Clinical trial NCT04159519
Conditions: Asthma Severe Eosinophilic Asthma
Keywords: Anti-Inflammatory Reduction period Inhaled corticosteroids long-acting β2 agonist
Sponsor: AstraZeneca
Start date: 2020-07-27; Completion date: 2023-01-31
Enrollment: 170 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicentre, randomised, open-label, parallel-group, active-controlled, phase IV study to assess the reduction of daily Symbicort® maintenance to anti-inflammatory reliever treatment only in participants with severe eosinophilic asthma on Fasenra® treatment, while maintaining asthma control.

Detailed description:
This study will be conducted at 24 study sites in 3-5 countries. The study duration for each participant will be approximately 52-56 weeks. Approximately 240 participants with severe eosinophilic asthma taking high-dose Inhaled corticosteroids/ long-acting β2-agonist (ICS/LABA) who have been treated for severe eosinophilic asthma with at least 3 consecutive doses of Fasenra® and have clinically responded since the start of Fasenra® treatment (defined for the purpose of this study as an Asthma control questionnaire-5 item (ACQ-5 score) \<1.5 at Visit 1 and Visit 2b) will be enrolled into this open-label study. The study consists of a Screening Visit (Visit 1) and 4- to 8-week screening and run-in period (to align the randomisation study visit with the next Fasenra® injection), a reduction period of 32 weeks, and a 16-week maintenance period.

Arms: arm 1: Participants will receive Benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks. arm 2: Participants will receive Benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance ×2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible participants randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.
Interventions: intervention 1: Symbicort® intervention 2: Fasenra® intervention 3: Ventolin®
Intervention descriptions: intervention 1: Participants will receive Budesonide 400 μg/formoterol fumarate 12 μg per inhalation or Budesonide 200 μg/formoterol fumarate 6 μg per inhalation. intervention 2: Participants will receive Benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 4 weeks for first 3 doses (prior to study inclusion), every 8 weeks thereafter. intervention 3: Participants will receive Salbutamol sulfate 100 μg per inhalation as needed.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
SHAMAL: A Multicentre, Randomised, Open-Label, Parallel- 
Group, Active-Controlled, Phase IV Study to Assess the Reduction 
of Daily Maintenance ICS/LABA Treatment Towards 
Anti-Inflammatory Reliever Treatment in Patients with Severe 
Eosinophilic Asthma Treated with Benralizumab 
 
ClinicalTrials.gov Identifier: NCT04159519 
 
 
Date of Protocol: 15 November 2022 
 


Cli nical St u d y Pr ot oc ol - 4. 0
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Cli nic al St u d y Pr ot oc ol
Dr u g S u bsta nce
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S H A M A L: A M u ltice ntre, R a n d o mise d, O pe n-L a bel, P ar allel -Gr o u p, 
Acti ve - Co ntr olle d, P h ase I V St u d y t o Assess t he Re d ucti o n of D ail y 
M ai nte n a nce I C S/ L A B A Tre at me nt T o w ar ds A nti -I nfl a m m at or y Relie ver 
Tre at me nt i n P atie nts wit h Se vere E osi n o p hilic Ast h m a Tre ate d wit h
Be nr aliz u m a b
 
S p o ns or: Astra Ze neca A B, 1 5 1 8 5 S ö dertälje, S we de n
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s) :
E u dra C T n u m ber: 2 0 1 9- 0 0 1 9 2 4- 3 7
T his d oc u me nt c o ntai ns tra de secrets a n d c o nfi de ntial c o m mercial i nf or mati o n, discl os ure of w hic h is pr o hi bite d 
wit h o ut pr o vi di n g a d va nce n otice t o Astra Ze neca a n d o p p ort u nit y t o o bject.


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P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E
D O C U M E N T HI S T O R Y
D oc u me nt
D ate
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0 4 J u ne 2 0 1 9
Cli nic al St u d y Pr ot oc ol, Versi o n 4 . 0, 1 5 N o ve m ber 2 0 2 2
T his cli nical st u d y pr ot o c ol ( C S P) a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he 
criteria set f ort h i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he 
C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt:

T o a d d a sec o n dar y e n d p o i nt.

T o cl arif y bli n di n g res ults of fract i onal e x hale d nit ric o xide ( Fe N O) m eas ure me nt will be 
a p plica ble t o all ‘st u d y site staff’ a n d patient s.

T o a d d Ve nt oli n t o a d verse e ve nt ( A E) ca usalit y c ollect i on sect i on.
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T o re m o ve refere nce t o a nal ysis after patie nts reac h Visit 6 ( 3 2 wee ks).

T o re m o ve refere nce t o t he i nit ial rea d-o ut of pri mar y  a nal ysis of t he re d uctio n peri o d .
Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
Secti o n 1. 2, 
S y n o psis ;
Secti o n 3, 
O bjecti ves a n d 
E n d p oi nts ;
Secti o n 9. 4. 1, 
O utc o m e 
m eas ures f or 
anal yses 
calc ulat i on or 
d eri vat i on of 
e fficac y 
varia bles
U p date d t o a d d a 
sec o n dar y e n d p oi nt ie, 
cli nical re missi o n
Cli nical Re missi o n 
c o mp osi te sc ore is a 
ne w e n d p o i nt, n ot 
a vaila ble d uri n g 
pre vi o us Cli nical 
St u d y  Pr ot oc ol ( C S P) 
versi o ns, s o i s a d de d 
as it is bec o mi n g a n 
i m p orta nt e mer gi n g 
e n d p o i nt i n t he se vere 
ast h ma c o m m u nit y
S u bsta nt ial


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Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
Secti o n 8. 1. 2. 2, 
Fract i onal 
ex hale d n itric 
o xi de
U p date d t o a d d te xt ‘st u d y  
site’ staff
T o cl arif y bli n di n g 
res ults of fracti onal 
e x hale d nitric o xi de 
( Fe N O) meas ure me nt 
will be a p plica ble t o 
all ‘st u d y site staff’ 
a n d pat ient s.
N o n -s u bsta ntial
Secti o n 8. 3. 5, 
Ca usalit y 
c ollect i on
U p date d t o a d d Ve nt oli n
T o cl arif y a d verse 
e ve nt ( A E) ca usalit y 
t o Ve nt oli n will be 
re p orte d.
N o n -s u bsta ntial
Secti o n 9. 1. 1, 
Esti mat i on a n d 
testi n g str at e g y
D el ete d refere nce t o 
a nal ysis after patie nts 
reac h V 6 ( 3 2 wee ks)
T he i nit ial rea d-o ut of 
a nal ysis at V 6 ( 3 2 
wee ks) will n o l o n ger 
be perf or m e d for t he 
st u d y as a nal ysis of 
V 6 data will be 
i ncl u de d i n t he fi nal 
rea d-o ut after V 8 ( 4 8 
wee ks).
S u bsta nt ial
Secti o n 9. 4. 2. 2, 
Sec o n dar y  
anal ysis
D el ete d te xt relate d t o 
pri mar y  rea d- o ut
Secti o n 9. 4. 6, 
St u d y  rea d- o ut
D el ete d te xt relate d t o 
pri mar y  a nal ysis
T his Cli nical St u d y  Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
sta n dar d pr oce d ures.  T he Cli nical St u d y Pr ot oc ol is p u blicl y re gistere d a n d t he res ults are 
di s close d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P olic y  o n Bioet hics a n d i n 
c o mplia nce wi t h pre vaili n g la ws a n d re g ulati ons.


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T A B L E O F C O N T E N T S
TI T L E P A G E ........................................................................................................................1
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E ....................................2
T A B L E O F C O N T E N T S ......................................................................................................4
1
P R O T O C O L S U M M A R Y ..................................................................................8
1. 1
Sc he d ule of Act i vities ( S o A)...............................................................................8
1. 2
S y n o psis ...........................................................................................................1 2
1. 3
Sc he ma .............................................................................................................1 8
2
I N T R O D U C TI O N ............................................................................................1 9
2. 1
St u d y  Ratio nale ................................................................................................1 9
2. 2
Bac k gr o u n d ......................................................................................................1 9
2. 3
Be nefit/ Ris k Assess me nt ...................................................................................2 0
3
O BJ E C TI V E S A N D E N D P O I N T S...................................................................2 3
4
S T U D Y D E SI G N .............................................................................................2 4
4. 1
O verall De si g n ..................................................................................................2 4
4. 1. 1
Treat me nt re d ucti o n ar m ta peri n g .....................................................................2 8
4. 1. 2
M o ni t ori n g ast h ma c o ntr ol a n d S y m bic ort® 2 0 0/ 6 μ g use ..................................2 9
4. 2
S ci e nt ific Rati o nale f or St u d y Desi g n ...............................................................3 0
4. 3
J ustificati o n f or D ose........................................................................................3 1
4. 4
E n d of St u d y  Defi niti on ....................................................................................3 2
5 
S T U D Y P O P U L A TI O N ...................................................................................3 2
5. 1
I ncl usi on Cri t eria ..............................................................................................3 2
5. 1. 1
Ra n d o misat i on cri t eria ......................................................................................3 4
5. 2
E xcl usi o n Cri t eria .............................................................................................3 4
5. 3
Li festyle Restrict i ons ........................................................................................3 6
5. 3. 1
Meals a n d dietar y  restrictio ns............................................................................ 3 6
5. 3. 2
Caffei ne, alc o h o l, a n d t o bacc o ..........................................................................3 6
5. 3. 3
Act i vity .............................................................................................................3 6
5. 3. 4
Bl o o d D o nati o n ................................................................................................3 6
5. 4
Scree n Fail ures ................................................................................................. 3 7
6
S T U D Y T R E A T M E N T S ..................................................................................3 7
6. 1
Treat me nts A d mi nistere d ..................................................................................3 7
6. 1. 1
I n vesti gati onal pr o d ucts ....................................................................................3 7
6. 1. 2
Me dical de vices ................................................................................................4 0
6. 1. 2. 1
Hailie T M I n haler De vice.....................................................................................4 0
6. 1. 2. 2
S pi r o metr y De vice............................................................................................4 0
6. 1. 2. 3
Fe N O M o ni t ori n g De vice .................................................................................4 0
6. 2
Pre parati o n/ ha n dli n g/st ora ge/acc o u nta bilit y ......................................................4 0


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Meas ures t o Mi ni mise Bias: Ra n d o misat i on a n d Bli n di n g ................................. 4 1
6. 4
Treat me nt C o m plia nce ......................................................................................4 2
6. 5
C o nc o mita nt T hera p y ........................................................................................4 2
6. 5. 1
Ot her c o nc o mita nt treat me nt .............................................................................4 4
6. 6
D ose M o dificat i on ............................................................................................4 4
6. 7
Treat me nt After t he E n d of t he St u d y ................................................................4 5
7  
DI S C O N TI N U A TI O N O F T R E A T M E N T A N D P A TI E N T WI T H D R A W A L
. 4 5
7. 1
Di sc o nti n uatio n of  St u d y Treat me nt ..................................................................4 5
7. 1. 1
Pr oce d ures f or disc o nt i n uati on of st u d y  treat me nt .............................................4 5
7. 2
L ost t o F oll o w - u p .............................................................................................4 6
7. 3
Wit h dra wal fr o m t he St u d y ...............................................................................4 6
8
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S .............................................4 7
8. 1
Efficac y Assess me nts ........................................................................................4 8
8. 1. 1
Electr o nic Pat ient -Re p orte d O utc o mes ..............................................................4 8
8. 1. 1. 1
Ast h ma C o ntr ol Q uest i on naire -5 i t e m...............................................................4 8
8. 1. 1. 2
Sta n dar di se d Ast h ma Q uality of  Life Q uesti on naire f or 1 2 y ears a n d older: 
A Q L Q( S) + 1 2 ....................................................................................................4 8
8. 1. 1. 3
..................................4 9
8. 1. 2
P h ysi o l ogical ast h ma assess me nts .....................................................................4 9
8. 1. 2. 1
P ul m o nar y  fu nct i on tests ( F E V 1 a n d F V C) ........................................................4 9
8. 1. 2. 2
Fract i onal e x hale d Nitric O xi de ........................................................................4 9
8. 1. 2. 3
Air wa y  os cillo m etr y .........................................................................................5 0
8. 1. 3
Assess me nt of ast h ma e xacer bat i ons ................................................................. 5 0
8. 2
S af et y Assess me nts ...........................................................................................5 0
8. 3
C o llecti on of A d verse E ve nts ............................................................................5 1
8. 3. 1
Met h o d of detecti n g A Es a n d S A Es ..................................................................5 1
8. 3. 2
Ti me peri o d a n d fre q ue nc y  for c ollect i n g A E a n d S A E i nf or mat i on ..................5 1
8. 3. 3
F o ll ow- u p of  A Es a n d S A Es.............................................................................5 1
8. 3. 4
A E data c ollect i on .............................................................................................5 2
8. 3. 5
Ca usalit y c ollecti o n...........................................................................................5 2
8. 3. 6
A Es base d o n si g ns a n d s y m pt o ms ....................................................................5 3
8. 3. 7
Di sease u n der st u d y ( D U S)...............................................................................5 3
8. 4
S af et y Re p orti n g a n d Me dical Ma na ge me nt ......................................................5 3
8. 4. 1
Re p orti n g of S A Es ............................................................................................5 3
8. 4. 2
Pre g na nc y .........................................................................................................5 4
8. 4. 2. 1
Mater nal e x p os ure
............................................................................................5 4
8. 4. 3
O ver d ose ..........................................................................................................5 5
8. 4. 4
Me dicat i on err or ...............................................................................................5 5
8. 4. 5
Me dical De vice Deficie ncies .............................................................................5 6
8. 4. 5. 1
Ti me Peri o d f or Detecti n g Me dical De vice Deficie ncies ...................................5 6
8. 4. 5. 2
F o ll ow- u p of  Me dical De vice Deficie ncies .......................................................5 6
8. 4. 5. 3
Pr o m pt Re p orti n g of Me dical De vice D efic ie ncies t o S p o ns or ..........................5 7
8. 4. 5. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or De vice Deficie ncies............................5 7
C CI


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8. 5
P har mac o ki net ics..............................................................................................5 7
8. 6
P har mac o d y na mics ...........................................................................................5 7
8. 7
Ge net ics............................................................................................................5 7
8. 8
Bi o m ar kers .......................................................................................................5 7
8. 8. 1
S u b -st u d y bio m ar kers .......................................................................................5 7
8. 8. 1. 1
Br o nc h osc o p y ...................................................................................................5 8
8. 8. 1. 2 
I n d uce d s p ut u m ................................................................................................6 0
8. 8. 1. 3
S er u m  sa m ples f or e x pl orat or y bio m ar kers .......................................................6 0
8. 8. 2
Bl o o d sa m pl e f or e osi n o p hils ............................................................................6 0
8. 8. 3
St ora ge, re -use a n d destr ucti o n of bi o mar ker sa m ples .......................................6 0
8. 9
Heal t h Ec o n o mics.............................................................................................6 1
9
S T A TI S TI C A L C O N SI D E R A TI O N S ...............................................................6 1
9. 1
Stati stical H y p ot heses.......................................................................................6 1
9. 1. 1
Esti mat i on a n d testi n g strate g y ..........................................................................6 1
9. 1. 2
Baseli ne a n d c ha n ge fr o m baseli ne ....................................................................6 1
9. 1. 3
Se nsit i vity a nal ysis ...........................................................................................6 2
9. 2
S a m ple Si ze Deter mi nat i on ...............................................................................6 2
9. 3
P o p ul at i ons f or A nal yses ..................................................................................6 3
9. 4
Stati stical A nal yses ...........................................................................................6 3
9. 4. 1
O utc o m e meas ures f or a nal yses- calc ulat i on or deri vat i on of efficac y  varia bles. 6 3
9. 4. 2
Efficac y a nal yses ..............................................................................................6 6
9. 4. 2. 1
Pri mar y a nal ysis ...............................................................................................6 6
9. 4. 2. 2
Sec o n dar y  a nal ysis............................................................................................6 7
9. 4. 3
S af et y a nal yses ................................................................................................. 6 8
9. 4. 3. 1
A d verse e ve nts ..................................................................................................6 8
9. 4. 4
E x pl or at or y  a nal yses.........................................................................................6 9
9. 4. 4. 1
C ha n ge fr o m baseli ne Fe N O .............................................................................6 9
9. 4. 4. 2
C ha n ge fr o m baseli ne i n bl o o d e osi n o p hil c o u nt ...............................................6 9
9. 4. 4. 3
..................................6 9
9. 4. 4. 4
C ha n ge fr o m baseli ne i n air w a y oscillo m etr y d uri n g t he st u d y p erio d ...............6 9
9. 4. 5
S u b -st u d y a nal ysis............................................................................................7 0
9. 4. 6
St u d y  rea d- o ut ..................................................................................................7 0
9. 5
I nteri m A nal yses...............................................................................................7 0
9. 5. 1
S ci e nt ific C om mittee ........................................................................................7 0
1 0
R E F E R E N C E S ................................................................................................. 7 1
1 1
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L
C O N SI D E R A TI O N S ........................................................................................7 4
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of assess me nts ............................................................................9
Ta ble 2
St u d y  o bject i ves.......................................................................................2 3
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Ta bl e 3
S y m bic ort ® d osi n g re gi me n f or patie nts w h o mai ntai n ast h ma c o ntr ol 
d uri n g t he re d ucti o n peri o d ......................................................................2 8
Ta ble 4
St u d y  treat me nts ......................................................................................3 8
Ta ble 5
Restricte d me dicati o ns .............................................................................4 3
Ta ble 6
Pr o hi bite d me dicat i ons .............................................................................4 3
Ta ble 7 
E x pecte d l o wer a n d u p per half- wi dt h of e xact 9 5 % CIs ( Cl o p per -
Pears o n) ar o u n d o bser ve d pr o p orti o n of patie nts s uccessf ull y ste p pi n g 
d o w n S M A R T .........................................................................................6 2
LI S T O F FI G U R E S
Fi g ure 1
St u d y  desi g n............................................................................................1 8
Fi g ure 2
Al g ori t h m for ste p pi n g d o w n/ u p treat me nt i n t he Re d ucti o n Peri o d .........2 9
LI S T O F A P P E N DI C E S
A p pe n di x A
Re g ulat or y , Et hical a n d St u d y O versi g ht C o nsi derati o ns..........................7 4
A p pe n di x B
A d verse E ve nt Defi nit i ons a n d A d dit i onal Safet y I nf or mat i on .................7 9
A p pe n di x C
Ha n dli n g of H u ma n Bi o l ogical  Sa m ples ..................................................8 3
A p pe n di x D
Cl assificat i on of I n Vi v o I n hi bit ors of C Y P 3 A 4 E nz y mes ........................8 5
A p pe n di x E
A Q L Q( S) + 1 2 ...........................................................................................8 6
A p pe n d i x F
A C Q - 5.....................................................................................................9 2
A p pe n di x G
G ui da nce o n C ha n ges Relate d t o Mit i gati on of St u d y  Disr u ptio ns D ue t o 
Cases of Ci vil Crisis, Nat ural Disa ster, or P u blic Healt h Crisis ................9 4
A p pe n di x H
Me dical De vice A Es, A D Es, S A Es, S A D Es, U S A D Es, a n d Me dical 
De vice Deficie ncies: Defi n iti ons a n d Pr oce d ures f or Rec or di n g, 
E val uat i n g, F oll o w-u p, a n d Re p orti n g i n Me dical De vice St u dies ............9 7
A p pe n di x I
A b bre viat i ons ........................................................................................1 0 3
A p pe n di x J
Pr ot oc ol  A me n d me nt Hist or y................................................................. 1 0 5


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1
P R O T O C O L S U M M A R Y
1. 1
Sc he d ule of A cti vities ( S o A)




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Scree ni n g
R u n -i n 
peri o d
Re d ucti o n peri o d
M ai nte n a nce peri o d
U nsc he d ule d 
visit
Det ails i n C S P secti o n 
or A p pe n di x
Visit
1 
- 
2 a a
2 b 
3 
4
5
6 b
7
8 a a or 
E O T c
8 b or 
E O T c
Wee k
-8 or - 4
- 8/- 4
t o 0
0 
0 
8 
1 6
2 4 
3 2 
4 0
4 7 or E O T c
4 8 or 
E O T c
D a y
-5 6 or - 2 8
-5 6/ -2 8
t o - 1
- 1 
1
5 7
1 1 3
1 6 9
2 2 5
2 8 1
3 3 6 or 
E O T c
3 3 7 or 
E O T c
Wi n d o w ( d a ys)
-
1 da y  pri or
t o V 2 b
± 7 
± 7 
± 7
± 7 
± 7 
± 7
1 da y  pri or 
t o V 8 b
± 7
I n d uce d s p ut u m (s u b-st u d y) l
X
X
Secti o n  8. 8. 1. 2
Br o nc h osc o p y (s u b -st u d y) l
X
X
Secti o n 8. 8. 1. 1
Hae m ostatic sa m ple (s u b -st u d y) l,n
X
X
Secti o n 8. 8. 1. 1
Ser u m sa m ples f or e x pl orat or y 
bi o mar kers (s u b -st u d y) l
X
X
X
Secti o n 8. 8. 1. 3
Bl o o d sa m ple f or e osi n o p hils
o
X
X
X
Secti o n 8. 8. 2
St u d y tre at me nt a d mi nistr ati o n
Fase nra ® S C i njecti o n
X  
X
X  
X  
X
X
R u n -i n treat me nt dis pe nse d
X
R u n -i n treat me nt c ollecte d
X
Ra n d o misati o n
X
Ra n d o mise d treat me nt dis pe nse d
X  
X
X  
X  
X
X
Ra n d o mise d treat me nt c ollecte d
X
X  
X  
X
X
X
Treat me nt re d ucti o n ar m ta peri n g (ste p 
d o w n of S M A R T) p
X  
X
X  
X
Secti o n 4. 1. 1


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nra liz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 of 1 1 7
A C Q -5 = Ast h ma co ntr ol q uesti o n naire -5 ite m; A Q L Q( S) + 1 2 = Sta n dar dise d ast h ma q ualit y of life q uesti o n naire f or 1 2 years a n d ol der; C S P = Cli nical st u d y 
pr ot oc ol; E O T = E n d of treat me nt; F V C = F orce d vital ca pacit y; Fe N O = Fracti o nal e x hale d nitric o xi de; F E V 1= F orce d e x pirat or y v ol u me i n 1 sec o n d;
S C = S u bc uta ne o us ; S M A R T = S ym bic ort ® mai nte na nce a n d relie ver t hera p y.
a
Visits 2a a n d 8a a n d t he assess me nts sc he d ule d f or t hese visits a p pl y o nl y t o patie nts i n t he s u b -st u d y.
b
Visit 6 is liste d u n der t he re d ucti o n peri o d; h o we ver, n o f urt her re d ucti o n of S y m bic ort ® is per mitte d at t his visit.  F or statistical a nal ysis p ur p oses, Visit 6 is 
t he e n d of t he re d ucti o n peri o d a n d als o t he baseli ne visit f or t he mai nte na nce peri o d.
c
T he E O T Visit is c o m prise d of t he assess me nts at Visit 8a a n d Visit 8 b.
d
A d verse e ve nt s ( A Es) a n d seri o us a d verse e ve nts ( S A Es) will be c ollecte d fr o m t he ti me of si g ni n g t he i nf or me d c o nse nt f or m (I C F).
e
Test t o be perf or me d a n d res ults o btai ne d pri or t o s p ut u m i n d ucti o n a n d s ho ul d be perf or me d as per sta n dar d of care i n t he partici pati n g site.
f
A ser u m pre g na nc y test will be d o ne f or w o me n of c hil d beari n g p ote ntial ( W O C B P) at scree ni n g.  A n al ysis will be perf or me d at a l ocal la b orat or y.  If 
ser u m test is p ositi ve, t he patie nt s h o ul d be e xcl u de d.
g
Patie nt e P R O/ de vice trai ni n g will be perf or me d at Vis it 1 f or all patie nts .  Fr o m Visit 2 b t o Visit 7, a d diti o nal trai ni n g will be perf or me d i n t he e ve nt of 
p o or c o m plia nce .
h
All patie nts will c o m plete t he A C Q -5 q uesti o n naire at t he st u d y site f or Visit 1 a n d wee kl y a n d at h o me t hereafter.  O n st u d y visit da y s ( Visit 2 b o n war ds) , 
patie nts will c o m plete t he q uesti o n naire pri or t o or  d uri n g t he st u d y visit.
i
Patie nts will c o m plete t he q uesti o n naire s at t he st u d y visit pri or t o a n y st u d y -relate d pr oce d ure.
j
All patie nts will c o m plete t he q uesti o n naire at Visit 2 b .  O nl y patie nts i n t he treat me nt re d ucti on ar m will c o m plete t he q uesti o n naire at Visit 6 a n d Visit 8 b.
k
S y m bic ort ® s ho ul d be wit h hel d f or 1 2 h o urs pri or t o t he st u d y visit.  Ve nt oli n ® s ho ul d be wit h hel d f or a mi ni m u m of 6 h o urs pri o r t o t he st u d y visit.  If 
eit her c o n diti o n is n ot met, t he visit s h o ul d be c o n d ucte d w he n t hese c o n diti o ns are met, eit her b y dela yi n g t he ti me of t he l u n g f u ncti o n e val uati o n or b y 
r e-sc he d uli n g t he st u d y visit.  Pr i or t o p ul m o nar y f u ncti on tests at Visit 2 b, t he hei g ht of t h e patie nt will be meas ure d.   E xce pti o nall y, c o nsiste nt wit h
A p pe n di x G , s pir o metr y ca n be o mitte d u n der circ u msta nces w here it is n ot rec o m me n de d beca use of preca uti o ns f or i nfecti o n c o ntr ol ar o u n d pa n de mic 
disease .
l
F or t he s u b- st u d y, patie nts will be stratifie d se paratel y fr o m t he mai n st u d y wit h a 3: 1 rati o b y treat me nt ar m (treat me nt re d ucti o n ar m: refere nce ar m).
m
T he Fe N O assess me nt m ust be perf or m e d pri or t o p ul m o nar y f u ncti o n tests.  Patie nts m ust n ot eat or dri n k 1 h o ur pri or t o ha vi n g t he Fe N O assess me nt.
n
A hae m ostatic a nal ysis will be perf or me d f or all patie nts u n der g oi n g a br o nc h osc o p y assess me nt .  A nal ysis will be perf or me d at a l ocal la b orator y.   Patie nts 
m ust fast f or 6 h o urs pr i or t o a n y br o nc h osc o p y pr oce d ures.
o
Bl o o d sa m ples will be c ollecte d fr o m all patie nts i n t he st u d y.  A n al ysis will be perf or me d at a l ocal la b orat or y.
p
Treat me nt r e d ucti o n ar m ta peri n g occ urs at W ee k 0, 8, 1 6, a n d 2 4.  At Wee k 2 4 d ose re d ucti o n occ urs o nl y i n patie nts w h o are still recei vi n g S M A R T a n d 
ha ve n ot ste p pe d d o w n t o S y m bic ort ® as a nti -i nfla m mat or y relie ver o nl y ( pr o vi de d t he patie nt meets all criteria t o ste p d o w n).


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 2 of 1 1 7
1. 2
S y n o psis
I nter n ati o n al C o or di n ati n g I n vesti g at or:
Dr. D a vi d J ac ks o n
G u y’s & St T h o mas’ N H S Tr ust
L o n d o n 
S E 1 9 R T
U nit e d K i n g d o m ( U K)
Pr ot oc ol Title:
S H A M A L: A M ult ice ntre, Ra n d o mise d, O pe n -La bel , Parallel-Gr o u p, Acti ve - Co ntr olle d, 
P hase I V St u d y t o Assess t he Re d uct i on of Dail y Mai nte na nce I C S/ L A B A Treat me nt 
T o war ds A nti -I nfla m mat or y Relie ver Treat me nt i n Patie nts wit h Se vere E osi n o p hilic Ast h ma 
Treate d wit h Be nraliz u ma b
R ati o n ale: 
T he rati o nale f or t his st u d y  is t o e x plore a ne w precisi o n -base d a p p r oac h t o treat se vere 
e osi n o p hilic p he n ot ype ast h ma pat ient s base d o n be nraliz u ma b ( Fase nra ® ) mai nte na nce 
treat me nt pl us b u des o ni de/f or m oter ol ( S y m bic ort ® 2 0 0/ 6 µ g) a nti-i nfla m mat or y relie ver as 
nee de d.  T heref ore, t his st u d y  ai ms t o assess t he p ote ntial for Fase nra ® -treate d se vere 
e osi n o p hilic ast h ma pat ient s t o safel y a n d effecti vel y re d uce t heir S y m bic ort ® ma i nte na nce 
ast h ma treat me nt b ur de n w hile m ai ntai ni n g ast h ma s y m pt o m c o ntr ol.
O bjecti ves a n d E n d p oi nts
Pri m ar y O bjecti ve:
E n d p oi nt/ V ari a ble:
T o assess t he p ote ntial f or Fase nra ® -
treate d patie nts t o re d uce S y m bic ort®
mai nte na nce treat me nt w hile mai ntai ni n g 
ast h ma s y m pt o m c o ntr ol a

Pr o p orti o n of patie nts w h o re d uce d t heir S y m bic ort ®
mai nte na nce d ose at t he e n d of t he re d ucti o n peri o d
( Wee k 3 2) t o:
o
Me di u m -d ose S y m bic ort ® mai nte na nce a n d relie ver 
t hera p y (S M A R T ), or
o
L o w -d ose S M A R T , or
o
S y m bic ort ® a nti -i nfla m mat or y relie ver o nl y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 of 1 1 7
O bjecti ves a n d E n d p oi nts
Sec o n d ar y O bjecti ves:
E n d p oi nt/ V ari a ble:
T o assess c ha n ges i n patie nt -re p orte d 
o utc o mes f or Fase nra ® -treate d patie nts 
w h il e ste p pi n g d o w n S y m bic ort ®
mai nte na nce treat me nt

C ha n ge f r om baseli ne i n A C Q -5 sc ore at t he e n d of t he 
re d ucti on p e ri o d.

C ha n ge f r om baseli ne i n A Q L Q( S) + 1 2 at t he e n d of t he 
re d ucti on p e ri o d.

Pr o p orti o n of patie nts wit h n o deteri orati o n i n A Q L Q( S) + 1 2 
( deteri orati o n defi ne d as a decrease of at least 0. 5 u nits
c o m pare d t o baseli ne) at t he e n d of t he re d ucti o n peri o d.

Pr o p orti o n of patie nts wit h n o deteri orati o n i n A C Q -5 
( deteri orati o n defi ne d as a n i ncrease of at least 0. 5 u nits
c o m pare d t o baseli ne) at t he e n d of t he re d ucti o n peri o d.
T o assess t he p ote ntial f or Fase nra ® -
treate d patie nts t o mai ntai n l u n g f u ncti o n 
w h ile ste p pi n g d o w n S y m bic ort®
mai nte na nce treat me nt

C ha n ge f r om baseli ne i n pre -br o n c h o dilat or F E V 1 d uri n g t he 
st u d y peri o d.
T o assess ast h ma e xacer bati o n rate 

A n n ualise d ast h ma e xacer bati o n rate d uri n g t he st u d y peri o d.
T o assess t he t otal I C S d ose e x p os ure

C u m ulati ve t otal dail y I C S d ose ( mai nte na nce + relie ver)
f or:
o
T he re d ucti o n peri o d .
o
T he mai nte na nce peri o d .
o
T he st u d y  peri o d .

T otal dail y I C S d ose ( mai nte na nce + relie ver) at t he e n d of 
t he re d ucti o n peri o d.
T o assess if re d ucti o ns i n S y m bic ort ®
mai nte na nce ac hie ve d at t he e n d of t he 
re d ucti on p e ri o d are mai ntai ne d u ntil t he 
e n d of t he mai nte na nce peri o d

Pr o p orti o n of pa tie nts usi n g t he sa me S y m bic ort® dail y  d ose 
at t he en d of t he mai nte na nce peri o d ( Wee k 4 8) t hat t he y 
ac hie ve d at t he e n d of t he re d ucti o n peri o d ( Wee k 3 2).

S u p p orti ve o utc o mes:
o
N u m ber of e xacer bati o ns occ urri n g fr o m e n d of t he 
re d ucti on p e ri o d t o e n d of t he mai nte na nce peri o d.
o
T otal dail y I C S d ose fr o m t he e n d of t he re d ucti o n 
peri o d t o t he e n d of t he mai nte na nce peri o d.
o
C ha n ge i n A C Q -5, A Q L Q( S) + 1 2, a n d F E V 1 fr o m t he 
e n d of t he re d ucti on p e ri o d t o t he e n d of t he 
mai nte na nce peri o d.
T o assess cli nical re missi o n i n patie nts at 
e n d of t he re d ucti o n a n d mai nte na nce 
peri o ds

N u m ber a n d pr o p orti o n of patie nts t hat met eac h c o m p osite 
e n d p oi nt defi ni n g cli nical re missi o n ( n o e xacer bati o ns, less 
t ha n 1 0 % deteri orati o n i n F E V 1, A C Q -5 < 1. 5 or 
A C Q - 5 ≤0. 7 5) at Vis it 6 ( Wee k 3 2) a n d Visit 8 b ( Wee k 4 8).

N u m ber a n d pr o p orti o n of patie nts t hat met 0, 1, 2 , a n d all 3 
c o m p osite re missi o n e n d p oi nts.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 of 1 1 7
O bjecti ves a n d E n d p oi nts
S afet y O bjecti ve:
E n d p oi nt/ V ari a ble:
T o assess t he safet y a n d t olera bilit y of 
Fase nra ® i n patie nts wit h se vere ast h ma, 
w h ile ste p pi n g d o w n S y m bic ort ®
mai nte na nce treat me nt a n d mai ntai ni n g 
ast h ma s y m pt o m c o ntr ol

A d verse E ve nts/ Seri o us A d verse E ve nts.
E x pl or at or y O bjecti ves:
E n d p oi nt/ V ari a ble:
T o assess c ha n ges i n i nfla m mati o n 
mar kers d uri n g a n d f oll o wi n g ste p pi n g 
d o w n S y m bic ort ® mai nte na nce treat me nt

Fe N O.

Bl o o d e osi n o p hil c o u nt.

Ser u m pr otei n bi o mar kers (s u b -st u d y).
T o assess patie nt e x perie nce

.
T o assess t he p ote ntial f or Fase nra ® -
treate d patie nts t o mai ntai n l u n g f u ncti o n 
w h ile ste p pi n g d o w n S y m bic ort®
mai nte na nce treat me nt (s u b -st u d y)
C ha n ge f r om baseli ne i n air wa y oscill o metr y d uri n g t he st u d y 
peri o d (s u b-st u d y).
T o c haracteri se t he effects of Fase nra ® o n 
air wa y i nfla m mati o n after re d uci n g dail y 
S y m bic ort ® t hera p y (s u b-st u d y)

Patie nt i nfla m mat or y bi o mar kers pr ofile i ncl u di n g 
e osi n o p hils, micr o bi o me, a n d s p ut u m bi o mar kers 
(c yt oki nes).
A C Q -5 = Ast h ma c o ntr ol q uesti o n naire -5 ite m; A Q L Q( S) + 1 2 = Sta n dar dise d ast h ma q ualit y of life q uesti o n naire 
f or 1 2 years a n d ol der; F E V 1= F orce d e x pirat or y v ol u me i n 1 sec o n d; I C S =I n hale d c ortic oster oi ds; 
Fe N O = Fracti o nal e x hale d nitric o xi de; S M A R T = S y m bic ort ® mai nte na nce a n d relie ver t hera p y
a
Ast h ma s y m pt o m c o ntr ol is defi ne d as 1) n o ast h ma e xacer bati o ns si nce t he last visit, a n d 2) n o i ncrease i n 
A C Q - 5 ≥0. 5 u nits i n t he last 4 wee ks (c o m pare d t o baseli ne; Visit 1) a n d n o si g nifica nt i ncrease i n 
S y m bic ort ® use i n t he last 4 wee ks (a wee kl y a vera ge of > 8 i n halati o ns of S y m bic ort® / da y).
O ver all D esi g n:
T his is a m ult ice ntre, ra n d o mise d, o pe n-label, parallel -gr o u p, acti ve -c o ntr olle d, P hase I V 
st u d y t o assess t he re d ucti o n of dail y S y m bic ort® mai nte na nce t o a nti-i nfla m mat or y relie ver 
treat me nt o nl y i n patient s wit h se vere e osi n o p hilic ast h ma o n Fase nra® tr e at me nt, w hile 
mai ntai ni n g ast h ma c o ntr ol.
I n t his st u d y, t he i n hale d c ortic oster oi ds (I C S)/ l o n g-acti n g β 2 a g o nist ( L A B A) will be 
sta n dar dise d f or all pat ient s w ho will  s wit c h fr o m a n y I C S/ L A B A t hera p y t o 
b u des o ni de/f or m oter ol ( S y m bic ort ® ).  At t he Scree ni n g Visit ( Visit 1), all pat ient s will s witc h 
t o hig h -d ose S y m bic ort ® ma i nte na nce treat me nt a n d Ve nt oli n ® relie ver treat me nt .  Patie nts 
ra n d omise d t o t he refere nce ar m will re mai n o n t he hi g h-d ose of S y m bic ort ® f or t he d urati o n 
of  t he st u d y; patie nts ra n d o mise d t o re d uce t he dail y S y m bic ort® ma i nte na nce tr e at me nt will 
f oll ow t he S M A R T treat me nt a p pr oac h.
T his st u d y  will be c o n d ucte d at a p pr o xi matel y 2 5 st u d y sit es in a p pr o xi matel y 3- 5 c o u ntries.  
T he st u d y  d uratio n f or eac h pati e nt will be a p pr o xi matel y 5 2- 5 6 wee ks.  A p pr o xi matel y 
2 4 0 pati e nts wit h se vere e osi n o p hilic ast h ma ta ki n g hi g h-d ose I C S/ L A B A w h o ha ve bee n 
C CI


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 5 of 1 1 7
treate d f or se vere e osi n o p hilic ast h ma wi t h at least 3 c o nsec ut i ve d oses of Fase nra® a n d ha ve 
cli nicall y res p o n de d si nce t he start of Fase nra ® treat me nt ( defi ne d f or t he p ur p ose of t his st u d y 
as a n A st h ma C o ntr ol  Quest i on naire -5 i t e m [ A C Q- 5] sc ore < 1. 5 at Visit 1 a n d Visit 2 b) will 
be e nr olle d i nt o t his o pe n -la bel st u d y.  Use of ot her mai nte na nce ast h ma t hera p y s uc h as dail y 
or al  c ortic oster oids, le u k otri e ne rece pt or a nta g o nists ( L T R As), lo n g- act i n g m u scari nic 
a nta g o nists ( L A M As) or t he o p h ylli nes is n ot all o we d d uri n g t he st u d y p eri o d .
T he st u d y  c o nsists of a S cree ni n g Visi t ( Visit 1) a n d 4 - t o 8-wee k scree ni n g a n d r u n-i n peri o d
(t o ali g n t he ra n d omisat i on st u d y visit wi t h t he ne xt Fase nra® i njecti on ), a re d uctio n peri o d of  
3 2 wee ks, a n d a 1 6 -wee k mai nte na nce peri o d.
P ati e nts will be ra n d o mise d i n a 3: 1 rati o t o eit her t he treat me nt re d ucti o n ar m or t he refere nce 
ar m.
St u d y Peri o d:
Esti mate d date of first patie nt e nr o lled: Q 3 2 0 2 0
Esti mate d date of last patie nt c o m plete d : Q 1 2 0 2 3
N u m ber of P atie nts :
A t otal o f a p pr o xi matel y 2 4 0 pat ient s will be scree ne d t o ac hie ve 2 0 0 ra n d o mise d patie nts, 
ass u mi n g a scree n fail ure rate of a p pr o xi matel y 1 5 %.  A t otal of 2 0 0 ra n d o mise d patie nts is 
c o nsi dere d s ufficie nt t o a d dress t he pri mar y o bjecti ve f or t he st u d y  ass u mi n g a dr o p-o ut rate 
of  n o mo re t ha n 1 5 % e val ua ble pat ient s i n b ot h ar ms res ulti n g i n a p pr o xi matel y 1 2 5 t o 
1 5 0 e val ua ble patie nts i n t he treat me nt re d uctio n ar m  a n d a p pr o xi matel y 4 0 t o 5 0 e val ua ble 
pati e nts i n t he refere nce ar m.   T he selecte d sa m ple size is e x pecte d t o pr o vi de a n o mi n al 9 5 % 
c o nfi de nce i nter val ( CI ) ar o u n d t he o bser ve d pr o p orti o ns wit h a half -wi dt h of less t ha n 
1 0 perce nta ge p oi nts i n t he treat me nt re d ucti o n ar m .
Tre at me nts a n d T re at me nt D ur ati o n:
Scree ni n g a n d r u n -i n peri o d: D uri n g t he 4- t o 8-wee k scree ni n g a n d r u n-i n p eri o d, pati e nts 
will recei ve S y m bic ort ® as mai nte na nce treat me nt a n d Ve nt oli n ® as relie ver treat me nt at t he 
f oll owi n g d ose:

Hi g h -d ose S y m bic ort ® ma i nte na nce ( bu des o ni de/f or m oter ol  4 0 0/ 1 2 μ g) × 2 i n halati ons
t wice per da y (BI D ) + Ve nt oli n ® (sal b uta m ol 1 0 0 μ g) relie ver as nee de d ( P R N) .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 6 of 1 1 7
Re d ucti o n peri o d: Patie nts will be ra n d o mise d at t he be gi n ni n g of t he re d ucti o n peri o d 
( Visit 2 b); eli gi ble pat ient s will be ra n d o ml y assi g ne d t o t he treat me nt re d ucti o n ar m or t o t he 
refere nce ar m i n a 3: 1 rati o:

Tre at me nt re d ucti o n ar m: Fase nra® 3 0 m g e ver y 8 wee ks ( Q 8 W ) + S M A R T or 
S y m bic ort ® relie ver o nl y (starti n g with me d i u m-d ose S y m bic ort ® 2 0 0/ 6 µ g × 2 i n halat i ons
BI D mai nte na nce + S y m bic ort ® 2 0 0/ 6 µ g relie ver P R N ; ta peri n g t o S y m bic ort® 2 0 0/ 6 µ g 
relie ver o nl y, as per taperi n g sc he me a n d de pe n di n g o n de gree of ast h ma c o ntr ol ).

Refere nce ar m : Fase nra® 3 0 m g Q 8 W + hi g h -d ose S y m bic ort ® ma i nte na nce 
× 2 i n halati ons BI D + Ve nt oli n ® (sal b uta mol  1 0 0 μ g) relie ver P R N .
T he re d ucti o n peri o d will last f or 3 2 wee ks.  At t he ra n d o misati on visit ( Visit 2 b ) eli gi ble 
pati e nts ra n d omise d t o t he treat me nt re d ucti o n ar m will a ut o mat icall y be ste p pe d d o w n t o 
me di u m -d ose S M A R T.  Pa tie nts w h o de m o nstrate mai ntai ne d ast h ma c o ntr ol will ta per (ste p 
d o w n) t heir S M A R T re gi me n u nt il t he y ac hie ve ei t her S y m bic ort ® as a nt i-i nfla m mat or y 
relie ver treat me nt o nl y or u ntil  no f urt her re d ucti o ns of S M A R T are per mitte d d ue t o l oss of 
ast h ma c o ntr ol.   If a patie nt is recei vi n g me di u m-d ose S M A R T a n d l oses ast h ma c o ntr ol, t he y  
ca n be ste p pe d u p t o hi g h-d ose S y m bic ort ® ma i nte na nce treat me nt a n d Ve nt oli n ® relie ver 
treat me nt (ie, ret ur ni n g t o t he st u d y treat me nt pr o vi de d d uri n g t he r u n-i n peri o d).
At  eac h p ost-ra n d o misati on st u d y  visit, t he I n vest i gat or will e val uate t he occ urre nce of ast h ma 
e xacer bati o ns, w orse ni n g of ast h ma c o ntr ol ( A C Q - 5 ≥0. 5 u nits c o mpare d t o baseli ne), a n d 
o ver use of S y m bic ort ® 2 0 0/ 6 μ g treat me nt (a wee kl y a vera ge of > 8 i n halati ons of  
S y m bic ort ® / da y).  T he I n vesti gat or will t he n deci de t o re d uce, mai ntai n, or i ncrease t he 
S y m bic ort ® d ose f or patie nts i n t he treat me nt re d ucti o n ar m base d o n a pres pecifie d al g orit h m .  
A pat ient  will st o p ste p pi n g d o w n f or t he d urati o n of t he re d ucti o n peri o d if 1) t he patie nt 
e x perie nces a n ast h ma e xacer bat i on si nce t he last visit or 2) if t he patie nt e x perie nces a 
w orse ni n g of ast h ma c o ntr ol A N D o ver use o f S y m bic ort ® 2 0 0/ 6 μ g treat me nt d uri n g t he 
4 wee ks pri or t o eac h st u d y visit .
M ai nte n a nce peri o d: At  t he e n d of t he re d ucti o n peri o d, patie nts i n b ot h ar ms will 
a ut o mat icall y e nter t he 1 6-wee k mai nte na nce peri o d d uri n g w hic h pati e nts i n t he treat me nt 
re d uctio n ar m  will c o nti n ue o n t he S y m bic ort ® treat me nt le vel t he y ac hie ve d at t he e n d of t he 
re d uctio n peri o d .  I n t he e ve nt of ast h ma w orse ni n g d uri n g t he mai nte na nce peri o d, t he 
I n vesti gat or ma y deci de t o ste p u p t he S y m bic ort ® d ose .  N o  re d ucti o ns i n S y m bic ort® d ose s
are all o we d d uri n g t he mai nte na nce peri o d.
S u b- st u dy: A s u bset of patie nts w h o c o nse nt t o part ici pati on i n t he s u b-st u d y (a p pr o xi matel y 
3 2 pati e nts are t o be i ncl u de d, s prea d acr oss t he 2 treat me nt ar ms) will u n der g o air wa y 
oscill o m etr y  t o assess a meas ure of l un g f u ncti o n a n d will u n der g o br o nc h osc o p y  a n d i n d uce d 
s p ut u m sa m pli n g at s pecific ti me p oi nts f or e x pl orat or y bio m ar ker researc h.  Pati e nts will be 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 of 1 1 7
e nr o lle d fr o m 1 st u d y site i n t he U K a n d will be stratifie d i nto t he s u b -st u d y se paratel y fr o m 
t he mai n st u d y wit h a 3: 1 ratio b y  tr e at me nt ar m (treat me nt re d uctio n ar m : r efere nce ar m).
Scie ntific C o m mittee:
A Scie ntific C o m mittee c o nsist i n g of i nter nal Astra Ze neca ( A Z ) a n d e xter nal e x perts w h o 
ha ve bee n i n v o l ve d i n t he desi g n of t he cli nical st u d y will a d vise t he S p o ns or o n c ha n ges t o 
t he st u d y desi g n a n d pr o vide rec o m me n dat i ons o n iss ues relate d t o t he st u d y  c o n d uct, if 
re q uire d.  I n a d diti on, t he c o m mittee will be i n v o l ve d i n t he re vie w a n d i nter pretati o n of t he 
st u d y res ults.  T he Scie nt ific C om mittee will be g o ver ne d b y  a c harter, detaili n g r oles a n d 
res p o nsi bilities an d pr ocesses o f t he Scie ntific C o m mittee.
St atistic al M et h o ds:
P o p ul at i ons f or a nal ysis i ncl u de a n A ll P atie nts S et ( A P S; all pat ient s scree ne d f or t he st u d y),
a F ull A nal ysis S et ( F A S ; all ra n d o mise d pat ient s irres pecti ve of pr ot oc ol a d here nce a n d 
c o nti n ue d partici p atio n i n t he st u d y ), a n d a Safet y A nal ysis Set ( S A F; all ra n d o mise d pat ient s 
w h o ha ve recei ve d at least o ne d ose of t he st u d y  treat me nt) .
P ati e nt dis p ositio n will be s u m marise d usi n g t he A P S.  De m o gra p h y, baseli ne, a n d pat ient  
c haracterist ic data will be e val uate d usi n g t he F A S.  T he efficac y  e n d p oi nts will be e val uate d 
usi n g t he F A S.   All safet y a nal yses will be perf or me d usi n g t he S A F b y act ual  treat me nt 
recei ve d.
T he pri mar y  o ut c o me will be assesse d usi n g a ta ble c o ntai ni n g t he n u m ber of pa tie nts a n d 
pr o p orti o n of  patient s at eac h ste p d o w n t o get her wit h e xact 2-si de d 9 5 % CI 
(Cl o p per -Pears o n ).  T he n u m ber a n d perce nta ge of  patie nts w h o d o n ot re d uce t heir 
mai nte na nce treat me nt will als o be i ncl u de d.
C ha n ges fr o m baseli ne t o p ost -ra n d o misati on visit s for A C Q -5, A Q L Q( S) + 1 2, F E V 1, a n d 
mea n t ot al dail y I C S d ose will be e val uate d usi n g Mi xe d M o del Re peate d Meas ures ( M M R M) 
m o delli n g a p pr oac hes i ncl u di n g baseli ne A C Q -5 (f or A C Q -5 o nl y ), visi t, treat me nt, a n d visit 
× treat me nt.
S af et y data will be s u m marise d f or all pat ient s i n t he S A F a n d data prese nte d b y act ual 
treat me nt recei ve d .
Se nsit i vity a nal yses t o assess t he effect of missi n g data or dr o p - o ut o n t he pri mar y e n d p oi nt 
will be o utli ne d i n t he statist ical a nal ysis pla n.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 of 1 1 7
1. 3
Sc he m a
T he ge neral st u d y  desi g n is s u m marise d i n Fi g ure 1.
Fi g ure 1
St u d y desi g n
BI D = T wice per da y ; I C S/L A B A = In hale d c ortic oster oi ds/ l o n g-acti n g β 2-a g onist ; P R N =A s nee de d; Q 8 W =E ver y 8 wee ks ; R = R a n d o mi sati o n; S C = S u bc uta ne o us;
S M A R T = S y m bic ort ® m ai nte na nce a n d relie ver th e r a p y.
a
If t he patie nt d oes n ot f ulfil all ra n d o misati o n criteria ( Secti o n 5. 1. 1 ) t he n t he patie nt will scree n fail.
b
S M A R T ste p d o w n s h o ul d f oll o w t he d osi n g re gi me n a n d al g orit h m s h o w n i n Secti o n 4. 1. 1 .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 of 1 1 7
2
I N T R O D U C TI O N
2. 1
St u d y R ati o n ale
T he rati o nale f or t his st u d y  is t o e x plore a ne w precisi o n -base d a p pr oac h t o treat se vere 
e osi n o p hilic p he n ot ype ast h ma pat ient s base d o n be nraliz u ma b ( Fase nra ® ) mai nte na nce 
treat me nt pl us b u des o ni de/f or m oter ol ( S y m bic ort ® 2 0 0/ 6 µ g) a nti -i nfla m mat or y relie ver as 
nee de d.  T heref ore, t his st u d y ai ms t o assess t he p ote ntial f or Fase nra ® -treate d se vere 
e osi n o p hilic ast h ma pat ient s t o safel y a n d effecti vel y re d uce t heir S y m bic ort® ma i nte na nce 
ast h ma treat me nt b ur de n w hile mai ntai ni n g ast h ma s y m pt o m  c o ntr ol.
2. 2
B ac k gr o u n d
T he c urre nt a p pr oac h t o a nti -i nfla m mat or y c o ntr oller t hera p y in ast h ma is base d o n a 
ste p-wise i nte nsificati o n of a dail y mai nte na nce re gi me n, pri maril y ce nt re d ar o u n d I C S, wit h 
t he a d ditio n of  L A B As i n patie nts wit h m ore se vere ast hma (N A E P P 2 0 0 7 , GI N A 2 0 1 9 ).  
A p pr o xi matel y  5 % t o 1 0 % of  pers o ns wit h ast h ma ha ve a se vere f or m of disease t hat is 
us uall y ma na ge d wit h hi g h -d ose I C S a n d br o nc h o dilat ors (Bate ma n et al 2 0 1 0 , 
C h u n g et al 2 0 1 4 ).  Bi o l ogi c t hera p ies tar getin g i m m u n o glo b uli n E (I g E), i nterle u ki n-5 (I L -5) 
or de plet i on of t he e osi n o p hil direct l y via I L -5 Ra -di recte d a nti b o d y- de pe n de nt cell-me diate d 
c yt ot o xicit y are rec o m me n de d as a n a d d- o n treat me nt i n pat ient s u nc o ntr olle d wit h 
I C S/L A B A treat me nt (GI N A 2 0 1 9 ).
Acc or di n g t o t he Gl o bal I nitiati ve f or Ast h ma ( GI N A ) 2 0 1 9 g ui deli nes, i n pat ient s w h o ha ve 
ha d a g o o d res p o nse t o bi ol o gic t hera p y, t he treati n g p h ysicia n s h o ul d c o nsi der re d uci n g t he 
I C S d ose fr om hi g h t o m e di u m d ose (GI N A 2 0 1 9) . GI N A descri bes t his g ui da nce as 
“c o nse ns us a d vice” rec o g nisi n g t hat n o data are a vaila ble t o g ui de t his cli nical decisi o n.
H o we ver, i n f ut ure cli nical pract ice, it is a ntici pate d t hat treati n g p h ysicians are li kel y t o 
de -escalate t he I C S d ose si g nifica ntl y or c o m pletel y at t he be hest of patie nts w h ose ast h ma 
bec o me s well c o ntr olle d after t he a d dit i on of bi o l ogi c t hera p y, s uc h as Fase nra ® .
O pti misat i on wi t h a n I C S-f or mot er ol  mai nte na nce a n d relie ver pri or t o ot her a d d -o n t hera p y  
str o n gl y s u p p orts t he use of S y m bic ort® a nti-i nfla m mat or y relie ver i n u nc o ntr olle d GI N A 3- 5 
pati e nts (GI N A 2 0 1 9 ).  Data t o g u i de cli nicia ns o n t he s pee d a n d e xte nt of t he mai nte na nce 
I C S de- escalat i on are l ac ki n g; si milarl y, de -escalati o n of mai nte na nce I C S d ose t o zer o wit h 
o nl y  a sal b uta mol  relie ver c o uld e x p ose pati e nts t o a n i ncrease d ris k of se vere e xacer bat i on 
(C A M P et al 2 0 0 0 , G uil bert et al 2 0 0 6 , Le m a ns ke et al 2 0 0 1 , Waal ke ns
et al 1 9 9 3 ).  T he 
GI N A g ui deli nes ac k n o wle d ge t hat o ver use of  s h ort-acti n g β-a g o nists ( S A B As; 
≥3 ca nisters/ year) is ass ociate d wit h a n i ncrease d ris k of se vere e xacer bat i ons a n d rec o m me n d 
I C S-c o ntai ni n g t reat me nt, s uc h as I C S -f or mot e r ol, s h o uld be i ni tiate d as s o o n as p ossi ble f or 
t he best o utc o mes (GI N A 2 0 1 9 ).  T o date, t here is n o cli nical st u d y p u blis he d t o assess t he 
re d uctio n of bac k gr o u n d S M A R T treat me nt i n se vere e osi n o p hilic ast h ma patie nts w hile o n 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 0 of 1 1 7
Fase nra ® treat me nt .  I n a d ditio n, t here is n o sta n dar di se d sc he me of re d ucti o n of S M A R T 
treat me nt i n t hese pat ient s.
T he pr o p ose d st u d y  is desi g ne d t o a d dress t hese e vi de nce ga ps a n d pr o vi de clear g uida nce o n 
h o w t o ste p d o w n S M A R T w hile retai ni n g t he pr otecti ve be nefit fr o m ast h ma w orse ni n g wi t h 
S y m bic ort ® a nti-i nfla m mat or y relie ver as nee de d i n place of t he mai nte na nce I C S/ L A B A.
T he o bj ect i ve of t he st u d y is t o assess t he p ote ntial f or Fase nra ® -treate d e osi n o p hilic 
p he n ot y pe ast h ma pat ient s t o safel y a n d effecti vel y re d uce t heir S y m bic ort ® ma i nte na nce 
ast h ma treat me nt b ur de n fr om hi g h -d ose dail y  S y m bic ort ® to ‘S y m bic ort ® a nti-i nflam mat or y  
relie ver as nee de d’ t hera p y w hile mai ntai ni n g ast h ma s y m pt o m c o ntr ol . A parallel refere nce 
ar m c o nsisti n g of patient s treate d wit h Fase nra ® Q 8 W a n d c o nti n ui n g o n hi g h-d ose 
S y m bic ort ® ma i nte na nce treat me nt ( 2 i n halati ons 4 0 0/ 1 2 µ g BI D) , a n d Ve nt oli n® relie ver 
treat me nt, is i ncl u de d t o hel p de m o nstrate t hat re d ucti o n of dail y S y m bic ort® ma i nte na nce 
treat me nt ca n be ac hie ve d wit h o ut m ea ni n gf ul los s of ast h ma c o ntr ol.
A detaile d descri pti o n o f t he c he mistr y, p har mac ol o g y, efficac y, a n d safety of  Fase nra ® ,
S y m bic ort ® , a n d Vent oli n ® are pr o vi de d i n t he ir res pecti ve S u m mar y  of Pr o d uct 
C haracteristics ( S m P C) .
2. 3
Be nefit/ R is k A ssess me nt
Fase nra ® is bei n g st u die d i n se vere e osi n o p hilic ast h ma w here t here are fe w treat me nt o pti o ns 
f or p atie nts w h ose ast h ma re mai ns u nc o ntr olle d o n hi g h -d ose I C S/ L A B A a n d/ or oral 
c ortic oster oids ( O C Ss) (GI N A 2 0 1 9 ). I n a d ult patie nts w h ose ast h ma was p o orl y c o ntr olle d 
b y hi g h -d ose I C S/ L A B A t hera p y , Fase nra ® 3 0 m g e ver y 8 wee ks pr o d uce d i m pr o ve me nts i n 
m ult i ple meas ures of ast h ma c o ntr ol i ncl u di n g t he a n n ual rate of ast h ma e xacer bati ons, l u n g 
f u ncti on s y m pt o ms, a n d Ast h ma C o ntr ol Q uest i on naire ( A C Q) sc ores i n 2 P hase III trials eac h 
a p pr o xi matel y 1 year i n d urati o n ( Blee ker et al 2 0 1 6 , Fi tz Gerald et al 2 0 1 6 ).  I n a d diti on, 
Fase n r a® has als o bee n s h o w n t o re d uce O C S d ose (Nair et al 2 0 1 7) .
I n E ur o pe, Fase nra ® is i n dicate d as a n “a d d- o n m ai nte n a nce tre at me nt i n a d ult p atie nts w it h 
severe e osi n o p hilic ast h m a i n a de q u ately c o ntr olle d des pite hi g h-d ose i n h ale d c ortic oster oi ds 
pl us l o n g -acti n g β -a g o nists ” ( please refer t o t he Fase nra ® S m P C).  Fase nra ® was de vel o pe d as 
a n a d d -o n treat m e nt t o mai nte na nce I C S/ L A B A treat me nt.  T o mit i gate t he ris k of ast h ma 
deteri or ati o n or e xacer bati o n d uri n g t he re d ucti o n of I C S/ L A B A mai nte na nce treat me nt, t he 
f oll owi n g meas ures will be i m ple me nte d:

Caref ul assess me nt o f ast h ma c o ntr ol bef ore a n y ta peri n g of I C S/ L A B A treat me nt (see 
Secti o n 4. 1. 1 ).

Wee kl y m o nit ori n g of ast h ma c o ntr ol a n d S y m bic ort ® 2 0 0/ 6 μ g use wit h alerts se nt t o 
pati e nts, I n vest i gat ors, a n d Astra Ze neca ( A Z ) or del e gate i n t he e ve nt of a n A C Q- 5 sc ore 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 1 of 1 1 7
i ncrease of at least 0. 5 u nits c o mpare d t o baseli ne or i n t he e ve nt of S y m bic ort ® o ver use 
( wee kl y a vera ge of > 8 i n halati ons/ da y ) [see Secti on 4. 1. 2 ].

Dail y m o nit ori n g of S y m bic ort ® 2 0 0/ 6 μ g use wit h alerts se nt t o patie nts, I n vest i gat ors, 
a n d A Z or d el e gate i n t he e ve nt of a n i ncrease of S y m bic ort ® use > 1 2 i n halati ons/ da y f or 
2 c o nsec uti ve da ys (see Sectio n 4. 1. 2 ).
P ote nti al ris ks of Fase nra ® are as f o ll ows:
Mali g na ncies ha ve bee n re p orte d at a l o w i nci de nce i n t he c o m plete d a n d o n g oi n g st u dies of 
Fase nra ® .  E osi n o p hils ha ve bee n f o u n d i n ass ociati on wi t h s oli d t u mo urs, es peci all y t u mo urs 
of  e pit helial origi n ( breast a n d c ol o n ) a n d ma y pla y a n acti ve r ole i n t u m o ur defe nce b y 
m o d ulati n g h ost defe nces, or ma y be a b ysta n der effect. H o we ver, t he ca use a n d 
c o nse q ue nces (ie, pr o -t u mori ge nic vers us a nt i-t u m orige nic) of e osi n o p hil recr uit me nt  a n d 
acc u m ulat i on i nto t u m o urs are u ncl ear (Jac o bse n et al 2 0 1 2 ).
S eri o us h y perse nsi tivi t y r e a ctio ns (i ncl u di n g a na p h yla x is) are a n i de ntifie d ris k of bi ol ogic 
t hera p y, i ncl u di n g Fase nra ® . A na p h yla xis ma y be life -t hreate ni n g. Ri s k mi ni misat i on 
i ncl u des a mi ni m u m of a 1-h o ur o bser vat i on peri o d at t he cli nical site f oll o wi n g dr u g
a d mi nistrati o n f or t he a p peara nce o f a n y ac ute dr u g reacti o ns.
De vel o p me nt of a nt i-dr u g a nt i b o dies ( A D A) t o Fase nra ® has bee n d oc u me nte d. T he oretical 
ris ks of de vel o pi n g A D A ma y  incl u de decrease d dr u g efficac y a n d h y perse nsit i vity reacti ons 
(e g, a na p h ylaxis or i m m u ne c o m p le x disease). T here was n o a p pare nt i m pact of A D A o n 
o verall Fase nra ® safety or efficac y  in t he pre vi o us P hase III stu dies i n c hr o nic o bstr ucti ve 
p ul m o nar y  disease ( C O P D) pati e nts.  
S eri o us i nfect i ons ha ve bee n re p orte d; h o we ver, a relatio ns hi p bet wee n e osi n o p hil de pleti o n 
a n d seri o us i nfecti o n has n ot bee n esta blis he d.  E osi n o p hils are a pr o mi ne nt feat ure of t he 
i nfla m mat or y res p o nse t o hel mi nthic parasit ic i nfecti o ns, a n d t he prese nce of i nfiltrati n g 
e osi n o p hils has bee n circ u msta ntial l y ass ociate d wit h a p ositive pr o g n osi s i n certai n s oli d 
t u mo urs . T heref ore, t here is a t he oretical ris k t hat pr ol o n ge d e osi n o p hil de plet i on ma y 
di mi nis h t he a bilit y t o d efe n d a gai nst hel mi nt hic parasites, or ne gati vel y i m pact t he nat ural 
hist or y  of certai n mali g na nt t u mo urs . Ris k mi ni mi satio n meas ures i ncl u de e xcl usi o n of 
pati e nts wit h u ntreate d parasitic i nfecti o n a n d acti ve or rece nt mali g na nc y, i n c o nj u ncti on wi t h 
t he perf or ma nce of r o ut i ne p har mac o vi gila nce acti vities.
T he S y m bic o rt® T ur b o haler is a well-k n o w n me dicati o n wit h efficac y a n d safet y pr ofiles 
esta blis he d i n n u mer o us cli nical st u dies a n d vast p ost -mar ket i n g e x perie nce. S y m bic ort ® is 
effect i ve as a relie ver me dicati o n (Pal m q vist et al 2 0 0 1 ).  I n t he S M A R T pr o gra m usi n g 
S y m bic ort 2 0 0/ 6 μ g per i n halat i on as t he met ere d d ose (c orres p o n di n g t o a deli vere d d ose of 
1 6 0/ 4. 5 μ g per i n halati o n ; please refer t o t he S y m bic ort ® T ur b o haler 2 0 0/ 6 μ g S m P C ),
pati e nts were all o we d t o use u p t o 1 2 i n halati ons per da y  ( 1 0 i n halati ons P R N i n a d dit i on t o 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 2 of 1 1 7
t heir mai nte na nce treat me nt) a n d t he safet y pr ofile of S y m bic ort ® was n o differe nt fr o m t hat 
of  a fi xe d-d ose m ai nte na nce tr eat me nt.  F urt her m ore, i n a n ot her st u d y assessi n g 1 0 i n halati o ns 
of  S y m bic ort® T ur b o haler 1 6 0/ 4. 5 μ g per i n halat i on as a n a d dit i on t o a dail y  S y m bic ort®
mai nte na nce d ose of 6 4 0/ 1 8 μ g , n o ne w safet y c o ncer ns c o m pare d t o w hat was alrea d y k n o w n 
f or I C S a n d L AB A were i de nt ifie d (A n kerst et al 2 0 0 3 ); t his de mo n strate d t hat occasi o nal 
hi g h d oses of S y m bic ort ® T ur b o haler are safe a n d well t olerate d. M o re rece ntl y, t he P hase III 
S Y G M A tri als de mo n strate d t hat S y m bic ort ® T ur b o haler as a re lie ver me dicati o n offere d 
s u perior ast h m a s y m pt o m c o ntr ol c o mpare d t o S A B A relie ver ( 3 4. 4 % vs. 3 1. 1 %) 
(O' B yr ne et al 2 0 1 8) .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 1 1 7
3
O B J E C TI V E S A N D E N D P O I N T S
T a ble 2
St u d y o bjecti ves
Pri m ar y O bjecti ve
E n d p oi nt/ V ari a ble
T o assess t he p ote ntial f or Fase nra ® -
treate d patie nts t o re d uce S y m bic ort®
mai nte na nce treat me nt w hile 
mai ntai ni n g ast h ma s y m pt o m c o ntr ol a

Pr o p orti o n of patie nts w h o re d uce d t heir S y m bic ort®
mai nte na nce d ose at t he e n d of t he re d ucti o n peri o d 
( Wee k 3 2) t o:
o
Me di u m -d ose S y m bic ort ® mai nte na nce a n d relie ver 
t hera p y ( S M A R T), or
o
L o w -d ose S M A R T , or
o
S y m bic ort ® a nti -i nfla m mat or y relie ver o nl y.
Sec o n d ar y O bjecti ves
E n d p oi nt/ V ari a ble
T o assess c ha n ges i n patie nt -re p orte d
o utc o mes f or Fase nra ® -treate d patie nts 
w h ile ste p pi n g d o w n S y m bic ort®
mai nte na nce treat me nt

C ha n ge f r om baseli ne i n A C Q -5 sc ore at t he e n d of t he 
re d ucti on p e ri o d.

C ha n ge f r om baseli ne i n A Q L Q( S) + 1 2 at t he e n d of t he 
re d ucti on p e ri o d.

Pr o p orti o n of patie nts wit h n o deteri orati o n i n A Q L Q( S) + 1 2 
( deteri orati o n defi ne d as a decrease of at least 0. 5 u nits
c o m pare d t o baseli ne) at t he e n d of t he re d ucti o n peri o d.

Pr o p orti o n of patie nts wit h n o deteri orati o n i n A C Q -5 
( deteri orati o n defi ne d as a n i ncrease of at least 0. 5 u nits
c o m pare d t o baseli ne) at t he e n d of t he re d ucti o n peri o d.
T o assess t he p ote ntial f or Fase nra ® -
treate d patie nts t o mai ntai n l u n g 
f u ncti o n w hile ste p pi n g d o w n 
S y m bic ort ® mai nte na nce treat me nt

C ha n ge f r om baseli ne i n pre -br o n c h o dilat or F E V 1 d uri n g t he 
st u d y peri o d.
T o assess ast h ma e xacer bati o n rate

A n n ualise d ast h ma e xacer bati o n rate d uri n g t he st u d y peri o d.
T o assess t he t otal I C S d ose e x p os ure

C u m ulati ve t otal dail y I C S d ose ( mai nte na nce + relie ver) f or:
o
T he re d ucti o n peri o d .
o
T he mai nte na nce peri o d .
o
T he st u d y  peri o d.

T otal dail y  I C S d ose ( mai nte na nce + relie ver) at t he e n d of t he 
re d ucti on p e ri o d.
T o assess if re d ucti o ns i n S y m bic ort ®
mai nte na nce ac hie ve d at t he e n d of t he 
re d ucti on p e ri o d are mai ntai ne d u ntil t he 
e n d of t he mai nte na nce peri o d

Pr o p orti o n of patie nts usi n g t he sa me S y m bic ort ® dail y  d ose 
at t he en d of t he mai nte na nce peri o d ( Wee k 4 8) t hat t he y 
ac hie ve d at t he e n d of t he re d ucti o n peri o d ( Wee k 3 2).

S u p p orti ve o utc o mes:
o
N u m ber of e xacer bati o ns occ urri n g fr o m e n d of t he 
re d ucti on p e ri o d t o e n d of t he mai nte na nce peri o d.
o
T otal dail y  I C S d ose fr o m t he e n d of t he re d ucti o n peri o d 
t o t he e n d of t he mai nte na nce peri o d.
o
C ha n ge i n A C Q -5, A Q L Q( S) + 1 2, a n d F E V 1 fr o m t he e n d 
of t h e re d ucti o n peri o d t o t he e n d of t he mai nte na nce 
peri o d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 1 1 7
T o assess cli nical re missi o n i n patie nts 
at e n d of t he re d ucti o n a n d mai nte na nce 
peri o ds

N u m ber a n d pr o p orti o n of patie nts t hat met eac h c o m p osite 
e n d p oi nt defi ni n g cli nical re missi o n ( n o e xacer bati o ns , less 
t ha n 1 0 % deteri orati o n i n F E V 1, A C Q -5 < 1. 5 or A C Q - 5 ≤
0. 7 5) at Visit 6 ( Wee k 3 2 ) a n d Visit 8 b ( Wee k 4 8).

N u m ber a n d pr o p orti o n of patie nts t hat met 0, 1, 2 , a n d all 3 
c o m p osite re missi o n e n d p oi nts.
S afet y O bjecti ve
E n d p oi nt/ V ari a ble
T o assess t he safet y a n d t olera bilit y of 
Fase nra ® i n patie nts wit h se vere ast h ma, 
w h ile ste p pi n g d o w n S y m bic ort ®
mai nte na nce treat me nt a n d mai ntai ni n g 
ast h ma s y m pt o m c o ntr ol

A d verse E ve nts/ Seri o us A d verse E ve nts.
E x pl or at or y O bjecti ves
E n d p oi nt/ V ari a ble
T o assess c ha n ges i n i nfla m mati o n 
mar kers d uri n g a n d f oll o wi n g ste p pi n g 
d o w n S y m bic ort ® mai nte na nce treat me nt

Fe N O.

Bl o o d e osi n o p hil c o u nt.

Ser u m pr otei n bi o mar kers (s u b -st u d y).
T o assess patie nt e x perie nce

.
T o assess t he p ote ntial f or Fase nra ® -
treate d patie nts t o mai ntai n l u n g 
f u ncti o n w hile ste p pi n g d o w n 
S y m bic ort ® mai nte na nce treat me nt 
(s u b-st u d y)

C ha n ge f r om baseli ne i n air wa y oscill o metr y d uri n g t he st u d y 
peri o d (s u b-st u d y).
T o c haracteri se t he effects of Fase nra ®
o n air wa y i nfla m mati o n after re d uci n g 
dail y  S ym b ic ort® t hera p y (s u b-st u d y)

Patie nt i nfla m mat or y bi o mar kers pr ofile i ncl u di n g 
e osi n o p hils, micr o bi o me, a n d s p ut u m bi o mar kers (c yt o ki nes).
A C Q - 5 =Ast h ma c o ntr ol q uesti o n naire -5 ite m ; A Q L Q( S) + 1 2 = Sta n dar dise d a st hma q ualit y of life q uesti o n naire 
f or 1 2 years a n d ol der; F E V 1= F orce d e x pirat or y v ol u me i n 1 sec o n d; I C S =I n hale d c ortic oster oi ds; 
Fe N O = Fracti o nal e x hale d n itric o xi de; S M A R T = S y m bic ort ® m ai nte na nce a n d relie ver th e r a p y
a
Ast h ma s y m pt o m c o ntr ol is defi ne d as 1) n o ast h ma e xacer bati o ns si nce t he last visit ( as defi ne d i n 
Secti o n 8. 1. 3 ), a n d 2) n o i ncrease i n A C Q -5 ≥0. 5 u n its i n t he last 4 wee ks (c o m pare d t o baseli ne; Visit 1)
a n d n o si g nifica nt i ncrease i n S y m bic ort ® use i n t he last 4 wee ks ( a wee kl y a vera ge of > 8 i n halati o ns of 
S y m bic ort ® / da y).
4
S T U D Y D E SI G N
4. 1
O ver all D esi g n
T his is a m ult ice ntre, ra n d o mise d, o pe n -la bel, p arallel- gr o u p, act i ve-c o ntr olle d, P hase I V 
st u d y t o assess t he re d ucti o n of dail y  S y m bic ort ® mai nte na nce t o a nti-i nfla m mat or y relie ver 
treat me nt o nl y i n patient s wit h se vere eosi n o p hilic ast h ma o n Fase nra ® tr e at me nt, w hile 
mai ntai ni n g ast h ma c o ntr ol .
F or t he p ur p ose of t his st u d y, mai ntai ne d ast h ma s y m pt o m c o ntr ol is defi ne d as 1) n o ast h m a 
e xacer bati o ns si nce t he last visit ( as defi ne d i n Secti o n 8. 1. 3 ), a n d 2) n o i ncrease i n A C Q - 5 
C CI


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 5 of 1 1 7
≥0. 5 u nits i n t he last 4 wee ks (c o m pare d t o baseli ne; Visit 1) a n d n o si g nifica nt i ncrease i n 
S y m bic ort ® use i n t he last 4 wee ks (a wee kl y a vera ge of > 8 i n halati o ns of S y m bic ort ® / da y).
I n t his st u d y, t he I C S/ L A B A will be sta n dar dise d f or all pat ient s w h o will s witc h fr om a n y 
I C S/ L A B A t hera p y t o b u des o ni de/f or mot er ol  ( S y m bic ort® ). At t he Scree ni n g Visit ( Visit 1),
all patie nts will s witc h t o hi g h- d ose S y m bic ort ® mai nt e na nce treat me nt a n d Ve nt oli n ® relie ver 
treat me nt .  Patie nts ra n d o mise d t o t he refere nce ar m will re mai n o n t he hi g h d ose of 
S y m bic ort ® f or t he d urati o n of t he st u d y; pati e nts ra n d o mise d t o re d uce t he dail y S y m bic ort ®
mai nte na nce treat me nt will f o ll ow t he SM A R T
a p pr oac h.
T his st u d y  will be c o n d ucte d at a p pr o xi matel y 2 5 st u d y sites i n a p pr o xi matel y 3- 5 c o u ntries.  
T he st u d y  d uratio n f or eac h pati e nt will be a p pr o xi matel y 5 2- 5 6 wee ks.  A p pr o xi matel y 
2 4 0 pati e nts wit h se vere e osi n o p hilic ast h ma ta ki n g hi g h-d ose I C S/ L A B A w h o ha ve bee n 
treate d f or se vere e osi n o p hilic ast h ma wi t h at least 3 c o nsec ut i ve d oses of Fase nra ® a n d ha ve 
cli nicall y res p o n de d si nce t he start of Fase nra ® treat me nt ( defi ne d f or t he p ur p ose of t his st u d y 
as a n A C Q-5 sc ore < 1. 5 at V isit 1 a n d Visit 2 b) will be e nr o lle d i nt o t his o pe n-label st u d y .  
Use of ot her mai nte na nce ast h ma t hera p y  s uc h as dail y O C Ss , L T R As, L A M As or 
t he o p h ylli nes is n ot all o we d d uri n g t he st u d y  p erio d .
T he st u d y  c o nsists of a Scree ni n g Visit ( Visit 1) a n d 4 - t o 8-wee k scree ni n g a n d r u n-i n peri o d 
(t o ali g n t he ra n d omisat i on st u d y  visit wit h t he ne xt Fase nra® i njecti on), a re d ucti o n peri o d of 
3 2 wee ks, a n d a 1 6 -wee k mai nte na nce peri o d.
Scree ni n g a n d r u n -i n peri o d : D uri n g t he st u d y peri o d, patie nts will c o nt i n ue t o recei ve 
Fase nra ® 3 0 m g Q 8 W treat me nt. At  Scree ni n g ( Visit 1), all pat ient s will s witc h fr o m t heir 
pre vi o us I C S/ L A B A mai nte na nce treat me nt a n d resc ue me dicatio n t o:

Hi g h -d ose S y m bic ort ® ma i nte na nce ( bu des o ni de/f or m oter ol  4 0 0/ 1 2 μ g) × 2 i n halat i ons
BI D + Ve nt oli n ® (sal b uta mol  1 0 0 μ g) relie ver P R N.
P ati e nts will c o nti n ue o n t his me dicati on f or t he d ur atio n of  t he 4- t o 8-wee k scree ni n g a n d 
r u n-i n peri o d. T he e n d of t he r u n -i n peri o d will c oi nci de with t he ne xt Fase nra ® i njecti o n. 
Re d ucti o n peri o d : At t he ra n d omisat i on visit ( Visit 2 b ), patie nts will u n der g o t he A C Q-5 
assess me nt a n d a n assess me nt of e xacer bat i on hist or y t o deter mi ne w het her t he y are eli gi ble 
f or ra n d o misati on (see Secti o n 5. 1. 1 ) or w het her t he y are scree n faile d fr o m t he st u d y (see 
Secti o n 5. 4 ).  Eli gi ble pat ient s will be ra n d oml y ass i gne d t o t he treat me nt re d ucti o n ar m or t o 
t he refere nce ar m i n a 3: 1 rati o :

Tre at me nt re d ucti o n ar m
Fase nra ® 3 0 m g Q 8 W + S M A R T or S y m bic ort ® relie ver o nl y (starti n g with me d i u m-
d ose S y m bic ort ® 2 0 0/ 6 µ g × 2 i n halat i ons BI D m ai nte na nce + S y m bic ort ® 2 0 0/ 6 µ g 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 6 of 1 1 7
relie ver P R N; ta peri n g t o S y m bic ort® 2 0 0/ 6 µ g relie ver o nl y, as per ta peri n g sc he me 
a n d de pe n di n g o n de gree of ast h ma c o ntr ol).

Refere nce a r m
Fase nra ® 3 0 m g Q 8 W + hi g h -d ose S y m bic ort ® ma i nte na nce × 2 i n halat i ons BI D + 
Ve nt oli n ® (sal b uta mol  1 0 0 μ g) relie ver P R N .
Tre at me nt re d ucti o n ar m: At  t he ra n d omisat i on visit ( Visit 2 b ) eli gi ble pat ient s ra n d o mise d t o 
t he treat me nt re d ucti o n ar m will a ut o m at icall y be ste p pe d d o w n t o me di u m -d ose S M A R T.  
P ati e nts w h o de m o nstrate mai ntai ne d ast h ma c o ntr ol will ta per (ste p d o w n) t heir S M A R T 
re gi me n u ntil t he y ac hie ve eit her S y m bic ort® as a nti-i nfla m mat or y relie ver treat me nt o nl y or 
u nt il n o f urt her re d ucti o ns o f S M A R T are per mitte d d ue t o l oss of ast h ma c o ntr ol (see 
Secti o n 4. 1. 1 ).  If a patie nt is recei vi n g me di u m-d ose S M A R T a n d l oses ast h ma c o ntr ol, t he y  
ca n be ste p pe d u p t o hi g h-d ose S y m bic ort ® ma i nte na nce treat me nt a n d Ve nt oli n ® relie ver 
treat me nt (ie, ret ur ni n g t o t he st u d y treat me nt pr o vi de d d uri n g t he r u n-i n peri o d).
T he re d ucti o n peri o d i n t his ar m will last 3 2 wee ks.  At eac h p ost -ra n d o misati on st u d y  visit 
( Visit 3 a n d Visit 4; Visit 5 if re q uire d) , t he I n vest i gat or will e val uate t he occ urre nce of 
ast h ma e xacer bati o ns, w orse ni n g of ast h ma c o ntr ol ( A C Q - 5 ≥0. 5 u nits c o mpare d t o baseli ne), 
a n d o ver use of S y m bic ort ® 2 0 0/ 6 μ g treat me nt (a wee kl y a vera ge of > 8 i n halati ons of  
S y m bic ort ® / da y).  T he I n vesti gat or will t he n deci de t o re d uce, mai ntai n, or i ncrease t he 
S y m bic ort ® d ose base d o n a pre s pecifie d al g orit h m (see Sectio n 4. 1. 1 ).  A patie nt will st o p 
ste p pi n g d o w n f or t he d urati o n of t he re d ucti o n peri o d if 1) t he patient  e x perie nces a n ast h ma 
e xacer bati o n si nce t he last visit or 2) if t he patie nt e x perie nces a w orse ni n g of ast h ma c o ntr ol 
A N D o ver use of S y m bic ort ® 2 0 0/ 6 μ g treat me nt d uri n g t he 4 wee ks pri or t o eac h st u d y visit .
P ati e nts w h o are n ot o n S y m bic ort ® relie ver o nl y  b y Visi t 4 will be gi ve n 1 a d ditio nal  
o p p ort u nit y t o ste p d o w n at Visit 5 if t he y  d e mo nstrate ast h m a c o ntr ol.  Patie nts w h o ste p 
d o w n t o S y m bic ort ® relie ver o nl y at Visit 4 will atte n d Visit 5 b ut will n ot re d uce t heir d ose 
a n y f urt her.  All pat ient s will be gi n t he mai nte na nce peri o d after Visit 6. 
Refere nce ar m: Eli gi ble p at ient s ra n d o mise d t o t he refere nce ar m will  c o nti n ue o n hi g h -d ose 
S y m bic ort ® ma i nte na nce treat me nt a n d Ve nt oli n ® relie ver treat me nt f or 3 2 wee ks.
M ai nte n a nce peri o d: Patie nts i n b ot h ar ms will a ut o mat icall y e nter t he 1 6- wee k mai nte na nce 
p eri o d d uri n g w hic h pat ient s i n t he treat me nt re d ucti o n ar m will c o nt i n ue o n t he S y m bic ort ®
tr eat me nt  le v el t he y ac hie ve d at t he e n d of t he re d ucti o n peri o d.  I n t he e ve nt of ast h ma 
w orse ni n g d uri n g t he mai nte na nce peri o d, t he I n vesti gat or ma y  deci de t o ste p u p t he 
S y m bic ort ® d ose.  N o re d ucti o ns i n S y m bic ort ® d ose s are all o we d d uri n g t he mai nte na nce 
p eri o d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 7 of 1 1 7
S u b- st u dy: A s u bset of patie nts w h o c o nse nt t o partici pat i on i n t he s u b-st u d y (a p pr o xi matel y 
3 2 pati e nts are t o be i ncl u de d, s prea d acr oss t he 2 treat me nt ar ms) will u n der g o air wa y 
oscill o m etr y  t o assess a meas ur e of lu n g f u n cti o n a n d will u n der g o br o nc h osc o p y  a n d i n d uce d 
s p ut u m sa m pli n g at s pecific ti me p oi nts (Ta ble 1 ) f or e x pl orat or y bio m ar ker researc h.  Pat ient s 
will be e nr o lle d fr o m 1 st u d y site i n t he U K a n d will be stratifie d i nto t he s u b -st u d y se paratel y 
fr om t he mai n st u d y wit h a 3: 1 ratio b y  treat me nt ar m (treat me nt re d ucti o n ar m: refere nce 
ar m).
St u d y c o m pleti o n/ e n d of tre at me nt : Patie nts will be c o nsi dere d t o ha ve c o m p lete d t he st u d y 
if t he y co m plete Visit 8 b (see Secti o n 4. 4 ).  Patie nts w h o disc o nt i n ue treat me nt pre mat urel y 
w ill atte n d an e n d of treat me nt ( E O T) visit, i ncl u di n g t h e sa me assess me nt s as i n Visits 8a a n d 
8 b t o e xit t he st u d y.
U nsc he d ule d V isit: St u d y  site e val uati ons f or ast h ma w orse ni n g ma y occ ur as a n 
u nsc he d ule d visit or as part of a r o uti ne ce ntre visit  if t he w orse ni n g ha p pe ns t o occ ur i n li ne 
wi t h a sc he d ule d visit.  A c o p y of t h e me dical rec or d s h o ul d be o btai ne d f or ast h ma s y m pt o m 
w orse ni n g or ast h ma e xacer bati o ns e val uate d a n d treate d at n o n -st u d y sites (e g, b y t he 
pri mar y  care pr o vider or at a n e m er ge nc y de part me nt/ h os pi t al).  Details s h o uld be e ntere d i nt o 
t he e xacer bat i on electr o nic case re p ort f or m (e C R F) mo d ul e i n a ti mel y fas hi on.  C ha n ges i n 
c o nc o mita nt me dicat i ons d ue t o ast h ma s y m pt o m w orse ni n g or ast h ma e xacer bati o ns m ust be 
rec or de d i n t he a p pr o priate mo d ul e of t he e C R F.
F or a n o ver vie w of t he st u d y  desi g n see Fi g ure 1 , Sectio n 1. 3 . F or details o n treat me nts gi ve n 
d uri n g t he st u d y , see Sectio n 6. 1 .
F or details o n w hat is i ncl u de d i n t he efficac y a n d safet y e n d p o i nts, see Secti o n 3.
St u d y c o n d uct miti g ati o n d uri n g st u d y disr u pti o ns d ue t o c ases of ci vil crisis, n at ur al 
dis aster, or p u blic he alt h crisi s: T he g ui da nce gi ve n bel o w s u perse des i nstr ucti o ns pr o vi de d 
else w here in t his cli nical st u d y  pr ot oc ol a n d s h o ul d be i m ple me nte d o nl y d uri n g cases of ci vil 
crisis, nat ural disaster, or p u blic health crisis (e g, d uri n g q uara nt i nes a n d res ulti n g site 
clos ures, re gi o nal  tra vel r estrict i ons, a n d c o nsi derati o ns if site pers o n nel or stu d y patie nts
bec o me i nfecte d wit h S A R S-C o V -2 or si milar pa n de mic i nfecti o n) w hic h w o ul d pre ve nt t he 
c o n d uct of st u d y-relate d acti vities at st u d y sites, t here b y c o mpr o misi n g t he st u d y  site staff or 
t he pati e nt’s a bilit y t o co n d uct t he st u d y .  T he i n vestigat or or desi g nee s h o ul d c o ntact t he 
st u d y S p o ns or t o disc uss w het her t he miti gati on pla ns bel o w s h o ul d be i m ple me nte d.
T o e ns ure c o nti n uit y of  t he cli nical st u d y d uri n g a ci vil crisis, nat ural disaster, or p u blic health 
crisis, c ha n ges ma y be i m ple me nte d t o e ns ure t he safety of  st u d y patie nts, mai ntai n 
c o mplia nce wi t h G o o d Cli nical Practice, a n d mi ni mize ris ks t o st u d y int e grit y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 8 of 1 1 7
W here all o wa ble b y  local heal t h a ut h orities, et hics c o m mittees, healt hcare pr o vid er g ui deli nes 
(e g, h os pital p olicies) or l ocal g o ver n me nt, t hese c ha n ges ma y i ncl u de t he f oll o wi n g o pti o ns:

O btai ni n g c o nse nt/rec o nse nt f or t he mit i gati on pr oce d ures ( n ote, i n t he case of ver bal 
c o nse nt/rec o nse nt, t he I nf or me d C o nse nt F or m (I C F) s h o ul d be si g ne d at t he patie nt’s 
ne xt c o ntact wit h t he st u d y sit e).

Rescree ni n g: A d dit i onal rescree ni n g f or scree n fail ure a n d t o c o nfir m eli gi bilit y t o 
parti ci pate i n t he cli nical st u d y ca n be perf or me d i n pre vi o usl y scree ne d partici pa nts.  T he 
i n vesti gat or s h o ul d c o nfir m t his with t he desi g nate d st u d y  p h ysicia n.

H o m e or Re mot e vi sit: P erfor m e d b y a site q ualifie d Healt h Care Pr ofessi on al  ( H C P) or 
H C P pr o vi de d b y a t hir d -part y  ve n d or ( T P V).

T el e me dici ne visit: Re m ote c o ntact wit h t he patie nts usi n g telec o m m u nicat i ons 
tec h n ol og y  incl u di n g p h o ne calls, virt ual o r vi de o visits, a n d mo bile heal t h de vices.

At -h o me I n vest i gati onal Pr o d uct (I P) a d mi nistrati o n: Perf or me d b y  a site q ualifie d H C P, 
H C P pr o vi de d b y a T P V, or b y  t he patie nts or t he patie nt’s care gi ver, if p ossi ble. 
A d dit i onal i nf or mati o n relate d t o t he visit ca n be o btai ne d via tele me dici ne.
F or f urt her details o n st u d y  c o n d uct d uri n g ci vil crisis, nat ural disaster, or p u blic healt h crisis, 
refer t o A p pe n di x G .
4. 1. 1
Tre at m e nt re d ucti o n ar m t a peri n g
A n e xa m ple of h o w t he dail y hi g h -d ose S y m bic ort ® ma i nte na nce tr e at me nt will be re d uce d t o 
eit her me di u m-d ose S M A R T , lo w -d ose S M A R T , or S y m bic ort® as a nti-i nfla mmat or y  relie ver 
is s h o w n i n Ta ble 3.
T a ble 3
S y m bic ort ® d osi n g re gi me n f or p atie nts w h o m ai nt ai n ast h m a c o ntr ol 
d uri n g t he re d ucti o n peri o d
Ste p
M ai nte n a nce Tre at me nt
Relie ver Tre at me nt
Visit 1 a n d r u n -i n peri o d ( 4 t o 
8 wee ks)
Hi g h -d ose S y m bic ort ®
( 4 0 0/ 1 2 μ g × 2 i n halati o ns BI D)
Ve nt oli n ® 1 0 0 μ g
Visit 2 b ( Wee k 0)
Me di u m -d ose S y m bic ort ®
( 2 0 0/ 6 μ g × 2 i n halati o ns BI D)
S y m bic ort ® 2 0 0/ 6 μ g 
1 st Ste p d o w n ( Visit 3 o n war ds)
L o w -d ose S y m bic ort ®
( 2 0 0/ 6 μ g × 1 i n halati o n BI D)
S y m bic ort ® 2 0 0/ 6 μ g
2 n d Ste p d o w n ( Visit 4 o n war ds)
N o ne
S y m bic ort ® 2 0 0/ 6 μ g
BI D =t wice per da y.
T he al g ori t h m f or ste p pi n g d o w n or ste p pi n g u p S y m bic ort® treat me nt is s h o w n i n  Fi g ure 2.   
Ast h ma e xacer bati o ns will be assesse d si nce t he last stu d y visit ; t he c ha n ge fr om baseli ne i n 
A C Q -5 a n d t he wee kl y a vera ge of S y m bic ort ® 2 0 0/ 6 μ g i n halati ons/ d a y will be assesse d f or
t he 4 wee ks pri or t o t he st u d y visit.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 9 of 1 1 7
Fi g ure 2
Al g orit h m f or ste p pi n g d o w n/ u p tre at me nt i n t he Re d ucti o n Peri o d
A C Q -5 = Ast h m a c o ntr ol q uesti o n naire -5 ite m. 
A patie nt will st o p ste p pi n g d o w n f or t he d urati o n of t he re d ucti o n peri o d if 1) t he patie nt e x perie nces an ast h ma 
e xacer bati o n (see Secti o n 8. 1. 3 ) si nce t he last visit or  2) if d uri n g t he last 4 wee ks pri or t o eac h st u d y visit t he 
patie nt e x perie nces a n A C Q -5 w orse ni n g of ≥0. 5 p oi nts c o m pare d t o baseli ne a n d has a wee kl y a vera ge of 
> 8 i n halati o ns of S y m bic ort ® / da y.  A patie nt will dela y ta per if d uri n g t he last 4 wee ks pri or t o eac h st u d y visit 1) 
t he patie nt e x perie nces a n A C Q-5 w orse ni n g of ≥0. 5 u n its c o m pare d t o baseli ne a n d has a wee kl y a vera ge of 
≤8 i n halati o ns of S y m bic ort ® / da y or  2) t he patie nt e x perie nces n o A C Q-5 w orse ni n g ( < 0. 5 u nits c o m pare d t o 
baseli ne ) a n d has a wee kl y a vera ge of > 8 i n halati o ns of S y m bic ort ® / da y.
4. 1. 2
M o nit ori n g ast h m a c o ntr ol a n d S y m bic ort ® 2 0 0/ 6 μ g use
T o mit i gate t he ris k of ast h ma deteri orati o n or e xacer bati on d uri n g t he re d ucti o n of 
S y m bic ort ® ma i nte na nce treat me nt, 3 alerts ( 2 wee kl y alerts a n d 1 dail y alert) will be use d f or 
t his st u d y:
Wee kl y A lerts

If a patie nt’s A C Q -5 sc ore deteri orates (i ncrease s) b y at least 0. 5 u nits c o mpare d t o 
baseli ne. 

If a patie nt has e xcessi ve t otal ( mai nte na nce a n d relie ver) S y m bic ort ® 2 0 0/ 6 μ g use wit h a 
wee kl y a vera ge of > 8 i n halati ons/ da y .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 0 of 1 1 7
D ail y A lerts

If a patie nt has a n e xcessi ve t otal ( mai nte na nce a n d relie ver) S y m bic ort ® 2 0 0/ 6 μ g use of
> 1 2 i n halati ons/ da y f or 2 c o nsec ut i ve da ys.
If a n alert is tri g gere d, t he patie nt, I n vesti gat or, a n d A Z or dele gate will recei ve a n alert a n d 
t he patie nt will be i nstr ucte d t o c o ntact t he st u d y site or a n ot her healt hcare pr o vi der as s o o n as 
p ossi ble.
4. 2
Scie ntific R ati o n ale f or S t u d y D esi g n
I n cli nical practice, re d ucti o n of sta n dar d of care bac k gr o u n d ast h ma treat me nt me dicati ons is 
a nt ici pate d t o be a n i ncreasi n gl y c o m mo n  sce nario i n patient s w h ose ast h ma bec o mes 
c o ntr olle d f o ll owi n g t he a d di tio n of  a n ast h ma bi ol o gic li ke Fase nra ® . Oral c ortic oster oi ds, 
I C S, a n d L A B A eac h ha ve p ote ntial safety a n d t olera bilit y iss ues. It w o ul d be a p ote ntial 
be nefit t o patie nts if Fase nra ® treatme nt  c o ul d e na ble re d ucti o n i n t hese t hera pies, w hile 
all o wi n g patie nts t o mai ntai n ast h ma c o ntr ol a n d i m pr o vi n g dr u g c o m plia nce . W het her 
treat me nt wit h Fase nra ® ca n e na ble pat ient s t o re d uce t heir sta n dar d of care ast h ma c o ntr oller 
re gi me n w hile mai ntai ni n g ast h ma c o ntr ol has n ot bee n pre vi o usl y e val uate d.
T his is a P hase I V, ra n d o mise d, o pe n-label, act i ve-c o ntr olle d st u d y desi g ne d t o f urt her 
i n vesti gate t he efficac y of Fase nra ® ( 3 0 m g) a d mi nistere d s u bc uta ne o usl y ( S C) i n se vere 
ast h ma patie nts wit h e osi no p hilic ast h ma o n sta n dar d of care t hera p y  (e g, hig h -d ose 
I C S/ L A B A) t o deter mi ne if t he I C S/ L A B A d ose ca n be safel y re d uce d with o ut l oss of ast h ma 
c o ntr ol.  A refere nce ar m is i ncl u de d i n w hic h patie nts are mai ntai ne d o n sta n dar d of care 
hi g h -d ose I C S/ L A B A s o t hat t he de gree of ast h ma c o ntr ol ca n be c o m pare d bet wee n t he 
2 ar ms.   T he 3 0 m g S C d ose a n d e ver y  8-wee k re gi me n of  Fase nra® was s h o w n t o be effect i ve 
acr oss m ult i ple meas ures of ast h ma c o ntr ol i n t his p o p ulati on, wi t h a n o verall safety pr ofile 
si milar t o place b o.  Base d o n t he pre vi o us P hase III e x perie nce, a p pr o xi matel y 2 0 0 pati e nts 
st u die d o ver a 3 2 - wee k treat me nt peri o d will be e n o u g h t o detect differe nces fr o m baseli ne f or 
I C S d ose a n d bet wee n treat me nt gr o u ps f or A C Q- 5.
T he p ur p ose of t his pr o of -of -c o nce pt st u d y is t o assess t he p ote ntial f or re d uci n g t he use of 
S y m bic ort ® ma i nte na nce treat me nt i n ast h ma pat ient s treate d wit h Fase nra ® 3 0 m g S C .  T his 
st u d y will allo w p ati e nts t o re d uce t heir hi g h -d ose S y m bic ort ® ma i nte na nce treat me nt t o t he
l owest d osa ge/ da y  w hile bei n g c o ntr olle d o n t heir ast h ma s y m pt o ms.  T his will e ve nt uall y 
all o w us t o ge nerate e vi de nce t o assess a n d e x pl ore:

T he p ote ntial f or se vere e osi n o p hilic ast h ma pat ients treate d wit h Fase nra ® t o s afel y a n d 
effect i vel y re d uce t heir S y m bic ort ® ast h ma treat me nt b ur de n .

A ne w precisi o n- base d a p pr oac h t o treat e osi n o p hilic p he n ot y pe pati e nts base d o n 
mai nte na nce treat me nt wit h Fase nra ® pl us a nt i-i nfla m mat or y relie ver as nee de d 
(S y m bic ort ® 2 0 0/ 6 µ g, as nee de d) .


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 1 of 1 1 7
4. 3
J u stific ati o n f or D ose
T he cli nical efficac y  of Fase nra ® 3 0 m g S C was c o nfir me d i n 2 lar ge P hase III glo bal  safet y 
a n d efficac y trials i n pat ient s o n hi g h- d ose I C S/ L A B A a n d bl o o d e osi n o p hil c o u nts 
≥3 0 0 cells/ μ L (Bl ee ker et al 2 0 1 6 , Fi tz Gerald et al 2 0 1 6 ). I n t hese st u dies, Fase nra ® was 
d ose d e ver y  8 wee ks f or a p pr o xi mate l y 1 year a n d pr o d uce d si g nifica nt decreases i n ast h ma 
e xacer bati o ns ( u p t o 5 1 %), a n d i m pr o ve me nts i n f orce d e x pirat or y  v ol ume i n 1 sec o n d ( F E V1; 
u p t o 1 5 9 m L) a n d t otal dail y ast h ma s y m pt o m sc ores. T here was n o a p pare nt a d va nta ge t o 
m o r e fre q ue nt d osi n g (e ver y 4 wee ks) i n t hese st u dies. Of n ote, t he P hase III pr o gra m als o 
st u die d t he efficac y of Fase nra ® i n patient s wit h bl o o d e osi n o p hil c o u nts < 3 0 0 cells/ μ L a n d i n 
a n O C S -de pe n de nt ast h ma p o p ulati o n ( Fi t z G er ald et al 2 0 1 6 , G o l dma n et al 2 0 1 7 , 
N ai r et al 2 0 1 7 ). T he res ults of t hese pre s pecifie d a n d p o ole d a nal yses de m o nstrate d br oa d 
efficac y in pat ient s wit h blo o d e osi n o p hil  le vels ≥1 5 0 cells/ μ L, a n d als o s u p p ort e d a n 
e n ha nce d res p o nse t o F ase nra ® treat me nt w he n certai n i de ntifia ble cli nical feat ures of t he 
e osi n o p hilic ast h ma p he n ot ype are prese nt. T hese feat ures i ncl u de O C S de pe n de nce, a hist or y  
of  fre q ue nt e xacer bati ons, nasal p o l y po sis, later o nset of disease, a n d l o w l u n g f u nct i on. T h e 
3 0 m g d ose of Fase nra ® is a p pr o ve d i n ma n y c o u ntries w orl d wi de, i ncl u di n g t he U K , Fra nce,
a n d Ger ma n y, w here t he c urre nt st u d y  will be c o n d ucte d.
All o f t he mai nte na nce d oses of S y m bic ort ® t hat are pr o p ose d t o be use d i n t he c urre nt st u d y 
are a p pr o ve d i n ma n y c o u ntries w orl d wi de, i ncl u di n g t he c o u ntries i nte n de d f or t his st u d y.  
T he S Y G M A trial 2 als o s u g gest e d t hat t he as nee de d use of S y m bic ort ® i n mil d ast h ma c o ul d 
a d dress patie nts’ c o ncer ns a b o ut t he ris ks of I C S treat me nt (O' B yr ne et al 2 0 1 8) .  Patie nt 
c o ncer n wit h safet y  is a n ot her iss ue t hat ca uses o verrelia nce o n S A B As a n d p o or a d here nce t o 
mai nte na nce treat me nt wit h I C S. Patie nts are ofte n m ore c o ncer ne d t ha n t heir healt hcare 
pr o vi ders a b o ut a d verse effects of I C S, e ve n w he n l o w i n hale d d oses are use d .
Co n versel y ,
pati e nts are less c o ncer ne d a b o ut t heir le vel o f s y m pt o m c o ntr ol. Si nce S y m bic ort ® use d as 
nee de d was as effect i ve as b u des o ni de mai nte na nce treat me nt i n re d uci n g e xacer bati on ris k, 
wi t ho ut t he nee d f or re g ular t wice -dail y treat m e nt, a n d res ulte d i n o nl y 1 7 % of t he i n hale d 
gl uc oc orti c o i d l oa d, it w o uld pr o ba bl y  be m o re acce pta ble t o patie nts w h o ha ve t his c o ncer n 
t o use S y m bic ort® as nee de d.
U nc o ntr olle d se vere ast h ma pat ient s o n hi g h- d ose I C S/ L A B A are ca n di dates t o recei ve a 
b i ol ogic treat m e nt ( Ste p 5 of  GI N A 2 0 1 9 ). Hi g h d ose s of  b u des o ni de dr y  p o w der i n haler is 
defi ne d as a d ose greater t ha n 8 0 0 μ g/ da y . T he hi g hest mai nte na nce d ose of S y m bic ort ® is 
4 0 0/ 1 2 μ g BI D ( 1 i n halati on i n t he m or ni n g a n d i n t he e ve ni n g); h o we ver , t o ac hie ve 
b u des o ni de d oses greater t ha n 8 0 0 μ g/ da y  2 i n halati o ns BI D of  S y m bic ort® 4 0 0/ 1 2 μ g are 
re q uire d (pl ease r efer t o t he S y m bic ort ® S m P C) .  T his is t he d ose a d mi nistere d d uri n g t he r u n-
i n perio d of  t he st u d y a n d mai ntai ne d i n t he refere nce ar m.
I n a d diti on, S M A R T i s deli vere d wit h S y m bic ort ® 2 0 0/ 6 μ g f or t he re d ucti o n peri o d i n t he 
treat me nt re d ucti o n ar m; t his d ose is use d as a mai nte na nce treat me nt a n d is t o be re d uce d b y 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 2 of 1 1 7
5 0 % at eac h ste p .
O verall, t his mea ns t hat patie nts i n t he treat me nt re d ucti o n ar m will be 
re d uce d fr om 2 0 0/ 6 μ g 2 i n halati o ns BI D , t hr o u g h 2 0 0/ 6 μ g 1 i n halati on BI D, a n d fi nall y  t o 
2 0 0/ 6 μ g as a nti-i nfla m mat or y relie ver use o nl y (see S ectio n 4. 1. 1 a n d Fi g ure 1) .
4. 4
E n d of S t u d y D efi niti o n
T he e n d o f st u d y is defi ne d as t he last e x pecte d visit/c o ntact of t he last patie nt u n der g oi n g t he 
st u d y.
A pat ient is c o nsi dere d t o ha ve c o m plete d t he st u d y w he n he/s he has c om p lete d his/ her last 
sc he d ule d visit.
See A p pe n di x A 6 f or g uideli nes f or t he disse mi nati o n of st u d y  res ults.
5
S T U D Y P O P U L A TI O N
P ati e nts will be recr uit e d fr o m sec o n dar y/t ertiar y care sites via i nter nal data bases, c o ntact wit h 
h os pi t al cli nics, a n d referrals fr o m ot her p h ysicia ns a n d pri mar y care ce ntres .
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o l me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Eac h patie nt s h o ul d meet all of t he i ncl usi o n a n d ra n d o misati o n crit eria, a n d n o ne of t he 
e xcl usi o n cri teria, f or t his st u d y in or der t o be assi g ne d/ra n d o mise d t o a st u d y tr e at me nt .  
U n der n o circ u msta nces ca n t here be e xce pt i ons t o t his r ule. Patie nts w h o d o n ot m eet t he 
e ntr y r e q uire me nts are scree n fail ures; r efer t o S ecti o n 5. 4 .
I n t his pr ot oc ol, “e nr olle d” pati e nt s are defi ne d as t h ose w h o pr o vi de i nf or me d c o nse nt at 
Vi sit 1.  “ Ra n d omi se d” pa tie nt s are defi ne d as t h ose w h o u n der g o ra n d o misat i on a n d recei ve a 
ra n d omi sat i on n u m ber at Visit 2 b.
F or pr oce d ures f or wit h dra wal o f i nc orrectl y e nr olle d pati e nt s, see Secti o n 7. 3 .
5. 1
I ncl usi o n C riteri a
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g i ncl usi o n a n d 
ra n d omisat i on crit eria, a n d n o ne of t he e xcl usi o n cri t eria a p pl y:
I nf or me d C o n se nt
1
Pr o visi o n of i nf or me d c o nse nt pri or t o a n y st u d y -s pecific pr oce d ures.
T he i nf or me d c o nse nt f or m (I C F) pr ocess i s descri be d i n A p pe n di x A 3.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 3 of 1 1 7
A g e
2
P ati e nt m u st be a ge d 1 8 year s ol d or a b o ve at t he time of c o nse nti n g t o st u d y 
parti ci pat i on.
T y pe of P atie nt a n d D ise ase C h ar acteristics
3
D oc u m e nte d c urre nt mai nte na nce treat me nt wit h hi g h-d ose I C S/ L A B A.
4
A C Q -5 sc ore < 1. 5 at Visit 1.
5
Treat me nt wit h Fase nra ® f or t he i n dicate d dia g n osis of se vere e osi n o p hilic ast h ma a n d 
has recei ve d at least 3 c o nsec ut i ve d oses ( >8 wee ks ) prior t o Visit 1.
Se x
6
Male or fe mal e.
Re pr o d ucti o n
7
Ne gati ve s er u m pre g na nc y  t est at  Visit 1 f or w o me n of  c hil d beari n g p ote nti al ( WO C B P) .
8  
W O C B P m u st a gree t o use a hi g hl y effecti ve met h o d of birt h c o ntr ol (c o nfir me d b y t he 
I n vesti gat or) fr o m ra n d omisat i on t hr o u g h o ut t he st u d y  d uratio n a n d wi t hi n 12 wee ks after 
t he last d ose of st u d y treat me nt.  Hig hl y  effecti ve f or ms of birt h c o ntr ol (t h ose 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 n d c orrectl y)
i ncl u de:

C o m bi ne d ( oestr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n 
ass ociat e d wit h in hi bit i on of o v ulat i on- or al , i ntra va gi nal, or tra ns der mal.

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- or al , i njecta ble, or i m pla nta ble.

I ntra uteri ne de vice (I U D).

I ntra uteri ne h or m o ne-releasi n g s yste m (I U S).

Bilateral t u bal occl usi o n.

Se x ual a bst i ne nce, ie, refrai ni n g fr o m heter ose x ual i nterc o urse ( the relia bilit y of  
se x ual a bsti ne nce nee ds t o be e val uate d i n relati on t o t he d urati o n of t he cli nical 
st u d y a n d t he preferre d a n d us ual lifest yle of t he patie nt).

Vasect o mi se d se x ual part ner ( pr o vide d t hat part ner is t he s ole se x u al  part ner of 
t he W O C B P st u d y patient  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) .
9
W o me n n ot of c hil d beari n g p ote ntial are defi ne d as w o me n w h o are eit her per ma ne nt l y 
sterilize d ( h ysterect o m y, bilateral o o p h orect o m y, or bilateral sal pi n gect o m y), or w h o are 
p ost m e n o pa usal.  W o me n will be c o nsi dere d p ost me n o pa usal if t he y ha ve bee n 
a me n orr h oeic for ≥1 2 m o nt hs pri or t o t he pla n ne d date of ra n d o mi sat i on wi t ho ut a n 
alter nati ve me dical ca use. 
1 0
T he f o ll owi n g a ge -s pecific re q uire me nts a p pl y:


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 4 of 1 1 7
1 1
W o me n < 5 0 years ol d will be c o nsi dere d p ost me n o pa usal if t he y ha ve bee n a me n orr h oeic 
f or 1 2 m o nt hs or m or e f ol l owi n g cessat i on of e x o ge n o us h or m o nal treat me nt a n d ha ve 
f ollicle sti m ulati n g h or m o ne ( F S H) l e vels i n t he p ost me n o pa usal ra n ge.  U ntil F S H is 
d oc u m e nte d t o be wit hi n me n o pa usal ra n ge, treat t he patient  as W O C B P.
1 2
W o me n ≥5 0 years o l d will be c o nsi dere d p ost me n o pa usal if t he y ha ve bee n a me n orr h oeic 
f or 1 2 m o nt hs or m or e f ol l owi n g cessat i on of all e x o ge n o us h or m o nal treat me nt.
5. 1. 1
R a n d o mi sati o n criteri a
F or ra n d o misat i on at Visit 2 b, p atie nts s h o uld f ulfil  t h e fol l owi n g cri t eria:
1
A C Q -5 < 1. 5 at Visit 2 b.
2
N o i ncrease ( w orse ni n g) i n A C Q- 5 of  at least ≥0. 5 u nits bet wee n Visit 1 a n d Visit 2 b
c o mpare d t o baseli ne .
3
N o ast h m a e xacer bat i on (see Secti o n 8. 1. 3 ) bet wee n Visit 1 a n d Visi t 2 b.
4
N o use of Ve nt oli n ® f or s y m pt o m w orse ni n g i n > 3 o ut of t he 7 da ys pri or t o Visit 2 b . 
N ote: U se of Ve nt oli n ® f or pr o p h ylactic reas o ns s uc h as e xercise is all o we d.
5. 2
E xcl usi o n C riteri a 
Me dic al
C o n diti o ns
1
As j u d ge d b y  t he I n vesti gat or, a n y e vi de nce of a se vere or seri o us treat me nt-relate d A E 
d uri n g Fase nra ® treat me nt w hic h i n t he I n vest i gat or’s o pi ni on ma kes it u n desira ble f or t he 
pati e nt t o partici pate i n t he st u d y.
2
Hi st or y of e xacer bati on re q uirin g s yste mic c ortic oster oi ds or h os pitali sat i on d uri n g t he 
last 3 m o nt hs pri or t o Visit 1 or d uri n g t he r u n -i n p e rio d .
3
Cli nicall y i m p orta nt p ul m o nar y disease ot her t ha n ast h ma (e g, acti ve l u n g i nfect i on, 
C O P D, br o nc hiectasis, p ul m o nar y  fi br osis, c ystic fi br osis), or e ver bee n dia g n ose d wit h 
p ul m o nar y  or s yste mic disease, ot her t ha n ast h ma, t hat are ass ociate d wit h ele vate d 
p eri p heral  e osi n o p hil c o u nts (e g, aller gic br o nc h o p ul m onar y  as per gillosi s/ m yc osis, 
C h ur g -Stra uss s y n dr o me, h y pere osi n o p hilic s y n dr o me).
4
C urre nt s mo kers or f or m er s mo kers wi t h a s mo ki n g hist or y  ≥2 0 pac k/ years.
5
Hi st or y of alc o h ol or dr u g a b use wit hi n 1 2 m o nt hs pri or t o Visit 1.
6
A hel mi nt h parasit ic i nfecti o n dia g n ose d wit hi n 2 4 wee ks pri or t o Visit 1 t hat has n ot 
bee n treate d wit h, or has faile d t o res p o n d t o , sta n dar d of care t hera p y.
7
Hi st or y of a na p h yla xis t o a n y biol o gic t hera p y .
8
K n o w n hist or y  of aller g y or r e actio n t o a n y  c o mp o ne nt of t he st u d y  treat me nt 
f or mulat i on.
9
A hist or y  of k n o w n i m m u n o deficie nc y dis or der, i ncl u di n g hist or y  of a p ositive h u ma n 
i m m u n o deficie nc y vir us ( HI V) test.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 5 of 1 1 7
1 0
C urre nt mali g na nc y, or hist or y  of mali g na nc y, e xce pt f or: 

P ati e nts w h o ha ve ha d basal cell carci n o ma, l ocalize d s q ua m o us cell carci n o ma 
of  t he s ki n or i n sit u carci n oma of t he cer vi x are eli gi ble pr o vi de d t hat t he patie nt 
is i n re missi on a n d c urat i ve t hera p y was c om p lete d at least 1 2 m o nt hs pri or t o 
t he date i nf o r me d c o nse nt was o btai ne d.

P ati e nts w h o ha ve ha d ot her mali g na ncies are eli gi ble pr o vi de d t hat t he patie nt is 
i n re missi on a n d c urat i ve t hera p y was c o m plete d at least 5 years pri or t o t he date 
i nf or me d c o nse nt was o btai ne d.
Pri or/ C o nc o mit a nt T her a p y
1 1
O r al corti c oster oid use d uri n g t he l ast 3 m o nt hs pri or t o Visit 1.
1 2
Recei pt of L A M As or t he o p h ylli nes fr o m Visi t 1 u nt il after Visit 8 b , or L T R As fr o m 
Vi sit 2 b u nt il after Visit 8 b (see Ta ble 6 ).
1 3
Use of i m m u n os u p pressi ve me dicat i on (i ncl u di n g b ut n ot li mite d t o: met h otre xate, 
tr olea n d o m yci n, c ycl os p ori ne, azat hi o pri ne, i ntra m usc ular l o n g -act i n g de p ot 
c ortic oster oid, or a n y  e x peri me ntal a nt i-i nfla m mat or y t hera p y) wit hi n 3 m o nt hs or 5 half -
li ves ( w hic he ver is l o n ger) pri or t o t he date i nf or me d c o nse nt is o btai ne d. 
1 4
Recei pt of li ve atte n uate d vacci nes 3 0 d a y s prior t o Visit 1.
1 5
It is rec o m me n de d t o all o w recei pt of i nacti ve/ kille d vacci nati ons (e g, i nact i ve i nfl ue nza) 
pr o vi de d t he y  are n ot a d mi nistere d wit hi n 1 wee k bef ore/after a n y  st u d y treat me nt
a d mi nistrati o n.
1 6
It is rec o m me n de d t o all o w recei pt of c or o na vir us disease 2 0 1 9 ( C O VI D -1 9) vacci nati o n 
pri or t o st u d y  start pr o vide d s uc h pat ient s are n ot ra n d omize d u nt il > 3 0 da ys after l ast 
vacci ne d ose .
1 7
It is rec o m me n de d t o all o w aller ge n i m m u n ot hera p y pr o vide d i t is sta ble f or at least 
3 0 d a y s prior t o Vi sit 1 a n d t here i s n o a ntici p ate d c ha n ge d uri n g t he treat me nt peri o d.  
Aller ge n i m m u n ot hera p y  s h o uld n ot be a d mi nistere d o n t he sa me da y as st u d y  visits.
1 8
Recei pt of i m m u n o gl o b uli n or bl o o d pr o d ucts wit hi n 3 0 da ys pri or t o t he date i nf or me d 
c o nse nt is o btai ne d.
1 9
Fi ve -li p o x y ge nase i n hi bitors (e g, zile ut o n) are pr o hi bite d a n d are n ot all o we d wit hi n 
3 0 d a y s of Visit 1 a n d u ntil after Visit 8 b.
2 0
Recei pt of a n y  mar kete d (e g, o maliz u ma b) or i n vesti gat i onal bi o l ogic wi t hi n 4 m o nt hs or 
5 half -li ves pri or t o t he date i nf or me d c o nse nt is o btai ne d, w hic he ver i s lo n ger .
2 1
Recei pt of s yste mic treat me nt wit h str o n g C Y P 3 A 4 i n hi bit ors (e g , ket oc o naz ole a n d 
itrac o naz ole) fr om Visi t 1 u ntil after Visit 8 b (for details, see  A p pe n di x D) .
2 2
Recei pt of b et a-a dre ner gic bl oc kers (i ncl u di n g e ye dr o ps) fr o m Visit 1 u ntil after Visit 8 b.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 6 of 1 1 7
Pri or/ C o nc urre nt C li nic al S t u d y E x perie nce
2 3
C o nc urre nt partici pat i on i n a n ot her cli nical st u d y wit h a n I n vesti gati onal Pr o d uct or a 
p ost -a ut h orisat i on safet y st u d y.
Ot her E xcl usi o ns
2 4
Pl a n ne d s ur gical pr oce d ures or ot her pla n ne d life e ve nts d uri n g t he c o n d uct of t he st u d y  
t hat w o uld affect t he patie nt's a bilit y t o c o mpl y wit h st u d y  treat me nt d osi n g or st u d y  
assess me nts.
2 5
I n v ol ve me nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o b ot h A Z staff a n d/ or 
staff at t he st u d y sit e).
2 6
J u d ge me nt b y t he I n vesti gat or t hat t he patie nt s h o ul d n ot partici pate i n t he st u d y if t he 
pati e nt is u nli kel y t o c o m pl y wit h st u d y pr oce d ures, restrict io ns , a n d re q uire me nts.
2 7
Pri or ra n d o misat i on i n t he prese nt st u d y. 
2 8
C urre nt l y pre g na nt, breast-fee di n g, or lactati n g w o me n .
5. 3
Lifest yle R estricti o ns
P ati e nts e nr olle d i n t he st u d y s h o uld a d here t o t he f o ll owi n g c o n dit i ons f or t he d uratio n of  t he 
st u d y.  A n y e ve nt li kel y t o i nterfere wit h t he c o n d uct of t he st u d y  will be c o m m u nicate d t o t he 
I n vesti gat or a n d re p orte d wit h o ut dela y t o t he S p o ns or.
5. 3. 1
Me als a n d diet ar y restricti o ns
P ati e nts s h o uld a v oi d eati n g a lar ge meal f or at least 2 h o urs pri or t o all p ul m o n ar y fu nct i on 
tests at  t he st u d y sit e a n d pat ient s s h o uld n ot eat or dri n k 1 h o ur pri or t o ha vi n g t he fract i onal 
e x hale d nitric o xi de ( Fe N O) test.  Patie nts m u st fast f or 6 h o urs pri or t o a n y br o nc h osc o p y  
pr oce d ures.
5. 3. 2
C affei ne, alc o h ol, a n d t o b acc o
T here are n o pr ot oc ol -s pecific restricti ons t o caffei ne or alc o h o l i nta ke.  S mo ki n g is n ot 
per mitte d as per e xcl usi o n cri t erio n 4 .
5. 3. 3
Acti vit y
P ati e nts s ho ul d a v oi d stre n u o us e xercise f or at least 3 0 mi n utes bef ore t he pla n ne d visit s t o t he 
st u d y sit e.
5. 3. 4
Bl o o d D o n ati o n
P ati e nts must a bstai n fr o m d o nati n g bl o o d, plas ma , or pl at elets fr o m t he ti me of i nf or me d 
c o nse nt a n d f or 1 2 wee ks after last d ose of st u d y treat me nt.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 7 of 1 1 7
5. 4
Scree n F ail ures
Scree n fail ures are defi ne d as pat ient s w h o sig ne d t he I C F t o partici pate i n t he cli nical st u d y 
b ut are n ot s u bse q ue ntl y ra n d o ml y assi g ne d t o 1 of t he 2 st u d y treat me nt ar ms .  A mi ni mal set 
of  scree n fail ure i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure 
pati e nt s t o meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C O N S O R T) p u blis hi n g 
re q uire me nts a n d t o res p o n d t o q ueries fr om re g ulat or y a ut h orities.  Mi ni mal i nf or mati on 
i ncl u des de m o gra p h y, scree n fail ure details, eli gi bility criteria, a n d a n y s erio us a d verse e ve nt 
( S A E).
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y n ot
be rescree ne d.   T hese pat ient s s h o ul d ha ve t he reas o n f or st u d y wit hdra wal rec or de d i n t he
eC R F .
P ati e nts w h o d o n ot f ulfil t he ra n d o misati o n criteria (see Secti o n 5. 1. 1 ) will be c o nsi dere d 
scree n faile d.
6
S T U D Y T R E A T M E N T S
St u d y  treat me nt is defi ne d as a n y I n vest i gati onal Pr o d uct(s) , mar kete d pr o d uct , or place b o 
i nte n de d t o be a d mi nistere d t o ut ilise d b y a st u d y partici pa nt acc or di n g t o t he st u d y pr ot oc ol.  
St u d y  treat me nt i n t his st u d y r efers t o Fase nra ® , S y m bic ort® , a n d Ve nt oli n ® .
6. 1
Tre at me nts A d mi nistere d
6. 1. 1
I n vesti g ati o n al pr o d ucts


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 8 of 1 1 7
T a ble 4
St u d y tre at me nts
F ase nr a ®
( be nr aliz u m a b)
S y m bic ort ® ( b u des o ni de/f or m oter ol)
Ve nt oli n ®
(s al b ut a m ol)
Hi g h -d ose
m ai nte n a nce
Me di u m -d ose 
S M A R T
L o w -d ose 
S M A R T
Reli e ver o nl y
St u d y tre at me nt 
n a me:
Fase nra ® 3 0 m g 
s ol uti o n
S y m bic ort ®
T ur b o haler ® 4 0 0/ 1 2, 
i n halati o n p o w der
S y m bic ort ®
T ur b o haler ® 2 0 0/ 6, 
i n halati o n p o w der
S y m bic ort ®
T ur b o haler ® 2 0 0/ 6, 
i n halati o n p o w der
S y m bic ort ®
T ur b o haler ® 2 0 0/ 6, 
i n halati o n p o w der
Ve nt oli n ® p M DI
D os a ge 
f or m ul ati o n:
Be nraliz u ma b 
3 0 m g/ m L, 1 m L fill 
v ol u me
B u des o ni de 
4 0 0 μ g/f or m oter ol 
f u marate 1 2 μ g per 
i n halati o n
B u des o ni de 
2 0 0 μ g/f or m oter ol 
f u marate 6 μ g per 
i n halati o n
B u des o ni de 
2 0 0 μ g/f or m oter ol 
f u marate 6 μ g per 
i n halati o n
B u des o ni de 
2 0 0 μ g/f or m oter ol 
f u marate 6 μ g per 
i n halati o n
Sal b uta m ol 
s ulfate 1 0 0 μ g 
per i n halati o n
R o ute of 
a d mi nistr ati o n:
S u bc uta ne o us i njecti o n
Oral i n halati o n  
Oral i n halati o n
Oral i n halati o n
Oral i n halati o n  
Oral i n halati o n
D osi n g 
i nstr ucti o ns:
Q 4 W f or first 3 d oses 
( pri or t o st u d y 
i ncl usi o n), Q 8 W 
t hereafter
Mai nte na nce:
2 i n halati o ns BI D, 
o nce i n t he m or ni n g 
a n d once i n t he 
e ve ni n g
Mai nte na nce:
2 i n halati o ns BI D, 
o nce i n t he 
m or ni n g a n d o nce 
i n t he e ve ni n g.
Relie ver use:
P R N
Mai nte na nce:
1 i n halati o n BI D, 
o nce i n t he 
m or ni n g a n d o nce 
i n t he e ve ni n g.
Relie ver use:
P R N
Relie ver use:
P R N
Relie ver use:
P R N
M ai nte n a nce
t ot al d os a ge: 
B u de s o ni de 
(t he S y m bic ort 
I C S c o m p o u n d)
1 6 0 0 μ g
(B u des o ni de 4 0 0 μ g 
× 2 i n halati o ns BI D )
8 0 0 μ g
(B u des o ni de 
2 0 0 μ g × 
2 i n halati o ns BI D )
4 0 0 μ g
(B u des o ni de 
2 0 0 μ g × 1
i n halati o n BI D )
2 0 0 μ g
(B u des o ni de 2 0 0 μ g
w h e n nee de d)


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 9 of 1 1 7
T a ble 4
St u d y tre at me nts
F ase nr a ®
( be nr aliz u m a b)
S y m bic ort ® ( b u des o ni de/f or m oter ol)
Ve nt oli n ®
(s al b ut a m ol)
Hi g h -d ose
m ai nte n a nce
Me di u m -d ose 
S M A R T
L o w -d ose 
S M A R T
Reli e ver o nl y
P ac k a gi n g a n d 
l a belli n g:
Fase nra ®
( be nraliz u ma b) will be 
pr o vi de d b y A Z or 
dele gate i n a n 
access orise d pre-fille d 
s yri n ge ( A P F S)
S y m bic ort ® ( b u des o ni de/f or m oter ol) will be pr o vi de d b y A Z or dele gate i n a 
T ur b o haler ®
Ve nt oli n ®
(sal b uta m ol) will 
be pr o vi de d b y 
A Z or dele gate i n 
a p M DI
All treat me nts will be la belle d i n acc or da nce wit h G o o d Ma n ufact uri n g Practice ( G M P) A n ne x 1 3 a n d per c o u ntr y re g ulat or y 
re q uire me nt.
A P F S = Access ori se d pr e-fille d s yri n ge; A Z = Astra Ze neca; BI D = T wice per da y; G M P = G o o d ma n ufact uri n g practice; p M DI = press urise d metere d d ose i n haler;
P R N = As nee de d; Q 4 W = e ver y 4 wee ks; Q 8 W = e ver y 8 wee ks ; S M A R T = S y m bic ort® mai nte na nce a n d relie ver t hera p y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 0 of 1 1 7
6. 1. 2
Me dic al de vices
M e dical de vices pr o vi de d f or use i n t his st u d y  are t he Hailie ™ se ns ors f or Ve nt oli n® a n d 
S y m bic ort ® , E R T Master Sc o pe T M S pir o met r y de vice, a n d Circassia NI O X Ver o Fe N O 
d e vice.
6. 1. 2. 1
H ailie T M I n h aler De vice
T he Hailie ™ i n haler de vices ( ma n ufact ure d b y Ad heri u m ) are Bl uet o ot h-e na ble d a n d 
a ut o mat icall y u pl oa d i n haler usa ge w he n t he y are near a s mart p h o ne t hat will be pr o vi de d f or 
t his st u d y.  T he Hailie ™ i n haler se ns ors will be use d t o trac k t he patie nts’ use of S y m bic ort®
T ur b o halers ® a n d Ve nt oli n ® press urise d m etere d d ose i n halers ( p M DIs ).
T he st u d y  site will e ns ure t he Hailie ™ i n haler de vices are i nstalle d pr o perl y o n t he 
a p pr o priate T ur b o haler ® / p M DI a n d t hat eac h de vice is pr o perl y p aire d wit h t he s mart p h o ne t o 
e na ble t he Bl uet o ot h-e na ble d de vice t o s y nc a n d tra ns mit data.
P ati e nts will als o be trai ne d o n h o w t o use, re m o ve, a n d re place t he Hailie ™ de vices o n refill 
T ur b o halers ® / pM DIs
at Visit 1.   Fr o m Visit 2 b t o Visit 7, a d di tio nal  trai ni n g will b e 
perf or m e d i n t he e ve nt of p o or c o m plia nce .
6. 1. 2. 2
S pir o metr y De vice
T he S pi r o meter use d i n t his st u d y is E R T Master Sc o pe T M .  T his is t he electr o nic p orta ble 
me dical de vice use d t o meas ure t he l u n g f u nct i on para meters F E V 1 a n d F V C .
6. 1. 2. 3
Fe N O M o nit ori n g De vice
T he Fe N O meas ure me nt will be perf or me d wit h t he p orta ble s yste m Ci rcassia NI O X Ver o ®
c o n necte d t o t he Master Sc o pe.  It will be use d t o pr ofile t he patie nt’s Fe N O.
I nstr ucti o ns f or me dical de vice use are pr o vi de d i n de vice-s pecific I nstr ucti o ns f or Use 
d oc u m e nts.
All me dical de vice deficie ncies (i ncl u di n g malf u ncti o n, use err or a n d i na de q uate la belli n g) 
s hall be d oc u me nte d a n d re p orte d b y t he In vest i gat or t hr o u g h o ut t he st u d y (see Secti o n 8. 4. 5 ) 
a n d a p pr o priatel y ma na ge d b y t he ma n ufact urer .
6. 2
Pre p ar ati o n/ h a n dli n g/st or a ge/ acc o u nt a bilit y
T he In vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n dit i ons ha ve bee n 
mai ntai ne d d u rin g tra nsit f or all st u d y  treat me nt recei ve d a n d a n y discre pa ncies are re p orte d 
a n d res o l ve d bef ore use of t he st u d y  treat me nt.
O nl y patie nt s e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nl y a ut h orise d site staff 
ma y s u p pl y  or a d mi nister st u d y treat me nt.  All st u d y treat me nts must be st ore d i n a sec ure, 


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e n vir o n me ntall y c o ntr olle d, a n d mo ni t or e d ( ma n ual or a ut o mate d) area in acc or da nce wit h t he 
la belle d st ora ge c o n diti o ns wit h access li mite d t o t he In vest i gat or a n d a ut h orise d site staff.
T he In ves tigat or, i nst ituti o n, or t he hea d of t he me dical i nst ituti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y tr e at me nt acc o u nta bilit y, rec o nciliat i on, a n d rec or d mai nte na nce (ie, 
receipt, rec o nciliat i on, a n d fi nal dis p osit i on rec or ds).
I nstr uctio ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d a d mi nistrati o n of Fase nra ® ,
S y m bic ort ® , a n d Ve nt oli n ® are pr o vide d i n t heir res pect i ve S m P C s.
T he m o ni t or will acc o u nt f or stu d y treat me nt pr o d ucts recei ve d at t he site, u n use d st u d y 
treat me nt s, a n d a p pr o priate destr ucti o n.  Certificates of deli ver y, destr ucti o n , a n d/ or ret ur n 
s h o uld be si g ne d.
I n t he e ve nt of a malf u ncti oni n g access orise d pre- fille d s yri n ge (A P F S ), t he ce ntre s h o ul d 
c o ntact t he st u d y mo ni t or t o i nitiate a pr o d uct c o m plai nt pr ocess acc or di n g t o a p plica ble 
g u i deli nes.
6. 3
Me as ures t o M i ni mise Bi as: R a n d o mis ati o n a n d B li n di n g
T his is a n o pe n -la bel st u d y a n d n ot bli n de d.  All p ati e nt s will be ce ntrall y assi g ne d t o 
ra n d omise d st u d y treat me nt usi n g a n i nteracti ve v oice/ we b res p o nse s yste m (I V R S/I W R S).  
Bef ore t he st u d y  is i nitiate d, t he tele p h o ne n u m ber a n d call- i n dir e ctio ns f or t he I V R S a n d/ or 
t he lo g -i n i nf or mati on a n d directi o ns f or t he I W R S will be pr o vi de d t o eac h site. 
At  Visit 2 b , a p pr o xi matel y 2 0 0 pat ient s will be ra n d o ml y assi g ne d t o 1 of t he 2 treat me nt ar ms 
usi n g a 3 : 1 ra n d omisat i on r atio , wit h t he ra n d o misatio n stratifie d b y  w het her or n ot t he patie nt 
c o nse nts t o partici pat e i n t he s u b-st u d y ( n ote t his is e q ui vale nt t o ra n d o misi n g patie nts i n t he 
s u b-st u d y se paratel y in t he sa me 3: 1 rati o) .  T h us, a p pr o xi matel y 5 0 pat ient s will be 
ra n d omise d t o t he refere nce ar m, a n d a p pr o xi matel y 1 5 0 pat ient s will be ra n d omise d t o t he 
treatme nt  re d ucti o n ar m.  T o e ns ure ra n d o m all ocati o n, eac h pat ient  will be gi ve n t he st u d y 
treat me nt beari n g t he l o west a vaila ble ra n d o misat i o n n u m ber at t he site.
T he I n vesti gat or(s) will:

O btai n si g ne d a n d date d i nf or me d c o nse nt fr o m t he patie nt bef ore a n y st u d y-s pecific 
pr oce d ures are perf or me d.

Assi g n t he p ote nti al patie nt a u niq ue e nr ol me nt n u m ber ( E -c o de), be gi n ni n g wit h ‘ E #’ .

Deter mi ne patie nt eli gi bilit y; see Secti o ns 5. 1 a n d 5. 2 .

F or pati e nts fulfilli n g t he eli gi bilit y a n d ra n d o misati o n cri t eria at Visit 2 b , t he I n vesti gat or 
will assi g n a u ni q ue ra n d o misat i on n u m ber.


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Ra n d o misat i on n u m bers will be assi g ne d strictl y se q ue nt iall y as patient s bec ome eli gi ble f or 
ra n d omisat i on.  T he ra n d o misat i on n u m bers will be gr o u pe d i n bl oc ks at a n o verall le vel.  T he
bl oc k size will n ot be c o m m u nicate d t o t he I n vest i gat ors.
W he n t he st u d y  is c o mplete d a n d t he data verifie d a n d l oc ke d a n d t he p o p ulat i ons defi ne d, t he 
ra n d omisat i on n u m bers will be ma de a vaila ble f or data a nal ysis.
If a patie nt wit h dra ws fr om t he st u d y, t he n his/ her e nr o l me nt/ra n d o misati on n u m ber ca n n ot be 
re use d.  Wit h dra w n patie nts will n ot be re place d.
6. 4
Tre at me nt C o m pli a nce
Fase nra ® a d mi nistrati o n will ta ke place at t he st u d y site a n d c o m plia nce will be rec or de d i n 
t he e C R F b y t he I n vesti gat or.
At  Visit 1, i nstr ucti o ns will be gi ve n t o t he patie nts o n h o w t o use t he S y m bic ort ® T ur b o haler ®
a n d Ve nt oli n ® p M DI (in halat i on tec h ni q ue) as well as t he Hailie ™se ns ors ( Sectio n 6. 1. 2 ).  
Bef ore ta ki n g t he first d ose of r u n -i n me dicat i on, t he patient  will be i nstr ucte d b y t he st u d y 
pers o n nel h o w t o ta ke t he me dicati o n.  I n or der t o i n hale pr o perl y acc or di n g t o t he 
i nstr uctio ns, t he patie nt will practice t he i n halati on tec h ni q ue wit h a trai ni n g de vice, as ma n y 
ti mes as j u d ge d necessar y b y t he s u per visi n g st u d y pers o n nel.
S y m bic ort ® a n d Ve nt oli n ® c o m p lia nce will be meas ure d fr om t he first d ose (ta ke n at Visit 1)
u nt il t he e n d of t he patie nt’s partici pati o n i n the st u d y  via t he Hailie ™se ns ors ( Secti o n 6. 1. 2 ).  
Fr o m  Visit 2 b t o Visit 7, a d di tio nal trai ni n g will be perf or me d i n t he e ve nt of p o or 
c o mplia nce.
A n y c ha n ge fr o m t he d osi n g sc he d ule, s uc h as d ose i nterr u pti o ns, d ose re d ucti o ns, or d ose 
di sc o nti n uati ons s h o ul d be rec or de d i n t he e C R F.
T he I n vestig at or is res p o nsi ble f or ma na gi n g t he st u d y treat me nt fr om recei pt b y t he st u d y sit e 
u nt il t he destr ucti o n or ret ur n of all u n use d st u d y treat me nt .  T he I n vesti gat or(s) is res p o nsi ble 
f or e ns uri n g t hat t he pati e nt has ret ur ne d all u n use d st u d y treat me nt .
6. 5
C o nc o mit a nt T her a p y
A n y me dicat i on or vacci ne t hat t he pati e nt has recei ve d i n t he 3 m o nt hs pri or t o t he date of 
i nf or me d c o nse nt a n d/ or is recei vi n g at t he ti me of e nr o l me nt or recei ves d uri n g t he st u d y 
m ust be rec or de d al o n g wit h:

Reas o n f or use .

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates .

D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y.

F or C O VI D -1 9 vacci ne, t he vacci ne bra n d als o nee ds t o be clearl y i n dicate d.


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Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
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4 3 of 1 1 7
T a ble 5  
Restricte d me dic ati o ns
All o we d me dic ati o n/ c l ass of dr u g
Us a ge
I nacti ve/ kille d vacci nati o ns
All o we d pr o vi de d t he y are n ot a d mi nistere d wit hi n 
1 wee k bef ore or after d osi n g wit h st u d y treat me nt.
C O VI D -1 9 vacci nati o n
All o we d pr o vi de d t he y are n ot a d mi nistere d wit hi n 
1 wee k bef ore or after d osi n g wit h st u d y treat me nt
( Fase nra® ), l o n ger i nter val is a d vise d w h e n  p ossi ble.  If 
nee de d , a d mi nistrati o n of st u d y treat me nt ca n be re-
sc he d ule d t o all o w f or s ufficie nt i nter val pri or/ p ost 
C O VI D - 1 9 vacci nati o n.   S u bse q ue nt st u d y treat me nt
d ose s h o ul d be gi ve n i n a differe nt l ocati o n fr o m t he 
vacci ne .
Aller ge n i m m u n ot hera p y
All o we d if patie nt has bee n recei vi n g sta ble t hera p y f or 
at least 3 0 da y s pri or t o Visit 1 a n d t here is n o a ntici pate d 
c ha n ge d uri n g t he treat me nt peri o d.  Aller ge n 
i m m u n ot hera p y s h o ul d n ot be a d mi nistere d o n t he sa me 
da y  as st u d y visit s.
Pre d nis o ne/ pre d nis ol o ne
Ma y  be all o we d as b urst t o treat ast h ma e xacer bati o ns, at 
t he discreti o n of t he I n vesti gat or.
T o pical o r nasal im m u n os u p pressi ve me dicati o n
T o pical o r nasal a d mi nistrati o n ma y be all o we d at t he 
discreti o n of t he I n vesti gat or .
S y m bic ort ®
Wit h hel d f or 1 2
h o urs pri or t o st u d y visits.
Ve nt oli n ®
Wit h hel d f or a mi ni m u m of 6
h o urs pri or t o st u d y visits .
C O VI D - 1 9 =C or o na vir us Disease 2 0 1 9 .
T a ble 6
Pr o hi bite d me dic ati o ns
Pr o hi bite d me dic ati o n/cl ass of dr u g
Us a ge
M ar kete d res pirat or y bi ol o gics
A n y  mar kete d res pirat or y bi ol o gic treat me nt ot her t ha n 
Fase nra ® (e g, o maliz u ma b, me p oliz u ma b, resliz u ma b) is 
n ot all o we d 4 m o nt hs or 5 half -li ves ( w hic he ver is 
l o n ger) pri or t o Visit 1 a n d u ntil after Visit 8 b.
N o n -res pirator y mar kete d bi ol o gics or a n y 
i n vesti gati o nal bi ol o gics
A n y  mar kete d ( n o n-res pirat or y) or i n vesti gati o nal
bi ol o gic treat me nt is n ot all o we d 4 m o nt hs or 5 half -li ves
( w hic he ver is l o n ger) pri or t o Visit 1 a n d u ntil after 
Visit 8 b.


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T a ble 6
Pr o hi bite d me dic ati o ns
Pr o hi bite d me dic ati o n/cl ass of dr u g
Us a ge
I m m u n os u p pressi ve me dicati o ns
Use of i m m u n os u p pressi ve me dicati o ns (i ncl u di n g, b ut
n ot li mite d t o, met h otre xate, tr olea n d o m yci n,
c ycl os p ori ne, azat hi o pri ne, i ntra m usc ular l o n g -acti n g
de p ot c ortic oster oi d, a n y e x peri me ntal a nti -i nfla m mat or y
t hera p y, or oral/ pare nteral/i ntra -artic ular c ortic oster oi ds
f or reas o ns ot her t ha n ast h ma) is n ot all o we d e xce pt
resc ue use of s yste mic c ortic oster oi ds ( oral, i ntra ve n o us, 
or  i ntra m usc ular) t o treat a n ast h ma e xacer bati o n or t o 
treat c o n diti o ns ot her t ha n ast h ma. I m mu n os u p pressi ve 
me dicati o ns m ust be disc o nti n ue d 3 m o nt hs or 5 half -
li ves ( w hic he ver is l on ger) pri or t o Visit 1 ; d uri n g t he 
treat me nt peri o d; a n d 3 m o nt hs or 5 half -li ves ( w hic he ver 
is l on ger) after t he last d ose of st u d y treat me nt .
Bl o o d pr o d ucts or i m m u n o gl o b uli n
t hera p y
Recei pt of i m m u n o gl o b uli n or bl o o d pr o d ucts is n ot
all o we d wit hi n 3 0 da y s pri or t o Visit 1 a n d u ntil after 
Visit 8 b.
Li ve atte n uate d vacci nes
N ot all o we d wit hi n 3 0 da ys of Visit 1 , d uri n g t he 
treat me nt peri o d, a n d f or 12 wee ks ( 5 half -li ves) after t he 
last d ose of t he st u d y treat me nt a d mi nistrati o n.
Li p o x y ge nase i n hi bit ors
Fi ve -li p o x yge nase i n hi bit ors (e g, zile ut o n) are pr o hi bite d
a n d are n ot all o we d wit hi n 3 0 da ys of Visit 1 a n d u ntil 
after Visit 8 b.
S y ste mic treat me nt wit h str o n g C Y P 3 A 4 
i n hi bit ors (e g, ket oc o naz ole a n d itrac o naz ole) a
N ot all o we d fr o m Visit 1 a n d u ntil after Visit 8 b.
Beta -a dre ner gic bl oc kers (i ncl u di n g e ye dr o ps)
N ot all o we d fr o m Visit 1 a n d u ntil after Visit 8 b.
L A M As or t he o p h ylli nes
N ot all o we d fr o m Visit 1 a n d u ntil after Visit 8 b.
L T R As
L T R As are n ot all o we d fr o m Visit 2 b a n d u ntil after 
Visit 8 b.  L T R A was h o ut ma y be gi n at or after Visit 1 
a n d m ust be c o m plete d at least 1 wee k pri or t o Visit 2 b.
A E = A d verse e ve nt; C Y P = C yt oc hr o me P 4 5 0; L A M A = L o n g -acti n g m uscari nic a nta g o nist; L T R A = Le u k otrie ne 
rece pt or a nta g o nists; S A E = Seri o us a d verse e ve nt.
a
F or details see  A p pe n di x D.
6. 5. 1
Ot her c o nc o mit a nt tre at me nt
Ot her me dicati o n , ot her t ha n t hat descri be d a b o ve, w hic h is c o nsi dere d necessar y  for t he 
pati e nt ’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 a n d rec or de d 
i n t he a p pr o priate secti o ns of t he e C R F.
6. 6
D ose M o dific ati o n
T h is pr ot oc ol all ows t he S y m bic ort ® d ose t o be m o difie d i n t he treat me nt re d ucti o n ar m o nl y 
(Ta ble 3 ), i n acc or da nce wit h t he ste p pi n g d o w n/ u p treat me nt alg ori t h m (Fi g ure 2 ).


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6. 7
Tre at me nt A fter t he E n d of t he S t u d y
N/ A.
7
DI S C O N TI N U A TI O N O F T R E A T M E N T A N D P A TI E N T
WI T H D R A W A L 
7. 1
Disc o nti n u ati o n of S t u d y T re at me nt 
P ati e nts ma y be di sc o nti n ue d fr o m t he st u d y treat me nt i n t he f oll owi n g si t u atio ns:

P ati e nt deci sio n . T he pati e nt is at a n y ti me free t o disc o nti n ue treat me nt, wit h o ut 
pr ej u dice t o f urt her treat me nt .

A Es t hat, in t he o pi ni o n of t he I n vest i gat or, c o ntrai n dicates f urt her d osi n g.

Se vere n o n -c o mplia nce wi t h t he c li nical st u d y pr ot oc ol ( C S P).

Eli gi bilit y re q uire me nt f o u n d n ot t o be f ulfille d.

Pre g na nc y.

L ost t o f oll o w -u p (see Secti o n 7. 2 ).

De vel o p me nt of a n y st u d y -s pecific criteria f or disc o nti n uati on:

A na p h ylactic reacti o n t o t he st u d y treat me nt

De vel o p me nt of hel mi nt h parasit ic i nfestati o ns re q uiri n g h os pitalisat i on

A n ast h ma -relate d e ve nt re q uiri n g mec ha nical ve ntilati on.
Ge nerall y, bef ore disc o nt i n uati on of a patie nt fr o m t he st u d y tr e at me nt , a disc ussi on bet wee n 
t he A Z St u d y  P h ysicia n or d el e gate a n d I n vest i gat or is e nc o ura ge d, as m uc h as feasi ble. 
See t he S o A (Ta ble 1) f or data t o be c ollecte d at t he ti me of treat me nt disc o nti n uati on a n d 
f oll ow -u p a n d f or a n y  furt her e val uat i ons t hat nee d t o be c o m plete d.
7. 1. 1
Pr oce d ures f or disc o nti n u ati o n of st u d y tre at me nt
Di sc o nti n uatio n of  st u d y tr e at me nt mea ns t hat t he patie nt m u st be wit h dra w n fr o m t he st u d y .  
A pat ient  w h o has disc o nt i n ue d st u d y treat me nt, f or a n y reas o n, d oes n ot nee d t o c o m plete 
f urt her assess me nts or f urt her pla n ne d visits for t his st u d y , h o we ver, t he y must atte n d a 
di sc o nti n uati on visit t o ret ur n all electr o nic de vices use d f or t he st u d y a n d c o m p lete all E O T
visit assess me nts .
T he I n vesti gat or s h o ul d i nstr uct t he patie nt t o c o ntact t he site bef ore or at t he ti me if st u d y 
treat me nt is st o p pe d.  A pati e nt w h o deci des t o disc o nti n ue st u d y treat me nt will al wa ys be 
as ke d a b o ut t he reas o n(s) a n d t he prese nce o f a n y A Es.  T he date of last i nta ke of st u d y 
treat me nt s h o uld be d oc u m e nte d i n t he eC R F.  All  st u d y tr e at me nt s h o uld be ret ur ne d b y  t he 
pati e nt at t heir disc o nt i n uati o n visit.  Patie nts per ma ne nt l y disc o nti n ui n g st u d y treat me nt 


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s h o uld be gi ve n treat me nt acc or din g t o l o c al  me dical practice, at t he discreti on of t he 
I n vesti gat or.
7. 2
L ost t o F oll o w -u p
A pat ient will be c o nsi dere d p ote ntiall y  los t t o foll o w -u p if he or s he fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e.
T he f o ll owi n g acti o ns m ust be ta ke n if a pati e nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:

T he site m ust atte m pt t o c o ntact t he patie nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he pat ient o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule.

L ost t o f oll o w -u p is w he n t he f o ll owi n g 3 atte mpts at c o ntact ha ve faile d: 

T hree ( 3) atte m pts of eit her p h o ne calls, fa xes, or e mails

Ha vi n g se nt 1 re gistere d letter/certifie d mail 

Eff orts t o reac h t he pati e nt s h o uld c o n ti n ue u ntil t he e n d of t he st u d y. S h o ul d t he pati e nt
be u nreac ha ble at t he e n d of t he st u d y  t he pati e nt s h o uld be c o nsi dere d t o be l ost t o 
f oll ow- u p.
7. 3
Wit h dr a w al fr o m t he S t u d y
A pat ient ma y wi t hdra w fr o m  t he st u d y (e g, wit hdra w c o nse nt), at a n y  ti me (st u d y treat me nt
a n d assess me nts) at his/ her o w n re q uest, wit h o ut prej u dice t o f urt her treat me nt.
If t he patie nt wit h dra ws c o nse nt f or discl o s ure of f ut ure i nf or mati on, t he S p o ns or ma y retai n 
a n d c o nt i n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.
If a patie nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr uctio n of  a n y sa m ples ta ke n, 
a n d t he In vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds .
A pat ient w h o wit h dra ws c o nse nt will al wa ys be as ke d a b o ut t he reas o n(s) a n d t he prese nce of 
a n y A E s.  T he I n vesti gat or will f oll ow- u p pati e nt s as me dicall y i n dicate d .  T he pati e nt will 
ret ur n all de vices use d f or t he st u d y .
See t he S o A (Ta ble 1) f or data t o be c ollecte d at t he ti me of st u d y disc o nti n uati on a n d 
f oll ow -u p a n d f or a n y  furt her e val uat i ons t hat nee d t o be c o m plete d. All st u d y treat me nt 
s h o uld be ret ur ne d b y  t he pat ient .
P ati e nts w h o fail t o meet t he eli gi bilit y a n d/ or ra n d o misati on cri t eria s h o uld n ot, u n der a n y  
circ u msta nces, be ra n d o mise d or recei ve st u d y treat me nt.  T here ca n be n o e xce pt i ons t o t his 
r ule.  Patie nts w h o are e nr olle d, b ut s u bse q ue ntl y f o u n d n ot t o meet all t he eli gi bilit y a n d/ or 


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ra n d omisat i on cri t eria m u st n ot be ra n d o mise d or i nitiate d o n-treat me nt a n d must be 
wi t hdra w n fr o m  t he st u d y.
W he n a pat ient  d oes n ot meet all t he eli gi bility a n d/ or ra n d o misat i on cri t eria b ut is 
ra n d omise d i n err or, or i nc orrectl y starte d o n -treat me nt, t he I n vesti gat or s h o ul d i nf or m t he A Z
St u d y  P h ysicia n or dele gate i m me diatel y, a n d a disc ussi on s h o ul d occ ur bet wee n t he A Z
St u d y  P h ysicia n or dele gate a n d t he I n vest i gat or re gar di n g w het her t o c o nti n ue or disc o nti n ue 
t he patie nt fr o m tr e at me nt.  T he A Z St u d y  P h ysicia n or dele gat e m ust e ns ure all decisi o ns are 
a p pr o priatel y d o c u me nte d.
A pat ient  will be wit h dra w n fr om t he st u d y if t he y wit hdra w c o nse nt t o t he a nal ysis of  
ma n dat or y  biol o gical sa m ples.  A pati e nt will n ot be wit h dra w n fr o m t he st u d y if t he y 
wi t hdra w c o nse nt t o t he u se of bi ol ogical  sa m ples ac q uire d as part of t he v olu ntar y  s u b-st u d y.
8
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marise d i n t he S o A (Ta ble 1) .
T he In vesti gat or will e ns ure t hat data are rec or de d o n t he e C R F.  T he We b Base d Data 
Ca pt ure ( W B D C) s yste m will be use d f or data c ollecti o n a n d q uer y ha n dli n g.
T he In vesti gat or e ns ures t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness of t he data 
rec or de d a n d of t he pr o visi on of a ns wers t o data q ueries acc or di n g t o t he Cli nical St u d y  
A gree me nt.  T he In vest i gat or will si g n t he c o m plete d e C R F.  A c o p y of t he c o mplete d e C R F
will be arc hi ve d at t he st u d y  sit e.
I mme diate safe t y c o ncer ns s h o uld be disc usse d wit h t he S p o ns or i m me diatel y u p o n 
occ urre nce or a ware ness t o deter mi ne if t he pati e nt s h o uld c o nti n ue or disc o nti n ue st u d y 
treat me nt.
A d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse ntial 
a n d re q uire d f or st u d y c o n d uct.
All scree ni n g e val uati ons m u st be c o mplete d a n d re vie we d t o c o nfir m t hat p ote ntial pat ient s 
meet all eli gi bilit y criteria.  T he In vesti gat or will mai ntai n a scree ni n g l o g t o rec or d details o f 
all patie nt s scree ne d a n d to c o nfir m eli gi bilit y or rec or d reas o ns f or scree ni n g fail ure, as 
a p plica ble.
Pr oce d ures c o n d ucte d as part of t he pati e nt ’s r o uti ne cli nical ma na ge me nt (e g, bl o o d c o u nt)
a n d o btai ne d bef ore si g ni n g of t he I C F ma y be utilise d f or scree ni n g or baseli ne p ur p oses 
pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he 
ti me fra me defi ne d i n t he S o A.


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8. 1
Effic ac y A ssess me nts 
8. 1. 1
Electr o nic P atie nt -Re p orte d O utc o mes
T his st u d y  incl u des 3 electr o nic P ati e nt -Re p orte d O utc o m es (e P R Os) t hat will be pr o vi de d t o 
t he patie nt o n a s mart p h o ne/ta blet.  T he e P R Os will be c o m plete d at t he ti me p oi nts i n dicate d 
i n t he S o A (Ta ble 1) ; t he A C Q-5 q uest i on naire will be c o m plete d ma i nl y at h o me, t he 
A Q L Q( S) + 1 2 a n d
 will be c o mplete d 
at t he st u d y sit e.  At  Visit 1 , t he I n vesti gat or or a ut h orise d dele gate will i nstr uct t he pati e nts o n 
h o w t o c o m plete eac h e P R O a n d a ns wer a n y  q ueries t hat t he patie nt ma y ha ve.   Fr o m  Visit 2 b
t o Visit 7, a d di tio nal trai ni n g will be perf or me d i n t he e ve nt of p o or c o m plia nce.
H o m e c o mplet i on of assess me nts f or patie nts n ot visit i n g t he st u d y site d ue t o C O VI D - 1 9 a n d 
i n case o f earl y disc o nti n uati on of st u d y  treat me nt is all o we d a n d descri be d i n t he e P R O 
Ma n ual .
8. 1. 1. 1
Ast h m a C o ntr ol Q uesti o n n aire -5 ite m
T he A C Q -5 i s a s h orte ne d versi o n of t he f ull 7-ite m A C Q Pati e nt -Re p orte d O utc o me ( P R O) 
(J u ni per et al 1 9 9 9 ) t hat assesses ast h ma s y m pt o ms ( ni g ht-ti me a wa ke ni n g, s y m pt o ms o n 
a wa ke ni n g, acti vit y li mitati o n, s h ort ness of breat h, a n d w heezi n g) b ut o mits t he F E V 1
meas ure me nt a n d S A B A use fr o m t he origi nal  AC Q assess me nt (see  A p pe n di x F ).
P ati e nts are as ke d t o recall h o w t heir ast h ma has bee n d uri n g t he pre vi o u s wee k b y res p o n di n g 
t o 5 s y m pt o m q uesti ons.  Q uesti o ns are wei g hte d e q uall y a n d sc ore d fr o m 0 (t otall y  
c o ntr olle d) t o 6 (se verel y u nc o ntr olle d).
T he m ea n A C Q-5 sc ore i s t he mea n of t he res p o nses.  Mea n sc ores of ≤0. 7 5 i n dicate well
c o ntr olle d ast h ma, sc or es bet wee n > 0. 7 5 a n d < 1. 5 i n dicate partl y c o ntr olle d ast h ma, a n d a 
sc ore ≥1. 5 i n dicates n ot well c o ntr olle d ast h ma ( J u ni per et al 2 0 0 6 ).  I n di vi d ual c ha n ges o f 
≥0. 5 are c o nsi dere d t o be cli nicall y mea ni n gf ul (J u niper et al 2 0 0 5 ).
8. 1. 1. 2
St a n d ar dise d Ast h m a Q u alit y of Life Q uesti o n n aire f or 1 2 ye ars a n d ol der:
A Q L Q( S) + 1 2
T he A Q L Q( S) + 1 2 (J u ni per et al 1 9 9 2 , J u niper et al 2 0 0 5 ) is a P R O t hat meas ures t he healt h-
r elate d q ualit y of life e x perie nce d b y ast h ma patient s (see A p pe n di x E ).
T he q uest i on naire c o m prises 4 se parate d o mai ns (s y m pt o ms, acti vity li mitati ons, e m oti o nal 
f u ncti on, a n d e n vir o n me ntal st i m uli).
P ati e nts are as ke d t o recall t heir e x perie nces d uri n g t he pre vi o us 2 wee ks bef ore eac h visit a n d 
t o sc ore eac h of t he q uesti ons o n a 7 -p oi nt scale ra n gi n g fr o m  7 ( n o i mp ai r me nt) t o 1 (se vere 
i m pair me nt).  T he o verall sc ore is calc ulate d as t he mea n res p o nse t o all q uesti ons.  T he 
4 i n di vi d ual d oma i n sc ores (s y m pt o ms, acti vity li mitati ons, e m oti o nal f u nct i on, a n d 
C CI


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e n vir o n me ntal sti m uli) are t he mea ns of t he res p o nses t o t he q uesti o ns i n eac h of t he d o mai ns.  
I n di vi d ual A Q L Q(s) + 1 2 T otal or d o mai n sc ore c ha n ges of ≥0. 5 are c o nsi dere d cli nicall y 
mea ni n gf ul ( J u ni per et al 1 9 9 4 ).
8. 1. 1. 3
 
 
 
 
 
 
 
 
 
8. 1. 2
P h ysi ol o gic al ast h m a assess me nts
8. 1. 2. 1
P ul m o n ar y f u ncti o n tests ( F E V1 a n d F V C )
Pre -br o nc h o dilat or F E V 1 a n d force d v ital ca pacit y (F V C ) will be perf or m e d at t he st u d y sit e 
a n d meas ure d b y s pir o metr y usi n g e q uip me nt pr o vi de d b y  ce ntral ve n d or.  P ul m o nar y 
f u ncti on tests will be perf or me d b y t he I n vest i gat or or a ut h orise d dele gate acc or di n g t o 
A merica n T h oracic S ociet y/ E ur o pea n Res pirat or y  S ociet y ( A T S/ E R S) g ui deli nes
(Mille r et al 2 0 0 5 ).
T he ce ntral ve n d or is res p o nsi ble f or ass uri n g t h at t he s pir o meter meets A T S/ E R S 
rec o m me n dati ons a n d t hat t he st u d y  ce ntre pers o n nel w h o will be perf or mi n g t he testi n g are 
pr o perl y cert ifie d.  S pir o metr y cali brati on will be detaile d i n a se parate s pir o met r y pr oce d ures 
ma n ual.
I m p ort a nt!  S y m bic ort ® s h o uld be wi t h h eld f or 1 2 h o urs pri or t o st u d y visit s.  Ve nt oli n®
s h o uld be wi t h h eld f or a mi ni m u m  of 6 h o urs pri or t o st u d y  visits.  If eit her c o n ditio n is n ot 
met, t he visit s h o ul d be c o n d ucte d w he n t hese c o n ditio ns are m et , eit her b y dela yi n g t he ti me 
of  t he l un g f u nct i on e val uati o n or b y  r e-sc he d uli n g t he st u d y visit.
Pri or t o p ul m o n ar y fu nct i on tests at Visit 2 b, t he hei g ht of t he patie nt will be meas ure d.
8. 1. 2. 2
 
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8. 1. 2. 3
 
 
 
8. 1. 3
Assess me nt of ast h m a e x acer b ati o ns
D uri n g t he st u d y , a n ast h ma e xacer bati on will be defi ne d as a w orse ni n g of ast h ma s y m pt o ms 
t hat lea ds t o a n y of t h e fol l owi n g (t hi s ma y lea d t o ste p pi n g u p of t he d osa ge i n t he treat me nt 
re d uctio n ar m ):

A te m p orar y  bol us/ b urst of s yste mic c ortic oster oi ds f or at least 3 c o nsec ut i ve da ys t o treat 
s y m pt o ms of ast h ma w orse ni n g; a si n gle de p o-i njecta ble d ose of c ortic oster oi ds will be 
c o nsi dere d e q ui vale nt t o a 3-d a y  b ol us/ b urst of s yste mic c ortic oster oi ds.

A n e mer ge nc y  r o o m or ur ge nt care visit ( defi ne d as e val uati on a n d treat me nt f or 
< 2 4 h o urs i n a n e mer ge nc y de part me nt  or ur ge nt care ce ntre) d ue t o ast h ma t hat re q uire d 
s yste mic c ortic oster oi ds (as per t he a b o ve).

I n-pati e nt h os pitalisatio n ( defi ne d as a d m issi on t o a n i n -pat ient  facility a n d/ or e val uat i on 
a n d treat me nt i n a healt hcare facilit y f or ≥2 4 h o urs) d ue t o ast h ma.
T he I n vesti gat or m ust j ustif y t he decisi o n f or defi ni n g a n e ve nt of w orse ni n g ast h ma as a n 
e xacer bati o n a n d rec or d it i n t he s o urce d oc u me nt s a n d e C R F.  A n ast h ma e xacer bati o n t hat 
occ urs wit hi n 7 da ys o f t he last d ose of s yste mic ster oi ds, prescri be d f or a pri or e xacer bati o n, 
will be c o u nte d as t he sa me e xacer bat i on e ve nt.  T he pat ient  ma y re mai n i n t he st u d y after a n 
e xacer bati o n a n d c o nti n ue t o recei ve st u d y treat me nt if t he I n vesti gat or j u d ges t hat it is 
me dicall y a p pr o priate f or t he patie nt t o d o s o a n d will be ma na ge d as per t he details pr o vi de d.
8. 2
S afet y A ssess me nts
Cli nical safet y la borat or y  assess me nts, p h ysical e xa mi nati ons, vital s i g ns, electr ocar dio gr a m  
assess me nts, pre g na nc y testi n g, or ot her testi n g /pr oce d ure s n ot re q uire d as part of t his st u d y 
ma y be c o n d ucte d as part of r o uti ne cli nical pract ice.
C CI
C CI
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O nl y f or p atie nts p artici p ati n g i n t he s u b -st u d y: F or patie nts partici pat i n g i n t he s u b-st u d y, 
a nasal or t hr oat s wa b will be d o ne f or S A R S-C o V -2 testi n g pri or t o s p ut u m  in d uct i on .  T he 
testi n g will be d o ne as per sta n dar d of care i n partici pati n g site.
8. 3
C ollecti o n of A d verse E ve nts
T he Pri nci pal I n vest i gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v o l ve d i n t he st u d y are 
fa miliar with t he c o nte nt of t his sect i on.
T he defi nit i ons of a n A E or S A E ca n be f o u n d i n  A p pe n di x B.
A E s will be re p orte d b y  t he pati e nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he 
pati e nt 's le gall y a ut h orise d re prese ntative).
T he In vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi nit i on of a n A E or S A E. F or i nf or mat i on o n h o w t o f oll o w/ u p A Es 
see S ectio n 8. 3. 3 .
8. 3. 1
Met h o d of detecti n g A Es a n d S A Es
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es.  O pe n -e n de d a n d 
n o n- lea di n g ver bal q uesti oni n g of t he pati e nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nces.
8. 3. 2
Ti m e peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or m ati o n
All A Es a n d S A Es will be rec or de d fr o m t he ti me of si g ni n g t he I C F.
All S A Es will be rec or de d a n d re p orte d t o t he S p o ns or or dele gate wi t hi n 2 4 h o urs, as 
i n dicate d i n A p pe n di x B .  T he In vest i gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or 
wi t hi n 2 4 h o urs of it bei n g a vaila ble.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A E or S A E i n f or mer st u d y pat ient s. H o we ver, 
if t he In vest i gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after a pati e nt ’s last visit 
a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y relate d t o t he st u d y treat me nt or st u d y 
parti ci pat i on, t he In vest i gat or s hall, wit ho ut a n y  dela y, re p ort t he S A E t o t he S p o ns or.
T he m et h o d of rec or di n g, e val uat i n g, a n d assessi n g ca usality of A E a n d S A E a n d t he 
pr oce d ures f or c o m plet i n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x B.
8. 3. 3
F oll o w -u p of A Es a n d S A Es
After t he i nit ial A E/ S A E re p ort, t he In vest i gat or is re q uire d t o pr oacti vel y f oll ow eac h pat ient
at s u bse q ue nt visits/c o ntacts.  All A Es a n d S A Es will be f o ll owe d u nt il res ol uti on, 
sta bilisat i on, t he e ve nt is ot her wise e x plai ne d, or t he pat ient is l ost t o f oll ow- u p.


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A n y A Es t hat are u nres ol ve d at t he patie nt ’s last visit i n t he st u d y ar e fol l 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 eC R F.  A Z
retai ns t he ri g ht t o re q uest a d diti o nal i nf or mati on f or a n y pat ient wit h o n g o i n g A E(s)/ S A E(s) 
at t he e n d of t he st u d y, if ju d ge d necessar y .
8. 3. 4
A E d at a c ollecti o n
T he f o ll owi n g varia bles will be c ollecte d f or eac h A E:

A E ( ver bat i m)

T he date a n d ti me w he n t he A E starte d a n d st o p pe d

M a xi m u m i nte nsit y

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 st u d y treat me nt(s) ( yes or n o)

Act i on ta ke n wit h re gar d t o st u d y treat me nt (s)

A E ca use d pat ient ’s wit h dra wal fr om st u d y ( yes or n o)

O utc o m e.
I n a d diti on, t he f o ll owi n g vari a bles will be c ollecte d f or S A Es:

Date A E m et crit eria for seri o us A E

Date I n vest i gat or beca me a ware of seri o us A E

A E i s s erio us d ue t o

Date of h os pitalisat i on

Date of disc har ge

Pr o ba ble ca use of deat h

Date of  deat h

A ut o ps y  p erfor m e d

Ca usalit y assess me nt i n relat i on t o st u d y pr oce d ure(s)

Ca usalit y assess me nt t o ot her me dicat i on.
8. 3. 5
C a us alit y c ollecti o n
T he I n vesti gat or will assess ca usal relat i ons hi p bet wee n st u d y tr e at me nt a n d eac h A E , a n d
a ns wer ‘ yes’ or ‘ n o’ t o t he q uesti o n ‘ D o yo 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 st u d y treat me nt?’ f or S y m bic ort® , Fase nra ® , a n d 
Ve nt oli n .  Ei t her n o ne , or o ne, or m ore of t he treat me nts ma y be selecte d as ca usal t o a n y 
gi ve n A E or S A E.
F or S A Es, ca usal relat i ons hi p will als o be assesse d f or ot her me dicat i on a n d st u d y  pr oce d ures.  
N ote t hat f or S A Es t hat c o ul d be ass ociate d wit h a n y  st u d y pr oce d ure t he ca usal relati o ns hi p is 
i m plie d as ‘ yes’.


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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 B.
8. 3. 6
A Es b ase d o n si g ns a n d s y m pt o ms
All A Es s p o nta ne o usl y re p orte d b y  t he pati e nt 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 site staff: ‘ H ave y o u h a d a ny he alt h pr o ble ms si nce t he previ o us visit/y o u were 
l ast aske d ?’ or re veale d b y o bser vatio n will  be c ollecte d a n d rec or de d i n t he eC R F.  W he n 
c ollect i n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n p ossi ble) t o rec or di n g a list of 
sig 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.
8. 3. 7
Dise ase u n der st u d y ( D U S)
S y m pt o m s of D U S are t h ose w hic h mi g ht be e x pecte d t o occ ur as a direct res ult of ast h ma. 
Ast h ma s y m pt o ms or si g ns, s uc h as w heeze, c o u g h, c hest ti g ht ness, d y s p n oea, breat hless ness,
a n d p hle g m, will be rec or de d as A Es w he n:

t he sig n or s y m pt o m  is s erio us a n d/ or

t he patie nt disc o nti n ues t he st u d y d ue t o t he sig n or s y m pt o m a n d/ or

t he sig n or s y m pt o m  is ne w t o t he patie nt or n ot c o nsiste nt wit h t he patie nt’s pre- e xist i n g 
ast h ma hist or y ( defi ne d as withi n 1 ye ar of Visit 1) as j u d ge d b y t he In vesti gat or.
E ve nts w hic h are u ne q ui v ocall y d ue t o D U S s h o ul d n ot be re p orte d as a n A E d uri n g t he st u d y 
u nless t he y  meet S A E crit eria or lea d t o disc o nti n uati o n of st u d y treat me nt .
8. 4
S afet y R e p orti n g a n d M e dic al M a n a ge me nt
8. 4. 1
Re p orti n g of S A Es
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he st u d y 
treat me nt , 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 eC R F.
If a n y S A E occ urs i n t he c o urse of t he st u d y, t he n I n vesti gat ors or ot her site pers o n nel i nf or m 
t he a p pr o priate A Z re prese ntati ves wit hi n 1 d a y , ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs 
of w he n he or s he bec o me s a ware of it.
T he desi g nate d A Z re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all t he necessar y 
i nf or mat i on is pr o vi de d t o t he A Z Patie nt Safet y data e ntr y  sit e wit hi n 1 c ale n d ar d a y of  
i nitial recei pt f or fatal a n d life-t hreate ni n g e ve nts a n d wit hi n 5 c ale n d ar d a ys of  init ial 
receipt f or all ot her S A Es.
F or fatal  or life-t hreate ni n g A Es w here i m p orta nt or rele va nt i nf or mat i on is missi n g, acti ve 
f oll ow- u p i s u n derta ke n i m me diatel y.  I n vestigat ors or ot her site pers o n nel i nf or m A Z


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re prese ntati ves of a n y foll o w -u p i nf or m at i on o n a pre vi o usl y re p orte d S A E wit hi n 1 cale n dar 
d a y , ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs of  w he n he or s he bec o mes a ware of it.
O nce t he I n vest i gat ors or ot her site pers o n nel i n dicate a n A E is seri o us i n t he W B D C s yste m , 
a n a ut o mate d e mail alert is se nt  t o t he desi g nate d A Z re prese ntati ve.
If t he W B D C
s yste m is n ot a vaila ble, t he n t he I n vesti gat or or ot her st u d y site staff re p orts a 
S A E t o t he a p pr o priate A Z re prese ntati ve b y tele p h o ne.  T he A Z re prese ntati ve will a d vise t he 
I n vesti gat or/st u d y sit e st aff h o w t o pr ocee d.
F or f urt her g ui da nce o n t he defi nit i on of a S A E, see  A p pe n di x B.
8. 4. 2
Pre g n a nc y
All ser u m pre g na nc y test a nal yses will be perf or me d at a l ocal la b orat or y.
All pre g na ncies a n d o utc o mes of pre g na nc y s h o ul d be re p orte d t o A Z e xce pt f or:

If t he pre g na nc y is disc o vere d bef ore t he st u d y patie nt has recei ve d a n y st u d y tr e at me nt
If a pre g na nc y is re p orte d, t he In vest i gat or s h o ul d i nf or m t he S p o ns or wi t hi n 2 4 h o urs of 
lear ni n g of t he pre g na nc y.
A b n or m al pre g na nc y o utc o mes (e g, s p o nta ne o us a b orti o n, f oetal deat h, still bi rt h, c o n ge nital 
a n o ma lies, ect o pic pre g na nc y) are c o nsi dere d S A Es.
8. 4. 2. 1
M ater n al e x p os ure
If a patie nt bec o mes pre g na nt d uri n g t he c o urse of t he st u d y , st u d y tr e at me nt s h o ul d be 
di sc o nti n ue d i m me diatel y.
Pre g na nc y itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t he st u d y treat me nt
u n der st u d y  ma y ha ve i nterfere d wit h t he effect i ve ness of a c o ntrace pti ve me dicati o n.  
C o n ge nital a n o ma lies / birt h defects a n d s p o nta ne o us miscarria ges s h o ul d be re p orte d a n d 
ha n dle d as S A Es.  Elect i ve a b orti o ns wit h o ut c o mplicat i ons s h o ul d n ot be ha n dle d as A Es.  
T he o utc o me o f all pre g na ncies (s p o nta ne o us miscarria ge, elect i ve ter mi nati on, ect o pic 
pre g na nc y, n or mal birt h , or c o n ge nital a n o ma l y/ birt h defect ) s h o ul d be f oll owe d u p a n d 
d oc u m e nte d e ve n if t he pati e nt was di sc o nti n ue d fr o m t he st u d y.
If a n y pre g na nc y occ urs i n t he c o urse of t he st u d y, t he n t he I n vesti gat or or ot her site pers o n nel 
i nf or ms t he a p pr o priate A Z re prese ntati ves wit hi n 1 d a y , ie, i m me diatel y b ut n o l ater t h a n
2 4 h o urs of  w he n he or s he bec ome s a ware of it.


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T he desi g nate d A Z re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all rele va nt 
i nf or mat i on is pr o vi de d t o t he A Z Patie nt Safet y data e ntr y  sit e wit hi n 1 or 5 cale n dar da ys f or 
S A Es (see Secti o n 8. 4. 1 ) a n d wit hi n 3 0 da ys f or all ot her pre g na ncies.
T he sa me ti meli nes a p pl y w he n o utc o me i nf or mat i o n is a vaila ble.
T he P R E G R E P m o d ule i n t he eC R F is use d t o re p ort t he pre g na nc y .
8. 4. 3
O ver d ose
F or t hi s st u d y, a n y d ose of Fase nra ® greater t ha n 2 0 0 m g , or for m ot e r ol greater t ha n 9 0 μ g,
wi t hi n 1 d a y will be c o nsi dere d a n o ver d ose.
A Z d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.

A n o ver d ose wit h ass ociate d A Es is rec or de d as t he A E dia g n o sis/s y m pt o ms o n t he 
r ele va nt A E mo d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ul e.

A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y  re p orte d o n t he O ver d ose e C R F
m o d ule .
If a n o ver d ose o n a n A Z st u d y treat me nt occ urs i n t he c o urse of t he st u d y , t he n t he 
In vest i gat or or ot her site pers o n nel i nf or m a p pr o priate A Z 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 mes a ware of it.
T he desi g nate d A Z re prese ntati ve w or ks wit h t he I n vestigat or t o e ns ure t hat all rele va nt 
i nf or mat i on is pr o vi de d t o t he A Z Patie nt Safet y data e ntr y  sit e.
F or o ver d oses ass ociate d wit h a S A E, t he sta n dar d re p orti n g t i meli nes a p pl y, see 
Secti o n 8. 3. 2 .  F or ot her o ver d oses, re p orti n g m ust occ ur wit hi n 3 0 da ys.
8. 4. 4
Me dic ati o n err or
Me dicat i on err ors wit h A Z st u d y treat me nt s are c ollecte d i n all st u dies w here me dicat i on err or 
is p ossi ble.
If a me dicat i on err or occ urs d uri n g t he c o urse of t he st u d y, t he n t he I n vesti gat or or ot her site 
pers o n nel i nf or ms t he a p pr o priate A Z re prese ntati ves wit hi n 1 d a y , ie, i m me diatel y b ut n o 
later t ha 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 A Z re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all rele va nt 
i nf or mat i on is c o m plete d wit hi n 1 (I nitial Fatal / Life-T hreate ni n g or f o ll ow- u p Fatal / Life-
T hreate ni n g) or 5 ( ot her seri o us i nit ial a n d f o ll ow- u p) cale n dar da ys if t here is a S A E 
asso ci at e d wit h t h e me dicat i on err or (see Secti o n 8. 3. 2 ) a n d wit hi n 3 0 da ys f or all ot her 
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T he defi nit i on of a m e dicat i on err or ca n be f o u n d i n A p pe n di x B.
8. 4. 5
Me dic a l De vice Deficiencies
I n a c o m bi nati on dr u g -de vice st u d y  treat me nt ( e g, A P F S), t he De vice C o nstit ue nt defici e nc y 
is a n i na de q uac y of a de vice c o nst itue nt wit h res pect t o its i de nt ity,  q uality, d ura bilit y,  
relia bility, safet y,  or perf or ma nce. T hese deficie ncies i ncl u de malf u nct i ons, use err ors, a n d 
i nf or mat i on s u p plie d b y t he ma n ufact urer.
I n or der t o f ulfil re gulat or y  re p orti n g o bli gati o ns w orl d wi de, t he In vesti gat or is res p o nsi ble f or 
t he detectio n a n d d oc u m e nt atio n of  e ve nts meet i n g t he defi niti ons of me dical de vice 
deficie nc y t hat occ ur d uri n g t he st u d y  wit h s uc h me dical de vices.
I n t his st u d y, deficie nc y o bs er ve d wit h a n y o f st u d y tr e at me nt de vices (Ve nt oli n ® a n d 
S y m bic ort ® i n halers a n d Fase nra ® pre -fille d s yri n ges) will be c o llecte d a n d re p orte d t o t he 
ma n ufact urer usi n g t he for m  a vaila ble o n t he P har mac y ma n ual (for m ore details please 
f oll ow u p P har m ac y ma n ual) .
F or t he t hir d -part y  me dical de vices ( Hailie ™ se ns ors f or Ve nt oli n ® a n d S y m bic ort ® , E R T 
Master Sc o pe 
T M s pir omet r y, 
) a n y deficie nc y or malf u nctio n
o bser ve d will be rec or de d o n t he e C R F f or m a n d re p orte d t o t he ma n ufact urer s o n a 
pre -defi ne d basis .
T he defi nit i on of a Me dical De vice deficie nc y ca n be f o u n d i n A p pe n di x H.
N O T E: I nci de nts a n d deficie ncies f ulfilli n g t he defi niti on of a n A E/ S A E will als o f o ll ow t he 
pr ocesses o utli ne d i n  A p pe n di x H of  t he pr ot oc ol.
8. 4. 5. 1
Ti me Peri o d f or Detecti n g Me dic al De v ice Deficie ncies

Me dical de vice i nci de nts or malf u nct i ons o f t he me dical de vice will  be detecte d, 
d oc u m e nte d, a n d re p orte d d uri n g all peri o ds of t he st u d y in w hic h t he me dical de vice is 
use d.

If t he In vesti gat or lear ns of a n y me dical de vice deficie nc y at a n y t i me after a patie nt has 
bee n disc har ge d fr o m t he st u d y , a n d s uc h i nci de nt is c o nsi dere d reas o na bl y relate d t o a 
me dical de vice pr o vi de d f or t he st u d y , t he In vest i gat or will pr o m pt l y n otif y  t he S p o ns or.
T he m et h o d of d oc u me nt i n g Me dical De vice Deficie ncy is pr o vi de d i n A p pe n di x H.
8. 4. 5. 2
F oll o w -u p of Me dic al De vice Deficie ncies

F o ll ow- u p a p plies t o all pat ient s, i ncl u di n g t h ose w h o disc o nt i n ue st u d y treat me nt .

T he In vesti g at or is res p o nsi ble f or e ns uri n g t hat f oll o w -u p i ncl u des a n y s u p ple me ntal 
i n vesti gati ons as i n dicate d t o el uci date t he nat ure a n d/ or ca usalit y of  t he deficie nc y.
C CI


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
Ne w or u p date d i nf or mat i on will be rec or de d o n t he ori gi nall y c o m p lete d f or m i n e C R F 
wi t h all c ha n ges si g ne d a n d date d b y t he In vest i gat or.
8. 4. 5. 3
Pr o m pt Re p orti n g of Me dic al De vice Deficie ncies t o S p o ns or

Me dical d e vice deficie ncies will be re p orte d t o t he S p o ns or wit hi n [ 2 4 h o urs] aft er t he 
In vest i gat or deter mi nes t hat t he e ve nt meets t he pr ot oc ol defi nit i on of a me dical de vice 
deficie nc y.

T he t hir d-part y  me dical d e vice d eficie nc y (Hailie ™ se ns ors f or Ve nt oli n ® a n d 
S y m bic ort ® , E R T Master Sc o pe T M s pir o metr y, 
) will be 
re p orte d b y I n vesti gat or o n t he e C R F f or m.  S t u d y treat me nt de vices deficie nc y
(Ve nt oli n ® a n d S y m bic ort ® i n halers a n d Fase nra ® pre -fille d s yri n ges) will be re p orte d
o ver pa per f or m a n d will be se nt t o t he S p o ns or b y e- ma il.

T he S p o ns or will be t he c o ntact f or t he recei pt of me dical de vice deficie nc y  re p orts.
8. 4. 5. 4
Re g ul at or y Re p orti n g Re q uire me nts f or De vice Deficie ncies

T he In vesti gat or will pr o m pt l y re p ort all me dical de vice deficie ncies occ urri n g wit h a n y  
me dical de vice pr o vi de d f or use i n t he st u d y  in or der f or t he S p o ns or t o f ulfil t he le gal 
res p o nsi bility t o n otif y a p pr o priate re g ulat or y  a ut h orities a n d ot her e ntities a b o ut certai n 
safety i nf or mati on rel at i n g t o me dical de vices bei n g use d i n cli nical st u dies.

T he In vesti gat or, or res p o nsi ble pers o n acc or di n g t o l ocal re q uire me nts (e g, t he hea d o f 
t he me dical i nstituti o n), will c o m p l y wit h t he a p plica ble l ocal re g ulat or y re q uire me nts 
r elat i n g t o t he re p orti n g of me d ical de vice deficie nci es t o t he i nstit uti o nal re vie w b oar d 
(I R B)/ i n de pe n de nt et hics c om mittee (I E C) .
F or f urt her g ui da nce o n t he defi nit i on of a n S A E , see A p pe n di x H of  t he pr ot oc ol .
8. 5
P h ar m ac o ki netics
P har mac o ki net ic para meters are n ot e val uate d i n t his st u d y .
8. 6
P h ar m ac o d y n a mics
P har mac o d y na mic para meters are n ot e val uate d i n t his st u d y .
8. 7
Ge netics
Ge net ic testi n g is n ot e val uate d i n t his st u d y.
8. 8
Bi o m ar kers
8. 8. 1
S u b -st u d y bi o m ar kers
All s u b-st u d y bio m ar ker a nal yses will be re p orte d se paratel y fr o m t he Cli nical St u d y Re p ort 
( C S R).
C CI


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A p pr o xi matel y  32 pat ient s w h o ha ve s pecificall y c o nse nte d t o partici pate i n t he s u b-st u d y will 
u n der g o t he f oll o wi n g assess me nts.
8. 8. 1. 1
 
 
 
.
 
 
 
 
 
  
 
 
 
.
  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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e d.
R.
 
 
 
 
 
s.
 
 
 
 
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C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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8. 8. 1. 2
I n d uce d s p ut u m
I n d uce d s p ut u m will be c ollecte d f or patie nts partici pati n g i n t he s u b-st u d y at Visit 2a 
( Wee k 0), Visi t 8a ( Wee k 4 7) or E O T, i n acc or da nce wit h t he S o A (Ta ble 1) . S p ut u m will be 
a nal yse d f or pat h o ge ns a n d c yt o ki nes a n d a cell differe ntial will be perf or me d.
Bri efl y, b efore t he i n d uct i on pr oce d ure, a baseli ne p ost -br o nc h o dilat or F E V 1 test is perf or me d 
(after i n halati ons of sal b uta m o l); t he meas ure me nt is d o ne 3 ti mes.  T he i n d uct i on pr oce d ure 
i ncl u des i n halati on of h y pert o nic sali ne s ol ut i on b y t he patie nt f or 5 mi n utes.  After ri nsi n g t he 
m o ut h a n d t hr oat a n d bl o wi n g t he n ose, t he pa tie nt will c o u g h s p ut u m i nt o a sterile plast ic 
s p ut u m p ot usi n g a dee p c o u g h.  F oll o wi n g t he s p ut u m i n d ucti on pr oce d ure, 1 F E V 1
meas ure me nt will be perf or me d ( 3 meas ure me nts will be ma de if s p ut u m F E V 1 falls b y 
greater t ha n 1 0 % or 2 0 0 m L, w hic he ver is less , c o m pare d wit h t he best s p ut u m 
p ost -br o nc h o dilat or F E V 1).
N ucl eic aci d a nal ysis will be e m pl o ye d t o deter mi ne t he micr o bi o me prese nt i n s p ut u m 
sa m ples.  Pr otei n a nal ysis a n d cell differe ntial a nal ysis o f i n d uce d s p ut u m will be perf or me d.
Details f or c o n d u cti n g s p ut u m c ollecti o n will be descri be d i n a se parate ma n ual o f pr oce d ures.
8. 8. 1. 3
Ser u m s a m ples f or e x pl or at or y bi o m ar kers
Bl o o d sa m pl es f or ser u m  e x plor at or y  bio m ar kers will be c o llecte d.  At eac h of t he ti me p oi nts 
i n dicate d i n t he S o A (Ta ble 1) , a ma xi m u m of 3 0 m L of bl o o d will be ta ke n f or a f ull bl o o d 
c o u nt ( Visit 2 b, Vi sit 6, a n d Visit 8 b) a n d clotti n g ( Vi sit 2 b).  T he cell ular pr ofile of bl o o d 
sa m ples will be i n vesti gate d usi n g mass c yt omet r y; R N A a n d pr otei n a nal ysis will be 
perf or m e d.  E x p l orat or y bio m ar ker a nal ysis ma y be perf or me d o n bio m ar ker varia nts t h o u g ht 
t o pla y a r ole i n se vere e osi n o p hilic p he n ot ype ast h ma i ncl u di n g, b ut n ot li mite d t o, e osi n o p hil 
gra n ule pr otei ns a n d i nfla m mat or y  c yt o ki nes.
8. 8. 2
Bl o o d s a m ple f or e osi n o p hils
Bl o o d e osi n o p hil sa m ples will be c ollecte d fr o m all patie nts at all st u d y visits i n dicate d i n t he 
S o A (Ta ble 1 ).  If t here is an E O T visit, a bl o o d sa m ple f or eosi n o p hils will be ta ke n.   
A nal ysis will be perf or me d at a l ocal la b orat or y .
8. 8. 3
St or a ge, re -use a n d destr ucti o n of bi o m ar ker s a m ples
S a m ples will  be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he Last Patie nt’s Last 
Vi sit, after w hic h t he y will be dest r o ye d.  T he res ults of t h e bi o mar ker researc h i n t he 
s u b-st u d y will  be re p orte d se paratel y fr om t he C S R .  T he res ults of t his bi omar ker researc h 
ma y be p o ole d wit h bi o mar ker data fr o m ot her st u dies t o ge nerate h y p ot heses t o be teste d i n 
f ut ure researc h.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 1 of 1 1 7
8. 9
He alt h Ec o n o mics
After t he e xacer bat i on assess me nt at eac h visit, as s h o w n i n  Ta ble 1 , t he I n vesti gat or or
a ut h orise d dele gate will assess w het her t he pati e nt has ha d a n y a d ditio n al  ast h ma-r elate d 
healt hcare res o urce utilisat i on e ve nt ot her t ha n e xacer bat i on -relate d e ve nts.  If yes, 
i nf or mat i on will be c o llecte d a n d rec or de d i n t he a p pr o priate e C R F m o d ule.
9
S T A TI S TI C A L C O N SI D E R A TI O N S 
9. 1
St atistic al H y p ot hes es
9. 1. 1
Esti m ati o n a n d testi n g str ate g y
T he pri mar y  ai m of t his st u d y is t o assess t he p ote ntial t o re d uce S y m bic ort ® ma i nte na nce 
treat me nt w hile mai ntai ni n g c o m para ble ast h ma s y m pt o m c o ntr ol i n Fase nra ® -treate d patie nts 
o n hi g h -d ose S y m bic ort ® ma i nte na nce treat me nt.
T he pri mar y  o ut c o me meas ure is t he pr o p orti o n of patie nts w h o re d uce d t heir S y m bic ort ®
mai nte na nce d ose w hile mai ntai ni n g ast h ma s y m pt o m c o ntr ol t o eit her m e di u m-d ose 
S M A R T , lo w -d ose S M A R T , or S y m bic ort ® as a nt i-i nfla m mat or y relie ver o nl y at t he e n d of 
t he re d ucti o n p eri o d (Vi sit 6; Wee k
3 2).
T he pri mar y  o ut c o me meas ure is o nl y assesse d i n t he treat me nt re d ucti o n ar m as t he 
hi g h -d ose refere nce ar m is n ot ta pere d, b y  desi g n.
T he pri mar y  a n d sec o n dar y o ut c o m e meas ures relate d t o t he re d ucti o n peri od will be a nal yse d 
o nce all patie nts ha ve c o m plete d t he st u d y ( Wee k 4 8/ E O T ) (see Secti o n 9. 4. 6 ).  T his will be 
descri be d i n m ore detail i n t he st atistical a nal ysis p la n ( S A P).
9. 1. 2
B aseli ne a n d c h a n ge fr o m b aseli ne
I n ge neral, t he last n o n-missi n g o bser vat i on pri or t o ra n d o mi sat i on will ser ve as t he baseli ne 
meas ure me nt f or c ha n ge fr o m start of ste p d o w n of S M A R T (Vi sit 2 b; Wee k
0 ).  If t here is n o 
val ue pri or t o t he first d ose of st u d y  treat me nt, t he n t he baseli ne val ue will n ot be i m p ute d a n d 
will be set t o missi n g.
I n s o me assess me nts of t he mai nte na nce perio d ar o u n d c ha n ges fr o m e n d of t he re d uctio n
p eri o d , t he baseli ne will be defi ne d as t he visit t he patie nt c o m plete d t heir re d ucti o n p eri o d .
T he a bs o l ute c ha n ge fr o m baseli ne is c o m p ute d as ( visit v al ue – b aseli ne v al ue ). Perce nta ge
c ha n ge fr o m baseli ne is c o m p ute d as (( visit v al ue – b aseli ne v al ue )/ b aseli ne v al ue) × 1 0 0 %. 
If either a visit val ue or t he baseli ne visit val ue is missi n g, t he a bs o l ute c ha n ge fr o m baseli ne 
val ue a n d t he perce nta ge c ha n ge fr o m baseli ne will als o be set t o missi n g. If baseli ne val ue is 
zer o, t he perce nta ge c ha n ge will be set t o missi n g.


Cli nical St u d y Pr ot oc ol - 4. 0
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Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 2 of 1 1 7
9. 1. 3
Se nsiti vit y a n al ysis
Se nsit i vity a nal yses t o assess t he effect of missi n g data or dr o p -o ut o n t he pri mar y  e nd p oi nt 
will be o utli ne d i n t he S A P.
9. 2
S a m ple S ize D eter mi n ati o n 
A t otal o f a p pr o xi matel y 2 4 0 pat ient s will be scree ne d t o ac hie ve 2 0 0 ra n d o mise d patie nts, 
ass u mi n g a scree n fail ure rate of a p pr o xi matel y 1 5 %.  A t otal of 2 0 0 ra n d o mise d patie nts, 
acc or di n g t o a ra n d o misat i on rati o of  3: 1 (treat me nt re d uctio n ar m : r efere nc e ar m), is 
c o nsi dere d s ufficie nt t o a d dress t he pri mar y o bjecti ve f or t he st u d y  ass u mi n g a dr o p-o ut rate 
of  n o more t ha n 1 5 % e val ua ble pat ient s i n b ot h ar ms res ulti n g i n a p pr o xi matel y 1 2 5 t o 
1 5 0 e val ua ble patie nts i n t he treat me nt re d uctio n ar m  a n d a p pr o xi matel y 4 0 t o 5 0 e val ua ble 
pati e nts i n t he refere nce ar m.   Ta ble 7 pr o vi des t he e x pecte d precisi o n ar o u n d t he pri mar y  
o utc o m e, t he pr o p ortio n of  patie nts s uccessf ull y re d uci n g t o me di u m-d ose S M A R T, l o w -d ose 
S M A R T, or S y m bic ort ® as a nt i-i nfla m mat or y relie ver o nl y.  T he selecte d sa m ple size is 
e x pecte d t o pr o vi de a n o mi nal 9 5 % CI ar o u n d t he o bser ve d pr o p orti o ns wit h a half -wi dt h of
less t ha n 1 0 perce nta ge p oi nt s i n t he treat me nt re d ucti o n ar m.
Scree ni n g fail ures are defi ne d as pat ient s w h o sig ne d t he I C F t o parti ci pate i n t he cli nical 
st u d y but are n ot s u bse q ue nt l y ra n d oml y assi g ne d t o a st u d y treat me nt ar m at Visit 2 b
( Sectio n 5. 4 ).
T a ble 7
E x pecte d l o wer a n d u p per h alf -wi dt h of e x act 9 5 % CIs ( Cl o p per-
Pe ars o n) ar o u n d o bser ve d pr o p orti o n of p atie nts s uccessf ull y ste p pi n g 
d o w n S M A R T
O bser ve d 
pr o p orti o n
N = 5 0
N = 1 0 0  
N = 1 2 5  
N = 1 5 0  
N = 2 0 0
2 5 %
1 1. 2 % / 1 4. 3 %
8. 1 % / 9. 7 % 
7. 3 % / 8. 5 % 
6. 7 % / 7. 7 % 
5. 8 % / 6. 6 %
3 5 %
1 2. 9 % / 1 4. 8 %
9. 3 % / 1 0. 2 %
8. 3 % / 9. 0 %
7. 6 % / 8. 2 %
6. 6 % / 7. 0 %
5 0 %
1 4. 5 % / 1 4. 5 % 
1 0. 2 % / 1 0. 2 %
9. 1 % / 9. 1 % 
8. 3 % / 8. 3 % 
7. 1 % / 7. 1 %
6 5 % 
1 4. 8 % / 1 2. 9 %
1 0. 2 % / 9. 3 %
9. 0 % / 8. 3 % 
8. 2 % / 7. 6 % 
7. 0 % / 6. 5 %
7 5 %
1 4. 3 % / 1 1. 2 %
9. 7 % / 8. 1 % 
8. 5 % / 7. 3 % 
7. 7 % / 6. 7 % 
6. 6 % / 5. 8 %
CI = C o nfi de nce i nter val; S M A R T = S y m bic ort ® mai nte na nce a n d relie ver t hera p y.


Cli nical St u d y Pr ot oc ol - 4. 0
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Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 3 of 1 1 7
9. 3
P o p ul ati o ns f or A n a l yses
F or p ur p oses of a nal ysis, t he f oll o wi n g p o p ulat i ons are defi ne d:
P o p ul ati o n
Descri pti o n
All Patie nts Set ( A P S)
T his a nal ysis set c o m prises all patie nts scree ne d f or t he st u d y a n d will be 
use d f or re p orti n g of dis p ositi o n a n d scree ni n g fail ures.
F ull A nal y sis S et ( F A S)
All ra n d o mise d patie nts will be i ncl u de d i n t he F A S, irres pecti ve of t heir 
pr ot oc ol a d here nce a n d c o nti n ue d partici pati o n i n t he st u d y.  Patie nts will 
be a nal yse d irres pecti ve of w het her t he y pre mat urel y disc o nti n ue, acc or di n g 
t o t he i nte nt-t o-treat pri nci ple.  Patie nts w h o wit h dra w fr o m t he st u d y will 
be i ncl u de d u p t o t he date of t heir st u d y ter mi nati o n.
All efficac y a nal yses will be perf or me d usi n g t he F A S.  F or c o nsiste nc y, 
de m o gra p hic a n d baseli ne c haracteristics will be prese nte d usi n g t he F A S.
Safet y A nal ysis Set ( S A F)
T he safet y a nal ysis set c o nsists of all ra n d o mise d patie nts w h o ha ve 
recei ve d at least o n e d ose of st u d y treat me nt. Err o ne o usl y  treate d patie nts 
(e g, t h ose ra n d o mise d t o Treat me nt A b ut act uall y gi ve n Treat me nt B) are 
acc o u nte d f or i n t he treat me nt gr o u p of t he treat me nt t he y act uall y recei ve d.
T he S A F will be use d f or all safet y a nal yses.
9. 4
St atistic al A n al yses
A nal yses will be perf or me d b y A Z or its re prese ntati ves.  A c o m pre he nsi ve S A P will be 
de vel o pe d a n d fi nalise d bef ore data base l oc k a n d will descri be t he pati e nt p o p ulat i ons t o be 
i ncl u de d i n t he a nal yses, a n d pr oce d ures f or acc o u nti n g f or missi n g, u n use d, a n d s p uri o us 
data.  T his sect i on is a s u m mar y of t he pla n ne d statist ical a nal yses of t he pri mar y a n d 
sec o n dar y e n d p oi nts.  A n y de viat i ons fro m t his pl a n will be re p orte d i n t he C S R .
P ati e nt dis p ositio n will be s u m marise d usi n g t he A P S.  De m o gra p h y, baseli ne, a n d pat ient  
c haracterist ic data will be e val uate d usi n g t he F A S.  T he efficac y e n d p oi nts will be e val uate d 
usi n g t he F A S.   All safet y a na l yses will be perf or me d usi n g t he S A F .
9. 4. 1
O utc o me m e as ures f or a n al yses -calc ul ati o n or deri v ati o n of effic ac y 
v ari a bles
S y m bic ort ® M ai nte n a nce D ose
T he pri mar y  o ut c o me varia ble is t he S y m bic ort ® mai nte na nce d ose prescri be d at Visit 6 
( Wee k 3 2).
T he prescri be d S y m bic ort ® d ose will be rec or de d at eac h p ost -baseli ne visit u p t o Wee k 4 8.  
T he S y m bic ort ® d ose varia ble is a n or di nal varia ble wit h t he le vels: hi g h -d ose S y m bic ort ® 
mai nte na nce treat me nt , me di u m-d ose S M A R T, l o w - d ose S M A R T, or S y m bic ort® as 
a nt i-i nfla m mat or y relie ver o nl y.  F or t he 3 visits d uri n g t he re d ucti o n peri o d , t he I n vest i gat or 
als o rec or ds if t he re d ucti o n is e n de d at t hat visit.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 4 of 1 1 7
Ast h m a C o ntr ol Q uesti o n n aire – 5 I te m
C ha n ge fr o m baseli ne A C Q -5 will  be calc ulate d as p ost-baseli ne A C Q -5 sc ore mi n us baseli ne 
A C Q -5 sc ore f or all p ost -baseli ne A C Q -5 m eas ure me nt p oi nts.
P ati e nts will be cate g orise d acc or di n g t o t he f oll owi n g li mits ( J u ni per et al 2 0 0 6 ):

I mpr o ve m e nt: A C Q-5 sc ore c ha n ge fr o m  baseli ne ≤-0. 5

N o C ha n ge: A C Q -5 sc ore c ha n ge fr o m  baseli ne >-0. 5 a n d < 0. 5

Deteri or ati o n: A C Q -5 sc ore c ha n ge fr o m  baseli ne ≥0. 5.
I n a d diti on, ast h ma c o ntr ol w orse ni n g res p o n der varia ble is defi ne d as a n at least 0. 5 - u nit 
w orse ni n g (i ncrease) i n A C Q -5 sc ore fr o m  baseli ne; ie, a n A C Q-5 w orse ni n g varia ble ta kes 
val ue 1 if c ha n ge fr o m baseli ne A C Q - 5 ≥0. 5 a n d 0 ot her wise. Patie nts wit h missi n g or 
n o n- e val ua ble A C Q -5 sc ore at a p ost -baseli ne assess me nt ti me p o i nt will be c o nsi dere d 
ast h ma w orse ni n g res p o n der s at t he ti me p oi nt.
F urt her m ore, pati e nts will be cate g orise d acc or di n g t o t heir A C Q-5 sc ore defi ne d ast h ma 
c o ntr ol stat us at p ost-baseli ne assess me nt s usi n g t he f oll owi n g sc ore t hres h ol ds 
(J u ni per et al 2 0 0 6 ):

Well c o ntr olle d: A C Q -5 sc ore ≤0. 7 5

P arti all y c o ntr olle d: 0. 7 5 < A C Q -5 sc ore < 1. 5

N ot well c o n tr olle d: A C Q-5 sc ore ≥1. 5.
T ot al I C S D ose E x p os ure
T o assess t he t otal dail y  I C S d ose d uri n g t he re d ucti o n a n d mai nte na nce peri o ds, t he patie nt’s 
dail y  d ose will be c ollecte d eac h da y a n d t he f ollo wi n g o utc o m e varia bles will be deri ve d:

T he patie nt’s t otal dail y I C S d ose o n eac h da y .

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose eac h da y si nce t he be gi n ni n g of t he 
re d uctio n peri o d u ntil t he e n d of re d ucti o n peri o d a n d u nt il t o t he e n d of mai nte na nce 
p eri o d .

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose eac h d a y  si nce t he be gi n ni n g of t he 
mai nte na nce peri o d t o t he e n d of mai nte na nce peri o d.
I n a d diti on, t he pati e nt’s mea n t otal I C S d ose ( mai nte na nce + relie ver) d uri n g t he pre vi o us 
8 wee ks will be deri ve d d uri n g t he st u d y  p erio d at Wee k 0, 8, 1 6, 2 4, 3 2, 4 0, a n d 4 8 as t he 
t otal rec or de d I C S d ose (µ g ) di vi de d b y t he n u m ber of da ys wit h rec or de d I C S d ose (i ncl u di n g 
a n y da ys wit h 0 µ g I C S d ose re p orte d).


Cli nical St u d y Pr ot oc ol - 4. 0
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Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 5 of 1 1 7
T he wi t hi n-pat ient  c ha n ge fr o m baseli ne i n mea n t otal I C S d ose f or t he pre vi o us 8 wee ks will 
be deri ve d as t he pati e nt’s mea n t otal dail y I C S d ose at eac h p ost-baseli ne visit mi n us t he 
pati e nt’s mea n t otal dail y I C S d ose at baseli ne ( Visit 2 b ; Wee k 0). 
T he wi t hi n-pat ient  perce nta ge c ha n ge fr o m baseli ne i n mea n t otal I C S d ose f or t he pre vi o us 
8 wee ks will als o be d eri ve d as: 1 0 0 *(t he patie nt’s mea n t otal dail y I C S d ose at eac h 
p ost -baseli ne visit mi n us t he patie nt’s mea n t otal dail y I C S d ose at baseli ne [ Wee k 0]) / (t he 
t otal dail y I C S d ose at baseli ne val ue).
A Q L Q( S) + 1 2
C ha n ge fr o m baseli ne A Q L Q( S) + 1 2 will be calc ulate d as p ost -baseli ne A Q L Q( S) + 1 2 sc ore 
mi n us baseli ne ( Visi t 2 b; Wee k
0) A Q L Q( S) + 1 2 sc ore f or all p ost -baseli ne A Q L Q( S) + 1 2 
meas ure me nt p oi nts.
A n A Q L Q( S) + 1 2 res p o n der will be defi ne d as a patie nt w h o ha d i m pr o ve me nt o n 
A Q L Q( S) + 1 2, ie, a n A Q L Q( S) + 1 2 r es p o n der varia ble ta kes val ue 1 if c ha n ge fr o m baseli ne t o 
e n d of treat me nt i n A Q L Q( S) + 1 2 ≥0. 5 a n d 0 ot her wise.
P atie nts will als o be cate g orise d acc or di n g t o t he f oll o wi n g li mits:

I mpr o ve m e nt: A Q L Q( S) + 1 2 ( p ost visit – baseli ne) ≥0. 5

N o c ha n ge: -0. 5 < A Q L Q( S) + 1 2 ( p ost visit – baseli ne) < 0. 5

Deteri or ati o n: A Q L Q( S) + 1 2 ( p ost visit – baseli ne) ≤- 0. 5.
Pre -b r o nc h o dil at or F E V 1
C ha n ge fr o m baseli ne pre -br o nc h o dilat or F E V 1 will be calc ulate d as p ost -baseli ne 
pre -br o nc h o dilat or F E V 1 ( L) mi n us baseli ne pre-br o nc h o dilat or F E V 1 ( L) f or all p ost-baseli ne 
meas ure me nt p oi nts .
Ast h m a E x acer b ati o ns
T o cal c ulate t he n u m ber of e xacer bati o ns e x perie nce d b y  a p atie nt d uri n g t he treat me nt 
p eri o d, t he f o ll owi n g r ul e will be a p plie d.
T he start of a n e xacer bat i on is defi ne d as t he start-date of s yste mic c ortic oster oi ds or start -date 
of  a t e mp orar y  increase i n a sta ble O C S bac k gr o u n d d ose, or start -date of a h os pital 
a d missi o n, w hic he ver occ urs earlier.  T he e n d -date is defi ne d as t he last da y  of s yste mic 
c ortic oster oids or t he last da y  of a te mp orar y  increase i n a sta ble O C S bac k gr o u n d d ose, or t he 
date of di sc har ge fr o m a h os pit al, w hic he ver occ urs later.  I n t he pri mar y a nal ysis, t he n u m ber 
of  e xacer bati ons o bser ve d f or a patie nt d uri n g t he 4 8 -wee k st u d y  p erio d will be use d as t he 
res p o nse varia ble.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 6 of 1 1 7
A d dit i onal s yste mic c ortic oster oid treat m e nts, e mer ge nc y r o o m/ ur ge nt care visits re q uiri n g 
use of s yste mic c ortic oster oi ds, or i n -pat ient h os pi talisatio n d ue t o ast h ma occ urri n g d uri n g a n 
e xacer bati o n s h o ul d n ot be re gar de d as a ne w e xacer bat io n.  I n or der t o be c o u nte d as a ne w 
e xacer bati o n, it m ust be prece de d b y at least 7 da ys i n w hic h neit her cri t erio n i s f ulfille d.
Ma xi m u m f o ll ow- u p ti me f or a patie nt is a p pr o xi matel y 4 8 wee ks; defi ne d as t he ti me fr o m 
first d ose of  Fase nra ® ta ke n i n t he re d uctio n peri o d t o t he e n d of t he st u d y.  F or a patie nt lost 
t o f oll ow- u p, t his will be defi ne d as t he ti me fr o m first d ose of Fase nra ® ta ke n i n t he re d ucti o n 
p eri o d t o t he ti me p oi nt after w hic h a n e xacer bati on c o ul d n ot be assesse d.
F or t he pr o d ucti o n of s u m mar y st atistics, t he a n n ual e xacer bati on rate ( A E R) per patie nt is 
calc ulate d a n d sta n dar dis e d usi n g data fr o m t he 5 2- 5 6 wee k treat me nt peri o d acc or di n g t o t he 
f or mula descri be d bel o w:
A E R = N u m ber of E xacer bati o ns × 3 6 5. 2 5/( F oll o w -U p Date -First Fase nra ® d ose date + 1).
T he pr o p orti o n of  p atie nts wit h ≥1 ast h ma e xacer bati o n d uri n g t he 4 8 -wee k re d uctio n a n d 
mai nte na nce peri o d will als o be deri ve d.
Cli nic al Re missi o n
Descri pt i ve s u m maries of t he n u m ber a n d pr o p orti o n of patient s meet i n g eac h c o m p osite 
e n d p o i nt criteria defi ni n g cli nical re missi o n ( n o e xacer bat i ons, l ess t ha n 1 0 % deteri orati o n i n 
F E V 1 fr o m ra n d o misat i on a n d A C Q -5 ≤ 0. 7 5 or A C Q -5 < 1. 5) at 3 2 wee ks ( Visit 6 b) a n d 
4 8 wee ks ( Visit 8 b) will be prese nte d f or b ot h treat me nt ar ms. A re missi o n sc ore calc ulate d 
f or eac h patient  a n d base d o n t he n u m ber of re missi on c o m p o ne nts ac hie ve d will descri be t he 
n u m ber a n d pr o p orti o n of pat ient s ac hie vi n g m ulti ple c o m bi natio ns of  t he e n d p oi nts:

0, 1, 2 , a n d 3 re missi o n e n d p o i nts ac hie ve d

O nl y e xacer bat i on a n d A C Q -5 e n d p o i nts ac hie ve d
9. 4. 2
Effic ac y a n al yses
9. 4. 2. 1
Pri m ar y a n al ysis
Re d ucti o n of S y m bic ort ® M ai nte n a nce Tre at me nt
T he pr o p orti o n of  p atie nts w h o re d uce t heir S y m bic ort ® ma i nte na nce treat me nt t o eit her 
me di u m -d ose S M A R T, l o w - d ose S M A R T, or S y m bic ort® as a nt i-i nfla m mat or y relie ver o nl y 
will be assesse d usi n g a ta ble c o ntai ni n g t he n u m ber of patie nts a n d pr o p orti o n of pat ient s at 
eac h ste p d o w n t o get her wit h e xact 2 -si de d 9 5 % CI ( Cl o p per-Pears o n).  T he n u m ber a n d 
perce nta ge of  p atie nts w h o d o n ot re d uce t heir mai nte na nce treat me nt will als o be i ncl u de d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 7 of 1 1 7
9. 4. 2. 2
Sec o n d ar y a n al ysis
A C Q - 5
C ha n ge fr o m baseli ne A C Q -5 will  be deri ve d wee kl y u p t o Wee k 4 8 as p ost -baseli ne sc ore 
mi n us baseli ne A C Q -5 sc ore ( Visit 2 b ; Wee k
0).  T he m ea n c ha n ge fr o m baseli ne A C Q -5 at 
t he en d of t he re d uctio n p eri o d is defi ne d as at Wee k 3 2.
C ha n ge fr o m baseli ne A C Q -5 t o p ost -ra n d o misati on visits will be e val uate d usi n g a M M R M
m o delli n g a p pr oac h i ncl u di n g baseli ne A C Q -5, visit, treat m e nt, a n d visit × treat me nt.  T he 
differe nce i n a vera ge mea n c ha n ge fr o m baseli ne A C Q -5 sc ore at Wee k 3 2 ( visits w he n t he 
pati e nt is i n t heir mai nte na nce peri o d) will be prese nte d t o get her wit h 9 5 % 2 -side d CI.
T he pr o p orti o n of  p atie nts ac hie vi n g a n i ncrease of < 0. 5 u nits c o mpare d t o b aseli ne i n eac h 
treat me nt gr o u p at t he e n d of t he re d ucti o n peri o d will be prese nte d.
A Q L Q( S) + 1 2
C ha n ge fr o m baseli ne A Q L Q( S) + 1 2 will be deri ve d u p t o Wee k 4 8 as p ost -baseli ne sc ore 
mi n us baseli ne A Q L Q( S) + 1 2 sc ore ( Visit 2 b ; Wee k
0).  T he mea n c ha n ge fr o m baseli ne 
A Q L Q( S) + 1 2 at t he e n d of t he re d uctio n p eri o d is defi ne d as at Wee k 3 2.
T he m ea n c ha n ge fr o m baseli ne A Q L Q( S) + 1 2 will be a nal yse d usi n g a M M R M a p pr oac h
i ncl u di n g visi t, treat me nt, a n d visit × treat me nt.  T he est i mate d mea n c ha n ge fr om baseli ne 
A Q L Q( S) + 1 2 d uri n g t he re d uctio n a n d m ai nte na nce perio ds will be prese nte d b y  tr e at me nt 
a n d visit t o get her wit h 2 -side d 9 5 % CI.
T he pr o p orti o n of  p atie nts ac hie vi n g a decrease i n A Q L Q( S) + 1 2 of < 0. 5 u nits c o mpare d t o 
baseli ne i n eac h treat me nt gr o u p at t he e n d of  t he re d ucti o n peri o d will be prese nte d.
C h a n ge fr o m B aseli ne F E V 1
C ha n ge fr o m baseli ne pre -br o nc h o dilat or F E V 1 will be assesse d at Wee k 8, 1 6, 2 4, 3 2, 4 0, a n d 
4 8.  T he m ea n c ha n ge fr o m baseli ne pre- br o nc h o dilat or F E V 1 at t he e n d of t he re d ucti o n 
p eri o d is defi ne d as at Wee k 3 2.  T he m ea n c ha n ge fr o m baseli ne pre- br o nc h o dilat or F E V 1
will be a nal yse d usi n g a M M R M a p pr oac h i ncl u di n g visi t, treat me nt, a n d visit × treat me nt.  
T he est i mate d mea n c ha n ge fr o m baseli ne pre-br o nc h o dilat or F E V 1 d uri n g t he re d uctio n a n d 
mai nte na nce peri o ds will be prese nte d b y treat me nt a n d visit t o get her wit h 2 -side d 9 5 % CI.
Ast h m a E x acer b ati o n R ate
T he a n n ualise d ast h ma e xacer bat i on rate fr o m Visit 2 b ( Wee k 0) u p t o Visit 8 b ( Wee k
4 8)
will be esti mate d f or eac h treat me nt ar m a n d prese nte d wit h 2- side d 9 5 % CIs.  B ot h cr u de 
rates a n d esti mates base d o n a ne gati ve-re gressi on m o d el  will be pr o d uce d. 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 8 of 1 1 7
T ot al D ail y I C S D ose
T he c u m ulat i ve dail y t otal I C S d ose ( mai nte na nce + relie ver d ose) will be prese nte d f or:

T he re d ucti o n peri o d.

T he m ai nte na nce perio d.

T he st u d y  p erio d.
T he t otal dail y  I C S d ose ( mai nte na nce + relie ver d ose) will be prese nte d b y  tr e at me nt gr o u p 
f or eac h da y d uri n g t he re d ucti o n a n d mai nte na nce peri o ds t o get her wit h 2-si de d 9 5 % 
c o nfi de nce ba n ds.
T he m ea n t otal dail y I C S d ose ( mai nte na nce + relie ver) d uri n g t he pre vi o us 8 wee ks will be 
e val uate d usi n g a M M R M a p pr oac h i ncl u di n g visit , treat me nt, a n d visit × treat me nt.
9. 4. 3
S afet y a n al yses
All safety varia bles will be s u m marise d usi n g t he S A F .  Safety data will be s u m marise d f or all 
pati e nts i n t he S A F a n d prese nte d b y tr e at me nt gr o u p of  t he treat me nt t he y act uall y recei ve d.
9. 4. 3. 1
A d verse e ve nts 
A n o verall s u m mar y ta ble will be pr o d uce d s h o wi n g t he n u m ber a n d perce nta ge of patie nts 
wi th at l east 1 A E i n a n y of t he f o ll owi n g cate g ories: A Es, deat hs d ue t o A E, S A Es, a n d A Es 
ca usi n g t he disc o nt i n uati on of st u d y  treat me nt ( D A Es).  T he t otal n u m ber of A Es i n t he 
differe nt A E cate g ories i n ter ms of A E c o u nts will als o be prese nte d (ie, acc o u n tin g f or 
m ult i ple occ urre nces of t he sa me e ve nt i n a patie nt).
A d verse e ve nts will be c o de d usi n g t he m ost rece nt versi o n of t he Me dical Dict i onar y  for 
Re g ulat or y  Act i vities ( Me d D R A) t hat will ha ve bee n release d f or e xec uti on at Astra Ze neca or 
desi g nee.
A E s, D A Es, a n d S A Es will be s u m marise d b y s yst e m or ga n class ( S O C) a n d preferre d ter m 
( P T) assi g ne d t o t he e ve nt b y Me d D R A.   F or eac h P T, t he n u m ber a n d perce nta ge of patie nts 
re p orti n g at least 1 occ urre nce will be prese nte d (ie, a patie nt wit h m ulti ple occ urre nces of a n 
A E will o nl y be c o u nte d o nce).  S A Es ca usi n g disc o nti n uat i on of t he st u d y  tr e at me nt /st u d y 
will als o be s u m marise d.
A Es a n d S A Es ( b y P T) will be s u m marise d b y I n vesti gat or's ca usalit y a n d ma xi m u m 
i nte nsit y.  If a patie nt re p orts mul tiple occ urre nces of t he sa me A E wit hi n t he sa me re p orte d 
p eri o d, t he m a xi m u m i nte nsit y will  be ta ke n as t he hig hest rec or de d m a xi mu m  int e nsit y (t he 
or der bei n g mil d, m o derate, a n d se vere).  Deat hs will als o be s u m marise d i n se parate ta bles.
A s u m mar y  of t h e most c o m m o n  (ie, fre q ue nc y of > 5 %) A Es will als o be prese nte d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 9 of 1 1 7
A Es of i nject i on site reacti o ns ( hi g h le vel ter m of a d mi nistrati o n a n d i nject i on site) will be 
s u m marise d b y P T f or t he treat me nt peri o d.  I n a d diti on, if t here is a s ufficie nt n u m ber of 
h y perse nsit i vity e ve nts (sta n dar dise d Me d D R A q uer y  of h y perse nsiti vity) , it will als o be 
s u m marise d b y P T f or t he o n-treat me nt perio d as well as t he o n-st u d y p erio d.  F urt her details 
will be pr o vi de d i n t he S A P.
Se parate list i n gs of patient s wit h A Es, S A Es, deat h d ue t o A E, D A Es , or adre nal 
ins ufficie nc y , will be prese nte d.
9. 4. 4
E x pl or at or y a n al yses
9. 4. 4. 1
C h a n ge fr o m b aseli ne Fe N O
T he c ha n ge fr o m b aseli ne Fe N O ( parts per billi o n [ p p b]) will be assesse d descri pti vel y a n d 
usi n g a M M R M a p pr oac h i ncl u di n g, treat me nt, visit, a n d visit × treat me nt.  T he esti mate d 
mea n c ha n ge fr o m baseli ne Fe N O d uri n g t he re d uctio n a n d mai nte na nce peri o ds will be 
prese nte d b y treat me nt a n d visit t o get her wit h 2-si de d 9 5 % CIs.
9. 4. 4. 2
C h a n ge fr o m b aseli ne i n bl o o d e osi n o p hil c o u nt
T he c ha n ge fr o m baseli ne bl o o d e osi n o p hil c o u nt will be assesse d descri pt i vel y a n d usi n g a 
M M R M a p pr oac h i ncl u di n g, treat me nt, visit, a n d treat me nt
x visi t.  T he esti mate d mea n 
c ha n ge fr o m baseli ne e osi n o p hil c o u nt d uri n g t he re d uctio n a n d m ai nte na nce perio ds will  b e 
prese nte d b y treat me nt a n d visit t o get her wit h 2-si de d 9 5 % CIs.  T hese a nal yses will be 
perf or m e d usi n g e osi n o p hil val ues prese nte d i n c o n ve nt i onal u nits.
9. 4. 4. 3
 
 
 
 
 
 
 
 
 
9. 4. 4. 4
C h a n ge fr o m b aseli ne i n air w a y oscill o metr y d uri n g t he st u d y peri o d
Air wa y  os cillo m etr y will be assesse d i n t he s u b-st u d y o nl y.  See Sectio n 9. 4. 5 f or details of 
a nal ysis.
C CI


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 0 of 1 1 7
9. 4. 5
S u b -st u d y a n al ysis
T he s u b -st u d y c o nsists of a p pr o xi matel y 3 2 pat ient s w h o will u n der g o air wa y oscill o metr y  t o 
assess ast h ma c o ntr ol a n d br o nc h osc o p y  a n d i n d uce d s p ut um sa m pli n g t o c haracterise t he 
effects of Fase nra ® o n ai r w a y infla m mati o n after re d uci n g dail y  S y m bic ort® t hera p y.  T he 
res ults of t his s u b-st u d y bi o mar ker researc h will be re p orte d se paratel y fr om t he C S R.
9. 4. 6
St u d y re a d -o ut
T he st u d y  will be a nal yse d a n d read- o ut aft er t he last patie nt has perf or me d t heir last visit 
( Wee k 4 8/ E O T). T he f ull st u d y will be a nal yse d i ncl u di n g b ot h t he re d ucti o n a n d mai nte na nce 
p eri o ds.  T hese a nal yses will i ncl u de all st u d y  data fr o m b ot h t he re d uctio n a n d m ai nte na nce 
p eri o ds.
T h e u n bli n di n g, ha n dli n g of data a n d res ults will be descri be d i n detail i n t he S A P a n d i n t he 
trial int e grit y d o c u me nt.
9. 5
I nteri m A n a l yses
N ot a p plica ble.
9. 5. 1
Scie ntific C o m mittee
A Scie ntific C o m mittee will be utili se d for t hi s st u d y.  A p pe n di x A 5 pr o vi des m ore details o n 
t he ratio nale f or a n d t he re mit of t he c o m mittee.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 1 of 1 1 7
1 0
R E F E R E N C E S
A n kerst et al 2 0 0 3
A n kerst J, Perss o n G, Wei b ull E.  T ole ra bility of  hi g h d ose of b u des o ni de/f or m oter ol i n a 
si n gle i n haler i n patient s wit h ast h ma.  P ul m P har mac ol T her 2 0 0 3; 1 3( 3): 1 4 7- 1 5 1.
B ate m a n et al 2 0 1 0
Bate ma n E D, Re d del H K, Eri kss o n G, Peters o n S, Ostl u n d O, Sears M R et al. O verall ast h ma 
c o ntr ol: T he r elat i ons hi p bet wee n c urre nt c o ntr ol a n d f ut ure ris k. J Aller g y Cli n I m m u n ol 
2 0 1 0; 1 2 5( 3): 6 0 0- 6 0 8.
Blee ker et al 2 0 1 6
Bl eec ker E R, Fitz Gerald J M, C ha nez P, Pa pi A, Wei nstei n S F, Bar ker P, et al.  Efficac y a n d 
safety of  be nraliz u ma b f or patie nts wit h se vere ast h ma u nc o ntr olle d with hi g h -d osa ge i n hale d 
c ortic oster oids a n d l o n g- act i n g β2-a g o nists ( SI R O C C O): a ra n d o mise d, m ult ice ntre, 
pl ace b o -c o ntr olle d p hase 3 trial.  La ncet 2 0 1 6; 3 8 8( 1 0 0 5 6): 2 1 1 5 -2 1 2 7.
C A M P et al 2 0 0 0
C hil d h o o d Ast h ma Ma na ge me nt Pr o gra m Researc h Gr o u p, Szefler S, Weiss S, T o nascia J, 
A d ki ns o n N F, Be n der B, et al.  L o n g-t er m effects of b u des o ni de or ne d ocr o mil i n c hil dre n 
wi t h ast h ma.  N E n gl J Me d. 2 0 0 0; 3 4 3( 1 5): 1 0 5 4- 1 0 6 3.
C h u n g et al 2 0 1 4 
C h u n g K F, We nzel S E, Br oze k J L, B us h A, Castr o M, Ster k PJ et al. I nter nati o nal E R S/ A T S 
g ui deli nes o n defi nit i on, e val uat i on a n d treat me nt of se vere ast h ma. E ur Res pir J 2 0 1 4; 4 3( 2):
3 4 3- 3 7 3.
Fitz Ger al d et al 2 0 1 6
Fi tz Geral d J M, Bleec ker E R, Nair P, K or n S, O hta K, L o m matzsc h M, et al. Be nraliz u ma b , 
a n a nt i-i nterle u ki n-5 rece pt or α m o n o cl o nal  a nti b o d y, as a d d-o n treat me nt f or patie nts wit h 
se vere, u nc o ntr olle d, e osi n o p hilic ast h ma ( C A LI M A): a ra n d omise d, d o u ble -bli n d, place b o -
c o ntr olle d p hase 3 trial.  La ncet 2 0 1 6; 3 8 8( 1 0 0 5 6): 2 1 2 8 - 2 1 4 1.
GI N A 2 0 1 9
G l obal Strate g y  for Ast h ma Ma na ge me nt a n d Pre ve nt i on, Gl o bal I nit iati ve f or Ast h ma 
( GI N A) 2 0 19.   [ Accesse d 1 2 A pril 2 0 1 9]. A vaila ble fr o m: ht t ps:// gi nast h ma. or g/ w p-
c o nte nt/ u pl oa ds/ 2 0 1 9/ 0 4/ GI N A-2 0 1 9- mai n -P oc ket -G ui de -w ms. p df .
G ol d m a n et al 2 0 1 7
G ol d ma n M, Hi rsc h I, Za n grilli J G, Ne w b ol d P, X u X.  T he ass ociati o n bet wee n bl o o d 
e osi n o p hil c o u nt a n d be nraliz u ma b efficac y for patie nts wi t h se vere, u nc o ntr olle d ast h ma: 
s u ba nal yses of t he P hase III SI R O C C O a n d C A LI M A st u dies.  C urr Me d Res O pi n. 2 0 1 7; 
3 3( 9): 1 6 0 5 - 1 6 1 3.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 2 of 1 1 7
G uil bert et al 2 0 0 6
G uil bert T W, M or ga n WJ, Zei ger R S, Ma u ger D T, B oe h mer SJ, Szefler SJ, et al. L o n g -t er m 
i n hale d c ortic oster oi ds i n presc h o ol c hil dre n at hi g h ris k f or ast h ma.  N E n gl J Me d. 2 0 0 6; 
3 5 4( 1 9): 1 9 8 5 - 1 9 9 7.
J ac o bse n et al 2 0 1 2
Jac o bse n E A, Hel mers R A, Lee JJ, Lee N A. T he e x pa n di n g r ole(s) of e osi n o p hils i n healt h 
a n d disease.  Bl o o d 2 0 1 2; 1 2 0( 1 9): 3 8 8 2 -3 8 9 0.
J u ni per et al 1 9 9 2
J u ni per E F, G u yatt G H, E pstei n R S, Ferrie PJ, Jaesc h ke R, Hiller T K.  E val uati o n o f 
i m pair me nt of healt h relate d q uality of life i n ast h ma: de vel o p me nt of a q uesti o n naire f or use 
i n cli nical trials.  T h ora x. 1 9 9 2; 4 7( 2): 7 6- 8 3.
J u ni per et al 1 9 9 4
J u ni per E F, G u yatt G H, Willa n A, Griffit h L E.  Deter mi ni n g a mi ni mal i m p orta nt c ha n ge i n a 
di sease-s pecific Q uality of  Life Q uesti on naire.  J Cli n E pi de mi o l. 1 9 9 4; 4 7( 1): 8 1-8 7.
J u ni per et al 1 9 9 9
J u ni per E F, B uist A S, C o x F M, Ferrie PJ, Ki n g D R.  Vali dati on of a sta n dar dize d versi o n o f 
t he Ast h ma Q ualit y of  Life Q uesti o n naire.  C hest. 1 9 9 9; 1 1 5( 5): 1 2 6 5-1 2 7 0.
J u ni per et al 2 0 0 5
J u ni per E F, S ve nss o n K, M ör k A C, Stå hl E.  M o dificati on of t he ast h ma q ualit y of  life 
q uesti o n naire (sta n dar dise d) f or patie nts 1 2 y ears a n d older.  Heal t h Q ual Life O utc o mes. 
2 0 0 5; 3: 5 8.
J u ni per et al 2 0 0 6
J u ni per E F, B o us q uet J, A betz L, Bate ma n E D , G O A L C o m mittee.  I de ntif yi n g ' well -
c o ntr olle d' a n d ' n ot well-c o ntr olle d' ast h ma usi n g t he Ast h ma C o ntr ol Q uesti o n naire.  Res pir 
Me d. 2 0 0 6; 1 0 0( 4): 6 1 6 - 6 2 1.
Le m a ns ke et al 2 0 0 1
Le ma ns ke R F Jr, S or k ness C A, Ma u ger E A, Lazar us S C, B o us he y H A, Fa h y  J V, et al.  
I n hale d c ortic oster oi d re d ucti on a n d eli mi nat i on i n patie nts wit h persiste nt ast h ma recei vi n g 
sal meter ol: a ra n d omize d c o ntr olle d trial.  J A M A. 2 0 0 1; 2 8 5( 2 0): 2 5 9 4- 2 6 0 3.
Mille r et al 2 0 0 5
Miller M R, Ha n ki ns o n J, Br usasc o V, B ur g os F, Casa b uri R, C oates A et al.  Sta n dar disati o n 
of  S pir o metr y.  E ur Res pir J. 2 0 0 5; 2 6: 3 1 9- 3 3 8.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 3 of 1 1 7
N A E P P 2 0 0 7 
Nati o nal Ast h ma E d ucati o n a n d Pre ve nt i on Pr o gra m.  E x pert Pa nel Re p ort 3: G ui deli nes f or 
t he Dia g n osis a n d Ma na ge me nt of Ast h ma 2 0 0 7.  [ Accesse d 0 1 Marc h
2 0 1 9].  A vaila ble 
fr om: htt p:// w w w. n hl bi. ni h. g o v/ g ui deli nes/ast h ma/ast h g dl n. p df .
N air et al 2 0 1 7
N ai r P, We nzel S, Ra be K F, B o ur di n A, L u g o g o N L, K u na P, et al.  Oral Gl uc oc ortic oi d-
S pari n g Effect of Be nraliz u ma b i n Se vere Ast h ma.  N E n gl J Me d. 2 0 1 7; 3 7 6( 2 5): 2 4 4 8 -2 4 5 8.
O' B yr ne et al 2 0 1 8
O' B yr ne P M, Fitz Geral d J M, Bate ma n E D, Bar nes PJ, Z h o n g N, Kee n C, et al.  I n hale d 
c o m bi ne d b u des o ni de-f or mot er ol  as nee de d i n mil d ast h ma.  N E n gl J Me d. 2 0 1 8; 3 7 8( 2 0): 
1 8 6 5- 1 8 7 6.
P al m q vist et al 2 0 0 1
Pal m q vist M, Ar vi dss o n P, Bec k ma n O, Peters o n S, L öt vall J.  O nset of br o nc h o dilati o n o f 
b u des o ni de/f or m oter ol vs. sal meter ol/fl ut icas o ne i n si n gle i n halers.  P ul m P har m T her 2 0 0 1; 
1 4( 1): 2 9- 3 4.
W a al ke ns
et al 1 9 9 3
Waal ke ns HJ, Va n Esse n - Za n d vliet E E, H u g hes M D, Gerritse n J, D ui ver ma n EJ, K n ol K, et 
al .  Cessat i on of l o n g -t er m treat me nt wit h in hale d c orti c oster oid ( b u des o ni de) i n c hil dre n wit h 
ast h ma res ults i n deteri orati o n. T he D utc h C N S L D St u d y Gr o u p .  A m Re v Res pi r Dis. 1 9 9 3; 
1 4 8( 5): 1 2 5 2 - 1 2 5 7.


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


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 5 of 1 1 7

E ur o pea n Me dical De vice Re g ulat i on 2 0 1 7/ 7 4 5 f or cli nical de vice researc h (if 
a p plica ble), a n d all ot her a p plica ble l ocal re g ulat i ons

A n I n vestigat or w h o recei ves a n ‘In vest i gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safety i nf or mati on (e g, s u m mar y or list i n g of S A Es) fr om t he S p o ns or will 
re vie w a n d t he n file it al o n g with t he I n vest i gat or’s Br oc h ure a n d will n otif y t he I R B/I E C, 
if a p pr o priate acc or di n g t o l ocal re q uire me nts.
A 2
Fi n a nci al D iscl os ure
I n vesti gat ors a n d s u b-i n vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities.  I n vest i gat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 year after c o mpleti o n of  t he st u d y.
A 3
I nfor me d C o nse nt P r ocess

T he In vesti gat or will e x plai n t he nat ure of t he st u d y t o t he pati e nt a n d a ns wer all 
q uesti o ns re gar di n g t he st u d y .

P ati e nt s must be i nf or me d t hat t heir partici pat i on is v ol unt ar y, a n d t he y ar e free t o ref use 
t o partici pate a n d ma y wit hdra w t hei r c onse nt at a n y t i me a n d f or a n y reas o n d uri n g t he 
st u d y.  P ati e nts will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of l ocal re g ulati ons, I C H g ui deli nes, a n d t he I R B/I E C or st u d y  ce ntre.

T he m e dical rec or d must i ncl u de a s t at e me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he pati e nt was e nr olle d i n t he st u d y  a n d t he date a n d ti me t he writte n c o nse nt was 
o btai ne d.  T he a ut h orise d pers o n o btai ni n g t he i nf o r me d c o nse nt m ust als o si g n t he I C F.

P ati e nt s must be re -c o nse nt e d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
parti ci pat i on i n t he st u d y.

A c o p y  of t he I C F(s) must be pr o vi de d t o t he pati e nt .
A 4
D at a P r otecti o n

Eac h patie nt will be assi g ne d a u ni q ue i de nt ifier b y t he S p o ns or.  A n y  pat ient rec or ds or 
datasets tra nsferre d t o t he S p o ns or will c o ntai n o nl y t he i de nt ifier; pat ient na mes or a n y  
i nf or mat i on w hic h w o ul d ma ke t he pati e nt i de ntifia ble will n ot be tra nsferre d.

T he pati e nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y t he 
S p o n s or i n acc or da nce wit h l ocal data pr otecti o n la w.  T he le vel o f discl os ure a n d use of 
t heir data m ust als o be e x plai ne d t o t he patie nt i n t he i nf or me d c o nse nt.

T he pati e nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orise d pers o n nel a p p o i nte d b y t he S p o ns or, b y  
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y  a ut h orities.
A 5
C o m mittees S tr uct ure
A Scie ntific C o m mittee c o nsist i n g of i nter nal A Z a n d e xter nal e x perts w h o ha ve bee n 
i n v ol ve d i n t he desi g n of t he cli nical st u d y will a d vise t he S p o ns or o n c ha n ges t o t he st u d y 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 6 of 1 1 7
desi g n a n d pr o vi de rec o m me n dat i ons o n iss ues relate d t o t he st u d y  c o n d uct, if re q uire d.  I n 
a d ditio n, t he c o m mittee will be i n v o l ve d i n t he re vie w a n d i nter pretati o n of t he st u d y res ults.  
T he Sci e nt ific C om mit tee will be g o ver ne d b y a c harter, detaili n g r oles a n d res p o nsi bilit ies 
a n d pr ocesses of  t he Scie ntific C o m mittee.
A 6
Disse mi n ati o n of cli nic al st u d y d at a
A descri pt i on of t his cli nical trial will be a vaila ble o n htt p://
astraze neca gr o u ptrials. p har mac m. c o m a n d htt p:// w w w.cli nicaltrials. g o v as will t he s u m mar y 
of  t h e mai n st u d y res ults w he n t he y are a vaila ble.  T he cli nical trial a n d/ or s u m mar y of mai n 
st u d y res ults m a y als o be a vaila ble o n ot her we bsites acc or di n g t o t he re g ulati o ns of t he 
c o u ntries i n w hic h t he mai n st u d y is c o n d ucte d.
A 7
D at a Q u a lit y A ss ur a nce

All patie nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or el ectr o nic case re p ort 
f or m ( eC R F ) u nless tra ns mitte d t o t he S p o ns or or d el e gate electr o nicall y (e g, la b orat or y 
data).  T he In vest i gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d 
c orrect b y electr o nicall y si g ni n g t he e C R F.

T he In vesti ga t or must m ai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he e C R F.

T he In vesti gat or m ust per mit st u d y -r elat e d mo ni t ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.

T he S p o ns or or dele gate is res p o nsi ble f or t he data ma na ge me nt of t his st u d y i ncl u di n g 
q ualit y c hec ki n g of t he data.

T he S p o ns or ass u mes acc o u nta bilit y f or actio ns dele gate d t o ot her i n di vi d uals (e g, 
C o ntract Researc h Or ga nisat i ons).

St u d y  m o nit ors will perf or m  o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nto t he e C R F b y a ut h orise d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m 
s o urce d oc u me nts; t hat t he safety a n d rig hts of  patie nt s are bei n g pr otecte d; a n d t hat t he 
st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y 
ot her st u d y  a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts.

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y  
m us t be retai ne d b y t he In vest i gat or f or 1 5 years after st u d y c o m plet i on u nless l ocal 
re g ulat i ons or i nst ituti o nal  p olicies re q uir e a lo n ger rete nti o n peri o d.  N o rec or ds m a y b e 
destr o y e d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he S p o ns or .  N o 
rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y wit ho ut wri tte n n otificati on t o t he 
S p o ns or. 
A 8
S o urce d oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he pati e nt a n d s u bsta nt iate t he 
i nte grit y of t he data c ollecte d.  S o urce d oc u me nts are file d at t he In vest i gat or’s site.

Data re p orte d o n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts m ust be c o nsiste nt 
wi t h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d.  T he In vest i gat or ma y 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nral iz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 7 of 1 1 7
nee d t o re q uest pre vi o us me dical r ec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y.  
Als o, c urre nt me dical rec or ds m ust be a vaila ble.

Defi nit i ons of w hat c o nst itut es s o urce data ca n be f o u n d i n t he s o urce data a gree me nt a n d 
c o mp ut eri se d data c hec k list f or electr o nic s o urce data.
A 9
St u d y a n d Site Cl os ure
T he S p o ns or or del e gate reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti on of t he S p o ns or.  T he st u d y  ma y be st o p pe d if, i n t he 
j u d ge me nt of  A Z , trial pat ient s are place d at u n d ue ris k beca use of cli nicall y si g nifica nt 
fi n di n gs t hat:

M eet i n di vi d ual st o p pi n g criteria or are ot her wise c o nsi dere d si g nifica nt.

A re assesse d as ca usall y relate d t o stu d y treat me nt .

A re n ot c o nsidere d t o be c o nsiste nt wit h c o nt i n uati o n of t he st u d y.
Re gar dless of t he reas o n f or ter mi nat i on, all data a vaila ble f or t he patie nt at t he ti me of 
di sc o nti n uati on of f o ll ow- u p m ust be rec or de d i n t he eC R F.  All  reas o ns f or disc o nti n uati on of 
treat me nt must be d oc u m e nte d.
I n ter mi nati n g t he st u d y, t he S p o ns or will e ns ure t hat a de q uate c o nsi derati on is gi ve n t o t he 
pr otecti o n of  t he patie nts’ i nterests.
St u d y  sites will be close d u p o n st u d y  c o mplet i on.  A st u d y  site is c o nsi dere d close d w he n all 
re q uire d d oc u me nts a n d st u d y s u p plies ha ve bee n c ollecte d a n d a st u dy sit e clos ure visit has 
bee n perf or me d.
T he I n vesti gat or ma y  ini tiate st u d y sit e clos ure at a n y  time, pr o vi de d t here i s reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nat i on.
Reas o ns f or t he earl y cl os ure of a st u d y  sit e by t he S p o ns or or In vest i gat or ma y i ncl u de b ut 
are n ot li mit e d t o:

Fail ure of t he In vest i gat or t o c o m pl y with t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l o c al  healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes.

I na de q uate recr uitme nt  of partici pa nts b y t he I n vestigat or .

Di sc o nti n uatio n of  furt her st u d y  int er ve nt i on de vel o p m e nt .
If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or s hall pr o m ptl y i nf or m t he 
I n vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y C R O(s) use d i n t he st u d y  of 
t he reas o n f or ter mi nat i on or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y  
re q uire me nts.  T he I n vesti gat or s hall pr o m ptl y i nf or m t he patie nt a n d s h o ul d ass ure 
a p pr o priate patie nt t hera p y a n d/ or f oll ow- u p.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 8 of 1 1 7
A 1 0
P u blic ati o n P olic y

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie nt ific meet i n gs.  If t his is 
f oresee n, t he In vest i gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or 
bef ore s u b missi o n.  T his all o ws t he S p o ns or t o pr otect pr o prietar y  i nf or mati on a n d t o 
pr o vi de c o m me nts.

T he S p o ns or will c o m p l y wit h t he re q uire me nts f or p u blicati on of st u d y  res ults.  I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort 
p u blicat i on of m ult ice ntre st u dies o nl y in t heir e ntiret y a n d n ot as i n di vi d ual site data.  I n 
t his case, a c oor di nat i n g In vest i gat or will be desi g nate d b y m ut ual a gree me nt.

A ut h ors hi p will be deter mi ne d b y  mut u al  a gree me nt a n d i n li ne with I nter nat i onal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 9 of 1 1 7
A p pe n di x B
A d verse E ve nt D efi niti o ns a n d A d diti o n al S afet y Inf or m ati o n
B 1
Defi niti o n of A d verse E ve nts
A n a d verse e ve nt ( A E ) is t he de vel o p me nt of a n y u nt o war d me dical occ urre nce i n a pat ient or 
cli nical st u d y patie nt a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a 
ca usal relat i ons hi p wi t h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v o ura ble a n d 
u ni nte n de d si g n (e g , a n a b n or mal la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na usea, c hest 
pai n), or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot 
c o nsi dere d relate d t o t he me dici nal pr o d uct.  
T he ter m  A E is use d t o i ncl u de b ot h seri o us a n d n o n-serio us A Es a n d ca n i ncl u de a 
deteri or ati o n of  a pre-e xist i n g me d ical occ urre nce.  A n A E ma y occ ur at a n y ti me, i ncl u di n g 
r u n-i n or was h o ut peri o ds, e ve n if n o st u d y treat me nt has bee n a d mi nistere d.
B 2
Defi niti o ns of S eri o us A d verse E ve nt
A seri o us a d verse e ve nt ( S A E ) is a n A E occ urri n g d uri n g a n y st u d y p eri o d (ie, r u n-i n, 
treat me nt, was h o ut, f o ll ow- u p), t hat f ulfil s 1 or m ore of t he f oll o wi n g criteria:

Res ults i n deat h .

Is i m me diatel y life-t hreate ni n g.

Re q ui res i n-pat ient h os pi talisati on or pr ol o n gat i on of e xist i n g h os pi talisati on.

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca paci t y.

Is a c o n ge nital a n o ma l y or bi rt h defect.

Is a n i m p orta nt me dical e ve nt t hat ma y je o par dise t he pati e nt or m a y re q uire me dical 
treat me nt t o pre ve nt 1 of  t he o utc o mes liste d a b o ve.
A d verse e ve nts f or mali g na nt t u m o urs re p orte d d uri n g a st u d y  s h o uld ge nerall y be assesse d as
serio us A Es.  If n o ot her seri o us ness criteria a p pl y , t he ‘I mp orta nt Me di cal E ve nt’ crit erio n 
s h o uld be use d.  I n certai n sit uati o ns, h o we ver, me dical j u d ge me nt o n a n i n di vi d ual e ve nt 
basis s h o ul d be a p plie d t o clarif y t hat t he mali g na nt t u m o ur e ve nt s h o u l d be assesse d a n d 
re p orte d as a n o n-serio us A E.  F or e xa m ple, if t he t u m o ur is i ncl u de d as me dical hist or y  a n d 
pr o gressi o n occ urs d uri n g t he st u d y , b ut t he pr o gressi on d oes n ot c ha n ge treat me nt a n d/ or 
pr o g n osi s of t h e mali g na nt t u mo ur, t he A E m a y n ot f ulfil t he attri b utes f or bei n g assesse d as 
serio us, al t ho u g h re p orti n g of t he pr o gressi o n of t he mali g na nt t u m o ur as a n A E is vali d a n d 
s h o uld occ ur.  Als o, s o m e t ypes of mali g na nt t u m o urs, w hic h d o n ot s prea d re m otel y after a 
r o utine treat m e nt t hat d oes n ot re q uire h os pitalisati o n, ma y be assesse d as n o n-s erio us; 
e xa m ples i ncl u de Sta ge 1 basal cell carci n o ma a n d Sta ge 1 A 1 cer vical ca ncer re m o ve d via 
c o ne bi o ps y.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 0 of 1 1 7
B 3
Life -t hre ate ni n g
‘ Life-t hreate ni n g’ mea ns t hat t he pati e nt was at i m me diate ris k of deat h fr o m t he A E as i t 
occ urre d or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d uct w o ul d res ult i n t he pati e nt ’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 patitis t hat res ol ve d wit ho ut he pati c fail ure).
B 4
H os pit alis ati o n
O ut pati e nt treat me nt i n a n e mer ge nc y r o o m is n ot i n itself a seri o us A E, alt h o u g h t he reas o ns 
f or it ma y be ( e g, br o nc h os pas m, lar y n geal oe de ma).  H os pital a d missi ons a n d/ or s ur gical 
o perati o ns pla n ne d bef ore or d uri n g a st u d y  are n ot c o nsidere d A Es if t he ill ness or disease 
e xiste d bef ore t he pati e nt was e nr olle d i n t he st u d y, pr o vi de d t hat it di d n ot deteri orate i n a n 
u ne x pecte d wa y  d uri n g t he st u d y.
B 5
I m p ort a nt M e dic al E ve nt or M e dic al T re at me nt
Me dical a n d scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her a case is seri o us i n 
sit u atio ns w here i m p orta nt m e dical e ve nts ma y not be i m me diatel y life- t hreate ni n g or res ult i n 
deat h, h os pi talisati on, di sa bilit y or i nca pacit y but ma y je o par di se t he pati e nt or m a y re q uire 
me dical treat me nt t o pre ve nt 1 or m ore o utc o m es liste d i n t he defi nit i on of seri o us.  T hese 
s h o 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 ge me nt m ust be use d.

A n gi oe de ma n ot se vere e n o u g h t o re q uire i nt u bati o n b ut re q uiri n g i v h y dr oc ortis o ne 
treat me nt

He pat ot o xicit y ca use d b y paraceta m o l (aceta mi n o p he n) o ver d ose re q uirin g treat m e nt wit h 
N- acet ylc ystei ne

I nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m

Bl o o d d y scrasias (e g, ne utr o pe nia or a nae mia re q uiri n g bl o o d tra nsf usi o n, etc) or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisat i on

De vel o p me nt of dr u g de pe n de nc y or dr u g a b use
B 6
I nte nsit y R ati n g S c ale:
1  
M il d (a ware ness of si g n or s y m pt o m, b ut easil y t olerate d)
2  
M o derate ( di sc omf o rt s ufficie nt t o ca use i nterfere nce wit h n or mal acti vities)
3 
S e vere (i nca pacitat i 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 verity is a meas ure of 
i nte nsit y w hereas serio us ness is defi ne d b y t he criteria i n A p pe n di x  B 2 .  A n A E of se vere 
i nte nsit y nee d n ot necessaril y be c o nsi dere d seri o us.  F or e xa m ple, na usea t hat persists f or 
se veral h o urs ma y be c o nsidere d se vere na usea, b ut n ot a S A E u nless it meets t he criteria 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 1 of 1 1 7
s h o w n i n A p pe n di x B 2 .  O n t he ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of 
di sa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a S A E w he n it satisfies t he crit eria 
s h o w n i n A p pe n di x B 2.
B 7
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n
W he n ma ki n g a n assess me nt of ca usalit y, c o nsi der t he f o ll ow i n g fact ors w he n deci di n g if 
t here is a ‘reas o na ble p ossi bilit y’ t hat a n A E ma y ha ve bee n ca use d b y t he dr u g.

Ti me C o urse.  E x p os ure t o s us pect dr u g.  Has t he pati e nt act uall y recei ve d t he s us pect 
dr u g?  Di d t he A E occ ur i n a reas o na ble te m p oral relat i ons h i 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 t he s us pect dr u g ( p har mac o l og y  a n d t o xic o l og y ) or dr u gs of t he sa me 
p har mac o l ogi cal class? Or c o ul d t he A E be a nt ici pate d fr o m its p har mac o l ogi cal 
pr o perties?

De -c halle n ge e x perie nce.  Did t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he 
d ose of t he s us pect dr u g?

N o al ter nati ve ca use.  T he A E ca n n ot be reas o na bl y e xplai ne d b y a n ot her aeti o l og y  s uc h 
as t he u n derl yi n g d isease, ot her dr u gs, ot her h ost or e n vir o n me ntal fact ors.

Re -c halle n ge e x perie nce.  Did t he A E re occ ur if t he s us pecte d dr u g was rei ntr o d uce d 
after ha vi n g bee n st o p pe d? Astra Ze neca ( A Z) w o ul d n ot n or m all y rec o m me n d or s u p p ort 
a r e-c halle n ge.

La b orat or y  tests.  A s pecific la b orat or y in vest i gati o n (if perf or me d) has c o nfir me d t he 
r elat i ons hi p .
I n diffic ult cases, ot her fact ors c o ul d be c o nsi dere d s uc h as:

Is t his a rec o g nise d feat ure of o ver d ose of t he dr u g?

Is t here a k n o w n mec ha nis m?
Ca usalit y of  ‘relate d’ is ma de if f oll 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 o ns hi p f or t he i n di vi d ual case.  T he e x pressi on 
‘reas o na ble p ossi bility’ o f a ca usal relati o ns hi p is mea nt t o c o n ve y, i n ge nera l, t hat t here are 
facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati ons hi p.
T he ca usalit y assess me nt is perf or me d base d o n t he a vaila ble data i ncl u di n g e n o u g h 
i nf or mat i on t o m a ke a n i nf or me d j u d g e 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 relat i ons hi p i n cases w here t he di sease u n der st u d y ( D U S) 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.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 2 of 1 1 7
B 8
Me dic ati o n Err or
F or t he p ur p oses of t his cli nical st u d y  a me dicat i on err or is a n u ni nte n de d fail ure or mista ke i n 
t he treat me nt pr ocess f or a n A Z st u d y tr e at me nt t hat eit her ca uses har m t o t he partici pa nt or 
has t he p ote ntial t o ca use har m t o t he partici pa nt.  
A me dicat i on err or is n ot l ac k of efficac y of t he dr u g, b ut rat her a h u ma n or pr ocess relate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y site staff or partici pa nt.
Me dicat i on err or i ncl u des sit uat i ons w here a n err or :

O cc urre d

W as ide nt ifie d a n d i nterce pte d bef ore t he partici pa nt recei ve d t he dr u g

D i d n ot occ ur, b ut circ u msta nces were rec o g nise d t hat c o uld ha ve le d t o a n err or .
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors:

Dr u g na me c o nf usi o n

Di s pe nsi n g err or e g, me d icatio n pre pare d i nc orrectl y , e ve n if it was n ot act uall y gi ve n t o 
t he partici pa nt

Dr u g n ot a d mi nistere d as i n dicate d, f or e xa m ple, wr o n g r o ute or wr o n g site of 
a d mi nistrati o n

Dr u g n ot ta ke n as i n dicate d e g , ta blet diss ol ve d i n water w he n it s h o ul d be ta ke n as a 
s oli d ta blet 

Dr u g n ot st ore d as i nstr ucte d e g, ke pt i n t he fri d ge w he n it s h o ul d be at r o o m te m perat ure 

Wr o n g partici pa nt recei ve d t he me dicat i on (e xcl u di n g i nteracti ve v o ice/ we b res p o nse 
s yste m [I V R S/I W R S] err ors)

Wr o n g dr u g a d mi nistere d t o p art ici pa nt (e xcl u di n g I V R S/I W R S err ors).
E xa m ples of e ve nts t hat d o n ot re q uire re p orti n g as me dicati on err ors i n cli nical st u dies:

Err ors relate d t o or res ulti n g fr o m I V R S/I W R S-i ncl u di n g t h ose w hic h lea d t o 1 of  t he 
a b o ve liste d e ve nts t hat w o ul d ot her wise ha ve bee n a me dicatio n err or 

P arti cip a nt a c ci de ntall y  misse d dr u g d ose(s) e g, f or g ot t o ta ke me dicati o n

Acci de ntal  o ver d ose ( will be ca pt ure d as a n o ver d ose)

P arti cip a nt f aile d t o ret ur n u n use d me dicat i on or e m pt y pac ka gi n g

Err ors relate d t o bac k gr o u n d a n d resc ue me dicat i on, or sta n dar d of care me dicat i on i n 
o pe n -label st u dies, e ve n if a n AZ pr o d uct .
Me dicat i on err ors are n ot re gar de d as A Es b ut A Es ma y  occ ur as a c o nse q ue nce of t he 
me dicat i on err or.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 3 of 1 1 7
A p pe n di x C
H a n dli n g of H u m a n Bi ol o gic al S a m ples
C 1
C h ai n of C ust o d y of B i ol o gic al S a m ples
A f ull c hai n of c ust o d y is mai ntai ne d f or all sa m ples t hr o u g h o ut t heir lifec ycle.
T he I n vesti gat or at eac h ce ntre kee ps f ull tracea bilit y  of c ollecte d biol o gi cal sa mpl es f r o m t he 
pati e nt s w hile i n st ora ge at t he ce ntre u ntil s hi p me nt or di s p osal ( w here a p pr o priate).
T he sa m ple recei ver kee ps f ull tracea bilit y of  t he sa mples w hile i n st ora ge a n d d uri n g use u nt il 
use d or dis p ose d of or u ntil f urt her s hi p me nt a n d kee ps d oc u me ntati o n of recei pt of arri val.
Astra Ze neca ( A Z) will kee p o versi g ht of t he e nt ire life c ycle t hr o u g h i nter nal pr oce d ures, 
m o nit ori n g of st u d y  sit es, a u diti n g or pr ocess c hec ks, a n d c o ntract ual re q uire me nts of e xter nal 
la b orat or y pr o vid ers .
S a m ples retai ne d f or f urt her use will be st ore d i n t he A Z -assi g ne d bio b a n ks a n d will be 
r e gistere d b y t h e AZ Bi o b a n k Tea m d uri n g t he e ntire life c ycle.
C 2
Wit h dr a w al of I nf or me d C o nse nt f or D o n ate d B i ol o gic al S a m ples 
If a patie nt wit h dra ws c o nse nt t o t he use of d o nate d bi o l ogi c al s a mples, t he sa m ples will  b e 
di s p ose d of/ destr o ye d, a n d t he actio n d oc u me nte d.  If sa m ples are alrea d y  a nal yse d, A Z is n ot 
o bli ge d t o destr o y  t he res ults of t his researc h.
As c ollect i on of t he bi o l ogical sa m ples (ie, bl o o d sa m ples ) is a n i nte gral part of t he st u d y, t he n 
t he pati e nt is with dra w n fr o m f urt her st u d y  partici patio n.
T he I n vesti gat or:

E ns ures pat ient s’ wit h dra wal of i nf or me d c o nse nt t o t he use of d o nate d sa m ples is 
n otifie d i m me diatel y t o A Z

E ns ures t hat bi ol o gi cal sa m ples fr o m t hat patie nt , if st ore d at t he st u d y site, are 
i m me diatel y ide nt ifie d, dis p ose d of / destr o ye d, a n d t he acti o n d oc u me nte d

E ns ures t he or ga ni satio n(s) h ol di n g t he sa m ples is/are i nf or me d a b o ut t he wit h dra w n 
c o nse nt i m me diate l y a n d t hat sa m ples are dis p ose d of/ destr o ye d, t he acti o n d oc u me nte d 
a n d t he si g ne d d oc u me nt ret ur ne d t o t he st u d y sit e

E ns ures t hat t he pati e nt a n d AZ are i nf or me d a b o ut t he sa m ple dis p osal.
A Z e ns ures t he or ga nisat i ons h o l di n g t he sa m ples is/are i nf or me d a b o ut t he wit hdra w n 
c o nse nt i m me diatel y a n d t hat sa m ples are dis p ose d of/ destr o y e d a n d t he actio n d oc u m e nte d 
a n d ret ur ne d t o t he st u d y sit e.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 4 of 1 1 7
C 3
I nter n ati o n al Airli ne Tr a ns p ort ati o n Ass oci ati o n (I A T A) 6. 2 
G u i d a nce D oc u me nt
L A B E L LI N G A N D S HI P M E N T O F BI O H A Z A R D S A M P L E S
I nter nati o nal Airli ne Tra ns p ortati o n Ass ociati on (I A T A) classifies bi o hazar d o us a ge nts i nt o 
3 cate g ories 
(htt p:// w w w.i at a. or g/ w h at we d o/c ar g o/ d a n ger o us _ g o o ds/i nfecti o us _s u bst a nces. ht m ).  F o r 
tra ns p ort p ur p oses t he classificati on of i nfect i ous s u bsta nces acc or di n g t o ris k gr o u ps was 
r e mo ve d fr o m  t he Da n ger o us G o o ds Re g ulati ons i n t he 4 6t h e diti o n ( 2 0 0 5) .  I nfecti ous 
s u bsta nces are n o w classifie d either as Cate g or y  A, Cate g or y B or E xe mpt .  T here i s n o direct 
r elat i ons 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 disa bilit y,  life-t hreate ni n g or fatal disease i n 
ot her wi se health y h u ma ns or a ni mals .  Cate g or y  A path o ge ns are e g, E b ola, Lassa fe ver vir us:

A re 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 nfect i ous S u bsta nces t hat d o n ot meet t he criteria f or 
i ncl usi on i n Cate g or y  A. Cate g or y  B pat h o ge ns are e g, He patitis A, B, C, D, a n d E vir uses, 
H u m a n i m m u n o deficie nc y vir us t ypes 1 a n d 2. T he y  are assi g ne d t he f oll o wi n g U N n u m ber 
a n d pr o per s hi p pi n g na me:

U N 3 3 7 3 – Bi o l ogi cal S u bsta nce, Cate g or y B

A re t o be pac ke d i n acc or da nce with U N 3 3 7 3 a n d I A T A 6 5 0
E xe m pt -all ot her mat erials wit h mi ni mal ris 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 a m bie nt t e mp er a t 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.i at a. or g/ w h at we d o/c ar g o/ d a n ger o us _ g o o ds/i nfecti o us _s u bst a nces. ht m)

Bi ol o gic al s a m ples tr a ns p orte d i n dr y ice re q uire a d diti o n al d a n ger o us g o o ds 
s pecific ati o n f or t he dr y ice c o nte nt

I A T A c om p lia nt c o urier a n d pac ka gi n g materials s h o ul d be use d f or pac ki n g a n d 
tra ns p ortati o n a n d 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 lo c al  re g ulatio ns w hic h 
re q uire t hat t he 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 i nfect i on or c o nta mi nat i on b y usi n g a p pr o ve d c o uriers a n d 
pac ka gi n g/c o ntai n me nt materials at all ti mes .  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 o ssi ble w he n r oa d or rail tra ns p ort is 
use d.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 5 of 1 1 7
A p pe n di x D
Cl assific ati o n of I n Vi v o I n hi bit ors of C Y P 3 A 4 E nz y mes
E x a m ples of C Y P e nz y me i n hi bit ors
C Y P e nz y me
Str o n g i n hi bit ors
M o der ate i n hi bit ors
We a k i n hi bit ors
C Y P 3 A
B oce pre vir, 
clarit hr o m yci n, 
c o bicistat, c o ni va pta n, 
da n o pre vir a n d rit o na vir, 
diltiaze m, el vite gra vir 
a n d rit ona vir, gra pefr uit 
j uice, i delalisi b, i n di na vir 
a n d rit ona vir, 
itrac o naz ole, 
ket oc o naz ole, l o pi na vir 
a n d rit ona vir, 
nefaz o d o ne, nelfi na vir, 
parita pre vir a n d rit o na vir 
a n d ( o m bitas vir a n d/ or 
dasa b u vir), 
p osac o naz ole, rit o na vir, 
sa q ui na vir a n d rit o na vir, 
tela pre vir, ti pra na vir a n d 
rit o na vir, 
tr olea n d o m yci n, 
v oric o naz ole
A pre pita nt, ci meti di ne, 
ci pr ofl o xaci n, 
cl otri maz ole, criz oti ni b, 
c ycl os p ori ne, 
dr o ne dar o ne, 
er yt hr o m yci n, 
fl uc onaz ole, 
fl u v o xa mi ne, i mati ni b, 
t ofis o pa m, vera pa mil
C hl orz o xaz o ne, 
cil ostaz ol, f osa pre pita nt, 
istra def ylli ne, i vacaft or, 
l o mita pi de, ra niti di ne, 
ra n olazi ne, tacr oli m us, 
tica grel or
C Y P =c yt oc hr o me P 4 5 0.
N ote: Str o n g, m o derate, a n d wea k i n hi bit ors are dr u gs t hat i ncrease t he A U C of se nsiti ve i n de x s u bstrates of a 
gi ve n meta b olic pat h wa y ≥5 -f ol d, ≥2 t o < 5 -f ol d, a n d ≥1. 2 5 t o < 2 -f ol d, res pecti vel y.
Please n ote t he f oll o wi n g: T his is n ot a n e x ha usti ve list.
F or a n u p date d list, see t he f oll o wi n g li n k: 
htt ps:// w w w.f da. g o v/ dr u gs/ de vel o p me nta p pr o val pr ocess/ de vel o p me ntres o urces/ dr u gi nteracti o nsla beli
n g/ uc m 0 8 0 4 9 9. ht m (accesse d o n 0 8 M a y
2 0 1 9).


















Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 4 of 1 1 7
A p pe n di x G
G u i d a nce o n C h a n ges Rel ate d t o Miti g ati o n of St u d y 
Disr u pti o n s D u e t o C ase s of Ci vil Crisis, N at ur al Dis aster, or 
P u blic He alt h Crisis
N ote: C ha n ges bel o w s h o ul d be i m ple me nte d o nl y d uri n g st u d y disr u pti o ns d ue t o a n y of or a 
c o m bi nat i on of ci vil crisis, nat ural disaster, or p u blic healt h cri sis (e g, d uri n g q uara nt i nes a n d 
res ultin g site cl os ures, re gi o nal tra vel restricti o ns a n d c o nsi derat i ons if site pers o n nel or st u d y 
patie nts bec o me i nfecte d wit h S A R S-C o V - 2 or si milar pa n de mic i nfect i on) d uri n g w hic h 
patie nts ma y n ot wis h t o or ma y be u na ble t o visit t he st u d y site f or s t u d y visits. T hese 
c ha n ges s h o ul d o nl y be i m ple me nte d if all o wa ble b y l o cal/re gio nal g ui deli nes a n d f oll o wi n g 
n otificati o n fr o m t he S p o ns or a n d i nstr ucti o ns o n h o w t o perf or m t hese pr oce d ures will be 
pr o vi de d at t he ti me of i m ple me ntati o n .
G 1
Rec o nse nt of St u d y P atie nts D uri n g St u d y I nterr u pti o ns
D uri n g st u d y  int err u ptio ns, i t ma y not be p ossi ble f or t he patie nts t o c o m plete st u d y  visits a n d 
assess me nts o n site a n d alter nat i ve mea ns f or carr yi n g o ut t he visits a n d assess me nts ma y be 
necessar y , e g, re mot e vi sits.  Rec o nse nt s h o uld be o btai ne d f or t he alter nat i ve mea ns of 
carr yi n g o ut visits a n d assess me nts a n d s h o ul d be o btai ne d pri or t o perf or mi n g t he pr oce d ures 
descri be d i n Secti o ns  G 2 t o G 6 .  L ocal a n d re gi onal re g ulat i ons a n d/ or g ui deli nes re gar di n g 
rec o nse nt of st u d y p atie nts s h o uld be c hec ke d a n d f o ll owe d.  Rec o nse nt ma y be ver bal if 
all o we d b y lo c al  a n d re gio nal g ui deli nes ( n ote, i n t he case of ver bal rec o nse nt t he I C F s h o ul d 
be si g ne d at t he patie nt’s ne xt c o ntact wit h t he st u d y site).  Visit i n g t he st u d y sit es for t he s ol e 
p ur p ose of o btai n i n g rec o nse nt s h o ul d be a v oi de d.
G 2
Rescree ni n g of P atie nts t o Rec o nfir m St u d y Eli gi bilit y
A d dit i onal rescree ni n g f or scree n fail ure d ue t o st u d y  disr u ptio n ca n be perf or me d i n 
pre vi o usl y scree ne d part ici pa nts.  T he i n vesti gat or s h o ul d c o nfir m t his wit h t he desi g nate d 
st u d y p h ysicia n.
I n a d diti on, d uri n g st u d y  disr u pti on t here ma y be a dela y bet wee n c o nfir mi n g eli gi bilit y of a 
pati e nt a n d eit her e nr ol me nt i nt o t he st u d y or c o m me nci n g of d osi n g wit h i n vesti gati onal 
pr o d uct.  If t his dela y is o utsi de t he scree ni n g wi n d o w s pecifie d i n  Ta ble 1 t he patie nt will 
nee d t o be rescree ne d t o rec o nfir m eli gi bilit y bef ore c o m me nci n g st u d y  pr oce d ures. T his will 
pr o vi de a n ot her o p p ort u nit y t o re-scree n a patie nt i n a d diti on t o t hat detaile d i n Sect i on 5. 4 . 
T he pr oce d ures detaile d i n Sect i on 5 m ust be u n derta ke n t o c o nfir m eli gi bilit y usi n g t he sa me 
ra n d omizat i on n u m ber as f or t he patie nt.
G 3
H o me or Re m ote Visit t o Re pl ace O n -site Visit ( w here a p plic a ble)
A q ualifie d H C P fr o m t he st u d y sit e or T PV ser vice ma y visit t he patie nts h o me/ or ot her 
r e mot e  lo c ati o n as per l o c al  Sta n dar d O perati n g Pr oce d ures, as a p plica ble.  S u p plies will be 


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pr o vi de d f or a safe a n d efficie nt visit.  T he q ualifie d H C P will be e x pecte d t o c ollect 
i nf or mat i on per t he cli nical st u d y pr ot oc ol ( C S P).  If a p plica ble, assess me nts will be 
perf or m e d acc or di n g t o t he re vise d Sc he d ule of Assess me nts ( S o A).
G 4
Tele me dici ne Visit t o Re pl ace O n -site Visit ( w here a p plic a ble)
I n t his a p pe n di x, t he ter m t ele me dici ne visit refers t o re m ote c o nta ct  wit h t he patie nts usi n g 
t elec o m m u nicat i ons tec h n o l og y  incl u di n g p h o ne calls, virt ual or vi de o visit s, a n d mo bile 
healt h de vices.
D uri n g a ci vil crisis, nat ural disaster, or p u blic healt h cri sis, o n-site visits m a y be re place d b y 
a tele me dici ne visit if allo w e d b y  lo c al/re gio n al g ui deli nes. Ha vi n g a tele me dici ne c o ntact 
wi t h t he patie nts will allo w a d verse e ve nts, c o nc o mita nt me dicati o n, a n d ot her i nf or mat i on 
i ncl u di n g efficac y data w here rele va nt t o be c ollecte d acc or di n g t o st u d y re q uire me nts t o be 
re porte d a n d d oc u me nte d.   If a p plica ble, safety pr oce d ures a n d bl o o d sa m ple c ollecti o n ma y
be perf or m e d acc or di n g t o t he re vise d S o A i n t he St u d y I nstr uctio n s f or Mitigat i on D ue t o 
Ci vil Crisis, Nat ural Disaster, or P u blic Healt h Crisis.
G 5
At -h o me or Re m ote L oc ati o n I P A d mi nistr ati o n I nstr ucti o ns
If a site visit is n ot p ossi ble, at-h o me or re m ote l ocati o n a d mi nistrati o n of I P ma y be 
perf or m e d b y a q ualifie d H C P, pr o vide d t his is acce pta ble wit hi n l ocal re g ulatio n/ g ui da nce, or 
b y t he patie nt or his/ her care gi ver.   T he o pti o n of  at-h o me or re m ote l ocati o n I P 
a d mi nistrati o n e ns ures pat ient s safety i n cases of a pa n de mic w here patie nts ma y be at 
i ncrease d ris k b y tra veli n g t o t he site/cli nic.  T his will als o mi ni mize i nterr u ptio n of  I P 
a d mi nistrati o n d uri n g ot her st u d y disr u pti o ns, e g, site cl os ures d ue t o nat ural disaster.
G 5. 1
At- h o me or Re m ote L oc ati o n I P A d mi nistr ati o n b y a Q u alifie d H C P or 
T P V Ser vice
A q ualifie d H C P fr o m t he st u d y site or T P V ser vice ma y a d mi nister t he I P at t he patie nt’s 
h o me or ot her re m ote l ocati o n acc or di n g t o t he C S P.  All necessar y s u p plies a n d i nstr ucti o ns 
f or a d mi nistrati o n a n d d oc u me nt atio n of  I P a d mi nistrati o n will be pr o vi de d.  A d diti on al  
i nf or mat i on rel ate d t o t he visit ca n be o btai ne d via a tele me dici ne or h o me visit.
G 5. 2
At- h o me or Re m ote L o c ati o n I P A d mi nistr ati o n b y t he P atie nt or 
His/ Her C are gi ver
Pri or t o at -h o me or re m ote l ocati o n I P a d mi nistrati o n t he i n vesti gat or m ust assess t he patie nt 
or hi s/ her care gi ver t o deter mi ne w het her t he y are a p pr o priate f or at-h o me or re m ote l ocati o n 
a d mi nistrati o n of I P.  O nce t he patie nt or his/ her care gi ver is dee me d a p pr o priate f or at -h o me 
or re m ot e  lo c ati o n a d mi nistrati o n, he/s he m ust recei ve a p pr o priate trai ni n g.  All necessar y  
s u p plies a n d i nstr ucti o ns f or a d mi nistrati o n a n d d oc u me ntati o n of I P a d mi nistrati o n will be 


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pr o vi de d.  M ore i nf or mat i on rel ate d t o t he visit ca n be o btai ne d via a tele me dici ne or 
h o me/re m ote visit.
G 6
D at a C a pt ure D uri n g Tele me dici ne or H o me/ Re m ote Visits
Data c ollecte d d uri n g tele me dici ne or h o me/re m ote visits will be ca pt ure d b y t he q ualifie d 
H C P fr o m t he st u d y site or T P V ser vice i n t he s o urce d oc u me nts, or b y t he patie nt t he msel ves.


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A p pe n di x H
Me dic al De vice A Es, A D Es, S A Es, S A D Es, U S A D Es , a n d 
Me dic al De vice Deficie ncies: Defi niti o ns a n d Pr oce d ures f or 
Rec or di n g, E v al u ati n g, F oll o w -u p, a n d Re p orti n g i n Me dic al 
De vice St u dies

T he defi nit i ons a n d pr oce d ures detaile d i n t his a p pe n di x are i n acc or da nce wit h 
Int er nati o nal O r ga nisat i on f or S ta n dar disatio n 1 4 1 5 5 a n d E ur o pea n M D R
2 0 1 7/ 7 4 5 f or 
cli nical de vice researc h (if a p plica ble).

B ot h t he In vesti gat or a n d t he S p o ns or will c o m p l y wi t h all lo c al  re p orti n g re q uire me nts
f or me d ical de vices.

T he detecti o n a n d d oc u m e nt atio n pr oce d ures descri be d i n t his pr ot oc ol a p pl y  t o all 
S p o ns or me dical de vices (see Secti o n 6. 1. 1 f or t he relate d list) a n d all t hir d -part y me d ical 
de vices (see Secti o n 6. 1. 2 f or t he relate d list) pr o vi de d f or use i n t he st u d y .
H 1
Defi niti o n of Me dic al De vice A E a n d A D E
Me dic al De vice A E a n d A D E Defi niti o n

A n A E i s a n y u nt o war d me dical occ urre nce i n a cli nical st u d y parti ci pa nt, users, or ot her 
pers o ns , t e mp orall y ass oci at e d wit h t he use of st u d y tr e at me nt , w het her or n ot c o nsi dere d 
r elate d t o t he i n vesti gati onal me dical de vice . A n A E ca n t heref ore be a n y  u nfa v o ura ble
a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y  fi n di n g), s y m pt o m, or disease 
( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he use of a n i n vesti gati onal me dical 
de vice . T his defi nit i on i ncl u des e ve nts relate d t o t he i n vesti gati onal me dical de vice or 
c o mparat or a n d e ve nts relate d t o t he pr oce d ures i n v o l ve d.

A n a d verse de vice effect ( A D E) is defi ne d as a n A E relate d t o t he use of a n 
i n vesti gati onal me dical de vice. T hi s defi niti on i ncl u des a n y A E res ultin g fr o m 
i ns ufficie nt or i na de q uate i nstr ucti o ns f or use, de pl o y me nt, i m pla ntati o n, i nstallati on, or 
o perati o n, or a n y  malf u nct i on of t he i n vest i gati onal me dical de vice as well as a n y e ve nt 
res ultin g fr o m use err or or fr o m i nte nti o nal mis use of t he i n vest i gati o nal me dical de vice.
H 2
Defi niti o n of Me dic al De vice S A E, S A D E , a n d U S A D E
A Me dic al De vice S A E is a n a n y S A E t h at:
a.
Le a ds t o d e at h.
b.
L ea ds t o serio us deteri or at i on i n t he healt h of  t he pati e nt , t hat eit her res ulte d i n:

A life-t hreate ni n g ill ness or i nj ur y. T he ter m “life-t hreate ni n g” i n t he defi niti on of 
“serio us ” r efers t o a n e ve nt i n w hic h t he patie nt was at ris k of deat h at t he ti me of t he 
e ve nt. It d oes n ot refer t o a n e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d deat h if it 
were m ore se vere .

A per ma ne nt i m pair me nt of a b o d y  str uct ure or a b o d y fu nct i on.


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
I npat ient  or pr ol o n ge d h os pitalisat i on. Pla n ne d h os pitali sat i on f or a pre-e xisti ng 
c o n ditio n, or a pr oce d ure re q uire d b y t he pr ot oc ol , wit ho ut seri o us deteri or ati o n i n healt h, 
is n ot c o nsi dere d a n S A E .

M e dical or s ur gical i nter ve nt i on t o pre ve nt life -t hreate ni n g ill ness or i nj ur y or per ma ne nt 
i m pair me nt t o a b od y str uct ure or a b o d y  f unct i on.

C hr o nic disease ( M D R 2 0 1 7/ 7 4 5).
c.
Le a ds t o fet al distress, fetal deat h, or a c o n ge nital a n o ma l y or birt h defect.
S A D E defi niti o n
S eri o us a d verse de vice effect ( S A D E ) is a n a d verse me d ical de vice effect t hat has res ulte d i n 
a n y of t he c o nse q ue nces c haracteristic of a n S A E.  A S A D E i s defi ne d as a n y De vice 
C o nst itue nt Deficie nc y t hat mi g ht ha ve le d t o a n S A E if a p pr o priate acti o n ha d n ot bee n 
ta ke n, i nter ve nti on ha d n ot occ urre d, or circ u msta nces ha d bee n less f ort u nate.
U n a ntici p ate d S A D E (U S A D E ) de fi niti o n

A n U S A D E (als o i de ntifie d as U A D E i n Unit e d S t at es Re g ul at i ons 2 1 C F R 8 1 3. 3), is 
defi ne d as a serio us a d verse me dical de vice effect t hat b y  its nat ure, inci de nce, se verit y,  
or o utc o me has n ot bee n i de nt ifie d i n t he c urre nt versi o n of t he ris k a nalysis re p ort (see 
Secti o n  2. 3 ).
H 3
Defi niti o n of Me dic al De vice Deficie nc y
Me dic al De vice Deficie nc y Defi niti o n

A me dical de vice deficie nc y is a n i na de q uac y of  a me dical de vice wi t h res pect t o its 
i de ntity,  q uality,  d ura bility,  reliabilit y, safet y,  or perf or ma nce. Me di cal de vice 
deficie ncies i ncl u de malf u ncti o ns, use err ors, a n d i nf or mati on s u p plie d b y  t he 
ma n ufact urer .
H 4
Rec or di n g a n d F oll o w - up of A E a n d/ or S A E a n d Me dic al De vice 
Deficie ncies
A E, S A E, a n d Me dic al De vice Deficie nc y Rec or di n g

W he n a n A E/ S A E/ me d ical de vice deficie nc y occ urs, it is t he res p o nsi bilit y of  t he 
In vest i gat or t o re vie w all d oc u me ntati o n (e g, h os pital pr o gress n otes, la b orat or y re p orts, 
a n d dia g n ostics re p orts) relate d t o t he e ve nt.

T he In vesti gat or will t he n rec or d all rele va nt A E/ S A E/ me dical de vice deficie nc y 
i nf or mat i on i n t he patie nt ’s me d ical rec or ds, i n acc or da nce wit h t he In vest i gat or’s n or mal 
cli nical practice a n d o n t he a p pr o pria t e for m .

It is n ot acce pta ble f or t he In vest i gat or t o se n d p h ot oc o pies of t he pati e nt’s me dical 
rec or ds t o t he C R O / S p o ns or i n lie u of c o m p leti on of t he A E/ S A E/ me dical de vice 
deficie nc y f or m.


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
T here m a y be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d .
I n t his case, all patie nt i de ntifiers, wit h t he e xce pti o n of t he pati e nt n u m ber, will be 
re dacte d o n t he c o pies of t he me dical rec or ds bef ore s u b missi on.

T he I n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n sig ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati on. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E.

F or me d ical de vice deficie ncies, it is ver y  i m p orta nt t hat t he In vesti gat or descri bes a n y 
c orrecti ve o r re me dial acti ons ta ke n t o pre ve nt rec urre nce of t he deficie nc y.

A re me dial act i on is a n y acti o n ot her t ha n r o uti ne mai nte na nce or ser vici n g of a 
me dical de vice w here s uc h act i on is necessar y  t o pre ve nt rec urre nce of a me dical 
de vice deficie nc y. T hi s i ncl u des a n y a me n d me nt t o t he me d ical de vice desi g n t o 
pre ve nt rec urre nce.
Assess me nt of I nte nsit y
T he In vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E/ S A E/ me dical de vice 
deficie nc y re p orte d d uri n g t he st u d y a n d assi g n it t o o ne of  t h e foll o wi n g cate g ories:

Mil d: A n e ve nt t hat is easil y t olerate d b y t he pat ient , ca usi n g mi ni mal disc omf o rt a n d n ot 
i nterferi n g wit h e ver y da y acti vities.

M o derate: A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or m al e ver yd a y  
acti vit ies.

Se vere: A n e ve nt t hat pre ve nts n or mal e ver y da y acti vi ties. A n A E t hat is assesse d as 
se vere s h o ul d n ot be c o nf use d wit h an S A E. “Se vere ” is a cate g or y use d f or rati n g t he 
i nte nsit y of a n e ve nt; b ot h A Es a n d S A Es ca n be assesse d as se vere.

A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi nit i on o f a n S A E, n ot w he n it is rate d as se vere.
Assess me nt of C a us alit y

T he In vesti gat or is o bli gate d t o assess t he relat i ons hi p bet wee n st u d y  treat me nt a n d eac h 
occ urre nce of eac h A E/ S A E / me dical de vice deficie nc y.

A “reas o na ble p ossi bilit y” o f a relat i ons hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relat i ons hi p, ca n n ot be r ule d o ut.

T he In vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relat i ons hi p.

Alt er nat i ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y tr e at me nt a d mi nistrati o n 
wi ll be c o nsi dere d a n d i n vest i gate d.

T he In vesti gat or will als o c o ns ult t he I n vesti gat or’s Br oc h ure (I B) or Pr o d uct 
I nf or mat i on, f or mar kete d pr o d ucts i n his/ her assess me nt.


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
F or eac h A E/ S A E / me dical de vice deficie nc y, t he In vesti gat or m ust
d oc u me nt i n t he 
me dical n otes t hat he/s he has re vie we d t he A E/ S A E/ me dical de vice deficie nc y a n d has 
pr o vi de d a n assess me nt of ca usalit y.

T here m a y be sit u atio ns i n w hic h a n S A E has occ urre d a n d t he In vesti gat or has mi ni mal 
i nf or mat i on t o i ncl u de i n t he i n itial re p ort t o S p o ns or . H o we ver, it is ver y i m p orta nt t hat 
t he In vest i gat or al wa ys ma ke a n assess me nt of ca usality f or e ver y e ve nt bef ore t he i nitial 
tra ns missi on of t he S A E data t o S p o ns or .

T he In vesti gat or ma y  c ha n ge his/ her o pi ni o n of ca usality i n li ght  of f oll ow- u p i nf or m at i on 
a n d se n d a n S A E f o ll ow- u p re p ort wi t h t he u p date d ca usality assess me nt.

T he ca usalit y assess me nt is o ne of t he crit eria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts.
M D C G 2 0 2 0 G ui d a nce 
F or t he p ur p ose of har m o nizi n g re p orts, eac h S A E will be classifie d acc or di n g t o fi ve
differe nt le vels of ca usalit y.
T h e Sp o ns or a n d t he I n vesti gat ors will use t he f oll owi n g
defi nit i ons t o assess t he relati o ns hi p of  t he seri o us a d verse e ve nt to t he i n vesti gati o nal1
de vice or pr oce d ures.
1
N ot relate d : Relat i ons hi p t o t he de vice or pr oce d ures ca n be e xcl u de d w he n:

t he e ve nt has n o t e mp oral relati ons hi p wi t h t he use of t he i n vesti gati o nal de vice or 
t he pr oce d ures.

t he serio us e ve nt d oes n ot f oll ow a
k n o w n res p o nse patter n t o t he me d ical
de vice (if t he res p o nse p atter n is pre vi o usl y k n o w n) a n d is bi o l ogicall y 
i m pla usi ble.

t he disc o nt i n uati o n of me d ical de vice a p plicat i on or t he re d ucti o n of t he level of
acti vat i on/e x p os ure - w he n
cli nicall y feasi ble - a n d rei ntr o d uctio n of its use ( or
i ncrease of t he level of acti vati o n/e x p os ure), d o n ot i m pact o n t he seri o us e ve nt .

t he e ve nt i n v ol ves a b o d y- sit e or a n or ga n n ot e x pecte d t o be affecte d b y t he de vice 
or pr oce d ure .

t he seri o us e ve nt ca n be attri b ute d t o a n ot her ca use (e g, a n u n derl yi n g or c o nc urre nt
ill ness/cli nical c o n ditio n , a n effect of a n ot her de vice,
dr u g, treat m e nt or ot her ris k 
fact ors).

t he e ve nt d oes n ot de pe n d o n a false res ult gi ve n b y t he i n vesti gati onal de vice use d 
f or dia g n osis, w he n a p plica ble.
I n or der t o esta blis h t he n o n- relate d ness, n ot all t h e criteria liste d a b o ve mi g ht be met
at t he
sa me ti me, de pe n di n g o n t he t yp e of de vice/ pr oce d ures a n d t he seri o us e ve nt.
                                               
1 I nv esti g ati o n al d evic e: a ny d evic e o bj ect of t h e cli nic al i nv esti g ati o n, i ncl u di n g t h e c o m p ar at ors


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 1 of 1 1 7
2
U nli kel y: T he relati ons hi p wi t h t he use of t he de vice see ms n ot rele va nt a n d/ or t he
e ve nt ca n be reas o na bl y e x plai ne d b y a n ot her ca use, b ut a d dit i onal i nf or mat i on ma y be 
o btai ne d.
3
P ossi ble : The r elatio ns hi p wi t h t he use of t he i n vesti gati onal de vice is wea k b ut
ca n n ot
be r ule d o ut c o m p letel y. Alt er nat i ve ca uses are als o p ossi ble (e g, a n u n derl yi n g or
c o nc urre nt ill ness/ cli nical c o n ditio n or/a n d a n effect of a n ot her
de vice, dr u g or
treat me nt). Cases w here relate d ness ca n n ot be assesse d or n o i nf or mati o n has bee n 
o btai ne d s h o ul d als o be classifie d as p ossi ble.
4
Pr o ba ble : T he relatio ns hi p wi t h t he use of t he i n vesti gati o nal de vice see ms rele va nt
a n d/ or t he e ve nt ca n n ot b e reas o na bl y e x plai ne d b y a n ot her ca use, b ut
a d dit i onal 
i nf or mat i on ma y be o btai ne d.
5
Ca usal relatio ns hi p : t he seri o us e ve nt is ass ociate d wit h t he i n vesti gati o nal de vice or 
wi t h pr oce d ures be y o n d reas o na ble d o u bt w he n:

t he e ve nt is a k n o w n side effect of t he pr o d uct cate g or y t he de vice bel o n gs t o or 
of  si milar de vices a n d pr oce d ures.

t he e ve nt has a t e mp oral relati ons hi p wi t h i n vesti gati onal de vice
use/a p plicat i on or 
pr oce d ures .

t he e ve nt i n v ol ves a b o d y-site or or ga n t hat

t he i n vest i gati onal de vice or pr oce d ures are a p plie d t o .

t he i n vest i gati onal de vice or pr oce d ures ha ve a n effect o n .

t he seri o us e ve nt f oll ows
a k n o w n res p o nse patter n t o t he me d ical de vice (if t he 
res p o nse patter n is pre vi o usl y k n o w n) .

t he disc o nti n uati o n of me dical
de vice a p plicat i on ( or re d uctio n of t he level of
activati o n/e x p os ure) a n d rei ntr o d ucti o n of its use ( or i ncrease of t he level of
activati o n/e x p os ure), i m pact o n t he seri o us e ve nt ( w he n cli nicall y feasi ble).

ot her p ossi ble ca uses (e g, a n u n derl yi n g or c o nc urre nt ill ness/cli nical c o n ditio n
or/a n d a n effect of a n ot her de vice, dr u g or treat me nt) ha ve bee n a de q uatel y r ule d 
o ut.

har m t o t he patie nt is d ue t o err or i n use .

t he e ve nt de pe n ds o n a false res ult gi ve n b y t he i n vesti gati o nal de vice use d f or 
dia g n osis , w he n a p plica ble.
I n or der t o esta blis h t he r elate d ness, n ot all t he criteria liste d a b o ve mi g ht
be met
at t he
sa me ti me, de pe n di n g o n t he t yp e of de vice/ pr oce d ures a n d t he seri o us e ve nt.
F oll o w -u p of A E/ S A E/ Me dic al De vice Deficie nc y

T he In vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uat i ons as me dicall y i n dicate d t o el uci date t he nat ure a n d/ or 
ca usalit y of  t he A E/ S A E/ me dical de vice deficie nc y as f ull y as p ossi ble. T his ma y  incl u de 


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 2 of 1 1 7
a d ditio nal  la b orat or y tests or i n vesti gati ons, hist o pat h ol o gical e xa mi nat i ons, or 
c o ns ultati o n wit h ot her healt h care pr ofessi o nals.

If a patie nt dies d uri n g partici pat i on i n t he st u d y or d uri n g a rec o g nize d f oll ow- u p peri o d, 
t he In vest i gat or will pr o vi de S p o ns or wit h a c o p y  of a n y p ost-m o rte m fi n di n gs i ncl u di n g 
hist o pat h ol o g y .

Ne w or u p date d i nf or mat i on will be rec or de d i n t he ori gi nall y c o m p lete d f or m.

T he In vesti gat or will s u b mit a n y  u p date d S A E data t o S p o ns or wit hi n 2 4 h o urs of recei pt 
of  t he i nf or mat i on.
H 5
Re p orti n g of S A Es
S A E Re p orti n g t o S p o ns or vi a P a per D at a C ollecti o n T o ol

T he S A Es, pre g na ncies a n d o ver d ose t o be re p orte d i n t he E D C first.   O nl y re p ort o n 
pa per if E D C is u na vaila ble.  Fa x c o ver s heet a n d S A E Re p ort F or m 2 4 3 9 6 1 -S ha mal -
S A E @ pare xel.c o m or Fa x: + 1 8 3 3 9 4 4 0 5 0 4 are t o be use d.

I nitial notificati o n via E D C d oes n ot re place t he nee d f or t he In vest i gat or t o c o m plete a n d 
sig n t he S A E pa per data c ollect i on t o ol wi t hi n t he desi g nate d re p orti n g ti me fra mes.

C o ntacts f or S A E re p orti n g ca n be f o u n d o n t he pa per S A E f or m a vaila ble i n t he Si te File.
H 6
Re p orti n g of S A D Es
S A D E Re p orti n g t o Re g ul at or y a ut h orities
N O T E: T here are a d dit i onal re p orti n g o bli gat i ons f or m e dical de vice deficie ncies t hat are 
p ote nti all y relate d t o S A Es t hat m ust f ulfill t he le gal res p o nsi bilit y t o n otif y a p pr o priate 
re g ulat or y a ut h orities a n d ot her e ntities a b o ut certai n safet y i nf or mati on rela ti n g t o me dical 
de vices bei n g use d i n cli nical st u dies.

A n y me dical de vice deficie nc y t hat is ass ociate d wit h a n S A E m ust be re p orte d t o t he 
S p o ns or wit hi n 2 4 h o urs after t he In vesti gat or deter mi nes t hat t he e ve nt meets t he 
defi nit i on o f a me d ical de vice d eficie nc y.

T he S p o ns or will re vie w all me dical de vice deficie ncies a n d deter mi ne a n d d oc u me nt i n 
wri ti n g w het her t he y c o uld ha ve l e d t o a n S A E. T hese me d ical de vice deficie ncies will 
be re p orte d t o t he re g ulat or y  a ut h orities a n d I R Bs/I E Cs as re q uire d b y natio n al  
re g ulat i ons.

C o ntacts f or S A E re p orti n g ca n be f o u n d o n t he pa per S A E f or m a vaila ble i n t he Site File.


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 3 of 1 1 7
A p pe n di x I
A b bre vi ati o ns
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
A C Q - 5
ast h ma c o ntr ol q uesti o n naire-5 ite m
A D A
a nti -dr u g a nti b o dies
A D E
a d verse de vice effect
A E
a d verse e ve nt
A E R
a n n ual e xacer bati o n rate
A P F S
access orise d pre-fille d s yri n ge
A P S
all patie nts set
A Q L Q( S) + 1 2
sta n dar dise d ast h ma q ualit y of life q uesti o n naire f or 1 2 years a n d ol der
A T S/ E R S
A merica n t h oracic s ociet y/ E ur o pea n res pirat or y s ociet y
A Z
Astra Ze neca
B A L
br o nc h oal ve olar la va ge
BI D
bis i n die (t wice per da y)
CI
c o nfi de nce i nter val
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 O
cli nical researc h or ga nisati o n
C S P
cli nical st u d y pr ot oc ol
C S R
cli nical st u d y re p ort
C Y P
c yt oc hr o me P 4 5 0
D A Es
A Es ca usi n g t he disc o nti n uati o n of st u d y treat me nt
D N A
de o x yri b o n ucleic aci d
D U S
disease u n der st u d y
E C
et hics c o m mittee, s y n o n y m o us t o i nstit uti o nal re vie w b oar d (I R B) a n d 
i n de pe n de nt et hics c o m mittee (I E C)
e C R F
electr o nic case re p ort f or m
E O T
e n d of treat me nt
e P R O
electr o nic patie nt -re p orte d o utc o me
F A S
f ull a nal ysis set
F E V 1
f orce d e x pirat or y v ol u me i n 1 sec o n d
F S H
f ollicle sti m ulati n g h or m o ne
F V C
f orce d vital ca pacit y
G C P
g o o d cli nical practice
GI N A
gl o bal i nitiati ve f or ast h ma
C CI


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 4 of 1 1 7
H C P
Healt h Care Pr ofessi o nal
I A T A
i nter nati onal airli ne tra ns p ortati o n ass ociati o n
I C F
i nf or me d c o nse nt f or m
I C H
i nter nati onal c o u ncil f or har m o nisati o n
I C S
i n hale d c ortic oster oi ds
I V R S/I W R S
i nteracti ve v oice/ we b res p o nse s yste m
L A B A
l o n g-acti n g β 2-a g o nist
L A M A
l o n g-acti n g m uscari nic a nta g o nist
L T R A
le u k otrie ne rece pt or a nta g o nist
Me d D R A
me dical dicti o nar y f or re g ulat or y acti vities
M M R M
mi xe d m o del re peate d meas ures
O C S
or al c ortic oster oi ds
p M DI
press urise d metere d d ose i n haler
P R N
pr o re nata (as nee de d)
P R O
patie nt -re p orte d o utc o me
P T
preferre d ter m
Q 8 W
e ver y 8 wee ks
R N A
ri b o n ucleic aci d
S A B A
s h ort-acti n g β-a g onist
S A D E
seri o us a d verse de vice effect
S A E
seri o us a d verse e ve nt 
S A M
s ynt hetic a bs or pti ve matri x
S A P
statistical a nal ysis pla n
S C
s u bc uta ne o us
S M A R T
S y m bic ort ® m ai nte na nce a n d relie ver th e r a p y
S m P C
s u m mar y of pr o d uct c haracteristics
S o A
sc he d ule of assess me nts
T P V
T hir d -part y ve n d or
U S A D E
u na ntici pate d seri o us a d verse de vice effect
U K
U nite d K i n g d o m
W B D C
we b base d data ca pt ure
W O C B P
w o me n of c hil d beari n g p ote ntial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 5 of 1 1 7
A p pe n di x J
Pr ot oc ol A me n d me nt Hist or y
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
di rectl y bef ore t he Ta ble of C o nte nts.
Cli nic al St u d y Pr ot oc ol, Versi o n 3. 0, 1 7 Se pte m ber 2 0 2 1
T his a me n d me nt is c o nsi dere d t o be s u bsta nt ial base d o n t he cri t eria set f ort h i n Art icle 1 0(a) 
of  Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt an d t he C o u ncil o f t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt:

T o u p date mi n or discre pa ncies i de ntifie d i n t he Gl o bal Cli nical St u d y  Pr ot oc ol, 
Versi o n 2 . 0 date d 1 0 J ul 2 0 2 0.

T o a d d details of safet y a nal ysis set t hat is pla n ne d t o be i ncl u de d i n t he st u d y.

T o i ncl u de rec o m me n dat i ons re gar di n g C or o na vi r us Disease 2 0 1 9 ( C O VI D-1 9) 
vacci nati o n, as pre vi o usl y  c o m m u nicate d t o In vesti gat ors i n t he I n vest i gat or Letter date d 
2 9 Ja n 2 0 2 1.

T o a d d details re gar di n g t he me dical de vices use d i n t he st u d y  a n d also a d dress m e dical 
de vice deficie ncies as per Astra Ze neca c urre nt pr ocesses f or me dical de vices use d i n t he 
st u dies a n d u p date d pr o d uct safet y i nf or mati on f or Fase nra ® .

T o i ncl u de mi n or u p dates a n d clarificat i ons i n li ne wit h Astra Ze neca c urre nt pr ocesses .

T o a d d A p pe n di x H
‘Me dical  De vice A Es, A D Es, S A Es, S A D Es, U S A D Es, a n d 
Me dical De vice Deficie ncies: Defi nit i ons a n d Pr oce d ures f or Rec or di n g, E val uat i n g, 
F o ll ow -u p, a n d Re p orti n g i n Me dical De vice St u dies ’ as per Astra Ze neca c urre nt 
pr ocesses f or me dical de vices use d i n t he st u dies a n d u p date d pr o d uct safet y i nf or mati o n 
f or Fase nra ® .
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
Secti o n 1. 1, Ta ble 1 
Sc he d ule of 
assess me nts
U p date d t o c orrect t he 
da ys calc ulate d f or 
Vi sit 8a a n d Visit 8 b
T o ali g n da ys 
calc ulat i on wi t h wee ks
N o n -S u bsta nt ial
Secti o n 1. 2, 
S y n o psis
U p date d t he esti mate d 
date of l ast patie nt 
c o mplete d
Per e xte n de d st u d y  
recr uit me nt/ti meli nes
S u bsta nt ial
Secti o n 1. 2, 
S y n o psis
Stati stical met h o ds i n 
t he s y n o psis were 
ali g ne d wit h re vise d 
Secti o n 9. 3
F or c o nsiste nc y wit h 
ot her secti o ns
S u bsta nt ial
Secti o n 5. 2, 
E xcl usi o n Cri t eria
A d de d ne w criteria t o 
i ncl u de details a b o ut 
T o pr o vi de g ui da nce 
o n h o w t o ha n dle 
S u bsta nt ial


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 6 of 1 1 7
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
pati e nts w h o recei ve d 
C O VI D - 1 9 
vacci nati o n
C O VI D- 1 9 
vacci nati o ns i n t he 
pati e nts partici pat i n g 
i n t his st u d y
Secti o n 5. 3. 4, Bl o o d 
D o nati o n
Ne w sect i on was 
a d de d t o e x plai n 
restrict i ons relate d t o 
bl o o d d o nati o n
Per u p date d pr o d uct 
safety i nf or mati on f or 
Fase nra ®
S u bsta nt ial
Secti o n 6. 1. 1,
Ta ble 4 St u d y  
Treat me nt
A d de d ne w r o w t o 
i ncl u de c o n versi on of 
2 0 0/ 6 a n d 4 0 0/ 1 2 
S y m bic ort i nt o 't otal' 
µ g
T o a d d cl arit y o n t otal 
d oses of S y m bic ort
S u bsta nt ial
Secti o n 6. 1. 2, 
Me dical de vices
U p date d t o i ncl u de a 
s h ort descri pti on of 
s pir o metr y de vice a nd 
 
T o ali g n wit h 
Astra Ze neca c urre nt 
pr ocesses f or me dical 
de vices use d i n t he 
st u dies
S u bsta nt ial
Secti o n 6. 1. 2, 
Me dical de vices
U p date d t o i ncl u de 
refere nce t o Secti o n 
8. 4. 5 Me dical De vice 
Deficie ncies
T o ali g n wit h 
Astra Ze neca c urre nt 
pr ocesses f or me dical 
de vices use d i n t he 
st u dies
S u bsta nt ial
Secti o n 6. 5, 
C o nc o mita nt 
t hera p y, Ta ble 5 
Restricte d 
me dicat i ons
A d de d details a b o ut 
C O VI D - 1 9 
vacci nati o n
T o pr o vi de g ui da nce 
o n h o w t o ha n dle 
C O VI D - 1 9 
vacci nati o ns i n t he 
pati e nts part ici pati n g 
i n t his st u d y
S u bsta nt ial
Secti o n 8. 1. 1, 
Electr o nic Pat ient -
Re p orte d O utc o mes
A d de d w or di n g a b o ut 
h o me c o m p leti o n of 
C O VI D - 1 9-relate d-
e P R O
T o a v oi d data l oss d ue 
t o o n-site visits n ot 
ha p pe ni n g
S u bsta nt ial
Secti o n 8. 3. 2, Ti me 
p eri o d a n d 
fre q ue nc y for 
A d de d clarificat i on 
t hat if t he I n vest i gat or 
lear ns of a n y S A Es i n 
T o ali g n wit h c urre nt 
Astra Ze neca S A E 
re p orti n g pr ocesses
N o n -s u bsta ntial
C CI


Cli nical St u d y Pr ot oc ol - 4. 0
Astra Ze neca
Be nraliz u ma b - D 3 2 5 0 C 0 0 0 7 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 7 of 1 1 7
Secti o n # a n d 
N a me
Descri pti o n of 
C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
c ollect i n g A E a n d 
S A E i nf or mat i on
a f or mer st u d y patie nt, 
t hese s h o uld be 
re p orte d wit h o ut a n y 
d el a y
Secti o n 8. 4. 5, 
Me dical De vice 
Deficie ncies
A d de d ne w sect i on
T o ali g n wit h 
Astra Ze neca c urre nt 
pr ocesses f or me dical 
de vices use d i n t he 
st u dies a n d t o alig n 
wi t h u p date d pr o d uct 
safety i nf or mati on f or 
Fase nra ®
S u bsta nt ial
Secti o n 9. 3, 
P o p ul at i ons f or 
A n al yses
A d de d ne w p o p ulati o n 
f or a nal yses – S af et y 
A nal ysis set
T o ali g n wit h 
statistical a nal ysis
S u bsta nt ial
Secti o n 9. 4. 1, 
O utc o m e meas ures 
f or a nal yses 
calc ulat i on or 
deri vat i on of 
efficac y v aria bles
I C S d ose re p orte d a n d 
rec or de d i n m g 
u p date d t o be re p orte d 
a n d rec or de d i n 
micr o gra ms ( µ g)
T o u nif y  t he u nits as 
per cli nical pract ise 
a n d Statist ical 
A nal ysis
N o n -s u bsta ntial
Secti o n 9. 4. 3, Safet y 
a nal yses
U p date d t o i ncl u de 
S af et y A nal ysis set
F or c o nsiste nc y wit h 
Secti o n 9. 3
S u bsta nt ial
Secti o n 9. 4. 3 . 1, 
A d verse e ve nts
A d de d details a b o ut 
a d verse e ve nts c o di n g
T o ali g n wit h 
Astra Ze neca sta n dar d 
pr ocesses f or safet y 
a nal yses
N o n -S u bsta nt ial
A p pe n di x A, 
Re g ulat or y , Et hical 
a n d St u d y O versi g ht 
C o nsi derati o ns
U p date d t o i ncl u de 
s o me te xt missi n g i n 
t he pr ot oc ol versi o n 
2. 0 ( date d 1 0 J ul 2 0 2 0)
T o ali g n wit h 
Astra Ze neca c urre nt 
pr ocesses
S u bsta nt ial
A p pe n di x H, 
Me dical De vice 
A Es, A D Es, S A Es, 
S A D Es, U S A D Es, 
a n d Me dical De vice 
A d de d ne w a p pe n di x
T o pr o vi de defi nit i ons 
a n d pr oce d ures f or 
A Es relate d t o S p o ns or 
a n d t hir d-part y  
me dical de vices, as 
S u bsta nt ial






















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 3 2 5 0c 0 0 0 7 2-cs p- v 4
D oc u me nt Title:
D 3 2 5 0 C 0 0 0 7 2 Cli nical St u d y Pr ot oc ol versi o n 4
D oc u me nt I D:
D oc I D- 0 0 3 9 9 8 7 5 2
Versi o n L a bel:
4. 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
2 1- N o v- 2 0 2 2 1 3: 4 7 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.
P P D

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SHAMAL: A Multicentre, Randomised, Open-Label, Parallel- 
Group, Active-Controlled, Phase IV Study to Assess the Reduction 
of Daily Maintenance ICS/LABA Treatment Towards 
Anti-Inflammatory Reliever Treatment in Patients with Severe 
Eosinophilic Asthma Treated with Benralizumab 
 
ClinicalTrials.gov Identifier: NCT04159519 
 
 
Date of Protocol: 15 December 2022 
 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 of 5 2
St atistic al A n al ysis Pl a n
St u d y C o de
D 3 2 5 0 C 0 0 0 7 2
E diti o n N u m ber
3. 0
Date
1 5 Dece m ber 2 0 2 2
S H A M A L: A M ultice ntre, R a n d o mise d, O pe n -L a bel, P ar allel -
Gr o u p, Acti ve -C o ntr olle d, P h ase I V  St u d y t o Assess t he Re d ucti o n 
of D ail y M ai nte n a nce I C S/ L A B A  Tre at me nt To w ar ds 
A nti -I nfl a m m at or y Relie ver Tre at me nt i n P atie nts wit h Se vere 
E osi n o p hilic Ast h m a T re ate d wit h Be nr aliz u m a b


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 of 5 2
T A B L E O F C O N T E N T S
TI T L E P A G E ........................................................................................................................ 1
T A B L E O F C O N T E N T S ......................................................................................................2
LI S T O F A B B R E VI A TI O N S ...............................................................................................5
A M E N D M E N T HI S T O R Y ...................................................................................................7
1 
S T U D Y D E T AI L S ........................................................................................... 1 0
1. 1
St u d y  o bjecti ves................................................................................................ 1 0
1. 1. 1
Pri mar y o bject i ve.............................................................................................. 1 0
1. 1. 2
Sec o n dar y  o bjecti ves ........................................................................................ 1 0
1. 1. 3
S af et y o bj ect i ves............................................................................................... 1 2
1. 1. 4
E x pl or at or y  O bjecti ves ..................................................................................... 1 2
1. 2
St u d y  desi g n..................................................................................................... 1 3
1. 2. 1
Scree ni n g a n d r u n -i n peri o d.............................................................................. 1 5
1. 2. 2
Re d ucti o n peri o d ............................................................................................... 1 6
Refere nce ar m ................................................................................................... 1 6
Treat me nt re d ucti o n ar m ................................................................................... 1 6
1. 2. 3
Mai nte na nce peri o d ........................................................................................... 1 8
S u b -st u d y.......................................................................................................... 1 9
1. 2. 4
St u d y  c o mplet i on/e n d of treat me nt ....................................................................1 9
1. 3
N u m ber of patie nts ........................................................................................... 1 9
2
A N A L Y SI S S E T S ............................................................................................ 2 0
2. 1
Defi nit i on o f a nal ysis sets ................................................................................. 2 0
2. 1. 1
All Pat ient  Set................................................................................................... 2 0
2. 1. 2
F ull  A nal ysis Set............................................................................................... 2 0
2. 1. 3
S u b -St u d y  A nal ysis Set..................................................................................... 2 0
2. 1. 4
S af et y A nal ysis Set ........................................................................................... 2 0
2. 2
Vi ol at i ons a n d de viat i ons .................................................................................. 2 1
3
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S ...............................................2 1
3. 1
Pri mar y Efficac y  V aria ble ................................................................................. 2 2
3. 2
Sec o n dar y  Efficac y V aria bles ........................................................................... 2 3
3. 2. 1
A C Q - 5.............................................................................................................. 2 4
3. 2. 2
I C S E x p os ure.................................................................................................... 2 5
3. 2. 3
A Q L Q( S) + 1 2 .................................................................................................... 2 6
3. 2. 4
Pre -br o nc h o dilat or F E V 1................................................................................... 2 7
3. 2. 5
Ast h ma E xacer bat i ons ...................................................................................... 2 7
3. 2. 6
S y m bic ort ® d o se at t he e n d of t he mai nte na nce peri o d ......................................2 9
3. 2. 7
Cli nical Re missi o n ............................................................................................ 2 9
3. 3
S af et y varia bles ................................................................................................ 2 9
3. 3. 1
A d verse e ve nts ..................................................................................................2 9


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 of 5 2
3. 4
E x pl or at or y  varia bles........................................................................................ 3 0
3. 4. 1
Bl o o d e osi n o p hils c o u nt .................................................................................... 3 0
3. 4. 2
..................................3 0
3. 4. 3
Heal t h ec o n o mics ............................................................................................. 3 1
3. 5
Assess me nt of st u d y  p o p ulatio n ........................................................................3 1
3. 5. 1
D e m o gra p hics ................................................................................................... 3 1
3. 5. 2
Me di cal a n d s ur gical hist or y............................................................................. 3 2
3. 5. 3
Pri or a n d c o nc o mita nt me dicat i ons ...................................................................3 2
3. 5. 4
E x p os ure t o Fase nra ® ........................................................................................ 3 2
4
A N A L Y SI S M E T H O D S ................................................................................... 3 2
4. 1
Ge nera l pri nci ples............................................................................................. 3 2
4. 1. 1
Missi n g data
..................................................................................................... 3 3
4. 1. 2
Vi sit wi n d o ws................................................................................................... 3 4
4. 2
A nal ys is met h o ds .............................................................................................. 3 5
4. 2. 1
Assess me nt of st u d y  p o p ulatio n ........................................................................3 5
P ati e nt dis p ositio n ............................................................................................. 3 5
D e m o gra p hic c haracteri stics ............................................................................. 3 5
Baseli ne c haracterist ics ..................................................................................... 3 6
Me dical a n d s ur gical hist or y ............................................................................. 3 7
Pri or a n d c o nc o mita nt me dicat i ons ...................................................................3 7
4. 2. 2
Pri mar y Efficac y  A nal ysis ................................................................................ 3 8
Se nsit i vity A nal ysis .......................................................................................... 3 8
4. 2. 3
Sec o n dar y  Efficac y A nal yses............................................................................ 3 8
A C Q - 5.............................................................................................................. 3 8
I C S E x p os ure.................................................................................................... 3 9
A Q L Q( S) + 1 2 .................................................................................................... 4 0
C ha n ge fr o m baseli ne i n F E V 1 .......................................................................... 4 1
Ast h ma E xacer bat i ons ...................................................................................... 4 1
Cli nical Re missi o n ............................................................................................ 4 2
4. 2. 4
E x pl or at or y  A nal yses........................................................................................ 4 2
C ha n ge fr o m baseli ne Fe N O ............................................................................. 4 2
C ha n ge fr o m baseli ne i n bl o o d e osi n o p hil c o u nt ...............................................4 3
..................................4 3
4. 2. 5
E x p os ure t o Fase nra .......................................................................................... 4 3
4. 2. 6
S af et y A nal yses ................................................................................................ 4 3
4. 2. 7
Heal t h ec o n o mics ............................................................................................. 4 4
4. 2. 8
I mpact o n a nal yses d ue t o C O VI D -1 9 pa n de mic ...............................................4 4
5
I N T E RI M A N A L Y S E S .................................................................................... 4 5
6
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L ............................................4 5
7
R E F E R E N C E S .................................................................................................4 7
8
A P P E N DI X ...................................................................................................... 4 8
8. 1
I mp utati o n  r ules f or partial dates .......................................................................4 8
C CI
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 of 5 2
8. 1. 1
A d verse e ve nts, me dical hist or y  a n d prior/c o nc o mita nt me dicat i ons .................4 8
8. 1. 2
P arti al dates f or date of birt h a n d date of first ast h ma dia g n osis.........................5 0
8. 1. 3
Part ial dates f or m ost rece nt e xacer bat i on date ..................................................5 0
8. 1. 4
P arti al dates f or s ur gical hist or y ........................................................................5 0
LI S T O F T A B L E S
Ta ble 1: S y m bic ort ® d osi n g re gi me n f or patie nts w h o mai ntai n ast h ma c o ntr ol d uri n g t he 
re d uctio n peri o d .......................................................................................1 7
Ta ble 2: E x pecte d l o wer a n d u p per half -wi dt h of e xact 9 5 % CIs ( Cl o p per -Pears o n) ar o u n d 
o bser ve d pr o p orti o n of pat ient s s uccessf ull y ste p pi n g d o w n S M A R T ......2 0
LI S T O F FI G U R E S
Fi g ure 1: St u d y  desi g n ........................................................................................................1 4
Fi g ure 2: Al g orit h m f or ste p pi n g d o w n/ u p treat me nt i n t he re d ucti o n peri o d .......................1 8


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 of 5 2
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
A C Q - 5
Ast h ma c o ntr ol q uesti o n naire -5 ite m
A E
A d verse e ve nt
A E R
A n n ual e xacer bati o n rate
A P S
All patie nts set
A T C
A nat o mical t hera pe utic c he mical
A Q L Q( S) + 1 2
Sta n dar dise d ast h ma q ualit y of life q uesti o n naire f or 1 2 years a n d ol der
A U C
Sta n dar dise d area u n der t he c ur ve
A Z
Astra Ze neca
BI D
bis i n die (t wice per da y)
CI
C o nfi de nce i nter val
C O VI D - 1 9
C or o na vir us Disease 2 0 1 9
C 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 Es
A Es ca usi n g t he disc o nti n uati o n of st u d y treat me nt
e C R F
Electr o nic case re p ort f or m
E O T
E n d of treat me nt
e P R O
Electr o nic patie nt -r ep orte d o utc o me
F A S
F ull A nal ysis Set
Fe N O
Fracti o nal e x hale d nitric o xi de
F E V 1
F orce d e x pirat or y v ol u me i n 1 sec o n d
F V C
F orce d vital ca pacit y
I C F
I nf orme d c o nse nt f or m
I C S
I n hale d c ortic oster oi ds
I P
I n vesti gati o nal pr o d uct
L A B A
L o n g -acti n g β 2-a g o nist
Me d D R A
Me dical dicti o nar y f or re g ulat or y acti vities
M M R M
Mi xe d m o del re peate d meas ures
n
T he n u m ber of n o n- missi n g o bser vati o ns or t he n u m ber of patie nts 
pr o vi di n g data at t he rele va nt ti me p oi nt
O C S
Oral c ortic oster oi ds


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 of 5 2
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
p p b
parts per billi o n
P R N
pr o re nata (as nee de d)
P R O
Patie nt -r ep orte d o utc o me
P T
Preferre d ter m
P Y
Pac k -years
Q 8 W
E ver y 8 wee ks
S A B A
S h ort -acti n g β-a g o nist
S A F
Safet y a nal ysis set
S A E
Seri o us a d verse e ve nt
S D
Sta n dar d de viati o n
S M A R T
S y m bic ort ® ma i nte na nce a n d relie ver t hera p y
S o A
Sc he d ule of assess me nts
S O C
S yste m or ga n class
W H O D D
W orl d Healt h Or ga nisati o n Dr u g Dicti o nar y


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 of 5 2
A M E N D M E N T HI S T O R Y
C ate g or y *:
C h a n ge 
refers t o
D ate
Descri pti o n of c h a n ge
I n li ne 
wit h t he 
C S P ?
R ati o n ale
Ot her
2 3 J ul y  2 0 2 0
1.
I ncl usi o n of Secti o n 4. 2. 8 .
2.
U p date of w or di n g “s u bject” t o 
“ patie nt” i n Secti o n 2. 2 a n d 
Secti o n 3. 4. 3.
3.
M o ve d se nte nce re gar di n g 
missi n g A C Q 5 a n d A Q L Q( S) + 1 2 
sc ores q uesti o n naire data fr o m 
Secti o n  3. 5. 3 t o Secti o n 4. 1. 1.
4.
Refere nces t o n u m bere d 
a p pe n dices i n t he C S P ha ve bee n 
u p date d.
5.
“ Ser u m pr otei n bi o mar kers 
(s u b-st u d y).” A d de d t o e x pl orat or y 
o bjecti ve e n d p oi nts.
6.
“ T o assess t he p ote ntial f or 
Fase nra ® -treate d patie nts t o mai ntai n 
l u n g f u ncti o n w hile ste p pi n g d o w n 
S y m bic ort ® mai nte na nce treat me nt 
( mai n a n d s u b-st u d y)” a d de d as 
e x pl orat or y o bjecti ve wit h “ C h a n ge 
fr o m baseli ne i n air wa y oscill o metr y 
d uri n g t he st u d y peri o d (s u b -st u d y).” 
as t he c orres p o n di n g varia ble.
7.
“ Nasal” re place d b y “s p ut u m” 
t hr o u g h o ut t he S A P.
8.
U p date t o Visit n u m beri n g as 
per C S P.
9.
Trial Desi g n sc he ma u p date d.
1 0.
Partial date of dia g n osis a n d
date of birt h i m p utati o n 
r ules/refere nces a d de d i n Secti o n 
4. 1. 1 , Secti o n 4. 2. 1. 2 a n d 
A p pe n di x 8. 1. 2 .
1 1.
A p pe n di x  8. 1 u p date d t o 
A p pe n di x  8. 1. 1 t o acc o u nt f or ne w 
partial date i m p utati o n r ules, 
refere nces t o A p pe n di x 8. 1. 1 u p date d 
t hr o u g h o ut.
1 2.
Pare xel Bi ostatistics Lea d 
si g n-off pa ge re m o ve d.
Yes
1.
D ue t o t he 
C O VI D -1 9 pa n de mic, 
alter nati ve mea ns of data 
c ollecti o n ma y be 
re q uire d, as o utli ne d i n 
t he C S P A me n d me nt/ 
pr ot oc ol versi o n 2. 0. 
A d d iti o nal data 
s u m maries/a nal yses ma y 
be re q uire d. 
2.
Mi n or u p dates t o 
w or di n g f or c o nsiste nc y.
3.
Pre vi o usl y l ocate d 
i n t he i nc orrect secti o n.
4.
U p date d t o reflect 
c ha n ges i n t he C S P.
5.
U p date d t o reflect 
c ha n ges i n t he C S P.
6.
U p date d t o reflect 
c ha n ges i n t he C S P.
7.
U p date d t o reflect 
c ha n ges i n t he C S P.
8.
U p date d t o ali g n 
wit h ne w Sc he d ule of 
Acti vities i n t he C S P. 
9.
U p date d t o reflect 
c ha n ges i n t he C S P.
1 0.
U p date d t o acc o u nt 
f or partial date relate d 
deri vati o ns i n c o u ntries 
w h ere date of birt h 
ca n n ot be c ollecte d. 
1 1.
U p date d t o acc o u nt 
f or partial date relate d 
deri vati o n r ules a n d 
c o nsiste nc y t hr o u g h o ut.
1 2.
U p date d i n li ne 
wit h A Z S A P si g n -off 
pr ocess.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 of 5 2
1 3.
U p dates t o w or di n g relate d t o 
c o m mercial Fase nra use i n Secti o n 
4. 2. 1. 3 t o ali g n wit h C R F u p dates.
1 4.
M M R M rea d o ut w or di n g 
c ha n ges fr o m “a vera ge mea n 
c han ge” a n d “esti mate d treat me nt 
effect” t o “ Least S q uare mea n 
c ha n ge” t hr o u g h o ut Secti o n  4.
1 5.
C o nfi de nce i nter val prese ntati o n 
r ules a d de d t o Secti o n 4. 1 .
1 3.
U p date d w or di n g of 
e xacer bati o n hist or y 
ite ms t o ali g n wit h C R F.
1 4.
U p date d f or clarit y.
1 5.
U p date d f or 
c o nsiste nc y.
1 1 
N o ve m ber 
2 0 2 2
1. T he o utc o me varia ble f or t he 
M M R M of A C Q -5 sc ore has bee n 
c ha n ge d fr o m “ C ha n ge fr o m baseli ne 
A C Q -5” t o “ C ha n ge fr o m baseli ne i n 
mea n A C Q -5 sc ore o ver t he pre vi o us 
8 wee ks” i n Secti o n 4. 2. 3.1.
2. A d diti o n of s u b -st u d y a nal ysis set
i n Secti o n 2. 1.3.
3. U p dates t o s pecif y t hat all I C S 
d ose a nal yses will be prese nte d i n 
micr o gra m ( mc g) t hr o u g h o ut.
4. U p dates t o visit wi n d o w f or 
q uesti o n naire data i n Secti o n 4. 1. 2.
5. A d diti o n of safet y a nal ysis set i n 
Secti o n 2. 1. 4.
6. A d diti o n of c o n versi o n of 
S y m bic or t d ose le vel t o micr o gra m i n 
Secti o n 4. 2. 3. 2.
7. U p date t o t he f or m ula of mea n 
t otal dail y I C S i n Secti o n 3. 2. 2.
8. U p date t o t he defi niti o n of 
c o nc o mita nt me dicati o n i n Secti o n 
3. 5. 3.
9. U p date t o t he defi niti o n of m ost 
c o m m o n a d verse e ve nts i n Secti o n 
4. 2. 6.
1 0. U p date t o clarif y defi niti o n of 
w orst A C Q -5 sc ore i n Secti o n 
4. 2. 3. 1.
1 1. U p date of i m p utati o n r ule f or 
pri or/c o nc o mita nt me dicati o n a n d 
1. U p date d t o ali g n wit h 
s u m mar y of A C Q- 5 
sc ore ta bles.
2. A d de d f or a d diti o nal 
s u m mar y ta bles re q uire d.
3. U p date d f or clarit y.
4. U p date d f or clarit y.
5. U p date d t o ali g n wit h 
Pr ot oc ol.
6. A d de d f or clarit y.
7. U p date d f or clarit y.
8. U p date d f or clarit y
9. U p date base d o n 
re q uest of safet y tea m
1 0. U p date d f or clarit y.
1 1. U p date d t o acc o u nt 
f or partial date relate d 
deri vati o n r ules a n d 
c o nsiste nc y t hr o u g h o ut.
1 2. U p date d t o ali g n wit h 
C S P.
1 3. U p date d t o ali g n wit h 
C S P.
1 4. S u m marise d 
else w here i n t he T F Ls
a n d u p date base d o n 
re q uest of safet y tea m.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 of 5 2
a d diti o n of i m p utati o n r ule f or partial 
date of e xacer bati o n hist or y, a n d 
me dical a n d s ur gical hist or y i n 
Secti o n 8. 1.
1 2. A d diti o n of cli nical re missi o n as 
a n e n d p oi nt i n Secti o n 1. 1. 2, Secti o n 
3. 2 a n d Secti o n 4. 2. 3.
1 3. Re m o val of refere nce t o a 
pri mar y  rea d-o ut at Wee k 3 2 i n 
Secti o n 4. 2. 3. 1.
1 4. S u m mar y  of injecti o n site 
reacti o ns u p date d t o o nl y if s ufficie nt 
n u m ber of e ve nts re p orte d a n d 
re m o val of S A Es ca usi n g 
disc o nti n uati o n of t he st u d y 
treat me nt/st u d y fr o m Secti o n 4.2. 6.
S u m mar y  of m ost c o m m o n A Es 
c ha n ge d t o fre q ue nc y of > 1 % . 
* Pre -s pecifie d cate g ories are:
Pri mar y  or sec o n dar y e n d p oi nts; Statistical a nal ysis met h o d f or t he pri mar y or sec o n dar y e n d p oi nts; Deri vati o n 
of pri mar y or sec o n dar y e n d p oi nts; M ulti ple Testi n g Pr oce d ure; Data prese ntati o ns; Ot her.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 of 5 2
1
S T U D Y D E T AI L S
1. 1
St u d y o bjecti ves
1. 1. 1
Pri m ar y o bjecti ve
O bjecti ve
O utc o me me as ures
T o assess t he p ote ntial f or Fase nra ® -treate d 
pati e nts t o re d uce S y m bic ort ® ma i nte na nce 
treat me nt w hile mai ntai ni n g ast h ma 
s y m pt o m c o ntr ol a
Pr o p orti o n of  patie nts w h o re d uce d t heir 
S y m bic ort ® ma i nte na nce d ose at t he e n d of 
t he re d ucti o n peri o d ( Visit 6; Wee k 3 2) t o:

Me di u m -d ose S y m bic ort ® ma i nte na nce 
a n d relie ver t hera p y ( S M A R T), or

L o w -d ose S M A R T, or

S y m bic ort ® a nti-i nfla m mat or y relie ver 
o nl y
a Ast h ma s y m pt o m c o ntr ol is defi n e d as 1) n o ast h ma e xacer bati o ns si nce t he last visit, a n d 2) n o i ncrease i n 
A C Q - 5 ≥0. 5 u nits i n t he last f o ur wee ks (c o m pare d t o Visit 1) a n d n o si g nifica nt i ncrease i n S y m bic ort ® use i n 
t he last f o ur wee ks (a wee kl y a vera ge of > 8 i n halati o ns of S y m bic ort® / da y).
1. 1. 2
Sec o n d ar y o bjecti ves
O bjecti ves
O utc o me me as ures
T o assess c ha n ges i n pat ient -re p orte d 
o utc o m es for Fase nra ® -treate d patie nts w hile 
ste p pi n g d o w n S y m bic ort ® ma i nte na nce 
treat me nt

C ha n ge fr o m baseli ne i n ast h ma c o ntr ol 
q uesti o n naire -5 i t e m ( AC Q -5) sc ore at 
t he e n d of t he re d ucti o n peri o d

C ha n ge fr o m baseli ne i n sta n dar dise d 
ast h ma q ualit y of  life q uesti on naire f or 
1 2 years a n d ol der ( A Q L Q( S) + 1 2) at 
t he e n d of t he re d ucti o n peri o d

Pr o p orti o n of  patie nts wit h no 
deteri or ati o n i n A Q L Q( S) + 1 2 
( deteriorat i on defi ne d as a decrease of at 
least 0. 5 u nits c o m pare d t o baseli ne) at 
t he e n d of t he re d ucti o n peri o d

Pr o p orti o n of  patie nts wit h no 
deteri or ati o n i n A C Q -5 ( deteri orati o n 
defi ne d as a n i ncrease of at least 0. 5 
u nits c o m pare d t o baseli ne) at t he e n d of 
the re d ucti o n peri o d


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 1 of 5 2
O bjecti ves
O utc o me me as ures
T o assess t he p ote ntial f or Fase nra ® -treate d 
pati e nts t o mai ntai n l u n g f u nct i on w hile 
ste p pi n g d o w n S y m bic ort ® ma i nte na nce 
treat me nt

C ha n ge fr o m baseli ne i n 
pre -br o nc h o dilat or f orce d e x pirat or y  
v o l ume i n 1 sec o n d ( F E V1) d uri n g t he 
st ud y peri o d
T o assess ast h ma e xacer bat i on rate

A n n ualise d ast h ma e xacer bat i on rate 
d uri n g t he st u d y  p erio d
T o assess t he t otal i n hale d c ortic oster oi ds 
(I C S) d ose e x p os ure

C u m ulat i ve t otal dail y I C S d ose 
( mai nte na nce + relie ver) f or:

T he re d ucti o n peri o d

T he m ai nte na nce perio d

T he st u d y  p erio d

T otal  dail y I C S d ose ( mai nte na nce + 
relie ver) at t he e n d of t he re d ucti o n 
p eri o d
T o assess if re d uct i ons i n S y m bic ort®
mai nte na nce ac hie ve d at t he e n d of t he 
re d uctio n peri o d are m ai ntai ne d u ntil t he e n d 
of  t h e mai nte na nce perio d

Pr o p orti o n of  patie nts usi n g t he sa me 
S y m bic ort ® dail y d ose at t he e n d of t he 
mai nte na nce peri o d ( Visit 8 b; Wee k 4 8) 
t hat t he y ac hie ve d at t he e n d of t he 
re d uctio n peri o d ( Visi t 6; Wee k 3 2)

S u p p orti ve o utc o mes:

N u m ber of e xacer bat i ons occ urri n g 
fr om e n d of t he re d ucti o n peri o d t o 
e n d of t he mai nte na nce peri o d

T otal  dail y I C S d ose fr o m t he e n d 
of  t he re d uctio n peri o d t o t he e n d of 
t he mai nte na nce peri o d

C ha n ge i n A C Q -5, A Q L Q( S) + 1 2, 
a n d F E V 1 fr o m t he e n d of t he 
re d uctio n peri o d t o t he e n d of  t he 
mai nte na nce peri o d




Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 of 5 2
ste p pi n g d o w n S y m bic ort ® ma i nte na nce 
treat me nt ( mai n a n d s u b-st u d y)
T o c haracterise t he effects of Fase nra ® o n 
air wa y i nfla m mati on after re d uci n g dail y 
S y m bic ort ® t hera p y (s u b-st u d y) b

Pati e nt i nfla m mat or y bio m ar kers pr ofile 
i ncl u di n g e osi n o p hils, micr o bi ome, a n d 
s p ut u m bio m ar kers (c yt o ki nes)
b All s u b -st u d y s pecific o bjecti ves will be re p orte d se paratel y fr o m t he Cli nical St u d y Re p ort.
1. 2
St u d y desi g n
T his is a m ult ice ntre, ra n d o mise d, o pe n-label, parallel -gr o u p, acti ve -c o ntr olle d, P hase I V 
st u d y t o assess t he re d ucti o n of dail y S y m bic ort® mai nte na nce t o a nti -i nfla m mat or y relie ver 
treat me nt o nl y i n pat ient s wit h se vere e osi n o p hilic ast h ma o n Fase nra® tr e at me nt, w hile 
mai ntai ni n g ast h ma c o ntr ol.  Ge neral st u d y  desi g n is s u m marise d i n Fi g ure 1.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 of 5 2
Fi g ure 1 : St u d y desi g n
BI D =t wice per da y; I C S/ L A B A =I n hale d c ortic oster oi ds/l o n g -acti n g β 2-a g o nist; P R N =as nee de d; Q 8 W =e ver y 8 wee ks; R = Ra n d o misati o n; 
S C =s u bc uta ne o us; S M A R T = S y m bic ort ® mai nte na nce a n d relie ver t hera p y.
a If t he patie nt d oes n ot f ulfil all ra n d o misati o n criteria ( Secti o n 5. 1. 1 of t he Cli nical St u d y Pr ot oc ol [ C S P]) t he n t he patient will be classe d as a scree n 
fail ure.
b S M A R T ste p d o w n s h o ul d f oll o w t he d osi n g re gi me n a n d al g orit h m s h o w n i n Secti o n 1. 2. 2. 2 .


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 5 of 5 2
F or t he p ur p ose of t his st u d y , mai ntai ne d ast h ma s y m pt o m c o ntr ol is defi ne d as:

N o ast h m a e xacer bat i ons si nce t he last visit (as defi ne d i n Sect i on  3. 2. 5 ), a n d

N o i ncrease i n A C Q -5 ≥0. 5 u nits i n t he last f o ur wee ks (c o m pare d t o Visit 1) a n d n o 
sig nifica nt i ncrease i n S y m bic ort® use i n t he last f o ur wee ks (a wee kl y a vera ge of > 8 
i n halati ons o f S y m bic ort ® / da y).
I n t his st u d y, t he I C S/lo n g- act i n g β2-a g o nist ( L A B A) will be sta n dar dise d f or all pat ient s w h o 
will s witc h fr o m a n y I C S/ L A B A t hera p y t o b u des o ni de/f o r mot er ol  ( S y m bic ort® ).  At t he 
Scree ni n g Visit ( Visit 1), all pat ient s will s witc h t o hi g h-d ose S y m bic ort ® ma i nte na nce 
treat me nt a n d Ve nt oli n ® relie ver treat me nt.  Patie nts ra n d o mise d t o t he Refere nce ar m will 
r e mai n o n t he hi g h d ose of S y m bic ort ® f or t he d urati o n of t he st u d y ; patient s ra n d omise d t o 
re d uce t he dail y S y m bic ort® ma i nte na nce treat me nt will f o ll ow t he S M A R T a p pr oac h.
T his st u d y  will be c o n d ucte d at a p pr o xi matel y 2 5 st u d y sites i n a p pr o xi matel y 3-5 c o u ntri es.  
T he st u d y  d uratio n f or eac h pati e nt will be a p pr o xi matel y 5 2 -5 6 wee ks.  A p pr o xi matel y  
2 4 0 pati e nts wit h se vere e osi n o p hilic ast h ma ta ki n g hi g h-d ose I C S/ L A B A w h o ha ve bee n 
treate d f or se vere e osi n o p hilic ast h ma wit h at least t hree c o nsec uti ve d oses of Fase nra® a n d 
ha ve cli nicall y  res po n de d si nce t he start of Fase nra ® treat me nt ( defi ne d f or t he p ur p ose of t his 
st u d y as a n A C Q-5 sc ore < 1. 5 at Visit 1 a n d Visit 2 b) will be e nr olle d i nt o t his o pe n -label 
st u d y.  Use of ot her mai nte na nce ast h ma t hera p y s uc h as dail y or al c ortic oster oids ( O C S ), 
le u k otrie ne rece pt or a nta g o nists, l o n g -act i n g m uscari nic a nta g o nists or t he o p h ylli nes is n ot 
all o we d d uri n g t he st u d y p erio d.
T he st u d y  c o nsists of a Scree ni n g Visit ( Visit 1) a n d 4- t o 8-wee k scree ni n g a n d r u n -i n peri o d 
(t o ali g n t he ra n d omisat i on st u d y visi t wit h t he ne xt Fase nra® i njecti on), a re d ucti o n peri o d 
of 3 2 wee ks, a n d a 1 6 -wee k mai nte na nce peri o d.
1. 2. 1
Scree ni n g a n d r u n -i n peri o d
D uri n g t he scree ni n g a n d r u n -i n peri o d, patie nts will c o nti n ue t o recei ve Fase nra® 3 0 m g e ver y 
eig ht wee ks ( Q 8 W).  At S cree ni n g ( Visit 1), all patie nts will s witc h fr o m t heir pre vi o us 
I C S/ L A B A mai nte na nce treat me nt a n d resc ue me dicati on t o hi g h -d ose S y m bic ort ®
mai nte na nce ( b u des o ni de/f or m oter ol 4 0 0/ 1 2 µ g) × 2 i n halati o ns t wice per da y  ( BI D) + 
Ve nt oli n ® (sal b uta mol  1 0 0 µ g) r elie ver as nee de d ( P R N).
P ati e nts will c o nti n ue o n t his me dicati on f or t he d uratio n of  t he 4- t o 8-wee k scree ni n g a n d 
r u n-i n peri o d.  T he e n d of t he r u n-i n peri o d will c oi nci de with t he ne xt Fase nra ® i njecti o n.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 6 of 5 2
1. 2. 2
Re d ucti o n peri o d
At  t he Ra n d o misati on visit ( Visit 2 b; Wee k 0), patie nts will u n der g o t he A C Q-5 assess me nt 
a n d a n assess me nt of e xacer bat i on hist or y  t o deter mi ne w het her t he y are eli gi ble f or 
ra n d omisat i on (see Secti o n 5. 1. 1 of t he C S P) or w het her t he y are a scree n fail ure (see 
Secti o n 1. 3 ).  Eli gi ble patient s will be ra n d oml y assi g ne d t o t he Treat me nt re d ucti o n ar m or t o 
t he Refere nce ar m i n a 3: 1 rati o:

Treat me nt re d ucti o n ar m

Fase nra ® 3 0 m g Q 8 W + S M A R T or S y m bic ort ® relie ver o nl y (starti n g with 
me di u m -d ose S y m bic ort ® 2 0 0/ 6 µ g × 2 i n halat i ons BI D mai nte na nce + S y m bic ort ®
2 0 0/ 6 µ g relie ver P R N; ta peri n g t o S y m bic ort ® 2 0 0/ 6 µ g relie ver o nl y, as per 
ta peri n g sc he me a n d de pe n di n g o n de gree of ast h ma c o ntr ol [see Sect i on  1. 2 f or 
defi nit i on])

Refere nce ar m 

Fase nra ® 3 0 m g Q 8 W + hi g h -d ose S y m bic ort ® ma i nte na nce × 2 i n halat i ons BI D + 
Ve nt oli n ® (sal b uta mol  1 0 0 µ g) relie ver P R N.
Refe re nce ar m
Eli gi ble pat ient s ra n d o mise d t o t he Refere nce ar m will c o nt i n ue hi g h -d ose S y m bic ort ®
mai nte na nce treat me nt a n d Ve nt oli n ® relie ver treat me nt f or 3 2 wee ks.
Tre at me nt re d ucti o n ar m
At  t he Ra n d o misati on visit ( Vi sit 2 b; Wee k 0) eli gi ble patie nts ra n do mise d t o t he Treat me nt 
re d uctio n  ar m will a ut o mat icall y be ste p pe d d o w n t o me di u m -d ose S M A R T.  Pati e nts w h o 
d e m o nstrate m ai ntai ne d ast h ma c o ntr ol will ta per (ste p d o w n) t heir S M A R T re gi me n u nt il 
t he y ac hie ve eit her S y m bic ort ® as a nti- i nfla m mat or y relie ver treat me nt o nl y, or u ntil n o  
f urt her re d ucti o ns of S M A R T are per mitte d d ue t o l oss of ast h ma c o ntr ol (see Sect i on  1. 2 ).  
I n case of l oss of ast h ma c o ntr ol, t he pati e nt i n t he re d ucti o n ar m ca n m o ve t o t he m ost rece nt 
pre vi o usl y assi g ne d hi g her d ose le vel. T he re d uct i o n peri o d i n t his ar m will last 3 2 wee ks.  At 
eac h p ost -ra n d o misati on st u d y  visit ( Visit 3 a n d Visit 4; Visit 5 if re q uire d), t he I n vesti gat or 
will e val uate t he occ urre nce of ast h ma e xacer bat i ons, w orse ni n g of ast h ma c o ntr ol ( A C Q -5 
≥0. 5 u nits c o m pare d t o baseli ne), a n d o ver use of S y m bic ort ® 2 0 0/ 6 µ g treat me nt (a wee kl y 
a vera ge o f > 8 i n halat i ons of S y m bic ort ® / da y).  T he I n vesti gat or will t he n deci de t o re d uce, 
mai ntai n, or i ncrease t he S y m bic ort
® d o se base d o n a pre-s pecifie d al g orit h m (see 
Secti o n 1. 2. 2. 2 , Fi g ure 2 ).
P ati e nts w h o are n ot o n S y m bic ort ® relie ver o nl y b y Visit 4 will be gi ve n o ne a d diti onal 
o p p ort u nit y t o ste p d o w n at Visit 5 if t he y d e mo n strate ast h ma c o ntr ol.  Patie nts w h o ste p 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 of 5 2
d o w n t o S y m bic ort ® relie ver o nl y at Visit 4 will atte n d Visit 5 b ut will n ot re d uce t heir d ose 
a n y f urt her.  All pat ient s will be gi n t he mai nte na nce peri o d after Visit 6 ( Wee k 3 2).
A n e xa m ple of h o w t he dail y  hi g h-d ose S y m bic ort ® ma i nte na nce treat me nt will be re d uce d t o 
eit her me di u m-d ose S M A R T, l o w -d ose S M A R T, or S y m bic ort ® as a nti-i nflam mat or y  relie ver 
is s h o w n i n Ta ble 1 wi t h t he alg ori t h m for ste p pi n g d o w n, or ste p pi n g u p, S y m bic ort ®
treat me nt s h o w n i n  Fi g ure 2 .
T a ble 1 : S y m bic ort® d osi n g re gi me n f or p atie nts w h o m ai nt ai n ast h m a c o ntr ol d uri n g 
t he re d ucti o n peri o d
Ste p
M ai nte n a nc e Tre at me nt
Relie ver Tre at me nt
Visit 1 a n d r u n -i n peri o d 
( 4 t o 8 wee ks)
Hi g h- d ose S y m bic ort ®
( 4 0 0/ 1 2 µ g × 2 i n halati o ns BI D)
Ve nt oli n ® 1 0 0 µ g
Visit 2 b ( Wee k 0)
Me di u m -d ose S y m bic ort ®
( 2 0 0/ 6 µ g × 2 i n halati o ns BI D)
S y m bic ort ® 2 0 0/ 6 µ g
1 st Ste p d o w n ( Visit 3 o n war ds)
L o w -d ose S y m bic ort ®
( 2 0 0/ 6 µ g × 1 i n halati o n BI D)
S y m bic ort ® 2 0 0/ 6 µ g
2 n d Ste p d o w n ( Visit 4 o n war ds)
N o ne
S y m bic ort ® 2 0 0/ 6 µ g
Ast h ma e xacer bati o ns will be assesse d si nce t he last st u d y  visit; t he c ha n ge fr om baseli ne i n 
A C Q -5 a n d t he wee kl y a vera ge of S y m bic ort ® 2 0 0/ 6 µ g i n halat i ons/ da y will be assesse d f or 
t he f o ur wee ks pri or t o t he st u d y visit.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 of 5 2
Fi g ure 2 : Al g orit h m f or ste p pi n g d o w n/ u p tre at me nt i n t he re d ucti o n peri o d
A pat ient  will st o p ste p pi ng d o w n f or t he d urati o n of t he re d ucti o n peri o d if:

T he patie nt e x perie nces a n ast h ma e xacer bati o n (see Secti o n  3. 2. 5 ) si nce t he last visit, O R

D uri n g t he last f o ur wee ks pri or t o eac h st u d y visit t he patie nt e x perie nces a n A C Q - 5 
w orse ni n g of ≥0. 5 p oi nts c o m pare d t o baseli ne a n d has a wee kl y  a vera ge of > 8 
i n halati ons o f S y m bic ort ® / da y.
A pat ient  will dela y ta per if d uri n g t he last f o ur wee ks pri or t o eac h st u d y visit:

T he patie nt e x perie nces a n A C Q - 5 w orse ni n g of ≥0. 5 u ni ts c o mpare d t o baseli ne a n d has 
a wee kl y a vera ge of ≤8 i n halati o ns of S y m bic ort ® / da y, O R 

T he patie nt e x perie nces n o A C Q -5 w orse ni n g ( < 0. 5 u nits c o m pare d t o baseli ne) a n d has a 
wee kl y a vera ge of > 8 i n halat i ons of S y m bic ort ® / da y.
1. 2. 3
M ai nte n a nce peri o d
P ati e nts i n b ot h ar ms will a ut o maticall y e nter t he 1 6-wee k m ai nte na nce peri o d d uri n g w hic h 
pati e nts i n t he Treat me nt re d ucti o n ar m will c o nt i n ue o n t he S y m bic ort® treat me nt le vel t he y 
ac hie ve d at t he e n d of t he re d ucti o n peri o d.  I n t he e ve nt of ast h ma w orse ni n g d uri n g t he 
mai nte na nce peri o d, t he I n vesti gat or ma y  d e cide t o ste p u p t he S y m bic ort ® d ose.  N o 
re d uctio ns i n S y m bic ort ® d oses are all o we d d uri n g t he mai nte na nce peri o d. 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 of 5 2
T he fi nal a nal y sis will be perf or me d after t he last patie nt has c o m p lete d t heir last visit 
( Visit 8 b; Wee k 4 8/e n d of treat me nt [ E O T]).  T he fi nal a nal ysis will i ncl u de all st u d y  data 
fro m  bot h  t he re d ucti o n a n d mai nte na nce peri o ds.
S u b -st u d y
A s u bset of patie nts w h o c o nse nt t o partici pat i on i n t he s u b-st u d y (a p pr o xi matel y 3 2 patie nts 
are t o be i ncl u de d, s prea d acr oss t he t w o treat me nt ar ms) will u n der g o a d dit i onal s u b -st u d y 
s pecific tests at pre-defi ne d t i me p oi nts (see Sc he d ule of Assess me nts [ S o A] i n t he C S P) f or 
e x p l orat or y bio m ar ker researc h.  T he res ults of t he s u b-st u d y will be re p orte d se paratel y fr om 
t he Cli nical St u d y Re p ort ( C S R) wit h a se parate e x plorat or y  a nal ysis pla n o utli ni n g t he 
c o nte nt of t he s u b-st u d y re p ort.
1. 2. 4
St u d y c o m pleti o n/e n d of tre at me nt
P ati e nts will be c o nsi dere d t o ha ve c o m plete d t he st u d y  if t he y c o mplete Vi sit 8 b, ie, t he last 
sc he d ule d visit.  Patie nts w h o disc o nt i n ue treat me nt pre mat urel y will atte n d a n E O T visit, 
w hic h i ncl u des all t he assess me nts at Visits 8a a n d 8 b, i n or der t o e xit t he s t u d y.
1. 3
N u m ber of p atie nts
A t otal o f a p pr o xi matel y 2 4 0 p atie nts will be scree ne d t o ac hie ve 2 0 0 ra n d o mise d patie nts, 
ass u mi n g a scree n fail ure rate of a p pr o xi matel y 1 5 %.  A t otal of 2 0 0 ra n d o mise d patie nts, 
acc or di n g t o a ra n d o misat i on rati o of  3: 1 ( Treat me nt  re d ucti o n ar m: Refere nce ar m), is 
c o nsi dere d s ufficie nt t o a d dress t he pri mar y o bjecti ve f or t he st u d y ass u mi n g a dr o p-o u t rate 
of  n o more t ha n 1 5 % e val ua ble pat ient s i n b ot h ar ms res ulti n g i n a p pr o xi matel y 1 2 5 t o 
1 5 0 e val ua ble patie nts i n t he Treat me nt re d ucti o n ar m a n d a p pr o xi matel y 4 0 t o 5 0 e val ua ble 
pati e nts i n t he Refere nce ar m.   Ta bl e 2 pr o vi des t he e x pecte d preci sio n  ar o u n d t he pri mar y 
o u t co m e, t he pr o p ortio n  of patie nts s uccessf ull y re d uci n g t o me di u m-d ose S M A R T, l o w -d o se 
S M A R T, or S y m bic ort ® as a nti- i nflam mat or y  relie ver o nl y.
T he selecte d sa m ple size is e x pecte d t o pr o vi de a n o mi nal 9 5 % c o nfi de nce i nter val ( CI) 
ar o u n d t he o bser ve d pr o p orti o ns wi t h a half-wi dt h of  less t ha n 1 0 perce nta ge p oi nts i n t he 
Treat me nt re d ucti o n ar m.
Scree n fail ures are defi ne d as pat ient s w h o sig n e d t he I nf or me d C o nse nt F or m (I C F) t o 
parti ci pate i n t he cli nical st u d y but are n ot s u bse q ue nt l y ra n d oml y assi g ne d t o a st u d y 
treat me nt ar m at Visit 2 b ( Wee k 0).  Patie nts w h o d o n ot f ulfil t he ra n d o misat i on cri t eria (see 
Secti o n 5. 1. 1 of t he C S P) will be c o nsi dere d scree n faile d.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 0 of 5 2
T a ble 2 : E x pecte d l o wer a n d u p per h alf-wi dt h of e x act 9 5 % CIs ( Cl o p per- Pe a rs o n) 
ar o u n d o bser ve d pr o p orti o n of p atie nts s uccessf ull y ste p pi n g d o w n S M A R T
O bser ve d 
pr o p orti o n
N = 5 0
N = 1 0 0  
N = 1 2 5  
N = 1 5 0  
N = 2 0 0
2 5 % 
1 1. 2 % / 1 4. 3 %
8. 1 % / 9. 7 %
7. 3 % / 8. 5 %
6. 7 % / 7. 7 %
5. 8 % / 6. 6 %
3 5 % 
1 2. 9 % / 1 4. 8 %
9. 3 % / 1 0. 2 %
8. 3 % / 9. 0 %
7. 6 % / 8. 2 %
6. 6 % / 7. 0 %
5 0 % 
1 4. 5 % / 1 4. 5 %
1 0. 2 % / 1 0. 2 %
9. 1 % / 9. 1 %
8. 3 % / 8. 3 %
7. 1 % / 7. 1 %
6 5 % 
1 4. 8 % / 1 2. 9 %
1 0. 2 % / 9. 3 %
9. 0 % / 8. 3 %
8. 2 % / 7. 6 %
7. 0 % / 6. 5 %
7 5 % 
1 4. 3 % / 1 1. 2 %
9. 7 % / 8. 1 %
8. 5 % / 7. 3 %
7. 7 % / 6. 7 %
6. 6 % / 5. 8 %
2
A N A L Y SI S S E T S
2. 1
Defi niti o n of a n al ysis sets
2. 1. 1
All P atie nt Set
T he All Patie nt Set ( A P S) will i ncl u de all pat ient s scree ne d f or t he st u d y a n d will be use d f or 
re p orti n g of patient  dis p ositi on a n d scree n fail ure i nf or mat i on.
P ati e nt dis p ositio n will be s u m marise d usi n g t he A P S.
2. 1. 2
F ull A n al ysis Set
T he F ul l A nal ysis Set ( F A S) will i ncl u de all ra n d o mise d pat ient s, irres pecti ve of t heir pr ot oc ol 
a d here nce a n d c o nt i n ue d partici pati on i n t he st u d y.  Patie nts will be a nal yse d irres pecti ve of 
w het her t he y  pre mat urel y disc o nti n ue st u d y treat me nt, acc or di n g t o t he i nte nt -t o-treat 
pri nci ple.  Patie nts w h o wit h dra w c o nse nt t o partici pate i n t he st u d y  will be i ncl u de d u p t o t he 
date of t heir st u d y  ter mi nati on.
All efficac y a nal yses will be perf or me d usi n g t he F A S.  F or c o nsiste nc y, de m o gra p hic, 
baseli ne, a n d patie nt c h aracteristics will be prese nte d usi n g t he F A S.
2. 1. 3
S u b -St u d y A n al ysis Set
T he s u b -st u d y a nal ysis set ( S S A S) will i ncl u de all patie nts fr o m t he site 2 8 0 1 e nr olle d f or t he 
s u b-st u d y.
2. 1. 4
S afet y A n al ysis Set
T he safet y a nal ysis set ( S A F) will i ncl u de all pat ient s fr om t he F A S w h o recei ve a n y a mo u nt 
of  st u d y tr e at me nt a n d will be use d f or all safet y a nal yses. Patie nts will be a nal yse d acc or di n g 
t o t he act ual treat me nt recei ve d.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 1 of 5 2
2. 2
Vi ol ati o ns a n d de vi ati o ns
T he fi nal list of all pr ot oc ol de viat i ons ( P Ds) will be fi nalise d a n d d oc u me nte d, a n d will be 
base d o n de viat i ons defi ne d i n t he st u d y  P D S pecificati on, wi t h all P Ds, eit her pr o gra m ma ble 
or o bser va ble, u n der g oi n g re g ular re vie w as per t he P D S pecificat i on d oc u me nt.
P ati e nts w h o d o n ot meet eli gi bilit y cri t eria b ut are st ill ra n d omise d will be a nal yse d 
acc or di n g t o t he a nal ysis sets descri be d i n Sect i on 2. 1 .  T his st u d y d oes n ot i ncl u de a 
Per- Pr ot oc ol Set, t h us n o patie nts will be e xcl u de d fr o m a nal yses.
Pr ot oc ol  de viati ons will be re vie we d a n d ma y be classifie d as i m p orta nt, de pe n di n g o n t he 
i m pact of t he de viati o n t o t he a nal ysis a n d/ or t he i m pact t o patie nts.  I m p orta nt pr ot oc ol 
de viat i ons are a s u bset of pr ot oc ol de viat i ons t hat ma y si g nifica ntl y i m pact t he c o m plete ness, 
acc urac y, a n d/ or relia bility of t he st u d y  data or t hat ma y sig nifica nt l y affect a patie nt’s ri g hts, 
safety,  or well-bei n g.  
O nl y i m p orta nt P Ds will be liste d a n d ta b ula te d i n t he Cli nical St u d y Re p ort ( C S R).
Pr ot oc ol  de viati ons c o nfir me d t o be d ue t o C or o na vir us Disease 2 0 1 9 ( C O VI D- 1 9) m a y be 
s u m marise d se paratel y. See Sectio n  4. 2. 8 f or more i nf or mat i on. 
3
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S
T he treat me nt peri o d refers t o t he c o m bi nat i on of r u n -i n, re d ucti o n a n d mai nte na nce peri o ds 
s pa n ni n g 5 2 t o 5 6 wee ks i n t otal, de pe n di n g o n t he d urati o n of t he r u n-i n peri o d.
T he st u d y p eri o d refers t o t he c o m bi nati o n o f re d uctio n a n d m ai nte na nce perio ds o nl y , 
s pa n ni n g 4 8 wee ks i n t otal.
U nless ot her wise s pecifie d, t he last n o n -missi n g o bser vat i on pri or t o ra n d o misat i on ( Vi sit 2 b; 
Wee k 0) will ser ve as t he baseli ne meas ure me nt f or c ha n g e fr o m start of ste p d o w n of 
S M A R T ( Visit 2 b; Wee k 0).  If t here is n o val ue pri or t o ra n d o misat i on, t he n t he baseli ne 
val ue will n ot be i m p ute d a n d will be set t o missi n g.
F or assess me nts of t he mai nte na nce peri o d l o o ki n g at t he c ha n ges fr o m e n d of t he re d ucti o n 
p eri o d, t he m ai nte na nce perio d baseli ne will be defi ne d as t he visit w he n t he patie nt 
c o mplete d t hei r re d uctio n peri o d ( Vi sit 6; Wee k 3 2).
T he a bs o l ute c ha n ge fr o m baseli ne: 
       ℎ              =
      –          

Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 2 of 5 2
De pe n di n g o n t he peri o d bei n g i n vest i gate d, baseli ne val ue will be eit her t hat of Visit 2 b 
( Wee k 0) or t he mai nte na nce peri o d baseli ne, as defi ne d a b o ve.
Perce nta ge ( %) c ha n ge fr o m baseli ne:
%
 ℎ              =
      −                  × 1 0 0
De pe n di n g o n t he peri o d bei n g i n vest i gate d, baseli ne val ue will be eit her t hat of Visit 2 b 
( Wee k 0) or t he mai nte na nce peri o d baseli n e, as defi ne d a b o ve.
If either a visit val ue or t he Visit 2 b ( baseli ne) val ue is missi n g, t he a bs o l ute c ha n ge fr o m 
baseli ne val ue a n d t he perce nta ge c ha n ge fr o m baseli ne will als o be set t o missi n g.  If baseli ne 
val ue is zer o, t he perce nta ge c ha n ge will be set t o missi n g.
F or t he c o m paris o ns o ver t he mai nte na nce peri o d, if eit her a visit val ue or t he Visit 6 
( mai nte na nce peri o d baseli ne) val ue is missi n g, t he a bs o l ute c ha n ge fr o m ma i nte na nce perio d 
baseli ne val ue a n d t he perce nta ge c ha n ge fr o m mai nte na nce p erio d baseli ne will als o be set t o 
missi n g.  If mai nte na nce peri o d baseli ne val ue is zer o, t he perce nta ge c ha n ge will be set t o 
missi n g.
3. 1
Pri m ar y Effic ac y V ari a ble
T he pri mar y  ai m of t his st u d y is t o assess t he p ote ntial t o re d uce S y m bic ort® ma i nte na nce 
tr eat me nt  w hile mai ntai ni n g c o m para ble ast h ma s y m pt o m c o ntr ol t o Fase nra® -treate d patie nts 
o n hi g h -d ose S y m bic ort ® ma i nte na nce treat me nt.
T he pri mar y  o ut c o me meas ure is t he pr o p orti o n of patie nts w h o re d uce d t heir S y m bic ort ®
mai nte na nce d ose w hile mai ntai ni n g ast h ma s y m pt o m c o ntr ol t o eit her me di u m-d ose 
S M A R T, l o w - d ose S M A R T, or S y m bic ort® as a nt i-i nfla m mat or y relie ver o nl y at t he e n d of 
t he re d ucti o n peri o d ( Visit 6; Wee k 3 2).
A 2 -si de d 9 5 % CI f or pr o p orti o ns c om p ute d usi n g t he e xact Cl o p per -Pears o n met h o d wi ll be 
prese nte d, as a p pr o priate.
S y m bic ort ® d ose, as prescri be d at t he visit, will be rec or de d at eac h p ost -baseli ne visit u p t o 
Vi sit 8 b ( Wee k 4 8).  T he S y m bic ort® d ose varia ble is a n or di nal varia ble wit h t he l e vels: 
hi g h -d ose S y m bic ort ® ma i nte na nce treat me nt, me di u m-d ose S M A R T, l o w -d ose S M A R T, or 
S y m bic ort ® as a nti-i nfla m mat or y relie ver o nl y.
T he pri mar y  o ut c o me meas ure is o nl y assesse d i n t he treat me nt re d ucti o n ar m as t he 
hi g h -d ose refere nce ar m is n ot ta pere d, b y  desi g n.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 5 2
T he pri mar y o utc o me meas ure r elate d t o t he re d ucti o n peri o d will be a nal yse d o nce all patie nts 
ha ve c o m plete d t heir Visit 6 ( Wee k 3 2) assess me nts, a n d s u bse q ue ntl y a nal yse d w he n all 
patie nts ha ve c o m plete d t he st u d y ( Visit 8 b; Wee k 4 8/ E O T).
T he pr o p orti o n of  p atie nts w h o re d uce t heir S y m bic ort ® ma i nte na nce d ose w hile mai ntai ni n g 
ast h ma c o ntr ol t o me di u m-d ose S M A R T i s calc ulate d as:
                             ®            -        =
                   -                                        T he pr o p orti o n of  p atie nts re d uci n g S y m bic ort ® d ose t o me di u m -d ose S M A R T will be 
e val uate d f or t he n u m ber of pat ient s, as ra n do mise d at Da y  1, as well as t he n u m ber of 
pati e nts wit h a vali d meas ure me nt at Visit 6; Wee k 3 2.
T he pr o p orti o n of  p atie nts w h o re d uce t heir S y m bic ort ® ma i nte na nce d ose w hile mai ntai ni n g 
ast h ma c o ntr ol t o l o w -d ose S M A R T is calc ulate d as:
                             ®         -        =
                 -                                       T he pr o p orti o n of patie nts re d uci n g S y m bic ort ® d ose t o l o w -d ose S M A R T will be e val uate d 
f or t he n u m ber of patient s, as ra n d o mise d at Da y 1, as well as t he n u m ber of patient s wit h a 
vali d meas ure me nt at Visit 6; Wee k 3 2.
T he pr o p orti o n of  p atie nts w h o re d uce t heir S y m bic ort® ma i nte na nce d ose w hile mai ntai ni n g 
ast h ma c o ntr ol t o S y m bic ort ® as a nti-i nfla m mat or y relie ver o nl y is calc ulate d as:
                             ®              ®    -                  =                       ®     -                                                 T he pr o p orti o n of  p atie nts re d uci n g S y m bic ort ® d ose t o a nti -i nfla m mat or y relie ver o nl y will 
be e val uate d f or t he n u m ber of patie nts, as ra n d o mise d at Da y  1, as well as t he n u m ber of 
p atie nts wit h a vali d meas ure me nt at Visit 6; Wee k 3 2.
T he n u m ber a n d perce nta ge of patie nts w h o d o n ot re d uce t heir mai nte na nce treat me nt will 
s u m marise d.
3. 2
Sec o n d ar y Effic ac y V ari a bles
T he sec o n dar y o utc o me meas ures relate d t o t he re d ucti o n peri o d will be a nal yse d o nce all 
patie nts ha ve c o m plete d t heir Visit 6 ( Wee k 3 2) assess me nts, a n d s u bse q ue ntl y a nal yse d w he n 
all patie nts ha ve c o m plete d t he st u d y ( Visit 8 b; Wee k 4 8/ E O T).


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 5 2
3. 2. 1
A C Q- 5
T he A C Q -5 i s a s h orte ne d versi o n of t he f ull 7-ite m A C Q Pati e nt - Re p orte d O utc ome ( P R O) 
(J u ni per et al 1 9 9 9) t hat assesses ast h ma s y m pt o ms ( ni g ht-ti me a wa ke ni n g, s y m pt o ms o n 
a wa ke ni n g, acti vit y li mitati o n, s h ort ness of breat h, a n d w heezi n g) b ut o mits t he F E V 1
meas ure me nt a n d s h ort -actin g β -a g o nist ( S A B A) use fr o m t he ori gi nal A C Q assess me nt (see 
A p pe n di x F o f t he C S P f or details).
P ati e nts are as ke d t o recall h o w t heir ast h ma has bee n d uri n g t he pre vi o us wee k b y res p o n di n g 
t o fi ve s y m pt o m q uesti ons.  Q uesti o ns are wei g hte d e q uall y a n d sc ore d fr o m 0 (t otall y 
c o ntr olle d) t o 6 (se verel y u nc o ntr olle d).
T he A C Q -5 sc ore i s t he u n-wei g hte d m ea n of t he res p o nses.  If res p o nse t o a n y of t he 
q uesti o ns is missi n g, t he A C Q - 5 sc ore will be missi n g.  Mea n sc ores of ≤0. 7 5 i n dicate well 
c o ntr olle d ast h ma, sc ores bet we e n > 0. 7 5 a n d < 1. 5 i n dicate partiall y c o ntr olle d ast h ma, a n d a 
sc ore ≥1. 5 i n dicates n ot well c o ntr olle d ast h ma ( J u ni per et al 2 0 0 6).  I n di vi d ual c ha n ges 
of ≥0. 5 are c o nsi dere d t o be cli nicall y mea ni n gf ul (J u ni per et al 2 0 0 5).
P ati e nts will be cate g orise d acc or di n g t o t he f oll owi n g li mits ( J u ni per et al 2 0 0 6):

I mpr o ve m e nt: A C Q-5 sc ore c ha n ge fr o m  baseli ne ≤- 0. 5

N o C ha n ge: -0. 5 < A C Q -5 sc ore c ha n ge fr o m baseli ne < 0. 5

Deteri or ati o n: A C Q -5 sc ore c ha n ge fr o m  baseli ne ≥0. 5.
I n a d diti on, ast h ma c o ntr ol w orse ni n g res p o n der varia ble is defi ne d as a n at least 0. 5 -u nit 
w orse ni n g (i ncrease) i n A C Q -5 sc ore fr o m  baseli ne; ie, a n A C Q-5 w orse ni n g varia ble ta kes 
val ue 1, if c ha n ge fr o m baseli ne A C Q - 5 ≥0. 5, a n d 0 ot her wise.  Patie nts wit h missi n g or 
n o n- e val ua ble A C Q -5 sc ore at a p ost -baseli ne assess me nt ti me p o i nt will be c o nsi dere d ast h ma 
w orse ni n g res p o n ders at t he ti me p o i nt.
C ha n ge fr o m mai nte na nce peri o d baseli ne (se e Sectio n  3 f or defi niti on) i n A C Q -5 will  b e 
deri ve d as Visit 8 b ( Wee k 4 8)/ E O T sc ore mi n us mai nte na nce peri o d baseli ne ( Visit 6; 
Wee k
3 2) A C Q -5 sc ore, wit h cate g orisa tio n of  AC Q -5 sc ore a nal o g o us t o t hat f or t he 
baseli ne.  T he c ha n ges i n A C Q -5 will  be s u m marise d f or t he mai nte na nce peri o d se paratel y.
C ha n ge fr o m baseli ne i n mea n A C Q -5 sc ore o ver t he pre vi o us 8 wee ks will als o be calc ulate d 
f or Wee k 8, 1 6, 2 4, 3 2, 4 0 a nd 4 8. T he m ea n A C Q -5 sc ore o ver t he pre vi o us 8 wee ks will be 
deri ve d as f o ll ows:
      −5        ℎ            ℎ        8                   ℎ         −5   ℎ                 8     

Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 5 of 5 2
3. 2. 2
I C S E x p os ure
C u m ulat i ve I C S will be calc ulate d as t he s u m of t he d oses a d mi nistere d eac h da y.  I n or der t o 
assess t he c u m ulat i ve t otal dail y I C S d ose d uri n g t he re d ucti o n a n d mai nte na nce p eri o ds, t he 
pati e nt’s dail y d ose will be c ollecte d eac h da y a n d t he f ollo wi n g o utc o m e varia bles will be 
deri ve d:

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose si nce t he be gi n ni n g of t he re d ucti o n peri o d 
u nt il t he e n d of re d ucti o n peri o d

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose t hr o u g h o ut t he d urati o n of t he st u d y peri o d

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose si nce t he be gi n ni n g of t he mai nte na nce 
p eri o d t o t he e n d of mai nte na nce peri o d.
I n a d diti on, t he pati e nt’s mea n t otal dail y I C S d ose ( mai nte na nce + relie ver) d uri n g t he 
pre vi o us f o ur/ei g ht wee ks, as re q uire d b y i n di vi d ual pat ient  d uratio n of  t he r u n-i n, will be 
deri ve d d uri n g t he st u d y  p erio d at Wee k 0, 8, 1 6, 2 4, 3 2, 4 0, a n d 4 8 as t he t otal rec or de d I C S 
d ose ( m c g) di vi de d b y t he n u m ber of d a y s wit h rec or de d I C S d ose (i ncl u di n g a n y da ys wit h 
0 mc g I C S d ose re p orte d).
                 (   )=
                  (   )   ℎ            ℎ        8                  ℎ               (                   )   ℎ                 8     T he wi t hi n-pat ient  c ha n ge fr o m baseli ne i n mea n t otal I C S d ose f or t he pre vi o us ei g ht wee ks 
will be deri ve d as t he patie nt’s mea n t otal dail y I C S d ose at eac h p ost -baseli ne visit mi n us t he 
pati e nt’s mea n t otal dail y I C S d ose at baseli ne ( Visit 2 b; Wee k 0).
T he wi t hi n-pat ient  perce nta ge c ha n ge fr o m baseli ne i n mea n t ot al I C S d ose f or t he pre vi o us 
eig ht wee ks will als o be deri ve d as: 1 0 0 × (t he patie nt’s mea n t otal dail y  I C S d ose at eac h 
p ost -baseli ne visit mi n us t he patie nt’s mea n t otal dail y I C S d ose at baseli ne [ Visit 2 b; 
Wee k
0])/(t he t otal dail y  I C S d ose at baseli ne val ue).
T he t otal dail y  I C S d ose f or t he mai nte na nce peri o d will be s u m marise d fr o m ma i nte na nce 
p eri o d baseli ne ( Visit 6; Wee k 3 2) t o Vi sit 8 b ( Wee k 4 8) se paratel y.
T he sta n dar dise d area u n der t he c ur ve ( A U C) of I C S d ose u p t o Visit 6, u p t o Visit 8 b, a n d 
fr om Visi t 6 t o Visit 8 b, will be calc ulate d as f oll o ws:
F or eac h i nsta nce of a dail y d ose le vel, t he d urati o n of t he gi ve n d ose le vel will be calc ulate d 
as e n d date – start date + 1.  If t he start date is bef o re Visit 2 b ( date of ra n d omisat i on), Vi sit 2b 
will be use d i nstea d f or calc ulat i n g t he A U C u p t o Visit 6, a n d u p t o Visit 8 b.  If t he start date 
is bef ore t he date of Visit 6, t he date of Visit 6 will be use d i nstea d f or calc ulat i n g t he A U C 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 6 of 5 2
fr om Visi t 6 t o Visit 8 b.  If t he e n d date is after t he date of Visit 6, or after t he date of Visit 8 b, 
t he date of Visit 6 a n d Visit 8 b res pect i vel y will be use d i nstea d f or calc ulati n g t he A U C u p t o 
Vi sit 6 a n d Visit 8 b.  T he A U C f or eac h d ose le vel will be deri ve d b y t he dail y d ose 
( mc g/ da y) m ultiplie d b y  t h e durati o n (i n da ys).  T he A U C is t he s u m o f t he A U Cs of t he 
i n di vi d ual d ose le vels.  T he A U C of I C S d ose will o nl y be calc ulate d if all necessar y data are 
a vaila ble u p t o Visit 6, or Visit 8 b, res pect i vel y.  F or patie nts w h o disc o nti n ue d t he st u d y 
bef ore Vis it 6 or Visit 8 b, res pecti vel y, t he A U C will be calc ulate d u p t o t he date of st u d y 
di sc o nti n uati on.
D oses t hat are rec or de d b y  t he i n haler se ns or b ut c o nfir me d b y t he patient  t o be k n o wi n gl y n ot 
i n hale d (e g, d ue t o t he patie nt pri mi n g t he i n haler bef ore use), a n d a p pr o ve d b y  t he site a n d 
st u d y t e a m, will be r e mo v e d fr o m t he data base a n d he nce n ot i ncl u de d i n t he a nal ysis of I C S.
T he sta n dar dise d A U C will be deri ve d as:

F or sta n dar dise d A U C u p t o Visit 6: A U C di vi de d b y t he a vaila ble da ys ( date of 
Vi sit 6/ E O T – date of Visit 2 + 1) m ult i plie d b y 2 2 4 (ie, 3 2 wee ks).

F or sta n dar dise d A U C fr o m Visi t 6 t o Visit 8 b: A U C di vi de d b y t he a vaila ble da ys ( date 
of  Visit 8 b/ E O T – date of Visit 6 + 1) m ult i plie d b y 1 1 2 (ie, 1 6 wee ks).

F or sta n dar dise d A U C u p t o V isit 8 b: A U C di vi de d b y t he a vaila ble da ys ( date of 
Vi sit 8 b/ E O T – date of Visit 2 + 1) m ul tiplie d b y  3 3 6 (ie, 4 8 wee ks).
3. 2. 3
A Q L Q( S) + 1 2
T he A Q L Q( S) + 1 2 (J u ni per et al 1 9 9 2, J u ni per et al 2 0 0 5 ) is a P R O t hat meas ures t he 
healt h -relate d q uality of life e x perie nce d b y  ast h ma patie nts (see A p pe n di x E of t he C S P f or 
details).
T he q uest i on naire c o m prises f o ur se parate d o mai ns (s y m pt o ms, acti vit y li mitati ons, e m oti o nal 
f u ncti on, a n d e n vir o n me ntal sti m uli).
P ati e nts are as ke d t o recall t heir e x perie nces d uri n g t he pre vi o us t w o wee ks bef ore eac h visit 
a n d t o sc ore eac h of t he q uesti o ns o n a 7 -p oi nt scale ra n gi n g fr o m 7 ( n o i m pair me nt) t o 1 
(se vere i m pair me nt).  T he o verall sc ore is calc ulate d as t he me a n res p o nse t o all q uest i ons.  
T he f o ur i n di vi d ual d o ma i n sc ores (s y m pt o ms, acti vity li mitati ons, e m oti o nal f u nct i on, a n d 
e n vir o n me ntal sti m uli) are t he mea ns of t he res p o nses t o t he q uesti o ns i n eac h of t he d o mai ns.  
I n di vi d ual A Q L Q(s) + 1 2 t otal or d o mai n sc ore c ha n ges of ≥0. 5 are c o nsi dere d cli nicall y 
mea ni n gf ul ( J u ni per et al 1 9 9 4).
A n A Q L Q( S) + 1 2 res p o n der will be defi ne d as a patie nt w h o ha d i m pr o ve me nt o n 
A Q L Q( S) + 1 2.  T he A Q L Q( S) + 1 2 res p o n der varia ble will ta ke t he f oll owi n g val ues:


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 7 of 5 2

1 if c ha n ge fr o m baseli ne t o e n d of treat me nt i n A Q L Q( S) + 1 2 ≥0. 5, a n d 

0, ot her wi se.
P ati e nts wit h missi n g or n o n-e val ua ble A Q L Q( S) + 1 2 sc ore at a p ost -baseli ne assess me nt 
ti me p oi nt will be c o nsi dere d n o n-res p o n ders at t he ti me p oi nt.
Pa tie nts will als o be cate g orise d acc or di n g t o t he f oll o wi n g li mits i n c ha n ge fr o m baseli ne, 
res pecti vel y:

I mpr o ve m e nt: A Q L Q( S) + 1 2 ( p ost -baseli ne visit – baseli ne visit) ≥0. 5

N o c ha n ge: -0. 5 < A Q L Q( S) + 1 2 ( p ost -baseli ne visit – baseli ne visit) < 0. 5

Deteri or at i on: A Q L Q( S) + 1 2 ( p ost -baseli ne visit – baseli ne visit) ≤-0. 5.
De pe n di n g o n t he a nal ysis, t he baseli ne visit will be eit her Visit 2 b ( Wee k 0) f or c o m paris o ns 
l oo ki n g at data fr o m  start of t he re d ucti o n peri o d, or t he mai nte na nce peri o d baseli ne (see 
Secti o n  3 f or defi niti on) f or a nal yses l o o ki n g at data fr o m start of t he mai nte na nce peri o d.
3. 2. 4
Pre -br o nc h o dil at or F E V 1
C ha n ge fr o m baseli ne pre -br o nc h o dilat or F E V 1 will be calc ulate d as p ost -baseli ne 
pre -br o nc h o dilat or F E V 1 ( L) mi n us baseli ne pre-br o nc h o dilat or F E V 1 ( L) f or all p ost-baseli ne 
meas ure me nt p oi nts.
C ha n ge fr o m t he e n d of t he re d ucti o n peri o d t o t he e n d of t he mai nte na nce peri o d f or 
pre -br o nc h o dilat or F E V 1 will be calc ulate d as Visit 8 b ( Wee k 4 8)/ E O T pre -br o nc h o dilat or 
F E V 1 ( L) mi n us mai nte na nce peri o d baseli ne pre-br o nc h o dilat or F E V 1 ( L).
3. 2. 5
Ast h m a E x acer b ati o ns
D uri n g t he st u d y , a n ast h ma e xacer bati on will be defi ne d as a w orse ni n g of ast h ma s y m pt o ms 
t hat lea ds t o a n y of t h e fol l owi n g (t hi s ma y lea d t o ste p pi n g u p of t he d osa ge i n t he Treat me nt 
re d uctio n ar m ):

A te m p orar y  bol us/ b urst of s yste mic c ortic oster oi ds f or at least t hree c o nsec ut i ve da ys t o 
treat s y m pt o ms of ast h ma w orse ni n g; a si n gle de p o-i njecta ble d ose of c ortic oster oi ds will 
be c o nsi dere d e q ui vale nt t o a 3 -da y b o l us/ b urst of s yste mic c ortic oster oi ds

A n e mer ge nc y  r o o m or ur ge nt care visit ( defi ne d as e val uati on a n d treat me nt f or < 2 4 
h o urs i n a n e mer ge nc y de part me nt or ur ge nt care ce ntre) d ue t o ast h ma t hat re q uire d 
s yste mic c ortic oster oi ds (as per t he a b o ve)

I n-pati e nt h os pitalisatio n ( defi ne d as a d missi o n t o a n i n -pat ient  facility a n d/ or e val uat i on 
a n d treat me nt i n a healt hcare facilit y f or ≥2 4 h o urs) d ue t o ast h ma.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 8 of 5 2
T he patie nt ma y  re mai n in t he st u d y  after a n e xacer bati on a n d c o nt i n ue t o recei ve st u d y 
treat me nt if t he I n vest i gat or j u d ges t hat it is me dicall y a p pr o priate f or t he patie nt t o d o s o a n d 
will be ma na ge d as per t he details pr o vi de d.
T o cal c ulate t he n u m ber of e xacer bati o ns e x perie nce d b y  a p atie nt d uri n g t he st u d y p erio d 
(t otal re d uctio n a n d mai nte na nce peri o ds), t he f o ll o wi n g r ule will be a p plie d.
T he start of a n e xacer bat i on is defi ne d as t he start-date of s yste mic c ortic oster oi ds or start -date 
of  a t e mp orar y  increase i n a sta ble O C S bac k gr o u n d d ose, or start -date of a h os pital 
a d missi o n, w hic he ver occ urs earlier.  T he e n d -date is defi ne d as t he last da y  of s yste mic 
c ortic oster oids, or t he l ast da y of a te mp or ar y  increase i n a sta ble O C S bac k gr o u n d d ose, or 
t he date of disc har ge fr o m a h os pit al, w hic he ver occ urs later.  T he n u m ber of e xacer bat i ons 
o bser ve d f or a patie nt d uri n g t he 4 8 -wee k st u d y  p erio d (t otal  of re d uctio n a n d m ai nte na nce 
p eri o ds) will be use d as t he res p o nse varia ble.
A d dit i onal s yste mic c ortic oster oid treat m e nts, emer ge nc y r o o m/ ur ge nt care visits re q uiri n g 
use of s yste mic c ortic oster oi ds, or i n -pat ient  h os pitalisati o n d ue t o ast h ma occ urri n g d uri n g a n 
e xacer bati o n s h o ul d n ot be re gar de d as a ne w e xacer bat i on.  I n or der t o be c o u nte d as a ne w 
e xacer bati o n, it m ust be prece de d b y  at least se ve n da ys i n w hic h neither cri t erio n is f ulfille d.
A n ast h ma e xacer bat i on t hat occ urs wit hi n se ve n da ys of t he last d ose of s yste mic ster oi ds, 
prescri be d f or a pri or e xacer bat i on, will be c o u nte d as t he sa me e xacer bat i on e ve nt.
Ma xi m u m f ol l ow -u p ti me f or a patie nt is a p pr o xi matel y 4 8 wee ks; defi ne d as t he ti me fr o m 
first d ose of Fase nra® ta ke n i n t he re d ucti o n peri o d t o t he e n d of t he st u d y.  F or a patie nt lost 
t o f oll ow- u p, t his will be defi ne d as t he ti me fr o m first d ose of Fase nra® ta ke n i n t he re d ucti o n 
p eri o d t o t he ti me p o i nt after w hic h a n e xacer bati on c o ul d n ot be assesse d.
F or t he pr o d ucti o n of s u m mar y statist ics, t he a n n ual e xacer bati on rate ( A E R) per patie nt is 
calc ulate d a n d sta n dar dise d usi n g data fr o m t he st u d y p erio d (t ot al of re d uct i on a n d 
mai nte na nce peri o ds), t he re d ucti o n peri o d a n d t he mai nte na nce peri o d se paratel y, acc or di n g 
t o t he f or m ula descri be d bel o w:
   =
                             -     −                ®            + 1 × 3 6 5 .2 5
F o ll ow- u p date f or t he st u d y  a n d mai nte na nce peri o ds is Visit 8 b ( Wee k 4 8) a n d t he f oll o w- u p 
date f or t he re d ucti o n peri o d is t he date of Visit 6 ( Wee k 3 2).
T he n u m ber of e xacer bat i ons d uri n g t he mai nte na nce peri o d will be s u m marise d fr o m e n d of 
Vi sit 6 ( Wee k 3 2) t o Visit 8 b ( Wee k 4 8) se paratel y.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 9 of 5 2
3. 2. 6
S y m bic ort ® d ose at t he e n d of t he m ai nte n a nce peri o d
Si milar t o t he pri mar y efficac y varia ble i n Sect i on  3. 1 , t he pr o p orti o n of patient s w h o were 
usi n g t he sa me S y m bic ort ® dail y d ose at t he e n d of t he mai nte na nce peri o d ( Visit 8 b; 
Wee k
4 8), as t he y  ac hie ve d at t he e n d of t he re d ucti on peri o d ( Visi t 6; Wee k 3 2), will b e 
calc ulate d.
3. 2. 7
Cli nic al Re m issi o n
T he n u m ber a n d pr o p orti o n of pat ient s ac hie vi n g c o m p osite e n d p o i nts defi ni n g cli nical 
re missi o n at t he e n d of t he re d ucti o n p hase ( Visit 6, Wee k 3 2) or at  t he e n d of t he st u d y p erio d
( Visit 8 b, Wee k 4 8) will be prese nte d.  Cli nical re missi o n at Wee k 3 2 or Wee k 4 8 is defi ne d 
as:

E xacer bat i on free bet wee n ra n d omisati o n ( Visit 2 b) a n d t he rele va nt ti me p oi nt

Less t ha n 1 0 % deteri orati o n i n F E V 1 at t he rele va nt ti me p o i nt c o mpare d t o 
ra n d omisat i on ( Visit 2 b)

A C Q -5 < 1. 5 at t he rele va nt ti me p oi nt
A d dit i onall y , cli nical re missio n  wit h AC Q -5 ≤ 0. 7 5 will be assesse d a n d re p orte d.
3. 3
S afet y v ari a bles
S af et y a n d t olera bilit y will  be e val uate d i n ter ms of re p orte d A Es (i ncl u di n g S A Es [refer t o 
C S P A p pe n di x B f or defi nit i on]).
All safety me as ure me nts will use all a vaila ble data f or a nal yses, i ncl u di n g data fr o m 
u nsc he d ule d visits a n d re peate d meas ure me nts, refer t o Secti o n  4. 1. 2 f or Visit Wi n d o ws.  
A d verse e ve nts prese nti n g d uri n g t he r u n -i n peri o d will be re p orte d as b y-pat ient  listi n gs o nl y.  
All A E s u m maries will be prese nte d f or t he st u d y  p erio d.
C ha n ge fr o m baseli ne t o eac h p ost -treat me nt ti me p oi nt w here sc he d ule d assess me nts were 
ma de will  be calc ulate d f or rele va nt meas ure me nts.  A Es will be s u m marise d b y mea ns of 
descri pt i ve statistics a n d q ualitati ve s u m maries.
N o safet y data will be i m p ute d.  T he ha n dli n g of partial/ missi n g dates f or A Es a n d 
pri or/c o nc o mita nt m e dicat i ons is detailed i n Sect i on  4. 1. 1 .  D urati o n of A Es a n d 
pri or/c o nc o mita nt m e dicat i ons will n ot be calc ulate d usi n g i m p ute d dates a n d will i nstea d be 
set t o missi n g.
3. 3. 1
A d verse e ve nts
A n a d verse e ve nt is t he de vel o p me nt of a n y u nt o war d me dical occ urre nce i n a pat ient  or 
cli nical st u d y patie nt a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 0 of 5 2
ca usal relat i ons hi p wi t h t his treat me nt.  A n A E ca n t heref o re be a n y u nfa v o ura ble a n d 
u ni nte n de d si g n (e g, a n a b n or mal la b orat or y  fi n di n g), s y m pt o m (f or e xa m ple na usea, c hest 
pai n), or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot 
c o nsi dere d relate d t o t he me dici nal pr o d uct.
T he t er m A E is use d t o i ncl u de b ot h seri o us a n d n o n-serio us A Es a n d ca n i ncl u de a 
deteri or ati o n of  a pre-e xist i n g me d ical occ urre nce.  A n A E ma y occ ur at a n y ti me, i ncl u di n g 
r u n-i n peri o d, e ve n if n o st u d y treat me nt has bee n a d mi nistere d.  All A Es a n d S A Es wi ll be 
rec or de d fr om t he ti me o f sig ni n g t he I C F.
D urati o n of  a n A E will be calc ulate d as f oll ows:
          (    ) =         −         + 1
A d verse e ve nt data will be cate g orise d acc or di n g t o t heir o nset date i nt o t he f o ll owi n g st u d y  
p eri o ds:

A Es i n t he r u n -i n peri o d are defi ne d as t h ose wit h o nset o n or after date of si g ni n g t he 
I C F a n d pri or t o ra n d o misati on date.

A Es i n t he st u d y  p erio d are defi ne d as t h ose wit h o nset o n or after date of ra n d o misat i on 
a n d o n or p rior t o t he Vi sit 8 b/ E O T visit.
If a n A E has a missi n g o nset date it will be c o nsi dere d a st u d y p erio d e ve nt u nless t he st o p 
date of t he A E i n dicates ot her wise.  Si milarl y, if a n A E has a partial o nset date it will be 
c o nsi dere d a st u d y p erio d A E u nless t h e partial o nset date or t he st o p date i n dicates ot her wise.
A d verse e ve nts t hat ha ve missi n g ca usalit y (after data q uer yi n g) will be ass u me d t o be relate d 
t o st u d y dr u g.
3. 4
E x pl or at or y v ari a bles
3. 4. 1
Bl o o d e osi n o p hils c o u nt
Bl o o d e osi n o p hil sa m ples will be c ollecte d f r o m all patie nts at all st u d y visits i n dicate d i n t he 
S o A (refer t o C S P f or details).  If t here is a n E O T visit, a bl o o d sa m ple f or e osi n o p hils will be 
ta ke n.  A nal ysis will be perf or me d at a l ocal la b orat or y.
T he res ults will be s u m marise d a n d re p orte d descri pti vel y wit hi n t he C S R after all pat ient s 
ha ve c o m p lete d Visit 8 b ( Wee k 4 8).  Fi nal res ults will be prese nte d f or all patient s wit h a n 
E O T vi sit as well.
3. 4. 2
T he
 
desi g ne d t o ca pt ure pati e nt beliefs a b o ut t he percei ve d i m p orta nce of 
 
C CI
C CI
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 1 of 5 2
 
.  Patie nts will be as ke d t o c o m plete t he q uesti o n naire at st u d y visits 
i n dicate d i n t he S o A (refer t o C S P f or details).  T he patie nt res p o nse t o eac h state me nt is 
ca pt ured usi n g a 3 -p oi nt scale f or Part 1 of t he q uesti o n naire a n d 5 -p oi nt Li kert Scal e 
(str o n gl y disa gree t o str o n gl y a gree) f or Part 2 of t he q uesti on naire.
3. 4. 3
He alt h ec o n o mics
After t he e xacer bat i on assess me nt at eac h visit, per S o A i n C S P, t he I n vest i gat or or a ut hori se d 
d el e gate will assess w het her t he patie nt has ha d a n y 
 
  If yes, 
 
 
 
T he n u m ber of da ys/t i mes t he f oll owi n g res o urces were utilize d will be prese nte d f or eac h 
pati e nt:

.
3. 5
Assess me nt of st u d y p o p ul ati o n
I n t his st u d y, “e nr olle d” patient s are defi ne d as t h ose w h o pr o vi de i nf or me d c o nse nt b y 
sig ni n g t he I C F at Visit 1.  “ Ra n d o mise d” patie nts are defi ne d as t h ose w h o u n der g o 
ra n d omisat i on a n d recei ve a ra n d o misat i on n u m ber at Visit 2 b.
3. 5. 1
De m o gr a p hics
D e m o gra p hic c haracteri stics a n d baseli ne disease c haracteristics will be assesse d.
C CI
C CI
C CI
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 2 of 5 2
3. 5. 2
Me dic al a n d s ur gic al hist or y
Me dical a n d s ur gical hist or y  will be c o de d usi n g t he latest versi o n of Me dical Dicti onar y  for 
Re g ulat or y  Act i vities ( Me d D R A).
3. 5. 3
Pri or a n d c o nc o mit a nt me dic ati o ns
All me dicati o ns will be classifie d i nt o A nat o mical T hera pe ut ic C he mical ( A T C) dr u g classes 
usi n g t he latest versio n  of t he W orld Heal t h Or ga nisatio n ( W H O) Dr u g Di ct i onar y 
( W H O D D).
A n y me dicat i ons or vacci nes recei ve d b y t he patie nt wit h a n e n d date prior t o 3 m o nt hs bef ore 
i nf or me d c o nse nt will be c o nsi dere d as pri or me dicati o ns.
A n y me dicat i on or vacci nes recei ve d b y t he patie nt i n t he 3 m o nt hs pri or t o t he date of 
i nf or me d c o nse nt a n d me dicat i ons recei ve d at t he ti me of e nr ol me nt or d uri n g t he st u d y will 
be c o nsi dere d as c o nc o mit a nt me dicat i on.
3. 5. 4
E x p os ure t o F ase nr a ®
T he d urati o n of  e x p os ure t o Fase nra® is defi ne d as t he n u m ber of da ys bet wee n first d ose of 
Fase nra ® f oll owi n g ra n d o misat i on a n d t he e n d dates of Fase nra ® pl us t he d osi n g fre q ue nc y 
ti me:
                         (    )
= (            + 5 6     )
−                                + 1
T he t otal n u m ber of i nject i ons will be c o u nte d per patie nt.  F urt her m ore, t he n u m ber of 
pati e nts wit h a n i njecti on will be assesse d i n 8 -wee kl y  cate g ories (ie, 8 wee ks, 1 6 wee ks, …, 
4 0 wee ks).
4
A N A L Y SI S M E T H O D S
4. 1
Ge ner al pri nci ples
C o nti n u o us data will be s u m marise d i n ter ms of t he n u m ber of n o n -missi n g o bser vat i ons ( n), 
mea n, sta n dar d de viat i on ( S D), 2 -side d 9 5 % c o nfi de nce i nter val ( CI) of t h e mea n (e xce pt 
safety data), m e dia n, mi ni m u m, a n d ma xi m u m, u nless state d ot her wise.
T he mi ni m u m a n d ma xi m u m will be re p orte d t o t he sa me n u m ber of deci mal places, as t he 
ra w data rec or de d i n t he data base.  T he mea n a n d me dia n will be re p orte d t o o ne m ore 
d eci mal place, a n d S D will be re p orte d t o t w o m ore deci mal places, t ha n t he ra w data 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 3 of 5 2
rec or de d i n t he data base.  A n y CIs will be prese nte d t o o ne m ore deci mal place t ha n t he ra w 
data.
A ma xi m u m of f o ur deci mal places will be use d f o r all s u m mar y st atistics.
C o nfi de nce i nter vals will be prese nte d t o o ne m ore deci mal place t ha n t he p oi nt esti mate.
Cate g orical data will be s u m marise d i n ter ms of t he n u m ber of patie nts pr o vi di n g data at t he 
r ele va nt ti me p o i nt ( n), wit h fre q ue nc y c o u nts a n d perce nta ges.
Perce nta ge s will be prese nte d t o o ne deci mal place.  Perce nta ges will n ot be prese nte d f or zer o 
c o u nts.  Perce nta ges will be calc ulate d usi n g n as t he de n o mi nat or, u nless state d ot her wise.
S A S ® versi o n 9. 3, or hi g her, will be use d f or t he data a nal ysis.
St u d y  D a y 1 is defi ne d as t he date of ra n d omisati o n.
F or vi sits ( or e ve nts) t hat occ ur o n or after ra n d o misati o n , st u d y d a y:
       =        [     ] −               + 1
F or vi sits ( or e ve nts) t hat occ ur pri or t o ra n d o misati on , st u d y da y: 
       =        [     ] −              T here i s n o St u d y D a y 0.
N o m ul tiplici t y a djust m e nts are pla n ne d f or t his st u d y.
4. 1. 1
Missi n g d at a
Pri or a n d c o nc o mita nt m e dicat i on par tial dates will be i m p ute d as o utli ne d i n A p pe n di x  8. 1. 1 .
A d verse e ve nts wit h partial dates missi n g t he da y , or b ot h da y a n d mo n t h of t h e year will 
a d here t o t he c o n ve nt i ons o utli ne d i n t he A p pe n di x  8. 1. 1.
F or details o f de ali n g wit h missi n g A C Q -5 a n d A Q L Q( S) + 1 2 sc ores, refer t o Secti o n 3. 2. 1
a n d Sect i on 3. 2. 3 , res pecti vel y.
P arti al d at e of birt h a n d date of first ast h ma dia g n osis will be i m p ute d, as descri be d i n 
A p pe n di x  8. 1. 2 .


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 4 of 5 2
4. 1. 2
Visit wi n d o ws
All visi t-base d s u m maries will use a nal ysis visits.  All p ost-ra n d o misati o n sc he d ule d a n d 
u nsc he d ule d visits (e xcl u di n g E O T), will be ma p pe d t o a n a p pr o priate a nal ysis visit as 
f oll ows:
T a ble 3 A n al ysis Visit M a p pi n g
C R F visit
T ar get d a y
Act u al ass ess me nt d a y
A n al ysis visit
Vi sit 1 (scree ni n g)
-D 5 6/ -D 2 8
-D 5 6/ -D 2 8 t o -D 1
Scree ni n g
Vi sit 2 b (ra n d o misati on)
D 1
D 1
Ra n d o misat i on
Vi sit 3
D 5 7
D 2 t o D 8 5
Wee k 8
Vi sit 4
D 1 1 3
D 8 6 t o D 1 4 1
Wee k 1 6
Vi sit 5
D 1 6 9
D 1 4 2 t o D 1 9 7
Wee k 2 4
Vi sit 6
D 2 2 5
D 1 9 8 t o D 2 5 3
Wee k 3 2
Vi sit 7
D 2 8 1
D 2 5 4 t o D 3 0 9
Wee k 4 0
Vi sit 8 b
D 3 3 7
D 3 1 0 t o D 3 6 5
Wee k 4 8
If m ult i ple rea di n gs are rec or de d wit hi n a si n gle visit wi n d o w, t he f oll owi n g r ul es will be 
f oll owe d.

If t here are t w o or m ore o bser vati ons wit hi n t he sa me visit wi n d o w, t he n t he n o n-missi n g 
o ne cl osest t o t he sc he d ule d visit will be use d i n t he a nal ysis. If n ot p ossi ble, t he earliest 
n o n- missi n g rec or d c ollecte d wit hi n t he visit wi n d o w will be use d i n a nal ysis.  

If t w o o bser vati ons are e q ui dista nt fr o m t he sc he d ule d visit, t he n t he n o n -missi n g 
o bser vat i on wi t h t he earlier c ollecti on date will be use d i n t he a nal ysis. 

If t w o o bser vati ons are c ollecte d o n t he sa me da y, t he n t he n o n -missi n g o ne wit h t he 
earlier c ollect i on t i me will be i ncl u de d i n t he a nal ysis. 
T he f o ll owi n g r u les will be f oll owe d f or q uesti o n n ai re relate d data:

If m ult i ple rec or ds o n t he sa me da y are c ollecte d b ut o nl y o ne wit h ti me rec or de d, t he n 
t he n o n-missi n g rec or d wit h t i me rec or de d will be use d i n t he a nal ysis.

If m ult i ple rec or ds are c ollecte d o n t he same da y , all wit h ti me rec or de d, t he n t he earliest 
of  t he n o n-missi n g rec or ds will be use d i n t he a nal ysis.  
A listi n g will be prese nte d f or all rec or ds, wit h fla gs i de ntif yi n g t he s o urce of t he rec or d a n d 
w het her t he sc ore was use d i n a nal ysis ta bles.
If a visit wi n d o w d oes n ot c o ntai n a n y o bser vati ons, t he n t he data will re mai n missi n g. 


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 5 of 5 2
4. 2
A n al ysis met h o ds
All efficac y a nal yses will be perf or me d usi n g t he F A S. Safet y  a nal yses will be perf or me d 
usi n g t he S A F.
T he e n d o f t he re d uctio n  p erio d i s c o nsidere d t o be Visit 6 ( Wee k 3 2).  T he e n d of t he 
mai nte na nce peri o d is c o nsi dere d t o be Visit 8 b ( Wee k 4 8) or E O T.
4. 2. 1
Assess me nt of st u d y p o p ul ati o n
P atie nt dis p ositi o n
P ati e nt dis p ositio n  will be s u m marise d usi n g t he A P S.  T he n u m ber a n d perce nta ge of patie nts 
will be prese nte d b y  t h e fol l owi n g cate g ori es: e nr olle d, ra n d o mise d, c o m plete d re d ucti o n 
p hase (ie, atte n de d Vi sit 6), c o mplete d t he st u d y  (ie, atte n de d Visit 8 b) a n d disc o nti n ue d fr om 
t he st u d y ( wit h reas o ns f or disc o nti n uati on).  A s u m mar y  of p atie nts w h o disc o ntin ue d 
treat me nt ( wit h reas o n f or disc o nti n uatio n ) will als o be pr o vide d.
De m o gr a p hic c h ar acteristics
D e m o gra p hic a n d baseli ne pat ient  c haracteristics will be prese nte d b y descri pti ve statistics b y 
treat me nt ar m, as well as o verall f or t he F A S.
A ge will be deri ve d fr o m t he date of i nf or me d c o nse nt mi n us date of birt h, r o u n de d d o w n t o 
t he nearest i nte ger.  F or patie nts i n c o u ntries w here date of birt h is n ot rec or de d, t he a ge as 
rec or de d i n t he e C R F will be use d.  Refer t o A p pe n di x 8. 1. 2 , for r ul es o n i m p utatio n  of p artial 
dates f or date of birt h a n d date of first ast h ma dia g n osis.
T he f o ll owi n g sta n dar d descri pt i ve statistics will be prese nte d f or data c ollecte d at Scree ni n g 
f or p atie nts i n t he F A S (as per l ocal re g ulati o ns):

A ge ( years) (c o nti n u o us)

A ge gr o u p ( y ears):

≥1 8 - < 5 0

≥5 0 - < 6 5

≥6 5.

Se x:

Male

Fe male.

Race:

W hite

Bl ac k or Africa n A merica n


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 6 of 5 2

Nati ve Ha waiia n or Ot her Pacific Isla n der

Asia n

A merica n I n dia n or Alas ka Nati ve

Ot her.

Et h nic gr o u p:

Hi s pa nic or Lati n o:
o
Yes
o
N o.

C o u ntr y :

Fra nce

Ital y

G er m a n y

U nite d Ki n g d o m.

S m o ki n g stat us:

C urre nt

F or mer

Ne ver.
A b y -pat ient  li ne-listi n g of d e m o gra p hic a n d baseli ne c haracterist ics will be prese nte d.
B aseli ne c h ar acteristics
T he f o ll owi n g pati e nt c haracteristics will be prese nte d f or data c ollecte d at baseli ne visit 
( Visit 2 b; Wee k 0 ).
F o ll owi n g e P R Os will be s u m marise d at baseli ne:

A C Q -5 sc ore

A Q L Q( S) + 1 2 sc ore.
F o ll owi n g di sease c haracteristics will be s u m marise d at baseli ne:

A ge at first ast h ma dia g n osis, calc ulate d as:
            ℎ          −         ℎ
3 6 5 .2 5

N u m ber of pac k -years ( P Y)

Ast h ma d urati o n  ( years), calc ulate d as:
(                 −             ℎ          ) + 1
3 6 5 .2 5


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 7 of 5 2

N u m ber of e xacer bat i ons i n t he 1 2 m o nt h p eri o d pri or t o fi rst c o m mercial Fase nra

N u m ber of e xacer bat i ons re q uiri n g s yste mic c ortic oster oi d treat me nt use i n t he 1 2 m o nt h 
p eri o d pri or t o fi rst c o m mercial Fase nra

N u m ber of e xacer bat i ons re q uiri n g e mer ge nc y r o o m treat me nt i n t he 1 2 m o nt h peri o d 
pri or t o fi rst c o m mercial Fase nra

N u m ber of e xacer bat i ons re q uiri n g h os pitalisat i on i n t he 1 2 m o nt h peri o d pri or t o fi rst 
c o m mercial Fase nra

N u m ber of e xacer bat i ons fr o m st artin g Fase nra ® treat me nt t o Visit 1

N u m ber of e xacer bat i ons re q uiri n g s yste mic c ortic oster oi d treat me nt use fr o m starti n g 
first c o m mercial Fase nra ® tr e at me nt t o Visit 1

N u m ber of e xacer bat i ons re q uiri n g e mer ge nc y r o o m treat me nt fr o m starti n g first 
co m mercial Fase nra ® tr e at me nt t o Visit 1

N u m ber of e xacer bat i ons re q uiri n g h os pitalisat i on fro m  starti n g first c o m mercial 
Fase nra ® treat me nt t o Visit 1

M ost rece nt e xacer bat i on t y p e:

Re q ui re d s yste mic c ortic oster oids treat m e nt

Ast h ma -r elate d h os pitalisati on

Re q ui re d s yste mic c ortic oster oids treat m e nt a n d ast h ma- relate d h os pitalisati on

Ti me si nce last e xacer bati o n ( da ys), calc ulate d as:
                 −                          
Pre -br o nc h o dilat or P ul m o nar y  Fu n ct i on Tests:

F E V 1 ( L)

Pr e di cte d F E V 1

F orce d vital ca pacit y ( F V C) ( L)

Pr e di cte d F V C.

Fe N O

Bl o o d e osi n o p hil c o u nt at baseli ne.
Me dic al a n d s ur gic al hist or y
Me dical hist or y  will be s u m marise d b y S O C a n d P T f or t he F A S. S ur gical hist or y will be 
listed.
Pri or a n d c o nc o mit a nt me dic ati o ns
T he f o ll owi n g s u m maries will be pr o d uce d:

S u m mar y  of pri or me dicat i ons b y  AT C le vel  3 c o de a n d P T, o verall for t he F A S.

S u m mar y  of prior ast h m a me dicat i ons b y  AT C le vel  3 c o de a n d P T, o verall f or t he F A S.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 8 of 5 2

S u m mar y  of c o nc o mita nt me dicat i on b y A T C le vel 3 c o de a n d P T, o verall a n d b y 
treat me nt for t he F A S.
M ul tiple rec or ds f or a pati e nt i n t he sa me A T C le vel 3 cate g or y a n d P T will be c o u nte d o nl y 
o n ce.
4. 2. 2
Pri m ar y Effic ac y A n al ysis
T he pr o p orti o n  of p atie nts i n t he re d uctio n ar m w h o re d uce t heir S y m bic ort® ma i nte na nce 
treat me nt t o eit her me di u m-d ose S M A R T, l o w -d o se S M A R T, or S y m bic ort ® as 
a nt i-i nfla m mat or y relie ver o nl y at Wee k 3 2 will be assesse d usi n g a ta ble c o ntai ni n g t he 
n u m ber of patie nts a n d pr o p orti o n of pat ient s at eac h ste p d o w n t o get her wit h e xact 2 -si de d 
9 5 % CI ( Cl o p per -Pears o n).
T he pri mar y  a nal ysis will e val uate t he data f or patie nts wit h n o n-missi n g Wee k 3 2 assess me nt 
val ues.
T he n u m ber a n d perce nta ge of patie nts rec or di n g eac h prescri be d S y m bic ort ® d ose l e vel will 
als o be s u m marise d b y visit.
T he pr o p orti o n  a n d perce nta ge of patient s w h o mai ntai n t he sa me S y m bic ort ® dail y d ose at 
t he e n d of t he mai nte na nce peri o d as t he y ac hie ve d at t he e n d of t he re d ucti o n peri o d will als o 
be i ncl u de d.
Fi nal a nal ysis will e val u ate t he data f or patie nts wit h n o n-missi n g Wee k 4 8 assess me nt val ues 
o n ce all ra n d o mise d patie nts ha ve c o m p lete d t heir treat me nt.
Se nsiti vit y A n al ysis
A se nsit i vity a nal ysis t o assess t he effect of missi n g data/ dr o p -o u t o n t he pri mar y o ut c o me 
meas ure will be perf or me d b y  incl u di n g all pat ient s wit h a missi n g Wee k 3 2 assess me nt, 
irres pecti ve of w het her a patie nt disc o nti n ue d treat me nt, as a “ N o n-res p o n der” (ie, u na ble t o 
re d uce t heir S y m bic ort® ma i nte na nce treat me nt t o eit her me di u m-d ose S M A R T, l o w -d ose 
S M A R T, or S y m bic ort ® as a nt i-i nfla m mat or y relie ver o nl y).
4. 2. 3
Sec o n d ar y Effic ac y A n al yses
A C Q - 5
C ha n ge fr o m baseli ne A C Q -5 will  be deri ve d wee kl y u p t o e n d of t he re d ucti o n peri o d a n d u p 
t o t he e n d of t he mai nte na nce peri o d as p ost -baseli ne sc ore mi n us baseli ne A C Q -5 sc ore ( Vi sit 
2 b; Wee k 0) f or t he re d ucti o n peri o d a nal ysis , a n d p ost -baseli ne sc ore ( Wee k 4 0, Wee k 
4 8/ E O T) mi n us mai nte na nce peri o d baseli ne ( Visit 6; Wee k 3 2) sc ore f or mai nte na nce peri o d 
a nal ysis.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 9 of 5 2
T he c ha n ge fr o m baseli ne i n mea n A C Q -5 sc ore o ver t he pre vi o us 8 wee ks will als o be 
s u m marise d f or Wee k 8, 1 6, 2 4, 3 2, 4 0 a n d 4 8. Baseli ne f or t he mea n A C Q-5 sc ore o ver t he 
pre vi o us 8 wee ks will be defi ne d as t he last n o n -missi n g A C Q -5 sc ore pri or t o ra n d o misat i on.
Missi n g A C Q -5 sc ore will n ot be i m p ute d. C ha n ge fr o m baseli ne i n mea n A C Q -5 o ver t he 
pre vi o us 8 wee ks will be e val uate d usi n g a mi xe d m o del re peate d meas ures ( M M R M) 
c o mpari n g t he re d ucti o n  ar m wit h t he refere nce ar m, with treat me nt ar m, visit, 
visit × treat me nt a n d baseli ne A C Q -5 sc ore as c o vari ates.  De n o mi nat or de grees of free d o m 
will be esti mate d usi n g t he Ke n war d -R o ger a p pr o xi mat i on.  A n u nstr uct ure d c orrelat i on 
patter n will be use d t o esti mate t he varia nce -c o varia nce of t he wit hi n-pat ient  re peate d 
meas ures.  I n t he case t hat t he m o del d oes n ot c o n ver ge usi n g a n u nstr uct ure d c o varia nce 
m atri x, t he heter o ge ne o us T oe plitz c o varia nce str uct ure will be e val uate d, f oll o we d b y t he 
heter o ge ne o us a ut ore gressi ve of first or der, heter o ge ne o us c o m p o u n d s y m metr y , a n d 
h o m o ge ne o us c o m p o u n d s y m metr y  c o varia nce str uct ures i n t he case of f urt her 
n o n- c o n ver ge nce.  T he restricte d ma xi m u m li keli h o o d met h o d will be use d. T he least-s q uare 
mea n a n d mea n differe nce i n A C Q -5 sc ore c ha n ge fr o m baseli ne bet wee n t he t w o treat me nt 
ar ms, sta n dar d err ors a n d t he 9 5 % CI at  eac h 8-wee kl y ti me p o i nt will be prese nte d.
T he pr o p orti o n  of p atie nts ac hie vi n g n o deteri orati o n i n A C Q -5 ( n o deteri orati o n  mea ns 
c ha n ge fr o m baseli ne < 0. 5) at t he e n d of t he re d ucti o n peri o d will be prese nte d f or eac h 
treat me nt ar m.  S u m mar y st atistics for A C Q -5 a n d c ha n ge fr o m baseli ne will be prese nte d b y 
visit.
Deteri or ati o n  is defi ne d as a n i ncrease i n A C Q-5 of ≥0. 5 u nits c o m pare d t o baseli ne, 
res pecti ve t o t he baseli ne of i nterest.
A s u m mar y  ta ble of w orst A C Q-5, defi ne d as t he ma xi m u m A C Q -5 sc ore wi t hin f our wee ks 
pri or t o t he sc he d ule d visit (i ncl u di n g t he visit) will be prese nte d f or eac h sc he d ule d visit 
t hr o u g h o ut t he re d ucti o n peri o d.
If t h e mo d el  ass u m pti ons of n or malit y are vi o late d f or t he efficac y o utc o me meas ure, 
a p pr o priate alter nat i ve n o n- par a metric a nal yses met h o ds will be c o nsi dere d.
I C S E x p os ure
I C S e x p os ure will be re p orte d usi n g t he f oll owi n g varia bles a n d will be s u m marise d b y  
treat me nt ar m for t he F A S, se paratel y f or t he re d ucti o n, mai nte na nce a n d st u d y  p erio ds:

C u m ulat i ve dail y I C S d ose ( mai nte na nce + relie ver)

Mea n t otal dail y  I C S d ose ( mai nte na nce + relie ver)

Sta n dar di se d A U C f or t he re d ucti o n, mai nte na nce a n d st u d y p erio ds.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 0 of 5 2
T he c ha n ge fr o m baseli ne i n t he mea n t otal dail y I C S d ose ( mai nte na nce + relie ver) d uri n g t he 
pre vi o us ei g ht wee ks will be e val uate d usi n g a n M M R M a p pr oac h i ncl u di n g mea n t otal dail y 
I C S d ose at baseli ne, visit, treat me nt ar m, a n d visit × treat me nt as c o variates.  T he Least 
S q uare mea n c ha n ge a n d c orres p o n di n g 9 5 % CIs will be prese nte d.
If t h e mo d el  ass u m pti ons o f n o r malit y are viol ate d f or t he efficac y o ut c o me meas ure, 
a p pr o priate alter nat i ve n o n- para m etric a nal yses met h o ds will be c o nsi dere d.
S u m mar y  statistics f or t otal dail y I C S d ose a n d c ha n ge fr om baseli ne will be prese nte d b y 
visit.
T he n u m ber a n d pr o p orti o n of pat ient s s ustai ni n g t he sa me S y m bic ort ® dail y d ose at t he e n d 
of  t h e mai nte na nce peri o d ( Visit 8 b; Wee k 4 8) as t he d ose t he y  ac hie ve d at t he e n d of t he 
re d uctio n  p erio d ( Visi t 6; Wee k 3 2) will be s u m marise d.
All I C S d ose a nal yses will be prese nte d i n micr o gra ms ( mc g). S y m bic ort 2 0 0/ 6 d oses will be 
c o n verte d t o 2 0 0 mc g a n d S y m bic ort 4 0 0/ 1 2 d oses will be c o n verte d t o 4 0 0 mc g f or t he 
p ur p ose of I C S d ose calc ulat i ons. 
A Q L Q( S) + 1 2
C ha n ge fr o m baseli ne A Q L Q( S) + 1 2 will be deri ve d u p t o Wee k 4 8 as p ost -baseli n e sc ore 
mi n us baseli ne A Q L Q( S) + 1 2 sc ore ( Visit 2 b; Wee k 0).  T he mea n c ha n ge fr o m baseli ne 
A Q L Q( S) + 1 2 at t he e n d of t he re d ucti o n peri o d is defi ne d as at Wee k 3 2.
T he m ea n c ha n ge fr o m baseli ne A Q L Q( S) + 1 2 will be a nal yse d usi n g a n M M R M a p pr oac h 
i ncl u di n g baseli ne A Q L Q( S) + 1 2 sc ore, visit a n d treat me nt ar m, a n d visit × treat me nt as 
c o variates.  T he esti mate d Least S q uare mea n c ha n ge fr o m baseli ne A Q L Q( S) + 1 2 d uri n g t he 
re d uctio n  a n d t he st u d y p erio ds will  be prese nte d b y tr e at me nt a n d visit t o get her wit h 2-si ded 
9 5 % CIs, res pecti vel y.
T he pr o p orti o n  of p atie nts ac hie vi n g n o deteri orati o n i n A Q L Q( S) + 1 2 at t he e n d of t he 
re d uctio n  p erio d will be prese nte d f or eac h treat me nt ar m.  S u m mar y statist ics for 
A Q L Q( S) + 1 2 a n d c ha n ge fr o m baseli ne will be prese nte d b y  visit.
Deteri or ati o n  is defi ne d as a decrease i n A Q L Q( S) + 1 2 of ≥0. 5 u nits c o m pare d t o baseli ne.
If t h e mo d el  ass u m pti ons of n or malit y are vi o late d f or t he efficac y o utc o me meas ure, 
a p pr o priate alter nat i ve n o n- para m etric a nal yses met h o ds ma y be c o nsi dere d.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 1 of 5 2
T he c ha n ge i n A Q L Q( S) + 1 2 fr o m t he mai nte na nce peri o d baseli ne t o t he e n d of mai nte na nce 
p eri o d/ E O T is defi ne d as Visit 8 b ( Wee k 4 8)/ E O T sc ore mi n us mai nte na nce peri o d baseli ne 
( Visit 6; Wee k 3 2) sc ore a n d will f oll ow cate g ori s atio n  o utli ne d i n Secti on 3. 2. 3 .
C h a n ge fr o m b aseli ne i n F E V 1
C ha n ge fr o m baseli ne ( Visit 2 b; Wee k 0) pre -br o nc h o dilat or F E V 1 will be assesse d at Wee ks 
8, 1 6, 2 4, 3 2, 4 0, a n d 4 8.  T he me a n c ha n ge fr o m baseli ne pre -br o nc h o dilat or F E V 1 at  t he e n d 
of  t he re d uctio n  p erio d is defi ne d as at Wee k 3 2.  S u m mar y  statistics f or F E V1 a n d c ha n ge 
fro m  baseli ne will be prese nte d b y visit.
T he m ea n c ha n ge fr o m baseli ne pre -br o nc h o dilat or F E V 1 will be a nal yse d usi n g a n M M R M 
a p pr oac h i ncl u di n g baseli ne F E V 1 visit, treat me nt ar m, a n d visit × treat me nt as c o variates.  
T he est i mate d Least S q uare mea n c ha n ge fr o m baseli ne pre-br o nc h o dilat or F E V 1 d uri n g t he 
re d uctio n  a n d t he st u d y p erio ds will  be prese nte d b y tr e at me nt a n d visit t o get her wit h 2-si de d 
9 5 % CIs, res pecti vel y.
If t h e mo d el  ass u m pti ons of n or malit y are vi o late d f or t he efficac y o utc o me meas ure, 
a p pr o priate alter nat i ve n o n- para m etric a nal yses met h o ds ma y be c o nsi dere d.
C ha n ge fr o m mai nte na nce peri o d baseli ne t o t he e n d of t he mai nte na nce peri o d f or 
pre -br o nc h o dilat or F E V 1 will be calc ulate d as Visit  8 b ( Wee k 4 8)/ E O T val ue mi n us 
mai nte na nce peri o d baseli ne ( Visit 6; Wee k 3 2) val ue.
Ast h m a E x acer b ati o ns
T he A E R fr o m Visi t 2 b ( Wee k 0) u p t o Visit 8 b ( Week 4 8) of t he re d ucti o n ar m will be 
c o mpare d t o t he A E R of t he refere nce ar m usi n g a ne gat i ve bi n o mia l m o del.  T he res p o nse 
varia ble i n t he m o del will be t he n u m ber of ast h ma e xacer bat i ons e x perie nce d b y t he pat ient  
o v er t he st u d y p erio d.  T he m o d el  will i ncl u de t he ra n d o mise d treat me nt ar m as a c o variate, 
wi t h t h e lo g ari t h m of t he patient ’s c orres p o n di n g f oll o w- u p use d as a n offset varia ble i n t he 
m o d el .
T he est i mate d treat me nt effect (ie, t he rate rati o of re d ucti o n ar m as c om pare d t o t he refere nce 
ar m) wit h c orres p o n di n g 9 5 % CI will be prese nte d, al o n g wit h m o del esti mate d rates f or eac h 
treat me nt ar m.
T he n u m ber of e xacer bat i ons will be s u m marise d f or t he re d ucti o n, mai nte na nce a n d st u d y  
p eri o ds si milarl y t o t he e xacer bat i on c o u nt deri vat i o n, fr o m Visit 2b ( Wee k 0) t o date of Visit 
6 ( Wee k 3 2), fr o m Visit 6 ( Wee k 3 2) t o Visit 8 b ( Wee k 4 8), a n d fr o m Vi sit 2 t o Visit 8 b, 
res pecti vel y.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 2 of 5 2
S u m mar y  statistics f or t he A E R will be prese nte d f or t he st u d y, re d uctio n  a n d mai nte na nce 
p eri o ds se paratel y.  T he c u m ulat i ve n u m ber of e xacer bat i ons o ver ti me will be pl otte d 
sta n dar dise d b y t he n u m ber of pat ient s i n t he ra n d o mise d treat me nt ar ms.
T he pr o p orti o n  of p atie nts wit h ≥1 ast h ma e xacer bati o n d uri n g t he 4 8 -wee k st u d y  p erio d will 
als o be deri ve d.
Cli nic al Re missi o n
Desc ript i ve s u m maries of t he n u m ber a n d pr o p orti o n of patient s meet i n g eac h c o m p osite 
e n d p o i nt crit eria defi ni n g cli nical re missi o n at Wee k 3 2 ( Visit 6) or at Wee k 4 8 ( Vi sit 8 b) 
(i.e., n o e xacer bat i ons bet wee n ra n d omisat i on a n d r ele va nt ti me p o i nts, less t ha n 10 % 
deteri or ati o n  in F E V 1 at r ele va nt ti me p o i nt, a n d A C Q -5 ≤ 0. 7 5 or A C Q -5 < 1. 5 at  rele va nt 
time p o i nts) will be prese nte d f or b ot h treat me nt ar ms. 
A re missi o n sc ore cal c ulate d f or eac h patie nt still i n t he st u d y at Wee k 3 2 or Wee k 4 8 a n d 
base d o n t he n u m ber of re missi o n c o m p o ne nts ac hie ve d will descri be t he n u m ber a n d 
pr o p orti o n  of patient s ac hie vi n g m ulti ple c om bi nati o ns of t he e n d p o i nts: 

0, 1, 2 a n d 3 re missi o n e n d p o i nts ac hie ve d (A C Q -5 < 1. 5, < 1 0 % F E V 1 deteri orati o n 
a n d zer o e xacer bat i ons; A C Q -5 ≤ 0. 7 5, < 1 0 % F E V 1 deteri orati o n  a n d zer o 
e xacer bati o ns)

O nl y  e xacer bat i on a n d A C Q -5 e n d p o i nts ac hie ve d, i. e., 0, 1 a n d 2 re missi o n e n d p o i nts 
ac hie ve d (A C Q -5 < 1. 5 a n d zer o e xacer bat i ons; A C Q -5 ≤ 0. 7 5 a n d zer o e xacer bat i ons)
P ati e nts will be i ncl u de d f or a n y in di vi d ual  c o mp o ne nt f or w hic h t he y  ha ve data. Patie nts will 
be e xcl u de d fr o m t he re missi o n s u m mar y  ( 0, 1, 2, 3) if t he y are missi n g o ne of t he rele va nt 
c o mp o ne nts.
4. 2. 4
E x pl or at or y A n al yses
C h a n ge fr o m b aseli ne Fe N O
T he c ha n ge fr o m baseli ne Fe N O ( parts per billi o n [ p p b]) will be assesse d descri pti vel y a n d 
usi n g a M M R M a p pr oac h i ncl u di n g, baseli ne Fe N O meas ure me nt, treat me nt ar m, visit, a n d 
visit × treat me nt as c o variates.  T he esti mate d Least S q uare mea n c ha n ge fr o m baseli ne Fe N O 
d uri n g t he re d ucti o n a n d t he st u d y  p erio ds will be prese nte d b y treat me nt a n d visit t o get her 
wi t h 2-side d 9 5 % CIs, res pecti vel y.
A s hift ta ble will be pr o d uce d f or Fe N O cate g ories t o dis pla y < 2 5, ≥2 5 - < 5 0, ≥5 0, a n d 
missi n g val ues.  T he s hift ta bles will prese nt baseli ne a n d val ue at t he e n d of t he re d ucti o n 
p eri o d, as well as e n d of st u d y  p erio d, as a p plica ble, a n d will i ncl u de pat ient s wit h b ot h 
baseli ne a n d p ost -baseli ne data t hr o u g h o ut t he st u d y peri o d.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 3 of 5 2
S hift pl ots s h o wi n g eac h i n di vi d ual pat ient ’s lab o rat or y val ue at baseli ne a n d at t he e n d of 
re d uctio n  p erio d a n d at t he e n d of t he st u d y  p erio d will  be pr o d uce d f or c o nti n u o us Fe N O 
data.
C h a n ge fr o m b aseli ne i n bl o o d e osi n o p hil c o u nt
T he c ha n ge fr o m baseli ne bl o o d e osi n o p hil c o u nt will be assesse d descri pt i vel y a n d usi n g a 
M M R M a p pr oac h i ncl u di n g baseli ne bl o o d e osi n o p hil c o u nt, treat me nt ar m, visit, a n d 
treat me nt × visit as c o variates.  T he esti mate d Least S q uare mea n c ha n ge fr o m baseli ne 
e osi n o p hil c o u nt d uri n g t he re d ucti o n a n d t he st u d y peri o ds will be prese nte d b y treat me nt a n d 
visit t o get her wit h 2 -side d 9 5 % CIs.  T hese a nal yses will be perf or me d usi n g e osi n o p hil 
val ues prese nte d i n c o n ve nt i onal u nit s.
 
 
l.
4. 2. 5
E x p os ure t o F ase nr a
E x p os ure will be s u m marise d b y treat me nt ar m f or t he F A S.
S u m mar y  statistics will be pr o vi de d f or t he c u m ulati ve d urati o n of e x p os ure. T he n u m ber a n d 
perce nta ge of patie nts treate d ≥8 wee ks, a n d u p t o 4 8 wee ks i n 8 -wee kl y i nter vals will be 
pr o vi de d. 
T he n u m ber a n d perce nta ge of patie nts wit h i nject i o ns will be prese nte d b y t otal n u m ber of 
i njecti ons (ie, 1, 2, …, 6) a n d i n 8- wee kl y  int er vals (ie, 8 wee ks, 1 6 wee ks, …, 4 0 wee ks).
4. 2. 6
S afet y A n al yses
All safety varia bles will be s u m marise d f or all patie nts i n t he S A F a n d prese nte d b y treat me nt 
ar m.
A Es will be s u m marise d f or t he st u d y  p erio d (re d ucti o n  a n d mai nte na nce perio ds c o m bi ne d), 
w he n a ttri b ute d t o S y m bic ort® , Ve nt oli n® or Fase nra ® , as defi ne d i n Secti on  3. 3. 1 .  All A Es 
will be liste d f or eac h pat ient , re gar dless of t he ti me peri o d.
A n o verall s u m mar y ta ble will be pr o d uce d s h o wi n g t he n u m ber a n d perce nta ge of patie nts 
wi t h at least o ne A E i n a n y o f t he f o ll owi n g cate g ori es: A Es, deat hs d ue t o A E, S A Es, a n d 
A Es ca usi n g t he disc o nt i n uati on of st u d y  treat me nt ( D A Es), f or t he st u d y p erio d.  T he t otal 
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 4 of 5 2
n u m ber of A Es i n t he differe nt A E cate g ories i n ter ms of A E c o u nts will als o be prese nte d (ie, 
acc o u nti n g f or m ult i ple occ urre nces of t he sa me e ve nt i n a pat ient ).
A d verse e ve nts, D A Es, a n d S A Es will be s u m marise d b y S O C a n d P T assi g ne d t o t h e e ve nt 
b y Me d D R A.  F or eac h P T, t he n u m ber a n d perce nta ge of patie nts re p orti n g at least o ne 
occ urre nce will be prese nte d (ie, a patie nt wit h m ult i ple occ urre nces of a n A E will o nl y be 
c o u nte d o nce). 
A Es a n d S A Es ( b y P T) will be s u m marise d b y I n vesti gat o r's ca usality (relate d vs n ot relate d) 
f or Fase nra® , Ve nt oli n ® a n d f or S y m bic ort ® , a n d ma xi m u m i nte nsity f or eac h of t he 
treat me nts.  If a patie nt re p orts m ult i ple occ urre nces of t he sa me A E wit hi n t he sa me re p orte d 
p eri o d, t he m a xi m u m i nte nsit y will  b e t ake n as t he hi g hest rec or de d ma xi m u m i nte nsit y (t he 
or der bei n g mil d, m o derate, a n d se vere).  Si milarl y, t he w orst ca usalit y will be attri b ute d a n d 
use d i n t he b y ca usalit y s u m maries.  Deat hs will als o be s u m marise d i n se parate ta bles.
A s u m mar y  of t h e most c o m m o n (i e, fre q ue nc y of > 1 %) A Es will als o be prese nte d b y P T.
If t her e is a s ufficie nt n u m ber of h y perse nsit i vity e ve nts (sta n dar dise d Me d D R A q uer y of 
h y perse nsit i vity) or A Es of i njecti o n site react i ons ( hi g h le vel ter m of a d mi nistratio n a n d 
i njecti on sit e), it will be s u m marise d b y P T for t he treat m e nt perio d as well  as t he st u d y 
p eri o d.  
Se parate list i n gs of patient s wit h A Es, S A Es, deat h d ue t o A E, or D A Es will be prese nte d.
4. 2. 7
He alt h ec o n o mics
T he n u m ber a n d perce nta ge of patie nts wit h ast h ma s pecific res o urce utilizati on ( defi ne d i n 
Secti o n 3. 4. 3 ) will be prese nte d b y ra n d omise d treat me nt ar m.
4. 2. 8
I m p act o n a n al yses d ue t o C O VI D-1 9 p a n de mic
Gi ve n t he u ncertai nt y s urr o u n di n g t he f ut ure i m pact of t he C O VI D-1 9 w orl d wi de pa n de mic 
o n cli nical trials, o perati o nal pr oce d ures are bei n g i m ple me nte d i n t his st u d y  t o mai ntai n t he 
i nte grit y of c ollecte d data.  Eff orts ma y be ma de t o c ollect data via alter nati ve mea ns w here 
p ossi ble, w he n o n -site visits ca n n ot be perf or me d.
If t here is a s ufficie nt n u m ber of pr ot oc ol de viati ons or st u d y  disr u pti ons as a res ult of 
C O VI D -1 9, t he n se nsit i vity a nal yses ma y be c o n d ucte d t o e val uate t heir i m pact o n t he 
i nter pretatio n of  res ults. Pr ot oc ol de viat i ons, i ncl u di n g d oses or visit s misse d d ue t o 
C O VI D -1 9 rel ate d pr ot oc ol de viati ons m a y be descri be d se paratel y i n t he C S R.  C o nfir me d or 
s us pecte d cases of C O VI D- 1 9 will be liste d a n d i ncl u de d as A Es as a p pr o priate.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 5 of 5 2
5
I N T E RI M A N A L Y S E S
N o i nt erim a nal yses are pla n ne d f or t his st u d y.
T he fi nal data base l oc k will be perf or me d after all patie nts ha ve c o m p lete d t he mai nte na nce 
p eri o d ( Vi sit 8 b/ E O T) a n d will i nf or m t he pre-defi ne d fi nal a nal ysis o ut p uts, as well as c o ver 
t he c o nte nts of t he C S R. 
6
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L
Secti o n 9. 4. 1 of t he C S P ( Ast h ma E xacer bati o ns):
T he calc ulat i on of t he n u m ber of e xacer bati o ns e x perie nce d b y a pat ient  will be d o ne f or 
t he st u d y p erio d (re d ucti o n a n d m ai nte na nce) i nstea d of treat me nt peri o d (r u n-i n, re d uctio n 
a n d mai nte na nce peri o d).
Secti o n 9. 4. 1 of t he C S P ( T otal I C S D ose E x p os ure):
I n hale d c ortic oster oi d e x p os ure secti o n assessi n g c u m ulati ve t otal dail y I C S d ose varia bles 
has bee n u p date d as per tea m re q uest:

T he patie nt’s t otal dail y I C S d ose o n eac h d a y  - will n ot be deri ve d

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose eac h da y si nce t he be gi n ni n g of t he 
re d uctio n peri o d u ntil t he e n d of re d ucti o n peri o d a n d u nt il t o t he e n d of mai nte na nce 
p eri o d – varia bles will be deri ve d f or t he peri o d b ut will n ot be s plit o ut f or eac h da y

T he patie nt’s c u m ulat i ve t otal dail y I C S d ose eac h da y si nce t he be gi n ni n g of t he 
mai nte na nce peri o d t o t he e n d of mai nte na nce peri o d - varia ble will be deri ve d f or t he 
p eri o d b ut will n ot be s plit o ut f or eac h da y .

Secti o n 9. 4. 2 of t he C S P ( A Q L Q( S) + 1 2, C ha n ge fr o m Baseli ne F E V 1, T otal Dail y I C S D ose):
All sec o n dar y e n d p oi nt M M R M a nal yses will i ncl u de baseli ne val ue as a c o variate.
Secti o n 9. 4. 3. 1 of t he C S P ( A d verse e ve nts):

All i nsta nces of s u m maries a n d listi n gs relate d t o a dre nal i ns ufficie nc y will n ot be 
pr o d uce d as per err o ne o us i ncl usi o n of a dre nal i ns ufficie nc y i n t he C S P v 1. 0.

S A Es ca usi n g disc o nt i n uati on of t he st u d y  tr e at me nt/st u d y will n ot be s u m marise d .

A s u m mar y  of t h e most c o m m o n  A Es will be prese nte d f or A Es wi t h fre q ue nc y > 1 % a n d 
n ot > 5 %

A Es of i nject i on site reacti o ns ( hi g h le vel ter m of a d mi nistrati o n a n d i nject i on site) will 
o nl y  be s u m marise d b y P T f or t he treat me nt peri o d if a s ufficie nt n u m ber of e ve nts are 
re p orte d.     


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 6 of 5 2
Secti o n 9. 4. 4 ( C ha n ge fr o m b aseli ne Fe N O a n d C ha n ge fr o m baseli ne i n bl o o d e osi n o p hil 
c o u nt):
All e x plor at or y  e n d p oi nt M M R M a nal yses will i ncl u de baseli ne val ue as a c o variate.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 7 of 5 2
7
R E F E R E N C E S
J u ni per et al 1 9 9 2
J u ni per E F, G u yatt G H, E pstei n R S, Ferrie PJ, Jaesc h ke R, Hiller T K. E val uat i on of 
i m pair me nt of health relate d q ualit y of life i n ast h ma: de vel o p me nt of a q uesti o n naire f or use 
i n cli nical trials. T h ora x. 1 9 9 2; 4 7( 2): 7 6 -8 3.
J u ni per et al 1 9 9 4
J u ni per E F, G u yatt G H, Willa n A, Griffit h L E. Deter mi ni n g a mi ni ma l i m p orta nt c ha n ge i n a 
di sease-s pecific Q uality of  Life Q uesti on naire. J Cli n E pi de mi o l. 1 9 9 4; 4 7( 1): 8 1-8 7.
J u ni per et al 1 9 9 9
J u ni per E F, B uist A S, C o x F M, Ferrie PJ, Ki n g D R. Vali dati o n o f a sta n dar dize d versi o n of 
t he Ast h ma Q ualit y of  Life Q uesti o n naire. C hest. 1 9 9 9; 1 1 5( 5): 1 2 6 5 -1 2 7 0.
J u ni per et al 2 0 0 5
J u ni per E F, S ve nss o n K, M ör k A C, Stå hl E. M o dificat i on of t he ast h ma q ualit y of life 
q uesti o n naire (sta n dar dise d) f or patie nts 1 2 y ears a n d older. Heal t h Q ual Life O utc o mes. 
2 0 0 5; 3: 5 8.
J u ni per et al 2 0 0 6
J u ni per E F, B o us q uet J, A betz L, Bate ma n E D, G O A L C o m mittee. I de ntif yi n g ' well-
c o ntr olle d' a n d ' n ot well- c o ntr olle d' ast h ma usi n g t he Ast h ma C o ntr ol Q uesti o n naire. Res pir 
Me d. 2 0 0 6; 1 0 0( 4): 6 1 6 - 6 2 1.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 8 of 5 2
8
A P P E N DI X
8. 1
I m p ut ati o n r ules f or p arti al d ates 
8. 1. 1
A d verse e ve nts , me dic al hist or y a n d pri or/c o nc o mit a nt m e dic ati o ns
Dates missi n g t he da y , or b ot h t he da y a n d mo nt h of  t h e year will a d here t o t he f o ll owi n g 
c o n ve nt i ons t o cl assif y me dical hist or y, prior a n d c o nc o mita nt me dicat i ons, a n d a d ver se 
e ve nts:
A d verse E ve nts

T he missi n g start da y  will be set t o:
-
Fi rst d a y of t he mo nt h of occ urre nce, if t he start Y Y Y Y -M M is after t he Y Y Y Y -M M 
of  first st u d y treat me nt
-
T he da y  of t he first st u d y treat me nt, if t he start Y Y Y Y -M M is t he sa me as Y Y Y Y -
M M of t he first st u d y tr e at me nt
-
T he date of i nf or me d c o nse nt, if t he o nset Y Y Y Y -M M is bef ore t he Y Y Y Y -M M of 
t he first st u d y treat me nt

T he missi n g e n d da y will be set t o:
-
T he l ast da y of t h e mo nt h of t he occ urre nce, if t he e n d Y Y Y Y- M M i s after t he Y Y Y Y-
M M of t he first st u d y tr e at me nt
-
Deat h date if t he patie nt die d i n t he sa me m o nt h
-
T he da y  of last st u d y tr e at me nt if t he Y Y Y Y -M M of  occ urre nce is t he sa me as t he last 
st u d y tr e at me nt

If t he start date is missi n g b ot h t he da y a n d mo n t h, t he start date will be set t o:
-
Ja n uar y 1 of t h e ye ar of occ urre nce if t he start year  is after t he year of first st u d y 
treat me nt
-
T he date of t he first st u d y  treat me nt, if t he start year is t he sa me as t he year of t he first 
st u d y tr e at me nt

If t he e n d date is missi n g b ot h t he da y a n d mo nt h , t he date will be set t o:
-
Dece m ber 3 1 of t he y ear of occ urre nce
-
Date of deat h if t he patie nt die d i n t he sa me year


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 9 of 5 2
-
Last st u d y  treat me nt date if t he year of occ urre nce is t he sa me as t he last st u d y 
treat me nt date

If t he start date is n ull, t he date will be set t o:
-
T he date of first st u d y  tr e at me nt
-
Ja n uar y 1 of t he sa me year as t he e n d date, if t he e n d date s u g gests t hat t he start date 
c o uld be pri or t o t he date of first st u d y  treat me nt

If t he e n d date is n ull a n d n ot rec or de d as o n g oi n g, t he date will be set t o:
-
T he date of t he first st u d y  treat me nt, if t he start date is prior t o t he date of first st u d y  
treat me nt
-
T he date of last visit, if t he start date is o n or after t he date of first st u d y  treat me nt

If t he e n d date is n ull a n d rec or de d as o n g oi n g, t he e n d date will n ot be i m p ute d.
Pri or/ C o nc o mit a nt me dic ati o n a n d Me dic al Hist or y

T he missi n g start da y  will be set t o:
-
Fi rst d a y of t he mo nt h of occ urre nce

T he missi n g e n d da y will be set t o:
-
T he l ast da y of t h e mo nt h of t he occ urre nce

If t he start date is missi n g b ot h t he da y  a n d mo n t h, t he start date will be set t o:
-
Ja n uar y 1 of t h e ye ar of occ urre nce

If t he e n d date is missi n g b ot h t he da y a n d mo nt h, t he date will be set t o:
-
Dece m ber 3 1 of t he y ear of occ urre nce

If t he start date of  pri or/c o nc o mi ta nt me dicat i on is n ull a n d t he e n d date is n ot a c o mplete 
date , t he start date will be set t o t he earlier of:
-
I mp ute d parti al e n d date, a n d 
-
Date of first st u d y  tr e at me nt

If t he start date of pri or/c o nc o mi ta nt me dicati on is n ull a n d t he e n d date is a c o m p lete date, 
t he start date will be set t o:


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 0 of 5 2
-
T he date of  t he first st u d y treat me nt, if t he e n d d at e i s aft er t he date of first st u d y 
treat me nt
-
T he e n d date of t he t hera p y ot her wise

If t he e n d date is n ull a n d rec or de d as o n g oi n g, t he e n d date will n ot be i m p ute d.

If t he start or e n d dates of me dical hist or y are n ull, t h e y will not be i m p ute d.
8. 1. 2
P arti al d ates f or d ate of birt h a n d d ate of first ast h m a di a g n osis
If t he first ast h ma dia g n osis date or date of birt h is a partial date, t he f oll owi n g i m p utati o n 
r ules will be im ple me nte d:

If t he year is prese nt b ut t he m o nt h a n d da y are missi n g, t he n J ul y 1 will be i m p ute d as t he 
start date.

If t he year a n d m o nt h are prese nt b ut t he da y is missi n g, t he n 1 5 will be i m p ute d as t he 
start date.
8. 1. 3
P arti al d ates f or m ost rece nt e x acer b a ti o n d ate
If t he m ost rece nt e xacer bati on date is a partial date, t he f o ll owi n g i m p utati o n r ul es will be 
i m ple me nte d:

If t he year is prese nt b ut t he m o nt h a n d da y are missi n g, t he n J ul y 1 will be i m p ute d as start 
date

If t he year a n d m o nt h are prese nt b ut t he da y is missi n g, t he n 1 5 will be i m p ute d as t he start 
date
8. 1. 4
P arti al d ates f or s ur gic al hist or y
If s ur gical hist or y d at e is a partial date, t he f ollo wi n g r ul es will be a p plie d:

If start or e n d date of s ur gical hist or y date is a partial date, t he n t he f ollo wi n g will  be 
a p plie d:
-
If t he start date is n ot partial a n d t he e n d date is partial, t he n t he e n d date will be 
i m p ute d as t he start date. 
-
If t he e n d date is n ot partial a n d t he start date is partial, t he n t he start date will be 
i m p ute d as t he e n d date. 
-
If t he start date a n d e n d date is missi n g t he m o nt h a n d da y  but y ear is prese nt, t he n 
J ul y 1 will be i m p ute d as t he start a n d e n d date


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 1 of 5 2
-
If t he start date a n d e n d date is missi n g t he m o nt h b ut da y a n d year is prese nt, t he n 
J ul y will be i m p ute d as t he start a nd e n d m o n t h
-
If t he start date a n d e n d date is missi n g t he da y but m o nt h a n d year i s prese nt, t he n 1 5 
will be i m p ute d as t he start a n d e n d d a y

If t he e n d date is n ull or rec or de d as o n g oi n g, t he n t he e n d date will n ot be i m p ute d.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 7 2 – 3. 0
1 5 Dece m ber 2 0 2 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 2 of 5 2


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 3 2 5 0c 0 0 0 7 2-sa p-e d- 3
D oc u me nt Title:
Statistical A nal ysis Pla n E diti o n 3
D oc u me nt I D:
D oc I D- 0 0 4 2 2 3 0 7 5
Versi o n L a bel:
4. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
1 7-Ja n- 2 0 2 3 1 3: 1 7 U T C
C o nte nt A p pr o val
1 1-Ja n- 2 0 2 3 0 8: 0 9 U T C
 C Y T E L
C o nte nt A p pr o val
1 2-Ja n- 2 0 2 3 1 5: 3 1 U T C
 P A R E X E L
A ut h or 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.
P P D
P P D
P P D


P ar e x el I nt er n ati o n al
A str a Z e n e c a
D 3 2 5 0 C 0 0 0 7 2
St ati sti c al A n al y si s P l a n A d d e n d u m
Pr oj e ct D o c u m e nt V er si o n N o.: 3 . 0; D o c u m e nt Eff e cti v e D at e:  D at e of l a st si g.
C O N FI D E N TI A L
T P -G D O -W W -1 6 9 -0 1
Eff e cti v e D at e:  2 2 D e c 2 1
R el at e d t o:   S O P- G D O -W W -0 1 9
P a g e 1 of  7
D e v el o p e d fr o m T P -B P M -W W -0 3 2 ; r el at e d t o S O P-B P M -W W -0 0 1
A str a Z e n e c a
D 3 2 5 0 C 0 0 0 7 2
S H A M A L: A M ulti c e ntr e, R a n d o mi s e d, O p e n -L a b el, P ar all el -Gr o u p, A cti v e -C o ntr oll e d, 
P h a s e I V St u d y t o A s s e s s t h e R e d u cti o n of D ail y M ai nt e n a n c e I C S/ L A B A Tr e at m e nt 
T o w ar d s A nti -I nfl a m m at or y R eli e v er Tr e at m e nt i n P ati e nt s wit h S e v er e E o si n o p hili c 
A st h m a Tr e at e d wit h B e nr ali z u m a b
St ati sti c al A n al y si s Pl a n A d d e n d u m
P ar e x el Pr oj e ct N u m b er: 2 4 3 9 6 1


P ar e x el I nt er n ati o n al
A str a Z e n e c a
D 3 2 5 0 C 0 0 0 7 2
St ati sti c al A n al y si s P l a n A d d e n d u m
Pr oj e ct D o c u m e nt V er si o n N o.: 3 . 0; D o c u m e nt Eff e cti v e D at e:  D at e of l a st si g.
C O N FI D E N TI A L
T P -G D O -W W -1 6 9 -0 1
Eff e cti v e D at e:  2 2 D e c 2 1
R el at e d t o:   S O P- G D O -W W -0 1 9
P a g e 2 of  7
D e v el o p e d fr o m T P -B P M -W W -0 3 2 ; r el at e d t o S O P-B P M -W W -0 0 1
S P O N S O R SI G N A T U R E P A G E
T hi s d o c u m e nt h a s b e e n a p pr o v e d a n d si g n e d el e ctr o ni c all y o n t h e fi n al p a g e b y t h e f oll o wi n g:
A p pr o v e d b y:
S e ni or Bi o st ati sti ci a n
A str a Z e n e c a
P P D




P ar e x el I nt er n ati o n al
A str a Z e n e c a
D 3 2 5 0 C 0 0 0 7 2
St ati sti c al A n al y si s P l a n A d d e n d u m
Pr oj e ct D o c u m e nt V er si o n N o.: 3 . 0; D o c u m e nt Eff e cti v e D at e:  D at e of l a st si g.
C O N FI D E N TI A L
T P -G D O -W W -1 6 9 -0 1
Eff e cti v e D at e:  2 2 D e c 2 1
R el at e d t o:   S O P- G D O -W W -0 1 9
P a g e 4 of  7
D e v el o p e d fr o m T P -B P M -W W -0 3 2 ; r el at e d t o S O P-B P M -W W -0 0 1
T A B L E O F C O N T E N T S
1
C H A N G E S T O T H E S T A TI S TI C A L A N A L Y SI S P L A N ......................................................6
1. 1
Sec o n dar y  Efficac y A nal yses – Ast h ma E xacer bat i o ns ........................................................6
1. 2
Sec o n dar y  Efficac y A nal yses – A C Q - 5................................................................................6
1. 3
Sec o n dar y  O bjecti ves – T o assess t he t otal i n hale d c ortic oster oi ds (I C S) d ose e x p os ure ......6
1. 4
Sec o n dar y  Efficac y A nal yses – A C Q - 5................................................................................6
1. 5
Sec o n dar y  Efficac y A nal yses – A Q L Q( S) + 1 2 .....................................................................6


P ar e x el I nt er n ati o n al
A str a Z e n e c a
D 3 2 5 0 C 0 0 0 7 2
St ati sti c al A n al y si s P l a n A d d e n d u m
Pr oj e ct D o c u m e nt V er si o n N o.: 3 . 0; D o c u m e nt Eff e cti v e D at e:  D at e of l a st si g.
C O N FI D E N TI A L
T P -G D O -W W -1 6 9 -0 1
Eff e cti v e D at e:  2 2 D e c 2 1
R el at e d t o:   S O P- G D O -W W -0 1 9
P a g e 5 of  7
D e v el o p e d fr o m T P -B P M -W W -0 3 2 ; r el at e d t o S O P-B P M -W W -0 0 1
R E VI SI O N HI S T O R Y
V er si o n N o.
Eff e cti v e D at e
S u m m ar y of C h a n g e( s)
1. 0
D at e of l a st 
si g n at ur e
N e w d o c u m e nt
2. 0
D at e of l a st 
si g n at ur e
A d diti o n of  se cti o n 1. 2 t o st at e t h e u p d at e d d ef i niti o n of b a s eli n e 
A C Q -5.
A d diti o n of
s e cti o n 1. 3 t o u p d at e t h e o ut c o m e m e a s ur e f or t h e 
s e c o n d ar y e n d p oi nt of I C S d o s e e x p o s ur e.
3. 0
D at e of l a st 
si g n at ur e
A d diti o n of s e cti o n 1. 4 a n d 1. 5 t o st at e t h at a “ Mi s si n g” c at e g or y will 
b e a d d e d t o di sti n g ui s h t h e n u m b er a n d p er c e nt a g e of p ati e nt s wit h 
mi s si n g s c or e c o ntri b uti n g t o N o n -R e s p o n d er s at e a c h ti m e p oi nt.


1
C H A N G E S T O T H E S T A TI S TI C A L A N A L Y SI S P L A N
1. 1
S e c o n d ar y Effi c a c y A n al y s e s – A st h m a E x a c er b ati o n s
S e cti o n 4. 2. 3. 5 of t h e st ati sti c al a n al y si s pl a n ( S A P) v e r si o n 3. 0 st at e d t h at a n e g ati v e bi n o mi al m o d el will 
b e u s e d t o m o d el t h e A st h m a E x a c er b ati o n R at e ( A E R) fr om vi sit 2 b ( W e e k 0) u p t o Vi sit 8 b ( W e e k 4 8) of 
t h e r e d u cti o n ar m c o m p ar e d t o t h e r efer e n c e ar m.
T hi s i s b ei n g u p d at e d t o a p oi s s o n m o d el. T h e r e s p o n s e v ari a b l e, c o v ari at e s a n d off s et v ari a bl e will r e m ai n 
t h e s a m e a s t h at m e nti o n e d i n th e S A P v er si o n 3. 0. T h e c h a n g e i s b ei n g m a d e
a s t h e n e g ati v e bi n o mi al 
m o d el d o e s n ot c o n v er g e w h e n a p pli e d t o t h e l o c k e d d at a.
1. 2
S e c o n d ar y Effi c a c y A n al y s e s – A C Q - 5
S e cti o n 4. 2. 3. 1 of t h e S A P v er si o n 3. 0 st at e d t h at b a s eli n e f or t h e m e a n A C Q -5 s c or e o v er t h e pr e vi o u s 8 
w e e k s will b e d efi n e d a s t h e l a st n o n -mi s si n g A C Q -5 s c or e pri or t o r a n d o mi s ati o n. 
T hi s h a s b e e n u p d at e d t o t h e f oll o wi n g: B a s eli n e f or t h e m e a n A C Q -5 s c or e o v er t h e pr e vi o u s 8 w e e k s i s 
d efi n e d a s t h e Vi sit 2 b ( W e e k 0) r e s ult. T h e c h a n g e i s b ei n g m a d e a s it w a s l at er n ot e d t h at s o m e s u bj e ct s 
h a d Vi sit 2 b ( We e k 0) pri or t o r a n d o mi s ati o n A C Q -5 s c or e s r e c or d e d o n p a p er C R F a n d e nt er e d i n t h e E D C 
aft er r a n d o mi s ati o n . 
1. 3
S e c o n d ar y O bj e cti v e s – T o a s s e s s t h e t ot al i n h al e d c orti c o st er oi d s (I C S) d o s e 
e x p o s ur e
S e cti o n 1. 1. 2 of t h e S A P v er si o n 3. 0 st at e d t h at o n e of t h e o ut c o m e m e a s ur e s f or t h e s e c o n d ar y o bj e cti v e s 
t o a s s e s s t h e t ot al I C S d o s e e x p o s ur e i s d efi n e d a s T ot al d ai l y I C S d o s e ( m ai nt e n a n c e + r eli e v er) at t h e 
e n d of t h e r e d u cti o n p eri o d.  
T hi s o ut c o m e m e a s ur e h a s b e e n u p d at e d t o t h e m e a n t ot al d ail y I C S d o s e i n th e pr e vi o u s 8 w e e k s. T h e 
d eri v ati o n of  th e M e a n t ot al d ail y I C S d o s e i n t h e pr e vi o u s 8 w e e k s i s gi v e n i n S e cti o n 3. 2. 2 of  t h e S A P 
v er si o n 3. 0. T hi s c h a n g e i s b ei n g m a d e a s m e a n t ot al d ail y I C S d o s e i n t h e pr e vi o u s 8 w e e k s m e a s ur e s 
m or e a c c ur at el y t h e S M A R T st e p -d o w n of s u bj e ct s a n d t o ali g n S e cti o n 1. 1. 2 i n t h e S A P wit h t h e a n al y s e s 
alr e a d y a p pr o v e d a n d d e s cri b e d i n S e cti o n 3. 2. 2 . 
1. 4
S e c o n d ar y Effi c a c y A n al y s e s – A C Q - 5
U p d at e d S e cti o n 3. 2. 1 of  th e S A P v er si o n 3. 0 t o s p e cif y t h at p ati e nt s will b e c at e g ori s e d a s R e s p o n d er s 
a n d N o n -r e s p o n d er s. P ati e nt s wit h a n i m pro v e m e nt i n t h eir A C Q -5 s c or e at t h e ti m e p oi nt will b e s u m m ari s e d 
u n d er t h e R e s p o n d er c at e g or y. P ati e nt s wit h n o c h a n g e or d et eri or ati o n i n t h eir A C Q -5 at t h e ti m e p oi nt will 
b e s u m m ari s e d u n d er t h e N o n -r e s p o n d er c at e g or y.
S e cti o n 3. 2. 1 of t h e S A P v er si o n 3. 0 st at e d t h at p ati e nt s wit h mi s si n g or n o n -e v al u a bl e A C Q -5 s c or e at a 
p o st -b a s eli n e a s s e s s m e nt ti m e p oi nt will b e c o n si d er e d a st h m a w or s e ni n g r e s p o n d er s at t h e ti m e p oi nt.
T hi s h a s b e e n u p d at e d t o: p ati e nt s wit h mi s si n g or n o n -e v al u a bl e A C Q -5 c h a n g e s c or e at a p o st -b a s eli n e 
a s s e s s m e nt ti m e p oi nt will b e c o n si d er e d a st h m a n o n -r e s p o n d er s at t h e ti m e p oi nt, a n d pr e s e nt e d a s Mi s si n g 
c at e g or y.
1. 5
S e c o n d ar y Effi c a c y A n al y s e s – A Q L Q( S) + 1 2
U p d at e d S e cti o n 3. 2. 3 of  th e S A P v er si o n 3. 0 t o s p e cif y t h at p ati e nt s will b e c at e g ori s e d a s R e s p o n d er s 
a n d N o n -r e s p o n d er s. P ati e nt s wit h a n i m pr o v e m e nt i n t h eir A Q L Q( S) + 1 2 s c or e at t h e ti m e p oi nt will b e 
s u m m ari s e d u n d er t h e R e s p o n d er c at e g or y. P ati e nt s wit h n o -c h a n g e or d et eri or ati o n i n t h eir A Q L Q( S) + 1 2 
at t h e ti m e p oi nt will b e s u m m ari s e d u n d er t h e N o n -r e s p o n d er c at e g or y.
S e cti o n 3. 2. 3 of t h e S A P v er si o n 3. 0 st at e d t h at p ati e nt s wit h mi s si n g or n o n -e v al u a bl e A Q L Q( S) + 1 2 s c or e 
at a p o st -b a s eli n e a s s e s s m e nt ti m e p oi nt will b e c o n si d er e d n o n -r e s p o n d er s at t h e ti m e p oi nt.


P ar e x el I nt er n ati o n al
A str a Z e n e c a
D 3 2 5 0 C 0 0 0 7 2
St ati sti c al A n al y si s P l a n A d d e n d u m
Pr oj e ct D o c u m e nt V er si o n N o.: 3 . 0; D o c u m e nt Eff e cti v e D at e:  D at e of l a st si g.
C O N FI D E N TI A L
T P -G D O -W W -1 6 9 -0 1
Eff e cti v e D at e:  2 2 D e c 2 1
R el at e d t o:   S O P- G D O -W W -0 1 9
P a g e 7 of  7
D e v el o p e d fr o m T P -B P M -W W -0 3 2 ; r el at e d t o S O P-B P M -W W -0 0 1
T hi s h a s b e e n u p d at e d t o: p ati e nt s wit h mi s si n g or n o n -e v al u a bl e A Q L Q( S) + 1 2 c h a n g e s c or e at a p o st -
b a s eli n e a s s e s s m e nt ti m e p oi nt will b e c o n si d er e d n o n -r e s p o n d er s at t h e ti m e p oi nt, a n d pr e s e nt e d a s 
Mi s si n g c at e g or y.


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 3 2 5 0c 0 0 0 7 2-sa p-a d de n d u m-e d- 3
D oc u me nt Title:
Statistical A nal ysis Pla n A d de n d u m E diti o n 3
D oc u me nt I D:
D oc I D- 0 0 5 1 5 5 7 8 1
Versi o n L a bel:
3. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
1 1-J ul- 2 0 2 3 0 6: 5 1 U T C
 C Y T E L
C o nte nt A p pr o val
1 7-J ul- 2 0 2 3 1 1: 2 1 U T C
 P A R E X E L
A ut h or 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.
P P D
P P D