Clinical trial NCT04046939
Conditions: Eosinophilic Asthma Asthma
Keywords: Eosinophilic Asthma Asthma dexpramipexole
Sponsor: Knopp Biosciences
Start date: 2019-08-15; Completion date: 2021-03-02
Enrollment: 534 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, multi-center study to evaluate the clinical effects of oral administration of dexpramipexole for 12 weeks on peripheral blood eosinophil count in subjects with eosinophilic asthma.

Detailed description:
One hundred subjects will receive study drug or matching placebo over 12 weeks of consecutive dosing. Following a short Run-in Period, eligible subjects will enter the Primary Assessment Period and receive twice-daily dosing of study drug or placebo for 12 weeks. Following 12 weeks of treatment, subjects will enter a 12-week Eosinophil Recovery Period. The primary endpoint for the study is the change in blood absolute eosinophil count from Baseline to Week 12.

Arms: arm 1: Following a 2-4 week placebo run-in, randomized subjects received 1 tablet placebo twice daily for 12 weeks. arm 2: Following a 2-4 week placebo run-in, randomized subjects received 1 tablet of 37.5 mg dexpramipexole twice daily for 12 weeks. arm 3: Following a 2-4 week placebo run-in, randomized subjects received 1 tablet of 75 mg dexpramipexole twice daily for 12 weeks. arm 4: Following a 2-4 week placebo run-in, randomized subjects received 1 tablet of 150 mg dexpramipexole twice daily for 12 weeks.
Interventions: intervention 1: Dexpramipexole intervention 2: Placebo
Intervention descriptions: intervention 1: dexpramipexole twice daily oral dosing for up to 12 weeks intervention 2: placebo twice daily oral dosing for up to 12 weeks

Protocol documents:
Prot_000.pdf: 
 
 
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 
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 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 
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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 
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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 
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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 
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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 
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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. 
2 9.   
Berli ner N. Ma na ge me nt of t he a d ult wit h n o nc he m ot hera p y-i n d uce d- 
ne utr o pe nia. U p T o Date, 2 0 1 9. 
3 0.   
I nter nati o nal C o nfere nce o n Har m o nisati o n. E 1 4: 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. 2 0 0 5. 
 

SAP_001.pdf: 
  
 
 
Statistical Analysis Plan 
A Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Biomarker 
Study of the Effects of Dexpramipexole on Eosinophils in Subjects with 
Eosinophilic Asthma 
 
SAP Status: Final  
SAP Date: 22 December 2020 
Investigational Product: Dexpramipexole (KNS-760704) 
Protocol Reference: KNS-760704-AS201 
 
 
 
Sponsor: 
Knopp Biosciences LLC 
2100 Wharton Street, Suite 615 
Pittsburgh, PA 15203 
Study Site: Multiple sites 
 
 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 


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TABLE OF CONTENTS 
TITLE PAGE ..................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................... 2 
FIGURES & TABLES........................................................................................................ 3 
LIST OF ABBREVIATIONS ............................................................................................. 4 
1. STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................... 6 
2. INTRODUCTION .......................................................................................................... 7 
3. STUDY OBJECTIVES ................................................................................................... 7 
Primary Objective........................................................................................................ 7 
Secondary Objectives .................................................................................................. 7 
Exploratory Objectives ................................................................................................ 8 
4. STUDY ENDPOINTS .................................................................................................... 8 
Primary Endpoint ........................................................................................................ 8 
Secondary Endpoints ................................................................................................... 8 
Exploratory Endpoints ................................................................................................. 8 
5. STUDY DESIGN ........................................................................................................... 9 
6. SAMPLE SIZE JUSTIFICATION .................................................................................10 
7. STUDY TREATMENTS ...............................................................................................10 
8. DEFINITIONS OF ANALYSIS POPULATIONS ..........................................................11 
8.1. All Subjects Population ...........................................................................................11 
8.2. Safety Population ....................................................................................................11 
8.3. Efficacy Population .................................................................................................11 
8.4. Recovery Phase Population ......................................................................................12 
8.5. Per-protocol Population ...........................................................................................12 
8.6. PK Population .........................................................................................................12 
9. STATISTICAL METHODOLOGY................................................................................12 
9.1. General ...................................................................................................................12 
9.1.1. Calculation of the Summary Statistics ................................................................13 
9.1.2. Triplicate Readings ...........................................................................................13 
9.1.3. Repeat and Unscheduled Readings.....................................................................13 
9.1.4. Definitions of Baseline, Change from Baseline, and Percentage Change from 
Baseline .....................................................................................................................14 
9.2. Spirometry ..............................................................................................................15 


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9.3. Subject Disposition and Population Assignment .......................................................16 
9.4. Screening Demographics and Baseline Characteristics ..............................................16 
9.5. Study Drug Details ..................................................................................................16 
9.6. Prior and Concomitant Medication ...........................................................................17 
9.7. Pharmacokinetic/Efficacy Assessments ....................................................................17 
9.8. Efficacy Assessments ..............................................................................................17 
9.8.1. General Methods of Analysis.............................................................................17 
9.8.2. Interim Analysis (IA) of the Primary Assessment Phase .....................................18 
9.8.3. Primary Endpoint Analyses ...............................................................................19 
9.8.4. Secondary Endpoint and Exploratory Endpoint Analyses....................................21 
9.9. Safety and Tolerability Assessments ........................................................................24 
9.9.1. Adverse Events .................................................................................................24 
9.9.2. Hematology Parameters, including Neutrophil Count .........................................26 
9.9.3. Clinical Laboratory Parameters..........................................................................26 
9.9.4. Vital Signs Parameters ......................................................................................27 
9.9.5. 12-lead Electrocardiogram Parameters ...............................................................28 
9.9.6. Protocol Deviations ...........................................................................................32 
9.9.7. Other Assessments ............................................................................................34 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........34 
11. REFERENCES ............................................................................................................35 
12. APPENDICES .............................................................................................................36 
 
FIGURES & TABLES 
Figure 1: 
Study Schematic ........................................................................................10 
Figure 2: 
ATS Spirometry Grading System ...............................................................15 
Figure 3: 
Protocol Deviation Processing....................................................................33 
 
Table 1: 
Presentation of Study Treatments in TFLs ..................................................11 
Table 2: 
List of Potentially Clinically Significant Laboratory Findings .....................27 
Table 3: 
Vital Sign Criteria for Abnormality ............................................................28 
Table 4: 
Protocol Deviations ...................................................................................32 
 


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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ACQ 
Asthma Control Questionnaire 
ADaM 
analysis data model 
AE 
adverse event 
AEC 
absolute eosinophil count 
 
 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AQLQ 
Asthma Quality of Life Questionnaire 
AV 
atrioventricular 
CBC 
complete blood count 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
ECG 
electrocardiogram 
FeNO 
exhaled nitric oxide 
GINA 
Global Initiative for Asthma 
GEE 
Generalized Estimating Equations 
HR 
heart rate 
IA 
interim analysis 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MMRM 
mixed-effect model, repeated-measures 
PCS 
potentially clinically significant 
PD 
Protocol deviation 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 


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QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RIM 
Risk and Issues Management 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
standard error 
SI 
International System of Units 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
WHODrug 
World Health Organization Drug Dictionary  
 




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2. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (
 
dated 16 July 2019) and electronic case report form. 
This SAP describes the planned analysis of the pharmacokinetic (PK), efficacy and safety, 
and tolerability data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shells 
document. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Knopp Biosciences LLC. A limited amount of information about 
this study (eg, objectives, study design) is given to help the reader’s interpretation. This SAP 
must be finalized prior to the lock of the clinical database for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR. 
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified and substantiated. If 
additional analyses are required to supplement the planned analyses described in this SAP, 
they may be performed and will be identified accordingly in the CSR. Any substantial 
deviations from this SAP will be approved by Knopp Biosciences LLC and detailed in the 
CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2 
The SAP history is presented in Appendix 1. 
3. STUDY OBJECTIVES 
Primary Objective 
The primary objective of this clinical trial is to evaluate the efficacy of dexpramipexole in 
reducing blood eosinophil count in subjects with eosinophilic asthma. 
Secondary Objectives 
The secondary objectives are as follows: 
● To evaluate the safety and tolerability of dexpramipexole administered for 12 weeks 
in subjects with eosinophilic asthma 
● To evaluate the efficacy of dexpramipexole on pulmonary function, asthma control, 
and quality of life 
● To evaluate the relative effect of dexpramipexole 75 mg/day, 150 mg/day, and 
300 mg/day on blood eosinophil count 






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A schematic of the study design is presented in Figure 1. 
Figure 1: Study Schematic 
 
 
6. SAMPLE SIZE JUSTIFICATION 
The primary endpoint for this study is reduction in blood eosinophils from Baseline to 
Week 12. In an open label study of dexpramipexole in subjects with chronic rhinosinusitis 
with nasal polyps, dexpramipexole reduced eosinophils by 94% (ratio of endpoint to 
baseline = -2.81 on the log base e scale). The standard deviation for the ratio of endpoint to 
baseline was 1.82 on the log base e scale. 
Nineteen subjects per arm will provide approximately 84% power if the true reduction in 
blood eosinophils is 85% with dexpramipexole and 10% with placebo. The power will be 
95% if the true reduction in blood eosinophils is 90% with dexpramipexole and 10% with 
placebo. The sample size was calculated using methodology for a two-sample t-test. 
Assuming an approximate 20% dropout rate of subjects who do not have the final observation 
for blood eosinophils yields a sample size of 25 subjects per arm to be randomized. 
7. STUDY TREATMENTS 
The study treatment names and ordering to be used in the TFLs are presented in the table 
below. 




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For the analysis of ACQ-7 (which includes an FEV1 item) the MMRM analysis will exclude 
subjects if they were missing both Week 8 and week 12 FEV1 due to COVID-19. 
Selected outputs as noted in the accompanying TFL shells document will be created for the 
subset of subjects in the efficacy population who were also hematological responders. 
8.4. Recovery Phase Population 
The Recovery Phase population consists of all subjects in the efficacy population who 
completed the Week 16/18 visit (started the Eosinophil Recovery Phase).  
8.5. Per-protocol Population 
The per-protocol population will include all subjects in the efficacy population who have an 
evaluable Week 8 or Week 12 AEC result while on study drug and had adherence ≥80% 
(based on number of tablets returned by subject compared to number expected to be taken 
during the period), and excludes subjects treated with systemic corticosteroids during the 
Primary Assessment Phase. Subjects that had a Baseline eosinophil count of ≤0.05x109/L at 
the Baseline visit lab draw will be excluded from the per protocol analysis, due to the lability 
of their eosinophil count prior to study drug.   
Prior to the IA snapshot and release of treatment codes for the interim analysis, a final 
determination will also be made as to which subjects will be excluded from the per-protocol 
population. This definition may not be modified after the IA snapshot. 
8.6. PK Population 
The PK population will consist of all subjects in the safety population who have at least 1 
quantifiable PK concentration. 
9. STATISTICAL METHODOLOGY 
9.1. General 
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all subjects population and include all available data. Any subject 
who discontinued from the study will be identified accordingly in the listings. Summaries and 
statistical analyses will include the subjects assigned to the relevant population based on data 
type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study). 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  


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Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, percentage changes 
from baseline, and any parameter derivations. 
9.1.1. Calculation of the Summary Statistics 
For continuous data the following rules will be applied: 
● Missing values will not be imputed, unless specifically stated otherwise. 
● Unrounded data will be used in the calculation of summary statistics. 
● If number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum 
Subjects who discontinue study drug prematurely will be asked to return within 4 days of the 
last dose of study drug for a premature discontinuation visit. Data will be assigned to the 
nearest scheduled visit, if the nearest scheduled visit is Week 12 then data will not be 
included in the Week 12 analyses if it occurred after Study Day 95. 
For categorical data the following rules will be applied: 
● If the categories of a parameter are ordered (eg, AE severity), all categories between 
the possible minimum and maximum categories will be included, even if n = 0 for a 
given category. If the categories are not ordered (eg, race), only those categories for 
which there is at least 1 subject represented will be included. 
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 9.9.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is 
missing. This will ensure that the population size totals are consistent across different 
parameters. 
9.1.2. Triplicate Readings 
For electrocardiogram (ECG) data only, where triplicate readings are intended to be taken, 
the mean of triplicate readings will be used in calculations. 
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean based on the number of readings available will be used in calculations. 
9.1.3. Repeat and Unscheduled Readings 
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the planned value(s) will be defined as an unscheduled value. 
For lab data, unscheduled data will be attributed to the nearest visit and for the visit-wise 
summaries and statistical analyses the last non-missing result within a visit will be used for 
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that value will be used for the visit-wise summaries and statistical analyses, if there was not 
then the last non-missing result mapped to Week 12 will be used. 
For non-lab data, unscheduled data will be attributed to the nearest visit and for the visit-wise 
summaries and statistical analyses the last non-missing result within a visit will be used. For 
occasions when a retest was performed, the data from the retest will be mapped to the 
appropriate visit and considered for inclusion in the analysis according to the rules specified 
in other sections of the SAP (i.e. for spirometry data after considering the rules detailed in 
section 9.2 and for other data using the last valid observation within a visit window).  
Unscheduled data for a specific data type (PARAMCD) is only mapped to visits where that 
data type was scheduled to be taken by the protocol Schedule of Events.  Unscheduled data 
will only be mapped to the last scheduled visit for a datatype if it is closer to that visit than to 
a subsequent visit where that procedure was not scheduled, otherwise it will be mapped to the 
nearest visit. Summaries and statistical analyses will only contain the specific protocol 
specified visits for each datatype.  
For the analysis of outliers (shifts) and potentially clinically significant changes (labs, vital 
signs, and ECGs) all data will be used including unscheduled values.  
9.1.4. Definitions of Baseline, Change from Baseline, and Percentage Change from 
Baseline 
Baseline will be defined as the last valid value recorded prior to the first randomized dose of 
study drug, except for blood absolute eosinophil count, for which the Baseline value will 
consist of the geometric mean of all eosinophil counts obtained prior to the first randomized 
dose of study drug. If the date of the value is missing, it will be excluded from the Baseline 
calculation. If the time is incomplete/missing, and if it was an assessment scheduled to occur 
predose, it will still be considered as Baseline unless the incomplete date/time indicates the 
value was recorded after the first randomized dose of study drug. During the Recovery Phase 
data will be compared to Baseline values as detailed above. 
Individual changes from Baseline will be calculated by subtracting the individual subject’s 
Baseline value from the value at the timepoint. The mean change from Baseline will be 
defined as the mean of the individual changes from Baseline for all subjects. 
Individual percentage changes from Baseline will be calculated by subtracting the individual 
subject’s Baseline value from the value at the timepoint, then dividing this calculated value 
by the individual subject’s Baseline value and multiplying by 100. The mean percentage 
change from Baseline will be defined as the mean of the individual percentage changes from 
Baseline for all subjects.  
For Log transformed data geometric means and geometric means of the ratio of observed 
value to Baseline will be presented. The geometric mean ratio will be calculated by 
subtracting the log of the Baseline value from the log of the result at a specific visit, then 
taking the mean, then taking the antilog to get geometric mean ratio. The CI are calculated on 
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See Section 9.1.3 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 9.1.2 for more detail on handling of triplicate readings in the 
calculations. 
9.2. Spirometry 
In accordance with professional guidelines available when study specifications were drafted, 
spirometry results were over-read by an independent vendor in accordance with American 
Thoracic Society/European Respiratory Society (ATS/ERS) Standardization of Spirometry 
2005 (Eur Respir J. 2005 Aug;26(2):319-38. doi: 10.1183/09031936.05.000348053). 
For these statistical analyses, subsequently published professional guidelines for grading 
FEV1 and FVC were applied (Standardization of Spirometry 2019 Update. An Official 
American Thoracic Society and European Respiratory Society Technical Statement. Am J 
Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88. doi: 10.1164/rccm.201908-1590ST)4; 
see Figure 2. Screening, Baseline, and Week 12 with either an FEV1 or FVC grade of less 
than A were repeated, if possible (codified in RAPID memo C101104101-626, 2/17/2020) 
(where RAPID stands for Risk, Actions, Protocol Deviations, Issues and Decisions). 
The 
 medical monitor will review the Vitalograph over-read and using the ATS/ERS 
grading system assign an FEV1 score to each spirometry session. 
Figure 2: ATS Spirometry Grading System 
 
Within a given visit window, the following hierarchy will designate which spirometry results 
will be used for statistical analyses. 
● Sessions with an “ACCEPTED” value in the SESSACC field. 
● Sessions with an “A” value in the “FEV1GRADE” field (using FEV1 grading above) 
● Sessions with an “B” value in the “FEV1GRADE” field (using FEV1 grading above) 
● Sessions with an “C” value in the “FEV1GRADE” field (using FEV1 grading above) 
Results from the above will be utilized according to the following data handling 
procedures and study visit windowing rules.  


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• If 2 sessions within a given visit window both have the same grade and that is the 
highest grade in the window, the latter session will be used in the analysis.   
• The choice of which prebronchodilator and/or post-bronchodilator sessions will be 
used in the analysis will be independently based on selecting the highest graded 
session for each test type, and not necessarily a session that corresponds to the 
same date of the other test type.  
• Any session with an FEV1 grade of D-F or U will be excluded from the analyses.  
• All grading of Week 12 spirometry will be completed before the IA snapshot. 
9.3. Subject Disposition and Population Assignment 
Subject disposition and population assignment will be listed. 
A summary table by treatment will be provided, based on the all randomized subjects 
population. 
9.4. Screening Demographics and Baseline Characteristics 
Demography, medical history and baseline disease characteristic data (duration of symptoms, 
severity of symptom scores, concomitant medication at baseline, etc.) will be summarized at 
study Baseline for the safety population and repeated for the efficacy and per-protocol 
populations.  
Sex, race, and ethnicity will be summarized using counts and percentages. Age, height (cm), 
weight (kg), and body mass index (kg/m2; calculated) will be summarized with descriptive 
statistics (number of subjects [n], mean, standard deviation [sd], median, minimum, and 
maximum). Age will also be summarized according to the categories of less than 50 years, 50 
to 65 years, and more than 65 years, using counts and percentages.  
9.5. Study Drug Details 
Randomization details will be listed. Details of randomized study drug allocation and 
administration will be listed along with adherence. Descriptive statistics will be provided for 
duration of dosing (days) and mean daily dose (mg) of study drug by treatment. The 
frequencies of duration of exposure will also be provided in monthly intervals.  
A frequency table by treatment will be provided for study drug adherence according to the 
following categories: 
● <60% 
● ≥60% and <80% 
● ≥80% and <120% 
● ≥120% 
● >90% and <105% 
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9.6. Prior and Concomitant Medication 
Medications classified as present at baseline are all medications taken prior to the date of first 
dose of randomized study drug which are either ongoing or with a stop date after the first day 
of randomized dosing. Concomitant medications include all medications present at baseline 
and all medications with a start date on or after the date of first dose of randomized study 
medication and prior to or on the date of last dose of randomized study medication. For 
inclusion in the summary of concomitant medications during the Primary Assessment Phase, 
the medication start date must be on or before the date of completion or date of 
discontinuation of the Primary Assessment Phase. Medications with a start date on or after 
the start date of the Recovery Phase will not be included in the summary of concomitant 
medications for the Primary Assessment Phase. 
If the end date/time of a medication is incomplete or missing it will be assumed to be 
concomitant unless the incomplete end date/time indicates the medication finished prior to 
the first dose of randomized study drug or the start date indicates it started in the Recovery 
Phase. 
Baseline and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHODrug) Global, Format B3, Version March 2019 (or later if 
upversioned during the study). Baseline and concomitant medications will be summarized by 
ATC Class, Preferred Term and treatment and listed. For the summaries subjects will only be 
counted once per ATC Class and Preferred Term. All baseline and concomitant medication 
will be listed. A separate listing will also be provided for subjects that changed ICS/LABA 
Inhaler Medication during the study (either the type of the medication or the dose). 
9.7. Pharmacokinetic/Efficacy Assessments 
Dexpramipexole concentrations in plasma will be summarized using means, SD, standard 
error of the mean, coefficient of variation, minimum, median, and maximum by treatment per 
visit. The mean of the trough concentrations at Weeks 4, 8 and 12 will be calculated for each 
individual subject and will also be summarized by treatment. A scatterplot of dexpramipexole 
trough concentrations (mean of the 3 trough samples) in plasma will be used to evaluate the 
relationship between dexpramipexole exposure and eosinophil-lowering response at Week 
12. Additional analyses may also be performed following review of the study data. 
A scatterplot of dexpramipexole concentrations in plasma versus change from baseline in 
heart rate (∆HR) and QTc interval (∆QTcF) will also be created for Week 8, predose and 2 h 
12-lead values versus observed dexpramipexole concentrations at the same time points.   
9.8. Efficacy Assessments 
9.8.1. General Methods of Analysis  
The study will use a blocked randomization stratified by study site. Due to the large number 
of study sites and the expected small number of subjects at each site, the data from all sites 
will be pooled. Site will not be included in any of the statistical analysis models. The safety 
population will be used for all safety analyses and the efficacy population will be used for 


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efficacy analyses. Descriptive statistics, including means, medians, and standard error will be 
presented for efficacy measures for observed values and changes from baseline by scheduled 
evaluation time and treatment group. If the endpoint is one that requires a log transformation, 
then descriptive statistics will be geometric means and ratios. If the endpoint is one that 
requires a rank transformation, then descriptive statistics will be median and intra-quartile 
values.  
To control the alpha level for testing three dose groups versus placebo for the primary 
endpoint and for testing FEV1, a closed hierarchical testing procedure will be used in the 
following order:  
1) First, the 300mg/day dose group will be tested versus placebo for change in blood 
absolute eosinophil count at Week 12, and if this reaches the <0.05 level then,  
2) the 150 mg/day dose group will be tested versus placebo at the 0.05 level for 
change in blood absolute eosinophil count at Week 12, and if this reaches the 
<0.05 level then, 
3) the pooled 150 and 300 mg/day dose groups will be tested versus placebo at the 
0.05 level for change in pre-bronchodilator FEV1 at Week 12 then, 
4) the 75 mg/day dose group will be tested versus placebo at the 0.05 level for 
change in blood absolute eosinophil count at Week 12, and if this reaches the 
<0.05 level. 
Statistical testing for the other secondary study endpoints will be performed at the 0.05 level 
without adjustment. 
The primary endpoint and the secondary endpoints will also be analyzed using the per-
protocol population. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to half of x, whereas >x and ≥x values will be set to x. 
9.8.2. Interim Analysis (IA) of the Primary Assessment Phase 
There will be an interim analysis of efficacy after the final subject has completed the Primary 
Outcome Visit (Week 12). The interim analysis will include the analyses of the primary and 
secondary efficacy endpoints through the Primary Outcome Visit (Week 12), but will also 
include a review of all available safety and clinical laboratory data, including all available 
data collected from subjects visits beyond Week 12.  
An unblinded statistics and programming team will be assembled to perform the interim 
analysis. The primary statistics and programming study team will retain responsibility for 
performing the final study analyses and will not have access to the IA results and will remain 
blinded until the final database lock.  
The data management, clinical and medical teams responsible for cleaning and performing 
the IA snapshot of the data for the interim analysis will not have access to the IA results and 


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will not have access to treatment assignments following the interim analysis.  However, the 
sponsor 
 will have access to the unblinded results and the treatment codes 
following the IA snapshot for the interim analysis.  
At the time of the interim analysis, it is expected that 100% of subjects will have completed 
the study through the Primary Outcome Visit (Week 12).  Furthermore, approximately 50% 
of subjects will also have completed the study through the end of the Eosinophil Recovery 
Phase (Week 24).  The remaining active subjects at the time of the interim analysis will be 
active in the Eosinophil Recovery Phase between Week 12 and Week 24 visits. 
Prior to the release of unblinded treatment codes for the interim analysis, all available data in 
the study database will be cleaned and there will be a formal snapshot of the database. This 
includes collection and cleaning of all data from all subject visits completed prior to the final 
subject randomized completing the Primary Outcome Visit (Week 12). 
Prior to the IA snapshot and release of treatment codes for the interim analysis, a final 
determination will also be made as to which subjects will be excluded from the per-protocol 
population. This definition may not be modified after the IA snapshot. 
There will be no adjustment of p-values for the interim analysis because all subjects will have 
completed the Primary Assessment Phase and the results of the final analysis of efficacy 
through the Primary Assessment Phase should be identical to the results of the interim 
analysis of efficacy through the Primary Assessment Phase. Any changes to the efficacy 
results between the interim analysis of efficacy through Week 12 and the final analysis of 
efficacy through Week 12 will be noted, although none is expected.  
At the same time an analysis of available safety data will be completed: Incidence of AEs and 
AEs leading to discontinuation of study drug; potentially clinically significant changes in 
vital signs, neutrophils; LFTs, and ECGs. This includes data from all subject all visits 
populated in the study database at the time of the interim analysis, 
Safety data from this analysis may be updated for the final analysis, for instance, if an AE 
that was ongoing at Week 12 resolves by the end of the Eosinophil Recovery Phase (final 
database lock). After all subjects complete the End of Study Visit (Week 24), the study 
database will be locked, and the final analysis will be completed see below sections. 
9.8.3. Primary Endpoint Analyses 
The primary endpoint of this study is the change in blood absolute eosinophil count from 
Baseline to Week 12. Absolute eosinophil count will be transformed to the log10 scale. To 
avoid taking the log of zero, zero values (not null values) will be replaced with 5/µL in 
conventional units or 0.005×109/L in the International System of Units (SI), which is 50% of 
the lower limit of quantification. The geometric mean of all eosinophil counts obtained 
between the Screening and Baseline visits will be used to establish the baseline eosinophil 
count used in the efficacy analyses. Geometric means and standard errors will be presented 
by treatment group for observed values ratio to baseline at each visit along with a p-value 
comparing each dexpramipexole treatment group to placebo (ratio to baseline) based on an 
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A Generalized Estimating Equations (GEE) model will be used to analyze the proportion of 
subjects with an AEC of ≤0.05x109/L over time to obtain an estimate of the treatment effect 
and p-value at Week 12. Parameters will be included for treatment, time and the treatment by 
time interaction and GINA as a covariate. A similar analysis will be performed for the 
proportion of subjects with a ≥ 90% reduction of AEC. 
The number and percentage of subjects with eosinophil count rebound (defined as an 
eosinophil count of >1.00x109/L (1000 cells/μL) and >200% of the baseline value during the 
Eosinophil Recovery Phase) will be presented by treatment and timepoint. 
Geometric mean (standard error) profiles for eosinophil counts and ratios to baseline will be 
plotted. 
Eosinophil count recovery (hematologic responders only) will be summarized in a frequency 
table with the number and percentage of subjects who have Eosinophil Count ≥50% of 
Baseline and will be presented from Week 12 to Week 24.  
The ratio to baseline in eosinophil counts will be plotted versus days since last dose of 
randomized study drug for the Recovery Phase population (hematologic responders only) 
including a lowess regression line.  
A scatterplot of change from baseline in FEV1 (y-axis) will be plotted versus the ratio to 
baseline in eosinophil count (x-axis log10 scale). A regression line and appropriate 
correlation coefficient will be added to the figure if appropriate. 
Data for the following endpoints including changes from baseline will be summarized using 
descriptive statistics by treatment and timepoint:  
● Pre and post-bronchodilator Spirometry data (including reversibility) 
● ACQ-7 and ACQ-6 
● AQLQ 
● Basophils 
● Eosinophil Progenitors 
● Nasal Eosinophil Peroxidase 
● Pharyngeal Eosinophil Peroxidase 
● Exhaled Nitric Oxide Test (FeNO) 
During the COVID-19 pandemic, pulmonary function testing was temporarily suspended, 
therefore there will be missing data for FEV1, which also contributes to question 7 of the 
ACQ-7. To minimize the amount of lost data the ACQ-6 will be used as the primary 
assessment of asthma symptoms.  
For ACQ-7, if the 7th item has a missing score then the corresponding total score will be set 
to missing. 


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For MMRM analysis of FEV1 the analysis will be performed excluding all results from 
subjects missing both Week 8 and week 12 FEV1 due to COVID-19 exigencies. Due to its 
known pharmacodynamics, dexpramipexole is unlikely to show an effect on FEV1 at the 
week 4 visit and including only week 4 data may lead to misleading bias against 
demonstrating treatment effect; that, the exclusion should not introduce and should eliminate 
bias. Subjects who are missing FEV1 results due to other reasons will be included in the 
analysis.  An analysis of all subjects in the efficacy population will also be performed. 
Additionally, an exploratory analysis of spirometry data using the MMRM analysis will be 
performed including Week 16/18 data in the place of missing Week 12 data, for those 
subjects missing both Week 8 and Week 12 spirometry. 
For MMRM analysis of ACQ-7 the analysis will also be performed excluding subjects 
missing both Week 8 and week 12 FEV1 due to COVID-19. An analysis of all subjects in the 
efficacy population will also be performed.  
At each visit the proportion of subjects with a ≥12% increase in FEV1 relative to Baseline 
will be compared between each active dose (as well as the pooled 150 and 300 mg/day dose 
groups) vs. placebo using a Fisher’s exact test.   
A GEE model will be used to analyse the proportion of subjects with a ≥12% increase in 
FEV1 relative to Baseline over time to obtain an estimate of the treatment effect and p-value 
at Week 12. Parameters will be included for treatment, time and the treatment by time 
interaction and GINA as a covariate. Subjects missing both Week 8 and week 12 FEV1 due 
to COVID-19 will excluded from the analysis. 
For continuous endpoints measured more than once on treatment, the analysis will use the 
method used for the analysis of the primary endpoint, MMRM. The model will contain terms 
for Baseline, the 3 levels of GINA treatment step as a categorical variable, treatment, visit, 
treatment by visit interaction, and baseline by visit interaction as fixed effects, and subject as 
a random effect to compare treatment group effects.  
For continuous endpoints measured only at Baseline and Week 12 the analysis will use 
ANCOVA, adjusting for the Baseline value and the 3 levels of GINA treatment step as a 
categorical variable. If a subject has a missing score at Week 12 and an evaluation was 
performed at the time of drop out, last observation carried forward (LOCF) will be used to 
impute the missing value at Week 12.  
During the analyses residual plots will be assessed to determine if log or rank transformations 
are required. Linear dose response with dose on the log10 scale will be assessed rather than 
log linear if the dependent variable is not log transformed for the analysis. For this analysis a 
value of 1 will be added to all the dose levels to allow for the log10 transformation of the 
placebo dose.   
For FEV1 Reversibility (%) is calculated as: 
 
[FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)] x 100)/ FEV1 
(pre-bronchodilator) 
 


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and Reversibility (mL) is calculated as:  
 
FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator). 
 
Frequency tables with the number and percentage of subjects that have a change from 
baseline in ACQ-6 Total Scores at Week 12 of ≥0, <0 to to-0.5, -0.5 to -1.0 and <-1.0 will 
also be presented. The proportion of subjects with a change from baseline in ACQ-6 score ≤-
0.5 will be compared between each active dose and placebo at Week 12 using a Fisher’s 
exact test.   
 
A GEE model will be used to analyze the proportion of change from baseline in ACQ-6 score 
≤-0.5 over time to obtain an estimate of the treatment effect and p-value at Week 12. 
Parameters will be included for treatment, time and the treatment by time interaction and 
GINA as a covariate.  
 
9.9. Safety and Tolerability Assessments 
9.9.1. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.0 (or higher if upversioned during the study).  
● A placebo run in adverse event will be defined as an AE that starts during the placebo 
run in phase or a pre-existing condition that increases in severity during the placebo 
run in. Placebo run in adverse events will be summarized by System organ class, 
preferred term, and treatment. 
● An Eosinophil Recovery Phase adverse event will be defined as an AE that starts 
during the Eosinophil Recovery phase or an AE that increases in severity during the 
Eosinophil Recovery Phase. Eosinophil Recovery Phase adverse events will be 
summarized by System organ class, preferred term, and treatment. 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose of randomized study drug and within 30 days of the last dose of study 
drug, or starts prior to the first dose of randomized study drug and increases in severity after 
the first dose of randomized study drug.  
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly, 
probably, or definitely related to the study treatment, as determined by the investigator. 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
first randomized dose for TEAEs only.  
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories: 
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by 
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● TEAEs by severity and treatment 
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment 
● Treatment-related TEAEs by severity and treatment 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following: 
● System organ class, preferred term, and treatment 
● Preferred term and treatment 
● System organ class, preferred term, week of onset from first dose of randomized study 
drug, and treatment for the system organ class of infections and infestations only. 
For the AE data the following rules will apply: 
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time 
or the end date/time indicates an AE started prior to the first dose. 
● For the derivation of treatment-related TEAE status: If the study treatment 
relationship for a TEAE is missing, a TEAE will be assumed to be a treatment-related 
TEAE. 
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, 
the minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of the first randomized dose is 01MAY2019/08:00 and 
recorded start date/time of an adverse event is 03MAY2019, then the minimum 
possible onset time will be calculated by assuming the adverse event started at the 
first hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as 
onset time ≥01:16:00 in the listing). 
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an adverse event date/time is 01MAY2019/08:00 and its 
recorded end date/time is 03MAY2019, then the maximum possible duration will be 
calculated by assuming the adverse event ended at the last hour and minute of 
03MAY2019 [03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in 
the listing). 
● For the calculation of summary statistics: AEs for which the severity is missing will 
not have the severity imputed so for summaries by severity are counted only in the 
overall total 
● For the calculation of summary statistics: If a subject experienced multiple TEAEs 
with the same preferred term for the same treatment, this will be counted as 1 TEAE 
for that treatment under the maximum severity recorded or the maximum relatedness 
category. 




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Table 2: 
List of Potentially Clinically Significant Laboratory Findings 
Hematology 
Test 
Low 
High 
White blood cells (WBC) 
< 3.0 x 109/L 
≥ 16 x 109/L 
Neutrophils 
< 1.5 x 109/L 
≥13.5 x 109/L 
Lymphocytes 
< 0.8 x 109/L 
> 12 x 109/L 
Monocytes 
N/A 
> 2.5 x 109/L 
Eosinophils 
N/A 
> 1.6 x 109/L 
Basophils 
N/A 
> 1.6 x 109/L 
Hemoglobin - Females 
≤ 9.5 g/dL 
≥ 17.5 g/dL 
Hemoglobin - Males 
≤ 11.5 g/dL 
≥ 19.0 g/dL 
Hematocrit - Females 
≤ 32% 
≥ 54% 
Hematocrit - Males 
≤ 37% 
≥ 60% 
Red blood cells (RBC) 
≤ 3.5 x 109/L 
≥ 6.4 x 109/L 
Platelet count 
≤ 75 x 109/L 
≥700 x 109/L 
Biochemistry 
Test 
Low 
High 
Sodium 
≤ 126 mmol/L 
≥156 mmol/L 
Potassium 
≤ 3 mmol/L 
≥ 6 mmol/L 
Chloride 
≤ 90 mmol/L 
≥118 mmol/L 
Bicarbonate 
≤ 16 mmol/L 
≥ 35 mmol/L 
Calcium 
≤ 2 mmol/L 
≥ 3 mmol/L 
Magnesium 
≤ 0.5 mmol/L 
≥1.2 mmol/L 
Inorganic phosphorus 
≤ 0.6 mmol/L 
≥1.7 mmol/L 
Aspartate aminotransferase (AST) 
N/A 
≥ 3 x ULN 
Alanine aminotransferase (ALT) 
N/A 
≥ 3 x ULN 
Alkaline phosphatase 
N/A 
≥ 1.5 x ULN 
Creatinine - Females 
N/A 
≥176.8 umol/L 
Creatinine - Males 
N/A 
≥176.8 umol/L 
Blood urea nitrogen (BUN) 
N/A 
≥10.7 mmol/L 
Total bilirubin 
N/A 
≥ 1.5 x ULN 
Total protein 
≤ 45 g/L 
≥ 100 g/L 
Albumin 
≤ 25 g/L 
N/A 
Uric acid - Females 
N/A 
≥ 506 umol/L 
Uric acid - Males 
N/A 
≥ 625 umol/L 
Glucose 
≤2.2 mmol/L 
≥ 9.7 mmol/L 
Hy’s Criteria  
Bilirubin ≥2 and (AST or ALT ≥ 3xULN) 
Urinalysis 
Test 
Low 
High 
Protein 
N/A 
≥ ++ 
Ketones 
N/A 
≥ ++++ 
Glucose 
N/A 
 ++++ 
Note: Defined PCS laboratory criteria. 
Note(s): N/A = not applicable; PCS = potentially clinically significant, ULN = upper limit of normal;  
Within each listing, laboratory values outside the normal ranges will be flagged as either high 
(H) or low (L). PCS laboratory values will also be flagged in the listings. 
9.9.4. Vital Signs Parameters 
Vital sign measurements as well as change from baseline will be summarized using 
descriptive statistics by visit and by treatment group.  


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Vital signs collected after the first dose of treatment will be examined to determine the 
incidence of the following clinically relevant abnormalities. 
Table 3: 
Vital Sign Criteria for Abnormality 
Vital Sign Parameter 
Criteria for Abnormalities 
systolic blood pressure 
>180 mmHg  
 an increase from pre-dosing of more than 40 mmHg  
 <90 mmHg  
 a decrease from pre-dosing of more than 30 mmHg 
diastolic blood pressure 
>105 mmHg 
 increase from pre-dosing of more than 30 mmHg 
 <50 mmHg 
 decrease from pre-dosing of more than 20 mmHg 
pulse 
>120 beats per minute 
 an increase from pre-dosing of more than 30 beats per minute 
 <50 beats per minute 
 a decrease from pre-dosing of more than 20 beats per minute 
temperature 
>38.5°C and an increase from pre-dosing of at least 1°C 
body weight 
≥7% from Baseline value, or ≤7% from Baseline value  
The number of subjects evaluated and the number and percentage of subjects with the defined 
abnormality at any time post-baseline will be presented by treatment group. The tabulation 
will use all the data up to the last visit of the Primary Assessment Phase including 
unscheduled visits and will also be repeated including the washout visits 
Summary tables by treatment and timepoint will be provided for all vital signs parameters, 
with changes from baseline and percentage changes from baseline.  
9.9.5. 12-lead Electrocardiogram Parameters 
ECG measures as well as change from baseline will be summarized using descriptive 
statistics by visit and by treatment group. Boxplots for HR, QTcF, PR, QRS as well as 
changes from baseline will be produced for the trough values by treatment group. Similar 
boxplots will also be produced containing all timepoints on Week 8 by treatment group. 
The analysis of the effect of dexpramipexole on ECG parameters (HR, QTcF, PR and QRS 
intervals) will be based on a  mixed-effects repeated measures model with change-from-
baseline (∆) of the parameter (∆HR, ∆QTcF, ∆PR and ∆QRS) as the dependent variable; time 
(i.e., post-baseline time point: categorical, using trough values only for Week 8); treatment 
(dexpramipexole and placebo); baseline and baseline by visit interaction and time by 
treatment interaction as fixed effects. An unstructured covariance matrix will be specified for 
the repeated measures at post-baseline time points within subjects. If the model with an 
unstructured covariance matrix fails to converge, other covariance matrices such as 


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compound symmetry and autoregressive will be considered. From this analysis, the LS mean 
and 2 sided 90% CIs will be calculated for the contrast “dexpramipexole versus placebo” for 
each dose of dexpramipexole at each post-baseline time point. 
The LS mean, standard error (SE), and 2-sided 90% CI from the statistical modeling for the 
change from baseline will be listed in the tables. 
At the Week 8 visit, subjects will have 3 separate ECG assessments performed to evaluate 
potential cardiac drug interactions of albuterol and dexpramipexole. A separate summary will 
be presented for the Week 8 visit, containing the actual values, changes from baseline and 
also the changes from the Week 8 trough value. 
ECG findings that are determined to be PCS will be summarized, examples of PCS ECG 
findings are given below:  
The tabulation will use all the data up to the last visit of the Primary Assessment Phase 
including unscheduled visits. 
Only potentially clinically significant ECG findings that were present on or after Day 1 and 
not present at baseline or screening will be tabulated. 
List of Potentially Clinically Significant ECG Findings 
Rate 
Sinus bradycardia 
Sinus tachycardia 
Bradycardia 
Tachycardia 
Rhythm 
Sinus arrhythmia 
Premature atrial complexes 
Ectopic atrial tachycardia 
Paroxysmal supraventricular tachycardia 
Premature ventricular complexes 
Ventricular tachycardia 
Bigeminy 
Trigeminy 
Wandering pacemaker 
Multifocal atrial tachycardia 
Sinus arrest 
Premature junctional beat 
Paroxysmal atrial tachycardia 
Paroxysmal junctional tachycardia 
Paroxysmal ventricular tachycardia 
Torsade de Pointes 
Ventricular flutter 
Wolff-Parkinson-White Syndrome 


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Lown-Ganong-Levine Syndrome 
Atrial fibrillation 
Atrial flutter 
Ventricular fibrillation 
Conduction 
First degree Atrioventricular (AV) block 
Second degree AV block 
Complete AV block 
AV dissociation 
Right bundle branch block 
Left bundle branch block 
Left anterior fascicular block 
Left posterior fascicular block 
Bifascicular block 
Nonspecific intraventricular block 
Wolf-Parkinson-White preexcitation 
Sino atrial exit block 
Wenckebach second degree AV block 
Sick sinus syndrome 
Mobitz second degree AV block 
Wave 
ST-T elevation 
ST-T depression 
T wave abnormality in inferior leads 
T wave abnormality in anterior leads 
RS transition zone displaced to right 
Non-specific T wave abnormality 
Non-specific ST-T elevation 
Non-specific ST-T depression 
QTc prolongation 
Wide QRS 
PR shortening 
Poor R wave progression 
Other Abnormality 
Possible artifact 
Possible myocardial Infarction (MI) 
Old MI 
Right atrial enlargement 
Left atrial enlargement 
Biatrial enlargement 
Left ventricular hypertrophy 
Right ventricular hypertrophy 
Biventricular hypertrophy 
Left axis deviation 


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Right axis deviation 
Possible normal variant 
Anteroseptal MI 
Inferior MI 
Pseudoinfarcts 
The QT/QTc analysis approach will follow the ICH E14 Guideline: The Clinical Evaluation 
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic 
Drugs.5 The incidence of AEs potentially related to QTc increase will be presented for 
individual AEs and the incidence will be presented for the pool of any AEs potentially related 
to QTc increase. AEs potentially related to QTc increase will include: torsade de pointes, 
sudden death, ventricular tachycardia, ventricular fibrillation and flutter, syncope, seizures, 
and others identified during a review of all AEs observed in the study. 
For the evaluation of heart rate change, absolute heart rate, and changes from baseline by 
scheduled evaluation time will be tabulated by treatment group. The incidence of subjects 
with >120 beats per minute or an increase from pre-dosing of more than 30 beats per minute 
will be tabulated by treatment group. The incidence of AEs potentially related to heart rate 
increase will be presented for individual AEs and the incidence will be presented for the pool 
of any AEs potentially related to heart rate increase. A tabulation of AEs that could be linked 
to a heart rate effect of the drug will be presented with appropriate grouping of terms, e.g.: 
a) Preferred terms: related to myocardial ischemia (angina, AMI, unstable angina, 
etc.) 
b) Preferred terms related to congestive heart failure 
c) Preferred terms related to tachycardia (atrial fibrillation, tachycardia, ventricular 
tachycardia, etc.) 
d) Cardiac serious adverse events (SAEs) and relevant SAEs in the general System 
Organ Class (e.g., sudden death). 
The maximum postdose QT and QTcF values in the Primary Assessment Phase will be 
summarized (number of subjects) by treatment according to the following categories: 
 Interval (ms) 
Observed  
> 450 ms  
  
  
> 480 ms  
  
  
> 500 ms 
  
Change from Baseline 
> 30 ms 
  
  
> 60 ms 
Summaries will also be produced for QT and QTcF fulfilling this criteria at each timepoint. 
PR and QRS values will be summarized by treatment (number of subjects and number of 
time points) according to the following categories: 
• ∆PR>25% AND a PR value >220 ms 
• ∆QRS>25% AND a QRS value > 110 ms 




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Category 
Subcategory 
Important 
Not Important 
Study Conduct / Procedures 
20. Other procedure performed out of window 
 
x 
Study Restrictions 
21. Non-compliance with Concomitant 
Therapy Restrictions / Requirements 
 
x 
Withdrawal Criteria 
22. Subject met discontinuation criteria but 
was not discontinued 
x 
 
 
Following the assignment of category and subcategory, each PD is assessed to assure the 
designation as Important or Not Important is valid. Important designation depends on the 
event having impinged on subject safety, subject well-being, or trial data. 
During execution of this clinical trial, procedural restrictions due the COVID-19 global 
pandemic were implemented for subject and site personnel protection. Spirometry, FeNO, 
and nasal/pharyngeal swab collection were temporarily discontinued from March 2020 to 
May 2020. PD resulting from these exigencies are additionally identified 
All PD will be listed in the CSR by subject and timepoint of occurrence and will specify if 
related to COVID-19 study restrictions. Important PD will be summarized by deviation type 
and by treatment assignment and will specify if related to COVID-19 study restrictions.  
Prior to the interim analysis, an attempt will be made to identify and characterize PD for the 
‘all subjects’ population (e.g., all subjects who signed the ICF and had any study assessment 
recorded in the database).  
Figure 3: Protocol Deviation Processing 
 
 
 
 
 
Potential PDs identified 
(programmatically and manually) 
Potential PDs reviewed for validity 
by 
 
Validated PD consolidated into unique 
PDs for each subject by Knopp 
Unique protocol deviations assigned 
category/subcategory by Knopp 
Unique protocol deviations reviewed for impact 
on the analyses and subject well-being 
(Important PDs). Performed by Knopp. 


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9.9.7. Other Assessments 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
The definition of hematologic responder was modified from the original protocol definition 
of “≥90% reduction of blood eosinophil count, from Baseline to Week 12” to “Week 12 
blood eosinophil count of ≤0.05x109/L”. The change was made to define the responder group 
more closely with the known pharmacodynamics of the drug.  
Several subjects missed Pulmonary Function Tests due to COVID-19.  For the analysis of 
pulmonary function tests the MMRM analysis will exclude subjects if they were missing both 
Week 8 and week 12 FEV1 due to COVID-19. Dexpramipexole is unlikely to show an effect 
on FEV1 at the week 4 visit and including only week 4 data may bias results against 
dexpramipexole. Normally it is inappropriate to exclude subjects with missing data from the 
analysis but when the exclusion is because they missed the evaluation because of COVID-19 
that should not introduce bias. Subjects who are missing FEV1 due to other reasons will be 
included in the analysis 
For the analysis of ACQ-7 (which includes an FEV1 item) the MMRM analysis will exclude 
subjects if they were missing both Week 8 and week 12 FEV1 due to COVID-19. 
To control the alpha level for testing 3 dose groups versus placebo for the primary endpoint 
and for testing FEV1, a closed hierarchical testing procedure was originally planned to be in 
the following order:  
1. First, the 300mg/day dose group will be tested versus placebo for change in blood 
absolute eosinophil count at Week 12, and if this reaches the <0.05 level then,  
2. the 150 mg/day dose group will be tested versus placebo at the 0.05 level for 
change in blood absolute eosinophil count at Week 12, and if this reaches the 
<0.05 level then, 
3. the 75 mg/day dose group will be tested versus placebo at the 0.05 level for 
change in blood absolute eosinophil count at Week 12, and if this reaches the 
<0.05 level then, 
4. the pooled 150 and 300 mg/day dose groups will be tested versus placebo at the 
0.05 level for change in FEV1 at Week 12. 
the pooled 150 and 300 mg/day dose groups analysis of change in FEV1 at Week 12 was 
moved up to the 3rd test and the 75 mg/day dose group tested versus placebo was moved 
down to the 4th test. 
For all the covariate adjustment analyses, GINA treatment steps 3-5 will be used as a 
categorical variable with 3 levels (3,4,5) instead of two levels 3 vs. 4/5 because each of the 3 
levels may have a different prognostic level for the outcome measures.  


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An analysis of the proportion of subjects with an AEC of ≤0.05x109/L and for proportion of 
subjects with a ≥ 90% reduction of AEC will be performed using GEE to obtain the estimated 
treatment effect at Week 12. Similar analyses will also be performed for the proportion of 
subjects with a ≥12% increase in FEV1 and the proportion of subjects with a change from 
baseline in ACQ-6 score ≤-0.5. 
Specific criteria defining the per-protocol population were included in section 7.5 of the 
current SAP. 
During the course of the trial consensus guidelines for the standardization of spirometry were 
updated. The updated guidelines were used to grade FEV1 results.  Standardization of 
Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory 
Society Technical Statement. Am J Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88. doi: 
10.1164/rccm.201908-1590ST 
11. REFERENCES 
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998. 
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
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