Clinical trial NCT03769090
Conditions: Asthma
Sponsor: Bond Avillion 2 Development LP
Start date: 2018-12-13; Completion date: 2022-02-07
Enrollment: 3132 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, multicenter, parallel-group, variable-length study to compare 2 doses of BDA MDI (PT027) with AS MDI (PT007) on the time to first severe asthma exacerbation in adult, adolescent, and pediatric subjects with moderate to severe asthma.

Detailed description:

Arms: arm 1: Budesonide/albuterol sulfate, BDA MDI, PT027 high dose arm 2: Budesonide/albuterol sulfate, BDA MDI, PT027 low dose arm 3: Albuterol sulfate MDI, PT007
Interventions: intervention 1: Budesonide/albuterol sulfate metered-dose inhaler 160/180 μg intervention 2: Budesonide/albuterol sulfate metered-dose inhaler 80/180 μg intervention 3: Albuterol sulfate metered-dose inhaler 180 μg
Intervention descriptions: intervention 1: Budesonide/albuterol sulfate combination inhalation aerosol intervention 2: Budesonide/albuterol sulfate combination inhalation aerosol intervention 3: Albuterol sulfate inhalation aerosol

Protocol documents:
Prot_000.pdf: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
3 of  1 5 9  
C LI NI C A L  S T U D Y  P R O T O C O L  S Y N O P SI S  
 
A  L o n g -t e r m,  R a n d o mi z e d,  D o u bl e-bli n d,  M ulti c e nt e r,  P a r all el -g r o u p, 
P h as e III  St u d y  E v al u ati n g t h e  Effi c a c y  a n d  S af et y  of  P T 0 2 7  C o m p a r e d t o 
P T 0 0 7  A d mi nist e r e d  as  N e e d e d i n  R es p o ns e t o  S y m pt o ms i n  S y m pt o m ati c 
A d ults  a n d  C hil d r e n  4  Ye a rs  of  A g e  o r  Ol d e r  wit h  Ast h m a ( M A N D A L A)  
 
 
 
I nt e r n ati o n al  c o o r di n ati n g i n v esti g at o rs 
 
 
 
 
 
 
 
 
St u d y sit e(s)  a n d  n u m b e r  of s u bj e cts  pl a n n e d  
A p pr o xi m at el y  3 8 0 st u d y sit es  ar e  a nti ci p at e d t o r a n d o mi z e  a p pr o xi m at el y  3 0 0 0  a d ult  a n d 
a d ol es c e nt s u bj e cts  wit h  m o d er at e t o s e v er e  ast h m a t o  1  of  3 tr e at m e nt  gr o u ps ( a p pr o xi m at el y 
1 0 0 0 s u bj e cts  p er  gr o u p). I n  a d diti o n,  u p t o 1 0 0 s u bj e cts i n t h e  4 t o  1 1- y e ar  a g e  gr o u p  wit h 
m o d er at e t o s e v er e  ast h m a  will  b e r a n d o mi z e d  wit h  a p pr o xi m at el y  5 0 s u bj e cts r a n d o mi z e d t o 
t h e  al b ut er ol s ulf at e ( h er e  aft er r ef err e d t o  as  al b ut er ol)  m et er e d- d os e i n h al er ( A S  M DI)  a n d 
5 0 s u bj e cts r a n d o mi z e d t o t h e l o w  d os e  b u d es o ni d e/ al b ut er ol  m et er e d- d os e i n h al er ( B D A 
M DI)  gr o u ps  o nl y.  A p pr o xi m at el y  6 0 0 0 s u bj e cts  will  n e e d t o  b e s cr e e n e d,  ass u mi n g  a n 
esti m at e d s cr e e n f ail ur e r at e  of  3 0 % t o  5 0 %.  
 
T his  P h as e III st u d y is  pl a n n e d t o  b e  c o n d u ct e d  gl o b all y. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
4 of  1 5 9  
St u d y  d esi g n  
T his is  a r a n d o mi z e d,  d o u bl e- bli n d,  m ulti c e nt er,  p ar all el - gr o u p,  v ari a bl e-l e n gt h,  e v e nt- dri v e n 
st u d y  wit h  a tr e at m e nt  p eri o d  of  at l e ast  2 4  w e e ks f or  e a c h s u bj e ct.  T h e  p ur p os e  of t his st u d y 
is t o  c o m p ar e  2  d os es  of  B D A  M DI  wit h  A S  M DI  o n t h e ti m e t o first s e v er e  ast h m a 
e x a c er b ati o n i n  a d ult,  a d ol es c e nt,  a n d  p e di atri c s u bj e cts  wit h  m o d er at e t o s e v er e  ast h m a  as 
d efi n e d  b y  Gl o b al  I niti ati v e f or Ast h m a  ( GI N A).  S u bj e cts  will  a d mi nist er r a n d o mi z e d 
i n v esti g ati o n al  pr o d u ct (I P)  as  n e e d e d ( pr n) i n r es p o ns e t o  ast h m a s y m pt o ms. 
S u bj e cts  m e eti n g  all  e ntr y  crit eri a  at t h e s cr e e ni n g  visit ( Visit  1/ 1 a,  as  a p pli c a bl e)  will  e nt er  a 
1 4-t o  2 8- d a y s cr e e ni n g  p eri o d. ( S u bj e cts  m a y  c o ns e nt f or t h e st u d y i n  a d v a n c e  of  Visit  1  a n d 
if r e q uir e d, r e q u est f or  m e di c al r e c or ds t o s u p p ort  e vi d e n c e  of  pri or  e x a c er b ati o ns  wit h o ut 
tri g g eri n g t h e  2 8- d a y s cr e e ni n g  p eri o d.) If  a s e v er e  e x a c er b ati o n  e v e nt  o c c urs  d uri n g t h e 
s cr e e ni n g  p eri o d, t h e s cr e e ni n g  p eri o d  m a y  b e  e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks.  S cr e e n e d 
s u bj e cts  will  c o nti n u e t o t a k e t h eir r e g ul ar  ast h m a  m ai nt e n a n c e t h er a p y t hr o u g h o ut t h e st u d y 
(fr o m  Visit  1 t hr o u g h t h e tr e at m e nt  p eri o d).  At  Visit  1,  eli gi bl e s u bj e cts  will  dis c o nti n u e t h eir 
us u al  pr n i n h al e d  pr o d u ct  us e d  as- n e e d e d f or s y m pt o m r eli ef  a n d  b e gi n  S p o ns or- pr o vi d e d 
V e nt oli n t o  b e  us e d  pr n i n r es p o ns e t o s y m pt o ms  or  pri or t o  e x er cis e  d uri n g t h e s cr e e ni n g 
p eri o d  o nl y.  S u bj e cts  will  b e  as k e d t o t ur n i n t h eir  o w n i n h al e d r eli e v er  pr o d u cts t o t h e 
i n v esti g ati o n al sit es f or st or a g e  u ntil t h e i n di vi d u al s u bj e ct l ast st u d y  visit.  Eli gi bl e s u bj e cts 
will  b e r a n d o mi z e d  at  Visit   2. 
 
O bj e cti v es  
P ri m a r y  O bj e cti v e:  
P ri m a r y  E n d p oi nt:  
T o  e v al u at e t h e  effi c a c y  of  b u d es o ni d e/ al b ut er ol 
m et er e d -d os e i n h al er  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms 
c o m p ar e d t o  al b ut e r ol  m et er e d -d os e i n h al er  1 8 0 
μ g  
Ti m e t o first s e v er e  ast h m a  e x a c er b ati o n   
S e c o n d a r y  O bj e cti v e:  
S e c o n d a r y  E n d p oi nt:  
T o  c h ar a ct eriz e t h e  eff e ct  of  b u d es o ni d e/ al b ut er ol 
m et er e d -d os e i n h al er  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms 
c o m p ar e d t o  al b ut er ol  m et er e d -d os e i n h al er  1 8 0 
μ g  
•   S e v er e  e x a c er b ati o n r at e ( a n n u aliz e d)  
•   T ot al s yst e mi c  c orti c ost er oi d  e x p os ur e  o v er t h e 
tr e at m e nt  p eri o d 
•   Ast h m a  C o ntr ol  Q u esti o n n air e  -5 ( A C Q -5)  c h a n g e 
fr o m  b as eli n e  a n d r es p o n d er  a n al ysis  at  W e e k  2 4 
•   Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars 
a n d  ol d er ( A Q L Q + 1 2)/ P e di atri c  Ast h m a  Q u alit y  of 
Lif e  Q u esti o n n air e ( P A Q L Q)  c h a n g e fr o m  b as eli n e 
a n d r es p o n d er  a n al ysis  at  W e e k  2 4  
S af et y  O bj e cti v e:  
S af et y  E n d p oi nts:  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
5 of  1 5 9  
T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of 
b u d es o ni d e/  al b ut er ol  m et er e d -d os e i n h al er 
8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g  a d mi nist er e d  pr n i n 
r es p o ns e t o s y m pt o ms  c o m p ar e d t o  al b ut er ol 
m et er e d -d os e i n h al er  1 8 0  μ g  
•   A d v ers e  e v e nts/s eri o us  a d v ers e  e v e nts  
•   Vit al si g ns  
•   Cli ni c al  c h e mistr y  a n d  h e m at ol o g y  p ar a m et e rs 
•   El e ctr o c ar di o gr a m  
E x pl o r at o r y  O bj e cti v e:  
E x pl o r at o r y  E n d p oi nts:  
T o  c h ar a ct eriz e t h e  eff e ct  of  b u d es o ni d e/ al b ut er ol 
m et er e d -d os e i n h al er  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms 
c o m p ar e d t o  al b ut er ol  m et er e d -d os e i n h al er  1 8 0  
  μ g  
•   Ast h m a  C o ntr ol  Q u esti o n n air e  -5  c h a n g e fr o m 
b as eli n e  a n d r es p o n d er  a n al ysis  at  W e e k  1 2  
•   Ast h m a  C o ntr ol  Q u esti o n n air e -5  c h a n g e fr o m 
b as eli n e  a n d r es p o n d er ( 3 -f a ct or)  a n al ysis  at 
W e e k  1 2  a n d  W e e k  2 4  
•   Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars 
a n d  ol d er/ P e di atri c  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e  c h a n g e fr o m  b as eli n e  a n d r es p o n d er 
a n al ysis  at  W e e k  1 2  
•   D et eri or ati o ns  of  ast h m a ( a n n u aliz e d r at e  a n d ti m e 
t o first) 
•   C h a n g e fr o m  b as eli n e i n  pr e br o n c h o dil at or f or c e d 
e x pir at or y  v ol u m e i n  1 s e c o n d  at  W e e k  1 2  a n d  W e e k 
2 4   
•   M or ni n g  a n d  e v e ni n g  p e a k  e x pir at or y fl o w  
•   Us e  of i n v esti g ati o n al  pr o d u ct (r eli e v er t h er a p y)   
•   Ast h m a  d a yti m e/ ni g ht -ti m e s y m pt o ms 
•   Ti m e t o tr e at m e nt  dis c o nti n u ati o n  or  c h a n g e i n 
m ai nt e n a n c e t h er a p y  
•   Ast h m a  C o ntr ol  T est ( A C T)  or  C hil d h o o d  Ast h m a 
C o ntr ol  T est ( C  A C T)  c h a n g e fr o m  b as eli n e  a n d 
r es p o n d er  a n al ysis  at  W e e k  2 4  
•   P er c e nt a g e  of  “ as  n e e d e d ” -fr e e  d a ys  
•   P er c e nt a g e  of s y m pt o m -fr e e  d a ys  
•   P er c e nt a g e  of  ast h m a  c o ntr ol  d a ys  
•   I n h al e d  c orti c ost er oi d  e x p os ur e  o v er t h e tr e at m e nt 
p eri o d  
 
 
T a r g et s u bj e ct  p o p ul ati o n 
T h e st u d y  will  e nr oll s u bj e cts  ≥ 4   y e ars  of  a g e i n  all  c o u ntri es  wit h t h e  e x c e pti o n  of t h e 
f oll o wi n g:  
•   I n  S er bi a,  o nl y s u bj e cts  ≥ 1 2  y e ars  of  a g e  will  b e  e nr oll e d.  
•   I n  G er m a n y,  Sl o v a ki a  a n d  U kr ai n e,  o nl y s u bj e cts  ≥ 1 8  y e ars  of  a g e  will  b e  e nr oll e d.  
A g e -s p e cifi c  ass ess m e nts  will  b e i m pl e m e nt e d  w h er e r el e v a nt f or t h e  p o p ul ati o n  e nr oll e d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
6 of  1 5 9  
M al e  a n d f e m al e s u bj e c ts  ≥ 4 y e ars  of  a g e  wit h  a  di a g n osis  of  m o d er at e t o s e v er e  ast h m a  as 
d efi n e d  b y  GI N A  crit eri a  a n d  h a vi n g  at l e ast  1 s e v er e  ast h m a  e x a c er b ati o n  wit hi n t h e  pr e vi o us 
1 2  m o nt hs  pri or t o  s cr e e ni n g ( Visit   1/ 1 a,  as  a p pli c a bl e)  w h o  h a v e  b e e n t a ki n g  a r e g ul ar 
s c h e d ul e  of  ast h m a  m ai nt e n a n c e t h er a pi es f or  3  m o nt hs  wit h st a bl e  d osi n g f or  at l e ast t h e l ast 
4  w e e ks  pri or t o  Visit  1  m a y  b e  eli gi bl e f or t his st u d y. 
 
D u r ati o n  of st u d y/t r e at m e nt 
T h e st u d y  will  c o nsist  of  3  p eri o ds:  
•   S cr e e ni n g  p eri o d ( 1 4 t o  2 8  d a ys),  e x c e pt  w h er e  a s e v er e  e x a c er b ati o n  e v e nt  o c c urs  a n d 
t h e s cr e e ni n g  p eri o d  m a y  b e  e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks. ( S u bj e cts  m a y 
c o ns e nt f or t h e st u d y i n  a d v a n c e  of  Visit  1  a n d if r e q uir e d, r e q u est f or  m e di c al r e c or ds 
t o s u p p ort  e vi d e n c e  of  pri or  e x a c er b ati o ns  wit h o ut tri g g eri n g t h e  2 8- d a y s cr e e ni n g 
p eri o d.) 
•   Tr e at m e nt  p eri o d  of  at l e ast  2 4  w e e ks.  T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e 
( e xt e nsi o n  p h as e)  u ntil t h e r e q uir e d  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts,  as  d efi n e d  p er 
pr ot o c ol,  h a v e  b e e n r e a c h e d  a n d t h e l ast  a d ult s u bj e ct  h as  c o m pl et e d  2 4  w e e ks  of 
tr e at m e nt,  w hi c h  will  b e  d efi n e d  as t h e  pri m ar y  c o m pl eti o n  d at e ( P C D). P a e di atri c 
s u bj e cts  will  c o nti n u e  u ntil  2 4  w e e ks  of tr e at m e nt  h a v e  b e e n r e a c h e d f or  e a c h 
p a e di atri c  p ati e nt,  d efi n e d  as t h e fi n al  c o m pl eti o n  d at e . 
o  I n t h e  e v e nt  5 7 0  e v e nts  ar e  c a pt ur e d b ef o r e  t h e l ast a d ult  p ati e nt  h as  h a d  2 4 
w e e ks  of tr e at m e nt,  all s u bj e cts  o n tr e at m e nt f or  ≥ 2 4  w e e ks  will  h a v e t h eir  e n d -
of- st u d y ( E O S)  visit  at t h eir  n e xt s c h e d ul e d  cli ni c  visit.   All s u bj e cts  o n 
tr e at m e nt f or  <  2 4  w e eks  will  c o nti n u e  u ntil  2 4  w e e ks  at  w hi c h  p oi nt t h e y  will 
c o m pl et e t h eir  E O S  visit  
o   I n t h e  e v e nt  5 7 0  e v e nts  will  b e  c a pt ur e d aft e r  t h e l ast s u bj e ct  h as  h a d  2 4  w e e ks 
of tr e at m e nt,  e a c h s u bj e ct  will r et ur n t o  c o m pl et e t h e  E O S  visit  at t h eir  n e xt 
s c h e d ul e d  cli ni c  visit 
•   S af et y f oll o w- u p  p eri o d:  w h er e  a s af et y f oll o w- u p t el e p h o n e  c o nt a ct  will  o c c ur  2 
w e e ks ( ± 4  d a ys)  aft er  E O S  or  pr e m at ur e  dis c o nti n u ati o n  visit ( P D V),  w hi c h e v er 
o c c urs first.  
T h e st u d y  will  b e  c o m pl et e d  w h e n t h e l ast s u bj e ct  h as  c o m pl et e d  his  or  h er  p ost-st u d y 
f oll o w- u p t el e p h o n e  c o nt a ct.  S u bj e cts  w h o  dis c o nti n u e I P  will  c o m pl et e  a  P D V,  a n d  a d v ers e 
e v e nts ( A Es)/s eri o us  a d v ers e  e v e nts ( S A Es)  will  b e f oll o w e d  u p if  m e di c all y i n di c at e d.  
Esti m at e d  d at e  of first s u bj e ct  e nr oll e d:  Q 4  2 0 1 8. 
Esti m at e d  d at e  of l ast s u bj e ct  c o m pl et e d:  Q 1  2 0 2 2. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
7 of  1 5 9  
I n v esti g ati o n al  p r o d u ct,  d os a g e,  a n d  m o d e  of  a d mi nist r ati o n 
B D A  M DI is f or m ul at e d  as  b ot h  mi cr o ni z e d  b u d es o ni d e  a n d  mi cr o ni z e d  al b ut er ol 
c o -s us p e n d e d  wit h s pr a y- dri e d  p or o us  p arti cl es i n  a  h y dr ofl u or o al k a n e ( H F A)  pr o p ell a nt.  T h e 
c o -s us p e nsi o n f or m ul ati o n  e ns ur es t h at s u bj e cts r e c ei v e  a  c o nsist e nt  d eli v er y  of t h e  dr u g fr o m 
e a c h  a ct u ati o n  of t h e  M DI.  
I n v esti g ati o n al  pr o d u ct  will  b e  us e d i n r es p o ns e t o  ast h m a s y m pt o ms  as t h e y  w o ul d  n or m all y 
t a k e t h eir r eli e v er m e di c ati o n. If s u bj e cts t a k e I P i n  a d v a n c e  of  e x er cis e f or t h e  pr e v e nti o n  of 
e x er cis e i n d u c e d s y m pt o ms, I P  us a g e i n r el ati o n t o  e x er cis e  will  b e  c a pt ur e d  wit hi n t h e 
e Di ar y.  N o  ot h er r eli e v er  pr o d u cts  will  b e  us e d  d uri n g t h e tr e at m e nt  p eri o d. 
At r a n d o mi z ati o n ( Visit  2),  a d ol es c e nts  a n d  a d ults ( a g e d  ≥ 1 2  y e ars)  w h o  m e et t h e  eli gi bilit y 
crit eri a  will  b e r a n d o ml y  assi g n e d t o  1  of t h e f oll o wi n g  3 tr e at m e nt  gr o u ps i n  a  1: 1: 1 r ati o  as 
r eli e v er t h er a p y  o n t o p  of  us u al  c ar e.  C hil dr e n  a g e d  4 t o  1 1  y e ars  will  b e r a n d o mi z e d i n  a  1: 1 
r ati o  o nl y t o t h e l o w er  B D A  M DI  d os a g e  or  A S  M DI: 
•   B D A  M DI  8 0/ 1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  B D A  M DI  4 0/ 9 0  μ g  p er  p uff)  pr n  
•   B D A  M DI  1 6 0/ 1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  B D A  M DI  8 0/ 9 0  μ g  p er  p uff)  pr n  
•   A S  M DI  1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  A S  M DI  9 0  μ g  p er  p uff)  pr n  
T h e  m a xi m u m  d ail y  d os a g e  of I P s h o ul d  n ot  e x c e e d  1 2  p uffs  p er  d a y. 
S u bj e cts  will  b e r e c o m m e n d e d  n ot t o t a k e  m or e t h a n  8  p uffs  p er  d a y  a n d  a d vis e d t o  c o nt a ct 
t h e st u d y sit e/i n v esti g at or if t h eir s y m pt o ms  n e c essit at e  m or e t h a n  8  p uffs i n  a  d a y.  
I n  or d er t o  e ns ur e s af et y  a n d  m o nit or  d ail y tr e at m e nt st at us,  all s u bj e cts  will  b e  pr o vi d e d  wit h 
a n  el e ctr o ni c  di ar y ( e Di ar y:  A M 3  d e vi c e).  T h e  e Di ar y tr a nsf ers  d at a  e v er y  2 4  h o urs  a cr oss  a 
r a n g e  of  ast h m a s y m pt o m s c or es  a n d  dr u g  us a g e (i e,  n u m b er  of  p uffs i n h al e d) t o  ass ess  a 
s u bj e ct’s  ast h m a st at us.  S u bj e cts  will  us e t h e  e Di ar y f or r e p orti n g  d ail y  us e  of I P  a n d  a n y 
s y m pt o ms. If s y m pt o ms  a n d/ or  d ail y  d os a g e  e x c e e d  a  pr ot o c ol-s p e cifi e d t hr es h ol d, t h e  e Di ar y 
will  g e n er at e  a n  al ert t o t h e s u bj e ct   a n d t h e i n v esti g ati o n al sit e. I n t his  w a y,  d ail y I P  us a g e  will 
b e  m o nit or e d  cl os el y  b y t h e i n v esti g at ors  a n d  m e di c al  m o nit ors t o  ass ess  a n y  w ors e ni n g  of 
s u bj e ct st at us.  A cti o n  will  b e t a k e n  w h er e  cli ni c all y i n di c at e d.  
 
St atisti c al  m et h o ds  
S a m pl e si z e  c al c ul ati o n 
A s a m pl e si z e  of  1 0 0 0  a d ult  a n d  a d ol es c e nt s u bj e cts  p er tr e at m e nt  gr o u p  a n d  o bs er v ati o n  of 
t h e  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts  pr o vi d es t his st u d y  wit h  8 7 %  p o w er t o  o bs er v e  a  2 5 % 
r e d u cti o n i n t h e ris k  of s e v er e  e x a c er b ati o n  wit h  at l e ast  1  d ose  of  B D A  M DI  v ers us  A S  M DI 
ass u mi n g t h e  H o c h b er g  pr o c e d ur e ( H o c h b er g  1 9 8 8 ) f or  m ulti pl e t esti n g  a n d  a  2-si d e d 
si g nifi c a n c e l e v el  of  5 %.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
8 of  1 5 9  
I n  a d diti o n, u p t o  1 0 0 s u bj e cts i n t h e  4 t o  1 1- y e ar  a g e  gr o u p  wit h  m o d er at e t o s e v er e  ast h m a 
will  b e r a n d o mi z e d  wit h  a p pr o xi m at el y  5 0 s u bj e cts r a n d o mi z e d t o t h e  A S  M DI  gr o u p  a n d 
5 0 s u bj e cts r a n d o mi z e d t o t h e l o w  d os e  B D A  M DI  gr o u p  o nl y. 
P ri m a r y  effi c a c y  a n al ysis 
T h e  pri m ar y  v ari a bl e, ti m e t o first s e v er e  ast h m a  e x a c er b ati o n,  will  b e  a n al y z e d  usi n g  a  C o x 
pr o p orti o n al  h a z ar ds r e gr essi o n  m o d el t o  c o m p ar e tr e at m e nt  ar ms.  T h e  m o d el  will  b e  a dj ust e d 
f or t h e r a n d o mi z ati o n str atifi c ati o n f a ct ors ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 t o  1 7,  ≥ 1 8]); r e gi o n 
( N ort h  A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d [ R e gi o n  2]); 
a n d  n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1) 
pl us  a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d u ri n g t h e s cr e e ni n g  p eri o d  a n d  k e y 
c o v ari at es  of i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e st atisti c al  a n al ysis  pl a n ( S A P). 
T h e  2  pri m ar y tr e at m e nt  c o m p aris o ns  will  b e  2 -si d e d  wit h t h e  5 %  o v er all  al p h a l e v el 
c o ntr oll e d  usi n g t h e  H o c h b er g  pr o c e d ur e.  T h e  pri m ar y  effi c a c y  a n al ysis  will i n cl u d e  all  d at a 
u p t o t h e  pri m ar y  o ut c o m e  d at a b as e l o c k ( p D B L), s c h e d ul e d t o  o c c ur f oll o wi n g t h e  P C D  a n d 
o n c e  all r a n d o mi z e d  a d ults  h a v e  att e n d e d t h eir  E O S  visit . 
S e c o n d a r y  effi c a c y  a n al ys es  
A n n u ali z e d s e v er e  ast h m a  e x a c er b ati o n r at e  will  b e  a n al y z e d  usi n g  n e g ati v e  bi n o mi al 
r e gr essi o n t o  c o m p ar e tr e at m e nt  gr o u ps.  T h e r es p o ns e  v ari a bl e i n t h e  m o d el  will  b e t h e 
n u m b er  of s e v er e  ast h m a  e x a c er b ati o ns.  T h e  m o d el  will  a dj ust f or ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 
t o  1 7,  ≥ 1 8]); r e gi o n ( N ort h  A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of 
w orl d [ R e gi o n  2]);  a n d  n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o 
s cr e e ni n g ( Visit  1)  pl us  a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g 
p eri o d  a n d  k e y  c o v ari at es  of i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e  S A P. 
R es p o n d er  v ari a bl es f or  Ast h m a  C o ntr ol  Q u esti o n n air e- 5 ( A C Q - 5)  a n d  Ast h m a  Q u alit y  of 
Lif e  Q u esti o n n air e f or  1 2  y e ars  a n d  ol d er ( A Q L Q + 1 2)/  P e di atri c  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e ( P A Q L Q)  at  W e e k  2 4  will  e a c h  b e  a n al y z e d  usi n g  a l o gisti c r e gr essi o n  m o d el 
t o  c o m p ar e tr e at m e nt  gr o u ps.  T h e  m o d el  will  b e  a dj ust e d f or t h e r a n d o mi z ati o n str atifi c ati o n 
f a ct ors  a n d  k e y  c o v ari at es  as  d es cri b e d  a b o v e. 
T h e t ot al s yst e mi c  c orti c ost er oi d ( S C S)  e x p os ur e  as t ot al  a n n u ali z e d  d os e  of  S C S ( m g/ y e ar) 
will  b e  pr es e nt e d  d es cri pti v el y  b y tr e at m e nt.  A  c o m p aris o n i n t ot al  a n n u ali z e d  S C S  d os e 
b et w e e n  B D A  M DI  8 0/ 1 8 0  vs  A S  M DI  1 8 0  a n d  B D A  M DI  1 6 0/ 1 8 0  vs  A S  M DI  1 8 0  will  b e 
a n al y z e d  usi n g  a  Wil c o x o n r a n k s u m  t est  a n d  ass o ci at e d  p- v al u es  will  b e  pr es e nt e d  al o n g  wit h 
t h e  d es cri pti v e s u m m ar y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y    
9 of  1 5 9  
A d diti o n all y, t ot al  S C S  e x p os ur e  will  b e s u m m ari z e d  d es cri pti v el y  as t h e t ot al  n u m b er  of  d a ys 
wit h  S C S tr e at m e nt  d u e t o  ast h m a f or  all s u bj e cts.  A si mil ar  d es cri pti v e s u m m ar y  will  b e 
c o m pl et e d f or  all s u bj e cts  w h o  a d mi nist er e d  at l e ast  1  d os e  of  S C S  d uri n g t h e st u d y.  
If  b ot h  d os es  of  B D A  M DI  ar e st atisti c all y s u p eri or t o  A S  M DI f or t h e  pri m ar y  e n d p oi nt, t h e 
f ull  al p h a  will  b e  a v ail a bl e t o  p ass t o t h e f a mil y  of s e c o n d ar y  e n d p oi nts.  
T h e t y p e-I  err or  will  b e  c o ntr oll e d f or s e c o n d ar y  e n d p oi nt tr e at m e nt  c o m p aris o ns  vi a  a 
hi er ar c hi c al t esti n g  pr o c e d ur e.  T h e s e c o n d ar y  o bj e cti v es  will  b e t est e d  u n d er t h e  effi c a c y 
esti m a n d i n t h e f oll o wi n g s e q u e nti al  or d er,  gr o u p e d  b y s e c o n d ar y  e n d p oi nt:  
A n n u ali z e d s e v er e  e x a c er b ati o n r at e  
1.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
2.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
T ot al  a n n u ali z e d  d os e  of s yst e mi c  c orti c ost er oi d 
3.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
4.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
Ast h m a  C o ntr ol  Q u esti o n n air e- 5 ( A C Q - 5)  c h a n g e fr o m  b as eli n e r es p o n d er  a n al ysis  at 
W e e k   2 4 
5.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
6.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars  a n d  ol d er ( A Q L Q + 1 2)  c h a n g e fr o m 
b as eli n e r es p o n d er  a n al ysis  at  W e e k  2 4   
7.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
8.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
St atisti c al t ests f or t h e s e c o n d ar y  a n al ys es  will  b e  c o n d u ct e d  at t h e  5 % l e v el  of si g nifi c a n c e 
( 2-si d e d). I nf er e n c e f or  a t est i n t h e  d efi n e d  or d er is  d e p e n d e nt  o n st atisti c al si g nifi c a n c e 
h a vi n g  b e e n  a c hi e v e d i n t h e  pr e c e di n g t ests, if t his is  n ot  a c hi e v e d t h e n  n o mi n al  p- v al u es  will 
b e  pr o vi d e d.  As  p er t h e  pri m ar y  a n al ysis,  c o m p aris o ns  of  B D A  M DI  1 6 0/ 1 8 0  v ers us  A S  M DI 
will  e x cl u d e t h e  p e di atri c   p o p ul ati o n,  w hilst  c o m p aris o ns  of  B D A  8 0/ 1 8 0  v ers us  A S  M DI  will 
i n cl u d e  all  a g es. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0  of  1 5 9  
St atisti c al si g nifi c a n c e  c a n  o nl y  b e  cl ai m e d  o n t h e  k e y s e c o n d ar y  e n d p oi nts if  a st atisti c all y 
si g nifi c a nt tr e at m e nt  eff e ct is  o bs er v e d  o n  b ot h  B D A  M DI  1 6 0/ 1 8 0  μ g  a n d  B D A  M D I 
8 0/ 1 8 0  μ g  v ers us  A S  M DI f or t h e  pri m ar y  e n d p oi nt  of ti m e t o first s e v er e  e x a c er b ati o n. T h e 
s e c o n d ar y  effi c a c y  a n al ys es  will i n cl u d e  all  d at a  u p t o t h e  p D B L . 
Esti m a n ds  
T hr e e  esti m a n ds  ar e  of i nt er est i n t his st u d y:   
T h e  pri m ar y  esti m a n d  of i nt er est is t h e  effi c a c y  esti m a n d,  d efi n e d  as t h e  eff e ct  of t h e 
r a n d o mi z e d tr e at m e nt i n  all s u bj e cts  ass u mi n g  c o nti n u ati o n  of r a n d o mi z e d tr e at m e nt f or t h e 
d ur ati o n  of t h e st u d y, r e g ar dl ess  of  a ct u al  us a g e  a n d  ass u mi n g t h at  m ai nt e n a n c e t h er a p y is  n ot 
c h a n g e d.  T his  esti m a n d  c o ul d  b e  c o nsi d er e d  as  a  w hil e- o n- tr e at m e nt str at e g y  or  a  h y p ot h eti c al 
str at e g y  as  d efi n e d i n t h e  dr aft I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni z ati o n (I C H)  E 9 
A d d e n d u m.  
T h e s e c o n d  esti m a n d  of i nt er est is t h e  attri b ut a bl e  esti m a n d,  d efi n e d  as t h e  eff e ct  of tr e at m e nt 
i n s u bj e cts  attri b ut a bl e t o t h e r a n d o mi z e d tr e at m e nt  ass u mi n g t h at  m ai nt e n a n c e t h er a p y is  n ot 
c h a n g e d.  F or t his  esti m a n d,  dis c o nti n u ati o n  of r a n d o mi z e d tr e at m e nt f or t ol er a bilit y  or  c h a n g e 
i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol is  c o nsi der e d  a  n e g ati v e  o ut c o m e.  T his 
esti m a n d is  a  mi xt ur e  of  c o m p osit e  a n d  h y p ot h eti c al str at e gi es  as  d efi n e d i n t h e  dr aft I C H  E 9 
a d d e n d u m.  
T h e t hir d  esti m a n d  of i nt er est is t h e  eff e cti v e n ess  esti m a n d  w hi c h is  a  c o m bi n ati o n  of t h e 
h y p ot h eti c al  a n d tr e at m e nt  p oli c y str at e gi es  as  d efi n e d i n t h e  dr aft I C H  E 9  a d d e n d u m.  T h e 
str at e g y is  h y p ot h eti c al i n t h at t h e tr e at m e nt  eff e ct  will  b e  esti m at e d  wit h o ut  c oll e cti n g  d at a 
p ost t h e i nt er c urr e nt  e v e nt  of  dis c o nti n u ati o n fr o m r a n d o mi z e d tr e at m e nt.  H o w e v er, t h e 
str at e g y is  c o nsist e nt  wit h t h e tr e at m e nt  p oli c y str at e g y i n t h at t h e tr e at m e nt  eff e ct is  esti m at e d 
irr es p e cti v e  of t h e  o c c urr e n c e  of t h e i nt er c urr e nt  e v e nt  of  a  c h a n g e i n t h e  m ai nt e n a n c e t h er a p y. 
T h e f o urt h  esti m a n d  of i nt er est is t h e  d e f a ct o  esti m a n d,  d efi n e d  as t h e  eff e ct  of  a tr e at m e nt 
p oli c y r e g ar dl ess  of  o c c urr e n c e  of i nt er c urr e nt  e v e nt;  c h a n g es i n  m ai nt e n a n c e t h er a p y  or 
pr e m at ur e  dis c o nti n u ati o n  of r a n d o mi z e d tr e at m e nt.  T his  esti m a n d is  c o nsi d er e d  a tr e at m e nt 
p oli c y str at e g y  as  d efi n e d i n t h e  dr aft I C H  E 9  a d d e n d u m. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1  of  1 5 9  
T A B L E  O F  C O N T E N T S  
Cli ni c al  St u d y  Pr ot o c ol  .............................................................................................................. 1 
TI T L E  P A G E  ............................................................................................................................. 1 
V E R SI O N  HI S T O R Y  ................................................................................................................ 1 
C LI NI C A L  S T U D Y  P R O T O C O L  S Y N O P SI S ......................................................................... 3 
T A B L E  O F  C O N T E N T S  ......................................................................................................... 1 1 
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N  O F  T E R M S  ............................................ 1 7 
1  
I N T R O D U C TI O N ................................................................................................ 1 9 
1. 1  
B a c k gr o u n d  a n d r ati o n al e f or  c o n d u cti n g t his st u d y ............................................ 1 9  
1. 2  
R ati o n al e f or st u d y  d esi g n,  d os es,  a n d  c o ntr ol  gr o u ps .......................................... 2 0  
1. 3  
B e n efit/ris k  a n d  et hi c al  ass ess m e nt  ....................................................................... 2 1 
1. 4  
St u d y  d esi g n .......................................................................................................... 2 2  
1. 5  
St u d y  g o v er n a n c e  a n d  o v ersi g ht ........................................................................... 2 4  
1. 5. 1  
I n d e p e n d e nt  d at a  m o nit ori n g  c o m mitt e e ............................................................... 2 4 
1. 5. 2  
A dj u di c ati o n  c o m mitt e e  ........................................................................................ 2 5 
2  
S T U D Y  O BJ E C TI V E S  ......................................................................................... 2 5 
2. 1  
Pri m ar y  o bj e cti v e  .................................................................................................. 2 5 
2. 2  
S e c o n d ar y  o bj e cti v e .............................................................................................. 2 5  
2. 3  
S af et y  o bj e cti v e  ..................................................................................................... 2 6 
2. 4  
E x pl or at or y  o bj e cti v e ............................................................................................ 2 6  
3  
S U BJ E C T  S E L E C TI O N,  E N R O L L M E N T,  R A N D O MI Z A TI O N, 
R E S T RI C TI O N S,  T R E A T M E N T  DI S C O N TI N U A TI O N,  A N D  S T U D Y 
T E R MI N A TI O N  ................................................................................................... 2 7 
3. 1  
I n cl usi o n  crit eri a ................................................................................................... 2 7 
3. 2  
E x cl usi o n  crit eri a  .................................................................................................. 3 0 
3. 3  
S u bj e ct  e nr oll m e nt  a n d r a n d o mi z ati o n ................................................................. 3 2  
3. 4  
Pr o c e d ur es f or  h a n dli n g i n c orr e ctl y  e nr oll e d  or r a n d o mi z e d s u bj e cts .................. 3 3  
3. 5  
M et h o ds f or  assi g ni n g tr e at m e nt  gr o u ps ............................................................... 3 3  
3. 6  
M et h o ds f or  e ns uri n g  bli n di n g .............................................................................. 3 4  
3. 7  
M et h o ds f or  u n bli n di n g ......................................................................................... 3 4  
3. 8  
R e stri cti o ns............................................................................................................ 3 5 
3. 9  
Tr e at m e nt  dis c o nti n u ati o n  b y s u bj e ct  a n d/ or  S p o ns or .......................................... 3 5  
3. 1 0  
St u d y t er mi n ati o n  .................................................................................................. 3 6 
3. 1 1  
S cr e e n f ail ur es  ....................................................................................................... 3 7 
4  
S T U D Y  P L A N  A N D  TI MI N G  O F  P R O C E D U R E S  ............................................ 3 8 
4. 1  
S cr e e ni n g  a n d r u n-i n  p eri o d .................................................................................. 4 3  
4. 2  
R a n d o mi z ati o n/tr e at m e nt  p eri o d/ e xt e nsi o n  p h as e ................................................ 4 3  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 2  of  1 5 9  
4. 3  
E n d - of-st u d y  visit .................................................................................................. 4 4 
4. 4  
U ns c h e d ul e d  visit  a n d  pr e m at ur e  dis c o nti n u ati o n  visit ........................................ 4 5  
4. 5  
S af et y f oll o w- u p  p eri o d ........................................................................................ 4 5  
4. 6  
F oll o w- u p .............................................................................................................. 4 5  
5  
S T U D Y  A S S E S S M E N T S ..................................................................................... 4 6 
5. 1  
Effi c a c y  ass ess m e nts  ............................................................................................. 4 6 
5. 1. 1  
Ast h m a  e x a c er b ati o n  d efi niti o n ............................................................................ 4 6  
5. 1. 1. 1  
D efi niti o n  of  ast h m a si g ns/s y m pt o ms  w ors e ni n g ................................................. 4 6  
5. 1. 1. 2  
I n v esti g at or-j ustifi e d  ast h m a  e x a c er b ati o ns .......................................................... 4 7 
5. 1. 1. 3  
S e v er e  ast h m a  e x a c er b ati o ns  ................................................................................ 4 7 
5. 1. 1. 4  
Tr e at m e nt f or s e v er e  ast h m a  e x a c er b ati o ns  .......................................................... 4 7 
5. 1. 1. 5  
O ns et  a n d  d ur ati o n  of  ast h m a  e x a c er b ati o ns ......................................................... 4 8  
5. 1. 1. 6  
A p pr o a c h f or  c a pt uri n g  ast h m a  e x a c er b ati o ns ...................................................... 4 8  
5. 1. 2  
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e + 1 2/ P e di atri c  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e ........................................................................................................ 4 9  
5. 1. 2. 1  
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e + 1 2............................................................ 4 9  
5. 1. 2. 2  
P e di atri c  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e ................................................... 5 0 
5. 1. 3  
Ast h m a  C o ntr ol  Q u esti o n n air e- 5  a n d  - 7 ............................................................... 5 0 
5. 1. 4  
Ast h m a  C o ntr ol  T est ............................................................................................. 5 1  
5. 1. 5  
C hil d h o o d  Ast h m a  C o ntr ol  T est ........................................................................... 5 1  
5. 1. 6  
e Di ar y  .................................................................................................................... 5 1 
5. 1. 6. 1  
P e a k  e x pir at or y fl o w ............................................................................................. 5 1  
5. 1. 6. 2  
Us e  of i n v esti g ati o n al  pr o d u ct (r eli e v er t h er a p y) ................................................. 5 2  
5. 1. 6. 3  
e Di ar y  m ai nt e n a n c e t h er a p y  c o m pli a n c e  .............................................................. 5 2 
5. 1. 6. 4  
e Di ar y r e c or di n g  of  ast h m a s y m pt o ms ................................................................. 5 2  
5. 1. 7  
D et eri or ati o n  of  ast h m a  ......................................................................................... 5 3 
5. 1. 8  
L u n g f u n cti o n  m e as ur e m e nt  b y s pir o m etr y .......................................................... 5 3  
5. 1. 8. 1  
R e v ersi bilit y  T est  .................................................................................................. 5 4 
5. 1. 8. 2  
C O VI D - 1 9  a n d  P ul m o n ar y  F u n cti o n  T esti n g ....................................................... 5 4 
5. 2  
S af et y  ass ess m e nts  ................................................................................................ 5 4 
5. 2. 1  
L a b or at or y s af et y  ass ess m e nts  .............................................................................. 5 5 
5. 2. 2  
R esti n g  1 2- l e a d  el e ctr o c ar di o gr a m ....................................................................... 5 6 
5. 2. 3  
Vit al si g n  m e as ur e m e nts  ....................................................................................... 5 6 
5. 2. 4  
A d v ers e  e v e nt  ass ess m e nts  ................................................................................... 5 6 
5. 3  
Ot h er  ass ess m e nts  ................................................................................................. 5 6 
5. 3. 1  
P h ysi c al  e x a mi n ati o n  ............................................................................................ 5 6 
5. 3. 2  
C o n c o mit a nt  m e di c ati o ns  ...................................................................................... 5 7 
5. 4  
P h ar m a c o ki n eti cs  .................................................................................................. 5 7 
5. 5  
P h ar m a c o d y n a mi cs ............................................................................................... 5 7  
5. 6  
G e n eti cs  ................................................................................................................. 5 7 
5. 7  
Bi o m ar k er  a n al ysis  ................................................................................................ 5 7 
6  
S A F E T Y  R E P O R TI N G  A N D  M E DI C A L  M A N A G E M E N T  ............................. 5 8 
6. 1  
D efi niti o n  of  a d v ers e  e v e nts ................................................................................. 5 8  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 3  of  1 5 9  
6. 2  
D efi niti o ns  of s eri o us  a d v ers e  e v e nt ..................................................................... 5 8  
6. 3  
R e c or di n g  of  a d v ers e  e v e nts ................................................................................. 5 9  
6. 3. 1  
P eri o d f or  c oll e cti o n  of  a d v ers e  e v e nts ................................................................. 5 9  
6. 3. 2  
F oll o w- u p  of  u nr es ol v e d  a d v ers e  e v e nts ............................................................... 5 9  
6. 3. 3  
V ari a bl es  ............................................................................................................... 5 9 
6. 3. 4  
C a us alit y  c oll e cti o n  ............................................................................................... 6 0 
6. 3. 5  
D et eri or ati o ns  of  ast h m a  a n d s e v er e  ast h m a  e x a c er b ati o ns  .................................. 6 0 
6. 3. 6  
A d v ers e  e v e nts  b as e d  o n si g ns  a n d s y m pt o ms ...................................................... 6 0  
6. 3. 7  
A d v ers e  e v e nts  b as e d  o n  e x a mi n ati o ns  a n d t ests .................................................. 6 1  
6. 3. 8  
H y’s  L a w  ............................................................................................................... 6 1 
6. 3. 9  
C O VI D - 1 9  A d vers e  E v e nts  .................................................................................. 6 2 
6. 4  
R e p orti n g  of s eri o us  a d v ers e  e v e nts ...................................................................... 6 2  
6. 5  
O v er d os e ............................................................................................................... 6 3  
6. 6  
Pr e g n a n c y  .............................................................................................................. 6 3 
6. 6. 1  
M at er n al  e x p os ur e  ................................................................................................. 6 3 
6. 6. 2  
P at e r n al  e x p os ur e .................................................................................................. 6 4 
6. 7  
M e di c ati o n  err or  .................................................................................................... 6 4 
6. 8  
M a n a g e m e nt  of i n v esti g ati o n al  pr o d u ct- r el at e d t o xi citi es .................................... 6 5 
7  
I N V E S TI G A TI O N A L  P R O D U C T  A N D  O T H E R  T R E A T M E N T S ................... 6 6 
7. 1  
I d e ntit y  of i n v esti g ati o n al  pr o d u ct(s) .................................................................... 6 6 
7. 2  
D os e  a n d tr e at m e nt r e gi m e ns  ................................................................................ 6 6 
7. 3  
L a b elli n g  ............................................................................................................... 6 7 
7. 4  
St or a g e .................................................................................................................. 6 8  
7. 5  
C o m pli a n c e ........................................................................................................... 6 8  
7. 6  
A c c o u nt a bilit y  ....................................................................................................... 6 8 
7. 7  
M et er e d - d os e i n h al er:  h a n dli n g  a n d  cl e a ni n g ....................................................... 6 9 
7. 8  
C o n c o mit a nt  a n d  ot h er tr e at m e nts ........................................................................ 6 9  
7. 8. 1  
M ai nt e n a n c e t h er a pi es  ........................................................................................... 6 9 
7. 8. 2  
M e di c ati o ns t h at  m a y  aff e ct r e v ersi bilit y  a n d  F E V
1 t esti n g ................................. 6 9 
7. 8. 3  
Pr o hi bit e d  m e di c ati o ns .......................................................................................... 7 0  
7. 8. 4  
Ot h er  c o n c o mit a nt tr e at m e nt  ................................................................................. 7 1 
8  
S T A TI S TI C A L  A N A L Y S E S  ............................................................................... 7 2 
8. 1  
St atisti c al  c o nsi d er ati o ns  ....................................................................................... 7 2 
8. 1. 1  
Esti m a n ds  .............................................................................................................. 7 2 
8. 1. 2  
Pri m ar y  o ut c o m e  a n al ysis ..................................................................................... 7 3  
8. 1. 3  
T y p e  1  err or  c o ntr ol .............................................................................................. 7 3  
8. 2  
S a m pl e si z e  esti m at e  ............................................................................................. 7 4 
8. 3  
D efi niti o ns  of  a n al ysis s ets  ................................................................................... 7 4 
8. 3. 1  
F ull  a n al ysis s et  ..................................................................................................... 7 4 
8. 3. 2  
S af et y  a n al ysis s et  ................................................................................................. 7 5 
8. 4  
Vi ol ati o ns  a n d  d e vi ati o ns ...................................................................................... 7 5  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 4  of  1 5 9  
8. 5  
O ut c o m e  m e as ur es f or  a n al ys es  ............................................................................ 7 5 
8. 5. 1  
Pri m ar y  effi c a c y  a n al ysis  ...................................................................................... 7 5 
8. 5. 1. 1  
D eri v ati o n  of ti m e t o first s e v er e  ast h m a  e x a c er b ati o n ......................................... 7 5 
8. 5. 2  
S e c o n d ar y  effi c a c y  a n al ys es  ................................................................................. 7 5 
8. 5. 2. 1  
D eri v ati o n  of  a n n u ali z e d s e v er e  ast h m a  e x a c er b ati o n r at e  ................................... 7 6 
8. 5. 2. 2  
D eri v ati o n  of t ot al s yst e mi c  c orti c ost er oi d  e x p os ur e ............................................ 7 6  
8. 5. 2. 3  
D eri v ati o n  of  Ast h m a  C o ntr ol  Q u esti o n n air e- 5  v ari a bl es  .................................... 7 6 
8. 5. 2. 4  
D eri v ati o n  of  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e  + 1 2  a n d  P e di atri c  Ast h m a 
Q u alit y  of  Lif e  Q u esti o n n air e  v ari a bl es  ................................................................ 7 7 
8. 5. 3  
E x pl or at or y  a n al ys es ............................................................................................. 7 8  
8. 5. 3. 1  
D eri v ati o n  of  d et eri or ati o n  of  ast h m a  v ari a bl es .................................................... 7 8  
8. 5. 3. 2  
D eri v ati o n  of ti m e t o tr e at m e nt  dis c o nti n u ati o n  or  c h a n g e i n  m ai nt e n a n c e t h er a p y 
f or l a c k  of  ast h m a  c o ntr ol ..................................................................................... 7 8 
8. 5. 3. 3  
D eri v ati o n  of  Ast h m a  C o ntr ol  T est r es p o n d er  v ari a bl e ........................................ 7 8  
8. 5. 3. 4  
D eri v ati o n  of  ot h er  e Di ar y  v ari a bl es ..................................................................... 7 8  
8. 5. 3. 5  
I n h al e d  c orti c ost er oi d  e x p os ur e ............................................................................ 7 9 
8. 6  
M et h o ds f or st atisti c al  a n al ys es  ............................................................................ 7 9 
8. 6. 1  
A n al ysis  of t h e  pri m ar y  v ari a bl e ........................................................................... 7 9  
8. 6. 2  
A n al ysis  of t h e s e c o n d ar y  effi c a c y  v ari a bl es  ........................................................ 8 0 
8. 6. 2. 1  
S e v er e  ast h m a  e x a c er b ati o n r at e  ........................................................................... 8 0 
8. 6. 2. 2  
Ast h m a  C o ntr ol  Q u esti o n n air e- 5 .......................................................................... 8 1  
8. 6. 2. 3  
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e  + 1 2  a n d  P e di atri c  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e ........................................................................................................ 8 2  
8. 6. 2. 4  
T ot al s yst e mi c  c orti c ost er oi d  e x p os ur e ................................................................. 8 2  
8. 6. 3  
A n al ysis  of s af et y  v ari a bl es  .................................................................................. 8 2 
8. 6. 3. 1  
A d v ers e  e v e nts  ...................................................................................................... 8 2 
8. 6. 3. 2  
Vi t al si g ns ............................................................................................................. 8 2 
8. 6. 3. 3  
Cli ni c al  c h e mistr y  a n d  h e m at ol o g y  ....................................................................... 8 3 
8. 6. 3. 4  
C o n c o mit a nt  m e di c ati o n  ....................................................................................... 8 3 
8. 6. 4  
A n al ysis  of  e x pl or at or y  v ari a bl es ......................................................................... 8 3  
8. 6. 4. 1  
D et eri or ati o n  of  ast h m a  ......................................................................................... 8 3 
8. 6. 4. 2  
Pr e br o n c h o dil at or  F E V 1 ........................................................................................ 8 3 
8. 6. 4. 3  
M or ni n g  p e a k  e x pir at or y  fl o w............................................................................... 8 4 
8. 6. 4. 4  
Ot h er  e Di ar y  v ari a bl es  .......................................................................................... 8 4 
8. 6. 4. 5  
Ti m e t o tr e at m e nt  dis c o nti n u ati o n  or  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of 
ast h m a  c o ntr ol ....................................................................................................... 8 4  
8. 6. 4. 6  
Ast h m a  C o ntr ol  T est ............................................................................................. 8 4  
8. 6. 4. 7  
I n h al e d  c orti c ost er oi d  e x p os ur e ............................................................................ 8 5 
8. 6. 5  
S u b gr o u p  a n al ysis ................................................................................................. 8 5  
8. 6. 6  
S e nsiti vit y  a n al ysis  ................................................................................................ 8 5 
8. 6. 6. 1  
Ti p pi n g  p oi nt  a n al ysis ........................................................................................... 8 5  
8. 6. 6. 2  
Attri b ut a bl e  esti m a n d  ............................................................................................ 8 5 
8. 6. 6. 3  
Eff e cti v e n ess  esti m a n d  .......................................................................................... 8 5 
8. 6. 6. 4  
D e f a ct o  esti m a n d .................................................................................................. 8 6 
8. 6. 6. 5  
C O VI D -1 9  p a n d e mi c i m p a cts  ............................................................................... 8 6 
9  
S T U D Y  A N D  D A T A  M A N A G E M E N T  .............................................................. 8 7 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 5  of  1 5 9  
9. 1  
Tr ai ni n g  of st u d y sit e st aff .................................................................................... 8 7  
9. 2  
M o nit ori n g  of t h e st u d y......................................................................................... 8 7  
9. 2. 1  
S o ur c e  d at a  ............................................................................................................ 8 8 
9. 2. 2  
St u d y  a gr e e m e nts .................................................................................................. 8 8  
9. 2. 3  
Ar c h i vi n g  of st u d y  d o c u m e nts .............................................................................. 8 8 
9. 3  
St u d y ti m et a bl e  a n d  e n d- of-st u d y ......................................................................... 8 8  
9. 4  
D at a  m a n a g e m e nt  .................................................................................................. 8 9 
1 0  
E T HI C A L  A N D  R E G U L A T O R Y  R E Q UI R E M E N T S  ........................................ 9 1 
1 0. 1  
Et hi c al  c o n d u ct  of t h e st u d y .................................................................................. 9 1  
1 0. 2  
S u bj e ct  d at a  pr ot e cti o n  .......................................................................................... 9 1 
1 0. 3  
Et hi cs  a n d r e g ul at or y r e vi e w ................................................................................. 9 1  
1 0. 4  
I nf or m e d  c o ns e nt/ ass e nt ........................................................................................ 9 2 
1 0. 5  
C h a n g es t o t h e  cli ni c al st u d y  pr ot o c ol  a n d i nf or m e d  c o ns e nt/ ass e nt f or m ........... 9 2  
1 0. 6  
A u dits  a n d i ns p e cti o ns .......................................................................................... 9 3  
1 1  
LI S T  O F  R E F E R E N C E S  ...................................................................................... 9 4 
1 2  
S U M M A R Y  O F  C H A N G E S  ................................................................................ 9 6 
1 2. 1  
C h a n g es  m a d e t o  V ersi o n  3. 0 ............................................................................... 9 6  
1 2. 2  
C h a n g es  m a d e t o  V ersi o n  2. 0 ............................................................................... 9 9  
1 2. 3  
C h a n g es  m a d e t o  V ersi o n  1. 0 ............................................................................. 1 0 5  
A P P E N DI X  A,  A VI L LI O N  P R O T O C O L  SI G N A T U R E  P A G E .......................................... 1 1 2 
A P P E N DI X  B,  P RI M A R Y I N V E S TI G A T O R  SI G N A T U R E  P A G E  .................................. 1 1 3 
A P P E N DI X  C,  G L O B A L I NI TI A TI V E  F O R  A S T H M A ( GI N A,  2 0 1 8)  ............................. 1 1 4 
A P P E N DI X  D,  A D DI TI O N A L  S A F E T Y I N F O R M A TI O N  ................................................ 1 1 6 
A P P E N DI X  E,  H Y’ S  L A W  ................................................................................................... 1 1 9 
A P P E N DI X  F,  A S T H M A  Q U A LI T Y  O F  LI F E  + 1 2  Q U E S TI O N N AI R E  ........................... 1 2 4 
A P P E N DI X  G,  P E DI A T RI C  A S T H M A  Q U A LI T Y  O F  LI F E  Q U E S TI O N N AI R E ............ 1 3 0 
A P P E N DI X  H,  A S T H M A  C O N T R O L  Q U E S TI O N N AI R E -5  A N D  - 7............................... 1 3 5 
A P P E N DI X I,  A S T H M A  C O N T R O L  T E S T  ........................................................................ 1 4 4 
A P P E N DI X J,  C HI L D H O O D  A S T H M A  C O N T R O L  T E S T  ............................................... 1 4 5 
A P P E N DI X  K,  LI S T  O F  E -DI A R Y  Q U E S TI O N S  ............................................................... 1 4 6 
A P P E N DI X  L,  M E T E R E D -D O S E I N H A L E R  H A N D LI N G  A N D  C L E A NI N G  ................ 1 4 8 
A P P E N DI X  M,  S PI R O M E T R Y  A S S E S S M E N T  C RI T E RI A  .............................................. 1 5 5 
A P P E N DI X  N,  C O VI D -1 9  E M E R G E N C Y  M E A S U R E S  P E R MI T T E D  T O  E N S U R E 
S U BJ E C T  S A F E T Y  ............................................................................................ 1 5 7 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 6  of  1 5 9  
LI S T  O F  T A B L E S  
T a bl e   1   
St u d y  Ass ess m e nts  a n d  Pr o c e d ur es ............................................................. 3 9 
T a bl e   2  
L a b or at or y  S af et y  V ari a bl es  ........................................................................ 5 5 
T a bl e   3   
I n v esti g ati o n al  Pr o d u ct  Str e n gt h  a n d  D os a g e  F or m .................................... 6 6 
T a bl e   4  
M e di c ati o ns  R estri ct e d  Ti m e  Li mit  Pri or t o  a n y  L u n g  F u n cti o n  T esti n g  
(r e v ersi bilit y  a n d  F E V1) ............................................................................... 7 0 
 
LI S T  O F  FI G U R E S  
Fi g ur e  1   
St u d y  d esi g n ................................................................................................ 2 4  
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 7  of  1 5 9  
LI S T  O F  A B B R E VI A TI O N S  A N D  D E FI NI TI O N  O F  T E R M S  
T h e f oll o wi n g  a b br e vi ati o ns  a n d s p e ci al t er ms  ar e  us e d i n t his  Cli ni c al  St u d y  Pr ot o c ol. 
A b b r e vi ati o n  o r s p e ci al 
t e r m 
E x pl a n ati o n  
A C Q - 5 
Ast h m a  C o ntr ol  Q u esti o n n air e - 5 
A C Q - 7 
Ast h m a  C o ntr ol  Q u esti o n n air e - 7 
A C T  
Ast h m a  C o ntr ol  T est  
A E  
a d v ers e  e v e nt  
AI T  
all er g y i m m u n ot h er a p y  
A L T  
al a ni n e  a mi n otr a nsf er as e ( or  al a ni n e tr a ns a mi n as e)  
A Q L Q + 1 2  
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars  a n d  ol d er  
A S  M DI ( P T 0 0 7)   
al b ut er ol s ulf at e  m et er e d -d os e i n h al er  
A S T  
as p art at e  a mi n otr a nsf er as e  
B D A  
b u d es o ni d e/ al b ut er ol  
B D A  M DI ( P T 0 2 7)   
b u d es o ni d e/ al b ut er ol  m et er e d -d os e i n h al er  
β -h C G  
β -h u m a n  c h ori o ni c  g o n a d otr o pi n  
B MI  
b o d y  m ass i n d e x  
C  A C T  
C hil d h o o d  Ast h m a  C o ntr ol  T est  
E C  
Et hi cs  C o m mitt e e, s y n o n y m o us t o I nstit uti o n al  R e vi e w  B o ar d (I R B)  a n d 
I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E C) 
E C G  
el e ctr o c ar di o gr a m  
e C R F  
el e ctr o ni c  c as e r e p ort f or m  
E O S  
e n d -of -st u d y 
e P R O  
el e ctr o ni c  p ati e nt r e p ort e d  o ut c o m e  
F A S  
f ull  a n al ysis s et 
F E V 1 
f or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d 
F V C  
f or c e d  vit al  c a p a cit y 
G C P  
G o o d  Cli ni c al  Pr a cti c e  
GI N A  
Gl o b al  I niti ati v e f or Ast h m a  
G M P  
G o o d  M a n uf a ct uri n g  Pr a cti c e  
H F A  
h y dr ofl u or o al k a n e  
H L  
H y’s  L a w  
I C F 
i nf or m e d  c o ns e nt f or m 
I C H 
I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni z ati o n 
I C S 
i n h al e d  c orti c ost er oi d 
I D M C 
I n d e p e n d e nt  D at a  M o nit ori n g  C o m mitt e e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 8  of  1 5 9  
A b b r e vi ati o n  o r s p e ci al 
t e r m 
E x pl a n ati o n  
I nt er n ati o n al 
C o or di n ati n g i n v esti g at or  
If  a st u d y is  c o n d u ct e d i n s e v er al  c o u ntri es, t h e I nt er n ati o n al  C o or di n ati n g 
I n v esti g at or is t h e i n v esti g at or  c o or di n ati n g t h e i n v esti g at ors  a n d/ or  a cti viti es 
i nt er n ati o n all y.  
I P 
i n v esti g ati o n al  pr o d u ct 
I W R S 
I nt er a cti v e  W e b  R es p o ns e  S yst e m 
L A B A  
l o n g-a cti n g  β 2 -a g o nist  
L A M A  
l o n g-a cti n g  m us c ari ni c  a nt a g o nist  
L T R A   
l e u k otri e n e r e c e pt or  a nt a g o nist 
M DI  
m et er e d -d os e i n h al er  
m e d  
m e di u m  
MI D  
mi ni m al i m p ort a nt  diff er e n c e  
M M R M  
mi x e d  m o d el r e p e at e d  m e as ur es  
O C S  
or al  c orti c ost er oi ds  
P A Q L Q  
P e di atri c  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e  
P C D  
pri m ar y  c o m pl eti o n  d at e  
P D V  
pr e m at ur e  dis c o nti n u ati o n  visit  
P E F  
p e a k  e x pir at or y  fl o w 
P F T  
p ul m o n ar y f u n cti o n t est  
P H L  
P ot e nti al  H y’s  L a w  
Pr n  
as  n e e d e d  
S A B A  
s h ort/r a pi d -a cti n g  β 2 -a dr e n or e c e pt or  a g o nist  
S A M A  
s h ort-a cti n g  m us c ari ni c  a nt a g o nist  
S A E  
s eri o us  a d v ers e  e v e nts 
S A P  
St atisti c al  A n al ysis  Pl a n  
S C S  
s yst e mi c  c orti c ost er oi ds  
S M A R T  
S y m bi c ort is  a p pr o v e d f or  m ai nt e n a n c e  a n d r eli e v er t h er a p y  
T B L  
t ot al  bilir u bi n 
T C  
t el e p h o n e  c all 
U L N  
u p p er li mit  of  n or m al  
W B D C  
W e b  B as e d  D at a  C a pt ur e  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 9  of  1 5 9  
1   
I N T R O D U C TI O N 
1. 1   
B a c k g r o u n d  a n d  r ati o n al e f o r  c o n d u cti n g t his st u d y  
B o n d  A villi o n  2  D e v el o p m e nt  L P ( S p o ns or) is  d e v el o pi n g  b u d es o ni d e/ al b ut er ol s ulf at e ( P T 0 2 7; 
h er e aft er r ef err e d t o  as  b u d es o ni d e  a n d  al b ut er ol  m et er e d -d os e i n h al er [ B D A  M DI]  a n d  al b ut er ol 
s ulf at e ( h er e aft er r ef err e d t o  as  al b ut er ol [ A S  M DI])  pr ess uri z e d i n h al ati o n s us p e nsi o n  pr o d u cts 
i n  a d ults  a n d  c hil dr e n  4  y e ars  of  a g e  or  ol d er  wit h  ast h m a.  Pl e as e r ef er t o t h e  c urr e nt I n v esti g at or 
Br o c h ur e ( 2 0 1 9)  f or  a d diti o n al i nf or m ati o n. 
Al b ut er ol is  a s h ort/r a pi d -a cti n g  β 2 - a dr e n or e c e pt or  a g o nist ( S A B A), i n d u ci n g  air w a y s m o ot h 
m us cl e r el a x ati o n  a n d r e d u ci n g  or  pr e v e nti n g  br o n c h o c o nstri cti o n.  Al b ut er ol is  a p pr o v e d i n 
m a n y  c o u ntri es i n  m ulti pl e f or m ul ati o ns f or tr e at m e nt  or  pr e v e nti o n  of  br o n c h o c o nstri cti o n,  a n d 
is  als o  k n o w n  u n d er t h e  g e n eri c  n a m e  of s al b ut a m ol. I n  cli ni c al  pr a cti c e,  al b ut er ol is  us e d  as  a n 
as  n e e d e d ( pr n) r eli e v er t h er a p y ( Gl o b al I niti ati v e f or  Ast h m a [ GI N A]  2 0 1 8 ). 
B u d es o ni d e is  a  w ell- est a blis h e d  a nti-i nfl a m m at or y  c orti c ost er oi d t h at  e x hi bits  p ot e nt 
gl u c o c orti c oi d  a n d  w e a k  mi n er al o c orti c oi d  a cti vit y  a n d is  a p pr o v e d  w orl d wi d e i n  or all y i n h al e d 
f or m ul ati o ns f or t h e tr e at m e nt  of  ast h m a  a n d  c hr o ni c  o bstr u cti v e  p ul m o n ar y  dis e as e  b ot h  as  a 
m o n o- pr o d u ct  a n d i n  c o m bi n ati o n  wit h  a l o n g/r a pi d- a cti n g  β 2 - a g o nist ( L A B A, f or m ot er ol).  
I n  vitr o st u di es  h a v e  d e m o nstr at e d t h at i n h al e d  c orti c ost er oi d (I C S)  a g e nts  p ot e nti at e t h e  eff e cts 
of  S A B As i n r e d u ci n g  air w a y s m o ot h  m us cl e t o n e ( M e n d es  2 0 0 8 )  a n d  c a n r e v ers e  a dr e n er gi c 
r e c e pt or t ol er a n c e  a n d  d es e nsiti z ati o n (C o o p er  a n d  P a n etti eri  2 0 0 8 ).  Cli ni c all y, si mil ar f u n cti o n al 
p ot e nti ati o n  wit h  c o m bi n e d I C Ss  a n d  al b ut er ol  h as  b e e n  o bs er v e d i n  p ati e nts  wit h  ast h m a f or 
f u n cti o n al  m e as ur es  of  air w a y s m o ot h  m us cl e  a n d  air w a y  bl o o d fl o w (M e n d es  2 0 1 5 ).  A n 
a n al ysis  of  4 2 5  ast h m a  e x a c er b ati o ns i n  p ati e nts fr o m t h e  F A C E T st u d y ( T att ersfi el d  1 9 9 9 ) 
r e v e al e d t h at  ast h m a s y m pt o ms  a n d i n cr e as e d r eli e v er t h er a p y  us e  w er e  n ot e d  o v er s e v er al  d a ys 
b ef or e t h e st art  of  a n  ast h m a  e x a c er b ati o n.  C o m bi ni n g t h e  us e  of  a  S A B A ( al b ut er ol)  wit h 
b u d es o ni d e i n t h e  pr o p os e d  b u d es o ni d e  a n d  al b ut er ol  m et er e d- d os e i n h al er ( B D A  M DI) 
c o m bi n ati o n  pr o d u ct s h o ul d  n ot  o nl y  pr o vi d e r a pi d  br o n c h o dil ati o n,  b ut  als o tr e at  w ors e ni n g 
air w a y i nfl a m m ati o n  b y t h e  a d diti o n  of t h e  b u d es o ni d e  c o m p o n e nt.  P er  c urr e nt tr e a t m e nt 
g ui d eli n es ( GI N A  2 0 1 8 ), I C S/f or m ot er ol  m ai nt e n a n c e  a n d r eli e v er  c a n  b e  us e d i n  p ati e nts  wit h 
m o d er at e  or s e v er e  ast h m a.  St u di es  of  b u d es o ni d e  a n d  a r a pi d- a cti n g  L A B A (f or m ot er ol)  as 
r eli e v er  h a v e  d e m o nstr ate d  e n h a n c e d  pr ot e cti o n fr o m s e v er e  e x a c er b ati o ns i n  p ati e nts  alr e a d y 
r e c ei vi n g  c o m bi n ati o n t h er a p y f or  m ai nt e n a n c e  wit h o ut  a n i n cr e as e i n  a d v ers e  eff e cts (R a b e 
2 0 0 6 ; O' B yr n e  2 0 0 5 ). I n  a d diti o n,  b u d es o ni d e/f or m ot er ol  as  m ai nt e n a n c e  a n d r eli e v er 
si g nifi c a ntl y r e d u c e d s e v er e  e x a c er b ati o n ris k i n  p e di atri c  p ati e nts ( O' B yr n e  2 0 0 7 ).  
I n s o m e  m ar k ets,  S y m bi c ort  T ur b u h al er ( her e aft er r ef err e d t o  as  S y m bi c ort) is  a p pr o v e d f or 
m ai nt e n a n c e  a n d r eli e v er t h er a p y ( S M A R T).  Wit h  S M A R T  a p pli c ati o n,  p ati e nts  wit h  ast h m a  us e 
S y m bi c ort  as  m ai nt e n a n c e i n h al ati o n  m e di c ati o n  a n d  als o  pr n i n r es p o ns e t o s y m pt o ms.  T h e 
si m ult a n e o us  a d mi nistr ati o n  of  b u d es o ni d e  wit h f or m ot er ol  w h e n s y m pt o ms  o c c ur  e ns ur es t h at 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 0  of  1 5 9  
p ati e nts  wit h  ast h m a r e c ei v e  b ot h  a r a pi d - a cti n g  br o n c h o dil at or f or s y m pt o m r eli ef  a n d  a nti-
i nfl a m m at or y  m e di c ati o n t o tr e at t h eir  p ersist e nt  air w a y i nfl a m m ati o n. It is i m p ort a nt t o  n ot e t h at 
t h e  pr n  a d mi nistr ati o n  of I C S i n t his tr e at m e nt r e gi m e n is  n ot  e x p e ct e d t o si g nifi c a ntl y i n cr e as e 
o v er all st er oi d l o a d ( m ostl y  b e c a us e  of  a r e d u cti o n i n t h e  n u m b er  of s e v er e  e x a c er b ati o n 
e pis o d es, r es ulti n g i n f e w er  p ati e nts r e q uiri n g s yst e mi c  c orti c ost er oi d ( S C S)  d os es  as  a c ut e 
tr e at m e nt).  B D A  M DI is  pr o p os e d t o  b e  a v ail a bl e  pr n f or s y m pt o m  c o ntr ol t o  all  p ati e nts  wit h 
ast h m a, r e g ar dl ess  of  m ai nt e n a n c e t h er a p y.  
W h e n  p ati e nts  us e t h e  B D A  M DI  pr o d u cts  as  n e e d e d i n r es p o ns e t o  ast h m a s y m pt o ms, it is 
e x p e ct e d t h at t h eir ris k  of  e x p eri e n ci n g  a n  ast h m a  e x a c er b ati o n  will  b e l o w er t h a n i n s u bj e cts 
usi n g  al b ut er ol  al o n e.   
1. 2   
R ati o n al e f o r st u d y  d esi g n,  d os es,  a n d  c o nt r ol  g r o u ps  
T h e st u d y  will  c o m p ar e  B D A  M DI  at  2  diff er e nt  d os es  wit h  A S  M DI i n  a d ults  a n d  c hil dr e n 
4  y e ars  of  a g e  or  ol d er  wit h  m o d er at e t o s e v er e  ast h m a.  
T h e  cli ni c al st a n d ar d  of  c ar e f or s u bj e cts  wit h  m o d er at e t o s e v er e  ast h m a is  a 
m e di u m- t o- hi g h- d os e I C S  or l o w-t o- hi g h- d os e I C S i n  c o m bi n ati o n  wit h  L A B A,  wit h  a  S A B A 
s u c h  as  al b ut er ol t o  us e  pr n i n r es p o ns e t o s y m pt o ms (i e, r eli e v er t h er a p y).  W h e n s u bj e cts r e q uir e 
fr e q u e nt r eli e v er t h er a p y,  a d diti o n al  a nti-i nfl a m m at or y  m e di c ati o n  m a y  pr o vi d e  b e n efit  b y  e arl y 
r e a cti o n t o i n cr e as e d  ast h m a s y m pt o ms t h at  ar e r efl e cti v e  of  a n i n ci pi e nt s e v er e  e x a c er b ati o n. 
B D A   M DI  w o ul d  pr e v e nt  or r e d u c e  br o n c h o c o nstri cti o n  a n d  pr o vi d e  a d diti o n al  a nti-
i nfl a m m at or y  m e di c ati o n  w h e n  n e e d e d  at t h e ti m e  of s y m pt o ms.  S af et y  a n d  effi c a c y  of  B D A 
M DI  will  b e  c o m p ar e d  wit h  A S  M DI  b e c a us e  al b ut er ol is t h e st a n d ar d  of  c ar e r eli e v er t h er a p y  i n 
r es p o ns e t o s y m pt o ms. 
T h e  o bj e cti v e  of t his r a n d o mi z e d,  d o u bl e- bli n d,  m ulti c e nt er,  p ar all el - gr o u p st u d y is t o  e v al u at e, 
wit hi n  a t y pi c al  d esi g n f or t h e  d e v el o p m e nt  of  n e w  ast h m a t h er a pi es, t h e  b e n efit  of  B D A  M DI 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms i n  a d ults  a n d  c hil dr e n  4  y e ars  of  a g e  or  ol d er  wit h 
m o d er at e t o s e v er e  ast h m a r e c ei vi n g  m e di u m -t o- hi g h- d os e I C S  or l o w-t o- hi g h- d os e I C S i n 
c o m bi n ati o n  wit h  L A B A,  wit h  or  wit h o ut  a n  a d diti o n al  c o ntr oll er t h er a p y (l e u k otri e n e r e c e pt or 
a nt a g o nist [ L T R A], l o n g- a cti n g  m us c ari ni c  a nt a g o nist [ L A M A]  or t h e o p h ylli n e).    
T h e  pri m ar y  e n d p oi nt is t h e ti m e t o first s e v er e  ast h m a  e x a c er b ati o n,  a n d s e c o n d ar y  e n d p oi nts 
i n cl u d e t h e  a n n u ali z e d s e v er e  e x a c er b ati o n r at e  a n d  ast h m a s y m pt o m  c o ntr ol  as  m e as ur e d  b y 
Ast h m a  C o ntr ol  Q u esti o n n air e- 5 ( A C Q - 5).   
T h e tr e at m e nt  d ur ati o n f or t h e st u d y  will  b e  at l e ast  2 4  w e e ks f or  e a c h s u bj e ct t o s u p p ort t h e 
s u bj e ct  e x p os ur e  d at a.  T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e ( e xt e nsi o n  p h as e)  u ntil t h e 
r e q uir e d  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts,  as  d efi n e d  p er  pr ot o c ol,  h a v e  b e e n r e a c h e d  a n d t h e 
l ast  a d ult s u bj e ct  h as  c o m pl et e d  2 4  w e e ks  of tr e at m e nt,  w hi c h  will  b e  d efi n e d  as t h e  pri m ar y 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 1  of  1 5 9  
c o m pl eti o n  d at e ( P C D).  N ot  all  p e di atri c s u bj e cts  will  h a v e  2 4  w e e ks  of tr e at m e nt  at ti m e  of 
P C D.  
T w o  d os a g e l e v els  of  B D A  M DI,  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g ( gi v e n  as  4 0/ 9 0  μ g  a n d  8 0/ 9 0  μ g, 
r es p e cti v el y,  p er  a ct u ati o n),  ar e i n cl u d e d i n t his st u d y t o s u p p ort fi n al  d os e s el e cti o n f or 
a p pr o v al.  C hil dr e n  a g e d  4 t o  1 1  y e ars  will  o nl y  b e r a n d o mi z e d t o t h e l o w er  d os a g e l e v el  of  B D A 
M DI,  8 0/ 1 8 0  μ g,  or  A S  M DI ( 9 0  μ g  p er  a ct u ati o n).    
B D A  M DI  a n d  A S  M DI  ar e I Ps.  T h e  d os e  c h os e n f or  A S  M DI ( al b ut er ol) is i n li n e  wit h t h e 
a p pr o v e d l a b el f or  Pr o v e ntil ® wit h  w hi c h  A S  M DI  h as  b e e n  d e m o nstr at e d t o  b e  e q ui v al e nt i n t h e 
D 6 9 3 0 C 0 0 0 0 2  c u m ul ati v e  d os e st u d y  a n d  D 6 9 3 0 C 0 0 0 0 1  d os e fi n di n g st u d y.  B u d es o ni d e  d os es 
w er e  ass ess e d i n t h e  d os e -r a n gi n g  St u d y  P T 0 0 8 0 0 1.  T h e  b u d es o ni d e  d os es  c h os e n f or  B D A  M DI 
will  all o w  ass ess m e nt  of t h e  p ot e nti al t o  pr o vi d e t h er a p e uti c  b e n efit i n  pr n  us e  w hil e  a v oi di n g 
e x c essi v e st er oi d  d osi n g  wit hi n t h e  a p pli c a bl e  a g e r a n g es. 
1. 3   
B e n efit/ ris k  a n d  et hi c al  ass ess m e nt  
B D A  M DI  m a y  pr o vi d e  b e n efit i n s u bj e cts i n t er ms  of  p ot e nti al r e d u cti o n i n t h e ris k  of  ast h m a 
e x a c er b ati o n  a n d i m pr o v e m e nt i n t h e  c o ntr ol  of  ast h m a s y m pt o ms  a n d l u n g f u n cti o n  b e y o n d 
w h at is t y pi c all y s e e n  wit h  al b ut er ol  al o n e ( R a b e   2 0 0 6; O' B yr n e  2 0 0 5 ; O' B yr n e  2 0 0 7 ). I n 
a d diti o n, t h e  S p o ns or  b eli e v es  t h at t h e a d mi nistr ati o n  of  B D A  M DI t o  s u bj e cts wit h  ast h m a  will 
a c hi e v e t h e r a pi d  i m pr o v e m e nt i n l u n g f u n cti o n fr o m  al b ut er ol, t h e a nti -i nfl a m m at or y eff e ct  
attri b ut a bl e  t o b u d es o ni d e,   a n d  p ot e nti all y a d diti o n al  b e n efits  attri b ut a bl e  t o t h e c o m bi n ati o n  of 
al b ut er ol  a n d   b u d es o ni d e. 
T h e ris k  of  a dr e n al s u p pr essi o n,  p arti c ul arl y  d uri n g  a  p eri o d  of str ess (i nf e cti o n, s ur g er y,  et c)  h as 
b e e n  n ot e d i n t h e  C a n a di a n  pr o d u ct  m o n o gr a p h f or  P ul mi c ort  T ur b u h al er ® .  Th e  S p o ns or 
c o nsi d ers it is r el e v a nt t o  m o nit or st er oi d  eff e cts i n s u bj e cts.   As s u c h, r o uti n e t ests  of  a dr e n al 
c ortis ol f u n cti o n  h a v e  b e e n  b uilt i nt o t his st u d y t o  m o nit or f or  a dr e n al s u p pr essi o n ris k:  m or ni n g 
s er u m  c ortis ol  will  b e  ass ess e d.    
F urt h er,  h ei g ht ( c m)  m e as ur e m e nts  will  b e  ass ess e d  m or e fr e q u e ntl y i n s u bj e cts  ≤ 1 8  y e ars  of  a g e, 
t o  m o nit or f or  a n y  p ossi bl e  eff e cts  o n  gr o wt h. 
C O VI D - 1 9 
R e c e nt i nf or m ati o n fr o m t h e  A m eri c a n  A c a d e m y  of  All er y  Ast h m a  a n d I m m u n ol o g y ( A A A AI) 
p u blis h e d  o n t h eir  w e bsit e ( htt ps:// w w w. a a a ai. or g/ c o n diti o ns- a n d -tr e at m e nts/li br ar y/ ast h m a-
li br ar y/ c o vi d-ast h m a)  i n   
i n di c at es t h at  c urr e ntl y t h er e is  n o  e vi d e n c e  of i n cr e as e d 
i nf e cti o n r at es i n  p ati e nts  wit h  ast h m a  a n d t h at  b est  pr a cti c e is t o  e ns ur e t h at  a  p ati e nt’s  ast h m a is 
c o ntr oll e d. I n t h e  M A N D A L A st u d y, s u bj e cts  ar e  m ai nt ai n e d  o n  a st a bl e  ast h m a tr e at m e nt 
r e gi m e n  a n d  cl os el y  m o nit or e d  w hil e st a yi n g i n t h e st u d y.  T h e s p o ns or  b eli e v es t h at t h e  b e n efit 
ris k  ass ess m e nt f or tri al  p arti ci p a nts t o  e nr oll  a n d  c o nti n u e i n t h e st u d y is  p ositi v e.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 2  of  1 5 9  
1. 4   
St u d y  d esi g n   
T his is  a r a n d o mi z e d,  d o u bl e- bli n d,  m ulti c e nt er,  p ar all el - gr o u p,  v ari a bl e-l e n gt h,  e v e nt- dri v e n 
st u d y  wit h  a tr e at m e nt  p eri o d  of  at l e ast  2 4  w e e ks f or  e a c h s u bj e ct.  T h e  p ur p os e  of t his st u d y is 
t o  c o mp ar e  2  d os es  of  B D A  M DI  wit h  A S  M DI  o n t h e ti m e t o first s e v er e  ast h m a  e x a c er b ati o n 
(S e cti o n  5. 1. 1 ) i n  a d ult,  a d ol es c e nt,  a n d  p e di atri c s u bj e cts  wit h  m o d er at e t o s e v er e  ast h m a  as 
d efi n e d  b y  GI N A.  S u bj e cts  will  a d mi nist er r a n d o mi z e d i n v esti g ati o n al  pr o d u ct (I P)  pr n i n 
r es p o ns e t o  ast h m a s y mpt o ms.  S e e  Fi g ur e  1  f or  a  gr a p hi c al  pr es e nt ati o n  of t h e st u d y s c h e m a  a n d 
T a bl e   1 f or  a list  of st u d y  ass ess m e nts. 
S u bj e cts  att e n di n g s cr e e ni n g ( Visit  1)  will  e nt er  a  1 4 - t o  2 8- d a y s cr e e ni n g  a n d r u n-i n  p eri o d.  T h e 
s cr e e ni n g  p eri o d  m a y  b e  e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks f or s u bj e cts  w h o  h a v e  a s e v er e 
ast h m a  e x a c er b ati o n  aft er  Visit  1.  S u bj e cts  m a y  c o ns e nt f or t h e st u d y i n  a d v a n c e  of  Visit  1  a n d if 
r e q uir e d, r e q u est f or  m e di c al r e c or ds t o s u p p ort  e vi d e n c e  of  pri or  e x a c er b ati o ns  wit h o ut 
tri g g eri n g t h e  2 8- d a y s cr e e ni n g  p eri o d.  S cr e e n e d s u bj e cts  will  c o nti nu e t o t a k e t h eir r e g ul ar 
ast h m a  m ai nt e n a n c e t h er a p y t hr o u g h o ut t h e st u d y (fr o m s cr e e ni n g [ Visit  1/ 1 a,  as  a p pli c a bl e]) 
t hr o u g h t h e tr e at m e nt  p eri o d).  At  Visit  1,  eli gi bl e s u bj e cts  will  dis c o nti n u e t h eir  us u al  pr n 
i n h al e d  pr o d u ct  us e d f or s y m pt o m r eli ef  a n d  b e gi n  S p o ns or- pr o vi d e d  V e nt oli n t o  b e  us e d  pr n i n 
r es p o ns e t o s y m pt o ms  or  pri or t o  e x er cis e  d uri n g t h e s cr e e ni n g  p eri o d  o nl y.  S u bj e cts  will  b e 
as k e d t o t ur n i n t h eir  o w n i n h al e d r eli e v er  pr o d u cts t o t h e i n v esti g ati o n al sit es f or st or a g e  u ntil 
t h e i n di vi d u al s u bj e ct l ast st u d y  visit.  Eli gi bl e s u bj e cts  will  b e r a n d o mi z e d  at  Visit  2.   
At r a n d o mi z ati o n ( Visit  2),  a d ult  a n d  a d ol es c e nt s u bj e cts ( a g e d  ≥ 1 2  y e ars)  w h o  m e et t h e 
eli gi bilit y  crit eri a  will  b e r a n d o ml y  assi g n e d t o  1  of t h e f oll o wi n g  3 tr e at m e nt  gr o u ps i n  a  1: 1: 1 
r ati o  as r eli e v er t h er a p y  o n t o p  of  us u al  c ar e.  C hil dr e n  a g e d  4 t o  1 1  y e ars  will  b e r a n d o mi z e d i n  a 
1: 1 r ati o  o nl y t o t h e l o w er  B D A  M DI  d os a g e  or  A S  M DI: 
•   B D A  M DI  8 0/ 1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  B D A  M DI  4 0/ 9 0  μ g  p er  p uff)  pr n   
•   B D A  M DI  1 6 0/ 1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  B D A  M DI  8 0/ 9 0  μ g  p er  p uff)  pr n  
•   A S  M DI  1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  A S  M DI  9 0  μ g  p er  p uff)  pr n  
T h e  m a xi m u m  d ail y  d os a g e  of I P s h o ul d  n ot  e x c e e d  1 2  p uffs  p er  d a y.  S u bj e cts  will  b e 
r e c o m m e n d e d  n ot t o t a k e  m or e t h a n  8  p uffs  p er  d a y  a n d  a d vis e d t o  c o nt a ct t h e i n v esti g at or if 
t h eir s y m pt o ms  n e c essit at e  m or e t h a n  8  p uffs i n  a  d a y. 
T h e  m a xi m u m  d ail y  d os a g e is  1 2  p uffs ( B D A  M DI  4 8 0/ 1 0 8 0  µ g  or  9 6 0/ 1 0 8 0  µ g,  or  A S  M DI 
1 0 8 0  µ g). I n  or d er t o  e ns ur e s af et y  a n d  m o nit or  d ail y tr e at m e nt st at u s,  all s u bj e cts  will  b e 
pr o vi d e d  wit h  a n  el e ctr o ni c  di ar y ( e Di ar y:  A M 3  d e vi c e).  T h e  e Di ar y tr a nsf ers  d at a  e v er y  2 4 
h o urs  a cr oss  a r a n g e  of  ast h m a s y m pt o m s c or es  a n d  dr u g  us a g e (i e,  n u m b er  of  p uffs i n h al e d) t o 
ass ess  a s u bj e ct’s  ast h m a st at us.  S u bj e cts  will   us e t h e  e Di ar y f or r e p orti n g  d ail y  us e  of I P  a n d 
a n y s y m pt o ms. If s y m pt o ms  a n d/ or  d ail y  d os a g e  e x c e e d  a  pr ot o c ol-s p e cifi e d t hr es h ol d, t h e 
e Di ar y  will  g e n er at e  a n  al ert t o t h e s u bj e ct  a n d t h e i n v esti g ati o n al sit e. I n t his  w a y,  d ail y I P 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 3  of  1 5 9  
us a g e  will  b e  m o nit o r e d  cl os el y  b y t h e i n v esti g at ors  a n d  m e di c al  m o nit ors t o  ass ess  a n y 
w ors e ni n g  of s u bj e ct st at us.  A cti o n  will  b e t a k e n  w h er e  cli ni c all y i n di c at e d. 
T h e st u d y  will  c o nsist  of  3  p eri o ds:  
•   S cr e e ni n g  p eri o d ( 1 4 t o  2 8  d a ys)  e x c e pt  w h er e  a s e v er e  e x a c er b ati o n  e v e n t  o c c urs  d uri n g t h e 
s cr e e ni n g  p eri o d,  a n d t his  m a y  b e  e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks. ( S u bj e cts  m a y 
c o ns e nt f or t h e st u d y i n  a d v a n c e  of  Visit  1  a n d if r e q uir e d, r e q u est f or  m e di c al r e c or ds t o 
s u p p ort  e vi d e n c e  of  pri or  e x a c er b ati o ns  wit h o ut tri g g eri n g t h e  2 8- d a y s cr e e ni n g  p eri o d.) 
•   Tr e at m e nt  p eri o d  of  at l e ast  2 4  w e e ks.  T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e ( e xt e nsi o n 
p h as e)  u ntil t h e r e q uir e d  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts,  as  d efi n e d  p er  pr ot o c ol,  h a v e 
b e e n r e a c h e d  a n d t h e l ast  a d ult  s u bj e ct  h as c o m pl et e d  2 4  w e e ks  of tr e at m e nt,  w hi c h  will  b e 
d efi n e d  as t h e  P C D . N ot  all  p e di atri c s u bj e cts  will  h a v e  2 4  w e e ks  of tr e at m e nt  at ti m e  of 
P C D.  
I n t h e  e v e nt  5 7 0  e v e nts  will  b e  c a pt ur e d b ef o r e  t h e l ast s u bj e ct  h as  h a d  2 4  w e e ks  of 
tr e at m e nt,  all s u bj e cts  o n tr e at m e nt f or  ≥ 2 4 w e e ks  will  h a v e t h eir  e n d -of -st u d y ( E O S) 
visit  at t h eir  n e xt s c h e d ul e d  cli ni c  visit.  All s u bj e cts  o n tr e at m e nt f or  < 2 4  w e e ks  will 
c o nti n u e  u ntil  2 4  w e e ks  at  w hi c h  p oi nt t h e y  will  c o m pl et e t h eir  E O S  visit  
I n t h e  e v e nt  5 7 0  e v e nts  will  b e  c a pt ur e d aft e r  t h e l ast s u bj e ct  h as  h a d  2 4  w e e ks  of tr e at m e nt, 
e a c h s u bj e ct  will r et ur n t o  c o m pl et e t h e  E O S  visit  at t h eir  n e xt s c h e d ul e d  cli ni c  visit  
•   S af et y f oll o w- u p  p eri o d:  w h er e  a s af et y f o ll o w- u p t el e p h o n e  c o nt a ct  will  o c c ur  2  w e e ks 
( ± 4  d a ys)  aft er t h e s u bj e ct’s  E O S  visit  or  pr e m at ur e  dis c o nti n u ati o n  visit ( P D V),  w hi c h e v er 
o c c urs first  
T h e st u d y  will  b e  c o m pl et e d  w h e n t h e l ast s u bj e ct  h as  c o m pl et e d  his/ h er  p ost-st u d y f oll o w- u p 
t el e p h o n e  c o nt a ct.  S u bj e cts  w h o  dis c o nti n u e I P  will  c o m pl et e  a  P D V,  a n d  a d v ers e  e v e nts 
( A Es)/s eri o us  a d v ers e  e v e nts ( S A Es)  will  b e f oll o w e d  u p if  m e di c all y i n di c at e d. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 4  of  1 5 9  
Fi g u r e   1  
St u d y  d esi g n   
 
A b br e vi ati o ns:   A S  M DI = al b ut er ol  m et er e d -d os e i n h al er;  B D A  M DI = b u d es o ni d e/ al b ut er ol  m et er e d -d os e i n h al er; 
I C S =i n h al e d  c orti c ost er oi d;  L A B A =l o n g-a cti n g  β 2 -a g o nist;  N = n u m b er;  P R N = as  n e e d e d;  R =r a n d o mi z ati o n; 
S A B A = s h ort -a cti n g  β 2 -a dr e n or e c e pt or  a g o nist;  S V =s cr e e ni n g  visit;  W = w e e k.   
 
1. 5   
St u d y  g o v e r n a n c e  a n d  o v e rsi g ht  
1. 5. 1   
I n d e p e n d e nt  d at a  m o nit o ri n g  c o m mitt e e 
A n i n d e p e n d e nt  d at a  m o nit ori n g  c o m mitt e e (I D M C)  will  b e  est a blis h e d t o  ass ess t h e  o n g oi n g 
s af et y  of t h e st u d y.  T h e I D M C  will r e vi e w  bli n d e d  d at a ( o p e n s essi o n)  a n d  u n bli n d e d s af et y 
d at a ( cl os e d s essi o n) t o  ass ess  a n y s af et y r el at e d r e as o ns  w h y t h e st u d y s h o ul d  c o nti n u e,  b e 
m o difi e d,  or st o p p e d.  Cl os e d s essi o ns  will  b e s u p p ort e d  b y t h e  u n bli n d e d st atisti ci a n  a n d 
r es p o nsi biliti es  of t h e I D M C  will  b e  cl arifi e d  wit hi n  a  c h art er  b ef or e i niti ati o n  of t h e st u d y.  
T h e I D M C  c h air  a n d  all  c o m mitt e e  m e m b ers  will  b e i n d e p e n d e nt i n v esti g at ors/s p e ci alists 
s e p ar at e fr o m t h e st u d y t e a m  or  c o ntr a ct r es e ar c h  or g a ni z ati o n.    
All  d e cisi o ns  m a d e  b y t h e I D M C  will  b e  d o c u m e nt e d  wit hi n  writ t e n r e c or ds  of  m e eti n gs  a n d 
r e c o m m e n d ati o n  m a d e t o t h e  S p o ns or.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 5  of  1 5 9  
1. 5. 2   
A dj u di c ati o n  c o m mitt e e 
A n i n d e p e n d e nt  a dj u di c ati o n  c o m mitt e e  will  a dj u di c at e  c e ntr all y  a n d i n  a  bli n d e d f as hi o n  aft er 
m e di c al  m o nit ori n g r e vi e w,  c as es  w h er e  a r e p ort e d  d e at h,  e m er g e n c y r o o m  v isit,  ur g e nt  c ar e 
visit  a n d/ or  h os pit ali z ati o n,  c h a n g e i n  m e di c ati o n  a n d/ or  ot h er si g n/s y m pt o m is i n di c ati v e  of  a 
w ors e ni n g  of  ast h m a  b ut  h as  n ot  b e e n r e c or d e d  as s u c h i n t h e  el e ctr o ni c  c as e r e p ort f or m 
( e C R F).  F or  a n y  e v e nt t h at  q u alifi es f or  a dj u di c ati o n, st u d y sit es  will  b e  as k e d t o  pr o vi d e  d e-
i d e ntifi e d ( a n o n y mi z e d)  cli ni c al  d o c u m e nt ati o n s u c h  as  dis c h ar g e s u m m ari es, t o s u p p ort t h e 
e xt er n al  e v e nt  a dj u di c ati o n.  T h e t as ks  a n d r es p o nsi biliti es  of t h e  a dj u di c ati o n  c o m mitt e e  will 
b e fil e d i n  a  c h art er  b ef or e  i niti ati o n  of t h e st u d y  a n d  will  c o nt ai n  writt e n  o p er ati n g 
pr o c e d ur es.  T h e  a dj u di c ati o n  c o m mitt e e  will  m ai nt ai n t h e  a dj u di c ati o n r es ults i n  writi n g  a n d 
will  e nt er  d et ails  of  e v e nts  n ot r e c or d e d  wit hi n t h e  e C R F i nt o  a n  a dj u di c ati o n  pl atf or m.  T his 
d at a  will   b e r e p ort e d  al o n gsi d e t h e  e C R F  d at a i n t h e  Cli ni c al  St u d y  R e p ort. 
 
2   
S T U D Y  O B J E C TI V E S  
2. 1   
P ri m a r y  o bj e cti v e  
P ri m a r y  O bj e cti v e:  
P ri m a r y  e n d p oi nt:  
T o  e v al u at e t h e  effi c a c y  of  b u d es o ni d e/ al b ut er ol 
m et er e d -d os e i n h al er  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms 
c o m p ar e d t o  al b ut er ol  m et er e d -d os e i n h al er  1 8 0 
μ g  
Ti m e t o first s e v er e  ast h m a  e x a c er b ati o n   
 
2. 2   
S e c o n d a r y  o bj e cti v e  
S e c o n d a r y  O bj e cti v e:  
S e c o n d a r y  e n d p oi nt:  
T o  c h ar a ct eriz e t h e  eff e ct  of  b u d es o ni d e/ al b ut er ol 
m et er e d -d os e i n h al er  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms 
c o m p ar e d t o  al b ut er ol  m et er e d -d os e i n h al er  1 8 0 
μ g  
•   S e v er e  e x a c er b ati o n r at e ( a n n u aliz e d)  
•   T ot al s yst e mi c  c orti c ost er oi d  e x p os ur e  o v er t h e 
tr e at m e nt  p eri o d 
•   Ast h m a  C o ntr ol  Q u esti o n n air e -5 ( A C Q -5)  c h a n g e 
fr o m  b as eli n e  a n d r es p o n d er  a n al ysis  at  W e e k  2 4 
•   Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars 
a n d  ol d er ( A Q L Q + 1 2)/ P e di atri c  Ast h m a  Q u alit y  of 
Lif e  Q u esti o n n air e ( P A Q L Q)  c h a n g e fr o m  b as eli n e 
a n d r es p o n d er  a n al ysis  at  W e e k  2 4  
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 6  of  1 5 9  
2. 3   
S af et y  o bj e cti v e  
S af et y  O bj e cti v e:  
S af et y  E n d p oi nts:  
T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of 
b u d es o ni d e/  al b ut er ol  m et er e d -d os e i n h al er 
8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g  a d mi nist er e d  pr n i n 
r es p o ns e t o s y m pt o ms  c o m p ar e d t o  al b ut er ol 
m et er e d -d os e i n h al er  1 8 0  μ g  
•   A d v ers e  e v e nts/s eri o us  a d v ers e  e v e nts  
•   Vit al si g ns  
•   Cli ni c al  c h e mistr y  a n d  h e m at ol o g y  p ar a m et ers  
•   El e ctr o c ar di o gr a m  
 
2. 4   
E x pl o r at o r y  o bj e cti v e  
Ot h e r  O bj e cti v e:  
E x pl o r at o r y  E n d p oi nts:  
T o  c h ar a ct eriz e t h e  eff e ct  of  b u d es o ni d e/ al b ut er ol 
m et er e d -d os e i n h al er  8 0/ 1 8 0  μ g  a n d  1 6 0/ 1 8 0  μ g 
a d mi nist er e d  pr n i n r es p o ns e t o s y m pt o ms 
c o m p ar e d t o  al b ut er ol  m et er e d -d os e i n h al er  1 8 0 
μ g  
•   Ast h m a  C o ntr ol  Q u esti o n n air e -5  c h a n g e fr o m 
b as eli n e  a n d r es p o n d er  a n al ysis  at  W e e k  1 2  
•   Ast h m a  C o ntr ol  Q u esti o n n air e -5  c h a n g e fr o m 
b as eli n e  a n d r es p o n d er ( 3 -f a ct or)  a n al ysis  at 
W e e k  1 2  a n d  W e e k  2 4  
•   Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars 
a n d  ol d er/ P e di atri c  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e  c h a n g e fr o m  b as eli n e  a n d r es p o n d er 
a n al ysis  at  W e e k  1 2  
•   D et eri or ati o ns  of  ast h m a ( a n n u aliz e d r at e  a n d ti m e 
t o first) 
•   C h a n g e fr o m  b as eli n e i n  pr e br o n c h o dil at or f or c e d 
e x pir at or y  v ol u m e i n  1 s e c o n d  at  W e e k  1 2  a n d  W e e k 
2 4   
•   M or ni n g  a n d  e v e ni n g  p e a k  e x pir at or y fl o w  
•   Us e  of i n v esti g ati o n al  pr o d u ct (r eli e v er t h er a p y)   
•   Ast h m a  d a yti m e/ ni g ht -ti m e s y m pt o ms 
•   Ti m e t o tr e at m e nt  dis c o nti n u ati o n  or  c h a n g e i n 
m ai nt e n a n c e t h er a p y  
•   Ast h m a  C o ntr ol  T est ( A C T)  or  C hil d h o o d  Ast h m a 
C o ntr ol  T est ( C  A C T)  c h a n g e fr o m  b as eli n e  a n d 
r es p o n d er  a n al ysis  at  W e e k  2 4  
•   P er c e nt a g e  of  “ as  n e e d e d ” -fr e e  d a ys  
•   P er c e nt a g e  of s y m pt o m -fr e e  d a ys  
•   P er c e nt a g e  of  ast h m a  c o ntr ol  d a ys  
•    I n h al e d  c orti c ost er oi d  e x p os ur e  o v er t h e tr e at m e nt 
p eri o d  
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 7  of  1 5 9  
3   
S U B J E C T  S E L E C TI O N,  E N R O L L M E N T,  R A N D O MI Z A TI O N, 
R E S T RI C TI O N S,  T R E A T M E N T  DI S C O N TI N U A TI O N,  A N D 
S T U D Y  T E R MI N A TI O N   
E a c h s u bj e ct  m ust  m e et  all  of t h e i n cl usi o n  crit eri a  a n d  n o n e  of t h e  e x cl usi o n  crit eri a f or t his 
st u d y.  N o  w ai v ers  will  b e  gr a nt e d fr o m t h e  S p o ns or f or  a n y s u bj e ct  n ot  m e eti n g i n cl usi o n  or 
e x cl usi o n  crit eri a.    
N o st u d y-r el at e d  pr o c e d ur es  m a y  b e  p erf or m e d  b ef or e t h e s u bj e ct  h as si g n e d t h e  Et hi cs 
C o m mitt e e ( E C)  a p pr o v e d I nf or m e d  C o ns e nt  F or m (I C F)/ ass e nt f or m. 
3. 1   
I n cl usi o n  c rit e ri a 
F or i n cl usi o n i n t h e  st u d y, s u bj e cts  m ust f ulfill t h e f oll o wi n g  crit eri a  wit hi n t h e s cr e e ni n g 
p eri o d: 
1   A bl e  a n d  willi n g t o  pr o vi d e  writt e n i nf or m e d  c o ns e nt  or si g n  a g e- a p pr o pri at e f or ms, 
s u bj e cts  b el o w l e g al  a g e  of  c o ns e nt  m ust  h a v e  p ar e nt(s)  or  g u ar di a n si g n t h e I C F  b ef or e 
p ar ti ci p ati o n  
2   F e m al e  or  m al e  a g e d  ≥ 4  y e ars  at t h e ti m e  of i nf or m e d  c o ns e nt i n  all  c o u ntri es  wit h t h e 
e x c e pti o n  of t h e f oll o wi n g: i n  S er bi a,  o nl y s u bj e cts  ≥ 1 2  y e ars  ol d  will  b e  e nr oll e d; i n 
G er m a n y,  Sl o v a ki a,  a n d  U kr ai n e,  o nl y s u bj e cts  ≥ 1 8  y e ars  ol d  will  b e  e nr oll e d.  
3   Di a g n osis  of  ast h m a  as  d efi n e d  b y  GI N A  crit eri a  at l e ast  1  y e ar  b ef or e  Visit  1  
4   R e c ei vi n g  1  of t h e f oll o wi n g s c h e d ul e d  ast h m a  m ai nt e n a n c e t h er a pi es f or  3  m o nt hs  wit h 
st a bl e  d osi n g f or  at l e ast t h e l ast  4  w e e ks  b ef or e  Visit  1: 
( a) M e di u m- t o-- hi g h- d os e I C S (A p p e n di x  C;  GI N A  2 0 1 8 ) 
( b) M e di u m- t o-- hi g h- d os e I C S  a n d  1  a d diti o n al  m ai nt e n a n c e t h er a p y fr o m t h e f oll o wi n g: 
L T R A,  L A M A,  or t h e o p h ylli n e 
( c) L o w -t o- hi g h- d os e I C S i n  c o m bi n ati o n  wit h  L A B A  wit h  or  wit h o ut  1  a d diti o n al 
m ai nt e n a n c e t h er a p y fr o m t h e f oll o wi n g:  L T R A,  L A M A,  or t h e o p h ylli n e 
i.  
U p t o  2 0 %  of  all r a n d o mi z e d s u bj e cts ( o n I C S  al o n e  or I C S i n  c o m bi n ati o n 
wit h  L A B A)  will  b e  p er mitt e d t o  h a v e  a n  a d diti o n al  m ai nt e n a n c e  m e di c ati o n 
(t h e o p h ylli n e, l e u k otri e n e r e c e pt or  a nt a g o nist,  or  L A M A).  
T h e  b el o w  d efi n es t h e  mi ni m all y  a c c e pt a bl e  d o c u m e nt ati o n r e q uir e d t o s u p p ort i n cl usi o n 
crit eri o n  4: 
o   Si g n e d  a n d  d at e d  n ot es fr o m  a r ef erri n g  p h ysi ci a n, i n cl u di n g  n a m e,  d os e,  a n d 
d ur ati o n  of t h e I C S  or I C S/ L A B A i n h al er ( or  n a m es  a n d  d os es, if  us e d  as 
s e p ar at e i n h al ers)  a n d  L T R A,  L A M A,  or t h e o p h ylli n e, if  a p pli c a bl e,  a n d/ or 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 8  of  1 5 9  
o   E vi d e n c e  of  pr es cri pti o ns f or  a n I C S, I C S/ L A B A,  a n d  L T R A,  L A M A,  or 
t h e o p h ylli n e if  a p pli c a bl e,  m e di c ati o ns t h at  d e m o nstr at e  c o v er a g e f or t h e 
d ur ati o n s p e cifi e d i n i n cl usi o n  crit eri a 
5   Pr e br o n c h o dil at or f or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d ( F E V 1)  of  ≥ 4 0 t o  < 9 0 %  pr e di ct e d 
n or m al  v al u e f or  a d ults,  a n d  ≥ 6 0 %   pr e di ct e d  n or m al  v al u e f or s u bj e cts  a g e d  4 t o  1 7 y e ars 
aft er  wit h h ol di n g t h e  m e di c ati o ns s p e cifi e d i n  T a bl e   4. If  F E V1  v al u es  ar e  n ot  wit hi n t h e 
p er mitt e d r a n g e  at  Visit  1,  1 r e -t est  m ust  b e  p erf or m e d  at  Visit  1 a  b ef or e  a d v a n ci n g t o 
Visit  2  or  c o nfir mi n g s cr e e n f ail ur e.  N ot e:  S u bj e cts  4 t o  1 7  y e ars  of  a g e  w h o  pr e vi o usl y 
f ail e d i n cl usi o n  crit eri o n  5  d u e t o t h e  pr e vi o us  u p p er  F E V1 li mit  will  b e  p er mitt e d t o r e-
s cr e e n  o n c e  a n d  will  b e r e q uir e d t o  m e et  all  ot h er  eli gi bilit y  crit eri a  u p o n r e -s cr e e ni n g. 
6   S u bj e cts  a g e d  ≥ 1 2  y e ars  of  a g e  m ust  d e m o nstr at e r e v ersi bilit y  at  Visit  1,  wit h  a n i n cr e as e 
i n  F E V1 ≥ 1 2 % ( a n d  ≥ 2 0 0  m L f or s u bj e cts  a g e d  ≥ 1 8  y e ars) r el ati v e t o  b as eli n e  aft er 
a d mi nistr ati o n  of  S p o ns or- pr o vi d e d  V e nt oli n  vi a  c e ntr al s pir o m etr y. If r e v ersi bilit y is  n ot 
d e m o nstr at e d  at  Visit  1,  1 r e- t est f or r e v ersi bilit y t esti n g  m ust  b e  d o n e  at  Visit  1 a  b efor e 
a d v a n ci n g t o  Visit  2  or  c o nfir mi n g s cr e e n f ail ur e.  S u bj e cts  a g e d  4 t o  1 1  y e ars  of  a g e  will 
p erf or m t h e r e v ersi bilit y t est,  b ut  d o  n ot r e q uir e  d e m o nstr ati o n  of r e v ersi bilit y  d uri n g 
Visit  1  a n d  m a y  e nr oll  pr o vi d e d  d o c u m e nt e d  hist ori c al r e v ersi bilit y  wit hi n  1  y e ar is 
a v ail a bl e.  S u bj e cts  a g e d  4 t o  1 1  y e ars  w h o  pr e vi o usl y f ail e d i n cl usi o n  crit eri o n  6  will  b e 
p er mitt e d t o r es cr e e n.  E a c h s u bj e ct  m a y r e -s cr e e n  o nl y  o n c e. 
7   D e m o nstr at e  a c c e pt a bl e s pir o m etr y  p erf or m a n c e (i e,  m e et  A m eri c a n  T h or a ci c 
S o ci et y/ E ur o p e a n  R es pir at or y  S o ci et y  a c c e pt a bilit y/r e p e at a bilit y  crit eri a) ( A p p e n di x  M, 
S pir o m etr y  Ass ess m e nt  Crit eri a ).  S u bj e cts  4 t o  1 1  y e ars  will  b e  eli gi bl e if t h e y  pr o vi d e 
2  a c c e pt a bl e/r e p e at a bl e  m e as ur e m e nts.  
8   A  d o c u m e nt e d  hist or y  of  at l e ast  1 s e v er e  ast h m a  e x a c er b ati o n  wit hi n  1 2  m o nt hs  b ef or e 
Visit   1 
F or i n cl usi o n,  a s e v er e  e x a c er b ati o n is  c o nsi d er e d t o  b e  a n y  d et eri or ati o n  of  ast h m a t h at 
l e d t o  at l e ast  1  of t h e f oll o wi n g  c o n diti o ns: 
o   A t e m p or ar y  b ol us/ b urst  of  S C S f or  at l e ast  3  c o ns e c uti v e  d a ys;  a si n gl e  d e p o -
i nj e ct a bl e  d os e  of  c orti c ost er oi ds  will  b e  c o nsi d er e d  e q ui v al e nt t o  a  3-d a y  c o urs e 
of  S C S  
o   A n  e m er g e n c y r o o m  or  ur g e nt  c ar e  visit ( d efi n e d  as  e v al u ati o n  a n d  tr e at m e nt f or 
< 2 4   h o urs i n  a n  e m er g e n c y  d e p art m e nt  or  ur g e nt  c ar e  c e nt er)  b e c a us e  of  ast h m a 
t h at r e q uir e  S C S ( as  p er t h e  a b o v e) 
o   A n i n - p ati e nt  h os pit ali z ati o n ( d efi n e d  as  a d missi o n t o  a n i n-p ati e nt f a cilit y  a n d/ or 
e v al u ati o n  a n d tr e at m e nt i n  a  h e alt h c ar e f a cilit y f or  ≥ 2 4  h o urs)  b e c a us e  of 
ast h m a  
T h e  b el o w  d efi n es  w h at is  a c c e pt a bl e t o  d o c u m e nt  e x a c er b ati o ns f or i n cl usi o n i n t his 
st u d y:  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
2 9  of  1 5 9  
o   Dis c h ar g e s u m m ari es fr o m  a  h os pit al,  e m er g e n c y r o o m,  or  a n  ur g e nt  c ar e f a cilit y 
i n di c ati n g t h at  a s u bj e ct  w as  h os pit ali z e d or tr e at e d  wit h  S C S f or  a n  ast h m a 
e x a c er b ati o n  
o   Si g n e d  a n d  d at e d  n ot es fr o m  a r ef erri n g  p h ysi ci a n, i n cl u di n g i nf or m ati o n 
r e g ar di n g  di a g n osis  a n d tr e at m e nt  of  a n  e x a c er b ati o n  wit h  S C S 
o   S u bj e cts  c a n  pr o vi d e  e vi d e n c e  of  pr es cri pti o ns f or  S C S  us e d  d uri n g  a n 
e x a c er b ati o n  
9   Ast h m a  C o ntr ol  Q u esti o n n air e- 7 ( A C Q - 7) s c or e  ≥ 1. 5  ass ess e d  at  Visit  1  
1 0   A C Q -5 s c or e  ≥ 1. 5  ass ess e d  at  Visit  2  
1 1   Us e  of  S p o ns or- pr o vi d e d  V e nt oli n  pr n  m e di c ati o n  b e c a us e  of  ast h m a s y m pt o ms  o n  at 
l e ast  3  d a ys  d uri n g t h e l ast  w e e k  of t h e r u n-i n  p eri o d  b ef or e  Visit  2 
1 2   D e m o nstr at e  a c c e pt a bl e  M DI  a d mi nistr ati o n t e c h ni q u e  as  ass ess e d  b y t h e i n v esti g at or; 
us e  of s p a c ers  pr o hi bit e d 
1 3   A bl e t o  p erf or m  a c c e pt a bl e  a n d r e pr o d u ci bl e  p e a k  e x pir at or y  fl o w ( P E F)  m e as ur e m e nts  as 
ass ess e d  b y t h e i n v esti g at or 
1 4   B o d y  m ass i n d e x  < 4 0  k g/ m 2 
1 5   Willi n g t o r e m ai n  at t h e st u d y sit e  as  r e q uir e d  p er  pr ot o c ol  a n d  c o m pl et e  all  visit 
ass ess m e nts  
1 6   N e g ati v e  pr e g n a n c y t est (s er u m  at  Visit  1) f or f e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al 
1 7   W o m e n  of  c hil d b e ari n g  p ot e nti al  a n d s e x u all y  a cti v e i n  h et er os e x u al r el ati o ns hi ps  m ust 
a gr e e t o  1  of t h e f oll o wi n g  o pti o ns t o  pr e v e nt  pr e g n a n c y: 
( a) Pr a cti c e  c o m pl et e  a bsti n e n c e  d efi n e d  as r efr ai ni n g fr o m  h et er os e x u al i nt er c o urs e 
d uri n g t h e  e ntir e  p eri o d  of ris k  ass o ci at e d  wit h t h e st u d y tr e at m e nts.  P eri o di c 
a bsti n e n c e is  n ot  a c c e pt a bl e.  T h e r eli a bilit y  of s e x u al  a bsti n e n c e  n e e ds t o  b e  e v al u at e d 
i n r el ati o n t o t h e  d ur ati o n  of t h e  cli ni c al tri al  a n d t h e  pr ef err e d  a n d  us u al lif est yl e  of 
t h e s u bj e ct.  T h er ef or e,  c o m pl et e  a bsti n e n c e is  a n  a c c e pt a bl e  m et h o d  of  c o ntr a c e pti o n 
o nl y if it is  c o nsist e nt  wit h t h e  pr ef err e d  a n d  us u al lif est yl e  of t h e s u bj e ct.  
( b) If  a f e m al e  of  c hil d b e ari n g  p ot e nti al  a gr e es t o  pr e v e nt  pr e g n a n c y  b y  usi n g  1  of t h e 
f oll o wi n g  m et h o ds  of  birt h  c o ntr ol fr o m t h e  d at e t h e I C F is si g n e d  u ntil  2  w e e ks  aft er 
t h e fi n al  d os e  of I P is t a k e n: 
i.  
H or m o n al  c o ntr a c e pti o n ( e g,  or al  c o ntr a c e pti v e,  c o ntr a c e pti v e i m pl a nt,  or 
i nj e ct a bl e  h or m o n al  c o ntr a c e pti v e) 
ii.  
D o u bl e- b arri er  birt h  c o ntr ol (i e,  a  c o m bi n ati o n  of  m al e  c o n d o m  wit h  eit h er  c a p, 
di a p hr a g m,  or s p o n g e  wit h s p er mi ci d e,  a  c o n d o m  wit h s p er mi ci d e, i ntr a ut eri n e 
d e vi c e  [I U D]  a n d i ntr a ut eri n e  h or m o n e-r el e asi n g s yst e m [I U S]) 
iii.  
M ai nt e n a n c e  of  a  m o n o g a m o us s e x u al r el ati o ns hi p  wit h  a  m al e  p art n er  w h o  h as 
b e e n s ur gi c all y st erili z e d  b y  v as e ct o m y  pr o vi d e d t h at t h e  m al e  p art n er is t h e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 0  of  1 5 9  
s ol e s e x u al  p art n er  of t h e f e m al e ( of  c hil d b e ari n g  p ot e nti al)  p arti ci p a nt  a n d t h at 
t h e  v as e ct o mi z e d  p art n er  h as r e c ei v e d  m e di c al  ass ess m e nt  of t h e s ur gi c al 
s u c c ess (i e,  d o c u m e nt e d  hist or y  of  m e di c al  c o nfir m ati o n  of s u c c ess  of 
v as e ct o m y).  
N ot e:  W o m e n  ar e  c o nsi d er e d t o  b e  of  n o n c hil d b e ari n g  p ot e nti al if t h e y  ar e 
p h ysi ol o gi c all y i n c a p a bl e  of  b e c o mi n g  pr e g n a nt, i n cl u di n g  a n y f e m al e  w h o is  2  y e ars 
p ost m e n o p a us al ( a  p ost m e n o p a us al st at e is  d efi n e d  as  n o  m e ns es f or  1 2  m o nt hs  wit h o ut 
a n  alt er n ati v e  m e di c al  c a us e),  or s ur gi c all y st eril e,  d efi n e d  as  h a vi n g  a  bil at er al  
s al pi n g e ct o m y,  bil at er al  o o p h or e ct o m y,  or  h yst er e ct o m y.  T u b al li g ati o n  will  b e 
c o nsi d er e d  a n  a c c e pt a bl e  p er m a n e nt  birt h  c o ntr ol  m e as ur e f or t his  pr ot o c ol.  F or  p ur p os es 
of t his  pr ot o c ol,  m e n o p a us al  w o m e n  ar e  d efi n e d  as  w o m e n  w h o  ar e  a m e n orr h ei c f or 
1 2  c o ns e c uti v e  m o nt hs  or  m or e  aft er  c ess ati o n  of  all  e x o g e n o us  h or m o n al tr e at m e nt. 
A d ol es c e nt s p e cifi c r e c o m m e n d ati o ns: If s u bj e ct is f e m al e  a n d  h as r e a c h e d  m e n ar c h e,  or 
h as r e a c h e d  T a n n er st a g e  3  br e ast  d e v el o p m e nt ( e v e n if  n ot  h a vi n g r e a c h e d  m e n ar c h e), 
t h e s u bje ct  will  b e  c o nsi d er e d  a f e m al e  of  c hil d  b e ari n g  p ot e nti al.  
C o ntr a c e pti v e  m et h o ds  m a y  b e r e c o m m e n d e d f or  a d ol es c e nt f e m al es  o nl y if t h e y  ar e 
alr e a d y s e x u all y  a cti v e.  Us e  of  h or m o n al  c o ntr a c e pti v es i n  a d ol es c e nt f e m al es  m ust 
al w a ys  b e i n  c o ns ult ati o n  wit h  a  g y n e c ol o gist. 
1 8   M al e s u bj e cts  w h o  ar e s e x u all y  a cti v e i n  h et er os e x u al r el ati o ns hi ps  m ust  b e s ur gi c all y 
st eril e  or  a gr e e t o  us e  a  d o u bl e - b arri er  m et h o d  of  c o ntr a c e pti o n (i e,  a  c o m bi n ati o n  of  m al e 
c o n d o m  wit h  eit h er  c a p,  di a p hr a g m,  or s p o n g e  wit h s p er mi ci d e) fr o m t h e first  d os e  of 
r a n d o mi z e d I P  u ntil  2 w e e ks  aft er t h eir l ast  d os e.  M al e s u bj e cts  m ust  n ot  d o n at e s p er m 
d uri n g t h eir st u d y  p arti ci p ati o n  p eri o d. 
 
3. 2   
E x cl usi o n  c rit e ri a   
S u bj e cts  m ust  n ot  e nt er t h e st u d y if  a n y  of t h e f oll o wi n g  e x cl usi o n  crit eri a  ar e f ul fill e d  wit hi n 
t h e s cr e e ni n g  p eri o d: 
1   C hr o ni c  o bstr u cti v e  p ul m o n ar y  dis e as e  or  ot h er si g nifi c a nt l u n g  dis e as e ( e g,  c hr o ni c 
br o n c hitis,  e m p h ys e m a,  br o n c hi e ct asis  wit h t h e  n e e d  of tr e at m e nt,  c ysti c fi br osis,  or 
br o n c h o p ul m o n ar y  d ys pl asi a), i n cl u di n g r e g ul ar  or  o c c asi o n al  us e  of  o x y g e n 
2   Or al/ S C S  us e ( a n y  d os e  a n d  a n y i n di c ati o n)  wit hi n  6  w e e ks  b ef or e  Visit  1  
o   S u bj e cts  w h o  h a v e  e x p eri e n c e d  a n  ast h m a  e x a c er b ati o n r e q uiri n g  or al/s yst e mi c 
gl u c o c orti c ost er oi d i n t h e  6  w e e ks  b ef or e  Visit  1  c a n n ot  b e  e nr oll e d i n t h e st u d y 
b e c a us e  of t h e  6  w e e ks  w as h  o ut  of t h e  or al/ S C S,  b ut  c a n  e nt er  Visit  1  o n c e t h e 
w as h  o ut  p eri o d  h as  b e e n  m et 
3   C hr o ni c  us e  of  or al  c orti c ost er oi ds ( O C S,  ≥ 3  w e e ks  us e i n  3  m o nt hs  pri or t o  Visit  1)  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 1  of  1 5 9  
4   H a vi n g r e c ei v e d  a n y  m ar k et e d ( e g,  o m ali z u m a b,  m e p oli z u m a b, r esli z u m a b, 
b e nr ali z u m a b,  d u pil u m a b)  or i n v esti g ati o n al  bi ol o gi c  wit hi n  3  m o nt hs  or  5  h alf- li v es 
b ef or e  Visit   1,  w hi c h e v er is l o n g er,  or  a n y  ot h er  pr o hi bit e d  m e di c ati o n 
5   C urr e nt s m o k ers, f or m er s m o k ers  wit h  > 1 0  p a c k- y e ars  hist or y,  or f or m er s m o k ers  w h o 
st o p p e d s m o ki n g  < 6  m o nt hs  b ef or e  Visit  1 (i n cl u di n g  all f or ms  of t o b a c c o,  e- ci g ar ett es 
[ v a pi n g],  a n d  m arij u a n a) 
6   Lif e -t hr e at e ni n g  ast h m a  d efi n e d  as  a n y  hist or y  of si g nifi c a nt  ast h m a  e pis o d e(s) r e q uiri n g 
i nt u b ati o n  ass o ci at e d  wit h  h y p er c a p ni a, r es pir at or y  arr est,  h y p o xi c s ei z ur es,  or 
ast h m a -r el at e d s y n c o p al  e pis o d e(s)  wit hi n  5  y e ars  of  Visit  1 
7   C o m pl et e d tr e at m e nt f or l o w er r es pir at or y i nf e cti o n  or  ast h m a  e x a c er b ati o n  wit hi n 
6  w e e ks  of  Visit  1  
8   U p p er r es pir at or y i nf e cti o n i n v ol vi n g  a nti bi oti c tr e at m e nt  n ot r es ol v e d  wit hi n  7  d a ys 
b ef or e  Visit  1  
9   Cli ni c all y si g nifi c a nt l a b or at or y  a b n or m aliti es, i n t h e  o pi ni o n  of t h e i n v esti g at or,  or 
h a vi n g  a n y  of t h e f oll o wi n g r es ults  at  Visit  1:  
( a) a s er u m  cr e ati ni n e  v al u e  > 1. 5  ti m es t h e  u p p er li mit  of t h e r ef er e n c e r a n g e 
( b) a s er u m t ot al  bilir u bi n  v al u e  > 1. 5 ti m es t h e  u p p er li mit  of t h e r ef er e n c e r a n g e 
( c) a s er u m  al a ni n e  a mi n otr a nsf er as e ( A L T)  or  as p art at e  a mi n otr a nsf er as e ( A S T)  v al u e 
> 2. 5 ti m es t h e  u p p er li mit  of t h e r ef er e n c e r a n g e  
N ot e:  L a b or at or y t ests  m a y  b e r e p e at e d  o n c e: if l a b or at or y t ests  h a v e t o  b e r e p e at e d, t h e 
r es ults  m ust  b e  a v ail a bl e f or r e vi e w  b ef or e  Visit  2 (r a n d o mi z ati o n). 
1 0   H a vi n g  a n y  of t h e f oll o wi n g r es ults  at  Visit  1:  
( a) a n  a b n or m al  el e ctr o c ar di o gr a m ( E C G) t h at is, i n t h e i n v esti g at or’s  o pi ni o n,  cli ni c all y 
si g nifi c a nt 
( b) a  Q T C F i nt er v al  > 4 8 0  ms (s u bj e cts  a g e d  ≥ 1 2  y e ars)/  ≥ 4 6 0  ms (s u bj e cts  a g e d  4 t o 
1 1  y e ars,  b as e d  o n t h e  Fri d eri ci a  c orr e cti o n  w h er e  Q T C F = Q T/ R R 0. 3 3) 
1 1   Hist ori c al  or  c urr e nt  e vi d e n c e  of  a  cli ni c all y si g nifi c a nt   dis e as e i n cl u di n g,  b ut  n ot li mit e d 
t o:  c ar di o v as c ul ar ( e g,  c o n g esti v e  h e art f ail ur e,  k n o w n  a orti c  a n e ur ys m,  cli ni c all y 
si g nifi c a nt  c ar di a c  arr h yt h mi a,  c or o n ar y  h e art  dis e as e),  h e p ati c, r e n al,  h e m at ol o gi c al, 
n e ur o ps y c h ol o gi c al,  e n d o cri n e ( e g,  u n c o ntr oll e d  di a b et es  m ellit us,  u n c o ntr oll e d t h yr oi d 
dis or d er,  A d dis o n’s  dis e as e,  C us hi n g’s s y n dr o m e),  or  g astr oi nt esti n al ( e g,  p o orl y 
c o ntr oll e d  p e pti c  ul c er,  g astr o es o p h a g e al r efl u x  dis e as e)  dis or d ers.  Si g nifi c a nt is  d efi n e d 
as  a n y  dis e as e t h at, i n t h e  o pi ni o n  of t h e i n v esti g at or,  w o ul d  p ut t h e s af et y  of t h e s u bj e ct 
at ris k t hr o u g h st u d y  p arti ci p ati o n,  or t h at  c o ul d  aff e ct t h e  effi c a c y  or s af et y  a n al ysis if t h e 
dis e as e/ c o n diti o n  e x a c er b at e d  d uri n g t h e st u d y 
1 2   C a n c er  n ot i n  c o m pl et e r e missi o n f or  at l e ast  5  y e ars  b ef or e  Visit  1  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 2  of  1 5 9  
N ot e:  S u bj e cts  wit h s q u a m o us  c ell  c ar ci n o m a  of t h e s ki n,  b as al  c ell  c ar ci n o m a  of t h e s ki n, 
i n sit u  c ar ci n o m a  of t h e  c er vi x,  or l o c ali z e d  pr ost at e  c a n c er  ar e  eli gi bl e, if i n t h e  o pi ni o n 
of t h e i n v esti g at or, t h e  c o n diti o n  h as  b e e n  cli ni c all y  c o ntr oll e d  a n d t h e s u bj e ct’s 
p arti ci p ati o n i n t h e st u d y  w o ul d  n ot r e pr es e nt  a s af et y  c o n c er n. 
1 3   H os pit ali z ati o n f or  ps y c hi atri c  dis or d er  or  att e m pt e d s ui ci d e  wit hi n  1  y e ar  of  Visit  1  
1 4   Hist or y  of  ps y c hi atri c  dis e as e, i nt ell e ct u al  d efi ci e n c y,  p o or  m oti v ati o n,  or  ot h er 
c o n diti o ns if t h eir  m a g nit u d e is li miti n g i nf or m e d  c o ns e nt  v ali dit y  
1 5   Si g nifi c a nt  a b us e  of  al c o h ol  or  dr u gs, i n t h e  o pi ni o n  of t h e i n v esti g at or 
1 6   H a vi n g  a  k n o w n  or s us p e ct e d  h y p ers e nsiti vit y t o  al b ut er ol/s al b ut a m ol,  or  b u d es o ni d e 
a n d/ or t h eir  e x ci pi e nts 
1 7   H a vi n g  a s c h e d ul e d/ pl a n n e d  h os pit ali z ati o n  d uri n g t h e st u d y 
1 8   I n a bilit y t o  a bst ai n fr o m  pr ot o c ol- d efi n e d  pr o hi bit e d  m e di c ati o ns  d uri n g t h e st u d y 
1 9   Usi n g  a n y  h er b al  pr o d u cts  b y i n h al ati o n  or  n e b uli z er  wit hi n  2  w e e ks  of  Visit  1  a n d  n ot 
a gr e ei n g t o st o p  d uri n g t h e st u d y  d ur ati o n 
2 0   H a vi n g r e c ei v e d  a li v e  att e n u at e d  v a c ci n ati o n  wit hi n  7  d a ys  of  Visit  1. 
2 1   C urr e ntl y  pr e g n a nt  or  br e astf e e di n g 
2 2   St u d y i n v esti g at ors, s u bi n v esti g at ors,  c o or di n at ors,  a n d t h eir  e m pl o y e es  or i m m e di at e 
f a mil y  m e m b ers,  or  e m pl o y e es  of t h e  S p o ns or 
2 3   Tr e at m e nt  wit h  a n y i n v esti g ati o n al tr e at m e nt  or  d e vi c e i n  a n ot h er  cli ni c al st u d y  wit hi n t h e 
l ast  3 0  d a ys ( or  5 h alf -li v es,  w hi c h e v er is l o n g er)  of  Visit  1 
2 4   C urr e ntl y  p arti ci p ati n g i n  a n y i nt er v e nti o n al st u d y 
2 5   H a vi n g  pr e vi o usl y  b e e n r a n d o mi z e d i n t his st u d y  or  a n y  ot h er  P T 0 0 7  or  P T 0 2 7  cli ni c al 
st u d y 
2 6   S u bj e cts  w h o  e x p eri e n c e  > 1  ast h m a  e x a c er b ati o n  d uri n g t h e s cr e e ni n g  p eri o d 
 
Pr o c e d ur es f or  wit h dr a w al  of i n c orr e ctl y  e nr oll e d s u bj e cts  ar e  d es cri b e d i n  S e cti o n  3. 4 . 
3. 3   
S u bj e ct  e n r oll m e nt  a n d  r a n d o mi z ati o n  
A p pr o xi m at el y  3 0 0 0  a d ult  a n d  a d ol es c e nt s u bj e cts  wit h  m o d er at e t o s e v er e  ast h m a  will  b e 
r a n d o mi z e d t o  1  of  3 tr e at m e nt  gr o u ps ( a p pr o xi m at el y  1 0 0 0 s u bj e cts  p er  gr o u p). I n  a d diti o n, 
u p t o  1 0 0 s u bj e cts i n t h e  4 t o  1 1- y e ar  a g e  gr o u p  wit h  m o d er at e t o s e v er e  ast h m a  will  b e 
r a n d o mi z e d  wit h  a p pr o xi m at el y  5 0 s u bj e cts r a n d o mi z e d t o t h e  A S  M DI  a n d  5 0 s u bj e cts 
r a n d o mi z e d t o t h e l o w  d os e  B D A  M DI  gr o u ps  o nl y.  A p pr o xi m at el y  6 0 0 0 s u bj e cts  will  n e e d t o 
b e s cr e e n e d,  ass u mi n g  a n  esti m at e d s cr e e n f ail ur e r at e  of  3 0 % t o  5 0 %.  T his  P h as e III st u d y is 
pl a n n e d t o  b e  c o n d u ct e d  gl o b all y.   
T h e i n v esti g at or(s)  a n d/ or st u d y  p ers o n n el  will: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 3  of  1 5 9  
1   O bt a i n si g n e d i nf or m e d  c o ns e nt/ ass e nt ( as  a p pli c a bl e) fr o m t h e  p ot e nti al s u bj e ct  a n d/ or 
t h eir  g u ar di a n/l e g al r e pr es e nt ati v e b ef or e  a n y st u d y s p e cifi c  pr o c e d ur es  ar e  p erf or m e d  
2   E nt er t h e s u bj e ct  d at a i nt o t h e  e nr oll m e nt  m o d ul e i n  R a v e  W e b  B as e d  D at a  C a pt ur e 
( W B DC)  e C R F t o  e n a bl e t h e  all o c ati o n  of s u bj e ct i d e ntifi c ati o n ( E c o d e) 
3   D et er mi n e s u bj e ct  eli gi bilit y (s e e  S e cti o ns  3. 1  a n d  3. 2 ) 
4   E nt er t h e i nf or m ati o n r e q uir e d t o  e n a bl e t h e I nt er a cti v e  W e b  R es p o ns e  S yst e m (I W R S) t o 
i niti at e r a n d o mi z ati o n  a n d  g e n er at e t h e r a n d o mi z ati o n  c o d e 
R a n d o mi z ati o n  c o d es  will  b e  assi g n e d t hr o u g h I W R S stri ctl y s e q u e nti all y t o s u bj e cts  eli gi bl e 
f or r a n d o mi z ati o n. If  a s u bj e ct  wit h dr a ws fr o m  p arti ci p ati o n i n t h e st u d y, t h e n  his/ h er 
r a n d o mi z ati o n  c o d e  c a n n ot  b e r e us e d. 
3. 4   
P r o c e d u r es f o r  h a n dli n g i n c o r r e ctl y  e n r oll e d  o r  r a n d o mi z e d 
s u bj e cts 
S u bj e cts  w h o f ail t o  m e et t h e  eli gi bilit y  crit eri a s h o ul d  n ot,  u n d er  a n y  cir c u mst a n c es,  b e 
r a n d o mi z e d  or r e c ei v e I P.  T h er e  c a n  b e  n o  w ai v ers  gr a nt e d fr o m t h e  S p o ns or f or  a n y s u bj e ct 
n ot  m e eti n g i n cl usi o n  or  e x cl usi o n  crit eri a.  S u bj e cts  w h o  ar e  e nr oll e d,  b ut s u bs e q u e ntl y f o u n d 
n ot t o  m e et  all t h e  eli gi bilit y  crit eri a  m ust  n ot  b e r a n d o mi z e d  or i niti at e d  o n tr e at m e nt,  a n d 
m ust  b e s cr e e n -f ail e d  a n d  wit h dr a w n fr o m t h e st u d y. 
W h er e  a s u bj e ct  d o es  n ot  m e et  all t h e  eli gi bilit y  crit eri a  b ut is r a n d o mi z e d i n  err or,  or 
i n c orr e ctl y st art e d  o n tr e at m e nt, t h e i n v esti g at or s h o ul d i nf or m t h e  m e di c al  m o nit or  assi g n e d 
t o t h e  pr oj e ct i m m e di at el y,  a n d  a  dis c ussi o n s h o ul d  o c c ur  b et w e e n t h e  m e di c al  m o nit or 
assi g n e d t o t h e  pr oj e ct  a n d t h e i n v esti g at or r e g ar di n g  w h et h er t o  c o nti n u e  or  dis c o nti n u e t h e 
s u bj e ct fr o m tr e at m e nt.  T h e  S p o ns or’s  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct  m ust  e ns ur e  all 
d e cisi o ns  a n d  pr ot o c ol  d e vi ati o ns, if  a n y,  ar e  a p pr o pri at el y  d o c u m e nt e d. 
3. 5   
M et h o ds f o r  assi g ni n g t r e at m e nt  g r o u ps  
A r a n d o mi z ati o n s c h e d ul e  will  b e  g e n er at e d  b y  a  d esi g n at e d st atisti c al r e pr es e nt ati v e 
p erf or mi n g st atisti c al s u p p ort f or t h e st u d y.  T his s c h e d ul e  will  b e  pr e p ar e d  b ef or e t h e st art  of 
t h e tr e at m e nt  p eri o d.  T h e  d esi g n at e d st atisti c al r e pr es e nt ati v e  will f oll o w t h eir  est a blis h e d 
st a n d ar d  o p er ati n g  pr o c e d ur es r e g ar di n g  g e n er ati o n, s e c urit y,  a n d  distri b uti o n  of t h e 
r a n d o mi z ati o n s c h e d ul e. 
R a n d o mi z ati o n  will  b e  c e ntr ali z e d . A d ult  a n d  a d ol es c e nt s u bj e cts ( a g e d  ≥ 1 2  y e ars)  will  b e 
r a n d o mi z e d i n  a  1: 1: 1 r ati o i nt o  1  of t h e  3 tr e at m e nt  gr o u ps  as r eli e v er t h er a p y  o n t o p  of  us u al 
c ar e ( B D A  M DI  8 0/ 1 8 0  μ g,  or  B D A  M DI  1 6 0/ 1 8 0  μ g,  or  A S  M DI  1 8 0  μ g)  a c c or di n g t o  a 
S A S -g e n er at e d r a n d o mi z ati o n s c h e d ul e.  C hil dr e n  a g e d  4 t o  1 1  y e ars  will  b e r a n d o mi z e d i n  a 
1: 1 r ati o  o nl y t o t h e l o w er  B D A  M DI  d os a g e ( 8 0/ 1 8 0  μ g)  or  A S  M DI  1 8 0  μ g.  R a n d o mi z ati o n 
f or  a d ol es c e nts  a n d  a d ults  will  b e str atifi e d  b y  a g e  gr o u p ( ≥ 1 2 t o  1 7,  ≥ 1 8); r e gi o n ( N ort h 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 4  of  1 5 9  
A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d [ R e gi o n  2]);  a n d 
n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1)  pl us 
a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d.  R a n d o mi z ati o n f or 
c hil dr e n  will  n ot  b e str atifi e d.    
U p o n  e nr oll m e nt, s u bj e cts  will  b e  assi g n e d  a  u ni q u e s u bj e ct i d e ntifi c ati o n  c o d e ( E c o d e)  w hi c h 
is  a ut o m ati c all y  g e n er at e d  b y t h e  el e ctr o ni c  d at a  c a pt ur e s yst e m ( R a v e  W B D C)  b as e d  o n t h e 
or d er  of  e ntr y.  O n c e it  h as  b e e n  d et er mi n e d t h at  a s u bj e ct  m e ets  all  eli gi bilit y  crit eri a, t h e 
s u bj e ct i nf or m ati o n  will  b e i nt e gr at e d i nt o t h e I W R S ( R a n d o mi z ati o n  a n d  Tri al  S u p pl y 
M a n a g e m e nt) f or r a n d o mi z ati o n. 
3. 6   
M et h o ds f o r  e ns u ri n g  bli n di n g  
T h e st u d y  bli n d is t o  b e  m ai nt ai n e d  u ntil  all  s u bj e cts  h a v e  c o m pl et e d t h e tr e at m e nt  p eri o d  a n d 
u ntil  aft er t h e  d at a b as e  h as  b e e n l o c k e d.  T h e st u d y sit e r e c ei v es  d o c u m e nt ati o n  of s u bj e ct 
st u d y i d e ntifi c ati o n  a n d  kit  all o c ati o n t hr o u g h t h e I W R S.  T h e r a n d o mi z ati o n  c o d e  will  n ot  b e 
a v ail a bl e,  wit h t h e  e x c e pti o n  of  u n bli n di n g  pr o c e d ur es  d es cri b e d i n  S e cti o n  3. 7 , t o t h e st u d y 
t e a m, st u d y  c e nt er  p ers o n n el,  S p o ns or  m o nit ors,  S p o ns or  pr oj e ct st atisti ci a ns,  or  a n y  ot h er 
p ers o n n el  e m pl o y e d  or  affili at e d  wit h t h e  S p o ns or,  as  w ell  as i n v esti g at ors  a n d s u bj e cts  u ntil 
aft er t h e  d at a b as e  h as  b e e n l o c k e d.   
T h e  3  diff er e nt  kit t y p es  of st u d y I P  ar e  vis u all y i d e nti c al,  pr ot e cti n g t h e  bli n d t hr o u g h t h eir 
si mil arit y in  a p p e ar a n c e.   
3. 7   
M et h o ds f o r  u n bli n di n g   
T h e tr e at m e nt  bli n d s h o ul d  n ot  b e  br o k e n  e x c e pt i n  m e di c al  e m er g e n ci es  a n d  b as e d  o n t h e 
i n v esti g at or’s  cli ni c al j u d g m e nt  w h e n t h e  a p pr o pri at e  m a n a g e m e nt  a n d  w elf ar e  of t h e s u bj e ct 
r e q uir es  k n o wl e d g e  of t h e tr e at m e nt  all o c ati o n. I n di vi d u al tr e at m e nt  d et ails, f or  e a c h s u bj e ct, 
will  b e  a v ail a bl e t o t h e i n v esti g at or(s)  or  p h ar m a cists fr o m t h e I W R S, if  n e e d e d. If  u n bli n di n g 
o c c urs, t h e i n v esti g at or  m ust  n otif y t h e  S p o ns or  as s o o n  as  p ossi bl e,  b ut  wit h o ut r e v e ali n g t h e 
tr e at m e nt  assi g n m e nt  of t h e  u n bli n d e d s u bj e ct.  R o uti n es f or t his  will  b e  d es cri b e d i n t h e I W R S 
us er  m a n u al t h at  will  b e  pr o vi d e d t o  e a c h  c e nt er.  T h e I W R S  pr o vi d es  u n bli n di n g  pr o c e d ur es, 
if  n e e d e d. 
T h e  d esi g n at e d r e pr es e nt ati v e r et ai ns t h e ri g ht t o  br e a k t h e  c o d e f or  S A Es t h at  ar e  u n e x p e ct e d 
a n d  ar e s us p e ct e d t o  b e  c a us all y r el at e d t o  a n I P  a n d t h at  p ot e nti all y r e q uir e  e x p e dit e d 
r e p orti n g t o r e g ul at or y  a ut h oriti es.  Tr e at m e nt  c o d es  will  n ot  b e  br o k e n f or t h e  pl a n n e d 
a n al ys es  of  d at a  u ntil  all  d e cisi o ns  o n t h e  e v al u a bilit y  of t h e  d at a fr o m  e a c h i n di vi d u al s u bj e ct 
h a v e  b e e n  m a d e  a n d  d o c u m e nt e d. 
Wit h t h e  e x c e pti o n  of  e m er g e n c y  u n bli n di n g  as  d es cri b e d  a b o v e,  all  m e m b ers  of t h e st u d y 
t e a m, i n v esti g at ors,  a n d sit e st aff  will  b e  bli n d e d.  T h e  o nl y i n di vi d u als  w ho  will  h a v e  a c c ess 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 5  of  1 5 9  
t o  u n bli n d e d i nf or m ati o n  d uri n g t h e  c o n d u ct  of t h e st u d y i n  a d v a n c e  of t h e  pri m ar y  o ut c o m e 
d at a b as e l o c k  will  b e t h e  u n bli n d e d st atisti ci a n s u p p orti n g t h e I D M C  cl os e d s essi o n r e vi e w 
w hi c h  will  b e  p erf or m e d i n  a c c or d a n c e  wit h t h e I D M C  c h a rt er.   
3. 8   
R est ri cti o ns  
S u bj e cts s h o ul d  b e  a d vis e d t h at  m ar k et e d ( e g,  o m ali z u m a b,  m e p oli z u m a b, r esli z u m a b, 
b e nr ali z u m a b,  d u pil u m a b)  or i n v esti g ati o n al  bi ol o gi c tr e at m e nts  or  ot h er i n v esti g ati o n al 
tr e at m e nts  ot h er t h a n t h e I Ps  ar e  n ot  all o w e d  d uri n g t h e tr e at m e nt  p eri o d/ e xt e nsi o n  p h as e. 
S u bj e cts r e q uiri n g  c hr o ni c  O C S  ar e  e x cl u d e d.  All  ast h m a  m ai nt e n a n c e t h er a pi es,  as 
d o c u m e nt e d  at  b as eli n e, s h o ul d r e m ai n st a bl e t hr o u g h o ut t h e st u d y. I n t h e i n v esti g at or’s 
o pi ni o n, if  a s u bj e ct r e q uir es  a  c h a n g e i n t h eir  ast h m a  m ai nt e n a n c e t h er a p y, t his s h o ul d  b e 
dis c uss e d  wit h t h e  m e di c al  m o nit or.  
C h a n g es t o  m ai nt e n a n c e t h er a p y  d os es  w o ul d  b e  p er missi bl e i n s p e cifi c  cir c u mst a n c es  a n d 
w h e n  cli ni c all y i n di c at e d. I n t h e  e v e nt t h at t h e i n v esti g at or  c o nsi d ers t h e i ntr o d u cti o n  of 
a d diti o n al  m ai nt e n a n c e t h er a p y  or i nt e nsifi c ati o n  of t h e  e xisti n g  m ai nt e n a n c e t h er a p y 
( c h a n g e) is r e q uir e d, t h e  m e di c al  m o nit ors s h o ul d  b e  c o nt a ct e d.  
3. 9   
T r e at m e nt  dis c o nti n u ati o n  b y s u bj e ct  a n d/ o r  S p o ns o r  
S u bj e cts  m a y  b e  wit h dr a w n fr o m t h e st u d y  at  a n y ti m e  at t h eir  o w n r e q u est,  u p o n r e q u est  of 
t h e i n v esti g at or,  or  b y t h e  S p o ns or  at  a n y ti m e  or f or  a n y r e as o n.   T h e s u bj e ct  or  his/ h er 
p ar e nt/l e g al r e pr es e nt ati v e is fr e e t o  dis c o nti n u e tr e at m e nt  at  a n y ti m e,  wit h o ut  pr ej u di c e t o 
f urt h er tr e at m e nt.  Ot h er r e as o ns f or I P  dis c o nti n u ati o n  m a y i n cl u d e: 
•   A d v ers e  e v e nt  
•   S u bj e cts  w h o s uff er  ≥ 3 s e v er e  e x a c er b ati o ns  wit hi n  a  3 -m o nt h  p eri o d  or  ≥ 5 t ot al s e v er e 
e x a c er b ati o n  e v e nts,  or  a si n gl e s e v er e  e x a c er b ati o n  e v e nt l o n g er t h a n  2 0  d a ys i n  d ur ati o n 
s h o ul d  b e  c o nsi d er e d f or  dis c o nti n u ati o n if  S p o ns or  a n d t h e i n v esti g at or  d e ci d e t h at it is 
i n t h e  b est i nt er est  of t h e s u bj e ct t o  dis c o nti n u e r a n d o mi z e d tr e at m e nt  a n d  wit h dr a w fr o m 
t h e st u d y ( a n  e x a c er b ati o n  al o n e  d o es  n ot r e q uir e s u bj e ct  dis c o nti n u ati o n) 
•   I n t h e  o pi ni o n  of t h e i n v esti g at or, t h e s u bj e ct is  n o n c o m pli a nt  wit h t h e  Cli ni c al  St u d y 
Pr ot o c ol ( e g,  p ost- e nr oll m e nt  eli gi bilit y  vi ol ati o n)  or is l ost t o f oll o w - u p  a n d  n o 
alt er n ati v e  c o nt a ct i nf or m ati o n is  a v ail a bl e (t his i m pli es t h at  at l e ast  2  d o c u m e nt e d 
att e m pts  h a v e  b e e n  m a d e t o  c o nt a ct t h e s u bj e ct)  
•   If f e m al e s u bj e ct  b e c o m es  pr e g n a nt, t h e s u bj e ct  will  a ut o m ati c all y  b e  dis c o nti n u e d fr o m 
I P 
•   I n s u bj e cts  w h o  h a v e  el e v at e d li v er  e n z y m es  A S T  a n d/ or  A L T  ≥ 3 ti m es t h e  u p p er li mit  of 
n or m al ( × U L N)  a n d t ot al  bilir u bi n ( T B L)  ≥ 2 × U L N (i e,  m e eti n g  t h e  crit eri a  of  at l e ast 
P ot e nti al  H y’s  L a w), I P  will  b e s us p e n d e d  u ntil t h e li v er t est  v al u es r et ur n t o t h e  n or m al 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 6  of  1 5 9  
r a n g e. If t h e  A S T,  A L T,  or  T B L r e a c h t h es e  el e v at e d l e v els  a g ai n,  aft er r e c o m m e n c e m e nt 
of I P, t h e s u bj e ct  will  b e  dis c o nti n u e d fr o m I P  a n d  wit h dr a w n fr o m t h e st u d y. 
 
T h e st u d y  will  b e  c o m pl et e d  w h e n t h e l ast s u bj e ct  h as  c o m pl et e d  his/  or  h er  p ost- st u d y 
f oll o w- u p t el e p h o n e  c o nt a ct.  S u bj e cts  w h o  dis c o nti n u e I P  will  c o m pl et e  a  P D V,  a n d  A Es/ 
S A Es  will  b e f oll o w e d  u p if  m e di c all y i n di c at e d.  
A s u bj e ct t h at  d e ci d es t o  dis c o nti n u e I P  will  al w a ys  b e  as k e d  a b o ut t h e r e as o n(s)  a n d t h e 
pr es e n c e  of  a n y  A Es. If  p ossi bl e, t h e y  will  b e s e e n  a n d  ass ess e d  b y  a n i n v esti g at or(s).  A d v ers e 
e v e nts  a n d  S A Es  will  b e f oll o w e d  u p ( S e e  S e cti o n  6 );  e Di ar y  a n d  all I Ps s h o ul d  b e r et ur n e d  b y 
t h e s u bj e ct. 
S u bj e cts  w h o  dis c o nti n u e st u d y tr e at m e nt  pri or t o  E O S  will  b e  e n c o ur a g e d t o r e m ai n i n t h e 
st u d y t o  c o m pl et e  all r e m ai ni n g st u d y  visits  d uri n g t h e tr e at m e nt/ e xt e nsi o n  p h as e  p eri o d. 
Tr e at m e nt  dis c o nti n u ati o n s u bj e cts  will r et ur n t o  a p pr o pri at e  m ai nt e n a n c e  ast h m a 
m e di c ati o ns,  p er t h e i n v esti g at or’s  dis cr eti o n.  F or s u bj e cts r e c or d e d  as  Tr e at m e nt 
Dis c o nti n u ati o ns  w h o  d o  n ot  c o m pl et e  at l e ast  1  p ost -tr e at m e nt  d at a  c oll e cti o n,  a t el e p h o n e 
f oll o w-u p  c all is r e q uir e d  at l e ast  1 4  d a ys  aft er l ast I P  d os e.   
If  a s u bj e ct  c h o os es  n ot t o  c o nti n u e  wit h st u d y  ass ess m e nts,  at  a  mi ni m u m t h e s u bj e ct  will 
c o m pl et e t h e  P D V ( as i n di c at e d i n  T a bl e   1).  T h es e s u bj e cts  will r et ur n t o  a p pr o pri at e 
m ai nt e n a n c e  m e di c ati o ns,  p er t h e i n v esti g at or’s  dis cr eti o n.  A f oll o w- u p t el e p h o n e  c all ( T C) 
will  b e  p erf or m e d  at l e ast  1 4  d a ys  aft er t h e l ast I P  d os e. I n t h e  e v e nt t h e  P D V is  p erf or m e d 
> 1 4  d a ys  p ost l ast I P  d osi n g,  a f oll o w- u p  T C  will  n ot  b e r e q uir e d.  T h es e s u bj e cts  w h o  d o  n ot 
wit h dr a w  c o ns e nt f or f oll o w- u p  will  b e f oll o w e d f or s ur vi v al/ d e at h, s e v er e  e x a c er b ati o ns, 
A Es/ S A Es,  a n d  c o n c o mit a nt  m e di c ati o ns i n cl u di n g  ast h m a tr e at m e nt ( m ai nt e n a n c e  a n d r es c u e 
t h er a pi es) at  q u art erl y i nt er v als  u ntil  E O S.  
3. 1 0   
St u d y t e r mi n ati o n  
If t h e  S p o ns or, i n v esti g at or, st u d y  m o nit or, I D M C,  or r e g ul at or y  offi ci als  dis c o v er  c o n diti o ns 
arisi n g  d uri n g t h e st u d y t h at i n di c at e t h at t h e s u bj e ct’s s af et y  a n d/ or s ci e ntifi c  v al u e  of t h e 
st u d y  a n d/ or  q u alit y  of t h e I Ps  h a v e  b e e n  c o m pr o mis e d, t h e st u d y  m a y  b e  h alt e d  or t h e st u d y 
c e nt er’s  p arti ci p ati o n  m a y  b e t er mi n at e d.  O n g oi n g s u bj e cts  will  b e  dis c o nti n u e d fr o m t h e 
st u d y  a n d  assi g n e d t o r e c ei v e tr e at m e nt  as  p er l o c al st a n d ar d  of  c ar e.   
C o n diti o ns t h at  m a y  w arr a nt t er mi n ati o n  of t h e st u d y i n cl u d e,  b ut  ar e  n ot li mit e d t o, t h e 
f oll o wi n g list: 
•   T h e st u d y  m a y  b e st o p p e d if, i n t h e j u d g m e nt  of t h e  S p o ns or, st u d y s u bj e cts  ar e  pl a c e d  at 
u n d u e ris k  b e c a us e  of  cli ni c all y si g nifi c a nt fi n di n gs t h at: 
-  ar e  c o nsi d er e d  si g nifi c a nt 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 7  of  1 5 9  
-  ar e  ass ess e d  as  c a us all y r el at e d t o I P  
-  ar e  n ot  c o nsi d er e d t o  b e  c o nsist e nt  wit h  c o nti n u ati o n  of t h e st u d y 
•   T h e  dis c o v er y  of  a n  u n e x p e ct e d, s eri o us,  or  u n a c c e pt a bl e ris k t o t h e s u bj e cts  e nr oll e d i n 
t h e st u d y 
•   A  d e cisi o n  o n t h e  p art  of t h e  S p o ns or t o s us p e n d  or  dis c o nti n u e t esti n g,  e v al u ati o n,  or 
d e v el o p m e nt  of t h e I P f or  a n y r e as o n 
C o n diti o ns t h at  m a y  w arr a nt t er mi n ati o n  of  a st u d y  c e nt er’s  p arti ci p ati o n i n cl u d e,  b ut  ar e  n ot 
li mit e d t o, t h e f oll o wi n g list: 
•   F ail ur e  of t h e i n v esti g at or t o  e nr oll s u bj e cts i nt o t h e st u d y  at  a n  a c c e pt a bl e r at e  or  wit hi n 
a n  a gr e e d ti m eli n e  
•   F ail ur e  of t h e i n v esti g at or t o  c o m pl y  wit h  p ert i n e nt  g o v er ni n g  b o d y r e g ul ati o ns 
•   S u b missi o n  of  k n o wi n gl y f als e i nf or m ati o n fr o m t h e r es e ar c h f a cilit y t o t h e  S p o ns or, 
st u d y  m o nit or,  m e di c al  offi c er,  or r e g ul at or y  offi ci al 
•   I ns uffi ci e nt  a d h er e n c e t o  pr ot o c ol r e q uir e m e nts 
 
R e g ar dl ess  of t h e r e as o n f or t er mi n ati o n,  all  d at a  a v ail a bl e f or t h e s u bj e ct  at t h e ti m e  of 
dis c o nti n u ati o n  of f oll o w- u p  m ust  b e r e c or d e d i n t h e  e C R F.  All r e as o ns f or  dis c o nti n u ati o n  of 
tr e at m e nt  m ust  b e  d o c u m e nt e d. 
I n t er mi n ati n g t h e st u d y, t h e  S p o ns or  will  e ns ur e t h at  a d e q u at e  c o nsi d er ati o n is  gi v e n t o t h e 
pr ot e cti o n  of t h e s u bj e cts’ i nt er ests. 
St u d y t er mi n ati o n  a n d f oll o w- u p  will  b e  p erf or m e d i n  c o m pli a n c e  wit h  a p pli c a bl e  g o v er ni n g 
b o d y r e g ul ati o ns. 
3. 1 1   
S c r e e n f ail u r es   
S cr e e ni n g f ail ur es  ar e s u bj e cts  w h o  d o  n ot f ulfill t h e  eli gi bilit y  crit e ri a f or t h e st u d y,  a n d 
t h er ef or e  m ust  n ot  b e r a n d o mi z e d.  T h es e s u bj e cts s h o ul d  h a v e t h e r e as o n f or st u d y  wit h dr a w al 
r e c or d e d  as  “ S cr e e n f ail ur e ”.  S u bj e cts  w h o s cr e e n f ail  will  n ot  b e r es cr e e n e d  e x c e pt f or 
c hil dr e n  a n d  a d ol es c e nts  w h o s cr e e n f ail e d  b e c a us e  t h e y  di d  n ot  m e et t h e  n o w  o bs ol et e  u p p er 
F E V 1  %  pr e di ct e d li mit.  C hil dr e n  a n d  a d ol es c e nts  w h o  pr e vi o usl y f ail e d t o  m e et t h e  u p p er 
F E V 1  %  pr e di ct e d t hr es h ol d,  b ut  w h o  m et  all  ot h er  eli gi bilit y r e q uir e m e nts,  m a y r e-s cr e e n 
o n c e.  U p o n r e-s cr e e ni n g, t h es e s u bj e cts  m ust  m e et  all  eli gi bilit y r e q uir e m e nts i n  or d er t o  b e 
r a n d o mi z e d.   
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
3 8  of  1 5 9  
4   
S T U D Y  P L A N  A N D  TI MI N G  O F  P R O C E D U R E S   
T a bl e   1 pr es e nts st u d y  ass ess m e nts  a n d  pr o c e d ur es.  R e p e at  ass ess m e nts, if  n e e d e d,  will  b e 
c a pt ur e d i n  u ns c h e d ul e d  visits. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y  
3 9  of  1 5 9  
T a bl e  1  
St u d y  Ass ess m e nts  a n d  P r o c e d u r es  
 
S cr e e ni n g 
a n d r u n -
i n 
D o u bl e -bli n d  Tr e at m e nt  P eri o d  
E xt e nsi o n 
P h as e  
E O S d 
(l ast  cli ni c 
visit ) 
P D V e 
(if 
a p pli c a bl e)  
S af et y  F oll o w -u p 
T C  
( 2  w e e ks [ ± 4 
d a ys] aft er  E O S  or 
P D V ) 
Visit a 
1/ 1 a b  
2   
3   
4   
5   
6  c  
7    
( e v er y  1 2-
w e e ks  ± 4  d a ys 
u ntil t h e  P C D)  
W e e k  
-4 t o  -2   
0   
4   
8   
1 2   
2 4   
3 6   
 
D a y   
-2 8 t o  -1 4   
1   
2 8  ± 2   5 6  ± 2   8 4  ± 4   1 6 8  ± 4   2 5 2  ± 4   
 
I nf or m e d  c o ns e nt/ ass e nt  
X  
  
  
  
  
  
  
  
  
  
  
 
 
Eli gi bi lit y  crit eri a 
X  
X  
  
  
  
  
  
  
  
  
  
 
 
 
Cli ni c al  p r o c e d u r es  
M e di c al/s ur gi c al  hist or y  
X  b  
  
  
  
  
  
  
  
  
  
  
 
 
D e m o gr a p h y  
X  
  
  
  
  
  
  
  
  
  
  
 
 
P h ysi c al  e x a mi n ati o n   
X  
  
  
  
  
  
  
X    
  
X  
  
X 
 
H ei g ht ( c m)  f 
X  
  
  
  
  
X  f  
  
  
  
X  f  
  
X  f 
 
C o n c o mit a nt  m e di c ati o ns  
X  b  
X  
X  
X  
X  
X  
X  
X  
  
X  
  
X 
X 
Al b ut er ol/s al b ut a m ol r e v ersi bilit y t est g  
X  
  
  
  
  
  
  
  
  
  
  
 
 
 
S af et y  m e as u r e m e nts  
Vit al si g ns  
X  b  
X  
X  
X  
X  
X  
X  
X  
  
X  
  
X 
 
1 2 -l e a d  E C G 
X  b  
X  
  
  
  
X  
  
  
  
X  
  
X 
 
A d v ers e  e v e nts  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
  
X 
X 
Pr e g n a n c y t est   h 
s er u m  
uri n e   uri n e h  uri n e h  uri n e h  s er u m  uri n e h  
uri n e h  
  
s er u m  
  
s er u m 
 
S af et y l a b or at or y  ass ess m e nts ( cli ni c al 
c h e mistr y  a n d  h e m at ol o g y)  
X  b  
  
  
  
  
X  
  
  
  
X  
  
X 
 
M or ni n g s er u m  c ortis ol  ass ess m e nt   
X  
  
  
  
  
X  
  
  
  
X  
  
X 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y  
4 0  of  1 5 9  
 
S cr e e ni n g 
a n d r u n -
i n 
D o u bl e -bli n d  Tr e at m e nt  P eri o d  
E xt e nsi o n 
P h as e  
E O S d 
(l ast  cli ni c 
visit ) 
P D V e 
(if 
a p pli c a bl e)  
S af et y  F oll o w -u p 
T C  
( 2  w e e ks [ ± 4 
d a ys] aft er  E O S  or 
P D V ) 
Visit a 
1/ 1 a b  
2   
3   
4   
5   
6  c  
7    
( e v er y  1 2-
w e e ks  ± 4  d a ys 
u ntil t h e  P C D)  
W e e k  
-4 t o  -2   
0   
4   
8   
1 2   
2 4   
3 6   
 
D a y   
-2 8 t o  -1 4   
1   
2 8  ± 2   5 6  ± 2   8 4  ± 4   1 6 8  ± 4   2 5 2  ± 4   
 
 
Effi c a c y  m e as u r e m e nts  
C oll e cti o n/r e vi e w  of  e x a c er b ati o ns i 
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
X 
 
A C Q -5 j 
  
X  
X  
X  
X  
X  
X  
X  
  
X  
X 
 
A C Q -7 k 
X  
  
  
  
  
  
  
  
  
 
 
 
A C T/ C  A C T  
  
X  
X  
X  
X  
X  
X  
X  
  
X  
X 
 
A Q L Q + 1 2/ P A Q L Q  
  
X  
X  
X  
X  
X  
X  
X  
  
X  
X 
 
R e vi e w  of  P E F,  us e  of I P (r eli e v er t h er a p y), 
ast h m a  d a yti m e/ ni g ht -ti m e s y m pt o ms,  ni g ht-
ti m e  a w a k e ni n gs  d u e t o  ast h m a s y m pt o ms  l 
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
X 
 
S pir o m etr y ( F E V 1) m  
X  
X  
  
  
X  
X  
  
  
  
  
  
 
 
e Di ar y  
d  
  
  
  
  
  
  
  
  
c  
c 
 
R e vi e w  c o m pli a n c e  wit h  e Di ar y  
  
X  
X  
X  
X  
X  
X  
X  
  
X  
X 
 
 
I n v esti g ati o n al  p r o d u ct  a d mi nist r ati o n  
R a n d o mi z ati o n  
  
X  
  
  
  
  
  
  
  
  
  
 
 
I P ( dis p e ns e/ c oll e ct)  
  
d  
c/ d   
c/ d   
c/ d   
c/ d   
c/ d   
c/ d   
  
c  
  
c 
 
V e nt oli n ( dis p e ns e)  
d  
  
  
  
  
  
  
  
  
  
  
 
 
A b br e vi ati o ns:  A C Q -5/ 7 = Ast h m a  C o ntr ol  Q u esti o n n air e -5/ 7;  A C T = Ast h m a  C o ntr ol  T est;  A Q L Q + 1 2 = Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars  a n d 
ol d er;  β -h C G = β -h u m a n  c h ori o ni c  g o n a d otr o pi n;  B MI = b o d y  m ass i n d e x;  c = c oll e ct;  C  A C T = C hil d h o o d  Ast h m a  C o ntr ol  T est;  d = dis p e ns e; 
E C G = el e ctr o c ar di o gr a m;  E O S = e n d -of -st u d y;  F E V 1=f or c e d  e x pir at or y  v ol u m e i n  1 s e c o n d; I P =i n v esti g ati o n al  pr o d u ct;  L A B A =l o n g -a cti n g  β 2 -a g o nist; 
P A Q L Q = P e di atri c  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e;  P C D = pri m ar y  c o m pl eti o n  d at e;  P D V = pr e m at ur e  dis c o nti n u ati o n  visit;  P E F = p e a k  e x pir at or y fl o w; 
T C =t el e p h o n e  c all;  V = visit   
a 
R e p e at  ass ess m e nts/ visits, if  n e e d e d,  will  b e  c a pt ur e d i n  u ns c h e d ul e d  visits.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y  
4 1  of  1 5 9  
b 
Visit  1  will  b e s plit  a n d  us e d f or r e p e at e d  ass ess m e nts, if  n e e d e d (i e,  Visit  1 a  will  b e  n e e d e d f or t h e r e p e at  ass ess m e nt  of  al b ut er ol/s al b ut a m ol r e v ersi bilit y 
t est  a n d  F E V1, if  a p pli c a bl e).  S u bj e cts  m a y  c o ns e nt f or t h e st u d y i n  a d v a n c e  of  Visit  1  a n d if r e q uir e d, r e q u est f or  m e di c al r e c or ds t o s u p p ort  e vi d e n c e  of  pri or 
ast h m a  e x a c er b ati o ns  wit h o ut tri g g eri n g t h e  2 8 -d a y s cr e e ni n g  p eri o d.   W h er e  a s e v er e  e x a c er b ati o n  e v e nt  o c c urs  d uri n g t h e s cr e e ni n g  p eri o d, t his  m a y  b e 
e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks (t o  a c c o u nt f or  a  c o urs e  of s yst e mi c  c orti c ost er oi ds  of  u p t o  1  w e e k  d ur ati o n f oll o w e d  b y  a  4 -w e e k  w as h o ut  p eri o d). I n t h e 
e v e nt  of  a n  e xt e nsi o n t o t h e s cr e e ni n g  p eri o d  d u e t o  a s e v er e  e x a c er b ati o n  e v e nt, t h e f oll o wi n g  will  b e r e p e at e d: s af et y l a b o r at or y  ass ess m e nts,  E C G,  vit al si g ns, 
c o n c o mit a nt  m e di c ati o ns,  a n d  m e di c al/s ur gi c al  hist or y.   
c 
T h e tr e at m e nt  d ur ati o n f or t h e st u d y  will  b e  at l e ast  2 4  w e e ks f or  e a c h s u bj e ct t o s u p p ort t h e s u bj e ct  e x p os ur e  d at a.  T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e 
( e xt e nsi o n  p h as e)  u ntil t h e r e q uir e d  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts,  as  d efi n e d  p er  p r ot o c ol,  h a v e  b e e n r e a c h e d;  a n d t h e l ast a d ult  s u bj e ct  h as  c o m pl et e d  2 4 
w e e ks  of tr e at m e nt,  w hi c h  will  b e  d efi n e d  as t h e  P C D.  Aft er  Visit  6,  visits  will  b e s c h e d ul e d  e v er y  1 2  w e e ks  wit h t h e  ass ess m e nts fr o m  Visit  7 t o  b e  p erf or m e d 
i n  all  of t h e m.  
d  
T h e  E O S  visit  will  b e  pl a n n e d  o n c e t h e first  5 7 0 s e v er e  e x a c er b ati o n  e v e nts  o c c ur. If  a s u bj e ct’s tr e at m e nt l asts  ≥ 2 4  w e e ks t h e n t h e s u bj e ct’s  E O S  visit  will 
o c c ur  at t h eir  n e xt s c h e d ul e d  cli ni c  visit.  O n c e t h e  P C D  h as  b e e n r e a c h e d,  a n y  o n g oi n g s u bj e ct  will r et u r n t o  c o m pl et e  a n  E O S  visit  at t h eir  n e xt s c h e d ul e d  cli ni c 
visit.  
e 
S u bj e cts  w h o  pr e m at ur el y  wit h dr a w fr o m t h e st u d y  will  u n d er g o  a  P D V.  I n t h e  e v e nt t h e  P D V is  p erf or m e d  > 1 4  d a ys  p ost l ast I P  d osi n g, a f oll o w -u p  T C 
will  n ot  b e r e q uir e d.  T h es e s u bj e cts  w h o  d o  n ot  wit h dr a w  c o ns e nt f or f oll o w -u p  will  b e f oll o w e d f or s ur vi v al/ d e at h, s e v er e  e x a c er b ati o ns,  A Es/ S A Es,  a n d 
c o n c o mit a nt  m e di c ati o ns i n cl u di n g  ast h m a tr e at m e nt ( m ai nt e n a n c e  a n d r es c u e t h er a pi es)  at  q u art erl y i nt er v als  u ntil  E O S.  
f 
A d diti o n al  h ei g ht ( c m)  ass ess m e nts t o  b e  c oll e ct e d f or s u bj e cts  ≤ 1 8  y e ars  of  a g e  O N L Y.  Ass ess m e nts  of  h ei g ht  will  c o nti n u e i n  a c c or d a n c e  wit h  a s u bj e ct’s 
a g e  at t h e ti m e  of si g n e d i nf or m e d  c o ns e nt/ ass e nt ( w h er e  a s u bj e ct  c h a n g es  a g e  d uri n g t h e st u d y).   
g 
D e m o nstr at e r e v ersi bilit y  at  Visit  1,  wit h  a n i n cr e as e i n  F E V 1 ≥ 1 2 % ( a n d  ≥ 2 0 0  m L f or s u bj e cts  ≥ 1 8  y e ars) r el ati v e t o  b as eli n e  aft er  a d mi nistr ati o n  of 
S p o ns or -pr o vi d e d  V e nt oli n  vi a  c e ntr al s pir o m etr y  at  eit h er  Visit  1  or  Vis it  1 a (r e v ersi bilit y  m ust  b e  d e m o nstr at e d  at  eit h er  Visit  1  or  Visit  1 a);  Visit  1 a  m ust  b e 
us e d f or r e -t esti n g, if  n e e d e d;  wit h  o nl y  1 r e v ersi bilit y r e-t est  p er mitt e d i n  a d v a n c e  of r a n d o mi z ati o n ( Visit  2).  
h 
A s er u m  pr e g n a n c y t est ( β -h C G)  will  b e  p erf or m e d  at  Visit  1,  6,  a n d  E O S/ P D V;  uri n e  β -h C G t est  will  b e  p erf or m e d  at  all  ot h er  cli ni c  visits (f or  w o m e n  of 
c hil d b e ari n g  p ot e nti al  o nl y). (I n  Ar g e nti n a,  w o m e n  of  c hil d b e ari n g  p ot e nti al  will  h a v e  a d diti o n al  pr e g n a n c y t esti n g  at  m o nt hl y ti m e  p oi nts.)   
i 
Ast h m a  e x a c er b ati o ns  d at a  will  b e r e vi e w e d,  a n d s e v er e  e x a c er b ati o ns i d e ntifi e d  as  p er  S e cti o n  5. 1. 1 .  S u bj e cts  ar e t o  b e r e mi n d e d  n ot t o t a k e  a n y  al b ut er ol 
pr o d u ct  e x c e pt f or t h e I P.  
j 
Ast h m a  C o ntr ol  Q u esti o n n air e -5 s elf -a d mi nist er e d  a d ult  v ersi o n t o  b e  us e d f or  a d ults  a n d  a d ol es c e nts  1 1  y e ars  a n d  ol d er; t h e i nt er vi e w er -a d mi nist er e d 
v ersi o n s h o ul d  b e  us e d f or  c hil dr e n  4 t o  1 0  y e ars.  S u bj e ct  will  n e e d t o s at isf y  A C Q-5 ( ≥ 1. 5)  e ntr y r e q uir e m e nts  at  Visit  2.  
k 
S u bj e ct  will  n e e d t o s atisf y  A C Q -7 ( ≥ 1. 5)  e ntr y r e q uir e m e nts  at  Visit  1.  
l 
T h e  A M 3  d e vi c e  will  b e  dis p e ns e d  at s cr e e ni n g  a n d  P E F  m e as ur e m e nts  will  b e t a k e n t hr o u g h t h e s cr e e ni n g  p eri o d i n  a d v a n c e  of  V isit 2.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y  
4 2  of  1 5 9  
m 
Pr e br o n c h o dil at or  F E V 1 will  b e  m e as ur e d i n t h e  m or ni n g  b et w e e n  0 6: 0 0  a n d  1 1: 0 0  A M  at  Visits  1,  2,  5,  a n d  6.  Pr e br o n c h o dil at or  F E V 1 of  ≥ 4 0  t o < 9 0 % 
pr e di ct e d  n or m al  v al u e f or  a d ults  a n d  ≥ 6 0 %  pr e di ct e d  n or m al  v al u e f or s u bj e cts  a g e d  4 t o  1 7  y e ars  aft er  wit h h ol di n g  S A B A  ≥ 6  h o urs ( a n d  at  Visit  1  a n d  Visit  1 a 
[ us e d f or r e p e at e d  ass ess m e nts, if  n e e d e d], if  a p pli c a bl e,  as  c o nfir m e d  b y  c e ntr ali z e d s pir o m etr y).  S p o ns or -pr o vi d e d  V e nt oli n s h o ul d  b e  wit h h el d  ≥ 6  h o urs  at 
Visit  2.  At s u bs e q u e nt tr e at m e nt  visits, I P s h o ul d  b e  wit h h el d  ≥ 6  h o urs  b ef or e  Visit  5  a n d  Visit  6.  At  all  visits  w h er e  F E V 1 is  m e as ur e d ( Visits,  1,  2,  5,  a n d  6), 
s u bj e cts  w h os e  m ai nt e n a n c e t h er a p y i n cl u d es  L A B A s h o ul d  b e i nstr u ct e d  n ot t o  us e t h eir  m ai nt e n a n c e t h er a p y  wit hi n t h e ti m efr a m e s p e cifi e d  i n T a bl e   4 i n 
a d v a n c e  of t h e  visit  as t h es e  ar e  c o nsi d er e d  br o n c h o dil at ors. If t h es e  m e di c ati o ns  w er e t a k e n  wit hi n t h e r estri ct e d ti m e  p eri o ds,  visits  s h o ul d  b e r e-s c h e d ul e d. 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 3  of  1 5 9  
4. 1   
S c r e e ni n g  a n d  r u n -i n  p e ri o d 
Pr o c e d ur es  will  b e  p erf or m e d  a c c or di n g t o st u d y  ass ess m e nts  a n d  pr o c e d ur es  pr es e nt e d i n 
T a bl e   1.  S u bj e cts  m a y  c o ns e nt f or t h e st u d y i n  a d v a n c e  of  Visit  1  a n d if r e q uir e d, r e q u est f or 
m e di c al r e c or ds t o s u p p ort  e vi d e n c e  of  pri or  e x a c er b ati o ns  wit h o ut tri g g eri n g t h e  2 8- d a y 
s cr e e ni n g  p eri o d.  T h e s cr e e ni n g  p eri o d  will  b e  1 4 t o  2 8  d a ys  e x c e pt  w h er e  a s e v er e  ast h m a 
e x a c er b ati o n  e v e nt  o c c urs  d uri n g t his  p eri o d.  W h er e  a s e v er e  ast h m a  e x a c er b ati o n  o c c urs  d uri n g 
t h e s cr e e ni n g  p eri o d, t h e  p eri o d  m a y  b e  e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks (t o  a c c o u nt f or  a 
c o urs e  of  S C S  of  u p t o  1  w e e k i n  d ur ati o n f oll o w e d  b y  a  4- w e e k  w as h o ut  p eri o d). I n t h e  e v e nt 
of  a n  e xt e nsi o n t o t h e s cr e e ni n g  p eri o d  d u e t o  a s e v er e  e x a c er b ati o n  e v e nt, t h e f oll o wi n g 
ass ess m e nts  a n d  pr o c e d ur es  will  b e r e p e at e d f oll o wi n g  w as h o ut  of  S C S  b ef or e  Visit  2: s af et y 
l a b or at or y  ass ess m e nts,  E C G,  vit al si g ns,  c o n c o mit a nt  m e di c ati o ns,  a n d  m e di c al/s ur gi c al 
hist or y. 
At s cr e e ni n g,  c o ns e nti n g s u bj e cts  ar e  ass ess e d t o  e ns ur e t h at t h e y  m e et  eli gi bilit y  crit eri a  at 
Visit  1  or  Visit  1 a,  as  a p pli c a bl e.  S u bj e cts  w h o  d o  n ot  m e et t h es e  crit eri a  m ust  n ot  b e  e nr oll e d i n 
t h e st u d y.  
T h e st u d y  pr o c e d ur es  c arri e d  o ut  d uri n g t his  p eri o d  will i n cl u d e  m e di c al  a n d s ur gi c al  hist or y, 
d e m o gr a p hi cs,  p h ysi c al  e x a mi n ati o n (i n cl u di n g  b o d y  m ass i n d e x [ B MI],  w ei g ht  a n d  h ei g ht), 
c o n c o mit a nt  m e di c ati o ns r e vi e w,  S p o ns or- pr o vi d e d  V e nt oli n r e v ersi bilit y t est (r e v ersi bilit y 
m ust  b e  d e m o nstr at e d  at  eit h er  Visit  1  or  Visit  1 a;  Visit  1 a  will  b e  us e d f or r e -t esti n g, if  n e e d e d; 
wit h  o nl y  1  r e v ersi bilit y r e-t est  p er mitt e d i n  a d v a n c e  of r a n d o mi z ati o n [ Visit  2]),  vit al si g ns, 
1 2-l e a d  E C G,  A Es,  pr e g n a n c y t est,  bl o o d s a m pl es f or  h e m at ol o g y  a n d  cli ni c al  c h e mistr y 
( 1 r e-t est is  p er mitt e d i n  a d v a n c e  of  Visit  2);  a n d  m or ni n g s er u m  c ortis ol  ass ess m e nt, 
c oll e cti o n/r e vi e w  of  e x a c er b ati o ns, s pir o m etr y (if  n e e d e d,  F E V 1, m ust  b e r e-t est e d  o n c e  at 
Visit  1 a;  o nl y  1  r e-t est is  p er mitt e d),  A C Q- 7,  P E F,  a n d  dis p e nsi n g  e Di ar y. 
S u bj e cts  a g e d  4 t o  1 1  y e ars  of  a g e  w h o  pr e vi o usl y f ail e d i n cl usi o n  crit eri o n  6  will  b e  p er mitt e d 
t o r es cr e e n. 
D e m o gr a p hi c  d at a  a n d  ot h er  c h ar a ct eristi cs  will  b e r e c or d e d  a n d  wi ll i n cl u d e t h e  a g e  a n d  y e ar  of 
birt h;  g e n d er, r a c e,  a n d/ or  et h ni cit y  a c c or di n g t o l o c al r e g ul ati o ns;  al c o h ol  c o ns u m pti o n;  a n d 
s m o ki n g  hist or y. 
A st a n d ar d  m e di c al,  m e di c ati o n,  a n d s ur gi c al  hist or y  will  b e  o bt ai n e d  wit h r e vi e w  of t h e 
s el e cti o n  crit eri a f or t h e s u bj e ct.  Pr e vi o us  ast h m a r el at e d tr e at m e nts  a n d  d ur ati o n  of  ast h m a 
r el at e d tr e at m e nts  will  b e r e c or d e d. 
4. 2   
R a n d o mi z ati o n/t r e at m e nt  p e ri o d/ e xt e nsi o n  p h as e  
Pr o c e d ur es  will  b e  p erf or m e d  a c c or di n g t o st u d y  ass ess m e nts  a n d  pr o c e d ur es  pr es e nt e d i n 
T a bl e   1. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 4  of  1 5 9  
S u bj e cts s h o ul d  n ot  a d mi nist er  S p o ns or- pr o vi d e d  V e nt oli n  o n t h e  m or ni n g  of t h eir 
r a n d o mi z ati o n  visit ( Visit  2).  S u bj e cts t a ki n g I C S,  L A B A,  or  ot h er  m ai nt e n an c e  m e di c ati o ns 
t h at  c a n i m p a ct t h e  p erf or m a n c e  of s pir o m etr y s h o ul d r ef er t o T a bl e   4 f or  m e di c ati o ns t h at  c a n 
i nt erf er e  wit h  p ul m o n ar y f u n cti o n t ests ( P F Ts).  
At r a n d o mi z ati o n ( Visit  2),  eli gi bl e s u bj e cts  will  e nt er  a  2 4 - w e e k  d o u bl e- bli n d tr e at m e nt  p eri o d.  
T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e ( e xt e nsi o n  p h as e)  u ntil t h e r e q uir e d  5 7 0 first s e v er e 
e x a c er b ati o n  e v e nts,  as  d efi n e d  p er  pr ot o c ol,  h a v e  b e e n r e a c h e d  a n d t h e l ast  a d ult s u bj e ct  h as 
c o m pl et e d  2 4  w e e ks  of tr e at m e nt,  w hi c h  will  b e  d efi n e d  as t h e  P C D. 
•   I n t h e  e v e nt  5 7 0  e v e nts  will  b e  c a pt ur e d  b ef or e t h e l ast  a d ult s u bj e ct  h as  h a d  2 4  w e e ks  of 
tr e at m e nt,  all s u bj e cts  o n tr e at m e nt f or  ≥ 2 4  w e e ks  will  h a v e t h eir  E O S  visit  at t h eir  n e xt 
s c h e d ul e d  cli ni c  visit.  All s u bj e cts  o n tr e at m e nt f or  <  2 4  w e e ks  will  c o nti n u e  u ntil  2 4  w e e ks 
at  w hi c h  p oi nt t h e y  will  c o m pl et e t h eir  E O S  visit.  
•   I n t h e  e v e nt  5 7 0  e v e nts  will  b e  c a pt ur e d  aft er t h e  a d ult l ast s u bj e ct  h as  h a d  2 4  w e e ks  of 
tr e at m e nt,  e a c h s u bj e ct  will r et ur n t o  c o m pl et e t h e  E O S  visit  at t h eir  n e xt s c h e d ul e d  cli ni c 
visit.  
•   C hil dr e n  a n d  a d ol es c e nts  o n g oi n g i n tr e at m e nt  aft er t h e  P C D  will  c o nti n u e i n f oll o w- u p 
u ntil t h e y  h a v e  c o m pl et e d  2 4  w e e ks  of tr e at m e nt.   
 
T h e st u d y  pr o c e d ur es  c arri e d  o ut  d uri n g t his  p eri o d  will i n cl u d e: r a n d o mi z ati o n,  c o n c o mit a nt 
m e di c ati o ns r e vi e w,  h ei g ht (f or s u bj e cts  ≤ 1 8  y e ars  of  a g e  at ti m e  of i nf or m e d  c o ns e nt),  vit al 
si g ns,  1 2-l e a d  E C G,  A Es,  pr e g n a n c y t est,  bl o o d s a m pl es f or  h e m at ol o g y,  a n d  cli ni c al  c h e mistr y; 
a n d  m or ni n g s er u m  c ortis ol  ass ess m e nt,  c oll e cti o n/r e vi e w  of  e x a c er b ati o ns, s pir o m etr y,  A C Q- 5, 
ast h m a  c o ntr ol t est ( A C T)/ c hil d h o o d  ast h m a  c o ntr ol t est( C  A C T),  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e f or  1 2  y e ars  a n d  ol d er ( A Q L Q + 1 2)/ P e di atri c  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e ( P A Q L Q) ( w h er e  p o p ul ati o ns  ar e  a p pr o v e d),  P E F,  us e  of I P (r eli e v er t h er a p y), 
ast h m a  d a yti m e/ ni g ht -ti m e s y m pt o ms,  ni g ht-ti m e  a w a k e ni n gs  d u e t o  ast h m a s y m pt o ms, 
e Di ar y/I P  c o m pli a n c e,  a n d  dis p e nsi n g  a n d/ or  c oll e cti o n  of I P.  
4. 3   
E n d -of -st u d y  visit 
Pr o c e d ur es  will  b e  p erf or m e d  a c c or di n g t o st u d y  ass ess m e nts  a n d  pr o c e d ur es  pr es e nt e d i n 
T a bl e   1.  T h e  E O S  visit  will  b e  pl a n n e d  o n c e t h e  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts  o c c ur. If  a 
s u bj e ct’s tr e at m e nt is  ≥ 2 4   w e e ks t h e n t h e s u bj e ct’s E O S  visit  will  o c c ur  at t h eir  n e xt s c h e d ul e d 
cli ni c  visit.  O n c e t h e  P C D  h as  b e e n r e a c h e d,  a n y  o n g oi n g s u bj e ct  will r et ur n t o  c o m pl et e t h eir 
E O S  visit  at t h eir  n e xt s c h e d ul e d  cli ni c  visit.  
T h e st u d y  pr o c e d ur es  c arri e d  o ut  d uri n g t his  visit  will i n cl u d e:  p h ysi c al  e x a mi n ati o n (i n cl u di n g 
w ei g ht),  c o n c o mit a nt  m e di c ati o ns r e vi e w,  h ei g ht (f or s u bj e cts  ≤ 1 8  y e ars  of  a g e  at ti m e  of 
i nf or m e d  c o ns e nt),  vit al si g ns,  1 2-l e a d  E C G,  A Es,  pr e g n a n c y t est,  bl o o d s a m pl es f or 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 5  of  1 5 9  
h e m at ol o g y,  a n d  cli ni c al  c h e mistr y;  a n d  m or ni n g s er u m  c ortis ol  ass ess m e nt, r e vi e w  of  ast h m a 
e x a c er b ati o ns,  A C Q- 5,  A C T/ C  A C T,  A Q L Q + 1 2/ P A Q L Q, r e vi e w  of  P E F,  us e  of I P (r eli e v er 
t h er a p y),  ast h m a  d a yti m e/ ni g ht-ti m e s y m pt o ms,  ni g ht-ti m e  a w a k e ni n gs  d u e t o  ast h m a 
s y m pt o ms,  e Di ar y/I P  c o m pli a n c e,  a n d  c oll e cti o n  a n d f i n al r e c o n cili ati o n  of t h e I P. 
4. 4   
U ns c h e d ul e d  visit  a n d  p r e m at u r e  dis c o nti n u ati o n  visit  
R e p e at  ass ess m e nts/ visits, if  n e e d e d,  will  b e  c a pt ur e d i n  u ns c h e d ul e d  visits  a n d t h e  pr o c e d ur es 
c arri e d  o ut  d uri n g  a n  u ns c h e d ul e d  visit  will  b e  d e ci d e d  b y t h e i n v esti g at or. 
Pr o c e d ur es  will  b e  p erf or m e d  a c c or di n g t o st u d y  ass ess m e nts  a n d  pr o c e d ur es  pr es e nt e d i n 
T a bl e   1.   
T h e st u d y  pr o c e d ur es  c arri e d  o ut  d uri n g t h e  P D V  vi sit  will i n cl u d e:  p h ysi c al  e x a mi n ati o n 
(i n cl u di n g  w ei g ht),  h ei g ht (f or s u bj e cts  ≤ 1 8  y e ars  of  a g e),  c o n c o mit a nt  m e di c ati o ns r e vi e w,  vit al 
si g ns,  1 2-l e a d  E C G,  A Es,  pr e g n a n c y t est,  bl o o d s a m pl es f or  h e m at ol o g y,  a n d  cli ni c al  c h e mistr y; 
a n d  m or ni n g s er u m  c ortis ol  ass ess m e nt, r e vi e w  of  ast h m a  e x a c er b ati o ns,  A C Q - 5,  A C T/ C  A C T, 
A Q L Q + 1 2/ P A Q L Q, r e vi e w  of  P E F,  us e  of I P (r eli e v er t h er a p y),  ast h m a  d a yti m e/ ni g ht- ti m e 
s y m pt o ms,  ni g ht-ti m e  a w a k e ni n gs  d u e t o  ast h m a s y m pt o ms,  e Di ar y  c o m pli a n c e, r a n d o mi z ati o n, 
a n d  c oll e cti o n  a n d r e c o n cili ati o n  of t h e I P. 
4. 5   
S af et y f oll o w -u p  p e ri o d  
Pr o c e d ur es  will  b e  p erf or m e d  a c c or di n g t o st u d y  ass ess m e nts  a n d  pr o c e d ur es  pr es e nt e d i n 
T a bl e   1.  T h e s af et y f oll o w- u p t el e p h o n e  c o nt a ct  will  o c c ur  2  w e e ks ( ± 4 d a ys)  aft er  E O S  or 
P D V,  w hi c h e v er  o c c urs first. 
T h e st u d y  pr o c e d ur es  c arri e d  o ut  d uri n g t his  p eri o d  will i n cl u d e: r e c or di n g  of  c o n c o mit a nt 
m e di c ati o ns  a n d  A Es. 
4. 6   
F oll o w -u p  
If  a s u bj e ct  c h o os es  not t o  c o nti n u e  wit h st u d y  ass ess m e nts,  at  a  mi ni m u m t h e s u bj e ct  will 
c o m pl et e t h e  P D V ( as i n di c at e d i n  T a bl e   1).  T h es e s u bj e cts  will r et ur n t o  a p pr o pri at e 
m ai nt e n a n c e  m e di c ati o ns,  p er t h e i n v esti g at ors  dis cr eti o n.  A f oll o w- u p  T C  will  b e  p erf or m e d  at 
l e ast  1 4  d a ys  aft er t h e l ast I P  d os e.  
I n t h e  e v e nt t h e  P D V is  p erf or m e d  > 1 4  d a ys  p ost l ast I P  d osi n g,  a f oll o w- u p  T C  will  n ot  b e 
r e q uir e d.  T h es e s u bj e cts  w h o  d o  n ot  wit h dr a w  c o ns e nt f or f oll o w- u p  will  b e f oll o w e d f or 
s ur vi v al/ d e at h, s e v er e  e x a c er b ati o ns,  A Es/ S A Es,  c o n c o mit a nt  m e di c ati o ns i n cl u di n g  ast h m a 
tr e at m e nt ( m ai nt e n a n c e  a n d r es c u e t h er a pi es)  at  q u art erl y i nt er v als  u ntil  E O S. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 6  of  1 5 9  
5   
S T U D Y  A S S E S S M E N T S  
T h e  R a v e  W B D C s yst e m  a n d t h e  el e ctr o ni c  p ati e nt r e p ort e d  o ut c o m e ( e P R O)  d e vi c e  will  b e 
us e d f or  d at a  c oll e cti o n  a n d  q u er y  h a n dli n g.  T h e i n v esti g at or  will  e ns ur e t h at  d at a  ar e r e c or d e d 
o n t h e  e C R F  a n d i n  a c c or d a n c e  wit h t h e i nstr u cti o ns  pr o vi d e d. 
T h e i n v esti g at or  e ns ur es t h e  a c c ur a c y,  c o m pl et e n ess,  a n d ti m eli n ess  of t h e  d at a r e c or d e d  a n d  of 
t h e  pr o visi o n  of  a ns w ers t o  d at a  q u eri es  a c c or di n g t o t h e  Cli ni c al  Tri al A gr e e m e nt.  T h e 
i n v esti g at or  will si g n t h e  c o m pl et e d  e C R F.  A  c o p y  of t h e  c o m pl et e d  e C R F  will  b e  ar c hi v e d  at 
t h e st u d y sit e. 
T h e l a b or at or y s af et y  ass ess m e nts  will  b e s e nt f or  a n al ysis t o  a  c e ntr al l a b or at or y.  
T h e s pir o m etr y  a n d  E C G  ass ess m e nts  will  b e  p erf or m e d  at sit e  usi n g  M ast er S c o p e  e q ui p m e nt 
pr o vi d e d  b y  e R es e ar c h  T e c h n ol o g y i n cl u di n g  a n  A M 3  d e vi c e  w hi c h  will  als o  b e  us e d t o  c oll e ct 
A C Q - 5,  A C Q- 7,  P E F,  a n d  e Di ar y  d at a. I n  a d diti o n t o t his,  a t a bl et  will  b e  us e d t o  c oll e ct t h e 
A Q L Q + 1 2  a n d  A C T/ C  A C T  q u esti o n n air e  d at a  usi n g t h e  St u d y W or ks s oft w ar e.  T his  d at a  will 
b e r e c or d e d i n t h e  v e n d or’s  c e ntr al  d at a b as e  a n d tr a nsf err e d/r e c o n cil e d  wit h t h e  e C R F  d at a  as 
s u m m ari z e d i n S e cti o n  9. 4 . 
5. 1   
Effi c a c y  ass ess m e nts  
Effi c a c y  ass ess m e nts i n cl u d e  ast h m a  e x a c er b ati o ns,  A Q L Q + 1 2/ P A Q L Q,  A C Q - 5,  A C T/ C  A C T, 
P E F,  us e  of I P (r eli e v er t h er a p y),  ast h m a  d a yti m e/ ni g ht-ti m e s y m pt o ms,  ni g ht- ti m e  a w a k e ni n gs 
d u e t o  ast h m a s y m pt o ms,  a n d r e vi e w  of  e Di ar y  c o m pli a n c e.  
5. 1. 1   
Ast h m a  e x a c e r b ati o n  d efi niti o n 
A n  ast h m a  e x a c er b ati o n is  d efi n e d  as  d et eri or ati o n  of  ast h m a  w hi c h i n cl u d es:  
•   W ors e ni n g  of  ast h m a si g ns/s y m pt o ms (s e e  S e cti o n  5. 1. 1. 1 ) 
•   I n cr e as e d  us e  of  “ as  n e e d e d ” r eli e v er t h er a p y 
•   D et eri or ati o n  of l u n g f u n cti o n (i e,  d e cr e as e d  P E F  a n d/ or  d e cr e as e d  F E V 1) 
•   A  m e di c al i nt er v e nti o n  as  d es cri b e d  b el o w (s e e  S e cti o n  5. 1. 1. 3 )  
T h es e  d es c ri pti o ns  a b o v e  a r e  p r o vi d e d f o r  d efi niti o n,  h o w e v e r,  o nl y s e v e r e  ast h m a 
e x a c e r b ati o ns  will  b e  ass ess e d  d u ri n g t his st u d y  (S e cti o n  5. 1. 1. 3 ). 
5. 1. 1. 1   
D efi niti o n  of  ast h m a si g ns/s y m pt o ms  w o rs e ni n g 
T h e  w ors e ni n g/ o ns et  of  s y m pt o ms  m ust i n cl u d e  at l e ast  1  of t h e f oll o wi n g: 
•   S h ort n ess  of  br e at h 
•   W h e e zi n g  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 7  of  1 5 9  
•   C h est ti g ht n ess 
•   C o u g h 
•   S p ut u m 
•   Ni g ht-ti m e  a w a k e ni n g  d u e t o  ast h m a 
•   A cti vit y li mit ati o n  d u e t o  ast h m a  
•   D e cr e as e d  P E F  
•   D e cr e as e d  F E V 1 
5. 1. 1. 2   
I n v esti g at o r-j ustifi e d  ast h m a  e x a c e r b ati o ns 
A  v ast  m aj orit y   of  ast h m a  e x a c er b ati o ns  ar e  ass o ci at e d  wit h  w ors e ni n g  of t h e si g ns/s y m pt o ms 
d es cri b e d i n  S e cti o n  5. 1. 1. 1 .  Cli ni c al  pr es e nt ati o ns  m a y,  h o w e v er,  v ar y  a m o n g s u bj e cts. If  a 
s u bj e ct’s s y m pt o ms  a n d t h e  o v er all  cli ni c al fi n di n gs s u p p ort t h e  di a g n osis  of  a n  ast h m a 
e x a c er b ati o n,  b ut t h e s y m pt o m ati c  w ors e ni n g  d o es  n ot  m e et t h e  d efi niti o n i n  S e cti o n  5. 1. 1. 1 , t h e 
i n v esti g at or  m ust j ustif y t h e  d e cisi o n f or  d efi ni n g t h e  e v e nt  as  a n  e x a c er b ati o n  a n d  d o c u m e nt 
t h e r e as o ni n g i n t h e  e C R F. 
5. 1. 1. 3   
S e v e r e  ast h m a  e x a c e r b ati o ns   
All  pr ot o c ol- d efi n e d s e v er e  ast h m a  e x a c er b ati o ns  n e e d t o f ulfill t h e s y m pt o m  crit eri a  as  d efi n e d 
i n S e cti o n  5. 1. 1. 1   a n d  b e s u p p ort e d  b y  a n  e Di ar y  al ert  or  a n i n v esti g at or j ustifi c ati o n. 
A n  ast h m a  e x a c er b ati o n  will  b e  c o nsi d er e d  s e v e r e if it r es ults i n  at l e ast  1  of t h e f oll o wi n g: 
•   A t e m p or ar y  b ol us/ b urst  of  S C S f or  at l e ast  3  c o ns e c uti v e  d a ys t o tr e at s y m pt o ms  of  ast h m a 
w ors e ni n g;  a si n gl e  d e p o -i nj e ct a bl e  d os e  of  c orti c ost er oi ds  will  b e  c o nsi d er e d  e q ui v al e nt t o 
a  3 - d a y  b ol us/ b urst  of  S C S  
•   A n  e m er g e n c y r o o m  or  ur g e nt  c ar e  visit ( d efi n e d  as  e v al u ati o n  a n d tr e at m e nt f or  < 2 4  h o urs 
i n  a n  e m er g e n c y  d e p art m e nt  or  ur g e nt  c ar e  c e nt er)  d u e t o  ast h m a t h at r e q uir e d  S C S ( as  p er 
t h e  a b o v e) 
•   A n i n - p ati e nt  h os pit ali z ati o n ( d efi n e d  as  a d missi o n t o  a n i n-p ati e nt f a cilit y  a n d/ or 
e v al u ati o n  a n d tr e at m e nt  i n  a  h e alt h c ar e f a cilit y f or  ≥ 2 4  h o urs)  d u e t o  ast h m a 
 
N ot e:  all  d e at hs  will  b e  a dj u di c at e d t o  d et er mi n e if t h e y  m e et t h e  crit eri a f or s e v er e  e x a c er b ati o n 
e v e nts.  
5. 1. 1. 4   
T r e at m e nt f o r s e v e r e  ast h m a  e x a c e r b ati o ns  
T h e tr e at m e nt f or  a  s e v e r e ast h m a  e x a c er b ati o n is  at l e ast  3  c o ns e c uti v e  d a ys  of  S C S.  
•   T h e r e c o m m e n d e d tr e at m e nt ( GI N A  2 0 1 8 ) f or  a s e v er e  e x a c er b ati o n is  pr e d nis ol o n e 
( 1  m g/ k g/ d a y  u p t o  5 0  m g f or  a d ults  a n d  a d ol es c e nts)  o n c e  p er  d a y ( pr ef er a bl y i n t h e 
m or ni n g) f o r  5 t o  7  d a ys 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 8  of  1 5 9  
•   T a p eri n g t h e  pr e d nis ol o n e  d os e is  n ot  n e e d e d if t h e tr e at m e nt  h as  b e e n  gi v e n f or l ess t h a n  2 
w e e ks ( GI N A  2 0 1 8 ) 
 
Tr e at m e nt f or l ess t h a n  3  d a ys  d o es  n ot  c o nstit ut e  a s e v er e  ast h m a  e x a c er b ati o n.  
5. 1. 1. 5   
O ns et   a n d  d u r ati o n  of  ast h m a  e x a c e r b ati o ns 
F or  s e v e r e  e x a c er b ati o ns, t h e  d ur ati o n is  d efi n e d  b y t h e p r es c ri b e d t r e at m e nt.  
F or  s e v e r e e x a c er b ati o ns:  
•   T h e st art  d at e  will  b e  d efi n e d  as t h e st art  d at e  of  pr es cri b e d tr e at m e nt  wit h  a  S C S.  
•   T h e st o p  d at e  will  b e  d efi n e d  as t h e l ast  d a y  of  pr es cri b e d tr e at m e nt  wit h  a  S C S.  
•   If t h e ti m efr a m e  b et w e e n s u c c essi v e  S C S  us e is  ≥ 7  d a ys, t h e  e v e nt  of s e v er e  ast h m a 
e x a c er b ati o n  will  b e  c o nsi d er e d  as  2 s e p ar at e  e v e nts  of s e v er e  ast h m a  e x a c er b ati o n.  A n 
e v e nt  of s e v er e  ast h m a  e x a c er b ati o n is  c o nsi d er e d  “si n g ul ar ”, if  S C S  us e is  < 7  d a ys.     
•   A si n gl e  d e p ot i nj e ct a bl e  d os e  of  c orti c ost er oi ds  will  b e  c o nsi d er e d  e q ui v al e nt t o  a  3- d a y 
c o urs e  of  S C S.  T h e  c orr es p o n di n g st o p  d at e f or t his tr e at m e nt  will  c o ns e q u e ntl y  b e 
d et er mi n e d  as t h e  d at e  of  a d mi nistr ati o n  pl us  2  d a ys. 
•   If  m ulti pl e tr e at m e nts  ar e pr es cri b e d f or t h e s a m e  e x a c er b ati o n, t h e  e arli est st art  d at e  a n d 
t h e l at est st o p  d at e  will  b e  us e d. 
•   F or  a s e v er e  ast h m a  e x a c er b ati o n r e q uiri n g  h os pit ali z ati o n  wit h  n o  d o c u m e nt e d 
c orti c ost er oi d tr e at m e nt,  h os pit ali z ati o n  a d missi o n/ dis c h ar g e  d at es,  or  e m er g e n c y  visit  d at e 
will  b e  us e d  as st art/st o p  d at es.  
5. 1. 1. 6   
A p p r o a c h f o r  c a pt u ri n g  ast h m a  e x a c e r b ati o ns 
5. 1. 1. 6. 1   
 S e v e r e  Ast h m a  E x a c e r b ati o n  e C R F  
All s cr e e ni n g  a n d  p ost- r a n d o mi z ati o n s e v er e  ast h m a  e x a c er b ati o ns (i n cl u di n g i n v esti g at or-
j ustifi e d  ast h m a  e x a c er b ati o ns)  m ust  b e  c a pt ur e d  usi n g t h e  S e v er e  Ast h m a  E x a c er b ati o n  e C R F.  
S e v er e  ast h m a  e x a c er b ati o ns  will  b e  c o nsi d er e d  e x p e ct e d st u d y  e n d p oi nts  a n d  will  n ot  b e 
r e p ort e d  as  A Es  u nl ess t h e y  als o  m e et t h e  crit eri a f or  a n  S A E (S e cti o n  6. 3. 5 ).  
5. 1. 1. 6. 2   
S y m pt o m  R e p o rti n g  
T h e s u bj e ct  will  us e t h e  e Di ar y f or  d ail y s y m pt o m r e p orti n g,  e nt eri n g s y m pt o ms t wi c e  d ail y. 
If s y m pt o ms  m e et t h e  b el o w t hr es h ol d, t h e  e Di ar y  g e n er at es  a n  al ert t o t h e s u bj e ct  a n d t h e 
i n v esti g ati o n al sit e:  
•   D e cr e as e i n  m or ni n g  p e a k fl o w  ≥ 2 0 %  o n  at l e ast  2  c o ns e c uti v e  d a ys  c o m p ar e d  wit h 
b as eli n e,  a n d/ or 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
4 9  of  1 5 9  
•   A n i n cr e as e i n r es c u e  m e di c ati o n  us e  of  ≥ 4  p uffs  o n  at l e ast  2  c o ns e c uti v e  d a ys  c o m p ar e d 
wit h t h e  a v er a g e  us e  d uri n g  b as eli n e  a n d/ or 
•   > 1 2  p uffs  of r es c u e  m e di c ati o n i n  1  d a y,  a n d/ or 
•   A  ni g ht- ti m e  ast h m a s y m pt o m s c or e  of  > b as eli n e  ni g ht-ti m e s c or e a n d  ≥ 2 f or  at l e ast 
2  c o ns e c uti v e  d a ys,  a n d/ or 
•   A  d a yti m e  ast h m a s y m pt o m s c or e  of  3 f or  at l e ast  2  c o ns e c uti v e  d a ys 
T his  al ert s h o ul d  g e n er at e  c o nt a ct  b et w e e n t h e s u bj e ct  a n d t h e i n v esti g ati o n al sit e.  T h e 
i n v esti g at or t h e n  m a k es t h e  d e cisi o n  w h et h er  or  n ot to i niti at e ( or  es c al at e,  as  a p pr o pri at e) 
tr e at m e nt (i e,  wit h i n h al e d  or  S C S  a n d/ or  h os pit ali z ati o n). 
N B:  A n  e Di a r y  al e rt is  n ot  a n  ast h m a  e x a c e r b ati o n  p er s e . 
Alt h o u g h t h e  e Di ar y  al ert  m a y i niti at e  c o nt a ct  b et w e e n t h e s u bj e ct  a n d t h e i n v esti g ati o n al sit e, 
t h e i n v esti g at or  or  d esi g n e e  will  al w a ys  ass ess t h e s u bj e ct’s s y m pt o ms  a n d  d et er mi n e  w h et h er 
t o tr e at t h e s u bj e ct f or  a n  e x a c er b ati o n.  S u bj e cts  will  als o  b e r e c o m m e n d e d  n ot t o t a k e  m or e 
t h a n  8  p uffs  p er  d a y  a n d  a d vis e d t o  c o nt a ct t h e st u d y sit e/i n v esti g at or if t h eir s y m pt o ms 
n e c essit at e  m or e t h a n  8  p uffs i n  a  d a y.  
Ast h m a si g ns  or s y m pt o ms  will  b e r e c or d e d  as  A Es  o nl y  w h e n: t h e si g n  or s y m pt o m is s eri o us, 
c a us es t h e s u bj e ct t o  dis c o nti n u e I P,  or is  n e w t o t h e s u bj e ct  or i n c o nsist e nt  wit h t h e s u bj e ct’s 
pr e -e x isti n g  ast h m a  hist or y (S e cti o n  6. 3. 6 ). 
5. 1. 2   
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n ai r e + 1 2/ P e di at ri c  Ast h m a  Q u alit y  of 
Lif e  Q u esti o n n ai r e  
5. 1. 2. 1   
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n ai r e + 1 2 
T h e  A Q L Q + 1 2  will  b e  us e d i n s u bj e cts  1 2  y e ars  a n d  ol d er.  T h e  A Q L Q + 1 2  will  b e s elf-
a d mi nist er e d  usi n g  a n  e P R O  d e vi c e  d uri n g sit e  visits  as i n di c at e d i n  T a bl e   1.  Li n g uisti c all y 
v ali d at e d tr a nsl ati o ns  of t h e  A Q L Q + 1 2 i nt o l o c al l a n g u a g es  will  b e  us e d. 
T h e  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e ( A Q L Q,  A p p e n di x  F,  Ast h m a  Q u alit y  of  Lif e  + 1 2 
Q u esti o n n air e )  w as  d e v el o p e d t o  m e as ur e t h e f u n cti o n al  pr o bl e ms ( p h ysi c al,  e m oti o n al, s o ci al, 
a n d  o c c u p ati o n al) t h at  ar e  m ost tr o u bl es o m e t o  a d ults  wit h  ast h m a. 
T h er e  ar e  3 2  q u esti o ns i n t h e  A Q L Q + 1 2  a n d t h e y  ar e i n  4  d o m ai ns (s y m pt o ms,  a cti vit y 
li mit ati o n,  e m oti o n al f u n cti o n,  a n d  e n vir o n m e nt al sti m uli).  T h e  a cti vit y  d o m ai n  c o nt ai ns 
5  s u bj e ct-s p e cifi c  q u esti o ns.  T his  all o ws s u bj e cts t o s el e ct  5  a cti viti es i n  w hi c h t h e y  ar e  m ost 
li mit e d  a n d t h es e  a cti viti es  will  b e  ass ess e d  at  e a c h f oll o w- u p.  S u bj e cts  ar e  as k e d t o t hi n k  a b o ut 
h o w t h e y  h a v e  b e e n  d uri n g t h e  pr e vi o us  2  w e e ks  a n d t o r es p o n d t o  e a c h  of t h e  3 2  q u esti o ns  o n  a 
7- p oi nt s c al e ( 7 = n ot i m p air e d  at  all; t o  1 =s e v er el y  i m p air e d).  T h e  o v er all  A Q L Q + 1 2 s c or e is t h e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 0  of  1 5 9  
m e a n  of  all  3 2  r es p o ns es  a n d t h e i n di vi d u al  d o m ai n s c or es  ar e t h e  m e a ns  of t h e it e ms i n t h os e 
d o m ai ns. 
5. 1. 2. 2   
P e di at ri c  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n ai r e   
T h e  P A Q L Q  will  b e s elf -a d mi nist er e d  d uri n g sit e  visits  as i n d i c at e d i n T a bl e   1 i n s u bj e cts 
a g e d   7 t o  1 1  y e ars.  S u bj e cts  a g e d  4 t o  6  y e ars  will  c o m pl et e t h e  q u esti o n n air e  wit h t h e  h el p  of  a 
c ar e gi v er.  As t h e  P A Q L Q is  n ot  v ali d at e d f or  c hil dr e n l ess t h a n  7  y e ars  of  a g e,  d at a f or s u bj e cts 
w h o  ar e  a g e d  4 t o  6  y e ars  will  b e  e x cl u d e d fr o m t h e  a n al ys es  of  P A Q L Q  e n d p oi nts. 
T h e s u bj e ct/ c ar e gi v er  will  c o m pl et e t h e  P A Q L Q  o n  p a p er  a n d r es p o ns es  will  b e tr a ns cri b e d t o 
t h e  e CR F  b y sit e st aff.  Li n g uisti c all y  v ali d at e d tr a nsl ati o ns  of t h e  P A Q L Q i nt o l o c al l a n g u a g es 
will  b e  us e d. 
T h e  P A Q L Q, ( A p p e n di x  G,  P e di atri c  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e )  w as  d e v el o p e d t o 
m e as ur e t h e f u n cti o n al  pr o bl e ms ( p h ysi c al,  e m oti o n al,  a n d s o ci al) t h at  ar e  m ost tr o u bl es o m e t o 
c hil dr e n  wit h  ast h m a.  
T h e  P A Q L Q  h as  2 3  q u esti o ns i n  3  d o m ai ns (s y m pt o ms,  a cti vit y li mit ati o n,  a n d  e m oti o n al 
f u n cti o n).  T h e  a cti vit y  d o m ai n  c o nt ai ns  3 s u bj e ct-s p e cifi c  q u esti o ns.  C hil dr e n (s u bj e cts  a g e d 
7 t o  1 1  y e ars)  ar e  as k e d t o t hi n k  a b o ut  h o w t h e y  h a v e  b e e n  d uri n g t h e  pr e vi o us  w e e k  a n d t o 
pr o vi d e r es p o ns es t o  e a c h  of t h e  2 3  q u esti o ns  o n  a  7- p oi nt s c al e ( 7 = n ot  b ot h er e d  at  all; 
1 = e xtr e m el y  b ot h er e d).  T h e  o v er all  P A Q L Q s c or e is t h e  m e a n  of  all  2 3 r es p o ns es  a n d t h e 
i n di vi d u al  d o m ai n s c or es  ar e t h e  m e a ns  of t h e it e ms i n t h os e  d o m ai ns. 
5. 1. 3   
Ast h m a  C o nt r ol  Q u esti o n n ai r e- 5  a n d  - 7 
T h e  A C Q - 5  will  b e  a d mi nist er e d  usi n g  a n  e P R O  d e vi c e  duri n g sit e  visits  as i n di c at e d i n  
T a bl e   1.  T h e  A C Q-5 s elf - a d mi nist er e d  a d ult  v ersi o n  will  b e  us e d f or  a d ults  a n d  a d ol es c e nts 
1 1  y e ars  a n d  ol d er.  As  t h e  A C Q- 5 is  n ot  v ali d at e d f or  c hil dr e n l ess t h a n  6  y e ars  ol d, t h e 
i nt er vi e w er- a d mi nist er e d  v ersi o n  will  b e i m pl e m e nt e d f or  c hil dr e n  a g e d  4 t o  1 0  y e ars.  T h e 
q u esti o ns t a k e  a p pr o xi m at el y  2 t o  3  mi n ut es t o  c o m pl et e.  Li n g uisti c all y  v ali d at e d tr a nsl ati o ns  of 
th e  A C Q - 5 i nt o l o c al l a n g u a g es  will  b e  us e d. 
I nt er n ati o n al  g ui d eli n es f or t h e tr e at m e nt  of  ast h m a  h a v e i d e ntifi e d t h at t h e  pri m ar y  cli ni c al  g o al 
of  ast h m a  m a n a g e m e nt is t o  o pti mi z e  ast h m a  c o ntr ol ( mi ni mi z ati o n  of s y m pt o ms,  a cti vit y 
li mit ati o n,  br o n c h o c o nstri cti o n,  a n d r es c u e  β 2- a g o nist  us e)  a n d t h us r e d u c e t h e ris k  of 
lif e-t hr e at e ni n g  e x a c er b ati o ns  a n d l o n g-t er m  m or bi dit y.  T h e  Ast h m a  C o ntr ol  Q u esti o n n air e 
( 5-it e m  v ersi o n; A p p e n di x  H,  Ast h m a  C o ntr ol  Q u esti o n n air e- 5  a n d - 7  )  w as  d e v el o p e d t o  m e et 
t h es e  crit eri a. It  m e as ur es  b ot h t h e  a d e q u a c y  of  ast h m a  c o ntr ol  a n d  c h a n g e i n  ast h m a  c o ntr ol, 
w hi c h  o c c urs  eit h er s p o nt a n e o usl y  or  as  a  r es ult  of tr e at m e nt. 
T h e  A C Q - 5  q u esti o n n air e  will  b e s elf- a d mi nist er e d f or  a d ults  a n d  a d ol es c e nts  1 1  y e ars  a n d 
ol d er.  T h e i nt er vi e w er- a d mi nist er e d  v ersi o n  will  b e  us e d f or  c hil dr e n  a g e d  4 t o  1 0  y e ars.   
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 1  of  1 5 9  
S u bj e cts  will  b e  as k e d t o  c o m pl et e t h e  A C Q -5,  c o nsis ti n g  of  5  q u esti o ns  o n s y m pt o m  c o ntr ol; 
e a c h  of t h e  q u esti o ns  will  b e s c or e d  o n  a  7- p oi nt s c al e ( 0 = e x c ell e nt  ast h m a  c o ntr ol;  6 = e xtr e m el y 
p o or  c o ntr ol). 
N ot e:  T h e  A C Q - 7  will  b e  c o m pl et e d  o n c e  at s cr e e ni n g  o nl y  a n d  c o nsists  of t h e t o p s c ori n g 
5 s y m pt o ms fr o m  t h e  A C Q- 5,  wit h t h e  a d diti o n  of  F E V1%  pr e di ct e d  v al u e  a n d  d ail y r es c u e 
br o n c h o dil at or  us e.  S u bj e cts  ar e r e q uir e d t o s c or e  ≥ 1. 5 f or  eli gi bilit y t o t h e st u d y.  
5. 1. 4   
Ast h m a  C o nt r ol  T est 
T h e  A C T  will  b e s elf - a d mi nist er e d  usi n g  a n  e P R O  d e vi c e  d uri n g sit e  visits  as in di c at e d i n  
T a bl e   1.  Li n g uisti c all y  v ali d at e d tr a nsl ati o ns  of t h e  A C T i nt o l o c al l a n g u a g es  will  b e  us e d. 
T h e  A C T ( A p p e n di x I,  Ast h m a  C o ntr ol  T est ) is  a  5- q u esti o n  h e alt h s ur v e y  us e d t o  m e as ur e 
ast h m a  c o ntr ol i n s u bj e cts  a g e d  1 2  a n d  ol d er.  T h e s ur v e y  m e as ur es t h e  el e m e nts  of  ast h m a 
c o ntr ol  as  d efi n e d  b y t h e  N ati o n al  H e art,  L u n g,  a n d  Bl o o d I nstit ut e.  T h e  A C T is  a n  effi ci e nt, 
r eli a bl e,  a n d  v ali d  m et h o d  of  m e as uri n g  ast h m a  c o ntr ol,  wit h  or  wit h o ut l u n g f u n cti o ni n g 
m e as ur es s u c h  as s pir o m etr y.  
T h e  d e v el o p m e nt  of t h e  A C T f oll o ws  a  p ar a di g m s hift i n t h e tr e at m e nt  of  ast h m a, fr o m  a f o c us 
o n  ast h m a s e v erit y t o  ast h m a  c o ntr ol.  S p e cifi c all y,  A C T  h el ps i d e ntif y  a n d  d et e ct  ast h m a 
s u bj e cts  w h o  ar e  n ot  w ell  c o ntr oll e d. It  w as  d esi g n e d  wit h i n p ut fr o m  ast h m a  e x p erts  w h o 
h el p e d  est a blis h  c ut- p oi nt s c or es t o i m pr o v e t h e  cli ni c al  utilit y  of t h e s ur v e y.   
5. 1. 5   
C hil d h o o d  Ast h m a  C o nt r ol  T est  
T h e  C  A C T  will  b e s elf - a d mi nist er e d  usi n g  a n  e P R O  d e vi c e  d uri n g sit e  visits  as i n di c at e d i n 
T a bl e   1.  Li n g uisti c all y  v ali d at e d tr a nsl ati o ns  of t h e  C  A C T i nt o l o c al l a n g u a g es  will  b e  us e d. 
T h e  C  A C T r e p ort ( A p p e n di x J,  C hil d h o o d  Ast h m a  C o ntr ol  T est ) is  a  v ali d at e d t o ol f or s u bj e cts 
a g e d  4 t o  1 1  y e ars t o  ass ess  ast h m a  c o ntr ol  a n d i d e ntif y  c hil dr e n  wit h i n a d e q u at el y  c o ntr oll e d 
ast h m a.    
5. 1. 6   
e Di a r y  
T h e  e Di ar y  will  b e  utili z e d  b y  all s u bj e cts  e nr oll e d i n t h e st u d y i n cl u di n g  c hil dr e n.  C hil dr e n,  as 
n e c ess ar y,  will  b e  assist e d  b y  a  c ar e gi v er f or t h e  p erf or m a n c e  of  ass ess m e nts  a n d  n a vi g ati o n  of 
t h e  a p pli c a bl e  q u esti o ns. 
5. 1. 6. 1   
P e a k  e x pi r at o r y fl o w 
S u bj e cts  will  b e tr ai n e d  at  Visit  1.  T hr o u g h o ut t h e st u d y, s u bj e cts  will r e c or d t h e  b est  of  3  P E F 
m e as ur es  o n risi n g i n t h e  m or ni n g  a n d  b ef or e  g oi n g t o  b e d i n t h e  e v e ni n g  pri or t o t a ki n g  a n y 
ast h m a t h er a p y.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 2  of  1 5 9  
5. 1. 6. 2   
Us e  of i n v esti g ati o n al  p r o d u ct ( r eli e v e r t h e r a p y)  
Us e  of I P  as r eli e v er t h er a p y  will  b e  c oll e ct e d  usi n g  a n  e P R O  d e vi c e.  S u bj e cts  will  b e  as k e d 
t wi c e  d ail y (i n t h e  e v e ni n gs  a n d i n t h e  m or ni n gs) t o  e nt er i nt o t h eir  e Di ar y ( d e vi c e  c all e d 
A M 3 +),  h o w  m a n y  p uffs  of r es c u e/r eli e v er  m e di c ati o n (i e, st u d y I P) t h e y t o o k si n c e t h e 
pr e vi o us  m e as ur e.  
5. 1. 6. 3   
e Di a r y  m ai nt e n a n c e t h e r a p y  c o m pli a n c e   
M o nit ori n g  of  c o m pli a n c e f or  m e di u m- t o- hi g h- d os e I C S  or l o w-t o- hi g h- d os e I C S i n 
c o m bi n ati o n  wit h  L A B A  will  b e  d o n e  o nl y t hr o u g h t h e  e Di ar y  q u esti o n  “ h a v e  y o u t a k e n  y o ur 
r e g ul ar  m ai nt e n a n c e t h er a p y t o d a y ? ” (A p p e n di x  K,  List  of  e- Di ar y  q u esti o ns ).  T h er e  will  b e  n o 
c oll e cti o n  of t h e  a ct u al  d e vi c es f or  m e as ur e m e nt/ ass ess m e nt  of  c o m pli a n c e; r at h er,  c o m pli a n c e 
will  b e  ass ess e d  b y s u bj e ct r e p ort e d r es p o ns e.  R es p o ns es  will  b e  “ Y es ”  or  “ N o ”,  w h er e  “ Y es ” is 
t a k e n  as  c o m pli a nt t o  d os e  a n d r e gi m e n  a n d  a  “ N o ”  e q u ati n g t o  n o n c o m pli a n c e ( miss e d  d os e). 
5. 1. 6. 4   
e Di a r y  r e c o r di n g  of  as t h m a s y m pt o ms 
T h e s u bj e ct  will  us e t h e  e Di ar y f or  d ail y s y m pt o m r e p orti n g,  e nt eri n g s y m pt o ms t wi c e  d ail y.  
T h e  d e vi c e  will  b e  pr o gr a m m e d t o  al ert  b ot h t h e s u bj e ct  a n d st u d y  c e nt er  w h e n t h e  b el o w 
pr es p e cifi e d  al ert t hr es h ol ds  ar e  cr oss e d.  T h e  p ur p os e  of t h e  al erts is t o tri g g er  a  d o c u m e nt e d 
c o nt a ct  b et w e e n t h e sit e  a n d s u bj e ct f or f urt h er  e v al u ati o n if  d e e m e d  n e c ess ar y  b y t h e 
i n v esti g at or.  S p o ns or  will  als o r e c ei v e  pr o gr a m m e d  al erts t o  m o nit or s u bj e ct f oll o w- u p. 
•   Tri g g ers i n t h e  e P R O  d e vi c e  will  al ert t h e s u b j e cts t o si g ns  of  c h a n g e  of  ast h m a  a n d t o 
c o nt a ct t h eir  p h ysi ci a n. 
•   A  d e di c at e d  p ers o n fr o m t h e  S p o ns or  will r e vi e w t h e  e P R O  a n d  c o m pli a n c e  al erts 
( 2  c o ns e c uti v e  d a ys  of  missi n g  d at a)  a n d  c o nt a ct t h e sit e. 
•   I n  c as e  of  e P R O  or  c o m pli a n c e  al erts,  a  q u alifi e d  pers o n fr o m t h e sit e  will  c o nt a ct t h e 
s u bj e ct.  F or  e P R O  al erts, t h e s u bj e ct’s  ast h m a st at us s h o ul d  b e  e v al u at e d  a n d it  will  b e 
d et er mi n e d if  a  cli ni c  visit is  n e c ess ar y.  
 
A n  e Di a r y  al e rt is  n ot  a n  ast h m a  e x a c e r b ati o n  p er s e . 
Alt h o u g h t h e  e Di ar y  al ert  m a y  i niti at e  c o nt a ct  b et w e e n t h e s u bj e ct  a n d t h e i n v esti g ati o n al sit e, 
t h e i n v esti g at or  or  d esi g n e e  will  al w a ys  ass ess t h e s u bj e ct’s s y m pt o ms  a n d  d et er mi n e  w h et h er 
t o tr e at t h e s u bj e ct f or  a n  e x a c er b ati o n. 
Ast h m a s y m pt o ms s h o ul d  b e  c a pt ur e d i n t h e  e Di ar y  b y t h e s u bj e ct  e v er y  m or ni n g  a n d  e v e ni n g 
(A p p e n di x  K,  List  of  e- Di ar y  q u esti o ns ). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 3  of  1 5 9  
5. 1. 7   
D et e ri o r ati o n  of  ast h m a  
I n t his st u d y,  d et eri or atio n  of  ast h m a is  d efi n e d  as  1  or  m or e  of t h e f oll o wi n g it e ms f or  ≥ 2 
c o ns e c uti v e  d a ys:  
•   P E F:  a  d e cli n e  of  ≥ 2 0 % fr o m  b as eli n e  
•   R eli e v er t h er a p y  us e:  > 4  p uffs/ d a y  a n d  ≥ 2 × b as eli n e   
•   S y m pt o ms:  ni g ht- ti m e s c or e t h at is  > b as eli n e a n d  ≥ 2  O R  a  d a yti m e s c or e t h at is  > b as eli n e 
a n d  = 3  
 
D a yti m e is  d efi n e d  as t h e  p eri o d  b et w e e n t h e  m or ni n g l u n g f u n cti o n  ass ess m e nt ( u p o n risi n g i n 
t h e  m or ni n g)  a n d t h e  e v e ni n g l u n g f u n cti o n  ass ess m e nt. 
Ni g ht-ti m e is  d efi n e d  as t h e  p eri o d  b et w e e n t h e  e v e ni n g l u n g f u n cti o n  ass ess m e nt ( at  b e dti m e) 
a n d t h e  m or ni n g l u n g f u n cti o n  ass ess m e nt.  
S e v er e  ast h m a  e x a c er b ati o ns  will  als o  b e  c o nsi d er e d t o  b e  d et eri or ati o n  of  ast h m a  a n d i n cl u d e d 
i n t h e  a n al ys es  of t his  e n d p oi nt. 
5. 1. 8   
L u n g f u n cti o n  m e as u r e m e nt  b y s pi r o m et r y 
Pr e br o n c h o dil at or s pir o m etr y  will  b e  p erf or m e d  o n  a  M ast er S c o p e  pr o vi d e d f or t h e st u d y  b y t h e 
c e ntr al r e a d er  at s cr e e ni n g ( Visit  1  a n d/ or  Visit  1 a,  as  a p pli c a bl e),  Visit  2 ( b as eli n e),  Visit  5  a n d 
Visit  6 ( e n d p oi nt  m e as ur e m e nts). It is i m p ort a nt t h at  all s pir o m etr y  ass ess m e nts  ar e  p erf or m e d 
aft er  0 6: 0 0  a n d  n o l at er t h a n  1 1: 0 0  A M  a n d t h at t h e s pir o m etr y  at  Visits  5  a n d  6  ar e  p erf or m e d 
± 1  h o ur i n r el ati o n t o t h e ti m e  of s pir o m etr y  at  Visit  2.  Pr ef er a bl y, t h e s a m e st u d y  p ers o n n el 
s h o ul d t est t h e s u bj e ct’s l u n g f u n cti o n t hr o u g h o ut t h e st u d y t o r e a c h  o p ti m al  p erf or m a n c e  a n d t o 
e n h a n c e r e pr o d u ci bilit y.  T h e s u bj e ct s h o ul d r est  at l e ast  1 5  mi n ut es  pri or t o t h e t est.  F or 
r e p e at e d  m e as ur e m e nts  e g, t o  ass ess  b est  of  3,  a s h ort  p a us e ( 1  mi n ut e)  b et w e e n  m e as ur e m e nts 
is r e c o m m e n d e d.  
T h e  m e as ur e m e nts  ar e t o  b e  m a d e  wit h t h e s u bj e ct s e at e d i n  a n  u pri g ht  p ositi o n ( pr ef er a bl y),  or 
if  n ot  c o mf ort a bl e st a n di n g  p ositi o n is  als o  a c c e pt a bl e.  T h e s a m e  p ositi o n s h o ul d  b e  us e d f or  all 
s pir o m etr y  m e as ur es  d uri n g t h e  e ntir e st u d y.  T h e  h e a d  m ust  n ot  b e tilt e d  d uri n g  m e as ur e m e nts. 
D uri n g t h e  br e at hi n g  m a n e u v ers, t h e t h or a x s h o ul d  b e  a bl e t o  m o v e fr e el y;  h e n c e ti g ht  cl ot hi n g 
s h o ul d  b e l o os e n e d.   
S u bj e cts s h o ul d  h a v e  pr e vi o usl y  dis c o nti n u e d  br o n c h o dil at or  m e di c ati o ns  as s p e cifi e d i n 
S e cti o n  7. 8. 2  f or r e v ersi bilit y t ests  as t h es e  c a n  aff e ct  br o n c h o dil ati o n. If t h es e  m e di c ati o ns 
w er e t a k e n  wit hi n t h e r estri ct e d ti m e  p eri o ds,  visits s h o ul d  b e r e -s c h ed ul e d. 
M e as ur e m e nt  pr o c e d ur es s h o ul d  b e  p erf or m e d i n  a c c or d a n c e  wit h t h e  us er  m a n u al f or t h e st u d y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 4  of  1 5 9  
5. 1. 8. 1   
R e v e rsi bilit y  T est  
T o f ulfill t h e r e v ersi bilit y i n cl usi o n  crit eri o n, t h e i n cr e as e i n  F E V 1 r el ati v e t o  b as eli n e  m ust  b e 
≥ 1 2 % ( a n d  ≥ 2 0 0  m L f or s u bj e cts  ≥ 1 8  y e ars)  a p pr o xi m at el y  3 0  mi n ut es  aft er i n h al ati o n  of 
S p o ns or- pr o vi d e d  V e nt oli n. 
R e v ersi bilit y t esti n g  will  b e  p erf or m e d  as f oll o ws:  
1.   D et er mi n e if  m or ni n g  d os es  of  all  m ai nt e n a n c e  ast h m a  m e di c at i o ns (T a bl e   4)  w er e 
wit h h el d  a n d t h at s h ort- a cti n g  br o n c h o dil at ors  w er e  n ot  a d mi nist er e d  wit hi n  6  h o urs  of 
t esti n g (if  a p pli c a bl e). 
2.   P erf or m  pr e br o n c h o d il at or  P F Ts  aft er  at l e ast  1 5  mi n ut es  of r est,  a n d  b ef or e 
a d mi nistr ati o n  of  V e nt oli n.  
3.   S u bj e cts  a g e d  ≥ 1 2  y e ars s h o ul d  a d mi nist er  4  p uffs  of  V e nt oli n.  S u bj e cts  a g e d  < 1 2  y e ars 
s h o ul d  a d mi nist er  2  p uffs  of  V e nt oli n. 
4.   P erf or m  p ost - br o n c h o dil at or  P F Ts  a p pr o xi m at el y  3 0  mi n ut es  aft er t h e  a d mi nistr ati o n  of 
V e nt oli n. 
T h e  r e v e rsi bilit y is  c al c ul at e d  as f oll o ws:  
   
  
R e v ersi bilit y =([ P ost  F E V 1-Pr e  F E V 1]/ Pr e  F E V1) × 1 0 0. 
Pr e - a n d  p ost br o n c h o dil at or  F E V1 m e as ur e m e nts  will  b e  c a pt ur e d  wit hi n t h e  M ast er S c o p e. If t h e 
r e v ersi bilit y i n cl usi o n  crit eri o n is  n ot  m et  at  Visit  1, t h e r e v ersi bilit y t est  m ust  b e r e p e at e d  at 
Visit  1 a i n  a d v a n c e  of  Visit  2 (r a n d o mi z ati o n).  
5. 1. 8. 2   
C O VI D -1 9  a n d  P ul m o n a r y  F u n cti o n  T esti n g  
I n- cli ni c s pir o m etr y  ass ess m e nts s h o ul d  n ot  b e  p erf or m e d f or s u bj e cts  e x hi biti n g si g ns  a n d 
s y m pt o ms f or  C O VI D- 1 9.  A n y s us p e ct e d  pri or  or  a cti v e  c as es s h o ul d  h a v e  a  di a g n osti c t est t o 
c o nfir m  C O VI D - 1 9 st at us.  A n y s u bj e cts  wit h  c o nfir m e d  C O VI D- 1 9 s h o ul d  n ot  p erf or m 
s pir o m etr y  ass ess m e nts  wit hi n  1 4  d a ys  of t h e  c ess ati o n  of s y m pt o ms  a n d  u n til t h e  PI  c o nsi d ers 
t h e s u bj e ct is  n o l o n g er i nf e cti o us.  D e vi c e  cl e a ni n g  a n d  h y gi e n e  g ui d a n c e s h o ul d  b e f oll o w e d  at 
all ti m es.    
5. 2   
S af et y  ass ess m e nts  
S af et y  ass ess m e nts i n cl u d e  cli ni c al l a b or at or y ( h e m at ol o g y,  c h e mistr y,  m or ni n g s er u m  c ortis ol, 
a n d  pr e g n a n c y t ests f or f e m al es  of  c hil d b e ari n g  p ot e nti al)  p ar a m et ers,  1 2-l e a d  E C G r e a di n gs, 
vit al si g n  m e as ur e m e nts,  a n d  c oll e cti o n  of  A Es. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 5  of  1 5 9  
5. 2. 1   
L a b o r at o r y s af et y  ass ess m e nts 
Bl o o d s a m pl es f or  d et er mi n ati o n  of  cli ni c al  c h e mistr y , h e m at ol o g y,  a n d m or ni n g s er u m  c ortis ol 
will  b e t a k e n  at t h e ti m es i n di c at e d i n  T a bl e   1. 
A d diti o n al s af et y s a m pl es  m a y  b e  c oll e ct e d if  cli ni c all y i n di c at e d,  at t h e  dis cr eti o n  of t h e  
i n v esti g at or.  
T h e  cli ni c al  c h e mistr y, h e m at ol o g y, s er u m  c ortis ol  ass ess m e nts  will  b e  p erf or m e d  usi n g  a 
c e ntr ali z e d l a b or at or y.  S a m pl e t u b es  a n d s a m pl e si z es  m a y  v ar y  d e p e n di n g  o n l a b or at or y 
m et h o d  us e d  a n d r o uti n e  pr a cti c e  at t h e sit e. 
T h e f oll o wi n g l a b or at or y  v ari a bl es  d es cri b e d i n  T a bl e   2 will  b e  m e as ur e d:  
T a bl e  2    
L a b o r at o r y  S af et y  V a ri a bl es 
H e m at ol o g y/ H e m ost asis ( w h ol e  bl o o d)  
Cli ni c al  C h e mist r y (s e r u m  o r  pl as m a)  
B as o p hils ( %)  
Al b u mi n  
B as o p hils  A bs  
Al a ni n e tr a ns a mi n as e  
E osi n o p hils ( %)  
Al k ali n e  p h os p h at as e  
E osi n o p hils  A bs  
As p art at e tr a ns a mi n as e  
H e m o gl o bi n   
Bilir u bi n, t ot al  
H e m at o crit  
C al ci u m, t ot al  
M e a n  C or p us c ul ar  H e m o gl o bi n  
C hl ori d e  
M e a n  C or p us c ul ar  H e m o gl o bi n  C o n c e ntr ati o n  
C h ol est er ol, t ot al  
M e a n  C or p us c ul ar  V ol u m e  
Cr e ati ni n e  
M o n o c yt es ( %)  
Cr e ati n e  ki n as e  
M o n o c yt es  A bs  
G a m m a -gl ut a m yl tr a ns p e pti d as e  
N e utr o p hils ( %)  
Gl u c os e (r a n d o m)  
N e utr o p hils  A bs  
M a g n esi u m  
R e d  bl o o d  c ells ( er yt hr o c yt es)  
P h os p h at e   
W hit e  bl o o d  c ells (l e u k o c yt es)   
P ot assi u m   
Pl at el et  c o u nt  
Pr ot ei n, t ot al  
L y m p h o c yt es ( %)  
S o di u m  
L y m p h o c yt es  A bs  
Tri gl y c eri d es  
 
M or ni n g  (s er u m)  c ortis ol 
U ri n e  
Ur e a  
Uri n e  β -h C G  pr e g n a n c y ( Visit  2) a 
S er u m  β -h C G  pr e g n a n c y ( Visit  1,  6  a n d  E O S/ P D V)  
A b br e vi ati o ns:  A bs = a bs ol ut e;  β -h C G = β -h u m a n  c h ori o ni c  g o n a d otr o pi n;  E O S = e n d -of -st u d y;  P D V = pr e m at ur e 
dis c o nti n u ati o n  visit  
N ot es:  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 6  of  1 5 9  
a I n  Ar g e nti n a  o nl y,  a d diti o n al  pr e g n a n c y t esti n g t o  b e  c o n d u ct e d  at  m o nt hl y ti m e  p oi nts i n  w o m e n  of  c hil d b e ari n g 
p ot e nti al.    
 
If  a s u bj e ct s h o ws  a n  A S T o r  A L T  ≥ 3 ×  U L N  a n d  t ot al  bilir u bi n ( T B L)  ≥ 2 × U L N  pl e as e r ef er t o 
S e cti o n  3. 9  a n d  A p p e n di x  E,  H y’s  L a w  f or f urt h er i nstr u cti o ns. 
5. 2. 2   
R esti n g  1 2-l e a d  el e ct r o c a r di o g r a m 
A  1 2 -l e a d  E C G  will  b e  p erf or m e d  at t h e  visits  d et ail e d i n T a bl e   1.  T h e ti mi n g  a n d  n u m b er  of 
E C Gs  m a y  b e  a dj ust e d i n r es p o ns e t o t h e  e m er gi n g s af et y  pr ofil e. 
T w el v e -l e a d  E C Gs  will  b e  o bt ai n e d  usi n g  a  c e ntr ali z e d l a b or at or y  aft er t h e s u bj e ct  h as  b e e n 
r esti n g s e mi-s u pi n e f or  at l e ast  1 0  mi n ut es.  All  E C Gs s h o ul d  b e r e c or d e d  wit h t h e s u bj e ct i n t h e 
s a m e  p h ysi c al  p ositi o n.  A st a n d ar di z e d  E C G  m a c hi n e s h o ul d  b e  us e d  a n d t h e s u bj e ct s h o ul d  b e 
e x a mi n e d  usi n g t h e s a m e  m a c hi n e t hr o u g h o ut t h e st u d y,  w h er e f e asi bl e. 
Aft er   p a p er  E C Gs  h a v e  b e e n r e c or d e d, t h e i n v esti g at or  or  d esi g n at e d  p h ysi ci a n  will r e vi e w  e a c h 
of t h e  E C Gs  a n d  m a y r ef er t o  a l o c al  c ar di ol o gist, if  a p pr o pri at e.  A  p a p er  c o p y s h o ul d  b e fil e d 
i n t h e s u bj e ct’s  m e di c al r e c or ds. If  a n  a b n or m al  E C G fi n di n g  at s cr e e ni n g/ b as eli n e is  c o nsi d er e d 
t o  b e  cli ni c all y si g nifi c a nt  b y t h e i n v esti g at or, it s h o ul d  b e r e p ort e d  as  a n  A E.  F or  all  E C Gs, 
d et ails  of r h yt h m,  P R,  R R,  Q R S,  a n d  Q T i nt er v als,  a n  o v er all  e v al u ati o n  will  b e r e c or d e d. 
5. 2. 3   
Vit al si g n  m e as u r e m e nts 
Vit al si g ns i n cl u di n g r esti n g  p uls e  a n d  bl o o d  pr ess ur e s h o ul d  b e  ass ess e d  at t h e  visits  d et ail e d i n 
T a bl e   1.  M e as ur e m e nts s h o ul d  b e t a k e n i n t h e sitti n g  p ositi o n  aft er  at l e ast  1 0 mi n ut es  of r est.  
A n y  cli ni c all y si g nifi c a nt  c h a n g es i n  vit al si g ns s h o ul d  b e r e c or d e d  as  a n  A E if  a p pli c a bl e. 
5. 2. 4   
A d v e rs e  e v e nt  ass ess m e nts 
A d v ers e  e v e nts  will  b e  c oll e ct e d fr o m ti m e  of si g n at ur e  of i nf or m e d  c o ns e nt/ ass e nt t hr o u g h t o 
t h e f oll o w- u p  peri o d  as  d es cri b e d i n  S e cti o n  6 . 
5. 3   
Ot h e r  ass ess m e nts  
5. 3. 1   
P h ysi c al  e x a mi n ati o n 
A  c o m pl et e  p h ysi c al  e x a mi n ati o n  will  b e  p erf or m e d  at s cr e e ni n g  a n d  E O S/ P D V  as  d et ail e d i n 
T a bl e   1.  T his  will i n cl u d e  a n  ass ess m e nt  of t h e f oll o wi n g it e ms:  B MI ( h ei g ht i n  c e nti m et ers [f or 
all s u bj e cts  at  Visit  1  a n d f or s u bj e c ts  ≤ 1 8  y e ars  of  a g e  o nl y  at  W e e k  2 4 ( Visit  6)  a n d 
E O S/ P D V,  as  d et ail e d i n  T a bl e   1]  a n d  w ei g ht),  g e n er al  a p p e ar a n c e, r es pir at or y s yst e m, 
c ar di o v as c ul ar s yst e m,  a b d o m e n, s ki n,  h e a d  a n d  n e c k (i n cl u di n g  e ars,  e y es,  n os e,  a n d t hr o at), 
l y m p h  n o d es, t h yr oi d,  m us c ul os k el et al s yst e m (i n cl u di n g s pi n e  a n d  e xtr e miti es),  a n d 
n e ur ol o gi c al s yst e m.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 7  of  1 5 9  
5. 3. 2   
C o n c o mit a nt  m e di c ati o ns 
T h e  c oll e cti o n  a n d r e c or di n g  of  all  c o n c o mit a nt  m e di c ati o ns, i n cl u di n g  all  ast h m a t h er a pi es, 
will  b e  p erf or m e d  at t h e  visits  d et ail e d i n  T a bl e   1.  P er mitt e d  a n d r estri ct e d  c o n c o mit a nt 
m e di c ati o ns  ar e  d es cri e d i n  S e cti o n  7. 8 . 
All  pr es cri pti o n  dr u gs,  h er b al  pr o d u cts,  vit a mi ns,  mi n er als,  a n d  o v er-t h e- c o u nt er  m e di c ati o ns 
t a k e n  wit hi n  3  m o nt hs  b ef or e s cr e e ni n g  will  b e r e c or d e d  as  pr e vi o us  m e di c ati o ns.  Ast h m a 
m e di c ati o n  hist or y  will  b e r e c or d e d f or  1 2  m o nt hs  b ef or e s cr e e ni n g.   All  m e di c ati o ns t a k e n  aft er 
s cr e e ni n g  a n d t hr o u g h t h e  E O S/ P D V  visit  will  b e r e c or d e d  as  c o n c o mit a nt t h er a p y.   
All  ast h m a t h er a pi es t a k e n  d uri n g t h e st u d y ( Visit  1 t hr o u g h  E O S/ P D V) i n cl u di n g  S C S f or 
e x a c er b ati o ns  as  w ell  as  c o n c o mit a nt I C Ss  will  b e r e c or d e d i n t h e  c o n c o mit a nt  m e di c ati o n f or m 
i n t h e s u bj e ct’s  e C R F.  Ast h m a  m ai nt e n a n c e t h er a p y (i e,  a n I C S,  or I C S/ L A B A  ±  1  of  L T R A, 
L A M A,  or t h e o p h ylli n e)  m ust  b e r e c or d e d  at  b as eli n e.  A n y  c h a n g es t o t h e  m ai nt e n a n c e t h er a p y 
pr es e nt e d  at s cr e e ni n g ( Visit  1/ 1 a,  as  a p pli c a bl e), i n cl u di n g  c h a n g es i n  d osi n g,  will  als o  b e 
c oll e ct e d  o n t h e  c o n c o mit a nt  m e di c at i o n  p a g e i n t h e  e C R F. 
S u bj e cts  will  b e  m ai nt ai n e d,  aft er  Visit  1,  o n t h eir  c urr e nt  m ai nt e n a n c e r e gi m e n.  C h a n g es t o 
m ai nt e n a n c e t h er a p y  ar e  dis c o ur a g e d  u nl ess  cli ni c all y i n di c at e d. I n v esti g at ors s h o ul d  c o nt a ct 
t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct i n  a d v a n c e  of  a n y  pr o p os e d  c h a n g e t o  m ai nt e n a n c e 
t h er a p y f or st u d y s u bj e cts;  c o nsi d er ati o ns s h o ul d  b e  m a d e t o s u bj e ct  dr u g  c o m pli a n c e  a n d  ot h er 
f a ct ors i n  a d v a n c e  of  m a ki n g  c h a n g es t o  m ai nt e n a n c e t h er a p y.   
F or r estri cti o ns r el ati n g t o  c o n c o mit a nt  m e di c ati o ns  s e e S e cti o ns  3. 1   a n d 3. 2 .   
5. 4   
P h a r m a c o ki n eti cs  
N ot  a p pli c a bl e.  
5. 5   
P h a r m a c o d y n a mi cs  
N ot  a p pli c a bl e.  
5. 6   
G e n eti cs  
N ot  a p pli c a bl e.  
5. 7   
Bi o m a r k e r  a n al ysis   
N ot  a p pli c a bl e.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 8  of  1 5 9  
6   
S A F E T Y  R E P O R TI N G  A N D  M E DI C A L  M A N A G E M E N T  
T h e i n v esti g at or is r es p o nsi bl e f or  e ns uri n g t h at  all st aff i n v ol v e d i n t h e st u d y is  f a mili ar  wit h 
t h e  c o nt e nt  of t his s e cti o n. 
S e v er e  ast h m a  e x a c er b ati o ns  will  b e  c o nsi d er e d st u d y  effi c a c y  e n d p oi nts  a n d  will  n ot  b e 
r e p ort e d  as  A Es  u nl ess  c o nsi d er e d  a n  S A E.  S A Es  will  b e r e p ort e d  as  p er st a n d ar d r e p orti n g 
g ui d a n c e.  Ass o ci at e d s y m pt o ms  of  ast h m a  ar e  c o nsi d er e d  as s y m pt o ms  of  dis e as e  u n d er st u d y 
a n d  will  n ot  b e r e c or d e d  as  A Es  u nl ess  c o nsi d er e d  a n  S A E. 
6. 1   
D efi niti o n  of  a d v e rs e  e v e nts  
A n  A E is t h e  d e v el o p m e nt  of  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a s u bj e ct  or  cli ni c al st u d y 
s u bj e ct  a d mi nist er e d  a m e di ci n al  pr o d u ct  a n d  w hi c h  d o es  n ot  n e c ess aril y  h a v e  a  c a us al 
r el ati o ns hi p  wit h t his tr e at m e nt.  A n  A E  c a n t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n 
( e g,  a n  a b n or m al l a b or at or y fi n di n g), s y m pt o m ( e g,  n a us e a,  c h est  p ai n),  or  dis e as e t e m p or all y 
ass o ci at e d  wit h t h e  us e  of  a  m e di ci n al  pr o d u ct,  w h et h er  or  n ot  c o nsi d er e d r el at e d t o t h e 
m e di ci n al  pr o d u ct.  
T h e t er m  A E is  us e d t o i n cl u d e  b ot h s eri o us  a n d  n o ns eri o us  A Es  a n d  c a n i n cl u d e  a  d et eri or ati o n 
of  a  pr e -e xisti n g  m e di c al  o c c urr e n c e.  A n  A E  m a y  o c c ur  at  a n y ti m e, i n cl u di n g t h e s cr e e ni n g 
p eri o d,  e v e n if  n o I P  h as  b e e n  a d mi nist er e d. 
6. 2   
D efi niti o ns  of s e ri o us  a d v e rs e  e v e nt  
A n  S A E is  a n  A E  o c c urri n g  d uri n g  a n y st u d y  p h as e (i e,  aft er t h e si g ni n g  of t h e i nf or m e d 
c o ns e nt/ ass e nt t hr o u g h t o t h e s af et y f oll o w- u p  visit), t h at f ulfills  1  or  m or e  of t h e f oll o wi n g 
crit eri a:  
•   R es ults i n  d e at h  
•   Is i m m e di at el y lif e- t hr e at e ni n g 
•   R e q uir es i n - p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n.  
•   R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y  or i n c a p a cit y   
•   Is  a  c o ng e nit al  a b n or m alit y  or  birt h  d ef e ct 
•   Is  a n i m p ort a nt  m e di c al  e v e nt t h at  m a y j e o p ar di z e t h e s u bj e ct  or  m a y r e q uir e  m e di c al 
i nt er v e nti o n t o  pr e v e nt  1  of t h e  o ut c o m es list e d  a b o v e 
 
F or f urt h er  g ui d a n c e  o n t h e  d efi niti o n  of  a n  S A E, s e e  A p p e n di x  D  t o t h e  Cli ni c al  St u d y 
Pr ot o c ol. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
5 9  of  1 5 9  
6. 3   
R e c o r di n g  of  a d v e rs e  e v e nts  
6. 3. 1   
P e ri o d f o r  c oll e cti o n  of  a d v e rs e  e v e nts 
A d v ers e  e v e nts  a n d  S A Es  will  b e  c oll e ct e d fr o m ti m e  of si g n at ur e  of i nf or m e d  c o ns e nt/ ass e nt, 
t hr o u g h t h e s af et y f oll o w- u p  p eri o d. 
6. 3. 2   
F oll o w- u p  of  u n r es ol v e d  a d v e rs e  e v e nts 
A n y  A Es t h at  ar e  u nr es ol v e d  at t h e s u bj e ct’s l ast  ass ess m e nt  visit i n t h e st u d y  ar e f oll o w e d  u p 
b y t h e i n v esti g at or f or  as l o n g  as  m e di c all y i n di c at e d,  b ut  wit h o ut f urt h er r e c or di n g i n t h e 
e C R F.  T h e  S p o ns or  or  a 
S af et y  a n d  P h ar m a c o vi gil a n c e  D e p art m e nt 
r e pr es e nt ati v e r et ai ns t h e ri g ht t o r e q u est  a d diti o n al i nf or m ati o n f or  a n y s u bj e ct  wit h  o n g oi n g 
A E(s)/ S A E(s)  at t h e  e n d  of t h e st u d y ( aft er t h e s u bj e ct’s fi n al st u d y  visit)  a n d  c a pt ur e t h at 
i nf or m ati o n i n t h e  e C R F, if j u d g e d  n e c ess ar y. 
6. 3. 3   
V a ri a bl es  
T h e f oll o wi n g  v ari a bl es  will  b e  c oll e ct e d f or  e a c h  A E:  
•   A E ( v er b ati m).  
•   T h e  d at e  w h e n t h e  A E st art e d  a n d st o p p e d 
•   M a xi m u m s e v erit y  
•   S eri o us n ess 
•   I n v esti g at or  c a us alit y r ati n g  a g ai nst t h e I P ( y es  or  n o) 
•   A cti o n t a k e n  wit h r e g ar d t o I P 
•   O ut c o m e 
 
I n  a d diti o n, t h e f oll o wi n g  v ari a bl es  will  b e  c oll e ct e d f or  S A Es: 
•   D at e  A E  m et  crit eri a f or s eri o us  A E  
•   D at e i n v esti g at or  b e c a m e  a w ar e  of s eri o us  A E  
•   R e as o n  w h y t h e  A E is  c o nsi d er e d s eri o us 
•   Tr e at m e nt  gi v e n f or t h e  S A E  
•   D a t e  of  h os pit ali z ati o n 
•   D at e  of  dis c h ar g e  
•   Pr o b a bl e  c a us e  of  d e at h. 
•   D at e  of  d e at h.  
•   W h et h er  a ut o ps y is  p erf or m e d. 
•   C a us alit y  ass ess m e nt i n r el ati o n t o st u d y  pr o c e d ur e(s). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 0  of  1 5 9  
•   C a us alit y  ass ess m e nt t o  ot h er  m e di c ati o n.  
•   D es cri pti o n  of  A E. 
 
It is i m p ort a nt t o  disti n g uis h  b et w e e n s eri o us  a n d s e v er e  A Es.  S e v erit y is  a  m e as ur e  of i nt e nsit y 
w h er e as s eri o us n ess is  d efi n e d  b y t h e  crit eri a i n  S e cti o n  6. 2 .  A n  A E  of s e v er e i nt e nsit y  n e e d  n ot 
n e c ess aril y  b e  c o nsi d er e d s eri o us.  F or  e x a m pl e,  n a us e a t h at  p ersists f or s e v er al  h o urs  m a y  b e 
c o nsi d er e d s e v er e  n a us e a,  b ut  n ot  a n  S A E  u nl ess it  m e ets t h e  crit eri a s h o w n i n  S e cti o n  6. 2 .  O n 
t h e  ot h er  h a n d,  a str o k e t h at r es ults i n  o nl y  a li mit e d  d e gr e e  of  dis a bilit y  m a y  b e  c o nsi d er e d  a 
mil d str o k e  b ut  w o ul d  b e  a n  S A E  w h e n it s atisfi es t h e  crit eri a s h o w n i n  S e cti o n  6. 2 . 
T h e s e v erit y  of t h e  e v e nt s h o ul d  b e  ass ess e d  as  mil d,  m o d er at e,  or s e v er e. 
6. 3. 4   
C a us alit y  c oll e cti o n 
T h e i n v esti g at or  a n d t h e  S p o ns or  w ill  ass ess  c a us al r el ati o ns hi p  b et w e e n I P  a n d  e a c h  A E,  a n d 
a ns w er  “ y es ”  or  “ n o ” t o t h e  q u esti o n  “ D o  y o u  c o nsi d er t h at t h er e is  a r e as o n a bl e  p ossi bilit y t h at 
t h e  e v e nt  m a y  h a v e  b e e n  c a us e d  b y t h e I P ? ” 
F or  S A Es,  c a us al r el ati o ns hi p  will  als o  b e  ass ess e d f or  ot h er  m e di c ati o n  a n d st u d y  pr o c e d ur es. 
N ot e t h at f or  S A Es t h at  c o ul d  b e  ass o ci at e d  wit h  a n y st u d y  pr o c e d ur e t h e  c a us al r el ati o ns hi p is 
i m pli e d  as  “ y es ”. 
A  g ui d e t o t h e i nt er pr et ati o n  of t h e  c a us alit y  q u esti o n is f o u n d i n  A p p e n di x  D  of t his  Cli ni c al 
St u d y  Pr ot o c ol. 
6. 3. 5   
D et e ri o r ati o ns  of  ast h m a  a n d s e v e r e  ast h m a  e x a c e r b ati o ns 
All s e v er e  ast h m a  e x a c er b ati o ns ( S e cti o n  5. 1. 1. 3 )  m ust  b e  c a pt ur e d  o n t h e  e C R F.  D et eri or ati o n  of 
ast h m a ( S e cti o n  5. 1. 7 )  will  b e  c a pt ur e d  o n t h e  b asis  of s y m pt o ms  as r e c or d e d  b y t h e s u bj e ct i n t h e 
e Di ar y.  S e v er e  ast h m a  e x a c er b ati o ns  will  b e  c o nsi d er e d  e x p e ct e d st u d y  e n d p oi nts  a n d  will  n ot  b e 
r e p ort e d  as  A Es  u nl ess t h e y  als o  m e et t h e  crit eri a f or  a n  S A E (S e cti o n  6. 2 ). 
6. 3. 6   
A d v e rs e  e v e nts  b as e d  o n si g ns  a n d s y m pt o ms 
All  A Es s p o nt a n e o usl y r e p ort e d  b y t h e s u bj e ct  or  c ar e  pr o vi d er  or r e p ort e d i n r es p o ns e t o t h e 
o p e n  q u esti o n fr o m t h e st u d y sit e st aff:  “ H a v e  y o u/  y o ur  c hil d  h a d  a n y  h e alt h  pr o bl e ms si n c e t h e 
pr e vi o us  visit/ y o u ( or  y o ur  c hil d)  w er e l ast  as k e d ? ”  or r e v e al e d  b y  o bs er v ati o n  will  b e  c oll e ct e d 
a n d r e c or d e d  i n t h e  e C R F.  W h e n  c oll e cti n g  A Es, t h e r e c or di n g  of  di a g n osis is  pr ef err e d ( w h e n 
p ossi bl e)  o v er r e c or di n g  a list  of si g ns  a n d s y m pt o ms.  H o w e v er, if  a  di a g n osis is  k n o w n  a n d 
t h er e  ar e  ot h er si g ns  or s y m pt o ms t h at  ar e  n ot  g e n er all y  p art  of t h e  di a g n osis, t h e  di a g n osis  a n d 
e a c h si g n  or s y m pt o m  will  b e r e c or d e d s e p ar at el y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 1  of  1 5 9  
Ast h m a s y m pt o ms  or si g ns, s u c h  as  w h e e z e,  c o u g h,  c h est ti g ht n ess,  d ys p n e a,  br e at hl ess n ess, 
a n d  p hl e g m,  will  b e r e c or d e d  as  A Es  o nl y  w h e n: 
 
•   T h e si g n  or s y m pt o m is s eri o us. 
•   T h e s u bj e ct  dis c o nti n u es I P  d u e t o t h e si g n  or s y m pt o m. 
•   T h e si g n  or s y m pt o m is  n e w t o t h e s u bj e ct  or  n ot  c o nsist e nt  wit h t h e s u bj e ct’s  pr e- e xisti n g 
ast h m a  hist or y ( d efi n e d  as  wit hi n  1  y e ar  of  Visit  1)  as j u d g e d  b y t h e i n v esti g at or. 
 
6. 3. 7   
A d v e rs e  e v e nts  b as e d  o n  e x a mi n ati o ns  a n d t ests 
T h e r es ults fr o m t h e  Cli ni c al  St u d y  Pr ot o c ol  m a n d at e d l a b or at or y t ests,  E C Gs,  vit al si g ns,  a n d 
ot h er s af et y  ass ess m e nts  will  b e s u m m ari z e d i n t h e  Cli ni c al  St u d y  R e p ort.  D et eri or ati o n fr o m 
b as eli n e i n t h es e  p ar a m et ers s h o ul d t h er ef or e  o nl y  b e r e p ort e d  as  a n  A E if it f ulfills  a n y  of t h e 
A E  crit eri a  or is t h e r e as o n f or  dis c o nti n u ati o n  of tr e at m e nt  wit h t h e I P  or is  c o nsi d er e d 
“ cli ni c all y si g nifi c a nt ”.  
T h e  crit eri a f or  d et er mi ni n g  w h et h er t h e  m a n d at e d l a b or at or y t ests,  E C Gs,  vit al si g ns,  a n d  ot h er 
s af et y  ass ess m e nts  ar e  cli ni c all y si g nifi c a nt  a n d s h o ul d  b e r e p ort e d  as  A Es  ar e  g e n er all y:   
•   T est r es ult is  ass o ci at e d  wit h  a c c o m p a n yi n g s y m pt o ms  or si g ns,  a n d/ or  
•   T est r es ult r e q uir es  a d diti o n al  di a g n osti c t esti n g  or  m e di c al/s ur gi c al i nt er v e nti o n,  a n d/ or  
•   T est r es u lt l e a ds t o  a  c h a n g e i n st u d y  d osi n g  or  dis c o nti n u ati o n fr o m t h e st u d y, si g nifi c a nt 
a d diti o n al  c o n c o mit a nt  dr u g tr e at m e nt,  or  ot h er t h er a p y,  a n d/ or  
•   T est r es ult is  c o nsi d er e d t o  b e  a n  A E  b y t h e i n v esti g at or  or  S p o ns or. 
 
If  d et eri or ati o n i n  a l a b or at or y  v al u e,  E C G,  vit al si g n,  or  ot h er s af et y  ass ess m e nt is  ass o ci at e d 
wit h  cli ni c al si g ns  a n d s y m pt o ms, t h e si g n  or s y m pt o m  will  b e r e p ort e d  as  a n  A E  a n d t h e 
ass o ci at e d l a b or at or y r es ult/ vit al si g n  will  b e  c o nsi d er e d  as  a d diti o n al i nf or m ati o n.  W h er e v er 
p ossi bl e, t h e r e p orti n g i n v esti g at or  us es t h e  cli ni c al, r at h er t h a n t h e l a b or at or y t er m ( e g,  a n e mi a 
v ers us l o w  h e m o gl o bi n  v al u e). I n t h e  a bs e n c e  of  cli ni c al si g ns  or s y m pt o ms,  cli ni c all y r el e v a nt 
d et eri or ati o ns i n  n o n m a n d at e d  p ar a m et ers s h o ul d  b e r e p ort e d  as  A E(s).  
A n y  n e w  or  a g gr a v at e d  cli ni c all y r el e v a nt  a b n or m al  m e di c al fi n di n g  at  a  p h ysi c al  e x a mi n ati o n 
as  c o m p ar e d  wit h fi n di n gs  at t h e  b as eli n e  ass ess m e nt  will  b e r e p ort e d  as  a n  A E.  
6. 3. 8   
H y’s  L a w  
C as es  w h er e  a s u bj e ct s h o ws  el e v ati o ns  i n li v er  bi o c h e mistr y  m a y r e q uir e f urt h er  e v al u ati o n  a n d 
o c c urr e n c es  of  A S T  a n d/ or  A L T  ≥ 3 × U L N  c o m bi n e d  a n d  wit h  T B L  ≥ 2 × U L N  m a y r e q uir e I P 
s us p e nsi o n/ dis c o nti n u ati o n  a n d st u d y  wit h dr a w al,  a n d  m a y  n e e d t o  b e r e p ort e d  as  S A Es.  Pl e as e 
r ef er t o S e cti o n  3. 9  a n d  A p p e n di x  E,  H y’s  L a w  f or f urt h er i nstr u cti o n  o n  c as es  of in cr e as es i n 
li v er  bi o c h e mistr y  a n d  e v al u ati o n  of  H y’s  L a w. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 3  of  1 5 9  
T h e  S p o ns or  will  als o r e p ort t o  all  a p pli c a bl e  h e alt h  a ut h oriti es  wit hi n  7  d a ys  of  a w ar e n ess f or 
a f at al  or lif e -t hr e at e ni n g r e a cti o n  or wit hi n  1 5  d a ys  f or  a r e a cti o n  n eit h er f at al  n or lif e-
t hr e at e ni n g  of  a n y s eri o us  u n e x p e ct e d  a d v ers e  dr u g r e a cti o n r el at e d t o t h e  dr u g  w hi c h  o c c urr e d 
d uri n g t h e st u d y. 
6. 5   
O v e r d os e  
F or t h e  p ur p os e  of t his st u d y,  a n  a c ci d e nt al  or  d eli b er at e i nt a k e  of  bli n d e d tr e at m e nt  of  m or e 
t h a n  1 2  p uffs  d uri n g  1  d a y is  d efi n e d  as  a n  o v er d os e  a n d  m ust  b e r e p ort e d  as s u c h  as  d es cri b e d 
b el o w. 
All  o v er d os es  m ust  b e r e c or d e d  o n t h e  O v er d os e/ M e di c ati o n  Err or  e C R F.  A n y  ass o ci at e d  A Es 
s h o ul d  als o  b e r e c or d e d  as t h e  A E  di a g n osis/s y m pt o m  o n t h e r el e v a nt  A E/ S A E  m o d ul es i n t h e 
e C R F.  
I n v esti g at ors  a n d t h e  m e di c al  m o nit ors  will r e c ei v e  a s af et y  n otifi c ati o n  al ert fr o m t h e s u bj e ct’s 
e Di ar y  o n  a  d ail y  b asis fr o m  a n y s u bj e ct  w h os e  d os a g e  e x c e e ds  1 2  p uffs i n  a si n gl e  d a y.  U p o n 
r e c ei pt  of  al erts, t h e i n v esti g at or  will  c o nt a ct t h e s u bj e ct t o r e mi n d t h e m t h at t h e y s h o ul d  n ot 
t a k e  m or e t h a n  1 2  p uffs  p er  d a y. If i n di c at e d, t h e i n v esti g at or  will  arr a n g e  a n  u ns c h e d ul e d  cli ni c 
visit  wit h t h e s u bj e ct.   
If  a n  o v er d os e  o c c urs  d uri n g t h e  c o urs e  of t h e st u d y  w hi c h  h as  a n  ass o ci at e d  S A E, t h e n t h e 
i n v esti g at or  or  ot h er sit e  p ers o n n el  will i nf or m t h e 
  S af ety  a n d  P h ar m a c o vi gil a n c e 
D e p art m e nt i m m e di at el y,  or  n o l at e r t h a n  2 4  h o u rs  of  w h e n  h e  or s h e  b e c o m es  a w ar e  of t h e 
o v er d os e. 
T h e 
  S af et y  a n d  P h ar m a c o vi gil a n c e  D e p art m e nt  w or ks  wit h t h e i n v esti g at or t o 
e ns ur e t h at  all r el e v a nt i nf or m ati o n is  pr o v i d e d t o t h e 
  S af et y  a n d 
P h ar m a c o vi gil a n c e  D e p art m e nt r e pr es e nt ati v e.  
F or  o v er d os es  ass o ci at e d  wit h  a n  S A E, t h e st a n d ar d  S A E r e p orti n g ti m eli n es  a p pl y, s e e 
S e cti o n  6. 4 .   
6. 6   
P r e g n a n c y  
All  pr e g n a n ci es  a n d  o ut c o m es  of t h e  pr e g n a n c y s h o ul d  b e r e p ort e d t o t h e 
  S af et y 
a n d  P h ar m a c o vi gil a n c e  D e p art m e nt r e pr es e nt ati v e  e x c e pt if t h e  pr e g n a n c y is  dis c o v er e d  b ef or e 
t h e st u d y s u bj e ct  h as r e c ei v e d  a n y I P. 
6. 6. 1   
M at e r n al  e x p os u r e 
If  a s u bj e ct  b e c o m es  pr e g n a nt  d uri n g t h e  c o urs e  of t h e st u d y, I P s h o ul d  b e  dis c o nti n u e d 
i m m e di at el y  a n d  “ Pr e g n a n c y ” r e c or d e d  as t h e r e as o n f or dis c o nti n u ati o n  o n t h e  e C R F. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 4  of  1 5 9  
Pr e g n a n c y its elf is  n ot r e g ar d e d  as  a n  A E  u nl ess t h er e is  a s us pi ci o n t h at t h e I P  u n d er st u d y  m a y 
h a v e i nt erf er e d  wit h t h e  eff e cti v e n ess  of  a  c o ntr a c e pti v e  m e di c ati o n.  C o n g e nit al 
a b n or m aliti es/ birt h  d ef e cts  a n d s p o nt a n e o us  mis c arri a g es s h o ul d  b e r e p ort e d  a n d  h a n dl e d  as 
S A Es.  El e cti v e  a b orti o ns  wit h o ut  c o m pli c ati o ns s h o ul d  n ot  b e  h a n dl e d  as  A Es.  T h e  o ut c o m e  of 
all  pr e g n a n ci es (s p o nt a n e o us  mis c arri a g e,  el e cti v e t er mi n ati o n,  e ct o pi c  pr e g n a n c y,  n or m al  birt h, 
or  c o n g e nit al  a b n or m alit y) s h o ul d  b e f oll o w e d  u p  a n d  d o c u m e nt e d  e v e n if t h e s u bj e ct  w as 
dis c o nti n u e d fr o m t h e st u d y. 
If  a n y  pr e g n a n c y  o c c urs i n t h e  c o urs e  of t h e st u d y, t h e n t h e i n v esti g at or  or  ot h er sit e  p ers o n n el 
will i nf or m t h e 
  S af et y  a n d  P h ar m a c o vi gil a n c e  D e p art m e nt  wit hi n  1  d a y i e, 
i m m e di at el y,  b ut n o l at e r t h a n  2 4  h o u rs  of  w h e n  h e  or s h e  b e c o m es  a w ar e  of it.  A n y 
c o n c e pti o n  o c c urri n g fr o m t h e  d at e  of  d osi n g t hr o u g h t h e  E O S/ P D V  s h o ul d  b e r e p ort e d. 
T h e 
  S af et y  a n d  P h ar m a c o vi gil a n c e D e p art m e nt  will  w or k  wit h t h e i n v esti g at or t o 
e ns ur e t h at  all r el e v a nt i nf or m ati o n is  pr o vi d e d. 
T h e s a m e ti m eli n es  a p pl y  w h e n  o ut c o m e i nf or m ati o n is  a v ail a bl e. 
6. 6. 2   
P at e r n al  e x p os u r e  
Pr e g n a n c y  of  a s u bj e ct’s  p art n er is  n ot  c o nsi d er e d t o  b e  a n  A E.  H o w e v er,  a n y  c o n c e pti o n 
o c c urri n g fr o m t h e  d at e  of  d osi n g t hr o u g h t h e  E O S/ P D V  s h o ul d  b e r e p ort e d t o t h e   
 
  S af et y  a n d  P h ar m a c o vi gil a n c e  D e p art m e nt r e pr es e nt ati v e  a n d f oll o w e d  u p f or its 
o ut c o m e. 
6. 7   
M e di c ati o n  e r r o r  
F or t h e  p ur p os es  of t his  cli ni c al st u d y,  a  m e di c ati o n  err or is  a n  u ni nt e n d e d f ail ur e  or  mist a k e i n 
t h e tr e at m e nt  pr o c ess f or t h e  S p o ns or’s I P t h at  eit h er  c a us es  h ar m t o t h e s u bj e ct  or  h as t h e 
p ot e nti al t o  c a us e  h ar m t o t h e s u bj e ct.  
A  m e di c ati o n  err or is  n ot l a c k  of  effi c a c y  of t h e  dr u g,  b ut r at h er  a  h u m a n  or  pr o c ess r el at e d 
f ail ur e  w hil e t h e  dr u g is i n  c o ntr ol  of t h e st u d y sit e st aff  or s u bj e ct. 
M e di c ati o n  err or i n cl u d es sit u ati o ns  w h er e  a n  err or:  
 
•   O c c urr e d  
•   W as i d e ntifi e d  a n d i nt er c e pt e d  b ef or e t h e s u bj e ct r e c ei v e d t h e  dr u g  
•   Di d  n ot  o c c ur,  b ut  cir c u mst a n c es  w er e r e c o g ni z e d t h at  c o ul d  h a v e l e d t o  a n  err or 
 
E x a m pl es  of  e v e nts t o  b e r e p ort e d i n  cli ni c al st u di es  as  m e di c ati o n  err ors: 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 5  of  1 5 9  
•   Dr u g  n a m e  c o nf usi o n 
•   Dis p e nsi n g  err or  e g,  m e di c ati o n  pr e p ar e d i n c orr e ctl y,  e v e n if it  w as  n ot  a ct u all y  gi v e n t o 
t h e s u bj e ct 
•   Dr u g  n ot  a d mi nist er e d  as i n di c at e d,  e g,  wr o n g r o ut e  or  wr o n g sit e  of  a d mi nistr ati o n 
•   Dr u g  n ot t a k e n  as i n di c at e d  
•   Dr u g  n ot st or e d  as i nstr u ct e d  e g,  k e pt i n t h e fri d g e  w h e n it s h o ul d  b e  at r o o m t e m p er at ur e  
•   Wr o n g s u bj e ct r e c ei v e d t h e  m e di c ati o n ( e x cl u di n g I W R S  err ors)  
•   Wr o n g  dr u g  a d mi nist er e d t o s u bj e ct ( e x cl u di n g I W R S  err ors) 
 
E x a m pl es  of  e v e nts t h at  d o  n ot  r e q uir e r e p orti n g  as  m e di c ati o n  err ors i n  cli ni c al st u di es: 
 
•   Err ors r e l at e d t o  or r es ulti n g fr o m I W R S-i n cl u di n g t h os e  w hi c h l e a d t o  1  of t h e  a b o v e list e d 
e v e nts t h at  w o ul d  ot h er wis e  h a v e  b e e n  a  m e di c ati o n  err or  
•   A c ci d e nt al  o v er d os e ( will  b e  c a pt ur e d  as  a n  o v er d os e)  
•   S u bj e ct f ail e d t o r et ur n  u n us e d  m e di c ati o n  or  e m pt y  p a c k a gi n g 
•   Err ors r el at e d t o  b a c k gr o u n d  m e di c ati o n,  or st a n d ar d  of  c ar e  m e di c ati o n i n  o p e n- l a b el 
st u di es,  e v e n if it is  a  S p o ns or’s  pr o d u ct 
 
M e di c ati o n  err ors  ar e  n ot r e g ar d e d  as  A Es  b ut  A Es  m a y  o c c ur  as  a  c o ns e q u e n c e  of t h e 
m e di c ati o n  err or.    
All  m e di c ati o n  err or s  m ust  b e r e c or d e d i n t h e  O v er d os e/ M e di c ati o n  Err or  e C R F.  A n y 
ass o ci at e d  A E s h o ul d  als o  b e r e c or d e d  as t h e  A E  di a g n osis/s y m pt o m  o n t h e r el e v a nt  A E/ S A E 
m o d ul es i n t h e  e C R F. If  a  m e di c ati o n  err or  o c c urs  d uri n g t h e  c o urs e  of t h e st u d y  w hi c h  h as  a n 
ass o ci at e d  S A E, t h e n t h e i n v esti g at or  or  ot h er sit e  p ers o n n el  will i nf or m t h e 
 
S af et y  a n d  P h ar m a c o vi gil a n c e  D e p art m e nt i m m e di at el y,  or  n o l at e r t h a n  2 4  h o u rs   of  w h e n  h e 
or s h e  b e c o m es  a w ar e  of t h e  m e di c ati o n  err or.  
T h e 
  S af et y  a n d  P h ar m a c o vigil a n c e  D e p art m e nt  will  w or k  wit h t h e  i n v esti g at or t o 
e ns ur e t h at  all r el e v a nt i nf or m ati o n is  pr o vi d e d t o t h e 
  S af et y  a n d 
P h ar m a c o vi gil a n c e  D e p art m e nt r e pr es e nt ati v e.  F or  m e di c ati o n  err ors  ass o ci at e d  wit h  a n  S A E, 
t h e st a n d ar d  S A E r e p orti n g ti meli n es  a p pl y (s e e  S e cti o n  6. 4 ). 
6. 8   
M a n a g e m e nt  of i n v esti g ati o n al  p r o d u ct -r el at e d t o xi citi es  
I n t h e  a bs e n c e  of  a s p e cifi c  a nti d ot e,  m a n a g e m e nt  of t o xi citi es  c a n  b e  d e alt  wit h  o n t h e  b asis  of 
t h e s y m pt o ms. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 6  of  1 5 9  
7   
I N V E S TI G A TI O N A L  P R O D U C T  A N D  O T H E R  T R E A T M E N T S  
7. 1   
I d e ntit y  of i n v esti g ati o n al  p r o d u ct(s)  
B D A  M DI is f or m ul at e d ( T a bl e   3)  as  b ot h  mi cr o ni z e d  b u d es o ni d e  a n d  mi cr o ni z e d  al b ut er ol 
c o -s us p e n d e d  wit h s pr a y- dri e d  p or o us  p arti cl es i n  a  h y dr ofl u or o al k a n e ( H F A)  pr o p ell a nt.  T h e 
c o -s us p e nsi o n f or m ul ati o n  e ns ur es t h at s u bj e cts r e c ei v e  a  c o nsist e nt  d eli v er y  of t h e  dr u g fr o m 
e a c h  a ct u ati o n  of t h e  M DI.   
T a bl e  3   
I n v esti g ati o n al  P r o d u ct  St r e n gt h  a n d  D os a g e  F o r m 
I n v esti g ati o n al 
p r o d u ct  n a m e  a n d 
d os e  
P r o d u ct st r e n gt h  
D os a g e  F o r m/  Fill 
C o u nt  
A d mi nist r ati o n   
M a n uf a ct u r e r  
B D A  M DI 
8 0/ 1 8 0  μ g   
B D A  M DI   
4 0  μ g  b u d es o ni d e  a n d 
9 0  μ g  al b ut er ol  p er 
p uff  
M DI/ 1 2 0  a ct u ati o ns  
T a k e n  as  2 
a ct u ati o ns  
 
B D A  M DI 
1 6 0/ 1 8 0  μ g  
B D A  M DI   
8 0  μ g  b u d es o ni d e  a n d 
9 0  μ g  al b ut er ol  p er 
p uff.  
M DI/ 1 2 0  a ct u ati o ns  
T a k e n  as  2 
a ct u ati o ns  
 
A S  M DI  1 8 0  μ g  
A S  M DI  
 9 0  μ g  al b ut er ol  p er 
p uff a 
M DI/ 1 2 0  a ct u ati o ns  
T a k e n  as  2 
a ct u ati o ns  
 
A d diti o n al st u d y  m e di c ati o n  
V e nt oli n  H F A b 
1 0 8  μ g  al b ut er ol 
s ulf at e ( 9 0  μ g 
al b ut er ol  b as e)  as  a n 
a er os ol f or m ul ati o n  
Al b ut er ol (s al b ut a m ol) 
s ulf at e i n h al ati o n 
a er os ol.  2 0 0  p uffs  p er 
c a nist er  
Us e  as  n e e d e d 
d uri n g s cr e e ni n g 
p eri o d  
 
 
Al b ut er ol s ulf at e (s al b ut a m ol s ulf at e) is  a  n o n -i n v esti g ati o n al  m e di ci n al  pr o d u ct si n c e it is t a k e n  as  dir e ct e d f or 
r e v ersi bilit y t esti n g ( Visit  1  a n d r e p e at  Visit  1 a, if  n e c ess ar y)  a n d  as  n e e d e d f or s y m pt o ms  d uri n g t h e  S cr e e ni n g  P eri o d.  
a E a c h  p uff  c o nt ai ns  1 0 8  μ g  al b ut er ol s ulf at e  c orr es p o n di n g t o  9 0  µ g  al b ut er ol  b as e  p er  a ct u ati o n  
b T a bl e r e pr es e nts  c o m m er ci all y  a v ail a bl e  V e nt oli n f or m ul ati o n f or t h e  U nit e d  St at es,  e a c h  c o u ntr y  will  utili z e 
c o m m er ci all y  a v ail a bl e  V e nt o li n i n t h at  c o u ntr y,  pr o d u ct str e n gt h  m a y  diff er 
7. 2   
D os e  a n d t r e at m e nt  r e gi m e ns  
I n v esti g ati o n al  pr o d u ct  will  b e  us e d i n r es p o ns e t o  ast h m a s y m pt o ms  as s u bj e cts  w o ul d 
n or m all y t a k e t h eir r eli e v er  m e di c ati o n. If s u bj e cts t a k e I P i n  a d v a n c e  of  e x er cis e f or t h e 
pr e v e nti o n  of  e x er cis e i n d u c e d s y m pt o ms, I P  us a g e i n r el ati o n t o  e x er cis e  will  b e  c a pt ur e d 
wit hi n t h e  e Di ar y.  N o  ot h er r eli e v er  pr o d u cts  will  b e  us e d  d uri n g t h e tr e at m e nt  p eri o d. 
At r a n d o mi z ati o n ( Visit  2),  a d ol es c e nts  a n d  a d ults ( a g e d  ≥ 1 2  y e ars)  w h o  m e et t h e  eli gi bilit y 
crit eri a  will  b e r a n d o ml y  assi g n e d t o  1  of t h e f oll o wi n g  3 tr e at m e nt  gr o u ps i n  a  1: 1: 1 r ati o  as 
r eli e v er t h er a p y  o n t o p  of  us u al  c ar e.  C hil dr e n  a g e d  4 t o  1 1  y e ars  will  b e r a n d o mi z e d i n  a  1: 1 
r ati o  o nl y t o t h e l o w er  B D A  M DI  d os a g e  or  A S  M DI: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 7  of  1 5 9  
•   B D A  M DI  8 0/ 1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  B D A  M DI  4 0/ 9 0  μ g  p er  p uff)  pr n  
•   B D A  M DI  1 6 0/ 1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  B D A  M DI  8 0/ 9 0  μ g  p er  p uff)  pr n  
•   A S  M DI  1 8 0  μ g ( gi v e n  as  2  a ct u ati o ns  of  A S  M DI  9 0  μ g  p er  p uff)  pr n  
 
R a n d o mi z ati o n f or  a d ol es c e nts  a n d  a d u lts  will  b e str atifi e d  b y  a g e  gr o u p ( ≥ 1 2 t o  1 7,  ≥ 1 8); 
r e gi o n ( N ort h  A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d 
[ R e gi o n 2]);  a n d  n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o 
s cr e e ni n g ( Visit   1 pl us  a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d. 
R a n d o mi z ati o n f or  c hil dr e n  will  n ot  b e str atifi e d.   
T h e  m a xi m u m  d ail y  d os a g e  of I P s h o ul d  n ot  e x c e e d  1 2  p uffs  p er  d a y  a n d s u bj e cts  will  b e 
a d vis e d t o  c o nt a ct t h e i n v esti g at or if t h eir s y m pt o m s  n e c essit at e  m or e t h a n  8  p uffs  p er  d a y (s e e 
S e cti o n  6. 5  f or  o v er d os e). 
H a n dli n g i nstr u cti o ns f or t h e  M DI  d e vi c e  will  b e  a v ail a bl e f or t h e sit e t o tr ai n s u bj e cts  a n d  als o 
f or t h e s u bj e cts t o r et ai n t hr o u g h o ut t h e st u d y. 
7. 3   
L a b elli n g  
L a b els  will  b e  pr e p ar e d i n  a c c or d a n c e  wit h  G o o d  M a n uf a ct uri n g  Pr a cti c e ( G M P)  a n d l o c al 
r e g ul at or y  g ui d eli n es.  T h e l a b els  will f ulfill  G M P  A n n e x  1 3 r e q uir e m e nts f or l a b elli n g.  L a b el 
t e xt  will b e tr a nsl at e d i nt o l o c al l a n g u a g e. 
T h e s u bj e ct  will r e c ei v e  a  kit  c o nt ai ni n g  2  M DI  d e vi c es, i n di vi d u all y  wr a p p e d i n f oil  b a gs  h el d 
wit hi n  a  c art o n.  T h e  M DI  d e vi c es  pr o vi d e d i n t his st u d y  a n d t h e  p a c k a gi n g  a n d l a b elli n g  of t h e 
kits  ar e  vis u all y  i d e nti c al t o  m ai nt ai n t h e  bli n d.  A  kit  will  b e  dis p e ns e d f or  e v er y  4  w e e ks  of 
tr e at m e nt.  E a c h  kit  will  c o nt ai n t h e f oll o wi n g  bli n d e d l a b els: 
•   Si n gl e  p a n el  c a nist er l a b el ( E n glis h  o nl y) 
•   Si n gl e  p a n el  a ct u at or l a b el ( U nit e d  St at es  o nl y)  or  m ultil a n g u a g e  a ct u at or  b o o kl et l a b el 
•   M DI  d e vi c e s hi el d l a b el (si n gl e  p a n el,  E n glis h  o nl y) 
•   F oil  b a g l a b el (si n gl e  p a n el,  E n glis h  o nl y) 
•   Si n gl e  p a n el  c art o n l a b el ( U nit e d  St at es  o nl y)  or  m ultil a n g u a g e  c art o n  b o o kl et l a b el 
 
T h e l a b els  will i n cl u d e t h e f oll o wi n g i nf or m ati o n:  
•   N a m e  of  S p o ns or ( B o n d  A villi o n  2  D e v el o p m e nt  L P  –  Cli ni c al  D e v el o p m e nt  C o m p a n y: 
A villi o n  L L P)  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 8  of  1 5 9  
•   I n v esti g ati o n al  pr o d u ct  d os a g e f or m, r o ut e  of  a d mi nistr ati o n,  a n d  q u a ntit y  of  d os a g e  u nits 
( bli n d e d  a cr oss  all  ar ms) 
•   St or a g e  c o n diti o ns 
•   St u d y  Tri al  R ef er e n c e  
•   M e di c ati o n I D  n u m b er 
•   Dir e cti o ns f or  us e 
•   T h e  n a m e  of t h e i n v esti g at or,  w h er e  a p pli c a bl e (t his  will  b e  a d d e d  o n t h e l a b el  m a n u all y 
w h e n t h e I P is  dis p e ns e d) 
•   T h e  p eri o d  of  us e  e g,  e x pir y  d at e 
 
T h e l a b el  will i n cl u d e t h e f oll o wi n g st a n d ar d st at e m e nts:  
•   “ F or  cli ni c al st u d y  us e  o nl y ” ( or t h e r e q uir e d l o c al st at e m e nt) 
•   “ K e e p  o ut  of r e a c h  of  c hil dr e n ” 
 
7. 4   
St o r a g e  
All I Ps s h o ul d  b e  k e pt i n  a s e c ur e  pl a c e  u n d er  a p pr o pri at e st or a g e  c o n diti o ns.  T h e I P l a b el  o n 
t h e  c art o n s p e cifi es t h e  a p pr o pri at e st or a g e. 
T e m p er at ur e r e a di n gs  of t h e st or a g e  ar e a ( mi ni m u m/ m a xi m u m) s h o ul d  b e r e c or d e d  o n  e v er y 
w or ki n g  d a y  at  a  mi ni m u m. 
7. 5   
C o m pli a n c e  
T h e  a d mi nistr ati o n  of  all I Ps  will  b e  c a pt ur e d i n t h e s u bj e ct’s  e Di ar y  d os e i n di c at or r e a di n gs 
a n d  will  b e  c a pt ur e d  wit hi n t h e  a p pr o pri at e s e cti o ns  of t h e  e C R F.  D at a fr o m t h e  d os e  c o u nt er 
will  b e  c o m p ar e d  wit h t h e s u bj e ct’s  e Di ar y  e ntri es  a n d  a n y  dis cr e p a n ci es  will  b e  us e d t o  h el p i n 
tr ai ni n g t h e s u bj e ct t o  a c c ur at el y  c a pt ur e  all I P  a d mi nistr ati o n i n t h e  e Di ar y. 
T h e s u bj e ct  will  b e  as k e d t o r e c or d i n t h eir  e Di ar y  w h et h er  or  n ot t h e y  h a v e t a k e n t h eir 
m ai nt e n a n c e t h er a p y t o d a y  vi a  a  y es/ n o  q u esti o n,  w hi c h  will  b e  c a pt ur e d i n t h e  a p pr o pri at e 
s e cti o ns  of t h e  e C R F.  
7. 6   
A c c o u nt a bilit y  
T h e I Ps  pr o vi d e d f or t his st u d y  will  b e  us e d  o nl y  as  dir e ct e d i n t h e  Cli ni c al  St u d y  Pr ot o c ol. 
All I Ps  will  b e r et ur n e d t o t h e  a p pr o v e d st u d y r et ur ns  v e n d or f or  d estr u cti o n  aft er  a c c o u nt a bilit y 
a n d r e c o n cili ati o n is  c o m pl et e.   
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
6 9  of  1 5 9  
7. 7   
M et e r e d -d os e i n h al e r:  h a n dli n g  a n d  cl e a ni n g  
D et ail e d  h a n dli n g i nstr u cti o ns  will  b e  pr o vi d e d t o t h e sit e i n t h e f or m  of  a  “ Sit e  M a n u al ” 
d o c u m e nt,  w hi c h  will  c o v er  all  as p e cts  of t h e tri al  wit h r e g ar ds t o I P.  A n  “I nstr u cti o ns  F or  Us e ” 
d o c u m e nt  c a n  b e f o u n d i n  A p p e n di x  L,  M et er e d- d os e I n h a l er  H a n dli n g  a n d  Cl e a ni n g, f o c usi n g 
o n t h e I P  M DI  d e vi c e.  
T h e i m p ort a n c e  of t h e  d e vi c e  cl e a ni n g  a n d  pri mi n g r e q uir e m e nts s h o ul d  b e  e m p h asi z e d t o 
s u bj e cts.  D e vi c e  pri mi n g s h o ul d  n ot  b e  c o n d u ct e d i n t h e s a m e r o o m  as s pir o m etr y  ass ess m e nts 
ar e  b ei n g  c o n d u ct e d. 
7. 8   
C o n c o mit a nt  a n d  ot h e r t r e at m e nts   
7. 8. 1   
M ai nt e n a n c e t h e r a pi es 
I n h al e d  c orti c ost er oi ds (I C S)/ L A B A,  L T R A, t h e o p h ylli n e,  a n d  L A M As  ar e  p er mitt e d t o  b e  us e d 
as  m ai nt e n a n c e t h er a p y  o n st u d y  as s p e cifi e d i n t h e i n cl usi o n  crit eri a.  N o s u bj e ct  c a n  b e  o n 
> 3  m ai nt e n a n c e t h er a pi es.  
D uri n g t h e st u d y, s u bj e cts s h o ul d  m ai nt ai n st a bl e  d osi n g  of t h eir  m ai nt e n a n c e t h er a pi es  as 
pr es e nt e d  at s cr e e ni n g ( Visit  1/ 1 a,  as  a p pli c a bl e).  D os e  c h a n g es t o  m ai nt e n a n c e t h er a p y  ar e 
dis c o ur a g e d  u nl ess  cli ni c all y i n di c at e d i n  a c c or d a n c e  wit h  GI N A  g ui d eli n es. I n v esti g at ors 
s h o ul d  n otif y t h e st u d y  m e di c al  m o nit ors  of  a n y  c h a n g e t o  m ai nt e n a n c e t h er a p y f or st u d y 
s u bj e cts;  c o nsi d er ati o ns s h o ul d  b e  m a d e t o s u bj e ct  dr u g  c o m pli a n c e  a n d  ot h er f a ct ors i n 
a d v a n c e  of  m a ki n g  c h a n g es t o  m ai nt e n a n c e t h er a p y.   
S u bj e cts r e c ei vi n g  m ai nt e n a n c e  all er g y i m m u n ot h er a p y ( AI T)  ar e  all o w e d t o  c o nti n u e t h eir 
AI T; t h e i niti ati o n  of  AI T  d uri n g t h e st u d y is  n ot  all o w e d.   
7. 8. 2   
M e di c ati o ns t h at  m a y  aff e ct  r e v e rsi bilit y  a n d  F E V
1 t esti n g 
T h e  m e di c ati o ns  pr es e nt e d i n  T a bl e   4 m a y  aff e ct r e v ersi bilit y  ass ess m e nts. I n v esti g at ors s h o ul d 
n otif y t h e st u d y  m e di c al  m o nit ors  of  a n y  c h a n g e t o  m ai nt e n a n c e t h er a p y f or st u d y s u bj e cts. If 
s u bj e cts  h a v e t a k e n  a n y  of t h e  m e di c ati o ns  b el o w  wit hi n t h e ti m efr a m e i n di c at e d  of t h e  pl a n n e d 
r e v ersi bilit y t est, t h e t est s h o ul d  n ot  b e  c arri e d  o ut  a n d t h e s u bj e ct s h o ul d r et ur n t o  p erf or m t h e 
r e v ersi bilit y t esti n g.    
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 0  of  1 5 9  
T a bl e  4  
M e di c ati o ns  R est ri ct e d  Ti m e  Li mit  P ri o r t o  a n y  L u n g  F u n cti o n  T esti n g  
( r e v e rsi bilit y  a n d  F E V1) 
M e di c ati o n  
R est ri ct e d ti m e li mit  b ef o r e l u n g f u n cti o n 
t esti n g 
S A B A/ S p o ns o r -p r o vi d e d  V e nt oli n/ St u d y 
I P 
6  h o urs  
I n h al e d  L A B A 
 
F or m ot er ol  
1 2  h o urs  
S al m et er ol  
1 2  h o urs  
Ol o d at er ol  
2 4  h o urs  
I n d a c at er ol 
2 4  h o urs  
Vil a nt er ol  
2 4  h o urs  
L T R A  
2 4  h o urs  
T h e o p h ylli n e t wi c e  d ail y  
1 2  h o urs  
T h e o p h ylli n e  o n c e  d ail y  
2 4  h o urs  
L A M A  
2 4  h o urs  
A b br e vi ati o ns:  I P =i n v esti g ati o n al  pr o d u ct;  L A B A =l o n g -a cti n g  β 2 -a g o nist;  L A M A = l o n g -a cti n g  m us c ari ni c 
a nt a g o nist;  L T R A =l e u k otri e n e r e c e pt or  a nt a g o nist.  
 
7. 8. 3   
P r o hi bit e d  m e di c ati o ns 
Pr o hi bit e d  c o n c o mit a nt  m e di c ati o ns  d uri n g t h e st u d y i n cl u d e:  
•   Or al,  p ar e nt er al,  or r e ct al  c orti c ost er oi ds ( e x c e pt if r e q uir e d t o tr e at s e v er e  ast h m a 
e x a c er b ati o n)  
•   A n y  ot h er  ast h m a  m e di c ati o n  e x c e pt st a bl e  d os es  of  m ai nt e n a n c e t h er a p y t a k e n  at  e ntr y i nt o 
t h e st u d y  a n d  pr o vi d e d  b y t h e  S p o ns or 
•   I n h al e d  dis o di u m  cr o m o gl y c at e  or i n h al e d  n e d o cr o mil s o di u m 
•   5-li p o x y g e n as e i n hi bit ors (i e,  zil e ut o n) 
•   I n h al e d s h ort-a cti n g  a nti c h oli n er gi cs ( or s h ort- a cti n g  m us c ari ni c  a nt a g o nists [ S A M A], i e, 
i pr atr o pi u m) 
•   I n h al e d l o n g- a cti n g  a nti c h oli n er gi cs ( L A M A),  e x c e pt t h os e t h at  w er e st art e d  b ef or e 
s cr e e ni n g  a n d  c o nti n u e d  as  p art  of  m ai nt e n a n c e tr e at m e nt (s e e i n cl usi o n  crit eri o n  4). 
•   P h os p h o di es t er as e i n hi bit ors (i e, r ofl u mil ast) 
•   O m ali z u m a b,  b e nr ali z u m a b,  m e p oli z u m a b, r esli z u m a b,  d u pil u m a b,  or  a n y  ot h er 
m o n o cl o n al  or  p ol y cl o n al  a nti b o d y t h er a p y f or  a n y r e as o n (i ntr a- o c ul ar  a d mi nistr ati o n  of 
m o n o cl o n al  or  p ol y cl o n al  a nti b o d y t h er a p y is  all o w e d) 
•   B et a 2 - a dr e n er gi c  bl o c k ers i n cl u di n g  e y e-dr o ps (s p e cifi c  c ar di o -s el e cti v e  b et a- bl o c k ers i n 
l o w  d ail y  d os es,  e g,  m et o pr ol ol i n  d os es  u p t o  1 0 0  m g/ d,  ar e  all o w e d) 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 1  of  1 5 9  
•   S yst e mi c tr e at m e nt  wit h  p ot e nt  c yt o c hr o m e  P 3 A 4 i n hi bit ors ( e g,  k et o c o n a z ol e, 
itr a c o n a z ol e,  a n d rit o n a vir) 
 
7. 8. 4   
Ot h e r  c o n c o mit a nt t r e at m e nt 
M e di c ati o n  ot h er t h a n t h at  d es cri b e d i n  S e cti o n  7. 8. 1 ,  w hi c h is  c o nsi d er e d  n e c ess ar y f or t h e 
s u bj e ct’s s af et y  a n d  w ell b ei n g, i n cl u di n g s h ort-t er m  c o n c o mit a nt tr e at m e nt  wit h  pr o hi bit e d 
ast h m a tr e at m e nts t o tr e at s e v er e  e x a c er b ati o ns,  m a y  b e  gi v e n  at t h e  dis cr eti o n  of t h e 
i n v esti g at or  a n d r e c or d e d i n t h e  a p pr o pri at e s e cti o ns  of t h e  e C R F.   
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 2  of  1 5 9  
8   
S T A TI S TI C A L  A N A L Y S E S   
8. 1   
St a tisti c al  c o nsi d e r ati o ns 
All  p ers o n n el i n v ol v e d  wit h t h e  a n al ysis  of t h e st u d y  will r e m ai n  bli n d e d  u ntil  d at a b as e l o c k 
a n d i d e ntifi c ati o n  of  Cli ni c al  St u d y  Pr ot o c ol  vi ol at ors.   
A n al ys es  will  b e  p erf or m e d  b y t h e  S p o ns or  or its r e pr es e nt ati v es. 
T h e I D M C  will   h a v e  a c c ess t o  u n bli n d e d  d at a i n  cl os e d s essi o ns  wit h  a n  u n bli n d e d st atisti ci a n 
u p o n t h eir r e q u est (s e e I D M C  c h art er).   
A  c o m pr e h e nsi v e st atisti c al  a n al ysis  pl a n ( S A P)  will  b e  pr e p ar e d  b ef or e t h e first  u n bli n d e d 
a n al ysis f or I D M C  a n d  a n y s u bs e q u e nt  a m e n d m e nts  will  b e  d o c u m e nt e d,  wit h fi n al 
a m e n d m e nts  c o m pl et e d  b ef or e t h e  u n bli n di n g  of t h e  d at a.  
8. 1. 1   
Esti m a n ds 
T hr e e  esti m a n ds  ar e  of i nt er est i n t his st u d y:  
T h e  pri m ar y  esti m a n d  of i nt er est is t h e  effi c a c y  esti m a n d,  d efi n e d  as t h e  eff e ct  of t h e 
r a n d o mi z e d tr e at me nt i n  all s u bj e cts  ass u mi n g  c o nti n u ati o n  of r a n d o mi z e d tr e at m e nt f or t h e 
d ur ati o n  of t h e st u d y, r e g ar dl ess  of  a ct u al  us a g e  a n d  ass u mi n g t h at  m ai nt e n a n c e t h er a p y is  n ot 
c h a n g e d.  T his  esti m a n d  c o ul d  b e  c o nsi d er e d  as  a  w hil e- o n-tr e at m e nt str at e g y  or  a  h y p ot h eti c al 
str at e g y  as  d efi n e d i n t h e  dr aft I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni z ati o n (I C H)  E 9  a d d e n d u m. 
T h e s e c o n d  esti m a n d  of i nt er est is t h e  attri b ut a bl e  esti m a n d,  d efi n e d  as t h e  eff e ct  of tr e at m e nt i n 
s u bj e cts  attri b ut a bl e t o t h e r a n d o mi z e d tr e at m e nt  ass u m i n g t h at  m ai nt e n a n c e t h er a p y is  n ot 
c h a n g e d.  F or t his  esti m a n d,  dis c o nti n u ati o n  of r a n d o mi z e d tr e at m e nt f or t ol er a bilit y  or  c h a n g e 
i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol is  c o nsi d er e d  a  n e g ati v e  o ut c o m e.  T his 
esti m a n d is  a  mi xt ur e  of  c o m p osit e  a n d  h y p ot h eti c al str at e gi es  as  d efi n e d i n t h e  dr aft I C H  E 9 
a d d e n d u m. 
T h e t hir d  esti m a n d  of i nt er est is t h e  eff e cti v e n ess  esti m a n d  w hi c h is  a  c o m bi n ati o n  of t h e 
h y p ot h eti c al  a n d tr e at m e nt  p oli c y str at e gi es  as  d efi n e d i n t h e  dr aft I C H  E 9  a d d e n d u m.  T h e 
str at e gy is  h y p ot h eti c al i n t h at t h e tr e at m e nt  eff e ct  will  b e  esti m at e d  wit h o ut i n cl u di n g  d at a  p ost 
t h e i nt er c urr e nt  e v e nt  of  dis c o nti n u ati o n fr o m r a n d o mi z e d tr e at m e nt.  H o w e v er, t h e str at e g y is 
c o nsist e nt  wit h t h e tr e at m e nt  p oli c y str at e g y i n t h at t h e tr e at m e nt  eff e ct is  esti m at e d irr es p e cti v e 
of t h e  o c c urr e n c e  of t h e i nt er c urr e nt  e v e nt  of  a  c h a n g e i n t h e  m ai nt e n a n c e t h er a p y.  
T h e f o urt h  esti m a n d  of i nt er est is t h e  d e f a ct o  esti m a n d,  d efi n e d  as t h e  eff e ct  of  a tr e at m e nt 
p oli c y r e g ar dl ess  of  c h a n g es i n  m ai nt e n a n c e t h er a p y  or  pr e m at ur e  dis c o nti n u ati o n  of 
r a n d o mi z e d tr e at m e nt.  T his  esti m a n d is  c o nsi d er e d  a tr e at m e nt  p oli c y str at e g y  as  d efi n e d i n t h e 
dr aft I C H  E 9  a d d e n d u m.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 3  of  1 5 9  
8. 1. 2   
P ri m a r y  o ut c o m e  a n al ysis  
Pri m ar y  o ut c o m e  d at a b as e l o c k ( p D B L)  will  c o m m e n c e  o n c e  all r a n d o mi z e d  a d ults ( ≥ 1 8  y e ars) 
h a v e  att e n d e d t h eir  E O S  visit  at t h e  P C D .  T h e  a n al ys es  of  pri m ar y, s e c o n d ar y,  e x pl or at or y  a n d 
s af et y  o bj e cti v es  will i n cl u d e  all  d at a  u p t o t h e  p D B L,  w hi c h  m a y i n cl u d e  d at a f or  c hil dr e n ( 4 t o 
1 1  y e ars)  w h o  ar e still  o n- g oi n g i n t h e tri al  a n d  h a v e  n ot  y et  c o m pl et e d t h e  2 4- w e e k tr e at m e nt 
p eri o d.  
A fi n al  d at a  b as e l o c k  will  o c c ur  aft er t h e  p D B L,  o n c e  all  c hil dr e n  h a v e  c o m pl et e d t h e  E O S  visit 
a n d s af et y f oll o w- u p. 
P ati e nt l e v el listi n gs  of  d at a f or  c hil dr e n  w h o  w er e  o n- g oi n g  at t h e  p D B L  will  b e r e p ort e d  at t h e 
fi n al  d at a b as e l o c k.  N o  effi c a c y  a n al ys es  will  b e c o n d u ct e d  o n  d at a  c oll e ct e d f oll o wi n g t h e 
p D B L . 
8. 1. 3   
T y p e  1  e r r o r  c o nt r ol 
C o m p aris o ns  of  B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  a n d  B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us 
A S  M DI f or t h e  pri m ar y  e n d p oi nt, ti m e t o first s e v er e  e x a c er b ati o n  usi n g t h e  effi c a c y  esti m a n d, 
will  b e  c o n d u ct e d  usi n g  H o c h b er g’s st e p- u p  m et h o d ( H o c h b er g  1 9 8 8 ).  
T h e t y p e-I  err or  will  b e  c o ntr oll e d f or s e c o n d ar y  e n d p oi nt tr e at m e nt  c o m p aris o ns  v i a  a 
hi er ar c hi c al t esti n g  pr o c e d ur e.  T h e f oll o wi n g s e c o n d ar y  e n d p oi nts  will  b e t est e d  u n d er t h e 
effi c a c y  esti m a n d i n t h e f oll o wi n g s e q u e nti al  or d er,  gr o u p e d  b y s e c o n d ar y  e n d p oi nt: 
A n n u ali z e d s e v er e  e x a c er b ati o n r at e  
1.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
2.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
T ot al  a n n u ali z e d  d os e  of s yst e mi c  c orti c ost er oi d 
3.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
4.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
Ast h m a  C o ntr ol  Q u esti o n n air e- 5 ( A C Q - 5)  c h a n g e fr o m  b as eli n e r es p o n d er  a n al ysis  at  W e e k  2 4 
5.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
6.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n air e f or  1 2  y e ars  a n d  ol d er ( A Q L Q + 1 2)  c h a n g e fr o m  b as eli n e 
r es p o n d er  a n al ysis  at  W e e k  2 4  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 4  of  1 5 9  
7.   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
8.   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  
St atisti c al t ests f or t h e s e c o n d ar y  a n al ys es  will  b e  c o n d u ct e d  at t h e  5 % l e v el  of si g nifi c a n c e 
( 2-si d e d). I nf er e n c e f or  a t est i n t h e  d efi n e d  or d er is  d e p e n d e nt  o n st atisti c al si g nifi c a n c e  h a vi n g 
b e e n  a c hi e v e d i n t h e  pr e c e di n g t ests, if t his is  n ot  a c hi e v e d t h e n  n o mi n al  p- v al u es  will  b e 
pr o vi d e d.  As  p er t h e  pri m ar y  a n al ysis,  c o m p aris o ns  of  B D A  M DI  1 6 0/ 1 8 0  v ers us  A S  M DI  will 
e x cl u d e t h e  p e di atri c  p o p ul ati o n,  w hilst  c o m p aris o ns  of  B D A  8 0/ 1 8 0  v ers us  A S  M DI  will 
i n cl u d e  all  a g es. 
St atis ti c al si g nifi c a n c e  c a n  o nl y  b e  cl ai m e d  o n t h e  k e y s e c o n d ar y  e n d p oi nts if  a st atisti c all y 
si g nifi c a nt tr e at m e nt  eff e ct is  o bs er v e d  o n  b ot h  B D A  M DI  1 6 0/ 1 8 0  μ g  a n d  B D A  M DI 
8 0/ 1 8 0  μ g  v ers us  A S  M DI f or t h e  pri m ar y  e n d p oi nt  of ti m e t o first s e v er e  e x a c er b ati o n.  
8. 2   
S a m pl e si z e  esti m at e  
A s a m pl e si z e  of  1 0 0 0  a d ult  a n d  a d ol es c e nt s u bj e cts  p er tr e at m e nt  gr o u p  a n d  o bs er v ati o n  of t h e 
5 7 0 first s e v er e  e x a c er b ati o n  e v e nts  pr o vi d es t his st u d y  wit h  8 7 %  p o w er t o  o bs er v e  a  2 5 % 
r e d u cti o n i n t h e ris k  of s e v er e  e x a c er b ati o n  wit h  at l e ast  1 d os e  of  B D A  M DI  v ers us  A S  M DI 
ass u mi n g t h e  H o c h b er g  pr o c e d ur e ( H o c h b er g  1 9 8 8 ) f or  m ulti pl e t esti n g  a n d  a  2-si d e d 
si g nifi c a n c e l e v el  of  5 %.  
I n  a d diti o n,  u p t o   1 0 0 s u bj e cts i n t h e  4 t o 1 1  y e ar  a g e  gr o u p  wit h  m o d er at e t o s e v er e  ast h m a  will 
b e r a n d o mi z e d  wit h  a p pr o xi m at el y  5 0 s u bj e cts r a n d o mi z e d t o t h e  A S  M DI  gr o u p  a n d 
5 0 s u bj e cts r a n d o mi z e d t o t h e l o w  d os e  B D A  M DI  gr o u p  o nl y. 
8. 3   
D efi niti o ns  of  a n al ysis s ets  
8. 3. 1   
F ull  a n al ysis s et 
T h e f ull  a n al ysis s et ( F A S) is  d efi n e d  as  all s u bj e cts  w h o  ar e r a n d o mi z e d t o tr e at m e nt  a n d t a k e 
a n y  a m o u nt  of I P.  S u bj e cts  will  b e  a n al y z e d  a c c or di n g t o t h e tr e at m e nt t h e y  w er e  assi g n e d  at 
r a n d o mi z ati o n.  
All  effi c a c y  a n al ys es  will  b e  c o n d u ct e d i n t h e  F A S.  
T h e  effi c a c y  a n d  attri b ut a bl e  esti m a n d  will i n cl u d e  all  d at a  o bt ai n e d  u p t o  p D B L,  b ef or e 
s u bj e cts  dis c o nti n u e r a n d o mi z e d tr e at m e nt  a n d/ or  b ef or e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or 
l a c k  of  ast h m a  c o ntr ol.  T h e  eff e cti v e n ess  esti m a n d  will  utili z e  all  o bs er v e d  d at a  u p t o 
r a n d o mi z e d tr e at m e nt  dis c o nti n u ati o n, r e g ar dl ess  of  w h et h er s u bj e cts  e x p eri e n c e  a  c h a n g e i n 
m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol.  T h e  d e f a ct o  esti m a n d  will  utili z e  all  o bs er v e d 
d at a, i n cl u di n g  p ostI P  dis c o nti n u ati o n  d at a, r e g ar dl ess  of  a  c h a n g e i n  m ai nt e n a n c e t h er a p y.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 5  of  1 5 9  
8. 3. 2   
S af et y  a n al ysis s et 
T h e s af et y  a n al ysis s et is  d efi n e d  as  all s u bj e cts r e c ei vi n g  a n y  a m o u nt  of t h e I P.  S u bj e cts  will  b e 
cl assifi e d  o n t h e  b asis  of tr e at m e nt t h e y  a ct u all y r e c ei v e d. If  a s u bj e ct r e c ei v es  m or e t h a n  1 I P, 
h e  or s h e  will  b e s u m m a ri z e d  a c c or di n g t o t h e tr e at m e nt t h e s u bj e ct r e c ei v e d t h e  m ost.  All 
s af et y s u m m ari es  will  b e  b as e d  o n t h e s af et y  a n al ysis s et.   
8. 4   
Vi ol ati o ns  a n d  d e vi ati o ns  
I m p ort a nt  pr ot o c ol  d e vi ati o ns  will  b e list e d  a n d s u m m ari z e d  b y r a n d o mi z e d tr e at m e nt  gr o u p.  A 
p er - pr ot o c ol  a n al ysis  e x cl u di n g s u bj e cts  wit h si g nifi c a nt  pr ot o c ol  d e vi ati o ns is  n ot  pl a n n e d. 
All s u bj e cts  w h o f ail e d  a n y i n cl usi o n/ e x cl usi o n  crit eri a  will  b e list e d  al o n g  wit h  d et ails  of t h e 
f ail e d  crit eri a.  T his i nf or m ati o n  will  als o  b e s u m m ari z e d i n t erms  of t h e  n u m b er  a n d  p er c e nt a g e 
of s u bj e cts f aili n g  a n y  of t h e i n cl usi o n/ e x cl usi o n  crit eri a  a n d  will  b e  b as e d  o n t h e  F A S. 
8. 5   
O ut c o m e  m e as u r es f o r  a n al ys es  
8. 5. 1   
P ri m a r y  effi c a c y  a n al ysis 
T h e  pri m ar y  a n al ysis  will i n cl u d e  all  d at a  o bt ai n e d  u p t o  p D B L,  b ef or e s u bj e ct s  dis c o nti n u e 
r a n d o mi z e d tr e at m e nt  a n d/ or  b ef or e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol 
a n d  will  us e t h e  F A S, i n  a c c or d a n c e  wit h t h e  pri m ar y  esti m a n d ( S e cti o n  8. 1. 1 ). 
 
8. 5. 1. 1   
D e ri v ati o n  of ti m e t o fi rst s e v e r e  ast h m a  e x a c e r b ati o n 
Ti m e t o first s e v er e  ast h m a  e x a c er b ati o n  will  b e  c al c ul at e d  as t h e ti m e fr o m r a n d o mi z ati o n  u ntil 
t h e st art  d at e  of t h e first s e v er e  ast h m a  e x a c er b ati o n: 
St art  d a t e  of first s e v er e  ast h m a  e x a c er b ati o n –  D at e  of r a n d o miz ati o n ( Visit  2)  + 1 
S u bj e cts  n ot  h a vi n g  a n y s e v er e  ast h m a  e x a c er b ati o n  will  b e  c e ns or e d  at t h e  d at e  of t h eir l at est 
f oll o w- u p  or  E O S, f or s u bj e cts  w h o  dis c o nti n u e I P/ h a v e  a  c h a n g e i n  m ai nt e n a n c e t h er ap y f or 
l a c k  of  ast h m a  c o ntr ol, t h e  e arli est  of  eit h er  d a y  of  dis c o nti n u ati o n  or  d a y t h er e  w as  a  c h a n g e t o 
m ai nt e n a n c e t h er a p y.  
8. 5. 2   
S e c o n d a r y  effi c a c y  a n al ys es 
T h e s e c o n d ar y  a n al ys es  will i n cl u d e  all  d at a  o bt ai n e d  u p t o t h e  p D B L,  b ef or e s u bj e cts 
dis c o nti n u e r a n d o mi z e d tr e at m e nt  a n d/ or  b ef or e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of 
ast h m a  c o ntr ol  a n d  will  us e t h e  F A S, i n  a c c or d a n c e  wit h t h e  pri m ar y  esti m a n d (s e e 
S e cti o n  8. 1. 1 ). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 6  of  1 5 9  
8. 5. 2. 1   
D e ri v ati o n  of  a n n u ali z e d s e v e r e  ast h m a  e x a c e r b ati o n  r at e 
F or t h e  pr o d u cti o n  of  s u m m ar y st atisti cs, t h e r a w  a n n u ali z e d s e v er e  ast h m a  e x a c er b ati o n r at e 
will  b e  c al c ul at e d  a c c or di n g t o t h e f oll o wi n g f or m ul a:  
A n n u aliz e d s e v er e  e x a c er b ati o n r at e = ∑  n u m b er  of s e v er e  e x a c er b ati o ns * 3 6 5. 2 5/ ∑ f oll o w - u p, 
w h er e t h e s u m m ati o ns  ar e  o v er  all s u bj e c ts  wit hi n  a tr e at m e nt  ar m.  
F or s u bj e cts  w h o  d o  n ot  dis c o nti n u e I P  or  d o  n ot r e c ei v e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or 
l a c k  of  ast h m a  c o ntr ol, f oll o w- u p is  c al c ul at e d  as:  
[ D at e  of l at est f oll o w - u p  or  E O S]  – [ d at e  of r a n d o miz ati o n ( Visit  2)]  – [ c u m ul ati ve  d ur ati o n  of 
s e v er e  e x a c er b ati o n(s)]  +  1. 
Ot h er wis e,  f oll o w- u p is  c al c ul at e d  as t h e  d at e  of  e arli est  o c c urr e n c e  of  eit h er I P  dis c o nti n u ati o n 
or  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol:  
[ D at e  of I P  dis c o nti n u ati o n/ c h a n g e i n  m ai nt e n a n c e t h er a p y]  – [ d at e  of r a n d o miz ati o n ( Visit  2)] 
- [ c u m ul ati v e  d ur ati o n  of s e v er e  e x a c er b ati o n(s)]  + 1.  
8. 5. 2. 2   
D e ri v ati o n  of t ot al s yst e mi c  c o rti c ost e r oi d  e x p os u r e 
T ot al s yst e mi c  c orti c ost er oi d ( S C S)  e x p os ur e r e p ort e d  as t h e t ot al  a n n u ali z e d  d os e  will  b e 
c al c ul at e d f or   e a c h s u bj e ct  as t h e s u m  of t h e  c u m ul ati v e  d os es  of  c orti c ost er oi d  di vi d e d  b y t h e 
d ur ati o n  of ti m e ( y e ars) t h e s u bj e ct  w as i n t h e st u d y, fr o m r a n d o mi z ati o n  a n d  u p t o tr e at m e nt 
dis c o nti n u ati o n. 
E a c h  S C S  will  b e  n or m ali z e d t o t h e  e q ui p ot e nt  d os e  of  pr e d nis o n e ( m g)  b ef or e  c al c ul ati n g t h e 
a n n u ali z e d t ot al  d os e.   
8. 5. 2. 3   
D e ri v ati o n  of  Ast h m a  C o nt r ol  Q u esti o n n ai r e- 5  v a ri a bl es  
All  5 s y m pt o m  q u esti o ns  ar e  ass ess e d  o n  a  7- p oi nt s c al e ( 0 = g o o d  c o ntr ol;  6 = p o or  c o ntr ol).  T h e 
o v er all s c or e is t h e  m e a n  of t h e  5 s y m pt o m it e ms.  At  l e ast  4  o ut  of t h e  5 s y m pt o m it e ms  ar e 
n e e d e d t o  pr o vi d e  a n  A C Q- 5 s c or e.  
T h e  mi ni m al i m p ort a nt  diff er e n c e ( MI D)  i n  A C Q- 5 s c or e is  esti m at e d t o  b e  0. 5 (J u ni p er  2 0 0 5). 
O n t h e  b asis  of t h e  MI D, r es p o n d ers  at  W e e k  2 4  ar e  d efi n e d  as s u bj e cts  a c hi e vi n g  a  d e cli n e 
fr o m  b as eli n e  of  at l e ast  0. 5: 
•   R es p o n d er: ( W e e k  2 4  –  b as eli n e)  ≤ - 0. 5 
•   N o nr es p o n d er: ( W e e k  2 4  –  b as eli n e)  > - 0. 5 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 7  of  1 5 9  
S u bj e cts  w h o  dis c o nti n u e tr e at m e nt f or  a n y r e as o n  or r e c ei v e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y 
f or l a c k  of  ast h m a  c o ntr ol  b ef or e  W e e k  2 4  will  b e  cl assifi e d  as  n o nr es p o n d ers.  B as eli n e is 
d efi n e d  as t h e  m ost r e c e nt  n o n - missi n g s c or e  b ef or e  a n d i n cl u di n g r a n d o mi z ati o n ( Visit  2).  
A si mil ar  a n al ysis  will  b e  c o n d u ct e d  at  W e e k  1 2.  T his  will  b e  c o nsi d er e d  a n  e x pl or at or y 
e n d p oi nt. 
A d diti o n all y,  c h a n g es fr o m  b as eli n e  A C Q- 5  o v er all s c or e  at  W e e k  1 2  a n d  W e e k  2 4  will  b e 
c at e g ori z e d i nt o t h e  e x pl or at or y  3- l e v el f a ct or: 
•   I mpr o v e m e nt: ( W e e k  2 4  –  b as eli n e)  ≤ - 0. 5 
•   N o  C h a n g e: - 0. 5  < ( W e e k  2 4  –  b as eli n e)  < 0. 5  
•   W ors e ni n g: ( W e e k  2 4  –  b as eli n e)  ≥ 0. 5  
T h e i nt er vi e w er - a d mi nist er e d  v ersi o n  will  b e i m pl e m e nt e d f or  c hil dr e n  a g e d  4 t o  1 0  y e ars.  As 
t h e  A C Q- 5 is  n ot  v ali d at e d f or  c hil dr e n l ess t h a n  6  y e ars  ol d,  d at a f or s u bj e cts  w h o  ar e  4  or  5 
y e ars  of  a g e  will  b e  e x cl u d e d fr o m t h e  a n al ys es  of  A C Q - 5  e n d p oi nts. 
8. 5. 2. 4   
D e ri v ati o n  of  Ast h m a  Q u alit y  of  Lif e  Q u esti o n n ai r e  + 1 2  a n d  P e di at ri c  Ast h m a 
Q u alit y  of  Lif e  Q u esti o n n ai r e  v a ri a bl es  
As  d es cri b e d i n  S e cti o n  5. 1. 2 , t h er e  will  b e s e p ar at e  q u esti o n n air es f or  b ot h  a d ults  a n d  c hil dr e n. 
B ot h s ets  of  q u esti o n n air es  will  b e  a n al y z e d i n  a si mil ar  m a n n er.  
A Q L Q  c o nsists  of  3 2  q u esti o ns i n  4  d o m ai ns  a n d  P A Q L Q  c o nsists  of  2 3  q u esti o ns i n  3 
d o m ai ns.  B ot h  ar e  ass ess e d  o n s e p ar at e  7 - p oi nt  Li k ert s c al es fr o m  1 t o  7,  wit h  hi g h er  v al u es 
i n di c ati n g  b ett er  h e alt h-r el at e d  q u alit y  of lif e.  
F or  o v er all  h e alt h -r el at e d  q u alit y  of lif e  a n d f or  e a c h  of t h e  d o m ai ns, t h e  MI D  h as  b e e n 
d et er mi n e d t o  b e  a  c h a n g e i n s c or e  of  0. 5 ( J u ni p er  1 9 9 4).  O n t h e  b asis  of t h e  MI D, r es p o n d ers  at 
W e e k  2 4  ar e  d efi n e d  as s u bj e cts  a c hi e vi n g  a n i n cr e as e fr o m  b as eli n e  of  at l e ast  0. 5:  
•   R es p o n d er: ( W e e k  2 4  –  b as eli n e)  ≥ 0. 5  
•   N o nr es p o n d er: ( W e e k  2 4  –  b as eli n e)  < 0. 5  
 
S u bj e cts  w h o  dis c o nti n u e tr e at m e nt  b ef or e  W e e k  2 4 f or  a n y r e as o n  will  b e  cl assifi e d  as 
n o nr es p o n d ers.  B as eli n e is  d efi n e d  as t h e  m ost r e c e nt  n o n- missi n g s c or e  b ef or e  a n d i n cl u di n g 
r a n d o mi z ati o n ( Visit  2).  
A si mil ar  a n al ysis  will  b e  c o n d u ct e d  at  W e e k  1 2.  T his  will  b e  c o nsi d er e d  a n  e x pl or at or y 
e n d p oi nt. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 8  of  1 5 9  
As t h e  P A Q L Q is  n ot  v ali d at e d f or  c hil dr e n l ess t h a n  7  y e ars  of  a g e,  d at a f o r s u bj e cts  w h o  ar e 
a g e d  4 t o  6  y e ars  will  b e  e x cl u d e d fr o m t h e  a n al ys es  of  P A Q L Q  e n d p oi nts. 
8. 5. 3   
E x pl o r at o r y  a n al ys es 
T h e  e x pl or at or y  a n al ys es  will i n cl u d e  all  d at a  o bt ai n e d  u p t o t h e  p D B L,  b ef or e s u bj e cts 
dis c o nti n u e r a n d o mi z e d tr e at m e nt  a n d/ or  b ef or e  a  c h a n g e  i n  m ai nt e n a n c e t h er a p y f or l a c k  of 
ast h m a  c o ntr ol  a n d  will  us e t h e  F A S, i n  a c c or d a n c e  wit h t h e  pri m ar y  esti m a n d (s e e 
S e cti o n  8. 1. 1 ). 
8. 5. 3. 1   
D e ri v ati o n  of  d et e ri o r ati o n  of  ast h m a  v a ri a bl es 
Ti m e t o first  d et eri or ati o n  of  ast h m a  a n d t h e r a w  d et eri or ati o n  of  ast h m a r at e  will  b e  c al c ul at e d 
i n  a si mil ar  w a y  as t o ti m e t o first s e v er e  ast h m a  e x a c er b ati o n (s e e S e cti o n  8. 5. 1. 1 )  a n d t h e r a w 
a n n u ali z e d s e v er e  ast h m a  e x a c er b ati o n r at e (s e e  S e cti o n  8. 5. 2. 1 ). 
8. 5. 3. 2   
D e ri v ati o n  of ti m e t o t r e at m e nt  dis c o nti n u ati o n  o r  c h a n g e i n  m ai nt e n a n c e 
t h e r a p y f o r l a c k  of  ast h m a  c o nt r ol 
Ti m e t o tr e at m e nt  dis c o nti n u ati o n  or  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol 
will  b e  c al c ul at e d  as t h e ti m e fr o m r a n d o mi z ati o n  u ntil t h e  e arli est  of tr e at m e nt 
dis c o nti n u ati o n/ c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol: 
D at e  of I P  dis c o nti n u ati o n/ c h a n g e i n  m ai nt e n a n c e t h er a p y  – d at e  of r a n d o miz ati o n ( Visit  2)  + 1 
S u bj e cts  n ot  h a vi n g  pr e m at ur el y  dis c o nti n u e d tr e at m e nt  or r e c ei vi n g  a  c h a n g e i n  m ai nt e n a n c e 
t h er a p y  will  b e  c e ns or e d  at t h e l at est f oll o w- u p  or  E O S.  
8. 5. 3. 3   
D e ri v ati o n  of  Ast h m a  C o nt r ol  T est  r es p o n d e r  v a ri a bl e 
T h e  MI D i n  A C T s c or e is  esti m at e d t o  b e  3 ( S c h at z  2 0 0 9 ).  O n t h e  b asis  of t h e  MI D, t h e 
r es p o n d ers  at  W e e k  2 4  ar e  d efi n e d  as s u bj e cts  a c hi e vi n g  a n i n cr e as e fr o m  b as eli n e  of  at l e ast  3:  
•   R es p o n d er: ( W e e k  2 4  –  b as eli n e)  ≥  3   
•   N o nr es p o n d er: ( W e e k  2 4  –  b as eli n e)  <  3  
S u bj e cts  w h o  dis c o nti n u e tr e at m e nt f or  a n y r e as o n  or r e c ei v e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y 
f or l a c k  of  ast h m a  c o ntr ol  b ef or e  W e e k  2 4  will  b e  cl assifi e d  as  n o nr es p o n d ers.  B as eli n e is 
d efi n e d  as t h e  m ost r e c e nt  n o n - missi n g s c or e  b ef or e  a n d i n cl u di n g r a n d o mi z ati o n ( Visit  2). 
8. 5. 3. 4   
D e ri v ati o n  of  ot h e r  e Di a r y  v a ri a bl es 
S y m pt o m -f r e e  d a ys 
A s y m pt o m-fr e e  d a y is  d efi n e d  as t h e f ulfill m e nt  of  b ot h  of t h e f oll o wi n g  crit eri a: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
7 9  of  1 5 9  
•   A  d a y  a n d  ni g ht  wit h  n o  ast h m a s y m pt o ms (i e,  ast h m a s y m pt o m s c or e = 0) 
•   A  ni g ht  wit h  n o  a w a k e ni n gs  d u e t o  ast h m a s y m pt o ms 
“ As  n e e d e d ” -f r e e  d a ys 
•   A n  “ as  n e e d e d ” -fr e e  d a y is  d efi n e d  as  a  d a y  a n d  ni g ht  wit h  n o  us e  of I P 
Ast h m a  c o nt r ol  d a ys 
A n  ast h m a  c o ntr ol  d a y is  d efi n e d  as t h e f ulfill m e nt  of  all  of t h e f oll o wi n g  crit eri a:  
•   A  d a y  a n d  ni g ht  wit h  n o  ast h m a s y m pt o ms (i e,  ast h m a s y m pt o m s c or e = 0) 
•   A  ni g ht  wit h  n o  a w a k e ni n gs  d u e t o  ast h m a s y m pt o ms 
•   A  d a y  a n d  ni g ht  wit h  n o  us e  of  “ as  n e e d e d ”  m e di c ati o n 
8. 5. 3. 5   
In h al e d  c o rti c ost e r oi d  e x p os u r e  
A d diti o n al i n h al e d  c orti c ost er oi d  e x p os ur e fr o m  B D A  M DI  will  b e  c al c ul at e d  as t h e t ot al  d ail y 
n u m b er  of  p uffs  of r a n d o mi z e d tr e at m e nt.   
B a c k gr o u n d  m ai nt e n a n c e t h er a p y  will  b e  c at e g ori z e d i nt o [l o w,  m e di u m,  hi g h]  d ail y st er oi d 
d os e.  M ai nt e n a n c e t h er a p y  c at e g ori z ati o ns  will  b e  b as e d  o n  pr es cri b e d  d ail y  d os e  of 
m ai nt e n a n c e t h er a p y st er oi ds.  
8. 6   
M et h o ds f o r st atisti c al  a n al ys es  
All t ests  will  b e  2 -si d e d  a n d  at  5 % l e v el  of si g nifi c a n c e  u nl ess  ot h er wis e st at e d.  A dj ust m e nt  will 
b e  m a d e  usi n g t h e  H o c h b er g  pr o c e d ur e ( H o c h b er g  1 9 8 8 ) f or t h e  pri m ar y  e n d p oi nt tr e at m e nt 
c o m p aris o ns. 
I n  a d diti o n t o t h e  a n al ys es  d es cri b e d  b el o w,  all  v ari a bl es  will  b e s u m m ari z e d  d es cri pti v el y 
w h er e  a p pr o pri at e.  
8. 6. 1   
A n al ysis  of t h e  p ri m a r y  v a ri a bl e 
T h e  pri m ar y  a n al ysis  will t ar g et t h e  effi c a c y  esti m a n d i n t h e  F A S  p o p ul ati o n.   T h e  pri m ar y 
v ari a bl e, ti m e t o first s e v er e  ast h m a  e x a c er b ati o n,  will  b e  a n al y z e d  usi n g  a  C o x  pr o p orti o n al 
h a z ar ds r e gr essi o n  m o d el t o  c o m p ar e tr e at m e nt  ar ms.  T h e  m o d el  will  b e  a dj ust e d f or t h e 
r a n d o mi z ati o n str atifi c ati o n f a ct ors ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 t o  1 7,  ≥ 1 8]); r e gi o n ( N ort h 
A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d [ R e gi o n  2]);  a n d 
n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1)  pl us 
a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d  a n d  k e y  c o v ari at es  of 
i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e  S A P. T h e s u m m ar y  m e as ur e t o  c o m p ar e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 0  of  1 5 9  
tr e at m e nts is t h e  esti m at e d  h a z ar d r ati o  w hi c h  will  b e  pr es e nt e d  wit h t h e  c orr es p o n di n g  9 5 % 
c o nfi d e n c e i nt er v al  a n d  p- v al u e.  
T h e  pl a n n e d tr e at m e nt  c o m p aris o ns f or t h e  pri m ar y  a n al ysis  ar e:  
1   B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g (s u p eri orit y,  pri m ar y  o bj e cti v e)  
2   B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g (s u p eri orit y,  pri m ar y  o bj e cti v e)  
 
T h e  c o m p aris o n  of  B D A  M DI  1 6 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  will  e x cl u d e t h e  p e di atri c 
s u bj e cts (s u bj e cts  a g e d  4 t o  1 1  y e ars)  as t h e y  will  n ot  b e r a n d o mi z e d t o  B D A  M DI  1 6 0/ 1 8 0  μ g. 
F or t his  a n al ysis t h e  a g e  c o v ari at e  will  o nl y  h a v e t h e  2 l e v els  ≥ 1 2 t o  1 7  a n d  ≥ 1 8.  H o w e v er, t h e 
pri m ar y  a n al ysis f or  c o m p aris o n  of  B D A  M DI  8 0/ 1 8 0  μ g  v ers us  A S  M DI  1 8 0  μ g  will i n cl u d e 
s u bj e cts fr o m  all  a g e  gr o u ps. 
F or m all y, t h e  n ull  a n d  alt er n ati v e  h y p ot h es es f or  c o m p aris o ns  1  a n d  2  ar e: 
𝐻𝐻0 : 𝐻𝐻 𝐻𝐻 𝐻𝐻 𝐻𝐻 𝐻𝐻 𝐻𝐻  𝐻𝐻 𝐻𝐻 𝑟𝑟𝑟𝑟 𝑟𝑟   (B D A  M D I  v ers us  A S  M DI) = 1, 
𝐻𝐻𝐴𝐴: 𝐻𝐻 𝐻𝐻 𝐻𝐻 𝐻𝐻 𝐻𝐻 𝐻𝐻  𝐻𝐻 𝐻𝐻 𝑟𝑟𝑟𝑟 𝑟𝑟   (B D A  M D I  v ers us  A S  M DI)≠ 1.  
All s u bj e cts  w h o  ar e  r a n d o mi z e d  a n d  ar e  p art  of t h e f ull  a n al ysis s et  will  b e  a n al y z e d  a c c or di n g 
t o t h e str at a t h e y  w er e  all o c at e d t o i n I V R S/I W R S.  A s e nsiti vit y  a n al ysis  will  b e  c o n d u ct e d 
b as e d  o n s u bj e cts’  a ct u al str at a t o  ass ess t h e i m p a ct  of  miss -str atifi c ati o n  o n t h e  m o d el r es ults.  
8. 6. 2   
A n al ysis  of t h e s e c o n d a r y  effi c a c y  v a ri a bl es 
A n al ysis  of t h e s e c o n d ar y  effi c a c y  v ari a bl es  will  b e  o n t h e  F A S  p o p ul ati o n.  F or  all s e c o n d ar y 
a n al ys es t h e s a m e tr e at m e nt  c o m p aris o ns  as f or t h e  pri m ar y  a n al ysis  will  b e  c o n d u ct e d (s e e 
S e cti o n  8. 6. 1 ).  Pl e as e s e e t h e  hi er ar c hi c al t esti n g str at e g y f or s e c o n d ar y  e n d p oi nts (s e e 
S e cti o n  8. 1. 2 ). 
8. 6. 2. 1   
S e v e r e  ast h m a  e x a c e r b ati o n  r at e  
A n al ysis  of s e v er e  ast h m a  e x a c er b ati o n r at e  will t ar g et t h e  effi c a c y  esti m a n d i n t h e  F A S 
p o p ul ati o n.  A n n u ali z e d s e v er e  ast h m a  e x a c er b ati o n r at e  will  b e  a n al y z e d  usi n g  n e g ati v e 
bi n o mi al r e gr essi o n t o  c o m p ar e tr e at m e nt  gr o u ps.  T h e r es p o ns e  v ari a bl e i n t h e  m o d el  will  b e 
t h e  n u m b er  of s e v er e  ast h m a  e x a c er b ati o ns.  T h e  m o d el  will  a dj ust f or ( a g e  gr o u p [ ≥  4 t o  1 1, 
≥ 1 2 t o  1 7,  ≥ 1 8]); r e gi o n ( N ort h  A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est 
of  w orl d [ R e gi o n  2]);  a n d  n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o 
r a n d o mi z ati o n)  a n d  k e y  c o v ari at es  of i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e  S A P.  
T h e l o g arit h m  of t h e ti m e  at ris k  of  e x p eri e n ci n g  a n  e x a c er b a ti o n  will  b e  us e d  as  a n  offs et 
v ari a bl e i n t h e  m o d el.  Ti m e  d uri n g  a n  e x a c er b ati o n  or i n t h e  7  d a ys  aft er  a n  e x a c er b ati o n  will 
n ot  b e i n cl u d e d i n t h e  c al c ul ati o n.  Fr o m t h e  n e g ati v e  bi n o mi al  m o d el, t h e  a n n u al s e v er e  ast h m a 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 1  of  1 5 9  
e x a c er b ati o n r at es  will  b e  esti m at e d,  a n d t h e s u m m ar y  m e as ur e f or t h e  c o m p aris o n  of tr e at m e nts 
will  b e t h e  esti m at e d r at e r ati o  w hi c h  will  b e  pr es e nt e d  wit h t h e  c orr es p o n di n g  9 5 %  c o nfi d e n c e 
i nt er v al  a n d  p-v al u e.  
T h e r a w  a n n u ali z e d  e x a c er b ati o n r at e  will  als o  b e s u m m ari z e d  d es cri pti v el y  b y tr e at m e nt,  usi n g 
t h e  d eri v ati o n  d es cri b e d i n S e cti o n  8. 5. 2. 1 . 
8. 6. 2. 2   
Ast h m a  C o nt r ol  Q u esti o n n ai r e- 5 
T h e r es p o n d er  v ari a bl e  d es cri b e d i n  S e cti o n  8. 5. 2. 3   at  W e e k  2 4  will  b e  a n al y z e d  usi n g  a l o gisti c 
r e gr essi o n  m o d el t o  c o m p ar e tr e at m e nt  gr o u ps.  T h e  m o d el  will  b e  a dj ust e d f or t h e 
r a n d o mi z ati o n str atifi c ati o n f a ct ors ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 t o  1 7,  ≥ 1 8]); r e gi o n ( N ort h 
A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afr i c a [ R e gi o n  1]  a n d r est  of  w orl d [ R e gi o n  2]);  a n d 
n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1)  pl us 
a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d  a n d  k e y  c o v ari at es  of 
i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e  S A P.  Fr o m t h e l o gisti c r e gr essi o n  m o d el, 
tr e at m e nt  eff e cts  will  b e  esti m at e d  b y  o d ds r ati os  a n d t h eir  c orr es p o n di n g  9 5 %  c o nfi d e n c e 
i nt er v als  a n d  p-v al u es.  
T h e  e x pl or at or y  e n d p oi nt f or r es p o n d er  a n al ysis  at  W e e k  1 2  a n d  3 f a ct or  c at e g ori z ati o n  of 
A C Q -5 (I m pr o v e m e nt;  N o  c h a n g e;  W ors e ni n g)  at  W e e k  1 2  a n d  W e e k  2 4  will  b e  a n al y z e d  usi n g 
a n  or di n al l o gisti c r e gr essi o n  a n d  a dj usti n g f or t h e si mil ar  c o v ari at es.   F ull  d et ails  of t h es e 
a n al ys es  will  b e  pr o vi d e d i n t h e  S A P. 
A n al ysis  of  c h a n g e fr o m  b as eli n e i n  A C Q- 5  at  W e e k  2 4  will t ar g et t h e  effi c a c y  esti m a n d i n t h e 
F A S  p o p ul ati o n.   T h e tr e at m e nt  eff e ct f or  c h a n g e fr o m  b as eli n e i n  A C Q- 5  will  b e  esti m at e d 
usi n g  a r e p e at e d  m e as ur es  a n al ysis.  All  d at a  u p t o  W e e k  2 4  will  b e i n cl u d e d i n t h e  m o d e l,  wit h 
t er ms f or tr e at m e nt,  visit, tr e at m e nt *  visit,  a n d  b as eli n e  A C Q- 5.  T h e  m o d el  will  als o  b e  a dj ust e d 
f or t h e r a n d o mi z ati o n str atifi c ati o n f a ct ors ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 t o  1 7,  ≥ 1 8]); r e gi o n 
( N ort h  A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d [ R e gi o n  2]); 
a n d  n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1) 
pl us  a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d  a n d  k e y  c o v ari at es 
of i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e  S A P.  Visit  will  b e fitt e d  as  a  c at e g ori c al 
v ari a bl e,  a n d t h e  v ari a n c e- c o v ari a n c e  m atri x  will  b e  ass u m e d t o  b e  u nstr u ct ur e d. If t h e 
pr o c e d ur e  d o es  n ot  c o n v er g e, t h e n  a  c o m p o u n d s y m m etri c  v ari a n c e- c o v ari a n c e  m atri x  will  b e 
us e d i nst e a d.  T his  m o d el  will  b e  us e d t o  gi v e  a n  o v er all  ass ess m e nt  of t h e tr e at m e nt  eff e ct  as 
w ell  as  9 5 %  c o nfi d e n c e i nt er v als.  
C h a n g e fr o m  b as eli n e  will  als o  b e  d es cri b e d  d es cri pti v el y f or  all st u d y  visits, i n cl u di n g t h e  E O S 
visit/ P D V  a n d t h e s af et y f oll o w - u p t el e p h o n e  c o nt a ct.   
I n  all t h e s c e n ari os  a b o v e,  b as eli n e is  d efi n e d  as t h e  m ost r e c e nt s c or e  b ef or e  a n d i n cl u di n g 
r a n d o mi zati o n ( Visit  2).   
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 2  of  1 5 9  
8. 6. 2. 3   
Ast h m a  Q u alit y  of  Lif e  Q u esti o n n ai r e  + 1 2  a n d  P e di at ri c  Ast h m a  Q u alit y  of 
Lif e  Q u esti o n n ai r e  
T h e r es p o n d er  a n al ysis  will  b e  c o n d u ct e d i n t h e s a m e  w a y  as  A C Q- 5 ( S e cti o n  8. 6. 2. 2 ).  T h e 
e x pl or at or y  e n d p oi nt f or r es p o n d er  a n al ysis  at  W e e k  1 2  will  als o  b e  a n al y z e d i n  a si mil ar  w a y. 
T h e  d o m ai n s c or es  as  w ell  as t h e  o v er all s c or es  ar e  c al c ul at e d fr o m t h e  u n w ei g ht e d  arit h m eti c 
m e a ns  of t h e i n di vi d u al  q u esti o n  s c or es.  T h e tr e at m e nt  eff e ct f or  c h a n g e fr o m  b as eli n e i n 
A Q L Q + 1 2  a n d  P A Q L Q  o v er all s c or es  u p t o  W e e k  2 4  will  b e  esti m at e d i n t h e s a m e  w a y  as 
A C Q -5,  usi n g  a r e p e at e d  m e as ur es  a n al ysis.   
C h a n g e fr o m  b as eli n e  will  als o  b e  d es cri b e d  d es cri pti v el y f or  all st u d y  visits, i n cl u di n g t h e  E O S 
visit/ P D V  a n d s af et y f oll o w - u p t el e p h o n e  c o nt a ct f or  e a c h  of t h e  d o m ai ns  a n d t h e  o v er all 
s c or es.  
I n  all t h e s c e n ari os  a b o v e,  b as eli n e is  d efi n e d  as t h e  m ost r e c e nt s c or e  b ef or e  a n d i n cl u di n g 
r a n d o mi z ati o n ( Visit  2).  
8. 6. 2. 4   
T ot al s yst e mi c  c o rti c ost e r oi d  e x p os u r e  
T h e t ot al s yst e mi c  c orti c ost er oi d  e x p os ur e  as t ot al  a n n u ali z e d  d os e  of  S C S ( m g/ y e ar)  will  b e 
pr es e nt e d  d es cri pti v el y  b y tr e at m e nt.  A  c o m p aris o n i n t ot al  a n n u ali z e d  S C S  d os e  b et w e e n 
B D A   M DI  8 0/ 1 8 0  vs  A S  M DI  1 8 0  a n d  B D A  M DI  1 6 0/ 1 8 0  vs  A S  M DI  1 8 0  will  b e  a n al y z e d 
usi n g  a  Wil c o x o n r a n k s u m t est  a n d  ass o ci at e d  p- v al u es  will  b e  pr es e nt e d  al o n g  wit h t h e 
d es cri pti v e s u m m ar y. 
A d diti o n all y, t h e t ot al  S C S  e x p os ur e  will  b e s u m m ari z e d  d es cri pti v el y  as t h e t ot al  n u m b er  of 
d a ys  wit h  S C S tr e at m e nt  d u e t o  ast h m a f or  all s u bj e cts.  A si mil ar  d es cri pti v e s u m m ar y  will  b e 
d o n e f or  all s u bj e cts  w h o  a d mi nist er e d  at l e ast  1  d os e  of  S C S  d uri n g t h e st u d y. 
8. 6. 3   
A n al ysis  of s af et y  v a ri a bl es 
T h e s af et y  a n al ys es  will i n cl u d e  all  d at a  o bt ai n e d  b ef or e s u bj e cts  dis c o nti n u e r a n d o mi z e d 
tr e at m e nt  a n d  will  us e t h e s af et y  a n al ysis s et.  
8. 6. 3. 1   
A d v e rs e  e v e nts  
A d v ers e  e v e nts  will  b e s u m m ari z e d  b y tr e at m e nt  gr o u p, s yst e m  or g a n  cl ass  a n d  pr ef err e d t er m 
assi g n e d t o t h e  e v e nt  b y t h e  M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es.  A d v ers e  e v e nts  will 
als o  b e list e d f or  e a c h s u bj e ct.   
8. 6. 3. 2   
Vit al si g ns  
C h a n g e fr o m  b as eli n e t hr o u g h o ut t h e st u d y  will  b e  ass ess e d f or r esti n g  p uls e  a n d  bl o o d 
pr ess ur e.   M e as ur e m e nts s h o ul d  b e t a k e n i n t h e sitti n g  p ositi o n  aft er  at l e ast  1 0 mi n ut es  of r est.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 3  of  1 5 9  
B as eli n e is  d efi n e d  as t h e  m ost r e c e nt  n o n- missi n g  m e as ur e m e nt  b ef or e  a n d i n cl u di n g 
r a n d o mi z ati o n ( Visit  2). 
8. 6. 3. 3   
Cli ni c al  c h e mist r y  a n d  h e m at ol o g y 
Cli ni c al  c h e mistr y,  h e m at ol o g y;  a n d  m or ni n g s er u m  c ortis ol  ass ess m e nts  will  b e s u m m ari z e d  b y 
tr e at m e nt  gr o u p  a n d  Visit  a n d will  als o  b e list e d  b y s u bj e ct.  
B as eli n e is  d efi n e d  as t h e  m ost r e c e nt  n o n - missi n g  m e as ur e m e nt  b ef or e  a n d i n cl u di n g 
r a n d o mi z ati o n ( Visit  2). 
8. 6. 3. 4   
C o n c o mit a nt  m e di c ati o n 
T h e  n u m b er  a n d  p er c e nt a g e  of s u bj e cts  w h o t a k e  all o w e d  c o n c o mit a nt  m e di c ati o ns,  a n d t h os e 
w h o t a k e  dis all o w e d  c o n c o mit a nt  m e di c ati o ns  d uri n g t h e st u d y,  will  b e  pr es e nt e d  b y tr e at m e nt 
gr o u p. 
8. 6. 4   
A n al ysis  of  e x pl o r at o r y  v a ri a bl es 
T h e tr e at m e nt  c o m p aris o ns i n t h e s e c o n d ar y  a n al ys es  gi v e n  b el o w  ar e  c o m p ar e d i n t h e s a m e 
w a y  as t h e  pri m ar y  a n al ysis.  
8. 6. 4. 1   
D et e ri o r ati o n  of  ast h m a 
A n n u ali z e d  d et eri or ati o n  of  ast h m a  a n d ti m e t o first  d et eri or ati o n  of  ast h m a  will  b e  a n al y z e d i n 
t h e s a m e  w a y  as t h e ti m e t o first s e v er e  ast h m a  e x a c er b ati o n (S e cti o n  8. 6. 1 )  a n d  a n n u ali z e d 
s e v er e  ast h m a  e x a c er b ati o n r at e ( S e cti o n  8. 6. 2. 1 ). 
8. 6. 4. 2   
P r e b r o n c h o dil at o r  F E V 1 
T h e tr e at m e nt  eff e ct f or  c h a n g e fr o m  b as eli n e i n  F E V 1 ( m L)  will  b e  esti m at e d  usi n g  a  M M R M 
a n al ysis.  F E V 1  d at a fr o m  all  visits  u p t o  W e e k  2 4  will  b e i n cl u d e d i n t h e  m o d el,  wit h t er ms f or 
tr e at m e nt,  visit  a n d tr e at m e nt * visit  wit h  b as eli n e  F E V1 i n cl u d e d  as  a  c o v ari at e. T h e  m o d el  will 
b e  a dj ust e d f or t h e r a n d o mi z ati o n str atifi c ati o n f a ct ors ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 t o  1 7,  ≥ 1 8]); 
r e gi o n ( N ort h  A m eri c a,  W est er n  E ur o p e  a n d  S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d 
[ R e gi o n 2]);  a n d  n u m b er  of  pri or s e v er e  e x a c er b ati o n s ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o 
s cr e e ni n g ( Visit  1)  pl us  a n y s e v er e  e x a c er b ati o n  e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d 
a n d  k e y  c o v ari at es  of i nt er est  wit h  m or e  d et ail t o  b e  pr o vi d e d i n t h e  S A P.  Visit  will  b e fitt e d  as 
a  c at e g ori c al  v ari a bl e,  a n d t h e  v ari a n c e- c o v ari a n c e  m atri x  will  b e  ass u m e d t o  b e  u nstr u ct ur e d. If 
t h e  pr o c e d ur e  d o es  n ot  c o n v er g e t h e n  a  c o m p o u n d s y m m etri c  v ari a n c e- c o v ari a n c e  m atri x  will 
b e  us e d i nst e a d.  T his  m o d el  will  b e  us e d t o  gi v e  ass ess m e nts  of t h e tr e at m e nt  eff e ct  as  w ell  as 
9 5 %  c o nfi d e n c e i nt er v als  at  W e e k  1 2  a n d  W e e k  2 4.  
B as eli n e is  d efi n e d  as t h e  m ost r e c e nt  n o n - missi n g  m e as ur e m e nt  b ef or e  a n d i n cl u di n g 
r a n d o mi z ati o n ( Visit  2). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 4  of  1 5 9  
8. 6. 4. 3   
M o r ni n g  p e a k  e x pi r at o r y  fl o w 
T h e  m e a n  v al u e  of  c h a n g e fr o m  b as eli n e i n  m or ni n g  P E F  d at a  d uri n g  tr e at m e nt  will  b e  a n al y z e d 
b y  a n al ysis  of  c o v ari a n c e  wit h tr e at m e nt  as  a f a ct or  a n d,  b as eli n e  m or ni n g  P E F s c or e  as  a 
c o nti n u o us  c o v ari at e.  T h e  m o d el  will  als o  b e  a dj ust e d f or t h e r a n d o mi z ati o n str atifi c ati o n 
f a ct ors ( a g e  gr o u p [ ≥  4 t o  1 1,  ≥ 1 2 t o  1 7,  ≥ 1 8]); r e gi o n ( N ort h  A m eri c a,  W est er n  E ur o p e  a n d 
S o ut h  Afri c a [ R e gi o n  1]  a n d r est  of  w orl d [ R e gi o n  2]);  a n d  n u m b er  of  pri or s e v er e 
e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1)  pl us  a n y s e v er e  e x a c er b ati o n 
e v e nt  e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d  a n d  k e y  c o v ari at es  of i nt er est  wit h  m or e  d et ail t o 
b e  pr o vi d e d i n t h e  S A P.  T h e s u m m ar y  m e as ur e f or t h e  c o m p aris o n  of tr e at m e nts  will  b e t h e 
esti m at e d  m e a n  diff er e n c e,  pr es e nt e d  wit h t h e  c orr es p o n di n g  9 5 %  c o nfi d e n c e i nt er v al. 
A d diti o n all y   a r e p e at e d  m e as ur es  a n al ysis  will  b e  c o n d u ct e d  a n d  will  b e  p artiti o n e d i nt o 
4- w e e kl y ti m e i nt er v als  a cr oss t h e r a n d o mi z e d tr e at m e nt  p eri o d.  T h e  a n al ysis  m o d el  will 
a d diti o n all y i n cl u d e ti m e  p oi nt  a n d tr e at m e nt *ti m e  p oi nt  as f a ct ors  a n d  ass o ci at e d  p -v al u e.  
C h a n g e fr o m  b as eli n e i n  m or ni n g  P E F  will  als o  b e s u m m ari z e d f or  e a c h s u bj e ct  b y tr e at m e nt 
gr o u p  usi n g s u m m ar y st atisti cs. 
F or  all s c e n ari os  a b o v e,  b as eli n e  m or ni n g  P E F is  d efi n e d  as t h e  a v er a g e  d uri n g t h e  1 0  d a ys  pri or 
t o r a n d o mi z ati o n ( Visit  2)  d uri n g r u n-i n.  M or ni n g  P E F  will  b e  c a pt ur e d  vi a t h e  e Di ar y. 
8. 6. 4. 4   
Ot h e r  e Di a r y  v a ri a bl es  
E v e ni n g  P E F, r eli e v er t h er a p y  us e,  ast h m a s y m pt o ms ( d a y,  ni g ht,  a n d t ot al),  ni g ht- ti m e 
a w a k e ni n gs  d u e t o  ast h m a s y m pt o ms, s y m pt o m- fr e e  d a ys,  “ as  n e e d e d ”-fr e e  d a ys  a n d  ast h m a 
c o ntr ol  d a ys  will  b e  a n al y z e d i n t h e s a m e  w a y  as t h e  m or ni n g  P E F. 
B as eli n e is  d efi n e d  as t h e  a v er a g e  d uri n g t h e  1 0  d a ys  pri or t o r a n d o mi z ati o n ( Visit  2)  d uri n g 
r u n-i n. 
8. 6. 4. 5   
Ti m e t o t r e at m e nt  dis c o nti n u ati o n  o r  c h a n g e i n  m ai nt e n a n c e t h e r a p y f o r l a c k 
of  ast h m a  c o nt r ol 
Ti m e t o tr e at m e nt  dis c o nti n u ati o n  or  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of  ast h m a  c o ntr ol 
will  b e  a n al y z e d  as  p er t h e  pri m ar y  a n al ysis  d es cri b e d i n  S e cti o n  8. 6. 1 . 
8. 6. 4. 6   
Ast h m a  C o nt r ol  T est 
T h e  A C T/ C  A C T  will  b e s u m m ari z e d  as  p er t h e s e c o n d ar y  a n al ysis  of  c h a n g e fr o m  b as eli n e  a n d 
r es p o n d er  a n al ysis i n  A C Q- 5 i n S e cti o n  8. 6. 2. 2 . 
B as eli n e is  d efi n e d  as t h e  m ost r e c e nt  n o n - missi n g s c or e  b ef or e  a n d i n cl u di n g r a n d o mi z ati o n 
( Visit  2).  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 5  of  1 5 9  
8. 6. 4. 7   
In h al e d  c o rti c ost e r oi d  e x p os u r e  
I n h al e d  c orti c ost er oi d  e x p os ur e  as  m e a n  d ail y  n u m b er  of  p uffs  of r a n d o mi z e d tr e at m e nt  will b e 
s u m m ari z e d  d es cri pti v el y.  A d diti o n all y,  d es cri pti v e s u m m ari es  of t h e  m ai n  d ail y  n u m b er  of 
p uffs  will  b e f urt h er  br o k e n  d o w n i nt o s u b gr o u ps  of  b a c k gr o u n d  m ai nt e n a n c e t h er a p y 
pr es cri b e d  us e  of [l o w,  m e di u m,  hi g h]  d ail y  d os e.   
8. 6. 5   
S u b g r o u p  a n al ysis 
T h e  ass ess m e nt  of tr e at m e nt  eff e ct  will  b e i n v esti g at e d i n t h e str atifi c ati o n  v ari a bl es  a n d  ot h er 
cli ni c all y i m p ort a nt s u b gr o u ps  a n d  will  b e  d efi n e d i n  m or e  d et ail i n t h e  S A P.  
. 
8. 6. 6   
S e nsiti vit y  a n al ysis 
8. 6. 6. 1   
Ti p pi n g  p oi nt  a n al ysis  
M ulti pl e i m p ut ati o n ti p pi n g  p oi nt  a n al ysis  u n d er t h e  missi n g  n ot  at r a n d o m  ass u m pti o n  will  b e 
c o n d u ct e d.  F or s u bj e cts i n t h e  B D A  M DI  gr o u ps, t his  m et h o d  will i m p ut e  missi n g  v al u es  p ost-
st u d y  dis c o nti n u ati o n/ c h a n g e i n  m ai nt e n a n c e f or l a c k  of  ast h m a  c o ntr ol  ass u mi n g t h e y  w er e 
m or e li k el y t o  h a v e  a s e v er e  ast h m a  e x a c er b ati o n  e v e nt t h a n  as i m pli e d  u n d er t h e  missi n g  at 
r a n d o m  ass u m pti o n.  T h e ti p pi n g  p oi nt  a n al ysis  will l o o k  at  b y  h o w  m u c h t h e  e v e nt r at e  w o ul d 
n e e d t o i n cr e as e  f or t h e r es ult t o  b e c o m e  n o nsi g nifi c a nt. T h e f ull  d et ails  of t h e  a n al ysis  will  b e 
s p e cifi e d i n t h e  S A P.  
8. 6. 6. 2   
Att ri b ut a bl e  esti m a n d  
A n al ysis  of t h e  attri b ut a bl e  esti m a n d  will  b e  c o n d u ct e d  usi n g  d at a  o bt ai n e d  b ef or e s u bj e cts 
dis c o nti n u e r a n d o mi z e d tr e at m e nt  a n d/ or  b ef or e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of 
ast h m a  c o ntr ol  a n d  will  u s e t h e  F A S.  H o w e v er, t h e  d at a t h at is  missi n g  d u e t o r a n d o mi z e d 
tr e at m e nt  dis c o nti n u ati o n  a n d/ or  a  c h a n g e i n  m ai nt e n a n c e t h er a p y  will  b e i m p ut e d  o n t h e  b asis 
of t h e  9 5t h  or  5t h  p er c e ntil e  of t h e  A S  M DI  pr n  distri b uti o n if t h e r e as o n is r e as o n a bl y 
attri b ut a bl e t o t ol er a bilit y  or l a c k  of  c o ntr ol.  T h e  9 5t h  p er c e ntil e  w o ul d  a p pl y t o  a n  e n d p oi nt f or 
w hi c h  a  hi g h er  v al u e is  a  w ors e  o ut c o m e  w hil e t h e  5t h  p er c e ntil e  w o ul d  a p pl y t o  a n  e n d p oi nt f or 
w hi c h  a  hi g h er  v al u e is  a  b ett er  o ut c o m e.  M or e  d et ail  a b o ut t h e  c o m p u t ati o n  of t h e  attri b ut a bl e 
esti m a n d  will  b e  pr o vi d e d i n t h e  S A P.  
8. 6. 6. 3   
Eff e cti v e n ess  esti m a n d  
A n al ysis  of t h e  eff e cti v e n ess  esti m a n d  will  b e  c o n d u ct e d i n t h e  F A S i n  w hi c h  all  o bs er v e d  d at a 
will  b e  utili z e d r e g ar dl ess  of  w h et h er s u bj e cts  e x p eri e n c e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or 
l a c k  of  ast h m a  c o ntr ol.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 6  of  1 5 9  
8. 6. 6. 4   
D e f a ct o  esti m a n d  
A n al ysis  of t h e  d e f a ct o  esti m a n d  will  b e  c o n d u ct e d  o n t h e  F A S i n  w hi c h  all  o bs er v e d  d at a  will 
b e  utili z e d, r e g ar dl ess  of  w h et h er s u bj e cts  e x p eri e n c e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y  or  ar e 
dis c o nti n u e d fr o m r a n d o mi z e d st u d y tr e at m e nt. 
8. 6. 6. 5   
C O VI D - 1 9  p a n d e mi c i m p a cts 
As t h e tri al is  o n- g oi n g  d uri n g  C O VI D- 1 9  p a n d e mi c, it  will  b e  n e c ess ar y t o  e v al u at e  a n y 
p ot e nti al i nt er c urr e nt  e v e nts  d u e t o  C O VI D- 1 9  a n d  q u a ntif y t h eir i m p a ct  o n t h e  effi c a c y  a n d 
s af et y  pr ofil e  of t h e st u d y I P. 
As  a  mi ni m u m, t h e  n u m b er  of  miss e d  visits,  pr e m at ur e  wit h dr a w als,  a n d  effi c a c y  ass ess m e nts 
n ot  c o n d u ct e d  will  b e s u m m ari z e d  d es cri pti v el y  b y tr e at m e nt  gr o u p  a n d  o v er all  a cr oss tr e at m e nt 
gr o u ps.  W h er e  a p pr o pri at e, t h e s u bj e ct l e v el  d at a f or  miss e d  visits  a n d  ass ess m e nts  will  b e list e d 
al o n g  wit h t h e  c orr es p o n di n g li n k t o  C O VI D- 1 9,  as r e c or d e d i n t h e  e C R F. It is  n ot  a nti ci p at e d 
t h at  missi n g  d at a  a n d  pr e m at ur e  wit h dr a w als  d u e t o  C O VI D- 1 9  will  b e r el at e d t o r a n d o mi z e d 
tr e at m e nt.  T h er ef or e,  missi n g  d at a  d u e t o  C O VI D- 1 9  will  b e  ass u m e d  missi n g  at r a n d o m i n 
a c c or d a n c e  wit h  t h e  effi c a c y  esti m a n d. If f urt h er s e nsiti vit y  a n al ys es  ar e  d e e m e d  n e c ess ar y 
f oll o wi n g  a  bli n d e d r e vi e w  of  missi n g  effi c a c y  d u e t o  C O VI D-1 9, f urt h er  d et ails  will  b e 
pr o vi d e d i n t h e  S A P,  pri or t o  d at a b as e l o c k  a n d  u n bli n di n g. 
Si mil arl y,  as  a  mi ni m u m, t h e  n u m b er  of s c h e d ul e d s af et y  ass ess m e nts  miss e d  d u e t o  C O VI D - 1 9 
will  b e s u m m ari z e d  d es cri pti v el y  b y tr e at m e nt  gr o u p  a n d  a cr oss tr e at m e nt  gr o u ps.  S u bj e cts  wit h 
s us p e ct e d  or  c o nfir m e d  di a g n osis  of  C O VI D- 1 9,  a n d/ or  C O VI D- 1 9 r el at e d  A Es  a n d  S A Es  will 
b e s u m m ari z e d   d es cri pti v el y.  S u bj e ct l e v el listi n gs  of  miss e d s c h e d ul e d s af et y  ass ess m e nts  a n d 
C O VI D -1 9 r el at e d ( S) A Es  will  b e list e d.  
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 7  of  1 5 9  
9   
S T U D Y  A N D  D A T A  M A N A G E M E N T   
9. 1   
T r ai ni n g  of st u d y sit e st aff  
B ef or e t h e first s u bj e ct is  e nt er e d i nt o t h e st u d y,  a  d esi g n at e d r e pr es e nt ati v e  will r e vi e w  a n d 
dis c uss t h e r e q uir e m e nts  of t h e  Cli ni c al  St u d y  Pr ot o c ol  a n d r el at e d  d o c u m e nts  wit h t h e 
i n v esti g ati o n al st aff  a n d  als o tr ai n t h e m i n  a n y st u d y s p e cifi c  pr o c e d ur es  a n d t h e  R a v e  W B D C 
s yst e m(s)  utili z e d. 
T h e i n v esti g at or  will  e ns ur e t h at  a p pr o pri at e tr ai ni n g r el e v a nt t o t h e st u d y is  gi v e n t o  all  of t h es e 
st aff,  a n d t h at  a n y  n e w i nf or m ati o n r el e v a nt t o t h e  p erf or m a n c e  of t his st u d y is f or w ar d e d t o t h e 
st aff i n v ol v e d. 
T h e i n v esti g at or  will  m ai nt ai n  a r e c or d  of  all i n di vi d u als i n v ol v e d i n t h e st u d y ( m e di c al, 
n ursi n g,  a n d  ot h er st aff). 
9. 2   
M o nit o ri n g  of t h e st u d y  
D uri n g t h e st u d y, t h e  S p o ns or  or  a  d esi g n at e d r e pr es e nt ati v e  will  h a v e r e g ul ar  c o nt a cts  wit h t h e 
st u d y sit e, i n cl u di n g  visits t o: 
•   Pr o vi d e i nf or m ati o n  a n d s u p p ort t o t h e i n v esti g at or(s) 
•   C o nfir m t h at f a ciliti es r e m ai n  a c c e pt a bl e  
•   C o nfir m t h at t h e i n v esti g ati o n al t e a m is  a d h eri n g t o t h e  Cli ni c al  St u d y  Pr ot o c ol, t h at  d at a 
ar e  b ei n g  a c c ur at el y  a n d ti m el y r e c or d e d i n t h e  e C R Fs, t h at  bi ol o gi c al s a m pl es  ar e  h a n dl e d 
i n  a c c or d a n c e  wit h t h e  L a b or at or y  M a nu al,  a n d t h at I P  a c c o u nt a bilit y  c h e c ks  ar e  b ei n g 
p erf or m e d  
•   P erf or m s o ur c e  d at a  v erifi c ati o n ( a  c o m p aris o n  of t h e  d at a i n t h e  e C R Fs  wit h t h e s u bj e ct’s 
m e di c al r e c or ds  at t h e  h os pit al  or  pr a cti c e,  a n d  ot h er r e c or ds r el e v a nt t o t h e st u d y) 
i n cl u di n g  v erifi c ati o n  of i nf or m e d  c o ns e nt/ ass e nt  of  p arti ci p ati n g s u bj e cts.  T his  will r e q uir e 
dir e ct  a c c ess t o  all  ori gi n al r e c or ds f or  e a c h s u bj e ct ( e g,  cli ni c  c h arts)  
•   E ns ur e  all  S A Es  a n d  A Es  h a v e  b e e n  c a pt ur e d  a n d r e p ort e d  c orr e ctl y,  pr o vi di n g  o v ersi g ht  of 
s u bj e ct s af et y  whil e  o n st u d y 
•   V erif y t h e  c orr e ct st or a g e,  h a n dli n g,  dis p e ns ati o n,  a n d r et ur n  of  all I P  
•   E ns ur e  wit h dr a w al  of i nf or m e d  c o ns e nt/ ass e nt t o t h e  us e  of t h e s u bj e ct’s  bi ol o gi c al s a m pl es 
is r e p ort e d  a n d  bi ol o gi c al s a m pl es  ar e i d e ntifi e d  a n d  dis p os e d  of/ d estr o y e d  a c c or di n gl y,  a n d 
t h e  a cti o n is  d o c u m e nt e d,  a n d r e p ort e d t o t h e s u bj e ct 
 
T h e  d esi g n at e d r e pr es e nt ati v e  will  b e  a v ail a bl e  b et w e e n  visits if t h e i n v esti g at or(s)  or  ot h er st aff 
at t h e  c e nt er  n e e ds i nf or m ati o n  a n d  a d vi c e  a b o ut t h e  c o n d u ct  of t h e st u d y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 8  of  1 5 9  
9. 2. 1   
S o u r c e  d at a  
S o ur c e  d o c u m e nts  pr o vi d e  e vi d e n c e f or t h e  e xist e n c e  of t h e s u bj e ct  a n d s u bst a nti at e t h e 
i nt e grit y  of t h e  d at a  c oll e ct e d.  S o ur c e  d o c u m e nts  ar e fil e d  at t h e i n v esti g at or’s sit e. 
D at a  e nt er e d i n t h e  e C R F t h at  ar e tr a ns cri b e d fr o m s o ur c e  d o c u m e nts  m ust  b e  c o nsist e nt  wit h 
t h e s o ur c e  d o c u m e nts  or t h e  dis cr e p a n ci es  m ust  b e  e x pl ai n e d.  T h e i n v esti g at or  m a y  n e e d t o 
r e q u est  pr e vi o us  m e di c al r e c or ds  or tr a nsf er r e c or ds.  Als o,  c urr e nt  m e di c al r e c or ds  m ust  b e 
a v ail a bl e.  
D efi niti o n  of  w h at  c o nstit ut es s o ur c e  d at a  c a n  b e f o u n d i n t h e  S o ur c e  D at a  A gr e e m e nt,  a gr e e d 
wit h  e a c h i n v esti g at or  b ef or e sit e i niti ati o n.  
9. 2. 2   
St u d y  a g r e e m e nts  
T h e i n v esti g at or/ p arti ci p ati n g  c e nt er s h o ul d  c o m pl y  wit h  all t h e t er ms,  c o n diti o ns,  a n d 
o bli g ati o ns  of t h e  Cli ni c al  St u d y  Pr ot o c ol,  or  e q ui v al e nt, f or t his st u d y.   
Cli ni c al  Tri al  A gr e e m e nts  wit h t h e i n v esti g at or/ p arti ci p ati n g  c e nt er s h o ul d  b e i n  pl a c e  b ef or e 
a n y st u d y- r el at e d  pr o c e d ur es  c a n t a k e  pl a c e,  or s u bj e cts  ar e  e nr oll e d. 
9. 2. 3   
A r c hi vi n g  of st u d y  d o c u m e nts 
T h e i n v esti g at or f oll o ws t h e  pri n c i pl es  o utli n e d i n t h e  Cli ni c al  Tri al  A gr e e m e nt. 
9. 3   
St u d y ti m et a bl e  a n d  e n d -of -st u d y 
All r a n d o mi z e d s u bj e cts  w h o  d o  n ot  pr e m at ur el y  dis c o nti n u e  will  h a v e  a  mi ni m u m  of  2 4  w e e ks 
of tr e at m e nt.  T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e ( e xt e nsi o n  p h as e)  u ntil t h e r e q uir e d  5 7 0 
first s e v er e  e x a c er b ati o n  e v e nts,  as  d efi n e d  p er  pr ot o c ol,  h a v e  b e e n r e a c h e d;  a n d t h e l ast s u bj e ct 
h as  c o m pl et e d  2 4  w e e ks  of tr e at m e nt.  T h e  E O S  visit  will  b e  pl a n n e d  o n c e t h e  5 7 0 first s e v er e 
e x a c er b ati o n  e v e nts  o c c ur. If  a s u bj e ct’s tr e at m e nt  is  ≥ 2 4 w e e ks t h e n t h e s u bj e ct’s  E O S  visit 
will  o c c ur  at t h eir  n e xt s c h e d ul e d  cli ni c  visit.  O n c e t h e  P C D  h as  b e e n r e a c h e d,  a n y  o n g oi n g 
s u bj e ct  ≥ 2 4 w e e ks  will r et ur n t o  c o m pl et e t h eir  E O S  visit  at t h eir  n e xt s c h e d ul e d  cli ni c  visit. 
T h e s af et y f oll o w- u p t el e p h o n e  c o nt a ct  will  o c c ur  2  w e e ks ( ± 4  d a ys)  aft er  E O S  or  P D V, if 
a p pli c a bl e.  T h e  e n d  of t h e st u d y is  d efi n e d  as  “t h e l ast  visit  of t h e l ast s u bj e ct  u n d er g oi n g t h e 
st u d y ”. 
T h e st u d y  m a y  b e t er mi n at e d  at i n di vi d u al  c e nt ers if t h e st u d y  pr o c e d ur es  ar e  n ot  b ei n g 
p erf or m e d  a c c or di n g t o  G o o d  Cli ni c al  Pr a cti c e ( G C P),  or if r e cr uit m e nt is sl o w.  T h e  S p o ns or 
m a y  als o t er mi n at e t h e  e ntir e st u d y  pr e m at ur el y if  c o n c er ns f or s af et y  aris e  wit hi n t his st u d y  or 
i n  a n y  ot h er st u d y  wit h  B D A  M DI. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
8 9  of  1 5 9  
9. 4   
D at a  m a n a g e m e nt   
D at a  m a n a g e m e nt  will  b e  p erf or m e d  b y t h e  D at a  M a n a g e m e nt  T e a m  at 
 
a c c or di n g t o t h e  D at a  M a n a g e m e nt  Pl a n .  
T h e  d at a  c oll e ct e d t hr o u g h t hir d  p art y s o ur c es  will  b e  o bt ai n e d  a n d r e c o n cil e d  a g ai nst st u d y 
d at a.  D at a fr o m t hir d  p arti es  will  b e tr a nsf err e d i n  a c c or d a n c e  wit h  d at a tr a nsf er s p e cifi c ati o ns 
a n d r e c o n cil e d i n  a c c or d a n c e  wit h t h e  D at a  M a n a g e m e nt  Pl a n.  
A d v ers e  e v e nts  a n d  m e di c al/s ur gi c al  hist or y  will  b e  cl assifi e d  a c c or di n g t o t h e t er mi n ol o g y  of 
t h e l at est  v ersi o n  of t h e  M e di c al  Di cti o n ar y f or  R e g ul at or y  Acti viti es  at t h e ti m e  of  d at a b as e 
l o c k.  M e di c ati o ns  will  b e  cl assifi e d  a c c or di n g t o t h e  W orl d  H e alt h  Or g a ni z ati o n  Dr u g 
Di cti o n ar y.  All  c o di n g  will  b e  p erf or m e d  b y t h e  M e di c al  C o di n g  T e a m  at 
 
D at a  q u eri es  will  b e r ais e d f or i n c o nsist e nt, i m p ossi bl e,  or  missi n g  d at a.  All  e ntri es t o t h e st u d y 
d at a b as e  will  b e  a v ail a bl e i n  a n  a u dit tr ail.  
T h e  d at a  will  b e  v ali d at e d  as  d efi n e d i n t h e  D at a  M a n a g e m e nt  Pl a n.  Q u alit y  c o ntr ol  pr o c e d ur es 
will  b e  a p pli e d t o  e a c h st a g e  of  d at a  h a n dli n g t o  e ns ur e t h at  all  d at a  ar e r eli a bl e  a n d  h a v e  b e e n 
pr o c ess e d  c orr e ctl y.  T h e  D at a  M a n a g e m e nt  Pl a n  will  als o  cl arif y t h e r ol es  a n d r es p o nsi biliti es 
of t h e  v ari o us f u n cti o ns  a n d  p ers o n n el i n v ol v e d i n t h e  d at a  m a n a g e m e nt  pr o c ess. 
S e ri o us  a d v e rs e  e v e nt  r e c o n cili ati o n  
S eri o us  A E r e c o n cili ati o n r e p orts  ar e  pr o d u c e d  a n d r e c o n cil e d  wit h t h e  a p pli c a bl e   
 
  S af et y  a n d  P h ar m a c o vi gil a n c e  D e p art m e nt s af et y  d at a b as e  a n d/ or t h e i n v esti g ati o n al 
sit e.  
M a n a g e m e nt  of  e xt e r n al  d at a 
  D at a  M a n a g e m e nt  will s et  u p i m p ort a gr e e m e nts  wit h t hir d  p art y  d at a s o ur c es, t o 
e ns ur e  e xt er n al  d at a is i nt e gr at e d i n li n e  wit h  a p pli c a bl e  d at a st a n d ar ds.  
P ri m a r y  o ut c o m e  d at a b as e l o c k 
W h e n  all r e q uir e d  5 7 0 first s e v er e  e x a c er b ati o n  e v e nts  h a v e  o c c urr e d  a n d t h e l ast  a d ult s u bj e ct 
h as  c o m pl et e d  2 4  w e e ks  of tr e at m e nt  a n d s af et y f oll o w- u p, t h e  d at a  cl e a ni n g s h o ul d  b e 
c o m pl et e d f or t h e  pri m ar y  o ut c o m e  d at a b as e l o c k.  D at a b as e l o c k  will  o c c ur  o n c e  all  d at a  h a v e 
b e e n  c o d e d,  v ali d at e d, si g n e d,  a n d l o c k e d,  a n d  cl e a n fil e  h as  b e e n  d e cl ar e d.  D at a  will  b e 
u n bli n d e d  at t h e  pri m ar y  o ut c o m e  d at a b as e l o c k. 
Fi n al  d at a b as e l o c k  
T h e st u d y tr e at m e nt  p eri o d  will  c o nti n u e f or  c hil dr e n ( 4 t o  1 1  y e ars)  a n d  a d ol es c e nts ( 1 2 t o 
1 7  y e ars)  w h o  h a v e  n ot  c o m pl et e d  2 4  w e e ks  of tr e at m e nt  b y t h e ti m e  of t h e  pri m ar y  o ut c o m e 
d at a b as e l o c k.  T h e s af et y f oll o w- u p t el e p h o n e  c o nt a ct  will  o c c ur  2  w e e ks ( ± 4   d a ys) aft er  E O S 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 0  of  1 5 9  
or  P D V, if  a p pli c a bl e.  D at a b as e l o c k  will  o c c ur  o n c e  all  d at a  h a v e  b e e n  c o d e d,  v ali d at e d, 
si g n e d,  a n d l o c k e d,  a n d  cl e a n fil e  h as  b e e n  d e cl ar e d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 1  of  1 5 9  
1 0   
E T HI C A L  A N D  R E G U L A T O R Y  R E Q UI R E M E N T S  
1 0. 1   
Et hi c al  c o n d u ct  of t h e st u d y  
T h e st u d y  will  b e  p erf or m e d i n  a c c or d a n c e  wit h  et hi c al  pri n ci pl es t h at  h a v e t h eir  ori gi n i n t h e 
D e cl ar ati o n  of  H elsi n ki  a n d  ar e  c o nsist e nt  wit h I C H/ G C P  a n d  a p pli c a bl e r e g ul at or y 
r e q uir e m e nts. 
1 0. 2   
S u bj e ct  d at a  p r ot e ct i o n 
T h e i nf or m e d  c o ns e nt/ ass e nt f or m  will i n c or p or at e ( or, i n s o m e  c as es,  b e  a c c o m p a ni e d  b y  a 
s e p ar at e  d o c u m e nt i n c or p or ati n g)  w or di n g t h at  c o m pli es  wit h r el e v a nt  d at a  pr ot e cti o n  a n d 
pri v a c y l e gisl ati o n. 
S u bj e cts  will  b e  assi g n e d  a  u ni q u e i d e ntifi er  b y t h e  S p o ns or.  A n y s u bj e ct r e c or ds  or  d at as ets 
t h at  ar e tr a nsf err e d t o t h e  S p o ns or  will  c o nt ai n t h e i d e ntifi er  o nl y; s u bj e ct  n a m es  or  a n y 
i nf or m ati o n  w hi c h  w o ul d  m a k e t h e s u bj e ct i d e ntifi a bl e  will  n ot  b e tr a nsf err e d.  S u bj e cts  m ust  b e 
i nf or m e d t h at  his/ h er  p ers o n al st u d y-r el at e d  d at a  will  b e  us e d  b y t h e  S p o ns or i n  a c c or d a n c e  wit h 
l o c al  d at a  pr ot e cti o n l a w.  T h e l e v el  of  dis cl os ur e  m ust  als o  b e  e x pl ai n e d t o t h e s u bj e ct.  S u bj e cts 
m ust  als o  b e i nf or m e d t h at  his/ h er  m e di c al r e c or ds  m a y  b e  e x a mi n e d  b y st u d y  m o nit ors,  c li ni c al 
q u alit y  ass ur a n c e  a u dit ors,  or  ot h er  a ut h ori z e d  p ers o n n el  a p p oi nt e d  b y t h e  S p o ns or,  b y 
a p pr o pri at e  E C  m e m b ers,  a n d  b y i ns p e ct ors fr o m r e g ul at or y  a ut h oriti es. 
1 0. 3   
Et hi cs  a n d  r e g ul at o r y  r e vi e w  
A n  E C s h o ul d  a p pr o v e t h e fi n al  Cli ni c al  St u d y  Pr ot o c ol, i n cl u di n g t h e fi n al  v ersi o n  of t h e 
i nf or m e d  c o ns e nt/ ass e nt f or m  a n d  a n y  ot h er  writt e n i nf or m ati o n  a n d/ or  m at eri als t o  b e  pr o vi d e d 
t o t h e s u bj e cts.  T h e i n v esti g at or  will  e ns ur e t h e  distri b uti o n  of t h es e  d o c u m e nts t o t h e  a p pli c a bl e 
E C  a n d t o t h e st u d y sit e st aff. 
T h e  o pi ni o n  of t h e  E C s h o ul d  b e  gi v e n i n  writi n g.  T h e i n v esti g at or s h o ul d s u b mit t h e  writt e n 
a p pr o v al t o t h e  S p o ns or  or  d esi g n at e d r e pr es e nt ati v e  b ef or e  e nr oll m e nt  of  a n y s u bj e ct i nt o t h e 
st u d y.  
T h e  E C s h o ul d  a p pr o v e  all  a d v ertisi n g  us e d t o r e cr uit s u bj e cts f or t h e st u d y. 
T h e  S p o ns or  or  d esi g n at e d r e pr es e nt ati v e s h o ul d  a p pr o v e  a n y  m o difi c ati o ns t o t h e i nf or m e d 
c o ns e nt/ ass e nt f or m t h at  ar e  n e e d e d t o  m e et l o c al r e q uir e m e nts.  
If r e q uir e d  b y l o c al r e g ul ati o ns, t h e  Cli ni c al  St u d y  Pr ot o c ol s h o ul d  b e r e- a p pr o v e d  b y t h e  E C 
a n n u all y. 
B ef or e  e nr oll m e nt  of  a n y s u bj e ct i nt o t h e st u d y, t h e fi n al  Cli ni c al  St u d y  Pr ot o c ol, i n cl u di n g t h e 
fi n al  v ersi o n  of t h e i nf or m e d  c o ns e nt/ ass e nt f or m, is  a p pr o v e d  b y t h e  n ati o n al r e g ul at or y 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 2  of  1 5 9  
a ut h orit y  or  a  n otifi c ati o n t o t h e  n ati o n al r e g ul at or y  a ut h orit y is  d o n e,  a c c or di n g t o l o c al 
r e g ul ati o ns. 
T h e  S p o ns or  or  d esi g n at e d r e pr es e nt ati v e  h a n dl es t h e  distri b uti o n  of  a n y  of t h es e  d o c u m e nts t o 
t h e  n ati o n al r e g ul at or y  a ut h oriti es. 
T h e  S p o ns or  or  d esi g n at e d r e pr es e nt ati v e  will  pr o vi d e r e g ul at or y  a ut h oriti es,  E Cs,  a n d 
i n v esti g at ors  wit h s af et y  u p d at es/r e p orts  a c c or di n g t o l o c al r e q uir e m e nts. 
1 0. 4   
I nf o r m e d  c o ns e nt/ ass e nt  
T h e i n v esti g at or(s)  at  e a c h  c e nt er  will:  
•   E ns ur e  e a c h s u bj e ct  a n d/ or  p ar e nt/l e g al r e pr es e nt ati v e ( as  a p pli c a bl e) is  gi v e n f ull  a n d 
a d e q u at e  or al  a n d  writt e n i nf or m ati o n  a b o ut t h e  n at ur e,  p ur p os e,  p ossi bl e ris ks,  a n d  b e n efit 
of t h e st u d y 
•   E ns ur e  e a c h s u bj e ct  a n d/ or  p ar e nt/l e g al r e pr es e nt ati v e is  n ot ifi e d t h at t h e y  ar e fr e e t o 
dis c o nti n u e fr o m t h e st u d y  at  a n y ti m e 
•   E ns ur e t h at  e a c h s u bj e ct  a n d/ or  p ar e nt/l e g al r e pr es e nt ati v e is  gi v e n t h e  o p p ort u nit y t o  as k 
q u esti o ns  a n d  all o w e d ti m e t o  c o nsi d er t h e i nf or m ati o n  pr o vi d e d 
•   E ns ur e  e a c h s u bj e ct  a n d/ or  p ar e nt/l e g al r e pr es e nt ati v e  pr o vi d es si g n e d  a n d  d at e d i nf or m e d 
c o ns e nt/ ass e nt  b ef or e  c o n d u cti n g  a n y  pr o c e d ur e s p e cifi c all y f or t h e st u d y 
•   E ns ur e t h e  ori gi n al, si g n e d i nf or m e d  c o ns e nt/ ass e nt f or m(s) is/ ar e st or e d i n t h e 
i n v esti g at or’s st u d y fil e 
•   E ns ur e  a  c o p y  of t h e si g n e d i nf or m e d  c o ns e nt/ ass e nt f or m is  gi v e n t o t h e s u bj e ct 
•   E ns ur e t h at  a n y i n c e nti v es f or s u bj e cts  w h o  p arti ci p at e i n t h e st u d y  as  w ell  as  a n y 
pr o visi o ns f or s u bj e cts  h ar m e d  as  a  c o ns e q u e n c e  of st u d y  p arti ci p ati o n  ar e  d es cri b e d i n t h e 
i nf or m e d  c o ns e nt/ ass e nt f or m t h at is  a p pr o v e d  b y  a n  E C 
 
1 0. 5   
C h a n g es t o t h e  cli ni c al st u d y  p r ot o c ol  a n d i nf o r m e d  c o ns e nt/ ass e nt 
f o r m 
St u d y  pr o c e d ur es  will  n ot  b e  c h a n g e d  wit h o ut t h e  m ut u al  a gr e e m e nt  of t h e i nt er n ati o n al 
c o or di n ati n g i n v esti g at or  a n d t h e  S p o ns or. 
If t h er e  ar e  a ny s u bst a nti al  c h a n g es t o t h e  Cli ni c al  St u d y  Pr ot o c ol, t h e n t h es e  c h a n g es  will  b e 
d o c u m e nt e d i n  a  n e w  v ersi o n  of t h e st u d y  pr ot o c ol. 
T h e  n e w  v ersi o n  of t h e  Cli ni c al  St u d y  Pr ot o c ol is t o  b e  a p pr o v e d  b y t h e r el e v a nt  E C  a n d if 
a p pli c a bl e,  als o t h e  n ati o n al r e g ul at or y  a ut h orit y,  b ef or e i m pl e m e nt ati o n.  L o c al r e q uir e m e nts 
ar e t o  b e f oll o w e d f or  n e w  v ersi o ns  of  Cli ni c al  St u d y  Pr ot o c ols. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 3  of  1 5 9  
T h e  S p o ns or  will  distri b ut e  a n y  n e w  v ersi o ns  of t h e  Cli ni c al  St u d y  Pr ot o c ol t o  e a c h 
i n v esti g at or(s) f or  distri b uti o n to  E C s e e  S e cti o n  1 0. 3 . 
If  a  c h a n g e t o  a  Cli ni c al  St u d y  Pr ot o c ol r e q uir es  a  c h a n g e t o  a  c e nt er’s i nf or m e d  c o ns e nt/ ass e nt 
f or m, t h e  S p o ns or  a n d t h e  c e nt er’s  E C  ar e t o  a p pr o v e ( or  a  n otifi c ati o n t o t h e  n ati o n al r e g ul at or y 
a ut h orit y is s u b mitt e d  w h er e  a p pli c a bl e f or) t h e r e vis e d i nf or m e d  c o ns e nt/ ass e nt f or m  b ef or e t h e 
r e vis e d f or m is  us e d.  
1 0. 6   
A u dits  a n d i ns p e cti o ns  
A ut h ori z e d r e pr es e nt ati v es  of t h e  S p o ns or,  a r e g ul at or y  a ut h orit y,  or  a n  E C  m a y  p erf or m  a u dits 
or i ns p e cti o ns  at t h e  c e nt er, i n cl u di n g s o ur c e  d at a  v erifi c ati o n.  T h e  p ur p os e  of  a n  a u dit  or 
i ns p e cti o n is t o s yst e m ati c all y  a n d i n d e p e n d e ntl y  e x a mi n e  all st u d y-r el at e d  a cti viti es  a n d 
d o c u m e nts t o  d et er mi n e  w h et h er t h es e  a cti viti es  w er e  c o n d u ct e d,  d at a  w er e r e c or d e d,  a n al y z e d, 
a n d  a c c ur at el y r e p ort e d  a c c or di n g t o t h e  Cli ni c al  St u d y  Pr ot o c ol,  G C P,  g ui d eli n es  of t h e I C H, 
a n d  a n y  a p pli c a bl e r e g ul at or y r e q uir e m e nts.  T h e i n v esti g at or  will  c o nt a ct t h e  S p o ns or 
i m m e di at el y if  c o nt a ct e d  b y  a r e g ul at or y  a g e n c y  a b o ut  a n i ns p e cti o n  at t h e  c e nt er. 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 4  of  1 5 9  
1 1   
LI S T  O F  R E F E R E N C E S  
1.     A m eri c a n  A c a d e m y  of  All er g y  Ast h m a  a n d I m m u n ol o g y ( A A A AI).  C O VI D- 1 9  a n d 
Ast h m a:  W h at  P ati e nts  N e e d t o  K n o w.  0 4 J u n  2 0 2 0.  A c c ess e d  1 9 J u n  2 0 2 0. 
htt ps:// w w w. a a a ai. or g/ c o n diti o ns- a n d -tr e at m e nts/li br ar y/ ast h m a-li br ar y/ c o vi d-ast h m a  
2.   C o o p er  P R,  P a n etti eri  R A.  St er oi ds  c o m pl et el y r e v ers e  al b ut er ol -i n d u c e d  β 2-a dr e n er gi c 
r e c e pt or t ol er a n c e i n  h u m a n s m all  air w a ys. J  All er g y  Cli n I m m u n ol  2 0 0 8; 1 2 2( 4): 7 3 4- 7 4 0. 
3.   H o c h b er g  Y.  A s h ar p er  B o nf err o ni  pr o c e d ur e f or  m ulti pl e t ests  of si g nifi c a n c e.  Bi o m etri k a 
1 9 8 8; 7 5( 4): 8 0 0 - 8 0 2.  
4.   Gl o b al I niti ati v e f or  Ast h m a.  Gl o b al str at e g y f or  ast h m a  m a n a g e m e nt  a n d  pr e v e nti o n.  2 0 1 8. 
A v ail a bl e fr o m:    htt ps:// gi n ast h m a. or g/ w p- c o nt e nt/ u pl o a ds/ 2 0 1 8/ 0 4/ w ms-GI N A - 2 0 1 8-
r e p ort-V 1. 3 - 0 0 2. p df. 
5.   I n v esti g at or  Br o c h ur e  E diti o n 2. 0.  B u d es o ni d e/ Al b ut er ol  S ulf at e  Pr ess uri z e d I n h al ati o n 
S us p e nsi o n ( B D A  M DI,  P T 0 2 7);  B u d es o ni d e  Pr ess uri z e d I n h al ati o n  S us p e nsi o n ( B D  M DI, 
P T 0 0 8);  Al b ut er ol  S ulf at e  Pr ess uri z e d I n h al ati o n  S us p e nsi o n ( A S  M DI,  P T 0 0 7) , 
2 0  S e pt e m b er  2 0 1 9. 
6.   J u ni p er  E F,  S v e nss o n  K,  M ör k  A C,  St å hl  E.  M e as ur e m e nt  pr o p erti es  a n d i nt er pr et ati o n  of 
t hr e e s h ort e n e d  v ersi o ns  of t h e  ast h m a  c o ntr ol  q u esti o n n air e.  R es pir  M e d  2 0 0 5; 9 9( 5): 5 5 3-
5 5 8. 
7.   J u ni p er  E F,  G u y att G H,  Will a n  A,  Griffit h  L E.  D et er mi ni n g  a  mi ni m al i m p ort a nt  c h a n g e i n 
a  dis e as e -s p e cifi c  q u alit y  of lif e  q u esti o n n air e. J  Cli n  E pi d e mi ol  1 9 9 4; 4 7: 8 1 - 8 7. 
8.   M e n d es  E S,  H or v at h  G,  C a m p os  M,  W a n n er  A.  R a pi d  c orti c ost er oi d  eff e ct  o n  β( 2) -
a dr e n er gi c  air w a y  a n d  air w a y  v as c ul ar r e a cti vit y i n  p ati e nts  wit h  mil d  ast h m a. J  All er g y 
Cli n I m m u n ol  2 0 0 8; 1 2 1( 3): 7 0 0 - 7 0 4. 
9.   M e n d es  E S,  C a d et  L,  Ar a n a J,  W a n n er  A.  A c ut e  eff e ct  of  a n i n h al e d  gl u c o c orti c ost er oi d  o n 
al b ut er ol-i n d u c e d  br o n c h o dil ati o n i n  p ati e nts  wit h  m o d er at el y s e v er e  ast h m a.  C h est 
2 0 1 5; 1 4 7( 4): 1 0 3 7 - 1 0 4 2.  
1 0.  O’ B yr n e  P M,  Bis g a ar d  H,  G o d ar d  P P,  Pist ol esi  M,  P al m q vist  M,  Z h u  Y,  et  al. 
B u d es o ni d e/f or m ot er ol  c o m bi n ati o n t h er a p y  as  b ot h  m ai nt e n a n c e  a n d r eli e v er  m e di c ati o n 
i n  ast h m a.  A m J  R es pir  Crit  C ar e  M e d  2 0 0 5; 1 7 1( 2): 1 2 9- 1 3 6. 
1 1.  O’ B yr n e  P M.  A c ut e  ast h m a i nt er v e nti o n: i nsi g hts fr o m t h e  S T A Y st u d y. J  All er g y  Cli n 
I m m u n ol  2 0 0 7; 1 1 9( 6): 1 3 3 2- 1 3 3 6. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 5  of  1 5 9  
1 2.  R a b e  K F,  Ati e n z a  T,  M a g y ar  P,  L arss o n  P, J or u p  C,  L all o o  U G.  Eff e ct  of  b u d es o ni d e i n 
c o m bi n ati o n  wit h f or m ot er ol f or r eli e v er t h er a p y i n  ast h m a  e x a c er b ati o ns:  a r a n d o mi z e d 
c o ntr oll e d,  d o u bl e- bli n d st u d y.  L a n c et  2 0 0 6; 3 6 8( 9 5 3 7): 7 4 4 - 7 5 3. 
1 3.  S c h at z  M,  K osi ns ki  M,  Y arl as  A S,  H a nl o n J,  W ats o n  M E, J hi n gr a n  P.  T h e  mi ni m all y 
i m p ort a nt  diﬀ er e n c e  of t h e  ast h m a  c o ntr ol t est. J  All er g y  Cli n I m m u n ol  2 0 0 9; 1 2 4: 7 1 9 –-
7 2 3. 
1 4.  T att ersfi el d  A E,  P ost m a  D S,  B ar n es  PJ,  S v e nss o n  K,  B a u er  C A,  O’ B yr n e  P M,  et  al. 
E x a c er b ati o ns  of  ast h m a:   a  d es cri pti v e st u d y  of  4 2 5 s e v er e  e x a c er b ati o ns.  T h e  F A C E T 
I nt er n ati o n al  St u d y  Gr o u p.  A m J  R es pir  Crit  C ar e  M e d  1 9 9 9; 1 6 0( 2): 5 9 4- 5 9 9. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 6  of  1 5 9  
1 2   
S U M M A R Y  O F  C H A N G E S   
1 2. 1   
C h a n g es  m a d e t o  V e rsi o n  3. 0  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  3. 0,  2 1  J ul y  2 0 2 0 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  4. 0, 
0 8 A p ril  2 0 2 1 
C o v er  p a g e/ V ersi o n  Hist or y   
D at e  a n d  v ersi o n  c h a n g e d;  u p d at e d s p o ns or  a d dr ess; 
bri ef  s u m m ar y  of  a m e n d m e nt  a d d e d. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis   U p d at e d t h e  esti m at e d  d at e  of l ast s u bj e ct  c o m pl et e d 
fr o m  Q 3  2 0 2 1 t o  Q 1  2 0 2 2. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis  
3. 3  S u bj e ct  e nr oll m e nt  a n d 
r a n d o mi z ati o n; 
8. 2  S a m pl e si z e  esti m at e  
Cl arifi c ati o n t h at  u p t o  1 0 0 s u bj e cts i n t h e  4 t o  1 1 -y e ar 
a g e  gr o u p  wit h  m o d er at e t o s e v er e  ast h m a  will  b e 
r a n d o mi z e d. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis  
1. 2  R ati o n al e f or st u d y  d esi g n, 
d os es,  a n d  c o ntr ol  gr o u ps, 
1. 4  St u d y  d esi g n;   
T a bl e  1, f o ot n ot e  c;  
4. 2  R a n d o mi z ati o n/tr e at m e nt 
p eri o d/ e xt e nsi o n  p h as e 
Cl arifi c ati o n t h at t h e tr e at m e nt  p eri o d  will  c o nti n u e 
u ntil  t h e l ast  a d ult s u bj e ct  h as  c o m pl et e d  2 4  w e e ks  of 
tr e at m e nt. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis    Cl arifi c ati o n t h at  p e di atri c s u bj e cts  will  c o nti n u e  u ntil 
2 4  w e e ks  of tr e at m e nt  h a v e  b e e n r e a c h e d f or  e a c h 
p e di atri c  p ati e nt,  d efi n e d  as t h e fi n al  c o m pl eti o n  d at e . 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis ; 
8. 5. 1  Pri m ar y  effi c a c y  a n al ys is 
 Cl arifi c ati o n t h at  th e  pri m ar y  effi c a c y  a n al ysis  will 
i n cl u d e  all  d at a  u p t o t h e  P C D. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis ; 
8. 5. 2  S e c o n d ar y  effi c a c y  a n al ys es  
Cl arifi c ati o n t h at  th e  s e c o n dar y  effi c a c y  a n al ysis  will 
i n cl u d e  all  d at a  u p t o t h e  P C D. 
1. 2  R ati o n al e f or st u d y  d esi g n; 
d os es,  a n d  c o ntr ol  gr o u ps;  
1. 4  St u d y  d esi g n 
Cl arifi c ati o n t h at  n ot  all  p e di atri c s u bj e cts  will  h a v e 
2 4  w e e ks  of tr e at m e nt  at ti m e  of  P C D.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 7  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  3. 0,  2 1  J ul y  2 0 2 0 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  4. 0, 
0 8 A p ril  2 0 2 1 
3. 1  I n cl usi o n  crit eri a # 6   
Cl arifi c ati o n  t h at s u bj e cts  a g e d  ≥ 1 2  y e ars  of  a g e  m ust 
d e m o nstr at e r e v ers i bilit y  at  Visit  1. 
A d d e d t h e f oll o wi n g s e nt e n c e:  S u bj e cts  a g e d  4 t o 
1 1  y e ars  of  a g e  will  p erf or m t h e r e v ersi b ilit y t est,  b ut 
d o  n ot r e q uir e  d e m o nstr ati o n  of r e v ersi bilit y  d uri n g 
Visit  1  a n d  m a y  e nr oll,  pr o vi d e d  d o c u m e nt e d  hist ori c al 
r e v ersi bilit y  wit hi n  1  y e ar is  a v ail a bl e.   S u bj e cts  a g e d 
4 t o  1 1  y e ars  w h o  pr e vi o usl y f ail e d i n cl usi o n  crit eri o n  6 
will  b e  p er mitt e d t o r es cr e e n.  E a c h s u bj e ct  m a y 
r e-s cr e e n  o nl y  o n c e. 
3. 1  I n cl usi o n  crit eri a  #1 7, 
s u b b ull et ii 
A d d e d  a d diti o n al f or ms  of  birt h  c o ntr ol:  a  c o n d o m  wit h 
s p er mi ci d e, i ntr aut eri n e  d e vi c e (I U D) ,  or i ntr a ut eri n e 
h or m o n e- r el e asi n g s yst e m (I U S). 
4 . 1 S cr e e ni n g  a n d r u n -i n  p eri o d  
U p d at e d t h at s u bj e cts  a g e d  4 t o  1 1  y e ars  of  a g e  w h o 
pr e vi o usl y f ail e d i n cl usi o n  crit eri o n  6  will  b e  p er mitt e d 
t o r es cr e e n. 
4. 2  R a n d o mi z ati o n/tr e at m e nt 
p eri o d/ e xt e nsi o n  p h as e 
A d d e d t h at  c hil dr e n  a n d  a d ol es c e nts  o n g oi n g i n 
tr e at m e nt  aft er t h e  P C D  will  c o nti n u e i n f oll o w- u p  u ntil 
t h e y  h a v e  c o m pl et e d  2 4  w e e ks  of tr e at m e nt. 
5. 2. 1  L a b or at or y s af et y 
ass ess m e nts   
A d d e d s er u m  c ortis ol  ass ess m e nts  al o n g  wit h t h os e f or 
c h e mistr y  a n d  h e m at ol o g y. 
N e w s e cti o n:  8. 1. 2  Pri m ar y 
o ut c o m e  a n al ysis(s u bs e q u e nt 
h e a di n g  n u m b eri n g  u p d at e d) 
Pri m ar y  o ut c o m e  d at a b as e l o c k ( p D B L)  will  c o m m e n c e 
o n c e  all r a n d o mi z e d  a d ults ( ≥ 1 8  y e ars)  h a v e  att e n d e d 
t h eir  E O S  visit at t h e  P C D .  T h e  a n al ys es  of  pri m ar y, 
s e c o n d ar y,  e x pl or at or y , a n d s af et y  o bj e cti v es  will 
i n cl u d e  all  d at a  u p t o t h e  p D B L,  w hi c h  m a y i n cl u d e 
d at a f or  c hil dr e n ( 4 t o  1 1  y e ars)  w h o  ar e still  o n- g oi n g 
i n t h e tri al  a n d  h a v e  n ot  y et  c o m pl et e d t h e  2 4-w e e k 
tr e at m e nt  p eri o d.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 8  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  3. 0,  2 1  J ul y  2 0 2 0 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  4. 0, 
0 8 A p ril  2 0 2 1 
A fi n al  d at a  b as e l o c k  will  o c c ur  aft er t h e  p D B L,  o n c e 
all  c hil dr e n  h a v e  c o m pl et e d t h e  E O S  visit  a n d s af et y 
f oll o w- u p. 
P ati e nt l e v el listi n gs  of  d at a f or  c hil dr e n  w h o  w er e  o n-
g oi n g  at t h e  p D B L  will  b e r e p ort e d  at t h e fi n al  d at a b as e 
l o c k.  N o  effi c a c y  a n al ys es  will  b e c o n d u ct e d  o n  d at a 
c oll e ct e d f oll o wi n g t h e  p D B L.  
8. 3. 1  F ull  a n al ysis s et  
Cl arifi c ati o n t h at  effi c a c y  a n d  attri b ut a bl e  esti m a n d  will 
i n cl u d e  all  d at a  o bt ai n e d  u p t o  p D B L.  
8. 5. 3  E x pl or at or y  a n al ys es   
Cl arifi c ati o n t h at t h e  e x pl or at or y  a n al ys es  will i n cl u d e 
all  d at a  o bt ai n e d  u p t o  p D B L.   
8. 5. 3. 5  T ot al i n h al e d 
c orti c ost er oi d  e x p os ur e;  
8. 6. 4. 7  T ot al i n h al e d 
c orti c ost er oi d  e x p os ur e 
H e a di n gs r e vis e d:  
8. 5. 3. 5 I n h al e d  c orti c ost er oi d  e x p os ur e 
8. 6. 4. 7 I n h al e d  c orti c ost er oi d  e x p os ur e 
T e xt r e vis e d t o  d es cri b e  c at e g ori es f or  m ai nt e n a n c e 
t h er a p y i n  a d diti o n t o  m et h o ds  us e d t o  c al c ul at e  a n d 
a n al y z e i n h al e d  c orti c ost er oi d  e x p os ur e.  
8. 6. 6  Pri m ar y  o ut c o m e  a n al ysis   
S e cti o n r e m o v e d;  s u bs e q u e nt  h e a di n g  n u m b eri n g 
u p d at e d 
9. 3  St u d y ti m et a bl e  a n d  e n d -of -
st u d y 
U p d at e d t h at  a ll r a n d o mi z e d s u bj e cts  w h o  d o  n ot 
pr e m at ur el y  dis c o nti n u e  will  h a v e  a  mi ni m u m  of 
2 4  w e e ks  of tr e at m e nt.    
D el et e d t e xt  d efi ni n g  P C D. 
O n c e t h e  P C D  h as  b e e n r e a c h e d,  a n y  o n g oi n g s u bj e ct 
≥ 2 4  w e e ks  will r et ur n t o  c o m pl et e t h eir  E O S  visit  at 
t h eir  n e xt s c h e d ul e d  cli ni c  visit 
9. 4  D at a  m a n a g e m e nt  
R e vis e d t o  cl arif y t h at  w h e n  t h e l ast  a d ult s u bj e ct  h as 
c o m pl et e d  2 4  w e e ks  of tr e at m e nt  a n d s af et y f oll o w- u p, 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
9 9  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  3. 0,  2 1  J ul y  2 0 2 0 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  4. 0, 
0 8 A p ril  2 0 2 1 
t h e  d at a  cl e a ni n g s h o ul d  b e  c o m pl et e d f or t h e  pri m ar y 
o ut c o m e  d at a b as e l o c k.  
Fi n al  d at a b as e l o c k r e vis e d t o  cl arif y t h at  st u d y 
tr e at m e nt  p eri o d  will  c o nti n u e f or  c hil dr e n ( 4 t o 
1 1  y e ars)  a n d  a d ol es c e nts ( 1 2 t o  1 7  y e ars)  w h o  h a v e  n ot 
c o m pl et e d  2 4  w e e ks  of tr e at m e nt  b y t h e ti m e  of t h e 
pri m ar y  o ut c o m e  d at a b as e l o c k .   
T hr o u g h o ut  d o c u m e nt  
A d diti o n al  n o ns u bst a nti al  c h a n g es f or  a d mi nistr ati v e, 
t y p o gr a p hi c al,  a n d/ or  gr a m m ati c al  c orr e cti o ns  w er e 
m a d e.   
 
1 2. 2   
C h a n g es  m a d e t o  V e rsi o n  2 . 0 
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
V ersi o n  Hist or y  
D at e  a n d  v ersi o n  c h a n g e d;  bri ef s u m m ar y  of 
a m e n d m e nt  a d d e d. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis   U p d at e d t h e  esti m at e d  d at e  of l ast s u bj e ct  c o m pl et e d 
fr o m  Q 3  2 0 2 0 t o  Q 3  2 0 2 1. 
1. 3  B e n efit/ris k  a n d  et hi c al 
ass ess m e nt  
A d d e d j ustifi c ati o n t o  c o nti n u e st u d y  e nr oll m e nt  a n d 
tr e at m e nt  d uri n g t h e  C O VI D- 1 9  p a n d e mi c. 
1. 5. 2  A dj u di c ati o n  c o m mitt e e   
Cl arifi c ati o n t h at t h e  c o m mitt e e  will  a dj u di c at e  “ aft er 
m e di c al  m o nit ori n g r e vi e w. ” 
2. 2  S e c o n d ar y  O bj e cti v e  a n d 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis 
U p d at e d  a s e c o n d ar y  e n d p oi nt t o t ot al  “s yst e mi c ” 
c orti c ost er oi d  e x p os ur e  o v er t h e tr e at m e nt  p eri o d. 
2. 4  E x pl or at or y  O bj e cti v e 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis 
A d diti o n  of  2  a d diti o n al  e x pl or at or y  e n d p oi nts:   
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 0  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
•   A C Q -5  c h a n g e fr o m  b as eli n e  a n d r es p o n d er 
( 3-f a ct or)  a n al ysis  at  W e e k  1 2  a n d  W e e k  2 4  
•   I n h al e d  c orti c ost er oi d  e x p os ur e  o v er t h e tr e at m e nt 
p eri o d 
3. 1 I n cl usi o n  crit eri a (it e m  2)  a n d 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis  
R e m o v e d t h e i n cl usi o n  of  c hil dr e n  ≥ 6  y e ars  of  a g e i n 
It al y. 
R e m o v e d t h e  i n cl usi o n  of  a d ol es c e nt s u bj e cts  ≥ 1 2  y e ars 
of  a g e i n  S p ai n. 
3. 1 I n cl usi o n  crit eri a (it e m  4)   
Cl arifi c ati o n t h at s u bj e cts  o n I C S  al o n e  or i n 
c o m bi n ati o n  wit h  L A B A  ar e  all o w e d t o  h a v e  a d diti o n al 
m ai nt e n a n c e  m e di c ati o n; s p e cifi e d l e u k otri e n e 
“r e c e pt or  a nt a g o nists ”  ar e  all o w e d.  
3. 1 I n cl usi o n  crit eri a (it e m  5)    
U p d at e d t o r efl e ct  pr e di ct e d  n or m al  F E V 1 v al u es  of 
≥ 4 0  t o  < 9 0 % f or  a d ults  a n d  ≥ 6 0 % f or s u bj e cts  a g e d  4 t o 
1 7. 
S p e cifi e d t h at  s u bj e cts  4 t o  1 7  y e ars  of  a g e  w h o 
pr e vi o usl y f ail e d t his i n cl usi o n  crit eri a  d u e t o t h e 
pr e vi o us  u p p er  F E V 1 li mit  ar e  p er mitt e d t o r e-s cr e e n 
o n c e.  
3. 1 I n cl usi o n  crit eri a (it e m  7)   
Cl arifi c ati o n t h at s u bj e cts  a g e d  4 t o  1 1  will  b e  eli gi bl e 
if t h e y  pr o vi d e  2  a c c e pt a bl e/r e p e at a bl e  m e as ur e m e nts 
f or s pir o m etr y. 
3. 1 I n cl usi o n  crit eri a (it e m  1 7)   
R e m o v al  of t h e r ef er e n c e t o  ≥ 5 0  y e ars  of  a g e  as  p art  of 
t h e  d efi niti o n  of  m e n o p a us al  w o m e n. 
3. 2  E x cl usi o n  crit eri a (it e m  2 5)   
S p e cifi c ati o n t h at s u bj e cts  ar e  e x cl u d e d if t h e y  h a d 
b e e n  pr e vi o usl y  “r a n d o mi z e d ” i n t his st u d y  or  a n ot h er 
P T 0 0 7  or  P T 0 2 7 st u d y.   
3. 3  S u bj e ct  e nr oll m e nt  a n d 
r a n d o mi z ati o n  a n d  Cli ni c al  St u d y 
Pr ot o c ol  S y n o psis 
U p d at e d t h e  n u m b er  of s u bj e cts s cr e e n e d fr o m  4 3 0 0 t o 
6 0 0 0. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 1  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
3. 5  M et h o ds f or  assi g ni n g 
tr e at m e nt  gr o u ps,  7. 2  D os e  a n d 
tr e at m e nt r e gi m e ns,  a n d  Cli ni c al 
St u d y  Pr ot o c ol  S y n o psis  
R e m o v e d r ef er e n c e t o s cr e e ni n g  Visit  1 a.   A d d e d 
cl arifi c ati o n t h at r a n d o mi z ati o n str atifi c ati o n  will 
i n cl u d e t h e  n u m b er  of  pri or s e v er e  e x a c er b ati o ns ( 1, 
> 1) i n t h e  1 2  m o nt hs  pri or t o s cr e e ni n g ( Visit  1)  “ pl us 
a n y s e v er e  e x a c er b ati o n  e v e n t  e x p eri e n c e d  d uri n g t h e 
s cr e e ni n g  p eri o d. ” 
3. 1 1  S cr e e n f ail ur es  
M o difi c ati o n t o  all o w f or r es cr e e ni n g  o n c e i n  c hil dr e n 
a n d  a d ol es c e nts  w h o f ail e d  b e c a us e t h e y  di d  n ot  m e et 
t h e  n o w  o bs ol et e  u p p er  F E V1 %  pr e di ct e d li mit.    
4  St u d y  pl a n  a n d ti mi n g  of 
pr o c e d ur es ( T a bl e  1) 
F o ot n ot e f  a n d  a p pli c a bl e  “ X ” i n di c at ors  w er e r e m o v e d 
d u e t o  c o u ntr y s p e cifi c  c h a n g es.  S u bs e q u e nt f o ot n ot e 
m ar k er l ett ers  w er e  u p d at e d.  
F o ot n ot e  h ( pr e vi o usl y f o ot n ot e i)  w as  u p d at e d t o 
r e m o v e It al y  a n d  a d d  Ar g e nti n a  as r e q uiri n g  a d diti o n al 
pr e g n a n c y t esti n g.  
F o ot n ot e  m ( pr e vi o usl y f o ot n ot e  n)  u p d at e d t o r efl e ct 
pr e di ct e d  n or m al  F E V 1 v al u es  of  ≥ 4 0 t o  < 9 0 % f or 
a d ults  a n d  ≥ 6 0 % f or s u bj e cts  a g e d  4 t o  1 7.  
4. 1  S cr e e ni n g  a n d r u n -i n  p eri o d, 
4. 2  R a n d o mi z ati o n/ tr e at m e nt 
p eri o d/ e xt e nsi o n  p h as e,  a n d 
5. 3. 1  P h ysi c al  e x a mi n ati o n  
It al y-s p e cifi c i nf or m ati o n r e g ar di n g f ull  e x a mi n ati o ns 
a n d  pr e g n a n c y t esti n g  w as r e m o v e d. 
5. 1. 8. 2  C O VI D -1 9  a n d 
P ul m o n ar y  F u n cti o n  T esti n g 
A d diti o n t o s p e cif y t h at s pir o m etr y s h o ul d  n ot  b e  d o n e 
if s u bj e cts  ar e s h o wi n g si g ns  a n d s y m pt o ms  of 
C O VI D - 1 9  a n d t o i n di c at e t h at  p arti ci p a nts  wit h 
s us p e ct e d  C O VI D - 1 9 s h o ul d r e c ei v e  a t est t o  c o nfir m 
di a g n osis.  Pr o p er  cl e a ni n g  a n d  h y gi e n e  g ui d a n c e is t o 
b e f oll o w e d. 
5. 2. 1  L a b or at or y s af et y 
ass ess m e nts ( T a bl e  2)  
R e m o v e d It al y  a n d  a d d e d  “ Ar g e nti n a ” t o f o ot n ot e  a 
( pr e g n a n c y t esti n g r e q uir e m e nts).  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 2  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
5. 3. 2  C o n c o mit a nt  m e di c ati o ns   
U p d at e d t o i n di c at e t h at  pr e vi o us  m e di c ati o ns s h o ul d 
b e r e c or d e d if t h e y  w er e t a k e n  wit hi n  3  m o nt hs  b ef or e 
s cr e e ni n g.  A d d e d t h at  ast h m a  m e di c at i o n  hist or y  will 
b e r e c or d e d f or  1 2  m o nt hs  b ef or e s cr e e ni n g. 
6. 3. 9  C O VI D -1 9  A d v ers e  E v e nts   A d d e d t o  pr o vi d e i nstr u cti o ns  o n  h o w t o  m a n a g e  A Es 
a n d  S A Es r el at e d t o t h e  C O VI D - 1 9  p a n d e mi c. 
7. 8. 1  M ai nt e n a n c e t h er a pi es   
A d diti o n t o  all o w  s u bj e cts r e c ei vi n g  m ai nt e n a n c e 
all er g y i m m u n ot h er a p y ( AI T) t o  c o nti n u e t h eir  AI T. 
S p e cifi e d t h at t h e i niti ati o n  of  AI T  d uri n g t h e st u d y is 
n ot  all o w e d. 
7. 8. 3  Pr o hi bit e d  m e di c ati o ns  
Cl arifi c ati o n t h at  p ol y cl o n al  a nti b o d y t h er a p y is 
pr o hi bit e d  b ut t h e  us e  of i ntr a- o c ul ar  m o n o cl o n al  or 
p ol y cl o n al  a nti b o d y t h er a p y is  all o w e d.  
Cl arifi c ati o n t h at t h e  us e  of s p e cifi c  c ar di o -s el e cti v e 
b et a - bl o c k ers i n l o w  d ail y  d os es,  e g,  m et o pr ol ol i n 
d os es  u p t o  1 0 0  m g/ d,  ar e  all o w e d. 
8. 1. 2  T y p e  1  err or  c o ntr ol  a n d 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis 
A d d e d i nf or m ati o n  a b o ut  hi er ar c hi c al t esti n g 
pr o c e d ur es t o  c o ntr ol t h e t y p e- 1  err or i n s e c o n d ar y 
e n d p oi nt  a n al ys es.  D et ails r e g ar di n g t esti n g  pr o c e d ur es, 
t h e  or d er  of t esti n g f or s e c o n d ar y  e n d p oi nts,  a n d  w h e n 
st atisti c al si g nifi c a n c e  c a n  b e  cl ai m e d,  ar e  pr o vi d e d.  
8. 3. 1  F ull  a n al ysis s et  
Cl arifi c ati o n t h at t h e  eff e cti v e n ess  esti m a n d  will  utili z e 
all  o bs er v e d  d at a  u p t o r a n d o mi z e d tr e at m e nt 
dis c o nti n u ati o n, r e g ar dl ess  of  w h et h er s u bj e cts 
e x p eri e n c e  a  c h a n g e i n  m ai nt e n a n c e t h er a p y f or l a c k  of 
as t h m a  c o ntr ol.  A d d e d t h at t h e  d e f a ct o  esti m a n d  will 
utili z e  all  o bs er v e d  d at a, i n cl u di n g  p ost- I P 
dis c o nti n u ati o n  d at a, r e g ar dl ess  of  a  c h a n g e i n 
m ai nt e n a n c e t h er a p y.  
8. 5. 2. 1  D eri v ati o n  of  a n n u ali z e d 
s e v er e  ast h m a  e x a c er b ati o n r at e  
U p d at e d t h e  c al c ul ati o ns  of f oll o w -u p  a n d I P 
dis c o nti n u ati o n/ c h a n g e i n  m ai nt e n a n c e t h er a p y  t o 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 3  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
e x cl u d e t h e  c u m ul ati v e  d ur ati o n  of s e v er e 
e x a c er b ati o n(s).  
8. 5. 2. 2  D eri v ati o n  of t ot al 
s yst e mi c  c orti c ost er oi d  e x p os ur e, 
8. 6. 2. 4  T ot al s yst e mi c 
c orti c ost er oi d  e x p os ur e,  a n d 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis 
U p d at e d  h e a di n gs  wit h  “s yst e mi c ”  a n d r e pl a c e d 
pr e vi o us t e xt r e g ar di n g i n h al e d  c orti c ost er oi d  e x p os ur e. 
S p e cifi e d  m et h o ds t o  c al c ul at e  a n d  a n al y z e t ot al  S C S 
e x p os ur e.  
8. 5. 2. 3  D eri v ati o n  of  Ast h m a 
C o ntr ol  Q u esti o n n air e- 5  v ari a bl es  
D efi niti o n  a d d e d f or  3 -l e v el f a ct or  c at e g ori z ati o n 
(I m pr o v e m e nt,  N o  C h a n g e,  a n d  W ors e ni n g) f or 
c h a n g es fr o m  b as eli n e i n t h e  A C Q- 5  o v er all s c or es  at 
W e e ks  1 2  a n d  2 4.  
8. 5. 3. 5  T ot al i n h al e d 
c orti c ost er oi d  e x p os ur e  a n d 
8. 6. 4. 7  T ot al i n h al e d 
c orti c ost er oi d  e x p os ur e 
A d diti o n  of s e cti o ns t o s p e cif y  m et h o ds  us e d t o 
c al c ul at e  a n d  a n al y z e t ot al i n h al e d  c orti c ost er oi d 
e x p os ur e.  
8. 6  M et h o ds f or st atisti c al 
a n al ys es  
R e m o v e d r ef er e n c e t o  “ 2 ”  pri m ar y  c o m p aris o ns  a n d 
r e pl a c e d  wit h  pri m ar y  “ e n d p oi nt tr e at m e nt ” 
c o m p aris o ns. 
8. 6. 1  A n al ysis  of t h e  pri m ar y 
v ari a bl e  
S p e cifi c ati o n t h at  a n al ys es  w o ul d t ar g et t h e  effi c a c y 
esti m a n d i n t h e  F A S  p o p ul ati o n. 
A d d e d st at e m e nt t h at  all s u bj e cts  w h o  ar e r a n d o mi z e d 
a n d  ar e  p art  of t h e f ull  a n al ysis s et  will  b e  a n al y z e d 
a c c or di n g t o t h e s tr at a t h e y  w er e  all o c at e d t o i n 
I V R S/I W R S.  A s e nsiti vit y  a n al ysis  will  b e  c o n d u ct e d 
b as e d  o n s u bj e cts’  a ct u al str at a t o  ass ess t h e i m p a ct  of 
miss -str atifi c ati o n  o n t h e  m o d el r es ults.  
8. 6. 1  A n al ysis  of t h e  pri m ar y 
v ari a bl e,  8. 6. 2. 2  Ast h m a  C o ntr ol 
Q u esti o n n air e - 5,  8. 6. 4. 2 
Pr e br o n c h o dil at or  F E V 1,  a n d 
8. 6. 4. 3  M or ni n g  p e a k  e x pir at or y 
S p e cifi e d t h at t h e  m o d els f or  a n al ys es  of  v ari a bl es 
w o ul d  b e  a dj ust e d f or t h e  n u m b er  of  pri or s e v er e 
e x a c er b ati o ns ( 1,  > 1) i n t h e  1 2  m o nt hs  pri or t o 
s cr e e ni n g ( Visit  1)  “ pl us  a n y s e v er e  e x a c er b ati o n  e v e nt 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 4  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
fl o w,  a n d  Cli ni c al  St u d y  Pr ot o c ol 
S y n o psis 
e x p eri e n c e d  d uri n g t h e s cr e e ni n g  p eri o d ”,  a n d r e m o v e d 
r ef er e n c es t o  Visit  1 a. 
8. 6. 2  A n al ysis  of t h e s e c o n d ar y 
effi c a c y  v ari a bl es  
S p e cifi e d t h at  a n al ys es  w o ul d  b e  c o n d u ct e d  o n t h e  F A S 
p o p u l ati o n. 
R ef er e n c e d  S e cti o n  8. 1. 2 f or  hi er ar c hi c al t esti n g 
str at e g y f or s e c o n d ar y  e n d p oi nts. 
8. 6. 2. 1  S e v er e  ast h m a 
e x a c er b ati o n r at e  
S p e cifi c ati o n t h at  a n al ys es  w o ul d t ar g et t h e  effi c a c y 
esti m a n d i n t h e  F A S  p o p ul ati o n. 
T h e  n u m b er  of  pri or s e v er e  e x a c er b ati o ns i n t h e 
1 2  m o nt hs  pri or t o  “r a n d o mi z ati o n ”  w as  u p d at e d  as  a 
k e y  c o v ari at e  of i nt er est.  
8. 6. 2. 2  Ast h m a  C o ntr ol 
Q u esti o n n air e- 5  
A d diti o n  of i nf or m ati o n f or  a n al ysis  of t h e  3 -f a ct or 
c at e g ori z ati o n  of  A C Q- 5  usi n g  or di n al l o gisti c al 
r e gr essi o n. 
S p e cifi c ati o n t h at t h e  a n al ysis  of  c h a n g e fr o m  b as eli n e 
i n  A C Q-5  at  W e e k  2 4  will t ar g et t h e  effi c a c y  esti m a n d 
i n t h e  F A S  p o p ul ati o n.  
8. 6. 2. 2  Ast h m a  C o ntr ol 
Q u esti o n n air e- 5  a n d  8. 6. 2. 3 
Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e  + 1 2  a n d  P e di atri c 
Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e 
U p d at e d  m et h o ds  of  a n al ysis fr o m  M M R M t o r e p e at e d 
m e as ur es  a n al ys es.  
8. 6. 4. 3  M or ni n g  p e a k  e x pir at or y 
fl o w 
A d diti o n  of  a r e p e at e d  m e as ur es  a n al ysis  of  4 -w e e kl y 
ti m e i nt er v als. 
8. 6. 6  Pri m ar y  o ut c o m e  a n al ysis   
R e m o v e d  “ a n d fi n al  a n al ysi s ” fr o m  h e a di n g.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 5  of  1 5 9  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  2. 0,  2 9  J ul y  2 0 1 9 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  3. 0, 
2 1  J ul y  2 0 2 0 
Cl arifi c ati o n  of t h e f oll o wi n g:  w h e n s u bj e cts  will r et ur n 
f or t h eir  E O S  visits,  w h e n  d at a  cl e a ni n g s h o ul d  b e 
d o n e,  a n d  w h e n t h e  pri m ar y (fi n al)  a n al ysis  will  o c c ur.  
8. 6. 7. 5  C O VI D -1 9  p a n d e mi c 
i m p a cts 
A d diti o n t o  d es cri b e st atisti c al  m et h o ds t h at  will  b e 
us e d t o  e v al u at e t h e i m p a ct  of t h e  C O VI D- 1 9  p a n d e mi c 
o n  effi c a c y  a n d s af et y  v ari a bl es.  
1 1  List  of  R ef er e n c es  
A d diti o n  of r ef er e n c e t o t h e  A m eri c a n  A c a d e m y  of 
All er g y  Ast h m a  a n d I m m u n ol o g y f or i nf or m ati o n 
r e g ar di n g  C O VI D- 1 9  a n d  Ast h m a. 
F or  I n v esti g at or  Br o c h ur e r ef er e n c e,  u p d at e d  e diti o n 
a n d  d at e.  
A p p e n di x  N,  C O VI D -1 9 
e m er g e n c y  m e as ur es  p er mitt e d t o 
e ns ur e s u bj e ct s af et y  
A d diti o n  of  pr o c ess es t o  e ns ur e s u bj e ct s af et y  d uri n g 
t h e  C O VI D- 1 9  p a n d e mi c. I nstr u cti o ns f or  m a n a g e m e nt 
of s u bj e cts  wit h  or s us p e ct e d  C O VI D- 1 9 i nf e cti o n, 
d el a y e d  visits, r e m ot e  visits, s u bj e ct  dis c o nti n u ati o n, 
s hi p m e nt  of I P t o s u bj e cts, l a b or at or y t esti n g,  a n d 
s pir o m etr y t esti n g  ar e  pr o vi d e d. 
T hr o u g h o ut  d o c u m e nt  
U p d at e d st u d y  dr u g t o  “I P ” f or  c o nsist e n c y.   
A d diti o n al  n o ns u bst a nti al  c h a n g es f or  a d mi nistr ati v e, 
t y p o gr a p hi c al,  a n d/ or  gr a m m ati c al  c orr e cti o ns  w er e 
m a d e.   
 
1 2. 3   
C h a n g es  m a d e t o  V e rsi o n  1. 0  
S e cti o n  
C h a n g es  m a d e t o  V e rsi o n  1. 0,  1 1  O ct  2 0 1 8 t o 
d e v el o p  gl o b al  a m e n d m e nt,  V e rsi o n  2. 0,  2 9  J ul y 
2 0 1 9 
V ersi o n  Hist or y  
D at e  a n d  v ersi o n  c h a n g e d,  bri ef s u m m ar y  of 
a m e n d m e nt  a d d e d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 6  of  1 5 9  
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis,  
1. 4  St u d y  d esi g n,  3. 3  S u bj e ct 
e nr oll m e nt  a n d r a n d o mi z ati o n,  4 
St u d y  pl a n  a n d ti mi n g  of 
pr o c e d ur es (f o ot n ot e  b i n  T a bl e 
1),  4. 1  S cr e e ni n g  a n d r u n-i n 
p eri o d 
U p d at e d t h e  n u m b er  of st u d y sit es/ c e nt ers fr o m  3 3 3 t o 
3 8 0  a n d  a n  esti m at e d s cr e e n f ail ur e r at e t o  a r a n g e  of 
3 0 % t o  5 0 %. 
Cl arifi c ati o n  o n t h e ti m efr a m e ( Visit  1  a n d  Visit  1 a) 
a n d  p ossi bl e  e xt e nsi o n  of t h e s cr e e ni n g  p eri o d  d u e t o 
a d mi nistr ati v e r e as o ns  or  a s e v er e  ast h m a  e x a c er b ati o n 
e v e nt (t o  a  m a xi m u m  of  9  w e e ks). 
Cl arifi c ati o n  o n t h e  us e  of  p ati e nts’  us u al  as -n e e d e d 
( pr n) i n h al e d  pr o d u cts  a n d  S p o ns or- pr o vi d e d  V e nt oli n 
( pr n  or  pri or t o  e x er cis e)  d uri n g s cr e e ni n g. 
A d diti o n  of t h e  d e f a ct o  esti m a n d  as  a tr e at m e nt  p oli c y 
str at e g y  d efi n e d i n t h e  dr aft I nt er n ati o n al  C o nf er e n c e 
o n  H ar m o ni z ati o n (I C H)  E 9  a d d e n d u m. 
1 I ntr o d u cti o n   
St at e m e nt  cl arif yi n g t h at  al b ut er ol is  als o  k n o w n  u n d er 
t h e  g e n eri c  n a m e  of s al b ut a m ol (t h e i nt er n ati o n al  n o n-
pr o pri et ar y  n a m e).  
1. 2  R ati o n al e f or st u d y  d esi g n, 
d os es,  a n d  c o ntr ol  gr o u ps 
Pr o vi d e d j ustifi c ati o n  of t h e  pr o p os e d  d os es f or 
al b ut er ol  a n d  b u d es o ni d e  b as e d  o n t h e  a p pr o v e d l a b el 
f or  Pr o v e ntil  a n d t h e  d os e-r a n gi n g  St u d y  P T 0 0 8 0 0 1, 
r es p e cti v el y. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis, 
1. 4  St u d y  d esi g n,  5. 1. 1. 6. 2 
S y m pt o m  R e p orti n g,  6. 5 
O v er d os e,  a n d  7. 2  D os e  a n d 
tr e at m e nt r e gi m e ns 
Cl arifi c ati o n  of t h e  m a xi m u m  d ail y  d osi n g 
r e c o m m e n d ati o n f or s u bj e cts  a n d  n otifi c ati o n/ e Di ar y 
al ert t o  m e di c al  m o nit ors  a n d i n v esti g at ors  of  a n y 
i n cr e as e d I P  d os a g e i n  or d er t o  cl os el y  m o nit or 
tr e at m e nt  us e  wit h  p ot e nti al  w ors e ni n g  ast h m a st at us. 
1. 5. 2  A dj u di c ati o n  c o m mitt e e   
Cl arifi c ati o n  o n  a dj u di c ati o n  c o m mitt e e  e v e nts -
r e c or di n g  a n d  c as e  d efi niti o n  of  “ w ors e ni n g  of  ast h m a ” 
w hi c h  w o ul d  n e c essit at e  a dj u di c ati o n  c o m mitt e e 
r e vi e w. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis 
a n d  3. 1 I n cl usi o n  crit eri a (it e m  2) 
S p e cif yi n g t h e i n cl usi o n  of s u bj e cts  4  y e ars  of  a g e i n  all 
c o u ntri es  wit h t h e  e x c e pti o n  of It al y,  S er bi a,  S p ai n, 
G er m a n y,  Sl o v a ki a,  a n d  U kr ai n e. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 7  of  1 5 9  
S p e cif yi n g t h e i n cl usi o n  of  c hil dr e n  ≥ 6  y e ars  of  a g e 
o nl y i n It al y. 
S p e cif yi n g t h e i n cl usi o n  of  a d ol es c e nt s u bj e cts  ≥ 1 2 
y e ars  o f  a g e  o nl y i n  S er bi a  a n d  S p ai n.  
S p e cif yi n g t h e i n cl usi o n  of  a d ult s u bj e cts  ≥ 1 8  y e ars  of 
a g e  o nl y i n  G er m a n y,  Sl o v a ki a,  a n d  U kr ai n e.  
3. 1 I n cl usi o n  crit eri a (it e m  4)   
A d diti o n al  cl arifi c ati o n t h at  u p t o  2 0 %  of  all 
r a n d o mi z e d  p ati e nts  will  b e p er mitt e d t o  h a v e  a n 
a d diti o n al  m ai nt e n a n c e  m e di c ati o n (t h e o p h ylli n e, 
l e u k otri e n e,  or  L A M A, i n  a d diti o n t o  eit h er I C S  al o n e 
or I C S/ L A B A fi x e d  d os e  c o m bi n ati o n). 
3. 1 I n cl usi o n  crit eri a (it e m  5)   
Cl arifi c ati o n t h at if  F E V 1 v al u es  ar e  n ot  wit hi n t h e 
p er mitt e d  r a n g e  at  Visit  1,  1 r e-t est is r e q uir e d  at  Visit 
1 a  b ef or e  a d v a n ci n g t o  Visit  2  or  b ei n g  c o nsi d er e d  as  a 
s cr e e n f ail ur e.  
3. 1 I n cl usi o n  crit eri a (it e m  6)   
Cl arifi c ati o n t h at if r e v ersi bilit y is  n ot  d e m o nstr at e d  at 
Visit  1,  1 r e- t est f or r e v ersi bilit y t estin g is r e q uir e d  at 
Visit  1 a  b ef or e  a d v a n ci n g t o  Visit  2  or  b ei n g  c o nsi d er e d 
as  a s cr e e n f ail ur e  
3. 1 I n cl usi o n  crit eri a (it e m  1 2)   
A d diti o n al s p e cifi c ati o n t h at t h e  us e  of s p a c ers  ar e 
pr o hi bit e d. 
3. 1 I n cl usi o n  crit eri a (it e ms  1 7 
a n d  1 8) 
A d diti o n  of  d efi niti o n  of  c o m pl et e  a bsti n e n c e ( a n d t h at 
is  a n  a c c e pt a bl e   m et h o d  of  c o ntr a c e pti o n  o nl y if it is 
c o nsist e nt  wit h t h e  pr ef err e d  a n d  us u al lif est yl e  of t h e 
s u bj e ct);  d efi niti o n  of  d o u bl e -b arri er  birt h  c o ntr ol; 
cl arifi c ati o n  o n s ur gi c al st erilit y  b y  v as e ct o m y (f or  
m al es);  d efi niti o n  of  p ost m e n o p a us al st at us;  a d diti o n  of 
bil at er al s al pi n g e ct o m y t o t h e  d efi niti o n  of s ur gi c al 
st erilit y;  a n d  cl arifi c ati o n t h at  c o ntr a c e pti v e  m et h o ds 
m a y  o nl y  b e r e c o m m e n d e d f or  a d ol es c e nts  w h o  ar e 
alr e a d y s e x u all y  a cti v e,  a n d t h at t h e  us e  of  h or m o n al 
c o ntr a c e pti v es  m ust  al w a ys  b e i n  c o ns ult ati o n  wit h  a 
g y n e c ol o gist (f or f e m al es). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 8  of  1 5 9  
3. 2  E x cl usi o n  crit eri a (it e m  1)    
A d diti o n al s p e cifi c ati o n r e g ar di n g r e g ul ar  or  o c c asi o n al 
us e  of  o x y g e n. 
3. 2.  E x cl usi o n  crit eri a (it e m  4)   
A d diti o n  of  d u pil u m a b  as  a n  e x a m pl e  of  pr o hi bit e d 
m e di c ati o n.  
3. 2  E x cl usi o n  crit eri a (it e m  2 1)   
A d diti o n al s p e cifi c ati o n t h at  c urr e ntl y  pr e g n a nt f e m al es 
will  als o  b e  e x cl u d e d fr o m st u d y  p arti ci p ati o n. 
3. 2.  E x cl usi o n  crit eri a ( n e w it e m 
2 6) 
A d diti o n  of  n e w  e x cl usi o n  crit eri o n  # 2 6: s u bj e cts  w h o 
e x p eri e n c e  > 1  ast h m a  e x a c er b ati o n  d uri n g t h e 
s cr e e ni n g  p eri o d. 
3. 7  M et h o ds f or  u n bli n di n g   
Cl arifi c ati o n t h at  u n bli n di n g s h o ul d  b e  b as e d  o n t h e 
i n v esti g at or’s  cli ni c al j u d g m e nt ( w h e n t h e  a p pr o pri at e 
m a n a g e m e nt  a n d  w elf ar e  of t h e  s u bj e ct r e q uir es 
k n o wl e d g e  of t h e tr e at m e nt  all o c ati o n)  a n d t h at it is  n ot 
r e q uir e d, f or t h e i n v esti g at or t o i nf or m t h e  S p o ns or  or 
S p o ns or’s  d esi g n e e  b ef or e  u n bli n di n g. 
3. 8  R estri cti o ns  
A d diti o n  of  d u pil u m a b  as  a n  e x a m pl e  of  pr o hi bit e d 
m e di c ati o ns  a n d  ot h er i n v esti g ati o n al tr e at m e nts ( ot h er 
t h a n t h e st u d y  dr u gs). 
3. 9  Tr e at m e nt  dis c o nti n u ati o n  b y 
s u bj e ct  a n d/ or  S p o ns or,  6. 3. 8 
H y’s  L a w,  a n d  A p p e n di x  E  H y’s 
L a w  
Cl arifi c ati o n t h at i n  c as e  of  el e v at e d li v er  e n z y m es  A S T 
a n d/ or  A L T  ≥ 3 × U L N  a n d t ot al  bilir u bi n  ≥ 2 × U L N, t h e 
us e  of t h e I P  will  b e s us p e n d e d  u ntil t h e li v er t est 
v al u es r et ur n t o t h e  n or m al r a n g e,  a n d t h at if t h e li v er 
e n z y m e  v al u es  b e c o m e  el e v at e d  a g ai n  aft er t h e 
r e c o m m e n c e m e nt  of t h e I P, t h e s u bj e ct  will  b e 
dis c o nti n u e d fr o m I P  a n d  wit h dr a w n fr o m t h e st u d y. 
3. 9  Tr e at m e nt  dis c o nti n u ati o n  b y 
s u bj e ct  a n d/ or  S p o ns or,  4  St u d y 
pl a n  a n d ti mi n g  of  pr o c e d ur es 
(f o ot n ot e  e i n  T a bl e  1),  4. 6 
F oll o w- u p 
A d diti o n al  cl arifi c ati o n  o n  P D V  pr o c e d ur es (i n cl u di n g 
p ot e nti al f oll o w - u p  T C) f or s u bj e cts  w h o  dis c o nti n u e 
tr e at m ent  pri or t o  E O S f or  a n y r e as o n;  a n d if t h e  P D V 
is  p erf or m e d  at l e ast  1 4  d a ys  aft er t h e l ast st u d y  dr u g 
d os e. 
4  St u d y  pl a n  a n d ti mi n g  of 
pr o c e d ur es (f o ot n ot e f  a n d i i n 
T a bl e  1),  4. 1  S cr e e ni n g  a n d r u n-
i n  p eri o d,  4. 2  S cr e e ni n g  a n d 
A d diti o n al  ass ess m e nts  a p pli c a bl e t o It al y  O N L Y;  i n 
It al y,  a f ull  p h ysi c al  e x a mi n ati o n  will  b e  p erf or m e d  at 
all  visits  wit h  a d diti o n al  pr e g n a n c y t esti n g t o  b e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 0 9  of  1 5 9  
e nr oll m e nt  p eri o d,  5. 2. 1 
L a b or at or y s af et y  ass ess m e nts 
( T a bl e  2  n ot es),  5. 3. 1  P h ysi c al 
e x a mi n ati o n  
c o n d u ct e d  at  m o nt hl y ti m e  p oi nts i n  w o m e n  of 
c hil d b e ari n g  p ot e nti al. 
1. 3  B e n efit/ris k  a n d  et hi c al 
ass ess m e nt,  4  St u d y  pl a n  a n d 
ti mi n g  of  pr o c e d ur es (f o ot n ot e  g 
i n  T a bl e  1),  4. 1  S cr e e ni n g  a n d 
e nr oll m e nt  p eri o d,  4. 2 
R a n d o mi z ati o n/tr e at m e nt 
p eri o d/ e xt e nsi o n  p h as e,  4. 3  E n d-
of-st u d y  visit,  4. 4  U ns c h e d ul e d 
visit  a n d  pr e m at ur e 
dis c o nti n u ati o n  visit,  5. 2  S af et y 
ass ess m e nts,  5. 2. 1  L a b or at or y 
s af et y  ass ess m e nts ( T a bl e  2), 
5. 3. 1  P h ysi c al  e x a mi n ati o n  a n d 
8. 6. 3. 3  Cli ni c al  c h e mistr y  a n d 
h e m at ol o g y 
A d diti o n  of  h ei g ht  ass ess m e nts f or  all s u bj e ct s  at  V 1 
a n d  a d diti o n al  h ei g ht  ass ess m e nts f or s u bj e cts  ≤ 1 8 
y e ars  of  a g e.  A d diti o n al  m or ni n g s er u m  c ortis ol 
ass ess m e nts f or  all s u bj e cts  at s p e cifi e d  visits 
( S cr e e ni n g,  W e e k  2 4,  E O S  a n d  P D V).  Cl arifi c ati o n t h at 
ass ess m e nts  of  h ei g ht  will  c o nti n u e i n  a c c or d a n c e  wit h 
a s u bj e ct’s  a g e  at t h e ti m e  of si g n e d i nf or m e d 
c o ns e nt/ ass e nt.  
4  St u d y  pl a n  a n d ti mi n g  of 
pr o c e d ur es (f o ot n ot e i i n  T a bl e  1) 
a n d  5. 2. 1  L a b or at or y s af et y 
ass ess m e nts ( T a bl e  2)  
A d diti o n  of  uri n e  pr e g n a n c y  ass ess m e nts t o s af et y 
m e as ur e m e nts f or  all  w o m e n  of  c hil d b e ari n g  p ot e nti al 
t hr o u g h o ut t h e  d ur ati o n  of t h e st u d y ( u nl ess  ot h er wis e 
s p e cifi e d).  
4  St u d y  pl a n  a n d ti mi n g  of 
pr o c e d ur es 
Cl arifi c ati o n  o n ti m e  p oi nts f or  dis p e nsi n g  a n d 
c oll e cti o n  of  e Di ar y. 
4  St u d y  pl a n  a n d ti mi n g  of  
pr o c e d ur es 
A d diti o n  of  dis p e nsi n g  V e nt oli n  at  V 1.  
5. 1. 1  Ast h m a  e x a c er b ati o n 
d efi niti o n  
Cl arifi c ati o n  of  d et eri or ati o n  of l u n g f u n cti o n  wit h 
e x a m pl es f or  cl arit y  a n d  c o nsist e n c y. 
5. 1. 1. 5  O ns et  a n d  d ur ati o n  of 
ast h m a  e x a c er b ati o ns  
Disti n cti o n  o n r e p orti n g  s e v er e  ast h m a  e x a c er b ati o ns  as 
s e p ar at e  or si n g ul ar  e v e nts,  b as e d  o n s u c c essi v e  S C S 
us e  wit hi n  7  d a ys ( or  m or e). 
5. 1. 1. 6. 1  S e v er e  ast h m a 
e x a c er b ati o n  e C R F  
Cl arifi c ati o n  o n t h e  a p pr o pri at e r e p orti n g  of s e v er e 
ast h m a  e x a c er b ati o ns  d uri n g t h e s cr e e ni n g  p eri o d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 0  of  1 5 9  
5. 1. 1. 6. 2  S y m pt o m r e p orti n g   
Cl arifi c ati o n  o n t h e  a p pr o pri at e r e p orti n g  of  ast h m a 
si g ns  or s y m pt o ms. 
5. 1. 2. 1  Ast h m a  Q u alit y  of  Lif e 
Q u esti o n n air e + 1 2 
Cl arifi c ati o n t h at t h e  A Q L Q + 1 2  will  b e  us e d i n s u bj e cts 
1 2  y e ars  a n d  ol d er.  
5. 1. 2. 2  P e di atri c  Ast h m a  Q u alit y 
of  Lif e  Q u esti o n n air e 
Cl arifi c ati o n t h at t h e  P A Q L Q  will  b e s elf -a d mi nist er e d 
i n s u bj e cts  a g e d  7 t o  1 1  y e ars.  
5. 1. 8. 1  R e v ersi bilit y  T est   
Cl arifi c ati o n t h at  pr e br o n c h o dil at or  P F Ts s h o ul d  b e 
p erf or m e d  aft er  at l e ast  1 5  mi n ut es  of r e st,  a n d b ef or e 
a d mi nistr ati o n  of  V e nt oli n.    
R e m o v e d  w or di n g t h at t h e  c o nfir m ati o n  of t h e  F E V 1 
m e as ur e m e nts s h o ul d  b e  e nt er e d i nt o t h e  e C R F t o 
c o nfir m  eli gi bilit y.  Ot h er t h a n  o v er all  eli gi bilit y 
c o nfir m ati o n, t h er e is  n o s p e cifi c  c o nfir m ati o n r el ati n g 
t o this ( ot h er t h a n  o v er all  eli gi bilit y  c o nfir m ati o n).  
5. 2. 3  Vit al si g n  m e as ur e m e nts 
a n d  8. 6. 3. 2   Vit al si g ns 
C orr e cti o n  of  bl o o d  pr ess ur e  m e as ur e m e nt t o  b e t a k e n 
i n t h e s e at e d  p ositi o n ( a n d  n ot s u pi n e). 
5. 3. 2  C o n c o mit a nt  m e di c ati o ns   
U p d at e  of ti m efr a m e f or  c o n c o mit a nt  m e di c ati o ns t o 
i n cl u d e t h os e t a k e n  b e gi n ni n g  wit hi n  1 2  m o nt hs  b ef or e 
s cr e e ni n g.  
6. 4  R e p orti n g  of s eri o us  a d v ers e 
e v e nts  
Pr o visi o n  of  a d diti o n al r e p orti n g r es p o nsi bilit y  of 
S p o ns or f or s eri o us  u n e x p e ct e d  a d v ers e  dr u g r e a cti o ns 
r el at e d t o I P. 
6 . 5  O v er d os e,  6. 7  M e di c ati o n 
err or  
Cl arifi c ati o n  o n t h e  a p pr o pri at e 
c oll e cti o n/r e c or di n g/r e p orti n g  of  a n 
O v er d os e/ M e di c ati o n  Err or  wit h  or  wit h o ut  a n 
ass o ci at e d  A E/ S A E.  
7. 8. 1  M ai nt e n a n c e t h er a pi es  a n d 
7. 8. 2  M e di c ati o ns t h at  m a y  aff e ct 
r e v ersi bilit y  a n d  F E V1 t esti n g 
M o difi c ati o n t o r e m o v e t h e  a d v a n c e  n otifi c ati o n f or 
i n v esti g at ors t o  n otif y t h e  S p o ns or  wit h r e g ar ds t o  a n y 
pr o p os e d  m ai nt e n a n c e t h er a p y  c h a n g es.  
7. 8. 3  Pr o hi bit e d  m e di c ati o ns   
Cl arifi c ati o n/ c orr e cti o n t h at i n h al e d s h ort -a cti n g 
a nti c h oli n er gi cs ( or s h ort- a cti n g  m us c ari ni c  a nt a g o nists 
[ S A M A]). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 1  of  1 5 9  
A d diti o n al  cl arifi c ati o n t h at i n h al e d l o n g -a cti n g 
a nti c h oli n er gi cs ( or  L A M A),  e x c e pt t h os e t h at  w er e 
st art e d  b ef or e s cr e e ni n g  a n d  c o nti n u e d  as  p art  of 
m ai nt e n a n c e tr e at m e nt  ar e  pr o hi bit e d.  
C orr e cti o n t o r efl e ct t h at  n o n gl u c o c orti c oi d  n as al 
s pr a ys  ar e  n ot  pr o hi bit e d. 
Cli ni c al  St u d y  Pr ot o c ol  S y n o psis, 
8. 1. 1  Esti m a n ds  a n d  8. 6. 7. 4  D e 
f a ct o  esti m a n d 
A d diti o n  of t h e  d e f a ct o  esti m a n d  as  a tr e at m e nt  p oli c y 
str at e g y  d efi n e d i n t h e  dr aft I C H  E 9  a d d e n d u m  a n d 
s p e cifi c ati o n  of  p o p ul ati o n  a n al ys es. 
8. 5. 2. 2  D eri v ati o n  of t ot al 
c orti c ost er oi d  e x p os ur e,  8. 6. 2. 4 
T ot al  c orti c ost er oi d  e x p os ur e 
C h a n g e i n  h o w I C S  a n d  S C S  ar e t o  b e  a n al y z e d: I C S t o 
b e s u m m ari z e d  as  a  m e a n  d ail y  d os e;  S C S t o  b e 
s u m m ari z e d  b y  d ur ati o n  of  a d mi nistr ati o n. 
A p p e n di x  D,  A d diti o n al s af et y 
i nf or m ati o n 
A dj ust m e nt t o r efl e ct r e p orti n g i n v esti g at ors  ar e  hi g hl y 
e n c o ur a g e d t o  e x pr ess t h eir  cli ni c al  o pi ni o n  w h e n 
pr es e nt e d  wit h li mit e d  or i ns uffi ci e nt i nf or m ati o n i n t h e 
c a us alit y  ass ess m e nts.  F u rt h er, t h at if t h e  c a us alit y 
ass ess m e nt  c a n n ot  b e  m a d e, t h es e s eri o us  a d v ers e 
e v e nts  will  b e  c o nsi d er e d t o  b e  “r el at e d ”.  
A p p e n di x  F  Ast h m a  Q u alit y  of 
Lif e  + 1 2  Q u esti o n n air e 
U p d at e d t o  A pril  2 0 0 8  v ersi o n.  
A p p e n di x  G  P e di atri c  Ast h m a 
Q u alit y  of  Lif e  Q u esti o n n air e 
U p d at e d t o J a n u ar y  2 0 0 1  v ersi o n.  
A p p e n di x  H  Ast h m a  C o ntr ol 
Q u esti o n n air e- 5  a n d  - 7 
U p d at e d t o  D e c e m b er  2 0 0 2  v ersi o n ( a n d J ul y  2 0 1 1 
v ersi o n  of t h e I nt er vi e w er- a d mi nist er e d  A C Q).  
T hr o u g h o ut  d o c u m e nt  
N o ns u bst a nti al  c h a n g es f or  a d mi nistr ati v e, 
t y p o gr a p hi c al  a n d/ or  gr a m m ati c al  c orr e cti o ns. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 3  of  1 5 9  
A P P E N DI X  B,  P RI M A R Y I N V E S TI G A T O R  SI G N A T U R E  P A G E  
I  a g r e e t o  c o n d u ct t h e st u d y i n  a c c o r d a n c e  wit h t h e  c u r r e nt  p r ot o c ol.  
 
 
Pl e as e  k e e p t h e si g n e d  ori gi n al f or m i n  y o ur st u d y fil es,  a n d r et ur n  a  c o p y t o  y o ur l o c al st u d y 
m o nit or. 
 
 
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 5  of  1 5 9  
Ci cl es o ni d e  
8 0  
> 8 0 -1 6 0  
> 1 6 0  
Fl uti c as o n e f ur o at e ( D PI)  
N A  
N A  
N A  
Fl uti c as o n e  pr o pi o n at e ( D PI)  
1 0 0 -2 0 0  
> 2 0 0 -4 0 0  
> 4 0 0  
Fl uti c as o n e  pr o pi o n at e ( H F A)  
1 0 0 -2 0 0  
> 2 0 0 -5 0 0  
> 5 0 0  
M o m et as o n e f ur o at e  
1 1 0  
≥ 2 2 0 -< 4 4 0  
≥ 4 4 0  
Tri a m ci n ol o n e  a c et o ni d e  
4 0 0 -8 0 0   
> 8 0 0 -1 2 0 0  
> 1 2 0 0  
A b br e vi ati o ns:  C F C = c hl or ofl u or o c ar b o n  pr o p ell a nt;  D PI = dr y  p o w d er i n h al er;  H F A = h y dr ofl u or o al k a n e 
pr o p ell a nt;  N A = n ot  a p pli c a bl e  
a  
B e cl o m et as o n e  di pr o pi o n at e  C F C is i n cl u d e d f or  c o m p aris o n  wit h  ot h er lit er at ur e.  
 
L o w  D ail y  D os es  of I n h al e d  C o rti c ost e r oi ds f o r  C hil d r e n  5  Y e a rs  a n d  Y o u n g e r 
D R U G  
L o w  d ail y  d os a g e ( µ g) a 
( a g e  g r o u p  wit h  a d e q u at e s af et y  a n d  eff e cti v e  d at a) 
B e cl o m et as o n e  di pr o pi o n at e ( H F A)  
1 0 0 ( a g es  ≥ 5  y e ars)  
B u d es o ni d e  n e b uli z e d  
5 0 0 ( a g es  ≥ 1  y e ar)  
Fl uti c as o n e  pr o pi o n at e ( H F A)  
1 0 0 ( a g es  ≥ 4  y e ars)  
M o m et as o n e f ur o at e  
1 1 0 ( a g es  ≥ 4  y e ars)  
B u d es o ni d e  p M DI  + s p a c er  
N ot s uffi ci e ntl y st u di e d i n t his  a g e  gr o u p  
Ci cl es o ni d e  
N ot s uffi ci e ntl y st u di e d i n t his  a g e  gr o u p  
Tri a m ci n ol o n e  a c et o ni d e  
N ot s uffi ci e ntl y st u di e d i n t his  a g e  gr o u p  
A b br e vi ati o ns:  H F A = h y dr ofl u or o al k a n e  pr o p ell a nt;  p M DI = pr ess uri z e d  m et er e d -d os e i n h al er  
a  
S u bj e cts  5  y e ars  a n d  y o u n g er  m e eti n g  GI N A st e p  3  eli gi bilit y s h o ul d  b e tr e at e d  wit h  d o u bl e l o w -d os e I C S 
or  L o w  d os e I C S  +  L T R A ( Gl o b al  I niti ati v e f or Ast h m a  [GI N A ] 2 0 1 8 ).    
 
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 6  of  1 5 9  
A P P E N DI X  D,  A D DI TI O N A L  S A F E T Y I N F O R M A TI O N  
F u rt h e r  g ui d a n c e  o n t h e  d efi niti o n  of  a s e ri o us  a d v e rs e  e v e nt ( S A E)  
 
Lif e  -t h r e at e ni n g 
“ Lif e  -t hr e at e ni n g ”  m e a ns t h at t h e s u bj e ct  w as  at i m m e di at e ris k  of  d e at h fr o m t h e  A E  as it 
o c c urr e d  or it is s us p e ct e d t h at  us e  or  c o nti n u e d  us e  of t h e  pr o d u ct  w o ul d r es ult i n t h e 
s u bj e ct’s  d e at h.  “ Lif e-t hr e at e ni n g ”  d o es  n ot  m e a n t h at  a n  A E  o c c urr e d i n  a  m or e s e v er e f or m, 
it  mi g ht  h a v e  c a us e d  d e at h ( e g,  h e p atitis t h at r es ol v e d  wit h o ut  h e p ati c f ail ur e). 
 
H os pit ali z ati o n  
O ut p ati e nt tr e at m e nt i n  a n  e m er g e n c y r o o m is  n ot i n its elf  a s eri o us  A E,  alt h o u g h t h e r e as o ns 
f or it  m a y  b e ( e g,  br o n c h os p as m, l ar y n g e al  e d e m a).  H os pit al  a d missi o ns  a n d/ or s ur gi c al 
o p er ati o ns  pl a n n e d  b ef or e  or  d uri n g  a st u d y  ar e  n ot  c o nsi d er e d  A Es if t h e ill n ess  or  dis e as e 
e xist e d  b ef or e t h e s u bj e ct  w as  e nr oll e d i n t h e st u d y,  pr o vi d e d t h at it  di d  n ot  d et eri or at e i n  a n 
u n e x p e ct e d  w a y  d uri n g t h e st u d y. 
 
I m p o rt a nt  m e di c al  e v e nt  o r  m e di c al i nt e r v e nti o n  
M e di c al  a n d s ci e ntifi c j u d g m e nt s h o ul d  b e  e x er cis e d i n  d e ci di n g  w h et h er  a  c as e is s eri o us i n 
sit u ati o ns  w h er e i m p ort a nt  m e di c al  e v e nts  m a y  n ot  b e i m m e di at el y lif e -t hr e at eni n g  or r es ult i n 
d e at h,  h os pit ali z ati o n,  dis a bilit y,  or i n c a p a cit y,  b ut  m a y j e o p ar di z e t h e s u bj e ct  or  m a y r e q uir e 
m e di c al i nt er v e nti o n t o  pr e v e nt  1  or  m or e  o ut c o m es list e d i n t h e  d efi niti o n  of s eri o us.  T h es e 
s h o ul d  us u all y  b e  c o nsi d er e d  as s eri o us. 
Si m pl y  st o p pi n g t h e s us p e ct  dr u g  d o es  n ot  m e a n t h at it is  a n i m p ort a nt  m e di c al  e v e nt;  m e di c al 
j u d g m e nt  m ust  b e  us e d.  E x a m pl es  of i m p ort a nt  m e di c al  e v e nts i n cl u d e  b ut  ar e  n ot li mit e d t o: 
-  A n gi o e d e m a  n ot s e v er e  e n o u g h t o r e q uir e i nt u b ati o n  b ut r e q uiri n g i ntr a v e n o us 
h y dr o c ortis o n e tr e at m e nt. 
-  H e p at ot o xi cit y  c a us e d  b y  p ar a c et a m ol ( a c et a mi n o p h e n)  o v er d os e r e q uiri n g tr e at m e nt 
wit h  N -a c et yl c yst ei n e.  
-  I nt e nsi v e tr e at m e nt i n  a n  e m er g e n c y r o o m  or  at  h o m e f or  all er gi c  br o n c h os p as m. 
-  Bl o o d  d ys cr asi as ( e g,  n e utr o p e ni a  or  a n e mi a r e q uiri n g  bl o o d tr a nsf usi o n,  et c.)  or 
c o n v ulsi o ns t h at  d o  n ot r es ult i n  h os pit ali z ati o n. 
-  D e v el o p m e nt  of  dr u g  d e p e n d e n c y  or  dr u g  a b us e. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 7  of  1 5 9  
A  g ui d e t o i nt e r p r eti n g t h e  c a us alit y  q u esti o n  
W h e n  m a ki n g  a n  ass ess m e nt  of  c a us alit y,  c o nsi d er t h e f oll o wi n g f a ct ors  w h e n  d e ci di n g if 
t h er e is  a “r e as o n a bl e  p ossi bilit y ” t h at  a n  A E  m a y  h a v e  b e e n  c a us e d  b y t h e  dr u g: 
•   Ti m e  C o urs e.  E x p os ur e t o s us p e ct  dr u g.  H as t h e s u bj e ct  a ct u all y r e c ei v e d t h e s us p e ct 
dr u g ?  Di d t h e  A E  o c c ur i n  a r e as o n a bl e t e m p or al r el ati o ns hi p t o t h e  a d mi nistr ati o n  of 
t h e s us p e ct  dr u g ? 
•   C o nsist e n c y  wit h  k n o w n  dr u g  pr ofil e.  Was t h e  A E  c o nsist e nt  wit h t h e  pr e vi o us 
k n o wl e d g e  of t h e s us p e ct  dr u g ( p h ar m a c ol o g y  a n d t o xi c ol o g y)  or  dr u gs  of t h e s a m e 
p h ar m a c ol o gi c al  cl ass ?  Or  c o ul d t h e  A E  b e  a nti ci p at e d fr o m its   p h ar m a c ol o gi c al 
pr o p erti es ? 
•   D e - c h all e n g e  e x p eri e n c e.  Di d t h e  A E r es ol v e  or i m pr o v e  o n st o p pi n g  or r e d u ci n g t h e 
d os e  of t h e s us p e ct  dr u g ? 
•   N o  alt er n ati v e  c a us e.  T h e  A E  c a n n ot  b e r e as o n a bl y  e x pl ai n e d  b y  a n ot h er  c a us e s u c h  as 
t h e  u n d erl yi n g  dis e as e,  ot h er  dr u gs,  a n d  ot h er  h ost  or  e n vir o n m e nt al f a ct ors. 
•   R e -c h all e n g e  e x p eri e n c e.  Di d t h e  A E r e o c c ur if t h e s us p e ct e d  dr u g  w as r ei ntr o d u c e d 
aft er  h a vi n g  b e e n st o p p e d ?  T h e  S p o ns or  w o ul d  n ot  n or m all y r e c o m m e n d  or s u p p ort  a 
r e c h all e n g e. 
•   L a b or at or y t ests.  A s p e cifi c l a b or at or y i n v esti g ati o n (if  p erf or m e d)  h as  c o nfir m e d t h e 
r el ati o ns hi p. 
 
I n  diffi c ult  c as es,  ot h er f a ct ors  c o ul d  b e  c o nsi d er e d s u c h  as: 
•   Is t his  a r e c o g ni z e d f e at ur e  of  o v er d os e  of t h e  dr u g ? 
•   Is t h er e  a  k n o w n  m e c h a nis m ? 
 
C a us alit y  of  “r el at e d ” is  m a d e if  aft er  a r e vi e w  of t h e r el e v a nt  d at a t h er e is  e vi d e n c e f or  a 
“r e as o n a bl e  p ossi bilit y ”  of  a  c a us al r el ati o ns hi p f or t h e i n di vi d u al  c as e.  T h e  e x pr essi o n 
“r e as o n a bl e  p ossi bilit y ”  of  a  c a us al r el ati o ns hi p is  m e a nt t o  c o n v e y, i n  g e n er al, t h at t h er e  ar e 
f a cts ( e vi d e n c e)  or  ar g u m e nts t o s u g g est  a  c a us al r el ati o ns hi p. 
T h e  c a us alit y  ass ess m e nt is  p erf or m e d  o n t h e  b asis  of t h e  a v ail a bl e  d at a, i n cl u di n g  e n o u g h 
i nf or m ati o n t o  m a k e  a n i nf or m e d j u d g m e nt.  Wit h li mit e d  or i ns uffi ci e nt i nf or m ati o n i n t h e 
c as e, it is  hi g hl y  e n c o ur a g e d f or t h e r e p orti n g i n v esti g at or t o  e x pr ess  his/ h er  cli ni c al  o pi ni o n. 
If ( d es pit e  all  eff orts) t h e  c a us alit y  ass ess m e nt  c a n n ot  b e  m a d e, t h es e  S A Es  will  b e  c o nsi d er e d 
t o  b e  “r el at e d ”. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 8  of  1 5 9  
C a us al r el ati o ns hi p i n  c as es  w h er e t h e  dis e as e  u n d er st u d y  h as  d e t eri or at e d  b e c a us e  of l a c k  of 
eff e ct s h o ul d  b e  cl assifi e d  as  n o r e as o n a bl e  p ossi bilit y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 1 9  of  1 5 9  
A P P E N DI X  E,  H Y’ S  L A W  
 
I nt r o d u cti o n  
T his  A p p e n di x  d es cri b es t h e  pr o c ess t o  b e f oll o w e d t o i d e ntif y  a n d  a p pr o pri at el y r e p ort  c as es 
of  H y’s  L a w ( H L). It  is  n ot i nt e n d e d t o  b e  a  c o m pr e h e nsi v e  g ui d e t o t h e  m a n a g e m e nt  of 
el e v at e d li v er  bi o c h e mistri es.    
D uri n g t h e  c o urs e  of t h e st u d y, t h e i n v esti g at or  will r e m ai n  vi gil a nt f or i n cr e as es i n li v er 
bi o c h e mistr y. I n s u bj e cts  w h o  h a v e  el e v at e d li v er  e n z y m es  as p art a t e  a mi n otr a nsf er as e ( A S T) 
a n d/ or  al a ni n e tr a ns a mi n as e ( A L T)  ≥  3 × U L N  a n d t ot al  bilir u bi n ( T B L)  ≥  2 × U L N, I P  will  b e 
s us p e n d e d  u ntil t h e li v er t est  v al u es r et ur n t o t h e  n or m al r a n g e. If t h e  A S T,  A L T  or  T B L r e a c h 
t h es e  el e v at e d l e v els  a g ai n,  aft er r e c o m m e n c e m ent  of I P, t h e s u bj e ct  will  b e  dis c o nti n u e d fr o m 
I P  a n d  wit h dr a w n fr o m t h e st u d y.  T h e i n v esti g at or is r es p o nsi bl e f or  d et er mi ni n g  w h et h er  a 
s u bj e ct  m e ets  P ot e nti al  H y’s  L a w ( P H L)  crit eri a  at  a n y  p oi nt  d uri n g t h e st u d y. 
T h e i n v esti g at or  p arti ci p at es,  wit h t h e  S p o ns or’s  cli ni c al  pr oj e ct r e pr es e nt ati v es, i n r e vi e w  a n d 
ass ess m e nt  of  c as es  m e eti n g  P H L  crit eri a t o  a gr e e  w h et h er  H L  crit eri a  ar e  m et.  H y’s  L a w 
crit eri a  ar e  m et if t h er e is  n o  alt er n ati v e  e x pl a n ati o n f or t h e  el e v ati o ns i n li v er  bi o c h e mistr y 
ot h er t h a n  dr u g i n d u c e d li v er i nj ur y  c a us e d  b y t h e I P.  
T h e i n v esti g at or is r es p o nsi bl e f or r e c or di n g  d at a  p ert ai ni n g t o  p ot e nti al  H L/ H L  c as es  a n d f or 
r e p orti n g  A E  a n d  S A E  a c c or di n g t o t h e  o ut c o m e  of t h e r e vi e w  a n d  ass ess m e nt i n li n e  wit h 
st a n d ar d s af et y r e p orti n g  pr o c ess es.  
 
D efi niti o ns  
P ot e nti al  H y’s  L a w 
A S T  a n d/ or  A L T  ≥ 3 ×  U L N  c o m bi n e d  wit h  T B L  ≥ 2 × U L N  at  a n y  p oi nt  d uri n g t h e st u d y  aft er 
t h e st art  of I P irr es p e cti v e  of  a n i n cr e as e i n  al k ali n e  p h os p h at as e ( A L P).  
H y’s  L a w 
A S T  a n d/ or  A L T  ≥ 3 × U L N  c o m bi n e d  wit h  T B L  ≥ 2 × U L N,  w h er e  n o  ot h er r e as o n,  ot h er t h a n 
t h e I P,  c a n  b e f o u n d t o  e x pl ai n t h e  c o m bi n ati o n  of i n cr e as es,  e g,  el e v at e d  A L P i n di c ati n g 
c h ol est asis,  vir al  h e p atitis,  or  a n ot h er  dr u g.   
F or  p ot e nti al  H L  a n d  H L, t h e  el e v ati o n i n tr a ns a mi n as es  m ust  pr e c e d e  or  b e  c oi n ci d e nt  wit h 
(i e,  o n t h e s a m e  d a y) t h e  el e v ati o n i n  T B L,  b ut t h er e is  n o s p e cifi e d ti m efr a m e  wit hi n  w hi c h 
t h e  el e v ati o ns i n tr a ns a mi n as es  a n d  T B L  m ust  o c c ur. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 2 0  of  1 5 9  
 
I d e ntifi c ati o n  of  P ot e nti al  H y’s  L a w  c as es 
T o i d e ntif y  c as es  of  P H L it is i m p ort a nt t o  p erf or m  a  c o m pr e h e nsi v e r e vi e w  of l a b or at or y  d at a 
f or  a n y s u bj e ct  w h o  m e ets  a n y  of t h e f oll o wi n g i d e ntifi c ati o n  crit eri a i n is ol ati o n  or i n 
c o m bi n ati o n:  
•   A L T  ≥ 3 × U L N  
•   A S T  ≥ 3 × U L N  
•   T B L  ≥ 2 × U L N  
W h e n  a s u bj e ct  m e ets  a n y  of t h e i d e ntifi c ati o n  crit eri a, i n is ol ati o n  or i n  c o m bi n ati o n, t h e 
c e ntr al l a b or at or y  will i m m e di at el y s e n d  a n  al ert t o t h e i n v esti g at or  a n d t h e  m e di c al  m o nit or 
assi g n e d t o t h e  pr oj e ct.  
T h e i n v esti g at or  will  als o r e m ai n  vi gil a nt f or  a n y l o c al l a b or at or y r e p orts  w h er e t h e 
i d e ntifi c ati o n  crit eri a  ar e  m et;  w h er e t his is t h e  c as e, t h e i n v esti g at or  will: 
-  N otif y t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct. 
-  R e q u est  a r e p e at  of t h e t est ( n e w  bl o o d  dr a w)  b y t h e  c e ntr al l a b or at or y. 
-  C o nt a ct t h e  m e di c al  m o nit or t o  dis c uss t h e  el e v at e d  l o c al l a bs  a n d  w h et h er t h es e 
c o nstit ut e  a n  A E.  W h er e  a n  A E is  e nt er e d  d u e t o  el e v ati o ns  of l o c al l a bs, t h e  A E  will 
b e  q u eri e d i n t h e  e C R F  a n d  el e v at e d l o c al l a b  v al u es,  u nits  a n d r a n g es  will  b e  e nt er e d 
t o t h e  q u er y r es p o ns e. 
-  W h e n t h e i d e ntifi c ati o n  crit er i a  ar e  m et fr o m  c e ntr al  or l o c al l a b or at or y r es ults, t h e 
i n v esti g at or  will  wit h o ut  d el a y: 
-  D et er mi n e  w h et h er t h e s u bj e ct  m e ets  P H L  crit eri a  b y r e vi e wi n g l a b or at or y 
r e p orts fr o m  all  pr e vi o us  visits (i n cl u di n g  b ot h  c e ntr al  a n d l o c al l a b or at or y 
r es ults). 
-  T h e i n v esti g at or  will,  wit h o ut  d el a y, r e vi e w  e a c h  n e w l a b or at or y r e p ort  a n d if t h e 
i d e ntifi c ati o n  crit eri a  ar e  m et,  will: 
-  N otif y t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct. 
-  D et er mi n e  w h et h er t h e s u bj e ct  m e ets  P H L  crit eri a  b y r e vi e wi n g l a b or at or y 
r e p orts fr o m  all  pr e vi o us  visits. 
-  Pr o m ptl y  e nt er t h e l a b or at or y  d at a i nt o t h e l a b or at or y  e C R F. 
 
F oll o w- u p  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 2 1  of  1 5 9  
P ot e nti al  H y’s  L a w  c rit e ri a  n ot  m et  
If t h e s u bj e ct  d o es  n ot  m e et  P H L  crit eri a, t h e i n v esti g at or  will: 
I nf or m t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct t h at t h e s u bj e ct  h as  n ot  m et  P H L  crit eri a.  
P erf or m f oll o w - u p  o n s u bs e q u e nt l a b or at or y r es ults  a c c or di n g t o t h e  g ui d a n c e  pr o vi d e d i n t h e 
Cli ni c al  St u d y  Pr ot o c ol. 
 
P ot e nti al  H y’s  L a w  c rit e ri a  m et  
If t h e s u bj e ct  d o es  m e et  P H L  crit eri a, t h e i n v esti g at or  will: 
D et er mi n e  w h et h er  P H L  crit eri a  w er e  m et  at  a n y st u d y  visit  b ef or e st arti n g I P ( S e e s e cti o n 
b el o w  o n  “ A cti o ns r e q uir e d  w h e n  P ot e nti al  H y’s  L a w  crit eri a  ar e  m et  b ef or e  a n d  aft er st arti n g   
I P”)  
N otif y t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct  w h o  will t h e n i nf or m t h e  c e ntr al st u d y t e a m   
T h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct  will  dis c uss t h e iss u e  wit h t h e i n v esti g at or t o 
pr o vi d e  g ui d a n c e,  a n d  a gr e e  a n  a p pr o a c h f or t h e st u d y s u bj e cts’ f oll o w- u p  a n d t h e  c o nti n u o us 
r e vi e w  of  d at a.  S u bs e q u e nt t o t his  c o nt a ct t h e i n v esti g at or  will: 
M o nit or t h e s u bj e ct  u ntil li v er  bi o c h e mistr y  p ar a m et ers  a n d  a p pr o pri at e  cli ni c al s y m pt o ms  a n d 
si g ns r et ur n t o  n or m al  or  b as eli n e l e v els,  or  as l o n g  as  m e di c all y i n di c at e d  
I n v esti g at e t h e  c a us e  of t h e  e v e nt  a n d  p erf or m  di a g n osti c i n v esti g ati o ns  as  dis c uss e d  wit h t h e 
m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct.  F or st u di es  usi n g  a  c e ntr al l a b or at or y  a d d:  T his 
i n cl u d es  d e ci di n g  w hi c h t h e t ests  a v ail a bl e i n t h e  H y’s  L a w l a b  kit s h o ul d  b e  us e d.  
C o m pl et e t h e  3  Li v er  e C R F  m o d ul es  as i nf or m ati o n  b e c o m es  a v ail a bl e   
If  at  a n y ti m e (i n  c o ns ult ati o n  wit h t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct) t h e  P H L  c as e 
m e ets s eri o us  crit eri a, r e p ort it  as  a n  S A E  usi n g st a n d ar d r e p orti n g  pr o c e d ur es. 
 
R e vi e w  a n d  ass ess m e nt  of  P ot e nti al  H y’s  L a w  c as es 
N o l at er t h a n  3  w e e ks  aft er t h e  bi o c h e mistr y  a b n or m alit y  w as i niti all y  d et e ct e d, t h e  m e di c al 
m o nit or  assi g n e d t o t h e  pr oj e ct  c o nt a cts t h e i n v esti g at or t o r e vi e w  a v ail a bl e  d at a  a n d  a gr e e  o n 
w h et h er t h er e is  a n  alt er n ati v e  e x pl a n ati o n f or  m e eti n g  P H L  crit eri a  ot h er t h a n  dr u g i n d u c e d 
li v er i nj ur y  c a us e d  b y t h e I P.  T h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct  a n d  gl o b al s af et y 
p h ysi ci a n  will  als o  b e i n v ol v e d i n t his r e vi e w  wit h  ot h er s u bj e ct  m att er  e x p erts,  as  a p pr o pri at e.    
A c c or di n g t o t h e  o ut c o m e  of t h e r e vi e w  a n d  ass ess m e nt, t h e i n v esti g at or  will f oll o w t h e 
i nstr u cti o ns  b el o w. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 2 2  of  1 5 9  
If t h er e is  a n  a gr e e d  alt er n ati v e  e x pl a n ati o n f or t h e  A L T  or  A S T  a n d  T B L  el e v ati o ns,  a 
d et er mi n ati o n  of  w h et h er t h e  alt er n ati v e  e x pl a n ati o n is  a n  A E  will  b e  m a d e  a n d s u bs e q u e ntl y 
w h et h er t h e  A E  m e ets t h e  crit eri a f or  a n  S A E:  
If t h e  alt er n ati v e  e x pl a n ati o n is n ot   a n  A E, r e c or d t h e  alt er n ati v e  e x pl a n ati o n  o n t h e 
a p pr o pri at e  e C R F  
If t h e  alt er n ati ve  e x pl a n ati o n is  a n  A E/ S A E, r e c or d t h e  A E/ S A E i n t h e  e C R F  a c c or di n gl y  a n d 
f oll o w t h e  S p o ns or’s st a n d ar d  pr o c ess es 
If it is  a gr e e d t h at t h er e is n o  e x pl a n ati o n t h at  w o ul d  e x pl ai n t h e  A L T  or  A S T  a n d  T B L 
el e v ati o ns  ot h er t h a n t h e I P: 
R e p ort  a n  S A E (r e p ort t er m  “ H y’s  L a w ”)  a c c or di n g t o t h e  S p o ns or’s st a n d ar d  pr o c ess es.  
T h e  “ M e di c all y I m p ort a nt ” s eri o us  crit eri o n s h o ul d  b e  us e d if  n o  ot h er s eri o us  crit eri a 
a p pl y. 
As t h er e is  n o  alt er n ati v e  e x pl a n ati o n f or t h e  H L  c as e,  a  c a us alit y  ass ess m e nt  of  “r el at e d ” 
s h o ul d  b e  assi g n e d. 
 
If, t h er e is  a n  u n a v oi d a bl e  d el a y,  of  o v er  3  w e e ks, i n  o bt ai ni n g t h e i nf or m ati o n  n e c ess ar y t o 
ass ess  w h et h er  or  n ot t h e  c as e  m e ets t h e  crit eri a f or  H L, t h e n it is  ass u m e d t h at t h er e is  n o 
alt er n ati v e  e x pl a n ati o n  u ntil s u c h ti m e  as  a n i nf or m e d  d e cisi o n  c a n  b e  m a d e:  
R e p ort  a n  S A E (r e p ort t er m  “ P ot e nti al  H y’s  L a w ”)  a p pl yi n g s eri o us  crit eri a  a n d  c a us alit y 
ass ess m e nt  as  p er  a b o v e  
C o nti n u e f oll o w- u p  a n d r e vi e w  a c c or di n g t o  a gr e e d  pl a n.  O n c e t h e  n e c ess ar y s u p pl e m e nt ar y 
i nf or m ati o n is o bt ai n e d, r e p e at t h e r e vi e w  a n d  ass ess m e nt t o  d et er mi n e  w h et h er  H L  crit eri a 
ar e  m et.  U p d at e t h e  S A E r e p ort  a c c or di n g t o t h e  o ut c o m e  of t h e r e vi e w  a m e n di n g t h e r e p ort e d 
t er m if  a n  alt er n ati v e  e x pl a n ati o n f or t h e li v er  bi o c h e mistr y  el e v ati o ns is  d et er mi n e d. 
 
A cti o ns  r e q ui r e d  w h e n  P ot e nti al  H y’s  L a w  c rit e ri a  a r e  m et  b ef o r e  a n d  aft e r st a rti n g I P   
T his s e cti o n is  a p pli c a bl e t o s u bj e cts  w h o  m e et  P H L  crit eri a  o n st u d y tr e at m e nt  h a vi n g 
pr e vi o usl y  m et  P H L  crit eri a  at  a st u d y  visit  b ef or e st arti n g I P.  
At t h e first  o n  st u d y tr e at m e nt  o c c urr e n c e  of  P H L  crit eri a  b ei n g  m et t h e i n v esti g at or  will:  
D et er mi n e if t h er e  h as  b e e n  a si g nifi c a nt  c h a n g e i n t h e s u bj e cts’  c o n diti o n  c o m p ar e d  wit h t h e 
l ast  visit  w h er e  P H L  crit eri a  w er e  m et 
If t h er e is  n o si g nifi c a nt  c h a n g e  n o  a cti o n is r e q uir e d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 2 3  of  1 5 9  
If t h er e is  a si g nifi c a nt  c h a n g e,  n otif y t h e  S p o ns or r e pr es e nt ati v e,  w h o  will i nf or m t h e 
c e ntr al st u d y t e a m, t h e n f oll o w t h e s u bs e q u e nt  pr o c ess  d es cri b e d i n t h e s e cti o n 
“ P ot e nti al  H y’s  L a w  crit er i a  m et”  of t his  A p p e n di x. 
 
A  “si g nifi c a nt ”  c h a n g e i n t h e s u bj e ct’s  c o n diti o n r ef ers t o  a  cli ni c all y r el e v a nt  c h a n g e i n  a n y 
of t h e i n di vi d u al li v er  bi o c h e mistr y  p ar a m et ers ( A L T,  A S T,  or  T B L) i n is ol ati o n  or i n 
c o m bi n ati o n,  or  a  cli ni c all y r el e v a nt  c h a n g e i n  ass o ci at e d s y m pt o ms.  T h e  d et er mi n ati o n  of 
w h et h er t h er e  h as  b e e n  a si g nifi c a nt  c h a n g e  will  b e  at t h e  dis cr eti o n  of t h e i n v esti g at or; t his 
m a y  b e i n  c o ns ult ati o n  wit h t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct if t h er e is  a n y 
u n c ert ai nt y. 
 
A cti o ns  r e q ui r e d f o r  r e p e at  e pis o d es  of  P ot e nti al  H y’s  L a w  
T his s e cti o n is  a p pli c a bl e  w h e n  a s u bj e ct  m e ets  P H L  crit eri a  o n st u d y tr e at m e nt  a n d  h as 
alr e a d y  m et  P H L  crit eri a  at  a  pr e vi o us  o n st u d y tr e at m e nt  visit.  
T h e r e q uir e m e nt t o  c o n d u ct f oll o w- u p, r e vi e w,  a n d  as s ess m e nt  of  a r e p e at  o c c urr e n c e(s)  of 
P H L is  b as e d  o n t h e  n at ur e  of t h e  alt er n ati v e  c a us e i d e ntifi e d f or t h e  pr e vi o us  o c c urr e n c e.    
T h e i n v esti g at or s h o ul d  d et er mi n e t h e  c a us e f or t h e  pr e vi o us  o c c urr e n c e  of  P H L  crit eri a  b ei n g 
m et  a n d  a ns w er t h e f oll o wi n g  q u esti o n: 
Was t h e  alt er n ati v e  c a us e f or t h e  pr e vi o us  o c c urr e n c e  of  P H L  crit eri a  b ei n g  m et f o u n d t o  b e 
t h e  dis e as e  u n d er st u d y  or  di d t h e s u bj e ct  m e et  P H L  crit eri a  b ef or e st arti n g st u d y tr e at m e nt 
a n d  at t h eir first  o n st u d y tr e at m e nt  visit  as  d es cri b e d i n t h e s e cti o n  “ A cti o ns r e q uir e d  w h e n 
P ot e nti al  H y’s  L a w  crit eri a  ar e  m et  b ef or e  a n d  aft er st arti n g  I P”.  
If  N o: f oll o w t h e  pr o c ess  d es cri b e d i n t h e s e cti o n  “P ot e nti al  H y’s  L a w  crit eri a  m et ”  of t his 
A p p e n di x. 
If  Y es:  d et er mi n e if t h er e  h as  b e e n  a si g nifi c a nt  c h a n g e i n t h e s u bj e ct’s  c o n diti o n  c o m p ar e d 
wit h  w h e n  P H L  crit eri a  w er e  pr e vi o usl y  m et  
If t h er e is  n o si gnifi c a nt  c h a n g e,  n o  a cti o n is r e q uir e d 
If t h er e is  a si g nifi c a nt  c h a n g e: 
A  “si g nifi c a nt ”  c h a n g e i n t h e s u bj e ct’s  c o n diti o n r ef ers t o  a  cli ni c all y r el e v a nt  c h a n g e i n  a n y 
of t h e i n di vi d u al li v er  bi o c h e mistr y  p ar a m et ers ( A L T,  A S T,  or  T B L) i n is ol ati o n  or i n 
c o m bi n ati o n,  or  a  cli ni c all y r el e v a nt  c h a n g e i n  ass o ci at e d s y m pt o ms.  T h e  d et er mi n ati o n  of 
w h et h er t h er e  h as  b e e n  a si g nifi c a nt  c h a n g e  will  b e  at t h e  dis cr eti o n  of t h e i n v esti g at or; t his 
m a y  b e i n  c o ns ult ati o n  wit h t h e  m e di c al  m o nit or  assi g n e d t o t h e  pr oj e ct  if t h er e is  a n y 
u n c ert ai nt y. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 5 5  of  1 5 9  
A P P E N DI X  M,  S PI R O M E T R Y  A S S E S S M E N T  C RI T E RI A   
A c c e pt a bl e  V e rs us  Us a bl e  T ests  
A c c e pt a bl e  T ests  m ust  m e et t h e f oll o wi n g  c rit e ri a:  
1.   A c c e pt a bl e st art  of  e x h al ati o n  wit h  bris k  u pstr o k e,  n o  h esit ati o n  or f als e st art,  a n d  b a c k 
e xtr a p ol ati o n  v ol u m e   < 5 %  of f or c e d  vit al  c a p a cit y ( F V C)  or  0. 1 5 0  L,  w hi c h e v er is t h e 
gr e at er (s e e  e x a m pl e i n  Fi g u r e   1) 
2.   N o  c o u g h  d uri n g t h e first s e c o n d 
3.   N o  v als al v a  m a n e u v er  
4.   N o l e a k  
5.   N o  o bstr u cti o n  of  m o ut h pi e c e 
6.   N o  e xtr a  br e at hs  
7.   Pl at e a u  a c hi e v e d: i e, t h e  v ol u m e -ti m e  c ur v e s h o ws  n o  c h a n g e i n  v ol u m e ( < 0. 0 2 5 L) f or 
≥ 1 s e c o n d,  a n d t h e s u bj e ct  h as tri e d t o  e x h al e f or  at l e ast  6  s e c o n ds 
 
A n  a c c e pt a bl e t est  m e ets  all  7  crit eri a list e d.   T his is t o  b e  c o nsi d er e d t h e  “ g ol d st a n d ar d ”.  
Us a bl e s pir o m etr y tr a ci n gs  ar e t h os e t h at  o nl y  m e et  crit eri a  1  a n d  2.   W h e n t his  o c c urs, r e p e at 
t esti n g  u p t o  8  att e m pts f or  pr e- d os e  a n d  5  att e m pts f or  p ost- d os e  ass ess m e nts, i n  a n  eff ort t o 
o bt ai n  3  a c c e pt a bl e s pir o gr a ms. If  o nl y  us a bl e t ests  ar e  o bt ai n e d, r e p ort r es ults  b as e d  o n t h e  3 
b est  us a bl e tri als  wit h  o bs er v e d li mit ati o ns.  
Fi g u r e   1    
E x a m pl e  of  a  Us a bl e  S pi r o g r a m 
 
E V = b a c k  e xtr a p ol ati o n  v ol u m e  
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 5 6  of  1 5 9  
T h e  e x p a n d e d  v ersi o n  of t h e  e arl y  p art  of  a s u bj e ct’s  v ol u m e- ti m e s pir o gr a m, ill ustr ati n g  b a c k 
e xtr a p ol ati o n t hr o u g h t h e st e e p est  p art  of t h e  c ur v e,  w h er e fl o w is  P E F r at e, t o  d et er mi n e t h e 
n e w  “ti m e  z er o ”.   F or c e d  vit al  c a p a cit y  -4. 2 9 1  L;  E V  –  0. 1 2 3  L ( 2. 9 %  F V C):   b a c k 
e xtr a p ol ati o n li n e t hr o u g h  P E F. 
B et w e e n -M a n e u v e r  R e p r o d u ci bilit y  C rit e ri a  
P r e - d os e ass ess m e nts  
Aft er  3   a c c e pt a bl e s pir o gr a ms  h a v e  b e e n  o bt ai n e d,  a p pl y t h e f oll o wi n g t ests: 
•   T h e  2 l ar g est  v al u es  of  F V C  m ust  b e  wit hi n  0. 1 5 0  L  of  e a c h  ot h er 
•   T h e  2 l ar g est  v al u es  of  F E V 1  m ust  b e  wit hi n  0. 1 5 0  L  of  e a c h  ot h er 
 
If t h es e  crit eri a  ar e  m et, t h e s pir o m etr y t esti n g f or t h at ti m e  p oi nt  m a y  c o n cl u d e,  h o w e v er, if 
p ossi bl e,  pl e as e  c o nti n u e  c oll e cti n g  a d diti o n al s pir o gr a ms t o  a  m a xi m u m  of  8  pr e- d os e  a n d  5 
p ost- d os e  att e m pts.   T h e  hi g h est  F E V 1  a n d t h e  hi g h est  F V C  o bt ai n e d  at  e a c h t esti n g ti m e  p oi nt 
( e v e n if fr o m  diff er e nt r e pro d u ci bl e tr a ci n gs),  will  b e  c oll e ct e d. 
If  a c c e pt a bilit y  crit eri a  ar e  n ot  m et,  c o nti n u e t esti n g  u ntil t h e y  ar e  m et  or t h e s u bj e ct  c a n n ot/ 
s h o ul d  n ot  c o nti n u e ( m a xi m u m  of  8  att e m pts).  
P ost -d os e  ass ess m e nts  
Aft er  2   a c c e pt a bl e s pir o gr a ms  h a v e  b e e n  o bt ai n e d,  a p pl y t h e f oll o wi n g t ests: 
•   T h e  2 l ar g est  v al u es  of  F V C  ar e  wit hi n  0. 1 5 0  L  of  e a c h  ot h er,  a n d/ or 
•   T h e  2 l ar g est  v al u es  of  F E V 1  ar e  wit hi n  0. 1 5 0 L  of  e a c h  ot h er  
 
If t h es e  crit eri a  ar e  m et, t h e s pir o m etr y t esti n g f or t h at ti m e  p oi nt  m a y  c o n cl u d e.   T h e  hi g h est 
F E V 1  a n d t h e  hi g h est  F V C  o bt ai n e d  at  e a c h t esti n g ti m e  p oi nt ( e v e n if fr o m  diff er e nt 
r e pr o d u ci bl e tr a ci n gs),  will  b e  c oll e ct e d. 
If  a c c e pt a bilit y/r e pr o d u ci bilit y  crit eri a  ar e  n ot  m et,  c o nti n u e t esti n g  u ntil t h e y  are  m et  or t h e 
s u bj e ct  c a n n ot/ s h o ul d  n ot  c o nti n u e ( m a xi m u m  of  5  att e m pts).  
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 5 7  of  1 5 9  
A P P E N DI X  N,  C O VI D -1 9  E M E R G E N C Y  M E A S U R E S  P E R MI T T E D  T O  E N S U R E 
S U B J E C T  S A F E T Y  
T h e f oll o wi n g  a cti viti es  w er e i m pl e m e nt e d i n  or d er t o  e ns ur e s u bj e ct s af et y  d uri n g t h e  gl o b al 
l o c k d o w n  d u e t o t h e  C O VI D- 1 9  p a n d e mi c.  W hil e  gl o b al l o c k d o w n r estri cti o ns  ar e  c urr e ntl y 
b ei n g r el e as e d, t h e  p a n d e mi c  c o nti n u es  a n d i n  c ert ai n t errit ori es,  c as es r e m ai n  o n t h e ris e. 
T h er ef or e,  n e c ess ar y  e m er g e n c y  m e as ur es  a c c e pt e d  d uri n g t h e i niti al  gl o b al l o c k d o w n  w ill  b e 
p er mitt e d t o  pr ot e ct s u bj e ct s af et y i n t h e  e v e nt t h at i nf e cti o n r at es r et ur n t o l e v els r e q uiri n g t h e 
r et ur n  of  g o v er n m e nt  or l o c al r estri cti o ns  o n  m o v e m e nt  of  p e o pl e  a n d  g o o ds. 
A n y  pr o c e d ur e  p erf or m e d  o utsi d e t h e  pr ot o c ol s p e cifi e d r e q uir e m e nts  will  b e  d o c u m e nt e d  as  a 
pr ot o c ol  d e vi ati o n. 
Visit  M a n a g e m e nt:  
D el a y e d  Visits  
 
o   O ut  of  wi n d o w  visits s h o ul d  b e  c o nsi d er e d if it is  n e c ess ar y t o 
s af e g u ar d t h e  h e alt h  of t h e s u bj e ct  a n d sit e st aff  or  e n a bl es  a n 
o n- sit e s u bj e ct  visit.  
o   If  a r et ur n t o l o c k d o w n is  a n n o u n c e d  or t h e sit e is  o n l o c k d o w n 
a n d  c a n n ot  pr o c ess  a  visit, if  p ossi bl e,  visits s h o ul d  b e r e-
s c h e d ul e d t o  e arli er/l at er  as r e q uir e d t o s af e g u ar d s u bj e cts  a n d 
sit e st aff.    
o   R a n d o mi z ati o n: If  a s u bj e ct is i n s cr e e ni n g  a n d  c a n n ot 
c o m pl et e t h e r a n d o mi z ati o n  visit  wit hi n  2 8  d a ys  d u e t o l o c al 
C O VI D - 1 9 l o c k d o w n r estri cti o ns, t h e s cr e e ni n g  p eri o d  m a y  b e 
e xt e n d e d t o  a  m a xi m u m  of  9  w e e ks. I n t h e  e v e nt  of  a n 
e xt e nsi o n t o t h e s cr e e ni n g  p eri o d  > 2 8  d a ys  d u e t o  C O VI D- 1 9, 
t h e f oll o wi n g s af et y  m e as ur e m e nts s h o ul d  b e r e p e at e d i n 
a d v a n c e  of r a n d o mi z ati o n: s af et y l a b or at or y  ass ess m e nts,  E C G, 
vit al si g ns,  c o n c o mit a nt  m e di c ati o ns,  a n d  m e di c al/s ur gi c al 
hist or y.   
o   Visit  6/ W e e k  2 4:  All  eff orts s h o ul d  b e  m a d e t o  c o m pl et e t h e 
ass o ci at e d  ass ess m e nts i n t h e  cli ni c,  e v e n if t his is  visit is 
d el a y e d.  If  n e c ess ar y,  w hil e  w aiti n g f or t h e ti m e t o  c o m pl et e 
t his  visit,  a n  u ns c h e d ul e d  c all  a n d  dr u g  dis p e nsi n g s h o ul d  b e 
d o n e t o  e ns ur e t h e s u bj e ct  h as s uffi ci e nt I P  d uri n g t his ti m e.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 5 8  of  1 5 9  
R e m ot e  Visits    
o   W h er e s u bj e cts  h a v e  C O VI D -1 9 i nf e cti o n, t h e sit e is  o n 
l o c k d o w n, l o c al r estri cti o ns  pr o hi bit  att e n d a n c e,  or si mil ar,  a 
t el e p h o n e  visit s h o ul d  b e  c o m pl et e d.  All  ass ess m e nts 
p erf or m e d s h o ul d  b e  d o c u m e nt e d i n t h e s a m e  w a y t h e y  w o ul d 
if t h e  visit  w o ul d  h a v e  h a p p e n e d  o n sit e.  
o   B ef or e  a r e m ot e  visit is  p erf or m e d,  v er b al  c o ns e nt  m ust  b e 
o bt ai n e d  a n d  d o c u m e nt e d i n t h e s u bj e ct’s  m e di c al  n ot es t o 
e ns ur e t h at t h e s u bj e ct  u n d erst a n ds t h e i m pli c ati o ns  of 
c o nti n ui n g i n t h e st u d y  w h e n f a c e -t o-f a c e  visits  ar e t e m p or aril y 
n ot  p ossi bl e  d u e t o  C O VI D- 1 9 r estri cti o ns.  W h er e  p ossi bl e, t h e 
i n v esti g at or s h o ul d  as k t h e s u bj e ct t o  c o nfir m t h eir  a gr e e m e nt 
i n  writi n g  eit h er  b y  e m ail  or  vi a  a l ett er.  W h er e  m ulti pl e i n-
cli ni c  visits  will  b e  miss e d,  writt e n  c o ns e nt  of t h e s u bj e ct  will 
b e r e q uir e d.   
o   If  a r e m ot e  visit is  c o m pl et e d  a n d it is  c o nsi d er e d  a p pr o pri at e 
a n d s af e t o  c o nti n u e I P, t his  c o ul d  b e  dis p at c h e d  dir e ct t o t h e 
s u bj e ct  b y  c o uri er.   
o   R a n d o mi z ati o n  visits  c a n n ot  b e  c o n d u ct e d r e m ot el y  a n d 
t h eref or e s u bj e cts i n s cr e e ni n g  w h o  d o  n ot  wis h t o  att e n d  a n 
o n-sit e  visit s h o ul d  b e s cr e e n- f ail e d  as  “ wit h dr a w al  of 
c o ns e nt ”.  
o   R e m ot e  Cl os e o ut  Visit s w h er e  n e c ess ar y f or sit es  t h at  h a v e  n o 
e nr oll e d  p ati e nts.  
S u bj e ct 
Dis c o nti n u ati o n 
o   W h er e r e p e at e d  visits  ar e li k el y t o  b e  miss e d, t h e sit e s h o ul d 
dis c uss  wit h t h e s u bj e ct  a n d  c o nsi d er  o n g oi n g tr e at m e nt 
o pti o ns.  W h er e  a s u bj e ct  d o es  n ot  wis h t o  att e n d f urt h er  cli ni c 
visits,  a  P D V  visit s h o ul d  b e s c h e d ul e d  a n d  c o ns e nt s h o ul d  b e 
r e q u est e d to  p erf or m  c o nti n u e d r e m ot e f oll o w- u p  of t h e s u bj e ct 
“ off tr e at m e nt  o n -st u d y ” i n li n e  wit h  gl o b al  a m e n d m e nt  1. 
S hi p m e nt  of  D r u g 
f r o m  Sit e t o  S u bj e cts 
 
o   S u bj e cts s h o ul d  pr o vi d e  v er b al  c o ns e nt  vi a  a t el e p h o n e  c all t o 
us e t h eir  p ers o n al  d et ails t o  c o m pl et e t h e  sit e-t o-s u bj e ct 
s hi p m e nt r e q u est.  C o ns e nt  m ust  b e  d o c u m e nt e d i n t h e s u bj e ct’s 
m e di c al r e c or ds  a n d  pr ef er a bl y  c o nfir m e d i n  writi n g  vi a  a n 
e m ail  or  ot h er  writt e n  m e a ns ( e g,  vi a  p ost).  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Cli ni c al  St u d y  Pr ot o c ol,  V ersi o n  4. 0   
B o n d  A villi o n  2  D e v el o p m e nt  L P  
B u d es o ni d e/ al b ut er ol ( B D A)  –  A V 0 0 3  
 0 8  A pril  2 0 2 1 
 
 
C O N FI D E N TI A L  A N D  P R O P RI E T A R Y   
1 5 9  of  1 5 9  
S af et y  L a bs   
o   W h er e  c e ntr al  a n al ysis is  n ot  p ossi bl e, l o c al t esti n g is 
p er mitt e d.  L a b  n or m al r a n g es  w o ul d  n e e d t o  b e  m a d e  a v ail a bl e. 
o   I n t h e  e v e nt t h at r o uti n e s af et y l a b t ests  ar e  miss e d  d u e t o 
t e m p or ar y i n a bilit y  of s u bj e ct t o  g et t o sit e  d u e t o  C O VI D- 1 9, 
a n  u ns c h e d ul e d l a b s h o ul d  b e  d o n e  at t h e s u bj e ct’s  n e xt  cli ni c 
visit if  p ossi bl e.  
S pi r o m et r y    
o   T h e i n v esti g at or s h o ul d r e q u est  c o nfir m ati o n fr o m t h e s u bj e cts 
t h at t h e y  ar e  n ot  a w ar e  of  h a vi n g  b e e n  e x p os e d t o  C O VI D- 1 9, 
t h at t h e y  ar e  n ot  c urr e ntl y i nf e ct e d  or i nf e cti o us,  a n d s h o ul d 
e x er cis e t h eir  m e di c al j u d g e m e nt  wit h r es p e ct t o t his 
i nf or m ati o n  pri or t o  c o n d u cti n g s pir o m etr y  ass ess m e nts.  Sit es 
s h o ul d  c o nti n u e t o f oll o w  h y gi e n e  a n d  cl e a ni n g  g ui d a n c e 
wit hi n t h e  m a n u als t o  mi ni mi z e  p ossi bl e  cr oss - c o nt a mi n ati o n.   
S u bj e cts  wit h 
c o nfi r m e d 
C O VI D - 1 9 i nf e cti o n 
o   If  a s u bj e ct  h as c o nfir m e d  C O VI D -1 9 t his is t o  b e r e p ort e d  as 
a n  A E/ S A E,  b ut is  n ot  p er s e  a r e as o n t o  wit h dr a w t h e s u bj e ct. 
o   T h e i n v esti g at or s h o ul d  d et er mi n e  w h et h er t h e s u bj e ct’s I P 
s h o ul d  c o nti n u e,  b e i nt err u pt e d,  or st o p p e d i n  a c c or d a n c e  wit h 
t h e  Cli ni c al  St u d y Pr ot o c ol. 
o   T h e i n v esti g at or s h o ul d  c o nti n u e t o r e ass ess t h e  b e n efit- ris k  of 
c o nti n u e d st u d y i n v ol v e m e nt f or  a st u d y s u bj e ct i nf e ct e d  wit h 
C O VI D -1 9. I n - cli ni c  visits f or t his s u bj e ct s h o ul d  o nl y r e-
c o m m e n c e  o n c e t h e i nf e cti o n  h as r es ol v e d  a n d t h e s u bj e ct is  n o 
l o n g er  c o nsi d er e d t o  b e i nf e cti o us. 
o   F or  n e w s u bj e cts  pr e vi o usl y i d e ntifi e d  as  C O VI D- 1 9  p ositi v e, 
a r et est  m ust  b e  p erf or m e d  aft er r es ol uti o n  of s y m pt o ms (if 
pr es e nt).  T h e s u bj e ct  c a n  o nl y  b e  c o nsi d er e d f or  e nr oll m e nt 
4  w e e ks  aft er  h a vi n g  a  n e g ati v e r es u lt. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n

SAP_001.pdf: 
Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 of 8 1 
 
 
St atistic al A n al ysis Pl a n 
 
St u d y C o de 
A V 0 0 3 
 
E diti o n N u m ber 
2. 0 
 
Date 
3 0/ 0 7/ 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 of 8 1 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y St atistici a n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 of 8 1 
 
 
 
 
 
 
 
 
 
 
A villi o n Se ni o r Gl o b al 
M e dic al Le a d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 of 8 1 
 
T A B L E O F C O N T E N T S 
TI T L E P A G E ............................................................................................................................. 1  
SI G N A T U R E O F S T U D Y S T A TI S TI CI A N ............................................................................ 2  
SI G N A T U R E O F G L O B A L P R O D U C T S T A TI S TI CI A N ..................................................... 3  
T A B L E O F C O N T E N T S .......................................................................................................... 4  
LI S T O F A B B R E VI A TI O N S ................................................................................................... 7  
A M E N D M E N T HI S T O R Y ..................................................................................................... 1 0  
1.  
S T U D Y D E T AI L S ............................................................................................... 1 1  
1. 1  
St u d y o bj ecti v es .................................................................................................... 1 1  
1. 1. 1  
Pri mar y o bjecti ve .................................................................................................. 1 1  
1. 1. 2  
Sec o n dar y o bjecti ve .............................................................................................. 1 1  
1. 1. 3  
Safet y o bj ecti v e .................................................................................................... 1 1  
1. 1. 4  
E x pl orat or y o bjecti ve............................................................................................ 1 2  
1. 2  
St u d y d esi g n ......................................................................................................... 1 2  
1. 3  
N u m ber of s u bj ects ............................................................................................... 2 0  
1. 4  
Pri mar y o utc o m e a nal ysis ..................................................................................... 2 0  
2.  
A N A L Y SI S S E T S ................................................................................................ 2 0  
2. 1  
Defi niti o n of a nal ysis sets ..................................................................................... 2 0  
2. 1. 1  
F ull a nal ysis s et..................................................................................................... 2 0  
2. 1. 2  
Safet y a nal ysis set ................................................................................................. 2 1  
2. 1. 3  
All patie nts e nr olle d .............................................................................................. 2 1  
2. 2  
Vi olati o ns a n d de viati o ns ..................................................................................... 2 1  
3.  
D E M O G R A P H Y A N D S U BJ E C T C H A R A C T E RI S TI C S V A RI A B L E S .......... 2 2  
3. 1  
De m o gra p hics ....................................................................................................... 2 2  
3. 2  
Me dical, ast h ma a n d s m o ki n g hist or y .................................................................. 2 3  
4.  
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S ................................................. 2 3  
4. 1  
Ge neral D efi niti o ns ............................................................................................... 2 3  
4. 1. 1  
Defi niti o n of b aseli n e ........................................................................................... 2 3  
4. 1. 2  
A bs ol ute c ha n ge fr o m b aseli n e ............................................................................. 2 4  
4. 1. 3  
Re versi bilit y .......................................................................................................... 2 4  
4. 1. 4  
St u d y d a y c alc ulati o n ............................................................................................ 2 4  
4. 1. 5  
Visit wi n d o wi n g ................................................................................................... 2 4  
4. 1. 6  
Dail y e Diar y v aria bles .......................................................................................... 2 5  
4. 1. 7  
Treat m e nt a vera ge ................................................................................................ 2 6  
4. 1. 8  
I m p utati o n r ules .................................................................................................... 2 6 
4. 1. 9  
Se v ere ast h ma e xacer bati o n d efi niti o n ................................................................. 2 7  
4. 1. 1 0  
Treat m e nt e x p os ure .............................................................................................. 2 7  
4. 2  
Pri mar y Efficac y Me as ure .................................................................................... 2 8  
4. 2. 1  
Ti me t o first se vere ast h ma e xacer b ati o n ............................................................. 2 8  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 of 8 1 
 
4. 3  
Sec o n dar y Efficac y Meas ures............................................................................... 2 8  
4. 3. 1  
A n n ualize d se v ere ast h ma e xacer bati o n rate ........................................................ 2 8  
4. 3. 2  
Deri v ati o n of t ot al s yste mic c ortic ost er oi d e x p os ure ........................................... 2 9  
4. 3. 3  
Ast h ma C o ntr ol Q uesti o n naire- 5 varia bles .......................................................... 3 0  
4. 3. 4  
Deri v ati o n of Ast h m a Q u alit y of Life Q uesti o n naire + 1 2 a n d Pe diatri c Ast h ma 
Q ualit y of Life Q uesti o n n aire varia bles ............................................................... 3 0  
4. 4  
E x pl orat or y Effi cac y Me as ur es ............................................................................ 3 2  
4. 4. 1  
Deteri orati o n of ast h ma varia bles ......................................................................... 3 2  
4. 4. 2  
Deri v ati o n of ti me t o treat me nt disc o nti n uati o n or c ha n ge i n mai nte na nce 
t h era p y f or l ac k of ast h ma c o ntr ol ........................................................................ 3 3 
4. 4. 3  
Deri v ati o n of Ast h m a C o ntr ol Test res p o n d er v ari a ble ........................................ 3 3  
4. 4. 4  
Deri v ati o n of ot h er e Diar y varia bles .................................................................... 3 4  
4. 4. 5  
Deri v ati o n of Ast h m a C o ntr ol Q u esti o n n aire 
 5 e x pl orat or y varia bl es .............. 3 8 
4. 4. 6  
Deri v ati o n of i n hal e d c ortic oster oi d e x p os ure ...................................................... 3 8  
4. 5  
Safet y v aria bl es ..................................................................................................... 3 9  
4. 5. 1  
Vital si g ns ............................................................................................................. 3 9  
4. 5. 2  
A d verse e ve nts (i ncl u di n g seri o us a d v erse e v e nts) .............................................. 3 9  
4. 5. 2. 1  
C ollecti o n of A Es a n d S A Es................................................................................. 3 9  
4. 5. 2. 2  
Defi niti o n of a d v ers e e ve nt lea di n g t o disc o nti n uati o n of i n v esti gati o nal 
pr o d u ct ( D A E) ...................................................................................................... 4 0  
4. 5. 2. 3  
Ot h er si g nifica nt a d v erse e ve nts ( O A Es) ............................................................. 4 1  
4. 5. 2. 4  
A d verse e ve nts d ata h a n dli n g ............................................................................... 4 1  
4. 5. 2. 5  
Defi niti o n of A Es ass o ci ate d wit h l ocal a n d s yst e mic I C S effects ....................... 4 1  
4. 5. 3  
La b orat or y Safet y Varia bles ................................................................................. 4 2  
4. 5. 3. 1  
1 2- Lea d E C G ........................................................................................................ 4 4  
4. 6  
Ot h er v aria bles ...................................................................................................... 4 4  
4. 6. 1  
C o nc o mita nt me dicati o ns ..................................................................................... 4 4  
4. 6. 2  
Disc o nti n uati o n of i n vesti gati o nal pr o d uct ........................................................... 4 4  
4. 6. 3  
Disc o nti n uati o n/ wit h dra wal fr o m t he st u d y ......................................................... 4 5  
4. 6. 4  
C o m plia nce of st u d y m ai nte na nce m e dicati o n ..................................................... 4 6  
4. 6. 5  
Deri v ati o n of GI N A criteria s u b gr o u p varia bles .................................................. 4 7  
5.  
A N A L Y SI S M E T H O D S ...................................................................................... 4 7  
5. 1  
Ge neral pri n ci ples ................................................................................................. 4 7  
5. 1. 1  
Esti ma n ds .............................................................................................................. 4 7  
5. 1. 2  
Disc o nti n uati o n of i n vesti gati o nal pr o d uct ........................................................... 4 8  
5. 1. 3  
C h a n ges i n m ai nt e n a nce t h era p y .......................................................................... 4 9  
5. 1. 4  
T y p e 1 err or c o ntr ol .............................................................................................. 4 9  
5. 1. 5  
A nal ysis met h o ds .................................................................................................. 5 0  
5. 2  
S u bject Dis p ositi o n ............................................................................................... 5 1  
5. 3  
De m o gra p hic a n d Baseli ne C h aracteristics .......................................................... 5 1  
5. 4  
Treat m e nt E x p os ure .............................................................................................. 5 2  
5. 5  
A nal ysis of t h e pri mar y varia ble........................................................................... 5 2  
5. 6  
A nal ysis of t h e sec o n d ar y efficac y varia bles........................................................ 5 4  
5. 6. 1  
Se v ere ast h ma e xacer bati o n rate ........................................................................... 5 4  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 of 8 1 
 
5. 6. 2  
Ast h ma C o ntr ol Q uesti o n naire- 5 .......................................................................... 5 5  
5. 6. 3  
Ast h ma Q ualit y of Life Q uesti o n n aire + 1 2 a n d P e diatric Ast h m a Q u alit y of 
Lif e Q uesti o n naire ................................................................................................ 5 6  
5. 6. 4  
T otal S yste mic c ortic oster oi d e x p os ure ................................................................ 5 7  
5. 7  
A nal ysis of safet y v aria bles .................................................................................. 5 8  
5. 7. 1  
A d verse e ve nts ...................................................................................................... 5 8  
5. 7. 2  
Vital si g ns ............................................................................................................. 6 0  
5. 7. 3  
Cli nical c he mistr y a n d h e m at ol o g y ...................................................................... 6 0  
5. 7. 4  
1 2- Lea d E C G ........................................................................................................ 6 1  
5. 7. 5  
C o nc o mita nt me dicati o n ....................................................................................... 6 1  
5. 8  
A nal ysis of e x pl orat or y v aria bles ......................................................................... 6 1  
5. 8. 1  
Deteri orati o n of ast h ma ........................................................................................ 6 2  
5. 8. 2  
Pre- br o nc h o dilat or F E V 1 ...................................................................................... 6 2 
5. 8. 3  
M or ni n g pea k e x pirat or y fl o w .............................................................................. 6 3  
5. 8. 4  
Ot h er e Diar y varia bles .......................................................................................... 6 3  
5. 8. 4. 1  
Relie ver t hera p y use ............................................................................................. 6 3  
5. 8. 5  
Ti me t o treat m e nt disc o nti n uati o n or c ha n ge i n mai nt e n a nce t h era p y f or lac k 
of ast h ma c o ntr ol .................................................................................................. 6 3  
5. 8. 6  
Ast h ma C o ntr ol Test ............................................................................................. 6 4  
5. 8. 7  
Ast h ma C o ntr ol Q uesti o n naire- 5 e x pl orat or y v aria bles ....................................... 6 4  
5. 8. 8  
Ast h ma C o ntr ol Q uesti o n naire- 5 e x pl orat or y v aria bles ....................................... 6 4  
5. 8. 9  
T otal a d diti o nal i n hale d c ortic oster oi d e x p os ure .................................................. 6 4  
5. 9  
S u b gr o u p a n al ysis ................................................................................................. 6 5  
5. 9. 1  
Efficac y s u b gr o u p a n al yses .................................................................................. 6 5  
5. 9. 2  
Safet y s u b gr o u p a nal ys es ...................................................................................... 6 7  
5. 1 0  
S u p p orti ve a nal ysis ............................................................................................... 6 8  
5. 1 0. 1  
Ti p pi n g p oi nt a nal ysis........................................................................................... 6 8  
5. 1 0. 2  
Attri b uta ble esti ma n d............................................................................................ 7 0  
5. 1 0. 3  
Effecti ve ness esti ma n d ......................................................................................... 7 0  
5. 1 0. 4  
De fact o esti ma n d ................................................................................................. 7 0  
5. 1 1  
C O VI D- 1 9 pa n de mic i m pacts .............................................................................. 7 1  
5. 1 1. 1  
Visits i m pacte d d ue t o C O VI D- 1 9 ....................................................................... 7 1  
5. 1 1. 2  
Pre m at ure disc o nti n uati o n d ue t o C O VI D- 1 9 ...................................................... 7 1  
5. 1 1. 3  
Treat m e nt i nterr u pti o ns d u e t o C O VI D- 1 9........................................................... 7 2  
5. 1 1. 4  
A C Q- 5 a n d A Q L Q + 1 2 data c ollecte d re m otel y d u e t o C O VI D- 1 9 ..................... 7 2  
5. 1 1. 5  
Sc h e d ule d safet y assess m e nts ............................................................................... 7 2  
5. 1 1. 5. 1  
A d verse e ve nts a n d seri o us a d v erse e ve nts d ue t o C O VI D- 1 9 ............................ 7 2  
5. 1 1. 5. 2  
O verall d es cri pti v e s u m mar y ................................................................................ 7 3  
6.  
H A N D LI N G O F D U P LI C A T E P A TI E N T S ........................................................ 7 4  
7.  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L .............................................. 7 5  
7. 1  
T y p e-I err or c o ntr ol f or s ec o n dar y e n d p oi nts ....................................................... 7 5  
7. 2  
Stratificati o n fact ors rec or de d at ra n d o misati o n ................................................... 7 5  
7. 3  
T otal c ortic oster oi d e x p os ure ............................................................................... 7 5  
7. 4  
E x pl orat or y a nal ysis of A C Q- 5 C ha n ges fr o m b aseli ne....................................... 7 5  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 of 8 1 
 
7. 5  
e Diar y varia bles gr o u pe d i nt o 4- wee kl y ti me i nter vals ........................................ 7 6  
7. 6  
Deteri orati o n of ast h ma ........................................................................................ 7 6  
7. 7  
A d diti o nal s u b gr o u p a n al ys es ............................................................................... 7 6  
7. 8  
C O VI D- 1 9 i m pacts ............................................................................................... 7 6  
8.  
R E F E R E N C E S ..................................................................................................... 7 7  
A P P E N DI X 1 .......................................................................................................................... 7 8  
LI S T O F E- DI A R Y Q U E S TI O N S .......................................................................................... 7 8  
A P P E N DI X 2 .......................................................................................................................... 8 0  
G L O B A L I NI TI A TI V E F O R A S T H M A ( GI N A, 2 0 1 8) ........................................................ 8 0  
 
LI S T O F T A B L E S 
Ta ble 1  
St u d y Assess me nts a n d Pr oce d ures ............................................................ 1 6  
Ta ble 2   
4- Wee kl y Ti me I nter v als f or e- Diar y d at a .................................................. 3 4  
Ta ble 3  
La b orat or y Safet y Varia bles ....................................................................... 4 3  
Ta ble 4  
S u b gr o u ps .................................................................................................... 6 6  
 
LI S T O F FI G U R E S 
Fi g ure 1  
St u d y d esi g n ................................................................................................ 1 5  
 
 
LI S T O F A B B R E VI A TI O N S 
A b bre vi ati o n o r s peci al 
ter m 
E x pl a n ati o n 
A C Q- 5 
Ast h ma C o ntr ol Q uesti o n naire- 5 
A C Q- 7 
Ast h ma C o ntr ol Q uesti o n naire- 7 
A C T 
Ast h ma C o ntr ol T est 
A E 
A d verse e ve nt 
A L T 
Ala ni ne tra nsa mi nase 
A Q L Q + 1 2 
Ast h ma Q ualit y of Life Q uesti o n naire f or 1 2 years a n d ol d er 
A S M DI 
Al b uter ol s ulfate metere d- d ose i n haler 
A S T
As partate tra nsa mi nase
B D A M DI  
B u des o ni de/al b ut er ol metere d- d ose i n haler 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 of 8 1 
 
A b bre vi ati o n o r s peci al 
ter m 
E x pl a n ati o n 
U L N 
U p p er li mit of n or mal 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 0 of 8 1 
 
A M E N D M E N T HI S T O R Y 
D ate 
Brief descri pti o n of c h a n g e 
3 0J U L Y 2 0 2 1  
A d d e d t he C O VI D- 1 9 esti ma n d. 
 
A d d e d s u p p orti ve a nal ysis t o t he pri mar y e n d p oi nt w here t he o nset of a C O VI D- 1 9 
relate d a d verse e ve nt or d ose i nt err u pti o n are c o nsi dere d i n t he ce ns ori n g r ule. 
 
A d d e d s u p p orti ve statistics t o descri be t he a n n ualise d os e of s yste mic c ortic oster oi ds.  
 
A d d e d s u b gr o u p s u m maries of c o m plia nce wit h mai nt e na nc e t hera p y. 
 
Detaile d met h o d ol o g y f or ha n dli n g d u plicate patie nts. 
 
A me n d e d t he list of A Es ass o ciate d wit h l o cal a n d s yste mic I C S effects w hic h were 
d ee me d n ot a p pr o priate f oll o wi n g t he p h ysi cia n re vie w (se cti o n 4. 5. 2. 5). 
 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 1 of 8 1 
 
1.  
S T U D Y D E T AI L S 
1. 1  
St u d y o bjecti ves 
1. 1. 1  
Pri m ar y o bjecti ve 
Pri m ar y O bjecti v e:  
Pri m ar y e n d p oi nt:  
T o ev al u ate t he effic acy of b u d es o ni de/ al b uter ol 
metere d- d ose i n h aler ( B D A M DI) 
sy m pt o ms c o m p are d t o al b ut er ol metere d- d ose 
i n h aler ( A S M DI) 
 
Ti m e t o first severe ast h m a ex acer b ati o n  
 
1. 1. 2  
Sec o n d a r y o bjecti v e 
Sec o n d a r y O bjecti ve:  
Sec o n d a r y e n d p oi nt:  
T o c h ar acterize t he effect of B D A M DI 
sy m pt o ms c o m p are d t o A S M DI 
 
S evere ex acer b ati o n r ate ( a n n u alize d) 
T ot al syste mic c ortic oster oi d ex p os ure o ver t he 
tr e at me nt p eri o d 
Ast h m a C o ntr ol Q uesti o n n aire- 5 ( A C Q- 5) c h a n ge 
fr o m b aseli ne a n d res p o n der a n alysis at Week 2 4 
Ast h m a Q u ality of Lif e Q u esti o n n air e f or 1 2 ye ars 
a n d ol d er ( A Q L Q + 1 2)/ P e di atri c Ast h m a Q u ality of 
Life Q u esti o n n aire ( P A Q L Q) c h a n g e fr o m b aseli n e 
a n d res p o n der a n alysis at We ek 2 4  
 
1. 1. 3  
S afet y o bjecti ve 
S af et y O bjecti ve:  
S af et y e n d p oi nts:  
T o ev al u ate t he s afety a n d t oler a bility of B D A 
M DI 
i n r es p o nse t o sy m pt o ms c o m p are d t o A S M DI 
 
A d verse eve nts ( A E) /s eri o us a dvers e eve nts ( S A E) 
Vit al si g ns 
Cli nic al c he mistry a n d h e m at ol o gy p ar a meters 
El ectr o c ar di o gr a m ( E C G)  
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 2 of 8 1 
 
1. 1. 4  
E x pl o r at or y o bjecti ve 
E x pl or at o r y O bjecti ve:  
E x pl or at o r y E n d p oi nts:  
T o c h ar acterize t he effect of B D A M DI 
sy m pt o ms c o m p are d t o A S M DI 
 
A C Q- 5 c h a n ge fr o m b aseli ne a n d res p o n der a n alysis 
at Wee k 1 2 
Ast h m a C o ntr ol Q uesti o n n aire- 5 c h a n ge fr o m 
b aseli n e a n d res p o n d er ( 3-f act or) a n alysis at Week 
1 2 a n d Week 2 4 
A Q L Q + 1 2 / P A Q L Q c h a n g e fr o m b aseli n e a n d 
res p o n der a n alysis at Week 1 2 
Deteri or ati o ns of ast h m a ( a n n u alize d r ate a n d ti me 
t o first deteri or ati o n) 
C h a n ge fr o m b aseli n e i n pre br o nc h o dil at or f orce d 
ex pir at ory v ol u m e i n 1 sec o n d at Week 1 2 a n d Week 
2 4  
M or ni n g a n d eve ni n g p e a k ex pir at ory fl o w 
Use of i nvesti g ati o n al pr o d uct (relie ver t her a p y)  
Ast h m a d a yti m e/ ni g ht-ti me s y m pt o ms 
Ti m e t o tre at me nt disc o nti n u ati o n or c h a n ge i n 
m ai nte n a n ce t her a py 
Ast h m a C o ntr ol Test ( A C T) or C hil d h o o d Ast h m a 
C o ntr ol Test ( C A C T) c h a n g e fr o m b aseli n e a n d 
res p o n der a n alysis at Week 2 4 
- fr ee d ays  
Perce nt a ge of sy m pt o m-fr ee d ays  
Perce nt a ge of ast h m a c o ntr ol d ays 
I n h ale d c ortic oster oi d ex p os ure over t h e tre at me nt 
p eri o d 
 
1. 2  
St u d y desi g n 
T his is a ra n d o mi ze d, d o u ble- bli n d, m ultice nter, parallel- gr o u p, v aria ble-le n gt h, e ve nt- dri ve n 
st u d y wit h a treat me nt peri o d of at least 2 4 w ee ks f or eac h s u bj ect. T h e p ur p ose of t his st u d y 
is t o c o m pare 2 d oses of B D A M DI wit h A S M DI o n t h e ti m e t o first se vere ast h ma 
e xacer bati o n i n a d ult, a d olesce nt, a n d p e diatric s u bjects wit h m o derate t o s e vere ast h ma as 
d efi ne d b y t he Gl o bal I nitiati v e f or Ast h m a ( GI N A). S u bjects will a d mi nister ra n d o miz e d 
i n vesti gati o nal pr o d u ct (I P) as nee de d ( pr n) i n res p o nse t o ast h m a s y m pt o ms. S ee Fi g ure 1 f or 
a gra p hical prese nt ati o n of t h e st u d y s c he ma a n d Ta ble 1 f or a list of st u d y assess me nts. 
S u bjects atte n di n g scree ni n g ( Visit 1) will e nter a 1 4- t o 2 8- da y s cree ni n g a n d r u n-i n peri o d. 
T he scree ni n g peri o d m a y b e e xte n d e d t o a ma xi m u m of 9 wee ks f or s u bj ects w h o ha v e a 
se vere ast h ma e x acer bati o n after Visit 1. S u bjects m a y c o nse nt f or t h e st u d y i n a d v a nce of 
Visit 1 a n d if re q uire d, re q uest f or me dical r ec or ds t o s u p p ort e vi de nce of pri or e xacer bati o ns 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 3 of 8 1 
 
wit h o ut tri g geri n g t h e 2 8- da y s cree ni n g peri o d. Scree ne d s u bjects will c o nti n ue t o ta ke t heir 
re g ular ast h ma mai nte na nce t h era p y t hr o u g h o ut t h e st u d y (fr o m s cree ni n g [ Visit 1/ 1a, as 
a p plica ble] t hr o u g h t h e treat m e nt peri o d). At Visit 1, eli gi ble s u bjects will disc o nti n u e t heir 
us ual pr n i n hal e d pr o d u ct use d f or s y m pt o m r eli ef a n d be gi n S p o ns or- pr o vi de d V e nt oli n t o be 
use d pr n i n res p o nse t o s y m pt o ms or pri or t o e xercis e d uri n g t he scree ni n g peri o d o nl y. 
S u bjects will be as ke d t o t ur n i n t h eir o w n i n hale d reli e v er pr o d u cts t o t h e i n vesti gati o n al sites 
f or st ora ge u ntil t he i n di vi d ual s u bject last st u d y visit. Eli gi bl e s u bjects will be ra n d o miz e d at 
Visit 2. 
At ra n d o mi zati o n ( Visit 2), a d ult a n d a d olesce nt s u bjects (a ge d 
e 
eli gi bilit y criteria will be ra n d o ml y assi g n e d t o 1 of t he f oll o wi n g 3 treat m e nt gr o u ps i n a 
1: 1: 1 rati o as relie ver t hera p y o n t o p of us u al c are. C hil dre n a ge d 4 t o 1 1 years will b e 
ra n d o mi ze d i n a 1: 1 rati o o nl y t o t h e l o wer B D A M DI d os a ge or A S M DI: 
B
M DI 
 
M DI 
 
 
 
T he m a xi m u m dail y d osa ge of I P s h o ul d n ot e xcee d 1 2 p uffs per da y. S u bjects will be 
rec o m m e n d e d n ot t o ta k e m ore t ha n 8 p uffs p er da y a n d a d vis e d t o c o ntact t h e i n vesti gat or if 
t h eir s y m pt o ms nec essitate m ore t ha n 8 p uffs i n a d a y. 
T he m a xi m u m dail y d osa ge is 1 2 p uffs ( B D A M DI 4 8 0/ 1 0 8 0 µ g or 9 6 0/ 1 0 8 0 µ g, or A S M DI 
1 0 8 0 µ g). I n or der t o e ns ure safet y a n d m o nit or dail y treat me nt stat us, all s u bjects will be 
pr o vi d e d wit h a n electr o nic diar y (e Diar y: A M 3 d e vice). T he e Diar y tra nsfers d ata e ver y 2 4 
h o urs acr oss a ra n g e of ast h ma s y m pt o m sc ores a n d dr u g us a ge (ie, n u m ber of p uffs i n hale d) 
a n d a n y s y m pt o ms. If s y m pt o ms a n d/ or dail y d os a ge e x cee d a pr ot o c ol-s p ecifie d t hres h ol d, 
t h e e Diar y will ge n erate a n alert t o t he s u bject a n d t h e i n vesti gati o n al site. I n t his w a y, d ail y 
I P usa ge will be m o nit ore d cl osel y b y t h e i n vesti gat ors a n d me dical m o nit ors t o assess a n y 
w orse ni n g of s u bject stat us. A cti o n will b e ta ke n w here cli nicall y i n dic ate d. 
 
T he st u d y will c o nsist of 3 p eri o ds:  
Scree ni n g peri o d ( 1 4 t o 2 8 da ys) e xce pt w here a se v ere e xacer b ati o n e ve nt occ urs d uri n g 
t h e scree ni n g peri o d, a n d t his ma y be e xte n de d t o a ma xi m u m of 9 wee ks. ( S u bjects ma y 
c o nse nt f or t h e st u d y i n a d va nce of Visit 1 a n d if re q uire d, re q u est f or m e di cal rec or ds t o 
s u p p ort e vi de nce of pri or e x acer bati o ns wit h o ut tri g geri n g t h e 2 8- da y s cree ni n g peri o d.)  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 4 of 8 1 
 
Treat m e nt peri o d of at l east 2 4 wee ks. T h e st u d y treat me nt peri o d will c o nti n u e 
(e xte nsi o n p hase) u ntil t he re q uire d 5 7 0 first se vere e x acer bati o n e ve nts, as defi ne d per 
pr ot oc ol, ha v e be e n reac h e d a n d t he last a d ult s u bject h as c o m plete d 2 4 wee ks of 
treat m e nt, w hic h will be d efi n e d as t h e pri m ar y c o m pl eti o n date ( P C D). N ot all pe diatric 
s u bjects will h a ve 2 4 wee ks of treat me nt at ti me of P C D. 
I n t h e e ve nt 5 7 0 e v e nts are ca pt ure d bef o re  t he last a d ult p atie nt has ha d 2 4 w ee ks of 
 w ee ks will h a ve t heir e n d- of-st u d y ( E O S) 
visit at t heir n e xt sc he d ule d cli nic visit. All s u bjects o n treat m e nt f or < 2 4 w ee ks will 
c o nti n ue u ntil 2 4 wee ks at w hic h p oi nt t he y will c o m plete t heir E O S visit  
I n t h e e ve nt 5 7 0 e v e nts will b e ca pt ure d after  t he last s u bj ect has ha d 2 4 wee ks of 
treat m e nt, eac h s u bj ect will ret ur n t o c o m plete t h e E O S visit at t heir ne xt sc he d ul e d 
cli nic visit 
Safet y f oll o w- u p peri o d: w here a safet y f oll o w- u p tele p h o ne c o ntact will occ ur 2 wee ks 
( ± 4 d a ys) after 
E O S visit or pre mat ure disc o nti n u ati o n visit ( P D V), 
w hic he ver occ urs first 
 
T he st u d y will be c o m plete d w he n t he last s u bject has c o m plete d his/ h er p ost st u d y f oll o w- u p 
tele p h o ne c o nta ct. S u bjects w h o disc o nti n ue will c o m plete a P D V, a n d A Es/ S A Es will b e 
f oll o we d u p if me dicall y i n di cate d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 5 of 8 1 
 
Fi g u re 1  
St u d y desi g n  
 
A b bre viati o ns: A S M DI =al b uter ol metere d- d ose i n haler; B D A M DI = b u des o ni d e/al b uter ol metere d- d ose i n haler; 
I C S =i n hale d c ortic oster oi d; L A B A =l o n g-
-a g o nist; N = n u m ber; P R N =as nee de d; R =ra n d o mizati o n; 
S A B A =s h ort-
-a dre n orece pt or a g o nist; S V =scree ni n g visit; W = wee k.  
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
 1 8 of 8 1 
 
b 
Visit 1 will b e s plit a n d use d f or re peate d assess me nts, if ne e d e d (ie, Visit 1a will b e nee d e d f or t he re p eat assess me nt of al b uter ol/sal b uta m ol re versi bilit y 
test a n d F E V1, if a p plica ble). S u bj ects ma y c o nse nt f or t he st u d y i n a d va nce of Visit 1 a n d if r e q uire d, re q uest f or me dic al rec or ds t o s u p p ort e vi de nce of pri or 
ast h ma e xacer bati o ns wit h o ut tri g geri n g t he 2 8- d a y scree ni n g p eri o d.  W here a se ver e e xacer b ati o n e ve nt o cc urs d uri n g t he scree ni n g p eri o d, t his ma y b e 
e xte n de d t o a ma xi m u m of 9 wee ks (t o acc o u nt f or a c o urse of s yste mic c ortic oster oi ds of u p t o 1 wee k d ur ati o n f oll o we d b y a 4- wee k was h o ut peri o d). I n t he 
e ve nt of a n e xte nsi o n t o t he scree ni n g peri o d d ue t o a se vere e xacer b ati o n e ve nt, t he f oll o wi n g will b e re peate d: safet y la b orat or y assess me nts, E C G, vital si g ns, 
c o nc o mit a nt me dicati o ns, a n d me dical/s ur gical hist or y.  
c 
T he treat me nt d urati o n f or t he st u d y will be at least 2 4 wee ks f or eac h s u bject t o s u p p ort t he s u bject e x p os ure d ata. T he st u d y treat me nt p eri o d will c o nti n ue 
(e xte nsi o n p hase) u ntil t he r e q uire d 5 7 0 first se vere e xacer bati o n e v e nts, as d efi ne d per pr ot o c ol, ha ve b ee n reac he d; a n d t he last a d ult s u bj ect has c o m plete d 2 4 
wee ks of treat me nt, w hic h will b e d efi ne d as t he P C D. After Visit 6, visits will b e sc he d ule d e ver y 1 2 wee ks wit h t he assess m e nts fr o m Visit 7 t o be perf or me d 
i n all of t he m.  
d 
 
o cc ur at t heir ne xt sc he d ule d cli nic visit. O nce t he P C D has bee n reac he d, a n y o n g oi n g s u bject will ret ur n t o c o m plete a n E O S visit at t heir ne xt sc he d ule d cli nic 
visit. 
e 
S u bj ects w h o pre mat urel y wit h dra w fr o m t he st u d y will u n d er g o a P D V.  I n t he e ve nt t he P D V is p erf or me d > 1 4 da ys p ost last I P d osi n g, a f oll o w- u p T C 
will n ot b e re q uire d. T hese s u bj ects w h o d o n ot wit h dra w c o nse nt f or f oll o w- u p will be f oll o we d f or s ur vi val/ deat h, se ver e e xacer b ati o ns, A Es/ S A Es, a n d 
c o nc o mit a nt me dicati o ns i ncl u di n g ast h ma treat me nt ( mai nte na nce a n d resc ue t hera pies) at q uarterl y i nter vals u ntil E O S. 
f 
 
a ge at t he ti me of si g ne d i nf or me d c o ns e nt/asse nt ( w here a s u bject c ha n ges a ge d uri n g t he st u d y).  
g 
De m o nstrate re versi bilit y at Visit 1, wit h a n i ncrease i n F E V 1 
S p o ns or- pr o vi de d Ve nt oli n vi a ce ntral s pir o metr y at eit her Visit 1 or Visit 1a (re versi bilit y m ust b e de m o nstrat e d at eit h er Visit 1 or Visit 1a); Visit 1 a m ust b e 
use d f or re-testi n g, if nee d e d; wit h o nl y 1 re versi bilit y re-test p er mitte d i n a d va nce of ra n d o mizati o n ( Visit 2).  
h 
- h C G) will b e p erf or me d at Visit 1, 6, a n d E O S/ P D V
- h C G test will b e p erf or me d at all ot her cli nic visits (f or w o me n of 
c hil d beari n g p ote ntial o nl y). (I n Ar ge nti na, w o me n of c hil d beari n g p ote ntial will ha ve a d diti o nal pre g na nc y testi n g at m o nt hl y ti me p oi nts.)  
i 
Ast h ma e xacer b ati o ns data will be re vie we d, a n d se vere e xacer bati o ns i d e ntifie d. S u bjects are t o b e re mi n de d n ot t o ta ke a n y al b uter ol pr o d uct e xce pt f or 
t he I P. 
j 
Ast h ma C o ntr ol Q uesti o n naire- 5 self-a d mi nistere d a d ult versi o n t o be use d f or a d ults a n d a d olesce nts 1 1 years a n d ol d er; t he i nter vie wer-a d mi nistere d 
versi o n s h o ul d be use d f or c hil dre n 4 t o 1 0 years. S u bj ect will nee d t o satisf y A C Q-
 
k 
S u bj ect will nee d t o satisf y A C Q-
 
l 
T he A M 3 d e vice will b e dis p e nse d at scree ni n g a n d P E F me as ure me nts will b e ta ke n t hr o u g h t he scree ni n g peri o d i n a d va nce of Visit 2. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y 
 1 9 of 8 1 
 
m 
Pre br o nc h o dil at or F E V 1 will b e meas ure d i n t he m or ni n g bet wee n 0 6: 0 0 a n d 1 1: 0 0 A M at Visits 1, 2, 5, a n d 6. Pre br o nc h o dilat or F E V1 
 t o < 9 0 % 
pre dic
a n d at Visit 1 a n d Visit 1a 
[ use d f or re p eate d assess me nts, if nee de d], if a p plica ble, as c o nfir me d b y ce ntrali ze d s pir o metr y). S p o ns or-
1 is meas ure d ( Visits, 1, 2, 5, a n d 6), 
s u bj ects w h ose mai nte na nce t hera p y i ncl u d es L A B A s h o ul d be i nstr ucte d n ot t o use t heir mai nte na nce t hera p y wit hi n t he ti mefra me s pecifi e d per pr ot o c ol  i n 
a d va nce of t he visit as t hese are c o nsi der e d br o nc h o dilat ors. If t hes e me dicati o ns wer e ta ke n wit hi n t he restricte d ti me p eri o ds, visits s h o ul d be re-sc he d ule d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 0 of 8 1 
 
 
1. 3  
N u m ber of s u bjects 
A sa m pl e size of 1 0 0 0 a d ult a n d a d olesce nt s u bje cts p er treat me nt gr o u p a n d o bser vati o n of 
t h e 5 7 0 first se vere e x acer bati o n e ve nts pr o vi des t his st u d y wit h 8 7 % p o wer t o o bser ve a 2 5 % 
re d ucti o n i n t h e ris k of se vere e x acer bati o n wit h at least 1 d ose of B D A M DI vers us A S M DI 
ass u mi n g t h e H oc h ber g pr oce d ure ( H o c h ber g, 1 9 8 8) f or m ulti ple t esti n g a n d a 2-si de d 
si g nifica nce le v el of 5 %. 
I n a d diti o n, u p t o 1 0 0 s u bjects i n t he 4-t o- 1 1 year a ge gr o u p wit h m o derate t o se v ere ast h ma 
will be ra n d o mize d wit h a p pr o xi m atel y 5 0 s u bjects ra n d o mize d t o t he A S M DI gr o u p a n d 
5 0 s u bjects ra n d o mi ze d t o t he l o w d ose B D A M DI gr o u p o nl y. 
1. 4  
Pri m ar y o utc o me a n al ysis 
Pri mar y o utc o m e dat a base l oc k ( p D B L) will c o m me nce o nce al
years) h a ve att e n d e d t heir E O S visit at t h e P C D. T he a nal ys es of pri mar y, s ec o n dar y, 
e x pl orat or y a n d s afet y o bjecti ves will i ncl u de all dat a u p t o t he p D B L, w hic h ma y i n cl u de 
d ata f or c hil dre n a n d a d olesce nts ( 4 t o 1 7 years) w h o are still o n- g oi n g i n t h e trial a n d ha ve 
n ot yet c o m plet e d t he 2 4- wee k treat me nt p eri o d.  
A fi nal data bas e l oc k will o cc ur after t he p D B L, o nce all c hil dre n a n d a d olesce nts h a ve 
c o m plete d t he E O S visit a n d safet y f oll o w- u p. 
Pati e nt le vel listi n gs f or c hil dre n a n d a d olesce nts w h o were o n- g oi n g at t he p D B L will be 
re p orte d at t he fi nal data b ase l o c k. N o effic ac y a n al yses will b e c o n d ucte d o n d ata c oll ecte d 
f oll o wi n g t he p D B L.  
All data c ollecte d will be a vaila ble i n t he S D T M datasets. 
2.  
A N A L Y SI S S E T S 
2. 1  
Defi niti o n of a n al ysis sets 
2. 1. 1  
F ull a n al ysis set 
T he f ull a n al ysis set ( F A S) is defi ne d as all s u bj ects w h o are ra n d o mi ze d t o treat me nt a n d ta ke 
a n y a m o u nt of I P. S u bjects will be a nal yze d acc or di n g t o t h e treat m e nt t h e y w ere assi g n e d at 
ra n d o mi zati o n. A d diti o nall y, d at a s us pecte d t o b e fra u d ule nt will be re vie we d o n a case- b y-
case basis a n d ma y lea d t o e xcl usi o n fr o m t he f ull a nal ysis s et. S u c h e x cl usi o ns will be f ull y 
d oc u me nte d (see Secti o n 2. 2) a n d all data will b e r ea dil y a vaila bl e i n t h e S D T M a n d A Da M 
d atasets. 
All efficac y a nal ys es will be c o n d u cte d i n t he F A S. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 1 of 8 1 
 
F or pri mar y, sec o n dar y a n d e x pl orat or y effic ac y a nal yses, a s u b p o p ulati o n of t he F A S 
i n cl u di n g p ati e nts a ge d 1 2 years a n d ol d er will be us e d t o ma ke c o m paris o ns b et wee n B D A 
1 6 0/ 1 8 0 vs A S M DI 1 8 0. F urt h er details are pr o vi de d i n Secti o n 5. 
T he effi cac y a n d attri b ut a ble esti ma n d will i ncl u de all data o btai ne d bef ore s u bjects 
disc o nti n ue ra n d o miz e d treat m e nt a n d/ or b ef ore a c ha n ge i n mai nte n a nce t h era p y f or lac k of 
ast h ma c o ntr ol. T he effe cti v e n ess esti ma n d will utili ze all o bs er v e d d ata pri or t o I P 
disc o nti n uati o n re gar dless of w het her s u bje cts e x perie nc e a c ha n ge i n mai nt e na n ce t h era p y f or 
lac k of ast h m a c o ntr ol. T h e de fact o esti m a n d will utilize all o bser ve d data, i n cl u di n g p ost-I P 
disc o nti n uati o n data, re gar dless of a c ha n ge i n m ai nte n a nce t h era p y.  
2. 1. 2  
S afet y a n al ysis set 
T he safet y a nal ysis set is defi n e d as all s u bjects recei vi n g a n y a m o u nt of t h e I P. S u bje cts will 
b e classifie d o n t h e b asis of treat m e nt t he y act uall y recei v e d. If a s u bject recei ves m ore t h a n 1 
I P, he or s h e will be s u m marize d acc or di n g t o t he treat m e nt t he s u bject recei v e d t h e m ost. All 
safet y s u m m aries will be base d o n t he safet y a nal ysis set. A d diti o nall y, d ata s us pecte d t o be 
fra u d ule nt will be re vie w e d o n a case- b y-case b asis a n d ma y lea d t o e xcl usi o n fr o m t he s afet y 
a nal ysis s et. S u c h e x cl usi o ns will be f ull y d oc u me nte d (see Se cti o n 2. 2) a n d all data will be 
rea dil y a vaila bl e i n t h e S D T M a n d A Da M d atasets. 
2. 1. 3  
All p atie nts e nr olle d 
 
2. 2  
Vi ol ati o ns a n d de vi ati o ns 
I m p orta nt pr ot o c ol d e viati o ns will b e liste d a n d s u m mari ze d b y ra n d o miz e d treat me nt gr o u p.  
A per- pr ot oc ol a n al ysis e x cl u di n g s u bjects wit h si g nifica nt pr ot o c ol de viati o ns is n ot pla n n e d. 
H o w e ver, a n y s u bj ects or sit e acti vit y i d e ntifie d or s us p ecte d t o b e fra u d ule nt (e. g. s u bj ects are 
e nr oll e d i n t his cli nical st u d y m ore t ha n o nce or a n ot h er i nter ve nti o n al cli nical st u d y, s u bjects 
re-e nr olli n g i nt o t h e st u d y or fa bricate d dat a) ma y be e x cl u de d fr o m t h e a nal ysis p o p ulati o ns 
d efi ne d i n S ecti o n 2. 1. S u c h i nst a nces will be re vie we d o n a case- b y-case b asis a n d f ull y 
d oc u me nte d b y t he S p o ns or pri or t o u n bli n di n g. 
All s u bjects w h o faile d a n y i n cl usi o n/e xcl usi o n criteria a n d were s u bse q u e ntl y ra n d o mi ze d 
i nt o st u d y will be liste d al o n g wit h details of t h e faile d criteria. T his i nf or mati o n will als o be 
s u m m arize d i n ter ms of t h e n u m ber a n d p erce nta ge of s u bjects faili n g a n y of t h e 
i n cl usi o n/e xcl usi o n criteria a n d will be b ase d o n t h e F A S.  
I m p orta nt pr ot o c ol d e viati o ns (I P Ds) are d efi ne d as a s u bs et of pr ot oc ol de viati o ns t hat ma y 
si g nifica ntl y affect t he c o m plete ness, acc urac y, a n d/ or relia bilit y of t h e st u d y d at a or t h at ma y 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 2 of 8 1 
 
si g nifica ntl y affect a s u bject's ri g hts, safet y, or w ell- b ei n g. All pr ot oc ol de vi ati o ns classifie d 
as i m p orta nt will be liste d al o n g wit h t h e f ull d e vi ati o n ter m a n d c o de d t er m as c ollecte d i n t h e 
Pr ot o c ol De viati o ns C R F p a ge. T he i m p orta nt d e viati o ns will be s u m mari ze d i n ter ms of t he 
n u m b er a n d perce nt a ge of s u bjects meeti n g t h e pre- defi n e d pr ot oc ol de viati o n c o d e d ter m as 
d efi ne d i n t h e Pr ot oc ol D e viati o ns C R F p a ge. I m p orta nt pr ot o c ol d e viati o ns will be i de ntifie d 
b y t he s p o ns or pri or t o t h e pri m ar y dat a bas e l oc k a n d u n bli n di n g of t he st u d y res ults. A n 
i n di cati o n o n w het her pr ot o c ol d e viati o ns are li n k e d t o C O VI D- 1 9 will be rec or d e d o n t he 
e C R F. I nci de n ce of C O VI D- 1 9 relate d pr ot oc ol d e viati o ns will be als o s u m mariz e d. 
A n y miss-stratifie d p atie nts will be i de ntifie d as i m p orta nt pr ot o c ol de viati o ns. All pati e nts 
w h o are ra n d o miz e d a n d are part of t he f ull a nal ysis s et will be a nal yz e d acc or di n g t o t h e 
strata t he y were all ocate d t o i n I V R S/I W R S, as o p p ose d t o t heir act u al strata. 
 
3.  
D E M O G R A P H Y A N D S U B J E C T C H A R A C T E RI S TI C S 
V A RI A B L E S 
3. 1  
De m o gr a p hics 
T he f oll o wi n g de m o gra p hic c haracteristi cs will be c ollecte d at Scree ni n g. 
Se x 
Et h nicit y 
Race 
A d diti o nall y, a ge will be c ollecte d at ra n d o miz ati o n. T h e a ge gr o u p strata will b e d eri v e d 
b ase d o n t he a ge at ra n d o mi zati o n a n d will b e cate g orize d as 
C hil dre n: 
 - < 1 2 years 
A d ol esce nts:  
- < 1 8 years 
 A d ults: 
 years 
Re gi o n will be cate g oriz e d i nt o t he 2-le vel fact or use d f or ra n d o mi zati o n a n d will b e c oll ecte d 
o n t he electr o nic case re p ort f or m (e C R F). 
Re gi o n 1: N ort h A merica, Wester n E ur o pe, a n d S o ut h Africa 
Re gi o n 2: R est of w orl d 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 3 of 8 1 
 
Vital si g ns c ollect e d at scree ni n g will i n cl u d e hei g ht, wei g ht a n d b o d y mass i n de x ( B MI).         
Hei g ht will be f urt her c ollecte d at 
1. B MI will b e re- deri ve d base d o n t he c olle cte d hei g ht a n d wei g ht m eas ure me nts rec or de d at 
scree ni n g t o all o w great er precisi o n c o m p are d t o t he B MI c ollecte d o n t h e e C R F, w hic h was 
rec or d e d t o 0 deci mal places.  
B MI will b e calc ulate d as [ wei g ht ( k g)] *[ h ei g ht ( m)] 2. 
3. 2  
Me di c al, ast h m a a n d s m o ki n g hist or y 
Me dical (i ncl u di n g s ur gi cal), ast h m a (i n cl u di n g e x acer bati o ns) a n d s m o ki n g hist or y will b e 
rec or d e d o n t h e e C R F at Visit 1. Me dical hist or y will be cate g orize d i nt o past a n d c urre nt 
me di cal hist or y. C urre nt me dical hist or y will b e defi ne d as a c o n diti o n t hat is eit h er classifie d 
as o n- g oi n g, or e n di n g after t he date of ra n d o miz ati o n. 
A d diti o n all y, t he ti m e si nce dia g n osis of ast h ma ( years) will be calc ulat e d as 
( D ate of r a n d o miz ati o n ( Visit 2) - D ate of di a g n osis of ast h m a + 1)/ 3 6 5. 2 5. 
T he d a y of m ost rece nt s e vere e xacer bati o n will b e calc ul ate d as 
D ate of r a n d o miz ati o n ( Visit 2) 
 D ate of m ost re ce nt severe ex ac er b ati o n pri or t o scree ni n g 
+ 1. 
Partial d ates f or t h e a b o v e calc ul ati o ns will b e h a n dle d as per secti o n 4. 1. 8. 
T he n u m ber of s e vere e xacer bati o ns i n t h e last 1 2 m o nt hs ( 1, > 1) will be c ollecte d o n t he 
e C R F. 
4.  
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S 
4. 1  
Ge ner al Defi niti o ns 
4. 1. 1  
Defi niti o n of b as eli ne  
I n g e n eral, t he last meas ure me nt(s) pri or t o a n d i n cl u di n g t h e d ate of ra n d o mi zati o n will ser ve 
as t h e b aseli ne m eas ure m e nt f or e n d p oi nts d escri b e d b el o w. 
F or e Diar y v aria bles rec or de d d ail y b y t h e s u bject, baseli n e will be cal c ulat e d as t h e a v er a ge 
res ult o ver t he last 1 0 da ys of t h e r u n-i n peri o d, pri or t o ra n d o miz ati o n. See secti o n 4. 1. 6 f or 
t h e d eri vati o n of d ail y sc ores fr o m t h e e Diar y. 
A n y alt er nati ve d eri vati o ns will be descri be d i n t he rele va nt secti o n f or t h e gi v e n e n d p oi nt. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 4 of 8 1 
 
4. 1. 2  
A bs ol ute c h a n ge fr o m b as eli ne 
A bs ol ute c ha n ge fr o m b aseli n e o utc o me varia bles is c o m p ute d as  
( p ost-r a n d o miz ati o n v al u e  b aseli n e v al ue).  
If eit her t he p ost-ra n d o mizati o n val u e or t h e baseli n e val ue is missi n g, t h e n t he a bs ol ute 
c ha n ge fr o m baseli n e v al ue will als o be s et t o missi n g. 
4. 1. 3  
Re versi bilit y 
Re versi bilit y perce nta ge will be c o m p ute d as  
Reversi bility ( %) = ([ P ost F E V 1- Pre F E V1]/ Pre F E V1) × 1 0 0. 
Pre- a n d p ost- br o nc h o dilat or F E V 1 meas ure me nts will b e ca pt ure d wit hi n t h e Master Sc o p e.  
4. 1. 4  
St u d y d a y c al c ul ati o n 
St u d y d a y will re prese nt t h e n u m ber of da ys si nce ra n d o mi zati o n t o st u d y tr eat me nt of a n 
o bser vati o n a n d will be calc ulate d as: 
 
 
4. 1. 5  
Visit wi n d o wi n g 
T he f oll o wi n g visit wi n d o ws will be a p pli e d t o t he sc he d ule d st u d y visits c oll ecte d: 
 
 
 
Visit 
T a r get D a y 
A dj ust e d  
wi n d o ws f or a n al yses ( d a ys): 
 
Bas eli ne ( Wee k 0) 
 
1 
 
1 1 
Wee k 4 
2 9 
2 2  3 6 (± 1 wee k) 
Wee k 8 
5 7 
5 0  6 4 (± 1 wee k) 
Wee k 1 2 
8 5 
7 1  9 9 (± 2 wee ks) 
Wee k 2 4 
1 6 9 
1 4 8  1 9 0 (± 3 wee ks) 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 5 of 8 1 
 
 
 
 
Visit 
T a r get D a y 
A dj ust e d  
wi n d o ws f or a n al yses ( d a ys): 
Wee k 3 6 
2 5 3 
2 3 2  2 7 4 (± 3 wee ks) 
Wee k < 3 6 + x> 2 
2 5 3 + 7 x  
± 3 wee ks 
E n d of St u d y 
N A 
N A 
 E n d of st u d y will b e d efi ne d as t he 
last s c he d ule d cli nic visit pri or t o st u d y 
ter mi nati o n.  
 
 
 
1 Baseli ne will be calc ulate d as s pecifie d i n secti o n 4. 1. 1. 
2 Visits i n t he e xt e nsi o n p hase will be sc h e d ule d e ver y 1 2 wee ks after W ee k 3 6 u ntil t he P C D. T he 
val u e x re prese nts t he n u m b er of wee ks fr o m wee k 3 6 t o eac h visit i n t h e e xte nsi o n p h ase (e. g. t he first 
visit of t h e e xte nsi o n p hase is Wee k 4 8; x = 1 2). 
Sc h e d ule d assess m e nts relati n g t o a pl a n n e d cli ni c visit will be assi g ne d a n a p pr o priate 
sc he d ule d visit fr o m t h e VI SI T m o d ul e. If m ore t h a n o ne sc he d ule d visit occ urs wit hi n t h e 
wi n d o w, t h e n t h e visit cl osest t o t he tar get da y will be fla g g e d f or a nal ysis. If t here are t w o ( or 
m ore) visits e q ui dista nt t o t h e tar get d a y, t h e n t he earlier of t he sc he d ul e d assess me nt will be 
use d i n a n al ysis. U ns c he d ule d visits will n ot be wi n d o we d t o a s c he d ule d assess me nt a n d will 
n ot be s u m m arize d descri pti v el y i n s u m m aries gr o u pe d b y visit. F or t he p ur p oses of visit 
wi n d o wi n g, t he P D V/ E O S visit will be c o nsi d ere d f or visit wi n d o wi n g t o s c he d ule d 
assess me nts i n t h e ra n d o mi ze d treat me nt peri o d a n d e xte nsi o n p hase. 
T he e Diar y varia bl es c oll ecte d dail y will n ot be wi n d o we d t o a n a n al ysis visit a n d a nal ys es of 
t h ese varia bl es will b e base d o n t he m ea n v al u e(s) acr oss t h e treat me nt peri o d (secti o n 4. 1. 7).  
4. 1. 6  
D ail y e Di a r y v a ri a bles  
T he e Diar y will be fille d i n b y t h e s u bject t wice d ail y, o nce i n t h e m or ni n g u p o n a wa ki n g t o 
rec or d i nf or mati o n relati n g t o t h e pre vi o us ni g ht-ti me a n d o nce i n t h e e v e ni n g pri or t o b e dti m e 
a n d t o rec or d i nf or mati o n relati n g t o t h e d a yti m e peri o d. 
F or t he p ur p os e of a nal ys es, d a yti m e res ults rec or d e d o n t he e ve ni n g of da y n  a n d ni g ht-ti m e 
res ults rec or d e d o n t he m or ni n g of d a y n  + 1 will c orres p o n d t o t he a n al ysis da y n. As s u c h, 
d ail y t ot als f or e Diar y v aria bles will be cal c ulate d as: 
D aily t ot al f or e Di ary v ari a ble f or a n alysis d ay n = ( d a yti me r es ult rec or de d i n t h e eve ni n g o n 
d ay n) + ( ni g ht-ti m e res ult rec or d e d i n t h e m or ni n g o n d a y n + 1) 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 6 of 8 1 
 
T his r ule is n ot a p plica ble t o t h e assi g n m e nt of dail y l u n g f u ncti o n data (e. g. dail y P E F) as 
t h ese res ults d o re prese nt t he ti m e p oi nt at w hic h t he y were rec or de d i n t h e e diar y.  
W here a p plica ble, d ail y t otals will o nl y be calc ulate d if b ot h t h e da yti me a n d ni g ht-ti m e 
c o m p o ne nts are n o n- missi n g. T h e dail y t ot als are calc ulate d f or; ast h ma s y m pt o m s c ore, 
relie ver t h era p y i n hal ati o n, s y m pt o m fre e da ys a n d ast h m a c o ntr ol da ys.   
4. 1. 7  
Tre at me nt a v er a ge 
F or A C Q- 5 a n d A Q L Q v aria ble s u m maries, t h e treat m e nt a vera ge s c ore will be calc ulate d b y 
a vera gi n g t h e o verall sc ores c oll ect e d d uri n g t he ra n d o mi ze d treat m e nt peri o d. T he treat m e nt 
a vera ge will als o be c alc ulate d wit hi n eac h of t h e i n di vi d u al d o mai n sc ores. 
F or dail y e Diar y v aria bles, t he treat m e nt a vera ge will b e calc ulate d as t h e s u m of all dail y 
t otals ( Secti o n 4. 1. 6) o ver t h e ra n d o miz e d treat m e nt peri o d a n d di vi di n g b y t he n u m ber of 
e val ua ble d a ys i n t he ra n d o mize d treat me nt peri o d. A n e val ua ble d a y c orres p o n ds t o t h e da ys 
w here b ot h t h e res ult rec or de d i n t h e e v e ni n g a n d t he res ult c oll ecte d o n t h e s u bs e q ue nt are 
n o n- missi n g.  
4. 1. 8  
I m p ut ati o n r ules 
I n or der t o cl assif y a d verse e ve nts a n d c o n c o mita nt me di cati o ns as occ urri n g d uri n g t h e r u n-i n 
p eri o d ( pri or t o r a n d o mizati o n), d uri n g t h e ra n d o mize d treat me nt peri o d ( o n-treat m e nt), or 
p ost ra n d o miz e d treat m e nt disc o nti n uati o n a c o nser vati ve i m p utati o n r ule will be a p pli e d i n 
t h e i nsta nces w here parti al start a n d/ or st o p d ates are rec or d e d.  
T he d at e i m p utati o n al g orit h m s h o ul d b e p erf or me d i n t he f oll o wi n g se q u e n ce: 
P arti al e n d d ate  
1. If missi n g da y [--/ m m/ y y y y] t h e n i m p ute as t he mi ni m u m (e n d of t h e m o nt h, treat m e nt 
disc o nti n uati o n /c o m pl eti o n d ate). 
2. If missi n g m o nt h [--/--/ y y y y] t h e n i m p ute as mi ni m u m ([ 3 1/ 1 2/ y y y y], tr eat me nt 
disc o nti n uati o n). 
3. If c o m pletel y missi n g t h e n i m p ute as date of tre at me nt disc o nti n u ati o n. 
P arti al st art d ate  
4. If missi n g da y [--/ m m/ y y y y] t h e n i m p ute as t he mi ni m u m of: 
Start of t h e m o nt h [ 0 1/ m m/ y y y y] u nless m m/ y y y y is sa me as ra n d o mi zati o n 
t h e n i m p ute as t h e ra n d o mi zati o n date; 
E n d date of me dicati o n/ e ve nt (after partial d ate h a n dli n g has b ee n a p plie d). 
5. If missi n g m o nt h [--/--/ y y y y] t h e n i m p ute as t h e mi ni m u m of: 
Start of t h e year [ 0 1/ 0 1/ y y y y]  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 7 of 8 1 
 
E n d date of me dicati o n/e ve nt (after partial dat e h a n dli n g has be e n a p plie d). 
6. If c o m pletel y missi n g t h e n i m p ute as t he mi ni m u m of: 
Date of ra n d o mi zati o n; 
E n d date of me dicati o n/ e ve nt (after partial d ate h a n dli n g has b ee n a p plie d). 
T he treat me nt disc o nti n uati o n/c o m pleti o n date will b e as rec or de d o n t he disc o nti n uati o n of 
i n vesti gati o nal pr o d u ct e C R F pa ge. 
T he ra w, ori gi n al d ates will be prese nte d i n a n y listi n gs pr o d u ce d. T he i nte nti o n f or date 
i m p utati o n is t o facilitate a pr o gra m matical decisi o n m a ki n g pr o cess t o classif y o n-treat me nt 
o bser vati o ns. 
4. 1. 9  
Se vere ast h m a e x acer b ati o n defi niti o n 
A se vere ast h ma e xacer bati o n is d efi n e d as a w orse ni n g of ast h m a res ulti n g i n at le ast o ne of 
t h e f oll o wi n g criteria: 
 
A te m p orar y b ol us/ b urst of s yste mic c ortic oster oi ds ( S C S) f or at least 3 c o nsec uti v e da ys 
t o treat s y m pt o ms of ast h ma w orse ni n g; a si n gle de p o-i njecta ble d os e of c orti c oster oi ds will 
b e c o nsi dere d e q ui vale nt t o a 3- da y b ol us/ b urst of S C S  
 
A n e mer ge nc y r o o m or ur ge nt care 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 nc y d e part m e nt or ur ge nt care ce ntre) d ue t o ast h ma t hat re q uire d S C S (as 
p er t h e a b o ve) 
 
A n i n-s u bject h os pitalizati o n ( defi ne d as a d missi o n t o a n i n-s u bject facilit y a n d/ or 
e val uati
 
All p ost-ra n d o mi zati o n se vere ast h ma e xacer bati o ns i d e ntifie d b y t h e i n v esti gat or m ust be 
ca pt ure d usi n g t h e Se v ere E x acer bati o n f or m o n t he e C R F. 
A n a dj u dicati o n c o m mittee will a d diti o nall y re vie w p ote nti al cases of se vere e x acer bati o ns 
w hic h ha ve b ee n i de ntifi e d. All a dj u dic ate d e xacer bati o ns a n d i n vesti gat or i de ntifie d 
e xacer bati o ns will be pr o vi de d i n t h e S D T M d ata. 
 s e vere ast h ma 
e xacer bati o n will b e c o nsi dere d as 2 se parate e v e nts of se v ere ast h ma e xacer bati o n. A n e ve nt 
ti me bet w ee n e pis o d es of S C S use 
is < 7 d a ys. 
4. 1. 1 0  
Tre at me nt e x p os ure  
T he t ot al d urati o n ( da ys) fr o m t he first d ose t o t he last d ose (i ncl usi v e) of ra n d o mi ze d st u d y 
dr u g is calc ulate d as: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 8 of 8 1 
 
D ate of l ast d ose of r a n d o mize d st u dy dr u g - D ate of first d os e of r a n d o mize d st u dy dr u g + 1 . 
T he d at e of l ast d os e of ra n d o mize d st u d y dr u g will be use d i n t h e a b o ve calc ulati o n 
re gar dl ess of a c ha n ge i n mai nte na nce t h era p y d u e t o a l ac k of ast h m a c o ntr ol. 
4. 2  
Pri m ar y Effic ac y Me as ure 
4. 2. 1  
Ti me t o first se vere ast h m a e x acer b ati o n 
Ti me t o first se vere ast h ma e xacer b ati o n will b e calc ulate d as t h e ti m e fr o m ra n d o mi zati o n 
u ntil t he start date of t he first se vere ast h m a e xacer bati o n: 
St art d ate of first severe ast h m a ex acer b ati o n  D ate of r a n d o miz ati o n ( Visit 2) + 1 
U n der t he effic ac y esti m a n d, s u bjects w h o d o n ot e x perie nce a s e vere e xacer bati o n pri or t o I P 
disc o nti n uati o n or a c ha n ge i n m ai nt e n a nce t h era p y will be ce ns ore d at t h e earliest oc c urre nce 
of t h ese i nt erc urre nt e ve nts. 
U n der t he attri b uta bl e esti ma n d, s u bjects w h o are ce ns ore d u n d er t h e r ules f or t he efficac y 
esti m a n d will ha ve t heir e ve nt ti mes i m p ute d. I m p utati o n m et h o ds f or t h e ti m e t o first se vere 
e xacer bati o n e n d p oi nt u n der t h e attri b ut a ble esti ma n d are detaile d i n S ecti o n 5. 1 0. 2. 
U n der t he de fact o esti m a n d, all se vere e x acer bati o n e ve nts p ost-treat m e nt dis c o nti n uati o n 
will be c o nsi dere d, re gar dless of a n y c h a n ges i n mai nte na nce t h era p y w hi c h mi g ht o cc ur. 
T heref ore, s u bjects n ot ha vi n g a se vere e xacer bati o n e ve nt pri or t o st u d y wit h dra wal will be 
ce ns ore d at t h e d ate of st u d y disc o nti n u ati o n. 
Se v ere e x acer bati o ns will b e rec or de d o n t he Se vere E xacer b ati o n e C R F p a ge, o n e e ntr y 
c orres p o n ds t o o ne s e vere e x acer bati o n, w hi c h i n cl u des t h e start ti m e of t h e cli nical e ve nt. 
4. 3  
Sec o n d ar y Effic a c y Me as ures 
4. 3. 1  
A n n u alize d se vere ast h m a e x acer b ati o n r ate 
F or t he pr o d u cti o n of s u m m ar y statistics, t h e ra w a n n ualiz e d s e vere ast h m a e x acer bati o n rate 
will be calc ulate d acc or di n g t o t h e f oll o wi n g f or m ula: 
 
W here t h e s u m m ati o ns are o ver all s u bjects wit hi n a treat m e nt ar m.  
F or s u bjects w h o d o n ot disc o nti n ue I P or d o n ot recei ve a c ha n ge i n mai nt e na nce t hera p y f or 
lac k of ast h m a c o ntr ol, f oll o w- u p is calc ulate d as t he d urati o n ( da ys) fr o m d ate of 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 9 of 8 1 
 
ra n d o mi zati o n, t o t he earliest occ urre n ce of eit h er I P disc o nti n uati o n/c o m pleti o n or c ha n ge i n 
mai nte na nce t hera p y:  
[ D ate of I P dis c o nti n u ati o n/c h a n ge i n m ai nte n a nce t her a py]  [ d ate of r a n d o miz ati o n ( Visit 
2)] - [c u m ul ative d ur ati o n of severe ex ac er b ati o n(s)] + 1. 
T he a n n ualiz e d se vere ast h ma e xacer b ati o n rat e will als o be d eri v e d a cc or di n g t o t he d e fact o 
esti m a n d, a n d c o nsi der all se vere e x acer bati o n e v e nts p ost-treat m e nt disc o nti n uati o n, u ntil 
c o m pleti o n/ wit h dra wal fr o m t he st u d y, re gar dless of c ha n ges i n m ai nte na nce t hera p y. U n d er 
t h e d e fact o esti ma n d, t h e f oll o w- u p as descri be d i n t h e a b o v e calc ulati o n will be defi n e d as 
t h e o bser vati o n p eri o d fr o m t he date of ra n d o mi zati o n, u p t o t he d at e of st u d y c o m pleti o n, or 
wit h dra wal f or eac h patie nt. 
4. 3. 2  
Deri v ati o n of t ot al s yste mic c ortic oster oi d e x p os ure 
T otal s yste mic c ortic oster oi d ( S C S) e x p os ure re p orte d as t h e t otal a n n ualiz e d d ose ( m g/ ye ar)  
will be calc ulate d f or eac h s u bject as t he s u m of t h e c u m ulati v e d oses of c orti c oster oi d di vi de d 
b y t he d urati o n of ti me ( years) t h e s u bj ect was i n t he st u d y, fr o m ra n d o mizati o n a n d u p t o 
treat m e nt disc o nti n uati o n. S p ecificall y t h e a n n u ali ze d t otal s yst e mic c ortic oster oi d d ose will 
b e calc ul ate d as f oll o ws: 
A n n u alize d t ot al syste mic c orti c oster oi d d ose = { T ot al syste mic c orti c oster oi d d ose / ( D ate of 
tre at me nt c o m pleti o n/ dis c o nti n u ati o n  D ate of r a n d o miz ati o n + 1)} × 3 6 5. 2 5 
Eac h S C S will b e n or malize d t o t he e q ui p ote nt d ose of pre d nis o n e ( m g) b ef ore calc ulati n g t he 
a n n ualiz e d t otal d ose. 
T otal c ortic oster oi d e x p os ure will be cal c ulate d u n d er t he efficac y esti m a n d a n d will c o nsi der 
ster oi d e x p os ure pri or t o disc o nti n u ati o n of I P or a c h a n ge i n m ai nte n a nce t h era p y. 
A d diti o nall y, t his e n d p oi nt will b e d eri v e d u n d er t h e effecti v e n ess esti m a n d a n d will c o nsi der 
ster oi d e x p os ure pri or t o t he disc o nti n u ati o n of I P, re gar dless of c h a n ges i n mai nte n a n ce 
t h era p y, a n d t h e d e fact o esti m a n d, w hic h will c o nsi d er ster oi d e x p os ure, re gar dless of 
c ha n ges i n mai nte na n ce t hera p y a n d u p t o wit h dra wal fr o m t h e st u d y. 
S yste mic c ortic oster oi ds t o b e c o nsi d ere d f or t he t otal a n n uali ze d d ose of S C S will b e 
i d e ntifie d wit h A T C c o d e H 0 2 A B a n d b ei n g ta ke n f oll o wi n g a s e vere e x ac er bati o n, w hic h is a 
s pecifie d fiel d pr o vi d e d o n t he C M m o d ule. 
 
T he t otal d ose f or t h es e ster oi ds will be deri v e d b y m ulti pl yi n g t h e t otal dail y d ose b y t h e 
d urati o n t h e treat me nt w as pres cri b e d (i n d a ys).  
D os es of S C S n ot c oll ecte d i n m g s h o ul d be c o n v erte d bef ore b ei n g us e d i n calc ulati o ns. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 0 of 8 1 
 
S C S m e di cati o n will be n or malize d t o t he e q ui p ote nt d ose of pre d nis o n e ( m g) b ef ore bei n g 
use d i n t he calc ulati o n of t otal c orti c oster oi d e x p os ure. T his will be facilitate d t hr o u g h a 
scie ntific re vie w of ster oi d me dicati o n re p orte d o n t h e C M m o d ule a n d t h e c o n versi o ns will 
b e pr o vi de d t o  
. A d diti o nall y, t he s cie ntific re vie w of S C S f or ast h m a will e ns ure 
t h e d ail y d ose f or s uc h m e di cati o n is a p pr o priat el y ca pt ure d a n d t h at t h e u nits are of a n 
acce pta ble f or mat t o all o w c o n versi o ns t o e q ui p ot e nt d oses of b u des o ni de (i. e. u g or m g, n ot 
 
T he c u m ulati v e d urati o n of s yste mic c ortic oster oi d use will be calc ulat e d as t h e o v erall 
n u m b er of d a ys d uri n g t h e ra n d o mi ze d treat me nt p eri o d f or w hic h pati e nts were prescri be d 
s yste mic c ortic oster oi ds. 
4. 3. 3  
Ast h m a C o ntr ol Q uesti o n n aire- 5 v ari a bles  
All 5 s y m pt o m q uesti o ns are ass esse d o n a 7- p oi nt scale ( 0 = g o o d c o ntr ol; 6 = p o or c o ntr ol). 
T he o verall sc ore is t he m ea n of t h e 5 s y m pt o m ite ms.  
T he A C Q- 5 o verall sc ore will be calc ulate d as t h e a vera ge of t he n o n- missi n g 5 s y m pt o m 
q uesti o ns. At least 4 o ut of t he 5 s y m pt o m it e ms are nee d e d t o pr o vi de a n A C Q- 5 o verall 
sc ore.  
A res p o n d er stat us at Wee k 2 4 will b e calc ul ate d as 
Res p o n der: ( Wee k 2 4 
 
 - 0. 5 
N o n-res p o n der: ( Wee k 2 4 
 baseli ne) > - 0. 5 
 
U n der t he effic ac y esti m a n d, s u bjects w h o disc o nti n ue treat me nt f or a n y reas o n or recei ve a 
c ha n ge i n mai nte na nce t h era p y f or lac k of ast h ma c o ntr ol bef ore W ee k 2 4 will be classifi e d as 
n o n-res p o n ders. Baseli ne is defi n e d as t he m ost rece nt n o n- missi n g sc ore b ef ore a n d i ncl u di n g 
ra n d o mi zati o n ( Visit 2).  
A si mil ar a nal ysis will be c o n d ucte d at W ee k 1 2. T his will b e c o nsi dere d a n e x pl orat or y 
e n d p oi nt. 
T he i nter vie wer-a d mi nistere d v ersi o n will be i m ple me nte d f or c hil dre n a ge d 4 t o 1 0 years. As 
t h e A C Q- 5 is n ot v ali date d f or c hil dre n less t ha n 6 years ol d, data f or s u bjects w h o ar e 4 or 5 
years of a ge will be e x cl u de d fr o m t he a n al ys es of A C Q- 5 e n d p oi nts a n d will b e liste d o nl y. 
4. 3. 4  
Deri v ati o n of Ast h m a Q u alit y of Life Q uesti o n n aire + 1 2 a n d P e di atric 
Ast h m a Q u alit y of Life Q uesti o n n aire v ari a bles 
T here will be s e p arate q u esti o n naires f or b ot h a d ults a n d c hil dre n. B ot h s ets of q uesti o n naires 
will be a nal yze d s e paratel y.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 1 of 8 1 
 
T he A Q L Q + 1 2 i ncl u des 3 2 q uesti o ns, o n a 7- p oi nt scale ( 1- 7), relati n g t o 4 disti nct d o mai ns, 
hi g her v al ues i n dicat e b ett er healt h-relate d q ualit y of life: 
S y m pt o ms ( 1 2 q u esti o ns; mi ni m u m 8 q u esti o ns re q uire d f or a vali d sc ore) 
Acti vit y li mitati o n ( 1 1 q uesti o ns; mi ni m u m 7 q uesti o ns re q uire d f or a v ali d sc ore) 
E m oti o nal f u ncti o n ( 5 q uesti o ns; mi ni m u m 3 q uesti o ns re q uire d f or a vali d s c ore) 
E x p os ure t o e n vir o n me ntal sti m uli ( 4 q uesti o ns; mi ni m u m 3 q uesti o ns re q uire d f or a 
v ali d sc ore) 
T he P A Q L Q i n cl u d es 2 3 q u esti o ns relati n g t o 3 disti nct d o mai ns, hi g her val ues i n dicate bett er 
h ealt h-relate d q ualit y of life: 
S y m pt o ms ( 1 0 q u esti o ns; mi ni m u m 6 q uesti o ns re q uire d f or a vali d s c ore) 
Acti vit y li mitati o n ( 5 q u esti o ns; mi ni m u m 3 re q uire d f or a v ali d s c ore) 
E m oti o nal f u ncti o n ( 8 q uesti o ns; mi ni m u m 5 re q uire d f or a v ali d sc ore) 
F or eac h of t h e d o mai ns, a d o m ai n sc ore is c alc ulate d as t h e m ea n s c ore of all its c o nstit u e nt 
q uesti o ns. A n o verall sc ore acr oss t he w h ole q uesti o n n aire is calc ulat e d as t he me a n sc ore of 
all q u esti o ns. I n case of a n y missi n g a ns wers, t h e o verall sc ore is calc ulat e d as a wei g hte d 
mea n of t he d o mai n sc ores, wit h t he n o mi nal fracti o n of it e ms i n eac h d o m ai n as wei g hts.  If 
o ne or m ore d o m ai ns are missi n g, t he o verall sc ore is als o missi n g. ( N ote: w he n t here are n o 
missi n g a ns wers, t his met h o d is e q ui v ale nt t o t h e a vera ge res p o nse of all 3 2 q uesti o ns ta ke n 
i n di vi d uall y). 
A res p o n d er stat us at Wee k 2 4 will b e calc ul ate d as s u bjects ac hie vi n g a c ha n ge fr o m b aseli ne 
of at l east 0. 5: 
Res p o n der: ( Wee k 2 4 
 
 0. 5 
N o n-res p o n der: ( Wee k 2 4 
 baseli ne) < 0. 5 
 
S u bjects w h o disc o nti n u e treat me nt bef ore Wee k 2 4 f or a n y reas o n or c ha n ge i n mai nte na n ce 
t h era p y will b e classifi e d as n o n-res p o n d ers. Baseli ne is defi ne d as t he m ost rece nt n o n-
missi n g sc ore b ef or e a n d i ncl u di n g ra n d o miz ati o n ( Visit 2).  
A si mil ar a nal ysis will be c o n d u cte d at Wee k 1 2. T his will b e c o nsi dere d a n e x pl orat or y 
e n d p oi nt. 
As t h e P A Q L Q is n ot v ali d ate d f or c hil dre n less t h a n 7 years of a ge, data f or s u bjects w h o are 
a ge d 4 t o 6 years will b e e xcl u de d fr o m t he a n al ys es of P A Q L Q e n d p oi nts a n d will b e liste d 
o nl y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 2 of 8 1 
 
4. 4  
E x pl o r at o r y Effic ac y Me as ures 
4. 4. 1  
Deteri o r ati o n of ast h m a v a ri a bles 
T he s u bject will use t h e e Diar y f or d ail y s y m pt o m re p orti n g, e nteri n g s y m pt o ms t wice d ail y. 
I n p artic ular t h e s u bject will rec or d t heir da yti me s y m pt o ms ( 0 = N o ast h ma s y m pt o ms; 3 = Y o u 
were u na ble t o d o y o ur n or mal acti vities beca us e of y o ur ast h ma), ni g ht-ti m e s y m pt o ms 
( 0 = N o s y m pt o ms; 1 = y o u were a ware of y o ur ast h ma s y m pt o ms b ut y o u ca n easil y t olerate 
t h e s y m pt o ms; 2 = y o ur ast h ma was ca usi n g y o u e n o u g h dis c o mf ort t o ca use pr o ble ms wit h 
slee p; 3 = Y o u w ere u n a ble t o sl ee p b eca use of y o ur ast h m a), a n d t h eir res c ue m e dicati o n use 
 9 9 p uff(s)): 
I n t his st u d y, deteri orati o n of ast h ma is defi n e d as 1 or m ore of t he f oll o wi n g ite ms f or at least 
2 c o nsec uti v e da ys:  
P E F: a decli n e of at least 2 0 % fr o m b aseli ne i n eit h er t h e m or ni n g or e ve ni n g res ult 
Relie ver t hera p y use: > 4 p uffs p er d a y a n d at le ast t wice as fre q u e nt t h a n rec or de d at 
b aseli ne ( p er d a y) 
S y m pt o ms: ni g ht-ti me sc ore t hat is greater t ha n b aseli n e a n d at least 2 O R a d a yti me 
sc ore t hat is greater t ha n baseli ne a n d 3 ( m ost s e vere o utc o m e) 
Se v ere ast h ma e xacer bati o n 1 
 
Relie ver t hera p y use a n d s y m pt o m sc ores will b e rec or d e d i n t he e Diar y. Baseli n e relie ver 
t h era p y use will be calc ul ate d as t h e a v era ge n u m b er of p uffs per d a y d uri n g t h e last 1 0 da ys 
of t h e r u n-i n peri o d.  
Da yti me is d efi n e d as t he ti m e peri o d bet wee n t h e m or ni n g l u n g f u n cti o n assess m e nt ( u p o n 
risi n g i n t h e m or ni n g) a n d t h e e ve ni n g l u n g f u ncti o n assess me nt. 
Ni g ht-ti me is defi ne d as t he ti me peri o d bet wee n t h e e ve ni n g l u n g f u n cti o n assess me nt (at 
b e dti m e) a n d t he m or ni n g l u n g f u ncti o n assess me nt. 
If t he a b o v e criteria are m et f or > = 2 c o nsec uti ve d a ys, it will b e c o nsi dere d as o ne 
d eteri orati o n of ast h ma u ntil t he criteria are n o l o n ger m et or b ec o me u n e val ua ble. 
Deteri orati o ns of ast h ma will be c o nsi dere d as a si n gle d eteri orati o n if t h ere are fe wer t h a n 3 
da ys b et wee n t he t w o e ve nts. 
Missi n g e Diar y res ults will n ot be c o nsi d ere d as a deteri orati o n of ast h ma.  
1Se v ere ast h ma e x acer bati o ns will als o be c o nsi dere d t o be d eteri orati o n of ast h ma a n d 
i n cl u de d i n t h e a nal yses of t his e n d p oi nt. Se vere e x acer bati o ns will b e rec or de d o n t he Se vere 
E x acer bati o n m o d ul e a n d 1 rec or d c orres p o n ds t o 1 se vere e x acer bati o n. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 3 of 8 1 
 
Ti me t o d et eri o r ati o n of ast h m a 
Ti me t o first d eteri orati o n of ast h m a will be cal c ulate d as 
St art d ate of first d eteri or ati o n of ast h m a  D ate of r a n d o miz ati o n ( Visit 2) + 1 
S u bjects n ot ha vi n g a n ast h ma d eteri orati o n will be ce ns ore d at t he d ate of t heir latest f oll o w-
u p or E O S, f or s u bjects w h o dis c o nti n ue I P/ h a ve a c ha n ge i n mai nte na nce t hera p y f or lac k of 
ast h ma c o ntr ol, t h e earliest of eit her da y of disc o nti n u ati o n or d a y t h ere was a c ha n ge t o 
mai nte na nce t hera p y. 
A n n u alize d r ate of ast h m a deteri o r ati o ns  
F or t he pr o d u cti o n of s u m m ar y statistics, t h e ra w a n n ualiz e d rate of d eteri orati o ns of ast h ma 
will be calc ulate d acc or di n g t o t h e f oll o wi n g f or m ula: 
 
W here t h e s u m mati o ns are o ver all s u bjects wit hi n a treat me nt ar m.  
T he f oll o w- u p ti me is calc ulate d as d es cri b e d i n S ecti o n 4. 3. 1.  
4. 4. 2  
D eri v ati o n of ti me t o tre at me nt disc o nti n u ati o n o r c h a n ge i n 
m ai nte n a nce t her a p y f or l ac k of ast h m a c o ntr ol 
Ti me t o treat m e nt disc o nti n uati o n or c ha n ge i n mai nt e n a nce t h era p y f or lac k of ast h m a c o ntr ol 
will be calc ulate d as t he ti m e fr o m ra n d o mi zati o n u ntil t he earliest of treat me nt 
disc o nti n uati o n (f or a n y reas o n) or c ha n ge i n m ai nte na nce t h era p y f or lac k of ast h ma c o ntr ol 
(i. e. a ste p- u p i n m ai nte n a nce t h era p y): 
D ate of I P dis c o nti n u ati o n/c h a n ge i n m ai nte n a nce t her a py 
 D ate of r a n d o miz ati o n ( Visit 2) 
+ 1 
S u bjects n ot ha vi n g pre mat urel y disc o nti n u e d treat m e nt or recei vi n g a c ha n ge i n mai nte na nce 
t h era p y d ue t o lac k of ast h ma c o ntr ol will be ce ns ore d at t he latest f oll o w- u p or E O S.  
4. 4. 3  
Deri v ati o n of Ast h m a C o ntr ol Test res p o n d er v ari a ble 
T he A C T is a 5- q uesti o n healt h s ur ve y use d t o m eas ure ast h ma c o ntr ol i n s u bjects a ge d 1 2 
a n d ol d er. Eac h q u esti o n is meas ure d o n a 5- p oi nt scale w here 1 re prese nts p o or c o ntr ol of 
s y m pt o ms a n d 5 re prese nts c o m plete c o ntr ol.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 4 of 8 1 
 
T he t otal A C T sc ore will be calc ul ate d t h e s u m of t he 5 q u esti o n s c ores (ra n gi n g fr o m 0 t o 
2 5). All 5 q u esti o n sc ores m ust be n o n- missi n g t o calc ulate t he t otal A C T s c ore. 
T he res p o n d ers at Wee k 2 4 are defi n e d as s u bje cts ac hie vi n g a n i n creas e fr o m baseli ne i n 
A C T t ot al sc ore of at l east 3: 
Res p o n der: ( Wee k 2 4 
 
 
N o n-res p o n d er: ( Wee k 2 4 
 baseli ne) < 3 
S u bjects w h o disc o nti n u e treat me nt f or a n y reas o n or recei ve a c ha n g e i n mai nt e na nc e t h era p y 
f or lac k of ast h ma c o ntr ol bef ore Wee k 2 4 will be classifie d as n o n-res p o n ders. Baseli ne is 
d efi ne d as t he m ost rece nt n o n- missi n g sc ore b ef ore a n d i ncl u di n g ra n d o mizati o n ( Visit 2). 
T he a b o ve a nal yses will be re peate d i n t h e c hil dre n c o h ort ( A ges 4 t o 1 1 ye ars) f or t he C 
A C T. 
4. 4. 4  
D eri v ati o n of ot her e Di ar y v ari a bles 
Please see A p p e n di x 1 f or e Diar y varia bles c ollect e d i n t his st u d y. 
Relie ver t her a p y use  
N u m ber of d a y a n d ni g ht i n h alati o ns of reli e ver t hera p y will b e c oll ecte d o n t he e Diar y. T h e 
t otal dail y n u m b er of i n halati o ns will be deri ve d as t he s u m of t he da yti me a n d f oll o wi n g 
ni g ht-ti m e rec or ds, b ot h t he da yti m e a n d ni g ht-ti m e s c ore m ust be n o n- missi n g t o cal c ulate 
t h e t otal.  
T he d a yti m e, ni g ht-ti me, a n d t otal dail y relie ver use will be gr o u p e d i nt o 4- wee kl y a v era ges 
acr oss t h e 2 4- wee k ra n d o mi ze d treat me nt peri o d. T h e 4- wee kl y ti me i nter v als are d efi n e d as 
2 8- da y l o n g p eri o ds st arti n g fr o m t he d ate of ra n d o mizati o n. T he f oll o wi n g Ta ble 4 ill ustrates 
h o w t he peri o ds will be assi g ne d usi n g t h e st u d y d a y of eac h rec or d. 
T a ble 2   
4- Wee kl y Ti me I nter v als f or e- Di a r y d at a 
Peri o d  
St art D ay 
E n d D ay 
P eri o d 1   
Da y 1 ( Date of ra n d o mizati o n)  
Da y 2 9 
P eri o d 2   
Da y 3 0 
Da y 5 7 ( Da y 3 0 + 2 7) 
P eri o d 3  
Da y 5 8 
Da y 8 5 ( Da y 5 8 + 2 7) 
P eri o d 4  
Da y 8 6 
Da y 1 1 3 ( Da y 8 6 + 2 7) 
P eri o d 5  
Da y 1 1 4 
Da y 1 4 1 ( Da y 1 1 4 + 2 7) 
P eri o d 6  
Da y 1 4 2 
Da y 1 6 9 ( Da y 1 4 2 + 2 7) 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 5 of 8 1 
 
A d diti o nall y, t he dail y a v era ge n u m b er of i n hal ati o ns o ver t he ra n d o miz e d treat me nt peri o d 
will be calc ulate d fr o m t h e date of ra n d o miz ati o n t o t he date of disc o nti n u ati o n of ra n d o mize d 
st u d y dr u g or a c h a n ge i n mai nte na nce t h era p y. 
T he d ail y a v era ge will b e s plit b y d a yti me, ni g ht-ti m e, a n d t otal.   T he dail y a vera ges will o nl y 
b e base d o n d a ys w here c o m pl ete diar y i nf or mati o n is a v ail a ble; o n t he date of ra n d o mi zati o n, 
t h ere will be n o m or ni n g res ult rec or de d i n t h e e Diar y, t heref ore t his da y will n ot c o ntri b ute t o 
t h e d ail y a vera ge. Si mil arl y, o n t he d ate of r a n d o mi ze d treat me nt dis c o nti n uati o n, n o e ve ni n g 
res ult will be a vaila ble i n t h e e Diar y a n d t heref ore will n ot c o ntri b ute t o t he d ail y a vera ge. As 
a res ult, t he de n o mi n at or f or t h e calc ulati o n of dail y a v era ge n u m b er of reli e ver t h era p y 
i n hal ati o ns will n ot e q ual t h e d urati o n of e x p os ure t o ra n d o mi ze d st u d y dr u g. 
T he relie v er t h era p y use is c ollecte d i n t h e e Di ar y i n res p o nse t o s y m pt o ms a n d f or a n y us e 
t h at t h e p atie nt m a y t a ke i n pr o p h yla xis t o e x ercise. S u m maries of dail y a v era ge n u m b er of 
i n hal ati o ns will be se parate d i n
 
rec or d e d i n t h e e Di ar y. T he n u m b er of reli e v er t hera p y free d a ys will b e deri v e d as t he 
p erce nta ge of e val u a ble d a ys acr oss t h e ra n d o mize d treat m e nt peri o d, pri or t o dis c o nti n u ati o n 
of ra n d o mi ze d st u d y dr u g or a c ha n g e i n mai nt e na nce t h era p y f or lac k of ast h m a c o ntr ol. 
Ast h m a s y m pt o m sc o re  
Ast h ma s y m pt o m sc ore, a 4- p oi nt scale ra n gi n g fr o m 0 ( n o ast h ma s y m pt o ms) t o 3 ( m ost 
se vere ast h ma s y m pt o ms), will be c ollecte d t wic e d ail y i n t h e m or ni n g a n d e ve ni n g i n t h e 
e Diar y. Please refer t o se cti o n 4. 1. 4 f or t h e assi g n me nt of st u d y da y, a n d t h e deri v ati o n of t he 
t otal s y m pt o m sc ore. T h e a vera ge da y, ni g ht a n d t otal ast h ma s y m pt o m sc ore will be 
calc ulate d o ver t he ra n d o miz e d treat me nt p eri o d, a n d i n 4- wee kl y i nter v als as per per Ta ble 4. 
Ni g ht-ti me a w a k e ni n gs  
Ni g ht-ti me a w a ke ni n gs d ue t o ast h ma s y m pt o ms will b e rec or d e d i n t he e Diar y o n a dail y 
b asis. T he t otal n u m b er of ni g ht-ti me a wa ke ni n gs will b e deri v e d as t he c u m ulati v e n u m b er of 
ni g ht-ti m e a wa ke ni n gs o ver t h e ra n d o miz e d treat m e nt peri o d. T his will be cate g orize d i nt o t h e 
4- wee kl y ti me i nter vals as p er Ta ble 4 a n d als o as a n o verall treat m e nt a v era g e a cr oss t he 
e ntire ra n d o mi ze d treat m e nt peri o d, fr o m t h e date of ra n d o miz ati o n u p t o a n d i n cl u di n g 
treat m e nt disc o nti n uati o n, or a c ha n g e i n mai nt e n a nce t h era p y. T he p erce nta ge of ni g ht-ti m e 
a wa ke ni n gs o ver t h e ra n d o miz e d treat me nt p eri o d will be re pres e nte d as t he t otal n u m ber of 
a wa ke ni n gs di vi de d b y t he t ot al n u m b er of da ys o ver t he ra n d o miz e d treat m e nt p eri o d f or 
eac h p atie nt. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 7 of 8 1 
 
Ast h m a c o ntr ol d a ys 
A n ast h m a c o ntr ol da y is defi n e d as t he f ulfil m e nt of all t h e f oll o wi n g criteria: 
A da y a n d ni g ht wit h n o ast h m a s y m pt o ms (i.e., ast h ma s y m pt o m sc ore = 0) 
A ni g ht wit h n o a wa k e ni n gs d ue t o ast h ma s y m pt o ms 
A da y a n d ni g ht wit h n o use of relie v er m e di cati o n. 
T he p erce nta ge of ast h m a c o ntr ol d a ys will b e c al c ulate d as d o ne f or s y m pt o m-free d a ys. 
st h m a c o ntr ol d a ys will b e cate g oriz e d 
i nt o t h e 4- wee kl y ti me i nter vals as per Ta ble 4 a n d als o as a n o verall treat me nt a v era ge a cr oss 
t h e e ntire ra n d o mi ze d treat m e nt peri o d. 
L u n g f u n cti o n 
Pre br o n c h o dilat or F E V 1 will b e perf or me d o n a Master Sc o p e pr o vi d e d f or t he st u d y b y t h e 
ce ntral rea d er at Visit 1 (scree ni n g), Visit 2, Visit 5 a n d Visit 6. Ass ess me nts at Visit 5 a n d 6 
will o nl y b e use d if c oll ecte d b et w ee n 6: 0 0 a n d 1 1: 0 0 A M a n d n o m ore t h a n ± 1 h o ur fr o m t h e 
s pir o metr y assess me nt rec or de d at b aseli ne. Baseli ne pre br o n c h o dilat or F E V 1 will b e t he 
m ost rece nt meas ure me nt pri or t o ra n d o mi zati o n, i n m ost cases t his s h o ul d b e t h e 
meas ure me nt c ollecte d at Visit 2. 
Pe a k e x pir at or y fl o w 
T hr o u g h o ut t he st u d y, s u bjects will rec or d t he b est of 3 Pea k e x pirat or y fl o w ( P E F) me as ures 
o n risi n g i n t h e m or ni n g a n d bef ore g oi n g t o b e d i n t he e ve ni n g pri or t o ta ki n g a n y ast h ma 
t h era p y. P ea k e x pirat or y fl o w will b e ca pt ure d i n t he e Diar y.  
As wit h t he calc ulati o n of relie ver t hera p y e n d p oi nts, Pea k e x pirat or y fl o w will b e cate g orize d 
i nt o t h e 4- wee kl y ti me i nter vals as per Ta ble 4 a n d als o as a n o verall treat me nt a v era ge a cr oss 
t h e e ntire ra n d o mi ze d treat m e nt peri o d. 
O ver all e Di a r y c o m pli a nce 
O verall e Di ar y c o m plia nce d uri n g t h e ra n d o mi ze d treat m e nt peri o d is calc ulate d as:  
 
W here t h e t otal e x pecte d c o m plia nce is:  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 8 of 8 1 
 
 
as s u bjects are e x pecte d t o fill i n t h e e Diar y o n ce i n t h e m or ni n g a n d o n ce i n t h e e ve ni n g, e ac h 
d a y. N ote t hat t h e e Diar y c o m pleti o n will n ot b e c o nsi dere d i n t h e m or ni n g of st u d y d a y 1 a n d 
e ve ni n g of t h e last d a y of p artici pati o n i n t he st u d y. 
A d diti o nall y, s u bjects will be cate g orize d i nt o t h ose ac hie vi n g a n o v erall e Diar y c o m plia nc e 
of at l east 8 0 %. 
4. 4. 5  
Deri v ati o n of Ast h m a C o ntr ol Q uesti o n n aire 
 5 e x pl or at or y v ari a bles 
T he c ha n ges fr o m b as eli ne A C Q- 5 o verall sc ore at Wee k 1 2 a n d W ee k 2 4 will b e cate g orize d 
i nt o t h e f oll o wi n g 3-le v el fact or: 
I m pr o v e me nt: ( Wee k 1 2  baseli ne)  - 0. 5 
N o C h a n g e: - 0. 5 < ( Wee k 1 2 
 baseli ne) < 0. 5 
W orse ni n g: ( Wee k 1 2 
 baseli ne)  0. 5 
4. 4. 6  
Deri v ati o n of i n h ale d c ortic oster oi d e x p os ure 
E x p os ure t o I C S will b e deri ve d usi n g t w o c o m p o ne nts; reli e ver t hera p y us e a n d b ac k gr o u n d 
mai nte na nce I C S recei ve d at baseli ne. 
C ortic oster oi d e x p os ure will be calc ulate d u n d er t he effecti ve n ess esti ma n d a n d will c o nsi d er 
ster oi d e x p os ure pri or t o disc o nti n uati o n of I P b ut will i ncl u de data f oll o wi n g c h a n ges i n 
mai nte na nce t hera p y. 
Relie ver t her a p y I C S 
Relie ver t hera p y I C S will be d eri v e d fr o m t h e t otal d ail y n u m ber of p uffs ( p uffs/ d a y) of 
ra n d o mi ze d treat m e nt, as rec or de d i n t h e e- Diar y. Pl ease refer t o secti o n 4. 4. 4 f or t otal dail y e-
diar y varia bl es. T h e c orres p o n di n g t otal dail y d os e 
d a y) of a d diti o n al I C S will be deri ve d 
usi n g t h e f oll o wi n g d eri v ati o n: 
 M DI 1 6 0/ 1 8 0  
 M DI 8 0/ 1 8 0 
 M DI 1 8 0 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 9 of 8 1 
 
B a c k gr o u n d m ai nte n a nce t her a p y I C S  
T he f oll o wi n g A T C c o des will be use d t o i d e ntif y mai nte na nce a n d a d diti o n al I C S treat me nts 
i n t h e c o n c o mita nt me dic ati o ns ( C M) m o d ule: 
R 0 3 B A  
R 0 3 A K 
R 0 1 A D 
R 0 3 A L 
All mai nte na nce I C S fla g ge d fr o m t he C M m o d ule will als o re q uire t he f oll o wi n g fiel d v al ues 
o n t he C M e ntr y:  
a n d  
 
 
T he t otal dail y I C S d ose of m ai nt e na nce t hera p y will be cate g orize d i nt o l o w, me di u m a n d 
hi g h d ose I C S as d efi ne d i n A p pe n di x 2. W he n calc ulati n g t he t otal d ail y d ose of m ai nte na nce 
t h era p y f or t his s u b gr o u p varia ble, o nl y t h e m ost rece ntl y prescri be d mai nt e na nc e t h era p y 
ta k e n d uri n g t h e r u n-i n p eri o d, pri or t o ra n d o mi zati o n, will be c o nsi dere d i n t he deri vati o n. 
T he I C S d osi n g cate g orizati o ns pr o vi d e d i n A p pe n di x 2 is n ot e x ha usti v e. As a res ult a 
me di cal re vie w of m ai nte na nce t hera p y I C S will be carrie d o ut pri or t o d at a base l oc k a n d 
u n bli n di n g t o c orrectl y assi g n d osi n g cate g ories t o eac h I C S ta ke n as bac k gr o u n d mai nte na nce 
t h era p y. 
4. 5  
S afet y v ari a bles 
4. 5. 1  
Vit al si g ns 
T he f oll o wi n g vit al si g ns meas ure me nts will b e c o n d u cte d: 
P uls e rate ( beats/ mi n) 
S yst olic bl o o d press ure ( m m H g) 
Diast olic bl o o d press ure ( m m H g) 
4. 5. 2  
A d v erse e v e nts (i n cl u di n g seri o us a d verse e v e nts) 
4. 5. 2. 1  
C ollecti o n of A Es a n d S A Es 
A Es a n d S A Es will b e c ollecte d fr o m ti m e of si g n at ure of i nf or me d c o nse nt/asse nt t hr o u g h t o 
t h e f oll o w- u p p eri o d. 
T he f oll o wi n g varia bles will be c ollecte d f or eac h A E: 
A E ( v er bati m). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 0 of 8 1 
 
T he d at e w he n t h e A E st arte d a n d st o p p e d 
Ma xi m u m i nte nsit y 
Seri o us ness 
I n v esti g at or ca us alit y rati n g a gai nst t h e I P ( yes or n o) 
Acti o n ta ke n wit h re gar ds t o I P 
A E re q uire d treat m e nt 
O utc o m e 
 
I n a d diti o n, t he f oll o wi n g v aria bles will be c ollecte d f or S A Es: 
Date A E met criteria f or seri o us A E 
Date i n vesti gat or beca me a ware of seri o us A E 
Reas o n w h y t he A E is c o nsi dere d seri o us 
S A E o nset date/ A E m et criteri a f or S A E 
S A E res ol uti o n date 
S A E o utc o me 
Ma xi m u m S A E i nt e nsit y 
Treat m e nt gi ve n f or t h e S A E 
Date of h os pitalizati o n 
Date of disc har ge 
Pr o ba ble ca use of d eat h. 
Date of deat h. 
W het her a ut o ps y is perf or me d. 
Ca usalit y ass ess me nt i n relati o n t o st u d y pr oce d ure(s). 
Ca usalit y ass ess me nt t o ot her me dicati o n. 
Descri pti o n of A E. 
 
4. 5. 2. 2  
Defi niti o n of a d v erse e ve nt le a di n g t o disc o nti n u ati o n of i n v esti g ati o n al 
pr o d u ct ( D A E) 
Dr u g per ma ne ntl y disc o nti n ue d
b e defi ne d as D A Es a n d re p orte d s e paratel y (i n 
a d diti o n t o b ei n g re p orte d as ge n eral A Es). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 1 of 8 1 
 
4. 5. 2. 3  
Ot her si g nific a nt a d v erse e ve nts ( O A Es) 
D uri n g t h e e val uati o n of t h e A E d ata, a n A villi o n m e di call y q u alifie d e x p ert will re vie w t he 
list of A Es t h at were n ot re p ort
si g nifica nt a d verse e ve nts of partic ular cli nical i m p orta nce m a y, after c o ns ultati o n wit h t h e 
Gl o bal S u bject Safet y P h ysicia n, be c o nsi dere d O A Es a n d re p orte d as s u c h i n t h e Cli nical 
St u d y R e p ort. 
O A Es will b e re p ort e d i n a s e parate ta ble (i n a d diti o n t o bei n g re p orte d as ge neral A Es). 
A d verse e ve nts rel ate d t o C O VI D- 1 9 (c o nfir me d or s us p ecte d c ases) will als o be i de ntifie d via 
t h e assi g n e d C O VI D- 1 9 relate d preferre d t er ms. Please refer t o secti o n 5. 7. 1 f or f urt h er 
d etails. 
4. 5. 2. 4  
A d v erse e ve nts d at a h a n dli n g 
A d verse e ve nts will b e re p orte d as starti n g d uri n g t h e r u n-i n p eri o d if t h e A E start date is o n 
or after t h e first date of r u n-i n me dic ati o n ( Ve nt oli n), a n d pri or t o ra n d o mi zati o n. 
A d verse e ve nts will b e c o nsi d ere d as starti n g d uri n g t h e ra n d o mi ze d treat m e nt peri o d if t h e 
o nset d ate is o n or aft er t he d ate of ra n d o mi zati o n a n d o nset is n o later t ha n t h e last da y of 
ra n d o mi ze d treat m e nt.   
A d verse e ve nts will b e c o nsi d ere d as starti n g d uri n g t h e f oll o w- u p peri o d if t he o nset date is 
after t he l ast da y of ra n d o mi ze d treat m e nt. 
If a n A E h as a missi n g o nset date, t he n, u nless t h e st o p d ate of t he A E i n di cates ot h er wise, t his 
will be c o nsi dere d as starti n g d uri n g t h e ra n d o mi ze d treat me nt peri o d.  Si milarl y, if a n A E has 
a partial o nset dat e, t h e n u nless t he p artial o nset date or t he st o p d ate i n dic ates ot h er wise, t his 
will be c o nsi dere d as starti n g d uri n g t h e ra n d o mi ze d treat me nt peri o d. 
Please refer t o Secti o n 4. 1. 8 f or t h e i m p ut ati o n r ule t o pr o gra m matic all y deter mi n e t h e 
classificati o n of A Es w h e n t here are p artial st art a n d/ or st o p d ates rec or de d. 
4. 5. 2. 5  
Defi niti o n of A Es ass oci ate d wit h l o c al a n d s yste mic I C S eff ects  
A d verse e ve nts t hat are ass ociate d wit h l o c al I C S effects will be i de ntifie d usi n g t he f oll o wi n g 
preferre d t er ms: 
Oral ca n di diasis 
Or o p har y n g eal ca n di diasis 
Oral f u n gal i nfecti o n 
Para d o xical br o nc h os p as m 
D ys p h o nia 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 2 of 8 1 
 
A d verse e ve nts t hat are ass ociate d wit h s yste mic I C S effects will be i de ntifie d usi n g t he 
f oll o wi n g preferre d ter ms: 
H y perc orticis m 
A dre nal s u p pressi o n 
Re d u cti o n i n b o ne mi n eral d e nsit y (i n cl u di n g fract ures) 
Gla uc o ma 
Cataracts 
Please n ot e t h at t hese lists of preferre d ter ms is n ot e x ha usti v e a n d a c o m pre he nsi v e list of 
ter ms ass ociate d wit h l ocal/s yste mic I C S effects will b e c o nfir me d at data base l o c k a n d bef ore 
u n bli n di n g of t he cli nical trial. 
4. 5. 3  
L a b or at or y S afet y V a ri a bles 
T he la b orat or y v aria bl es descri be d i n Ta bl e 3 a n d m or ni n g ser u m c ortis ol will b e c ollecte d 
d uri n g t he st u d y acc or di n g t o t he sc he d ule pr o vi de d i n Ta ble 1. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 3 of 8 1 
 
T a ble 3  
L a b o r at or y S afet y V a ri a bles 
He m at ol o g y/ He m ost asis ( w h ole bl o o d) 
Cli nic al C he mistr y (ser u m o r pl as m a) 
Bas o p hils ( %) 
Al b u mi n 
Bas o p hils A bs 
Ala ni ne tra nsa mi nase ( A L T) 
E osi n o p hils ( %) 
Al kali ne p h os p hatase ( A L P) 
E osi n o p hils A bs 
As partate tra nsa mi nase ( A S T) 
He m o gl o bi n  
Bilir u bi n, t otal ( T B L) 
He mat o crit 
Cal ci u m, t otal 
Mea n C or p usc ular He m o gl o bi n 
C hl ori de 
Mea n C or p usc ular He m o gl o bi n C o nce ntrati o n  
C h olester ol, t otal 
Mea n C or p usc ular V ol u me 
Creati ni ne 
M o n oc yt es ( %) 
Creati ne ki nas e 
M o n oc yt es A bs 
Ga m ma- gl uta m yl tra ns pe pti d as e ( G G T) 
Ne utr o p hils ( %) 
Gl uc ose (ra n d o m) 
Ne utr o p hils A bs 
Ma g nesi u m 
Re d bl o o d cells (er yt hr o c ytes) 
P h os p hate  
W hite bl o o d cells (le u k o c ytes)  
P otassi u m  
Platelet c o u nt 
Pr otei n, t otal 
 
S o di u m 
L y m p h oc ytes A bs 
Tri gl yceri des 
L y m p h oc ytes ( %) 
 
Uri ne  
Urea 
- h C G pre g na nc y ( Visit 2) 
- h C G pre g na nc y ( Visit 1, 6 a n d 
E O S/ P D V) 
-
- h u ma n c h ori o nic g o na d otr o pi n; E O S =e n d- of-st u d y; P D V = pr e mat ure 
disc o nti n uati o n visit 
 
 
Cases w here a s u bject s h o ws ele vati o ns i n li ver bi oc he mistr y m a y re q uire f urt her e v al u ati o n 
 3 × u p per li mit of n or mal ( U L N) c o m bi n e d wit h t otal 
 2 × U L N ma y n ee d t o be re p orte d as S A Es.   
T o i d e ntif y cases of 
 ( H L) it is i m p orta nt t o perf or m a c o m pre he nsi ve 
re vie w of l a b orat or y d ata f or a n y s u bje ct w h o meets a n y of t h e f oll o wi n g i d e ntificati o n criteria 
i n is olati o n or i n c o m bi nati o n: 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 4 of 8 1 
 
 
 
 
4. 5. 3. 1  
1 2- Le a d E C G 
A 1 2-lea d E C G will be p erf or me d at t h e visits d etaile d i n Ta ble 1. T he ti mi n g a n d n u m b er of 
E C Gs m a y b e a dj uste d i n res p o nse t o t he e mer gi n g safet y pr ofil e. 
T wel v e-le a d E C Gs will b e o btai n e d usi n g a c e ntraliz e d la b orat or y. If a n a b n or mal E C G 
fi n di n g at scree ni n g/ b aseli n e is c o nsi dere d t o b e cli ni call y si g nifi ca nt b y t he i n vesti gat or, it 
s h o ul d b e re p orte d as a n A E. F or all E C Gs, details of r h yt h m, p ulse rate ( P R), R R, Q R S, a n d 
Q T i nt er vals, a n o v erall e val uati o n will b e rec or de d. 
4. 6  
Ot her v a ri a bles 
4. 6. 1  
C o nc o mit a nt me dic ati o ns 
All pri or a n d c o nc o mita nt me dicati o n rec or d e d d uri n g t he st u d y will b e e nt ere d o nt o t h e C M 
m o d ule.  
A me dicati o n w hic h has starte d o n t he d a y of, or after ra n d o mi zati o n will b e c o nsi dere d t o be 
c o n c o mita nt. A d diti o n all y, all me dic ati o n starti n g pri or t o ra n d o mi zati o n a n d c o nti n ui n g aft er 
t h e first d ose of ra n d o mi ze d treat me nt will als o be c o nsi dere d c o nc o mita nt. All me dicati o n 
rec or d e d w hi c h e n ds pri or t o t he first d ose of ra n d o mi ze d treat m e nt will be classifie d as a 
pri or me dicati o n. Me dic ati o n w hic h o cc urs p ost-ra n d o mi ze d treat m e nt disc o nti n uati o n will be 
d efi ne d as c o n c o mit a nt me dicati o n occ urri n g d uri n g t h e f oll o w- u p p eri o d. 
If a c o nc o mita nt me dicati o n is rec or d e d wit h p artial start d ate a n d/ or e n d date of 
a d mi nistrati o n, a c o nser vati v e a p pr oac h will be c o nsi dere d s uc h t hat u nless it ca n be 
u ne q ui v ocall y deter mi n e d t h at t he me dicati o n st arte d a n d e n d e d pri or t o t he first d os e of 
ra n d o mi ze d st u d y dr u g, b ase d o n a vaila bl e i nf or m ati o n fr o m t h e partial dat e(s), t he 
me di cati o n will b e cl assifie d as c o n c o mita nt. 
T o facilit ate t his d ecisi o n- ma ki n g pr ocess pr o gra m m aticall y, t he i m p utati o n pr ocess defi ne d i n 
Secti o n 4. 1. 8 will b e c o nsi dere d. 
4. 6. 2  
Disc o nti n u ati o n of i n v esti g ati o n al pr o d uct 
S u bjects m a y be wit h dra w n fr o m t he st u d y at a n y ti m e at t heir o w n re q u est, u p o n re q uest of 
t h e i n vesti gat or, or b y t he S p o ns or at a n y ti me or f or a n y reas o n.  T h e s u bject or his/ h er 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 5 of 8 1 
 
p are nt/le gal re pres e ntati v e is free t o disc o nti n ue treat me nt at a n y ti me, wit h o ut prej u dice t o 
f urt her treat m e nt. 
T he d at e of I P dis c o nti n u ati o n, al o n g wit h t he m ai n reas o n f or disc o nti n u ati o n of 
i n vesti gati o nal pr o d u ct will be c oll ecte d i n t he Dis c o nti n uati o n of I n vesti g ati o nal Pr o d uct 
C R F p a g e. I P ca n b e disc o nti n ue d f or t h e f oll o wi n g reas o ns: 
S u bject Decisi o n 
A d verse e ve nt 
Se v ere n o n-c o m plia nce t o pr ot oc ol 
C o n diti o n u n der i n vesti gati o n w orse ne d 
Lac k of T h era p e uti c Res p o nse 
De vel o p me nt of st u d y s pecific disc o nti n uati o n crit eria 
o
- m o nt h peri o d 
o
s 
o
A si n gle se vere e x acer b ati o n e ve nt l o n ger t ha n 2 0 da ys i n d urati o n 
o
Pre g na nc y 
S u bject l ost t o f oll o w- u p 
C o m plete d 
Ot h er 
4. 6. 3  
Disc o nti n u ati o n/ wit h dr a w al fr o m t he st u d y 
If t he S p o ns or, i n vesti gat or, st u d y m o nit or, I D M C, or re g ulat or y officials disc o v er c o n diti o ns 
st u d y a n d/ or q u alit y of t h e I Ps h a ve bee n c o m pr o mis e d, t h e st u d y m a y b e halte d or t h e st u d y 
ma y b e t er mi nate d. O n g oi n g s u bjects will b e disc o nti n ue d fr o m t h e 
st u d y a n d assi g ne d t o recei ve treat m e nt as p er l ocal sta n dar d of care.   
Reas o ns f or wit h dra wal will be rec or d e d o n t h e Dis p ositi o n C R F (st u d y c o m pl eti o n) wit h t he 
f oll o wi n g reas o ns f or dis c o nti n u ati o n: 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 6 of 8 1 
 
A d verse E v e nt 
C o m plete d 
Deat h 
L ost t o F oll o w- U p 
Pr ot o c ol De viati o n 
Scree n Fail ure 
Wit h dra wal b y S u bje ct 
Wit h dra wal b y Pare nt/ G uar dia n 
Ot h er 
4. 6. 4  
C o m pli a nce of st u d y m ai nte n a nce me dic ati o n  
M o nit ori n g of c o m pli a nce f or m ai nte na nce m e di cati o n will be d o n e o nl y t hr o u g h t h e e Diar y 
q uesti o n ' ha v e y o u ta ke n y o ur re g ular m ai nte na nce t h era p y t o da y as prescri b e d ?' ( A p pe n di x 
1). 
a n d a ' N o' e q u ati n g t o n o n-c o m plia nce ( miss e d d ose). 
O verall c o m plia nce wit h mai nte na nce t hera p y ( %) will b e calc ulate d as 
 
C o m plia nce wit h st u d y m ai nte na nce m e di cati o n will be calc ulate d u n der t he effi cac y a n d t h e 
effecti ve ness esti ma n d. T heref ore, t h e o bs er vati o n peri o d gi v e n i n t h e a b o ve e q uati o n will b e 
e q ui v ale nt t o t h e ti m e fr o m ra n d o miz ati o n, t o t h e earliest of I P dis c o nti n uati o n or a c ha n ge i n 
mai nte na nce t hera p y u n der t he efficac y esti ma n d, a n d pri or t o I P disc o nti n uati o n re gar dless of 
a c ha n ge i n mai nte na nce t h era p y u n der t he effecti v e n ess esti m a n d. 
Per t he a b o ve d eri vati o n, if t here are missi n g c o m plia nce d ata i n t he e Diar y f or da ys d uri n g 
t h e o bser vati o n p eri o d, t his tra nslates t o a n o n-c o m plia nt ( misse d d ose). If a p ati e nt has 
c o m pletel y missi n g e- diar y i nf or mati o n d uri n g t he gi v e n o bs er vati o n peri o d, t heir esti m ate d 
c o m plia nce will be 0 %. 
A d diti o nall y, s u bjects will be cate g orize d i nt o t h os e ac hie vi n g a n o v erall c o m plia nce of at 
least 7 0 %. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 7 of 8 1 
 
4. 6. 5  
Deri v ati o n of GI N A criteri a s u b gr o u p v ari a bles 
Patie nts will be cate g orize d i nt o t h e f oll o wi n g bac k gr o u n d t h era p y s u b gr o u ps, re pres e ntati v e 
of  GI N A ( 2 0 2 0) ste ps 3- 5, wit h f oc us o n  I C S e x p os ure cat e g oriz ati o n, acc or di n g t o 
prescri be d m ai nte na nce t h era p y rec or de d at bas eli ne: 
GI N A St e p 3: L o w d ose I C S- L A B A ( ± L T R A, L A M A, or t h e o p h ylli ne) or Me di u m 
d ose I C S ( ± L T R A, L A M A, or t he o p h ylli n e) 
GI N A St e p 4: Me di u m d os e I C S- L A B A ( ± L T R A, L A M A, or t he o p h ylli ne) or Hi g h 
d ose I C S ( ± L T R A, L A M A, or t he o p h ylli n e) 
GI N A St e p 5: Hi g h d ose I C S- L A B A ( ± L T R A, L A M A, or t he o p h ylli ne)  
I n or der t o defi n e t h e a b o ve s u b gr o u ps, pati e nts will b e cate g orize d i nt o l o w/ me di u m/ hi g h 
d ose usi n g bac k gr o u n d m ai nte na n ce I C S d osi n g cate g orisati o ns (l o w/ m e di u m/ hi g h) acc or di n g 
t o secti o n 4. 4. 6. 
5.  
A N A L Y SI S M E T H O D S 
5. 1  
Ge ner al pri nci ples 
5. 1. 1  
Esti m a n ds 
F o ur esti m a n ds are of i nt erest i n t his st u d y: 
T he pri m ar y esti ma n d of i nterest is t h e effic ac y esti ma n d, defi ne d as t he effect of t he 
ra n d o mi ze d treat m e nt i n all s u bjects ass u mi n g c o nti n u ati o n of ra n d o miz e d treat m e nt f or t h e 
d urati o n of t he st u d y, re gar dless of act u al usa ge a n d ass u mi n g t h at mai nte na nce t hera p y is n ot 
c ha n ge d. T his esti ma n d c o ul d b e c o nsi dere d as a w hile- o n-treat me nt strate g y or a h y p ot hetic al 
strate g y as d efi n e d i n t he draft I nter nati o nal C o nfere nce o n H ar m o nizati o n (I C H) E 9 
A d de n d u m. All pri mar y, sec o n dar y a n d e x pl orat or y e n d p oi nts will be a nal yze d u n der t h e 
effic ac y esti m a n d. 
T he sec o n d esti ma n d of i nterest is t h e attri b uta ble esti m a n d, defi ne d as t he effe ct of treat m e nt 
i n s u bjects attri b ut a ble t o t he ra n d o miz e d treat me nt ass u mi n g t hat mai nte na nce t hera p y is n ot 
c ha n ge d. F or t his esti m a n d, disc o nti n u ati o n of ra n d o miz e d treat m e nt f or t ol era bilit y or c ha n g e 
i n m ai nt e na nce t h era p y f or lac k of ast h m a c o ntr ol is c o nsi d ere d a n e gati v e o utc o me. T his 
esti m a n d is a mi xt ure of c o m p osite a n d h y p ot h etical strate gies as defi ne d i n t he draft I C H E 9 
a d d e n d u m. T h e pri m ar y e n d p oi nt of ti me t o first s e vere ast h ma e xacer b ati o n will be a nal yze d 
u n d er t h e attri b uta ble esti ma n d. 
T he t hir d esti m a n d of i nterest is t h e effecti ve n ess esti ma n d w hic h is a c o m bi nati o n of t he 
h y p ot h etic al a n d treat me nt p olic y strate gi es as defi n e d i n t he draft I C H E 9 a d de n d u m. T he 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 8 of 8 1 
 
strate g y is h y p ot h etic al i n t hat t he treat me nt effect will b e esti mate d wit h o ut c oll ecti n g d ata 
p ost t he i nterc urre nt e ve nt of disc o nti n u ati o n fr o m ra n d o mize d treat m e nt. H o we ver, t he 
strate g y is c o nsiste nt wit h t he treat me nt p olic y str ate g y i n t h at t he treat me nt effect is esti mate d 
irres pecti ve of t he oc c urre n ce of t h e i nterc urre nt e v e nt of a c ha n ge i n t h e m ai nt e n a nce t h era p y. 
T he s u m m ar y of t otal c ortic oster oi d e x p os ure will be a nal yz e d u n d er t h e effecti ve ness 
esti m a n d. 
T he f o urt h esti ma n d of i nterest is t h e de fact o esti ma n d, defi n e d as t h e effect of a treat m e nt 
p oli c y re gar dl ess of c ha n ges i n m ai nte na nce t h era p y or pre mat ure disc o nti n u ati o n of 
ra n d o mi ze d treat m e nt. T his esti ma n d is c o nsi dere d a treat m e nt p olic y strat e g y as defi n e d i n 
t h e draft I C H E 9 a d de n d u m. 
T he fift h esti ma n d of i nterest is t h e C O VI D- 1 9 esti ma n d. T his esti ma n d is s u p p orti v e t o t h e  
effic ac y esti m a n d, d efi ne d as t he effect of t h e ra n d o miz e d treat m e nt i n all s u bjects ass u mi n g 
c o nti n uati o n of ra n d o miz e d treat me nt f or t he d ur ati o n of t h e st u d y, ass u mi n g t h at mai nte na nce 
t h era p y is n ot c h a n g e d, a n d i n t he a bse nce of C O VI D- 1 9 i m pacts. T h e pri mar y e n d p oi nt of 
ti me t o first se vere e xacer bati o n will be a nal yz e d u n der t h e C O VI D- 1 9 esti ma n d. C O VI D- 1 9 
relate d treat me nt e mer ge nt a d v erse e ve nts ca n b e i d e ntifie d t hr o u g h a pre- defi ne d list of 
preferre d t er ms i n Me d D R A. D ose i nt err u pti o ns are i n v esti g at or i de ntifie d brea ks i n 
me di cati o n t h at are c olle cte d i n t he e C R F, t he i n v esti gat or will als o fla g w h et her or n ot t he 
i nterr u pti o n was rel ate d t o C O VI D- 1 9 i n t he e C R F. 
 
5. 1. 2  
Disc o nti n u ati o n of i n v esti g ati o n al pr o d uct 
T he d at e of I P dis c o nti n u ati o n a n d t he m ai n reas o n f or dis c o nti n uati o n will b e c ollecte d o n t he 
e C R F. T he f oll o wi n g reas o ns f or disc o nti n uati o n will be i n dicati v e of a la c k of ast h ma 
c o ntr ol: 
De vel o p me nt of st u d y s p ecific disc o nti n uati o n crit eria w h e n t h e f oll o wi n g criteri a ar e 
s pecifie d i n t he ver b ati m fiel d 
o
- m o nt h peri o d 
o
 
o
A si n gle se vere e x acer b ati o n e ve nt l o n ger t ha n 2 0 da ys i n d urati o n 
Lac k of t h era p e uti c res p o nse 
C o n diti o n u n der i n vesti gati o n w orse ne d 
S u bject Decisi o n w h e n t h e f oll o wi n g criteri a ar e s pecifie d i n t h e ver b ati m fiel d : 
o
S u bject percei v es t he i n vesti gati o nal pr o d uct t o be i n effecti ve 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 9 of 8 1 
 
o
S u bject percei v es t he l o gisti cs t o be u n acce pt a ble 
Deat h 
 
W hilst t he a b o ve list ca n directl y li n k a n I P disc o nti n uati o n e ve nt as bei n g d u e t o a lac k of 
ast h ma c o ntr ol, t h e list is n ot e x ha usti ve. As a res ult, a s p o ns or re vie w will be c o n d u ct e d o n a 
case- b y-case basis t o i de ntif y a n y a d diti o n al disc o nti n u ati o n e v e nts w hi c h ca n b e attri b ute d t o 
a lac k of ast h ma c o ntr ol. T he fi n al re vi e w of I P disc o nti n u ati o n reas o ns will be c o n d ucte d 
pri or t o d ata base l o c k a n d u n bli n di n g of t h e st u d y.  
5. 1. 3  
C h a n g es i n m ai nte n a nce t her a p y 
All c ha n ges i n mai nte na n ce t hera p y will b e rec or d e d o n t he e C R F, s p ecificall y u n der t h e 
a n d i de ntifia ble b y ha vi n g start d ate o n, or after t he date of ra n d o mizati o n. 
A prescri be d ste p- u p i n mai nte na nce m e dicati o n will be i n dicati v e of a c ha n ge i n mai nte na n ce 
t h era p y d ue t o a l ac k of ast h ma c o ntr ol. C ha n ges d ue t o ste p u p or or ste p d o w n i n 
mai nte na nce tr eat me nt will be i d e ntifia ble o n t h e e C R F. 
5. 1. 4  
T y p e 1 err or c o ntr ol 
O nl y dat a c ollecte d u p t o t he pri m ar y data b ase l oc k (see s ecti o n 1. 4) will b e i n cl u d e d i n 
pri mar y, sec o n dar y, a n d e x pl orat or y effic ac y a nal ys es. T h ere will be n o efficac y a n al ys es 
c o n d ucte d o n a n y data w hic h m a y b e c olle cte d after t he pri mar y d ata bas e l oc k a n d u p t o t he 
fi nal d ata bas e l o c k f or p atie nts a ge d 4 t o 1 7 years. 
M DI f or t h e pri mar y e n d p oi nt, ti me t o first s e vere e x acer bati o n usi n g t he effic ac y esti ma n d, 
will be c o n d ucte d usi n g H oc h ber g
- u p met h o d ( H oc h ber g, 1 9 8 8). 
T he t y pe-I err or will b e c o ntr olle d f or sec o n d ar y e n d p oi nt treat me nt c o m paris o ns via a 
hierarc hical testi n g pr oce d ure. T he f oll o wi n g se c o n dar y e n d p oi nts will b e teste d u n d er t h e 
effic ac y esti m a n d i n t he f oll o wi n g se q ue ntial or d er, gr o u p e d b y sec o n d ar y e n d p oi nt: 
A n n ualize d se v ere e x acer bati o n rate 
1.
B D A M DI 1 6 0/ 1 8 0 
 v ers us A S M DI 1 8 0 
 
2.
B D A M DI 8 0/ 1 8 0 
 vers us A S M DI 1 8 0 
 
T otal a n n ualize d d ose of s yste mic c ortic oster oi d 
3.
B D A M DI 1 6 0/ 1 8 0 
 v ers us A S M DI 1 8 0 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 0 of 8 1 
 
4.
B D A M DI 8 0/ 1 8 0 
 vers us A S M DI 1 8 0 
 
Ast h ma C o ntr ol Q uesti o n naire- 5 ( A C Q- 5) c ha n ge fr o m b aseli ne res p o n d er a nal ysis at W ee k 
2 4 
5.
B D A M DI 1 6 0/ 1 8 0 
 v ers us A S M DI 1 8 0 
 
6.
B D A M DI 8 0/ 1 8 0 
 vers us A S M DI 1 8 0 
 
Ast h ma Q u alit y of Life Q uesti o n naire f or 1 2 years a n d ol d er ( A Q L Q + 1 2) c ha n ge fr o m 
b aseli n e res p o n d er a n al ysis at Wee k 2 4  
7.
B D A M DI 1 6 0/ 1 8 0 
 v ers us A S M DI 1 8 0 
 
8.
B D A M DI 8 0/ 1 8 0 
A S M DI 1 8 0 
 
Statistical tests f or t he sec o n d ar y a n al yses will b e c o n d ucte d at t he 5 % le vel of si g nifica n ce 
( 2-si de d). I nfere nce f or a test i n t h e d efi n e d or der is de pe n de nt o n statistical si g nifica nce 
h a vi n g b ee n ac hie ve d i n t he prece di n g tests, if t his is n ot ac hie ve d t h e n n o mi n al p- val u es will 
b e pr o vi de d. As per t h e pri mar y a nal ysis, c o m paris o ns of B D A M DI 1 6 0/ 1 8 0 v ers us A S M DI 
will e xcl u de t he pe diatric p o p ulati o n, w hilst c o m paris o ns of B D A 8 0/ 1 8 0 v ers us A S M DI will 
i n cl u de all a ges. 
Statistical si g nifica nc e ca n o nl y be clai me d o n t he k e y s ec o n dar y e n d p oi nts if a statisticall y 
si g nifica nt treat m e nt effect is o bs er ve d o n b ot h 
 a n d B D A M DI 8 0/ 1 8 0 
 vers us A S M DI f or t h e pri mar y e n d p oi nt of ti m e t o first s e vere e x acer bati o n. 
5. 1. 5  
A n al ysis met h o ds 
All tests will be 2-si de d a n d at 5 % le vel of si g nifica nce u nless ot her wise state d. A dj ust me nt 
will be ma de usi n g t he H oc h b er g pr o ce d ure ( H o c h ber g, 1 9 8 8) f or t he 2 pri mar y c o m p aris o ns.  
I n a d diti o n t o t h e a nal yses d escri be d bel o w, all varia bles will be s u m m ariz e d descri pti vel y 
w here a p pr o priat e. 
U nless ot her wis e state d, descri pti ve s u m m aries of c o nti n u o us e n d p oi nts will i ncl u d e: t he 
n u m b er of e val u a ble s u bj ects i n t he a nal ysis ( n); Mea n; St a n d ar d De viati o n; Me dia n; 
Mi ni m u m; M a xi m u m. S u m maries of cate g oric al e n d p oi nts will i ncl u d e t he a bs ol ute c o u nts 
a n d perce nta ge, wit h t h e de n o mi nat or use d i n t he p erce nt a ge calc ulati o n cl earl y d efi n e d i n t he 
f o ot n ote of t he ta ble. U nl ess state d ot her wise, t h e de n o mi nat or will b e t h e n u m ber of s u bjects 
i n t h e a nal ysis s et us e d f or t h e d escri pti ve s u m m aries of c o u nts a n d p erce nta ges. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 1 of 8 1 
 
5. 2  
S u bject Dis p ositi o n 
S u bject dis p ositi o n will be s u m m arise d f or all s u bjects. T h e n u m ber of s u bjects w h o were 
e nr oll e d ( pr o vi d e d i nf or me d c o nse nt), r u n-i n a n d n ot r u n-i n will b e s u m m aris e d.  T he n u m ber 
a n d perce nta ge of s u bjects will b e prese nte d b y t he f oll o wi n g cate g ories; ra n d o mi ze d, n ot 
ra n d o mi ze d (a n d reas o ns), ra n d o mi ze d w h o recei v e d ra n d o mi ze d treat m e nt, ra n d o mi ze d w h o 
di d n ot recei v e ra n d o mi ze d treat m e nt (a n d reas o ns), c o m pl ete d, a n d disc o nti n ue d t h e st u d y 
(reas o ns). 
De vel o p me nt of st u d y s pecific 
disc o nti n uati o n criteria  t he n t he s pecif y fiel d, w hic h c o ntai ns st a n d ar d t e xt, will b e re p orte d 
as a s u b-fiel d i n t h e s u m mar y t a bl e. F or cate g ories t h at are p ost-ra n d o mi zati o n, s u m maries 
will be f urt her s plit b y tr eat me nt gr o u p. 
A se parate ta ble will pres e nt t he n u m ber a n d p erce nta ge of s u bjects ra n d o miz e d t o eac h 
treat m e nt gr o u p, b y re gi o n, c o u ntr y a n d ce ntre.  T his ta ble will b e b ase d o n t h e F ull a nal ysis 
set.   
5. 3  
De m o gr a p hic a n d B as eli ne C h ar acteristics 
A ge ( years), se x, race, et h nic gr o u p a n d re gi o n will be s u m marise d b y tr eat m e nt gr o u p f or t h e 
f ull a n al ysis set. Perce nta ges f or de m o gra p hics c h aract eristics will b e base d o n n u m ber of 
s u bjects wit h e val u a ble data. B aseli n e c h aracteristics will be s u m m arise d b y treat me nt f or t h e 
f ull a n al ysis set.  T h ese i n cl u de s u bject c haracteristics ( wei g ht, hei g ht, B MI), pre vi o us 
dise ase-relate d treat me nts, me dical a n d s ur gical hist ories, ast h m a hist or y v aria bles c oll ecte d 
o n t he C R F, a n d t h e e Diar y v aria bles. T h e s u m mar y of d e m o gra p hic i nf or m ati o n will be 
re peat e d o n t he patie nts a ge d 4 t o 1 1 years i n t h e f ull a nal ysis set. 
F E V 1 ( pre a n d p ost- br o n c h o dilat or at scree ni n g)- a n d re versi bilit y will b e s u m marize d at 
scree ni n g a n d baseli n e b y tre at me nt. If pre- br o nc h o dil at or F E V 1 was n ot i n t h e re q uire d ra n ge 
at Visit 1, patie nts m a y atte n d a retest at Visit 1a, i n t h ese i nst a n ces, t h e pre- br o nc h o dilat or 
res ult at Visit 1 a will be c h ose n i n t he s u m mar y of l u n g f u ncti o n at scree ni n g. L u n g f u n cti o n 
re p orte d at b aseli ne will b e re peate d f or patie nts a ge d 4 t o 1 1 years i n t h e f ull a nal ysis set. 
Baseli n e A C Q- 5, a n d P E F rec or de d at baseli n e will be s u m m ariz e d descri pti vel y b y treat m e nt 
gr o u p. Ast h ma d urati o n ( defi ne d b y Ti me i n ye ars si nce ast h m a dia g n osis, a n d Ti me i n years 
si nce ast h ma s y m pt o ms starte d) a n d t h e n u m ber of se vere e x acer b ati o ns i n t h e pre vi o us 1 2 
m o nt hs will be s u m m arize d b y ra n d o mi ze d treat m e nt gr o u p, f or all s u bjects i n t h e f ull a nal ysis 
set. 
Me dical a n d s ur gical hist ories will be s u m m ari ze d b y M e d D R A preferre d t er m wit hi n 
Me d D R A s yste m or ga n class.  
S m o ki n g stat us will be s u m marize d cate g oricall y as t he n u m ber of s u bje cts w h o h a v e n e v er 
s m o k e d or are f or m er s m o kers a n d gr o u pe d b y ra n d o mi ze d treat m e nt gr o u p. Nic oti ne p ac k 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 2 of 8 1 
 
years, e-ci garette pa c k ye ars a n d t otal ( nic oti n e + e-ci garett e) p ac k years will be s u m mari ze d 
as a c o nti n u o us e n d p oi nt b y ra n d o miz e d treat me nt gr o u p. 
A d diti o nall y, ast h m a hist or y v aria bles c ollecte d o n t h e e C R F will b e s u m mariz e d 
cate g oric all y, a n d ti me si nce dia g n osis of ast h ma a n d ti me si n ce se vere e x acer bati o n will be 
s u m m arize d as a c o nti n u o us s cale a n d prese nt t he m e dia n, mi ni m u m a n d ma xi m u m res ult b y 
treat m e nt gr o u p. 
5. 4  
Tre at me nt E x p os ure 
E x p os ure t o st u d y m e di cati o n will b e s u m m ari ze d descri pti vel y f or t he s afet y a n al ysis s et as 
t h e t otal d urati o n ( da ys) fr o m t he first d ose t o t h e last d ose (i ncl usi v e) of ra n d o mi ze d st u d y 
dr u g.  
S u m mar y of e x p os ure will als o be dis pl a ye d as t he t ot al dail y n u m ber of p uffs of I P. Please 
refer t o S ecti o n 5. 8. 4 f or f urt her d et ails.  
5. 5  
A n al ysis of t he pri m ar y v ari a ble 
O nl y dat a c ollecte d u p t o t he pri m ar y data b ase l oc k (see s ecti o n 1. 4) will b e i n cl u d e d i n 
pri mar y efficac y a nal yses. T h ere will be n o effic ac y a nal ys es c o n d ucte d o n a n y data w hic h 
ma y b e c ollecte d after t he pri mar y dat a b ase l oc k a n d u p t o t h e fi n al d ata bas e l o c k f or p atie nts 
a ge d 4 t o 1 7 years. 
T he pla n ne d treat me nt c o m p aris o ns f or t he pri mar y a n al ysis of ti m e t o first se vere ast h ma 
e xacer bati o n are: 
 
B D A M DI 
 
 
A S 
p e diatric 
s u bjects (s u bjects a ge d 4 t o 1 1 years) as t h e y will n ot be ra n d o mi ze d t o B D A M DI 
1 6 0/ 1 8 0 
ysis t he a ge c o variate will o nl y ha ve t h e 2 le vels 
1 2 t o 1 7 a n d 1 8. 
A S M DI 
1 8 0 
 
F or mall y, t he n ull a n d alt er nati ve h y p ot heses f or c o m paris o ns are: 
B D A M DI v ers us A S M DI) = 1, 
B D A M DI v ers us A S M DI) 
1. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 3 of 8 1 
 
T he pri m ar y varia ble, ti me t o first se vere ast h ma e x acer bati o n, will be a nal yze d usi n g a C o x 
pr o p orti o nal hazar ds re gressi o n m o del t o c o m p are treat me nt ar ms. T h e m o d el will b e a dj uste d 
f or t h e ra n d o miz ati o n stratificati o n fact ors (
( N ort h A meri ca, Wester n E ur o pe a n d S o ut h Africa [ Re gi o n 1] a n d rest of w orl d [ Re gi o n 2]); 
a n d n u m b er of pri or se vere e x acer bati o ns ( 1, > 1) i n t h e 1 2 m o nt hs pri or t o ra n d o mi zati o n. T he 
s u m m ar y meas ure t o c o m p are treat me nts is t he esti mate d hazar d rati o w hi c h will b e prese nte d 
wit h t he c orres p o n di n g 9 5 % c o nfi d e nce i nter val a n d p- val ue. 
Pri maril y, ti m e t o first se vere e x acer bati o n will be c o n d u cte d u n der t he efficac y esti m a n d a n d 
will c o nsi der se vere e xacer bati o n e ve nts o cc urri n g pri or t o t h e disc o nti n uati o n of I P or a 
c ha n ge i n mai nte na nce t h era p y. All patie nts w h o are ra n d o mi ze d a n d are p art of t h e f ull 
a nal ysis s et will be a nal yze d acc or di n g t o t h e strata t he y were all oc ate d t o i n I V R S/I W R S. A 
miss-stratificati o n o n t he m o d el res ults. T he pri m ar y a nal ysis of ti me t o first se vere 
e xacer bati o n will c o nsi d er e ve nts i d e ntifie d via a n i n d e pe n de nt a dj u dicati o n c o m mittee. A 
se nsiti vit y a n al ysis will be perf or me d w hic h e xcl u des t he a dj u di cate d e ve nts fr o m t h e 
e n d p oi nt deri v ati o n. 
A s u p p orti ve a nal ysis will b e perf or me d i n w hic h patie nts will b e ce ns ore d at t he earliest 
o cc urre nc e of: ra n d o mize d treat me nt disc o nti n uati o n, c h a n ges i n mai nt e na n ce t h era p y, t he 
o nset of a C O VI D- 1 9 rel ate d treat m e nt e mer ge nt a d v erse e ve nt or a tr eat m e nt i nterr u pti o n d ue 
t o C O VI D- 1 9. 
A d diti o nal s u p p orti v e a nal yses u n d er t h e d e fact o esti ma n d, usi n g a n al ysis met h o ds as per t he 
effic ac y esti m a n d (a b o ve), b ut i n cl u di n g d ata p ost-I P disc o nti n uati o n or c ha n ges i n 
mai nte na nce t hera p y will be c o n d ucte d.  
Fi nall y, t h ese a n al ys es will b e re peate d u n d er t he attri b uta ble esti ma n d, i n w hic h ce ns ore d 
res ults will ha ve e ve nt ti mes i m p ute d u n d er a n i nf or mati ve ce ns ori n g ass u m pti o n. F urt h er 
d etails are pr o vi d e d i n S ecti o n 5. 1 0.  
T he ass u m pti o n of pr o p orti o nalit y will be assesse d.  Pr o p orti o nal h azar ds will be teste d firstl y 
b y e xa mi ni n g pl ots of c o m ple me ntar y l o g-l o g (e ve nt ti m es) vers us l o g (ti me) a n d, if t h es e 
rais e c o n cer ns, b y fitti n g a ti m e d e p e n de nt c o v ariate (a d di n g a treat me nt- b y-ti m e or treat me nt-
b y-l n(ti me) i nteracti o n ter m) t o assess t he e xte nt t o w hic h t his re prese nts ra n d o m v ariati o n. If 
a lac k of pr o p orti o nalit y is e vi de nt t h e v ariati o n i n treat me nt effect ca n be d escri b e d b y 
prese nti n g pie ce wise haz ar d rati os. If l ac k of pr o p orti o nalit y is f o u n d t his ma y b e a res ult of a 
treat m e nt- b y-c o v ariat e i nteracti o ns, w hic h will be i n vesti gate d. 
T he n u m ber a n d p erce nta ge of s u bjects wit h at l east o n e s e vere e x acer b ati o n p ost-
ra n d o mi zati o n a n d pri or t o disc o nti n u ati o n of ra n d o miz e d treat m e nt/ c ha n ge i n mai nte na nce 
t h era p y d ue t o lac k of ast h ma c o ntr ol will be s u m m ariz e d b y tr eat m e nt gr o u p. A d diti o nall y, 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 4 of 8 1 
 
t h e n u m ber of s u bjects w h o ha ve bee n ce ns ore d al o n g wit h t h e reas o n f or ce ns ori n g 
(c o m plete d st u d y pri or t o first e x acer b ati o n; dis c o nti n ue d tr eat me nt d ue t o ast h ma; c ha n ge i n 
mai nte na nce t hera p y d u e t o p o or ast h m a c o ntr ol; d eat h; ot h er). T h ese des cri pti ve s u m maries 
will be re peate d u n der effecti v e ness esti ma n d. 
Re verse K a pla n- M eier pl ots f or ti me t o first se vere e xacer b ati o n will be i n cl u d e d a n d will b e 
prese nte d b y ra n d o miz e d treat m e nt. 
5. 6  
A n al ysis of t he sec o n d a r y effic ac y v ari a bles 
F or all sec o n dar y a nal yses t he s a me treat me nt c o m paris o ns as f or t he pri mar y a nal ysis will be 
c o n d ucte d (s ee Secti o n 5. 5). Ple ase s ee s ecti o n 5. 1. 4 f or h a n dli n g of t h e t y p e-I err or c o ntr ol 
f or t h e sec o n dar y a nal yses. 
O nl y dat a c ollecte d u p t o t he pri m ar y data b ase l oc k (see s ecti o n 1. 4) will b e i n cl u d e d i n 
sec o n dar y effi cac y a nal yses. T here will be n o effi cac y a nal yses c o n d u cte d o n a n y d ata w hic h 
ma y b e c ollecte d after t he pri mar y dat a b ase l oc k a n d u p t o t h e fi nal data bas e l o c k f or pati e nts 
a ge d 4 t o 1 7 years. 
5. 6. 1  
Se vere ast h m a e x acer b ati o n r ate 
A nal ysis of se vere ast h m a e xacer b ati o n rate will tar get t h e effic ac y esti ma n d i n t he F A S 
p o p ulati o n. A n n ualiz e d se vere ast h ma e xacer b ati o n rate will b e a nal yze d usi n g ne gati v e 
bi n o mial r e gressi o n t o c o m pare treat me nt gr o u ps. T he res p o ns e v aria ble i n t he m o del will b e 
t h e n u m ber of s e vere ast h ma e x acer bati o ns. T h e m o d el will a dj ust f or (
rest of w orl d [ Re gi o n 2]); a n d n u m ber of pri or s e v ere e xacer bati o ns ( 1, > 1) i n t h e 1 2 m o nt hs 
pri or t o ra n d o mi zati o n. A n al yses of t he a n n u ali ze d se vere ast h ma e xacer bati o n rate will be 
re peat e d u n der t h e de fact o esti ma n d, a n d will c o nsi d er all se v ere e xacer bati o ns u p t o p atie nt 
wit h dra wal fr o m t he trial. 
T he l o garit h m of t he ti m e at ris k of e x perie n ci n g a se vere ast h ma e xacer bati o n will be use d as 
a n offset varia ble i n t h e m o del. Ti m e d uri n g a s e vere ast h ma e xacer bati o n or i n t h e 7 da ys 
after a n e xacer bati o n will n ot be i ncl u de d i n t h e calc ulati o n. Fr o m t h e ne g ati ve bi n o mi al 
m o d el, t he a n n ual se vere ast h m a e x acer b ati o n rates will be esti mate d, a n d t h e s u m mar y 
meas ure f or t he c o m p aris o n of treat me nts will be t h e esti mate d rate rati o w hic h will be 
prese nte d wit h t h e c orres p o n di n g 9 5 % c o nfi d e nc e i nter val a n d p- v al u e. T h e o ver dis persi o n 
p ara meter esti m ate will b e i n cl u d e d i n t h e o ut p ut. 
Se v ere ast h ma e xacer bati o ns will be s u m marise d descri pti v el y as t he fre q u e nc y a n d 
p erce nta ge of s u bjects wit h at least 1 s e vere e x acer bati o n, t h e n u m ber of s e vere e xacer bati o ns 
pri or t o I P disc o nti n uati o n or a c ha n ce i n mai nte n a nce t h era p y a n d t h e t otal n u m ber of se vere 
e xacer bati o ns p er treat m e nt- year. N u m b er of s e vere e x acer bati o ns per treat m e nt- year will b e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 5 of 8 1 
 
calc ulate d as descri be d i n Secti o n 4. 3. 1. T he af ore me nti o ne d d escri pti ve statistics will be 
s u m m arise d f or all se v ere e x acer b ati o ns a n d will b e f urt her br o ke n d o w n i nt o: Se vere 
e xacer bati o ns re q uiri n g s yste mic c ortic oster oi d us e; se vere e xacer bati o ns re q uiri n g 
h os pitalizati o n; se ver e e xacer bati o ns re q uiri n g e m er ge nc y r o o m visit/ ur ge nt care visit. 
A n o verall s u m mar y of se vere ast h ma e xacer b ati o ns d uri n g t h e treat me nt p eri o d will be 
s u m m arize d descri pti vel y, prese nti n g t he fre q ue n c y a n d perce nta ge of s u bj ects w h o h a d at 
least o ne se v ere e xacer bati o n d uri n g t he st u d y ( Yes/ N o); T he n u m ber of e x acer b ati o ns per 
s u bject, descri b e d b ot h as a cate g orical a n d as a c o nti n u o us e n d p oi nt.  
T he c u m ulati v e t otal d a ys of se v ere e xacer b ati o ns will be s u m m arize d b y treat m e nt gr o u p. 
T he t otal n u m b er of d a ys of s e vere e xacer bati o ns p er s u bject will b e s u m mariz e d as a 
c o nti n u o us e n d p oi nt. 
T he si g ns a n d s y m pt o ms of ast h ma w orse ni n g will b e s u m m aris e d cat e g oric all y as t he 
fre q ue n c y eac h s y m pt o m is o bser ve d p er s e v ere e xacer bati o n pri or t o I P disc o nti n uati o n or a 
c ha n ge i n mai nte na nce t h era p y. T he de n o mi n at or f or perce nta ge calc ul ati o ns will be t he 
n u m b er of e xacer bati o ns.  
Ti me-e ve nt pl ots f or se v ere e xacer bati o ns will be pr o d uce d fr o m t he f ull a n al ysis set a n d will 
b e gr o u pe d b y ra n d o mize d treat me nt. 
5. 6. 2  
Ast h m a C o ntr ol Q uesti o n n aire- 5 
O ver all A C Q- 5 Sc ore 
T he o verall A C Q- 5 sc ore a n d i n di vi d u al d o mai ns, i ncl u di n g c h a n ge fr o m baseli ne, will b e 
d escri pti v el y s u m m arise d b y treat me nt a n d visit, pri or t o I P disc o nti n uati o n or a c ha n ge i n 
mai nte na nce t hera p y.  
A nal ysis of c ha n ge fr o m b aseli ne i n A C Q- 5 at W ee k 2 4 will t ar get t he effic ac y esti ma n d i n 
t h e F A S p o p ulati o n. T h e treat me nt effect f or c h a n ge fr o m baseli ne i n O v erall A C Q- 5 will b e 
esti m ate d usi n g a mi x e d m o del re peat e d me as ures ( M M R M) a nal ysis. All sc h e d ule d 
assess me nts u p t o a n d i n cl u di n g Wee k 2 4 t hat are wit hi n t h e visit wi n d o ws (secti o n 4. 1. 5) will 
b e i ncl u de d i n t h e m o del, wit h ter ms f or treat me nt, visit, treat me nt * visit, a n d baseli ne A C Q-
5. T he m o del will als o be a dj ust e d f or t h e ra n d o mi zati o n stratificati o n fact ors (
4 
a n d rest of w orl d [ Re gi o n 2]); a n d n u m ber of pri or se vere e x acer bati o ns ( 1, > 1) i n t h e 1 2 
m o nt hs pri or t o ra n d o mi zati o n. T h e varia n ce-c o v aria nce m atri x will b e ass u me d t o be 
u nstr uct ure d. K e n w ar d- R o ger de n o mi n at or de grees of free d o m will be use d ( Ke n w ar d a n d 
R o ger 1 9 9 7). If t h e pr oce d ure d oes n ot c o n v er ge, t h e n a c o m p o u n d s y m metric varia n ce-
c o v aria nce m atri x will b e use d i nstea d. T his m o del will be use d t o gi ve a n o v erall assess me nt 
of t h e treat me nt effect as well as 9 5 % c o nfi de nce i nter vals a n d ass o ciate d p- v al u es. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 6 of 8 1 
 
C h a n ge fr o m bas eli ne will als o be descri be d d escri pti v el y f or all st u d y visits, i n cl u di n g t h e 
E O S visit/ P D V a n d t h e safet y f oll o w- u p tel e p h o n e c o ntact.   
I n all t h e sce nari os a b o ve, baseli ne is defi ne d as t he m ost rece nt sc ore bef ore a n d i n cl u di n g 
ra n d o mi zati o n ( Visit 2).
Gra p hical pl ots of c h a n ge fr o m baseli ne A C Q- 5 o ver ti me will als o be pres e nte d usi n g m o del 
esti m ates.  
Res p o n der A n al ysis 
Res p o n der stat us will be descri pti vel y s u m m aris e d b y treat me nt a n d visit as t h e n u m b er ( %) 
of res p o n ders a n d n o n-res p o n ders. 
T he res p o n der vari a ble d escri b e d i n Secti o n 4. 3. 3 at Wee k 2 4 will be a nal yse d usi n g a l o gistic 
re gr essi o n m o d el t o c o m pare treat me nt gr o u ps. T he m o del will be a dj uste d f or b aseli ne A C Q-
5 a n d ra n d o mi zati o n stratificati o n fact ors (
 
( N ort h A meri ca, Wester n E ur o pe a n d S o ut h Africa [ Re gi o n 1] a n d rest of w orl d [ Re gi o n 2]); 
a n d n u m b er of pri or se vere e x acer bati o ns ( 1, > 1) i n t h e 1 2 m o nt hs pri or t o ra n d o mi zati o n. 
Fr o m t he l o gistic re gressi o n m o del, treat m e nt effects will b e esti m ate d b y o d ds rati os a n d t h eir 
c orres p o n di n g 9 5 % c o nfi de nce i nter vals a n d p- v al u es. 
T he e x pl orat or y e n d p oi nt f or res p o n der a n al ysis at Wee k 1 2 will be a nal ys e d i n a si milar wa y. 
T he n u m ber a n d p erce nta ge of res p o n d ers will b e s u m m arise d d escri pti v el y f or all ti me p oi nts. 
5. 6. 3  
Ast h m a Q u alit y of Life Q uesti o n n aire + 1 2 a n d Pe di atric Ast h m a Q u alit y 
of Life Q uesti o n n aire 
T he d e n o mi nat or f or t he A Q L Q + 1 2 a n d P A Q L Q s u m m aries will b e base d o n t he n u m ber of 
s u bjects wit hi n t he res pecti ve a ge gr o u p f or w h o m eac h q u esti o n n aire is a p plica ble; 
A Q L Q + 1 2 will i n cl u de s u bjects a ge d 1 2 ye ars a n d o ver w hilst t h e P A Q L Q will i ncl u de a ges 7 
t o 1 1 years ol d. C hil dre n a ge d 4 t o 6 years ol d will n ot be i ncl u de d i n t he de n o mi nat or f or 
P A Q L Q e n d p oi nt s u m maries a n d t his i nf or mati o n will be liste d o nl y. 
T he res p o n der a n al ysis will b e c o n d ucte d i n t h e sa m e wa y as A C Q- 5 ( Secti o n 5. 6. 2). T he 
e x pl orat or y e n d p oi nt f or res p o n der a nal ysis at Wee k 1 2 will als o be a nal ys e d i n a si milar w a y.  
T he d o m ai n sc ores as w ell as t he o verall sc ores are calc ul ate d fr o m t h e u n wei g ht e d arit h metic 
mea ns of t he i n di vi d u al q u esti o n sc ores. T he treat me nt effect f or c ha n ge fr o m baseli n e i n 
A Q L Q + 1 2 a n d P A Q L Q o verall sc ores u p t o Wee k 2 4 will be esti mat e d i n t he sa me wa y as 
A C Q- 5, usi n g a M M R M a nal ysis ( Secti o n 5. 6. 2).
T he P A Q L Q will be a nal ys e d s e paratel y t o 
t h e A Q L Q + 1 2. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 7 of 8 1 
 
C h a n ge fr o m bas eli ne will als o be descri be d d escri pti v el y f or all st u d y visits, i n cl u di n g t h e 
E O S visit a n d safet y f oll o w- u p tele p h o ne c o ntact f or eac h of t h e d o mai ns a n d t h e o verall 
sc ores. 
I n all t h e sce nari os a b o ve, baseli ne is defi ne d as t he m ost rece nt sc ore b ef ore a n d i n cl u di n g 
ra n d o mi zati o n ( Visit 2).
Gra p hical pl ots of c h a n ge fr o m baseli ne A Q L Q + 1 2 a n d P A Q L Q o ver ti m e will als o be 
prese nte d usi n g m o d el esti mates. 
5. 6. 4  
T ot al S yste mic c ortic oster oi d e x p os ure 
T he t otal s yste mic c ortic oster oi d e x p os ure as t otal a n n uali ze d d ose of S C S will be prese nte d 
d escri pti v el y b y treat me nt. A c o m paris o n i n t otal a n n ualize d S C S d ose bet wee n B D A M DI 
8 0/ 1 8 0 vs A S M DI 1 8 0 a n d B D A M DI 1 6 0/ 1 8 0 vs A S M DI 1 8 0 will be a nal yse d usi n g a 
Wil c o x o n ra n k s u m test a n d ass o ciate d p- v al u es will be prese nte d al o n g wit h t h e des cri pti ve 
s u m m ar y. T h e sec o n dar y a nal ysis of t otal s yste mi c c ortic oster oi d e x p os ure wit h b e a nal yse d 
u n d er t h e efficac y esti ma n d. T h e a d diti o nal d escri pti v e statisti cs of 7 5 t h, 8 0t h a n d 9 0t h 
p erce ntiles will be prese nte d i n t he s u m mar y of a n n ualize d S C S d ose. 
T o h el p descri b e t h e differe nce i n t otal a n n ualiz e d d os e of S C S bet wee n treat me nt gr o u ps, t he 
pre dicte d me a n a n n u alize d d ose of S C S will be esti mate d f or eac h treat me nt gr o u p fr o m a l o g-
n or mal h ur dle m o del a dj uste d f or ra n d o miz e d treat m e nt gr o u p. T he l o g- n or mal h ur dl e m o d el 
will be fit i n S A S usi n g P R O C F M M wit h t w o m o del c o m p o ne nts: A c o nst a nt distri b uti o n t o 
d escri be t h e zer o e v e nts a n d a l o g- n or mal distri b uti o n c o m p o n e nt t o d escri be t h e patie nts wit h 
a n o n-zer o a n n u alize d d ose. E xa m ple c o de is pr o vi d e d bel o w: 
p r o c  f m m  d a t a = a d a m . a d e x s u m ;  
 
w h e r e  p a r a m c d  =  ' S Y S T O T 1 '  a n d  F A S F L  =  ' Y ' ;  
 
 
c l a s s  t r t 0 1 p n ;  
 
m o d e l  a v a l  =  t r t 0 1 p n  /  d i s t = l o g n o r m a l ;  
  
m o d e l      +      /  d i s t = c o n s t a n t ;  
 
p r o b m o d e l  t r t 0 1 p n  /  C L ;  
 
o u t p u t  o u t = p r e d _ y  /  a l l s t a t s ;  
r u n ;  
A d diti o nall y, t he t otal S C S e x p os ure will be s u m marise d d escri pti vel y as t he t otal n u m b er of 
d a ys wit h S C S treat me nt d u e t o ast h m a f or all pati e nts. A n e x pl orat or y descri pti ve s u m mar y 
will be d o n e f or all pati e nts w h o a d mi nistere d at l east 1 d ose of S C S d uri n g t h e st u d y. 
E x pl orat or y a nal ys es will be re peate d u n der t he effecti v e n ess a n d de fact o esti ma n ds. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 8 of 8 1 
 
5. 7  
A n al ysis of s afet y v ari a bl es 
T he safet y a nal yses will i ncl u de all data o btai ne d u p t o t he pri mar y d ata base l o c k (see s ecti o n 
1. 4) b ef ore s u bj ects dis c o nti n ue ra n d o mi ze d treat me nt a n d will us e t h e safet y a nal ysis set.  
All descri pti ve s u m maries a n d listi n gs of p ati e nt e x p os ure t o ra n d o mi ze d treat m e nt, a d verse 
e ve nts, vit al si g ns, la b orat or y ass ess me nts a n d 1 2- Le a d E C G will be pr o d u ce d t o s u m marise 
t h e safet y of  d ata f or p atie nts a ge d 4 t o 1 7 years t h at was c ollect e d f oll o wi n g t h e pri mar y 
d ata base l o c k a n d u p t o t h e fi n al data b ase l oc k. 
5. 7. 1  
A d v erse e v e nts 
A Es will b e s u m mariz e d b y treat me nt gr o u p, s yste m or ga n class a n d preferre d t er m assi g n e d 
t o t h e e ve nt b y t h e M e dical Dicti o nar y f or R e g ulat or y A cti viti es, usi n g t he m ost rece nt v ersi o n 
a vail a ble at t he ti m e of d ata base l o c k. T he f oll o wi n g s u m m aries will be i ncl u de d: 
A Es i n a n y cate g or y, w hic h will i ncl u de t he n u m ber of s u bjects wit h: a n y A E; a n y A E 
t h at is relate d t o I P; a n y A E wit h a n o utc o m e of d eat h; a n y seri o us A E ( S A E); a n d a n y 
A E lea di n g t o disc o nti n uati o n of i n v esti gati o nal pr o d uct; a n y O A E. 
N u m ber of p atie nts wit h A Es d uri n g t h e ra n d o mi ze d treat me nt peri o d, b y s yste m or g a n 
class a n d preferre d ter m. 1 
N u m ber of p atie nts wit h m ost fre q ue ntl y o cc urri n g A Es (at l east 2 % s u bj ects i n a n y 
treat m e nt gr o u p), b y preferre d t er m. 1 
N u m ber of p atie nts wit h A Es d uri n g t h e r u n-i n p eri o d b y s yste m or g a n class a n d 
preferre d t er m. 
N u m ber of A Es a n d e ve nt rate d uri n g t h e ra n d o mi ze d treat m e nt peri o d, b y s yste m 
or ga n class a n d preferre d ter m. 2 
N u m ber of p atie nts wit h A Es wit h a n o utc o me of d eat h, b y s yst e m or ga n cl ass a n d 
preferre d t er m. 
N u m ber of p atie nts wit h A Es d uri n g t h e ra n d o mi ze d treat me nt peri o d b y ma xi m u m 
re p orte d i nte nsit y, s yst e m or ga n class a n d preferre d ter m. 1 
N u m ber of p atie nts wit h A Es d uri n g t h e ra n d o mi ze d treat me nt peri o d, b y preferre d 
ter m a n d relati o ns hi p t o I P, as assesse d b y t he i n vesti gat or. 1 
N u m ber of p atie nts wit h A Es d uri n g t h e ra n d o mi ze d treat me nt peri o d b y preferre d 
ter m a n d o utc o me. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 9 of 8 1 
 
N u m ber of p atie nts wit h S A E d uri n g t h e ra n d o mi ze d treat m e nt peri o d, b y s yste m 
or ga n class a n d preferre d ter m. 1 
N u m ber of S A Es d uri n g t he ra n d o mi ze d treat m e nt peri o d, b y s yst e m or ga n class a n d 
preferre d t er m. 2 
N u m ber of p atie nts wit h A Es d uri n g t h e ra n d o mi ze d treat me nt peri o d le a di n g t o 
disc o nti n u ati o n of ra n d o miz e d treat me nt, b y s yste m or ga n class a n d preferre d ter m. 
A Es d uri n g t h e ra n d o mi ze d treat m e nt peri o d assesse d b y t h e s p o ns or t o be si g nifica nt, 
b y s yste m or ga n class a n d preferre d t er m. 
N o n-seri o us A Es (fre q ue nc y > = 2 %) b y preferre d ter m.  1 
N u m ber of p atie nts wit h A Es d uri n g t h e f oll o w- u p p eri o d, b y s yst e m or ga n class a n d 
preferre d t er m. 3 
1 A Es o cc urri n g d uri n g t h e ra n d o miz e d treat me nt peri o d will i ncl u de t he i n ci de nce rat e. T he 
i n ci d e n ce rate is d efi n e d as t he n u m ber of s u bj ects w h o h a ve e x p erie nce d t h e e ve nt per 1 0 0 
s u bject treat me nt years.   
2 N u m ber of e ve nts a n d e ve nt rates f or A Es a n d S A Es will als o b e prese nte d.  E v e nt rates are 
d efi ne d as t he t otal n u m b er of e ve nts acr oss all s u bj ects i n t he treat m e nt gr o u p per 1 0 0 s u bj ect 
treat m e nt years. 
T he n u m ber of p ati e nts wit h a d verse e ve nts o cc urri n g p ost-ra n d o mi ze d treat me nt 
disc o nti n uati o n will b e s u m m arise d se paratel y. 
F or A Es le a di n g t o d eat h, A Es lea di n g t o disc o nti n uati o n of ra n d o miz e d treat m e nt, a n d all 
S A Es will be liste d b y s u bject a n d treat me nt gr o u p, a n d will i n cl u d e t he f oll o wi n g k e y p atie nt 
i nf or mati o n: S e x; A ge at st u d y e ntr y; A E ter m as re p orte d b y t he i n vesti gat or; A E preferre d 
ter m; ti me fr o m start of treat me nt t o o nset of A E ( d a ys); ti m e fr o m start of treat me nt t o 
b ec o mi n g s eri o us ( da ys); o utc o me; Acti o n ta k e n wit h ra n d o mi ze d treat m e nt; Ca usalit y t o 
ra n d o mi ze d treat m e nt. 
All A Es will als o be liste d f or eac h s u bject a n d will i n cl u de a nal ysis p h ase (r u n-i n; 
ra n d o mi ze d treat m e nt peri o d; f oll o w- u p); a ge/se x/race; A E re p orte d ter m a n d preferre d t er m; 
start of A E rel ati ve t o ra n d o mi zati o n a n d d urati o n of e v e nt ( d a ys); m a xi m u m i nte nsit y; seri o us 
( Y/ N); acti o n ta ke n wit h ra n d o miz e d treat me nt; ca us alit y wit h ra n d o mi ze d treat me nt; o utc o me 
of A E. 
A s u m mar y of n u m b er of pati e nts wit h a d verse e ve nts, b y s yste m or g a n class a n d preferre d 
ter m will be pr o d u ces a n d gr o u p e d wit hi n mai nte na nce I C S d osi n g cate g or y 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 0 of 8 1 
 
(l o w/ m e di u m/ hi g h). Pl eas e refer t o s ecti o n 5. 8. 9 f or d etails o n t he deri v ati o n of t otal dail y 
d ose of mai nte na n ce I C S. 
A d diti o nall y, t he n u m ber ( %) of p ati e nts wit h a d v erse e ve nts ass ociate d wit h l o cal I C S (as 
d efi ne d i n secti o n 4. 5. 2. 5) will be prese nte d o v erall (at least 1 l ocal I C S-relate d A E) a n d b y 
preferre d t er m f or patie nts i n t h e safet y a nal ysis s et. A d diti o nall y, t h ese A Es will be 
s u m m arise d wit hi n mai nte na nce I C S d osi n g cate g or y (l o w/ m e di u m/ hi g h). A listi n g of I C S 
relate d A Es will be pr o d uce d w hic h will i ncl u d e t h e t ot al dail y n u m ber of p uffs of ra n d o mize d 
treat m e nt ( p uffs/ d a y) a n d bac k gr o u n d mai nte na nce I C S d osi n g cate g or y (l o w/ m e di u m/ hi g h). 
A si mil ar o ut p ut will b e pr o d uce d dis pla yi n g t he n u m ber ( %) of patie nts wit h a d verse e v e nts 
t h at are ass o ciate d wit h s yste mic I C S effects ( as d efi n e d i n secti o n 4. 5. 2. 5). 
Se p arate ta b ul ati o ns of pati e nts wit h A Es of P n e u m o nia ( n o n- C O VI D- 1 9 relate d; C O VI D- 1 9 
relate d) will be prese nte d b y treat me nt gr o u p a n d dail y mai nte n a nce I C S d ose. 
Se p arate ta b ul ati o ns of pati e nts wit h A Es ass o ciat e d wit h C O VI D- 1 9 will b e prese nt e d b y 
treat m e nt gr o u p a n d d ail y mai nte n a nce I C S d os e. 
5. 7. 2  
Vit al si g ns 
A bs ol ute v al ues a n d c ha n ges fr o m b aseli ne i n vit al si g ns varia bles ( Secti o n 4. 5. 1) will be 
d escri pti v el y s u m m arise d b y visit a n d treat me nt gr o u p. 
Baseli n e is d efi n e d as t he m ost rece nt n o n- missi n g meas ure me nt b ef ore a n d i ncl u di n g 
ra n d o mi zati o n ( Visit 2). 
Hei g ht will be c ol
st u d y or Pre mat ure disc o nti n u ati o n visit, w h ere a p plica ble. T hese a d diti o nal assess m e nts of 
h ei g ht will be liste d o nl y. 
5. 7. 3  
Cli nic al c he mistr y a n d he m at ol o g y 
A bs ol ute v al ues a n d c ha n ges fr o m baseli ne i n cli nical c he mistr y, h ae mat ol o g y p ara meters a n d 
c ortis ol will b e s u m m arize d b y treat me nt gr o u p a n d visit a n d will als o b e liste d b y s u bject. 
A bs ol ute v al ues will b e c o m pare d t o t he rel e va nt refere nc e ra n ge a n d cl assifi e d as l o w ( bel o w 
ra n ge), n or mal ( wit hi n ra n ge or o n li mits) or hi g h (a b o v e ra n ge). All val u es (a bs ol ute a n d 
c ha n ge) falli n g o utsi d e t he refere n ce ra n ges will b e fla g ge d. A d diti o nall y, s hift ta bles 
prese nti n g t he s hift fr o m baseli ne refere nce ra n ge i n dicat or ( L o w; N or m al; Hi g h) t o t he 
ma xi m u m o n-treat me nt res ult will be s u m m ariz e d d escri pti vel y b y ra n d o mize d treat m e nt 
gr o u p a n d la b orat or y para meter. 
Baseli n e is d efi n e d as t he m ost rece nt n o n- missi n g meas ure me nt b ef ore a n d i ncl u di n g 
ra n d o mi zati o n ( Visit 2). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 1 of 8 1 
 
S u bjects wit h cases meeti n g p ote ntial H L criteria (see Secti o n 4. 5. 3) will be a d diti o nall y 
liste d. Scatter pl ots gr o u pe d b y ra n d o miz e d treat m e nt will s h o w t he ma xi m u m p ost- b aseli ne 
A L T a n d bilir u bi n c o n ce ntrati o ns, as m ulti ples of t he U L N, o n t he x a n d y- a xis res p ecti v el y. 
Refere nce li nes of A L T ( m ulti ple of U L N) = 3 a n d bilir u bi n ( m ulti pl e of U L N) = 2 
re pres e nti n g t he t hres h ol d criteria f or H L ( Secti o n 4. 5. 3) will be a d d e d t o t h e fi g ure. 
I n all d escri pti ve s u m maries b y tr eat me nt gr o u p, la b orat or y res ults w hic h are a b o ve t h e u p p er 
li mit, or bel o w t he l o wer li mit of q u a ntificati o n will be re pres e nte d n u meric all y as t h e 
< x
> x
t h e listi n gs. 
5. 7. 4  
1 2- Le a d E C G 
T he 1 2- Lea d E C G varia bl es d escri be d i n Secti o n 4. 5. 3. 1 will be s u m m ariz e d d escri pti vel y b y 
treat m e nt gr o u p a n d visit. 
Baseli n e is d efi n e d as t he m ost rece nt n o n- missi n g meas ure me nt ta k e n bef ore a n d i ncl u di n g 
ra n d o mi zati o n ( Visit 2). 
5. 7. 5  
C o nc o mit a nt me dic ati o n 
T he n u m ber a n d p erce nta ge of s u bjects w h o t a k e all o w e d c o nc o mita nt m e dicati o ns, a n d t h os e 
w h o ta ke disall o we d c o n c o mita nt m e dicati o ns d uri n g t h e st u d y, will be prese nte d b y treat me nt 
gr o u p a n d A T C classifi cati o n ( 5 t h le vel) a n d g e neric ter m. 
S u m maries will be gr o u pe d b y pri or me dicati o n, c o nc o mita nt me dicati o n occ urri n g d uri n g t he 
ra n d o mi ze d treat m e nt peri o d a n d c o nc o mita nt me dicati o n occ urri n g d uri n g t he f oll o w- u p 
p eri o d (i. e. p ost-ra n d o mi ze d treat m e nt disc o nti n uati o n). Defi niti o ns are pr o vi d e d i n Secti o n 
4. 6. 1. Mai nte na n ce me dicati o n will n ot c o ntri b ute t o t hese s u m maries a n d will be prese nte d i n 
a se parate ta ble.   
5. 8  
A n al ysis of e x pl or at or y v ari a bles 
T he treat me nt c o m p aris o ns i n t he e x pl orat or y a nal ys es gi ve n b el o w are c o m pare d i n t he s a me 
wa y as t he pri mar y a nal ysis. 
O nl y dat a c ollecte d u p t o t he pri m ar y data b ase l oc k (see s ecti o n 1. 4) will b e i n cl u d e d i n 
e x pl orat or y efficac y a nal ys es. T h ere will be n o efficac y a n al ys es c o n d u cte d o n a n y data w hic h 
ma y b e c ollecte d after t he pri mar y dat a b ase l oc k a n d u p t o t h e fi nal data bas e l o c k f or pati e nts 
a ge d 4 t o 1 7 years. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 2 of 8 1 
 
5. 8. 1  
Deteri o r ati o n of ast h m a 
A n n ualize d deteri orati o n of ast h ma a n d ti me t o first d eteri orati o n of ast h m a will be a nal ys e d 
i n t h e sa me wa y as t h e ti me t o first se vere ast h ma e x acer bati o n ( Secti o n 4. 2. 1) a n d a n n ualiz e d 
se vere ast h ma e x acer bati o n rate ( Secti o n 5. 6. 1). 
Ti me-e ve nt pl ots f or ast h m a d eteri orati o ns will be pr o d uce d fr o m t he f ull a nal ysis set a n d will 
b e gr o u pe d b y ra n d o mize d treat me nt. 
Re verse K a pla n- M eier pl ots f or ti me t o first d eteri orati o n of ast h m a will b e i ncl u d e d a n d will 
b e prese nt e d b y ra n d o mi z e d treat m e nt.  
Pl ots of  mea n dail y m or ni n g P E F, d ail y t otal reli e ver t h era p y use a n d dail y t ot al ast h ma 
s y m pt o m sc ore, al o n g wit h sta n dar d err or b ars, will be pl otte d o v er a 1 5 da y i nter val eit h er 
 
5. 8. 2  
Pre- br o nc h o dil at or F E V 1 
T he treat me nt effect f or c ha n ge fr o m b aseli ne i n F E V 1 ( L) will be esti mate d usi n g a M M R M 
a nal ysis. F E V 1 data fr o m all visits u p t o t h e earliest of Wee k 2 4 a n d pri or t o I P 
disc o nti n uati o n or c ha n ge i n m ai nte na nce t h era p y will b e i ncl u de d i n t he m o d el, wit h ter ms 
f or treat m e nt, visit a n d treat me nt * visit wit h b aseli n e F E V1 i ncl u de d as a c o v ariate. T h e m o del 
will be a dj uste d f or t he ra n d o mi zati o n stratificati o n fact ors (
[ Re gi o n 2]); a n d n u m ber of pri or se vere e xacer bati o ns ( 1, > 1) i n t h e 1 2 m o nt hs pri or t o 
ra n d o mi zati o n. Visit will be fitte d as a cate g orical varia ble, a n d t h e varia nc e-c o v aria nc e 
matri x will b e ass u m e d t o be u nstr uct ure d. K e n war d- R o ger d e n o mi n at or d e grees of free d o m 
will be use d ( Ke n w ar d a n d R o ger 1 9 9 7). If t h e pr oce d ure d o es n ot c o n ver ge t h e n a c o m p o u n d 
s y m m etric varia n ce c o v aria nce matri x will b e use d i nstea d. T his m o d el will be use d t o gi ve 
assess me nts of t h e treat me nt effect as w ell as 9 5 % c o nfi de nce i nt er v als a n d ass o ciate d p-
v al ues at W ee k 1 2 a n d Wee k 2 4. 
A fi g ure s h o wi n g t h e c ha n ge fr o m b aseli ne i n pre- br o nc h o dilat or F E V 1 at e ac h p ost- b aseli ne 
visit u p t o Wee k 2 4 will be prese nte d usi n g t h e L S mea ns a n d 9 5 % c o nfi d e nc e i nter vals fr o m 
t h e M M R M m o d el descri b e d a b o v e. 
Baseli n e is d efi n e d as t he m ost rece nt n o n- missi n g meas ure me nt b ef ore a n d i ncl u di n g 
ra n d o mi zati o n ( Visit 2). 
F E V 1 pre- br o nc h o dilat or will be s u m marise d descri pti vel y b y treat me nt gr o u p a n d all 
sc he d ule d visits.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 3 of 8 1 
 
5. 8. 3  
M or ni n g pe a k e x pir at or y fl o w 
T he m ea n val u e of c ha n ge fr o m baseli ne i n m or ni n g P E F d ata fr o m ra n d o mi zati o n t o I P 
disc o nti n uati o n or a c ha n ge i n m ai nt e n a nce t h era p y will be a nal ys e d b y a n al ysis of c o varia n ce 
wit h treat me nt as a fact or a n d, b aseli ne m or ni n g P E F sc ore as a c o nti n u o us c o variate. T he 
m o d el will als o be a dj uste d f or t he ra n d o mi zati o n stratificati o n fact ors (
rest of w orl d [ Re gi o n 2]); a n d n u m b er of pri or s e vere e x acer bati o ns ( 1, > 1) i n t h e 1 2 m o nt hs 
pri or t o ra n d o mi zati o n. T he s u m m ar y meas ure f or t h e c o m p aris o n of treat m e nts will be t he 
esti m ate d me a n differe nc e, prese nt e d wit h t he c orres p o n di n g 9 5 % c o nfi d e nce i nter val a n d 
ass o ciate d p- v al u e. 
A d diti o nall y, a R M a nal ysis will b e c o n d ucte d a n d will b e p artiti o ne d i nt o 4- wee kl y ti me 
i nter vals a cr oss t h e ra n d o mi ze d treat me nt peri o d. T he a nal ysis m o d el will a d diti o nall y i ncl u d e 
ti me p oi nt a n d treat me nt *ti me p oi nt as fact ors a n d ass o ciate d p- v al u e. 
C h a n ge fr o m bas eli ne i n m or ni n g P E F will als o be s u m marize d b y treat me nt gr o u p usi n g 
s u m m ar y statisti cs. 
F or all sce nari os a b o v e, baseli ne m or ni n g P E F is defi ne d as t he a vera ge d uri n g t he 1 0 d a ys 
pri or t o ra n d o mizati o n ( Visit 2) d uri n g r u n-i n. M or ni n g P E F will be ca pt ure d via t h e e Diar y. 
5. 8. 4  
Ot her e Di a r y v ari a bles 
E ve ni n g P E F, ast h ma s y m pt o m sc ore ( da yti me, ni g ht-ti m e, t otal), ni g ht-ti me a wa ke ni n gs ( %), 
s y m pt o m-free d a ys ( %), reli e ver t h era p y free da ys ( %) a n d ast h m a c o ntr ol d a ys ( %) will b e 
a nal ys e d i n t he sa me wa y as m or ni n g P E F.  
Baseli n e is d efi n e d as t he a vera ge d uri n g t he 1 0 d a ys pri or t o ra n d o mi zati o n ( Visit 2) d uri n g 
r u n-i n. 
5. 8. 4. 1  
Relie ver t her a p y use 
Relie ver t hera p y use, dis pla ye d as t otal dail y n u m ber of p uffs of I P will be a nal ys e d i n t h e 
sa me wa y as m or ni n g P E F.  
Relie ver t hera p y use will als o be s u m m aris e d descri pti vel y t o d escri b e t h e a d diti v e ster oi d 
effect of B D A M DI treat m e nts. M ore detail o n t hese dat a prese ntati o ns are d etaile d i n s ecti o n 
5. 8. 9. 
5. 8. 5  
Ti me t o tre at me nt dis c o nti n u ati o n or c h a n g e i n m ai nt e n a nce t her a p y f or 
l ac k of ast h m a c o ntr ol 
Ti me t o treat m e nt disc o nti n uati o n or c ha n ge i n mai nt e n a nce t h era p y f or lac k of ast h m a c o ntr ol 
will be a nal ys e d as p er t h e pri mar y a nal ysis d escri be d i n Secti o n 4. 2. 1. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 4 of 8 1 
 
5. 8. 6  
Ast h m a C o ntr ol Test 
T he A C T/ C A C T will be s u m m arize d as per t he s ec o n dar y a nal ysis of c h a n ge fr o m b aseli n e 
a n d res p o n der a nal ysis i n A C Q- 5 i n Secti o n 5. 6. 2. 
Baseli n e is d efi n e d as t he m ost rece nt n o n- missi n g sc ore bef ore a n d i ncl u di n g ra n d o mizati o n 
( Visit 2).  
5. 8. 7  
Ast h m a C o ntr ol Q uesti o n n aire- 5 e x pl or at o r y v ari a bles 
T he 3 fact or cat e g orizati o n of A C Q- 5 (I m pr o v e me nt; N o c ha n ge; W orse ni n g) will b e a nal yse d 
usi n g a l o gistic re gressi o n m o del i n t he sa me ma n ner as f or t he bi nar y res p o nse of A C Q- 5, see 
Secti o n 4. 4. 5. 
T he c ha n ges fr o m b as eli ne A C Q- 5, 2-fact or cli ni call y mea ni n gf ul differe nce (res p o nse; n o n-
res p o nse) a n d 3-fact or cate g orizati o n of A C Q- 5 (I m pr o v e me nt; N o c ha n g e; W orse ni n g) will 
b e f urt her a nal yse d i n all s u bjects w h o are, at m ost, p artl y c o ntr oll e d at b as eli ne (i.e. baseli n e 
A C Q- 5 
 0. 7 5). 
T he sec o n dar y a nal ysis of A C Q- 5 res p o n der st at us (secti o n 5. 6. 2) will be re peate d a n d 
e xcl u de patie nts w h ere t h eir Wee k 2 4 A C Q- 5 res ult was c oll ecte d re m ot el y. T his will be 
c o n d ucte d t o assess t he i m pact of C O VI D- 1 9 o n t h e sec o n dar y a nal ysis of A C Q- 5. 
5. 8. 8  
Ast h m a C o ntr ol Q uesti o n n aire- 5 e x pl or at o r y v ari a bles 
T he sec o n dar y a nal ysis of A Q L Q + 1 2 res p o n d er stat us (secti o n 5. 6. 3) will b e re peate d a n d 
e xcl u de patie nts w h ere t h eir Wee k 2 4 A Q L Q + 1 2 res ult was c ollecte d re m otel y. T his will be 
c o n d ucte d t o assess t he i m pact of C O VI D- 1 9 o n t h e sec o n dar y a nal ysis of A Q L Q + 1 2. 
5. 8. 9  
T ot al a d diti o n al i n h ale d c ortic ost er oi d e x p os ure 
Descri pti ve s u m maries of t h e t ot al d ail y n u m ber of p uffs of I P will be prese nte d f or all 
p ati e nts i n t he f ull a nal ysis set a n d p er t he effecti ve ness esti ma n d will i n cl u d e resc u e 
me di cati o n i n halati o ns o cc urri n g fr o m t h e d ate of ra n d o miz ati o n a n d u p t o treat me nt 
disc o nti n uati o n, re gar dless of a n y c ha n ges i n m ai nt e na nce t h era p y. T h ese d escri pti v e 
s u m m aries will be f urt her br o ke n d o w n i nt o t he I C S mai nte na n ce d osi n g cate g ories 
(l o w/ m e di u m/ hi g h, as des cri b e d i n secti o n 4. 4. 6) acr oss all bac k gr o u n d me dicati o n. T h e 
c o nti n u o us s u m m aries of t ot al n u m ber of dail y p uffs will a d diti o nall y r e p ort t he 2 5 t h, 7 5t h a n d 
9 0 t h perce ntiles per treat me nt gr o u p, al o n g wit h t he sta n d ar d d escri pti ve st atistics.  
Ta bles of mea n t otal dail y I C S s plit b y mai nte na n ce I C S s u b gr o u ps will be re peat e d, b ut 
s h o wi n g t h e 
t otal n u m b er of p uffs. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 5 of 8 1 
 
A d diti o nall y, descri pti v e s u m m aries of t otal dail y d ose wit hi n bac k gr o u n d I C S d osi n g 
cate g or y (l o w/ m e di u m/ hi g h) will be re peate d f or t he f oll o wi n g i n di vi d ual b ac k gr o u n d 
me di cati o n dr u g n a me cate g ori es: 
B u des o ni de 
Fl uti cas o ne pr o pi o n ate 
Becl o m et as o ne 
Fl uti cas o ne f ur oate 
M o m etas o n e 
Dr u g na me c ate g ories will i ncl u de all m ai nte na n ce treat me nt of t h e I C S re gar dless of i n hal er 
t y pe or w het her a d mi nistere d as a m o n ot hera p y or a c o m bi n ati o n t hera p y. 
S u m mar y statisti cs dis pla yi n g hi g h use of relie v er me dicati o n ( > = 4, > = 8 a n d > = 1 2 i n halati o ns 
o n o n e d a y) will b e pr o d uce d. T he s u m mar y will b e f urt her gr o u pe d b y s u bjects m eeti n g t h e 
a b o ve t hres h ol d o n at least o ne o ccasi o n; o n at le ast 7 c o nsec uti ve da ys; a n d o n at least 1 4 
c o nsec uti ve d a ys.  
T otal d ail y n u m b er of p uffs of I P will b e f urt h er s u m mariz e d b y t he fre q ue nc y of pati e nts 
meeti n g t he f oll o wi n g m ea n t otal dail y cate g ories o ver t he ra n d o miz e d treat m e nt p eri o d: 
 
 
 
 
 
 
5. 9  
S u b gr o u p a n al ysis 
5. 9. 1  
Effic ac y s u b g r o u p a n al yses 
All pri mar y a n d sec o n d ar y e n d p oi nts, a n d e x pl orat or y e n d p oi nts of ti me t o first deteri orati o n 
of ast h ma, s y m pt o m-free da ys, relie ver t hera p y free da ys a n d ast h ma c o ntr ol da ys o v er t h e 
ra n d o mi ze d treat m e nt peri o d will be f urt her a nal ys e d b y s u b gr o u p v aria bl es as defi ne d i n 
Ta ble 4.  
A d diti o nall y, c o m pli a nce wit h b aseli ne mai nte na n ce t hera p y des cri pti v e s u m maries will b e 
re peat e d u n der t h e s u b gr o u p cate g ories d efi ne d i n Ta ble 4. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 8 of 8 1 
 
N u m ber of p atie nts (a n d i n ci de nce rate) wit h S A Es d uri n g t he ra n d o miz e d treat me nt 
p eri o d, b y s yst e m or ga n class a n d preferre d ter m. 
5. 1 0  
S u p p orti ve a n al ysis 
5. 1 0. 1  
Ti p pi n g p oi nt a n al ysis 
 M ulti pl e i m p utati o n ti p pi n g p oi nt a nal ysis u n d er a n i nf or mati v e c e ns ori n g ass u m pti o n 
( Ce ns ore d n ot at ra n d o m; C N A R) will b e c o n d ucte d f or t h e pri m ar y e n d p oi nt of ti me t o first 
se vere e x acer bati o n usi n g t he f ull a nal ysis s et. F or s u bjects i n t h e B D A M DI treat me nt 
gr o u ps, t his met h o d will i m p ute u n o bser ve d e ve nt ti mes p ost earl y I P disc o nti n uati o n/ c ha n g e 
i n m ai nt e na nce t h era p y f or lac k of ast h m a c o ntr ol, ass u mi n g t he y were m ore li k el y t o h a v e a 
se vere ast h ma e x acer bati o n e ve nt t h a n was i m pli e d u n d er t he c e ns ori n g at ra n d o m ( C A R) 
ass u m pti o n. F or s u bjects i n t h e A S M DI treat me nt gr o u p, e ve nt ti m es will be i m p ute d usi n g 
m ulti ple i m p utati o n b ut will ass u me n o n-i nf or mati ve C A R.  
Reas o ns f or e arl y I P dis c o nti n uati o n a n d c ha n ges i n mai nte na nce t h era p y will be c ollecte d i n 
t h e e C R F a n d are d et ail e d i n S ecti o n 5. 1. 2 a n d Secti o n 5. 1. 3, res p ecti v el y, al o n g wit h crit eria 
w hic h will be use d t o deter mi n e w het h er t hese i nt erc urre nt e v e nts are d u e t o a lac k of ast h ma 
c o ntr ol or ot her wis e. 
A p pli n g i nf o r m ati v e ce ns ori n g ass u m pti o n  
C o nsi d er t h e C o x pr o p orti o n al h azar ds m o del f or o bser ve d e ve nts of s e v ere e x acer bati o ns: 
 
                                                           
                                                    ( 1) 
 
f or s u bject i a n d c o v ariates as s pecifi e d f or t he pri mar y a nal ysis 
, 
 is t he baseli ne hazar d 
f u n cti o n f or t he C o x m o del a n d  are t h e para m eter esti mates fr o m t he re gressi o n m o del.  
F or a s u bje ct ce ns ore d at ti me 
, we ca n i m p ute t h e e ve nt ti m e b ase d o n t h e hazar d f u ncti o n 
                                                
                                          ( 2) 
 
W here 
 a n d c orres p o n ds t o t h e i ncrease d l o g- h azar d of a s e vere 
e xacer bati o n. F or s u bjects i n t he A S M DI, 
 will b e a p plie d a n d t his will c orres p o n d t o 
i m p uti n g u n d er a C A R ass u m pti o n. F or s u bjects i n t h e B D A M DI gr o u ps, 
 will b e 
assi g ne d if t he y h a v e dis c o nti n ue d I P a n d/ or h a d a c ha n g e i n mai nt e na nce t h era p y d ue t o a 
lac k of ast h m a c o ntr ol. Ot her wise 
will be a p plie d as wit h t h e A S M DI treat me nt gr o u p. 
T his will c orres p o n d t o a n i ncreas e d hazar d a n d c o nse q ue ntiall y a re d u ce d ti m e t o e ve nt t o 
w hat w o ul d b e ass u me d u n der a C A R ass u m pti o n (Jac ks o n et al 2 0 1 4).  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 9 of 8 1 
 
T he ti p pi n g p oi nt a nal ysis will i niti aliz e wit h a 
 f or i m p uti n g t he e ve nt ti m e f or all 
s u bjects w h o are ce ns ore d. F or s u bjects i n t he B D A M DI treat me nt gr o u ps w h o disc o nti n ue 
t h e st u d y a n d/ or mai nte n a nce t hera p y d u e t o a lac k of ast h m a c o ntr ol, t he pe nalt y will be 
s u bse q ue ntl y i n cre m e nte d wit h a ste p of 0. 1 u ntil eit her n ull h y p ot h esis is n ot rejecte d or  
 is reac h e d. A n a p plie d p e n alt y of 
 w o ul d c orres p o n d t o i m p uti n g e ve nt ti m es 
i m m e di atel y aft er t h e o bs er ve d c e ns ori n g date. 
T he m ulti ple i m p utati o n pr ocess will be c o n d u cte d usi n g b o otstra p p e d sa m pl es wit h 
re place me nt wit hi n eac h treat me nt gr o u p t o create 1 0 0 b o otstra p sa m ples, o n e f or eac h 
i m p ute d d ataset. 
T o i m p ute a n e v e nt ti me f or a s u bject w h o has bee n ce ns ore d at ti me 
, t he f oll o wi n g h azar d 
f u n cti o n will b e use d t o pr o p ose 
, a ti m e-t o-e ve nt fr o m ce ns ori n g; w here 
 is t he ori gi n of 
f oll o w u p. T he f oll o wi n g hazar d f u ncti o n ca n be use d: 
 
                                                
                                            ( 3) 
W here 
a n d  are t h e esti mate d baseli n e hazar d f u ncti o n a n d para m eter esti m ates fr o m 
t h e C o x re gressi o n m o del f or a si n gle b o otstra p sa m ple. 
Be n der et al ( 2 0 0 5) pr o p ose a met h o d t o si m ul ate e ve n ti mes fr o m t h e hazar d f u ncti o n gi v e n 
i n ( 3) w hic h re q uires t h e c u m ulati v e b aseli ne hazar d f u ncti o n. F or t h e e ve nt ti m e 
, t he 
c u m ulati ve b aseli ne h azar d f u ncti o n is 
 
                                               
                                        ( 4) 
W here 
 de n otes t h e c u m ul ati v e baseli ne h az ar d f u ncti o n fr o m t he c o x re gressi o n m o del 
of a si n gl e b o otstra p s a m ple. T he f oll o wi n g f or m ula pr o p ose d b y Be n d er et al ( 2 0 0 5) ca n be 
use d t o pr o p ose a n e ve nt ti m e: 
                                                
                                        ( 5) 
 
W here 
 de n otes t h e i n verse of t he c u m ulati v e b aseli ne haz ar d f u ncti o n f or 
 a n d 
. T h e i n v erse c u m ulati v e hazar d 
 ca n be cal c ulat e d as 
                                              
                                        ( 6) 
O nce we ha ve 
, t he o verall e ve nt ti me ca n be c alc ulate d as 
. 
If a ra n d o m n u m b er 
 is ge nerate d s u c h t h at 
; t he e ve nt ti me t o 
b e w o ul d be greater t h a n t he last e ve nt o bser ve d i n t h e st u d y, a n d i n s uc h cases we will i m p ute 
t h e s u bject as bei n g ce ns ore d at t h e e n d of t he f oll o w- u p peri o d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 0 of 8 1 
 
Eac h f ull y i m p ute d d ataset will be i n di vi d uall y a n al yse d usi n g a c o x pr o p orti o nal hazar ds 
m o d el as s p ecifie d i n t h e pri mar y a nal ysis. T he esti mates of t h e treat me nt effect, c o nfi d e nc e 
i nter vals a n d p-
( R u bi n, 1 9 8 7). As t h e ti me t o 
e ve nt d ata are n ot n or m all y distri b ute d, res ults will be c o m bi ne d o n t he l o g-s cale a n d will b e 
b ac k-tra nsf or me d f or re p orti n g i n dis pla ys. 
5. 1 0. 2  
Attri b ut a bl e esti m a n d 
A nal ysis of t h e attri b uta ble esti ma n d will be c o n d ucte d f or t h e pri m ar y e n d p oi nt ti m e t o first 
se vere e x acer bati o n usi n g d ata o btai ne d b ef ore s u bjects dis c o nti n ue ra n d o mi ze d treat m e nt 
a n d/ or b ef ore a c h a n ge i n mai nte na n ce t hera p y a n d will use t he F A S. H o w e ver, t he d ata t h at is 
ce ns ore d d u e t o ra n d o mi ze d treat me nt disc o nti n u ati o n a n d/ or a c ha n ge i n mai nte na nce t hera p y 
will ha v e t heir e ve nt ti me i m p ute d o n t he basis of t he p erce ntile of t he A S M DI pr n 
distri b uti o n if t he reas o n is reas o na bl y attri b uta ble t o t ol era bilit y or lac k of c o ntr ol. F or all 
ot her s u bjects w h o d o n ot e x perie nce a s e vere e x acer bati o n d uri n g t he treat me nt p eri o d, e ve nt 
ti mes will be i m p ute d usi n g m ulti ple i m p utati o n b ut will ass u me n o n-i nf or mati ve C A R.  
I m p utati o n met h o ds s pe cifie d i n S ecti o n 5. 1 0. 1 will be i m ple me nte d, usi n g t he 5t h perce ntile 
of t h e A S M DI tre at me nt gr o u p ti me t o first se v ere e xacer bati o n i nstea d of a d elta-a dj ust me nt. 
i.e., w he n i m p uti n g t he B D A M DI or A S M DI treat m e nt gr o u ps u n d er t he i nf or mati ve 
ce ns ori n g ass u m pti o n, w e will i m p ute t h e ti me fr o m ce ns ori n g as
. T h e 
m ulti ple i m p ute d d atasets will be a nal ys e d wit h a C o x pr o p orti o nal hazar ds m o del as i n t h e 
p
( R u bi n, 1 9 8 7). As t h e ti me 
t o e ve nt data are n ot n or mall y distri b ute d, res ults will be c o m bi ne d o n t he l o g-s cale a n d will 
b e bac k-tra nsf or m e d f or re p orti n g i n dis pla ys. 
5. 1 0. 3  
Effecti ve ness esti m a n d 
A nal ysis of t h e effecti v e ness esti m a n d f or t h e ti me t o first se vere e xacer bati o n will be 
c o n d ucte d i n t h e F A S i n w hic h all o bser ve d d ata will be utili ze d re gar dless of w het her 
s u bjects e x perie nce a c ha n ge i n mai nte na nce t h era p y f or lac k of ast h m a c o ntr ol.  
U n der t his esti m a n d, s u bjects n ot h a vi n g a n y se vere ast h m a e xacer bati o n will be ce ns ore d at 
t h e d ate of t heir lat est c o ntact pri or t o I P dis c o nti n uati o n, re gar dl ess of a c ha n ge i n 
mai nte na nce t hera p y. 
5. 1 0. 4  
De f act o esti m a n d 
A nal ysis of t h e de fact o esti m a n d will be c o n d u cte d o n t he F A S i n w hic h all o bser ve d d at a 
will be utiliz e d, re gar dless of w het her s u bje cts e x p erie nce a c h a n ge i n m ai nt e na nc e t h era p y or 
are disc o nti n ue d fr o m ra n d o mi ze d st u d y tr eat me nt. 
T he pri m ar y a n al ysis of ti m e t o first se vere e x acer b ati o n a n d sec o n d ar y effi cac y a nal ys es of 
se vere e x acer bati o n rate will b e re peat e d u n der t he d e fact o esti ma n d a n d will i n cl u de all 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 1 of 8 1 
 
o bser ve d d at a p ost-ra n d o mi ze d treat m e nt disc o nti n uati o n, u p u ntil st u d y 
c o m pleti o n/ wit h dra wal. A d diti o nall y, all o bser v e d data will be utiliz e d re gar dless of a n y 
c ha n ges i n mai nte na n ce t hera p y w hic h m a y o cc ur p ost-ra n d o mi zati o n.  
Please see secti o n 4. 2. 1 f or t h e calc ul ati o n of ti me t o first se vere e x acer b ati o n a n d secti o n 
4. 3. 1 f or t h e deri vati o n of t h e a n n ualize d se vere e x acer b ati o n rate u n d er t h e de f act o esti m a n d. 
5. 1 1  
C O VI D- 1 9 p a n de mic i m p a cts 
Ma n d ala is a n o n- g oi n g tri al t hr o u g h o ut t he c or o n a vir us diseas e 2 0 1 9 ( C O VI D- 1 9) o ut brea k. 
It is i m p orta nt t o be a ble t o i de ntif y a n y p ote ntial i nterc urre nt e ve nts d u e t o C O VI D- 1 9 a n d t o 
b e a ble t o q ua ntif y t heir i m pa ct o n t h e efficac y a n d safet y pr ofile of t h e st u d y. 
5. 1 1. 1  
Visits i m p a cte d d ue t o C O VI D- 1 9 
A n y misse d visits d ue t o C O VI D- 1 9 will be s u m marize d b y t h e s c he d ule d visit t hat was 
misse d a n d treat m e nt gr o u p a n d will prese nt t h e n u m ber a n d perce nt a ge of patie nts i n t he f ull 
a nal ysis s et wit h a misse d visit d ue t o C O VI D- 1 9. F or eac h visit, t h e reas o n f or missi n g n ess 
will be f urt her s plit i nt o t he f oll o wi n g cate g ories as c oll ecte d o n t h e e C R F: 
S u bject decisi o n d ue t o p a n de mic c o n cer ns 
Pa n de mic relate d l o gistic iss ues 
Ot h er 
Si milarl y, visits t hat ha v e bee n dela ye d, or c o m pl ete d re m otel y will be s u m mariz e d 
d escri pti v el y b y treat me nt gr o u p. 
A listi n g will be pr o vi d e d t o s h o w t he p atie nt le v el i nf or mati o n f or all visits t h at ha v e bee n 
i m p acte d b y C O VI D- 1 9. 
5. 1 1. 2  
Pre m at ure disc o nti n u ati o n d ue t o C O VI D- 1 9 
If a s u bject ca n n ot c o nti n ue wit h pr oce d ures a n d sc h e d ule d ass ess m e nts d ue t o C O VI D- 1 9 
p ost-ra n d o mi zati o n, t h e y will be wit h dra w n fr o m t h e trial a n d will b e as ke d t o c o m plete t h e 
P D V. A n a d diti o nal fiel d has bee n pr o vi d e d o n t he disc o nti n u ati o n of i n vesti gati o n al pr o d uct 
e C R F pa ge t o i n dic at e w het her or n ot t he mai n re as o n f or disc o nti n u ati o n is a res ult of 
C O VI D- 1 9 c o m plicati o ns.  
All pre mat ure disc o nti n u ati o ns d ue t o C O VI D- 1 9 will b e s u m m ariz e d descri pti v el y pr o vi di n g 
t h e n u m ber a n d perce nta ge of patie nts i n t h e f ull a nal ysis set gr o u p e d b y ra n d o miz e d 
treat m e nt. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 2 of 8 1 
 
A se parate listi n g of s u bj ects w h o pre m at urel y wit h dra w d ue t o C O VI D- 1 9 will b e pr o vi de d. 
T he listi n g will d etail t he reas o n f or wit h dra w al a n d relati o ns hi p t o C O VI D- 1 9. T he listi n g of 
pre mat ure wit h dra wals d ue t o C O VI D- 1 9 will be b ase d o n t he f ull a nal ysis set.  
It is n ot e x p ecte d t h at pre mat ure wit h dra w als will b e relate d t o ra n d o mi ze d treat me nt. 
T heref ore, t he missi n g data s u bse q u e nt t o wit h dra wal will be c o nsi dere d as missi n g at 
ra n d o m, i n acc or da nce wit h t h e efficac y esti ma n d. 
5. 1 1. 3  
Tre at me nt i nterr u pti o ns d ue t o C O VI D- 1 9 
Treat m e nt i nterr u pti o ns will be liste d b y patie nt a n d t h e le n gt h of eac h d os e i nterr u pti o n t hat 
are d ue t o c o m plic ati o ns i m p ose d b y C O VI D- 1 9. 
5. 1 1. 4  
A C Q- 5 a n d A Q L Q + 1 2 d at a c ollecte d re m otel y d ue t o C O VI D- 1 9 
A C Q- 5 a n d A Q L Q + 1 2 ma y be c ollecte d re m otel y d ue t o reas o ns relat e d t o C O VI D- 1 9. 
Alt h o u g h t h ese q u esti o n n aires are pati e nt r e p orte d o utc o mes of ast h ma c o ntr ol a n d q u alit y of 
life, it is u n k n o w n t o w hat e xte nt t he sec o n dar y a nal yses of res p o n der stat us mi g ht b e affect e d 
d ue t o t he c ha n g e i n f or mat of t h e assess me nts. As a res ult, t h e res p o n d er a nal ys es will b e 
re peat e d, b ut e xcl u de p atie nts w h os e Wee k 2 4 A C Q- 5/ A Q L Q + 1 2 w as perf or me d re m otel y, 
please refer t o s ecti o n 5. 8. 7 a n d 5. 8. 8 f or det ails. 
5. 1 1. 5  
Sc he d ule d s afet y assess me nts 
A n y sc he d ule d safet y dat a, i n cl u di n g cli nical la b orat or y, pre g n a nc y tests, E C G a n d vit al si g ns 
t h at are missi n g d u e t o C O VI D- 1 9 will b e liste d f or eac h s u bj ect. T he listi n g will detail t h e 
safet y pr oc e d ure misse d a n d its relati o ns hi p t o C O VI D- 1 9. T h e listi n g of misse d safet y 
assess me nts will be prese nte d i n t he safet y a n al ysis set.  
5. 1 1. 5. 1  A d v erse e ve nts a n d seri o us a d v erse e ve nts d ue t o C O VI D- 1 9 
All s u bjects wit h a s us p ecte d or c o nfir me d dia g n osis of C O VI D- 1 9 will be liste d. T he listi n g 
will prese nt a n y A Es wit h eit her a s us p ecte d or c o nfir me d relati o ns hi p t o C O VI D- 1 9. T h e 
relati o ns hi p bet wee n a n A E a n d C O VI D- 1 9 will b e deter mi ne d b y t he i n vesti gat or a n d 
a p pr o priatel y ca pt ure d i n t he e C R F. T he listi n gs will pr o vi de a n i n di cati o n of w het her t h e A E 
was seri o us or n o n-seri o us. 
Listi n gs of a d verse e ve nts li n ke d t o C O VI D- 1 9 will b e b ase d o n t he safet y a n al ysis s et. 
A s u m mar y of C O VI D- 1 9 relate d a d v erse e ve nts will be re p orte d b y preferre d ter m a n d 
b ac k gr o u n d t h era p y d osi n g c ate g oriz ati o n (l o w/ me di u m/ hi g h). Please refer t o secti o n 5. 7. 1 f or 
f urt her d et ails. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 3 of 8 1 
 
5. 1 1. 5. 2  O ver all d escri pti v e s u m m a r y 
A hi g h-le v el descri pti v e s u m mar y will be pr o vi de d a n d gr o u pe d b y ra n d o mi ze d treat m e nt 
gr o u p a n d t otal n u m ber of s u bjects (acr oss treat me nt gr o u ps). T he f oll o wi n g fre q ue n cies a n d 
p erce nta ges of s u bjects i n t he f ull a nal ysis s et will be prese nte d: 
1.
N u m ber of s u bj ects affecte d b y C O VI D- 1 9 [a] 
2.
N u m ber of p atie nts wit h d ose i nt err u pti o ns d u e t o C O VI D- 1 9 
3.
N u m ber of pre mat ure wit h dra wals d ue t o C O VI D- 1 9 
4.
N u m ber of p atie nts wit h a n y misse d visit d ue t o C O VI D- 1 9 
5.
N u m ber of p atie nts wit h a n y A C Q- 5 n ot d o ne d ue t o C O VI D- 1 9 
6.
N u m ber of p atie nts wit h W ee k 2 4 A C Q- 5 n ot d o ne d ue t o C O VI D- 1 9 
7.
N u m ber of p atie nts wit h a n y A C Q- 5 p erf or me d re m otel y d ue t o C O VI D- 1 9 
8.
N u m ber of p atie nts wit h W ee k 2 4 A C Q- 5 perf or me d re m ot el y d ue t o C O VI D- 1 9 
9.
N u m ber of p atie nts wit h a n y A Q L Q + 1 2 n ot d o ne d u e t o C O VI D- 1 9 
1 0. N u m ber of p atie nts wit h W ee k 2 4 A Q L Q + 1 2 n ot d o n e d u e t o C O VI D- 1 9 
1 1. N u m ber of p atie nts wit h a n y A Q L Q + 1 2  perf or me d re m otel y d u e t o C O VI D- 1 9 
1 2. N u m ber of p atie nts wit h W ee k 2 4 A Q L Q + 1 2 p erf or me d re m ot el y d u e t o C O VI D- 1 9 
1 3. N u m ber of s u bj ects wit h cli nical la b orat or y n ot d o ne d ue t o C O VI D- 1 9 
1 4. N u m ber of s u bj ects wit h pre g n a n c y t ests n ot d o ne d ue t o C O VI D- 1 9 
1 5. N u m ber of s u bj ects wit h E C G n ot d o ne d u e t o C O VI D- 1 9 
1 6. N u m ber of s u bj ects wit h vital si g ns n ot d o n e d u e t o C O VI D- 1 9 
1 7. N u m ber of s u bj ects wit h C O VI D- 1 9 relate d A Es 
1 8. N u m ber of s u bj ects wit h C O VI D- 1 9 relate d S A Es 
[a] Defi n e d as t h e n u m ber of s u bjects w h o meet at l east o ne of t he list e d criteria i n p oi nts 2- 1 8. 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 5 of 8 1 
 
7.  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L 
T he f oll o wi n g t a ble pr o vi des a brief s u m m ar y of c ha n g es of a n al ysis fr o m t h e pr ot oc ol 
Versi o n 1. 0 (fi n alise d 1 7 t h Dece m b er 2 0 1 8). 
7. 1  
T y pe-I err or c o ntr ol f or sec o n d a r y e n d p oi nts 
I n or der t o ma k e clai ms o n t h e ke y sec o n d ar y e n d p oi nts f or t h e st u d y, a m ulti pl e testi n g 
strate g y h as bee n i m ple me nte d o n t he sec o n d ar y a nal yses, c o ntr olli n g t he t y p e-I err or rate. 
Please see secti o n 5. 1. 4 f or m ore details. 
7. 2  
Str atific ati o n f act o rs rec or de d at r a n d o mis ati o n 
T he stratificati o n fact ors use d t o assi g n pati e nts t o a ra n d o mi ze d treat me nt gr o u p will b e 
a dj uste d f or i n t he i nfere nti al m o dels of t his st u d y. Clarif yi n g te xt has bee n a d de d t o t h e S A P 
t o state t hat i n a n y cases of miss-stratificati o n, patie nts will be a nal ys e d acc or di n g t o t h eir 
assi g ne d strat u m i n I V R S/I W R S. As a se nsiti vit y a nal ysis, t he pri mar y e n d p oi nts will b e 
a nal ys e d usi n g t he act u al strata of patie nts. 
7. 3  
T ot al c ortic oster oi d e x p os ure 
T he t otal s yste mic c ortic oster oi d e x p os ure will b e calc ulate d as t h e t otal a n n ualiz e d d ose. 
A d diti o nall y, s yste mic c ortic oster oi d e x p os ure will b e prese nte d as a t otal a n n ualiz e d d ose of 
s yste mic ster oi ds f or ast h ma. T ot al i n hale d c ortic oster oi d e x p os ure a n d t otal s yste mic 
c ortic oster oi d e x p os ure will b e a nal ys e d se p aratel y d u e t o t he differi n g ma g nit u d es of t he 
d oses ta ke n i n t h e t w o re gi m e ns. Please s ee se cti o n 4. 3. 2 f or f urt h er d etails. 
T he s yste mic st er oi d c o m p o ne nt will b e c o nsi d ere d t h e k e y sec o n dar y e n d p oi nt a n d i n h ale d 
I C S will be a n e x pl orat or y me as ure. T h e c o ntri b uti o n of mai nte na nce I C S t o t his e n d p oi nt will 
b e esti mate d usi n g t h e t otal dail y d ose rec or de d i n t he C M m o d ule. 
I n or der t o ass ess t he differe nce b et w ee n treat m e nts i n s yste mic ster oi d e x p os ure, a n 
i nfere nti al a nal ysis will b e c o n d u cte d. Pl ease refer t o secti o n 5. 6. 4 f or f urt h er details. 
T otal i n hale d c ortic oster oi d e x p os ure will b e s u m maris e d descri pti vel y as t he t ot al dail y 
n u m b er of p uffs of ra n d o mi ze d treat me nt. T o assess t he a d diti v e effects of ra n d o mize d I C S, 
t h e t otal dail y n u m ber of p uffs will b e gr o u pe d b y o verall a n d b y l o w/ m e di u m/ hi g h d ose 
b ac k gr o u n d mai nte na nce t hera p y I C S cate g ories. Pl ease refer t o 4. 4. 6 f or t he b ac k gr o u n d I C S 
cate g oris ati o n deri vati o ns a n d 5. 8. 9 f or f urt her details o n descri pti ve s u m m aries of I C S 
e x p os ure. 
7. 4  
E x pl o r at o r y a n al ysis of A C Q- 5 C h a n ges fr o m b aseli ne 
A C Q- 5 c ha n ges fr o m b as eli ne will b e assesse d as t he f oll o wi n g 3-le v el fact or: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 6 of 8 1 
 
I m pr o v e me nt: ( Wee k 1 2  baseli ne)  - 0. 5 
N o C h a n g e: - 0. 5 < ( Wee k 1 2 
 baseli ne) < 0. 5 
W orse ni n g: ( Wee k 1 2 
 baseli ne)  0. 5 
T he e n d p oi nt will be a nal ys e d usi n g a n or di n al l o gisti c re gressi o n as per t h e A C Q- 5 sec o n dar y 
e n d p oi nt of cli nic all y m ea ni n gf ul differe nc e. 
7. 5  
e Di ar y v ari a bles gr o u pe d i nt o 4- wee kl y ti me i nter v als 
T he d ail y e Diar y v aria bl es f or relie ver t hera p y us e, ni g htti m e a w a k e ni n gs, s y m pt o m-free 
-free da ys, ast h m a c o ntr ol d a ys a n d P E F will be gr o u pe d i nt o 4- wee kl y ti me 
i nter vals o ver t h e 2 4- w ee k treat me nt p eri o d (secti o n 4. 4). A d diti o nal re pe ate d meas ures 
a nal ys es of t hese e n d p oi nts ha ve b ee n s p ecifie d as e x pl orat or y a nal ys es (s ecti o n 5. 8). 
7. 6  
Deteri o r ati o n of ast h m a 
Pl ots of a vera ge d ail y P E F, reli e v er t h era p y use, a n d ast h m a s y m pt o m sc ore will be pr o d uces 
ar o u n d t he +/- 1 5 d a ys of t he o nset of t h e first deteri orati o n of ast h m a e v e nt. 
7. 7  
A d diti o n al s u b gr o u p a n al ys es 
E x pl orat or y a n al ys es stratifie d b y a ge h a v e b ee n s p ecifie d t o a d diti o nall y re prese nt t he el d erl y 
a ge p o p ulati o n (  6 5 years).  
A s u b gr o u p f oc usi n g o n U S A vs n o n- U S A pati e nts has bee n s pecifie d as a n a d diti o nal 
s u b gr o u p t o t h e str atificati o n fact ors use d i n ra n d o mizati o n ( N ort h A merica, Wester n E ur o pe 
a n d S o ut h Africa; R est of W orl d). 
T he s u b gr o u ps a nal ys es of b ac k gr o u n d I C S h a v e b ee n defi n e d base d o n GI N A criteria h a ve 
b ee n s p ecifie d. See secti o n 4. 6. 5 f or d etails o n t his deri vati o n. 
S u b gr o u p a n al ys es f or a d verse e v e nts h a ve b ee n s pecifie d (s ee se cti o n 5. 9. 2). 
7. 8  
C O VI D- 1 9 i m p acts 
A d diti o nal a nal ys es h a ve bee n s pecifie d t o q ua ntif y t h e i m pact of t he C or o na vir us o ut brea k 
2 0 1 9 ( C O VI D- 1 9) o n t he trial data. Please refer t o secti o n 5. 1 1 f or f ull details. 
 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 7 of 8 1 
 
8.  
R E F E R E N C E S 
1.
J ac ks o n D., W hite I. R., Sea ma n S., E va ns H., Baisle y K., a n d Car pe nter J. 
( 2 0 1 4), Rela xi n g t h e i n de pe n d e nt ce ns ori n g ass u m pti o n i n t h e C o x pr o p orti o n al 
h azar ds m o d el usi n g m ulti ple i m p utati o n, St atist. Me d.,  2 7, 4 6 8 1 4 6 9 4. 
D OI: 1 0. 1 0 0 2/si m. 6 2 7 4 
(htt ps:// o nli neli brar y. wile y. c o m/ d oi/f ull/ 1 0. 1 0 0 2/si m. 6 2 7 4 ) 
2.
R u bi n D B.  M ulti ple I m p utati o n f or N o nres p o ns e i n S ur v e ys.  Wile y: Ne w Y or k, 1 9 8 7 
3.
H oc h ber g Y. A s har per B o nferr o ni pr oce d ure f or m ulti ple tests of si g nifica n ce. 
Bi o metri ka 1 9 8 8; 7 5( 4): 8 0 0- 8 0 2.  
4.
Be n der, R., A u g usti n, T. a n d Bl ett n er, M. ( 2 0 0 5), G e nerati n g s ur vi val ti mes t o 
si m ulate C o x pr o p orti o nal h azar ds m o dels. St atist. Me d ., 2 4: 1 7 1 3- 1 7 2 3. 
d oi: 1 0. 1 0 0 2/si m. 2 0 5 9  
(htt ps:// o nli neli brar y. wile y. c o m/ d oi/f ull/ 1 0. 1 0 0 2/si m. 5 4 5 2 ) 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 8 of 8 1 
 
A P P E N DI X 1  
LI S T O F E- DI A R Y Q U E S TI O N S  
Da yti me is d efi n e d as t he ti m e peri o d bet wee n t h e m or ni n g l u n g f u n cti o n assess me nt ( u p o n 
risi n g i n t h e m or ni n g) a n d t h e e ve ni n g l u n g f u ncti o n assess me nt.  
Ni g ht-ti me is defi ne d as t he ti m e p eri o d bet wee n t h e e ve ni n g l u n g f u ncti o n assess m e nt (at 
b e dti m e) a n d t he m or ni n g l u n g f u ncti o n assess me nt. 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pla n  
A villi o n 
A V 0 0 3 2. 0  
3 0/ 0 7/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 9 of 8 1 
 
 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n