
Ta ble 3. 2 - 8


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 6 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 1
Sc he d ule of Assess me nts P art 1 a ( S A D)
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
Visit
C o m me nts
D a ys -2 8 
t o-- 2
D a y - 1
D a ys 1 
t o 3 a
D a y 4 a
( 6 ± 1 d a ys 
p ost -d ose )
Tele metr y
X  
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose ( D a y 2)
Hei g ht, wei g ht a n d B MI
X  
X
Cli nical la b orat or y e val uati o ns
X  
X  
X  
X  
X
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose 
Da y 4: 7 2 h p ost -d ose
All sa m ples will be c ollecte d after a 1 0 h fasti n g peri o d.
If t he assess me nt peri o d is e xte n de d, Da y 4 assess me nts will 
be perf or me d o n t he da y t h e healt h y  v ol u nteer are disc har ge d
Pre g na nc y testi n g
X (ser u m)
X ( uri ne)
X (ser u m)
Fe males o nl y
P h y sical e xa mi nati o n
X
X ( brief)  
X ( brief)
X ( brief)
X
Da y 3: 4 8 h p ost -d ose
Da y 4: 7 2 h p ost -d ose
P h ar m ac o ki netics:


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
P har mac o ki netic bl o o d sa m pli n g
X
d)
X
d)
X
e
C o h ort 1:
Da y 1: Pr e -d ose a n d 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 1 0 h a n d 
1 2 h after start of d osi n g
Da y 2: 2 4 h, 3 0 h a n d 3 6 h p ost -d ose
Da y 3: 4 8 h a n d 6 0 h p ost -d ose .
C o h orts 2- 3:
Da y 1: Pr e -d ose, as s o o n as p ossi ble after e n d of i n halati o n, 
1 5 mi n after e n d of i n halati o n, a n d 1 h, 1. 5 h, 2 h, 3 h, 4 h, 
6 h, 8 h, 1 0 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h, 3 0 h a n d 3 6 h p ost -d ose
C o h orts 4:
Da y 1: Pr e -d ose, as s o o n as p ossi ble after e n d o f i n halati o n, 
1 5 mi n after e n d of i n halati o n, a n d 1 h, 1. 5 h, 2 h, 3 h, 4 h, 
6 h, 8 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h, 3 0 h a n d 3 6 h p ost -d ose
Da y 3: 4 8 h
C o h orts 5:
Da y 1: Pr e -d ose, as s o o n as p ossi ble after e n d of i n halati o n, 
1 5 mi n after e n d of i n halati o n , a n d 1 h, 1. 5 h, 2 h, 3 h, 4 h, 
6 h, 8 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h, 3 0 h a n d 3 6 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
Da y 4: 7 2 h p ost -d ose
C o h orts 6 :
Da y 1: Pr e -d ose, as s o o n as p ossi ble after e n d of i n halati o n, 
1 5 mi n after e n d of i n halati o n, a n d 1 h, 1. 5 h, 2 h, 3 h, 4 h, 
6 h, 8 h, 1 0 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h, 3 0 h a n d 3 6 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
Da y 4: 7 2 h p ost -d ose
F oll o w -u p Visit (si n gle sa m ple)




Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 2
Sc he d ule of Assess me nts P art 1 b ( First I V C o h ort)
Assess me nts
Scree ni n g a
Tre at me nt Peri o d
F oll o w -u p 
Visit
C o m me nts
D a ys -2 8 
t o - 2
D a y - 1
D a ys 1 t o 
2 b
D a y 3 b
( 6 ± 1 d a ys 
p ost -d ose)
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n cr iteria
X
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d c oti ni ne 
scree n 
X
X
Ser ol o g y
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g h or m o ne 
testi n g
X
P ost -me n o pa usal fe males o nl y (see Secti o n 5. 2. 3. 2 f or defi niti o n)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
At least 6 0 h p ost -d ose, ma y be e xte n de d u p t o 9 6 h p ost -d ose 
de pe n di n g o n e mer gi n g data
N o n -resi de ntial visit
X
X
I n vesti g ati o n al Me dici n al 
Pr o d uct A d mi nistr ati o n:
A Z D 0 4 4 9 I V a d mi nistrati o n
c
Da y 1 
( 0 h o urs)
6 0 mi n i nf usi o n d urati o n
S afet y a n d T oler a bilit y:
A d verse e ve nt q uesti o ni n g
O nl y S A Es
O nl y S A Es
X  
X  
X
S pir o metr y
X
X  
X  
X  
X
Da y 1: Pr e -d ose a n d 1 h, 1. 5 h, 3 h, 6 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
P ulse O xi metr y
X
X  
X  
X  
X
Da y 1: Pr e -d ose a n d 3 0 mi n, 1 h, 1. 5 h, 3 h, 6 h a n d 1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 2
Sc he d ule of Assess me nts P art 1 b ( First I V C o h ort)
Assess me nts
Scree ni n g a
Tre at me nt Peri o d
F oll o w -u p 
Visit
C o m me nts
D a ys -2 8 
t o - 2
D a y - 1
D a ys 1 t o 
2 b
D a y 3 b
( 6 ± 1 d a ys 
p ost -d ose)
Bl o o d press ure, p ulse a n d 
res pirat or y rate (s u pi ne) a n d 
b o d y te m perat ure
X
X  
X  
X  
X
Da y 1: Pr e -d ose a n d 3 0 mi n, 1 h, 1. 5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
1 2 -lea d d E C G
X  
X
See Ta ble 3. 2 -9
1 2 -lea d safet y E C G
X
X  
X  
X  
X
1 2- lea d safet y E C G will be c ollecte d at t he start of eac h d E C G 
e xtracti o n wi n d o w w he n ti me -p oi nts c oi nci de, see Ta ble 3. 2 - 9
Tele metr y
X  
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose ( D a y 2)
Hei g ht, wei g ht a n d B MI
X
X
Cli nical la b orat or y e val uati o ns
X
X  
X  
X  
X
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
All sa m ples will be c ollecte d after a 1 0 h fasti n g peri o d.
If t he assess me nt peri o d is e xte n de d, Da y 3 assess me nts will be 
perf or me d o n t he da y healt h y  v ol u nteers are disc har ge d
Pre g na nc y testi n g
X (ser u m)
X ( uri ne)
X (ser u m)
Fe males o nl y
P h y sical e xa mi nati o n
X
X ( brief)
X 
( brief)
X
Da y 3: 4 8 h p ost -d ose
P h ar m ac o ki netics:
P har mac o ki netic bl o o d 
sa m pli n g
X  
X
Da y 1: Pr e -d ose a n d at 1 5, 3 0, 4 5 mi n after i nf usi o n start, directl y 
after t he e n d of i nf usi o n (c a. 6 0 mi n), 5, 1 0 a n d, 1 5 mi n after e n d 
of i nf usi o n, a n d 1. 5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 1 0 h, 1 2 h, 1 4 h, 
a n d 1 6 h after i nf usi o n start
Da y 2: 2 4 h, 3 6 h a n d 4 8 h after i nf usi o n start
O pti o nal p har mac o ge netic 
sa m ple
X
Da y 1: O nl y  if healt h y  v ol u nteer a grees b y si g ni n g a se parate 
i nf or me d c o nse nt f or m a n d has n ot partici pate d i n Part 1a of t he 
st u d y




Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 3
Sc he d ule of Assess me nts P art 1 b ( Sec o n d I V C o h ort)
Assess me nts
Scree ni n g a
Tre at me nt Peri o d
F oll o w -u p 
Visit
C o m me nts
D a y - 2 8
t o D a y -4 or - 3
D a y -3 
t o - 2
D a y - 1
D a ys 1 t o 
2 b
D a y 3 b
( 6 ± 1 d a ys 
p ost -d ose)
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n criteria
X
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d c oti ni ne 
scree n 
X
X
Ser ol o g y
X
C O VI D - 1 9 serol o g y testi n g d)
X
X
C O VI D -1 9 P C R testi n g d)
X
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g h or m o ne 
testi n g
X
P ost -me n o pa usal fe males o nl y (see Secti o n 5. 2. 3. 2 f or 
defi niti o n)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
At least 6 0 h p ost -d ose, ma y be e xte n de d u p t o 9 6 h 
p ost -d ose de pe n di n g o n e mer gi n g data
N o n -resi de ntial visit
X
X
I n vesti g ati o n al Me dici n al 
Pr o d uct A d mi nistr ati o n:
A Z D 0 4 4 9 I V 
a d mi nistrati o n c
Da y 1 
( 0 h o urs)
4 8 mi n i nf usi o n d urati o n
S afet y a n d T oler a bilit y:
A d verse e ve nt q uesti o ni n g
O nl y S A Es
O nl y 
S A Es
O nl y S A Es
X  
X  
X


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 3
Sc he d ule of Assess me nts P art 1 b ( Sec o n d I V C o h ort)
Assess me nts
Scree ni n g a
Tre at me nt Peri o d
F oll o w -u p 
Visit
C o m me nts
D a y - 2 8
t o D a y -4 or - 3
D a y -3 
t o - 2
D a y - 1
D a ys 1 t o 
2 b
D a y 3 b
( 6 ± 1 d a ys 
p ost -d ose)
S pir o metr y
X
X  
X  
X
Da y 1: Pr e -d ose a n d 1 h, 1. 5 h, 3 h, 6 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
P ulse O xi metr y
X
X  
X  
X  
X
Da y 1: Pr e -d ose a n d 3 0 mi n, 1 h, 1. 5 h, 3 h, 6 h a n d 
1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
Bl o o d press ure, p ulse a n d 
res pirat or y rate (s u pi ne) a n d 
b o d y te m perat ure
X
X  
X  
X  
X
Da y 1: Pr e -d ose a n d 3 0 mi n, 1 h, 1. 5 h, 2 h, 3 h, 4 h, 
6 h, 8 h, 1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
B o d y te m perat ure
X
1 2 -lea d d E C G
X  
X
See Ta ble 3. 2 - 9
1 2 -lea d safet y E C G
X
X  
X  
X  
X
1 2- lea d safet y E C G will be c ollecte d at t he start of 
eac h d E C G e xtracti o n wi n d o w w he n ti me-p oi nts 
c oi nci de, see Ta ble 3. 2 - 9
Tele metr y
X  
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose ( Da y 2)
Hei g ht, wei g ht a n d B MI
X
X
X
Hei g ht t o be meas ure d at scree ni n g o nl y
Cli nical la b orat or y 
e val uati o ns
X
X
X  
X  
X
Da y 2: 2 4 h p ost -d ose
Da y 3: 4 8 h p ost -d ose
All sa m ples will be c ollecte d after a 1 0 h fasti n g 
peri o d.
If t he assess me nt peri o d is e xte n de d, Da y 3 
assess me nts will be perf or me d o n t he da y v ol u nteers 
are disc har ge d




Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
fr o m Da y -3 if re q uire d. A d h oc nasal a n d/ or t h r oat -s wa b s peci me n is t o be c ollecte d f or t he i de ntificati o n of a s us pecte d res pirat or y i nfecti o n d uri n g a n y visit. Healt h y 
v ol u nteers w h o test p ositi ve f or ha vi n g acti ve C O VI D -1 9 i nfecti o n will be disc o nti n ue d fr o m t he st u d y a n d f oll o we d u p u ntil t he fi na l o utc o me of t he A E.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 7 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 4
Sc he d ule of Assess me nts P art 2 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
C o m me nts
D a y -2 8 
t o
D a y - 3
D a y - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a 
D a y 1 3 
t o 1 5
D a y 2 2 ± 1
( 1 0 ± 1 d a ys 
p ost -l ast 
d ose)
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n criteria
X
X  
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d c oti ni ne 
scree n 
X  
X
Ser ol o g y
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g h or m o ne 
testi n g 
X
P ost -me n o pa usal fe males o nl y (see 
Secti o n 5. 2. 3. 2 f or defi niti on)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
Disc har ge o n Da y 1 4
N o n -resi de ntial visit
X
X  
X
O nl y Da y 1 5 is n o n- resi de ntial
I n vesti g ati o n al Me dici n al
Pr o d uct A d mi nistr ati o n:
I n haler Ne b ulizer Trai ni n g
X
Ra n d o mizati o n
X
Da y 1
A Z D 0 4 4 9/ Place b o 
a d mi nistrati o n via Ne b ulizer a
X
b
X
b
First d ose o n Da y 1, sec o n d d ose o n 
Da y 3 ( 4 8 h o urs p ost -d ose), t he n o nce 
dail y  d osi n g fr o m Da y 4 t o Da y 1 2
S afet y a n d T oler a bilit y:
A d verse e ve nt q uesti o ni n g
O nl y 
S A Es
O nl y 
S A Es
O nl y 
S A Es
X
X
X  
X


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 4
Sc he d ule of Assess me nts P art 2 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
C o m me nts
D a y -2 8 
t o
D a y - 3
D a y - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a 
D a y 1 3 
t o 1 5
D a y 2 2 ± 1
( 1 0 ± 1 d a ys 
p ost -l ast 
d ose)
S pir o metr y 
X
X
c)
X
c)
X
c)
X
c)
X
c)
Da y -1: pre -d ose, 6 h, 1 2 h 
(c orres p o n di n g cl oc k ti me)
Da y 1, Da y 8 a n d Da y 1 2:
Pr e -d ose, 3 0 mi n, 1. 5 h, 3 h, 6 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3 t o 7 a n d Da y 9 t o 1 1: pre -d ose a n d 
3 0 mi n p ost -d ose
Da y 1 3: 2 4 h p os t-d ose, Da y 1 4: 4 7 h 
p ost -d ose, Da y 1 5: 7 1 h p ost -d ose, a n d 
Da y 2 2: 2 3 9 h p ost -d ose
P ulse o xi metr y
X
X  
X
X
X  
X
Da y  -1: pre -d ose, 3 h a n d 1 2 h p ost -d ose 
(c orres p o n di n g cl oc k ti me)
Da y  1 a n d Da y 3 t o Da y 1 2: Pre-d ose, 
1 h, 1. 5 h, 3 h, 6 h, 1 2 h -p ost -d ose
Da y  2: 2 4 h p ost -d ose
Da y  1 3: 2 4 h p ost -d ose
Da y  1 4: 4 7 h p ost-d ose, Da y 1 5: 7 1 h 
p ost -d ose, a n d Da y 2 2: 2 3 9 h p ost -d ose
Bl o o d press ure, p ulse a n d 
res pirat or y rate (s u pi ne) a n d 
b o d y te m perat ure
X
X  
X
X
X  
X
Da y 1 (first d ose) a n d Da y 1 2 (last 
d ose): Pre -d ose a n d 1 h, 2 h a n d 6 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da ys 3 t o 1 1: pre -d ose
Da y 1 3: 2 4 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 4
Sc he d ule of Assess me nts P art 2 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
C o m me nts
D a y -2 8 
t o
D a y - 3
D a y - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a 
D a y 1 3 
t o 1 5
D a y 2 2 ± 1
( 1 0 ± 1 d a ys 
p ost -l ast 
d ose)
1 2 -lea d d E C G
X
X
X
See Ta ble 3. 2 -1 0
1 2 -lea d safet y E C G
X
X  
X
X
X  
X
1 2- lea d safet y E C G will be c ollecte d at 
t he start of eac h d E C G e xtracti o n wi n d o w 
w h e n ti me-p oi nts c oi nci de see 
Ta ble 3. 2 - 1 0
Tele metr y
X  
X
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose 
( Da y 2)
Pr e -d ose ( Da y 1 2) t o 2 4 h p ost -d ose 
( Da y 1 3)
Hei g ht, wei g ht a n d B MI
X
X
Cli nical la b orat or y e val uati ons
X  
X
X
X
X  
X
Da y 2: 2 4 h p ost -d ose
Da y 3: pr e-d ose
Da y 1 3: 2 4 h p ost -d ose
All sa m ples will be c ollecte d after a 1 0 h 
fasti n g peri o d
Pre g na nc y testi n g
X
(ser u m)
X 
( uri ne)
X (ser u m)
Fe males o nl y
P h y sical e xa mi nati o n
X
X
X
( brief)
X
( brief)
X
( brief)
X
Da y 1: pr e-d ose
Da y 2: 2 4 h after t he first d ose
Da y 6: pre -d ose
Da y 1 0: pre -d ose
Da y 1 3: 2 4 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 4
Sc he d ule of Assess me nts P art 2 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
F oll o w -u p
C o m me nts
D a y -2 8 
t o
D a y - 3
D a y - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a 
D a y 1 3 
t o 1 5
D a y 2 2 ± 1
( 1 0 ± 1 d a ys 
p ost -l ast 
d ose)
P h ar m ac o ki netics:
P har mac o ki netic bl o o d 
sa m pli n g
X
c)
X
c)
X
c)
X
c)
Da y 1 a n d 1 2: pre -d ose, as s o o n as 
p ossi ble after e n d of i n halati o n, 1 5 mi n 
after e n d of i n halati o n, a n d 1 h, 1. 5 h, 2 h, 
3 h, 4 h, 6 h, 8 h, 1 0 h d), a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h, 3 0 h, a n d 3 6 h p ost -d ose.
Da y 3 – Da y 1 1: pr e-d ose
Da y 1 3: 2 4 h, 3 0 h, a n d 3 6 h p ost -last 
d ose
Da y 1 4: 4 8 h p ost -last d ose
Da y 1 5: 7 2 h p ost -last d ose
Da y 2 2: 2 4 0 h p ost -last d ose






Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 5
Sc he d ule of Assess me nts P art 2 b i n he alt h y v ol u nteers
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a)
D a y 1 3 
t o 1 6
D a y 1 7 t o 2 7
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n criteria
X
X  
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d c oti ni ne 
scree n 
X  
X
Ser ol o g y
X
C O VI D -1 9 ser ol o g y testi n g 
d)
X
X
Da y 2 7
C O VI D -1 9 P C R testi n g d)
X  
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g 
h or m o ne testi n g 
X
P ost -me n o pa usal fe males o nl y (see 
Secti o n 5. 2. 3. 2 f or defi niti on)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
Disc har ge o n Da y 2 7
N o n -resi de ntial visit
X
I n vesti g ati o n al Me dici n al 
Pr o d uct A d mi nistr ati o n:
I n haler Ne b ulizer Trai ni n g
X
Ra n d o mizati o n
X
Da y 1
A Z D 0 4 4 9/ Place b o 
a d mi nistrati o n via 
Ne b ulizer
a)
X
b)
X
b)
First d ose o n Da y 1, sec o n d d ose o n 
Da y 3 ( 4 8 h o urs p ost -d ose), t he n 
o nce dail y d osi n g fr o m Da y 4 t o 
Da y 1 2


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 5
Sc he d ule of Assess me nts P art 2 b i n he alt h y v ol u nteers
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a)
D a y 1 3 
t o 1 6
D a y 1 7 t o 2 7
S afet y a n d T oler a bilit y:
A d verse e ve nt q uesti o ni n g
O nl y S A Es
O nl y 
S A Es
O nl y 
S A Es
X
X
X
X
S pir o metr y 
X
X
c)
X
c)
X
c)
X
c)
X
c)
Da y -1: p r e-d ose, 6 h, 1 2 h 
(c orres p o n di n g cl oc k ti me)
Da y 1, Da y 8 a n d Da y 1 2:
Pr e -d ose 3 0 mi n, 1. 5 h, 3 h, 6 h a n d
1 2 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3 t o 7 a n d Da y 9 t o 1 1: pre -d ose 
a n d 3 0 mi n p ost -d ose
Da y 1 3: 2 4 h p ost -d ose, Da y 1 4: 4 7 h 
p ost -d ose, Da y 1 5: 7 1 h p ost -d ose, 
Da y  1 6: 9 5 h p ost -d ose, Da y 1 7: 
1 2 0 h p ost -d ose, Da y 2 0: 1 9 2 h p ost -
d ose, Da y 2 3: 2 6 4 h p ost -d ose, 
Da y 2 6: 3 3 6 h p ost -d ose, a n d Da y 2 7: 
3 6 0 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 5
Sc he d ule of Assess me nts P art 2 b i n he alt h y v ol u nteers
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a)
D a y 1 3 
t o 1 6
D a y 1 7 t o 2 7
P ulse o xi metr y
X
X  
X
X
X
X
Da y 1 a n d Da y 3 t o Da y 1 2: Pr e-
d ose, 1 h, 1. 5 h, 3 h, 6 h, 1 2 h - p ost -
d ose
Da y 2: 2 4 h p ost -d ose
Da y 1 3: 2 4 h p ost -d ose, Da y 1 4: 4 8 h 
p ost -d ose , Da y 1 5: 7 2 h p ost -d ose , 
Da y 1 6: 9 6 h p ost -d ose , Da y 1 7 : 
1 2 0 h p ost -d ose, Da y 1 8: 1 4 4 h p ost -
d ose, Da y 1 9: 1 6 8 h p ost -d ose, 
Da y 2 0: 1 9 2 h p ost -d ose, Da y 2 1: 
2 1 6 h p ost -d ose, Da y 2 2: 2 4 0 h p ost -
d ose, Da y 2 3: 2 6 4 h p ost -d ose, 
Da y 2 4: 2 8 8 h p ost -d ose, Da y 2 5: 
3 1 2 h p ost -d ose, Da y 2 6: 3 3 6 h p ost -
d ose, a n d Da y 2 7: 3 6 0 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 5
Sc he d ule of Assess me nts P art 2 b i n he alt h y v ol u nteers
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a)
D a y 1 3 
t o 1 6
D a y 1 7 t o 2 7
Bl o o d press ure, p ulse a n d 
res pirat or y rate (s u pi ne) 
a n d b o d y te m perat ure
X
X  
X
X
X
X
Da y 1 (first d ose) a n d Da y 1 2 (last 
d ose): Pre -d ose a n d 1 h, 2 h a n d 6 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da ys 3 t o 1 1: Pre -d ose
Da y 1 3: 2 4 h p ost -d ose, Da y 1 4: 4 8 h 
p ost -d ose, Da y 1 5: 7 2 h p ost -d ose, 
Da y 1 6: 9 6 h p ost -d ose, Da y 1 7:
1 2 0 h p ost -d ose, Da y 1 8: 1 4 4 h p ost -
d ose, Da y 1 9: 1 6 8 h p ost -d ose, 
Da y 2 0: 1 9 2 h p ost -d ose, Da y 2 1: 
2 1 6 h p ost -d ose, Da y 2 2: 2 4 0 h p ost -
d ose, Da y 2 3: 2 6 4 h p ost -d ose, 
Da y 2 4: 2 8 8 h p ost -d ose, Da y 2 5: 
3 1 2 h p ost -d ose, Da y 2 6: 3 3 6 h p ost -
d ose, a n d Da y 2 7: 3 6 0 h p ost -d ose
B o d y te m perat ure
X
1 2 -lea d d E C G
X
X
X
See Ta ble 3. 2 -1 0
1 2 -lea d safet y E C G
X
X  
X
X
X
X
Da y 2 7
1 2 -lea d safet y E C G will be c ollecte d 
at t he start of eac h d E C G e xtracti o n 
wi n d o w w he n ti me -p oi nts c oi nci de 
see Ta ble 3. 2 -1 0


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 8 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 5
Sc he d ule of Assess me nts P art 2 b i n he alt h y v ol u nteers
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 (st art of 
o nce d ail y 
d osi n g) a t o 
D a y 1 2 (l ast 
d osi n g d a y) a)
D a y 1 3 
t o 1 6
D a y 1 7 t o 2 7
Tele metr y
X  
X
X
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose 
( Da y 2)
Pr e -d ose ( Da y 1 2) t o 2 4 h p ost -d ose 
( Da y 1 3)
Hei g ht, wei g ht a n d B MI
X
X
X
Da y 2 7
Hei g ht t o be meas ure d at scree ni n g 
o nl y
Cli nical la b orat or y 
e val uati o ns
X  
X
X
X
X
X
Da y 2: 2 4 h p ost -d ose
Da y 3: pre -d ose
Da y 1 3: 2 4 h p ost -d ose
Da y 2 7: 3 6 0 h p ost -last d ose
All sa m ples will be c ollecte d after a 
1 0 h fasti n g peri o d
Pre g na nc y testi n g
X
(ser u m)
X 
( uri ne)
X
(ser u m)
Da y 2 7
Fe males o nl y
P h y sical e xa mi nati o n
X
X
X
( brief)
X
( brief)
X
( brief)
X
( brief)
Da y 1: pre -d ose
Da y 2: 2 4 h after t he first d ose
Da y 6: pre -d ose
Da y 1 0: pre -d ose
Da y 1 4: 4 8 h p ost -d ose, Da y 1 7: 
1 2 0 h p ost -d ose, Da y 2 0: 1 9 2 h p ost -
d ose, Da y 2 3: 2 6 4 h p ost -d ose, 
Da y 2 6: 3 3 6 h p ost -d ose, a n d Da y 2 7: 
3 6 0 h p ost -d ose (f ull e xa mi nati o n)






Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n 
criteria
X
X  
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d c oti ni ne 
scree n 
X
X
Ser ol o g y
X
C O VI D -1 9 ser ol o g y 
testi n g d)
X
X
Da y 2 7
C O VI D -1 9 P C R testi n g d)
X  
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g 
h or m o ne testi n g
X
P ost -me n o pa usal fe males o nl y (see 
Secti o n 5. 2. 3. 2 f or defi niti on)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
Disc har ge o n Da y 2 7
N o n -resi de ntial visit
X
X
Da y 1 7 t o Da y 2 7 (If per mitte d b y l ocal 
rele va nt re g ulat or y a ut h orities a n d 
c o nsi dere d feasi ble a n d safe)


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
I n vesti g ati o n al 
Me dici n al Pr o d uct 
D PI Trai ni n g
X
Ra n d o mizati o n
X
Da y  1
A Z D 0 4 4 9/ Place b o 
a d mi nistrati o n via D PI a)
X
b)
X
b)
First d ose o n Da y 1, sec o n d d ose o n Da y 
3 ( 4 8 h o urs p ost -d ose), t he n o nce dail y 
d osi n g f r om Da y 4 t o Da y 1 2
S afet y a n d T oler a bilit y:
A d verse e ve nt q uesti o ni n g
O nl y 
S A Es
O nl y 
S A Es
O nl y 
S A Es
O nl y 
S A Es
X  
X  
X
X
S pir o metr y
X
X
c)
X
c)
X c)
X
c)
X
c)
Da y -1: pre -d ose, 6 h, 1 2 h 
(c orres p o n di n g cl oc k ti me)
Da y 1, Da y 8 a n d Da y 1 2:
Pr e -d ose, 3 0 mi n, 1. 5 h, 3 h, 6 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3 t o 7 a n d Da y 9 t o 1 1: pre -d ose a n d 
3 0 mi n p ost -d ose
Da y 1 3: 2 4 h p ost -d ose, Da y 1 4: 4 7 h 
p ost -d ose, Da y 1 5: 7 1 h p ost -d ose, Da y  
1 6: 9 5 h p ost -d ose, Da y  1 7: 1 2 0 h p ost -
d ose, Da y 2 0: 1 9 2 h p ost -d ose, Da y 2 3: 
2 6 4 h p ost -d ose, Da y 2 6: 3 3 6 h p ost -d ose, 
a n d Da y 2 7: 3 6 0 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
P ulse o xi metr y
X
X  
X  
X  
X
X
Da y  -1: pre -d ose, 3 h a n d 1 2 h p ost -d ose 
(c orres p o n di n g cl oc k ti me) 
Da y  1 a n d Da y 3 t o Da y 1 2: Pre-d ose, 1 
h, 1. 5 h, 3 h, 6 h, 1 2 h -p ost -d ose
Da y  2: 2 4 h p ost-d ose
Da ys 1 3 : 2 4 h p ost -d ose, Da y 1 4: 4 8 h 
p ost -d ose, Da y 1 5: 7 2 h p ost -d ose, 
Da y 1 6: 9 6 h p ost -d ose, Da y 1 7: 1 2 0 h 
p ost -d ose, Da y 1 8: 1 4 4 h p ost -d ose, 
Da y 1 9: 1 6 8 h p ost -d ose, Da y 2 0: 1 9 2 h 
p ost -d ose, Da y 2 1: 2 1 6 h p ost -d ose, 
Da y 2 2: 2 4 0 h p ost -d ose, Da y 2 3: 2 6 4 h 
p ost -d ose, Da y 2 4: 2 8 8 h p ost -d ose, 
Da y 2 5: 3 1 2 h p ost - d ose, Da y 2 6: 3 3 6 h 
p ost -d ose, a n d Da y 2 7: 3 6 0 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
Bl o o d press ure, p ulse a n d 
res pirat or y rate 
(s u pi ne)a n d b o d y 
te m perat ure
X
X  
X  
X  
X
X
Da y 1 (first d ose) a n d Da y 1 2 (last d ose): 
Pr e -d ose a n d 1 h, 2 h a n d 6 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da ys 3 t o 1 1: Pre-d ose
Da y 1 3 : 2 4 h p ost -d ose, Da y 1 4: 4 8 h 
p ost -d ose, Da y 1 5: 7 2 h p ost -d ose, 
Da y 1 6: 9 6 h p ost -d ose, Da y 1 7: 1 2 0 h 
p ost -d ose, Da y 1 8: 1 4 4 h p ost -d ose, 
Da y 1 9: 1 6 8 h p ost -d ose, Da y 2 0: 1 9 2 h 
p ost -d ose, Da y 2 1: 2 1 6 h p ost -d ose, 
Da y 2 2: 2 4 0 h p ost -d ose, Da y 2 3: 2 6 4 h 
p ost -d ose, Da y 2 4: 2 8 8 h p ost -d ose, 
Da y 2 5: 3 1 2 h p ost -d ose, Da y 2 6: 3 3 6 h 
p ost -d ose, a n d Da y 2 7: 3 6 0 h p ost -d ose
B o d y te m perat ure
X  
X
1 2 -lea d d E C G
X  
X  
X
See Ta ble 3. 2 - 1 0
1 2 -lea d safet y E C G
X
X  
X  
X  
X
X
Da y 2 7
1 2- lea d safet y E C G will be c ollecte d at 
t he start of eac h d E C G e xtracti o n wi n d o w 
w h e n ti me-p oi nts c oi nci de, see 
Ta ble 3. 2 - 1 0


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
Tele metr y
X  
X  
X  
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose 
( Da y 2)
Pr e -d ose ( Da y 1 2) t o 2 4 h p ost -d ose 
( Da y 1 3)
Hei g ht, wei g ht a n d B MI
X
X
X
Da y 2 7
Hei g ht t o be meas ure d at scree ni n g o nl y
Cli nical la b orat or y 
e val uati o ns
X  
X
X  
X  
X
X
Da y 2: 2 4 h p ost -d ose
Da y 3: pre -d ose
Da y 1 3: 2 4 h p ost -d ose
Da y 2 7: 3 6 0 h p ost -last d ose
All sa m ples will be c ollecte d after a 1 0 h 
fasti n g peri o d
Pre g na nc y testi n g
X
(ser u m)
X 
( uri ne)
X
(ser u m)
Da y 2 7
Fe males o nl y
P h y sical e xa mi nati o n
X
X
X 
( brief)
X
( brief)
X 
( brief)
X
( brief)
Da y 1: pre -d ose
Da y 2: 2 4 h after t he first d ose
Da y 6: pre -d ose
Da y 1 0: pre -d ose
Da y 1 4: 4 8 h p ost -d ose, Da y 1 7: 1 2 0 h 
p ost -d ose, Da y 2 0: 1 9 2 h p ost -d ose, 
Da y 2 3: 2 6 4 h p ost -d ose, Da y 2 6: 3 3 6 h 
p ost -d ose, a n d Da y 2 7: 3 6 0 h p ost -d ose
(f ull e xa mi nati o n)


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
P h ar m ac o ki netics:
P har mac o ki netic bl o o d 
sa m pli n g
X
c)
X c)
X c)
X c)
Da ys 1 a n d 1 2: pre -d ose, as s o o n as 
p ossi ble after e n d of i n halati o n, 1 5 mi n 
after e n d of i n halati o n, a n d 1 h, 1 . 5 h, 2 h, 
3 h, 4 h, 6 h, 8 h, 1 0 h, a n d 1 2 h p ost -d ose
Da y  2: 2 4 h, 3 0 h, a n d 3 6 h p ost -d ose.
Da y  3 t o Da y 1 1: pre-d ose
Da y  1 3: 2 4 h, 3 0 h, a n d 3 6 h p ost-last 
d ose
Da y 1 4: 4 8 h, 5 4 h, a n d 6 0 h p ost -last 
d ose
Da y 1 5: 7 2 h, 7 8 h, a n d 8 4 h p ost -last 
d ose
Da y 1 6: 9 6 h, 1 0 2 h, a n d 1 0 8 h p ost -last 
d ose
Da y 1 7: 1 2 0 h p ost -last d ose, Da y 2 0: 
1 9 2 h p ost -last d ose, Da y 2 3: 2 6 4 h p ost -
last d ose, Da y 2 6: 3 3 6 h p ost -last d ose, 
a n d Da y 2 7: 3 6 0 h p ost -last d ose
P h ar m ac o d y n a mics:


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 9 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 6
Sc he d ule of Assess me nts P art 3 a i n p atie nts wit h mil d ast h m a
Assess me nts
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
C o m me nts
D a y -2 8 
t o D a y -4 
D a y -3 
D a y -
2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
Fracti o nal e x hale d nitric 
o xi de
X
X  
X  
X  
X
X
Si n gle assess me nt at Scree ni n g Visit
Da y  -1: c orres p o n di n g cl oc k ti mes t o pre -
d ose, 3 0 mi n a n d 2 h, 6 h, a n d 1 2 h 
p ost -d ose
Da ys 1, 2, 3, 4, 6, 8, 1 0, a n d 1 2: Pre -d ose 
(c orres p o n di n g cl oc k ti me), 3 0 mi n a n d 2 
h, 6 h, a n d 1 2 h p ost -d ose
Da ys 5, 7, 9, a n d 1 1: Pre -d ose 
(c orres p o n di n g cl oc k ti me) a n d 2 h 
p ost -d ose
Da y 1 3: 2 3 h, 2 4. 5 h, 2 6 h, 3 0 h, a n d 3 6 h 
p ost -last d ose
Da y 1 4: 4 7 h, 4 8. 5 h, 5 0 h, 5 4 h, a n d 6 0 h 
p ost -last d ose
Da y 1 5: 7 1 h, 7 2. 5 h, 7 4 h, 7 8 h, a n d 8 4 h 
p ost -last d ose
Da y 1 6: 9 5 h, 9 6. 5 h, 9 8 h, 1 0 2 h, a n d 
1 0 8 h p ost -last d ose
Da y 1 7, 2 0, 2 3, a n d 2 6: 5 meas ure me nts 
of Fe N O ( pre -d ose, 3 0 mi n, 2 , 6 h, a n d 
1 2 h p ost -h y p ot hetical d ose) f
Da y 2 7: 2 meas ure me nts of Fe N O ( pre -
d ose a n d 2 h p ost -h y p ot hetical d ose)
E x pl or at or y A n al yses:




Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
a)
T he ti me -p oi nts f or all pr oce d ures are relati ve t o t he start of t he i n halati o n.
b)
Si n gle d ose o n Da y 1 a n d o nce dail y d osi n g o n Da y 3 – Da y 1 2.
c)
Ti me- p oi nts f or assess me nts a n d sa m ple c ollecti o n ma y c ha n ge base d o n e mer gi n g data . T he Da y 3 pre -d ose bl o o d sa m pli n g c orres p o n ds t o 4 8 h p ost -Da y 1 d ose.
d)
A sa m ple f or C O VI D -1 9 ser ol o g y testi n g will be c ollecte d at scree ni n g a n d at t he disc har ge visit ( or last n o n- resi de ntial visit). A s wa b sa m ple f or P C R will be c ollecte d 
at scree ni n g o nl y  f or patie nts w h o are I g M ne gati ve a n d I g G p ositi ve. P C R will be perf or me d f or all patie nts at a d missi o n t o t he Cli nical U nit; f urt her sa m ples f or P C R 
a n d/ or ser ol o g y testi n g will be c ollecte d at t he discreti o n of t he I n vesti gat or. In t he e ve nt of re d uce d C O VI D -1 9 sa m ple a nal y sis ca pacit y sites ma y i nitiate resi de nc y 
visits fr o m Da y  -3 if re q uire d. A d h oc nasal a n d/ or t hr oat-s wa b s peci me n is t o be c ollecte d f or t he i de ntificati o n of a s us pecte d res pirat or y i nfecti o n d uri n g a n y visit. 
Patie nts w h o test p ositi ve f or ha vi n g acti ve C O VI D -1 9 i nfecti o n wil l be disc o nti n ue d fr o m t he st u d y a n d f oll o we d u p u ntil t he fi nal o utc o me of t he A E.
e)
Patie nts will re mai n i n h o use f or t he d urati o n of t he e xte n de d safet y m o nit ori n g peri o d a n d will be disc har ge d fr o m t he Cli nical U nit o n Da y 2 7, 1 5 da y s after t he last 
d ose a d mi nistrati o n. If per mitte d b y l ocal rele va nt re g ulat or y a ut h orities a n d c o nsi dere d feasi ble a n d safe t o d o s o, t he e xte n de d safet y m o nit o ri n g peri o d ma y be 
c o n d ucte d as n o n -resi de ntial visits.
f)
If it is per mitte d b y l ocal rele va nt re g ulat or y a ut h orities t hat t he e xte n de d safet y m o nit ori n g peri o d ma y be c o n d ucte d as n o n-resi de ntial visits, Fe N O assess me nts will 
be perf or me d at t he f oll o wi n g ti me p oi nts; Da y  1 7: 1 2 0 h p ost-last d ose, Da y 2 0: 1 9 2 h p ost-last d ose, Da y 2 3: 2 6 4 h p ost-last d ose, Da y 2 6: 3 3 6 h post -last d ose, a n d 
Da y  2 7: 3 6 0 h p ost-last d ose.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 7
Sc he d ule of Assess me nts P art 3 b i n he alt h y v ol u nteers
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
I nf or me d c o nse nt
X
I ncl u des o pti o nal ge netic c o nse nt
I ncl usi o n/e xcl usi o n 
criteria
X
X  
X
De m o gra p hic data
X
Me dical hist or y
X
Dr u g, alc o h ol a n d 
c oti ni ne scree n 
X
X
Ser ol o g y
X
C O VI D -1 9 ser ol o g y 
testi n g d)
X
X
Da y 2 7
C O VI D -1 9 P C R testi n g d)
X  
X
Q ua nti F E R O N ® T B
X
F ollicle -sti m ulati n g 
h or m o ne testi n g
X
P ost -me n o pa usal fe males o nl y (see 
Secti o n 5. 2. 3. 2 f or defi niti on)
St u d y Resi de nc y:
A d missi o n
X
Disc har ge
X
Disc har ge o n Da y 2 7
N o n -resi de ntial visit
X
X
Da y 1 7 t o Da y 2 7 (If per mitte d b y l ocal 
rele va nt re g ulat or y a ut h orities a n d 
c o nsi dere d feasi ble a n d safe)
I n vesti g ati o n al 
Me dici n al Pr o d uct 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 7
Sc he d ule of Assess me nts P art 3 b i n he alt h y v ol u nteers
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
D PI Trai ni n g
X
Ra n d o mizati o n
X
A Z D 0 4 4 9/ Place b o 
a d mi nistrati o n via D PI a)
X
b)
X
b)
First d ose o n Da y 1, sec o n d d ose o n Da y 3 
( 4 8 h o urs p ost -d ose), t he n o nce dail y d osi n g 
fr o m Da y 4 t o Da y 1 2
S afet y a n d T oler a bilit y:
A d verse e ve nt 
q uesti o ni n g
O nl y 
S A Es
O nl y 
S A Es
O nl y 
S A Es
X  
X  
X
X
S pir o metr y
X
X
c)
X
c)
X
c)
X
c)
X
c)
Da y -1: pre -d ose, 6 h, 1 2 h (c orres p o n di n g 
cl oc k ti me)
Da y 1, Da y 8 a n d Da y 1 2:
pr e -d ose, 3 0 mi n, 1. 5 h, 3 h, 6 h a n d 1 2 h 
p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da y 3 t o 7 a n d Da y 9 t o 1 1: pre -d ose a n d 
3 0 mi n p ost -d ose
Da y 1 3: 2 4 h p ost -d ose, Da y 1 4: 4 7 h p ost -
d ose, Da y 1 5: 7 1 h p ost -d ose, Da y  1 6: 9 5 h 
p ost -d ose, Da y  1 7: 1 2 0 h p ost -d ose, Da y 2 0: 
1 9 2 h p ost -d ose, Da y 2 3: 2 6 4 h p ost -d ose, 
Da y 2 6: 3 3 6 h p ost -d ose, a n d Da y 2 7: 3 6 0 h 
p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 7
Sc he d ule of Assess me nts P art 3 b i n he alt h y v ol u nteers
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
P ulse o xi metr y
X
X  
X  
X  
X
X
Da y  -1: pre -d ose, 3 h a n d 1 2 h p ost -d ose 
(c orres p o n di n g cl oc k ti me) 
Da y  1 a n d Da y 3 t o Da y 1 2: Pre-d ose, 1 h, 
1. 5 h, 3 h, 6 h, 1 2 h -p ost -d ose
Da y  2: 2 4 h p ost-d ose
Da ys 1 3 : 2 4 h p ost -d ose, Da y 1 4: 4 8 h p ost -
d ose, Da y 1 5: 7 2 h p ost -d ose, Da y 1 6: 9 6 h 
p ost -d ose, Da y 1 7: 1 2 0 h p ost -d ose, Da y 1 8: 
1 4 4 h p ost -d ose, Da y 1 9: 1 6 8 h p ost -d ose, 
Da y 2 0: 1 9 2 h p ost -d ose, Da y 2 1: 2 1 6 h p ost -
d ose, Da y 2 2: 2 4 0 h p ost -d ose, Da y 2 3: 2 6 4 h 
p ost -d ose, Da y 2 4: 2 8 8 h p ost -d ose, Da y 2 5: 
3 1 2 h p ost -d ose, Da y 2 6: 3 3 6 h p ost -d ose, 
a n d Da y 2 7: 3 6 0 h p ost -d ose


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 7
Sc he d ule of Assess me nts P art 3 b i n he alt h y v ol u nteers
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
Bl o o d press ure, p ulse 
a n d res pirat or y rate 
(s u pi ne)a n d b o d y 
te m perat ure
X
X  
X  
X  
X
X
Da y 1 (first d ose) a n d Da y 1 2 (last d ose): 
pr e -d ose a n d 1 h, 2 h a n d 6 h p ost -d ose
Da y 2: 2 4 h p ost -d ose
Da ys 3 t o 1 1: pre -Pr e-d ose
Da y 1 3 : 2 4 h p ost -d ose, Da y 1 4: 4 8 h p ost -
d ose, Da y 1 5: 7 2 h p ost -d ose, Da y 1 6: 9 6 h 
p ost -d ose, Da y 1 7: 1 2 0 h p ost -d ose, Da y 1 8: 
1 4 4 h p ost -d ose, Da y 1 9: 1 6 8 h p ost -d ose, 
Da y 2 0: 1 9 2 h p ost -d ose, Da y 2 1: 2 1 6 h p ost -
d ose, Da y 2 2: 2 4 0 h p ost -d ose, Da y 2 3: 2 6 4 h 
p ost -d ose, Da y 2 4: 2 8 8 h p ost -d ose, Da y 2 5: 
3 1 2 h p ost -d ose, Da y 2 6: 3 3 6 h p ost -d ose, 
a n d Da y 2 7: 3 6 0 h p ost -d ose
B o d y te m perat ure
X  
X
1 2 -lea d d E C G
X  
X  
X
See Ta ble 3. 2 - 1 0
1 2 -lea d safet y E C G
X
X  
X  
X  
X
X
Da y 2 7
1 2- lea d safet y E C G will be c ollecte d at t he 
start of eac h d E C G e xtracti o n wi n d o w w he n 
ti m e-p oi nts c oi nci de, see Ta ble 3. 2 - 1 0
Tele metr y
X  
X  
X  
X
Da y -1: at least 4 h
Pr e -d ose ( Da y 1) t o 2 4 h p ost -d ose ( Da y 2)
Pr e -d ose ( Da y 1 2) t o 2 4 h p ost -d ose ( Da y 1 3)
Hei g ht, wei g ht a n d B MI
X
X
X
Da y 2 7
Hei g ht t o be meas ure d at scree ni n g o nl y


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 7
Sc he d ule of Assess me nts P art 3 b i n he alt h y v ol u nteers
Scree ni n g
Tre at me nt Peri o d
S afet y M o nit ori n g 
P eri o d e
D a y -2 8 t o 
D a y -4 
or - 3
D a y -3 
t o - 2
D a y - 1
D a y 1 
a n d 
D a y 2
D a y 3 
(sec o n d 
d osi n g 
d a y) t o 
D a y 1 2 
(l ast 
d osi n g 
d a y)
D a y 1 3 
t o 1 6
D a y 1 7 t o D a y 2 7
Cli nical la b orat or y 
e val uati o ns
X  
X
X  
X  
X
X
Da y 2: 2 4 h p ost -d ose
Da y 3: pre -d ose
Da y 1 3: 2 4 h p ost -d ose
Da y 2 7: 3 6 0 h p ost -last d ose
All sa m ples will be c ollecte d after a 1 0 h 
fasti n g peri o d
Pre g na nc y testi n g
X
(ser u m)
X 
( uri ne)
X
(ser u m)
Da y 2 7
Fe males o nl y
P h y sical e xa mi nati o n
X
X
X 
( brief)
X ( brief)  
X ( brief)
X
( brief)
Da y 1: pre -d ose
Da y 2: 2 4 h after t he first d ose
Da y 6: pre -d ose
Da y 1 0: pre -d ose
Da y 1 4: 4 8 h p ost -d ose, Da y 1 7: 1 2 0 h p ost -
d ose, D a y 2 0: 1 9 2 h p ost -d ose, Da y 2 3: 2 6 4 h 
p ost -d ose, Da y 2 6: 3 3 6 h p ost -d ose, a n d 
Da y 2 7: 3 6 0 h p ost -d ose (f ull e xa mi nati o n)






Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 8
Ti me Sc he d ule f or Di git al Electr oc ar di o gr a m P art 1 a ( S A D)
St u d y D a ys
E C G
N u m ber
Ti me -p oi nt
St art Ti me
h o ur: mi n a) , b)
D ose
St o p Ti me
d E C G c o nt. c), d) , e)
Ot her
f)
1
-0 1: 3 0
-0 1: 0 0
A p pl y t he electr o des d)
1
-0 0: 4 0
-0 0: 3 0
Rest i n be d
1
1
Pr e -d ose
-0 0: 3 0
Pr e -d ose
-0 0: 2 0
1 0 mi n utes
1
-0 0: 2 0
-0 0: 0 5
T oilet use rec o m me n de d
1
0 0: 0 0
A d mi nistrati o n of A Z D 0 4 4 9/ place b o
1
2 
1 h
0 0: 5 5
0 1: 0 0
5 mi n utes
e)
1 
3 g)
2 h
0 1: 5 5
0 2: 0 0
5 mi n utes e)
1
4 
3 h
0 2: 5 5
0 3: 0 0
5 mi n utes
e)
1
5 
4 h
0 3: 5 5
0 4: 0 0
5 mi n utes
e)
1 
6 h)
5 h
0 4: 5 5
0 5: 0 0
5 mi n utes e)
1
7 
6 h
0 5: 5 5
0 6: 0 0
5 mi n utes
e)
1
8 
8 h
0 7: 5 5
0 8: 0 0
5 mi n utes
e)
1 
9 h)
1 0 h
0 9: 5 5
1 0: 0 0
5 mi n utes
e)
1 
1 0 
1 2 h
1 1: 5 5
1 2: 0 0
5 mi n utes
e)
2 
1 1 
2 4 h
2 3: 5 5
2 4: 0 0
5 mi n utes
e)
2 
1 2 
3 6 h
3 5: 5 5
3 6: 0 0
5 mi n utes
e)
3 
1 3 
4 8 h
4 7: 5 5
4 8: 0 0
5 mi n utes
e)
3 
1 4 h)
6 0 h
5 9: 5 5
6 0: 0 0
5 mi n utes
e)
E C G: Electr ocar di o gra m; d E C G: Di gital E C G; P K: P har mac o ki netics
a)
Ti me- p oi nts f or d E C G ma y be a dj uste d acc or di n g t o e mer gi n g P K data.
b)
Ti mes are a p pr o xi mate as d E C G a n d safet y E C Gs nee d t o be c o m plete d bef ore bl o o d sa m pli n g.
c)
T he healt h y  v ol u nteer m ust be i n t he sa me s u pi ne b o d y p ositi o n ( ma x. 3 0 de grees fle xi o n i n t he hi p) at eac h ti me -p oi nt a n d at all visits. Healt h y v ol u nteer ’s feet s h o ul d 
n ot c o ntact t he f o ot b oar d of t he be d.
d)
S ki n m ust be clea ne d, a n d electr o de p ositi o ns mar ke d wit h a n i n deli ble pe n. Electr o des s h o ul d be a p plie d at least 3 0 mi n utes bef ore first rec or di n g.
e)
Healt h y  v ol u nteer m ust rest i n be d f or at least 1 0 mi n utes bef ore eac h E C G ti me -p oi nt.
f)
Safet y E C G will be c ollecte d at t he start of eac h d E C G e xtracti o n wi n d o w.
g)
F or co h orts 1 t o 4 o nl y.
h)
F or co h orts 1 t o 3 o nl y.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 0 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 9
Ti me Sc he d ule f or Di git al Electr oc ar di o gr a m P art 1 b (I V C o h ort s)
St u d y D a ys
E C G
N u m ber
Ti me -p oi nt
St art Ti me
h o ur: mi n a) b) , c)
D ose
St o p Ti me
d E C G c o nt. c), d) e)
Ot her
f)
1
-0 1: 3 0
-0 1: 0 0
A p pl y t he electr o des d)
1
-0 0: 4 0
-0 0: 3 0
Rest i n be d
1
1
Pr e -d ose
-0 0: 3 0
Pr e -d ose
-0 0: 2 0
1 0 mi n utes
1
-0 0: 2 0
-0 0: 0 5
T oilet use rec o m me n de d
1
0 0: 0 0
I nf usi o n start
1
2 
5 mi n
0 0: 0 5
0 0: 1 0
5 mi n utes
e)
After i nf usi o n start
1
3 
3 0 mi n
0 0: 2 5
0 0: 3 0
5 mi n utes
e)
1
4 
4 8 mi n
h)
0 0: 4 3
0 0: 4 8
5 mi n utes
e)
1
5 
1 h g)
0 0: 5 5
0 1: 0 0
5 mi n utes
e)
1
6
1. 5 h
0 1: 2 5
0 1: 3 0
5 mi n utes
e)
1
7
2 h
0 1: 5 5
0 2: 0 0
5 mi n utes
e)
1
8
3 h
0 2: 5 5
0 3: 0 0
5 mi n utes
e)
1
9
4 h
0 3: 5 5
0 4: 0 0
5 mi n utes
e)
1
1 0 
5 h
0 4: 5 5
0 5: 0 0
5 mi n utes
e)
1
1 1 
6 h
0 5: 5 5
0 6: 0 0
5 mi n utes
e)
1
1 2 
8 h
0 7: 5 5
0 8: 0 0
5 mi n utes
e)
1
1 3 
1 0 h
0 9: 5 5
1 0: 0 0
5 mi n utes
e)
1
1 4 
1 2 h
1 1: 5 5
1 2: 0 0
5 mi n utes
e)
2
1 5 
2 4 h
2 3: 5 5
2 4: 0 0
5 mi n utes
e)
2
1 6 
3 6 h
3 5: 5 5
3 6: 0 0
5 mi n utes
e)
3
1 7 
4 8 h
4 7: 5 5
4 8: 0 0
5 mi n utes
e)
E C G: Electr ocar di o gra m; d E C G: Di gital E C G; P K: P har mac o ki netics
a)
Ti me- p oi nts f or d E C G ma y be a dj uste d acc or di n g t o e mer gi n g P K data.
b)
Ti mes are a p pr o xi mate as d E C G a n d safet y E C Gs nee d t o be c o m plete d bef ore bl o o d sa m pli n g.
c)
T he healt h y v ol u nteer m ust be i n t he sa me s u pi ne b o d y p ositi o n ( ma x. 3 0 de grees fle xi o n i n t he hi p) at eac h ti me p oi nt a n d at all visits. Healt h y v ol u nteer’s feet s h o ul d 
n ot c o n tact t he f o ot b oar d of t he be d.
d)
S ki n m ust be clea ne d, a n d electr o de p ositi o ns mar ke d wit h a n i n deli ble pe n. Electr o des s h o ul d be a p plie d at least 3 0 mi n utes bef ore first rec or di n g.
e)
Healt h y  v ol u nteer m ust rest i n be d f or at least 1 0 mi n utes bef ore eac h E C G t i me p oi nt.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
f)
Safet y E C G will be c ollecte d at t he start of eac h d E C G e xtracti o n wi n d o w.
g)
F or c o h ort 1 o nl y.
h)
F or c o h ort 2 o nl y.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 2 - 1 0 Ti me Sc he d ule f or Di git al Electr oc ar di o gr a m P art 2 a/ b , P art 3 a/ b
St u d y
D a ys
E C G
N u m ber
Ti me -p oi nt
St art Ti me
h o ur: mi n a) ,b)
D ose
St o p Ti me
d E C G c o nt.
c),d) ,e)
Ot her f)
1, 1 2
-0 1: 3 0
Pr e -d ose
-0 1: 0 0
A p pl y t he electr o des 
d)
1, 1 2
-0 0: 4 0
-0 0: 3 0
Rest i n be d
1, 1 2 
1 
1 2
Pr e -d ose
-0 0: 3 0
-0 0: 2 0
1 0 mi n utes
1, 1 2
-0 0: 2 0
-0 0: 0 5
T oilet use 
rec o m me n de d
1, 1 2
0 0: 0 0
A d mi nistrati o n of 
A Z D 0 4 4 9/ place b o
1, 1 2 
2 
1 3
0. 5 h g)
0 0: 2 5
0 0: 3 0
5 mi n utes e)
1, 1 2 
3 
1 4 
1 h
0 0: 5 5
0 1: 0 0
5 mi n utes e)
1, 1 2 
4 
1 5 
3 h
0 2: 5 5
0 3: 0 0
5 mi n utes e)
1, 1 2 
5 
1 6 
4 h
0 3: 5 5
0 4: 0 0
5 mi n utes e)
1, 1 2 
6 
1 7 
6 h
0 5: 5 5
0 6: 0 0
5 mi n utes e)
1, 1 2 
7 
1 8 
8 h
0 7: 5 5
0 8: 0 0
5 mi n utes e)
1, 1 2 
8 
1 9 
1 0 h h)
0 9: 5 5
1 0: 0 0
5 mi n utes e)
1, 1 2 
9 
2 0 
1 2 h
1 1: 5 5
1 2: 0 0
5 mi n utes e)
2, 1 3 
1 0 
2 1 
2 4 h
2 3: 5 5
2 4: 0 0
5 mi n utes e)
2, 1 3 
1 1 
2 2 
3 6 h
3 5: 5 5
3 6: 0 0
5 mi n utes e)
1 4
2 3 
4 8 h
4 7: 5 5
4 8: 0 0
5 mi n utes e)
E C G: Electr ocar di o gra m; d E C G: Di gital E C G; P K: P har mac o ki netics
a)
Ti me- p oi nts f or d E C G ma y be a dj uste d acc or di n g t o e mer gi n g P K data.
b)
Ti mes are a p pr o xi mate as d E C G a n d safet y E C Gs nee d t o be c o m plete d bef ore bl o o d sa m pli n g.
c)
T he patie nt m ust be i n t he sa me s u pi ne b o d y p ositi o n ( ma x. 3 0 de grees fle xi o n i n t he hi p) at eac h ti me-p oi nt a n d at all visits. Patie nt ’s feet s h o ul d n ot c o ntact t he 
f o ot b oar d of t he be d.
d)
S ki n m ust be clea ne d, a n d electr o de p ositi o ns mar ke d wit h a n i n deli ble pe n. Electr o des s h o ul d be a p plie d at least 3 0 mi n utes bef ore first rec or di n g.
e)
Patie nt m ust rest i n be d f or at least 1 0 mi n utes bef ore eac h E C G ti me -p oi nt.
f)
Safet y E C G will be c o n d ucte d at t he start of eac h d E C G e xtracti o n wi n d o w.
g)
Part 3a/ b o nl y.
h)
Part 2 C o h ort 1 o nl y.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 2. 3.
Or der of Assess me nts
It is i m p orta nt t hat P K sa m pli n g occ urs as cl ose as p ossi ble t o sc he d ule d ti me. T o ac hie ve t his, 
ot her assess me nts sc he d ule d at t he sa me ti me ma y  be i nit iate d bef ore t he ti me-p oi nt.
1.
Electr ocar di o gra ms ( E C Gs)/ d E C Gs prece de d b y 1 0 mi n utes s u pi ne rest, s u pi ne rest ma y 
be re d uce d acc or di n gl y f or E C Gs/ d E C Gs wi t hi n first h o ur of d osi n g.
2.
Vi t al si g ns (s yst olic a n d di ast olic B P, p ul se, res pirat or y rate a n d b o d y  te m perat ure) a n d 
p ul se o xi metr y.
3.
P har mac o ki net ic bl o o d sa m pli n g ( will be dra w n at t he s pecifie d ti me p oi nt).
4.
E x pl or at or y  bl oo d sa m ples 
 
5.
Fract i onal e x hale d nit ric o xi de ( o nl y ap plica ble t o c o h orts wit h pati e nts wi t h ast h ma i n 
Part 2a a n d Part 3 a).
6.
 
7.
S pi r o metr y.
Pre -d ose assess me nts ma y be p erf or m e d bef ore d osi n g as s pecifie d i n t he se parate wi n d o w 
all o wa nce d oc u me nt.
3. 2. 4.
T ot al Bl o o d V ol u me
T he a p pr o xi mate t otal vol u me of  bl oo d t hat will be c ollecte d fr om eac h s u bject i n t his st u d y, 
e xcl u di n g re peat sa mples, is s u m marize d i n Ta ble 3. 2 - 1 1 ( Part 1a [ S A D]),Ta ble 3. 2 - 1 2
( Part 1 b), Ta ble 3. 2 - 1 3 ( Part 2 a/ b), a n d Ta ble 3. 2 - 1 4 (Part 3a/ b ).
C CI
C CI








Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1

C o va nce P har mac o ki net icist ( n o n v otin g me m ber)
T he S R C ma y als o re q uest t o ha ve atte n da nce of  or off -li ne s u p p ort a n d i n p ut fr om t he 
f oll owi n g f u nct i ons as re q uire d:

Astra Ze neca Tea m P har mac o met ricia n

P are xel a n d Astra Ze neca Statist icia ns

Astra Ze neca a n d/ or P are xel a n d/ or e xter nal Me dical  Speci alists (e g, Ne ur ol o gist, 
E C G Ce nter car di o l ogi sts)

Astra Ze neca Patie nt Safet y P h ysicia n
Wr itte n state me nts a n d c o ncl usio n s b y t he S R C will be i n place bef ore all o wi n g st u d y
pr o gressi o n at t he n ote d ti mes as per Cli nical St u d y  Pr ot oc ol (C S P) . T his i ncl u des 
d oc u m e nt atio n of  a p pr o priate q ualit y c o ntr ol c hec ks o n t he data re vie we d.
3. 3. 1.
D at a Re vie we d b y S afet y Re vie w C o m mittee f or D ose Esc al ati o n Decisi o n
3. 3. 1. 1.
S afet y Re vie w C o m mittee Decisi o n o n Ne xt D ose
T he S R C will ma ke t he deci sio n  for t he ne xt d ose level or w het her t o st o p t he stu d y aft er 
re vie wi n g all t he perti ne nt safety a n d a n y ot her rele va nt data.
T he PI (s) at t he st u d y site(s) or a me dical dele gate will be a c ore me m ber of t he S R C as a v oti n g 
me m ber . T he C hief In vest i gat or at  Pare xel Earl y P hase Cli nical U ni t ( E P C U) will c hair t he 
meet i n g a n d will ha ve t he fi nal decisi on s h o ul d t h e S R C n ot be a ble t o reac h a fi nal decisio n .
I n or der t o escalate t o a ne xt d ose le vel a u na ni m o us S R C deci sio n  is nee de d. A d dit i onal details, 
i nclu di n g t he i n v ol ve me nt of  a Me dical Mo ni t or ( M M) w he n a d di n g a d ditio nal  site(s) f or 
Part 2a/ b of  t he st u d y, ar e pr o vide d i n t he S R C Meeti n g C harter a n d t he Me di cal M o ni t ori n g 
Pl a n. T he Pare xel M M will ser ve as a v oti n g me m ber of  the S R C a n d is res p o nsi ble for 
re vie wi n g a n d assessi n g all the perti ne nt safety i nf or mati on bef ore t he meet i n g. T he M M is 
res p o nsi ble f or t he re vie w of t he me dical/safety c o nte nt of t he S R C i nteri m re p orts, safet y data 
listi n gs a n d s u p p orti n g t he CI a n d PI f or ma k i n g t he fi nal rec om m e n dat i ons a n d c o nclusi o n s 
o n d ose escalat i on or o n t he pr o gress of t he st u d y base d o n re p orts a n d data pr o vi de d . T he M M 
will si g n t he d ose escalat i on me m o  in a gree me nt wit h t he S R C v oti n g me m bers .
T he decisi o ns of  the S R C o n t he ne xt d ose le vel will be d o c u m e nte d a n d pr o vi de d t o all t he 
a p pr o priate parties i n v o l ve d with t he st u d y, i ncl u di n g t he P har macist t o e na ble IM P pre parati o n 
f or t he ne xt sc he d ule d d osi n g da y.

W here st o p pi n g criteria ha ve n ot bee n met, t he decisi o n of t he S R C ma y be t o gi ve 
t he ne xt hi g her d ose acc or di n g t o t he pre defi ne d d ose i ncre me nt, a s maller d ose 
t ha n pre vi o usl y gi ve n, a re peate d d ose or t o st o p d osi n g.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1

A d o se i n w hic h t he safety st o p pi n g crit eria ha ve bee n met ( please r efer t o Secti o n 6 , 
St u d y  St o p pin g R ules) will n ot be re peate d a n d f urt her d ose escalati o n m ust n ot
occ ur.

I n t his case, t he S R C will re vie w t he t otality o f data a n d restart of d osi n g is p ossi ble 
wi t ho ut a s u bsta ntial a me n d me nt (e g, i n t he case of  a la b orat or y err or) if S R C 
re vie w c o ncl u des t hat t he rele va nt st o p pi n g criteri o n was n ot f ulfille d.

A l ower d ose level e x pecte d t o be t olera ble a n d n ot t o me et t he st o p pi n g crit eria, 
w o ul d be acce pta ble i n t his cas e.

If t he safety st o p pi n g crit eria are met  an d t he S R C deci des t hat t here are reas o ns 
t hat t he d ose lev el  sh o ul d be re peate d, or f urt her d ose escalat i on is warra nte d a 
s u m mar y of  the data a n d j ustificati on ( pr ot oc ol a me n d me nt) will be s u b mitt e d t o 
I n vesti gat i onal Me dici nes S af et y Re vie w B oar d (I S R B), t he Re g ul at or y Aut h ori t y 
a n d I n de pe n de nt Et hics C o m mittee (I E C) f or t heir a p pr o val bef ore f urt her d osi n g.

T he S R C will deci de t he pr o gress of t he st u d y fr o m Part 2 b t o Part 3a ( patie nts wit h 
mil d 
ast h ma) or Part 3 b (healt h y v o l unt eers) aft er c o n d ucti n g ris k-be nefit  
assess me nt a n d d o c u m e nt i n g t he o ut c o m e of  the assess me nt as part of  the S R C 
decisi o n. T he assess me nt will c o nsi der t he c urre nt sit u atio n of  the C O VI D - 1 9 
pa n de mic, e mer gi n g data i n t he st u d y  a n d o verall st u d y o bjecti ves a n d e n d p o i nts.
3. 3. 1. 2.
Bli n di n g at S afet y Re vie w C o m mittee Meeti n g
T he ra n d omizat i on c o de will be a vaila ble at t he S R C meet i n g a n d t he data will be re vie we d 
u n bli n de d.
3. 3. 1. 3.
Assess me nts A d a pt ati o n
F o ll owi n g re vie w of  data fr om a c o h ort of  su bjects, t he ti mi n g of  assess me nts a n d/ or bl o o d 
sa m ples ma y be a dj uste d f or s u bse q ue nt c o h orts.
A d dit i onal assess me nt or sa mpli n g ti mes ma y be a d de d if i n dicate d b y t he data; h o we ver, t he 
ma xi m u m bl o o d v ol u me ta ke n fr o m eac h s u bject will n ot e xcee d 5 0 0 m L.
3. 3. 1. 4.
S afet y D at a C o m m u nic ati o n Bet wee n St u d y Sites O utsi de t he S afet y Re vie w 
C o m mittee Meeti n gs
Per pr ot oc ol, serio us a d verse e ve nts ( S A Es) will be re p orte d b y Cli nical U nit s t o Astra Ze neca 
wi t hi n 2 4 h o urs . I n a d dit i on t o t he Astra Ze neca a n d P are xel sta n dar d safety a n d S A E  
pr ocessi n g a n d re p orti n g pr ocesses t hat will be f o ll o we d f or t his st u d y, if a n S A E occ urs at o ne 
sit e, t he PI or dele gate will i m me diatel y inf or m  ot her sites, a n d vice -versa . T his will e ns ure 
pr o m pt di stri b utio n a n d s hari n g of i m p orta nt safet y i nf or mati on bet wee n sites . As per sta n dar d 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Astra Ze neca 
a n d P are xel re p orti n g pr ocesses, P are xel Gl o b al  Phar mac o vi gila nce ( P V) 
Re p orti n g Gr o u p will als o be res p o nsi ble f or di strib ut i n g u n bli n de d s us pecte d u ne x pecte d 
serio us a d verse reacti o n ( S U S A R) re p orts t o et hics c o m mittees a n d st u d y sit es.
C o m m u nicat i on bet wee n sites a n d In vest i gat ors s h o uld be d o ne p eri o di call y acc or di n g t o t he 
safety m o nit ori n g pla n , in a d dit i on t o S R C escalat i o n meeti n gs a n d ex pe di ti n g S A Es.
3. 4.
O ver all D ose Str ate g y B ase d o n Re g ul at or y G ui d a nce
3. 4. 1.
S u m m ar y of D ose a n d E x p os ure R a n ge
T he d ose ra n ge was defi ne d b y c o nsi deri n g b ot h t he e x pecte d h u ma n t hera pe utic ra n ge a n d 
o bser vat i ons fr o m  no n -cli nical safet y st u dies.
T he 
st artin g d ose f or Part 1a ( S A D) was 
c h ose n wi t h co nsi derati o n t o b ot h t he
P har mac o l ogi call y 
Act i ve D ose 
( P A D), t he 
Ma xi m u m Rec o m me n de d 
Starti n g D ose 
( M R S D) [1 4 ], N O A E L a n d t he Mi ni m u m A ntici pate d Effect Le vel ( M A B E L) d ose [1 5 ].
T he P A D was 
deter mi ne d t o be 
 A Z D 0 4 4 9 
deli vere d d ose, as descri be d i n 
Secti o n 3. 4. 4 . T he M R S D was calc ulate d t o be 
 A Z D 0 4 4 9 deli vere d d ose; detaile d 
calc ulat i ons are pr o vi de d i n S e cti o n 3. 4. 2 . T he M A B E L d ose was calc ulate d t o be
 
A Z D 0 4 4 9 deli vere d d ose; details are descri be d i n Secti o n 3. 4. 3 .
C o ns er vat i vel y, t he M A B E L d ose was selecte d as t he starti n g d ose f or Part 1a ( S A D); m o re 
details o n t he d ose rati o nale are pr o vi de d i n Sect i on 3. 5. 1. 2 .
F or scali n g L D Ds fr o m r at t o h u ma n, b o d y  wei g ht -base d scali n g was c h ose n as t he m o st 
a p pr o priate a p pr oac h, a n d has bee n a p plie d t o MA B E L d ose, P A D a n d pre dicte d t hera pe utic 
d ose . M R S D was calc ulate d base d o n b o d y s urface area f or refere nce o nl y.
T he h u ma n t hera pe utic d ose is pre di cte d t o be 
 A Z D 0 4 4 9 deli vere d d ose; t he 
ass u m pt i ons a n d calc ulat i ons are descri be d i n detail i n Sect i on 3. 4. 5 .
T he est i mate d h u ma n t hera pe ut ic d ose ra n ge is 
 A Z D 0 4 4 9 deli vere d d ose, 
base d o n t he c o nsi derat i ons descri be d i n Sect i on 3. 4. 6 .
T he N O A E L -base d ma xi m u m allo we d l un g d ose of  
 A Z D 0 4 4 9 deli vere d d ose was 
calc ulate d as descri be d i n Sect i on 3. 4. 7 .
T he 
ma xi m u m allo we d e x p os ure, C ma x = 1 8 8 n m o l/ L a n d A U C = 1 2 0 0 n m o l * h/ L, was 
deter mi ne d as descri be d i n Sect i on 3. 4. 8 . N ote, A U C f or si n gle d oses or A U C ( 0-2 4) at stea d y 
state f oll owi n g re peate d d osi n g.
C CI
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 1 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Mar gi ns 
bet wee n starti n g d ose, t hera pe utic d ose a n d ma xi m u m allo we d d ose as well as 
pre di cte d e x p os ures are s u m marize d i n Sect i on 3. 6 .
3. 4. 2.
N O A E L -B ase d M a xi m u m Rec o m me n de d St arti n g D ose
T he M R S D as defi ne d b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) [ 1 4 ] was calc ulate d t o be 
 A Z D 0 4 4 9 deli vere d d ose.
T he val ue is base d o n t he 6 -m o nt h G o o d La b orat or y  Pr a ctice ( G L P) t o xic o l og y  d at a fr o m t he 
rat; si nce t he rat ha d a l o wer h u ma n e q ui vale nt d ose ( H E D) t ha n t he d o g, it was selecte d as t he 
m o st se nsitive s pecies.
T he N O A E L was 0. 1 8 8 m g / k g/ da y (lu n g- de p osi t e d d os e) in t he 6-m o nt h r at t o xic o l og y  st u d y 
a n d t his d ose has bee n use d f or calc ulatio n of  a p ote ntial starti n g d ose. T he basis f or t he H E D 
calc ulat i on has bee n t he b o d y  bur de n d oses i n t he t o xicit y st u dies defi ne d b y t he fracti on of 
i n hale d dr u g deli vere d t o l u n g.
T he l u n g -de p osi te d d ose gi ve n i n t he rat t o xicity st u d y  was 0. 1 8 8 m g/ k g/ da y . A c orres p o n di n g 
H E D of  0. 0 3 0 m g/ k g ca n be calc ulate d b y usi n g t he scali n g fact or ( 6. 2) f or rat. A p pl yi n g a 
1 0 -f ol d safety fact or a n d c o n vert i n g t he d ose t o t otal hu ma n b o d y  dose (ass u mi n g a b o d y 
w ei g ht of  60 k g) t he starti n g d ose res ults i n 
. W he n ta ki n g i nto acc o u nt t he pre di cte d 
l u n g-de p osi te d fracti on of  0. 8 i n ma n (fr om t he Pr o v o. X s yst e m), t he deli vere d M R S D is 
0. 2 2 m g.
A b o d y  wei g ht of 60 k g was c h ose n as a n es peciall y co nser vat i ve ass u m pt i on f or t he starti n g 
d ose, b ut  for all t hera pe ut ic effect -r elate d d oses, 7 0 k g is ass u me d t o be m o re realistic f or a 
E ur o pea n p o p ulat i on.
3. 4. 3.
Mi ni m u m A ntici p ate d Bi ol o gic al Effect Le vel D ose
I n t his pr ot oc ol , t he M A B E L [ 1 5 ] d ose is defi ne d as t he l owest d ose f or w hic h a n effect i n 
h u ma ns ca n be a nt ici pate d. It was esti mate d t o be 
 A Z D 0 4 4 9 deli vere d d ose.
T he M A B E L 
was deter mi ne d base d o n data fr o m a r at O V A m o d el  with i ntratrac heal 
a d mi nistrati o n. I n t his mo d el , a lu n g- de p osi te d d ose of 0. 3 µ g/ k g A Z D 0 4 4 9 s h o we d n o effect .
T he ne xt hi g her i n vesti gate d d ose, 3 µ g/ k g, ga ve a 3 8 % re d ucti o n of  the e o si n o p hil c o u nt i n 
t he br o nc h oal ve o lar lava ge fl ui d ( B A L F). T he mi ni m u m effect ca n be a nt ici pate d t o lie 
bet wee n t hese 2 d oses . All d at a of  t his e x peri me nt were fitt e d i n a d os e-res p o nse m o d el . T his 
m o d el  was t he n use d t o i nter p olate bet wee n t he 0. 3 a n d 3 µ g/ k g d oses . A n i n hi biti on level of  
2 0 % was selecte d f or rea d o ut, res ulti n g i n a d ose of  1. 3 µ g/ k g . T hi s i n hi biti on lev el  is 
a nt ici pate d t o be cl ose t o a mi ni m u m bi ol ogical  eff e ct le vel.
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he i de nt ifie d l u n g-de p osi te d M A B E L d ose of 1. 3 µ g/ k g was tra nslate d t o a n a bs ol ute h u ma n 
d ose wit h t he f oll owi n g calc ulat i on. A c o nser vat i ve ass u m pt i on f or h u ma n b o d y  wei g ht of 
6 0 k g was ma de . T he l un g -de p osi te d fracti on was pre di cte d t o be 8 0 %. T hi s r es ults i n a n 
esti mate d M A B E L d ose of  
 A Z D 0 4 4 9 deli vere d d ose, w hic h is 3 7 % of  P A D a n d 4 4 % 
of  M R S D.
As f or t he M R S D, a b o d y wei g ht of  6 0 k g was c h ose n as a n es peciall y c o nser vat i ve ass u m pti on 
f or t he starti n g d ose, b ut f or all t hera pe ut ic effect -r elate d d oses, 7 0 k g is ass u me d t o be m o re 
realistic f or a E ur o pea n p o p ulat i on.
3. 4. 4.
P h ar m ac ol o gic all y Acti ve D ose
T he P A D is defi ne d as t he l ow est d ose teste d i n a n a ni mal s pecies wi t h the i nte n de d 
p har mac o l ogi c act i vity acc or di n g t o t he F D A g ui da nce [ 1 4 ].
T he P A D was deter mi ne d t o be 3. 0 µ g/ k g (e x presse d as free base of A Z D 0 4 4 9) l u n g -de p osi te d 
d ose base d o n data fr o m a rat O V A m o del . T his d ose ca use d a 3 8 % re d ucti o n of t he e osi n o p hil 
c o u nt i n t he B A L F. Ass u mi n g a h u ma n b o d y  wei g ht of 7 0 k g a n d a l u n g- de p osi t e d fracti on i n 
h u ma n of 8 0 %, t he a bs ol ute h u ma n P A D is 
 A Z D 0 4 4 9 deli vere d d ose.
3. 4. 5.
Pre dicte d H u m a n T her a pe utic D ose/ A ntici p ate d T her a pe utic D ose
I n t his pr ot oc ol, pr e dicte d ( h u ma n) t hera pe utic d ose a n d A nt ici pate d T hera pe utic D ose ( A T D) 
are use d as s y n o n y ms.
T he h u ma n t hera pe uti c d ose was pre dicte d base d o n data fr o m a r at O V A mo d el  wit h D PI . I n 
t his m o d el , A Z D 0 4 4 9 re d uce d t he e osi n o p hil c o u nt i n t he B A L F b y a ma xi m u m 
of  
a p pr o xi matel y 6 0 % . T he d ose res ultin g i n 8 0 % of t his ma xi m u m i n hi biti on ( E D 8 0) was selecte d 
t o be t he e x pecte d h u ma n t hera pe ut ic d ose. T his selectio n was ma de c o nsi deri n g t hat A Z D 0 4 4 9 
w or ks as a c o mpet iti ve a nta g o nist o n J A K 1. I n c o ntr ast t o a g o nists w hic h ma y s h o w cli nical 
effects at  lo w e x p os ures, c o m pet iti ve a nta g o nists li ke A Z D 0 4 4 9 ma y ge nerall y  re q uir e 
r elat i vel y hi g h e x p os ures t o i n hi bit t he tar get.
T he selecte d d ose, E D 8 0, was 1 3 µ g/ k g (e x presse d as free base of  AZ D 0 4 4 9) l un g -de p osi t e d 
d ose . H u ma n b o d y  wei g ht was ass u me d t o be 7 0 k g. L u n g -de p osite d fracti o n i n h u ma n is 
ass u me d t o be 8 0 %. A p pl yi n g t hese n u m bers, t he pre dicte d h u ma n t hera pe ut ic d ose is 
 
A Z D 0 4 4 9 deli vere d d ose.
3. 4. 6.
Esti m ate d H u m a n P h ar m ac o d y n a mic D ose R a n ge
T he l ower e n d of t he esti mate d h u ma n p har mac o d y na mic ( P D) d ose ra n ge ca n be ass u me d t o 
be si milar t o t he M A B E L d ose of 
 A Z D 0 4 4 9 (see Secti o n 3. 4. 3 ).
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he u p per e n d o f t he est i mate d h u ma n P D d ose ra n ge is ass u me d t o mat c h t he N O A E L-base d 
ma xi m u m all o we d d ose of  
 A Z D 0 4 4 9 ( Sectio n 3. 4. 7 ), as t his d ose c orres p o n ds t o t he 
d ose gi vi n g 9 6 % re d ucti o n of  eosi n o p h ils i n t he rat O V A m o d el  (E D 9 6). T hi s u p per li mit of 
 is a p pr o xi matel y 4-ti mes hi g her t ha n t he pre dicte d h u ma n t hera pe utic d ose (see 
Secti o n 3. 4. 5 ).
3. 4. 7.
N O A E L - B ase d M a xi m u m All o we d D ose
T he ma xi m u m allo we d d ose has bee n calc ulate d b y usi n g a n a p pr oac h w hic h c o n verts t he 
N O A E L fr o m a  dose per b o d y  wei g ht ( mg/ k g) t o a d ose per g of  l un g wei g ht ( mg/ g l u n g tiss ue), 
f oll owe d b y a l u n g wei g ht scali n g t o h u ma n a n d a p plicat i on of safet y mar gi ns ( 1 0 -f ol d f or t he 
r at a n d 6- f ol d f or t he d o g [1 3 ]). Se parate calc ulat i ons f o r b ot h s pecies are gi ve n i n t he f o ll owi n g 
para gra p hs.
I n t he 6- m o nt h rat t o xicit y st u d y, t he N O A E L was o bser ve d at a t otal in hale d d ose of 
1. 8 8 m g/ k g/ da y, c orres p o n di n g t o 0. 1 8 8 m g/ k g/ da y l u n g d ose, wit h 1 0 % l u n g de p osit i on [ 1 3 ].
T his tra nslates t o 0. 0 6 m g/a ni mal ( usi n g t he gr o u p mea n b o d y wei g ht of 3 1 8 g) a n d 0. 0 5 m g/ g 
of  lu n g tiss ue ( usi n g t he gr o u p mea n l u n g wei g ht of 1. 1 9 g) . Ass u mi n g a l u n g wei g ht of 1 0 0 0 g 
i n h u ma n, t he c orres p o n di n g h u ma n d ose is 5 0 m g.
As t he res pirat or y tract pat h ol o g y fi n di n gs are c o nsi dere d n o n -m o nit ora ble i n t he cli nic, it was 
c o nsi dere d t hat t he ma xi m u m cli nical d ose lev el  sh o ul d be li mite d t o 1 0- f ol d l ower t ha n t he 
d ose level at w hic h there were n o res pirat or y tract pat h ol o g y fi n di n gs i n t he m o st se nsiti ve 
s pecies (rat). A p pl yi n g a 1 0 -f ol d safety mar gi n res ults i n a h u ma n deli vere d d ose of 
I n t he 3- m o nt h d o g t o xi cit y st u d y, t he e q ui vale nt calc ulat i on was base d o n N O A E L at a t otal 
in hale d d ose of 2. 0 1 m g/ k g/ da y, wit h 2 5 % l un g de p osi tio n [ 1 3 ] a n d usi n g gr o u p mea n val ues 
of  9. 1 0 k g f or b o d y wei g ht a n d 8 6. 1 g f or l u n g wei g ht . T hi s res ults i n a h u ma n d ose of 5 3 m g .
A p pl yi n g a 6 -f ol d safety mar gi n tra nslates t o a h u ma n deli vere d d ose of 9 m g .
N ote, l u n g de p osi tio n i n h u ma n is de pe n de nt u p o n i n halat i on de vice, b ut ca n here be e x pecte d 
t o be a p pr o xi matel y 8 0 %; a t otal dose of  eg, 5 m g t heref ore c o rres p o n ds t o a l u n g-de p osi t e d 
d ose of 4 m g.
C o ncl usi o n
T he ma xi m u m allo we d d ose was c h ose n t o be 
 ( deli vere d d ose) a n d is base d 
u p o n t he data fr o m t he m ost se nsit i ve s pecies (rat).
A deli vere d d ose of  
 is c o nsi dere d t o be at t he hi g her e n d of  the esti mate d h u ma n 
t hera pe utic ra n ge a n d a p pr o xi matel y 4 ti mes hi g her t ha n t he pre di cte d t hera pe utic d ose 
(see Secti o n 3. 4. 5 ).
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he pre di cte d h u ma n plas ma e x p os ure f oll owi n g t he pr o p ose d ma xi m u m d ose of  
 is 
1 9. 8 n m o l/ L ( Cma x ) a n d 6 5 4 n m o l * h/ L ( A U C) f or a si n gle i n hale d d ose.
3. 4. 8.
S yste mic E x p os ure Li mits
T he ma xi m u m allo we d t ot al hu ma n e x p os ure is a C ma x of  18 8 n m o l/L a n d a n A U C of 
1 2 0 0 n m o l.h/ L, c orres p o n di n g t o a p pr o xi mate free ( n o n-pl as ma pr otei n b o u n d) e x p os ures of  
0. 1 8 8 n m o l/ L a n d 1. 2 0 n m o l.h/ L, res pecti vel y. N ote, A U C f or si n gle d oses or A U C ( 0-2 4) at 
stea d y state f oll owi n g re peate d d osi n g.
Pl as ma pr otei n bi n di n g i n b ot h t he rat a nd d o g are hi g her t ha n h u ma n, h o we ver t he e x p os ure 
li mit was set o n t he m ore c o nser vat i ve total  c o nce ntrati o n ( % n o n-pl as ma pr otei n b o u n d [free]; 
rat: 0. 2 4 %; d o g: 0. 1 5 %; h u ma n: 0. 1 0 %). Mar gi ns ( bet wee n h u ma n plas ma c o nce ntrati o ns a n d 
s yste mic e x p os ure li mits) base d o n free c o nce ntratio ns are al wa ys ca. 2. 5 -f ol d (r at) a n d ca. 
1. 5 -f ol d ( d o g) hi g her t ha n mar gi ns base d o n t otal c o nce ntrati o ns.
T he a d verse effects o bser ve d i n b ot h s pecies were li mite d t o t he res pir at or y tract a n d were 
c o nsi dere d t o be dri ve n b y ad mi nistrati o n of  hi g h i n hale d d ose levels w hic h o verl oa de d 
cleara nce mec ha nis ms; t here were n o a d verse s yste mic effects u p t o t he hi g hest d ose le vels a n d 
e x p os ures i n b ot h t he rat a n d d o g.
Gi ve n t hat a n a d verse s yste mic e x p os ure lev el  w as n ot ide nt ifie d, it is c o nsi dere d a p pr o priate 
t o li mit s yste mic e x p os ure t o half of that ac hie ve d i n s pecies wit h t he l o wer e x p os ure (rat; usi n g 
t he e x p os ure val ues fr o m t he 6-m o nt h st u d y ):

A U C ( 0-2 4) ac hie ve d i n rat i n 6-m o nt h st u d y = 2 4 0 0 n m o l.h/ L/ 2 = 1 2 0 0 n m o l.h/ L

C ma x ac hie ve d i n rat i n 6 -m o nt h st u d y = 3 7 6 n m o l/ L/ 2 =1 8 8 n m o l/L
F or c o m par is o n t he ac hie ve d e x p os ure val ues i n t he d o g wit h n o a d verse s yste mic fi n di n gs 
were a C ma x of  5 4 4 0 n m o l/ L a n d a n A U C( 0-2 4) of  5 9 4 0 n m o l.h/ L.
3. 5.
D ose Str ate g y i n t he I n di vi d u al St u d y P arts
3. 5. 1.
D osi n g P ar t 1 a
3. 5. 1. 1.
T ar gete d Deli vere d D oses
F or i n hale d d ose a d mi nistrati o n, a j et ne b ulizer a n d a d osi meter will be use d as per a se parate 
ha n dli n g i nstr uctio n . T he tar gete d deli vere d d oses will be ac hie ve d b y usi n g t he differe nt 
stre n gt hs of  the ne b ulizer s us pe nsi on a n d var yi n g t he n u m ber of  breat hs. T he n u m ber of  breat hs 
will al wa ys be selecte d t o deli ver a d ose as cl ose as p ossi ble t o t he tar get deli vere d d ose w hile 
ta ki n g i nt o acc o u nt t he pre-s pecifie d li mits f or d ose escalat i on ste ps . F or t he tar gete d deli vere d 
starti n g d ose 
 bet wee n 1 0- 2 0 breat hs of  the l owest stre n gt h s us pe nsi on will be 
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
a d mi nistere d, a n d t he act ual d os e, if it ca n n ot be e xactl y 
, will be sli g htl y l ower, b ut 
n ot hi g her.
3. 5. 1. 2.
St arti n g D ose P art 1 a
F or Part 1a, 
 A Z D 0 4 4 9 deli vere d d ose has bee n selecte d as t he starti n g d ose.
T his starti n g d ose was c h ose n wi t h co nsi derati o n t o bot h t he P A D, t he M R S D [1 4 ], N O A E L 
a n d t he M A B E L d ose [ 1 5 ].
S el ect i n g t he M A B E L d ose as starti n g d ose re prese nts t he m o st c o nser vat i ve a p pr oac h as t he 
M A B E L d ose of  
 is 3 7 % of  PA D ( 0. 2 6 m g ) a n d 4 4 % of  MR S D ( 0. 2 2 m g) . T he M R S D 
is base d o n t he N O A E L d ose b ut c o nt ai ns a 1 0- f ol d safety fact or (see Secti o n 3. 4. 2 ), s o a 
starti n g d ose of 
 re prese nts 4. 4 % of t he N O A E L d ose (ie, t he M R S D wit h o ut t he 1 0-
f ol d safety fact or). As t he starti n g d ose was t hus c h ose n ver y  co nser vat i vel y, as t he m o de of  
actio n is well -u n derst o o d a n d as t here is ric h cli nical data fr o m or al  JA K i n hi bit ors (see 
Se ctio n 4. 2. 1 ), a safety fact or was n ot a p plie d t o t he starti n g d ose.
3. 5. 1. 3.
Se nti nel D osi n g P art 1 a
D osi n g f or eac h asce n di n g d ose c o h ort will start wi t h 2 v o l unt eer s i n a se nti nel c o h ort, s uc h 
t hat 1 v ol u nteer will be ra n d o mize d t o recei ve A Z D 0 4 4 9 a n d 1 v ol u nteer will be ra n d omize d 
t o recei ve place b o . T he safety data ( A Es, vit al si g ns, E C G, t ele metr y an d cli nical la b orat or y 
e val uat i ons) fr om t he se nti nel v o l unt eer s u p t o 2 4 h o urs p ost -d ose will be re vie we d b y t he PI 
bef ore t he re mai ni n g v o l unt eer s i n t he c o h ort are d ose d.
3. 5. 1. 4.
D ose Esc al ati o n P art 1 a
T he d ose rati o nale a n d t he select i on of  t he starti n g d ose are descri be d i n Secti o n 3. 5. 1 . D o se 
escalat i on will be g ui de d b y s pecific st o p pi n g r ules (see Secti o n 6 ).
I n t otal, 6 d ose le vels are pl a n ne d, wi t h the o pti o n of  ad di n g 3 e xtra c o h orts ( wit hi n t he 
pre -s pecifie d d ose ra n ge). T he starti n g d ose is fi xe d at 
, h o we ver t he s u bse q ue nt d oses 
of  AZ D 0 4 4 9 ma y be a dj uste d base d o n a vaila ble safety a n d P K data fr o m t he c o mplete d 
c o h orts, ie, t he d ose escalat i on s h o w n i n t he fl ow c harts ( Secti o n 3. 2. 1 ) is preli mi nar y .
Escal at i on t o t he ne xt d ose lev el  will o nl y  ta ke place aft er t he safety data ( A Es, vit al si g ns, 
E C G, t ele m etr y an d cli nical la b orat or y eval uati o ns) fr om t he pre vi o us c o h ort has bee n 
re vie we d (see Sect i on 3. 3 ). Data fr o m a mi ni m u m of 5 v o l unt eer s o n A Z D 0 4 4 9 or 7 s u bjects 
i n t otal per c o h ort m ust be re vie we d a n d c o nsi dere d satisfact or y befor e eac h d ose escalat i on.
D ose escalat i on bel o w t he pre di cte d t hera pe utic d ose will n ot e xcee d 3 -f ol d. T he est i mate d 
h u ma n p har mac o d y na mic d ose ra n ge s pa ns m o re t ha n o ne or der of  ma g nit u de ( 5 0-f ol d) (see 
Secti o n 3. 4. 6 ). T heref ore, a 3- f ol d ste p is n ot e x pecte d t o c o ver t he stee p part of  the 
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
d ose -res p o nse c ur ve w he n escalati n g bet wee n 2 d oses, i e, 3-f ol d d ose escalati on is c o nsi dere d 
ca uti o us.
Fr o m  t he pre dicte d t hera pe utic d ose le vel o n war ds, t he d ose will i ncrease n o more t ha n 2 -f ol d.
T his is b ot h d ue t o ge neral safety c o nsi derat i ons a n d t o e ns ure a t h or o u g h c haracterizat i on of  
t he P K i n t he d ose ra n ge of pre dicte d hi g h p har mac ol o gical act i vity.
D uri n g d ose escalat i on, t he d ose i n t he ne xt c o h ort d oes n ot ha ve t o be hi g her t ha n t he pre vi o us 
o ne. I nter me diate d ose levels ma y be a d de d. If the e x p os ure li mit has n ot bee n reac he d, a n y 
d ose i ncl u di n g t he hi g hest d ose ma y be re peate d or t he size of  an y c o h ort ma y be i ncrease d.
T his m a y be re q uire d d ue t o n o n-safety- relate d reas o ns, e g, s u bject dr o p o ut or l oss of sa m ples 
or u ne x pecte d or hi g hl y varia ble P K, w hic h ma kes it necessar y t o a d d m ore data p oi nts ar o u n d 
a certai n d ose le vel.
3. 5. 1. 5.
St o p pi n g Criteri a/ E n d of Esc al ati o n P art 1 a
D osi n g will be st o p pe d at a n y  time base d o n t he safet y crit eria descri be d i n Sect i on 6. 1 .
I n a d ditio n, d ose escalat i on will be st o p pe d if a n y of  t he P K crit eria descri be d i n Sect i on 6. 2
ha ve bee n met.
3. 5. 2.
D osi n g P art 1 b
3. 5. 2. 1.
D ose P art 1 b
T he d ose i n t he first c o h ort of  Part 1 b will be 
 A Z D 0 4 4 9 a d mi nistere d as a n I V 
i nf usi on o v er a 6 0 -mi n ute peri o d ( 0. 1 mL/ mi n) . T he d ose i n t he sec o n d c o h ort of Part 1 b will 
be 
 A Z D 0 4 4 9 a d mi nistere d as a n I V i nf usi o n o ver a 4 8-mi n ute peri o d ( 0. 5 m L/ mi n).
T h e first (a n d l owest ) I V d ose was selecte d base d o n t he P K pre dicti o ns t hat t he d ose is hi g h
e n o u g h t o all o w f or q ua ntificat i on of  plas ma A Z D 0 4 4 9 levels 2 4 h o urs aft er d osi n g . F or 
ge neral safet y r eas o ns, t he selecte d d ose le vel is at t he l o w e n d of t he esti mate d h u ma n P D d ose 
ra n ge. T he res ulti n g o bser ve d e x p os ure at t he l owest d ose wa s, as pre di cte d, well bel o w t he 
ma xi m u m all o we d e x p os ure ( 1 % of C ma x , 0. 3 % of A U C) . T he rati o nale f or t he safet y o f the I V 
d ose i s disc usse d i n Secti o n 4. 1. 2 .
T he sec o n d I V d ose was selecte d after c o m plet i on of Part 1a a n d t he first I V c o h ort i n Part 1 b.
F or t he first I V d ose, t he c o nce ntrati o ns i n plas ma were q ua nt ifia ble 1 0 t o 1 2 h aft er 
a d mi nistrati o n a n d t hat was n ot s ufficie nt t o f ull y c haracterize t he P K o f A Z D 0 4 4 9 f oll owi n g 
I V a d mi nistrati o n. Wit h t he k n o wl e d ge gai ne d fr o m t he first I V d ose a n d t he Part 1a i n hale d 
d ose c o h orts, it is pre dicte d t hat wit h a n I V d ose of 
, s ufficie nt c o nce ntrati o ns will be 
ac hie ve d t o all o w f or q ua ntificat i on of  plas ma A Z D 0 4 4 9 levels 2 4 h o urs aft er d osi n g . T he 
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
e x p os ure at t he sec o n d d ose is als o pre dicte d t o be well bel o w t he ma xi m u m all o we d e x p os ure 
( 4. 4 % of Cma x , 1. 2 % of A U C).
3. 5. 2. 2.
Se nti nel D osi n g P art 1 b
D osi n g of  b ot h I V co h ort s will st art wit h 1 v o l unt eer i n a se nti nel c o h ort, a n d t he safety data 
( A Es, vit al si g ns, E C G, tele metr y an d cli nical la b orat or y eval uat i ons) fr o m t he se nti nel 
v o l unt eer u p t o 2 4 h o urs p ost -d ose will be re vie we d b y t he PI bef ore t he re mai ni n g v o l unt eer s 
i n t he c o h ort are d ose d .T he r e mai ni n g 5 v o l unt eer s i n t he c o h ort will be d ose d after t he 2 4- h o ur 
safety data ha ve bee n re vie we d.
3. 5. 2. 3.
St o p pi n g Criteri a P art 1 b
D osi n g will be st o p pe d at a n y  time base d o n t he safet y crit eria descri be d i n Sect i on 6. 1 .
3. 5. 3.
D osi n g P art 2 a/ b
3. 5. 3. 1.
St arti n g D ose P art 2 a/ b
T he starti n g d ose f or Part 2a will be a d ose level t hat is ar o u n d t he mi d d ose ra n ge teste d i n 
Part 1a ( S A D) a n d was pre dicte d t o be 
 A Z D 0 4 4 9 deli vere d d ose. A mi d d ose level 
a v o i ds ge neral safety c o ncer ns c o n necte d t o starti n g wit h a hi g h d ose. It als o ma kes it p ossi ble 
t o escalate i nt o t he t hera pe uticall y rele va nt ra n ge wit h 3 d ose l e vels. As per t he di sc ussi ons at 
t he S R C meet i n g f oll owi n g c o mplet i on o f Part 1a c o h ort 6 , the starti n g d ose le vel selecte d was 
 A Z D 0 4 4 9 deli vere d d ose.
3. 5. 3. 2.
Se nti nel D osi n g P art 2 a/ b
D osi n g f or eac h asce n di n g d ose c o h ort will start wit h 2 s u bjects i n a se nti nel c o h ort, s uc h t hat 
1 s u bject will be ra n d o mize d t o recei ve A Z D 0 4 4 9 a n d 1 s u bject will be ra n d o mize d t o recei ve 
pl ace b o . T he safet y data ( A Es, vital si g ns, E C G, tele metr y a n d cli nical la b orat or y e val uat i ons)  
fr om t he se nti nel s u bjects u p t o 2 4 h o urs p ost -first d ose will be re vie we d b y t he PI bef ore t he 
r e mai ni n g s u bjects i n the c o h ort are d ose d . T he re mai ni n g s u bjects i n eac h c o h ort will be d ose d 
at least 4 8 h o urs after t he se nt i nel c o h ort.
T he rati o nale f or t he se nti nel d osi n g is prese nte d i n Secti o n 4. 1. 3 .
3. 5. 3. 3.
D ose Esc al ati o n P art 2 a/ b
T he d ose rati o nale a n d t he selecti o n of t he starti n g d ose are descri be d i n Sect i on 3. 5. 3. 1 . D o se 
escalat i on will be g ui de d b y s pecific st o p pi n g r ules (see Secti o n 6 ).
I n t ot al, 3 d ose levels are pla n ne d, wi t h the o pti o n of  ad di n g a d ditio nal c o h orts ( wit hi n t he 
pre -s pecifie d d ose ra n ge). Escal at i on t o t he ne xt d ose c o h ort will o nl y ta ke pl ace aft er t he safety 
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
data ( A Es, vit al sig ns, E C G, t ele m etr y an d cli nical la b orat or y e val uat i ons) fr om t he pre vi o us 
c o h ort ha ve bee n re vie we d . D at a f r o m a mi ni m u m of 6 s u bjects o n A Z D 0 4 4 9 or 8 s u bjects i n 
t otal ( 7 v o l unt eers f or c o h ort 3 i n Part 2 b) per c o h ort m ust be re vie we d a n d c o nsi dere d 
satisfact or y before eac h d ose escalat i on.
D ose le vels o f A Z D 0 4 4 9 will be a dj uste d base d o n re vie w of a vaila ble safety a n d P K data fr o m 
Part 1a a n d pre vi o us c o h orts i n Part 2, ie, t he d ose escalat i on s h o w n i n t he fl ow c harts 
( Sectio n 3. 2. 1 ) is preli mi nar y.
W he n select i n g t he d ose le vels, t he f oll o wi n g criteria will be c o nsi dere d:

D ose escalat i on bel o w t he pre dicte d t hera pe utic d ose will n ot e xcee d 3- f ol d. T he 
esti mate d h u ma n P D d ose ra n ge s pa ns m o re t ha n o ne or der of ma g nit u de ( 5 0 -f ol d 
[see Secti o n 3. 4. 6 ]). T heref ore, a 3 -f ol d ste p is n ot e x pecte d t o c o ver t he stee p part 
of  th e d ose -res p o nse c ur ve w he n escalat i n g bet wee n 2 d oses, ie, 3 -f ol d d ose 
escalat i on is c o nsi dere d ca uti o us.

Fr o m  t he pr e dicte d t hera pe utic d ose level o n war ds, t he d ose will  increase n o m o re 
t ha n 2- f ol d. T his is b ot h d ue t o ge neral safety c o nsi derati o ns a n d to e ns ure a 
t hor o u g h c haracterizati o n of  the P K i n t he d ose ra n ge of  pr e dicte d hi g h 
p har mac o l ogi cal act i vity.

D uri n g d ose escalat i on, t he d ose i n t he ne xt c o h ort d oes n ot ha ve t o be hi g her t ha n 
t he pre vio us o n e . I nter me diate d ose le vels ma y be a d de d. If t he e x p os ure li mit has 
n ot bee n reac he d, a n y d ose i ncl u di n g t he hi g hest d ose ma y be re peate d or t he size 
of  an y c o h ort ma y be i ncrease d. T his ma y be r e q uire d d ue t o n o n -safety- r elate d 
reas o ns, e g, patie nt dr o p o ut or l oss of sa m ples, u ne x pecte d or hi g hl y varia ble P K .

T he hi g hest d ose i n vesti gate d i n Part 2a/ b will n ot e xcee d t he hi g hest d oses 
i n vesti gate d i n Part 1a.
C urre nt l y t he d ose le vels are pla n ne d t o be selecte d as f oll ows:

T he starti n g d ose is a d ose fr o m t he mi d dle of t he d ose ra n ge i n Part 1a ( S A D) (see 
Secti o n 3. 5. 3. 1 a b o ve).

T he hi g hest d ose i n Part 2a/ b ( M A D) will be t he hi g hest d ose teste d i n Part 1a 
( S A D), pr o vi de d t hat n o safety c o ncer ns r elate d t o C ma x were rai se d d uri n g Part 1a 
a n d c o nsi deri n g t he s pecific st o p pi n g r ules (see Secti o n 6 ).
I ncl u di n g t he hi g hest d ose fr o m P art 1 a ( S A D st u d y) i nto Part 2a/ b ( M A D st u d y) is pre di cte d 
t o res ult i n a b o ut a 5 0 % i ncrease d C ma x at t he e n d of  the M A D treat me nt c o mpare d wi t h the 
S A D part w hile mai ntai ni n g t he sa me A U C (see Ta ble 3. 6 -1 ). T his i ncrease i n C ma x is re gar de d 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
safe as t he res ultin g pre dicte d C ma x val ue ( 3 2. 9 n m o l/ L) still lies a b o ut 6- f ol d bel o w t he 
ma xi m u m all o we d C ma x of  1 8 8 n m o l/L.
Acc or di n g t o E M A g ui da nce [1 5 ], t he e x pecte d e x p os ure aft er m u lti ple d osi n g s h o uld ha ve 
bee n c o vere d i n t he S A D parts, b ut hi g her e x p os ures i n t he M A D part ca n be c o nsi dere d 
p r o vide d t his o pti o n is pre -s pecifie d a n d bel o w t he set ma xi m u m e x p os ure. B ot h criteria are 
f ulfille d i n t his pr ot oc ol.
I n a d diti on, t he f o ll owi n g as pects s u p p ort t he safet y  of t he c h ose n a p pr oac h:

I n t he d o g, dail y I V d osi n g of 1 m g/ k g f or a peri o d of 3 m o nt hs was well t olerate d, 
wi t h a n ac hie ve d Cma x of  5 4 4 0 n m o l/ L. T his val ue lies 2 9 -f ol d hi g her t ha n t he Cma x
li mit of  18 8 n m o l/L a n d 1 6 5- f ol d hi g her t ha n t he pre dicte d C ma x aft er 1 4- da y 
i n hale d d osi n g of 
 A Z D 0 4 4 9 i n t he hi g hest M A D c o h ort.

T here were n o a d verse s yste mic fi n di n gs i n t he pre -cli nical t o xic o l og y  stu di es ( b ot h 
s pecies) relate d t o eit her pea k c o nce ntratio n ( C ma x) or pr olo n ge d e x p os ure ( A U C) .
T he a d verse res pirat or y tract pat h ol o g y fi n di n gs i n t he pre -cli nical t o xic o l og y  
st u dies are c o nsi dere d t o be dri ve n b y t o pical effects of  the l un g d ose . T heref ore, 
t he ma xi m u m allo we d h u ma n d ose level is li mite d t o 1 0- f ol d l ower t ha n t he n o 
effect le vel i n t he m ost se nsit i ve s pecies (rat).

E xte nsi ve safet y m o nit ori n g c o veri n g b ot h l ocal res pirat or y  a n d s yste mic effects is 
perf or m e d t hr o u g h o ut t he st u d y (see Sect i ons 6 a n d Secti o n 8. 2 ), a n d t he M A D part 
will be perf or me d wit h a well -c o ntr olle d cli nical e n vir o n me nt.
3. 5. 3. 4.
St o p pi n g Criteri a/ E n d of Esc al ati o n P art 2 a/ b

D osi n g will  be st o p pe d at  an y ti me base d o n t he safety crit eria descri be d i n 
Secti o n 6. 1 .

I n a d ditio n, d ose escalatio n will be st o p pe d if a n y of  the P K  crit eria descri be d i n 
Secti o n 6. 2 ha ve bee n met.
3. 5. 4.
D osi n g P art 3 a/ b
3. 5. 4. 1.
D ose P art 3 a/ b
T he d ose level f or Part 3a/ b will be 
 or e q ual t o t he hi g hest M A D d ose . De pe n di n g o n 
e mer gi n g data fr o m Part 2, t he d ose f or Part 3a/ b c o uld be l o wer t ha n 
 a n d t he n e q ual t o 
t he hi g hest M A D d ose t hat was safe a n d wi t hi n t he allo we d e x p os ure ra n ge. T hi s d ose leve l 
will all o w f or direct c o m paris o n of P K pr ofiles . As t he D PI f or m ulat i on ( Part 3) is e x pecte d t o 
res ult i n a lo w er l u n g- de p osi t e d fracti on t ha n t he ne b ulize d f or mulat i on ( Part 2), it is e x pecte d 
t hat res ulti n g e x p os ure will re mai n bel o w t he e x p os ure e x pl ore d i n Part 2. I n Part 3a/ b, 
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
treat me nt will
be a d ministere d wi t h t he S D 3 F L versi o n of  Ge n uair, a si n gle i nte gral, n o n-
re usa ble D PI a p pr o ve d i n E U.
T he u ncertai nt ies ass ociate d wit h D PI d osi n g are disc usse d i n Secti o n 4. 2. 5 .
3. 5. 4. 2.
Se nti nel D osi n g P art 3 a/ b
D osi n g of t he c o h ort i n Part 3a as well as Part 3 b will start wit h 2 s u bjects i n a se nti nel c o h ort, 
s u c h t h at 1 s u bject will be ra n d o mize d t o recei ve A Z D 0 4 4 9 a n d 1 s u bject will be ra n d omize d 
t o recei ve place b o. T he safety data ( A Es, vit al si g ns, E C G, t ele metr y an d cli nical la b orat or y 
e val uat i ons) fr o m t he se nti nel s u bjects u p t o 2 4 h o urs p ost -first d ose will be re vie we d b y t he 
PI bef ore t he re mai ni n g s u bjects i n eac h c o h ort c o uld be d ose d. T he re mai ni n g 3 4 pati e nts 
( Part 3a) or 6 v ol u nteers ( Part 3 b) i n t he res pecti ve c o h ort will be d ose d at least 4 8 h o urs after 
t he se nt i nel c o h ort.
T he rati o nale f or t he se nti nel d osi n g is prese nte d i n Secti o n 4. 1. 4 .
3. 5. 4. 3.
St o p pi n g Criteri a P art 3 a/ b
D osi n g will be st o p pe d at a n y  time base d o n t he safet y a n d P K crit eria descri be d i n Sect i on 6 .
3. 6.
Pre dicti o ns of E x p os ures a n d M ar gi ns f or Differe nt D ose Le vels
3. 6. 1.
Met h o ds f or M o deli n g D oses a n d Esti m ate d E x p os ure Le vels
Pl as ma P K  of A Z D 0 4 4 9 were pre di cte d usi n g a P h ysi o l og y Base d P h ar mac o ki netic ( P B P K) 
M o d el . I n s h ort, t his m o d el  mec ha nist icall y descri bes l u n g de p osit i on a n d P K i n l u n g a n d 
pl as ma b y c o m bi ni n g i nf or mati on a b o ut t he pr o perties of c o m p o u n d, f or m ulat i on, p h ysi o l og y  
a n d pre dicte d h u ma n P K para meters . T he P B P K m o del was fitt e d t o descri be e x peri me ntal 
l u n g a n d pl as ma P K  data fr o m A Z D 0 4 4 9 i n t he rat. Pre dict i ons f or h u ma n P K were ma de 
c o nsi deri n g t he differe nces bet wee n rat a n d h u ma n p h ysi o l og y .
M o d el  b uil di n g a n d e val uati on ha ve bee n p u blis he d b y  B o ger et al. i n 2 0 1 6 [1 8 ].


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 2 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 3. 6 - 1
Pre dicte d E x p os ures a n d M ar gi ns
Descri pti o n
D ose
a)
Pre dicte d P K p ar a meter b)
O bser ve d P K p ar a meter
f)
M ar gi n s yst. e x p. li mit/ p ar a meter
b) ,d)
[ m g]
C m a x
[ n m ol/ L]
A U C
c)
[ h * n m ol/ L]
C m a x
[ n m ol/ L]
A U C
c)
[ h * n m ol/ L]
C m a x
(-f ol d)
A U C
(-f ol d)
P art 1 a ( S A D)
St art d ose
0. 4 3 6
1. 7 1
4 3 1
7 0 2 g)
M a x d ose i n 
S A D e)
2 6. 1
1 3 6
7
9 g)
P art 1 b (I V)
I V d ose ( 6 0 mi n 
i nf usi o n)
2. 0 5 
3. 6 7
9 2
3 2 7 g)
8. 2
1 4
2 3
8 6
P art 2 a/ b ( M A D)
St art d ose
4. 6 8 
2 7. 3
4 0
4 4 g)
M a x d ose i n 
M A D
e)
3 6
1 3 1
5
9 h)
P art 3 a/ b ( D PI mil d 
ast h m atics)
D ose
3 6
1 3 1
5
9 h) ,i)
A U C: Area U n der t he C ur ve; C ma x : ma xi m u m o bser ve d plas ma c o nce ntrati o n; i. v: i ntra ve n o us; M A D: M ulti ple asce n di n g d ose; P K: P har mac o ki netics; S A D: Si n gle asce n di n g 
d ose; S yst. e x p. li mit: s yste mic e x p os ure li mit
a)
Tar get d ose A Z D 0 4 4 9 (e x presse d as free base). Part 1a a n d Part 2: i n hale d del i vere d; Part 1 b: i ntra ve n o us.
b)
P K para meters base d o n t otal bl o o d plas ma c o nce ntrati o ns, see als o c o m me nt bel o w. F or Part 2, para meters are gi ve n f or t he la st treat me nt da y, ie. stea d y state.
c)
A U C is A U C ( 0-i nfi nit y) f or si n gle d osi n g ( Part 1a a n d Part 1 b) a nd A U C (stea d y state, 0-2 4 h) f or m ulti ple d osi n g ( Part 2).
d)
S y ste mic e x p os ure li mits fr o m 6-m o nt h rat st u d y ( C ma x= 1 8 8 n m ol/ L, A U C = 1 2 0 0 h * n m ol/ L)
e)
T he ma xi m u m all o we d d ose re prese nts b ot h t he u p per e n d of t he esti mate d h u ma n p har mac o d y na mic d ose ra n ge ( Secti o n 3. 4. 6 ) a n d t he N O A E L -base d Ma xi m u m 
All o we d D ose ( Secti o n 3. 4. 7 ).
f)
O bser ve d P K para meter fr o m Interi m A nal y sis (I A).
g)
O bser ve d mar gi n.
h)
Pre dicti o n base d o n a vaila ble data i n S A D +I V ; t he pre dicti o n is t hat v ol u nteers a n d patie nts wit h mil d ast h ma will ha ve si milar P K.
i)
Hi g h li keli h o o d t o get l o wer e x p os ures wit h D PI a n d a n ass u me d l o wer L D D .
C o m me nts:
F or i m pr o ve d rea da bilit y, data is o nl y s h o w n f or selecte d d oses, i ncl u di n g t he l o west a n d hi g hest p ossi ble d ose; t hese f or m a ra n ge t hat i ncl u des t he pre dicte d e x p os ure f or all 
ot her d oses me nti o ne d i n t his pr ot oc ol.
All para meters a n d mar gi ns s h o w n are base d o n t otal plas ma c o nce ntrati o ns as t his is t he m ost c o nser vati ve a p pr oac h . T he free ( n o n -plas ma pr otei n b o u n d) fracti o ns i n plas ma 
are ver y l o w f or b ot h rat ( 0. 2 4 %) a n d h u ma n ( 0. 1 0 %) . Mar gi ns base d o n free c o nce ntrati o ns are al wa ys ca. 2. 5 -f ol d hi g her t ha n mar gi ns base d o n t otal c o nce ntrati o ns.
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
4.
R A TI O N A L E, U N C E R T AI N T Y A N D RI S K S
4. 1.
St u d y Desi g n R ati o n ale a n d J ustific ati o n
4. 1. 1.
R ati o n ale f or Desi g n of P art 1 a
A Z D 0 4 4 9 has n ot bee n st u die d i n ma n pre vi o usl y . T his FI H cli nical st u d y will assess t he safet y 
a n d t olera bilit y as well as t he si n gle d ose P K of i n hale d A Z D 0 4 4 9 i n v o l unt eers.
St u d y P o p ul ati o n
T he st u d y will be p erf or me d i n heal t h y ma le v ol u nteers a n d healt h y female v o l unt eer s of 
n o n- c hil d beari n g p ot e nti al. Heal t hy v o l unt eers will be selecte d t o mi ni mize i nterfere nce wi t h 
ot her dr u gs or wit h disease pr ocesses. T he i ncl usi o n a n d e xcl usio n criteria are defi ne d s uc h 
t hat t he selecte d v ol u nteer s will be free of  an y si g nifica nt ill ness w he n i ncl u de d i n t he st u d y 
a n d t hat t he y d o n ot recei ve me dicati o n e x pecte d t o i m pact o bser vati ons (see Secti o n 4. 4. 1 ).
Ge ner al D osi n g Str ate g y
A Z D 0 4 4 9 will be a d mi nistere d i n a sta n dar d S A D se q ue nt ial gr o u p desi g n, ie, eac h v o l unt eer
i n t his st u d y part will recei ve A Z D 0 4 4 9 or place b o o nl y  once a n d d ose will be i ncrease d 
ste p-wise bet wee n c o h orts.
T he r atio nale f or d osi n g a n d d ose escalat i on is descri be d i n detail i n Secti on 3. 5. 1 .
Eac h c o h ort will be prece de d b y a se nti nel c o h ort (see Secti o n 3. 5. 1. 3 ). T he re mai ni n g 
v o l unt eer s of  eac h c o h ort will o nl y be d ose d aft er t he 2 4- h o ur safety data fr o m t he se nti nel 
v o l unt eer s ha ve bee n re vie we d. Li ke wise, escalati o n t o t he ne xt d ose c o h ort will o nl y t a k e 
pl ace after safet y a n d P K data fr o m t he pre vi o us c o h ort ha ve bee n re vie we d.
Pl ace b o C o ntr ol
T he st u d y incl u des place b o c o ntr ol in or der i de ntif y effects t hat relate t o dr u g a d mi nistrati o n 
rat her t ha n t he st u d y pr oce d ures or sit uati o n.
R a n d o miz ati o n a n d Bli n di n g
Treat me nts are ra n d o mize d, a n d st u d y v o l unt eer s will be bli n de d t o treat me nt all ocat i on 
(si n gle-bli n d desi g n) t o mi ni mize bias . T he st u d y is si n gle rat her t ha n d o u ble -bli n d as s pecifie d 
P are xel pers o n nel nee d t o be u n bli n de d f or t he d ose escalat i on decisi o ns ma d e b y t he S R C .
H o we ver, site pers o n nel ma na gi n g t he st u d y v o l unt eer s will be bli n de d t o t he e xte nt p ossi ble 
w hile mi ni mizi n g a n y  i m pact o n data c ollecti on.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
4. 1. 2.
R ati o n ale f or Desi g n of P a rt 1 b
I n Part 1 b, A Z D 0 4 4 9 will be a d mi nistere d as a si n gle I V d ose at 2 differe nt d ose levels 
 t o 2 c o h ort s of  heal t h y v ol u nteers i n or der t o c o m pare t he P K bet wee n 
I V a n d i n hale d a d mi nistratio n . T he res ults will be use d t o i m pr o ve fut ure st u d y desi g n a n d 
i nter pretatio n.
St u d y P o p ul ati o n
T he st u d y will be perf or me d i n healt h y male v ol u nteers a n d heal t h y female v o l unt eer s. Fe male 
v o l unt eers m ust be of n o n-c hil d beari n g p ote ntial f o r Part 1 b fir st I V c o h ort. Healt h y v ol u nteers
will be selecte d t o mi ni mize i nterfere nce wi t h ot her dr u gs or wit h disease pr ocesses . T he 
i ncl usi on a n d e xcl usi o n criteria are defi ne d s uc h t hat t he selecte d v o l u nteer s will be free of a n y 
sig nifica nt ill ness w he n i ncl u de d i n t he st u d y a n d t hat t he y d o n ot recei ve m e dicat i on e x pecte d 
t o i m pact o bser vati ons (see Secti o n 4. 4. 1 ).
B ac k gr o u n d - I n h al ati o n P K
C o ntrar y  to plas ma c o nce ntratio n -ti me ( P K) pr ofiles of  oral dr u g a d mi nistrati o n, pr ofiles of 
i n hale d a d mi nistrati o n are i nfl ue nce d b y a bs or pti o n fr om t he l u n g . Pa rtic ularl y f or c o m p o u n ds 
wi t h lo w s olu bili t y, l u n g a bs or ptio n ma y be slo w a n d ma y str o n gl y affect t he o bser ve d P K 
pl as ma pr ofile.
If t his is t he case, t he late p hase of  t he pl as ma P K pr ofile is dri ve n b y b ot h pr ocesses – l un g 
a bs or ptio n a n d plas ma cleara nc e – at t he sa me time . Esti mat i n g plas ma cleara nce base d o n 
s uc h a n i n halati o n pr ofile al one is mislea di n g, as t he cleara nce est i mate will al wa ys c o ntai n t he 
u n k n o w n c o m p o ne nt of l u n g a bs or pti o n.
B ac k gr o u n d - Rele v a nce a n d A p plic ati o n of I V P K I nf or m ati o n
T he i n di vi d ual c o ntri b utio ns of  plas ma cleara nce a n d l u n g a bs or ptio n ca n be se parate d b y 
deter mi ni n g plas ma cleara nce fr o m a n I V a d mi nistrati o n pr ofile . Wit h I V a d mi nistrati o n, l u n g 
a bs or ptio n ca n n ot i nfl ue nce t he eli mi nat i on p hase, t hus all o wi n g f or a n u n b iase d 
c haracterizat i on of  plas ma cleara nce. O nce plas ma cleara nce is k n o w n, t he i m pact of  lu n g 
a bs or ptio n o n t he pr ofile after i n halat i on ca n be de d uce d.
C haracterizi n g t he e xte nt a n d ti me c o urse of l u n g a bs or ptio n will  aid d os e s el ect i on f or f ut ure 
st u die s. I ncl u di n g e x peri me ntal i nf or mati o n o n l u n g a bs or ptio n i nto P K m o dels will ma ke 
pre di ct i ons m o re i nf or mati ve a n d relia ble; t his i n t ur n will ma ke t he m o dels m o re val ua ble i n 
s u p p orti n g t he desi g n a n d i nter pretati o n of t he o n g oi n g a n d f ut ure st u dies.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
S afe t y of I V A d mi nistr ati o n
T he first (a n d l owest) I V d ose i n t he pr o p ose d st u d y was c h ose n t o be at t he l ow e n d of  the 
i n vesti gate d d ose ra n ge (see Sect i on 3. 4. 6 ). T he res ultin g e x p os ure fr o m t his d ose wa s, as
pre di cte d, well
b el o w t he ma xi m u m allo we d e x p os ure ( 1% of  Cma x, 0. 3 % of  AU C) . T h e 
e x p os ure at t he sec o n d d ose is als o pre dicte d t o be well bel o w t he ma xi m u m all o we d e x p os ure 
( 4. 4 % of Cma x , 1. 2 % of A U C) . T he res ult i n g Cma x is pre dicte d t o be 3 2 % of t he pre dicte d C ma x
a n d 3 % of t he pre dicte d A U C f or t he hi g hest pla n ne d S A D d ose, 
 (see Ta ble 3. 6 - 1).
R o utes of meta b o lis m a n d e xcreti on of A Z D 0 4 4 9 i n plas ma after I V a d mi nistrati o n will be t he 
sa me as f or t he s yste micall y a vaila ble d ose part after i n halat i on . As n o l u n g a bs or pti o n ca n ta ke 
pl ace wit h I V a d mi nistrati o n, plas ma half-life is e x pecte d t o be s h orter t ha n after i n halat i on.
As t he st u di e d I V d ose is at t he lo w e n d of t he i n vesti gate d d ose ra n ge (see Secti o n 3. 4. 6 ) a n d 
o nl y  a si n gle d ose is gi ve n, s yste mic effects are n ot e x pecte d base d o n pre-cli nical data. I n t he 
d o g, dail y I V d osi n g of 1 m g/ k g f or a peri o d of 3 m o nt hs was well t olerate d, wit h a n ac hie ve d 
C ma x of  54 4 0 n m o l/ L a n d A U C of  59 4 0 n m o l.h/ L, gi vi n g a n 8 5 0 -f ol d mar gi n f or C ma x a n d a 
2 8 3- f ol d mar gi n f or AU C c o m pare d t o t he pre di cte d e x p os ure of t he pla n ne d h u ma n I V d ose .
Cli nical data fr om or al  JA K i n hi bit ors i ncl u di n g r u x olitini b or t of acitini b [1 7 ] s u g gest t hat a 
si n gle d ose is li kel y t o be well t olerate d (see als o Secti o n 4. 2. 1 ).
Ge ner al D osi n g Str ate g y
In Part 1 b, A Z D 0 4 4 9 will  be a d mi nistere d i nitiall y (first I V co h ort) as a si n gle, fi xe d I V d ose 
 t o 6 v ol u nteer s w h o partici pate d i n a n d recei ve d a si n gle i n hale d d ose of A Z D 0 4 4 9 
i n P art 1a . If t he v ol u nteer is a naï ve v o l unt eer , t he n t he y will first recei ve t he I V d ose of  
A Z D 0 4 4 9 f o ll owe d b y a si n gle i n hale d d ose of A Z D 0 4 4 9 . F or t he sec o n d I V co h ort, A Z D 0 4 4 9 
will be a d mi nistere d as a si n gle, fi xe d I V d ose 
 t o 6 naï ve v o l unt eer s. T he rati o nale 
f or t he c h oice of d ose is descri be d i n detail i n Secti o n 3. 5. 2 .
B ot h I V co h ort s will be prece de d b y a se nti nel c o h ort (see Secti o n 3. 5. 2. 2 ). T he re mai ni n g 
v o l unt eer s of  eac h c o h ort will o nl y be d ose d aft er t he 2 4 -h o ur safety data fr o m t he se nti nel 
v o l unt eer s ha ve bee n re vie we d.
2 -st a ge Desi g n
T he 2 -sta ge desig n ma kes it p ossi ble t o st u d y diffe re nt treat me nts wit hi n t he sa me i n di vi d ual, 
s o t hat eac h v o l unt eer
ser ves as t heir o w n c o ntr ol. T his 
re d uces t he i m pact of  
bet wee n -v o l unt eer varia bilit y,  t hus m a ki n g t he st u d y r es ults clearer a n d m o re relia ble. T his i n 
t ur n hel ps t o re d uce p o p ulati on size a n d ma kes t he res ults more i nf or m at i ve.
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he v o l unt eer recei vi n g t he first I V d ose of  AZ D 0 4 4 9 will alrea d y ha ve bee n e x p ose d t o a 
si n gle i n hale d d ose of A Z D 0 4 4 9 i n Part 1a ( S A D), or if t he v o l unt eer is a naï ve v o l unt eer (first 
I V c o h ort) t he n t he y will first recei ve t he I V d ose of  AZ D 0 4 4 9 f oll owe d b y a si n gle i n hale d 
d ose of A Z D 0 4 4 9.
T his will ma ke t his t he first v o l unt eer recei vi n g m ulti ple d osi n g of A Z D 0 4 4 9. T o pre ve nt carr y 
o ver, b ot h d osi n g occasi o ns will be se parate d b y  a was h o ut peri od of at least 2 wee ks.
4. 1. 3.
R ati o n ale f or Desi g n of P art 2 a/ b
St u d y  Part 2a/ b will assess t he safet y,  t olera bilit y, a n d m ult i ple d ose P K i n healt hy v o l unt eers 
a n d patie nts wit h mil d ast h ma. I n a d dit i on, t he effect of i n hale d A Z D 0 4 4 9 o n Fe N O i n patie nts 
wi t h mil d ast h ma will be e xa mi ne d. T he Fe N O data fr o m Part 2a will be a nal y se d t o get her wit h 
t he data fr o m Part 3 a.
T he c o m bi ne d data fr o m P art 2 - 3 will g ui de t he desi g n o f t he f ut ure d ose ra n ge fi n di n g st u d y.
T he P K a n d safety data fr om Part 2a/ b will be i m p orta nt t o g ui de a p ote nti al treat me nt of 
C O VI D -1 9 ass oci ate d i nfla m mat or y res pirat or y disease.
St u d y P o p ul ati o n
Part 2 will be per f or me d i n patie nts wi t h mil d ast h ma( Part 2a) a n d healt h y v o l unt eers ( Part 2 b) . 
U nli ke i n Part 1 a a n d Part 1 b (first I V c o h ort) , female patie nts of  chil d beari n g p ote nti al w h o 
meet t he rele va nt i ncl usi on/e xcl usi o n  crit eria (e g ne gat i ve pre g na nc y test, n o breastfee di n g, 
usi n g a hi g hl y effect i ve c o ntrace ptio n met h o d wi t h a n a d ditio nal barri er met h o d of eit her t he 
fe male patie nt or t he part ner) ma y als o be e nr o lle d. T he i ncl usi on a n d e xcl usi o n crit eria are 
defi ne d s uc h t hat t he selecte d pati e nts will be free of  an y sig nifica nt ill ness ot her t ha n mil d 
ast h ma w he n i ncl u de d i n t he st u d y. T his mil d ast h ma p o p ulat i on will be ot her wise healt h y a n d 
sta ble, wit h n o ot her c o m o r bidi ties. Me di cat i on use will be li mite d b y treat me nt hist or y  an d 
occasi o nal s h ort acti n g beta a g o nists f or resc ue, t his will e ns ure i ncl usi on of  a sta ble/r o b ust 
p o p ul at i on wi t h a lo w ris k f or i nterfere nces ca use d b y  disease or me dicat i on.
P ati e nts were c h ose n f or t he l o w d ose le vels i n t he M A D t o i de nt if y tar get e n ga ge me nt, t o ha ve 
a disease mar ker, a n d t o m eas ure a res p o nse t o treat me nt. Alt ho u g h n ot all  pat ient s wit h mil d 
ast h ma ha ve ele vate d Fe N O, t here is a s u b p o p ulati on t hat will ha ve ele vate d Fe N O. Heal t h y 
v o l unt eers were c h ose n f or t he hi g hest d ose lev el  
 i n t he M A D t o n ot stu d y tar get 
e n ga ge me nt i n t his c o h ort a n d i nstea d p erf or m  that assess me nt i n t he Part 3a/ b wi t h D PI 
f or mulat i on. T he D PI f or m ulat i on is i nte n de d t o be use d i n f ut ure cli nical d e v el o p me nt st u di es 
f or treat me nt of  ast h ma.
Fract i onal e x hale d nit ric o xi de will be use d as a mar ker of tar get e n ga ge me nt si nce nitric o xi de 
is d o w n -strea m fr o m IL 1 3/I L 4 me d iate d acti vat i o n of  JA K 1/ S T A T 6 via i N O S. Fract i ona l 
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
e x hale d nit ric o xi de le vels are als o ass ociate d wit h ast h ma disease act i vity i ncl u di n g i ncrease d 
ris k f or e xacer bati ons. I n t his st u d y, t he a bility o f A Z D 0 4 4 9 t o decrease Fe N O b ot h as a mar ker 
of  tar get e n gage me nt will be teste d.
Part 2a/ b of  t his st u d y will i ncl u de b ot h pati e nts a n d healt h y v o l unt eers. T he i n vesti gati on of  
P K a n d safet y ca n be d o ne e q uall y s afe a n d i nf or mati ve i n b ot h p o p ul at i ons. I n Part 2a, t ar get 
e n ga ge me nt ca n als o be st u die d.
Ge ner al D o si n g Str ate g y
A Z D 0 4 4 9 will be a d mi nistere d i n a sta n dar d M A D se q ue nt ial gr o u p desi g n, i e, eac h patie nt i n 
t his st u d y part will recei ve A Z D 0 4 4 9 o ver 1 2 da ys a n d t he d ose will be i ncrease d ste p-wi s e 
bet wee n c o h orts.
T he rati o nale f or d osi n g a n d d ose escalat i o n is descri be d i n detail i n Secti on 3. 5. 3 .
Eac h c o h ort will be prece de d b y a se nt i nel c o h ort (see Secti o n 3. 5. 3. 2 ) w hic h will first recei ve 
a si n gle d ose of A Z D 0 4 4 9 . D osi n g f or t he se nti nel patie nts will be c o nt i n ue d a n d t he re mai ni n g 
patie nts of  eac h c o h ort will o nl y be d ose d aft er t h e 2 4- h o ur safety data fr o m t he first d ose i n 
t he se nt i nel pat ient s ha ve bee n re vie we d . T he re ma i ni n g patie nts f or eac h c o h ort will be d ose d 
at least 4 8 h o urs after t he se nt i nel c o h ort.
O bser vi n g t he se nti nel c o h orts aft er t he first d ose o ver 2 4 h o urs is dee me d s ufficie nt as t he 
p har mac o l og y  of J A K i n hi biti on is well  -u n derst o o d . T he ris k of  off -t arget effects is l ow as 
descri be d i n Secti o n 4. 2. 3 . Cli nical data are a vaila ble f or or al  JA K i n hi bit ors, s u g gesti n g 
ge nerall y g o o d safety a n d t olera bility ( mor e details i n Secti o n 4. 2. 1 ). K n o w n a d verse effects 
of  JA K i n hi bit i on are u nli kel y t o be o bser ve d i n a se nt i nel c o h ort i n t his st u d y, e ve n o ver a ti me 
l on ger t ha n 2 4 h o urs . As a n e xa m ple, t he oral J A K i n hi bit or t ofaciti ni b is a p pr o ve d i n E U f or 
t he treat me nt of  rhe u mat oi d art hritis. F or t his me dicat i on a n i ncrease d ris k of  infect i ons 
i ncl u di n g reacti vati on of  viral i nfecti o ns a n d t u berc ulosis ( T B) has bee n re p orte d. Lar ge 
o verl a p has bee n re p orte d i n t he safety pr ofiles of vari o us J A K i n hi bit ors [2 0 ]. Wit h t he l ow 
s yste mic e x p os ure ac hie ve d aft er i n halati on, a n d t he li mite d d urati o n of  st u d y treat me nt, t he 
ris k f or i nfecti ons is l ow. Se nti nel d osi n g of a n y le n gt h d oes n ot see m s uita ble t o a d dress t his 
l ow ris k. T he 2 4- h o ur se nti nel d osi n g i n t his st u d y was i ncl u de d as a ge neral preca uti o n i n a 
first-i n patient - setti n g.
Pl ace b o C o ntr ol
T he st u d y incl u des place b o c o ntr ol in or der i de ntif y effects t hat relate t o dr u g a d mi nistrati o n 
rat her t ha n t he st u d y pr oce d ures or sit uati o n.
R a n d o miz ati o n a n d Bli n di n g


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Treat me nts are ra n d o mize d, a n d st u d y pati e nts will be bli n de d t o treat me nt all ocat i on 
(si n gle-bli n d desi g n) t o mi ni mize bias . T he st u d y is si n gle rat her t ha n d o u ble -bli n d as s pecifie d 
P are xel pers o n nel nee d t o be u n bli n de d f or t he d ose escalat i on decisi o ns ma d e b y t he S R C .
H o we ver, site pers o n nel ma na gi n g t he st u d y patie nt s will be bli n de d t o t he e xte nt p ossi ble 
w hile mi ni mizi n g a n y  i m pact o n data c ollecti on.
4. 1. 4.
R ati o n ale f or Desi g n of P art 3 a/ b
I n Part 3a a n d Part 3 b , A Z D 0 4 4 9 will be a d mi nistere d as a D PI i n pati e nts wi t h mil d ast h ma 
a n d heal t hy v o l unt eers. F or later cli nical st u dies a n d c o m mercial use a D PI f or m ulat i on will be 
de vel o pe d . A P K, P D, a n d safet y D PI/ P o M stu d y will be p erf or m e d i n Part 3a t o c haracterize 
t he pr o perties of  AZ D 0 4 4 9 w he n a d mi nistere d as a D PI f or mulat i on. Part 3a will ha ve 
statistical p o wer t o st u d y P o M base d o n Fe N O . T he res ults will be use d t o s u p p ort f ut ure st u d y 
desi g n. T he decisi o n  t o start Part 3a w o ul d be ma de at an S R C meet i n g w he n Part 2a/ b of  t he 
st u d y has bee n c om p lete d. I n a sit uati o n w here mil d ast h matics ca n n ot be recr uite d t o t he st u d y 
t here will be a n o pti o n t o stu d y safety a n d P K, b ut n ot P D, i n a n o pti o nal  co h ort i n healt h y 
v o l unt eers ( Part 3 b) .
B ac k gr o u n d D PI/ P o M
T he pr o perti es of  ne b ulize d f or mulati o ns differ fr o m th ose of  DPI f or mulat i ons, lea di n g t o 
differe nces i n l u n g de p ositio n patter ns a n d P K pr ofiles . It will be p ossi ble t o c o m p ar e pl as m a 
P K pr ofiles f or b ot h f or mulat i ons. T he c urre nt st u d y desi g n will n ot all o w f or direct c o mparis o n 
bet wee n 2 i de ntical c o h orts w he n t he o nl y differe nce is f or m ulat i on. I nstea d a c o m bi nat i on o f 
all a vaila ble lear ni n gs fr om t he differe nt st u d y p arts will be use d t o c haracterize t he p ossi ble 
P K a n d P D differe nces bet wee n D PI a n d ne b ulize d f or mulat i on. C o m pari n g t he plas ma P K 
pr ofiles of  bot h  for m ulat i ons will hel p t o better u n dersta n d t he c haracteristics of  th e 
f or mulat i ons.
T he res ults will be use d t o s u p p ort f ut ure st u d y  desi g n a n d i nter pretati o n.
St u d y P o p ul ati o n
T his st u d y part ca n be p erf or me d i n pat ient s wi t h mil d ast h ma wi t h ele vate d Fe N O wi t h th e 
sa me i ncl usi o n a n d e xcl usi on crit eria as f or Part 2 a or alter nati vel y i n heal t h y v o l unt eers wit h 
t he sa me i ncl usi o n a n d e xcl usi o n cr iteria as f or Part 2 b . T hi s is t o e ns ure t hat res ults are direct l y 
c o mpara ble .
Ge ner al D osi n g Str ate g y
A Z D 0 4 4 9 will be a d mi nistere d at o ne d ose le v el. T he d ose will be u p t o t he hi g hest d ose t hat 
will be use d i n Part 2a/ b ( M A D).


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he rati o nale f or d osi n g is descri be d i n detail i n Secti o n 3. 5. 4 .
T he c o h ort will start wit h a se nt i nel pair (see Secti o n 3. 5. 4. 2 ) w hic h will recei ve a si n gle d ose 
of  A Z D 0 4 4 9 first.
T he details o n t his se nt i nel c o h ort a n d t he rati o nale f or it are t he sa me as descri be d f or Part 2a/ b 
( M A D) i n t he pre vi o us secti on ( Secti o n 4. 1. 3 ).
Pl ace b o C o ntr ol
T he st u d y incl u des place b o c o ntr ol in or der i de ntif y effects t hat relate t o dr u g a d mi nistrati o n 
rat her t ha n t he st u d y pr oce d ures or sit uati o n.
R a n d o miz ati o n a n d Bli n di n g
Treat me nts are ra n d o mize d, a n d st u d y pati e nt s will be bli n de d t o treat me nt all ocat i on 
(si n gle-bli n d desi g n) t o mi ni mize bias . T he st u d y is si n gle rat her t ha n d o u ble -bli n d as s pecifie d 
P are xel pers o n nel nee d t o be u n bli n de d f or t he d ose escalat i on decisi o ns ma d e b y t he S R C . 
H o we ver, site pers o n nel ma na gi n g t he st u d y patie nt s will be bli n de d t o t he e xte nt p ossi ble 
w hile mi ni mizi n g a n y  i m pact o n data c ollecti on.
4. 2.
De gree of U ncert ai nt y
4. 2. 1.  
U ncert ai nt y Ass oci ate d wit h t he M o de of Acti o n
T his will be t he first ti me t hat A Z D 0 4 4 9 is st u die d i n h u ma ns, h o wever, A Z D 0 4 4 9 is n ot fi rst 
i n class, as t here are J A K i n hi bit ors b ot h i n cli nical de vel o p me nt a n d o n t he mar ket.
G D C - 0 2 1 4 ( R G-6 1 5 1) a n d V R 5 8 8 are e xa m ples of  in hale d p a n -J A K i n hi bit ors t hat are i n 
cli nical de vel o p me nt . G D C -0 2 1 4 ( R G -6 1 5 1) is a J A K i n hi bit or de vel o pe d b y Ge ne ntec h a n d 
is c urre ntl y un der g o i n g P hase I cli nical trials. V R 5 8 8 is a n i n hale d J A K i n hi bit or de vel o pe d b y 
Verte x t hat is c urre nt l y i n pre-cli nical de vel o p me nt.
R u x o liti ni b a n d t ofacitini b are e xa m ples of  ap pr o ve d or al  JA K i n hi bit ors. R u x olit i ni b is a 
p ote nt a n d selecti ve J A K 1 a n d J A K 2 i n hi bit or a p pr o ve d f or t he treat me nt of  myel o fi br osis.
T of acitini b is s a p ote nt, selecti ve J A K i n hi bit or t hat prefere ntiall y in hi bi ts J A K 1 a n d J A K 3.
T he oral  J A K i n hi bit or t ofaciti ni b is a p pr o ve d i n E U f or t he treat me nt of r he u mat oid art hri tis.
T his me d icati on has bee n ass ociate d wit h a n i ncrease d ris k of  reactivati o n of  viral i nfecti o ns 
i ncl u di n g her pes z oster, as well as p ote ntiall y T B.
Ris ks Rel ate d t o I m m u ne S u p pressi o n
Ja n us ki nase i n hi bit ors ha ve i m m u n os u p pressi ve pr o perties a n d t he maj o r effect has bee n 
s u g geste d t o be o n l y m p h oc y t es. T he ris k of  serio us i nfecti ons of  JA K i n hi bit ors is si milar t o 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
t u mor necr osis fact or bl oc kers a n d ot her bi o l ogi cs i n r he u mat oi d art hrit is patient s. T he ‘ her pes 
z ost er si gnal’ see ms t o be a “class effect” as m o st J A K i n hi bit ors s h o w a n ele vate d ris k [2 0 ].
It is c o nsi dere d t hat i n hale d A Z D 0 4 4 9 has a l o wer o verall ris k of ca usi n g i nfecti o ns c o m pare d 
wi t h oral J A K i n hi bit ors. H o we ver, i n hale d a d mi nistratio n of  the dr u g necessitates s pecial 
atte ntio n o n p ul m o n ar y infect i ons (see Sect i on 4. 4. 2 ).
D ose -res p o nse Rel ati o ns hi p
A Z D 0 4 4 9 acts as a n a nta g o nist o n J A K 1 a n d is a c o mpet iti ve, re versi ble i n hi bit or of 
I L 4-sig nali n g , see Secti o n 1. 2. 1 f or m o re i nf or mati o n o n t he m o de of  actio n. T he d ose -res p o nse 
of  AZ D 0 4 4 9 is well descri be d i n pre -cli nical data o ver a wi de d ose ra n ge, s pa n ni n g 4 or ders 
of  ma g nit u de. T he d ose-e x p os ure relat i ons hi p was a p pr o xi matel y  li near; w hile t he d ose-effect  
r elat i ons hi p c o ul d be descri be d i n sta n dar d si g m o i dal mo dels.
I n t he h u ma n pri mar y cell s yste ms a n d a ni mal i n vi v o m o dels teste d, t here is n o i n dicat i on of 
stee p d ose -res p o nse c ur ves. Si milarl y, t here is n o i n dicati o n of  a stee p d ose-res p o nse c ur ve 
wi t h re gar ds t o pre -cli nical t o xicit y, w hile t he pr o p ose d cli nical d ose ra n ge is ≥1 0- f ol d l ower 
t ha n N O A E L d ose le vel i n t he m ost se nsit i ve s pecies.
4. 2. 2.
U ncert ai nt y Ass oci ate d wit h Bi o m ar kers
Fract i onal e x hale d nit ric o xi d e will be use d as a bi o m ar ker t o c haracterize t he pri mar y  PD of 
A Z D 0 4 4 9 . Ni tric o xi de is pr o d uce d b y iN O S i n l u n g e pit heli u m w hic h is a ge ne c o ntr olle d b y 
J A K 1/ S T A T 6.
C urre nt l y t here is n o bi omar ker a vaila ble f or safet y i n h u ma ns . As it is n ot possi ble t o m o nit or 
f or t h e l u n g pat h o l og y  fi n di n gs o bser ve d i n t he t o xic olo g y  st u dies, a 1 0-f ol d safety fact or has 
bee n a p plie d t o t he N O A E L d ose le vel i n t he m ost se nsit i ve s pecies t o deter mi ne t he ma xi m um 
all o we d i n hale d d ose (see Secti o n 3. 4. 7 ).
4. 2. 3.
U ncert ai nt y Ass oci ate d wit h t he N at ure of t he T ar get
T here is e xte nsi ve k n o wl e d ge a vaila ble a b o ut t he nat ure of  the tar get (J A K 1). Ti ss u e 
di stri b uti on is b r oa d a n d J A K 1 is e x presse d i n l u n g e pit heli u m a n d i m m u ne cells. Ja n us ki nase 
acti vat i on i n res p o nse t o c yt o ki ne rece pt ors (e g, I L 4/I L 1 3 rece pt or, I L 6 rece pt or) is well 
descri be d . T he d o w n -strea m effects of J A K are me diate d b y S T A T p h os p h or ylati on i ncl u di n g 
S T A T 3, 5, 6 . T he s yste mic i n hi bit i on of J A K res ults i n i m m u ne m o d ulati o n.
T here is a p ote ntial f or off -tar get i n hi biti on o f tar gets t hat are f u ncti o nall y cl o sel y relate d t o t he 
tar get. Cl osel y  relate d ki nases i n t he J A K famil y ma y be i n hi bite d, h o we ver, g o o d o verall 
ki nase selecti vity has bee n d e m o n strate d, wit h a di verse set of  in vit r o ra di oli ga n d bi n di n g, 
e nz y me a n d f u ncti onal a n d electr o p h ysiol o gi c al assa ys i ncl u di n g car diac i on c ha n nels, n ot 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
i de ntif yi n g a n y off-tar get acti vit ies li kel y t o be rele va nt i n or near t he e x pecte d pl as ma e x p os ure 
ra n ge i n h u ma ns.
Tar get i nteractio n st u dies ha ve bee n p erf or m e d. I n I L- 1 3-c halle n ge d mice, t he i n hi biti on of  
S T A T 6 
p h os p h or ylat i on 
was 
d e m o n strate d.
I n hi biti on 
of  aller gic i nfla m mati on 
i n 
O V A -c halle n ge d mic e was als o de mo nstrate d.
4. 2. 3. 1.
U ncert ai nt y Ass oci ate d wit h t he A v ail a ble A ni m al M o dels
T he st u die d a ni mal m o dels are direct l y rele va nt t o h u ma ns.
Act i vati on of  IL 4 rece pt or lea ds t o do w n -strea m a cti v atio n of  JA K 1 . T he cli nical efficac y of  
I L 4/I L 1 3 rece pt or a nta go ni sts (e g, d u pil u ma b) ha ve bee n d e m o nstrate d i n ast h ma. Si milar 
p ote nc y  on t he tar get has bee n o bser ve d bet wee n t est s pecies a n d h u ma n cell m o dels . T h e 
tra nslata bilit y bet wee n a ni mals a n d h u ma ns is g o o d, as J A K 1 is well c o nser ve d acr oss s pecies.
G o o d tr a nslat i on bet wee n test s pecies a n d cli nical efficac y has bee n d e m o n strate d f or 
a ut oi m m u ne diseases (e g, f or t ofacit i ni b w hic h is a p pr o ve d f or r he u mat oi d art hritis, as well as 
m ult i ple ot her c o m p o u n ds i n P hase II/III).
T he pre -cli nical data i ncl u de re peate d d ose data i n t he rat O V A m o d el . S y ste mic e x p os ure i n 
rat was describ e d at t h e p h ar m ac o d y na micall y act i ve d ose le vels. W hile s yste mic e x p os ure is 
n ot direct l y r ele v a nt t o l ocal effects i n t he l un g, t he relati ons hi p bet wee n L D D a n d plas ma 
le vels was esta blis he d pre -cli nicall y a n d descri be d i n t he P B P K m o d el  (see Secti o n 3. 6. 1 ).
K n o wl e d g e of t his relati ons hi p will s u p p ort i nter pretati o n of cli nical data.
T he M A B E L, P A D a n d pre dicte d h u ma n t hera pe utic d ose are base d o n data fr o m t he rat O V A 
m o d el . T he direct tra nslata bilit y of effects i n t he O V A m o del t o h u ma n ast h ma has n ot yet bee n 
s h o w n.
T he P D effects i n m o use, r at a n d d o g ha ve bee n descri be d (ie, t here is n o e vi de nce of  hi gh 
s pecies [ h u ma n] s pecificity of  t he I M P). Si milar p ote nci es ha ve bee n o bser ve d i n a ni mal a n d 
h u ma n cell -base d s yste ms, s u g gesti n g si milar bi n di n g affi nit ies a n d bi n di n g ki netics i n a ni mals 
a n d h u ma ns.
Pre -cli nical P K were a p pr o xi mate l y d ose li near. T he e x p os ure was n ot hi g her t ha n d ose 
pr o p orti o nal. Q uali tati vel y, t he met a b o lism bet wee n s pecies use d i n t he pre -cli nical st u dies is 
si milar t o h u ma ns. T he plas ma half -life aft er i n halati on is esti mate d t o lie ar o u n d 1 0 t o 
2 0 h o urs. T he h u ma n P K pre di ct i ons are dri ve n b y l u n g a bs or ptio n, pl as ma cleara nce a n d 
di stri b uti on. Cl eara nce is est i mate d base d o n well -esta blis he d h u ma n he pat oc y t e assa ys. 
A bs or pti o n a n d di stri b uti on pre di ct i ons are t he o utc o m e of  a pre vi o usl y esta blis he d P B P K 
m o d el  (see Secti o n 3. 6. 1 ). He nce, h u ma n P K pr e di ct i ons are well -s u p p orte d b y pre -cli nical
data.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 3 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
4. 2. 4.
U ncert ai nt y Ass oci ate d wit h N o n -cli nic al S afet y Fi n di n gs
A Z D 0 4 4 9 was well t olerate d i n all a ni mal t o xicit y st u dies a n d t here were n o A Z D 0 4 4 9 relate d 
deat hs or a d verse cli nical si g ns.
T he tar get or ga n of t o xicit y is t he l u n g.
N ota bl e l u n g pat h o l og y  (see Sect i on 1. 2. 2. 1 ) was o bser ve d i n t he r at b ut o nl y at hi g h d oses 
( greater t ha n 1 0- f ol d hi g her t ha n t he ma xi m u m pr o p ose d h u ma n i n hale d d ose) of  AZ D 0 4 4 9 .
T he mec ha nis m b y w hic h t he l un g pat h o l og y  fi n di n gs occ ur is u ncertai n, b ut t he y ar e 
c o nsi dere d t o be pri maril y dri ve n b y t he l o w s ol u bilit y of  AZ D 0 4 4 9 a n d d ose le vel (s u p p orte d 
b y a d ose -res p o nse relati o ns hi p a n d t he i de ntificati o n of  a clear n o effect level), h o we ver a 
p har mac o l ogi cal c o ntri b ut i on t o t he pat h o ge nesis of t he fi n di n gs ca n n ot be e ntirel y e xcl u de d.
4. 2. 5.
U ncert ai nties Ass oci ate d wit h t he D osi n g i n P art 3 a/ b
I n Part 3 a/ b, t he d ose is pla n ne d t o be t he sa me as i n t he c o h ort fr om Part 2a/ b ( M A D) wi t h t he 
hi g hest d ose level
 T here is a h y p ot heti cal ris k t hat t he D PI f or mulat i on use d i n 
Part 3a/ b res ults i n a hi g her s yste mic e x p os ure t ha n t he sa me d ose i n t he ne b ulize d f or m ulati on 
i n Part 2a/ b . T his is h o we ver u nli kel y as t he D PI f or m ulati o n is e x pecte d t o res ult i n l ower l u n g 
de p osi tio n t ha n t he ne b ulize d f or mulat i on . If n o safety c o ncer ns arise i n Part 2a/ b a n d t h e 
u p date d pre dict i ons f or Part 3a/ b s u g gest t hat t he s yste mic e x p os ure li mits will n ot be reac he d, 
t he o verall ris k ca n be re gar de d as l o w.
4. 3.
Ris ks Ass oci ate d wit h St u d y Desi g n a n d Pr oce d u res
4. 3. 1.  
Ris ks Deri vi n g fr o m t he C h ar acteristics of t he St u d y P o p ul ati o n
It is n ot e x pecte d t hat p ol y m or p his ms i n t he st u d y p o p ulati o ns will p ose a ris k as s yste mic 
e x p os ure will be l ow a n d n o i n dicati o n of  a si gnifica nt ris k f or dr u g -dr u g i nteractio ns w as 
f ou n d i n pre -cli nical st u dies (see Sect i on 4. 3. 2 ).
I n ge neral, a patie nt p o p ul atio n is re gar de d m o re v ul nera ble t ha n a heal t h y p o p ul atio n. 
H o we ver, t he mil d ast h mat ic p o p ulati o n i n Part 2a a n d Part 3a will be ot her wi se healt h y a n d 
sta ble, wit h n o ot her c o mor bi di ties (see Sectio n 4. 1. 3 ).
4. 3. 2.
Ris k f or D r u g -D r u g I nter acti o ns
N o ris ks of  PK dr u g -dr u g i nteractio ns ha ve bee n i de ntifie d base d o n pre -cli nical data . T he 
maj or meta b o lic pat h wa y f or A Z D 0 4 4 9 i n h u ma n he pat oc ytes is di rect gl uc ur o ni dat i on. I n vit r o
data as well  as t he l ow s yste mic e x p os ure res ult i n g fr o m i n halati on s u g gest a ver y lo w ris k of 
A Z D 0 4 4 9 t o alter t he P K of ot her c o m p o u n ds.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
As A Z D 0 4 4 9 is n ot ass ociate d wit h a n y dr u g -dr u g -i nteractio n ( D DI) ris k via C Y P 3 A 4 
i n d ucti on, h or m o nal  co ntrace pti o n will be c o nsi dere d as a n acce pta ble hi g hl y c o ntrace pti ve 
met h o d i n t he earl y p hase cli nical st u dies wit h A Z D 0 4 4 9 . A n y C Y P 3 A 4 i n d uci n g or i n hi bit i n g 
dr u g t hat m a y re d uce t he effect of h or m o nal c o ntrace pti ves will n ot be all o we d.
I n s u m mar y, t he ris k f or dr u g-dr u g i nteracti o ns wit h i n hale d A Z D 0 4 4 9 is c o nsi dere d l o w.
4. 3. 3.
Ris ks Deri vi n g fr o m St u d y Pr oce d ures
Pr oce d ures f or dr u g a d mi nistrati o n, sa m pli n g a n d assess me nts use d i n t his st u d y ar e 
well -esta blis he d a n d c o nsi dere d safe. N o c halle n ge a ge nts will be a d mi nistere d d uri n g t his 
st u d y.
Wit h I V a d mi nistratio n, t here is a ge neral ris k t hat ma xi m u m c o nce ntrati o ns are hi g her t ha n 
pre di cte d, as t his para meter is i ntri nsicall y diffic ult t o pre dict, partic ularl y i n a bse nce of h u ma n 
P K data . T hi s ris k will be mit i gate d b y selecti n g a ver y  lo w I V d ose, see Secti o n 3. 5. 2. 1 .
Secti o n 4. 1. 2 c o nt ai ns a de di cate d s u b-secti on disc ussi n g t he rati o nale f or safety of  IV 
a d mi nistrati o n.
4. 4.
Ris k - Be nefit Assess me nt
4. 4. 1.
Miti g ati o n Pl a n f or R at L u n g S afet y Fi n di n gs
T he ma xi m u m all o wa ble d ose of  
 has bee n calc ulate d b y a p pl yi n g a 1 0 -f ol d safety mar gi n 
t o t he N O A E L ( o n a m g d ose/ g l u n g ti ss ue basis) i n t he 6-m o nt h t o xicit y st u d y in t he rat . Rat 
was t he m ost se nsi tive s pecies f or l u n g pat h ol o g y  fi n di n gs (see Secti on 1. 2. 2. 1 ).
W hile it is n ot p ossi ble t o mo ni t or for t he l un g pat h ol o g y  fi n di n gs o bser ve d i n t he t o xic o l og y 
st u dies, l un g f unct i on will be m o nit or e d wi t h s pir o m etr y t o e val uate a n y br o nc h oc o nstrict i on.
P eri p heral  o x y ge n sat uratio n will be m o ni t or e d wit h p ulse o xi metr y .
4. 4. 2.
Miti g ati o n Pl a n f or Ris ks Rel ate d t o I m m u ne S u p pressi o n
E xcl usi o n crit eria ha ve bee n defi ne d i n or der t o a v o i d i ncl u di n g s u bjects wi t h rece nt ac ute 
i nfecti ons or ris k o f reacti vati on o f late nt i nfecti ons s uc h as T B a n d her pes z oster . Parti ci pat i ng 
s u bjects will be m o nit ore d f or i nfecti ons a n d will ha ve re g ular c o m plete bl o o d c o u nts i ncl u di n g 
differe nt ial w hite cell c o u nt d uri n g t he st u d y.
4. 4. 3.
Be nefit of Tre at me nt wit h I n h ale d A Z D 0 4 4 9
I n hale d A Z D 0 4 4 9 is e x pecte d t o be nefit patie nts wit h mo derate t o se v ere ast h ma b y re d uci n g 
o verall i nfla m mati on, re d uci n g res pirat or y e x a c er b atio ns as well  as i m pr o vi n g l u n g f unct i on.
It ma y als o re d uce t he nee d f or i n hale d a n d or al  corti c oster oids, w hic h ca n ca use h oarse ness 
a n d t hr us h f or s o me pat ient s, as well as pre ve nt t he nee d f or biol o gi cs, w hic h ca n be c ostl y.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
N o be nefit f or i n di vi d uals i n t his st u d y is ex pecte d .T here is h o we ver p ote nti al benefit f or f ut ure 
pati e nts recei vi n g A Z D 0 4 4 9.
4. 4. 4.
C o ncl usi o n Ris k -Be nefit Assess me nt
Base d o n p oi nts descri be d a b o ve, t he ris k -be ne fit r atio of  AZ D 0 4 4 9 is c o nsi dere d acce pta ble.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
5.
S T U D Y P O P U L A TI O N A N D R E S T RI C TI O N S
5. 1.
S u bject Selecti o n Criteri a
T he I n vestig at or s h o ul d kee p a s u bject scree ni n g l o g of  all p ote ntial  su bjects w h o c o nse nte d 
a n d were s u bjecte d t o scree ni n g pr oce d ures.
S u bjects w h o fail t o meet t he i ncl usi on crit eria or meet a n y e xcl usi o n crit erio n s h o uld n ot, 
u n der a n y circ u msta nces, be ra n d o mize d i nt o t he st u d y. T here ca n be n o e xce pti o ns t o t his r ule.
5. 1. 1.
P art 1 a/ b
5. 1. 1. 1.
I ncl usi o n Criteri a
F or i ncl usi o n i n t he st u d y healt h y v o l unt eers sh o ul d f ulfill t he f o ll owi n g cri t eria:
1.
Pr o visi o n of  si gne d a n d date d, wri tte n i nf or me d c o nse nt bef ore a n y st u d y specific 
pr oce d ures.
2.
Heal t h y male v o l unt eers a n d healt h y female v ol u nteers (for Part 1a a n d Part 1 b first I V 
c o h ort, fe male v o l unt eers must be of n o n- c hil d beari n g p ote ntial) , a ge d 1 8 t o 5 5 years wit h 
s uita ble vei ns f or ca n n ulati on or re peate d ve ni p u nct ure.
3.
Fe male pat ient s m u st n ot be lactati n g a n d m ust ha ve a ne gat i ve pre g na nc y t est at  the 
Scree ni n g Visi t a n d o n a d missi o n t o t he Cli nical U ni t. W o me n of  no n -c hil d beari n g 
p ote nti al must f ulfill  o n e of t h e foll o wi n g criteria :
3. 1. P os t me n o pa usal defi ne d as a me n orr hea f or at  least 1 2 m o nt hs or m o re f oll owi n g cessati o n 
of  all e x o ge n o us h or mo n al tr e at m e nts a n d f ollicle-sti m ulati n g h or m o ne ( F S H) levels i n t h e 
p ost m e n o pa usal ra n ge.
3. 2. D oc u m e nt atio n 
of  irre versi ble 
s ur gical 
sterilizati on 
b y 
h ysterect o m y, 
bilateral 
o o p h orect o m y  or bilateral sal pi n gect o m y b ut n ot t u bal li gati o n.
4.
Ha ve a b o d y mass i n de x ( B MI) bet wee n 1 8 a n d 3 0 k g/ m 2 i ncl usi ve a n d wei g h at least 6 0 k g.
5.
H ealt h y v o l unt eer has a F orce d E x pi rat or y Vol u me i n o ne sec o n d ( F E V1) ≥8 0 % of  th e 
pre di cte d val ue re gar di n g a ge, hei g ht, ge n der a n d et h nicit y at t he Scree ni n g Visit.
6.
Male 
v ol u nteers a n d t heir W O C B P part ners s h o uld be willi n g t o use hi g hl y effect i ve 
c o ntracept i on meas ures a n d s h o uld r efrai n fr om d o nati n g s per m or fat heri n g a c hil d fr om 
t he first da y of d osi n g u ntil 3 m o nt hs after t he last d ose of I M P .
7.
Fe male v o l unt eers i n Part 1 b sec o n d I V c o h ort s h o ul d be willi n g t o use hi g hl y effect i ve 
c o ntrace pti o n meas ure s fr om t he first d a y  of d osi n g u nt il 1 m o nt h aft er t he last d ose of 
I M P.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
8.
Pr o visi o n of  sig ne d, wri tte n a n d date d i nf or me d c o nse nt for o pti o nal  g e n etic researc h. If a 
v o l unt eer decli nes t o partici pate i n t he ge net ic c o m p o ne nt of  the st u d y, t here will be n o  
p e nalt y or l oss of  be nefit t o t he v o l unt eer . T he v o l u nteer will n ot be e xcl u de d fr om ot h er 
as pects of t he st u d y descri be d i n t his pr ot oc ol.
5. 1. 1. 2.
E xcl usi o n Criteri a
Heal t h y v ol u nteers m ust n ot be ra n d o mize d i n t he st u d y if a n y of t he f oll owi n g e xcl usi o n 
criteria are f ulfille d:
1.
Hi st or y of a n y cli nicall y i m p orta nt disease or di s or der w hic h, i n t he o pi ni o n of  th e 
I n vesti gat or, ma y eit her p ut t he v o l unt eer at ris k beca use of  partici pat i on i n t he st u d y, or 
i nfl ue nce t he res ults or t he v o l unt eer’s a bilit y t o p artici pate i n t he st u d y.
2.
Hi st or y of a n y res pirat or y dis or ders s uc h as ast h ma, c hr o nic o bstr ucti ve p ul m onar y  disease 
( C O P D) or i di o pat hic p ul m on ar y  fi br osis (I P F).
3.
Heal t h y v olu nteer has a n i ncrease d ris k of i nfecti o n:
3. 1. Hi st or y an d/ or prese nce of  TB; p osi tive res ult f or i nterfer o n ga m ma r elease assa y (I G R A) 
(ie, Q ua nti F E R O N T B -G ol d), v ol u nteers w h o ha ve resi de d i n r e gio ns w here T B a n d 
m yc osis are e n de mic d uri n g 9 0 d a y s bef ore scree ni n g, or w h o i nte n d t o visit s uc h a re gi o n 
d uri n g t he d urati o n o f the st u d y ie, desert a reas, Easter n E ur o pe, Ce ntral a n d S o ut h A merica, 
Afr ica (e xce pt E g y pt), R ussia, Asia, I n d o nesia. T he t est ma y be re peate d if t he i nitial t est 
res ult is i n deter mi nate.
3. 2. Hi st or y of her pes z oster i nfect i on.
3. 3. A n y p osi tive res ult f or ser u m he pat itis B s urface a nt i ge n, he pat itis C a nt i b o d y, h u ma n 
i m m u n o deficie nc y vir us ( HI V) a n d/ or T B at t he Scree ni n g Visit.
3. 4. Is i n hi g h ris k-gr o u p f or HI V i nfecti on wi t hi n t he last 6 m o nt hs (ie, me n w h o ha ve ha d 
u n pr otecte d se x wit h me n, w o me n w h o ha ve ha d se x wit h o ut a c o n d o m wit h me n w h o ha ve 
se x wi t h me n, pe o pl e w h o ha ve ha d se x wi t ho ut a c o n d o m wit h a pers o n w h o has li ve d or 
tra velle d i n Afr ica, p e o pl e w h o i nject dr u gs, pe o ple w h o ha ve ha d se x wi t ho ut a c o n d o m 
wi t h so m e b o d y wh o has i njecte d dr u gs, pe o ple w h o ha ve ca u g ht a n ot her se x uall y 
tra ns mitte d i nfecti on, pe o ple w h o ha ve recei ve d a bl o o d tra nsf usi o n w hile i n Africa, Easter n 
E ur o pe, t he c o u ntries of t he f or mer S o viet U ni o n, Asia or Ce ntral a n d S o ut h A merica).
3. 5. Ot her late nt or c hr o nic i nfecti ons (e g, rec urre nt si n usitis, ge ni t al or oc ul ar her pes, uri nar y 
tract i nfecti on) or at ris k of  infect i on (s ur ger y, tra u ma, or si gnifica nt i nfecti on) wit hi n 
9 0 d a y s of scree ni n g, or hist or y of s ki n a bscesses wit hi n 9 0 da ys o f scree ni n g.
3. 6. Cli nicall y si g nifica nt l ower res pirat or y tr a ct infecti o n n ot res ol ve d wi t hi n 4 wee ks pri or t o 
scree ni n g, as deter mi ne d b y t he I n vest i gat or.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 7. Hi st or y a n d / or prese nce of C O VI D- 1 9:
3. 7. 1. Heal t h y v o l unt eer w h o
has ha d a se vere c o urse of  CO VI D - 1 9 (ie, h os pi talizati on, 
e xtrac or p oreal me m bra ne o x y ge nat i on [E C M O ], mec ha nicall y ve nt ilate d).
3. 7. 2. Heal t h y v ol u nteer has cli nical si g ns a n d s y m pt o ms c o nsiste nt wit h C O VI D -1 9, e g,
fe ver, dr y  co u g h, d ys p nea, s ore t hr oat, fati g ue or c o nfir me d c urre nt i nfecti on b y 
a p pr o priate la b orat or y test wit hi n t he last 4 wee ks pri or t o scree ni n g or o n a d missi o n t o 
t he Cli nical U nit.
3. 7. 3. Heal t h y v o l unt eer has c o nfir me d C O VI D - 1 9 i nfecti o n b y P C R 
t est bef ore 
ra n d omizat i on.
3. 8. Hi st or y of ca ncer wi t hi n t he last 1 0 years ( 2 0 year s f or breast ca ncer) e xce pt f or basal a n d 
s q ua m o us cell carci n o ma o f the s k i n or i n situ carci n o ma o f the cer vi x treate d a n d c o nsi dere d 
c ure d. A n y hist or y  of ly m p h o ma is n ot all o we d.
3. 9. Di sease hist or y s u g gesti n g a b n or mal i m m u ne f u ncti o n.
3. 1 0. Ha ve recei ve d li ve or li ve -atte n uate d vacci ne i n t he 4 wee ks pri or t o d osi n g.
3. 1 1. Hi g h -se nsitivit y C- reacti ve pr otei n a b o ve u p per li mit of  la b orat or y refere nce ra n ge at  
scree ni n g a n d o n a d missi o n t o t he C li nical U nit .
3. 1 2. Has a b o d y  t e mperat ure of > 3 7. 7° C o n Da y -1, or as j u d ge d b y  t he I n vesti gat or.
3. 1 3. Has a n a bs ol ute ne utr o p hil c o u nt <l o wer li mit of n or mal ( L L N) at t he Scree ni n g Visit.
3. 1 4. Has a n a bs ol ute l y m p h oc y te c o u nt < L L N at t he Scree ni n g Visit.
4.
Hi st or y or prese nce of  gastr oi ntesti nal, he pat ic or re nal disease or a n y ot her c o n ditio n 
k n o w n t o i nterfere wit h a bs or pti o n, distri b ut i on, meta b olis m or e xcreti o n of dr u gs.
5.
A n y cli nicall y im p orta nt ill ness, me dical/s ur gical pr oce d ure or tra u ma wi t hi n 4 wee ks of  
t he first a d mi nistrati o n o f I M P.
6.
A n y la b orat or y val ues wi t h the f oll owi n g de viati o ns at t he Scree ni n g Visi t a n d o n 
a d missi o n t o t he Cli nical U nit . A b n or mal val ues ma y be r e peate d o nce at t he discreti o n of 
t he I n vest i gat or:
6. 1. Ala ni ne a mi n otra nsferase ( A L T) > u p per li mit of n or mal ( U L N).
6. 2. As partate a mi n otra nsferase ( A S T) > U L N.
6. 3. Creati ni ne > U L N.
6. 4. W hite bl o o d cell ( W B C) c o u nt < L L N.
6. 5. H e m o gl o bi n < L L N.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
7.
A n y cli nicall y im p orta nt a b n or malit ies i n cli nical c he mistr y, he mat ol o g y  or uri nal ysis 
res ults, ot her t ha n t h ose descri be d u n der e xcl usio n cri t eria n u m ber s 3 a n d 6, as j u d ge d b y 
t he I n vest i gat or.
8.
A b n or m al vital si g ns, after 1 0 mi n utes s u pi ne rest, as defi ne d bel o w. A b n or mal val ues ma y 
be re peate d o nce at t he discret i on of t he I n vest i gat or.
8. 1. S y st olic B P < 9 0 m m H g or > 1 4 0 m m H g.
8. 2. Di ast olic B P < 5 0 m m H g or > 9 0 m m H g.
8. 3. P ul se < 4 5 or > 8 5 beats per mi n ute ( b p m).
9.
A n y cli nicall y i m p orta nt a b n or malit ies i n r h yth m, c o n d ucti o n or m or p h o l og y  of t he resti n g 
E C G a n d a n y cli nicall y i m p orta nt a b n or malit ies i n t he 1 2 -lea d E C G as c o nsi dere d b y t h e 
I n vesti gat or t hat ma y i nterfere wi t h the i nter pretati o n of  QTc i nter val c ha n ges, i ncl u di n g 
a b n or mal S T - T-wa ve m o r p h ol o g y, partic ularl y in t he pr ot oc ol defi ne d pri mar y lea d o r left 
ve ntri c ular h y pertr o p h y.
9. 1. Pr ol o n ge d Q Tc F > 4 5 0 ms.
9. 2. S h orte ne d Q Tc F < 3 4 0 ms.
9. 3. Fa mil y  hist or y of lo n g Q T s y n dr o me.
9. 4. P R ( P Q) i nter val  s horte ni n g < 1 2 0 ms ( P R > 1 1 0 ms b ut < 1 2 0 ms is acce pta ble if t here is n o 
e vi de nce of ve ntric ular pre- e xcitat i on).
9. 5. P R ( P Q) i nter val pr ol o n gat i on ( > 2 2 0 ms) i nter mitte nt sec o n d ( We nc ke bac h bl oc k w hile 
aslee p is n ot e xcl usi ve) or t hir d -de gree atri o ve ntri c ular ( A V) bl oc k, or A V diss ociat i on.
9. 6. Persi ste nt or i nter mitte nt c o mplete b u n dle bra nc h bl oc k ( B B B), I B B B, or i ntra ve ntric ular 
c o nd ucti o n dela y  (I V C D) wi t h QR S > 1 1 0 ms . Heal t h y vol u nteers wi t h QR S > 1 1 0 ms b ut 
< 1 1 5 ms 
are acce pta ble if t here is n o e vi de nce of  eg, ve ntric ular h y pertr o p h y  or 
pre -e xcitat i on.
1 0. K n o w n or s us pecte d hist or y  of dr u g a b use as j u d ge d b y t he I n vesti gat or.
1 1. C urre nt s m okers or t hose w h o ha ve s mo ke d or use d nic oti ne pr o d ucts (i ncl u di n g e-
cigarettes ) wit hi n t he pre vi o us 6 m o nt hs or has s m o ki n g hist or y  of > 5 pac k years .
1 2. Hi st or y of alc o h ol a b use or e xcessi ve i nta ke of alc o h ol as j u d ge d b y t he I n vesti gat or.
1 3. P osi tive scree n f or dr u gs of a b use, c oti ni ne ( nic oti ne) or alc o h o l at t h e Scree ni n g Visi t or 
o n a d missi o n t o t he Cli nical U nit .
1 4. Hi st or y 
of 
se vere 
aller g y/ h y perse nsit i vity 
or 
o n g oi n g 
cli nicall y 
i m p orta nt 
aller g y/ h y perse nsit i vity, as j u d ge d b y t he I n vesti gat or or hist or y  of h y perse nsit i vity t o 
dr u gs wi t h a si milar c he mical str uct ure or class t o A Z D 0 4 4 9.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5. E xcessi ve i nta ke of caffei ne-c o ntai ni n g dri n ks or f o o d (e g, c offee, tea, c h oc olate) as j u d ge d 
b y t he I n vest i gat or.
1 6. Use of  dr u gs wi t h enz y me i n d uci n g pr o perti es s uc h as St J oh n’s W o rt wit hi n 3 wee ks 
bef ore t he first a d mi nistrati o n of I M P.
1 7. Use of  an y prescri be d or n o n prescri be d me dicati o n i ncl u di n g a ntacids, a nal gesics ( ot h er 
t ha n paraceta m o l/aceta mi n o p he n), her bal re me dies, me ga d ose vit a mi ns (int a ke of  20 t o 6 0 0 
ti mes t he rec o mme n de d dail y  dose) a n d mi nerals d uri n g t he 2 wee ks bef ore t he first 
a d mi nistrati o n of I M P or l o n ger if t he me dicat i on has a l o n g half -life.
1 8. Pl as ma d o nat i on wi t hi n 1 m o nt h of  the Scree ni n g Vi sit or a n y bl o o d d o nati o n/ bl o o d l oss 
> 5 0 0 m L d uri n g t he 3 m o nt hs b efore t he Scree ni n g Visit.
1 9. N o n -sterilize d male patient s w h o are se x uall y acti ve wit h a W O C B P a n d w h o d o n ot a gree 
t o a hi g hl y effecti ve met h o d of c o ntrace pti o n fr o m Da y 1 t o 3 m o nt hs after t he last d ose of 
t he I M P. W O C B P w h o are se x uall y act i ve wit h a fertile male part ner a n d w h o d o n ot a gree 
t o a hig hl y  effecti ve met h o d of c o ntrace pti o n t hat is descri be d i n Secti o n 5. 2. 3. 1 .
2 0. Has recei ve d a n ot her ne w c he mical ent ity ( defi ne d as a c o mp o u n d w hic h has n ot bee n 
a p pr o ve d f or mar keti n g) wi t hi n 3 m o nt hs of  t he first a d mi nistrati o n of  IM P i n t his st u d y.
T he peri o d of  e x clusi o n  be gi ns 3 m o nt hs af ter t he fi nal d os e or 1 m o nt h after t he last visit 
w hic he ver i s t he l on gest.
N ote: He alt hy v ol u nteers c o nse nte d a n d scree ne d, b ut n ot r a n d o mize d i n t his st u dy or a 
previ o us P h ase I st u dy, are n ot excl u de d.
2 1. Heal t h y v o l unt eers w h o ha ve pre vi o usl y recei ve d A Z D 0 4 4 9 ( Part 1 b sec o n d I V C o h ort 
o nl y).
2 2. I n v ol ve me nt of a n y Astra Ze neca or Cli nical U nit e m pl o yee or t heir cl ose relat i ves.
2 3. J u d g me nt b y t he I n vesti gat or t hat t he v o l unt eer s h o ul d n ot partici pate i n t he st u d y if t h e y 
ha ve a n y o n g o i n g or rece nt (ie, d uri n g t he scree ni n g peri o d ) mi n or me dical c om p lai nts t hat 
ma y i nter fere wi t h the i nter pretati o n of  st u d y data or are c o nsi dere d u nli kel y  to c o m p l y 
wi t h st u d y pr oce d ures, restricti ons a n d re q uire me nts.
2 4. Heal t h y v olu nteers w h o ca n n ot c o m m u nicate relia bl y wit h t he I n vesti gat or.
2 5. V ul nera ble heal t hy v o l unt eers, e g, ke pt i n dete n tio n, pr otecte d a d ults u n der g uar di a ns hi p, 
tr ustees hi p, or c o m mitte d t o a n i nstituti o n b y g o ver n me ntal  or juri dical  or der.
I n a d ditio n, a n y of  the f oll owi n g is re gar de d as a crit erio n f or e xcl usi o n fr om t he ge netic 
researc h:
2 6. Pre vi o us b o ne marr o w tra ns pla nt .


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
2 7. N o n -le u k oc yte de plete d w h ole bl o o d tra nsf usi on wit hi n 1 2 0 da ys o f the date of t he ge net ic 
sa m ple c ollecti on.
5. 1. 2.
P art 2 a/ b a n d P art 3 a/ b
5. 1. 2. 1.
I ncl usi o n Criteri a
F or i ncl usi o n i n t he st u d y s u bjects s h o ul d f ulfill t he f oll owi n g cri t eria:
5. 1. 2. 1. 1.
P atie nts wit h mil d ast h m a (P art 2 a a n d P art 3 a)
1.
Pr o visi o n of  si gne d a n d date d, wri tte n i nf or me d c o nse nt bef ore a n y st u d y specific 
pr oce d ures.
2.
Male a n d female (i ncl u di n g W O C B P) patie nts wi t h mil d ast h ma a ge d 1 8 t o 5 5 ye ars wit h 
s uita ble vei ns f or ca n n ulati on or re peate d ve ni p u nct ure.
3.
P ati e nts m ust be willi n g t o re mai n i n h o use at t he st u d y ce nter f or 1 6 c o nsec ut i ve d a ys
( Part 2a) or f or 3 0 c o nsec uti ve da ys ( Part 3a).
4.
Fe male pat ient s m u st n ot be lactati n g a n d m ust ha ve a ne gat i ve pre g na nc y t est at  the 
Scree ni n g Visi t a n d o n a d missi o n to t he Cli nical U ni t. W o me n of  no n -c hil d beari n g 
p ote nti al must f ulfil l o n e of  t h e foll o wi n g criteria:
4. 1. P os t me n o pa usal defi ne d as a me n orr hea f or at  least 1 2 m o nt hs or m o re f oll owi n g cessati o n 
of  all e x o ge n o us h or m o nal treat me nts a n d F S H le vels i n t he p ost me n opa usal ra n ge.
4. 2. D oc u m e nt atio n 
of  irre versi ble 
s ur gical 
sterilizati on 
b y 
h ysterect o m y, 
bilateral 
o o p h orect o m y  or bilateral sal pi n gect o m y b ut n ot t u bal li gati o n.
5.
Ha ve a B MI bet wee n 1 8 a n d 3 5 k g/ m 2 i ncl usi ve a n d wei g h at least 5 0 k g.
6.
P h ysicia n dia g n ose d ( mil d) ast h ma f or at least 6 m o nt hs pri or t o scree ni n g.
7.
L u n g f uncti o n ≥7 0 % pre di cte d f or F orce d E x pi r at or y Vol u me i n 1 sec o n d ( F E V1) at t he 
Scree ni n g Vi sit A N D at t he 1 2 h ti me p oi nt o n Da y -1, i n acc or da nce wi t h the A merica n 
T h oracic S ociet y ( A T S)/ E ur o pea n Res pirat or y S ociety ( E R S) crit eria.
8.
Ha ve a Fe N O of ≥3 0 p p b at t he Scree ni n g Visit a n d at t he 1 2 h ti me p o i nt o n Da y - 1.
9.
Male 
pati e nts a n d t heir W O C B P part ners s h o ul d be willi n g t o use hi g hl y effect i ve 
c o ntrace pti o n meas ures a n d s h o uld r efrai n fr om d o nati n g s per m or f at heri n g a c hil d fr om 
t he first da y of d osi n g u ntil 3 m o nt hs after t he last d ose of I M P.
1 0. Fe male pati e nts s h o uld be willi n g t o use hi g hl y  effecti ve c o ntrace ptio n meas ures fr o m  t he 
first d a y of d osi n g u ntil 1 m o nt h after t he last d ose of I M P.
1 1. Pr o visi o n o f sig ne d, wri tte n a n d date d i nf or me d c o nse nt for o pti o nal  g e n etic researc h. If a 
patie nt decli nes t o partici pate i n t he ge net ic c om p o ne nt of  the st u d y, t here will be n o pe nalt y 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
or l oss of  be nefit t o t h e p atie nt. T he patie nt will not be e xcl u de d fr om ot her as pects of t he 
st u d y descri be d i n t his pr ot oc ol.
5. 1. 2. 1. 2.
He alt h y v ol u nteers ( P art 2 b a n d P art 3 b)
1.
Pr o visi o n of  si gne d a n d date d, wri tte n i nf or me d c o nse nt bef ore a n y st u d y specific 
pr oce d ures.
2.
Heal t h y male a n d fe male (i ncl u di n g W O C B P) v o l unt eers a ge d 1 8 t o 5 5 years wi t h s uita ble 
vei ns f or ca n n ulat i on or re peate d ve ni p u nct ure.
3.
Fe males m ust n ot be lactati n g a n d m ust ha ve a ne gati ve pre g na nc y  test at t he Scree ni n g 
Vi sit a n d o n a d missi o n t o t he Cli nical U ni t. W o me n of  no n -c hil d beari n g p ote nti al must  
f ulfill o n e of  t he f oll owi n g cri t eria:
3. 1. P os t me n o pa usal defi ne d as a me n orr hea f or at  least 1 2 m o nt hs or m o re f oll owi n g cessati o n 
of  all e x o ge n o us h or m o nal treat me nts a n d F S H le vels i n t he p ost me n o pa usal ra n ge.
3. 2. D oc u m e nt atio n 
of  irre versi ble 
s ur gical 
sterilizati on 
b y
h ysterect o m y, 
bilateral 
o o p h orect o m y  or bilateral sal pi n gect o m y b ut n ot t u bal li gati o n.
4.
Ha ve a B MI bet wee n 1 8 a n d 3 0 k g/ m 2 i ncl usi ve a n d wei g h at least 6 0 k g.
5.
Heal t h y v o l unt eer has a F orce d E x pi rat or y Vol u me i n o ne sec o n d ( F E V1) ≥8 0 % of  th e 
pre di cte d val u e re gar di n g a ge, hei g ht, ge n der a n d et h nicit y at  the Scree ni n g Visit a n d at t he 
1 2 h ti me p o i nt o n Da y -1, i n acc or da nce wit h t he A T S/ E R S criteria .
6.
Fe male v o l unt eers s h o uld be willi n g t o use hi g hl y effect i ve c o ntrace pti o n meas ures fr om 
t he first da y of d osin g u nt il 1 m o nt h after t he last d ose of I M P
7.
Male 
v ol u nteers a n d t heir W O C B P part ners s h o uld be willi n g t o use hi g hl y effecti ve 
c o ntrace pti o n meas ures a n d s h o uld r efrai n fr om d o nati n g s per m or fat heri n g a c hil d fr om 
t he first da y of d osi n g u ntil 3 m o nt hs a fter t he last d ose of I M P.
8.
Pr o visi o n of  sig ne d, wri tte n a n d date d i nf or me d c o nse nt for o pti o nal  g e n etic researc h. If a 
healt h y v ol u nteer decli nes t o partici pate i n t he ge neti c c o m p o ne nt of t he st u d y, t here will 
be n o pe nal t y or loss of be nefi t t o t h e healt h y v o l unt eer . T he healt h y v o l unt eer will n ot be 
e xcl u de d fr o m ot her as pects of t he st u d y  descri be d i n t his pr ot oc ol.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 4 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
5. 1. 2. 2.
E xcl usi o n Criteri a
S u bject s m ust n ot be ra n d omize d i n t he st u d y if a n y of  the f oll owi n g e xcl usio n criteria are 
f ulfille d:
5. 1. 2. 2. 1. 
P atie nts wit h mil d ast h m a ( P art 2 a a n d P art 3 a)
1.
Hi st or y of a n y cli nicall y im p orta nt disease ot her t ha n ast h ma, or dis or der w hic h, i n t he 
o pi ni o n of t he I n vesti gat or, ma y eit her p ut t he patie nt at ris k beca use of partici pat i on i n t he 
st u d y, or i nfl ue nce t he res ults or t he pati e nt’s a bilit y t o p artici pate i n t he st u d y.
2.
Hi st or y of a n y r es pir at or y dis or ders s uc h as, C O P D or I P F.
3.
P ati e nt has a n i ncrease d ris k o f i nfecti on:
3. 1. Hi st or y an d/ or prese nce of  TB; p osit i ve res ult f or I G R A (ie, Q ua nti F E R O N T B -G ol d), 
pati e nts w h o ha ve resi de d i n r e gio ns w here T B a n d m yc osis are e n de mic d uri n g 9 0 d a y s 
bef ore scree ni n g, or w h o i nte n d t o visit s uc h a r e gio n d uri n g t he d urati o n of  the stu d y ie, 
desert areas, Easter n E ur o pe, Ce ntral a n d S o ut h A merica, Afr ica (e xce pt E g y pt), R ussia, 
Asia, I n d o nesia. T he test ma y be re peate d if t he i nitial test res ult is i n deter mi nate.
3. 2. Hi st or y of her pes z oster i nfect i on.
3. 3. A n y p osit i ve res ult f or ser u m he patitis B s urface a nti ge n ( or a nti-H Bc a nt i b o d y i n Ger ma n y 
o nl y) , he patitis C a nt i b o d y, HI V a n d/ or T B at t he Scree ni n g Visit.
3. 4. Is i n hi g h ris k-gr o u p f or HI V i nfecti on wi t hi n t he last 6 m o nt hs (ie, me n w h o ha ve ha d 
u n pr otecte d se x wit h me n, w o me n w h o ha ve ha d se x wit h o ut a c o n d o m wit h me n w h o ha ve 
se x wi t h me n, pe o pl e w h o ha ve ha d se x wi t ho ut a c o n d o m wit h a perso n w h o has li ve d or 
tra velle d i n Afr ica, p e o pl e w h o i nject dr u gs, pe o ple w h o ha ve ha d se x wi t ho ut a c o n d o m 
wi t h so m e b o d y wh o has i njecte d dr u gs, pe o ple w h o ha ve ca u g ht a n ot her se x uall y 
tra ns mitte d i nfecti on, pe o ple w h o ha ve recei ve d a bl o o d tra nsf usi o n w hi le i n Africa, Easter n 
E ur o pe, t he c o u ntries of t he f or mer S o viet U ni o n, Asia or Ce ntral a n d S o ut h A merica).
3. 5. Ot her late nt or c hr o nic i nfecti ons (e g, rec urre nt si n usitis, ge ni tal or oc ul ar her pes, uri nar y 
tract i nfecti on) or at ris k of  infect i on (s ur ger y, tra u ma, or si gnifica nt i nfecti on) wit hi n 
9 0 d a y s of scree ni n g, or hist or y of s ki n a bscesses wit hi n 9 0 da ys o f scree ni n g.
3. 6. Cli nicall y si g nifica nt l ower res pirat or y tr a ct infecti o n n ot res ol ve d wi t hi n 4 wee ks pri or t o 
scree ni n g, as deter mi ne d b y t he I n vest i gat or.
3. 7. Hi st or y a n d / or prese nce of C O VI D- 1 9:
3. 7. 1. P ati e nt w h o has ha d a se vere c o urse of  CO VI D - 1 9 (ie, h os pi talizati on, E C M O, 
mec ha nicall y ve nt ilate d).


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 7. 2. P ati e nt has cli nical si g ns a n d s y m pt o ms c o nsiste nt wi t h CO VI D -1 9, e g, fever, dr y 
c o u g h, d ys p nea, s ore t hr oat, fati g ue or c o nfir me d c urre nt i nfecti on b y a p pr o priat e 
la b orat or y test wit hi n t he last 4 wee ks pri or t o scree ni n g or o n a d missi o n t o t he Cli nica l 
U nit.
3. 7. 3. P ati e nt has c o nfir me d C O VI D -1 9 i nfect i on b y P C R test bef ore ra n d o mizat i on.
3. 8. Hi st or y of ca ncer wi t hi n t he last 1 0 years ( 2 0 year s f or breast ca ncer) e xce pt f or basal a n d 
s q ua m o us cell carci n o ma o f the s k i n or i n situ carci n o ma o f the cer vi x treate d a n d c o nsi dere d 
c ure d. A n y hist or y  of ly m p h o ma is n ot all o we d.
3. 9. Di sease hist or y s u g gesti n g a b n or mal i m m u ne f u ncti o n.
3. 1 0. Ha ve recei ve d li ve or li ve -atte n uate d vacci ne i n t he 4 wee ks pri or t o d osi n g.
3. 1 1. Hi g h -se nsitivit y C- reacti ve pr otei n a b o ve u p per li mit of  la b orat or y refere nce ra n ge at  
scree ni n g a n d o n a d missi o n t o t he Cli nical U nit.
3. 1 2. Has a b o d y  t e mperat ure of > 3 7. 7° C o n Da y -1, or as j u d ge d b y  t he I n vesti gat or.
3. 1 3. Has a n a bs ol ute ne utr o p hil c o u nt < L L N at t he Scree ni n g Visit.
3. 1 4. Has a n a bs ol ute l y m p h oc y te c o u nt < L L N at t he Scree ni n g Visit.
4.
Hi st or y or prese nce of  gastr oi ntesti nal, he pat ic or re nal disease or a n y ot her c o n ditio n 
k n o w n t o i nterfere wit h a bs or pti o n, distri b ut i on, meta b olis m or e xcreti o n of dr u gs.
5.
A n y cli nicall y im p orta nt ill ness, me dical/s ur gical pr oce d ure or tra u ma wi t hi n 4 wee ks of  
t he first a d mi nistrati o n o f I M P.
6.
S us pi cio n  of Gil bert’s s y n dr ome.
7.
A n y la b orat or y val ues wi t h the f oll owi n g de viati o ns at t he Scree ni n g Visi t a n d o n 
a d missi o n t o t he Cli nical U nit . A b n or mal val ues ma y  be re peate d o nce at t he discreti o n of 
t he I n vest i gat or:
7. 1. Ala ni ne a mi n otra nsferase > 1. 5 U L N.
7. 2. As partate a m i n otra nsferase > 1. 5 U L N.
7. 3. Creati ni ne > U L N.
7. 4. W hite bl o o d cell c o u nt < L L N.
7. 5. H e m o gl o bi n < L L N.
8.
A n y cli nicall y im p orta nt a b n or malit ies i n cli nical c he mistr y, he mat ol o g y  or uri nal ysis 
res ults, ot her t ha n t h ose descri be d u n der e xcl usio n cri t eria n u m bers 3 a n d 7, as j u d ge d b y 
t he I n vest i gat or.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
9.
A b n or m al vit al si g ns, after at least 1 0 mi n utes s u pi ne rest, de viat i ons at t he Scree ni n g Visit  
a n d o n a d missi o n t o t he Cli nical U nit , as defi ne d bel o w. A b n or mal val ues ma y be re peate d 
o nce at t he discreti o n of t he I n vesti gat or:
9. 1. S y st olic B P < 9 0 m m H g or > 1 4 0 m m H g ( or < 8 9 m m H g or > 1 3 9 m m H g i n Ger ma n y)
9. 2. Di ast olic B P < 5 0 m m H g or > 9 0 m m H g.
9. 3. P ul se < 4 5 or > 8 5 b p m ( or < 5 0 or > 9 0 b p m i n Ger ma n y).
1 0. A n y cli nicall y i m p orta nt a b n or malit ies i n r h yth m, c o n d ucti o n or m or p h o l og y  of t he resti n g 
E C G a n d a n y cli nicall y  im p orta nt a b n or m alities i n t he 1 2 Lea d E C G as c o nsidere d b y t h e 
I n vesti gat or t hat ma y i nterfere wi t h the i nter pretati o n of  QTc i nter val c ha n ges, i ncl u di n g 
a b n or mal S T - T-wa ve m o r p h ol o g y, partic ularl y in t he pr ot oc ol defi ne d pri mar y lea d or left  
ve ntri c ular h y pertr o p h y at t he Scree ni n g Visit a n d Da y -1, as defi ne d bel o w.
1 0. 1. Pr ol o n ge d Q Tc F > 4 5 0 ms.
1 0. 2. S h orte ne d Q Tc F < 3 4 0 ms.
1 0. 3. Fa mil y  hist or y of lo n g Q T s y n dr o me.
1 0. 4. P R ( P Q) i nter val s h orte ni n g < 1 2 0 ms ( P R > 1 1 0 ms  b ut < 1 2 0 ms is acce pta ble if t here is n o  
e vi de nce of ve ntric ular pre- e xcitat i on).
1 0. 5. P R ( P Q) i nter val pr ol o n gat i on ( > 2 4 0 ms) i nter mit te nt sec o n d ( We nc ke bac h bl oc k w hile 
aslee p is n ot e xcl usi ve) or t hir d -de gree A V bl oc k, or A V di ss o ciat i on.
1 0. 6. Persi ste nt or i nter mitte nt c o mpl ete B B B . Patie nts wit h I V C D a n d Q R S > 1 1 0 ms b ut  
< 1 2 0 ms 
are acce pta ble if t here is n o e vi de nce of  eg, ve ntric ular h y pertr o p h y  or 
pre -e xcitat i on.
1 1. K n o w n or s us pecte d hist or y  of dr u g a b use wi t hi n t he past 2 years as j u d ge d b y t h e 
I n vesti gat or.
1 2. C urre nt s m okers or t hose w h o ha ve s mo ke d or use d nic oti ne pr o d ucts (i ncl u di n g e-
cigarettes ) wit hi n t he pre vi o us 6 m o nt hs or has s m o ki n g hist or y  of > 5 pac k years .
1 3. Hi st or y of alc o h ol a b use or e xcessi ve i nta ke of alc o h ol wit hi n t he past 2 years as j u d ge d b y 
t he I n vesti gat or (in Ger ma n y  onl y: e xcessi ve i nta ke of  alc oh o l defi ne d as t he re g ular 
c o ns u m pti o n of  mor e t ha n 3 u ni ts [ 2 4 g] of  alc o h ol per da y f or me n or 2 u nits [1 6 g ] of  
alc o h o l per da y  for w o m e n).
1 4. P osi tive scree n f or dr u gs o f a b use, alc o h o l or c oti ni ne ( nic oti ne) at t he Scree ni n g Visi t 
a n d/ or o n a d missi o n t o t he Cli nical U nit .


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5. Hi st or y 
of 
se vere 
aller g y/ h y perse nsit i vity 
or 
o n g oi n g 
cli nicall y 
i m p orta nt 
aller g y/ h y perse nsit i vity, as j u d ge d b y t he I n vesti gat or or hist or y  of h y pers e nsitivit y t o 
dr u gs wi t h a si milar c he mical str uct ure or class t o A Z D 0 4 4 9.
1 6. E xcessi ve i nta ke of  caffei ne-c o ntai ni n g dri n ks or f oo d (e g, c o ffee, tea, c h oc olate,) as j u d ge d 
b y t he I n vest i gat or.
1 7. Use of  dr u gs wi t h enz y me i n d uci n g pr o perti es s uc h as St J oh n’s W o rt wit hi n 3 wee ks 
bef ore t he first a d mi nistrati o n of I M P.
1 8. E xacer bat i on of  ast h ma s y m pt o ms wi t hi n 6 m o nt hs pri or t o Scree ni n g a n d Da y - 1 a n d 
re q uirin g t he use of  or al or I V ster oi ds, a nt i bi otics, Acci de nt a n d E m er ge nc y visit, or 
h os pi t al a d missio n .
1 9. Use of t he f oll o wi n g me dici nes wit hi n t he s pecifie d ti me bef ore S cree ni n g:
1 9. 1. L o n g -acti n g β 2 a g o nists; n o ne f or 4 wee ks pri or t o Scree ni n g.
1 9. 2. A nt i-I g E or a nti−I L -5 or a nti -I L 4 R t hera p y; f or 6 m ont hs pri or t o Scree ni n g.
1 9. 3. I n hale d c ortic oster oids (I C S) > 5 0 0 µ g per d a y  of becl o met as o ne di pr o pi o nate (B D P ) or 
e q ui vale nt wit hi n 1 6 wee ks pri or t o Scree ni n g.
1 9. 4. A n y I C S at a n y d ose at scree ni n g or wit hi n 4 wee ks pri or t o scree ni n g or at ra n d o mizati o n.
1 9. 5. Or al  or i njecta ble st er oids f or treat me nt of  ast h ma or res pirat or y tract i nfecti on wi t hi n 
6 m o nt hs pri or t o Scree ni n g.
1 9. 6. I ntra nasal ster oi ds wit hi n 4 wee ks pri or t o Scree ni n g.
1 9. 7. Le u k otrie ne a nta g o nists wit hi n 2 wee ks pri or t o Scree ni n g.
1 9. 8. Xa nt hi nes (e xcl u di n g caffei ne), a nt ich o li ner gics, or cr o m o gl ycate wit hi n 1 wee k pri or t o 
Scree ni n g .
1 9. 9. S h ort acti n g br o nc h o dilat or ot her t ha n f or resc ue a n d wi t hi n 1 2 h o urs of  Scree ni n g a n d 
D a y -1 assess me nts.
2 0. Use of  an y prescri be d or n o n prescri be d me d icatio n i ncl u di n g, b ut n ot li mite d t o a ntaci ds, 
a nal gesics ot her t ha n paraceta m ol /aceta mi n o p he n, her bal re me dies, me ga d ose
vit a mi ns 
(int a k e of 20 t o 6 0 0 ti mes t he rec o m me n de d dail y d ose) a n d mi nerals d uri n g t he 2 wee ks 
bef ore t he first a d mi nistrati o n of I M P or l o n ger if t he me dicat i on has a l o n g half -life. Sh ort -
acti n g i n hale d beta a g o nist f or t he p ur p oses of  resc ue o nl y  is all owe d f or Part 2a a n d Part 3a 
( P atie nts wit h mil d ast h ma).
2 1. Pl as ma d o nat i on wi t hi n 1 m o nt h of  the Scree ni n g Vi sit or a n y bl o o d d o nati o n/ bl o o d l oss 
> 5 0 0 m L d uri n g t he 3 m o nt hs bef ore t he Scree ni n g Vi sit.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
2 2. Fe male pat ient s w h o are pre g na nt, breastfee di n g, or are pla n ni n g a pre g na nc y d uri n g t he 
st u d y p erio d or wi t hi n 1 mo n t h after t he last d ose of I M P.
2 3. N o n -sterilize d male patient s w h o are se x uall y acti ve wit h a W O C B P
a n d w h o d o n ot a gree 
t o a hi g hl y effective met h o d of c o ntrace pti o n fr o m Da y 1 t o 3 m o nt hs after t he last d ose o f 
t he I M P . W O C B P
w h o are se x uall y act i ve wit h a fertile male part ner a n d w h o d o n ot a gree 
t o a hig hl y  effecti ve met h o d of c o ntrace pti o n t hat is descri be d i n Secti o n 5. 2. 3. 1 .
2 4. Has recei ve d a n ot her ne w c he mical ent ity ( defi ne d as a c o mp o u n d w hic h has n ot bee n 
a p pr o ve d f or mar keti n g) wi t hi n 3 m o nt hs of  t he first a d mi nistrati o n of  IM P i n t his st u d y.
T he peri o d of  e x clusi o n  be gi ns 3 m o nt hs af ter t he fi nal d os e or 1 m o nt h after t he last visit 
w hic he ver i s t he l o n gest.
N ote: P atie nts c o nse nte d a n d scree ne d, b ut n ot r a n d o mize d i n t his st u dy or a previ o us 
P h ase I st u dy, are n ot excl u de d.
2 5. Pat ient s w h o ha ve pre vi o usl y recei ve d A Z D 0 4 4 9.
2 6. I n v ol ve me nt of a n y Astra Ze neca or Cli nical U nit e m pl oyee or t heir cl ose relat i ves.
2 7. J u d g me nt b y t he I n vesti gat or t hat  the patie nt s h o ul d n ot partici pate i n t he st u d y if t he y ha ve 
a n y o n g o i n g or rece nt (ie, d uri n g t he scree ni n g peri o d) mi n or me dical c o m p lai nts t hat ma y 
i nterfere wi t h the i nter pretati o n of  st u d y data or are c o nsi dere d u nli k el y t o c o m p l y with 
st u d y pr oce d ures, restrict i ons a n d re q uire me nts.
2 8. P ati e nts w h o ca n n ot c o m m u nicate relia bl y wit h t he I n vesti gat or.
2 9. V ul nera ble patie nts, e g, ke pt i n dete nt i on, pr otecte d a d ults u n der g uar dia ns hi p, tr ustees hi p, 
or c o m mitte d t o a n i nst itut i on b y g o ver n me ntal or j uri dical or der.
I n a d ditio n, a n y of  the f oll owi n g is re gar de d as a crit erio n f or e xcl usi o n fr om t he ge netic 
researc h:
3 0. Pre vi o us b o ne marr o w tra ns pla nt.
3 1. N o nl e u k oc yt e de pl ete d w h ole blo o d tra nsf usi o n  wit hi n 1 2 0 da ys of t he date of t he ge n et ic 
sa m ple c ollecti on.
5. 1. 2. 2. 2.
He alt h y v ol u nteers ( P art 2 b a n d P art 3 b)
1.
Hi st or y of a n y cli nicall y i m p orta nt disease or di s or der w hic h, i n t he o pi ni o n of  th e 
I n vesti gat or, ma y eit her p ut t he v o l unt eer at ris k beca use of  partici pat i on i n t he st u d y, or 
i nfl ue nce t he res ults or t he v olu nteer’s a bilit y t o p artici pate i n t he st u d y.
2.
Hi st or y of a n y r es pir at or y dis or ders s uc h as ast h ma, C O P D or I P F.
3.
Heal t h y v olu nteer has a n i ncrease d ris k of i nfecti o n:


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 1. Hi st or y an d/ or prese nce of  TB; p osit i ve res ult f or I G R A (ie, Q ua nti F E R O N T B -G ol d), 
v o l unt eers w h o ha ve resi de d i n r e gio ns w here T B a n d m yc osis are e n de mic d uri n g 9 0 d a y s 
bef ore scree ni n g, or w h o i nte n d t o visit s uc h a r e gio n d uri n g t he d urati o n of  the stu d y ie, 
desert areas, Easter n E ur o pe, Ce ntral a n d S o ut h A merica, Afr ica (e xce pt E g y pt), R ussia, 
Asia, I n d o nesia. T he test ma y be re peate d if t he i nitial test res ult is i n deter mi nate.
3. 2. Hi st or y of her pes z oster i nfect i on.
3. 3. A n y p osit i ve res ult f or ser u m he patitis B s urface a nti ge n ( or a nti-H Bc a nt i b o d y i n Ger ma n y 
o nl y), he pat itis C a nt i b o d y, HI V a n d/ or T B at t he Scree ni n g Visit.
3. 4. Is i n hi g h ris k-gr o u p f or HI V i nfecti on wi t hi n t he last 6 m o nt hs (ie, me n w h o ha ve ha d 
u n pr otecte d se x wit h me n, w o me n w h o ha ve ha d se x wit h o ut a c o n d o m wit h me n w h o ha ve 
se x wi t h me n, pe o pl e w h o ha ve ha d se x wi t ho ut a c o n d o m wit h a pers o n w h o has li ve d or 
tra velle d i n Afr ica, p e o pl e w h o i nject dr u gs, pe o ple w h o ha ve ha d se x wi t ho ut a c o n d o m 
wi t h so m e b o d y wh o has i njecte d dr u gs, pe o ple w h o ha ve ca u g ht a n ot her se x uall y 
tra ns mitte d i nfecti on, pe o ple w h o ha ve rec ei ve d a bl o o d tra nsf usi o n w hile i n Africa, Easter n 
E ur o pe, t he c o u ntries of t he f or mer S o viet U ni o n, Asia or Ce ntral a n d S o ut h A merica).
3. 5. Ot her late nt or c hr o nic i nfecti ons (e g, rec urre nt si n usitis, ge ni tal or oc ul ar her pes, uri nar y 
tract i nfecti on) or at ris k of  infect i on (s ur ger y, tra u ma, or si gnifica nt i nfecti on) wit hi n 
9 0 d a y s of scree ni n g, or hist or y of s ki n a bscesses wit hi n 9 0 da ys o f scree ni n g.
3. 6. Cli nicall y si g nifica nt l ower res pirat or y tr a ct infecti o n n ot res ol ve d wi t hi n 4 wee ks pri or t o 
scree ni n g, as deter mi ne d b y t he I n vest i gat or.
3. 7. Hi st or y a n d / or prese nce of C O VI D- 1 9:
3. 7. 1. Heal t h y v o l unt eer w h o has ha d a se vere c o urse of  CO VI D - 1 9 (ie, h os pi talizati on, 
E C M O, mec ha nicall y ve ntilate d).
3. 7. 2. Heal t h y v ol u nteer has cli nical si g ns a n d s y m pt o ms c o nsiste nt wit h C O VI D - 19, e g, 
fe ver, dr y  co u g h, d ys p nea, s ore t hr oat, fati g ue or c o nfir me d
c urre nt i nfecti on b y 
a p pr o priate la b orat or y test wit hi n t he last 4 wee ks pri or t o scree ni n g or o n a d missi o n t o 
t he Cli nical U nit.
3. 7. 3. Heal t h y v o l unt eer has c o nfir me d C O VI D -1 9 i nfecti o n b y P C R 
t est bef ore 
ra n d omizat i on.
3. 8. Hi st or y of ca ncer wi t hi n t he last 1 0 years ( 2 0 year s f or breast ca ncer) e xce pt f or basal a n d 
s q ua m o us cell carci n o ma o f the s k i n or i n situ carci n o ma o f the cer vi x treate d a n d c o nsi dere d 
c ure d. A n y hist or y of ly m p h o ma is n ot all owe d.
3. 9. Di sease hist or y s u g gesti n g a b n or mal i m m u ne f u ncti o n.
3. 1 0. Ha ve recei ve d li ve or li ve -atte n uate d vacci ne i n t he 4 wee ks pri or t o d osi n g.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3. 1 1. Hi g h -se nsitivit y C- reacti ve pr otei n a b o ve u p per li mit of  la b orat or y refere nce ra n ge at  
scree ni n g a n d o n a d missi o n t o t he Cli nical U nit .
3. 1 2. Has a b o d y  t e mperat ure of > 3 7. 7° C o n Da y -1, or as j u d ge d b y  t he I n vesti gat or.
3. 1 3. Has a n a bs ol ute ne utr o p hil c o u nt < L L N at t he Scree ni n g Visit.
3. 1 4. Has a n a bs ol ute l y m p h oc y te c o u nt < L L N at t he Scree ni n g Visit.
4.
Hi st or y or prese nce of  gastr oi ntesti nal, he pat ic or re nal disease or a n y ot her c o n ditio n 
k n o w n t o i nterfere wit h a bs or pti o n, distri b ut i on, meta b olis m or e xcreti o n of dr u gs.
5.
A n y cli nicall y im p orta nt ill ness, me dical/s ur gical pr oce d ure or tra u ma wi t hi n 4 wee ks of  
t he first a d mi nistr atio n of  I M P.
6.
A n y la b orat or y val ues wi t h the f oll owi n g de viati o ns at t he Scree ni n g Visi t a n d o n 
a d missi o n t o Cli nical U nit . A b n or mal val ues ma y be re peate d o nce at t he discreti o n of t he 
I n vesti gat or:
6. 1. Ala ni ne a mi n otra nsferase > U L N.
6. 2. As partate a mi n otra nsfer ase > U L N.
6. 3. Creati ni ne > U L N.
6. 4. W hite bl o o d cell c o u nt < L L N.
6. 5. H e m o gl o bi n < L L N.
7.
A n y cli nicall y im p orta nt a b n or malit ies i n cli nical c he mistr y, he mat ol o g y  or uri nal ysis 
res ults, ot her t ha n t h ose descri be d u n der e xcl usio n cri t eria n u m ber s 3 a n d 6 , as j u d ge d b y 
t he I n vesti gat or.
8.
A b n or m al vit al si g ns, aft er at least 1 0 mi n utes s u pi ne rest, as defi ne d bel o w. A b n or ma l 
val ues ma y be re peate d o nce at t he discreti o n o f t he I n vest i gat or:
8. 1. S y st olic B P < 9 0 m m H g or > 1 4 0 m m H g ( or < 8 9 m m H g or > 1 3 9 m m H g i n Ger ma n y) .
8. 2. Di ast olic B P <5 0 m m H g or > 9 0 m m H g.
8. 3. P ul se < 4 5 or > 8 5 b p m ( or < 5 0 or > 9 0 b p m i n Ger ma n y).
9.
A n y cli nicall y i m p orta nt a b n or malit ies i n r h yth m, c o n d ucti o n or m or p h o l og y  of t he resti n g 
E C G a n d a n y cli nicall y i m p orta nt a b n or malit ies i n t he 1 2-l ea d E C G as c o nsi dere d b y t h e 
I n vestigat or t hat ma y i nterfere wi t h the i nter pretati o n of  QTc i nter val c ha n ges, i ncl u di n g 
a b n or mal S T T wa ve m o r p h ol og y , parti c ularl y i n t he pr ot oc ol  defi ne d pri mar y  lea d or left 
ve ntri c ular h y pertr o p h y at t he Scree ni n g Visit a n d Da y 1, as defi ne d bel o w.
9. 1. Pr ol o n g e d Q Tc F > 4 5 0 ms.
9. 2. S h orte ne d Q Tc F < 3 4 0 ms.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
9. 3. Fa mil y  hist or y of lo n g Q T s y n dr o me.
9. 4. P R ( P Q) i nter val  s horte ni n g < 1 2 0 ms ( P R > 1 1 0 ms b ut < 1 2 0 ms is acce pta ble if t here is n o 
e vi de nce of ve ntric ular pre- e xcitat i on).
9. 5. P R ( P Q) i nter val pr ol o n gat i on ( >2 2 0 ms) i nter mitt e nt sec o n d ( We nc ke bac h bl oc k w hile 
aslee p is n ot e xcl usi ve) or t hir d -de gree A V bl oc k, or A V diss ociat i on.
9. 6. Persi ste nt or i nter mitte nt c o mplete B B B, I B B B, or I V C D wit h Q R S > 1 1 0 ms. Heal t h y 
v o l unt eers wi t h QR S > 1 1 0 ms b ut < 1 1 5 ms are acce pta ble if t here is n o e vi de nce of  eg, 
ve ntri c ular h y pertr o p h y or pre e xcit atio n .
1 0. K n o w n or s us pecte d hist or y  of dr u g a b use as j u d ge d b y t he I n vesti gat or.
1 1. C urre nt s m okers or t hose w h o ha ve s mo ke d or use d nic oti ne pr o d ucts (i ncl u di n g e-
cigarettes ) wit hi n t he pre vi o us 6 m o nt hs or has s m o ki n g hist or y of > 5 pac k years .
1 2. Hi st or y of alc o h o l a b use or e xcessi ve i nta ke of  alc o h ol as j u d ge d b y t he I n vesti gat or (i n 
G er m a n y onl y: excessi ve i nta ke of alc o h o l defi ne d as t he re g ular c o ns u m pti on o f m ore t ha n 
3 u nits [ 2 4 g] of  alc o h ol per da y for m e n or 2 u nits [ 1 6 g ] of  alc o h o l per da y  for w o me n ).
1 3. P osi tive scree n f or dr u gs of  ab use, c oti ni ne ( nic oti ne) or alc o h o l at t he Scree ni n g Visit  
a n d/ or o n a d missi o n t o t he Cli nical U nit.
1 4. Hi st or y 
of 
se vere 
aller g y/ h y perse nsit i vity 
or 
o n g oi n g 
cli nicall y 
i m p ortant  
aller g y/ h y perse nsit i vity, as j u d ge d b y t he I n vesti gat or or hist or y  of h y perse nsit i vity t o 
dr u gs wi t h a si milar c he mical str uct ure or class t o A Z D 0 4 4 9.
1 5. E xcessi ve i nta ke of  caffei ne-c o ntai ni n g dri n ks or f oo d (e g, c o ffee, tea, c h oc olate,) as j u d ge d 
b y t he I n vest i gat or.
1 6. Use of  dr u gs wi t h enz y me i n d uci n g pr o perti es s uc h as St J oh n’s W o rt wit hi n 3 wee ks 
bef ore t he first a d mi nistrati o n of I M P.
1 7. Use of  an y prescri be d or n o n prescri be d me dicati o n i ncl u di n g a ntacids, a nal gesics (ot h er 
t ha n paraceta m o l/aceta mi n o p he n), her bal re me dies, me ga d ose vit a mi ns (int a ke of  20 t o 6 0 0 
ti mes t he rec o m me n de d dail y  dose) a n d mi nerals d uri n g t he 2 wee ks bef ore t he first 
a d mi nistrati o n of I M P or l o n ger if t he me dicat i on ha s a lo n g half -life.
1 8. Pl as ma d o nat i on wi t hi n 1 m o nt h of  the Scree ni n g Vi sit or a n y bl o o d d o nati o n/ bl o o d l oss 
> 5 0 0 m L d uri n g t he 3 m o nt hs bef ore t he Scree ni n g Visit.
1 9. Fe male heal t hy v o l unt eer s w h o are pre g na nt, breastfee di n g, or are pla n ni n g a pre g na nc y 
d uri n g t he st u d y p erio d or wi t hi n 1 mo nt h after t he last d ose of I M P.
2 0. N o n -sterilize d male heal t h y v o l unt eer s w h o are se x uall y act i ve wi t h a WO C B P a n d w h o  
d o n ot a gree t o a hi g hl y effect i ve met h o d of  co ntrace pti o n fr om Da y 1 t o 3 m o nt hs aft er 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
t he last d ose of t he I M P. W O C B P w h o are se x uall y acti ve wi t h a fertile male part ner a n d 
w h o d o n ot a gree t o a hi g hl y effect i ve met h o d of  co ntrace pti o n t hat is descri be d i n 
Secti o n 5. 2. 3. 1 .
2 1. Has recei ve d a n ot her ne w c he mical ent ity ( defi ne d as a c o mp o u n d w hic h has n ot bee n 
a p pr o ve d f or mar keti n g) wi t hi n 3 m o nt hs of  t he first a d mi nistrati o n of  IM P i n t his st u d y. 
T he peri o d of  e x clusi o n  be gi ns 3 m o nt hs af ter t he fi nal d os e or 1 m o nt h after t he last visit 
w hic he ver i s t he l o n gest.
N ote: He alt hy v ol u nteers c o nse nte d a n d scree ne d, b ut n ot r a n d o mize d i n t his st u dy or a 
previ o us P h ase I st u dy, are n ot excl u de d.
2 2. Heal t h y v olu nteer s w h o ha ve pre vi o usl y recei ve d A Z D 0 4 4 9.
2 3. I n v ol ve me nt of a n y Astra Ze neca or Cli nical U nit e m pl o yee or t heir cl ose relat i ves.
2 4. J u d g me nt b y t he I n vesti gat or t hat t he heal t h y v ol unt eer s s h o ul d n ot partici pate i n t he st u dy 
if t h e y ha ve a n y o n g oi n g or rece nt (ie, d uri n g t he scree ni n g p eri o d) mi n or me d ical 
c o mplai nts t hat ma y i nterfere wi t h the i nter pretatio n of  st u d y data or are c o nsi dere d 
u nli kel y  t o c o mpl y  wit h st u d y pr oce d ures, restricti o ns a n d re q uire me nts.
2 5. Heal t h y v olu nteers w h o ca n n ot c o m m u nicate relia bl y wit h t he I n vesti gat or.
2 6. V ul nera ble heal t hy v o l unt eer s, e g, ke pt i n dete nti o n, pr otecte d a d ults u n der g uar di a ns hi p, 
tr ustees hi p, or c o m mitte d t o a n i nstituti o n b y g o ver n me ntal  or juri dical  or der.
I n a d ditio n, a n y of  the f oll owi n g is re gar de d as a crit erio n f or e xcl usi o n fr om t he ge netic 
researc h:
2 7. Pre vi o us b o ne mar r o w tra ns pla nt.
2 8. N o nl e u k oc yt e de pl ete d w h ole blo o d tra nsf usi o n  wit hi n 1 2 0 da ys of t he date of t he ge netic 
sa m ple c ollecti on.
5. 2.
Restricti o ns D uri n g t he St u d y
5. 2. 1.
P art 1 a/ b
T he f o ll owi n g restri ct i ons a p pl y f or t he s pecifie d ti mes d uri n g t he st u d y  p erio d:
1.
F or Part 1a, o n D a y 1, healt h y v o l unt eer s will be faste d f or 1 0 h o urs bef ore I M P 
a d mi nistrati o n u ntil 2 h o urs after I M P a d mi nistrati o n, w he n healt h y v ol u nteer s will recei ve 
a li g ht brea kfast . N o  fl ui ds will be allo we d a p art fr o m water w hic h ca n be gi ve n u n til 1 h o ur 
bef ore I M P a d mi nistrati o n a n d t he n fr o m 1 h o ur after I M P a d mi nistrati o n.
2.
Heal t h y v ol u nteers s h o ul d n ot e n ga ge i n a n y stre n u o us acti vity fr om 7 2 h o urs bef ore (first) 
a d missi o n t o t he Cli nical U nit u nt il after t heir F o ll o w- u p Visit.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
3.
Pri or t o (eac h) treat me nt p eri o d healt h y v o l unt eer s s h o uld a bstai n fr o m a lc o h ol f or 7 2 h o urs 
bef ore a d missi o n t o t he Cli nical U ni t u ntil aft er t heir last P K sa mpli n g visit. Heal t h y 
v o l unt eer s s h o ul d als o a bstai n fr om alc o h o l f or 7 2 h o urs bef ore t heir F o ll ow- u p Vi sit.
4.
Pr i or t o (eac h) treat me nt peri o d healt h y v o l unt eer s s h o ul d a bstai n fr om caffei ne-c o ntai ni n g
f oo ds a n d be vera ges f or 2 4 h o urs bef ore a d missi o n t o t he Cli nical U nit u nt il disc har ge fr om 
t he Cli nical U nit.
5.
Heal t h y v o l unt eer s s h o uld a bstai n fr om gra pefr uit or gr a pefr uit j uice, Se ville ora n ges, 
q ui ni ne (e g, t o nic water) fr o m 7 d a y s bef ore a d missi o n t o t he Cli nical U nit u nt il after t heir 
F o ll ow- u p Vi sit.
6.
D uri n g a d missi o n p eri o ds, healt h y v o l unt eer s will recei ve a sta n dar d diet, w hic h e xcl u des 
all alc o h o l a n d gra pef r uit-c o ntai ni n g pr o d ucts. N o a d dit i onal f oo d or be vera ges m u st be 
c o ns u me d w hile i n t he Cli nical U nit.
7.
D uri n g t he healt h y v o l unt eer s’ o ut pati e nt peri o ds, healt h y v ol u nteer s s h o uld a bstai n fr om 
c o ns u mi n g hi g h e ner g y dri n ks (e g, Re d B ull), a n d f oo d c o nt ai ni ng p o p p y  see ds a n d a n y 
o ver -t he- c o u nter ( O T C) me dicati on or her bal pre parati o ns u ntil after t heir F o ll ow- u p Vi sit 
has bee n c o m plete d. Heal t h y v ol unt eer s s h o ul d als o li mit t heir caffei ne i nta ke t o e q ui vale nt 
of  3 c u ps of c offee per da y ( 1 c u p = 1 2 oz s o da, 6 o z  c offee, or 8 oz tea). Healt h y v o l unt eer s 
s h o uld c o ns u me n o m o re t ha n 2 u nits of  alc oh o l per da y a n d c o mpletel y  abstai n fr om 
alc o h o l fr om 7 2 h o urs be f ore t heir ne xt a d missi on t o t he Cli nical U nit.
8.
Heal t h y v ol u nteer s will be re q uire d t o a bstai n fr o m bl o o d or plas ma d o nati o n u ntil 3 m o nt hs 
after t he fi nal me dical e xa mi nati on at t he st u d y  F o ll ow- u p Visi t.
9.
Heal t h y v olu nteer s m ust o bser ve a n d c o m p l y wit h st u d y site C O VI D-1 9 pr oce d ures.
1 0. F or m e dicat i on restrict i ons, pl ease refer t o Secti o n 7. 7 .
5. 2. 2.
P art 2 a/ b a n d P art 3 a/ b
T he f oll owi n g r estrict i ons a p pl y to all s u bjects (pati e nts wi t h ast h ma a n d heal t hy v o l unt eers)
f or t he s pecifie d ti mes d uri n g t he st u d y p erio d:
1.
O n D a y  1 an d 1 2 f or Part 2a/ b a n d Part 3a/ b , s u bjects will be faste d f or 1 0 h o urs bef ore 
I M P a d mi nistrati o n u ntil 2 h o urs aft er I M P a d mi nistrati o n, w he n s u bjects will recei ve a 
li g ht brea kfast. O n Da y 3 t o 1 1 f or Part 2a/ b a n d Part 3a/ b , s u bjects will be faste d f or 
1 0 h o urs bef ore I M P a d mi nistrati o n u nt il 1 h o ur aft er I M P a d mi nistrati o n, w he n s u bjects 
will recei ve a li g ht brea kfast. N o fl ui ds will be allo w e d a part fr o m water w hic h ca n be gi ve n 
u nt il 1 h o ur bef ore I M P a d mi nistrati o n a n d t he n fr o m 1 h o ur after I M P a d mi nistrati o n.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 5 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
2.
S u bject s s h o ul d n ot e n ga ge i n a n y stre n u o us acti vity fr o m 7 2 h o urs bef ore (first) a d missi o n 
t o t he Cli nical U n it u ntil after t heir F oll ow- u p Visit ( Part 2a)/last da y of st u d y ( Part 2 b, 3a, 
a n d 3 b) .
3.
S u bject s s h o uld a bstai n fr o m alc o h o l f or 7 2 h o urs bef ore a d missi o n t o t he Cli nical U nit 
u nt il aft er t heir last P K sa m pli n g visi t. S u bject s s h o ul d als o a bstai n fr o m alc o h ol f or 
7 2 h o urs bef ore t heir F o ll ow- u p Visi t ( Part 2a)/last da y  of st u d y ( Part 2 b, 3a, a n d 3 b) .
4.
S u bject s m ust n ot c o ns u me a n y fo o d or be vera ges f or 1 h o ur pri or t o eac h Fe N O 
meas ure me nt . T he i nta ke of  fo o ds  with hi g h nit rate c o nt e nt m u st be li mite d as far as 
p ossi ble (e g, ve geta ble j uices, sala ds, lett uce, ra dis hes, celer y, br occ oli, ca ulifl o wer, 
s pi nac h, r oc ket, beets, parsle y, lee ks, ca b ba ge, fe n nel, t ur ni ps, carr ots, c ure d meats, bac o n 
a n d car b o nate d dri n ks) wit hi n 6 h o urs pri or t o eac h Fe N O meas ure me nt.
5.
S u bject s s h o uld a bstai n fr o m caffei ne-c o ntai ni n g f o o ds a n d be vera ges f or 2 4 h o urs bef ore 
a d missi o n t o t he Cli nical U ni t u nt il disc har ge fr om t he Cli nical U ni t. Decaffei nate d 
be vera ges are all o we d.
6.
S u bject s s h o uld a bstai n fr om gra pefr uit or gra pefr uit j uice, Se ville ora n ges, q ui ni ne ( e g, 
t o nic water) fr o m 7 da ys bef ore a d missi o n t o t h e Cli nical U ni t u ntil aft er t heir F o ll ow- u p 
Vi sit ( Part 2a)/last da y  of st u d y ( Part 2 b, 3a, a n d 3 b) .
7.
D uri n g a d missi o n, s u bjects will recei ve a sta n dar d diet, w hic h e xcl u des all alc o h o l a n d 
gra pefr uit -c o ntai ni n g pr o d ucts. N o  ad diti o nal f oo d or be vera ges m u st be c o ns u me d w hile 
i n t he Cli nical U nit.
8.
S u bject s will be re q uire d t o a bstai n fr om bl o o d or plas ma d o nati o n u nt il 3 m o nt hs after t he 
fi nal me dical e xa mi nati on at t he st u d y F o ll ow- u p Vi sit ( Part 2a)/last da y  of st u d y ( Part 2 b, 
3a, a n d 3 b) .
9.
S u bjects m ust o bser ve a n d c o m pl y wit h st u d y  site C O VI D-1 9 pr oce d ures.
1 0. F or m e dicat i on restrict i ons, pl ease refer t o Secti o n 7. 7 .
1 1. If per mitte d b y  lo c al  r ele va nt re g ulat or y a ut h orities a n d c o nsid er e d f easi ble a n d safe t o d o 
s o, t he e xte n de d safety m o nit ori n g peri o d ma y be c o n d ucte d as n o n- reside nt ial visi ts f or 
s u bjects parti ci pat i n g i n Part 2 b, Part 3a a n d 3 b. Pl ease r efer t o Secti o n 5. 2. 1 f or restricti ons 
o n n o n -reside nt ial/ o ut patie nt visits.
5. 2. 3.
Re pr o d ucti ve Restrict i o ns
F e male s u bjects w h o are e nr olle d i n t his st u d y must ha ve a ne gat i ve s er u m pre g na nc y at t he 
Scree ni n g Visi t, a n d a ne gat i ve uri ne pre g na nc y t est perf or m e d o n a d missi o n t o t he Cli nical 
U nit, a n d a date of last m e nstr uatio n c o nsiste nt wi t h no n -pre g na nc y pri or t o ra n d o mizat i on. A 
pre g na nc y test will als o be c o n d ucte d at t he st u d y  F o ll ow- u p Vi sit/last da y of st u d y.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
5. 2. 3. 1.
W o me n of C hil d be ari n g P ote nti al
W O C B P defi ne d as w o me n bet wee n me narc he a n d me n o pa use w h o ha ve n ot bee n p er m a ne ntl y 
or s ur gicall y sterilize d a n d are ca pa ble of pr ocreati o n.
I n st u d y Part 1 b (sec o n d I V c o h ort), Part 2 a/ b, a n d Part 3 a/ b, W O C B P s u bjects s h o uld be sta ble 
o n t heir c h ose n met h o d of birt h c o ntr ol f or at least 1 m o nt h bef ore first d osi n g.
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 year w he n use d c o nsiste ntl y a nd 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 wi t h a no n -sterilize d male part ner m u st a gree t o use o ne hi g hl y 
effect i ve met h o d of birt h c o ntr ol, as defi ne d bel o w, f r o m e nr olme nt t hr o u g h o ut t he st u d y  a nd 
u nt il at least 1 m o nt h aft er last d ose of st u d y i nter ve nti on. Cessat i on of c o ntrace pti o n after t his 
p oi nt s h o uld be disc usse d wi t h a res p o nsi ble p h ysicia n. P eri o di c a bsti ne nce (cale n dar, 
s y m pt ot her mal, p ost -o v ulati o n 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 lactatio nal  ame n orr hea met h o d are n ot acce pta ble met h o ds of  co ntrace pti o n. Fe male 
c o n d o m an d male c o n d o m sh o ul d n ot b e use d t o get her. All W O C B P
m ust ha ve a ne gat i ve 
ser u m pre g na nc y test res ult at Visit 1.

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 ptio n 
ass ociat e d wit h in hi bit i on of o v ulat i on.
o
Or al
o
I ntra va gi nal (e g, N u va Ri n g® , et o n o gestrel/et hi n yl estra di o l va gi nal ri n g)
o
Tra ns der mal (e g, N o rel gestr o mi n/et hi n yl estra diol  tr a ns d er mal syste m , e g, 
Ort h o E vra ® )

Pr o gest o ge n -o nl y  hor m o nal  c o ntrace ptio n ass oci ate d wit h in hi bit i on o f o v ul at i on.
o
Or al  (e g, Cerazette® , pr o gesti n/ des o gestrel)
o
I njecta ble (e g, De po- Pr o vera ® )
o
I mpla nta ble (e g, Et o n o gestrel  im pla nts, I m pla n o n ® , N or pla n ® )

I ntra uteri ne de vice (I U D).

I ntra uteri ne h or m o n e -r eleasi n g s yste m (I U S) (e g, lev o n or gestrel -releasi n g I U S, 
Mi re na® ).

Bilateral t u bal occl usi o n.

Vasect o mise d part ner ( o nl y acce pta ble pr o vi de d t hat part ner is t he s ole se x ual 
part ner of  the s u bject a n d t hat t he vasect o mise d part ner has recei ve d me dical 
assess me nt of t he s ur gical s uccess).


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1

Se x ual a bst i ne nce is defi ne d as refrai ni n g fr om heter ose x ual i nt erc o urse d uri n g t he 
e nt ire p erio d of  ris k ass o ciat e d wit h t he st u d y tr e at m e nts. It is o nl y acce pta ble if it 
is t he s u bject’s pr ef erre d a n d us ual lifest yle.
I n 
a d ditio n, 
o ne
barri er 
met h o d 
m u st 
als o 
be 
use d, 
ie, 
c o n d o m 
(wit h o ut
f oa m/ gel/fil m/crea m/s u p p osit or y or fat- or oil -c o ntai ni n g l u brica nts); or o c cl usi ve c a p 
( dia p hra g m or cer vical/ va ult c a ps) wit h s per mici dal f oa m/ g el/fil m/crea m/s u p p osit or y. D o u ble 
barrier met h o ds (a c o m bi nati o n of  male c o n d o m wit h eit her a ca p, dia p hra g m or s p o n ge wit h 
s per mici de) are n ot c o nsidere d t o be hi g hl y effecti ve met h o ds of c o ntrace pti o n.
Pre g n a nc y Testi n g
I n st u d y Part 1 b (sec o n d I V c o h ort), Part 2 a/ b, a n d Part 3 a/ b, W O C B P
ca n be i ncl u de d o nl y 
aft er a ne gat i ve hi g hl y se nsiti ve s er u m pre g na nc y test. A d diti o nall y uri ne pre g na nc y testi n g 
will be d o ne as per t he S c he d ule of  A ssess me nts (Ta ble 3. 2 - 3, Ta ble 3. 2 - 4, Ta ble 3. 2 -5 , 
Ta ble 3. 2 -6 , Ta ble 3. 2 -7 ).
Pre g n a nc y
If a s u bject bec o mes pre g na nt d uri n g t he st u d y t his s h o ul d be re p orte d t o t he I n vesti gat or. T he 
I n vesti gat or s h o ul d als o be n otifie d of  pre g na nc y occ urri n g d uri n g t he st u d y but c o nfir me d 
after c o mplet i on of t he st u d y . T he pre g na nc y  will be fol l owe d u p a n d t he stat us of m ot her a n d 
c hil d will be re p orte d t o t he S p o ns or after deli ver y.
A pre g na nc y  notificat i on f or m a n d fol l ow- u p will be c o m plete d.
5. 2. 3. 2.
W o me n of N o n -C hil d be ari n g P ote nti al
I n all st u d y parts of  the st u d y w o me n o f n on- c hil d beari n g p ote ntial ca n be e nr o lle d i n t he st u d y.
W o me n of  no n -c hil d beari n g p ot e nti al are defi ne d as female s u bjects w h o are per ma ne nt l y 
s ur gicall y sterilize d or p ost me n o pa usal.
P er m a ne nt sterilizat i on i ncl u des h ysterect o m y  an d/ or bilateral o o p h orect o m y  an d/ or bilateral 
sal pi n gect o m y at least 6 wee ks bef ore scree ni n g b ut e xcl u des bilateral t u bal li gati on. Bilate r al 
o o p h orect o m y  al one is acce pta ble o nl y  whe n t he re pr o d uctive stat us of  the w o m a n has bee n 
c o nfir me d b y f oll o w- u p h or m o ne le vel assess me nt . W o me n w h o ha ve u n der g o ne t u bal 
occl usi o n  s h o uld be ma na ge d o n t he st u d y  as if t he y ar e of W O C B P.
Fe males are c o nsi dere d p ost m e n o pa usal if t h e y ha ve ha d a me n orr hea f or at least 1 2 m o nt hs or 
m o re f oll owi n g cessat i on of  all e x o ge n o us h or m o nal treat me nts a n d wi t ho ut a n alter nati ve 
me dical ca use, a n d t he F S H le vels are i n t he p ost me n o pa usal ra n ge.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
5. 2. 3. 3.
M ale S u bjects
Restricti o ns f or M ale S u bjects
T here i s n o i nf or mat i on a b o ut t he effects t hat A Z D 0 4 4 9 c o ul d ha ve o n t he de vel o p me nt of t he 
fet us i n h u ma ns . T heref ore, it is i m p orta nt t hat W O B C P part ners of  male s u bjects d o n ot 
bec o me pre g na nt d uri n g t he st u d y an d s h o uld f ol l o w hi g hl y effect i ve c o ntrace pti ve met h o ds 
(see list i n Sect i on 5. 2. 3. 1 ) f or a t otal perio d of  3 m o nt hs aft er t he ma le s u bject has recei ve d 
his last d ose of I M P.
As a preca uti o n, all n o n -sterilize d male s u bjects s h o ul d:

Use a c o n d o m with o ut s per mici de ( Ger ma n y onl y) or c o n d o m a n d s per mici de t o 
pre ve nt pre g na nc y a n d dr u g e x p os ure of  a part ner fr om t he d a y  of t he first 
a d mi nistrati o n of t he I M P u ntil 3 m o nt hs after t he last a d mi nistrati o n of t he I M P.

I n a d diti on t o a c o n d o m wit h / wit ho ut s per mici de, a sec o n d hi g hl y effecti ve met h o d 
of  co ntrace pti o n (see list i n Secti o n 5. 2. 3. 1 ) or tr ue se x ual a bst i ne nce* s h o uld b e 
use d wi t h fe male part ners of  chil d beari n g p ote ntial u nt il 3 m o nt hs aft er t he last 
a d mi nistrati o n of t he I M P . D o u ble barrier met h o ds (a c o m bi nat i on of male c o n d o m 
wi t h either a ca p, dia p hra g m or s p o n ge wit h s per mici de) are n ot c o nsi dere d t o be 
hi g hl y  effecti ve met h o ds of c o ntrace pti o n.
*
Tr ue a bst i ne nce refers t o: W he n t his is i n li ne with t he preferre d a n d us ual lifestyle of  
t he s u bject. Peri o di c a bst i ne nce (e g, cale n dar, o v ulati o n, s y m pt ot her mal, p ost -o v ul at i on 
met h o ds), declarati o n o f a bst i ne nce f or t he d urati o n of a st u d y, a n d wit hdra wal are n ot 
acce pta ble met h o ds of c o ntrace pti o n.
Male s u bjects/ patient s w h o ha ve bee n sterilize d are re q uire d t o use o ne barri er met h o d of 
c o ntrace pti o n (e g, c o n d o m wi t h sper mici de) fr o m t he ti me of  IM P a d mi nistrati o n 
u nt il 
3 m o nt hs after t he last d ose of t he I M P . T he s u bject m ust ha ve recei ve d me dical assess me nt o f 
t he s ur gical s uccess.
S per m D o n ati o n
Male s u bjects s h o uld n ot d o nate s per m f or t he d urati o n of  t he st u d y an d f or at least 3 m o nt hs 
after t he last d ose of I M P.
Pre g n a nc y of a fe m ale p art ner of a m ale s u bject
S u bjects will be i nstr ucte d t hat if t heir part ner bec o m es pre g na nt d uri n g t he st u d y  t his s h o ul d 
be re p orte d t o t he I n vest i gat or. T he I n vest i gat or s h o ul d als o be n otifie d of pre g na nc y occ urri n g 
d uri n g t he st u d y but c o nfir me d aft er c o m p leti on of  the stu d y. I n t he e ve nt t hat a s u bject’s 
part ner is s u bse q ue ntl y f ou n d t o be pre g na nt aft er t he v ol u nteer is i ncl u de d i n t he st u d y, t he n 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
c o nse nt will be s o u g ht fr o m t he part ner a n d if gra nte d a n y  pre g na nc y will b e fol l owe d a n d t he 
stat us of m ot her a n d c hil d will be re p orte d t o t he S p o ns or after deli ver y.
A pre g na nc y  notifica tio n f or m  a n d fol l ow- u p will be c o m plete d.
5. 3.
Re pl ace me nt of S u bjects
S u bjects w h o are wi t hdra w n fr om t he st u d y due t o AEs or c ha n ges i n s afet y para meters ma y 
be re place d t o e ns ure t hat a de q uate c o h ort sizes are mai ntai ne d a n d if t he S p o ns or’s res p o nsi ble 
p h y sicia n a n d t he PI a gree it is safe t o d o s o. S u bjects w h o wit h dra w or are wit h dra w n fr om 
t he st u d y for ot her reas o ns ma y als o be r e place d f oll owi n g di sc ussi on wi t h the S p o ns or. 
Re place me nt s u bjects will be all ocate d t he sa me treat me nt as t he s u bject bei n g r e place d.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
6.
S T U D Y S T O P PI N G R U L E S
If r ules s pecifie d i n t his Sect i on are f ulfille d, d osi n g m ust
be st o p pe d ( please r efer t o 
Secti o n 3. 3 f or furt her i nf or m at i on) .
6. 1.
St o p pi n g f or a n I n di vi d u al S u bject, at A n y Ti me i n t he St u d y
D osi n g f or a n y i n di vi d ual s u bject m ust
be st o p pe d if t he s u bject e x perie nces a p ossi ble 
dr u g -relate d S A E or a p ossi bl y dr u g -relate d si gnifica nt n o n- serio us A E, w hic h i n t he o pi nio n 
of  the S R C or PI warra nts disc o nt i n uati on of  the s u bject fr o m t he act i ve C S P f or his or her 
well -bei n g.
T he s u bject is free t o wit h dra w t heir c o nse nt t o partici pate i n t he st u d y at a n y t i me. If the s u bject  
wi t hdra ws t heir c o nse nt, t he s u bject’ s partici pat i on i n t he st u d y  will be st o p pe d.
6. 2.
St o p pi n g R ules f or a W h ole C o h ort, D ose Esc al ati o n, Pr o gressi o n t o Ne xt St u d y 
P art a n d Ter mi n ati o n of St u d y
St o p pi n g r ules as detaile d bel o w ( ge neral, c ar dio vasc ular, lab orat or y  a nd A Z D 0 4 4 9 s pecific) 
are a p plica ble f or eac h of t he f oll o wi n g sit uat i on:

St o p pi n g d osi n g f or a w h ole c o h ort

W he n s u bjects i n a c o h ort are d ose d sta g gere d

D uri n g m ul tiple d osi n g

St o p pi n g d ose escalat i on

St o p pi n g pr o gressi o n t o t he ne xt part of t he st u d y

Fi nal st o p of st u d y
Ge ner al Criter i a
T he st u d y will be place d o n te m p orar y h o l d ( defi ne d as treat me nt st o p pe d f or e nr olle d s u bjects; 
a n d st o p of e nr ol me nt of s u bjects i nto t he st u d y ) pe n di n g f urt her safety data a nal ysis if a n y of 
t he f o ll owi n g cri t eria occ ur i n s u bjects recei vi n g A Z D 0 4 4 9:

A “serio us” a d verse reacti on (ie, a S A E c o nsi dere d at least p ossi bl y relate d t o t h e 
I M P a d mi nistrati o n) i n o ne s u bject;

A “se vere” n o n- serio us a d verse reacti ons (ie, se vere n o n- serio us A Es c o nsi dere d 
as, at least, p ossi bl y relate d t o t he A Z D 0 4 4 9 a d mi nistratio n) i n 2 s u bjects i n t he 
sa me c o h ort, i n de pe n de nt of wit hi n or n ot wit hi n t he sa me s yste m or ga n class.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he ris k t o all part ici pati n g s u bjects will be e val uate d t hor o u g hl y bef ore a decisi o n as t o 
w het her t o ter mi nate t he st u d y pre mat urel y or c o nti n ue d osi n g i n a gree me nt wit h t he re g ulat or y 
a ut h orities.
T he S R C will caref ull y re vie w t he t otality of  data, ta ki n g i nto acc o u nt m o derate n o n- serio us 
A Es at least p ossi bl y relate d t o t he I M P a d mi nistrati o n i n u n bli n de d fas hio n, t he n u m ber of  
s u bjects i n w hic h t he y occ ur, c o nc urre nc y of  mor e t ha n o ne wi t hi n t he sa me s u bject a n d 
p ote nti al safet y sig nals i de ntifie d f or ot her I M Ps i n t he sa me class ( mec ha nist ic a n d/ or 
c he mical) . Alt h o u g h c ha n ges o utsi de n or mal ra n ges t hat a p pl y f or healt h y v o l unt eers are m ost 
r ele va nt, c ha n ges fr o m baseli ne meas ure me nts will als o c o nsi dere d o bser vi n g a n y tre n ds.
C ar di o v asc ul ar Criteri a

T w o or m o re s u bjects, t hat recei ve A Z D 0 4 4 9, ha ve Q Tc pr ol o n gati o n defi ne d as 
Q Tc F > 5 0 0 ms, or a pr ol o n gat i on fr o m baseli ne of  >6 0 ms, c o nfir me d ( persistent  
f or at least 5 mi n utes) a n d deter mi ne d p ost -d ose eit her d uri n g c o nti n u o us 1 2- lea d 
E C G m o ni t orin g or o n a re peat 1 2 -lea d E C G.

T w o or m ore s u bjects, w h o recei ve A Z D 0 4 4 9, ha ve tac h y car dia defi ne d as resti n g 
s u pi ne H R > 1 2 5 b p m persist i n g f or at least 1 0 mi n utes.

T w o or m o re s u bjects, w h o recei ve A Z D 0 4 4 9, ha ve s y m pt o mat ic bra d ycar dia 
defi ne d as resti n g s u pi ne H R < 4 5 b p m or as y m pt o mat ic bra d ycar dia defi ne d as 
resti n g s u pi ne H R < 3 0 b p m w hile a wa ke persist i n g f or at least 1 0 mi n utes.

T w o or m ore s u bj ects, w h o recei ve A Z D 0 4 4 9, de vel o p h yperte nsi o n defi ne d as a n 
i ncrease i n resti n g s u pi ne s yst olic B P > 4 0 m m H g 
t o a b o ve 1 8 0 m m H g 
a n d 
persisti n g f or at least 1 0 mi n utes.
L a b or at or y Fi n di n gs

O ne or m ore s u bjects, w h o recei ve A Z D 0 4 4 9, f ulfill H y’s La w ( H L) defi ne d as “ An 
i ncrease i n A S T or A L T ≥3 x U L N a n d T otal bilir u bi n ( T B L) ≥2 x U L N, w here n o  
ot her reas o n ca n be f ou n d t o e x plai n t he c o m bi natio n of  increases, e g, ele vate d 
ser u m al kali ne p h os p hatase ( A L P) i n dicati n g c h olestasis, viral he pati tis, a n ot her 
dr u g.” T he el e vat i ons d o n ot ha ve t o be at t he sa me ti me or wit hi n a s pecifie d t i me 
fra me (see A p pe n di x 1 5. 3 f or fol l ow- u p pr oce d ures).

T w o or m ore s u bj ects, w h o recei ve A Z D 0 4 4 9, ha ve c o nfir me d > 3 x U L N of either 
A L T or A S T, or > 2 x U L N f or bilir u bi n or A L P.

T w o or m o re s u bjects, w h o recei ve A Z D 0 4 4 9, ha ve c o nfir me d le u k oc yt e c o u nt 
< 2. 0 x 1 0 9/ L.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1

T w o or m o re s u bjects, w h o recei ve A Z D 0 4 4 9, ha ve c o nfir me d ne utr o p hil c o u nt 
< 1. 0 x 1 0 9/ L.

T w o or m ore s u bjects, w h o recei ve A Z D 0 4 4 9, ha ve c o nfir me d platelet c o u nt < 7 5 x 
1 0 9/ L.

T w o or m o re s u bjects, w h o recei ve A Z D 0 4 4 9, ha ve c o nfir me d ser u m creati ni ne 
i ncrease t o > 1. 5 x U L N.
C O VI D - 1 9
P ati e nts w h o test p ositi ve f or ha vi n g acti ve C O VI D -1 9 i nfect i on will be disc o nt i n ue d fr om t he 
st u d y a n d fol l owe d u p u nt il t he o utc o me of t he A E is esta blis he d.
St u d y S pecific St o p pi n g Criteri a Rel ate d t o A Z D 0 4 4 9
Pl ease refer t o Secti o n 3. 4. 1 w here rati o nale f or e x p os ure li mits is e x plai ne d i n detail . T he t otal 
a n d free e x p os ure li mits ha ve bee n c o nsidere d a n d t he m o st c o nser vat i ve a p pr oac h has bee n 
c h ose n.
W he n e mer gi n g P K  data will be re vie we d, t he ma xi m u m e x p os ure o bser ve d i n i n di vi d ual 
s u bjects wit hi n a c o h ort rat her t ha n t he mea n e x p os ure s h o ul d be ta ke n i nt o acc o u nt.
P ul m o n ar y Criteri a

T w o or m o re s u bjects/ patie nts w h o recei ve A Z D 0 4 4 9 i n a c o h ort, or 3 or m o re 
s u bjects/ patie nts i n total  wh o recei ve d A Z D 0 4 4 9, ha ve a fall i n F E V 1 ≥3 0 % 
c o mpare d wi t h the baseli ne val ue at pre -d ose o n Da y 1, wi t hi n 1 h o ur aft er 
a d mi nistrati o n of t he I M P.
If br o nc h oc o nstrict i on occ urs lea di n g t o a re d ucti on of  12 % ( 2 0 0 cc) i n F E V 1, t he s u bject 
s h o uld be tr eate d wit h br o nc h o dilat ors a n d meas ure me nts s h o ul d be re peate d u ntil F E V 1 val ues 
ha ve n or malize d.
D ose a n d P K Criteri a f or St o p pi n g D ose Esc al ati o n i n P art 1 a
W he n e mer gi n g P K  data will be re vie we d, t he ma xi m u m e x p os ure o bser ve d i n i n di vi d ual 
v o l unt eers wi t hi n a c o h ort rat her t ha n t he mea n e x p os ure will be ta ke n i nto acc o u nt . D o se 
escalat i on will be st o p pe d if a n y of t he f o ll owi n g cri t eria has bee n met or if t he escalate d d ose 
le vel is pre dicte d t o meet a n y of t h e fol l owi n g cri t eria:

T he N O A E L -base d ma xi m u m d ose has bee n reac he d (
 A Z D 0 4 4 9 deli vere d 
d ose).

T he u p per e n d of  the est i mate d h u ma n P D d ose ra n ge has bee n reac he d ( E D9 6) 
(
 A Z D 0 4 4 9 deli vere d d ose).
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1

A n y i n di vi d ual v o l unt eer reac hes t he Cma x of  1 8 8 n m o l/ L.

A n y i n di vi d ual v o l unt eer reac hes t he A U C of 1 2 0 0 n m o l *h/ L.

A C ma x of  1 8 8 n m o l/ L is pre dicte d t o be reac he d i n t he ne xt c o h ort.

A n A U C of 1 2 0 0 n m o l * h/ L is pre dicte d t o be reac he d i n t he ne xt c o h ort.
D ose a n d P K -criteri a f or St o p pi n g D ose Esc al ati o n i n P art 2 a/ b ( M A D)
W he n e mer gi n g P K  data will be re vie we d, t he ma xi m u m e x p os ure o bser ve d i n i n di vi d ual 
patie nts wi t hi n a c o h ort rat her t ha n t he me a n e x p os ure will be ta ke n i nto acc o u nt . D o se 
escalat i on will be st o p pe d if a n y of t he f o ll owi n g cri t eria has bee n met or if t he e scalate d d ose 
le vel is pre dicte d t o meet a n y of t h e fol l owi n g cri t eria:

T he N O A E L -base d ma xi m u m d ose has bee n reac he d (
 A Z D 0 4 4 9 deli vere d 
d ose).

T he u p per e n d of  the est i mate d h u ma n P D d ose ra n ge has bee n reac he d ( E D9 6) 
(
 A Z D 0 4 4 9 deli vere d d ose).

A n y i n di vi d ual pat ien t reac hes t he Cma x of  1 8 8 n m ol / L.

A n y i n di vi d ual pat ien t reac hes t he A U C ( 0-2 4) (stea d y state) of 1 2 0 0 n m o l * h/ L.

A C ma x of  1 8 8 n m o l/ L is pre dicte d t o be reac he d i n t he ne xt c o h ort.

A n A U C
( 0-2 4) (stea d y state) of 1 2 0 0 n m o l * h/ L is pre dicte d t o be reac he d i n t he ne xt 
c o h ort.
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
7.
T R E A T M E N T S
7. 1.
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d ucts
T he I M Ps use d i n t his st u d y  are descri be d i n Ta ble 7. 1 - 1.
T a ble 7. 1 - 1
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d ucts
A Z D 0 4 4 9 f or I n h al ati o n
S u p plier:
Astra Ze neca A B, R & D G ot he n b ur g
F or m ul ati o n 1:
A Z D 0 4 4 9 ne b ulizer s us pe nsi o n 
F or m ul ati o n 2:
A Z D 0 4 4 9 ne b ulizer s us pe nsi o n 
F or m ul ati o n 3:
A Z D 0 4 4 9 ne b ulizer s us pe nsi o n 
P ac k a gi n g U nit:
T y pe I glass vials
D ose:
D ose ra n ge 
 deli vere d d ose
R o ute of A d mi nistr ati o n:
I n halati o n
S pecific De vice f or Dr u g A d mi nistr ati o n:
Jet Ne b uliz er ( Pr o v o. X s yste m)
Re gi me n:
Si n gle a n d m ulti ple asce n di n g d ose
S peci al H a n dli n g Re q uire me nts:
S o nicati o n of s us pe nsi o n bef ore use
Pl ace b o f or A Z D 0 4 4 9 f or I n h al ati o n
S u p plier:
Astra Ze neca A B, R & D G ot he n b ur g
F or m ul ati o n:
Place b o f or A Z D 0 4 4 9 ne b ulizer s us pe nsi o n
Stre n gt h/ C o nce ntr ati o ns:
N/ A
D ose:
N/ A
R o ute of A d mi nistr ati o n:
I n halati o n
S pecific De vice f or Dr u g A d mi nistr ati o n:
Jet Ne b uliz er ( Pr o v o. X s yste m)
Re gi me n:
Si n gle a n d m ulti ple asce n di n g d ose
S peci al H a n dli n g Re q uire me nts:
N o
A Z D 0 4 4 9 f or I ntr a ve n o us A d mi nistr ati o n
S u p plier:
Astra Ze neca A B, R & D G ot he n b ur g
F or m ul ati o n:
A Z D 0 4 4 9 s ol uti o n f or i nf usi o n 
Stre n gt h/ C o nce ntr ati o ns:
P ac k a gi n g U nit:
T y pe I glass vials
D ose:
C o h ort 1: 
 t otal d ose; co h ort 2: 
 t otal d ose
R o ute of A d mi nistr ati o n:
I ntra ve n o us
S pecific De vice f or Dr u g A d mi nistr ati o n:
I nf usi o n p u m p set
Re gi me n:
T w o s i n gle d oses
S peci al H a n dli n g Re q uire me nts:
S o nicati o n of s ol uti o n bef ore use
A Z D 0 4 4 9 f or I n h al ati o n vi a D PI
F or m ul ati o n:
A Z D 0 4 4 9 i n halati o n p o w der: 
D ose:
D ose ra n ge 
 deli vere d d ose
R o ute of A d mi nistr ati o n:
I n halati o n via D PI
S pecific De vice f or Dr u g A d mi nistr ati o n:
S D 3 F L versi o n of Ge n uair
Re gi me n:
Re peate d i n hale d a d mi n istrati o n
S peci al H a n dli n g Re q uire me nts:
N o
Pl ace b o f or I n h al ati o n vi a D PI
F or m ul ati o n:
Place b o f or A Z D 0 4 4 9 i n halati o n p o w der
Stre n gt h/ C o nce ntr ati o ns/ D ose:
N/ A
R o ute of A d mi nistr ati o n:
I n halati o n via D PI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 6 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
S pecific De vice f or Dr u g A d mi nistr ati o n:
S D 3 F L versi o n of Ge n uair
Re gi me n:
Re peate d i n hale d a d mi n istrati o n
S peci al H a n dli n g Re q uire me nts:
N o
Details of t he batc h n u m bers will be i ncl u de d i n t he trial master file a n d t he fi nal C S R.
7. 2.
S u p pl y of I n vesti g ati o n al Me dici n al Pr o d uct
A Z D 0 4 4 9 will be s u p plie d b y Astra Ze neca as n o n -s u bject s pecific o p e n -lab el  bul k t o t he 
Cli nical U nits .
A tec h nical agree me nt bet wee n t he I n vesti gat or a n d Astra Ze neca will be i n place t o c o ver all 
p har mac y relate d acti vit ies, detaili n g r oles a n d res p o nsi bilities bef ore receipt of  the I M Ps at  
t he Cli nical U nit s.
A rel ease d oc u me nt sig ne d b y  a le gall y a ut h orize d Q ualifie d Pers o n ( Q P) at t he Cli nical U nit s
will be pl ace d i n t he a p pr o priate secti o n of  the Tri al Master File t o d o c u me nt labeli n g a n d 
di s pe nsi n g of t he I M P t o t he s u bject.
7. 3.
St or a ge a n d H a n dli n g Pr oce d ures
T he I M P will be st ore d i n a sec ure facility u n der a p pr o priate st ora ge c o n dit i ons . Details of  
st ora ge c o n diti ons will be pr o vi de d o n t he la bel of t he I M P.
Astra Ze neca will be per mitte d u p o n re q uest t o a u dit t he s u p plies, st ora ge, dis pe nsi n g 
pr oce d ures a n d rec or ds pr o vi de d t hat t he bli n d of t he st u d y  is n ot c o mpr o mise d.
7. 4.
L a beli n g
La bels will be pre pare d i n acc or da nce wi t h Go o d Ma n ufact uri n g Practice ( G M P) a n d l oc al 
re g ulat or y g uideli nes . T he la bels will f ulfill G M P A n ne x 1 3 re q uire me nts a n d me d ical de vice 
di recti ve f or la beli n g.
7. 5.
Dr u g Acc o u nt a bilit y, Dis pe nsi n g a n d Destr ucti o n
T he I M P pr o vi de d f or t his cli nical st u d y  will be use d o nl y as directe d i n t he C S P.
I n acc or da nce wi t h Go o d Cli nical Pract ice ( G C P), t he Cli nical U ni ts will acc o u nt f or all 
s u p plies of  the I M P. Details of  receipt, st ora ge, asse m bl y/ dis pe nsi n g a n d ret ur n will b e 
rec or de d.
Si nce c o m p o u n d i n halat i on ma y lea d t o c o nta mi nati o n of t he plas ma P K sa m ples, a p pr o pri at e 
meas ures will  be t a k e n t o a v oid s uc h c o nta mi nati on. D ue t o t he l ow li mit of q ua nt ificati on of  
t he a nal yt ical assa y, e ve n s mallest a m o u nts ma y p ose a pr o bl e m. C o nta mi nati o n is t he or eticall y 
p ossi ble t hr o u g h aer os ol de p osi tin g or t hr o u g h c o mp o u n d s pilli n g o nt o e g, vials, bl o o d 
sa m pli n g e q ui p me nt, s ki n, cl ot hes or gl o ves. Re me di al meas ures will incl u de:


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1

T he st u d y site tea m will be ma de a ware of  the ris k of  sa m ple c o nta mi nat i on i n t h e 
pr oj ect -s pecific trai ni n g

A d mi nistrati o n of  IM P will ta ke pl ace i n a r o o m s e p ar at e fr o m t he r o o m where bl o o d 
sa m ples will be dra w n . D uri n g a d mi nistratio n patie nts a n d st u d y pers o n nel will w e ar 
di s p osa ble g o w ns a n d gl o ves w hic h 
will 
be di scar de d i m me diatel y aft er eac h 
a d mi nistrati o n i n t he r o o m use d f or i n halati on, t o a v oid s u bse q ue nt c o nta mi nat i on of  
bl o o d sa m ples.
All use d a n d u n use d s u p plies of t he I M P will  be destr o ye d b y eac h Cli nical U nit at t he e n d of 
t he st u d y. T he certificate of  deli ver y a n d destr ucti o n m u st be si g ne d, i n acc or da nce wi t h 
i nstr uctio n b y Astra Ze neca . Destr uctio n m ust n ot ta ke place u nless t he res p o nsi ble pers o n at 
Astra Ze neca has a p pr o ve d it.
7. 6.
D ose a n d Tre at me nt Re gi me ns
7. 6. 1.
P art 1 a
Eac h v o l unt eer will recei ve a si n gle i n hale d d ose of A Z D 0 4 4 9 or place b o a d mi nistere d wit h a 
ne b ulizer.
T he d ose will be a d mi nistere d after a n o ver ni g ht fast of at least 1 0 h o urs.
V ol u nteer s will be allo we d t o dri n k water t o pre ve nt de h y drat i on u nt il 1 h o ur bef ore I M P 
a d mi nistrati o n.
Water will be allo we d a d li bit u m fr om 1 h o ur aft er I M P a d mi nistrati o n a n d a li g ht brea kfast  
will be pr o vi de d 2 h o urs after I M P a d mi nistrati o n.
Ot her restricti ons, i ncl u di n g p ost ure c o ntr ol are descri be d i n Secti o n 5. 2 . Data of  v o l unt eer s 
m a y be e xcl u de d fr o m t he P K a nal ysis set as descri be d i n Sect i on 1 0. 3. 2 .
7. 6. 2.
P art 1 b
I n t he first I V c o h ort, eac h v o l unt eer will recei ve a si n gle I V d ose of  
 A Z D 0 4 4 9 
a d mi nistere d o ver 6 0 mi n utes (see Secti o n 3. 5. 2 ). I n t he sec o n d I V c o h ort, eac h v o l unt eer will 
r ecei ve a si n gle I V d ose of  
 A Z D 0 4 4 9 
a d mi nistere d o ver 4 8 mi n utes 
(see 
Secti o n 3. 5. 2 ).
Ot her restricti ons, i ncl u di n g p ost ure c o ntr ol are descr i be d i n Secti o n 5. 2 . Data of  v o l unt eer s 
ma y be e xcl u de d fr o m t he P K a nal ysis set as descri be d i n Sect i on 1 0. 3. 2 .
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
7. 6. 3.
P art 2 a/ b
Eac h s u bject will recei ve a m ult i ple i n hale d d ose of A Z D 0 4 4 9 or place b o a d mi nistere d wit h a 
ne b ulizer.
Ot her restricti o ns, i ncl u di n g p ost ure c o ntr ol are descri be d i n Sect i on 5. 2 . Data of s u bjects ma y 
be e xcl u de d fr o m t he P K a nal ysis set as descri be d i n Secti o n 1 0. 3. 2 .
7. 6. 4.
P art 3 a/ b
Eac h s u bject will recei ve a m ult i ple i n hale d d ose of 
 A Z D 0 4 4 9 or place b o a d mi nistere d 
wi t h a D PI.
Ot her restricti o ns, i ncl u di n g p ost ure c o ntr ol are descri be d i n Sect i on 5. 2 . Data of s u bjects ma y 
be e xcl u de d fr o m t he P K a nal ysis set as descri be d i n Secti o n 1 0. 3. 2 .
7. 7.
C o nc o mit a nt a n d P ost -st u d y Tre at me nt(s)
A part fr o m paraceta m o l/aceta mi n o p he n n o c o nc o mita nt me dicati on o r thera p y will be all o we d.
A S h ort Act i n g Beta A g o nist ( S A B A), ma y be use d f or t he p urp oses of resc ue o nl y a n d n ot as 
a re g ular use me dicat i on.
T he s u bjects s h o uld be i nstr ucte d t hat n o ot her me d icati on is all o we d, i ncl u di n g her bal 
r e me dies, vit a mi n s u p ple me nts a n d o ver -t he- c o u nter pr o d ucts, wit h o ut t he c o nse nt of  the 
I n vesti gat or. C o nt racept i ve me dicat i on will be per mitte d as descri be d i n Sect i on 5. 2. 3 .
Me dicat i on, w hic h is c o nsi dere d necessar y f or t he s u bject’s safety a n d well -bei n g, ma y be 
gi ve n at t he discret i on of t he I n vest i gat or d uri n g t he resi de ntial p eri o d.
W he n a n y  me dicat i on is re q uire d, t he I n vestigat or s h o ul d prescri be it. F oll o wi n g c o ns ultati o n 
wi t h Astra Ze neca Lea d P h ysicia n, t he I n vesti gat or s h o uld deter mi ne w het her or n o t t he s u bject  
s h o uld c o nt i n ue i n t he st u d y. A d mi nistrati o n of  co nc o mita nt me d icati ons t hat ma y i nfl ue nce 
t he meas ure me nt of  t he P K a n d/ or P D e n d p oi nts ma y be d o c u m e nte d as a pr ot oc ol  de viatio n 
after c o ns ult atio n of  t he I n vesti gat or wit h Astra Ze neca Lea d P hys icia n.
7. 8.
Tre at me nt C o m pli a nce
D osi n g will ta ke pl ace at t he Cli nical U ni t. S u bject c o mplia nce will be ass ure d b y direct  
s u per visi on a n d wit nessi n g of I M P a d mi nistrati o n.
A d mi nistrati o n of  I M P will be rec or de d i n Data La bs ® .
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
7. 9.
R a n d o miz ati o n
7. 9. 1.
S u bject E nr ol me nt a n d R a n d o miz ati o n
T he PI will e ns ure:

Si g ne d i nf or me d c o nse nt is o btai ne d fr om eac h p ote nti al s u bject bef ore a n y st u d y 
s pecific pr oce d ures are perf or me d.

Eac h p ote ntial s u bject is assi g ne d a u ni q ue e nr ol me nt n u m ber at t he Scree ni n g Visit  
u p o n si g ni n g t he I nf or me d C o nse nt F or m (I C F).

T he eli gi bilit y of  eac h s u bject is i n acc or da nce wi t h the i ncl usi on a n d e xcl usio n 
criteria.

Eac h eli gi ble s u bject is assi g ne d a u ni q ue ra n d o mizati o n c o de (s u bject n u m ber).
Ra n d o mizati o n c o des will  be assi g ne d strict l y se q ue ntiall y as s u bjects bec o me eli gi ble f or 
ra n d omizat i on, starti n g fr o m e g, 1 0 1 ( n o lea di n g zer o(s)).
W he n 
usi n g u ni q ue e nr o l me nt n u m ber, t he s pecific f or mat m u st be f oll owe d (ie, re d uce d 
e nr o l me nt n u m ber, e g, “ 1 0 0 1” i n Data La bs 
a n d o n labels, f ull e nr ol me nt n u m b er, 
e g, “ E 0 0 0 1 0 0 1” f or o ut p uts).
If a s u bject wit h dra ws his/ her partici pati on i n t he st u d y, t he n his/ her e nr ol me nt/ra n d o mizati on 
c o de ca n n ot be re use d.
Re place me nt s u bjects will be all ocate d t he sa me treat me nt as t he s u bject bei n g r e place d, i n 
or der t o e ns ure t hat t he mi ni m u m n u m ber of s u bjects are d ose d wit h A Z D 0 4 4 9 or place b o . F or 
eac h c o h ort, a n a d ditio nal set of  ra n d o m n u m bers will be ge nerate d wi t hi n t he Astra Ze neca 
ra n d omizat i on s yste m ( A Z Ra n d) acc or di n g t o t he sa me tr e at me nt all ocat i on r atio. T he 
u n b li n de d P h ar macist at t he Cli nical U ni t will all ocate a re place me nt n u m ber s uc h t hat t he 
r e place me nt s u bject recei ves a ra n d o m n u m ber ha vi n g t he sa me treat me nt all ocat i on.
7. 9. 2.
Pr oce d ures f or R a n d o miz ati o n
U p o n c o mplet i on of  the ra n d o mizati o n re q uire me nts s pecificati ons f or m, t he ra n d omizat i on 
will be pr o d uce d b y  Pare xel acc or di n g t o A Z Ra n d.
T he ra n d o mizati o n will be c o m p lete d f or eac h part a n d c o h ort usi n g c o nsec ut i ve ra n d omizat i on 
c o des.
O nce a ra n d omizat i on n u m ber has bee n allocate d t o o ne s u bject, it ma y not be assi g ne d t o 
a n ot her s u bject. If s u bjects wi t hdra w pre mat urel y fr o m t he st u d y an d are re place d u n der t he 
di recti on of t he S p o ns or, t he n a ne w ra n d o mizat i on n u m ber will be assi g ne d . T he re place me nt 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
s u bjects will 
be assig ne d t o t he sa me treat me nt as t he di sc o nti n ue d s u bject usi n g a 
ra n d omizat i on n u m ber t hat c orres p o n ds t o t he s pecific treat me nt.
7. 9. 3.
Pr oce d ures f or H a n dli n g I nc orrectl y R a n d o mize d S u bjects
S u bjects w h o fail t o meet t he i ncl usi on crit eria or meet a n y e xcl usi o n crit erio n s h o uld n ot, 
u n der a n y circ u msta nces, be ra n d o mize d i nt o t he st u d y. T here ca n be n o e xce pti o ns t o t his r ule.
W here a s u bject, w h o d oes n ot meet t he select i on criteria, is ra n d omize d i n err or a n d t his is 
i de ntifie d bef ore d osi n g, t he s u bject s h o ul d be wi t hdra w n fr o m t he st u d y. If a s ubject is 
wi t hdra w n bef ore d osi n g t he y  will be re place d.
If a s u bject, w h o d oes n ot meet t he sele ctio n criteria, has bee n d ose d bef ore t he err or is 
i de ntifie d, t he s u bject s h o uld b e a d vis e d t o c o n ti n ue safety assess me nts t o e ns ure t heir s af et y.
T he PI will i nf or m t he A Z Lea d P h ysicia n of t he err or a n d a j oi nt decisi on ma de as t o w het her 
t he s u bject s h o ul d be re place d.
7. 1 0.
Bli n di n g a n d Pr oce d ures f or U n bli n di n g t he St u d y
7. 1 0. 1.
Met h o ds f or E ns uri n g Bli n di n g
T he ra n d omizati o n list s h o uld be ke pt i n a sec ure l ocatio n u nti l t he data base is l oc k or 
e q ui vale nt l y, clea n file is declare d.
T he p har mac o ki net icist will be u n bli n de d t o perf or m t he P K a nal yses after eac h c o h ort, f or t he 
S R C m eet i n g.
T he f o ll owi n g pers o n nel will ha ve access t o t he ra n d o mizat i on list:

T he Cli nical U ni t pers o n nel carr yi n g o ut t he la beli n g a n d pac ka gi n g of  su bject 
s pecific treat me nts

T he p har mac y pers o n nel pre pari n g I M P at t he site

T he pers o n nel perf or mi n g t he bi oa nal yses of t he plas ma/ uri ne sa m ples
T he ra n d o mizat i on list s h o ul d be ke pt i n a sec ure l ocati o n u ntil t he e n d of t he st u d y.
7. 1 0. 1. 1.
P art 1 a
T his st u d y  is si n gle-bli n d wit h re gar d t o treat me nt ( A Z D 0 4 4 9 or place b o) at eac h d ose le vel.
A Z D 0 4 4 9 a n d place b o will be matc he d f or f or m ulati o n a n d a m o u nt . V o l unt eer s ra n d o mize d t o 
pl ace b o will recei ve t he sa me ne b ulize d v ol u me as v ol u nteer s o n acti ve dr u g.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
7. 1 0. 1. 2.
P art 1 b
Part 1 b will be o pe n -lab el .
7. 1 0. 1. 3.
P art 2 a/ b
T his st u d y  is si n gle-bli n d wit h re gar d t o treat me nt ( A Z D 0 4 4 9 or place b o) at eac h d ose le vel.
A Z D 0 4 4 9 a n d pl ace b o will be mat c he d f or f or mulat i on a n d a mo u nt. S u bjects ra n d o mize d t o 
pl ace b o will recei ve t he sa me ne b ulize d v ol u me as s u bjects o n acti ve dr u g.
7. 1 0. 1. 4.
P art 3 a/ b
T his st u d y  is si n gle-bli n d wit h re gar d t o treat me nt ( A Z D 0 4 4 9 or place b o).
A Z D 0 4 4 9 a n d pl ace b o will be mat c hed f or f or mul at i on a n d a mo u nt . T he sa me D PI will be 
use d f or s u bjects ra n d o mize d t o place b o as s u bjects o n acti ve dr u g.
7. 1 0. 2.
Met h o ds f or U n bli n di n g t he St u d y
T he treat me nt c o de s h o ul d n ot be br o ke n e xce pt i n me dical e mer ge ncies w he n t he a p pr o priate 
ma na ge me nt 
of
t he s u bject re q uires k n o wl e d ge of  the tr e at me nt ra n d o mizati o n. T h e 
I n vesti gat or d oc u me nts a n d re p orts t he acti o n t o Astra Ze neca, wit h o ut re veali n g t he treat me nt 
gi ve n t o s u bject t o t he Astra Ze neca staff . U n der s o me c o n dit i ons, t he S R C ma y be re q uire d t o 
re vie w “ u n bli n de d” data a n d a n a de q uate pr oce d ure s h o uld be f oll owe d t o mai ntai n t h e 
bli n di n g or all o w brea ki n g t he bli n d f or n o n -e mer ge nc y reas o ns.
I n t he e ve nt of  a me dical e mer ge nc y w he n ma na ge me nt of  a su bject’s c o n ditio n  re q uir es 
k n o wl e d ge of  the trial me dicat i on, t he treat me nt recei ve d ma y be re veale d b y pers o n nel 
a ut h orize d b y t he PI . If p ossi ble, s uc h e mer ge ncies are t o be disc usse d wit h Astra Ze neca bef ore 
di s clos ure of  the tr e at me nt all ocati o n. Reas o ns f or brea ki n g a c o de will be clearl y e x plai ne d 
an d j ust ifie d i n Data La bs. T he date o n w hic h t he c o de was br o ke n t o get her wit h t he i de nt ity o f 
t he pers o n res p o nsi ble will als o be d oc u me nte d.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
8.
M E A S U R E M E N T S A N D M E T H O D S O F A S S E S S M E N T
8. 1.
A p pr o pri ate ness of Me as ure me nts
Sta n dar d meas ures t o assess P K, safet y  a nd t olera bilit y ap pl y  d uri n g t h e st u d y. F or t he si n gle 
d oses of A Z D 0 4 4 9 pla n ne d t o be gi ve n d uri n g t his st u d y , n o safety iss ues are e x pecte d.
T he ti mi n g of assess me nts are i n dicate d i n t he Sc he d ule of Assess me nts, Ta ble 3. 2 - 1 ( Part 1a), 
Ta ble 3. 2 - 2 a n d Ta ble 3. 2 - 3 ( Part 1 b), Ta ble 3. 2 - 4, a n d Ta ble 3. 2 -5 ( Part 2 a/ b), Ta ble 3. 2 - 6 a n d 
Ta ble 3. 2 - 7 ( Part 3 a/ b).
8. 2.
S afet y a n d Eli gi bilit y Me as ure me nts
S af et y a n d t olera bilit y varia bles will i ncl u de:

A d verse e ve nts

A d dit i onal safety m o nit ori n g

Vi t al si g ns (s yst olic a n d diast olic B P, p ulse, res pirat or y rate a n d b o d y te m perat ure)

Electr ocar di o gra ms ( 1 2 -lea d E C Gs a n d tele metr y)

P h ysical e xa mi nat i on

S pi r o metr y

P ul se o xi metr y

La b orat or y  assess me nts ( he mat ol o g y, cli nical c he mistr y [i ncl u di n g plas ma gl uc ose 
a n d trigl yceri des] a n d uri nal ysis )
S er ol o g y , uri ne dr u gs of  ab use, alc o h ol a n d c oti ni ne will be assesse d f or eli gi bilit y.  Fol licle-
sti m ulati n g h or m o ne (fe male v o l unt eer s o nl y i n Part 1 a a n d Part 1 b [first I V c o h ort], a n d 
p ost m e n o pa usal pat ient s o nl y i n Part 1 b [sec o n d I V c o h ort], Part 2 a/ b, a n d Part 3 a/ b), 
pre g na nc y testi n g (fe male s u bjects o nl y) a n d use of  co nc o mita nt me d icati on will als o be 
assesse d a n d re p orte d.
8. 2. 1.
A d verse E ve nts
See Secti o n 1 1. 2. 3 .
8. 2. 2.
Vit al Si g ns
T he f o ll owi n g varia bles will be c ollecte d after t he s u bject has reste d i n t he s u pi ne p osit i on f or 
at least 1 0 mi n utes, i n acc or da nce wit h t he site’s sta n dar d o perati n g pr oce d ure ( S O Ps):

S y st olic B P ( m m H g)


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1

Di ast olic B P ( m m H g)

P ul se ( b p m)

Res pirat or y  rate (s u pi ne)

Or al  or ty m pa nic b o d y  t e mperat ure
8. 2. 3.
Electr oc ar di o gr a p h y
8. 2. 3. 1.
T wel ve le a d S afet y Electr oc ar di o gr a m
At  the ti me-p oi nts s pecifie d i n t he Sc he d ule of Assess me nts ( Sectio n 3. 2. 2 ), 1 2- lea d E C Gs will 
be o btai ne d aft er t he s u bject reste d i n t he s u pi ne p osi tio n f or at least 1 0 mi n utes ( usi n g t he 
Cli nical U ni t’s o w n E C G de vice w he n n ot perf or mi n g d E C Gs a n d usi n g t he sa me de vice as 
use d f or t he d E C Gs w he n ti me -p oi nts c oi nci de).
T he PI will j u d ge t he o verall int er pretatio n as n or mal or a b n or m al a n d t his e val uat i on will b e 
re p orte d i n Data La bs . If ab n or mal, it will be f urt her 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 sig nifica nt b y t he PI . F or all a b n or malit ies (re gar dless of  cli nical 
sig nifica nce) t he s pecific t y pe a n d nat ure of t he a b n or malit y will be d oc u m e nte d i n Data La bs.
Cli nicall y sig nifica nt fi n di n gs s h o uld als o be d o c u m e nte d o n t he A E pa ge of  the case re p ort 
f or m ( C R F) if a p plica ble.
T he PI ma y a d d e xtra 1 2- lea d resti n g safety E C Gs assess me nts if t here are a n y a b n or mal 
fi n di n gs or if t he PI c o nsi ders it is re q uire d f or a n y ot h er safety reas o n. T hese assess me nts 
sh 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. 3. 2.
Electr o nic C a pt ure of 1 2 -le a d C o nti n u o us Di git al Electr oc ar di o gr a m
C o nti n u o us 1 2- lea d di gi t al E C G rec or di n gs will  be p erf or m e d usi n g t he site´s M o rtara 
T el e metr y Sur ve y or e q uip me nt . At t he ti me-p oi nts s pecifie d i n t he Sc he d ule of  Assess me nts
( Sectio n 3. 2. 2 ), 1 2- lea d c o nti n u o us d E C G files will b e e xtracte d o ver at  least 5 mi n utes fr om 
t he M ortara Tele m etr y S ur ve yor or H 1 2 + c o nti n u o us files a n d tra ns mi tte d t o t he Astra Ze neca 
ce ntral dE C G re p osit or y, acc or di n g t o Astra Ze neca E C G Ce nter´s sta n dar d pr oce d ures, 
setti n gs, rec or di n g a n d tra ns missi on of d E C Gs.
T he sa me rec or di n g de vice will be use d f or eac h s u bject at all t i me-p oi nts, w he n p ossi ble . D at e 
a n d t i me s ettin gs m u st be c hec ke d o n t he M ortara Tele metr y S ur v e yor or H 1 2 + at t he start of 
eac h st u d y da y a n d ali g ne d with a n o fficial ti me kee per.
S ki n pre parati o n m ust be t hor o u g h a n d electr o de p osi tio ns m u st be acc or di n g t o sta n dar d 
1 2- lea d E C G place me nt.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Electr o de p ositi o ns will be mar ke d wit h a n i n deli ble pe n at t he start of  eac h st u d y da y t o e ns ure 
e xact re p ositi on. Per m a n e nt electr o des will be a p plie d at least 3 0 mi n utes bef ore first stu d y 
rec or di n g a n d left i n place f or t he d urati o n of eac h rele va nt st u d y d a y.
S u bjects will rest i n a s u pi ne p osi tio n f or at least 1 0 mi n utes (ca n be re d uce d acc or di n gl y at  
c ollect i on t i me-p oi nts wit hi n t he first h o ur a fter d osi n g) bef ore t he start of eac h rec or di n g . T h e 
s u bject s h o uld be i n t he sa me s u pi ne b o d y  posi tio n ( ma xi m u m 3 0 de grees fle xi on of  the hi p 
a n d feet n ot i n c o ntact wit h t he f o ot b oar d) at eac h rec or di n g ti me -p oi nt d uri n g t he st u d y .
T he meta data f or all d E C G files will  be c hec ke d b y t he res p o nsi ble pers o n nel at t he st u d y sit e 
t o e ns ure t hat t he files tra nsferre d t o t he Astra Ze neca ce ntral dE C G files re p osit or y ca n b e 
a p pr o ve d b y t he A Z E C G Ce nter t o be ma de accessi ble t o t he E C G Scie nt ific A d vis ors f or 
a na l ysis. As sta n dar d, 1 0 -sec o n d E C Gs will be e xtracte d b y t he E Cl ysis © s yste m twi ce p er 
mi n ute fr o m t he c o nti n u o us rec or di n g a n d i nit iall y a ut o mat icall y a nal yse d b y t he s oft ware.
Lea d V 2 will be a nal yse d a n d re p orte d as pri mar y. Lea d V 5 will be a nal yse d, for all  visits, as 
bac k u p f or t he i n di vi d ual w here a nal ysis i n lea d V 2 is n ot dee m e d p ossi ble f or p re-d ose, f or 
sig nifica nt parts of visits or f or w h ole visit s.
T he E C G Scie nt ific A d vis or will p erf or m  all re q uire d ma n ual c orrectio ns t o t he E C G 
a n n otatio ns pr o vi de d a ut o mat icall y b y E Cl ysis ©.
T o pr o vi d e a d e cisi o n  basis f or d os e escalatio n, t h e E C G S ci e nt ific A d vis or(s) will  p erfor m  a 
preli mi nar y a nal ysis of t he first 2 4 h o urs of d E C G rec or di n gs i n lea d V 2, wit h t he ma i n f oc us 
o n Q T c ha n ges, wa ve m or p h o l og y  c ha n ges a n d d ysr h yt hmia.
T he A Z E C G Ce nter Car di ol o gi st will re vie w t he d at a, perf or m a n e val uat i on a n d i nt er pretatio n 
of  t he fi n di n gs a n d will pr o vi de a safety re p ort f or t he S R C meeti n g.
T he A Z E C G Ce nter Car di ol o gist will re vie w t he t otalit y o f the data a n d perf or m all necessar y 
a djust m e nts b ef or e l oc ki n g t he E Cl ysis © data i nto a rea d-o nl y state, bef ore t he data will b e 
e x p orte d.
T he n u merical val ues f or E C G i nter vals a n d a m plit u des will be e x p orte d a n d m a de accessi ble 
o n t he Astra Ze neca d E C G Ce ntral r e p osit or y to accre dite d data ma na ge me nt s pecialists f or 
c o n versi o n i nto S A S ® files.
T he f o ll owi n g d E C G varia bles will be re p orte d b y t he Astra Ze neca E C G Ce nter: R R, P R, Q R S 
a n d Q T i nter vals fr om t he lea d defi ne d as t he pri mar y  anal yses lea d. Deri ve d para meters 
( Q Tc F, H R a n d ot hers, as a p plica ble) are calc ulate d b y t he st u d y st atisticia n or dele gate.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
8. 2. 3. 3.
Re al - Ti me E C G ( C ar di ac Tele metr y)
A mi ni m u m of 2- lea d r e al-ti m e t ele m etr y E C G will be p erfor m e d at t he ti me-p oi nts s pecifie d 
i n t he Sc he d ule of Assess me nts ( Sectio n 3. 2. 2 ).
T he tele metr y mo ni t ori n g s yste m will be re vie we d b y t he I n vestig at or a n d pa per pri nt o uts of 
a n y cli nicall y i m p orta nt e ve nts will be store d as s o urce data.
8. 2. 4.
P h ysic al E x a mi n ati o n
F ull
T he c o mplete p h ysical e xa mi nat i ons will i ncl u de a n assess me nt of  the ge neral  ap peara nce, 
s ki n, car dio vasc ular, res pir at or y, a b d o me n, hea d, a n d nec k (in cl u di n g ears, e yes, n ose, a n d 
t hr oat), l y m p h n o des, t h yr oid, m us c ul os k el et al  a n d ne ur ol o gical s yste ms.
Brief ( A b bre vi ate d)
T he br ief p h ysical  exa mi nat i ons will i ncl u de a n assess me nt of  the ge neral  ap peara nce, s ki n, 
car dio vasc ular s yste m , res pirat or y a n d a b d o me n.
8. 2. 5.
S pir o metr y
S pi r o metr y meas ure me nts, F E V 1 a n d f orce d vit al ca pacit y (F V C) ( ma xi mal vol u me of  air 
e x hale d i n liters wi t h 
ma xi mall y f orce d e x pirat or y eff ort fr o m a p osi tio n of  
ma xi mal 
i ns pirati on) will be perf or m e d at t he ti me-p oi nts o utli ne d t he Sc he d ule of  Assess me nts
( Sectio n 3. 2. 2 ), a n d i n acc or da nce wit h t he site’s S O Ps.
8. 2. 6.
P ulse O xi metr y
P ul se o xi metr y  will be perf or m e d a n d S p O 2 will be meas ure d at t he ti me-p oi nt s o utli ne d t he 
Sc he d ule of Assess me nt s ( Sectio n 3. 2. 2 ), a n d i n acc or da nce wit h t he site’s S O Ps.
8. 2. 7.
L a b or at or y Assess me nts
T a ble 8. 2 - 1
He m at ol o g y
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 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 7 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 8. 2 - 2
Cli nic al C he mistr y
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)
Ur ic aci d
Ga m ma gl uta m yl tra ns pe pti dase ( G G T)
Creati ni ne
T otal Bilir u bi n ( T B L)
Al b u mi n
U n c o nj u gate d bilir u bi n
Calci u m
Tri gl yceri des
P h os p hate
F ollicle -sti m ulati n g h or m o ne ( F S H) a (p ost -me n o pa usal
fe males o nl y)
Gl uc ose (fasti n g i n plas ma)
T h y r oi d-sti m ulati n g h or m o ne ( T S H) a
Hi g h -Se nsiti vit y C -reacti ve pr otei n ( hs-C R P)
a)
Scree ni n g o nl y
T a ble 8. 2 - 3
Uri n al ysis
Uri n al ysis
Gl uc ose
Pr otei n
Bl o o d
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)
T a ble 8. 2 - 4
Pre g n a nc y Testi n g
Pre g n a nc y test (fe m ales o nl y)
H u ma n beta c h ori o nic g o na d otr o p hi n
T a ble 8. 2 - 5
Ser ol o g y
Ser ol o g y
H u ma n i m m u n o deficie nc y vir us ( HI V) I a n d II  
He patitis C Vir us a nti b o d y
He patitis B s urface a nti ge n ( H Bs A g)
A nti- H Bc a nti b o d y
a
Q ua nti F E R O N ® T B
a)
Ger ma n y o nl y
T a ble 8. 2 - 6
Dr u gs of A b use, Alc o h ol a n d C oti ni ne
Dr u gs of A b use a n d Alc o h ol
A m p heta mi ne
Be nz o diaze pi nes
Et ha n ol
Met ha d o ne Meta b olites
Ca n na bi n oi ds
Bar bit urates
C ocai ne
P he nc y cli di ne
O piates 
Ur i ne Creati ni ne
C oti ni ne
Tric yclic a nti -de pressa nts ( T C A)


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T a ble 8. 2 - 7
C O VI D -1 9 Testi n g
C O VI D -1 9 Testi n g
A nti b o d y, P C R, or alter nati ve C O VI D -1 9 test will be c o n d ucted s u bject t o l ocal a vaila bilit y a n d site g ui da nce
8. 2. 8.
C o nc o mit a nt Me dic ati o n
See Secti o n 7. 7 .
8. 3.
P h ar m ac o ki netics
8. 3. 1.
S a m ple C ollecti o n a n d H a n dli n g
Bl o o d s a m ples f or t h e deter mi nat i on of  plas ma c o nce ntratio ns of  AZ D 0 4 4 9 will be c o llecte d 
as s pecifie d i n t he Sc he d ule o f Assess me nts ( Sectio n 3. 2. 2 ).
 
S a m ples will be c o llecte d, ha n dle 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.
8. 3. 2.
P h ar m ac o ki netic Dr u g Ass a ys
Bl o o d sa m ples f or deter mi nat i on of A Z D 0 4 4 9 a n d 
 
c o nce ntrati o ns i n plas ma will be a nal yse d b y C o va nce L a b orat ories Lt d o n be half of  
Astra Ze neca, usi n g vali date d assa ys. A d dit i on al  a nal yses ma y be c o n d ucte d o n t he biol o gi c al 
sa m ples t o f urt her i n vesti gate t he prese nce a n d/ or i de ntity of  dr u g meta b o lites.
 
Pl ace b o sa mples will n ot be a nal yse d, u nless t here is a nee d t o c o nfir m t hat c o rrect treat me nt 
has bee n gi ve n t o st u d y  s u bjects.
F ull details of  the a nal yt ical met h o d s a n d a nal yses perf or m e d will be descri be d i n a se parate 
bi oa nal yt ical re p ort.
 
 
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
 
8. 5.
P h ar m ac o d y n a mic Assess me nts
8. 5. 1.
Fr acti o n al E x h ale d Nitric O xi de P art 2 a a n d P art 3 a
T he Fe N O assess me nts will be p erf or me d at t he ti me-p oi nts s pecifie d i n t he Sc he d ule of  
Assess me nts
( Sectio n 3. 2. 2 ). See Secti o n 5. 2. 2 f or restricti ons t hat nee ds t o be met  befor e 
Fe N O assess me nt ca n be perf or me d .
D uri n g i nfla m mati on ass o ciate d wit h br o nc hial ast h ma, nit ric o xi de ( N O) will be r elease d b y 
cells wi t hi n t he br o nc hial tree, i ncl u di n g e osi n o p hil le uc oc ytes, via act i vati on of  in d uci ble 
nit ric o xi de s y nthase (iN O S) . Si nce N O is a gas, it will be e x hale d a n d is belie ve d t o be a 
val ua ble bi o mar ker of air wa y i nfla m mat i on.
T he me as ure me nt of e x hale d N O is p erf or me d d uri n g re g ul ar slo w e x h al ati o n . T he ma ne u ver 
will be descri be d detail i n st u d y  s pecific ma n ual.
 
 
 
 
 
 
 
 
8. 6.
E x pl or at or y Assess me nts
 
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
 
 
 
 
8. 7.
Pr oce d ures f or H a n dli n g of Bi ol o gic al S a m ples
S a m ples will be dis p ose d of , o n i nstr ucti o n fr om As tra Ze neca, aft er t he C S R has bee n fi nalize d,
u nless sa m ples are retai ne d f or a d dit i onal or f ut ure a nal yses.
8. 7. 1.
St or a ge a n d Destr ucti o n of Bi ol o gic al S a m ples
S a m ples will be dis p ose d of , o n i nstr ucti o n fr om As tra Ze neca, aft er t he C S R has bee n fi nalize d, 
u nless sa m ples are retai ne d f or a d dit i onal or f ut ure a nal yses.
8. 7. 1. 1.
P h a r m ac o ki netic S a m ples a n d 
P har mac o ki net ic a n d 
 sa mples will be dis p ose d of after t he bi oa nal yt ical 
re p ort fi nalizati on or 6 m o nt hs aft er iss ua nce of  the dr af t bi oa nal yt ical re p ort ( w hic he ver is 
earlier), u nless re q ueste 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 dit i 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 e val uate a n d vali date t he 
a nal yt ical met h o d. 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 o m t he C S R.
I nc urre d sa m ple re pr o d uci bility a nal ysis, if a n y, will be perf or me d al o n gsi de t he bi o a nal ysis o f 
t he test sa m ples. T he res ults fr o m t he e val uat i on will n ot be re p orte d i n t he C S R b ut se paratel y 
i n a bi oa nal ytical re p ort.
 
 
 
 
C CI
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 7. 2.
L a beli n g a n d S hi p me nt of Bi o h az ar d S a m ples
S a m ples will  be la bele d a n d s hi p pe d i n acc or da nce wi t h the La b orat or y  Ma n ual a n d t he 
Bi o l ogi cal S u bsta nce, Cate g or y  B re g ulat i ons ( materials c o ntai ni n g or s us pecte d t o c o nt ai n 
i nfecti ous s u bsta nces t hat d o n ot meet 
Cate g or y  A crit eria) (f or I nter nati o nal Airli ne 
Tra ns p ortati o n Ass ociat i on [I A T A] g ui da nce, see A p pe n di x 1 5. 2 of  t his C S P).
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A n y sa m ples i de ntifie d as I nfecti ous Cate g or y  A mat erials will n ot be s hi p pe d a n d n o f urt her 
sa m ples will be ta ke n fr om t he s u bject u nless a gree d wi t h Astra Ze neca a n d a p pr o priat e 
la beli n g, s hi p me nt a n d c o ntai n me nt pr o visi ons are a p pr o ve d.
8. 7. 3.
C h ai n of C ust o d y of Bi ol o gic al S a m ples
A f ull c hai n of c ust o d y will be mai ntai ne d f or all sa mples t hr o u g h o ut t heir life c ycle.
T he PI will e ns ure f ull tracea bility of  col lecte d bi ol o gi cal sa m ples fr o m t he s u bjects w hile i n 
st ora ge at t he Cli nical U nit u nt il s hi p me nt a n d will kee p d oc u me ntati o n of recei pt of arri val.
T he sa m ple recei ver will kee p f ull tracea bilit y o f sa m ples w hile i n st ora ge a n d d uri n g use, u ntil 
use d, dis p ose d of , or u ntil f urt her s hi p me nt or dis p osal ( w here a p pr o priate) a n d will k e e p 
d oc u m e nt atio n of  recei pt of arri val.
S a m ples retai ne d f or f urt her use will be re gistere d i n t he Astra Ze neca bi o -ba n k s yste m d uri n g 
t he e nt ire life c ycle.
8. 7. 4.
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
If a s u bject wit h dra ws c o nse nt t o t he use of  do nate d bi o l ogical  sa m ples, t he sa mples will b e 
di s p ose d if n ot alrea d y a nal yse d a n d t he act i on d o c u me nte d. As c o llecti o n of  do nate d bi o l ogi c al 
sa m ples is a n i nte gral part of  the st u d y, c o nse nt wi t hdra wal i m plies t hat t he s u bject is 
wi t hdra w n fr o m  furt her st u d y  p artici pat i on.
If a s u bject o nl y  with dra ws c o nse nt t o use t he d o nate d sa mples f or t he o pti o nal  ge net ic a n d 
bi o mar ker a nal yses, t he s u bject’s partici pat i on i n t he st u d y will n ot be i nfl ue nce d.
Astra Ze neca e ns ures t he lab orat or y  hol di n g t he sa m ples is i nf or me d a b o ut t he wit h dra w n 
c o nse nt i m me diatel y a n d t hat sa mples are dis p ose d of  or destr o ye d, t he act i on d o c u m e nte d, 
a n d t he si g ne d d oc u me nt ret ur ne d t o t he Cli n ical U nit.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
9.
D A T A Q U A LI T Y A S S U R A N C E A N D D A T A M A N A G E M E N T
9. 1.
Q u alit y C o ntr ol a n d S o urce D at a Verific ati o n
S o urce data verificati o n will be c o n d ucte d wit h d ue re gar d t o s u bject c o nfi de nt iality.
T he Cli nical  U nit will allo w t h e st u d y  mo ni t or a n d S p o ns or re prese ntati ve di rect access t o all 
st u d y d o c u me nts, me dical files a n d s o urce d oc u me nts t o e na ble verificat i on of  t he st u d y d at a, 
w hile mai ntai ni n g t he a n o n y mit y of t he s u bject a n d c o nfi de nt iality of t he data.
I nter nal q uality c o ntr ol will be perf or me d at all sta ges of  t he st u d y b y t he Cli nical U nit.
9. 2.
A u dit/I ns pecti o ns
T he Cli nical U ni t facilities a n d all st u d y data/ d oc u me ntatio n ma y be a u dite d/i ns pecte d b y 
i n de pe n de nt a u dit or/ins pect or/a n y  re prese ntati ves of  re g ulat or y aut h ori ties. T he I n vestig at or 
m ust all o w t he a p plica ble pers o ns access t o all r ele va nt facilities a n d data/ d oc u m e nts. T he 
I n vesti gat or m ust be a vaila ble t o disc uss a n y fi n di n gs/iss ues.
If a n a u dit was perf or me d, t he a u dit certificate will be i ncl u de d i n t he C S R.
9. 3.
St u d y M o nit ori n g
T he c o n d uct of  the st u d y will be m o nit ore d b y a n i n de pe n de nt P are xel m o nit or or a 
s u bc o ntracte d m o nit or t o e ns ure c o m plia nce with a p plica ble re g ulat or y re q uire me nts a n d G C P .
T he s u m mar y of  the d oc u m e nt atio n of  the m o nit ori n g visi ts will f or m part of  the st u d y 
d oc u m e nt atio n a n d wil l be arc hi ve d as s uc h.
9. 4.
D at a C ollecti o n
T he Data La bs s yste m is a n electr o nic s o urce data ca pt uri n g a n d i nf or mati o n ma na ge me nt 
s yste m. T he s yste m co m bi nes all as pects of  so urce data ca pt uri n g wi t h pr ocess c o ntr ol an d 
cli nical st u d y 
ma na ge me nt . All 
cli nical a n d la b orat or y data, e xce pt t hose w hic h 
are 
pa per -base d, will be c o llecte d i n Data La bs. O nl y pa per -base d data will be s u bject t o data e ntr y .
F or el e ctr o nic s o urce data, n o data e ntr y will be perf or me d.
T he res p o nsi ble st u d y m o nit or will c hec k data at t he m o nit ori n g visits t o t he Cli nical U nit . T he 
I n vesti gat or will e ns ure t hat t he data c ollecte d are acc urate, c o m plete a n d le gi ble. Data will be 
m o nit ore d wit hi n Data La bs b y t he st u d y mo ni t or bef ore bei n g e x p orte d. A n y c ha n ges ma d e 
d uri n g m o ni t ori n g will be d ocu m e nte d wit h a full  a u dit trail wit hi n Data La bs.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
9. 4. 1.
C ase Re p ort F or ms a n d S o urce D oc u me nts
All data o btai ne d usi n g pa per c ollecti o n met h o ds d uri n g t he cli nical  st u d y will be rec or de d i n 
Data La bs . All s o urce d oc u me nts fr o m w hic h Data La bs e ntries are deri ve d s h o uld be pl ace d i n 
t he s u bject’s pers o nal rec or ds.
T he ori gi nal Data La bs e ntries f or eac h s u bject will be c hec ke d a gai nst s o urce d oc u me nts b y 
t he st u d y mo ni t or. I nsta nces of  missi n g or u ni nter preta ble data will be di sc usse d wi t h the 
I n vesti gat or f or res ol uti on.
9. 4. 2.
Access t o S o urce D oc u me nts
D uri n g t he c o urse of t he cli nical st u d y, a st u d y m o nit or will ma ke Cli nical U nit visit s t o re vie w 
pr ot oc ol  co m plia nce, c o mpare Data La bs e ntries a n d i n di vi d ual s u bject’s pers o nal rec or ds, 
assess I M P acc o u nta bilit y a n d e ns ure t hat t he cli nical st u d y is bei n g c o n d ucte d acc or di n g t o 
perti ne nt re g ulat or y  re q uire me nts. Data La bs e ntries will be verifie d a gai nst s o urce d oc u me nts .
T he re vie w of me dical rec or ds will be ha n dle d c o nfi de ntiall y t o e ns ure s u bject a n o n y mit y.
C hec ki n g
of  the Data La bs e ntries f or c o mplete ness a n d clarit y an d verif yi n g wi t h so ur c e 
d oc u m e nts, will be re q uire d t o m o nit or t he cli nical st u d y for c o m plia nce wi t h GC P a n d ot her 
re g ulat i ons . M ore o ver, re g ul at or y a ut h orities of certai n c o u ntries, I E Cs ma y wis h t o carr y o ut 
s o urce data i ns pecti ons o n -sit e, a n d t he S p o ns or’s cli nical q ualit y ass ura nce gr o u p ma y wis h 
t o carr y o ut a u dits. Direct access t o s ource data will be re q uire d f or t hese i ns pect i ons a n d a u dits; 
t he y will be carrie d o ut gi vi n g d ue c o nsi derati o n to data pr otecti o n a n d s u bject c o nfi de nt iality.
T he I n vesti gat or ass ures t he S p o ns or of t he necessar y  s u p p ort at all ti mes.
9. 5.
D at a M a n a ge me nt
P are xel will utilize sta n dar dize d a n d vali date d pr oce d ures a n d s yste ms t o c ollect, pr ocess a n d 
file t he cli nical data of  this st u d y. A n y s yste m use d will be c o m p lia nt wi t h FD A 2 1 C F R Part 1 1 
re q uire me nts.
A data ma na ge me nt pl a n ( D M P) will be pre pare d t o descri be t he pr ocesses a n d data -fl ow 
wi t hi n t he cli nical st u d y. Ti meli nes, versi o ns f or t he c o mp ut er s y ste ms a n d t he c odi n g will b e 
defi ne d i n t he D M P, a n d if a p plica ble, S p o ns or -s pecific re q uests will als o be d o c u m e nte d 
wi t hi n. T he D M P will be fi nalize d bef ore first d ose w here p ossi ble b ut bef ore data base l oc k.
A data vali dat i on s pecificati on ( D V S) will be create d t o o utl i ne t he vali dat i on c hec ks t o be 
perf or m e d d uri n g t he st u d y. T he D V S m ust be fi nalize d bef ore data vali dat i on.
After t he data has bee n m o nit ore d b y t he res p o nsi ble st u d y mo ni t or all d at a recei ve d will b e 
re vie we d, l o g ge d a n d file d.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he ra w data i nte n de d f or f urt her pr ocessi n g will be c hec ke d b y sta n dar d r o uti nes or acc or di n g 
t o t he D V S a n d q ueries will be ge nerate d a n d se nt t o t he I n vest i gat or f or re vie w a n d res ol uti on.
C orrecti o ns res ultin g fr o m t hese q ueries will be c o nfir me d o n t he data clarificat i on f or ms 
( D C Fs). T his pr ocess will be re peate d u nt il n o f urt her di scre pa ncies are f ou n d . T he data will 
t he n be declare d as clea n . A p plica ble d oc u me ntati o n will be st ore d i n t he st u d y  files.
O nl y trai ne d st u d y  staff will ha ve access t o t he cli nical data base a n d e ver y c ha n ge i n data will 
ha ve a f ull a u dit trail.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 8 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 0.
S T A TI S TI C A L A N A L Y S E S
1 0. 1.
O ver vie w
T he st atistical met h o d ol o g y  belo w descri bes t he statistical a nal ysis as it is f oresee n w he n t h e 
st u d y is bei n g pla n ne d.
If circ u msta nces s h o ul d arise d uri n g t he st u d y re n deri n g t he a nal ysis i na p pr o priate, or if i n t he 
mea nt i me i m pr o ve d met h o ds of a nal ysis s h o uld c o me t o li g ht, e g trig gere d b y c ha n ges t o t h e 
desi g n of  t he st u d y, differe nt a nal yses ma y be p erf or m e d. All f urt her details of  t he st atistical 
a nal yses a n d met h o ds will be c o ntai ne d i n a se parate S A P w hic h will be fi nalize d bef ore t he 
fi nal u n bli n di n g of  the data . A n y de viat i ons fr om t he statistical met h o d ol o g y  defi ne d i n t his 
pr ot oc ol , reas o ns f or s uc h de viati ons a n d all alter nati ve/a d dit i onal statistical a nal yses t hat m a y 
be perf or m e d will be descri be d i n t he C S R.
1 0. 2.
Ge ner al St atistic al Met h o d ol o g y
All r es ults will be prese nte d b y tr e at me nt ( d ose le vel of  AZ D 0 4 4 9 or p o ole d place b o) a n d 
o verall, w here a p plica ble, wi t h descript i ve st atistics a p pr o priate t o t he nat ure of t he v aria bles 
f or eac h st u d y part se paratel y. F or c o nt i n u o us varia bles, t he n u m ber of  no n -missi n g 
o bser vat i ons, mea n, S D , me d ia n, mi ni m u m a n d ma xi m u m, will be prese nte d; f or cate g orical 
varia bles: c o u nts ( n) a n d perce nta ges ( %) ( w here s pecifie d) will be prese nt e d. T hese s u m maries 
will be pr o vi de d b y t i me-p oi nt of assess me nt as a p pr o priate . If at a gi ve n ti me- p oi nt, n < 3, t he n 
o nl y n, mi ni m u m a n d ma xi m u m will  be prese nte d.If n = 3, t he n o nl y n, mea n, me dia n, mi ni m um 
a n d ma xi m u m will be prese nte d . T he ot her descri pt i ve statistics will be left bla n k.
All ori gi nal a n d deri ve d para meters as well as de m o gra p hi c a n d dis p ositio n data will be liste d 
a n d descri be d usi n g s u m mar y st atistics. All safet y data (sc he d ule d a n d u nsc he d ule d) will b e 
prese nte d i n t he data list i n gs.
T h e f oll owi n g r ules will  ap pl y t o a n y re peate d safety assess me nts occ urri n g wi t hi n e a c h 
treat me nt perio d:

If t he re peate d me as ure me nt of  a specific para m eter occ urs bef ore I M P 
a d mi nistrati o n ( D a y 1), t he n t he last o btai ne d v al u e bef ore d osi n g will  be use d i n
t he descript i ve statistics a n d i n t he calc ulati on of c ha n ges fr o m baseli ne;

If the re peate d meas ure me nt of  a specific para meter occ urs aft er I M P a d mi nistrati o n 
( D a y 1), t he n t he first ( n o n-missi n g) val ue aft er d osi n g will be use d i n descri pt i ve 
statistics a n d i n t he calc ulat i on of c ha n ges fr o m baseli ne.
T he pl a n ne d se q ue nce f or meas ure me nt of  mul ti ple assess me nts at t he sa me ti me-p oi nt is 
descri be d i n Secti o n 3. 2. 3 .


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
F or safety assess me nts perf or m e d at scree ni n g a n d t he F oll o w - u p Vi sit/last da y of  st u d y, t he 
f oll owi n g r ules will a p pl y  for a n y re peate d assess me nts:

If t he re peate d assess me nt occ urs at t he Scree ni n g Visit t he last a vaila ble val ue will 
be use d i n t he s u m mar y  st atistics;

If t he re peate d assess me nt occ urs at t he F oll o w -u p Vi sit/last da y of st u d y, t he first 
n o n- missi n g assess me nt will be use d i n t he s u m mar y  st atistics.
All st atistical a nal yses a n d pr o d ucti o n of  ta bles, fi g ures a n d listi n gs will be p erf or m e d usi n g 
S A S ® versi o n 9. 4. or later . A c o m p lete set of  ra w data listi n gs will be a p pe n de d t o t he fi nal 
C S R . All ta bles, fi g ures a n d listi n gs will be prese nte d i n p orta bl e d o c u m e nt f or mat ( P D F) 
d oc u m e nts wi t ho ut a n y ma n ual e ditin g, ie, t he y will a p pear u n m o difie d as pr o gra m me d b y 
mea ns of t he statistical pac ka ge.
1 0. 2. 1.
Missi n g D at a
T here will be n o i m p utati o n of  missi n g data e xce pt of  data a nal ysis me nti o ne d bel o w i n t his 
secti on. All s u bjects will be i ncl u de d i nt o t he safet y a nal yses as far as t he data per mit.
T he A E r el ate d missi n g data will be ha n dle d as descri be d i n Sect i on 1 0. 6. 4. 1 . C o nce ntrati o ns 
t hat are bel o w li mit of  qua ntificat i on ( BL Q) i n t he P K data will be ha n dle d as descri be d i n 
Secti o n 1 0. 6. 5. 2 .
T he a nal ysis of  t he c ha n ge fr o m baseli ne t o D a y 1 2 i n 2- h o ur p ost -d ose Fe N O a nd A U C ( 0-1 2)
will be base d o n a mi xe d effect m o d el  of re peate d meas ures ( M M R M) a nal ysis. T his a nal ysis 
will be c o n d ucte d usi n g data f or o bser ve d cases ( O C) wit h n o data i m p utati o n. I n a d ditio n, 
f urt her a nal ysis of  co varia nce ( AN C O V A) (see Secti o n 1 0. 6. 6. 1 ) will be c o n d ucte d f or t he 
c ha n ge fr o m baseli ne t o Da y 1 2 i n 2- h o ur p ost -d ose Fe N O a n d A U C ( 0-1 2) usi n g t he last 
o bser vat i on carrie d f or war d ( L O C F) met h o d. U n der t he L O C F met h o d ol o g y , t he last 
p ost -baseli ne o bser vat i on, ie, Fe N O assess me nt or A U C ( 0-1 2), b efore t he missi n g val ue will  be 
carrie d for war d t o t he missi n g t i me-p oi nts.
1 0. 3.
St u d y A n al yses Sets
1 0. 3. 1.
S a fet y A n al ysis Set
T he S af et y anal ysis set ( S A F) will i ncl u de all su bjects w h o receive d at least 1 d ose of  AZ D 0 4 4 9 
a n d f or w h o m a n y safet y p ost -d ose data are a vaila ble.
U nless ot h er wise state d t he S A F will be use d f or t he prese ntati o n of  all d e m o gra p hic a n d
di s p ositio n data, as well as all safety a nal yses. E x p os ure t o I M P will als o be prese nte d usi n g 
t he S A F.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 0. 3. 2.
P h ar m ac o ki netic A n al ysis Set
T he P K a nal ysis set ( P K S) will c o nsist of all s u bjects w h o recei ve d at least 1 d ose of A Z D 0 4 4 9 
a n d w h o ha ve e val ua ble P K d ata, wit h n o maj o r pr ot oc ol de viat i ons t ho u g ht t o i m pact o n t he 
a nal ysis o f t he P K data. All pr ot oc ol de viat i ons t hat occ ur d uri n g t he st u d y  will be c o nsi dere d 
f or t heir se verit y/i m pact a n d will be ta ke n i nt o c o nsi derati o n w he n s u bjects are assi g ne d t o t he
P K a nal ysis sets.
Data fr o m s u bjects f or w h o m t he pre -d ose c o nce ntrati o n is > 5 % of  Cma x f or t he first d ose of 
A Z D 0 4 4 9 o n D a y 1 of  the d osi n g p eri o d ma y be e xcl u de d fr om t he statistical a nal ysis a n d 
c orres p o n di n g fi g ures. If t here are n o ot her re p orta ble PK data f or a s u bject, t he n t he y ma y be 
e xcl u de d fr o m the P K  anal ysis set. T he e xcl usi o n of  an y s u bjects or ti me-p oi nts fr o m t h e 
calc ulat i on of  the P K para meters a n d/ or P K s u m mar y st atistics will be a gree d at t he bli n de d 
re vie w me eti n g a n d will be d o c u m e nted b y t he P K Scie ntist i ncl u di n g t he reas o n(s) f or 
e xcl usi o n.
T he a vaila ble c o nce ntrati o n data a n d P K para meter data f or a n y s u bjects e xcl u de d fr o m t he P K 
a nal ysis set will be liste d o nl y. C o nce ntrati o n data f or s u bjects e xcl u de d fr o m t he P K a nal ysis 
set will be prese nte d i n t he i n di vi d ual fi g ures of c o nce ntrati o n vers us ti me pl ots.
1 0. 3. 3.  
R a n d o mize d Set
T he Ra n d o mize d Set ( R S) will c o nsist of all s u bjects ra n d o mize d i nt o t he st u d y.
1 0. 3. 4.
E nr olle d A n al ysis Set
T he E nr olle d A nal ysis Set ( E N) will i ncl u de all s u bjects w h o sig ne d i nf or me d c o nse nt.
1 0. 3. 5.
F ull A n al ysis Set
T he F ull A nal ysis Set ( F A S) will c o nsist of all s u bjects ra n d o mize d i nt o t he st u d y, recei vi n g at  
least 1 d ose of I M P a n d ha vi n g at least o ne 2- h o ur p ost -d ose Fe N O assess me nt aft er t h e first 
I M P i nta ke.
1 0. 3. 6.
Per Pr ot oc o l Set
T he Per Pr ot oc ol  a nal ysis set ( P P) will c o nsist of all s u bjects w h o belo n g t o t he F A S a n d w h o 
ha ve n o maj or pr ot oc ol de viat i ons t hat mi g ht i m pact res ults of Fe N O.
1 0. 4.
Deter mi n ati o n of S a m ple Size
T his is a P hase I st u d y to i n vesti gate t he safety a n d t olera bility of  a no vel  co m p o u n d. T h e 
sa m ple size was c h ose n t o o btai n reas o na ble e vi de nce of  safet y a n d t olera bilit y with o ut 
e x p osi n g u n d ue n u m bers of  su bjects t o t he c o mp o u n d at t his p hase of  cli nical de vel o p me nt .


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Pre vi o us e x perie nce i n P h ase I st u dies has sh o w n t hat t he sa mple size bei n g pr o p ose d is 
reas o na ble t o acc o mplis h t he o bj ecti ves of t he st u d y. T h us, n o f or mal sa m ple size calc ulati on 
was d o ne f or Part 1 a n d t he n o n -P o M c o h orts i n P art 2a/ b a n d Part 3.
F or Part 3a ( P o M c o h ort ):

E n d p oi nt: c ha n ge fr om baseli ne i n e x hale d Fe N O (lo g scale) w hile recei vi n g 
m ult i ple i n hale d d oses of A Z D 0 4 4 9, i n acti ve a n d place b o ar ms.

Treat me nt differe nce ( Treat m e nt – Pl ace b o) of c ha n ge fr om baseli ne o f mea n L o g 
Fe N O, e q ui vale nt t o a 2 5 % re d ucti o n of t he rati o of ge omet ric mea n .
F or Part 3a , ass u mi n g a l og mea n baseli ne Fe N O level of  4. 2 4 wi t h SD of  0. 3 8 ( ge o metric 
c oefficie nt of  variati on [ G C V] = 3 9. 4 %) a n d a c orrelatio n bet wee n baseli ne a n d last d a y  of stu d y
data of 0. 7, as s u g geste d b y  pre vio us st u di es [ 1 9 ], t he re q uire d sa m ple size f or a 2 5 % a bs ol ute 
re d uctio n i n t he rati o of ge o m etric mea ns (a 0. 2 8 8 re d ucti o n of  t he me a n l og Fe N O levels) is 
1 8 e val ua ble patie nts pe r ar m usi n g a o ne-si de d test at 5 % si g nifica nce le vel.
T he c urre nt desi g n prese nts a n o p p ort u nit y t o perf or m a sa m ple size calc ulati on at a n I A ta ki n g 
pl ace w he n
a p pr o xi matel y half t he data fr om Part 3a is a vaila ble. If t he act ual est i mate of  
baseli ne Fe N O S D is hi g her t ha n e x pecte d, reac hi n g S D = 0. 5 5, t he sa m ple size of  the P o M 
c o h ort i n Part 3a will be p ote ntiall y i ncrease d u p t o n = 2 6 per ar m .
S h o ul d t he vari at i on be e ve n hi g her, re q uiri n g a dj ust me nts be y o n d t his, a n a me n d me nt will be 
s u b mitte d. 
1 0. 4. 1.
I nteri m A n al ysis
As me nt i one d a b o ve, an u n bli n de d I A will be p erf or m e d w he n a p pr o xi matel y 5 0 % of  the 
patie nts ha ve c o m p lete d Part 3a. T he c ollecte d data will be use d t o i nf or m vari o us decisi o ns or 
actio ns s uc h as assessi n g t he efficac y o f A Z D 0 4 4 9 i n a n u n bli n de d ma n ner a n d t o perf or m  a n 
u n bli n de d sa m ple size r e-esti mat i on. Base d o n t he res ults fr o m t he I A ( P K, P D [ Fe N O] a n d 
safety) , t he P o M c o h ort size will be deci de d . F urt her details will be i ncl u de d i n t he S A P f or 
Part 3. T he latter will detail t he nat ure a n d t he e xact criteria of the decisi o ns as well as ha n dli n g 
of  t he data a n d act ual decisi on ma kers.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 0. 5.
Pr ot oc ol De vi ati o ns
Pr ot oc ol  de viat i ons are c o nsi dere d a n y de viat i on fr o m  the C S P relat i n g t o a s u bject, a n d i ncl u de 
t he f o llo wi n g:

I ncl usi on/e xcl usi o n cri teria de viati ons.

D osi n g de viat i ons (e g, i nc orrect treat me nt recei ve d, s u bject was n ot faste d as per 
t he C S P re q uire me nts bef ore a n d after d osi n g).

Ti me wi n d o w de viat i ons f or safety a n d/ or P K assess me nts.

S u bjects recei vi n g pr o hi bite d c o nc o mit a nt me dicati o ns.

Ot her pr oce d ural a n d st u d y co n d uct de viat i ons rec or de d b y t he Cli nical U ni t o n a 
C S P de viati o n l o g .
T he criteria f or t he assess me nt a n d re p orti n g of  pr ot oc ol de viat i ons will be stip ulate d i n a 
se parate st u d y specific pr ot o c o l de viati o n s pecificatio n ( P D S) d oc u m e nt . T hi s will  incl u de a 
Wi n d o ws All o wa nce D oc u me nt ( W A D), w hic h sti p ulates t olera nce wi n d o ws f or safety,  PK 
a n d P D assess me nts. Meas ure me nts p erf or m e d wi t hi n t hese t olera nce wi n d o ws will n ot be 
c o nsi dere d as pr ot oc ol de viat i ons a n d will n ot be re p orte d.
All pr ot oc ol  de viati ons will be disc usse d at t he Data Re vie w Meet i n g ( D R M) bef ore data base 
har d l oc k i n or der t o defi ne t he a nal ysis sets f or t he st u d y. T he precise reas o ns f or e xcl u di n g 
pati e nts fr o m t he st u d y p o p ulat i ons will be f ull y a gree d o n i n t he D R M re p ort.
I mp orta nt pr ot oc ol de viati o ns will be s u m marize d a n d liste d b y s u bject f or all ra n d o mize d 
s u bjects.
Pr ot oc ol  de viati ons will be ha n dle d i n acc or da nce wit h P are xel S O Ps.
F or ha n dli n g of C S P a me n d me nts, see Sec tio n 1 2. 6 .
1 0. 6.
St atistic al Met h o ds
1 0. 6. 1.
S u bject Dis p ositi o n
S u bjects a n d/ or data e xcl u de d fr om t he P K a nal ysis set will be liste d i ncl u di n g t he reas o n f or 
e xcl usi o n.
S u bject dis p osit i on will be s u m marize d se paratel y for scree ni n g fail ures a n d ra n d omize d 
s u bjects f or eac h part of t he st u d y. Scree ni n g fail ures data will be base d o n t he E N set a n d will 
i ncl u de t he f oll owi n g i nf or mati on: n u m ber of  su bjects scree ne d, n u m ber a n d perce nta ge of 
s u bjects wit h scree n failure i ncl u di n g t he reas o n wit hdra wal . Perce nta ge will be base d o n t he 
n u m ber of scree ni n g fail ures.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Di s p ositio n  su m mari es of  ra n d o mize d s u bjects will be prese nte d b y treat me nt gr o u p a n d 
o verall a n d i ncl u de t he f oll owi n g i nf or mati on: n u m ber of  su bjects ra n d omize d, n u m ber a n d 
perce nta ge of  su bjects w h o recei ve d/ di d n ot recei ve t he treat me nt, c o m p lete d t he treat me nt 
p eri o d/st u d y  an d t he n u m ber a n d perce nta ge of  su bjects w h o 
were 
wit h dra w n aft er 
ra n d omizat i on ( i ncl u di n g reas o ns f or wit h dra wal). Di s p ositio n  data will be prese nte d base d o n 
all s u bjects ra n d omize d.
S u bject disc o nt i n uati ons will be liste d i ncl u di n g t he date of  st u d y exit , d urati o n of  treat me nt 
a n d reas o n f or disc o nt i n uati on.
A n i nf or m c o nse nte d/ra n d o mizat i on listi n g will be prese nte d a n d i ncl u de t he f oll owi n g: eac h 
s u bject’s ra n d omizat i on n u m ber, date of  inf or me d c o nse nt, date of  ra n d o mizat i on a n d t he 
d ose/treat me nt t o w hic h t he s u bject has bee n ra n d o mize d.
N u m ber a n d perce nta ge of s u bjects i n eac h a nal ysis set will be prese nte d.
1 0. 6. 2.
De m o gr a p hic a n d B ase li ne D at a
D e m o gra p hic varia bles (a ge, ge n der, race, et h nicit y,  hei g ht, wei g ht a n d B MI) will be liste d b y 
s u bject. De m o gra p hic 
c haracterist ics (a ge, ge n der, race a n d et h nicit y)  an d s u bject 
c haracterist ics ( hei g ht, wei g ht a n d B MI) will be s u m marize d b y treatme nt  (d ose level of  
A Z D 0 4 4 9 a n d p o ol e d place b o), f or all s u bjects i n t he S A F, f or eac h part of  the st u d y. T h e 
de n o mi nat or f or perce nta ges will be t he n u m ber of s u bjects i n t he S A F f or eac h tr e at me nt or 
f or all s u bjects as a p plica ble, i n t hat st u d y part.
Me dical  hist or y data will 
be liste d b y s u bject i ncl u di n g visi t, descri pt i on of  the 
di sease/ pr oce d ure, Me dical Dict i onar y  for Re g ulat or y  Act i vities ( Me d D R A) S yste m  Or ga n 
Cl ass ( S O C), Me d D R A Preferre d Ter m, start date, a n d st o p date ( or o n g oi n g if a p plica ble), f or 
eac h st u d y p art.
1 0. 6. 3.
Pri or a n d C o nc o mit a nt Me dic ati o n a n d Dr u g A d mi nistr ati o n
1 0. 6. 3. 1.
Pri or a n d C o nc o mit a nt Me dic ati o n
Pri or me d icatio ns are t hose t hat starte d a n d st o p pe d bef ore t he first d ose of  IM P; 
all 
me dicat i ons ta ke n after first d osi n g are c o nsi dere d as c o nc o mita nt (i ncl u di n g me dicat i ons t hat 
starte d bef ore d osi n g a n d c o nti n ue d after). Pri or me dicat i on starte d wit hi n 3 m o nt hs bef ore t he 
first d ose of I M P will be rec or de d als o i n t he c o nc o mita nt me dicati o n m o d ule of Data La bs.
Pri or a n d c o nc o mita nt me d icati o n me d icatio ns will be liste d b y s u bject a n d will i ncl u de t h e 
f oll owi n g i nf or mati o n: re p orte d na me, preferre d t er m, t he r o ute of  ad mi nistrati o n, d ose, 
fre q ue nc y, start date/ti me, d urati o n a n d i n dicati o n, f or eac h part of  the st u d y. Pri or a n d 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
c o nc o mita nt me di c ati o n will be c o de d acc or di n g t o t he W o rld Heal t h Or ga nizatio n Dr u g 
Di ct i onar y  ( WH O D D).
T he d urati o n will be calc ulate d as:
D urati o n = e n d date/ti me – start date/ti me
T he d urati o n m a y be prese nte d i n h o urs or da y s i n t he listi n g de pe n di n g o n t he a p plica bilit y t o 
t he e mer gi n g data . F or me d icatio ns wi t h partial or co m pletel y  missi n g start date/ti mes a n d/ or 
e n d date/ti mes, t he d urati o n will n ot be calc ulate d.
Me dicat i ons wi t h missi n g or partial start date/ti me a n d/ or e n d date/ti me s uc h t hat it is n ot
p ossi ble t o classif y as pri or or c o nc o mita nt will be c o nsi dere d as c o nc o mita nt i n t he list i n gs.
1 0. 6. 3. 2.
Dr u g A d mi nistr ati o n
Dr u g a d mi nistrati o n dates a n d ti mes will be liste d f or eac h s u bject f or all parts of t he st u d y .
E x p os ure i n da ys a n d treat me nt c o m plia nce w ill be s u m marize d usi n g descri pti ve statist ics b y 
treat me nt ( d ose le vel of A Z D 0 4 4 9 a n d p o ole d place b o) f or all s u bjects i n t he S A F f or Part 2a/ b 
a n d Part 3 a/ b. As well as n u m ber a n d perce nt of s u bjects i n t he f o ll owi n g cate g ori es:

< 7 0 % of c o m p lia nce

≥7 0 % a n d ≤1 3 0 % of c o m plia nce

> 1 3 0 % of c o m p lia nce
1 0. 6. 4.
A n al ysis of S afet y D at a
All safety data (sc he d ule d a n d u nsc he d ule d) will be prese nte d i n t he data listi n gs. If n ot 
ot her wi se state d, c o nti n u o us varia bles will be s u m marize d usi n g descri pt i ve statistics ( n, mea n, 
S D, mi ni m u m, me dia n, ma xi m u m) b y treat me nt, f or eac h st u d y part . Cate g orical varia bles will 
be s u m marize d i n fre q ue nc y ta bles (fre q ue nc y a n d pr o p orti o n) b y treat me nt a n d st u d y part . All 
s u m maries will be base d o n t he S A F u nless ot her wise state d.
1 0. 6. 4. 1.
A d verse E ve nts
All A Es will be c o de d usi n g Me d D R A v oca b ular y  a n d will be liste d f or eac h s u bject.
A d verse e ve nts wit h missi n g start dates/ti mes will be ha n dle d as f o ll ows:

A d verse e ve nts wi t h un k n o w n start ti mes, b ut wi t h start date k n o w n, will b e 
i m p ute d wit h a ti me of  0 0: 0 0, u nless t he start date c orres p o n ds t o a n y gi ve n d osi n g 
date . I n t his case, t he start ti me will be i m p ute d wi t h the ti me of  dosi n g . If t his 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
res ults i n a start date/ti me after e n d date/ti me of t he A E, t he n t he ti me will als o be 
i m p ute d wit h 0 0: 0 0.

A d verse e ve nts wi t h c o mpletel y  u n k n o w n start dates will be i m p ute d wit h t he date 
a n d t i me of d osi n g, u nless t he e n d date is k n o w n a n d bef ore d osi n g; i n t hat case t he 
start date will be i m p ute d as t he date of scree ni n g a n d a ti me of 0 0: 0 0.

A d verse e ve nts wi t h p artiall y k n o w n start dates/ti mes will be treate d as f o ll ows:

If o nl y t he da y is missi n g, t he n t he da y will be i m p ute d wi t h the first d a y  of t he 
m o nt h, u nless t he m o nt h a n d year i n w hic h t he A E starte d is a m o nt h a n d ye ar i n 
w hic h I M P was a d mi nistere d, t he n t he da y will be i m p ute d wi t h the first d a y  on 
w hic h I M P was a d mi nistere d i n t hat m o nt h. If t his res ults i n a start date aft er t he 
e n d date, t he n t he da y will be i m p ute d wit h t he first d a y of t h e mo nt h.

If o nl y t h e mo nt h is missi n g a n d t he y e ar is a year i n w hic h I M P was a d mi nistere d, 
t he n t he m o nt h w ill be i m p ute d wit h t he fir st m o nt h i n w hic h I M P was a d mi nistere d .
If t his res ults i n a st art date aft er t he e n d date of  the A E, t he n t he m o nt h will b e 
i m p ute d wit h Ja n uar y (J A N). If t he k n o w n year part is n ot a year i n w hic h I M P was 
a d mi nistere d, t he n t he m o nt h will als o be i m p ute d wit h J A N.

If b ot h t he d a y  an d m o nt h is missi n g a n d t he year is a year i n w hic h I M P was 
a d mi nistere d, t he n t he d a y  an d m o nt h will be i m p ute d wit h t he d a y  an d m o nt h of  
d osi n g . If t his res ults i n a start date aft er e n d date, t he n t he d a y  an d m o nt h will b e 
i m p ute d wit h 0 1J A N. If t he year is n ot a year i n w hic h I M P was a d mi nistere d, t he n 
t he da y a n d mo n t h will als o be i m p ute d wit h 0 1J A N.

If o nl y t he year is missi n g, t he n t he year wil l be i m p ute d wit h t he year of d osi n g.
A d verse e ve nts wit h U n k n o w n I nte nsit y,  Relati ons hi p a n d Seri o us ness:

F or t he p ur p oses of t he A E s u m maries, A Es wit h U n k n o w n I nte nsit y w ill be treate d 
as ‘se vere’ f or t he ta b ulat i ons. A d verse e ve nts wi t h un k n o w n r elat i ons hi p will  be 
treate d as ‘relate d’ f or t he ta b ulatio ns . A d verse e ve nts wi t h un k n o w n serio us ness 
will be treate d as seri o us f or t he ta b ulat i ons.
T here will be n o i m p utati o n of A E data f or t he data list i n gs. All data will be liste d as rec or de d 
i n t he C R F.
A d verse e ve nts will  be s u m marize d b y e a c h d os e of A Z D 0 4 4 9 or p o ole d place b o, a n d p o ole d 
A Z D 0 4 4 9 d oses, f or eac h st u d y part . Ta b ulat i ons will i ncl u de ca usalit y an d se verit y (mil d, 
m o derate a n d se vere). All ta b ulati ons will be prese nte d b y S O C a n d Prefe rre d Ter m .
F urt her m ore, list i n gs of S A Es a n d A Es t hat le d t o wit h dra wal will be ma de a n d t he n u m ber of 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
s u bjects w h o ha d a n y A Es, S A Es, A Es t hat le d t o disc o nti n uat i on ( D A Es) will be s u m marize d .
T he A Es t hat occ ur bef ore first d osi n g will be e xcl u de d fr o m the s u m mar y ta bles.
T he f oll owi n g i nf or mati on will be i ncl u de d i n t he listi n gs: ver bati m t er m, Me d D R A S O C, 
Preferre d T er m  an d l owest level t er m, start date/ti me, e n d date/ti me, ti me fr om last d ose, 
ca usalit y,  acti on ta ke n, w het her t he A E was classifie d as s erio us a n d t he o utc o m e.
All ta b ulat i ons will i ncl u de t he n u m ber a n d perce nta ge of s u bjects.
1 0. 6. 4. 2.
Vit al Si g ns
T he res ults of  the vit al si g ns meas ure me nts, s yst olic a n d di ast olic B P, p ulse, res pirat or y rate 
a n d or al /t y m pa nic b o d y  te mperat ure, will be liste d b y s ubject a n d ti me-p oi nt i ncl u di n g t h e 
date/ti me of t he assess me nt, fla gs f or meas ure me nts t hat are o utsid e t h e r ef ere nce ra n ge ( L or 
H, if a p plica ble), c ha n ges fr om baseli ne a n d re peat/ u nsc he d ule d me as ure me nts. T he baseli ne 
f or vit al si g ns me as ure me nts will b e t he last meas ure me nt bef ore t he first a d mi nistrati o n of 
I M P. Descri pt i ve st atistics ( n, mea n, S D, mi ni m u m, Q 1, me dia n, Q 3, ma xi m u m) will b e 
prese nte d b y treat m e nt (eac h d ose level of A Z D 0 4 4 9, p o ol e d place b o, a n d p o ole d A Z D 0 4 4 9) 
a n d ti me-p oi nt f or b ot h o bser ve d val ues a n d c ha n ges fr o m baseli ne, f or eac h part of t he st u d y.
1 0. 6. 4. 3.
Resti n g 1 2 -le a d Electr oc ar di o gr a m
T he t wel ve-lea d E C G o verall i nter pretatio n ( nor mal/a b n or m al), s pecificati on of  ab n or malit y 
a n d cli nical si g nifica nce will be liste d b y s u bject a n d ti me -p oi nt base d o n t he S A F f or eac h part 
of  t he st u d y.
T he n u m ber a n d perce nta ge of  su bjects wit h cli nicall y si g nifica nt 1 2- lea d E C G fi n di n gs will 
be s u m marize d b y tr e at me nt gr o u p ( d ose level of  AZ D 0 4 4 9, p o ol e d place b o, a n d p o ol e d 
A Z D 0 4 4 9) b y  eac h da y for P ar t 1a/ b, Part 2 a/ b, a n d Part 3a/ b base d o n t he S A F.
1 0. 6. 4. 4.
1 2- le a d C o nti n u o us Di git al Electr oc ar di o gr a m
T he f o ll owi n g para m eters will be deri ve d fr o m t he d E C G:

Q Tc F will be calc ulate d as Q Tc F =
 √ w here t he Q T i nter val is i n millisec o n ds 
a n d t he R R i nter val is i n sec o n ds

Heart rate will be calc ulate d, base d o n t he R R i nter val as H R =
        , w h er e 
t he R R i nter val is i n sec o n ds
T he d E C G data will be s mo ot he d o n a n i n di vi d ual basis bef ore perf or mi n g t he deri vati o ns 
a b o ve a n d bef ore calc ulat i on of  an y c ha n ges fr o m baseli ne or descri pt i ve st atistics. F or eac h 
s u bject it will be d o ne as f oll ows: t he mea n val ue of  all t he meas ure me nts will be ta ke n f or 
tar get ti me- p oi nt rec or di n gs . At  le ast 4 meas ure me nts wit h t he time bet wee n t he first a n d last 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
rec or d greater t ha n 2. 7 5 mi n utes f or a tar get ti me -p oi nt s h o ul d be prese nt or else, t he s m o ot he d 
val ue at t he c orres p o n di n g tar get ti me -p oi nt will be set t o missi n g.
Di gi t al EC G res ults will be liste d b y tr e at me nt ( d ose level of  AZ D 0 4 4 9, p o ol e d pl ace b o, a n d 
p o ol e d A Z D 0 4 4 9) for eac h s u bject a n d ti me -p oi nt a n d will i ncl u de all i n di vi d ual a n d s m o ot he d 
val ues of  PR, R R, Q R S, Q T i nter val a n d t he deri ve d val ues of  QTc F a n d H R . T he c ha n ges 
fr om baseli ne f or s m o ot he d a n d deri ve d para meters will be liste d as well.
Descri pt i ve statistics o f s mo ot he d P R, R R, Q R S, Q T val ues a n d deri ve d Q Tc F a n d H R val ues 
as well as c ha n ge fr o m baseli ne will be s u m marize d b y tr e at me nt gr o u p ( d ose level of  
A Z D 0 4 4 9, p o ol e d place b o, a n d p o ol e d A Z D 0 4 4 9) a n d ti me-p oi nt , f or eac h st u d y part. T he 
baseli ne f or t h e d E C G me as ure me nts will be t he s m oot h e d pre -d ose assess me nt o n Da y 1 f or 
eac h part of t he st u d y.
O utliers wit h res pect t o Q Tc F will als o be ta b ulate d f or t he f oll o wi n g cate g ories:

A bs ol ute val ue > 4 5 0 ms a n d ≤4 8 0 ms

A bs ol ute val ue > 4 8 0 ms a n d ≤5 0 0 ms

A bs ol u te val ue > 5 0 0 ms

I ncrease fr o m baseli ne > 3 0 ms a n d ≤6 0 ms

I ncrease fr o m baseli ne > 6 0 ms
All calc ulati o ns of d E C G para meters a n d re p orti n g descri be d i n t his sect i on will be perf or me d 
b y P ar e x el.
1 0. 6. 4. 5.
Re al Ti me E C G ( C ar di ac Tele metr y)
T he res ults of car diac t ele m etr y will be liste d b y treat me nt gr o u p, s u bject a n d ti me p oi nt base d 
o n t he S A F.
1 0. 6. 4. 6.
P h ysic al E x a mi n ati o n
T he baseli ne/scree ni n g res ults of  the p h ysical e xa mi nat i on will be d oc u m e nte d i n me d ical 
hist or y  for eac h s u bject.
A n y ne w or a g gra vate d cli nicall y rele va nt a b n or mal me dical p h ysical e xa mi nat i on fi n di n g 
c o mpare d t o t he baseli ne assess me nt will be re p orte d as a n A E.
1 0. 6. 4. 7.
S pir o metr y
F or s pir o metr y variables, t he baseli ne val ue f or eac h st u d y part is defi ne d as t he pre -d ose val ues 
rec or de d o n D a y 1 of  eac h stu d y  perio d ( or Da y -1, if n ot rec or de d o n Da y 1). If a su bject’s 
baseli ne val ue is missi n g, t he n t he val ue at scree ni n g will be use d. N ote t hat wit hi n a st u d y 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 1 9 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
part, f or all F E V 1 e n d p o i nts, t he sa me baseli ne F E V1 val ue will be use d; si milarl y, f or t he F V C 
en d p o i nts, t he sa me baseli ne F V C val ue will be use d.
S pi r o metr y val ues ( FE V 1 a n d F V C) will be liste d b y tr e at me nt ( d ose level of  AZ D 0 4 4 9 a n d 
p o ol e d place b o), s u bject a n d ti me-p oi nt i ncl u di n g a bs o l ute val ues, a bs o l ute a n d perce nta ge 
c ha n ges fr om baseli ne . S u m mar y  ta b ulat i ons f or a bs o l ute val ues a n d c ha n ges fr om baseli ne 
will be prese nte d b y treat me nt (eac h d ose level of  AZ D 0 4 4 9, or p o ole d pl ace b o, a n d p o ol e d 
A Z D 0 4 4 9 a n d time -p oi nt f or t he S A F . F or t he p ur p ose of  the s u m mar y t a b ulat i ons, w here m ore 
t ha n o ne F E V 1 or F V C meas ure me nts are assesse d at a gi ve n ti me -p oi nt, t he a vera ge F E V 1 or 
F V C val ue at t hat ti me -p oi nt will be s u m marize d.
1 0. 6. 4. 8.
P ulse O xi metr y
P eri p heral  ca pillar y o x y ge n sat uratio n will be liste d b y  tr e at me nt ( d ose le vel of AZ D 0 4 4 9 a n d 
p o ol e d place b o), s ubject a n d time p o i nt incl u di n g a bs o l ute val ues, c ha n ges fr om baseli ne a n d 
perce nta ges c ha n ges fr o m baseli ne. T he baseli ne f or t he meas ure me nts will be t he pre -d ose 
assess me nt o n Da y 1 (i n eac h treat me nt peri o d). C ha n ges fr o m baseli ne will be calc ulate d a n d 
prese nte d f or pre -d ose t o eac h p ost -d ose ti me p oi nt i n eac h of  these p eri o ds. S u m mar y 
ta b ulat i ons f or a bs o l ute val ues a n d c ha n ges fr o m baseli ne will be prese nte d b y treat me nt (eac h 
d ose lev el  of A Z D 0 4 4 9, or p o ole d place b o, a n d p o ole d A Z D 0 4 4 9) or b y r o ute of a d mi nistrati o n 
(f oll owi n g i n hale d a n d I V d oses), a n d ti me p o i nt for t he S A F.
1 0. 6. 4. 9.
L a b or at or y Assess me nts
H e m at olo g y  an d cli nical c he mistr y val ues will be liste d b y s u bject a n d ti me-p oi nt i ncl u di n g 
c ha n ges fr o m baseli ne a n d re peat/ u nsc he d ule d meas ure me nts . S u m ma r y ta b ulat i ons will be 
prese nte d b y treat me nt (eac h d ose le vel of A Z D 0 4 4 9 or p o ole d place b o, a n d p o ole d A Z D 0 4 4 9) 
or b y r o ute of  a d mi nistrati o n (f oll owi n g i n hale d a n d I V d oses) f or t he S A F, f or eac h st u d y part .
T he baseli ne f or t he meas ure me nts will be t he last assess me nt a vaila ble bef ore t he first I M P 
a d mi nistrati o n. C ha n ges fr om baseli ne will  be calc ulate d a n d prese nte d f or all p ost -baseli ne 
ti me p oi nts i ncl u di n g t he F oll ow- u p Visi t/last da y of st u d y. S hift ta bles s h o wi n g c ha n ges wi t h 
res pect t o t he n or mal ra n ges bet wee n baseli ne a n d a n y post -baseli ne visit will als o be prese nte d.
A n y la b orat or y para meters wi t h res ults fr o m t he lab orat or y  gi ve n as ' < x x' or ' > x x' i n t he 
data base will be i m p ute d wit h t he a bs o l ute val ue of t he n u m ber wit h o ut t he si g n (e g, < 2. 2 will 
be i m p ute d as 2. 2) f or t he descri pti ve statistics a n d c ha n ges fr o m baseli ne.
T he list i n gs will i ncl u de t he f oll owi n g i nf or mat i on: test na me, date of meas ure me nt, refere nce 
ra n ge, res ult a n d fla gs f or a n y meas ure me nts 
t hat are o utsi de t he refere nce ra ng e 
(e g, Astra Ze neca, pr o gra m  or lab orat or y  ra n ges) as well as assess me nt of  cli nicall y rele va nt 
a b n or malit y assesse d b y I n vesti gat or. Data listi n gs f or s u bjects t hat s h o ws ele vat i ons i n li ver 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
bi oc he mistr y  (ie, occ urre nces of  AS T or A L T ≥3 x U L N t o get her wit h t ot al bilir u bi n ≥2 x 
U L N) will be prese nte d t o e v aluate H L . Cli nical la b orat or y data will be re p orte d i n t he u ni ts 
pr o vi de d b y t he cli nical la b orat or y for t he S R C me eti n g (if a p plica ble), a n d i n S y st e m 
I nter nati o nal u nits i n t he C S R.
A d dit i onal listi ngs will be prese nte d f or t he f oll o wi n g:

Uri nal ysis ( macr osc o pic a n d micr osc o pic, if a p plica ble)

Pre g na nc y testi n g (i ncl u di n g F S H)
1 0. 6. 5.
P h ar m ac o ki netic A n al ysis
1 0. 6. 5. 1.
P h ar m ac o ki netic P ar a meters
W here p ossi ble t he f oll owi n g P K para m eters will be deter mi ne d fr om t he A Z D 0 4 4 9 a n d, i n 
Part 2 b ( co h ort 3 ) a n d Part 3 a/ b,
 pl as ma 
c o nce ntrati o ns o n Da y 1 f ol l owi n g t he fi rst d ose a n d o n Da y 1 2 f oll o wi n g o nce dail y m ulti pl e 
d osi n g as a p pr o priate f or eac h St u d y  Part.
1 0. 6. 5. 1. 1.
Pl as m a P ar a meters
F oll o wi n g I n h ale d D osi n g ( P arts 1 a, P art 2 , a n d P art 3)
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
tma x
Ti me of ma xi m u m o bser ve d c o nce ntrati o n (first occ urre nce)
A U C ( 0-t)
Area u n der t he plas ma c o nce ntrati o n -c ur ve fr o m ti me zer o t o t he ti me of last q ua ntifia ble
c o nce ntrati o n
A U C ( 0-1 2)
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 1 2 h o urs p ost -d ose
A U C ( 0-2 4)
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 2 4 h o urs p ost -d ose 
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o i nfi nit y
λz
Ter mi nal eli mi nati o n rate c o nsta nt
t1/ 2λz
Ter mi nal eli mi nati o n half -life
C L/ F
A p pare nt t otal cleara nce of dr u g fr o m plas ma ( E xtra vasc ular a d mi nistrati o n [ pare nt dr u g 
o nl y ]) 
Vz/ F
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase ( E xtra vasc ular a d mi nistrati o n
[ pare nt dr u g o nl y])
C ma x / D
D ose n or malize d C ma x
A U C/ D
D ose n or malize d A U C
A U C ( 0-t)/ D
D ose n or malize d A U C ( 0-t)
tlast
Ti me of last q ua ntifia ble c o nce ntrati o n
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
F oll o wi n g I ntr a ve n o us D osi n g ( P art 1 b)
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
tma x
Ti me of ma xi m u m o bser ve d c o nce ntrati o n (first occ urre nce)
A U C ( 0-t)
Area u n der t he plas ma c o nce ntrati o n -c ur ve fr o m ti me zer o t o t he ti me of last q ua ntifia ble 
c o nce ntrati o n
A U C ( 0-1 2)
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 1 2 h o urs p ost -d ose
A U C ( 0-2 4)
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 2 4 h o urs p ost -d ose
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o i nfi nit y
λz
Ter mi nal eli mi nati o n r ate c o nsta nt
t1/ 2λz
Ter mi nal eli mi nati o n half -life
C L
T otal cleara nce of dr u g fr o m plas ma (I V a d mi nistrati o n) 
Vz
V ol u me of distri b uti o n d uri n g t he ter mi nal p hase (I V a d mi nistrati o n)
C ma x / D
D ose n or malize d C ma x
A U C/ D
D ose n or malize d A U C
A U C ( 0-t)/ D
D ose n or malize d A U C ( 0-t)
tlast
Ti me of last q ua ntifia ble c o nce ntrati o n
T he f oll o wi n g P K p ar a meters will be c alc ul ate d f or di a g n ostic p ur p oses a n d liste d b ut n ot 
s u m m arize d:
t l o wer
Start of e x p o ne ntial fit of ter mi nal p hase
t u p per
E n d of e x p o ne ntial fit of ter mi nal p hase 
λz N
N u m ber of data p oi nts i ncl u de d i n t he l o g -li near re gressi o n a nal ysis
Rs q -a dj
Re gressi o n c oefficie nt a dj uste d f or λz N, G o o d ness - of-fit statistic f or 
calc ulati o n of λz
% A U C
e xtr
Perce nta ge of A U C e xtra p olate d 
A d dit i onal P K para meters ma y  be deter mi ne d w here a p pr o priate.
1 0. 6. 5. 2.
C alc ul ati o n or Deri v ati o n of P h ar m ac o ki netic P ar a meters
T he P K a nal yses of  the plas ma c o nce ntrati o n data f or A Z D 0 4 4 9 a n d 
 
 as a p pr o priate,
will 
be p erf or m e d b y C o va nce, 
Cli nica l 
P har mac o ki net ic Allia nce ( C P K A) o n be half o f Astra Ze neca R & D.
Sta n dar d O perati n g Pr oce d ures a n d W or k I nstr ucti o ns will be use d as t he defa ult met h o d ol o g y 
if n ot ot her wise s pecifie d.
T he act ual sa m pli n g ti mes will be use d i n t he fi nal plas ma P K para meter calc ulati o ns . If act ual 
ti mes are missi n g, n omi nal t i mes ma y be use d.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
N o mi nal sa m pli n g times will  be use d f or i nteri m pl as ma P K  para meter calc ulat i ons f or t he 
p ur p ose of t he S R C meet i n gs.
P har mac o ki net ic para meters will be derive d usi n g n o n -c o m part me ntal met h o ds wit h P h oe ni x ® 
Wi n N o nli n ® Versi o n  8. 1, or hi g her . All d escri pt i ve a n d i nfere nt ial statistical c om p utati o ns will 
be perf or m e d usi n g S A S ® Versi o n 9. 4, or hi g her.
Pl as ma c o nce ntrati o ns B L Q fr o m t he ti me of pre -d ose sa m pli n g (t = 0) u p t o t he ti me of t he first 
q ua nt ifia ble c o nce ntrati o n will be set t o a val ue of  0. After t his p oi nt, B L Q plas ma 
c o nce ntrati o ns will be s et t o missi n g f or all c o nce ntratio n pr ofiles. Als o, if 2 or m o r e 
c o nsec ut i ve B L Q c o nce ntratio ns are f oll owe d b y q ua nt ifia ble c o nce ntratio ns i n t he ter mi nal 
p orti o n of t he c o nce ntrati o n -c ur ve, t he pr ofile will be dee me d t o ha ve ter mi nate d a n d t heref ore 
t hese q ua nt ifia ble val ues will be set t o missi n g f or t he calc ulati on of t he P K para meters u nless 
t here is a scie ntific ratio nale n ot t o d o s o, t hi s is d oc u me nte d i n t he P K a nal ysis n otes.
If a n e ntire c o nce ntrati o n-ti me pr ofile is B L Q, t he pr ofile is e xcl u de d fr om t he P K a nal ysis.
Ter mi nal eli mi nat i on half -life (t1/ 2λz) will be calc ulate d as (l n 2)/ λz, w here λz will be es ti mate d 
b y l o g -li near least s q uares re gressi on o f t he ter mi nal p art of t he c o nce ntratio n -ti me c ur ve. F or 
t he deter mi nat i on of  λz, t he start of  the ter mi nal eli mi nat i on p hase f or eac h s u bject will b e 
defi ne d b y vis ual i ns pect i on a n d will be t he first p oi nt at w hic h t here is n o s yste mat ic de viati on 
fr om t he l og- li near decli ne i n plas ma c o nce ntrati o ns (t l o wer) . T he last p oi nt (t u p per) will b e 
t he ti me of  the last q ua ntifia ble plas ma c o nce ntratio n. A mi ni m u m of  3 data p oi nts n ot 
i ncl u di n g C ma x a n d i ncl u di n g tlast will be use d i n calc ulat i n g λz, a n d t he d urati o n of  time o ver 
w hic h λz is calc ulate d is rec o m me n de d t o be at least 3 ti mes t he s u bse q ue ntl y esti mate d 
ter mi nal half -life. W here 
a n eli mi nat i on half -life is esti mate d o ver less t ha n 3 ti mes t he 
s u bse q ue ntl y esti mate d ter mi nal half-life, it will be fla g ge d a n d c o m me nte d u p o n i n t he st u d y 
re p ort b y a gree me nt wit h t he S p o ns or . T he Rs q -a dj val ue will be calc ulate d t o s h o w t he 
g o o d ness -of -fit of  the l o g -li near re gressi on t a ki n g i nt o c o nsi derati o n t he n u m ber of p oi nts use d 
i n the est i mati o n ( λz N). T o ac hie ve a g o o d precisi o n i n t he esti mati o n, t he Rs q -a dj val ue s h o ul d 
be hi g h, a val ue of  ≥0. 8 bei n g i n dicati ve of  go o d c orrelat i on. A n y λz wi t h a Rs q-a dj of < 0. 8 
will be fla g ge d i n t he data list i n gs al on g wit h a n y pa r a meters deri ve d fr o m λz (e g, t 1/ 2λz, A U C, 
C L, C L/ F, Vz, Vz/ F a n d % A U C
e xtr) a n d a gree me nt reac he d wi t h the S p o ns or re gar di n g a n y 
e xcl usi o n of data fr o m t he s u m maries.
A U Cs (incl u di n g A U C, A U C ( 0-t), A U C ( 0-1 2), A U C ( 0-2 4)) will be calc ulate d usi n g t he li near 
tra pez oidal met h o d w he n c o nce ntrati o ns are i ncreasi n g a n d t he l o garit h mic tra pez oi dal met h o d 
w he n c o nce ntratio ns are decreasi n g (li near u p, l o g d o w n) . A U C is est i mate d b y A U C ( 0-
t)+ C last/ λz w here C last is t he o bser ve d last q ua ntifia ble dr u g c o nce ntrati o n. The A U C v al u es 
w here perce nta ge e xtra p olat i on ( % A U Ce xtr) is greater t ha n 2 0 % will be fla g ge d i n t he data 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
listi n gs a n d a gree me nt reac he d wi t h the S p o ns or o n w het her e xcl usi o ns fr om t he s u m maries 
are re q uire d.
T he mi ni m u m re q uir e m e nt f or t he calc ulat i on of  AU C will be t he i ncl usi on of  at least 
3 c o nsec uti ve plas ma c o nce ntratio ns a b o ve t he l ower li mit of  qua nt ificati on ( L L O Q), wi t h at 
least o ne of t hese c o nce ntrati o ns f oll owi n g C ma x.
C ma x, tma x a n d t last will be ta ke n direct l y fr om t he c o nce ntrati o n-ti me pr ofiles.
Cl eara nce ( C L) a n d a p pare nt cleara nce ( C L/ F) will be deter mi ne d fr o m t he rati o of d ose/ A U C .
V ol u me of  distri b uti on ( Vz) a n d a p pare nt v ol u me of  distri b utio n base d o n t he t er mi nal p h as e 
( Vz/ F) will be deter mi ne d fr o m t he rati o of d ose/ λz * A U C.
D ose n or m alize d para meters will be deter mi ne d b y di vi di n g t he para meter b y t he d ose.
1 0. 6. 5. 3.
Prese nt ati o n a n d St atistic al A n al ysis of P h ar m ac o ki netic D at a
A listi n g of P K bl o o d sa m ple c ollecti on ti mes as well as deri ve d sa m pli n g ti me de viat i ons a n d 
all re p orta ble c o nce ntratio ns will be prese nte d f or A Z D 0 4 9 9 a n d 
 
 as a p pr o priate, f or all s u bjects i n t he S A F.
Pl as ma c o nce ntrati o ns will be s u m marize d f or t he P K  anal ysis set f or eac h a nal yt e a n d
ti me p oi nt by treat me nt ( d ose lev el  of A Z D 0 4 4 9 ) St u d y  Part a n d St u d y  Da y usi n g pr ot oc ol 
sc he d ule d ti mes a n d a p pr o priate descri pt i ve st atistics (ie, n, n bel o w L L O Q, ge o met ric me a n 
[ g mea n], g m ea n + ge o metric sta n dar d de viat i on [ g S D], g mea n -g S D, ge o m etric c oefficie nt of 
varia nce e x presse d as a perce nta ge [ g C V %], arit h met ic mea n [ mea n], arit h met ic S D [ S D], 
me dia n, mi ni m u m a n d ma xi m u m) .
T he g mea n is calc ulate d as e x p o ne nt ial ( μ), w here μ is t he arit h metic mea n calc ulate d usi n g 
l og- tra nsf or me d data.
T he g C V % is calc ulate d as 1 0 0 x s qrt[e x p(s 2)-1], w here s is t he S D of  the l og- tra nsf or me d 
data.
T he g m ea n ± g S D ( g mea n-g S D a n d g mea n + g S D) are calc ulate d as e x p[ μ ±s].
I n di vi d ual c o nce ntratio ns wi t h ti me de viat i ons of  greater t ha n ± 1 0 % fr o m t he pr ot oc ol 
sc he d ule d time will be use d i n t he P K  anal ysis b ut will be fla g ge d f or e xcl usi o n fr om t he 
s u m mar y ta bles a n d c orres p o n di n g fi g ures.
I n di vi d ual c o nce ntratio ns bel o w t he L L O Q of  t he bi oa nal yt ical assa y will be re p orte d as N Q 
i n t he listi n gs wit h t he L L O Q defi ne d i n t he f o ot n otes of t he rele va nt T F Ls. I n di vi d ual plas ma 
c o nce ntratio ns t hat are n ot re p orta ble will be re p orte d as N R a n d t h ose t hat are missi n g will be 
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
re p orte d as N S ( N o Sa m ple) i n t he listi n gs. Plas ma c o nce ntratio ns t hat are N Q, N R or N S will 
be ha n dle d as f o ll ows f or t he pr o vi sio n  of descript i ve statistics:

A n y val ues re p orte d as N R or N S will be e xcl u de d fr om t he s u m mar y ta bles a n d 
c orres p o n di n g fi g ures

At  a ti me p oi nt w here less t ha n or e q ual t o 5 0 % of t he c o nce ntrati o n val ues are N Q, 
all N Q val ues will be set t o t he L L O Q, a n d all descri pt i ve statistics will be
calc ulate d acc or di n gl y

At  a ti me p oi nt w here m ore t ha n half of the val ues are N Q, t he g mea n, g mea n + g S D, 
g m ea n-g S D a n d g C V % will be set t o N C . T he ma xi m u m val ue will be re p orte d 
fr om t he i n di vi d ual data, a n d t he mi ni m u m a n d me dia n will be set t o N Q

If all v al ues are N Q at a ti me p oi nt, n o descri pt i ve statistics will  be calc ulate d f or 
t hat ti me p oi nt. T he g m ea n, mi ni m u m, me d ia n a n d ma xi m u m will  be re p orte d as 
N Q a n d g mea n ± g S D a n d g C V % as N C
T he n u m ber of val ues bel o w L L O Q ( n < L L O Q) will be re p orte d f or eac h ti me p o i nt. t o get her 
wi t h t he t otal n u m ber of c ollecte d val ues ( n).
T hree o bser vat i ons > L L O Q are re q uir e d as a mi ni m u m f or a plas ma c o nce ntratio n t o be 
s u m marize d. T w o val ues > L L O Q are prese nte d as a mi ni m u m a n d ma xi m u m wi t h the ot h er 
s u m mar y statistics as N C.
Pl as ma c o nce ntrati o ns t hat are N Q will be ha n dle d as f o ll ows f or di s pla y i n fi g ures:

F or g mea n c o nce ntratio n -ti me pl ots: N Q c o nce ntrati o ns will  be ha n dle d as 
descri be d f or t he descript i ve st atistics. If t his ha n dli n g res ults i n a g e o metric mea n 
of  “ N Q”, the n t he val ue pl otte d at t hat ti me p o i nt will be zer o f or li near pl ots a n d set 
t o missi n g f or se mi-l og ari t h mic pl ots. A n y g mea n ± g S D err or bar val ues t hat are 
ne gat i ve will be tr u ncate d at zer o o n li near c o nce ntratio n -ti me pl ots a n d o mitte d 
fr om se mi-l og ari th mic pl ots.

F or i n di vi d ual pl ots a n d c o m bi ne d i n di vi d ual pl ots : N Q val ues pri or t o t he first 
q ua nt ifia ble c o nce ntrati o n i n t hat pr ofile will be set t o zer o (li near pl ots o nl y); after 
t he first q ua ntifia ble c o nce ntrati o n of  the pr ofile  an y N Q val ues will be set t o 
missi n g.
All re p orta ble P K para m eters will be liste d f or A Z D 0 4 4 9 a n d
 
as a p pr o priat e, f or all su bjects ( Safet y a nal ysis set). A se parate list i n g will  be 
pr o vi de d f or t he dia g n ostic para meters.
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Pl as ma P K para meters will be s u m marize d f or t he P K a nal ysis set b y a nal yt e, treat me nt ( d ose 
le vel of A Z D 0 4 4 9), St u d y  Part, a n d St u d y Da y usi n g t he f o ll owi n g descri pt i ve statistics:

C ma x, AU C, A U C ( 0-1 2), AU C ( 0-2 4) a n d A U C ( 0-t) will prese nt n, g mea n, g m ea n + g S D, 
g m ea n-g S D, g C V( %), me dia n, mi n a n d ma x.

C ma x/ D, A U C/ D, A U C ( 0-t)/ D a n d λz will prese nt n, g m ea n, g C V %, mea n, S D, 
me dia n, mi n a n d ma x .

t1/ 2λz, C L/ F, C L, Vz/ F, Vz, will  pr es e nt n, g mea n, g C V %, me a n, S D, me dia n, mi n 
a n d ma x.

tma x a n d t last will prese nt o nl y n, me dia n, m i n a n d ma x.

di a g n ostic para meters (t u p per, t lo wer, λz N, Rs q -a dj a nd % A U C e xtr) will be liste d 
o nl y  a nd n ot s u m marize d.
F or t he calc ulat i on of  su m mar y  st atistics of  PK para meters, all n ot re p orta ble ( N R) a n d n ot 
calc ulate d ( N C) val ues will be set t o missi n g. T hree re p orta ble val ues are re q uire d as a 
mi ni m u m f or a P K para meter t o be s u m marize d . T w o val ues are prese nte d as a mi ni m u m a n d 
ma xi m u m wit h t he ot her s u m mar y statistics as N C. If o ne or m ore val ues f or a gi ve n para meter 
is zer o ( or i m p ute d wit h zer o), t he n n o ge o metric statist ics will be calc ulate d f or t hat para meter 
a n d t he res ults f or ge o metric statist ics will be set t o “ N A”, n ot a p plica ble.
P K c o nce ntratio n a n d para meter data f or patie nts e xcl u de d fr om t he P K S will be i ncl u de d i n 
t he data listi n gs, b ut n ot i n t he descri pti ve or i nfere ntial st atistics or i n mea n fi g ures or 
c o m bi ne d i n di vi d ual fi g ures.
I n di vi d ual plas ma c o nce ntrati o ns vers us act ual ela pse d ti me after d ose will be pl otte d o n b ot h 
t he li near a n d se mi-l og ari t h mic scale se paratel y f or A Z D 0 4 4 9 a n d 
 
wi t h t he Da y 1 a n d Da y 1 2 data o verl ai d o n t he sa me pl ot f or stu d y parts 2 a n d 3 .
C o m bi ne d i n di vi d ual plas ma c o nce ntrati o n vers us act ual ela pse d ti mes aft er d ose will b e 
pl otte d o n b ot h t he li near a n d se mi-l og ari t h mi c s c ale separatel y f or A Z D 0 4 4 9 a n d 
 
Pl ots will be gr o u pe d b y  d ose le vel of A Z D 0 4 4 9 f or eac h St u d y Part a n d St u d y 
D a y .
G m ea n ( ± g S D) plas ma c o nce ntratio n vers us n o mi nal sa m pli n g t i me will be pl otte d se paratel y 
f or eac h a nal yt e o n b ot h t he li near a n d se mi-l og ari t hmic scale ( n o err or bars) f or eac h St u d y 
Part a n d St u d y  Da y wi t h all d ose levels o verlai d o n t he sa me pl ot f or Part 1a Da y 1 a n d 
Part 2a/ b D a y 1 a n d Da y 1 2 , wit h D a y 1 a n d Da y 1 2 o verl ai d o n t he sa me plot f or Part 3a/ b .
All pl ots will be base d o n t he P K S, wi t h the e xce ptio n of  in di vi d ual pl ots b y s u bject, w hic h 
will be base d o n t he S A F.
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Precisi o n a n d R o u n di n g R ules
P K c o nce ntrati o n data will be prese nte d i n t he list i n gs t o t he sa me n u m ber of si g nifica nt di gits 
as t he data recei ve d fr o m t he bi oa nal yt ical la b orat or y (us uall y t o 3 sig nifica nt fi g ures) a n d 
a gai nst t he sa me u nit s as recei ve d. P K c o nce ntrati o n descri pti ve statist ics will all be prese nte d 
t o 4 si gnifica nt fi g ures wi t h the e xce pt i on of  the mi n a n d ma x w hic h will be prese nte d t o 3 
si gnifica nt fi g ures a n d n a n d n < L L O Q w hic h will be prese nte d as i nte gers. F or plas ma P K 
para m eters, t he list i n gs will be prese nte d acc or di n g t o t he f oll owi n g r ul es:

C ma x– will be prese nte d t o t he sa me n u m ber of si g nifica nt fi g ures as recei ve d fr o m 
t he bi oa nal yt ical la b orat or y

tma x , tlast, t lo wer a n d t u p per – will be prese nte d as recei ve d i n t he data, us uall y t o 2 
deci mal places

C ma x/ D, A U C, A U C/ D, A U C ( 0-t), A U C ( 0-1 2), A U C ( 0-2 4), A U C ( 0-t)/ D, % A U C
e xtr, λz, 
t1/ 2λz, C L/ F, C L, Vz/ F, Vz, Rs q -a dj will be prese nte d t o 3 sig nifica nt fi g ures

λz N – will be prese nte d as a n i nte ger ( n o deci mals)
F or P K c o nce ntrati o n data all descri pti ve st atistics will be prese nte d t o 4 sig nifica nt fi g ures 
wi t h the e xce pt i on of  the mi ni m u m a n d ma xi m u m w hic h will  be prese nte d t o 3 sig nifica nt 
fi g ures a n d n a n d n < L L O Q, w hic h will be prese nte d as i nte gers.
F or P K para m eter data t he descri pt i ve st atistics will  be prese nte d acc or din g t o t he f oll owi n g 
r ules:

C ma x, C ma x/ D, A U C, A U C/ D, A U C ( 0-t), A U C ( 0-1 2), A U C ( 0-2 4), A U C ( 0-t)/ D, t1/ 2λz, 
C L/ F, C L, Vz/ F, a n d Vz, – all descri pt i ve statistics will be prese nte d t o 4 si g nifica nt  
fi g ures wit h t he e xce ptio n of  t he mi ni m u m a n d ma xi m u m w hic h will  be prese nte d 
t o 3 si g nifica nt fi g ures a n d n w hic h will be prese nte d as i nte gers

λz – will be prese nte d t o 5 si gnifica nt fi g ures wi t h the e xce pt i on of  the mi ni m u m 
a n d ma xi m u m w hic h will be prese nte d t o 3 si g nifica nt fi g ures a n d n w hic h will b e 
prese nte d as a n i nte ger

tma x a n d tlast – all descri pti ve st atistics will be prese nte d as recei ve d i n t he data, 
us uall y t o 2 deci mal places wi t h the e xce pt i on of  n whic h will be prese nte d as a n 
i nte ger
1 0. 6. 5. 4.
St atistic al A n al ysis of P h ar m ac o ki netic D at a
T he p o wer m o d el  will be use d f or t he a nal ysis of d ose -pr o p orti o nalit y f oll owi n g a si n gle d ose 
a n d f o ll owi n g m ult i ple d osi n g as a p pr o priate f or Part 1a, Part 2a/ b a n d Part 3. T he p o wer m o del 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
is de n ote d as y = α * d ose β, w here “ y” refers t o t he P K para meter, A U C ( A U C or A U C ( 0-t)) a n d 
C ma x fr o m t he last da y of d osi ng, u n der c o nsi derati o n.
D ose -pr o p orti o nalit y will  be assesse d f oll owi n g a si n gle d ose a n d f oll owi n g m ult i ple d osi n g 
via least s q uares li near re gressio n of  the l og- tra nsf or me d P K  para meters vers us t he 
l og- tra nsf or me d d ose, ie, l og ( P K para meter) = α + βl o g( D ose ). A n est i mate of  the slo pe a n d 
i nterce pt of t he re gressi o n li ne a n d t he c orres p o n di n g 2 -si de d 9 5 % c o nfi de nce i nter val ( CI) f or 
t he slo pe will be o btai ne d a n d ta b ulate d f or A U C a n d C ma x .
If A U C ca n n ot be f ull y c haracterize d, t he n A U C ( 0-t) ma y be use d i nste a d for t he a nal ysis.
T he p o wer m o d el  will be fitt e d b y r estricte d ma xi m u m li keli h o o d ( R E M L) usi n g S A S Pr oc 
Mi xe d . B ot h t he i nterce pt a n d sl o pe will be fitte d as fi xe d effects .
Scatter pl ots f or eac h of  the l og- tra nsf or me d P K para m eters C ma x , A U C ( 0-t) a n d A U C vers us 
l og -tra nsf or me d d ose will be prese nte d wit h t he re gressi on li ne fr o m t he a nal ysis o verlai d o n 
t he sa me plot f or Part 1a Da y 1, a n d Part 2a/ b Da y 1, Da y 1 2.
I n a d ditio n, fi g ures of  dose n or m alize d C ma x, A U C ( 0-t) a n d A U C vers us d ose, s h o wi n g 
i n di vid ual  val ues a n d ge o metric mea n will be prese nte d se paratel y  for e a c h P K p ar a m eter f or 
Part 1a Da y 1 a n d f or Part 2 Da y 1 a n d Da y 1 2, t o vis uall y de m onstrate d ose -pr o p orti o nalit y.
Si g nifica nt fi g ures or deci mal places f or statistical o ut p uts, e g, t he sl o pe esti mate i nterce pt a n d 
9 5 % CIs will be prese nte d t o 4 deci mal places ( p-val ues t hat are s maller t ha n 0. 0 0 0 1 will b e 
prese nte d as “ < 0. 0 0 0 1”).
1 0. 6. 6.
A n al ysis of P h ar m ac o d y n a mic D at a
1 0. 6. 6. 1.
Fr acti o n al E x h ale d Nitric O xi de - P art 2 a a n d P art 3 a
T he c ha n ge fr o m baseli ne i n 2 h o urs p ost -d ose Fe N O le vel t o Da y 1 2 ( Part 2a a n d Part 3a) will 
be a nal yse d base d o n a M M R M usi n g all p ost -baseli ne 2 h o urs p ost -d ose Fe N O assess me nts .
Baseli ne will be defi ne d as me a n Fe N O val ue at Da y -1 . T he m o d el  will i ncl u de t he fi xe d, 
cate g orical e ffects of  treat me nt, d a y , a n d treat me nt- b y-da y i nteract i on, as well  as t h e 
c o nti n u o us, fi xe d c o variate of  baseli ne Fe N O val ue . Patie nt will be i ncl u de d as a r a n d o m effect.
T his a nal ysis will be base d o n t he F A S . A nal yses will be p erf or m e d o n t he l og- tra nsfor m e d 
Fe N O data t o n or malize t he s ke we d distri b ut i on of t his e n d p o i nt.
T h e wi t hi n-pat ient  c orrelatio n will be m o dele d usi n g t he u nstr uct ure d c o varia nce matri x . T h e 
Ke n war d -R o ger a p pr o xi mati o n will be use d t o esti mate de n o mi nat or de grees of free d o m . T h e 
a na l ysis will be p erf or m e d usi n g o nl y t he O C wit h o ut i m p utati o n of  missi n g val ues . If t he 
m o del d oes n ot c o n ver ge, t he n t he c o m p o u n d s y m metr y co v ari a nce str uct ure will be use d .
R E M L met h o d will be use d f or esti mat i on.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Treat me nt effect a n d tr e at me nt differe nce s will 
be est i mate d usi n g c o ntrasts of  the 
Least -S q uare ( L S) mea ns o n t he c orres p o n de nt treat me nt - b y-d a y  int eractio n, alo n g wi t h t heir 
S E a n d 2 -si de d 9 0 % CI, a n d t he p -val ue c orres p o n di n g t o t he bet wee n -treat me nt gr o u p 
differe nce.
T he sa me m o d el  will be us e d t o e val uate treat me nt effect bet wee n t he gr o u ps i n Part 2a a n d 
Part 3a . T he f o ll owi n g treat m e nt gr o u ps will be c o m pare d at Part 2a:

A Z D 0 4 4 9 

p o ol e d place b o
T he f o ll owi n g treat m e nt gr o u ps will be c o m pare d usi n g Part 3a data:

D PI A Z D 0 4 4 9 

Pl ace b o
I n a d ditio n, treat me nt effect of  the c ha n ge fr om baseli ne i n 2 h o urs p ost -d ose Fe N O le vel at 
D a y 1 2 will be a nal yse d usi n g A N C O V A wi t h treat me nt as a fi xe d effect, a n d baseli ne as a 
c o variat e. T he L O C F met h o d will be use d t o deal wi t h missi n g val ues . N o m u lti plicity 
a djust m e nts will be a p plie d.
I n a d ditio n, as se nsitivit y a nal ysis, t he c ha n ge fr o m ba seli ne i n Fe N O area u n der t he effect -ti me 
c ur ve t o D a y 1 2 ( A U C ( 0– 1 2)) will be a nal yse d usi n g t he sa me met h o ds as t he c ha n ge fr om 
baseli ne i n 2 h o u rs p ost-d ose Fe N O le vel t o 1 2 da ys.
Fract i onal e x hale d nit ric o xide will  be liste d b y s u bject, da y a n d ti me-p oi nt i ncl u di n g a bs o l ute 
val ues, a bs o l ute a n d perce nta ge c ha n ges fr o m baseli ne . S u m mar y ta b ulati ons as well as 
ge o m etric mea n f or a bs olut e v al u es a n d c ha n ges fro m  baseli ne will be prese nte d b y tr e at me nt 
( d ose le vel of AZ D 0 4 4 9, a n d p o ole d place b o), da y a n d ti me- p oi nt f or t he F A S a n d P P S.
Fe N O A U C
( 0-1 2) will be liste d b y s u bject a n d st u d y da y i ncl u di n g a bs ol ute val ues a n d c ha n ge 
fr om baseli ne . Descri pt i ve statistics of Fe N O A U C ( 0-1 2) i ncl u di n g c ha n ge fr o m baseli ne at eac h 
st u d y da y will be prese nte d b y treat me nt ( d ose level of  AZ D 0 4 4 9, a n d p o ol e d pl ace b o) a n d 
d a y  for t he F A S a n d P P.
Gra p hs will be pr o d uce d t o ill ustrate t he a nal ysis.
 
 
 
C CI
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 0 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
 
1 0. 6. 7.
A n al ysis of E x pl or at or y D at a
 
 
 
 
 
 
 
C CI
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 1.
A D V E R S E E V E N T S
1 1. 1.
Defi niti o ns
1 1. 1. 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  an u n desira ble me di cal c o n ditio n or t he deteri orati o n of  a 
pre -e xist i n g me d ical co n di tio n  fol l owi n g or d uri n g e x p os ure t o a p har mace ut ical pr o d uct, 
w het her or n ot c o nsi dere d ca usall y relate d t o t he pr o d uct.
A n u n desi ra ble me dical c o n ditio n  ca n be s y m pt o ms (e g, na usea, c hest pai n), sig ns ( e g, 
tac h yc ar dia, e nlar ge d li ver) or t he a b n or mal res ults of a n i n vest i gati on (e g, la b orat or y fi n di n gs, 
E C G).
I n cli nical st u dies, a n A E ca n i ncl u de a n u n desira ble me d ical c o n ditio n occ urri n g at a n y ti me 
after t he s u bject has si g ne d i nf or me d c o nse nt, 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  
s pecific treat me nt has bee n a d mi nistere d.
T he ter m  A E is use d ge nerall y t o i ncl u de a n y A E w het her seri o us or n o n-serio us.
1 1. 1. 2.
Defi niti o ns of Seri o us A d verse E ve nt
A 
S A E is a n A E 
occ urri n g d uri n g a n y st u d y phase (ie, r u n-i n, treat me nt, was h o ut, 
f oll ow- u p/ safet y m o nit ori n g peri o d ), t hat f ulfills o ne or m ore of t he f oll owi n g cri t eria:

Res ults i n deat h

Is i m me diatel y life-t hreate ni n g

Re q ui res i n-pat ient  h os pi talizati on or pr ol o n gat i on of e xist i n g h os pi talizatio n

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca paci t y or s u bsta ntial disr u pti on 
of  t he a bility t o c o n d uct n or mal lif e fu nct i ons

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 d ical eve nt t hat ma y je o par dize t he s u bject or ma y re q uire 
me dical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve.
F or f urt her g ui da nce o n t he defi nit i on of a S A E, see A p pe n di x 1 5. 1 of  t his C S P.
1 1. 1. 3.
Ot her Si g nific a nt A d verse E ve nts
D uri n g t he e val uati o n of  t he A E data, a n Astra Ze neca me d icall y q ualifie d e x pert will re vie w 
t he list of  AEs t hat were n ot re p orte d as S A Es or w here r ele va nt D A Es an d wi t hdra wal fr om 
t he st u d y. Base d o n t he e x pert’s j u d g me nt, sig nifica nt A Es of  part ic ular cli nical i m p orta nce 
ma y, after c o ns ul t atio n wi t h t he Glo bal  S af et y P h ysicia n, be c o nsi dere d ot her sig nifica nt A Es 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
( O A Es) a n d re p orte d as s uc h i n t he C S R. A si milar re vie w of ot her data fr o m  la b orat or y tests, 
vit al si g ns, E C Gs a n d ot her safety assess me nts will be perf or me d f or i de ntificat i on of O A Es.
E xa m ples of  these are mar ke d he mat ol o gical  an d ot her lab orat or y  ab n or malit ies, a n d certai n 
e ve nts t hat lea d t o i nter ve ntio n ( ot her t ha n t h ose alrea d y  classifie d as serio us), d ose re d ucti o n 
or si g nifica nt a d dit i onal treat me nt.
1 1. 2.
Rec or di n g of A d verse E ve nts
1 1. 2. 1.
Ti me Peri o d f or C ollecti o n of A d verse E ve nts
A d verse E ve nts will be c ollecte d fr o m t he start of  ra n d o mizati o n t hr o u g h o ut t he treat me nt 
p eri o d u p t o a n d i ncl u di n g t he F oll o w -u p Visi t/last da y of st u d y.
S eri o us a d verse e ve nts will be rec or de d fr o m t he ti me of i nf or me d c o nse nt.
1 1. 2. 2.
F oll o w -u p of U nres ol ve d A d verse E ve nts
A n y A Es t hat are u nres ol ve d at t he s u bject’s last visit i n t he st u d y are f oll owe d u p b y t he 
I n vesti gat or f or as l o n g as me dicall y i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he Data La bs.
Astra Ze neca retai ns t he rig ht t o re q uest a d dit i onal i nf or mati o n f or a n y s u bject 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 j u d ge d necessar y.
1 1. 2. 3.
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 d verse e ve nt dia g n osis/ descri pt i on

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

I nte nsity

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 ( yes or n o)

Act i on ta ke n wit h re gar d t o i n vest i gati onal pr o d uct

A d verse e ve nt ca use d s u bject’s wit h dra wal fr o m st u d y ( yes or n o)

O utc o m e
A d dit i onal v ari a bles will be c ollecte d f or all S A Es i ncl u di n g treat me nt gi ve n f or t he e ve nt.
T he f o ll owi n g i nte nsit y rati n gs will be use d:
1.
mil d (a ware ness of si g n or s y m pt o m, b ut easil y t olerate d)


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
2.
m o derate ( di s c o mfort s ufficie nt t o ca use i nterfere nce wit h n or mal act i vities)
3.
se vere (i nca pacitati n g, wit h i na bility t o perf or m n or m al acti vities)
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d se vere A Es.
Se verit y is a meas ure 
of  int e nsit y 
whereas s erio us ness is defi ne d b y t he crit eria i n 
Secti o n 1 1. 1. 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 nsi dere d se vere na usea, b ut n ot a S A E . O n t he ot her ha n d, 
a str o ke t hat res ults i n o nl y a li mit e d d e gr e e of disa 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.
1 1. 2. 4.
C a us alit y C ollecti o n
T he I n vest i gat or will assess ca usal relati ons hi p bet wee n i n vesti gati onal pr o d uct a n d eac h A E, 
a n d a ns wer “ yes” or “ n o” t o t he q uest i on “ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y 
t hat t he e ve nt ma y ha ve bee n ca use d b y t he i n vesti gati o nal pr o d uct?”
F or S A Es ca usal relati ons hi p will als o be assesse d f or ot her me dicat i on, a n y a d ditio nal dr u g 
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 wi t h an y st u d y pr oce d ure 
t he ca usal relat 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 uest i o n is f o u n d i n A p pe n di x 1 5. 1 of  t his C S P.
1 1. 2. 5.
A d verse E ve nts B ase d o n S y m pt o ms a n d Si g ns
All A Es s p o nta ne o usl y re p orte d b y t he s u bject or re p orte d i n res p o nse t o t he o pe n q uesti o n 
fr om t he st u d y pers o n nel: “ H ave y o u h a d a ny he alt h pr o ble ms si nce y o u were l ast aske d ? ” or 
re veale d b y o bs er v atio n will be c o llecte d a n d rec or de d i n t he Data La bs.
W he n c o llecti n g A Es, t he rec or di n g of  dia gn oses is pr ef erre 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.
1 1. 2. 6.
A d verse E ve nts B ase d o n E x a mi n ati o ns a n d Tests
T he res ults fr om 
C S P -ma n date d 
lab orat or y  tests, vit al si g ns, E C Gs a n d ot h er safet y 
assess me nts will be s u m marize d i n t he C S R.
D eterior ati o n as c o m pare d t o baseli ne i n C S P -ma n date d lab orat or y  val ues, vit al si g ns, E C Gs 
a n d ot her safet y assess me nts s h o ul d 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 or are t he reas o n f or disc o nt i n uati on of treat me nt wit h t he i n vest i gati onal pr o d uct


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
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 vesti gat or ( w hic h ma y i ncl u de b ut 
n ot li mite d t o c o nsi derati o ns as t o w het her treat me nt or n o n- pla n ne d visit s were re q uire d or 
ot her acti o n was ta ke n wit h t he i n vesti gati onal pr o d uct) .
If deteri or ati o n i n a lab orat or y  valu e or 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 si g 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 
or vi t al si g n will be c o nsi dere d as a d diti 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 s h o ul d use 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 et ers s h o ul d be re p orte d as A E(s).
A n y ne w or a g gra vate d cli nicall y rele va nt a b n or mal me dical fi n di n g at a p h ysical e xa mi nat i on 
as c o mpare d wi t h t he baseli ne assess me nt will be re p orte d as a n A E.
H y's L a w
Cases w here a s u bject s h o ws ele vati o n i n li ver bi oc he mistr y  may re q uire f urt her e val uat i on a n d 
occ urre nces of A S T or A L T ≥3 x U L N t o get her wit h t otal bilir u bi n ≥2 x U L N ma y  nee d t o be 
re p orte d as S A Es. Pl ease refer t o A p pe n di x 1 5. 3 f or f urt her i nstr ucti o n o n cases of i ncreases i n 
li ver bi oc he mistr y a n d e val uati on of H L.
1 1. 3.
Re p orti n g of Seri o us A d verse E ve nts
All S A Es m ust be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he i n vesti gati ona l 
pr o d uct, or t o t he st u d y  pr oce d ure(s). All S A Es will be rec or de d i n t he Data La bs.
If a n y S A E occ urs i n t he c o urse of  the st u d y, t he n I n vesti gat ors or ot her site pers o n nel will 
i nf or m ap pr o pri ate Astra Ze neca re prese ntati ves i m me diatel y, or 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 will w or k wit h t he I n vesti gat or t o e ns ure t hat all 
t he necessar y i nf or mati on is pr o vi de d t o t he Astra Ze neca pati e nt s afet y d at a e ntr y  sit e wit hi n 
1 c ale n d ar d a y of  in itial recei pt f or fatal an 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 mati on is missi n g, acti ve 
f oll ow -u p will be u n derta ke n i m me diatel y.
I n vest i 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 f oll 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 i m me diatel y, or 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.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he r efere nce d o c u m e nt f or defi nit i on o f ex pe cte d ness/liste d ness is t he I n vesti gat or’s Br oc h ure 
(I B) f or t he Astra Ze neca dr u g [2 ].


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 2.
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S
1 2. 1.
Et hic al C o n d uct of t he St u d y
T he st u d y  will be perf or m e d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir origi n i n t h e 
Declarati o n of  Helsi n ki ( versio n 1 9 9 6) a n d are c o nsiste nt wi t h Int er nat i onal C o u ncil f or 
H ar m o nisat i on (I C H) G C P a n d t he Astra Ze neca p olic y  on Bi oet hics a n d H u ma n Bi ol o gi c al 
S a m ples.
1 2. 2.
S u bject D at a Pr otecti o n
T he I C F will i nc or p orate ( or, i n s ome cases, be acc o m pa nie d b y a se parate d oc u m e nt 
i nc or p orati n g) w or di n g t hat c o m plies wit h rele va nt data pr otecti o n a n d pri vac y le gislati on.
All cli nical st u d y fi n di n gs a n d d o c u m e nts will be re gar de d as c o nfi de nt ial. T he PI a n d me m bers 
of  his/ her researc h tea m m ust n ot discl ose s uc h i nf o r mat i on w ith o ut pri or wri tte n a p pr o val fr o m 
t he S p o ns or.
T he a n o n y mit y of  partici pat i n g s u bjects m u st be ma i ntai ne d. S u bjects will be s pecified i n 
o ut p uts a n d ot her d oc u me nts c o nt ai ni n g s u bject data b y t heir s u bject n u m ber, n ot b y na me .
D oc u m e nts t hat i de ntif y t he s u bject (e g, si gne d I C F) will be mai ntai ne d i n c o nfi de nce b y t he 
PI.
St u d y  data will be st ore d i n acc or da nce wit h l ocal a n d gl obal da ta pr otectio n l a ws.
1 2. 3.
Et hics a n d Re g ul at or y Re vie w
T he st u d y will be s u b mitt e d t o t he nati o nal re g ulat or y age nc y  for re vie w a n d a p pr o val, b y 
P are xel i n acc or da nce wit h l ocal re g ulat or y pr oce d ures.
T he st u d y  will be s u b mitte d t o t he I E C f or et hical re vie w a n d a p pr o val b y t he PI i n acc or da nce 
wi t h lo c al  pr oce d ures.
P are xel will  pr o vi de t he I E C a n d PI wi t h safet y u p dates/re p orts acc or di n g t o l ocal 
re q uire me nts, i ncl u di n g S us pecte d U ne x pecte d A d verse Reacti ons ( S U S A Rs), w here rele va nt.
Astra Ze neca will pr o vi de t he Re g ul at or y Aut h ori t y with safety u p dates/re p orts acc or di n g t o 
l ocal re q uire me nts, i ncl u di n g S U S A Rs, w here rele va nt.
C o m pe nsat i on will be reas o na ble a n d r elate d t o t he nat ure a n d de gree of  inc o n ve nie nce a n d 
di sc o mf ort as a res ult of  partici pat i on i n t he st ud y . I nf or mat i on o n h o w s u bjects will b e 
c o mpe nsate d is c o ntai ne d i n t he I C F.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 2. 4.
I ns ur a nce
T he S p o ns or has c o vere d t his cli nical st u d y by mea ns of  an i ns ura nce of  the cli nical st u d y 
acc or di n g t o nati o nal re q uire me nts. T he na me a n d a d dress of t he rele va nt i ns ura nce c o m pa n y, 
t he certificate of  ins ura nce, t he p olic y n u m ber a n d t he s u m i ns ure d are pr o vi de d i n t he 
I n vesti gat or’s Site File.
1 2. 5.
I nf or me d C o nse nt
T he s u bjects s hall be i nf or me d of t he nat ure, sig nifica nce, i m plicat i ons a n d ri s ks of t he st u d y, 
a n d i nf or me d c o nse nt will be freel y gi ve n a n d e vi de nce d i n wri tin g, date d a n d sig ne d or 
ot her wi se mar ke d, b y t he s u bject as e vi de nce t o i n dicate his/ her free i nf or me d c o nse nt, bef ore 
t he start of t he st u d y.
T he nat ure of  the i nf or me d c o nse nt will 
c o m pl y wi t h the Decla rati on of  
Helsi n k i 
( versi on 1 9 9 6), t he c urre nt re q uire me nts of  GC P ( C P M P/I C H/ 1 3 5/ 9 5) a n d l ocal re g ulat i on 
w hic h e ver offers t he greater s u bject pr otecti o n.
1 2. 6.
C h a n ges t o t he Pr ot oc ol a n d I nf or me d C o nse nt D oc u me nt
St u d y  pr oce d ures will n ot be c ha n ge d wit h o ut the m ut u al  a gree me nt of t he PI a n d Astra Ze neca.
If t here are a n y s u bsta ntial c ha n ges t o t he C S P, t he n t hese c ha n ges will be d oc u me nte d i n a 
C S P a m e n d me nt a n d w here re q uire d i n a ne w versi o n of t he C S P.
If a C S P a me n d me nt re q uires a c ha n ge t o t he I C F, t he I E C s h o uld a p pr o ve t he re vise d I C F 
bef ore t he re vise d f or m is use d.
If l ocal re g ulatio ns re q uire, a n y ad mi nistrati ve c ha n ge will be c o m m u nicate d t o or a p pr o ve d 
b y t he I E C.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 3.
L E G A L A N D A D MI NI S T R A TI V E A S P E C T S
1 3. 1.
Arc hi vi n g of St u d y D oc u me nts
All s o urce d oc u me nts g e nerate d i n c o n nect i on wit h t he st u d y will be retai ne d i n t he li mite d 
access file st ora ge area, res pecti n g t he pri vac y a n d c o nfi de nt iality of  all rec or ds t hat c o uld 
i de ntif y t he s u bjects. Di rect access is all o we d o nl y f or a ut h orize d p e o pl e f or m o nit ori n g an d 
a u ditin g p ur p oses . S o urce d oc u me nts will be ha n dle d, st ore d a n d arc hi ve d acc or di n g t o i n 
h o use pr oce d ures.
T he I n vesti gat or's Si t e File will  be arc hi ve d b y t he c o ntract researc h or ga nizat i on ( C R O) f or 
1 5 years after c o m pleti o n o f t he st u d y.
1 3. 2.
P u blic ati o n of St u d y Res ults
All of  the st u d y inf or mat i on a n d data c ollecte d d uri n g t he st u d y are c o nfi de nt ial a n d t he 
pr o pert y  of Astra Ze neca . After c o mplet i on of  the st u d y, Astra Ze neca ma y pre pare a j oi nt 
p u blicat i on wit h t he I n vest i gat or. T he I n vesti gat or m ust u n de rta ke n ot t o s u b mit a n y data fr om 
t his C S P f or p u blicati on wi t ho ut pri or c o nse nt of Astra Ze neca at a m ut uall y a gree d ti me.
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 wit h I nter nati o nal 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.
1 3. 3.
Cli nic al St u d y Re p ort
A n i nte grate d C S R will be pre pare d i n acc or da nce wit h t he sta n dar ds of t he I C H g ui deli ne f or 
str uct ure a n d c o nte nt of cli nical st u d y re p orts (I C H E 3). C o pies of t he C S R will be pr o vi de d t o 
t he I E C a n d t he nati o nal Re g ulat or y A ut h orit y i n acc or da nce wit h re g ulat or y re q uire me nts a n d 
P are xel S O Ps . I n t he e ve nt of pre mat ure ter mi nati on of t he st u d y  or ot her c o n ditio ns s pecifie d 
i n I C H E 3, a n a b bre viate d C S R ma y be pre pare d.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 4.
R E F E R E N C E LI S T
1.
Rec o m me n dat i ons relate d t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical trials. 
Cli nical Trial Facilitat i on a n d C o or di nat i on Gr o u p ( C T F G), Hea ds of Me dici nes 
A ge ncies ( H M A). 1 5 Se pte m ber 2 0 1 4. A vaila ble fr o m: 
ht t ps:// w w w. h ma.e u/filea d mi n/ dateie n/ H u ma n _ Me dici nes/ 0 1-
A b o ut _ H M A/ W or ki n g _ Gr o u ps/ C T F G/ 2 0 1 4 _ 0 9 _ H M A _ C T F G _ C o ntrace pti o n. p df .
2.
I n vesti gat or’s Br oc h ure, A Z D 0 4 4 9, E diti o n 2 . 1, a p pr o val e x pecte d 1 4 Fe br uar y 2 0 2 0.
3.
W o rld Heal t h Or ga nizati on, Gl o bal  s ur veilla nce, preve nt i on a n d c o ntr ol of c hr o nic 
res pir at or y diseases: a c o mpre he nsi ve a p pr oac h. 2 0 0 7. D oc I D -0 0 3 6 5 0 7 4 2 v 1. 0 .
4.
Israel E a n d Re d del H K. Se vere a n d diffic ult -t o-treat ast h ma i n a d ults. N E n gl J Me d. 
2 0 1 7; 3 7 7( 1 0): 9 6 5 -9 7 6.
5.
Fa h y J V. T y pe 2 i nfla m mat i on i n ast h ma--prese nt i n m o st, a bse nt i n ma n y. Nat Re v 
I mm u n o l. 2 0 1 5; 1 5( 1): 5 7- 6 5.
6.
Deli u M, S perri n M, Bel gra ve D, C ust o vic A. I de ntificati o n o f ast h ma s u bt y pes usi n g 
clusteri n g met h o d ol o gies. P ul m T her. 2 0 1 6; 2: 1 9 - 4 1.
7.
Gl o bal I nit iati ve f or Ast h ma. Gl o bal Strate g y for A st h ma Ma na ge me nt a n d Pre ve nt i on, 
2 0 1 8. A vaila ble fr o m: w w w. gi nast h ma. or g.
8.
Bar nes PJ. Gl uc oc ortic oi ds. C he m I m m u n o l Aller g y. 2 0 1 4; 1 0 0: 3 1 1 6.
9.
Dar vea u x J a n d B usse W W. Bi o l ogi cs i n Ast h ma – t he ne xt ste p t o war ds pers o nalize d 
treat me nt. J Aller g y Cli n I m m u n ol Pract. 2 0 1 5; 3( 2): 1 5 2-6 0.
1 0. Draze n J M a n d Harri n gt o n D. Ne w Bi o l ogi cs f or Ast h ma. N E n gl J Me d. 
2 0 1 8; 3 7 8( 2 6): 2 5 3 3 - 2 5 3 4.
1 1. Ni k ula KJ, Mc Cart ne y J E, Mc G o ver n T, Miller G K, O di n M, Pi n o M V Ree d M D. S T P 
p osi tio n pa per: i nter preti n g t he si g nifica nce of i ncrease d al ve ol ar macr o p ha ges i n r o de nts 
f oll owi n g i n halat i on of p har mace ut ical materi als. T o xic ol P at h ol. 2 0 1 4; 4 2( 3): 4 7 2- 8 6.
1 2. Pi zzic hi ni E, Pizzic hi ni M M, Lei g h R, Dj u ka n o vic R, Ster k PJ. Safet y of  s p ut u m 
i n d ucti on. E ur Res pir J S u p pl. 2 0 0 2; 3 7: 9s 1 8s .
1 3. Te p per, J, K ue hl, PJ, Crac k nell, S, Ni k ula, KJ, Pei, L, a n d Bla nc har d, J D. S y m p osi u m 
S u m mar y  “Breat he I n, Breat he O ut, Its Eas y : W hat Y o u Nee d t o K n o w A b o ut 
De vel o pi n g I n hale d Dr u gs”. I nt J T o xic o l. 2 0 1 6; 3 5( 4), 3 7 6 3 9 2.
1 4. F o o d a n d Dr u g A d mi nistrati o n G ui da nce f or I n d ustr y. Esti mati n g t he ma xi m u m safe 
starti n g d ose i n i nitial cli nical trials f or t hera pe utics i n a d ult health y v o l unt eers. A vaila ble 
fr om: htt ps:// w w w.f da. g o v/ me dia/ 7 2 3 0 9/ d o w nl oa d.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 1 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5. E ur o pea n Me dici nes A ge nc y. G ui deli ne o n strate gies t o i de nt if y a n d miti gate ris ks f or 
first-i n-h u ma n a n d earl y cli nical trials wit h in vest i gati o nal me dici nal pr o d ucts. 
E M E A/ C H M P/ S W P/ 2 8 3 6 7/ 0 7 Re v. 1. 2 0 1 7. A vaila ble fr o m: 
ht t ps:// w w w.e ma.e ur o pa.e u/e n/ d oc u me nts/scie ntific-g ui deli ne/ g ui deli ne -strate gies-
i de ntif y-mit i gate-ris ks-first-h u ma n -earl y-cli nical-trials-i n vesti gati onal _e n. p df.
1 6. Fa h y J V, B o us he y H A, Lazar us S C, Ma u ger E A, C her niac k R M, C hi nc hilli V M, et al. 
S af et y a n d re pr o d uci bilit y of  s p ut u m in d uct i on i n ast h matic s u bjects i n a m ultice nter 
st u d y. A m J Res pir Crit Care Me d. 2 0 0 1; 1 6 3( 6): 1 4 7 0 5.
1 7. I wata S. Ta na ka Y. Pr o gress i n u n dersta n di n g t he safety a n d efficac y of ja n us ki nase 
i n hi bit ors f or treat me nt of r he u mat oi d art hritis. E x pert Re v Cli n I m m u n ol. 
2 0 1 6; 1 2( 1 0): 1 0 4 7 5 7.
1 8. B o ger E, E va ns N, C ha p pell M, L u n d q vist A, E wi n g P, W i ge n b or g A, et al. S yste ms 
p har mac o l og y  a p pr oac h f or pre dict i on of p ul m o n ar y  a n d s yste mic p har mac o ki netics a n d 
rece pt or occ u pa nc y of i n hale d dr u gs. C P T P har mac o metrics S yst. P har mac ol. 2 0 1 6; 
5( 4): 2 0 1 – 2 1 0.
1 9. P o wer S, Willia ms M, Se m pri ni A, M u nr o C, Cas well - Smit h R, Pilc her J, et al. R C T of 
t he effect of berr yfr uit p ol y p he n o lic c ulti var e xtract i n mil d ster oi d naï ve ast h ma: a cr oss 
o ver, pl ace b o -c o ntr olle d st u d y. B MJ O pe n 2 0 1 7; 7( 3):e 0 1 3 8 5 0.
2 0. Wi nt hr o p K L. T he e mer gi n g safet y pr ofile of J A K i n hi bit ors i n r he u mat ic disease. Nat 
Re v R he u mat ol . 2 0 1 7; 1 3( 4): 2 3 4-4 3.
2 1. C orre n J , Par nes J R , Wa n g L , M o M , R o seti S L, Griffit hs J M , va n der Mer we R.
Teze pel u ma b i n A d ults wit h U nc o ntr olle d Ast h ma. N E n gl J Me d. 2 0 1 7; 3 7 7( 1 0): 9 3 6 -
9 4 6.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5.
A P P E N DI C E S
1 5. 1.
A d diti o n al S afet y I nf or m ati o n
F ur t her G ui d a nce o n t he Defi niti o n of a Seri o us A d verse E ve nt
Life -t hre ate ni n g
‘ Life-t hreate ni n g’ me a ns t hat t he s u bject was at  im me diate ris k of  deat h fr om t he A E as it 
occ urre d or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d uct w o ul d res ult i n t he s u bject’s 
deat h . ‘ Life-t hreate ni n g’ d oes n ot mea 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 patit is 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 tr e at me nt i n a n e mer ge nc y r o o m is n ot i n itself a S A E, alt ho u g h t he reas o ns f or it 
ma y be (e g, br o nc h os pas m, lar y n geal e de ma) . H os pi t al a d missio ns a n d/ or s ur gi c al o p er atio ns 
pl a n ne d bef ore or d uri n g a st u d y are n ot c o nsi dere d A Es if t he ill ness or disease e xiste d bef ore 
t he s u bject was e nr olle d i n t he st u dy,  pr o vide d t hat i t did n ot deteri orate i n a n u ne x pecte d wa y 
d uri n g t he st u d y .
I m p ort a nt Me dic al E ve nt or Me dic al I nter ve nti o n
Me dical a n d scie ntific j u d g me nt s h o uld be e xercise d i n deci di n g w het her a case is serio us i n 
sit u atio ns w here i m p orta nt me dical e ve nts ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n 
deat h, h os pi talizati on, disa bilit y or i nca pacity b ut ma y je o par dize t he s u bject or ma y re q uire 
me dical i nter ve nt i on t o pre ve nt 1 or m o re o utc o mes liste d i n t he defi nit i on of  serio us . T hese 
s h o uld 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.
E xa m ples of s uc h e ve nts are:

A n gi oe de ma 
n ot 
se vere e n o u g h t o re q uire i ntu bat i on 
b ut re q uiri n g I V 
h y dr oc or tis o ne treat me nt.

He pat ot o xicit y ca use d b y paraceta m o l/aceta mi n o p he n o ver d ose re q uirin g treat me nt  
wi t h N-acet yl c 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 yscrasias (e g, ne utr o pe ni a or a ne mia r e q uirin g b l oo d tra nsf usi on) 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.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n
T he f o ll owi n g fact ors s h o ul d be c o nsi dere d w he n deci di n g if t here is a “reas o na ble p ossi bil ity ” 
t hat a n A E ma y ha ve bee n ca use d b y t he I M P.

Ti me C o urse / E x p os ure t o s us pect dr u g:
Has t he s u bject act uall y recei ve d t he s us pect dr u g? Di d t he A E occ ur i n a reas o na ble 
t e mp or al  r elat i ons hi p t o t he a d mi nistrati o n of t he s us pect dr u g?

C o nsiste nc y 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  the s us pect dr u g 
( p har mac ol og y  an d t o xic o l og y ) or dr u gs of  the sa me p har mac o l ogi cal class? O R, 
c o uld t he A E be a nt ici pate d fr om it s p har mac ol ogical  pr o perties ?

Dec halle n ge e x perie nc e:
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  the 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 ot h er etiol o g y  suc h as t he u n derl yi n g 
di sease, ot her dr u gs, ot her h ost or e n vir o n me ntal fact ors.

Rec hall e n ge e x perie nce:
Di d t he A E re occ ur if t he s us pecte d dr u g was rei ntr o d uce d aft er ha vi n g bee n 
st o p pe d? N ote: Astr a Ze nec a w o ul d n ot n or m ally rec o m me n d or s u p p ort a 
rec h alle n ge.

La b orat or y  tests:
A s pecific la b orat or y  in vest i gati on (if perf or me d) has c o nfir me d t he relati o ns hi p?
I n diffic ult cases, ot her fact ors c o ul d be c o nsi dere d s uc h as:

Is t his a rec o g 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 de 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 o n 
‘reas o na ble p ossi bilit y’ of  a ca usal relatio 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 p erf or me d base d o n t he a vaila ble data i ncl u di n g e n o u g h 
i nf or mat i on t o ma k e a n i nf or me d j u d g me nt. Wit h li mite d or i ns ufficie nt i nf or mati on i n t he 
case, it is li kel y t hat t he e ve nt(s) will be assesse d as ‘ n ot relate d’.
Ca usal relatio ns hi p i n cases w here t he disease u n der st u d y has deteri orate d d ue t o lac k of effect 
s h o uld be classifie d as n o reas o na ble p ossi bilit y.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5. 2.
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 beli n g a n d S hi p me nt of Bi o h az ar d S a m ple s
I nter nati o nal Airli ne 
Tra ns p ortati o n 
Ass oci at i o n classifies bi o hazar d o us 
a ge nts i nto 
3 cate g ories ( htt p:// w w w.iata. or g/ w hat we d o/car g o/ da n ger o us _ g o o ds/i nfecti o us _s u bsta nces. ht
m) . F or tra ns p ort p ur p oses t he cl assificat i on of  infecti o us s u bsta nces acc or di n g t o ris k gr o u ps 
was r e mo ve d fr om t he Da n ger o us G o o ds Re g ulati o ns ( D G R) i n t he 4 6t h e ditio n ( 2 0 0 5).
I nfecti o us s u bsta nces are n o w classifie d eit her as Cate g or y A, Cate g or y B or E xe m pt. T here is 
n o di r e ct r elatio ns hi p bet wee n Ris k Gr o u ps a n d Cate g ories A a n d B.
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 di sa 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 . Cate g or y A pat h o ge ns are f or e xa m ple, E b ola a n d Lassa 
Fe ver vir uses . Cate g or y A pat h o ge ns:

Are t o be pac ke d a n d s hi p pe d i n acc or da nce wit h I A T A I nstr ucti o n 6 0 2.
C ate g or y B I nfecti o us S u bst a nces are i nfecti ous s u bsta nces t hat d o n ot meet t he criteria f or 
i ncl usi on i n Cate g or y  A. Cate g o r y B pat h o ge ns are f or e xa m ple, he pati tis A, B, C, D a n d E 
vir uses a n d HI V t yp es 1 a n d 2. T he y are assi g ne d t he f oll owi n g U N n u m ber a n d pr o per 
s hi p pi n g na me:

U N 3 3 7 3 – Bi o l ogi cal S u bsta nce, Cate g or y B

Are t o be pac ke d i n acc or da nce wit h U N 3 3 7 3 a n d I A T A I ns tr u ctio n 6 5 0.
E xe m pt r efers t o all ot her materials wit h mi ni mal ri s k of c o ntai ni n g pat h o ge ns.

Cli nical trial 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 o ns.

Cli nical trial sa m ples will 
r o uti nel y be pac ke d a n d tra ns p orte d at  am bie nt  
t e mperat ure i n I A T A 6 5 0 c o m plia nt pac ka gi n g.
( htt p:// w w w.iata. or g/ w hat we d o/car g o/ da n ger o us _ g o o ds/i nfecti ous _s u bsta nces. ht
m)

Bi ol o gi cal s a mples tra ns p orte d i n dr y  ice re q uire a d ditio n al  da n ger o us g o o ds 
s pecificati o n f or t he dr y ice c o nte nt.

I nter nati o nal Airli ne Tra ns p ortati o n Ass oci at i on c o mplia nt c o uri er a n d pac ka gi n g 
materi als s h o ul d be use d f or pac ki n g a n d tra ns p ortati o n . Pac ki n g s h o ul d be d o ne b y 
a n I A T A certifie d pers o n, as a p plica ble.

S a m ples r o uti nel y tra ns p orte d b y  r oa d or rail are s u bject t o l ocal re gulat i ons w hic h 
re q uire t hat t h e y are als o pac ke d a n d tra ns p orte d i n a safe a n d a p pr o priate wa y  t o 
c o ntai n a n y ris k of  infect i on or c o nta mi nati on b y usi n g a p pr o ve d c o uriers a n d 


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
pac ka gi n g/c o ntai n me nt mat erials at all times . T he I A T A 6 5 0 bi o l ogical sa m ple 
c o ntai n me nt sta n dar ds are e nc o ura ge d w here ver p ossi ble w he n r oa d or rail tra ns p ort 
is use d.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 4 of 2 3 3
0 4 Fe br uar y 2 0 2 1
1 5. 3.
Acti o ns Re q uire d i n C ases 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
1 5. 3. 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 ntif y a n d a p pr o priatel y 
re p ort P ote ntial H y’s La w ( P H L) cases a n d H y’s La w ( H L) cases. It is n ot i nte n de d t o be a 
c o mpre he nsi ve g ui de t o t he m a na ge me nt of ele vate d li ver bi oc he mistries.
D uri n g t he c o urse of t he st u d y  t he I n vesti gat or will re mai n vi gila nt for 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 s u bject meets 
p ote nti al P H L crit eria at a n y p oi nt d urin g t he st u d y.
All s o urces of la b orat or y data are a p pr o priate f or t he deter mi nat i on of P H L a n d H L e ve nts; 
t his i ncl u des sa m ples ta ke n at sc he d 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 visit s; for e xa m ple, P H L 
criteria c o uld b e m et b y a n ele vate d A L T fr o m a ce ntral la b orat or y a n d/ or ele vate d T B L 
fr om a lo c al  la b orat or y.
T he I n vesti gat or will als o re vie w A d verse E ve nt ( A E) data (f or e xa m ple, f or A Es t hat ma y 
i n dicate ele vati 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 cli 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 criteria t o a gree w het her H L criteria are met.
H L cri teria 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 Dr u g-I n d uce d Li ver I nj ur y ( DI LI) ca use d b y t he I n vesti gati onal 
Me dici nal Pr o d uct (I M P).
T he I n vest i gat or is res p o nsi ble f or rec or di n g data pertai ni n g t o P H L/ H L cases a n d f or re p orti n g 
S eri o us A d verse E ve nts ( S A Es) a n d A Es acc or di n g t o t he o ut c o m e of  the re vie w a n d 
assess me nt i n li ne wit h sta n dar d safet y re p orti n g pr ocesses.
1 5. 3. 2.
Defi niti o ns
P ote nti al H y’s L a w ( P H L)
As partate A mi n otra nsferase ( A S T) or Ala ni ne A mi n otra nsferase ( A L T) ≥3 × U p per Li mit of 
N or m al ( U L N) t o get her wit h T otal Bilir u bi n ( T B L) ≥2 × U L N at a n y  p oi nt d uri n g t he st u d y 
f oll owi n g t he start of st u d y  me dicat i on irres pecti ve of a n i ncrease i n Al kali ne P h os p hatase 
( A L P).
H y’s L a w ( H L)
A S T or A L T ≥3 × U L N t o get her wit h T B L ≥2 × U L N, w here n o ot her reas o n, ot her t ha n t he 
I M P, ca n be f o u n d t o e x plai n t he c o m bi nati 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.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 5 of 2 3 3
0 4 Fe br uar y 2 0 2 1
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 vat i on 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 m ust occ ur.
1 5. 3. 3. 
I de ntific ati o n of P ote nti al H y’s L a w C ases
I n or der t o i de ntif y cases of  PH L it is i m p orta nt t o perf or m a c o m pre he ns i ve re vie w of  
la b orat or y data f or a n y s u bject w h o meets a n y of  the f oll owi n g i de ntificat i on criteria 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
T he I n vesti gat or will wit h o ut dela y re vie w eac h ne w la b orat or y  re p ort a n d if t he 
i de ntificat i on cri teria are met will:

N otif y  t he Astra Ze neca re prese ntati ve

Deter mi ne w het her t he s u bject meets P H L criteria (see Sect i on 2 Defi nit i ons wit hi n 
t his A p pe n di x f or defi nit i on) b y re vie wi n g la b orat or y re p orts fr o m all pr e vio us 
visit s

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 C R F
1 5. 3. 4.
F oll o w -U p
1 5. 3. 4. 1.
P ote nti al H y’s L a w Criteri a N ot Met
If t he s u bject d oes n ot meet P H L criteria t he I n vesti gat or will:

I nf or m t he Astra Ze neca re prese ntati ve t hat t he s u bject d oes n ot meet P H L criteria

Perf or m  fol l ow- u p o n s ubse q ue nt lab orat or y  res ults acc or di n g t o t he g ui da nce 
pr o vi de d i n t he Cli nical St u d y  Pr ot oc ol.
1 5. 3. 4. 2.
P ote nti al H y’s L a w Criteri a Met
If t he s u bject d oes meet P H L criteria t he I n vesti gat or will:

N otif y  the 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 Tea m.

Wit hi n 1 d a y  of PH L criteria bei n g met , t he I n vesti gat or will re p ort t he case as a n 
S A E of  PH L; serio us crit eria ‘I mp orta nt me d ical e ve nt’ a n d ca usalit y assess me nt 
‘ yes/relate d’ acc or di n g t o C S P pr ocess f or S A E re p orti n g.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 6 of 2 3 3
0 4 Fe br uar y 2 0 2 1

F or s u bjects that met  PH L criteria pri or t o starti n g I M P, t he In 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 s u bject’s 
c o n ditio n.

T he St u d y  Ph ysicia n c o ntacts t he I n vestig at or, t o pr o vi de g ui da nce, disc uss a n d 
a gree a n a p proac h f or t he st u d y su bjects’ f oll 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 s u bject u nt il li ver bi oc he mistr y  para meters a n d a p pr o priate cli nica l 
s y m pt o ms a n d si g ns ret ur n t o n or mal or baseli ne levels, or as l on 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 aetiol o g y  of t he e ve nt a n d perf or m  dia gn osti c 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 C R F M o d ules as i nf or mati o n bec o mes a vaila ble .
# A ‘si g nifica nt’ c ha n ge i n t he s u bject’s c o n dit i on 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 L T, A S T or t otal bilir u bi n) i n 
is olati on o r i n c om bi nat io n, or a cli nicall y rele va nt c ha n ge i n ass ociate d s y m pt o ms . T he 
deter mi nat i on of  whet her t here has bee n a si gnifica nt c ha n ge will be at t he discret i on 
of  t he I n vestigat or, t his m a y be i n c o ns ult atio n wi t h t he St u d y P h ysicia n if t here is a n y 
u ncertai nt y.
1 5. 3. 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 uld be f ol l owe d f or all cases w here P H L criteria were met.
As s o o n as p ossi ble after t he bi oc he mistr y  a b n or mality was i ni tiall y detecte d, t he St u d y  
P h ysicia n c o ntacts t he I n vest i gat or i n or der t o re vie w a vaila ble data a n d a gree o n w het her 
t here is a n alter nat i ve e x pla nati on f or meet i n g P H L criteria ot her t ha n DI LI ca use d b y t he 
I M P, t o e ns ure ti mel y a nal ysis a n d re p orti n g t o health a ut h orit ies withi n 1 5 cale n dar da ys 
fr om da te P H L crit eria was met. T he Astra Ze neca Gl o bal Cli nical Lea d or e q ui vale nt a n d 
Gl o bal Safet 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 m e of  the re vie w a n d assess me nt, the I n vesti gat or will f oll ow t h e 
i nstr uctio ns bel o w.
W here t here is
a n a gree d alter n ati ve e x pl a n ati o n f or t he A L T or A S T a n d T B L ele vat i ons, 
a deter mi nati o n of w het her t he alter nat i ve e x pla nati on is a n A E will be ma de a n d 
s u bse q ue ntl y w het her t he A E meets t he criteria f or a S A E:


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 7 of 2 3 3
0 4 Fe br uar y 2 0 2 1

If t he alter nati ve e x pla nati on is n ot a n A E, rec or d t he alter nat i ve e x pla nati o n o n t he 
a p pr o priate C R F.

If t he alter nati ve e x pla nat i on is a n A E/ S A E:
u p date t he pre vi o usl y s u b mitt e d 
P ote nti al Hy’s La w S A E a n d A E C R Fs acc or di n gl y wi t h t he ne w i nf or mat i on 
(reassessi n g e ve nt t er m; ca usalit y an d serio us ness criteria) f oll owi n g t he A Z 
sta n dar d pr ocesses.
If it is a gree d t hat t here is n o e x pla nat i on t hat w o ul d clarif y t he A L T or A S T a n d T B L 
ele vat i ons ot her t ha n I M P:

Se n d u p date d S A E (re p ort t er m ‘H y’s La w’) acc or di n g t o Astra Ze neca sta n dar d 
pr ocesses.

T he ‘ Me dicall y Im p orta nt’ serio us crit erio n s h o uld be use d if n o ot her seri o us 
criteria a p pl y.

As t here is n o alt er nat i ve e x pla nat i on f or t he H L case, a ca usalit y assess me nt of  
‘relate d’ s h o ul d be assi g ne d.
If, t here is a n u na v oi da ble dela y, of o ver 1 5 cale n dar da ys i n o btai ni n g t he i nf or mati on 
necessar y  t o assess w het her or n ot t he case meets t he criteria f or H L, t he n it is ass u me d t hat 
t here is n o alter nat i ve e x pla nati o n u ntil s uc h ti me as a n i nf or me d decisi on ca n be ma de:

Pr o vi des a n y f urt her u p date t o t he pre vio usl y s u b mi tt e 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 usalit y assess me nt is relate d t o I M P a n d 
serio us ness crit eria is me d icall y i m p orta nt, acc or di n g t o C S P pr ocess f or S A E 
re p orti n g.

C o nti n ue f oll o w- u p a n d re vie w acc or di n g t o a gree d pl a n. O nce t he necessar y 
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 w het her H L criteria are still met . U p date t he pre vi o usl y s u b mitt e d P H L 
S A E re p ort f oll o wi 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 o f 
t he re vie w a n d a me n di n g t he re p orte d t er m if a n alter nati ve e x pla nati on f o r t he li ver 
bi oc he mistr y  ele vati ons is deter mi ne d.
1 5. 3. 6.
Acti o ns Re q uire d f or Re pe at E pis o des of P ote nti al H y’s L a w
T his sect i on is a p plica ble w he n a s u bject meets P H L criteria o n st u d y treat me nt a n d has alrea d y 
met P H L criteria at a pre vi o us o n st u d y  treat me nt visit.
T he re q uire me nt t o c o n d uct f oll ow- u p, re vie w a n d assess me nt of  a re peat occ urre nce(s) of  PH L 
is bas e d o n t he nat ure of t he alter nat i ve ca use i de ntifie d f or t he pre vi o us occ urre nce.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 8 of 2 3 3
0 4 Fe br uar y 2 0 2 1
T he In vest i gat or s h o ul d deter mi ne t he ca use f or t he pre vi o us occ urre nce of P H L criteria bei n g 
met a n d a ns wer t he f o ll owi n g q uest i on:
Was t he alter nati ve ca use f or t he pre vi o u s occ urre nce of P H L cri teria bei n g met f o u n d 
t o be t he di sease u n der st u d y, e g, c hr o nic or pr o gressi n g ma li g na nt di sease, se vere 
i nfecti on or li ver disease
If N o : fol l ow t he pr ocess descri be d i n Sect i on 1 5. 3. 4. 2 f or re p orti n g P H L as a n S A E
If Y es : Deter mi ne if t her e h as b e e n a sig nifica nt c ha n ge i n t he s u bject’s c o n ditio n # c o m pare d 
wi t h w he n P H L criteria were pre vi o usl y met
If t here is n o si g nifica nt c ha n ge n o acti o n is re q uire d
If t here is a sig nifica nt c ha n ge f oll ow t he pr ocess descri be d i n Secti o n 1 5. 3. 4. 2 f or re p orti n g 
P H L as a n S A E
# A ‘si g ni fica nt’ c ha n ge i n t he s u bject’s c o n diti on refers t o a cli nicall y rele va nt c ha n ge i n 
a n y of  the i n di vi d ual li ver bi oc he mistr y  para meters ( A L T, A S T or t otal bilir u bi n) 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 h e 
deter mi nat i on of  whet her t here has bee n a sig nifica nt c ha n ge will be at t he di screti on of 
t he I n vesti gat or, t his ma y be i n c o ns ultat i on wi t h the St u d y  Ph ys icia n if t here is a n y 
u ncertai nt y.
1 5. 3. 7.
L a b or at or y T ests
H y’s L a w l a b kit f or l oc al l a b or at ories ( 1 8 Dec e m ber 2 0 1 8)
A d dit i onal sta n dar d c he mistr y a n d 
c oa g ulat i on tests
G G T
L D H
Pr ot hr o m bi n t i me
I N R
Vi r al he p atitis
I g M a nti-H A V 
I g M a n d I g G a nti-H Bc
H Bs A g
H B V D N A *
A nt i-H C V
H C V R N A * 
I g M a nti-H E V
H E V R N A
Ot her viral i nfect i ons
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 o lic he pat itis
Car b o h y drate deficie nt tra nsferri n ( C D -
tra nsferri n)
A ut oi m m u ne he patit is
A nt i n uclear a nti b o d y ( A N A)
A nt i-Li ver/ Ki d ne y  Micr os o mal A b ( A nti-
L K M)
A nt i-S m o ot h M uscle A b ( A S M A)


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 2 9 of 2 3 3
0 4 Fe br uar y 2 0 2 1
Meta b o lic diseases
alp ha- 1- a nt itr ypsi n
Cer ul o pl as mi n
Ir o n
Ferri tin
Tra nsferri n
Tra nsferri n sat urati o n
* H C V R N A a n d H B V D N A are o nl y teste d w he n a nti -H C V is p ositi ve or i nc o ncl usi ve
R E F E R E N C E S
Ait hal et al 2 0 1 1, Cli nical P har mac ol og y  a n d T hera pe uti cs 8 9( 6): 8 0 6 - 8 1 5.
F D A G ui da nce f or I n d ustr y (iss ue d J ul y 2 0 0 9) Dr u g -i n d uce d li ver i nj ur y: Pr e m ar keti n g cli nical 
e val uat i on.


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 3 0 of 2 3 3
0 4 Fe br uar y 2 0 2 1
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 3 1 of 2 3 3
0 4 Fe br uar y 2 0 2 1
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 3 2 of 2 3 3
0 4 Fe br uar y 2 0 2 1
C CI


Astra Ze neca
Cli nical St u d y Pr ot oc ol
St u d y C o de: D 5 3 7 1 C 0 0 0 0 1
Re vise d Acc or di n g t o Pr ot oc ol A me n d me nt N o. 1 0
Dr u g s u bsta nce: A Z D 0 4 4 9
C O N FI D E N TI A L
Fi nal
Pa ge 2 3 3 of 2 3 3
0 4 Fe br uar y 2 0 2 1
C CI


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

SAP_001.pdf: 
A Single-Blind, Randomized, Placebo-Controlled 3-Part 
Study in Healthy Volunteers and Patients with Mild Asthma 
to Investigate the Safety, Tolerability and Pharmacokinetics 
of Inhaled AZD0449 Following Single and Multiple 
Ascending Doses and to Investigate the Anti-Inflammatory 
Effect of Inhaled AZD0449 
ClinicalTrials.gov Identifier: NCT03766399 
Statistical Analysis Plan: Final 1.0, 05 November 2021


Parexel International 
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Parexel International 
AstraZenca 
D5371C00001 
A Single-blind, Randomized, Placebo-controlled 3-part Study in Healthy Volunteers and Patients 
with Mild Asthma to Investigate the Safety, Tolerability and Pharmacokinetics of Inhaled 
AZD0449 Following Single and Multiple Ascending Doses and to Investigate the Anti-
inflammatory Effect of Inhaled AZD0449  
Statistical Analysis Plan 
Version: Final 1.0 
Parexel Project Number: CCI
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SPONSOR SIGNATURE PAGE 
Approved by: 
_________________________ 
_______________ 
Date 
Global Product Statistician 
AstraZeneca 
PPD
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Parexel SIGNATURE PAGE 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with 
 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the following: 
 
 
 
 
 
Signatory 
Author 
 
Project Role: Biostatistics Lead  
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5 
REFERENCES ..........................................................................................................................45 
6 
APPENDICES ..........................................................................................................................46 
6.1 
Schedule of Assessments ..........................................................................................................46 
 
 
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REVISION HISTORY 
 
Version No. 
Effective Date 
Summary of Change(s) 
Draft 1.0 
21 Aug 20 
New document after approval of PA 7 and combining all studies 
parts in one file. 
Draft 2.0 
20 Jan 21 
Updated as per Szilárd comments and as per PA8. Moreover, 
text for Interim Analysis section has been updated as per last 
discussion regarding this topic. 
Draft 3.0 
08 Feb 21 
Tables 14.2.9.x have been included. IA text aligned with 
proposal for PA10. 
Draft 4.0 
01 Jul 21 
PK section updated as per additional comments from AZ and 
Covance. 
Draft 5.0 
07 Jul 21 
Updates for last comments from Covance. 
Final 1.0 
08 Jul 2021 
Draft 5.0 has named to Final 1.0. 
 
 
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LIST OF ABBREVIATIONS 
List and define all acronyms and abbreviations used in the document here.  Abbreviations should be 
spelled out in full and the abbreviation indicated in parentheses at first appearance in the text.  
Abbreviations should appear in alphabetical order. 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUCextr 
Extrapolated area under the curve from tlast to infinity, expressed 
as percentage of AUCinf 
AUCinf 
Area under the plasma concentration-time curve from time zero to 
infinity 
AUCinf/D  
Dose normalized area under the plasma concentration-time curve 
from time zero to infinity 
AUClast  
Area under the plasma concentration-time curve from time zero to 
time of last quantifiable concentration 
AUC(0-24)/D 
Dose normalized area under the plasma concentration-time curve 
from time zero up to 24 hours post-dose 
AUC(0-24) 
Area under the plasma concentration-time curve from time zero up 
to 24 hours post-dose 
BDRM 
Blinded data review meeting 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
Bpm 
Beats per minute 
CI 
Confidence interval 
CL 
Total body clearance of drug from plasma after intravascular 
administration (parent drug only) 
CL/F 
Apparent total body clearance of drug from plasma after 
extravascular administration (parent drug only) 
Cmax 
Maximum observed plasma (peak) concentration 
Cmax/D 
Dose normalised maximum observed plasma (peak) concentration 
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Abbreviation / Acronym 
Definition / Expansion 
CPKA 
Covance Clinical Pharmacology Alliance 
CRF 
Case Report Form 
CS 
Clinically significant 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
dECG 
Digital electrocardiogram 
DPI 
Dry-powder inhaler 
ECG 
Electrocardiogram 
 
 
 
 
EN 
Enrolled analysis set 
 
 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FEV 
Forced vital capacity 
FIH 
First in human 
 
 
FVC 
Forced vital capacity 
GGT 
Gamma glutamyl transpeptidase 
Hb 
Hemoglobin 
HBc 
Hepatitis B core 
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
HR 
Heart rate 
hs-CRP 
High-Sensitivity C-reactive protein 
IA 
Interim Analysis 
ICF 
Informed consent form 
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Abbreviation / Acronym 
Definition / Expansion 
ICH 
International Council for Harmonization 
 
 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
 
 
IV 
Intravenous 
LLOQ 
Lower limit of quantification 
LLT 
Lowest level term 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not available 
OC 
Observed cases  
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PDF 
Portable document format 
PDS 
Protocol deviation specification 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic analysis set 
PoM 
Proof of mechanism 
PPS 
Per protocol analysis set 
PR 
The PR interval is the ECG interval measured until the onset of the 
QRS complex 
PT 
Preferred term 
QRS 
The ECG interval measured from the onset of the QRS complex to 
the J point 
QT 
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave 
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Abbreviation / Acronym 
Definition / Expansion 
 
 
QTcF 
QT corrected using Fridericia’s formula 
RBC 
Red blood cell 
REML 
Restricted maximum likelihood 
RR 
The RR interval is measured as the time between corresponding 
points on 2 consecutive R waves on an ECG 
RS 
Randomized set 
Rsq-adj 
Statistical measure of fit for the regression used for λz 
determination adjusted for the number of used data points (λzN) 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation or single dose 
SE 
Standard error of the mean 
SoA 
Schedule of Assessments 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRC 
Scientific review committee 
TBL 
Total Bilirubin 
TCA 
Tricyclic anti-depressants 
TEAE 
Treatment-emergent adverse event 
TFLs 
Tables, figures and listings 
 
tlast 
Time of last observed (quantifiable) concentration 
tmax 
Time to reach peak or maximum observed concentration or 
response following drug administration 
 
 
TSH 
Thyroid stimulating  hormone 
t½λz 
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve 
ULN 
Upper limit of normal 
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Abbreviation / Acronym 
Definition / Expansion 
Vz 
Volume of distribution following intravenous administration (based 
on terminal phase) (parent drug only) 
Vz/F 
Apparent volume of distribution following extravascular 
administration (based on terminal phase) (parent drug only) 
WAD 
Windows Allowance Document 
WBC 
White blood cell 
WHO-DD 
World Health Organisation - Drug Dictionary 
λz 
Terminal elimination rate constant 
λz lower 
Lower (earlier) t used for λz determination 
λz,N 
Number of data points used for λz determination 
λz span ratio 
Time period over which λz was determined as ratio of t½λz 
λz upper 
Upper (later) t used for λz determination 
 
 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) details the statistical methodology to be used for analyzing the 
study data and outlines the statistical programming specifications for the tables, figures and listings 
(TFLs). It describes the variables and analysis sets anticipated data transformations and manipulations 
and other details of the analyses not provided in the Clinical Study Protocol (CSP).  
The analyses described in this SAP are based upon the following study documents: 
 
Study Protocol, Version 1.0, September 18, 2018 
 
Protocol Amendment No. 1, Final 1.0, 23 October 2018 
 
Protocol Amendment No. 2, Final 1.0, 04 December 2018 
 
Protocol Amendment No. 3, Final 1.0, 09 May 2019 
 
Protocol Amendment No. 4, Final, 03 December 2019 
 
Protocol Amendment No. 5, Final, 11 February 2020 
 
Protocol Amendment No. 6, Final, 27 May 2020  
 
Protocol Amendment No. 7, Final, 26 June 2020 
 
Protocol Amendment No. 8, Final, 11 September 2020 
 
Protocol Amendment No. 9, Final, 08 December 2020 
The SAP describes the statistical analysis as it is foreseen when the study is being planned. If 
circumstances should arise during the study rendering this analysis inappropriate, or if in the 
meantime improved methods of analysis should come to light, different analyses may be performed. 
Any deviations after database lock, reasons for such deviations and all alternative or additional 
statistical analyses that may be performed, will be described in an SAP addendum and discussed in 
the Clinical Study Report (CSR). Any changes to this SAP prior to database lock will be described in 
a new version of the SAP. 
The content of this SAP is compatible with the International Council for Harmonization (ICH)/Food 
and Drug Administration (FDA) E9 Guidance documents. 
 
2 
STUDY OBJECTIVES 
This study consists of three study parts: Part 1a, single ascending dose (SAD) in healthy volunteers; 
Part 1b, bioavailability in single intravenous (IV) dose cohorts; Part 2a, multiple ascending dose 
(MAD) in patients with asthma; Part 2b, MAD in healthy volunteers; Part 3a, proof of mechanism 
(PoM) in patients with mild asthma; Part 3b (optional), PoM in healthy volunteers. 
 
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The first IV cohort will consist of the 6 volunteers that received an inhaled dose of AZD0449 
nebulized suspension in Part 1a of the study. If Part 1b cannot be completed with 6 volunteers from 
Part 1a or if some of the data are considered not evaluable, up to 6 additional naïve volunteers may 
be enrolled. 
All 6 volunteers will receive a single IV dose 
 of AZD0449 solution. Dosing will start with 
1 healthy volunteer in a sentinel cohort, for more details see Section 3.1.2.1 of the CSP. 
There will be a washout period of at least 2 weeks for the volunteers receiving both inhaled dosing in 
Part 1a and IV dosing in Part 1b. 
A second IV dose cohort in Part 1b will be initiated after the evaluation of the PK and safety results 
from all cohorts in Part 1a and completion of the first IV dose cohort in Part 1b. 
The second IV cohort will consist of the 6 healthy volunteers who have not previously participate in 
the study.  
All 6 volunteers will receive a single IV dose 
 of AZD0449 solution. Dosing will start with 
1 healthy volunteer in a sentinel cohort, for more details see Section 3.1.2.2 of the CSP. 
Part 2a/b is a randomized, single-blind, placebo-controlled, MAD, sequential group design study 
performed at approximately 3 study centers. Subjects aged 18 to 55 years will be included in this part 
of the study. Unlike in Part 1a or Part 1b (first IV dose cohort), female subjects of childbearing 
potential may also be enrolled. This part of the study will recruit up to 56 subjects. A total of 26 
evaluable subjects are needed for completion of Part 2a/b. Potentially, 30 extra subjects may be 
randomized to counteract drop-outs and allow for an extra cohort if needed. 
Three dose levels of AZD0449 nebulized suspension are planned to be investigated in 3 cohorts. The 
cohorts could comprise either patients with mild asthma or healthy volunteers. 
Part 2a includes cohorts 1 and 2, each comprising of 9 patients with mild asthma. Within each of 
these cohorts 6 patients will be randomized to receive AZD0449 nebulized suspension and 3 patients 
randomized to receive placebo. Additional cohorts with 9 patients could be added to study PK, 
pharmacodynamic (PD) and safety for doses lower than 
 
Part 2b will consist of 1 cohort of 8 healthy volunteers; 6 volunteers will be randomized to receive 
AZD0449 nebulized suspension and 2 volunteers will be randomized to receive placebo. 
Dosing for each ascending dose cohort will start with 2 subjects in a sentinel cohort, such that 1 
subject will be randomized to receive AZD0449 nebulized suspension and 1 subject will be 
randomized to placebo. 
Part 3a/b of the study will be initiated after the completion of Part 2b. Part 3a/b is a randomized, 
single-blind, placebo-controlled, DPI/PoM study. Part 3 will be conducted in up to 36 patients with 
mild asthma (Part 3a) and 8 healthy volunteers (Part 3b, optional). 
Part 3a will consist of 36 patients, aged 18 to 55 years, where 18 patients will be randomized to 
AZD0449 DPI and 18 patients to placebo. An Interim Analysis (IA) will be conducted when 9 patients 
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on each arm have completed the study (50% Part 3a). Should new data on the variability of the FeNO 
measurements emerge at the IA, the sample size in Part 3a could be changed. 
If the optional Part 3b is conducted, it will comprise 8 healthy volunteers; 6 volunteers will be 
randomized to AZD0449 DPI and 2 volunteers to placebo.  
Further details regarding the study design are provided in Section 3.1 of the CSP. 
3.2 
Endpoints and Associated Variables 
3.2.1 Demographics and Baseline Characteristics 
The following demographics and baseline characteristics variables will be collected: birth year, age 
at informed consent, gender, race, ethnicity, height (cm), weight (kg). Body mass index (BMI) will 
be derived. 
3.2.2 Prior and Concomitant Medications 
Medication started within 3 months before the first dose of Investigational Medicinal Product (IMP) 
as well as all medications taken during the conduct of the study will be recorded in the concomitant 
medication module of DataLabs®.  
The following variables will be collected: 
 
Medication or therapy 
 
Start/stop dates and times, or ongoing 
 
Total daily dose/ dose per administration 
 
Units 
 
Frequency 
 
Route of administration/ inhalator type 
 
Indication 
 
Therapy reason, AE/medical history number 
Prior and concomitant medication will be coded according to the World Health Organization Drug 
Dictionary (WHO DD), version September 2018.  
3.2.3 Safety Variables 
3.2.3.1 Adverse Events 
Adverse Events (AEs) will be collected from the start of randomization throughout the treatment 
period up to and including the Follow-up Visit. Serious adverse events (SAEs) will be recorded from 
the time of informed consent. All AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1. The following variables will be collected for each AE: 
 
Adverse event diagnosis/description 
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 
The date and time when the AE started and stopped 
 
Intensity 
 
Whether the AE is serious or not 
 
Investigator causality rating against the IMP (yes or no) 
 
Action taken with regard to investigational product 
 
Adverse event caused subject’s withdrawal from the study (yes or no) 
 
Outcome 
Additional variables will be collected for all SAEs including treatment given for the event: 
 
Date AE met criteria for SAE 
 
Date investigator aware of SAE 
 
Result in death 
 
Required or prolongs hospitalization 
 
Congenital anomaly or birth defect 
 
Life threatening 
 
Persistent or significant disability or incapacity 
 
Date of hospitalization/ discharge 
 
Primary/secondary cause of death 
 
Date of death 
 
Autopsy 
 
SAE caused by other medication, additional drug or study procedure 
The following intensity ratings will be used: 
1. mild (awareness of sign or symptom, but easily tolerated) 
2. moderate (discomfort sufficient to cause interference with normal activities) 
3. severe (incapacitating, with inability to perform normal activities) 
3.2.3.2 Laboratory Assessments 
Laboratory assessments (hematology, clinical chemistry, urinalysis, serology, pregnancy tests, drug 
and alcohol abuse) will be performed at the time-points specified in the Schedule of Assessments 
(SoA), Section 6.1. The following parameters will be assessed: 
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Hematology  
White blood cell (WBC) count 
Neutrophils absolute count  
Red blood cell (RBC) count 
Lymphocytes absolute count  
Hemoglobin (Hb) 
Monocytes absolute count  
Hematocrit (HCT) 
Eosinophils absolute count  
Mean corpuscular volume (MCV) 
Basophils absolute count  
Mean corpuscular hemoglobin (MCH) 
Platelets 
Mean corpuscular hemoglobin concentration (MCHC) 
Reticulocytes absolute count  
 
 
Clinical Chemistry 
Sodium 
Alkaline phosphatase (ALP) 
Potassium 
Alanine aminotransferase (ALT) 
Urea 
Aspartate aminotransferase (AST) 
Uric acid 
Gamma glutamyl transpeptidase (GGT) 
Creatinine 
Total Bilirubin (TBL) 
Albumin 
Unconjugated bilirubin 
Calcium 
Triglycerides 
Phosphate 
High-Sensitivity C-reactive protein (hs-CRP) 
Glucose (fasting in plasma) 
Thyroid-stimulating- hormone (TSH) a 
Follicle stimulating hormone (FSH)a (post-menopausal 
females only) 
 
a Screening only 
 
 
Urinalysis 
 
Glucose 
Protein 
Blood 
 
Microscopy (if positive for protein or blood): RBC, WBC, Casts (Cellular, Granular, Hyaline) 
 
 
Pregnancy test (females only) 
Human beta chorionic gonadotrophin 
 
 
 
Serology 
 
Human immunodeficiency virus (HIV) I and II 
Hepatitis C Virus antibody 
Hepatitis B surface antigen (HBsAg) 
QuantiFERON® TB 
Anti-HBc antibody a 
 
a Germany only 
 
 
Drugs of Abuse and Alcohol 
Amphetamine 
Benzodiazepines 
Ethanol 
Methadone Metabolites 
Cannabinoids 
Barbiturates 
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Cocaine 
Phencyclidine 
Opiates  
Urine Creatinine 
Cotinine 
Tricyclic anti-depressants (TCA) 
 
 
COVID-19 Testing 
Antibody, PCR, or alternative COVID-19 test will be conducted subject to local availability and site guidance 
 
 
3.2.3.3 Vital Signs 
The vital signs assessments will be performed at the time-points specified in the SoA, Section 6.1. 
The following variables will be collected after the subject has rested in the supine position for at least 10 
minutes, in accordance with the site’s standard operating procedure (SOPs): 
 
Systolic blood pressure (BP) (mmHg)  
 
Diastolic BP (mmHg)  
 
Pulse rate (bpm)  
 
Oral or tympanic body temperature (C)  
 
Respiratory rate (breath per minute) 
Flag for values outside reference range (L/H) and clinical significance (Yes/No) will be collected in 
the case report form (CRF). 
3.2.3.4 Twelve-lead Safety Electrocardiogram 
At the time-points specified in the SoA, Section 6.1. Twelve-lead electrocardiograms (ECGs) will be 
obtained after the subject rested in the supine position for at least 10 minutes. The principal 
investigator (PI) will judge the overall interpretation as normal or abnormal as well as details of 
abnormality. If abnormal, it will be further documented as to whether or not the abnormality is 
clinically significant by the PI. 
3.2.3.5 Electronic Capture of 12-lead Continuous Digital Electrocardiogram 
The following digital electrocardiogram (dECG) variables will be reported by the AstraZeneca ECG 
Center:  
 
RR interval – the time between corresponding points on 2 consecutive R waves on ECG 
 
PR interval – ECG interval measured until the onset of the QRS complex 
 
QRS – ECG interval measured from the onset of the QRS complex to the J point 
 
QT interval – ECG interval measured from the onset of the QRS complex to the end of the T 
wave 
The following parameters will be derived: 
 
QTcF – QT interval corrected for heart rate using Fridericia’s formula 
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 
HR – heart rate 
3.2.3.6 Telemetry 
A 12-lead real-time telemetry ECG will be performed at the time-points specified in the SoA, Section 
6.1. The telemetry monitoring system will be reviewed by the Investigator and paper printouts of any 
clinically important events will be stored as source data. Overall telemetry evaluation (normal/ 
abnormal), reason of abnormality as well as flag for a clinical significance will be collected in the 
CRF. 
3.2.3.7 Physical Findings 
The full and brief physical examinations will be performed at the time-points outlined the SoA, 
Section 6.1.  
Full 
The complete physical examinations will include an assessment of the general appearance, skin, 
cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph 
nodes, thyroid, musculoskeletal and neurological systems. 
Brief (Abbreviated) 
The brief physical examinations will include an assessment of the general appearance, skin, 
cardiovascular system, respiratory and abdomen. 
The baseline/screening results of the physical examination will be documented in medical history for 
each subject. 
Any new or aggravated clinically relevant abnormal medical physical examination finding compared 
to the baseline assessment will be reported as an AE. 
3.2.3.8 Spirometry 
Spirometry measurements, forced expiratory volume in one second (FEV1) (L), forced vital capacity 
(FVC) (L) and FEV1 % predicted, will be performed at the time-points outlined the SoA, Section 6.1. 
3.2.3.9 Pulse Oximetry 
Pulse oximetry will be performed and peripheral capillary oxygen saturation (SpO2) (%) will be 
measured at the time-points outlined the SoA, Section 6.1. Flag for values outside reference range 
(L/H) and clinical significance (Yes/No) will be collected in the CRF. 
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t½λz  
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve  
CL  
Total body clearance of drug from plasma after intravascular (IV) 
administration (parent drug only) 
Vz  
Volume of distribution following intravenous (IV) administration (based on 
terminal phase) (parent drug only) 
Cmax/D  
Dose normalized maximum observed plasma concentration (calculated as 
Cmax divided by dose 
AUCinf/D  
Dose normalized area under the plasma concentration-time curve from time 
zero to infinity (calculated as AUCinf divided by dose)   
AUC(0-24)/D  
Dose normalized area under the plasma concentration-curve from time zero 
up to 24 hours post-dose (calculated as AUC(0-24)  divided by dose)  
tlast  
Time of last observed (quantifiable) concentration  
 
The following PK parameters will be calculated for diagnostic purposes and listed and summarized: 
 
Diagnostic PK parameters 
λz lower 
Lower (earlier) t used for λz determination 
λz upper 
Upper (later) t used for λz determination  
λzN  
Number of data points used for λz determination  
λz span ratio 
Time period over which λz was determined as ratio of t½λz 
Rsq-adj  
Statistical measure of fit for the regression used for λz determination 
adjusted for the number of used data points (λzN) 
AUCextr  
Extrapolated area under the curve from tlast to infinity, expressed as 
percentage of AUCinf  
 
The PK analyses of the plasma concentration data for AZD0449 
 
 will be performed by Covance Clinical Pharmacology Alliance (CPKA) on behalf of 
AstraZeneca, in accordance with current AZ Guidelines for Pharmacokinetic Evaluations in Clinical 
Studies. 
PK parameters will be derived using non-compartmental analysis (NCA) methods with Phoenix® 
WinNonlin® (WNL) Version 8.1 or higher. 
The actual sampling times recorded in the raw data will be used in the PK analysis. If actual times 
are missing, nominal times may be used. Nominal sampling times were used for interim plasma PK 
parameter calculations for the purpose of the scientific review committee (SRC) meetings. 
Plasma concentrations below the lower limit of quantification (BLQ) from the time of pre-dose 
sampling (t=0) up to the time of the first quantifiable concentration will be set to a value of 0. After 
this point, BLQ plasma concentrations will be set to missing for all concentration profiles. If 2 or 
more consecutive BLQ concentrations are followed by quantifiable concentrations in the terminal 
portion of the concentration-curve, the profile will be deemed to have terminated and therefore these 
quantifiable values will be set to missing for the calculation of the PK parameters unless there is a 
scientific rationale not to do so; this will be documented in the PK analysis notes. If an entire 
concentration-time profile is BLQ, the profile is excluded from the PK analysis. 
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Daylight saving dates will be considered in the calculation of the absolute scheduled and actual times 
and in the duration when this is based on times. Therefore, if any daylight saving change occurs 
during the study development, this will impact the description of the blood sample collections, the 
calculation of the PK parameters, FeNO, AUC(0-12) and any AE duration in case the time is included 
in the calculation of the duration. 
4.3 
Software 
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and validated 
environment.  
 
A complete set of raw data listings will be appended to the final CSR. All tables, figures and listings 
will be presented in portable document format (PDF) documents without any manual editing, i.e., 
they will appear unmodified as programmed by means of the statistical package. 
4.4 
Analysis Sets 
4.4.1 
Enrolled Analysis Set 
The Enrolled analysis set (EN) will include all subjects who signed informed consent. 
4.4.2 
Randomized Analysis Set 
The Randomized set (RS) will consist of all subjects randomized into the study. 
4.4.3 
Safety Analysis Set 
The Safety analysis set (SAF) will include all subjects who received at least 1 dose of AZD0449 or 
placebo and for whom any safety post-dose data are available. 
Unless otherwise stated the SAF will be used for the presentation of all demographic and disposition 
data, as well as all safety analyses. Exposure to IMP will also be presented using the SAF. 
4.4.4 
Pharmacokinetic Analysis Set 
The PK analysis set (PKS) will consist of all subjects who received at least 1 dose of AZD0449 and 
who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of 
the PK data. All protocol deviations that occur during the study will be considered for their 
severity/impact and will be taken into consideration at the blinded data review meeting when subjects 
are assigned to the PK analysis sets. 
Data from subjects for whom the pre-dose concentration is > 5% of Cmax for the first dose of 
AZD0449 on Day 1 of the dosing period may be excluded from the descriptive and inferential 
statistical analyses and corresponding figures. If there are no other reportable PK data for a subject, 
then they may be excluded from the PK analysis set.  
 
Any subjects to be excluded from the PK analysis set, PK data to be excluded from the descriptive 
and/or inferential statistical analyses or PK concentrations to be excluded from the PK non-
compartmental analysis, will be agreed by the PK Scientist with the AZ Clinical Pharmacology 
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Scientist prior to the final PK analysis and handover of parameters to programming and identified in 
the PK flagging file and/or PK handover document. Current AZ guidance for PK data handling will 
be applied.   
All available reportable concentration data and PK parameter data will be listed using the SAF. The 
available concentration data and PK parameter data for any subjects excluded from the PKS will be 
listed only. Concentration data for subjects excluded from the PKS will be presented in the individual 
figures of concentration versus time plots.  
4.4.5 
Full Analysis Set 
The Full analysis set (FAS) will consist of all subjects randomized into the study, receiving at least 1 
dose of IMP or placebo and having at least one 2-hour post-dose FeNO assessment after the first IMP 
intake.  
4.4.6 
Per Protocol Set 
The Per Protocol analysis set (PPS) will consist of all subjects who belong to the FAS and who have 
no major protocol deviations that might impact results of FeNO. 
 
4.5 
Study Subjects 
4.5.1 Disposition of Subjects 
Subject disposition will be summarized for screening failures and randomized subjects separately. 
Screening failures data will be summarized on the EN. The following information will be provided 
with the percentage based on the number of screening failures:  
 
Number of subjects screened 
 
Number and percentage of screening failures including the reason of failing 
Disposition summaries for randomized subjects will be presented by treatment group (each dose level 
of AZD0449, pooled placebo and pooled AZD0449) and include the following information:  
 
Number of subjects randomized 
 
Number and percentage of subjects who received treatment  
 
Number and percentage of subjects not receiving the treatment 
 
Number and percentage of subjects who completed the treatment 
 
Number and percentage of subjects who discontinued the treatment 
 
Number and percentage of subjects who completed the study  
 
Number and percentage of subjects who withdrawn from the study, including the reasons of 
withdrawal 
Percentage will be based on number of subjects randomized.  
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A subject who completed the study is defined as a subject who completed all scheduled visits up to 
the Follow-up visit.  
Subjects’ discontinuations will be listed including the date of study discontinuation, treatment 
duration (in days) as well as reason of discontinuation for each study part.  
Treatment duration (in days) will be calculated as follows: 
Treatment duration (in days) = (date of last dose received - date of first dose received) + 1 
The listing of subject disposition will include subject’s randomization number, date of informed 
consent, date of randomization, the dose/treatment to which subject was randomized and study 
completion status. 
The number and percentage of subjects included in each of the analysis sets will be summarized for 
all subjects based on the RS. 
Subjects excluded from the analysis sets will be listed including the reason for exclusion based on the 
RS. Listing of data excluded from the PKS will be provided including the reason for exclusion based 
on the SAF. 
4.5.2 Protocol Deviations 
Protocol deviations are considered as any deviation from the CSP relating to a subject, and include 
the following: 
 
Inclusion/exclusion criteria deviations 
 
Dosing deviations (e.g., incorrect treatment received, subject was not fasted as per the CSP 
requirements before and after dosing) 
 
Time window deviations for safety and/or PK assessments 
 
Subjects receiving prohibited concomitant medications 
 
Other procedural affecting the study endpoints and study conduct deviations recorded by the 
clinical unit on a CSP deviation log 
The criteria for the assessment and reporting of protocol deviations will be stipulated in a separate 
study specific protocol deviation specification (PDS) document. This will include a Windows 
Allowance Document (WAD), which stipulates tolerance windows for safety, PK and PD 
assessments. Measurements performed within these tolerance windows will not be considered as 
protocol deviations and will not be reported. 
All protocol deviations will be discussed at the blinded data review meeting (BDRM) before database 
hard lock in order to define the analysis sets for the study. The precise reasons for excluding patients 
from the study populations will be fully defined in the BDRM report. 
Important protocol deviations will be summarized by treatment group (each dose level of AZD0449, 
pooled placebo, and pooled AZD0449) and will be listed for all randomized subjects. 
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4.6 
Demographics and Baseline Characteristics 
Demographic and baseline characteristic variables will be listed by subject and treatment group for 
all randomized subjects on each study part. Demographic and subject characteristics will be 
summarized by treatment (each dose level of AZD0449, pooled placebo and pooled AZD0449), for 
all subjects in the SAF, for part each study part separately. The denominator for percentages will be 
the number of subjects in the SAF for each treatment or for all subjects as applicable.  
4.7 
Medical History and Concomitant Illnesses 
A listing of medical history data will be presented by subject and treatment group, for each study part 
and will include description of the disease/procedure, Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC), MedDRA preferred term (PT), start date, and stop date (or 
ongoing if applicable). 
4.8 
Prior and Concomitant Medications 
Medications that started and stopped prior to the first dose of IMP will be considered as prior 
medications. All medications taken at or after the first dosing are considered as concomitant 
(including medications that started before dosing and continued after).  
Prior and concomitant medications will be listed by subject, treatment group and study part and will 
include the following information: reported name, anatomical therapeutic chemical (ATC) preferred 
term (PT), the route of administration, dose, frequency, start and end date/time and duration and 
indication.  
The duration will be calculated as: 
Duration (in hours) = end date/time – start date/time, in case date and time is available 
Duration (in days) = (end date – start date) + 1, in case only date is provided. 
The duration may be presented in hours or days in the listing depending on the applicability to the 
emerging data. For medications with partial or completely missing start date/times and/or end 
date/times, the duration will not be calculated. 
Medications with missing or partial start date/time and/or end date/time such that it is not possible to 
classify as prior or concomitant will be considered as concomitant in the listings. 
4.9 
Treatment Exposure / Compliance 
4.9.1 Treatment Exposure  
Drug administration dates and times and comments will be listed for each subject for each study part 
based on the SAF.  
In addition, volume planned to be administrated, volume actually administrated, percentage of 
planned volume (defined as actual volume divided by planned volume and expressed as percentage), 
as well as interruption of infusion will be listed for Part 1b.  
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Date of inhaler nebulizer/DPI training will be presented in the listing for all study parts except Part 
1b. 
4.9.2 Compliance  
Exposure in days and treatment compliance will be summarized using descriptive statistics by 
treatment (each dose level of AZD0449 and pooled placebo) for all subjects in the SAF for Part 2a/b 
and Part 3a/b. As well as number and percent of subjects in the following categories: 
 
<70% of compliance 
 
≥70% and ≤130% of compliance 
 
>130% of compliance 
 
Treatment compliance is defined as the number of days the subject received treatment divided by the 
number of days the subject should have received treatment (i.e. 12 days) multiplied by 100. 
4.10 Safety Evaluation 
All safety summaries and analyses will be based on the SAF. 
4.10.1 Adverse Events 
Adverse events (AE) with missing start dates/times will be handled as follows: 
 
Adverse events with unknown start times, but with start date known, will be imputed with a 
time of 00:00, unless the start date corresponds to any given dosing date. In this case, the start 
time will be imputed with the time of dosing. If this results in a start date/time after end 
date/time of the AE, then the time will also be imputed with 00:00 
 
Adverse events with completely unknown start dates will be imputed with the date and time of 
dosing, unless the end date is known and before dosing; in that case the start date will be 
imputed as the date of screening and a time of 00:00 
 
Adverse events with partially known start dates/times will be treated as follows: 
o If only the day is missing, then the day will be imputed with the first day of the month, 
unless the month and year in which the AE started is a month and year in which IMP 
was administered, then the day will be imputed with the first day on which IMP was 
administered in that month. If this results in a start date after the end date, then the day 
will be imputed with the first day of the month 
o If only the month is missing and the year is a year in which IMP was administered, 
then the month will be imputed with the first month in which IMP was administered.  
If this results in a start date after the end date of the AE, then the month will be imputed 
with JAN. If the known year part is not a year in which IMP was administered, then 
the month will also be imputed with JAN 
o If both the day and month is missing and the year is a year in which IMP was 
administered, then the day and month will be imputed with the day and month of 
dosing.  If this results in a start date after end date, then the day and month will be 
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imputed with 01JAN. If the year is not a year in which IMP was administered, then 
the day and month will also be imputed with 01JAN 
o If only the year is missing, then the year will be imputed with the year of dosing 
For the purposes of the AE summaries, AEs with unknown or missing intensity will be treated as 
‘severe’ for the tabulations. Adverse events with unknown causality will be treated as with assessment 
‘yes’ for the tabulations. Adverse events with unknown seriousness will be treated as serious for the 
tabulations. There will be no imputation of AE data for the data listings. All data will be listed as 
recorded in the CRF. 
The number and percentage of subjects who experience AEs will be summarized by SOC, PT and 
will be presented by each dose level of AZD0449, pooled placebo, and pooled AZD0449 based on 
the SAF. The AEs that occur before first dosing will be excluded from the summary tables. 
Summaries of AEs will include the following: 
 
Summary of incidence of AEs (overview including number and percentage of subjects with any 
AE, AEs leading to death, serious AEs, AEs leading to discontinuation of IMP and the study). 
 
Incidence of AEs 
 
Incidence of AEs by worst causality 
 
Incidence of AEs by maximum intensity 
Subjects with multiple events in the same category are counted only once in that category. Subjects 
with events in more than one category are counted once in each of those categories.  
In addition, an overview table with number of AEs will be provided, the summary will include the 
following: 
 
Number of all AEs 
 
Number of causally related AEs 
 
All AEs leading to death 
 
All causally related AEs leading to death 
 
All serious AEs 
 
All serious, causally related AEs leading to death 
 
All AEs leading to discontinuation of IMP 
 
All AE leading to withdrawal from study 
Listings with the key information for serious AEs (SAEs), AEs leading to death and AEs leading to 
discontinuation of IMP will be provided for each study part. The following information will be 
included in the listings: verbatim term, PT, time from start date/time, end date/time and last dose, 
causality, action taken, seriousness and the outcome. 
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A listing of all AEs MedDRA coding will be presented by treatment and subject and will include 
verbatim name, lowest level term (LLT), PT and SOC. A separate listing of AEs severity and causality 
will be presented by treatment and subject and will include verbatim term, PT, severity, action taken, 
an AE outcome, causality, seriousness and information weather it led to withdrawal. A separate listing 
for AE onset and resolution will be presented as well. 
 
4.10.2 Clinical Laboratory Evaluation 
For by-visit summaries, the last non-missing assessment (including repeat assessments) recorded at 
each visit will be summarized. The baseline will be the last assessment available before the first 
IMP administration at each part of the study. 
Hematology and clinical chemistry variables will be listed by treatment group, subject and timepoint 
and will include scheduled and repeat/unscheduled measurements. The listings will include the 
following information: test name, date of measurement, reference range, result and flags for any 
measurements that are outside the reference range and change from baseline.  
Summary tabulations will be presented by treatment (each dose level of AZD0449, pooled placebo, 
and pooled AZD0449) based on the SAF, for each study part and include absolute values as well as 
absolute change from baseline. Changes from baseline will be calculated and presented for all post 
baseline timepoints including the Follow-up Visit.  
Shift tables showing changes with respect to the normal ranges between baseline and any post-
baseline at each study part visit will also be presented for select laboratory parameters (chemistry and 
hematology). 
Any laboratory parameters with results from the laboratory given as '<xx' or '>xx' in the database will 
be imputed with the absolute value of the number without the sign (eg, <2.2 will be imputed as 2.2) 
for the descriptive statistics and changes from baseline. 
Data listings for subjects that shows elevations in liver biochemistry (ie, occurrences of AST or ALT 
≥ 3 x ULN together with total bilirubin ≥ 2 x ULN) will be presented to evaluate HL.  
Clinical laboratory data will be reported in the units provided by the clinical laboratory for the SRC 
meeting (if applicable), and in System International units in the CSR. 
Additional listings will be presented for the following: 
 
Urinalysis (macroscopic and microscopic, if applicable) 
 
Pregnancy testing (including FSH) 
 
Serology 
 
Drug of abuse, alcohol and cotinine 
 
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4.10.3 Vital Signs 
The results of the vital signs measurements will be listed by treatment, subject and timepoint 
including the date/time of the assessment, flags for measurements that are outside the reference range 
(L or H, if applicable), changes from baseline and repeat/unscheduled measurements.  
The baseline for vital signs measurements will be the last measurement before the first administration 
of IMP at each part of the study.  
Descriptive statistics will be presented by treatment (each dose level of AZD0449, pooled placebo, 
and pooled AZD0449) and timepoint for both observed values and changes from baseline, for each 
part of the study. 
 
4.10.4 Electrocardiography 
4.10.4.1 Twelve-lead Safety Electrocardiogram 
The twelve-lead ECG overall interpretation (normal/abnormal), specification of abnormality and 
clinical significance will be listed by treatment, subject and timepoint based on the SAF by each part 
of the study. 
The number and percentage of subjects with clinically significant 12-lead ECG findings will be 
summarized by treatment group (each dose level of AZD0449, pooled placebo, and pooled AZD0449) 
by each day for Part 1a/b, Part 2a/b and Part 3a/b based on the SAF. 
4.10.4.2 Electronic Capture of 12-lead Continuous Digital Electrocardiogram 
The following parameters will be derived from the dECG: 
 
QTcF will be calculated as 
where the QT interval is in milliseconds and the RR 
QTcF =
QT
3 RR 
interval is in seconds 
 
Heart rate will be calculated, based on the RR interval as HR= 60/RR interval, where the RR 
interval is in seconds 
The dECG data will be smoothed on an individual basis before performing the derivations above and 
before calculation of any changes from baseline or descriptive statistics. For each subject it will be 
done as follows: the mean value of all the measurements will be taken for target timepoint recordings. 
At least 4 measurements with the time between the first and last record greater than 2.75 minutes for 
a target timepoint should be present or else, the smoothed value at the corresponding target timepoint 
will be set to missing. 
The digital ECG results will be listed by treatment (each dose level of AZD0449 and pooled placebo), 
subject and timepoint and will include all individual and smoothed values of PR, RR, QRS, QT 
interval and the derived values of QTcF and HR. The changes from baseline for smoothed and derived 
parameters will be listed as well. 
Descriptive statistics of smoothed PR, RR, QRS, QT values and derived QTcF and HR values as well 
as change from baseline will be summarized by treatment group (each dose level of AZD0449, pooled 
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placebo, and pooled AZD0449) and timepoint, for each study part. The baseline for the dECG 
measurements will be the smoothed pre-dose assessment on Day 1 for each part of the study. 
Outliers with respect to QTcF will also be tabulated for the following categories 
 
Absolute value > 450 ms and ≤ 480 ms 
 
Absolute value > 480 ms and ≤ 500 ms 
 
Absolute value > 500 ms 
 
Increase from baseline > 30 ms and ≤ 60 ms 
 
Increase from baseline > 60 ms 
The number and percentage of subjects with electrocardiogram outlier values by each dose level of 
AZD0449, pooled AZD0449 and pooled placebo will be provided for each study part. 
4.10.4.3 Real Time ECG (Cardiac Telemetry)  
Overall telemetry evaluation (normal/ abnormal), reason of abnormality as well as flag for a clinical 
significance will be listed by treatment group, subject and timepoint based on SAF. 
 
4.10.5 Physical Examination  
The baseline/screening results of the physical examination will be documented in medical history for 
each subject. 
During the study conduct, any physical examination findings will not be listed or summarized in a 
separate listing or summary table. All physical examinations will be documented, summarized and 
listed as AEs. 
 
4.10.6 Spirometry 
For the spirometry variables the baseline value for each study part is defined as the pre-dose values 
recorded on Day 1 of each study period. If pre-dose value at Day 1 is missing, then the value at Day -1 
of each study period for will be used as baseline value.  
Spirometry values (FEV1, FVC and FEV1% predicted) will be listed by treatment group, subject and 
timepoint including absolute values, absolute and percentage changes from baseline.  
Summary tabulations for absolute values and changes from baseline will be presented by treatment 
(each dose level of AZD0449, or pooled placebo, and pooled AZD0449) and timepoint for each study 
part for the SAF. For the purpose of the summary tabulations, where more than one FEV1 or FVC 
measurements are assessed at a given time-point, the average FEV1or FVC value at that time-point 
will be summarized. 
 
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4.10.7 Pulse Oximetry 
Peripheral capillary oxygen saturation SpO2 (%) will be listed by treatment group, subject and 
timepoint including absolute values, changes from baseline and percentages changes from baseline 
as well as flag for values outside reference range and clinical significance.  
The baseline for the measurements will be the pre-dose assessment on Day 1 (in each study part).  
Summary tabulations for absolute values and changes from baseline will be presented by treatment 
(each dose level of AZD0449, or pooled placebo, and pooled AZD0449) and timepoint for each study 
part based on the SAF. 
4.11 Pharmacokinetics 
4.11.1 Presentation and Statistical Analysis of Pharmacokinetic Data 
PK concentration and parameter data will be presented in accordance to the Standards for reporting 
clinical data in CSR or HLD v3.3, that include applicable descriptive statistics, handling of individual 
concentrations below the LLOQ for listings, descriptive statistics and figures, and precision and 
rounding rules for concentrations and PK parameter data. A listing of PK blood sample collection 
times as well as derived sampling time deviations and all reportable concentrations will be presented 
for AZD0499 and 
 as appropriate for each study part, 
based on the SAF.  
Plasma concentrations will be summarized for the PKS for each time-point by study part, treatment 
(i.e. each dose level of each AZD0449 formulation) and study day, using protocol scheduled times 
and appropriate descriptive statistics.  
The following rules will be followed with regards to the handling of individual concentrations below 
the lower limit of quantification (LLOQ) of the bioanalytical assay: 
Individual concentrations below the LLOQ will be reported as NQ in the listings with the LLOQ 
defined in the footnotes of the relevant TFLs.  
Individual plasma concentrations that are Not Reportable will be reported as NR and those that are 
missing will be reported as NS (No Sample) in the listings.  
Plasma concentrations that are NQ, NR or NS will be handled as follows for the provision of 
descriptive 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. 
 
At a time-point where more than half of the values are NQ, the mean, SD, gmean, gmean - gSD, 
gmean + gSD and gCV% will be set to NC. The maximum value will be reported from the 
individual data, and the minimum and median will be set to NQ. 
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 
If all values are NQ at a time-point, no descriptive statistics will be calculated for that time-
point. The gmean, mean, minimum, median and maximum will be reported as NQ and gmean -
/+gSD, gCV% and SD 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 to be summarized. 
Two observations ≥ LLOQ are presented as a minimum and maximum with the other summary 
statistics as not calculated (NC). 
For summary figures geometric mean concentrations that are NQ will be handled as described for the 
descriptive statistics. If this handling results in a mean value of “NQ”, then for visual presentation 
purposes the value plotted at that time point will be zero for linear plots and set to missing for semi 
logarithmic plots.  The geometric mean concentration-time plots will include gmean-/+gSD error 
bars. Any error bar values that are negative will be truncated at zero on linear concentration-time 
plots and omitted from semi-logarithmic plots. 
 
For individual figures, concentrations that are NQ will be regarded as missing, with the exception of 
NQ values prior to the first quantifiable concentration in that profile which will be set to 0 for linear 
scale plots. 
  
An LLOQ line should be included in all concentration-time-time plots except where there are multiple 
LLOQs for the same plot or for baseline corrected data, 
All reportable PK parameters will be listed for AZD0449 
 
 as appropriate for each study part, based on the SAF. A separate listing will be 
provided for the diagnostic parameters. 
Plasma PK parameters will be summarized for the PK analysis set by study part, dose level of  
AZD0449 and study day using appropriate descriptive statistics.  
PK concentration and parameter data for subjects excluded from the PKS will be included in the 
data listings, but not in the descriptive or inferential statistics or in geometric mean figures or 
combined individual figures.  
Individual plasma concentrations versus actual elapsed time after dose will be plotted on both the 
linear and semi-logarithmic scale for AZD0449 and 
 with the Day 1 and Day 
12 data overlaid on the same plot for study Parts 2 and Part 3. 
Combined individual plasma concentration versus actual elapsed time after dose will be plotted on 
both the linear and semi-logarithmic scale for AZD0449 and 
 Plots will be 
grouped by dose level of AZD0449 for each study part and study day. 
Geometric mean (-/+ gSD) plasma concentration versus nominal sampling time will be plotted 
separately for each analyte, as appropriate, on both the linear and semi-logarithmic scale for each 
study part and study day, with all dose levels overlaid on the same plot for Part 1a Day 1 and Part 1b 
Day 1 and with Day 1 and Day 12 overlaid on the same plot for Part 2a (separately for each dose 
level), Part 2b, Part 3a and Part 3b.  
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Geometric mean plasma trough concentration for the MAD cohorts (Part 2a, Part 2b, Part 3a and Part 
3b) will also be plotted versus study day with all dose levels overlaid on the same plot where 
applicable.  
All plots will be based on the PKS, with the exception of individual plots by subject, which will be 
based on the SAF. 
Precision and Rounding Rules 
PK concentration data will be presented in the listings to the same number of significant digits as the 
data received from the bioanalytical laboratory (usually to 3 significant figures) and against the same 
units as received.  
 
The following descriptive statistics will be presented for the plasma PK concentration data :  
• 
n 
• 
n < LLOQ 
• 
arithmetic mean (mean) 
• 
standard deviation (SD) 
• 
geometric mean (gmean) 
• 
gmean -/+geometric SD (gmean - gSD and gmean + gSD) 
• 
geometric coefficient of variance (%) (gCV%) 
• 
median 
• 
minimum (min)  
• 
maximum (max) 
The gmean is calculated as the exponential of the arithmetic mean calculated from data on a log scale. 
The gCV% is calculated as 
 where sg is the SD of the data on a log scale. 
100 ⋅(𝑒𝑥𝑝(𝑠2
𝑔) ‒ 1)
 
The gmean -/+ gSD are calculated as: 
gmean - gSD: exp(mean(log(PK Conc)) – std(log(PK Conc))),  
gmean + gSD: exp(mean(log(PK Conc)) + std(log(PK Conc))). 
PK concentration descriptive statistics will all be presented to 4 significant figures with the exception 
of the min and max which will be presented to 3 significant figures and n and n <LLOQ which will 
be presented as integers. The minimum values in the PK concentration descriptive statistics will 
present NQ instead of the LLOQ value (where needed). 
The plasma PK parameters, will all be presented to 3 significant figures in the listings with the 
exception of: 
 
Cmax which will be presented to the same number of significant figures as received from the 
bioanalytical laboratory 
 
tmax, tlast, λ lower and λ upper will be presented as received in the data 
 
λz,N will be presented as an integer (no decimals) 
 
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The descriptive statistics presented in the listings for all PK parameters will be n, arithmetic mean, 
SD, gmean, gmean - gSD, gmean + gSD, gCV%, median, min and max with the exception of: 
 The diagnostic PK parameters (AUCextr, Rsq-adj, λz span ratio) which will present n, 
arithmetic mean, SD, median, min, max.  
 tmax, λz lower, λz upper, tlast and λzN which will present n, median, min and max.  
The descriptive statistics for PK parameter data will be presented to 4 significant figures (as an 
exception min and max that will be presented to 3 significant figures) apart from the following: 
 
tmax, tlast, λz lower and λz upper which will be presented as received in the data  
 
number of values (n) and λzN which will be presented as an integer  
 
an extra digit of precision will be added (typically four significant digits in total) for reporting 
of the geometric least-squares (LS) means and bounds of all confidence intervals (CI) within 
inferential analyses 
 
ratios and any corresponding CI values which are obtained during inferential statistical 
analysis shall be reported as a percent with at least four decimal places (e.g., 0.9999). 
 
p values that are smaller than 0.0001 will be presented as <0.00001 
 
For the calculation of summary statistics of PK parameters, all not reportable (NR) and not calculated 
(NC) values will be set to missing. Three reportable values are required as a minimum for a PK 
parameter to be summarised. Two values are presented as a min and max with the other summary 
statistics as NC. If one or more values for a given parameter is zero (or imputed with zero), then no 
geometric statistics will be calculated for that parameter and the results for geometric statistics will 
be set to not applicable (NA). 
 
4.11.2 Inferential Statistical Analysis of Pharmacokinetic Data 
The power model will be used for the analysis of dose-proportionality for AZD0449 in Part 1a 
following a single dose on study Day 1 using the PK parameters Cmax, AUCinf and AUC(0-24 for 
all dose levels.  The power model is denoted as y=α* doseβ, where “y” refers to the PK parameter 
under consideration. 
Dose-proportionality will be assessed via least squares (LS) linear regression of the log-transformed 
PK parameters versus the log-transformed dose, ie, log (PK parameter) = α+βlog(Dose). An estimate 
of the slope and intercept of the regression line and the corresponding 2-sided 95% confidence 
interval (CI) for the slope will be obtained and tabulated for Cmax,,AUCinf and AUC(0-24. 
The power model will be fitted by restricted maximum likelihood (REML) using SAS Proc Mixed. 
Both the intercept and slope will be fitted as fixed effects. The following SAS code will be used: 
PROC MIXED DATA = <data>;  
   MODEL <log_var> = <log_Dose> / CL ALPHA=0.05 SOLUTION DDFM=KR;  
RUN; 
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Separate scatter plots for each of the log-transformed AZD0449 PK parameters versus 
log-transformed dose (Cmax, AUCinf and AUC(0-24)) will be presented with the regression line 
from the analysis overlaid on the same plot. 
In addition, separate figures for each of the dose normalized AZD0449 parameters (Cmax, AUCinf 
and AUC(0-24) for Day 1 and Cmax and AUC(0-24) for Day 12) versus dose, showing individual 
and geometric mean values for each dose level, will be presented separately for Part 1a Day 1, Part 
1b Day 1, Part 2a Day 1 and Part 2a Day 12, to visually demonstrate dose-proportionality. 
4.12 Pharmacodynamics 
4.12.1 Fractional Exhaled Nitric Oxide Analysis (FeNO) – Part 2a and Part 3a 
The change from baseline in 2 hours post-dose log FeNO level to Day 12, will be analyzed based on 
MMRM using all post-baseline 2 hours post-dose FeNO assessments. Baseline will be defined as 
mean FeNO value at Day -1. The model will include the fixed, categorical effects of treatment, Day, 
and treatment-by-day interaction, as well as the continuous, fixed covariate of baseline FeNO value. 
Patient will be included as a random effect. This analysis will be based on the FAS. Analyses will be 
performed on the log-transformed FeNO data to normalize the skewed distribution of this endpoint. 
Change from baseline will be calculated based on the log-transformed data. 
The within-patient correlation will be modeled using the unstructured covariance matrix. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. The 
analysis will be performed using only the observed cases (OC) without imputation of missing values. 
If the model does not converge, then the compound symmetry covariance structure will be used. 
Restricted maximum likelihood method will be used for estimation. 
Treatment effect and treatment differences will be estimated using contrasts of the LS means on the 
correspondent treatment-by-day interaction, along with their standard error (SE) and 2-sided 90% CI, 
and the p-value corresponding to the treatment group difference.  
The estimated treatment differences and the 90% CIs on the log scale will be back-transformed to 
obtain the geometric mean ratios for two groups compared. The geometric LS means and its 90% 
CIs, geometric LS means ratio between the treatments and its 90% CIs will be tabulated. 
The same model will be used to evaluate treatment effect between the groups in Part 2a and Part 3a. 
The following treatment groups will be compared at Part 2a: 
 
AZD0449 
 (Part 2a Cohort 1) and 
 (Part 2a Cohort 2)  
 
pooled placebo (Part 2a Cohort 1 to 2) 
The following treatment groups will be compared at Part 3a: 
 
DPI AZD0449 
  
 
placebo  
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suggested by previous studies, the required sample size for a 25% absolute reduction in the ratio of 
geometric means (a 0.288 reduction of the mean log FeNO levels) is 18 evaluable patients per arm 
using a one-sided test at 5% significance level.  
The current design presents an opportunity to perform a sample size calculation at an IA taking place 
when approximately half the data from Part 3a is available. If the actual estimate of baseline FeNO 
SD is higher than expected, reaching SD=0.55, the sample size of the PoM cohort in Part 3a will be 
potentially increased up to n=26 per arm. 
Should the variation be even higher requiring adjustments beyond this, an amendment will be 
submitted.  
4.16 Interim Analysis and IND submission  
An unblinded IA will be performed when approximately 50% of the patients in have completed Part 
3a. The collected data will be used to inform various decisions or actions such as assessing the 
efficacy of AZD0449 in an unblinded manner and to perform an unblinded sample size re-estimation.  
For this IA, outputs for safety and FeNO data from all MAD cohorts up to that time points will be 
provided.   Considering the SD observed for the FeNO endpoint, a decision will be made on either 
additional subjects than those described in section 4.14 should be included or not. 
In order to have the required for the Investigational New Drug (IND) submission on December 2020, 
prior to the achievement of the data-cut for the IA, outputs for safety and FeNO data will be delivered 
for study Part 1a/b, Part 2a/b and Part 3b. Hence, at the time of the IA only outputs for study Part 3a 
will be delivered. 
The outputs that will be delivered between IND submission and IA will be the followings according 
to TFLs shells draft 2.0: 
- 
Table 14.2.5.1 and Table 14.2.5.2: Summary of FeNO (Full analysis set) 
- 
Table 14.2.6.1 and Table 14.2.6.2: Summary of FeNO (AUC(0-12)) (Full analysis set) 
- 
Table 14.2.7.1 and Table 14.2.7.2: FeNO, change from baseline in 2 hours post-dose, linear 
mixed model with observed cases (Full analysis set) 
- 
Table 14.2.8.1 and Table 14.2.8.2: FeNO (AUC(0-12)), change from baseline in 2 hours post-
dose, linear mixed model with observed cases (Full analysis set) 
- 
Table 14.2.9.1 and Table 14.2.9.2: FeNO, change from baseline in 2 hours post-dose, linear 
mixed model with observed cases (LS means ratio)  (Full analysis set) 
- 
Figure 14.2.5.1 Geometric mean (90% CI) of change from baseline of 2h post-dose FeNO 
values versus study day by treatment group (Full analysis set)  
- 
Table 14.3.1.1.1 through Table 14.3.1.1.6: Summary of number (%) of subjects who had at 
least one adverse event in any category (Safety analysis set) 
- 
Table 14.3.1.2.1 through Table 14.3.1.2.6: Adverse events in any category – episode level 
(Safety analysis set) 
- 
Table 14.3.1.3.1 through Table 14.3.1.3.6: Number (%) of subjects who had at least one 
adverse event, by preferred term, arranged by system organ class (Safety analysis set) 
- 
Table 14.3.1.4.1 through Table 14.3.1.4.6: Number (%) of subjects who had at least one 
adverse event by preferred term, presented by investigator's causality assessment (Safety 
analysis set) 
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- 
Table 14.3.5.1.1 through Table 14.3.5.1.6: Descriptive statistics for Haematology laboratory 
results and change from baseline results (Safety analysis set)     
- 
Table 14.3.5.2.1 through Table 14.3.5.2.6: Descriptive statistics for Clinical Chemistry 
laboratory results and change from baseline results (Safety analysis set) 
- 
Table 14.3.6.1.1 through Table 14.3.6.1.6: Descriptive statistics for vital signs and change 
from baseline results (Safety analysis set) 
- 
Table 14.3.7.1.1 through Table 14.3.7.1.6: Descriptive statistics for electrocardiogram results 
and change from baseline results (Safety analysis set): digital ECGs 
- 
Table 14.3.8.1.1 through Table 14.3.8.1.6: Summary of spirometry and absolute and 
percentage change from baseline (Safety analysis set)       
 
 
5 
REFERENCES 
Not applicable. 
 
 
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6 
APPENDICES 
6.1 
Schedule of Assessments 
 
 
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Table 6.1 
Schedule of Assessments Part 1a (SAD) 
Schedule of Assessments Part 1a (SAD) 
Screening 
Treatment Period 
Follow-up 
Visit 
Comments 
Assessments 
Days -28 
to--2 
Day -1 
Days 1 
to 3 a 
Day 4 a 
(6±1 days 
post-dose) 
 
Informed consent 
X 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Drug, alcohol and cotinine screen  
X 
X 
 
 
 
 
Serology 
X 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
Follicle-stimulating hormone testing 
X 
 
 
 
 
Post-menopausal females only (see CSP Section 5.2.3.2 for 
definition) 
Study Residency: 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
Discharge 
 
 
 
X 
 
At least 60 h post-dose, may be extended up to 96 h post-dose 
depending on emerging data 
Non-residential visit 
X 
 
 
 
X 
 
Investigational Medicinal Product 
Administration: 
 
 
 
 
 
 
Inhaler Nebulizer Training 
 
X 
 
 
 
 
Randomization 
 
 
Day 1 
 
 
 
AZD0449/Placebo administration via 
nebulizer 
 
 
Day 1 
(0 h) b 
 
 
 
Safety and Tolerability: 
 
 
 
 
 
 
Adverse event questioning 
Only SAEs 
Only SAEs 
X 
X 
X 
 
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Schedule of Assessments Part 1a (SAD) 
Screening 
Treatment Period 
Follow-up 
Visit 
Comments 
Assessments 
Days -28 
to--2 
Day -1 
Days 1 
to 3 a 
Day 4 a 
(6±1 days 
post-dose) 
 
Spirometry 
X 
X 
X 
X 
X 
Day 1: Pre-dose and 30 min, 1.5 h, 3 h, 6 h and 12 h post-dose 
Day 2: 24 h post-dose 
Day 4: 72 h post-dose 
Pulse oximetry 
X 
X 
X 
X 
X 
Cohorts 1-4: 
Day 1: Pre-dose and 30 min, 1.5 h, 3 h, 6 h and 12 h post-dose 
Day 2: 24 h post-dose  
Day 4: 72 h post-dose 
Cohorts 5-6: 
Day 1: Pre-dose, 1 h, 1.5 h, 3 h, 6 h and 12 h post-dose 
Day 2: 24 h post-dose  
Day 4: 72 h post-dose 
Blood pressure, pulse and respiratory 
rate (supine) and body temperature 
X 
X 
X 
X 
X 
Cohorts 1-4: 
Day 1: Pre-dose and 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h and 
12 h post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose  
Day 4: 72 h post-dose 
Cohorts 5-6: 
Day 1: Pre-dose and 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h and 12 h 
post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose  
Day 4: 72 h post-dose 
12-lead dECG 
 
 
X 
 
 
See Table 3.2-8 from the CSP 
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Schedule of Assessments Part 1a (SAD) 
Screening 
Treatment Period 
Follow-up 
Visit 
Comments 
Assessments 
Days -28 
to--2 
Day -1 
Days 1 
to 3 a 
Day 4 a 
(6±1 days 
post-dose) 
 
12-lead safety ECG 
X 
X 
X 
 
X 
12-lead safety ECG will be collected at the start of each dECG 
extraction window when time-points coincide, see Table 3.2-8 
from the CSP 
Telemetry 
 
X 
X 
 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose (Day 2) 
Height, weight and BMI 
X 
X 
 
 
 
 
Clinical laboratory evaluations 
X 
X 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose  
Day 4: 72 h post-dose 
All samples will be collected after a 10 h fasting period. 
If the assessment period is extended, Day 4 assessments will be 
performed on the day the healthy volunteer are discharged 
Pregnancy testing 
X (serum) 
X (urine) 
 
 
X (serum) 
Females only 
Physical examination 
X 
X (brief) 
X (brief) 
X (brief) 
X 
Day 3: 48 h post-dose 
Day 4: 72 h post-dose 
Pharmacokinetics: 
 
 
 
 
 
 
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Schedule of Assessments Part 1a (SAD) 
Screening 
Treatment Period 
Follow-up 
Visit 
Comments 
Assessments 
Days -28 
to--2 
Day -1 
Days 1 
to 3 a 
Day 4 a 
(6±1 days 
post-dose) 
 
Pharmacokinetic blood sampling 
 
 
X d)  
X d)  
X e  
Cohort 1: 
Day 1: Pre-dose and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h and 12 h 
after start of dosing 
Day 2: 24 h, 30 h and 36 h post-dose 
Day 3: 48 h and 60 h post-dose. 
 
Cohorts 2-3: 
Day 1: Pre-dose, as soon as possible after end of inhalation, 
15 min after end of inhalation, and 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 
8 h, 10 h and 12 h post-dose 
Day 2: 24 h, 30 h and 36 h post-dose 
 
Cohorts 4: 
Day 1: Pre-dose, as soon as possible after end of inhalation, 
15 min after end of inhalation, and 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 
8 h and 12 h post-dose 
Day 2: 24 h, 30 h and 36 h post-dose 
Day 3: 48 h 
 
Cohorts 5: 
Day 1: Pre-dose, as soon as possible after end of inhalation, 
15 min after end of inhalation, and 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 
8 h and 12 h post-dose 
Day 2: 24 h, 30 h and 36 h post-dose 
Day 3: 48 h post-dose 
Day 4: 72 h post-dose 
 
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b) The time-points for all procedures are relative to the start of the inhalation unless stated otherwise. 
c) Only applicable to cohort 5 onwards. 
d) Time-points may be updated based on emerging data. 
e) For cohort 6 as indicated in the “Comments” column. 
 
 
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Table 6.2 
Schedule of Assessments Part 1b (First IV Cohort) 
Schedule of Assessments Part 1b (First IV Cohort) 
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Screening a 
Treatment Period 
Follow-up 
Visit 
Comments 
Assessments 
Days -28 
to -2 
Day -1 
Days 1 to 
2 b 
Day 3 b 
(6±1 days 
post-dose) 
 
Informed consent 
X 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Drug, alcohol and cotinine screen  
X 
X 
 
 
 
 
Serology 
X 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
Follicle-stimulating hormone 
testing 
X 
 
 
 
 
Post-menopausal females only (see CSP Section 5.2.3.2 for definition) 
Study Residency: 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
Discharge 
 
 
 
X 
 
At least 60 h post-dose, may be extended up to 96 h post-dose 
depending on emerging data 
Non-residential visit 
X 
 
 
 
X 
 
Investigational Medicinal 
Product Administration: 
 
 
 
 
 
 
AZD0449 IV administration c 
 
 
Day 1 
(0 hours) 
 
 
60 min infusion duration 
Safety and Tolerability: 
 
 
 
 
 
 
Adverse event questioning 
Only SAEs 
Only SAEs 
X 
X 
X 
 
Spirometry 
X 
X 
X 
X 
X 
Day 1: Pre-dose and 1 h, 1.5 h, 3 h, 6 h and 12 h post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
Pulse Oximetry 
X 
X 
X 
X 
X 
Day 1: Pre-dose and 30 min, 1 h, 1.5 h, 3 h, 6 h and 12 h post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
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Blood pressure, pulse and 
respiratory rate (supine) and body 
temperature 
X 
X 
X 
X 
X 
Day 1: Pre-dose and 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h 
post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
12-lead dECG 
 
 
X 
X 
 
See Table 3.2-9 from the CSP 
12-lead safety ECG 
X 
X 
X 
X 
X 
12-lead safety ECG will be collected at the start of each dECG 
extraction window when time-points coincide, see Table 3.2-9 from the 
CSP 
Telemetry 
 
X 
X 
 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose (Day 2) 
Height, weight and BMI 
X 
X 
 
 
 
 
Clinical laboratory evaluations 
X 
X 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
All samples will be collected after a 10 h fasting period. 
If the assessment period is extended, Day 3 assessments will be 
performed on the day healthy volunteers are discharged 
Pregnancy testing 
X (serum) 
X (urine) 
 
 
X (serum) 
Females only 
Physical examination 
X 
X (brief) 
 
X 
(brief) 
X 
Day 3: 48 h post-dose 
Pharmacokinetics: 
 
 
 
 
 
 
Pharmacokinetic blood sampling 
 
 
X 
X 
 
Day 1: Pre-dose and at 15, 30, 45 min after infusion start, directly after 
the end of infusion (ca. 60 min), 5, 10 and, 15 min after end of 
infusion, and 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 14 h, and 16 h 
after infusion start 
Day 2: 24 h, 36 h and 48 h after infusion start 
Optional pharmacogenetic 
sample 
 
 
X 
 
 
Day 1: Only if healthy volunteer agrees by signing a separate informed 
consent form and has not participated in Part 1a of the study 
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Table 6.3 
Schedule of Assessments Part 1b (Second IV Cohort) 
Schedule of Assessments Part 1b (Second IV Cohort) 
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Screening a 
Treatment Period 
Follow-up 
Visit 
Comments 
Assessments 
Day -28 
to Day -4 or -3 
Day -3 to 
-2 
Day -1 
Days 1 to 
2 b 
Day 3 b 
(6±1 days 
post-dose) 
 
Informed consent 
X 
 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Drug, alcohol and cotinine 
screen  
X 
X 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
COVID-19 serology testing d) 
X 
 
 
 
 
X 
 
COVID-19 PCR testing d) 
X 
X 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
 
Follicle-stimulating hormone 
testing 
X 
 
 
 
 
 
Post-menopausal females only (see CSP Section 5.2.3.2 for 
definition) 
Study Residency: 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
Discharge 
 
 
 
 
X 
 
At least 60 h post-dose, may be extended up to 96 h 
post-dose depending on emerging data 
Non-residential visit 
X 
 
 
 
 
X 
 
Investigational Medicinal 
Product Administration: 
 
 
 
 
 
 
 
AZD0449 IV administration c 
 
 
 
Day 1 
(0 hours) 
 
 
48 min infusion duration 
Safety and Tolerability: 
 
 
 
 
 
 
 
Adverse event questioning 
Only SAEs 
Only 
SAEs 
Only SAEs 
X 
X 
X 
 
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Spirometry 
X 
 
X 
X 
X 
 
Day 1: Pre-dose and 1 h, 1.5 h, 3 h, 6 h and 12 h post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
Pulse Oximetry 
X 
 
X 
X 
X 
X 
Day 1: Pre-dose and 30 min, 1 h, 1.5 h, 3 h, 6 h and 12 h 
post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
Blood pressure, pulse and 
respiratory rate (supine) and 
body temperature 
X 
 
X 
X 
X 
X 
Day 1: Pre-dose and 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 
8 h, 12 h post-dose 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
Body temperature 
 
X 
 
 
 
 
 
12-lead dECG 
 
 
 
X 
X 
 
See Table 3.2-9 from the CSP 
12-lead safety ECG 
X 
 
X 
X 
X 
X 
12-lead safety ECG will be collected at the start of each 
dECG extraction window when time-points coincide, 
see Table 3.2-9 from the CSP 
Telemetry 
 
 
X 
X 
 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose (Day 2) 
Height, weight and BMI 
X 
 
X 
 
 
X 
Height to be measured at screening only 
Clinical laboratory evaluations 
X 
X 
 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: 48 h post-dose 
All samples will be collected after a 10 h fasting period. 
If the assessment period is extended, Day 3 assessments will 
be performed on the day volunteers are discharged 
Pregnancy testing 
X (serum) 
X (urine) 
 
 
 
X (serum) 
Females only 
Physical examination 
X 
 
X (brief) 
 
X 
(brief) 
X 
Day 3: 48 h post-dose 
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Table 6.4 
Schedule of Assessments Part 2a in patient with mild asthma 
Schedule of Assessments Part 2a in patients with mild asthma 
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Screening 
Treatment Period 
Follow-up 
Comments 
Assessments 
Day -28 
to 
Day -3 
Day -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (start of 
once daily 
dosing) a to 
Day 12 (last 
dosing day) a  
Day 13 
to 15 
Day 22±1 
(10±1 days 
post-last 
dose) 
 
Informed consent 
X 
 
 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Drug, alcohol and cotinine 
screen  
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
 
 
Follicle-stimulating hormone 
testing  
X 
 
 
 
 
 
 
Post-menopausal females only (see CSP 
Section 5.2.3.2 for definition) 
Study Residency: 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
Discharge on Day 14 
 
Non-residential visit 
X 
 
 
 
 
X 
X 
Only Day 15 is non-residential 
Investigational Medicinal 
Product Administration: 
 
 
 
 
 
 
 
 
Inhaler Nebulizer Training 
 
 
X 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
Day 1 
AZD0449/Placebo 
administration via Nebulizer a 
 
 
 
X b 
X b 
 
 
First dose on Day 1, second dose on Day 3 
(48 hours post-dose), then once daily dosing 
from Day 4 to Day 12 
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Safety and Tolerability: 
 
 
 
 
 
 
 
 
Adverse event questioning 
Only 
SAEs 
Only 
SAEs 
Only 
SAEs 
X 
X 
X 
X 
 
Spirometry  
X 
 
X c) 
X c) 
X c) 
X c) 
X c) 
Day -1: pre-dose, 6 h, 12 h (corresponding clock 
time) 
Day 1, Day 8 and Day 12: 
Pre-dose, 30 min, 1.5 h, 3 h, 6 h and 12 h 
post-dose 
Day 2: 24 h post-dose 
Day 3 to 7 and Day 9 to 11: pre-dose and 30 min 
post-dose 
Day 13: 24 h post-dose, Day 14: 47 h post-dose, 
Day 15: 71 h post-dose, and Day 22: 239 h 
post-dose 
Pulse oximetry 
X 
 
X 
X 
X 
X 
X 
Day -1: pre-dose, 3 h and 12 h post-dose 
(corresponding clock time) 
Day 1 and Day 3 to Day 12: Pre-dose, 1 h, 1.5 h, 
3 h, 6 h, 12 h -post-dose 
Day 2: 24 h post-dose 
Day 13: 24 h post-dose 
Day 14: 47 h post-dose, Day 15: 71 h post-dose, 
and Day 22: 239 h post-dose 
Blood pressure, pulse and 
respiratory rate (supine) and 
body temperature 
X 
 
X 
X 
X 
X 
X 
Day 1 (first dose) and Day 12 (last dose):Pre-
dose and 1 h, 2 h and 6 h post-dose 
Day 2: 24 h post-dose 
Days 3 to 11: pre-dose 
Day 13: 24 h post-dose 
12-lead dECG 
 
 
 
X 
X 
X 
 
See Table 3.2-10 from the CSP 
12-lead safety ECG 
X 
 
X 
X 
X 
X 
X 
12-lead safety ECG will be collected at the start 
of each dECG extraction window when 
time-points coincide see Table 3.2-10 from the 
CSP 
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Telemetry 
 
 
X 
X 
X 
 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose (Day 2) 
Pre-dose (Day 12) to 24 h post-dose (Day 13) 
Height, weight and BMI 
X 
 
X 
 
 
 
 
 
Clinical laboratory evaluations 
X 
X 
 
X 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: pre-dose 
Day 13: 24 h post-dose 
All samples will be collected after a 10 h fasting 
period 
Pregnancy testing 
X 
(serum) 
X 
(urine) 
 
 
 
 
X (serum) 
Females only 
Physical examination 
X 
 
X 
X 
(brief) 
X 
(brief) 
X 
(brief) 
X 
Day 1: pre-dose 
Day 2: 24 h after the first dose 
Day 6: pre-dose 
Day 10: pre-dose 
Day 13: 24 h post-dose 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling  
 
 
 
X c) 
X c)  
X c) 
X c) 
Day 1 and 12: pre-dose, as soon as possible after 
end of inhalation, 15 min after end of inhalation, 
and 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h d), and 
12 h post-dose 
Day 2: 24 h, 30 h, and 36 h post-dose. 
Day 3 – Day 11: pre-dose 
Day 13: 24 h, 30 h, and 36 h post-last dose 
Day 14: 48 h post-last dose 
Day 15: 72 h post-last dose  
Day 22: 240 h post-last dose 
 
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Table 6.5 
Schedule of Assessments Part 2b in healthy volunteers 
Table 3.2-5 
Schedule of Assessments Part 2b in healthy volunteers 
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Screening 
Treatment Period 
Follow-up 
Comments 
Assessments 
Day -28 to 
Day -4 or -3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (start of once 
daily dosing) a to 
Day 12 (last dosing 
day) a)  
Day 13 
to 16 
Day 17 to 
27 
 
Informed consent 
X 
 
 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Drug, alcohol and cotinine 
screen  
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
COVID-19 serology testing d) 
X 
 
 
 
 
 
X 
 
COVID-19 PCR testing d) 
X 
X 
 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
 
 
Follicle-stimulating hormone 
testing  
X 
 
 
 
 
 
 
Post-menopausal females only (see CSP 
Section 5.2.3.2 for definition) 
Study Residency: 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
Discharge on Day 27. 
Non-residential visit 
X 
 
 
 
 
 
X 
 
Investigational Medicinal 
Product Administration: 
 
 
 
 
 
 
 
 
Inhaler Nebulizer Training 
 
 
X 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
Day 1 
AZD0449/Placebo 
administration via Nebulizer a) 
 
 
 
X b) 
X b) 
 
 
First dose on Day 1, second dose on Day 3 
(48 hours post-dose), then once daily dosing 
from Day 4 to Day 12 
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Safety and Tolerability: 
 
 
 
 
 
 
 
 
Adverse event questioning 
Only SAEs 
Only 
SAEs 
Only 
SAEs 
X 
X 
X 
X 
 
Spirometry  
X 
 
X c) 
X c) 
X c) 
X c) 
X c) 
Day -1: pre-dose, 6 h, 12 h 
(corresponding clock time) 
Day 1, Day 8 and Day 12: 
Pre-dose 30 min, 1.5 h, 3 h, 6 h and 
12 h post-dose 
Day 2: 24 h post-dose 
Day 3 to 7 and Day 9 to 11: pre-dose 
and 30 min post-dose 
Day 13: 24 h post-dose, Day 14: 47 h 
post-dose, Day 15: 71 h post-dose, 
Day 16: 95 h post-dose, Day 17: 
120 h post-dose, Day 20: 192 h post-dose, 
Day 23: 264 h post-dose, 
Day 26: 336 h post-dose, and Day 27: 
360 h post-dose 
Pulse oximetry 
X 
 
X 
X 
X 
X 
X 
Day 1 and Day 3 to Day 12: Pre-dose, 
1 h, 1.5 h, 3 h, 6 h, 12 h -post-dose 
Day 2: 24 h post-dose 
Day 13: 24 h post-dose, Day 14: 48 h 
post-dose, Day 15: 72 h post-dose, 
Day 16: 96 h post-dose, Day 17: 
120 h post-dose, Day 18: 144 h post-dose, 
Day 19: 168 h post-dose, 
Day 20: 192 h post-dose, Day 21: 
216 h post-dose, Day 22: 240 h post-dose, 
Day 23: 264 h post-dose, 
Day 24: 288 h post-dose, Day 25: 
312 h post-dose, Day 26: 336 h post-dose, 
and Day 27: 360 h post-dose 
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Blood pressure, pulse and 
respiratory rate (supine) and 
body temperature 
X 
 
X 
X 
X 
X 
X 
Day 1 (first dose) and Day 12 (last 
dose): Pre-dose and 1 h, 2 h and 6 h 
post-dose 
Day 2: 24 h post-dose 
Days 3 to 11: Pre-dose 
Day 13: 24 h post-dose, Day 14: 48 h 
post-dose, Day 15: 72 h post-dose, 
Day 16: 96 h post-dose, Day 17: 
120 h post-dose, Day 18: 144 h post-dose, 
Day 19: 168 h post-dose, 
Day 20: 192 h post-dose, Day 21: 
216 h post-dose, Day 22: 240 h post-dose, 
Day 23: 264 h post-dose, 
Day 24: 288 h post-dose, Day 25: 
312 h post-dose, Day 26: 336 h post-dose, 
and Day 27: 360 h post-dose 
Body temperature 
 
X 
 
 
 
X 
 
 
12-lead dECG 
 
 
 
X 
X 
X 
 
See Table 3.2-10 from the CSP 
12-lead safety ECG 
X 
 
X 
X 
X 
X 
X 
12-lead safety ECG will be collected at the 
start of each dECG extraction window when 
time-points coincide see Table 3.2-10 from 
the CSP 
Telemetry 
 
 
X 
X 
X 
X 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose (Day 2) 
Pre-dose (Day 12) to 24 h post-dose 
(Day 13) 
Height, weight and BMI 
X 
 
X 
 
 
 
X 
Height to be measured at screening only 
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Clinical laboratory evaluations 
X 
X 
 
X 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: pre-dose 
Day 13: 24 h post-dose 
Day 27: 360 h post-last dose 
All samples will be collected after a 10 h 
fasting period 
Pregnancy testing 
X 
(serum) 
X 
(urine) 
 
 
 
 
X 
(serum) 
Day 27 
Females only 
Physical examination 
X 
 
X 
X 
(brief) 
X 
(brief) 
X 
(brief) 
X 
Day 1: pre-dose 
Day 2: 24 h after the first dose 
Day 6: pre-dose 
Day 10: pre-dose 
Day 14: 48 h post-dose, Day 17: 
120 h post-dose, Day 20: 192 h post-dose, 
Day 23: 264 h post-dose, 
Day 26: 336 h post-dose, and Day 27: 
360 h post-dose (full examination) 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Informed consent 
X 
 
 
 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
 
 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Drug, alcohol and cotinine 
screen  
X 
X 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
COVID-19 serology 
testing d) 
X 
 
 
 
 
 
 
X 
Day 27 
COVID-19 PCR testing d) 
X 
X 
 
 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
 
 
 
Follicle-stimulating 
hormone testing 
X 
 
 
 
 
 
 
 
Post-menopausal females only (see CSP 
Section 5.2.3.2 for definition) 
Study Residency: 
 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
X 
 
Discharge on Day 27 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Non-residential visit 
X 
 
 
 
 
 
 
X 
Day 17 to Day 27 (If permitted by local 
relevant regulatory authorities and 
considered feasible and safe) 
Investigational Medicinal 
Product  
 
 
 
 
 
 
 
 
 
DPI Training 
 
 
 
X 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
Day 1 
AZD0449/Placebo 
administration via DPI a) 
 
 
 
 
X b) 
X b) 
 
 
First dose on Day 1, second dose on Day 
3 (48 hours post-dose), then once daily 
dosing from Day 4 to Day 12 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Safety and Tolerability: 
 
 
 
 
 
 
 
 
 
Adverse event questioning 
Only SAEs 
Only 
SAEs 
Only 
SAEs 
Only 
SAEs 
X 
X 
X 
X 
 
Spirometry 
X 
 
 
X c) 
X c) 
X c) 
X c) 
X c) 
Day -1: pre-dose, 6 h, 12 h 
(corresponding clock time) 
Day 1, Day 8 and Day 12: 
Pre-dose, 30 min, 1.5 h, 3 h, 6 h and 12 h 
post-dose 
Day 2: 24 h post-dose 
Day 3 to 7 and Day 9 to 11: pre-dose and 
30 min post-dose 
Day 13: 24 h post-dose, Day 14: 47 h 
post-dose, Day 15: 71 h post-dose, Day 
16: 95 h post-dose, Day 17: 120 h post-
dose, 
Day 20: 192 h post-dose, Day 23: 
264 h post-dose, Day 26: 336 h post-
dose, 
and Day 27: 360 h post-dose 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Pulse oximetry 
X 
 
 
X 
X 
X 
X 
X 
Day -1: pre-dose, 3 h and 12 h post-dose 
(corresponding clock time) 
Day 1 and Day 3 to Day 12: Pre-dose, 1 
h, 1.5 h, 3 h, 6 h, 12 h -post-dose 
Day 2: 24 h post-dose 
Days 13: 24 h post-dose, Day 14: 48 h 
post-dose, Day 15: 72 h post-dose, 
Day 16: 96 h post-dose, Day 17: 120 h 
post-dose, Day 18: 144 h post-dose, 
Day 19: 168 h post-dose, Day 20: 192 h 
post-dose, Day 21: 216 h post-dose, 
Day 22: 240 h post-dose, Day 23: 264 h 
post-dose, Day 24: 288 h post-dose, 
Day 25: 312 h post-dose, Day 26: 336 h 
post-dose, and Day 27: 360 h post-dose 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Blood pressure, pulse and 
respiratory rate (supine)and 
body temperature 
X 
 
 
X 
X 
X 
X 
X 
Day 1 (first dose) and Day 12 (last dose): 
Pre-dose and 1 h, 2 h and 6 h post-dose 
Day 2: 24 h post-dose 
Days 3 to 11: Pre-dose 
Day 13: 24 h post-dose, Day 14: 48 h 
post-dose, Day 15: 72 h post-dose, 
Day 16: 96 h post-dose, Day 17: 120 h 
post-dose, Day 18: 144 h post-dose, 
Day 19: 168 h post-dose, Day 20: 192 h 
post-dose, Day 21: 216 h post-dose, 
Day 22: 240 h post-dose, Day 23: 264 h 
post-dose, Day 24: 288 h post-dose, 
Day 25: 312 h post-dose, Day 26: 336 h 
post-dose, and Day 27: 360 h post-dose 
Body temperature 
 
X 
X 
 
 
 
X 
 
 
12-lead dECG 
 
 
 
 
X 
X 
X 
 
 See Table 3.2-10 from the CSP 
12-lead safety ECG 
X 
 
 
X 
X 
X 
X 
X 
12-lead safety ECG will be collected at 
the start of each dECG extraction 
window when time-points coincide, see 
Table 3.2-10 from the CSP 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Telemetry 
 
 
 
X 
X 
X 
X 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose 
(Day 2) 
Pre-dose (Day 12) to 24 h post-dose 
(Day 13) 
Height, weight and BMI 
X 
 
 
X 
 
 
 
X 
Day 27 
Height to be measured at screening only 
Clinical laboratory 
evaluations 
X 
X 
 
 
X 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: pre-dose 
Day 13: 24 h post-dose 
Day 27: 360 h post-last dose 
All samples will be collected after a 10 h 
fasting period 
Pregnancy testing 
X 
(serum) 
X 
(urine) 
 
 
 
 
 
X 
(serum) 
Day 27 
Females only 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Physical examination 
X 
 
 
X 
X (brief) 
X (brief) 
X 
(brief) 
X 
Day 1: pre-dose 
Day 2: 24 h after the first dose 
Day 6: pre-dose 
Day 10: pre-dose 
Day 14: 48 h post-dose, Day 17: 120 h 
post-dose, Day 20: 192 h post-dose, 
Day 23: 264 h post-dose, Day 26: 336 h 
post-dose, and Day 27: 360 h post-dose 
(full examination) 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Pharmacokinetic blood 
sampling 
 
 
 
 
X c) 
X c) 
X c) 
X c) 
Days 1 and 12: pre-dose, as soon as 
possible after end of inhalation, 15 min 
after end of inhalation, and 1 h, 1.5 h, 2 
h, 
3 h, 4 h, 6 h, 8 h, 10 h, and 12 h post-
dose 
Day 2: 24 h, 30 h, and 36 h post-dose. 
Day 3 to Day 11: pre-dose 
Day 13: 24 h, 30 h, and 36 h post-last 
dose 
Day 14: 48 h, 54 h, and 60 h post-last 
dose 
Day 15: 72 h, 78 h, and 84 h post-last 
dose 
Day 16: 96 h, 102 h, and 108 h post-last 
dose 
Day 17: 120 h post-last dose, Day 20: 
192 h post-last dose, Day 23: 264 h post-
last 
dose, Day 26: 336 h post-last dose, 
and Day 27: 360 h post-last dose 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Pharmacodynamics: 
 
 
 
 
 
 
 
 
 
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Table 6.7 
Schedule of Assessments Part 3a in patients with mild asthma 
Schedule of Assessments Part 3a in patients with mild asthma 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4  
Day -3  
Day -
2 
Day -1 
Day 1 
and 
Day 2 
Day 3 
(second 
dosing day) 
to Day 12 
(last dosing 
day) 
Day 13 
to 216 
Day 17 to 
Day 27 
Comments 
Fractional exhaled nitric 
oxide 
X 
 
 
X 
X 
X 
X 
X 
Single assessment at Screening Visit 
Day -1: corresponding clock times to 
pre-dose, 
30 min and 2 h, 6 h, and 12 h 
post-dose 
Days 1, 2, 3, 4, 6, 8, 10, and 12: Pre-dose 
(corresponding clock time), 30 min and 2 
h, 6 h, and 12 h post-dose 
Days 5, 7, 9, and 11: Pre-dose 
(corresponding clock time) and 2 h 
post-dose 
Day 13: 23 h, 24.5 h, 26 h, 30 h, and 36 h 
post-last dose 
Day 14: 47 h, 48.5 h, 50 h, 54 h, and 60 h 
post-last dose 
Day 15: 71 h, 72.5 h, 74 h, 78 h, and 84 h 
post-last dose 
Day 16: 95 h, 96.5 h, 98 h, 102 h, and 
108 h post-last dose 
Day 17, 20, 23, and 26: 5 measurements 
of FeNO (pre-dose, 30 min, 2 , 6 h, and 
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Table 6.8 
Schedule of Assessments Part 3b in healthy volunteers 
Schedule of Assessments Part 3b in healthy volunteers 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4 or 
-3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (second 
dosing day) to 
Day 12 (last 
dosing day) 
Day 13 
to 16 
Day 17 to 
Day 27 
Comments 
Informed consent 
X 
 
 
 
 
 
 
Includes optional genetic consent 
Inclusion/exclusion criteria 
X 
 
X 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Drug, alcohol and cotinine 
screen  
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
COVID-19 serology testing 
d)  
X 
 
 
 
 
 
X 
Day 27 
COVID-19 PCR testing d) 
X 
X 
 
 
 
 
 
 
QuantiFERON® TB 
X 
 
 
 
 
 
 
 
Follicle-stimulating 
hormone testing 
X 
 
 
 
 
 
 
Post-menopausal females only (see CSP 
Section 5.2.3.2 for definition) 
Study Residency: 
 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
X 
 
Discharge on Day 27. 
Non-residential visit 
X 
 
 
 
 
 
X 
Day 17 to Day 27 (If permitted by local 
relevant regulatory authorities and 
considered feasible and safe) 
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Table 6.8 
Schedule of Assessments Part 3b in healthy volunteers 
Schedule of Assessments Part 3b in healthy volunteers 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4 or 
-3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (second 
dosing day) to 
Day 12 (last 
dosing day) 
Day 13 
to 16 
Day 17 to 
Day 27 
Comments 
Investigational Medicinal 
Product  
 
 
 
 
 
 
 
 
DPI Training 
 
 
X 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
AZD0449/Placebo 
administration via DPI a) 
 
 
 
X b) 
X b) 
 
 
First dose on Day 1, second dose on Day 3 
(48 hours post-dose), then once daily dosing 
from Day 4 to Day 12 
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Table 6.8 
Schedule of Assessments Part 3b in healthy volunteers 
Schedule of Assessments Part 3b in healthy volunteers 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4 or 
-3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (second 
dosing day) to 
Day 12 (last 
dosing day) 
Day 13 
to 16 
Day 17 to 
Day 27 
Comments 
Safety and Tolerability: 
 
 
 
 
 
 
 
 
Adverse event questioning 
Only SAEs 
Only 
SAEs 
Only 
SAEs 
X 
X 
X 
X 
 
Spirometry 
X 
 
X c) 
X c) 
X c) 
X c) 
X d) 
Day -1: pre-dose, 6 h, 12 h (corresponding 
clock time) 
Day 1, Day 8 and Day 12: 
pre-dose, 30 min, 1.5 h, 3 h, 6 h and 12 h 
post-dose 
Day 2: 24 h post-dose 
Day 3 to 7 and Day 9 to 11: pre-dose and 
30 min post-dose 
Day 13: 24 h post-dose, Day 14: 47 h post-
dose, 
Day 15: 71 h post-dose, Day 16: 95 h 
post-dose, Day 17: 120 h post-dose, Day 20: 
192 h post-dose, Day 23: 264 h post-dose, 
Day 26: 336 h post-dose, and Day 27: 360 h 
post-dose 
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Table 6.8 
Schedule of Assessments Part 3b in healthy volunteers 
Schedule of Assessments Part 3b in healthy volunteers 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4 or 
-3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (second 
dosing day) to 
Day 12 (last 
dosing day) 
Day 13 
to 16 
Day 17 to 
Day 27 
Comments 
Pulse oximetry 
X 
 
X 
X 
X 
X 
X 
Day -1: pre-dose, 3 h and 12 h post-dose 
(corresponding clock time) 
Day 1 and Day 3 to Day 12: Pre-dose, 1 h, 
1.5 h, 3 h, 6 h, 12 h -post-dose 
Day 2: 24 h post-dose 
Days 13: 24 h post-dose, Day 14: 48 h post-
dose, 
Day 15: 72 h post-dose, Day 16: 96 h 
post-dose, Day 17: 120 h post-dose, Day 18: 
144 h post-dose, Day 19: 168 h post-dose, 
Day 20: 192 h post-dose, Day 21: 216 h post-
dose, 
Day 22: 240 h post-dose, Day 23: 264 h 
post-dose, Day 24: 288 h post-dose, Day 25: 
312 h post-dose, Day 26: 336 h post-dose, 
and Day 27: 360 h post-dose 
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Table 6.8 
Schedule of Assessments Part 3b in healthy volunteers 
Schedule of Assessments Part 3b in healthy volunteers 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4 or 
-3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (second 
dosing day) to 
Day 12 (last 
dosing day) 
Day 13 
to 16 
Day 17 to 
Day 27 
Comments 
Blood pressure, pulse and 
respiratory rate (supine)and 
body temperature 
X 
 
X 
X 
X 
X 
X 
Day 1 (first dose) and Day 12 (last dose): 
pre-dose and 1 h, 2 h and 6 h post-dose 
Day 2: 24 h post-dose 
Days 3 to 11: pre-Pre-dose 
Day 13: 24 h post-dose, Day 14: 48 h post-
dose, 
Day 15: 72 h post-dose, Day 16: 96 h 
post-dose, Day 17: 120 h post-dose, Day 18: 
144 h post-dose, Day 19: 168 h post-dose, 
Day 20: 192 h post-dose, Day 21: 216 h post-
dose, 
Day 22: 240 h post-dose, Day 23: 264 h 
post-dose, Day 24: 288 h post-dose, Day 25: 
312 h post-dose, Day 26: 336 h post-dose and 
Day 27: 360 h post-dose 
Body temperature 
 
X 
 
 
 
X 
 
 
12-lead dECG 
 
 
 
X 
X 
X 
 
 See Table 3.2-10 from the CSP 
12-lead safety ECG 
X 
 
X 
X 
X 
X 
X 
12-lead safety ECG will be collected at the 
start of each dECG extraction window when 
time-points coincide, see Table 3.2-10 from the 
CSP 
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Table 6.8 
Schedule of Assessments Part 3b in healthy volunteers 
Schedule of Assessments Part 3b in healthy volunteers 
Screening 
Treatment Period 
Follow-up 
Assessments 
Day -28 to 
Day -4 or 
-3 
Day -3 
to -2 
Day -1 
Day 1 
and 
Day 2 
Day 3 (second 
dosing day) to 
Day 12 (last 
dosing day) 
Day 13 
to 16 
Day 17 to 
Day 27 
Comments 
Telemetry 
 
 
X 
X 
X 
X 
 
Day -1: at least 4 h 
Pre-dose (Day 1) to 24 h post-dose (Day 2) 
Pre-dose (Day 12) to 24 h post-dose (Day 13) 
Height, weight and BMI 
X 
 
X 
 
 
 
X 
Day 27 
Height to be measured at screening only 
Clinical laboratory 
evaluations 
X 
X 
 
X 
X 
X 
X 
Day 2: 24 h post-dose 
Day 3: pre-dose 
Day 13: 24 h post-dose 
Day 27: 360 h post-last dose 
All samples will be collected after a 10 h 
fasting period 
Pregnancy testing 
X 
(serum) 
X (urine) 
 
 
 
 
X 
(serum) 
Day 27 
Females only 
Physical examination 
X 
 
X 
X (brief) 
X (brief) 
X 
(brief) 
X 
Day 1: pre-dose 
Day 2: 24 h after the first dose 
Day 6: pre-dose 
Day 10: pre-dose 
Day 14: 48 h post-dose, Day 17: 120 h post-
dose, 
Day 20: 192 h post-dose, Day 23: 264 h 
post-dose, Day 26: 336 h post-dose, and 
Day 27: 360 h post-dose (full examination) 
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Table 6.9 
Time Schedule for Digital Electrocardiogram Part 1a (SAD) 
Study Days 
ECG 
Number 
Time-point 
Start Time 
hour:min a), b)  
Dose 
Stop Time 
dECG cont. c), d), e)  
Other f)  
1 
 
 
-01:30 
 
-01:00 
 
Apply the electrodes d)  
1 
 
 
-00:40 
 
-00:30 
 
Rest in bed 
1 
1 
Pre-dose 
-00:30 
Pre-dose 
-00:20 
10 minutes 
 
1 
 
 
-00:20 
 
-00:05 
 
Toilet use recommended 
1 
 
 
00:00 
Administration of AZD0449/placebo 
 
 
 
1 
2 
1 h 
00:55 
 
01:00 
5 minutes e) 
 
1 
3g) 
2 h 
01:55 
 
02:00 
5 minutes e) 
 
1 
4 
3 h 
02:55 
 
03:00 
5 minutes e) 
 
1 
5 
4 h 
03:55 
 
04:00 
5 minutes e) 
 
1 
6 h)  
5 h 
04:55 
 
05:00 
5 minutes e)  
 
1 
7 
6 h 
05:55 
 
06:00 
5 minutes e) 
 
1 
8 
8 h 
07:55 
 
08:00 
5 minutes e) 
 
1 
9 h) 
10 h 
09:55 
 
10:00 
5 minutes e) 
 
1 
10 
12 h 
11:55 
 
12:00 
5 minutes e) 
 
2 
11 
24 h 
23:55 
 
24:00 
5 minutes e) 
 
2 
12 
36 h 
35:55 
 
36:00 
5 minutes e) 
 
3 
13 
48 h 
47:55 
 
48:00 
5 minutes e) 
 
3 
14 h) 
60 h 
59:55 
 
60:00 
5 minutes e) 
 
ECG: Electrocardiogram; dECG: Digital ECG; PK: Pharmacokinetics 
a) Time-points for dECG may be adjusted according to emerging PK data. 
b) Times are approximate as dECG and safety ECGs need to be completed before blood sampling. 
c) The healthy volunteer must be in the same supine body position (max. 30 degrees flexion in the hip) at each time-point and at all visits. Healthy volunteer’s feet should not 
contact the footboard of the bed. 
d) Skin must be cleaned, and electrode positions marked with an indelible pen. Electrodes should be applied at least 30 minutes before first recording. 
e) Healthy volunteer must rest in bed for at least 10 minutes before each ECG time-point. 
f) 
Safety ECG will be collected at the start of each dECG extraction window. 
g) For cohorts 1 to 4 only. 
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h) For cohorts 1 to 3 only. 
 
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Table 6.10 
Time Schedule for Digital Electrocardiogram Part 1b (IV Cohorts) 
Study Days 
ECG 
Number 
Time-point 
Start Time 
hour:mina) b), c) 
Dose 
Stop Time 
dECG cont. c), d) e) 
Other f)  
1 
 
 
-01:30 
 
-01:00 
 
Apply the electrodes d)  
1 
 
 
-00:40 
 
-00:30 
 
Rest in bed 
1 
1 
Pre-dose 
-00:30 
Pre-dose 
-00:20 
10 minutes 
 
1 
 
 
-00:20 
 
-00:05 
 
Toilet use recommended 
1 
 
 
00:00 
Infusion start 
 
 
 
1 
2 
5 min 
00:05 
 
00:10 
5 minutes e)  
After infusion start 
1 
3 
30 min 
00:25 
 
00:30 
5 minutes e)  
 
1 
4 
48 min h) 
00:43 
 
00:48 
5 minutes e)  
 
1 
5 
1 h g) 
00:55 
 
01:00 
5 minutes e) 
 
1 
6 
1.5 h 
01:25 
 
01:30 
5 minutes e)  
 
1 
7 
2 h 
01:55 
 
02:00 
5 minutes e)  
 
1 
8 
3 h 
02:55 
 
03:00 
5 minutes e)  
 
1 
9 
4 h 
03:55 
 
04:00 
5 minutes e)  
 
1 
10 
5 h 
04:55 
 
05:00 
5 minutes e)  
 
1 
11 
6 h 
05:55 
 
06:00 
5 minutes e)  
 
1 
12 
8 h 
07:55 
 
08:00 
5 minutes e)  
 
1 
13 
10 h 
09:55 
 
10:00 
5 minutes e)  
 
1 
14 
12 h 
11:55 
 
12:00 
5 minutes e)  
 
2 
15 
24 h 
23:55 
 
24:00 
5 minutes e)  
 
2 
16 
36 h 
35:55 
 
36:00 
5 minutes e)  
 
3 
17 
48 h 
47:55 
 
48:00 
5 minutes e)  
 
ECG: Electrocardiogram; dECG: Digital ECG; PK: Pharmacokinetics 
a) Time-points for dECG may be adjusted according to emerging PK data. 
b) Times are approximate as dECG and safety ECGs need to be completed before blood sampling. 
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c) The healthy volunteer must be in the same supine body position (max. 30 degrees flexion in the hip) at each timepoint and at all visits. Healthy volunteer’s feet should not 
contact the footboard of the bed. 
d) Skin must be cleaned, and electrode positions marked with an indelible pen. Electrodes should be applied at least 30 minutes before first recording. 
e) Healthy volunteer must rest in bed for at least 10 minutes before each ECG timepoint. 
f) 
Safety ECG will be collected at the start of each dECG extraction window. 
g) For cohort 1 only. 
h) For cohort 2 only. 
 
 
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Table 6.11 
Time Schedule for Digital Electrocardiogram Part 2a/b and Part 3a/b 
Study 
Days 
ECG 
Number 
Time-point 
Start Time 
hour:min a),b) 
Dose 
Stop Time 
dECG cont. 
c),d),e) 
Other f) 
1, 12 
 
 
 
-01:30 
-01:00 
 
Apply the electrodes d) 
1, 12 
 
 
 
-00:40 
-00:30 
 
Rest in bed 
1, 12 
1 
11 
Pre-dose 
-00:30 
-00:20 
10 minutes 
 
1, 12 
 
 
 
-00:20 
Pre-dose 
-00:05 
 
Toilet use 
recommended 
1, 12 
 
 
 
00:00 
Administration of 
AZD0449/placebo 
 
 
 
1, 12 
2 
12 
0.5 h g) 
00:25 
 
00:30 
5 minutes e)  
 
1, 12 
3 
13 
1 h 
00:55 
 
01:00 
5 minutes e)  
 
1, 12 
4 
14 
3 h 
02:55 
 
03:00 
5 minutes e)  
 
1, 12 
5 
15 
4 h 
03:55 
 
04:00 
5 minutes e)  
 
1, 12 
6 
16 
6 h 
05:55 
 
06:00 
5 minutes e)  
 
1, 12 
7 
17 
8 h 
07:55 
 
08:00 
5 minutes e)  
 
1, 12 
8 
18 
12 h 
11:55 
 
12:00 
5 minutes e)  
 
2, 13 
9 
19 
24 h 
23:55 
 
24:00 
5 minutes e)  
 
2, 13 
10 
20 
36 h 
35:55 
 
36:00 
5 minutes e)  
 
14 
 
21 
48 h 
47:55 
 
48:00 
5 minutes e) 
 
ECG: Electrocardiogram; dECG: Digital ECG; PK: Pharmacokinetics 
a) Time-points for dECG may be adjusted according to emerging PK data. 
b) Times are approximate as dECG and safety ECGs need to be completed before blood sampling. 
c) The patient must be in the same supine body position (max. 30 degrees flexion in the hip) at each time-point and at all visits. Patient’s feet should not contact the footboard 
of the bed. 
d) Skin must be cleaned, and electrode positions marked with an indelible pen. Electrodes should be applied at least 30 minutes before first recording. 
e) Patient must rest in bed for at least 10 minutes before each ECG time-point. 
f) 
Safety ECG will be conducted at the start of each dECG extraction window. 
g) Part 3a/b only. 
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