Conditions: Asthma
Keywords: Persistent Eosinophilic Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 97
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the efficacy of TEV-53275 administered subcutaneously (sc) in adult participants with persistent asthma and an eosinophilic phenotype compared to placebo. A secondary objective is to evaluate the efficacy of TEV-53275 compared to placebo assessed by lung function, asthma symptoms, rescue medication use, and quality of life measures. Another secondary objective is to evaluate the safety and tolerability of TEV-53275 administered sc in adult participants with persistent asthma and an eosinophilic phenotype compared with placebo, and lastly, to evaluate the immunogenicity of TEV-53275 administered sc in adult participants with persistent asthma and an eosinophilic phenotype.

Detailed description:
The planned study duration is approximately 16 months.

The total duration of study participation is approximately 34 weeks including up to a 2-week screening period, a 2-week run-in period, a 16-week treatment period, and a follow-up visit 14 weeks after the final treatment visit.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: TEV-53275 Dose A intervention 2: TEV-53275 Dose B intervention 3: Placebo
Intervention descriptions: intervention 1: subcutaneous (sc) injection intervention 2: subcutaneous (sc) injection intervention 3: Matching subcutaneous (sc) placebo injection

Protocol document:
Prot_000.pdf: 
 
 
 
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. 
 
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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  
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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  
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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  
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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  
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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  
 
 
 
 
 
 
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
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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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 8  
O bjecti ves  
E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
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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 
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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  
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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 
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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  
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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


 
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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


 
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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 
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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 
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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.  
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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 . 
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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. 
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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 
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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 
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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 
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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. 
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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 
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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 
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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:  
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•  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.  
 
 
 
 
 
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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)  
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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 
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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 
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•  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.  
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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  
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•  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  
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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. 
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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. 
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•  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 . 
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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 
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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 
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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. 
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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 . 
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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. 
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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. 
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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. 
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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.  
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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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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


 
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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.  
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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.  
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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. 
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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. 
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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. 
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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. 
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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.  
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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  
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•  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.  
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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.  
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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  
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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.  
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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.  
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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 ). 
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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.  
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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. 
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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 
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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. 
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St atistic al A n al ysis Pl a n  
 
 
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  
 
 
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S A P A p pr o val Date: 2 2 J u ne 2 0 2 2  


 
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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  
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: N ot a p plic a ble  
 
 
 
A p pr o v al D ate: 2 2  J u ne  2 0 2 2  
 
S p o ns or  
Te v a Br a n de d P h ar m ace utic al  
Pr o d ucts R & D, I nc .  
1 4 5 Br a n d y wi ne P ar k w a y  
West C hester, Pe n ns yl v a ni a 1 9 3 8 0  
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Pre p are d b y:  
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St u d y N o.:  
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St u d y Title:  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 a c 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   
 
St atistic al A n al ysis Pl a n f or:  
 
 I nteri m A n al ysis  
 
 I nte gr ate d S u m m ar y of Effic ac y 
 
 Fi n al A n al ysis  
 
 
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, Te v a Gl o b al St atistics  
 
 
 
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T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L  ..........................................................................2  
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  ..................................................8  
I N T R O D U C TI O N .........................................................................................................................1 0  
1.  
S T U D Y E N D P OI N T S  ................................................................................................1 1  
1. 1.  
Pri mar y a n d Sec o n dar y O bjecti ves a n d E n d p oi nts  .....................................................1 1  
1. 2.  
 .......................................................................1 2  
1. 3.  
Esti ma n d f or Pri mar y Efficac y E n d p oi nt  ...................................................................1 4  
1. 3. 1.  
Pri mar y Esti ma n d  .......................................................................................................1 4  
1. 3. 2.  
Sec o n dar y Esti ma n d  ...................................................................................................1 5  
2.  
S T U D Y D E SI G N  .......................................................................................................1 6  
2. 1.  
Ge neral  Desi g n  ...........................................................................................................1 6  
2. 2.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................1 7  
2. 3.  
Data M o nit ori n g C o m mittee  .......................................................................................1 8  
2. 4.  
Sa m ple Siz e a n d P o wer C o nsi derati o ns  .....................................................................1 8  
2. 5.  
Se q ue nce of Pla n n e d A n al yses  ...................................................................................1 9  
2. 5. 1.  
Pla n ne d I nteri m A nal yses  ...........................................................................................1 9  
2. 5. 2.  
Fi nal A nal yses a n d Re p orti n g  .....................................................................................1 9  
3.  
A N A L Y SI S S E T S  ......................................................................................................2 0  
3. 1.  
I nte nt-t o-Treat A nal ysis Set  ........................................................................................2 0  
3. 2.  
M o difie d I nte nt -t o-Treat A nal ysis Set  ........................................................................2 0  
3. 3.  
Safet y A nal ysis Set  .....................................................................................................2 0  
3. 4.  
Per -Pr ot oc ol A nal ysis Set  ...........................................................................................2 0  
3. 5.  
P har mac o ki netic A n al ysis Set  ....................................................................................2 0  
3. 6.  
A nti -dr u g A nti b o d y A n al ysis Set  ...............................................................................2 1  
4.  
G E N E R A L I S S U E S F O R D A T A A N A L Y SI S  ..........................................................2 2  
4. 1.  
Ge neral  ........................................................................................................................2 2  
4. 2.  
S pecificati o n of Baseli ne Val ues  ................................................................................2 2  
4. 3.  
Ha n dli n g Wit h dra wals a n d Missi n g Data  ...................................................................2 2  
4. 4.  
St u d y Da ys a n d Visits  .................................................................................................2 2  
5.  
S T U D Y P O P U L A TI O N  .............................................................................................2 4  
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5. 1.  
Ge neral  ........................................................................................................................2 4  
5. 2.  
Patie nt Dis p ositi o n  ......................................................................................................2 4  
5. 3.  
De m o gra p hics a n d Baseli ne C haract eristics  ...............................................................2 4  
5. 4.  
Me dical Hist or y  ..........................................................................................................2 5  
5. 5.  
Pri or T hera p y a n d Me dic ati o n  ....................................................................................2 5  
5. 6.  
C hil d beari n g P ote ntial a n d Met h o ds of C o ntrace pti o n  ..............................................2 5  
5. 7.  
St u d y Pr ot o c ol De viati o ns  ..........................................................................................2 5  
6.  
E F FI C A C Y A N A L Y SI S  ............................................................................................2 6  
6. 1.  
Ge neral  ........................................................................................................................2 6  
6. 1. 1.  
A nal ysis Wi n d o ws a n d Baseli ne f or Data C ollecte d Dail y  ........................................2 6  
6. 1. 2.  
A nal ysis Wi n d o ws f or P ul m o nar y F u ncti o n Dat a C ollecte d o n Site  .........................2 6  
6. 2.  
Pri mar y Efficac y E n d p oi nt a n d A nal ysis  ...................................................................2 7  
6. 2. 1.  
Defi niti o n  ....................................................................................................................2 7  
6. 2. 2.  
Pri mar y Efficac y A nal ysis  ..........................................................................................2 7  
6. 2. 3.  
S u b gr o u p A n al ysis  ......................................................................................................2 9  
6. 2. 4.  
Se nsiti vit y/ S u p p orti ve A nal ysis f or t h e Pri mar y Efficac y E n d p oi nt  ..........................3 0  
6. 2. 4. 1.  
Se nsiti vit y A nal ys es  ....................................................................................................3 0  
6. 2. 4. 2.  
S u p p orti ve A nal ysis  ....................................................................................................3 0  
6. 2. 4. 3.  
S u p ple me ntar y A nal ysis  .............................................................................................3 2  
6. 3.  
Sec o n dar y Efficac y E n d p oi nts a n d A nal ys es  .............................................................3 3  
6. 3. 1.  
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 W ell -C o ntr olle d Ast h ma 
Stat us Fr o m Wee k 1 T hr o u g h  1 6  ................................................................................3 3  
6. 3. 2.  
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 -Res c ue Br o nc h o dilat or) F E V 1 as Meas ure d b y a Ha n d hel d 
De vice 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  ....................................................................................................3 4  
6. 3. 3.  
O verall C ha n ges fr o m Baseli ne i n Wee kl y A vera ge of 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 
Wee k 1 T hr o u g h 1 6  ....................................................................................................3 6  
6. 3. 4.  
C ha n ges Fr o m Bas eli 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 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  ......................................3 6  
6. 3. 5.  
C ha n ge Fr o m Bas eli ne i n Cli nic -Base d Sta n dar dize d Bas eli ne -A dj uste d 
M or ni n g Tr o u g h F E V
1 at Wee k 1 6  ............................................................................3 7  
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6. 3. 6.  
Pr o p orti o ns of Patie nts W h o Ac hie ve Cli nic -Bas e d F E V 1 ≥8 0 % Pre dict e d at 
Wee ks  1 2, 1 6, a n d at E n d p oi nt  ...................................................................................3 7  
6. 3. 7.  
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 F
2 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  ..............3 8  
6. 3. 8.  
Ti me t o First Cli nical Ast h ma E x acer bati o n ( C A E) T h r o u g h o ut t he St u d y ..............3 8  
6. 3. 9.  
C ha n ges Fr o m Bas eli 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  .........................................................................................................3 9  
6. 3. 1 0.  
C ha n ges Fr o m Bas eli ne i n Ast h ma C o ntr ol Test ( A C T) at Wee ks 1 2 a n d 1 6  ...........4 0  
6. 3. 1 1.  
C ha n ges Fr o m Bas eli ne i n Sta n dar dize d Ast h ma Q ualit y of Lif e 
Q uesti o n naire ( A Q L Q[ S]) at Wee ks  1 2 a n d 1 6  ..........................................................4 0  
6. 3. 1 2.  
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 W ee ks  1 2, 1 6, A n d at E n d p oi nt  ..........................................................4 1  
6. 4.  
 ............................................................4 1  
6. 4. 1.  
 ..........................................................................4 3  
6. 4. 2.  
 .......................................................4 4  
7.  
M U L TI P L E C O M P A RI S O N S  A N D M U L TI P LI CI T Y  ............................................4 6  
8.  
S A F E T Y A N A L Y SI S  ................................................................................................4 7  
8. 1.  
Ge neral  ........................................................................................................................4 7  
8. 2.  
D urati o n of  E x p os ure t o St u d y Dr u g  ..........................................................................4 7  
8. 3.  
A d verse E v e nts  ...........................................................................................................4 7  
8. 4.  
I nje cti o n Site Assess me nts .........................................................................................4 7  
8. 5.  
H y p erse nsiti vit y/ A na p h yla xis  .....................................................................................4 8  
8. 6.  
Deat hs  .........................................................................................................................4 8  
8. 7.  
Cli nical La b orat or y Tests  ...........................................................................................4 9  
8. 7. 1.  
Ot her Cli nical La b orat or y Tests  .................................................................................5 0  
8. 8.  
P h ysical E x a mi nati o ns  ................................................................................................5 0  
8. 9.  
Vital Si g ns  ..................................................................................................................5 1  
8. 1 0.  
Electr ocar di o gra p h y  ....................................................................................................5 1  
8. 1 1.  
C o nc o mita nt Me dicati o ns or T hera pi es  ......................................................................5 2  
9.  
T O L E R A BI LI T Y V A RI A B L E S A N D A N A L Y SI S ..................................................5 4  
1 0.  
...........5 5  
1 1.  
........................................................................................5 6  
1 2.  
I M M U N O G E NI CI T Y A N A L YSI S  ............................................................................5 7  
1 3.  
P L A N N E D I N T E RI M A N A L Y SI S  ...........................................................................5 8  
V V- 0 0 4 6 5 5 1 7 v 2. 0


 
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Statistical A nal ysis Pla n  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
6  
 
1 3. 1.  
T he U n bli n de d I nteri m Efficac y A nal ysis  ..................................................................5 8  
1 3. 1. 1.  
 ....................................................................................5 8  
1 3. 1. 2.  
..........................................................................................................5 9  
1 3. 1. 3.  
Earl y St o p pi n g wit h a S maller Sa m ple Size  ...............................................................6 0  
1 3. 2.  
T he E x ec uti o n of t he I nteri m A nal ysis  .......................................................................6 1  
1 4.  
S T A TI S TI C A L S O F T W A R E  ....................................................................................6 2  
1 5.  
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N T H E S T U D Y P R O T O C O L  ..............6 3  
1 6.  
A P P E N DI X .................................................................................................................6 4  
1 6. 1.  
..............................................6 4  
1 6. 2.  
A p pe n di x B: Si m ulati o n Res ults t o Assess t he Ba yesia n A nal ysis usi n g 
M ulti ple I m p utati o ns f or Missi n g Data Ha n dli n g  ......................................................6 7  
1 7.  
R E F E R E N C E S  ...........................................................................................................6 9  
 
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St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
7  
 
 LI S T O F T A B L E S  
Ta ble 1:      A nal ysis Wi n d o ws f or O n -Site P ul m o nar y F u n cti o n Test Para meters  ......................2 7  
Ta ble  2:  
Se verit y Assess me nt of L ocal T olera bilit y  .................................................................4 8  
Ta ble  3:  
Criteria f or P ote ntiall y Cli nicall y Si g nifica nt La b orat or y Val u es  ..............................4 9  
Ta ble  4:  
Criteria f or P ote ntiall y Cli nicall y Si g nifica nt Vital Si g ns  ..........................................5 1  
 
 ..............5 9  
 
 ...................6 1  
      
 .............................................6 7  
      
 
 ..................................................................................................6 8  
 
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Statistical A nal ysis Pla n  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
8  
 
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  
A C Q -6  
Ast h ma C o ntr ol Q uesti o n naire 6 -q uesti o n versi o n  
A C T  
Ast h ma C o ntr ol Q uesti o n naire  
A D A  
a nti dr u g a nti b o dies  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A N C O V A  
a nal ysis of c o varia nce  
A 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  
B MI  
b o d y mass i n de x  
C A E  
cli nical ast h ma e xacer bati o n  
C R F  
case re p ort f or m  
CI  
C o nfi de nce i nter val  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C S  
c o m p o u n d s y m metr y  
C V  
c o efficie nt of variati o n  
D o R  
Da y of ra n d o mizati o n  
e-diar y  
electr o nic diar y  
E C G  
electr ocar di o gra m/electr ocar di o gra p h y  
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  
P E F  
M or ni n g pea k e x pirat or y fl o w  
F E V 1 
f orce d e x pirat or y v ol u me i n t he first sec o n d  
F S H  
f ollicle sti m ulati n g h or m o ne 
F V C  
f orce d vital ca pacit y 
H Bs A g  
he p atitis B s urface a nti ge n  
H C G  
H u ma n c h ori o nic g o na d otr o pi n  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H C V  
he p atitis C vir us  
I C E 
Inter -c urre nt e ve nts  
I C S 
i n hale d c ortic oster oi d 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I T T 
i nte nt-t o-treat 
V V- 0 0 4 6 5 5 1 7 v 2. 0


 
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St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
9  
 
A b bre vi ati o n  
Ter m  
K M  
Ka pla n -Meier  
L A B A  
l o n g-acti n g β 2 a g o nist  
L S  
least s q uare 
M A R  
a missi n g at ra n d o m  
M D PI  
m ul ti 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 T T  
m o difie d i nte nt -t o-treat 
M C M C  
M o nte Carl o Mar k o v C hai n  
M M R M  
mi xe d m o del f or re p eate d meas ures  
M N A R  
missi n g n ot at ra n d o m  
N R S  
n u merical res p o nse scale  
P E F  
pea k e x pirat or y fl o w  
P D A E SI  
pr ot oc ol -defi ne d a d verse e ve nts of s pecial i nterest  
P P  
per -pr ot oc ol  
R & D  
Researc h a n d De vel o p me nt  
R T S M  
Trial S u p pl y Ma na ge me nt  
S A P  
statistical a nal ysis pla n 
sc 
s u bc uta ne o us(l y) 
S D  
sta n dar d de viati o n 
S E  
sta n dar d err or 
 
 
SI  
sta n dar d i nter nati o nal 
 
 
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  
U L N  
u p per li mit of n or mal  
U N  
u nstr uct ure d c o varia nce  
V  
visit  
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
V V- 0 0 4 6 5 5 1 7 v 2. 0


 
Place b o -C o ntr olle d – Ast h ma  
Statistical A nal ysis Pla n  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 0  
 
I N T R O D U C TI O N 
T his Statistical A nal ysis Pla n descri bes t he pla n n e d a nal ysis a n d re p orti n g f or Te va Bra n de d 
P har mace utical Pr o d ucts R & D, I nc. 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, 
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) , a n d was writte n i n acc or da nce wit h G S D_ S O P _ 7 0 2 ( Statistical 
A nal ysis Pla n).  
T he rea der of t his S A P  is e nc o ura ge d t o rea d t he st u d y pr ot oc ol  a m e n d me nt 0 1 (A p pr o val Dat e: 
1 8 N o ve m ber  2 0 2 1 ) f or d etails o n t he c o n d uct of t his st u d y, t h e o perati o nal as pects of cli nical 
assess me nts , a n d t he ti mi n g f or c o m pleti n g t he partici pati o n of a patie nt i n t his st u d y. 
T he S A P is i nte n de d t o be i n a gree me nt wit h t he pr ot oc ol, es peci all y wit h r e gar d t o t he pri mar y 
a n d all sec o n dar y e n d p oi nts a n d t heir res pecti ve a nal yses.  H o we v er, t he S A P ma y c o nt ai n m ore 
details re gar di n g t hes e partic ular p oi nts of i nterest, or ot her t y p es of a nal yses (e g , ot her 
e n d p oi nts). W he n differe nces e xist i n descri pti o ns or e x pla nati o ns pr o vi de d i n t he st u d y pr ot oc ol 
a n d t his S A P , t he S A P  pre vails; t he differe nces  will be e x plai ne d i n t he cli nical st u d y re p ort. 
W he n t he st u d y is ter mi nate d earl y d u e t o f utilit y at i nteri m a nal ysis or d ue t o s p o nss or’s 
strate gic decisi o n, t he pla n ne d a nal yses ma y b e si m plifie d t o prese nt t he necessar y i nf or mati o n 
f or a n a b bre viate d  cli nical  st u d y re p ort ( C S R). T he Be yesi a n a nal ysis f or t h e pri mar y efficac y 
e n d p oi nt  a n d t he statistical a nal yses f or s o me of t he sec o n dar y efficac y e n d p oi nts ma y n ot be 
c o n d ucte d f or t he a b bre viate d C S R. T he a nal ysis pla n will be f oll o we d w here  a p plica ble .  
V V- 0 0 4 6 5 5 1 7 v 2. 0


 
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Statistical A nal ysis Pla n  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 1  
 
1.  
S T U D Y E N D P OI N T S  
1. 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 h e 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 V1) 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 de fi 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 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  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 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 ni c -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 F 2 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  
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Statistical A nal ysis Pla n  
St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 2  
 
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 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 
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 dverse 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 the 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 ni cit 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  
1. 2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 3.  
Esti m a n d f or Pri m ar y Effic ac y E n d p oi nt  
1. 3. 1.  
Pri m ar y Esti m a n d  
A n esti ma n d, i n ge n eral, i ncl u des 5  i nter-relate d attri b utes –  treat me nt c o n diti o n, 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 
ha n dli n g I C E, a n d p o p ul ati o n -le vel s u m mar y f or t he e n d p oi nt. 
Treat me nt c o n diti o n:  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 or  
1 2 0 0  m g vers us place b o  as a n a d d-o n t h era p y t o t he patie nt’s c urre nt sta bl e ist h ma mai nte na nce 
t hera p y.  
P o p ulati o n of i nterest: 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 p e  o n ast h ma mai nte na nce t her a p y  
T he pri mar y esti ma n d sel ecte d f or t he pri mar y effi cac 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 u e 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 m o difie d i nte nt -t o-treat (mI T T ) p o p ulati o n. T his esti ma n d 
assesses t he treat me nt efficac y at w ee k 1 2 attri b uta ble t o t he 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 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 nue 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 , 
im 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 wit hi n 1 wee k f or pl ace b o p atie nts 
place d o n  I C S (Szefler et al 1 9 9 9 ). It has als o be e n s h o w n t hat patie nts place d o n I C S 
wit h l o n g acti n g bet a -a g o nists ca n ha ve si g nifica nt i m pr o ve me nt i n serial F E V 1 
meas ure me nts o n t he s a me da y ( C orre n et al 2 0 0 7 , Pearl ma n et al 1 9 9 9 ).I n a d diti o n, 
i m pr o ve me nt i n F E V1 ca n occ ur  1  da y after treat me nt wit h I C S ( Ker wi n et al 2 0 1 9).  T he 
i ncl usi o n of data after a p atie nt recei ves a d diti o nal mai nte na nce me di cati o ns w o ul d  
p ote ntiall y bias t he treat me nt res 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 n al ysis, t he strate g y t o ha n dle t h ese I C Es will be 
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St u d y T V 5 3 2 7 5 -A S -2 0 0 3 3  
 
1 5  
 
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 dicati o ns (re gar dless of 
a vaila bilit y of data o btai ne d after war ds).  
2.  C o nfir me d  m o derate or s e vere  C O VI D -1 9 i nfecti o ns  or a n y seri o us A E d u e t o C O VI D -
1 9 : Si nce C O VI D-1 9 is a k n o w n res pirat or y dis ease w hic h ca n a d versel y affect l u n g 
f u ncti o n, t he sa me strat e 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 h at occ urre d after t he 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 n al ysis.  
Missi n g data , i ncl u di n g t h ose as a res ult of I C E ha n dli n g strate gies, will be ha n dle d usi n g a 
m ulti ple  i m p utati o n met h o d i n t he Ba yesi a n a nal ysis, ass u mi n g a missi n g  at ra n d o m 
( M A R)mec ha nis m.  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 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 m e nt effect bet wee n eac h of t he T E V-5 3 2 7 5 
treat me nt gr o u ps vs place b o bei n g greater t ha n 0, ie: 
P osteri or pr o b a bility  ( T E V-5 3 2 7 5 d ose  vs place b o > 0).   
As a se nsiti vit y a nal ysis, t he refere n ce -b ase d m ulti ple i m p utati o n met h o d will be use d as a 
missi n g data ha n dli n g m et h o d t o assess t he r o b ust ness of t he res ults u n der a missi n g n ot at 
ra n d o m ( M N A R) mec ha nis m. 
1. 3. 2.  
Sec o n d ar y Esti m a n d  
A s u p ple me ntar y a n al ysis will  be c o n d ucte d assessi n g a sec o n dar y esti ma n d  i n t he sa me 
treat me nt c o n diti o n a n d patie nt p o p ulati o n. T he sec o n dar y esti ma n d will assess t he pri mar y 
effic ac y e n d p oi nt d ue t o t he i nitiall y ra n d o mize d tr eat me nt re gar dless of act ual treat me nts ta ke n 
or a n y ot her o cc urre nce of I C Es i n t he mI T T p o p ulati o n. T he s u p ple me ntar y a nal ysis will re p eat 
t he pri mar y a n al ysis i ncl u di n g all o bser vati o ns retrie ve d after t he o cc urre n ces of I C Es i n t he 
a nal ysis as a mea ns of ha n dli n g t he I C Es. Missi n g data will be ha n dle d i n t he sa me ma n ner . 
M ore details will be i n se cti o ns Se cti o n 6. 2. 2  a n d Secti o n  6. 2. 4 .  
 
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2.  
S T U D Y D E SI G N  
2. 1.  
Ge ner al  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 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 wi t 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 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 (see A p pe n di x F i n t he st u d y pr ot oc ol):  
•  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 n t 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/e n d of treat me nt visit ( E o T V)]. 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 uires a c ha 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 ves t here is n o i n here nt har m 
i n c ha n gi n g t h e 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 up 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 
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 ( 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 ul fate ( 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 acc e pta ble) 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. 
                                                 
1  Pr o Air ®  Di gi haler ™ is a re gistere d tra de mar ks of Te va P har mace utical I n d ustries Lt d.  
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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  
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 of t he st u d y pr ot oc ol . 
T he st u d y s c he matic di a gra m is prese nte d i n  Fi g ure  1 . 
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.  
2. 2.  
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 ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p st u d y.  
Patie nts w h o meet all of t he ra n d o mizati o n criteria 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 , stratifie d base d o n mai nte na nce t h era p y a n d scree ni n g 
e osi n o p hil c o u nt :  
•  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  
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 arat e 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). T he str atificati o n s are: 
•  I C S al o ne (me di u m or hi g h d ose ) or  l o w d ose I C S/ L A B A a n d e osi n o p hil c o u nt < 4 0 0 
cells/u L  
•  I C S al o ne ( me di u m or hi g h d ose) or  l o w d ose I C S/ L A B A a n d  e osi n o p hil c o u nt ≥4 0 0 
cells/ u L 
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•  me di u m or hi g h d ose I C S/ L A B A a n d e osi n o p hil c o u nt < 4 0 0 cells/ u L  
•  me di u m or hi g h d ose I C S/ L A B A a n d e osi n o p hil c o u nt ≥4 0 0 cells/ u L  
Patie 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 o f 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 ele 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.  
2. 3.  
D at a M o nit ori n g C o m mittee  
T here is n o i n de pe n d e nt Data M o nit ori ng C o m mittee t o re vie w o n g oi n g s afet y d ata.  
D ata re vi e w c o m mittee s will  be set u p t o re vie w t he pla n ne d i nt eri m a n al ysis res ults, t he pr ocess 
f or w hic h will be des cri b e d i n a se parate d oc u me nt (t he i nteri m a nal ysis c h arter) . 
2. 4.  
S a m ple Size a n d P o wer C o nsi der a ti 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 tro u g h F E V 1: 
      
 
 
 
 
 
  
 
 
 
  
 
 
 
Wit h  t he sa me base ass u m pti o ns  (treat me nt effect = 0. 1 L a n d S D = 0. 3 5 L), t he c o m paris o n  
bet wee n t he 1 2 0 0 m g tr eat m e nt gr o u p vs pl ace b o usi n g a t w o -s a m ple t-test at o ne -si de d al p h a of 
                                                 
2  Ci n q Air ® is a re gistere d t o T e va P har mace utical I n d ustries Lt d. 
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1 5 % w o ul d pr o vi de a st u d y p o w er of 8 0. 6 %. T he statistical s oft ware E ast versi o n 6. 5 was use d 
f or t he calc ulati o n. 
2. 5.  
Se q ue nce of Pl a n ne d A n al yses  
2. 5. 1.  
Pl a n ne d I nteri m A n al yses 
A n 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 p atie nts per ar m) h a ve 
c o m plete d t he wee k  8 visit or wit h dra w n fr o m t he st u d y, t o assess t he safet y dat a ( bli n de d data) 
a n d earl y effic ac y si g nal  ( u n bli n de d data). T h e det ails are i n Secti o n  1 3  a n d t he I nt eri m A nal ysis 
C harter . 
2. 5. 2.  
Fi n al A n al yses a n d Re p orti n g  
All fi nal a nal yses i de ntifi e d i n t his S A P wil l be perf or me d after t he fi nal data base l oc k.  
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3.  
A N A L Y SI S S E T S  
3. 1.  
I nte nt-t o-Tre at A n al ysi s 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. 
3. 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 a partial 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.  I n t h e m I T T 
a nal ysis s et, patie nts will be assi g n e 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 ve d. 
3. 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.   
T he act ual tr eat me nt gr o u p  assi g n me nt f or safet y a nal ys es  is base d o n t he act ual T E V -5 3 2 7 5 
d ose recei ve d b y t he p atie nt:  
•  T he patie nt is assi g n e d t o T E V -5 3 2 7 5 1 2 0 0 m g treat me nt gr o u p, if t he patie nt 
recei v e d  T E V-5 3 2 7 5, a n d t he rec or de d d ose was > 7 5 0  m g;  T he p atie nt is assi g ne d t o 
T E V -5 3 2 7 5 6 0 0 m g treat me nt gr o u p, if t h e patie nt recei v e d  T E V-5 3 2 7 5, b ut t he 
rec or de d d ose w as  ≤ 7 5 0  m g;  
•  T he patie nt is assi g n e d t o place b o treat me nt gr o u p, if patie nt o nl y recei ve d place b o . 
3. 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  deter mi ne d t o i m pact efficac y assess me nts . T hese 
im p orta nt pr ot oc ol de viati o ns  will be deter mi ne d b ef ore u n bli n di n g f or t h e fi nal a nal ysis a n d will 
be d oc u me nte d se p aratel y. T he list will i ncl u de , b ut are n ot li mite d t o, i nc orrect I M P recei v e 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. 
3. 5.  
P h ar m ac 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.  
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3. 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 ose 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. 
 
 
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4.  
G E N E R A L I S S U E S F O R D A T A A N A L Y SI S  
4. 1.  
Ge ner al  
Descri pti ve statistics f or c o nti n u o us varia bles i ncl u de c o u nt (n ), mea n, S D, sta n dar d err or (S E ), 
me dia n, mi ni m u m, a n d ma xi m u m. I n a d diti o n, f or T E V -5 3 2 7 5 c o n ce ntr ati o n , perce nta ge 
c oeffi cie nt of variati o n (% C V ) a n d ge o m etric mea n will als o be calc ul ate d. Descri pti ve statistics 
f or cat e g orical v aria bles i ncl u de patie nt c o u nts a n d perce nt a ges, a n d a missi n g cate g or y will be 
dis pla ye d as  a p pr o priate . 
S u m maries of p ote ntiall y cli nicall y si g nifica nt a b n or mal val ues f or cli nical la b orat or y tests a n d 
vital si g ns val ues will i ncl u de all p ost baseli ne val u es (i ncl u di n g s c he d ule d, u nsc he d ule d, a n d 
earl y wit h dra wal  visits).  
4. 2.  
S pecific ati o n of B aseli ne V al ues  
U nle ss ot her wise s pecifie d, baseli ne val ue is defi ne d as t he last o bser ve d val ue bef ore t he 
a d mi nistrati o n of I M P .  
T he baseli ne f or ha n d -h el d s pir o metr y para met ers a n d e-diar y varia bl es will be t he a vera ge of t he 
val ues o ver t he 7 d a ys pr ece di n g da y of ra n d o m izati o n.  
4. 3.  
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 esti mate missi n g data, u nless ot her wise s pecifie d. 
Dates t hat ha ve i n c o m plete i nf or mati o n (t he m o nt h a n d year or j ust t he year is  a vaila ble) will be 
esti mate d f or t he p ur p os e of calc ulati n g varia bles t hat are d e pe n de nt o n ti m e if necessar y. Da y 
will be esti mate d as t he first da y ( 0 1) of t he m o nt h (if m o nt h a n d year of partial date a re 
a vaila ble) or mi d dle (J ul y 1) of t he year (if o nl y year is a v aila ble), u nless ot her wise n ote d.  T he 
i m p utati o ns f or partial dates are o nl y f or cal c ulati o n p ur p ose. Ori gi nal date varia bles will n ot be 
m o difie d . Listi n gs will list dates as c ollecte d. 
4. 4.  
St u d y  D a ys a n d Visits  
F or b y -visit s u m maries, if t here are m ulti ple assess me nts at a p ost baseli ne visit  t he n t he last 
n o n -missi n g assess me nt at t hat visit will be use d f or t he s u m mar y  (this i ncl u des sc he d ule d a n d 
u nsc he d ule d ass ess me nts ), e x ce pt  f or tri plicate E C G assess me nts  (see Secti o n  8. 1 0  f or f urt her 
details ). 
St u d y visits  are i n Ta ble 2  of t he st u d y pr ot oc ol . 
‘ Last Assess me nt’ ma y b e deri ve d f or a n al ysis p ur p ose  a n d is defi ne d as t he last o bser ve d 
p ost baseli ne data  d uri n g t he treat me nt peri o d . F or patie nts w h o wit h dra w fr o m t he st u d y  earl y, 
t heir data at t he earl y wit h dra wal  visit will be e x cl u de d fr o m t he  b y -v isit s u m maries b ut will be 
i ncl u de d i n t he L ast A ssess me nt s u m maries. 
St u d y  d a ys are n u m bere d relati ve t o t he first da y  of t he I M P  a d mi nistrati o n. T he start of 
treat me nt (d a y 1) is defi n e d as t he date o n w hic h a patie nt ta kes t he first d ose of t he I M P , as 
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rec or de d o n t he case re p ort f or m ( C R F ). Da ys will be n u m bere d relati ve t o treat me nt start (ie, ..., 
– 2, – 1, 1, 2, ...; wit h da y  1 bei n g t he first da y of t h e I M P  a d mi nistrati o n a n d da y – 1 b ei n g t he da y 
bef ore t h e first da y of t h e I M P  a d mi nistrati o n ). 
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5.  
S T U D Y P O P U L A TI O N  
5. 1.  
Ge ner al  
S t u d y p o p ul ati o n s u m maries will be base d o n  the I T T a nal ysis set (see Secti o n  3. 1 ), 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 all patie nts.  All data 
will be liste d a n d s orte d b y treat me nt gr o u p a n d s u bject i de ntif yi n g n u m ber.  
5. 2.  
P atie 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 I T T, mI T T, s afet y a n d 
P P a nal ysis set s a n d ot her a nal ysis sets  (Secti o n  3 ), a n d patie nts w h o c o m pl ete t he d o u ble -bli n d 
treat me nt peri o d a n d c o m plete t he st u d y (see Secti o n  2. 1  f or defi niti o ns of t he d o u ble-bli n d 
treat me nt peri o d a n d e n d of st u d y) will be s u m marize d. Data fr o m scree n fail ures, patie nts w h o 
di d n ot c o m plete t he d o u ble -bli n d treat me nt peri o d a n d  patie nts w h o di d n ot c o m plete 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 usi n g descri pti ve statistics.  
T his s u m mar y will i ncl u de all patie nts.  
5. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
T he de m o gra p hi c data will be c ollecte d at t he s cree ni n g visit after t he patie nt si g ns t he i nf or me d 
c o nse nt for m. Patie nt de m o gra p hi c data  i ncl u di n g a ge, a ge gr o u p ( < 6 5 years vs ≥6 5 years), 
ge n d er , race, race gr o u p (w hite or ot her), et h nicit y, baseli ne wei g ht  ( k g), baseli ne hei g ht (c m), 
ba seli ne b o d y mass i n dex ( B MI; k g/ m 2), a n d baseli ne B MI gr o u p ( < 3 0 vs ≥3 0) , ra n d o mizati o n 
stratificati o n varia bles p er I R T a n d per C R F: pri or t hera p y ( me di u m - a n d hi g h-d os e I C S al o ne 
a n d l o w-d ose I C S/ L A B A  vs.  me di u m - a n d hi g h-d ose 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, or ≥4 0 0  cells/ μ L)  will be  s u m marize d usi n g descri pti ve statistics 
f or t he I T T, s afet y, mI T T, a n d P P a nal ysis sets.  I n a d diti o n, baseli ne c haract eristics i ncl u di n g 
ast h ma hist or y a n d E G C  fi n di n gs at scree ni n g will be s u m marize d f or t he I T T a n d safet y 
a nal ysis s et s usi n g des cri pti ve statistics. N o i nfere ntial a nal ys es will be perf or me d.  
Ast h ma hist or y i ncl u des  
•  M o nt hs si nce ast h ma dia g n osis  ( deri ve d) 
•  T he d urati o n of ast h ma  
•  T he n u m ber of i n p atie nt h os pitalizati o n d ue t o ast h ma o ver t he past 1 2 m o nt hs  
•  M o nt hs si nce m ost rece nt i n patie nt e ve nt  d ue t o ast h ma ( deri ve d)  
•  T he n u m ber of e mer ge nc y  de p art me nt visit d ue t o ast h ma o ver t he p ast 1 2 m o nt hs  
•  M o nt hs si nce m ost rece nt e mer ge nc y d e part me nt visit  d ue t o ast h ma ( deri v e d)  
•  t he n u m ber  of ti mes oral  or i njecta ble  c ortic oster oi ds were pres cri be d f or ast h ma i n 
t he last 1 2 m o nt hs  
•  M o nt hs  si nce last prescri pti o n of oral c ortic oster oi ds  f or ast h ma ( deri ve d) 
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T he m o nt h will be calc ul ate d as ( d ate of i n f or m e d co nse nt - t he dat e of  t he e ve nt + 1)/ 3 0. 4 4 . 
R ules f or ha n dli n g p artial date s are i n Secti o n  4. 3 . 
5. 4.  
Me dic al Hist or y  
All me dical hist or y a b n or malities will be c o de d usi n g t he Me dical Dicti o n ar y f or R e g ul at or y 
Acti vities ( Me d D R A). T he i nci de nce of me dical hist or y a b n or malities will be s u m mar ize d usi n g 
descri pti ve statistics b y s yste m or ga n c lass ( S O C) a n d preferre d ter m. Patie nts are c o u nte d o nl y 
o nce i n eac h S O C a n d o nl y o nce i n eac h preferre d ter m . 
5. 5.  
Pri or T her a p y a n d Me dic ati o n  
All pri or me dicati o ns or t hera p y will be c o d e d usi n g t he W orl d Healt h Or ga nizati o n Dr u g  
D icti o nar y of me dical c o des ( W H O Dr u g). T h e i n ci de nce of pri or me dicati o ns or t hera p y will be 
s u m marize d b y t hera pe utic class a n d preferre d t er m  usi n g descri pti ve stati stics. Patie nts are 
c o u nte d o nl y o n ce i n e ac h t hera pe utic class ca t e g or y, a n d o nl y o nce i n eac h preferre d t er m 
cate g or y. Pri or me di cati o ns will i ncl u de all me dicati o ns ta ke n pri or t o t he a d mi nistrati o n of t he 
first d ose of t he I M P. 
5. 6.  
C hil d be ari n g P ote nti al  a n d Met h o ds  of C o ntr ace pti o n  
I nf or mati o n relate d t o re pr o d ucti ve s yste m fi n di n gs will be c ollecte d at t he scree ni n g visit. Data 
will be liste d.  
5. 7.  
St u d y Pr ot oc ol De vi ati o ns  
Data fr o m p atie nts wit h a n y i m p orta nt pr ot oc ol d e viati o ns  d uri n g t he st u d y will be s u m marize d 
o verall a n d f or eac h cate g or y usi n g des cri pti ve statistics.  All st u d y pr ot oc ol de viati o ns will be 
liste d. 
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6.  
E F FI C A C Y A N A L Y SI S  
6. 1.  
Ge ner al  
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. 
C o nfi de nce /cre di ble i nter vals will be pr o vi de d  at t he t w o-si de d 9 5 %  c o nfi d e 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.  
F or t he p ur p os e of t he efficac y a n al ysis,  t he ti me p oi nt of “e n d p oi nt” will be deri ve d a n d is 
defi ne d as t he l ast assess me nt d uri n g 1 6 wee ks  f or a patie nt.  
6. 1. 1.  
A n al ysis Wi n d o ws  a n d B aseli ne f or D at a  C ollecte d D ail y   
F or  data c ollecte d o n e -di ar y a n d ha n d -hel d s pir o metr y d ail y , t he wee kl y a nal ysis wi n d o ws  
( wee k 1 t o w ee k 1 6) will be deri ve d  b ase d o n t he st u d y da ys  as f oll o ws:  
Wee k x : da y ( x -1) * 7 + 1 t o da y x * 7  
eg Wee k 1 is fr o m da y s 1 t o 7 ; W ee k 1 2 is da ys 7 8 t o 8 4, etc. 
N otes: Da y 1 is t he I M P a d mi nistrati o n date;  f or p atie nts w h o wit h draw fr o m t he st u d y earl y, t he 
last wi n d o w ma y b e less t ha n 7 da ys. 
T he dail y a vera ge of t he effic ac y dat a wit h eac h wee kl y a nal ysis wi n d o w  will be calc ulat e d 
base d o n n o n -missi n g e -diar y as f oll o w:  
∑𝑎𝑛 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑎𝑛 𝑎𝑛𝑎𝑙𝑦𝑠𝑖𝑠 𝑤𝑖𝑛𝑑𝑜𝑤  
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑛𝑜𝑛𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑑𝑎𝑡𝑎 𝑖𝑛 𝑡ℎ𝑒 𝑎𝑛𝑎𝑙𝑦𝑠𝑖𝑠 𝑤𝑖𝑛𝑑𝑜𝑤  [ 1] 
Baseli ne  d ail y a vera ge  f or data c ollecte d dail y will be  calc ul ate d usi n g t h e s a me f or m ula a b o ve  
base d o n n o n -missi n g d ata.  
6. 1. 2.  
A n al ysis Wi n d o ws f or P ul m o n ar y F u ncti o n D at a  C ollecte d o n Site   
F or p ul m o nar y f u ncti o n tests c o n d ucte d o n site at st u d y visits, t he f oll o wi n g a n al ysis wi n d o ws 
will be a p plie d t o i ncl u de o bse r vati o ns i n deri vi n g t he a nal ysis visits. W he n m ulti ple eli gi ble 
val ues are a vaila ble i n t h e sa me a n al ysis wi n d o w, t he sc he d ule d val u e , if a v aila ble, will be use d; 
a n d if t he sc he d ul e d val u e is n ot a vaila ble, t he n t h e val ue t hat is cl osest t o t he tar get da t e will be 
use d.  
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T a ble 1 :      A n al ysis Wi n d o ws f or O n-Site P ul m o n ar y F u ncti o n Test P ar a meters  
A n al ysis Visit  
T ar get St u d y D a y  
A n al ysis Wi n d o w  
Visit 4/ Da y 4  
4  
Da y 1 p ost -d ose t o Da y 7  
Visit 5/ Wee k 2  
1 5  
Da y 8 t o Da y 2 1  
Visit 6/ W ee k 4  
2 9  
Da y 2 2 t o Da y 4 2  
Visit 7/ Wee k 8  
5 7  
Da y 4 3 t o Da y 7 0  
Visit 8/ Wee k 1 2  
8 5  
Da y 7 1 t o Da y 9 9  
Visit 9/ Wee k 1 6  
1 1 3  
Da y 9 9 t o Da y 1 2 6  
6. 2.  
Pri m ar y Effic ac y E n d p oi nt  a n d A n al ysis  
6. 2. 1.  
Defi niti o n  
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 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.  
6. 2. 2.  
Pri m ar y Effic ac y A n al ysis  
 
 
 
 
 
                                                      
 
 
 
 
 
 
 
 
                               
                                                  
 
 
 
  
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  Secti o n  1. 3 . I n t he pri mar y a n al ysis, th e missi n g data will be ha n dle d usi n g m ulti ple 
i m p utati o ns wit h 1 0 0 i m p ute d datasets. 
 
 
 
 
 
 
 
 
 
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6. 2. 3.  
S u b gr o u p A n al ysis  
S u b -gr o u p a nal yses will be perf or me d o n t he pri m ar y  e n d p oi nt  a n d sel ecte d sec o n dar y e n d p oi nts  
f or  
•  g e n d er ( m ale vs fe m ale) 
•  race ( w hite vs ot her races) 
•  a ge gr o u p ( < 6 5  years  vs ≥6 5  years)  
•  Ra n d o mizati o n fact or per I R T: e osi n o p hil c o u nt  (< 4 0 0 cells/ u L  vs. ≥4 0 0 
cells/ u L)R a n d o mizati o n fact or p er I R T: pri or ast h ma mai nte na nce t h era p y ( I C S al o n e 
or l o w d ose I C S/ L A B A  vs. me di u m a n d hi g h d ose I C S/ L A B A)  
T he select e d sec o n d ar 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 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) 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 t he wee kl y a vera ge 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 
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•  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  
 F or 
c o nti n u o us e n d p oi nts, t he sa me M M R M a nal ysis as descri be d i n Secti o n  6. 3. 2  will be a p plie d,  b y 
eac h s u b gr o u p v aria ble. F or t he bi nar y e n d p oi nt of wee kl y ast h ma c o ntr ol stat us, t he a nal ysis 
descri be d i n Secti o n  6. 3. 1  will be a p plie d, b y eac h s u b gr o u p v aria ble. T h e fi nal esti mate d 
treat me nt differe nces will be prese nte d t o get her wit h t he 2-si de d 9 5% CI a n d p -val ues b y t he 
s u b gr o u p v aria bles usi n g t he F orest Pl ot.  
6. 2. 4.  
Se nsiti vit y /S u p p orti ve  A n al ysi s f or t he Pri m ar y Effic ac y E n d p oi nt  
6. 2. 4. 1.  
Se nsiti vit y A n al yses  
As se nsiti vit y a nal 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 peate d 
usi n g t he P P p o p ulati o n  a n d I T T p o p ulati o n  if t he differe n ce b et wee n mI T T a n d I T T is m ore 
t ha n 5 %. 
I n or der t o ass ess t he r o b ust ness of t he res ults u n d er a missi n g n ot at ra n d o m ( M N A R) 
mec ha nis m, a n ot her s e nsiti vit y a n al ysis usi n g t he refere nce -b ase d m ulti ple i m p utati o n met h o d as 
t he missi n g data ha n dli n g met h o d will be c o n d u ct e d. T he refere nce -bas 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 ) 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 -tr eate d p atie nt data, re prese nti n g a missi n g n ot at r a n d o m ( M N A R) mec ha nis m. A  
sa m ple S A S c o de f or t he refere nce-b ase d m ulti ple i m o utati o ns is gi ve n bel o w:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. 2. 4. 2.  
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 pri mar y  esti ma n d wit h res pect t o treat me nt c o n diti o n, 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 I C E ha n dli n g str ate gies will be a p plie d. B ot h t he m ulti ple 
i m utati o n met h o d a n d t he refere n ce-base d m ulti ple i m p utati o ns met h o d will be use d t o ha n dle 
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t he missi n g data. T he p o p ulati o n -le vel s u m mary statistics will be t he c o m bi ne d least s q uares 
mea ns i n t he treat me nt gr o u ps a n d t he c o m bi ne d least s q uares me a n treat me nt differe n ces 
deri ve d fr o m a nal yses of t he m ulti pl y i m p ute d dat asets usi n g t he mi x e d-effects m o del f or 
re peat 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 a bs ol ute e osi n o p hil c o u nt  at scree ni n g), 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 -tr eat 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 ( U N) c o varia nce 
str uct ure will first be use d; h o we ver,  I n t h e cas e U N c o varia n ce str u ct ure d oes n ot c o n ver ge, t he 
c o m p o u n d s y m metr y ( C S) c o varia n ce str uct ur e will b e use d. 
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.  
MI ste ps  a n d S A S e x a m ple c o des  are as f oll o ws:  
Ste p 1:  F oll o wi n g o bs er vati o ns will be c o nsi dere d as “a nal ysis dr o p o uts” a n d be e x cl u de d fr o m 
t he a nal ysis (set t o missi n g) 
•  o bser vati o ns after t he use of ast h ma mai nte na n ce me dicati o ns (re gar dless of 
a vaila bilit y of data o btai ne d after war ds);  
•  o bser vati o ns t hat occ urre d after t he di a g n osis of C O VI D -1 9 i nf ecti o ns.  
F or all earl y dr o p o uts a n d “a nal ysis dr o p o uts” , re gar dless of assi g ne d treat me nt ar m, missi n g 
i m p utati o n will be base d o n data fr o m t he place b o-treate d patie nts (e g, refere nce-base d 
i m p utati o n). 
Ste p 2 : M issi n g data will be i m p ute d wit h 1 0 0 i m p utati o ns usi n g m ulti ple i m p utati o n a n d 
refere nce-b ase d m ulti ple i m p utati o ns. T he sa me sa m ple c o des f or i m p utati o ns f or t he Ba yesia n 
a nal ysis will be use d (see Secti o n  6. 2. 2  a n d Secti o n  6. 2. 4. 1 , res pecti vel y).   
 
 
 
 
  
  
      
  
      
 
      
 
       
  
      
 
 
 
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W here T R T P de n otes t he pla n ne d treat me nt gr o u p; A VI SI T de n otes visit/ wee k; R S T R A T A  t he 
ra n d o mizati o n stratificati o n; B A S E de n otes t he baseli ne F E V 1; C H G _i  de n otes t he c ha n ge fr o m 
baseli ne at e ac h visit  bas e d o n i m p ute d data . 
Ste p 4 : T he res ults fr o m t he 1 0 0 a nal yses fr o m Ste p 3 will be c o m bi ne d usi n g R u bi n’s f or m ulae. 
T he least s q uare ( L S) mea n esti mates f or t he m ea n c ha n ge fr o m baseli ne t o eac h ti me p oi nt, as 
well as t he differe n ce o f t he esti mates bet wee n t he acti ve a n d place b o gr o u p, wit h t he 
c orres p o n di n g S E, p -v al ue a n d ass oci ate d 9 5 % CI will be pr o vi de d.  
 
  
      
 
 
 
  
  
      
  
      
  
      
  
 
 
  
 
 
      
 
 
  
  
        
  
        
  
         
  
 
 
 
 
6. 2. 4. 3.  
S u p ple me nt ar y  A n al ysis  
A s u p ple me ntar y a n al ysis usi n g all data, i ncl u di n g retrie ve d o bs er vati o ns f oll o wi n g alter nati ve  
ast h ma 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 t he sec o n dar y 
esti ma n d, defi ne d i n Secti o n  1. 3 . T he pri mar y Ba yesia n a nal ysis  a n d t he fre q ue ntist s u p p orti ve 
a nal ysis will be use d.  
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6. 3.  
Sec o n d ar y Effic ac y E n d p oi nts  a n d A n al yse s 
T he ke y sec o n dar y effic ac y e n d p oi nts are liste d i n Secti o n  1. 1 . A nal ys es will be base d o n t he 
m I T T a nal ysis set. 
6. 3. 1.  
O ver all Wee kl y Well -C o ntr olle d Ast h m a St at us Defi ne d b y t he Ast h m a C o ntr ol 
C o m p osite Sc ore a n d Wee kl y Ast h m a C o ntr ol St at us ( Yes Vers us N o) Fr o m 
Wee k 1 T hr o u g h 1 2  a n d O ver all Wee kl y Well -C o ntr olle d Ast h m a St at us Fr o m 
Wee k 1 T hr o u g h 1 6  
T he wee kl y ast h ma c o ntr ol stat us ( Yes or N o) is t he deri ve d ast h ma c o ntr ol c o m p osite sc ore 
base d o n t he f oll o wi n g criteria  (als o see Sect i o n 6.1 .7  of t he st u d y pr ot oc ol) : 
1.  T w o or m ore of t h e f oll o wi n g criteria are f ulfille 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 n t 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)  
an d  
2.  B ot h of t he f oll o wi n g criteria are f ulfille d:  
•  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  
F or t he a nal ysis p ur p ose, wee kl y a n al ysis w i n d o ws ( wee ks 1 t o 1 6) will be deri ve d as d escri be d 
i n Secti o n 6. 1. 1 . T he a st h ma c o ntr ol stat us i n eac h wee kl y  a n al ysis wi n d o w will be Yes if t he 
c o n diti o ns 1 a n d 2 a b o ve met , N o o t her wise. 
T he o verall wee kl y ast h ma c o ntr o l stat us fr o m w ee k 1 t hr o u g h 1 2 or wee k 1 t hr o u g h 1 6 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, baseli ne stat us, 
a n d t he ra n d o mizatio n stratificati o n fact or , 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 the u nstr uct ure d ( U N) c o v aria nce str uct ur e . I n t he case U N c o varia nce 
str uct ure d oes n ot c o n v er ge, t h e c o m p o u n d s y m m etr y c o varia nce str uct ure ( C S) will be use d.  All 
wee kl y ast h ma c o ntr ol stat uses fr o m wee ks 1 t o 1 6 will be i ncl u de d i n t he re peat e d meas ures 
m o del.   
T o esti mate t he pr o ba bilit y of o verall ast h ma c o ntr ol o ver 1 2 wee ks i n eac h treat me nt gr o u p, or 
t o c o n d uct a c o m paris o n bet wee n t he treat me nt gr o u ps, a ppr o priate c o ntrast state me nts nee d t o 
be use d.  
 
 
      
  
      
 
      
 
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6. 3. 2.  
O ver all C h a n ges Fr o m B aseli ne i n t he Wee kl y A ver a ge o f D ail y M or ni n g 
Tr o u g h ( Pre -Res c ue Br o nc h o dil at or) F E V 1 as Me as ure d b y a  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  
T he F E V 1 is meas ur e d b y a h a n d hel d de vi ce dail y. T he wee kl y a nal ysis w i n d o w will be deri ve d 
as descri be d  i n Secti o n 6. 1. 1 . T he dail y a vera ge wit hi n eac h wee kl y a nal ysis wi n d o w will be 
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d eri ve d usi n g f or m ula [ 1] i n Secti o n 6. 1. 1 . Meas ure me nt val ues ta k e n wit hi n 4 h o urs of  a res c ue 
br o nc h o dilat or use will b e set t o missi n g.   
T he  e n d p oi nt s will be a n al yze d usi n g  a M M R M i ncl u di n g bas eli ne F E V 1, ra n d o mizati o n 
stratificati o n fact ors, wee k, treat me nt gr o u p, 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 wit h U N  c o varia n ce str uct ur e . I n t he case U N c o varia nce str uct ure d oes n ot c o n ver ge, t he 
c o m p o u n d s y m metr y ( C S) c o varia n ce str uct ur e will be use d . 
O ne M M R M m o del will be r u n i ncl u di n g all 1 6 -wee k data. T h e o verall a n d b y-wee k  res ults will 
be deri ve d usi n g a p pr o priate c o ntrast state me nts a n d prese nte d. T h e e n d p oi nt will be meas ure d 
b y t he o v erall res ults. L S mea n a n d S E f or eac h treat me nt gr o u p, L S mea ns a n d c orres p o n di n g 
9 5 % c o nfi de n ce i nter vals f or t he treat me nt differe nces ( acti ve - place b o), a n d t he ass ociate d p -
val ues fr o m t he o verall res ults f or treat me nt c o m p aris o ns.  
Descri pti ve statistics fr o m eac h w ee k  will be pr o vi de d.  
 
 
      
  
      
 
      
 
      
  
                           
  
                           
 
       
   
   
   
 
                                                       
   
   
   
  
                           
 
       
  
                           
   
                           
 
                                         
   
   
   
  
                                                     
   
   
   
 
                           
 
       
  
                   
 
       
 
 
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6. 3. 3.  
O ver all C h a n ges f r o m B aseli ne i n Wee kl y A ver a ge of Resc ue Me dic ati 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  
T he n u m ber of ti mes ast h ma resc u e me dicati o n ( n u m be r of i n halati o ns/ p uffs) use d will be 
rec or de d o n e -di ar y.  
T he p ost -baseli ne a nal ysis wi n d o w f or o ver 1 2 wee ks will be fr o m t he first da y of I M P u p t o  t he  
da y 8 4. T he p ost -bas eli ne a nal ysis wi n d o w f or o ver 1 6 wee ks will be fr o m t he first da y of I M P 
u p t o t he da y 1 1 2. Bas eli ne wi n d o w will i ncl u de d a ys u p t o t he first d ose of I M P. Dat a i n eac h 
a nal ysis wi n d o w  will be n or malize d t o 7 da ys as  
(∑ res c ue me dicati o n  uses d uri n g  a n a nal ysis wi n d o w / n u m ber of n o n-missi n g e -d air y da ys 
d uri n g t he a nal ysis wi n d o w)  * 7  
T he c ha n ges fr o m bas eli ne i n wee kl y a v era ge of resc ue me dicati o n o ver w ee k 1 2 a n d o v er wee k -
1 6 will be  calc ulate d a n d  a nal yze d usi n g Wilc o x o n ra n k -s u m test stratifie d o n ra n d omizati o n 
stratificati o n fact ors, res p ecti vel y. T he H o d ges-Le h ma n n esti mat or of t he treat me nt differe nces 
( T E V 4 3 2 7 5 treat me nt gr o u ps vs place b o) will be prese nte d. 
 
  
       
  
       
 
       
 
 
 
 
6. 3. 4.  
C h a n ges Fr o m B aseli ne i n Perce nt a ge o f Ast h m a C o ntr ol D a ys ( N o S y m pt o ms 
a n d N o Resc ue Me dic ati 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  
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. 
T he p ost -baseli ne a nal ysis wi n d o w f or o ver 1 2 wee ks will be fr o m t he first da y of I M P u p t o t he 
da y 8 4. T he p ost -bas eli ne a nal ysis wi n d o w f or o ver 1 6 wee ks will be fr o m t he first da y of I M P 
u p t o t he da y 1 1 2. Bas eli ne wi n d o w will i ncl u de da ys u p t o t he first d ose of I M P.  
Pe rce nta ge of ast h ma c o ntr ol da ys i n e ac h a nal ysis wi n d o w will be calc ulat e d as  
(∑ ast h ma c o ntr ol d a ys i n  a n a nal ysis wi n d o w / n u m ber of n o n -missi n g e -dair y d a ys d uri n g 
t he a nal ysis wi n d o w ) * 1 0 0 
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3 7  
 
T he c ha n ges fr o m bas eli ne i n perce nta ge of ast h ma c o ntr ol da ys o ver 1 2 wee ks (u p t o da y 8 4 )  
a n d o ver 1 6 wee ks (u p t o da y 1 1 2 ) will be a nal yze d, res pecti vel y, usi n g a n al ysis of c o v aria nce  
( A N C O V A) i n cl u di n g b aseli ne perce nta ge of ast h ma c o ntr ol da ys , ra n d o mi zati o n stratificati o n 
fact ors, a n d treat me nt gr o u p i n t he m o del.  
 
  
      
  
      
  
      
  
      
 
 
 
 
 
6. 3. 5.  
C h a n ge Fr o m B aseli ne in Cli nic -B ase d St a n d ar dize d B aseli ne -A dj uste d 
M or ni n g Tr o u g h F E V 1 a t Wee k 1 6 
T he  a nal ysis will be base d o n data c ollecte d at site visits . F E V 1 meas ures at visit 1/scree ni n g, 
visit 3/ D o R , visit 4/ wee k 1, visit 5/ wee k 2, visit 6/ wee k 4, visit 7/ wee k 8, visit 8/ wee k 1 2, a n d 
visit 9/ wee k 1 6 or t he earl y wit h dra wal visit. T he a nal ysis will i ncl u de p ost -baseli ne d at a u p t o 
t he visit 6/ wee k 1 6.  Bas eli ne will be t he last meas ure bef ore t he first d ose of I M P.  
T he c ha n ge fr o m bas eli ne i n cli nic -base d m or ni n g tr o u g h F E V 1 at wee k 1 6 will be a nal yze d 
usi n g M M R M met h o d i n a ma n ner a nal o g o us t o t he a nal ysis as des cri be d i n Secti o n 6. 3. 2 . 
Baseli ne  cli nic-bas e d  m or ni n g tr o u g h F E V 1 will be use d i n m o del.  W E E K  will de n ote t o t he 
visit.  
F or m o del -b ase d res ults, o nl y wee k 1 6 res ults will be dis pla ye d. S u m mar y statistics will be 
pr o vi de d b y visit/ wee k.  
6. 3. 6.  
Pr o p orti o ns o f P atie nts W h o Ac hie ve Cli nic-B ase d F E V 1 ≥8 0 % Pre dic te d at 
Wee ks  1 2, 1 6, a n d a t E n d p oi nt 
T he  perce nt of pre dicte d F E V 1 will be meas ure d b y ha n d h el d de vice. T he a nal ysis will be base d 
o n data c ollecte d at site visits  a n d will be a p plie d i n patie nts wit h baseli ne F E V 1 < 8 0 % Pre dicte d . 
F or a n al ysis p ur p os es, a dic h ot o m o us scale of ‘ Yes’  (F E V 1 ≥8 0 % Pre dicte d)  or ‘ N o’  
(F E V 1< 8 0 % Pre dicte d)  will be deri ve d  a n d a nal yze d usi n g t he re p eate d m eas ures l o gistic 
re gressi o n m o del. Baseli ne perce nt of pre dicte d F E V 1 will be use d i n t he m o del. Wee ks / visits 
i ncl u de site visits visit 8/ wee k 1 2 , visit 9/ wee k 1 6 , a n d “e n d p oi nt”. S u m mar y statistics will be 
pr o vi de d.  
  
 
      
  
      
 
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6. 3. 7.  
Pr o p orti o ns o f P atie nts W h o Ac hie ve F orce d E x pir at or y Fl o w at 2 5 % t o 7 5 % o f 
F V C (F E F 2 5 -7 5) ≥7 0 % Pre dicte d at Wee ks  1 2, 1 6, a n d a t E n d p oi nt 
T he f orce d vital ca p acit y ( F V C) is t he v ol u me of air t hat ca 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 f orce d e x pirat or y fl o w at 2 5 % t o 7 5 % of F V C 
a n d will be meas ur e d b y ha n d hel d de vice.  
F or a n al ysis p ur p os e, a dic h ot o m o us sc ore of ‘ Yes’ ( F E F 2 5 -7 5 ≥7 0 % ) or ‘ N o’ (F E F 2 5 -7 5 < 7 0 % ) 
will be deri ve d a n d a nal yze d  usi n g t he re p eate d m eas ures l o gistic re gressi o n m o del i n a ma n ner 
a nal o g o us t o t he a nal ysis as descri be d  S ecti o n  6. 3. 1 . Baseli ne F E F 2 5 -7 5 will be use d i n t he m o del.  
Wee ks/ visits i ncl u de all p ost -baseli ne site visits u p t o visit 8/ wee k 1 2 (f or Wee k 1 2 a nal ysis) or 
u p t o visit 9/ wee k 1 6 (f or Wee k 1 6 a nal ysis).  S u m mar y st atistics will be pr o vi de d b y visit/ wee k.  
6. 3. 8.  
Ti me t o Fi rst Cli nic al Ast h m a E x acer b ati o n ( C A E ) T hr o u g h o ut the St u d y  
T he ti me ( da ys) t o t he first C A E is t he i nter val fr o m t he ra n d o mizati o n t o t he occ urre n ce of t he 
first C A E . 
T he o bser vati o n f or eac h patie nt is t he i nter val fr o m ra n d o mizati o n t o t he occ urre nce of t he first 
C A E, or ce ns ori n g, w hi c he ver occ urs earlier. It is deri ve d as:  
t he date of ce ns ori n g or t he date C A E  - t he date of ra n d o mizati o n + 1.  
Patie nts w h o earl y ter mi nate d fr o m t he st u d y wit h o ut C A E d u e t o lac k of efficac y or a n ast h ma -
relate d A E will be als o treate d as  e x perie nci n g C A E  at t he ti me of earl y wit h dra w visit .  
Patie nts w h o c o m plete t he wee k 1 6 visit wit h o ut C A E will be ri g ht -ce ns ore d at t he ti me of Wee k 
1 6  visit . Patie nts wit h o ut C A E a n d earl y wit h dra w n fr o m t he st u d y b ef ore t he wee k 1 6 wit h 
reas o ns ot her t h a n lac k of effic ac y or ast h ma -relat e d A Es will be ri g ht -ce ns ore d at t he ti me of 
earl y wit h dra wal visit . 
T he Ka pla n -Meier ( K M) met 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 treat me nt gr o u ps. Distri b uti o n differe nce 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 mizati o n stratificati o n fact ors. 
 
  
 
  
 
     
 
     
 
 
 
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6. 3. 9.  
C h a n ges Fr o m B aseli ne i n Ast h m a C o ntr ol Q u esti o n n aire (A C Q -6) at Wee ks  1 2 
a n d 1 6  
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. T he 6 q uesti o ns are 
self-assess me nts ( c o m plete d b y t he p atie 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. A C Q -6 will be a d mi nistere d 
at visit 2/r u n -in, visit 3/ D o R, visit 5/ wee k  2, visit 6/ wee k 4, visit 7/ wee k 8, visit 8/ wee k 1 2, a n d 
visit 9/ wee k 1 6 or earl y wit h dra w n visit.   
T he mea n t otal sc ore of t he A C Q -6 is deri ve d as t he a vera ge of t he i n di vi d ual ite m sc ores. F or 
i nc o m plete data, t he f oll o wi n g rules will a p pl y:  
1.  Mea n t otal sc ore f or a visit will n ot be calc ulate d if Q uesti o n 1 is left bla n k, irres pecti ve 
of t he c o m pleti o n of t he re mai ni n g q u esti o ns.  
2.  A missi n g sc ore o n p ost -baseli ne q uesti o n naire f or Q uesti o ns 2 -6 will be i m p ute d base d 
o n t he t otal  sc ores fr o m t he pre vi o us visit, as l o n g as at least 3 o ut of t he 5 q uesti o ns ha ve 
res p o nses f or t h e c urre nt visit (ie, at least half of t he re mai ni n g q uesti o ns are a ns w ere d).  
T he f or m ula is: (t otal s u m of n o n -missi n g sc ores f or t he c urre nt visit / t otal s u m of sc ores 
f or t he pre vi o us visit f or q uesti o ns a ns were d f or t he c urre nt visit) * (sc ore f or t he missi n g 
q uesti o n o n t he pre vi o us visit)  
3.  Mea n t otal sc ore at baseli ne will n ot be calc ulate d if Q uesti o n 1 or t w o or m ore a m o n g 
Q uesti o ns 2 -6 is left bla n k. A missi n g sc ore f or Q uesti o ns 2 -6 at baseli ne will be re place d 
b y a n a vera ge of t he a v aila ble sc ores.  
T he c ha n ges fr o m bas e li ne i n A C Q-6 mea n t otal sc ore at Wee ks 1 2 a n d 1 6 will be a nal yze d 
usi n g M M R M met h o d i n a ma n ner a nal o g o us t o t he a nal ysis as des cri be d i n Secti o n  6. 3. 2 . 
B aseli ne A C Q -6 t otal sc ore  will be use d i n t he m o del.  
T he a nal ysis i ncl u des dat a u p t o visit 9/ wee k 1 6.  
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6. 3. 1 0.  
C h a n ges Fr o m B aseli ne i n Ast h m a C o ntr ol Test (A C T ) at W ee ks 1 2 an d 1 6  
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). It assesses t he fre q u e nc 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 res c 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 scale (f or s y m pt o ms a n d acti vities: 
1 =all t he ti m e 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 otal 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.  A C T will be meas ure d at visit 3/ D o R, visit 6/ wee k 4, visit 7/ wee k 8, 
visit 8/ wee k 1 2, a n d visit 9/ wee k 1 6 or earl y wit h dra w n visit.  
T he t otal sc ore will be calc ulate d base d o n t he a vaila ble data  a n d will be set t o missi n g if a n y 
q uesti o ns are i nc o m plete .  
T he c ha n ges fr o m bas e li ne i n A C T t otal sc ore at Wee ks 1 2 a n d 1 6 will be a nal yze d usi n g 
M M R M met h o d i n a ma n ner a nal o g o us t o t he anal ysis as descri be d i n Secti o n  6. 3. 2 . Baseli ne  
A C T  t otal sc ore will be use d i n t he m o del. 
T he a nal ysis i ncl u des dat a u p t o visit 9/ wee k 1 6.  
6. 3. 1 1.  
C h a n ges Fr o m B aseli ne i n St a n d ar dize d Ast h m a Q u alit y o f Life Q uesti o n n aire 
(A Q L Q [S ]) a t Wee ks 1 2 a n d 1 6  
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]) will be self -a d mi nistere d b y 
patie nts. T he q uesti o n naire is a t o ol t o meas ure t h e i m pact of ast h ma o n a patie nt’s q ualit y of life 
( p h ysic al, e m oti o nal, s ocial, a n d occ u p ati o nal). T he 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 o i nt Li k ert scale ( 7 = n ot i m pair me nt at all t o 1 =se verel y 
i m pair me nt). Sc ores r a n ge fr o m 1 t o 7, wit h hi g h er sc ores i n dicati n g b etter q ualit y of life. T h e 3 2 
q uesti o ns (ite ms) i n  the A Q L Q( S) are di vi de d i n t o 4 d o mai ns a n d t he c orres p o n di n g q u esti o n s 
are:  
•  S y m pt o ms: 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, 2 0, 2 2, 2 4, 2 9, 3 0  
•  Acti vit y Li mitati o n: 1, 2, 3, 4, 5, 1 1, 1 9, 2 5, 2 8, 3 1, 3 2  
•  E m oti o nal F u ncti o n: 7, 1 3, 1 5, 2 1, 2 7  
•  E n vir o n me ntal Sti m uli:  9, 1 7, 2 3, 2 6  
A Q L Q( S) will be meas ur e d at visit 3/ D o R, visit 8/ wee k 1 2, a n d visit 9/ wee k 1 6 or earl y 
wit h dra w n visit.  
T he o verall a n d d o mai n mea n sc ores of t he A Q L Q will be  deri ve d as t h e a vera ge of t he 
c orres p o n di n g ite ms. F or i nc o m plete data, t he o verall mea n sc ore f or a partic ular visit will n ot be 
calc ulate d if 3 or m ore res p o nses are missi n g wit h n o m ore t ha n 1 per d o m ai n. F or t he s y m pt o m 
a n d acti vit y d o m ai n mea n sc ores, calc ulati o n will re q uire n o m or e t ha n 1 missi n g ite m. T he 
mea n d o mai n sc ore f or t h e ot her 2 d o mai ns will be re gar de d as missi n g if 1 or m ore ite m is 
missi n g.  
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T he c ha n ges fr o m bas e li ne i n A Q L Q( S) at wee k 1 2 a n d wee k 1 6 w ill be a nal yze d,  res pecti vel y,  
us i n g A N C O V A  i n a ma n ner a nal o g o us t o t he a nal ysis as descri be d  Secti o n  6. 3. 4 . T he a nal yses 
will be f or t he o verall me a n sc ore a n d mea n s c ore of eac h d o m ai n. T he bas eli ne  i n t he m o del will 
be baseli ne o verall mea n sc ore  of A Q L Q( S)  or bas eli ne mea n sc ore  of A Q L Q( S)  f or t he d o mai n, 
res pecti vel y. 
6. 3. 1 2.  
Pr o p orti o ns o f P atie nts W h o Ac hie ve F E V 1:F V C (F orce d Vit al C a p acit y) R ati o 
≥0. 8 0 a t Wee ks 1 2, 1 6, A n d a t E n d p oi nt 
T he pr o p orti o ns of patie nts w h o ac hie ve  F E V 1: F V C rati o ≥8 0 % will be a nal yz e d  usi n g t he 
re peat e d meas ur es l o gistic re gressi o n m o del i n a ma n ner a n al o g o us t o t he a nal ysis as descri be d  
Secti o n  6. 3. 1 . Baseli ne F E V 1: F V C rati o will be use d i n t he m o del.  T he a n al ysis will be a p plie d 
t h ose wit h baseli ne F E V 1 : F V C rati o < 0. 8 0. 
T he a nal ysis will i ncl u de data u p t o visit 9/ wee k 1 6 . 
6. 4.  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. 4. 1.  
 
 
 
 
 
 
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6. 4. 2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.  
M U L TI P L E C O M P A RI S O N S A N D M U L TI P LI CI T 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 . 
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8.  
S A F E T Y A N A L Y SI S  
8. 1.  
Ge ner al  
T he safet y a nal ysis set ( Secti o n 3. 3  ) will be use d f or all safet y a n al ys es. S u m maries will be 
prese nte d usi n g des cri pti ve statistics b y treat me nt gr o u p as act u all y recei ve d  u nless ot her wise 
state d. All data will be liste d usi n g I T T a nal ysis set u nless ot her wise s pecifi e d.  
8. 2.  
D ur ati o n of E x p os ure t o St u d y Dr u g   
P atie nts will  be a d mi nistere d t he st u d y dr u g at visit 3  a n d recei v e a t otal of 4 sc i njecti o ns i n t he 
a b d o me n.  
T he n u m ber of patie nts w h o recei ve d t he st u d y dr u g, t he n um ber of i njecti o n recei v e d, a n d 
reas o ns f or I M P n ot a d mi nistrate d (a d verse e v e nt or ot her) will be s u m mari ze d usi n g descri pti ve 
statistics. 
I M P a d mi nistrati o n a n d I M P acc o u nta bilit y dat a will be liste d usi n g safet y a nal ysis s et. 
8. 3.  
A d verse E ve nts  
A d verse e ve n ts will be rec or de d fr o m ti me i nf or me d c o nse nt is o btai ne d t hr o u g h t he e n d of st u d y 
partici pati o n.  
All a d verse e ve nts will be c o de d usi n g Me d D R A . Eac h patie nt will be c o u nte d o nl y o nce i n eac h 
preferre d t er m or S O C  cate g or y f or t he a nal yses of safet y.  S u m maries will i ncl u de 
treat me nt-e mer ge nt a d v erse e ve nts w hi c h are defi ne d as a d verse e v e nts oc c urri n g at or after t h e 
first d ose of t he I M P t hr o u g h t he e n d of t he f oll o w-u p visit. Listi n gs will i ncl u de all a d verse 
e ve nts rec or de d.  
S u m maries will be prese n te d f or all 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 he i n vesti gat or t o b e rel ate d t o test I M P ( defi 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 d verse e v e nts ca usi n g dr u g 
w it h dra wal or disc o nti n u ati o n  fr o m t he st u d y, pr ot oc ol -defi ne d a d verse e v e nts of s pecial i nterest 
( P D A E SI), a n d P D A E SI re q uire c o m pleti o n of s us pecte d a n a p h yla xis . A d verse e v e nts wit h t he 
missi n g fla g i n dicati n g s eri o us will be e x cl u de d fr o m t he s u m mar y of s eri o us a d verse e ve nts b ut 
i ncl u de d i n t he s u m mar y of n o n-seri o us a d v erse e ve nts. 
Listi n gs f or deat hs, seri o us a d verse e ve nts, a d v erse e ve nts lea di n g t o dr u g wit h dra w n or t he 
st u d y disc o nti n uati o n,  P D A E SI , a n d P D A E SI re q uire c o m pleti o n of s us pecte d a na p h yl a xis. I n 
a d diti o n, listi n gs f or Me d D R A dicti o nar y ter ms f or a d verse e ve nt  d esc ri pti o ns a n d a d verse e v e nt 
preferre d t er ms  b y patie nt n u m ber a n d treat me nt gr o u p will be prese nte d.  
A d verse e ve nts f or p atie nts w h o di d n ot meet scree ni n g criteria will be liste d. 
8. 4.  
I njecti o n Site Assess me nts 
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 
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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 a ble  2 : 
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  
T he i njecti o n site assess me nts (er yt he ma, ecc h y m osis, i n d urati o n, te n der ness, war mt h, a n d 
s welli n g) at eac h visit  will be s u m marize d usi n g descri pti ve statistics . F or N R S -1 1 scale, t he 
w orst pai n sc ore o v erall a n d t he pai n sc ore at eac h visit will be s u m marize d descri pti vel y.   
I n or der t o a cc o u nt f or b ot h place b o a n d T E V-5 3 2 7 5 i njecti o ns i n t he 6 0 0 m g d ose, t he 
s u m maries will be s plit i nt o t hree c ol u m ns: place b o i njecti o ns, T E V-5 3 2 7 5 i njecti o ns a n d t otal.  
T he data will be liste d usi n g safet y a nal ysis set , s orte d b y treat me nt gr o u p, s u bject I D, visit, a n d 
i njecti o n. T he st u d y me di cati o n a d mi nistere d f or eac h i njecti o n will als o be liste d.  
8. 5.  
H y perse nsiti vit y/ A n a p h yl a xis  
T he e ve nt of a na p h yla xis is c o nsi dere d as a P D A E SI . T he i nf or mati o n a b o ut all s us pecte d 
a na p h yla xis a n d h y perse nsiti vit y e v e nts will be rec or de d o n t he S us pecte d A na p h yl a xis C R F. 
P D A E SI will be s u m maries ( Secti o n  8. 3 ).  
S us pecte d a na p h yla xis data will b e liste d. 
8. 6.  
De at h s 
If a n y patie nt dies d uri n g t he st u d y , all rele va nt i nf or mati o n will be disc usse d i n t he patie nt 
narrati ve i n cl u de d i n t he cli nical st u d y re p ort . 
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8. 7.  
Cli nic al L a b or at or y Tests  
Cli nical la b orat or y tests (ser u m c he mistr y, he mat ol o g y , c o a g ulati o n, 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 of t he st u d y pr ot oc ol. Cli nical la b orat or y tests 
will be perf or me d usi n g t he ce ntr al la b orat or y.  
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 nifica 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 be d 
i n Secti o n 7. 1. 2 of t he st u d y pr ot o c ol. ( 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 nterin 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 vers e e ve nts.)  
La b orat or y test r es ults will be prese nte d i n  sta n dar d i nter nati o nal ( SI) u nits i n s u m maries. 
La b orat or y v al ues a n d c h a n ges fr o m bas eli ne t o eac h visit a n d Last Assess me nt will be 
s u m marize d usi n g descri pti ve statistics.  S hifts ( bel o w [l o w], wit hi n [ n or mal], a n d a b o ve [ hi g h] 
t he n or mal ra n ge) fr o m b aseli ne t o eac h p ost baseli ne visit a n d t he Last Assess me nt will be 
s u m marize d usi n g patie nt c o u nts. Baseli ne is defi ne d as t he last o bser ve d data b ef ore t he 
a d mi nistrati o n of t he first d ose of t he I M P (als o see Secti o n  4. 2 ). 
T he p ote ntiall y cli nicall y si g nifica nt a b n or mal val ues will be deri ve d usi n g criteria s pecifie d i n 
Ta ble  3  base d o n all p ost baseli ne val ues (i n cl u di n g s c h e d ule d, u nsc h e d ule d, a n d wit h dra wal 
visits). T he o verall i nci de nce of p ote ntiall y cli nicall y si g nifica nt a b n or mal v al ues will be 
s u m marize d f or la b orat or y varia bles usi n g descri pti ve statistics b y treat me nt gr o u p.  Listi n gs f or 
patie nts w h o ha ve p ote ntial l y cli nicall y si g nifica nt a b n or mal la b orat or y dat a will be prese nt e d. 
N ote t hat: T he U L N f or s o me test para meters ma y de pe n d o n de m o gra p hic para meters s uc h as 
ge n d er  (e. g. creati ne p h os p h o ki nase).   
T a ble  3 : 
Criteri a f or P ote nti all y Cli nic all y Si g nific a nt L a b or at or y V al ues  
Test  
Criteri o n v al ue  
Ser u m c he mistr y  
 
  Ala ni ne a mi n otra nsferase ( A L T)  
3 x U L N  
  As partate a mi n otra nsferase ( A S T)  
3 x U L N  
 Al kali ne p h os p hatase ( A L P ) 
3 x U L N  
  Ga m ma -gl uta m yl tra ns pe pti d ase ( G G T)  
3 x U L N  
  Lactate de h y dr o ge nase ( L D H)  
3 x U L N  
  Bl o o d urea nitr o ge n ( B U N)  
1 0. 7 1 m m ol/ L  
  Creati ni ne  
1 7 7 m ol/ L  
  Bilir u bi n (t otal)  
3 4. 2 m ol/ L  
C reati ne p h os p h o ki nase 
3 x U L N  
He m at ol o g y  
 
He mat ocrit  
Me n  
< 0. 3 7 L/ L  
 
W o me n  
< 0. 3 2 L/ L  
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Test  
Criteri o n v al ue  
He m o gl o bi n  
Me n  
1 1 5 g/ L  
 
W o me n  
9 5 g/ L  
W B C c o u nts  
3 x 1 0 9/ L  
2 0 x 1 0 9/ L 
 
 
A bs ol ute ne utr o p hil c o u nt ( A N C ) 
1 x 1 0 9/ L 
Platelet c o u nts  
7 5 x 1 0 9/ L  
7 0 0 x 1 0 9/ L 
Uri n al ysis  
 
   He m o gl o bi n  
2 u nit i ncrease fr o m baseli ne  
Gl uc ose  
2 u nit i ncrease fr o m baseli ne  
Ket o nes  
2 u nit i ncrease fr o m baseli ne  
T otal pr otei n  
2 u nit i ncrease fr o m baseli ne  
U L N = u p per li mit of n or mal ra n ge; W B C = w hite bl o o d cell  
8. 7. 1.  
Ot her Cli nic al L a b or at or y Tests  
At scree ni n g, p atie nts will be teste d f or he p atitis B s urface a nti ge n ( H Bs A g), a nti b o dies t o 
he patitis C vir us ( H C V), 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 n d T u berc ul osis 
test. 
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 ollicle sti m ulati n g h or m o n e ( F S H) assess me nt t o c o nfir m 
p ost me n o pa usal stat us.  
B eta h u ma n c h ori o nic g o na d otr o pi n  (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 of t he st u d y pr ot oc ol . 
Testi n g of patie nts as y m pt o matic f or C O VI D -1 9 ac ti 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 . C O VI D -1 9 testi n g ma y b e c o n d uct e d 
b y t he ce ntral la b orat or y or l ocall y.  
Ot her  cli nical la b orat or y tests res ults will be liste d.  
8. 8.  
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 of t he st u d y 
pr ot oc ol.  
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 of t he st u d y pr ot oc ol.  
A b n or mal p h ysi cal e x a m i nati o n fi n di n gs will be liste d a n d s u m marize d des cri pti vel y. 
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8. 9.  
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  of  t he st u d y pr ot oc ol. A n y vital si g n 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 me ntati o n a n d t he C R F as a n a d v erse e ve nt, a n d m o nit ore d as descri b e d i n Secti o n  7. 1. 2 of 
t he pr ot oc ol. 
Hei g ht a n d wei g ht will be o btai ne d at t he at t he ti me p oi nts detaile d i n Ta ble 2 of t he st u d y 
pr ot oc ol.  
Vital si g ns  (i ncl u di n g wei g ht  a n d B MI) v al ues a n d c ha n ges fr o m baseli ne t o eac h visit a n d t he 
Last Ass ess me nt will be s u m mariz e d usi n g descri pti ve statistics.  T h e i nci de nce of p ot e ntiall y 
cli nicall y si g nifica nt a b n or mal val ues will be s u m marize d f or selecte d vital si g ns usi n g 
descri pti ve statistics.  Bas eli ne is defi ne d as t he l ast o bser ve d data bef ore t h e a d mi nistrati o n of 
t he first d ose of t he I M P (als o see Sectio n 4. 2 ). 
Ta ble  4  s pecifi es t he crit eria f or i d e ntif yi n g vital si g ns as p ote ntiall y cli nicall y si g nifi ca nt 
a b n or mal  val ues . N ot e t hat i n or der t o q ualif y  as p ote ntiall y cli nicall y si g nifica nt a b n or m al, a 
val ue nee d s t o meet b ot h criteria b el o w: ie, ha ve a val ue be y o n d t he criteri o n val ue a n d a c ha n ge 
of at least t he ma g nit u de s pecifie d i n t he c h a n ge  relati ve t o baseli ne c ol u m n.  T he p ote ntiall y 
cli nicall y si g nifica nt a b n or mal vital si g ns val ues will i ncl u de all p ost baseli ne val ues (i ncl u di n g 
sc he d ule d, u nsc h e d ule d, a n d earl y wit h dr a wal  visits) f or t he s u m maries.  
T a ble  4 : 
Criteri a f or P ote nti all y Cli nic all y Si g nific a nt Vit al Si g ns  
Vit al Si g n  
Criteri o n v al ue  
C h a n ge rel ati ve t o b aseli ne  
P ulse  
1 2 0 b p m  
I ncrease of 1 5 b p m  
 
5 0 b p m  
Decrease of 1 5 b p m  
S yst olic bl o o d press ure  
1 8 0 m m H g  
I ncrease of 2 0 m m H g  
 
9 0 m m H g  
Decrease of 2 0 m m H g  
Diast olic bl o o d press ure  
1 0 5 m m H g  
I ncrease of 1 5 m m H g  
 
5 0 m m H g  
Decrease of 1 5 m m H g  
T e m perat ure  
≥3 8. 3 C  
C ha n ge of 1. 1 C  
Res pirat or y rate  
> 2 4  breat hs/ mi n  
I ncrease > = 1 0 
 
< 6  breat hs/ mi n  
N ot a p plica ble  
B p m = beats per mi n ute  
8. 1 0.  
Electr oc ar di 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 of t h e st u d y pr ot o c ol. 
E C Gs s h o ul d be perf or m e d i n a s u pi ne p ositi o n.  Sta n dar d E C Gs para meters will be rec or de d 
usi n g a ce ntralize d pr ocess a n d t he E C G will be i nter prete d l o call y b y t h e pri nci pal i n vesti gat or 
( or q ualifie d p h ysicia n). A d diti o nall y, a q ualifie d 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 h e ce ntral r ea der s h o ul d b e use d.  All E C G res ults o utsi de 
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t he refere n ce ra n ges will be j u d ge d b y t he i n vesti gat or ( or q ualifi e d p h ysi cia n) as bel o n gi n g t o 
o ne of t he 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 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 esti 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 of t he st u d y 
pr ot oc ol.  
W here tri plicate meas ur e me nts are re q uire d ( at 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.  
At D o R visit E C G will be perf or me d i n tri plicate , 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.   F or a nal ysis p ur p ose, t he mea n of rec or de d res ults fr o m t he 3 meas ure me nts  
will be calc ulate d a n d us e d f or t he a nal ysis.  F or E C G fi n di n gs , t he last meas ure me nt bef ore t he  
first d ose of I M P will be use d f or a n al ysis.  
E C G varia ble res ults a n d c ha n ges fr o m baseli ne t o eac h visit a n d t he Last Assess me nt will be 
s u m marize d usi n g descri pti ve statistics.  
Baseli ne E C G fi n di n gs a n d s hifts ( n or mal , a b n or mal  n ot cli nical l y si g nifica nt, a n d a b n or mal 
cli nicall y si g nifica nt) fr o m baseli ne t o  eac h visit,  o verall  ( w orst v al ue f or a patie nt), a n d t he Last 
Assess me nt  will be s u m mariz e d usi n g patie nt c o u nts . 
I n a d diti o n, t he i nci de nce of patie nts meeti n g t he f oll o wi n g p ote ntiall y cli nicall y si g nifica nt 
t hres h ol ds will be prese nte d usi n g des cri pti ve statistics:  
•  C o m bi ne d a bs ol ute Q Tc Bazett a n d Fri derici a i nter val pr ol o n gati o ns pl us c ha n ge 
fr o m baseli ne i n Q T c Bazett a n d Fri dericia i nter val t o wee k 5 2 a n d e n d p oi nt 
− Q Tc i nter val > 4 5 0 msec a n d Q Tc i nter val i ncreas es fr o m baseli ne > 3 0 msec  
− Q Tc  i nter val > 4 5 0 msec a n d Q Tc i nter val i ncreas es fr o m baseli ne > 6 0 msec 
− Q Tc i nter val > 5 0 0 msec a n d Q Tc i nter val i ncreas es fr o m baseli ne > 3 0 msec  
− Q Tc i nter val > 5 0 0 msec a n d Q Tc i nter val i ncreas es fr o m baseli ne > 6 0 msec   
•  Q R S d urati o n > 1 1 0 msec a n d a 2 5 % i ncrea s e fr o m baseli ne 
•  P R i nter val > 2 0 0 msec a n d a 2 5 % i ncrease fr o m baseli ne  
8. 1 1.  
C o nc o mit a nt Me dic ati o ns or T her a pies  
C o nc o mita nt me dicati o n s, treat me nts, or pr oce d ures will be c ollecte d  u p t o t he e n d of st u d y . 
All c o nc o mita nt me dicati o ns will be c o de d usi n g t he W H O Dr u g. T he i nci d e nce of c o nc o mita nt 
me dicati o ns will be s u m marize d usi n g descri pti ve statistics b y  t hera pe utic class a n d preferre d 
ter m. Patie nts are c o u nt e d o nl y o nce i n eac h t hera pe utic class cate g or y, a n d o nl y o nce i n eac h 
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preferre d t er m cat e g or y.  T h e c o nc o mita nt me dicati o ns will i ncl u de a ll me dicati o ns ta ke n after 
a d mi nistrati o n of t he first I M P. 
Ast h ma me dicati o ns will be s u m marize d b y t he m e dicati o n class se p arat el y . 
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9.  
T O L E R A BI LI T Y V A RI A B L E S A N D A N A L Y SI S  
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 will be 
s u m marize d descri pti vel y. 
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1 2.  
I M M U N O G E NI CI T Y A N A L YSI S  
I m m u n o ge nicit y a n al yses are o utsi de of t he s c o pe of t his S A P.  
Listi n g(s) of patie nts wit h p ositi ve A D A sa m ple(s) a n d patie nt  A D A stat us will be pr o vi de d  if 
a p plica ble.  
 
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1 3.  
P L A N N E D I N T E RI M A N A L Y SI S  
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 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  p atie 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 assess t he earl y efficac y data. 
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 detect 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 nal ysis, s o t hat t he st u d y m a y be ter mi nate d earl y 
if b ot h T EV -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 criteri a. T hese a nal yses will be descri b e d i n details i n Secti o n  1 3. 1 . 
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 .  
 
 
 
 
 
 
 
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 utilit 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 . H o we ver, t h e fea bilit y of st o ppi n g  
t he trial earlier wit h a s maller sa m ple siz e is e val u ate d base d o n t he wee k 1 2  efficac y e n d p oi nt, 
ie, c ha n ge fr o m baseli ne at wee k 1 2  i n m or ni n g tr o u g h F E V1. 
T he sa me Ba yesi a n a nal ysis f or t he fi nal pri mar y efficac y a nal ysis will be a p plie d t o t he wee k 8 
a n d wee k 1 2 e n d p oi nts, as a p plica ble, t o deri v e t he  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 p erf or mi n g b etter t ha n t he place b o gr o u p i n ter ms of t he wee k 8 e n d p oi nt a n d t he p osteri or 
p r 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 h a n t he place b o gr o u p  i n ter ms of 
t he wee k 1 2 e n d p oi nt  usi n g t he i nteri m a n al ysis data . 
1 3. 1. 1.  
 
 
 
 
 
 
 
  
 
 
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1 3. 1. 3.  
E arl y S t o p pi n g wit h a S m aller S a m ple S ize 
D ue t o c halle n ges i n patie nt e nr oll me nt i n t he face of C O VI D -1 9 p a n de mic, t he feasi bilit y of a n 
earl y st o p pi n g of t he trial wit h s maller sa m ple siz es will  als o be e val uate d d uri n g t he i nteri m 
a nal ysis.  T h e u n bli n de d assess me nt is base d 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)  
f or t he pri mar y effi cac y e n d p oi nt ( 1 2-wee k e n d p oi nt).  
T he fi nal trial sa m ple siz e w o ul d be re d uce d t o a s maller n u m ber acc or di n g t o t he f oll o wi n g 
criteria:  
1.  Re d uce t o  8 0 per ar m i n case of “ Ver y g o o d” effi cac y si g nal:  
P osteri or pr o b a bility  ≥ 0. 9 5;  
2.  Re d uce t o  9 0 per ar m i n case of “ G o o d” effi cac y si g nal:  
0. 9 5  > P osteri or pr o b a bility  ≥ 0. 9 ; 
3.  Kee p 1 0 0  per ar m w h e n t he effi cac y si g nal is n ot as g o o d, b ut n ot f utile:  
P osteri or pr o b a bility  < 0. 9.  
Si m ulati o ns were c o n d ucte d t o assess t he o perati n g c h aracteristics of t he earl y st o p pi n g r ules . 
T he si m ulati o ns t o o k i nt o acc o u nt t he  n o n -bi n di n g f utilit y st o p pi n g  s pecifie d i n Secti o n  1 3. 1. 2 . 
W he n t he f utilit y criteri o n is met,  a si m ulate d trial is st o p pe d d ue t o f utilit y wit h a pr o ba bilit y of 
5 0 % or 3 0 %. F or t he p ur p ose  of esti mati n g t y pe 1 err or rates a n d st u d y p o wers usi n g 
si mulati o ns , t he p osteri or distri b uti o ns f or t he mea n res p o nses were d eri ve d usi n g t he c o nj u gat e 
pri ors f or t he mea ns  wit h a k n o w n sta n dar d de viati o n of 0. 3 5 L  i n t he Ba yesia n a nal ysis. T he 
pri ors f oll o w  n or mal dist ri b uti o ns wit h mea n 0 f or all treat me nt gr o ups . T h e si m ulati o ns ass u me d 
a 1 0 % dr o p o ut r ate a n d 5 0 0 0 si m ulati o ns r u n were use d i n eac h s ce nari o.  
Ta ble  6  bel o w  s u m marizes t he si m ulati o n res ults f or a ra n ge of treat me nt effects, i ncl u di n g t he 
o verall st u d y p o wer u n der t he st u d y d esi g n, t he pr o ba bilit y of meeti n g t he “ Ver y g o o d ” a n d 
“ G o o d” effic ac y criteria at t he i nteri m a nal ysis, as well as t he c o n diti o nal p o wer gi ve n t hat t he 
sa m ple siz e re d ucti o n criteria are met at t he i nteri m a nal ysis.  T he res ults   s h o we d t hat t he earl y 
st o p pi n g r ules di d n’t c o m pr o mise t he t y pe 1 err or c o ntr ol (c o ntr olle d at 1 5 % u n der t he n ull 
h y p ot hesis ). T h e o verall st u d y p o wer is mai ntai ne d at a p pr o xi matel y t he sa me le vel 
(a p pr o xi matel y 8 0 % w h e n t he hig h -d os e treat me nt effect = 0. 1 L) . I n a dditi o n, it is reass uri n g t hat, 
w he n t he earl y st o p pi n g criteria are met a n d t he s a m ple siz e is re d uce d, t h e c o n diti o nal p o wer is 
hi g h  ( > 9 4 % i n all sce n ari os). It e ns ures t hat t he d ecisi o n t o st o p earl y wit h a s maller sa m ple siz e 
is ma de wit h hi g h ass ur a nce of fi n al s uccess, d es pite a s maller sa m ple siz e t o be use d. It’s als o 
w ort h n oti n g t hat t here is a 4 4 % t o 6 8 % of c ha nce t o meet t he earl y st o p pi n g criteria d u e t o 
“ Ver y g o o d ” a n d “ G o o d” e ffic ac y res ults u n der t h e alter nati ve h y p ot h eses, b ut a n a p pr o xi matel y 
1 0 % c ha nce u n der t he n ull h y p ot hesis.  
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Fr o m a practical sta n d p oi nt, if t he site pers o n nel lear ne d a b o ut t he pl a n f or t he earl y st o p pi n g 
wit h re d uce d s a m ple siz e u si n g t he u n bli n de d assess ms net of i nteri m data, t here ca n be a 
p ote ntial u n bli n di n g a n d biasi n g  ris k. W he n t he decisi o n is ma de t o earl y st o p t he trial wit h a 
s maller sa m ple siz e, t he site pers o n nel ca n g uess a b o ut t he treat me nt efficac y a n d it ca n bias t heir 
vie ws. T heref ore, fa v ora ble acti o ns ma y be ta ke n t o war d s t he acti ve treat m e nt s u bc o nsci o usl y or 
c o nsci o usl y. I n or der t o alle vi ate t his c o ncer n, t he earl y st o p pi n g pl a n is c o nceale d i n t he 
pr ot oc ol a me n d me nt 1, b ut is o nl y d escri be d i n t h e S A P.  W he n a  decisi o n o n earl y st o p pi n g is 
ma de, it will be d oc u me nte d a n d t he re d u ce d s a m ple siz e ( 2 4 0 or 2 7 0) will be c o m m u nicate d t o 
t he st u dy tea m. H o we ver, i n or der t o mi ni mize t he p ote ntial ris k of biasi n g t he site pers o n nel , t he 
decisi o n  will n ot be re veale d t o sites u ntil  t he e nr ol me nt is cl ose t o reac hi n g t he re d uce d sa m ple 
siz e g oal.     
1 3. 2.  
T he E xec uti o n of t he I nteri m An al 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 statisticia 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 
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 the 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 uct i nte grit y, a data re vie w c h arter will be 
fi nalize d pri or t o t he i nteri m a nal ysis. T h e c harter will s pecif y t h e pr ocesses f or pr o perl y 
u n bli n di n g , st ori n g a n d a nal yzi n g t h e i nteri m data, a n d t he c o m m u nicati o n pla n t o disse mi nate 
t he u n bli n de d st u d y res ults i n a sec ure fas hi o n. T h e pr ocess es will be f oll o we d t o e ns ure t h at t he 
st u d y bli n d be mai ntai ne d i n t he bli n de d st u d y pers o n nel 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 b li n de d 
safet y re vi e w. 
 
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1 4.  
S T A TI S TI C A L S O F T W A R E  
All data listi n gs, s u m maries, a n d statistical a nal ys es will be ge nerate d usi n g S A S ®  versi o n 9. 4 or 
later. 
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1 5.  
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N T H E S T U D Y 
P R O T O C O L  
I n t he pr ot oc ol, it is pr o p ose d t o esti mate t he p osteri ors of t he Ba yesia n l o n git u di nal li near 
m o del, t o get her wit h t he Ba yesi a n d ose -res p o nse m o del, b y usi n g a m ulti ple i m p utati o n wit h 
c hai ne d e q u ati o ns ( MI C E) pr oce d ure. T his met h o d i m p utes missi n g wee k 1 2 data, b y usi n g t he 
l o n git u di nal m o del i n t he case of c o m plete o bser vati o ns of pri or visit data a n d c o vari ates i n t he 
m o del, or b y t he d os e -res p o nse m o del i n t he case of missi n g pri or visit data or c o variates i n t he 
l o n git u di nal m o del . T he t w o m o del para met ers are u p date d i n  l o o ps a n d t he i m p utati o n of 
missi n g data uses t he m ost u p date d m o del para m eters at eac h ste p. T his al g orit h m i s diffic ult t o 
i m ple me nt a n d ca n ha v e c o n ver ge n ce iss ues.  
It is re pl ace d b y a m ulti ple i m p utati o n met h o d descri be d i n Secti o n  6. 2. 2  of t he statistical 
a nal ysis pla n . T h e re place me nt met h o d is e x pecte d t o be t o pr o d uce relia bl e esti mates ( Z h o u et 
al, 2 0 1 0) a n d is eas y t o i m ple me nt. Si m ulati o n st u dies were p erf or me d t o c o m pare t he m et h o d 
wit h a c o m para bl e fre q ue ntist a nal ysis usi n g m ulti ple i m p utati o ns a n d s h o we d c o m para ble 
res ults (Secti o n  1 6. 2 ). 
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1 6.  
A P P E N DI X  
1 6. 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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1 6. 2.  
A p pe n di x B: Si m ul ati o n Res ults t o Assess t he B a yesi a n A n al ysis 
usi n g M ulti ple I m p ut ati o ns  f or Missi n g D at a H a n dli n g  
A ra n d o m sa m ple is ta ke n fr o m a pre vi o us st u d y ( C E P 3 8 0 7 2-A S -3 0 8 2) c o m pari n g t he s afet y a n d 
effic ac y of a n ot her aI L 5 pr o d uct wit h place b o. T h e sa m ple i ncl u de d 1 0 0 s u bjects i n eac h 
treat me nt gr o u p f or a t otal of 2 0 0 s u bjects wit h t he f oll o wi n g data: t w o stratificati o n varia bles, 
bas eli ne F E V 1 val ue, c ha n ges fr o m baseli ne i n m or ni n g tr o u g h F E V 1 at wee k 4, wee k 8, wee k 1 2 
a n d wee k 1 6. T he w ee k 1 6 e n d p oi nt was use d as t he pri mar y e n d p oi nt i n t his si m ulati o n.  
T he missi n g / o bser ve d d ata patter ns fr o m t his sa m ple are s h o w n i n T a ble 7 , w hic h ma y be 
i n dicati ve of t he missi n g data patter n i n t he c urre nt st u d y. T he patter ns s u m marize d i ncl u de t hree 
cate g ories: t he c o m plete cases, s u bjects wit h i nter mitte nt missi n g data, a n d s u bjects w h o ha d 
o bser vati o ns a vaila ble pri or t o dr o p pi n g o ut fr o m st u d y wit h o ut f urt her o bs er vati o ns.  
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
T he res ults fr o m t he Ba yesia n a nal ysis wit h m ulti ple i m p utati o ns f or missi n g dat a ha n dli n g, 
descri be d i n  Secti o n  6. 2. 2  , are c o m p are d wit h t he a nal ysis of c o varia nce wit h m ulti ple 
i m p utati o ns. T w o m ulti ple i m p utati o n met h o ds are use d: 1) b y treat me nt gr o u p ( T R T-base d); 2) 
usi n g t he c o ntr ol gr o u p d ata f or b ot h  treat me nt gr o u ps (C o ntr ol -base d). T a ble 8  bel o w s h o w t he 
a nal ysis res ults.  
T he res ults s h o w t hat t he Ba yesi a n a nal ysis a n d A N C O V A wit h m ulti ple i m p utati o ns pr o d uce d 
si milar res ults. T his is e x pecte d beca use t h e Ba yesia n a nal ysis uses n o n -i nf or mati ve pri ors f or 
t he mea n a n d v aria nce para meters.  I n a d diti o n, t he treat me nt differe n ce esti mates usi n g t he 
c o ntr ol-base d m ulti ple i m p utati o ns pr o d uce d a s maller treat me nt effect, b ut it was si milar t o t he 
res ult o btai ne d wit h m ulti ple i m p utati o ns b y tr eat me nt gr o u p. T h e c o ntr ol-base d m ulti ple 
i m p utati o n met h o d is e x pecte d t o be c o nser vati ve f or esti mati n g t he treat me nt effect. Si nce t he 
o verall perce nta ge of missi n g data is s mall ( < 1 0 % o verall), t he differe nc e was s mall. As a res ult, 
t he sa me c o ncl usi o ns ca n be ma de bas e d o n t he p osteri or pr o ba bilit y or t he p -val ue .  
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I n c o ncl usi o n, t he si m ulati o n st u d y s h o ws t h at t he Ba yesi a n a nal ysis wit h m ulti ple i m p utatio ns 
met h o d ge n erat es relia bl e esti mates.  
      
 
 
 
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 7.  
R E F E R E N C E S  
1.  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 d e. Ne w Y or k: Ca m bri d ge 
U ni versit y Press, 2 0 1 3; 1 0 3 -1 0.  
2.  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 
spir o metr y me as ure m e nts i n ast h ma patie nts recei vi n g becl o met has o ne. Res pir Me d 
2 0 1 9; 1 5 1: 3 5 -4 2.  
3.  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 des o ni de a n d f or m oter ol i n o ne metere d -d os e i n haler c o m pare d wit h b u d es o ni de al o ne 
a n d f or m oter ol al o n e 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.  
4.  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 nh ale d sal meter ol a n d fl uticas o ne: 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.  
5.  Z h o u X, Reiter J. A n ote o n Ba yesi a n I nfere n ce after M ulti ple I m p utati o n. T he A merica n 
Statisticia n. Ma y 2 0 1 0, V ol 6 4, N o. 2: 1 5 9 -1 6 3.  
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