A Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Biomarker Study of the Effects of Dexpramipexole on Eosinophils in Subjects With Eosinophilic Asthma
Phase: PHASE2
Conditions: Eosinophilic Asthma, Asthma
Sponsor: Knopp Biosciences

 
 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 
S P O N S O R:  
K n o p p Bi oscie nces L L C  
2 1 0 0 W hart o n Street, S uite 6 1 5 
Pitts b ur g h, P A 1 5 2 0 3 
P R O T O C O L N U M B E R:  
K N S - 7 6 0 7 0 4- A S 2 0 1 
P R O T O C O L TI T L E:   
A Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d D ose- Ra n gi n g 
Bi o mar ker St u d y of t he Effects of De x pra mi pe x ole o n E osi n o p hils 
i n S u bjects wit h E osi n o p hilic Ast h ma 
I N D #: 
1 2 2, 7 4 6 
P R O D U C T: 
De x pra mi pe x ole ( K N S- 7 6 0 7 0 4)  
D A T E: 
J ul y 1 6, 2 0 1 9 
V E R SI O N:  
 

Pr ot o c ol   K  N S- 7 6 0 7 0 4-  A S 2 0 1 
 
Eff e cts  of  d e x pr a  mi p e x ol e  o n  e osi n o p hil  bi o  m ar k ers i n  ast h  m a 
J ul y  1 6,  2 0 1 9 
C  O  N FI  D E  N TI  A L 
T h e i nf or  m ati o n  c o nt ai n e d  h er ei n   m a y  n ot  b e  us e d,  dis cl os e d,  or   p u blis h e d   wit h o ut t he   writt e n  c o ns e nt  of  
K n o p p   Bi os ci e n c es  L L  C 
2 
1.    
SI  G  N  A  T  U  R  E  P  A  G  E 
 
Pr ot o c ol   K  N S- 7 6 0 7 0 4-  A S 2 0 1,  Fi n al     
   w as  a p pr o v e d  b y: 
J ul y  1 6,  2 0 1 9    
 
D at e 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 
2.    
S P O N S O R/ C R O I N F O R M A TI O N 
K n o p p Bi oscie nces L L C   
2 1 0 0 W hart o n Street, S uite 6 1 5 
Pitts b ur g h, P A 1 5 2 0 3, U S A  
 
 
K n o p p Me dic al M o nit or 
 
 
 
 
 
 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 
 T A B L E O F C O N T E N T S 
1.  
SI G N A T U R E P A G E .................................................................................................... 2 
2.  
S P O N S O R/ C R O I N F O R M A TI O N .............................................................................. 3 
3.  
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 ................................................. 1 0  
4.  
S Y N O P SI S ................................................................................................................. 1 3  
5.  
S C H E D U L E O F E V E N T S ......................................................................................... 1 9  
6.  
I N T RO D U C TI O N A N D R A TI O N A L E ..................................................................... 2 2  
6. 1.  
O ver vi e w ..................................................................................................................... 2 2  
6. 2.  
De x pra m i pe x ole Bac k gr o u n d ..................................................................................... 2 2 
6. 3.  
Pre vi o us E x perie nce  ................................................................................................... 2 3 
6. 3. 1.  
N o ncli nical De vel o p me nt ........................................................................................... 2 3  
6. 3. 2.  
Cli ni cal E x perie nce wit h De x pra mi pe x ole ................................................................. 2 3  
6. 4.  
Rati o nale f or St u d y P o p ulati o n ................................................................................... 2 4  
6. 5.  
Rati o nale f or St u d y Desi g n ......................................................................................... 2 5  
6. 6.  
Rati o nale f or D ose a n d Re gi me n Selecti o n ................................................................ 2 5  
7.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S .............................................................. 2 8  
7. 1.  
O bject i ves ................................................................................................................... 2 8 
7. 1. 1.  
Pri m ar y O bjecti ve ....................................................................................................... 2 8  
7. 1. 2.  
Sec o n dar y O bjecti ves ................................................................................................. 2 8  
7. 1. 3.  
E x pl or at or y O bjecti ves ............................................................................................... 2 8  
7. 2.  
E n d p oi nt s .................................................................................................................... 2 9 
7. 2. 1.  
Pri m ar y E n d p oi nt ........................................................................................................ 2 9  
7. 2. 2.  
Sec o n dar y E n d p oi nts .................................................................................................. 2 9  
7. 2. 3.  
E x pl or at or y E n d p oi nts ................................................................................................ 2 9  
8.  
S T U D Y D E SI G N ....................................................................................................... 3 1  
8. 1.  
St u d y O ver vi e w .......................................................................................................... 3 1 
8. 1. 1.  
O veral l St u d y D urati o n a n d F oll o w-U p  ..................................................................... 3 2 
8. 2.  
St u d y Per i o ds .............................................................................................................. 3 3 
8. 2. 1.  
R u n -i n Peri o d .............................................................................................................. 3 3 
8. 2. 2.  
Pri m ar y Assess me nt Peri o d ........................................................................................ 3 3  
8. 2. 3.  
E osi n o p hi l Rec o ver y Peri o d ....................................................................................... 3 4 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 
8. 3.  
St u d y Sc he d ul e ........................................................................................................... 3 4  
8. 3. 1.  
Scre e ni n g .................................................................................................................... 3 4  
8. 3. 1. 1.  
Scre e ni n g P ul m o nar y F u ncti o n Testi n g ...................................................................... 3 5  
8. 3. 2.  
Basel i ne ....................................................................................................................... 3 5 
8. 3. 2. 1.  
Basel i ne P ul m o nar y F u ncti o n Testi n g ........................................................................ 3 7 
8. 3. 3.  
W ee k 2 Visit ............................................................................................................... 3 7  
8. 3. 4.  
W ee k 4 Visit ............................................................................................................... 3 7  
8. 3. 5.  
W ee k 6 Visit ............................................................................................................... 3 8  
8. 3. 6.  
W ee k 8 Visit ............................................................................................................... 3 8  
8. 3. 7.  
W ee k 1 2 - Pri mar y O utc o me Visit  ............................................................................. 3 9 
8. 3. 8.  
W ee k 1 6/ 1 8 Visit ........................................................................................................ 4 0  
8. 3. 9.  
W ee k 2 0 Visit ............................................................................................................. 4 0 
8. 3. 1 0.  
W ee k 2 4 E n d of St u d y Visit  ....................................................................................... 4 1 
8. 3. 1 1.  
Pre m at ure Disc o nti n uati o n Visit ................................................................................. 4 1  
8. 4.  
St u d y St o p pi n g R ules ................................................................................................. 4 1  
8. 5.  
E n d of  St u d y ............................................................................................................... 4 1 
9.  
S E L E C TI O N O F S U BJ E C T S .................................................................................... 4 2  
9. 1.  
I ncl usi o n Criteria ........................................................................................................ 4 2 
9. 2.  
E xcl usi o n Criteria ....................................................................................................... 4 2  
1 0.  
E N R O L L M E N T P R O C E D U R E S .............................................................................. 4 5  
1 0. 1.  
E n r oll me nt .................................................................................................................. 4 5 
1 0. 2.  
Ra n d o mizati o n ............................................................................................................ 4 5  
1 0. 3.  
Bli n di n g ...................................................................................................................... 4 5  
1 0. 3. 1.  
Bli n di n g of C B C Res ults ............................................................................................ 4 5  
1 1.  
S T U D Y D R U G, C O N C O MI T A N T T H E R A P Y A N D C O N C O MI T A N T 
P R O C E D U R E S .......................................................................................................... 4 7  
1 1. 1.  
De x pra m i pe x ole a n d Place b o ..................................................................................... 4 7 
1 1. 2.  
St u d y Dr u g St or a ge ..................................................................................................... 4 7  
1 1. 3.  
St u d y Dr u g Acc o u nt a bilit y ......................................................................................... 4 7  
1 1. 4.  
St u d y D osi n g a n d D osi n g A d here nce ......................................................................... 4 8  
1 1. 5.  
S mart B ottle Ma na ge me nt .......................................................................................... 4 8  
1 1. 6.  
St u d y Dr u g Pre ca uti o ns .............................................................................................. 4 9  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 
1 1. 7.  
Disc o nt i n uati o n of St u d y Dr u g ................................................................................... 4 9 
1 1. 8.  
St u d y Dr u g Dis p os al ................................................................................................... 5 0  
1 1. 9.  
C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................................ 5 0  
1 1. 9. 1.  
C o nc o mita nt T hera p y ................................................................................................. 5 0  
1 1. 9. 2.  
C o nc o mita nt T hera p y Restricti o ns ............................................................................. 5 0  
1 1. 9. 3.  
C o nc o mita nt Pr oce d ures ............................................................................................. 5 0  
1 2.  
S T U D Y A S S E S S M E N T S .......................................................................................... 5 2  
1 2. 1.  
Safet y Assess me nts ..................................................................................................... 5 2  
1 2. 1. 1.  
Cli ni cal La b orat or y Tests ........................................................................................... 5 2  
1 2. 1. 2.  
Vita l Si g ns .................................................................................................................. 5 3 
1 2. 1. 3.  
E C G Assess me nts ....................................................................................................... 5 3  
1 2. 1. 4.  
P h ysic al E xa mi nati o ns ................................................................................................ 5 3  
1 2. 1. 5.  
Ne utr o pe nia M o nit ori n g a n d Cli nical Ma na ge me nt ................................................... 5 4  
1 2. 1. 6.  
C o ntrac e pti o n C o u nseli n g .......................................................................................... 5 5  
1 2. 2.  
Ef ficac y Assess me nts ................................................................................................. 5 5 
1 2. 2. 1.  
Peri p heral Bl o o d A bs ol ute E osi n o p hil C o u nt ............................................................. 5 5  
1 2. 2. 2.  
P ul m o nar y F u ncti o n Testi n g ( P F T, F E V 1) ................................................................ 5 5  
1 2. 2. 3.  
Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) .................................................................... 5 7  
1 2. 2. 4.  
Ast h m a Q ualit y of Life Q uesti o n naire ( A Q L Q) ......................................................... 5 7  
1 2. 3.  
P har m ac o d y na mic Assess me nts ................................................................................. 5 8  
1 2. 3. 1.  
Bl o o d A bs ol ut e E osi n o p hil C o u nt .............................................................................. 5 8  
1 2. 3. 2.  
Bas o p hil s ..................................................................................................................... 5 8 
1 2. 3. 3.  
E osi n o p hi l Pr o ge nit ors ................................................................................................ 5 8 
1 2. 3. 4.  
Nasal  a n d P har y n geal S wa bs f or E osi n o p hil Per o xi dase ........................................... 5 8 
1 2. 3. 5.  
Uri ne  E osi n o p hil Gra n ule Pr otei ns ............................................................................. 5 8 
1 2. 3. 6.  
Ser u m  I g E ................................................................................................................... 5 8 
1 2. 3. 7.  
Ser u m  Bi o mar kers a n d Bi o ba n k ................................................................................. 5 8 
1 2. 3. 8.  
W h ole Ge n o me D N A Se q ue nci n g .............................................................................. 5 9  
1 2. 3. 9.  
E x hale d Ni tric O xi de Test ( Fe N O) ............................................................................. 6 0 
1 2. 4.  
P har m ac o ki netic Assess me nts .................................................................................... 6 0  
1 3.  
S A F E T Y D E FI NI TI O N S, M O NI T O RI N G, A N D R E P O R TI N G ............................. 6 2  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 
1 3. 1.  
Def i niti o ns .................................................................................................................. 6 2 
1 3. 1. 1.  
A d verse  E ve nt ............................................................................................................. 6 2 
1 3. 1. 2.  
S us pecte d A d verse Reacti o n ....................................................................................... 6 2  
 
 
1 3. 1. 4.  
Seri o us A d verse E ve nt ................................................................................................ 6 3  
1 3. 2.  
M o ni t ori n g a n d Rec or di n g A d verse E ve nts ............................................................... 6 3 
1 3. 2. 1.  
All E ve nt s (a n y u nt o war d me dical occ urre nce) .......................................................... 6 3  
1 3. 2. 2.  
A d verse  E ve nts ........................................................................................................... 6 4 
 
 
1 3. 2. 4.  
Seri o us A d verse E ve nts .............................................................................................. 6 4  
1 3. 2. 5.  
I m me diate Re p orti n g of Seri o us A d verse E ve nts ....................................................... 6 4  
1 3. 2. 6.  
Deat hs  ......................................................................................................................... 6 5 
1 3. 2. 7.  
Pre g na nc y ................................................................................................................... 6 5  
1 3. 3.  
Safet y Classificati o ns  .................................................................................................. 6 6 
1 3. 3. 1.  
Relat i o ns hi p of E ve nts t o St u d y Dr u g ........................................................................ 6 6 
1 3. 3. 2.  
Se ver it y of E ve nts ....................................................................................................... 6 7 
1 3. 3. 3.  
E x pect e d ness of E ve nts .............................................................................................. 6 8  
1 3. 4.  
Pres c he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ule d Treat me nts ................ 6 8  
1 3. 5.  
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ............................................................... 6 8  
1 3. 5. 1.  
O ver d ose  ..................................................................................................................... 6 8 
1 3. 5. 2.  
Me di cal E mer ge nc y .................................................................................................... 6 9  
1 3. 5. 3.  
C o ntrac e pti o n Re q uire me nts ...................................................................................... 6 9  
1 3. 5. 4.  
Re g ulat or y Re p orti n g .................................................................................................. 7 0  
1 3. 6.  
Sit e I n vesti gat or Res p o nsi bilities ............................................................................... 7 1  
1 3. 7.  
K n o p p R es p o nsi bilities ............................................................................................... 7 1  
1 4.  
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F S A M P L E SI Z E ........... 7 2  
1 4. 1.  
Descr i pti o n of O bjecti ves ........................................................................................... 7 2 
1 4. 2.  
Descr i pti o n of E n d p oi nts ............................................................................................ 7 2 
1 4. 3.  
A nal ysi s P o p ulati o ns .................................................................................................. 7 2 
1 4. 4.  
De m o gra p h y a n d Baseli ne C haracteristics ................................................................. 7 2  
1 4. 5.  
Ge nera l Met h o ds of A nal yses ..................................................................................... 7 2 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 
1 4. 5. 1.  
I nteri m A nal ysis of t he Pri mar y Assess me nt Peri o d .................................................. 7 3  
1 4. 6.  
Ef ficac y A nal yses ....................................................................................................... 7 4 
1 4. 6. 1.  
Pri m ar y E n d p oi nt A nal yses  ........................................................................................ 7 4 
1 4. 6. 2.  
Sec o n dar y E n d p oi nt a n d E x pl orat or y E n d p oi nt A nal yses .......................................... 7 5  
1 4. 7.  
P har m ac o ki netics ........................................................................................................ 7 5  
1 4. 8.  
Safet y A nal yse s .......................................................................................................... 7 5 
1 4. 8. 1.  
Met h o ds of A nal yses - Safet y ..................................................................................... 7 5  
1 4. 8. 1. 1.  
A d verse  E ve nts ........................................................................................................... 7 6 
1 4. 8. 1. 2 . 
Cli ni cal La b orat or y E val uati o ns ................................................................................. 7 6  
1 4. 8. 1. 3.  
Vita l Si g ns .................................................................................................................. 7 6 
1 4. 8. 1. 4.  
Elec tr ocar di o gra ms ..................................................................................................... 7 7 
1 4. 8. 1. 5.  
P h ysic al E xa mi nati o n ................................................................................................. 7 8  
1 4. 9.  
Sa m ple Size C o nsi derati o ns ....................................................................................... 7 8  
1 5.  
E T H I C A L R E Q UI R E M E N T S ................................................................................... 7 9 
1 5. 1.  
I nstit uti o nal Re vie w B oar d ......................................................................................... 7 9 
1 5. 2.  
S u bjec t I nf or mati o n a n d C o nse nt ............................................................................... 7 9 
1 5. 3.  
S u bjec t Data Pr otecti o n .............................................................................................. 8 0 
1 5. 4.  
C o nf lict of I nterest ...................................................................................................... 8 0 
1 5. 5.  
Re gist rati o n of St u d y a n d Discl os ure of St u d y Res ults .............................................. 8 0  
1 6.  
A D MI NI S T R A TI V E P R O C E D U R E S ....................................................................... 8 1  
1 6. 1.  
St u d y Sit e I nitiati o n .................................................................................................... 8 1  
1 6. 2.  
Q uali t y Ass ura nce ....................................................................................................... 8 1 
1 6. 3.  
M o ni t ori n g of t he St u d y .............................................................................................. 8 1 
1 7.  
G E N E R A L I N F O R M A TI O N ..................................................................................... 8 2  
1 7. 1.  
E xter nal C o ntract Researc h Or ga nizati o ns ................................................................. 8 2  
1 7. 2.  
Elec tr o nic or Re m ote Data Ca pt ure ............................................................................ 8 2 
1 7. 3.  
Ce ntra l La b orat ories f or La b orat or y Assess me nts ..................................................... 8 2 
1 7. 4.  
Ce ntra l P har mac o vi gila nce Or ga nizati o n ................................................................... 8 2 
1 7. 5.  
Ce ntra l Facilit y f or Bi oa nal ytical ser vices ................................................................. 8 2 
1 7. 6.  
C ha n ges t o Fi nal St u d y Pr ot oc ol ................................................................................ 8 2  
1 7. 7.  
I R B Notificati o n of St u d y C o m pleti o n or Ter mi nati o n .............................................. 8 3  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
9 
1 7. 8.  
Rete nt i o n of St u d y Data .............................................................................................. 8 3 
1 8.  
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L ......................................... 8 4  
1 9.  
A P P E N DI X A: S E L E C T E D D R U G S K N O W N T O H A V E S U B S T A N TI A L 
RI S K O F N E U T R O P E NI A 1 9, 2 0 ................................................................................. 8 5 
2 0.  
R E F E R E N C E S  ........................................................................................................... 8 6 
 
 
LI S T O F T A B L E S 
 
Ta ble 1:  
Ne utr o pe nia D ose I nterr u pti o n a n d La b orat or y Test Re peat 
Rec o m me n dati o ns ....................................................................................................... 5 4  
Ta ble  2:  
I nter vals f or H ol di n g Ast h ma Me dicati o ns Pri or t o P ul m o nar y F u ncti o n 
Testi n g ........................................................................................................................ 5 6  
Ta ble  3:  
Hi g hl y Effecti ve Birt h C o ntr ol ................................................................................... 6 9  
Ta ble  4:  
Pr ot oc ol Acce pta ble Birt h C o ntr ol ( w he n use d i n ta n de m) ........................................ 7 0  
Ta ble  5:  
Criteria t o Deter mi ne P ote ntiall y Cli nicall y Si g nifica nt Vital Si g n 
A b n or malities ............................................................................................................. 7 7  
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 0  
3.    
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 
° C 
de grees Celsi us  
A C Q -7    
ast h ma co ntr ol q uesti o n naire  ( 7-q uesti o n)  
A E  
a d verse e ve nt  
A E C  
a bs ol ute e osi n o p hil c o u nt  
A L S  
a m y otr o p hic lateral scler osis  
A L T  
ala ni ne a mi n otra nsferase  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A N C O V A    
a nal ysis of c o varia nce  
A N O V A    
a nal ysis of varia nce  
A Q L Q    
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/ E R S    
A merica n T h oracic S ociet y / E ur o pea n Res pirat or y S ociet y  
BI D  
t wice dail y 
B P  
bl o o d press ure  
b p m  
beats per mi n ute  
C B C  
c o m plete bl o o d c o u nt  
CI  
c o nfi de nce i nter val  
C K  
creati ne ki nase  
C K D -E PI    
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n e G F R f or m ula  
C ma x    
ma xi m u m o bser ve d c o nce ntrati o n  
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  
C Y P  
c yt oc hr o me  
C Y P 2 C 8    
c yt oc hr o me P 2 C 8  
C Y P 2 C 9    
c yt oc hr o me P 2 C 9  
D DI  
dr u g -dr u g i nteracti o n  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 1  
d L  
deciliter  
E A D  
e osi n o p hil ass ociate d dis or ders  
E C G  
electr ocar di o gra m  
E D C  
electr o nic data ca pt ure  
e G F R   
esti mate d gl o mer ular filtrati o n rate 
Fe N O    
fracti o n of e x hale d nitric o xi de 
F E V 1    
f orce d e x pirat or y v ol u me i n 1 sec o n d 
G C P  
g o o d cli nical practice  
GI N A    
Gl o bal I nitiati ve f or Ast h ma  
h C G  
h u ma n c h ori o nic g o na d otr o p hi n  
H E S  
h y pere osi n o p hilic s y n dr o me  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R  
heart rate  
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 Har m o nisati o n of Tec h nical 
Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n Use  
I g E 
i m m u n o gl o b uli n E 
I R B 
instit uti o nal re vie w boar d  
I T T 
i nte nt t o treat 
k g  
kil o gra m  
K N S -7 6 0 7 0 4    
de x pra mi pe x ole  
L D H  
lactic aci d de h y dr o ge nase 
L O C F    
last o bser vati o n carrie d f or war d 
L S  
least s q uare 
P K  
p har mac o ki netic  
μ M  
micr o m olar  
m A bs    
m o n ocl o nal a nti b o dies  
M DI  
metere d d ose i n haler  
m g  
milli gra m  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 2  
ml  
milliliter  
m m H g    
milli meters merc ur y  
M M R M    
mi xe d -effect m o del , re peat meas ure me nt 
ms  
millisec o n d  
NI AI D/ NI H  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases i n t he Nati o nal 
I nstit utes of Healt h 
P T  
preferre d ter m  
Q T  
i nter val bet wee n t he start of t he Q R S c o m ple x a n d t he e n d of t he 
T  wa ve  
Q Tc  
i nter val bet wee n t he start of t he Q R S c o m ple x a n d t he e n d of t he 
T  wa ve, c orrecte d f or heart rate  
R B C  
re d bl o o d cell c o u nt 
R R  
res pirat or y rate 
S A E  
seri o us a d verse e ve nt 
s d 
sta n dar d de viati o n 
S O C  
s yste m or ga n class 
S U S A R    
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
t ½ 
ter mi nal half-life 
T ma x    
ti me after a d mi nistrati o n of dr u g w he n C ma x occ urre d  
T P S  
total p ol y p s c ore ( bilateral) 
W B C    
w hite bl o o d cell  
W O C B P    
w o ma n of c hil d beari n g p ote ntial  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 3  
4.    
S Y N O P SI S 
Pr ot oc ol #:  
K N S -7 6 0 7 0 4 -A S 2 0 1  
Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d D ose -Ra n gi n g Bi o mar ker St u d y 
of t he Effects of De x pra mi pe x ole o n E osi n o p hils i n S u bjects wit h E osi n o p hilic 
Ast h ma  
Versi o n #:  
 
Tre at me nt:  
De x pra mi pe x ole  
I n dic ati o n: 
E osi n o p hilic ast h ma  
P h ase:  
2  
O bjecti ves:    
Pri m ary O bjective  
 T o e val uate t he efficac y of de x pra mi pe x ole i n re d uci n g bl o o d e osi n o p hil c o u nt i n 
s u bjects wit h e osi n o p hilic ast h ma 
Sec o n d ary O bjectives  
 T o e val uate t he safet y a n d t olera bilit y of de x pra mi pe x ole a d mi nistere d f or 
1 2  wee ks i n s u bjects wit h e osi n o p hilic ast h ma  
 T o e val uate t he efficac y of de x pra mi pe x ole o n p ul m o nar y f u ncti o n, ast h ma 
c o ntr ol, a n d q ualit y of life  
 T o e val uate t he relati ve effect of de x pra mi pe x ole 7 5 m g/ da y, 1 5 0 m g/ da y, a n d 
3 0 0 m g/ da y  o n bl o o d e osi n o p hil c o u nt  
E x pl or at ory O bjectives  
 T o e val uate t he efficac y of de x pra mi pe x ole i n re d uci n g tiss ue e osi n o p hil 
bi o mar kers  
 T o e val uate t he efficac y of de x pra mi pe x ole i n re d uci n g bl o o d bas o p hil c o u nt  
 T o e val uate t he effect of de x pra mi pe x ole o n bl o o d e osi n o p hil pr o ge nit or 
p o p ulati o ns  
 T o e val uate t he o nset of bl o o d e osi n o p hil l o weri n g  
 T o assess t he rec o ver y of bl o o d e osi n o p hil c o u nt after de x pra mi pe x ole 
disc o nti n uati o n  
 T o e val uate t he effect of de x pra mi pe x ole o n ast h ma bi o mar kers  
 T o assess t he c orr elati o n bet wee n  e osi n o p hil l o weri n g wit h c ha n ges i n p ul m o nar y 
f u ncti o n a n d ast h ma c o ntr ol  
 T o e val uate t he e x p os ure of de x pra mi pe x ole acr oss t he d ose  ra n ge use d i n t he 
st u d y 
 T o e xa mi ne t he relati o ns hi p bet wee n de x pra mi pe x ole e x p os ure a n d e osi n o p hil -
l o weri n g res p o nse 
 T o i n vesti gate p ote ntial pre dicti ve bi o mar kers  t o i de ntif y he mat ol o gic res p o n ders 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 4  
E n d p oi nts:    
Pri m ary E n d p oi nt  
 C ha n ge i n bl o o d a bs ol ute e osi n o p hil c o u nt fr o m Baseli ne t o Wee k 1 2  
Sec o n d ary E n d p oi nts  
 C ha n ge i n pre -br o nc h o dilat or F E V 1, fr o m Baseli ne  t o Wee k 1 2 
 C ha n ge i n Ast h ma C o ntr ol Q uesti o n naire ( A C Q -7 ) sc ore, fr o m Baseli ne t o Wee k 
1 2  
 C ha n ge i n  p ost -br o nc h o dilat or F E V 1, fr o m Baseli ne t o Wee k 1 2  
 C ha n ge i n q ualit y of life, as meas ure d b y t he Ast h ma Q ualit y of Life 
Q uesti o n naire ( A Q L Q), fr o m Baseli ne  t o Wee k 1 2 
 I nci de nce a n d se verit y of A Es, c ha n ges i n vital si g ns, cli nical la b orat or y safet y 
tests, p h ysical e xa mi nati o n, b o d y wei g ht, a n d E C Gs 
E x pl or at ory E n d p oi nts  
 C ha n ge i n p har y n geal a n d nasal e osi n o p hil per o xi dase c o nce ntrati o n fr o m 
Baseli ne t o Wee k 1 2  
 C ha n ge i n bl o o d bas o p hils, fr o m Baseli ne t o Wee k 1 2 
 C ha n ge i n bl o o d e osi n o p hil pr o ge nit or p o p ulati o ns, fr o m Baseli ne t o Wee k 1 2 
 C ha n ge i n fracti o nal e x hale d nitric o xi de ( Fe N O) , fr o m Baseli ne t o Wee k 1 2 
 T he fracti o n of he mat ol o gic res p o n ders, defi ne d as  s u bjects wit h a ≥9 0 % 
re d ucti o n of bl o o d e osi n o p hil c o u nt, fr o m Baseli ne t o Wee k 1 2 
 Ki netics of e osi n o p hil res p o nse, defi ne d at eac h ti me p oi nt as t he fracti o n of 
s u bjects ha vi n g a he mat ol o gic res p o n se at t hat ti me p oi nt or pre vi o usl y , fr o m 
Baseli ne t o Wee k 1 2  
 Ki netics of bl o o d e osi n o p hil rec o ver y after disc o nti n uati o n of de x pra mi pe x ole 
d uri n g t he E osi n o p hil Rec o ver y Peri o d , defi ne d as t he fracti o n of s u bjects wit h a n 
A E C  ≥5 0 % of t he Baseli ne val ue o ver ti me , Wee k 1 2 t o Wee k 2 4 ( he mat ol o gic 
res p o n der p o p ulati o n)  
 C ha n ges i n bi o mar kers (e. g., c yt o ki nes) i n peri p heral bl o o d: c ha n ge fr o m 
Baseli ne t o Wee k 1 2. Ser u m sa m ples will be c ollecte d at t he Baseli ne, Wee k 1 2, 
a n d Wee k 2 4 visits f or st ora ge a n d testi n g of sa m ples f or bi o mar ker e val uati o ns 
of t y pe 2 i n fla m mati o n ass ociate d me diat ors, i ncl u di n g I L -5, I L -1 3, I L -3 3, S T 2, 
C C L 2, C C L 3, C C L 4, C C L 1 1, a n d C C L 1 7.  
 C ha n ges i n uri ne e osi n o p hil gra n ule pr otei ns, fr o m Baseli ne t o Wee k 1 2  
 De x pra mi pe x ole plas ma c o nce ntrati o n acr oss t he st u d y d ose  ra n ge use d i n t he 
st u d y 
 C orrelati o n bet wee n de x pra mi pe x ole e x p os ure , as meas ure d b y de x pra mi pe x ole 
tr o u g h plas ma c o nce ntrati o n, a n d e osi n o p hil -l o weri n g res p o nse 
 W h ole ge n o me D N A se q ue nci n g t o disc o ver p ote ntial pre dicti ve ge netic 
bi o mar kers t o i de ntif y he mat ol o gic res p o n ders  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 5  
St u d y D r u g: 
Oral a d mi nistrati o n of de x pra mi pe x ole st u d y dr u g ta blets BI D f or 1 2  wee ks at 
7 5  m g/ da y, 1 5 0 m g/ da y, 3 0 0 m g/ da y, or place b o  
St u d y C e nters:  
U p t o 2 5 sites i n t he U nite d States  
# of S u bjects:  
1 0 0 s u bjects ra n d o mize d 1: 1: 1: 1 ; place b o, de x pra mi pe x ole 7 5 m g/ da y, 1 5 0 m g/ da y, 
a n d 3 0 0 m g/ da y ( 2 5 per ar m)  
St u d y  
P o p ul ati o n : 
T he pr ot oc ol will e nr oll s y m pt o matic e osi n o p hilic ast h matic s u bjects 1 8 -7 5 years 
wit h m o derate or greater disease se verit y as defi ne d b y GI N A ste ps 3 -5. 1 S u bjects 
m ust ha ve a n F E V 1 of < 8 0 % of pre dicte d at Scree ni n g a n d Baseli ne a n d ha ve 
br o nc h o dilat or F E V 1 re versi bilit y of ≥1 2 % a n d ≥ 2 0 0 ml  at Scree ni n g .  
R ati o n ale f or 
St u d y:  
I n a rece ntl y c o m plete d o pe n-la bel pil ot st u d y i n e osi n o p hilic c hr o nic r hi n osi n usitis 
wit h nasal p ol y ps, de x pra mi pe x ole 3 0 0 m g / da y d ose l o were d bl o o d a n d n asal p ol y p 
e osi n o p hil c o u nts 2 0 -f ol d.2 T he a p pr o ve d t hera pe utic m o n ocl o nal a nti b o d y dr u gs t o 
i nterle u ki n-5 (I L -5) a n d t he I L -5 rece pt or, be nraliz u ma b, me p oliz u ma b , a n d 
resliz u ma b, are u n derst o o d t o e xert t heir cli nical efficac y i n e osi n o p hilic ast h ma 
t hr o u g h t heir e osi n o p hil-l o weri n g acti vit y.3 -7 T his s u g gests t hat de x pra mi pe x ole ma y 
ha ve efficac y i n e osi n o p hilic ast h ma. Bl o o d e osi n o p hil l o weri n g was c h ose n as t he 
pri mar y e n d p oi nt t o i nf or m selecti o n of a n o pti ma l d ose f or use i n P hase 3 cli nical 
de vel o p me nt.  
St u d y Desi g n  
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, d ose -ra n gi n g, 
m ulti -ce nter st u d y. S u bjects will recei ve o pe n -la bel place b o d uri n g t he R u n-i n Peri o d 
a n d d o u ble -bli n d st u d y dr u g  d uri n g t he Pri mar y Assess me nt Peri o d of t he st u d y . 
D ur ati o n of 
Tre at me nt a n d 
F oll o w -u p : 
St u dy Peri o ds  
R u n -i n Peri o d: Scree n i n g t hr o u g h i nitiati o n of Baseli ne . 
 S u bjects will u n der g o Scree ni n g  assess me nts  t o assess w het her  t he y satisf y 
t he eli gi bilit y criteria. T he y will partici pate i n t he R u n -i n Peri o d ( of at least 1 2 
da ys d urati o n) t o c o nfir m a sta ble ast h ma me dicati o n re gi me n a n d t o assess 
a d here nce t o t he d osi n g sc he d ule, after w hic h eli gi ble s u bjects will  be 
ra n d o mize d.  
Pri m ar y Assess me nt Peri o d : Baseli ne t hr o u g h c o m pleti o n of Wee k 1 2.  
 After t he c ollecti o n of all Baseli ne assess me nts, s u bjects will be gi n recei vi n g 
st u d y dr u g  f or 1 2 wee ks. S u bjects will ha ve a site visit  at Wee k 4, Wee k 8,  
a n d Wee k 1 2 , a n d wit h a C B C will be c ollecte d  at Wee k 2  a n d Wee k  6  ( o n 
site or re m otel y). T he Wee k 1 2 visit is t he Pri mar y O utc o me Visit  f or t he 
st u d y. S u bjects will ta ke t he last d ose of st u d y dr u g at t he Wee k  1 2  visit.  
E osi n o p hil Rec o ver y Peri o d : C o ncl usi o n of Wee k 1 2  assess me nts t hr o u g h 
Wee k  2 4.  
 F oll o wi n g t he Pri mar y Assess me nt Peri o d, s u bjects will e nter t he E osi n o p hil 
Rec o ver y Peri o d. D uri n g t his peri o d, s u bjects will be see n  at t he site at eit her 
Wee k  1 6 or Wee k  1 8. S pecific s ites will be desi g nate d t o perf or m eit her 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 6  
Wee k 1 6 or  Wee k  1 8 visits f or s u bjects e nr olle d at t heir site. T he Wee k 2 0 
a n d Wee k  2 4  visits ma y be at t he site or ma y be at a desi g nate d re m ote 
la b orat or y facilit y. 
R ati o n ale f or D ose 
S electi o n: 
T he de x pra mi pe x ole 3 0 0 m g/ da y d ose was selecte d base d o n t he cli nical, safet y, a n d 
e osi n o p hil-l o weri n g data de m o nstrate d i n P hase 2 a n d P hase 3  trials i n s u bjects wit h 
a m y otr o p hic lateral scler osis 8 ( A L S), a n d a P hase 2 trial i n s u bjects wit h c hr o nic 
r hi n osi n usitis wit h nasal p ol y ps.2 T he 1 5 0 m g/ da y d ose was c h ose n base d o n t he 
res ults fr o m t he P hase 2 A L S trial, w hic h als o s h o we d effecti ve  bl o o d e o si n o p hil 
l o weri n g at t hat d ose i n 2 6 s u bjects.8 I n t hat sa me P hase 2 trial, s u bjects treate d wit h 
5 0 m g / da y s h o we d a bi ol o gicall y m o dest , b ut statisticall y si g nifica nt, effect o n 
l o weri n g e osi n o p hil  c o u nt. T he 7 5 m g/ da y d ose was selecte d f or t his st u d y base d o n 
t he li keli h o o d it w o ul d  pr o vi de usef ul off -platea u d ose -res p o nse data t hat w o ul d 
i nf or m f ut ure cli nical de vel o p me nt decisi o ns . 
E v al u ati o n of 
S afet y : 
P h ysical e xa mi nati o n , vital si g ns (s yst olic a n d diast olic bl o o d press ure, res pirat or y 
rate, heart rate, a n d te m perat ure), b o d y wei g ht , 1 2 -lea d E C G, cli nical la b orat or y 
e val uati o ns ( he mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis) , pre g na nc y testi n g , a d verse 
e ve nt m o nit ori n g , a n d c o nc o mita nt me dicati o n m o nit ori n g t hr o u g h o ut t he st u d y.  
 
 ne utr o p hil 
c o u nts will be re p orte d usi n g a ce ntral la b orat or y a n d m o nit ore d b y t he    
 
Me dical M o nit or. A ne utr o pe nia case re p ort f or m will be utilize d d uri n g t he st u d y t o 
ca pt ure detaile d cli nical i nf or mati o n c o nc urre nt wit h a n y la b orat or y e ve nts of 
ne utr o pe nia. T o assess p ote ntial car diac dr u g i nteracti o ns of al b uter ol a n d 
de x pra mi pe x ole, Wee k  8 E C Gs will be ti me d t o c orres p o n d wit h a p pr o xi mate C ma x 
de x pra mi pe x ole plas ma c o nce ntrati o ns.  
E v al u ati o n of 
E ffic ac y: 
 Bl o o d e osi n o p hil c o u nt , c ha n ges i n p ul m o nar y f u ncti o n ( F E V 1) , Ast h ma C o ntr ol 
Q uesti o n naire  ( A C Q-7) , Ast h ma Q ualit y of Life Q uesti o n naire  ( A Q L Q), p har y n geal 
a n d nasal e osi n o p hil per o xi dase  will be c ollecte d peri o dicall y d uri n g  t he st u d y. 
P h ar m ac o ki netic 
E v al u ati o ns : 
Bl o o d f or plas ma dr u g c o nce ntrati o n  will be c ollecte d at t he Wee k 4  (tr o u g h), 
Wee k  8  (tr o u g h a n d p ost-d ose  at 2 h o urs ), a n d Wee k 1 2 (tr o u g h) v isits. 
D e x pra mi pe x ole tr o u g h plas ma c o nce ntrati o n will be use d t o e val uate t he 
relati o ns hi p bet wee n de x pra mi pe x ole e x p os ure a n d e osi n o p hil-l o weri n g res p o nse.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 7  
St atistics:  
T he st u d y will use a bl oc ke d ra n d o mizati o n stratifie d b y st u d y site. T he safet y 
sa m ple p o p ulati o n will be use d f or all safet y a nal yses a n d t he m o difie d I T T 
p o p ulati o n will be use d f or efficac y a nal yses. T he m o difie d I T T p o p ulati o n , w hic h 
c o nsists of all s u bjects w h o recei ve d at least o ne d ose of st u d y dr u g  a n d w h o ha ve at 
least o ne p ost-ra n d o mizati o n e val uati o n f or at least o ne of t he efficac y e n d p oi nts, will 
be use d f or effica c y a nal yses. 
T he pri mar y e n d p oi nt of t his st u d y is t he c ha n ge i n bl o o d a bs ol ute e osi n o p hil c o u nt 
fr o m Baseli ne t o Wee k 1 2. A bs ol ute e osi n o p hil c o u nts will be tra nsf or me d t o t he 
l o g 1 0 scale. T o a v oi d ta ki n g t he l o g of zer o, zer oes will be re place d wit h 5  cells/ µ L 
i n c o n ve nti o nal u nits a n d 0. 0 0 5 × 1 09/ L i n t he I nter nati o nal S yste m of U nits ( SI), 
w hic h is 5 0 % of t he l o wer li mit of q ua ntificati o n . T he ge o metric mea n of all 
e osi n o p hil c o u nts o btai ne d bet wee n t he S cree ni n g a n d B aseli ne visits will be use d t o 
esta blis h t he baseli ne e osi n o p hil c o u nt use d i n t he efficac y a nal yses. Ge o metric 
mea ns a n d sta n dar d de viati o ns will be prese nte d b y treat me nt gr o u p f or o bser ve d 
val ues at eac h visit al o n g wit h a p -val ue c o m pari n g eac h de x pra mi pe x ole treat me nt 
gr o u p t o place b o ba se d o n a n a nal ysis of varia nce ( A N O V A). 
T he pri mar y a nal ysis will be a mi xe d -effect m o del wit h re peate d -meas ures ( M M R M) 
wit h ter ms f or baseli ne, GI N A treat me nt ste ps 3 vs. 4/ 5, treat me nt, visit, treat me nt b y 
visit i nteracti o n, a n d baseli ne b y visit i nterac ti o n as fi xe d effects, a n d s u bjects as a 
ra n d o m effect. A n u nstr uct ure d c o varia nce will be use d. 
De x pra mi pe x ole gr o u p treat me nt effects a n d treat me nt gr o u p effects vers us place b o 
at Wee k 1 2 will be teste d b y c o ntrasts wit hi n t he M M R M. Esti mate d L S mea ns of  
treat me nt effects a n d esti mate d differe nce i n treat me nt effects at eac h visit will be 
bac k tra nsf or me d t o t he ori gi nal scale t o prese nt esti mate d ge o metric mea ns f or 
treat me nt effects a n d rati o of ge o metric mea ns of treat me nt effects al o n g wit h 9 5 % 
CI.  
A c o ntrast will be create d t o test t he treat me nt effect at Wee k 1 2 f or t he p o ole d 
1 5 0  m g / da y a n d 3 0 0 m g/ da y gr o u p vers us t he place b o gr o u p. A c o ntrast will be 
create d t o test t he treat me nt effect at Wee k 1 2 f or l o g -li near d ose res p o nse. 
T o c o ntr ol t he al p ha le vel f or testi n g 3 d ose gr o u ps vers us place b o f or t he pri mar y 
e n d p oi nt a n d f or testi n g F E V 1, a cl ose d hierarc hical testi n g pr oce d ure will be use d i n 
t he f oll o wi n g or der:  
1.  First, t he 3 0 0  m g/ da y d ose gr o u p will be teste d vers us place b o f or c ha n ge i n 
bl o o d a bs ol ute e osi n o p hil c o u nt, a n d if t his reac hes t he < 0. 0 5 le vel  t he n,  
2.  t he 1 5 0 m g/ da y d ose gr o u p will be teste d vers us place b o at t he 0. 0 5 le vel f or 
c ha n ge i n bl o o d a bs ol ute e osi n o p hil c o u nt, a n d if t his reac hes t he < 0. 0 5 le vel 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
1 8  
t he n, 
3.  t he 7 5 m g/ da y d ose gr o u p will be teste d vers us place b o at t he 0. 0 5 le vel f or 
c ha n ge i n bl o o d a bs ol ute e osi n o p hil c o u nt, a n d if t his reac hes t he < 0. 0 5 le vel 
t he n, 
4.  t he p o ole d 1 5 0 a n d 3 0 0 m g/ da y d ose gr o u ps will be teste d vers us place b o at 
t he 0. 0 5 le vel f or c ha n ge i n F E V 1 at Wee k 1 2. 
T here ma y be a n i nteri m a nal ysis of efficac y after all s u bjects ha ve c o m plete d t he 
Wee k 1 2 visit ( Pri mar y O utc o me Visit ). T here will be n o p-val ue a dj ust me nt f or t he 
i nteri m a nal ysis beca use s u bjects will be off st u d y dr u g after t he Wee k 1 2 visit an d 
t he y will ha ve c o m plete d t he assess me nt of t he pri mar y e n d p oi nt. T he pri mar y 
p ur p ose of visits after Wee k 1 2 is t o o bser ve  e osi n o p hil rec o ver y f oll o wi n g 
disc o nti n uati o n  of st u d y dr u g a n d t o m o nit or s u bjects f or safet y. 
S a m ple S ze 
D eter mi n ati o n : 
S a m ple Size  
T he pri mar y e n d p oi nt f or t his st u d y is c ha n ge i n bl o o d a bs ol ute e osi n o p hil  c o u nt 
fr o m Baseli ne t o Wee k 1 2. I n a n o pe n la bel st u d y of de x pra mi pe x ole i n s u bjects wit h 
c hr o nic r hi n osi n usitis wit h nasal p ol y ps  (K N S -7 6 0 7 0 4 -C S 2 0 1) , de x pra mi pe x ole 
re d uce d e osi n o p hils b y 9 4 % (rati o of e n d p oi nt t o baseli ne =-2. 8 1 o n t he l o g base e 
scale). T he sta n dar d de viati o n f or t he rati o of e n d p oi nt t o baseli ne was 1. 8 2 o n t he 
l o g base e scale. 
Ni netee n s u bjects per ar m will pr o vi de a p pr o xi matel y 8 4 % p o wer if t he tr ue 
re d ucti o n i n bl o o d e osi n o p hils is 8 5 % wit h de x pra mi pe x ole a n d 1 0 % wit h place b o. 
T he p o wer will be 9 5 % if t he tr ue re d ucti o n i n bl o o d e osi n o p hils is 9 0 % wit h 
de x pra mi pe x ole a n d 1 0 % wit h place b o. T he sa m ple size was calc ulate d usi n g 
met h o d ol o g y f or a t w o -sa mple t -test. Ass u mi n g a n a p pr o xi mate 2 0 % dr o p o ut rate of 
s u bjects w h o d o n ot ha ve t he fi nal o bser vati o n f or bl o o d e osi n o p hils yiel ds a sa m ple 
size of 2 5 s u bjects ra n d o mize d per ar m . 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 1  
 
1.  
S u bject eli gi bilit y will be assesse d d uri n g t he Scree ni n g visit a n d c o nfir me d at t he Baseli ne visit. Scree ni n g 
assess me nts are t o be c o m plete d bet wee n 1 2- 3 0 da ys pri or t o t he Baseli ne visit (first d ose of st u d y dr u g ).  
2.  S u bjects s h o ul d wit h h ol d t heir A M ast h m a me dic ati o n t he m or ni n g of t he B aseli ne, Wee k 4, Wee k 8, 
Wee k 1 2, a n d Wee k 1 6/ 1 8 visits . If t he s u bject has n ot wit h hel d ast h ma me dicati o ns o n t he m or ni n g of t he visit, 
t he e ntire visit m ust be resc he d ule d. 
3.  Baseli ne assess me nts m ust be perf or me d pri or t o t he a d mi nistrati o n of t he first d ose of st u d y dr u g. 
4.  T he bl o o d sa m ple f or s u b missi o n t o t he ce ntral cli nical la b orat or y ma y eit her be c ollecte d at t he st u d y site or at a 
desi g nate d re m ote la b orat or y facilit y at t he Wee k 2, Wee k 6, Wee k 2 0, a n d/ or Wee k 2 4 visits. If t he bl o o d sa m ple 
is c ollecte d re m otel y, wit h ass ociate d tele p h o ne c o ntact wit h t he s u bject b y a p pr o priatel y dele gate d site pers o n nel. 
5.  S u bjects w h o disc o nti n ue st u d y dr u g pre mat urel y will be as ke d t o ret ur n wit hi n 4 da ys of t he last d ose of st u d y 
dr u g t o ha ve t he Wee k 1 2 ( Pri mar y O utc o me Visit) assess me nts perf or me d. I n s uc h disc o nti n ue d s u bjects, a well-
bei n g c hec k (tele p h o ne i nter vie w) will be als o c o m plete d 3 0 da ys after t he last d ose of st u d y dr u g a n d will be 
d oc u me nte d i n t he C R F. See Secti o n 8. 3. 1 1 . 
6.  S pecific sites will be selecte d t o ha ve all s u bjects e nr olle d at t heir site ha ve t his visit sc he d ule d t o occ ur o n eit her 
Wee k 1 6 or  Wee k 1 8. 
7.  Eli gi bilit y re vie w base d o n c o m plete d Scree ni n g a n d Baseli ne assess me nts 
8.  Vital si g ns will be meas ure d i n t he seate d u pri g ht p ositi o n after t he s u bject has bee n reste d f or 5 mi n utes (s yst olic 
a n d diast olic s yste mic bl o o d press ure [ B P] i n m m H g, res pirat or y rate [ R R] per mi n ute, a n d heart rate [ H R] per 
mi n ute). 
9.  T he cli nical la b orat or y test para meters will be perf or me d b y at a desi g nate d ce ntral la b orat or y.  
1 0.  T he C B C (e osi n o p hil c o u nt) s h o ul d be c ollecte d bet wee n 6 A M a n d 1 2 n o o n, t o mi ni mize di ur nal variati o n. 
1 1.  C B C o nl y. 
1 2.  C o ntrace pti o n c o u nseli n g re q uire d f or  male s u bjects o nl y (as nee de d wit hi n 3 m o nt hs of last d ose of st u d y dr u g). 
1 3.  1 2 -lea d E C G tri plicate traci n gs at least 1 mi n ute a part will be rec or de d wit h t he s u bject i n t he s u pi ne p ositi o n after 
resti n g f or at least 5 mi n utes. 
1 4.  T o assess p ote ntial car diac dr u g i nteracti o ns of al b uter ol a n d de x pra mi pe x ole, 2 h o urs ( ± 3 0 mi n utes) after ta ki n g 
st u d y dr u g i n cli nic at Wee k 8, s u bjects will ha ve a tri plicate E C G c ollecte d, as n ote d a b o ve. After war ds, t he y will 
i n hale f o ur p uffs of al b uter ol M DI ( 9 0- 1 0 0 μ g al b uter ol base per act uati o n) u n der t he directi o n of st u d y staff, wait 
1 5 mi n utes ( ± 5 mi n utes), a n d ha ve a sec o n d, p ost- br o nc h o dilat or E C G c ollecti o n. See Secti o n 1 2. 1. 3 . 
1 5.  If a s u bject e x perie nces a la b orat or y- defi ne d e ve nt of ne utr o pe nia (a bs ol ute ne utr o p hil c o u nt < 1. 5 0 x 1 0 9/ L), a 
ne utr o pe nia case re p ort f or m will be c o m plete d. T he i nf or mati o n re q uire d f or t his f or m will be o btai ne d b y t he 
site staff t hr o u g h a n i nter vie w wit h t he s u bject c o nte m p ora ne o us wit h t he e ve nt.   
1 6.  T he A C Q- 7 a n d A Q L Q s h o ul d be c ollecte d as earl y as feasi ble d uri n g eac h visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E ca pt ure). 
1 7.  Pre- br o nc h o dilat or P F Ts at eac h st u d y visit s h o ul d be c ollecte d bet wee n 6 A M a n d 1 2 n o o n l ocal ti me a n d s h o ul d 
be c ollecte d wit hi n ± 2 h o urs of t he Baseli ne visit t o mi ni mize di ur nal variati o n. 
1 8.  S u bjects w h o prese nt f or Scree ni n g b ut ha ve alrea d y ta ke n t heir A M ast h ma me dicati o n (see Ta ble 2), s h o ul d 
ha ve all ot her Scree ni n g assess me nts perf or me d a n d will be re q uire d t o resc he d ule t he Scree ni n g P F T as s o o n as 
feasi ble. 
1 9.  T he Wee k 1 2 p re- br o nc h o dil at or P F T s h o ul d be perf or me d wit hi n ± 1 h o ur of t he ti me of d a y t h at t he 
B aseli ne P F T w as c ollecte d.  
2 0.  After c o m pleti n g t he pre- br o nc h o dilat or P F Ts, s u bjects will i n hale t he sa me n u m ber of p uffs of al b uter ol metere d 
d ose i n haler use d t o q ualif y t he s u bject f or t he st u d y. S pir o metr y will be re peate d 1 5 - 3 0 mi n utes after i n halati o n 
of al b uter ol. See Secti o n 1 2. 2. 2 . 
2 1.  Fracti o nal e x hale d Nitric O xi de ( Fe N O) s h o ul d be c ollecte d pri or t o t he P F T tests. 
2 2.  Wee k 4 a n d Wee k 1 2 plas ma f or de x pra mi pe x ole c o nce ntrati o n c ollecte d pre- d ose (tr o u g h) 
2 3.  Wee k 8 plas ma f or de x pra mi pe x ole c o nce ntrati o n pre- d ose (tr o u g h) a n d 2 h o urs ( ± 1 0 mi n utes) after d ose – See 
Secti o n 1 2. 4 . 
2 4.  De x pra mi pe x ole d osi n g after c o m pleti n g all Baseli ne assess me nts. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 2  
 
6.    
I N T R O D U C TI O N A N D R A TI O N A L E  
6. 1.    
O ver vie w 
Ast h ma is a c hr o nic l u n g disease c haracterize d b y air wa y i nfla m mati o n a n d o bstr ucti o n 
( decrease d airfl o w). Ast h ma pre vale nce varies acr oss differe nt c o u ntries, wit h s o me of t he 
hi g hest rates ( > 8 %) i n t he U nite d States. 9 I n t he past deca des, ast h ma pre vale nce has i ncrease d i n 
de vel o pi n g c o u ntries, partic ularl y i n ur ba n p o p ulati o ns. 9 Beca use of its hi g h pre vale nce, ast h ma 
has a  maj or i m pact o n q ualit y of life a n d is a n i m p orta nt s o urce of healt h care c osts, esti mate d at 
$ 5 6 billi o n/ year i n t he U nite d States. 
I n rece nt years, it has bec o me clear t hat ast h ma is act uall y a s y n dr o me c o m prise d of se veral 
differe nt e n d ot y pes, eac h defi ne d b y differe nt u n derl yi n g pat h o p h ysi ol o g y. E osi n o p hilic ast h ma 
is the best- defi ne d ast h ma e n d ot y pe a n d re prese nts m ore t ha n 5 0 % of ast h ma patie nts. 1 0 
Alt h o u g h e osi n o p hilic ast h ma was ori gi nall y defi ne d base d o n s p ut u m e osi n o p hilia, i n rece nt 
years ele vate d bl o o d e osi n o p hils ha ve bec o me a n acce pte d a n d m ore c o n ve nie nt mea ns t o 
i de ntif y t hese cases. T he last deca de has bee n n ota ble f or t he cli nical de vel o p me nt of a nti-
e osi n o p hil bi ol o gic t hera pies, i ncl u di n g t he a nti- I L- 5 m o n ocl o nal a nti b o dies ( m A bs) 
me p oliz u ma b a n d resliz u ma b a n d t he a nti- I L- 5 rece pt or m A b be nraliz u ma b. T hese a nti-
e osi n o p hil bi ol o gics ha ve clearl y s h o w n t hat l o weri n g e osi n o p hils is s ufficie nt t o i m pr o ve 
ast h ma cli nical o utc o mes, s uc h as ast h ma e xacer bati o ns. 1 1 Hi g h- ma g nit u de e osi n o p hil l o weri n g 
was o bser ve d i n a pre vi o us o pe n-la bel trial of de x pra mi pe x ole i n c hr o nic r hi n osi n usitis wit h 
nasa l p ol y ps ( C R S w N P) ( K N S- 7 6 0 7 0 4- C S 2 0 1; “ C S 2 0 1”).2 Acc or di n gl y, t his trial see ks t o 
i n vesti gate if si milar e osi n o p hil l o weri n g is see n i n patie nts wit h e osi n o p hilic ast h ma.  
6. 2.    
De x pr a mi pe x ole B ac k gr o u n d 
De x pra mi pe x ole is a n oral s mall m olec ule i nitiall y de vel o pe d b y K n o p p Bi oscie nces L L C 
( K n o p p) as a treat me nt f or a m y otr o p hic lateral scler osis ( A L S). De x pra mi pe x ole is t he ( R)-( +) 
e na nti o mer of pra mi pe x ole, ( 6 S)- 4, 5, 6, 7-tetra h y dr o- N 6 -pr o p yl- 2, 6- be nz ot hiaz ole- dia mi ne 
di h y dr oc hl ori de m o n o h y drate. T he ( S)-(- ) e na nti o mer, pra mi pe x ole, is a p ote nt d o pa mi ne a g o nist 
a p pr o ve d as a treat me nt f or Par ki ns o n’s disease a n d restless le gs s y n dr o me i n t he U. S. a n d i n 
E ur o pe. De x pra mi pe x ole is a p pr o xi matel y 1 0, 0 0 0 - 2 0, 0 0 0 ti mes less p ote nt a h u ma n d o pa mi ne 
a g o nist t ha n pra mi pe x ole. 
I n 2 0 1 3, a lar ge P hase 3 trial of de x pra mi pe x ole faile d t o de m o nstrate efficac y o n pri mar y a n d 
sec o n dar y e n d p oi nts i n s u bjects wit h A L S ( 2 3 3 A S 3 0 2; “ E M P O W E R”). U ne x pecte dl y, d uri n g 
t he precli nical a n d cli nical de vel o p me nt pr o gra m i n A L S, a s u bsta ntial, d ura ble, a n d tar gete d 
re d ucti o n i n bl o o d e osi n o p hil c o u nts was o bser ve d. 8 T his fi n di n g le d K n o p p t o e x pl ore t he 
safet y, t olera bilit y, a n d preli mi nar y e vi de nce of effecti ve ness i n e osi n o p hil-ass ociate d dis or ders 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 3  
 
( E A D). I n 2 0 1 6, K n o p p c o m plete d a n o pe n-la bel P hase 2 st u d y t o e val uate de x pra mi pe x ole i n 
s u bjects wit h e osi n o p hilic C R S w N P ( C S 2 0 1). I n a 2 0 1 7 c olla b orati o n wit h Dr. A m y Kli o n of t he 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases i n t he Nati o nal I nstit utes of Healt h 
( NI AI D/ NI H), K n o p p c o m plete d a P hase 2 st u d y of de x pra mi pe x ole i n s u bjects wit h 
h y per e osi n o p hilic s y n dr o me ( 1 4-I- 0 0 6 3). T hese st u dies are n o w c o m plete, a n d i n b ot h, 
de x pr a mi pe x ole de m o nstrate d si g nifica nt e osi n o p hil-l o weri n g acti vit y i n b ot h bl o o d a n d 
tiss ue.2,  1 2 
F or f urt her details, see t he de x pra mi pe x ole I n vesti gat or’s Br oc h ure. 
6. 3.    
Pre vi o us E x perie nce 
6. 3. 1.    
N o ncli nic al De vel o p me nt   
N o ncli nical st u dies de m o nstrate t hat de x pra mi pe x ole is meta b olicall y sta ble, wit h hi g h oral 
bi oa vaila bilit y. Plas ma c o nce ntrati o n a n d s yste mic e x p os ure are ge nerall y li near. I n a ni mal 
st u dies, T ma x ge nerall y ra n ge d fr o m 1 t o 4 h o urs; plas ma t ½ ra n ge d fr o m 3 t o 8 h o urs 
a p pro xi matel y. N o hi g h-affi nit y i nteracti o ns were o bser ve d f or a n y rece pt ors a n d ot her tar gets 
e xa mi ne d after scree ni n g de x pra mi pe x ole i n sta n dar d i n vitr o p har mac ol o g y pa nels. F or its 
de vel o p me nt i n C N S t hera pe utic i n dicati o ns, de x pra mi pe x ole has bee n s h o w n t o cr oss t he bl o o d-
bra i n barrier i n rats, mice, a n d mi ni pi gs a n d t o c o nce ntrate i n t he brai n relati ve t o plas ma. 
De x pra mi pe x ole was de m o nstrate d t o be ne gati ve f or a n y m uta ge nic or ge n ot o xic si g nal i n t he 
f ull batter y of i n vitr o a n d i n vi v o assess me nts rec o m me n de d b y I C H g ui deli nes. 
De x pra m i pe x ole de m o nstrate d ver y l o w pr otei n bi n di n g i n plas ma fr o m precli nical s pecies 
( S pra g ue Da wle y rats a n d G ötti n ge n mi ni pi gs) a n d h u ma ns. It was sta ble i n h u ma n li ver 
micr os o mes a n d s h o we d n o si g nifica nt i n hi biti o n of t he maj or C Y P is of or ms. Alt h o u g h 
de x pr a mi pe x ole ma y be a wea k i n d ucer of C Y P 2 C 8 i n vitr o, at 3 0 0 m g/ da y it is e x pecte d t o ha ve 
a l o w p ote ntial f or dr u g- dr u g i nteracti o n ( D DI) via m o d ulati o n of C Y P 2 C 8. T he c o nce ntrati o n of 
de x pr a mi pe x ole re q uire d f or i n d ucti o n of C Y P 2 C 8 is ≥ 1 0 0 μ M, w hic h is si g nifica ntl y greater 
t han its o bser ve d t hera pe utic u n b o u n d plas ma C ma x c o nce ntrati o n of 2 t o 4 μ M i n h u ma ns after 
c hro nic a d mi nistrati o n of de x pra mi pe x ole 3 0 0 m g/ da y. Beca use a si g nal f or C Y P 2 C 9 i n d ucti o n 
b y de x pra mi pe x ole was o bser ve d at 1 0 μ M, a cli nical D DI st u d y t o e val uate de x pra mi pe x ole’s 
p ote ntial t o m o d ulate C Y P 2 C 9 acti vit y was c o n d ucte d ; n o cli nicall y si g nifica nt dr u g- dr u g 
i nteracti o n was o bser ve d.  
6. 3. 2.    
C li nic al E x perie nce wit h De x pr a mi pe x ole 
O ne t h o usa n d, t w o h u n dre d a n d t hirt y-si x ( 1, 2 3 6) s u bjects ha ve recei ve d de x pra mi pe x ole i n 
P hase 1 t o P hase 3 cli nical st u dies c o n d ucte d t o date. A t otal of 2 9 4 healt h y a d ult s u bjects a n d 2 4 
re nall y i m paire d s u bjects recei ve d de x pra mi pe x ole dail y d oses ra n gi n g fr o m 5 0 m g/ da y t o 
6 0 0  m g/ da y i n 1 0 c o m plete d P hase 1 cli nical st u dies.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 4  
 
A t otal of 8 8 8 A L S s u bjects recei ve d de x pra mi pe x ole d oses of 5 0 m g/ da y t o 3 0 0 m g/ da y i n 4 
c o m plete d cli nical trials. T hese i ncl u de t he P hase 3 d o u ble- bli n d A L S st u d y ( E M P O W E R), i n 
w hic h 4 7 4 s u bjects recei ve d de x pra mi pe x ole 3 0 0 m g/ da y, wit h a mea n e x p os ure ti me of 
1 1. 7 5 m o nt hs; 4 0 7 were treate d f or 6 m o nt hs or l o n ger; 3 3 5 of t hese s u bjects recei ve d 
de x pr a mi pe x ole f or 1 2 m o nt hs or l o n ger. 
A n o pe n-la bel P hase 2 st u d y of de x pra mi pe x ole 3 0 0 m g/ da y ( C S 2 0 1 ) was c o n d ucte d i n s u bjects 
wit h C R S w N P wit h a baseli ne a bs ol ute e osi n o p hil c o u nt ( A E C) ≥0. 3 0 x 1 0
9/ L a n d p ol y p 
e osi n o p hilia. T he c o- pri mar y e n d p oi nts were c ha n ge i n A E C a n d c ha n ge fr o m baseli ne i n T otal 
P ol y p Sc ore ( T P S, a meas ure of bilateral p ol y p b ur de n) after 6 m o nt hs of treat me nt. A t otal of 
2 0 s u bjects e ntere d t he st u d y a n d recei ve d at least 1 d ose of st u d y dr u g; a n d 1 6 s u bjects were 
i ncl u de d i n t he efficac y p o p ulati o n. T he A E C was 0. 5 2 5 × 1 09/ L at baseli ne a n d decrease d t o 
0. 0 3 1 × 1 0 9/ L after 6 m o nt hs of de x pra mi pe x ole treat me nt, a 9 4 % re d ucti o n ( p < 0. 0 0 1, ge o metric 
mea ns). I n 1 2 s u bjects wit h nasal p ol y p bi o psies at baseli ne a n d after 6 m o nt hs of 
de x pra mi pe x ole treat me nt, tiss ue e osi n o p hils were re d uce d fr o m a mea n of 1 6 8 t o 5 per hi g h-
p o wer fiel d ( p = 0. 0 0 1), a 9 7 % re d ucti o n. T here was n o si g nifica nt re d ucti o n i n T P S or 
i mpr o ve me nt i n ot her cli nical e n d p oi nts. De x pra mi pe x ole was well-t olerate d i n t his st u d y, wit h 
n o dr u g-relate d S A Es re p orte d. I n t his st u d y a n d t he o pti o nal e xte nsi o n, t he me dia n d urati o n of 
e x p os ure was 1 7 9. 5 da ys, wit h a mi ni m u m e x p os ure of 5 da ys a n d a ma xi m u m e x p os ure of 
5 9 8 da ys.  
I n a c olla b orati o n bet wee n K n o p p a n d t he NI H, a n o pe n-la bel P hase 2 st u d y was c o n d ucte d t o 
e val uate t he safet y a n d preli mi nar y e vi de nce of efficac y of de x pra mi pe x ole as a ster oi d-s pari n g 
a ge nt i n 1 0 h y pere osi n o p hilic s y n dr o me ( H E S) s u bjects ( 1 4-I- 0 0 6 3). I n t his c o m plete d trial a n d 
its o n g oi ng e xte nsi o n p hase, 1 0 s u bjects recei ve d at least 1 d ose of de x pra mi pe x ole; as of as of 
Mar c h 2 0 1 9, t he me dia n d urati o n of e x p os ure was 3 0 0 da ys wit h a mi ni m u m e x p os ure of 9 3 
da ys a n d a ma xi m u m e x p os ure of 4 years a n d 2 m o nt hs. F o ur of t hese 1 0 s u bjects recei ve d 
de x pra mi pe x ole f or m ore t ha n 1 2 m o nt hs. De x pra mi pe x ole was well-t olerate d i n t his st u d y. N o 
deat hs or A Es lea di n g t o dr u g i nterr u pti o n or disc o nti n uati o n were o bser ve d. T w o s u bjects 
rep orte d tra nsie nt pal pitati o ns a n d f o ur s u bjects re p orte d i ns o m nia, all of w hic h res ol ve d wit h o ut 
dr u g disc o nti n uati o n or m o dificati o n of d ose. 
6. 4.    
R ati o n ale f or St u d y P o p ul ati o n 
I n t his st u d y ( K N S- 7 6 0 7 0 4- A S 2 0 1, “ A S 2 0 1”), de x pra mi pe x ole will be a d de d t o e xisti n g ast h ma 
t hera p y i n s u bjects wit h Gl o bal I nitiati ve f or Ast h ma 1 ( GI N A) ste ps 3 - 5 persiste nt ast h ma 
(re q uiri n g at mi ni m u m a l o w d ose i n hale d c ortic oster oi d i n c o m bi nati o n wit h a l o n g-acti n g 
β-a g o nist). T he st u d y p o p ulati o n is li mite d t o s u bjects wit h a p h ysicia n dia g n osis of ast h ma f or 
≥1 2  m o nt hs a n d eli gi bilit y criteria descri be d i n Secti o n 9 . 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 5 
 
I n a d diti o n t o its r ole i n defi ni n g e osi n o p hilic ast h ma, bl o o d e osi n o p hil c o u nt is als o a bi o mar ker 
ass ociate d wit h greater ris k of ast h ma e xacer bati o n. 1 3 A d diti o nall y, A E C is pre dicti ve of patie nts 
wit h gr eater cli nical i m pr o ve me nt t o a nti-e osi n o p hil t hera pies. 7, 1 4 Acc or di n gl y, t he eli gi bilit y 
criteria f or t his trial re q uires a n A E C of ≥0. 3 0 x 1 09/ L. T his eli gi bilit y criteri o n was utilize d 
pre vi o usl y i n t he C S 2 0 1 trial i n C R S w N P s u bjects a n d is i nte n de d t o select a n ast h matic 
p o p ula ti o n c o m para ble t o t he pac ka ge la bel f or a p pr o ve d e osi n o p hil-l o weri n g bi ol o gics. 
6. 5 .   
R ati o n ale f or St u d y Desi g n 
A p pr o xi matel y half of ast h ma patie nts fail t o ac hie ve a de q uate c o ntr ol of ast h ma s y m pt o ms a n d 
e xacer bati o ns w he n treate d wit h a p pr o ve d ast h ma t hera p y, t y picall y c o nsisti n g of i n hale d 
c ortic oster oi ds a n d l o n g acti n g β-a g o nists. 1 5, 1 6 Alt h o u g h s o me of t he res p o nsi ble fact ors are 
m o dif ia ble, s uc h as s u b o pti mal me dicati o n a d here nce a n d p o or i n haler tec h ni q ue, ot hers reflect 
i ntri nsic deficie ncies i n a vaila ble ast h ma p har mac ot hera p y. T his deficie nc y is partic ularl y 
a p pare nt i n patie nts pr o ne t o se vere ast h ma e xacer bati o ns. E osi n o p hil-l o weri n g bi ol o gics, s uc h 
as me p oliz u ma b, resliz u ma b, a n d be nraliz u ma b, ha ve clearl y de m o nstrate d t h at si g nifica nt 
l o weri n g of bl o o d a n d/ or tiss ue e osi n o p hils res ults i n re d ucti o n of ast h ma e xacer bati o ns a n d 
i mpr o ve me nt i n ast h ma s y m pt o ms. 
H o we ver, all of t he bi ol o gics re q uire pare nteral a d mi nistrati o n.
3- 7 T h us, t here is a nee d a n d 
o p p ort u nit y f or a n oral e osi n o p hil-l o weri n g dr u g, s uc h as de x pra mi pe x ole, f or t he ma na ge me nt 
of e osi n o p hilic ast h ma. 
A 4-ar m d ose ra n gi n g place b o-c o ntr olle d desi g n was c h ose n t o pr o vi de a ra n ge of dr u g 
e x p os ur e. 1 7, 1 8 Bl o o d e osi n o p hil l o weri n g was c h ose n as t he pri mar y e n d p oi nt t o facilitate 
i dentificati o n of t he l o west effecti ve d ose f or use i n f ut ure cli nical de vel o p me nt. T he Pri mar y 
Assess me nt Peri o d of 1 2 wee ks was c h ose n t o pr o vi de a de q uate ti me t o o bser ve b ot h 
p har mac o d y na mic e n d p oi nts, s uc h as e osi n o p hil l o weri n g, as well as t he cli nical e n d p oi nts t hat 
m a y i m pr o ve as a c o nse q ue nce of e osi n o p hil l o weri n g ( F E V 1, A C Q- 7, a n d A Q L Q). T he 
1 2- wee k E osi n o p hil Rec o ver y Peri o d was c h ose n base d o n e x pecte d rec o ver y t o near baseli ne 
c o u nt i n m ost s u bjects. 
6. 6.    
R ati o n ale f or D ose a n d Re gi me n Selecti o n 
Cli nical p har mac ol o g y st u dies ha ve de m o nstrate d t hat de x pra mi pe x ole a d mi nistere d orall y at 
si n gle d oses u p t o 6 0 0 m g a n d m ulti ple d oses u p t o 3 0 0 m g BI D ( 6 0 0 m g/ da y) f or 5 - 7 da ys is 
well t olerate d wit h hi g h bi oa vaila bilit y a n d li near p har mac o ki netics (P K ). P hase 2 a n d P hase 3 
cli nical st u dies of de x pra mi pe x ole i n A L S a n d e osi n o p hil ass ociate d dis or ders ( E A D) wit h 
d urati o ns fr o m t hree t o greater t ha n 1 2 m o nt hs ha ve de m o nstrate d t hat de x pra mi pe x ole pr o d uces 
a s u bsta ntial, d ura ble, a n d tar gete d re d ucti o n i n peri p heral bl o o d e osi n o p hil c o u nt f oll o wi n g 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 6  
 
pr ol o n ge d dr u g e x p os ure. 8 De x pra mi pe x ole e osi n o p hil l o weri n g ta kes fr o m se veral wee ks t o 
se veral m o nt hs a n d t h us is n ot a n ac ute effect of t he dr u g. 
E vi de nce  f or t he e osi n o p hil-l o weri n g effects of de x pra mi pe x ole was first o bser ve d i n t he t w o-
part, place b o-c o ntr olle d, d o u ble- bli n d P hase 2 st u d y of de x pra mi pe x ole i n 1 0 2 A L S s u bjects 
(K N S - 7 6 0 7 0 4- C L 2 0 1; “ C L 2 0 1”). I n Part 1 of C L 2 0 1 ( 1 2 wee ks of treat me nt), mea n bl o o d 
e osin o p hil c o u nt i ncrease d b y 2 9. 2 % i n t he place b o gr o u p a n d decli ne d b y 1 7. 7 % ( p = 0. 0 3 8), 
6 9. 9 %, ( p < 0. 0 0 0 1), a n d 4 3. 5 % ( p = 0. 0 0 0 8) i n t he 5 0 m g/ da y, 1 5 0 m g/ da y, a n d 3 0 0 m g/ da y 
gr o u ps, res pecti vel y. 8 T he decrease i n bl o o d e osi n o p hil c o u nt was partiall y re verse d b y t he e n d 
of  a 4- wee k was h o ut peri o d t hat f oll o we d Part 1. F oll o wi n g a 4- wee k place b o was h o ut peri o d, 
s u bjects were re-ra n d o mize d t o 5 0 m g/ da y or 3 0 0 m g/ da y i n Part 2. After a n a d diti o nal 6 m o nt hs 
of  treat me nt, s u bjects re-ra n d o mize d t o 3 0 0 m g/ da y ha d a greater decli ne i n bl o o d e osi n o p hil 
c o u nt t ha n s u bjects re-ra n d o mize d t o 5 0 m g/ da y ( 7 8. 9 % vs. 1 7. 6 %, res pecti vel y). T his was 
c o nsiste nt wit h t he d ose- de pe n de nt effect of de x pra mi pe x ole o n bl o o d e osi n o p hil c o u nt o bser ve d 
i n Part 1 of C L 2 0 1. 
C o nfir mati o n of t he e osi n o p hil-l o weri n g effect of de x pra mi pe x ole was o bser ve d i n t he d o u ble-
bli n d P hase 3 st u d y ( E M P O W E R ) of de x pra mi pe x ole i n 9 4 2 A L S s u bjects ra n d o mize d 1: 1 t o 
place b o or de x pra mi pe x ole 3 0 0 m g dail y treat me nt f or u p t o 1 8 m o nt hs. At M o nt h 6, t he c ha n ge 
fr om baseli ne i n bl o o d e osi n o p hil c o u nt was + 1 8. 7 % i n t he place b o gr o u p a n d - 6 9. 1 % i n t he 
de x pra mi pe x ole-treate d gr o u p ( p < 0. 0 0 0 1). 8  
A L S patie nts are ge nerall y n o n-at o pic a n d ha ve n or mal e osi n o p hil c o u nts. T o e x pl ore t he 
relati o ns hi p bet wee n baseli ne A E C a n d t he ma g nit u de of e osi n o p hil l o weri n g, a p ost h oc 
a nal ysis of t he P hase 3 A L S st u d y ( E M P O W E R ) was per f or me d i n s u b gr o u ps stratifie d b y 
baseli ne A E C. T he perce nta ge of s u bjects wit h hi g h- ma g nit u de e osi n o p hil l o weri n g, defi ne d as 
≥9 0 %  re d ucti o n fr o m baseli ne t o M o nt hs 4- 6, was assesse d. I n t he de x pra mi pe x ole ar m, 1 8. 0 % 
of  s u bjects ha d hi g h- ma g nit u de e osi n o p hil l o weri n g. I n t he s u b gr o u p wit h baseli ne A E C 
> 0. 2 0 x 1 0 9/L,  4 0 % of s u bjects ha d hi g h- ma g nit u de e osi n o p hil l o weri n g. I n c o ntrast, fe w s u bjects 
wit h a  baseli ne A E C < 0. 1 0 x 1 09/ L ha d hi g h ma g nit u de l o weri n g. T hese fi n di n gs s u g gest t hat 
de x pr a mi pe x ole ma y m ore efficaci o usl y l o wer bl o o d e osi n o p hil c o u nts i n s u bjects wit h baseli ne 
e osi n o p hilia. 
Data fr o m t he P hase 2 st u d y of de x pra mi pe x ole 3 0 0 m g/ da y i n C R S w N P ( C S 2 0 1) c o nfir me d t he 
e osin o p hil-l o weri n g effects of de x pra mi pe x ole i n s u bjects wit h a n e osi n o p hil ass ociate d dis or der 
( E A D). T he ge o metric mea n baseli ne A E C of 0. 5 3 x 1 09/ L was re d uce d 9 2 % b y M o nt h 2 
( p < 0. 0 0 1, n = 1 6), a n d t his re d ucti o n was d ura ble t hr o u g h t he M o nt h 6 pri mar y e n d p oi nt, 9 4 % 
( p <0. 0 0 1). 2 P ol y p tiss ue e osi n o p hil c o u nts decrease d si g nifica ntl y fr o m 1 6 8 t o 5. 1 cells/ hi g h-
p o were d fiel d ( Baseli ne vs. M o nt h 6; 9 7 % re d ucti o n, p = 0. 0 0 1, n = 1 2). N ota bl y, 8 0 % of t he 
s u bjects i n C S 2 0 1 ha d c o nc o mita nt ast h ma, al m ost all of w hic h was mil d. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 7  
 
I n C S 2 0 1, A E C re d ucti o ns i n res p o nse t o de x pra mi pe x ole were bi m o dal, wit h 1 0 of 1 6 s u bjects 
( 6 2. 5 %) ha vi n g attai ne d a n A E C ≤0. 0 2 x 1 0 9/ L (9 9 % re d ucti o n fr o m baseli ne) at t he M o nt h 6 
visit. T he re mai ni n g 6 s u bjects all ha d a M o nt h 6 A E C ≥0. 1 0 x 1 0 9/ L (ra n ge: 1 5 % i ncrease t o 7 6 % 
re d ucti o n). De x pra mi pe x ole plas ma c o nce ntrati o n 2 h o urs p ost- d ose (at or near esti mate d C ma x) 
at M o nth 3 di d n ot acc o u nt f or t he heter o ge ne o us e osi n o p hil l o weri n g a m o n g s u bjects. 
I n the P hase 2 H E S st u d y ( 1 4-I- 0 0 6 3), 1 0 s u bjects wit h a ge o metric mea n baseli ne A E C of 
0. 6 9 x 1 0 9/ L, w h o were ta ki n g a sta ble oral c ortic oster oi d d ose at baseli ne ( mea n = 1 8. 3 5 m g 
pre d nis o ne ), recei ve d de x pra mi pe x ole 3 0 0 m g/ da y f or 3 m o nt hs. Ge o metric mea n A E C was 
0. 2 2 x 1 0 9/ L at M o nt h 1 ( 6 8 % decrease), 0. 1 1 x 1 0 9/ L at M o nt h 2 ( 8 4 % decrease, p = 0. 0 4), a n d 
0. 1 5 x 1 0 9/ L at M o nt h 3 ( 7 8 % decrease, p = 0. 0 1).1 2 
B ot h t he C R S w N P a n d H E S trials ( C S 2 0 1 a n d 1 4-I- 0 0 6 3, res pecti vel y) s h o we d a faster o nset of 
e osin o p hil l o weri n g t ha n was o bser ve d i n t he A L S st u dies ( C L 2 0 1 a n d E M P O W E R). 
A d diti o nall y, i n t he C R S w N P st u d y, t he ma g nit u de of e osi n o p hil l o weri n g was greater t ha n t hat 
seen i n t he A L S st u dies. T hese fi n di n gs s u g gest t hat de x pra mi pe x ole has greater e osi n o p hil-
l o weri n g acti vit y i n patie nts wit h e osi n o p hilia, w hic h ma y be c o nsiste nt wit h a mec ha nis m of  
acti o n of de x pra mi pe x ole t hat i n hi bits e osi n o p hil mat urati o n. 
T he 3 0 0 m g/ da y hi g h d ose f or A S 2 0 1 was c h ose n beca use of t he e xte nsi ve cli nical, safet y, a n d 
e osi n o p hil-l o weri n g data o bser ve d i n t he P hase 2 A L S ( C L 2 0 1), P hase 3 A L S ( E M P O W E R), 
P hase 2 C R S w N P ( C S 2 0 1), a n d P hase 2 H E S ( 1 4-I- 0 0 6) st u dies wit h de x pra mi pe x ole.
2 , 8 T he 
1 5 0 m g/ da y mi d d ose was selecte d base d o n t he e vi de nce fr o m t he P hase 2 A L S trial ( C L 2 0 1), 
w hic h s h o we d eff ecti ve bl o o d e osi n o p hil l o weri n g i n 2 6 s u bjects at t hat d ose. 8 I n t hat sa me trial, 
s u bjects treate d wit h 5 0 m g/ da y ha d bi ol o gicall y m o dest b ut statisticall y si g nifica nt bl o o d 
e osin o p hil l o weri n g. T he 7 5 m g/ da y l o w d ose was selecte d as it is e x pecte d t o pr o vi de usef ul 
of f-platea u d ose res p o nse data.  
T he use of de x pra mi pe x ole at 7 5 m g/ da y, 1 5 0 m g/ da y, a n d 3 0 0 m g/ da y i n t he c urre nt st u d y 
( A S 2 0 1) is e x pecte d t o yiel d t he greatest a m o u nt of data o n e osi n o p hil-l o weri n g d ose-res p o nse 
relati o ns hi ps t o i nf or m f ut ure cli nical de vel o p me nt. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 8  
 
7.    
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 
7. 1.    
O bjecti ves 
7. 1. 1.    
Pri m ar y O bjecti ve 
 T he pri mar y o bjecti ve of t his cli nical trial is t o e val uate t he efficac y of 
de x pra mi pe x ole i n re d uci n g bl o o d e osi n o p hil c o u nt i n s u bjects wit h e osi n o p hilic 
asth ma. 
7. 1. 2.    
Sec o n d ar y O bje cti ves 
T he sec o n dar y o bjecti ves are as f oll o ws: 
 T o e val uate t he safet y a n d t olera bilit y of de x pra mi pe x ole a d mi nistere d f or 1 2 wee ks 
i n s u bjects wit h e osi n o p hilic ast h ma 
 T o e val uate t he efficac y of de x pra mi pe x ole o n p ul m o nar y f u ncti o n, ast h ma c o ntr ol, 
a n d q ualit y of life 
 T o e val uate t he relati ve effect of de x pra mi pe x ole 7 5 m g/ da y, 1 5 0 m g/ da y, a n d 
3 0 0 m g / day o n bl o o d e osi n o p hil c o u nt 
7. 1. 3.    
E x p l or at or y O bjecti ves 
T he e x pl orat or y o bjecti ves are: 
 T o e val uate t he efficac y of de x pra mi pe x ole i n re d uci n g tiss ue e osi n o p hil bi o mar kers 
 T o e val uate t he efficac y of de x pra mi pe x ole i n re d uci n g bl o o d bas o p hil c o u nt 
 T o e val uate t he effect of de x pra mi pe x ole o n bl o o d e osi n o p hil pr o ge nit or p o p ulati o ns 
 T o e val uate t he o nset of bl o o d e osi n o p hil l o weri n g 
 T o assess t he rec o ver y of bl o o d e osi n o p hil c o u nt after de x pra mi pe x ole 
disc o nti n uati o n 
 T o e val uate t he effect of de x pra mi pe x ole o n ast h ma bi o mar kers  
 T o assess t he c orrelati o n bet wee n e osi n o p hil l o weri n g wit h c ha n ges i n p ul m o nar y 
f u ncti o n an d ast h ma c o ntr ol 
 T o e val uate t he e x p os ure of de x pra mi pe x ole acr oss t he d ose ra n ge use d i n t he st u d y 
 T o e xa m i ne t he relati o ns hi p bet wee n de x pra mi pe x ole e x p os ure a n d e osi n o p hil-
l o weri n g res p o nse 
 T o i n vesti gate p ote ntial pre dicti ve bi o mar kers t o i de ntif y he mat ol o gic res p o n ders 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
2 9  
 
7. 2.    
E n d p oi nts 
7. 2. 1.    
Pri m ar y E n d p oi nt 
 T he pri mar y e n d p oi nt of t his st u d y is t he relati ve c ha n ge i n bl o o d a bs ol ute e osi n o p hil 
c o u nt fr o m Baseli ne t o Wee k 1 2. 
7. 2. 2.    
Sec o n d ar y E n d p oi nts 
F oll o wi n g are t he sec o n dar y e n d p oi nts of t he st u d y:  
 C ha n ge i n p re- br o nc h o dilat or F E V 1, fr o m Baseli ne t o Wee k 1 2 
 C ha n ge i n Ast h ma C o ntr ol Q uesti o n naire ( A C Q- 7) sc ore, fr o m Baseli ne t o Wee k 1 2 
 C ha n ge i n p ost- br o nc h o dilat or F E V 1, fr o m Baseli ne t o Wee k 1 2 
 C ha n ge i n q ualit y of life, as meas ure d b y t he Ast h ma Q ualit y of Life Q uesti o n naire 
( A Q L Q), fr o m Baseli ne t o Wee k 1 2 
 I nci de nce a n d se verit y of A Es, c ha n ges i n vital si g ns, cli nical la b orat or y safet y tests, 
p h ysical e xa mi nati o n, b o d y wei g ht, a n d E C Gs 
7. 2. 3.    
E x p l or at or y E n d p oi nts 
T he f oll o wi n g are t he e x pl orat or y e n d p oi nts: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 0  
 
 
 
 
 
 
 
 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 1  
 
8.    
S T U D Y D E SI G N 
8. 1.    
St u d y O ver vie w 
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, d ose-ra n gi n g, m ulti-
ce nter st u d y t o e val uate t he cli nical effects of oral a d mi nistrati o n of de x pra mi pe x ole f or 
1 2 wee ks o n peri p heral bl o o d e osi n o p hil c o u nt i n s u bjects wit h e osi n o p hilic ast h ma.  
O ne h u n dre d s u bjects will recei ve st u d y dr u g ( place b o, de x pra mi pe x ole 7 5 m g/ da y, 1 5 0 m g/ da y, 
or 3 0 0 m g/ da y ra n d o ml y all ocate d i n a 1: 1: 1: 1 rati o) d uri n g t he Pri mar y Assess me nt Peri o d of 
t he st u d y ( 1 2 wee ks of c o nsec uti ve d osi n g). T he st u d y is e x pecte d t o be c o n d ucte d i n 
a p pro xi matel y 2 5 ce nters i n t he U nite d States. After t he Scree ni n g e val uati o ns are c o m plete d, 
eli gi ble s u bjects will e nter a R u n-i n Peri o d of at least 1 2 da ys. F oll o wi n g t he R u n-i n Peri o d, 
eli gi ble s u bjects will e nter t he Pri mar y Assess me nt Peri o d a n d recei ve t wice- dail y d osi n g of 
st u d y dr u g f or 1 2 wee ks. D uri n g t he Pri mar y Assess me nt Peri o d, s u bjects will ha ve st u d y 
assess me nts perf or me d at t he site e ver y 4 wee ks, wit h a d diti o nal safet y a n d la b orat or y 
assess me nts at Wee k 2 a n d Wee k 6. F oll o wi n g Wee k 1 2, s u bjects will disc o nti n ue st u d y dr u g 
a n d will be gi n a 1 2- wee k E osi n o p hil Rec o ver y Peri o d, d uri n g w hic h s u bjects will be m o nit ore d 
f or rec o ver y of e osi n o p hil c o u nt. See Fi g. 1 f or details. 
Fi g ure 1   St u d y Sc he m atic 
 
A sc he d ule of st u d y visits a n d assess me nts is pr o vi de d i n Secti o n 5 . 
T o ma xi mize st u d y d osi n g a d here nce a n d pr o vi de m ore detaile d a d here nce data, s u bjects will 
ta ke st u d y dr u g fr o m a “s mart b ottle”. T he s mart b ottle de vice re mi n ds s u bjects t o ta ke 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 4  
 
8. 2. 3.    
E osi n o p hil Rec o ve r y Peri o d 
T he E osi n o p hil Rec o ver y Peri o d will be gi n wit h t he c o m pleti o n of t he Wee k 1 2 ( Pri mar y 
O utc o me Visit ) assess me nts a n d c o nti n ues t hr o u g h t he c o m pleti o n of t he Wee k 2 4 ( E n d of St u d y 
Visi t) assess me nts. T he E osi n o p hil Rec o ver y Peri o d is sc he d ule d t o be 1 2 wee ks i n d urati o n. 
St u d y vi sits will occ ur at Wee k 1 6/ 1 8, Wee k 2 0 a n d Wee k 2 4. T he c ollecti o n of cli nical 
lab orat or y safet y tests at Wee k 2 0 a n d Wee k 2 4 ma y be c o n d ucte d at a desi g nate d re m ote 
la b orat or y facilit y, or as a site visit f or c o n ve nie nce. If a desi g nate d re m ote la b orat or y facilit y is 
uti lize d f or t hese visits, q ualifie d site pers o n nel will c o n d uct a tele p h o ne i nter vie w wit h t he 
s u bject t o c ollect a d verse e ve nt a n d c o nc o mita nt me di cati o n data. 
8. 3.    
St u d y Sc he d ule 
See Secti o n 1 2  f or details re gar di n g i n di vi d ual St u d y Assess me nts. 
8. 3. 1.    
Scree ni n g  
Pri or t o c o n d ucti n g a n y st u d y-relate d assess me nts, writte n i nf or me d c o nse nt m ust be o btai ne d 
fr o m t he s u bject. Partici pati o n i n t his st u d y is v ol u ntar y. T he nat ure of t he st u d y will be f ull y 
e x plai ne d t o eac h s u bject d uri n g t he i nf or me d c o nse nt pr ocess a n d t he s u bject will ha ve t he 
o p p ort u nit y t o as k q uesti o ns. A c o p y of t he i nf or me d c o nse nt f or m (I C F) will be pr o vi de d t o t he 
s u bject. 
S u bject eli gi bilit y will be assesse d d uri n g t he Scree ni n g visit a n d c o nfir me d at t he Baseli ne visit. 
Scre e ni n g assess me nts are t o be c o m plete d bet wee n 1 2- 3 0 da ys pri or t o t he Baseli ne visit (first 
d ose of st u d y dr u g).  
At t he Scree ni n g visit, t he f oll o wi n g assess me nts are t o be c o m plete d (t he ge neral se q ue nce f or 
per f or mi n g assess me nts s h o ul d f oll o w t he or der bel o w): 
 C o nf ir m I nf or me d C o nse nt 
 Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n t he visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 Me dical hist or y  
 Ast h m a hist or y 
 P h ysic al e xa mi nati o n 
 Vita l si g ns – See Secti o n 1 2. 1. 2  
 B o d y w ei g ht 
 Cli nical safet y la b orat or y tests 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 C o ntrac e pti o n c o u nseli n g, all s u bjects 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 5  
 
 1 2 -lea d E C G (pri or t o P F Ts)  –  See Secti o n 1 2. 1. 3  
 A d verse  e ve nts 
 Pri or  & c o nc o mita nt me dicati o n 
 Pre - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
o  If t he s u bject h as wit h hel d t heir ast h m a me dic ati o ns, perf or m pre-
br o nc h o dil at or P F Ts f oll o we d by p ost- br o nc h o dil at or P F Ts  
o  If t he s u bject h as n ot wit h hel d t heir ast h m a me dic ati o ns, sc he d ule a ret ur n 
visit t o perf or m pre- br o nc h o dil at or a n d p ost- br o nc h o dil at or P F Ts – See 
Sect i o n 8. 3. 1. 1  
 P ost - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 Eli gi bilit y re vie w base d o n Scree ni n g assess me nts 
 S mart b ottle i n ve nt or y a n d str uct ure d st u d y d osi n g a d here nce c o u nseli n g –  See St u d y 
Refere nce Ma n ual 
 O bser ve d a d mi nistrati o n of st u d y dr u g ( o pe n-la bel place b o) 
 Disc ha r ge fr o m site wit h s mart b ottle 
8. 3. 1. 1.  
Scree ni n g P ul m o n ar y F u ncti o n Testi n g 
S u bjects w h o prese nt f or Scree ni n g a n d ha ve ta ke n t heir A M ast h ma me dicati o n (see Ta ble  2), 
s h o ul d ha ve all Scree ni n g assess me nts perf or me d e xce pt t he Scree ni n g P F T. T hese s u bjects will 
be re q ueste d t o resc he d ule t he Scree ni n g P F T as s o o n as feasi ble o n a m or ni n g w he n t he ast h ma 
m e dicati o n has bee n wit h hel d.   
T he pre- br o nc h o dilat or F E V 1 i ncl usi o n criteri o n m ust be me t at t he Scree ni n g a n d Baseli ne 
visi ts. T he p ost- br o nc h o dilat or F E V 1 i ncl usi o n criteri o n m ust be met at t he Scree ni n g visit.  
 S u bjec ts w h o d o n ot meet t he pre- br o nc h o dilat or F E V 1 i ncl usi o n criteri o n of < 8 0 % 
pre dicte d at Scree ni n g a n d Baseli ne, des pite wit h h ol di n g ast h ma me dicati o n per 
Ta ble  2, ma y n ot re peat P F Ts i n or der t o q ualif y f or t he st u d y. 
 At Scree ni n g, s u bjects w h o d o n ot meet t he p ost- br o nc h o dilat or re versi bilit y 
i ncl usi o n criteri o n, b ut ha ve ≥1 0 % or ≥1 6 0 m L re versi bilit y, ma y re peat t he 
re versi bilit y P F T assess me nt o nce d uri n g t he R u n-i n Peri o d.  
8. 3. 2.    
B aseli ne 
F oll o wi n g t he c o m pleti o n of t he R u n-i n Peri o d a n d c o nfir mati o n of eli gi bilit y, Baseli ne 
assess me nts will be perf or me d pri or t o d osi n g o n Da y 1 of st u d y dr u g.  
S u bjects s h o ul d h ol d t heir A M ast h m a me dic ati o n t he m or ni n g of t he B aseli ne visit. If t he 
s u bject has n ot wit h hel d t heir ast h ma me dicati o ns acc or di n g t o Ta ble 2 , t he e ntire Baseli ne visit 
m ust be resc he d ule d. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 6  
 
At t he Baseli ne visit, t he f oll o wi n g assess me nts are t o be c o m plete d (t he ge neral se q ue nce f or 
per f or mi n g assess me nts s h o ul d f oll o w t he or der bel o w): 
 C o nf ir m I nf or me d C o nse nt 
 Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n t he visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 Ast h m a Q ualit y of Life Q uesti o n naire ( A Q L Q) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 1 2 -lea d E C G ( pri or t o d osi n g dex pr a mi pex ole) – See Secti o n 1 2. 1. 3  
 Cli ni cal safet y la b orat or y tests 
 Ser u m  f or I g E 
 W h ole bl o o d c ollecti o n (e osi n o p hil pr o ge nit ors a n d bas o p hils) 
 W h ole bl o o d f or w h ole ge n o me D N A se q ue nci n g 
 Ser u m  c ollecti o n f or e x pl orat or y bi o mar kers 
 Uri ne  e osi n o p hil gra n ule pr otei ns 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 C o ntrac e pti o n c o u nseli n g, all s u bjects 
 Vita l si g ns – See Secti o n 1 2. 1. 2  
 B o d y w ei g ht 
 Frac ti o nal e x hale d Nitric O xi de ( Fe N O) ( pri or t o P F Ts) 
 Pre - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 P os t- br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 P h ysic al e xa mi nati o n 
 A d verse  e ve nts 
 Ne utr o pe nia case re p ort f or m i nter vie w 
 Pri or  & c o nc o mita nt me dicati o n 
 Nasal  a n d p har y n geal e osi n o p hil per o xi dase 
 Eli gi bilit y re vie w base d o n Baseli ne assess me nts 
 Ra n d o mizati o n 
 S mart b ottle i n ve nt or y a n d str uct ure d st u d y d osi n g a d here nce c o u nseli n g. See St u d y 
Refere nce Ma n ual 
 O bser ve d a d mi nistrati o n of st u d y dr u g 
 Disc ha r ge fr o m site wit h s mart b ottle 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 7  
 
8. 3. 2. 1.  
B aseli ne P ul m o n ar y F u ncti o n Testi n g 
S u bjec ts w h o prese nt f or t he Baseli ne visit, b ut ha ve n ot wit h hel d t heir ast h ma me dicati o n 
acc or di n g t o Ta ble 2 , s h o ul d n ot be ra n d o mize d a n d m ust resc he d ule t he Baseli ne visit.   
8. 3. 3.    
Wee k  2 Visit  
At t he Wee k 2 visit, a C B C will be perf or me d. 
T he cl i nical la b orat or y bl o o d sa m ple ( C B C) ma y eit her be c ollecte d at t he st u d y site or at a 
desi g nate d re m ote la b orat or y facilit y f or c o n ve nie nce.  
8. 3. 4.    
Wee k  4 Visit 
S u bjects s h o ul d h ol d t heir st u d y dr u g  A N D  A M ast h m a me dic ati o n t he m or ni n g of t he 
Wee k 4 visit.  If t he s u bject has n ot wit h hel d t heir ast h ma me dicati o ns, t he Wee k 4 visit m ust be 
resc he d ule d. 
At t he Wee k 4 visit, t he f oll o wi n g assess me nts are t o be c om plete d (t he ge neral se q ue nce f or 
perf or mi n g assess me nts s h o ul d f oll o w t he or der bel o w): 
 Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n t he visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 1 2 -lea d E C G ( pri or t o d osi n g st u dy dr u g) – See Secti o n 1 2. 1. 3  
 Cli ni cal safet y la b orat or y tests 
 Plas m a f or de x pra mi pe x ole c o nce ntrati o n ( tr o u g h) 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 S mart b ottle i n ve nt or y a n d str uct ure d st u d y d osi n g a d here nce c o u nseli n g. See St u d y 
Refere nce Ma n ual 
 P h ysic al e xa mi nati o n 
 Vita l si g ns – See Secti o n 1 2. 1. 2  
 B o d y w ei g ht 
 C o ntrac e pti o n c o u nseli n g, all s u bjects 
 A d verse  e ve nts 
 Ne utr o pe nia case re p ort f or m i nter vie w 
 C o nc o mita nt me dicati o n 
 Frac ti o nal e x hale d Nitric O xi de ( Fe N O) ( pri or t o P F Ts) 
 Pre - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 O bser ve d a d mi nistrati o n of st u d y dr u g 
 Dist ri b ute c o mi n g m o nt h’s st u d y dr u g i n s mart b ottle – See Secti o n 1 1. 2  
 Disc ha r ge fr o m site wit h s mart b ottle 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 8  
 
8. 3. 5.    
Wee k  6 Visit 
At t he Wee k 6 visit, a C B C will be perf or me d. 
T he cl i nical la b orat or y bl o o d sa m ple ( C B C) ma y eit her be c ollecte d at t he st u d y site or at a 
desi g nate d re m ote la b orat or y facilit y f or c o n ve nie nce.  
8. 3. 6.    
Wee k  8 Visit 
S u bjects s h o ul d h ol d t heir st u d y dr u g  A N D  A M ast h m a me dic ati o n t he m or ni n g of t he 
Wee k 8 visit. If t he s u bject has n ot wit h hel d t heir ast h ma me dicati o ns, t he Wee k 8 visit m ust be 
resc he d ule d. 
T he e x pecte d d urati o n of t he Wee k 8  visit is a p pr o xi matel y 3 h o urs. 
At t he  Wee k 8 visit, t he f oll o wi n g assess me nts are t o be c o m plete d (t he ge neral se q ue nce f or 
per f or mi n g assess me nts s h o ul d f oll o w t he or der bel o w): 
 Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n t he visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 1 2 -lea d E C G ( pri or t o d osi n g st u dy dr u g) – See Secti o n 1 2. 1. 3  
 Cli ni cal safet y la b orat or y tests 
 Plas m a f or de x pra mi pe x ole c o nce ntrati o n ( tr o u g h) 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 S mart b ottle i n ve nt or y a n d str uct ure d st u d y d osi n g a d here nce c o u nseli n g. See St u d y 
Refere nce Ma n ual 
 P h ysical e xa mi nati o n 
 Vita l si g ns – See Secti o n 1 2. 1. 2  
 B o d y w ei g ht 
 O bser ve d a d mi nistrati o n of st u d y dr u g 
 Plas m a f or de x pra mi pe x ole c o nce ntrati o n at 2 h o urs after d ose – See Secti o n 1 2. 4  
 C o ntrac e pti o n c o u nseli n g, all s u bjects 
 A d verse  e ve nts 
 Ne utr o pe nia case re p ort f or m i nter vie w 
 C o nc o mita nt me dicati o n 
 Frac ti o nal e x hale d Nitric O xi de ( Fe N O) ( pri or t o P F Ts) 
 Pre - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 1 2 -lea d E C G ( after P F Ts) at 2 h o urs p ost d ose ( ± 3 0 mi n utes) – See Secti o n 1 2. 1. 3  
o  I niti al E C G f oll o we d by i m me di ate i n h al ati o n of al b uter ol 4 p uffs vi a metere d 
d ose i n h aler ( 9 0- 1 0 0 μ g al b uter ol b ase per act u ati o n) 
o  Re pe at 1 2-le a d E C G 1 5 mi n utes ( ± 5 mi n utes) after l ast p uff of al b uter ol 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
3 9  
 
 Dist ri b ute c o mi n g m o nt h’s st u d y dr u g i n s mart b ottle – See Secti o n 1 1. 2  
 Disc ha r ge fr o m site wit h s mart b ottle 
8. 3. 7.    
Wee k  1 2 - Pri m ar y O utc o me Visit 
Wee k 1 2 is desi g nate d as t he Pri mar y O utc o me Visit a n d will be perf or me d at t he site. 
S u bjects s h o ul d h ol d t heir st u d y dr u g  A N D  A M ast h m a me dic ati o n t he m or ni n g of t he 
Wee k 1 2 visit.  If t he s u bject has n ot wit h hel d t heir ast h ma me dicati o ns acc or di n g t o Ta ble 2 , t he 
Wee k 1 2 visit m ust be resc he d ule d.  
T he e x pecte d d urati o n of t he Wee k 1 2 visit is 2 h o urs. 
At t he  Wee k 1 2 visit, t he f oll o wi n g assess me nts are t o be c o m plete d (t he ge neral se q ue nce f or 
per f or mi n g assess me nts s h o ul d f oll o w t he or der bel o w: 
 Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n t he visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 Ast h m a Q ualit y of Life Q uesti o n naire ( A Q L Q) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n t he visit t o mi ni mize t he i nfl ue nce of 
ot he r assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 1 2 -lea d E C G ( pri or t o d osi n g st u dy dr u g) – See Secti o n 1 2. 1. 3  
 Cli ni cal safet y la b orat or y tests 
 Plas m a f or de x pra mi pe x ole c o nce ntrati o n (tr o u g h) 
 W h ole bl o o d c ollecti o n (e osi n o p hil pr o ge nit ors a n d bas o p hils) 
 Ser u m  c ollecti o n f or e x pl orat or y bi o mar kers 
 Uri ne  e osi n o p hil gra n ule pr otei ns 
 S mart b ottle i n ve nt or y  
 P h ysic al e xa mi nati o n 
 Vita l si g ns – See Secti o n 1 2. 1. 2  
 B o d y w ei g ht 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 C o ntrac e pti o n c o u nseli n g, all s u bjects 
 A d verse  e ve nts 
 Ne utr o pe nia case re p ort f or m i nter vie w 
 C o nc o mita nt me dicati o n 
 Frac ti o nal e x hale d Nitric O xi de ( Fe N O) ( pri or t o P F Ts) 
 Pre - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
o  T he We ek 1 2 Pre- br o nc h o dil at or P F T s h o ul d be c ollecte d wit hi n ± 1 h o ur of 
t he ti me of d ay t h at t he B aseli ne P F T w as c ollecte d.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 0  
 
 P ost - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 Nasal  a n d p har y n geal e osi n o p hil per o xi dase 
 O bser ve d a d mi nistrati o n of fi nal a d mi nistrati o n of st u d y dr u g 
 C ollec t re mai ni n g st u d y dr u g a n d s mart b ottle 
 Disc ha r ge fr o m site  
8. 3. 8.    
Wee k  1 6/ 1 8 Visit 
S pecific sites will be selecte d t o ha ve all s u bjects e nr olle d at t he site t o ha ve t his visit sc he d ule d 
t o occ ur o n eit her Wee k 1 6 or Wee k 1 8. T he di visi o n of Wee k 1 6 a n d Wee k 1 8 visits acr oss sites 
all o ws t he e val uati o n of e osi n o p hil rec o ver y o ver m ore ti me p oi nts. 
S u bjects s h o ul d h ol d t heir A M ast h m a me dic ati o n t he m or ni n g of t he Wee k 1 6/ 1 8 visit. If 
t he s u bject has n ot wit h hel d t heir ast h ma me dicati o ns, t he Wee k 1 6/ 1 8 visit m ust be resc he d ule d. 
At t he Wee k 1 6/ 1 8 visit, t he f oll o wi n g assess me nts are t o be c o m plete d (t he ge neral se q ue nce f or 
per f or mi n g assess me nts s h o ul d f oll o w t he or der bel o w): 
 Ast h m a C o ntr ol Q uesti o n naire ( A C Q- 7) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 Ast h m a Q ualit y of Life Q uesti o n naire ( A Q L Q) 
o  S h o ul d be  c ollecte d as e arly as fe asi ble i n visit t o mi ni mize t he i nfl ue nce of 
ot her assess me nts (e. g., P F Ts, E C G, a n d A E c a pt ure) 
 P h ysic al e xa mi nati o n 
 Vita l si g ns – See Secti o n 1 2. 1. 2  
 B o d y w ei g ht 
 Cli ni cal safet y la b orat or y tests 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 C o ntrac e pti o n c o u nseli n g 
 A d verse  e ve nts 
 C o nc o mita nt me dicati o n 
 Pre - br o nc h o dilat or p ul m o nar y f u ncti o n ( F E V 1) – See Secti o n 1 2. 2. 2  
 Disc ha r ge fr o m site 
8. 3. 9.    
Wee k  2 0 Visit 
At t he Wee k 2 0 visit, t he f oll o wi n g assess me nts are t o be c o m plete d: 
 Cli ni cal safet y la b orat or y tests 
 C o ntrac e pti o n c o u nseli n g, male s u bjects 
 A d verse  e ve nts 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 1  
 
 C o nc o mita nt me dicati o n 
T he cli nical la b orat or y bl o o d sa m ple ma y eit her be c ollecte d at t he st u d y site or at a desi g nate d 
re m ote la b orat or y facilit y f or c o n ve nie nce. If safet y la b tests are c ollecte d re m otel y, a d verse 
e ve nt a n d c o nc o mita nt me dicati o n use will be c ollecte d t hr o u g h d oc u me nte d tele p h o ne c o ntact 
wit h t he s u bject b y a p pr o priate site pers o n nel. 
8. 3. 1 0.   
Wee k  2 4 E n d of St u d y Visit 
At t he  Wee k 2 4 visit, t he f oll o wi n g assess me nts are t o be c o m plete d: 
 Cli ni cal safet y la b orat or y tests 
 Uri ne  β- h C G/ pre g na nc y test f or fe males of c hil d beari n g p ote ntial 
 C o ntrac e pti o n c o u nseli n g, male s u bjects (as nee de d wit hi n 3 m o nt hs of last d ose of 
st u d y dr u g) 
 A d verse e ve nts 
 C o nc o mita nt me dicati o n 
 Ser u m  c ollecti o n f or e x pl orat or y bi o mar kers 
T he cli nical la b orat or y a n d ser u m bi o mar ker bl o o d sa m ple ma y eit her be c ollecte d at t he st u d y 
site or at a desi g nate d re m ote la b orat or y facilit y f or c o n ve nie nce. If safet y la b tests are c ollecte d 
rem otel y, a d verse e ve nt a n d c o nc o mita nt me dicati o n use will be c ollecte d t hr o u g h d oc u me nte d 
tele p h o ne c o ntact wit h t he s u bject b y a p pr o priate site pers o n nel. 
8. 3. 1 1.   
Pre m at ure Disc o nti n u ati o n Visit 
S u bjec ts w h o disc o nti n ue st u d y dr u g pre mat urel y will be as ke d t o ret ur n wit hi n 4 da ys of t he last 
d ose of st u d y dr u g t o ha ve t he Wee k 1 2 ( Pri mar y O utc o me Visit ) assess me nts  perf or me d.  
I n suc h disc o nti n ue d s u bjects, a well- bei n g c hec k (tele p h o ne i nter vie w) will be als o c o m plete d 
3 0 da ys a fter t he last d ose of st u d y dr u g a n d will be d oc u me nte d i n t he C R F. 
8. 4 .   
St u d y St o p pi n g R ules 
K n o p p ma y ter mi nate t his st u d y at a n y ti me, after i nf or mi n g Site I n vesti gat ors. Site I n vesti gat ors 
will be n otifie d b y K n o p p if t he st u d y is place d o n h ol d, c o m plete d, or cl ose d pre mat urel y.  
8. 5 .   
E n d of St u d y 
T he E n d of St u d y is defi ne d as t he last s u bject’s last st u d y-relate d visit. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 2  
 
9.    
S E L E C TI O N O F S U B J E C T S 
9. 1.    
I ncl usi o n Criteri a 
T o be eli gi ble t o partici pate i n t his st u d y, ca n di dates m ust meet t he f oll o wi n g criteria: 
1.  S i g ne d i nf or me d c o nse nt. 
2.  Mal e or fe male ≥1 8 a n d < 7 5 years of a ge at t he ti me of c o nse nt.  
3.  W illi n g t o practice o ne hi g hl y effecti ve met h o d of c o ntrace pti o n or 2 pr ot oc ol 
acce pta ble met h o ds of c o ntrace pti o n i n ta n de m, fr o m t he ti me of i nf or me d c o nse nt 
t hro u g h 1 m o nt h (fe males) or 3 m o nt hs ( males) after t he last d ose of st u d y dr u g.  
4.  P h ysic ia n dia g n osis of ast h ma f or ≥1 2 m o nt hs (relati ve t o Baseli ne) base d o n Gl o bal 
I nitiati ve f or Ast h ma ( GI N A) 2 0 1 8 G ui deli nes. 1 
5.  Ast h m a re q uiri n g treat me nt wit h, at a mi ni m u m, l o w d ose i n hale d c ortic oster oi ds 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 ( GI N A ste ps 3- 5 1), o n a sta ble d ose f or at 
least 1 m o nt h bef ore Scree ni n g. S u bjects usi n g ot her c o ntr oller o pti o ns wit h o ut l o n g-
acti n g β 2 a g o nist are n ot eli gi ble f or t he st u d y. 
6.  Br o nc h o dil at or re versi bilit y, as e vi de nce d b y ≥1 2 % a n d ≥2 0 0 m L i m pr o ve me nt i n 
F E V 1 1 5 t o 2 5 mi n utes f oll o wi n g i n halati o n of al b uter ol at Scree ni n g. 
7.  Pre - br o nc h o dilat or F E V 1 ≥4 0 % a n d < 8 0 % of pre dicte d at Scree ni n g a n d Baseli ne. 
8.  A E C  ≥0. 3 0 x 1 09/ L at t he Scree ni n g visit. Ma y be re peate d o nce if t he i nitial val ue is 
bet wee n 0. 2 5- 0. 2 9 x 1 0 9/ L; the sec o n d A E C m ust be ≥0. 3 0 x 1 0 9/ L. 
9.  A C Q - 7 ≥1. 5 at Scree ni n g.  
1 0.  Ne gati ve pre g na nc y test at Baseli ne. 
1 1.  A d here nc e ≥8 5 % wit h t wice- dail y place b o ta ke n d uri n g t he R u n-i n Peri o d  
( mi ni m u m 1 2 da ys of a d here nce data), as d oc u me nte d b y t he s mart b ottle. 
9. 2 .   
E xcl usi o n Criteri a 
Ca n di dates will be e xcl u de d fr o m st u d y e ntr y if a n y of t he f oll o wi n g ha ve bee n d oc u me nte d b y 
Baseli ne: 
1.  Ast h m a c o nsi dere d b y t he Site I n vesti gat or as u nsta ble at Baseli ne. 
2.  Treat me nt f or a n ast h ma e xacer bati o n wit hi n 8 wee ks pri or t o Baseli ne visit. 
3.  C urre nt dia g n osis of aller gic br o nc h o p ul m o nar y as per gill osis, e osi n o p hilic 
gra n ul o mat osis wit h p ol ya n giitis, e osi n o p hilic gastr oi ntesti nal diseases, or 
h y pere osi n o p hilic s y n dr o me, or l u n g diseases (e. g., c hr o nic o bstr ucti ve p ul m o nar y 
disease, i di o pat hic p ul m o nar y fi br osis) w hic h ma y c o nf o u n d i nter pretati o n of t his 
trial’s fi n di n gs. 
4.  I nfecti o n of t he u p per or l o wer res pirat or y tract, i ncl u di n g para nasal si n uses a n d 
mi d dle ear wit hi n t he 4 wee ks pri or t o Baseli ne. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 3  
 
5.  Trea t me nt wit h s yste mic c ortic oster oi ds i n t he 8 wee ks pri or t o Scree ni n g. 
6.  Trea t me nt wit h a n i n vesti gati o nal dr u g i n t he pre vi o us 3 0 da ys or 5- half-li ves pri or t o 
Baseli ne, w hic he ver is l o n ger. 
7.  Trea t me nt wit h m o n ocl o nal a nti b o d y t hera p y, i ncl u di n g be nraliz u ma b, d u pil u ma b, 
me p oliz u ma b, resliz u ma b, o maliz u ma b, or T N F i n hi bit ors, wit hi n 5- half-li ves pri or t o 
Basel i ne. 
8.  Trea t me nt wit h pra mi pe x ole wit hi n 4 wee ks of Baseli ne. 
9.  Trea t me nt wit h selecte d dr u gs k n o w n t o ha ve a s u bsta ntial ris k of ne utr o pe nia (see 
A p pe n di x A). 
1 0.  Pla n ne d s ur gical pr oce d ures d uri n g t he c o n d uct of t he st u d y. 
1 1.  Hist or y of mali g na nc y. S u bjects wit h basal cell carci n o ma, l ocalize d s q ua m o us cell 
carci n o ma of t he s ki n, or i n-sit u carci n o ma of t he cer vi x are n ot e xcl u de d, pr o vi de d 
t hat t he s u bject is i n re missi o n a n d c urati ve t hera p y was c o m plete d ≥1 2 m o nt hs pri or 
t o Scree ni n g. S u bjects wit h ot her mali g na ncies are n ot e xcl u de d, pr o vi de d t hat t he 
s u bject is i n re missi o n a n d c urati ve t hera p y was c o m plete d ≥5 years pri or t o 
Scre e ni n g. 
1 2.  K n o w n hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n.  
1 3.  Acti ve he patitis B or C i nfecti o n. S u bjects wit h a hist or y of he patitis C wit h 
u n detecta ble viral l oa d f or ≥1 year are n ot e xcl u de d. 
1 4.  Re nal d ysf u ncti o n, defi ne d as a n esti mate d gl o mer ular filtrati o n rate (e G F R) 
< 6 0 m L/ mi n/ 1. 7 3 m 2 at Scree ni n g ( usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b or ati o n [ C K D- E PI] f or m ula). 
1 5.  Hist or y of u nsta ble or se vere car diac, he patic, or re nal disease, or ot her me dicall y 
sig nifica nt ill ness. 
1 6.  Me di cal or ot her c o n diti o n li kel y t o i nterfere wit h s u bject’s a bilit y t o u n der g o st u d y 
assess me nts, a d here t o visit sc he d ule, or c o m pl y wit h st u d y re q uire me nts.  
1 7.  Hel m i nt h i nfecti o n wit hi n 6 m o nt hs pri or t o Baseli ne. 
1 8.  Use of  a n y s m o ke or i n hale d nic oti ne deli ver y de vice wit hi n 1 year pri or t o Scree ni n g 
or a  s m o ki n g hist or y ≥1 0 pac k- years. 
1 9.  K n o w n or s us pecte d alc o h ol or ot her s u bsta nce a b use. 
2 0.  K n o w n or s us pecte d n o n-a d here nce wit h st u d y d osi n g sc he d ule. 
2 1.  U n w illi n g ness or i na bilit y t o f oll o w t he pr oce d ures o utli ne d i n t he pr ot oc ol, i ncl u di n g 
t hr oat or nasal s wa b. 
2 2.  A bs ol ut e ne utr o p hil c o u nt < 2. 0 x 1 0 9/ L at Scree ni n g, or a n y d oc u me nte d hist or y of 
a bs ol ute ne utr o p hil c o u nt < 2. 0 x 1 0 9/ L. 
2 3.  Hist or y of l o n g Q T s y n dr o me or arr h yt h mia. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 4  
 
2 4.  E C G s h o wi n g pr ol o n gati o n of Q Tc i nter val calc ulate d usi n g Fri dericia’s heart rate 
c orrecti o n f or m ula ( Q Tc F) > 4 5 0 ms at t he Scree ni n g visit or pre- d ose at Baseli ne. 
Q Tc F i nter val calc ulate d as t he mea n of tri plicate deter mi nati o ns. 
2 5.  Cli ni call y i m p orta nt a b n or malities i n resti n g E C G at Scree ni n g or Baseli ne, i ncl u di n g 
a n y of t he f oll o wi n g: 
a) P R i nter val > 2 1 0 ms; 
b)  Q R S > 1 1 0 ms;  
c) Heart rate < 4 5 b p m or > 1 0 0 b p m (a vera ge of 3 assess me nts). 
2 6.  Pre g na nt or breastfee di n g w o me n. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 5  
 
1 0.    
E N R O L L M E N T P R O C E D U R E S 
1 0. 1.   
E nr oll me nt 
A si g ne d a n d date d I nstit uti o nal Re vie w B oar d-a p pr o ve d i nf or me d c o nse nt f or m (I C F) m ust be 
o bta i ne d fr o m s u bjects bef ore a n y st u d y assess me nts occ ur.  
Partici pati n g st u d y sites are re q uire d t o d oc u me nt all ca n di dates i nitiall y c o nsi dere d f or i ncl usi o n 
i n t his st u d y. If a s u bject is e xcl u de d fr o m t he st u d y, t he reas o ns f or e xcl usi o n s h o ul d be 
d oc u m e nte d i n t he s u bject’s s o urce d oc u me nts a n d o n t he s u bject scree ni n g l o g. 
S u bjects si g ni n g t he i nf or me d c o nse nt f or m are c o nsi dere d e nr olle d. A n y s u bject i de ntificati o n 
n u m ber all ocate d t o a n e nr olle d s u bject will n ot be re use d. 
1 0. 2.   
R a n d o miz ati o n 
S u bjects ma y be r a n d o mize d after all Baseli ne assess me nts ha ve bee n c o m plete d a n d after t he 
Sit e I n vesti gat or has c o nfir me d eli gi bilit y. N o s u bject ma y be ra n d o mize d pri or t o t he c ollecti o n 
a n d assess me nt of all Baseli ne assess me nts a n d c o nfir mati o n of eli gi bilit y ( S ee Secti o n 9 ). 
A fter t he s u bject has bee n ra n d o mize d, t he first d ose of st u d y dr u g will be a d mi nistere d at t he 
site u n der direct o bser vati o n of t he st u d y staff.  
1 0. 3.   
Bli n di n g 
S u bjects e nr olle d i nt o t he Pri mar y Assess me nt Peri o d will be ra n d o ml y all ocate d i n a 1: 1: 1: 1 
rati o t o recei ve de x pra mi pe x ole 7 5 m g/ da y ( 3 7. 5 m g BI D), de x pra mi pe x ole 1 5 0 m g/ da y 
( 7 5 m g  BI D), de x pra mi pe x ole 3 0 0 m g/ da y ( 1 5 0 m g BI D), or place b o ( BI D). S u bjects, site staff, 
ve n d ors,    
 ( C R O), a n d K n o p p pers o n nel will re mai n bli n de d t o st u d y assi g n me nt.  
T he st u d y will utilize a n a ut o mate d tele-ra n d o mizati o n s yste m i nc or p orati n g a ce ntral 
ra n d o mizati o n sc he me. S u bjects will be ra n d o ml y assi g ne d t o t heir treat me nt gr o u p acc or di n g t o 
a c o m p uter- ge nerate d pse u d ora n d o m c o de usi n g a met h o d of ra n d o m per m ute d bl oc ks stratifie d 
b y st u d y site. 
1 0. 3. 1.   
Bli n di n g of  C B C Res ults 
De x pra mi pe x ole l o wers e osi n o p hil a n d bas o p hil c o u nts s uc h t hat t hese val ues c o ul d i n dicate 
acti ve treat me nt assi g n me nt. All st u d y-relate d la b res ults will be pr ocesse d t hr o u g h a ce ntral 
la b orat or y facilit y c o ntracte d f or t he st u d y. 
Scre e ni n g a n d Baseli ne C B C res ults will n ot be bli n de d t o a n y st u d y pers o n nel. H o we ver, t he 
site staff, C R O, a n d K n o p p pers o n nel will be bli n de d t o a bs ol ute e osi n o p hil c o u nt, a bs ol ute 
bas o p hil c o u nt, t otal w hite bl o o d cell ( W B C) c o u nt, a n d W B C % differe ntial res ults fr o m t he 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 6  
 
ce ntral la b orat or y c ollecte d d uri n g t he Pri mar y Assess me nt Peri o d a n d E osi n o p hil Rec o ver y 
Peri o d ( Baseli ne t hr o u g h Wee k 2 4).  
Ot her  C B C res ults, i ncl u di n g a bs ol ute ne utr o p hil c o u nt, a bs ol ute l y m p h oc yte c o u nts, a bs ol ute 
m o n oc yte c o u nt, a bs ol ute c o u nts of i m mat ure or at y pical cells, platelet c o u nt, a n d all re d bl o o d 
cell i n dices will n ot be bli n de d d uri n g t he st u d y. 
Site staff m ust als o a v oi d ha vi n g s u bjects ( or t he msel ves) i na d verte ntl y u n bli n de d b y n o n-st u d y 
C B C res ults fr o m tests perf or me d at a la b u naffiliate d wit h t he st u d y (i.e., a n u n desi g nate d l ocal 
lab) d uri n g t he ti me a gi ve n s u bject is partici pati n g i n t his trial. At eac h site, t o mai ntai n bli n di n g 
of t he st u d y staff, a p h ysicia n n ot ot her wise i n v ol ve d i n t he st u d y will be desi g nate d t o re vie w 
a n y u n bli n de d o utsi de la b orat or y res ults. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 7  
 
1 1.    
S T U D Y D R U G, C O N C O MI T A N T T H E R A P Y A N D 
C O N C O MI T A N T P R O C E D U R E S  
1 1. 1.   
De x pr a mi pe x ole a n d Pl ace b o 
K n o p p will pr o vi de de x pra mi pe x ole ( K N S- 7 6 0 7 0 4), a n d bli n de d matc hi n g place b o. 
De x pra m i pe x ole (a n d matc hi n g place b o) will be s u p plie d at t he d ose stre n gt hs of 3 7. 5 m g, 
7 5 m g, a n d 1 5 0 m g. S u bjects will be ra n d o ml y all ocate d i n a 1: 1: 1: 1 rati o t o recei ve 
de x pr a mi pe x ole 7 5 m g/ da y, de x pra mi pe x ole 1 5 0 m g/ da y, de x pra mi pe x ole 3 0 0 m g/ da y, or 
place b o (as BI D d osi n g).  
De x pra mi pe x ole is s u p plie d as 
 ta blets w hic h c o ntai n 
 
.  
Place b o is s u p plie d as 
 ta blets w hic h c o ntai n 
 
 
.  
All st u d y dr u g pr o d ucts will be dis pe nse d t o t he s u bject i n well-cl ose d c o ntai ners wit h c hil d-
pr o of cl os ure (
). 
T he la bel will i ncl u de c o n diti o ns f or st ora ge a n d a place h ol der f or rec or di n g t he s u bject i de ntifier 
a n d pr ot oc ol n u m ber. De x pra mi pe x ole a n d place b o s h o ul d n ot be use d after t he retest date u nless 
a p pr o priate retest d oc u me ntati o n is pr o vi de d b y K n o p p. 
1 1. 2.   
St u d y Dr u g St or a ge 
St u d y dr u g m ust be st ore d i n a sec ure l oc ke d l ocati o n wit h access li mite d t o site pers o n nel. St u d y 
dr u g s h o ul d be st ore d at c o ntr olle d r o o m te m perat ure ( 
 t o 
C,  
 t o 
F) a n d s h o ul d be 
m o nit ore d at least wee kl y. St ora ge l ocati o n te m perat ure rec or ds m ust be mai ntai ne d a n d 
a vaila ble f or i ns pecti o n at eac h m o nit ori n g visit. 
1 1. 3.   
St u d y Dr u g Acc o u nt a bilit y 
T he st u d y site m ust mai ntai n acc urate rec or ds de m o nstrati n g dates a n d a m o u nt of st u d y dr u g 
recei ve d, t o w h o m dis pe nse d (s u bject- b y-s u bject acc o u nti n g), a m o u nt ret ur ne d b y t he s u bject, 
a n d acc o u nts of a n y st u d y dr u g acci de ntall y or deli beratel y destr o ye d.  
U nless ot her wise s pecifie d, all st u d y dr u g, b ot h use d a n d u n use d, m ust be sa ve d f or st u d y dr u g 
acco u nta bilit y. At t he e n d of t he st u d y, rec o nciliati o n m ust be ma de bet wee n t he a m o u nt of st u d y 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 8  
 
dr u g s u p plie d, dis pe nse d, a n d s u bse q ue ntl y ret ur ne d t o K n o p p or desi g nee. A writte n e x pla nati o n 
m ust be pr o vi de d f or a n y discre pa ncies. 
Acc o u nta bilit y f or st u d y dr u g is t he res p o nsi bilit y of t he Site I n vesti gat or. 
1 1 . 4.  
St u d y D osi n g a n d D osi n g A d here nce 
St u d y dr u g ma y be dis pe nse d o nl y b y a p har macist or me dicall y q ualifie d staff. St u d y dr u g is t o 
be dis pe nse d o nl y t o s u bjects e nr olle d i n t his st u d y. Ret ur ne d st u d y dr u g ma y n ot be dis pe nse d t o 
or a d mi nistere d t o a n ot her s u bject. 
T he f irst d ose of st u d y dr u g will be a d mi nistere d at t he site b y a ut h orize d site staff at t he 
c o ncl usi o n of t he Baseli ne assess me nts. S u bjects will be i nstr ucte d t o ta ke t he sec o n d d ose of 
st u d y dr u g a p pr o xi matel y 1 2 h o urs after t he first d ose. S u bjects s h o ul d be i nstr ucte d t o ta ke a 
d ose at a p pr o xi matel y t he sa me ti me of da y eac h m or ni n g a n d a gai n a p pr o xi matel y 1 2 h o urs 
later (e ve ni n g d ose) f or t he d urati o n of t heir partici pati o n i n t he st u d y. If a d ose of st u d y dr u g is 
misse d, t he s u bject s h o ul d be i nstr ucte d t o ta ke t he misse d d ose i m me di atel y if less t ha n 2 4 h o urs 
ha ve ela pse d si nce t heir pre vi o us d ose. H o we ver, n o m ore t ha n 1 misse d d ose ( 1 ta blet) s h o ul d 
be ta ke n at a n y o ne ti me a n d n o m ore t ha n 2 ta blets of st u d y dr u g s h o ul d be ta ke n i n a n y 1 2- h o ur 
peri o d. 
A d here nce wit h st u d y dr u g d osi n g is t o be m o nit ore d a n d rec or de d b y site staff. T o ma xi mize 
st u d y d osi n g a d here nce, s u bjects will be gi ve n st u d y dr u g i n a “s mart b ottle”. T he de vice 
remi n ds s u bjects t o ta ke t heir st u d y dr u g via li g hts, c hi me, a n d te xt messa ge. It rec or ds t he b ottle 
o pe ni n g. All data it c ollects is u pl oa de d t o a ser ver via a m o bile li n k, fr o m w hic h is pr o vi de d 
fee d bac k t o b ot h t he s u bject a n d st u d y staff o n a d here nce. I n a d diti o n t o pr o vi di n g a ti mel y dr u g 
d osi n g re mi n der f or c o m plia nt s u bjects, t he ai m is t o pr o vi de o p p ort u nities f or ti mel y c o u nselli n g 
of p o orl y a d here nt s u bjects. D uri n g t he R u n-i n Peri o d a n d Pri mar y Assess me nt Peri o d site visits, 
s u bjects will ha ve a str uct ure d a d here nce c o u nselli n g sessi o n wit h t he st u d y staff.  
1 1. 5.    
 B ottle M a n a ge me nt 
 
 
 
 
 
  
Be gi n ni n g wit h Scree ni n g, s u bjects will be dis pe nse d s ufficie nt q ua ntities of st u d y dr u g pr o d uct 
or pl ace b o i n t he s mart b ottle t o last u ntil t he ne xt site visit.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
4 9  
 
S u bjects will be as ke d t o ret ur n all u n use d stu d y dr u g f or acc o u nta bilit y at eac h site visit, 
i nclu di n g t he s m art b ottle f or a d here nce c hec ks a n d refills . T he Site I n vesti gat or is res p o nsi ble 
f or t he acc o u nti n g of o pe ne d a n d u n o pe ne d st u d y dr u g b ottles. Fi nal st u d y dr u g rec o nciliati o n 
will be perf or me d at t he Wee k 1 2 visit.  
1 1. 6.   
St u d y Dr u g Prec a uti o ns 
De x pra mi pe x ole is eli mi nate d fr o m t he b o d y b y t he ki d ne ys. A p pr o xi matel y 8 0 % of 
de x pra mi pe x ole is rec o vere d i n t he uri ne as u nc ha n ge d dr u g.  
T he area u n der t he plas ma c o nce ntrati o n-ti me c ur ve ( A U C ) of de x pra mi pe x ole i ncreases wit h 
i ncreasi n g se verit y of re nal i m pair me nt. T here is str o n g c orrelati o n bet wee n re nal f u ncti o n 
(e G F R) a n d de x pra mi pe x ole re nal cleara nce. T heref ore, ca uti o n s h o ul d be ta ke n w he n 
a d mi nisteri n g de x pra mi pe x ole t o s u bjects wit h ki d ne y (re nal) i m pair me nt. S u bjects wit h 
m o derate t o se vere re nal i m pair me nt s h o ul d n ot ta ke de x pra mi pe x ole. 
 ne utr o p hil 
c o u nts d uri n g t he st u d y will be re p orte d usi n g a ce ntral la b orat or y a n d m o nit ore d b y t he    
 
Me di cal M o nit or. H o we ver, s u bjects s h o ul d be c o u nsele d re gar di n g t he ris k f or ne utr o pe nia, 
a v oi d ta ki n g c o nc o mita nt me dicati o n ass ociate d wit h a ris k of ne utr o pe nia ( See Secti o n 1 1. 9. 1 ) 
a n d instr ucte d t o i m me diatel y re p ort t o t he st u d y site a n y s y m pt o ms of i nfecti o n, i ncl u di n g fe ver 
> 3 9° C, s ore t hr oat, a n d m o ut h s ores.  
1 1. 7.   
Disc o nti n u ati o n of St u d y Dr u g 
A s u bject m ust per ma ne ntl y disc o nti n ue st u d y dr u g f or a n y of t he f oll o wi n g reas o ns: 
 T he s u bj ect bec o mes pre g na nt. St u d y dr u g m ust be disc o nti n ue d i m me diatel y a n d t he 
s u bject f oll o we d u ntil res ol uti o n of t he pre g na nc y. Re p ort t he pre g na nc y, acc or di n g 
t o t he i nstr ucti o ns i n Secti o n 1 3. 2. 7   
 T he s u bj ect wit h dra ws c o nse nt. 
 T he s u bj ect e x perie nces a me dical e mer ge nc y t hat necessitates per ma ne nt 
disc o nti n uati o n of st u d y dr u g.  
 At t h e discreti o n of t he Site I n vesti gat or f or me dical reas o ns. 
 At t he  discreti o n of t he Site I n vesti gat or or K n o p p f or s u bject n o n-a d here nce t o t he 
st u d y re q uire me nts. 
S u bjects w h o disc o nti n ue st u d y dr u g pre mat urel y will be as ke d t o ret ur n wit hi n 4 da ys of t he last 
d ose of st u d y dr u g t o ha ve t he Wee k 1 2 ( Pri mar y O utc o me Visit) assess me nts perf or me d.  
I n suc h disc o nti n ue d s u bjects, a well- bei n g c hec k (tele p h o ne i nter vie w) will be c o m plete d 
3 0 da ys after t he last d ose of st u d y dr u g. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 0  
 
1 1. 8.   
St u d y Dr u g Dis p os al 
T he Site I n vesti gat or m ust ret ur n all u n use d st u d y dr u g, as i nstr ucte d b y K n o p p. 
If a n y st u d y dr u g s u p plies are t o be destr o ye d at t he site, t he i nstit uti o n/ Site I n vesti gat or m ust 
o bta i n pri or a p pr o val b y K n o p p. After s uc h destr ucti o n, t he i nstit uti o n/ Site I n vesti gat or m ust 
n otif y K n o p p, i n writi n g, of t he met h o d, t he date, a n d t he l ocati o n of destr ucti o n. 
1 1. 9.   
C o nc o mit a nt T her a p y a n d Pr oce d ures 
1 1. 9. 1.   
C o n c o mit a nt T her a p y 
A c o nc o mita nt t hera p y is a n y dr u g or s u bsta nce a d mi nistere d bet wee n t he Scree ni n g visit a n d t he 
s u bject’s last st u d y visit. All c o nc o mita nt me dicati o n m ust be rec or de d i n t he s u bject’s s o urce 
d oc u m e nt a n d o n t he case re p ort f or m ( C R F ). 
1 1. 9. 2.   
C o n c o mit a nt T her a p y Restricti o ns 
I n h ale d c ortic oster oi ds 
T he d ose of a n y i n hale d or i ntra nasal c ortic oster oi ds m ust be sta bilize d f or at least 4 wee ks pri or 
t o t he first d ose of st u d y dr u g a n d s h o ul d re mai n c o nsta nt t hr o u g h o ut t he st u d y. 
Syste mic c ortic oster oi ds 
Me dicall y i n dicate d use of s yste mic c ortic oster oi d s t o treat a n ast h ma e xacer bati o n occ urri n g 
w hile o n st u d y are all o we d o n t he st u d y.  
I nvesti g ati o n al dr u gs 
Use of i n vesti gati o nal dr u gs is pr o hi bite d f or t he d urati o n of t he st u d y. 
M o n ocl o n al a nti b o dy t her a py 
T he use of m o n ocl o nal a nti b o d y t hera p y, i ncl u di n g be nraliz u ma b, d u pil u ma b, me p oliz u ma b, 
resliz u ma b, o maliz u ma b, or T N F i n hi bit ors is pr o hi bite d t hr o u g h o ut t he d urati o n of t he st u d y.  
Pr a mi pex ole 
T he use of pra mi pe x ole is pr o hi bite d t hr o u g h o ut t he d urati o n of t he st u d y. 
Selecte d dr u gs k n o w n t o h ave s u bst a nti al risk of ne utr o pe ni a 
Dr u gs k n o w n t o ha ve a s u bsta ntial ris k of ne utr o pe nia, as liste d i n A p pe n di x A, are pr o hi bite d 
f or t he d urati o n of t he st u d y.1 9, 2 0 
1 1. 9. 3.   
C o nc o mit a nt Pr oce d ures 
A c o nc o mita nt pr oce d ure is a n y t hera pe utic i nter ve nti o n (e. g., s ur ger y, p h ysical t hera p y) or 
dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, bacterial c ult ures) perf or me d bet wee n t he 
Scree ni n g visit a n d t he s u bject’s last st u d y visit.    

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 1  
 
C o nc o mita nt t hera pies or pr oce d ures m ust be rec or de d o n t he s u bject’s C R F, acc or di n g t o 
i nstr ucti o ns f or C R F c o m pleti o n. A Es relate d t o a d mi nistrati o n of t hese t hera pies or pr oce d ures 
m ust be d oc u m e nte d o n t he a p pr o priate C R F. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 2  
 
1 2.    
S T U D Y A S S E S S M E N T S 
Refer t o Secti o n 5  per Sc he d ule of E ve nts f or t he ti mi n g of assess me nts. 
1 2 . 1.  
S afet y Assess me nts 
Cli nical safet y assess me nts s h o ul d be perf or me d b y t he sa me staff at eac h site, w he ne ver 
p ossi ble.  
T he f oll o wi n g cli nical assess me nts will be perf or me d t o assess t he safet y pr ofile of 
de x pra mi pe x ole: 
 cli nical la b orat or y tests  
 vit al si g n meas ure me nts ( seate d u pri g ht p ositi o n): s yst olic a n d diast olic B P (after 
s u bject has reste d f or 5 mi n utes, i n m m H g), R R per mi n ute, H R per mi n ute, 
te m perat ure 
 1 2 -lea d E C G meas ure me nts: tri plicate rea di n gs will be c ollecte d at eac h s pecifie d 
ti me- p oi nt 
 m e dical hist or y a n d ast h ma hist or y e val uati o n 
 p h ysi cal e xa mi nati o ns  
 b o d y wei g ht  
 c o nc o mita nt t hera p y a n d pr oce d ure rec or di n g 
 a d verse e ve nt a n d seri o us a d verse e ve nt m o nit ori n g a n d rec or di n g 
1 2. 1. 1.   
Cli ni c al L a b or at or y Tests 
T he cli nical la b orat or y test para meters will be perf or me d b y a desi g nate d ce ntral la b orat or y. 
Detaile d c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt i nstr ucti o ns will be pr o vi de d i n t he St u dy 
Refere nce M a n u al . 
T he f oll o wi n g cli nical la b orat or y tests will b e perf or me d acc or di n g t o t he sc he d ule of e ve nts – 
See Sec ti o n 5 : 
 He mat ol o g y a n d differe ntial pa nel: 
 
 
 
 
). Certai n C B C res ults will be bli n de d as 
det aile d i n Secti o n 1 0. 3. 1 . 
 Bl o o d c he mist r y pa nel: 
 
 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 3  
 
 
 
. 
 Uri na l ysis: 
 
 
 Uri ne  β- h C G/ pre g na nc y, qualitati ve (f or w o me n of c hil d beari n g p ote ntial).  
1 2. 1. 2.   
Vit al  Si g ns 
Vital si g ns will be meas ure d i n t he seate d u pri g ht p ositi o n after t he s u bject has bee n reste d f or 
5 mi n utes (s yst olic a n d diast olic s yste mic bl o o d press ure [ B P] i n m m H g, res pirat or y rate [ R R] 
per  mi n ute, a n d heart rate [ H R] per mi n ute).  
1 2. 1. 3.   
E C G Assess me nts  
All 1 2 -lea d E C Gs will be perf or me d i n tri plicate wit h traci n gs at least 1 mi n ute a part.  S u bjects 
s h o ul d be i n t he s u pi ne p ositi o n after resti n g f or at least 5 mi n utes f or eac h assess me nt. 
E C Gs will be perf or me d pri or t o t he A M d ose of st u d y dr u g at t he Baseli ne, Wee k 4, Wee k 8, 
a n d Wee k 1 2 ( Pri mar y O utc o me Visit) visits. Circ u msta nces t hat ma y i n d uce c ha n ges i n heart 
rate or ot her wise sti m ulate t he s u bject s h o ul d be a v oi de d t hr o u g h o ut t he resti n g a n d E C G 
rec or di n g peri o ds. 
At t he Wee k 8 visit, s u bjects will ha ve 3 se parate E C G assess me nts perf or me d t o e val uate 
p ote ntia l car diac dr u g i nteracti o ns of al b uter ol a n d de x pra mi pe x ole. 
 First, a 1 2-lea d E C G (t hree traci n gs se parate d b y 1 mi n ute) will be perf or me d pri or t o t he 
A M d ose of st u d y dr u g A N D  A M ast h ma me dicati o n, f oll o we d b y a n o bser ve d 
a d mi nistrati o n of st u d y dr u g.  
 Sec o n d, a n a d diti o nal 1 2-lea d E C G (t hree traci n gs se parate d b y 1 mi n ute) will be 
c ollecte d 2 h o urs ( ± 3 0 mi n utes) after ta ki n g st u d y dr u g.  
 F oll o wi n g t he sec o n d E C G, s u bjects will i n hale f o ur p uffs of al b uter ol M DI ( 9 0- 1 0 0 μ g 
al b uter ol base per act uati o n) u n der t he directi o n of st u d y staff, wait 1 5 mi n utes 
( ± 5 mi n utes), a n d ha ve a p ost- br o nc h o dilat or E C G c ollecti o n perf or me d (t hree traci n gs 
se parate d b y 1 mi n ute). 
1 2. 1. 4.   
P h ysic al E x a mi n ati o ns 
P h ysical e xa mi nati o ns ma y be c o n d ucte d b y a q ualifie d, dele gate d p h ysicia n, trai ne d p h ysicia n's 
assista nt, or n urse practiti o ner as acce pta ble acc or di n g t o l ocal re g ulati o n. T he f ull p h ysical 
e xa mi nati o n will i ncl u de hea d, ears, e yes, n ose, m o ut h, t hr oat, s ki n, heart a n d l u n g e xa mi nati o ns, 
l y m p h n o des, gastr oi ntesti nal, a n d m usc ul os keletal s yste ms. A b n or mal fi n di n gs will be 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 4  
 
c haracterize d as “cli nicall y si g nifica nt” or “ n ot cli nicall y si g nifica nt ” f or t he p ur p oses of 
re p orti n g as a d verse e ve nts. 
1 2. 1. 5.   
Ne utr o pe ni a M o nit ori n g a n d Cli nic al M a n a ge me nt 
I n cli nical st u dies t o date, s o me A L S s u bjects treate d wit h de x pra mi pe x ole at a d ose of 
3 0 0 m g/ da y de vel o pe d re d ucti o ns i n a bs ol ute ne utr o p hil c o u nt ( A N C) t hat were re versi ble a n d 
t y picall y brief ( < 1 0 da ys). 
 
S u bjects m ust be m o nit ore d f or t he p ossi ble de vel o p me nt of 
ne utr o pe nia ( A N C < 1. 5 0 x 1 0 9/ L) a n d a p pr o priate acti o n a n d testi n g s h o ul d be perf or me d, as 
o utli ne d i n Ta ble 1 . Ne utr o pe nia has n ot bee n see n at de x pra mi pe x ole d oses < 3 0 0 m g/ da y. 
All c ases of ne utr o pe nia will be f oll o we d b y re peati n g t he C B C wit h differe ntial u ntil t he 
ne utr o pe nia res ol ves. T he C B C bl o o d sa m ple ma y eit her be c ollecte d at t he st u d y site or at a 
desi g nate d re m ote la b orat or y facilit y f or c o n ve nie nce.  
T a ble 1 :     
Ne utr o pe ni a D ose I nterr u pti o n a n d L a b or at or y Test Re pe at 
Rec o m me n d ati o ns 
Ne utr o p hils  
St u d y Dr u g    
Re pe at C B C w/ diff  Ne utr o pe ni a C ase 
Re p ort F or m  
Decrease of ≥5 0 % pre vi o us val ue a n d 
≥2. 0 0 x 1 0 9/ L 
N o acti o n    
E ver y 2 wee ks    
N ot i n dicate d  
≥1. 5 0 x 1 0 9/ L  t o < 2. 0 0 x 1 0 9/ L  
N o acti o n    
E ver y 2 wee ks    
N ot i n dicate d  
≥1. 0 0 x 1 0 9/ L t o < 1. 5 0 x 1 0 9/ L  
N o acti o n  
W ee kl y 
Wee kl y *  
< 1. 0 0 x 1 0 9/ L 
Wit h h ol d    
E ver y 4 da ys  
Wee kl y *  
* Site staff t o c ollect t he ne utr o pe nia case re p ort f or m wee kl y u ntil t he A N C is ≥1. 5 0 x 1 0 9/ L. 
T he    
 Me dical M o nit or s h o ul d be c o ns ulte d re gar di n g all cases of ne utr o pe nia. I n cases 
w here st u d y dr u g is wit h hel d, t he    
 Me dical M o nit or m ust be i nf or me d.  
Restarti n g st u d y dr u g after wit h h ol di n g f or ne utr o pe nia re q uires a ut h orizati o n fr o m t he K n o p p 
Me dical M o nit or, or desi g nee.  
La b ora t or y- defi ne d e ve nts of ne utr o pe nia ( A N C < 1. 5 0 x 1 0 9/ L) s h o ul d be re p orte d b y t he site t o 
t he    
 Me dical M o nit or wit hi n 2 4 h o urs of a ware ness. If a s u bject e x perie nces a n 
A N C  < 1. 5 0 x 1 09/ L t he ne utr o pe nia case re p ort f or m will be c o m plete d b y t he site staff. T he 
i nf or mati o n re q uire d f or t his f or m will be o btai ne d b y t he site staff t hr o u g h a n i nter vie w wit h t he 
s u bject c o nte m p ora ne o us wit h t he e ve nt. T he site staff s h o ul d re peat t he ne utr o pe nia case re p ort 
f orm wee kl y u ntil t he A N C is ≥1. 5 0 x 1 0
9/ L. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 5  
 
T o o btai n c o ntr ol cases, t he ne utr o pe nia case re p ort f or m will be c ollecte d fr o m all s u bjects at 
t he Baseli ne, Wee k 4, Wee k 8, a n d Wee k 1 2 visits. 
1 2. 1. 6.   
C o n tr ace pti o n C o u nseli n g  
T he Sit e I n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he s u bject, will c o nfir m t hat t he 
s u bject has selecte d a n all o we d met h o d of c o ntrace pti o n fr o m t he list of per mitte d met h o ds a n d 
will  c o u nsel t he s u bject re gar di n g t he nee d f or c o nti n ue d c o ntrace pti o n a d here nce. 
See Secti o n 1 3. 5. 3 . 
1 2. 2.   
Effic ac y Assess me nts 
T he f oll o wi n g cli nical tests/assess me nts will be perf or me d t o assess t he efficac y of 
de x pra mi pe x ole, as f o u n d i n t he s u bsecti o ns bel o w. Refer t o Secti o n 5  f or t he ti mi n g of 
assess me nts. 
1 2. 2. 1.   
Peri p her al Bl o o d A bs ol ute E osi n o p hil C o u nt 
Bl o o d e osi n o p hil c o u nts will be o btai ne d at e ver y st u d y visit. Sa m ples nee d t o be c ollecte d 
bet wee n 6 A M a n d 1 2 n o o n t o mi ni mize di ur nal variati o n. Sa m ples s h o ul d be c ollecte d at 
a p pr o xi matel y t he sa me ti me of da y t hr o u g h o ut t he st u d y ( wit hi n ± 1 h o ur of t he Baseli ne visit 
c ollecti o n). 
1 2. 2. 2.   
P ul m o n ar y F u ncti o n Testi n g ( P F T, F E V 1) 
F or i n-cli nic site visits, ( Baseli ne, Wee k 4, Wee k 8, Wee k 1 2, a n d Wee k 1 6/ 1 8) s u bjects will be 
i nstr ucte d t o wit h h ol d t heir A M ast h ma me dicati o n o n t he m or ni n g of t he visit. E ver y eff ort 
s h o ul d be m a de to c ollect t he Wee k 1 2 Pre- br o nc h o dil at or P F T wit hi n ± 1 h o ur of t he ti me 
of d a y t h at t he B aseli ne P F T w as c ollecte d.  
S u bjects w h o prese nt f or Scree ni n g, b ut ha ve n ot wit h hel d t heir ast h ma me dicati o n (see Ta ble 2 ), 
s h o uld ha ve all ot her Scree ni n g assess me nts perf or me d a n d will be re q ueste d t o resc he d ule t he 
Scree ni n g P F T as s o o n as feasi ble.   
T he pre- br o nc h o dilat or F E V 1 i ncl usi o n criteri o n m ust be f ulfille d d uri n g t he R u n-i n Peri o d.  
 S u bjects w h o d o n ot meet t he i nitial pre- br o nc h o dilat or F E V 1 i ncl usi o n criteri o n at 
Scree ni n g a n d Baseli ne ma y n ot re peat P F T i n or der t o q ualif y f or t he st u d y. 
 S u bjects w h o d o n ot meet t he p ost- br o nc h o dilat or re versi bilit y i ncl usi o n criteri o n at 
t he Scree ni n g visit, b ut ha ve ≥1 0 % or ≥1 6 0 m L re versi bilit y, ma y re peat t he 
re versi bilit y P F Ts assess me nt o nce d uri n g t he R u n-i n Peri o d.  
Pre- br o nc h o dilat or F E V 1 is c o nsi dere d t he c ore cli nical o utc o me meas ure of air wa y o bstr ucti o n 
i n efficac y trials i n ast h ma.2 1, 2 2 F E V 1 is t he v ol u me of air t hat ca n f orci bl y be e x pire d i n o ne 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 6  
 
sec o n d. T he F E V 1 v ol u me i n liters ma y be c o n v erte d t o a perce nta ge of t he pre dicte d val ue 
base d o n hei g ht, wei g ht, a n d race.  
P F Ts  will be c ollecte d acc or di n g t o t he A T S/ E R S g ui deli nes o n sta n dar dizati o n of s pir o metr y 2 3 
accor di n g t o Secti o n 5 , Sc he d ule of E ve nts. P F Ts  will be o btai ne d o n all s u bjects d uri n g t he 
st u d y. Pre- br o nc h o dilat or P F Ts at eac h st u d y visit m ust be c ollecte d bet wee n 6 A M a n d 1 2 n o o n 
l ocal ti me a n d s h o ul d be c ollecte d wit hi n ± 2 h o urs of t he Baseli ne visit t o mi ni mize di ur nal 
var iati o n. T he Wee k 1 2 P F T assess me nt s h o ul d be c ollecte d wit hi n 1 h o ur of t he ti me of da y t he 
Basel i ne visit P F Ts were c ollecte d. 
F or all site visits w here p ul m o nar y f u ncti o n testi n g is perf or me d, s u bjects m ust wit h h ol d t heir 
A M ast h ma me dicati o ns.  Ta ble 2  pr o vi des was h o ut i nter vals f or vari o us ast h ma me dicati o ns f or 
pre - br o nc h o dilat or P F T testi n g at t he Scree ni n g, Baseli ne, Wee k 4, Wee k 8, Wee k 1 2, a n d 
Wee k 1 6/ 1 8 visits. 
T a b le 2:     
I nter v als f or H ol di n g Ast h m a Me dic ati o ns Pri or t o P ul m o n ar y F u ncti o n 
Testi n g 
Me dic ati o n  
E x a m ples   
( pr o priet ar y n a mes C a pit alize d) 
Mi ni m u m w as h o ut pri or t o 
perf or mi n g P F T  
S h ort -acti n g br o nc h o dilat or    
al b uter ol, le val b uter ol, X o pe ne x    
6 h o urs  
L o n g -acti n g br o nc h o dilat or  
A d vair, arf or m oter ol , Bre o , D ulera , 
f or m oter ol, i n dacater ol, ol o dater ol , 
S y m bic ort , vila nter ol , sal meter ol  
1 2 h o urs  
Xa nt hi nes  
t he o p h ylli ne 
1 2 h o urs  
S h ort -acti n g m uscari nic a nta g o nist  
Atr o ve nt, i pratr o pi u m  
8 h o urs  
L o n g -acti n g m uscari nic  a nta g o nist 
acli di ni u m, gl yc o p yrr olate , 
gl yc o p yrr o ni u m, ti otr o pi u m, 
u mecli di ni u m  
2 4 h o urs  
Le u k otrie ne a nta g o nist ( L T R A)  
Acc olate,  m o ntel u kast, Si n g ulair, 
zafirl u kast 
1 2 h o urs  
5 -Li p o x y ge nase I n hi bit or  
zile ut o n, Z yfl o 
6 h o urs (i m me diate release)  
1 2 h o urs (e xte n de d release)  
At t he Scree ni n g, Baseli ne a n d Wee k 1 2 visits, s u bjects will als o perf or m a p ost - br o nc h o dilat or 
P F T  re versi bilit y test.  
At t he Scree ni n g visit, s u bjects will a d diti o nall y perf or m p ost- br o nc h o dilat or P F Ts. After 
c o m pleti n g t he pre- br o nc h o dilat or P F Ts, s u bjects will i n hale 2- 4 p uffs of al b uter ol M DI 
( 9 0- 1 0 0 μ g al b uter ol base per act uati o n). S pir o metr y ma y be re peate d se veral ti mes wit hi n 
1 5- 3 0 mi n utes after i n halati o n of al b uter ol a n d a d diti o nal al b uter ol p uffs ma y be a d mi nistere d u p 
t o a ma xi m u m of 4 p uffs. Re versi bilit y, w hic h is defi ne d as a n i ncrease i n a bs ol ute F E V 1 of 
≥1 2 % o ver t he pre- br o nc h o dilat or val ue, wit h a n a bs ol ute i ncrease of at least 2 0 0 m L, m ust be 
de m o nstrate d wit hi n 3 0 mi n utes of al b uter ol a d mi nistrati o n f or t he s u bject t o be c o nsi dere d 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 7  
 
eli gi ble f or ra n d o mizati o n. If t he s u bject d oes n ot meet t he re versi bilit y eli gi bilit y criteri o n at t he 
first Scree ni n g P F T visi t, b ut has a n i m pr o ve me nt of ≥1 0 % or ≥1 6 0 m L F E V 1 re versi bilit y, a 
sec o n d re versi bilit y P F T atte m pt ca n be perf or me d at a later visit pri or t o t he Baseli ne visit. 
At t he  Baseli ne a n d Wee k 1 2 visits, s u bjects will re peat t he pre- a n d p ost- br o nc h o dilat or P F T 
reversi bilit y test.  D uri n g t hese visits, t he s u bject will be a d mi nistere d t he sa me n u m ber of 
al b uter ol p uffs utilize d d uri n g t he Scree ni n g P F T re versi bilit y testi n g use d t o q ualif y t he s u bject.  
Detaile d met h o d ol o g y f or perf or mi n g t he P F T  pr oce d ure ca n be f o u n d i n t he St u dy Refere nce 
M a n u al .  
1 2. 2. 3.   
Ast h m a C o ntr ol  Q uesti o n n aire ( A C Q- 7) 
T he Ast h ma C o ntr ol Q uesti o n naire ( A C Q) is a vali date d t o ol desi g ne d f or use as a meas ure me nt 
of ast h ma s y m pt o m c o ntr ol. 2 4 T he A C Q meas ures b ot h t he a de q uac y of ast h ma c o ntr ol a n d 
c ha n ge i n ast h ma c o ntr ol, w hic h ma y occ ur eit her s p o nta ne o usl y or as a res ult of treat me nt.  
T he A C Q has 7 q uesti o ns (t he t o p sc ori n g 5 s y m pt o ms, F E V 1 % pre d., a n d dail y resc ue 
br o nc h o dilat or use). S u bjects are as ke d t o recall h o w t heir ast h ma has bee n d uri n g t he pre vi o us 
wee k a n d t o res p o n d t o t he s y m pt o m a n d br o nc h o dilat or use q uesti o ns o n a 7- p oi nt scale 
( 0 = n o i m pair me nt, 6 = ma xi m u m i m pair me nt). Cli nic staff sc ore t he F E V 1 % pre dicte d o n a 
7- p oi nt scale. T he q uesti o ns are e q uall y wei g hte d a n d t he A C Q sc ore is t he mea n of t he 7 
q uest i o ns a n d t heref ore bet wee n 0 (t otall y c o ntr olle d) a n d 6 (se verel y u nc o ntr olle d). 
A c o p y of t he A C Q- 7 q uesti o n naire a n d i nstr ucti o ns f or a d mi nisteri n g t he q uesti o n naire ma y be 
f o u n d i n t he St u dy Refere nce M a n u al.  
1 2. 2. 4.   
Ast h m a Q u alit y of Life Q uesti o n n aire ( A Q L Q) 
T he A Q L Q is a q uesti o n naire de vel o pe d t o meas ure healt h stat us ( q ualit y of life) i n patie nts wit h 
asth ma a n d will be a d mi nistere d at t he site. 2 5  
T here are 3 2 q uesti o ns i n t he A Q L Q i n 4 d o mai ns (s y m pt o ms, acti vit y li mitati o n, e m oti o nal 
f u ncti o n a n d e n vir o n me ntal sti m uli). T he acti vit y d o mai n c o ntai ns 5 ‘s u bject-s pecific’ q uesti o ns. 
T his all o ws s u bjects t o select 5 acti vities i n w hic h t he y are m ost li mite d a n d t hese acti vities will 
be as sesse d at eac h f oll o w- u p. S u bjects are as ke d t o t hi n k a b o ut h o w t he y ha ve bee n d uri n g t he 
pre vi o us t w o wee ks a n d t o res p o n d t o eac h of t he 3 2 q uesti o ns o n a 7- p oi nt scale (ra n ge, 
‘ 7 = n ot i m paire d at all’ t o ‘ 1 =se verel y i m paire d’). T he o verall A Q L Q sc ore is t he mea n of all 
3 2 res p o nses a n d t he i n di vi d ual d o mai n sc ores are t he mea ns of t he ite ms i n t h ose d o mai ns. 
A c o p y of  t he A Q L Q a n d i nstr ucti o ns f or a d mi nisteri n g t he q uesti o n naire ma y be f o u n d i n t he 
St u dy Refere nce M a n u al.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 8  
 
1 2. 3.   
P h ar m ac o d y n a mic Assess me nts 
Met h o ds f or t he c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt of ser u m, w h ole bl o o d, a n d 
nasal/ p har y n geal s wa bs will be descri be d i n t he S t u dy Refere nce M a n u al.  
Met h o ds f or e x hale d nitric o xi de testi n g ( Fe N O) are descri be d i n t he St u dy Refere nce M a n u al . 
1 2. 3. 1.   
Bl o o d A bs ol ute E osi n o p hil C o u nt 
W h ole bl o o d A E C will be meas ure d as part of t he C B C a n d differe ntial, per Secti o n 5  Sc he d ule 
of E ve nts.  
1 2. 3. 2.   
B as o p h ils 
W h ole bl o o d will be c ollecte d f or bas o p hil q ua ntificati o n b y fl o w c yt o metr y, per Secti o n 5  
Sc he d ul e of E ve nts.  
1 2. 3. 3.   
E osi n o p hil Pr o ge nit ors 
W h ole bl o o d will be c ollecte d f or e osi n o p hil pr o ge nit or q ua ntificati o n b y fl o w c yt o metr y, per 
Sect i o n 5  Sc he d ule of E ve nts.   
1 2. 3. 4.   
N as al a n d P h ar y n ge al S w a bs f or E osi n o p hil Per o xi d ase 
Nasal a n d p har y n geal s wa bs will be c ollecte d f or e osi n o p hil per o xi dase, per Secti o n 5  Sc he d ule 
of  E ve nts.  
I nstr ucti o ns f or c ollecti n g nasal a n d p har y n geal s wa bs are descri be d i n t he St u dy Ref ere nce 
M a n u al . 
1 2. 3. 5.   
Uri ne E osi n o p hil Gr a n ule Pr otei ns 
Uri ne will be c ollecte d f or e osi n o p hil gra n ule pr otei n i m m u n oassa y, per Secti o n 5  Sc he d ule of 
E ve nts .  
1 2. 3. 6.   
Ser u m I g E 
Ser u m I g E will be c ollecte d at Baseli ne. 
1 2. 3. 7.   
Ser u m Bi o m ar kers a n d Bi o b a n k 
Ser u m will be c ollecte d f or bi o mar ker researc h at t he Baseli ne, Wee k 1 2, a n d Wee k 2 4 visits, per 
Sect i o n 5  Sc he d ule of E ve nts. T hese sa m ples will be use d t o c o n d ucte d e x pl orat or y researc h 
i ncl u di n g I L- 5, I L- 1 3, I L- 3 3, S T 2, C C L 2, C C L 3, C C L 4, C C L 1 1, a n d C C L 1 7.  
S pecific pr oce d ures f or c ollecti o n, st ora ge, a n d s hi p pi n g of bi o mar ker sa m ples will be pr o vi de d 
i n t he St u dy Refere nce M a n u al .  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
5 9  
 
Bi o ba n k sa m ples ma y als o be use d f or retr os pecti ve e x pl orat or y a nal yses ass ociate d wit h t he 
st u d y e n d p oi nts (e. g., safet y a nd/ or  efficac y), t he disease bei n g st u die d i n t his trial (e osi n o p hilic 
ast h ma), t he mec ha nis m of acti o n of de x pra mi pe x ole, a n d/ or t o s u p p ort f ut ure a p pr oac hes t o 
pers o nalize d me dici ne. C ollecti o n of ser u m f or bi o mar ker researc h is re q uire d of all s u bjects 
u nless pr o hi bite d b y l ocal la w or t he b y t he decisi o n of a n I R B. 
All bi o ba n k sa m ples will be c o de d wit h t he s u bject’s st u d y i de ntificati o n n u m ber t o e ns ure 
s u bject c o nfi de ntialit y. N o s u bject i de ntif yi n g i nf or mati o n (e. g., na me, ge n der, date of birt h) or 
ot her i nf or mati o n t hat c o ul d be use d t o directl y i de ntif y t he s u bject will be o n t he sa m ple. T he 
ke y bet wee n t he st u d y i de ntificati o n n u m ber a n d t he s u bject’s pr otecte d healt h i nf or mati o n will 
be hel d o nl y b y t he site i n vesti gat or. T he researc hers wit h access t o t he sa m ples a n d data 
ge ner ate d fr o m t he bi o ba n k will n ot ha ve access t o t he ke y n or a n y pers o nall y i de ntif yi n g 
i nf or mati o n re gar di n g t he s u bject. 
I nf or mati o n o btai ne d o n i n di vi d ual s u bjects will be a g gre gate d a n d teste d at t he gr o u p le vel. 
N o ne of t he bi o mar kers bei n g teste d ha ve bee n vali date d f or dia g n ostic, pr o g n ostic or t hera pe utic 
use, a n d t heref ore t here are n o k n o w n healt h or ot her i m plicati o ns f or a n y i n di vi d ual s u bject 
base d o n his or her e x pl orat or y bi o mar ker res ult.  
A s u bject ma y, wit h o ut prej u dice, wit h dra w his or her c o nse nt fr o m partici pati o n i n t he 
c ollecti o n a n d st ora ge of sa m ples f or e x pl orat or y bi o mar ker testi n g or f ut ure testi n g at a n y ti me 
b y n otif yi n g t he Site I n vesti gat or i n writi n g. At t he s u bject’s re q uest, n o f urt her sa m ples will be 
c ollecte d, n o f urt her a nal ysis will be c o n d ucte d t heir sa m ples, a n d a n y sa m ples re mai ni n g i n 
st ora ge will be destr o ye d. H o we ver, data ge nerate d fr o m testi n g bef ore t he s u bject’s re q uest t o 
wit h dr a w c o nse nt will c o nti n ue t o be st ore d t o pr otect t he i nte grit y of e xisti n g a nal yses. 
Bi o ba n k sa m ples will be st ore d at a n access-c o ntr olle d facilit y t hat s pecializes i n bi o me dical 
sa m ple st ora ge, bi o ba n ki n g, a n d sa m ple ma na ge me nt. U nless restricte d b y l ocal la w or a n I R B, 
sa m ples f or e x pl orat or y bi o mar ker testi n g ma y be st ore d i n defi nitel y f or st u dies t o be deter mi ne d 
i n t he f ut ure. A n y s uc h f ut ure bi o ba n k st u d y will be s u b mitte d f or I R B re vie w a n d a p pr o val pri or 
t o st u d y i nitiati o n.  
Res ults o btai ne d o n i n di vi d ual s u bjects will n ot be ma de a vaila ble t o t he s u bject a n d s u bjects 
will be n otifie d of t his sti p ulati o n i n t he i nf or me d c o nse nt d oc u me nt. N o i n di vi d ual s u bject 
res ults will be rec or de d i n t he s u bject’s me dical rec or d a n d n o f oll o w- u p c o ntact wit h i n di vi d ual 
s u bjects is pla n ne d. 
1 2. 3. 8.   
W h ole Ge n o me D N A Se q ue nci n g 
W h ole bl o o d will be c ollecte d f or w h ole ge n o me D N A se q ue nci n g at t he Baseli ne visit, per 
Secti o n 5  Sc he d ule of E ve nts. S pecific pr oce d ures f or c ollecti o n, st ora ge, a n d s hi p pi n g of 
sa m ples will be pr o vi de d i n t he St u dy Refere nce M a n u al .  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 0  
 
D N A sa m ples ma y be use d t o deter mi ne a p ossi ble relati o ns hi p bet wee n s pecific ge nes a n d 
res p o nse t o treat me nt wit h de x pra mi pe x ole, or t heir p ossi ble relati o ns hi p t o a d verse reacti o ns t o 
de x pra mi pe x ole. T he a nal ysis of w h ole ge n o me se q ue nce data will use a ge n o me- wi de 
associati o n a p pr oac h t o i de ntif y si n gle- n ucle oti de varia nts a n d s mall i nserti o n/ deleti o n varia nts 
t hat differ bet wee n de x pra mi pe x ole he mat ol o gic res p o n ders a n d n o n-res p o n ders. A d diti o nal 
bi oi nf or matic a p pr oac hes will be use d as nee de d t o i de ntif y a n d vali date ca n di date ge nes. 
T he D N A e xtracte d fr o m t he bl o o d sa m ple as well as all d o w nstrea m ge netic a nal yses will 
utilize a sec o n d n u m ber, a Ge netic I D ( de-i de ntificati o n c o de) differe nt fr o m t he S u bject I D. T his 
“ d o u ble c o di n g” is perf or me d t o f urt her se parate a s u bject’s me dical a n d st u d y i nf or mati o n fr o m 
t heir D N A data. T he cli nical st u d y data (c o de d b y S u bject I D) will be st ore d i n t he pass w or d-
pr ot ecte d data ma na ge me nt s yste m, w hic h is a disti nct data base i n a se parate e n vir o n me nt fr o m 
t he data base c o ntai ni n g t he p har mac o ge netic data (c o de d b y Ge netic I D). T he ke y li n ki n g 
S u bject I D a n d Ge netic I D will be mai ntai ne d b y a t hir d part y, u n der a p pr o priate access c o ntr ol. 
T he matc hi n g of cli nical st u d y data a n d p har mac o ge netic data, f or t he p ur p ose of data a nal ysis, 
will be p ossi ble o nl y b y usi n g t his ke y, w hic h will be u n der strict access c o ntr ol.  
T he e xt racte d D N A re mai ni n g u n use d after D N A se q ue nci n g will be destr o ye d after c o m pleti o n 
of t hat s pecific a nal ysis a n d iss ua nce of t he relate d a nal ytical data.  
Res ults o btai ne d o n i n di vi d ual s u bject will n ot be ma de a vaila ble t o t he s u bject a n d s u bjects will 
be n otifie d of t his sti p ulati o n i n t he i nf or me d c o nse nt d oc u me nt. N o i n di vi d ual s u bject res ults 
will be rec or de d i n t he s u bject’s me dical rec or d a n d n o f oll o w- u p c o ntact wit h i n di vi d ual s u bject 
re gar di n g t he res ult is pla n ne d. 
If re q uire d b y t he I R B, w h ole ge n o me D N A se q ue nci n g ma y be a n o pti o nal pr oce d ure f or t hat 
site, wit h that site’s I C F reflecti n g t hat stat us.  
After i nf or me d c o nse nt, a s u bject ma y, wit h o ut prej u dice, wit h dra w his or her c o nse nt fr o m 
par tici pati o n i n t he w h ole ge n o me D N A se q ue nci n g b y n otif yi n g t he Site I n vesti gat or i n writi n g. 
At t he  s u bject’s re q uest, n o f urt her a nal ysis will be c o n d ucte d a n d a n y D N A se q ue nci n g sa m ples 
re mai ni n g i n st ora ge will be destr o ye d. 
1 2. 3. 9.   
E x h ale d Nitric O xi de Test ( Fe N O) 
E x hale d nitric o xi de a nal ysis will be perf or me d at eac h site usi n g t he NI O X Ver o i nstr u me nt 
wit h t he res ult re p orte d i n parts per billi o n. Fe N O s h o ul d be c ollecte d pri or t o t he P F T tests. 
F urt her details o n t he Fe N O pr oce d ure are pr o vi de d i n t he St u dy Refere nce M a n u al . 
1 2. 4.   
P h ar m ac o ki netic Assess me nts 
Bl o o d will be c ollecte d fr o m eac h s u bject t o deter mi ne t he de x pra mi pe x ole plas ma 
c o nce ntrati o ns.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 1  
 
 W ee k 4: Pre- d ose  
 W ee k 8: Pre- d ose a n d 2 ( ± 1 0 mi n utes) h o urs after d ose 
 W ee k 1 2: Pre- d ose 
Met h o ds f or t he c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt of P K sa m ples will be pr o vi de d i n 
t he St u dy Refere nce M a n u al.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 2  
 
1 3.    
S A F E T Y D E FI NI TI O N S, M O NI T O RI N G, A N D R E P O R TI N G 
U p o n si g ni n g t he I C F, eac h s u bject m ust be pr o vi de d t he na mes a n d tele p h o ne n u m bers of st u d y 
site staff f or re p orti n g A Es a n d me dical e mer ge ncies. All s u bject re p orts of a d verse e ve nts as 
defi ne d bel o w, w het her s olicite d or s p o nta ne o us, m ust be d oc u me nte d i n t he s o urce d oc u me nts. 
T he i nter vie w f or a d verse e ve nts s h o ul d be c o n d ucte d ofte n t hr o u g h o ut t he c o urse of t he st u d y. 
At a m i ni m u m, s uc h i nter vie ws s h o ul d occ ur d uri n g eac h s u bject visit, i ncl u di n g tele p h o ne 
c o ntacts. 
Refer t o Secti o n 5  per Sc he d ule of E ve nts f or t he ti mi n g of assess me nts. 
1 3 . 1.  
Defi niti o ns 
1 3. 1. 1.   
A d verse E ve nt 
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n 
h u ma ns, w het her or n ot c o nsi dere d dr u g relate d.   
A n a dverse eve nt (als o referre d t o as a n a d verse e x perie nce) ca n be a n y u nfa v ora ble a n d 
u ni nte n de d si g n, s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a dr u g, a n d d oes n ot 
i m pl y a n y j u d g me nt a b o ut ca usalit y. A n a d verse e ve nt ca n arise wit h a n y use of t he dr u g (e. g., 
off-la bel use, use i n c o m bi nati o n wit h a n ot her dr u g) a n d wit h a n y r o ute of a d mi nistrati o n, 
f or m ulati o n, or d ose, i ncl u di n g a n o ver d ose. 
Is olate d la b orat or y, vital si g ns, or E C G a b n or malities s h o ul d be rec or de d as a d verse e ve nts o nl y 
if ass ociate d wit h o ne of t he f oll o wi n g: 
a) cli nical fi n di n gs ( me dical hist or y, p h ysical e xa m si g ns, s y m pt o ms, or disease),  
b)  c orrecti ve treat me nt, or c o ns ultati o n,  
c) st u d y dr u g i nterr u pti o n or disc o nti n uati o n, or 
d)  h os pitalizati o n or e mer ge nc y r o o m a d missi o n 
T o pr o vi de a c o m pre he nsi ve re vie w of a b n or mal la b orat or y fi n di n gs, t he cli nical st u d y re p ort 
will i ncl u de ta bles s h o wi n g all s u bjects wit h cli nical la b orat or y val ues o utsi de of t he refere nce 
ra n ge. 
1 3. 1. 2.   
S us pecte d A d verse Re acti o n 
S us pecte d a d verse reacti o n mea ns a n y a d verse e ve nt f or w hic h t here is a reas o na ble p ossi bilit y 
t hat t he dr u g ca use d t he a d verse e ve nt. F or t he p ur p oses of I N D safet y re p orti n g, ‘reas o na ble 
p ossi bilit y’ mea ns t here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he 
a d verse e ve nt. A s us pecte d a d verse reacti o n i m plies a lesser de gree of certai nt y a b o ut ca usalit y 
t ha n a d verse reacti o n, w hic h mea ns a n y a d verse e ve nt ca use d b y a dr u g. A d verse reacti o ns are a 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 3  
 
s u bset of all s us pecte d a d verse reacti o ns w here t here is reas o n t o c o n cl u de t hat t he dr u g ca use d 
t he e ve nt. 
1 3. 1. 3.   
A d verse E ve nt 
 
Ne utr o pe nia is ge nerall y defi ne d as a n A N C < 1. 5 x 1 0
9/ L2 0, 2 6- 2 9. 
 
 ne utr o p hil c o u nts will 
be re p orte d usi n g a ce ntral la b orat or y a n d m o nit ore d b y t he    
 Me dical M o nit or.  
If a s u bject e x perie nces ne utr o pe nia, a ne utr o pe nia case re p ort f or m will be c o m plete d. T he 
i nf or mati o n re q uire d f or t his f or m will be o btai ne d b y t he site staff t hr o u g h a n i nter vie w wit h t he 
s u bject c o nte m p ora ne o us wit h t he e ve nt. 
T o o btai n c o ntr ol cases, t he ne utr o pe nia case re p ort f or m will be c ollecte d fr o m all s u bjects at 
t he Baseli ne, Wee k 4, Wee k 8, a n d Wee k 1 2 visits. 
1 3. 1. 4.   
Seri o us A d verse E ve nt 
A n a d verse e ve nt or s us pecte d a d verse reacti o n is c o nsi dere d “seri o us” if, i n t he vie w of eit her 
t he Site I n vesti gat or or K n o p p, it res ults i n a n y of t he f oll o wi n g o utc o mes:  
 Deat h  
 A life-t hreate ni n g a d verse e ve nt 
 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,  
 A persi ste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct 
n or mal life f u ncti o ns  
 A c o n ge nital a n o mal y/ birt h defect  
I mp orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y 
ma y je o par dize t he patie nt/s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h me dical e ve nts i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias 
or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de nc y or dr u g a b use.  
1 3 . 2.  
M o nit ori n g a n d Rec or di n g A d verse E ve nts 
1 3. 2. 1.   
All E ve nts  ( a n y u nt o w ar d me dic al occ urre nce) 
All e ve nts m ust be assesse d t o deter mi ne t he f oll o wi n g: 
 E ve nt meets t he criteria f or a n S A E, as defi ne d i n Secti o n 1 3. 1. 4  
 Relat i o ns hi p of t he e ve nt t o st u d y dr u g, as defi ne d i n Secti o n 1 3. 3. 1  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 4  
 
 Se ver it y of t he e ve nt, as defi ne d i n Secti o n 1 3. 3. 2  
1 3. 2. 2.   
A d verse E ve nts 
A n y A E e x perie nce d b y t he s u bject bet wee n t he ti me t he s u bject pr o vi des i nf or me d c o nse nt a n d 
t he last st u d y visit is t o be rec or de d o n t he C R F, re gar dless of t he se verit y of t he e ve nt or its 
relati o ns hi p t o st u d y dr u g. 
1 3. 2. 3.  
 
La b ora t or y- defi ne d e ve nts of ne utr o pe nia ( A N C is < 1. 5 0 x 1 0 9/ L) s h o ul d be re p orte d b y t he site t o 
t he    
 Me dical M o nit or wit hi n 2 4 h o urs of a ware ness. If a s u bject e x perie nces a n 
A N C  < 1. 5 0 x 1 09/ L t he ne utr o pe nia case re p ort f or m will be c o m plete d. T he i nf or mati o n re q uire d 
f or t his f or m will be o btai ne d b y t he site staff t hr o u g h a n i nter vie w wit h t he s u bject 
c o nte m p ora ne o us wit h t he e ve nt. T he ne utr o pe nia case re p ort f or m s h o ul d be re peate d wee kl y 
u ntil t he A N C is ≥1. 5 0 x 1 0 9/ L.  
All cases of la b orat or y- defi ne d ne utr o pe nia s h o ul d be re p orte d t o t he Me dical M o nit or a n d will 
be f oll o we d b y r e peati n g cli nical safet y la b orat or y w or k u ntil t he ne utr o pe nia res ol ves. 
See A p pe n di x A. 
1 3. 2. 4.   
Seri o us A d verse E ve nts 
A n y S A E e x perie nce d b y t he s u bject after t he s u bject si g ns t he I C F t hr o u g h t he last st u d y visit is 
t o be rec or de d o n t he S A E F or m, re gar dless of t he se verit y of t he e ve nt or its relati o ns hi p t o 
st u d y dr u g. S A Es m ust be re p orte d t o K n o p p or its desi g nate d re prese ntati ve.  
A n y S A E o n g oi n g w he n t he s u bject c o m pletes t he st u d y or disc o nti n ues fr o m t he st u d y will be 
f oll o we d b y t he Site I n vesti gat or u ntil t he e ve nt has res ol ve d, sta bilize d, or ret ur ne d t o baseli ne 
stat us. 
1 3. 2. 5.   
I mme di ate Re p orti n g of Seri o us A d verse E ve nts 
I n or der t o a d here t o all a p plica ble la ws a n d re g ulati o ns f or re p orti n g a n S A E, t he st u d y site m ust 
f or mall y n otif y K n o p p wit hi n 2 4 h o urs of t he st u d y site staff bec o mi n g a ware of t he S A E. It is 
t he Site I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t he S A E re p orti n g i nf or mati o n a n d pr oce d ures 
are use d a n d f oll o we d a p pr o priatel y. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 8  
 
1 3. 3. 3.   
E x p ecte d ness of E ve nts 
A n a d verse e ve nt or s us pecte d a d verse reacti o n is c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n 
t he c urre ntl y a p pr o ve d i n vesti gat or br oc h ure or is n ot liste d at t he s pecificit y or se verit y t hat has 
bee n o bser ve d. F or e xa m ple, u n der t his defi niti o n, he patic necr osis w o ul d be u ne x pecte d ( b y 
vir t ue of greater se verit y) if t he i n vesti gat or br oc h ure referre d o nl y t o ele vate d he patic e nz y mes 
or he patitis. Si milarl y, cere bral t hr o m b oe m b olis m a n d cere bral vasc ulitis w o ul d be u ne x pecte d 
( b y virt ue of greater s pecificit y) if t he i n vesti gat or br oc h ure liste d o nl y cere bral vasc ular 
acci de nts. " U ne x pecte d," as use d i n t his defi niti o n, als o refers t o a d verse e ve nts or s us pecte d 
a d verse reacti o ns t hat are me nti o ne d i n t he i n vesti gat or br oc h ure as occ urri n g wit h a class of 
dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g, b ut are n ot s pecificall y 
me nt i o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.   
1 3 . 4.  
Presc he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ule d 
Tre at me nts 
A presc he d ule d or electi ve pr oce d ure or a r o uti nel y sc he d ule d treat me nt will n ot be c o nsi dere d 
a n S A E, e ve n if t he s u bject is h os pitalize d; t he st u d y site m ust d oc u me nt all of t he f oll o wi n g: 
 T he pre sc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt was 
sc he d ule d ( or was o n a waiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he s u bject’s 
c o nse nt t o partici pate i n t he st u d y. 
 T he c o n di ti o n re q uiri n g t he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he Site 
I n vesti gat or bet wee n t he s u bject’s c o nse nt t o partici pate i n t he st u d y a n d t he ti me of 
t he pr oce d ure or treat me nt. 
 T he pre sc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n. 
1 3. 5.   
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns 
1 3. 5. 1.   
O ver d ose 
A n o ver d ose is a n y d ose of st u d y dr u g gi ve n t o a s u bject or ta ke n b y a s u bject t hat e xcee ds t he 
d ose de scri be d i n t he pr ot oc ol ( m ore t ha n 2 d oses i n a 1 2 h o ur peri o d). O ver d oses are n ot 
c o nsi dere d A Es; h o we ver, all o ver d oses s h o ul d be rec or de d o n a n S A E F or m a n d fa xe d t o 
 Dr u g Safet y wit hi n 2 4 h o urs. A n o ver d ose s h o ul d be re p orte d e ve n if it d oes n ot res ult 
i n a n A E. O ver d oses d o n ot nee d t o be rec or de d i n t he C R F; d osi n g i nf or mati o n is rec or de d o n a 
C R F. 
T here is n o k n o w n a nti d ote f or a n o ver d ose of de x pra mi pe x ole.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
6 9  
 
1 3. 5. 2.   
Me dic al E mer ge nc y 
I n a me dical e mer ge nc y re q uiri n g i m me diate atte nti o n, st u d y site staff will a p pl y a p pr o priate 
me dical i nter ve nti o n, acc or di n g t o c urre nt sta n dar ds of care. T he Site I n vesti gat or or desi g nee 
s h o uld c o ntact t he    
 Me dical M o nit or.      
1 3. 5. 3.   
C o n tr ace pti o n Re q uire me nts 
F or t he p ur p ose of t his pr ot oc ol, a w o ma n is c o nsi dere d of c hil d beari n g p ote ntial ( W O C B P), i.e. 
fertile, f oll o wi n g me narc he a n d u ntil bec o mi n g p ost- me n o pa usal u nless per ma ne ntl y sterile. 
Per ma ne nt sterilizati o n met h o ds i ncl u de h ysterect o m y, bilateral sal pi n gect o m y a n d bilateral 
o o p h orect o m y. 
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 
ca use. A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y be use d 
t o c o nfir m a p ost- me n o pa usal state 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. H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H 
m eas ure me nt is i ns ufficie nt. 
F or t he p ur p ose of t his d oc u me nt, a ma n is c o nsi dere d fertile after p u bert y u nless per ma ne ntl y 
sterile b y bilateral orc hiect o m y. 
All fertile male s u bjects a n d w o me n of c hil d beari n g p ote ntial w h o are, i n t he o pi ni o n of t he Site 
I n vesti gat or, se x uall y acti ve a n d at ris k f or pre g na nc y wit h t heir part ner(s) m ust a gree t o use at 
least o ne hi g hl y effecti ve  met h o d of c o ntrace pti o n, or 2 pr ot oc ol acce pta ble met h o ds of 
c o ntrace pti o n use d i n ta n de m c o nsiste ntl y a n d c orrectl y f or t he d urati o n of t he acti ve treat me nt 
peri o d a n d f or 1 m o nt h (fe males) or 3 m o nt hs ( males) after t he last d ose of st u d y dr u g ( See Ta ble  
3  a n d Ta ble  4). T he Site I n vesti gat or or his or her desi g nee, i n c o ns ultati o n wit h t he s u bject, will 
c o nfir m t hat t he s u bject c o nti n ues t o use a hi g hl y effecti ve / pr ot oc ol acce pta ble birt h c o ntr ol 
met h o d  d uri n g t his ti me peri o d of t he st u d y.  
Hi g hl y e ffecti ve birt h c o ntr ol met h o ds t hat res ult i n a fail ure rate of less t ha n 1 % per year w he n 
use d c o nsiste ntl y a n d c orrectl y i ncl u de t h ose met h o ds i n Ta bl e 3. 
T a b le 3:     
Hi g hl y Effecti ve Birt h C o ntr ol  
 c o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n 1 
o  oral  
o  i ntra va ginal  
o  tra ns der mal 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 0  
 
 pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 1 
o  oral  
o  i njecta ble 
o  i m pla nta ble 2 
 i ntra uteri ne de vice (I U D) 2 
 i ntra uteri ne h or m o ne-releasi n g s yste m ( I U S) 2 
 bilateral t u bal occl usi o n 2 
 vasect o mize d  part ner 2, 3 
 se x ual a bsti ne nce 4 
1 H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he 
efficac y of t he c o ntrace pti o n met h o d. 
2 C o ntrace pti o n met h o ds c o nsi dere d t o ha ve l o w user de pe n de nc y. 
3 Vasect o mize d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi de d t hat part ner is t he s ole 
se x ual part ner of t he W O C B P trial partici pa nt a n d t hat t he vasect o mize d part ner has recei ve d 
me dical assess me nt of t he s ur gical s uccess. 
4 I n t he c o nte xt of t his pr ot oc ol se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if 
defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h 
t he st u d y treat me nts. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he 
d urati o n of t he cli nical trial a n d t he preferre d a n d us ual lifest yle of t he s u bject. 
Pr ot oc ol acce pta ble birt h c o ntr ol met h o ds t hat res ult i n a fail ure rate of m ore t ha n 1 % per year 
i ncl u de t h ose met h o ds i n Ta ble 4 . If a hi g hl y effecti ve met h o d of birt h c o ntr ol is n ot use d b y t he 
s u bject or part ner, a c o m bi nati o n of t w o f or ms of pr ot oc ol acce pta ble birt h c o ntr ol m ust be use d 
i n ta n de m, c o nsiste ntl y a n d c orrectl y f or t he s u bject t o q ualif y f or t he st u d y. 
T a b le 4:     
Pr ot oc ol Acce pt a ble Birt h C o ntr ol ( w he n use d i n t a n de m)  
 pr o gest o ge n -o nl y oral h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot t he 
pri mar y m o de of acti o n  
 male or fe male c o n d o m wit h or wit h o ut s per mici de 
1 
 ca p, dia p hra g m or s p o n ge wit h s per mici de 1 
1 A c o m bi nati o n of male c o n d o m wit h eit her ca p, dia p hra g m or s p o n ge wit h s per mici de ( d o u ble 
barrier met h o ds) are als o c o nsi dere d acce pta ble 
Peri o dic a bsti ne nce (cale n dar, s y m pt ot her mal, p ost- o v ulati o n met h o ds), wit h dra wal (c oit us 
i nterr u pt us), s per mici des o nl y, a n d lactati o nal a me n orr hea met h o d ( L A M) are n ot acce pta ble 
met h o ds of c o ntrace pti o n. 
1 3. 5. 4.   
Re g ul at or y Re p orti n g 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns ( S U S A Rs) are S A Es t hat are u ne x pecte d a n d 
j u d ge d b y K n o p p t o be relate d t o t he st u d y dr u g a d mi nistere d. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 1  
 
K n o p p will s u b mit S U S A Rs t o Site I n vesti gat ors a n d Re g ulat or y A ge ncies acc or di n g t o l ocal 
req uire me nts. 
1 3 . 6.  
Site I n vesti g at or Res p o nsi bilities 
T he Site I n vesti gat or’s res p o nsi bilities i ncl u de t he f oll o wi n g: 
 M o ni t or a n d rec or d all A Es, i ncl u di n g S A Es, re gar dless of t he se verit y or relati o ns hi p 
t o st u d y dr u g. 
 Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y of eac h e ve nt. 
 Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt. 
 M o ni t or a n d rec or d all pre g na ncies a n d f oll o w- u p o n t he o utc o me of t he pre g na nc y. 
 C o m plete a n S A E f or m f or eac h seri o us e ve nt a n d fa x it t o    
 Dr u g Safet y 
wit hi n 2 4 h o urs of t he st u d y site staff bec o mi n g a ware of t he e ve nt. 
 P urs ue  S A E f oll o w- u p i nf or mati o n acti vel y a n d persiste ntl y. F oll o w- u p i nf or mati o n 
m ust be re p orte d t o    
 Dr u g Safet y wit hi n 2 4 h o urs of t he st u d y site staff 
bec o m i n g a ware of ne w i nf or mati o n. 
 E ns ure  all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or ds. 
 Re p ort  S A Es t o l ocal et hics c o m mittees, as re q uire d b y l ocal la w. 
1 3. 7.   
K n o p p Res p o nsi bilities 
K n o p p’s res p o nsi bilities i ncl u de t he f oll o wi n g: 
 K n o p p w ill a d here t o its res p o nsi bilities as st u d y s p o ns or, as s pecifie d i n rele va nt 
F D A a n d I C H g ui da nce d oc u me nts. 
 Bef ore st u d y site acti vati o n a n d s u bject e nr oll me nt, K n o p p or its desi g nee is 
res p o nsi ble f or re vie wi n g wit h st u d y site staff t he defi niti o ns of A E a n d S A E, as well 
as t he i nstr ucti o ns f or m o nit ori n g, rec or di n g, a n d re p orti n g A Es a n d S A Es. 
 K n o p p  or its desi g nee is t o n otif y all a p pr o priate re g ulat or y a ut h orities, ce ntral et hics 
c o m mittees, a n d Site I n vesti gat ors of S A Es, as re q uire d b y l ocal la w, wit hi n re q uire d 
time fra mes. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 2  
 
1 4.    
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F 
S A M P L E SI Z E  
1 4. 1.   
Descri pti o n of O bjecti ves 
See Secti o n 7 : St u d y O bjecti ves a n d E n d p oi nts. 
1 4. 2.   
Descri pti o n of E n d p oi nts 
See Secti o n 7 : St u d y O bjecti ves a n d E n d p oi nts. 
1 4. 3.   
A n a l ysis P o p ul ati o ns 
T he safet y p o p ulati o n will c o nsist of all s u bjects w h o were ra n d o mize d a n d recei ve d at least o ne 
d ose of st u d y dr u g. T he efficac y p o p ulati o n will be a m o difie d I T T sa m ple a n d c o nsist of all 
s u bjects i n t he safet y p o p ulati o n w h o ha ve at least o ne p ost-ra n d o mizati o n e val uati o n f or at least 
o ne of t he efficac y e n d p oi nts. T he per- pr ot oc ol p o p ulati o n will c o nsist of all s u bjects i n t he 
efficac y p o p ulati o n w h o c o m plete t he Wee k 8 C B C a n d d o n ot ha ve a maj or pr ot oc ol de viati o n. 
Maj or pr ot oc ol de viati o ns will be defi ne d i n t he S A P pri or t o st u d y u n- bli n di n g. 
1 4. 4.   
De m o gr a p h y a n d B aseli ne C h ar acteristics 
De m o gra p h y, me dical hist or y a n d baseli ne disease c hara cteristic data ( d urati o n of s y m pt o ms, 
se verit y of s y m pt o m sc ores, c o nc o mita nt me dicati o n at baseli ne, etc.) will be s u m marize d at 
st u d y baseli ne f or t he safet y p o p ulati o n.  
Ge n der, race, a n d et h nicit y will be s u m marize d usi n g c o u nts a n d perce nta ges. A ge, hei g ht (c m), 
wei g ht ( k g), a n d b o d y mass i n de x ( k g/ m 2; calc ulate d) will be s u m marize d wit h descri pti ve 
statistics ( n u m ber of s u bjects [ n], mea n, sta n dar d de viati o n [s d], me dia n, mi ni m u m, a n d 
ma xi m u m). A ge will als o be s u m marize d acc or di n g t o t he cate g ories of less t ha n 5 0 years, 5 0 t o 
6 5 years, a n d m ore t ha n 6 5 years, usi n g c o u nts a n d perce nta ges.  
1 4 . 5.  
Ge ner al Met h o ds of A n al yses 
T he st u d y will use a bl oc ke d ra n d o mizati o n stratifie d b y st u d y site. T he safet y p o p ulati o n will be 
use d f or all safet y a nal yses a n d t he m o difie d I T T p o p ulati o n will be use d f or efficac y a nal yses. 
Descr i pti ve statistics, i ncl u di n g mea ns, me dia ns, a n d sta n dar d err or will be prese nte d f or efficac y 
m eas ures f or o bser ve d val ues a n d c ha n ges fr o m baseli ne b y sc he d ule d e val uati o n ti me a n d 
treat me nt gr o u p. If t he e n d p oi nt is o ne t hat re q uires a l o g tra nsf or mati o n, t he n descri pti ve 
statistics will be ge o metric mea ns a n d rati os. If t he e n d p oi nt is o ne t hat re q uires a ra n k 
tra nsf or mati o n, t he n descri pti ve statistics will be me dia n a n d i ntra- q uartile val ues.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 3  
 
T o c o ntr ol t he al p ha le vel f or testi n g t hree d ose gr o u ps vers us place b o f or t he pri mar y e n d p oi nt 
a n d f or te sti n g F E V 1, a cl ose d hierarc hical testi n g pr oce d ure will be use d i n t he f oll o wi n g or der:  
1)  Firs t, t he 3 0 0 m g/ da y d ose gr o u p will be teste d vers us place b o f or c ha n ge i n bl o o d 
a bs olute e osi n o p hil c o u nt at Wee k 1 2, a n d if t his reac hes t he < 0. 0 5 le vel t he n,  
2)  t he 1 5 0 m g/ da y d ose gr o u p will be teste d vers us place b o at t he 0. 0 5 le vel f or c ha n ge 
i n blo o d a bs ol ute e osi n o p hil c o u nt at Wee k 1 2, a n d if t his reac hes t he < 0. 0 5 le vel 
t hen, 
3)  t he 7 5 m g/ da y d ose gr o u p will be teste d vers us place b o at t he 0. 0 5 le vel f or c ha n ge i n 
bl o o d a bs ol ute e osi n o p hil c o u nt at Wee k 1 2, a n d if t his reac hes t he < 0. 0 5 le vel t he n, 
4)  t he p o ole d 1 5 0 a n d 3 0 0 m g / day d ose gr o u ps will be teste d vers us place b o at t he 
0. 0 5 le vel f or c ha n ge i n pre- br o nc h o dilat or F E V 1 at Wee k 1 2. 
Stat istical testi n g f or t he ot her sec o n dar y st u d y e n d p oi nts will be perf or me d at t he 0. 0 5 le vel 
wit h o ut a dj ust me nt. 
T he pri mar y e n d p oi nt a n d t he sec o n dar y e n d p oi nts will als o be a nal yze d usi n g t he per- pr ot oc ol 
p o p ulati o n.  
1 4. 5. 1.   
I nteri m A n al ysis of t he Pri m ar y Assess me nt Peri o d 
T here ma y be a n i nteri m a nal ysis of efficac y after all s u bjects ha ve c o m plete d t he Pri mar y 
Assess me nt Peri o d ( Wee k 1 2 visit). T his i nteri m a nal ysis of efficac y ma y i ncl u de t he f oll o wi n g 
dat a t hr o u g h Wee k 1 2: pri mar y a n d sec o n dar y efficac y e n d p oi nts a n d cli nical la b orat or y data. 
S u bjec ts will be off st u d y dr u g after t he Wee k 1 2 visit a n d t he pri mar y p ur p ose of visits after 
Wee k 1 2 is t o c ollect e osi n o p hil rec o ver y data a n d f oll o w- u p safet y data. Pri or t o a n i nteri m 
a nalysis of efficac y t hr o u g h Wee k 1 2, all t he data (efficac y a n d safet y) u p t o a n d t hr o u g h Wee k 
1 2 will be ‘s oft’ l oc ke d. T here will be n o a dj ust me nt of p- val ues f or t he i nteri m a nal ysis beca use 
all s u bjects will ha ve c o m plete d t he Pri mar y Assess me nt Peri o d a n d t he res ults of t he fi nal 
a nal ysis of efficac y t hr o u g h t he Pri mar y Assess me nt Peri o d s h o ul d be i de ntical t o t he res ults of 
t he i nteri m a nal ysis of efficac y t hr o u g h t he Pri mar y Assess me nt Peri o d. A n y c ha n ges t o t he 
efficac y res ults bet wee n t he i nteri m a nal ysis of efficac y t hr o u g h Wee k 1 2 a n d t h e fi nal a nal ysis 
of efficac y t hr o u g h Wee k 1 2 will be n ote d, alt h o u g h n o ne is e x pecte d. T he tea m carr yi n g o ut t he 
i nteri m a nal ysis of efficac y t hr o u g h Wee k 1 2 will be a differe nt tea m fr o m t he tea m res p o nsi ble 
f or clea ni n g a n d l oc ki n g t he data after Wee k 1 2. T he tea m res p o nsi ble f or clea ni n g a n d l oc ki n g 
t he data after Wee k 1 2 will n ot ha ve access t o a n y of t he u n bli n de d data fr o m t he i nteri m 
a nal ysis. 
At t he sa me ti me as t he i nteri m a nal ysis of efficac y t hr o u g h Wee k 1 2, a n i nteri m a nal ysis of ke y 
safet y data t hr o u g h Wee k 1 2 ma y be carrie d o ut: I nci de nce A Es a n d A Es lea di n g t o 
disc o nti n uati o n of st u d y dr u g; p ote ntiall y cli nicall y si g nifica nt c ha n ges i n vital si g ns, 
ne utr o p hils; L F Ts, a n d E C Gs. T he tea m carr yi n g o ut t he i nteri m a nal ysis of safet y t hr o u g h 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 4  
 
W ee k 1 2 will be a differe nt tea m fr o m t he tea m res p o nsi ble f or clea ni n g a n d l oc ki n g t he data 
after Wee k 1 2. T he tea m res p o nsi ble f or clea ni n g a n d l oc ki n g t he data after Wee k 1 2 will n ot 
ha ve access t o a n y of t he u n bli n de d data fr o m t he i nteri m a nal ysis. Safet y d ata fr o m t his i nteri m 
a nal ysis ma y be u nl oc ke d, f or i nsta nce, if a n A E t hat was o n g oi n g at Wee k 1 2 has res ol ve d. 
Af ter all s u bjects c o m plete t he E n d of St u d y Visit, t he st u d y data will be l oc ke d, a n d t he fi nal 
a nal ysis will be c o m plete d. 
1 4. 6.   
Effic ac y A n al yses 
1 4. 6. 1.   
Pri m ar y E n d p oi nt A n al yses 
T he pri mar y e n d p oi nt of t his st u d y is t he c ha n ge i n bl o o d a bs ol ute e osi n o p hil c o u nt fr o m 
Baseli ne t o Wee k 1 2. A bs ol ute e osi n o p hil c o u nt will be tra nsf or me d t o t he l o g 1 0 scale. T o a v oi d 
ta ki n g t he l o g of zer o, zer o val ues ( n ot n ull val ues) will be re place d wit h 5/ µ L i n c o n ve nti o nal 
u nits or 0. 0 0 5 × 1 0 9/ L i n t he I nter nati o nal S yste m of U nits ( SI), w hic h is 5 0 % of t he l o wer li mit of 
q ua ntificati o n. T he ge o metric mea n of all e osi n o p hil c o u nts o btai ne d bet wee n t he Scree ni n g a n d 
Baseli ne visits will be use d t o esta blis h t he baseli ne e osi n o p hil c o u nt use d i n t he efficac y 
a nal yses. Ge o metric mea ns a n d sta n dar d de viati o ns will be prese nte d b y treat me nt gr o u p f or 
o bser ve d val ues at eac h visit al o n g wit h a p- val ue c o m pari n g eac h de x pra mi pe x ole treat me nt 
gr o u p t o place b o base d o n a n a nal ysis of varia nce ( A N O V A). 
T he pri mar y a nal ysis will be a mi xe d-effect m o del, re peate d- meas ures ( M M R M) wit h ter ms f or 
baseli ne, GI N A treat me nt ste ps 3 vs. 4/ 5, treat me nt, visit, treat me nt b y visit i nteracti o n, a n d 
baseli ne b y visit i nteracti o n as fi xe d effects, a n d s u bject as a ra n d o m effect. A n u nstr uct ure d 
c o varia nce will be use d. De x pra mi pe x ole d ose gr o u p treat me nt effects a n d treat me nt gr o u p 
effects vers us place b o at Wee k 1 2 will be teste d b y c o ntrasts wit hi n t he M M R M. Esti mate d L S 
mea ns of treat me nt effects a n d esti mate d differe nce i n treat me nt effects at eac h visit will be bac k 
tra nsf or me d t o t he ori gi nal scale t o prese nt esti mate d ge o metric mea ns f or treat me nt effects a n d 
rati o of ge o metric mea ns of treat me nt effects vers us place b o al o n g wit h 9 5 % CI. 
A c o ntr ast will be create d t o test t he treat me nt effect at Wee k 1 2 f or t he p o ole d 1 5 0 m g/ da y a n d 
3 0 0 m g/ da y gr o u p vers us t he place b o gr o u p. A c o ntrast will be create d t o test t he treat me nt 
effect at Wee k 1 2 f or l o g-li near d ose res p o nse.  
T w o  se nsiti vit y a nal yses will be perf or me d.  
1)  A n  a nal ysis of c o varia nce ( A N C O V A) m o del a dj usti n g f or baseli ne a n d GI N A 
treat me nt ste ps 3 vs. 4/ 5. Missi n g data will be re place d usi n g m ulti ple i m p utati o n. 
T he Mar k o v c hai n M o nte Carl o met h o d will be use d a n d pre dicti o n varia bles will be 
baseli ne e osi n o p hil c o u nt, e osi n o p hil c o u nt at visits pri or t o t he missi n g data, a n d 
GI N A treat me nt ste ps 3 vs. 4/ 5. S A S P R O C MI will be use d t o ge nerate m ulti ple 
c o m plete datasets. T o e ns ure r o b ust ness of res ults, 1 0 c o m plete datasets will be 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 5  
 
create d. Eac h of t he 1 0 c o m plete data sets will be se paratel y a nal yze d as i n t he 
A N C O V A descri be d a b o ve, a n d t he res ults s y nt hesize d b y S A S pr oce d ure 
MI A nal yze.  
2)  De x pra mi pe x ole d ose gr o u p treat me nt effects vers us place b o at Wee k 1 2 will be 
teste d o n t he ori gi nal ( n o n-l o g 1 0 tra nsf or me d) scale (rati o of Wee k 1 2 val ue t o 
base li ne val ue) usi n g a Wilc o x o n/ Ma n n- W hit ne y ra n k s u m test wit h last o bser vati o n 
carrie d f or war d t o re place missi n g Wee k 1 2 o bser vati o ns. 
1 4. 6. 2.   
Sec o n d ar y E n d p oi nt a n d E x pl or at or y E n d p oi nt A n al yses 
F or c o nti n u o us e n d p oi nts meas ure d m ore t ha n o nce o n treat me nt ( pre- br o nc h o dilat or F E V 1, 
A C Q - 7), t he a nal ysis will use t he met h o d use d f or t he a nal ysis of t he pri mar y e n d p oi nt, M M R M. 
T he m o del will c o ntai n ter ms f or baseli ne, GI N A treat me nt ste ps 3 vs. 4/ 5, treat me nt, visit, 
treat me nt b y visit i nteracti o n, a n d baseli ne b y visit i nteracti o n as fi xe d effects, a n d s u bject as a 
ran d o m effect t o c o m pare treat me nt gr o u p effects.  
F or c o nti n u o us e n d p oi nts meas ure d o nl y at Baseli ne a n d Wee k 1 2 ( p ost- br o nc h o dilat or F E V 1, 
A Q L Q) t he a nal ysis will use A N C O V A, a dj usti n g f or t he Baseli ne val ue a n d GI N A treat me nt 
step 3 vs. 4/ 5. If a s u bject has a missi n g sc ore at Wee k 1 2 a n d a n e val uati o n was perf or me d at t he 
time of dr o p o ut, last o bser vati o n carrie d f or war d ( L O C F) will be use d t o i m p ute t he missi n g 
val ue at Wee k 1 2. 
1 4. 7.   
P h ar m ac o ki netics 
De x pra mi pe x ole c o nce ntrati o ns i n plas ma will be s u m marize d usi n g mea ns, S D, sta n dar d err or 
of  t he mea n, c oefficie nt of variati o n, mi ni m u m, me dia n, a n d ma xi m u m b y treat me nt per visit. 
De x pra mi pe x ole tr o u g h c o nce ntrati o ns i n plas ma will be use d t o e val uate t he relati o ns hi p 
bet wee n de x pra mi pe x ole e x p os ure a n d e osi n o p hil-l o weri n g res p o nse. A d diti o nal details of t he 
a nal ysis pla n a n d t he res ults will be pr o vi de d i n a se parate d oc u me nt.  
1 4. 8.   
S afet y A n al yses 
1 4. 8. 1.   
Met h o ds of A n al yses - S afet y 
T he safet y s u m mar y will i ncl u de a d verse e ve nts ( A Es), seri o us a d verse e ve nts ( S A Es), cli nical 
la b orat or y safet y data, vital si g ns, p h ysical e xa mi nati o n, a n d E C G data. Descri pti ve statistics will 
be prese nte d f or cli nical safet y la b orat or y data, vital si g ns, a n d E C G meas ures f or o bser ve d 
val ues a n d c ha n ges fr o m baseli ne b y sc he d ule d e val uati o n ti me a n d treat me nt gr o u p. P ote ntiall y 
cli nicall y si g nifica nt c ha n ges f or select cli nical safet y la b orat or y data, vital si g ns, a n d E C G 
meas ures will be defi ne d i n t he statistical a nal ysis pla n a n d t he i nci de nce of eac h will be 
prese nte d b y treat me nt gr o u p.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 6  
 
1 4. 8. 1. 1.  A d verse E ve nts 
All treat me nt-e mer ge nt A Es will be s u m marize d b y s yste m or ga n class ( S O C) a n d preferre d 
ter m ( P T). Treat me nt-e mer ge nt A Es will be defi ne d as t h ose wit h a n o nset date o n or after t he 
first da y of st u d y dr u g a n d wit hi n 3 0 da ys of t he last d ose of st u d y dr u g. A E wit h o nset date 
m ore t ha n 3 0 da ys after t he last d ose of st u d y dr u g will be liste d a n d cli nicall y re vie we d. All 
treat me nt-e mer ge nt A Es, re gar dless of i nte nsit y (i.e., se verit y) a n d relati o ns hi p t o st u d y 
treat me nt will be s u m marize d. A Es will als o be prese nte d b y ma xi m u m i nte nsit y a n d t he hi g hest 
relati o ns hi p t o st u d y treat me nt. A Es lea di n g t o pre mat ure disc o nti n uati o n a n d treat me nt-
e mer ge nt S A Es will be classifie d b y P T a n d S O C a n d ta b ulate d. A n y re p orte d deat hs will be 
liste d.  
A Es will o nl y be c o u nte d o nce per S O C a n d o nce per P T. F or t he s u m mar y of A Es b y se verit y, if 
a s u bject has m ulti ple e ve nts occ urri n g i n t he sa me b o d y s yste m or sa me preferre d ter m, t he n t he 
e ve nt wit h t he hi g hest se verit y will be c o u nte d. T he relati o ns hi p t o st u d y treat me nt will be 
classifie d as relate d or n ot relate d.  
Listi n gs will be prese nte d b y s u bject f or all A Es as well as f or S A Es, A Es ass ociate d wit h deat h, 
a n d A Es lea di n g t o disc o nti n uati o n of st u d y dr u g. 
1 4. 8. 1. 2.  Cli ni c al L a b or at or y E v al u ati o ns 
F or he mat ol o g y a n d bl o o d c he mistr y, descri pti ve statistics f or ra w val ues as well as c h a n ge fr o m 
baseli ne f or eac h test will be prese nte d f or eac h visit a n d treat me nt gr o u p. F or he mat ol o g y a n d 
bl o o d c he mistr y, t he n u m ber a n d perce nta ge of s u bjects wit h p ote ntiall y cli nicall y si g nifica nt 
la b orat or y res ults will be ta b ulate d. 
 
. T o better c haracterize a n y 
e pis o des of ne utr o pe nia t hat ma y occ ur, a ne utr o pe nia case re p ort f or m will be utilize d t o ca pt ure 
detaile d cli nical i nf or mati o n c o nc urre nt wit h a n y la b orat or y- defi ne d e ve nts of ne utr o pe nia.  
F or t he a nal ysis of ne utr o pe nia, t here will be ta b ulati o n of A N C < 0. 5 0 x 1 0 9/ L, A N C < 1. 0 0 x 1 09/ L, 
a n d A N C < 1. 5 0 x 1 0 9/ L wit h a te m p orall y occ urri n g A E p ote ntiall y relate d t o ne utr o pe nia. T he 
i nci de nce of i nfecti o n te m p orall y relate d t o ne utr o pe nia f or de x pra mi pe x ole a n d place b o s u bjects 
will be c o m pare d wit h t he i nci de nce f or de x pra mi pe x ole a n d place b o s u bjects wit h o ut 
ne utr o pe nia.  
1 4. 8. 1. 3.  Vit al Si g ns 
Vital si g n meas ure me nts as well as c ha n ge fr o m Baseli ne will be s u m marize d usi n g descri pti ve 
statistics b y visit a n d b y treat me nt gr o u p.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 7  
 
Vital si g ns c ollecte d after t he first d ose of treat me nt will be e xa mi ne d t o deter mi ne t he i nci de nce 
of cli nicall y rele va nt a b n or malities. T hese a b n or malities are defi ne d i n Ta ble 5 . 
T a ble 5 :     
Criteri a t o Deter mi ne P ote nti all y Cli nic all y Si g nific a nt Vit al Si g n 
A b n or m alities 
Vit al Si g n P ar a meter   
Criteri a f or A b n or m alities  
s yst olic bl o o d press ure 
> 1 8 0 m m H g or a n i ncrease fr o m pre -d osi n g of m ore t ha n 4 0 m m H g, 
or < 9 0  m m H g or a decrease fr o m pre -d osi n g of m ore t ha n 3 0 m m H g  
diast olic bl o o d press ure  
> 1 0 5 m m H g or a n i ncrease fr o m pre -d osi n g of m ore t ha n 3 0 m m H g, 
or < 5 0  m m H g or a decrease fr o m pre -d osi n g of m ore t ha n 2 0 m m H g  
p ulse  
> 1 2 0 beats per mi n ute  or  a n i ncrease fr o m pre -d osi n g of m ore t ha n 
3 0  beats per mi n ute, or < 5 0 beats per mi n ute or a decrease fr o m pre -
d osi n g of m ore t ha n 2 0  beats per mi n ute  
te m perat ure 
> 3 9 ° C a n d a n i ncrease fr o m pre-d osi n g of at least 1° C 
b o d y wei g ht  
> 7 % fr o m B aseli ne val ue, or ≤7 % fr o m B aseli ne val ue  
T he n u m ber of s u bjects e val uate d a n d t he n u m ber a n d perce nta ge of s u bjects wit h t he defi ne d 
a b n or malit y at a n y ti me p ost- baseli ne will be prese nte d b y treat me nt gr o u p. 
1 4. 8. 1. 4.  Electr oc ar di o gr a ms 
E C G meas ures as well as c ha n ge fr o m Baseli ne will be s u m marize d usi n g descri pti ve statistics 
b y visit a n d b y treat me nt gr o u p.  
E C G fi n di n gs t hat are deter mi ne d t o be p ote ntiall y cli nicall y si g nifica nt will be s u m marize d. 
T he Q T/ Q Tc a nal ysis a p pr oac h will f oll o w t he I C H E 1 4 G ui deli ne: T he Cli nical E val uati o n of 
Q T/ Q Tc I nter val Pr ol o n gati o n a n d Pr oarr h yt h mic P ote ntial f or N o n- A ntiarr h yt h mic Dr u gs. 3 0 T he 
i nci de nce of A Es p ote ntiall y relate d t o Q Tc i ncrease will be prese nte d f or i n di vi d ual A Es a n d t he 
i nci de nce will be prese nte d f or t he p o ol of a n y A Es p ote ntiall y relate d t o Q Tc i ncrease. A Es 
p ote ntiall y relate d t o Q Tc i ncrease will i ncl u de: t orsa de de p oi ntes, s u d de n deat h, ve ntric ular 
tac h ycar dia, ve ntric ular fi brillati o n a n d fl utter, s y nc o pe, seiz ures, a n d ot hers i de ntifie d d uri n g a 
re vie w of all A Es o bser ve d i n t he st u d y.  
F or t he e val uati o n of heart rate c ha n ge, a bs ol ute heart rate, a n d c ha n ges fr o m Baseli ne b y 
sc he d ule d e val uati o n ti me will be ta b ulate d b y treat me nt gr o u p. T he i nci de nce of s u bjects wit h 
> 1 2 0 beats per mi n ute or a n i ncrease fr o m pre- d osi n g of m ore t ha n 3 0 beats per mi n ute will be 
tab ulate d b y treat me nt gr o u p. T he i nci de nce of A Es p ote ntiall y relate d t o heart rate i ncrease will 
be prese nte d f or i n di vi d ual A Es a n d t he i nci de nce will be prese nte d f or t he p o ol of a n y A Es 
p ote ntiall y relate d t o heart rate i ncrease. A ta b ulati o n of A Es t hat c o ul d be li n ke d t o a heart rate 
effect of t he dr u g will be prese nte d wit h a p pr o priate gr o u pi n g of ter ms, e. g.: 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 8  
 
a) Preferre d ter ms: relate d t o m y ocar dial isc he mia (a n gi na, A MI, u nsta ble a n gi na, etc.) 
b)  Preferre d ter ms relate d t o c o n gesti ve heart fail ure 
c) Preferre d ter ms relate d t o tac h ycar dia (atrial fi brillati o n, tac h ycar dia, ve ntric ular 
tac h ycar dia, etc.) 
d)  Car diac S A Es a n d rele va nt S A Es i n t he ge neral S yste m Or ga n Class (e. g., s u d de n 
deat h). 
1 4. 8. 1. 5.  P h ysic al E x a mi n ati o n 
T he p h ysical e xa mi nati o n fi n di n gs will be prese nte d i n data listi n gs.  
1 4. 9.   
S a m ple Size C o nsi der ati o ns 
T he pri mar y e n d p oi nt f or t his st u d y is re d ucti o n i n bl o o d e osi n o p hils fr o m Baseli ne t o Wee k 1 2. 
I n a n o pe n la bel st u d y of de x pra mi pe x ole i n s u bjects wit h c hr o nic r hi n osi n usitis wit h nasal 
p ol y ps, de x pra mi pe x ole re d uce d e osi n o p hils b y 9 4 % (rati o of e n d p oi nt t o baseli ne = - 2. 8 1 o n t he 
l o g base e scale). T he sta n dar d de viati o n f or t he rati o of e n d p oi nt t o baseli ne was 1. 8 2 o n t he l o g 
base e scale. 
Ni netee n s u bjects per ar m will pr o vi de a p pr o xi matel y 8 4 % p o wer if t he tr ue re d ucti o n i n bl o o d 
e osi n o p hils is 8 5 % wit h de x pra mi pe x ole a n d 1 0 % wit h place b o. T he p o wer will be 9 5 % if t he 
tr ue re d ucti o n i n bl o o d e osi n o p hils is 9 0 % wit h de x pra mi pe x ole a n d 1 0 % wit h pla ce b o. T he 
sa m ple size was calc ulate d usi n g met h o d ol o g y f or a t w o-sa m ple t-test. Ass u mi n g a n a p pr o xi mate 
2 0 % dr o p o ut rate of s u bjects w h o d o n ot ha ve t he fi nal o bser vati o n f or bl o o d e osi n o p hils yiel ds a 
sa mple size of 2 5 s u bjects per ar m t o be ra n d o mize d . 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
7 9  
 
1 5.    
E T HI C A L R E Q UI R E M E N T S 
T he st u d y will be c o n d ucte d i n acc or da nce wit h le gal a n d re g ulat or y re q uire me nts, as well as t he 
ge neral pri nci ples set f ort h i n t he I nter nati o nal Et hical G ui deli nes f or Bi o me dical Researc h 
I n v ol vi n g H u ma n S u bjects ( C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces 2 0 0 2), 
G ui deli nes f or G C P (I C H 1 9 9 6), a n d t he Declarati o n of Helsi n ki ( W orl d Me dical Ass ociati o n 
1 9 9 6 a n d 2 0 0 8).  
I n a d diti o n, t he st u d y will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol, t he I C H g ui deli ne o n 
G C P, a n d a p plica ble l ocal re g ulat or y re q uire me nts a n d la ws. 
1 5 . 1.  
I nstit uti o n al Re vie w B o ar d 
T he Site I n vesti gat or m ust o btai n a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d st u d y 
d oc u m e nts pri or t o starti n g t he st u d y.  
If t he Site I n vesti gat or ma kes a n y c ha n ges t o t he I C F, K n o p p m ust a p pr o ve t he c ha n ges bef ore 
t he I C F is s u b mitte d t o t he I R B. A c o p y of t he a p pr o ve d I C F m ust be pr o vi de d t o K n o p p. After 
a p pro val, t he I C F m ust n ot be altere d wit h o ut t he a gree me nt of t he rele va nt I R B a n d K n o p p. 
It is t he res p o nsi bilit y of t he Site I n vesti gat or t o e ns ure t hat all as pects of i nstit uti o nal re vie w are 
c o n d ucte d i n acc or da nce wit h c urre nt g o ver n me ntal re g ulati o ns. 
K n o p p m ust recei ve a letter d oc u me nti n g I R B a p pr o val, w hic h s pecificall y i de ntifies t he 
pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y. Pr ot oc ol a me n d me nts will 
be s u bj ect t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol. 
A pr o gress re p ort m ust be s u b mitte d t o t he I R B at re q uire d i nter vals a n d n ot less t ha n a n n uall y. 
At t he  c o m pleti o n or ter mi nati o n of t he st u d y, t he i n vesti gati o nal site m ust s u b mit a cl ose- o ut 
letter t o t he I R B a n d K n o p p. 
1 5. 2.   
S u bject I nf or m ati o n a n d C o nse nt 
Pri or t o perf or mi n g a n y st u d y-relate d acti vities u n der t his pr ot oc ol, writte n i nf or me d c o nse nt 
wit h t he a p pr o ve d I C F m ust be o btai ne d fr o m t he s u bject or t he s u bject’s le gall y a ut h orize d 
re prese ntati ve, as a p plica ble, i n acc or da nce wit h l ocal practice a n d re g ulati o ns. Writte n i nf or me d 
c o nsent m ust be o btai ne d fr o m all s u bjects partici pati n g i n a cli nical st u d y c o n d ucte d b y K n o p p. 
T he bac k gr o u n d of t he pr o p ose d st u d y, t he assess me nts, t he be nefits, a n d t he ris ks of t he st u d y 
a n d t he v ol u ntar y nat ure of st u d y partici pati o n m ust be e x plai ne d t o t he s u bject. T he s u bject m ust 
be gi ve n s ufficie nt ti me t o c o nsi der w het her t o partici pate i n t he st u d y. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 0  
 
A c o p y of t he I C F, si g ne d a n d date d b y t he s u bject, m ust be pr o vi de d t o t he s u bject. 
C o nfir mati o n of a s u bject’s i nf or me d c o nse nt m ust als o be d oc u me nte d i n t he s u bject’s me dical 
rec or d pri or t o a n y testi n g u n der t his pr ot oc ol. 
Eac h c o nse nt f or m s h o ul d c o ntai n a n a ut h orizati o n all o wi n g t he Site I n vesti gat or a n d K n o p p t o 
use a n d discl ose s u bject/ patie nt healt h i nf or mati o n i n c o m plia nce wit h l ocal la w. 
T he si g ne d c o nse nt f or m will be retai ne d wit h t he st u d y rec or ds. 
1 5. 3.   
S u bject D at a Pr otecti o n 
All parties will e ns ure pr otecti o n of s u bject pers o nal data a n d will n ot i ncl u de s u bject na mes or 
ot her i de ntifia ble data i n a n y re p orts, p u blicati o ns, or ot her discl os ures, e xce pt w here re q uire d b y 
la w. T he s u bjects will n ot be i de ntifie d b y na me i n t he C R F or i n a n y st u d y re p orts, a n d t hese 
rep orts will be use d f or researc h p ur p oses o nl y.  
1 5. 4.   
C o nflict of I nterest 
T he Site I n vesti gat or a n d staff m ust discl ose all p ote ntial c o nflicts of i nterest (e. g., fi na ncial 
i nterest i n K n o p p, or i n a K n o p p c o m petit or). T he Site I n vesti gat or m ust als o discl ose all 
p ote ntial c o nflicts of i nterest t o t he s u bject bef ore t he s u bject is i n vite d t o partici pat e i n t he 
st u d y. 
1 5. 5.   
Re gistr ati o n of St u d y a n d Discl os ure of St u d y  Res ults 
K n o p p will re gister t he st u d y a n d p ost st u d y res ults re gar dless of o utc o me o n a p u blicl y 
accessi ble we bsite ( w w w. Cli nical Trials. g o v ) i n acc or da nce wit h t he a p plica ble la ws a n d 
re g ulati o ns. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 1  
 
1 6.    
A D MI NI S T R A TI V E P R O C E D U R E S 
1 6. 1.   
St u d y Site I niti ati o n 
Bef ore s u bjects are scree ne d, K n o p p or its desi g nee will re vie w st u d y res p o nsi bilities wit h t he 
Site I n vesti gat ors a n d ot her st u d y site staff. T he Site I n vesti gat or m ust n ot e nr oll/scree n a n y 
s u bjects pri or t o c o m pleti o n of a st u d y i nitiati o n visit. T he i nitiati o n visit will i ncl u de a detaile d 
revie w of t he pr ot oc ol a n d st u d y assess me nts.  F or mal a p pr o val t o be gi n e nr olli n g s u bjects will 
be pr o vi de d b y K n o p p, or t heir desi g nee. 
1 6. 2.   
Q u alit y Ass ur a nce 
D uri n g a n d/ or after c o m pleti o n of t he st u d y, q ualit y ass ura nce officers na me d b y K n o p p or t he 
reg ulat or y a ut h orities ma y wis h t o perf or m o n-site a u dits. T he Site I n vesti gat or will be e x pecte d 
t o co o perate wit h a n y a u dit a n d t o pr o vi de assista nce a n d d oc u me ntati o n (i ncl u di n g s o urce data) 
as re q ueste d. 
1 6. 3.   
M o nit ori n g of t he St u d y 
T he Site I n vesti gat ors m ust per mit st u d y-relate d m o nit ori n g b y pr o vi di n g direct access t o s o urce 
dat a a n d t o t he s u bjects’ me dical hist ories. 
K n o p p, or its desi g nee, will visit t he Site I n vesti gat or at re g ular i nter vals d uri n g t he c o urse of t he 
st u d y a n d after t he st u d y has c o m plete d, as a p pr o priate. D uri n g t hese visits, C R Fs a n d s u p p orti n g 
d oc u m e ntati o n relate d t o t he st u d y will be re vie we d a n d a n y discre pa ncies or o missi o ns will be 
res ol ve d.  
T he m o nit ori n g visits m ust be c o n d ucte d acc or di n g t o t he a p plica ble I C H a n d G C P g ui deli nes t o 
e ns ure pr ot oc ol a d here nce, q ualit y of data, st u d y dr u g acc o u nta bilit y, c o m plia nce wit h re g ulat or y 
re q uire me nts, a n d c o nti n ue d a de q uac y of t he i n vesti gati o nal site a n d its facilities. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 2  
 
1 7.    
G E N E R A L I N F O R M A TI O N 
K n o p p will be res p o nsi ble f or all a d mi nistrati ve as pects of t his st u d y. 
1 7. 1.   
E xter n al C o ntr act Rese arc h Or g a niz ati o ns 
K n o p p will be res p o nsi ble f or ve n d or o versi g ht of t he selecte d C o ntract Researc h Or ga nizati o n 
(  
    
 will be t he desi g nate d c o ntact f or t he q ualit y e xec uti o n of pr oce d ural 
as pects of t he st u d y.  
1 7. 2.   
Electr o nic or Re m ote D at a C a pt ure 
S u bject i nf or mati o n will be ca pt ure d a n d ma na ge d b y st u d y sites o n electr o nic C R Fs b y a 
we b - base d electr o nic data ca pt ure ( E D C) t o ol. 
1 7 . 3.  
Ce ntr al L a b or at ories f or L a b or at or y Assess me nts 
A ce ntral la b orat or y has bee n selecte d b y K n o p p t o a nal yze all he mat ol o g y, bl o o d c he mistr y, a n d 
uri ne sa m ples c ollecte d f or t his st u d y. F urt her details o n t he c ollecti o n, pr ocessi n g, st ora ge, a n d 
s hi p me nt re q uire me nts of st u d y sa m ples ca n be f o u n d i n t he St u dy Refere nce M a n u al.  
1 7. 4.   
Ce ntr al P h ar m ac o vi gil a nce Or g a niz ati o n 
A Ce ntral P har mac o vi gila nce Or ga nizati o n will be selecte d b y K n o p p as t he p har mac o vi gila nce 
ve n d or f or de x pra mi pe x ole. T he i de ntifie d part ner will be res p o nsi ble f or acti vities relate d t o 
seri o us a d verse e ve nt re p orts fr o m t he Site I n vesti gat ors, i ncl u di n g recei vi n g re p orts, e val uati n g 
rep orts f or f oll o w- u p, e val uati n g e ve nts f or re g ulat or y re p orti n g, a n d disse mi nati n g safet y 
i nf or mati o n o n K n o p p’s be half.  
1 7. 5.   
Ce ntr al F acilit y f or Bi o a n al ytic al ser vices 
Ce ntral researc h/la b orat or y facilities will be selecte d b y K n o p p t o pr o vi de b i oa nal ytical ser vices 
t o perf or m plas ma dr u g c o nce ntrati o n a n d bi o mar ker a nal yses. 
1 7 . 6.  
C h a n ges t o Fi n al St u d y Pr ot oc ol 
All pr ot oc ol a me n d me nts m ust be s u b mitte d t o t he et hics c o m mittee a n d Re g ulat or y A ut h orities 
if re q uire d b y re gi o nal a n d l ocal la w. Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe 
of t he i n vesti gati o n, or t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he I R B bef ore 
i m ple me ntati o n of s uc h m o dificati o ns t o t he c o n d uct of t he st u d y. If re q uire d b y l ocal la w, s uc h 
ame n d me nts m ust als o be a p pr o ve d b y t he a p pr o priate re g ulat or y a ge nc y pri or t o 
i m ple me ntati o n. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 3  
 
H o we ver, K n o p p ma y at a n y ti me, a me n d t his pr ot oc ol t o eli mi nate a n a p pare nt i m me diate 
hazar d t o a s u bject. I n t his case, t he a p pr o priate re g ulat or y a ut h orities will be n otifie d s u bse q ue nt 
t o t he a me n d me nt, i n acc or da nce wit h l ocal re g ulati o ns. 
I n t he e ve nt of a pr ot oc ol m o dificati o n, t he s u bject c o nse nt f or m ma y re q uire si milar 
m o dificati o ns ( See Secti o n 1 5. 1  a n d Secti o n 1 5. 2 ). 
1 7 . 7.  
I R B N otific ati o n of St u d y C o m pleti o n or Ter mi n ati o n 
W here re q uire d, t he Healt h A ut h orities a n d I R Bs m ust be n otifie d of c o m pleti o n or ter mi nati o n 
of  t his st u d y. As re q uire d b y l ocal la ws, a c o p y of t he st u d y re p ort s y n o psis will be pr o vi de d t o 
t he I R B i n acc or da nce wit hi n t he l ocal ti meli ne re q uire me nts. 
1 7 . 8.  
Rete nt i o n of St u d y D at a 
T he Site I n vesti gat or m ust mai ntai n all Esse ntial D oc u me nts (as liste d i n t he I C H G ui deli ne f or 
G C P) u ntil n otifie d b y K n o p p a n d i n acc or da nce wit h all re gi o nal a n d l ocal la ws re gar di n g 
rete nti o n of rec or ds. 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 4  
 
1 8.    
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L 
I ha ve rea d t he f ore g oi n g pr ot oc ol, “ A ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d d ose-
ra n gi n g bi o mar ker st u d y of t he effects of de x pra mi pe x ole o n e osi n o p hils i n s u bjects wit h 
e osi n o p hilic ast h ma”    
, a n d a gree t o c o n d uct t he st u d y acc or di n g t o t he pr ot oc ol a n d 
t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m all w h o assist me i n t he 
c o n d uct of t his st u d y of t heir res p o nsi bilities a n d o bli gati o ns. 
 
 
 
    
 
 
Site I n vesti gat or’s Si g nat ure 
    
Date 
 
 
 
Site I n vesti gat or’s Na me ( Pri nt) 
 
 
  
I nstit uti o n ( Pri nt) 
 
 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 5  
 
1 9.  
A P P E N D I X A: S E L E C T E D D R U G S K N O W N T O H A V E 
S U B S T A N TI A L RI S K O F N E U T R O P E NI A 1 9, 2 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, 
 
htt p:// w w w. u pt o d ate.c o m/c o nte nts/ dr u g -i n d uce d-ne utr o pe ni a -a n d -a gr a n ul ocyt osis  
 
 

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 6  
 
2 0.    
R E F E R E N C E S 
  
 
1.    
Gl o bal Strate g y f or Ast h ma Ma na ge me nt a n d Pre ve nti o n ( 2 0 1 8 u p date). 2 0 1 8.] A vaila ble 
fr om htt ps:// gi nast h ma. or g . 
2.     
Lai dla w T M, et al. De x pra mi pe x ole de pletes bl o o d a n d tiss ue e osi n o p hils i n nasal p ol y ps 
wit h n o c ha n ge i n p ol y p size. Lar y n g osc o pe 2 0 1 9; 1 2 9: E 6 1- E 6. 
3.    
Orte ga H G, et al. Me p oliz 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 M e d 2 0 1 4; 3 7 1: 1 1 9 8- 2 0 7. 
4.    
Bleec ker E R, et al. Efficac y a n d safet y of be nraliz u ma b f or patie nts wit h se vere ast h ma 
u nc o nt r olle d wit h hi g h- d osa ge i n hale d c ortic oster oi ds a n d l o n g-acti n g beta 2-a g o nists 
( SIR O C C O): a ra n d o mise d, m ultice ntre, place b o-c o ntr olle d p hase 3 trial. La ncet 2 0 1 6; 
3 8 8: 2 1 1 5- 2 7. 
5.    
Castr o M, 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 osin 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 hase 3 trials. La ncet Res pir Me d 2 0 1 5; 3: 3 5 5- 6 6. 
6.    
Fitz Geral d J M, et al. Be nraliz u ma b, a n a nti-i nterle u ki n- 5 rece pt or al p ha 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 vere, u nc o ntr olle d, e osi n o p hilic ast h ma 
( C A LI M A): a ra n d o mise d, d o u ble- bli n d, place b o-c o ntr olle d p hase 3 trial. La ncet 2 0 1 6; 
3 8 8: 2 1 2 8- 4 1. 
7.    
Ya nce y S W, et al. Bi o mar kers f or se vere e osi n o p hilic ast h ma. J Aller g y Cli n I m m u n ol 
2 0 1 7; 1 4 0: 1 5 0 9- 1 8. 
8.    
D w oretz k y SI, et al. T he tar gete d e osi n o p hil-l o weri n g effects of de x pra mi pe x ole i n 
cli nical st u dies. Bl o o d Cells M ol Dis 2 0 1 7; 6 3: 6 2- 5. 
9.    
Marti nez F D, et al. Ast h ma. La ncet 2 0 1 3; 3 8 2: 1 3 6 0- 7 2. 
1 0.   
C o u m o u H, et al. I m pr o vi n g t he dia g n osis of e osi n o p hilic ast h ma. E x pert Re v Res pir 
Me d 2 0 1 6;  1 0: 1 0 9 3- 1 0 3. 
1 1.    
Mc Brie n C N, et al. T he Bi ol o g y of E osi n o p hils a n d T heir R ole i n Ast h ma. Fr o nt Me d 
( La usa n ne) 2 0 1 7; 4: 9 3. 
1 2.   
Pa nc h S R, et al. De x pra mi pe x ole as a n oral ster oi d-s pari n g a ge nt i n h y pere osi n o p hilic 
s y n dro mes. Bl o o d 2 0 1 8; 1 3 2: 5 0 1- 9. 
1 3.   
Price D B, 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 ncet Res pir Me d 2 0 1 5; 3: 8 4 9- 5 8. 
1 4.    
Fitz Geral d J M, et al. Pre dict ors of e n ha 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 ncet Res pir 
Me d 2 0 1 8; 6: 5 1- 6 4. 
1 5.   
Fitz Geral d J M, et al. Ast h ma c o ntr ol i n Ca na da re mai ns s u b o pti mal: t he Realit y of 
Ast h m a C o ntr ol ( T R A C) st u d y. Ca n Res pir J 2 0 0 6; 1 3: 2 5 3- 9. 
1 6.   
C ha p ma n K R, et al. S u b o pti mal ast h ma c o ntr ol: pre vale nce, detecti o n a n d c o nse q ue nces 
i n general practice. E ur Res pir J 2 0 0 8; 3 1: 3 2 0- 5. 
1 7.   
I nter nati o nal C o nfere nce o n Har m o nisati o n. E 4: D ose- Res p o nse I nf or mati o n t o S u p p ort 
Dr u g Re gistrati o n. 1 9 9 4.  

Pr ot oc ol K N S- 7 6 0 7 0 4- A S 2 0 1 
 
Effects of de x pra mi pe x ole o n e osi n o p hil bi o mar kers i n ast h ma 
J ul y 1 6, 2 0 1 9 
C O N FI D E N TI A L 
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of  
K n o p p Bi oscie nces L L C 
8 7  
 
1 8.    
U. S. F o o d a n d Dr u g A d mi nistrati o n. E x p os ure- Res p o nse Relati o ns hi ps: St u d y Desi g n, 
Data A nal ysis, a n d Re g ulat or y A p plicati o ns- G ui da nce f or I n d ustr y. 1 9 9 3. 
1 9.    
A n ders o h n F, et al. S yste matic re vie w: a gra n ul oc yt osis i n d uce d b y n o nc he m ot hera p y 
dr u gs . A n n I nter n Me d 2 0 0 7; 1 4 6: 6 5 7- 6 5. 
2 0.   
C oates T D. Dr u g-i n d uce d ne utr o pe nia a n d a gra n ul oc yt osis. U p T o Date, 2 0 1 9. 
2 1.    
Re d del H K, et al. A n official A merica n T h oracic S ociet y/ E ur o pea n Res pirat or y S ociet y 
state me nt: ast h ma c o ntr ol a n d e xacer bati o ns: sta n dar dizi n g e n d p oi nts f or cli nical ast h ma 
trials a n d cli nical practice. A m J Res pir Crit Care Me d 2 0 0 9; 1 8 0: 5 9- 9 9. 
2 2.   
Te p per R S, et al. Ast h ma o utc o mes: p ul m o nar y p h ysi ol o g y. J Aller g y Cli n I m m u n ol 
2 0 1 2; 1 2 9: S 6 5- 8 7. 
2 3.    
Miller M R, et al. Sta n dar disati o n of s pir o metr y. E ur Res pir J 2 0 0 5; 2 6: 3 1 9- 3 8. 
2 4.   
J u ni per E F, et al. De vel o p me nt a n d vali dati o n of a q uesti o n naire t o meas ure ast h ma 
c o ntr ol. E ur Res pir J 1 9 9 9; 1 4: 9 0 2- 7. 
2 5.   
J u ni per E F, et al. Vali dati o n of a sta n dar dize d versi o n of t he Ast h ma Q ualit y of Life 
Q uesti o n naire. C hest 1 9 9 9; 1 1 5: 1 2 6 5- 7 0. 
2 6.   
B o xer L A. H o w t o a p pr oac h ne utr o pe nia. He mat ol o g y A m S oc He mat ol E d uc Pr o gra m 
2 0 1 2; 2 0 1 2: 1 7 4 - 8 2. 
2 7.    
Ne w b ur ger P E, et al. E val uati o n a n d ma na ge me nt of patie nts wit h is olate d ne utr o pe nia. 
S e mi n He mat ol 2 0 1 3; 5 0: 1 9 8- 2 0 6. 
2 8.   
Pal m bla d J, et al. H o w we dia g n ose a n d treat ne utr o pe nia i n a d ults. E x pert Re v He mat ol 
2 0 1 6; 9: 4 7 9- 8 7. 
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