A Randomized, Double-Blind, Parallel Group, Multicenter 12 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler in Participants With Inadequately Controlled Asthma (LITHOS)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
Cli nic al St u d y Pr ot oc ol 
St u d y I nter ve nti o n  
B u des o ni de a n d F or m oter ol 
F u marate  
St u d y C o de  
D 5 9 8 2 C 0 0 0 0 5  
Versi o n  
4 . 0 
Date  
1 5 Oct 2 0 2 4  
TI T L E P A G E
A R a n d o mize d, D o u ble -Bli n d, P ar allel Gr o u p, M ulti ce nter 
1 2  Wee k St u d y t o Assess t he Effic ac y a n d S afet y of B u des o ni de 
a n d F or m oter ol F u m ar ate Metere d D ose I n h aler Rel ati ve t o 
B u des o ni de Metere d D ose I n h aler i n P artici p a nts wit h 
I n a de q u atel y C o ntr olle d Ast h m a ( LI T H O S)  
S p o ns or N a me:  
Le gal Re gistere d A d dress: Astra Ze n eca A B, 1 5 1 8 5 S ö dertälje, S we de n.  
Re g ul at or y A g e nc y I de ntifier N u m ber(s)  
I N D N u m ber: 1 2 2 1 6 6 
E u dr a C T N u m ber : 2 0 2 1-0 0 3 3 3 4 -3 6  
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 
discl ose d a n d/ or p u blis he d acc or di n g t o t he Astra Z e neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o m plia nce wit h pre v aili n g la ws a n d re g ul ati o ns.  
Pr ot oc ol N u m ber: D 5 9 8 2 C 0 0 0 0 5  
A me n d me nt N u m ber: 3  
St u d y I nter v e nti o n: B u des o ni de a n d F or m oter ol F u marate, B u des o ni de  
R e d a ct e d f or P u bli c Di s cl o s ur e

Cli nical St u d y P r ot oc ol - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
St u d y P hase: III  
S h ort Title: A 1 2 -Wee k Efficac y a n d Safet y St u d y t o Assess B u des o ni de a n d F or m oter ol 
F u marate Metere d D ose I n haler i n A d ult a n d A d ol esce nt Partici pa nts wit h  I na de q uatel y 
C o ntr olle d Ast h ma ( LI T H O S)  
St u d y P h ysici a n N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y  
I nter n ati o n al C o-or di n ati n g I n vesti g at or  
 
U ni versit y of Ferrara  
Via C os m è T ura 2 6  
4 4 1 2 1 Ferrara F E  
Ital y 
P P D

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
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 m e nt  
D ate  
C S P Versi o n 4. 0  
1 5 -Oct -2 0 2 4  
C S P Versi o n 3. 0  
0 5 -Dec -2 0 2 3  
C S P Versi o n 2. 0  
1 3 -Oct -2 0 2 2  
C S P Versi o n 1. 0  
1 9 -A u g -2 0 2 1  
 
C S P Versi o n  4. 0: 1 5 -Oct -2 0 2 4   
T his 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 criteri a set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E D 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 
a n d i n t he E U Cli nical Tria l Re g ulati o n Article 2, 2 ( 1 3). 
O ver all R ati o n ale f or t he M o dific ati o n:  
A n a me n d me nt was re q uire d t o u p date  t he statistical met h o d ol o gical a p pr oac hes t o ha n dli n g 
i nterc urre nt e ve nts a n d t h e Ty pe 1 err or c o ntr ol pr oce d ure f or 
. 
S u m m ar y of C h a n ges:  
List of S u bst a nti al M o dific ati o ns  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1  S y n o psis, 
3  O bjecti ves a n d 
E n d p oi nts,  
9  Statistical 
C o nsi derati o ns  
T he strate gies f or ha n dli n g 
i nterc urre nt e ve nts were u p date d t o 
reflect a c o m p osite strate g y 
(treat me nt fail ure) if ne w ast h ma 
t hera p y or a d mi nistrati o n of 
pr o hi biti ve me dicati o n t h o u g ht t o 
i m pact efficac y occ urs i n 
c o nj u ncti o n wit h pre mat ure  I P 
disc o nti n uati o n . Ot her wise 
treat me nt p olic y will be use d . 
T o  si m plif y re p orti n g t o healt h 
a ut h orities, t he sa me a p pr oac h t o 
ha n dli n g i nterc urre nt e ve nts will be 
use d acr oss re gi o ns.  
A n a p pr oac h usi n g “W hile O n 
Treat me nt ” strate g y f or interc urre nt 
eve nt s will be use d as s u p p orti ve 
T he s u p p orti ve H y bri d strate g y f or 
i nterc urre nt e ve nts was re m o ve d. 
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Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
9 .2. 1. 2  
 
A p pr oac h  
T he te xt f or t he T y pe I err or 
c o ntr ol pr oce d ure f or 
 
has bee n u p date d t o reflect t hat 
O nset of Acti o n is teste d 
se p aratel y (as f or 
 o utsi de 
t he H oc h ber g test pr oce d ure. 
C orrecti o n  t o ali g n Statistical A nal ysis Pla n 
a n d C S P . 
 
List of N o n -S u bst a nti al M o dific ati o ns  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
3  O bjecti ves a n d E n d p oi nts  
I C Es of ne w ast h ma t hera p y a n d 
pr o hi bite d me dicati o ns 
c o ns oli date d t o be I C E of:  
I nitiati o n of ne w ast h ma t hera p y 
or a d mi nistrati o n of pr o hi bite d 
ast h ma me dicati o ns t h o u g ht t o 
i m pact efficac y. 
Si m plificati o n as ke y me dicati o ns 
i de ntifie d as i ncl u di n g bi ol o gical t hera p y/ 
m o n ocl o nal a nti b o dies, L A B A, L A M A , 
or L T R A . 
9. 3  Sa m ple Size 
Deter mi nati o n  
F or sa m ple size deter mi nati o n, 
ad de d t he refere nces  f or t he 
st u dies t hat t he treat me nt effect 
a n d varia bilit y ass u m pti o ns were 
base d o n.  
Clarificati o n i n res p o nse t o q uesti o ns 
raise d fr o m t he State I nstit ute f or Dr u g 
C o ntr ol, 
 o n C S P 
a me n d me nt v 3. 0 . 
9. 5. 2. 3  Tertiar y/ E x pl orat or y 
E n d p oi nt(s)  
A nal ysis f or t he perce nta ges of 
resc ue-free da ys a n d 
s y m pt o m-free da ys u p date d t o 
re p eate d meas ures a nal ysis of 
c o varia nce. 
C orrecti o n . 
9. 5. 2. 2 Sec o n dar y 
E n d p oi nts(s)  
9. 5. 2. 3 Tertiar y/ E x pl orat or y 
E n d p oi nt(s)  
Clarificati o n of m o dels use d f or 
t he p o ole d a nal ysis. 
F urt her m ore, it has bee n clarifie d  
t hat all a v aila ble data fr o m st u dies 
D 5 9 8 2 C 0 0 0 0 5 a n d C 5 9 8 2 C 0 0 0 0 6 
will be use d i n t he p o ole d a nal ysis.  
Clarificati o n i n res p o nse t o q uesti o ns 
raise d fr o m t he State I nstit ute f or Dr u g 
C o ntr ol, 
 o n C S P 
a me n d me nt v 3. 0 . 
9. 5. 3. 2 Vital si g ns  
T he baseli ne defi niti o n f or vital 
si g ns was u p date d t o last 
n o n -missi n g val ue pri or t o t he first 
d ose of ra n d o mize d I P.  
C o nsiste nc y of baseli ne defi niti o n acr oss 
e n d p oi nts.  
T hr o u g h o ut  
Mi n or e dit orial a n d d oc u me nt 
f or matti n g re visi o ns. 
Mi n or, t heref ore, ha ve n ot bee n 
s u m marize d. 
 
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Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marat e - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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T A B L E  O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1  
S U M M A R Y O F C H A N G E S T A B L E  ....................................................................................... 3  
T A B L E O F C O N T E N T S  ........................................................................................................... 5  
1  
P R O T O C O L S U M M A R Y  .................................................................................... 1 2  
1. 1  
S y n o ps is ................................................................................................................ 1 2  
1. 2  
Sc he ma  .................................................................................................................. 1 8  
1. 3  
Sc he d ule of Acti vities  ........................................................................................... 1 9  
2  
I N T R O D U C TI O N ................................................................................................ 2 4  
2. 1  
St u d y Rati o nale  ..................................................................................................... 2 4  
2. 2  
Bac k gr o u n d  ........................................................................................................... 2 4  
2. 3  
Be nefit/ Ri s k Assess me nt ...................................................................................... 2 5  
3  
O BJ E C TI V E S A N D E N D P OI N T S  ...................................................................... 2 6  
4  
S T U D Y D E SI G N  ................................................................................................. 3 4  
4. 1  
O verall De si g n ...................................................................................................... 3 4  
4. 2  
St u d y C o n d uct Miti gati o n D uri n g St u d y Disr u pti o ns D ue t o Cases of Ci vil 
Crisis, Nat ural Disaster, or P u blic Healt h Crisis  .................................................. 3 6  
4. 2. 1  
C o m pleti n g Partici pa nt N u m bers t o Mai ntai n St u d y I nte grit y  ............................. 3 7  
4. 3  
Scie ntific Rati o nale f or St u d y Desi g n  .................................................................. 3 7  
4. 3. 1  
Partici pa nt I n p ut i nt o Desi g n  ................................................................................ 3 7  
4. 3. 1. 1  
C o or di nat or I n p ut .................................................................................................. 3 7  
4. 3. 1. 2  
Partici pa nt I n p ut .................................................................................................... 3 8  
4. 4  
J ustificati o n f or D ose ............................................................................................ 3 8  
4. 5  
E n d of St u d y Defi niti o n  ........................................................................................ 3 8  
5  
S T U D Y P O P U L A TI O N  ....................................................................................... 3 9  
5. 1  
I ncl usi o n Criteria .................................................................................................. 3 9  
5. 2  
E xcl usi o n Criteria  ................................................................................................. 4 2  
5. 3  
Lifest yle C o nsi derati o ns  ....................................................................................... 4 4  
5. 3. 1  
Caffei ne, To bacc o, a n d Alc o h ol  ............................................................................ 4 4  
5. 3. 2  
Illicit Dr u gs or Dr u gs of A b use ............................................................................ 4 4  
5. 4  
Scree n Fail ures ...................................................................................................... 4 4  
6  
S T U D Y I N T E R V E N TI O N  ................................................................................... 4 5  
6. 1  
St u d y I nter ve nti o n(s) A d mi nistere d  ...................................................................... 4 6  
6. 1. 1  
I n vesti gati o nal Pr o d ucts........................................................................................ 4 6  
6. 1. 2  
Me dical De vic es I ncl u di n g C o m bi nati o n Pr o d ucts wit h De vice C o nstit ue nt  ...... 4 7  
6. 2  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ...................................................... 4 7  
6. 3  
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  .................................. 4 7  
6. 4  
St u d y I nter ve nti o n C o m plia nce  ............................................................................ 4 8  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
6. 5  
C o nc o mita nt T hera p y  ........................................................................................... 4 8  
6. 5. 1  
Resc ue Me dici ne  ................................................................................................... 4 9  
6. 5. 2  
Pri or Me dicati o ns .................................................................................................. 4 9  
6. 5. 3  
C o nc o mita nt Me dicati o ns  ..................................................................................... 5 0  
6. 5. 3. 1  
Vacci nati o ns  .......................................................................................................... 5 1  
6. 5. 4  
Pr o hi bite d Me dicati o ns  ......................................................................................... 5 1  
6. 6  
D ose M o dificati o n  ................................................................................................ 5 4  
6. 7  
I nter ve nti o n After t he E n d of t he St u d y ................................................................ 5 4  
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ............................................................. 5 4  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n  ................................................................. 5 4  
7. 2  
Partici pa nt Wit h dra w al fr o m t he St u d y  ................................................................ 5 5  
7. 3  
L ost t o F oll o w -u p  ................................................................................................. 5 5  
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ................................................ 5 6  
8. 1  
Efficac y Assess me nts  ............................................................................................ 5 6  
8. 1. 1  
P ul m o nar y F u ncti o n Tests  .................................................................................... 5 6  
8. 1. 1. 1  
I n-Cli nic S pir o metr y Sta n dar dizati o n  ................................................................... 5 6  
8. 1. 1. 2  
I n-Cli nic S pir o metr y Sc he d ule  ............................................................................. 5 7  
8. 1. 1. 3  
Re versi bilit y t o Al b uter ol  ..................................................................................... 5 9  
8. 1. 2  
Partici pa nt’s e Diar y Data C ollecti o n  .................................................................... 6 0  
8. 1. 2. 1  
e Diar y C o m plia nce Re q uire me nt  ......................................................................... 6 0  
8. 1. 2. 2  
Dail y e Diar y Re p orti n g ......................................................................................... 6 0  
8. 1. 2. 3  
Ast h ma S y m pt o ms  ................................................................................................ 6 1  
8. 1. 2. 4  
Resc ue Me dic ati o n Use  ........................................................................................ 6 1  
8. 1. 2. 5  
Pea k E x pirat or y Fl o w  ........................................................................................... 6 2  
8. 1. 2. 6  
I n hale d Ast h ma Mai nte n a nce Us e ........................................................................ 6 2  
8. 1. 2. 7  
St u d y Visit e Diar y Data C ollecti o n  ...................................................................... 6 2  
8. 1. 2. 8  
S y m pt o m Worse ni n g Ass ess me nt a n d e Diar y Al ert S yste m  ................................ 6 5  
8. 2  
Safet y Assess me nts  ............................................................................................... 6 6  
8. 2. 1  
Me dical/ S ur gical Hist or y  ...................................................................................... 6 6  
8. 2. 2  
P h ysical E xa m  ...................................................................................................... 6 6  
8. 2. 3  
Hei g ht a n d Wei g ht  ................................................................................................ 6 6  
8. 2. 4  
Vital Si g ns  ............................................................................................................. 6 6  
8. 2. 5  
Electr ocar di o gra ms  ............................................................................................... 6 6  
8. 2. 6  
Cli nical Safet y La b orat or y Assess me nts  .............................................................. 6 7  
8. 2. 7  
Ast h ma E xacer bati o ns  .......................................................................................... 6 8  
8. 2. 7. 1  
Defi niti o n of Wors e ni n g of Ast h ma Si g ns/ S y m pt o ms  .......................................... 6 8  
8. 2. 7. 2  
I n vesti gat or J ustifie d Ast h ma E xacer bati o ns ........................................................ 6 8  
8. 2. 7. 3  
Se verit y of Ast h ma E x acer bati o n  ......................................................................... 6 9  
8. 2. 7. 4  
Treat me nt f or Ast h ma E xacer bati o ns  ................................................................... 6 9  
8. 2. 7. 5  
O nset a n d D urati o n of Ast h ma E xacer bati o ns  ...................................................... 7 0  
8. 2. 7. 6  
A p pr oac h f or Ca pt uri n g Ast h ma E xacer bati o ns  ................................................... 7 1  
8. 2. 8  
Ot her Safet y A ssess me nts ..................................................................................... 7 1  
8. 2. 8. 1  
Para d o xical Br o nc h os p as m  ................................................................................... 7 1  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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8. 3  
A d verse E v e nts a n d Seri o us A d verse E ve nts  ....................................................... 7 1  
8. 3. 1  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E I nf or mati o n  ................. 7 2  
8. 3. 2  
F oll o w -u p of A Es a n d S A Es  ................................................................................. 7 2  
8. 3. 3  
Ca usalit y C ollecti o n .............................................................................................. 7 3  
8. 3. 4  
A d verse E v e nts Base d o n Si g ns a n d S y m pt o ms  .................................................. 7 3  
8. 3. 5  
A d verse E v e nts Ass oci ate d wit h Use of I C S a n d L A B As  .................................... 7 3  
8. 3. 6  
A d verse E v e nts Base d o n E xa mi nati o ns a n d Tests  .............................................. 7 3  
8. 3. 7  
 ....................................................................... 7 4  
8. 3. 8  
Disease U n d er St u d y ............................................................................................. 7 4  
8. 3. 9  
Re p orti n g of Seri o us A d verse E ve nts  ................................................................... 7 4  
8. 3. 1 0  
Pre g na nc y  ............................................................................................................. 7 5  
8. 3. 1 0. 1  
Mat er nal E x p os ur e  ................................................................................................ 7 5  
8. 3. 1 1  
Me dicati o n Err or, Dr u g A b use, a n d Dr u g Mis use  ................................................ 7 6  
8. 3. 1 1. 1  
Ti meli nes  .............................................................................................................. 7 6  
8. 3. 1 1. 2  
Me dicati o n Err or  ................................................................................................... 7 6  
8. 3. 1 1. 3  
Dr u g A b us e  ........................................................................................................... 7 6  
8. 3. 1 1. 4  
Dr u g Mis use .......................................................................................................... 7 7  
8. 3. 1 2  
De vice C o nstit ue nt Deficie ncies ........................................................................... 7 7  
8. 3. 1 2. 1  
Ti me Peri o d f or Detecti n g De vice C o nstit ue nt Deficie ncies  ................................ 7 7  
8. 3. 1 2. 2  
F oll o w -u p of De vice C o nstit ue nt Deficie ncies ..................................................... 7 7  
8. 3. 1 2. 3  
Pr o m pt Re p orti n g of De vice C o nstit ue nt Deficie ncies t o Astra Ze n eca  ............... 7 8  
8. 4  
O ver d ose  ............................................................................................................... 7 8  
8. 5  
H u ma n Bi ol o gical Sa m ples  .................................................................................. 7 8  
8. 5. 1  
P har mac o ki netics  .................................................................................................. 7 8  
8. 5. 2  
I m m u n o ge nicit y Assess me nts ............................................................................... 7 8  
8. 5. 3  
P har mac o d y na mics  ............................................................................................... 7 8  
8. 6  
H u ma n Bi ol o gical Sa m ple Bi o mar kers  ................................................................ 7 9  
8. 7  
O pti o nal Ge n o mics I nitiati ve Sa m ple  ................................................................... 7 9  
8. 8  
Healt hcare Res o ur ce Utilizati o n Data  .................................................................. 7 9  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................... 7 9  
9. 1  
Statistical H y p ot heses  ........................................................................................... 7 9  
9. 2  
A nal ysis Met h o ds f or Esti ma n ds  .......................................................................... 8 0  
9. 2. 1  
Ty pe I Err or C o ntr ol  ............................................................................................. 8 0  
9. 2. 1. 1  
 A p pr oac h ......................................................................................................... 8 0  
9. 2. 1. 2  
 A p pr oac h ......................................................................................... 8 2  
9. 3  
Sa m ple Size Deter mi nati o n  .................................................................................. 8 3  
9. 4  
P o p ulati o ns f or A nal yses  ...................................................................................... 8 4  
9. 5  
Statistical A nal yses  ............................................................................................... 8 4  
9. 5. 1  
Ge neral C o nsi derati o ns  ......................................................................................... 8 4  
9. 5. 1. 1  
De m o gra p hic a n d Baseli ne C haracteristics  .......................................................... 8 4  
9. 5. 1. 2  
Visit Wi n d o ws  ....................................................................................................... 8 4  
9. 5. 1. 3  
Baseli ne ................................................................................................................. 8 5  
9. 5. 2  
Efficac y  ................................................................................................................. 8 5  
9. 5. 2. 1  
Pri mar y E n d p oi nt(s) .............................................................................................. 8 5  
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Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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9. 5. 2. 2  
Sec o n dar y E n d p oi nt(s) .......................................................................................... 8 6  
9. 5. 2. 3  
Tertiar y/ E x pl orat or y E n d p oi nt(s)  .......................................................................... 8 8  
9. 5. 2. 4  
1 2 -H o ur P F T S u b -St u d y  ....................................................................................... 9 2  
9. 5. 2. 5  
Healt hcare Res o ur ce Utilizati o n  ........................................................................... 9 3  
9. 5. 3  
Safet y  .................................................................................................................... 9 3  
9. 5. 3. 1  
A d verse  E v e nts  ..................................................................................................... 9 3  
9. 5. 3. 2  
Vital Si g ns  ............................................................................................................. 9 3  
9. 5. 3. 3  
Cli nical La b orat or y Val ues  ................................................................................... 9 3  
9. 5. 4  
S u b gr o u p A nal yses  ............................................................................................... 9 4  
9. 6  
I nteri m A nal ys es ................................................................................................... 9 4  
9. 7  
Data M o nit ori n g C o m mittee  ................................................................................. 9 4  
1 0  
S U P P O R TI N G  
D O C U M E N T A TI O N  
A N D  
O P E R A TI O N A L 
C O N SI D E R A TI O N S  ............................................................................................ 9 5  
1 1  
R E F E R E N C E S  ................................................................................................... 1 2 1  
 
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  
 T y pe I Err or C o ntr ol Pr oce d ure ............................................................ 8 1  
 
LI S T O F T A B L E S  
Ta ble  1  
Sc he d ule of A cti vities  ................................................................................. 1 9  
Ta ble  2  
Ti mi n g of I n-Cli nic S pir o metr y Meas ure me nts  .......................................... 2 3  
Ta ble  3  
O bjecti ves a n d E n d p oi nts  ............................................................................ 2 6  
Ta ble  4  
Ta ble re m o v e d i n A me n d me nt 0 2  ............................................................... 3 3  
Ta ble  5  
I n v esti gati o nal/ N o n-I n vesti gati o nal Pr o d ucts ............................................. 4 6  
Ta ble  6  
Re q uire d I C S D osa ges ( M o n ot hera p y or i n C o m bi nati o n wit h L A B A) 
Pri or t o Visit  1  ............................................................................................. 5 0  
Ta ble  7  
All o we d Me dicati o ns wit h Defi ne d Sta ble D osi n g Peri o d Pri or t o Visit  1  5 1  
Ta ble  8  
Pr o hi bite d Me dicati o ns T hr o u g h o ut t he St u d y a n d Re q uire d Cessati o n 
Peri o d Pri or t o Visit  1  ................................................................................. 5 3  
Ta ble  9  
Pr o hi bite d Ast h ma a n d Aller g y Me dicati o ns fr o m Visit  1 O n war ds  .......... 5 4  
Ta ble  1 0  
Patie nt Re p orte d O utc o m es A d mi nistere d at t he Cli nic Visit  ..................... 6 3  
Ta ble  1 1  
La b orat or y Varia bl es  ................................................................................... 6 8  
Ta ble 1 2  
P o p ulati o ns f or A nal yses  ............................................................................. 8 4  
 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
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  .......................... 9 6  
A p pe n di x  B  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, E val u ati n g, 
F oll o w -u p, a n d Re p orti n g  ......................................................................... 1 0 4  
A p pe n di x  C  
O pti o nal Ge n o mics I nitiati ve Researc h  .................................................... 1 1 0  
A p pe n di x  D  
Pr ot oc ol A me n d me nt Hist or y  ................................................................... 1 1 3  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 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  
Ast h ma C o ntr ol Q uesti o n naire  
A E  
a d verse e ve nt 
AI R Q  
Ast h ma I m pair me nt a n d Ris k Q uesti o n naire  
A N C O V A  
a n al ysis of c o varia nce  
A Q L Q(s) + 1 2  
Ast h ma Q ualit y of Life Q uesti o n naire  
A T S  
A merica n T h oracic S ociet y  
A U C  
area u n der t he c ur ve  
B D  
B u des o ni de  
B F F  
b u des o ni de a n d f or m oter ol f u marate 
B G F  
b u des o ni de, gl yc o p yrr o ni u m, a n d f or m oter ol f u marate  
BI D  
t wice dail y 
C F R  
C o de of Fe deral Re g ulati o n  
CI  
c o nfi de n ce i nter val  
C O P D  
c hr o nic o bstr ucti ve p ul m o nar y disease  
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 E S  
Data E ntr y Site  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
e Diar y  
electr o nic diar y  
E Q -5 D  
E ur o pea n Q ualit y -of -Life -5 Di me nsi o ns  
E R  
e mer ge nc y r o o m  
E R S  
E ur o pea n Res pirat or y S ociet y  
F E F 2 5 -7 5 
f orce d e x pirat or y fl o w at 2 5-7 5 %  
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 
G C P  
G o o d Cli nical Practice  
GI N A  
Gl o bal I nitiati ve f or Ast h ma  
H F A  
h y dr ofl u or oal ka ne  
H C R U  
healt hcare res o urce utilizati o n  
I C E 
i nterc urre nt e ve nt 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce of Har m o nisati o n 
I C S 
i n hale d c ortic oster oi d 
I E C 
I n de p e n de nt Et hics C o m mittee 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y 
I V 
Intra v e n o us  
L A B A  
l o n g-acti n g beta 2-a g o nist 
L A M A  
l o n g-acti n g m uscari nic a nta g o nist  
M DI  
metere d d ose i n haler  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
NI M P  
N o n -I n vesti gati o nal Me dici nal Pr o d uct 
P E F  
pea k e x pirat or y fl o w  
P F T  
p ul m o nar y f u ncti o n test  
P R O  
Patie nt Re p orte d O utc o me  
Q Tc F  
Fri d ericia -c orrecte d Q T i nter val  
R o W  
Rest of W orl d  
R R  
Rate rati o  
S A E  
seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S D  
sta n dar d de viati o n 
S o A  
Sc he d ule of Acti vities  
V A S  
vis ual a n al o g ue scale  
 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
1  
P R O T O C O L S U M M A R Y   
1. 1  
S y n o psis   
Pr ot oc ol Title:  A R a n d o mize d, D o u ble -Bli n d, Parallel Gr o u p, M ultice nter 1 2 Wee k St u d y t o 
Assess t he Efficac y a n d Safet y of B u des o ni de a n d F or m oter ol F u marat e Metere d D os e I n hal e r 
Relati ve t o B u des o ni de Metere d D os e I n hal er i n Partici pa nts wit h I n a de q u atel y C o ntr olle d 
Ast h ma ( LI T H O S)  
S h ort Title:  A 1 2 -Wee k Efficac y a n d Safet y St u d y t o Assess B u des o ni de a n d F or m oter ol 
F u marate Metere d D ose I n haler i n A d ult a n d A d ol esce nt Partici pa nts wit h I na de q uatel y 
C o ntr olle d Ast h ma ( LI T H O S)  
R ati o n ale: T his st u d y will e val uate t he efficac y a n d safet y of B u des o ni de a n d F or m oter ol 
F u marat e Metere d D ose I n h aler ( B F F M DI) 1 6 0/ 9. 6  µ g BI D c o m pare d wit h B u des o ni de M DI 
1 6 0  μ g, herei nafter referre d t o as B D M DI, o ver 1 2 wee ks. T he st u d y p o p ulati o n will c o nsist 
of a d ult a n d a d oles ce nt p artici pa nts wit h ast h ma w h o re mai n i n a de q u atel y c o ntr olle d, as 
de m o nstrate d b y a n A C Q -7 t otal sc ore ≥ 1. 5, des pite treat me nt wit h l o w d os e I C S or 
I C S/ L A B A. T his st u d y is t o assess t he be nefits a n d safet y of B F F M DI o n l u n g f u ncti o n a n d 
ast h ma healt h -relate d q u alit y of life. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
O bjecti v es a n d E n d p oi nts  
O bjecti ve  
Esti m a n d  
Pri m ar y  
 A p pr o ac h  a 
 A p pr o ac h  a 
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n l u n g f u ncti o n.  
•  
Tre at me nt : Ra n d o mize d treat me nt of B F F M DI 1 6 0/ 9. 6 μ g or  B D M DI 1 6 0  μ g  
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n c ha n ge fr o m baseli ne 
•  
E n d p oi nt :  
-  C ha n ge fr o m baseli ne i n F E V 1 A U C 0 -3 at Wee k  1 2  
•  
E n d p oi nt : 
-  C ha n ge fr o m baseli ne i n m or ni n g pre -d ose tr o u g h 
F E V 1 o ver 1 2 Wee ks  
•  
Pri m ar y met h o d f or h a n dli n g I C Es:  
-  Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n: Treat me nt p olic y  
-  Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: Treat me nt p olic y  
-  I nitiati on of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: C o m p osite 
(treat me nt fail ure) if i n c o nj u ncti o n wit h pre mat ure I P disc o nti n uati o n, else Treat me nt P olic y 
S u p p orti ve  a p pr oac h f or ha n dli n g of I C Es uses W hile o n Treat me nt (ie , data after I C E will n ot be use d) f or all I C Es.  
-  Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n: W hile o n Treat me nt  
-  Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: W hile o n Treat me nt  
-  I nitiati o n of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: W hile o n 
Treat me nt  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Sec o n d ar y  
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n l u n g f u ncti o n.  
•  
E n d p oi nt: C ha n ge fr o m baseli ne i n m or ni n g pre -d ose 
tr o u g h F E V1 at Wee k  1 2  
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n 
c ha n ge fr o m baseli ne  
•  
H a n dli n g of I C Es: Sa me as f or pri mar y e n d p oi nt  
•  
E n d p oi nt: C ha n ge fr o m baseli ne i n F E V 1 A U C 0 -3 o ver 
1 2  Wee ks  
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n 
c ha n ge fr o m baseli ne  
•  
H a n dli n g of I C Es: Sa me as f or pri mar y e n d p oi nt  
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n ast h ma 
e xacer bati o ns.  
•  
E n d p oi nt: Se vere ast h ma e xacer bati o n  
•  
P o p ul ati o n s u m m ar y me as ure : Rate Rati o 
•  
H a n dli n g of I C Es: Sa me as f or pri mar y met h o d f or t he 
pri mar y e n d p oi nt  
N/ A  
T o assess t he effect of 
B F F M DI 3 2 0/ 9. 6  μ g or 
B F F 1 6 0/ 9. 6  μ g relati ve 
t o B D M DI o n ast h ma 
e xacer bati o ns (c o m bi ne d 
data fr o m St u dies 
D 5 9 8 2 C 0 0 0 0 5 a n d 
D 5 9 8 2 C 0 0 0 0 6).  
•  
E n d p oi nt: Se vere ast h ma e xacer bati o n  
•  
P o p ul ati o n s u m m ar y me as ure : Rate Rati o 
•  
H a n dli n g of I C Es: Sa me as f or pri mar y e n d p oi nt  
•  
S u p p orti ve a p pr oac h f or ha n dli n g of I C Es uses W hile 
o n Treat me nt (i e, data after I C E  will n ot be use d) f or all 
I C Es 
N/ A  
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n l u n g f u ncti o n, 
s y m pt o ms, a n d P R Os. 
•  
E n d p oi nt : C ha n ge fr o m baseli ne i n t he mea n n u m ber of p uffs of resc ue me dicati o n use ( p uffs/ da y) o ver 1 2 Wee ks 
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n c ha n ge fr o m baseli ne  
•  
H a n dli n g of I C Es: Sa me as pri mar y met h o d f or pri mar y e n d p oi nt  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -7 ( ≥ 0. 5 
decrease e q uals res p o nse) at Wee k  1 2  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -7 ( ≥ 0. 5 
decrease e q uals res p o nse) o ver 1 2 Wee ks  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y met h o d f or h a n dli n g I C Es:  
-  Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n: Treat me nt p olic y  
-  Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: Treat me nt p olic y  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
-  I nitiati on of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: C o m p osite 
(treat me nt fail ure) if i n c o nj u ncti o n wit h pre mat ure  I P disc o nti n uati o n, else Treat me nt P olic y 
•  
S u p p orti ve C o m p osite  
•  
Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n:  
-  F or reas o ns relate d t o gl o bal/c o u ntr y sit uati o n, data f oll o wi n g s uc h I C E will be c o nsi dere d missi n g a n d will n ot be 
i m p ute d.  
-  F or ot her reas o ns, n o n -res p o n der stat us will be ass u me d f or partici pa nts f oll o wi n g s uc h IC E ( C o m p osite strate g y).  
•  
Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: n o n-res p o n der stat us will be ass u me d f or partici pa nts f oll o wi n g s uc h I C E ( C o m p osite strate g y). 
•  
I nitiati o n of ne w ast h ma t hera p y or a d diti o nal pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: n o n-res p o n der stat us will 
be ass u me d f or partici pa nts fr o m (a n d i ncl u di n g) da y of first I C E ( C o m p osite strate g y).  
 
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -5 ( ≥ 0. 5 
decrease e q uals res p o nse) at Wee k  1 2  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or 
A C Q -7  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -5 ( ≥ 0. 5 
decrease e q uals res p o nse) at Wee k  1 2 or o ver 1 2 Wee ks  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or A C Q -7  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A Q L Q(s) + 1 2 
( ≥ 0. 5 i ncrease e q uals res p o nse) at Wee k  1 2  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or 
A C Q -7  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A Q L Q(s) + 1 2 
( ≥ 0. 5 i ncrease e q uals res p o nse) at Wee k  1 2 or o ver 
1 2  Wee ks  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or A C Q -7  
•  
E n d p oi nt: O nset of acti o n o n Da y  1: A bs ol ute c ha n ge i n F E V 1 at 5 mi n utes p ost -d ose o n Da y  1  
•  
P o p ul ati o n S u m m ar y Me as ure: Differe nce i n mea n c ha n ge fr o m baseli ne  
•  
Pri m ar y h a n dli n g of I C Es:  Sa me as pri mar y met h o d f or pri mar y e n d p oi nt  
a 
Refers t o s u b missi o n stra te g y wit h res pect t o Healt h A ut h orit y res p o nsi ble f or re vie wi n g mar keti n g a ut h orizati o n, n ot t he recr uit me nt l ocati o n/ nati o nalit y of 
t he partici pa nts. 
 
F or Tertiar y/ E x pl orat or y a n d Safet y o bjecti ves, esti ma n ds descri pti o ns, a n d e n d p oi nts, see Secti o n 3  of t he pr ot oc ol.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m o ter ol F u marate - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
O ver all Desi g n  
T his is a P hase III ra n d o mize d, d o u ble -bli n d, acti ve c o m parat or, parallel gr o u p, m ultice nter 
st u d y c o m pari n g B F F M DI 1 6 0/ 9. 6 µ g t o B D M DI 1 6 0  µ g i n a d ult a n d a d olesce nt partici pa nts 
w h o ha ve ast h ma w hic h re mai ns i na de q uatel y c o ntr olle d ( A C Q -7 t otal sc ore ≥ 1. 5) des pite 
treat me nt wit h l o w d ose I C S or I C S/ L A B A. All st u d y i nter ve nti o ns will be a d mi nistere d as 
2  act uati o ns BI D f or 1 2 wee ks.  
T his st u d y will be c o n d ucte d at a p pr o xi mat el y 9 0 sites w orl d wi de a n d will ra n d o mize 
a p pr o xi matel y 3 4 0 a d ult a n d a d olesce nt partici pa nts.  
At Visit  1, all partici pa nts m ust be ta ki n g a sta ble dail y l o w d ose I C S or l o w d ose c o m bi nati o n 
of I C S/ L A B A f or at least 8  wee ks pri or t o Visit  1. After meeti n g t he scree ni n g eli gi bilit y 
criteria, p artici pa nts will disc o nti n ue t hei r l o w d ose I C S or I C S/ L A B A at Visit 1 a n d i nitiate 
r u n-i n B D M DI 1 6 0 µ g ta ke n BI D u ntil t he e ve ni n g pri or t o Visit  4 (ra n d o mizati o n), w he n 
r u n-i n B D M DI will be disc o nti n ue d.  
At Visit  4, partici pa nts eli gi ble f or t he st u d y will disc o nti n ue r u n -i n B D M DI an d be 
ra n d o mize d i n a 
 sc h e me t o B F F M DI 1 6 0/ 9. 6 μ g or B D M DI 1 6 0  μ g.  
Ra n d o mizati o n will be stratifie d b y baseli ne ast h ma treat me nt (I C S vs I C S/ L A B A) a n d a ge 
( 1 2 t o < 1 8 years of a g e vers us ≥ 1 8 years of a g e).  
T his st u d y i ncl u des a 1 2 -h o ur serial s pir o m etr y s u b -st u d y. 
1 2 -h o ur S pir o metr y S u b -St u d y : Serial s pir o metr y will be c o n d ucte d o ver 1 2 h o urs i n a 
s u bset of a d ult a n d a d olesce nt partici pa nts at Visit 4 ( Da y  1) a n d Visit  7 ( Wee k  1 2). O n t h e test 
da y, a d diti o nal serial s pir o metr y will be o btai ne d at 6 -, 9 -, a n d 1 2-h o urs p ost -d ose. T he 
s u b-st u d y will be c o n d ucte d at s pecific sites t hat h a ve a gree d t o partici pate. T he tar g et is t o 
ha ve a p pr o xi mat el y 
 a n d u p t o 
 partici pa nts (
 t o 
 per treat me nt ar m) ra n d o mize d t o 
t he s u b-st u d y. 
Discl os ure St ate me n t: T his is a parallel gr o u p  st u d y wit h 2 treat me nt a r ms t hat is partici pa nt 
a n d I n vesti gat or bli n de d . 
N u m ber of P artici p a nts:  
A t otal of 3 4 0 partici pa nts will be recr uite d wit h 
 partici pa nts i n eac h tr eat me nt ar m.  
I nter ve nti o n Gr o u ps a n d D ur ati o n: 
T he treat me nt peri o d is 1 2 wee ks i n d urati o n wit h u p t o 7 i n -cli nic visits d uri n g scree ni n g a n d 
treat me nt. T he e n d of st u d y is defi ne d as t he last e x pecte d visit/c o ntact of t he last partici pa nt 
u n der g oi n g t he st u d y. Partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n will be e nc o ura ge d t o 
c o nti n ue i n t he st u d y a n d c o m plete all re mai ni n g st u d y visits a n d pr oce d ures.  
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
D at a M o nit ori n g C o m mittee: N o  
St atistic al Met h o ds  
C ha n ge fr o m bas eli ne i n F E V 1 A U C 0 -3 ( pri mar y f or 
 ke y sec o n dar y f or 
) a n d 
c ha n ge fr o m bas eli ne i n m or ni n g pre -d ose tr o u g h F E V 1 ( pri mar y f or 
; ke y sec o n dar y 
f or 
) will be a n al yze d usi n g a re peate d meas ures A N C O V A m o del. T he m o del will i ncl u de 
treat me nt, visit, pri or mai nte na nce m e dicati o n (I C S vers us I C S/ L A B A), a n d treat me nt-b y -visit 
i nteracti o n as cate g oric al c o variates a n d baseli ne tr o u g h F E V1 a n d perce nt al b uter ol 
re versi bilit y as c o nti n u o us c o variates. A n u nstr uct ure d vari a nce-c o varia nce matri x will be 
use d t o m o del t he varia n ce -c o v aria n ce str u ct ure. C o ntrasts will be use d t o o btai n esti mates of 
t he treat me nt differe n ces at Wee k 1 2. T w o -si de d p-val ues a n d p oi nt esti mates wit h t w o -si de d 
9 5 % CIs will be pr o d uce d f or eac h treat me nt differe nce. T he m o del -b ase d statistics f or ot her 
visits a n d o ver 1 2 Wee ks will als o be re p orte d.  
S a m ple Siz e: Sa m ple size calc ul ati o ns eit her ass u me d a W hile o n Treat me nt or Treat me nt 
P olic y strate g y f or I C Es. Usi n g t he W hile o n Treat me nt esti ma n d strate g y f or I C Es, a sa m ple 
size of 
 partici pa nts per treat me nt ar m will pr o vi de m ore t ha n 9 9 % p o wer t o detect a 
 m L differe nce i n t he a nal ysis of c ha n g e fr o m baseli ne i n F E V 1 A U C 0 -3 a n d 9 2 % p o wer t o 
detect a 
 m L differe n ce i n t he a n al ysis of c ha n ge fr o m baseli ne i n tr o u g h F E V
1 o ver 1 2 
Wee ks. E ac h c o m p aris o n is base d o n a t w o -si de d al p ha =
 test a n d S D of 
 m L f or F E V 1 
A U C 0 -3 a n d 
 m L f or tr o u g h F E V 1 at eac h visit wit h effecti ve S D of 
 m L a n d 
 m L, 
res pecti vel y. T he effecti v e S D f or eac h e n d p oi nt o ver 1 2 Wee ks ass u mes 2 visits o ver t he 
i nter val a n d t hat t he c orrelati o n a m o n g visits is 
. T hese sa m ple siz es ass u me t hat 
a p pr o xi matel y 
% of ra n d o mize d partici pa nts will ha ve disc o nti n ue d st u d y i nter ve nti o n pri or 
t o Wee k 1 2.  
Usi n g t he Treat me nt P olic y esti ma n d strate g y f or I C Es, a s maller treat me nt differe nce (t ha n 
f or t he W hile o n Treat me nt  strate g y) of 
 m L f or tr o u g h F E V 1 is ass u me d, pr o vi di n g a 
p o wer at 1 2 w ee ks i n tr o u g h F E V 1 of 8 0 %. Ass u mi n g a s maller treat me nt effect of 
 m L f or 
F E V 1 A U C 0 -3, t he p o wer w o ul d re mai n at least 9 9 %. 
P o p ul ati o ns f or A n al yses : T he f oll o wi n g p o p ulati o ns f or anal yses are d efi n e d f or t his st u d y. 
T he Scree ne d set is defi n e d as all partici pa nts w h o si g n t he I C F. T he Ra n d o mize d set is 
defi ne d as all partici pa nts w h o are ra n d o mize d t o st u d y i nter ve nti o n. T he Efficac y set is 
defi ne d as all partici pa nts w h o are ra n d o m ize d t o st u d y i nter ve nti o n a n d recei ve a n y a m o u nt 
of st u d y i nter ve nti o n a n d will be a nal y ze d acc or di n g t o t he st u d y i nter ve nti o n assi g ne d at 
ra n d o mizati o n, re g ar dless of t he act ual i nter ve nti o n recei v e d. T he Safet y set is defi ne d as all 
partici pa nts w h o ar e ra n d o mize d t o st u d y i nter ve nti o n a n d recei ve a n y a m o u nt of t he st u d y 
i nter ve nti o n a n d will be a nal yze d acc or di n g t o t he act ual st u d y i nter ve nti o n recei v e d rat h er 
t ha n t he ra n d o mize d st u d y i nter ve nti o n. T he P ul m o nar y F u ncti o n S u b-St u d y set is defi ne d as 
all partici pa nts w h o are ra n d o mize d a n d h a ve at least o ne p ost -baseli ne s pir o metr y assess me nt 
i n t he s u b-st u d y (after t h e first d ose of st u d y me di cati o n).  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
1. 2  
Sc he m a   
Fi g ure  1  
St u d y Desi g n   
 
 
B D = B u des o ni de; B F F = B u des o ni de a n d F or m oter ol F u marate; BI D =t wice dail y; F/ U =f oll o w -u p; M DI = metere d 
d ose i n haler; W k = wee k  
a. 
St o p dail y I C S)/ L A B A or I C S re gi me n a n d start r u n -i n B D M DI 1 6 0 µ g BI D  
 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
1. 3  
Sc he d ule of Acti vities   
Ta ble  1  
Sc he d ule of Acti vities   
 
Scree ni n g  
Tre at me nt Peri o d  
St u d y 
I nter ve nti o n 
Disc o nti n u ati o n 
or St u d y 
Wit h dr a w al  
F/ U T C  
Det ails i n C S P Secti o n or 
A p pe n di x  
Visit a, b 
1  
2  
3  
4  
5  
6  
7  
2 wee ks ( ±  2 
d a ys) after l ast 
d ose  
 
Wee k  
 
 
 
R a n d  
4  
8  
1 2  
St u d y D a y c 
-2 1  
-1 4 ( +  2)  
-7 ( ±  2)  
1  
2 9 ( ±  2)  
5 7 ( ±  5)  
8 5 ( ±  5)  
I nf or me d c o nse nt/asse ntd 
X  
 
 
 
 
 
 
 
 
Secti o n 4. 1 , Secti o n 5. 1 , 
A p pe n di x A  3  
I ncl usi o n/e xcl usi o n criteria 
X  
X  
X  
X  
 
 
 
 
 
Secti o n 5. 1 , Secti o n 5. 2  
Verif y c o nti n ui n g eli gi bilit y  
 
 
 
 
X  
X  
X  
 
 
Secti o n 7. 1  
Calc ulate F E V 1 sta bilit y li mit 
X  
 
 
 
 
 
 
 
 
Secti o n 5. 1  
Calc ulate P E F sta bilit y li mit  
 
 
 
X  
 
 
 
 
 
Secti o n 8. 1. 2. 5  
R o uti ne cli nic al pr oce d ures  
De m o gra p h y a n d me dical/s ur gical 
hist or y  
X  
 
 
 
 
 
 
 
 
Secti o n 5. 1 , Secti o n 8. 2. 1  
Pri or/c o nc o mita nt me dicati o n 
re vie w 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Secti o n 6. 5  
Dis pe nse a n d c ollect e Diar y  
X e 
 
 
 
 
 
X  
X  
 
Secti o n 8. 1. 2  
Dis pe nse a n d c ollect pea k fl o w 
meter  
X e 
 
 
 
 
 
X  
X  
 
Secti o n 8. 1. 2. 5  
e Diar y trai ni n g a n d re vie w  
X e 
X  
X  
X  
X  
X  
X  
X  
 
Secti o n 8. 1. 2  
Pea k fl o w meter trai ni n g a n d 
re vie w 
X e 
X  
X  
X  
X  
X  
X  
X  
 
Secti o n 8. 1. 2. 5  
Dis pe nse/c ollect al b uter ol (as 
nee de d)  
X e 
X  
X  
X  
X  
X  
X  
X  
 
Secti o n 4. 1 , Secti o n 6 , 
Secti o n 6. 5. 1  

Cli nical St u d y Pr o t oc ol - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
 
Scree ni n g  
Tre at me nt Peri o d  
St u d y 
I nter ve nti o n 
Disc o nti n u ati o n 
or St u d y 
Wit h dr a w al  
F/ U T C  
Det ails i n C S P Secti o n or 
A p pe n di x  
Visit a, b 
1  
2  
3  
4  
5  
6  
7  
2 wee ks ( ±  2 
d a ys) after l ast 
d ose  
 
Wee k  
 
 
 
R a n d  
4  
8  
1 2  
St u d y D a y c 
-2 1  
-1 4 ( +  2)  
-7 ( ±  2)  
1  
2 9 ( ±  2)  
5 7 ( ±  5)  
8 5 ( ±  5)  
Re versi bilit y t o al b uter ol  
 
X f 
X f 
 
 
 
 
 
 
Ta ble  2 , Secti o n 8. 1. 1. 3  
Disc o nti n ue I C S or I C S/ L A B A  
X e 
 
 
 
 
 
 
 
 
Secti o n 4. 1 , Secti o n 6  
Dis pe nse/c ollect R u n -i n B D M DI 
X e 
 
 
X  
 
 
 
 
 
Secti o n 4. 1 , Secti o n 6  
Dis pe nse/c ollect bli n de d st u d y 
i nter ve nti o n 
 
 
 
X  
X  
X  
X  
X  
 
Secti o n 4. 1 , Secti o n 6  
S afet y assess me nts ( pre -d ose)  
A d verse e ve nt assess me nts g 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Secti o n 8. 3 , A p pe n di x  B  
Ast h ma e xacer bati o n assess me nt  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Secti o n 8. 2. 1 , Secti o n 8. 2. 7   
Pre g na nc y testi n gg 
X  
X  
X  
X  
X  
X  
X  
X  
 
Secti o n 5. 1 , Secti o n 8. 3. 1 0  
Safet y la b orat or y assess me nts 
( bl o o d) 
X  
 
 
 
 
 
X  
X  
 
Secti o n 8. 2 . 6 
P h ysical e xa mi n ati o n  
X  
 
 
X  
 
 
X  
X  
 
Secti o n 8. 2. 2  
Hei g ht a n d wei g ht  
X  
 
 
 
 
 
X  
 
 
Secti o n 8. 2. 3  
Vital si g ns ( bl o o d press ure a n d 
p ulse)  
X  
 
 
X  
 
 
X  
X  
 
Secti o n 8. 2. 4  
1 2 -lea d E C G 
X  
 
 
 
 
 
 
 
 
Secti o n 8. 2. 5  
Ge n o mics I nitiati v e, o pti o nal 
e x pl orat or y ge netic sa m ple  
 
 
 
X  
 
 
 
 
 
Secti o n 8. 7 , A p pe n di x  C  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
 
Scree ni n g  
Tre at me nt Peri o d  
St u d y 
I nter ve nti o n 
Disc o nti n u ati o n 
or St u d y 
Wit h dr a w al  
F/ U T C  
Det ails i n C S P Secti o n or 
A p pe n di x  
Visit a, b 
1  
2  
3  
4  
5  
6  
7  
2 wee ks ( ±  2 
d a ys) after l ast 
d ose  
 
Wee k  
 
 
 
R a n d  
4  
8  
1 2  
St u d y D a y c 
-2 1  
-1 4 ( +  2)  
-7 ( ±  2)  
1  
2 9 ( ±  2)  
5 7 ( ±  5)  
8 5 ( ±  5)  
Effic ac y me as ure me nts h  
I n-cli nic serial s pir o metr y i 
 
 
 
X  
 
X  
X  
X  
 
Ta ble  2 , Secti o n 8. 1. 1  
I n-cli nic pre -d ose s pir o metr y i 
X j 
X  
X  
X  
X  
X  
X  
X  
 
Ta ble  2 , Secti o n 8. 1. 1  
A C Q ( pre -d ose)  
X  
 
 
X  
X  
X  
X  
X  
 
Secti o n 8. 1. 2. 7  
A Q L Q(s) + 1 2 ( pre -d ose)  
 
 
 
X  
X  
X  
X  
X  
 
Secti o n 8. 1. 2. 7  
E Q -5 D ( pre -d ose)  
 
 
 
X  
X  
X  
X  
X  
 
Secti o n 8. 1. 2. 7  
AI R Q ( pre -d ose)  
X  
 
 
X  
 
 
X  
 
 
Secti o n 8. 1. 2. 7  
Healt hcare res o urce utilizati o n  
 
 
X  
 
X  
X  
X  
X  
 
Secti o n 8. 8  
Serial s pir o metr y 1 2 -h o urs p ost -
d ose (s u b -st u d y) 
 
 
 
X  
 
 
X  
 
 
Ta ble  2 , Secti o n 8. 1. 1  
St u d y i nter ve nti o n a d mi nistr ati o n  
C hec k of i n halati o n de vice 
tec h ni q ue a n d trai ni n g 
X e 
X  
X  
X  
X  
X  
 
 
 
Secti o n 6  
A d mi nister R u n -i n B D M DI i n 
cli nic j 
X  
X  
X  
 
 
 
 
 
 
Secti o n 4. 1 , Secti o n 6  
A d mi nister bli n de d st u d y 
i nter ve nti o n i n cli nicj 
 
 
 
X  
X  
X  
X  
 
 
Secti o n 4. 1 , Secti o n 6  
A b bre viati o ns: A C Q = Ast h ma C o ntr ol Q uesti o n naire; A Es =a d verse e ve nts; AI R Q = Ast h ma I m pair me nt a n d Ris k Q uesti o n naire; A Q L Q(s) + 1 2 = Ast h ma Q ualit y of Life 
Q uesti o n naire f or 1 2 years a n d ol der; B D = b u des o ni de; C S P = Cli nical St u d y Pr ot oc ol; E C G =electr o car di o gra m; e Diar y =electr o nic diar y; P R O = Patie nt Re p orte d O utc o me; E Q -
5 D = E ur o pea n Q ualit y of Life -5 Di me nsi o ns; F/ U =f oll o w -u p; I C S/ L A B A =i n hale d c ortic oster oi d/l o n g -acti n g beta 2-a g o nist; M DI = metere d d ose i n haler; P E F = pea k e x pirat or y fl o w; 
Ra n d =ra n d o mizati o n; S A E =seri o us  a d verse e ve nt; T C =tele p h o ne call  
a 
Ris k assess me nts f or t he S A R S -C o V -2 pa n de mic m ust b e ma de pri or t o e ver y i n -cli nic visit i n li ne wit h t he St u d y Disr u pti o n Miti gati o n I nstr ucti o ns.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
b 
Sites s h o ul d call partici pa nts 1  t o 2 da ys bef ore eac h sc he d ule d visit t o re mi n d t he partici pa nt of t he visit a n d t he re q uire d me dicati o n was h o uts ( 6 h o urs f or 
s h ort-acti n g br o nc h o dilat ors a n d 1 2 h o urs f or r u n -i n B D M DI a n d bli n de d st u d y i nter ve nti o n). Partici pa nts will be re q uire d t o ret ur n t o t he cli nic at 
a p pr o xi matel y t he sa me ti me ±  1 h o ur as Visit  1 t hr o u g h o ut t he st u d y. F or all visits after Visit  1, if al b uter ol a n d st u d y i nter ve nti o n ha v e n ot b ee n wit h hel d 
f or t he s pecifie d ti mefra mes, t he visit s h o ul d be resc he d ule d a n d c o n d ucte d wit hi n t he s pecifie d visit wi n d o w.  
c 
Site s h o ul d ma k e e v er y eff ort t o mai ntai n partici pa nts wit hi n t he sc he d ule d visit wi n d o ws. Partici pa nts w h o fall o utsi de t he visit wi n d o w s h o ul d be place d 
i n t he pr ot oc ol-defi ne d wi n d o w at t he ne xt sc he d ule d visit.  
d 
I nf or me d c o nse nt f or m ma y be si g ne d at or pri or t o Visit 1.  
e 
At Visit  1, iss ue/trai n partici pa nts o n e Diar y/ pea k fl o w meter use, disc o nti n ue I C S or I C S/ L A B A, a n d dis pe nse al b uter ol a n d r u n -i n B D M DI o nl y  after t he 
partici pa nt h as bee n f o u n d eli gi ble t o pr ocee d t o Visit  2. S h o ul d t here be a n y c o ncer n t ha t t he I C S or I C S/ L A B A was ta ke n pri or t o Visit 1, t his visit ca n be 
resc he d ule d wit hi n 2 da ys.  
f 
If re v ersi bilit y criteri o n is n ot met at Visit 2, partici pa nts ma y c o nti n ue t o Visit 3. Re versi bilit y criteri o n m ust b e met eit her i n t he 1 2 m o nt hs pri or t o Vis it 1 
or at Visit  2 or Visit  3, ot her wise t he partici pa nt will be scree n faile d.  
g 
F or all scree n fail ures, a n assess me nt of A Es a n d hi g hl y se nsiti ve uri ne pre g na nc y testi n g (f or w o me n of c hil d beari n g p ote nti al) m ust b e perf or me d wit hi n 7 
da ys of t he scree n f ail ure date. 
h 
T he s u g geste d or der of assess me nts is vital si g ns, A E/ S A E assess me nts, -6 0 -mi n ute s pir o metr y, P R O q uesti o n naires, -3 0 -mi n ute s pir o metr y, E C G, bl o o d 
dra w, a n d t he n st u d y i nter ve nti o n a d mi nistrati o n. S pir o m etr y M U S T be perf or m e d i n acc or d a nce wi t h t he s pecifie d ti mi n g. 
i 
All pre -d ose (tr o u g h) s pir o metr y will be re q uire d t o be c ollecte d i n t he m or ni n g ( 0 8 0 0 ±  2 h o urs).  
j 
Partici pa nts w h o ha v e n ot wit h hel d ast h ma me dicati o ns pri or t o Visit  1 a n d faile d s pir o metr y i ncl usi o n criteria at Visit  1 s h o ul d ret ur n t o t he cli nic t o re p eat 
s pir o metr y testi n g ( or ha ve t he s pir o metr y p ost p o ne d if it is k n o w n i n a d va nce t hat t he partici pa nt has n ot was he d o ut) wit hi n 2 da ys. If re p eat s pir o metr y 
fails t o meet t he i ncl usi o n criteria, t he n t he partici pa nt m ust be scree n faile d. 
k 
All i n -cli nic d osi n g m ust o cc ur pri or t o 1 0 0 0 ( +  1 h o ur all o wa nce)  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Ta ble  2  pr o vi des ti mi n g of s pecific assess me nts. E ns ure pre -d ose  s pir o metr y assess me nts are c o n d u cte d as cl ose t o t he s p ecifie d 
ti me p oi nts as p ossi ble. All st u d y pr oce d ures will b e c o n d ucte d pri or t o d osi n g, wit h t he e xce pti o n of p ost-d ose s pir o metr y.  
Ta ble  2  
Ti mi n g of I n -Cli nic S pir o metr y Me as ure me nts   
Visits  
Pre -d ose  
P ost -d ose  
Mi n utes  
Mi n utes  
H o urs  
-6 0 
( ± 1 0) 
-3 0 
( ± 1 0) 
5  
( ± 2) 
1 5 
( ± 5) 
3 0 
( ± 5) 
1  
( ± 1 0 mi n) 
2  
( ± 1 0 mi n) 
3  
( ± 1 0 mi n) 
6  
(± 1 0 mi n)  
9  
(± 1 0 mi n)  
1 2  
( ±1 0 mi n)  
1 a n d 5  
X  
X  
 
 
 
 
 
 
 
 
 
2 (re v ersi bilit y t o al b uter ol) a n d 3 
(re v ersi bilit y t o al b uter ol, if 
nee de d)  
X  
X  
 
 
X  
X a 
 
 
 
 
 
4  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
6 a n d 7 or St u d y I nter ve nti o n 
Disc o nti n uati o n/ Wit h dra wal  
X  
X  
 
X  
X  
X  
X  
X  
 
 
 
1 2 -h o ur s pir o metr y s u b-st u d y at 
Visits 4 a n d 7  
X  
X  
X b 
X  
X  
X  
X  
X  
X  
X  
X  
a. F or re v ersi bilit y, 1 -h o ur p ost -d ose s pir o metr y ma y be assesse d if n ot re versi ble at 3 0 mi n utes p ost -d ose  
b.  O nl y a p plies at Visit  4  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
2  
I N T R O D U C TI O N  
Astra Ze neca is de v el o pi n g orall y i n hale d dr u g pr o d ucts c o ntai ni n g b u des o ni de ( a n I C S) a n d 
f or m oter ol f u marate (a L A B A) f or t he treat me nt of ast h ma. T hes e dr u g pr o d ucts are 
f or m ulate d as a s us p e nsi o n wit h micr o nize d acti v e p har mace utical i n gre die nts a n d C o-
S us pe nsi o n ™ Deli ver y Tec h n ol o g y i n M DIs. T he C o -S us pe nsi o n Deli ver y Tec h n ol o g y 
c o nsists of s pra y -drie d p or o us particle s c o m pris e d of t he p h os p h oli pi d 1, 2-distear o yl -s n-
gl ycer o -3 -p h os p h o c h oli ne a n d calci u m c hl ori de s us pe n de d i n a n H F A pr o pella nt. W he n use d 
i n c o m bi nati o n M DI pr o d ucts, t hese particles f or m str o n g n o n-s pecific ass ociati o ns wit h t he 
acti ve p har m ace utical i n gr e die nts, pre v e nti n g t he dr u gs fr o m i nteracti n g wit h eac h ot her i n t he 
s us pe nsi o n a n d pr o vi di n g re pr o d uci ble dr u g deli ver y a n d l o n g-ter m sta bilit y. 
T he test f or m ulati o n t o be e val uat e d i n t his st u d y is a n M DI wit h a 
 
c o ntai ni n g a fi xe d -d os e c o m bi nati o n of b u des o ni de a n d f or m oter ol f u marate.  
2. 1  
St u d y R ati o n ale   
B u des o ni de a n d F or m oter ol F u marate M DI, herei nafter referre d t o as B F F M DI, is bei n g 
de vel o pe d f or use i n t he treat me nt of ast h ma. Per GI N A g ui da nce [ GI N A  2 0 2 1] 
I C S-c o ntai ni n g treat me nt s h o ul d be i nitiate d earl y i n t he disease c o urse t o i m pr o ve s y m pt o ms 
a n d l u n g f u ncti o n a n d t o re d uce ris k. L o n g-acti n g beta 2-a g o nist is a d v ocate d as a n a d diti o nal 
c o ntr oller i n t h ose w h o re mai n u nc o ntr olle d wit h I C S al o ne.  
T his st u d y will e val uate t he effi cac y a n d safet y of B F F M DI 1 6 0/ 9. 6  µ g BI D c o m pare d wit h 
B u des o ni de M DI 1 6 0  μ g BI D, h erei nafter referre d t o as B D M DI, o v er 1 2  wee ks. T he st u d y 
p o p ulati o n will c o nsist of a d ult a n d a d olesce nt partici pa nts wit h ast h ma w h o re m ai n 
i na de q uatel y c o ntr olle d, as de m o nstrate d b y a n A C Q-7 t otal sc ore ≥ 1. 5, d es pite treat me nt 
wit h l o w d ose I C S or l o w d ose c o m bi nati o n of I C S/ L A B A. T his st u d y is t o assess t he be nefits 
a n d safet y of B F F M DI o n l u n g f u ncti o n a n d ast h ma healt h -relate d q ualit y of life. 
2. 2  
B ac k gr o u n d   
Ast h ma is a heter o ge n e o us disease t hat is c haract erize d b y c hr o nic air wa y i nfla m mati o n a n d 
br o nc hial h y perreacti vit y. It is defi ne d b y a hist or y of res pira t or y s y m pt o ms s uc h as w heeze, 
s h ort ness of breat h, c hest ti g ht ness, a n d c o u g h t hat var y o ver ti me a n d i n i nte nsit y, t o get her 
wit h varia ble e x pir at or y airfl o w o bstr ucti o n [ GI N A  2 0 2 1].  
T he l o n g -ter m g oals of ast h ma ma na ge me nt are ris k re d ucti o n a n d s y m pt o m c o ntr ol. T he ai m 
is t o re d uce t he p atie nt b ur de n a n d ris k of ast h ma-relate d deat h, e xacer bati o ns, air wa y 
da ma ge, a n d m e dicati o n si de effects. T he p atie nt’s o w n g oals re gar di n g t heir ast h ma a n d its 
treat me nt s h o ul d als o be i de ntifie d [GI N A  2 0 2 1]. T his c o nce pt e nc o m passes 2 c o m p o ne nts: 
( 1) patie nt’s rece nt cli nical stat us a n d c urre nt disease i m pact w hic h i ncl u d es assess me nt of 
s y m pt o ms, ni g ht a wa ke ni n gs, use of resc u e me dicati o n, a n d l u n g f u ncti o n a n d ( 2) patie nt 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
assess me nt f or f ut ur e ris k of e xacer bati o ns, decli ne i n l u n g f u ncti o n, or treat me nt -relate d si d e 
effects.  
D ual  c o m bi nati o ns of I C S a n d a L A B A ca n pr o vi de i m p orta nt treat me nt o pti o ns i n ast h ma, as 
descri be d i n Secti o n 2. 1 . 
A detaile d descri pti o n of t he c he mist r y, p har mac ol o g y, efficac y, a n d safet y of B D M DI a n d 
B F F M DI ca n be f o u n d i n t he B u des o ni de, Gl yc o p yrr o ni u m, a n d F or m oter ol F u marate  ( B G F) 
M DI I n vesti gat or’s Br oc h ure. N ote: I nf or mati o n pertai ni n g t o gl yc o p yrr o ni u m i n t he B G F 
I n vesti gat or’s Br oc h ure is n ot rele va nt f or t his st u d y. 
2. 3  
Be nefit/ Ris k Assess me nt   
B u des o ni de a n d f or m oter ol f u marate are a p pr o ve d i n ma n y c o u ntries w orl d wi de i n m ulti ple 
f or m ulati o ns f or differe nt i n dicati o ns, s uc h as t he treat me nt of C O P D a n d ast h ma. 
I n or der t o e v al uate t he cli nical be nefit/ris k bala nce, efficac y a n d safet y dat a are a vaila ble 
fr o m P hase I, II, a n d III st u dies ( Astra Ze n eca C O P D/ast h ma pr o gra ms) e val uati n g data wit h 
b u des o ni de a n d f or m oter ol f u marate as si n gle a ge nts or i n d ual c o m bi nati o ns. B u des o ni de a n d 
f or m oter ol ha ve b ee n w ell t olerate d wit h fa v ora ble safet y pr ofiles i de ntifie d i n st u dies t o date.  
P ote ntial ris ks wit h B F F M DI will be miti gate d b y t he selecte d i ncl usi o n/e xcl usi o n criteria 
a n d c o nti n u o us m o nit ori n g of safet y d ata d uri n g t he st u d y. Be nefits of B F F M DI o ver 
B D  M DI i n t his st u d y are e x pecte d t o i ncl u d e a n i m pr o ve me nt i n l u n g f u ncti o n a n d ast h ma 
s y m pt o ms. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits  a n d p ote ntial ris ks of B F F 
M DI a n d B D M DI  is pr o vi de d i n t he I n vesti gat or’s Br oc h ure a n d d etaile d a b o ve.  
T his gl o bal st u d y ma y be i nitiate d or c o n d ucte d d uri n g t he S A R S -C o V -2 pa n de mic, a n ot her 
ci vil crisis, nat ural disaster, or p u blic healt h crisis; t he r e gi o nal a n d/ or c o u ntr y le vel ris k ma y 
var y d uri n g t he c o n d u ct of t he st u d y. G ui da nce will be ratifie d wit h l ocal r e g ulati o ns, healt h 
a ut h orit y a n d rele v a nt pr ofessi o nal b o dies t o mi ni mize t he e x pecte d direct ris ks t o site 
pers o n nel a n d st u d y partici pa nts. Alter n ati ve meas ures a n d pr o ce d ures ma y be i m ple me nte d 
d uri n g t he c o n d uct of t he st u d y as descri be d i n Secti o n 4. 2 . Ris k assess me nts f or t he 
S A R S -C o V -2 pa n de mic per l ocal sta n d ar ds m ust be ma de pri or t o e ver y i n -cli nic visit i n li ne 
wit h t he St u d y Disr u pti o ns Miti gati o n I nstr ucti o ns.  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
3  
O B J E C TI V E S A N D E N D P OI N T S   
F or t he f oll o wi n g esti ma n ds, t he esti ma n d p o p ulati o n is a d ults a n d a d olesce nts wit h i na de q uatel y c o ntr olle d ast h ma (s y m pt o mat ic o n 
l o w d ose I C S or I C S/ L A B A) wit h t he e xce pti o n of t he esti ma n d use d f or p o ole d a nal yses of s e vere ast h ma e xacer bati o ns w hic h als o 
i ncl u des t he p o p ulati o n fr o m St u d y D 5 9 8 2 C 0 0 0 0 6 o n me di u m d ose I C S or I C S/ L A B A. 
Ta ble  3  
O bjecti ves a n d E n d p oi nts   
O bjecti ve  
Esti m a n d  
Pri m ar y  
 A p pr o ac h a 
 A p pr o ac h a 
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n l u n g f u ncti o n.  
•  
Tre at me nt : Ra n d o mize d treat me nt of B F F M DI 1 6 0/ 9. 6 μ g or  B D M DI 1 6 0 μ g  
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n c ha n ge fr o m baseli ne  
•  
E n d p oi nt : C ha n ge fr o m baseli ne i n F E V 1 A U C 0 -3 at 
Wee k  1 2  
•  
E n d p oi nt : C ha n ge fr o m baseli ne i n m or ni n g pre -d ose tr o u g h 
F E V 1 o ver 1 2 Wee ks  
•  
Pri m ar y met h o d f or h a n dli n g I C Es:  
-  Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n: Treat me nt p olic y  
-  Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: Treat me nt p olic y  
-  I nitiati o n of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: C o m p osite 
(treat me nt fail ure) if i n c o nj u ncti o n wit h pre mat ure I P disc o nti n uati o n, else Treat me nt P olic y 
S u p p orti ve a p pr o ac h f or h a n dli n g of I C Es  uses W hile o n Treat me nt (ie , data after I C E will n ot be use d) f or all I C Es.  
-  Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n: W hile o n Treat me nt  
-  Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: W hile o n Treat me nt  
-  I nitiati o n of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: W hile o n 
Treat me nt  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o n i de a n d F or m oter ol F u marate - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Sec o n d ar y  
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n l u n g f u ncti o n.  
•  
E n d p oi nt: C ha n ge fr o m baseli ne i n m or ni n g 
pre -d ose tr o u g h F E V 1 at Wee k 1 2  
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n 
c ha n ge fr o m baseli ne  
•  
H a n dli n g of I C Es: Sa me as f or pri mar y e n d p oi nt  
•  
E n d p oi nt: C ha n ge fr o m baseli ne i n F E V 1 A U C 0 -3 o ver 
1 2  Wee ks  
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n c ha n ge 
fr o m baseli ne 
•  
H a n dli n g of I C Es: Sa me as f or pri mar y e n d p oi nt  
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n ast h ma 
e xacer bati o ns.  
•  
E n d p oi nt: Se vere ast h ma e xacer bati o n  
•  
P o p ul ati o n s u m m ar y me as ure : Rate Rati o  
•  
H a n dli n g of I C Es: Sa me as f or pri mar y met h o d f or 
t he pri mar y e n d p oi nt  
N/ A  
T o assess t he effect of 
B F F M DI 3 2 0/ 9. 6  μ g or 
B F F 1 6 0/ 9. 6  μ g relati ve 
t o B D M DI o n ast h ma 
e xacer bati o ns (c o m bi ne d 
data fr o m St u dies 
D 5 9 8 2 C 0 0 0 0 5 a n d 
D 5 9 8 2 C 0 0 0 0 6 ). 
•  
E n d p oi nt: Se vere ast h ma e xacer bati o n  
•  
P o p ul ati o n s u m m ar y me as ure : Rate Rati o 
•  
H a n dli n g of I C Es: Sa me as f or pri mar y met h o d f or 
t he pri mar y e n d p oi nt  
•  
S u p p orti ve  a p pr oac h f or ha n dli n g of I C Es uses 
W hile o n Treat me nt (ie , data after I C E will n ot be 
use d) f or all I C Es.  
N/ A  
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g o n l u n g f u ncti o n, 
s y m pt o ms, a n d P R Os. 
•  
E n d p oi nt : C ha n ge fr o m baseli ne i n t he mea n n u m ber of p uffs of resc ue me dicati o n use ( p uffs/ da y) o ver 1 2 Wee ks 
•  
P o p ul ati o n s u m m ar y me as ure : Differe nce i n mea n c ha n ge fr o m baseli ne  
•  
H a n dli n g of I C Es: Sa me as pri mar y met h o d f or pri mar y e n d p oi nt  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -7 
( ≥ 0. 5 decrease e q uals res p o nse) at Wee k  1 2  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -7 ( ≥ 0. 5 decrease 
e q uals res p o nse) o ver 1 2 Wee ks  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y met h o d f or h a n dli n g I C Es:  
-  Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n: Treat me nt p olic y  
-  Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: Treat me nt p olic y  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
-  I nitiati o n of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o ns t h o u g ht t o i m pact efficac y: C o m p osite 
(treat me nt fail ure) if i n c o nj u ncti o n wit h pre mat ure I P disc o nti n uati o n, else Treat me nt P olic y 
•  
S u p p orti ve C o m p osite  
•  
Pre mat ure d isc o nti n uati o n fr o m st u d y i nter ve nti o n:  
-  F or reas o ns relate d t o gl o bal/c o u ntr y sit uati o n, data f oll o wi n g s uc h I C E will be c o nsi dere d missi n g a n d will n ot be 
i m p ute d.  
-  F or ot her reas o ns, n o n -res p o n der stat us will be ass u me d f or partici pa nts f oll o wi n g s uc h I C E ( C o m p osite strate g y). 
•  
Pr ol o n ge d e x p os u re t o s yste mic c ortic oster oi ds, i ncrease d I C S d ose f or m ore t ha n 1 4 da ys, or de p ot c ortic oster oi d 
i njecti o n: n o n-res p o n der stat us will be ass u me d f or partici pa nts f oll o wi n g s uc h I C E ( C o m p osite strate g y). 
•  
I nitiati o n of ne w ast h ma t hera p y or a d diti o nal pr o hibite d me dicati o ns t h o u g ht t o i m pact efficac y: n o n-res p o n der stat us will 
be ass u me d f or partici pa nts fr o m (a n d i ncl u di n g) da y of first I C E ( C o m p osite strate g y).  
 
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -5 
( ≥ 0. 5 decrease e q uals res p o nse) at Wee k  1 2  
•  
P o p ul a ti o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or 
A C Q -7  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A C Q -5 ( ≥ 0. 5 
decrease e q uals res p o nse) at Wee k  1 2 or o ver 1 2 Wee ks  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or A C Q -7  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A Q L Q(s) + 1 2 
( ≥ 0. 5 i ncrease e q uals res p o nse) at Wee k  1 2  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or 
A C Q -7  
•  
E n d p oi nt: Perce nta ge of res p o n ders i n A Q L Q(s) + 1 2 ( ≥ 0. 5 
i ncrease e q uals res p o nse) at Wee k 1 2 or o ver 1 2 Wee ks  
•  
P o p ul ati o n S u m m ar y Me as ure: O d ds Rati o  
•  
Pri m ar y a p pr o ac h f or h a n dli n g of I C Es: As f or A C Q -7  
•  
E n d p oi nt: O nset of acti o n o n Da y  1: A bs ol ute c ha n ge i n F E V 1 at 5 mi n utes p ost -d ose o n Da y  1  
•  
P o p ul ati o n S u m m ar y Me as ure: Differe nce i n mea n c ha n ge fr o m baseli ne  
•  
Pri m ar y h a n dli n g of I C Es:  Sa me as pri mar y met h o d f or pri mar y e n d p oi nt  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
S afet y  
 
 
O bjecti ve  
P o p ul ati o n  
E n d p oi nt  
P o p ul ati o n 
S u m m ar y Me as ure  
Str ate g y f or I nterc urre nt E ve nts 
T o assess t he safet y of 
B F F M DI 1 6 0/ 9. 6  μ g 
relati ve t o B D M DI 
1 6 0  μ g.  
Partici pa nts wit h 
i na de q uatel y 
c o ntr olle d ast h ma 
(s y m pt o matic o n 
l o w d ose I C S or 
I C S/ L A B A) 
A Es  
Perce nta ge a n d ris k 
differe nce i n 
e x p os ure -a dj uste d 
i nci de nce rates per 
1 0 0 patie nt -years (f or 
selecte d e ve nt t y pes) 
A Es will be a nal yze d b y st u d y/treat me nt 
peri o ds defi ne d i n t he S A P  
Vital si g ns  
Mea n a bs ol ute val ue 
a n d mea n c ha n ge fr o m 
baseli ne  
O nl y o n -treat me nt o bser vati o ns will be 
a nal yze d. 
Cli nical la b orat or y val ues 
Mea n a bs ol ute val ue 
a n d mea n c ha n ge fr o m 
baseli ne  
O nl y o n -treat me nt o bser vati o ns will be 
a nal yze d. 
Terti ar y/ E x pl or at or y  
 
 
T o f urt her assess t he 
effect of B F F M DI 
1 6 0/ 9. 6  μ g relati ve t o B D 
M DI 1 6 0  μ g o n l u n g 
f u ncti o n, s y m pt o ms, 
P R Os, a n d ast h ma 
e xacer bati o ns.  
Partici pa nts wit h 
i na de q uatel y 
c o ntr olle d ast h ma 
(s y m pt o matic o n 
l o w d ose I C S or 
I C S/ L A B A) 
Perce nta ge of resc ue -free da ys 
( 2 4-h o ur peri o d wit h o ut resc ue 
me dicati o n use)  
Differe nce i n mea n 
perce nta ge  
W hile o n Treat me nt  
-  Data a fter a n y I C E will n ot be 
use d  
Perce nta ge of s y m pt o m -free da ys 
( 2 4-h o ur peri o d wit h o ut s y m pt o ms)  
Differe nce i n mea n 
perce nta ge  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
Pea k c ha n ge fr o m baseli ne i n F E V 1  
Mea n differe nce  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Ti me t o pea k F E V 1 o n Da y  1  
Mea n differe nce  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C ha n ge fr o m baseli ne i n F V C, P E F, 
a n d F E F 2 5 -7 5 e val uate d usi n g A U C 0 -3 
Differe nce i n mea n 
c ha n ge fr o m baseli ne  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C ha n ge fr o m baseli ne i n m or ni n g 
pre -d ose tr o u g h P E F  
Differe nce i n mea n 
c ha n ge fr o m baseli ne  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C ha n ge fr o m baseli ne i n e ve ni n g 
pre -d ose P E F  
Differe nce i n mea n 
c ha n ge fr o m baseli ne 
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
Perce nta ge of res p o n ders i n A C Q -6 
( ≥ 0. 5 decrease e q uals res p o nse)  
O d ds Rati o  
•  
Pri mar y a p pr oac h f or ha n dli n g of 
I C Es: As f or A C Q-7  
C ha n ge fr o m baseli ne i n A C Q -5, 
A C Q -6, A C Q -7 a n d A Q L Q(s) + 1 2  
Differe nce i n mea n 
c ha n ge fr o m baseli ne 
Pri mar y a p pr oac h f or ha n dli n g of I C Es: 
As f or pri mar y  e n d p oi nt 
M o derate/se vere ast h ma 
e xacer bati o n 
I nci de nce/a n n ualize d 
rate 
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
Se vere ast h ma e xacer bati o n  
I nci de nce/a n n ualize d 
rate 
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
Ti me t o first se vere ast h ma 
e xacer bati o n i n t he c o m bi ne d data 
fr o m St u dies D 5 9 8 2 C 0 0 0 0 5 a n d 
Hazar d rati o  
W hile o n Treat me nt  
•  
Data after a n y I C E will n ot be 
use d   

Cli ni cal St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
D 5 9 8 2 C 0 0 0 0 6 ( B F F M DI 3 2 0/ 9  μ g 
or 1 6 0/ 9. 6  μ g relati ve t o B D M DI)  
 
Hazar d rati o  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
 
I nci de nce/a n n ualize d 
rate/ hazar d rati o 
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C ha n ge fr o m baseli ne i n E Q -5 D 
Q uesti o n naire i n de x sc ore  a n d V A S 
Q uesti o n naire sc ore  
Differe nce i n mea n 
c ha n ge fr o m baseli ne 
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
AI R Q  
Mea n val ue a n d mea n 
c ha n ge fr o m baseli ne  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
AI R Q perce nta ge of partici pa nts t hat 
are well -c o ntr olle d, n ot 
well -c o ntr olle d, a n d ver y p o orl y 
c o ntr olle d 
Perce nta ge  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
He alt hc are R es o urce Utiliz ati o n  
 
 
T o assess t he o verall a n d 
ast h ma -s pecific 
Healt hcare Res o urce 
Utilizati o n of B F F M DI 
1 6 0/ 9. 6  μ g relati ve t o B D 
M DI 1 6 0  μ g.  
Partici pa nts wit h 
i na de q uatel y 
c o ntr olle d ast h ma 
(s y m pt o matic o n 
l o w d ose I C S or 
I C S/ L A B A) 
Perce nta ge of partici pa nts wit h E R 
visits  
Perce nta ge  
W hile o n Treat m e nt 
-  Data after a n y I C E will n ot be 
use d  
N u m ber of visits t o E Rs per patie nt -
year  
Mea n A n n ualize d Rate  W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Perce nta ge of partici pa nts 
h os pitalize d  
Perce nta ge  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
N u m ber of partici pa nt 
h os pitalizati o ns per patie nt -year  
Mea n A n n ualize d Rate  W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
N u m ber of da ys i n t he h os pital per 
patie nt -year  
Mea n A n n ualize d Rate  W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
1 2 -H o ur P ul m o n ar y F u ncti o n Test S u b -St u d y  
 
 
T o assess t he effect of 
B F F M DI 1 6 0/ 9. 6  μ g  
relati ve t o 
B D  M DI  1 6 0  μ g  o n P F T 
para meters o ver 1 2 h o urs.  
Partici pa nts wit h 
i na de q uatel y 
c o ntr olle d ast h ma 
(s y m pt o matic o n 
l o w d ose I C S or 
I C S/ L A B A) 
C ha n ge fr o m baseli ne i n F E V 1 
A U C 0 -1 2 at Wee k  1 2  
Differe nce i n mea n 
c ha n ge fr o m baseli ne  
Sa me as f or pri mar y esti ma n d f or 
pri mar y e n d p oi nt  
F E V 1 at eac h ti me p oi nt 
Mea n a bs ol ute val ue 
a n d mea n c ha n ge fr o m 
baseli ne  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C ha n ge fr o m baseli ne i n F E V 1 
A U C 0 -6, F E V1 A U C 6 -1 2, a n d pea k 
F E V 1 
Differe nce i n mea n 
c ha n ge fr o m baseli ne  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
C ha n ge fr o m baseli ne i n F V C, P E F, 
a n d F E F 2 5 -7 5 e val uate d usi n g A U C 0 -1 2 
Differe nce i n mea n 
c ha n ge fr o m baseli ne  
W hile o n Treat me nt  
-  Data after a n y I C E will n ot be 
use d  
a 
Refers t o s u b missi o n strate g y wit h res pect t o Healt h A ut h orit y res p o nsi ble f or re vie wi n g mar keti n g a ut h orizati o n, n ot t he rec r uit me nt l ocati o n/ nati o nalit y of 
t he partici pa nts. 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
I nterc urre nt E ve nts  
•  
Disc o nti n uati o n fr o m ra n d o mize d st u d y i nter ve nti o n ( ma y be f urt her br o k e n d o w n f or lac k of efficac y or f or t olera bilit y/ ot her  as 
well as reas o ns relate d t o gl o bal/c o u ntr y sit uati o n) 
•  
Pr ol o n ge d e x p os ure t o s yste mic c ortic oster oi ds or i ncreas e d I C S f or m ore t ha n 1 4 da ys or ha vi n g recei ve d de p ot c ortic oster oi d  
i njecti o n. F urt her m ore, use of s yste mic c ortic oster oi ds or i ncreas e d I C S f or 1 4 da ys or less will als o be c o nsi dere d as a n I C E f or 
l u n g f u ncti o n assess me nts d uri n g t his te m p orar y a d diti o nal use. 
•  
I nitiati o n of ne w ast h ma t hera p y or a d mi nistrati o n of pr o hi bite d me dicati o n s t h o u g ht t o i m pact efficac y, i ncl u di n g bi ol o gic al 
th era p y/ m o n ocl o nal a nti b o dies , L A B A, L A M A , or L T R A (f urt h er details pr o vi de d i n t he S A P)  
 
Ta ble  4  
Ta ble re m o ve d i n A me n d me nt 0 2   
T his ta ble was re m o v e d i n A me n d me nt 2; h o we v er, details are n o w c o ntai n e d i n Ta ble  3 . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m ote r ol F u marate - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
4  
S T U D Y D E SI G N   
4. 1  
O ver all Desi g n   
T his is a P hase III ra n d o mize d, d o u ble -bli n d, acti ve c o m parat or, parallel gr o u p, m ul tice nter 
st u d y c o m pari n g B F F M DI 1 6 0/ 9. 6 µ g t o B D M DI 1 6 0  µ g i n a d ult a n d a d olesce nt partici pa nts 
w h o ha ve ast h ma w hic h re mai ns i na de q uatel y c o ntr olle d ( A C Q -7 t otal sc ore ≥ 1. 5) des pite 
treat me nt wit h l o w d ose I C S or I C S/ L A B A. All st u d y i nter ve nti o ns will be a d mi nistere d as 
2  act uati o ns BI D f or 1 2 wee ks.  
F or a n o ver vie w of t he st u d y desi g n see Fi g ure  1 . F or details o n-st u d y i nter ve nti o ns gi ve n 
d uri n g t h e st u d y, see Secti o n 6. 1  St u d y I nter ve nti o n(s) A d mi nistere d.  
T his st u d y will be c o n d ucte d at a p pr o xi mat el y 9 0 sites w orl d wi de a n d will ra n d o mize 
a p pro xi matel y 3 4 0 a d ult a n d a d olesce nt partici pa nts.  
At Visit  1, partici pa nts ( or t he pare nts or le gal g uar dia ns of partici p a nts 1 2 t o <  1 8 years of 
a ge) will si g n a n I C F a n d partici pa nts 1 2 t o <  1 8 y ears of a ge will si g n a n asse nt f or m. All 
partici pa nts m ust be ta ki n g a sta ble dail y l o w d os e I C S or a c o m bi nati o n of I C S/ L A B A (see 
Ta ble  6 ) f or at least 8 w ee ks pri or t o Visit 1. Partici pa nts w h o ha ve n ot wit h hel d ast h ma 
me dicati o ns pri or t o Visit  1 a n d faile d s pir o metr y i ncl usi o n criteria at Visit  1 s h o ul d ret ur n t o 
t he cli nic t o re peat s pir o metr y testi n g wit hi n 2 da ys. If t he re p eat s pir o metr y a gai n f ails t o 
meet t he i ncl usi o n criteri a, t he partici pa nt m ust be scree n faile d. After meeti n g t he scree ni n g 
eli gi bilit y criteria, partici pa nts will disc o nti n ue t heir l o w d ose I C S or I C S/ L A B A at Visit  1 a n d 
i nitiate r u n-i n B D M DI 1 6 0 µ g ta ke n BI D u ntil t he e ve ni n g pri or t o Visit  4 (ra n d o mizati o n), 
w he n r u n -i n B D M DI will be disc o nti n ue d. All partici pa nts will recei ve al b uter ol s ulfate 
i n halati o n aer os ol or sal b uta m ol s ulfate i n halati o n aer os ol, herei naft er referre d t o as al b uter ol, 
at Visit 1 f or resc u e use d uri n g t he st u d y (see Secti o n 6. 5. 1 ). 
Partici pa nts will ret ur n f or Visit  2 aft er a de q uat e was h o ut of pr o hi bite d ast h ma me dicati o ns. 
T here will be a mi ni m u m of 7 da ys bet wee n Visit  1 a n d Visit  2. Partici pa nts m ust de m o nstrate 
a pre-br o nc h o dilat or F E V 1 of <  9 0 % of pre dicte d n or mal val ue at Visits  1, 2, a n d 3, a pre -d ose 
F E V 1 of 5 0 % t o  9 0 % at Visit  4 ( pre -ra n d o mizati o n), a n d a n A C Q-7 t otal sc ore of ≥ 1. 5 at 
Visit  1 a n d Visit  4 ( pre -ra n d o mizati o n). All partici pa nts m ust be assesse d f or re versi bilit y t o 
al b uter ol at Visit  2 (a n d Visit  3 if re versi bilit y is n ot de m o nstrate d at Visit  2; see  Secti o n  5. 1  
a n d Secti o n  8. 1. 1. 3 ) t o pr o vi de re versi bilit y baseli ne data f or c haract erizati o n. H o we ver, 
partici pa nts w h o ha v e hist oricall y d oc u me nte d re v ersi bilit y wit hi n 1 2 m o nt hs of Visit  1 ca n 
still be ra n d o mize d t o t he st u d y e ve n if t he y fail re versi bilit y testi n g at Visits  2 a n d 3.  
R u n -i n B D M DI d uri n g t he Scree ni n g Peri o d a n d st u d y i nter ve nti o n d uri n g t he treat me nt 
peri o d m ust be ta ke n i n t he e ve ni n g 1 2 h o urs ( ±  1 h o ur) pri or t o t he e x p ecte d i n -cli nic d osi n g 
ti me at t he f oll o wi n g m or ni n g visit. T he m or ni n g d ose m ust be wit h hel d u ntil after pre-d ose 
s pir o metr y assess me nts i n t he cli nic. Al b uter ol m ust be wit h hel d at least 6 h o urs pri or t o t he 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
start ti me of t he m or ni n g visit. If b ot h c o n diti o ns a b o ve are n ot met, t he n t h e visit will nee d t o 
be resc h e d ule d. All pre -d ose (tr o u g h) s pir o metr y asses s me nts will be re q uir e d t o be c o n d uct e d 
i n t he m or ni n g ( 0 8 0 0 ±  2 h o urs).  
Partici pa nts s h o ul d ret ur n t o t he cli nic at a p pr o xi matel y t he sa me ti me of da y ( ±  1 h o ur) f or all 
visits. All i n -cli nic d osi n g m ust occ ur pri or t o 1 0 0 0 ( +  1 h o ur all o wa nce) i n t he m or ni n g a n d 
visits m ust be pla n ne d acc or di n gl y. T he partici pa nts will be re q uire d t o re m ai n at t he cli nic 
u ntil c o m pleti o n of all pr ot oc ol -defi ne d assess me nts a n d pr oce d ures.  
Partici pa nts will use a n e Diar y BI D ( m or ni n g a n d e ve ni n g) t o rec or d al b uter ol use , ast h ma 
s y m pt o m sc ores, P E F, a n d c o nfir mati o n of i n halati o ns of r u n-i n B D M DI d uri n g t he Scree ni n g 
Peri o d (see Secti o n 8. 1. 2 ). C o m plia nce of ≥ 7 0 % d u ri n g scree ni n g ( defi ne d as c o m pleti n g t he 
dail y e Diar y a n d a ns weri n g “ Yes” t o ta ki n g 2 p uffs f or r u n -i n B D M DI f or a n y 1 0 m or ni n gs 
a n d a n y 1 0 e v e ni n gs i n t he last 1 4 da ys pri or t o ra n d o mizati o n) m ust be de m o nstrate d i n or der 
f or a partici pa nt t o be ra n d o mize d t o st u d y i nter ve nti o n at Visit  4 (see Secti o n 8. 1. 2. 1 ). 
At Visit  4, partici pa nts eli gi ble f or t he st u d y will disc o nti n ue r u n -i n B D M DI a n d be 
ra n do mize d i n a  
sc h e me t o B F F M DI 1 6 0/ 9. 6  μ g or B D M DI 1 6 0  μ g (see Fi g ure  1  a n d 
Secti o n 6. 1 ). 
Ra n d o mizati o n will be stratifie d b y baseli ne ast h ma treat me nt (I C S vs I C S/ L A B A) a n d a ge 
( 1 2 t o < 1 8 years of a g e vers us ≥ 1 8 years of a g e).  
F oll o wi n g ra n d o mizati o n, partici pa nts will u n der g o  3 a d diti o nal treat me nt visits o ver a 
treat me nt peri o d of 1 2 w ee ks. Partici pa nts will rec or d dail y ast h ma s y m pt o m sc ores, al b uter ol 
use, P E F, a n d st u d y i nter ve nti o n use as well as P R O q uesti o n naire res p o nses as descri be d i n 
t he S o A (Ta ble  1 ) a n d Secti o n 8. 1. 2 . 
All partici pa nts w h o disc o nti n ue ra n d o miz e d st u d y i nter ve nti o n pri or t o t he e n d of t he st u d y 
will be e nc o ura g e d t o re mai n i n t he st u d y t o c o m plete all re mai ni n g st u d y visits a n d 
pr oce d ures (see Secti o n 7. 1 ). 
T his st u d y i ncl u des a 1 2 -h o ur serial s pir o metr y s u b -st u d y. 
1 2 -h o ur S pir o metr y S u b -St u d y : Serial s pir o metr y will be c o n d ucte d o ver 1 2 h o urs i n a 
s u bset of a d ult a n d a d olesce nt partici pa nts at Visit 4 ( Da y  1) a n d Visit  7 ( Wee k  1 2). O n t h e test 
da y, a d diti o nal serial s pir o metr y will be o btai ne d at 6 -, 9-, a n d 1 2-h o urs p ost -d ose (see Ta ble  2  
f or details). T h e s u b-st u d y will be c o n d ucte d at s p ecific sites t hat ha v e a gree d t o partici pate. 
T he tar g et is t o ha ve a p pr o xi matel y  
a n d u p t o  
parti ci pa nts (
 t o 
 per treat me nt 
ar m) ra n d o mize d t o t he s u b -st u d y.  
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
4. 2  
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 Crisis   
T he g ui da nce gi v e n bel o w s u perse d es i nstr ucti o ns pr o vi de d else w h ere i n t his C S P 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 healt h crisis 
(e g, d uri n g q uara nti nes a n d res ulti n g site cl os ures, re gi o nal tra v el restricti o ns, a n d 
c o nsi derati o ns if site pers o n nel or st u d y partici pa nts bec o me i nfecte d wit h S A R S -C o V -2 vir us 
or a si milar pa n de mic i nf ecti o n) w hic h w o ul d pr e 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 m pr o misi n g t he st u dy site staff or t h e partici p a nt’s a bilit y t o c o n d uct t he 
st u d y. T he I n vesti gat or or desi g nee s h o ul d c o ntact Astra Z e neca t o disc uss w het her t he 
miti gati o n pla ns i n t he St u d y Disr u pti o n Miti gati o n I nstr ucti o ns s h o ul d be i m ple me nte d.  
I n t he sce n ari o of a ci vil crisis, nat ural disaster, or p u blic healt h crisis, c ha n ges ma y be 
i m ple me nte d t o e ns ure t h e safet y of st u d y p artici p a nts, mai ntai n c o m plia nce wit h G C P a n d 
mi ni mize ris ks t o trial i nte grit y.  
W here all o wa ble b y l ocal healt h a ut h orities, et hics c o m mittees, healt hcare pr o vi der g ui deli nes 
(e g, h os pital p olicies), or l ocal g o ver n me nt, if st u d y partici pa nts ca n n ot atte n d t he visits at t he 
st u d y site d ue t o si g nifica nt re gi o nal disr u pti o n, e v ol vi n g gl o bal pa n de mic or si milar nat ural 
disaster, tele me di ci ne s essi o ns ( vi de o c o nfere nce or tele p h o ne call) will be i m ple me nte d f or 
all partici pa nts c urre ntl y ra n d o mize d i n t he st u d y a n d st u d y i nter ve nti o n s u p pl y mai ntai ne d f or 
t he partici pa nt gi ve n t his c o m prises t heir ast h ma c o ntr oller me dicati o ns. T h ese sessio ns 
s h o ul d i ncl u de all S o A (Ta ble  1 ) assess m e nts w hic h ca n be p erf or m e d virt u all y, t o c ollect 
safet y i nf or mati o n as a mi ni m u m re q uire me nt. Ass ess me nts i n t he S o A ( Ta ble  1 ) w hic h ca n n ot 
be perf or me d virt uall y s h o ul d be ca pt ure d at t he n e xt o p p ort u nit y f or a n i n -cli nic visit, 
pr o vi de d t he I n v esti gat or assesses t he partici pa nt t o be safe t o c o nti n ue i n t he st u d y. 
Alter nati vel y, if t he I n vesti gat or c o nsi ders it a p pr o priate f or t he p artici pa nt t o st o p st u d y 
i nter ve nti o n a n d ha ve alter nati ve ast h ma c o ntr oller me dicati o ns, arra n ge m e nts f or t his will 
nee d t o be ma d e b y t he st u d y staff, i n acc or da nce wit h l ocal re g ulat or y re q uire me nts a n d 
g ui da nce. All partici pa nts w h o st o p st u d y i nter ve nti o n a n d are prescri b e d alter nati ve ast h ma 
c o ntr oller me dicati o ns will re q uire f oll o w -u p wit h a tele p h o ne call 2 we e ks f oll o wi n g t he 
cessati o n of st u d y i nter ve nti o n t o assess safet y.  
If a n e m er ge nt e ve nt r es ults i n ce ntralize d la b orat or y testi n g of sa m ples n ot bei n g a vaila ble, 
Astra Ze neca ma y d eci de t o use l ocal la b orat ori es.  
Visits 1 t hr o u g h 4 m ust be c o n d ucte d at t he  st u d y site. If miti gati o n practices are i m ple me nte d 
at a site, u ntil a gree d ot h er wise wit h Astra Ze n eca, n o f urt her partici pa nts ca n be e nr olle d a n d 
all partici pa nts w h o are c urre ntl y i n Scree ni n g ( Visits 1 t hr o u g h 4), m ust be scree n faile d (see 
Secti o n 5. 4 ). 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
4. 2. 1  
C o m pleti n g P artici p a nt N u m bers t o M ai nt ai n St u d y I nte g rit y   
I n t he e ve nt of a nat ur al disaster or ci vil or p u blic healt h crisis t hat pre v e nts partici pa nts fr o m 
atte n di n g o n -site visits (as descri be d i n Secti o n 4. 2 ), partici pa nts will be f oll o we d re m otel y t o 
c ollect s y m pt o ms, P R Os, a n d safet y assess me nts f or t he e ve nt’s d urati o n; h o we ver, it will n ot 
be p ossi ble t o c ollect s pir o metr y assess me nts f or t he pri mar y e n d p oi nt d uri n g t his ti me. 
A d diti o nall y, o wi n g t o t he li keli h o o d of s o me partici pa nt dr o p -o uts d uri n g t he e ve nt a n d t o 
mai ntai n st u d y i nte grit y w hic h re q uir es s uffici e nt l u n g f u ncti o n data at Wee k  1 2 b y 
c o m pleti n g partici pa nts, m ore partici pa nts ma y b e re q uire d a n d s u bse q ue ntl y e nr olle d. 
A d diti o nal a nal ytic a n d o perati o nal a p pr oac h es ma y be c o nsi dere d t o a d dress data li mitati o ns 
ca use d b y t he crisis. If t his occ urs, a d diti o nal details ma y be i ncl u de d i n t he S A P.  
4. 3  
Scie ntific R ati o n ale f or St u d y Desi g n   
T he pr o d uct bei n g teste d i n t his st u d y, B F F M DI 1 6 0/ 9. 6  μ g BI D, is bei n g c o m pare d wit h 
B D  M DI 1 6 0  μ g BI D. T h era p y wit h a n I C S f or ast h ma is well esta blis he d i n cli nical practice  
a n d t he i ncl usi o n of a L A B A has de m o nstrate d a d diti o nal be nefit i n ma na gi n g patie nts wit h 
p o orl y c o ntr olle d ast h ma [ GI N A  2 0 2 1]. T h e a d diti o n of a L A B A is e x pec te d t o i m pr o ve l u n g 
f u ncti o n a n d healt h-relat e d q ualit y of life i n t his p o p ulati o n. T he de vel o p m e nt of a d ual 
c o m bi nati o n pr o d uct als o pr o vi des t he c o n ve ni e nce of a si n gle i n haler f or patie nts, i ncreasi n g 
t he li keli h o o d of a d here n ce. T he l e n gt h of t his st ud y will all o w safet y t o be ca pt ure d a n d 
pr o vi de a de q u ate ti me t o o bser ve l u n g f u n cti o n c ha n ges aft er 1 2 wee ks of treat me nt.  
4. 3. 1  P artici p a nt I n p ut i nt o Desi g n   
O btai ni n g c o or di nat or a n d partici pa nt i nsi g ht earl y has pr o vi de d o p p ort u nities f or i nf or mi n g 
st u d y desi g n, i m pr o vi n g o perati o nal f easi bilit y, re d uci n g patie nt/site b ur de n, a n d retai ni n g 
i nterest, e nt h usias m, a n d e n ga ge me nt i n a st u d y.  
4. 3. 1. 1  
C o or di n at or I n p ut   
F o ur face -t o-face c o or di n at or meeti n gs i n v ol vi n g 2 5 c o or di nat ors fr o m 1 7 c o u ntries were 
c o n d ucte d. C o or di nat or p ers pecti ves a n d i nsi g hts were c ollecte d ar o u n d c o nse nti n g, 
eli gi bilit y, re q uesti n g me dical rec or ds, scree ni n g, ra n d o mizati o n, safet y/efficac y meas ures, 
st u d y i nter ve nti o n, tec h n ol o g y, rete nti o n, data, a n d a n o pti o nal 1 2-h o ur s pir o metr y s u b -st u d y. 
T he f oll o wi n g c ha n g es t o t he pr ot oc ol were ma de base d o n c o or di n at or i n p ut:  
•  
Re d uce d t he n u m b er of s erial s pir o metr y ass ess me nts  
•  
Br oa de ne d t he wi n d o w f or perf or mi n g m or ni n g assess me nts  
•  
A d de d va pi n g t o s m o ki n g hist or y eli gi bilit y criteria  
•  
Refi ne d c ortic oster oi d eli gi bilit y criteria t o i ncl u de oral a n d I V us e  
 
E x plai ni n g t he “ w h y” be hi n d a st u d y a n d acti vities i n t he S o A ( Ta ble  1 ) a n d i m pr o vi n g 
trai ni n g materials t o s u p p ort ge o gra p hical c halle n g es will be i nc or p orat e d i nt o I n vesti gat or 

Cli nical St u d y Pr ot o c ol - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
a n d site trai ni n g. 
4. 3. 1. 2  
P artici p a nt I n p ut   
T w o virt ual meeti n gs were c o n d ucte d wit h 7 ast h ma patie nts fr o m 4 c o u ntri es. I nsi g hts were 
c ollecte d ar o u n d e xacer bati o ns a n d t he a bilit y t o c ollect me di cal rec or ds t o s u p p ort eli gi bilit y 
a n d/ or a n o n -st u d y e v e nt, e Diar y b ur d e n, s pir o metr y s u b-st u d y, a n d virt ual st u d y visits. 
Patie nts i n dicate d t hat e ns uri n g direct li nes of c o m m u nicati o n wit h site staff, all o wi n g 
“i n-cli nic” ass ess me nts t o be d o ne at h o me,  utilizi n g a pers o nal d e vice t o c ollect data, a n d 
e x plai ni n g w h y P R Os are nee d e d a n d h o w P R O data will be use d, is i m p orta nt t o t he m. T hese 
i nsi g hts will be c o nsi dere d a n d w he n p ossi ble, i nc or p orate d i nt o t he pr ot oc ol, I n vesti gat or, site 
a n d P R O e Diar y tra i ni n g. 
4. 4  
J ustific ati o n f or D ose   
T he b u des o ni de d ose of 1 6 0  µ g a d mi nistere d as 2 p uffs BI D (t otal dail y d ose of 3 2 0  µ g) t hat 
is bei n g e val uate d as p art of B F F M DI is c o nsi dere d a l ow I C S d ose as part of a n I C S/ L A B A 
c o m bi nati o n b y GI N A. T he GI N A treat me nt g ui deli nes a d v ocate t he a d diti o n of a L A B A t o 
I C S, s uc h as B F F M DI, as a ste p-u p t hera p y t o ast h ma patie nts w h o are i na de q uatel y 
c o ntr olle d o n a l o w d ose I C S al o ne [ GI N A  2 0 2 1]. T he efficac y a n d safet y pr ofile of B D, as 
part of B F F M DI 3 2 0/ 9. 6  µ g a n d B G F M DI 3 2 0/ 1 4. 4/ 9. 6  µ g, has bee n esta blis he d i n C O P D as 
part of t he P hase III pr o gra m a n d is use d i n t he a p pr o ve d B G F M DI fi xe d -d ose c o m bi nati o n 
s u b mitte d gl o ball y. T he b u des o ni de d ose i ncl u de d i n t his st u d y is t he sa me d ose, a n d t he 
f or m oter ol f u marate d ose is si milar, t o t h ose i n S y m bic ort, a c o m bi nati o n I C S/ L A B A 
c o ntai ni n g t he sa me m olec ules, t hat has b ee n a p pr o ve d gl o ball y i n ast h ma at a n e q ui vale nt 
d ose of 1 6 0/ 9 µ g (a d mi nistere d as 2 i n halati o ns) BI D.  
T he f or m oter ol f u m arat e d ose of 9. 6  µ g a d mi nistere d as 2 p uffs BI D (t otal d ail y d ose of 
1 9. 2  µ g) is bei n g e val uat e d as part of t h e c urre nt B G F M DI P hase III pr o gra m i n ast h ma. T he 
efficac y a n d safet y pr ofil e of f or m oter ol f u marate, as part of Gl y c o p yrr o ni u m a n d F or m oter ol 
F u marate M DI 1 4. 4/ 9. 6  µ g a n d B G F M DI 3 2 0/ 1 4. 4/ 9. 6  µ g, has bee n esta blis he d i n t he P hase 
III C O P D pr o gra ms a n d is part of t he a p pr o ve d d oses of Be ves pi Aer os p here a n d 
Breztri/ Tri xe o A er os p here.  
4. 5  
E n d of St u d y Defi niti o n   
F or t he p ur p ose of Cli nical Trial Tra ns pare nc y, t he defi niti o n of t he e n d of t he st u d y differs 
u n der F D A a n d E U re g ulat or y re q uir e me nts:  
E ur o pea n U ni o n re q uire me nts defi ne st u d y c o m pleti o n as t he last visit of t he last st u d y 
partici pa nt f or a n y pr ot oc ol relate d acti vit y.  
F o o d a n d Dr u g A d mi nistrati o n re q uire m e nts defi n e 2 c o m pleti o n dates:  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Pri mar y C o m pleti o n Date –  t he date t hat t he fi nal partici pa nt is e xa mi ne d or recei ves a n 
i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y o utc o me meas ure, 
w het her t he cli nical st u d y c o ncl u de d acc or di n g t o t he pre -s pecifie d pr ot o c ol or was 
ter mi nate d. I n t he case of cli nical st u dies wit h m ore t ha n o ne pri mar y o utc o me meas ure wit h 
differe nt c o m pleti o n dates, t his ter m refers t o t he date o n w hic h dat a c ollecti o n is c o m plete d 
f or all of t he pri mar y o utc o mes. 
St u d y C o m pleti o n Date –  t he date t he fi nal p artici pa nt is e xa mi ne d or recei ves a n i nter ve nti o n 
f or p ur p oses of fi nal c oll ecti o n of data f or t he pri mar y a n d sec o n dar y o utc o me meas ures a n d 
A Es (f or e xa m ple, last partici pa nt’s last visit), w het her t he cli nical st u d y c o ncl u des acc or di n g 
t o t he pre-s pecifie d pr ot o c ol or is ter mi nate d. 
A partici pa nt 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 o m plete d his/ her 
last sc he d ule d pr oce d ure s h o w n i n t he S o A (Ta ble  1 ).  
Partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n will be e nc o ura g e d t o c o nti n ue i n t he st u d y 
a n d c o m plete all re mai ni n g st u d y visits a n d pr oce d ures.  
5  
S T U D Y P O P U L A TI O N   
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
5. 1  
I ncl usi o n Criteri a  
Partici pa 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 criteria a p pl y:  
A ge  
1  
Partici pa nt m ust be 1 2  t o 8 0  years of a ge i ncl usi ve, at t he ti me of si g ni n g t he I C F.  
N ote : F or partici pa nts 1 2 t o < 1 8 years of a ge, t heir pare nts or l e gal g uar di a ns m ust gi ve 
t heir si g ne d writte n i nf or me d c o nse nt, as a p pr o pri ate, a n d partici pa nts will si g n a n asse nt 
f or m. 
 
T y pe of P artici p a nt a n d Dise ase C h ar acteristi cs  
2  
Partici pa nts w h o ha ve a d oc u me nte d hist or y of p h ysicia n -dia g n ose d ast h ma ≥ 6 m o nt hs 
pri or t o Visit  1, acc or di n g t o GI N A g ui deli nes [ GI N A  2 0 2 1]. Healt hcare rec or ds f or 
o ne  year pri or t o Visit  1 m ust be pr o vi de d f or a d olesce nt partici pa nts ( 1 2 t o <  1 8 years of 
a ge) t o e ns ur e c o nsiste nt e val uati o n a n d f oll o w -u p of treat me nt i n t h ose partici pa nts.  
3  
Partici pa nts w h o ha ve b ee n re g ularl y usi n g a sta ble dail y I C S or a n I C S/ L A B A re gi me n 
(i ncl u di n g a sta ble I C S d ose), wit h t he I C S d oses all o we d i n Ta ble  6 , f or at least 8 wee ks 
pri or t o Visit  1.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
4  
A C Q -7 t otal sc ore ≥ 1. 5 at Visits  1 a n d 4.  
5  
6  
Re versi bilit y t o al b uter ol, defi ne d as a p ost -al b uter ol i ncreas e i n F E V 1 of ≥ 1 2 % a n d 
≥ 2 0 0  m L f or partici pa nts ≥ 1 8 years of a ge O R a p ost -al b uter ol i ncrease i n F E V 1 of 
≥ 1 2 % f or partici pa nts 1 2 t o <  1 8 years of a ge, eit her i n t he 1 2 m o nt hs pri or t o Visit  1, or 
at Visit 2 or Visit  3.  
N ote : E ve n if t here is d o c u me nte d hist or y of re versi bilit y, all partici pa nts m ust be 
assesse d f or re v ersi bilit y at Visit 2 (a n d Visit 3, if re versi bilit y is n ot de m o nstrate d at 
Visit  2) t o e val uate pres e nce of re versi bilit y d uri n g scree ni n g.  
7  
8  
Ast h ma sta bilit y d uri n g r u n -i n base d o n I n v esti gat or discreti o n usi n g t he s y m pt o m 
w orse ni n g assess me nt defi ne d i n Secti o n 8. 1. 2. 8  as a g ui deli ne . 
9  
Willi n g a n d, i n t he o pi ni o n of t he I n vesti gat or, a ble t o a dj ust c urre nt ast h m a t hera p y, as 
re q uire d b y t he pr ot oc ol. 
1 0  De m o nstrate acce pta ble M DI a d mi nistrati o n tec h ni q ue.  
N ote : Hist orical use of a s pacer de vice wit hi n t he 8 wee ks pri or t o a n d/ or d uri n g t he 
Scree ni n g a n d Ra n d o mize d Treat me nt Peri o ds is n ot per mitte d.  
1 1  e Diar y c o m plia n ce ≥ 7 0 % d uri n g scree ni n g, defi ne d as c o m pleti n g t he dail y e Diar y a n d 
a ns weri n g “ Yes” t o ta ki n g 2 p uffs of r u n -i n B D M DI f or a n y 1 0 m or ni n gs a n d 
1 0  e ve ni n gs i n t he last 1 4 da ys pri or t o ra n d o mizati o n.  
 
Wei g ht  
1 2  B o d y mass i n de x <  4 0  k g/ m 2. 
 
Se x  
1 3  Male a n d/ or fe male; fe m ales m ust be n ot of c hil d beari n g p ote ntial or usi n g a f or m of 
hi g hl y effecti ve birt h c o ntr ol as defi ne d bel o w:  
•  
Fe male p artici pa nts: W o me n n ot of c hil d beari n g p ote ntial are defi ne d as w o me n w h o are 
eit her per m a ne ntl y sterilize d ( h ysterect o m y, bilateral o o p h orect o m y, or bilateral 
sal pi ngect o m y), or w h o are p ost me n o pa usal. W o m e n will be c o nsi dere d p ost me n o pa usal 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
if t he y ha ve bee n a me n orr h oeic f or 1 2 m o nt hs pri or t o t he pla n ne d date of ra n d o mizati o n 
wit h o ut a n alter nati ve me dical ca use. T he f oll o wi n g a ge -s pecific re q uire me nts a p pl y: 
− 
W o me n <  5 0 years ol d w o ul d be c o nsi dere d p ost me n o pa usal if t he y ha v e bee n 
a me n orr h oeic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of e x o ge n o us h or m o nal 
treat me nt a n d f ollicle sti m ulati n g h or m o ne le vels i n t he p ost me n o pa usal ra n ge. 
− 
W o me n ≥ 5 0 years ol d w o ul d be c o nsi dere d p ost me n o pa usal if t he y ha v e bee n 
a me n orr h oeic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of all e x o ge n o us h or m o nal 
treat me nt. 
•  
Fe male p artici pa nts of c hil d beari n g p ote ntial m ust use a hi g hl y effecti ve f or m of birt h 
c o ntr ol. A hi g hl y effecti ve met h o d  of c o ntr ace pti o n is defi ne d as o ne t hat ca n ac hie ve a 
fail ure rate of less t ha n 1 % per year w h e n use d c o nsiste ntl y a n d c orrectl y. W o me n of 
c hil d beari n g p ote ntial w h o are se x u all y acti ve wit h a n o n -sterilize d mal e part ner m ust 
a gree t o us e a hi g hl y effecti ve met h o d of birt h c o ntr ol, as defi ne d bel o w, fr o m e nr oll me nt 
t hr o u g h o ut t he st u d y a n d u ntil at least 1 6 wee ks aft er last d ose of st u d y i nter ve nti o n. 
Cessati o n of c o ntrace pti o n after t his p oi nt s h o ul d be disc usse d wit h a res p o nsi ble 
p h ysicia n. All w o me n of  c hil d beari n g p ote ntial m ust ha ve a ne g ati ve hi g hl y se nsiti ve 
uri ne (at all visits). A d olesce nt partici pa nts s h o ul d be c o u nselle d a p pr o pri atel y b y t he 
I n v esti gat or. 
•  
Hi g hl y effecti ve birt h c o ntr ol met h o ds are liste d b el o w:  
•  Se x ual a bsti ne nce d efi ne d as c o m p lete a bsti ne n ce fr o m i nterc o urse w he n it is t he 
preferre d a n d us ual lifest yle of t he partici p a nt ( h o we ver, peri o dic a bsti ne n ce 
e g, cale n d ar, o v ulati o n, s y m pt ot her mal, p ost -o v ulati o n met h o ds, declarati o n of 
a bsti ne nce f or t he d urati o n of e x p os ure t o st u d y i nter ve nti o n, a n d wit h dr a wal are n ot 
acce pta ble met h o ds of c o ntrace pti o n)  
− 
C o ntrace pti ve s u b der mal i m pla nt  
− 
I ntr a uteri ne d e vice or i ntra uteri ne s yste m 
− 
Oral c o ntrace pti ve (c o m bi ne d a n d pr o gester o ne o nl y)  
− 
I nje cta ble pr o gest o ge n [Hatc her  2 0 1 1]  
− 
C o ntrace pti ve va gi n al ri n g [ Hatc her  2 0 1 1]  
− 
Perc uta ne o us c o ntrace pti ve patc hes [ Hatc her  2 0 1 1]  
•  Male part ner sterilizati o n wit h d oc u me ntati o n of az o os per mia pri or t o t he fe male 
partici pa nt’s e ntr y i nt o t h e st u d y, a n d t his male is t he s ole part ner f or t hat p artici pa nt 
[Hatc her  2 0 1 1]. T h e d oc u me ntati o n o n male sterilit y ca n c o me fr o m t he site 
pers o n nel’s re vie w of partici pa nt’s me dical rec or ds, me dical e xa mi nati o n a n d/ or 
se me n a nal ysis or me dic al hist or y i nter vie w pr o vi de d b y her or h er part ner.  
•  Bilateral t u bal li gati o n  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
I nf or me d C o nse nt 
1 4  Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as d es cri be d i n A p pe n di x  A  w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restri cti o ns liste d i n t he I C F a n d i n t his pr ot oc ol.  
1 5  Pr o visi o n of si g ne d a n d date d writte n O pti o nal Ge n o mics I nitiati ve Researc h I nf or mati o n 
c o nse nt f or m pri or t o c oll e cti o n of sa m ples f or O pti o nal Ge n o mics I nitiati ve Researc h 
t hat s u p p orts Ge n o mic I nitiati ve. 
 
5. 2  
E xcl usi o n Criteri a   
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
Me dic al C o n diti o ns  
1  
Life -t hreate ni n g ast h ma as defi ne d as a hist or y of si g nifica nt ast h ma e pis o d e(s) re q uiri n g 
i nt u bati o n ass ociate d wit h h y perca p ni a, res pir at or y arrest, h y p o xic s eiz ures, or 
ast h ma-relat e d s y nc o pal e pis o de(s). 
2  
A n y res pirat or y i nfecti o n or ast h ma e xacer bati o n treate d wit h s yste mic c ortic oster oi ds 
a n d/ or a d diti o nal I C S treat me nt  i n t he 8 wee ks pri or t o Visit 1 a n d t hr o u g h o ut t he 
Scree ni n g Peri o d.  
3  
H os pitalizati o n f or ast h m a wit hi n 8 wee ks of Visit  1.  
4  
Hist orical or c urre nt e vi d e nce of a cli nicall y si g nifica nt disease i ncl u di n g, b ut n ot li mite d 
t o: car di o vasc ular, he pati c, re nal, h emat ol o gical, n e ur ol o gical, e n d ocri ne, g astr oi ntesti nal, 
or p ul m o nar y (e g, acti ve t u berc ul osis, br o nc hiectasis, p ul m o nar y e osi n o p hilic s y n dr o mes, 
a n d C O P D). Si g nifica nt is defi ne d as a n y disease t hat, i n t he o pi ni o n of t he I n v esti gat or, 
w o ul d p ut t he safet y  of t he partici pa nt at ris k t hr o u g h partici pati o n, or t hat c o ul d affect 
t he effic ac y or s afet y a nal ysis. 
5  
K n o w n hist or y of dr u g or alc o h ol a b use wit hi n 1 2 m o nt hs of Visit  1.  
6  
U nresecta ble ca ncer t hat has n ot bee n i n c o m plete re missi o n f or at least 5 y ears pr i or t o 
Visit  1.  
N ote : S q ua m o us cell a n d basal cell carci n o mas of t he s ki n are n ot e xcl usi o nar y. 
 
Pri or/ C o nc o mit a nt T her a p y  
7  
Partici pati o n i n a n ot her cli nical st u d y wit h a st u d y i nter ve nti o n a d mi nistere d i n t he last 
3 0  da ys or 5 half -li ves, w hic he ver is l o n ger. A n y ot her st u d y i nter ve nti o n t hat is n ot 
i de ntifie d i n t his pr ot oc ol is pr o hi bite d f or use d uri n g st u d y d urati o n. 
8  
Pre vi o us or c urre nt ra n d o mizati o n i nt o st u dies wit hi n t he A E R O S P H E R E pr o gra m 
i ncl u di n g K A L O S, L O G O S, V A T H O S, LI T H O S, or a n y gl yc o p yrr o ni u m st u dies 
( P T 0 0 1).  
9  
Use of a n e b ulizer or a h o me ne b ulizer f or recei vi n g ast h ma me dicati o ns.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
N ote:  A c ute use of a ne b ulizer f or a n ast h ma e x acer bati o n d uri n g h os pitalizati o n is 
all o we d as l o n g as t here is n o occ urre nce wit hi n 8 wee ks of Visit  1.  
1 0  D o n ot meet  t he sta ble d osi n g peri o d pri or t o Visit 1 (see Ta ble  7 ) or u na bl e t o a bstai n 
fr o m pr ot oc ol-defi ne d pr o hi bite d me dicati o ns d uri n g Scree ni n g a n d Treat m e n t Peri o ds 
(see Ta bl e  8  a n d T a ble  9 ). 
1 1  Recei pt of C O VI D -1 9 vacci ne (re gar dless of vacci ne deli ver y platf or m, e g, vect or, li pi d 
na n o particle) ≤ 7 da ys pri or t o Visit  1 (fr o m last vacci nati o n or b o oster d ose).  
1 2  Partici pa nts wit h k n o w n h y perse nsiti vit y t o beta 2-a g o nists, c ortic oster oi ds, or a n y 
c o m p o ne nt of t he M DI. 
 
Di a g n ostic Assess m e nts  
1 3  A n y cli nicall y rele v a nt a b n or mal fi n di n gs i n p h ysical e xa mi nati o n, cli nical c he mistr y, 
he mat ol o g y, vital si g ns, or E C G, w hic h i n t he o pi ni o n of t he  I n vesti gat or, ma y p ut t he 
partici pa nt at ris k be ca us e of his/ her partici pati o n i n t he st u d y.  
N ote : Partici pa nts wit h E C G Q Tc F > 4 8 0  msec will be e xcl u de d. Partici pa nts wit h hi g h 
de gree atri o ve ntric ul ar bl oc k II or III, or wit h si n us n o de d ysf u ncti o n wit h cli nicall y 
si g nifica nt pa uses w h o d o n ot ha ve a pace ma ker will als o be e xcl u de d.  
 
Ot her E xcl usi o ns  
1 4  C urre nt s m o kers, f or m er s m o kers wit h >  1 0 pac k -years hist or y, or f or mer s m o kers w h o 
st o p pe d s m o ki n g < 6 m o nt hs pri or t o Visit  1 (i ncl u di n g all f or ms of t o bac c o, e-ci garettes 
or ot her va pi n g de vi ces, a n d marij ua na).  
1 5  Pla n ne d h os pitalizati o n d uri n g t he st u d y.  
1 6  I n v ol ve m e 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 Astra Ze neca 
staff a n d/ or staff at t he st u d y site). 
1 7  St u d y I n vesti gat ors, s u b-I n v esti gat ors, c o or di nat ors, a n d t heir e m pl o yees or i m me diate 
fa mil y me m bers. 
1 8  J u d g me nt b y t he I n v esti gat or t hat t he partici pa nt is u nli kel y t o c o m pl y wit h st u d y 
pr oce d ures, restri cti o ns, a n d re q uir e me nts.  
1 9  F or w o me n o nl y –  c urre ntl y pre g n a nt (c o nfir me d wit h p ositi ve hi g hl y se nsiti ve uri ne 
pre g na nc y t est), breast -fee di n g, or pla n ne d pre g na nc y d uri n g t he st u d y or n ot usi n g 
acce pta ble c o ntr ace pti o n meas ures, as j u d g e d b y t he I n vesti gat or.  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
5. 3  
Lifest yle C o nsi der ati o ns   
5. 3. 1  
C affei ne, T o b acc o, a n d Alc o h ol   
1  
Partici pa nts will a bstai n fr o m i n gesti n g caffei ne - or xa nt hi ne -c o nt ai ni n g pr o d ucts 
(e g, c offee, t ea, c ol a dri n ks, a n d c h oc olate) f or 6 h o urs bef ore a n d f or t he d urati o n of eac h 
i n-cli nic st u d y visit. 
2  
Use of t o bacc o pr o d u cts or va pi n g will n ot be all o we d fr o m 6 m o nt hs pri or t o Visit  1  u ntil 
after t he fi nal f oll o w -u p visit.  
3  
Partici pa nts will a b stai n fr o m c o ns u mi n g a n y i nt o xica nts wit hi n 2 4 h o urs bef ore 
s pir o metr y testi n g. 
 
5. 3. 2  
Illicit Dr u gs or Dr u gs of A b use  
Illicit dr u gs or dr u gs of a b use will n ot be all o we d fr o m Visit 1 t o t he e n d of t he f oll o w-u p 
tele p h o ne call or t o w he n e ver t he p artici pa nt wit h dra ws fr o m t he st u d y. If a n y illicit dr u gs or 
dr u gs of a b use are us e d b y t he partici pa nt d uri n g t he st u d y, t he dates of use a n d t he a m o u nt 
will be d oc u me nte d, a n d t he partici pa nt  will be disc o nti n ue d fr o m ra n d o mize d st u d y 
i nter ve nti o n a n d will be wit h dra w n fr o m t he st u d y at t he discreti o n of t he I n vesti gat or. 
5. 4  
Scree n F ail ures   
Scree n fail ures are defi ne d a s partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
are n ot s u bse q u e ntl y ra n d o ml y assi g ne d t o st u d y i nter ve nti o n. 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 p are nt re p orti n g of scree n fail ure partici pa nts t o meet 
t he C o ns oli date d Sta n dar ds of Re p orti n g Trials 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 o m r e g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure 
details, eli gi bilit y criteria, a n d a n y A Es.  
Rescree ni n g is all o w e d f or sc ree n fail ure reas o n(s) t hat are tr a nsie nt (i ncl u di n g, b ut n ot 
li mite d t o, pre-defi ne d ti me peri o d re q uir e me nts, res pirat or y tract i nfecti o n n ot treate d wit h 
s yste mic c ortic oster oi ds, e q ui p me nt/ pr oce d ure fail ure [e g, pr o ble ms wit h t he e Diar y 
i m pacti n g a vaila bilit y of data], re q uire d st u d y d oc u me ntati o n, or u nf ores ee n pers o nal 
reas o ns). 
Eac h partici pa nt will ha ve a ma xi m u m of 2 res cree ni n g o p p ort u nities d uri n g t he recr uit me nt 
peri o d.  
Partici pa nts ma y n ot be rescree ne d d u e t o fail ure t o meet t he st u d y re q uire m e nts of 
pre -br o nc h o dilat or F E V 1 (i ncl u di n g sta bilit y) a n d A C Q sc ore d uri n g t he Scree ni n g Peri o d. 
Rescree n e d partici pa nts will be assi g ne d t he sa me partici pa nt n u m ber as f or t he i nitial 
scree ni n g. Res cree ne d partici pa nts will si g n a ne w I C F. All pr oce d ures re q uire d f or t he 
scree ni n g/r u n-i n peri o ds, starti n g at Visit 1, s h o ul d be re peate d. Rescree ni n g s h o ul d be 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni d e a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
d oc u me nte d s o t hat its effect o n t he st u d y res ults, if a n y, ca n be assesse d.  
If a partici pa nt is rescree ne d a n d fails f or a n y reas o n ot her t ha n pre-br o nc h o dilat or F E V 1 a n d 
A C Q sc ore, a n ot her rescree ni n g is all o we d after a 3 -m o nt h peri o d.  
F or all partici pa nts w h o are scree n fail ures, a n A E assess me nt a n d hi g hl y se nsiti ve uri ne 
pre g na nc y t est (f or w o me n of c hil d beari n g p ote ntial ) m ust be perf or m e d wit hi n 7 da ys of t he 
scree n fail ure d ate. 
6  
S T U D Y I N T E R V E N TI O N   
St u d y i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s)  or 
place b o i nte n d e d t o b e a d mi nistere d t o, or me dical de vice(s) utilize d b y, a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol.  
Place b o M DI de vi ces will be pr o vi de d at Visit  1 f or i n -cli nic trai ni n g p ur p oses. R u n -i n B D 
M DI will be pr o vi de d d uri n g t he Scree ni n g Peri o d.  
I nstr ucti o ns f or use of I n vesti gati o nal Pr o d ucts will be pr o vi de d. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistere d   
6. 1. 1  
I n vesti g ati o n al Pr o d u cts  
Ta ble  5  
I n vesti g ati o n al/ N o n-I n vesti g ati o n al Pr o d ucts  
 
B F F M DI 1 6 0/ 9. 6  µ g  
R u n -i n B D/ Bli n de d B D M DI 
1 6 0  µ g  
Al b uter ol s ulf ate i n h al ati o n aer os ol 
( 
/ S al b ut a m ol s ulf ate i n h al ati o n aer os ol 
( 
) 
I nter v e nti o n 
N a m e  
B u des o ni de/f or m oter ol f u marate press urize d 
i n halati o n s us pe nsi o n, 
 
de vice  
B u des o ni de press urize d i n halati o n 
s us pe nsi o n, 
 
de vice  
Al b uter ol/sal b uta m ol  
T y pe  
C o m bi nati o n Pr o d uct  
C o m bi nati o n Pr o d uct  
C o m bi nati o n Pr o d uct  
D ose F or m ul ati o n  I n haler 
I n haler 
I n haler 
U nit D ose 
Stre n gt h 
( Deli vere d D ose) 
8 0/ 4. 8  µ g per act uati o n  
8 0  µ g per act uati o n  
9 0  µ g per act uati o n (
 
1 0 0  μ g per act uati o n ( 
)  
D os a ge Le vel(s)  
2 i n halati o ns BI D  
2 i n halati o ns BI D  
2 i n halati o ns as nee de d; as directe d f or re v ersi bilit y 
testi n g at Visits 2 or 3 
T ot al D ail y D ose  
3 2 0/ 1 9. 2  µ g  
3 2 0  µ g  
N/ A  
R o ute of 
A d mi nistr ati o n  
Oral i n halati o n  
Oral i n halati o n  
Oral i n halati o n  
Use  
E x peri me ntal  
E x peri me ntal/ C o m parat or  
Resc ue me dicati o n/re v ersi bilit y testi n g  
I M P a n d NI M P 
I M P 
I M P 
NI M P  
S o urci n g  
Pr o vi de d ce ntrall y b y Astra Ze neca  
Pr o vi de d ce ntrall y b y Astra Ze neca  
Pr o vi de d l ocall y b y t he st u d y site, s u bsi diar y, or 
desi g nee.  
P ac k a gi n g a n d 
L a belli n g  
St u d y i nter ve nti o n will be pr o vi de d i n a n 
M DI. Eac h M DI will be la bele d as re q uire d 
per c o u ntr y re q uire me nt  
St u d y i nter ve nti o n will be pr o vi de d 
i n a n M DI. Eac h M DI will be la bele d 
as re q uire d per c o u ntr y re q uire me nt  
N/ A  
BI D =t wice dail y;  
, I M P =I n vesti gati o nal Me dici nal Pr o d uct; NI M P = N o n -I n vesti gati o nal Me dici nal Pr o d uct; 
; 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
6. 1. 2  
Me dic al De vices I ncl u di n g C o m bi n ati o n Pr o d ucts wit h De vi ce 
C o nstit ue nt   
1  
T he Astra Z e neca ma n ufact ure d c o m bi nati o n pr o d uct wit h a de vice c o nstit ue nt pr o vi de d 
f or use i n t his st u d y are t he Metere d D ose I n h aler ( A p pr o ve d) a n d Press uri ze d Metere d 
D ose I n haler ( A p pr o ve d).  
2  
I nstr u cti o ns f or c o m bi nati o n pr o d ucts wit h a de vice c o nstit ue nt use are pr o vi de d i n t he 
I n v esti gat or Br oc h ure a n d C o m bi nati o n Pr o d ucts secti o n of t he S u m mar y of Me dical 
Pr o d uct C haracteristics.  
3  
All de vice c o nstit ue nt deficie ncies (i n cl u di n g malf u ncti o n, use err or a n d i n a de q uate 
la beli n g) s hall be d oc u m e nte d a n d re p orte d b y t he I n v esti gat or t hr o u g h o ut t he cli nical 
i n vesti gati o n (see Secti o n 8. 3. 1 2 ) a n d a p pr o priatel y ma na ge d b y Astra Z e n eca. 
 
6. 2  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y   
T he I n vesti gat or or d esi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei v e d a n d a n y dis cre p a ncies are 
re p orte d a n d res ol ve d b ef ore use of t he st u d y i nter ve nti o n. 
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n a n d o nl y a ut h orize d site 
staff ma y s u p pl y st u d y i nter ve nti o n. All st u d y i nter ve nti o n m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n u al or a ut o mate d) area i n acc or da n ce wit h t he 
la bele d st ora g e c o n diti o ns wit h access li mite d t o t he I n vesti gat or a n d a ut h orize d site staff.  
T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
All ha n dli n g i nstr ucti o ns a n d f urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of 
u n use d st u d y i nter ve nti o ns are pr o vi de d se paratel y o utsi de of t he pr ot oc ol.  
6. 3  
Me as ures t o Mi ni mize Bi as: R a n d o miz at i o n a n d Bli n di n g  
All partici pa nts will be ce ntrall y assi g ne d t o o ne of 2 ra n d o mize d st u d y i nter ve nti o ns usi n g a n 
I R T s yste m. Bef ore t he st u d y is i nitiate d, t he l o g-i n i nf or mati o n a n d directi o ns f or t he I R T 
s yste m will be pr o vi de d t o eac h site. 
T he I R T s yste m will pr o vi de t o t he I n vesti gat ors or p har macists t he kit i de ntificati o n n u m ber 
t o be all ocate d t o t he partici pa nt at t he dis pe nsi n g visit (as s u m marize d i n t he S o A, Ta ble  1 ). 
R o uti nes f or t his will be descri be d i n t he I R T s yst e m user ma n ual t hat will be pr o vi de d t o eac h 
ce nter.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
T he ra n d o mizati o n c o de s h o ul d n ot be br o ke n e xce pt i n me dical e mer ge nci es w he n t he 
a p pr o priate m a na ge me nt of t he partici pa nt re q uires k n o wle d ge of t he tr eat me nt 
ra n d o mizati o n. T he I n vesti gat or d oc u me nts a n d re p orts t he acti o n t o Astra Z e neca, wit h o ut 
re veali n g t he treat me nt t hat was gi ve n t o t he partici pa nt t o t he Astra Ze neca staff. 
Astra Ze n eca retai ns t he ri g ht t o brea k t he c o de f or S A Es t hat are u ne x p ecte d a n d are 
s us pecte d t o be ca usall y relate d t o a st u d y i nter ve nti o n a n d t hat p ote ntiall y re q uire e x p e dite d 
re p orti n g t o re g ulat or y a ut h orities. Ra n d o mizati o n c o des will n ot be br o ke n f or t he pla n ne d 
a nal yses of dat a u ntil all decisi o ns o n t he e val ua bilit y of t he data fr o m eac h i n di vi d ual 
partici pa nt ha ve b ee n ma de a n d d oc u me nt e d.  
T he I R T s yste m will be pr o gra m me d wit h bli n d -brea ki n g i nstr ucti o ns. I n case of a n 
e mer ge n c y, i n w hic h t he k n o wle d g e of t he s p ecifi c bli n de d st u d y i nter ve nti o n will affect t he 
i m me diate ma na ge me nt of t he partici pa nt’s c o n diti o n, t he I n vesti gat or has t he s ole 
res p o nsi bilit y f or deter mi ni n g if u n bli n di n g of a partici pa nts’ i nter ve nti o n assi g n me nt is 
warra nte d. Partici pa n t safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s uc h a 
deter mi nati o n. If a p artici pa nt’s i nter ve nti o n assi g n me nt is u n bli n de d, Astra Ze neca m ust be 
n otifie d wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he I n vesti gat or d o c u me nts a n d re p orts t he 
acti on t o Astra Z e neca, wit h o ut re veali n g t he treat me nt gi ve n t o partici pa nt t o t he Astra Z e neca 
staff. 
6. 4  
St u d y I nter ve nti o n C o m pli a nce   
W he n partici p a nts are d ose d at t he site, t he y will recei ve st u d y i nter v e nti o n directl y fr o m t he 
I n vesti gat or or desi g ne e, u n der me dical s u p er visi o n. T he date, a n d ti me if a p plica ble, of d ose 
a d mi nistere d i n t he cli nic will be rec or de d i n t he s o urce d oc u m e nts a n d rec or de d i n t he e C R F.  
C o m plia nce wit h st u d y  i nter ve nti o n will be assesse d at eac h visit. C o m plia nce will be 
assesse d b y re vie wi n g t h e dail y e Diar y rec or di n g a n d t he re mai ni n g d oses of t he d ose c o u nter 
d uri n g t he site visits. T he d ose c o u nter rea di n g s h o ul d be d oc u me nte d i n t he s o urce 
d oc u me nts.  
A rec or d of t h e n u m ber of M DIs  dis pe nse d t o a n d use d b y eac h partici pa nt m ust be 
mai ntai ne d a n d rec o ncile d wit h st u d y i nter ve nti o n a n d c o m plia nce rec or ds. I nter ve nti o n start 
a n d st o p dates will als o be rec or de d i n t he e C R F.  
6. 5  
C o nc o mit a nt T her a p y   
A n y me dicati o n or vacci ne (i ncl u di n g o ver t he c o u nter or pres cri pti o n me dici nes, vita mi ns, 
a n d/ or her bal s u p ple me nts or ot her s pecific cat e g ories of i nterest) t h at t he p artici pa nt is 
recei vi n g fr o m u p t o 3 m o nt hs pri or t o Visit 1 or recei ves d uri n g t he st u d y m ust be rec or de d 

Cli nica l St u d y Pr ot oc ol - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
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 m ati o n i ncl u di n g d ose a n d fre q ue nc y  
 
T he Me dical M o nit or s h o ul d be c o ntacte d if  t h ere are a n y q u esti o ns re gar di n g c o nc o mita nt or 
pri or t hera p y.  
6. 5. 1  Resc ue Me dici ne   
Al b uter ol f or partici pa nts t o use as resc u e me dicati o n a n d f or re versi bilit y testi n g at Visits 2 
a n d 3 (if nee de d) is n ot r e gar de d as st u d y i nter ve nti o n b ut will be pr o vi de d/rei m b urse d b y 
Astra Ze neca acc or di n g t o l ocal re g ulati o ns i n or d er t o mai ntai n a p pr o pri ate o versi g ht a n d 
access t o t his c o nc o mita nt me dicati o n. T he o nl y resc ue me dicati o n all o we d i n t his st u d y is 
al b uter ol; all ot her me dicati o ns f or resc ue use are pr o hi bite d.  
Alt h o u g h t he use of al b ut er ol is all o wa ble at a n y ti me d uri n g t he st u d y, t he use of res c ue 
me dicati o ns s h o ul d be wit h hel d, if p ossi ble, f or at least 6 h o urs pri or t o t he start a n d d uri n g 
eac h cli nic visit. If al b uter ol is use d wit hi n 6 h o urs fr o m t he start of a cli nic visit, t he n t he visit 
will nee d t o be res c he d ul e d wit hi n t he all o we d visit wi n d o w. T he n u m ber of p uffs of resc u e 
me dicati o n will be rec or de d b y t he partici pa nt d ai l y i n t he e Diar y. 
6. 5. 2  
Pri or Me dic ati o ns   
Partici pa nts eli gi ble f or t his st u d y are re q uir e d t o be o n a sta ble re gi me n i n cl u di n g fi xe d dail y 
d osi n g of a n i n hale d ast h ma mai nte na nce t h era p y defi ne d as a n I C S or I C S/ L A B A f or at least 
8 wee ks pri or t o Visit  1. T he per mitte d t otal dail y I C S d osa ge t o q ualif y f or t he st u d y is 
defi ne d i n Ta bl e  6 . A n y I C S n ot liste d i n t he GI N A 2 0 2 1 g ui deli nes or c o nsi derati o ns o utsi de 
t his list s h o ul d be disc usse d with t he Me dical M o nit or pri or t o e ntr y of t he partici pa nt.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
Ta ble  6  
Re q uire d I C S D os a ges ( M o n ot her a p y or i n C o m bi n ati o n wit h L A B A) 
Pri or t o Visit  1   
I n h ale d C ortic oster oi d 
T ot al D ail y D ose ( µ g/ d a y) a 
Becl o met has o ne di pr o pi o nate ( p M DI, sta n dar d particle, H F A)  
2 0 0 -5 0 0  
Becl o met has o ne di pr o pi o nate ( D PI or p M DI, e xtrafi ne particle, 
H F A)  
1 0 0 -2 0 0  
B u des o ni de ( D PI or p M DI, sta n dar d particle, H F A)  
2 0 0 -4 0 0  
Cicles o ni de ( p M DI, e xtrafi ne particle, H F A)  
8 0 -1 6 0  
Fl uticas o ne f ur oate ( D PI)  
1 0 0  
Fl uticas o ne pr o pi o nate ( D PI or p M DI, sta n dar d particle, H F A)  
1 0 0 -2 5 0  
M o metas o ne f ur oate ( D PI)  
D ue t o c o m ple xit y ar o u n d 
d osi n g i n differe nt 
de vices/f or m ulati o ns, please 
disc uss wit h t he St u d y 
P h ysicia n  
M o metas o ne f ur oate ( p M DI, sta n dar d particle, H F A)  
2 0 0 -4 0 0  
D PI = Dr y P o w der I n haler; H F A = h y dr ofl u or oal ka ne; p M DI = Press urize d Metere d D ose I n haler  
a. Dail y d oses i n t his ta ble are s h o w n as metere d d oses.  
 
6. 5. 3  
C o nc o mit a nt Me dic ati o ns   
A n y c urre nt o n g oi n g me dicati o ns, i ncl u di n g o ver t he c o u nter me dicati o ns, her bal 
s u p ple me nts, a n d vacci nati o ns, will be all o we d pr o vi de d t he y are n ot e x plicitl y pr o hi bite d b y 
t he pr ot oc ol. Partici pa nts s h o ul d als o be i nstr ucte d t o c o ntact t he I n vesti gat or if t he y de vel o p 
a n y ill nesses, es peci all y t h ose re q uiri n g me dici nal i nter ve nti o ns.  
Me dicati o ns meeti n g t he sta ble d osi n g peri o d pri or t o Visit  1 are all o we d d uri n g t he st u d y a n d 
liste d i n Ta ble  7 . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
Ta ble  7  
All o we d Me dic ati o ns wit h Defi ne d St a ble D osi n g Peri o d Pri or t o Visit  1   
Me dic ati o n  
Mi ni m u m St a ble D osi n g Peri o d Pri or t o 
Visit  1  
Selecti ve ser ot o ni n re u pta ke i n hi bit ors/ser ot o ni n a n d 
n ore pi ne p hri ne re u pta ke i n hi bit ors a 
4 wee ks  
Tric yclic a nti de pressa nts  
2 wee ks  
A nti ps yc h otics  
4 wee ks  
A ntic o n v ulsa nts  
5 2 wee ks f or seiz ure dis or ders b 
1 2 wee ks f or ot her c o n diti o ns  
N o n -se dati n g l o n g- a n d s h ort -acti n g a nti hista mi nes  
4 wee ks  
I ntra nasal c ortic oster oi ds 
4 wee ks  
I ntra nasal a nti hista mi nes or c o m bi nati o n pr o d ucts of 
i ntra nasal a nti hista mi nes/c ortic oster oi ds 
4 wee ks  
I ntra nasal i pratr o pi u m br o mi dec 
4 wee ks  
a. M ust b e o n a sta ble d ose f or at least 4 wee ks pri or t o Visit  1 a n d n ot altere d d uri n g t he Scree ni n g Peri o d.  
b.  M ust b e free of seiz ures f or o ne  year pri or t o Visit  1  
c. Intra n asal i pratr o pi u m br o mi de s h o ul d be wit h hel d f or at least 6 h o urs pri or t o eac h visit.  
 
6. 5. 3. 1  
V acci n ati o ns   
All partici pa nts s h o ul d be vacci nate d wit h a n n ual i nfl ue nza vacci ne [ GI N A  2 0 2 1] or a n y ot her 
i nacti ve/ kille d vacci nes p er l ocal p olicies, a vaila bilit y, a n d aff or da bilit y. If a partici pa nt has 
e g g i nt olera nce or ref uses t o be vacci nat e d, t he vacci nati o n ma y be o mitte d. T he a n n ual 
i nfl ue nza vacci ne ca n b e gi ve n at Visit 1 or at a n y ot her visit t hr o u g h o ut t he st u d y at t he 
discreti o n of t he I n v esti gat or; h o we ver, a d mi nistrati o n s h o ul d occ ur after o btai ni n g all 
re q uisite s pir o metr y assess me nts f or t hat s pecific t est da y. T here s h o ul d be at least 7 da ys 
bet wee n v acci n ati o n a n d s u bse q u e nt s pir o metr y assess me nts.  
If a partici pa nt is bei n g c o nsi dere d f or e nr oll me nt i nt o t he st u d y a n d als o bei n g c o nsi dere d f or 
C O VI D -1 9 vacci nati o n, t he partici pa nt m ust n ot be ra n d o mize d u ntil at least 7 da ys after t he 
last d ose of vacci ne or b o oster. If C OVI D -1 9 v acci nati o n is i n t he best i nterest of t he 
partici pa nt a n d t he p artici pa nt is vacci nate d d uri n g t he st u d y, t here s h o ul d be at least 7 da ys 
bet wee n v acci n ati o n a n d s u bse q ue nt s pir o metr y assess me nts.  
Li ve atte n uate d v acci n es are n ot all o we d wit hi n 3 0 da ys pri or t o Visit  1 or d uri n g t he st u d y.  
6. 5. 4  
Pr o hi bite d Me dic ati o ns   
Partici pa nts re q uiri n g me dicati o ns prese nte d i n Ta ble  8  are pr o hi bite d fr o m partici pati n g i n 
t his st u d y. Partici pa nts w h o rece ntl y disc o nti n ue d use of t hese me dicati o ns ma y be c o nsi dere d 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter o l F u marate - D 5 9 8 2 C 0 0 0 0 5  
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 1 2 2  
 
f or st u d y e nr oll me nt pr o vi de d t he y ha ve met t he mi ni m u m cessati o n peri o d prior t o Visit  1. 
T hese me dicati o ns are pr o hi bite d t hr o u g h o ut t he c o urse of t he st u d y. If partici pa nts re q uire 
a n y of t he pr o hi bite d me dicati o ns liste d i n Ta ble  8 , t he I n vesti gat or s h o ul d disc uss wit h t he 
Me dical M o nit or t he s uita bilit y of t he partici pa nt c o nti n ui n g st u d y i nter ve nti o n.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 3  of 1 2 2  
 
Ta ble  8  
Pr o hi bite d Me dic ati o ns T hr o u g h o ut t he St u d y a n d Re q uire d Cess ati o n 
Peri o d Pri or t o Visit  1   
Me dic ati o n  
Mi ni m u m Cess ati o n Peri o d Pri or t o Visit  1  
L o n g -acti n g beta 2-a g o nist as relie v er  
8 wee ks  
L o n g -acti n g m uscari nic a nta g o nist  
1 2 wee ks  
Le u k otrie ne a nta g o nists/ m o difiers (e g, Zile ut o n ® ) 
3 m o nt hs  
Oral beta 2-a g o nist 
3 m o nt hs  
T he o p h ylli ne  
7 da ys  
Oral a n d I V c ortic oster oi ds a 
8 wee ks  
I njecta ble s yste mic c ortic oster oi ds (e g, de p ot f or m ulati o n, 
i ntra-artic ular, i ntra d er mal, i ntra m usc ular)  
3 m o nt hs  
A n y mar kete d (e g, o maliz u ma b, me p oliz u ma b, 
be nraliz u ma b, resliz u ma b) or i n vesti gati o nal bi ol o gical 
t hera p y f or ast h ma or a n y ot her c o n diti o n 
6 m o nt hs or 5 half -li ves, w hic he ver is l o n ger 
Pr o p h ylactic a nti bi otics  
8 wee ks  
R ofl u milast  
3 0 da ys  
A n y i m m u n o m o d ulat ors or i m m u n os u p pressi vesb 
3 m o nt hs or 5 half -li ves, w hic he ver is l o n ger 
Me dicati o ns n ot c urre ntl y lice nse d f or use i n t he treat me nt 
of ast h ma a n d n ot part of c urre nt sta n dar d of care  
3 0 da ys  
A n y dr u g wit h p ote ntial t o si g nifica ntl y pr ol o n g t he Q T 
i nter valc 
1 4 da ys or 5 half -li ves, w hic he ver is l o n ger 
Ot her i n vesti gati o nal dr u gs  
3 0 da ys or 5 half -li ves, w hic he ver is l o n ger 
Li ve atte n uate d vacci nes  
3 0 da ys  
N o n -selecti ve n o n-oc ular β -bl oc ki n g a ge nts (e xce pt 
car ve dil ol) 
7 da ys  
M o n oa mi ne o xi dase i n hi bit ors  
1 4 da ys  
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, itrac o naz ole, a n d rit o na vir)  
3 0 da ys  
S yste mic a ntic h oli ner gics d 
7 da ys  
Her bal re me dies f or t he treat me nt of aller gic, 
i nfla m mat or y, or res pirat or y diseases (e g, C hi nese 
c o m ple me ntar y a n d alter nati ve br o nc h o dilat or y me dici nes)  
1 0 da ys  
a. Use of s yste mic c ortic oster oi ds f or a n y ot her reas o n e xce pt f or t he ac ute treat me nt of a se vere ast h ma 
e x acer bati o n is pr o hi bite d f or t he d urati o n of t he st u d y.  
b.  T o pical a d mi nistrati o n of i m m u n os u p pressi ve me dicati o n ma y be all o we d at t he discreti o n of t he 
I n vesti gat or after disc ussi o n wit h t he St u d y P h ysicia n. 
c. Partici pa nts w h o are o n me dicati o ns t hat ha ve t he p ote ntial t o pr ol o n g t he Q Tc i nter val ma y be e nr olle d 
pr o vi de d t he d ose has re mai ne d sta ble f or at least 3 m o nt hs pri or t o Visit  1, t he partici pa nt meets all of t he 
E C G i ncl usi o n criteria a n d n o ne of t he E C G e xcl usi o n criteria, a n d if, i n t he o pi ni o n of t he I n vesti gat or, 
t here are n ot safet y c o ncer ns f or t he partici pa nt t o partici pate i n t he st u d y.  
d.  If s yste mic a ntic h oli ner gics are use d f or t he treat me nt of irrita ble b o wel s y n dr o me or o veracti ve bla d der 
a n d t he treat me nt h as bee n c o nsta nt f or at least o ne  m o nt h, t he y are all o we d.  
 
S pecific pr o hi bite d ast h ma a n d  aller g y m e dicati o ns a n d t heir re q uir e d was h o ut peri o ds pri or t o 
Visit  2 are dis pla ye d i n Ta ble  9 . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 4  of 1 2 2  
 
Ta ble  9  
Pr o hi bite d Ast h m a a n d Aller g y Me dic ati o ns fr o m Visit  1 O n w ar ds   
Me dic ati o n  
Mi ni m u m W as h o ut Peri o d Pri or t o Visit  2  
I C S ot her t ha n s p o ns or-pr o vi de d a 
7 da ys  
I C S/ L A B A ot her t ha n s p o ns or-pr o vi de d a 
7 da ys  
Cr o m o gl ycate b 
7 da ys  
Ne d ocr o mil b 
7 da ys  
Ket otife n b 
7 da ys  
S h ort -acti n g m uscari nic a nta g o nists a n d/ or s h ort-
acti n g beta 2-a g o nists al o ne, l o ose, or fi xe d 
c o m bi nati o n ot her t ha n s p o ns or -pr o vi de d al b uter ol  
7 da ys  
a. A d mi nistrati o n as fi xe d or l o ose c o m bi nati o ns  
b.  Cr o m o gl ycate, ne d ocr o mil, a n d ket otife n e ye dr o ps are all o we d f or aller gic c o nj u ncti vitis; n o was h o ut 
peri o d  
 
6. 6  
D ose M o dific ati o n   
N ot a p plica ble f or t his st u d y.  
6. 7  
I nter ve nti o n After t he E n d of t he St u d y  
At t he e n d of t he Ra n d o mize d Treat me nt Peri o d, t he I n vesti gat or or tr eati n g p h ysicia n of t he 
partici pa nt will prescri be alter nati ve ast h ma t hera p y f or t he partici p a nt. T h ere wil l be n o 
pr o visi o ns t o s u p pl y B F F M DI or B D M DI after t h e e n d of t he treat me nt peri o d.  
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N/ WI T H D R A W A L   
7. 1  
Disc o nti n u a ti o n of St u d y I nter ve nti o n  
It ma y be necessar y f or a partici pa nt t o per ma ne ntl y disc o nti n ue st u d y i nter ve nti o n. If st u d y 
i nter ve nti o n is per ma ne ntl y disc o nti n ue d, t he partici pa nt will be e nc o ura ge d t o re mai n i n t he 
st u d y a n d c o m plete t he re mai n der of t h e st u d y visits a n d pr oce d ures.  
N ote t hat disc o nti n uati o n fr o m st u d y i nter ve nti o n is N O T t he sa me t hi n g as a wit h dra wal fr o m 
t he st u d y. 
If a partici pa nt e x perie nces a n y of t he b el o w, t he st u d y i nter ve nti o n M U S T be disc o nti n ue d:  
•  
De vel o p me nt of e x cl usi o n criteria or ot h er safet y r eas o ns as j u d ge d b y t he I n vesti gat or 
d uri n g t he treat me nt peri o d  
•  
Pre g na nc y (s ee Secti o n 8. 3. 1 0 ) 
•  
A n ast h ma e xacer bati o n re q uiri n g i n -patie nt h os pitalizati o n  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 5  of 1 2 2  
 
•  
M ore t ha n 2 se v ere ast h ma e xacer bati o ns re q uiri n g oral c ortic oster oi d treat me nt  
 
See t he S o A ( Ta ble  1 ) f or data t o be c ollect e d at t h e ti me of i nter ve nti o n disc o nti n uati o n a n d 
f oll o w-u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.  
7. 2  
P artici p a nt Wit h dr a w al fr o m t he St u d y  
•  
A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n v esti gat or f or safet y, be ha vi oral, 
c o m plia nce, or a d mi nistrati ve reas o ns. T his is e x p ecte d t o be u n c o m m o n.  
•  
If a partici pa nt is u n willi n g t o atte n d t he sc he d ule d cli nic visits, he/s he will be i nf or me d 
b y t he I n vesti gat or a b o ut m o difie d f oll o w -u p o pti o ns (e g, tele p h o ne c o ntact, a c o nt act 
wit h a relati ve or tr eati n g p h ysicia n, or i nf or mati o n fr o m me dical r ec or ds).  
•  
At t he ti me of wit h dra wal fr o m t he st u d y, if p ossi ble, a n Earl y St u d y I nter ve nti o n 
Disc o nti n uati o n visit s h o ul d be c o n d ucte d, as s h o w n i n t he S o A ( Ta ble  1 ). See S o A f or 
data t o be c ollect e d at t he ti me of st u d y wit h dra wal a n d f oll o w -u p f or a n y f urt her 
e val uati o ns t hat nee d t o b e c o m plete d.  
•  T he partici pa nt will disc o nti n ue t he  st u d y i nter ve nti o n a n d be wit h dra w n fr o m t he 
st u d y at t hat ti me. 
•  
If t he partici p a nt wit h dra ws c o nse nt f or discl os ur e of f ut ure i nf or mati o n, Astra Ze neca 
ma y retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s u c h a wit h dr a wal of c o nse nt.  
•  
If a partici pa nt wit h dra ws fr o m t he st u d y, it s h o ul d be c o nfir me d if h e/s he still a grees f or 
e xisti n g sa m ples t o be use d i n li ne wit h t he ori gi nal c o nse nt. If he/s he re q u ests wit h dra wal 
of c o nse nt f or us e of sa m ples, destr ucti o n of a n y s a m ples ta ke n a n d n ot test e d s h o ul d be 
carri e d o ut i n li ne wit h w hat was state d i n t he i nf or me d c o nse nt a n d l o cal r e g ulati o n t he 
I n v esti gat or m ust d oc u me nt t he decisi o n o n use of e xisti n g sa m ples i n t he site st u d y 
rec or ds a n d i nf or m t he Gl o bal St u d y Tea m. 
 
7. 3  
L ost t o F oll o w -u p   
A partici pa nt  will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns m ust be ta ke n if a p artici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit: 
•  
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he partici pa nt o n t he i m p orta nce of m ai ntai ni n g t he assi g ne d visi t 
sc he d ule a n d ascertai n w het her or n ot t he p artici p a nt wis hes t o a n d/ or s h o ul d c o nti n ue i n 
t he st u d y. 

Cli nical St u d y Pr ot oc o l - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 6  of 1 2 2  
 
•  
Bef ore a p artici pa nt is dee me d l ost t o f oll o w -u p, t he I n vesti gat or or d esi g nee m ust ma ke 
e ver y eff ort t o r e gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne calls a n d, 
if necessar y, a certifie d l etter t o t he partici pa nt’s last k n o w n maili n g a d dress or l ocal 
e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he p artici pa nt’s 
me dical rec or d.  
•  
S h o ul d t he partici pa nt c o nti n ue  t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y.  
 
Disc o nti n uati o n of s pecific sites or of t he st u d y as a w h ole are ha n dle d as p art of A p pe n di x  A . 
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S   
•  
St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A ( Ta ble  1 ). Pr ot oc ol wai vers 
or e xe m pti o ns are n ot all o we d.  
•  
T he s u g geste d or d er of assess me nts is vital si g ns, A E/ S A E assess me nts, -6 0 -mi n ute 
s pir o metr y, P R O q uesti o n naires, -3 0 -mi n ute s pir o metr y, E C G, bl o o d dr a w, a n d t he n 
st u d y i nter ve nti o n a d mi nistrati o n. S pir o metr y M U S T be perf or me d i n acc or d a nce 
wit h t he s pecifie d ti mi n g.  
•  
I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h Astra Ze neca i m me diatel y u p o n 
occ urre nce or a w are ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue 
st u d y i nter ve nti o n. 
•  
A d here n ce t o t he st u d y d esi 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 
(Ta ble  1 ), is ess e 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 v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he I n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all parti ci pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g f ail ure, as a p plica ble. 
 
8. 1  
Effic ac y Assess me nts   
8. 1. 1  
P ul m o n ar y F u n cti o n Tests   
8. 1. 1. 1  
I n-Cli nic S pir o metr y St a n d ar diz ati o n   
All s pir o metr y i ncl u di n g F E V 1, F V C, a n d F E F2 5 -7 5 as defi ne d i n A T S/ E R S g ui deli nes will be 
perf or me d  i n acc or da n ce wit h A T S/ E R S acce pta bilit y a n d re peat a bilit y criteria [Miller  2 0 0 5] 
a n d will be assesse d usi n g a s pir o meter t hat meets or e xcee ds mi ni m u m perf or ma nce 
rec o m me n dati o ns. Calc ul ate d pre dict e d s pir o metr y res ults will be o btai ne d usi n g t he Gl o bal 
L u n g I nitiati ve  e q uati o ns  [Q ua njer  2 0 1 2].  
T he ce ntr al s pir o metr y v e n d or is res p o nsi ble f or ass uri n g t hat t he i n -cli nic s pir o meter meets 
A T S/ E R S rec o m me n dati o ns [ Miller  2 0 0 5] a n d t hat t he st u d y site pers o n nel w h o will be 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 7  of 1 2 2  
 
perf or mi n g t he testi n g are pr o perl y certifie d. A d diti o nal details will be pr o vi de d i n a 
S pir o metr y Pr oce d u res Ma n ual.  
As t he i n -cli nic s pir o metr y res ults are pri mar y a n d sec o n dar y efficac y e n d p oi nts f or t his st u d y, 
it is i m p orta nt f or t he me dicati o n wit h h ol di n g c o n ve nti o ns a n d ti mi n g of s pir o metr y t o be 
c o nsiste ntl y ma na ge d t hr o u g h o ut t he st u d y (see Secti o n 8. 1. 1. 2 ). 
8. 1. 1. 2  
I n-Cli nic S pir o metr y Sc he d ule   
I n-cli nic s pir o metr y c ollecti o n is briefl y o utli ne d bel o w. F or e xact s pir o metr y c ollecti o n a n d 
s pecificati o ns, pleas e refer t o t he S o A (Ta ble  1 ) a n d Ti mi n g of I n-Cli nic S pir o metr y 
Meas ure me nts ( Ta ble  2 ). 
I m p ort a nt re q uire me nts t o s u p p ort c o nsiste nt i n-cli nic s pir o metr y assess me nts d uri n g 
st u d y: 
•  
Partici pa nts will be re q uire d t o ret ur n t o t he cli nic at a p pr o xi matel y t he sa m e ti me of t he 
da y ±  1  hr as Visit  1 t hr o u g h o ut st u d y.  
•  
All pre -d ose (tr o u g h) s pir o metr y will be re q uir e d t o be c o n d ucte d i n t he m or ni n g 
( 0 8 0 0 ±  2  h o urs)  
•  
D uri n g t he Scree ni n g a n d Treat me nt Peri o ds, sites s h o ul d  call 2 4 t o 4 8 h o urs pri or t o eac h 
visit t o re mi n d partici pa nts t hat t he e ve ni n g d ose of st u d y i nter ve nti o n (r u n -i n B D M DI or 
st u d y i nter ve nti o n) s h o ul d be 1 2 ±  1  hr pri or t o t h e e x pecte d d osi n g ti me at t he ne xt 
m or ni n g visit.  
N ote:  If t he site m or ni n g d ose ti me is g oi n g t o be > 1 3 h o urs fr o m t he pri or e ve ni n g d ose 
ti me, t he n t he visit s h o ul d be resc h e d ule d wit hi n t he all o we d visit wi n d o w. 
•  
All i n -cli nic d osi n g s h o ul d occ ur pri or t o 1 0 0 0 ( +  1 h o ur all o wa nce) i n t he m or ni n g a n d 
visits m ust be pla n ne d acc or di n gl y. Partici pa nts will be dis pe nse d a n d a d mi nistere d ne w 
st u d y i nter ve nti o n at eac h cli nic visit d uri n g t he treat me nt peri o d.  
•  
T he m or ni n g d ose o n t he da y of t he cli nic visit m ust be wit h hel d u ntil after all pre -d ose 
assess me nts are c o m plete d at t he cli nic .  
N ote:  Al b uter ol m ust be wit h hel d at least 6 h o urs pri or t o t he start ti me of t he m or ni n g 
visit. If t hese re q uir e me nts are n ot met, t he n t he visit will nee d t o be resc he d ule d wit hi n 
visit wi n d o ws.  
•  
Partici pa nts will be re q uire d t o re mai n at t he cli nic u nt il c o m pleti o n of all 
pr ot oc ol -defi ne d assess m e nts a n d pr oce d ures.  
 
Scree ni n g Peri o d ( Visit  1 t hr o u g h Visit  4) : 
•  
T he a vera ge of t he 2 pre -br o nc h o dilat or F E V 1 val ues ( -6 0 a n d -3 0 mi n utes) will be 
calc ulate d t o det er mi ne if t he partici pa nt meets t he i ncl usi o n criteria. If a partici pa nt d oes 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 8  of 1 2 2  
 
n ot meet t his criteri o n at a n y o ne of t he s cree ni n g visits, t he partici pa nt will be scree n 
faile d at t hat visit. 
•  
Partici pa nts w h o ha ve n ot wit h hel d ast h ma me dicati o ns pri or t o Visit  1 a n d faile d 
s pir o metr y testi n g per criteri o n at Visit 1 s h o ul d ret ur n t o t he cli nic t o re peat s pir o metr y 
testi n g wit hi n 2 da ys. Partici pa nts w h ose re peat s pir o metr y testi n g fails t o meet  t he 
criteri o n will be scree n faile d.  
N ote:  R u n -i n B D M DI a n d al b uter ol will o nl y be dis pe nse d t o partici pa nts after meeti n g 
eli gi bilit y criteria t o pr ocee d t o Visit  2  
 
Visit  1:  
•  
S pir o metr y will be c o n d ucte d 6 0 a n d 3 0 mi n utes pri or t o r u n -i n B D M DI a d mi nistrati o n. 
 
Visit  2:  
•  
S pir o metr y will be c o n d ucte d at 6 0 a n d 3 0 mi n utes pri or t o al b uter ol a d mi nistrati o n a n d 
3 0 mi n utes p ost -al b uter ol (see Secti o n  8. 1. 1. 3 ).  
•  
Al b uter ol re versi bilit y testi n g s h o ul d be c o n d ucte d f or all partici pa nts at Visit  2; 
partici pa nts w h o fail t o meet t he re v ersi bilit y criteri o n at Visit  2 ca n still pr ocee d t o 
Visit  3 f or f urt her re versi bilit y testi n g (i ncl u di n g t h ose wit h d oc u me nte d  hist orical 
re versi bilit y). 
•  
If partici pa nts are n ot r e v ersi ble t o al b uter ol at 3 0 mi n utes p ost-d ose, t he p ost -d ose 
s pir o metr y ca n be re p eat e d at 6 0 mi n utes p ost-d ose.  
•  
A d mi nister r u n -i n B D M DI after c o m pleti o n of re versi bilit y test. 
 
Visit  3 : 
•  
F or partici pa nts w h o di d meet t he al b uter ol re versi bilit y criteri o n at Visit  2, s pir o metr y 
will be c o n d ucte d 6 0 a n d 3 0 mi n utes pri or t o r u n -i n B D M DI a d mi nistrati o n. 
•  
F or partici pa nts w h o di d n ot meet al b uter ol re v ersi bilit y criteri o n at Visit  2 (i ncl u di n g 
t h ose wit h d oc u me nte d hist orical re versi bilit y t o al b uter ol wit hi n 1 2 m o nt hs pri or t o 
Visit  1), al b uter ol re versi bilit y testi n g m ust be re peate d at Visit  3. T he al b uter ol 
re versi bilit y testi n g at Visit 2 (a n d Visit  3 if re versi bilit y is n ot de m o nstrate d at Visit  2) is 
re q uire d t o e v al uate pres e nce of re v ersi bilit y d uri n g scree ni n g. 
•  
Partici pa nts w h o fail t o meet t he al b uter ol re versi bilit y criteri o n at b ot h Visit  2 a n d Visit  3 
ca n still pr ocee d t o Visit  4 if t he y meet all ot her st u d y criteria, pr o vi de d  t he y ha ve a 
d oc u me nte d hist or y of re versi bilit y i n t he 1 2 m o nt hs pri or t o Visit  1.  
•  
Partici pa nts w h o ha ve n ot met hist orical re versi bilit y i n t he 1 2 m o nt hs pri or t o Visit  1 a n d 
d o n ot meet t he re versi bilit y criteri o n at Visit  2 or Visit  3 will be scree n faile d.  
•  
A d mi nister r u n -i n B D M DI after c o m pleti o n of re versi bilit y test. 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 9  of 1 2 2  
 
Visit  4 ( R a n d o miz ati o n):  
•  
Serial s pir o metr y will be c o n d ucte d 6 0 mi n utes a n d 3 0 mi n utes pri or t o t he first d ose of 
st u d y i nter ve nti o n a n d 5, 1 5, a n d 3 0 mi n utes, a n d 1 -, 2-, a n d 3-h o urs p ost -d ose.  
•  
F or 1 2 -h o ur serial s pir o metr y s u b -st u d y partici pa nts o nl y, a d diti o nal serial s pir o metr y 
will be c o n d ucte d at 6 -, 9-, a n d 1 2-h o urs p ost -d os e.  
 
Visit  5:  
•  
S pir o metr y will be c o n d ucte d 6 0 mi n utes a n d 3 0 mi n utes pri or t o st u d y i nter ve nti o n 
a d mi nistrati o n.  
 
Visits  6 a n d 7 or t he Tre at me nt Disc o nti n u ati o n/ St u d y Wit h dr a w al Visit:  
•  Serial s pir o metr y will be c o n d ucte d 6 0 mi n utes a n d 3 0 mi n utes pri or t o st u d y i nter ve nti o n 
a d mi nistrati o n a n d 1 5 a n d 3 0  mi n utes, a n d 1 -, 2-, a n d 3-h o urs p ost -d ose.  
•  At V isit 7, f or 1 2 -h o ur serial s pir o metr y s u b -st u d y partici pa nts o nl y, a d diti o nal serial 
s pir o metr y will be c o n d u cte d at 6-, 9-, a n d 1 2-h o urs p ost -d ose.  
 
8. 1. 1. 3  
Re versi bilit y t o Al b uter ol   
R e versi bilit y t o al b uter ol will be e val uate d f or partici pa nt q ualificati o n p ur p oses a n d baseli ne 
data c haract erizati o n. F or partici pa nts wit h o ut hist oricall y d oc u me nte d re versi bilit y, t he 
re versi bilit y criteri o n m ust be met at Visit 2 or Visit  3 (see Secti o n  5. 1 ), ot h er wise t he 
partici pa nt will be scree n faile d. F or partici pa nts w h o meet re v ersi bilit y at Visit  2, re versi bilit y 
testi n g will n ot be re peat ed at Visit  3. Partici pa nts wit h hist oricall y d oc u me nte d re versi bilit y 
w h o fail t o meet re v ersi bilit y criteri o n at Visit  2 a n d Visit  3 ca n still pr ocee d t o Visit  4 if t he y 
meet all ot her criteria.  
All p artici p a nts m ust de m o nstr ate re versi bilit y eit her t hr o u g h hist oric all y d oc u me nte d 
re versi bilit y i n t he 1 2 m o nt hs pri or t o Visit  1 or t hr o u g h de m o nstr ati n g re versi bilit y at 
Visit  2 or Visit  3.  
T he pr oce d ures f or testi n g re versi bilit y t o al b uter ol are as f oll o ws:  
1.  C o nfir m r u n -i n B D M DI was ta ke n t he pri or e ve ni n g 1 2 h o urs ( ±  1 h o ur) bef ore t he 
e x pecte d d osi n g ti me of t he ne xt m or ni n g visit. T he m or ni n g d ose m ust n ot ha ve bee n 
ta ke n a n d al b uter ol wit h hel d at least 6 h o urs pri or t o t he start ti me of t he visit. 
2.  Perf or m pre -br o nc h o dilat or s pir o metr y at 6 0 a n d 3 0 mi n ut es pri or t o a d mi nistrati o n of 
br o nc h o dilat or.  
3.  A d mi nister 4 p uffs of al b uter ol.  
4.  Perf or m p ost -br o nc h o dil at or s pir o metr y 3 0 mi n utes after t h e a d mi nistrati o n of al b uter ol. If 
partici pa nts are n ot re v ersi ble t o al b uter ol at 3 0  mi n utes, t he p ost -d ose s pir o metr y ca n be 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 0  of 1 2 2  
 
re peat e d at 6 0 mi n utes p ost-d ose.  
 
Re versi bilit y will be a c o m paris o n of  t he a vera g e best F E V1 eff ort o btai ne d at 6 0 - a n d 3 0-
mi n utes pre -br o nc h o dilat or t o t he best F E V 1 eff ort o btai ne d at 3 0 mi n utes ( or u p t o 6 0 
mi n utes, if re peate d) p ost -br o nc h o dilat or f oll o wi n g a d mi nistrati o n of al b uter ol. A partici p a nt 
≥ 1 8 years of a ge is c o nsi dere d re versi ble if t h e i m pr o ve me nt i n F E V 1 at 3 0 mi n utes ( or at 6 0 
mi n utes) p ost -d ose is ≥ 1 2 % a n d ≥ 2 0 0  m L. A partici pa nt 1 2 t o <  1 8 years of a ge is c o nsi dere d 
re versi ble if t h e i m pr o ve me nt i n F E V1 at 3 0 mi n utes ( or at 6 0 mi n utes) p ost -d ose is ≥ 1 2 % . 
Please n ote, re v ersi bilit y testi n g is still re q uire d at Visit  2 a n d/ or Visit  3, e ve n if t he partici pa nt 
has d oc u me nte d hist orical re versi bilit y re p orte d i n t he 1 2 m o nt hs pri or t o Visit  1.  
8. 1. 2  
P artici p a nt’s e Di a r y D at a C olle cti o n   
Partici pa nts will be s u p plie d wit h a ha n d -hel d e Di ar y de vice at Visit  1 t o ta ke h o me a n d e nt er 
data ele ctr o nicall y at h o me i n t he m or ni n g a n d i n t he e ve ni n g of eac h d a y. Partici pa nts will 
als o be trai ne d o n t he d e vice at Visit 1. Pri or t o iss ui n g t he e Diar y t o t he partici pa nt, site 
pers o n nel will recei ve e Diar y trai ni n g. T he site st aff are res p o nsi ble f or setti n g u p t he e Diar y 
f or eac h partici p a nt’s use a n d f or e ns uri n g eac h partici pa nt is trai ne d t o c o m plete t he 
q uesti o n naires o n t he e Di ar y acc or di n g t o t he S o A ( Ta ble  1 ). 
I m p orta nt re mi n ders re gar di n g e Diar y use pri or t o cli nic visits: 
•  
O n t he e ve ni n g pri or t o t he cli nic visit, partici pa nts will c o m plete t heir e Di ar y bef ore 
d osi n g. D osi n g s h o ul d be 1 2 h o urs ( ±  1 h o ur) pri or t o t he e x pecte d d osi n g ti me at t he ne xt 
m or ni n g visit.  
•  
O n t he m or ni n g of t he cli nic visit, partici pa nts will n ot  c o m plete t heir e Di ar y at h o me, 
b ut will i nstea d bri n g t heir e Diar y t o t he visit t o c o m plete at t he cli nic.  
 
8. 1. 2. 1  
e Di ar y C o m pli a nce Re q uire me nt   
C o m plia nce wit h e Diar y is re q uire d t hr o u g h o ut t h e st u d y. Partici pa nts m ust ha ve a n e Diar y 
c o m plia nce of ≥ 7 0 % d uri n g Scree ni n g t o be eli gi ble f or ra n d o mizati o n ( defi ne d as 
c o m pleti n g t he dail y e Diar y a n d a ns weri n g “ Yes” t o ta ki n g 2 p uffs of r u n -i n B D M DI f or a n y 
1 0 m or ni n gs a n d a n y 1 0 e ve ni n gs i n t he last 1 4 da ys pri or t o Visit  4). D uri n g t he treat me nt 
peri o d, dail y e Diar y c o m plia nce is critical f or ca pt uri n g w orse ni n g s y m pt o ms a n d use of st u d y 
i nter ve nti o ns. T he I n vesti gat or/a ut h orize d d ele gate will c hec k t he partici pa nt’s a d here nce t o 
t he e Diar y at eac h visit d uri n g t he st u d y. A n alert will be ge nerat e d w he n a partici pa nt is n ot 
c o nsiste ntl y c o m pleti n g t he e Diar y a n d/ or c o nfir mi n g o n t he e Diar y t hat t he y ha ve ta ke n t h eir 
st u d y i nter ve nti on. Sites will res p o n d t o t he alert as per Secti o n 8. 1. 2. 8 . 
8. 1. 2. 2  
D ail y e Di ar y Re p orti n g   
T he e Diar y will i ncl u de t he f oll o wi n g dail y rec or di n gs: m or ni n g a n d e ve ni n g h o me P E F data 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
( o btai ne d fr o m t he h o me pea k fl o w meter), ast h ma s y m pt o ms, i n halati o ns of resc u e 
me dicati o n use, ni g hts wit h a wa ke ni n gs d ue t o ast h ma s y m pt o ms, a n d bac k gr o u n d 
( mai nte na nce) me dic ati o n use. 
T he e Diar y will alert t he partici pa nt wit h a n alar m w he n it is ti me t o fill o ut t he q uesti o ns a n d 
will als o pr o m pt t he partici pa nt t o c ollect P E F. Re p orti n g via t he e Diar y will occ ur bef ore 
a d mi nistrati o n of r u n -i n B D M DI duri n g t he Scree ni n g Peri o d a n d st u d y i nter ve nti o n or 
ast h ma mai nte na nce me dicati o n d uri n g t he Treat m e nt Peri o d.  
Partici pa nts will rec or d t he f oll o wi n g i n t heir e Di ar y eac h da y ( pre -d ose):  
•  
Res p o n d t o e Diar y alerts, as a p plica ble ( Secti o n 8. 1. 2. 1  a n d Secti o n 8. 1. 2. 8 ) 
•  
Dail y ast h ma s y m pt o ms, acti vit y li mitati o ns, a n d ni g htti me a wa ke ni n g q uesti o ns ( Secti o n 
8. 1. 2. 3 ) 
•  
N u m ber of p uffs o f resc u e me dicati o n (al b uter ol) ( Secti o n 8. 1. 2. 4 ) 
•  
E ns ure c ollecti o n of P E F ( Secti o n 8. 1. 2. 5 ) 
•  
Dail y use of i n hale d ast h ma mai nte na nce treat me nt i ncl u di n g r u n -i n B D M DI a n d st u d y 
i nter ve nti o ns ( Secti o n 8. 1. 2. 6 ) 
 
8. 1. 2. 3  
Ast h m a S y m pt o ms   
T he partici pa nt will rec or d t heir s y m pt o ms i n t he e Diar y bef ore d osi n g eac h m or ni n g 
(reflecti n g ni g htti me s y m pt o ms) a n d eac h e ve nin g (reflecti n g da yti me s y m pt o ms).  
T he dail y e Diar y q uesti o ns will as k partici pa nts a b o ut se verit y of ni g htti me a n d da yti me 
s y m pt o ms of ast h ma; li mitati o ns o n acti vities, al b uter ol use, a n d pr o m pt t h e partici pa nt t o 
electr o nicall y rec or d P E F. Da yti me is def i ne d as t h e ti me peri o d bet wee n t h e m or ni n g pea k 
fl o w/l u n g f u ncti o n assess me nt ( u p o n risi n g i n t he m or ni n g) a n d t he e v e ni n g pea k fl o w/l u n g 
f u ncti o n assess me nt. Ni g htti me is defi ne d as t he ti me peri o d bet wee n t he e ve ni n g pea k 
fl o w/l u n g f u ncti o n assess me nt (at be dti me) a n d t h e m or ni n g pea k fl o w/l u n g f u ncti o n 
assess me nt.  
N oct ur nal a wa ke ni n gs d u e t o ast h ma s y m pt o ms will be rec or de d b y t he partici pa nt i n t he dail y 
e Diar y eac h m or ni n g b y a ns weri n g t he q uesti o ns w het her he/s h e w o ke u p d uri n g t he ni g ht d ue 
t o ast h ma s y m pt o ms b y a “ yes” or “ n o” res p o nse.  
8. 1. 2. 4  
Resc ue Me dic ati o n Use   
Use of resc ue me di cati o n (al b uter ol) will be rec or de d i n t he e Diar y eac h m or ni n g (refl ecti n g 
ni g htti me al b uter ol use ) a n d eac h e ve ni n g (refl ecti n g da yti me al b uter ol use). T he partici pa nt 
will rec or d t he t otal n u m ber of “ p uffs” of al b uter ol use d o ver t he ti me peri o d. F or e xa m ple, 
w he n res c ue me dicati o n is re q uire d, a n d 2 act uati o ns are i n hale d, t his s h o ul d be rec or de d as  
2  “ p uffs ”. If t he p artici pa nt re q uires 4 act uati o ns, t his s h o ul d be rec or de d as 4 “ p uffs”.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
8. 1. 2. 5  
Pe a k E x pir at or y Fl o w   
T he P E F is t o be assesse d usi n g t he S p o ns or -pr o vi de d P E F meter t h at is li n ke d t o t he e Diar y 
de vice. Partici pa nts will be dis pe nse d a n d tr ai ne d o n t he de vice at Visit  1. T he e Diar y will 
pr o m pt t he partici pa nt t o o btai n 3  pea k fl o w ass ess me nts e ver y m or ni n g a n d 3  e ver y e v e ni n g. 
O nce t he p artici pa nt has c o m plete d t he pea k fl o w assess me nt, t he data will be a ut o maticall y 
tra ns mitte d fr o m t he P E F t o t he e Diar y. T he b est ( hi g hest) of 3 P E F eff orts BI D will be 
ca pt ure d i n t he e Diar y.  
Partici pa nts will c o m plete t he P E F ma ne u ver at h o me i n t he m or ni n g a n d i n t he e ve ni n g aft er 
rec or di n g ast h ma s y m pt o ms a n d bef ore d osi n g wit h r u n-i n B D M DI d uri n g t he Scree ni n g 
Peri o d or st u d y i nter ve nti o n d uri n g t he Treat me nt Peri o d. I n a d diti o n, P E F will be meas ure d 
bef ore us e of resc ue al b uter ol.  
At Visit  4, a P E F baseli ne will be calc ulat e d t o  defi ne a sta bilit y li mit. T he sta bilit y li mit is 
defi ne d as t he a vera ge of t he a vaila ble m or ni n g P E F e Diar y rec or di n gs d uri n g t he last 7 da ys 
bef ore Visit  4 (ie, t he bas eli ne P E F), m ulti plie d b y 0. 8. T he P E F sta bilit y li mit will be use d t o 
defi ne a t hr es h ol d f or a n e Diar y al ert.  
8. 1. 2. 6  
I n h ale d Ast h m a M ai nte n a nce Use  
I n hale d ast h ma mai nte n a nce use i ncl u des r u n-i n B D M DI, st u d y i nter ve nti o n or ast h ma 
mai nte na nce me di cati o n (f or partici pa n ts w h o disc o nti n ue st u d y i nter ve nti o n). T he e Diar y will 
as k partici pa nts a b o ut dail y i n hale d ast h ma mai nte na nce use eac h m or ni n g a n d eac h e ve ni n g. 
Partici pa nts will rec or d t he pri or e v e ni n g d ose i n t he m or ni n g e Diar y e ntr y, a n d t he m or ni n g 
d ose will be rec or de d i n t he e ve ni n g e Diar y e ntr y.  
Resc ue i n haler us e will be c ollecte d i n a s e parate e Diar y q uesti o n.  
8. 1. 2. 7  
St u d y Visit e Di ar y D at a C ollecti o n   
Partici pa nts will als o fill o ut P R O q uesti o n naires electr o nicall y o n t he e Diar y at cli nic visits 
acc or di n g t o t he S o A ( Ta ble  1 ). O n t he m or ni n g of a visit da y, partici pa nts will wait u ntil t he 
visit bef ore filli n g o ut t he e Diar y. Partici pa nts will c o m plete all re q uir e d e Di ar y q uesti o ns 
pri or t o d osi n g at t he visit; all P R Os s h o ul d be c o m plete d after t he -6 0 -mi n ute s pir o metr y 
assess me nt. Partici pa nts will bri n g t heir e Diar y t o e ver y cli nic visit after Visit  1.  
Ta ble  1 0  descri bes t he n u m ber of ite ms a n d a n esti mate of t he ti me t o c o m plete t he P R Os 
a d mi nistere d at cli nic visits; h o we ver, n ot e ver y q uesti o n naire is a d mi nistere d at e ver y visit 
a n d ti me of c o m ple ti o n varies b y partici p a nt. T he e Diar y de vi ce will be pr o gra m me d t o 
a d mi nister t he a p pr o pri ate q uesti o n naires i n t he c orrect or d er i n acc or da nce wit h t he S o A 
(Ta ble  1 ). Site pers o n nel m ust tri g ger a st u d y visit f or t he P R Os t o a p pear o n t he e Diar y 
de vice. Trai ni n g o n t he e Diar y de vice will be pr o vi de d pri or t o st u d y start u p.  
T he esti mate d ti mefra m e f or c o m pleti o n of all t he P R Os d uri n g a cli nic visit is a b o ut 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
2 0  mi n utes.  
Ta ble  1 0  
P atie nt Re p orte d O utc o mes A d mi nistere d at t h e Cli nic Visit   
 
N u m ber of Q uesti o ns  
Esti m ate d Mi n utes t o C o m plete  
e Diar y –  m or ni n g ( pre -d ose)  
1 0  
3  
A C Q ( pre -d ose)  
6  
2  
A Q L Q(s) + 1 2 ( pre -d ose)  
3 2  
8  
E Q -5 D ( pre -d ose)  
6  
2  
AI R Q ( pre -d ose)  
1 0  
3  
Ast h ma C o ntr ol Q uesti o n naire ( A C Q), Ast h ma I m pair me nt a n d Ris k Q uesti o n naire ( AI R Q), Ast h ma Q ualit y of Life 
Q uesti o n naire 1 2 Years of A ge a n d Ol der ( A Q L Q(s) + 1 2), E ur o pea n Q ualit y of Life -5 Di me nsi o ns ( E Q -5 D)  
 
Ast h ma C o ntr ol Q uesti o n naire  
T he A C Q [ J u ni p er 1 9 9 9a] was de v el o pe d t o meas ure ast h ma c o ntr ol a n d h as bee n f ull y 
vali date d f or use i n a d ults ( 1 8 years a n d ol der) a n d c hil dre n 6 t o 1 7 years of a ge. I nt er nati o nal 
g ui deli nes f or t he treat me nt of ast h ma ha v e i de ntifie d t hat t he pri mar y cli nical g oal of as t h ma 
ma na ge me nt is t o o pti mize ast h ma c o ntr ol ( mi ni mizati o n of s y m pt o ms, acti vit y li mitati o n, 
br o nc h oc o nstricti o n, a n d resc ue br o nc h o dilat or us e) a n d t h us re d uce t he ris k of 
life-t hreat e ni n g e xacer bati o ns a n d l o n g-ter m m or bi dit y. T he A C Q was de vel o pe d t o meet 
t hese criteri a b y meas uri n g b ot h t he a de q uac y of ast h ma c o ntr ol a n d c h a n ge i n ast h ma c o ntr ol, 
w hic h occ urs eit her s p o nta ne o usl y or as a res ult of treat me nt.  
T here are 3  w a ys t o sc ore t he A C Q t hat are b ei n g a nal yze d i n t his st u d y t o s u p p ort t he 
e n d p oi nts: A C Q -5, A C Q -6, a n d A C Q -7. T he A C Q -5 a n d A C Q -6 sc ores are s u p p orte d e ntirel y 
b y patie nt -re p ort e d s y m pt o m a n d reli ver use d ata. T he A C Q-7 s c ori n g i ncl u des b ot h t he 
A C Q -6 P R O ite ms a n d a cli nicia n re p orte d pre -br o nc h o dilat or F E V 1 perce nt pre dicte d n or m al 
val ue i n t he sc ori n g al g orit h m.  
T he A C Q -6 will be a d mi nistere d t o partici pa nts. P artici pa nts are as ke d 6 q u esti o ns 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 o ne  br o nc h o dilat or use 
q uesti o n a n d 5 s y m pt o m q uesti o ns.  Q uesti o ns are wei g hte d e q uall y a n d s c ore d fr o m 0 (t otall y 
c o ntr olle d) t o 6 (se v erel y u nc o ntr olle d). T he m ea n A C Q -6 sc ore is t he mea n of t he res p o nses 
t o ite ms 1 t o 6 a n d t he mea n A C Q-5 sc ore is t he mea n of t he res p o nses t o ite ms 1  t o 5.  
T he sc ore f or t he  A C Q -7 i ncl u des t he A C Q -6 P R O ite ms a n d F E V 1 re p orte d b y t he cli nicia n. 
T he mea n A C Q -7 sc ore is t he mea n of res p o nses t o t he A C Q -6 P R O ite ms a n d t he 1 cli nicia n 
re p orte d F E V1 ite m. 
C o ntr ol cate g ories bas e d o n t he A C Q -5, A C Q -6, a n d A C Q -7 sc ores are t he sa me . A mea n 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
6 4  of 1 2 2  
 
sc ore of ≤ 0. 7 5 i n dicates well -c o ntr olle d ast h ma, s c ores bet w ee 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 2 0 0 6]. 
I n di vi d ual c ha n ges of at least 0. 5 are c o nsi dere d cli nicall y mea ni n gf ul.  
T he I n vesti gat or/a ut h ori ze d dele gat e will c hec k p artici pa nt’s a d here n ce t o t he A C Q at eac h 
visit per t he S o A ( Ta ble  1 ). 
Ast h ma Q ualit y of Life Q uesti o n naire 1 2 Years of A ge a n d Ol der  
T he A Q L Q(s) + 1 2 is a 3 2 -ite m q uesti o n naire t hat meas ures healt h-rel ate d q ualit y of life 
e x perie n ce d b y patie nts wit h ast h ma w h o are 1 2 years or ol der i n a ge [ J u ni per 2 0 0 5, 
J u ni per 1 9 9 9 b, J u ni per 1 9 9 4, J u ni per 1 9 9 3, J u ni per 1 9 9 2].  
T he A Q L Q(s) + 1 2 c o m prises 4 se parate d o mai ns (s y m pt o ms, acti vit y li mitati o n, e m oti o nal 
f u ncti o n, a n d e n vir o n me ntal sti m uli) a n d a gl o bal sc ore.  
Partici pa nts are as ke d t o recall t he pre vi o us 2 wee ks a n d 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 (s e 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 o ns. T he i n di vi d ual d o mai n sc ores (s y m pt o ms, 
acti vit y li mitati o n, e m oti o nal f u ncti o n, 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 m ai ns. I n di vi d ual A Q L Q(s) + 1 2 t otal or d o mai n 
sc ore c h a n ges ≥ 0. 5 are c o nsi dere d cli nicall y mea ni n gf ul.  
T he q uesti o n naire will be c o m plete d acc or di n g t o t he S o A ( Ta ble  1 ), starti n g at ra n d o mizati o n.  
T he I n vesti gat or/a ut h ori ze d dele gat e will c hec k p artici pa nt a d here nce t o t he A Q L Q(s) + 1 2 at 
eac h visit per t he S o A ( Ta ble  1 ). 
E ur o pea n Q u alit y of Life -5 Di me nsi o ns  
T he E Q -5 D [ E ur o Q ol Gr o u p  2 0 2 0] is a sta n dar dize d i nstr u me n t f or use as a meas ure of healt h 
o utc o me. A p plica bl e t o a wi de ra n ge of healt h c o n diti o ns a n d treat me nts, it pr o vi des a si m ple 
descri pti ve pr ofile a n d a si n gle i n de x val ue f or healt h stat us. T he E Q -5 D data will be c ollecte d 
usi n g E Q -5 D -Y f or t he p artici pa n ts a ge b et wee n 1 2 a n d 1 5 years ol d at ra n d o mizati o n a n d 
E Q -5 D -5 L f or t he p artici pa nts a ge 1 6 years a n d ol der  [E Q -5 D User G ui des : E Q-5 D -Y 2 0 1 4, 
E Q -5 D -5 L 2 0 1 9]. T h e partici pa nts will c o m plete t he sa me q uesti o n nair e us e d at 
ra n d o mizati o n t hr o u g h o ut t he st u d y. T he E Q-5 D -5 L c o nsists of 2 assess me nts, a descri pti ve 
s yste m, a n d a V A S. T h e descri pti ve s yste m c o m prises t he f oll o wi n g 5 di me nsi o ns: m o bilit y, 
self-care, us ual acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n. Eac h di me nsi o n has 5 
se verit y le vels: n o pr o ble ms, sli g ht pr o ble ms, m o derate pr o ble ms, se vere pr o ble ms, a n d 
e xtre me pr o bl e ms. T he E Q -5 D -Y c o nsists of 2 ass ess me nts, a descri pti ve s yste m, a n d a V A S. 
T he descri pti ve s yste m c o m prises t he sa me 5 di me nsi o ns as t he E Q -5 D -5 L, b ut usi n g a 
c hil d-frie n dl y w or di n g ( m o bilit y, l o o ki n g after m yself, d oi n g us ual acti vities, ha vi n g pai n or 
disc o mf ort, feeli n g w orri e d, sa d, or u n ha p p y). Eac h di me nsi o n has 3 le vels: n o pr o ble ms, 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
s o me pr o ble ms, a l ot of pr o ble ms. 
E Q -5 D -5 L a n d E Q -5 D -Y i n de x sc ore ca n be calc ulate d base d u p o n partici p a nts’ res p o nses t o 
t he 5 di me nsi o ns a n d usi n g a n a p pr o pri ate val ue s et [ E Q -5 D User G ui d es : E Q-5 D -5 L 2 0 1 9, 
E Q -5 D -Y 2 0 1 4]. A v al ue set pr o vi des val ues ( wei g hts) f or eac h healt h state descri pti o n 
acc or di n g t o t he prefere n ces of t he g e neral p o p ulati o n of a c o u ntr y/re gi o n.  
T he V A S r ec or ds t he res p o n de nt’s self -rate d healt h o n a 2 0 c m, 0 t o 1 0 0 vertical scale wit h 
e n d p oi nts la bele d “t he b est healt h y o u ca n i ma gi ne” a n d “t he w orst healt h y o u ca n i ma gi ne” 
wit h hi g her sc ores c orres p o n di n g t o a better healt h state. T his i nf or mati o n is use d as a 
q ua ntitati ve meas ure of healt h as j u d ge d b y t he i n di vi d ual res p o n de nts.  
T he E Q -5 D will be c o m plete d o n t he e Diar y b y t he partici pa nt per t he S o A ( Ta ble  1 ). T he 
I n vesti gat or/a ut h orize d d ele gate will c hec k partici pa nt’s a d here n ce t o t he E Q-5 D at eac h visit.  
Ast h ma I m p air me nt a n d Ris k Q uesti o n naire  
T he AI R Q ™ is a P R O t o ol i nte n de d t o i de ntif y patie nts 1 2 years a n d ol der w h ose healt h ma y 
be at ris k beca use of u nc o ntr olle d ast h ma [ M ur p h y  2 0 2 0]. It has 1 0 q uesti o ns t hat as k a b o ut 
res pirat or y s y m pt o ms, acti vit y li mitati o n, slee p, resc ue me dicati o n use, s o cial acti vities, 
e xercis e, diffic ult y c o ntr olli n g ast h ma, a n d e xacer bati o ns.  All ite ms ha ve a yes/ n o res p o nse 
o pti o n, a n d t he t o ol is sc ore d b y s u m mi n g t he t otal n u m ber of  ‘ yes’ res p o ns es. T his s u m sc ore 
is use d t o assess le vel of ast h ma c o ntr ol w here: 0-1 is well -c o ntr olle d, 2 -4 is n ot 
well -c o ntr olle d, a n d 5 -1 0 is ver y p o orl y c o ntr olle d. T h us, a hi g her sc ore i n dicates w orse 
c o ntr ol stat us.  
T he AI R Q T M ite ms ha ve 2  differe nt  recall peri o ds: T he first 7 i m pair me nt ite ms are e val uate d 
o ver t he past 2 w ee ks a n d t he last 3  ris k ite ms o ver t he past 3 m o nt hs or t he past year. T his 
st u d y will use t he past 3 m o nt hs recall. T he AI R Q ™ will be a d mi nistere d a n d c o m plete d o n 
t he e Diar y b y t he p artici p a nt as per So A ( Ta ble  1 ).  
8. 1. 2. 8  
S y m pt o m W orse ni n g Assess me nt a n d e Di ar y Alert S yste m   
T he e Diar y will be pr o gra m me d t o alert b ot h t he partici pa n t a n d st u d y site if a n y of t he 
t hres h ol ds liste d bel o w are met o n at least 2 c o nsec uti ve da ys: 
•  
P E F: a decreas e i n m or ni n g P E F of ≥ 2 0 % as c o m pare d wit h bas eli ne a vera ge ( baseli ne is 
defi ne d i n Secti o n 9. 5. 1. 3 ), a n d/ or 
•  
Resc ue al b uter ol us e: a n i ncreas e of ≥ 4 i n halati o ns c o m pare d wit h bas eli ne a vera g e use, 
a n d/ or 
•  
Ni g htti me a wa ke ni n g: a n i ncreas e of 2 or m ore ni g hts wit h a wa ke ni n gs d u e t o ast h ma 
re q uiri ng res c ue me dicati o n use o ver a 7 -da y p eri o d c o m pare d wit h t he a vera ge baseli ne 
a n d/ or ≥ 6 o ut of t he 7 pre vi o us ni g hts wit h a wa ke ni n gs d ue t o ast h ma re q uiri n g resc ue 
me dicati o n, a n d/ or  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
•  
Ast h ma s y m pt o ms: a n i ncreas e of t otal ast h ma s y m pt o m sc ore (t he s u m of da yti me pl us 
ni g htti me) of at least 2 u nits a b o ve t he a vera ge b aseli ne or t he hi g hest p ossi ble sc ore 
( dail y sc ore of 6) 
 
A n e Diar y alert is n ot a n ast h ma e xacer bati o n per se. Alt h o u g h t he e Di ar y alert s h o ul d i nitiate 
c o ntact bet w ee n t he partici pa nt a n d t he i n vesti gati o nal site wit hi n 4 8 h o urs of t he alert, t he 
I n vesti gat or or desi g ne e will al wa ys assess t he partici pa nt’s s y m pt o ms a n d deter mi ne w het h er 
t o treat t he partici pa nt f or a n ast h ma e xacer bati o n. 
8. 2  
S afet y Assess me nts   
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A ( Ta ble  1 ). 
8. 2. 1  
Me dic al/ S ur gic al Hist or y   
Me dical hist or y will be c ollecte d at Visit  1 a n d u p date d d uri n g t he Scree ni n g Peri o d, i f 
necessar y. T he n u m ber of ast h ma e xacer bati o ns re q uiri n g s yste mic c ortic oster oi ds, E R visits, 
a n d/ or h os pitalizati o ns wit hi n t he pre vi o us 1 2 m o nt hs will be c ollecte d at Visit  1.  
8. 2. 2  
P h ysic al E x a m   
A brief p h ysical e x a mi nati o n will be perf or me d as s pecifie d i n t he S o A ( Ta ble  1 ). T he bri ef 
p h ysical e xa mi nati o n will i ncl u de t he f oll o wi n g:  
Ge neral a p peara n ce, res pirat or y, car di o vas c ular, a n d a b d o me n  
8. 2. 3  
Hei g ht a n d Wei g ht   
Hei g ht a n d wei g ht will be meas ur e d as s pecifie d i n t he S o A ( Ta ble  1 ). B o d y mass i n de x will 
be a ut o maticall y cal c ulat e d i n t he e C R F.  
8. 2. 4  
Vit al Si g ns   
Vital si g ns will be perf or me d at ti meli nes as s pecifie d i n t he S o A ( Ta ble  1 ). 
Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece d e d b y at least 5 mi n utes of rest f or 
t he partici pa nt i n eit her a s u pi ne or seate d p ositi o n i n a q uiet setti n g wit h o ut distracti o ns (e g, 
tele visi o n, cell p h o nes).  
8. 2. 5  
Electr oc ar di o gr a ms   
A n E C G will be perf or me d at Visit  1 as s pecifi e d i n t he S o A ( Ta ble  1 ). 
T he 1 2 -lea d E C G will be ta ke n i n s u pi ne p ositi o n after 1 0 mi n utes of rest. T he I n vesti gat or or 
a ut h orize d del e gate will be res p o nsi ble f or t he o v erall i nter pretati o n a n d deter mi nati o n of 
cli nical si g nifica nce of a n y p ote ntial E C G fi n di n gs. I n case of discre p a nc y bet wee n t he 
In vesti gat or's i nter pretati o n a n d t hat pr o vi de d b y t he E C G mac hi ne (if a p plica ble), t he 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
I n vesti gat or's i nter pretati o n will ta ke prece de nce a n d s h o ul d be n ote d o n t he pri nt o ut a n d 
rec or de d i n t he e C R F. A c o p y of t he E C G will be pr o d uce d, q ualit y c hec ke d, a n d ke pt i n case 
of f urt her nee d f or re -e v al uati o n.  
8. 2. 6  
Cli nic al S afet y L a b or at or y Assess m e nts   
Bl o o d a n d uri ne sa m ples f or deter mi nati o n of cli nical c he mistr y a n d h e mat ol o g y will be ta ke n 
pre -d ose pri or t o 1 0 0 0 +  1 h o ur at t he visits i n dicate d i n t he S o A ( Ta ble  1 ). 
Cli nical safet y la b orat or y tests will be a nal yze d b y a ce ntr al la b or at or y acc or di n g t o 
sta n dar dize d, v ali date d assa ys wit h t he e xce pti o n of hi g hl y se nsiti ve uri ne pre g na nc y t ests. 
T he la b orat or y will s u p pl y detaile d pr oce d ures f or t he pre parati o n a n d c ollecti o n of bl o o d 
sa m ples al o n g wit h all c o ntai ners nee d e d f or t h eir c ollecti o n. Uri ne pre g na n c y tests will be 
perf or me d at t he cli nical site usi n g a hi g hl y se nsiti ve test pr o d uct pr o vi de d t o t he site.  
T he I n vesti gat or s h o ul d assess t he a vaila ble res ults wit h re gar d t o cli nicall y rele va nt 
a b n or malities. T he la b orat or y res ult s s h o ul d be si g ne d a n d date d a n d ret ai ne d at t he ce nter as 
s o urce dat a f or la b orat or y varia bles. 
A d diti o nal safet y sa m ples ma y be c ollecte d if cli nicall y i n dicate d at t he dis creti o n of t he 
I n vesti gat or at u nsc h e d ule d visits. T he date of c ollecti o n will be rec or de d o n t he a p pr o priat e 
e C R F. 
F or i nf or mati o n o n h o w A Es base d o n la b orat or y tests s h o ul d be rec or de d a n d re p ort e d, see 
Secti o n 8. 3. 6 . 
T he f oll o wi n g la b orat or y varia bles will be meas ure d ( Ta ble  1 1 ): 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
Ta ble  11  
L a b or at or y Vari a bles   
He m at ol o g y ( w h ole bl o o d)  
Cli nic al C he mistr y (ser u m or pl as m a)  
He m o gl o bi n  
Creati ni ne  
Le u k oc yte c o u nt (i ncl u di n g differe ntial c o u nt)  
Bilir u bi n, t otal  
E osi n o p hil c o u nt  
Al kali ne p h os p hatase  
Platelet c o u nt  
As partate tra nsa mi nase  
 
Ala ni ne tra nsa mi nase  
Ot her Tests  
Al b u mi n  
Hi g hl y se nsiti ve uri ne pre g na nc y test f or w o me n 
of c hil d beari n g p ote ntial  
P otassi u m  
Calci u m, t otal  
S o di u m  
Gl uc ose  
 
8. 2. 7  
Ast h m a E x acer b ati o ns   
A n ast h ma e xacer bati o n is defi ne d as w orse ni n g of ast h ma t hat re q uires a m e dical i nter ve nti o n 
as descri be d i n Secti o n 8. 2. 7. 3 . 
Worse ni n g of ast h ma is d efi ne d as at least o ne of t he f oll o wi n g 3 ele me nts of w orse ni n g liste d 
bel o w f ulfille d f or at least 2 c o nsec uti ve da ys (s ee Secti o n 8. 1. 2. 8  f or e Diar y alerts): 
•  
w orse ni n g of ast h ma si g ns/s y m pt o ms (see Secti o n 8. 2. 7. 1 ) 
•  
i ncreas e d use of ‘as-nee d e d’ res c ue/r elie ver me di cati o n (see Secti o n 8. 1. 2. 4 ) 
•  
deteri o rati o n of P E F (see Secti o n 8. 1. 2. 5 ) 
 
8. 2. 7. 1  
Defi niti o n of W orse ni n g of Ast h m a Si g ns/ S y m pt o ms   
T he w orse ni n g/ o nset of si g ns/s y m pt o ms i ncl u de deteri orati o n i n at least o n e of t he f oll o wi n g:  
•  
ast h ma s y m pt o ms (e g, s h ort ness of breat h, w heezi n g, c hest ti g ht ness, c o u g h)  
•  
ni g htti me a wa ke ni n g d ue t o ast h ma  
•  
acti vit y li mitati o n d ue t o ast h ma  
•  
p h ysical e xa m fi n di n g c o nsiste nt wit h deteri orati o n of ast h ma  
 
8. 2. 7. 2  
I n vesti g at or J ustifie d Ast h m a E x acer b ati o ns  
T he maj orit y of ast h ma e xacer bati o ns s h o ul d be ass ociate d wit h w orse ni n g of ast h ma 
si g ns/s y m pt o ms descri be d i n Secti o n 8. 2. 7. 1 . H o we ver, cli nical prese nt ati o ns ma y var y a m o n g 
partici pa nts a n d t he ass ociate d ast h ma w orse ni n g si g ns/s y m pt o ms a n d/ or d urati o n ma y n ot 
meet t he defi niti o n of a m o derate or s e vere e x acer bati o n . F or m o derate a n d se vere 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
e xacer bati o ns wit h o ut a n e Diar y al ert date rec or de d i n t he e C R F, t he I n vesti gat or will rec or d 
t he w orse ni n g si g ns/s y m pt o ms wit h d urati o n a n d pr o vi de t he j ustificati o n(s) f or dia g n osi n g 
t he e xacer bati o n (e g, ra pi d o nset a n d/ or se verit y of w orse ni n g ast h ma) i n t h e e C R F. If a n 
e xacer bati o n is rec or de d i n t he setti n g of treat me nt wit h a d diti o nal s yste mic c ortic oster oi ds f or 
less t ha n 3 da ys ( Secti o n 8. 2. 7. 3 ), t he I n vesti gat or will rec or d w h et her it is c o nsi dere d se vere 
or m o derate a n d t he j ustificati o n(s) f or dia g n osis a n d treat me nt d ur ati o n (e g, si n gle 
a d mi nistrati o n of I V c orti c oster oi d wit h o ut f oll o w -u p oral c ortic oster oi d presc ri be d) i n t he 
e C R F. 
8. 2. 7. 3  
Se verit y of Ast h m a E x acer b ati o n   
All pr ot oc ol -defi ne d ast h ma e xacer bati o ns will be classifie d as se vere or m o derate base d o n 
t he f oll o wi n g treat me nt criteria [Re d d el  2 0 0 9].  
A n ast h ma e xacer bati o n will be c o nsi dere d se v ere if it res ults i n at least o ne of t he f oll o wi n g:  
•  
A c o urse of s yste mic c ortic oster oi ds f or at le ast 3 c o nsec uti ve da ys t o tr eat s y m pt o ms of 
ast h ma w orse ni n g.  
•  
A n E R or ur ge nt c are visit ( defi ne d as e v al uati o n a n d treat me nt f or <  2 4 h o urs i n a n 
e mer ge n c y de part me nt or ur ge nt care ce nter) d ue t o ast h ma t hat re q uire d treat me nt wit h 
s yste mic c ortic oster oids  
•  
A n i n -patie nt h os pitalizati o n ( defi ne d as a d missi o n t o a n i n -patie nt facilit y a n d/ or 
e val uati o n 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  
•  
Deat h rel ate d t o ast h ma  
 
A m o derate ast h ma e x acer bati o n is defi ne d as a w orse ni n g of ast h ma s y m pt o ms ( defi ne d i n 
Secti o n 8. 2. 7. 1 ) t hat res ults i n a n a d diti o nal I C S f or at least 3 da ys a n d di d n ot meet a n y of t he 
criteria f or a se v ere ast h ma e xacer bati o n.  
8. 2. 7. 4  
Tre at me nt f or Ast h m a E x acer b ati o ns   
Ast h ma e xacer bati o ns s h o ul d be treate d at t he discreti o n of t he  I n vesti gat or. If a partici p a nt 
e x perie n ces a n ast h ma e x acer bati o n, t he y s h o ul d c o nti n ue d osi n g wit h st u d y i nter ve nti o n if 
I n vesti gat or or treati n g p h ysicia n assess it is safe d o s o. 
I n t he i nsta nce a partici p a nt is h os pitalize d f or a s e vere ast h ma e x acer bati o n a n d st u d y 
i nter ve nti o n is i nterr u pte d, t he partici pa nt ma y be a ble t o restart st u d y i nter ve nti o n u p o n 
st o p pi n g t he ast h ma me dicati o ns.  
T he rec o m me n de d treat me nt [ GI N A  2 0 2 1] f or a se vere ast h ma e x acer bati o n is pre d nis ol o ne 
u p t o  5 0  m g/ da y ( or e q ui vale nt) f or a d ults o nce dail y i n t he m or ni n g f or 5 t o 7 da ys. A 
pre d nis ol o ne d ose 1  t o 2  m g/ k g/ da y u p t o a t otal of 5 0  m g/ da y  ma y be c o nsi dere d a p pr o priate 
i n a d olesce nts w h o ma y alter nati vel y be treate d i n t he sa me ma n ner as a d ults. Ta peri n g t he 
pre d nis ol o ne d ose is n ot nee de d if t he treat me nt h as bee n gi ve n f or less t ha n 2  wee ks 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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[GI N A  2 0 2 1]. A ma xi m u m d urati o n f or a s h ort c o urse of s yste mic c ortic oster oi ds is defi ne d as 
1 4 da ys . 
Use of de p ot c ortic oster oi ds i n t he treat me nt of ast h ma e xacer bati o ns is pr o hi bite d.  
T he rec o m me n de d treat me nt f or a m o der ate  ast h ma e xacer bati o n is a s h ort c o urse of a n 
a d diti o nal I C S f or 5 t o 7 da ys if dee me d cli nicall y rele va nt. If a partici pa nt has n ot a de q uatel y 
i m pr o ve d at t he e n d of 2 wee ks of treat me nt wit h a n a d diti o nal I C S, a s h ort c o urse of syste mic 
c ortic oster oi ds s h o ul d be gi ve n, a n d t he ast h ma e x acer bati o n will be c o nsi d ere d as a se vere 
ast h ma e xacer bati o n.  
8. 2. 7. 5  
O nset a n d D ur ati o n of Ast h m a E x acer b ati o ns   
F or m o der ate  o r se vere ast h ma e xacer bati o ns, t he d urati o n is defi ne d b y t he prescri be d 
tre at me nt. F or se v ere ast h ma e xacer bati o ns, t he d urati o n of h os pitalizati o n or E R visit c o ul d 
re place t he d urati o n of prescri be d s yste mic c ortic oster oi ds as descri b e d bel o w. 
F or se vere ast h ma e x acer bati o ns:  
•  
T he start date will be d efi ne d as t he start date of prescri be d treat me nt wit h a s yste mic 
c ortic oster oi d, t he h os pit al/ E R a d missi o n date, or t he date of deat h (if t he e xacer bati o n 
res ulte d i n deat h), w hi c h e ver is earlier. 
•  
N ote:  T h e s tart date c o ul d be t he start date of a n a d diti o nal I C S w he n treat me nt is 
s witc he d t o at least 3 da ys of s yste mic c ortic oster oi ds as descri be d i n Secti o n 8. 2. 7. 4 . 
•  
T he st o p date is defi ne d as t he last da y of prescri b e d s yste mic c ortic oster oi ds, h os pital/ E R 
disc har ge d ate or t he d ate of deat h (fr o m t he e x acer bati o n), w hic he v er is lat er.  
•  
If m ulti ple treat me nts are prescri be d f or t he s a me e xacer bati o n, t he earliest start date a n d 
t he latest st o p date will be use d. 
•  
F or a s e vere ast h ma e x acer bati o n re q uiri n g h os pit alizati o n wit h n o d oc u me nte d s yste mic 
c ortic oster oi d treat me nt, h os pitalizati o n a d missi o n/ disc har ge dat es will be use d as 
start/sto p dates as descri b e d i n Secti o n 8. 2. 7. 3 . 
 
F or m o der ate  ast h ma e x acer bati o ns:  
•  
T he start date is defi ne d as t he first da y of t he a d diti o nal d ose of I C S treat me nt. 
•  
T he e n d date is d efi ne d as t he last da y of t he a b o v e treat me nt.  
 
I n or der t o e ns ure t hat t h e sa me e v e nt is n ot c o u nte d t wice, c o ns ec uti ve e x acer bati o ns wit h 
start a n d st o p da ys ≤ 7 da ys a part will be c o nsi dere d t he sa me e ve nt of t he hi g hest se verit y. If 
t here is a > 7 -da y ti me peri o d bet wee n I C S or s yste mic c ortic oster oi d treat me nts, t he n 
se parat e e xacer bati o ns s h o ul d be rec or de d i n t he e C R F. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
8. 2. 7. 6  
A p pr o ac h f or C a pt uri n g Ast h m a E x acer b ati o ns   
A c o p y of t he me dical r ec or ds s h o ul d be o btai ne d f or e xacer bati o ns e val uat e d a n d treate d at a 
n o n -st u d y ce nter (e g, b y t he pri mar y care Healt h Care Pr o vi der or at a n e mer ge nc y 
de part me nt/ h os pital) a n d details e ntere d i n t he e xacer bati o n e C R F i n a ti mel y fas hi o n. 
C ha n ges i n c o nc o mita nt me dicati o n d ue t o t he e x acer bati o n m ust be rec or de d i n t he 
a p pr o priate m o d ule of t he e C R F.  
All m o derate or se v ere ast h ma e xacer bati o ns (i ncl u di n g I n vesti gat or j ustifie d ast h ma 
e xacer bati o ns) f oll o wi n g Visi t 1 m ust be ca pt ure d usi n g t he Ast h ma E xacer bati o n e C R F.  
If t here were e Di ar y alerts wit hi n t he wi n d o w of -7 t o +  1 da ys of t he i nitiati o n of 
e xacer bati o n treat me nt, t he e xacer bati o n will be c o nsi dere d a n e Diar y s u p p orte d e xacer bati o n. 
O ne of t he e Diar y al ert d ates wit hi n t he defi ne d wi n d o w s h o ul d be ca pt ure d o n t he 
e xacer bati o n e C R F. If a n e xacer bati o n is n ot s u p p orte d b y a n e Di ar y al ert date i n t he defi ne d 
wi n d o w, t he n I n vesti gat ors will pr o vi de j ustificati o ns a n d rec or d i n t he e C R F.  
If a n ast h ma e xacer bati o n meets t he defi niti o n of a n S A E, t he e xacer bati o n will be re p orte d as 
a n S A E as well as o n t he Ast h ma E xacer bati o n e C R F.  
A n y s y m pt o ms of ast h ma or a n ast h ma e xacer bati o n of a n y se verit y will be c o nsi dere d t he 
disease u n der st u d y a n d will n ot be re p orte d as A Es u nless meeti n g t he defi niti o n of a n S A E 
or lea ds t o disc o nti n uati o n of st u d y i nter ve nti o n.  
8. 2. 8  
Ot her S afet y Assess m e nts   
8. 2. 8. 1  
P ar a d o xic al Br o nc h os p as m   
M o nit ori n g f or para d o xic al br o nc h os pas m will occ ur at eac h i n -cli nic visit i n w hic h t here are 
p ost -d ose s pir o metr y ass ess me nt d uri n g t he Treat me nt Peri o d ( Visits 4, 6, a n d 7 or Treat me nt 
Disc o nti n uati o n/ St u d y Wit h dra wal Visit) at 1 5 - a n d 3 0 -mi n utes p ost -d ose. I n t his st u d y, 
para d o xic al br o nc h os pas m is defi ne d as a re d ucti o n i n F E V 1 of >  2 0 % fr o m baseli ne (ie, t he 
mea n F E V 1 val ues o btai ne d 6 0 a n d 3 0 mi n utes pri or t o st u d y i nter ve nti o n a d mi n istrati o n) t hat 
occ urs wit hi n 3 0 mi n utes p ost -d osi n g wit h ass ociate d s y m pt o ms of w heezi n g, s h ort ness of 
breat h, or c o u g h. If a n e v e nt meets b ot h t he s pir o metr y a n d t he s y m pt o ms f or a para d o xic al 
br o nc h os pas m, t he n it will be re p orte d as a n A E.  
8. 3  
A d verse E ve n ts a n d Seri o us A d verse E ve nts  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are 
fa miliar wit h t he c o nte nt of t his secti o n. 
T he defi n iti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x  B . 
A d verse e ve nts will be re p orte d b y t he partici p a nt ( or, w he n a p pr o priat e, b y a care gi ver, 
s urr o gate, or t h e partici p a nt's le gall y a ut h orize d re prese nt ati ve).  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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T he I n 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 niti o n of a n A E.  
8. 3. 1  
Ti m e Peri o d a n d Fre q ue nc y f o r C ollecti n g A E a n d S A E I nf or m ati o n   
A d verse e ve nts will be c ollecte d fr o m first i nta ke of st u d y i nter ve nti o n after Visit  1, d uri n g 
scree ni n g a n d t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w-u p per i o d. 
All S A Es will be rec or de d fr o m t he ti me of si g ni n g of t he i nf or me d c o ns e nt f or m.  
If t he I n vesti gat or b ec o m es a ware of a n S A E wit h a s us pecte d ca usal r elati o ns hi p t o t he I M P 
t hat occ urs after t he e n d of t he cli nical st u d y i n a partici pa nt treat e d b y hi m or her, t he 
I n vesti gat or s hall, wit h o ut u n d ue dela y, re p ort t he S A E t o Astra Ze n eca. 
8. 3. 2  
F oll o w -u p of A Es a n d S A Es   
A n y A Es t hat are u nres ol ve d at t he partici p a nt’s last  A E assess me nt or ot her assess me nt/ visit 
as a p pr o priat e i n t he st u d y are f oll o w e 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 e C R F. Astra Ze n eca retai ns t h e ri g ht t o re q uest 
a d diti o nal i nf or mati o n f or a n y partici p a nt wit h o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, 
if j u d ge d necess ar y. 
A d verse e v e nt v ari a bles  
T he f oll o wi n g varia bles will be c ollecte d f or eac h A E:  
•  
A E ( ver bati m)  
•  
T he date w h e n t he A E st arte d a n d st o p pe d  
•  
Ma xi m u m i nte nsit y  
•  
W het her t he A E is seri o us or n ot 
•  
I n v esti gat or ca us alit y rati n g a gai nst t he st u d y i nter ve nti o n(s) ( yes or n o) 
•  
Acti o n ta ke n wit h re g ar d t o st u d y i nter ve nti o n(s)  
•  
O utc o me  
 
I n a d diti o n, t he f oll o wi n g varia bles will be c ollecte d f or S A Es: 
•  
Date A E met criteria f or S A E  
•  
Date I n vesti gat or b eca me a ware of S A E  
•  
A E is seri o us d ue t o  
•  
Date of h os pitalizati o n  
•  
Date of disc h ar ge  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
•  
Pr o ba ble ca us e of deat h  
•  
Date of deat h  
•  
A ut o ps y perf or me d  
•  
Ca usalit y assess me nt i n relati o n t o st u d y pr oce d ure(s)  
•  
Ca usalit y assess me nt t o ot her me dicati o n  
 
8. 3. 3  
C a us alit y C oll ecti o n  
T he I n vesti gat or  s h o ul d assess ca usal r elati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h A E 
a n d a ns wer ‘ yes’ or ‘ n o’ t o t he q uesti o n ‘ D o y o u c o nsi der t hat t here is a reas o na ble p ossi bilit y 
t hat t he e ve nt ma y ha v e bee n ca use d b y t he I n v esti gati o nal Pr o d uct?’ 
F or S A Es, ca usal rel ati o ns hi p s h o ul d als o be assesse d f or ot her m e dicati o n a n d st u d y 
pr oce d ur es. N ote t hat f or S A Es t hat c o ul d be ass o ciate d wit h a n y st u d y pr oce d ure t h e ca us al 
relati o ns hi p is i m plie d as ‘ yes’. 
A g ui de t o t he i nter pretati o n of t he ca usalit y q uesti o n is f o u n d i n A p pe n di x  B . 
8. 3. 4  
A d verse E ve nts B ase d o n Si g ns a n d S y m pt o ms   
All A Es s p o nta ne o usl y re p orte d b y t he partici p a nt or care pr o vi der  or re p ort e d i n res p o nse t o 
t he o pe n q uesti o n fr o m t he st u d y site staff: ‘ Ha ve y o u/t he c hil d ha d a n y healt h pr o ble ms si nce 
t he pre vi o us visit/ y o u were last as ke d ?’, or re veale d b y o bser vati o n will be c ollecte d a n d 
rec or de d i n t he e C R F. W he n c ollecti n g A Es, t he rec or di n g of dia g n os es is preferre d ( w he n 
p ossi ble) t o rec or di n g a list of si g ns a n d s y m pt o ms. H o we ver, if a dia g n osis is k n o w n a n d 
t here are ot her si g ns or s y m pt o ms t hat are n ot ge nerall y part of t h e 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. 5  
A d verse E ve nts Ass oci ate d wit h Use of I C S a n d L A B As   
Certai n A Es ha v e bee n i de ntifie d as ass oci ate d t o t he class of dr u gs b ei n g st u die d. K n o w n 
effects of L A B As i ncl u d e car di o v asc ular a n d tre m or effects. L ocal c ortic oster oi d effects 
i ncl u de oral c a n di diasis, or o p har y n geal ca n di diasis, d ys p h o nia, a n d t hr oat irritati o n. T hese 
A Es will be ca pt ure d as descri be d i n Secti o n 8. 3. 4  a n d prese nt e d i n s u m mar y ta b ulati o n i n t he 
C S R.  
8. 3. 6  
A d verse E ve nts B ase d o n E x a mi n ati o ns a n d Tests   
T he res ults fr o m t he C S P ma n date d la b orat or y tests a n d vital si g ns will be s u m marize d i n t he 
C S R.  
Deteri or ati o n as c o m pare d t o baseli ne i n pr ot oc ol -ma n date d la b orat or y val u es or vital si g ns 
s h o ul d t heref ore o nl y be re p orte d as A Es if t he y f ulfill a n y of t he S A E crit eria, are t he reas o n 

Cli nical St u d y Pr ot oc ol  - 4 . 0 
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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f or disc o nti n uati o n of st u d y i nter ve nti o n or are c o nsi dere d t o be cli nicall y rele va nt as j u d ge d 
b y t he I n vesti gat or ( w hi c h ma y i ncl u de b ut n ot li mite d t o c o nsi derati o n as t o w het her 
treat me nt or n o n-pla n n e d visits were re q uir e d or ot her acti o n was t a ke n wit h t he st u d y 
i nter ve nti o n, e g, d ose a dj ust me nt or dr u g i nterr u pti o n).  
If deteri orati o n i n a la b orat or y val ue/ vital si g n is ass ociate d wit h cli nical si g ns a n d s y m pt o ms, 
t he si g n or s y m pt o m will be re p ort e d as a n A E a n d t he ass ociate d la b orator y res ult/ vital si g n 
will be c o nsi dere d as a d diti o nal i nf or mati o n. W here ver p ossi ble t he re p orti n g I n vesti gat or 
uses t he cli nical, rat h er t ha n t he la b orat or y ter m (e g, a ne mia v ers us l o w he m o gl o bi n val ue). I n 
t he a bse nce of cli nical si g ns or s y m pt o ms, cli nicall y rele va nt deteri orati o ns i n n o n-ma n date d 
para meters s h o ul d be re p orte d as A E(s).  
A n y ne w or a g gra v ate d cli nicall y rele va nt a b n or m al me dical fi n di n g at a p h ysical e xa mi nati o n 
as c o m pare d wit h t he bas eli ne assess me nt will be re p orte d as a n A E u nl ess u n e q ui v ocall y 
relate d t o t he dise ase u n d er st u d y. 
8. 3. 7  
  
8. 3. 8  
Dise ase U n der St u d y   
S y m pt o ms of disease u n der st u d y are t h os e w hic h mi g ht be e x pecte d t o oc c ur as a dir ect r es ult 
of ast h ma a n d are ca pt ur e d i n t he e Diar y. E ve nts w hic h are u n e q ui v ocall y d ue t o disease u n der 
st u d y 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 criteria or lea d 
t o disc o nti n uati o n of t he st u d y i nter ve nti o n or t he si g n or s y m pt o m is ne w t o t he partici pa nt or 
n ot c o nsiste nt wit h t he partici pa nt’s pre -e xisti n g ast h ma hist or y.  
Ass ociate d s y m pt o ms of ast h ma are c o nsi dere d as s y m pt o ms of disease u n der st u d y a n d will 
n ot be rec or de d as A Es u nless c o nsi dere d a n S A E o r lea d t o disc o nti n uati o n of st u d y 
i nter ve nti o n. 
8. 3. 9  
Re p orti n g of Seri o us A d verse E ve nts   
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relat e d t o t he st u d y 
i nter venti o n, or t o t he st u d y pr oce d ure(s). All S A Es will be rec or de d i n t he e C R F.  
If a n y S A E occ urs i n t he c o urse of t he st u d y, I n vesti gat ors or ot her site pers o n nel will i nf or m 
t he a p pr o priat e Astr a Ze n eca re prese ntati ves wit hi n o ne da y (ie, i m me diatel y b ut n o l ater t h a n 
2 4 h o urs ) of w he n he or s he bec o mes a ware of it . 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
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T he desi g nate d Astra Z e n eca re prese ntati ve will w or k wit h t he I n vesti gat or t o e ns ure t hat all 
t he necess ar y i nf or mati o n is pr o vi de d t o t he Astra Ze neca Patie nt Safet y D E S wit hi n 
o ne  c ale n d ar d a y  of i nitial recei pt f or fatal a n d life -t hreate ni n g e ve nts a n d wit hi n 5  c ale n d ar 
d a ys of i nitial recei pt f or all ot her S A Es.  
F or fatal or life -t hreate ni n g A Es w here i m p orta nt or rele va nt i nf or mati o n is missi n g, acti ve 
f oll o w-u p will be u n derta ke n i m me diatel y. I n vesti gat ors or ot her site pers o n nel will i nf or m 
Astra Ze neca re prese ntati ves of a n y f oll o w -u p i nf or mati o n o n a pre vi o usl y r e p orte d S A E 
wit hi n o ne cale n dar da y (ie, i m me diatel y b ut  n o l ater t h a n 2 4 h o urs ) of w he n he or s he 
bec o mes a w are of it . 
O nce t he I n vesti gat or or ot her site pers o n nel i n dicate a n A E is seri o us i n t he e C R F, a n 
a ut o mate d e mail alert is se nt t o t he desi g nate d Astra Ze neca re pres e ntati ve.  
If t he e C R F 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 n S A E t o 
t he ap pr o priat e Astr a Ze n eca re prese ntati ve b y tele p h o ne.  
T he Astr a Ze neca re prese ntati ve will a d vise t he I n vesti gat or/st u d y site staff h o w t o pr ocee d.  
F or f urt her g ui da n ce o n t he defi niti o n of a n S A E, see A p pe n di x  B  of t he C S P.  
T he refere nce d o c u me nt f or defi niti o n of e x p ecte d ness/liste d ness is t he I n vesti gat or Br oc h ures 
f or Astr a Ze n eca dr u gs a n d f or t he c o m parat or pr o d ucts (i ncl u di n g a n y Astra Ze neca 
c o m parat or). 
8. 3. 1 0  
Pre g n a nc y   
All pre g na ncies a n d o utc o mes of pre g n a nc y s h o ul d be re p ort e d t o Astra Ze n eca fr o m Visit  1 
e xce pt f or:  
•  
If t he pre g n a nc y is disc o vere d bef ore t h e st u d y partici pa nt has recei ve d a n y st u d y 
i nter ve nti o n 
 
8. 3. 1 0. 1  
M ater n al E x p os ure   
If a partici pa nt bec o m es pre g na nt d uri n g t he c o urse of t he st u d y, st u d y i nter ve nti o n s h o ul d be 
disc 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 h e st u d y i nter ve nti o n 
u n der st u d y ma y ha ve i nt erfere d wit h t he effecti ve ness of a c o ntr ace pti ve me dicati o n. 
C o n ge nital a n o malies/ birt h defects a n d s p o nta ne o us miscarria ges s h o ul d b e re p ort e d a n d 
ha n dle d as S A Es. Electi v e a b orti o ns wit h o ut c o m plicati o ns s h o ul d n ot be ha n dle d as A Es. T h e 
o utc o me of all pre g n a nci es ( s p o nta ne o us miscarri a ge, electi ve ter mi nati o n, ect o pic pre g n a nc y, 
n or mal birt h, or c o n ge nit al a n o mal y/ birt h defect) s h o ul d be f oll o we d u p a n d d oc u me nte d e v e n 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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if t he partici pa nt w as disc 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 priat e Astra Ze neca re prese ntati ves wit hi n o ne  d a y ( ie, i m me diatel y b ut n o 
l ater t h a n 2 4 h o urs) of w he n he or s he bec o m es a ware of it . 
T he desi g nate d Astra Z e n eca 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 m ati o n is pr o vi de d t o t he Astra Z e neca Patie nt Safet y D E S wit hi n o ne  or 
5  c ale n d ar d a ys  f or S A Es (see Secti o n 8. 3. 9 ) a n d wit hi n 3 0 d a ys  f or all ot her pre g n a ncies. 
T he sa me ti meli nes a p pl y w he n o utc o me i nf or m ati o n is a vaila ble.  
T he P R E G R E P m o d ule i n t he e C R F is use d t o re p ort t he pre g na n c y a n d t he pa per bas e d 
P R E G O U T m o d ule is use d t o re p ort t he o utc o m e of t he pre g n a nc y.  
8. 3. 1 1  
Me dic ati o n Err or, Dr u g A b us e, a n d Dr u g Mis use   
8. 3. 1 1. 1  
Ti m eli nes   
If a n e v e nt of me dic ati o n err or, dr u g a b use, o r  dr u g mis use occ urs d uri n g t he st u d y, t he n t he 
I n vesti gat or or ot her site pers o n nel i nf or ms t he a p pr o priate Astra Z e neca re prese ntati ves wit hi n 
o ne  c ale n d ar 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 t he y bec o me a w are 
of it.  
T he desi g nate d Astra Z e n eca 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 m ati o n is c o m plete d wit hi n 1  (I nitial Fatal/ Life-T hreate ni n g or f oll o w -u p 
Fatal/ Life -T hreate ni n g) o r 5  ( ot her seri o us i nitial a n d f oll o w-u p) c ale n d ar d a ys  if t here is a n 
S A E ass ociate d wit h t he me dicati o n err or, dr u g a b use, or mis use (see Secti o n 8. 3. 9 ) a n d 
wit hi n 3 0 d a ys  f or all ot her e ve nts. 
8. 3. 1 1. 2  
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 dicati o n err or is a n u ni nte n de d fail ure or mista ke 
i n t he treat me nt pr ocess f or a n I M P or Astra Z e neca NI M P t hat eit her ca uses har m t o t he 
partici pa nt or has t he p ot e ntial t o ca use har m t o t he partici pa nt.  
T he f ull defi niti o n a n d e x a m ples of me dicati o n err or ca n be f o u n d i n A p pe n di x B  4 . 
8. 3. 1 1. 3  
Dr u g A b use   
Dr u g a b use is t he p ersiste nt or s p ora dic i nte nti o n al, n o n-t hera pe utic e xcessi ve use of I M P or 
Astra Z e neca NI M P f or a percei v e d re war d or desir e d n o n -t hera pe utic effect. 
T he f ull defi niti o n a n d e x a m ples of dr u g a b us e ca n be f o u n d i n A p pe n di x B  4 . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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8. 3. 1 1. 4  
Dr u g Mis use   
Dr u g mis use is t he i nte nti o n al a n d i na p pr o priate use ( b y a st u d y partici p a nt) of I M P or 
Astra Ze neca NI M P f or m e dici nal p ur p oses o utsi de of t he a ut h orize d pr o d uct i nf o r mati o n, or 
f or u na ut h orize d I M Ps or Astra Z e neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute.  
T he f ull defi niti o n a n d e x a m ples of dr u g mis use ca n be f o u n d i n A p pe n di x  B  4 . 
8. 3. 1 2  
De vice C o nstit ue nt D eficie ncies   
C o m bi nati o n pr o d ucts wit h a de vic e c o nstit ue nt are bei n g pr o vi de d f or use i n t his st u d y. I n 
or der t o f ulfill re g ulat or y re p orti n g o bli gati o ns w orl d wi de, t he I n vesti gat or is res p o nsi ble f or 
t he detecti o n a n d d o c u me ntati o n of e ve nts meeti n g t he defi niti o n of a de vi ce c o nstit ue nt 
deficie nc y t h at occ ur d uri n g t he st u d y wit h t he de vice c o nstit ue nt of t he B F F c o m bi nati o n 
pr o d uct.  
De vice c o nstit ue nt defici e ncies fr o m t his st u d y will be c ollecte d a n d m o nit ore d t o e ns ure t he 
safet y of partici pa nts a n d i m pr o ve t he safet y a n d p erf or ma n ce of t he de vic e.  
De vice c o nstit ue nt defici e ncies will n ot be pres e nte d i n t he C S R, b ut w here re q uire d b y l ocal 
re g ulati o ns, deficie n cies will be s u m marize d i n t he rele va nt peri o dic re p ort. 
T he defi niti o n of a de vi ce c o nstit ue nt deficie n c y is a n i na de q uac y of a d e vi ce c o nstit ue nt wit h 
res pect t o its i de ntit y, q ualit y, d ura bilit y, relia bilit y, safet y, or perf or m a nce. De vice c o nstit ue nt 
deficie nci es i ncl u de malf u ncti o ns, use err ors, a n d i nf or mati o n s u p plie d b y t he ma n ufact urer.  
T he Astr a Ze neca D e vice C o nstit ue nt Re p ort F or m a n d/ or Pr o d uct C o m plai nt I nta ke F or m will 
be use d t o c ollect t he d eficie nc y.  
8. 3. 1 2. 1  
Ti m e Peri o d f or Detecti n g De vice C o nstit ue nt Deficie ncies   
De vice c o nstit ue nt i nci de nts or m alf u ncti o ns will be detect e d, d oc u me nte d, a n d re p ort e d 
d uri n g all peri o ds of t he st u d y i n w hic h t he de vice c o nstit ue nt is use d.  
If t he I n vesti gat or l ear ns of a n y de vice c o nstit ue nt deficie nc y at a n y ti me after a partici pa nt 
has bee n disc h ar 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 
de vice c o nstit ue nt pr o vi d e d f or t he st u d y, t he I n v esti gat or will pr o m ptl y n otif y Astra Ze neca.  
8. 3. 1 2. 2  
F oll o w -u p of De vice C o nstit ue nt Deficie ncies   
F oll o w -u p a p plies t o all partici pa nts, i ncl u di n g t h ose w h o disc o nti n ue st u d y i nter ve nti o n. T he 
I n v esti gat 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 o ns as i n dicate d t o el uci date t he nat ur e a n d/ or ca us alit y of t he deficie nc y. Ne w or 
u p date d i nf or mati o n will be rec or de d o n t he ori gi nall y c o m plete d f or m wit h all c ha n ges 
si g ne d a n d date d b y t he I n vesti gat or. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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8. 3. 1 2. 3  
Pr o m pt Re p orti n g of De vice C o nstit ue nt Defici e ncies t o Astr a Ze nec a   
De vice c o nstit ue nt defici e ncies will be re p orte d t o Astra Ze neca wit hi n 2 4 h o urs after t h e 
I n v esti gat or deter mi nes t hat t he e ve nt meets t he pr ot oc ol defi niti o n of a de vice c o nstit ue nt 
deficie nc y.  
T he Astra Z e neca De vi ce C o nstit ue nt Deficie nc y R e p ort F or m a n d/ or Pr o d u ct C o m plai nt 
I nta k e F or m will be se nt t o Astra Ze neca b y e m ail t o t he Astra Ze neca D E S. If pa per is 
u na vaila ble, t he n I n v esti gat or or ot her st u d y site staff re p orts t he de vice c o nstit ue nt c o m plai nt 
t o t he a p pr o priate Astra Z e neca re prese ntati ve b y t ele p h o ne. Astra Ze neca will be t he c o ntact 
f or t he recei pt of de vice c o nstit ue nt deficie nc y re p orts. 
8. 4  
O ver d ose   
F or t his st u d y, a n y  d osi n g of B F F  or B D of m ore t ha n 2 i n halati o ns BI D  will be c o nsi dere d a n 
o ver d ose.  
•  A n o ver d ose wit h ass o ciate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
rele va nt A E m o d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule. 
•  A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y re p orte d o n t he O ver d ose e C R F 
m o d ule.  
 
If a n o ver d ose o n a n Astr a Ze neca st u d y i nter ve nti o n occ urs i n t he c o urse of t he st u d y, t he 
I n vesti gat or or ot her site pers o n nel i nf or m a p pr o priate Astra Ze neca re pres e ntati ves 
i m me diatel y, but n o l ater t h a n 2 4 h o urs  of w he n he or s he bec o mes a ware of it.  
T he desi g nate d Astra Z e n eca 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 m ati o n is pr o vi de d t o t he Astra Z e neca Patie nt Safet y D E S wit hi n o ne or 
5  c ale n d ar d a ys  for o ver d oses ass ociate d wit h a n S A E (see Secti o n 8. 3. 9 ) a n d wit hi n 3 0  d a ys  
f or all ot her o ver d oses. 
8. 5  
H u m a n Bi ol o gic al S a m ples   
8. 5. 1  
P h ar m ac o ki netics   
P har mac o ki netic para met ers are n ot e val uat e d i n t his st u d y . 
8. 5. 2  
I m m u n o ge nicit y Assess m e nts  
I m m u n o ge nicit y assess me nts are n ot e val uate d i n t his st u d y. 
8. 5. 3  
P h ar m ac o d y n a mics   
P har mac o d y na mic p ara m eters are n ot e val u at e d i n t his st u d y. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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8. 6  
H u m a n Bi ol o gic al S a m ple Bi o m ar kers   
Bi o mar kers are n ot e val u ate d i n t his st u d y.  
8. 7  
O pti o n al Ge n o mics I niti ati ve S a m ple   
C ollecti o n of o pti o nal sa m ples f or Ge n o mics I niti ati ve researc h is als o part of t his st u d y as 
s pecifie d i n t he S o A a n d is s u bject t o a gree me nt i n t he O pti o nal Ge n o mics I nitiati ve Researc h 
I nf or mati o n of t he I C F. 
Bl o o d sa m ple f or D N A is olati o n will be c ollecte d fr o m partici pa nts w h o ha v e c o nse nte d t o 
partici pate i n t he ge n etic a nal ysis c o m p o ne nt of t h e st u d y. Partici pati o n is o pti o nal. 
Partici pa nts w h o d o n ot wis h t o part ici pate i n t he ge netic res earc h ma y still partici pate i n t he 
st u d y. 
See A p pe n di x  C  f or i nf or mati o n re gar di n g t he Ge n o mics I nitiati ve ge netic sa m ple. Details o n 
pr ocesses f or c ollecti o n, s hi p me nt, a n d destr ucti o n of t hese sa m ples ca n be f o u n d eit her i n t he 
a p pe n dices or i n t he La b orat or y Ma n u al.  
F or st ora ge a n d d estr ucti o n of ge netic sa m ples s ee A p pe n di x  C .  
8. 8  
He alt hc are Res o urce Utiliz ati o n D at a   
Healt hcare res o urce utilizati o n data ass o ciate d wit h me dical e nc o u nters will be  c ollecte d i n 
t he e C R F b y t he I n vesti gat or a n d st u d y site pers o n nel f or all partici p a nts t hr o u g h o ut t he st u d y. 
D uri n g scree ni n g at Visit  3, H C R U i nf or mati o n will be c ollecte d wit h a ‘ o ne year’ recall 
peri o d. All t he s u bse q u e nt visits after Visit  4, will c o llect H C R U i nf or mati o n wit h a recall 
peri o d of ‘si nce t he last s c he d ule d visit’. Pr ot oc ol -ma n date d pr oce d ures, tests, a n d e nc o u nters 
are e x cl u de d.  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S   
9. 1  
St atistic al H y p ot heses   
F or t he efficac y c o m paris o ns of t he pri mar y o bjecti ve, t he n ull h y p ot hesis w ill be t hat t he 
mea n treat me nt differe nce ( B F F M DI 1 6 0/ 9. 6  μ g vs B D M DI 1 6 0  μ g) is zer o ( mea n tr eat me nt 
effects are e q u al). T he alter nati ve h y p ot hesis is t hat t he mea n treat me nt differe nce is n ot zer o 
( mea n treat me nt effects are n ot e q ual). All p-val u es wi ll be re p orte d as t w o-si de d. 
F or t he p o ole d a nal ysis of e xacer bati o n rate, it is ass u me d t hat t he rate rati o ( R R) c o m pari n g 
B F F a n d B D will n ot de pe n d o n t he d ose of B D, t hat is R R B F F 3 2 0/ 9. 6 vs B D 3 2 0  =  R R B F F 1 6 0/ 9. 6 vs B D 
1 6 0 = R R B F F vs B D . T he n ull a n d alter nati ve h y p ot heses are h e nce:  
•  
H 0: R RB F F vs B D  =  1  
•  
H 1: R RB F F vs B D  ≠ 1  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
 
9. 2  
A n al ysis Met h o ds f or Esti m a n ds   
D ue t o variati o n i n t he re gistrati o nal re q uire me nts acr oss re gi o ns, t he esti ma n d strate g y will 
be differe nt de p e n di n g o n t he re gi o n.  
A nal yses utilizi n g t he pri mar y esti ma n d strate g y f or I C Es a ns wer t he cli nical q uesti o n of w hat 
t he effect of ra n d o mize d treat me nt at t he e n d of t he pla n ne d treat me nt peri o d is re gar d less of 
t he occ urre nce of a n y I C Es u nless ast h ma me dicati o n is i nitiate d i n c o nj u ncti o n wit h 
pre mat ure disc o nti n uati o n of t hera p y ( w hic h will be c o nsi dere d a n u nfa v o ura ble  o utc o me ). 
A nal yses utilizi n g t he W hile o n Treat me nt esti ma n d strate g y f or I C Es  a ns wer t he cli nical 
q uesti o n of w hat t he effect of t he ra n d o mize d treat me nts is ass u mi n g c o nti n uati o n of 
ra n d o mize d tr eat me nts f or t he d urati o n of t he pla n ne d treat me nt peri o d re g ar dless of act ual 
c o m plia nce. 
A nal yses of lu n g fu ncti o n e n d p oi nts utilizi n g t he pri mar y strate g y, w here i nitiati n g ne w  
treat me nt f or ast h ma i n c o nj u ncti o n wit h pre mat urel y disc o nti n ui n g ra n d o mize d treat me nt  is 
c o nsi dere d a n u nfa v o ura ble o utc o me,  will i m p ute t he w orst F E V 1 val ue of: 
% decrease 
fr o m partici pa nt’s baseli n e  val ue  or p artici pa nt’s w orst o bser ve d val u e p ost baseli ne d uri n g the 
st u d y. F or bi nar y o utc o me varia bles, t h e occ urre n ce of a n I C E utilizi n g t he c o m p osite strate g y 
is ta ke n t o be a c o m p o ne nt of t he varia ble res ulti n g i n a n o n-res p o n d er stat us, ie, t he I C E is 
i nte grate d wit h o ne or m ore ot her meas ures of cli nical o utc o me as t he v ari a ble of i nterest. 
M ore details o n t he i m p utati o n a p pr oac h es will be pr o vi de d i n t he S A P.  
9. 2. 1  
T y pe I Er r or C o ntr ol   
D ue t o variati o n i n t he re gistrati o nal re q uire me nts acr oss re gi o ns, t he m ulti ple testi n g 
pr oce d ure will be differe nt de pe n di n g o n t he re gi o n. T he c ha n g e fr o m b aseli ne i n F E V 1 
A U C 0 3 will be t he pri mar y e n d p oi nt f or  
a n d ke y sec o n dar y e n d p oi nt  f or  
 T he 
c ha n ge fr o m baseli ne i n m or ni n g pre -d ose tr o u g h F E V 1 will be t he pri mar y e n d p oi nt f or 
 a n d ke y sec o n d ar y e n d p oi nt f or 
 
9. 2. 1. 1  
A p pr o ac h   
T he Ty pe I err or c o nt r ol pr oce d ure f or t h e  
a p plies a se q ue ntial testi n g pr oce d ure descri be d 
gra p hicall y i n Fi g ure  2 . 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
Fi g ure  2  
T y pe I Err or C o ntr ol Pr oce d ure  
a
T he pr oce d ure is a p plie d t o b ot h t his st u d y, D 5 9 8 2 C 0 0 0 0 5, as well as St u d y  D 5 9 8 2 C 0 0 0 0 6 i n 
or der t o all o w dat a fr o m b ot h st u dies t o be c o m bi ne d f or a n al yses of se v ere e xacer bati o n, t h us 
utilizi n g data fr o m hi g her n u m bers of partici pa nts t o s u p p ort t hat e n d p oi nt. T he a nal ys es i n 
t his st u d y, D 5 9 8 2 C 0 0 0 0 5, will be c o m pari n g B F F M DI 1 6 0/ 9. 6 µ g BI D t o B D 1 6 0  μ g M DI 
BI D at Wee k  1 2 (e x ce pt f or testi n g o nset of acti o n, w here at t he ti me p oi nt of i nterest is at t he 
5 mi n ute p ost -d ose ti me p oi nt o n Da y  1, as well as t he a nal yses o n c h a n ge fr o m baseli ne i n 
p uffs of resc ue m e dicati o n a n d se vere e x acer bati o n rate, w here t he e val uati o n is ma de o ver t he 
d urati o n of t he st u d y), w hereas t h e a nal yses i n St u d y  D 5 9 8 2 C 0 0 0 0 6 will be c o m pari n g B F F 
M DI 3 2 0/ 9. 6  µ g BI D t o B D 3 2 0  μ g M DI B I D at Wee k 2 4 (e xce pt f or testi n g o nset of acti o n, 
w here at t he ti me p oi nt of i nterest is at t he 5 mi n ute p ost -d ose ti me p oi nt o n Da y  1).  
T he pr oce d ure starts b y testi n g t he pri mar y e n d p oi nt, c ha n ge fr o m b aseli ne i n F E V 1 A U C 0 -3 
wit hi n eac h of t he 2  st u di es ( D 5 9 8 2 C 0 0 0 0 5 a n d D 5 9 8 2 C 0 0 0 0 6). If t his res ult is statisticall y 
si g nifica nt (al p ha = 0. 0 5, t w o-si de d) wit hi n a st u d y, t he ke y sec o n dar y e n d p oi nt, c ha n ge fr o m 
baseli ne i n tr o u g h F E V 1 will be teste d at t w o -si de d al p ha of 0. 0 5 f or t hat st u d y. If t his res ult is 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
statisticall y si g nifica nt wit hi n t hat st u d y, t he o nset of acti o n o n Da y 1 will be teste d at 
al p ha =  0. 0 5 (t w o -si de d) f or t hat st u d y. 
If t he test f or o ns et of acti o n o n Da y 1 is statisticall y si g nifica nt wit hi n a st u d y, 0. 0 2 5 al p ha 
(t w o-si de d) will be all ocate d fr o m t hat st u d y t o testi n g t he p o ole d se vere e xacer bati o n rate, 
a n d t he re mai ni n g 0. 0 2 5 al p ha (t w o -si de d) will be all ocate d t o testi n g t he sec o n dar y 
e n d p oi nts: c ha n ge fr o m b aseli ne i n p uffs of resc u e me dicati o n, t he perce nta ge of res p o n d er 
e n d p oints f or A C Q -7, A C Q -5, A Q L Q(s) -1 2, usi n g i n di vi d ual st u d y data. T h ose e n d p oi nts will 
be si m ulta ne o usl y teste d (al p ha = 0. 0 2 5, t w o -si de d) wit h a H oc h ber g pr oce d ure [G o u  2 0 1 4].  
T heref ore, if t he t est f or o nset of acti o n o n Da y  1 is statisticall y si g nifica nt i n b ot h st u dies, t he 
p o ole d se vere e xacer bati o n rate will be teste d at al p ha = 0. 0 5 (t w o -si de d). If t he test f or t he 
p o ole d se vere e xacer bati o n rate is statisticall y  si g nifica nt, a d diti o nal 0. 0 2 5 al p ha (t w o-si de d) 
will be all ocate d t o testi n g t he sec o n dar y e n d p oi nts f or eac h st u d y: c ha n ge fr o m baseli ne i n 
p uffs of resc ue m e dicati o n, t he perce nta ge of res p o n der e n d p oi nts f or A C Q -7, A C Q -5, 
A Q L Q(s) -1 2. T h ose e n d p oi nts wi ll be si m ulta ne o usl y teste d (al p ha = 0. 0 5, t w o-si de d) wit h a 
H oc h ber g pr oce d ure  [G o u  2 0 1 4].  
Ot her wise, if t he test f or o nset of acti o n o n Da y  1 is statisticall y si g nifica nt i n o nl y o ne st u d y, 
t he p o ole d se vere e x acer bati o n rate will be teste d at al p ha = 0. 0 2 5 (t w o-si de d). If t he t est f or 
t he p o ole d se vere e x acer bati o n rate is statisticall y si g nifica nt, a d diti o nal 0. 0 2 5 al p ha (t w o-
si de d) will be all ocate d t o testi n g the sec o n dar y e n d p oi nts f or t he res pecti ve st u d y: c ha n ge 
fr o m baseli ne i n p uffs of resc ue m e dicati o n, t he perce nta ge of res p o n der e n d p oi nts f or A C Q-7, 
A C Q -5, A Q L Q(s) -1 2. T h ose e n d p oi nts will be si m ulta ne o usl y teste d (al p ha = 0. 0 5, t w o -si de d) 
wit h a H oc h ber g p r oce d ure [G o u  2 0 1 4].  
If all e n d p oi nts teste d wit hi n t he H oc h ber g pr oce d ure are statisticall y si g nifica nt wit hi n a 
st u d y, t he se vere e x acer bati o n rate will be tested usi n g i n di vi d ual st u d y data f or t hat st u d y.  
9. 2. 1. 2  
 A p pr o ac h  
T he Ty pe I err or f or ot h er re gi o ns, i ncl u di n g  
, will be str o n gl y c o ntr olle d acr oss t he 
pri mar y a n d sec o n dar y e n d p oi nts of B F F M DI 1 6 0/ 9. 6 μ g vers us B D M DI 1 6 0  μ g 
(al p ha =  0. 0 5, t w o -si de d). T he pr oce d ure will test t he pri mar y, c ha n ge fr o m baseli ne i n tr o u g h 
F E V 1, a n d ke y sec o n dar y, F E V1 A U C 0 -3, e n d p oi nts o ver 1 2 Wee ks i n se q ue ntial or der. If t he 
res ult is statisticall y si g nifica nt (al p h a = 0. 0 5, t w o-si de d) f or t he pri mar y a n d ke y sec o n dar y 
e n d p oi nt, t he o nset of acti o n o n Da y 1 will be teste d  b y c o m pari n g B F F M DI 1 6 0/ 9. 6  μ g vs 
B D M DI 1 6 0  μ g (al p ha =  0. 0 5 , t w o-si de d). If t h at test is statisticall y si g nifica nt, t he re mai ni n g 
sec o n dar y e n d p oi nts will be si m ulta ne o usl y teste d (al p ha =  0. 0 5, t w o -si de d) wit h a 
H oc h ber g -t y pe pr o ce d ure [G o u  2 0 1 4].  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
9. 3  
S a m ple Size Deter mi n ati o n   
Sa m ple size calc ul ati o ns eit her ass u me d a W hile o n Treat me nt or Treat me nt P olic y strat e g y 
f or I C Es. 
A t otal of 3 4 0 partici pa nts will be recr uite d wit h  
 partici pa nts i n eac h st u d y i nter ve nti o n 
ar m. U n der t h e W hile o n Treat me nt esti ma n d strat e g y f or I C Es, t his sa m ple size will pr o vi de 
m ore t ha n 9 9 % p o w er t o detect a 
 m L differe n ce i n F E V 1 A U C 0 -3 a n d 9 2 % p o wer t o det ect 
a 
m L differe n ce i n tr o u g h F E V 1 o ver 1 2 Wee ks. Eac h c o m paris o n is base d o n a t w o -si de d 
al p ha = 
test a n d S D of 
 m L f or F E V 1 A U C 0 -3 a n d 
 m L f or tr o u g h F E V 1 at eac h visit 
wit h effecti ve S D of 
 m L a n d 
m L res p ecti vel y. T he effecti ve S D f or eac h e n d p oi nt 
o ver 1 2 Wee ks ass u mes 2 visits o ver t he i nter val a n d t hat t he c orrelati o n a m o n g visits is  
 
T hese sa m ple siz es ass u me t hat a p pr o xi matel y 
% of ra n d o mize d partici pa nts will ha ve 
disc o nti n ue d st u d y i nter ve nt i o n pri or t o Wee k 1 2.  
Usi n g t he Treat me nt P olic y esti ma n d strate g y f or I C Es, a s maller treat me nt differe n ce  (t ha n 
f or t he W hile o n Treat me nt strate g y) of 
m L f or tr o u g h F E V 1 is ass u me d, pr o vi di n g a 
p o wer at 1 2 w ee ks i n tr o u g h F E V 1 of 8 0 %. Ass u mi n g a s ma ller treat me nt effect of 
 m L f or 
F E V 1 A U C 0 -3, t he p o wer w o ul d re mai n at least 9 9 %. 
T he treat me nt effect a n d varia bilit y f or t he p o wer calc ulati o n was b ase d o n 4 S y m bic ort 
st u dies (as S y m bic ort is a si milar stre n gt h of B F F i n a p M DI) (C orre n  2 0 0 7,  N o o na n  2 0 0 6,  
Peters  2 0 0 8, a n d  Za n grilli  2 0 1 1 ). 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
9. 4  
P o p ul ati o ns f or A n al yses   
T he f oll o wi n g p o p ulati o ns are defi ne d:  
Ta ble 1 2  
P o p ul ati o ns f or A n al yses   
A n al ysis set  
Descri pti o n  
Scree ne d set  
All p artici pa nts w h o si g n t he I C F.  
Ra n d o mize d set  
All p artici pa nts w h o are ra n d o mize d t o st u d y i nter ve nti o n. 
Efficac y set  
All p artici pa nts w h o are ra n d o mize d t o st u d y i nter ve nti o n a n d recei ve a n y 
a m o u nt of st u d y i nter ve nti o n. Partici pa nts will be a nal yze d acc or di n g t o t he 
st u d y i nter ve nti o n t he y were assi g ne d at ra n d o mizati o n, r e gar dless of t he 
act ual st u d y i nter ve nti o n recei ve d.  
Safet y set  
All p artici pa nts w h o are ra n d o mize d t o st u d y i nter ve nti o n a n d recei ve a n y 
a m o u nt of t he st u d y i nter ve nti o n. Partici pa nts will be a nal yze d acc or di n g t o 
t he act ual st u d y i nter ve nti o n recei ve d rat her t ha n ra n d o mize d. 
P F T S u b -St u d y set  
All p artici pa nts w h o are ra n d o mize d a n d ha ve at least o ne  p ost -baseli ne 
s pir o metr y assess me nt i n t he s u b-st u d y (after t he first d ose of st u d y 
me dicati o n).  
 
9. 5  
St atistic al A n al yses   
T he S A P will be fi nalize d bef ore t h e earliest of t he f oll o wi n g milest o nes: 9 0 da ys after first 
partici pa nt i n, first Data M o nit ori n g C o m mittee or first Dr y R u n a n d will i ncl u de a m ore 
tec h nical a n d d etaile d descri pti o n of t he statistical a nal yses descri bed i n t his secti o n. T his 
secti o n is a s u m mar y of t he pla n ne d statistical a nal yses of t he m ost i m p orta nt e n d p oi nts 
i ncl u di n g pri mar y a n d sec o n dar y e n d p oi nts. A d diti o nal a nal yses assessi n g t he i m pact of 
S A R S -C o V -2 pa n de mic or a n y ot her n at ural e ve nt ma y be i n cl u de d i n t he S A P. 
9. 5. 1  
Ge ner al C o nsi de r ati o ns   
9. 5. 1. 1  
De m o gr a p hic a n d B aseli ne C h ar acteristics   
De m o gra p hic a n d b aseli n e c haracteristics data will be s u m marize d b y tr eat me nt f or t he 
Efficac y a n d Safet y sets.  
9. 5. 1. 2  
Visit Wi n d o ws   
F or p ost -ra n d o mizati o n visit base d a nal yses, t he varia bles are s u m marize d base d o n data fr o m 
sc he d ule d or re peat visits (i ncl u di n g pre mat ure st u d y i nter ve nti o n disc o nti n uati o n visits) b y 
ma p pi n g t he visit date t o a n a dj uste d a nal ysis -d efi ne d visit wi n d o w irres pecti ve of t he visits’ 
la bel n u m beri n g. T he a dj uste d a nal ysis-def i ne d wi n d o ws will be s pecifie d i n t he S A P. F or 
s pir o metr y e n d p oi nts b y ti me p oi nt pre- a n d p ost -d osi n g, t he assess me nts will be all ocate d t o 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
deri ve d n o mi nal c ollecti o n ti me wi n d o ws of mi n utes fr o m st u d y i nter ve nti o n d osi n g. T hese 
will be s pecifie d i n t he S A P. Act ual ti me will be use d f or t he A U C calc ulati o ns.  
9. 5. 1. 3  
B aseli ne   
F or F E V 1 a n d o nset of acti o n o n Da y  1, baseli ne is defi ne d as t he m ea n of t he pre -d os e F E V 1 
assess me nts o n Visit  4 ( Da y  1). F or t he ast h ma P R Os, baseli ne is defi ne d as t he last 
n o n -missi n g val ue bef ore  first d ose of ra n d o mize d I P. F or dail y e Diar y metrics (resc u e 
me dicati o n, a wa k e ni n gs, P E F, a n d ast h ma s y m pt o ms sc ores), bas eli ne is defi ne d as t he 
a vera g e of e Diar y metrics meas ure d d uri n g last 7 da ys bef ore ra n d o mizati o n. F or se vere 
ast h ma e xacer bati o n hist or y i n t he past 1 2 m o nt hs bef ore Visit  1, baseli ne is t he n u m ber of 
se vere ast h ma e xacer bati o ns re p orte d o n t he Res pirat or y Diseas e Hist or y e C R F pa ge.  
9. 5. 2  
Effic ac y   
9. 5. 2. 1  
Pri m ar y E n d p oi nt(s)   
C ha n ge fr o m Baseli ne i n F E V 1 A U C 0 -3 ( 
Pri mar y E n d p oi nt) 
C ha n ge fr o m bas eli ne i n F E V 1 A U C 0 -3 will be a nal yze d usi n g a re p eate d m eas ures A N C O V A 
m o del. T he m o del will i ncl u de tre at me nt, visit, pri or mai nte na nce me dicati o n (I C S vers us 
I C S/ L A B A), a n d treat me nt-b y -visit i nteracti o n as cate g orical c o variates a n d baseli ne tr o u g h 
F E V 1 a n d perce nt al b uter ol re versi bilit y as c o nti n u o us c o variates. A n u nstr uct ure d 
varia nce -c o v aria n ce matri x will be use d t o m o del t he varia n ce -c o vari a nce str uct ure. If t his 
m o del fails t o c o n ver g e, a n alter nati ve str u ct ure will be e m pl o ye d as pre -s p ecifie d i n t he S A P. 
C o ntrasts will be use d t o o btai n esti mates of t he tr eat me nt differe n ces at Wee k  1 2. T w o -si de d 
p -val ues a n d p oi nt esti mates wit h t w o -si de d 9 5 % CIs will be pr o d uce d f or eac h tr eat me nt 
differe nce. T he m o del -b ase d statistics f or ot her visits a n d o ver 1 2 Wee ks will als o be re p orte d.  
Deri vati o n of t he F E V 1 A U C 0 -3 
T he F E V 1 A U C 0 -3 will be calc ulate d f or t he c h a n g es fr o m baseli ne usi n g t h e tra pez oi dal r ule 
a n d will be n or malize d b y di vi di n g b y t he ti me (i n h o urs) fr o m d osi n g t o t he last meas ure m e nt 
i ncl u de d (t y picall y 3 h o urs). O nl y o ne n o n -missi n g, p ost -d ose val ue is re q uire d f or t he 
calc ulati o n of F E V 1 A U C 0 -3. Act ual ti me fr o m d osi n g will be use d i n t he calc ulati o n if 
a vaila ble; ot her wis e, sc h e d ule d ti me will be use d.  
C ha n ge fr o m Baseli ne i n M or ni n g Pre -d ose Tr o u g h F E V 1 ( 
 Pri mar y E n d p oi nt) 
C ha n ge fr o m bas eli ne i n m or ni n g pre -d ose tr o u g h F E V 1 will be a nal yze d usi n g a re peate d 
meas ures A N C O V A m o d el. T he m o del will be si milar t o t he o ne use d f or F E V
1 A U C 0 -3. 
C o ntrasts will be use d t o o btai n esti mates of t he tr eat me nt differe n ce o ver 1 2 Wee ks. 
T w o -si de d p-val u es a n d p oi nt esti mates wit h t w o -si de d 9 5 % CIs will be pr o d uce d f or t h e 
treat me nt differe n ce. T h e m o del-base d statistics f or at Wee k  1 2 a n d ot her visits will als o be 
re p orte d. 
I nter mitte nt missi n g data f or t he pri mar y e n d p oi nt (all re gi o ns) will n ot be i m p ute d a n d will be 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 6  of 1 2 2  
 
ha n dle d t hr o u g h t he a n al ysis m o del.  
Se nsiti vit y a nal yses will be c o n d ucte d f or t he pri mar y e n d p oi nt (all re gi o ns) t o e val uate t he 
r o b ust ness of t he pri mar y a nal ysis fi n di n gs t o missi n g data. R o b ust ness of res ults t o missi n g 
data will be e x pl ore d usi n g ti p pi n g p oi nt a nal yses . M ore details will be pr o vi de d i n t he S A P.  
9. 5. 2. 2  
Sec o n d ar y E n d p oi nt(s)   
C ha n ge fr o m bas eli ne i n m or ni n g pre -d ose tr o u g h F E V 1 is t he ke y sec o n dar y e n d p oi nt f or t he 
. F or  
, t he ke y sec o n dar y e n d p oi nt is c ha n ge fr o m b aseli ne i n F E V 1 A U C 0 -3. T he 
a nal yses are si milar as descri be d i n t he pre vi o us secti o n.  
Rate of Se vere Ast h ma E xacer bati o ns  
T he rates of se vere ast h m a e xacer bati o ns will be a nal yze d  usi n g ne gati ve bi n o mial re gressi o n 
i n t he D 5 9 8 2 C 0 0 0 0 5 a n d D 5 9 8 2 C 0 0 0 0 6 st u dies se parat el y. T he ne g ati ve bi n o mial m o del f or 
eac h st u d y will i ncl u de tr eat me nt, baseli ne tr o u g h F E V 1, perce nt al b uter ol r e versi bilit y, 
baseli ne se vere ast h ma e xacer bati o n hist or y ( 0, ≥ 1), pri or mai nte na n ce me dicati o n ( I C S 
vers us I C S/ L A B A), a n d re gi o n as c o variates. F urt her m ore, t he rates o f se v ere ast h ma 
e xacer bati o ns will be a n al yze d  f or the p o ol e d i n di vi d ual partici pa nt data fr o m b ot h st u dies 
( D 5 9 8 2 C 0 0 0 0 6: B F F 3 2 0/ 9. 6 μ g, B F F 1 6 0/ 9. 6  μ g,  a n d B D 3 2 0  μ g treat me nt ar ms; 
D 5 9 8 2 C 0 0 0 0 5: B F F 1 6 0/ 9. 6  μ g  a n d B D 1 6 0  μ g treat me nt ar ms). T he  p o ol e d a nal ysis will use 
all a vaila ble data ( o ver t h e pla n ne d 1 2 wee k treat me nt peri o d i n D 5 9 8 2 C 0 0 0 0 5 a n d o ver t he 
2 4  wee k treat me nt peri o d f or st u d y D 5 9 8 2 C 0 0 0 0 6 ) t o ma xi mize t he a m o u nt of data i ncl u de d . 
F or t he p o ole d a nal ysis, a  ne gati ve bi n o mial  a d diti ve m o del will be use d wit h t he sa me 
c o variates, e xce pt it will als o i ncl u de st u d y, a n d b u des o ni de ( 1 if t he b u des o ni de d ose is 
3 2 0  μ g, a n d 0 if t he b u des o ni de d ose is 1 6 0  μ g) a n d  f or m oter ol ( 1 if t he f or m oter ol d ose is 
9. 6  μ g, a n d 0 if n o f or m oter ol d ose) i nstea d of treat me nt as c o variates. T he c o m paris o n of 
i nterest is t he f or m oter ol effect. F or t h e p o ole d a n al ysis , o ne dis persi o n para meter will be 
esti mate d. F urt her  details will  be s pecifie d i n t he S A P.  
U n der t he pri mar y strate g y f or ha n dli n g I C Es , all a vaila ble data will be utilize d irres p ecti vel y 
of a n y I C E , e x ce pt  ne w me dicati o n i n c o nj u ncti o n wit h  pre mat ure I P disc o nti n uati o n w hic h 
will be c o nsi dere d a n u nfa v o ura ble o utc o m e . I n a d diti o n, a s u p p orti ve a nalysis utilizi n g W hile 
o n Treat me nt strat e g y will be perf or me d. 
Ast h ma e xacer bati o ns will be c o nsi dere d se p arate e ve nts if m ore t ha n 7 da ys are bet w ee n t he 
rec or de d st o p date of t h e earlier e ve nt a n d start dat e of t he later e ve nt. Ti me at ris k of 
e x perie n ci n g a se v ere e x acer bati o n will be use d as a n offset v aria ble i n t he m o del. Ti me 
d uri n g a se vere e x acer bati o n or i n t he 7 da ys f oll o wi n g a se vere e x acer bati o n will n ot be 
i ncl u de d i n t he calc ulati o n of e x p osure. T he ne g ati ve bi n o mial m o del will i ncl u de baseli ne 
tr o u g h F E V1, perce nt al b uter ol re versi bilit y, baseli ne se vere ast h ma e x acer bati o n hist or y 
( 0, ≥ 1), pri or mai nte na n ce me dicati o n (I C S vers us I C S/ L A B A), a n d re gi o n as c o vari ates.  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 7  of 1 2 2  
 
T he n u m ber a n d p erce nta ge of partici p a nts wit h se vere e x acer bati o ns i n eac h treat me nt gr o u p 
will be ta b ulate d f or i n di vi d ual st u d y a n d p o ole d st u dies.  
C ha n ge fr o m Baseli ne i n Mea n N u m ber of P uffs of Resc ue Me di cati o n Use ( p uffs/ da y)  
T he mea n dail y n u m ber of p uffs of resc u e me dicati o n use will be calc ulate d o verall a n d f or 
eac h of t h e 4 -w ee k i nter vals d uri n g t he Treat me nt Peri o d. F or e ver y peri o d of ti me f or w hic h 
t he mea n n u m ber of p uffs of resc u e me dicati o n will be calc ulate d, missi n g val ues will be 
i g n ore d i n b ot h t he nu merat or a n d d e n o mi nat or. As s uc h, t he de n o mi nat or will be a dj uste d 
base d o n t he n u m ber of da ys (i ncl u di n g half da ys) wit h n o n -missi n g val ues. U n der t he 
pri mar y  strate g y f or ha n dli n g I C Es, all a vaila ble data will be utilize d irres p ecti vely of a n y I C E  
e xce pt ne w me dicati o n i n c o nj u ncti o n wit h  pre mat ure I P disc o nti n uati o n w hic h will be 
c o nsi dere d a n u nfa v o ura ble o utc o me . A re p eate d meas ures A N C O V A m o d el will be use d t o 
a nal yze c ha n g e fr o m bas eli ne i n a vera ge dail y res c ue al b uter ol us e. T he m o del will i ncl u de 
treat me nt, t he n u m ber of t he rele va nt 4-wee k i nter val (i nter val 1 t o 3), pri or mai nte na nce 
me dicati o n (I C S vers us I C S/ L A B A), se vere ast h ma e xacer bati o n hist or y ( 0, ≥ 1), a n d t he 
treat me nt-b y -4 -wee k i nter val i nteracti o n as cate g orical c o variates a n d  b aseli ne dail y resc u e 
al b uter ol use, baseli ne tr o u g h F E V 1, a n d perce nt r e versi bilit y as c o nti n u o us c o variates. A n 
u nstr uct ure d varia nce -c o varia nce matri x will be fit. If t his m o del fails t o c o n ver ge, a n 
alter nati ve str uct ure will be e m pl o ye d as pre -s pecifie d i n t he S A P. C o ntrasts will be use d t o 
o btai n esti mates of t he tr eat me nt differe n ce o ver 1 2 Wee ks a n d f or eac h 4 -wee k i nter val. T w o -
si de d p-val ues a n d p oi nt esti mates wit h t w o -si de d 9 5 % CIs will be pr o d uce d f or t he treat me nt 
differe nce.  
Perce nta g e of Re s p o n ders i n A C Q-7 a n d A C Q -5 ( ≥ 0. 5 Decrease E q u als Res p o nse)  
Res p o n der a n al yses will be perf or me d f or A C Q -7 a n d A C Q -5 at Wee k  1 2 a n d o ver 1 2 Wee ks. 
Res p o n ders are defi n e d as partici pa nts wit h a decrease i n t otal sc ore of ≥ 0. 5 p oi nts fr o m 
baseli ne. U n der t he pri m ar y strate g y f or ha n dli n g I C E , all a vaila ble dat a will be utilize d  t o 
deter mi ne res p o n se irres pecti vel y of a n y I C E e xce pt ne w me dicati o n i n c o nj u ncti o n wit h  
pre mat ure I P disc o nti n uati o n w here a p artici pa nt will be c o nsi dere d n o n -res p o n der. 
I nter mitte ntl y missi n g data will be classifie d as n o n-res p o nse. F or s u p p orti ve a nal yses 
partici pa nts w h o e x p erie nce a n I C E (e xce pt f or disc o nti n uati o n of st u d y i nter ve nti o n f or 
reas o ns r elate d t o gl o bal/ c o u ntr y sit uati o n) will be classifie d as n o n-res p o n ders at visits 
s u bse q ue nt t o t he I C E u n der t he C o m p osite esti ma n d a p pr oac h t o I C Es. Dat a f oll o wi n g st u d y 
i nter ve nti o n disc o nti n uati o n f or reas o ns relate d t o gl o bal/c o u ntr y sit uati o n will be c o nsi dere d 
missi n g a n d will n ot be i m p ute d. T h ose dat a p oi nts are c o nsi dere d t o be missi n g c o m pletel y at 
ra n d o m a n d will be e x cl u de d fr o m t he a n al ysis. I nter mitte ntl y missi n g data will be classifie d 
as n o n-res p o ns e. M ore d etails o n t he i m p utati o n will be pr o vi de d i n t he S A P. L o gistic 
re gressi o n will be use d to c o m pare t he treat me nt gr o u ps wit h treat me nt a n d pri or mai nte na nce 
me dicati o n (I C S vers us I C S/ L A B A) as cate g orical c o variates a n d baseli ne i nstr u me nt sc ore, 
baseli ne tr o u g h F E V 1, a n d perce nt re versi bilit y as c o nti n u o us c o variates. P-val ues a n d O d ds 
Rati os  wit h 9 5 % CIs will be pr o d uce d f or t he treat me nt c o m paris o n.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 8  of 1 2 2  
 
Perce nta g e of Res p o n ders i n A Q L Q(s) + 1 2 ( ≥ 0. 5 I n crease E q u als Res p o nse)  
Res p o n der a n al yses will be perf or me d f or A Q L Q(s) + 1 2 at Wee k  1 2 a n d o v er 1 2 Wee ks f or 
partici pa nts 1 2 years a n d ol der. Res p o n ders are defi ne d as partici pa nts wit h a n i m pr o ve me nt 
of ≥ 0. 5 p oi nts i ncrease o ver baseli ne. T he strat e gies f or ha n dli n g I C Es a n d missi n g data are 
si milar t o t he o nes use d f or perce nta ge of res p o n d ers i n A C Q-5. L o gistic re gressi o n will be 
use d t o c o m pare t h e treat me nt gr o u ps, si milar t o t he o ne use d f or perce nta ge of res p o n d ers i n 
A C Q -5. P -val ues a n d O d ds Rati os wit h 9 5 % CIs will be pr o d uce d f or t he treat me nt 
c o m paris o n.  
O nset of Acti o n o n Da y  1  
All s pir o metr y atte m pts at Visit  4 ( Da y  1) t hat meet A T S/ E R S acce pta bilit y criteria 
[Miller  2 0 0 5] will be rec or de d al o n g wit h t he act ual ti me. T he o nset of acti o n will be 
e val uate d o n D a y  1 b y c o m pari n g B F F M DI 1 6 0/ 9. 6  μ g vs B D M DI i n t he mea n c ha n g e fr o m 
baseli ne i n F E V 1 at t he 5 -mi n ute p ost -d ose ti me p oi nt. C o m paris o ns will als o be ma de at 
a d diti o nal ti me p oi nts b ut will n ot be c o ntr olle d f or m ulti plicit y. A re peate d meas ures 
A N C O V A will be fit t o t he Da y  1 p ost -bas eli ne d ata. T his m o del will i ncl u de treat me nt, 
ti me p oi nt, pri or mai nte na nce me dicati o n (I C S vers us I C S/ L A B A), a n d treat me nt-b y -ti me p oi nt 
i nteracti o n as cate g oric al c o variates a n d baseli ne tr o u g h F E V1 a n d perce nt re versi bilit y as 
c o nti n u o us c o variates. A n u nstr uct ure d varia nce -c o varia nce matri x will be use d t o m o del t he 
varia nce -c o v aria n ce str u ct ure. If t his m o del f ails t o c o n ver g e, a n alter nati v e str uct ure will be 
e m pl o ye d as pre -s pecifi e d i n t he S A P. C o ntrasts will be use d t o o btai n esti mates of t he 
treat me nt differe n ces o n Da y  1 at t he 5 -mi n ute p ost -d ose ti me p oi nts. T w o -si de d p-val ues a n d 
p oi nt esti mates wit h t w o -si de d 9 5 % CIs will be pr o d uce d f or eac h treat me nt differe n ce of 
B F F  M DI  1 6 0/ 9. 6  μ g vs B D M DI. F urt her m ore, d escri pti ve statistics will be pre se nt e d b y 
treat me nt gr o u p. A s u p p orti ve wit hi n-gr o u p test t o de m o nstrate t hat t he mea n c ha n ge fr o m 
baseli ne i n F E V 1 at 5 mi n utes p ost -d ose is statisticall y great er t ha n 1 0 0  m L will als o be 
pr o vi de d wit h c orres p o n di n g p -val ue a n d 9 5 % CI.  
9. 5. 2. 3  
Terti ar y/ E x pl or at or y E n d p oi nt(s)   
Tertiar y/ E x pl orat or y e n d p oi nt efficac y a n al yses will be c o n d ucte d f or t h e W hile o n Treat me nt 
strate g y f or I C Es, e xce pt f or A C Q a n d A Q L Q(s) + 1 2 e n d p oi nts  w hic h will u se t he p ri mar y 
strate g y f or h a n dli n g of I C Es. Res ults fr o m tertiar y/e x pl orat or y a n al yses ma y be re p orte d 
o utsi de of t he C S R.  
Perce nta g e of Resc u e -Free a n d S y m pt o m -Free Da ys  
T he perce nta g es of res c u e -free da ys a n d s y m pt o m-free da ys will eac h be a nal yze d  o ver 
1 2  Wee ks. A d diti o nall y, a nal yses will be c o n d u cte d o ver eac h 4 -wee k i nter val i n t he st u d y. A 
re peat e d meas ur es a n al ysis of c o varia n ce m o del will be use d wit h treat me nt, t he n u m ber of 
t he rele va nt 4-wee k i nter val (i nter val 1 t o 3), pri or mai nte na nce me di cati o n  (I C S vers us 
I C S/ L A B A), se vere ast h ma e xacer bati o n hist or y ( 0, ≥ 1), a n d t he treat me nt -b y -4 -wee k 
i nter val i nteracti o n as cat e g orical c o variates. Bas eli ne perce nt a ge of e n d p oi nt da ys ( w here 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
8 9  of 1 2 2  
 
e n d p oi nt is resc ue -free or s y m pt o m-free), baseli ne tr o u g h F E V1, a n d perce nt re versi bilit y will 
be c o nti n u o us c o vari ates.  
Pea k C ha n ge fr o m Baseli ne i n F E V 1  
Pea k c ha n g e fr o m bas eli ne i n F E V 1 will be a nal yze d usi n g a re peat e d meas ures A N C O V A 
m o del. T he m o del will be si milar as t he o ne use d f or t he pri mar y a nal yses. C o ntrasts  f or 
treat me nt c o m paris o ns o ver 1 2 Wee ks a n d f or eac h visit will be deri ve d fr o m t he m o del. 
Ti me t o Pea k F E V 1 o n D a y  1  
Ti me t o pea k F E V 1 o n Da y  1 will be a nal yze d wit h A N C O V A m o del t o c o m pare t he treat me nt 
gr o u ps, a dj uste d f or pri or mai nte na nce me di cati o n (I C S vers us I C S/ L A B A), baseli ne tr o u g h 
F E V 1, a n d perce nt r e versi bilit y. T he ti me t o pea k will be base d o n t he act ual rat her t h a n 
n o mi nal assess me nt ti me. If necessar y, n o n -p ara m etric or se mi -p ara metri c met h o ds ma y be 
use d. Details will be pr o vi de d i n t he S A P.  
Perce nta g e of Pea k F E V 1 I m pr o v e me nt Ac hi e ve d at 5 Mi n utes P ost-D ose o n Da y  1  
Descri pti ve statistics will be prese nt e d b y treat me nt gr o u p f or t he perce nt a ge of pea k F E V 1 
i m pr o ve me nt ac hie v e d at 5 mi n utes p ost-d ose o n t he da y of ra n d o mizati o n.  
S u p p orti ve  a nal yses of t h e pr o p orti o n of partici pa nts meeti n g i m pr o ve me nt t hres h ol ds o n 
Da y  1 will als o be c o n d u cte d t o c o m pare t he s pee d of o nset bet wee n treat me nts. T he 
perce nt a ge of partici pa nts wit h ≥ 1 2 % i m pr o ve me nt o ver baseli ne i n F E V1 at 5 mi n utes p ost -
d ose a n d at ot her ti me p oi nts o n Da y  1 will be c o m pare d bet w ee n tr eat me nt gr o u ps usi n g 
l o gistic re gressi o n a dj uste d f or pri or m ai nte na nce me dicati o n (I C S vers us I C S/ L A B A), 
baseli ne tr o u g h F E V 1, a n d perce nt re versi bilit y. Details will be g i ve n i n t he S A P, w here 
alter nati ve t hres h ol ds a n d ti me p oi nts ma y be defi ne d.  
C ha n ge fr o m Baseli ne i n F V C, P E F, a n d F E F 2 5 -7 5 E val uate d Usi n g A U C 0 -3  
C ha n ge fr o m bas eli ne i n F V C, P E F, a n d F E F 2 5 -7 5 e val uate d usi n g A U C 0 -3 will be a nal yze d 
usi n g a re peate d meas u res A N C O V A m o del si milar t o t he o ne use d f or t he pri mar y a nal yses. 
C o ntrasts f or treat me nt c o m paris o ns o ver 1 2 Wee ks a n d f or eac h visit will be deri ve d fr o m t he 
m o del.  
C ha n ge fr o m Baseli ne i n M or ni n g Pre -D ose Tr o u g h P E F  
C ha n ge fr o m bas eli ne i n m or ni n g pre -d ose tr o u g h P E F will be a nal yze d usi n g a re peate d 
meas ures A N C O V A m o d el. T he m o del will i ncl u de treat me nt, 4 -wee k i nter val (i nter val 1 t o 
3), pri or mai nte na n ce me dicati o n (I C S vers us I C S/ L A B A), a n d treat me nt -b y -4 -wee k i nter val 
i nteracti o n as cate g oric al c ovariates a n d baseli ne m or ni n g pre -d ose tr o u g h P E F, baseli ne 
tr o u g h F E V1, a n d perce nt re versi bilit y as c o nti n u o us c o variates. A n u nstr uct ure d varia n ce-
c o varia n ce matri x will be use d t o m o del t he varia n ce -c o v aria n ce str u ct ure. If t his m o del fails 
t o c o n ver ge, a n alter nati ve str uct ure will be e m pl o ye d as pre-s pecifi e d i n t he S A P. C o ntrasts 
will be use d t o o btai n esti mates of t he treat me nt differe nces o ver 1 2 Wee ks a n d f or eac h 4 -

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 0  of 1 2 2  
 
wee k i nter val. T w o -si de d p-val ues a n d p oi nt esti mates wit h t w o -si de d 9 5 % CIs will be 
pr o d uce d f or t he treat me nt differe n ce.  
C ha n ge fr o m Baseli ne i n E ve ni n g Pre -D ose P E F  
C ha n ge fr o m bas eli ne i n e ve ni n g pre -d ose P E F will be a nal yze d o v er 1 2 Wee ks a n d o ver eac h 
4 -wee k i nter val usi n g a re peate d m eas ures A N C O V A m o del. T he m o del will be si mil ar as t he 
o ne use d f or t h e c ha n g e fr o m baseli ne i n m or ni n g pre -d ose P E F.  
Perce nta g e or Res p o n ders i n A C Q -6 ( ≥ 0. 5 Decrease E q uals Res p o nse)  
Res p o n der a n al yses will be perf or me d f or A C Q -6 at Wee k  1 2 a n d o ver 1 2 Wee ks. Res p o n d ers 
are defi ne d as p artici pa nts wit h a n i m pr o ve me nt ( decrease of ≥ 0. 5 p oi nts) o ver baseli ne. T he 
strate gies f or h a n dli n g I C Es a n d missi n g data are si milar t o t he o nes use d f or perce nta ge of 
res p o n ders i n A C Q-5. L o gistic re gressi o n will be use d t o c o m pare t h e treat me nt gr o u ps, 
si milar t o t he o ne use d f or perce nta ge of res p o n d ers i n A C Q-5. P -val ues a n d O d ds Rati os wit h 
9 5 % CIs will be pr o d uce d f or t he treat me nt c o m p aris o n.  
C ha n ge fr o m Baseli ne i n A C Q -5, A C Q -6, A C Q -7, a n d A Q L Q(s) + 1 2  
C ha n ge fr o m bas eli ne i n A C Q -5, A C Q -6, A C Q -7 a n d A Q L Q(s) + 1 2  will eac h be a n al yze d 
usi n g a re peate d meas ures A N C O V A m o del. T he m o del will i ncl u de treat me nt, visit, pri or 
mai nte na nce me di cati o n (I C S vers us I C S/ L A B A), a n d treat me nt -b y -visit i nteracti o n as 
cate g oric al c o variates a n d baseli ne tr o u g h F E V 1, perce nt re versi bilit y, a n d baseli ne sc ore f or 
t he patie nt-re p orte d o utc o me i nstr u me nt as c o nti n u o us c o variates. C o ntrasts will be use d t o 
o btai n esti mates of t he tr eat me nt differe n ce b y visit f or meas ures assesse d at cli nic visits a n d 
o ver 1 2 Wee ks. T w o -si de d p-val ues a n d p oi nt esti mates wit h t w o -si de d 9 5 % CIs will be 
pr o d uce d f or t he treat me nt differe n ce.  T he strate gies f or ha n dli n g I C Es a n d missi n g data are 
si milar t o t he o nes use d f or perce nta ge of res p o n d ers i n A C Q-5 . 
Ast h ma E xacer bati o ns  
M o derate/se v ere ast h ma e xacer bati o ns a n d se v ere ast h ma e xacer bati o ns will eac h be a nal yze d 
se parat el y i n a si milar ma n ner as d escri b e d f or t h e sec o n dar y e n d p oi nt of rate of se v ere 
ast h ma e xacer bati o ns utilizi n g t he W hile o n Treat me nt  strate g y f or h a n dli n g I C Es base d o n 
data fr o m St u d y D 5 9 8 2 C 0 0 0 0 5 o nl y.  
Ti me t o first se vere ast h ma e xacer bati o n will be a nal yze d wit h a C o x re gressi o n m o del i n 
St u dies D 5 9 8 2 C 0 0 0 0 5 a n d D 5 9 8 2 C 0 0 0 0 6 se parat el y  a n d wit h t he p o ole d i n di vi d ual 
partici pa nt data fr o m b ot h st u dies ( D 5 9 8 2 C 0 0 0 0 6: B F F 3 2 0/ 9. 6  μ g, B F F 1 6 0/ 9. 6  μ g, 
B D  3 2 0  μ g a n d D 5 9 8 2 C 0 0 0 0 5: B F F 1 6 0/ 9. 6  μ g, B D 1 6 0  μ g treat me nt ar ms. T he S y m bic ort 
treat me nt ar m i n St u d y D 5 9 8 2 C 0 0 0 0 6 will n ot be i ncl u de d i n t he p o ole d a n al ysis.), utilizi n g 
t he W hile o n Treat me nt strate g y f or I C Es. T h e C o x re gressi o n m o del f or eac h st u d y will be 
a dj uste d f or se v ere ast h ma e xacer bati o n hist or y ( 0, ≥ 1), pri or mai nte na n ce me dicati o n 
(I C S vers us I C S/ L A B A), re gi o n, baseli ne tr o u g h F E V 1, a n d perce nt r e versi bilit y. F or t he 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 1  of 1 2 2  
 
p o ole d a nal ysis a C o x re gressi o n a d diti ve m o del will be use d w hic h will als o i ncl u de st u d y, 
a n d b u des o ni de ( 1 if t he b u des o ni de d ose is 3 2 0  μ g, a n d 0 if t he b u des o ni d e d ose is 1 6 0  μ g) 
a n d f or m oter ol ( 1 if t h e f or m oter ol d ose is 9. 6  μ g, a n d 0 if n o f or m oter ol d ose) i nstea d of 
treat me nt as c o v ariates. T he c o m paris o n of i nterest is t he f or m oter ol effect. Ti me t o  first 
se vere ast h ma e xacer bati o n is t he ti me fr o m t he first d ose of st u d y i nter ve nti o n t o t he ti me of 
o nset of t he first se vere ast h ma e xacer bati o n.  
Partici pa nts n ot ha vi n g a n y se v ere ast h ma e xacer bati o ns will be ce ns ore d at t he date of t heir  
last asth ma stat us assess me nt + 1  da y, last st u d y visit i n t he pla n ne d treat me nt p hase, or deat h .  
 
will be a nal yze d i n a ma n ner si milar t o t he a nal ysis of ti me t o first 
m o derate/se v ere ast h ma e xacer bati o n.  
 
 will be a nal yze d u p t o t he 
Wee k  1 2 visit wit h a C o x re gressi o n m o del t o c o m pare t he treat me nt gr o u ps, a dj usti n g f or 
se vere ast h ma e xacer bati o n hist or y ( 0, ≥ 1), pri or mai nte na nce me di cati o n (I C S vers us 
I C S/ L A B A), re gi o n, baseli ne tr o u gh F E V 1, a n d perce nt r e versi bilit y. A re d u ce d m o del or o nl y 
descri pti ve statistics will be prese nt e d if i ns uffici e nt e ve nts occ ur. Des cri pti ve statistics will 
i ncl u de t he n u m ber a n d p erce nt a ge of partici pa nts wit h a n e ve nt, n u m ber of e ve nts, a n n ualize d 
rate, a n d p ers o n years at ris k. Partici pa nts n ot ha vi n g a n y e ve nts will be ce ns ore d at t he dat e of 
t heir latest f oll o w-u p or e n d of st u d y visit. A d diti o nall y, u n der t he W hile o n Treat me nt 
esti ma n d, partici pa nts e x perie nci n g o ne  or m ore I C Es will  be ce ns ore d o n t he da y of t heir first 
I C E. 
 
e ve nt a n d t he rate of  
e ve nts will be a n al yze d i n a ma n n er 
si milar t o t he a nal ysis of m o derate or s e vere e x acer bati o ns. 
E Q -5 D  
T he E Q -5 D d ata will be sc ore d t o  calc ulate a n i n d e x sc ore b ase d u p o n p artici pa nts’ res p o nses 
t o t he 5 di me nsi o ns. T he V A S will be sc ore d fr o m 0 ( w orst i ma gi na ble healt h state) t hr o u g h 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 2  of 1 2 2  
 
1 0 0 ( best i ma gi na ble healt h state) t o re pres e nt t he partici pa nt’s self -re p ort c o ncer ni n g h o w b a d 
or h o w g o o d t heir healt h was d uri n g t hat da y. T he perce nt a ge of partici pa nt’s cate g orical 
res p o nses t o eac h of t he 5-di me nsi o ns will be s u m marize d f or t h e E Q -5 D -Y a n d E Q -5 D -5 L 
q uesti o n naires. Des cri pti ve statistics ( n u m ber, mea n, mea n c h a n ges fr o m baseli ne, S D, 
m i ni m u m, ma xi m u m) f or t he i n de x sc ore a n d V A S will be prese nte d b y treat me nt gr o u p a n d 
t y pe of q uesti o n naire. T h e i n de x a n d V A S sc ores at eac h p ost-ra n d o mizati o n visit a n d e n d of 
st u d y visit will be a nal yze d usi n g re peate d meas ures A N C O V A m o del wit h a ge a n d  b aseli ne 
sc ore as c o nti n u o us c o variates a n d re gi o n, ge n der, treat me nt, pri or mai nte n a nce tr eat me nt 
(I C S vs I C S/ L A B A), visit, a n d treat me nt-b y -visit as cate g orical c o variates.  
AI R Q  
T he AI R Q is a 1 0 -ite m q uesti o n naire wit h e q uall y wei g hte d yes/ n o res p o ns es. Greater val u es 
i n dicate a partici pa nt has less c o ntr ol. Perce nt a ge of c o ntr ol Well ( 0 t o 1), N ot Well ( 2 t o 4) 
a n d Ver y P o orl y ( 5 t o 1 0) will be prese nte d b y treat me nt gr o u p.  
9. 5. 2. 4  
1 2 -H o ur P F T S u b -St u d y   
Serial P F Ts will be c o n d ucte d o ver 1 2 h o urs i n a s u bset of partici pa nts at Visit  4 ( Da y  1) a n d 
Visit  7 ( Wee k  1 2).  
F E V 1 A U C 0 -1 2 at Da y 1 a n d Wee k  1 2  
T he F E V 1 A U C 0 -1 2 will be calc ul ate d usi n g t he tra pez oi dal r ule a n d tra nsf or me d i nt o a 
w ei g hte d a vera ge b y di vi di n g b y t he ti me i n h o urs fr o m d osi n g of t he last meas ure me nt 
i ncl u de d (t y picall y 1 2 h o urs). O nl y o ne n o n-missi n g p ost -d ose val ue is re q uire d f or t he 
calc ulati o n of A U C. A ct u al ti me fr o m d osi n g will be use d if a v aila ble; ot her wise, s c he d ul e d 
ti me will be use d. T he differe nce bet wee n treat me nt gr o u ps i n F E V1 A U C 0 -1 2 at Da y 1 a n d 
Wee k 1 2 will be e val uate d usi n g a re peate d meas ures A N C O V A m o del wit h baseli ne tr o u g h 
F E V 1 a n d perce nt r e versi bilit y as c o nti n u o us c o variates a n d treat me nt, a n d  pri or mai nte na nce 
me dicati o n (I C S vers us I C S/ L A B A) as a cate g orical c o variate. T w o -si de d p-val ues a n d p oi nt 
esti mates wit h t w o -si de d 9 5 % CIs will be pr o d uce d f or t he treat me nt differe nce.  
C ha n ge fr o m Baseli ne i n F E V 1 at Eac h Ti me p oi nt at Da y  1 a n d Wee k  1 2  
T he differe n ces bet w ee n treat me nt gr o u ps i n c ha n ge fr o m baseli ne i n F E V 1 at eac h ti me p oi nt 
at Da y 1 a n d Wee k  1 2 will be e val uate d usi n g a re peate d meas ures A N C O V A m o del. T he 
m o del will i ncl u de treat me nt, assess me nt ti me, pri or mai nte na nce me dicati o n (I C S vers us 
I C S/ L A B A), a n d treat me nt-b y -ti me i nteracti o n as cate g orical c o variates a n d baseli ne tr o u g h 
F E V 1 a n d perce nt r e versi bilit y as c o nti n u o us c o variates. C o ntrasts will be use d t o o btai n 
esti mates of t he treat me nt differe n ce at eac h ti me p oi nt. T w o -si de d p -val ues a n d p oi nt 
esti mates wit h t w o -si de d 9 5 % CIs will be pr o d uce d f or t he treat me nt differe nce.  
Serial S pir o metr y Para m eters I ncl u di n g F E V 1 A U C 0 -6, F E V1 A U C 6 -1 2, a n d Pea k F E V1  
F E V 1 A U C 0 -6 a n d F E V 1 A U C 6 -1 2 will be a nal yze d i n a ma n ner si milar t o t he a nal ysis of F E V 1 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 3  of 1 2 2  
 
A U C 0 -1 2. 
Pea k F E V 1 will be a nal y ze d usi n g a re peat e d meas ures A N C O V A m o d el wit h baseli ne tr o u g h 
F E V 1 a n d perce nt r e versi bilit y as c o nti n u o us c o variates a n d treat me nt, visit, treat me nt -b y -visit 
i nteracti o n, a n d pri or m ai nte na nce m e dicati o ns (I CS vers us I C S/ L A B A) as cate g orical 
c o variates.  
F V C, P E F, a n d F E F 2 5 -7 5 e val uate d usi n g A U C 0 -1 2  
F V C, P E F, a n d F E F 2 5 -7 5 e val uate d usi n g A U C 0 -1 2 will be a nal yze d i n a ma n ner si milar t o t he 
a nal ysis of F E V 1 A U C 0 -1 2. 
9. 5. 2. 5  
He alt hc are R es o urce Utiliz ati o n   
All H C R U e n d p oi nts will be s u m marize d f or mea n a n n ualize d rate or p erce nta ge b y treat me nt 
gr o u p. B ot h o verall a n d ast h ma -s pecific H C R U will be re p orte d. 
9. 5. 3  
S afet y   
All safet y s u m maries will be perf or m e d o n t he Safet y set. Partici pa nts will be a nal yze d 
acc or di n g t o t he act ual tr eat me nt recei ve d.  
9. 5. 3. 1  
A d verse E ve nts   
A d verse e ve nts d uri n g t h e Treat me nt Peri o d will b e s u m marize d b y t he n u m ber of partici p a nts 
e x perie n ci n g a n e v e nt. A d verse e v e nts will be ta b ulate d at t he le vel of t h e Me d D R A s y ste m 
or ga n class a n d preferre d ter m. T he versi o n of Me d D R A c urre nt at t he ti me of data bas e l oc k 
will be use d i n t he ta b ulati o ns a n d listi n gs. Ta b ulati o ns will be br o ke n d o w n b y i nte nsit y, 
seri o us ness, A Es le a di n g t o disc o nti n uati o n, a n d b y relati o ns hi p t o st u d y i nter ve nti o n. N o 
h y p ot hesis tests will be perf or me d. H o we v er, treat me nt gr o u ps will be c o m pare d as d etaile d i n 
t he S A P. A d verse e ve nts ass ociate d wit h use of I C S a n d L A B As will be prese nte d i n s u m mar y 
ta b ulati o ns i n t he C S R. T he selecti o n of Me d D R A ter ms pr o p ose d t o be use d i n t he 
assess me nt of t hese A Es will be descri be d i n t he S A P.  
9. 5. 3. 2  
Vit al Si g ns   
S u m mar y statistics ( mea n, me dia n, S D, a n d ra n g e) of c ha n g e fr o m b aseli ne will be  ta b ulate d 
b y vital si g n para meter a n d treat me nt f or eac h s c h e d ule d assess me nt ti me. F or vital si g ns, 
baseli ne will be defi n e d as t he last n o n -missi n g val ue pri or t o t he first d ose of ra n d o mized I P. 
I n a d diti o n, p ote ntiall y cli nicall y si g nifica nt val ues will be i de ntifie d a n d s u m marize d. 
9. 5. 3. 3  
Cli nic al L a b or at or y V al ues   
S u m mar y statistics ( mea n, me dia n, S D, a n d ra n g e) of c ha n g e fr o m b aseli ne val ues will be 
ta b ulate d f or eac h tr eat m e nt an d eac h assess me nt ti me. F or cli nical la b orat or y meas ure m e nts, 
baseli ne will be defi n e d as t he last a vaila ble val ue pri or t o ra n d o mizati o n. P ote ntiall y 
cli nicall y si g nifica nt val ues will be i de ntifie d a n d s u m marize d.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
9. 5. 4  
S u b gr o u p A n al yses   
A nal yses of t he pri mar y, sec o n dar y, a n d tertiar y e n d p oi nts ma y be perf or m e d b y vari o us 
s u b gr o u ps. A n y p ote ntial s u b gr o u p a nal yses will b e descri b e d f ull y i n t he S A P.  
9. 6  
I nteri m A n al yses  
N ot a p plica ble  
9. 7  
D at a M o nit ori n g C o m mittee   
A Data M o nit ori n g C o m mittee will n ot be use d i n t his st u d y . 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 5  of 1 2 2  
 
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S   

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 6  of 1 2 2  
 
A p pe n di x  A  Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns   
A  1  
Re g ul at or y a n d Et hic al C o nsi der ati o ns   
•  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he f oll o wi 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 nizati o ns of Me dical 
Scie nces I nter nati o nal Et hical G ui deli nes  
•  A p plica ble I C H G C P G ui deli nes  
•  A p plica ble la ws a n d re g ulati o ns  
•  
T he pr ot oc ol, re vis e d pr ot oc ol, I C 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 R B/I E C b y t he I n vesti gat or a n d re vie we d 
a n d a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d.  
•  
A n y re vise d pr ot o c ol will re q uire I R B/I E C a n d a p plica bl e Re g ulat or y A ut h orit y a p pr o val 
bef ore i m ple me nt ati o n of c ha n ges ma d e t o t he st u d y desi g n, e xce pt f or c ha n ges necess ar y 
t o eli mi nate a n i m me diate hazar d t o st u d y partici p a nts. 
•  
Astra Ze neca will be res p o nsi ble f or o btai ni n g t he re q uire d a ut h orizati 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 A ut h orit y. T his res p o nsi bilit y ma y be dele gate d t o a 
C o ntract Researc h Or g a nizati o n, b ut t he acc o u nta bilit y re mai ns wit h Astra Ze neca.  
•  
T he I n vesti gat or will be res p o nsi ble f or pr o vi di n g o versi g ht of t he c o n d uct o f t he st u d y at 
t he site a n d a d here nce t o re q uire me nts of 2 1 C F R, I C H g ui deli nes, t he I R B/I E C, 
E ur o pea n Re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), E ur o pea n Me dical 
De vice Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vi ce researc h (if a p plica ble), a n d a ll ot her 
a p plica ble l ocal re g ulati o ns  
 
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es  
•  
Pr o m pt n otificati o n b y t he I n vesti gat or t o Astra Ze neca of a n S A E is esse nti al s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of 
a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
•  
Astra Ze neca h as a le g al r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli n ical 
i n vesti gati o n. Astra Ze neca will c o m pl y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts 
relati n g t o safet y r e p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d I n vesti gat ors. 
•  
F or all st u dies e xce pt t h ose utilizi n g me dical de vices, I n vesti gat or s afet y r e p o rts m ust be 
pre pare d f or s us p ecte d u ne x pecte d s eri o us a d verse reacti o ns acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d S p o ns or p olic y a n d f or war de d t o I n v esti gat ors as necessar y. 
•  
A n I n vesti gat or w h o recei ves a n I n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A Es) fr o m Astra Ze n eca will 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 7  of 1 2 2  
 
re vie w a n d t h e n file it al o n g wit h t he I n v esti 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 uir e me nts. 
 
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us Bre ac hes  
•  
Pr o m pt n otificati o n b y t he I n vesti gat or t o Astra Ze neca of a n y ( p ote ntial) s eri o us breac h 
of t he pr ot oc ol or re g ulati o ns is esse ntial s o t hat le gal a n d et hical o bli gati o ns are met.  
•  A ‘seri o us breac h’ mea ns a breac h li kel y t o affect t o a si g nifica nt de gree t he safet y a n d 
ri g hts of a partici pa nt or t he relia bilit y a n d r o b ust n ess of t he data ge nerate d i n t he 
cli nical st u d y.  
•  
If a n y ( p ote ntial) seri o us breac h o cc urs i n t he c o urse of t he st u d y, I n vesti gat ors or ot her 
site pers o n nel will i nf or m t he a p pr o priate Astra Z e neca re prese ntati ves i m me diatel y after 
he or s he bec o mes a ware of it.  
•  
I n cert ai n re gi o ns/c o u ntri es, Astra Ze n eca has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal 
re g ulat or y a ut h orit y a n d ot her re g ulat or y a ge n cies a b o ut s uc h breac hes. 
•  Astra Ze neca will c o m pl y wit h c o u ntr y -s pecifi c re g ulat or y re q uire m e nts rel ati n g t o 
seri o us breac h re p orti n g t o t he re g ulat or y a ut h orit y I R B/I E C, a n d I n v esti gat ors. If E U 
Cli nical Trials Re g ulati o n 5 3 6/ 2 0 1 4 a p plies,  Astra Ze neca is re q uire d t o e nter details of 
seri o us breac hes i nt o t he E ur o pea n Me dici nes A ge nc y Cli nical Trial I nf or m ati o n 
S yste m. It is i m p orta nt t o n ote t hat re dacte d versi o ns of seri o us breac h re p orts will be 
a vaila ble t o t he p u blic vi a Cli nical Trial I nf or mati o n S yste m . 
•  
T he I n vesti gat or s h o ul d ha ve a pr ocess i n place t o e ns ure t hat:  
•  T he site staff or s er vice pr o vi ders dele gate d b y t he I n v esti gat or/I nstit uti o n are a ble t o 
i de ntif y t he occ urre nce of a ( p ote ntial) s eri o us breac h. 
•  
A ( p ote ntial) seri o us breac h is pr o m ptl y re p orte d t o Astra Ze neca or dele gate d part y, 
t hr o u g h t he c o ntacts ( e mail a d dress or tel e p h o ne n u m ber) pr o vi de d b y Astra Ze neca. 
 
A  2  
Fi n a nci al Discl os ure   
I n vesti gat ors a n d s u b-I n vesti gators will pr o vi de Astra Ze neca wit h s ufficie nt, acc urate 
fi na ncial i nf or mati o n as re q ueste d t o all o w Astra Z e neca 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 pri ate re g ul at or y a ut h orities. 
I n vesti gat ors are resp o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse 
of t he st u d y a n d f or o ne  year after c o m pleti o n of t he st u d y.  
A  3  
I nf or me d C o nse nt Pr ocess  
•  
T he I n vesti gat or  or his/ h er re prese nt ati ve will e x plai n t he nat ure of t h e st u d y t o t he 
partici pa nt or his/ her le g all y a ut h orize d re pres e nt ati ve a n d a ns w er all q uesti o ns re gar di n g 
t he st u d y. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 8  of 1 2 2  
 
•  
Partici pa nts m ust be i nf or me d t hat t heir partici p ati o n is v ol u ntar y, a n d t he y are free t o 
ref use t o partici pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me a n d f or a n y reas o n 
d uri n g t he st u d y. Partici pa nts or t heir le gall y a ut h orize d re pres e ntati ve will be re q uir e 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 uir e me nts of 2 1 C F R  5 0, l ocal 
re g ulati o ns, I C H g ui deli nes, Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
re q uire me nts, w h ere a p plica ble, a n d t he I R B/I E C or st u d y ce nter. 
•  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d 
bef ore t h e partici pa nt w as e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h ori ze d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.  
•  
Partici pa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
pa rtici pati o n i n t he st u d y. 
•  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y 
a ut h orize d re pres e ntati ve.  
 
A  4  
D at a Pr otecti o n   
•  
Partici pa nts will be a ssi g ne d a u ni q ue i de ntifier b y Astra Ze neca. A n y parti ci pa nt rec or ds 
or datasets t hat are tra nsferre d t o Astra Ze n eca will c o ntai n t he i de ntifier o nl y; partici pa nt 
na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be 
tra nsferre d. 
•  
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d d ata will be use d b y 
Astra Ze neca i n a cc or da n ce wit h l ocal data pr otecti o n la w. T he le vel of 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 partici p a nt i n t he i nf or me d c o nse nt  
•  
T he partici pa 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 orize d pers o n nel a p p oi nte d b y 
Astra Ze neca, b y a p pr o pri ate I R B/I E C me m b ers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut h orities.  
•  
T he partici pa nt m ust be i nf or me d t hat data will be c ollecte d o nl y f or t h e b usi ness nee ds. 
We will o nl y c ollect a n d use t he mi ni m u m a m o u nt of pers o nal d ata t o s u p p ort o ur 
b usi ness acti vities a n d will n ot ma ke pers o nal data a vaila ble t o a n y o n e ( i ncl u di n g i nter nal 
staff) w h o is n ot a ut h orize d or d oes n ot ha v e a b usi ness nee d t o k n o w t he i nf or mati o n.  
•  
T he partici pa nt m ust be i nf or me d t hat i n s o me cas es t heir data ma y b e pse u d o n y mize d. 
T he Ge neral D ata Pr otecti o n Re g ulati o n defi nes pse u d o n y mizati o n as t he pr ocessi n g of 
pers o nal data i n s uc h a w a y t hat t he pers o nal data ca n n o l o n ger b e attri b ute d t o a s pecific 
i n di vi d ual wit h o ut t he use of a d diti o nal i nf or mati o n, pr o vi de d t hat s uc h a d diti o nal 
i nf or mati o n is ke pt se paratel y a n d pr otecte d b y tec h nical a n d or g a nizati o n al meas ures t o 
e ns ure t hat t he p ers o nal d ata are n ot attri b ute d t o a n i de ntifie d or i de ntifia bl e nat ural 
pers o n.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
9 9  of 1 2 2  
 
Pers o n al D at a Bre ac hes  
A ‘ pers o n al data breac h’ mea ns a breac h of sec urit y lea di n g t o t he acci de ntal or u nla wf ul 
destr ucti o n, l oss, alterati o n, u na ut h orize d discl os ure of, or access t o, pers o nal data tra ns mitte d, 
st ore d or ot her wis e pr ocesse d. 
•  
I n c o m plia nce wit h a p pli ca ble la ws, t he Data C o ntr oller1 f or t he pro cessi n g acti vit y w here 
t he pers o nal dat a breac h occ urre d ( Astr a Ze n eca or res pecti vel y t he site), will n otif y t he 
data pr otecti o n a ut h orities wit h o ut u n d ue dela y wit hi n t he le gal ter ms pr o vi de d f or s uc h 
n otificati o n a n d wit hi n t he prescri be d f or m a n d c o nte nt.  
•  
W hile Astra Ze n eca has pr ocesses i n place t o deal wit h pers o nal data breac hes it is 
i m p orta nt t hat I n v esti gat ors t hat w or k wit h Astra Ze neca ha ve c o ntr ols i n place t o pr otect 
patie nt data pri vac y.  
T he I n vesti gat or s h o ul d ha ve a pr ocess i n place t o e ns ure  t hat: 
•  
all o w site staff or ser vice pr o vi ders dele gate d b y t he I n vesti gat or/i nstit uti o n t o i de ntif y t he 
occ urre nce of a ( p ote ntial) pers o nal data breac hes.  
•  
A n y ( p ote ntial) pers o n al data breac h is pr o m ptl y re p orte d t o Astra Z e neca or dele gate d 
part y, t hr o u g h t he c o nta cts (e mail a d dress or t ele p h o ne n u m ber) pr o vi de d b y 
Astra Ze neca.  
Astra Ze neca a n d t he site m ust de m o nstrate t hat t he y:  
•  
ha ve ta ke n all necess ar y ste ps t o a v oi d pers o nal d ata breac hes a n d  
•  
ha ve u n dert a ke n me as ures t o pre ve nt s uc h breac h es fr o m occ urr i n g i n t he first place a n d 
t o miti gate t he i m pact of occ urre d data breac hes (e g, a p pl yi n g e ncr y pti o n, mai ntai ni n g 
a n d kee pi n g s yste ms a n d I T s ec urit y meas ures u p -t o-date, re g ular re vie ws a n d testi n g, 
re g ular tr ai ni n g of e m pl o yees, a n d de v el o pe d sec urit y p olicies a n d sta n dar ds). 
•  
w here p ossi ble, h a ve de v el o pe d a n i nter nal data breac h re p orti n g a n d i n vesti gati o n 
pr ocess a n d i nter nal pr ot oc ols wit h g ui da nce o n h o w t o res p o n d s wiftl y a n d dili ge ntl y t o 
t he occ urre nce of a p ers o nal data breac h. 
 
 
 
 
 
1 T he d at a c o ntr oller  d et er mi nes t he p ur p oses  f or w hic h a n d t he me a ns b y w hic h pers o nal 
data are pr ocesse d, as d efi ne d b y t he E ur o pea n C o m missi o n  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 0  of 1 2 2  
 
•  
w here it has n ot be e n p ossi ble t o de vel o p a n i nter n al data breac h re p orti n g a n d 
i n vesti gati o n pr ocess, t he site f oll o ws Astra Ze neca’s i nstr ucti o ns. 
N otificati o n of pers o n al data breac h t o partici pa nts:  
•  
n otificati o n t o partici pa nts is d o ne b y t he site f or t he data breac h es t h at occ urre d wit hi n 
t he pr ocessi n g acti vities f or w hic h t he site is t he Data C o ntr oller a n d f or dat a breac hes 
occ urre d wit hi n t he pr ocessi n g acti vities of Astra Ze neca as t he Data C o ntr oller, t he 
n otificati o n is d o ne i n c olla b orati o n wit h t he site a n d is per f or me d b y t he site a n d/ or 
Pri nci pal I n v esti gat or, acti n g o n be half of Astra Z e neca, s o t hat Astra Ze n eca has n o access 
t o t he i de ntif yi n g pers o nal i nf or mati o n of t he partici pa nts. T he site a n d/ or Pri nci pal 
I n v esti gat or s hall c o n d uct t he n otificati o n b y c o ntacti n g t he partici pa nts usi n g t he 
i nf or mati o n t hat t he y ga v e f or c o m m u nicati o n p ur p oses i n cli nical researc h. 
•  
If a pers o nal data breac h occ urs i n a pr ocess or’s s yste ms, e n ga ge d b y Astra Ze neca, t he 
pr ocess or u n d er c o ntr act ual o bli gati o ns wit h Astra Ze neca pr o m ptl y a n d i n d ue c o urse 
after disc o v eri n g t he breac h n otifies Astra Ze n eca a n d pr o vi des f ull c o o perati o n wit h t he 
i n vesti gati o n. I n t hese cases, t o t he e xte nt Astra Z e neca is t he Data C o ntr oller f or t he 
pr ocessi n g acti vit y w here t he breac h occ urre d, it will be res p o nsi ble f or t he n otificati o n t o 
data pr otecti o n a ut h orities a n d, if a p plica ble, t o p artici pa nts. If t he pers o nal data breac h 
nee ds t o be n otifie d t o t h e partici pa nts, t he n otificati o n t o partici pa nts is d o ne i n 
c olla b orati o n wit h t he site a n d is per f or me d b y t he site a n d/ or Pri nci pal I n v esti gat or, 
acti n g o n be half of t he S p o ns or, s o t hat Astra Ze n eca h as n o access t o t he i de ntif yi n g 
pers o nal i nf or mati o n of t he partici pa nts.  
•  
If a pers o nal data breac h i n v ol vi n g a n Astra Ze neca's re prese ntati ve de vice (ie, St u d y 
M o nit or la pt o p), Astra Ze neca re prese ntati ve will pr o vi de Astra Z e neca wit h all of t he 
i nf or mati o n nee de d f or n otificati o n of t he breac h, wit h o ut discl osi n g data t hat all o ws 
Astra Ze neca dir ectl y or i n directl y t o i de ntif y t he partici pa nts. T he n otific ati o n will be 
d o ne b y Astra Z e neca s olel y wit h t he i nf or mati o n pr o vi de d b y t he St u d y M o nit or a n d i n 
n o e ve nt wit h access t o i nf or mati o n t hat c o ul d e nt ail a ris k of re -i de ntificati o n of t he 
partici pa nts. If t he d ata breac h m ust be n otifie d t o t he data partic i p a nts, t he n otificati o n 
will be d o ne directl y b y t he St u d y M o nit or i n c olla b orati o n wit h t he site a n d/ or Pri nci pal 
I n v esti gat or, acti n g o n be half of t he S p o ns or, s o t h at Astra Ze n eca h as n o access t o t he 
i de ntif yi n g pers o nal i nf or mati o n of t he partici pa nts. T he c o ntract bet wee n Astra Ze neca 
a n d t he St u d y M o nit or s hall e x pressl y s pecif y t h es e c o n diti o ns.  
•  
T he c o ntract bet wee n t he site a n d Astra Ze n eca f or perf or mi n g t he cli nical r esearc h 
i ncl u des t he pr o visi o ns a n d r ules re gar di n g w h o is res p o nsi ble f or c o-or di n ati n g a n d 
directi n g t he acti o ns i n relati o n t o t he breac h es a n d perf or mi n g t he ma n dat or y 
n otificati o ns t o a ut h orities a n d partici pa nts, w here a p plica ble.  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
A  5  
Disse mi n ati o n of Cli nic al St u d y D at a   
A n y res ults, b ot h tec h nic al a n d la y s u m maries f or t his trial, will be s u b mitte d t o E U C TI S 
wit hi n a year fr o m gl o bal E n d of Trial Date i n all partici pati n g c o u ntries, d ue t o sci e ntific 
reas o ns, as ot her statistical a nal ysis is n ot rele va nt. 
A descri pti o n of t his cli nical st u d y will be a vaila bl e o n 
htt p://astraze neca gr o u ptri als. 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 he st u d y res ults w he n t he y are a vaila ble. T he cli nical st u d y a n d/ or s u m mar y of 
st u d y res ults ma y als o be a vaila ble o n ot her we bsites acc or di n g t o t he re g ul ati o ns of t he 
c o u ntries i n w hic h t he st u d y is c o n d ucte d.  
A  6  
D at a Q u alit y Ass ur a nce   
•  
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n e C R F u nless tr a ns mitte d t o 
Astra Ze neca or desi g nee electr o nicall y (e g, la b orat or y data). T he I n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate an d c orrect b y electr o nicall y 
si g ni n g t he e C R F. 
•  
T he I n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce dat a) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e e C R F. 
•  
T he I n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulator y a g e 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.  
•  
M o nit ori n g details descri bi n g strate g y, i ncl u di n g defi niti o n of st u d y -critical data ite ms 
a n d pr ocess es (e g, ris k -b ase d i nitiati ves i n o perati o ns a n d q ualit y s uc h as Ris k 
Ma na ge me nt  a n d Miti gati o n Strate gies a n d A nal ytical Ris k -Base d M o nit ori n g), met h o ds, 
res p o nsi bilities, a n d re q uire me nts, i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, re m ote, or o n -site m o nit ori n g) are pr o vi de d i n t he 
M o nit ori n g Pla n . 
•  
Astra Ze neca or desi g nee is res p o nsi ble f or me dical o versi g ht t hr o u g h o ut t he c o n d uct of 
t he st u d y w hic h i ncl u des cli nical re vie ws of st u d y data i n acc or da n ce wit h t he c urre ntl y 
a p pr o ve d pr ot o c ol. M o nit ori n g details descri bi n g cli nical re vie ws of st u d y dat a fr o m a 
me dical pers p ecti ve are i ncl u de d i n m ore detail i n t he M o nit ori n g Pla n.  
•  
Astra Ze neca or desi g nee is res p o nsi ble f or t he dat a ma na ge m e 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 d ata.  
•  
Astra Ze neca ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals (e g, 
C o ntract Researc h Or g a nizati o ns).  
•  
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 as p er t he M o nit ori n g Pla n 
t o c o nfir m t hat data e ntere d i nt o t he e C R F b y a ut h orize d site pers o n nel are acc urate, 
c o m plete, a n d verifia bl e fr o m s o urce d o c u me nts; t hat t he safet y a n d ri g hts of partici pa nts 
are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d i n acc or da n ce wit h t he 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2 2  
 
c urre ntl y a p pr o ve d pr ot o c 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 uireme nts.  
•  
Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he I n vesti gat or f or a mi ni m u m of 2 5  years after arc hi vi n g or as 
re q uire d b y l oc al re g ulati o ns, acc or di n g t o t he Astra Ze n eca Gl o bal Rete nti o n an d 
Dis p osal Sc he d ule. N o rec or ds ma y be d estr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he 
writte n a p pr o val of Astra Ze neca. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or 
part y wit h o ut writte n n otificati o n t o Astra Ze n eca.  
A  7  
S o urce D oc u me nts   
•  
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he p artici pa nt a n d s u bsta ntiate 
t he i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he I n vesti gat or’s site. 
•  
Data e nter e d i n t he e C R F t hat are tr a nscri be d fr o m s o urce d oc u m e nts m ust be c o nsiste nt 
wit h t he s o urce d oc u m e nts or t he discre pa n cies m ust be e x plai ne d. T he I n vesti gat or ma y 
nee d t o re q u est pre vi o us me dical rec or ds or tr a nsfer rec or ds, de p e n di n g o n t he st u d y. 
Als o, c urre nt me dic al rec or ds m ust be a vaila ble.  
•  
Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n t he M o nit ori n g Pla n. 
 
A  8  
St u d y a n d Site St art a n d Cl os ure   
T he st u d y start date is t he date o n w hic h t h e cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts.  
T he first act of recr uit me nt is t he first site o pe n a n d will be t he st u d y start date.  
Astra Ze neca d esi g nee res er ves t he ri g ht t o cl ose t h e 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 o n of Astra Z e neca. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl os e d w he n all re q uire d d o c 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 d y site cl os ure visit has b ee n perf or m e d.  
T he I n vesti gat or ma y i nitiate st u d y site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y Astra Ze neca or I n vesti gat or ma y i ncl u de b ut 
are n ot li mite d t o:  
•  
Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, Astra Ze neca’s pr oce d ures, or G C P g ui deli nes  
•  
I n a de q uat e recr uit me nt of partici pa nts b y t he I n v esti gat or 
•  
Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, Astra Z e neca 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 o ntract Researc h 
Or ga niz ati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n 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 h e I n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt 
a n d s h o ul d ass ure a p pr o priate partici pa nt t hera p y a n d/ or f oll o w -u p . 
A  9  
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 pres e nte d at scie ntific meeti n gs. If t his is 
f oresee n, t he I n v esti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o Astra Ze neca 
bef ore s u b missi o n. T his all o ws Astra Ze n eca t o pr otect pr o prietar y i nf or mati o n a n d t o 
pr o vi de c o m me nts.  
•  
Astra Ze neca will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical p ractice, Astra Ze n eca will ge nerall y 
s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n 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 o -or di nati n g I n vesti gat or will be desi g nate d b y m ut ual a gree m e nt.  
•  
A ut h ors hi p will be deter mi ne d b y m ut ua l a gree m e nt a n d i n li ne wit h I nt er nati o nal 
C o m mittee of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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A p pe n di x  B  A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g   
B  1  
Defi niti o n of A d verse E ve nts   
A n A E is t he de v el o p me nt of a n y u nt o war d me di cal occ urre n ce i n a patie nt or cli nical st u d y 
partici pa nt a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m (f or e xa m ple na us ea, c hest pai n), or diseas e 
te m p orall y ass ociate d wit h t he use of a me di ci nal pr o d uct, w het her or n ot c o nsi dere d rel ate 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 -seri o us A Es a n d ca n i ncl u de a 
deteri orati o n of a pre -e xisti n g me dical occ urre nce. A n A E ma y occ ur at a n y ti me, i ncl u di n g 
r u n-i n or was h o ut peri o ds, e ve n if n o st u d y i nter v e nti o n has bee n a d mi nist ere d. 
B  2  
Defi niti o n of Seri o us A d verse E ve nts   
A seri o us a d verse e ve nt is a n A E o cc urri n g d u ri n g a n y st u d y p hase (ie, r u n-i n, treat me nt, 
was h o ut, f oll o w -u p), t hat f ulfils o ne or m ore of t h e 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 uires i n -partici pa nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
•  
Res u lts i n persiste nt or si g nifica nt disa bilit y or i nca pacit y.  
•  
Is a c o n ge nital a n o mal y or birt h defect 
•  
Is a n i m p orta nt me dical e ve nt t hat ma y je o par dize t he partici pa nt or ma y re q uire me dical 
treat me nt t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
 
A d verse E v e nts ( A Es) f or m ali g n a nt t u m ors  re p orte d d uri n g a st u d y s h o ul d ge nerall y be 
assesse d as Seri o us A Es . If n o ot her seri o us ness criteria a p pl y, t he ‘I m p ort a nt Me dical E ve nt’ 
criteri o n s h o ul d be use d. I n cert ai n sit uati o ns, h o we ver, me dical j u d g me nt o n a n i n di vi d ual 
e ve nt basis s h o ul d be a p plie d t o clarif y t hat t he mali g na nt t u m or e ve nt s h o ul d be assesse d a n d 
re p orte d as a n o n -seri o us A E. F or e xa m ple, if t he t u m or 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 o n d oes n ot c ha n ge tr eat me nt a n d/ or 
pr o g n osis of t he mali g na nt t u m or, t he A E ma y n ot f ulfill t he attri b utes f or b ei n g assesse d as 
seri o us, alt h o u g h re p orti n g of t he pr o gressi o n of t he mali g na nt t u m or as a n A E is vali d a n d 
s h o ul d occ ur. Als o, s o me t y pes of mali g na nt t u m ors, w hic h d o n ot s prea d re m otel y after a 
r o uti ne treat me nt t hat d o es n ot re q uire h os pitalizati o n, ma y be assesse d as n o n-seri o us; 
e xa m ples i n a d ults i ncl u de Sta ge 1 basal cell carci n o ma a n d S ta ge 1 A 1 cer vical ca n cer 
re m o ve d via c o n e bi o ps y. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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Life -t hre ate ni n g 
‘ Life-t hr eate ni n g’ mea ns t hat t he partici pa nt was at i m me diate ris k of deat h fr o m t he A E as it 
occ urre d, or it is s us pecte d t hat use or c o nti n ue d use of t he pr o d u ct w o ul d r es ult i n t he 
partici pa 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 v ere 
f or m it mi g ht ha ve ca use d deat h (e g, h e patitis t hat res ol ve d wit h o ut he patic fail ure). 
H os pit aliz ati o n  
O ut patie nt treat me nt i n a n E R 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 p as m, lar y n geal e de m a). H os pital a d missi o ns 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 nsi dere d A Es if t he ill ness or disease e xist e d bef ore t h e 
partici pa nt was e nr olle d i n t he st u d y, pr o vi de d t hat it di d n ot deteri orate i n a n u ne x pecte d wa y 
d uri n g t he st u d y.  
I m p ort a nt Me dic al E ve nt or Me dic al Tre at me nt 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her a case is seri o us i n 
sit uati o ns w here i m p orta nt me dical e ve nts ma y n ot be i m me diatel y life-t hreate ni n g or res ult i n 
deat h, h os pitalizati o n, disa bilit y, or i nca pacit y b ut ma y je o par dize t he partici pa nt or ma y 
re q uire me di cal treat me nt t o pre ve nt o ne or m or e o utc o mes liste d i n t he defi niti o n of seri o us. 
T hese s h o ul d us uall y be c o nsi dere d as seri o us.  
Si m pl y st o p pi n g t he s us pect dr u g d oes n ot mea n t hat it is a n i m p orta nt me dical e ve nt; me dical 
j u d g me nt m ust be use d. 
E xa m ples i ncl u de:  
•  
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 ol (aceta mi n o p he n) o ver d ose re q uiri n g treat me nt wit h 
N -acet ylc ystei ne  
•  
I nte nsi v e treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m 
•  
Bl o o d d yscras ias (e g, n e utr o pe nia or a n e 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 pitalizati o n  
•  
De vel o p me nt of dr u g d e pe n de nc y or dr u g a b us e  
 
I nte nsit y R ati n g Sc ale: 
•  
Mil d (a ware n ess of si g n or s y m pt o m, b ut easil y t olerate d)  
•  
M o derate ( dis c o mf ort s ufficie nt t o ca use i nterfere n ce wit h n or mal acti vities)  
•  
Se vere (i n ca pacitati n g, wit h i na bilit y t o perf or m n or mal acti vities)  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u ma rate - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d s e vere A Es. Se v erit y is a meas ure of 
i nte nsit y w hereas seri o 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 necess aril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or 
se veral h o urs m a y be c o nsi dere d se vere n a usea, b ut n ot a n S A E u nless it meets t he criteria 
s h o w n i n A p pe n di x B  2 . O n t he ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of 
disa bilit y ma y be c o nsi dere d a mil d str o ke b ut w o ul d be a n S A E w he n it satisfies t he criteria 
s h o w n i n A p pe n di x B  2 . 
B  3  
A G ui de t o I nter preti n g t he C a us alit y Q uesti o n   
W he n ma ki n g a n assess me nt of ca usalit y c o nsi der t he f oll o wi n g fact ors w he n deci di n g if t here 
is a ‘reas o n a ble p ossi bilit y’ t hat a n A E ma y ha ve b ee 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 p artici pa nt act u all y recei ve d t he s us pect 
dr u g? Di d t he A E o cc ur i n a reas o n a ble te m p or al r elati o ns hi p t o t he a d mi nistrati o n of t he 
s us pect dr u g? 
•  
C o nsiste nc y wit h k n o w n dr u g pr ofile. Was t he A E c o nsiste nt wit h t he pre vi o us 
k n o wle d ge of t he s us p ect dr u g ( p har mac ol o g y a n d t o xic ol o g y) or dr u gs of t he sa me 
p har mac ol o gical class? Or c o ul d t he A E b e a ntici pate d fr o m its p har mac ol o gical 
pr o pert ies? 
•  
De -c h alle n ge e x p erie n ce. Di d t he A E res ol ve or i m pr o ve o n st o p pi n g or re d uci n g t he d ose 
of t he s us pect dr u g ?  
•  
N o alter nati ve ca use. T h e A E ca n n ot be reas o n a bl y e x plai ne d b y a n ot her eti ol o g y s uc h as 
t he u n derl yi n g disease, ot her dr u gs, ot her h ost, or e nvir o n me ntal fact ors.  
•  
Re -c halle n g e e x perie nce. Di d t he A E re o cc ur if t h e s us pecte d dr u g was rei ntr o d uce d after 
ha vi n g bee n st o p pe d? Astra Ze neca w o ul d n ot n or mall y rec o m me n d or s u p p ort a re-
c halle n ge. 
•  
La b orat or y tests. A s p ecific la b orat or y i n v esti gati o n (if  perf or me d) has c o nfir me d t he 
relati o ns hi p. 
 
I n diffic ult cas es, 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 niz e d feat ure of o ver d ose of t h e dr u g? 
•  
Is t here a k n o w n mec h a nis m? 
 
Ca usalit y of ‘relate d’ is ma de if f oll o wi n g a re vie w of t he rel e v a nt data, t h ere is e vi de n ce f or a 
‘reas o n a ble p ossi bilit y’ of a ca us al relati o ns hi p f or t he i n di vi d ual case. T he e x pressi o n 
‘reas o n a ble p ossi bilit y’ of a ca us al relati o ns hi p is mea nt t o c o n ve y, i n ge neral, t hat t here are 
facts (e vi d e nce) or ar g u m e nts  t o s u g gest a ca usal r elati o ns hi p. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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T he ca us alit y assess me nt is perf or me d b ase d o n t h e a vaila ble data i ncl u di n g e n o u g h 
i nf or mati o n t o ma ke a n i nf or me d j u d g me nt. Wit h n o a vaila ble facts or ar g u me nts t o s u g gest a 
ca usal r elati o ns hi p, t he e ve nt(s) will be assess e d as ‘ n ot relate d’.  
Ca usal relati o ns hi p i n cases w here t he diseas e u n der st u d y has deteri orate d d ue t o lac k of 
effect s h o ul d be classifi e d as n o reas o n a ble p ossi bilit y.  
B  4  
Me dic ati o n Err or, Dr u g A b use, a n d Dr u g Mis use   
Me dic ati o n Err or  
F or t he p ur p oses of t his cli nical st u d y a me dicati o n err or is a n u ni nte n d e d fail ure or mista ke i n 
t he treat me nt pr ocess f or a n I M P or Astra Ze n eca NI M P t hat eit her ca uses har m t o t he 
partici pa nt or has t he p ot e ntial t o ca use har m t o t he partici pa nt.  
A me dicati o n err or is n ot lac k of efficac y of t h e dr u g, b ut rat her a h u m a n or pr ocess r elate d 
fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y site staff or p artici pa nt. 
Me dicati o n err o r i ncl u des sit uati o ns w here a n err or.  
•  
Occ urre d  
•  
Was i de ntifie d a n d t h e partici pa nt recei ve d t he dr u g  
•  
Di d n ot occ ur, b ut circ u msta nces were rec o g nize d t hat c o ul d ha ve le d t o a n err or  
 
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err or s: 
•  
Dr u g na me c o nf usi o n  
•  
Dis pe nsi n g err or, e g, me dicati o 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, e g, wr o n g r o ute or wr o n g site of a d mi nistrati o n  
•  
Dr u g n ot ta ke n as i n dicate d e g, ta blet di ss 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 u cte d e g, ke pt i n t he refri g erat or w h e n it s h o ul d be at r o o m 
te m perat ur e  
•  
Wr o n g partici p a nt recei v e d t he me dicati o n (e xcl u di n g I R T/ R T S M err ors)  
•  
Wr o n g dr u g a d mi nistere d t o p artici pa nt (e x cl u di n g I R T/ R T S M err ors)  
 
E xa m ples of e ve nts t hat d o n ot  re q uire re p orti n g as me dicati o n err ors i n cli nical st u dies: 
•  
Err ors r elate d t o or res ulti n g fr o m I R T/ R T S M –  i ncl u di n g t h ose w hic h lea d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot her w ise ha v e bee n a me dicati o n err or  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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•  
Partici pa nt acci d e 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 v er d ose ( will be ca pt ure d as a n o v er d ose)  
•  
Partici pa nt faile d t o ret ur n u n use d me dicati o n or e m pt y pac ka gi n g  
 
Me dicati o n err ors are n ot re gar de d as A Es, b ut A Es ma y occ ur as a c o ns e q u e nce of t h e 
me dicati o n err or.  
Dr u g A b use  
F or t he p ur p ose of t his st u d y, dr u g a b use is defi ne d as t he persiste nt or s p ora dic i nte nti o nal, 
n o n -t hera p e utic e xcessi ve use of I M P or Astra Ze n eca NI M P f or a percei ve d re war d or desir e d 
n o n -t hera p e utic effect. 
A n y e ve nts of dr u g a b use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ur e d a n d f or war d t o 
t he D E S usi n g t he Dr u g A b use Re p ort F or m. T his f or m s h o ul d be use d b ot h i n t he dr u g a b use 
ha p pe ne d i n a st u d y pa rtici pa nt or if t he dr u g a b us e i n v ol ves a pers o n n ot e nr olle d i n t he st u d y 
(s uc h as a relati ve of t h e st u d y partici pa nt). 
E xa m ples of dr u g a b us e i ncl u de, b ut are n ot li mite d t o:  
•  
T he dr u g is use d wit h t he i nte nt of getti n g a percei ve d re war d ( b y t h e st u d y p artici pa nt or 
a pers o n n ot e nr olle d i n t he st u d y)  
•  
T he dr u g i n t he f or m of a ta blet is cr us he d a n d i njecte d or s n orte d wit h t he i nte nt of 
getti n g hi g h.  
 
Dr u g Mis use  
Dr u g mis use is t he i nte nti o nal a n d i na p pr o priat e use ( b y a st u d y partici p a nt) of I M P or 
Astr a Ze neca NI M P f or m e dici nal p ur p oses o utsi de of t he a ut h orize d pr o d uct i nf or mati o n, or 
f or u na ut h orize d I M Ps or Astra Z e neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute . 
E ve nts of dr u g mis use, wit h or wit h o ut ass ociate d A Es, are t o be ca pt ur e d a n d f or war de d t o 
t he D E S usi n g t he Dr u g Mis use Re p ort F or m. T his f or m s h o ul d be use d b ot h if t he dr u g 
mis use ha p pe ne d i n a st u d y partici pa nt or if t he dr u g mis use re gar ds a pers o n n ot e nr olle d i n 
t he st u d y (s uc h as a relati ve of t he st u d y partici pa nt). 
E xa m ples of dr u g mis use i ncl u de, b ut are n ot li mite d t o:  
•  
T he dr u g is use d wit h t he i nte nti o n t o ca use a n effect i n a n ot her p ers o n  
•  
T he dr u g is s ol d t o ot her pe o ple f or recreati o nal p ur p oses  
•  
T he dr u g is use d t o facilitate assa ult i n a n ot her p ers o n  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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•  
T he dr u g is deli beratel y a d mi nistere d b y t he wr o n g r o ute  
•  
T he dr u g is s plit i n half beca use it is e asier t o s wall o w, w he n it is state d i n t he pr ot oc ol 
t hat it m ust be s wall o we d w h ole 
•  
O nl y half t he d ose is ta ke n beca use t h e st u d y parti ci pa nt feels t hat h e/s he is feeli n g better 
w he n n ot ta ki n g t he w h ol e d ose  
•  
S o me o ne w h o is n ot e nr olle d i n t he st u d y i nte nti o nall y ta kes t he dr u g  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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A p pe n di x  C  O pti o n al Ge n o mics I niti ati ve Rese arc h   
C  1  
Use/ A n al ysis of D N A a n d Bl o o d Deri v ati ves   
•  
Astra Ze neca i nte n ds t o c ollect a n d st ore D N A f or ge netic res earc h t o e x pl ore h o w ge n etic 
varia ti o ns ma y affect cli nical para m eters, ris k a n d pr o g n osis of diseases, a n d t he res p o nse 
t o me dicati o ns. T his ge netic researc h m a y lea d t o better u n dersta n di n g of diseases, better 
dia g n osis of diseases or ot her i m pr o ve me nts i n healt h care a n d t o t he dis c o v er y of ne w 
dia g n ostics, treat me nts, or me dicati o ns. T heref ore, w here l ocal re g ul ati o ns a n d I R B/I E C 
all o w, a bl o o d  sa m ple will be c ollecte d f or D N A a nal ysis fr o m c o nse nti n g partici pa nts.  
•  
T his o pti o nal ge netic res earc h m a y c o nsist of t he a nal ysis of t he str uct ure of t he 
partici pa nt´s D N A, ie, t he e ntire ge n o m e.  
•  
T he res ults of ge n etic a n al yses ma y be re p orte d i n a se parate st u d y s u m mar y.  
•  
Astra Ze neca will st ore t h e D N A sa m ples i n a s ec ure st ora ge s p ace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y.  
 
C  2  
M ulti -o m ics Rese arc h Pl a n a n d Pr oce d ures  
Selecti o n of M ulti -o mics Rese arc h P o p ul ati o n  
•  
All partici pa nts will be as ke d t o partici pate i n t his ge netic res earc h. Partici pati o n is 
v ol u ntar y a n d if a p artici pa nt decli nes t o partici pate t here will be n o pe n alt y or l oss of 
be nefit. T he p artici pa nt will n ot be e xcl u de d fr o m a n y as pect of t h e mai n st u d y.  
 
I ncl usi o n Criteri a 
F or i ncl usi o n i n t his ge netic researc h, partici pa nts m ust f ulfil l all of t he i ncl usi o n criteria 
descri be d i n t he mai n b o d y of t he C S P a n d pr o vi de i nf or me d c o ns e nt f or t h e Ge n o mics 
I nitiati ve sa m pli n g a n d a nal yses. 
E xcl usi o n Criteri a  
•  
E xcl usi o n fr o m t his ge netic researc h ma y be f or a n y of t he e xcl usi o n criteria s pecifie d  i n 
t he mai n st u d y or a n y of t he f oll o wi n g: 
•  Pre vi o us all o ge neic b o ne marr o w tra ns pl a nt  
•  N o n -le u k oc yte d e plete d w h ole bl o o d tra nsf usi o n i n 1 2 0 da ys of ge netic s a m ple 
c ollecti o n  
•  A d olesce nt partici pa nts ( 1 2 t o <  1 8 years of a ge) sa m ples will n ot be c ollecte d f or 
Ge n o mics I nitiati ve.  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1  of 1 2 2  
 
Wit h dr a w al of C o nse nt f or M ulti -o mics Rese a rc h  
•  
Partici pa nts ma y wit h dra w fr o m t his ge netic researc h at a n y ti me, i n de pe n d e nt of a n y 
decisi o n c o ncer ni n g parti ci pati o n i n ot her as pects of t he mai n st u d y. V ol u ntar y 
wit h dra wal will n ot  prej u dice f urt her treat me nt. Pr oce d ures f or wit h dr a wal are o utli ne d i n 
Secti o n 7. 2 . 
 
C ollecti o n of S a m ples f or M ulti -o mics Rese arc h  
•  
T he bl o o d sa m ple f or t his ge netic res earc h will be o btai ne d fr o m t he partici pa nts at 
Visit  4 after  ra n d o mizati o n. Alt h o u g h D N A is sta ble, earl y sa m ple c ollecti o n is preferre d 
t o a v oi d i ntr o d uci n g bias t hr o u g h e xcl u di n g partici pa nts w h o ma y wit h dra w d ue t o a n 
A E. If f or a n y  reas o n t he sa m ple is n ot dra w n at Visit 4,  it ma y be ta ke n at a n y visit u ntil 
t he last st u d y visit. O nl y o ne sa m ple s h o ul d be c ollecte d per partici pa nt f or ge netics 
d uri n g t he st u d y.  
 
C o di n g a n d St or a ge of D N A a n d M ulti -o mics S a m ples  
•  
T he pr ocesses a d o pte d  f or t he c o di n g a n d st ora g e of sa m ples f or g e netic a n al ysis are 
i m p orta nt t o mai ntai n partici pa nt c o nfi de ntialit y. Sa m ples will be st ore d f or a ma xi m u m 
of 1 5  years, fr o m t he dat e of last partici pa nt last visit, after w hic h t he y will be destr o ye d. 
D N A is a fi nite res o urce t hat is use d u p d uri n g a nal yses. Sa m ples will be st ore d a n d use d 
u ntil n o f urt her a nal yses are p ossi ble or t he m a xi m u m st ora ge ti me has bee n reac he d.  
•  
A n a d diti o nal sec o n d c o d e will be assi g ne d t o t he sa m ple eit her bef ore or at t he ti me of 
D N A e xtr acti o n re pla ci n g t he i nf or mati o n o n t he sa m ple t u be. T hereafter, t he sa m ple will 
be i de ntifia ble o nl y b y t he sec o n d, u ni q ue n u m ber. T his n u m ber is use d t o i de ntif y t he 
sa m ple a n d c orres p o n di n g data at t he Astra Ze neca a nal ysis la b orat ories, or at t he  
desi g nate d or ga ni zati o n. N o pers o nal det ails i de ntif yi n g t he i n di vi d ual will be a vaila ble t o 
a n y pers o n ( Astra Ze n eca e m pl o yee or desi g n ate d or ga nizati o ns w or ki n g wit h t he D N A).  
•  
T he li n k bet wee n t he p artici pa nt e nr oll me nt/ra n d o mizati o n c o de a n d t he s ec o n d n u m ber 
will be mai ntai ne d a n d st ore d i n a sec ure e n vir o n me nt, wit h restricte d access at 
Astra Ze neca or desi g nate d or ga nizati o ns. T he li n k will be use d t o i de ntif y t he rele va nt 
D N A sa m ples f or a nal ysis, facilitate c orrelati o n of ge n ot y pic res ults wit h cli ni cal data, 
all o w re g ulat or y a u dit, a n d per mit traci n g of sa m ples f or destr u cti o n i n t he case of 
wit h dra wal of c o nse nt.  
 
Et hic al a n d Re g ul at or y Re q uire me nts  
•  T he pri nci ples f or et hical a n d re g ulat or y re q uir e me nts f or t he st u d y, i ncl u di n g t his 
ge netics res earc h c o m p o ne nt, are o utli ne d i n A p pe n di x  A . 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2  of 1 2 2  
 
I nf or me d C o nse nt 
•  
T he ge n o mic a n d m ulti -o mics c o m p o ne nt of t his st u d y is o pti o nal, a n d t he partici pa nt 
ma y partici pate i n ot her c o m p o ne nts of t he mai n st u d y wit h o ut partici pati n g i n t his m ulti -
o mics c o m p o ne nt. T o partici pate i n t he ge netic c o m p o ne nt of t he st u d y t he partici pa nt 
m ust si g n a n d date b ot h t he c o nse nt f or m f or t he mai n st u d y a n d t he O pti o nal Ge n o mics 
I nitiati ve Researc h I nf or mati o n a n d C o nse nt F or m. C o pies of b ot h si g ne d a n d date d 
c o nse nt f or ms m ust be gi ve n t o t he partici pa nt a n d t he ori gi nal file d at t he st u d y ce nter. 
T he Pri nci pal I n vesti gat or(s) is res p o nsi ble f or e ns uri n g t hat c o nse nt is gi ve n freel y, a n d 
t hat t he partici pa nt u n dersta n ds t hat t he y ma y freel y wit h dra wal fr o m t he g e netic as pect 
of t he st u d y at a n y ti me.  
 
P artici p a nt D at a Pr otecti o n  
•  
Astra Ze neca will n ot pr o vi de i n di vi d ual ge n ot y pe res ults t o partici pa nts, a n y i ns ura nce 
c o m pa n y, a n y e m pl o yer, t heir fa mil y me m bers, ge neral p h ysicia n u nless re q uire d t o d o s o 
b y la w.  
•  
E xtra preca uti o ns are ta k e n t o preser ve c o nfi de ntialit y a n d pre ve nt ge netic data bei n g 
li n ke d t o t he i de ntit y of t he partici pa nt. I n e xce pti o nal circ u msta nces, h o w e ver, certai n 
i n di vi d uals mi g ht see b ot h t he ge netic data a n d t he pers o nal i de ntifiers of a partici pa nt. 
F or e x a m ple, i n t he cas e of a me dical e mer ge n c y, a n Astra Ze n eca P h ysicia n or a n 
I n v esti gat or mi g ht k n o w a partici pa nt’s i de ntit y a n d als o ha ve access t o his or her ge n etic 
data. Re g ulat or y a ut h orities ma y re q uire access t o t he rele va nt files, t h o u g h t he 
partici pa nt’s me dical i nf or mati o n a n d t he ge netic files w o ul d re mai n p h ysi call y se parate.  
 
D at a m a n a ge me nt  
•  
A n y ge netic dat a ge nerat e d i n t his st u d y will be st ore d at a s ec ure s yste m at Astra Ze neca 
a n d/ or desi g nate d or ga ni zati o ns t o a nal yze t h e sa m ples.  
•  
Astra Ze neca a n d its desi g nate d or ga nizati o ns ma y s hare s u m mar y res ults (s uc h as ge n etic 
differe n ces fr o m gr o u ps of i n di vi d ual s wit h a disease) fr o m t his ge n o mics researc h wit h 
ot her researc hers, s uc h as h os pitals, aca de mic or ga nizati o ns, or healt h i ns ura nce 
c o m pa nies. T his ca n b e d o ne b y placi n g t he res ults i n scie ntific data bas es, w here t he y ca n 
be c o m bi ne d wit h t he res ults of si milar st u dies t o lear n e v e n m ore a b o ut healt h a n d 
disease. T he researc h ers ca n o nl y use t his i nf or mati o n f or healt h -relate d res earc h 
p ur p oses. Researc hers ma y see s u m mar y res ults, b ut t he y will n ot be a ble t o see 
i n di vi d ual partici pa nt data or a n y pers o nal i de ntifi ers.  
•  
S o me or all of t he cli nical datasets fr o m t he mai n st u d y ma y be mer ge d wit h t he m ulti -
o mics data i n a s uita ble s ec ure e n vir o n me nt se p arate fr o m t he cli nical data base.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 3  of 1 2 2  
 
A p pe n di x  D  Pr ot oc ol A me n d me nt Hist or y   
T he S u m mar y of C ha n ge Ta ble f or t h e c urre nt a m e n d me nt is l ocate d directl y bef ore t he Ta ble 
of C o nte nts.  
D  1  
A me n d me nt 3 ( 0 5 Dec 2 0 2 3)   
C S P Versi o n 3. 0 : 0 5-Dec -2 0 2 3  
T his 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 criteri a set f ort h i n Article 1 0(a) 
of Directi ve 2 0 0 1/ 2 0/ E D 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 
a n d i n t he E U Cli nical Trial Re g ulati o n Article 2, 2 ( 1 3) . 
O ver all R ati o n ale f or t he M o dific ati o n:  
A n a me n d me nt was re q uire d t o u p date statistical met h o d ol o g y, i ncl u di n g c ha n ges t o 
esti ma n ds, t he Ty pe 1 err or c o ntr ol pr oce d ure, c o v ariates i n t he a n al ysis m o dels, a n d a nal ysis 
sets a n d t o a d d u p date d w or di n g fr o m t he ne w Astra Ze neca pr ot o c ol sta n d ar d te m plate. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 4  of 1 2 2  
 
S u m m ar y of C h a n ges:  
List of S u bst a nti al M o dific ati o ns  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1  S y n o psis, 3  O bjecti ves 
a n d E n d p oi nts, 9. 1  Statistical 
H y p ot heses, 9. 2   A nal ysis 
Met h o ds f or Esti ma n ds, 
9. 2. 1. 1  
A p pr oac h, 
9. 5. 2. 1   Pri mar y E n d p oi nts, 
9. 5. 2. 2  Sec o n dar y 
E n d p oi nt(s)  
T he T y pe I err or c o ntr ol pr oce d ure 
f or t he  
 has bee n u p date d t o: 
•  
Reflect t he use of Treat me nt 
P olic y as t he pri mar y I C E 
strate g y acr oss re gistrati o nal 
en d p oi nts f or t he  
. T he 
W hile o n Treat me nt a p pr oac h 
a n d C o m p osite a p pr oac h are 
n o l o n ger pla n ne d t o be 
c o n d ucte d o n re gistrati o nal 
e n d p oi nts f or t he  
 
s u b missi o n. 
•  
I ncl u de t he a nal ysis of se vere 
ast h ma e xacer bati o n rate i n 
t he p o ole d D 5 9 8 2 C 0 0 0 0 6 a n d 
D 5 9 8 2 C 0 0 0 0 5 data as well as 
i n t he i n di vi d ual st u dies as 
sec o n dar y a nal yses. 
I nf or mati o n o n p o wer esti mates 
base d o n a nal yses u n der t he W hile 
o n Treat me nt strate g y f or ha n dli n g 
I C Es at Wee k 1 2 has bee n 
re m o ve d. 
1. 1  S y n o psis, 3  O bjecti ves 
a n d E n d p oi nts, 
9. 5. 2. 2  Sec o n dar y 
E n d p oi nt(s)  
T he p o p ulati o n s u m mar y meas ure 
f or t he test of o nset of acti o n o n 
Da y  1 has bee n c ha n ge d t o 
“ differe nce i n mea n c ha n ge fr o m 
baseli ne” a n d will n o l o n ger be 
perf or me d as a wit hi n -gr o u p test 
b ut will c o m pare t he B F F M DI 
1 6 0/ 9. 6  μ g relati ve t o B D M DI 
1 6 0  μ g i n t he m ulti ple testi n g 
pr oce d ure. T he wit hi n -gr o u p test 
was ke pt as a 
s u p p orti ve/e x pl orat or y a nal ysis. 
T o all o w assess me nt of t he relati ve 
perf or ma nce of B F F M DI 1 6 0/ 9. 6  μ g 
c o m pare d wit h B D M DI 1 6 0  μ g ar m.  
 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 5  of 1 2 2  
 
List of N o n -S u bst a nti al M o dific ati o ns  
Secti o n # a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
List of A b bre viati o ns  
T he List of A b bre viati o ns has 
bee n m o ve d fr o m A p pe n di x D t o 
t he be gi n ni n g of t he pr ot oc ol a n d 
defi niti o ns ha ve bee n re m o ve d 
fr o m t he b o d y of t he d oc u me nt.  
T o matc h u p date d Pr ot oc ol Sta n dar d 
te m plate. 
1. 1  S y n o psis  
Details of sa m ple size fr o m t he 
mai n b o d y of t he pr ot oc ol ha ve 
bee n i ncl u de d i n t he S y n o psis.  
T o pr o vi de clarit y.  
1. 1  S y n o psis, 3  O bjecti ves 
a n d E n d p oi nts 
A d diti o nal details a d de d o n t he  
ha n dli n g of eac h I C E wit h eac h 
esti ma n d wit hi n t he O bjecti ves 
a n d E n d p oi nts Ta ble.  
Pr o vi di n g clarit y o n esti ma n ds strate g y.  
1. 1  S y n o psis, 3  O bjecti ves 
a n d E n d p oi nts, 9. 2  A nal ysis 
Met h o ds f or Esti ma n ds  
T he Attri b uta ble esti ma n d f or 
I C Es a p pr oac h was re m o ve d.  
Attri b uta ble esti ma n d re m o ve d t o 
si m plif y t he n u m ber of esti ma n ds use d 
as s u p p orti ve t hat w o ul d be re p orte d i n 
t he C S R.  
1. 1   S y n o psis, 9. 4  P o p ulati o ns 
a n d A nal yses, 
9. 5. 1. 1  De m o gra p hics a n d 
Baseli ne C haracteristics, 
9. 5. 2. 2  Sec o n dar y 
E n d p oi nt(s)  
Resc ue Al b uter ol Use set was 
re m o ve d. 
W o ul d pr o vi de i ns ufficie nt sa m ple size 
f or c o n d ucti n g t hat a nal ysis. 
1. 3  Sc he d ule of Acti vities  
F o ot n ote “ d” a d de d stati n g I C F 
c o ul d be si g ne d at or bef ore 
Visit  1.  
T o pr o vi de clarit y.  
1. 3  Sc he d ule of Acti vities  
N ote a d de d t o f o ot n ote “e” 
all o wi n g f or resc he d uli n g of 
Visit  1 if t here are c o ncer ns t hat 
I C S/ L A B A was n ot wit hhel d.  
T o pr o vi de clarit y.  
1. 3 Sc he d ule of Acti vities  
N ote a d de d t o f o ot n ote “j” t hat 
s pir o metr y s h o ul d be p ost p o ne d if 
partici pa nt has n ot was he d -o ut of 
ast h ma me dicati o ns.  
T o pr o vi de clarit y.  
3  O bjecti ves a n d E n d p oi nts, 
Ta ble  4  
Ta ble  4 Strate gies f or I n terc urre nt 
E ve nts re m o ve d.  
Details fr o m Ta ble  4 are n o w i ncl u de d 
i n Ta ble 3.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 6  of 1 2 2  
 
3  O bjecti ves a n d E n d p oi nts, 
9. 5. 2. 3  Tertiar y/ E x pl orat or y 
E n d p oi nt(s)  
A n a nal ysis o n t he rate of 
m o derate/se vere ast h ma 
e x acer bati o ns utilizi n g t he 
Treat me nt P olic y esti ma n d was 
a d de d as a n e x pl orat or y a nal ysis.  
A n a n al ysis of ti me t o first se vere 
ast h ma e xacer bati o n i n t he 
c o m bi ne d D 5 9 8 2 C 0 0 0 0 6 a n d 
D 5 9 8 2 C 0 0 0 0 5 data utilizi n g t he 
Treat me nt P olic y strate g y f or 
I C Es has bee n a d de d as a n 
e x pl orat or y a nal ysis.  
T o s u p p ort a nal ysis o n se vere 
e xacer bati o n rate, i ncl u de d i n t he 
m ulti plicit y strate g y f or 
 
4. 1  O verall Desi g n, 
5. 1   I ncl usi o n Criteria, 
8. 1. 1. 2   I n-Cli nic S pir o metr y 
Sc he d ule 8. 1. 1. 3  Re versi bilit y 
t o Al b uter ol 
Re v ersi bilit y testi n g w or di n g 
m o difie d.  
W or di n g t hr o u g h o ut pr ot oc ol m o difie d 
t o matc h t he i ncl usi o n criteri o n. 
5. 1  I ncl usi o n Criteria, 
6. 1. 2  Me dical De vices 
I ncl u di n g C o m bi nati o n 
Pr o d ucts wit h De vice 
C o nstit ue nts, 
8. 3. 1 1  Me dicati o n Err or, 
Dr u g A b use, a n d Dr u g 
Mis use, 8. 3. 1 2  De vice 
C o nstit ue nt Deficie n cies, 
8. 7  O pti o nal Ge n o mics 
I nitiati ve Sa m ple, 
A 1  Re g ulat or y a n d Et hical 
C o nsi derati o ns, A 4  Data 
Pr otecti o n, A 5  Disse mi nati o n 
of Cli nical St u d y Data, 
A 6  Data Q ualit y Ass ura nce, 
B 4  Me dicati o n Err or, Dr u g 
A b use, a n d Dr u g Mis use, 
A p pe n di x C  O pti o nal 
Ge n o mics I nitia ti ve Researc h 
U p date d Astra Ze neca sta n dar d 
pr ot oc ol te m plate w or di n g a d de d.  
Pr ot oc ol sta n dar d te m plate was rece ntl y 
u p date d a n d re q uire d w or di n g has bee n 
a d de d t o t his pr ot oc ol.  
5. 2  E xcl usi o n Criteria  
W or di n g a d de d t o E xcl usi o n 
Criteri o n # 8 t o i de ntif y e x act 
st u dies w here pre vi o us or c urre nt 
i ncl usi o n is pr o hi bite d. 
T o pr o vi de clarit y.  
6. 5. 2  Pri or Me dicati o ns, 
Ta ble  6  
F or m o metas o ne f ur oate, t he 
s pecific d ose was re m o ve d, a n d a 
state me nt a d de d t o disc uss wit h 
st u d y p h ysicia n. 
T o ali g n wit h GI N A 2 0 2 2 a n d 
c o m ple xities ar o u n d differe nt d oses 
acr oss f or m ulati o ns.  
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F o r m oter ol F u marate - D 5 9 8 2 C 0 0 0 0 5  
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 7  of 1 2 2  
 
6. 5. 4  Pr o hi bite d Me dicati o n, 
Ta ble  8  
Decrease d cessati o n peri o d f or 
L A M As t o 1 2 wee ks.  
A me n de d t o alle viate c o nstrai nts o n 
st u d y recr uit me nt. 
9. 5. 2. 2  Sec o n dar y 
E n d p oi nt(s)  
It was clarifie d t hat data will n ot 
be i m p ute d f or t he a nal yses of t he 
pri mar y e n d p oi nt a n d t hat 
se nsiti vit y a nal yses e x pl ori n g t he 
r o b ust ness of res ults d ue t o 
missi n g data will be c o n d ucte d.  
T o pr o vi de clarit y. A d diti o nal details 
will be pr o vi de d i n t he S A P.  
9 . 5. 2. 2 Sec o n dar y 
E n d p oi nt(s), 
9. 5. 2. 3  Tertiar y/ E x pl orat or y 
E n d p oi nts  
It h as bee n clarifie d t hat t he 
e n d p oi nts of o nset of acti o n a n d 
perce nta ge of pea k F E V 1 
i m pr o ve me nt ac hie ve d are base d 
o n data 5 mi n utes p ost -d ose o n 
Da y  1.  
T o pr o vi de clarit y.  
9. 5. 2. 3  Tertiar y/ E x pl orat or y 
E n d p oi nts  
It was clarifie d t hat t he E Q-5 D 
i n de x sc ore will be a nal yze d usi n g 
re p eate d meas ures A N C O V A 
m o del si milar t o t he V A S sc ore.  
T o pr o vi de clarit y.  
9. 5. 2. 3  Tertiar y/ E x pl orat or y 
E n d p oi nts  
T he c o variate “se vere ast h ma 
e x ac er bati o n hist or y ( 0, ≥ 1)” has 
bee n a d de d t o t he a nal ysis of t he 
perce nta ges of resc ue -free da ys 
a n d s y m pt o m -free da ys. 
C o nsiste nc y of c o variates acr oss 
a nal yses. C o variate of se vere ast h ma 
e xacer bati o n hist or y is cli nicall y 
rele v a nt. 
T hr o u g h o ut  
Mi n or e di t orial a n d d oc u me nt 
f or matti n g re visi o ns. 
Mi n or, t heref ore, ha ve n ot bee n 
s u m marize d. 
 
D  2  
A me n d me nt 2  ( 1 3 Oct 2 0 2 2)  
C S P Versi o n 2. 0: 1 3 -Oct -2 0 2 2  
I nter nal d oc u m e nt wit h c ha n ges ma de pri or t o C T A s u b missi o ns.  
O ver all R ati o n ale f or t he M o dific ati o n:  
H o me -c oac he d s pir o metr y re m o ve d fr o m st u d y t o re d uce p artici pa nt a n d cli nical st u d y site 
b ur de n as w ell as re d u ce t he st u d y o perati o nal c o m ple xit y; clarificati o ns/a d diti o ns t o t he 
statistical a nal ysis; a n d re q uire d w or di n g fr o m t he u p date d Astra Z e neca pr ot oc ol sta n dar d 
te m plate a d de d. 
S u m m ar y of C h a n ge s: 
Secti o n N u m ber 
a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 1 S y n o psis, 1. 2 
Sc he ma, 1. 3 
Re m o val of h o me -c oac he d s pir o metr y s u b -
st u d y. 
T he h o me -c oac he d s pir o metr y s u b -st u d y, t he 
a nal ysis o f w hic h was e x pl orat or y, was 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 8  of 1 2 2  
 
Secti o n N u m ber 
a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Sc he d ule of 
Acti vities, 3 
O bjecti v es a n d 
E n d p oi nts, 4. 1 
O verall Desi g n, 
8. 1. 1. 4 H o me -
c o ac he d S pir o metr y 
Assess me nts f or 
S u b -St u d y, 9. 5. 1. 3 
Baseli ne, 9. 5. 2. 5 
H o me -c o ac he d 
S pir o metr y S u b -
St u d y  
re m o ve d t o re d uce partici pa nt a n d cli nical st u d y 
site b ur de n as well as re d uce t he st u d y 
o perati o nal c o m ple xit y.  
1. 1 S y n o psis, 
9. 5. 2. 1 Pri mar y 
E n d p oi nt(s), 9. 5. 2. 2 
Sec o n dar y 
E n d p oi nt(s), 9. 5. 2. 3 
Tertiar y/ E x pl orat or y 
E n d p oi nt(s), 9. 5. 2. 4 
1 2 -H o ur P F T S u b -
St u d y  
Details of c o variates u p date d:  
 
Baseli ne tr o u g h F E V 1 a n d 
perce nt al b uter ol re versi bilit y 
a d de d t o all a nal yses.  
 
Se vere ast h ma e xacer bati o n 
hist or y ( 0, ≥ 1) a d de d as a 
c o variate t o t he a nal ysis of 
c h a n ge fr o m baseli ne i n t he 
mea n n u m ber of p uffs of resc ue 
me dicati o n use a n d ti me t o first 
CI D.  
 
P ost -al b uter ol F E V 1 perce nt 
pre dicte d is n o l o n ger use d as a 
c o variate i n a n y a nal ysis.  
C o nsiste nc y of c o variates acr oss a n al yses. 
C o variates are d ee me d cli nicall y rele v a nt t o t he 
res pecti ve e n d p oi nts of i nterest a n d ha ve bee n 
u p date d acc or di n gl y.  
1. 1 S y n o psis, 9. 2 
A nal ysis Met h o ds 
of Esti ma n ds, 9. 4 
P o p ulati o ns f or 
A nal ysis, 9. 5. 1. 1 
De m o gra p hics a n d 
Baseli ne 
C haracteristics, 
9. 5. 2. 1 Pri mar y 
E n d p oi nt (s), 9. 5. 2. 2 
Sec o n dar y 
E n d p oi nt(s)  
I nte nt-t o-Treat P o p ulati o n was re place d 
wit h Efficac y P o p ulati o n;  
m o difie d I nte nt -t o-Treat P o p ulati o n was 
re m o ve d; 
Ra n d o mize d a n d Resc ue Al b uter ol Use 
P o p ulati o ns were a d de d;  
“ A n al ysis set” was c ha n ge d t o “a nal ysis 
p o p ula ti o n” 
T o a v oi d a n y c o nf usi o n wit h a nal ysis sets a n d 
a nal ysis p o p ulati o ns, t he refere nce t o sets was 
re m o ve d fr o m t his secti o n as it refers t o a n al ysis 
p o p ulati o ns. T he ter ms “I nte nt -t o-Treat a nal ysis 
set” a n d m o difie d I nte nt-t o-Treat a nal ysis set” 
were re p lace d wit h “ Efficac y P o p ulati o n” t o be 
better ali g ne d wit h t he esti ma n d fra me w or k.  
T he Resc ue Al b uter ol Use P o p ulati o n was 
a d de d f or c o n d ucti n g t he a nal ysis o n resc ue 
me dicati o n use as t his p o p ulati o n is m ore 
a p pr o priate t o i de ntif y treat me nt effects o n 
resc ue me dicati o n use. 
Ra n d o mize d P o p ulati o n defi ne d f or clarit y.  
1. 1 S y n o psis, 
9. 5. 2. 1 Pri mar y 
E n d p oi nt(s), 9. 5. 2. 2 
Sec o n dar y 
E n d p oi nt(s), 9. 5. 2. 3 
Tertiar y/ E x pl orat or y 
Clarifie d t hat t he m o del f or a nal ysis of 
re p eate dl y meas ure d c o nti n u o us varia bles 
is “re p eate d meas ures a nal ysis of 
c o varia nce” ( A N C O V A).  
M o del i ncl u des b ot h c o nti n u o us a n d cate g orical 
pre dict or varia bles.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 9  of 1 2 2  
 
Secti o n N u m ber 
a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
E n d p oi nt(s), 9. 5. 2. 4 
1 2 -H o ur P F T S u b -
St u d y  
1. 1 S y n o psis, 
3  O bjecti ves a n d 
E n d p oi nts, 
9. 2  A nal ysis 
Met h o ds f or 
Esti ma n ds, 9. 5. 2. 1 
Pri m ar y E n d p oi nts 
H y bri d esti ma n d was a d de d as a 
s u p ple me ntal esti ma n d f or pri mar y a n d 
sec o n dar y e n d p oi nts a n d Attri b uta ble 
esti ma n d is c o nsi dere d e x pl orat or y f or 
; 
W hile -o n -Treat me nt esti ma n d (as defi ne d 
f or efficac y) is n o l o n ger use d as t he 
strate g y for Safet y  
T he H y bri d esti ma n d is dee me d t o a ns wer a n 
i m p orta nt cli nical q uesti o n of i nterest, w here 
o utc o mes f oll o wi n g a n o n -attri b uta ble I C E will 
use a Treat me nt P olic y strate g y a n d o utc o mes 
f oll o wi n g a n attri b uta ble I C E will be c o nsi dere d 
a n u nfa v ora ble o utc o me.  
F or Safet y, t he o nl y I C E of i nterest is 
disc o nti n uati o n of st u d y i nter ve nti o n. 
M ore o ver, data f oll o wi n g t his I C E is als o of 
i nterest f or s o me a nal yses. T h ose a n al yses are 
t heref ore defi ne d o utsi de of t he esti ma n d 
fra me w or k s pecifie d f or t he Efficac y a n al ysis. 
3 O bjecti ves a n d 
E n d p oi nts  
E x pa n de d defi niti o ns of I C E t o i m pr o ve 
clarit y ar o u n d pr ol o n ge d e x p os ure t o 
c ortic oster oi ds.  
I ncl u de a n a d diti o nal I C E: “ Ot her I C Es 
t h o u g ht t o i m pact efficac y”. 
A d diti o nal details a d de d o n t he ha n dli n g of 
eac h I C E w it h eac h esti ma n d. 
Pr o vi di n g clarit y o n esti ma n ds strate g y.  
3 O bjecti ves a n d 
E n d p oi nts  
T he e n d p oi nt of ti me f or t he partici pa nt t o 
first p ercei ve t he me dicati o n is w or ki n g 
re m o ve d fr o m O bjecti ves a n d E n d p oi nts 
ta ble 
Data is n ot c ollecte d i n st u d y, s o u na b le t o 
a nal yses e n d p oi nt.  
4. 5 E n d of St u d y 
Defi niti o n, 8. 3. 1 1 
Me dicati o n Err or, 
Dr u g A b use, a n d 
Dr u g Mis use, 8. 3. 1 2 
De vice C o nstit ue nt 
Deficie n cies, A 1 
Re g ulat or y a n d 
Et hical 
C o nsi derati o ns, B 4 
Me dicati o n Err or, 
Dr u g A b use, a n d 
Dr u g Mis use  
U p date d Astra Ze neca pr ot oc ol te m plate 
w or di n g a d de d.  
Pr ot oc ol sta n dar d te m plate was rece ntl y u p date d 
a n d re q uire d w or di n g has bee n a d de d t o t his 
pr ot oc ol  
6. 5. 4 Pr o hi bite d 
Me dicati o n, Ta ble 8  
Re m o ve d refere nce t o i ntra oc ular 
c ortic oster oi ds a n d decrease d cessati o n  
peri o d f or i nfecta ble s yste mic 
c ortic oster oi ds t o 3 m o nt hs.  
A me n de d t o alle viate c o nstrai nts o n st u d y 
recr uit me nt. 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 0  of 1 2 2  
 
Secti o n N u m ber 
a n d N a m e  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 2 Sc he ma, 1. 3 
Sc he d ule of 
Acti vities, 4. 1 
O verall Desi g n, 5. 1 
I ncl usi o n Criteria, 
8. 1. 1. 2 I n -Cli nic 
S pir o metr y 
Sc he d ule a n d 
Pr o ce d ure, 8. 1. 1. 3 
Re v ersi bilit y t o 
Al b uter ol  
Re v ersi bilit y testi n g w or di n g m o difie d.  
Res ol ve d i nc o nsiste nces acr oss t he secti o ns 
t o reflect I ncl usi o n Criteri o n relati n g t o 
hist orical re v ersi bilit y i n t he last 1 2 m o nt hs.  
W or di n g t hr o u g h o ut pr ot oc ol m o difie d t o matc h 
t he i ncl usi o n criteri o n.  
9. 5. 1. 2 Visit 
Wi n d o ws  
Visit wi n d o ws f or a nal ysis ha ve bee n 
defi ne d.  
T o ma p data t o cl osest sc he d ule d visit.  
9. 5. 2. 3 
Tertiar y/ E x pl orat or y 
E n d p oi nts  
C ha n ge fr o m baseli ne i n e ve ni n g pre -d ose 
pea k e x pirat or y fl o w will n ot be a nal yze d 
b y visit f or meas ure me nts assesse d at cli nic 
visits.  
Data n ot c ollecte d.  
9. 5. 2. 3 
Tertiar y/ E x pl orat or y  
E n d p oi nts  
E Q -5 D prese ntati o n will be s plit b y a d ult 
a n d a d olesce nt p o p ulati o ns.  
Practical c o nsi derati o ns i n ma p pi n g q uesti o ns 
fr o m t he t w o q uesti o n naires (a d ults a n d 
a d olesce nts).  
9. 5. 2. 4 1 2 -H o ur 
P F T S u b -St u d y  
T he a n al ysis of 1 2 -H o ur P F T S u b -St u d y 
e n d p oi nts at Da y 1 was a d de d.  
T he a n al ysis m o del f or Wee k 1 2 was 
s witc he d fr o m a li near mi xe d A N C O V A 
m o del i nt o a re p eate d meas ures A N C O V A 
f or 1 2-H o ur P F T S u b -St u d y e n d p oi nts  
1 2 -H o ur P F T S u b -St u d y e n d p oi nts will be 
a vaila ble at Da y 1 a n d Wee k 1 2, s o t he a n al ysis 
was a d de d f or Da y 1.  
T he a nal ysis m o del was s witc he d t o a re p eate d 
meas ures A N C O V A t o i ncl u de data fr o m Da y 1 
a n d data fr o m Wee k 1 2.  
T hr o u g h o ut  
Mi n or e dit orial a n d d oc u me nt f or matti n g 
re visi o ns 
Mi n or, t heref ore ha ve n ot bee n s u m marize d  
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 1  of 1 2 2  
 
1 1  
R E F E R E N C E S   
C orre n J, K ore n blat P E, Miller CJ, O' Brie n C D, Mezza n otte W S. T wel v e-wee k, ra n d o mize d, 
place b o -c o ntr olle d, m ultice nter st u d y of t he efficac y a n d t olera bilit y of b u d es o ni de a n d 
f or m oter ol i n o ne metere d-d ose i n haler c o m pare d wit h b u des o ni de al o ne a n d f or m oter ol al o ne 
i n a d olesce nts a n d a d ults wit h ast h ma. Cli n T her. 2 0 0 7 Ma y; 2 9( 5): 8 2 3 -4 3.  
E Q -5 D User G ui des: E Q -5 D -5 L us er g ui de 2 0 1 9; E Q -5 D -Y user g ui de 2 0 1 4. Accesse d at 
htt ps://e ur o q ol. or g/ p u blicati o ns/ user -g ui des/ ( A pril, 2 0 2 0).  
E ur o Q ol Gr o u p. E Q -5 D. Access e d at htt ps://e ur o q ol. or g/e q -5 d -i nstr u me nts/ h o w-ca n -e q-5 d -
be -use d/ ( Fe br uar y, 2 0 2 0).  
Gl o bal I nitiati ve f or Ast h ma ( GI N A). Gl o bal Strat e g y f or Ast h ma Ma na g e me nt a n d 
Pre ve nti o n, 2 0 2 1. htt p:// gi nast h ma. or g/.  
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u p m ulti ple test pr oce d ures. Bi o metri ka 2 0 1 4; 1 0 1: 8 9 9 -9 1 1.  
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C o ntrace pti ve Tec h n ol o g y. 2 0 th e diti o n. Atla nta, Ge or gia: Ar de nt Me di a, I nc., 2 0 1 1: 5 0; 
Ta ble  3 -2.  
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q uesti o n naire (sta n d ar dis e d) f or patie nts 1 2 years a n d ol der. Healt h Q ual Life O utc o mes. 
2 0 0 5; 3: 5 8.  
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Ast h ma Q ualit y of Life Q uesti o n naire. C hest. 1 9 9 9 b; 1 1 5( 5): 1 2 6 5 -7 0.  
J u ni per E F, Gu 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 
disease -s pecific Q u alit y of Life Q uesti o n nair e. J Cli n E pi de mi ol. 1 9 9 4; 4 7( 1): 8 1 -7.  
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze n eca  
B u des o ni de a n d F or m oter ol F u marate  - D 5 9 8 2 C 0 0 0 0 5  
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 2  of 1 2 2  
 
J u ni per E F, G u yatt G H, Ferrie PJ, Griffit h L E. M eas uri n g q ualit y of life i n ast h ma. A m Re v 
Res pi r Dis. 1 9 9 3 A pr; 1 4 7( 4): 8 3 2-8.  
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i m pair me nt of healt h-relate d q ualit y of life i n ast h ma: de vel o p me nt of a q u esti o n naire f or us e 
i n cli nical trials. T h ora x. 1 9 9 2 Fe b; 4 7( 2): 7 6-8 3 . 
Miller M R, Ha n ki ns o n J, Br usasc o V, B ur g os F, C asa b uri R, C oates A, Cra p o R, E nri g ht P, 
va n der Gri nte n C P M, G ustafss o n P, Je nse n R, J o h ns o n D C, MacI nt yre N, Mc Ka y R, Na v ajas 
D, Pe derse n O F, Pelle gri n o R, Vie gi G, Wa n g er J. Sta n dar disati o n of s pir o metr y.  E ur Res pir J. 
2 0 0 5; 2 6( 2): 3 1 9 -3 8.  
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H N, Har di n g G, C o y ne K S, Zei ger R S, U S P R E CI SI O N A d vis or y B oar d. De vel o p me nt of t he 
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wit h m o derat e t o se vere ast h ma: a ra n d o mise d cli nical trial. Dr u gs. 2 0 0 6; 6 6( 1 7): 2 2 3 5 -5 4.  
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ast h ma patie nts. Aller g y Ast h ma Pr oc. 2 0 0 8; 2 9( 5): 4 9 9-5 1 6.  
Q ua njer P H, Sta n oje vic S, C ole TJ, Ba ur X, Hall G L, C ul ver B H, E nri g ht P L, Ha n ki ns o n J L, 
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s pir o metr y f or t he 3-9 5 -yr a ge ra n ge: t he gl o bal l u n g f u ncti o n 2 0 1 2 e q uati o ns. E ur Res pir J. 
2 0 1 2 Dec; 4 0( 6): 1 3 2 4 -4 3.  
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O B yr ne P M, Partri d ge M R, Pa v or d I D, Sears M R, Ster k PJ St ol off S W, S ulli va n S D, Szefler 
SJ, T h o mas M D, We nzel S E. A n offici al A merica n T h oraci c S ociet y/ E ur o pea n Res pirat or y 
S ociet y state me nt: ast h ma c o ntr ol a n d e x acer bati o ns: sta n dar dizi n g e n d p oi nts f or cli nical 
ast h ma trials a n d cli nical practice. A m J Res pir Crit Care Me d. 2 0 0 9 J ul: 1 8 0( 1): 5 9 -9 9.  
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press urize d m etere d -d ose i n haler vers us b u d es o ni de press urize d metere d -d ose i n h aler al o n e i n 
His pa nic a d ults a n d a d ol esce nts wit h ast h ma: a ra n d o mize d, c o ntr olle d trial. A n n Aller g y 
Ast h ma I m m u n ol. 2 0 1 1; 1 0 7( 3): 2 5 8 -6 5.e 2.