A Phase 2, Multicenter, Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Assess the Safety, Efficacy and Pharmacodynamics of TEV 53275 Administered Subcutaneously in Adult Patients With Persistent Eosinophilic Asthma
Phase: PHASE2
Conditions: Asthma
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

 
 
 
Cli nic al St u d y Pr ot oc ol  
 
 
A P hase 2, M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, Parallel -
Gr o u p St u d y t o Assess t he Safet y, Efficac y a n d P har mac o d y na mics of T E V -5 3 2 7 5 
A d mi nistere d S u bc uta ne o usl y i n A d ult Patie nts wit h Persiste nt E osi n o p hilic 
Ast h ma  
 
 
St u d y N u m ber T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
 
N C T 0 4 8 4 7 6 7 4  
 
 
Pr ot oc ol wit h A me n d me nt 0 1  A p pr o val Date: 1 8 N o ve m ber 2 0 2 1  

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1  
 
 
Cli nic al St u d y Pr ot oc ol  wit h A me n d me nt 0 1  
 
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
A P h ase 2, M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P ar allel -Gr o u p 
St u d y t o Assess t he S afet y, Effic ac y a n d P h ar m ac o d y n a mics of T E V -5 3 2 7 5 A d mi nistere d 
S u bc ut a ne o usl y i n A d ult P atie nts wit h Persiste nt E osi n o p hilic Ast h m a  
S h ort title:  A R a n d o miz e d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d Effic ac y a n d S afet y St u d y of 
T E V -5 3 2 7 5 i n A d ults wit h Persiste n t E osi n o p hilic Ast h m a 
Title of t he pr ot oc ol f or l ay pe o ple:  A St u d y t o T est if T E V -5 3 2 7 5 is Effecti ve i n Relie vi n g 
Ast h m a  
Effic ac y a n d S afet y St u d y  ( P h ase 2) 
I N D n u m ber: 1 3 8 6 8 7 
E u dr a C T n u m ber: 2 0 2 1 -0 0 1 4 3 9 -2 2  
E M A Decisi o n n u m ber of Pe di atric I n vesti g ati o n P l a n: N ot a p plic a ble 
Article 4 5 o r 4 6 of 1 9 0 1/ 2 0 0 6 d oes n ot a p pl y  
Ori gi n al Cli nic al St u d y Pr ot oc ol V ersi o n D ate: 2 2  Dece m b er 2 0 2 0  
Pr ot oc ol wit h A me n d me nt 0 1 Versi o n D ate: 1 8  N o ve m ber 2 0 2 1  
S p o ns or  
Te va Bra n d e d P har mace utical  
Pr o d ucts R & D, I nc.  
1 4 5 Bra n d y wi n e  Par k wa y,  
West C hester, Pe n ns yl va nia 1 9 3 8 0  
U nite d States  
I nf or m ati o n re g ar di n g cli nic al l a b or at ories a n d ot her de p art me nts a n d i nstit uti o ns is 
f o u n d i n A p pe n di x  A  
C O VI D -1 9 p a n de mic -rel ate d o per ati o n al u p d ates are pr o vi de d i n A p pe n di x  N  
 
T his cli nical st u d y will be c o n d ucte d i n acc or da nce wit h c urre nt G o o d Cli nical Practice ( G C P) as directe d 
b y t he pr o visi o ns of t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H); U nite d States  ( U S) C o de of 
Fe deral Re g ulati o ns ( C F R), a n d E ur o pea n U ni o n ( E U) Directi ves a n d Re g ulati o ns (as a p plica ble i n t he 
re gi o n of t he st u d y); nati o nal c o u ntr y le gislati o n; a n d t he s p o ns or’s Sta n dar d O perati n g Pr oce d ures 
( S O Ps). 
C o nfi de nti alit y St ate me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial a n d pr o prietar y i nf or mati o n (i ncl u di n g c o nfi de ntial c o m mercial 
i nf or mati o n p urs ua nt t o 2 1 C F R § 2 0. 6 1) a n d is a c o nfi de ntial c o m m u nicati o n of T e va Bra n de d 
P har mace utical Pr o d ucts R & D, I nc. T he reci pie nt a grees t hat n o i nf or mati o n c o ntai ne d herei n ma y be 
p u blis he d or discl ose d wit h o ut writte n a p pr o val fr o m t he s p o ns or.  
© 2 0 2 1 T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc. All ri g hts reser ve d.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2  
D O C U M E N T HI S T O R Y  
A me n d me nt 0 1  
1 8  N o ve m ber 2 0 2 1  
6 3  patie nts ra n d o mize d/e nr olle d t o date  
A d mi nistrati ve L etter 0 1  
2 3 Marc h 2 0 2 1  
Ori gi nal Pr ot oc ol  
2 2  Dece m b er 2 0 2 0  
T he S u m mar y of C ha n ges t o t he Pr ot oc ol i ncl u des t he c orres p o n di n g reas o n/j ustificati o n f or 
eac h c ha n ge a n d is pr o vi de d i n Secti o n  1 6 . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3  
S P O N S O R P R O T O C O L A P P R O V A L  
Cli nic al St u d y Pr ot oc ol  wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
A P h ase 2, M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P ar allel -Gr o u p 
St u d y t o Asses s t he S af et y, Effic ac y a n d P h ar m ac o d y n a mics of T E V-5 3 2 7 5 A d mi nistere d 
S u bc ut a ne o usl y i n A d ult P atie nts wit h Persiste nt E osi n o p hilic Ast h m a  
Ori gi n al Versi o n D ate: 2 2  Dece m b er 2 0 2 0  
Pr ot oc ol wit h A me n d me nt 0 1 Versi o n D ate: 1 8  N o ve m ber 2 0 2 1  
I h a ve rea d t he pr ot oc ol wit h A me n d me nt 0 1 a n d a p pr o ve t he desi g n of t his st u d y.  
S p o ns or’s A ut h orize d 
Re prese nt ati ve  
 
 
, Cli nical 
De vel o p me nt  
Si g n at ure  
D ate  
E xec ute d si g n at ure p a ges are m ai nt ai ne d se p ar atel y wit hi n  t he Tri al M aster File 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4  
I N V E S TI G A T O R A G R E E M EN T  
Cli nic al St u d y Pr ot oc ol  wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
A P h ase 2, M ultice nter, R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d, P ar allel -Gr o u p 
St u d y t o Assess t he S afet y, Effic ac y a n d P h ar m ac o d y n a mics of  T E V -5 3 2 7 5 A d mi nistere d 
S u bc ut a ne o usl y i n A d ult P atie nts wit h Persiste nt E osi n o p hilic Ast h m a  
Ori gi n al Versi o n D ate: 2 2  Dece m b er 2 0 2 0  
Pr ot oc ol wit h A me n d me nt 0 1 Versi o n D ate: 1 8  N o ve m ber 2 0 2 1  
Pri nci p al I n vesti g at or:   
Title:  
 
A d dress of I n vesti g ati o n al Ce nter:  
 
 
 
 
 
Tel:  
 
I h a ve rea d t he pr ot oc ol wit h A me n d me nt 0 1 a n d a gree t h at it c o ntai ns all necessar y details f or 
carr yi n g o ut t his st u d y. I a m q ualifie d b y e d ucati o n, e x perie nce, a n d trai ni n g t o c o n d uct t his 
cli nical researc h st u d y. T he si g nat ure bel o w c o nstit utes a gree m e nt wit h t his pr ot oc ol a n d 
attac h me nts, a n d pr o vi d es ass ura nce t hat t his st u d y will be c o n d u cte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d acc or di n g t o 
nati o nal or l ocal l e gal a n d re g ulat or y re q uire me nts a n d a p plica ble re g ulati o ns a n d g ui d eli nes.  
I will ma ke a vaila ble t h e pr ot oc ol a n d all i nf or mati o n o n t he i n vesti gati o nal me dici nal pr o d uct 
(I M P) t hat were f ur nis he d t o me b y t he s p o ns or t o all p h ysicia ns a n d ot her st u d y pers o n n el 
re p orti n g t o me w h o parti ci pate i n t his st u d y a n d will disc uss t his material wit h t he m t o e ns ure 
t hat t he y are f ull y i nf or me d re gar di n g t he I M P a n d t he c o n d uct of t he st u d y. I a gree t o kee p 
rec or ds o n all patie nt i nf or mati o n, I M P s hi p me nt a n d ret ur n f or ms, a n d all ot her i nf or mati o n 
c ollecte d d uri n g t he st u d y, i n a cc or da nce wit h nati o nal a n d l ocal G C P re g ulati o ns  as well as all 
ot her nati o nal a n d i nter n ati o nal la ws a n d re g ulati o ns . 
Pri nci p al I n vesti g at or 
 
Si g n at ure  
D ate  
E xec ute d si g n at ure p a ges are m ai nt ai ne d se p ar atel y wit hi n t he Tri al M aster File  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5  
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  
wit h A me n d me nt 0 1  
St u d y: T V 5 3 2 7 5 -A S -2 0 0 3 3  
Title of St u d y:  A P hase 2, M ultice nter, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, 
Parallel -Gr o u p St u d y t o Assess t he Safet y, E fficac y a n d P har mac o d y na mi cs of T E V-5 3 2 7 5 
A d mi nistere d S u bc uta ne o usl y i n A d ult Patie nts wit h Persiste nt E osi n o p hilic Ast h ma  
S p o ns or: Te va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
I n vesti g ati o n al Ne w Dr u g (I N D) N u m ber: 1 3 8 6 8 7  
E u dr a C T n u m ber:  2 0 2 1 -0 0 1 4 3 9 -2 2  
E M A Decisi o n n u m ber of Pe di atric I n vesti g ati o n Pl a n: Arti cle 4 5 or 4 6 of 1 9 0 1/ 2 0 0 6 d oes 
n ot a p pl y  
N a me of Test I n vesti g ati o n al Me dici n al Pr o d uct (I M P): T E V -5 3 2 7 5  
E u dr a Vi gil a nce ( E V) c o de f or t he I M P, if a p plic a ble:  N ot a p plica ble  
Acti ve S u bst a nce : F ull y h u ma n I g G 4 m o n ocl o nal a nti b o d y t hat bl oc ks t he bi ol o gical f u n cti o n of 
I nterle u ki n 5 (I L-5)  
T y pe of St u d y:  Safet y a n d Efficac y  
P h ase of Cli nic al De vel o p me nt:  2  
I n dic ati o n: Mai nte na nce treat me nt of ast h ma i n  a d ult  patie nts wit h a n e osi n o p hilic p he n ot y pe  
Is t his st u d y c o n d ucte d t o i n vesti g ate t he Ne w Use of a n a p pr o ve d, m ar kete d pr o d uct ? N o  
N u m ber of I n vesti g ati o n al Ce nters Pl a n ne d : T he st u d y is pla n ne d t o b e c o n d ucte d i n 
a p pr o xi matel y 8 0 i n vesti gati o nal ce nters d e pe n di n g o n feasi bilit y . 
C o u ntries Pl a n ne d:  T h e st u d y is pla n ne d t o be c o n d ucte d i n t he U nite d States ( U S), Ca na da a n d 
else w here i nter nati o nall y, pe n di n g feasi bilit y assess me nts.  
Pl a n ne d St u d y Peri o d:  T he st u d y is pla n ne d t o b e gi n i n a p pr o xi matel y Q uarter ( Q) 2/ 2 0 2 1 a n d 
c o m plete i n a p pr o xi matel y Q 4/ 2 0 2 2 (e n d of t he f oll o w -u p peri o d).  
N u m ber of P atie nts Pl a n ne d (t ot al):  A p pr o xi matel y 8 6 0 patie nts will be scree n e d t o ac hi e ve 
3 0 0 ra n d o mize d patie nts. T he n u m ber of e val ua bl e patie nts is pla n ne d t o b e a p pr o xi matel y 2 5 5.  
A dj ust me nts ma y be ma d e f oll o wi n g t he i nteri m a nal ysis. 
St u d y P o p ul ati o n: Fe male or male patie nts ≥1 8  years of a ge wit h persiste nt ast h ma a n d a n 
e osi n o p hilic p he n ot y pe . 
St u d y O bjecti ves a n d E n d p oi nts: T he o bjecti ves of t his st u d y are t o e val u ate t he safet y a n d 
effic ac y of T E V -5 3 2 7 5 c o m pari n g 2 d os e stre n gt hs t o place b o i n patie nts wit h persiste nt ast h ma 
a n d a n e osi n o p hilic p he n ot y pe. T h e pri mar y a n d s ec o n dar y st u d y o bjecti ves a n d e n d p oi nts are 
prese nte d b el o w . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6  
St u d y O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
T he pri m ar y o bj ecti ve  of t he st u d y 
is t o e val uate t he efficac y of 
T E V -5 3 2 7 5 a d mi nistere d 
s u bc uta ne o usl y (sc) i n a d ult patie nts 
wit h persiste nt ast h ma a n d a n 
e osi n o p hilic p he n ot y pe c o m pare d t o 
place b o  
T he pri mar y e n d p oi nt is t he c ha n ge fr o m baseli ne i n cli nic -base d 
sta n dar dize d baseli ne-a dj uste d tr o u g h ( pre -br o nc h o dilat or) m or ni n g f orce d 
e x pirat or y v ol u me i n 1 sec o n d ( F E V 1) at wee k 1 2  
A sec o n d ar y o bjecti ve of t he st u d y 
is t o e val uate t he efficac y of 
T E V -5 3 2 7 5 c o m pare d t o place b o 
assesse d b y l u n g f u ncti o n, ast h ma 
s y m pt o ms, resc ue me dicati o n use, 
a n d q ualit y of life meas ures  
T he sec o n dar y efficac y e n d p oi nts are:  
•  
o verall wee kl y well -c o ntr olle d ast h ma stat us defi ne d b y t he 
ast h ma c o ntr ol c o m p osite sc ore a n d wee kl y ast h ma c o ntr ol stat us 
( Yes vers us N o) fr o m wee k 1 t hr o u g h 1 2 a nd o verall wee kl y 
well -c o ntr olle d ast h ma stat us fr o m wee k 1 t hr o u g h 1 6  
•  
o verall c ha n ges fr o m baseli ne i n t he wee kl y a vera ge of dail y 
m or ni n g tr o u g h ( pre -resc ue br o nc h o dilat or) F E V1 as meas ur e d b y 
a ha n d hel d de vice o ver 1 2  we e ks fr o m wee k 1 t hr o u g h 1 2 a n d 
o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  
o verall c ha n ges fr o m baseli ne i n wee kl y a vera ge of resc ue 
me dicati o n use o ver 1 2 wee ks fr o m wee k 1 t hr o u g h 1 2 a n d o ver 
1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  
c ha n ges fr o m baseli ne i n perce nta ge of ast h ma c o ntr ol da ys ( n o 
s y m pt o ms a n d n o resc ue me di cati o n use) o ver 1 2 wee ks fr o m 
wee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  
c ha n ge fr o m baseli ne i n cli nic -base d sta n dar dize d 
baseli ne -a dj uste d mor ni n g tr o u g h F E V 1 at wee k 1 6  
•  
pr o p orti o ns of patie nts w h o ac hie ve cli nic -base d F E V 1 ≥8 0 % 
pre dicte d at wee ks  1 2, 1 6, a n d at e n d p oi nt  
•  
pr o p orti o ns of patie nts w h o ac hie ve f orce d e x pirat or y fl o w at 2 5 % 
t o 7 5 % of f orce d vital ca pacit y ( F E F2 5 -7 5) ≥7 0 % pre dicte d at 
wee ks  1 2, 1 6, a n d at e n d p oi nt  
•  
ti me t o first cli nical ast h ma e xacer bati o n ( C A E) t hr o u g h o ut t he 
st u d y 
•  
c ha n ges fr o m baseli ne i n Ast h ma C o ntr ol Q uesti o n naire ( A C Q -6) 
at wee ks 1 2 a n d 1 6  
•  
c ha n ges fr o m baseli ne i n Ast h ma C o ntr ol T est ( A C T) at wee ks 1 2 
a n d 1 6  
•  
c ha n ges fr o m baseli ne i n Sta n dar dize d Ast h ma Q ualit y of Life 
Q uesti o n naire ( A Q L Q[ S]) at wee ks  1 2 a n d 1 6  
•  
pr o p orti o ns of patie nts w h o ac hie ve F E V 1: F V C (f orce d vital 
ca pacit y) rati o ≥0. 8 0 at wee ks 1 2, 1 6, a n d at e n d p oi nt  
A sec o n d ar y o bjecti ve of t he st u d y is 
t o e val uate t he safet y a n d t olera bilit y 
of T E V -5 3 2 7 5 a d mi nistere d s c i n 
a d ult patie nts wit h persiste nt ast h ma 
a n d a n e osi n o p hilic p he n ot y pe 
c o m pare d wit h place b o  
T he sec o n dar y safet y a n d t olera bilit y e n d p oi nts are:  
•  
fre q ue nc y of a d verse e ve nts 
•  
c ha n ges fr o m baseli ne i n cli ni cal la b orat or y test res ults (ser u m 
c he mistr y, he mat ol o g y, a n d uri nal ysis) t hr o u g h o ut t he st u d y  
•  
c ha n ges fr o m baseli ne i n vital si g ns ( bl o o d press ure, p ulse rate, 
res pirat or y rate, a n d b o d y te m perat ure) t hr o u g h o ut t he st u d y 
•  
c ha n ges fr o m base li ne i n 1 2-le a d electr ocar di o gra m ( E C G) 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7  
O bjecti ves  
E n d p oi nts  
fi n di n gs t hr o u g h o ut t he st u d y 
•  
use of c o nc o mita nt me dicati o n  
•  
l ocal t olera bilit y 
•  
n u m ber ( %) of patie nts w h o di d n ot c o m plete t he st u d y d ue t o 
a d verse e ve nts  
A sec o n d ar y o bjecti ve of t he st u d y is 
t o e val uate t he i m m u n o ge nicit y of 
T E V -5 3 2 7 5 a d mi nistere d sc i n a d ult 
patie nts wit h persiste nt ast h ma a n d a n 
e osi n o p hilic p he n ot y pe  
T he i m m u n o ge nicit y will be assesse d b y meas uri n g t he de vel o p me nt 
a nti -dr u g a nti b o dies ( A D A), a n d t he titer a n d ne utralizi n g acti vit y of t he 
A D A at baseli ne a n d t hr o u g h o ut t he st u d y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8  
O bjecti ves  
E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge ner al St u d y Desi g n:  T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
parallel -gr o u p st u d y t o e val uate t he safet y a n d efficac y of T E V -5 3 2 7 5 a d mi nistere d 
s u bc uta ne o usl y (sc) at d oses of 6 0 0 m g a n d 1 2 0 0  m g or place b o i n a d ult patie nts wit h m o derate 
t o se vere ast h ma wit h a n e osi n o p hilic p he n ot y pe. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9  
Patie nts ma y be eli gi ble t o partici pate if t he y h a ve a dia g n osis of ast h ma f or at least 6 m o nt hs 
a n d t heir c urre nt ast h ma mai nte na nce t hera p y h as bee n sta ble f or at least 1  m o nt h a n d i ncl u des 
1  of t he f oll o wi n g:  
•  me di u m or hi g h d ose i n h ale d c ortic oster oi d (I C S) ±a n ot her c o ntr oller  
•  a n y fi x e d d ose c o m bi nati o n I C S (l o w, me di u m or hi g h) wit h a l o n g -acti n g 
β -a dre n er gic a g o nist ( L A B A) ± a n ot her c o ntr oll er  
T he patie nt will c o nti n ue o n t his ast h ma mai nte na nce t hera p y t hr o u g h o ut t he treat me nt peri o d 
( visit [ V 9]). F or patie nts ta ki n g o nce-dail y i n hale d treat me nt, it m ust be ta ke n i n t he m or ni n g t o 
e na ble tr o u g h l u n g f u ncti o n assess me nts. If a p atie nt re q uire s a c ha n ge i n t h e ti mi n g of d osi n g, it 
is all o wa ble as l o n g as t h e i n vesti gat or belie ves t h ere is n o i n here nt har m i n c ha n gi n g t he ti mi n g 
of t he d ose a n d t he p atie nt a grees t o s uc h c ha n ge.  
T he st u d y will c o nsist of 4 peri o ds:  
•  scree ni n g p eri o d of u p t o a p pro xi matel y 2 wee ks  
•  r u n-i n peri o d of a p pr o xi matel y 1 4 d a ys  
•  d o u ble -bli n d treat me nt p eri o d of 1 6  wee ks  
•  f oll o w-u p peri o d of a p pr o xi matel y 1 4 wee ks be gi n ni n g at t he e n d of t he d o u ble -bli n d 
treat me nt peri o d 
After o btai ni n g i nf or me d c o nse nt, a scree ni n g peri o d of u p t o a p pr o xi matel y 2 wee ks is all o we d. 
Patie nts ma y be e val uate d f or i ncl usi o n i nt o t he r u n -i n peri o d d uri n g t he scree ni n g peri o d . A n 
a bs ol ute e osi n o p hil c o u nt of ≥3 0 0  cells/ μ L is re q uire d t o partici pate i n t he st u d y. A c o m plete 
bl o o d c o u nt ( C B C) will be o btai ne d a n d ma y b e re peate d o nce d uri n g t he scree ni n g peri o d t o 
de m o nstrate a n a bs ol ute e osi n o p hil c o u nt of ≥3 0 0  cells/ μ L (a t ota l of 2 atte m pts d uri n g t he 
scree ni n g p eri o d). Ot her la b orat or y testi n g, me dical hist or y ass ess me nts, bl o o d c ollecti o n f or 
bi o mar kers , p h ysical e x a mi nati o n, a n d ot her assess me nts will be c o m plete d d uri n g t he s cree ni n g 
peri o d a n d ma y be c o n d u cte d at m ore t ha n o n e visit.  
F or mal p ul m o nar y f u ncti o n testi n g (s pir o metr y a n d re versi bilit y testi n g) will be c o n d ucte d i n t he 
m or ni n g bet w ee n 0 5 3 0 a n d 1 1 0 0 h o urs usi n g t he st u d y -pr o vi d e d s pir o metr y e q ui p me nt. T esti n g 
will be perf or me d i n t he cli nic u nless s pecifie d as b y  ha n d h el d de vice. Patie nts are re q uire d t o 
wit h h ol d ast h ma mai nte na nce me di cati o ns pri or t o a n y f or mal p ul m o nar y f u ncti o n testi n g. If t he 
patie nt has ta ke n ast h ma mai nte na nce me di cati o n wit hi n 2 4 ± 2  h o urs f or me dicati o n d ose d o nce 
dail y ( Q D), or wit hi n 1 2 ± 2  h o urs f or me dicati o ns d ose d m ore fre q ue ntl y t ha n o nce d ail y or has 
ta ke n s h ort-acti n g β 2-a dre ner gic a g o nist ( S A B A) resc ue m e dicati o n wit hi n 6 h o urs or i n hale d 
c ortic oster oi d i n c o m bi nati o n wit h l o n g -acti n g β 2 -a der ner gi c a g o nist (I C S/ L A B A) us e d as resc ue 
m e dicati o n wit hi n 1 2  h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g, t he visit m ust be 
resc he d ul e d. Patie nts w h o meet t he pre-al b uter ol/sal b uta m ol l u n g f u ncti o n re q uire me nts ma y 
u n der g o re v ersi bilit y testi n g a p pr o xi matel y 3 0  mi n utes after 4 i n hal ati o ns of al b uter ol/sal b uta m ol 
h y dr ofl ur oal ka n e ( H F A) i n halati o n aer os ol ( 9 0  μ g e x -act uat or or e q ui v ale nt). Patie nts w h o 
de m o nstrate re v ersi bilit y ≥1 2 % a n d a ≥2 0 0  m L i ncrease i n f orce d e x pirat or y v ol u me i n 1 sec o n d 
(F E V 1) fr o m bas eli ne ma y e nt er t he r u n-i n peri o d if t he y meet ot her eli gi bilit y re q uir e me nts as 
s pecifie d. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0  
Patie nts w h o meet t he criteria f or i ncl usi o n a n d n o ne of t he e x cl usi o n criteri a ma y e nter i nt o t he 
r u n-i n peri o d at V 2 a n d will c o nti n ue t he c urre nt ast h ma mai nte na nce me dicati o n. T he patie nt’s 
c urre nt r esc u e me dicati o n will be disc o nti n ue d a n d t he patie nt will be pr o vi de d wit h al b uter ol 
s ulfate ( 1 1 7 μ g per i n hal ati o n) electr o nic m ulti d ose dr y p o w der i n haler (al b uter ol/sal b uta m ol 
e M D PI) ( Pr o Air ®  Di gi haler T M 1) or e q ui v ale nt al b ut er ol/sal b uta m ol ( dr y p o w der or aer os ol 
f or m ulati o ns are acce pta ble) f or use as nee de d as resc ue m e dicati o n t o c o ntr ol ast h ma s y m pt o ms. 
Patie nts will be pr o vi de d a n d trai ne d o n t he us e of a n electr o ni c diar y a n d h a n d hel d de v ice t o 
meas ure d ail y F E V 1 a n d pea k e x pirat or y fl o w ( P E F). D uri n g t he r u n -i n peri o d, patie nts will 
meas ure F E V 1 a n d P E F eac h m or ni n g usi n g t h e ha n d hel d de vice pri or t o t he use of resc ue 
me dicati o n ( w he n e ver p ossi ble) a n d pri or t o t he m or ni n g d ose of ast h ma m ai nte na nce 
me dicati o n(s). Patie nts will als o rec or d ast h ma ( da yti me or ni g ht -ti me) s y m pt o m sc ore a n d 
resc ue m e dicati o n ( n u m b er of p uffs) t wice d ail y w het her use d or n ot. Patie nts ma y be e val uate d 
f or ra n d o mizati o n i nt o t he st u d y after a mi ni m u m of 1 4 ± 2 days after e nteri n g t he r u n -i n peri o d. 
T he ra n d o mizati o n visit ( V 3) will occ ur after a mi ni m u m of 1 4 ± 2 da ys after e nteri n g t he r u n -i n 
peri o d. At t his visit t he patie nt’s diar y data s h o ul d be re vie we d pri or t o f or mal l u n g f u ncti o n 
testi n g, la b orat or y testi n g a n d t he vari o us q uesti o n naires t o e ns ure c o m plia nce wit h diar y e ntries 
a n d t o deter mi ne if l u n g f u ncti o n, s y m pt o ms a n d resc ue me dicati o n use meet t he ra n d o mizati o n 
criteria. If t he patie nt f ails t o meet t he diar y re q uire me nts, t he patie nt will be c o nsi dere d a 
ra n d o mizati o n fail ure. F urt her pr oce d ures f or V 3 will o nl y b e c o n d u cte d f or patie nts w h o meet 
t he diar y re q uir e me nts. 
Patie nts w h o meet all of t he ra n d o mizati o n criteria will be stratifie d base d o n mai nte na nce 
t hera p y (I C S a n d l o w d os e I C S/ L A B A will be stratifie d se paratel y fr o m t he me di u m a n d hi g h 
d ose I C S/ L A B A [ 2 se parate strata]), a bs ol ute e osi n o p hil c o u nt deter mi ne d at scree ni n g ( 3 0 0  t o 
< 4 0 0 or ≥4 0 0  cells/ μ L) i nt o 1 of 2  treat me nt gr o u ps or place b o via a n i nteracti ve res p o ns e 
tec h n ol o g y (I R T) s yste m: 
•  T E V -5 3 2 7 5 6 0 0  m g sc  
•  T E V -5 3 2 7 5 1 2 0 0  m g sc  
•  Place b o sc  
A p pr o xi matel y 9 0 p atie nts w h o ha ve bee n mai ntai ne d o n me di u m or hi g h d ose I C S or l o w d os e 
I C S/ L A B A a n d a p pr o xi matel y 2 1 0 p atie nts ( ma y be a dj uste d base d o n t h e i nteri m a nal ysis) o n 
me di u m or hi g h d ose I C S/ L A B A will be ra n d o mi ze d a n d stratifie d acr oss all treat me nt ar ms. 
Scree ni n g ma y be a dj uste d as nee d e d t o meet t hes e criteri a as m uc h as p ossi ble.  
Patie nts w h o meet t he re q uire me nts f or ra n d o mizati o n, after t he pr oce d ures f or s peci me n 
c ollecti o n a n d ot h er testi n g ha v e bee n c o m plete d, will be ra n d o mize d via t he I R T. Eac h p atie nt 
will recei ve a t otal of 4  s c i njecti o ns i n t he a b d o me n at V 3, a d mi nistere d b y a q u alifie d healt h 
care pr o vi der (acc or di n g t o l ocal re g ulati o ns) w h o is pre pare d t o ma n a ge a n a p h yl a x is, as 
descri be d i n t he st u d y refere nce ma n ual. T h e kit n u m ber a n d l ocati o n will be rec or de d i n t he 
s o urce d oc u m e nts a n d e ntere d i n t he case re p ort f or m ( C R F) f or eac h of t he 4 i njecti o n site 
l ocati o ns al o n g wit h a n y i njecti o n site reacti o n f or eac h site, e v al uate d at a p pr o xi matel y 1  h o ur 
                                                 
1 Pr o Air ®  Di gi haler ™ is a re gistere d tra d e mar ks of T e va P har mace utical I n d ustries Lt d.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1  
after d osi n g. If t he patie nt de vel o ps cli nical s y m pt o ms, vital si g ns s h o ul d be rec or de d a n d t he 
patie nt s h o ul d be assesse d f or a na p h yl a xis/ h y perse nsiti vit y reacti o ns. Patie nts will be o bser ve d 
f or a mi ni m u m of 1 h o ur after  d osi n g. Bef ore lea vi n g t he cli nic, patie nts will a d diti o nall y be 
a d vise d of s y m pt o ms/si g ns f or w hic h t he y s h o ul d see k me dical a d vice or me dical treat me nt. At 
all ot her visits, patie nts will be free t o lea ve t he cli nic w he n all pr oce d ures ha ve bee n c o m plet e d.  
D uri n g t h e treat me nt p eri o d ( baseli ne/ da y of ra n d o mizati o n [ D o R, V 3] t hr o u g h wee k 1 6 [ V 9]), 
patie nts will perf or m m or ni n g l u n g f u ncti o n assess me nts ( F E V 1 a n d P E F) b y ha n d h el d de vice 
pri or t o m or ni n g ast h ma mai nte na nce me di cati o n a n d pri or t o res c ue me d icati o n use ( w he n e ver 
p ossi ble), assess a n d rec or d da yti me a n d ni g ht -ti me ast h ma s y m pt o m sc ores, rec or d resc u e 
me dicati o n use ( n u m ber of p uffs) t wice dail y a n d c o nfir m (i n t he e v e ni n g) t hat t he y h a ve ta ke n 
t hat da y's ast h ma mai nte na nce me di cati o n. D uri n g the tr eat me nt peri o d visits, f or mal p ul m o nar y 
f u ncti o n testi n g (as re q uire d) will be c o m plet e d i n t he m or ni n g bet w ee n 0 5 3 0 a n d 1 1 0 0 ± 1 h o ur 
o n t he st u d y -pr o vi de d s pir o metr y e q ui p me nt. If a patie nt has ta ke n resc ue me dicati o n wit hi n 
6  h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g or has ta ke n t he m or ni n g d ose of ast h ma 
mai nte na nce me di cati o n, t he testi n g s h o ul d be ca n celle d, a n d t he visit s h o ul d be resc h e d ule d. All 
f or mal p ul m o nar y f u ncti o n testi n g s h o ul d be c o n d ucte d at a p pr o xi matel y t h e sa me ti me of da y 
± 1  h o ur of t he ti me it was c o n d ucte d at bas eli ne/ D o R ( V 3).  
Patie nts w h o c o m plete wee k 1 6 (e n d of treat me nt visit [ E o T V; V 9]) will e nter t he f oll o w -u p 
peri o d. T he ha n d h el d de vice a n d diar y, al o n g wit h st u d y pr o vi de d resc u e me dicati o n will be 
c ollecte d. T he i n v esti gat or s h o ul d deter mi ne a n d i m ple me nt a p pr o priate ast h ma t hera p y 
(i ncl u di n g resc ue treat me nt) t o be use d d uri n g t he f oll o w-u p peri o d. Me dicati o n starte d f or t he 
p ur p ose of o n g oi n g ast h ma treat me nt will n ot be c o nsi dere d a pr ot oc ol vi olati o n, pr o vi de d i t is 
starte d after t he fi nal s pir o metr y assess me nts are c o m plete d at wee k 1 6 ( V 9). Patie nts will be 
c o ntacte d a p pr o xi matel y m o nt h l y b y t ele p h o ne t o assess C A Es, a d verse e v e nts, a n d c o nc o mita nt 
me dicati o ns. A fi nal f oll o w -u p visit will occ ur at a p pr o xi matel y wee k  3 0 f or fi nal assess me nts. A 
C A E is defi ne d as w ors e ni n g ast h ma re q uiri n g treat me nt wit h a s yste mic c ortic oster oi d f or 
≥3  da ys, e mer ge n c y r o o m visit res ulti n g i n s yste mic c ortic oster oi d treat me nt or h os pitalizati o n 
d ue t o ast h ma. All i nsta nces of a C A E s h o ul d b e rec or de d i n t he C R F.  
Alert criteri a f or i n di vi d u al patie nts w h o de vel o p w orse ni n g ast h ma ha v e b ee n desi g ne d t o 
e ns ure patie nt safet y. If a n y of t he criteri a liste d bel o w are m et, t he i n vesti gat or will deter mi ne 
w het her t he p atie nt’s o verall cl i nical pict ure is c o nsiste nt wit h w orse ni n g ast h ma a n d if t he 
patie nt s h o ul d be place d o n a d diti o nal ast h ma mai nte na nce t h era p y i n t he i nterest of patie nt 
safet y. Meeti n g 1 of t h ese criteri a d oes n ot a ut o m aticall y re q uire a patie nt t o be place d o n 
alter nat i ve ast h ma t hera p y; rat h er it re q uir es a cli nical e val uati o n t o deter mi ne if t he patie nt’s 
ast h ma ca n c o nti n ue t o b e ma na ge d o n t h e c urre nt re gi me n per t h e st u d y or necessitates a c ha n ge 
i n ast h ma mai nte na nce t h era p y: 
•  m or ni n g F E V 1 b y h a n d h el d s pir o meter, a s me as ure d at h o me, falls bel o w t he F E V 1 
sta bilit y li mit ( F E V1 < 8 0 % of t he scree ni n g visit F E V 1 meas ure m e nt t hat was 
meas ure d i n t he cli nic d uri n g t he s cree ni n g p eri o d) f or t he r u n -i n peri o d a n d t he 
baseli ne val ue ( b y ha n d h el d de vice) deter mi ne d at t he ra n d o mizati o n visit ( V 3) f or 
t he treat me nt peri o d o n 4 or m ore da ys o ut of a n y 7-da y peri o d. T hese val u es are 
base d o n t he ha n d h el d de vice.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2  
•  F E V 1, as meas ur e d at t he st u d y ce nter, is bel o w t h e F E V1 sta bilit y li mit val ue 
calc ulate d at t he ra n d o mi zati o n visit ( V 3) ( < 8 0 % of baseli ne b y cli nic -b ase d 
s pir o metr y). 
•  base d u p o n a re vie w of patie nt diar y data, t he p atie nt has e x perie nce d a n y of t he 
f oll o wi n g d uri n g a n y 7-d a y p eri o d (t he da ys nee d n ot be c o nsec uti ve a n d ma y o v erla p 
visits):  
− 3 or m ore da ys i n w hic h 1 2 or m ore i n halati o ns/ da y of res c ue me dicati o n 
(al b uter ol e M D PI or e q ui vale nt al b uter ol/sal b uta m ol) were us e d 
− 3 or m ore da ys wit h a ni g ht -ti me ast h ma s y m pt o m sc ore of 3 or hi g h er. 
•  patie nts w h o, b y t he assess me nt of t he i n vesti gat or, are i d e ntifie d as ha vi n g 
e x perie nce d a cli nicall y mea ni n gf ul w orse ni n g of t heir ast h ma warra nti n g a c ha n ge i n 
t heir ast h ma treat me nt ( b ase d o n t he i n vesti gat or’s j u d g me nt) will start a p pr o priate 
treat me nt. A patie nt ma y be dee me d b y t h e i n vesti gat or as ha vi n g a cli nicall y 
mea ni n gf ul w orse ni n g of t heir ast h ma e ve n w he n t he y d o n ot meet t he alert criteria 
a b o ve.  
Patie nts w h o re q uire a c h a n ge i n bac k gr o u n d ast h ma mai nte na nce treat me nt s h o ul d c o m plete 
assess me nts as o utli ne d f or V 8 a n d c o nti n ue t o partici pate i n all la b orat or y a n d safe t y 
assess me nts l u n g f u ncti o n, c o m pleti o n of q uesti o n naires a n d d ail y diar y ass ess me nts. (If a 
patie nt re q uires a c ha n ge i n me dicati o n bet wee n V 8 a n d V 9, t he pr oce d ures f or V 9 s h o ul d be 
c o m plete d. If a c ha n ge of me dicati o n occ urs wit hi n 2 wee ks of t he n e xt pla n ne d visit, t hat visit 
ma y b e s ki p pe d). Patie nts w h o wit h dra w c o ns e nt or are wit h dra w n fr o m partici pati o n i n t he 
st u d y s h o ul d c o m plete t h e pr oce d ures f or t he Earl y Wit h dra wal Visit ( E W V).  
Met h o d of R a n d o miz ati o n a n d Bli n di n g:  T his is a ra n d o mize d, d o u bl e-bli n d, 
place b o -c o ntr olle d, parallel -gr o u p st u d y. Patie nts will be ra n d o ml y assi g n e d t o 1 of 2 treat me nt 
gr o u ps or place b o i n a 1: 1: 1 rati o a n d will be stratifie d b y pri or ast h ma mai nte na nce t h era p y (I C S 
a n d l o w d ose I C S/ L A B A, or me di u m a n d hi g h d os e I C S/ L A B A) a n d a bs ol ute e osi n o p hil c o u nt 
( 3 0 0 t o < 4 0 0  cells/ μ L, ≥4 0 0  cells/ μ L). A p pr o xi matel y 9 0 p atie nts w h o ha ve bee n mai ntai ne d o n 
me di u m or hi g h d ose I C S or l o w d ose I C S/ L A B A a n d a p pr o xi matel y 2 1 0 patie nts ( ma y be 
a dj uste d base d o n t he i nt eri m a nal ysis)  o n me di u m or hi g h d ose I C S/ L A B A will be i ncl u de d a n d 
scree ni n g will be a dj uste d as nee de d t o meet t hese criteria. 
I n vesti g ati o n al Me dici n al Pr o d ucts: D ose, P h ar m a ce utic al F or m, R o ut e of A d mi nistr ati o n, 
a n d A d mi nistr ati o n R ate:  T he sc r o ute of a d mi nistrati o n w as c h ose n b eca use it is t he i nte n de d 
h u ma n t hera pe utic r o ute. T he l o west pr o p ose d d os e ( 6 0 0  m g) was c h ose n b ase d o n t he s p o ns or’s 
i nte nti o n t o e x pl ore p ote ntial efficac y of 2 d oses of T E V -5 3 2 7 5. A place b o c o ntr ol desi g n is 
scie ntificall y a p pr o priate as place b o will be c o m pare d t o T E V -5 3 2 7 5 as a d d -o n t hera p y i n 
patie nts wit h m o derate t o se vere e osi n o p hilic ast h ma.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3  
I M P n a me 
Test I M P  
Pl ace b o I M P  
Tr a de n a me a n d I N N, if 
a p plic a ble, or c o m p a n y -assi g ne d 
n u m ber  
T E V -5 3 2 7 5  
T E V -5 3 2 7 5 Place b o  
F or m ul ati o n  
 
 
 
 
 
 
 
 
U nit d ose stre n gt h(s)/ D os a ge 
le vel(s) 
3 0 0  m g/ vial  
Ve hicle b uffer a bse nt of pr otei n  
R o ute of a d mi nistr ati o n  
sc i nj ecti o n 
sc i nj ecti o n 
D osi n g i nstr ucti o ns/ D osi n g 
sc he d ule/ Titr ati o n 
peri o ds/ Tre at me nt peri o ds  
As i nstr ucte d i n t he cli nical pr ot oc ol 
a n d p har mac y ma n ual  
As i nstr ucte d i n t he cli nical pr ot oc ol 
a n d p har mac y ma n ual  
P ac k a gi n g  
T y pe  1 glass vial wit h b ut yl r u b ber 
st o p per a n d cri m p seal wit h a plastic 
fli p-off ca p  
T y pe 1 glass vial wit h b ut yl r u b ber 
st o p per a n d cri m p seal wit h a plastic 
fli p-off ca p  
M a n uf act urer  
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc., West C hester, 
P e n ns yl va nia, U S A  
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc., West C hester, 
P e n ns yl va nia, U S A  
St o r a ge c o n diti o ns  
2° C t o 8° C ( 3 6° F t o 4 6° F) a n d 
pr otecte d fr o m li g ht. D o n ot fr eeze  
2° C t o 8° C ( 3 6° F t o 4 6° F) a n d 
pr otecte d fr o m li g ht. D o n ot fr eeze  
I M P =i n vesti gati o nal me dici nal pr o d uct; I N N =i nter nati o nal n o n pr o prietar y na me; sc =s u bc uta ne o us; U S A = U nite d 
States of A merica.  
D ur ati o n of P atie nt P artici p ati o n a n d M a xi m al E x p os ure t o I M P: T he t otal d urati o n of 
patie nt partici pati o n i n t he st u d y is pla n ne d t o b e a p pr o xi matel y 3 4  wee ks i ncl u di n g u p t o a n 
a p pr o xi mate 2 -wee k scree ni n g p eri o d, a p pr o xi matel y a 2 -wee k r u n -i n p eri o d, a 1 6-wee k 
treat me nt peri o d, a n d a f oll o w-u p visit 1 4  wee ks after t he fi nal treat me nt visit. 
St u d y D ur ati o n:  A p pr o xi matel y 1 6 m o nt hs, fr o m Q 2/ 2 0 2 1 t o Q 4/ 2 0 2 2.  
E n d of St u d y:  E n d of st u d y is defi n e d as t he last visit of t he last patie nt at t he f oll o w -u p visit.  
Pl a ns f or Tre at me nt or C are after t he P atie nt H as E n de d P artici p ati o n i n t he St u d y:  N o 
T E V -5 3 2 7 5 treat me nt is pla n ne d after t he e n d of t he st u d y.  
Selecti o n of P atie nts/ St u d y P o p ul ati o n  
I ncl usi o n Criteri a: Patie nts ma y be i ncl u d e d i n t he st u d y o nl y if t he y meet all of t he f oll o wi n g 
criteria:  
a. T he patie nt is ca p a ble of gi vi n g si g n e d i nf or me d c o nse nt. 
b.  T he patie nt is a n a d ult fe male or male ≥1 8  years of a ge. N ote: A ge re q uire me nts are 
as s pecifie d or all o we d b y l ocal re g ulati o ns.  
c. [ Re visi o n 1] T he patie nt has a dia g n osis of ast h ma f or at least 6 m o nt hs as defi ne d b y 
t he Nati o nal I nstit utes of Healt h ( NI H) a n d h as bee n sta ble wit h o ut e xacer bati o n or 
c ha n ge i n m e dic ati o ns f or at least 1  m o nt h . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4  
d.  T he patie nt has a n a bs ol ute bl o o d e osi n o p hil c o u nt ≥3 0 0  cells/ μ L de m o nstrate d 
d uri n g t he s cree ni n g p eri o d . N ote: R o u n di n g of t he v al ue (c o u nt) is n ot per mitte d . 
e. Se verit y of Diseas e: T he patie nt has persiste nt ast h ma, wit h a tr o u g h F E V 1 ≥4 0 % a n d 
≤8 5 % of t he val ue pre dicte d as per t he Nati o nal H ealt h a n d N utriti o n E x a mi nati o n 
S ur ve y ( Ha n ki ns o n et al 1 9 9 9 , N H A N E S III 1 9 9 8 ) a n d a dj uste d f or et h nicit y 
(Ha n ki ns o n et al 2 0 1 0 ). N ote: P atie nts w h o d o n ot q u alif y f or t he st u d y d ue t o 
f ail ure t o meet b aseli ne s pir o metr y o r f ail t o ac hie ve s pir o metr y c o nsiste nt wit h 
t he A meric a n T h or acic S ociet y ( A T S)/ E ur o pe a n Res pir at or y S ociet y ( E R S) 
criteri a (Miller et al 2 0 0 5 ) will be per mitte d t o perf or m re pe at s pir o metr y 
d uri n g t he scree ni n g peri o d o n 1 occ asi o n a n d if criteri a are n ot met, will be 
c o nsi dere d t o h a ve f aile d scree ni n g.  
f. Re versi bilit y of Dise ase: T he patie nt has de m o nstr ate d re v ersi bilit y of ≥1 2 % 
(i ncrease) of F E V1 a n d a mi ni m u m 2 0 0  m L i ncrease fr o m pre -al b uter ol/sal b uta m ol 
F E V 1 a p pr o xi matel y 3 0  m i n utes after 4 i n halati o ns of al b uter ol/sal b uta m ol 
h y dr ofl u or oal ka n e ( H F A) metere d -d ose i n haler ( M DI) ( 9 0  µ g e x -act uat or) or 
e q ui vale nt d uri n g t he scree ni n g peri o d.  
g.  [ Re visi o n 1] C urre nt Ast h ma T hera p y: T h e patie nt has bee n mai ntai ne d f or at least 
1  m o nt h o n sta ble d oses of:  
− me di u m or hi g h d ose I C S ±a n ot her c o ntr oller.  
− a n y fi x e d d ose c o m bi nati o n I C S (l o w, me di u m, or hi g h) wit h L A B A ±a n ot h er 
c o ntr oller.  
h.  W o me n of n o n -c hil d beari n g p ote ntial w h o are eit h er s ur gicall y ( d oc u me nte d 
h ysterect o m y, bilateral o o p h orect o m y, or bilateral sal pi n gect o m y) or c o n ge nitall y 
sterile as assess e d b y a p h ysicia n, or 1-year p ost me n o pa usal ( n o me nses f or at least 
1 2 m o nt hs wit h o ut a n alter nati ve me dical ca us e pl us a n i ncrease d c o n ce ntr ati o n of 
f ollicle sti m ulati n g h or m o ne [ F S H] of m ore t ha n 3 5 U/ L i n w o me n n ot usi n g 
h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y). W o me n of c hil d beari n g 
p ote ntial m ust ha ve a ne gati ve β -h u ma n c h ori o nic g o na d otr o pi n ( β -H C G) test res ult 
a n d practice a hi g hl y effecti ve met h o d of birt h c o ntr ol ( met h o d s t hat ca n ac hie ve a 
fail ure rate of less t ha n 1 % per year w h e n use d c o nsiste ntl y a n d c orrectl y) pri or t o 
I M P a d mi nistrati o n a n d 3 0 wee ks after t he d os e of I M P. Hi g hl y effecti ve 
c o ntrace pti o n i ncl u des:  
− c o m bi ne d estr o ge n a n d pr o gest o ge n h or m o nal c o ntrace pti o n ( oral, i ntra va gi nal, 
tra ns der mal) ass ociate d wit h i n hi biti o n of o v ulati o n; t hese s h o ul d be i nitiate d at 
least 7 da ys bef ore t he first d ose of I M P 
− pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ( oral, i njecta ble, i m pla nta ble) 
ass ociate d wit h i n hi biti o n of o v ulati o n; t hese s h o ul d be i nitiate d at least 1 4 da ys 
bef ore t h e first d ose of I M P  
− i ntra uteri ne de vic e (I U D) a n d i ntra uteri ne h or m o ne-rel easi n g s yste m (I U S) nee d 
t o be i n place at least 2 m o nt hs bef ore scree ni n g 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5  
− bilateral t u bal occl usi o n, e x ce pt f or h yst er osc o pic bi -t u bal li gati o n f or w hi c h a 
h yster os al pi n g o gra m ( H S P) is re q uire d 3 m o nt hs p ost pr oce d ure t o assess s ur gical 
s uccess 
− vasect o miz e d part ner pr o vi de d he is t he s ole se x ual part ner a n d h as recei ve d 
me dical assess me nt of t h e s ur gical s uc cess  
− se x ual a bsti ne nce is o nl y c o nsi dere d a hi g hl y effecti ve met h o d if defi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse i n t he st u d y peri o d. 
i. T he patie nt m ust be willi n g a n d a ble t o c o m pl y wit h st u d y restricti o ns a n d t o re mai n 
at t he i n vesti gati o nal ce nter f or t he re q uire d d urati o n d uri n g t he st u d y peri o d a n d t he 
f oll o w-u p pr oce d ures a n d assess me nts as s pecifi e d, a n d be willi n g t o r et ur n t o t he 
i n vesti gati o nal c e nter f or f urt her visits, as a p plica ble. 
j. T he patie nt, as j u d ge d b y t he i n vesti gat or, is a bl e t o c o nti n ue t hei r c urre nt ast h ma 
mai nte na nce me di cati o ns t hr o u g h o ut t he st u d y.  
E xcl usi o n Criteri a:  Patie nts will be e x cl u de d fr o m partici pati n g i n t his st u d y if t he y meet a n y of 
t he f oll o wi n g criteria: 
a. Lif e t hreat e ni n g ast h ma, defi ne d as a hist or y of ast h ma e pis o de(s) re q uiri n g 
i nt u bati o n a n d/ or ass ociate d h y p erca p nea, res pir at or y arrest, h y p o xic seiz ures, or 
ast h ma-relat e d s y nc o pal e pis o de(s). 
b.  T he patie nt has a s us p ect e d bacterial or viral i nfecti o n of t he u p per or l o wer 
res pirat or y tr act, si n us, or mi d dle ear t hat h as n ot res ol ve d at least 2 wee ks bef ore t h e 
scree ni n g p eri o d. N ote: Patie nts w h o de vel o p a n u p per res pir at or y i nfecti o n/l o wer 
res pirat or y i nf ecti o n ( U RI/ L RI) d uri n g t he r u n-i n peri o d ma y res cree n 2 wee ks aft er 
s y m pt o ms res ol ve a n d u n der g o c or o na vir us diseas e 2 0 1 9 ( C O VI D -1 9) testi n g as 
o utli ne d i n e x cl usi o n criteria “ d ”.  
c. Patie nts wit h a c o nfir me d i nfecti o n wit h C O VI D -1 9 wit hi n 3 m o nt hs pri or t o t he 
scree ni n g visit. 
d.  Patie nts wit h cli nical s y m pt o ms t hat ma y i n dicat e C O VI D -1 9 i nf ecti o n, a n d/ or 
patie nts w h o i n t he i n vesti gat or’s o pi ni o n were at hi g h ris k of e x p os ure t o C O VI D-1 9 
wit hi n 4 wee ks bef ore scree ni n g or d uri n g s cree ni n g/r u n -i n, will be teste d f or acti ve 
C O VI D -1 9 i nfecti o n a n d will o nl y b e i ncl u de d if t he y t est ne gati ve f or C O VI D -1 9.  
e. T he patie nt has a n e osi n o p hilic c o n diti o n i ncl u di n g h y pere osi n o p hilic s y n dr o me, 
e osi n o p hilic p ne u m o nia, e osi n o p hilic gra n ul o mat osis wit h p ol ya n giitis ( E G P A 
[ C h ur g Stra uss s y n dr o me]), or aller gic br o nc h o p ul m o nar y as per gill osis. 
f. T he patie nt has a n acti ve hel mi nt hic or parasitic i nf ecti o n c urre ntl y or wit hi n t he last 
6 m o nt hs.  
g.  T he patie nt has a hist or y of mali g na n c y ot her t h a n f ull y resecte d basal cell carci n o ma 
of t he s ki n.  
h.  T he patie nt has a n y cli nicall y si g nifica nt, u nc o ntr olle d me dical or ps yc hiatric 
c o n diti o n (treate d or u ntreate d) t hat w o ul d i nterfere wit h t he st u d y sc h e d ule or 
pr oce d ures, i nter pretati o n of efficac y res ults, or c o m pr o mise t he patie nt’s safet y. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 6  
( N ote: C hr o nic o bstr ucti ve p ul m o nar y disease [e m p h yse ma], br o nc hiectasis re q uiri n g 
treat me nt, c ystic fi br osis, c hr o nic bro n c hitis, a n d ot her diseases of t he l u n g t hat ma y 
c o m plicate i nter pretati o n of t he st u d y res ults are pr o hi bite d).  
i. T he patie nt has k n o w n hist or y of, or a p ositi ve test res ult f or, he p atitis B s urface 
a nti ge n ( H Bs A g), he p atitis C vir us ( H C V) a nti b o dies ( A b),  or h u ma n 
i m m u n o deficie nc y vir us ( HI V) T y p es 1 or 2 A b (acc or di n g t o 4t h ge nerati o n ser ol o g y 
testi n g). 
j. T he patie nt is a pre g n a nt or lactati n g w o ma n, or pl a ns t o bec o me pre g na nt d uri n g t he 
st u d y. 
k.  T he patie nt has ta k e n pr o hi bite d pri or me dicati o ns wit hi n t he  was h o ut peri o d. 
Pr o hi bite d me dicati o ns are liste d i n t he pr ot oc ol wit h t he a p pr o priate was h o ut peri o ds  
(see A p p e n di x  G ). 
l. T he patie nt has pre vi o usl y partici pate d i n a st u d y wit h T E V -5 3 2 7 5.  
m.  T he patie nt has partici pat e d i n a n ot her st u d y of a n I M P ( or a me dical de vice) wit hi n 
t he pre vi o us 3 0 da ys or 5 half-li ves of t he I M P ( w hic he ver is l o n ger) or is c urre ntl y 
partici pati n g i n a n ot her st u d y of a n I M P ( o r a m e dical de vice). 
n.  [ Re visi o n 1] T he patie nt has bee n tr eate d wit h a m o n ocl o nal a nti b o d y  us e d t o treat 
ast h ma or ot her i nfla m m at or y c o n diti o ns wit hi n t he was h o ut peri o d ( 5 half -li ves), has 
de m o nstrate d h y pers e nsiti vit y or a na p h yl a xis t o a m o n ocl o nal a nti b o d y  
(A p pe n di x  G ), or is c urre ntl y usi n g or has use d a s yste mic i m m u n os u p pressi ve 
me dicati o n wit hi n t he last 6 m o nt hs.  N O T E: Pri or de pe m o ki ma b e x p os ure is 
pr o hi bite d wit h o ut e x ce pti o n.  
o.  T he patie nt has a k n o w n  h y perse nsiti vit y t o a n y c o m p o ne nts of t he I M P state d or 
st u d y s u p plie d res c ue me dicati o n. 
p.  T he patie nt has a hist or y of c hr o nic alc o h ol or dr u g a b us e wit hi n t he pre vi o us 2 years.  
q.  [ Re visi o n 1] T he patie nt c urre ntl y s m o kes or has a s m o ki n g hist or y of 1 0 pac k  years 
or m ore (a p ac k year is d efi ne d as s m o ki n g 1 pac k of ci garettes [ 2 0 ci garett es]/ da y f or 
1 year), O R t he patie nt use d t o bacc o pr o d ucts wit hi n t he past year (e g, ci garettes, 
ci gars, c h e wi n g t o bacc o, or pi pe t o bacc o), O R t he patie nt has s m o ke d marij ua n a 
wit hi n 1  m o nt h, O R t he patie nt has a hist or y of “ v a pi n g” t o bacc o, marij ua n a, or a n y 
ot her s u bsta nce wit hi n 2 4 m o nt hs.  
r. V ul nera ble p atie nts (e g, pe o ple ke pt i n dete nti o n).  
R a n d o miz ati o n Crit eri a:  
T he f oll o wi n g criteri a m ust be f ulfille d at t he ra n d o mizati o n visit ( da y 0):  
a. T he patie nt c o nti n ues t o be i n ge neral g o o d h ealt h, meeti n g t he e ntr y criteri a.  
b.  T he patie nt’s a v era ge of 5 m ost rece nt hi g hest  dail y tr o u g h val ues (fr o m 3 atte m pts) 
f or m or ni n g F E V1 o btai n e d at h o me ( b y ha n d h el d s pir o metr y) o ver 7  d a ys pri or t o V 3 
is wit hi n 4 0 % t o 8 0 % pre dicte d f or a ge, hei g ht, se x, a n d race (Ha n ki ns o n et al 1 9 9 9 , 
Ha n ki ns o n et al 2 0 1 0 , N H A N E S III 1 9 9 8 ). If resc ue me dicati o n was ta k e n wit hi n 
4  h o urs of t he F E V 1 assess me nt, or ast h ma mai nte na nce me di cati o n was ta ke n bef ore 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 7  
t he meas ure m e nt, t he dat a fr o m t hat da y s h o ul d be e x cl u de d a n d data fr o m a pre vi o us 
da y d uri n g t he 7 -da y p eri o d s h o ul d be i ncl u de d.  
c. T he patie nt has a n F E V 1 as assesse d  b y cli nic -bas e d p ul m o nar y f u ncti o n testi n g t hat is 
wit hi n 4 0 % t o 8 5 % or t he val ue pre dicte d f or a ge, hei g ht, se x, a n d race ( Ha n ki ns o n et 
al 1 9 9 9, Ha n ki ns o n et al 2 0 1 0 , N H A N E S III 1 9 9 8 ). 
d.  T he patie nt has de m o nstr ate d F E V 1 re versi bilit y as re q uire d d uri n g t he s cree ni n g 
peri o d.  
e. T he patie nt’s A C Q -6 s c ore assess e d o n V 3 da y 0 is ≥1. 5.  
f. T he patie nt has re mai ne d o n bac k gr o u n d ast h ma mai nte na nce me di cati o n wit h o ut 
c ha n ges d uri n g t he r u n -i n peri o d ot her t ha n st u d y resc ue m e dicati o n (al b ut er ol 
e M D PI [ Pr o Air Di gi haler f or use as nee d e d or e q ui vale nt al b uter ol/sal b uta m ol 
de pe n di n g o n a vaila bilit y]) a n d al b uter ol/sal b uta m ol use d f or re v ersi bilit y t esti n g.  
g.  T he patie nt has ha d n o e x ace r bati o n of ast h ma d uri n g t he r u n-i n peri o d, d efi ne d as 
a n y w orse ni n g of ast h ma re q uiri n g si g nifi ca nt treat me nt ot her t ha n resc u e me dicati o n 
(al b uter ol e M D PI [ Pr o Air Di gi hal er f or use as n ee de d or e q ui vale nt 
al b uter ol/sal b uta m ol de pe n di n g o n a vaila bilit y]).  Si g nifica nt treat me nt i ncl u des a n y 
of t he f oll o wi n g: use of s yste mic c ortic oster oi ds or t he a d diti o n of I C S -c o ntai ni n g 
ast h ma me dicati o ns, L A B A, l o n g -acti n g m usc ari nic a nta g o nist ( L A M A), bi ol o gic or 
ot her n o n -c ortic ost er oi d ast h ma me dicati o ns, e mer ge nc y r o o m/ ur ge nt care visit, or 
h os pitaliz ati o n f or ast h ma. N ote: A si n gle d ose of ne b ulize d al b uter ol/s al b ut a m ol 
will n ot meet t he criteri a f or a n ast h m a e x acer b ati o n. E mer g e nc y r o o m/ ur ge nt 
c are cli nic visits w here t he tre at me nt is li mite d t o a si n gle d ose of n e b ulize d 
al b uter ol/s al b ut a m ol will n ot meet t he criteri a of a n ast h m a e x acer b ati o n.  
h.  T he patie nt has c o m plie d wit h h o me s pir o metr y a n d diar y e ntr y o n at least 5 of t he 
last 7 da ys pri or t o t he visit i ncl u di n g:  
− c o m pleti o n of da yti me a n d ni g ht -ti me ast h ma s y m pt o m sc ores 
− c o m pleti o n of da yti me a n d ni g ht -ti me res c ue me dicati o n use, w het her use d or n ot 
− c o m pleti o n of t he m or ni n g F E V 1 a n d P E F b y ha n d hel d de vice  
− c o nfir me d dail y use of ast h ma mai nte na nce me di cati o n as prescri be d  
i. T he patie nt has n ot ha d a n  u p per res pir at or y i nfecti o n ( U RI ) or l o wer res pir at or y 
i nfecti o n (L RI ) d uri n g t h e r u n -i n peri o d. Patie nts w h o de vel o p a U RI or L RI d uri n g 
t he r u n-i n peri o d ma y b e disc o nti n ue d fr o m t he st u d y a n d all o we d t o res cree n 
2  wee ks after res ol uti o n of s y m pt o ms. T he y m ust ha ve a n e gati ve test f or C O VI D -1 9 
acti ve i nfecti o n.  
j. T he patie nt has use d resc ue me dicati o n or ha d a d a yti me or ni g ht -ti me ast h ma 
s y m pt o m sc ore ≥1 o n 3 or m ore da ys i n t he 7 da ys pri or t o t he ra n d o mizati o n visit as 
re p orte d i n t he p atie nt diar y. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 8  
St atistic al  C o nsi der ati o ns  
S a m ple Size R ati o n ale: T he sa m ple siz e is cali brate d base d o n si m ulati o n st u dies t o assess t he 
o perati n g c haracteristics of t he f oll o wi n g Ba yesia n s uccess criteri o n f or t h e fi nal a nal ysis of t he 
pri mar y efficac y e n d p oi nt : a dj uste d mea n c ha nge fr o m baseli ne at w ee k 1 2 i n tr o u g h F E V 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
A n al ysis Sets  
I nte nt-t o-Tre at A n al ysis Set:  T he i nte nt -t o-tr eat (I T T) a n al ysis set will i ncl u de all ra n d o mize d 
patie nts.  
I n t he I T T a n al ysis set, p atie nts will be assi g ne d t o t he treat me nt t he y were ra n d o mize d, 
re gar dl ess of w hic h treat me nt t he y act uall y recei v e d. 
M o difie d I nte nt -t o-Tre at A n al ysis Set:  T he m o difie d i nte nt -t o-treat ( mI T T) a nal ysis set is a 
s u bset of t he I T T a n al ysis set i ncl u di n g onl y patie nts w h o recei v e at least 1 d ose of I M P.  
T he mI T T a n al ysis set will ser ve as t he pri mar y a n al ysis set f or efficac y a nal yses.  
S afet y A n al ysis Set:  T he safet y a nal ysis set will i ncl u de all ra n d o mize d patie nts w h o recei ve at 
least 1 d ose of I M P. 
I n t he s afet y a nal ysis set, patie nts will be assi g ne d t o t he treat me nt t he y act uall y recei v e d 
re gar dl ess of w hic h treat me nt t he y w ere ra n d o mize d, u nless ot her wise s p ecifie d.  
Per -Pr ot oc ol A n al ysis Set:  T he p er -pr ot oc ol ( P P) a nal ysis s et is a s u bset of t he mI T T a n al ysis 
set i ncl u di n g o nl y patie nts wit h o ut i m p orta nt pr ot oc ol vi olati o ns. I m p orta nt pr ot oc ol vi olati o ns 
will be deter mi ne d bef ore u n bli n di n g a n d will i ncl u de i nc orrect I M P recei ve d b y a patie nt.  
T he P P a nal ysis will ser ve as a s u p p orti ve a nal ysis f or t he pri mar y effi cac y a nal ysis as well as 
t he sec o n dar y efficac y a n al ysis. 
P h ar m a c o ki netic A n al ysis Set: T he p har m ac o ki netic a nal ysis set will i ncl u de t h ose patie nts i n 
t he safet y a n al ysis set w h o ha ve at least 1 a vaila bl e ser u m c o n ce ntrati o n val ue. 
                                                 
1 CI N Q AI R ® is a re gistere d t o T e va P har mace utical I n d ustries Lt d. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 9  
A nti -dr u g A nti b o d y A n al ysis Set: T he A D A a nal ysis set (f or a nti -T E V -5 3 2 7 5 a nti b o dies) will 
i ncl u de t h ose patie nts treate d wit h T E V-5 3 2 7 5 i n t he safet y a n al ysis set.  
Effic ac y A n al ysis  
Pri m ar y Effic ac y A n al ysis:  A n esti ma n d, i n ge n eral, i ncl u des 4 i nter -relat e d attri b utes –  
p o p ulati o n of i nterest, varia ble (e n d p oi nt) of i nterest, i nter -c urre nt e ve nts (I C E) al o n g wit h t he 
strate g y f or h a n dli n g I C E, a n d p o p ulati o n-le vel s u m mar y f or t he e n d p oi nt. 
T he esti ma n d select e d f or t he pri mar y efficac y e n d p oi nt will assess t he c ha n ge fr o m baseli ne i n 
m or ni n g tr o u g h F E V 1 at wee k 1 2 d ue t o t he i nitiall y ra n d o mize d treat me nt as act uall y ta ke n 
(Malli nc kr o dt 2 0 1 3 ) i n t he mI T T p o p ulati o n. T his esti ma n d assesses t he treat me nt efficac y at 
wee k 1 2 attri b uta ble t o t h e i nitiall y ra n d o mize d me dicati o n.  
I nter-c urre nt  e ve nts (I C Es) t hat are e x pecte d t o affect t he efficac y e n d p oi nt will i ncl u de:  
1.  I nsta n ces w h ere a patie nt e x perie nces w ors e ni n g of ast h ma or a n ast h ma e x acer bati o n 
a n d t he patie nt is place d o n s yst e mic c ortic oster oi ds, or a d diti o nal ast h ma t hera p y 
treat me nt. I n s uc h cases, t he i n vesti gat ors will be i nstr ucte d t o e nc o ura ge t h e patie nt t o 
c o nti n ue i n t he st u d y a n d ret ur n f or pl a n ne d visits u ntil st u d y c o m pleti o n i n or der t o 
c ollect safet y d ata after a d diti o nal mai nte na nce treat me nts are use d. H o we v er, f or t hes e 
patie nts, i m pr o ve me nt i n F E V 1 w o ul d be e x pecte d as ra pi dl y as 1  da y after treat me nt 
wit h I C S ( Ker wi n et al 2 0 1 9 ) a n d wit hi n 1 wee k after a p atie nt recei ves t he I C S/ L A B A 
treat me nt (C orre n et al 2 0 0 7 , Pearl ma n et al 1 9 9 9 ). T he i ncl usi o n of data after a p atie nt 
recei v es alter nati ve me di cati o ns w o ul d p ote ntiall y bias t he treat me nt r es p o nse esti mates 
d ue t o i niti all y ra n d o mize d st u d y me dicati o ns. T heref ore, f or t he pri mar y a nal ysis, t he 
strate g y t o ha n dle t hese I C Es will be t o e x cl u de o bser vati o ns after t he use of ast h ma 
mai nte na nce me di cati o ns (re gar dless of a v aila bilit y of data o btai ne d after war ds).  
2.  C o nfir me d C O VI D -1 9 i nfecti o ns: Si nce C O VI D -1 9 is a k n o w n res pirat or y disease w hic h 
ca n a d v ersel y affect l u n g f u ncti o ns, as a res ult, t he sa me strate g y f or ha n dli n g s uc h I C Es 
will be a p plie d i n t he pri mar y a nal ysis. O bs er vati o ns t hat occ urre d aft er t h e dia g n osis of 
C O VI D -1 9 i nfecti o ns will n ot be use d i n t he pri mar y a nal ysis.  
T he p o p ulati o n -le vel s u m maries w o ul d be t he Ba yesia n esti mates of ( p ost eri or) mea n c ha n ges 
fr o m baseli ne at w ee k 1 2 f or t he treat me nt gr o u ps a n d c orres p o n di n g 9 5 % cre di ble i nter vals, as 
well as p osteri or pr o ba bilit y of treat me nt effect bet wee n eac h of t h e T E V -5 3 2 7 5 treat me nt 
gr o u ps vs place b o b ei n g greater t ha n 0, ie:  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 0  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
T a ble  1 : 
Pri o r P ar a meters f or t he L o n git u di n al M o del  
 
𝝁𝜶 
𝝈𝜶 
𝝁𝜷 
𝝈𝜷 
𝒂𝝀 
𝒃𝝀 
All visits  
0  
5  
0  
5  
0. 5  
0. 0 2  
T he pri ors f or t h e strata p ara meters will be pr o vi de d i n t he statistical a nal ysis pla n.  
T he p osteri or is e val u ate d usi n g M o nte Carl o Mar k o v C hai n ( M C M C) wit h i n di vi d ual 
para meters u p date d b y M etr o p olis Hasti n gs ( or Gi b bs sa m pli n g w here p ossi ble), usi n g o nl y t he 
𝑦𝑖 a n d 𝑦𝑖𝑡 data a v aila ble at t he ti me of t he u p date.  
Usi n g t he p osteri or f or eac h treat me nt gr o u p, t h e Ba yesia n esti mates of m ea n c ha n ges fr o m 
baseli ne at wee k  1 2 f or t he treat me nt gr o u ps a n d c orres p o n di n g 9 5 % cre di ble i nter vals ca n b e 
deri ve d. F urt her m ore, we calc ulate t he f oll o wi n g p osteri or pr o ba bilit y f or eac h T E V -5 3 2 7 5 d ose 
gr o u p:  
P osteri or pr o b a bility  ( T E V-5 3 2 7 5 treat me nt effect vs place b o > 0)  
B a yesi a n Fi n al A n al ysis S uccess R ule: A T E V -5 3 2 7 5 treat me nt gr o u p is c o nsi dere d t o ha ve 
pr o misi n g efficac y if it meets t he f oll o wi n g criteri o n at t he fi nal a nal ysis:  
P osteri or pr o b a bility  ( T E V-5 3 2 7 5 1 2 0 0  m g treat me nt effect vs place b o > 0 at fi nal a nal ysis) 
> 0. 8 5.  
S u p p orti ve A n al ysis:  T he fre q u e ntist a p pr oac h will be use d f or a n al yzi n g t he pri mar y efficac y 
e n d p oi nt as a s u p p orti ve a nal ysis. T h e sa me esti ma n d wit h res pect t o st u d y  p o p ulati o n, efficac y 
e n d p oi nt a n d I C Es al o n g wit h t he sa me ha n dli n g strate gies will be a p plie d. T he p o p ulati o n -le vel 
s u m mar y statistics will be t he least s q uares mea ns i n t he treat me nt gr o u ps deri ve d fr o m t he 
mi x e d -effects m o del f or re peat e d meas ures ( M M R M).  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 1  
T he M M R M m o del will i ncl u de baseli ne m or ni n g tr o u g h F E V 1, t he ra n d o mizati o n stratificati o n 
fact or (pri or t hera p y use), baseli ne e osi n o p hil c o u nt  visit ( wee ks 2, 4, 8, 1 2, a n d 1 6), treat me nt 
gr o u p, a n d visit -b y -treat me nt gr o u p i nteracti o ns. C o ntrasts f or pair wise treat me nt c o m paris o ns of 
i nterest will be c o nstr uct e d. T he u nstr uct ur e d c o v aria nce matri x will first be use d; h o we v er, i n 
case of c o n ver ge nce iss ues, t he c o m p o u n d s y m m etr y c o v aria n ce matri x str uct ure will be use d 
i nstea d. 
Missi n g data are e x pecte d t o occ ur d ue t o earl y dr o p o uts fr o m st u d y or “a n al ysis dr o p o uts” 
res ulti n g fr o m t he use of a d diti o nal or alter nati ve me dicati o ns a n d C O VI D-1 9 i nfecti o ns, as 
me nti o ne d a b o ve. We pla n t o use t he refere n ce -b as e d m ulti ple i m p utati o ns met h o d ( Malli nc kr o dt 
et al 2 0 1 7) t o ha n dle t he missi n g data pr o ble m. T his a p pr oac h i m p utes missi n g data base d o n 
re gressi o n m o dels fr o m t he place b o-treate d patie nt data, re prese nti n g a missi n g n ot at ra n d o m 
( M N A R) mec h a nis m. It is e x pecte d t o yiel d a c o nser vati ve treat me nt effect esti mate as c o m pare d 
t o t he esti mate o btai ne d fr o m m ulti ple i m p utati o ns ( MI) u n der a missi n g at ra n d o m ( M A R) 
mec ha nis m. T his a p pr oac h has rece ntl y bee n s uccessf ull y a p plie d i n a P has e 3 pe diatric trial 
c o m pari n g fl uticas o ne pr o pi o nate m ulti d ose dr y p o w der i n haler ( M D PI) wit h fl uticas o ne 
pr o pi o nate/sal meter ol M D PI ( St u d y F S S -A S -3 0 0 0 3). M ore det ails o n i m ple me nti n g t he 
refere nce-b ase d MI will be pr o vi de d i n t he pr ot oc ol a n d statistical a nal ysis pla n.  
T he R u bi n’s met h o d will be use d t o c o m bi ne esti mates fr o m m ulti pl y -i m p ute d datasets. T he fi nal 
esti mate d treat me nt differe nces will be prese nt e d t o get h er wit h t he 2 -si de d 9 0 % c o nfi de n ce 
i nter vals ( CI) a n d p -val u es.  
Se nsiti vit y A n al yses: T he pri mar y efficac y a n al ysis a n d s u p p orti ve a nal ysis will be re peat e d 
usi n g t he P P p o p ulati o n.  
Ot her se nsiti vit y a n al ys es will be c o n d ucte d b y e v al uati n g t he i m pact of missi n g data o n t he 
s u p p orti ve M M R M a nal ysis usi n g a 2-di me nsi o nal “ti p pi n g -p oi nt”, m ulti ple -i m p utati o n 
a p pr oac h u n d er t he M N A R ass u m pti o n. S hifts t o t he distri b uti o ns of missi n g o bser vati o ns i n 
b ot h t he place b o a n d acti ve treat me nt ar ms will be a p plie d t o re prese nt differe nt de grees of effect 
l osses. M ore details will be pr o vi de d i n t he statistical a nal ysis pla n. 
Se nsiti vit y a n al ysis usi n g all data, i ncl u di n g retrie ve d o bser vati o ns f oll o wi n g alter nati ve 
me dicati o n use will be r u n t o assess t he r o b ust ness of st u d y res ults t o a differe nt esti ma n d.  
Sec o n d ar y Effic ac y A n al ysis: F or t he o verall wee kl y ast h ma c o ntr ol stat us fr o m wee k 1 
t hr o u g h 1 2, t he wee kl y bi nar y e n d p oi nts fr o m wee k 1 t hr o u g h 1 2 will be a nal yze d usi n g t he 
re peat e d meas ur es l o gistic re gressi o n wit h treat me nt gr o u p, b aseli ne stat us, pri or t hera p y us e, 
wee k, a n d wee k -b y -treat me nt gr o u p i nteracti o ns i n t he m o del a n d wit h a n u nstr uct ure d 
c o varia n ce matri x. I n t h e case of c o n ver ge nce iss ues wit h t he u nstr uct ure d c o varia n ce f or m, t he 
e x c ha n gea ble c o varia n ce matri x will be use d. T he o verall pr o ba bilit y esti mate of wee kl y ast h ma 
c o ntr ol o ver 1 2 wee ks i n eac h tr eat me nt gr o u p,  as well as t he o verall esti mate of o d ds rati o of 
wee kl y ast h ma c o ntr ol o ver 1 2 wee ks, c o m pari n g eac h T E V -5 3 2 7 5 treat me nt gr o u p vers us 
place b o wit h c orres p o n di n g 9 5 % CI a n d p -val u e will be deri ve d . 
Usi n g t he mI T T a nal ysis set, eac h of t he f oll o wi n g sec o n da r y effi cac y e n d p oi nts will be 
s u m marize d descri pti vel y a n d a nal yz e d usi n g a M M R M i ncl u di n g baseli ne val ue, ra n d o mizati o n 
stratificati o n fact ors, visit/ wee k, treat me nt gr o u p, a n d visit/ wee k -b y -tr eat me nt gr o u p i nteracti o ns 
i n t he m o del wit h a n u nstr uct ure d c o varia n ce matri x:  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 2  
•  o verall c ha n ges fr o m b aseli ne i n wee kl y a v era ge of dail y m or ni n g tr o u g h ( pre -resc ue 
br o nc h o dilat or) F E V 1 as meas ure d b y h a n d hel d de vice o ver 1 2  wee ks fr o m wee k 1 
t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6 
•  o verall c ha n ges fr o m b a seli ne i n wee kl y a v era ge of resc u e me dicati o n use o ver 
1 2  wee ks fr o m wee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  c ha n ges fr o m baseli ne i n cli nic -base d sta n d ar dize d baseli ne -a dj uste d m or ni n g tr o u g h 
F E V 1 at wee k  1 6  
•  c ha n ges fr o m baseli ne i n A C Q -6 at wee ks  1 2 a n d 1 6  
•  c ha n ges fr o m baseli ne i n A C T at wee ks  1 2 a n d 1 6  
•  c ha n ges fr o m baseli ne i n A Q L Q( S) at w ee ks  1 2 a n d 1 6  
F or wee kl y bi nar y e n d p oi nts, s uc h as t he f oll o wi n g:  
•  pr o p orti o ns of patie nts w h o ac hie ve cli nic -base d F E V 1 ≥8 0 % pre dicte d at w ee ks  1 2, 
1 6, a n d at e n d p oi nt  
•  pr o p orti o ns of patie nts w h o ac hie ve f orce d e x pirat or y fl o w at 2 5 % t o 7 5 % of f orce d 
vital ca pacit y  ( F V C) ( F E F2 5 -7 5) ≥7 0 % pre dicte d at wee ks  1 2, 1 6, a n d at e n d p oi nt  
•  pr o p orti o ns of patie nts w h o ac hie ve F E V 1: F V C rati o ≥0. 8 0 at wee ks 1 2, 1 6,  a n d at 
e n d p oi nt  
T he re p eate d meas ures l o gistic re gressi o n m o del wit h treat me nt gr o u p, c orres p o n di n g b aseli ne 
para meter val ue, pri or t h era p y use, wee k, a n d wee k -b y -treat me nt gr o u p i nteracti o ns i n t he m o del 
a n d wit h a n u nstr uct ure d c o varia n ce matri x will be  use d. I n t he case of c o n v er ge nce iss ues wit h 
t he u nstr uct ure d c o v aria n ce f or m, t he e x c ha n gea bl e c o vari a nce m atri x will be use d. T he wee kl y 
pr o ba bilit y esti mates of ac hie vi n g t h e i m pr o ve me nt criteri o n i n eac h treat m e nt gr o u p, as well as 
t he esti mates of wee kl y o d ds rati os c o m pari n g eac h T E V -5 3 2 7 5 treat me nt gr o u p v ers us place b o 
wit h c orres p o n di n g 9 5 % CI a n d p -val ues will be deri ve d.  
All re peate d m eas ur es m o del will be r u n i ncl u di n g meas ure me nts at all visits/ wee ks t hr o u g h 
wee k 1 6.  
F or c h a n ges fr o m baseli n e i n wee kl y a v era ge of resc ue me dicati o n use o v er 1 2 wee ks fr o m 
wee k  1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6, a n d c ha n ges fr o m baseli ne i n 
perce nt a ge of ast h ma c o ntr ol da ys ( n o s y m pt o ms a n d n o resc ue m e dicati o n use) o ver 1 2 wee ks 
fr o m wee k 1 t hro u g h 1 2 a n d  o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6, Wilc o x o n ra n k-s u m test 
will be use d stratifie d o n ra n d o mizati o n stratificati o n fact ors.  
T he fre q u e nc y of C A Es will be a nal yze d usi n g a ne gati ve bi n o mial re gressi o n met h o d i ncl u di n g 
ra n d o mizati o n stratificati o n fact ors a n d treat me nt gr o u p i n t he m o del a n d t he l o garit h m of 
f oll o w-u p ti me as a n offs et varia ble. T h e rati o of C A E rate bet w ee n t he treat me nt gr o u ps a n d its 
9 5 % CI will be esti mate d fr o m t he ne gati ve bi n o mial re gressi o n m o del. Treat me nt effects will be 
teste d usi n g t he li keli h o o d-base d C hi -s q uare test. 
T he Ka pla n -Meier m et h o d will be use d t o esti mate a n d c o m pare t he distri b uti o ns of ti me t o t he 
first C A E bet wee n tr eat me nt gr o u ps. Distri b uti o n differe n ce will be c o m pare d b y a l o g ra n k test 
a dj usti n g f or t he ra n d o mi zati o n stratificati o n fact ors. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M ulti ple C o m p aris o ns a n d M ulti plicit y: N o a dj ust me nts will be ma de f or t he pre pla n ne d 
m ulti ple c o m paris o ns/e n d p oi nts.  
S afet y A n al yses: T he safet y of T E V -5 3 2 7 5 will be assesse d t hr o u g h o ut t he st u d y b y e v al uati n g 
a d verse e ve nts, cli nical l a b orat or y test res ults, vital si g ns meas ure me nts, el ectr ocar di o gra m 
( E C G) fi n di n gs, p h ysi cal e x a mi nati o n res ults, l ocal t olera bilit y a n d pai n, a n d c o nc o mita nt 
me dicati o n usa ge. Pr ot oc ol -defi ne d a d v erse e ve nts of s pecial i nterest ( P D A E SI) i ncl u d e s yste mic 
se vere reacti o ns (i ncl u di n g a n a p h yla xis), i njecti o n site fi n di n gs, o p p ort u nistic i nfecti o ns, 
hel mi nt h i nfecti o ns, a n d mali g na n cies.  
Safet y a nal yses will be perf or me d o n t h e safet y a n al ysis set.  
All a d verse e ve nts will be c o de d usi n g t he Me di cal Di cti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). E ac h patie nt will be c o u nte d o nl y o n ce i n eac h preferre d ter m or s yste m or ga n class 
( S O C) cate g or y f or t he a nal yses of safet y. S u m maries will be prese nt e d f or all treat me nt-
e mer ge nt a d v erse e ve nts ( o verall a n d b y s e verit y), a d verse e ve nts deter mi ne d b y t h e i n vesti gat or 
t o be relate d t o test I M P/ n o n-I M P (ie, reas o na ble p ossi bilit y) ( d efi ne d as relate d or wit h missi n g 
relati o ns hi p) ( o verall a n d b y se v erit y), seri o us a d v erse e v e nts, a n d a d v erse e ve nts ca usi n g 
wit h dr a wal fr o m t he st u d y. S u m maries will be prese nte d b y treat me nt gr o u p a n d f or all patie nts. 
Patie nt listi n gs of all a d verse e v e nts, seri o us a d v erse e ve nts a n d a d verse e v e nts lea di n g t o 
wit h dra wal will be prese nte d.  
Val ues a n d c h a n ges fr o m baseli ne i n cli nica l la b orat or y, E C G, a n d vital si g ns meas ure me nt dat a 
(i ncl u di n g t he i nci d e nce of a b n or malities) will be s u m marize d descri pti vel y. 
L ocal t olera bilit y at t he i njecti o n site (er yt he ma, ecc h y m osis, i n d urati o n, te n der ness, w ar mt h, 
a n d s welli n g, a n d pai n) will be  assesse d usi n g sta n dar dize d scales a n d s u m marize d descri pti vel y.  
T he use of c o nc o mita nt me dicati o ns will be s u m marize d b y t hera pe utic class usi n g des cri pti ve 
statistics. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 4  
F or c o nti n u o us varia bles, descri pti ve statistics ( n, mea n, sta n dar d de viati o n [ S D], sta n dar d err or, 
me dia n, mi ni m u m, a n d ma xi m u m) will be pr o vi de d f or act ual val ues a n d c ha n ges fr o m baseli ne 
t o eac h ti me p oi nt. F or cate g ori cal varia bles, patie nt c o u nts a n d perce nta ges will be pr o vi de d. 
P h ar m a c o ki netic A n al ysis:  S u m maries of T E V -5 3 2 7 5 ser u m c o nce ntrati o ns will be prese nte d 
b y n o mi nal ti me p oi nt a n d d ose. Pl ots of i n di vi d ual T E V -5 3 2 7 5 ser u m c o n ce ntrati o ns will be 
prese nte d b y act ual da y (li near a n d l o g scales). Pl ots of mea n or me dia n T E V -5 3 2 7 5 ser u m 
c o nce ntr ati o ns will be prese nte d b y n o mi n al da y (li near a n d l o g scales).  
P h ar m a c o d y n a mi c/ Bi o m a r ker A n al ysis: Bl o o d e osi n o p hil c o u nt a n d ser u m I L -5 (free a n d 
t otal) le vels will be s u m marize d b y tr eat me nt a n d ti me p oi nt usi n g descri pti ve statistics. 
I n di vi d ual dat a will be liste d. 
 
 
 
 
 
I m m u n o ge nicit y A n al ysis: A nti -T E V -5 3 2 7 5 a nti b o d y i nf or m ati o n, n u m ber a n d perce nt of 
patie nts p ositi ve f or A D A a n d t heir a nti b o d y titers, a n d t h e n u m ber of A D A p ositi ve patie nts 
w h o are p ositi ve f or ne utralizi n g a nti b o d y, will be descri be d. T h e i m pact of t he prese n ce of A D A 
o n p har mac o ki netics, effi cac y, a n d cli nical safet y will be e val uate d, if a p pr o priate, a n d res ults 
will be pr o vi de d i n t he cli nical st u d y re p ort.  
A ncill ar y St u dies A n al ysis:  D uri n g t he r u n -i n a n d treat me nt peri o ds of t his st u d y, patie nts will 
be s u p plie d wit h Pr o Air Di gi haler. Data fr o m t hes e i n halers will be c ollecte d ce ntrall y.  
 
 
 
 
 
 
 
Pl a n ne d I nteri m A n al ysis:  T he fi nal pri mar y effi cac y a nal yses will be perf or me d w he n all 
patie nts ha ve c o m plete d V 9 ( wee k 1 6) or wit h dra w n fr o m t he st u d y. A n u n bli n de d i nteri m 
a nal ysis is pla n ne d, w he n a p pr o xi matel y 1 2 0 patie nts ( 4 0 patie nts per ar m) ha ve c o m plete d t h e 
wee k 8 visit or wit h dra w n fr o m  t he st u d y, t o ass ess t he earl y efficac y data. T he o bjecti ves of t he 
u n bli n de d i nteri m a nal ysis are 1) t o det ect a n  earl y efficac y s uccess  si g nal; 2) t o c o n d uct a 
f or mal f utilit y a n al ysis, a n d; 3) t o e val uate earl y st o p pi n g criteria.  
It is of n ote t hat me eti n g t he i nteri m efficac y s uccess criteri o n will n ot res ult i n ter mi nati n g t he 
st u d y earl y. T he earl y efficac y s uccess r es ult, c o m bi ne d wit h satisfact or y safet y d ata, ma y assist 
wit h pre parati o n / i nitiati o n of f urt her safet y a n d efficac y st u dies , a n d e n a ble c o m m u nicati o ns  
wit h re g ul at or y a ge ncies re gar di n g f urt her cli nical de vel o p me nt. H o we v er, meeti n g t he st u d y 
f utilit y criteri o n ma y res ult i n earl y ter mi nati o n of t he st u d y d u e t o f utilit y. 
At t he ti me of t he i nteri m a nal ysis, a bli n de d safet y a n al ysis will be c o n d ucte d . If t here is a n y 
safet y si g nal of c o n cer n at t he ti me of t he i nteri m a nal ysis, u n bli n de d safet y a nal ys es ma y be 
warra nte d. 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 5  
 
 
 
 
 
 
F urt her, d ue t o c halle n ges i n patie nt e nr ol lme nt i n t he face of t he C O VI D -1 9  pa n de mic, t he 
feasi bilit y of a n earl y st o p pi n g of t he tri al wit h s maller sa m ple siz es ma y als o be e val uate d 
d uri n g t he i nteri m a nal ysis. T he feasi bilit y a nal ysis will be  descri be d i n t he statistical a nal ysis 
pla n.  
F or t he earl y effic ac y s uccess a n d f utilit y a nal ysis, t h e wee k 8 efficac y e n d p oi nt, ie,  c ha n ge fr o m 
baseli ne at wee k 8 i n m or ni n g tr o u g h F E V 1, will be  a nal yz e d. T he s a me Ba yesia n a n al ysis f or 
t he fi nal pri mar y effic ac y a nal ysis will be a p plie d, a n d b ot h t he earl y s u ccess a n d f utilit y criteria 
will be  base d o n t he deri ve d p o steri or pr o b a bilit y of t he T E V-5 3 2 7 5 d os e gr o u p perf or mi n g 
better t ha n t he pla ce b o i n i m pr o vi n g t he wee k 8 e n d p oi nt.  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 6  
 
 
 
 
 
 
 
 
T he e x ec uti o n of t he u n bli n de d i nteri m a nal ysis  
T he u n bli n de d i nteri m a n al ysis will be c o n d u cte d b y i n de pe n de nt, u n bli n de d st atisticia n(s)  a n d 
pr o gra m mer(s) w h o are n ot part of t he st u d y t ea m, f oll o wi n g t he pre -s pecifi e d al g orit h ms a n d 
rules. A n i n de pe n d e nt u n bli n de d data re vie w c o m mittee will be set u p t o re vie w t he u n bli n de d 
i nteri m efficac y a n al ysis res ults. A gr o u p of t he s po ns or’s ma na ge m e nt tea m, w h o are n ot a part 
of t he st u d y te a m, ma y h a ve access t o t he u n bli n d e d i nteri m a nal ysis res ults. I n or der t o mai ntai n 
t he st u d y bli n d a n d t he st u d y c on d u ct i nte grit y, a data re vie w c harter will b e fi nalize d pri or t o t he 
i nteri m a nal ysis, w hic h s pecifies t he pr o cesses f or sec urel y u n bli n di n g t he i nteri m a nal ysis 
res ults. T he pr ocesses will be f oll o we d t o e ns ure t hat t he st u d y bli n d will be mai ntai ne d i n t he 
bli n de d st u d y pers o n n el w h o are i n v ol ve d i n ma n a gi n g t he st u d y acti vities u nt il t he st u d y is 
u n bli n de d at t he fi nal a nal ysis.  T his c harter will als o detail t he bli n de d safet y re vie w.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 7  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
D O C U M E N T HI S T O R Y .................................................................................................................2  
S P O N S O R P R O T O C O L A P P R O V A L  ...........................................................................................3  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................4  
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 ...............................................................................5  
T A B L E O F C O N T E N T S  ...............................................................................................................2 7  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ................................................3 4  
1.  
I N T R O D U C TI O N A N D B A CK G R O U N D I N F O R M A TI O N  ..................................3 9  
1. 1.  
I ntr o d u cti o n .................................................................................................................3 9  
1. 1. 1.  
I nterle u ki n 5 ................................................................................................................3 9  
1. 1. 2.  
T E V -5 3 2 7 5  .................................................................................................................3 9  
1. 1. 3.  
T E V -5 3 2 7 5 a n d Ast h ma  .............................................................................................3 9  
1. 1. 4.  
P ur p ose of t he St u d y  ...................................................................................................4 0  
1. 2.  
Fi n di n gs fr o m N o ncli nic al a n d Cli nical St u dies  .........................................................4 0  
1. 2. 1.  
N o ncli nical St u dies  .....................................................................................................4 0  
1. 2. 1. 1.  
P har mac ol o g y  .............................................................................................................4 0  
1. 2. 1. 2.  
P har mac o ki netics  ........................................................................................................4 0  
1. 2. 1. 3.  
N o ncli nical Safet y  ......................................................................................................4 1  
1. 2. 2.  
Cli nical St u dies  ...........................................................................................................4 2  
1. 2. 2. 1.  
St u d y T V 5 3 2 7 5 -P K -1 0 1 5 2  .........................................................................................4 2  
1. 3.  
K n o w n a n d P ote ntial Be nefits a n d Ris ks t o Patie nts  ..................................................4 4  
1. 3. 1.  
K n o w n a n d P ote ntial Be nefits a n d Ris ks of t he Test I n v esti gati o nal 
Me dici nal Pr o d uct(s)  ..................................................................................................4 4  
1. 3. 2.  
O vera ll Be nefit a n d Ris k Assess me nt f or T his St u d y ................................................4 5  
2.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  ..............................................................4 6  
2. 1.  
Pri mar y a n d Sec o n dar y O bjecti ves a n d E n d p oi nts  .....................................................4 6  
2. 1. 1.  
J ustificati o n of Pri mar y E n d p oi nt ...............................................................................4 7  
2. 2.  
 .......................................................................4 7  
3.  
S T U D Y D E SI G N  .......................................................................................................5 0  
3. 1.  
Ge neral St u d y D esi g n a n d St u d y Sc h e matic Dia gra m  ...............................................5 0  
3. 2.  
Pla n ne d N u m ber of Patie nts a n d C o u ntries  ................................................................5 4  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 8  
3. 3.  
J ustificati o n f or St u d y D esi g n a n d Selecti o n of P o p ulati o n .......................................5 4  
3. 4.  
St o p pi n g R ules f or t he St u d y  ......................................................................................5 6  
3. 5.  
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts  ........................................................5 6  
4.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  ..............................................6 3  
4. 1.  
Patie nt I ncl usi o n Criteria  ............................................................................................6 3  
4. 2.  
Patie nt E x cl usi o n Criteria  ...........................................................................................6 4  
4. 3.  
Ra n d o mizati o n Criteria  ...............................................................................................6 6  
4. 4.  
W it h dra wal Criteria a n d Pr oce d ures f or t he Patie nt ...................................................6 7  
4. 5.  
Re place me nt of Patie nts  .............................................................................................6 8  
4. 6.  
Rescree ni n g  .................................................................................................................6 8  
4. 7.  
Scree ni n g Fail ure  ........................................................................................................6 9  
5.  
T R E A T M E N T S  ..........................................................................................................7 0  
5. 1.  
I n v esti gati o nal Me dici nal Pr o d ucts Use d i n t he St u d y ...............................................7 0  
5. 1. 1.  
Test I n v esti gati o nal Me dici nal Pr o d uct  ......................................................................7 0  
5. 1. 2.  
Place b o I n vesti gati o nal Me dici nal Pr o d uct  ................................................................7 0  
5. 2.  
Pre parati o n, H a n dli n g, La beli n g, St ora ge, a n d Acc o u nta bilit y f or I M Ps  ...................7 1  
5. 2. 1.  
St ora ge a n d Sec urit y  ...................................................................................................7 1  
5. 2. 2.  
La b eli n g  ......................................................................................................................7 1  
5. 2. 3.  
Acc o u nta bilit y  .............................................................................................................7 2  
5. 3.  
J ustificati o n f or I n vesti gati o nal Me dici nal Pr o d ucts ..................................................7 2  
5. 3. 1.  
J ustificati o n f or D ose of Test I n v esti gati o nal Me dici nal Pr o d uct ..............................7 2  
5. 3. 2.  
J ustificati o n f or Use of Place b o I n v esti gati o nal Me dici nal Pr o d uct  ..........................7 3  
5. 4.  
Ot her Me dici nal Pr o d ucts/ N o n -I n vesti gati o nal Me dici nal Pr o d ucts ..........................7 3  
5. 5.  
Treat me nt Aft er t he E n d of t he St u d y  .........................................................................7 3  
5. 6.  
Restricti o ns  .................................................................................................................7 4  
5. 6. 1.  
Acti vit y  .......................................................................................................................7 4  
5. 6. 2.  
T o bacc o  .......................................................................................................................7 4  
5. 6. 3.  
Bl o o d D o nat i o n ...........................................................................................................7 4  
5. 7.  
Pri or a n d C o nc o mita nt Me dicati o n or T hera p y  ..........................................................7 4  
5. 8.  
Pr oce d ures f or M o nit ori n g Patie nt C o m plia nce  .........................................................7 4  
5. 9.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................7 5  
5. 1 0.  
Mai nte na nce of Ra n d o mizati o n a n d Bli n di n g  ............................................................7 5  
5. 1 0. 1.  
Mai nte na nce of Ra n d o mizati o n  ..................................................................................7 5  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
2 9  
5. 1 0. 2.  
Bli n di n g a n d U n bli n di n g  ............................................................................................7 5  
5. 1 1.  
T otal Bl o o d V ol u me  ...................................................................................................7 6  
6.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................7 7  
6. 1.  
Assess me nts of Efficac y  .............................................................................................7 7  
6. 1. 1.  
P ul m o nar y F u ncti o n Testi n g .......................................................................................7 7  
6. 1. 2.  
Cli nical Ast h ma E x acer bati o n  ....................................................................................7 8  
6. 1. 3.  
Ast h ma C o ntr ol Da ys  .................................................................................................7 8  
6. 1. 4.  
Ast h ma C o ntr ol Test  ...................................................................................................7 8  
6. 1. 5.  
Ast h ma S y m pt o m Sc ore  .............................................................................................7 8  
6. 1. 6.  
Ast h ma Resc ue Me dic ati o n Use  .................................................................................7 9  
6. 1. 7.  
Ast h ma C o ntr ol C o m p osite Sc ore  ..............................................................................7 9  
6. 1. 8.  
Sta n dar dize d Ast h ma Q ualit y of Lif e Q uesti o n nair e  ..................................................8 0  
6. 1. 9.  
Ast h ma C o ntr ol Q uesti o n naire  ...................................................................................8 0  
6. 1. 1 0.  
 .......................................................................................8 0  
6. 1. 1 1.  
 .....................................................................8 0  
7.  
A S S E S S M E N T O F S A F E T Y  .....................................................................................8 1  
7. 1.  
A d verse E v e nts  ...........................................................................................................8 1  
7. 1. 1.  
Defi niti o n of a n A d verse E ve nt  ..................................................................................8 1  
7. 1. 2.  
Rec or di n g a n d Re p orti n g of A d verse E ve nts  .............................................................8 2  
7. 1. 3.  
Se verit y of a n A d v erse E ve nt  .....................................................................................8 2  
7. 1. 4.  
Relati o ns hi p of a n A d verse E ve nt t o t he I n vesti gati o nal Me dici nal Pr o d uct  .............8 3  
7. 1. 5.  
Seri o us A d verse E v e nts  ..............................................................................................8 3  
7. 1. 5. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  .......................................................................8 3  
7. 1. 5. 2.  
E x pecte d ness  ...............................................................................................................8 4  
7. 1. 5. 3.  
Re p orti n g a Seri o us A d v erse E ve nt  ............................................................................8 5  
7. 1. 6.  
Pr ot oc ol -Defi ne d A d vers e E ve nts of S pecial I nterest f or Re p orti n g t o t he 
Gl o bal Patie nt Safet y & P har mac o vi gila nce De part me nt  ..........................................8 7  
7. 1. 7.  
Pr ot oc ol -Defi ne d A d vers e E ve nts of S pecial I nterest t hat d o n ot Re q uire 
Re p orti n g t o t he Gl o bal Patie nt Safet y & P har m ac o vi gila n ce De part me nt  ...............8 7  
7. 1. 8.  
Pr ot oc ol De viati o ns Beca use of a n A d verse E v e nt  ....................................................8 7  
7. 2.  
Pre g n a nc y  ...................................................................................................................8 7  
7. 3.  
Me dicati o n Err or a n d S pecial Sit uati o ns Relate d t o t he I n v esti gati o nal 
Me dici nal Pr o d ucts  .....................................................................................................8 8  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 0  
7. 4.  
Cli nical La b orat or y Tests  ...........................................................................................8 9  
7. 4. 1.  
Ser u m C he mistr y, He m at ol o g y, a n d Uri nal ysis  .........................................................8 9  
7. 4. 2.  
Ot her Cli nical La b orat or y Tests  .................................................................................9 0  
7. 4. 2. 1.  
Ser ol o g y T ests  ............................................................................................................9 0  
7. 4. 2. 2.  
F ollicle Sti m ulati n g H or m o ne  ....................................................................................9 0  
7. 4. 2. 3.  
H u ma n C h ori o nic G o na d otr o pi n Tests  .......................................................................9 0  
7. 4. 2. 4.  
C O VI D -1 9 Testi n g  .....................................................................................................9 0  
7. 5.  
P h ysical E x a mi nati o ns  ................................................................................................9 1  
7. 6.  
V ital Si g ns ..................................................................................................................9 1  
7. 7.  
Electr ocar di o gra p h y  ....................................................................................................9 1  
7. 8.  
Assess me nt of L ocal T ol era bilit y a n d Pai n  ................................................................9 2  
8.  
A S S E S S M E N T O F P H A R M A C O KI N E TI C S, I M M U N O G E NI CI T Y, 
BI O M A R K E R S, A N D P H A R M A C O G E N E TI C S  ....................................................9 4  
8. 1.  
P har mac o ki netic Assess me nt  ......................................................................................9 4  
8. 2.  
 .................................................................................9 4  
8. 3.  
I m m u n o ge nicit y ..........................................................................................................9 4  
8. 4.  
 .....................................................................9 5  
8. 4. 1.  
P har mac o d y na mic a n d Bi o mar ker Meas ures  .............................................................9 5  
8. 5.  
P har mac o ge n etic Assess me nt  .....................................................................................9 5  
9.  
S T A TI S TI C S  ..............................................................................................................9 6  
9. 1.  
Sa m ple Siz e a n d P o wer C o nsi derati o ns  .....................................................................9 6  
9. 2.  
A nal ysis Sets  ...............................................................................................................9 6  
9. 2. 1.  
I nte nt-t o-Treat A nal ysis Set  ........................................................................................9 6  
9. 2. 2.  
M o difie d I nte nt -t o-Treat A nal ysis Set  ........................................................................9 7  
9. 2. 3.  
Safet y A nal ysis Set  .....................................................................................................9 7  
9. 2. 4.  
Per -Pr ot oc ol A nal ysis Set  ...........................................................................................9 7  
9. 2. 5.  
P har mac o ki netic A n al ysis Set  ....................................................................................9 7  
9. 2. 6.  
A nti -dr u g A nti b o d y A n al ysis Set  ...............................................................................9 7  
9. 3.  
Data Ha n dli n g C o n ve nti o ns  ........................................................................................9 7  
9. 3. 1.  
Ha n dli n g Wit h dra wals a n d Missi n g Data  ...................................................................9 7  
9. 4.  
St u d y P o p ulati o n  .........................................................................................................9 7  
9. 4. 1.  
Patie nt Dis p ositi o n  ......................................................................................................9 7  
9. 4. 2.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................9 8  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 1  
9. 5.  
Efficac y A nal ysis  ........................................................................................................9 8  
9. 5. 1.  
Pri mar y Efficac y E n d p oi nts  ........................................................................................9 8  
9. 5. 2.  
Sec o n dar y Efficac y E n d p oi nts  ....................................................................................9 8  
9. 5. 3.  
 ......................................................................................9 9  
9. 5. 4.  
Pla n ne d Met h o d of A nal ysis  .....................................................................................1 0 1  
9. 5. 4. 1.  
Pri mar y Efficac y A nal ysis  ........................................................................................1 0 1  
9. 5. 4. 2.  
Se nsiti vit y/ S u p p orti ve A nal ysis ................................................................................1 0 3  
9. 5. 4. 3.  
Sec o n dar y Efficac y A nal ysis  ....................................................................................1 0 4  
9. 5. 4. 4.  
 ..................................................................................1 0 5  
9. 6.  
M ulti ple C o m paris o ns a n d M ulti plicit y ....................................................................1 0 5  
9. 7.  
Safet y a n d T olera bilit y A nal ysis  ..............................................................................1 0 6  
9. 8.  
P har mac o ki netic A n al ysis  ........................................................................................1 0 6  
9. 9.  
P har mac o d y na mic/ Bi o mar ker A nal ysis  ...................................................................1 0 7  
9. 1 0.  
 .......................................1 0 7  
9. 1 1.  
I m m u n o ge nicit y A n al ysis .........................................................................................1 0 7  
9. 1 2.  
A ncillar y St u dies A nal ysis  .......................................................................................1 0 7  
9. 1 3.  
Pla n ne d I nteri m A nal ysis  ..........................................................................................1 0 7  
9. 1 3. 1.  
T he U n bli n de d I nteri m Efficac y A nal ysis  ................................................................1 0 8  
9. 1 4.  
Re p orti n g D e viati o ns fr o m t he Statistical Pla n  ........................................................1 0 9  
1 0.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .......................................1 1 0  
1 1.  
C O M P LI A N C E S T A T E M E N T  ................................................................................1 1 0  
1 2.  
D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  ............................................1 1 1  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  ...........................................................................1 1 1  
1 4.  
P U B LI C A TI O N P O LI C Y  ........................................................................................1 1 1  
1 5.  
R E F E R E N C E S  .........................................................................................................1 1 2  
1 6.  
S U M M A R Y O F C H A N G E S T O P R O T O C O L  .......................................................1 1 7  
1 6. 1.  
A me n d me nt 0 1 Date d 1 7 N o ve m ber 2 0 2 1  ...............................................................1 1 7  
1 6. 2.  
A d mi nistrati ve Letter 0 1 Date d 2 3 Marc h 2 0 2 1  .......................................................1 2 9  
A P P E N DI X  A.  C LI NI C A L L A B O R A T O RI E S A N D O T H E R D E P A R T M E N T S A N D 
I N S TI T U TI O N S .......................................................................................................1 3 2  
A P P E N DI X  B.  S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S B Y VI SI T  .........................1 3 3  
A P P E N DI X  C.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ..............................1 4 2  
A P P E N DI X  D.  E T HI C S  ...........................................................................................................1 4 4  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 2  
A P P E N DI X  E.  L O S T T O F O L L O W -U P  .................................................................................1 4 5  
A P P E N DI X  F.  LI S T O F I N H A L E D C O R T I C O S T E R OI D T H E R A P Y RE Q UI R E D 
F O R I N C L U SI O N I N T O T H E R U N -I N P E RI O D ..................................................1 4 6  
A P P E N DI X  G.  LI S T O F P R O HI BI T E D M E DI C A TI O N S  .....................................................1 4 7  
A P P E N DI X  H.  C LI NI C A L C RI T E RI A F O R DI A G N O SI N G A N A P H Y L A XI S  ...................1 4 8  
A P P E N DI X  I. LI S T O F E X A M P L E S O F O P P O R T U NI S TI C I N F E C T I O N S .......................1 4 9  
A P P E N DI X  J. P H A R M A C O G E N E TI C A S S E S S M E N T S  ......................................................1 5 1  
A P P E N DI X  K.  P R O D U C T C O M P L AI N T S  ............................................................................1 5 2  
A P P E N DI X  L.  D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  ....................................1 5 4  
A P P E N DI X  M.  P U B LI C A TI O N P O LI C Y  ..............................................................................1 5 7  
A P P E N DI X  N.  M A N A G E M E N T O F S T U D Y A C TI VI TI E S D U RI N G C O VI D -1 9 
O U T B R E A K S  ..........................................................................................................1 5 8  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 3  
LI S T O F T A B L E S  
Ta ble  1:  
Pri or Para meters f or t he L o n git u di nal M o del  .............................................................2 0  
Ta ble  2:  
St u d y Pr oce d ures a n d Assess me nts  ............................................................................5 7  
Ta ble  3:  
I n v esti gati o nal Me dici nal Pr o d ucts Use d i n t he St u d y ...............................................7 1  
Ta ble  4:  
T he Relati o ns hi p of a n A d verse E ve nt t o t he I M P S us pects  ......................................8 3  
Ta ble  5:  
Cli nical La b orat or y Tests  ...........................................................................................9 0  
Ta ble  6:  
Se verit y Assess me nt of L ocal T olera bilit y  .................................................................9 3  
Ta ble  7:  
Pri or Para meters f or t he L o n git u di nal M o del  ...........................................................1 0 2  
 
 ............1 0 9  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
O verall St u d y Sc h e matic Dia gra m  .............................................................................5 4  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
A b bre vi ati o n  
Ter m  
β -H C G  
beta h u ma n c h ori o nic g o na d otr o pi n  
A C Q  
Ast h ma C o ntr ol Q uesti o n naire  
A C T  
Ast h ma C o ntr ol T est  
A D A  
a nti -dr u g a nti b o d y/a nti b o dies  
A E SI  
a d verse e ve nt(s) of s pecial i nt erest  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A Q L Q( S)  
Sta n dar dize d Ast h ma Q ualit y of Life Q uesti o n naire  
A S T  
as partate a mi n otra nsferase  
A T S  
A merica n T h oracic S ociet y  
A U C  
area u n der t he c o nce ntrati o n -ti me c ur ve 
A U C 0 – 2 8 d 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 8 da ys 
A U C 0 -∞ 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y 
A U C 0 – t 
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he last meas ura ble 
c o nce ntrati o n  
A U C τ 
area u n der t he c o nce ntrati o n -ti me c ur ve d uri n g a d osi n g i nter val  
B P  
bl o o d press ure  
C A E  
cli nical ast h ma e xacer bati o n  
C B C  
c o m plete bl o o d c o u nt  
C D C  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n  
C D M S  
cli nical data ma na ge me nt s yst e m  
C F R  
C o de of Fe deral Re g ulati o ns ( U S)  
CI  
c o nfi de nce i nter val  
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
C L/ F  
a p pare nt cleara nce  
C ma x  
ma xi m u m o bser ve d dr u g c o nc e ntrati o n  
C M V  
c ha n ge of me dicati o n visit  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C P K  
creati ne p h os p h o ki nase  
C R F  
case re p ort f or m  
C R O  
Cli nical Researc h Or ga nizati o n  
C R S w N P  
c hr o nic r hi n osi n usitis wit h nas al p ol y p osis  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 5  
A b bre vi ati o n  
Ter m  
C S R  
cli nical st u d y re p ort  
D  
da y  
D N A U C 0 -t  
d ose n or malize d area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
meas ura ble c o nce ntrati o n  
D N A U C 0 -∞ 
d ose n or malize d area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y 
D N C ma x  
d ose n or malize d ma xi m u m o bser ve d dr u g c o nce ntrati o n  
D o R  
da y of ra n d o miz ati o n  
D R F  
d ose -ra n ge fi n di n g 
E C G  
electr ocar di o gra p h y, electr ocar di o gra m  
E D N  
e osi n o p hil -deri ve d ne ur ot o xi n  
E G P A  
e osi n o p hilic gra n ul o mat osis wit h p ol ya n giitis ( C h ur g -Stra uss s y n dr o me)  
e M D PI 
electr o nic m ulti d ose dr y p o w d er i n haler  
E o T V  
e n d of treat me nt visit  
E Q -5 D -5 L  
E ur o pea n Q ualit y of Life 5 -di me nsi o n healt h state utilit y i n de x ( 5 -le vel versi o n) 
E R S  
E ur o pea n Res pirat or y S ociet y  
E T  
earl y ter mi nati o n visit  
E U  
E ur o pea n U ni o n  
E V  
E u dra Vi gila nce  
Fc  
cr ystalliza ble fra g me nt  
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
F E F 2 5 -7 5 
f orce d e x pirat or y fl o w at 2 5 % t o 7 5 % of F V C  
F E V 1 
f orce d e x pirat or y v ol u me i n 1 sec o n d 
F S H  
f ollicle sti m ulati n g h or m o ne 
F V C  
f orce d vital ca p acit y 
G C P  
G o o d Cli nical Practice  
GI N A  
Gl o bal I nitiati ve f or Ast h ma  
G L P  
G o o d La b orat or y Practice  
G M -C S F  
gra n ul oc yte macr o p ha ge c ol o n y -sti m ulati n g fact or 
G P S P  
Gl o bal P atie nt Safet y a n d P har mac o vi gila nce  
H Bs A g  
he p atitis B s urface a nti ge n  
H C V  
he p atitis C vir us  
H E E N T  
hea d, e yes, ears, n ose, a n d t hr oat  
H F A  
h y dr ofl u or oal ka ne  
HI V  
h u ma n i m m u n o deficie nc y vir us  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 6  
A b bre vi ati o n  
Ter m  
H S P  
h yster osal p y n g o gra m  
I B 
I n vesti gat or’s Br oc h ure  
I C5 0 
c o nce ntrati o n res ulti n g i n 5 0 % re d ucti o n of ma xi mal i n hi bit or y effect  
I C9 0 
c o nce ntrati o n res ulti n g i n 9 0 % re d ucti o n of ma xi mal i n hi bit or y effect  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n H ar m o nisati o n 
I C S 
i n hale d c ortic oster oi ds 
I E C 
I n de p e n de nt Et hics C o m mitte e 
I g 
i m m u n o gl o b uli n 
I L-5  
i nterle u ki n 5 
I L-5 R α  
i nterle u ki n 5 rece pt or s u b u nit α 
I L C 2 
gr o u p 2 i n nate l y m p h oi d cells  
I M P 
i n vesti gati o nal me dici nal pr o d uct  
I N D 
I n vesti gati o nal Ne w Dr u g 
I N N 
i nter nati o nal n o n pr o prietar y na me 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I T T 
i nte nt-t o-treat 
I U D 
i ntra uteri ne de vice 
I U S 
i ntra uteri ne h or m o ne-releasi n g s yste m 
i v 
i ntra ve n o us 
K D  
e q uili bri u m diss ociati o n c o nst a nt  
L A B A  
l o n g-acti n g β 2 a g o nist  
L A M A  
l o n g-acti n g m uscari nic a nta g o nist  
L RI  
l o wer res pirat or y i nfecti o n 
L S O  
l ocal safet y officer 
m A b  
m o n ocl o nal a nti b o d y  
M A D  
m ulti ple asce n di n g d ose  
M A R  
missi n g at ra n d o m  
M DI  
metere d -d ose i n haler  
M D PI  
m ulti d ose dr y p o w der i n haler  
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
MI  
m ulti ple i m p utati o ns  
MI D  
mi ni mal i m p orta nt differe nce  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 7  
A b bre vi ati o n  
Ter m  
mI T T  
m o difie d i nte nt -t o-treat 
M M R M  
mi xe d -effects m o del f or re peate d meas ures  
M N A R  
missi n g n ot at ra n d o m mec ha nis m  
N/ n  
n u m ber of patie nts  
NI AI D/ F A A N  
J oi nt Nati o nal I nstit ute of Aller g y a n d I nfecti o us Disease/ F o o d Aller g y a n d A na p h yla xis 
Net w or k  
NI H  
Nati o nal I nstit utes of Healt h  
N O A E L  
n o o bser ve d a d verse effect le vel  
N R S -1 1  
1 1 -p oi nt p ai n i nte nsit y n u meri cal res p o nse scale  
P D A E SI  
pr ot oc ol defi ne d a d verse e ve nt(s) of s pecial i nterest  
P E F  
pea k e x pirat or y fl o w  
PI  
Prescri bi n g I nf or mati o n  
P P  
per pr ot oc ol  
Q  
Q uarter  
Q 1 2 W  
e ver y 1 2 wee ks  
R SI  
refere nce safet y i nf or mati o n 
R T -P C R  
re verse tra nscri pti o n p ol y merase c hai n reacti o n  
R T S M  
Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt  
S A B A  
s h ort-acti n g β 2 a g o nist  
S A D  
si n gle asce n di n g d ose 
S A E/ P D A E SI  
seri o us a n d pr ot oc ol defi ne d a d verse e ve nt of s pecial i nterest  
S A P  
statistical a nal ysis pla n  
sc 
s u bc uta ne o us/s u bc uta ne o usl y 
S E M  
sta n dar d err or of t he mea n 
 
 
S M P  
seri o us a d verse e ve nt ma na ge me nt pla n 
 
 
S O C  
s yste m or ga n class  
S O P  
sta n dar d o perati n g pr oce d ure 
S P R  
s urface plas m o n res o na nce 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
t1/ 2 
half -life 
T C R  
tiss ue cr oss reacti vit y 
tma x  
ti me t o ma xi m u m o bser ve d dr u g c o nce ntrati o n 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 8  
A b bre vi ati o n  
Ter m  
U L N  
u p per li mit of t he n or mal ra n ge  
U RI  
u p per res pirat or y i nfecti o n  
U S( A)  
U nite d States ( of A merica)  
V  
visit  
V C  
vi de o c o nfere nce  
V z/ F 
a p pare nt v ol u me of distri b uti o n  
W  
wee k  
W H O  
W orl d Healt h Or ga nizati o n  
W O C B P  
w o me n of c hil d beari n g p ote ntial  
X M L  
E xte nsi ble Mar k u p La n g ua ge  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
3 9  
1.  
I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N 
1. 1.  
I ntr o d ucti o n 
1. 1. 1.  
I nterle u ki n 5 
I nterle u ki n 5 (I L-5) is a h o m o di meric c yt o ki n e pr o d uce d pri maril y b y T hel per 2 T cells, gr o u p 2 
i n nate l y m p h oi d cells (I L C 2), mast cells, nat ural killer T cells, a n d e osi n o p hils (re vie we d i n 
Ba g nas c o et al 2 0 1 7 ). It si g nals via a h eter o di meric rece pt or c o nsisti n g of a n al p ha s u b u nit, 
I L-5 R α ( C D 1 2 5), u ni q u e t o I L -5 a n d a b eta s u b u nit, βc ( C D 1 3 1), s hare d wit h I L -3 a n d 
gra n ul oc yte macr o p ha ge c ol o n y -sti m ulati n g fact or ( G M-C S F). I n h u ma ns, t he I L -5  rece pt or is 
pri maril y e x presse d o n e osi n o p hils a n d bas o p hils. I L -5 si g n ali n g i n d u ces pr oliferati o n, 
differe ntiati o n, a n d acti v ati o n of e osi n o p hils ( F ul kers o n a n d R ot he n ber g 2 0 1 3 ), a n d 
differe ntiati o n a n d pri mi n g of bas o p hils (Stei ner et al 2 0 1 6 ). 
1. 1. 2.  
T E V -5 3 2 7 5  
T E V -5 3 2 7 5, a f ull y -h u m a n i m m u n o gl o b uli n (I g) G 4 m o n ocl o nal a nti b o d y ( m A b), is a ne w 
bi ol o gical e ntit y bei n g de vel o pe d b y Te va f or t he treat me nt of ast h ma patie nts wit h a n 
e osi n o p hilic p he n ot y pe. T E V -5 3 2 7 5 is a ne utr alizi n g a nti -h u ma n I L -5 m A b s pecificall y 
e n gi n eere d t o e n ha n ce its ser u m half -life (t½ ) a n d, as s uc h, ma y all o w f or less fre q ue nt d osi n g 
a n d a si g nifica ntl y l o wer treat me nt b ur de n o v er e xisti n g bi ol o gic t hera pies f or t he mai nte na nce 
treat me nt of ast h ma. It is a hi n ge -sta bilize d cr ystalliza ble fra g me nt ( Fc) m o difie d I g G 4 (la m b da) 
a nti b o d y t hat bl oc ks t he bi ol o gical f u n cti o n of I L -5 w hic h is res p o nsi ble f or t he mat urati o n, 
recr uit me nt, a n d acti vati o n of e osi n o p hils fr o m marr o w t o e n d-or ga n  tiss ue, t here b y re d uci n g 
circ ulati n g a n d tiss ue e osi n o p hils.  
1. 1. 3.  
T E V -5 3 2 7 5 a n d Ast h m a  
A p pr o xi matel y h alf of p atie nts wit h ast h ma ca n be classifie d as e osi n o p hilic base d o n air wa y or 
peri p heral bl o o d cell ular pr ofiles ( Carr et al 2 0 1 8 ). Air wa y e osi n o p hilia has bee n ass oci ate d wit h 
a re d ucti o n i n l u n g f u ncti o n a n d ris k f or de v el o pi n g e x acer bati o ns i n ast h ma patie nts ( Gree n et al 
2 0 0 2 , J ata ka n o n et al 2 0 0 0, Le u p pi et al 2 0 0 1 , L o uis et al 2 0 0 0 , Mira n da et al 2 0 0 4 , te n Bri n k e et 
al 2 0 0 1). Bl o o d e osi n o p hil le vels are acce pt e d as a m ore practical bi o mar ker (c o m pare d t o 
s p ut u m e osi n o p hil le vels) f or i de ntif yi n g patie nts wit h acti ve air wa y e osi n o p hilia w h o c o ul d 
be nefit fr o m a nti -I L-5 t h era p y. Patie nts wit h ast h ma a n d ele vate d e osi n o p hils ha ve a hi g h er ris k 
of e x acer bati o n i n t he ne xt 1 2 m o nt hs c o m pare d t o t h ose wi t h l o wer e osi n o p hils (Tra n et al 2 0 1 4 , 
Zei ger et al 2 0 1 4 ) a n d patie nts wit h peri p heral e osi n o p hil c o u nts ≥4 0 0 cells/ µ L t e n d t o be less 
well -c o ntr olle d a n d h a ve m ore fre q u e nt a n d se v ere e x acer bati o ns. Hi g her peri p heral bl o o d 
e osi n o p hils ha ve bee n ass ociate d wit h hi g h er rates of e x acer bati o n ( Price et al 2 0 1 5 ). 
Treat me nt of s e vere e osi n o p hilic ast h ma wit h a nti -I L-5 m A bs (ie, m e p oliz u ma b a n d resliz u ma b) 
res ults i n re d ucti o ns i n e osi n o p hil le vels, as well as i n cli nicall y si g nifica nt re d ucti o ns i n ast h ma 
e x acer bati o ns, i m pr o ve d l u n g f u ncti o n a n d i m pr o ve d q ualit y of life meas ures ( Castr o et al 2 0 1 5 , 
Pa v or d et al 2 0 1 2 , Orte ga et al 2 0 1 4 ). Treat me nt wit h a m A b tar geti n g t he I L-5 R α (a nti -I L-5 R α 
directe d c yt ol ytic m A b, i e, be nraliz u ma b) res ults i n a near c o m plete eli mi n ati o n of e osi n o p hils 
a n d bas o p hils, a re d u cti o n i n e x acer bati o ns, a n d i m pr o ve me nt i n l u n g f u ncti o n a n d q ualit y of life 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 0  
meas ures ( Fitz Geral d et al 2 0 1 6 , Fitz Geral d et al, 2 0 1 8 ). Eac h of t hese a ge nts is i n dicate d f or t he 
a d d-o n mai nte na n ce tr eat me nt of patie nt s wit h se vere ast h ma wit h a n e osi n o p hilic p he n ot y pe. 
1. 1. 4.  
P ur p ose of t he St u d y  
T he p ur p ose of t his st u d y is t o e val uate t he safet y a n d effi cac y of 2 d ose le vels of T E V -5 3 2 7 5 i n 
patie nts wit h persiste nt e osi n o p hilic ast h ma defi ne d as ast h ma i n patie nts wit h a ba seli ne 
a bs ol ute e osi n o p hil c o u nt of ≥3 0 0  cells/ μ L. Treat me nt wit h T E V -5 3 2 7 5 will be assesse d as 
“a d d-o n tr eat me nt” i n patie nts w h o ha ve bee n mai ntai ne d o n me di u m or hi g h d ose i n h ale d 
c ortic oster oi d (I C S) me di cati o ns or a n y d ose of I C S i n c o m bi nati o n wit h a  l o n g-acti n g β 2 a g o nist 
( L A B A). 
1. 2.  
Fi n di n gs fr o m N o ncli nic al a n d Cli nic al St u dies  
Brief s u m maries of n o ncli nical p har mac ol o g y, p h ar mac o ki netic, t o xic ol o g y, a n d cli nical st u dies 
are pr o vi d e d i n t he f oll o wi n g secti o ns. M ore detaile d i nf or mati o n is pr o vi de d i n t he c urre nt 
versi o n of t he I n v esti gat or’s Br oc h ure (I B).  
1. 2. 1.  
N o ncli nic al St u dies  
1. 2. 1. 1.  
P h ar m a c ol o g y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 2. 1. 2.  
P h ar m a c o ki netics  
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 1  
 
 
 
 
 
 
 
1. 2. 1. 3.  
N o ncli nic al S afet y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 2. 2.  
Cli nic al St u dies  
1. 2. 2. 1.  
St u d y T V 5 3 2 7 5 -P K -1 0 1 5 2  
T V 5 3 2 7 5 -P K -1 0 1 5 2 is a n o n g oi n g P hase 1 st u d y wit h a ra n d o mize d, d o u ble -bli n d, 
place b o -c o ntr olle d, si n gl e asce n di n g d os e ( S A D) part ( Part A) a n d a n o p e n -la bel, 
n o n -ra n d o mize d, m ulti ple asce n di n g d os e part ( Part B) t o ass ess t he safet y, t olera bilit y, 
p har mac o ki netics, p h ar m ac o d y na mics, a n d i m m u n o ge ni cit y of T E V -5 3 2 7 5 a d mi nistere d sc i n 
a d ult healt h y v ol u nteers. As of t he date of t his pr ot oc ol, t he S A D  part ( Part A ) of t he st u d y ha d 
s uccessf ull y d ose d 5 9 h ealt h y s u bjects wit h si n gle d oses of T E V-5 3 2 7 5 at 5 0, 1 5 0, 4 5 0, 9 0 0, or 
1 8 0 0  m g, a n d 1 0 s u bjects recei v e d place b o. T he fi nal data a n al ysis is o n g oi n g. I n t he m ulti ple 
asce n di n g d ose ( M A D) p art ( Part B) of t he st u d y , T E V-5 3 2 7 5 was a d mi nistere d sc e ver y 2 8 d a ys 
3 ti mes at d ose le vels of 4 5 0 or 9 0 0  m g. Part B of t he st u d y is c o m plete a n d t he a nal ysis is  
o n g oi n g.  
1. 2. 2. 1. 1.  Si n gle Asce n di n g D ose P h ar m a c o ki netics  
T E V -5 3 2 7 5 c o n ce ntrati o ns i ncrease d wit h i ncrease d d ose acr oss all 5  S A D c o h orts ( 5 0, 1 5 0, 
4 5 0, 9 0 0, a n d 1 8 0 0  m g). Me dia n t
ma x  val ues ra n ge d fr o m 
. T he Cma x  a n d t otal 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 3  
e x p os ure ( A U C 0 -t, area u n der t he c o n ce ntr ati o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y [ A U C0 -∞]) 
val ues i ncrease d wit h e ac h d ose le vel aft er a d mi nistrati o n of T E V -5 3 2 7 5. T he mea n t ½  val ues 
ra n ge d fr o m
 acr oss all treat me nt c o h orts. T E V-5 3 2 7 5 c o n ce ntrati o ns a p p eare d 
t o decrease i n a bi-e x p o ne ntial fas hi o n f oll o wi n g s c a d mi nistrati o n of T E V -5 3 2 7 5. T he rate of 
eli mi nati o n a p peare d si milar acr oss d os e le vels. D ose n or malize d e x p os ure para meters ( d ose 
n or malize d ma xi m u m o bser ve d dr u g c o nce ntrati o n [ D N C ma x ], d ose n or malize d area u n der t he 
c o nce ntr ati o n -ti me c ur ve fr o m ti me 0 t o t he ti me of t he last meas ura ble c o nce ntrati o n 
[ D N A U C0 -t], d ose n or maliz e d area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y 
[ D N A U C0 -∞]), a p pare nt cleara n ce ( C L/ F), a n d a p p are nt v ol u me of distri b uti o n ( Vz/ F) were 
si milar acr oss t he d oses st u die d i n t he S A D part of t he st u d y ( Part A) . 
D ose pr o p orti o nalit y of T E V -5 3 2 7 5 was e val uate d o ver t he d ose ra n ge of 5 0 t o 1 8 0 0  m g usi n g a 
p o wer m o del. A cr oss test e d e x p os ure para m eters ( C ma x  a n d A U C 0 -∞), t he esti mate d sl o pe was 
cl ose t o 1 a n d t he 9 0 % c o nfi de nce i nter val ( CI) f or t he sl o pe c o ntai ne d 1, i n dicati n g t hat t he 
i ncreas e i n T E V-5 3 2 7 5 e x p os ure is d ose pr o p orti o nal.  
1. 2. 2. 1. 2.  Si n gle Asce n di n g D ose P h ar m a c o d y n a mi cs  
Re d ucti o n i n bl o o d e osi n o p hils was d ose a n d ti me de pe n de nt a n d o bs er ve d as earl y as 2  da ys 
after d osi n g i n all acti ve treat me nt c o h orts. E osi n o p hil c o u nts decrease d fr o m  baseli ne val ues t o 
a ma xi m u m effect val ue wit hi n a p pr o xi matel y 1  wee k fr o m d osi n g after a d mi nistrati o n of 5 0, 
1 5 0, 4 5 0, 9 0 0, a n d 1 8 0 0  m g T E V -5 3 2 7 5. Mea n e osi n o p hils be ga n t o ret ur n t o baseli ne val ues 
fr o m ar o u n d 8 5 d a ys ( 5 0  m g c o h ort), 1 1 3  da ys ( 1 5 0  m g c o h ort), 1 4 1  da ys ( 4 5 0  m g c o h ort), a n d 
1 6 9  da ys ( 9 0 0  m g c o h ort) after a d mi nistrati o n of T E V -5 3 2 7 5. At t he hi g hest d ose le vel 
( 1 8 0 0 m g), m ea n e osi n o p hil c o u nts be ga n t o sl o wl y ret ur n t o baseli ne v al ues fr o m 2 2 5  da ys  aft er 
a d mi nistrati o n of T E V -5 3 2 7 5 , alt h o u g h re mai ne d mar ke dl y l o wer t h a n bas eli ne, a n d l o wer t h a n 
t hat f or t he ot her c o h orts, at last sa m pli n g ( 2 6 7 da ys).  
1. 2. 2. 1. 3.  Si n gle Asce n di n g D ose S afet y  
As of t he date of t his pr ot oc ol, n o deat hs, seri o us a d verse e v e nts, or wit h dra wals d ue t o a d verse 
e ve nts ha ve b ee n re p orte d. Si xtee n ( 2 7 %) of t he 5 9 s u bjects recei vi n g T E V-5 3 2 7 5 a n d 3 ( 3 0 %) 
of t he 1 0  s u bjects recei vi n g pla ce b o i n t he S A D p art ( Part A) of t he st u d y e x perie nce d 
treat me nt-e mer ge nt a d v erse e ve nts.  
All a d verse e ve nts, wit h t he e x ce pti o n of 2  hea d ac hes ( mil d  a n d m o derate i n i nte nsit y), were 
c o nsi dere d b y t he i n v esti gat or as n ot relat e d t o st u d y dr u g. T h e m ost c o m m o n a d verse e ve nt 
re p orte d ( 7 s u bj ects recei vi n g T E V-5 3 2 7 5 a n d 1  s u bject recei vi n g pl ace b o) was as y m pt o matic 
tra nsie nt bl o o d creati ne p h os p h o ki nase (C P K) i ncrease d ( preferre d ter m).  
O ne a d verse e v e nt of s pecial i nterest ( A E SI) of di arr hea was re p orte d i n c o h ort  2 ( 1 5 0  m g 
T E V -5 3 2 7 5). I nj ecti o n site fi n di n gs w ere mai nl y mil d tra nsie nt er yt h e ma. T here were n o A E SIs 
of o p p ort u nistic i nfecti o ns, hel mi nt h i n fecti o ns, s yste mic se vere reacti o ns, mali g na n c y, or se v ere 
h y perse nsiti vit y reacti o ns.  
F o ur pre g na nci es were re p orte d d uri n g t he S A D part ( Part A) of t he st u d y: 3 i n s u bjects 
recei vi n g T E V-5 3 2 7 5 a n d 1  i n a s u bject recei vi n g place b o. O ne cas e was a bi oc he mical 
pre g na nc y a n d i n t he ot h er 3  pre g n a ncies, all s u bjects elect e d t o u n der g o earl y t er mi nati o n a n d 
were disc o nti n ue d.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 4  
N o a nti -T E V -5 3 2 7 5 a nti b o dies ha ve bee n detecte d i n a n y of t he 5 9  s u bjects recei vi n g 
T E V -5 3 2 7 5 i n t he S A D part of t he st u d y ( Part  A). N o c li nical si g ns s u g gesti n g i m m u n o ge ni c 
pr o perties were i de ntifie d i n t he s u bjects d ose d wit h T E V -5 3 2 7 5.  
T he M A D part of t he st u d y ( Part  B) is o n g oi n g a n d n o m ulti ple d ose i m m u n o ge ni cit y d ata are 
a vaila ble.  
O verall, t he safet y pr ofil e of t he st u d y dr u g has i n dicate d a hi g h le vel of t olera bilit y i n ter ms of 
a n y a d vers e e v e nts a n d n o safet y si g nals ha ve b ee n i de ntifie d.  
1. 3.  
K n o w n a n d P ote nti al Be nefits a n d Ris ks t o P atie nts  
1. 3. 1.  
K n o w n a n d P ote nti al Be nefits a n d Ris ks of t he Test I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
O ver all, bas e d o n t he res ults fr o m t he P hase 1 st u d y ( T V 5 3 2 7 5 -P K -1 0 1 5 2) a n d ot her a nti -I L-5 
c o m p o u n ds, t here are n o e x pecte d u n ma na gea ble ris ks f or t he st u d y p o p ulati o n.  
Gi ve n t he tar get e d acti o n of T E V -5 3 2 7 5 o n I L -5, a n d c o nsi deri n g t hat t he pr o d uct is a m A b,  
i m m u n os u p pressi o n, h y p erse nsiti vit y, a n d i m m u n o ge ni cit y ma y b e c o nsi dere d p ote ntial class 
effect ris ks of T E V -5 3 2 7 5; h o we ver, t his h u ma n a nti b o d y is e x pecte d t o ha ve a re d u ce d 
te n de nc y t o elicit a n u n wa nte d i m m u ne res p o nse cli nicall y. C urre ntl y, t here ha ve bee n n o 
s yste mic h y perse nsiti vit y reacti o ns or i m m u n o ge nicit y ass oci ate d wit h t he a d mi nistrati o n of 
T E V -5 3 2 7 5.  
Base d o n its m olec ular str uct ure (rec o m bi na nt m A b), T E V -5 3 2 7 5 is n ot e x pecte d t o be 
m uta ge ni c. F urt h er m ore, t he c urre ntl y a vaila ble scie ntific literat ure o n t he r ole of I L-5 a n d 
e osi n o p hils i n t u m or de vel o p me nt or a nti -t u m or i m m u nit y (Le u n g et al 2 0 1 7 , R o uf osse 2 0 1 8 , 
Za y n a get di n o v et al 2 0 1 5 ), al o n g wit h n o ncli nical a n d cli nical data fr o m 3 a p pr o ve d m A bs 
tar geti n g i n hi biti o n of I L-5 or I L -5 rece pt ors, d oes n ot i n dicate a n i ncrease d ris k f or 
mali g na n cies f oll o wi n g I L -5 p at h wa y bl oc ka de. I n patie nts wit h se vere ast h ma recei vi n g 
a nti-I L-5 m A b treat me nt, ca ncers occ urre d i n si milar n u m bers a m o n gst a nti -I L-5 treate d patie nts 
c o m pare d wit h place b o c o ntr ols, a n d t he t y p es of ca ncers were si milar t o t h ose occ urri n g 
ge n erall y i n pe o ple n o m atter w hat me dici n es t he y ta ke. T here are als o r ece ntl y des cri be d 
i m m u n o m o d ulat or y r oles of e osi n o p hils i n t u m or s ur veilla nce t hat h a ve be n efite d fr o m a nti-I L-5 
m A b t hera p y ( Za y na get di n o v et al 2 0 1 5 ). 
Cli nical trials wit h T E V -5 3 2 7 5 a n d ot her a nti -I L-5 m A bs di d n ot de m o nstrate a n i ncreas e d ris k 
f or hel mi nth a n d or o p p ort u nistic i nfecti o ns i n patie nts treate d wit h a nti -I L-5 m A bs c o m pare d t o 
place b o. H o we ver, i n vie w of t he p ossi bilit y of a n i m m u n o m o d ulat or y r ole of decrease d 
e osi n o p hils i n i nfecti o ns, a n d s pecificall y i n h el mi nt h i nfecti o ns, t hese are c o nsi d ere d p ote ntial 
ris ks f or a nti-I L-5 treat m e nt.  
I n t he c urre nt st u d y, T E V-5 3 2 7 5 will be a d mi nistere d via t he s c r o ute a n d n o nseri o us i njecti o n 
site reacti o ns ma y be s ee n. I n t he S A D part ( Part A) of St u d y T V 5 3 2 7 5-P K -1 0 1 5 2 i njecti o n site 
fi n di n gs were all mild e xce pt f or 1  s u bject i n t he 1 8 0 0-m g d ose gr o u p w h o e x perie nce d m o derate 
i njecti o n site er yt h e ma a n d i n d urati o n w hic h res ol ve d o ver 4 h o urs. T h e m ost c o m m o n i njecti o n 
site fi n di n g was mil d er yt he ma see n at 2 0 mi n utes after i njecti o n. 
Ol der a d ults a n d pe o p l e of a n y a ge w h o ha v e seri o us u n derl yi n g me di cal c o n diti o ns, i ncl u di n g 
m o derate t o se v ere ast h ma, ma y be at hi g her ris k f or a m ore se v ere c or o na vir us disease 2 0 1 9 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 5  
( C O VI D-1 9) c o urs e w he n i nfecte d (Ce nt ers f or Disease C o ntr ol a n d Pre ve nti o n [ C D C] 
C or o na vir us [ C O VI D -1 9] ). Testi n g of patie nts as y m pt o matic f or C O VI D-1 9 acti ve i nfecti o n 
ma y b e c o n d uct e d at t he discreti o n of t he i n vesti gat or wit hi n 7 2 h o urs of a n y visit w here 
s pir o metr y assess me nts are t o be c o n d u cte d or as re q uire d b y healt h a ut h orities, l ocal et hics 
c o m mittees, or st u d y ce nter S O Ps . T he testi n g ma y be c o n d ucte d b y t h e ce ntral la b orat or y or 
l ocall y d e pe n di n g o n feasi bilit y. T h ose p atie nts at ris k f or C O VI D-1 9 i nfecti o n s h o ul d be 
e val uate d wit h testi n g a n d b y t he i n vesti gat or t o esta blis h w het her t he patie nt s h o ul d partici pate 
i n t he st u d y. Ot her m eas ures are o utli ne d i n A p pe n di x  N . 
A d diti o nal i nf or mati o n re gar di n g p ote ntial ris ks t o patie nts ma y b e f o u n d i n t he I B.  
1. 3. 2.  
O ver all Be nefit a n d Ris k Assess me nt f or T his St u d y  
I n t his st u d y patie nts will mai ntai n t heir ast h ma mai nte na nce t hera p y a n d will recei ve o ne of 
2  d oses of I M P ( 6 0 0  m g or 1 2 0 0  m g) or place b o f or I M P. T he c urre nt st u d y is desi g ne d t o 
m o nit or safet y d uri n g t he r u n -i n peri o d, at t he ti me of I M P a d mi nistrati o n (i ncl u di n g t he 
m o nit ori n g of i njecti o n site reacti o ns), a n d t hr o u g h o ut t he st u d y, i ncl u di n g cl ose dail y re m ote 
m o nit ori n g of eac h patie nt’s safet y ele ctr o nicall y wit h pre defi ne d alert criteria t o ca pt ure patie nts 
wit h w orse ni n g ast h ma b y dail y l u n g f u ncti o n meas ure me nts, resc ue me di cati o n use, a n d ast h ma 
s y m pt o ms all o wi n g f or earl y rec o g niti o n of ast h ma w orse ni n g a n d i nter ve nti o n.  
Treat me nt of ast h matics a n d e x p os ure t o healt h y v ol u nteers has de m o nstrate d t he safet y of t h e 
a nti-I L-5 m A b cl ass ( CI N Q AI R [resliz u ma b] Prescri bi n g I nf or mati o n [ PI] 0 2/ 2 0 2 0 , N U C A L A 
[ me p oliz u ma b] PI 0 9/ 2 0 1 9, CI N Q AI R [resliz u ma b] Pr o d uct M o n o gra p h, 0 3/ 2 0 1 7;  Ts u ka m ot o et 
al 2 0 1 6) wit h a d vers e reacti o ns ge n erall y si milar bet wee n tr eate d a n d u ntreate d s u bjects. B ot h 
a nti-I L-5 m A bs are a p pr o ve d i n U S A, E ur o pe a n d Ca na da, a n d are b ei n g use d t o safel y treat 
patie nts wit h se vere ast h ma a n d ot her c o n diti o ns. Me p oliz u ma b rece ntl y gai ne d a p pr o val i n 
c hil dre n wit h safet y si milar t o t hat see n i n t he a d ult pr o gra m ( N U C A L A [ me p oliz u ma b] PI 
0 9/ 2 0 1 9 ). T he safet y pr ofile of T E V-5 3 2 7 5 t h us far de m o nstrate d i n St u d y T V 5 3 2 7 5 -P K -1 0 1 5 2 
is c o nsiste nt wit h t he o verall pr ofile of b ot h r esliz u ma b a n d me p oliz u ma b. I n a d diti o n, n o A D A 
has bee n det ecte d i n t he S A D part ( Part A) of t he st u d y. Ta k e n t o get her, t h e safet y pr ofile of t he 
class a n d t he de m o nstr ate d safet y of T E V -5 3 2 7 5 i n li ne wit h t he a p pr o ve d m olec ules s u g gest a 
p ositi ve be nefit -ris k assess me nt f or t his st u d y. 
T he res ults of t his st u d y ma y facilitate t he d e vel o p me nt of T E V-5 3 2 7 5, wit h p ote ntial be nefits 
f or patie nts wit h m o derat e t o se vere e osi n o p hilic ast h ma as a n a d d-o n t hera p y i n patie nts wit h 
se vere e x acer bati o n-pr o ne e osi n o p hilic ast h ma.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 6  
2.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  
Pri m ar y a n d Sec o n d ar y O bjecti ves a n d E n d p oi nts  
T he pri mar y a n d s ec o n d ar y st u d y o bje cti ves a n d e n d p oi nts are: 
O bjecti ves  
E n d p oi nts  
T he pri m ar y o bjecti ve  of t he st u d y 
is t o e val uate t he efficac y of 
T E V -5 3 2 7 5 a d mi nistere d 
s u bc uta ne o usl y (sc) i n a d ult patie nts 
wit h persiste nt ast h ma a n d a n 
e osi n o p hilic p he n ot y pe c o m pare d t o 
place b o  
T he pri mar y e n d p oi nt is t he c ha n ge fr o m baseli ne i n cli nic -base d 
sta n dar dize d baseli ne-a dj uste d tr o u g h ( pre -br o nc h o dilat or) m or ni n g f orce d 
e x pirat or y v ol u me i n 1 sec o n d ( F E V 1) at wee k 1 2  
A sec o n d ar y o bjecti ve  of t he st u d y 
is t o e val uate t he efficac y of 
T E V -5 3 2 7 5 c o m pare d t o place b o 
assesse d b y l u n g f u ncti o n, ast h ma 
s y m pt o ms, resc ue me dicati o n use, 
a n d q ualit y of life meas ures  
T he sec o n dar y efficac y e n d p oi nts are:  
•  
o verall wee kl y well -c o ntr olle d ast h ma  stat us defi ne d b y t he 
ast h ma c o ntr ol c o m p osite sc ore a n d wee kl y ast h ma c o ntr ol stat us 
( Yes vers us N o) fr o m wee k 1 t hr o u g h 1 2 a n d o verall wee kl y 
well -c o ntr olle d ast h ma stat us fr o m wee k 1 t hr o u g h 1 6  
•  
o verall c ha n ges fr o m baseli ne i n t he wee kl y a vera ge of dai l y 
m or ni n g tr o u g h ( pre -resc ue br o nc h o dilat or) F E V1 as meas ur e d b y 
a ha n d hel d de vice o ver 1 2  we e ks fr o m wee k 1 t hr o u g h 1 2 a n d 
o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  
o verall c ha n ges fr o m baseli ne i n wee kl y a vera ge of resc ue 
me dicati o n use o ver 1 2 wee ks fr o m we e k 1 t hr o u g h 1 2 a n d o ver 
1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  
c ha n ges fr o m baseli ne i n perce nta ge of ast h ma c o ntr ol da ys ( n o 
s y m pt o ms a n d n o resc ue me di cati o n use) o ver 1 2 wee ks fr o m 
wee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  
c ha n ge fr o m baseli n e i n cli nic -base d sta n dar dize d 
baseli ne -a dj uste d m or ni n g tr o u g h F E V 1 at wee k 1 6  
•  
pr o p orti o ns of patie nts w h o ac hie ve cli nic -base d F E V 1 ≥8 0 % 
pre dicte d at wee ks  1 2, 1 6, a n d at e n d p oi nt  
•  
pr o p orti o ns of patie nts w h o ac hie ve f orce d e x pirat or y fl o w at 2 5 % 
t o 7 5 % of F V C  ( F E F2 5 -7 5) ≥7 0 % pre dicte d at wee ks  1 2, 1 6, a n d at 
e n d p oi nt  
•  
ti me t o first cli nical ast h ma e xacer bati o n ( C A E) t hr o u g h o ut t he 
st u d y 
•  
c ha n ges fr o m baseli ne i n Ast h ma C o ntr ol Q uesti o n naire ( A C Q -6) 
at wee ks 1 2 a n d 1 6  
•  
c ha n ges fr o m baseli ne i n Ast h ma C o ntr ol T est ( A C T) at wee ks 1 2 
a n d 1 6  
•  
c ha n ges fr o m baseli ne i n Sta n dar dize d Ast h ma Q ualit y of Life 
Q uesti o n naire ( A Q L Q[ S]) at wee ks  1 2 a n d 1 6  
•  
pr o p orti o ns of patie nts w h o ac hie ve F E V 1: F V C (f orce d vital 
ca pacit y) rati o ≥0. 8 0 at wee ks  1 2, 1 6, a n d at e n d p oi nt  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 7  
O bjecti ves  
E n d p oi nts  
A sec o n d ar y o bjecti ve of t he st u d y is 
t o e val uate t he safet y a n d t olera bilit y 
of T E V -5 3 2 7 5 a d mi nistere d s c i n 
a d ult patie nts wit h persiste nt ast h ma 
a n d a n e osi n o p hilic p he n ot y pe 
c o m pare d wit h place b o  
T he sec o n dar y safet y a n d  t olera bilit y e n d p oi nts are: 
•  
fre q ue nc y of a d verse e ve nts 
•  
c ha n ges fr o m baseli ne i n cli ni cal la b orat or y test res ults (ser u m 
c he mistr y, he mat ol o g y, a n d uri nal ysis) t hr o u g h o ut t he st u d y  
•  
c ha n ges fr o m baseli ne i n vital si g ns ( bl o o d press ure, p ulse rate, 
res pirator y rate, a n d b o d y te m perat ure) t hr o u g h o ut t he st u d y  
•  
c ha n ges fr o m baseli ne i n 1 2 -le a d electr ocar di o gra m ( E C G) 
fi n di n gs t hr o u g h o ut t he st u d y 
•  
use of c o nc o mita nt me dicati o n  
•  
l ocal t olera bilit y 
•  
n u m ber ( %) of patie nts w h o di d n ot c o m plete t he st u d y d ue t o 
a d verse e ve nts  
A sec o n d ar y o bjecti ve of t he st u d y is 
t o e val uate t he i m m u n o ge nicit y of 
T E V -5 3 2 7 5 a d mi nistere d sc i n a d ult 
patie nts wit h persiste nt ast h ma a n d a n 
e osi n o p hilic p he n ot y pe  
T he i m m u n o ge nicit y will be assesse d b y meas uri n g t he de vel o p me nt 
a nti -dr u g a nti b o dies ( A D A), a n d t he titer a n d ne utralizi n g acti vit y of t he 
A D A at baseli ne a n d t hr o u g h o ut t he st u d y  
2. 1. 1.  
J ustific ati o n of Pri m ar y E n d p oi nt  
C ha n ge fr o m bas eli ne i n cli nic -base d sta n d ar dize d baseli ne -a dj uste d f orce d e x pirat or y v ol u me i n 
1 sec o n d ( F E V 1) is a well -esta blis he d e n d p oi nt use d t o assess t he efficac y of ast h ma t hera pi es. 
A d diti o nall y, 1 2 -wee k d urati o n cli nical trials wit h F E V 1 as pri mar y efficac y e n d p oi nt ha ve b ee n 
acce pte d b y F D A as t he pi v otal desi g n i n pr o gra ms e val uati n g ast h ma.  
2. 2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 8  
O bjecti ves  
E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
4 9  
O bjecti ves  
E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 0  
3.  
S T U D Y D E SI G N  
3. 1.  
Ge ner al St u d y Desi g n a n d St u d y Sc he m atic Di a gr a m  
T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p st u d y t o 
e val uate t he s afet y a n d efficac y  of T E V -5 3 2 7 5 a d mi nistere d s u bc uta ne o usl y (sc) at d oses of 
6 0 0  m g a n d 1 2 0 0  m g or place b o i n a d ult patie nts wit h m o derate t o se vere ast h ma wit h a n 
e osi n o p hilic p he n ot y pe.  
Patie nts ma y be eli gi ble t o partici pate if t he y h a ve a dia g n osis of ast h ma f or at leas t 6 m o nt hs 
a n d t heir c urre nt ast h ma  mai nte na nce  t hera p y h as bee n sta ble f or at least 1 m o nt h  a n d i ncl u des 
1  of t he f oll o wi n g (see A p pe n di x  F ): 
•  me di u m  or hi g h d ose i n h ale d c ortic oster oi d (I C S) ±a n ot her c o ntr oller  
•  a n y fi x e d d ose c o m bi nati o n I C S (l o w, me di u m or hi g h) wit h a l o n g -acti n g 
β -a dre n er gic a g o nist ( L A B A) ± a n ot her c o ntr oller  
T he patie nt will c o nti n ue o n t his ast h ma mai nte na nce t hera p y t hr o u g h o ut t he  treat me nt peri o d 
( V 9). F or patie nts ta ki n g o nce-dail y i n hale d treat m e nt, it m ust be ta ke n i n t he m or ni n g t o e n a ble 
tr o u g h l u n g f u ncti o n assess me nts. If a patie nt r e q uires a c h a n ge i n t he ti mi n g of d osi n g, it is 
all o wa ble as l o n g as t he i n vesti gat or b elie v es t here is n o i n here nt har m i n c h a n gi n g t he ti mi n g of 
t he d ose a n d t he patie nt a grees t o s uc h c ha n ge. 
T he st u d y will c o nsist of 4 peri o ds:  
•  scree ni n g p eri o d of u p t o a p pr o xi matel y 2 wee ks  
•  r u n-i n peri o d of a p pr o xi matel y 1 4 d a ys  
•  d o u ble -bli n d treat me nt p eri o d  of 1 6  wee ks  
•  f oll o w-u p peri o d of a p pr o xi matel y 1 4 wee ks be gi n ni n g at t he e n d of t he d o u ble -bli n d 
treat me nt peri o d 
After o btai ni n g i nf or me d c o nse nt, a scree ni n g peri o d of u p t o a p pr o xi matel y 2 wee ks is all o we d. 
Patie nts ma y be e val uate d f or i ncl usi o n i nt o t he r u n -i n peri o d d uri n g t he scree ni n g peri o d . A n 
a bs ol ute e osi n o p hil c o u nt of ≥3 0 0  cells/ μ L is re q uire d t o partici pate i n t he st u d y. A c o m plete 
bl o o d c o u nt ( C B C) will be o btai ne d a n d ma y b e re peate d o nce d uri n g t he scree ni n g peri o d t o 
de m o nstrate a n a bs ol u te e osi n o p hil c o u nt of ≥3 0 0 cells/ μ L (a t otal of 2 atte m pts d uri n g t he 
scree ni n g p eri o d). Ot her la b orat or y testi n g, me dical a n d ast h ma hist or y ass ess me nts, p h ysic al 
e x a mi nati o n a n d a n y ot h er assess me nts as n ot e d i n Ta ble  2  will be c o m plete d d uri n g t he 
scree ni n g p eri o d a n d ma y be c o n d ucte d at m ore t ha n o ne visit. 
F or mal p ul m o nar y f u ncti o n testi n g (s pir o metr y a n d re versi bilit y testi n g) will be c o n d ucte d i n t he 
m or ni n g bet w ee n 0 5 3 0 a n d 1 1 0 0 h o urs usi n g t he st u d y -pr o vi d e d s pir o metr y e q ui p me nt. T esti n g 
will be perf or me d i n t he cli nic u nless s pecifie d as b y ha n d h el d de vice. Patie nts are re q uire d t o 
wit h h ol d ast h ma mai nte na nce me di cati o ns pri or t o a n y f or mal p ul m o nar y f u ncti o n testi n g. If t he 
patie nt has ta ke n ast h ma mai nte na nce me di cati o n wit hi n 2 4 ± 2  h o urs f or me dicati o n d ose d o nce 
dail y ( Q D), or wit hi n 1 2 ± 2  h o urs f or me dicati o ns d ose d m ore fre q ue ntl y t ha n o nce d ail y or has 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 1  
ta ke n s h ort-acti n g β 2-a dre ner gic a g o nist  ( S A B A) resc ue m e dicati o n wit hi n 6 h o urs or i n hale d 
c ortic oster oi d i n c o m bi nati o n wit h l o n g -acti n g β 2 -a der ner gi c a g o nist (I C S/ L A B A) us e d as resc ue 
me dicati o n wit hi n 1 2  h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g, t he visit m ust be 
resc he d ul e d. Patie nts w h o meet t he pre -al b uter ol/sal b uta m ol l u n g f u ncti o n re q uire me nts ma y 
u n der g o re v ersi bilit y testi n g a p pr o xi matel y 3 0  mi n utes after 4 i n hal ati o ns of al b uter ol/sal b uta m ol 
h y dr ofl ur oal ka n e ( H F A) i n halati o n aer os ol ( 9 0  μ g e x -act uat or or e q ui v ale nt). Patie nts w h o 
de m o nstrate re v ersi bilit y ≥1 2 % a n d a ≥2 0 0  m L i ncrease i n f orce d e x pirat or y v ol u me i n 1 sec o n d 
(F E V 1) fr o m bas eli ne ma y e nt er t he r u n-i n peri o d if t he y meet ot her eli gi bilit y re q uir e me nts as 
s pecifie d. 
Patie nts w h o meet t he criteria f or i ncl usi o n a n d n o n e of t he e x cl usi o n criteri a ma y e nter i nt o t he 
r u n-i n peri o d at ( visit [ V] 2) a n d will c o nti n ue t he c urre nt ast h ma mai nte na nce me dicati o n. T he 
patie nt’s c urre nt res c ue me dicati o n will be disc o nti n ue d a n d t he patie nt will be pr o vi de d wit h 
al b uter ol s ulfate ( 1 1 7 μ g per i n halati o n) electr o nic m ulti d ose dr y p o w der i n haler 
(al b uter ol/sal b uta m ol e M D PI) ( Pr o Air®  Di gi haler T M 1) or e q ui val e nt al b uter ol/sal b uta m ol ( dr y 
p o w der or aer os ol f or m ulati o ns are acce pta b le) f or use as nee d e d as resc u e me dicati o n t o c o ntr ol 
ast h ma s y m pt o ms. Patie nts will be pr o vi de d a n d tr ai ne d o n t he use of a n electr o nic diar y a n d 
ha n d hel d de vice t o meas ure dail y F E V 1 a n d pea k e x pirat or y fl o w ( P E F). D uri n g t he r u n -i n 
peri o d, patie nts will  meas ure F E V 1 a n d P E F eac h m or ni n g usi n g t he ha n d h el d de vice pri or t o t he 
use of res c ue me dicati o n ( w he ne v er p ossi ble) a n d pri or t o t he m or ni n g d os e of ast h ma 
mai nte na nce me di cati o n(s). Patie nts will als o rec or d ast h ma ( da yti me or ni g ht -ti me) s y m pt o m 
sc ore a n d resc u e me dicati o n ( n u m ber of p uffs) t wi ce dail y w het h er use d or n ot. Patie nts ma y be 
e val uate d f or ra n d o mizati o n i nt o t he st u d y after a mi ni m u m of 1 4 ± 2 da ys after e nteri n g t h e 
r u n-i n peri o d. 
T he ra n d o mizati o n visit ( V 3) will occ ur after a mi ni m u m of 1 4 ± 2 da ys after e nteri n g t he r u n -i n 
peri o d. At t his visit t he patie nt’s diar y data s h o ul d be re vie we d pri or t o f or mal l u n g f u ncti o n 
testi n g, la b orat or y testi n g a n d t he vari o us q uesti o n naires t o e ns ure c o m plia nce wit h diar y e ntries 
a n d t o deter mi ne if l u n g f u ncti o n, s y m pt o ms a n d resc ue me dicati o n use meet t he ra n d o mizati o n 
criteria. If t he patie nt f ails t o meet t he diar y re q uire me nts, t he patie nt will be c o nsi dere d a 
ra n d o mizati o n fail ure. F urt her pr oce d ures f or V 3 will o nl y b e c o n d u cte d f or patie nts w h o meet 
t he diar y re q uir e me nts. 
Patie nts w h o meet all of t he ra n d o mizati o n criteria will be stratifie d base d o n m ai nte na nce 
t hera p y (I C S a n d l o w d os e I C S/ L A B A will be stratifie d se paratel y fr o m t he me di u m a n d hi g h 
d ose I C S/ L A B A [ 2 se parate strata])  a n d a bs ol ute e osi n o p hil c o u nt deter mi ne d at scree ni n g 
( 3 0 0 t o < 4 0 0 or ≥4 0 0 cells/ μ L) i nt o 1 of 2  treat me nt gr o u ps or pl ace b o via a n i nteracti ve 
res p o nse tec h n ol o g y (I R T) s yste m: 
•  T E V -5 3 2 7 5 6 0 0  m g sc  
•  T E V -5 3 2 7 5 1 2 0 0  m g sc  
•  Place b o sc  
                                                 
1 Pr o Air ®  Di gi haler ™ is a re gistere d tra d e mar ks of T e va P har mace utical I n d us tries Lt d. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 2  
A p pr o xi matel y 9 0 p atie nts w h o ha ve bee n mai ntai ne d o n me di u m or hi g h d ose I C S or l o w d os e 
I C S/ L A B A a n d a p pr o xi matel y 2 1 0 p atie nts ( ma y be a dj uste d base d o n t h e i nteri m a nal ysis) o n 
me di u m or hi g h d ose I C S/ L A B A will be ra n d o mi ze d a n d stratifie d acr oss all treat me nt ar ms.  
Scree ni n g ma y be a dj uste d as nee d e d t o meet t hes e criteri a as m uc h as p ossi ble.  
Patie nts w h o meet t he re q uire me nts f or ra n d o mizati o n, after t he pr oce d ures f or s peci me n 
c ollecti o n a n d ot her testi n g as d escri be d i n A p pe n di x  B , will be ra n d o mize d via t he I R T. Eac h 
patie nt will recei ve a t otal of 4  sc i njecti o ns i n t he a b d o me n at V 3, a d mi nistere d b y a q u alifie d 
healt h care pr o vi der (acc or di n g t o l ocal re g ulati o ns) w h o is pre pare d t o ma na ge a n a p h yl a xis, as 
descri be d i n t he st u d y refere nce ma n ual. T h e kit n u m ber a n d l ocati o n will be rec or de d i n t he 
s o urce d oc u m e nts a n d e ntere d i n t he case re p ort f or m ( C R F) f or eac h of t he 4 i njecti o n site 
l ocati o ns al o n g wit h a n y i njecti o n site reacti o n f or eac h site, e v al uate d at a p pr o xi matel y 1 h o ur 
after d osi n g. If t he patie nt de vel o ps cli nical s y m pt o ms, vital si g ns s h o ul d be rec or de d a n d t he 
patie nt s h o ul d be assesse d f or a na p h yl a xis/ h y perse nsiti vit y reacti o ns as det ailed i n A p pe n di x  H . 
Patie nts will be o bser ve d f or a mi ni m u m of 1  h o ur after d osi n g. Bef ore lea vi n g t he cli nic, 
patie nts will a d diti o nall y be a d vise d o f s y m pt o ms/si g ns f or w hi c h t he y s h o ul d see k me dical 
a d vice or me di cal treat me nt. At all ot her visits, patie nts will be free t o lea v e t he cli nic w he n all 
pr oce d ures ha ve b ee n c o m plete d.  
D uri n g t h e treat me nt p eri o d ( baseli ne/ da y of ra n d o mizati o n [ D o R , V 3] t hr o u g h wee k 1 6 [ V 9]), 
patie nts will perf or m m or ni n g l u n g f u ncti o n assess me nts ( F E V 1 a n d P E F) b y ha n d h el d de vice 
pri or t o m or ni n g ast h ma mai nte na nce me di cati o n a n d pri or t o res c ue me dicati o n use ( w he n e ver 
p ossi ble), assess a n d rec or d da yti me a n d ni g ht -ti me ast h ma s y m pt o m sc ores, rec or d resc u e 
me dicati o n use ( n u m ber of p uffs) t wice dail y a n d c o nfir m (i n t he e v e ni n g) t hat t he y h a ve ta ke n 
t hat da y's ast h ma mai nte na nce me di cati o n. D uri n g t he treat me nt peri o d visits, f or mal p ul m o nar y 
f u ncti o n testi n g (as re q uire d) will be c o m plet e d i n t he m or ni n g bet w ee n 0 5 3 0 a n d 1 1 0 0 ± 1  h o ur 
o n t he st u d y -pr o vi de d s pir o metr y e q ui p me nt. If a patie nt has ta ke n resc ue me dicati o n wit hi n 
6  h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g or has ta ke n t he m or ni n g d ose of ast h ma 
mai nte na nce  me di cati o n, t he testi n g s h o ul d be ca n celle d, a n d t he visit s h o ul d be resc h e d ule d. All 
f or mal p ul m o nar y f u ncti o n testi n g s h o ul d be c o n d ucte d at a p pr o xi matel y t h e sa me ti me of da y 
± 1  h o ur of t he ti me it was c o n d ucte d at bas eli ne/ D o R ( V 3). Ot her pr oce d ures f or eac h visit are 
o utli ne d i n  Ta ble  2 . 
Patie nts w h o c o m plete wee k 1 6 (e n d of treat me nt visit [ E o T V; V 9]) will e nter t he f oll o w -u p 
peri o d. T he ha n d h el d de v ice a n d diar y, al o n g wit h st u d y pr o vi de d resc u e me dicati o n will be 
c ollecte d. T he i n v esti gat or s h o ul d deter mi ne a n d i m ple me nt a p pr o priate ast h ma t hera p y 
(i ncl u di n g resc ue treat me nt) t o be use d d uri n g t he f oll o w-u p peri o d. Me dicati o n starte d f or t he 
p ur p ose  of o n g oi n g ast h ma treat me nt will n ot be c o nsi dere d a pr ot oc ol vi olati o n, pr o vi de d it is 
starte d after t he fi nal s pir o metr y assess me nts are c o m plete d at wee k 1 6 ( V 9). Patie nts will be 
c o ntacte d a p pr o xi matel y m o nt h l y b y t ele p h o ne t o assess C A Es, a d verse e v e nts, a n d c o nc o mita nt 
me dicati o ns. A fi nal f oll o w -u p visit will occ ur at a p pr o xi matel y wee k  3 0 f or fi nal assess me nts. A 
C A E is defi ne d as w ors e ni n g ast h ma re q uiri n g treat me nt wit h a s yste mic c ortic oster oi d f or 
≥3  da ys, e mer ge n c y r o o m visit res ulti n g i n s yste mic c ortic oster oi d treat me nt or h os pitalizati o n 
d ue t o ast h ma. All i nsta nces of a C A E s h o ul d b e rec or de d i n t he C R F.  
Alert criteri a f or i n di vi d u al patie nts w h o de vel o p w orse ni n g ast h ma ha v e b ee n desi g ne d t o 
e ns ure patie nt safet y. If a n y of t he criteri a liste d bel o w are m et, t he i n vesti gat or will deter mi ne 
w het her t he p atie nt’s o verall cli nical pict ure is c o nsiste nt wit h w orse ni n g ast h ma a n d if t he 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 3  
patie nt s h o ul d be place d o n a d diti o nal ast h ma mai nte na nce t h era p y i n t he i nterest of patie nt 
safet y. Meetin g 1 of t h ese criteri a d oes n ot a ut o m aticall y re q uire a patie nt t o be place d o n 
alter nati ve ast h ma t hera p y; rat h er it re q uir es a cli nical e val uati o n t o deter mi ne if t he patie nt’s 
ast h ma ca n c o nti n ue t o b e ma na ge d o n t h e c urre nt re gi me n per t h e st u d y or nec essitates a c ha n ge 
i n ast h ma mai nte na nce t h era p y: 
•  m or ni n g F E V 1 b y h a n d h el d s pir o meter, as me as ure d at h o me, falls bel o w t he F E V 1 
sta bilit y li mit ( F E V1 < 8 0 % of t he scree ni n g visit F E V 1 meas ure m e nt t hat was 
meas ure d i n t he cli nic d uri n g t he s cree ni n g p eri o d)  f or t he r u n‑i n peri o d a n d t he 
baseli ne val ue ( b y ha n d h el d de vice) deter mi ne d at t he ra n d o mizati o n visit ( V 3) f or 
t he treat me nt peri o d o n 4 or m ore da ys o ut of a n y 7‑ da y peri o d. T hese val u es are 
base d o n t he ha n d h el d de vice.  
•  F E V 1, as meas ur e d at t he st u d y ce nter, is bel o w t h e F E V 1 sta bilit y li mit val ue 
calc ulate d at t he ra n d o mi zati o n visit ( V 3) ( < 8 0 % of baseli ne b y cli nic -b ase d 
s pir o metr y). 
•  base d u p o n a re vie w of patie nt diar y data, t he p atie nt has e x perie nce d a n y of t he 
f oll o wi n g d uri n g a n y 7-d a y p eri o d (t he d a ys nee d n ot be c o nsec uti ve a n d ma y o v erla p 
visits):  
− 3 or m ore da ys i n w hic h 1 2 or m ore i n halati o ns/ da y of res c ue me dicati o n 
(al b uter ol e M D PI or e q ui vale nt al b uter ol/sal b uta m ol) were us e d 
− 3 or m ore da ys wit h a ni g ht -ti me ast h ma s y m pt o m sc ore of 3 or hig h er.  
•  patie nts w h o, b y t he assess me nt of t he i n vesti gat or, are i d e ntifie d as ha vi n g 
e x perie nce d a cli nicall y mea ni n gf ul w orse ni n g of t heir ast h ma warra nti n g a c ha n ge i n 
t heir ast h ma treat me nt ( b ase d o n t he i n vesti gat or’s j u d g me nt) will start a p pr o priate 
treat me nt. A patie nt ma y be dee me d b y t h e i n vesti gat or as ha vi n g a cli nicall y 
mea ni n gf ul w orse ni n g of t heir ast h ma e ve n w he n t he y d o n ot meet t he alert criteria 
a b o ve.  
Patie nts w h o re q uire a c h a n ge i n bac k gr o u n d ast h ma mai nte na nce treat me nt s h o ul d c o m plete 
assess me nts as o utli ne d f or V 8 a n d c o nti n ue t o partici pate i n all la b orat or y a n d safet y 
assess me nts l u n g f u ncti o n, c o m pleti o n of q uesti o n naires a n d d ail y diar y ass ess me nts. (If a 
patie nt re q uires a c ha n ge i n me dicati o n bet wee n V 8 a n d V 9, t he pr oce d ures f or V 9 s h o ul d be 
c o m plete d. If a c ha n ge of me dicati o n occ urs wit hi n 2 wee ks of t he n e xt pla n ne d visit, t hat visit 
ma y b e s ki p pe d ). Patie nts w h o wit h dra w c o ns e nt or are wit h dra w n fr o m partici pati o n i n t he 
st u d y s h o ul d c o m plete t h e pr oce d ures f or t he Earl y Wit h dra wal Visit ( E W V). 
T he e n d of st u d y is defi n e d as t he last visit of t he last patie nt at t he f oll o w -u p visit.  
T he assess me nts a n d pr oce d ures p erf or me d d uri n g eac h st u d y visit are d etaile d i n Ta ble  2  a nd 
A p pe n di x  B . 
T he st u d y s c he matic dia gra m is prese nte d i n  Fi g ure  1 . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 4  
Fi g ure  1 : 
O ver all St u d y Sc he m ati c Di a gr a m  
 
A D A =a nti -dr u g a nti b o d y; P K = p har mac o ki netics.  
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
3. 2.  
Pl a n ne d N u m ber of P atie nts a n d C o u ntries  
A p pr o xi matel y 8 6 0 p atie nts will be scree ne d t o ac hie ve a p pr o xi matel y 3 0 0 ra n d o mize d patie nts , 
w hic h ma y be a dj uste d b ase d o n a n i nteri m a n al ysis . Details o n t he defi niti o n of e val ua ble 
patie nts a n d sa m ple siz e are gi ve n i n Secti o n  9 . 
T he st u d y is pla n ne d t o b e c o n d ucte d i n t he U S , Ca na da a n d else w here i nter nati o nall y, p e n di n g 
feasi bilit y ass ess me nts, i n a p pr o xi matel y 8 0 i n vesti gati o nal ce nt ers. T he st u d y is e x pecte d t o 
start i n a p pr o xi matel y Q 2 2 0 2 1 a n d last u ntil a p pr o xi matel y Q 4 2 0 2 2 (e n d of f oll o w -u p peri o d).  
3. 3.  
J ustific ati o n f or St u d y Desi g n a n d Selecti o n of P o p ul ati o n  
T his is a st u d y t o e val uat e t he safet y, effi cac y a n d p har mac o d y n a mics of T E V -5 3 2 7 5 w he n 
a d mi nistere d t o patie nts wit h u nc o ntr olle d ast h ma as “a d d -o n tr eat me nt” t o t he patie nt’s c urre nt 
ast h ma mai nte na nce re gi me n.  
T he criteri a f or i ncl usi o n a n d e x cl usi o n al o n g wit h t he ra n d o mizati o n criteri a all o w f or sel ecti o n 
of a patie nt p o p ulati o n wit h persiste nt ast h ma t hat is u nc o ntr olle d. T he criteria als o all o w f or 
selecti o n of patie nts w h o ha ve ast h ma wit h a n e osi n o p hilic p he n ot y pe as defi n e d b y ele vat e d 
peri p heral bl o o d e osi n o p hils. Patie nts wit h ast h ma a n d ele vat e d bl o o d e osi n o p hils are m ore 
li kel y t o be u nc o ntr olle d a n d s uffer e x acer bati o n of ast h ma. T he st u d y p o p ulati o n i ncl u des 
patie nts w h o ha ve m o derate t o se vere ast h ma bas e d o n c urre n t ast h ma treat me nt a n d fall i nt o 
Gl o bal I nitiati ve f or Ast h ma ( GI N A) ste ps 3, 4, a n d 5 ( GI N A 2 0 2 0 ), b ut d o n ot meet t he criteria 
of se vere diffic ult -t o-tr eat ast h ma base d o n m ulti ple e x acer bati o ns i n t he pre vi o us 1 2 m o nt hs, 
ne e d f or s yste mic c ortic oster oi ds, or ha ve re q uire d bi ol o gicals t o c o ntr ol ast h ma ( GI N A 2 0 2 0 , 
C h u n g 2 0 1 8 ). Patie nts wit h ot her l u n g c o n diti o ns i ncl u di n g s m o ki n g-rel ate d disease, ot her 
e osi n o p hilic c o n diti o ns, mali g na n c y, a n d rece nt p arasitic i nfecti o n are e x cl u de d. It is a ntici pate d 
t hat t he patie nt p o p ulati o n selecte d is well-s uite d f or tar gete d m o n ot hera p y wit h a nti-I L-5 
m A b -directe d t h era p y t o c o ntr ol u n derl yi n g e osi n o p hilic i nfla m mati o n.  
Safet y will be m o nit ore d d uri n g t he r u n -i n peri o d, at t he ti me of I M P a d mi nistrati o n (i ncl u di n g 
t he m o nit ori n g of i njecti o n site reacti o ns), a n d t hr o u g h o ut t he st u d y. T here will be cl ose 
assess me nt of vital si g ns f or a n y a d v erse e ve nt occ urri n g wit hi n 1  h o ur of d osi n g as w ell as 
i ns pecti o n of t he i njecti o n site t o detect si g ns of i njecti o n site reacti o n. I n a d diti o n t o t he o n-site 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 5  
sc he d ule d e v al uati o ns, cl ose dail y re m ote m o nit ori n g of eac h p atie nt’s safet y will be perf or me d 
electr o nicall y wit h pr e defi ne d alert cr iteria t o ca pt ure patie nts wit h w orse ni n g ast h ma b y d ail y 
l u n g f u ncti o n me as ure me nts, resc ue me dicati o n use, a n d ast h ma s y m pt o ms all o wi n g f or earl y 
rec o g niti o n of ast h ma w orse ni n g a n d i nter ve nti o n. T he st u d y will als o e m pl o y sta n dar d safet y 
m o nit ori n g i ncl u di n g a d v erse e v e nt re p orti n g, p h ysical e xa mi nati o ns, cli nical la b orat or y testi n g, 
vital si g ns assess me nts, c o nc o mita nt me dicati o n m o nit ori n g, a n d i m m u n o ge nicit y assess me nts, 
at pre defi ne d sc he d ul e d visits. A d diti o nall y, pr ot oc ol -defi ne d a d verse e v e nts of s pecial i nterest 
will i ncl u de s yste mic se v ere reacti o ns (i ncl u di n g a na p h yl a xis), i njecti o n site fi n di n gs, 
o p p ort u nistic i nfecti o ns, hel mi nt h i nfecti o ns, a n d mali g na n cies. T he safet y f oll o w -u p visit is 
a ntici pate d t o all o w f or A D A dete cti o n w he n T E V -5 3 2 7 5 i s l o w or n o n-d etecta ble b y t he c urre nt 
assa y base d o n t h e P hase 1 pr o gra m a n d t o ass ess f or a n y a d v erse e ve nt t hat ma y de v el o p o ver 
ti me. 
T he d urati o n of t his place b o -c o ntr olle d st u d y is n ot u nli ke ma n y ot her st u dies c o n d ucte d 
s uccessf ull y wit h o ut t his le vel of m o nit ori n g ( L öt vall et al 2 0 1 4 , B usse et al 2 0 1 4 , A mar et al 
2 0 1 6 , S her et al 2 0 1 7 , Ber nstei n et al 2 0 1 7 , Ra p hael et al 2 0 1 8 ). T he o v erall desi g n of t he st u d y 
is well acce pt e d a n d T e v a has si g nifica nt e x pertise a n d e x perie nce i n place b o-c o ntr olle d ast h ma 
st u dies of si milar d urati o n (A mar et al 2 0 1 6 , S her et al 2 0 1 7 , Ra p hael et al 2 0 1 8 ). 
T he sc r o ute of a d mi nistrati o n was c h ose n b eca us e it is t he i nte n de d h u ma n t hera pe utic r o ute. 
T he l o west pr o p ose d d os e ( 6 0 0 m g) was c h ose n b ase d o n t he s p o ns or’s i nt e nti o n t o e x pl ore 
p ote ntial efficac y of l o wer d oses of T E V -5 3 2 7 5.  
T he pri mar y effic ac y e n d p oi nt (sta n dar dize d baseli ne -a dj uste d tr o u g h [ pre -br o nc h o dilat or] 
m or ni n g F E V 1 at wee k 1 2) is a well -esta blis he d, cli nicall y rel e va nt e n d p oi nt a n d is sta n dar d i n 
m ost ast h ma st u dies. T he 1 2 -wee k e n d p oi nt was s electe d base d o n t he p har mac o d y na mic effects 
de m o nstrate d i n t he S A D part ( Part A) of St u d y T V 5 3 2 7 5 -P K -1 0 1 5 2 i n w hic h t he 
p har mac o d y n a mic effect was e val uat e d base d o n t he c ha n ge i n a bs ol ute e osi n o p hil c o u nts. A 
sec o n dar y e n d p oi nt is i ncl u de d t o assess t he p har m ac o d y na mic effect at wee k 1 6 gi ve n t he 
p har mac o d y n a mic effect was pr ol o n ge d w he n i ncreasi n g d os es were gi ve n t o healt h y v ol u nteers.  
F or mal p ul m o nar y f u ncti o n testi n g at wee ks 2, 4, 8, 1 2, a n d  1 6, a n d dail y F E V 1 testi n g, will 
all o w f ull c haracteriz ati o n of t he res p o nse t o T E V -5 3 2 7 5 acr oss t he vari o us d oses a n d ti me 
p oi nts. T he s p o ns or belie ves t hat l o n ger d urati o n of t he st u d y is u n warra nte d as t he F E V 1 
res p o nse, as w ell as i m pr o ve me nts i n ot her cli nicall y rele va nt e n d p oi nts, is o bser ve d a n d 
ac hie ves its ma xi m u m effects wit hi n wee ks of t he first dr u g a d mi nistrati o n, as has bee n 
de m o nstrate d f or t his mec ha nis m of acti o n a n d all m A bs t hat bel o n g t o t his class of dr u gs 
(Castr o et al 2 0 1 5 , Orte ga et al 2 0 1 4 ). Fi nall y, 1 2-wee k d urati o n cli nical trials wit h F E V 1 as 
pri mar y efficac y e n d p oi nt ha ve bee n acce pte d b y F D A as t h e pi v otal desi g n i n pr o gra ms 
e val uati n g ast h ma t hera pies a n d t heref ore m e et t h e ri g or ge n erall y re q uire d of t o P hase 3 cli nical 
pr o gra ms. F urt her c o nti n uati o n of t he effi cac y ass ess me nts i n t he st u d y be y o n d 1 6 wee ks will 
n ot a d d f urt her t o t he p h ar mac o d y na mics assess me nt i n t his p o p ulati o n.  
T he sec o n d ar y efficac y meas ures are d esi g n e d t o s u p p ort t he pri mar y o utc o me meas ure t o 
e val uate T E V -5 3 2 7 5 a n d c o nfir m t he effects o n ast h ma c o ntr ol a n d l u n g f u ncti o n o ver 1 2 a n d 
1 6  wee ks, i ncl u di n g wee kl y well -c o ntr olle d ast h ma stat us, dail y ass ess me nt of F E V 1, assessi n g 
ast h ma c o ntr ol b y dai l y s y m pt o m sc ores a n d res c u e me dicati o n use, ti me t o cli nical ast h ma 
e x acer bati o n ( C A E), a n d sta n dar dize d q uesti o n naires t hat assess ast h ma c o ntr ol a n d q ualit y of 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Pl ace b o-C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
5 6  
life. I n a d diti o n, f or mal p ul m o nar y f u ncti o n testi n g will be c o n d u cte d at w ee k 1 6 t o e val u ate f or 
effic ac y be y o n d 1 2  wee ks.  
Bl o o d e osi n o p hil le vels are acce pte d as a m or e practical bi o mar ker (c o m pare d t o s p ut u m 
e osi n o p hil le vels) f or i de ntif yi n g patie nts wit h acti ve air wa y e osi n o p hilia w h o c o ul d be nefit fr o m 
a nti-I L-5 t hera p y. Patie nts wit h ast h ma  a n d ele vat e d e osi n o p hils ha ve a hi g her ris k of 
e x acer bati o n i n t he ne xt 1 2 m o nt hs c o m pare d t o t h ose wit h l o wer e osi n o p hils ( Tra n et al 2 0 1 4 , 
Zei ger et al 2 0 1 4 ) a n d patie nts wit h peri p heral e osi n op hil c o u nts ≥4 0 0  cell/ µ L te n d t o be less 
well -c o ntr olle d a n d h a ve m ore fre q u e nt e xacer bati o ns, a n d e x acer bati o ns i ncreas e d as t he 
peri p heral bl o o d e osi n o p hil c o u nts i ncrease ( Price et al 2 0 1 5 ). 
3. 4.  
St o p pi n g R ules f or t he St u d y  
T he re are n o f or mal r ules f or earl y t er mi nati o n of t his st u d y. D uri n g t he c o n d uct of t he st u d y, 
seri o us a d vers e e v e nts will be re vie we d ( Secti o n 7. 1. 5 ) as t he y are re p orte d fr o m t he 
i n vesti gati o nal c e nters t o i de ntif y safet y c o n cer ns.  
T he st u d y ma y b e ter mi n ate d b y t he s p o ns or f or a n y reas o n at a n y ti me. F or e x a m ple, t he 
s p o ns or s h o ul d ter mi nate t he st u d y i n t he e v e nt of: 
•  ne w t o xic ol o gical or p har mac ol o gical fi n di n gs or safet y iss ues t hat i n vali date t he 
earlier p ositi ve be n efit -ris k assess me nt 
•  disc o nti n uati o n of t he de vel o p me nt of t he I M P  
If t he w h ole st u d y or ar ms of t he st u d y are st o p pe d, t he patie nts t hat are ter mi nate d earl y will be 
f oll o we d acc or di ng t o Wit h dra wal Criteria a n d Pr oce d ures f or t he Patie nt (Secti o n  4. 4 ). 
3. 5.  
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts  
St u d y pr oce d ures a n d ass ess me nts  wit h t heir ti me p oi nts are pres e nte d i n T a ble  2 . Detaile d 
descri pti o ns of eac h met h o d of pr oce d ures a n d assess me nts are pr o vi d e d i n Secti o n  6  (efficac y 
assess me nts), Secti o n  7  (safet y assess me nts), a n d Secti o n  8  ( p har mac o ki netics, i m m u n o ge nicit y, 
bi o mar kers, a n d p h ar mac o ge n etics). St u d y pr oce d ures a n d ass ess me nts b y visit are liste d i n 
A p pe n di x  B . F or det ails of t he ma na ge m e nt of st u d y acti vities d uri n g C O VI D-1 9 o ut brea ks, see 
A p pe n di x  N . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
5 7  
T a ble  2 : 
St u d y Pr oce d ures a n d Assess me nts  
St u d y pe ri o d  
Pretre at me nt  
D o u ble -bli n d tre at me nt peri o d  
F oll o w -u p peri o d  
F oll o w -
u p a  
Visit n u m ber  
V 1 b  
V 2 c 
V 3 d  
V 4  
V 5  
V 6  
V 7  
V 8  
V 9 e  
( E o T V) 
E W V f 
Tele p h o ne g 
V 1 0  
D a y a n d  all o w e d ti me 
wi n d o ws  
U p t o 2 
w ee ks  
1 4 ± 2 
d a ys  
D a y  0  
D a y  
3 ± 2  
D a y  
1 4 ± 2  
D a y  
2 8 ± 2  
D a y  
5 6 ± 2  
D a y  
8 4 ± 2  
D a y 
1 1 2 ± 2  
N A  
D a y  
1 4 0 ± 2  
D a y 
1 6 8 ± 2  
D a y 
1 9 6 ± 2  
D a y 
2 1 0 ± 5  
Pr oce d ures a n d assess me nts  
Scree ni n g  
R u n - 
i n 
B aseli ne/
D o R  
W 1  
W 2  
W 4  
W 8  
W 1 2  
W 1 6  
N A  
W 2 0  
W 2 4  
W 2 8  
W 3 0  
I nf or me d c o nse nt h 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n a n d e xcl usi o n criteria 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n criteria  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
P erf or m ra n d o mizati o n a n d 
treat me nt assi g n me nt i n I R Ti 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Ast h ma hist or y j 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C urre nt ast h ma me dicati o n 
assess me nt k 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or me dicati o n a n d treat me nt  
hist or y l 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
F ull p h ysical e xa mi n ati o n m  
 
 
X  
 
 
 
 
 
X  
X  
 
 
 
 
Brief p h ysical e xa mi n ati o n n 
X  
 
 
 
X  
X  
X  
X  
 
 
 
 
 
X  
Hei g ht (c m)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht ( k g)  
X  
 
 
 
 
 
 
 
X  
X  
 
 
 
 
P ul m o nar y f u ncti o n testi n g 
wit h re versi bilit y o 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
P ul m o nar y f u ncti o n testi n g p 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
He mat ol o g y ( C B C wit h 
differe ntial q) 
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
5 8  
St u d y pe ri o d  
Pretre at me nt  
D o u ble -bli n d tre at me nt peri o d  
F oll o w -u p peri o d  
F oll o w -
u p a  
Visit n u m ber  
V 1 b  
V 2 c 
V 3 d  
V 4  
V 5  
V 6  
V 7  
V 8  
V 9 e  
( E o T V) 
E W V f 
Tele p h o ne g 
V 1 0  
D a y a n d  all o w e d ti me 
wi n d o ws  
U p t o 2 
w ee ks  
1 4 ± 2 
d a ys  
D a y  0  
D a y  
3 ± 2  
D a y  
1 4 ± 2  
D a y  
2 8 ± 2  
D a y  
5 6 ± 2  
D a y  
8 4 ± 2  
D a y 
1 1 2 ± 2  
N A  
D a y  
1 4 0 ± 2  
D a y 
1 6 8 ± 2  
D a y 
1 9 6 ± 2  
D a y 
2 1 0 ± 5  
Pr oce d ures a n d assess me nts  
Scree ni n g  
R u n - 
i n 
B aseli ne/
D o R  
W 1  
W 2  
W 4  
W 8  
W 1 2  
W 1 6  
N A  
W 2 0  
W 2 4  
W 2 8  
W 3 0  
He mat ol o g y ( b li n de d C B C 
wit h differe ntial r) 
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
 
 
X  
Ser u m c he mistr y s 
X  
 
X s 
 
 
X  
X  
X  
X s 
X  
 
 
 
X  
O pti o nal bl o o d sa m ple f or 
bi o mar ker ba n ki n g t 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d sa m ple f or He patitis B, 
He patitis C a n d HI V testi n g u 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d sa m ple f or P ha diat o p 
aller g y test a n d t otal I g E  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Bl o o d sa m ple f or 
p har mac o ge netic testi n g v , w  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Bl o o d sa m ple f or ser u m 
c o nce ntrati o n of I M P w  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
X  
Bl o o d sa m ple f or A D A w  
 
 
X  
 
 
 
 
 
X  
X  
 
 
 
X  
Bl o o d sa m ple f or ser u m 
bi o mar ker (I L -5) a nal ysis w  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
X  
Uri nal ysis  
X  
 
X  
 
 
 
 
 
X  
X  
 
 
 
 
Uri ne pre g na nc y test f or 
W O C B P ( β -H C G)  
X  
 
X  
 
 
X  
X  
X  
X  
X  
 
 
 
X  
F S H x 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2 -lea d E C Gy 
 
 
X z 
 
 
 
 
 
X  
X  
 
 
 
 
Vital si g ns meas ure me nt aa 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
 
 
 
X  
 
 
 
X  
 
 
 
 
X  
 
X  
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
5 9  
St u d y pe ri o d  
Pretre at me nt  
D o u ble -bli n d tre at me nt peri o d  
F oll o w -u p peri o d  
F oll o w -
u p a  
Visit n u m ber  
V 1 b  
V 2 c 
V 3 d  
V 4  
V 5  
V 6  
V 7  
V 8  
V 9 e  
( E o T V) 
E W V f 
Tele p h o ne g 
V 1 0  
D a y a n d  all o w e d ti me 
wi n d o ws  
U p t o 2 
w ee ks  
1 4 ± 2 
d a ys  
D a y  0  
D a y  
3 ± 2  
D a y  
1 4 ± 2  
D a y  
2 8 ± 2  
D a y  
5 6 ± 2  
D a y  
8 4 ± 2  
D a y 
1 1 2 ± 2  
N A  
D a y  
1 4 0 ± 2  
D a y 
1 6 8 ± 2  
D a y 
1 9 6 ± 2  
D a y 
2 1 0 ± 5  
Pr oce d ures a n d assess me nts  
Scree ni n g  
R u n - 
i n 
B aseli ne/
D o R  
W 1  
W 2  
W 4  
W 8  
W 1 2  
W 1 6  
N A  
W 2 0  
W 2 4  
W 2 8  
W 3 0  
A C Q -6 cc 
 
X  
X  
 
X  
X  
X  
X  
X  
X  
 
 
 
 
A C T  
 
 
X  
 
 
X  
X  
X  
X  
X  
 
 
 
 
A Q L Q( S) cc 
 
 
X  
 
 
 
 
X  
X  
X  
 
 
 
 
 
 
 
X  
 
 
 
 
X  
 
X  
 
 
 
 
Dis pe nse ha n d hel d de vice a n d 
diar y  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
C o n d uct trai ni n g f or ha n d hel d 
de vice a n d diar y use d d 
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
Re vie w c o m plia nce wit h diar y 
a n d ha n d hel d de vice ee 
 
 
X  
 
X  
X  
X  
X  
 
 
 
 
 
 
C ollect ha n d hel d de vice a n d 
diar y  
 
 
 
 
 
 
 
 
X  
X  
 
 
 
 
I M P d osi n gff 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
I njecti o n site e val u ati o ng g 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Dis pe nse resc ue me dicati o n h h 
 
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
C ollect resc ue me dicati o n h h 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
C A E i n q uir y ii 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts i n q uir y  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt me dicati o n 
i n q uir y 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P erf or m C O VI D -1 9 s y m pt o ms 
i n q uir yjj 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
6 0  
a T he st u d y is c o m plete d w he n t he last patie nt c o m pletes t he f oll o w -u p visit.  
b T he scree ni n g visit will ta ke place n ot m ore t ha n a p pr o xi mat el y 4 wee ks bef ore t he baseli ne/ D o R visit ( V 3) a n d is li mite d t o a p pr o xi matel y 1 4  da ys d urati o n. It 
is u n derst o o d t hat n ot all pr oce d ures ca n be c o m plete d o n t he sa me da y. I n partic ular, t he patie nt ma y nee d t o ret ur n f or re peat C B C testi n g as nee de d or t o 
satisf y t he me dicati o n was h o ut f or p ul m o nar y f u ncti o n testi n g or t o u n der g o re peat p ul m o nar y  f u ncti o n testi n g. 
c V 2 is t he be gi n ni n g of t he r u n -i n peri o d. T he r u n-i n peri o d s h o ul d be a p pr o xi matel y 1 4± 2 da ys i n d urati o n wit h all o wa nces ma d e f or sc he d uli n g. P atie nts will 
be trai ne d o n pr o per use of t he ha n d hel d de vice a n d electr o ni c diar y wit h e m p hasis o n pr o per use a n d c o m plia nce wit h pr oce d ures.  
d V 3 s h o ul d be hel d after t he patie nt has c o m plete d 1 2 da ys at mi ni m u m i n t he r u n -in peri o d. Assess me nt of ra n d o mizati o n criteria s h o ul d be c o m plete d pri or t o 
ta ki n g bl o o d sa m ples or a d mi nisteri n g I M P t o e ns ure t hat t he patie nt q ualifies t o e nter t he treat me nt peri o d. Dail y l u n g f u ncti o n a n d diar y c o m plia nce will b e 
calc ulate d electr o nic all y a n d s h o ul d be assesse d f or c o m plia nce. At t his visit t he patie nt’s diar y data s h o ul d be re vie we d pri or t o f or mal l u n g f u ncti o n t esti n g, 
la b orat or y testi n g a n d t he vari o us q uesti o n naires t o e ns ure c o m plia nce wit h diar y e ntries a n d t o deter mi ne if l u n g f u ncti o n, s y m pt o ms a n d resc ue me di cati o n 
use meet t he ra n d o mizati o n criteria or if t he patie nt s h o ul d be c o nsi dere d t o ha ve faile d ra n d o mizati o n. O nce all of t he ra n d o mizati o n criteria are met, t he bl o o d 
sa m ples will be c ollecte d pri or t o ra n d o mizati o n i n t he I R T s yste m a n d I M P d osi n g. 
e V 9 is t he last visit d uri n g t he d o u ble -bli n d treat me nt peri o d. P atie nts w h o c o m plete t his visit s h o ul d be a d vise d re gar di n g o n g oi n g ast h ma mai nte na nc e 
treat me nt. St u d y pr o vi de d resc ue me dicati o n s h o ul d be c ollecte d (al b uter ol/sal b uta m ol). P atie nts w h o re q uire a c ha n ge i n me dicati o n d ue t o a C A E or t o 
mai ntai n ast h ma c o ntr ol (see alert criteria f or w orse ni n g ast h ma) s h o ul d c o m plete V 8 pr oce d ures pri or t o t he c ha n ge i n me dicati o n w he ne ver p ossi ble a n d t hese 
patie nts s h o ul d c o nti n ue partici pati o n f or c ollecti o n of l u n g f u ncti o n testi n g, q uesti o n naires, bl o o d sa m ples a n d safet y m o ni t ori n g u ntil t he e n d of t he st u d y. If a 
c ha n ge occ urs after V 8, t he V 9 pr oce d ures s h o ul d be c o m pl ete d a n d t he patie nt s h o ul d e nt er t he f oll o w -u p peri o d.  
f P atie nts w h o wit h dra w c o nse nt or ca n n ot p artici pate i n t he re mai ni n g st u d y assess me nts.  
g Res ults fr o m t he tele p h o ne f oll o w -u p calls s h o ul d be rec or de d o n t he C R F a n d n ote d wit hi n t he patie nts' s o urce d oc u me nts.  
h I nf or me d c o nse nt s h o ul d be o btai ne d pri or t o a n y ot her st u d y pr oce d ures.  
i Ra n d o mizati o n via t he I R T s yste m s h o ul d n ot be d o ne u ntil all l u n g f u ncti o n, q uesti o n nair es a n d cli nical assess me nts ha ve bee n c o m plete d t o e ns ure t hat 
patie nts meet t he  st u d y re q uire me nts a n d are a p pr o priate f or d osi n g.  
j T he patie nt's hist or y of ast h ma s h o ul d be e val uate d i ncl u di n g d urati o n, c urre nt me dicati o n, a n d hist or y of e xacer bati o ns i n t he last year.  
k T he patie nts ast h ma mai nte na nce me dicati o n s h o ul d be e val uate d base d o n I C S d ose. Me di u m or hi g h d ose I C S ( wit h o ut L A B A) a n d l o w d ose I C S/ L A B A 
t o get her a n d me di u m or hi g h d ose I C S/ L A B A c o m bi nati on will be gr o u pe d t o get her a n d e ntere d i nt o t he I R T s yste m at V 2.  
l A n y pri or or c o nc o mita nt t her a p y, me dicati o n, or pr oce d ure a patie nt has ha d u p t o 3 0 da ys bef ore scree ni n g will be rec or de d i n t he s o urce d oc u me ntati o n a n d 
i n t he C R F. 
m  T he f ull p h ysical e xa mi nati o n will i ncl u de H E E N T, c hest, car di o vasc ular, a b d o mi nal, s ki n, e xtre mit y a n d ne ur ol o gical e x a mi nat i o ns. 
n T he brief p h ysical e xa mi nati o n will i ncl u de, at mi ni m u m, c hest, car di o vasc ular, a b d o mi nal, a n d s ki n e xa mi nati o ns.  
o P ul m o nar y f u ncti o n testi n g (s pir o met r y) a n d re versi bilit y testi n g will be c o n d ucte d i n t he m or ni n g bet wee n 0 5 3 0 a n d 1 1 0 0 h o urs usi n g t he st u d y -pr o vi de d 
s pir o metr y e q ui p me nt. P atie nts are re q uire d t o wit h h ol d ast h ma mai nte na nce me dicati o ns f or a p pr o xi matel y 2 4 h o urs pri or t o l u n g f u ncti o n tes ti n g f or o nce 
dail y me dicati o ns, 1 2 h o urs f or t wice dail y or m ore fre q ue ntl y d ose d me dicati o n. If t he pati e nt has ta ke n ast h ma mai nte na nce me dicati o n wit hi n 2 4 ± 2 ( dail y 
d ose d) or 1 2 ± 2 h o urs ( d ose d t wice dail y or m ore fre q ue ntl y) or S A B A resc ue me dicati o n w it hi n 6 h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g or 
I C S/ L A B A use d as resc ue me dicati o n wit hi n 1 2 h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g, t he visit m ust b e resc he d ule d. P atie nts w h o meet t he 
pre -al b uter ol/sal b uta m ol l u n g f u ncti o n re q uire me nt s a n d de m o nstrate re versi bilit y ≥1 2 % a n d a 2 0 0  m L i ncrease fr o m pre -al b uter ol/sal b uta m ol F E V 1 
a p pr o xi matel y 3 0 mi n utes after 4 i n halati o ns of al b uter ol/sal b uta m ol H F A M DI ( 9 0  µ g e x -act uat or) or e q ui vale nt ma y e nter t he r u n -i n peri o d if t he y meet ot her 
eli gi bilit y re q uire me nts as s pe cifie d. P atie nts ma y re peat p ul m o nar y f u ncti o n testi n g (s pir o metr y) a n d re versi bilit y testi n g o nce d uri n g t he scree ni n g peri o d as 
nee de d t o q ualif y.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
6 1  
p P ul m o nar y f u ncti o n testi n g (s pir o metr y) will occ ur i n t he m or ni n g bet wee n t he h o urs of 0 5 3 0 t o 1 1 0 0 at V 3. F or s u bse q ue nt visits, testi n g s h o u l d be wit hi n 
a p pr o xi matel y 1 h o ur of t he ti me t he testi n g occ urre d at baseli ne/ D o R ( V 3), ie 0 5 3 0 -1 1 0 0 ± 1 h o ur . T he patie nt s h o ul d wit h h ol d ast h ma mai nte na nce me dicati o n 
f or 2 4± 2 ( dail y d ose d) or 1 2 ± 2 h o urs ( d ose d t wice dail y or m ore fre q ue ntl y) or S A B A res c ue me dicati o n wit hi n 6 h o urs of t he pla n ne d p ul m o nar y f u ncti o n 
testi n g. 
q C B C wit h differe ntial i ncl u di n g a n e osi n o p hil c o u nt d uri n g s cree ni n g t o esta blis h safet y a n d mi ni m u m e osi n o p hil c o u nt. T o be i ncl u de d i n t he st u d y, t he 
e osi n o p hil c o u nt m ust b e ≥3 0 0 cells/ μ L. T esti n g ma y be re peate d o nce d uri n g scree ni n g. N o r o u n di n g o f t he res ult is per mitte d. 
r Bli n de d C B C wit h differe ntial c o u nt will be dra w n at visits after  V 3 o n war d  t o mai ntai n st u d y bli n di n g. T he e osi n o p hil a n d m o n oc yte c o u nts will n ot b e 
re p orte d t o t he st u d y pers o n nel. 
s Ser u m c he mistr y assess me nts s h o ul d be dra w n wit h t he patie nt fasti n g f or at least 8 h o urs pri or t o testi n g at V 3 a n d V 9.  
t A bl o o d sa m ple f or bi o mar ker ba n ki n g s h o ul d be dra w n fr o m all s u bj ects at scree ni n g w h o ha ve pr o vi de d i nf or me d c o nse nt f or t h e st ora ge a n d p ote ntial f ut ure 
testi n g of sa m ples i n t his or ot her ast h ma pr o gra ms, or ot her diseases t hat ma y be e x pl ore d b y t he s p o ns or. 
u T esti n g f or He p atitis B s urfac e a nti ge n, He p atitis C a n d HI V are re q uire d t o partici p ate i n t he st u d y. P atie nts m ust pr o vi de c o nse nt a n d re p orti n g will f oll o w 
l ocal re g ulati o ns. 
v Bl o o d f or p har mac o ge netic testi n g will b e o btai ne d s pecific all y t o test 2 ge ne varia nts H S D 3 B 1 -( 1 2 4 5A) a n d H S D 3 B 1 -( 1 2 4 5 C) w hic h ma y pre dict 
c ortic oster oi d se nsiti vit y i n ast h ma. I nf or me d c o nse nt m ust be o btai ne d f or t his testi n g.  
w  Date a n d ti me of sa m ple c ollecti o n will be rec or de d. I nstr ucti ons f or t he pr o per c ollecti o n, ha n dli n g, la beli n g, a n d s hi p pi n g of t he sa m ples are a vaila bl e i n t he 
st u d y refere nce ma n ual. 
x F S H o nl y f or w o me n t o c o nfir m p ost -me n o pa usal state.  
y Sta n dar d 1 2 -lea d E C G will be perf or me d wit h t he patie nt i n t he s u pi ne p ositi o n usi n g sta n dar dize d e q ui p me nt a n d will b e re vie we d l ocall y a n d ce ntrall y.  
z E C G will be perf or me d i n tri plicate o n D o R. Eac h E C G will be ta ke n wit hi n 1 t o 5 mi n utes of t he pre vi o us o ne.  
aa Vital si g ns s h o ul d be ta ke n wit h t he patie nt seate d, se mi -rec u m be nt or s u pi ne after a p pr o xi matel y 5 mi n utes rest. Vital si g ns s h o ul d i ncl u de bl o o d press ure 
(s yst olic/ diast olic), p ulse rate, res pirat or y rate, a n d b o d y te m perat ure. T he sa me p ositi o n a n d ar m s h o ul d be use d f or bl o o d press ure rea di n gs as m uc h as 
p ossi ble. If t he o p p osi te ar m is use d it will n ot be c ollecte d as a pr ot oc ol de viati o n. 
b b
 
cc
 
d d P atie nts s h o ul d be trai ne d o n t he pr o per use of t he ha n d hel d de vice t o meas ure l u n g f u nct i o n i ncl u di n g perf or mi n g rea di n gs pri or t o ta ki n g dail y ast h ma 
mai nte na nce me dicati o n a n d pri or t o ta ki n g resc ue me dicati o n wit hi n 6 h o urs of testi n g (as p ossi ble). T he patie nt s h o ul d be r etrai ne d at eac h visit as i n dicate d.  
ee Re vie w c o m plia nce wit h ha n d hel d de vice meas ure me nts a n d wit h diar y e ntries, i ncl u di n g t he pr o per use i n relati o n t o ast h ma ma i nte na nce me dicati o n a n d 
resc ue me dicati o n use/ti mi n g. 
ff P atie nts w h o meet t he re q uire me nts f or ra n d o mizati o n, after t he pr oce d ures f or s peci me n c ollecti o n a n d ot her testi n g, will ea c h recei ve 4 sc i nj ecti o ns i n t he 
a b d o me n, a d mi nistere d b y a q ualifie d healt h care pr o vi der (acc or di n g t o l oca l re g ulati o ns) w h o is pre pare d t o ma na ge a n a p h yla xis, as descri be d i n t he st u d y 
refere nce ma n ual. T he kit n u m ber a n d l ocati o n will be rec or de d i n t he s o urce d oc u me nts a n d e ntere d i n t he C R F f or eac h of t he  4 i nj ecti o n site l ocati o ns al o n g 
wit h a n y i nj ecti o n site reacti o ns e val uate d at a p pr o xi matel y 1 h o ur after d osi n g. If t he patie nt de vel o ps cli nical s y m pt o ms, vital si g ns s h o ul d be rec or de d a n d 
t he patie nt s h o ul d be assesse d f or a na p h yla xis/ h y perse nsiti vit y reacti o ns. Bef ore lea vi n g t he cli nic, patie nts will a d diti o nall y be a d vise d of s y m pt o ms/si g ns f or 
w hic h t he y s h o ul d see k me dical a d vice or me dical treat me nt.  
g g E val uati o n of i nj ecti o n site f or reacti o n will be perf or me d at a p pr o xi matel y 1 h o ur  after d osi n g usi n g t he i nj ecti o n site C R F. I nj ecti o n site fi n di n gs will n ot b e 
ca pt ure d as a d verse e ve nts u nl ess t he y f ulfill c haracteristics t hat are be y o n d t h ose i n t he s p ecifie d f or ms/scales (e g, necr o sis, a bscess, etc.) or f ulfill seri o us ness 
criteria ; if f ulfille d, t he y m ust be rec or de d a n d re p orte d. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
6 2  
h h Resc ue me dicati o n: Al b uter ol s ulfate i n halati o n p o w der 1 1 7  µ g (al b uter ol e M D PI) or e q ui vale nt al b uter ol/sal b uta m ol will be distri b ute d t o pa tie nts at t he start 
of t he r u n -i n peri o d a n d t hr o u g h o ut t he st u d y as nee de d. P atie nts ma y be gi ve n a sec o n d i n haler f or w or k or sc h o ol if re q uire d. Resc ue me dicati o n will n ot b e 
pr o vi de d after wee k 1 6 ( V 9). Resc ue me dicati o n s h o ul d be c ollecte d w he n a pati e nt c o m pletes wee k 1 6 ( V 9) a n d i nter mitte ntl y t hr o u g h o ut t he st u d y w he ne ver 
a patie nt re q uires a refill. T he i n haler d ose c o u nter s h o ul d be i ns pecte d, a n d t he d ose c o u nt er s h o ul d be rec or de d, at eac h v isit. P atie nts w h o re q uire a ne w 
i n haler t o mai ntai n s up pl y s h o ul d ret ur n t he c urre nt i n haler d e vice, t he d ose c o u nter s h o ul d be rec or de d, a n d t he i n haler st ore d f or ret ur n as o utl i ne d i n t he 
st u d y refere nce ma n ual. Acc o u nta bilit y f or n o n-I M P resc ue me dicati o n is re q uire d. 
ii I n t he e ve nt of a C A E d uri n g t he treat me nt peri o d, P ul m o nar y f u ncti o n testi n g s h o ul d be o btai ne d if t he i n vesti gat or dee ms it  is safe t o d o s o. Bl o o d sa m ples t o 
test T E V-5 3 2 7 5 ser u m c o nce ntrati o n, A D A a n d free a n d t otal ser u m I L -5 le vels s h o ul d be c ollecte d if p ossi ble a n d st u d y pr oce d ures as o utli ne d i n V 8 s h o ul d 
be c o m plete d. C A Es t hat occ ur d uri n g t he f oll o w -u p peri o d s h o ul d be n ote d a n d rec or de d b ut n o f urt her testi n g is i n dicate d ot her t ha n t h ose at V 1 0.  
jj If a patie nt e x hi bits cli nical s y m pt o ms d uri n g t he st u d y t hat ma y i n dicate C O VI D-1 9 i nfecti o n, t he patie nt will be teste d f or acti ve C O VI D -1 9 i nfecti o n. 
A d diti o nall y, testi n g of patie nts w h o are as y m pt o matic f or C O VI D -1 9 acti ve i nfecti o n ma y be c o n d ucte d at t he discreti o n of t he i n vesti gat or wit hi n 7 2 h o urs of 
a n y visit w here s pir o metr y ass ess me nts are t o be c o n d ucte d or as re q uire d b y healt h a ut h orities, l ocal et hics c o m mittees, or st u d y ce nter S O Ps. T he testi n g ma y 
be c o n d ucte d b y t he ce ntral la b orat or y or l ocall y de pe n di n g o n feasi bilit y. P C R testi n g s h o ul d be c o n d ucte d t o c o nfir m a n y p o siti ve test f or a nti ge n (ra pi d 
testi n g). 
β -H C G = beta h u ma n c h ori o nic g o na d otr o pi n; A C Q -6 = Ast h ma C o ntr ol Q uesti o n naire; A C T = Ast h ma  C o ntr ol T est; A D A =a nti -dr u g a nti b o d y; 
A Q L Q( S) = Sta n dar dize d Ast h ma Q ualit y of Life Q uesti o n naire; C A E =cli nical ast h ma e xac er bati o n; C B C =c o m plete bl o o d c o u nt; C O VI D -1 9 =c or o na vir us 2 0 1 9; 
C R F = Case Re p ort F or m; C R S w N P =c hr o nic r hi n osi n usitis wit h nasal p ol y ps; D o R = da y of ra n d o mizati o n; E C G =electr o car di o gra m; e M D PI =electr o nic 
m ulti d ose dr y p o w der i n haler; E o T V =e n d of treat me nt visit; E W V =earl y wit h dra wal visit; F E V
1=f orce d e x pirat or y v ol u me i n 1 sec o n d; F S H =f ollicle sti m ulati n g 
h or m o ne; H E E N T = hea d, e yes, ears, n ose, a n d t hr oat; H F A = h y dr ofl u or oal ka ne; HI V = h u ma n i m m u n o deficie nc y vir us; I C S =i n hale d c ortic oster oi d; 
I g E =i m m u n o gl o b uli n E; I L-5 =  i nterle u ki n 5 ; I M P =i n vesti gati o nal me dici nal pr o d uct; I R T =i nteracti ve res p o nse tec h n ol o g y; L A B A =l o n g-acti n g β a dre ner gic 
a g o ni st; M DI = metere d-d ose i n haler; S A B A =s h ort -acti n g β -a dre ner gic a g o nist; sc =s u bc ut a ne o us; 
; 
; S O P =sta n dar d o perati n g pr oce d ure; V = visit; W = wee k; W O C B P = w o me n of c hil d-beari n g p ote ntial.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 3  
4.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
Pr os pecti ve wai vers (e x ce pti o ns) fr o m st u d y i ncl usi o n a n d e x cl usi o n criteria t o all o w patie nts t o 
be ra n d o mize d/e nr olle d are n ot gra nte d b y T e va.  
4. 1.  
P atie nt I ncl usi o n Criteri a  
Patie nts ma y be i ncl u d e d i n t his st u d y o nl y if t he y meet all of t he f oll o wi n g criteria:  
a. T he patie nt is ca p a ble of gi vi n g si g n e d i nf or me d c o ns e nt. 
b.  T he patie nt is a n a d ult fe male or male ≥1 8  years of a ge. N ote: A ge re q uire me nts are 
as s pecifie d or all o we d b y l ocal re g ulati o ns.  
c. [ Re visi o n 1] T he patie nt has a dia g n osis of ast h ma f or at least 6  m o nt hs as defi ne d b y 
t he Nati o nal I nstit utes of Healt h ( NI H) a n d h as bee n sta ble wit h o ut e xacer bati o n or 
c ha n ge i n me dic ati o ns f or at least 1  m o nt h . 
d.  T he patie nt has a n a bs ol ute bl o o d e osi n o p hil c o u nt ≥3 0 0  cells/ μ L de m o nstrate d 
d uri n g t he s cree ni n g p eri o d . N ote: R o u n di n g of t he v al ue (c o u nt) is n ot per mitte d . 
e. S e verit y of Diseas e: T he patie nt has persiste nt ast h ma, wit h a tr o u g h F E V 1 ≥4 0 % a n d 
≤8 5 % of t he val ue pre dicte d as per t he Nati o nal H ealt h a n d N utriti o n E x a mi nati o n 
S ur ve y ( Ha n ki ns o n et al 1 9 9 9 , N H A N E S III 1 9 9 8 ) a n d a dj uste d f or et h nicit y 
(Ha n ki ns o n et al 2 0 1 0 ). N ote: P atie nts w h o d o n ot q u alif y f or t he st u d y d ue t o 
f ail ure t o meet b aseli ne s pir o metr y o r f ail t o ac hie ve s pir o metr y c o nsiste nt wit h 
t he A meric a n T h or acic S ociet y ( A T S)/ E ur o pe a n Res pir at or y S ociet y ( E R S) 
criteri a (Miller et al 2 0 0 5 ) will be per mitte d t o perf or m re pe at s pir o metr y 
d uri n g t he scree ni n g peri o d o n 1 occ asi o n a n d if criteri a are n ot met, will be 
c o nsi dere d t o h a ve f a ile d scree ni n g. 
f. Re versi bilit y of Dise ase: T he patie nt has de m o nstr ate d re v ersi bilit y of ≥1 2 % 
(i ncrease) of F E V1 a n d a mi ni m u m 2 0 0  m L i ncrease fr o m pre -al b uter ol/sal b uta m ol 
F E V 1 a p pr o xi matel y 3 0  mi n utes after 4  i n halati o ns of al b uter ol/sal b uta m ol 
h y dr ofl u or oal ka n e ( H F A) metere d -d ose i n haler ( M DI) ( 9 0  µ g e x -act uat or) or 
e q ui vale nt d uri n g t he scree ni n g peri o d.  
g.  [ Re visi o n 1] C urre nt Ast h ma T hera p y: T h e patie nt has bee n mai ntai ne d f or at least 
1  m o nt h  o n sta ble d oses of:  
− me di u m or hi g h d ose I C S ±a n ot her c o ntr oller.  
− a n y fi x e d d ose c o m bi nati o n I C S (l o w, me di u m, or hi g h) wit h L A B A ±a n ot h er 
c o ntr oller.  
h.  W o me n of n o n -c hil d beari n g p ote ntial w h o are eit h er s ur gicall y ( d oc u me nte d 
h ysterect o m y, bilateral o o p h orect o m y, or bilateral sal pi n gect o m y) or c o n ge nitall y 
sterile as assess e d b y a p h ysicia n, or 1-year p ost me n o pa usal ( n o me nses f or at least 
1 2 m o nt hs wit h o ut a n alter nati ve me dical ca us e pl us a n i ncrease d c o n ce ntr ati o n of 
f ollicle sti m ulati n g h or m o ne [ F S H] of m ore t ha n 3 5 U/ L i n w o me n n ot usi n g 
h or m o nal c o ntrace pt i o n or h or m o nal re place me nt t hera p y). W o me n of c hil d beari n g 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 4  
p ote ntial m ust ha ve a ne gati ve β -h u ma n c h ori o nic g o na d otr o pi n ( β -H C G) test res ult 
a n d practice a hi g hl y effecti ve met h o d of birt h c o ntr ol ( met h o ds t hat ca n ac hie ve a 
fail ure rate of less t ha n 1 % per year w h e n use d c o nsiste ntl y a n d c orrectl y) pri or t o 
I M P a d mi nistrati o n a n d 3 0 wee ks after t he d os e of I M P. Hi g hl y effecti ve 
c o ntrace pti o n i ncl u des:  
− c o m bi ne d estr o ge n a n d pr o gest o ge n h or m o nal c o ntrace pti o n ( oral, i ntra va gi nal, 
tra ns der mal) ass ociate d with i n hi biti o n of o v ulati o n; t hese s h o ul d be i nitiate d at 
least 7 da ys bef ore t he first d ose of I M P 
− pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ( oral, i njecta ble, i m pla nta ble) 
ass ociate d wit h i n hi biti o n of o v ulati o n; t hese s h o ul d be i nitiate d at least 1 4 da ys 
be f ore t h e first d ose of I M P 
− i ntra uteri ne de vic e (I U D) a n d i ntra uteri ne h or m o ne-rel easi n g s yste m (I U S) nee d 
t o be i n place at least 2 m o nt hs bef ore scree ni n g 
− bilateral t u bal occl usi o n, e x ce pt f or h yst er osc o pic bi -t u bal li gati o n f or w hi c h a 
h yster os al pi n g o gra m ( H S P) is re q uire d 3 m o nt hs p ost pr oce d ure t o assess s ur gical 
s uccess 
− vasect o miz e d part ner pr o vi de d he is t he s ole se x ual part ner a n d h as recei ve d 
me dical assess me nt of t h e s ur gical s uc cess  
− se x ual a bsti ne nce is o nl y c o nsi dere d a hi g hl y effecti ve met h o d if defi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse i n t he st u d y peri o d. 
i. T he patie nt m ust be willi n g a n d a ble t o c o m pl y wit h st u d y restricti o ns a n d t o re mai n 
at t he i n vesti gati o nal ce nter f or t he re q uire d d urati o n d uri n g t he st u d y peri o d a n d t he 
f oll o w-u p  pr oce d ures a n d assess me nts as s pecifi e d, a n d be willi n g t o r et ur n t o t he 
i n vesti gati o nal c e nter f or f urt her visits, as a p plica ble. 
j. T he patie nt, as j u d ge d b y t he i n vesti gat or, is a bl e t o c o nti n ue t heir c urre nt ast h ma 
mai nte na nce me di cati o ns t hr o u g h o ut t he st u d y. 
4. 2.  
P atie nt E xcl usi o n Criteri a  
Patie nts will be e x cl u de d fr o m partici pati n g i n t his st u d y if t he y meet a n y of t he f oll o wi n g 
criteria:  
a. Lif e t hreat e ni n g ast h ma, defi ne d as a hist or y of ast h ma e pis o de(s) re q uiri n g 
i nt u bati o n a n d/ or ass ociate d h y p erca p nea, res pir at or y arrest, h y p o xic seiz ures, or 
ast h ma-relat e d s y nc o pal e pis o de(s). 
b.  T he patie nt has a s us p ect e d bacterial or viral i nfecti o n of t he u p per or l o wer 
res pirat or y tr act, si n us, or mi d dle ear t hat h as n ot res ol ve d at least 2 wee ks bef ore t h e 
scree ni n g p eri o d. N ote: Patie nts w h o de vel o p a n u p per res pir at or y i nfecti o n/l o wer 
res pirat or y i nf ecti o n ( U RI/ L RI) d uri n g t he r u n-i n peri o d ma y res cree n 2 wee ks aft er 
s y m pt o ms res ol ve a n d u n der g o c or o na vir us diseas e 2 0 1 9 ( C O VI D -1 9) testi n g as 
o utli ne d i n e x cl usi o n cr iteria “ d ”. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 5  
c. Patie nts wit h a c o nfir me d i nfecti o n wit h C O VI D -1 9 wit hi n 3 m o nt hs pri or t o t he 
scree ni n g visit. 
d.  Patie nts wit h cli nical s y m pt o ms t hat ma y i n dicat e C O VI D -1 9 i nf ecti o n, a n d/ or 
patie nts w h o i n t he i n vesti gat or’s o pi ni o n were at hi g h ris k of e x p os ure t o C O VI D -1 9 
wit hi n 4 wee ks bef ore scree ni n g or d uri n g s cree ni n g/r u n -i n, will be teste d f or acti ve 
C O VI D -1 9 i nfecti o n a n d will o nl y b e i ncl u de d if t he y t est ne gati ve f or C O VI D -1 9. 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o u t br ea ks, see 
A p pe n di x  N . 
e. T he patie nt has a n e osi n o p hilic c o n diti o n i ncl u di n g h y pere osi n o p hilic s y n dr o me, 
e osi n o p hilic p ne u m o nia, e osi n o p hilic gra n ul o m at osis wit h p ol ya n giitis ( E G P A 
[ C h ur g Stra uss s y n dr o me]), or aller gic br o nc h o p ul m o nar y as per gill osis. 
f. T he patie nt has a n acti ve hel mi nt hic or parasitic i nfecti o n c urre ntl y or wit hi n t he last 
6 m o nt hs.  
g.  T he patie nt has a hist or y of mali g na n c y ot her t h a n f ull y resecte d basal cell carci n o ma 
of t he s ki n.  
h.  T he patie nt has a n y cli nicall y si g nifica nt, u nc o ntr olle d me dical or ps yc hiatric 
c o n diti o n (treate d or u ntreate d) t hat w o ul d i nterfere wit h t he st u d y sc h e d ule or 
pr oce d ures, i nter pretati o n of efficac y res ults, or  c o m pr o mise t he patie nt’s safet y. 
( N ote: c hr o nic o bstr ucti ve p ul m o nar y disease [e m p h yse ma], br o nc hiectasis re q uiri n g 
treat me nt, c ystic fi br osis, c hr o nic br o nc hitis, a n d ot her diseases of t he l u n g t hat ma y 
c o m plicate i nter pretati o n of t he st u d y res ults are pr o hi bite d).  
i. T he patie nt has k n o w n hist or y of, or a p ositi ve test res ult f or, he p atitis B s urface 
a nti ge n ( H Bs A g), he p atitis C vir us ( H C V) a nti b o dies ( A b), or h u ma n 
i m m u n o deficie nc y vir us ( HI V) T y p es 1 or 2 A b (acc or di n g t o 4t h ge nerati o n ser ol o g y 
testi n g). 
j. T he patie nt is a pre g n a nt or lactati n g w o ma n, or pl a ns t o bec o me pre g na nt d uri n g t he 
st u d y. 
k.  T he patie nt has ta k e n pr o hi bite d pri or me dicati o ns wit hi n t he was h o ut peri o d. 
Pr o hi bite d me dicati o ns are liste d i n A p pe n di x  G  wit h t he a p pr o priate was h o ut 
peri o ds.  
l. T he patie nt has pre vi o usl y partici pate d i n a st u d y wit h T E V -5 3 2 7 5.  
m.  T he patie nt has partici pat e d i n a n ot her st u d y of a n I M P ( or a me dical de vice) wit hi n 
t he pre vi o us 3 0 da ys or 5 half-li ves of t he I M P ( w hic he ver is l o n ger) or is c urre ntl y 
partici pati n g i n a n ot her st u d y of a n I M P ( or a m e dical de vice).  
n.  [ Re visi o n 1] T he patie nt has bee n tr eate d wit h a m o n ocl o nal a nti b o d y us e d t o treat 
ast h ma or ot her i nfla m m at or y c o n diti o ns wit hi n t he was h o ut peri o d ( 5 half-li ves), has 
de m o nstrate d h y pers e nsiti vit y or a na p h yl a xis t o a m o n ocl o nal a nti b o d y  (A p pe n di x  G ) 
, or is c urre ntl y usi n g or has use d a s yste mic i m m u n os u p pressi ve me dicati o n wit hi n 
t he last 6 m o nt hs. N O T E: Pri or de pe m o ki ma b e x p os ure is pr o hi bite d wit h o ut 
e x ce pti o n.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 6  
o.  T he patie nt has a k n o w n h y perse nsiti vit y t o a n y c o m p o ne nts of t he I M P state d or 
st u d y s u p plie d res c ue me dicati o n. 
p.  T he patie nt has a hist or y of c hr o nic alc o h ol or dr u g a b us e wit hi n t he pre vi o us 2 years.  
q.  [ Re visi o n 1] T he patie nt c urre ntl y s m o kes or has a s m o ki n g hist or y of 1 0 pac k years 
or m ore (a p ac k year is d efi ne d as s m o ki n g 1 pac k of ci garettes [ 2 0 ci garett es]/ da y f or 
1 year), O R t he patie nt use d t o bacc o pr o d ucts wit hi n t he past year (e g, ci garettes, 
ci gars, c h e wi n g t o bacc o, or pi pe t o bacc o), O R t he patie nt has s m o ke d marij ua na 
wit hi n 1  m o nt h, O R t he patie nt has a hist or y of “ v a pi n g ” t o bacc o, marij ua n a, or a n y 
ot her s u bsta nce wit hi n 2 4 m o nt hs.  
r. V ul nera ble p atie nts (e g, pe o ple ke pt i n dete nti o n).  
4. 3.  
R a n d o miz ati o n Criteri a  
T he f oll o wi n g criteri a m ust be f ulfille d at t he ra n d o mizati o n visit ( da y  0):  
a. T he patie nt c o nti n ues t o be i n ge neral g o o d h ealt h, meeti n g t he e ntr y criteri a.  
b.  T he patie nt’s a v era ge of 5 m ost rece nt hi g hest  dail y tr o u g h val ues (fr o m 3 atte m pts) 
f or m or ni n g F E V1 o btai n e d at h o me ( b y ha n d h el d s pir o metr y) o ver 7  d a ys pri or t o V 3 
is wit hi n 4 0 % t o 8 0 % pre dicte d f or a ge, hei g ht, se x, a n d race ( Ha n ki ns o n et al 1 9 9 9 , 
Ha n ki ns o n et al 2 0 1 0 , N H A N E S III 1 9 9 8 ). If resc ue me dicati o n was ta k e n wit hi n 
4  h o urs of t he F E V 1 assess me nt, or ast h ma mai nte na nc e me di cati o n was ta ke n bef ore 
t he meas ure m e nt, t he dat a fr o m t hat da y s h o ul d be e x cl u de d a n d data fr o m a pre vi o us 
da y d uri n g t he 7 -da y p eri o d s h o ul d be i ncl u de d.  
c. T he patie nt has a n F E V 1 as assesse d b y cli nic -bas e d p ul m o nar y f u ncti o n testi n g t hat is 
wit hi n 4 0 % t o 8 5 % or t he val ue pre dicte d f or a ge, hei g ht, se x, a n d race ( Ha n ki ns o n et 
al 1 9 9 9, Ha n ki ns o n et al 2 0 1 0 , N H A N E S III 1 9 9 8 ). 
d.  T he patie nt has de m o nstr ate d F E V 1 re versi bilit y as re q uire d d uri n g t he s cree ni n g 
peri o d.  
e. T he patie nt’s A C Q -6 s c ore assess e d o n V 3 da y 0 is ≥1. 5.  
f. T he patie nt has re mai ne d o n bac k gr o u n d ast h ma mai nte na nce me di cati o n wit h o ut 
c ha n ges d uri n g t he r u n -i n peri o d ot her t ha n st u d y resc ue m e dicati o n (al b ut er ol 
e M D PI [ Pr o Air Di gi haler f or use as nee d e d or e q ui vale nt al b uter ol/sal b uta m ol 
de pe n di n g o n a vaila bilit y]) a n d al b uter ol/sal b uta m ol use d f or re v ersi bilit y t esti n g.  
g.  T he patie nt has ha d n o e x acer bati o n of ast h ma d uri n g t he r u n -i n peri o d, d efi ne d as 
a n y w orse ni n g of ast h ma re q uiri n g si g nifi ca nt treat me nt ot her t ha n resc u e me dicati o n 
(al b uter ol e M D PI [ Pr o Air Di gi hal er f or use as n ee de d or e q ui vale nt 
al b uter ol/sal b uta m ol de pe n di n g o n a vaila bilit y]). Si g nifica nt treat me nt i ncl u des a n y 
of t he f oll o wi n g: use of s yste mic c ortic oster oi ds or t he a d diti o n of I C S -c o ntai ni n g 
ast h ma me dicati o ns, L A B A, l o n g -acti n g m usc ari nic a nta g o nist ( L A M A), bi ol o gic or 
ot her n o n -c ortic ost er oi d ast h ma me dicati o ns, e mer ge nc y r o o m/ ur ge nt care visit, or 
h os pitaliz ati o n f or ast h ma. N ote: A si n gle d ose of ne b ulize d al b uter ol/s al b ut a m ol 
will n ot meet t he criteri a f or a n ast h m a e x acer b ati o n. E mer g e nc y r o o m/ ur ge nt 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 7  
c are cli nic visits w here t he tre at me nt is li mite d t o a si n gle d ose of ne b ulize d 
al b uter ol/s al b ut a m ol will n ot meet t he criter i a of a n ast h m a e x acer b ati o n. 
h.  T he patie nt has c o m plie d wit h h o me s pir o metr y a n d diar y e ntr y o n at least 5 of t he 
last 7 da ys pri or t o t he visit i ncl u di n g:  
− c o m pleti o n of da yti me a n d ni g ht -ti me ast h ma s y m pt o m sc ores 
− c o m pleti o n of da yti me a n d ni g ht -ti me res c ue me dicati o n use, w het her use d or n ot  
− c o m pleti o n of t he m or ni n g F E V 1 a n d P E F b y ha n d hel d de vice  
− c o nfir me d dail y use of ast h ma mai nte na nce me di cati o n as prescri be d  
i. T he patie nt has n ot ha d a n u p per res pir at or y i nfecti o n ( U RI) or l o wer res pir at or y 
i nfecti o n (L RI)  d uri n g t h e r u n -i n peri o d. Patie nts w h o de vel o p a U RI or L RI d uri n g 
t he r u n-i n peri o d ma y b e disc o nti n ue d fr o m t he st u d y a n d all o we d t o res cree n 
2  wee ks after res ol uti o n of s y m pt o ms. T he y m ust ha ve a n e gati ve test f or C O VI D -1 9 
acti ve i nfecti o n.  
j. T he pat ie nt has use d resc ue me dicati o n or ha d a d a yti me or ni g ht-ti me ast h ma 
s y m pt o m sc ore ≥1 o n 3 or m ore da ys i n t he 7 da ys pri or t o t he ra n d o mizati o n visit as 
re p orte d i n t he p atie nt diar y. 
4. 4.  
Wit h dr a w al Criteri a a n d Pr oce d ures f or t he P atie nt  
Eac h patie nt is fre e t o wit h dra w fr o m t he st u d y at a n y ti me, wit h o ut prej u di ce t o t heir c o nti n ue d 
care. Patie nts m ust be wit h dra w n fr o m t he st u d y if a n y of t he f oll o wi n g e v e nts occ ur:  
1.  Patie nt wit h dra ws c o nse nt or re q uests wit h dra wal fr o m t he st u d y f or a n y reas o n.  
2.  Patie nt de v el o ps a n ill ness t hat w o ul d i nterfere wit h his/ her c o nti n ue d partici pati o n.  
3.  Patie nt is n o nc o m plia nt wit h t he st u d y pr oce d ures a n d assess me nts i n t he o pi ni o n of t he 
i n vesti gat or. 
4.  Patie nt ta kes pr o hi bite d c o nc o mita nt me dicati o ns as defi ne d i n t his pr ot oc ol. T he decisi o n 
t o wit h dra w a patie nt s h o ul d be disc usse d wit h t he s p o ns or, f or e x a m ple, me dicati o ns t o 
treat a n ast h ma e x acer bati o n ma y n ot re q uire t hat t he patie nt be wit h dra w n fr o m 
c o nti n ue d partici pati o n.  
5.  A fe male p atie nt has a c o nfir mati o n of pre g n a nc y d uri n g t he st u d y fr o m a p ositi ve 
pre g na nc y t est.  
6.  T he s p o ns or re q u ests wit h dra wal of t h e patie nt.  
7.  Patie nt e x perie nces a n a d verse e v e nt or ot her m e dical c o n diti o n w hic h i n dicates t o t he 
i n vesti gat or t hat c o nti n ue d partici pati o n is n ot i n t he best i nterest of t he patie nt. 
Patie nts s h o ul d be treate d wit h sta n dar d of care after wit h dra wal fr o m or ter mi nati o n of t he st u d y 
as a p pr o priat e.  
I n v esti gat ors s h o ul d atte m pt t o o btai n i nf or mati o n o n patie nts i n t he case of wit h dra wal fr o m t he 
st u d y. Res ults of a n y e v al uatio ns a n d o bser vati o ns, t o get her wit h a narrati v e descri bi n g t he 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 8  
reas o n(s) f or wit h dra wal fr o m t he st u d y, m ust be rec or de d i n t he s o urce d o c u me nts. T he C R F 
m ust d oc u me nt t he pri mar y reas o n f or wit h dra wal fr o m t he st u d y.  
If a patie nt e x hi bits cli nical s y m pt o ms t hat ma y i n dicate C O VI D-1 9 i nfecti o n after e nteri n g t he 
st u d y, t he patie nt s h o ul d be teste d f or acti ve C O VI D-1 9. If t h e patie nt tests p ositi ve f or acti ve 
C O VI D -1 9  ( p ositi ve a nti ge n t ests m ust be c o nfir me d b y re verse tra ns cri pti o n p ol y m eras e c h ai n 
reacti on [ R T -P C R ] testi n g), h e/s he ma y c o nti n ue f or sc he d ule d visits w he n rec o vere d (i e, aft er 
1 0  da ys fr o m t he o nset of s y m pt o ms , re mai ns afe brile f or 2 4 h o urs wit h o ut usi n g a nti -p yretics 
a n d ot her s y m pt o ms are i m pr o vi n g)  (see A p pe n di x  G  a n d A p pe n di x  N ). 
If t he reas o n f or wit h dra wal fr o m t he st u d y is a n a d verse e ve nt a n d/ or cli nicall y si g nifica nt 
a b n or mal la b orat or y test res ult, m o nit ori n g will be c o nti n ue d as a p plica bl e (e g, u ntil t he e v e nt 
has res ol ve d, sta bilize d, or ret ur ne d t o b aseli ne; or u ntil t he patie nt is refe rre d t o t he care of a 
healt h care pr ofessi o nal, or u ntil a deter mi nati o n of a ca us e u nrel ate d t o t he I M P or st u d y 
pr oce d ure is ma de). T h e s pecific e v e nt or test res ult (i ncl u di n g re p eate d test res ults, as 
a p plica ble) m ust be rec or de d b ot h o n t he s o urce d oc u me ntati o n a n d i n t he C R F; b ot h t he a d verse 
e ve nts pa ge a n d t he rele v a nt pa ge of t he C R F will be c o m plete d at t hat ti me . 
T he i n vesti gat or m ust i nf or m t he s p o ns or’s me dical e x pert as s o o n as p ossi ble of eac h patie nt 
w h o is bei n g c o nsi dere d f or wit h dra w al d u e t o a d verse e v e nts. A d diti o nal re p orts m ust be 
pr o vi de d w he n re q ueste d.  
If a patie nt is wit h dra w n fr o m t he st u d y f or m ulti ple reas o ns t hat als o i ncl u de a d verse e v e nts, t he 
rele va nt pa ge of t he C R F s h o ul d i n dicate t hat t he wit h dra wal w as relate d t o a n a d verse e v e nt. A n 
e x ce pti o n t o t his re q uire me nt will be t he occ urre n ce of a n a d verse e v e nt t hat i n t he o pi ni o n of t he 
i n vesti gat or is n ot se vere e n o u g h t o w arra nt disc o nti n uati o n b ut t hat re q uires t he use of a 
pr o hi bite d me dicati o n, t here b y re q uiri n g disc o nti n uati o n of t he patie nt. I n s uc h a case, t he reas o n 
f or disc o nti n uati o n w o ul d be “ nee d t o ta ke a pr o hi bite d me dicati o n”, n ot t he a d verse e v e nt. 
I n t he cas e of patie nts l ost t o f oll o w-u p, atte m pts t o c o ntact t he patie nt m ust be ma de a n d 
d oc u me nte d i n t he pati e nt’s me dical rec or ds a n d tr a nscri be d t o t he C R F. See A p pe n di x  E  f or 
i nf or mati o n re gar di n g h o w t he st u d y will defi n e a n d a d dress l ost t o f oll o w-u p p atie nts t o hel p 
li mit t he a m o u nt a n d i m pact of missi n g dat a. 
4. 5.  
Re pl ace me nt of P atie nts  
A patie nt w h o is ra n d o mi ze d b ut d oes n ot c o m plete t he treat me nt p eri o d will n ot be re place d. F or 
details of t he ma na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut brea ks, see A p pe n di x  N . 
4. 6.  
Rescree ni n g  
T he scree ni n g visit will ta ke place n ot m ore t ha n a p pr o xi matel y 4 wee ks b ef ore t h e baseli ne/ D o R 
visit ( V 3) a n d is li mite d t o a p pr o xi matel y 1 4  da ys d urati o n. It is u n derst o o d t hat n ot all 
pr oce d ures ca n b e c o m pl ete d o n t he sa me da y. I n partic ular, t he patie nt ma y nee d t o ret ur n f or 
re peat C B C testi n g as n ee de d or t o satisf y t he me dicati o n was h o ut f or p ul m o nar y f u ncti o n 
testi n g or t o u n der g o re p eat p ul m o nar y f u ncti o n testi n g. 
A patie nt w h o scree n -fails ma y be per mitte d t o res cree n o n ce after 3 0 da ys d urati o n if t here is a 
reas o na bl e e x pectati o n t hat t his patie nt will bec o me eli gi ble f or t he st u d y, i ncl u di n g 
re q uire me nts f or e osi n o p hil c o u nts a n d/ or s pir o metr y. T h e s p o ns or ma y gra nt per missi o n t o 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6 9  
rescree n m or e t ha n o nce u n der e xte n uati n g circ u msta nces a n d o nl y wit h t he a p pr o val of t he 
s p o ns or’s me dical e x pert or dele gate. N ote: Patie nts w h o de vel o p a U RI/ L RI d uri n g  t he r u n-i n 
peri o d ma y res cree n 2  w ee ks aft er s y m pt o ms res ol ve a n d after a p pr o priate C O VI D -1 9 testi n g 
has bee n c o m plet e d as s p ecifie d.  A d diti o nall y, patie nts w h o fail ra n d o mizati o n f or reas o ns ot h er 
t ha n s pir o metr y re q uir e me nts ma y b e res cree ne d o nce. 
4. 7.  
Scre e ni n g F ail ure  
Scree n fail ure occ urs w h e n a patie nt w h o c o nse nts t o partici pate i n t he cli nical st u d y is n ot 
s u bse q ue ntl y e ntere d i nt o t he r u n-i n peri o d beca us e t hat patie nt di d n ot meet i ncl usi o n criteria, 
met e x cl usi o n criteria, or wit h dre w c o nse nt. Patie nts w h o e nter t he r u n -i n peri o d b ut w h o d o n ot 
meet t he criteri a f or ra n d o mizati o n or wit h dra w c o nse nt will be c o nsi dere d ra n d o mizati o n 
fail ures. 
Selecte d i nf or mati o n a b o ut patie nts w h o scree n -fail or fail ra n d o mizati o n will be c ollecte d t o 
c o m pl y wit h re p orti n g a n d p u blis hi n g re q uire m e nts. T his i nf or mati o n ma y i ncl u de, b ut is n ot 
li mite d t o, de m o gra p h y, scree ni n g fail ure d etails, eli gi bilit y criteria, a n d a n y seri o us a d verse 
e ve nts.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 0  
5.  
T R E A T M E N T S  
I n v esti gati o nal me dici nal pr o d ucts i n t his st u d y i n cl u de T E V-5 3 2 7 5 (test I M P) a n d matc hi n g 
place b o ( pla ce b o I M P). P atie nts will recei ve 4 i njecti o ns  ( 3 ml eac h)  of test I M P a n d/ or pl ace b o 
I M P, a d mi nistere d b y a q ualifie d healt h care pr o vi der (acc or di n g t o l ocal re g ulati o ns) w h o is 
pre pare d t o ma na ge a na p h yla xis, t o ac hie ve t he f oll o wi n g d oses a d mi nistere d o n a si n gle 
occasi o n:  
•  T E V -5 3 2 7 5 6 0 0  m g sc  
•  T E V -5 3 2 7 5 1 2 0 0  m g sc  
•  Place b o sc  
Detaile d i nf or mati o n a b o ut t he c o m p ositi o n of t he test I M P a n d place b o I M P ca n be f o u n d i n t he 
f oll o wi n g secti o ns. 
Ot her st u d y pr o vi de d me dicati o ns (s h ort -acti n g br o nc h o dilat ors) are c o nsi d ere d n o n -I M P i n t his 
st u d y (see Secti o n 5. 4  f or details). 
5. 1.  
I n vesti g ati o n al Me dici n al Pr o d ucts Use d i n t he St u d y  
I n v esti gati o nal me dici nal pr o d uct is defi ne d as t h e test I M P a n d matc hi n g place b o I M P. 
5. 1. 1.  
Test I n vesti g ati o n al Me dici n al Pr o d uct  
T E V -5 3 2 7 5 is pr o vi de d as a li q ui d s ol uti o n wit h a n o mi nal c o nce ntrati o n of 1 0 0 m g/ m L. R efer 
t o Ta ble  3  f or s pecific details re gar di n g T E V-5 3 2 7 5. A d diti o nal details ma y be f o u n d i n t he 
p har mac y ma n u al a n d i n t he I B f or T E V -5 3 2 7 5.  
5. 1. 2.  
Pl ac e b o I n vesti g ati o n al Me dici n al P r o d uct  
Place b o I M P is pr o vi de d as a li q ui d s ol uti o n i n t he sa me f or m ulati o n as T E V -5 3 2 7 5, e x ce pt f or 
a bse nce of acti ve pr otei n. Refer t o Ta bl e  3  f or s pecific details re gar di n g place b o I M P . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 1  
T a ble  3 : 
I n vesti g ati o n al Me dici n al Pr o d ucts Us e d i n t he St u d y  
I M P n a me 
Test I M P  
Pl ace b o I M P  
Tr a de n a me a n d I N N, if 
a p plic a ble, or c o m p a n y -assi g ne d 
n u m ber  
T E V -5 3 2 7 5  
T E V -5 3 2 7 5 Place b o  
F or m ul ati o n  
 
 
 
 
 
 
 
 
U nit d ose stre n gt h(s)/ D os a ge 
le vel(s) 
3 0 0  m g/ vial  
Ve hicle b uffer a bse nt of pr otei n  
R o ute of a d mi nistr ati o n  
sc i nj ecti o n 
sc i nj ecti o n 
D osi n g i nstr ucti o ns/ D osi n g 
sc he d ule/ Titr ati o n 
peri o ds/ Tre at me nt peri o ds  
As i nstr ucte d i n t he cli nical pr ot oc ol 
a n d p har mac y ma n ual  
As i nstr ucte d i n t he cli nical pr ot oc ol 
a n d p har mac y ma n ual  
P ac k a gi n g  
T y pe 1 glass vial wit h b ut yl r u b ber 
st o p per a n d cri m p seal wit h a plastic 
fli p-off ca p  
T y pe 1 glass vial wit h b ut yl r u b ber 
st o p per a n d cri m p seal wit h a plastic 
fli p-off ca p  
M a n uf act urer  
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc ., West C hester, 
P e n ns yl va nia, U S A  
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc., West C hester, 
P e n ns yl va nia, U S A  
St o r a ge c o n diti o ns  
2° C t o 8° C ( 3 6° F t o 4 6° F) a n d 
pr otecte d fr o m li g ht. D o n ot fr eeze  
2° C t o 8° C ( 3 6° F t o 4 6° F) a n d 
pr otecte d fr o m li g ht. D o n ot fr eeze  
I M P =i n vesti gati o nal me dici nal pr o d uct; I N N =i nter nati o nal n o n pr o prietar y na me; sc =s u bc uta ne o us; U S A = U nite d 
States of A merica.  
5. 2.  
Pre p ar ati o n, H a n dli n g, L a beli n g, St or a ge, a n d Acc o u nt a bilit y f or 
I M Ps 
5. 2. 1.  
St or a ge a n d Sec urit y  
T he i n vesti gat or or desi g nee  m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d f or all I M Ps r ecei ve d a n d a n y discre pa ncies are re p orte d a n d res ol ve d bef ore use of 
t he I M Ps. 
T he I M Ps ( T E V -5 3 2 7 5 a n d place b o I M P) m ust be st ore d at a c o ntr olle d t e m perat ure ( 2° C t o 
8° C)  i n a sec ure area. T h e site s h o ul d ha ve a pr ocess f or m o nit ori n g t he st ora ge te m perat ur e of 
u n use d I M P.  
5. 2. 2.  
L a beli n g  
S u p plies of I M Ps will be la bele d acc or di n g t o t he c urre nt I nt er nati o nal C o u ncil f or 
Har m o nisati o n (I C H) g ui deli nes o n G o o d Cli nical Practice ( G C P) a n d G o o d Ma n ufact uri n g 
Practice a n d will i ncl u de a n y l o call y re q uir e d state me nts. If necessar y, la bels will be tra nslate d 
i nt o t he l ocal la n g u a ge. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 2  
5. 2. 3.  
Acc o u nt a bilit y  
Eac h I M P s hi p me nt will i ncl u de a pac ki n g sli p listi n g t he c o nt e nts of t he s hi p me nt, ret ur n  
i nstr ucti o ns, a n d a n y a p plica ble f or ms. 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat d eli veries of I M Ps a n d ot h er st u d y m aterials 
fr o m t he s p o ns or are c orrectl y recei ve d, rec or de d, ha n dle d, a n d st ore d s afel y a n d pr o perl y i n 
acc or da nce wit h t he C F R  or  nati o nal a n d l ocal re g ulati o ns, a n d use d i n acc or da nce wit h t his 
pr ot oc ol.  
O nl y patie nts e nr olle d i n t he st u d y ma y recei ve I M Ps a n d o nl y a ut h orize d staff at t he 
i n vesti gati o nal c e nter ma y s u p pl y or a d mi nister I M Ps. All I M Ps m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n u al or a ut o mate d) area i n acc or da n ce wit h t he 
la bele d st ora ge c o n diti o ns or a p pr o priat e i nstr ucti o ns wit h access li mite d t o t he i n vesti gat or a n d 
a ut h orize d staff at t he i n v esti gati o nal ce nter.  
T he i n vesti gat or, i n stit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or I M P acc o u nta bilit y, rec o n ciliati o n, a n d rec or d mai nte na n ce (ie, recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 
A rec or d of I M P acc o u nt a bilit y (ie, I M P a n d ot h er st u d y materi als recei ve d, use d, retai ne d, 
ret ur ne d, or d estr o ye d) m ust be pre pare d a n d si g ne d b y t he pri nci pal i n vesti gat or or desi g nee, 
wit h a n acc o u nt gi ve n f or a n y discre p a ncies. E m pt y, partiall y us e d, a n d u n use d I M P will be 
dis p ose d of or ret ur n e d t o Te va or its desi g nee.  
F urt her g ui d a nce a n d i nf or mati o n (i ncl u di n g n o n-I M P resc ue me di cati o n) are pr o vi d e d i n t he 
p har mac y ma n u al.  
5. 3.  
J ustific ati o n f or I n vesti g ati o n al Me dici n al Pr o d ucts  
5. 3. 1.  
J ustific ati o n f or D ose of Test I n vesti g ati o n al Me dici n al Pr o d uct  
T he d oses a d mi nistere d i n t his st u d y ( 6 0 0, 1 2 0 0  m g T E V -5 3 2 7 5) were s electe d o n t he basis of 
p har mac o ki netic a n d safet y data fr o m t he healt h y v ol u nteer P hase  1 st u d y, T V 5 3 2 7 5 -P K -1 0 1 5 2 
( Secti o n 1. 2. 2. 1 ), i n w hic h si n gle sc d os es of T E V-5 3 2 7 5 u p t o 1 8 0 0  m g a d mi nistere d i n Part A, 
a n d d ose le vels of 4 5 0 or 9 0 0  m g a d mi nistere d s c e ver y 2 8  da ys 3 ti mes i n Part  B, were s h o w n t o 
be well t olerate d; t he a vaila ble a nt i-I L-5 m A b d ata; a n d t he m o deli n g a n d si m ulati o n of 
T E V -5 3 2 7 5 p har m ac o ki netic a n d p har m ac o d y na mic data o btai ne d i n 
St u d y  T V 5 3 2 7 5 -P K -1 0 1 5 2.  
T o s u p p ort t he pr o p ose d d ose selecti o n, a p h ar mac o ki netic/ p har mac o d y na mic a nal ysis was 
c o n d ucte d t o c h aracteriz e t he T E V -5 3 2 7 5 e x p os ure/ bl o o d e osi n o p hil s u p pressi o n data c ollect e d 
fr o m St u d y T V 5 3 2 7 5-P K -1 0 1 5 2.  
Firstl y, a p ote ntial t hera p e utic d ose was esti mate d fr o m t he p har mac o ki neti c/ p har mac o d y n a mic 
data c ollecte d i n St u d y T V 5 3 2 7 5 -P K -1 0 1 5 2. After treat me nt wit h T E V -5 3 2 7 5, t he bl o o d 
e osi n o p hils fr o m all treat e d c o h orts were re d uce d b y a p pr o xi matel y 7 5 % fr o m baseli ne. T he 
l o west le vels were reac h e d wit hi n 1 wee k wit h a d ose-de pe n d e nt d urati o n of e osi n o p hil 
s u p pressi o n, fr o m w hic h t he bl o o d e osi n o p hil c o u nts re b o u n de d earlier i n i n di vi d uals fr o m l o wer 
d ose c o h orts t ha n hi g her d ose c o h orts. T he d ata were c h aracterize d b y a n i n direct -res p o nse 
m o del (e P D Re p ort # 0 2 2 0 -2). T he I C 5 0 was esti mate d ( 1. 1 1  µ g/ m L) wit h acce pta bl e precisi o n 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 3  
( 1 5. 3 % sta n dar d err or of t he mea n [ S E M]), a n d wit h a ser u m c o nce ntrati o n res ulti n g i n 9 0 % 
re d ucti o n of ma xi m u m i n hi bit or y effect (I C9 0) of T E V-5 3 2 7 5 of 1 0  µ g/ m L. T he effi caci o us d ose 
pr ojecti o n strate g y ai me d t o mai ntai n T E V -5 3 2 7 5 c o nce ntr ati o ns i n 9 0 % of t he patie nt 
p o p ulati o n a b o ve t he I C 9 0 f or t he st u d y d urati o n, a n d was esti mate d t o be a 6 0 0-m g d ose e ver y 
1 2 wee ks ( Q 1 2 W).  
I n a sec o n d st e p, i nsi g hts fr o m resliz u ma b were us e d t o g ui de t h e selecti o n of t he pr o p ose d hi g h 
d ose, 1 2 0 0 m g Q 1 2 W. A n e x p os ure -res p o nse relati o ns hi p has bee n de m o nstrate d f or 
resliz u ma b-treate d patie nts (Bjer mer et al 2 0 1 6 ). F or e x a m ple, resliz u ma b 3. 0 m g/ k g i v 
i m pr o ve d l u n g f u ncti o n a n d vari o us meas ures of ast h ma c o ntr ol a n d q ualit y of life t o a greater 
de gree t h a n resliz u ma b 0. 3  m g/ k g, e ve n t h o u g h b ot h d oses de m o nstrate d a si g nifica nt re d ucti o n 
i n e osi n o p hil c o u nts c o m pare d t o place b o. I n a d diti o n, treat me nt of m o derate t o se vere ast h ma 
wit h resliz u ma b 3. 0  m g/ k g i v de m o nstrat e d re d u cti o n i n ast h ma e x acer bati o ns, i m pr o ve me nt i n 
l u n g f u ncti o n, a n d a re d u cti o n i n e osi n o p hils ( Castr o et al 2 0 1 5 ); h o we v er, w he n e val u ate d b y 
t he sc r o ute, resliz u ma b 1 1 0 m g sc d osi n g faile d t o de m o nstrate a si g nifica nt re d ucti o n i n 
e x acer bati o ns e v e n t h o u g h e osi n o p hil re d ucti o ns a n d i m pr o ve me nt s i n l u n g f u ncti o n, ast h ma 
c o ntr ol, a n d q ualit y of lif e meas ur es ( Ber nstei n et al 2 0 2 0 ) were de m o nstrat e d. O verall, data 
s h o w t hat w hile s u p pressi o n of e osi n o p hils ca n be ac hie ve d wit h mi ni mal d ose le vels of 
resliz u ma b, cli nicall y me a ni n gf ul i m pr o ve me nt i n l u n g f u ncti o n, ast h ma c o ntr ol, q ualit y of life, 
a n d re d ucti o n of e x acer bati o ns i n patie nts wit h se vere e osi n o p hilic ast h ma re q uire d si g nifica ntl y 
hi g her a n d i ncreasi n g e x p os ures t o resliz u ma b.  
5. 3. 2.  
J ustific ati o n f or Use of Pl ace b o  I n vesti g ati o n al Me dici n al Pr o d uct 
A d va nta ges of pl ace b o -c o ntr olle d trials are s u m m arize d i n t he  I C H E 1 0 C h oice of C o ntr ol 
Gr o u p a n d Relate d Iss ues i n Cli nical Trials G ui deli ne a n d i ncl u de mi ni mizi n g i n vesti gat or a n d 
patie nt b ias. St u dies ma y use a place b o-c o ntr olle d desi g n w he n t he ris k of s eri o us har m 
i ncl u di n g deat h or irre v ersi ble m or bi dit y (I C H E 1 0) is l o w a n d t he patie nt’s f ull i nf or me d 
c o nse nt is o btai ne d.  
A place b o c o ntr ol desi g n is scie nti ficall y a p pr o pri ate as place b o will be c o m pare d t o T E V-5 3 2 7 5 
as a d d-o n t hera p y i n pati e nts wit h m o derate t o se v ere e osi n o p hilic ast h ma. T he st u d y i ncl u d es 
cl ose dail y re m ote m o nit ori n g of eac h patie nt’s safet y electr o nicall y wit h pre defi n e d alert criteria 
t o ca pt ure patie nts wit h w orse ni n g ast h ma b y m o nit ori n g dail y l u n g f u ncti o n meas ure me nts, 
resc ue m e dicati o n use, a n d ast h ma s y m pt o ms. I n a d diti o n, o nl y patie nts f or w h o m it is 
c o nsi dere d safe t o partici pate i n t he st u d y, i n t he o pi ni o n of t he i n vesti gat or,  will be per mitte d t o 
partici pate.  
5. 4.  
Ot her Me dici n al Pr o d ucts/ N o n -I n vesti g ati o n al Me dici n al Pr o d ucts 
N ote t hat ot her me dici nal pr o d ucts, ie, res c ue me di cati o n (al b uter ol e M D PI [ Pr o Air Di gi haler or 
e q ui vale nt al b uter ol/sal b uta m ol de pe n di n g o n a vaila bilit y]), are ma n dat e d f or use i n t his st u d y; 
h o we ver, f or t he p ur p os es of t his st u d y it is c o nsi d ere d a n o n -I M P. I n a d diti o n, patie nts will 
mai ntai n t heir us ual ast h ma mai nte na nce m e dicati o n.  
5. 5.  
Tre at me nt After t he E n d of t he St u d y  
At  wee k 1 6 ( E o T V; V 9) , t he i n vesti gat or will disc uss wit h t he patie nt t he ret ur n t o a p pr o priat e 
me dical care a n d m e dicati o n as part of sta n dar d of care pr o vi de d b y t he patie nt’s pri mar y 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 4  
p h ysicia n a n d s peci alists. N o a d diti o nal e xte nsi o n or c o m passi o nate use of T E V -5 3 2 7 5 is 
pla n ne d after c o m p leti o n of t his st u d y. 
5. 6.  
Restricti o ns  
Patie nts will be re q uire d t o c o m pl y wit h restricti o ns detaile d bel o w.  
5. 6. 1.  
Acti vit y  
Patie nts m ust re mai n seate d, se mi -rec u m be nt, or s u pi ne as nee d e d f or assess me nts or ot her 
pr oce d ures, i ncl u di n g d osi n g.  
Patie nts are n ot t o e n ga ge i n stre n u o us e x ercise wit hi n 5 da ys pri or t o t he d ose of I M P a n d 
s h o ul d a v oi d stre n u o us e x ercise f or 4 8 h o urs pri or t o a n y cli nic visit. 
5. 6. 2.  
T o b acc o  
Use of t o bacc o pr o d u cts will n ot be all o we d fr o m scree ni n g u ntil after t he fi nal f oll o w -u p visit. 
Patie nts  are n ot eli gi ble t o partici pate if t he y h a ve use d t o bacc o pr o d ucts wit hi n t he year pri or t o 
scree ni n g. 
5. 6. 3.  
Bl o o d D o n ati o n  
Patie nts ma y n ot d o nate bl o o d d uri n g t he st u d y.  
5. 7.  
Pri or a n d C o nc o mit a nt Me dic ati o n or T her a p y  
A n y pri or or c o n c o mita nt t hera p y, me dicati o n (i ncl u di n g pri or ast h ma me di cati o n), or pr o ce d ure 
a patie nt has ha d fr o m 3 0 da ys b ef ore scree ni n g t hr o u g h t he e n d of t he st u d y will be rec or de d i n 
t he s o urce d o c u me ntati o n a n d i n t he C R F. Tra d e na me a n d I N N (if a vaila ble), i n dicati o n, d ose, 
a n d start a n d en d d ates of t he a d mi nistere d me dicati o n or treat me nt will be rec or de d. T he 
s p o ns or will e nc o de all t hera p y a n d m e dicati o n acc or di n g t o t he W orl d Healt h Or ga nizati o n dr u g 
dicti o nar y ( W H O Dr u g).  
Pr o hi bite d a n d restricte d me dicati o ns are liste d i n A p pe n di x  G . 
At eac h visit at t he i n vesti gati o nal c e nter after t h e scree ni n g visit, t he i n vesti gat or will as k 
patie nts w het her t he y h a ve ha d a n y c ha n ge i n mai n te na nce m e dicati o n (i ncl u di n g ast h ma 
mai nte na nce me di cati o n), ta ke n a n y ot her m e dicati o ns, i ncl u di n g o ver -t h e-c o u nter me dicati o ns, 
vita mi ns, or her bal or n utriti o nal s u p ple me nts, si nce t he pre vi o us visit.  
C o nc o mita nt me dicati o n a n d treat me nt will be rec or d e d u ntil t he f oll o w -u p visit.  
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
5. 8.  
Pr oce d ures f or M o nit ori n g P atie nt C o m pli a nce  
T he i n vesti gat or will be res p o nsi ble f or m o nit ori n g patie nt c o m plia nce wit h t his pr ot oc ol fr o m 
t he start of t he scree ni n g/r u n-i n peri o d t hr o u g h t he f oll o w-u p visit.  If t he i n vesti gat or or t he 
s p o ns or deter mi nes t hat t he patie nt is n ot i n c o m plia nce wit h t he st u d y pr ot oc ol, t he i n vesti gat or 
a n d t he s p o ns or s h o ul d deter mi ne w het h er t he p atie nt s h o ul d be wit h dra w n fr o m t he st u d y. T h e 
I n d e pe n de nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d  (I E C/I R B) s h o ul d be n otifie d if 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 5  
re q uire d b y l oc al re g ulati o n. C o m plia nce wit h t he patie nt diar y will be dee me d a de q uat e if 8 0 % 
of t he data is ca pt ure d t hr o u g h V 9.  
5. 9.  
R a n d o miz ati o n a n d Bli n di n g  
T his is a ra n d o mize d, d o u b le-bli n d, place b o -c o ntr olle d, parallel -gr o u p  st u d y. 
Patie nts a n d i n vesti gat ors will re mai n bli n de d t o I M P assi g n me nt d uri n g t he st u d y. Patie nts w h o 
meet all i ncl usi o n criteria, n o ne of t he e x cl usi o n criteria a n d all of t he ra n d o mizati o n criteria will 
be ra n d o ml y assi g ne d t o 1 of 2 treat me nt gr o u ps or place b o i n a 1: 1: 1 r ati o a n d will be stratifie d 
b y pri or ast h ma mai nte na nce t hera p y (I C S a n d l o w d ose I C S/ L A B A will be stratifie d se paratel y 
fr o m t he me di u m a n d hi g h d ose I C S/ L A B A [ 2 se p arate strata]) a n d a bs olut e e osi n o p hil c o u nt 
( 3 0 0 t o < 4 0 0, ≥4 0 0  cells/ μ L). A p pr o xi matel y 9 0  p atie nts w h o ha ve bee n m ai ntai ne d o n me di u m 
or hi g h d ose I C S or l o w d ose I C S/ L A B A a n d a p pr o xi matel y 2 1 0  p atie nts ( ma y b e a dj uste d bas e d 
o n t he i nteri m a nal ysis) o n me di u m or hi g h d ose I C S/ L A B A will be i ncl u de d a n d scree ni n g ma y  
be a dj uste d as nee de d t o meet t hese criteria. T his s yste m is use d t o e ns ure a bala nce acr oss 
treat me nt gr o u ps; n o eff ort will be ma de t o mai ntai n a bala nce a m o n g treat me nt gr o u ps wit hi n a n 
i n vesti gati o nal c e nter. 
Pat ie nts will be ra n d o ml y assi g ne d t o treat me nt gr o u ps b y mea ns of a c o m p uter-ge n erate d 
ra n d o mizati o n list. T he s pecificati o ns f or ra n d o mi zati o n will be u n der t he res p o nsi bilit y a n d 
o versi g ht of Te va Gl o bal Statistics.  
T he s p o ns or’s cli nical p ers o n nel (a n d d e le gates) i n v ol ve d i n t he st u d y will be bli n de d t o t he 
i de ntit y of t he I M Ps u ntil t he data base is l oc k e d f or a nal ysis a n d the I M P assi g n me nt is k n o w n. 
H o we ver, if a pri oritiz e d sa m ple a nal ysis is nee de d, bi oa nal ytical a n d/ or cli nical p har mac ol o g y 
pers o n nel ma y be u n bli n de d.  
T he ra n d o mizati o n list will be assi g ne d t o t he rele va nt treat me nt gr o u ps t hr o u g h a q u alifie d 
ser vice pr o vi d er, e g, vi a t he Ra n d o mizati o n a n d Trial S u p pl y M a na ge m e nt ( R T S M) s yst e m. T he 
ge n erati o n of t h e ra n d o miz ati o n list a n d ma na ge m e nt of  t he R T S M s yste m will be d o ne b y a 
q ualifie d ser vice pr o vi der u n der t he o v ersi g ht of t he res p o nsi ble f u n cti o n at Te va.  
5. 1 0.  
M ai nte n a nce of R a n d o miz ati o n a n d Bli n di n g  
5. 1 0. 1.  
M ai nte n a nce of R a n d o miz ati o n  
Patie nt ra n d o mizati o n c o des will be mai ntai ne d i n a sec ure l ocati o n at t he s er vice pr o vi der 
c o ntracte d t o ge nerate t h e c o des. At t he ti me of a nal ysis (after t he l ast patie nt c o m pletes V 9), 
after recei vi n g u n bli n di n g re q uest fr o m T e va statisticia n, t he ser vice pr o vi der will pr o vi de t he 
u n bli n de d I M P assi g n me nts acc or di n g t o t he pr ocesses defi ne d i n t he rele va nt SO P . A n i nteri m 
a nal ysis is pla n ne d f or t his st u d y. T he details f or mai ntai ni n g t he st u d y bli n d will be o utli ne d i n 
t he c harter f or t h e i nteri m a nal ysis. 
5. 1 0. 2.  
Bli n di n g a n d U n bli n di n g  
Bli n de d p har m ac o ki netic a n d i m m u n o ge nicit y dat a ma y be ass esse d d uri n g t he st u d y. F or 
patie nts w h o ha ve p har m ac o ki netic or i m m u n o ge nicit y sa m ple bi oa nal ysis or data a n al ysis 
c o n d ucte d, t he i n di vi d uals res p o nsi ble f or sa m ple bi oa nal ysis a n d ot h er res p o nsi ble pers o n nel 
will k n o w w h o re cei ve d test I M P a n d w h o recei ve d place b o I M P d uri n g t he st u d y ( of t h ose 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 6  
patie nts o nl y). Pers o n n el res p o nsi ble f or bi oa n al ysis will be pr o vi de d wit h t he ra n d o mizati o n 
c o de t o facilitate t he a nal ysis. H o we v er, t he p ers o n nel res p o nsi ble f or sa m ple bi oa nal ysis  a n d 
p har mac o ki netic d ata a n al ysis will n ot ha ve access t o cli nical safet y a n d effi cac y d ata, a n d will 
pr o vi de c o nce ntrati o n dat a t o ot her pers o n nel i n a ma n ner t hat will n ot i de ntif y i n di vi d ual 
patie nts (ie, a d u m m y patie nt i de ntifier will be li n ke d t o t h e c o nce ntrati o n d ata of a n i n di vi d ual 
patie nt).  
I n case of a n e m er ge n c y, seri o us a d verse e v e nt, or pre g na nc y (see Secti o n 7. 1. 5  a n d Secti o n  7. 2 ), 
or i n cases w h e n k n o wle d ge of t he I M P assi g n me nt is nee de d t o ma ke tr eat me nt decisi o ns, t he 
i n vesti gat or ma y u n bli n d t he patie nt’s I M P assi g n me nt as dee me d necess ar y, mai nl y i n 
e mer ge n c y sit uati o ns. I n di vi d ual ra n d o mizati o n c o des, i n dicati n g t he I M P assi g n me nt f or eac h 
ra n d o mize d patie nt, will be a vaila ble t o t he i n vesti gat or(s) or p har macist(s) at t he i n vesti gati o nal 
ce nter via t h e R T S M s yst e m, b ot h via  tele p h o ne a n d i nter net. Brea ki n g of t he treat me nt c o de ca n 
al wa ys be perf or m e d b y t he i n vesti gat or wit h o ut pri or a p pr o val b y t he s p o ns or; h o we ver, t h e 
s p o ns or s h o ul d be n otifie d f oll o wi n g t he brea ki n g of t he treat me nt c o de. T h e patie nt’s I M P 
assi g n me nt s h o ul d n ot be re veal e d t o t he s p o ns or.  
W he n a bli n d is br o ke n f or safet y reas o ns, t he p atie nt will be wit h dra w n fr o m t he st u d y a n d t he 
e ve nt will be rec or de d o n t he C R F. T he cir c u msta nces lea di n g t o t he brea ki n g of t he c o de s h o ul d 
be f ull y d o c u me nte d i n t he i n vesti gat or’s st u d y files a n d i n t he patie nt’s s o urce d oc u m e ntati o n. 
Assi g n me nt of I M P s h o ul d n ot be rec or de d i n a n y st u d y d oc u me nts or s o urce d oc u me nt.  
F or a n a d vers e e v e nt defi ne d as a s us pecte d u ne x pecte d seri o us a d verse reacti o n ( S U S A R) (ie, 
reas o na ble p ossi bilit y; se e Secti o n  7. 1. 4 ), Gl o bal Patie nt Safet y a n d P har m ac o vi gila nce ( G P S P) 
ma y i n de p e n de ntl y re q u est t hat t he bli n de d c o de b e br o ke n ( o n a case-b y -case basis) t o c o m pl y 
wit h re g ul at or y re q uire m e nts. T he re p ort will be pr o vi de d i n a n u n bli n de d ma n ner f or re g ulat or y 
s u b missi o n. If t his occ urs, bli n di n g will be mai ntai ne d f or t he i n vesti gat or a n d f or ot her 
pers o n nel i n v ol ve d i n t he c o n d uct of t he st u d y, a n d a nal ysis a n d re p orti n g of t he data. 
5. 1 1.  
T ot al Bl o o d V ol u me  
T he t otal bl o o d v ol u me t o be c ollecte d f or eac h p atie nt i n t his st u d y is a p pr o xi matel y 1 5 7. 5  m L.  
Details o n bl o o d v ol u mes t o be c ollecte d d uri n g t he st u d y are pr o vi de d i n t he i nf or me d c ons e nt 
f or m (I C F) a n d st u d y refere nce ma n ual. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 7  
6.  
A S S E S S M E N T O F E F FI C A C Y  
Data fr o m a n y efficac y assess me nts perf or me d aft er t he s pecifie d ti me will n ot be c ollecte d o n 
t he C R F; i n t he e ve nt, h o we ver, t hat s u c h data are c ollecte d, t hese d ata will n ot be a nal yz e d.  F or 
details of t he ma na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut brea ks, see A p pe n di x  N . 
6. 1.  
Assess me nts of Effic ac y  
Refer t o Ta bl e  2  f or t he ti mi n g of ass ess me nts a n d pr oce d ures. See A p pe n di x  B  f or a detaile d 
descri pti o n of assess me nts a n d pr oce d ures.  
6. 1. 1.  
P ul m o n ar y F u ncti o n Testi n g  
P ul m o nar y f u ncti o n testi n g (s pir o m etr y a n d re versi bilit y testi n g) will be c o n d ucte d i n t he 
m or ni n g bet w ee n 0 5 3 0 a n d 1 1 0 0 d uri n g t he s cree ni n g peri o d a n d V 3 , a n d 05 3 0 -1 1 0 0 ± 1  h o ur 
(s u bse q ue nt visits) o n st u d y-pr o vi de d s pir o metr y e q ui p me nt. Testi n g will be perf or me d i n t he 
cli nic u nless s pecifie d as b y ha n d h el d de vice, w hic h will be pr o vi de d t o patie nts u p o n e nteri n g 
t he r u n-i n peri o d f or t he assess me nt of l u n g f u nctio n.  
L u n g f u ncti o n will be me as ure d usi n g sta n dar d s pir o metr y  c o nsiste nt wit h A T S/ E R S 2 0 0 5 
pr oce d ural g ui deli nes ( Miller et al 2 0 0 5 ). T he F E V1 is t he v ol u me of air t hat ca n be f orci bl y 
e x hale d fr o m t he l u n gs i n t he first sec o n d, meas ure d i n liters. T he f orce d vital ca pacit y ( F V C) is 
t he v ol u me of air t hat c a n be f orci bl y bl o w n o ut after f ull i ns pirati o n, meas ure d i n liters. T he 
F E F 2 5 -7 5 is t he force d e x pirat or y fl o w at 2 5 % t o 7 5 % of F V C . T h e Nati o nal Healt h a n d N utriti o n 
S ur ve y III refere n ce e q u ati o ns ( N H A N E S III 1 9 9 8 ) will be use d wit h a dj ust me nts f or et h nicit y 
(Ha n ki ns o n et al 1 9 9 9 , H a n ki ns o n et al 2 0 1 0 ). 
At t he scree ni n g visit, F E V 1 will be meas ure d i m me diatel y bef ore a n d 3 0  ( ± 1 5) mi n utes after 
a d mi nistrati o n of 4 i n halati o ns of al b uter ol/sal b uta m ol H F A M DI ( 9 0  µ g e x -act uat or) or 
e q ui vale nt. T he s pir o metr y e q ui p me nt will pr o vi de t he re v ersi bilit y as a perce nt val ue.  T his 
val ue s h o ul d n ot be r o u n de d. F E V 1 re v ersi bilit y ≥1 2 % a n d a 2 0 0-m L i ncrease fr o m bas eli ne 
F E V 1 is re q uire d. 
T he F E V 1 sta bilit y li mit (cli nic-base d s pir o metr y) will be calc ulate d fr o m eac h pa tie nt at t he 
ra n d o mizati o n visit ( V 3) usi n g t he f oll o wi n g e q u ati o n: 
•  best pre -al b uter ol/sal b uta m ol F E V 1 × 8 0 %  
T his val ue will be use d f or t he re mai n d er of t he st u d y a n d will be use d t o deter mi ne alert criteri a 
f or w orse ni n g ast h ma. T he F E V1 sta bilit y li mit is a ut o maticall y calc ulat e d a n d st ore d i n t he 
s pir o metr y s oft ware. If a patie nt falls bel o w t he F E V 1 sta bilit y li mit, a n alert will be ge n erate d. 
T he F E V 1 sta bilit y li mit f or t he ha n d hel d de vi ce will be 8 0 % of t he val ue o btai ne d at t he 
scree ni n g visit ( usin g t h e cli nic -base d e q ui p me nt val ue) a n d f or t he r u n -i n peri o d a n d 8 0 % of t he 
baseli ne val ue as deter mi ne d b y t h e ha n d hel d d e vice f or t h e treat me nt p eri o d.  
F E V 1 a n d P E F i n bet w ee n visits will be meas ure d usi n g t he ha n d h el d de vice (as a b o v e) eac h 
m or ni n g be f ore t he p atie nt ta kes t heir ast h ma mai nte na nce m e dicati o n. Patie nts s h o ul d a v oi d 
ta ki n g m or ni n g resc ue m e dicati o n wit hi n 6 h o urs of t he meas ure me nt w he ne ver p ossi ble. P E F is 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 8  
t he ma xi m u m s pee d of e x halati o n. P E F will be meas ure d b y t h e patie nt a n d will be rec or de d 
a ut o maticall y i n t he d ata base.  
6. 1. 2.  
Cli nic al Ast h m a E x acer b ati o n  
F or t his st u d y, a C A E is defi ne d as w orse ni n g ast h ma re q uiri n g treat me nt wit h a s yste mic 
c ortic oster oi d f or ≥3  d a ys, e mer ge n c y r o o m visit res ulti n g i n s yste mic c orti c oster oi d treat me nt, 
or h os pitalizati o n d ue t o ast h ma.  
W orse ni n g ast h ma i ncl u d es ne w or i ncreas e d s y m pt o ms or si g ns t hat eit her w orr y t he patie nt, or 
are relate d t o a n ast h ma -s pecific al ert (if a v aila ble t hr o u g h t he electr o ni c diar y/ h a n d hel d 
s pir o meter) a n d re q uir e t he a d diti on of mai nte na n ce me dicati o ns ( ot her t ha n s yste mic 
c ortic oster oi ds) t o c o ntr ol t he patie nts ast h ma s y m pt o ms base d o n t he i n vesti gat or ’s j u d g me nt. 
A patie nt w h o meets criteria f or a n ast h ma e x acer bati o n will be treate d per t he l ocal sta n dar d of 
care. A d diti o nal me dicati o n a n d/ or me dical i nter v e nti o n t hat w o ul d satisf y t he defi niti o n of 
ast h ma e x acer bati o n occ urri n g wit hi n 7  da ys of t he last da y of a pri or ast h ma e x acer bati o n e v e nt 
will be c o nsi dere d as part of t he sa me e v e nt f or a n al ysis p ur p oses.  
T he ast h ma e x acer bati o n start a n d st o p dates will be c ollecte d i n or d er t o d eter mi ne t he 
e x acer bati o n d urati o n. T he start date of a n ast h ma e x acer bati o n will be t he start date of t he i nitial 
me dical i nter ve nti o n (ie, use of s yst e mic c ortic ost er oi ds [ oral or i njecti o n ] ast h ma-s pecifi c 
h os pital a d missi o n, or ast h ma -s pecific e mer ge nc y de part me nt visit res ulti n g i n s yste mic 
c ortic oster oi d treat me nt, w hic he ver c o mes first). T he st o p date is t he last d a y of s yste mic 
c ortic oster oi ds or t he last da y of a n ast h ma -s pecifi c h os pitalizati o n w hic he ver is later. 
I n t he e ve nt of a C A E, F E V1 a n d P E F meas ure me nts s h o ul d be o btai ne d if it is safe t o d o s o i n 
t he i n vesti gat or’s o pi ni o n. Bl o o d sa m ples t o test T E V-5 3 2 7 5 ser u m c o n ce ntrati o n, A D A, a n d 
free a n d t otal ser u m I L-5 le vels s h o ul d be c ollecte d if p ossi ble.  
6. 1. 3.  
Ast h m a C o ntr ol D a ys  
A n ast h ma c o ntr ol da y is defi ne d as a da y o n w hic h t he patie nt uses zer o p uffs of i n hale d S A B A, 
has n o ni g ht -ti me a wa ke ni n gs, a n d e x perie nces n o ast h ma e x acer bati o ns. 
6. 1. 4.  
Ast h m a C o ntr ol Test  
T he Ast h ma C o ntr ol Test  ( A C T) is a patie nt self-a d mi nistere d t o ol f or i de ntif yi n g t h ose wit h 
p o orl y c o ntr olle d ast h ma c o m prisi n g 5 ite ms, wit h 4 -wee k recall ( o n s y m pt o ms a n d dail y 
f u ncti o ni n g) (Nat ha n et al 2 0 0 4 , Sc hatz  et al 2 0 0 6). It ass esses t he fre q ue n c y of s h ort ness of 
breat h a n d ge neral ast h ma s y m pt o ms, t he use of resc ue me dicati o ns, t he effect of ast h ma o n 
dail y f u ncti o ni n g, a n d t h e o verall self -assess me nt of ast h ma c o ntr ol meas ure d o n a 5 -p oi nt scal e 
(f or s y m pt o ms a n d acti vities: 1 =all t he ti me t o 5 = n ot at all; f or ast h ma c o ntr ol rati n g: 1 = n ot 
c o ntr olle d at all t o 5 =c o m pletel y c o ntr olle d). T ot al sc ores ra n ge fr o m 5 ( p o or c o ntr ol of ast h ma) 
t o 2 5 (c o m plete c o ntr ol of ast h ma), wit h hi g h er sc ores reflecti n g greater ast h ma c o ntr ol. A n A C T 
sc ore > 1 9 i n dicates well-c o ntr olle d ast h ma.  
6. 1. 5.  
Ast h m a S y m pt o m Sc ore  
T he ast h ma s y m pt o m sc ore will be deter mi ne d fr o m t he i nf or mati o n rec or de d i n t he ast h ma 
c o ntr ol diar y. A Li kert -st yl e scale will be use d t o q ua ntif y s y m pt o mat ol o g y. T his scale has bee n 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7 9  
use d pre vi o usl y t o assess c ha n ges i n ast h ma s y m pt o ms i n res p o nse t o n o vel ast h ma treat me nts 
(S ha pir o et al 2 0 0 0 ). 
Ast h ma s y m pt o m sc ores s h o ul d be deter mi ne d t wi ce dail y, i n t he m or ni n g a n d e ve ni n g:  
D a yti me S y m pt o m Sc o re ( deter mi ne d i n t he e ve ni n g)  
0 = N o s y m pt o ms d uri n g t he da y  
1 = S y m pt o ms f or 1 s h ort peri o d d uri n g t he da y  
2 = S y m pt o ms f or 2 or m ore s h ort peri o ds d uri n g t h e da y  
3 = S y m pt o ms f or m ost of t he da y w hic h di d n ot affect m y n or mal dail y acti vities  
4 = S y m pt o ms  f or m ost of t he da y w hic h di d affect m y n or mal dail y acti vities 
5 = S y m pt o ms s o se vere t hat I c o ul d n ot g o t o w or k or perf or m n or mal dail y acti vities  
Ni g ht -ti me S y m pt o m Sc ore ( deter mi ne d i n t he m o r ni n g) 
0 = N o s y m pt o ms d uri n g t he ni g ht  
1 = S y m pt o ms ca usi n g me t o wa ke o nce ( or wa ke earl y) 
2 = S y m pt o ms ca usi n g me t o wa ke t wice or m ore (i ncl u di n g wa ki n g earl y)  
3 = S y m pt o ms ca usi n g me t o be a wa k e f or m ost of t he ni g ht  
4 = S y m pt o ms s o se vere t hat I di d n ot sle e p at all  
S y m pt o m -free da ys are d efi ne d as 2 4-h o ur peri o ds wit h  ast h ma s y m pt o m sc ore of 0.  
Ast h ma c o ntr ol da ys are defi ne d as 2 4 -h o ur peri o ds wit h ast h ma s y m pt o m sc ores of 0 a n d n o 
resc ue m e dicati o n use. 
6. 1. 6.  
Ast h m a Resc ue Me dic ati o n Use  
T he n u m ber of ti mes ast h ma resc u e me dicati o n ( n u m ber of i n halati o ns/ p uffs) is use d wil l be 
assesse d (e g, b y re vie wi n g t he electr o nic di ar y or if re q uire d d u e t o missi n g data i n t he diar y, b y 
site trac ki n g of t he i n halati o n c o u nter o n t he i n haler). N ote: S A B A t hera p y use d f or re versi bilit y 
testi n g s h o ul d n ot be i ncl u de d i n t his meas ure. 
6. 1. 7.  
Ast h m a C o ntr ol C o m p osite Sc ore  
T he wee kl y ast h ma c o ntr ol c o m p osite sc ore will be base d o n t he f oll o wi n g, m o difie d fr o m 
O’ B yr ne et al ( 2 0 1 8)  t o i ncl u de dail y m or ni n g F E V1 i nstea d of P E F: 
1.  T w o or m ore of t h e f oll o wi n g criteria are f u lfille d 
•  ≤2 da ys wit h a d ail y ast h ma s y m pt o m sc ore > 1  
•  ≤2 da ys of al b uter ol/sal b uta m ol use d as resc u e me dicati o n u p t o a ma xi m u m of 
4  occasi o ns per wee k ( m ulti ple occasi o ns per da y are c o u nt e d as se parat e o ccasi o ns)  
•  m or ni n g F E V 1 ≥8 0 % pre dicte d f or eac h d a y ( b y h a n d hel d de vice)  
A n d  
2.  B ot h of t he f oll o wi n g criteria are f ulfille d:  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 0  
•  n o ni g ht -ti me a w a ke ni n gs d ue t o ast h ma 
•  n o use of ast h ma mai nte n a nce me di cati o ns  
6. 1. 8.  
St a n d ar dize d Ast h m a Q u alit y of Life Q uesti o n n aire  
T he Sta n dar dize d Ast h ma Q ualit y of Life Q uesti o n naire A Q L Q[ S]) ( patie nts ≥1 8 years of a ge 
versi o n) will be self -a d mi nistere d b y p atie nts. T he q uesti o n naire is a t o ol t o meas ure t he i m pact 
of ast h ma o n a patie nt’s q ualit y of life ( p h ysical, e m oti o nal, s ocial, a n d occ u pati o nal). T he ai m 
of t he q uesti o n naire is t o  e val uate t he pr o ble ms t hat are m ost tr o u bles o me t o patie nts i n t heir da y 
t o da y li ves. T h e q uesti o n naire c o ntai ns 3 2 ite ms wit h a 2-wee k recall peri o d a n d uses a 7 -p oi nt 
Li kert scale ( 7 = n ot i m paire d at all t o 1 =se v erel y i m paire d). Sc ores ra n ge fr o m 1 t o 7 , wit h hi g her 
sc ores i n dicati n g better q ualit y of life. 
6. 1. 9.  
Ast h m a C o ntr ol Q uesti o n n aire  
T he A C Q -6 is a vali dat e d ast h ma assess me nt t o ol t hat has bee n wi del y us e d ( J u ni per et al 1 9 9 9). 
T he 6 q uesti o ns are s elf -assess me nts (c o m plet e d b y t he patie nt). Eac h ite m o n t he A C Q -6 has a 
p ossi ble sc ore ra n gi n g fr o m 0 t o 6, a n d t he t otal sc ore is t he mea n of all res p o nses.  
6. 1. 1 0.  
 
 
 
 
 
6. 1. 1 1.  
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 1  
7.  
A S S E S S M E N T O F S A F E T Y  
I n t his st u d y, safet y will be assesse d b y q u alifie d st u d y pers o n nel b y e val u ati n g re p orte d a d verse 
e ve nts , l ocal t olera bilit y at t he i njecti o n site, cli nical la b orat or y test res ults, vital si g ns 
meas ure me nts, el ectr o car di o gra m ( E C G) fi n di n gs, p h ysical e x a mi nati o n fi n di n gs, a n d use of 
c o nc o mita nt me dicati o ns . Refer t o Ta bl e  2  f or t he ti mi n g of assess me nts a n d pr oce d ures. F or 
details of t he ma na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut brea ks, see A p pe n di x  N . 
7. 1.  
A d verse E ve nts  
7. 1. 1.  
Defi niti o n of a n A d verse E ve nt  
A n a d vers e e ve nt is a n y u nt o war d me dical o cc urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p h ar mace utical pr o d uct a n d w hic h d oes not necessaril y ha v e t o ha ve a 
ca usal r elati o ns hi p wit h t his treat me nt.  
I n t his st u d y, a n y a d v erse e ve nt occ urri n g aft er t he patie nt has si g n e d t he I C F t hr o u g h t he e n d of 
t he st u d y s h o ul d be rec or de d a n d re p orte d as a n a d verse e v e nt. 
A n a d vers e e ve nt ca n, t h eref ore, be a n y u nfa v ora ble a n d u ni nte n de d p h ysi cal si g n, s y m pt o m, or 
la b orat or y para meter t hat de vel o ps or w orse ns i n se verit y d uri n g t he c o urse of t his st u d y. 
De vel o p me nt of a n e w c o n diti o n or t he w orse ni n g of a pre -e xisti n g c o n diti o n will be c o nsi dere d 
a n a d vers e e v e nt, w het her or n ot c o nsi dere d relat e d t o T E V -5 3 2 7 5. Sta ble c hr o nic c o n diti o ns 
(s uc h as art hritis) t hat are prese nt bef ore st u d y e ntr y a n d d o n ot w orse n d uri n g t his st u d y will n ot 
be c o nsi dere d a d verse e v e nts.  
Acc or di n gl y, a n a d vers e e ve nt c a n i n cl u de a n y of t he f oll o wi n g:  
•  i nter-c urre nt  ill nesses 
•  p h ysical i nj uries  
•  e ve nts p ossi bl y relate d t o c o nc o mita nt me dicati o n  
•  si g nifica nt w orse ni n g (c h a n ge i n nat ure, s e verit y, or fre q u e nc y) of pre -e xisti n g 
c o n diti o ns  
( N ote: A c o n diti o n rec or de d as pre-e xisti n g t hat is i nter mitte ntl y s y m pt o matic [e g, 
hea dac he] a n d t hat occ urs d uri n g t his st u d y s h o ul d be rec or de d as a n a d v erse e ve nt) 
•  dr u g i nteracti o ns  
•  e ve nts occ urri n g d uri n g dia g n ostic pr o ce d ures or d uri n g a n y was h o ut p has e of t his 
st u d y 
•  la b orat or y or dia g n ostic t est a b n or malities, t hat res ult i n t he wit h dra wal of t he patie nt 
fr o m t he st u d y, are ass ociate d wit h cli nical si g ns a n d s y m pt o ms or a seri o us a d verse 
e ve nt, or re q uire me dical treat me nt or f urt her dia g n ostic w or k -u p, or are c o nsi dere d 
b y t he i n vesti ga t or t o b e cli nicall y si g nifica nt  
( N ote: A b n or mal la b orat or y test res ults at t he scree ni n g visit t hat precl u de a patie nt 
fr o m e nteri n g t he st u d y or recei vi n g st u d y tr eat me nt are n ot c o nsi dere d a d v erse 
e ve nts)  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 2  
Ast h ma ma nifestati o n, w orse ni n g a n d e x acer bati o n are a n effi cac y v aria ble f or t his st u d y a n d 
s h o ul d be ca pt ure d o n t h e ast h ma e x acer bati o n C R F; acc or di n gl y, ast h ma e x acer bati o ns s h o ul d 
n ot be rec or de d as a d vers e e ve nts u nless t he y meet t he criteria f or a s eri o us a d verse e ve nt.  
7. 1. 2.  
Rec or di n g a n d Re p orti n g o f A d verse E ve nts 
F or rec or di n g of a d verse e ve nts, t he st u d y p eri o d is defi ne d f or eac h patie nt as t he ti me peri o d 
fr o m si g n at ure of t he I C F t o t he e n d of t he st u d y. T he peri o d f or re p orti n g treat me nt-e mer ge nt 
a d verse e ve nts is defi ne d as t he peri o d after t he first d ose of I M P is a d mi nistere d u ntil t he e n d of 
t he st u d y. 
All a d verse e ve nts t hat o cc ur d uri n g t he defi ne d st u d y peri o d m ust be rec or de d b ot h o n t he 
s o urce d oc u m e ntati o n a n d t he C R F, re gar dless of t he se verit y of t he e ve nt or j u d ge d relati o ns hi p 
t o t he I M P. F or seri o us a d verse e v e nts, t he seri o us a n d pr ot oc ol defi n e d a d v erse e v e nt of s pecial 
i nterest f or m ( S A E/ P D A E SI f or m) m ust be c o m pl ete d a n d t he seri o us a d verse e ve nt s h o ul d be 
re p orte d wit hi n 2 4 h o urs of w he n t he i n vesti gat or bec o mes a ware of t he seri o us a d verse e ve nt 
( Secti o n 7. 1. 5. 3. 1 ). T he i n vesti gat or d o es n ot nee d t o acti vel y m o nit or patie nts f or a d verse e v e nts 
after t he st u d y peri o d defi ne d a b o ve ( defi ne d p eri o d).  
At eac h c o ntact wit h t he patie nt, t he i n vesti gat or or desi g n ee m ust q uesti o n t he patie nt a b o ut 
a d verse e ve nts b y as ki n g o pe n -e n de d q uesti o ns s uc h as “ Ha ve y o u h a d a n y u n us ual s y m pt o ms or 
me dical pr o ble ms si nce t he last visit? If  yes, pleas e descri b e.” A precise di a g n osis s h o ul d be 
rec or de d w he n e ver p ossi ble. W he n s uc h a dia g n osis is ma de, all relate d si g ns, s y m pt o ms, a n d 
a n y t est fi n di n gs will be rec or de d c ollecti vel y as a si n gle dia g n osis o n t he C R F a n d, if it is a 
seri o us a d vers e e v e nt, o n t he seri o us a d verse e v e nt f or m. Re p orte d or o bser ve d si g ns a n d 
s y m pt o ms t hat are n ot m a nifestati o ns of a k n o w n dia g n osis s h o ul d be re p orte d i n di vi d uall y.  
T he cli nical c o urs e of eac h a d vers e e v e nt will be m o nit ore d at s uita ble i nter vals u ntil r es ol ve d, 
sta bilize d, or ret ur ne d t o baseli ne; or u ntil t he patie nt is referre d f or c o nti n u e d care t o a healt h 
care pr ofessi o nal; or u ntil a deter mi nati o n of a ca use u nrelate d t o t he I M P or st u d y pr oce d ure is 
ma de.  
T he o nset a n d e n d d ates, d urati o n (i n case  of a d v erse e ve nt d ur ati o n of less t ha n 2 4  h o urs), acti o n 
ta ke n re gar di n g I M P, treat me nt a d mi nistere d, a n d o utc o me f or eac h a d verse e ve nt m ust be 
rec or de d b ot h o n t he s o ur ce d oc u me nt ati o n a n d t he C R F. 
T he relati o ns hi p of eac h a d verse e ve nt t o I M P a n d t he s e verit y a n d seri o us ness of eac h a d verse 
e ve nt, as j u d ge d b y t he i n vesti gat or, m ust be rec or de d as descri be d bel o w.  
F urt her details are gi ve n i n t he Safet y M o nit ori n g Pla n.  
7. 1. 3.  
Se verit y of a n A d verse E ve nt  
T he se verit y of eac h a d v erse e v e nt m ust be rec or de d as 1 of t he f oll o wi n g:  
Mil d:  
N o li mitati o n of us ual acti vities  
M o der ate:  S o me li mitati o n of us ual acti vities  
Se vere:  
I n a bilit y t o carr y o ut us u al acti vities 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 3  
7. 1. 4.  
Rel ati o ns hi p of a n A d verse E ve nt t o t he I n vesti g ati o n al Me dici n al Pr o d uct  
T he relati o ns hi p of a n a d verse e v e nt t o a n I M P s us pect, as a p plica ble i n t he re p ort, will be 
ca pt ure d s e paratel y. Deter mi nati o n of t his relati o ns hi p will be ma de acc or di n g t o t he criteria i n 
Ta ble  4 . 
T a ble  4 : 
T he Rel ati o ns hi p of a n A d verse E ve nt t o t he I M P S us pects  
Ter m  
Defi niti o n  
Cl arific ati o n  
N o reas o na ble 
p ossi bilit y  
( n ot relate d) 
T his cate g or y a p plies t o a d verse 
e ve nts t hat, after caref ul 
c o nsi derati o n, are clearl y d ue t o 
e xtra ne o us ca uses ( disease, 
e n vir o n me nt, etc.) or t o a d verse 
e ve nts t hat, after caref ul me di cal 
c o nsi derati o n at t he ti me t he y are 
e val uate d, are j u d ge d t o be u nrelate d 
t o t he I M P. 
T he relati o ns h i p of a n a d verse e ve nt ma y be c o nsi dere d 
“ n o reas o na ble p ossi bilit y” if it is clearl y d ue t o 
e xtra ne o us ca uses or if at least 2 of t he f oll o wi n g a p pl y:  
•  
It d oes n ot f oll o w a reas o na bl e te m p oral se q ue nce 
fr o m t he a d mi nistrati o n of t he I M P. 
•  
It c o ul d rea dil y ha ve bee n pr o d uce d b y t he patie nt’s 
cli nical state, e n vir o n me ntal, or t o xic fact ors, or ot her 
m o des of t hera p y a d mi nistere d t o t he patie nt.  
•  
It d oes n ot f oll o w a k n o w n patter n of res p o nse t o t he 
I M P. 
•  
It d oes n ot rea p pear or w orse n w he n t he I M P is 
re-a d mi nistere d.  
Reas o na ble 
p ossi bilit y  
(relate d) 
T his cate g or y a p plies t o a d verse 
e ve nts f or w hic h, after caref ul 
me dical c o nsi derati o n at t he ti me 
t he y are e val uate d, a c o n necti o n wit h 
t he I M P/ n o n-I M P a d mi nistrati o n 
ca n n ot b e r ule d o ut wit h certai nt y.  
T he relati o ns hi p of a n a d verse e ve nt ma y be c o nsi dere d 
“reas o na ble p ossi bilit y” if at l east 2 of t he f oll o wi n g 
a p pl y:  
•  
It f oll o ws a reas o na ble te m p or al se q ue nce fr o m 
a d mi nistrati o n of t he I M P.  
•  
It ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n 
c haracteristics of t h e patie nt’s cli nical state, 
e n vir o n me ntal or t o xic fact ors or ot her m o des of 
t hera p y a d mi nistere d t o t he patie nt. 
•  
It disa p pears or decreases o n cessati o n or re d ucti o n i n 
d ose. T here are i m p orta nt e xc e pti o ns w he n a n 
a d verse e ve nt d oes n ot disa p pear u p o n 
dis c o nti n uati o n of t he I M P, yet a n I M P relati o ns hi p 
clearl y e xists.  
•  
It f oll o ws a k n o w n patter n of res p o nse t o t he I M P. 
I M P =i n vesti gati o nal me dici nal pr o d uct. 
7. 1. 5.  
Seri o us A d verse E ve nts  
F or rec or di n g of s eri o us a d verse e ve nts, t he st u d y peri o d is defi ne d f or eac h  patie nt as t hat ti me 
peri o d fr o m si g nat ure of t he I C F t o t he e n d of t h e f oll o w -u p peri o d. Seri o us a d verse e ve nts 
occ urri n g i n a p atie nt aft er t he e n d of t he f oll o w -u p peri o d s h o ul d be re p orte d t o t he s p o ns or if 
t he i n vesti gat or b ec o mes a ware of t he m, f ollo wi n g t he pr oce d ures des cri be d i n Secti o n  7. 1. 5. 3. 1 . 
7. 1. 5. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  
A seri o us a d verse e v e nt is a n a d vers e e ve nt o cc urri n g at a n y d os e t hat res ults i n a n y of t he 
f oll o wi n g o utc o mes or acti o ns: 
•  res ults i n deat h 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 4  
•  is life-t hreate ni n g a d vers e e ve nt (ie, t h e patie nt w as at ris k of deat h at t he ti me of t he 
e ve nt); it d oes n ot refer t o a n e ve nt w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h if it 
were m or e se vere  
•  re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, w hic h 
mea ns t hat h os pital i n patie nt a d missi o n or pr ol o n gati o n of h os pital sta y were re q uire d 
f or treat me nt of a n a d v erse e ve nt, or t hat t he y o cc urre d as a c o nse q u e nce of t he e ve nt.  
H os pitalizati o ns sc he d ule d bef ore t he patie nt si g n e d t he I C F will n ot be c o nsi dere d 
seri o us a d vers e e v e nts, u nless t here was w orse ni n g of t he pre-e xisti n g c o n diti o n 
d uri n g t he p atie nt’s parti ci pati o n i n t his st u d y.  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y (refers t o a s u bsta nti al 
disr u pti o n of o ne’s a bilit y t o c o n d uct n or mal life f u ncti o ns)  
•  is a c o n ge nital a n o mal y/ birt h defect 
•  a n i m p orta nt me dical e v e nt t hat ma y n ot res ult i n deat h, be life -t hreat e ni n g, or re q uire 
h os pitaliz ati o n, b ut ma y j e o par dize t he patie nt a n d ma y re q uire m e dical i nter ve nti o n 
t o pre ve nt o ne of t h e o utc o mes liste d i n t his defi niti o n. E x a m ples of s uc h e ve nts are 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m; 
bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or t he 
de vel o p me nt of dr u g d e p e n de nc y or dr u g a b us e. N ote: A n y s us p ecte d tra ns missi o n of 
a n i nfecti o us a ge nt via a me dici nal pr o d uct is c o nsi dere d a n i m p orta nt me dical e ve nt.  
•  all occ urre nces of p ossi ble dr u g-i n d uce d li ver i nj ur y t hat meet H y’s la w criteria, 
defi ne d as all  of t he b el o w, m ust be re p orte d b y t h e i n vesti gat or t o t he s p o ns or as a 
seri o us a d vers e e v e nt: 
− ala ni ne a mi n otra nsf eras e ( A L T) or as partat e a mi n otra nsferase ( A S T) i ncre ase of 
> 3 × u p per li mit of n or mal ( U L N)  
− t otal bilir u bi n i ncrease of > 2 × U L N 
− a bse nce of i nitial fi n di n gs of c h olestasis (ie, n o s u bsta ntial i ncrease of al kali ne 
p h os p hatase [ A L P])  
A n a d vers e e ve nt t hat d o es n ot meet a n y of t he criteria f or seri o us ness list e d a b o ve will be 
re gar de d as a n o ns eri o us a d verse e ve nt. 
Ast h ma ma nifestati o n, w orse ni n g a n d e x acer bati o n are a n effi cac y v aria ble f or t his st u d y a n d 
s h o ul d be ca pt ure d o n t h e ast h ma e x acer bati o n C R F; acc or di n gl y, ast h ma e x acer bati o ns s h o ul d 
n ot be rec or de d as a d vers e e ve nts u nless t he y meet t he criteria f or a s eri o us a d verse e ve nt.  
7. 1. 5. 2.  
E x pecte d ness  
I n t his st u d y, t he refere nce safet y i nf or mati o n ( R SI) f or deter mi nati o n of e x pecte d ness of 
s us pecte d seri o us a d vers e reacti o ns f or t he I M P is i ncl u de d i n t he I B. A seri o us a d verse e ve nt 
t hat is n ot i ncl u de d i n t he rele va nt R SI b y its s pecificit y, se v erit y, o utc o me, or fre q u e nc y is 
c o nsi dere d a n u ne x pecte d a d verse e ve nt.  
T he s p o ns or’s G P S P will deter mi ne t he e x pecte d ness f or all seri o us a d verse e ve nts.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 5  
F or t he p ur p os e  of S U S A R re p orti n g, t he versi o n of t he I B at t he ti me of o cc urre nce of t he 
S U S A R a p plies.  
7. 1. 5. 3.  
Re p orti n g a Seri o us A d verse E ve nt  
7. 1. 5. 3. 1.  I n vesti g at or Res p o nsi bilit y 
T o satisf y re g ulat or y re q uire me nts, a ll seri o us a d v erse e v e nts t hat occ ur d uri n g t he st u d y, 
re gar dl ess of j u d ge d relati o ns hi p t o a d mi nistrati o n of t he I M P, m ust be re p orte d t o t he s p o ns or 
b y t he i n vesti gat or. T h e e ve nt m ust be re p orte d wit hi n 2 4  h o urs of w he n t he i n vesti gat or lear ns 
a b o ut it. C o m pleti n g t he seri o us a d vers e e v e nt f or m a n d re p orti n g t he e v e nt  m ust n ot be dela ye d, 
e ve n if n ot all t he i nf or m ati o n is a vaila ble. T he i n vesti gat or d o es n ot nee d t o acti vel y m o nit or 
patie nts f or a d verse e v e nts o nce t his st u d y has e n d e d.  
Seri o us a d verse e ve nts o cc urri n g t o a patie nt after t he last a d mi nistrati o n of I M P  t o t hat patie nt 
has e n de d s h o ul d be re p orte d t o t he s p o ns or if t he i n vesti gat or b ec o mes a ware of t h e m . 
T he seri o us a d v erse e ve nt f or m s h o ul d be se nt t o t he l ocal safet y officer ( L S O) or desi g nee, i e, a 
Cli nical Researc h Or ga ni zati o n ( C R O) i n a c o u ntr y wit h o ut a s p o ns or L S O (t he e mail a d dress 
will be pr o vi de d o n t he S A E re p ort f or m).  
T he f oll o wi n g i nf or mati o n s h o ul d be pr o vi de d t o rec or d t he e ve nt acc uratel y a n d c o m pletel y:  
•  st u d y n u m ber 
•  i n vesti gat or a n d i n vesti gati o nal ce nter i d e ntificati o n 
•  patie nt n u m be r 
•  o nset date a n d det aile d d escri pti o n of a d verse e v e nt  
•  i n vesti gat or’s assess me nt of t he relati o ns hi p of t he a d verse e ve nt t o t he I M P ( n o 
reas o na bl e p ossi bilit y, or reas o na bl e p ossi bilit y, as descri be d i n Ta bl e  4 ) 
A d diti o nal i nf or mati o n i ncl u des:  
•  a ge a n d se x of patie nt  
•  date of first d ose of I M P  
•  date a n d a m o u nt of last a d mi nistere d d ose of I M P  
•  acti o n ta ke n  
•  o utc o me, if k n o w n  
•  se verit y 
•  e x pla nati o n of assess me nt of relate d n ess  
•  c o nc o mita nt me dicati o n (i ncl u di n g st u d y -pr o vi de d i n halers, d oses, r o utes of 
a d mi nistrati o n, a n d re gi me ns)  
•  treat me nt of t he e ve nt 
•  perti ne nt la b orat or y or ot her dia g n ostic test data  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 6  
•  me dical hist or y  
•  res ults of dec h alle n ge/rec halle n ge, if k n o w n 
•  f or a n a d v erse e ve nt r es ulti n g i n deat h 
− ca use of deat h ( w het her or n ot t he deat h was relat e d t o I M P)  
− a ut o ps y fi n di n gs (if a vail a ble)  
Eac h re p ort of a s eri o us a d verse e v e nt will be re vi e we d a n d e val uat e d b y t he i n vesti gat or a n d t he 
s p o ns or t o assess t he nature of t he e ve nt a n d t he relati o ns hi p of t he e ve nt t o t he I M P.  
A d diti o nal i nf or mati o n (f oll o w -u p) a b o ut a n y seri o us a d verse e ve nt u na vaila ble at t he i nitial 
re p orti n g s h o ul d be f or w ar de d b y t he i n vesti gat or wit hi n 2 4 h o urs of w he n it bec o mes k n o w n t o 
t he sa me a d dress as t he i nitial re p ort.  
F or all c o u ntri es, t he s p o ns or’s G P S P will distri b ute t he C o u ncil f or I nter n ati o nal Or ga nizati o ns 
of Me dical Scie n ces ( CI O M S) f or m/ E xte nsi ble Mar k u p La n g u a ge ( X M L) file or Me d Watc h of 
S A Es t o t he L S O/ C R O f or s u b missi o n t o  t he c o m pete nt a ut h orities, I E C/I R Bs a n d i n vesti gat ors, 
acc or di n g t o l ocal re g ulati o ns. T he i n vesti gat or m ust e ns ure t hat t he I E C/I R B is als o i nf or me d of 
t he e ve nt, i n acc or da n ce wit h nati o nal a n d l ocal re g ulati o ns. 
T he s p o ns or’s G P S P will s u b mit t he X M L o f S U S A Rs t o t he E M A i n a n u n bli n de d ma n ner, 
w he n a p plica bl e a n d acc or di n g t o l ocal re g ulati o ns. S u b missi o n of S U S A Rs t o t he F D A usi n g 
Me d Watc h f or ms is d o ne b y t he Re g ulat or y Affairs de part me nt u p o n recei pt fr o m t he L S O.  
Bli n di n g will be mai ntai ne d f or all  st u d y pers o n nel. T heref ore, i n case of a S U S A R, o nl y t he 
L S O/ u n bli n de d pers o n n el fr o m t he C R O will recei ve t he u n bli n de d re p ort f or re g ulat or y 
s u b missi o n; t he ot hers will recei ve a bli n de d re p ort. 
F urt her details re gar di n g re p orti n g of S A E/ P D A E SI will be gi ve n i n t he safet y m a na ge m e nt pla n 
( S M P). 
7. 1. 5. 3. 2.  S p o ns or Res p o nsi bilit y  
If a seri o us u ne x pecte d a d verse e v e nt is belie ve d t o be relate d t o t he I M P or st u d y pr oce d ures, 
t he s p o ns or will ta ke a p pr o priate ste ps t o n otif y all i n vesti gat ors partici pati n g i n s p o ns ore d 
cli nical st u dies of T E V -5 3 2 7 5 a n d t he a p pr o priate c o m pete nt a ut h orities (a n d I E C/I R B, as 
a p pr o priate).  
I n a d diti o n t o n otif yi n g t he i n vesti gat ors a n d c o m pete nt a ut h orities (a n d I E C/I R B, as 
a p pr o priate), ot her acti o n ma y b e re q uir e d, i ncl u di n g t he f oll o wi n g:  
•  alteri n g e xisti n g researc h b y m o dif yi n g t he pr ot oc ol  
•  disc o nti n ui n g or s us pe n di n g t he st u d y  
•  m o dif yi n g t he e xisti n g c o nse nt f or m a n d i nf or mi n g all st u d y partici p a nts of ne w 
fi n di n gs 
•  m o dif yi n g listi n gs of e x pecte d t o xicities t o i ncl u de a d verse e v e nts ne wl y  i de ntifie d as 
relate d t o T E V-5 3 2 7 5  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 7  
7. 1. 6.  
Pr ot oc ol -D efi ne d A d verse E ve nts of S peci al I nterest f or Re p orti n g t o t he Gl o b al 
P ati e nt S af et y & P h ar m a c o vi gil a nce De p art me nt  
F or t he p ur p os es of t his pr ot oc ol, t he f oll o wi n g are c o nsi dere d P D A E SI f or e x pe dite d re p orti n g  
t o t he G P S P de part me nt: 
•  s yste mic se v ere reacti o ns (i ncl u di n g a n a p h yla xis) t hat f oll o w t he dia g n ostic criteria 
f or a na p h yl a xis as o utli ne d b y t h e 2 0 0 6 J oi nt Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Dise ase/ F o o d Aller g y a n d A na p h yl a xis Net w or k ( NI AI D/ F AA N) Sec o n d 
S y m p osi u m o n A n a p h yl a xis ( Sa m ps o n et al 2 0 0 6 , [A p pe n di x  H ]). 
•  o p p ort u nistic i nfecti o ns as liste d i n t he Pa ne l o n O p p ort u nistic I nfecti o ns i n 
HI V -I nfect e d A d ults a n d A d olesce nts g ui deli nes f or t he pre v e nti o n a n d treat me nt of 
o p p ort u nistic i nfecti o ns i n HI V -i nf ecte d a d ults a n d a d olesce nts: rec o m me n dati o ns 
fr o m t he Ce nters f or Dise ase C o ntr ol a n d Pre ve nti o n, t he Nati o nal I nstit utes of 
Healt h, a n d t he HI V Me dici ne Ass ociati o n of t he I nfecti o us Diseas es S ociet y of 
A merica ( A p pe n di x  I). 
•  hel mi nt h i nfecti o ns  
•  mali g na n cies (i ncl u di n g n o n -mela n o ma s ki n ca n cer)  
T he pr ocess f or re p orti n g t hese P D A E SI is t he sa me as t hat f or re p orti n g a seri o us a d verse e v e nt 
(see Secti o n 7. 1. 5. 3 ). T h ese e ve nts ca n be eit her seri o us or n o nseri o us, acc or di n g t o t he criteria 
o utli ne d i n Secti o n  7. 1. 5. 1 . 
7. 1. 7.  
Pr ot oc ol -D efi ne d A d verse E ve nts of S peci al I nterest t h at d o n ot Re q uire 
Re p orti n g t o t he Gl o b al P ati e nt S afet y & P h ar m a c o vi gil a nce De p art me nt  
I nje cti o n site fi n di n gs will be assesse d usi n g a sta n dar dize d scale as descri be d i n Secti o n  7. 8 . 
I nje cti o n site fi n di n gs will n ot be ca pt ure d as a d verse e ve nts u nless t he y f ulfill c haracteristics 
t hat are be y o n d t h os e i n t he s pecifie d f or ms/scales (e g, necr osis, a bscess, et c.) or f ulfill 
seri o us ness criteria; if f ulfille d, t he y m ust be rec or de d a n d re p orte d as s p ecifie d i n Secti o n  7. 1. 2 . 
7. 1. 8.  
Pr ot oc ol D e vi ati o ns Bec a use of a n A d verse E ve nt  
If a patie nt e x perie nces a n a d verse e ve nt or me di cal e mer ge n c y, de viati o ns fr o m t he pr ot oc ol 
ma y b e all o we d o n a cas e -b y -case basis. T o e ns ure patie nt safet y, after t h e e ve nt has sta bilize d or 
treat me nt has bee n a d mi nistere d ( or b ot h), t he i n v esti gat or or ot her p h ysici a n i n atte n da nce m ust 
c o ntact t he C R O me dical m o nit or as s o o n as p ossi ble t o disc uss t he sit uati o n. T he i n vesti gat or, i n 
c o ns ultati o n wit h t he s p o ns or, will deci de w het h er t he patie nt s h o ul d c o nti n ue t o partici pate i n 
t he st u d y. 
7. 2.  
Pre g n a nc y  
A n y fe male p atie nt bec o mi n g pre g n a nt d uri n g t he st u d y will be disc o nti n ue d fr o m t he st u d y.  
All pre g n a ncies of w o me n partici pati n g i n t he st u d y t hat occ ur d uri n g t he st u d y, or wit hi n 
5  half -li ves aft er I M P a d mi nistrati o n, or is re p orte d t o the i n vesti gat or, are t o be re p ort e d 
i m me diatel y t o t he C R O me dical m o nit or , a n d t he i n vesti gat or m ust pr o vi d e t he s p o ns or ( L S O) 
wit h t he c o m plete d pre g n a nc y f or m. T h e pr ocess f or re p orti n g a pre g na n c y is t he sa me as t hat f or 
re p orti n g a seri o us a d verse e vent ( Secti o n  7. 1. 5. 3. 1 ) b ut usi n g t he pre g na nc y f or m. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 8  
T he i n vesti gat or is n ot re q uire d t o re p ort patie nts w h o are f o u n d t o be pre g na nt bet wee n 
scree ni n g a n d baseli ne, pr o vi de d n o pr ot oc ol-relat e d pr oce d ures w ere a p plie d. 
All fe male patie nts w h o bec o me pre g na nt will be m o nit ore d  f or t he o utc o me of t he pre g n a nc y 
(i ncl u di n g s p o nta n e o us, electi ve, or v ol u ntar y a b orti o n). If t he pre g na nc y c o nti n ues t o ter m, t he 
o utc o me ( healt h of t h e i nfa nt u p t o 8  wee ks of a ge), i ncl u di n g det ails of birt h a n d prese n ce or 
a bse nce of a n y birt h defect, c o n ge nital a b n or m alities, or mater nal a n d ne w b or n c o m plicati o ns, 
will be re p orte d t o t he s p o ns or. A n y c o m plicati o n of pr e g na n c y d uri n g t he st u d y a n d a n y 
c o m plicati o n of pre g n a nc y t hat t he i n vesti gat or b ec o mes a ware of after wit h dra wal fr o m t he 
st u d y will be re p orte d as a n a d vers e e v e nt or seri o us a d verse e ve nt, as a p pr o priate.  
Si nce t here is n o e vi de n ce of re pr o d ucti ve ris k , h u ma n m uta ge nicit y or ge n ot o xicit y f or t his I M P, 
fe male part ners will n ot be as ke d t o si g n a n I C F t o m o nit or t he o utc o me of t he pre g na n c y. 
If t he pre g n a nc y i n t he w o ma n partici pati n g i n t he st u d y d oes n ot c o nti n ue t o ter m, 1 of t he 
f oll o wi n g acti o ns will be ta ke n:  
•  f or a s p o nta ne o us a b orti o n, re p ort as a s eri o us a d v erse e v e nt. 
•  f or a n el ecti ve a b orti o n d ue t o de vel o p me ntal a n o malies, re p ort as a seri o us a d verse 
e ve nt.  
•  f or a n el ecti ve a b orti o n n ot  d ue t o de vel o p me ntal a n o malies, re p ort o n t he pre g na nc y 
f or m; d o n ot re p ort as a n a d verse e ve nt.  
7. 3.  
Me dic ati o n Err or a n d S peci al Sit u ati o ns Rel ate d t o t he 
I n vesti g ati o n al Me dici n al Pr o d ucts 
A n y a d mi nistrati o n of I M P t hat is n ot i n acc or da nce wit h t he st u d y pr ot oc ol s h o ul d be re p orte d 
as a pr ot oc ol de vi ati o n a n d i n t he patie nts’ s o urce d oc u me nts, re gar dless of w het her or n ot a n 
a d verse e ve nt oc c urs as a res ult.  W he n meeti n g i m p orta nt pr ot oc ol de viati o n criteria, all 
i nsta nces of i nc orrect I M P a d mi nistrati o n s h o ul d be cate g orize d as “ N o nc o m plia nce t o 
I n v esti gati o nal Me dici nal Pr o d uct (I M P).” 
T he f oll o wi n g are t y p es of me dicati o n err ors a n d s pecial sit uati o ns:  
•  me dicati o n err or: A n y u ni nte nti o nal err or i n t he prescri bi n g, dis pe nsi n g, or 
a d mi nistrati o n of a me dici nal pr o d uct w hile i n t he c o ntr ol of t he healt hcare 
pr ofessi o nal , patie nt, or c o ns u mer. 
•  o ver d ose: A d mi nistrati o n of a q ua ntit y of a me di ci nal pr o d uct gi ve n per 
a d mi nistrati o n or c u m ulati vel y w hic h is a b o v e t he ma xi m u m rec o m me n de d d ose 
acc or di n g t o t he pr ot oc ol or a ut h orize d pr o d uct i nf or mati o n as a p plica ble. Cli nical 
ju d g me nt s h o ul d al wa ys be a p plie d. A n y d ose of I M P ( w het her t he test I M P or 
place b o I M P), w h et her ta ke n i nte nti o nall y or u ni nt e nti o nall y, i n e xcess of t hat 
prescri be d m ust be i m me diatel y re p orte d t o t he s p o ns or.  
•  mis use: A n y i nte nti o nal t hera pe utic us e of a dr u g pr o d uct i n a n i na p pr o pri ate wa y or 
o pi oi d use c o ntrar y t o t he directe d or prescri be d patter n of use, re gar dless of t he 
prese nce or a bs e nce of har m or a d v erse effects. E x a m ples: u n der usa ge, erratic or 
dis or ga niz e d use, i na p pr o priate use (f or a n xiet y),  use i n c o nj u ncti o n wit h alc o h ol or 
ille gal s u bsta nces, o ver us e. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8 9  
•  a b use: A n y i nte nti o nal, n o nt hera pe utic us e of a dr u g pr o d u ct or s u bsta nce, e ve n o nce, 
f or t he p ur p ose of ac hie vi n g a d esira ble ps yc h ol o gical or p h ysi ol o gical effect, or 
i nte nti o nal use of a n o pi oi d f or a n o n me dical p ur p ose, s uc h as e u p h oria or alteri n g 
o ne’s state of c o nsci o us n ess.  
•  off -la bel us e: Sit uati o ns w here a n I M P is i nte nti o nall y use d f or a me di cal p ur p ose n ot 
i n acc or da nce wit h t he pr ot oc ol or a ut h orize d pr o d uct i nf or mati o n as a p plica ble. 
•  occ u pati o nal e x p os ure: E x p os ure t o a n I M P, as a res ult of o ne’s pr ofessi o nal or 
n o n -pr ofessi o nal o cc u pati o n.  
•  breastfee di n g: S us pecte d a d verse e ve nts w hic h o cc ur i n i nfa nts f oll o wi n g e x p os ure t o 
a me dici nal pr o d uct fr o m breast mil k.  
7. 4.  
Cli nic al L a b or at or y Tests  
All cli nical la b orat or y test res ults o utsi de t he refere nce ra n ge will be j u d ge d b y t he i n vesti gat or 
as bel o n gi n g t o o ne of t h e f oll o wi n g cate g ories:  
•  a b n or mal a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt  
A la b orat or y test r es ult t hat is j u d ge d b y t he i n vesti gat or as cli nicall y si g nifi ca nt will be rec or de d 
b ot h o n t he s o urce d oc u me ntati o n a n d t he C R F as a n a d verse e ve nt, a n d m o nit ore d as descri b e d 
i n Secti o n 7. 1. 2 . A la b orat or y or dia g n ostic test a b n or malit y ( o nce c o nfir me d b y re peate d testi n g) 
t hat res ults i n t he wit h dra wal of t he patie nt fr o m t he st u d y; t he te m p orar y or per ma ne nt 
wit h dra wal of I M P or m e dical treat me nt, or f urt her dia g n ostic w or k-u p ma y be c o nsi dere d 
a d verse e ve nts. If f urt her dia g n ostic w or k -u p of a n a b n or mal la b orat or y res ult lea ds t o t he 
i n vesti gat or c o ncl u di n g t hat t he i nitial a b n or malit y was n ot cli nicall y si g nifica nt, it is at t he 
i n vesti gat or's discreti o n w het her or n ot t he res ult tri g geri n g t h e w or k-u p is a n a d verse e v e nt. 
( N ote: A b n or mal la b orat or y or dia g n ostic test res ults at t he scree ni n g visit t hat precl u de a patie nt 
fr o m e nteri n g t he st u d y or recei vi n g I M P are n ot c o nsi dere d a d v erse e ve nts.) 
Det ails of cli nical la b orat or y tests will be i ncl u de d i n t he st u d y refere nce ma n ual.  
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
7. 4. 1.  
Ser u m C he mistr y, He m at ol o g y, a n d Uri n al ysis  
Cli nical la b orat or y tests (ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis) will be perf or me d at t he 
ti me p oi nts detaile d i n Ta ble  2 . Cli nical la b orat or y tests will be perf or me d usi n g t he ce ntral 
la b orat or y. D etails are pr o vi de d i n A p pe n di x  A . S pecific ser u m c he mistr y, he mat ol o g y a n d 
c oa g ulati o n la b orat or y tests t o be perf or me d are liste d i n Ta ble  5 . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 0  
T a ble  5 : 
Cli nic al L a b or at or y Tests  
Ser u m C he mistr y  
He m at ol o g y a n d C o a g ul ati o n  
Calci u m ( Ca)  
P h os p h or o us  
S o di u m ( Na)  
P otassi u m ( K)  
C hl ori de ( Cl)  
Creati ni ne  
Creati ni ne p h os p h o ki nase ( C P K)  
Gl uc ose  
Bl o o d urea nitr o ge n ( B U N)  
Ala ni ne a mi n otra nsferase ( A L T/ S G P T)  
As partate a mi n otra nsferase ( A S T/ S G O T)  
Ga m ma -gl uta m yl tra ns pe pti dase ( G G T)  
Al kali ne p h os p hatase ( A L P)  
Bicar b o nate  
Pr otei n, t otal  
Al b u mi n  
Bilir u bi n, t otal  
He mat ocrit ( Hct)  
He m o gl o bi n ( H b)  
Re d bl o o d cell ( R B C) c o u nt  
W hite bl o o d cell ( W B C) c o u nt  
Platelet c o u nt  
Mea n c or p usc ular he m o gl o bi n ( M C H)  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
( M C H C) 
Mea n c or p usc ular v ol u me ( M C V)  
Mea n Platelet V ol u me ( M P V)  
Re d Cell Distri b uti o n Wi dt h ( R D W)  
C B C, N ucleate d R B C  ( %, a bs) 
W B C Differe ntial  
- 
Bas o p hils ( %, a bs)  
- 
E osi n o p hils ( %, a bs)  
- 
I m mat ure g ra n ul oc yte ( %, a bs) 
- 
L y m p h oc ytes ( %, a bs)  
- 
M o n oc ytes ( %, a bs)  
- 
Ne utr o p hils, T otal ( %, a bs)  
7. 4. 2.  
Ot her Cli nic al L a b or at or y Tests  
7. 4. 2. 1.  
Ser ol o g y Tests  
At scree ni n g, p atie nts will be teste d f or H Bs A g, a nti b o dies t o H C V, a n d HI V T y p es 1 a n d 2. 
Patie nts wit h c o nfir me d p ositi ve res ults will n ot be eli gi ble t o p artici pate i n t he st u d y.  
7. 4. 2. 2.  
F ollicle Sti m ul ati n g H or m o ne  
At scree ni n g, w o m e n w h o ha ve bee n a me n orr heic f or at least 1  year wit h o ut a n alter nati ve 
me dical ca us e will ha ve a ser u m F S H assess me nt t o c o nfir m p ost me n o pa us al stat us (a n i ncrease d 
c o nce ntr ati o n of F S H of m ore t ha n 3 5  I U/ L i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or 
h or m o nal re pla ce me nt t h era p y).  
7. 4. 2. 3.  
H u m a n C h ori o nic G o n a d otr o pi n Tests  
β -H C G tests i n uri ne will be perf or me d f or w o me n of c hil d beari n g p ote ntial as detaile d i n 
Ta ble  2 . 
7. 4. 2. 4.  
C O VI D -1 9 Testi n g  
Testi n g of patie nts as y m pt o matic f or C O V I D-1 9 acti ve i nfecti o n ma y b e c o n d ucte d at t he 
discreti o n of t he i n vesti gat or wit hi n 7 2 h o urs of a n y visit w here s pir o metr y ass ess me nts are t o b e 
c o n d ucte d or as re q uir e d b y healt h a ut h orities, l ocal et hics c o m mittees, or st u d y ce nter S O Ps . 
T he testi n g ma y  b e c o n d ucte d b y t he ce ntral la b orat or y or l ocall y de p e n di n g o n feasi bilit y. T he 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 1  
testi n g ma y be c o n d ucte d b y t he ce ntral la b orat or y or l ocall y d e pe n di n g o n feasi bilit y. P ositi ve 
tests t hat meas ure C O VI D-1 9 a nti ge n m ust be c o nfir me d b y R T -P C R . 
F or details o f t he m a na ge me nt of st u d y acti vities d uri n g C O VI D-1 9 o ut br ea ks, see A p pe n di x  N . 
7. 5.  
P h ysic al E x a mi n ati o ns  
P h ysical e x a mi nati o ns will be perf or me d at t he ti me p oi nts detaile d i n Ta ble  2 . Hei g ht i n 
ce nti meters a n d wei g ht i n kil o gra ms will be rec or de d at scree ni n g. Wei g ht o nl y will be meas ure d 
at ot her ti mes s pecifie d. B o d y mass i n de x will be deter mi ne d. 
A f ull p h ysic al e x a mi nati o n will i ncl u de, at a mi ni m u m, hea d, e yes, ears, n ose, a n d t hr oat 
( H E E N T), c hest, c ar di o v asc ular, a b d o mi nal, s ki n e x a mi nati o n a n d a b bre vi ate d ne ur ol o gical 
e x a mi nati o n i ncl u di n g cra nial  ner ves, d ee p te n d o n refle x es a n d stre n gt h. A brief p h ysical 
e x a mi nati o n will i ncl u de, at a mi ni m u m, c hest, car di o vasc ular, a b d o mi nal, a n d s ki n 
e x a mi nati o ns. 
A n y p h ysic al e x a mi nati o n fi n di n g t hat is j u d ge d b y t he i n vesti gat or as cli nicall y si g nifica nt 
(e x ce pt at t he i nitial scree ni n g visit, w hic h will be ca pt ure d as me dical hist or y) ma y be 
c o nsi dere d a n a d verse e v e nt, rec or de d o n t he C R F  a n d t he s o urce d oc u me nt , a n d m o nit ore d as 
descri be d i n Secti o n  7. 1. 2 . 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
7. 6.  
Vit al Si g ns  
Vital si g ns ( p ulse rate, bl o o d press ure [s yst olic/ diast olic], res pirat or y rate, a n d b o d y te m perat ur e) 
will be meas ure d at t he ti me p oi nts detaile d i n Ta ble  2 . All vital si g ns res ults o utsi de t he 
refere nce ra n ges will be j u d ge d b y t h e i n vesti gat or as bel o n gi n g t o o ne of t h e f oll o wi n g 
cate g ories:  
•  a b n or mal  a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt  
Bef ore bl o o d pr ess ure a n d p ulse are meas ure d, t h e patie nt m ust rest i n a s u pi ne, se mi -rec u m b e nt 
or seate d p ositi o n f or at l east 5  mi n utes. T he sa me p ositi o n a n d ar m s h o ul d be use d as m uc h as 
p ossi ble eac h ti me vital si g ns are meas ure d f or a gi ve n patie nt. If t he o p p osite ar m is use d it will 
n ot be c ollecte d as a pr ot oc ol de viati o n. F or  a n y a b n or mal vital si g ns val ue, t he meas ure m e nt 
s h o ul d be re peate d as s o o n as p ossi ble. A n y vital si g ns val ue t hat is j u d ge d b y t he i n vesti gat or as 
cli nicall y si g nifica nt will be rec or de d b ot h o n t he s o urce d oc u m e ntati o n a n d t he C R F as a n 
a d verse e ve nt, a n d m o nit ore d as des cri be d i n Secti o n  7. 1. 2 . 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
7. 7.  
Electr oc ar d i o gr a p h y 
A 1 2 -lea d E C G will be rec or de d at t he ti me p oi nts detaile d i n Ta ble  2 . W here tri plicate 
meas ure me nts are re q uir e d ( D o R), eac h E C G will be ta ke n wit hi n 1 t o 5 mi n utes of t he pre vi o us 
o ne.  
Sta n dar d E C Gs para meters will be rec or de d usi n g a ce ntr alize d pr ocess a n d t he E C G will be 
i nter prete d l ocall y b y t he pri nci pal i n vesti gat or ( or q ualifie d p h ysi cia n). A d diti o nall y, a q ualifie d 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 2  
ce ntral r ea d er will i nter pret all E C G. I n cas es of disa gree m e nt, t he i nter pretati o n b y t he ce ntral 
rea der s h o ul d be use d. All E C G res ults o utsi de t he refere nce ra n ges will be j u d ge d b y t he 
i n vesti gat or ( or q ualifie d p h ysicia n) as bel o n gi n g t o o ne of t he f oll o wi n g cate g ori es:  
•  a b n or mal a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt  
A n y E C G fi n di n g t hat is j u d ge d b y t he i n v es ti gat or ( or q ualifie d p h ysici a n) as cli nicall y 
si g nifica nt ( e x ce pt at t he scree ni n g visit) will be c o nsi dere d a n a d verse e ve nt, rec or de d o n t he 
s o urce d oc u m e ntati o n a n d i n t he C R F, a n d m o nit ore d as des cri be d i n Secti o n  7. 1. 2 . 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
7. 8.  
Assess me nt of L oc al T oler a bilit y a n d P ai n  
L ocal t olera bilit y at t he i njecti o n site (er yt he ma, ecc h y m osis, i n d urati o n, te n der ness, w ar mt h, 
s welli n g, a n d p ai n) will be assesse d usi n g sta n dar dize d scales. Patie nt re p ort e d pai n at t he 
i njecti o n site will be re p orte d usi n g a sta n dar dize d 1 1 -p oi nt pai n i nte nsit y n u merical r es p o nse 
scale ( N R S-1 1) w here 0 is “ N o pai n” a n d 1 0 is “ W orst p ossi ble pai n”; patie nts will be as ke d t o 
res p o n d t o t he f oll o wi n g q uesti o n: “ H o w m uc h pai n d o y o u feel at t he dr u g i njecti o n site, w here 
0 is ‘ N o pai n’ a n d 1 0 is ‘ W orst p ossi ble pai n’? ”.  
T he assess me nts will be perf or me d at a p pr o xi matel y 1 h o ur after d osi n g ( Ta ble  2 ). 
Se verit y of l ocal t olera bilit y s y m pt o ms s h o ul d be assesse d as descri be d i n T a ble  6 . Er yt he ma, 
ecc h y m osis, a n d i n d urati o n will be c o nsi dere d o nl y if t he y reac h a dia met er of at least 5  m m. 
T he s urface dia m eter i n milli meters will be rec or de d a n d er yt h e ma, i n d urati o n, a n d ecc h y m osis 
at t he i njecti o n site will be gra de d acc or di n g t o t he dia meter meas ure me nts: A bse nt, 5  t o ≤5 0 m m 
( mil d), > 5 0 t o ≤1 0 0 m m ( m o derate), a n d > 1 0 0  m m (se vere). I n d urati o n m ust be assesse d b y 
caref ul s u perfi cial pal pati o n a v oi di n g press uri n g or s q ueezi n g t he i njecti o n site. 
I n cases w here s y m pt o ms d o n ot res ol ve, assess m e nts will pr ocee d at eac h a m b ulat or y visit. 
A p pr o priate treat me nt m a y b e pr o vi de d if n ecessar y, i n w hi c h cas e it m ust be rec or de d as 
c o nc o mita nt me dicati o n. I n case t h e site(s) of i njecti o n  nee d vis ual re prese ntati o n, i n a d diti o n t o 
c o m me nts i n t he s o urce d oc u me nts, t he i njecti o n site(s) ma y be p h ot o gra p he d al o n g wit h a 
metric r uler a n d patie nt i de ntificati o n n u m ber f or later re vi e w. A n y feat ur es t hat c o ul d be use d t o 
i de ntif y t he p atie nt will n ot be ca pt ure d o n t h e p h ot o gra p h. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 3  
T a ble  6 : 
Se verit y Assess me nt of L oc al T oler a bilit y  
Test  
Res p o nse  
Er yt he ma  
- A bse nt  
- Er yt he ma s urface dia meter 5 t o ≤5 0 m m ( mil d)  
- Er yt he ma s urface dia meter > 5 0 t o ≤1 0 0 m m ( m o derate)  
- Er yt he ma s urface dia meter > 1 0 0 m m (se vere)  
Ecc h y m osis  
- A bse nt  
- Ecc h y m osis s urface dia meter 5 t o ≤5 0 m m ( mil d)  
- Ecc h y m osis s urface dia meter > 5 0 t o ≤1 0 0 m m ( m o derate)  
- Ecc h y m osis s urface dia meter > 1 0 0 m m (se vere)  
I n d urati o n 
- A bse nt  
- I n d urati o n s urface dia meter 5 t o ≤5 0 m m ( mil d) 
- I n d urati o n s urface dia meter > 5 0 t o ≤1 0 0 m m ( m o derate) 
- I n d urati o ns s urface dia meter > 1 0 0 m m (se vere) 
T e n der ness  
W ar mt h  
S welli n g  
- N o ne  
- Mil d  
- M o derate  
- Se vere  
I nje cti o n site fi n di n gs will n ot be ca pt ure d as a d verse e ve nts u nless t he y f ulfill c haracteristics 
t hat are be y o n d t h os e i n t he s pecifie d f or ms/scales (e g, necr osis, a bscess, et c.) or f ulfill 
seri o us ness criteria; if f ulfille d, the y m ust be rec or de d a n d re p orte d as s p ecifie d i n Secti o n  7. 1. 2 . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 4  
8.  
A S S E S S M E N T O F P H A R M A C O KI N E TI C S, I M M U N O G E NI CI T Y, 
BI O M A R K E R S, A N D P H A R M A C O G E N E TI C S  
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
8. 1.  
P h ar m ac o ki netic Assess me nt  
Bl o o d sa m ples will be c ollecte d via ve ni p u nct ure at t he ti me p oi nts detaile d i n Ta ble  2  for 
meas ure me nts of s er u m c o nce ntrati o n of T E V -5 3 2 7 5. T he dates a n d ti mes of I M P a d mi nistrati o n 
a n d t he date a n d ti me p oi nt ( 2 4 -h o ur cl oc k ti me) of eac h p h ar mac o ki netic s a m ple will be 
rec or de d b ot h o n t he s o ur ce d oc u me nt ati o n a n d t he C R F. 
Sa m ples will be a nal yze d f or c o nce ntrati o n of T E V -5 3 2 7 5 usi n g a n a p pr o priate vali date d 
met h o d. Bl o o d sa m ples fr o m  patie nts w h o recei ve d place b o ma y n ot be a nal yz e d.  
Bl o o d v ol u mes are pr o vi de d i n t he I C F a n d st u d y refere nce ma n ual.  
Details o n sa m ple ha n dli n g, st ora ge, s hi p me nt, a n d a nal ysis are gi ve n i n t h e st u d y refere n ce 
ma n ual.  
8. 2.  
 
 
 
8. 3.  
I m m u n o ge nicit y 
Bl o o d sa m ples ( 1 2  m L) f or assess me nt of A D A res p o nse will be ta ke n at t h e ti me p oi nts 
i n dicate d i n Ta ble  2 . 
A d diti o nall y, eff orts s h o ul d be ma de t o c ollect A D A sa m ples w he n a se vere h y perse nsiti vit y 
reacti o n (e g, a n a p h yl a xis) is s us pecte d, or a n ast h ma e x acer bati o n, a s eri o us a d verse e ve nt, or a n 
i m m u n o ge nicit y-relate d a d verse e ve nt is o bser v e d, as cl ose t o t he o nset of t he e ve nt as p ossi ble, 
at t he res ol uti o n of t he e v e nt,  a n d at 3 0 da ys f oll o wi n g t he e ve nt o nset, if p ossi ble. A nti b o dies t o 
T E V -5 3 2 7 5 will be e val u ate d i n ser u m sa m ples of patie nts treate d wit h T E V -5 3 2 7 5. All sa m ples 
c ollecte d f or detecti o n of a nti b o dies t o T E V -5 3 2 7 5 ma y als o be e val u ate d f or T E V -5 3 2 7 5 ser u m 
c o nce ntr ati o n t o facilitate i nter pretati o n of t he a nti b o d y dat a. A nti b o dies ma y b e f urt h er 
c haracteriz e d i ncl u di n g e val uati o n of T E V -5 3 2 7 5 -ne utralizi n g a nti b o dies (if p ossi ble).  
W he n a n u m ber of ass ess me nts are t o be c o n d ucte d at t he sa me ti me p oi nt, t he i m m u n o ge nicit y 
bl o o d sa m ple s h o ul d be ta ke n aft er ot her assess me nts. T he date a n d ti me of I M P a d mi nistrati o n 
a n d t he date a n d ti me p oi nt of eac h i m m u n o ge nicit y sa m ple will be rec or de d b ot h o n t he s o urce 
d oc u me ntati o n a n d t he C R F.  
T he detecti o n a n d c haracter iz ati o n of a nti b o dies t o T E V -5 3 2 7 5 will be perf or me d usi n g 
vali date d met h o ds b y or u n der t he s u per visi o n of t he s p o ns or. Bl o o d sa m pl es fr o m patie nts w h o 
recei v e d place b o ma y n ot be a nal yz e d f or t he pres e nce of A D As. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 5  
Sa m ples ma y be st or e d, if per mitte d b y t he I C F a n d l ocal re g ulati o ns, aft er t he last patie nt’s last 
visit f or t he st u d y at a facilit y sel ecte d b y t he s p o ns or t o e na ble f urt her a n al ysis of i m m u ne 
res p o nses t o T E V-5 3 2 7 5.  
Details o n sa m ple ha n dli n g, st ora ge, s hi p me nt, a n d a nal ysis are gi ve n i n t h e st u d y refere n ce 
ma n ual.  
8. 4.  
 
8. 4. 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 5.  
P h ar m ac o ge netic Assess me nt  
W h ole  bl o o d ( 2. 5 m L) will be c ollecte d at bas eli ne/ D o R. M ore details re gar di n g 
p har mac o ge netic a n al yses are pr o vi de d i n A p pe n di x  J a n d t he st u d y refere n ce ma n ual.  
P har mac o ge n etic data will be ke pt c o nfi de ntial a n d st ore d se paratel y.  
H S D 3 B 1 ge n etic alleles (ass ociate d wit h ster oi d resista nce/res p o nses) will be st u die d t o 
deter mi ne t he relati ve fre q ue nc y of allel e stat us i n ra n d o mize d patie nts a n d t o assess t he 
differe ntial effect of I M P wit h res pect t o H S D 3 B 1 allele stat us.  
T his testi n g re q uir es i nf or me d c o nse nt t o be o btai ne d. Patie nts ma y d ecli ne t his testi n g w hile still 
partici pati n g i n t he st u d y.  
P har mac o ge n etic a nal ys es ma y be pre s e nte d i n a s e parat e a nal ytical pla n a n d re p ort at t he e n d of 
t he st u d y. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 6  
9.  
S T A TI S TI C S  
T his secti o n descri bes t h e statistical a nal ysis as f oresee n at t he ti me of pla n ni n g t he st u d y. 
C ha n ges, a d diti o ns, a n d f urt her details a b o ut t he a nal yses will be descri b e d in t he statistical 
a nal ysis pla n . After fi nalizati o n of t he statistical a nal ysis pla n, a n y a d diti o nal a nal ys es or 
c ha n ges t o a n al ys es t hat ma y b e re q uir e d will be f ull y discl ose d i n t he cli nical st u d y re p ort 
( C S R). 
 
 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
9. 1.  
S a m ple Size a n d P o wer C o nsi der ati o ns  
T he sa m ple siz e is cali brate d base d o n si m ulati o n st u dies t o assess t he o perati n g c h aracteristics 
of t he f oll o wi n g Ba yesia n s uccess criteri o n f or t h e fi nal a nal ysis of t he pri mar y effi cac y 
e n d p oi nt : a dj uste d mea n c ha n ge fr o m baseli ne at wee k 1 2 i n tr o u g h F E V1: 
 
 
 
 
 
Data fr o m pre vi o us i nter nal cli nical st u dies of a n ot her a nti -I L 5 bi ol o gic treat me nt ( Ci n q Air® 1) i n 
patie nts wit h  persiste nt e osi n o p hilic ast h ma were use d t o deri ve t he e x pecte d ra n ge of treat me nt 
effects of T E V -5 3 2 7 5 vers us place b o a n d t he sta n dar d de viati o n esti mate of 0. 3 5 0  L f or t he 
pri mar y efficac y e n d p oi nt, w he n T E V -5 3 2 7 5 is gi ve n as a n a d d -o n mai nte na nce t hera p y o n t o p 
of t he bac k gr o u n d I C S or I C S/ L A B A treat me nts.  
T he  statistical s oft ware F A C T S v 6. 4 was use d f or c o n d ucti n g t h e si m ulati o ns ass u mi n g a 1 5 % 
dr o p o ut rate f or t he place b o gr o u p a n d a n 8 % dr o p o ut rate f or eac h of t he T E V -5 3 2 7 5 treat me nt 
gr o u ps.  
9. 2.  
A n al ysi s Sets 
9. 2. 1.  
I nte nt-t o-Tre at A n al ysis Set  
T he i nte nt -t o-treat (I T T) a nal ysis s et will i ncl u de all ra n d o mize d patie nts. 
I n t he I T T a n al ysis set, p atie nts will be assi g ne d t o t he treat me nt t he y were ra n d o mize d, 
re gar dl ess of w hic h treat me nt t he y act uall y recei v e d. 
                                                 
1 Ci n q Air ® is a re gistere d t o T e va P har mace utical I n d ustries Lt d. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 7  
9. 2. 2.  
M o difie d I nte nt -t o-Tre at A n al ysis Set  
T he m o difie d i nte nt -t o-tr eat ( mI T T) a nal ysis set is a s u bset of t he I T T a nal ysis set i ncl u di n g o nl y 
patie nts w h o recei ve at least 1 d ose of I M P.  
T he mI T T a n al ysis set will ser ve as t he pri mar y a n al ysis set f or efficac y a nal yses.  
9. 2. 3.  
S afet y A n al ysis Set  
T he safet y a nal ysis set will i ncl u de all ra n d o mize d patie nts w h o recei ve at least 1 d ose of I M P.  
I n t he s afet y a nal ysis set, patie nts will be assi g ne d t o t he treat me nt t he y act uall y recei v e d 
re gar dl ess of w hic h treat me nt t he y w ere ra n d o mize d , u nless ot her wise s p ecifie d.  
9. 2. 4.  
Per -Pr ot oc ol A n al ysis Set  
T he per -pr ot oc ol ( P P) a n al ysis set is a s u bset of t h e mI T T a nal ysis set i ncl u di n g o nl y patie nts 
wit h o ut i m p orta nt pr ot oc ol de viati o ns. I m p orta nt pr ot o c ol vi olati o ns will be deter mi ne d b ef ore 
u n bli n di n g a n d will i ncl u de i nc orrect I M P recei ve d b y a p atie nt.  
T he P P a nal ysis will ser ve as a s u p p orti ve a nal ysis f or t he pri mar y effi cac y a nal ysis as well as 
t he sec o n dar y efficac y a n al ysis. 
9. 2. 5.  
P h ar m a c o ki netic A n al ysis Set  
T he p har mac o ki netic a n al ysis set will i ncl u de t h ose patie nts i n t he safet y a n al ysis set w h o h a ve 
at least 1 a vaila ble s er u m c o nce ntr ati o n val ue.  
9. 2. 6.  
A nti -dr u g A nti b o d y A n al ysis Set  
T he A D A a nal ysis set (f or a nti -T E V -5 3 2 7 5 a nti b o dies) will i ncl u de t h os e patie nts treate d wit h 
T E V -5 3 2 7 5 i n t he safet y a nal ysis s et.  
9. 3.  
D at a H a n dli n g C o n ve nti o ns  
9. 3. 1.  
H a n dli n g Wit h dr a w als a n d Missi n g D at a  
F or all varia bles, o nl y t he o bser ve d d ata fr o m t he patie nts will be use d i n t he statistical a nal yses, 
ie, t here is n o pla n t o estimate missi n g data, u nless ot her wise s pecifie d. Det aile d data i m p utati o n 
r ules will be descri b e d i n t he statistical a nal ysis pl a n. 
9. 4.  
St u d y P o p ul ati o n  
T he I T T a n al ysis set ( Secti o n  9. 2. 1 ) will be use d f or all st u d y p o p ulati o n s u m maries u nless 
ot her wise s pecifie d. S u m maries will be pres e nte d b y treat me nt gr o u p a n d f or all patie nts.  
9. 4. 1.  
P ati e nt Dis p ositi o n  
Data fr o m p atie nts scree ne d, patie nts scree ne d b ut n ot ra n d o mize d, patie nts ra n d o mize d t o 
treat me nt i n t he st u d y, p atie nts ra n d o mize d b ut n ot treate d, patie nts i n t he safet y a nal ysis set, 
patie nts i n t he P P a nal ysis set, a n d patie nts w h o c o m plete t he st u d y (see Secti o n  3. 1  f or 
defi niti o n of e n d of st u d y) will be s u m marize d. Data fr o m patie nts w h o wit h dra w fr o m t he st u d y 
will als o be s u m marize d b y reas o n f or wit h dra wal u si n g descri pti ve statistics. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 8  
9. 4. 2.  
De m o gr a p hic  a n d B aseli ne C h ar acteristics  
Patie nt de m o gra p hic a n d baseli ne c haracteristics, i ncl u di n g b ut n ot li mite d t o me dical hist or y, 
pri or me dicati o ns a n d t hera pies, a n d E C G fi n di n gs, will be e x a mi ne d t o assess t he c o m para b ilit y 
of t he treat me nt gr o u ps a n d will be s u m marize d usi n g descri pti ve statistics. T he prese n ce of 
restricti ve alleles will be s u m mariz e d b y treat me nt gr o u p usi n g patie nt c o u nts a n d perce nta ges. 
Ge nerall y, f or c o nti n u o us varia bles, des cri pti ve statistics ( n u m ber [ n], mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m) will be pr o vi de d. F or cate g orical varia bles, patie nt c o u nts a n d 
perce nt a ges will be pr o vi de d. Cate g ories f or missi n g dat a will be pres e nte d if necessar y.  
9. 5.  
Effic ac y A n al ysis  
9. 5. 1.  
Pri m ar y Effic ac y  E n d p oi nts  
T he pri mar y e n d p oi nt is t he c ha n ge fr o m bas eli ne i n cli nic -base d sta n dar dize d baseli ne -a dj uste d 
tr o u g h ( pre-br o nc h o dilat or) m or ni n g F E V 1 at w ee k 1 2.  
9. 5. 2.  
Sec o n d ar y Effic ac y E n d p oi nts  
T he sec o n d ar y efficac y e n d p oi nts are:  
•  o verall wee kl y well -c o ntr olled ast h ma stat us defi ne d b y t h e ast h ma c o ntr ol c o m p osite 
sc ore a n d wee kl y ast h ma c o ntr ol stat us ( Yes vers us N o) fr o m wee k 1 t hr o u g h 1 2  a n d 
o verall wee kl y well -c o ntr olle d ast h ma stat us fr o m wee k 1 t hr o u g h 1 6  
•  o verall c ha n ges fr o m b aseli ne i n t he wee kl y a vera g e of dail y m or ni n g tr o u g h 
( pre-resc u e br o nc h o dilat or) F E V1 as meas ure d b y a ha n d hel d de vi ce o ver 1 2  wee ks 
fr o m wee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6 
•  o verall c ha n ges fr o m b aseli ne i n wee kl y a v era ge of resc u e me dicati o n use o ver 1 2 
wee ks  fr o m wee k 1 t hr o u g h 1 2 a n d o v er 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6 
•  c ha n ges fr o m baseli ne i n perce nt a ge of ast h ma c o ntr ol da ys ( n o s y m pt o ms a n d n o 
resc ue m e dicati o n use) o ver 1 2 wee ks fr o m w ee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks 
fr o m wee k 1 t hr o u g h 1 6 
•  c ha n ge fr o m  baseli ne i n cli nic -base d sta n d ar dize d baseli ne -a dj uste d m or ni n g tr o u g h 
F E V 1 at wee k 1 6  
•  pr o p orti o ns of patie nts w h o ac hie ve cli nic -base d F E V 1 ≥8 0 % pre dicte d at w ee ks  1 2, 
1 6, a n d at e n d p oi nt  
•  pr o p orti o ns of patie nts w h o ac hie ve f orce d e x pirat or y fl o w at 2 5 % t o 7 5 % of F V C  
( F E F2 5 -7 5) ≥7 0 % pre dicte d at wee ks 1 2, 1 6, a n d at e n d p oi nt  
•  ti me t o first C A E  t hr o u g h o ut t he st u d y 
•  c ha n ges fr o m baseli ne i n Ast h ma C o ntr ol Q uesti o n naire ( A C Q -6) at w ee ks  1 2 a n d 1 6  
•  c ha n ges fr o m baseli ne i n A C T at wee ks 1 2 a n d 1 6  
•  c ha n ges fr o m baseli ne i n Sta n dar dize d Ast h ma Q ualit y of Lif e Q uesti o n nair e 
( A Q L Q[ S]) at wee ks 1 2 a n d 1 6  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9 9  
•  pr o p orti o ns of patie nts w h o ac hie ve F E V 1: F V C rati o ≥0. 8 0 at wee ks 1 2, 1 6, a n d at 
e n d p oi nt  
9. 5. 3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 1  
9. 5. 4.  
Pl a n ne d Met h o d of A n al ysis  
T h e mI T T  a nd  P P  a naly sis sets will be use d f or t he efficac y a naly ses. T he mI T T a naly sis set will 
ser ve as t he pri mar y efficac y a nal ysis p o p ulati o n, w hile t he P P a nal y sis set will ser ve as t he 
s u p p orti ve po p ulati o n  f or t he pri mar y  effi cac y e n d p oi nt as well as t he sec o n dar y efficac y 
e n d p oi nts.  
Descri pti ve statistics ( n, mea n, sta n dar d de viati o n, sta n dar d err or, me dia n, mi ni m u m, a n d 
ma xi m u m f or c o nti n u o us varia bles, a n d p atie nt  c o u nts a n d perce nta ge f or cate g orical v aria bles) 
will be pr o vi de d f or eac h effic ac y  varia ble b y  visi t o r wee k , as a p pr o priate. S u m marie s wil l b e 
prese nte d  b y  treat me nt gr o u p. 
All statistical tests will be c o n d ucte d at t he t w o-si de d 0. 0 5 si g nifica nce le vel. 
U nless ot her wise s pecifie d, baseli ne val ue is defi ne d as t he last a v aila ble val ue bef ore t he 
a d mi nistrati o n of I M P.  
9. 5. 4. 1.  
Pri m ar y Effic ac y A n al ysis  
Pri m ar y Effic ac y A n al ysis:  A n esti ma n d, i n ge n eral, i ncl u des 4 i nter -relat e d attri b utes –  
p o p ulati o n of i nterest, varia ble (e n d p oi nt) of i nterest, i nter-c urre nt  e v e nts (I C E) al o n g wit h t he 
strate g y f or h a n dli n g I C E, a n d p o p ulati o n-le vel s u m mar y f or t he e n dp oi nt.  
T he esti ma n d select e d f or t he pri mar y efficac y e n d p oi nt will assess t he c ha n ge fr o m baseli ne i n 
m or ni n g tr o u g h F E V 1 at wee k 1 2 d ue t o t he i nitiall y ra n d o mize d treat me nt as act uall y ta ke n 
(Malli nc kr o dt 2 0 1 3 ) i n t he mI T T p o p ulati o n. T his esti ma n d assesses t he treat me nt efficac y at 
wee k 1 2 attri b uta ble t o t h e i nitiall y ra n d o mize d me dicati o n.  
I nter-c urre nt  e ve nts (I C Es) t hat are e x pecte d t o affect t he efficac y e n d p oi nt will i ncl u de:  
1.  I nsta n ces w h ere a patie nt e x perie nces w orse ni n g of ast h ma or a n ast h ma e x acer bati o n 
a n d t he patie nt is place d o n s yste mic c ortic oster oi ds, or a d diti o nal ast h ma t hera p y 
treat me nt. I n s uc h cases, t he i n vesti gat ors will be i nstr ucte d t o e nc o ura ge t h e patie nt t o 
c o nti n ue i n t he st u d y a n d ret ur n f or pl a n ne d visits u ntil st u d y c o m pleti o n i n or der t o 
c ollect safet y d ata after a d diti o nal mai nte na nce treat me nts are use d. H o we v er, f or t hes e 
patie nts, i m pr o ve me nt i n F E V 1 w o ul d be e x pecte d as ra pi dl y as 1  da y after treat me nt 
wit h I C S ( Ker wi n et al 2 0 1 9 ) a n d wit hi n 1 wee k after a p atie nt recei ves t he I C S/ L A B A 
treat me nt (C orre n et al 2 0 0 7 , Pearl ma n et al 1 9 9 9 ). T he i ncl usi o n of data after a p atie nt 
recei v es alter nati ve me di cati o ns w o ul d p ote ntiall y bias t he treat me nt r es p o nse esti mates 
d ue t o i nitiall y ra n d o mize d st u d y me dicati o ns. T heref ore, f or t he pri mar y a nal ysis, t he 
strate g y t o ha n dle t hese I C Es will be t o e xcl u de o bser vati o ns after t he use of ast h ma 
mai nte na nce me di cat i o ns (re gar dless of a v aila bilit y of data o btai ne d after war ds). 
2.  C o nfir me d C O VI D -1 9 i nfecti o ns: Si nce C O VI D -1 9 is a k n o w n res pirat or y disease w hic h 
ca n a d v ersel y affect l u n g f u ncti o ns  as a res ult, t he sa me strate g y f or ha n dli n g s uc h I C Es 
will be a p plie d i n t he pri mar y a nal ysis. O bser vati o ns  t hat occ urre d aft er t h e dia g n osis of 
C O VI D -1 9 i nfecti o ns will n ot be use d i n t he pri mar y a nal ysis.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 2  
T he p o p ulati o n -le vel s u m maries w o ul d be t he Ba yesia n esti mates of mea n c ha n ges fr o m baseli ne 
at wee k 1 2 f or t he treat me nt g r o u ps a n d c orres p o n di n g 9 5 % cre di ble i nter vals, as well as 
p osteri or pr o ba bilit y of treat me nt effect bet wee n eac h of t he T E V -5 3 2 7 5 tr eat me nt gr o u ps vs 
place b o bei n g greater t ha n 0, ie:  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 3  
 
 
 
 
 
 
 
 
 
9. 5. 4. 2.  
Se nsiti vit y/ S u p p orti ve A n al ysis  
9. 5. 4. 2. 1.  S u p p orti ve A n al ysis  
T he fre q u e ntist a p pr oac h will be use d f or a n al yzi n g t he pri mar y efficac y e n d p oi nt as a s u p p orti ve 
a nal ysis. T h e sa me esti ma n d w it h res pect t o st u d y p o p ulati o n, efficac y e n d p oi nt a n d I C Es al o n g 
wit h t he sa me ha n dli n g strate gies will be a p plie d. T he p o p ulati o n -le vel s u m mar y statistics will 
be t he least s q uares mea ns i n t he treat me nt gr o u ps deri ve d fr o m t he mi x e d -effects m o del f or 
repeat e d meas ur es ( M M R M).  
T he M M R M m o del will i ncl u de baseli ne m or ni n g tr o u g h F E V 1, t he ra n d o mizati o n stratificati o n 
fact ors ( pri or t hera p y use a n d baseli ne E O S le vels ), visit ( wee ks 2, 4, 8, 1 2, a n d 1 6), treat me nt 
gr o u p, a n d visit -b y -treat me nt gr o u p i nteracti o ns. C o ntrasts f or pair wise treat me nt c o m paris o ns of 
i nterest will be c o nstr uct e d. T he u nstr uct ur e d c o v aria nce matri x will first be use d; h o we v er, i n 
case of c o n ver ge nce iss ues, t he c o m p o u n d s y m m etr y c o v aria n ce matri x str uct ure will be use d 
i nstea d. 
Miss i n g data are e x pecte d t o occ ur d ue t o earl y dr o p o uts fr o m st u d y or “a n al ysis dr o p o uts” 
res ulti n g fr o m t he use of a d diti o nal or alter nati ve me dicati o ns a n d C O VI D-1 9 i nfecti o ns, as 
me nti o ne d a b o ve. We pla n t o use t he refere n ce -b as e d m ulti ple i m p utati o ns met h o d ( Malli nc kr o dt 
et al 2 0 1 7) t o ha n dle t he missi n g data pr o ble m. T his a p pr oac h i m p utes missi n g data base d o n 
re gressi o n m o dels fr o m t he place b o-treate d patie nt data, re prese nti n g a missi n g n ot at ra n d o m 
( M N A R) mec h a nis m. It is e x pecte d t o yiel d a c o nser vati ve treat me nt effect esti mate as c o m pare d 
t o t he esti mate o btai ne d fr o m m ulti ple i m p utati o ns ( MI) u n der a missi n g at ra n d o m ( M A R) 
mec ha nis m. T his a p pr oac h has rece ntl y bee n s uccessf ull y a p plie d i n a P has e 3 pe diatric trial 
c o mpari n g fl uticas o ne pr o pi o nate m ulti d ose dr y p o w der i n haler ( M D PI) wit h fl uticas o ne 
pr o pi o nate/sal meter ol M D PI ( St u d y F S S -A S -3 0 0 0 3). M ore det ails o n i m ple me nti n g t he 
refere nce-b ase d MI will be pr o vi de d i n t he pr ot oc ol a n d statistical a nal ysis pla n. 
T he R u bi n’s met h o d will be use d t o c o m bi ne esti mates fr o m m ulti pl y -i m p ute d datasets. T he fi nal 
esti mate d treat me nt differe nces will be prese nt e d t o get h er wit h t he 2 -si de d 9 0 % CI a n d p-val u es.  
9. 5. 4. 2. 2.  Se nsiti vit y A n al yses  
T he pri mar y effic ac y a n al ysis a n d s u p p orti ve a n al ysis will be re p eate d usi n g t he P P p o p ulati o n.  
Ot her se nsiti vit y a n al ys es will be c o n d ucte d b y e v al uati n g t he i m pact of missi n g data o n t he 
s u p p orti ve M M R M a nal ysis usi n g a 2-di me nsi o nal “ti p pi n g -p oi nt”, m ulti ple -i m p utati o n 
a p pr oac h u n d er t he M N A R ass u m pti o n. S hifts t o t he distri b uti o ns of missi n g o bser vati o ns i n 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 4  
b ot h t he place b o a n d acti ve treat me nt ar ms will be a p plie d t o re prese nt differe nt de grees of effect 
l osses. M ore details will be pr o vi de d i n t he statistical a nal ysis pla n. 
Se nsiti vit y a n al ysis usi n g all data, i ncl u di n g retrie ve d o bser vati o ns f oll o wi n g alter nati ve 
me dicati o n use will be r u n t o assess t he r o b ust ness of st u d y res ults t o a differe nt esti ma n d.  
9. 5. 4. 3.  
Sec o n d ar y Effic ac y A n al ysis  
F or t he o v erall wee kl y ast h ma c o ntr ol stat us fr o m wee k 1 t hr o u g h 1 2, t he wee kl y bi nar y 
e n d p oi nts fr o m wee k 1 t hr o u g h 1 2 will be a nal yz e d usi n g t he re peat e d meas ures l o gistic 
re gressi o n wit h treat me nt gr o u p, b aseli ne stat us, pri or t hera p y use, wee k, a n d wee k-b y -treat me nt 
gr o u p i nteracti o ns i n t he m o del a n d wit h a n u nst r uct ure d c o v aria n ce matri x. I n t he cas e of 
c o n ver ge n ce iss ues wit h t he u nstr uct ure d c o v aria n ce f or m, t he e x c ha n gea bl e c o vari a nce m atri x 
will be use d. T he o verall pr o ba bilit y esti mate of wee kl y ast h ma c o ntr ol o v er 1 2 wee ks i n eac h 
treat me nt gr o u p, as w ell as t he o verall esti mate of o d ds rati o of wee kl y ast h ma c o ntr ol o ver 1 2 
wee ks, c o m pari n g eac h T E V -5 3 2 7 5 treat me nt gr o u p vers us place b o wit h c orres p o n di n g 9 5 % CI 
a n d p-val ue will be d eri v e d . 
Usi n g t he mI T T a nal ysis set, eac h of t he f oll o wi n g sec o n dar y effi cac y e n d p oi nts will be 
s u m marize d descri pti vel y a n d a nal yz e d usi n g a M M R M i ncl u di n g baseli ne val ue, ra n d o mizati o n 
stratificati o n fact ors, visit/ wee k, treat me nt gr o u p, a n d visit/ wee k -b y -tr eat me nt gr o u p i nteracti o ns 
i n t he m o del wit h a n u nstr uct ure d c o varia n ce matri x:  
•  o verall c ha n ges fr o m b aseli ne i n wee kl y a v era ge of dail y m or ni n g tr o u g h ( pre -resc ue 
br o nc h o dilat or) F E V 1 as meas ure d b y h a n d hel d de vice o ver 1 2  wee ks fr o m wee k 1 
t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6 
•  o verall c ha n ges fr o m b aseli ne i n wee kl y a v era ge of resc u e me dicati o n use o ver 
1 2  wee ks fr o m wee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6  
•  c ha n ges fr o m baseli ne i n cli nic -base d sta n d ar dize d baseli ne -a dj uste d m or ni n g tr o u g h 
F E V 1 at wee k  1 6  
•  c ha n ges fr o m baseli ne i n A C Q -6 at wee k s 1 2 a n d 1 6  
•  c ha n ges fr o m baseli ne i n A C T at wee ks  1 2 a n d 1 6  
•  c ha n ges fr o m baseli ne i n A Q L Q( S) at w ee ks  1 2 a n d 1 6  
F or wee kl y bi nar y e n d p oi nts, s uc h as t he f oll o wi n g:  
•  pr o p orti o ns of patie nts w h o ac hie ve cli nic -base d F E V 1 ≥8 0 % pre dicte d at w ee ks  1 2, 
1 6, a n d at  e n d p oi nt  
•  pr o p orti o ns of patie nts w h o ac hie ve f orce d e x pirat or y fl o w at 2 5 % t o 7 5 % of F V C  
( F E F2 5 -7 5) ≥7 0 % pre dicte d at wee ks  1 2, 1 6, a n d at e n d p oi nt  
•  pr o p orti o ns of patie nts w h o ac hie ve F E V 1: F V C rati o ≥0. 8 0 at wee ks 1 2, 1 6, a n d at 
e n d p oi nt  
T he re p eate d measures l o gistic re gressi o n m o del wit h treat me nt gr o u p, c orres p o n di n g b aseli ne 
para meter val ue, pri or t h era p y use, wee k, a n d wee k -b y -treat me nt gr o u p i nteracti o ns i n t he m o del 
a n d wit h a n u nstr uct ure d c o varia n ce matri x will be use d. I n t he case of c o n v er ge nce iss ues wit h 
t he u nstr uct ure d c o v aria n ce f or m, t he e x c ha n gea bl e c o vari a nce m atri x will be use d. T he wee kl y 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 5  
pr o ba bilit y esti mates of ac hie vi n g t h e i m pr o ve me nt criteri o n i n eac h treat m e nt gr o u p, as well as 
t he esti mates of wee kl y o d ds rati os c o m pari n g eac h T EV -5 3 2 7 5 treat me nt gr o u p v ers us place b o 
wit h c orres p o n di n g 9 5 % CI a n d p -val ues will be deri ve d.  
All re peate d m eas ur es m o del will be r u n i ncl u di n g meas ure me nts at all visits/ wee ks t hr o u g h 
wee k 1 6.  
F or c h a n ges fr o m baseli n e i n wee kl y a v era ge of resc ue me dicat i o n use o v er 1 2 wee ks fr o m 
wee k  1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m wee k 1 t hr o u g h 1 6, a n d c ha n ges fr o m baseli ne i n 
perce nt a ge of ast h ma c o ntr ol da ys ( n o s y m pt o ms a n d n o resc ue m e dicati o n use) o ver 1 2 wee ks 
fr o m wee k 1 t hr o u g h 1 2 a n d o ver 1 6 wee ks fr o m week 1 t hr o u g h 1 6, Wilc o x o n ra n k -s u m test 
will be use d stratifie d o n ra n d o mizati o n stratificati o n fact ors.  
T he fre q u e nc y of C A Es will be a nal yze d usi n g a ne gati ve bi n o mial re gressi o n met h o d i ncl u di n g 
ra n d o mizati o n stratificati o n fact ors a n d treat me nt gr o u p i n t he m o del a n d t he l o garit h m of 
f oll o w-u p ti me as a n offs et varia ble. T h e rati o of C A E rate bet w ee n t he treat me nt gr o u ps a n d its 
9 5 % CI will be esti mate d fr o m t he ne gati ve bi n o mial re gressi o n m o del. Treat me nt effects will be 
teste d usi n g t he li keli h o o d-bas e d C hi-s q uare test. 
T he Ka pla n -Meier m et h o d will be use d t o esti mate a n d c o m pare t he distri b uti o ns of ti me t o t he 
first C A E bet wee n tr eat me nt gr o u ps. Distri b uti o n differe n ce will be c o m pare d b y a l o g ra n k test 
a dj usti n g f or t he ra n d o mi zati o n stratificati o n  fact ors. 
9. 5. 4. 4.  
 
 
 
 
 
9. 5. 4. 4. 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 6.  
M ulti ple  C o m p aris o ns a n d M ulti plicit y  
N o a dj ust me nts will be ma de f or t he pre pla n ne d m ulti ple c o m paris o ns/e n d p oi nts.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 6  
9. 7.  
S afet y a n d T oler a bilit y A n al ysis  
T he sec o n d ar y safet y a n d t olera bilit y e n d p oi nts are:  
•  fre q ue n c y of a d v erse e ve nts 
•  c ha n ges fr o m baseli ne i n cli nical  la b orat or y test res ults (ser u m c he mistr y, 
he mat ol o g y, a n d uri nal ysis) t hr o u g h o ut t he st u d y  
•  c ha n ges fr o m baseli ne i n vital si g ns ( bl o o d press ur e, p ulse rate, res pirat or y rate, a n d 
b o d y te m perat ur e) t hr o u g h o ut t he st u d y  
•  c ha n ges fr o m baseli ne i n 1 2 -lea d electr ocar di o gra m ( E C G) fi n di n gs t hr o u g h o ut t he 
st u d y 
•  use of c o nc o mita nt me di cati o n  
•  l ocal t olera bilit y 
•  n u m ber ( %) of patie nts w h o di d n ot c o m plete t he st u d y d ue t o a d verse e ve nts  
Safet y a nal yses will be perf or me d o n t h e safet y a n al ysis set ( Secti o n  9. 2. 3 ). 
Safet y assess me nts a n d ti me p oi nts are pr o vi de d i n Ta ble  2 . 
All a d verse e ve nts will be c o de d usi n g t he Me di cal Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). E ac h patie nt will be c o u nte d o nl y o n ce i n eac h preferre d ter m or s yste m or ga n class 
( S O C) cate g or y f or t he a nal yses of safet y. S u m maries will be prese nt e d f or all treat me nt -
e mer ge nt a d v erse e ve nts ( o verall a n d b y s e verit y), a d verse e ve nts deter mi ne d b y t h e i n vesti gat or 
t o be relate d t o test I M P (ie, reas o n a ble p ossi bilit y) ( defi ne d as rel ate d or wit h missi n g 
relati o ns hi p) ( o verall a n d b y se v erit y), seri o us a d v erse e v e nts, a n d a d v erse e ve nts ca usi n g 
wit h dra wal fr o m t he st u d y. S u m maries will be prese nte d b y treat me nt gr o u p a n d f or all patie nts. 
Patie nt listi n gs of all a d verse e v e nts, seri o us a d v erse e ve nts a n d a d verse e v e nts lea di n g t o 
wit h dra wal will b e prese nte d.  
Val ues a n d c h a n ges fr o m baseli ne i n cli nical la b orat or y, E C G, a n d vital si g ns meas ure me nt dat a 
(i ncl u di n g t he i nci d e nce of a b n or malities) will be s u m marize d descri pti vel y. 
L ocal t olera bilit y at t he i njecti o n site (er yt he ma, ecc h y m osis, i n d urat i o n, te n der ness, w ar mt h, 
s welli n g, a n d p ai n) will be assesse d usi n g sta n dar dize d scales a n d s u m marize d descri pti vel y.  
T he use of c o nc o mita nt me dicati o ns will be s u m marize d b y t hera pe utic class usi n g des cri pti ve 
statistics. 
F or c o nti n u o us varia bles, descri pti ve statistics ( n, mea n, sta n dar d de viati o n, sta n dar d err or, 
me dia n, mi ni m u m, a n d ma xi m u m) will be pr o vi de d f or act ual val ues a n d c ha n ges fr o m baseli ne 
t o eac h ti me p oi nt. F or cate g ori cal varia bles, patie nt c o u nts a n d perce nta ges will be pr o vi de d. 
If a n y patie nt dies d uri n g t he st u d y, a listi n g of deat hs will be pr o vi de d a n d all rele va nt 
i nf or mati o n will be disc usse d i n t he patie nt narrati ve i ncl u de d i n t he C S R. 
9. 8.  
P h ar m ac o ki netic A n al ysis  
S u m maries of T E V -5 3 2 7 5 ser u m c o nce ntrati o ns will be prese nte d b y n o mi nal ti me p oi nt a n d 
d ose. Pl ots of i n di vi d ual T E V -5 3 2 7 5 ser u m c o nce ntrati o ns will be prese nte d b y act ual da y 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 7  
(li near a n d l o g scales). Pl ots of mea n or me dia n T E V-5 3 2 7 5 ser u m c o n ce ntrati o ns will be 
prese nte d b y n o mi nal da y (li near a n d l o g scales).  
9. 9.  
P h ar m ac o d y n a mic/ Bi o m ar ker A n al ysis  
Bl o o d e osi n o p hil c o u nt a n d ser u m I L -5 (free a n d t otal) le vels will be s u m marize d b y tr eat me nt 
a n d ti me p oi nt usi n g descri pti ve statistics. I n di vi d ual data will be liste d.  
9. 1 0.  
 
 
 
 
 
9. 1 1.  
I m m u n o ge nicit y A n al ysis 
A nti -T E V -5 3 2 7 5 a nti b o d y i nf or m ati o n, t he n u m ber a n d perce nt of p atie nts p ositi ve f or A D A a n d 
t heir a nti b o d y titers, a n d t he n u m ber of A D A p ositi ve patie nts w h o are p ositi ve f or ne utr alizi n g 
a nti b o d y, will be des cri b e d. T he i m pact of t h e prese nce of A D A o n p har mac o ki netics, effi cac y, 
a n d cli nical safet y will be e val uat e d, if a p pr o priat e, a n d res ults will be pr o vi de d i n t he C S R . 
9. 1 2.  
A ncill ar y St u dies A n al ysis  
D uri n g t h e r u n -i n a n d treat me nt peri o ds of t his st u d y, patie nts will be s u p plie d wit h Pr o Air 
Di gi haler. Data fr o m t hes e i n halers will be c ollecte d ce ntrall y. 
 
 
 
 
 
 
 
9. 1 3.  
Pl a n ne d I nteri m A n al ysis  
T he fi nal pri mar y effic ac y a n al ys es will be perf or me d w he n all patie nts ha ve c o m plete d V 9 
( wee k 1 6) or wit h dra w n fr o m t he st u d y. A n u n bli n de d i nteri m a nal ysis is pla n ne d, w he n 
a p pr o xi matel y 1 2 0  patie nts ( 4 0 patie nts per ar m) ha ve c o m plete d t he wee k  8 visit or wit h dr a w n 
fr o m t he st u d y, t o ass ess t he earl y efficac y dat a . T he o bjecti ves of t he u n bli n de d i nteri m efficac y 
a nal ysis are: 1) t o d etect a n earl y effic ac y s u ccess si g nal; 2) t o c o n d u ct a f or mal f utilit y a nal ysis , 
s o t hat t he st u d y ma y be t er mi nate d earl y if b ot h T E V -5 3 2 7 5 d ose gr o u ps are f utile, ie, meet t he 
f utilit y criteri o n., a n d; 3) t o e val uate earl y st o p pi n g criteria. T h e statistical a nal ysis a n d t he 
s uccess a n d f utilit y criteria are s p ecifie d i n Secti o n  9. 1 3. 1  bel o w.  
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 8  
 
 
 
 
F urt her, d ue t o c halle n ges i n patie nt e nr ollme nt  i n t he face of t he C O VI D -1 9  pa n de mic, t he 
feasi bilit y of a n earl y st o p pi n g of t he tri al wit h s maller sa m ple siz es ma y als o be e val uate d 
d uri n g t he i nteri m a nal ysis. T he feasi bilit y a nal ysis will be descri be d i n t he statistical a nal ysis 
pla n . 
9. 1 3. 1.  
T he U n bli n de d I nteri m Effic ac y A n al ysis  
F or t he  earl y effic ac y s uccess a n d f uti lit y a nal ysis, t he wee k 8 efficac y e n d p oi nt, ie,  c ha n ge fr o m 
baseli ne at wee k 8 i n m or ni n g tr o u g h F E V 1 will be  a nal yz e d. T he s a me Ba yesia n a nal ysis f or t he 
fi nal pri mar y efficac y a n al ysis will be a p plie d a n d b ot h t he earl y s uccess a n d f utilit y criteria will  
be base d o n t he d eri ve d p osteri or pr o ba bilit y of t he T E V -5 3 2 7 5 d ose gr o u p perf or mi n g better 
t ha n t he place b o gr o u p  i n i m pr o vi n g t he wee k 8 e n d p oi nt. 
E arl y effic ac y s uccess  
T he earl y effi cac y s u ccess will be  assesse d i n t he T E V -5 3 2 7 5 1 2 0 0 m g treat me nt g r o u p wit h t he 
s uccess defi ne d as me eti n g t he f oll o wi n g criteri o n: 
P osteri or pr o b a bility  ( T E V-5 3 2 7 5 1 2 0 0 m g treat me nt effect vs place b o > 0 at i nteri m a nal ysis) 
> 0. 9 5.  
T he  earl y s u ccess t hres h ol d val ue of 0. 9 5 is set hi g her t ha n t he fi n al a nal ysis s uccess thres h ol d of 
0. 8 5 t o de m o nstrate a n u ne q ui v ocal e vi de nce of T E V -5 3 2 7 5 1 2 0 0 m g treat me nt efficac y s uccess 
c o m pare d t o place b o at t he i nteri m a nal ysis.  
 
 
 
 
 
  
Ot her efficac y e n d p oi nts, s uc h as c ha n ge s fr o m b aseli ne i n m or ni n g tr o u g h F E V1 at wee ks 1 , 2 , 
4, 1 2  a n d wee k 1 6  will be s u m mariz e d descri pti vel y  b y treat me nt gr o u p t o pr o vi de s u p p orti ve 
data . 
It is of n ote t hat me eti n g t he i nteri m efficac y s uccess criteri o n will n ot res ult i n ter mi nati n g t he 
st u d y earl y. T he earl y efficac y s uccess r es ult, c o mbi ne d wit h satisfact or y safet y d ata, ma y  assist 
wit h  pre parati o n  / i nitiati o n of f urt her  s afet y a n d efficac y st u dies, a n d e n a ble c o m m u nicati o ns  
wit h re g ul at or y a ge ncies re gar di n g f urt her cli nical de vel o p me nt.  
 
 
 
  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0 9  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meeti n g t he st u d y f utilit y criteri o n ma y res ult i n earl y t er mi nati o n of t he st u d y d ue t o f utilit y.  
T he e xec uti o n of t he u n bli n de d i nteri m a n al ysis  
T he u n bli n de d i nteri m an al ysis will be c o n d u cte d b y i n de pe n de nt, u n bli n de d statisticia n(s) a n d 
pr o gra m mer(s) w h o are n ot part of t h e st u d y t ea m, f oll o wi n g t he pre -s pecifi e d al g orit h ms a n d 
r ules. A n i n de pe n d e nt u n bli n de d data re vie w c o m mittee will be set u p t o re vie w t he u n bli n de d 
i nteri m efficac y a n al ysis res ults. A gr o u p of t he s p o ns or’s ma na ge m e nt tea m, w h o are n ot a part 
of t he st u d y te a m, ma y h a ve access t o t he u n bli n d e d i nteri m a nal ysis res ults. I n or der t o mai ntai n 
t he st u d y bli n d a n d t he st u d y c o n d u ct i nte grit y, a data re vie w c harter  will b e fi nalize d pri or t o t he 
i nteri m a nal ysis, w hic h s pecifies t he pr o cesses f or sec urel y u n bli n di n g i nteri m a nal ysis res ults. 
T he pr ocesses will be  f oll o we d t o e ns ure t hat t he st u d y bli n d wil l be mai ntai ne d i n t he bli n de d 
st u d y pers o n n el w h o are i n v ol ve d i n ma na gi n g  t he st u d y acti vities u ntil t he st u d y is u n bli n de d at 
t he fi nal a nal ysis. T his c harter will als o detail t he bli n de d safet y re vi e w.  
9. 1 4.  
Re p orti n g De vi ati o ns fr o m t he St atistic al Pl a n  
De v iati o ns fr o m t he statistical pla n, al o n g wit h t he reas o ns f or t he de viati o ns, will be descri be d 
i n pr ot oc ol a me n d me nts, t he statistical a nal ysis pla n, t he C S R, or a n y c o m bi nati o n of t hese, as 
a p pr o priate, a n d i n acc or da nce wit h a p plica ble nati o nal, l ocal, a n d re gi o n al re q uire me nts a n d 
re g ulati o ns. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 0  
1 0.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
Refer t o A p pe n di x  C  f or i nf or mati o n re gar di n g q u alit y c o ntr ol a n d q ualit y ass ura nce. T his 
i ncl u des i nf or mati o n a b o ut pr ot oc ol a me n d me nts, de viati o ns, res p o nsi bilities of t he i n vesti gat or 
t o st u d y pers o n n el, st u d y m o nit ori n g, a u dit a n d i ns pecti o n.  
Refer t o A p pe n di x  K  f or t he defi niti o n of a cli nical pr o d uct c o m plai nt a n d i n vesti gat or 
res p o nsi bilities i n t he ma na ge me nt of a cli nical pr o d uct c o m plai nt. 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
Details are gi v e n i n t he st u d y refere nce ma n ual.  
1 1.  
C O M P LI A N C E S T A T E M E N T  
T his st u d y will be c o n d u cte d i n f ull acc o r da nce wit h t he I C H Har m o nise d Tri partite G ui deli ne, 
G ui deli ne f or G o o d Cli nical Practice E 6 a n d a n y a p plica ble nati o nal a n d l o cal la ws a n d 
re g ulati o ns (e g, Title 2 1 C o de of Fe d eral Re g ul ati o ns [ 2 1 C F R] Parts  1 1, 5 0, 5 4, 5 6, 3 1 2, 
a n d 3 1 4, Directi ve 2 0 0 1/ 2 0/ E C of t he E u r o pea n P arlia me nt a n d of t h e C o u ncil o n t he 
a p pr o xi mati o n of t he la ws, re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he me m ber states 
relati n g t o t he i m ple me nt ati o n of G o o d Cli nical Practice i n t he c o n d uct of cli nical trials o n 
me dici nal pr o d uc ts f or h u ma n use). A n y e pis o d e of n o nc o m plia nce will be d oc u me nte d.  
T he i n vesti gat or is res p o nsi ble f or perf or mi n g t h e cli nical st u d y i n acc or da nce wit h t his pr ot oc ol 
a n d t he a p plica ble G C P g ui deli nes refere n ce d a b o ve f or c ollecti n g, rec or di n g, a n d re p orti n g t he 
data acc urat el y a n d pr o p erl y. A gree me nt of t he i n vesti gat or t o c o n d uct a n d a d mi nister t his 
cli nical st u d y i n a cc or da nce wit h t he pr ot oc ol will be d oc u me nte d i n se parate cli nical st u d y 
a gree m e nts wit h t he s p o ns or a n d ot her f or ms as re q uire d b y nati o n al c o m pete nt a ut h orities  i n t he 
c o u ntr y w here eac h i n vesti gati o nal ce nt er is l ocate d.  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he pri vac y, healt h, a n d welfare of t he patie nts d uri n g 
a n d after t he cli nical st u d y; a n d m ust e ns ure t hat tr ai ne d pers o n nel are i m m e diatel y a vaila ble i n 
t he e ve nt of a m e dical e mer ge nc y. T h e i n vesti gat or a n d t he i n v ol ve d cli nical st u d y pers o n nel 
m ust be fa miliar wit h t he bac k gr o u n d a n d re q uir e me nts of t he st u d y; a n d wit h t he pr o perties of 
t he I M Ps as d escri be d i n t he I B or prescri bi n g i nf or mati o n.  
T he pri nci pal i n vesti gat or at eac h i n vesti gati o nal ce nter  has t he o v erall res p o nsi bilit y f or t h e 
c o n d uct a n d a d mi nistrati o n of t he cli nical st u d y at t hat i n vesti gati o nal ce nter  a n d f or c o ntacts 
wit h st u d y ma na ge m e nt, wit h t he I E C/I R B, a n d wit h c o m pete nt a ut h orities.  
See A p pe n di x  D  f or t he et hics e x pectati o ns of i nf or me d c o nse nt or asse nt, c o m pete nt a ut h orities 
a n d I E C/I R B, c o nfi de ntialit y re gar di n g st u d y pati e nts, a n d re q uir e me nts f or re gistrati o n of t he 
cli nical st u d y. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 1  
1 2.  
D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  
See A p pe n di x  L  f or i nf or mati o n re gar di n g dat a ma na ge me nt a n d rec or d kee pi n g. T his i ncl u des 
direct access t o s o urce data a n d d oc u me nts, data c ollecti o n, data q ualit y c o ntr ol, a n d arc hi vi n g of 
C R Fs a n d s o urce  d o c u m e nts.  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  
A se parate cli nical st u d y a gree m e nt, i ncl u di n g a st u d y b u d get, will be si g ne d bet wee n eac h 
pri nci pal i n vesti gat or a n d t he s p o ns or ( or t he C R O desi g nat e d b y t he s p o ns or) bef ore t he I M P is 
deli vere d.  
T he patie nts i n t his c li nical st u d y are i ns ure d i n acc or da nce wit h a p plica bl e le gal pr o visi o ns. T he 
p olic y c o v era ge is s u bject t o t he f ull p olic y ter ms, c o n diti o ns, e xte nsi o ns, a n d e x cl usi o ns. 
E x cl u de d fr o m t he i ns ura nce c o v era ge are e g, d a ma ges t o healt h, a n d w orse ni n g of pre v i o us 
e xisti n g disease t hat w o ul d ha ve occ urre d or c o nti n ue d if t he patie nt ha d n ot ta ke n part i n t he 
cli nical st u d y.  
T he p olic y of Cli nical Trials I ns ur a nce will be pr o vi de d t o t he i n vesti gati o n al ce nters b y t h e 
s p o ns or. 
F or c o v ere d cli nical st u dies (see 2 1 C F R 5 4), t he i n vesti gat or will pr o vi de t he s p o ns or wit h 
fi na ncial i nf or mati o n r e q uire d t o c o m plete F D A 3 4 5 4 f or m. Eac h i n vesti gat or will n otif y t he 
s p o ns or of a n y rele va nt c ha n ges d uri n g t he c o n d u ct of t he st u d y a n d f or 1 year after t he st u d y h as 
bee n c o m pl ete d.  
1 4.  
P U B LI C A TI O N P O LI C Y  
See A p pe n di x  M  f or i nf or mati o n re gar di n g t he p u blicati o n p olic y. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 2  
1 5.  
R E F E R E N C E S  
A mar NJ, M oss M H, Ker wi n E M, Li J, S mall CJ. S afet y a n d efficac y of becl o met has o ne 
di pr o pi o nate deli vere d b y breat h -act uate d or metere d -d ose i n hal er f or persiste nt ast h ma. Aller g y 
Ast h ma Pr oc 2 0 1 6; 3 7( 5): 3 5 9 -6 9.  
Ba g nas c o D, Ferra n d o M, Varric c hi G, P u g gi o ni F, Passalac q ua G, C a n o nica G W. 
A nti -I nt erle u ki n 5 (I L-5) a n d I L -5 Ra bi ol o gical dr u gs: efficac y, safet y, a n d f ut ure pers pecti ves i n 
se vere e osi n o p hilic ast h ma. Fr o nt Me d ( La usa n n e) 2 0 1 7; 3 1( 4): 1 3 5. d oi: 
1 0. 3 3 8 9/f me d. 2 0 1 7. 0 0 1 3 5.  
Barr J T, Sc h u mac her G E, Free ma n S, Le M oi ne M, Ba kst A W, J o nes P W. A merica n tr a nslati o n, 
m o dificati o n, a n d vali dati o n of t he St. Ge or ge’s R es pirat or y Q uesti o n naire. Cli n T her 
2 0 0 0; 2 2( 9): 1 1 2 1 -4 5.  
Ber nstei n DI, Gilles pie M, S o n g S, Stei nfel d J. Safet y, efficac y, a n d d os e res p o nse of fl uticas o ne 
pr o pi o nate deli vere d via t he n o vel M D P I i n p atie nts wit h se vere ast h ma: A ra n d o mize d, 
c o ntr olle d, d ose -ra n gi n g st u d y. J Ast h ma 2 0 1 7; 5 4( 6): 5 5 9-6 9.  
Ber nstei n J A, Virc h o w J C, M ur p h y K, Mas p er o J F, J ac o bs J, A dir Y, et al. Effect of fi x e d -d ose 
s u bc uta ne o us r esliz u ma b o n ast h ma e x acer bati o ns i n patie nts wit h se vere u nc o ntr olle d ast h ma 
a n d c ortic oster oi d s p ari n g i n patie nts wit h oral c ortic oster oi d -de p e n de nt ast h ma: res ults fr o m t w o 
p hase 3, ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d trials. La n cet Res pir Me d 
2 0 2 0; 8( 5): 4 6 1 -7 4.  
Bjer mer L, Le miere C,  Mas per o J, Weiss S, Za n grilli J, Ger mi nar o M. Resliz u ma b f or 
i na de q uatel y c o ntr olle d ast h ma wit h ele vate d bl o o d e osi n o p hil le vels - a ra n d o mize d P hase 3 
st u d y. C hest 2 0 1 6; 1 5 0( 4): 7 8 9-9 8.  
B usse W W, Bate ma n E D, O’ B yr ne P M, L öt vall J, W o o dc oc k A, Me dle y H, et  al. O nce -dail y 
fl uticas o ne f ur o ate 5 0 mc g i n mil d t o m o derate ast h ma: a 2 4-wee k place b o -c o ntr olle d 
ra n d o mize d trial. Aller g y 2 0 1 4; 6 9( 1 1): 1 5 2 2-3 0.  
Carr T F, Ze ki A A, Kraft M. E osi n o p hilic a n d n o ne osi n o p hilic ast h ma. A m J Res pir Crit Care 
Me d 2 0 1 8; 1 9 7( 1): 2 2 -3 7.  
Castr o M, Za n grilli J, Wec hsler M E, Bate m a n E D, Br usselle G G, Bar di n P, et al. Resliz u ma b f or 
i na de q uatel y c o ntr olle d ast h ma wit h ele vate d bl o o d e osi n o p hil c o u nts: res ults fr o m t w o 
m ultice ntre, parallel, d o u ble -bli n d, ra n d o mise d, place b o -c o ntr olle d, p has e 3 trials. La n cet Res pir 
Me d 2 0 1 5; 3( 5): 3 5 5 -6 6.  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n. C or o na vir us ( C O VI D -1 9).  A vaila ble at: 
htt ps:// w w w.c dc. g o v/c or o na vir us/ 2 0 1 9 -nc o v/i n de x. ht ml. Accesse d 0 3  J u ne 2 0 2 0. 
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n. Pla n  a n d O perati o n of t he T hir d Nati o nal Healt h a n d 
N utriti o n E x a mi nati o n S ur ve y ( N H A N E S III), 1 9 8 8 -9 4.  1 9 9 8. Vital Healt h Stat Series N o. 
1 1( 2 A). Nati o nal Ce nter f or Healt h Statistics. A vaila ble at: 
htt ps:// w w w n.c dc. g o v/ nc hs/ Data/ N ha nes 3/ 2 A/ N H 3 E C G -acc. p df. Ac cesse d 2 4  J a n uar y 2 0 2 0. 
C h u n g K F. Dia g n osis a n d ma na ge me nt of s e vere ast h ma. Se mi n Res pir Crit Care Me d 
2 0 1 8; 3 9( 1): 9 1 -9.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 3  
CI N Q AI R ®  (resliz u ma b). U S Prescri bi n g I nf or mati o n, Te va P har mace utical I n d ustries Lt d., 
2 0 2 0. A vaila ble at htt ps:// w w w.ci n qair. c o m/ gl o b al assets/ci n qair/ pres cri bi n gi nf or mati o n. p df. 
Access e d 2 3 J u ne 2 0 2 0 . 
CI N Q AI R ®  (resliz u ma b) Pr o d uct M o n o gra p h, Te v a Ca na da Li mite d, Marc h 2 0 1 7. A vaila ble at: 
htt p:// w w w.te vaca na d ai n n o vati o n.c o m/ d o w nl oa ds/ Ci n qair _ P M _ E N. p df. Accesse d o n 1 2 
Dece m b er 2 0 2 0.  
C orre n J, K ore n blat P E, Miller CJ, O’ Brie n C D, Mezza n otte W S. T wel ve -wee k, ra n d o mize d, 
place b o -c o ntr olle d, m ultice nter st u d y of t he effi cac y a n d t olera bilit y of b u d es o ni de a n d 
f or m oter ol i n o ne metere d-d ose i n haler c o m pare d wit h b u des o ni de al o ne a n d f or m oter ol al o ne i n 
a d olesce nts a n d a d ults wit h ast h ma. Cli n T her 2 0 0 7; 2 9( 5): 8 2 3 – 4 3.  
Fitz Geral d J M, Bleec k er E R, Me nzies -G o w A, Za n grilli J G, Hirsc h I, Metcalfe P, et al. 
Pre dict ors of e n h a nce d res p o nse wit h be nraliz u ma b f or patie nts wit h se vere ast h ma: p o ole d 
a nal ysis of t he SI R O C C O a n d C A LI M A st u dies. La n cet Res pir Me d 2 0 1 8; 6( 1): 5 1-6 4.  
Fitz Geral d J M, Bleec k er E R, Nair P, K or n S, O hta K, L o m matzsc h M, et al. Be nraliz u ma b, a n 
a nti-i nterle u ki n-5 rece pt or α m o n ocl o nal a nti b o d y, as a d d -o n treat me nt f or patie nts wit h se ve re, 
u nc o ntr olle d, e osi n o p hilic ast h ma ( C A LI M A): a ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d 
p hase 3 trial. La n cet 2 0 1 6; 3 8 8( 1 0 0 5 6): 2 1 2 8 -4 1.  
F ul kers o n P C, R ot he n ber g M E. Tar geti n g e osi n o p hils i n aller g y, i nfla m mati o n a n d be y o n d. Nat 
Re v Dr u g Disc o v 2 0 1 3; 1 2( 2): 1 1 7 -2 9.  
GI N A ( Gl o b al I nitiati ve f or Ast h ma). A d oles ce nts a n d a d ults wit h diffic ult -t o-treat a n d s e vere 
ast h ma, 2 0 2 0 . A vaila ble at: htt ps:// gi nast h ma. or g. Access e d 0 3 Marc h 2 0 2 0.  
Gree n R H, Bri g htli n g C E, Mc Ke n na S, Har ga d o n B, Par ker D, Bra d di n g P, et al. Ast h ma 
e x acer bati o ns a n d s p ut u m e osi n o p hil c o u nts: a ra n d o mise d c o ntr olle d trial. La n cet 
2 0 0 2; 3 6 0( 9 3 4 7): 1 7 1 5 -2 1.  
G ui da nce f or I n d ustr y: E 1 0: C h oice of C o ntr ol Gr o u p a n d Relate d Iss ues i n Cli nical Trials. U S 
De part me nt of Healt h a n d H u ma n Ser vices  F o o d a n d Dr u g A d mi nistrati o n, C D E R, a n d C B E R 
Ma y 2 0 0 1. A vaila ble at: htt ps:// w w w.f da. g o v/ me dia/ 7 1 3 4 9/ d o w nl oa d. Accesse d 0 3 J u ne 2 0 2 0.  
Ha n ki ns o n J L, Ka w ut S M, S ha har E, S mit h LJ, St u k o vs k y K H, Barr R G. Perf or ma nce of 
A merica n T h oraci c S ociet y -rec o m me n d e d spir o metr y refere nce v al ues i n a m ulti -et h nic sa m ple 
of a d ults: t he m ulti -et h nic st u d y of at her os cler osis ( M E S A) l u n g st u d y. C h est 
2 0 1 0; 1 3 7( 1): 1 3 8 -4 5.  
Ha n ki ns o n J L, O de ncra ntz J R, Fe da n K B. S pir o m etric refere nce val ues fr o m a sa m ple of t he 
ge n eral U. S. p o p u lati o n. A m J Res pir Crit Care Me d  1 9 9 9; 1 5 9( 1): 1 7 9 – 8 7.  
H o ga n S P, Wa d dell A, F ul kers o n P C. E osi n o p hils i n i nfecti o n a n d i ntesti nal i m m u nit y. C urr 
O pi n Gastr oe nter ol 2 0 1 3; 2 9( 1): 7 -1 4.  
H o p ki ns C, Gillett S, Slac k R, L u n d VJ, Br o w ne J P. Ps yc h o metric vali dit y of t he 2 2-ite m 
Si n o nasal O utc o me Test. Cli n Ot olar y n g ol 2 0 0 9; 3 4( 5): 4 4 7 -5 4.  
J ata ka n o n A, Li m S, Bar nes PJ. C ha n ges i n s p ut u m e osi n o p hils pre dict l oss of ast h ma c o ntr ol. 
A m J Res pir Crit Care Me d 2 0 0 0; 1 6 1( 1): 6 4 – 7 2.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 4  
J u n g Y, R ot he n ber g M E. R oles a n d re g ulati o n of gastr oi ntesti nal e osi n o p hils i n i m m u nit y a n d 
disease. J I m m u n ol 2 0 1 4; 1 9 3( 3): 9 9 9 -1 0 0 5.  
J u ni per E F, O' B yr ne P M, G u yatt G H, Ferrie PJ, Ki n g D R. De v el o p me nt a n d vali dati o n of a 
q uesti o n naire t o meas ur e ast h ma c o ntr ol. E ur Res pir J 1 9 9 9; 1 4( 4): 9 0 2 -7.  
Ker wi n E M,  Hic k e y L, S mall CJ. Relati o ns hi p bet wee n ha n d h el d a n d cli nic -base d s pir o metr y 
meas ure me nts i n ast h ma patie nts recei vi n g b ecl o met has o ne. Res pir Me d 2 0 1 9; 1 5 1: 3 5 -4 2.  
K yri a ki des T, A n geli ni C, Sc haefer J, Sacc o ni S, Sicilia n o G, Vilc hez JJ, et al. E F N S g ui del i nes 
o n t he dia g n ostic a p pr oac h t o pa uci - or as y m pt o m atic h y p er C Ke mia. E ur o pea n J Ne ur ol 
2 0 1 0; 1 7( 6): 7 6 7 -7 3.  
Le u n g E, Efraij K A, Fitz Geral d J M. T he safet y of me p oliz u ma b f or t he treat me nt of ast h ma. 
E x pert O pi n Dr u g Saf 2 0 1 7; 1 6( 3): 3 9 7 -4 0 4.  
Le u p pi J D, Sal o me  C M, J e n ki ns C R, A n ders o n S D, X ua n W, Mar ks G B, et al. Pre dicti ve 
mar kers of ast h ma e x acer bati o n d uri n g ste p wise d ose re d ucti o n of i n hal e d c ortic oster oi ds. A m J 
Res pir Crit Care Me d 2 0 0 1; 1 6 3( 2): 4 0 6 -1 2.  
L öt vall J, Bleec k er E R, B usse W W, O’ B yr ne P M, W o o dc oc k  A, Ker wi n E M, et al. Efficac y a n d 
safet y of fl utic as o ne f ur o ate 1 0 0 µ g o n ce -d ail y i n patie nts wit h persiste nt ast h ma: a 2 4 -wee k 
place b o a n d acti ve -c o ntr olle d ra n d o mise d trial [ p u blis he d c orri ge n d u m a p pears i n Res pir Me d 
2 0 1 5; 1 0 9( 1): 1 4 6]. Res pir Me d 2 0 1 4; 1 0 8( 1): 4 1 – 9.  
L o uis R, La u L C, Br o n A O, R ol daa n A C, Ra der mec ker M, Dj u k a n o vić R. T he relati o ns hi p 
bet wee n air wa ys i nfla m mati o n a n d ast h ma se verit y. A m J Res pir Crit Care Me d 
2 0 0 0; 1 6 1( 1): 9 -1 6.  
Malli nc kr o dt C. C h o osi n g pri mar y esti ma n ds a n d a nal ys es. I n: Pre v e nti n g a n d treati n g missi n g 
data i n l o n git u di nal cli nical trials: A practical g ui de. Ne w Y or k: Ca m bri d ge U ni versit y Press, 
2 0 1 3; 1 0 3 -1 0.  
Miller M R, Cra p o R, Ha n ki ns o n J, Br usasc o V, B ur g os F, Casa b uri R, et al. Ge neral 
c o nsi derati o ns f or l u n g f u ncti o n testi n g. E ur Res pir J 2 0 0 5; V ol u me 1; 2 6( 1): 1 5 3 -6 1.  
Mira n da C, B us ac ker A, Balz ar S, Tr u dea u J, We nzel S E. Disti n g uis hi n g se vere ast h ma 
p he n ot y p es: r ole of a ge at o nset a n d e osi n o p hilic i nfla m mati o n. J Aller g y Cli n I m m u n ol 
2 0 0 4; 1 1 3( 1): 1 0 1 -8.  
Nat ha n R A, S or k ness C A , K osi ns ki M, Sc hatz M, Li J T, Marc us P, et al. De vel o p me nt of t he 
ast h ma c o ntr ol test: A s ur ve y f or assessi n g ast h ma c o ntr ol. J Aller g y Cli n I m m u n ol 
2 0 0 4; 1 1 3( 1): 5 9 -6 5.  
N U C A L A ®  ( me p oliz u ma b). U S Prescri bi n g I nf or mati o n, Gla x o S mit h Kli ne Tra di n g Ser vices 
Lt d ., 2 0 1 9. A v aila ble at: 
htt ps:// gs ks o urce.c o m/ p h ar ma/c o nte nt/ da m/ Gla x o S mit h Kli ne/ U S/e n/ Prescri bi n g _I nf or mati o n/ N u
cala/ p df/ N U C A L A -PI -PI L -I F U-C O M BI N E D. P D F. Accesse d 2 3 J u ne 2 0 2 0.  
O' B yr ne P M, Fitz Geral d J M, Bate ma n E D, Bar nes PJ, Z h o n g N, Kee n C, et al. I n h ale d c o m bi ne d 
b u des o ni de -f or m oter ol as nee de d i n mil d ast h ma [ S Y G M A 1: S u p ple me ntar y A p pe n di x a p pears 
i n N E n gl J Me d. 2 0 1 8; 3 7 8( 2 0): 1 8 6 5-7 6]. N E n gl J Me d. 2 0 1 8; 3 7 8( 2 0): 1 8 6 5 -7 6.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 5  
Orte ga H G, Li u M C, Pa v or d I D, Br usselle G G, Fit z Geral d J M, C hetta A, et al. Me p ol iz u ma b 
treat me nt i n patie nts wit h se vere e osi n o p hilic ast h ma. N E n gl J Me d 2 0 1 4; 3 7 1( 1 3): 1 1 9 8-2 0 7.  
Pa v or d I D, K or n S, H o wart h P, Bleec ker E R, B u hl R, Kee ne O N, et al. Me p oliz u ma b f or se vere 
e osi n o p hilic ast h ma ( D R E A M): a m ultice ntre, d o u ble -bli n d, place b o -co ntr olle d trial. La ncet 
2 0 1 2; 3 8 0( 9 8 4 2): 6 5 1 -9.  
Pearl ma n D S, Stric ker W, Wei nstei n S, Gr oss G, C her vi ns k y P, W o o dri n g A, et al. I n hale d 
sal meter ol a n d fl uticas o n e: a st u d y c o m pari n g m o n ot hera p y a n d c o m bi nati o n t hera p y i n ast h ma. 
A n n Aller g y Ast h ma I m m u n ol 1 9 9 9; 8 2( 3): 2 5 7 – 6 5.  
P o uli q ue n IJ, K or n ma n n O, Bart o n S V, Price J A, Orte ga H G. C haracterizati o n of t he relati o ns hi p 
bet wee n d ose a n d bl o o d e osi n o p hil res p o nse f oll o wi n g s u bc ut a ne o us a d mi nistrati o n of 
me p oliz u ma b. I nt J Cli n P har mac ol T her 2 0 1 5; 5 3( 1 2): 1 0 1 5 – 2 7.  
Price D B, Ri gazi o A, Ca m p bell J D, Bleec ker E R, C orri ga n CJ, T h o mas M et al. Bl o o d 
e osi n o p hil c o u nt a n d pr os pecti ve a n n ual ast h ma disease b ur de n: a U K c o h ort st u d y. La n cet 
Res pir Me d 2 0 1 5; 3( 1 1): 8 4 9 -5 8.  
Ra p hael G, Yi u G, Sa k o v A, Li u S, Caracta C. Ra n d o mize d , d o u ble-bli n d trial e val uati n g t he 
effic ac y a n d s afet y of fl uticas o ne pr o pi o nate a n d fl uticas o ne pr o pi o nate/sal meter ol deli vere d via 
m ulti d ose dr y p o w der i n halers i n patie nts wit h persiste nt ast h ma a ge d 1 2 years a n d ol d er. J 
Ast h ma 2 0 1 8; 5 5( 6): 6 4 0 -5 0.  
R o uf osse F. Tar geti n g t he i nterle u ki n -5 pat h w a y f or treat me nt of e osi n o p hilic c o n diti o ns ot her 
t ha n ast h ma. Fr o nt Me d ( La us a n ne) 2 0 1 8; 5( 4 9): 1-2 7. d oi: 1 0. 3 3 8 9/f me d. 2 0 1 8. 0 0 0 4 9.  
Sa m ps o n H A, M u ñ oz -F url o n g A, Ca m p b ell R L, A d ki ns o n N F Jr, B oc k S A, Bra n u m A, et al. 
Sec o n d s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yla xis: s u m mar y re p ort -Sec o n d 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas e/ F o o d Aller g y a n d A na p h yla xis Net w or k 
s y m p osi u m. J Aller g y Cli n I m m u n ol 2 0 0 6; 1 1 7( 2): 3 9 1-7.  
Sc hatz M, S or k ness C A , Li J T, Marc us P, M urra y JJ, Nat ha n R A, et al. Ast h ma C o ntr ol Test: 
relia bilit y, vali dit y, a n d res p o nsi ve ness i n patie nts n ot pre vi o usl y f oll o we d b y ast h ma s p ecialists. 
J Aller g y Cli n I m m u n ol 2 0 0 6; 1 1 7( 3): 5 4 9-5 6.  
S ha pir o G S, Kli n ger N M, E k h ol m B P, C olice G L. C o m para ble br o nc h o dilati o n wit h 
h y dr ofl u or oal ka n e -1 3 4a ( H F A) al b uter ol a n d c hl or ofl u or ocar b o ns -1 1/ 1 2 ( C F C) al b uter ol i n 
c hil dre n wit h ast h ma. J Ast h ma 2 0 0 0; 3 7( 8): 6 6 7 -7 5.  
S her L D, Yi u G, Sa k o v A, Li u S, Caracta C F. Fl uticas o ne pr o pi o nate a n d fl uticas o ne 
pr o pi o nate/sal meter ol m ulti d ose dr y p o w der i n halers c o m pare d wit h place b o f or persiste nt 
ast h ma. Aller g y Ast h ma Pr oc 2 0 1 7; 3 8( 5): 3 4 3 -5 3.  
S mit h D A, Mi nt h or n E A, Beera h ee M. P har mac o ki netics a n d p har mac o d y n a mics of 
me p oliz u ma b, a n a nti -i nterle u ki n-5 m o n ocl o na l a nti b o d y. Cli n P har mac o ki net 
2 0 1 1; 5 0( 4): 2 1 5 -2 7.  
Stei ner M, H u ber S, Harrer A, Hi ml y M. T he e v ol uti o n of h u ma n bas o p hil bi ol o g y fr o m ne gl ect 
t o war ds u n dersta n di n g of t heir i m m u ne f u ncti o ns. Bi o Me d Res I nt 2 0 1 6; 2 0 1 6: 8 2 3 2 8 3 0. 
d oi: 1 0. 1 1 5 5/ 2 0 1 6/ 8 2 3 2 8 3 0. [ E p u b ] Accesse d 2 3 J u ne 2 0 2 0. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 6  
te n Bri n ke A, Z wi n der m a n A H, Ster k PJ, Ra be K F, Bel E H. Fact ors ass oci ate d wit h persiste nt 
airfl o w li mitati o n i n se vere ast h ma. A m J Res pir Crit Care Me d 2 0 0 1; 1 6 4( 5): 7 4 4 -8.  
Tra n T N, K h atr y D B, Ke X, War d C K, G ossa ge D. Hi g h bl o o d e osi n o p hil c o u nt is ass ociate d 
wit h m ore fre q u e nt ast h ma attac ks i n ast h ma pati e nts. A n n Aller g y Ast h m a I m m u n ol 
2 0 1 4; 1 1 3( 1): 1 9 -2 4.  
Ts u ka m ot o N, Ta ka has hi N, It o h H, P o uli q ue n I. P har mac o ki netics a n d p h ar mac o d y n a mics of 
me p oliz u ma b, a n a nti – i nterle u ki n 5 m o nocl o nal a nti b o d y i n healt h y J a pa nes e male s u bjects. Cli n 
P har mac ol Dr u g D e v 2 0 1 6; 5( 2): 1 0 2 -8.  
Y o u n g T C, Sri ni vasa n S, Vetter M L, Set h ura m a n V, B ha g wa gar Z, Z wirtes R, et al. A 
s yste matic re vie w a n d p o ole d a nal ysis of select safet y p ara met ers a m o n g n or mal he alt h y 
v ol u nteers ta ki n g place b o i n p hase 1 cli nical trials. J Cli n P har mac ol 2 0 1 7; 5 7( 9): 1 0 7 9 -8 7.  
Za y n a get di n o v R, S herrill T P, Glea ves L A, Mc L o e d A G, Sa x o n J A, Ha ber ma n n A C, et al. 
I nterle u ki n-5 facilitates l u n g metastasis b y m o d ul ati n g t he i m m u ne micr oe n v ir o n me nt. Ca ncer 
Res 2 0 1 5; 7 5( 8): 1 6 2 4 -3 4.  
Zei ger R S, Sc hatz M, Li Q, C he n W, K hatr y D B, G ossa ge D, et al. Hi g h bl o o d e osi n o p hil c o u nt 
is a ris k fact or f or f ut ure ast h ma e x acer bati o ns i n a d ult persiste nt ast h ma. J Aller g y Cli n 
I m m u n ol Pract 2 0 1 4; 2( 6): 7 4 1-5 0.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 7  
1 6.  
S U M M A R Y O F C H A N G E S T O P R O T O C O L  
1 6. 1.  
A me n d me nt 0 1 D ate d 1 8  N o ve m ber 2 0 2 1  
T he pri mar y reas o n f or t his a me n d me nt is t o  m o dif y t he e ntr y/eli gi bilit y criteria t o assist wit h 
recr uit me nt r ates; t o clarif y t hat st u d y sa m ple siz e ma y b e a dj uste d bas e d o n t he res ults of a n 
i nteri m a nal ysis, usi n g u n bli n de d effic ac y data ; a n d t o clarif y t hat t he i nteri m a nal ysis will 
i ncl u de a n u n bli n de d f utilit y a nal ysis. A d diti o nall y, t he a me n d me nt c o ntai ns a clarificati o n of 
c ollecti o n of bli n de d/ u n bli n de d bl o o d c o u nts at baseli ne a n d u p dates t o t he C O VI D -1 9  
m o nit ori n g criteri a. All maj or c ha n ges t o t he pr ot oc ol b o d y are liste d bel o w i n t he ta ble a n d are 
reflecte d i n t he s y n o psis, as a p plica ble. Mi n or e dit orial c ha n ges (e g, t y p os an d p u nct uati o n ) ha ve 
bee n ma de t o t he pr ot oc ol (a n d pr ot oc ol s y n o psis, as a p pr o priat e ). Ta bl e  2  has bee n re vise d t o 
reflect t he descri be d c ha n ges. 
C h a n ges  t o t he Pr ot oc ol 
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
Title P a ge  
E u dr a C T n u m ber: N ot A p plic a ble 2 0 2 1 -
0 0 1 4 3 9 -2 2  
E u dr a C T n u m ber: 2 0 2 1 -0 0 1 4 3 9 -2 2  
A d de d E u dra C T st u d y 
i de ntifier. 
3 St u d y Desi g n  
3. 1  Ge ner al St u d y Desi g n a n d St u d y Sc he m atic Di a gr a m  
P atie nts ma y be eli gi ble t o partici pate if t he y 
ha ve a dia g n osis of ast h ma f or at least 6 
m o nt hs a n d t heir c urre nt ast h ma mai nte na nce 
t hera p y has bee n sta ble f or at least 3 m o nt hs  
1 m o nt h  a n d i ncl u des 1  of t he f oll o wi n g (see 
A p pe n di x  F ). 
P atie nts ma y be eli gi ble t o partici pate if 
t he y ha ve a dia g n osis of ast h ma f or at 
least 6 m o nt hs a n d t heir c urre nt ast h ma 
mai nte na nce t hera p y has bee n sta ble f or 
at least 1 m o nt h  a n d i ncl u des 1  of t he 
f ollo wi n g (see A p pe n di x  F ). 
U p date d t o i m pr o ve 
patie nt e nr oll me nt.  
A p pr o xi matel y 9 0 patie nts w h o ha ve bee n 
mai ntai ne d o n me di u m or hi g h d ose I C S or 
l o w d ose I C S/ L A B A a n d a p pr o xi matel y 
2 1 0  patie nts ( m a y be a dj uste d b ase d o n t he 
i nteri m a n al ysis) o n me di u m or h i g h d ose 
I C S/ L A B A will be ra n d o mize d a n d stratifie d 
acr oss all treat me nt ar ms. Scre e ni n g ma y be 
a dj uste d as nee de d t o meet t hese criteria as 
m uc h as p ossi ble.  
A p pr o xi matel y 9 0 patie nts w h o ha ve 
bee n mai ntai ne d o n me di u m or hi g h 
d ose I C S or l o w d ose I C S/ L A B A a n d 
a p pr o xi matel y 2 1 0 patie nts ( ma y be 
a dj uste d base d o n t he i nteri m a nal ysis) 
o n me di u m or hi g h d ose I C S/ L A B A will 
be ra n d o mize d a n d stratifie d a cr oss all 
treat me nt ar ms. Scree ni n g ma y be 
a dj uste d as nee de d t o meet t hese criteria 
as m uc h as p ossi ble.  
Cl arificati o n.  
3. 2 Pl a n ne d N u m ber of P atie nts a n d C o u ntries  
A p pr o xi matel y 8 6 0 patie nts will be scree ne d 
t o ac hie ve a p pr o xi matel y 3 0 0 ra n d o mize d 
patie nts, w hic h m a y be a dj uste d b ase d o n 
a n i nteri m a n al ysis . Details o n t he 
defi niti o n of e val ua ble patie nts a n d sa m ple 
size are gi ve n i n Secti o n 9.  
A p pr o xi matel y 8 6 0 patie nts will be 
scree ne d t o ac hie ve a p pr o xi matel y 3 0 0 
ra n d o mize d patie nts, w hic h ma y be 
a dj uste d base d o n a n i nteri m a nal ysis. 
Details o n t he defi niti o n of e val ua ble 
patie nts a n d sa m ple size are gi ve n i n 
Secti o n  9.  
Clarificati o n . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 8  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
T a ble 2: St u d y Pr o ce d ures a n d Assess me nts  
See ne w w or di n g c ol u m n  
T a ble 2 ( St u d y Pr oce d ures a n d 
Assess me nts) has bee n re vise d as 
descri be d bel o w:  
•  
He mat ol o g y ( C B C wit h 
differe ntial) –  assess me nt 
a d de d t o V 3  
•  
He mat ol o g y ( bli n de d C B C wit h 
differe ntial) –  assess me nt 
delete d fr o m V 3  
C orrecti o n . 
F o ot n ote b: T he scree ni n g visit will ta ke 
place n ot m ore t ha n a p pr o xi matel y 4 wee ks 
bef ore t he baseli ne/ D o R visit ( V 3) a n d is 
li mite d t o a p pr o xi m atel y  1 4 ± 2 da ys 
d urati o n. It is u n derst o o d t hat n ot all 
pr oce d ures ca n be c o m plete d o n t he sa me 
da y. I n partic ular, t he patie nt ma y nee d t o 
ret ur n f or re p eat C B C testi n g as nee de d or t o 
satisf y t he me dicati o n was h o ut f or 
p ul m o nar y f u ncti o n testi n g or t o u n der g o 
re p eat p ul m o nar y f u ncti o n testi n g. 
F o ot n ote b: T he scree ni n g visit will ta ke 
place n ot m ore t ha n a p pr o xi matel y 4 
wee ks bef ore t he baseli ne/ D o R visit 
( V 3) a n d is li mite d t o a p pr o xi matel y 1 4 
da ys d urati o n. It is u n derst o o d t hat n ot 
all pr oce d ures ca n be c o m plet e d o n t he 
sa me da y. I n partic ular, t he patie nt ma y 
nee d t o ret ur n f or re peat C B C testi n g as 
nee de d or t o satisf y t he me dicati o n was h 
o ut f or p ul m o nar y f u ncti o n testi n g or t o 
u n der g o re peat p ul m o nar y f u ncti o n 
testi n g. 
Clarificati o n . 
F o ot n ote r: Bli n de d C B C wit h differe ntial 
c o unt will b e dra w n at visits fr o m after V 3 
a n d  o n war d t o mai ntai n st u d y bli n di n g. T he 
e osi n o p hil a n d m o n oc yte c o u nts will n ot b e 
re p orte d t o t he st u d y pers o n nel. 
F o ot n ote r: Bli n de d C B C wit h 
differe ntial c o u nt will be dra w n at visits 
after  V 3 o n war d t o mai nt ai n st u d y 
bli n di n g. T he e osi n o p hil a n d m o n oc yte 
c o u nts will n ot be re p orte d t o t he st u d y 
pers o n nel.  
C orrecti o n . 
4 Selecti o n a n d wit h dr a w al of p atie nts  
4. 1 P atie nt I ncl usi o n Criteri a  
c. [ Re visi o n 1] T he patie nt has a dia g n osis of 
ast h ma f or at least 6  m o nt hs as defi ne d b y 
t he Nati o nal I nstit utes of Healt h ( NI H) a n d 
has bee n sta ble wit h o ut e xacer bati o n or 
c ha n ge i n me dicati o ns f or at least 3 m o nt hs  
1  m o nt h . 
c. [ Re visi o n 1] T he patie nt has a 
dia g n osis of ast h ma f or at least 6  m o nt hs 
as defi ne d b y t he Nati o nal I nstit utes of 
Healt h ( NI H) a n d has bee n sta ble 
wit h o ut e xacer bati o n or c ha n ge i n 
me dicati o ns f or at least 1  m o nt h.  
U p date d t o i m pr o ve 
patie nt e nr oll me nt.  
g. [ Re visi o n 1] C urre nt Ast h ma T hera p y: 
T h e patie nt has bee n mai ntai ne d f or at least 3 
m o nt hs  1  m o nt h  o n sta ble d oses of:  
- 
me di u m or hi g h d ose I C S ±a n ot her 
c o ntr oller.  
- 
a n y fi xe d d ose c o m bi nati o n I C S (l o w, 
me di u m, or hi g h) wit h L A B A ±a n ot her 
c o ntr oller.  
g. [ Re visi o n 1] C urre nt Ast h ma 
T hera p y: T he pati e nt has bee n 
mai ntai ne d f or at least 1 m o nt h o n sta ble 
d oses of:  
- 
me di u m or hi g h d ose I C S ±a n ot her 
c o ntr oller.  
- 
a n y fi xe d d ose c o m bi nati o n I C S 
(l o w, me di u m, or hi g h) wit h 
L A B A ±a n ot her c o ntr oller.  
U p date d t o i m pr o ve 
patie nt e nr oll me nt.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1 9  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
4. 2  P atie nt E xcl usi o n Criteri a  
n. [ Re visi o n 1] T he patie nt has bee n treate d 
wit h a m o n ocl o nal a nti b o d y use d t o tre at 
ast h m a or ot her i nfl a m m at or y c o n diti o ns 
wit hi n t he w as h o ut peri o d ( 5 h alf -li ves), 
h as de m o nstr ate d h y perse nsiti vit y or 
a n a p h yl a xis t o a m o n ocl o n al a nti b o d y  
( A p pe n di x G), or is c urre ntl y usi n g or has 
use d a s yste mic i m m u n os u p pressi ve 
me dicati o n wit hi n t he last 6 m o nt hs. N O T E: 
Pri or de pe m o ki m a b e x p os ur e is 
pr o hi bite d wit h o ut e xce pti o n.  
n. [ Re visi o n 1] T he patie nt has bee n 
treate d wit h a m o n ocl o nal a nti b o d y use d 
t o treat ast h ma or ot her i nfla m mat or y 
c o n diti o ns wit hi n t he was h o ut peri o d ( 5 
half -li ves), has de m o nstrate d 
h y perse nsiti vit y or a na p h yla xis t o a 
m o n ocl o nal a nti b o d y ( A p pe n di x G), or 
is c urre ntl y usi n g or has use d a s yste mic 
i m m u n os u p pressi ve me dicati o n withi n 
t he last 6 m o nt hs. N O T E: Pri or 
de pe m o ki ma b e x p os ure is pr o hi bite d 
wit h o ut e xce pti o n.  
U p date d t o i m pr o ve 
patie nt e nr oll me nt.  
q. [ Re visi o n 1] T he patie nt c urre ntl y s m o kes 
or has a s m o ki n g hist or y of 1 0 pac k years or 
m ore (a pac k year is defi ne d as s m o ki n g 1 
pac k of ci garettes [ 2 0 ci garettes]/ d a y f or 1 
year), O R t he patie nt use d t o bacc o or 
marij ua na  pr o d ucts wit hi n t he past year (e g, 
ci garettes, ci gars, c he wi n g t o bacc o, or pi pe 
t o bacc o), O R t he p atie nt h as s m o ke d 
m arij u a n a wit hi n 1 m o nt h , O R t he patie nt 
h as a hist or y of “ va pi n g” t o bacc o, marij ua na, 
or a n y ot her s u bsta nce wit hi n 2 4 m o nt hs.  
q. [ Re visi o n 1] T he patie nt c urre ntl y 
s m o kes or has a s m o ki n g hist or y of 1 0 
pac k years or m ore (a pac k ye ar is 
defi ne d as s m o ki n g 1 pac k of ci garettes 
[ 2 0 ci garettes]/ da y f or 1 year), O R t he 
patie nt use d t o bacc o pr o d ucts wit hi n t he 
past year (e g, ci garettes, ci gars, c he wi n g 
t o bacc o, or pi pe t o bacc o), O R t he patie nt 
has s m o ke d marij ua na wit hi n 1 m o nt h, 
O R t he patie nt has a hist or y of “ va pi n g” 
t o bacc o, marij ua na, or a n y ot her 
s u bsta nce wit hi n 2 4 m o nt hs. 
Clarificati o n . 
4. 4 Wit h dr a w al Criteri a a n d Pr o ce d ures f or t he P atie nt  
If a patie nt e x hi bits cli nical s y m pt o ms t hat 
ma y i n dicate C O VI D -1 9 i nfecti o n after 
e nteri n g t he st u d y, t he patie nt s h o ul d be 
teste d f or acti ve C O VI D-1 9. If t he patie nt 
tests p ositi ve f or acti ve C O VI D-1 9 ( p ositi ve 
a nti g e n tests m ust be c o nfir me d b y re verse 
tr a nscri pti o n p ol y mer ase c h ai n re acti o n 
[ R T-P C R] testi n g) , he/s he ma y c o nti n ue f or 
sc he d ule d visits w he n rec o ver e d rec o vere d 
(ie, ne gati ve real ti me p ol ymerase c hai n 
reacti o n [ R T P C R] test f or C O VI D 1) 
ass u mi n g he/s he has n o pr ot oc ol vi olati o ns 
i ncl u di n g use of disall o we d me dicati o n (ie, 
after 1 0  d a ys fr o m t he o nset of s y m pt o ms, 
re m ai ns afe brile f or 2 4 h o urs wit h o ut 
usi n g a nti -p yretics a n d ot he r s y m pt o ms 
a re i m pr o vi n g)  (see A p pe n di x G a n d 
A p pe n di x  N.  
If a patie nt e x hi bits cli nical s y m pt o ms 
t hat ma y i n dicate C O VI D-1 9 i nfecti o n 
after e nteri n g t he st u d y, t he patie nt 
s h o ul d be teste d f or acti ve C O VI D-1 9. If 
t he patie nt tests p ositi ve f or acti ve 
C O VI D -1 9 ( p ositi ve a nti ge n t ests m ust 
be c o nfir me d b y re verse tra ns cri pti o n 
p ol y merase c hai n reacti o n [ R T -P C R]) 
testi n g), he/s he ma y c o nti n ue f or 
sc he d ule d visits w he n rec o ver e d (ie, 
after 1 0  da ys fr o m t he o nset of 
s y m pt o ms, re mai ns afe brile f or 2 4  h o urs 
wit h o ut usi n g a nt i-p yretics a n d ot her 
s y m pt o ms are i m pr o vi n g) (see 
A p pe n di x  G a n d A p pe n di x  N).  
U p date d t o ali g n wit h 
c urre nt g ui deli nes.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 0  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
4. 6 Rescree ni n g  
A patie nt w h o scree n -fails ma y be per mitte d 
t o rescree n o nce after 3 0 d a ys d ur ati o n  if 
t here is a reas o na ble e x pectatio n t hat t his 
patie nt will bec o me eli gi ble f or t he st u d y, 
i ncl u di n g re q uire me nts f or e osi n o p hil 
c o u nts a n d/ or s pir o metr y . T he s p o ns or ma y 
gra nt p er missi o n t o rescree n m ore t ha n o nce 
u n der e xte n uati n g circ u msta nc es a n d o nl y 
wit h t he a p pr o val of t he s p o ns or’s  me dical 
e x pert or dele gate. N ote: P atie nts w h o 
de vel o p a U RI/ L RI d uri n g t he r u n -i n peri o d 
ma y rescree n 2  wee ks after s y m pt o ms 
res ol ve a n d after a p pr o priate C O VI D-1 9 
testi n g has bee n c o m plete d as s pecifie d. 
A d diti o n all y, p atie nts w h o f ail 
r a n d o miz ati o n f or  re as o ns ot her t h a n 
s pir o metr y re q uire me nts m a y be 
rescree ne d o nce.  
A patie nt w h o scree n -fails ma y be 
per mitte d t o rescree n o nce aft er 3 0 da ys 
d urati o n if t here is a reas o na bl e 
e x pectati o n t hat t his patie nt will bec o me 
eli gi ble f or t he st u d y, i ncl u di n g 
re quire me nts f or e osi n o p hil c o u nts 
a n d/ or s pir o metr y. T he s p o ns or ma y 
gra nt per missi o n t o rescree n m ore t ha n 
o nce u n der e xte n uati n g circ u msta nces 
a n d o nl y wit h t he a p pr o val of t he 
s p o ns or’s me dical e x pert or dele gate. 
N ote: P atie nts w h o de vel o p a U RI/ L RI 
d uri n g t he r u n -i n peri o d ma y rescree n 
2  wee ks after s y m pt o ms res ol ve a n d 
after a p pr o priate C O VI D -1 9 testi n g has 
bee n c o m plete d as s pecifie d. 
A d diti o nall y, patie nts w h o fail 
ra n d o mizati o n f or reas o ns ot her t ha n 
s pir o metr y re q uire me nts ma y be 
rescree ne d o nce 
U p date d t o i m pr o ve 
patie nt e nr oll me nt.  
5 Tre at me nts  
5. 8 Pr o ce d ures f or M o nit o ri n g P atie nt C o m pli a nce  
T he i n vesti gat or will be res p o nsi ble f or 
m o nit ori n g patie nt c o m plia nce wit h t his 
pr ot oc ol fr o m t he start of t he 
scree ni n g/r u n-i n peri o d t hr o u g h t he 
f oll o w-u p visit. If t he i n vesti gat or or t he 
s p o ns or deter mi nes t hat t he patie nt is n ot i n 
c o m plia nce wit h t he st u d y pr ot oc ol, t he 
i n vesti gat or a n d t he s p o ns or s h o ul d 
deter mi ne w het her t he patie nt s h o ul d be 
wit h dra w n fr o m t he st u d y. T he I n de p e n de nt 
Et hics C o m mittee/I nstit uti o nal Re vie w 
B oar d  (I E C/I R B) s h o ul d be n otifie d if 
re q uire d b y l ocal re g ulati o n. C o m pli a nce 
wit h t he p atie nt di ar y will be dee me d 
a de q u ate if 8 0 % of t he d at a is c a pt ure d 
t hr o u g h V 9. 
T he i n vesti gat or will be res p o nsi ble f or 
m o nit ori n g patie nt c o m plia nce wit h t his 
pr ot oc ol fr o m t he start of t he 
scree ni n g/r u n-i n peri o d t hr o u g h t he 
f oll o w-u p visit. If t he i n vesti gat or or t he 
s p o ns or deter mi nes t hat t he patie nt is n ot 
i n c o m plia nce wit h t he st u d y pr ot oc ol, 
t he i n vesti gat or a n d t he s p o ns or s h o ul d 
deter mi ne w het her t he patie nt s h o ul d be 
wit h dra w n fr o m t he st u d y. T he 
I n de pe n de nt Et hics 
C o m mittee/I nstit uti o nal Re vie w B oar d  
(I E C/I R B) s h o ul d be n otifie d if re q uire d 
b y l ocal re g ulati o n. C o m plia nce wit h t he 
patie nt diar y will be dee me d a de q uate if 
8 0 % of  t he data is ca pt ure d t hr o u g h V 9. 
Clarificati o n . 
5. 9 R a n d o miz ati o n a n d Bli n di n g  
P atie nts w h o meet all i ncl usi o n criteria, n o ne 
of t he e xcl usi o n criteria a n d all of t he 
ra n d o mizati o n criteria will b e ra n d o ml y 
assi g ne d t o 1 of 2 treat me nt gr o u ps or 
place b o  i n a 1: 1: 1 rati o a n d will be stratifie d 
b y pri or ast h ma mai nte na nce t hera p y (I C S 
a n d l o w d ose I C S/ L A B A will be stratifie d 
se p aratel y fr o m t he me di u m a n d hi g h d ose 
I C S/ L A B A [ 2 se p arate strata]) a n d a bs ol ute 
P atie nts w h o meet all i ncl usi o n criteria, 
n o ne of t he e xcl usi o n criteria a n d all of 
t he ra n d o mizati o n criteria will be 
ra n d o ml y assi g ne d t o 1 of 2 treat me nt 
gr o u ps or place b o  i n a 1: 1: 1 rati o a n d 
will be stratifie d b y pri or ast h ma 
mai nte na nce t hera p y (I C S a n d l o w d ose 
I C S/ L A B A will be stratifie d s e paratel y 
fr o m t he me di u m a n d hi g h d ose 
C orrecti o n f or 
c o nsiste nc y wit hi n t he 
pr ot oc ol a n d 
clarificati o n sa m ple size 
ma y be a dj uste d base d 
o n i nteri m a nal ysis.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 1  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
e osi n o p hil c o u nt ( 3 0 0 t o 4 0 0 cells/ μ L, > 4 0 0 
cells/ μ L 3 0 0 t o < 4 0 0  cells/ μ L, 
≥4 0 0  cells/ μ L). A p pr o xi matel y 9 0 patie nts 
w h o ha ve bee n mai ntai ne d o n me di u m or 
hi g h d ose I C S or l o w d ose I C S/ L A B A a n d 
a p pr o xi matel y 2 1 0  patie nts ( m a y be 
a dj uste d b ase d o n t he i nteri m a n al ysis)  o n 
me di u m or hi g h d ose I C S/ L A B A will  be 
i ncl u de d a n d scree ni n g will  m a y  be a dj uste d 
as nee de d t o meet t hese criteri a.  
I C S/ L A B A [ 2 se parate strata]) a n d 
a bs ol ute e osi n o p hil c o u nt ( 3 0 0 t o 
< 4 0 0  cells/ μ L, ≥4 0 0  cells/ μ L). 
A p pr o xi matel y 9 0  patie nts w h o ha ve 
bee n mai ntai ne d o n me di u m or hi g h 
d ose I C S or l o w d ose I C S/ L A B A a n d 
a p pr o xi matel y 2 1 0  patie nts ( ma y be 
a dj uste d base d o n t he i nteri m a nal ysis) 
o n me di u m or hi g h d ose I C S/ L A B A will 
be i ncl u de d  a n d scree ni n g ma y be 
a dj uste d as nee de d t o meet t hese criteria.  
5. 1 1 T ot al Bl o o d V ol u me  
T he t otal bl o o d v ol u me t o be c ollecte d f or 
eac h patie nt i n t his st u d y is a p pr o xi matel y 
1 8 3. 5  1 5 7. 5  m L.  
T he t otal bl o o d v ol u me t o be c ollecte d 
f or eac h patie nt i n t his st u d y is 
a p pr o xi matel y 1 5 7. 5 m L.  
C orrecti o n f or 
miscalc ulati o n of t he 
t otal bl o o d v ol u me 
c ollecte d f or eac h 
patie nt.  
7  Assess me nt of S afet y  
7. 4. 2. 4  C O VI D -1 9 testi n g  
T esti n g of patie nts as y m pt o matic f or 
C O VI D -1 9 acti ve i nfecti o n ma y be 
c o n d ucte d at t he discreti o n of t he 
i n vesti gat or wit hi n 7 2 h o urs of a n y visit 
w here s pir o metr y assess me nts a re t o be 
c o n d ucte d or as re q uire d b y healt h 
a ut h orities, l ocal et hics c o m mittees, or st u d y 
ce nter S O Ps. T he testi n g ma y be c o n d ucte d 
b y t he ce ntral la b orat or y or l ocall y 
de p e n di n g o n feasi bilit y. base d o n R T P C R 
a nal ysis. If a patie nt has a  p P ositi ve tests 
t h at me as ure C O VI D -1 9 a nti ge n test t he 
res ult m ust b e c o nfir me d base d o n  b y  R T -
P C R  a nal ysis. 
T esti n g of patie nts as y m pt o matic f or 
C O VI D -1 9 acti ve i nfecti o n ma y be 
c o n d ucte d at t he discreti o n of t he 
i n vesti gat or wit hi n 7 2 h o urs of a n y visit 
w here s pir o metr y assess me nts are t o be 
c o n d ucte d or as re q uire d b y healt h 
a ut h orities, l ocal et hics c o m mittees, or 
st u d y ce nter S O Ps. T he testi n g ma y be 
c o n d ucte d b y t he ce ntral la b orat or y or 
l ocall y de pe n di n g o n feasi bilit y. T he 
testi n g ma y be c o n d ucte d b y t he ce ntral 
la b orat or y or l ocall y de pe n di n g o n 
feasi bilit y. P ositi ve tests t hat meas ure 
C O VI D -1 9 a nti ge n m ust be c o nfir me d 
b y R T -P C R.  
Clarificati o n.  
9 St atistics  
9. 1 S a m ple Size a n d P o w er C o nsi der ati o ns  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarificati o n . 
9. 5. 4. 1 Pri m ar y Effic ac y A n al ysis  
w here "I G"(a, b) is t he i n verse ga m ma 
w here "I G"(a, b) is t he i n verse ga m ma 
Clarificati o n . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 2  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
distri b uti o n. T o h a n dle missi n g d at a wit h a 
m ulti ple i m p ut ati o n a p pr o ac h,  T the li near 
re gressi o n m o del w hic h  fits a si m ple li near 
m o del fr o m t he data at pre vi o us visits (𝝁𝜶,) 
will be use d:  w here t = baseli ne, 2, 4, …. 1 0  
a n d stratificati o n varia bles s:  
𝝈𝜶|𝝁𝜷,t𝝈∼𝜷𝒂+ 𝝀𝒃𝝀𝑦,𝑖+ 𝑦𝑖
+ 𝑡(0 ,𝜆𝑡
2 ), 
w here T = 1 2 a n d s re prese nts t he 
str atific ati o n v ari a bles. T he  wit h  pri ors f or 
re gressi o n m o del p ar a meters are:  
distri b uti o n. T o ha n dle mi ssi n g data wit h 
a m ulti ple i m p utati o n a p pr oac h, t he 
li near re gressi o n m o del, w hic h fits a 
si m ple li near m o del fr o m t he data at 
pre vi o us visits (𝑦𝑖,), will be us e d:  
𝑌𝑖|𝑦𝑖,𝑇∼𝛼𝑡+ 𝛽𝑡𝑦𝑖,𝑡+ 𝜂𝑠
+ 𝑁(0 ,𝜆𝑡
2 ), 
w here T = 1 2 a n d s re prese nts t he 
stratificati o n varia bles. T he pri ors f or 
re gressi o n m o del para meters are: 
9. 1 3 Pl a n ne d I nteri m A n al ysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 3  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 1 3. 1 T he U n bli n de d I nteri m Effic a cy A n al ysis  
 
 
See ne w w or di n g c ol u m n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 4  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 5  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A p pe n di x A. Cli nic al L a b or at ories a n d ot her De p art me nts a n d I nstit uti o ns  
See ne w w or ki n gs c ol u m n  
A p pe n di x A ( Cli nical) has bee n re vise d 
as descri be d bel o w:  
•  
S p o ns or’s Me dical 
E x pert/ C o ntact P oi nt … F urt her 
I nf or mati o n o n t he St u d y - 
A d de d:  
 
, Res pirat or y R & D 
T e va Bra n de d P har mace utical 
Pr o d ucts R & D, I nc  
 
 
E mail: 
 
•  
St u d y Pri nci ple I n vesti gat or –  
re m o ve d 
•  
P har mac o ge netics/ Bi o mar ker 
E val uati o n –  A d de d: 
U p date d t he c o ntacts f or 
S p o ns or Me dical E x pert 
a n d 
P har mac o ge netics/ Bi o m
ar ker E val uati o n.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 6  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
G E N E WI Z  
1 1 1 C or p orate B o ule var d S uit e  
H L oa di n g D oc k S o ut h 
Plai nfiel d,  
NJ 0 7 0 8 0 U S A  
A p pe n di x B. St u d y Pr o ce d u res a n d Assess me nts  
2. Pr o ce d ures D uri n g t he R u n -i n P eri o d 
( Visit 2; 1 4 ± 2 Da ys) 
•  
patie nt t o c o m plete t he Ast h ma 
C o ntr ol Q uesti o n naire ( A C Q -6) t o 
c o nfir m eli gi bilit y.( A C Q 6 sc ore of 
≥1. 5 is re q uire d)  
2. Pr o ce d ures D uri n g t he R u n -i n P eri o d 
( Visit 2; 1 4 ± 2 Da ys) 
•  
patie nt t o c o m plete t he Ast h ma 
C o ntr ol Q uesti o n naire ( A C Q -6)  
C orrecti o n f or 
c o nsiste nc y wit hi n t he 
pr ot oc ol; A C Q -6 sc ore 
of ≥1. 5 is n ot re q uire d at 
visit 2. P er t he 
ra n d o mizati o n criteria, 
t his is a re q uire me nt at 
visit 3.  
3. Pr oce d ures D uri n g B aseli ne Visit f or 
D o u ble -Bli n d Treat me nt P eri o d ( Visit 3 Da y 
0)  
•  
he ma t ol o g y (bli n de d  C B C wit h 
differe ntial a nal ysis)  
3. Pr oce d ures D uri n g Baseli ne Visit f or 
D o u ble -Bli n d Treat me nt P eri o d ( Visit 3 
Da y 0)  
•  
he mat ol o g y ( C B C wit h 
differe ntial a nal ysis)  
Clarificati o n.  
A p pe n di x D. Et hics  
I nf or me d C o nse nt 
A d ult patie nts wit h a le gall y a cce pta ble 
re prese ntati ve s h o ul d pr o vi de i nf or me d 
c o nse nt acc or di n g t o nati o nal a n d l ocal 
re q uire me nts. 
N ot a p plica ble; te xt was delete d.  
Re m o ve d d ue t o c o nflict 
wit h I ncl usi o n Criteri o n 
a, t he patie nt is ca pa ble 
of gi vi n g si g ne d 
i nf or me d c o nse nt. 
A p pe n di x G. List of Pr o hi bite d M e dic ati o ns  
See ne w w or di n g c ol u m n  
A p pe n di x G ( List of pr o hi bite d 
me dicati o ns) has bee n re vise d as 
descri be d bel o w:  
•  
M o n ocl o nal a nti b o d y t hera p y –  
Was h o ut peri o d u p date t o; 
Pr o hi bite d wit hi n 5 half -li ves 
•  
Le u k otri ne m o difiers  (e g, 
m o ntel u kast, zile ut o n) –  
re m o ve d fr o m ta ble 
•  
I n hale d marij ua na –  Was h o ut 
peri o d u p date t o; 1 m o nt h  
Pr o vi des c o nsiste nc y 
wit h e xcl usi o n criteria 
a n d clarifies t hat 
le u k otrie nes are 
per mitte d d uri n g t he 
st u d y. 
F o ot n ote b Pre vi o us e x p os ure or treat me nt 
wit h m o n ocl o nal a nti b o d y t hera p y w het her 
i n vesti gati o nal or mai nte na nce t hera p y. 
P atie nts wit h hist or y of 
h y perse nsiti vit y/ a n a p h yl a xis t o a n y 
m o n ocl o n al a nti b o d y are e xcl u de d fr o m 
p artici p ati n g. M o n ocl o n al a nti b o dies use d 
t o tre at n o n-i nfl a m m at or y or n o n-
m ali g n a nt c o n diti o ns (ie, mi gr ai ne 
he a d ac he) m a y be all o w e d after 
F o ot n ote b P atie nts wit h hist or y of 
h y perse nsiti vit y/a na p h yla xis t o a n y 
m o n oc l o nal a nti b o d y are e xcl u de d fr o m 
partici pati n g. M o n ocl o nal a nti b o dies 
use d t o treat n o n -i nfla m mat or y or n o n-
mali g na nt c o n diti o ns (ie, mi gr ai ne 
hea dac he) ma y be all o we d aft er 
c o ns ultati o n wit h t he st u d y me dical 
m o nit or. N ote: pre vi o us de pe m o ki m a b 
e x p os ure i s pr o hi bite d wit h o ut 
U p date d t o pr o vi de 
c o nsiste nc y wit h 
e xcl usi o n criteria.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 7  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
c o ns ult ati o n wit h t he st u d y me dic al 
m o nit or. N ote: pre vi o us de pe m o ki m a b 
e x p os ure is pr o hi bite d wit h o ut e xce pti o n.  
e xce pti o n . 
A p pe n di x N. M a n a ge me nt of St u d y Acti vities D uri n g C O VI D -1 9 O ut bre a ks  
Secti o n 1. 3. 1  K n o w n a n d P ote ntial B e nefits 
a n d Ris ks of t he T est I n vesti gati o nal 
Me dici nal Pr o d uct(s)  
T he pr ot oc ol als o states t hat if a patie nt 
e x hi bits cli nical s y m pt o ms t hat ma y i n dicate 
C O VI D -1 9 i nfecti o n after e nt eri n g t he st u d y, 
he/s he s h o ul d be teste d f or acti ve 
C O VI D -1 9. If t he patie nt tests p ositi ve f or 
acti ve C O VI D -1 9 ( p ositi ve a nti g e n testi n g 
m ust be c o nfir me d b y re verse 
tr a nscri pti o n p ol y mer ase c h ai n re acti o n 
[ R T-P C R]),  he/s he ma y c o nti n ue f or 
sc he d ule d visits w he n rec o ver e d (ie, after a 
ne gati ve R T P C R test f or C O VI D 1 9 1 0  d a ys 
after o nset of s y m pt o ms, is afe brile f or 2 4 
h o urs wit h o ut  use of a nti -p yretics a n d 
de m o nstr ates i m p r o ve me nt i n ot her 
s y m pt o ms), ass u mi n g he/s he has n o pr ot oc ol 
vi olati o ns i ncl u di n g use of dis all o we d 
me dicati o ns  (see Secti o n 4. 4). 
Secti o n 1. 3. 1  K n o w n a n d P ote ntial 
Be nefits a n d Ris ks of t he T est 
I n vesti gati o nal Medici nal Pr o d uct(s)  
T he pr ot oc ol als o states t hat if a patie nt 
e x hi bits cli nical s y m pt o ms t hat ma y 
i n dicate C O VI D-1 9 i nfecti o n after 
e nteri n g t he st u d y, he/s he s h o ul d be 
teste d f or acti ve C O VI D-1 9. If t he 
patie nt tests p ositi ve f or acti ve 
C O VI D -1 9 ( p ositi ve  a nti ge n t esti n g 
m ust be c o nfir me d b y re verse 
tra nscri pti o n p ol y merase c hai n reacti o n 
[ R T-P C R]), he/s he ma y c o nti n ue f or 
sc he d ule d visits w he n rec o ver e d (ie, 1 0 
da ys after o nset of s y m pt o ms, is afe brile 
f or 2 4 h o urs wit h o ut use of a nti-p yretics 
a n d de m o nst rates i m pr o ve me nt i n ot her 
s y m pt o ms), ass u mi n g he/s he has n o 
pr ot oc ol vi olati o ns i ncl u di n g use of 
disall o we d me dicati o ns  (see S ecti o n 
4. 4).  
U p date d t o ali g n wit h 
c urre nt g ui deli nes.  
Secti o n 3. 1 Ge neral St u d y Desi g n a n d St u d y 
Sc he matic Dia gra m; Secti o n 3. 5 . Sc he d ule of 
St u d y Pr oce d ures a n d Assess me nts; 
A p pe n di x B. St u d y Pr oce d ures a n d 
Assess me nts b y Visit  
If t he patie nt tests p ositi ve f or acti ve 
C O VI D -1 9, he/s he ma y c o nti n ue f or 
sc he d ule d visits w he n rec o ver e d, as 
s pecifie d a b o ve (ie, after testi n g ne gati ve f or 
acti ve C O VI D 1 9) , ass u mi n g he/s he has n o 
pr ot oc ol vi olati o ns i ncl u di n g use of 
disall o we d me dicati o ns (see S ecti o n 4. 4).  
W here a p pr o priate, re m ote assess me nt of 
safet y via tele p h o ne a n d/ or vi de o c o nfere nce 
( V C), wit h V C bei n g t he preferre d met h o d, 
is rec o m me n de d u ntil t he pati e nt atte n ds 
his/ her ne xt sc he d ule d visit. All ot her tests 
(i ncl u di n g safet y la b orat or y tests, 
p har mac o ki netics, A D A, a n d bi o mar kers) are 
t o be c o n d ucte d o nce t he patie nt ca n ret ur n t o 
t he st u d y ce nter f or his/ her ne xt sc he d ule d 
visi t u nless c ollecte d at a l ocal la b orat or y or 
h o me n urse visit de p e n di n g o n a vaila bilit y 
a n d l ocal re g ulati o n. Sa m ples fr o m patie nts 
wit h k n o w n acti ve  C O VI D -1 9 i nfecti o n 
Secti o n 3. 1 Ge neral St u d y Desi g n a n d 
St u d y Sc he matic Dia gra m; S e cti o n 3. 5. 
Sc he d ule of St u d y Pr oce d ures a n d 
Assess me nts; A p pe n di x B. St u d y 
Pr oce d ures a n d Assess me nts b y Visit  
If t he patie nt tests p ositi ve f or acti ve 
C O VI D -1 9, he/s he ma y c o nti n ue f or 
sc he d ule d visits w he n rec o ver e d, as 
s pecifie d a b o ve, ass u mi n g he/s he has n o 
pr ot oc ol vi olati o ns i ncl u di n g use of 
disall o we d me dicati o ns (see S ecti o n 
4. 4).  
W here a p pr o priate, re m ote assess me nt 
of safet y via tele p h o ne a n d/ or 
vi de oc o nfere nce ( V C), wit h V C bei n g 
t he preferre d met h o d, is rec o m me n de d 
u ntil t he patie nt atte n ds his/ her ne xt 
sc he d ule d visit. All ot her tests (i ncl u di n g 
safet y la b orat or y tests, 
p har mac o ki netics, A D A, a n d 
bi o mar kers) are t o be c o n d ucte d o nce 
t he patie nt ca n ret ur n t o t he st u d y ce nter 
f or his/ her ne xt sc he d ule d visit u nless 
c ollecte d at a l ocal la b ora t or y or h o me 
n urse visit de pe n di n g o n a vail a bilit y a n d 
l ocal re g ulati o n. Sa m ples fr o m patie nts 
U p date d t o ali g n wit h 
c urre nt g ui deli nes.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 8  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n 
f or c h a n ge 
s h o ul d n ot b e c ollecte d. 
wit h k n o w n acti ve C O VI D -1 9 i nfecti o n 
s h o ul d n ot be c ollecte d. 
Secti o n 4. 4 Wit h dra wal Criteria a n d 
Pr oce d ures f or t he P atie nt  
If a patie nt e x hi bits cli nical s y m pt o ms t hat 
ma y i n dicate C O VI D -1 9 i nfecti o n after 
e nteri n g t he st u d y, t he patie nt s h o ul d be 
teste d f or acti ve C O VI D-1 9. If t he patie nt 
tests p ositi ve f or acti ve C O VI D-1 9 
(c o nfir me d b y R T-P C R) , he/s he ma y 
c o nti n ue f or  sc he d ule d visits w he n 
rec o vere d, as s pecifie d a b o ve  (ie, tests 
ne gati ve f or acti ve C O VI D 1 9) , ass u mi n g 
he/s he has n o pr ot oc ol vi olati o ns i ncl u di n g 
use of disall o we d me dicati o ns ( A p pe n di x  G).  
Secti o n 4. 4 Wit h dra wal Criteria a n d 
Pr oce d ures f or t he P atie nt  
If a patie nt e x hi bits cli nical s y m pt o ms 
t hat ma y i n dicate C O VI D-1 9 i nfecti o n 
after e nteri n g t he st u d y, t he patie nt 
s h o ul d be teste d f or acti ve C O VI D-1 9. If 
t he patie nt tests p ositi ve f or acti ve 
C O VI D -1 9 (c o nfir me d b y R T -P C R), 
he/s he ma y c o nti n ue f or sc he d ul e d visits 
w he n rec o vere d, as s pecifie d a b o ve, 
ass u mi n g he/s he has n o pr ot oc ol 
vi olati o ns i ncl u di n g use of disall o we d 
me dicati o ns ( A p pe n di x  G).  
U p date d t o ali g n wit h 
c urre nt g ui deli nes.  
Secti o n  7 Assess me nt of Safet y   
Acti ve C O VI D -1 9 c ases will be m o nit o re d 
t hr o u g h o ut t he st u d y. If a t ot al n u m ber of 
C O VI D -1 9 i nfecti o ns are c o nfir me d i n 
r a n d o mize d p atie nts w h o recei ve d I M P 
( pl ace b o or T E V-5 3 2 7 5) a n d rel ate d t o a n 
S A E t o re ac h a mi ni m u m t h res h ol d ( b ase d 
o n t ot al r a n d o mize d p atie nts, det aile d i n 
t he me dic al m onit o ri n g pl a n), t he 
P h ar m ac o vi gil a nce p h ysici a n i n 
c o ns ult ati o n wit h t he Cli nic al St u d y 
P h ysici a n will deter mi ne if a n u n bli n de d 
re vie w of t he c ases is w arr a nte d t o e ns ure 
p atie nt s afet y. A n y u n bli n de d re vie w will 
be c o n d ucte d b y a p pr o pri at e pers o n nel 
t h at are n ot c o n necte d wit h t he st u d y.  
Secti o n  7 Assess me nt of Safet y  
Acti ve C O VI D -1 9 cases will be 
m o nit ore d t hr o u g h o ut t he st u d y. If a 
t otal n u m ber of C O VI D-1 9 i nfecti o ns 
are c o nfir me d i n ra n d o mize d patie nts 
w h o recei ve d I M P ( place b o or T E V -
5 3 2 7 5) a n d relat e d t o a n S A E t o reac h a 
mi ni m u m t hres h ol d ( base d o n t otal 
ra n d o mize d patie nts, detaile d i n t he 
me dical m o nit ori n g pla n), t he 
P har mac o vi gila nce p h ysicia n i n 
c o ns ultati o n wit h t he Cli nical St u d y 
P h ysicia n will deter mi ne if a n u n bli n de d 
re vie w of t he cases is warra nt e d t o 
e ns ure patie nt safet y. A n y u n bli n de d 
re vie w will be c o n d ucte d b y a p pr o priate 
pers o n nel t hat are n ot c o n nect e d wit h t he 
st u d y. 
T o pr o vi de clarificati o n 
sec o n dar y t o u p date d 
F D A C O VI D -1 9 
g ui da nce.  
Secti o n  7. 4. 2. 4 C O VI D -1 9 T esti n g  
T esti n g of pa tie nts as y m pt o matic f or 
C O VI D -1 9 acti ve i nfecti o n ma y be 
c o n d ucte d at t he discreti o n of t he 
i n vesti gat or wit hi n 7 2 h o urs of a n y visit 
w here s pir o metr y assess me nts are t o be 
c o n d ucte d or as re q uire d b y healt h 
a ut h orities, l ocal et hics c o m mittees, or st u d y 
ce nter st a n d ar d o per ati n g pr oce d ures 
(S O Ps ). T he testi n g ma y be c o n d ucte d b y t he 
ce ntral la b orat or y or l ocall y de p e n di n g o n 
feasi bilit y. P ositi ve tests t h at me as ure 
C O VI D -1 9 a nti g e n m ust be c o nfir me d b y 
R T -P C R.  
Secti o n  7. 4. 2. 4 C O VI D -1 9 T esti n g  
T esti n g of pa tie nts as y m pt o matic f or 
C O VI D -1 9 acti ve i nfecti o n ma y be 
c o n d ucte d at t he discreti o n of t he 
i n vesti gat or wit hi n 7 2 h o urs of a n y visit 
w here s pir o metr y assess me nts are t o be 
c o n d ucte d or as re q uire d b y healt h 
a ut h orities, l ocal et hics c o m mittees, or 
st u d y ce nter sta n dar d o perati n g 
pr oce d ures ( S O Ps ). T he testi n g ma y be 
c o n d ucte d b y t he ce ntral la b orat or y or 
l ocall y de pe n di n g o n feasi bilit y. P ositi ve 
tests t hat meas ure C O VI D-1 9 a nti ge n 
m ust be c o nfir me d b y R T -P C R.  
U p date d t o ali g n wit h 
c urre nt g ui deli nes.  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2 9  
1 6. 2.  
A d mi nistr ati ve Letter 0 1 D ate d 2 3 M arc h 2 0 2 1  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 0  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 1  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 2  
A P P E N DI X  A.  C LI NI C A L L A B O R A T O RI E S A N D O T H E R 
D E P A R T M E N T S A N D I N S T I T U TI O N S 
S p o ns or’s A ut h orize d Re prese nt ati ve  
 
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
, Cli nical De vel o p me nt  
P h o ne: 
 
Cell: 
 
E mail:
 
S p o ns or’s M e dic al E x pert/ C o nt a ct P oi nt desi g n ate d 
b y t he S p o ns or f or F urt her I nf o r m ati o n o n t he 
St u d y  
F or seri o us a d verse e v e nts:  
Se n d b y e mail t o t he a d dres s of t he l ocal safet y 
officer/c o ntract researc h or ga nizati o n ( L S O/ C R O) 
pr o vi de d o n t he S A E re p ort f or m. I n t he e ve nt of 
diffic ult y tra ns mitti n g t he f or m, c o ntact a n e mail 
a d dress as i n dicate d i n t he safet y m a na ge me nt p la n 
( S M P). 
 
, Res pirat or y R & D 
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc  
 
 
E mail:
 
C o ntr act Rese arc h Or g a niz ati o n  
I C O N Cli nical Researc h  
S o ut h C o u ntr y B usi ness P ar k  
Le o par dst o w n  
D u bli n 1 8, Irela n d  
Ce ntr al Cli nic al L a b or at or y  
P P D Cli nical La bs  
2 T esse nee r Dri ve  
Hi g hla n d Hei g hts, Ke nt uc k y, 4 1 0 7 6  
U S A  
Ce ntr al S pir o metr y, e Di a r y, Ce ntr al 
Electr o c a r di o gr a m E v al u ati o n  
e Researc h T ec h n ol o g y G m b H  
Sie b ol dstrasse 3  
9 7 2 3 0 Este nfel d  
Ger ma n y  
Bi o a n al ytic al P h ar m ac o ki netics E v al u ati o n  
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
Bi o a n al ytic al I m m u n o ge nicit y E v al u ati o n  
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
P h ar m ac o ge netics/ Bi o m ar ke r E v al u ati o n  
G E N E WI Z  
1 1 1 C or p orate B o ule var d S uit e  
H L oa di n g D oc k S o ut h Plai nfi el d,  
NJ 0 7 0 8 0 U S A  
R a n d o miz ati o n a n d Tri al S u p pl y M a n a ge me nt 
( R T S M) ve n d or 
P are xel  
2 5 2 0 Meri dia n P ar k wa y  
Researc h Tria n gle P ar k  
S uite 2 0 0, D ur ha m, N C 2 7 7 1 3  
U S A  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 3  
A P P E N DI X  B.  S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S B Y VI SI T  
T he f oll o wi n g st u d y pr oc e d ures a n d assess me nts b y visit are a s u m mar y of t he s pecific 
re q uire me nts liste d i n Ta ble  2  a n d ass ociat e d f o ot n otes.  
1.  Pr o ce d ures f or Scree ni n g ( Visit 1;  U p t o 2 -wee k Peri o d)  
T he scree ni n g visit ( V) ( V 1) will ta ke place n ot m ore t ha n a p pr o xi matel y 4  wee ks bef ore t he 
baseli ne visit ( V 3). T he f oll o wi n g pr oce d ures will be perf or me d at V 1:  
•  o btai n si g ne d a n d d ate d i nf or me d c o ns e nt bef ore a n y st u d y -relate d pr oced ures are 
perf or me d  
•  de m o gra p hics  
•  re vie w i ncl usi o n a n d e x cl usi o n criteria 
•  me dical hist or y  
•  ast h ma hist or y, i ncl u di n g d urati o n, c urre nt me dicati o n, a n d hist or y of e x acer bati o ns 
i n t he last year 
•  pri or me dicati o n a n d tr eat me nt hist or y. N ote: a n y pri or or c o nc o mita nt t hera p y, 
me dicati o n, or pr oce d ure a patie nt has ha d 3 0 d a ys bef ore s cree ni n g will be rec or de d 
i n t he s o urce d oc u m e ntati o n a n d i n t he case re p ort f or m ( C R F) 
•  brief p h ysical e x a mi nati o n i ncl u di n g (at mi ni m u m) c hest, c ar di o vasc ul ar, a b d o mi nal 
a n d ski n e x a mi nati o ns  
•  rec or d hei g ht i n ce nti meters 
•  rec or d wei g ht i n kil o gra ms 
•  p ul m o nar y f u ncti o n testi n g wit h r e versi bilit y:  
p ul m o nar y f u ncti o n testi n g (s pir o m etr y) a n d re versi bilit y testi n g will be c o n d ucte d i n 
t he m or ni n g bet w ee n 0 5 3 0 a n d 1 1 0 0 h o urs. Patie nts are re q uire d t o wit h h ol d ast h ma 
mai nte na nce me di cati o ns f or a p pr o xi matel y 2 4  h o urs pri or t o l u n g f u ncti o n testi n g f or 
o nce dail y me dicati o ns, 1 2  h o urs f or t wice d ail y or m ore fre q u e ntl y d os e d 
me dicati o ns. If t he patie nt has ta ke n ast h ma mai nt e na nce me dica ti o n wit hi n 
2 4 ± 2  h o urs ( dail y d os e d) or 1 2 ± 2  h o urs ( d ose d t wice dail y or m ore fre q u e ntl y) or 
S A B A res c ue me di cati o n wit hi n 6  h o urs of t he pla n ne d p ul m o nar y f u ncti o n testi n g or 
I C S/ L A B A use d as resc u e me dicati o n wit hi n 1 2 h o urs of t he pla n ne d p ul m o nar y 
f u ncti o n testi n g, t he visit m ust be resc he d ule d. Pati e nts w h o meet t he 
pre -al b uter ol/sal b uta m ol l u n g f u ncti o n re q uire me nts a n d de m o nstrate re versi bilit y 
≥1 2 % a n d a 2 0 0  m L i ncrease fr o m pre -al b uter ol/s al b uta m ol F E V 1 a p pr o xi matel y 
3 0  mi n utes after 4 i n halati o ns of al b uter ol/sal b uta m ol H F A M DI ( 9 0  µ g e x -act uat or) 
or e q ui vale nt ma y e nt er t he r u n -i n peri o d if t h e y meet ot her eli gi bilit y re q uire me nts as 
s pecifie d. Patie nts ma y re peat p ul m o nar y f u ncti o n testi n g (s pir o metr y) a n d 
re versi bilit y testi n g o nce d uri n g t he s cree ni n g p eri o d as nee de d t o q u alif y 
•  he mat ol o g y ( C B C wit h differe ntial a nal ysis)  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 4  
•  ser u m c he mistr y 
N ote: a n a bs ol ute e osi n o p hil c o u nt of ≥3 0 0 cells/ μ L is re q uir e d t o be i ncl u de d i n t he 
st u d y. Gi ve n t he k n o w n varia bilit y i n t his meas ure, t he e osi n o p hil c o u nt ( C B C) ma y 
be re peate d o nce d uri n g s cree ni n g (t otal of 2  atte m pts d uri n g scree ni n g peri o d), at t he 
discreti o n of t he i n vesti gat or i n or der t o f ulfill t his i ncl usi o n criteri o n. Hist orical 
e osi n o p hil c o u nts will n ot q ualif y a p atie nt t o parti ci pate . 
La b orat or y  testi n g, me di cal hist or y assess me nts, s er u m c ollecti o n f or bi o m ar kers, 
p h ysical e x a mi nati o n, a n d ot her assess me nts as n ote d i n Ta ble  2  will be c o m plete d 
d uri n g t he s cree ni n g p eri o d a n d ma y be c o n d u cte d at m ore t ha n o ne visit.  
•  o btai n a bl o o d sa m ple f or ser u m bi o mar ker ba n ki n g fr o m patie nts w h o pr o vi de d 
i nf or me d c o nse nt 
•  o btai n a bl o o d sa m ple f or ser ol o g y t esti n g ( He patitis B, He patitis C, a n d h u ma n 
i m m u n o deficie nc y vir us [ HI V] testi n g) 
•  uri nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  ser u m f ollicle sti m ulati n g h or m o n e ( F S H) test, as a p plica ble 
•  o btai n vital si g ns  
•  C O VI D -1 9 s y m pt o ms i n q uir y. T esti n g of patie nts as y m pt o matic f or C O VI D -1 9 
acti ve i nfecti o n ma y b e c o n d ucte d at t he discreti o n of t he i n vesti gat or wit hi n 7 2 h o urs 
of t he visit or as re q uir e d b y healt h a ut h orities, l ocal et hics c o m mittees, or st u d y 
ce nter S O Ps  
2.  Pr o ce d ures D uri n g t he R u n -i n Peri o d ( Visit 2; 1 4 ± 2 D a ys) 
Visit 2 is t he be gi n ni n g of t he r u n -i n peri o d. T he f oll o wi n g pr oce d ures will be perf or me d 
d uri n g t he r u n -i n peri o d: 
•  c o nfir m eli gi bilit y t o e nter t he r u n -i n (i ncl usi o n/e xcl usi o n criteria) 
•  meas ure a n d rec or d vital si g ns  
•  patie nt t o c o m plete t he Ast h ma C o ntr ol Q uesti o n nai re ( A C Q-6)  
•  distri b ute ha n d hel d de vice a n d electr o nic diar y  
•  c o n d uct trai ni n g f or h a n d hel d de vice a n d electr o nic diar y use  
•  dis pe nse resc u e me dicati o n  
•  i n q uire a b o ut cli nical ast h ma e x acer bati o n ( C A E) d uri n g t he s cree ni n g p eri o d 
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 5  
3.  Pr o ce d ures D uri n g B aseli ne Visit f or D o u ble -Bli n d Tre at me nt Peri o d ( Visit  3, 
D a y  0)  
T he baseli ne/r a n d o mizati o n visit ( V 3) will occ ur after a mi ni m u m of 1 4 ± 2  da ys after 
e nteri n g t he r u n -i n p erio d. Patie nts w h o meet t he i ncl usi o n a n d e x cl usi o n criteria t o e nter t h e 
r u n-i n peri o d will c o nti n ue t o V 3, w he n bas eli ne assess me nts will be c o n d ucte d. 
At t his visit t he patie nt’s diar y d ata s h o ul d be re vi e we d pri or t o f or mal l u n g f u ncti o n testi n g, 
la b orator y testi n g a n d t he vari o us q uesti o n naires t o e ns ure c o m plia nce wit h diar y e ntries a n d 
t o deter mi ne if l u n g f u ncti o n, s y m pt o ms a n d resc u e me dicati o n use meet t he ra n d o mizati o n 
criteria. If t he patie nt f ails t o meet t he diar y re q uire me nts, t he patie nt will be c o nsi dere d a 
ra n d o mizati o n fail ure. F urt her pr oce d ures f or V 3 will o nl y b e c o n d u cte d f or patie nts w h o 
meet t he diar y re q uire me nts.  
T he f oll o wi n g pr oce d ures will be perf or me d:  
•  re vie w i ncl usi o n a n d e x cl usi o n criteria 
•  re vie w ra n d o mizati o n criteria 
•  re vie w co m plia n ce wit h diar y a n d st u d y ra n d o mizati o n re q uire me nts  
•  f ull p h ysical e x a mi nati o n (t o i ncl u de, at a mi ni m u m, hea d, e yes, ears, n os e, a n d t hr oat 
[ H E E N T], c hest, car di o v asc ular, a b d o mi nal, s ki n, a n d ne ur ol o gical e x a mi nati o n) 
•  p ul m o nar y f u ncti o n testi n g (s pi r o m etr y) 
•  he mat ol o g y ( C B C wit h differe ntial a nal ysis)  
•  fasti n g ser u m c he mistr y t ests 
•  o btai n a bl o o d sa m ple f or P ha diat o p Aller g y Test a n d T otal I g E  
•  o btai n a bl o o d sa m ple f or p har mac o ge netics ( c o nfir m patie nt has pr o vi de d i nf or me d 
c o nse nt f or t his pr oce d ure)  
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or ser u m a nti -dr u g a nti b o d y ( A D A) assa y  
•  o btai n a bl o o d sa m ple f or bi o mar ker i nterle u ki n 5 (I L -5) a nal ysis  
•  uri nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  1 2 -lea d ele ctr ocar di o gra m (| E C G) i n tri plicat e. E ac h E C G will be ta ke n wit hi n 1 t o 5 
mi n utes of t he pre vi o us o ne.  
•  vital si g ns meas ur e me nts  
•  
 
 
•  c o m plete A C Q -6  
•  Ast h ma C o ntr ol Test ( A C T)  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 6  
•  Sta n dar dize d Ast h ma Q ualit y of Lif e Q uesti o n nair e ( A Q L Q[ S])  
•  
 
•  c o n d uct trai ni n g o n ha n d hel d de vice a n d re vie w diar y us e a n d c o m plia nce  
•  perf or m ra n d o mizati o n a n d t reat me nt assi g n me nt i n i nteracti ve res p o ns e tec h n ol o g y 
(I R T) aft er c o nfir mi n g eli gi bilit y i ncl u di n g di ar y a n d p ul m o nar y f u ncti o n testi n g, 
A C Q 6 sc ore a n d t he re m ai ni n g ra n d o mizati o n criteria ha v e bee n m et.  
•  i n vesti gati o nal me dici nal pr o d uct (I M P) d osi n g (N o te: d osi n g ma y n ot occ ur u ntil all 
cli nical la b orat or y s a m ples, a n d q uesti o n naires h a ve bee n c o m plete d). D os es will be 
a d mi nistere d b y a q ualifi e d healt h care pr o vi der (acc or di n g t o l ocal r e g ulati o ns) w h o 
is pre pare d t o ma n a ge a n a p h yl a xis 
•  p ost d ose  o bser vat i o n peri o d of 1 h o ur 
•  i njecti o n site e val uati o n 
•  dis pe nse resc u e me dicati o n ( if nee d e d)  
•  c ollect res c ue me dicati o n  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
4.  Pr o ce d ures D uri n g D o u ble -Bli n d Tre at me n t Peri o d ( Visits 4 t hr o u g h 7)  
a.  Visit 4 ( Wee k 1 [ D a ys  3 ± 2])  
T he f oll o wi n g pr oce d ures will be perf or me d:  
•  p ul m o nar y f u ncti o n testi n g (s pir o m etr y)  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or ser u m bi o mar ker (I L -5) a nal ysis  
•  dis pe nse/c ollect res c ue m e dicati o n ( if nee de d)  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
b.  Visit 5 ( Wee k 2 [ D a y 1 4 ± 2])  
T he  f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d: 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 7  
•  brief p h ysical e x a mi nati o n (t o i ncl u de, at a mi ni m u m, c hest, car di o v asc ular, 
a b d o mi nal, a n d s ki n e x a mi nati o ns)  
•  p ul m o nar y f u ncti o n testi n g (s pir o m etr y)  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ys is) 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or ser u m bi o mar ker (I L -5) a nal ysis  
•  vital si g ns meas ur e me nts  
•  c o m plete A C Q -6  
•  re vie w c o m plia n ce wit h diar y a n d st u d y re q uir e m e nts 
•  dis pe nse/c ollect res c ue m e dicati o n (if nee de d)  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
c. Visit 6 ( Wee k 4 [ D a y 2 8 ± 2])  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d:  
•  brief p h ysical e x a mi nati o n (t o i ncl u de, at a mi ni m u m, c hest, car di o v asc ular, 
a b d o mi nal, a n d s ki n e x a mi nati o ns)  
•  p ul m o nar y f u ncti o n testi n g (s pir o m etr y)  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  ser u m c he mistr y tests 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or bi o mar ker (I L -5) a nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  vital si g ns meas ur e me nts  
•  c o m plete A C Q -6  
•  c o m plete A C T  
•  re vie w c o m plia n ce wit h diar y a n d st u d y re q uir e m e nts 
•  dis pe nse/c ollect res c ue m e dicati o n (if nee de d)  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 8  
•  C O VI D -1 9 s y m pt o ms i n q uir y  
d.  Visit 7 ( Wee k 8 [ D a y 5 6 ± 2]):  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d:  
•  brief p h ysical e x a mi nati o n (t o i ncl u de, at a mi ni m u m, c hest, car di o v asc ular, 
a b d o mi nal, a n d s ki n e x a mi nati o ns)  
•  p ul m o nar y f u ncti o n testi n g (s pir o m etr y)  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  ser u m c he mistr y tests 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d s a m ple f or bi o mar ker (I L -5) a nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  vital si g ns meas ur e me nts  
•  c o m plete A C Q -6  
•  c o m plete A C T  
•  re vie w c o m plia n ce wit h diar y a n d st u d y re q uir e m e nts 
•  dis pe nse/c ollect res c ue m e dicati o n (if nee de d)  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
5.  Pr o ce d ures D uri n g Visit 8 ( Wee k 1 2 [ D a y 8 4 ± 2])  
T he f oll o wi n g pr oce d ures will be perf or me d:  
•  brief p h ysical e x a mi nati o n  
•  p ul m o nar y f u ncti o n testi n g  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  ser u m c he mistr y tests 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or bi o mar ker (I L -5) a nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  vital si g n meas ur e me nts  
•  
 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 3 9  
•  c o m plete A C Q -6  
•  c o m plete A C T  
•  c o m plete A Q L Q( S)  
•  
 
•  re vie w c o m plia n ce wit h diar y a n d st u d y re q uir e m e nts 
•  dis pe nse/c ollect res c ue m e dicati o n (if nee de d) 
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
6.  Pr o ce d ures D uri n g Visit 9 ( Wee k 1 6 [ D a y 1 1 2 ± 2]) ( E n d of Tre at me nt Visit)  
T he f oll o wi n g pr oce d ures will be perf or me d:  
•  f ull p h ysical e x a mi nati o n (t o i ncl u de, at a mi ni m u m, H E E N T, c hest, c ar di o vasc ular, 
a b d o mi nal, s ki n, a n d ne ur ol o gical e xa mi nati o n)  
•  wei g ht ( k g)  
•  p ul m o nar y f u ncti o n testi n g  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  fasti n g ser u m c he mistr y t ests 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or ser u m a nti -dr u g a nti b o d y ( A D A) assa y  
•  o btai n a bl o o d sa m ple f or bi o mar ker (I L -5) a nal ysis  
•  uri nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  1 2 -lea d E C G 
•  vital si g n  meas ur e me nts  
•  c o m plete A C Q -6  
•  c o m plete A C T  
•  c o m plete A Q L Q( S)  
•  c ollect ha n d hel d d e vice a n d electr o nic diar y  
•  c ollect res c ue me dicati o n  
•  disc uss o n g oi n g ast h ma treat me nt  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 0  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
7.  Pr o ce d ures D uri n g Tele p h o ne F oll o w -u p ( Wee ks 2 0 [ D a y 1 4 0 ± 2], 2 4 [ D a y 1 6 8 ± 2], 
2 8  [ D a y 1 9 6 ± 2]) 
Patie nts will be c o ntacte d a p pr o xi matel y m o nt hl y  b y tele p h o n e t o i n q uire a b o ut C A Es, 
a d verse e ve nts, c o n c o mita nt me dicati o ns a n d C O VI D -1 9 s y m pt o ms.  
8.  Pr o ce d ures D uri n g Visit 1 0 ( Wee k 3 0 [ D a y 2 1 0 ± 5]) ( F oll o w -u p Visit)  
Patie nts will ret ur n t o t he i n vesti gati o nal ce nter, w here u p o n t he f oll o wi n g pr oce d ures will be 
perf or me d : 
•  brief p h ysical e x a mi nati o n (t o i ncl u de, at a mi ni m u m, c hest, car di o v asc ular, 
a b d o mi nal, a n d s ki n e x a mi nati o ns)  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  ser u m c he mistr y tests 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or A D A assa y  
•  o btai n a bl o o d sa m ple f or bi o mar ker (I L -5) a nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  vital si g ns meas ur e me nts  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
9.  U nsc he d ule d Visits  
A n u nsc he d ule d visit ma y be p erf o r me d at a n y ti me d uri n g t he st u d y at t he patie nt’s re q u est 
a n d as dee m e d necessar y b y t he i n vesti gat or. T he date a n d reas o n f or t he u nsc he d ule d visit 
will be rec or de d o n t he C R F as well as a n y ot her d ata o btai ne d fr o m pr oce d ures a n d 
assess me nts.  
Pr oce d ures  p erf or me d d uri n g u nsc h e d ule d visits ma y i ncl u d e:  
•  vital si g ns meas ur e me nt  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 1  
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
Ot her pr oce d ures a n d ass ess me nts ma y b e perf or me d at t he discreti o n of t he i n vesti gat or.  
1 0.   E arl y Wit h dr a w al Visit  
Patie nts w h o wit h dra w c o nse nt or patie nts w h o are u na ble t o c o nti n ue p artici pati o n i n t he 
st u d y s h o ul d partici pate i n t he Earl y Wit h dra wal Visit ( E W V) w he ne ver p ossi ble.  
Pr oce d ures p erf or me d d uri n g t he E W V ma y i ncl u de:  
•  full p h ysical e x a mi nati o n  
•  wei g ht ( k g)  
•  p ul m o nar y f u ncti o n testi n g  
•  he mat ol o g y ( bli n de d C B C wit h differe ntial a nal ysis)  
•  ser u m c he mistr y tests 
•  o btai n a bl o o d sa m ple f or p har mac o ki netics (ser u m I M P c o nce ntrati o n)  
•  o btai n a bl o o d sa m ple f or A D A assa y  
•  o btai n bl o o d f or ser u m bi o mar ker (I L-5) a nal ysis  
•  uri nal ysis  
•  uri ne pre g n a nc y test f or w o me n of c hil d beari n g p ote ntial ( β H C G)  
•  1 2 -lea d E C G 
•  vital si g ns meas ur e me nt  
•  
 
•  c o m plete A C Q -6  
•  c o m plete A C T  
•  c o m plete A Q L Q( S)  
•  
 
•  c ollect ha n d hel d d e vice a n d electr o nic diar y  
•  c ollect res c ue me dicati o n  
•  assess C A Es  
•  i n q uire a b o ut a d verse e v e nts 
•  i n q uire a b o ut c o nc o mita nt me dicati o ns 
•  C O VI D -1 9 s y m pt o ms i n q uir y  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 2  
A P P E N DI X  C.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
Pr ot oc ol A me n d me nts a n d I m p ort a nt Pr ot oc ol De vi ati o ns  
Pr ot oc ol A me n d me nts  
N o c ha n ges fr o m t he fi nal a p pr o ve d (si g ne d) pr ot o c ol will be i nitiate d wit h o ut t he pri or writte n 
a p pr o val or fa v ora ble o pi ni o n of a writte n a me n d me nt b y t he I E C/I R B  a n d nati o nal a n d l ocal 
c o mpete nt a ut h orities, as a p plica ble , e x ce pt w he n necessar y t o a d dress i m me diate safet y 
c o ncer ns t o t he p atie nts or w he n t he c h a n ge i n v ol v es o nl y l o gistics or a d mi nistrati o n. T he 
pri nci pal i n vesti gat or at e ac h i n vesti gati o nal ce nt er, t he c o or di nati n g i n vesti g at or (if a p plica ble), 
a n d t he s p o ns or will si g n t he pr ot oc ol a me n d me nt.  
I m p ort a nt Pr ot oc ol De vi ati o ns 
A n y d e viati o n fr o m t he pr ot oc ol t hat affects, t o a si g nifica nt d e gree, (a) t he safet y, p h ysical, or 
me ntal i nte grit y of t he p atie nts i n t he st u d y a n d/ or ( b) t he scie ntific v al ue of t he st u d y will be 
c o nsi dere d a n i m p orta nt pr ot oc ol de viati o n. I m p orta nt pr ot oc ol de viati o ns ma y i ncl u d e 
n o na d here n ce  o n t he p art of t he patie nt, t he i n vesti gat or, or t he s p o ns or t o pr ot oc ol -s pecifi c 
i ncl usi o n a n d e x cl usi o n criteria, pri mar y o bj ecti ve varia ble criteria, or G C P g ui deli nes; 
n o nc o m plia nce t o I M P a d mi nistrati o n; use of pr o hi bite d me dicati o ns. I m p orta nt pr ot oc ol 
de viati o ns will be i de ntifie d a n d rec or de d b y i n v esti gati o nal ce nt er pers o n nel. All i m p orta nt 
pr ot oc ol de viat i o ns will be re p ort e d t o t he res p o nsi ble I E C/I R B, as re q uire d. 
W he n a n i m p orta nt pr ot oc ol de viati o n is re p orte d, t he s p o ns or will deter mi ne w het her t o 
wit h dra w t he patie nt fr o m t he st u d y or per mit t he patie nt t o c o nti n ue i n t he st u d y, wit h 
d oc u me nte d a p pr o v al fr o m t he me dical e x pert. T he decisi o n will be base d o n e ns uri n g t h e safet y 
of t he patie nt a n d preser vi n g t he i nte grit y of t he st u d y.  
If a patie nt e x perie nces a n a d verse e ve nt or me di cal e mer ge n c y, de viati o ns fr o m t he pr ot oc ol 
ma y b e all o we d o n a cas e -b y -case basis. T o e ns ure patie nt safet y, after t h e e ve nt has sta bilize d or 
treat me nt has bee n a d mi nistere d ( or b ot h), t he i n v esti gat or or ot her p h ysici a n i n atte n da nce m ust 
c o ntact t he p h ysicia n i de ntifie d i n t he Cli nical St u d y Pers o n nel C o ntact I nf or mati o n  secti o n of 
t his pr ot oc ol as s o o n as p ossi ble t o disc uss t he sit uati o n. T he i n vesti gat or, i n c o ns ultati o n wit h 
t he s p o ns or, will deci de w het her t he p atie nt s h o ul d c o nti n ue t o partici pate i n t he st u d y. 
C ha n ges i n t he i n cl usi o n a n d e x cl usi o n criteria of t he pr ot oc ol are n ot  pr os pecti vel y gra nte d b y 
t he s p o ns or. If i n vesti gati o nal ce nter p ers o n nel lear n t hat a patie nt w h o di d n ot meet pr ot oc ol 
i ncl usi o n a n d e x cl usi o n criteria was e ntere d i n a st u d y, t he y m ust i m me diatel y i nf or m t he 
s p o ns or of t he i m p orta nt pr ot oc ol de viati o n. If s uc h patie nt has alrea d y c o m plete d t he st u d y or 
has wit h dra w n earl y, n o acti o n will be ta ke n b ut t he de viati o n will be rec or de d.  
I nf or m ati o n t o St u d y Pers o n nel 
T he i n vesti gat or is res p o nsi ble f or gi vi n g i nf or m ati o n a b o ut t he st u d y t o all pers o n nel me m b ers 
i n v ol ve d i n t he st u d y or i n a n y ele me nt of p atie nt ma na ge me nt, b ot h bef ore starti n g t he st u d y a n d 
d uri n g t he c o urse of t he st u d y (e g, w he n n e w pers o n nel bec o me i n v ol ve d). T he i n vesti gat or m ust 
e ns ure t hat all st u d y pers o n nel are q u alifie d b y e d ucati o n,  e x perie nce, a n d trai ni n g t o perf or m 
t heir s pecific tas k. T h ese st u d y pers o n nel me m bers m ust be liste d o n t he i n vesti gati o nal ce nter 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 3  
a ut h orizati o n f or m, w hic h i ncl u des a clear des cri pti o n of eac h pers o n nel m e m ber’s 
res p o nsi bilities. T his list m ust be u p date d t hr o u g h o ut t he st u d y, as necessar y.  
T he st u d y m o nit or is res p o nsi ble f or e x plai ni n g t he pr ot oc ol t o all st u d y p ers o n nel, i ncl u di n g t he 
i n vesti gat or, a n d f or e ns uri n g t he y c o m pl y wit h t h e pr ot oc ol. 
St u d y M o nit ori n g  
T o e ns ure c o m plia n ce wit h G C P g ui deli nes, t he st u d y m o nit or or re pres e ntati ve is res p o nsi ble 
f or e ns uri n g t hat patie nts ha ve si g n e d t he i nf or m e d c o nse nt f or m a n d t he st u d y is c o n d u cte d 
acc or di n g t o a p plic a ble S O Ps, t he pr ot oc ol, a n d ot her writte n i nstr ucti o ns a n d re g ulat or y 
g ui deli nes.  
T he st u d y m o nit or is t he pri mar y ass ociati o n bet w ee n t he s p o ns or a n d t he i n vesti gat or. T he mai n 
res p o nsi bilities of t he st u d y m o nit ors are t o visit t he i n vesti gat or bef ore, d uri n g, a n d after t he 
st u d y t o e ns ure a d here nce t o t he pr ot oc ol, t o e ns ure t hat all data are c orrectl y a n d c o m pletel y 
rec or de d a n d re p orte d, a n d t o c o nfir m t hat i nf or me d c o nse nt is o btai ne d a n d rec or de d f or all 
patie nts bef ore t h e y parti ci pate i n t he st u d y a n d w he n c ha n ges t o t he c o nse nt f or m are warra nte d, 
i n acc or da nce wit h I E C/I R B a ppr o vals.  
T he st u d y m o nit ors will c o ntact t he i n vesti gat or a n d visit t he i n vesti gati o nal ce nter acc or di n g t o 
t he m o nit ori n g pla n. T he st u d y m o nit or will be per mitte d t o re vie w a n d verif y t he vari o us 
rec or ds ( C R Fs a n d ot her perti ne nt s o urce d ata rec or ds, i ncl u di n g s pecific electr o nic s o urce 
d oc u me nt relati n g t o t he st u d y) t o verif y a d here nce t o t he pr ot oc ol a n d t o e ns ure t he 
c o m plete ness, c o nsiste nc y, a n d acc urac y of t he d ata bei n g rec or de d.  
As part of t he s u per visi o n of st u d y pr o gress, ot her s p o ns or pers o n ne l ma y, o n re q uest, 
acc o m pa n y t h e st u d y m o nit or o n visits t o t he i n vesti gati o nal ce nt er. T he i n vesti gat or a n d 
assisti n g pers o n n el m ust a gree t o c o o perate wit h t he st u d y m o nit or t o res ol ve a n y pr o ble ms, 
err ors, or p ossi ble mis u n dersta n di n gs c o ncer ni n g t he fi n di n gs det ecte d d uri n g t he c o urse of t hese 
m o nit ori n g visits or pr o vi de d i n f oll o w -u p writte n c o m m u nicati o n.  
A u dit a n d I ns pecti o n  
T he s p o ns or ma y a u dit t h e i n vesti gati o nal ce nter t o e val uate st u d y c o n d u ct a n d c o m plia nce wit h 
pr ot oc ols, S O Ps, G C P g ui deli nes , a n d a p plica ble re g ul at or y re q uir e me nts. T he s p o ns or’s Gl o bal 
Cli nical Q ualit y Ass ura n ce, i n de pe n d e nt of Gl o bal S pecialt y De vel o p me nt, is res p o nsi ble f or 
deter mi ni n g t he n ee d f or (a n d ti mi n g of) a n i n vesti gati o nal ce nter a u dit.  
T he i n vesti gat or m ust acce p t t hat c o m pete nt a ut h orities a n d s p o ns or re prese ntati ves ma y c o n d uct 
i ns pecti o ns a n d a u dits t o verif y c o m plia nce wit h G C P g ui deli nes. 
F or details of t he m a na ge me nt of st u d y acti vities d uri n g C O VI D -1 9 o ut br ea ks, see A p pe n di x  N . 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 4  
A P P E N DI X  D.  E T HI C S  
I nf or me d C o nse nt 
T he i n vesti gat or, or a q u alifie d pers o n desi g n ate d b y t he i n vesti gat or, s h o ul d f ull y i nf or m t he 
patie nt of all perti ne nt as pects of t he st u d y, i ncl u di n g t h e writte n i nf or mati o n a p pr o ve d b y t he 
I E C/I R B. All writte n a n d oral i nf or mati o n a b o ut t he st u d y will be pr o vi d e d i n a la n g u a ge as 
n o ntec h nical as practical t o be u n derst o o d b y t he patie nt. T he patie nt s h o ul d be gi v e n a m ple ti me 
a n d o p p ort u nit y t o i n q uir e a b o ut details of t he st u d y a n d t o d eci de w h et her or n ot t o partici pate i n 
t he st u d y. T he a b o ve s h o ul d be detaile d i n t he s o urce d oc u m e nts. I nf or me d c o nse nt ma y be 
c o n d ucte d b y a n electr o nic platf or m (ie,  e C o nse nt) if all o we d b y l ocal re g ulati o n a n d as 
i m pleme nte d d uri n g t he st u d y.  
Writte n i nf or me d c o nse nt will be o btai ne d fr o m eac h patie nt bef ore a n y st u d y s pecific 
pr oce d ures or ass ess me nts are d o ne a n d aft er t he ai ms, met h o ds, a ntici pate d be nefits, a n d 
p ote ntial hazar ds are e x plai ne d. T he patie nt’s willi n g n ess t o partici pate i n t he st u d y will be 
d oc u me nte d i n t he i nf or me d c o nse nt f or m, w hic h will be si g ne d a n d p ers o nall y dat e d b y t he 
patie nt a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n. T he i n vesti gat or will 
kee p t he ori gi nal i nf or m e d c o ns e nt f or ms, a n d c o pies will be gi ve n t o t he patie nts. It will als o be 
e x plai ne d t o t he patie nts t hat t he patie nt is free t o ref use p artici pati o n i n t he st u d y a n d free t o 
wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice t o f ut ure tr eat me nt.  
C o m pete nt A u t h oriti es a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al Re vie w B o ar ds 
Bef ore t his st u d y starts, t he pr ot oc ol will be s u b mitte d t o t he nati o nal c o m pete nt a ut h orit y a n d t o 
t he res pecti ve I E C/I R B f or re vie w. As re q uir e d, t he st u d y will n ot start at a gi v e n i n vesti gati o nal 
ce nter b ef ore t he I E C/I R B a n d c o m p ete nt a ut h orit y (as a p plica bl e) f or t h e i n vesti gati o nal ce nter 
gi ve writte n a p pr o val or a fa v ora ble o pi ni o n.  
C o nfi de nti alit y Re g ar di n g St u d y P atie nts  
T he i n vesti gat or m ust e ns ure t hat t he pri vac y of t he pat ie nts, i ncl u di n g t heir i de ntit y a n d all 
pers o nal me dic al i nf or mati o n, will be mai ntai ne d at all ti mes. I n C R Fs a n d ot her d oc u me nts or 
i ma ge m aterial s u b mitte d t o t he s p o ns or, patie nts will be i de ntifie d n ot b y t heir na mes, b ut b y a n 
i de ntificati o n n u m ber. 
Pers o nal me dical i nf or m ati o n ma y b e re vie we d f or t he p ur p ose of patie nt safet y or f or verif yi n g 
data i n t he s o urce a n d t he C R F. T his re vie w ma y b e c o n d ucte d b y t h e st u d y m o nit or, pr o perl y 
a ut h orize d pers o ns o n be half of t he s p o ns or, Gl o b al Q ualit y Ass ura nc e, or c o m pete nt a ut h orities. 
Pers o nal me dical i nf or m ati o n will al wa ys b e treate d as c o nfi d e ntial.  
Re gistr ati o n of t he Cli nic al St u d y  
I n c o m plia nce wit h nati o nal a n d l ocal r e g ulati o ns a n d i n acc or da nce wit h T e va sta n dar d 
pr oce d ures, t his cli nical st u d y will  be re gistere d o n trials re gistr y we bsites.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 5  
A P P E N DI X  E.  L O S T T O F O L L O W -U P  
A patie nt will be c o nsi dere d l ost t o f oll o w -u p if he/s he re p eate dl y fails t o ret ur n f or sc h e d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he i n v esti gati o nal ce nter.  
T he f oll o wi n g acti o ns m ust b e ta ke n if a p atie nt f ails t o ret ur n t o t he i n vesti gati o nal ce nter f or a 
re q uire d st u d y visit: 
•  t he i n vesti gati o nal c e nter m ust atte m pt t o c o ntact t he patie nt a n d resc he d ul e t he 
misse d visit as s o o n as p ossi ble a n d c o u nsel t he p atie nt o n t he i m p orta nce of 
m ai ntai ni n g t he assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he p atie nt 
wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y.  
•  i n cases i n w hic h t he p atie nt is dee me d l ost t o f oll o w-u p, t he i n vesti gat or or desi g n ee 
m ust ma ke e ver y eff ort t o re gai n c o ntact wit h t he patie nt ( w here p ossi ble, 3  tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he pati e nt’s last k n o w n maili n g a d dress or 
l ocal e q ui vale nt met h o ds). T hese c o nt act atte m pts s h o ul d be d oc u me nte d i n t he 
patie nt’s me dical r ec or d.  
•  s h o ul d t he patie nt c o nti n ue t o be u nreac ha bl e, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of ‘l ost t o f oll o w -u p’.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 6  
A P P E N DI X  F.  LI S T O F I N H A L E D C O R T I C O S T E R OI D T H E R A P Y 
R E Q UI R E D F O R I N C L U SI O N I N T O T H E R U N -I N 
P E RI O D  
Ast h m a m ai nte n a nce ther a p y a 
D ail y d ose ( mc g/ d a y)  
M e di u m d ose  
D ail y d ose ( mc g/ d a y)  
Hi g h d ose  
Fl uticas o ne pr o pi o nate H F A p M DI  
> 2 5 0 mc g ( metere d d ose b) 
> 2 2 0 mc g ( deli vere d d ose)  
> 5 0 0 mc g ( metere d d ose)  
> 4 4 0 mc g ( deli vere d d ose)  
Fl uticas o ne pr o pi o nate D PI  
> 2 5 0 mc g ( metere d d ose)  
> 5 0 0 mc g ( metere d d ose)  
Fl uticas o ne pr o pi o nate D PI 
( A m o nair® / Air D u o® ) 
2 2 6 mc g ( metere d d ose)  
4 6 4 mc g ( metere d d ose)  
Fl uticas o ne f ur oate D PI  
1 0 0 mc g  
2 0 0 mc g  
B ecl o met has o ne di pr o pi o nate D PI 
( E A S Y H A L E R® ) ( Ori o n 
C or p orati o n)  
> 5 0 0 mc g ( metere d d ose)  
> 1 0 0 0 mc g ( metere d d ose)  
B ecl o met has o ne di pr o pi o nate H F A 
p M DI ( Q V A R ®)  
> 2 0 0 mc g ( metere d d ose)  
> 1 6 0 mc g ( deli vere d d ose)  
> 4 0 0 mc g ( metere d d ose)  
> 3 2 0 mc g ( deli vere d d ose)  
B u des o ni de D PI  
> 4 0 0 mc g ( metere d d ose)  
> 3 2 0 mc g ( deli vere d d ose)  
> 8 0 0 mc g ( metere d d ose)  
> 6 4 0 mc g ( deli vere d d ose)  
M o metas o ne f ur oate D PI  
2 0 0 mc g  
4 0 0 mc g  
M o metas o ne f ur oate H F A p M DI  
> 2 0 0 mc g  
> 4 0 0 mc g  
Cicles o ni de H F A p M DI  
> 1 6 0 mc g ( deli vere d d ose)  
> 3 2 0 mc g ( deli vere d d ose)  
S o urce: A da pte d fr o m Gl o bal I nitiati ve f or Ast h ma ( 2 0 2 0) . 
a D oes n ot i ncl u de I C S/ L A B A use d as resc ue me dicati o n.  
b C o ns ult prescri bi n g i nf or mati o n t o deter mi ne metere d or deli vere d d ose if re q uire d.  
D PI = dr y p o w der i n haler H F A = h y dr ofl u or oal ka ne ( H F A); I C S =i n hale d c ortic oster oi d; p M DI = press urize d metere d 
d ose i n haler; L A B A =l o n g -acti n g β 2 a g o nist.  
N O T E: l o w d ose I C S/ L A B A fi xe d d ose c o m bi nati o ns are all o we d.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 7  
A P P E N DI X  G.  LI S T O F P R O HI BI T E D M E DI C A TI O N S  
T y pe of M e dic ati o n or Dr u g a 
W as h o ut Peri o d bef ore St u d y Visit V 2 ( U nless 
Ot her wise  S pecifie d)  
M o n ocl o nal a nti b o d y t hera p y
b 
Pr o hi bite d  wit hi n 5 half -li ves 
A n y ot her i n vesti gati o nal dr u g  
3 0  da ys or 5 half -li ves ( w hic he ver is l o n ger) 
I n hale d or oral cr o m ol y n 
1 4  da ys  
C ortic oster oi ds ( oral, i v, i ntra -artic ular, or i ntra m usc ular)  
3 0  da ys  
T o pical der mat ol o gic c ortic ost er oi ds (i nter me diate t o hi g h 
p ote nc y, e g, C U TI V A T E ®  [ P har ma Der m], E L O C O N®  
[ Sc heri n g C or p orati o n] or tria mci n ol o ne crea m, l oti o n or 
oi nt me nt) c 
1 4  da ys  
Dec o n gesta nts (e g, pse u d oe p he dri ne, 
p he n yl pr o pa n ola mi ne, or p he n yle p hri ne)  
Disc o nti n ue 2 4  h o urs bef ore a n y visit w here 
p ul m o nar y f u ncti o n will be assesse d  
I m m u n os u p pressi ve t hera p y ( e g, met h otrexate, g ol d, or 
azat hi o pri ne)  
6  m o nt hs  
I m m u n ot hera p yd 
I nitiati o n wit hi n 9 0 da ys or cli nicall y mea ni n gf ul 
c ha n ge i n d ose wit hi n 3 0  da ys  
I n hale d a ntic h oli ner gic (a nti-m uscari nic) me dicati o n (e g, 
ti otr o pi u m, u mecli di ni u m, gl yc o p yrr olate)  
7  da ys pri or t o l u n g f u ncti o n t esti n g d uri n g t he 
scree ni n g peri o d a n d t hr o u g h wee k 1 6 ( V 9) 
Oral 2-a g o nists (ta blets, s yr u p)  
7  da ys  
Oral or nasal a nti hista mi nes (e g, l orata di ne, 
di p he n h y dra mi ne, or cetirizi ne)  
C hr o nic sta ble  d oses are all o we d a n d are a ntici pate d t o 
re mai n sta ble t hr o u g h o ut t he treat me nt peri o d 
( wee k 1 6 [ V 9])  
I n hale d marij ua na 
1  m o nt h  
Va pi n g nic oti ne/ marij ua na or a n y ot her s u bsta nce  
2 4 m o nt hs  
a Me dicati o ns pr o hi bite d d uri n g t he st u d y t hr o u g h wee k 1 6 ( V 9) a n d re q uire d was h o ut peri o ds are liste d. P atie nts 
w h o re q uire a d diti o n of ast h ma me dicati o ns d uri n g t he st u d y t o c o ntr ol ast h ma pri or t o t he wee k 1 6 visit ( V 9) are 
all o we d b ut will b e rec or de d as  a pr ot oc ol de viati o n.  
b P atie nts wit h hist or y of h y pers e nsiti vit y/a na p h yla xis t o a n y m o n ocl o nal a nti b o d y are e xcl u de d fr o m partici pati n g. 
M o n ocl o nal a nti b o dies use d t o treat n o n -i nfla m mat or y or n o n-mali g na nt c o n diti o ns (ie, mi grai ne hea dac he) ma y 
be all o we d after c o ns ultati o n wit h t he st u d y me dical m o nit or. N ote: pre vi o us de pe m o ki m a b e x p os ure is 
pr o hi bite d wit h o ut e xce pti o n.  
c L o w -p ote nc y t o pical c ortic ost er oi ds are all o we d a n d ma y i ncl u de (as e xa m ples) h y dr oc ortis o ne cr ea m 2. 5 % or 
l o wer, Des o ni de gel or f oa m 0. 0 5 %, fl u oci n ol o ne acet o ni de crea m or s ol uti o n 0. 0 1 %, or alcl o metas o ne 
di pr o pi o nate 0. 0 5 % crea m or oi nt me nt.  
d P atie nts w h o ha ve bee n treate d wit h i m m u n ot hera p y a n d t he treat me nt is e x pecte d t o re mai n sta ble d uri n g t he 
st u d y ma y partici pate i n t he st u d y. 
I C S =i n hale d c ortic oster oi d; i v =i ntra ve n o us; L A B A =l o n g-acti n g β -a dre ner gic a g o nist ; V = visit. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 8  
A P P E N DI X  H.  C LI NI C A L C RI T E RI A F O R DI A G N O SI N G 
A N A P H Y L A XI S  
As detaile d b y Sa m ps o n et al 2 0 0 6 , a na p h yla xis is br oa dl y defi ne d as, “a s eri o us aller gic reacti o n 
t hat is ra pi d i n o nset a n d ma y ca use d eat h.” Di a g n ostic criteria defi ne d b y t he Nati o nal I nstit ute 
of Aller g y a n d I nfecti o us Disease/ F o o d Aller g y  a n d A na p h yl a xis Net w or k d uri n g t he s ec o n d 
s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yl a xis, m o difie d fr o m Sa m ps o n et al 
2 0 0 6 , are as f oll o ws:  
A na p h yl a xis is hi g hl y li kel y w h e n a n y 1 of t he f oll o wi n g 3 criteria is f ul fille d: 
1.  Ac ute o nset of a n ill ness ( mi n utes t o se veral h o urs) wit h i n v ol ve me nt of t he s ki n, 
m uc osal tiss ue, or b ot h (e g, ge neralize d hi ves, pr urit us or fl us hi n g, s w olle n li ps -t o n g ue, 
u v ula) a n d at least 1 of t he f oll o wi n g:  
− res pirat or y c o m pr o mise (e g, d ys p n ea, w heeze-br o nc h os pas m, stri d or, re d u ce d 
pea k e x pirat or y fl o w [ P E F], h y p o x e mia)  
− re d uce d bl o o d press ur e ( B P) or ass o ciate d s y m pt o ms of e n d-or ga n d ysf u ncti o n 
(e g, h y p ot o nia [c olla pse], s y nc o p e, i nc o nti ne nce) 
2.  T w o or m ore of t h e f oll o wi n g t hat occ ur ra pi dl y af ter e x p os ure t o a likely aller ge n  f or 
t hat patie nt ( mi n utes t o se veral h o urs): 
− i n v ol ve me nt of t he s ki n-m uc osal tiss ue (e g, ge n eralize d hi ves, itc h -fl us h, s w olle n 
li ps-t o n g ue-u v ula)  
− res pirat or y c o m pr o mise (e g, d ys p n ea, w heeze-br o nc h os pas m, stri d or, re d u ce d 
P E F, h y p o x e mia)  
− re d uce d B P or ass ociate d s y m pt o ms (e g, h y p ot o ni a [c olla pse], s y nc o pe, 
i nc o nti ne nce) 
− persiste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o mi nal pai n, v o miti n g)  
3.  Re d uce d B P after e x p os ure t o a k n o w n aller ge n  f or t hat patie nt ( mi n utes t o se veral 
h o urs):  
− a d ults: s yst olic B P of < 9 0  m m  H g or > 3 0 % decrease fr o m t hat pers o n’s baseli ne  
I n t he e ve nt of s us p ecte d se vere h y p erse nsiti vit y (i ncl u di n g a n a p h yla xis), vital si g ns, i ncl u di n g 
o x y ge n s at urati o n a n d res pirati o n rate, will be meas ure d. Ot her assess me nts will be perf or me d at 
t he discreti o n of t he i n vesti gat or. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 4 9  
A P P E N DI X  I. LI S T O F E X A M P L E S O F O P P O R T U NI S TI C 
I N F E C TI O N S 
•  Bact erial e nteric i nfecti o ns  
•  Bart o n ell osis  
•  Ca n di diasis (e x cl u di n g v ul v o va gi nal ca n di diasis)  
•  C ha gas dis ease  
•  C occi di oi d o m yc osis  
•  Cr y pt oc o cc osis  
•  Cr y pt os p ori di osis  
•  C yst ois os p oriasis (f or merl y is os p oriasis)  
•  C yt o m e gal o vir us d iseas e 
•  He patitis B  
•  He patitis C  
•  Her pes si m ple x 
•  Hist o plas m osis  
•  H u ma n h er pes vir us -8  
•  H u ma n p a pill o ma vir us  
•  Leis h ma ni asis  
•  Malaria  
•  Micr os p ori di osis  
•  M yc o b acte ri u m a vi u m 
•  M yc o b acteri u m t u berc ul osis  
•  P ne u m oc ystis p ne u m o ni a  
•  Pr o gressi ve m ultif ocal le u k oe nce p h al o pat h y/J C vir us i nfecti o n  
•  S y p hilis  
•  Talar o m yc osis (f or merl y pe nicilli osis)  
•  T ox o pl as m a g o n dii  
•  Varicella -z oster  
A n y s us pe cte d o p p ort u nistic i nfecti o ns (ie, i nfecti o ns t hat occ ur m ore fre q ue ntl y a n d are m ore 
se vere t h a n e x pecte d) are t o be re p orte d. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 0  
F urt her details are a vaila ble i n “ G ui deli nes f or Pre ve nti o n a n d Treat me nt of O p p ort u nistic 
I nfecti o ns i n A d ults a n d A d olesce nts wit h HI V”. A vaila ble at: 
htt ps://ai dsi nf o. ni h. g o v/ g ui deli nes/ ht ml/ 4/a d ult -a n d-a d olesce nt -o p p ort u nistic -i nfecti o n/ 0). 
Access e d 2 0 -Ma y -2 0 2 0. C o m m u nit y -ac q uire d p n e u m o nia a n d v ul v o va gi n al ca n di diasis were 
re m o ve d fr o m t he list a b o ve as t he y ma y be e x pecte d i n t he st u d y p atie nt p o p ulati o n. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 1  
A P P E N DI X  J.  P H A R M A C O G E N E TI C A S S E S S M E N T S  
Bl o o d sa m ples ( 2. 5  m L) f or p har mac o ge n etic assess me nts will be c ollecte d at t he ra n d o mizati o n 
visit ( V 3) fr o m all patie nts i n t he st u d y w h o si g n e d t he i nf or me d c o nse nt f or m (I C F) f or t he 
p har mac o ge netic ass ess me nts . Eac h patie nt wil l si g n a se p arat e I C F f or t h e ge netic assess me nt. 
Partici pati o n i n t he ge n etic researc h is o pti o nal. Patie nts w h o d o n ot wis h t o partici pate i n t he 
ge n etic res earc h ma y still partici pate i n t he st u d y. P har mac o ge n etic data will be ke pt c o nfi de ntial 
a n d st ore d se p aratel y.  
P har mac o ge n etic assess me nt p ote ntiall y i ncl u des t he ass ociati o n of D N A variati o ns i n t he I L -5 
ge n e wit h cli nical r es p o nses t o T E V -5 3 2 7 5 (e g, efficac y, p h ar mac o ki netics, t olera bilit y, a n d 
safet y feat ures or disease s usce pti bilit y a n d se verit y feat ur es). 
I L-5 se q ue n ce ma y b e st u die d i n a d diti o n t o ot her p ote ntial ge n es i n relati o n wit h res pirat or y 
disease or wit h t he T E V -5 3 2 7 5. T he fi nal list of ge nes t hat mi g ht be i n v esti gat e d will be select e d 
at a later sta ge bef ore t he a nal ysis t o all o w t he list t o be u p date d wit h ne w s cie ntific i nf or mati o n. 
Ge netic a n al ysis c o ul d als o i ncl u de a se q ue n ci n g of t he w h ole ge n o me if re q uire d. 
P har mac o ge n etic assess me nt ma y b e perf or me d base d o n st u d y res ults. Sa m ples will be use d 
o nl y f or i n v esti gati o ns r elate d t o res pirat or y dise ases a n d/ or res p o ns e t o rel ate d i n vesti gati o nal 
dr u gs. P har mac o ge n o mic assess me nt ma y occ ur after t his cli nical st u d y is c o m plete d.  
Details o n pr ocess es f or c ollecti o n a n d s hi p me nt of t hese sa m ples ca n be f o u n d i n t he st u d y 
refere nce ma n ual.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 2  
A P P E N DI X  K.  P R O D U C T C O M P L AI N T S  
Cli nic al Pr o d uct C o m pl ai nts  
A cli nical pr o d uct c o m pl ai nt is defi ne d as a pr o ble m or p ote ntial pr o ble m wit h t he p h ysical 
q ualit y or c h aracteristics of cli nical I M P s u p plies or cli nical de vice s u p plies use d i n a cli nical 
researc h st u d y s p o ns ore d b y Te v a. E x a m ples of a pr o d uct c o m plai nt i ncl u de b ut are n ot li mite d 
t o: 
•  s us pecte d c o nta mi nati o n 
•  q uesti o na ble sta bilit y (e g, c ol or c ha n ge, fla ki n g, cr u m bli n g, etc.)  
•  defecti ve c o m p o ne nts  
•  missi n g or e xtra u nits (e g, pri mar y c o ntai ner is recei ve d a t t he i n vesti gati o n al ce nter 
wit h m ore or less t ha n t h e desi g n ate d n u m ber of u nits i nsi de)  
•  i nc orrect pac k a gi n g, or i nc orrect or missi n g la beli n g/la bels 
•  u ne x pecte d or u na ntici pate d taste or o d or, or b ot h  
•  de vice n ot w or ki n g c orrectl y or a p pears defecti ve i n s o me ma n ner 
Eac h i n vesti gati o nal ce nt er will be res p o nsi ble f or re p orti n g a p ossi ble cli ni cal pr o d uct c o m plai nt 
b y c o m pleti n g t he pr o d u ct c o m plai nt f or m pr o vi d e d b y T e va a n d e maili n g it t o 
cli nical. pr o d uctc o m plai nts @te va p har m.c o m wit hi n 4 8  h o urs of bec o mi n g a ware of t he iss ue.  
F or c o m plai nts i n v ol vi n g a de vice or ot her retrie v a ble ite m, it is re q uire d t hat t he de vice ( or 
ite m) be se nt bac k t o t he s p o ns or f or i n vesti gati ve testi n g w he n e ver p ossi bl e. F or c o m plai nts 
i n v ol vi n g a n I M P, all rel e va nt sa m ples (e g, t h e re mai n der of t he patie nt’s I M P s u p pl y) s h o ul d be 
se nt bac k t o t he s p o ns or f or i n vesti gati ve t esti n g w he ne ver p ossi ble.  
1.  Pr o d uct C o m pl ai nt I nf or m ati o n Nee de d fr o m t he I n vesti g ati o n al Ce nter  
I n t he e ve nt t hat t he pr o d uct c o m plai nt f or m ca n n ot be c o m plete d, t he i n vesti gat or will pr o vi de 
t he f oll o wi n g i nf or m ati o n, as a vaila ble: 
•  i n vesti gati o nal c e nter n u m ber a n d pri nci p al i n vesti gat or n a me 
•  na me, p h o ne n u m ber, a n d a d dress of t he s o urce of t he c o m plai nt  
•  cli nical pr ot oc ol n u m ber  
•  patie nt i de ntifier ( patie nt st u d y  n u m ber) a n d c orres p o n di n g visit n u m bers, if 
a p plica ble  
•  patie nt n u m ber, b ottle, a n d kit n u m bers (if a p plica ble) f or d o u bl e -bli n d or o pe n -la bel 
st u dies 
•  pr o d uct a vaila ble f or ret ur n Yes/ N o  
•  pr o d uct was ta k e n or use d acc or di n g t o pr ot o c ol Yes/ N o  
•  descri pti o n or  nat ur e of c o m plai nt  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 3  
•  ass ociate d seri o us a d vers e e ve nt Y es/ N o  
•  cli nical s u p plies u n bli n de d (f or bli n de d st u dies) Yes/ N o  
•  date a n d na m e of pers o n recei vi n g t he c o m plai nt  
N ote: Re p orti n g a pr o d uct c o m plai nt m ust n ot be dela ye d e v e n if n ot all t he re q uire d i nf or mati o n 
ca n be o btai n e d i m me diatel y. K n o w n i nf or mati o n m ust be re p orte d i m me di atel y. T h e s p o ns or 
will c olla b orate wit h t he i n vesti gat or t o o btai n a n y o utsta n di n g i nf or mati o n.  
2.  H a n dli n g of I n vesti g ati o n al Me dici n al Pr o d uct(s) at t he I n vesti g ati o n al Ce nter(s)  
T he i n vesti gat or is res p o nsi ble f or retai ni n g t he pr o d uct i n q uesti o n i n a l ocati o n se parat e fr o m 
t he i n vesti gat or’s cli nical st u d y s u p plies. T he s p o ns or ma y re q uest t hat t he i n vesti gat or ret ur n t he 
pr o d uct f or f urt her e val u ati o n a n d/ or a nal ysis. If t his i s necessar y, t he cli nical st u d y m o nit or or 
desi g nee will pr o vi de t he i nf or mati o n nee de d f or ret ur ni n g t he I M P.  
If it is deter mi ne d t hat t he i n vesti gati o nal ce nter m ust ret ur n all I M P, t he s p o ns or will pr o vi de t he 
i nf or mati o n nee de d t o h a n dle t he ret ur n. 
T h e i nte grit y of t he ra n d o mizati o n c o de a n d c orres p o n di n g bli n de d cli nical s u p plies will be 
mai ntai ne d w he ne v er p ossi ble. A seri o us a d verse e ve nt or t he p ote ntial f or a pr o d uct q ualit y 
pr o ble m e xisti n g be y o n d t he sc o pe of t he c o m plai nt ma y be a reas o n t o u n b li n d t he cli nical 
s u p plies f or a n affecte d p atie nt. 
3.  A d verse E ve nts or Seri o us A d verse E ve nts Ass oci ate d wit h a Pr o d uct C o m pl ai nt  
If t here is a n a d verse e v e nt or seri o us a d verse e v e nt d ue t o pr o d uct c o m plai nt, t he pr ot oc ol 
s h o ul d be f oll o we d f or rec or di n g an d re p orti n g ( Secti o n  7. 1. 2  a n d Secti o n  7. 1. 5. 3 , res pecti vel y). 
4.  D oc u me nti n g a Pr o d uct C o m pl ai nt  
T he i n vesti gat or will rec or d i n t he s o urce d o c u me ntati o n a descri pti o n of t he pr o d uct c o m plai nt, 
a n d a n y acti o ns ta ke n t o res ol ve t he c o m plai nt a n d t o preser ve t h e safet y of t he patie nt. O nce t he 
c o m plai nt has bee n i n vesti gate d b y t he s p o ns or a n d t he i n vesti gat or, if necessar y, a n e v e nt 
cl os ure letter ma y b e se nt t o t he i n vesti gati o nal ce nter w here t he c o m plai nt ori gi nate d or t o all 
i n vesti gati o nal c e nters usi n g t he pr o d u ct. 
Me dical de vice i nci de nts, i ncl u di n g t h ose res ulti n g fr o m malf u ncti o ns of t he de vice, m ust be 
detecte d, d o c u me nte d, a n d re p orte d b y t he i n v esti gat or t hr o u g h o ut t he st u d y.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 4  
A P P E N DI X  L.  D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  
Direct Access t o S o urce D at a a n d D oc u me nts  
All patie nt data m ust ha ve s u p p orti ve ori gi nal s o urce d oc u m e ntati o n i n t he me dical rec or ds, or 
e q ui vale nt, bef ore t he y are tra nscri b e d t o t he C R F. Data ma y n ot be rec or de d directl y o n t h e C R F 
a n d c o nsi dere d as s o ur ce data u nless t he s p o ns or pr o vi des writte n i nstr ucti o ns s pecif yi n g w hic h 
dat a are per mitte d t o be rec or de d directl y t o t he C R F.  
If data are pr ocess e d fr o m ot her i nstit uti o ns or b y ot her mea ns (e g, cli nical la b orat or y, ce ntral 
i ma ge ce nter, or ele ctr o ni c diar y data) t he res ults will be se nt t o t he i n vesti gati o nal ce nter, w here 
t he y will be retai ne d b ut n ot tra nscri be d t o t he C R F, u nless ot her wise n ot e d i n t he pr ot oc ol. 
T hese data m a y als o be s e nt electr o nicall y t o t he s p o ns or ( or or ga nizati o n perf or mi n g data 
ma na ge me nt).  
T he me dical e x perts, st u d y m o nit ors, a u dit ors, I E C/I R B, a n d i n s pect ors fr o m c o m pete nt 
a ut h orit y ( or t heir a ge nts) will be gi ve n direct access t o s o urce dat a a n d d o c u me nts (e g, me dical 
c harts/rec or ds, la b orat or y test res ults, pri nt o uts, vi de ota pes) f or s o urce data verificati o n, pr o vi de d 
t hat patie nt c o nfi de ntialit y is mai ntai ne d i n acc or da nce wit h nati o nal a n d l ocal re q uir e me nts.  
T he i n vesti gat or m ust mai ntai n t he ori gi nal rec or ds (ie, s o urce d o c u me nts) of eac h p atie nt’s dat a 
at all ti mes.  T he i n vesti gat or m ust mai ntai n a c o nfi de ntial patie nt i de ntificati o n list t hat all o ws 
t he u na m bi g u o us i de ntifi cati o n of eac h patie nt. 
D at a C ollecti o n  
Data will be c ollecte d usi n g C R Fs t hat are s pecificall y desi g ne d f or t his st u d y. T he d ata c ollecte d 
o n t h e C R Fs will be ca pt ure d i n a cli nical d ata ma na ge me nt s yste m ( C D M S) t hat meets t he 
tec h nical r e q uire me nts d escri be d i n 2 1 C F R Part  1 1 ( U S A) a n d d oc u m e nts of ot her c o n cer ne d 
c o m pete nt a ut h orities. Bef ore usi n g t he C D M S, it will be f ull y vali date d a n d all use rs will 
recei v e trai ni n g o n t he s yste m a n d st u d y-s p ecific trai ni n g. After t he y are trai ne d, users will be 
pr o vi de d wit h i n di vi d ual s yste m access ri g hts.  
Data will be c ollecte d at t he i n vesti gati o nal ce nter b y a p pr o priatel y d esi g n ate d a n d trai ne d 
pers o n nel,  a n d C R Fs m ust be c o m plete d f or eac h patie nt w h o pr o vi de d i nf or me d c o nse nt. Patie nt 
i de ntit y s h o ul d n ot be discer ni ble fr o m t he data pr o vi de d o n t he C R F. 
If data are pr ocess e d fr o m ot her s o urces (e g, ce ntral la b orat or y, bi o a nal ytical la b orat or y, ce ntr al 
i ma ge ce nter, ele ctr o nic diar y d ata, el ectr o nic p atie nt -re p ort e d o utc o me [e P R O] ta blet), t hese 
data will be se nt t o t he i n vesti gati o nal ce nter, w here t he y will be retai ne d b ut n ot tra nscri be d t o 
t he C R F, u nless ot her wis e n ote d i n t he pr ot oc ol. T hese data ma y als o be se nt electr o nicall y t o t he 
s p o ns or ( or or ga niz ati o n perf or mi n g data m a na ge me nt). All patie nt data m ust ha ve s u p p orti ve 
ori gi nal s o ur ce d oc u m e ntati o n i n t he me dical rec or ds, or e q ui vale nt, bef ore t he y are tra nscri be d 
t o t he C R F. Data ma y n ot be recor de d directl y o n t he C R F a n d c o nsi dere d as s o urce d ata u nless 
t he s p o ns or pr o vi des writte n i nstr ucti o ns s pecif yi n g w hic h d ata are per mitte d t o be rec or de d 
directl y t o t he C R F.  
F or patie nts w h o e nter a st u d y b ut d o n ot meet e ntr y criteria, at a mi ni m u m, data f or scree ni n g 
fail ure reas o n, de m o gra p h y, a n d a d verse e v e nts fr o m t he ti me of i nf or me d c o nse nt will be 
e ntere d i n t he C R F.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 5  
D at a Q u alit y C o ntr ol  
Data Ma na ge me nt is res p o nsi ble f or t he acc urac y, q ualit y, c o m plete ness, a n d i nter nal 
c o nsiste nc y of t he dat a fr o m t his st u d y. O versi g ht will be carri e d o ut as des cri be d i n t he 
s p o ns or’s S O Ps f or cli nic al st u dies. Da y t o da y dat a ma na ge m e nt tas ks f or t his st u d y are 
dele gate d t o a c o ntract or ga niz ati o n, a n d t hese f u ncti o ns ma y be carrie d o ut as descri be d i n t he 
S O Ps f or cli nical st u dies at t hat or ga nizati o n. T hese S O Ps will be re vie we d b y t he s p o ns or b ef ore 
t he start of data ma n a ge me nt acti vities. 
Data will be verifie d b y t he st u d y m o nit or usi n g t he data s o urce, a n d re vie we d b y d ata 
ma na ge me nt usi n g b ot h a ut o mate d  l o gi cal c hec ks a n d ma n ual re vi e w. Dat a i de ntifie d as 
err o ne o us, or data t hat are missi n g, will be referre d t o t he i n vesti gati o nal ce nter f or res ol uti o n 
t hr o u g h d ata q ueri es. A n y necessar y c ha n ges will be ma de i n t he cli nical d ata base, a n d data 
re vie w a n d v ali dati o n pr oce d ures will be re peate d as nee de d. Data fr o m e xter nal s o urces will be 
c o m pare d wit h t he i nf or mati o n a vaila ble i n t he C D M S a n d a n y discre p a ncies will be q uerie d.  
A p plica ble ter ms will be c o de d acc or di n g t o t he c o di n g c o n v e nti o ns f or t his st u d y.  
At t he c o ncl usi o n of t he st u d y, t he C D M S a n d all ot her st u d y d ata will be l oc ke d t o f urt her 
a d diti o ns or c orrecti o ns. L oc ki n g t he st u d y d ata re prese nts t he ac k n o wle d ge me nt t hat all data 
ha ve bee n ca pt ur e d a n d c o nfir me d as acc urate. All data c ollecte d wi ll be a p pr o ve d b y t he 
i n vesti gat or at t he i n vesti gati o nal ce nter. T his a p pr o val ac k n o wle d ges t he i n vesti gat or’s re vie w 
a n d acce pta n ce of t he d at a as bei n g c o m plete a n d acc urate.  
Arc hi vi n g of C ase Re p ort F or ms a n d S o urce D oc u me nts  
S p o ns or Res p o nsi bilities  
T he ori gi nal C R Fs will be arc hi v e d b y t he s p o ns or. I n v esti gati o nal ce nter -s pecific C R Fs will be 
pr o vi de d t o t he res pecti ve i n vesti gati o nal ce nters f or arc hi vi n g.  
I n v esti gat or Res p o nsi bilities 
T he i n vesti gat or m ust mai ntai n all writte n a n d electr o nic rec or ds , acc o u nts, n otes, re p orts, a n d 
data relat e d t o t he st u d y a n d a n y a d diti o nal rec or ds re q uire d t o be mai ntai n e d u n der c o u ntr y, 
state/ pr o vi nce, or nati o nal a n d l ocal la ws, i ncl u di n g, b ut n ot li mite d t o: 
•  f ull case hist ories 
•  si g ne d i nf or me d c o nse nt f or ms 
•  patie nt i de ntificati o n lists  
•  case re p ort f or ms f or eac h patie nt o n a per -visit basis  
•  data fr o m ot her s o urces (e g, ce ntr al la b orat or y, bi oa nal yti cal la b orat or y, ce ntral i ma ge 
ce nter, electr o nic di ar y)  
•  safet y re p orts 
•  fi na ncial discl os ure re p orts/f or ms 
•  re p orts of recei pt, use, a n d dis p ositi o n of t he I M Ps 
•  c o pies of all c orres p o n de nce wit h s p o ns or, t he I E C/I R B, a n d a n y c o m p ete nt a ut h orit y  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 6  
T he i n vesti gat or will retai n all rec or ds relate d t o t he st u d y a n d a n y a d diti o nal rec or ds re q uir e d, as 
i n dicate d b y t he pr ot oc ol a nd acc or di n g t o a p plica ble la ws a n d re g ulati o ns, u ntil t he C R O or 
s p o ns or n otifies t he i nstit uti o n i n writi n g t hat rec or ds ma y b e destr o ye d. If, after 2 5  years fr o m 
st u d y c o m pleti o n, or earlier i n t he cas e of t he i n vesti gati o nal ce nt er cl osi n g or g oi n g o ut of 
b usi ness, t he i n vesti gat or reas o na bl y d eter mi nes t hat st u d y rec or d rete nti o n has bec o me u n d ul y 
b ur de ns o me, a n d s p o ns or has n ot pr o vi de d writte n n otificati o n of destr ucti o n, t he n t he 
i n vesti gat or ma y s u b mit a writte n re q u est t o s p o ns or at least 6 0 da ys b ef ore a n y pl a n ne d 
dis p ositi o n of st u d y rec or ds. After recei pt of s uc h re q uest, t he s p o ns or ma y ma ke arra n ge m e nts 
f or a p pr o priate arc hi val or dis p ositi o n, i ncl u di n g re q uiri n g t hat t he i n v esti gat or deli ver s uc h 
rec or ds t o t he s p o ns or. T he i n vesti gat or s hall n otif y t he s p o ns or of a n y acci de ntal l oss or 
destr ucti o n of st u d y rec or ds.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 7  
A P P E N DI X  M.  P U B LI C A TI O N P O LI C Y  
All u n p u blis he d i nf or mati o n gi ve n t o t he i n vesti gat or b y t he s p o ns or s h all n ot be p u blis he d or 
discl ose d t o a t hir d part y wit h o ut t he pri or writte n c o nse nt of t he  s p o ns or. 
T he res ults of t his st u d y ma y b e p u blis he d or pres e nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or bef ore s u b missi o n. 
T his all o ws t he s p o ns or t o pr otect pr o priet ar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
T he s p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults: 
“ Rec o m me n dati o ns  f or t he C o n d uct, Re p orti n g, E diti n g, a n d P u blicati o n of Sc h olarl y W or k i n 
Me dical J o ur nals” ( w w w.I C MJ E. or g). P u blicati o n of  t he res ults will occ ur i n a ti mel y ma n ner 
acc or di n g t o a p plic a ble re g ul ati o ns. I n acc or da n ce wit h sta n dar d e dit orial a n d et hical practice, 
t he s p o ns or will ge n erall y s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot 
as i n di vi d ual i n vesti gati o nal ce nter d ata. I n t his case, a c o or di n ati n g i n vesti gat or , if a p plica bl e, 
will be desi g nat e d b y m ut ual a gree m e nt.  
A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nt er nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p r e q uire m e nts:  
•  s u bsta ntial c o ntri b uti o ns t o t he c o nce pti o n or desi g n of t he w or k; or t he ac q uisiti o n, 
a nal ysis, or i nter pret ati o n of data f or t h e w or k  
•  drafti n g t he w or k or re visi n g it criticall y f or i m p ort a nt i ntellect ual c o nte nt  
•  fi nal a p pr o val of t h e versi o n t o be p u blis he d  
•  a gree m e nt t o be acc o u nta ble f or all as pects of t he w or k i n e ns uri n g t hat q uesti o ns 
relate d t o t he acc urac y or i nte grit y of a n y part of t he w or k are a p pr o priatel y 
i n vesti gate d a n d res ol ve d 
T he p u blicati o ns c o m mittee esta blis he d b y t h e s p o ns or will o versee t his pr ocess. A d diti o nal 
p u blicati o ns ma y f oll o w. P olicies re gar di n g t he p u blicati o n of t he st u d y res ults are defi ne d i n t he 
fi na ncial a gree me nt. 
N o pate nt a p plicati o ns base d o n t he res ults of t he st u d y ma y be m a de b y t he i n vesti gat o r n or m a y 
assista nce be gi ve n t o a n y t hir d part y t o ma k e s uc h a n a p plicati o n wit h o ut t he writte n 
a ut h orizati o n of t he s p o ns or.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 8  
A P P E N DI X  N.  M A N A G E M E N T O F S T U D Y A C TI VI TI E S D U RI N G 
C O VI D -1 9 O U T B R E A K S  
T his a p pe n di x a d dresses t he m o dificati o ns i n st u d y c o n d u ct d uri n g c or o na vir us disease 2 0 1 9 
( C O VI D-1 9) o ut brea ks.  
T he c ha n ges will be effecti ve f or t he p eri o d of t he C O VI D -1 9 o ut brea ks a n d will be 
i m ple me nte d e x cl usi vel y at t he sites i m pacte d b y C O VI D-1 9. W he n t he sit uati o n at s pecific 
sites/c o u ntries all o ws t he ret ur n t o re g ular st u d y acti vities, t he f ull pr ot oc ol will g o ver n t he st u d y 
f or all sites i ncl u di n g t h ose w h o were i m pacte d b y C O VI D-1 9.  
T he f oll o wi n g s ecti o ns of t he pr ot oc ol are affecte d:  
Secti o n  1. 3. 1 . K n o w n a n d P ote nti al Be nefits a n d Ris ks of t he Test I n vesti g ati o n al 
Me dici n al Pr o d uct(s)  
I n t he e ve nt of a n e mer ge nc y sit uati o n (e g, C O VI D-1 9 o ut brea ks), t he s p o ns or, i n cl ose 
c olla b orati o n wit h t he i n vesti gat ors, w ill deter mi ne if t he be nefit-ris k assess me nt re mai ns 
p ositi ve as a w h ole, a n d will assess a n y a d diti o nal ris ks o n a patie nt -b y -pati e nt basis. T he 
meas ures o utli ne d i n t his a p pe n di x are ai me d at f urt her miti gati n g t he a d diti o nal ris ks i n a n 
e mer ge n c y sit uat i o n. 
It s h o ul d be n ote d t h at patie nts dia g n ose d wit h C O VI D-1 9 will be e x cl u de d fr o m e nteri n g r u n -i n 
peri o d a n d will n ot be ra n d o mize d i nt o t he st u d y as t he y w o ul d meet e xcl usi o n criteri o n “ d”, 
w hic h e x cl u des patie nts wit h “cli nical s y m pt o ms t hat ma y i n dica te C O VI D-1 9 i nfecti o n, a n d/ or 
patie nts w h o i n t he i n vesti gat or’s o pi ni o n are at hi g h ris k of e x p os ure t o C O VI D -1 9 wit hi n 
4  wee ks bef ore s cree ni n g or d uri n g s cree ni n g/r u n -i n”. S uc h patie nts will be teste d f or acti ve 
C O VI D -1 9 i nfecti o n a n d will o nl y b e i ncl u de d if t he y t est ne gati ve f or C O VI D -1 9. F urt her m ore, 
e x cl usi o n criteri o n “c” sti p ulates:  
•  T he patie nt has a s us p ect e d bacterial or viral i nfecti o n (i ncl u di n g C O VI D -1 9) of t he 
u p per or l o wer res pir at or y tract, si n us, or mi d dle ear t hat has n ot res ol v e d at le ast 
2  wee ks bef ore t h e scree ni n g peri o d. N ote: Patie nts w h o de vel o p a n u p per res pirat or y 
i nfecti o n/l o wer res pirat or y i nfecti o n ( U RI/ L RI) d uri n g t he r u n-i n peri o d ma y rescree n 
2  wee ks after s y m pt o ms res ol ve a n d u n d er g o C O VI D -1 9 testi n g as o utli ne d i n 
e x cl us i o n criteria “ d”. 
Ol der a d ults a n d pe o pl e of a n y a ge w h o ha v e seri o us u n derl yi n g me di cal c o n diti o ns, i ncl u di n g 
m o derate t o se v ere ast h ma, ma y be at hi g her ris k f or a m ore se v ere C O VI D -1 9 c o urse w he n 
i nfecte d (Ce nt ers f or Disea se C o ntr ol a n d Pre v e nti o n [ C D C] C or o na vir us [ C O VI D-1 9] ). 
T he pr ot oc ol als o states t hat if a patie nt e x hi bits cli nical s y m pt o ms t hat ma y i n dicat e C O VI D -1 9 
i nfecti o n after e nteri n g t h e st u d y, h e/s he s h o ul d be teste d f or acti ve C O VI D-1 9. If t he patie nt 
tests p ositi ve f or acti ve C O VI D -1 9  ( p ositi ve a nti ge n testi n g m ust be c o nfir me d b y re verse 
tra nscri pti o n p ol y merase c hai n reacti o n [R T -P C R] ), he/s he ma y c o nti n ue f or sc he d ule d visits 
w he n rec o vere d (ie, 1 0 d a ys after o ns et of s y m pt o ms, is afe brile f or 2 4 h o urs wi t h o ut use of a nti-
p yretics a n d de m o nstr ate s i m pr o ve me nt i n ot her s y m pt o ms), ass u mi n g h e/s he has n o pr ot oc ol 
vi olati o ns i ncl u di n g use of disall o we d me dicati o ns  (see Secti o n 4. 4 ). 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5 9  
Secti o n 3. 1. Ge ner al St u d y Desi g n a n d St u d y Sc he m atic Di a g r a m; Secti o n 3. 5. Sc he d ule of 
St u d y Pr oce d ures a n d Assess me nts; A p pe n di x B. St u d y Pr oce d ures a n d Assess me nts b y 
Visit  
I n t he e ve nt of a n e mer ge nc y sit uati o n (e g, C O VI D-1 9 o ut brea ks), i n cas e a patie nt ca n n ot r et ur n 
t o t he cli nic f or t he sc h e d ule d visits (e g, d ue t o q u ara nti ne, is olati o n, patie nt’s c o ncer n, acti ve 
C O VI D -1 9 i nfecti o n, or cl os ure of t he site cli nic), t he patie nt will c o nti n ue wit h dail y ha n d -h el d 
s pir o metry me as ure m e nts a n d e -diar y c o m pleti o n, a n d sc he d ule d a d verse e ve nt a n d c o nc o mita nt 
me dicati o n m o nit ori n g. Patie nt q uesti o n naires ma y be c o m plete d wit h t he assista nce of st u d y 
ce nter p ers o n nel w h ere p er mitte d b y lice nsi n g a gree me nts.  If t he p atie nt tests p ositi ve f or acti ve 
C O VI D -1 9, he/s he m a y c o nti n ue f or sc he d ule d visits w he n rec o v ere d , as s p ecifie d a b o v e, 
ass u mi n g he/s he h as n o pr ot oc ol vi olati o ns i ncl u di n g use of disall o we d me dicati o ns (see 
Secti o n  4. 4 ). W here a p pr o priate, re m ote assess me nt of safet y via tele p h o ne a n d/ or 
vi de oc o nfere nce ( V C), wit h V C bei n g t he preferre d met h o d, is rec o m me n d e d u ntil t he patie nt 
atte n ds his/ her ne xt sc he d ule d visit. All ot her tests (i ncl u di n g safet y la b orat or y tests, 
p har mac o ki netics, A D A, a n d bi o mar kers) are t o be c o n d ucte d o nce t he patie nt ca n ret ur n t o t he 
st u d y ce nt er f or his/ her n e xt sc he d ule d visit u nless c ollecte d at a l o cal la b orat or y or h o me n urse 
visit de pe n di n g o n a v aila bilit y a n d l ocal r e g ulati o n. Sa m ples fr o m patie nts wit h k n o w n acti ve 
C O VI D -1 9 i n fecti o n s h o ul d n ot be c ollecte d. 
I n t he e ve nt t hat a p atie nt c o m pletes t he r u n-i n b ut ca n n ot c o me t o t he site f or t he da y of 
ra n d o mizati o n ( D o R) visit f or ra n d o mizati o n (e g, d ue t o q uara nti ne, is olati o n, patie nt's c o n cer n, 
or cl os ure of t h e site cli nic), it ma y b e p ossi ble t o e xte n d t he d urati o n of r u n -i n o n a cas e-b y -case 
basis, f oll o wi n g disc ussi o n bet wee n t he i n v esti gat or a n d t he s p o ns or st u d y p h ysicia n. 
Rescree ni n g of t he patie nt will als o be all o we d.  
M o dificati o ns t o ot her pr oce d ures a n d assess me nts (electr o car di o gra m [ E C G], la b orat or y s a m ple 
c ollecti o n, p har mac o ki netic sa m pli n g, etc.) will be perf or me d p er i m ple me nte d c o nti n ge nc y 
meas ures acc or di n g t o s p o ns or i nstr ucti o ns a n d t he c orres p o n di n g ma n ual. F or e x a m ple, if 
ce ntral la b orat or y sa m ples ca n n ot be c ollecte d f or safet y assess me nts, sites ma y h a ve patie nts 
visit a l ocal refere nce la b orat or y or dis patc h a h o me healt h n urse t o perf or m t he assess me nts, b ut 
o nl y aft er c o ns ultati o n wit h t he s p o ns or a n d as all o we d b y l ocal r e g ulati o n. 
T hese meas ures will be i m ple me nte d o n a case -b y -case b asis, a n d o nl y w he n a n d w here t he y are 
warra nte d d ue t o t he e mer ge nc y sit uati o n. Prefera bl y, t he ori gi nal pr ot o c ol i nstr ucti o ns will be 
f oll o we d w he n e ver t he m o difie d i nstr ucti o ns are n ot re q uire d.  
Secti o n 4. 2 P atie nt E xcl usi o n Criteri a; Secti o n 4. 3. R a n d o miz ati o n Criteri a; Secti o n 5. 7. 
Pri o r a n d C o nc o mit a nt Me dic ati o n or T her a p y  
I n t he e ve nt t hat ne w C O VI D-1 9 t hera pies or v acci nes bec o me a v aila ble d uri n g t he st u d y, t he 
eli gi bilit y crit eria a n d list of pr o hi bite d me dicati o ns ca n be u p dat e d t o refl ect t hese 
de vel o p me nts. If a p atie nt recei ves n e w C O VI D -1 9 t hera pies n ot i n c o m plia nce wit h t he 
eli gi bilit y criteria a n d list of pr o hi bite d me dicati o ns c urre nt at t he ti me of t he patie nt’s 
parti ci pati o n i n t he st u d y, t he i n vesti gat or a n d s p o ns or will disc uss h o w t o pr ocee d o n a 
case-b y -cas e basis.  
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 6 0  
Secti o n 4. 4. Wit h dr a w al Criteri a a n d Pr oce d ures f or t he P atie nt  
If a patie nt e x hi bits cli nical s y m pt o ms t hat ma y i n dicate C O VI D-1 9 i nfecti o n after e nte ri n g t he 
st u d y, t he patie nt s h o ul d be teste d f or acti ve C O VI D-1 9. If t h e patie nt tests p ositi ve f or acti ve 
C O VI D -1 9  (c o nfir me d b y R T-P C R) , he/s he ma y c o nti n ue f or sc h e d ule d visits w he n rec o v ere d, 
as s pecifie d a b o ve,  ass u mi n g he/s he has n o pr ot oc ol vi olati o ns i ncl u di n g use of disall o we d 
me dicati o ns ( A p pe n di x  G ). 
W here a p pr o pri ate, r e m ote assess me nt of safet y via tele p h o ne a n d/ or V C, wit h V C bei n g t he 
p referre d m et h o d, is rec o m me n de d u ntil t he patie nt atte n ds his/ her ne xt sc he d ule d visit. All ot her 
tests (i ncl u di n g safet y la b orat or y tests, p har mac o ki netics, A D A, a n d bi o m ar kers) are t o be 
c o n d ucte d o nce t he patie nt ca n ret ur n t o t he st u d y ce nter f or his/ h er ne xt sc he d ule d visit.  
Secti o n 4. 5 Re pl ace me nt of P atie nts  
I n t he e ve nt of a n e mer ge nc y sit uati o n (e g, C O VI D-1 9 o ut brea ks), if t he pr o p orti o n of patie nts 
w h o ter mi nate t he st u d y earl y d ue t o r eas o ns ot her t ha n l oss of ast h ma c o ntr ol e x cee ds t he 
a ntici pate d 1 5 %, t he n u m ber of patie nts t o be ra n d o mize d ma y be i ncreas e d t o e ns ure t he 
tar gete d n u m ber of c o m pleters per ar m. 
Secti o n 6. Assess me nt of Effic ac y  
I n t he e ve nt of a n e mer ge nc y sit uati o n (e g, C O VI D-1 9 o ut brea ks ), if a p atie nt ca n n ot ret ur n t o 
t he cli nic f or t he sc h e d ul e d visits (e g, d u e t o q uara nti ne, is olati o n, patie nt’s c o ncer n, acti ve 
C O VI D -1 9 i nfecti o n, or cl os ure of t he site cli nic), re m ote assess me nt of efficac y via tele p h o ne 
call a n d/ or V C, wit h V C bei n g t he preferre d met h o d, ma y b e all o we d. U pl oa de d electr o nic diar y 
data f or resc u e me dicati o n usa ge, da yti me a n d ni g ht -ti me ast h ma s y m pt o m sc ores, a n d u pl o a de d 
ha n d -hel d s pir o metr y d ata will be re vie we d re m otel y. T ele p h o ne/ V C ass ess me nt b y t he 
i n vesti gat or will be assesse d at t he sc he d ul e d visit. Cli nic-base d f orce d e x pirat or y v ol u me i n 
1  sec o n d ( F E V1) assess m e nts will n ot be p ossi ble u nless a satisfact or y h o m e s pir o metr y de vice 
t hat is ge nerall y e q ui vale nt ca n be i m ple me nte d. T he res ults of t he cli nical ast h ma e x acer bati o n 
( C A E) i n q uir y will be e ntere d directl y i nt o t he C R F per t he us ual pr ocess. Q uesti o n naire dat a 
will be c o m plete d a n d e ntere d i nt o t he C R F per t h e us ual pr ocess or will be c ollecte d b y 
vali date d pa per q uesti o n naire a n d e ntere d i nt o t he data base b y t he st u d y p ers o n nel.  
Prefera bl y, t h e ori gi nal pr ot oc ol i nstr ucti o ns will be f oll o we d w he n e ver t he ne w i nstr ucti o ns are 
n ot re q uire d.  
T hese meas ures will be i m ple me nte d o n a case -b y -case b asis, a n d o nl y w he n a n d w here t he y are 
warra nte d d ue t o t he e mer ge nc y sit uati o n. Prefera bl y, t he ori gi nal pr ot o c ol i nstr ucti o ns will be 
f oll o we d w he n e ver t he m o difie d i nstr ucti o ns are n ot re q uire d.  
Secti o n 7. Assess me nt of S afet y  
I n t he e ve nt of a n e mer ge nc y sit uati o n (e g, C O VI D-1 9 o ut brea ks), if a p atie nt ca n n ot ret ur n t o 
t he cli nic f or t he sc h e d ul e d visits (e g, d u e t o q uara nti ne, is olati o n, patie nt’s c o ncer n, acti ve 
C O VI D -1 9 i nfecti o n, or cl os ure of t he site cli nic), re m ote assess me nt of s afet y (as well as 
i n q uiries re gar di n g a d verse e ve nts a n d us e of c o n c o mita nt me dicati o n) via tele p h o ne call a n d/ or 
V C, wit h V C bei n g t he preferre d m et h o d, ma y be all o we d. T he res ults will be directl y e ntere d 
i nt o t he C R F per t he us u al pr ocess. 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 6 1  
M o dificati o ns t o ot her pr oce d ures a n d assess me nts ( E C G, la b orat or y s a m ple c ollecti o n, 
p har mac o ki netic s a m pli n g, et c.) will be perf or me d per i m ple me nte d c o nti n ge n c y meas ures 
acc or di n g t o s p o ns or i nstr ucti o ns a n d t he c orres p o n di n g st u d y refere nce m a n ual. F or e x a m ple, if 
ce ntral la b orat or y sa m ples ca n n ot be c ollecte d f or safet y assess me nts, sites ma y h a ve patie nts 
visit a l ocal refere nce la b orat or y or dis patc h a h o me healt h n urse t o perf or m t he assess me nts, b ut 
o nl y aft er c o ns ultati o n wit h t he s p o ns or  a n d as all o we d b y l ocal r e g ulati o n . 
T hese meas ures will be i m ple me nte d o n a case -b y -case b asis, a n d o nl y w he n a n d w here t he y are 
warra nte d d ue t o t he e mer ge nc y sit uati o n. Prefera bl y, t he ori gi nal  pr ot o c ol i nstr ucti o ns will be 
f oll o we d w he n e ver t he m o difie d i nstr ucti o ns are n ot re q uire d. 
Acti ve C O VI D -1 9 cas es will be m o nit ore d t hr o u g h o ut t he st u d y. If a t otal n u m ber of C O VI D -1 9 
i nfecti o ns are c o nfir me d i n ra n d o mize d patie nts w h o recei v e d I M P ( place bo or T E V -5 3 2 7 5) a n d 
relate d t o a n S A E t o r eac h a mi ni m u m t hres h ol d ( base d o n t otal ra n d o mize d patie nts, detaile d i n 
t he me dical m o nit ori n g pla n ), t he P har mac o vi gila nce p h ysicia n i n c o ns ultati o n wit h t he Cli nical 
St u d y P h ysicia n will deter mi ne if a n u n bli n d e d re vie w of t he cases is warra nte d t o e ns ure patie nt 
safet y. A n y u n bli n de d re vie w will be c o n d ucte d b y a p pr o priate p ers o n nel t hat are n ot c o n necte d 
wit h t he st u d y.  
Secti o n 7. 4. Cli nic al L a b or at or y Tests  
If ce ntr al la b orat or y sa m ples ca n n ot be c ollecte d f or safet y ass ess me nts, sites ma y h a ve p atie nts 
visit a l ocal refere nce la b orat or y or arra n ge a h o m e healt h visit t o perf or m t he assess me nts aft er 
disc ussi o n wit h a n d a p pr o val b y t he s p o ns or  a n d as all o we d b y l ocal r e g ulati o n . 
Secti o n 7. 4. 2. 4. C O VI D -1 9 Testi n g  
Testi n g of patie nts as y m pt o matic f or C O VI D -1 9 acti ve i nfecti o n ma y b e c o n d ucte d at t he 
discreti o n of t he i n vesti gat or wit hi n 7 2 h o urs of a n y visit w here s pir o metr y ass ess me nts are t o b e 
c o n d ucte d or as re q uir e d b y healt h a ut h orities, l ocal et hics c o m mit tees, or st u d y ce nter sta n d ar d 
o perati n g pr oce d ures ( S O Ps ). T he testi n g ma y b e c o n d ucte d b y t he ce ntral la b orat or y or l ocall y 
de pe n di n g o n feasi bilit y.  P ositi ve tests t hat meas ure C O VI D -1 9 a nti ge n m ust be c o nfir me d b y 
R T -P C R.  
Secti o n 7. 5. P h ysic al E x a mi n at i o ns; Secti o n 7. 6. Vit al Si g ns; Secti o n 7. 7. 
Electr oc a r di o gr a p h y; Secti o n 7. 8. Assess me nt of L oc al T oler a bilit y a n d P ai n  
After c o ns ultati o n wit h t he s p o ns or a n d as all o we d b y l ocal re g ulati o n, a t h o me healt h visits ma y 
be use d t o perf or m safet y assess me nts  s uc h as p h ysical e xa mi nati o ns, vital si g ns, E C G, a n d l ocal 
t olera bilit y, a n d n ursi n g assess me nts t o deter mi ne a n y n e w a d v erse e ve nts. T he patie nt will 
c o nti n ue wit h dail y h a n d -hel d s pir o metr y meas ure me nts a n d e -diar y c o m pleti o n d uri n g t his ti me.  
Secti o n 8 . Assess me nts of P h ar m ac o ki netics, I m m u n o ge nicit y, Bi o m a r kers, a n d 
P h ar m a c o ge netics  
If p har mac o ki netic, i m m u n o ge ni cit y, a n d/ or bi o mar ker sa m ples ca n n ot b e c ollecte d d ue t o 
li mitati o ns i n t he a bilit y t o carr y o ut t he pr oce d ure or li mitati o ns i n st ora ge a n d s hi p me nts, t he 
sa m ples will n ot be c ollecte d f or t h ose res pecti ve visits. St u d y sa m ples c oll ecte d fr o m c o nfir me d 
C O VI D -1 9 p ositi ve patie nts d uri n g t he st u d y, wit h c o nfir mati o n eit her b ef ore or after t he s a m ple 
c ollecti o n, will be ke pt at t he ce ntral la b ora t or y a n d will n ot be s hi p pe d t o Te va bi oa nal ytical 
la b orat ories n or a nal yz e d. Te va bi oa nal ytical la b orat ories will be i nf or me d b y t he s p o ns or wit hi n 
V V- 0 0 0 5 7 3 4 9 v 3. 0

 
Place b o -C o ntr olle d Safet y a n d  P D St u d y – Persiste nt Ast h ma  
Cli nical St u d y Pr ot oc ol  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 6 2  
a p pr o xi matel y 1 wee k of a n y p atie nts c o nfir me d C O VI D -1 9 p ositi ve after sa m ples ha ve bee n 
c ollecte d.  
Secti o n  9. St atistics  
Se nsiti vit y a n d s u p ple m e ntar y a nal yses ma y b e c o n d ucte d t o e val uat e t he i m pact of t he c h a n ge t o 
re m ote m o nit ori n g (t ele p h o ne calls a n d V C visits) a n d t he i m pact of C O VI D-1 9 o ut brea ks  o n 
st u d y e n d p oi nts, e g, as f oll o ws: 
1.  A se nsiti vit y a nal ysis w hic h will i ncl u de eli gi ble h o me -base d efficac y assess me nt val ues 
f or t h ose w h o ca n n ot be re m otel y e val uate d d u e t o o ut brea k e mer ge n c y sit uati o ns. 
2.  A se nsiti vit y a nal ysis w hic h will treat t he efficac y assess me nt val ues c ollecte d t hr o u g h 
re m ote e val u ati o n as missi n g a n d a p pl y t he us u al missi n g data ha n dli n g a p pr oac h 
(refere n ce-b ase d m ulti ple i m p utati o n ). 
I n a d diti o n, t he a m o u nt of h o me-base d effi cac y assess me nts a n d missi n g d ata d ue t o t he o ut brea k 
will be m o nit ore d c o nti n u o usl y a n d t he s a m ple siz e will be r e-assess e d t o e ns ure s ufficie nt st u d y 
p o wer.  
Details of t he s u p ple me ntar y a n d se nsiti vit y a n al yses will be prese nte d i n t he statistical a nal ysis 
pla n  or a d de n d u m t here of, f oll o wi n g a bli n de d re vie w meeti n g pri or t o data base l oc k.  
Secti o n 1 0. Q u alit y C o ntr o l a n d Q u alit y Ass ur a nce 
De viati o ns fr o m t he st u d y c o n d u ct d ue t o e mer ge nc y sit uati o ns (e g, C O VI D -1 9 o ut brea ks), 
i ncl u di n g i m ple me nte d c o nti n ge nc y m eas ures a n d t heir i m pact (e g, p atie nt disc o nti n uati o n fr o m 
t he st u d y, alter nati ve pr oce d ures us e d t o c ollect critical safet y a n d/ or efficac y d ata, et c.), will be 
descri be d i n t he a p pr o pri ate secti o ns of t he cli nical st u d y re p ort ( C S R) as a p plica ble.  
A p pe n di x C. Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce  
I m p ort a nt Pr ot oc ol De vi ati o ns 
De viati o ns fr o m t he st u d y c o n d u ct d ue t o e mer ge nc y sit uati o ns (e g, C O VI D -1 9 o ut brea ks), 
i ncl u di n g i m ple me nte d c o nti n ge nc y m eas ures a n d t heir i m pact (e g, p atie nt disc o nti n uati o n fr o m 
t he st u d y, alter nati ve pr oce d ures us e d t o c ollect critical safet y a n d/ or efficac y d ata, et c.), will be 
descr i be d i n t he a p pr o pri ate secti o ns of t he C S R as a p plica ble. 
St u d y M o nit ori n g  
I n case of a n e m er ge n c y sit uati o n (e g, C O VI D-1 9 o ut brea ks ), m o nit ors ma y n ot be a ble t o access 
t he i n vesti gati o nal c e nters f or o n-site visits i n a ti mel y ma n ner. A re m ote m o nit ori ng ris k 
miti gati o n pla n will be utiliz e d f or sites w here o n -site m o nit ori n g visits are n ot per mitte d d ue t o 
a n i ncrease d p u blic healt h ris k, i n acc or da nce wit h I R B/I E C a p pr o v al. Det ails will be pr o vi de d i n 
t he m o nit ori n g pla n. 
V V- 0 0 0 5 7 3 4 9 v 3. 0