Clinical trial NCT03218917
Conditions: Non-Cystic Fibrosis Bronchiectasis
Keywords: P aeruginosa bronchiectasis active neutrophil elastase
Sponsor: Insmed Incorporated
Start date: 2017-10-31; Completion date: 2019-12-12
Enrollment: 256 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate if INS1007 can reduce pulmonary exacerbations over a 24-week treatment period in participants with non-cystic fibrosis bronchiectasis.

Detailed description:
Phase 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter, multi-national study to assess the efficacy, safety and tolerability, and pharmacokinetics (PK) of INS1007 administered once daily for 24 weeks in participants with non-cystic fibrosis bronchiectasis (NCFBE).

Arms: arm 1: Participants received brensocatib 10 mg once daily (QD) before breakfast, for 24 weeks. arm 2: Participants received brensocatib 25 mg QD before breakfast, for 24 weeks. arm 3: Participants received the matching placebo QD before breakfast, for 24 weeks.
Interventions: intervention 1: Brensocatib 10 mg intervention 2: Brensocatib 25 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Administered once per day for 24 weeks intervention 2: Administered once per day for 24 weeks intervention 3: Administered once per day for 24 weeks

Protocol documents:
Prot_000.pdf: 
Offi ci al Titl e:  A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d, P ar all el -Gr o u p, 
M ulti -C e nt er  St u d y t o A s s e s s t h e Effi c a c y, S af et y a n d T ol er a bilit y, a n d 
P h ar m a c o ki n eti c s of  I N S 1 0 0 7 A d mi ni st er e d O n c e D ail y f or 2 4 W e e k s 
i n S u bj e ct s Wit h N o n -C y sti c  Fi br o si s Br o n c hi e ct a si s – T h e Will o w 
St u d y  
N C T N u m b er:  N C T 0 3 2 1 8 9 1 7  
D o c u m e nt  D at e s: 
P r ot o c ol Ver si o n 5 . 0: 04 -O ct o b er - 20 1 8  


Si g nat ure Pa ge f or V V- C LI N- 0 0 3 6 3 2 v 1. 0
A p pr o ve
0 1- Oct- 2 0 1 8 1 2: 1 9: 4 7 G M T + 0 0 0 0
A p pr o ve
0 1- Oct- 2 0 1 8 1 2: 3 9: 2 0 G M T + 0 0 0 0
A p pr o ve
0 1- Oct- 2 0 1 8 1 7: 4 2: 0 6 G M T + 0 0 0 0
A p pr o ve
0 4- Oct- 2 0 1 8 1 6: 4 1: 5 5 G M T + 0 0 0 0


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n 5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1  of 1 5 5  
 
C LI NI C A L S T U D Y P R O T O C O L  
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, M ulti -Ce nter 
St u d y t o Assess t he Efficac y, Safet y a n d T olera bilit y, a n d P har mac o ki netics of 
I N S 1 0 0 7 A d mi nistere d O nce Dail y f or 2 4 Wee ks i n S u bjects Wit h N o n -C ystic 
Fi br osis Br o nc hiectasis –  T he Will o w St u d y  
St u d y N u m ber: I N S 1 0 0 7 -2 0 1  
St u d y P hase: 2  
I N D N u m ber: 1 3 3 7 9 0  
E U D R A C T N u m ber: 2 0 1 7 -0 0 2 5 3 3 -3 2  
I ns me d I nc or p or ate d 
1 0  Fi n der n e A ve n u e, B uil di n g 1 0  
Bri d ge water, NJ 0 8 8 0 7 -3 3 6 5  
 
Versi o n N u m ber  
A me n d me nt  
D ate  
Ori gi nal Pr ot oc ol  
1. 0  
 
2 1 J u ne 2 0 1 7  
A me n de d Pr ot oc ol  
2. 0  
1. 0  
2 4 A u g ust 2 0 1 7  
A me n de d Pr ot oc ol  
3. 0  
2. 0  
1 2 Marc h 2 0 1 8  
A me n de d Pr ot oc ol  
4. 0  
3. 0  
2 7 A pril 2 0 1 8  
A me n de d Pr ot oc ol  
5. 0  
4. 0  
2 4  Se pte m ber 2 0 1 8  
 
 
 
 
 
 
 
 
 
 
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
Pr o pert y of I ns me d I n c or p orate d  
T his d oc u me nt is c o nfi de ntial a n d ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d 
wit h o ut c o nse nt of I ns me d I n c or p orate d  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n 5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2  of 1 5 5  
 
I N V E S TI G A T O R A G R E E M EN T  
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, M ulti -Ce nter 
St u d y t o Assess t he Efficac y, Safet y a n d T olera bilit y, a n d P har mac o ki netics of 
I N S 1 0 0 7 A d mi nistere d O nce Dail y f or 2 4 Wee ks i n S u bjects Wit h N o n-C ystic 
Fi br osis Br o nc hiectasis –  T he Will o w St u d y  
I n vesti g at or’s Si g n at ure: 
I h a ve f ull y disc usse d t he o bjecti ves of t his st u d y a n d t he c o nte nts of t his pr ot oc ol wit h t he 
S p o ns or’s re pres e ntati ve.  
I will pr o vi de c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his st u d y.  I will disc uss t his material wit h t he m t o e ns ure t hat 
t he y are f ull y i nf or me d re gar di n g t he st u d y dr u g a n d t he c o n d uct of t he st u d y.  
I a gree t o c o n d uct t his st u d y per t his pr ot oc ol a n d t o c o m pl y wit h its re q uir e me nts, s u bject t o 
et hical a n d safet y c o nsi d erati o ns a n d g ui deli nes, a n d t o c o n d uct t he st u d y i n acc or da nce wit h t he 
Declarati o n of Helsi n ki, I nter nati o nal C o u ncil f or Har m o nizati o n g ui deli nes o n G o o d Cli nical 
Practice (I C H E 6), a n d a p plica ble re gi o nal re g ulat o r y re q uire m e nts.  I will use o nl y t he i nf or me d 
c o nse nt a p pr o v e d b y t he I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee (I R B/I E C) 
a n d will f ulfill all res p o nsi bilities f or s u b mitti n g perti ne nt i nf or mati o n t o t he I R B/I E C 
res p o nsi ble f or t his st u d y. 
I u n d ersta n d t hat i nf or m ati o n c o ntai ne d i n or pertai ni n g t o t his pr ot oc ol is c o nfi de ntial a n d 
s h o ul d n ot be discl ose d, ot her t ha n t o t h ose directl y i n v ol ve d i n t he e x ec uti o n or t he et hical 
re vie w of t h e st u d y, wit h o ut writte n a ut h orizati o n fr o m I ns me d.  It is, h o we ver, per missi ble t o 
pr o vi de i nf or mati o n t o a s u bject t o o btai n c o nse nt.  
I a gree t o ma ke a vaila ble t o I ns me d p ers o n nel, t heir re pres e ntati ves a n d rel e va nt re g ulat or y 
a ut h orities, m y s u bjects’ st u d y rec or ds t o verif y t he data t hat has b ee n e nt ere d t o  t he case re p ort 
f or ms.  I a m a ware of m y res p o nsi bilities as a Pri nci pal I n vesti gat or as pr o vi de d b y I ns m e d. 
I u n d ersta n d t hat I ns me d ma y d eci de t o s us pe n d or pre mat urel y ter mi nate t h e st u d y at a n y ti me 
f or w hate v er reas o n; s uc h a decisi o n will be c o m m u nicate d t o me i n writi n g.  C o n versel y, s h o ul d 
I d eci de t o wit h dr a w fr o m e x ec uti o n of t he st u d y, I will c o m m u nicate m y i nte nti o n i m me diatel y 
i n writi n g t o I ns me d. 
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n 5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3  of 1 5 5  
 
I M P O R T A N T C O N T A C T S 
I ns me d I nc or p or ate d 
1 0  Fi n der n e A ve n u e, B uil di n g 1 0  
Bri d ge w ater, NJ 0 8 8 0 7 -3 3 6 5  
I ns me d Gl o b al Cli nic al a n d Re g ul at or y Aff airs  
N a me:  
Title  
Tele p h o ne  
e-M ail A d dress  
 
Cli nic al Rese arc h Or g a niz ati o n  
 
Ve n d or N a me  
Gl o b al S p o ns or S ol uti o ns I N C Rese arc h L L C  
A d dress  
3 2 0 1 Beec hleaf C o urt, S uite 6 0 0, Ralei g h, N C 2 7 6 0 4 -1 5 4 7  
T ele p h o ne N u m ber  
Fa x N u m ber  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4  of 1 5 5  
 
S U M M A R Y O F C H A N G E S  T O A M E N D E D P R O T O C O L  V E R SI O N 5. 0 , D A T E D 2 4  S E P T E M B E R 2 0 1 8  
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
I m p ort a nt C o nt a cts 
U p date d c o ntact i nf or mati o n f or 
Re g ulat or y Affairs pers o n nel  
S y n o psis: Dr u g Pr o d uct, 
Stre n gt h, D osa ge F or m, 
a n d R o ute of 
A d mi nistrati o n  
T he st u d y dr u gs (I N S 1 0 0 7 a n d place b o) 
will b e s u p plie d b y t he S p o ns or  i n 
b ottles c o ntai ni n g 3 5 ta blets per b ottle as 
descri be d bel o w . 
 
Re vise d t o be ali g n wit h details i n 
Secti o n 5. 1  
S y n o psis: Ef ficac y 
A nal ysis  
T he efficac y a nal ysis of t he ti me t o t he 
first e xacer bati o n will be perf or me d f or 
t he i nte nt-t o-treat (I T T) p o p ulati o n usi n g 
Ka pla n Meier c ur ves , w hic h will be 
ge nerate d f or t he treat me nt ar ms at t he 
2 si de d si g nifica nce le vel of 0. 0 5.   
 
Re vise d t o ali g n wit h Secti o n 9. 5. 1. 2  
S y n o psis: Data M o nit ori n g 
C o m mittee  
T he D M C me m bers will re vie w t he data 
at pre d eter mi ne d i nter vals i n a mas ke d 
ma n ner, wit h t he p ote ntial f or u n bli n de d 
re vie w if dee me d necessar y b y its 
me m bers.  
T he D M C me m bers will  re vie w t he data 
i n a se mi-bli n de d or u n -bli n de d ma n ner 
at pre deter mi ne d i nter vals.   
Re vise d t o ali g n wit h Secti o n 3. 5  
3. 1.  O ver all St u d y Desi g n 
a n d Pl a n  
Scree ni n g P eri o d ( Visit 1)  
 
S u bj ects w h ose past c hest ra di o gra p hic 
i ma ge rec or ds are n ot a vaila ble will 
u n der g o a c hest c o m p ute d t o m o gra p h y 
(C T ) sca n d uri n g Scree ni n g ( Visit 1).   
A d de d t o ali g n wit h t he 
pr oce d ures/assess me nts liste d i n T a ble 6  
Sc he d ule of E ve nts  
3. 1.  O ver all St u d y Desi g n 
a n d Pl a n  
Treat me nt P eri o d ( Visits 2 
t hr o u g h 9) 
Tre at me nt Peri o d ( Visits 2 t hr o u g h 9) 
O n Da y  1 ( Visit 2), vital si g ns, s p ut u m 
a n d bl o o d sa m ples f or bi o mar kers will 
be c ollecte d, a n d bl o o d c he mistr y, 
he mat ol o g y a n d uri nal ysis tests, E C G, 
Tre a t me nt Peri o d ( Visits 2 t hr o u g h 9) 
O n Da y  1 ( Visit 2), vital si g ns, s p ut u m 
a n d bl o o d sa m ples f or bi o mar kers will 
be c ollecte d, a n d bl o o d c he mistr y, 
he mat ol o g y a n d uri nal ysis tests, E C G, 
Clarifie d te xt t o e ns ure s u bj ect 
eli gi bilit y pri or t o ra n d o mizati o n 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
a n d pre g na nc y test (fe males of c hil d 
beari n g p ote ntial [ W O C B P] o nl y) will 
be c o n d uct e d.  After re -c o nfir mi n g t heir 
eli gi bilit y, s u bj ects will be ra n d o mize d 
via t he Me di data Bala nce ra n d o mizati o n 
a n d trial s u p pl y ma na ge me nt ( R T S M) 
s yste m i nt o 1 of 3 ar ms t o recei ve eit her 
1 0 m g or 2 5 m g of I N S 1 0 0 7 or matc hi n g 
place b o i n a 1: 1: 1 rati o.  
a n d pre g na nc y test (fe males of c hil d 
beari n g p ote ntial [ W O C B P] o nl y) wi ll 
be c o n d ucte d.  St u d y sites m ust  c o nfir m 
s u bj ect eli gi bilit y base d o n scr ee ni n g la b 
res ults pri or t o ra n d o mizati o n.  After re -
c o nfir mi n g t heir eli gi bilit y, s u bj ects will 
be ra n d o mize d via t he Me di data Bala nce 
ra n d o mizati o n a n d trial s u p pl y 
ma na ge me nt ( R T S M) s yste m i nt o 1 of 3 
ar ms t o recei ve eit her 1 0 m g or 2 5 m g of 
I N S 1 0 0 7 or matc hi n g place b o i n a 1: 1: 1 
rati o. 
 
3. 1.  O ver all St u d y Desi g n 
a n d Pl a n  
Fi g ure 1 St u d y Desi g n 
Dia gra m  
Da y  1 t o Da y  1 6 8  ( 2 4 Wee k Treat me nt 
P eri o d)  
Da y  1 6 9 t o Da y  1 9 2 ( 4 wee ks)  
Da y  1 t o Da y  1 6 9 ( 2 4 Wee k Treat me nt 
P eri o d)  
Da y  1 9 7 ( ± 3 Da ys)  
U p date d st u d y da ys i n Fi g ure 1 t o ali g n 
wit h t he Sc he d ule of E ve nts  
4. 1. 1.  
I ncl usi o n Criteri a 
n u m ber 5  
Are c urre nt s p ut u m pr o d ucers wit h a 
hist or y of c hr o nic e x pect orati o n, a n d 
a ble t o pr o vi de s p ut u m sa m ple d uri n g 
Scree ni n g;  
 
Are c urre nt s p ut u m pr o d ucers wit h a 
hist or y of c hr o nic e x pect orati o n, a n d 
a ble t o pr o vi de s p ut u m sa m ple d uri n g 
Scree ni n g.  If a s u bject is u na ble t o 
pr o d uce s p ut u m s p o nta ne o usl y d uri n g 
Scree ni n g  ( Visit 1), t he s u bj ect will be 
c o nsi dere d a scree n fail ure.  T he s u bj ect 
ma y n ot u n der g o a s p ut u m i n d ucti o n 
pr oce d ure d uri n g Scree ni n g  ( Visit 1) t o 
meet i ncl usi o n criteri o n.  
 
A d de d clarificati o n t o e ns ure t hat 
s u bj ects d o n ot u n der g o a s p ut um 
i n d ucti o n d uri n g Scree ni n g 
 
A d diti o nal re visi o n t o f o ot n ot e “e” t o 
ali g n wit h A p pe n di x 1  
T a ble 6: Sc he d ule of 
E ve nts  
F o ot n ote “e”  
 
e 
S u bj ects will be re q uire d t o pr o vi de 
a s p ut u m sa m ple d uri n g t he s p ecifie d 
visits.  O n Da y  1, t he s p ut u m sa m ple 
s h o ul d be c ollecte d pri or t o t he first 
d osi n g of t he st u d y dr u gs.  If a s u bj ect is 
u na ble t o pr o vi de a s p o nta ne o us s p ut u m 
sa m ple d uri n g a n y visit, c hest 
e 
S u bj ects will be re q uire d t o pr o vi de 
a s p ut u m sa m ple d uri n g t he s p ecifie d 
visits.  A s u bj ect ma y n ot u n d er g o a 
s p ut u m i n d ucti o n pr oce d ure d uri n g 
Scree ni n g  ( Visit 1) t o meet eli gi bilit y 
( Secti o n 4. 1, i ncl usi o n criteri o n 5).  O n 
Da y  1, t he s p ut u m sa m ple s h o ul d be 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
p h ysi ot hera p y s h o ul d be perf or me d first 
t o facilitate e x pect orati o n.  If c hest 
p h ysi ot hera p y fails, t he s p ut u m 
i n d ucti o n pr oce d ure detaile d i n t he 
pr ot oc ol will  be perf or me d t o o btai n a 
s p ut u m sa m ple.   
c ollecte d pri or t o t he first d osi n g of t he 
st u d y dr u gs.  If a s u bj ect is u na ble t o 
pr o vi de a s p o n ta ne o us s p ut u m sa m ple 
d uri n g a n y visit, c hest p h ysi ot hera p y 
s h o ul d be perf or me d first t o fa cilitate 
e x pect orati o n.  If c hest p h ysi ot hera p y 
fails, t he rec o m me n de d s p ut u m 
i n d ucti o n pr oce d ure detaile d i n t he 
pr ot oc ol s h o ul d be perf or me d t o o btai n a 
s p ut u m sa mple.   
 
7. 3. 5.  
I nfl a m m at or y 
Bi o m ar ker Le v els -
S p ut u m  
If a s u bj ect is u na ble t o pr o d uce s p ut u m 
s p o nta ne o usl y d uri n g a n y visit, t he 
s u bj ect s h o ul d u n der g o a s p ut u m 
i n d ucti o n pr oce d ure.  T he detaile d 
s p ut u m i n d ucti o n pr oce d ure is descri be d 
i n A p pe n di x 1. 
If a s u bj ect is u na ble t o pr o d uce s p ut u m 
s p o nta ne o usl y d uri n g a n y visit, t he 
s u bj ect s h o ul d u n der g o a s p ut u m 
i n d ucti o n pr oce d ure (a s u bj ect ma y n ot 
u n der g o a s p ut u m i n d ucti o n pr oce d ure 
d uri n g Scree ni n g  [ Visit 1] t o meet 
eli gi bilit y [ Secti o n 4. 1, i ncl usi o n 
criteri o n 5]) .  T he detaile d s p ut u m 
i n d ucti o n pr oce dure is descri be d i n 
A p pe n di x 1.  
 
 
A p pe n di x 1 . S p ut u m 
I n d ucti o n G ui deli nes 
 
N ote: If a s u bj ect is u na ble t o pr o d uce 
s p ut u m s p o nta ne o usl y d uri n g Scree ni n g 
( Visit 1), t he s u bj ect will be c o nsi dere d 
a scree n fail ure.  T he s u bj ect ma y n ot 
u n der g o a s p ut u m i n d ucti o n pr oce d ure 
d uri n g Scree ni n g  ( Visit 1) t o meet 
eli gi bilit y ( Secti o n 4. 1, i ncl usi o n 
criteri o n 5 ). 
 
4. 1. 2 . E xcl usi o n Criteri a  
n u m ber 5  
Ha ve a n y ac ute i nfecti o ns (i ncl u di n g 
res pirat or y i nfecti o ns) t hat re q uire d 
a nti bi otic treat me nt wit hi n 4 wee ks 
bef ore Scree ni n g or wit hi n 1 2 wee ks 
Ha ve a n y ac ute i nfecti o ns (i ncl u di n g 
res pirator y i nfecti o ns) t hat re q uire d 
a nti bi otic treat me nt wit hi n 4 wee ks 
bef ore Scree ni n g or wit hi n 1 2 wee ks 
F urt her clarifie d t hat a n y s u bj ect w h o 
s uffers a n e xacer bati o n or i nfe cti o n 
re q uiri n g a nti bi otic treat me nt pri or t o 
ra n d o mizati o n will be c o nsi dere d a 
scree n failure  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
bef ore Scree ni n g if t he a nti bi otic 
prescri pti o n is a macr oli de;  
bef ore Scree ni n g if t he a nti bi otic 
prescri pti o n is a macr oli de;  
If a s u bj ect s uffers a n e xacer bati o n or 
i nfecti o n re q uiri n g a nti bi otic treat me nt 
after t he  Scree ni n g visit, b ut pri or t o 
ra n d o mizati o n, t he s u bj ect will be 
c o nsi dere d a scree n fail ure  
4. 1. 2 . E xcl usi o n Criteri a  
n u m ber 2 3  
M e dic al c o n diti o ns ass oci ate d wit h t he 
o nset of n o n -here dit ar y p al m o pl a nt a r 
ker at osis:  
Ha ve  h y p ot h yr oi dis m, or  m y x e de ma, or  
c hr o nic l y m p he de ma, or  acr oc ya n osis, 
or li ve d o retic ularis;  
H a ve t he f oll o wi n g me dic al c o n diti o ns 
ass oci ate d wit h t he o nset of n o n -
here dit ar y p al m o pl a nt a r ker at osis:  
H y p ot h yr oi dis m, m y xe de ma, c hr o nic 
l y m p he de ma, acr oc ya n osis, or li ve d o 
retic ularis; 
N ote:  If a s u bj ect has h y p ot h yr oi dis m 
b ut is c urre ntl y bei n g treate d, a n d 
t h yr oi d-sti m ulati n g h or m o ne ( T S H) 
a n d/ or trii o d ot h yr o ni ne ( T 3)/ t h yr o xi ne 
( T 4) are wit hi n n or mal ra n ges, t he 
s u bj ect is all o we d i nt o t he trial.   
Clarifie d criteri o n t o per mit e nr oll me nt 
of eli gi ble s u bj ects w h o ha ve 
h y p ot h yr oi dis m  
7. 7 . 6. 
Der m at ol o gic al 
Assess me nt  
T he e ntr y  criteria i n t he st u d y ha ve bee n 
defi ne d t o e xcl u de s u bj ects wit h 
u n derl yi n g der mat ol o gic c o n diti o ns t hat 
c o ul d i m pair t he a bilit y t o detect a 
p ote ntial safet y si g nal or mi g ht p ut t he 
s u bj ect at i ncrease d ris k.  S pecificall y, 
t he rele va nt e xcl usi o n criteria are: 
Ha ve h y p ot h yr oi dis m, or m y x e de ma, or 
c hr o nic l y m p he de ma, or acr oc ya n osis, 
or li ve d o retic ularis;  
T he e ntr y criteria i n t he st u d y ha ve bee n 
defi ne d t o e xcl u de s u bj ects wit h 
u n derl yi n g der mat ol o gic c o n diti o ns t hat 
c o ul d i m pair t he a bilit y t o detect a 
p ote ntial safet y si g nal or mi g ht p ut t he 
s u bj ect at i ncrease d ris k.  S pecificall y, 
t he rele va nt e xcl usi o n criteria are: 
Ha ve h y p ot h yr oi dis m, or m y x e de ma, or 
c hr o nic l y m p he de ma, or acr oc ya n osis, 
or li ve d o retic ularis.  If a s u bj ect has 
h y p ot h yr oi dis m b ut is  c urre ntl y bei n g 
treate d, a n d T S H a n d/ or T 3/ T 4 are 
wit hi n n or mal ra n ges, t he s u bject is 
all o we d i nt o t he trial.   
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
4. 2. 2.  
S u bject Re -
Scree ni n g Pr o ce d ures  
 
S u bj ects w h o d o n ot meet eli gi bilit y 
criteria d uri n g Scree ni n g ma y be re -
scree ne d u p t o 2 ti mes if a p pr o ve d b y 
I ns me d’s Me dical M o nit or. 
S u bj ects w h o d o n ot meet eli gi bilit y 
criteria d uri n g Scree ni n g ma y be re -
scree ne d u p t o 2 ti mes if a p pr o ve d b y 
I ns me d’s Me dical M o nit or. 
D uri n g Scree ni n g  ( Visit 1), if a s u bj ect 
d oes n ot q ualif y d ue t o E C G s t hat d o n ot 
meet t he q ualit y criteria, t he s u bj ect ca n 
re peat t he test u p t o 2 ti mes wit h o ut 
bei n g re -scree ne d. 
S u bj ects w h o nee d t o re peat P F T s 
beca use t he y d o n ot meet e xcl usi o n 
criteri o n 6 ( Secti o n 4. 1. 2), ca n re p eat t he 
test u p t o 2 ti mes wit h o ut bei ng re -
scree ne d. 
S u bj ects w h o are c o nsi dere d a scree n 
fail ure f or reas o ns n ot relate d t o t he 
de ntal e xcl usi o n criteria ( Secti o n 4. 1. 2, 
e xcl usi o n criteria 2 9 t hr o u g h 3 2) d o n ot 
nee d t o re peat t he de ntal e xa mi nati o n if 
t hey are  re-scree ne d wit hi n 3  m o nt hs of 
the first Scree ni n g visit . 
 
A d de d clarificati o n t o per mit e nr oll me nt 
of eli gi ble s u bj ects w h o nee d t o re p eat 
a n E C G a n d/ or P F T t hat  are n ot 
cli nicall y si g nifica nt  
 
U n der re -scree ni n g pr oce d ures, clarifie d 
de ntal e xa m re q uire me nt f or s u bj ects 
w h o scree n fail  f or reas o ns n ot relate d t o 
t he de ntal e xcl usi o n criteria 
4. 1. 2.  
E xcl usi o n 
Criteri a  
n u m ber 6  
 
6. Are u na ble t o perf or m tec h nicall y 
acce pta ble s pir o metr y meeti n g 
A merica n T h oracic S ociet y 
( A T S)/ E ur o pea n T h oracic S ociet y 
( E R S) acce pta bilit y criteria wit h at least 
3 acce pta ble fl o w -v ol u me c ur ves wit h at 
least 2 meeti n g t he A T S/ E R S 
re p eata bilit y criteria f or F E V 1 d uri n g 
Scree ni n g ; 
6. Are u na ble t o perf or m tec h nicall y 
acce pta ble s pir o metr y meeti n g 
A merica n T h oracic S ociet y 
( A T S)/ E ur o pea n T h oracic S ociet y 
( E R S) acce pta bilit y criteria wit h at least 
3 acce pta ble fl o w -v ol u me c ur ves wit h at 
least 2 meeti n g t he A T S/ E R S 
re peata bilit y criteria f or F E V 1 d uri n g 
Scree ni n g  
a. 
S u bj ects w h o nee d t o re peat P F T s 
beca use t he y d o n ot meet t he 
e xcl usi o n criteri o n ca n re peat t he 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
test u p t o 2 ti mes wit h o ut b ei n g re -
scree ne d. 
4. 1. 2.  
E xcl usi o n 
Criteri a  
n u m ber 1 9  
 
1 9. Ha ve a baseli ne -c orrecte d Q T 
i nter val b y Fri dericia ( Q T c F) > 4 5 0 
millisec o n ds ( males) or 4 7 0 
millisec o n ds (fe males) or hist or y of 
c o n ge nital l o n g Q T s y n dr o me, or 
T orsa d es de P oi ntes or ot her a b n or mal 
E C G at Scree ni n g or Baseli ne ( u nless 
t he E C G fi n di n gs are n ot cli ni call y 
si g nifica nt a n d are a p pr o ve d b y t he 
I n vesti gat or a n d d oc u me nte d b y 
si g nat ure); 
1 9. Ha ve a baseli ne -c orrecte d Q T 
i nter val b y Fri dericia ( Q T c F) > 4 5 0 
millis ec o n ds ( males) or 4 7 0 
millisec o n ds (fe males) or hist or y of 
c o n ge nital l o n g Q T s y n dr o me, or 
T orsa des de P oi ntes or ot her a b n or mal 
E C G at Scree ni n g or Baseli ne ( u nless 
t he E C G fi n di n gs are n ot cli ni call y 
si g nifica nt a n d are a p pr o ve d b y t he 
I n vesti gator a n d d oc u me nte d b y 
si g nat ure) 
a. 
If a s u bj ect d oes n ot q ualif y d ue t o 
E C G s t hat d o n ot meet t he q ualit y 
criteria, t he s u bj ect ca n re peat t he 
test u p t o 2 ti mes wit h o ut bei n g 
re-scree ne d. 
 
5. 1. 9.  
Dr u g Us a ge a n d 
Acc o u nt a bilit y  
T he st u d y dr u gs are t o be prescri be d 
o nl y b y t he I n vesti gat ors or s u b - 
I n vesti gat ors na me d o n t he F or m F D A 
1 5 7 2 . 
T he st u d y dr u gs are t o be prescri be d 
o nl y b y t he I n vesti gat ors or s u b - 
I n vesti gat ors partici pati n g i n t he trial . 
U p date d t o c o ver all  gl o bal  stu d y sites  
5. 3.  Pr o hi bite d 
M e dic ati o ns  
Use of a n y i m m u n o m o d ulat or y a ge nts 
(e g, b ortez o mi b, i xaz o mi b, a n d 
t hali d o mi de) is pr o hi bite d d uri n g t he 
st u d y u ntil  Visit 1 0 ( E O S).  
C o nti n u o us use of hi g h d ose n o n -
ster oi dal a nti-i nfla m mat or y dr u gs is 
pr o hi bite d d uri n g t he st u d y u ntil  Visit 1 0 
( E O S) u nless t he use is c o nsi d ere d 
necessar y per I n vesti gat or discreti o n.  
Me dicati o ns t hat ma y ca use a 
pal m o pla ntar kerat o der ma are pr o hi bite d 
d uri n g t he st u d y u ntil  Visit 1 0 ( E O S).   
Use of a n y i m m u n o m o d ulat or y a ge nts 
(e g, b ortez o mi b, i xaz o mi b, a n d 
t hali d o mi de) is pr o hi bite d d uri n g t he 
st u d y t hr o u g h Visit 1 0 ( E O S).  
C o nti n u o us use of hi g h d ose n o n -
ster oi dal a nti-i nfla m mat or y dr u gs is 
pr o hi bite d d u ri n g t he st u d y t hr o u g h Visit 
1 0 ( E O S) u nless t he use is c o nsi dere d 
necessar y per I n vesti gat or discreti o n.  
Me dicati o ns t hat ma y ca use a 
pal m o pla ntar kerat o der ma are pr o hi bite d 
d uri n g t he st u d y t hr o u g h Visit 1 0 ( E O S).   
Clarifie d t hat t he d urati o n is t hr o u g h 
Visit  1 0  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
 
5. 3.  Pr o hi bite d 
M e dic ati o ns  
T a ble 1:  Pr o hi bite d 
Me dicati o ns ( Ma y Ca use 
P al m o pla ntar Kerat o der ma)  
6  W ee ks Pri or t o Da y 1 t o 2 8 -Da y ( +/ - 3 
Da ys) Safet y F oll o w -U p  
4 Wee ks Pri or t o Da y 1 t o 2 8 -Da y ( +/ - 3 
Da ys) Safet y F oll o w -U p  
C orrecte d t y p o s i n T a bles 1 a n d 2 
T a ble 2: List of M o derate 
a n d Str o n g C Y P 2 D 6 a n d 
C Y P 2 C 8 I n hi bit ors ( n ot t o 
be C o -A d mi nistere d Wit h 
C Y P 3 A 4/ 5 I n hi bit ors b ut 
Ot her wise P er mitte d)  
M o derate C Y P 2 D 6 I n hi bit ors  
6  wee ks pri or t o Da y 1 t o 2 8 -da y Safet y 
F oll o w -U p  
M o derate C Y P 2 D 6 I n hi bit ors 
4  wee ks pri or t o Da y 1 t o 2 8 -da y Safet y 
F oll o w -U p  
 
5. 4.  Per mitte d 
M e dic ati o ns a n d 
Pr o ce d ures  
H o we ver, e xce pt u n der u nf oreseea ble 
cli nical circ u msta nces, t he air wa y 
cleara nce mai nte na nce 
treat me nt/ pr oce d ures a n d p ul m o nar y 
re ha bilitati o n s h o ul d c onti n ue 
u nc ha n ge d t hr o u g h o ut t he d ur ati o n of 
t he st u d y u ntil  Visit 1 0 ( E O S).  
H o we ver, e xce pt u n der u nf oreseea ble 
cli nical circ u msta nces, t he air wa y 
cleara nce mai nte na nce 
treat me nt/ pr oce d ures a n d p ul m o nar y 
re ha bilitati o n s h o ul d c o nti n ue 
u nc ha n ge d t hr o u g h o ut t he d ur ati o n of 
t he st u d y t hr o u g h Visit 1 0 ( E O S).  
 
Clarifie d t hat t he d urati o n is t hr o u g h 
Visit  1 0  
T a ble 6: Sc he d ule of 
E ve nts  
Pri or/ C o nc o mita nt 
Me dicati o ns  
 
X  
I n dicate d t hat re vie w a n d 
d oc u me ntati o n of pri or a n d c o nc o mita nt 
me dicati o ns  m ust als o ta ke pla ce d uri n g 
Scree ni n g ( Visit 1) t o ali g n wit h Secti o n 
6. 1. 1.  
T a ble 6: Sc he d ule of 
E ve nts  
C ollecti o n of P K sa m ple 
f or I N S 1 0 0 7 at E n d of 
St u d y Visit  
 
X  
I nte nse P K Tr o u g h  Sa m pli n g  
X  
I nte nse P K Sa m pli n g 
Re vise d t he ta ble t o be c o nsist e nt wit h  
c orres p o n di n g f o ot n ote “j ”  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
T a ble 6: Sc he d ule of 
E ve nts  
F o ot n ote “c”  
Vital Si g ns ( B P, H R, T, 
R R)  
Cli nical La b orat or y T ests 
( He mat ol o g y, Bl o o d 
C he mistr y a n d Uri nal ysis)  
 
c 
Cli nical la b orat or y bl o o d sa m ples 
s h o ul d be c ollecte d pri or t o t he first d ose 
of t he  st u d y dr u g o n Da y 1.  
c 
Vital si g ns a n d cli nical la b orat or y 
bl o o d sa m ples s h o ul d be c ollecte d pri or 
t o t he first d ose of t he st u d y dr u g o n 
Da y  1.  
Re vise d f o ot n ote t o ali g n wit h 
Secti o n  9. 5. 1. 3. 3  
A d de d f o ot n ote t o c orres p o n di n g r o ws 
i n t he Sc he d ule of E ve nts ta bl e 
 
T a ble 6: Sc he d ule of 
E ve nts  
F o ot n ote “ g”  
 
7. 7 . 5. 
De nt al 
E x a mi n ati o n  
g  
S u bj ects w h o are e de nt ul o us will 
n ot b e re q uire d t o ha ve t he de ntal 
e xa mi nati o n.   All ot her s u bj ects w h o 
meet all i ncl usi o n b ut n o ne of t he 
e xcl usi o n criteria are re q uire d t o h a ve a 
de ntal e xa mi nati o n t hat i ncl u des a f ull 
m o ut h de ntal ra di o gra p h y a n d oral 
e xa mi nati o n t o e val uate t he c o n diti o ns 
of oral s oft tiss ue, gi n gi va, a n d teet h 
d uri n g Scree ni n g.   
g  
All s u bj ects nee d a de ntal e xa m.  If 
a s u bj ect states t hat he/s he has n o te et h, 
a de ntist s h o ul d c o nfir m t hat t he s u bj ect 
has n o teet h a n d/ or i m pla nts s u p p orti n g 
a de nt ure.  A n y de nt ure s ores or a n y 
ot her pat h ol o g y s h o ul d be n ote d b ut will 
n ot e xcl u de t he s u bj ect fr o m t he st u d y.  
All ot her s u bj ects w h o meet all i ncl usi o n 
b ut n o ne  of t he e xcl usi o n criteria are 
re q uire d t o ha ve a de ntal e xa mi nati o n 
t hat i ncl u des a f ull m o ut h de nt al 
ra di o gra p h y a n d oral e xa mi nati o n t o 
e val uate t he c o n diti o ns of oral s oft 
tiss ue, gi n gi va, a n d teet h d uri n g 
Scree ni n g.   
S u bj ects w h o are c o nsi dere d a scr ee n 
fail ure f or reas o ns n ot relate d t o t he 
de ntal e xcl usi o n criteria ( Secti o n 4. 1. 2, 
e xcl usi o n criteria 2 9 t hr o u g h 3 2) d o n ot 
nee d t o re peat t he de ntal e xa mi nati o n if 
t hey are  re-scree ne d wit hi n 3 m o nt hs of 
t he first Scree ni n g visit. 
 
Re vise d beca use e d e nt ul o us patie nts 
ma y ha ve de nt ure s ores pr o d uce d b y 
de nt ures.  A n e xa mi nati o n a n d re -
i nstr ucti o n de nt ure mai nte na nce ma y 
pre ve nt a n y f urt her deteri orati o n d uri n g 
t he st u d y peri o d. 
 
Clarifie d de ntal e xa m re q uire me nt f or 
s u bj ects w h o scree n fail f or reas ons n ot 
relate d t o t he de ntal e xcl usi o n criteria 
T a ble 6: Sc he d ule of 
E ve nts  
i 
S u bj ects will c o m plete t he Q O L -B 
a n d L C Q e ver y 2 wee ks u ntil Visit  1 0.  
i 
S u b j ects will c o m plete t he S G R Q , 
Q O L -B , a n d L C Q e ver y 2 we e ks u ntil 
Re vise d f o o t n ote t o ali g n wit h 
Secti o n  3. 1  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 2  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
F o ot n ote “i”  
S G R Q C o m pleti o n a n d 
Re vie w  
 
T he s u bj ects will c o m plete t he 
q uesti o n naires w hile t he y are i n t he 
cli nic at eac h of t he st u d y visits a n d at 
h o me f or t he wee ks i n bet wee n t he st u d y 
visits.  T he c o m plete d q uesti o n naires 
s h o ul d be re vie we d d uri n g eac h visit.  
S u bj ects will be retrai ne d o n h o w t o 
c o m plete t he q uesti o n naires c orrectl y if 
nee de d.   
Visit  1 0.  S u bj ects will be re q uire d t o 
c o m plete all 3 q uesti o n naires after t he 
trai ni n g a n d pri or t o t he a d mi nistrati o n 
of t he first d ose of t heir assi g ne d st u d y 
dr u g o n Visit 2 ( Da y  1).  T h e s u bj ects 
will c o m plete t he q uesti o n naires w hile 
t he y are i n t he cli nic at eac h of t he st u d y 
visits a n d at h o me f or t he wee ks i n 
bet wee n t he st u d y visits.  T he c o m plete d 
q uesti o n naires s h o ul d be re vie we d 
d uri n g eac h visit.  S u bj ects will be 
retrai ne d o n ho w t o c o m plete t he 
q uesti o n naires c orrectl y if nee de d.   
A d de d f o ot n ote t o c orres p o n di n g r o w i n 
t he Sc he d ule of E ve nts ta ble 
7. 2. 1.  
Q u alit y of Life 
Q uesti o n n aire -
B r o nc hiect asis  
 
T he Q O L -B will be pr o vi de d t o t he 
st u d y s u bj ects i n a n electr o nic f or mat o n 
a ha n d -hel d c o m p uter ta blet after 
ra n d o mizati o n.  S u bj ects will c o m plete 
t he q uesti o n naire directl y o n t he 
c o m p uter ta blet e ver y 2 wee ks fr o m 
Visits 2 t hr o u g h 9 (refer t o T a ble 6).  
T he Q O L -B will be pr o vi de d t o t he  
st u d y s u bj ects i n a n electr o nic f or mat o n 
a ha n d -hel d c o m p uter ta blet after 
ra n d o mizati o n.  S u bj ects will be 
re q uire d t o c o m plete t he Q O L-B after 
t he trai ni n g a n d pri or t o t he 
a d mi nistrati o n of t he first d ose of t heir 
assi g ne d st u d y dr u g o n Visit 2 ( Da y  1 ).  
S u bj ects will c o m plete t he q uesti o n naire 
directl y o n t he c o m p uter ta blet e ver y 2 
wee ks fr o m Visits 2 t hr o u g h 9 (refer t o 
T a ble 6).  
Re vise d t o ali g n wit h Secti o n 3. 1  
7. 3. 1.  
Leicester C o u g h 
Q uesti o n n aire  
 
T he L C Q will be pr o vi de d t o t he st u d y 
s u bj ects i n a n electr o nic f or mat o n a 
ha n d hel d c o m p uter ta blet after 
Ra n d o mizati o n.  S u bj ects will c o m plete 
t he q uesti o n naire directl y o n t he 
c o m p uter ta blet e ver y 2 wee ks fr o m 
Visits 2 t hr o u g h 9 (refer t o T a ble 6).  
T he L C Q will be pr o vi de d t o t he st u d y 
s u bj ects i n a n electr o nic f or mat o n a 
ha n d hel d c o m p uter ta blet after 
Ra n d o mizati o n.  S u bj ects will be 
re q uire d t o c o m plete t he L C Q after t he 
trai ni n g a n d pri or t o t he a d mi nistrati o n 
of t he first d ose of t heir assi g ne d st u d y 
dr u g o n Visit 2 ( Da y  1).  S u bjects will 
c o mplete t he q uesti o n naire directl y o n 
t he c o m p uter ta blet e ver y 2 wee ks fr o m 
Visits 2 t hr o u g h 9 (refer t o T a ble 6).  
Re vise d t o ali g n wit h Secti o n 3. 1  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 3  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
7. 3. 2.  
St . Ge o r g e’s 
Res pir at or y 
Q uesti o n n aire  
 
T he S G R Q will be pr o vi de d t o t he st u d y 
s u bj ects i n a n electro nic f or mat o n a 
ha n d hel d c o m p uter ta blet after 
ra n d o mizati o n.  S u bj ects will c o m plete 
t he q uesti o n naire directl y o n t he 
c o m p uter ta blet at Baseli ne ( Visit 2), 
W ee k 1 2 ( Visit 6) a n d Wee k 2 4 ( Visit 
9).  It is i m p orta nt f or t he site staff t o 
re mi n d t he s u bj ects t o bri n g t heir 
c o m p uter ta blets wit h t he m t o eac h 
cli nic visit.  
T he S G R Q will be pr o vi de d t o t he st u d y 
s u bj ects i n a n electr o nic f or mat o n a 
ha n d hel d c o m p uter ta blet after 
ra n d o mizati o n.  S u bj ects will be 
re q uire d t o c o m plete t he S G R Q after t he 
trai ni ng a n d pri or t o t he a d mi nistrati o n 
of t he first d ose of t heir assi g ne d st u d y 
dr u g o n Visit 2 ( Da y  1).  S u bjects will 
c o m plete t he q uesti o n naire directl y o n 
t he c o m p uter ta blet at Baseli ne ( Visit 2), 
Wee k 1 2 ( Visit 6) a n d Wee k 2 4 ( Visit 
9).  It is i m p orta nt f or t he site staff t o 
re mi n d t he s u bj ects t o bri n g t heir 
c o m p uter ta blets wit h t he m t o eac h 
cli nic visit.  
Re vise d t o ali g n wit h Secti o n 3. 1  
T a ble 6: Sc he d ule of 
E ve nts  
F o ot n ote “j ”  
 
7. 6 . 1. 
P h ar m ac o ki netic 
S a m pli n g  
 
 
F or s u bj ects partici pati n g i n t he 
i nte nsi ve P K s u b st u d y, a meal will b e 
gi ve n after t he 1 -h o ur bl o o d dra w  at 
Visits 2 a n d 4 ( refer t o A p pe n di x 4 f or 
bl o o d sa m pli n g ti mes) . 
 
A d de d i nstr ucti o ns o n fee di n g ti me f or 
s u bj ects w h o u n der g o i nte nsi ve P K 
sa m pli n g at 1, 2, 3, 4, 6, a n d 8 h o urs 
p ost -d ose  
A p pe n di x 4 . I nte nse 
P h ar m ac o ki netic 
S a m pli n g Sc he me  
 
 
At Visits 2 a n d 4, s u bj ects will be fe d 
after t he 1 -h o ur bl o o d dra w.  
 
T a ble 6: Sc he d ule of 
E ve nts  
 
6. 1. 1.  
Visit 1 ( D a ys -4 2 
t o -1)  
 
C hil d – P u g h Sc ore ( o nl y f or s u bj ects 
w h ose li ver f u ncti o n tests are a b n or mal 
a n d s us pecte d t o ha ve c hr o nic li ver 
disease t o assess f or eli gi bilit y)  
A d de d C hil d -P u g h Sc ore t o Ta ble 6 a n d 
Secti o n 6. 1. 1 t o ali g n wit h Secti o n 7. 4. 8  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 4  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
7. 5 .5 . 
C o nc o mit a nt 
M e dic ati o ns a n d 
Pr o ce d ures  
Re vie w a n d d oc u me ntati o n of pri or a n d 
c o nc o mita nt me dicati o ns f or eac h 
s u bj ect will b e c ollecte d fr o m Visit 2 
( B aseli ne, Da y 1) u ntil  Visit 1 0 ( E O S, 
Da y  1 9 7), a n d rec or de d i n t he st u d y 
s o urce d oc u me nt a n d e C R F.   
C o nc o mita nt pr oce d ures will be 
c ollecte d fr o m Visit 1 ( Baseli ne, Da y  1) 
u ntil  Vis it 1 0 ( E O S, Da y 1 9 7).   
Re vie w a n d d oc u me ntati o n of pri or a n d 
c o nc o mita nt me dicati o ns f or eac h 
s u bj ect will be c ollecte d fr o m Visit 2 
( Baseli ne, Da y 1) t hr o u g h Visit 1 0 
( E O S, Da y 1 9 7), a n d rec or de d i n t he 
st u d y s o urce d oc u me nt a n d e C R F.   
C o nc o mita nt pr oce d ures will be 
c ollecte d fr o m Visit 1 ( Baseli ne, Da y  1) 
t hr o u g h Visit 1 0 ( E O S, Da y  1 9 7).   
 
Clarifie d t hat t he d urati o n is t hr o u g h 
Visit  1 0  
7. 7 . 5. 
De nt al 
E x a mi n ati o n  
All ot her s u bj ects w h o meet all i ncl usi o n 
b ut n o ne of t he e xcl usi o n criteria e xce pt 
t he dental e xcl usi o n criteria are re q uire d 
t o ha ve a de ntal e xa mi nati o n t hat 
i ncl u des a f ull-m o nt h  de ntal ra di o gra p h y 
a n d oral e xa mi nati o n t o e val uate t he 
c o n diti o ns of oral s oft tiss ue, gi n gi va 
a n d teet h b y t he st u d y desi g nate d l ocal 
de ntist ( prefera bl y a peri o d o ntist) d uri n g 
Visit 1 ( Scree ni n g).  S u bj ects w h o ha ve 
t he i ma ges of a f ull-m o nt h  de ntal 
ra di o gra p h y t hat are perf or me d wit hi n 6 
m o nt hs of Visit 1 ( Scree ni n g) a n d 
a vaila ble f or re vie w at Visit 1 are n ot 
re q uire d t o ha ve a n ot her de ntal 
ra di o gra p h y d o ne d uri n g Visit 1. 
All ot her s u bj ects w h o meet all i ncl usi o n 
b ut n o ne of t he e xcl usi o n criteria e xce pt 
t he de ntal e xcl usi o n criteria are re q uire d 
t o ha ve a de ntal e xa mi nati o n t hat 
i ncl u des a f ull-m o ut h de ntal ra di o gra p h y 
a n d oral e xa mi nati o n t o e val uate t he 
c o n d iti o ns of oral s oft tiss ue, gi n gi va 
a n d teet h b y t he st u d y desi g nate d l ocal 
de ntist ( prefera bl y a peri o d o ntist) d uri n g 
Visit 1 ( Scree ni n g).  S u bj ects w h o ha ve 
t he i ma ges of a f ull- m o ut h de ntal 
ra di o gra p h y t hat are perf or me d wit hi n 6 
m o nt hs of Visit 1 ( Scr ee ni n g) a n d 
a vaila ble f or re vie w at Visit 1 are n ot 
re q uire d t o ha ve a n ot her de ntal 
ra di o gra p h y d o ne d uri n g Visit 1. 
 
C orrecte d t y p o  
8. 4. 1.  
Peri o d of 
O bser v ati o n f or A d verse 
E ve nts  
 
All A Es will be f oll o we d u ntil t he 
res ol uti o n or sta bilizati o n of t he A Es .   
A d de d  t o clarif y t hat s u bj ects s h o ul d 
re mai n u n der o bser vati o n u ntil t he 
res ol uti o n or c o ns oli dati o n of t he 
a d verse effects.  Data base l oc k will 
occ ur at t he desi g nate d ti mes, b ut 
f oll o w-u p of a d verse e ve nts will 
c o nti n ue u ntil res ol uti o n or sta bilizat i o n. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
8. 4. 2.  
Seri o us A d verse 
E ve nts  
Deat hs a n d life -t hreate ni n g e ve nts wit h 
a n y p ossi ble relati o ns hi p t o a st u d y 
i nter ve nti o n m ust be re p orte d t o t he 
F D A  b y tele p h o ne or fa x as s o o n as 
p ossi ble, b ut wit hi n 7 cale n dar da ys of 
n otificati o n t o I ns me d.  T his i nitial 
re p ort m ust b e f oll o we d b y a m ore 
c o m plete writte n re p ort wit hi n 8 
a d diti o nal  cale n dar da ys.  S A Es, 
i ncl u di n g t h ose t hat d o n ot me et 
re q uire me nts f or e x pe dite d re p orti n g, 
a n d all ot her A Es will be re p orte d t o t he 
F D A  i n t he I n vesti gati o nal Ne w Dr u g 
a n n ual re p ort a n d t o t he E ur o pea n 
Me dici nes A ge nc y  i n t he Dr u g Safet y 
U p date Re p or t. 
Deat hs a n d life -t hreate ni n g e ve nts wit h 
a n y p ossi ble relati o ns hi p t o  a st u d y 
i nter ve nti o n m ust be re p orte d t o t he 
Re g ulat or y A ge ncies  b y tele p h o ne or fa x 
as s o o n as p ossi ble, b ut wit hi n 7 
cale n dar da ys of n otificati o n t o I ns me d.  
T his i nitial re p ort m ust be f oll o we d b y a 
m ore c o m plete writte n re p ort wit hi n 1 5 
cale n dar da ys .  S A Es, i ncl u di n g t h ose 
t hat d o n ot meet re q uire me nts f or 
e x pe dite d re p orti n g, a n d all ot her A Es 
will be re p orte d t o t he Re g ulat or y 
A ge ncies  i n t he I n vesti gati o nal Ne w 
Dr u g a n n ual re p ort a n d t he Dr u g Safet y 
U p date Re p ort , as a p pr o priate. 
U p date d t o a d here  t o c urre nt re g ulat or y 
re p orti n g re q uire me nt 
9. 5. 2. 1.  P h ar m ac o ki netic 
A n al ysis  
F or s u bj ects n ot partici pati n g i n t he P K 
s u b-st u d y, I N S 1 0 0 7 plas ma 
c o nce ntrati o n data fr o m t his st u d y will 
be p o ole d wit h data fr o m ot her st u dies 
f or t he p ur p oses of de vel o pi n g a 
p o p ulati o n P K m o del.   
F or s u bj ects n ot partici pati n g i n t he P K 
s u b-st u d y, s parse P K sa m pli n g will be 
c o n d ucte d i n s u bj ects at all sit es wit h P K 
sa m pli n g pr ocessi n g ca pa biliti es.  
I N S 1 0 0 7 plas ma c o nce ntrati o n data 
fr o m t his st u d y will be p o ole d wit h data 
fr o m ot her st u dies f or t he p ur p oses of 
de vel o pi n g a p o p ulati o n P K ( P P K) 
m o del.   
A d de d t o ali g n wit h t he pr ot oc ol 
s y n o psis 
9. 5. 2. 2.  
P h ar m ac o d y n a mic 
A n al ysis  
 
T he N E acti vit y i n s p ut u m a n d bl o o d 
will be calc ulate d as perce nt i n hi biti o n 
fr o m t he pre-treatme nt acti vit y a n d 
n or malize d b y A N C ( bl o o d o nl y).  Pre -
treat me nt val ue is defi ne d as t he mea n 
val ue of N E acti vities at Scree ni n g a n d 
Baseli ne a n d  will be liste d a n d 
s u m marize d t o get her wit h t he A N C 
meas ure me nts.  
A d de d t o ali g n wit h t he pr ot oc ol 
s y n o psis 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 6  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
1 3.  Refere nces  
 
K u na P, J e n ki ns M, O’ Brie n C D, Fa h y 
W A. A Z D 9 6 6 8, a ne utr o p hil elastase 
i n hi bit or, pl us o n g oi n g 
b u des o ni de/f or m oter ol i n pati e nts wit h 
C O P D. Res pir Me d. 2 0 1 2 
A pr; 1 0 6( 4): 5 3 1 -5 3 9.  
A d de d literat ure refere nce f or citati o n i n 
Secti o n 1. 5. 1  
T hr o u g h o ut  
C orrecte d gra m matical, mec ha nical, a n d t y p o gra p hical err ors  f or clarit y a n d c o nsiste nc y  
U p date d t he List of A b bre viati o ns a n d Defi niti o ns of T er ms a n d t he use of a b bre viati o ns t hr o u g h o ut t he d oc u me nt  
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 7  of 1 5 5  
 
S U M M A R Y O F C H A N G E S T O A M E N D E D P R O T O C O L V E R SI O N 4 . 0, D A T E D 2 7  A P RI L 2 0 1 8  
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
8. 4. 1 P eri o d of O bser vati o n 
f or A d verse E ve nts 
F or t he p ur p oses of t his st u d y, t he peri o d 
of o bser vati o n f or c ollecti o n of all A Es 
will b e fr o m t he ti me t he s u bj ect si g ns 
t he I C F u ntil t he res ol uti o n or 
sta bilizati o n of t he a d verse e ve nts.  All 
A Es will  be rec or de d o n t he A Es F or m 
of t he e C R F.  I n t he safet y a nal ysis, A Es 
t hat occ ur bet wee n t he ti me t he s u bj ect 
si g ns t he I C F f or t he st u d y a n d t he ti me 
w he n t he s u bj ect recei ves his/ her first 
d ose will be s u m marize d as me dical 
hist or y a n d n ot as a T E A E u nl ess t he 
e ve nt meets t he defi niti o n of a n S A E as 
de fi ne d bel o w. 
F or p ur p oses of t his st u d y, t he peri o d of 
o bser vati o n f or c ollecti o n of a n y A Es 
will be fr o m t he ti me t he s u bj ect si g ns 
t he I C F u ntil 3 0 da ys after t he fi nal d ose 
of st u d y dr u g or t o t he date of s u bj ect’s 
E n d of St u d y Visit, w hic he ver date is 
later.  All A Es s h o ul d be rec or de d o n t he 
A Es F or m of t he e C R F a n d s h o ul d be 
o bser ve d u ntil t he res ol uti o n or 
sta bilizati o n of t he a d verse e ve nts.  I n 
t he safet y a nal ysis, A Es t hat occ ur 
bet wee n t he ti me t he s u bj ect si g ns t he 
I C F f or t he st u d y a n d t he ti me w he n t he 
s u bj ect recei ves his/ her first d ose will b e 
s u m marize d as me dical hist or y a n d n ot 
as a T E A E u nless t he e ve nt meets t he 
defi niti o n of a n S A E as defi ne d bel o w.  
 
Secti o n re vise d t o clarif y t he d urati o n of 
a d verse e ve nt d ata c ollecti o n f oll o wi n g 
last a d mi nistrati o n of st u d y dr u g a n d 
e ns ure c o nsiste nc y wit h sc he d ule of 
e ve nts b y ta ki n g i nt o c o nsi der ati o n ti me 
all ocate d f or visit wi n d o ws.     
3. 3. 4. 1 St u d y 
Disc o nti n u ati o n  
If t he st u d y is pre mat urel y ter mi nate d, 
all s u bj ects w h o recei ve d a d ose of a n y 
of  t he st u d y dr u gs a n d ha ve n ot 
c o m plete d t heir st u d y peri o d will be 
disc o nti n ue d fr o m t he st u d y 
i m me diatel y; all t he safet y pr oce d ures 
(refer t o safet y pr oce d ures d uri n g Visit 
9) re q uire d t o be perf or me d will be 
c o n d ucte d.  All disc o nti n ue d s u bj ects 
will b e  f oll o we d u p b y a p h o ne call 2 8 
da ys after disc o nti n uati o n f or c ollecti o n 
of A Es.  
If t he st u d y is pre mat urel y ter mi nate d, 
all s u bj ects w h o recei ve d a d ose of a n y 
of t he st u d y dr u gs a n d ha ve n ot 
c o m plete d t heir st u d y peri o d will b e 
disc o nti n ue d fr o m t he st u d y 
i m me diatel y; all t he safet y pr oce d ures 
(refer t o safet y pr oce d ures d uri n g Visit 
9) re q uire d t o be perf or me d will be 
c o n d ucte d.  All disc o nti n ue d s u bj ects 
will be f oll o we d u p b y a p h o ne call 2 8 
da ys ( +/- 3 da ys) after disc o nti n uati o n 
f or c ollecti o n of A Es. 
Secti o n re vise d t o e na ble a wi n d o w of 
+/ - 3 da ys f or data c ollecti o n c o nsiste nt 
wit h ti me wi n d o ws all o we d f or st u d y 
visits.     
5. 3 Pr o hi bite d 
M e dic ati o ns  
T a ble 1  
Re q uire d Was h o ut P eri o d  
T a ble 1  
Re q uire d Was h o ut P eri o d  
Secti o n re vise d t o e na ble a wi n d o w of 
+/ - 3 da ys c o nsiste nt wit h ti me wi n d o ws 
all o we d f or st u d y visits.     


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 8  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
6 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -u p  
 
6 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 3 
da ys) Safet y F oll o w -u p  
 
 
T a ble 2  
Re q uire d Was h o ut P eri o d  
 
M o derate  C Y P 2 D 6  I n hi bit ors 
6 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
 
Str o n g  C Y P 2 D 6  I n hi bit ors 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
 
M o derate  C Y P 2 C 8  I n hi bit ors 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
 
Str o n g  C Y P 2 C 8  I n hi bit ors 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
 
T a ble 2  
Re q uire d Was h o ut P eri o d  
 
M o derate  C Y P 2 D 6  I n hi bit ors 
6 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3 da ys) Safet y F oll o w -U p  
 
Str o n g  C Y P 2 D 6  I n hi bit ors 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3  da ys) Safet y F oll o w -U p  
 
M o derate  C Y P 2 C 8  I n hi bit ors 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3  da ys) Safet y F oll o w -U p  
 
Str o n g  C Y P 2 C 8  I n hi bit ors 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/ - 
3  da ys) Safet y F oll o w -U p  
Secti o n re vise d t o e na ble a wi n d o w of 
+/ - 3 da ys c o nsiste nt wit h ti me wi n d o ws 
all o we d f or st u d y visits.     
 
T a ble 3  
Re q uire d Was h o ut P eri o d  
 
M o derate  C Y P 3 A 4/ 5  I n hi bit or 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
 
Str o n g  C Y P 3 A 4/ 5  I n hi bit ors 
T a ble 2  
Re q uire d Was h o ut P eri o d  
 
M o derate  C Y P 3 A 4/ 5  I n hi bit or 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3  da ys)  Safet y F oll o w -U p  
 
Str o n g  C Y P 3 A 4/ 5  I n hi bit ors 
Secti o n re vise d t o e na ble a wi n d o w of 
+/ - 3 da ys c o nsiste nt wit h ti me wi n d o ws 
all o we d f or st u d y visits.     


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 9  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3  da ys)  Safet y F oll o w -U p  
 
T a ble 4  
Re q uire d Was h o ut P eri o d  
 
M o derate  C Y P 3 A 4/ 5  I n hi bit ors  
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
 
Str o n g  C Y P 3 A 4/ 5  I n d ucers 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y Safet y 
F oll o w -U p  
T a ble 4  
Re q uire d Was h o ut P eri o d  
 
M o derate  C Y P 3 A 4/ 5  I n hi bit ors  
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3  da ys)  Safet y F oll o w -U p  
 
Str o n g  C Y P 3 A 4/ 5  I n d ucers 
4 w ee ks pri or  t o Da y 1  t o 2 8-da y ( +/- 
3  da ys)  Safet y F oll o w -U p  
Secti o n re vise d t o e na ble a wi n d o w of 
+/ - 3 da ys c o nsiste nt wit h ti me wi n d o ws 
all o we d f or st u d y visits.     


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 0  of 1 5 5  
 
S U M M A R Y O F C H A N G E S T O A M E N D E D P R O T O C O L V E R SI O N 3. 0, D A T E D 1 2  M A R C H 2 0 1 8  
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
1. 3. 2   
Cli nical 
E x perie nce  
I N S 1 0 0 7 has bee n assesse d i n 2 healt h y 
v ol u nteer st u dies ( D 6 1 9 0 C 0 0 0 1 a n d 
D 6 1 9 0 C 0 0 0 0 3).  
I N S 1 0 0 7 has bee n assesse d i n 2 healt h y 
v ol u nteer st u dies ( D 6 1 9 0 C 0 0 0 1 a n d 
D 6 1 9 0 C 0 0 0 0 3).  
St u d y  D 6 1 9 0 C 0 0 0 0 1  
St u d y D 6 1 9 0 C 0 0 0 0 1 was a P hase 1, 
ra n d o mized, si n gle -bli n d, place b o -
c o ntr olle d, m ulti -part st u d y i n healt h y a d ult 
male v ol u nteers.  
P art 1a was a si n gle asce n di n g d ose ( S A D) 
st u d y i n w hic h 4 5 s u bj ects recei ve d eit her 
place b o ( 1 5 s u bj ects) or I N S 1 0 0 7 ( 5, 1 5, 
3 5, 5 0, or 6 5 m g [ 6  s u bj ects per d ose 
le vel]) u n der fasti n g c o n diti o ns.  
P art 1 b was a si n gle -d ose f o o d effect st u d y 
i n w hic h 8 s u bj ects ( C o h ort 3 fr o m P art 1a 
after a was h o ut of at least 7 da ys) recei ve d 
eit her place b o ( 3 s u bj ects) or 3 5 m g 
I N S 1 0 0 7 ( 5 s u bj ects) after a hi g h-fat 
brea kfast.  
P art 2 was a m ulti ple asce n di n g d ose 
( M A D) st u d y i n w hic h 3 6 s u bj ects ( w h o 
di d n ot partici pate i n P art  1) recei ve d eit her 
place b o ( 1 2  s u bj ects) or I N S 1 0 0 7 ( 6 
s u bj ects recei ve d 1 0 m g/ da y f or 2 1 da ys, 8 
s u bj ects recei ve d 2 5 m g/ da y f or 2 8 da ys, 
a n d 1 0 s u bj ects rec ei ve d 4 0 m g/ da y f or 
2 8  da ys) u n der fasti n g c o n diti o ns.  
T he safet y varia bles f or I N S 1 0 0 7 were 
a d verse e ve nts ( A Es); safet y l a b orat or y 
assess me nts ( he mat ol o g y, cli nical 
c he mistr y, uri nal ysis); vital si g ns ( p ulse 
rate, bl o o d press ure, oral b o d y 
Secti o n re vise d t o pr o vi de 
a d diti o nal i nf or mati o n o n t he 
c o m plete d P hase 1 st u dies.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 1  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
te m perat ure); 1 2 -lea d pa per a n d di gital 
electr ocar di o gra m ( E C G, pre -h os pital E C G 
[ p E C G], a n d direct E C G [ d E C G]); 
tele metr y; p h ysical e xa mi nati o n res ults 
(i ncl u di n g e val uati o n of gi n gi va a n d teet h, 
a n d e val uati o n of pal ms a n d s oles). I n 
a d diti o n, part 2 la b orat or y assess me nts als o 
i ncl u de d ne utr o p hil p ha g oc yt osis, 
o xi dati ve b urst, s per mat o gra m [fertile male 
s u bj ects partici pati n g i n C o h ort 3 a n d 
o n war ds] a n d re pr o d ucti ve h or m o nes 
[ C o h ort 3 a n d o n war ds]); 
St u d y  D 6 1 9 0 C 0 0 0 0 3  
St u d y D 6 1 9 0 C 0 0 0 0 3 was a n o pe n -la bel, 
fi xe d se q ue nce, 3 -peri o d, dr u g -dr u g 
i nteracti o n ( D DI) st u d y of t he effects of 
c o nc o mita nt vera pa mil ( m o derate C Y P 3 A 4 
i n hi bit or) a n d itrac o naz ole (str o n g 
C Y P 3 A 4 i n hi bit or) o n t he si n gle -d ose P K 
of I N S 1 0 0 7 a n d its t olera bilit y a n d safet y 
i n healt h y a d ult male v ol u nteers. T he st u d y 
c o nsiste d of 3  peri o ds wit h at l east a 7 -da y 
was h o ut bet wee n P eri o ds 1 a n d 2 a n d at 
least a 1 4-da y was h o ut bet wee n P eri o ds 2 
a n d 3. D uri n g P eri o d 1, 1 5 s u bj ects 
recei ve d a si n gle d ose of I N S 1 0 0 7 ( 2 5 m g). 
D uri n g P eri o d 2, t he sa me s u bj ects 
recei ve d vera pa mil ( 2 4 0 m g, e xte n de d 
release f or m ulati o n) o n Da ys 1 t hr o u g h 1 0 
pl us a si n gle d ose of I N S 1 0 0 7 ( 2 5 m g) o n 
Da y  5. D uri n g P eri o d 3, t he sa me s u bj ects 
recei ve d itrac o naz ole ( 2 0 0 m g as oral 
s ol uti o n of 1 0 m g/ m L) t wice o n Da y  1 a n d 
t he n o nce dail y o n Days 2 t hr o u g h 1 1 pl us 
a si n gle d ose of I N S 1 0 0 7 ( 2 5  m g) o n Da y  
6. All dr u gs were a d mi nistere d u n der 
fasti n g c o n diti o ns. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 2  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
Safet y varia bles i ncl u de d A Es, vital si g ns 
(s yst olic a n d diast olic bl o o d press ure, p ulse 
rate a n d te m perat ure), electr ocar di o gra ms 
(safet y a n d d E C Gs), la b orat or y 
assess me nts ( he mat ol o g y, cli nical 
c he mistr y a n d uri nal ysis) a n d p h ysical 
e xa mi nati o ns (i ncl u di n g e val uati o n of 
gi n gi va a n d teet h a n d e val uati o n of pal ms 
a n d s oles). Viral ser ol o g y, t u b erc ul osis 
( T B) scree n a n d uri ne dr u gs of a b use, 
alc o h ol a n d c oti ni ne were assesse d f or 
eli gi bilit y. T he use of c o nc o mita nt 
me dicati o ns was als o assesse d a n d 
re p orte d. 
1. 5. 2. 2  I nfecti o ns 
8. 3. 3  
Ot her I nfecti o ns  
All seri o u s i nfecti o ns a n d all s pecific 
i nfecti o ns belie ve d t o be ass ociate d wit h 
ne utr o pe nia, s uc h as s ki n i nfe cti o n, s oft 
tiss ue i nfecti o n, uri nar y tract i nfecti o n, 
gi n gi vitis s h o ul d be e ntere d i n t he i nfecti o n 
m o d ule of t he electr o nic case re p ort f or m 
(e C R F).  
 
A ll seri o us i nfecti o ns a n d all s pecific 
i nfecti o ns belie ve d t o be ass ociate d wit h 
ne utr o pe nia, s uc h as s oft tiss ue i nfecti o n, 
uri nar y tract i nfecti o n s h o ul d be e ntere d i n 
t he i nfecti o n m o d ule of t he e C R F.  
 
All s ki n a n d gi n gi vitis e ve nts 
s h o ul d be re p orte d i n t he s pecific 
pa ge of A Es of s pecial i nterest f or 
s ki n a n d de ntal a d verse e ve nts. 
S y n o psis a n d Secti o n 
2. 1. 2  
Sec o n dar y 
O bj ecti ves  
1. T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n q ualit y of life 
( Q O L), as assesse d b y t he Q ualit y of Life 
Q ues ti o n naire-Br o nc hiectasis ( Q O L -B), 
Res pirat or y S y m pt o ms D o mai n sc ore, o ver 
t he 2 4-wee k treat me nt peri o d.  
2.  T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n l u n g f u ncti o n, 
as meas ure d b y f orce d e x pirat or y v ol u me 
i n 1 sec o n d ( F E V1 ), o ver t he 2 4-we e k 
treat me nt p eri o d. 
3.  T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
c o nce ntrati o n of acti ve ne utr o p hil elastase 
1. T o e va l uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n q ualit y of life 
( Q O L), as assesse d b y t he Q ualit y of Life 
Q uesti o n naire -Br o nc hiectasis ( Q O L -B), 
Res pirat or y S y m pt o ms D o mai n sc ore, o ver 
t he 2 4-wee k treat me nt peri o d.  
2.  T o e val uate t he effect of I N S 1 0 0 7  
c o m pare d wit h place b o o n l u n g f u ncti o n, 
as meas ure d b y f orce d e x pirat or y v ol u me 
i n 1 sec o n d ( F E V1 ), o ver t he 2 4-wee k 
treat me nt peri o d. 
3.  T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
c o nce ntrati o n of acti ve ne utr o p hil elastase 
Details o n calc ulati o n of N E 
acti vit y will be descri be d i n t he 
Statistical A nal ysis Pla n.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 3  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
( N E) i n s p ut u m, as meas ure d b y t he 
differe nce bet wee n t he pre -tre at me nt 
c o nce ntrati o n ( defi ne d as t he a vera ge of 
t he val ues at Scree ni n g a n d D a y  1)  a n d o n-
treat me nt c o nce ntrati o n ( defi ne d as t he 
a vera ge of t he val ues at wee ks 1 2 a n d 2 4) . 
4.  T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he rate of 
p ul m o nar y e xacer bati o ns o ver t he 2 4 -wee k 
treat me nt p eri o d. 
( N E) i n sp ut u m, as meas ure d b y t he 
differe nce bet wee n t he pre -tre at me nt 
c o nce ntrati o n a n d o n -treat me nt 
c o nce ntrati o n.  
4.  T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he rate of 
p ul m o nar y e xacer bati o ns o ver t he 2 4 -wee k 
treat me nt peri o d 
S y n o psis a n d Secti o n 
2. 1. 3  
E x pl orat or y 
O bj ecti ves  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n Q O L, as 
assesse d b y t he  Q O L -B d o mai ns 
(e xcl u di n g t he Res pirat or y S y m pt o ms 
D o mai n) o ver t he 2 4 -wee k treat me nt 
peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n Q O L, as 
assesse d b y t he Leicester C o u g h 
Q uesti o n naire ( L C Q), o ver t he 2 4 -wee k 
treat me nt p eri o d. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pa re d wit h place b o o n res pirat or y-
relate d healt h stat us, as assesse d b y t he St 
Ge or ge’s Res pirat or y Q uesti o n naire 
( S G R Q), o ver t he 2 4-wee k tre at me nt 
peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
c o nce ntrati o n of acti ve N E i n s p ut u m, as 
meas ure d b y t he differe nce bet wee n t he 
pre -treat me nt c o nce ntrati o n a n d t he 
c o nce ntrati o ns at Wee ks 2, 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
c o nce ntrati o n of acti ve N E i n rea ge nt -
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n Q O L, as 
assesse d b y t he  Q O L -B d o mai ns 
(e xcl u di n g t he Res pirat or y S y m pt o ms 
D o mai n) o ver t he 2 4 -wee k treat me nt 
peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n Q O L, as 
assesse d b y t he Leicester C o u g h 
Q uesti o n naire ( L C Q), o ver t he 2 4 -wee k 
treat me nt peri o d. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n res pirat or y -
relate d healt h status, as assesse d b y t he St 
Ge or ge’s Res pirat or y Q uesti o n naire 
( S G R Q), o ver t he 2 4-wee k tre at me nt 
peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
c o nce ntrati o n of acti ve N E i n s p ut u m, as 
meas ure d b y t he differe nce bet wee n t he 
pre -treatme nt c o nce ntrati o n a n d t he 
c o nce ntrati o ns at Wee ks 2, 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
c o nce ntrati o n of acti ve N E i n rea ge nt -
E dits i m ple me nte d t o ali g n 
E x pl orat or y St u d y O bj ecti ves wit h 
t he c orres p o n di n g E x pl orat or y 
St u d y E n d p oi nt s.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 4  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
sti m ulate d bl o o d, as meas ure d b y t he 
di ffere nce bet wee n t he pre-tre at me nt 
c o nce ntrati o n a n d t he c o nce ntrati o ns at 
W ee ks 2, 4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n s p ut u m c ol or at 
W ee ks 2, 4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h pl ace b o o n t he 
c o nce ntrati o n of acti ve N E i n s p ut u m, 
stratifie d b y Baseli ne s p ut u m c ol or, as 
meas ure d b y t he differe nce bet wee n t he 
pre -treat me nt c o nce ntrati o n a n d t he 
c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 
2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n i nfl a m mat or y 
a n d tiss ue de gra dati o n bi o mar kers i n 
s p ut u m at W ee ks 2, 4, 1 2, 2 4, a n d 2 8. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n i nfl a m mat or y 
a n d tiss ue de gra dati o n bi o mar kers i n bl o o d 
a n d uri ne  at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he f oll o wi n g 
p ul m o nar y f u ncti o n para meters (as 
meas ure d b y s pir o metr y) o ver t he 2 4 -wee k 
treat me nt p eri o d:  
F orce d vital ca pacit y ( F V C)  
P ea k e x pirat or y fl o w rate ( P E F R)  
F orce d e x pirat or y fl o w ( F E F) 2 5 t o 7 5 % 
( F E F2 5 -7 5)  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he t otal 
sti m ulate d bl o o d, as meas ure d b y t he 
differe nce bet wee n t he pre -tre at me nt 
c o nce ntrati o n a n d t he c o nce ntrati o ns at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n s p ut u m c ol or 
(assesse d b y t he s p ut u m c ol or c hart ) at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he 
co nce ntrati o n of acti ve N E i n s p ut u m, 
stratifie d b y Baseli ne s p ut u m c ol or, as 
meas ure d b y t he differe nce bet wee n t he 
pre -treat me nt c o nce ntrati o n a n d t he 
c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 
2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n i nfl a m mat or y 
a n d tiss ue de gra dati o n bi o mar kers i n 
s p ut u m (bi o mar kers w hic h ma y be 
assesse d are pr otei nase 3 a n d cat he psi n G)  
at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n i nfl a m mat or y 
a n d tiss ue de gra dati o n bi o mar kers i n bl o o d 
(bi o mar kers w hic h ma y be ass esse d are 
a bs ol ute ne utr o p hil c o u nt [ A N C], 
pr otei nase  3, a n d cat he psi n  G ) at W ee ks 2, 
4, 1 2, 2 4, a n d 2 8.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n i nfl a m mat or y 
a n d tiss ue de gra dati o n bi o mar kers i n uri ne 
( des m osi ne) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he f oll o wi n g 
p ul m o nar y f u ncti o n para meters as 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 5  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
d urati o n of all e xacer bati o ns ( da ys per 
s u bj ect) o ver t he 2 4-wee k treat me nt peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he n u m ber of 
e xacer bati o ns per s u bj ect o ver t he 2 4 -wee k 
treat me nt p eri o d. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n ti me t o first 
p ul m o nar y e xacer bati o n, e xac er bati o n rate, 
Q O L meas ures a n d p ul m o nar y f u ncti o n 
para meters ( F E V 1 , F V C, P E F R, a n d F E F), 
stratifie d b y Baseli ne Br o nc hi ectasis 
Se verit y I n de x, sc ore, o ver t he 2 4 -wee k 
treat me nt p eri o d. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n ti me t o first 
p ul m o nar y e xacer bati o n, e xac er bati o n rate, 
Q O L meas ures a n d p ul m o n ar y f u ncti o n 
para meters ( F E V 1 , F V C, P E F R, a n d 
F E F 2 5 -7 5), stratifie d b y t he pres e nce or 
a bse nce of Pse u d o m o n as aer u gi n os a  at 
Scree ni n g, o ver t he 2 4 -wee k treat me nt 
peri o d.   
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he use of 
resc ue me dicatio ns o ver t he 2 4 -wee k 
treat me nt p eri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n h os pitalizati o ns 
f or p ul m o nar y e xacer bati o ns o ver t he 2 4-
wee k treat me nt peri o d.  
T o assess t he c orrelati o ns a m o n g 
i nfla m mat or y a n d tiss ue de gra dati o n 
bi o mar kers, c o nce ntrati o n of a cti ve N E i n 
bl o o d, s p ut u m, a n d, uri ne a n d efficac y 
meas ures.  
meas ure d b y s pir o metr y ( F orc e d vital 
ca pacit y [ F V C] ) o ver t he 2 4-wee k 
treat me nt peri o d.  
T o e val ua te t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he f oll o wi n g 
p ul m o nar y f u ncti o n para meters as 
meas ure d b y s pir o metr y ( P ea k e x pirat or y 
fl o w rate [ P E F R]) o ver t he 2 4-wee k 
treat me nt peri o d. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he f ol l o wi n g 
p ul m o nar y f u ncti o n para meters as 
meas ure d b y s pir o metr y ( F orc e d e x pirat or y 
fl o w [ F E F] 2 5 t o 7 5 % [ F E F2 5 -7 5]) o ver t he 
2 4 -wee k treat me nt peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he t otal 
d urati o n of all e xacer bati o ns ( da ys p er 
s u bj ect) o ver t he 2 4-wee k treat me nt p eri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he n u m ber of 
e xacer bati o ns per s u bj ect o ver t he 2 4 -wee k 
treat me nt peri o d. 
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n ti me t o first 
p u l m o nar y e xacer bati o n, e xac er bati o n rate, 
Q O L meas ures a n d p ul m o nar y f u ncti o n 
para meters ( F E V 1 , F V C, P E F R, a n d 
F E F 2 5 -7 5), stratifie d b y Br o nc hiectasis 
Se verit y I n de x sc ore at baseli ne, o ver t he 
2 4 -wee k treat me nt peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o mpare d wit h place b o o n ti me t o first 
p ul m o nar y e xacer bati o n, e xac er bati o n rate, 
Q O L meas ures a n d p ul m o nar y f u ncti o n 
para meters ( F E V 1 , F V C, P E F R, a n d 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 6  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
F E F 2 5 -7 5), stratifie d b y t he pres e nce or 
a bse nce of Pse u d o m o n as aer u gi n os a  (P a ) 
at Scree ni n g, o ver t he 2 4 -we e k treat me nt 
peri o d.   
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n t he use of 
resc ue me dicati o ns (resc ue me dicati o ns 
i ncl u de s h ort-acti n g beta a g o nists 
[ S A B As], s h ort-acti n g m uscari nic 
a nta g o nists [ S A M As], ne wl y prescri be d 
l o n g-acti n g beta a g o nists [ L A B As], l o n g -
acti n g m uscari nic a nta g o nists [ L A M As], 
a n d o x y ge n) o ver t he 2 4 -wee k treat me nt 
peri o d.  
T o e val uate t he effect of I N S 1 0 0 7 
c o m pare d wit h place b o o n h os pitalizati o ns 
f or p ul m o nar y e xacer bati o ns o ver t he 2 4-
wee k treat me nt peri o d.  
T o assess  t he c orrelati o ns a m o n g 
i nfla m mat or y a n d tiss ue de gra dati o n 
bi o mar kers, c o nce ntrati o n of a cti ve N E i n 
bl o o d, s p ut u m, a n d, uri ne a n d efficac y 
meas ures.  
S y n o psis a n d Secti o n  
3. 2. 3  
E x pl orat or y 
E n d p oi nts  
C ha n ge fr o m Baseli ne i n Q O L -B sc ores 
(all d o mai ns e xcl u di n g t he Res pirat or y 
S y m pt o ms D o mai n) o ver t he 2 4 -wee k 
treat me nt p eri o d. 
C ha n ge fr o m Baseli ne i n L C Q sc ore o ver 
t he 2 4-wee k treat me nt peri o d.  
C ha n ge fr o m Baseli ne i n S G R Q t otal sc ore 
o ver t he 2 4 -wee k treat me nt peri o d.  
C ha n ge i n c o nce ntrati o n of acti ve N E i n 
s p ut u m fr o m pre-treat me nt t o Wee ks 2, 4, 
a n d 2 8.  
C ha n ge fr o m Baseli ne i n Q O L -B sc ores 
(all d o mai ns e xcl u di n g t he Res pirat or y 
S y m pt o ms D o mai n) o ver t he 2 4 -wee k 
treat me nt peri o d. 
C ha n ge fr o m Baseli ne i n Q O L as assesse d 
b y t he  L C Q sc ore o ver t he 2 4 -wee k 
treat me nt peri o d. 
C ha n ge fr o m Baseli ne i n S G R Q t otal sc ore 
o ver t he 2 4 -wee k treat me nt peri o d.  
C ha n ge i n c o nce ntrati o n of acti ve N E i n 
s p ut u m fr o m pre-treat me nt t o W ee ks 2, 4, 
a n d 2 8.  
E dits i m ple me nte d t o ali g n St u d y 
O bj ecti ves wi t h t he c orres p o n di n g 
St u d y E n d p oi nts.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 7  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
C ha n ge i n c o nce ntrati o n of acti ve N E i n 
rea ge nt-sti m ulate d bl o o d fr o m pre-
treat me nt t o Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
C ha n ge fr o m Baseli ne i n s p ut u m c ol or 
(assesse d b y t he s p ut u m c ol or c hart) at 
W ee ks 2, 4, 1 2, 2 4, a n d 2 8.   
C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d 
tiss ue de gra d ati o n bi o mar ker le vels i n 
s p ut u m at W ee ks 2, 4, 1 2, 2 4, a n d 2 8 (t he 
bi o mar kers t hat ma y be e x pl ore d c o nsist of 
pr otei nase 3 a n d cat he psi n G).  
C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d 
tiss ue de gra d ati o n bi o mar ker le vels i n 
bl o o d at W ee ks 2, 4, 1 2, 2 4, a n d 2 8 (t he 
bi o mar kers t hat ma y be e x pl ore d c o nsist of 
a bs ol ute ne utr o p hil c o u nt ( A N C), 
pr otei nase 3, a n d cat he psi n G).  
C ha n ge fr o m Baseli ne i n des m osi ne i n 
uri ne at W ee ks 2, 4, 1 2, 2 4, a n d 2 8.  
C ha n ge fr o m Scree ni n g of  F V C at Wee ks 
1 2 a n d 2 4.  
C ha n ge fr o m Scree ni n g of  P E F R at Wee ks 
1 2 a n d 2 4.  
C ha n ge fr o m Scree ni n g of  F E F 2 5 -7 5 at 
W ee ks 1 2 a n d 2 4.  
T otal d urati o n (i n da ys) of e xa cer bati o ns, 
per s u bj ect, o ver t he 2 4 -wee k treat me nt 
peri o d.  
Fre q ue nc y of use of resc ue me dicati o ns 
o ver t he 2 4 -wee k  treat me nt peri o d (resc ue 
me dicati o ns i ncl u de s h ort-acti n g beta 
a g o nists, s h ort -acti n g m uscari nic a g o nists, 
ne wl y prescri be d l o n g -acti n g beta a g o nists, 
l o n g-acti n g a nti -m uscari nic a g o nists , a n d 
o x y ge n).   
C ha n ge i n c o nce ntrati o n of acti ve N E i n 
rea ge nt-sti m ulate d bl o o d fr o m pre-
treat me nt t o Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
C ha n ge fr o m Baseli ne i n s p ut u m c ol or 
(assesse d b y t he s p ut u m c ol or c hart) at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8.   
C ha n ge i n c o nce ntrati o n of acti ve  N E i n 
s p ut u m (stratifie d b y s p ut u m c ol or) at 
baseli ne fr o m pre -treat me nt t o W ee ks 2, 4, 
1 2, a n d 2 8 . 
C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d 
tiss ue de gra dati o n bi o mar ker le vels i n 
s p ut u m (t he bi o mar kers w hic h ma y be 
assesse d are e.g . pr otei nase 3 a n d cat h e psi n 
G ) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d 
tiss ue de gra dati o n bi o mar ker le vels i n 
bl o o d ( bi o mar kers w hic h ma y be assesse d 
are e. g. A N C, pr otei nase 3, a n d cat he psi n 
G ) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
C ha n ge fr o m Baseli ne  i n tiss ue de gra d ati o n 
mar ker le vel i n uri ne ( des m osi ne) at W ee ks 
2, 4, 1 2, 2 4, a n d 2 8.  
C ha n ge fr o m Scree ni n g i n F V C at Wee ks 
1 2 a n d 2 4.  
C ha n ge fr o m Scree ni n g i n P E F R at W ee ks 
1 2 a n d 2 4.  
C ha n ge fr o m Scree ni n g i n F E F 2 5 -7 5 at 
Wee ks 1 2 a n d 2 4.  
T otal d urati o n (i n da ys) of e xa cer bati o ns, 
per s u bj ect, o ver t he 2 4 -wee k treat me nt 
peri o d.  
T otal n u m ber of e xacer bati o ns per s u bj ect 
o ver t he 2 4 -wee k treat me nt peri o d.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 8  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
N u m ber of s u bj ects h os pitaliz e d d ue t o 
p ul m o nar y e xa cer bati o ns b y t he e n d of t he 
2 4 -wee k treat me nt peri o d.  
Ti me t o first p ul m o nar y e xacer bati o n, 
e xacer bati o n rate, Q O L Meas ures, a n d 
p ul m o nar y f u ncti o n para met ers ( F E V 1 , 
F V C, P E F R, a n d F E F 2 5 -7 5), str atifie d 
Br o nc hiectasis Se verit y I n de x ( B SI) sc ore 
at baseli ne, o ver t he 2 4 -wee k treat me nt 
peri o d.  
Ti me t o first p ul m o nar y e xacer bati o n, 
e xacer bati o n rate, Q O L Meas ures, a n d 
p ul m o nar y f u ncti o n para meters ( F E V 1 , 
F V C, P E F R, a n d F E F 2 5 -7 5), str atifie d b y t he 
prese nce or a bse nce of Pse u d o m o n as 
aer u gi n os a  at Scree ni n g, o ver t he 2 4 -wee k 
treat me nt peri o d. 
Fre q ue nc y of use of resc ue me dicati o ns 
(resc ue me dicati o ns i ncl u de s h ort-acti n g 
beta a g o nists [ S A B As], s h ort -acti n g 
m uscari nic a nta g o nists [ S A M As], ne wl y 
prescri be d l o n g -acti n g beta a g o nists 
[ L A B As], l o n g-acti n g m uscari nic 
a nta g o nists [ L A M As] , a n d o x y ge n) o ver 
t he 2 4-wee k treat me nt peri o d.   
N u m ber of s u bj ects h os pitaliz e d d ue t o 
p ul m o nar y e xacer bati o ns b y t he e n d of t he  
2 4 -wee k treat me nt peri o d.  
Descri pti ve assess me nt of t he c ha n ge i n 
i nfla m mat or y a n d tiss ue de gra dati o n 
bi o mar kers a n d c o nce ntrati o n of acti ve N E 
i n bl o o d, s p ut u m, a n d uri ne, o ver t he 
2 4 -wee k treat me nt peri o d.  
S y n o psis St u d y Desi g n 
a n d 3. 1  O verall St u d y 
Desi g n a n d Pla n  
Scree ni n g Peri o d  
T here will be a scree ni n g peri o d of u p t o  
4  wee ks per s u bj ect.  D uri n g t he scree ni n g 
peri o d, t he s u bj ect’s de m o gra p hic 
i nf or mati o n, me dical hist or y a n d s m o ki n g 
hist or y will be o btai ne d, a p h ysical e xa m, 
Scree ni n g Peri o d  
T here will be a scree ni n g peri o d of u p t o 
6  wee ks per s u bj ect. D uri n g t he scree ni n g 
peri o d, t he s u bj ect’s de m o gra p hic 
i nf or mati o n, me dical hist or y a n d s m o ki n g 
hist or y will be o btai ne d, a p h ysical e xa m, 
De ntal clea ni n g pr oce d ures ma y 
re q uire 2 sessi o ns at t he de ntal 
office. Sc he d uli n g s uc h 
a p p oi nt me nts ca n ma ke it diffi c ult 
t o ra n d o mize a patie nt wit hi n 4 
wee ks. T he e xte nsi o n of t he 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 2 9  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
vital si g ns a n d a s p ut u m sa m ple f or s p ut u m 
c ult ure a n d acti ve N E c o nce ntrati o n will be 
c ollecte d, a n d c he mistr y/ he mat ol o g y a n d 
uri nal ysis tests, ser u m pre g na nc y test, 
E C G, a n d p ul m o nar y f u ncti o n test ( P F T). 
an d peri o d o ntal clea ni n g a n d e xa mi nati o n 
will b e c o n d ucte d.   
vital si g ns a n d a s p ut u m sa m ple f or s p ut u m 
c ult ure a n d acti ve N E c o nce ntrati o n will be 
c ollecte d, a n d c he mistr y/ he mat ol o g y a n d 
uri nal ysis tests, ser u m pre g na nc y test f or 
w o me n of c hil d beari n g p ote ntial 
( W O C B P), E C G, a n d p ul m o nar y f u ncti o n 
test ( P F T) will be c o n d ucte d.  P eri o d o ntal 
e xa mi nati o n a n d de ntal clea ni n g 
pr oce d ures f or i ncl usi o n s h o ul d be 
perf o r me d pri or t o ra n d o mizati o n.  
 
scree ni n g peri o d fr o m 4 t o 6 wee ks 
will al l o w f or t he fi nalizati o n of all 
pr oce d ures pri or t o ra n d o mizati o n.   
3. 1  O verall St u d y Desi g n 
a n d Pla n 
Tre at me nt Peri o d ( Visits 2 t hr o u g h 9)  
O n Da y  1 ( Visit 2), vital si g ns, s p ut u m a n d 
bl o o d sa m ples f or bi o mar kers will be 
c ollecte d, a n d bl o o d c he mistr y, 
he mat ol o g y a n d uri nal ysis tests, E C G, a n d 
pre g na nc y test (fe males of c hil d beari n g 
p ote ntial [ W O C B P] o nl y) will be 
c o n d ucte d.  After re -c o nfir mi n g t he ir 
eli gi bilit y, s u bj ects will be ra n d o mize d via 
a n i nteracti ve res p o nse tec h n ol o g y (I R T)  
s yste m i nt o 1 of 3 ar ms t o recei ve eit her 1 0 
m g or 2 5 m g of I N S 1 0 0 7 or matc hi n g 
place b o i n a 1: 1: 1 rati o.  
 
Tre at me nt Peri o d ( Visits 2 t hr o u g h 9)  
O n Da y  1 ( Visit 2), vi tal si g ns, s p ut u m a n d 
bl o o d sa m ples f or bi o mar kers will be 
c ollecte d, a n d bl o o d c he mistr y, 
he mat ol o g y a n d uri nal ysis tests, E C G, a n d 
pre g na nc y test (fe males of c hil d beari n g 
p ote ntial [ W O C B P] o nl y) will be 
c o n d ucte d.  After re -c o nfir mi n g t heir 
eli gi bilit y,  s u bj ects will be ra n d o mize d via 
t he Me di data Bala nce ra n d o mizati o n a n d 
trial s u p pl y ma na ge me nt ( R T S M) s yste m 
i nt o 1 of 3 ar ms t o recei ve eit her 1 0 m g or 
2 5 m g of I N S 1 0 0 7 or matc hi n g place b o i n 
a 1: 1: 1 rati o.  
 
T o s pecif y t he s yste m use d t o 
ra n d o mize patie nts  
S y n o psis St u d y Desi g n 
a n d  
3. 1  O verall St u d y Desi g n 
a n d Pla n 
E n d -of -St u d y Visit ( Visit 1 0)  
S u bj ects will be re q uire d t o ha ve a n E O S 
visit ( Visit 1 0) at wee k 2 8 t o c ollect bl o o d 
a n d s p ut u m sa m ples f or bi o mar ker 
assess me nt a n d t o c ollect i nf or mati o n o n 
A Es  a n d c o nc o mita nt me dicati o ns use.  A 
P K sa m ple will be c ollecte d fr o m eac h 
s u bj ect p artici pati n g i n t he P K s u b-st u d y.  
 
E n d -of -St u d y Visit ( Visit 1 0)  
S u bj ects will be re q uire d t o ha ve a n E O S 
visit ( Visit 1 0) at wee k 2 8 t o c ollect bl o o d, 
s p ut u m a n d uri ne  sa m ples f or bi o mar ker 
assess me nt a n d pre g na nc y test f or W O C B P  
a n d t o c ollect i nf or mati o n o n A Es  a n d 
c o nc o mita nt me dicati o ns use.  A P K 
sa m ple will be c ollecte d fr o m eac h s u bj ect 
partici pati n g i n t he P K s u b -st u d y.  
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 0  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
 
S y n o psis: Tre at me nt 
D ur ati o n  
3. 1  O verall St u d y Desi g n 
a n d Pla n 
3. 3. 2  
St u d y D urati o n  
 
Eac h s u bj ect will recei ve st u d y treat me nt 
f or 2 4 wee ks.  T he e ntire st u d y is 
sc he d ule d t o ta ke a ma xi m u m of 3 2  wee ks 
f or eac h i n di vi d ual s u bj ect fr o m Scree ni n g 
( Visit 1) t o t he E n d of St u d y ( Visit 1 0).   
 
Eac h s u bj ect will recei ve st u d y treat me nt 
f or 2 4 wee ks.  T he e ntire st u d y is 
sc he d ule d t o ta ke a ma xi m u m of 3 4  wee ks 
f or eac h i n di vi d ual s u bj ect fr o m Scree ni n g 
( Visit 1) t o t he E n d of St u d y ( Visit 1 0).   
 
St u d y d urati o n i ncrease d b y 2 
wee ks d ue t o all o wa n ce f or a 
scree ni n g peri o d u p t o 6 wee ks. 
4. 1. 1  
I ncl usi o n Criteria  
I ncl usi o n criteria # 8 
W o me n m ust b e p ost -me n o pa usal, 
s ur gicall y sterile, or usi n g hi g hl y effecti ve 
c o ntrace pti o n met h o ds ( i.e., met h o ds t hat 
al o ne or i n c o m bi nati o n ac hie ve < 1 % 
u ni nte n de d pre g na nc y rates per year). S uc h 
met h o ds i ncl u de tr ue a bsti ne nce (refrai ni n g 
fr o m heter ose x ual i nterc o urse d uri n g t he 
st u d y), 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) or 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, i ntra uteri ne 
de vices, i ntra uteri ne h or m o ne -releasi n g 
s yste ms, or vasect o mize d part ner.  All 
w o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve pre g na nc y 
test bef ore ra n d o mizati o n. 
I ncl usi o n criteria # 8 
W o me n m ust be p ost -me n o pa usal, ( defi ne d 
as no me nses f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use), s ur gicall y 
sterile, or usi n g hi g hl y effecti ve 
c o ntrace pti o n met h o ds ( i.e., met h o ds t hat 
al o ne or i n c o m bi nati o n ac hie ve < 1 % 
u ni nte n de d pre g na nc y rates per year) fr o m 
Da y  1 t o at least 9 0 da ys after t he last d ose. 
S uc h met h o ds i ncl u de tr ue a bsti ne nce 
(refrai ni n g fr o m heter ose x ual i nterc o urse 
d uri n g t he st u d y), 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) or 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 a n d 
s u p ple me nte d wit h a d o u ble barrier 
( prefera bl y male c o n d o m), i ntra uteri ne 
de vices, i ntra uteri ne h or m o ne -releasi n g 
s yste ms, or vasect o mize d part ner.  All 
w o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve pre g na nc y 
test bef ore ra n d o mizati o n.  
N ote:  A bsti ne nce is o nl y c o nsi dere d t o be 
a hi g hl y effecti ve met h o d of c o ntrace pti o n 
w he n t his is t he preferre d a n d us ual life 
st yle of a s u bj ect. P eri 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 nter r u pt us), 
Secti o n was re vise d:  
T o a d d defi niti o n of “ w o me n of 
c hil d beari n g p ote ntial”  
T o a d vise fe male partici pa nts t o use 
c o ntrace pti o n f or a mi ni m u m of  9 0 
after t he last d ose:  
P er Cli nical Trial Facilitati o n 
Gr o u p ( C T F G) rec o m me n dati o ns, 
c o ntrace pti o n s h o ul d be mai nt ai ne d 
d uri n g treat me nt a n d u ntil t he e n d 
of rele va nt s yste mic e x p os ure.  
T he pr o p ose d d urati o n of 9 0 da ys 
s ur passes t he e n d of rele va nt 
s yste mic e x p os ure a n d is 
rec o m me n de d t o be c o nsiste nc y 
wit h t he rec o m me n dati o n ma d e t o 
male partici pa nts.  
T o clarif y t hat h or m o nal 
c o ntrace pti o n met h o ds s h o ul d be 
s u p ple me nte d wit h a d o u ble barrier, 
c o nsi deri n g it ca n n ot b e r ule d o ut, 
base d i n vitr o data, t hat I N S 1 0 0 7 is 
a C Y P 3 A 4 i n d ucer i n viv o. P er 
C T F G rec o m me n dati o ns: “If a n 
i nteracti o n wit h c o ntrace pti ve 
ster oi ds has bee n o bser ve d or is 
s us pecte d, b ut t he effect is 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 1  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
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 ntrac e pti o n.  
c o nsi dere d t o be of li mi te d cli nical 
si g nifica nce, t he h or m o nal 
c o ntrace pti o n met h o d m ust b e 
s u p ple me nte d wit h a barrier met h o d 
( prefera bl y male c o n d o m).” 
T o clarif y t hat a bsti ne nce is o nl y 
c o nsi dere d t o be a hi g hl y effe cti ve 
met h o d of c o ntrace pti o n w he n t his 
is t he preferre d a n d us ual life st yle 
of a s u bj ect. P eri o dic a bsti ne n ce 
(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 d es 
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.  
T o re m o ve t he st ate me nt "t he 
defi niti o n of effecti ve c o ntrac e pti o n 
will b e base d o n t he j u d ge me nt of 
t he in vesti gat or ". 
4. 1. 1  
I ncl usi o n Criteria 
I ncl usi o n criteria # 9 
Males wit h fe male part ners of c hil d beari n g 
p ote ntial m ust be usi n g effecti ve 
c o ntrace pti o n (t he defi nitio n of effecti ve 
c o ntrace pti o n will be base d o n t he 
j u d ge me nt of t he I n vesti gat or) fr o m Da y 1 
t o at least 3 0 da ys after t he last d ose;  
N ote:  Male s u bj ects will be a d vise d of t he 
p ote ntial t o xicit y t o s per m o bs er ve d i n 
n o ncli nical st u dies a n d will be a d vise d n ot 
t o partici pate i n t he st u d y if t he y pla n t o 
fat her a c hil d i n t he f ut ure. 
I ncl usi o n criteria # 9 
Males wit h fe male part ners of c hil d beari n g 
p ote ntial m ust be usi n g effecti ve 
c o ntrace pti o n fr o m Da y  1 t o at least 9 0  
da ys after t he last d ose.   S uc h met h o ds 
i ncl u de tr ue a bsti ne nce (refrai ni n g fr o m 
heter ose x ual i nterc o urse d uri n g t he st u d y), 
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) or 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, i ntra uteri ne de vices, i ntra uteri ne 
h o r m o ne-releasi n g s yste ms, or 
vasect o mize d part ner.   
N ote:  A bsti ne nce is o nl y c o nsi dere d t o be 
a hi g hl y effecti ve met h o d of c o ntrace pti o n 
w he n t his is t he preferre d a n d us ual life 
Secti o n was re vise d:  
T o list acce pta ble met h o ds of 
c o ntrace pti o n:  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 oci ate d 
wit h i n hi biti o n of o v ulati o n ( oral, 
i ntra va gi nal, tra ns der mal), 
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 ( oral, 
i nj ecta ble, i m pla nta ble), 
i ntra uteri ne de vice (I U D), 
i ntra uteri ne h or m o ne-releasi n g 
s yste m (I U S), bilateral t u bal 
occl usi o n, vasect o mize d part ner, 
a n d se x ual a bsti ne nce.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 2  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
st yle of a s u bj ect. P eri o dic a bsti ne nce 
(cale n dar, s y m pt ot her mal, p ost-o v ulat i 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 ntrac e pti o n.  
N ote:  Male s u bj ects will be a d vise d of t he 
p ote ntial t o xicit y t o s per m o bs er ve d i n 
n o ncli nical st u dies a n d  will be a d vise d n ot 
t o partici pate i n t he st u d y if t he y pla n t o 
fat her a c hil d i n t he f ut ure. 
T o clarif y t hat a bsti ne nce is o nl y 
c o nsi dere d t o be a hi g hl y effe cti ve 
met h o d of c o ntrace pti o n w he n t his 
is t he preferre d a n d us ual life st yle 
of a s u bj ect. P eri o dic a bsti ne n ce 
(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 d es 
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.  
T o re m o ve t he state me nt "t he 
defi niti o n of effecti ve c o ntrac e pti o n 
will b e base d o n t he j u d ge m e nt of 
t he in vesti gat or ". 
T o a d vise male partici pa nts t o use 
c o ntrace pti o n f or a mi ni m u m of 9 0 
da ys after t he last d ose.  
J ustific ati o n:  Ris k miti gati o n d ue 
t he testic ular t o xicities o bser ve d i n 
t he 6 m o nt hs d o g st u d y a n d i n 
c o nsi derati o n of t he life -c ycle a n d 
d urati o n of s per mat o ge nesis.  
 
4. 1. 2  
E xcl usi o n Criteria   
E xcl usi o n criteria # 3 3  
Ha ve a cli nical dia g n osis of P a pill o n -
Lefè vre S y n dr o me.  
Secti o n re vise d t o e xcl u de pati e nts 
w h o ha ve bee n dia g n ose d wit h 
P a pill o n -Lefè vre s y n dr o me a n d 
ha ve t he p he n ot y pe t hat 
c haracterizes it, as I N S 1 0 0 7 will 
offer n o be nefit.  
4. 2. 1  
Reas o ns f or 
Wit h dra wal/ Earl y 
Disc o nti n uati o n  
A s u bj ect ma y deci de t o wit h dra w  fr o m t he 
st u d y at a n y ti me, f or a n y reas o n, wit h o ut 
prej u dice t o s u bse q ue nt care or treat me nt 
b y t he I n vesti gat or.  W he n t his occ urs, t he 
A s u bj ect ma y deci de t o wit h dra w  fr o m t he 
st u d y at a n y ti me, f or a n y reas o n, wit h o ut 
prej u dice t o s u bse q ue nt care or treat me nt 
b y t he I n vesti gat or. W he n t his occ urs, t he 
s u bj ect s h o ul d c o m plete all t he pr oce d ures 
Secti o n re vise d t o clarif y t hat 
patie nts disc o nti n ui n g t he treat me nt 
d ue t o a d verse effects s h o ul d 
re mai n u n der o bser vati o n u ntil t he 
res ol uti o n or c o ns oli dati o n of t he 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 3  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
s u bj ect s h o ul d c o m plete all t he pr oce d ures 
at t he Visit 9 ( E n d of Treat me nt) Visit.  
 
at t he Visit 9 ( E n d of Treat me nt) Visit. 
S u bj ects w h o disc o nti n ue t he treat me nt d ue 
t o a d verse e ve nts s h o ul d re mai n u n der 
o bser vati o n u ntil t he res ol uti o n or 
sta bilizati o n of t he a d verse e ve nts.  
a d verse effects. Data base l oc k will 
occ ur at t he desi g nate d ti mes, b ut 
f oll o w-u p of a d verse e ve nts will 
c o nti n ue u ntil res ol uti o n or 
sta bilizati o n. 
4. 2. 2  
S u bj ect 
Re -Scree ni n g Pr oce d ures  
S u bj ects w h o d o n ot meet eli gi bilit y 
criteria d uri n g Scree ni n g ma y be re -
scree ne d u p t o 2 ti mes if a p pr o ve d b y 
I ns me d’s Me dical M o nit or. 
If a s u bj ect has 1 or 2 a b n or mal la b orat or y 
val ues at scree ni n g (c o nsi dere d n o n -
cli nicall y si g nifica nt b y t he in vesti gat or ) 
t he site ca n re-test t h ose a b nor mal val ues 
u p t o 2 ti mes t hr o u g h t he ce ntr al 
la b orat or y, t his will n ot be c o nsi dere d a re-
scree ni n g pr oce d ure.   
S u bj ects w h o d o n ot meet eli gi bilit y 
criteria d uri n g Scree ni n g ma y be re -
scree ne d u p t o 2 ti mes if a p pr o ve d b y 
I ns me d’s Me dical M o nit or. 
 
A p atie nt w h o d oes n ot meet 
eli gi bilit y criteria s h o ul d be 
scree ne d faile d. If dee me d 
a p pr o priate, t he PI ca n re -scree n t he 
patie nt.  
5. 1. 4  
U n bli n di n g 
Pr oce d ures  
I n t he case of a rare e mer ge nc y w here, i n 
t he o pi ni o n of t he I n vesti gat or, 
disc o nti n uati o n of st u d y treat me nt is n ot 
s ufficie nt a n d t he st u d y treat me nt m ust be 
u n bli n de d t o e val uate f urt her c o urse of 
acti o n, t he I n vesti gat or s h o ul d c o ntact t he 
I ns me d Me dical M o nit or or a p pr o priate 
I ns me d st u d y pers o n nel pri or t o t he 
u n bli n di n g.  T he I n vesti gat or m ust b e a ble 
t o c o nfir m t hat u n bli n di n g of t he s u bj ect is 
necessar y a n d directl y i m pacts t he 
s u bj ect’s i m me diate me dical ma na ge me nt 
or welfare of t he s u bj ect.  T he s u bj ect will 
be c o nsi dere d disc o nti n ue d fr o m t he st u d y.  
If t his is n ot p ossi ble, t he I n vesti gat or m ust 
n otif y t he S p o ns or as s o o n as p ossi ble.  
T he date a n d reas o n f or u n bli n di n g m ust be 
d oc u me nte d a n d si g ne d b y t he st u d y 
I n vesti gat or.  T he ori gi nall y si g ne d c o p y is 
mai ntai ne d i n t he st u d y file at t he site, a n d 
I n t he case of a rare e mer ge nc y w here, i n 
t he o pi ni o n of t he I n vesti gat or, 
disc o nti n uati o n of st u d y treat me nt is n ot 
s ufficie nt a n d t he st u d y treat me nt m ust b e 
u n bli n de d t o e val uate f urt her c o urse of 
acti o n, t he I n vesti gat or ca n u n bli n d st u d y 
treat me nt f or a s pecific patie nt. It is 
s u g geste d t hat t he I n vesti gat or c o ntact t he 
I ns me d Me dical M o nit or or a p pr o priate 
I ns me d st u d y pers o n nel pri or t o t he 
u n bli n di n g. T he I n vesti gat or m ust b e a ble 
t o c o nfir m t hat u n bli n di n g of t he s u bj ect is 
necessar y a n d directl y i m pacts t he 
s ubj ect’s i m me diate me dical ma na ge me nt 
or welfare of t he s u bj ect. T he s u bj ect will 
be c o nsi dere d disc o nti n ue d fr o m t he st u d y.  
If t his is n ot p ossi ble, t he I n vesti gat or m ust 
n otif y t he S p o ns or as s o o n as p ossi ble.  
T he date a n d reas o n f or u n bli n di n g m ust b e 
d oc u me nte d a n d si g ne d b y t he st u d y 
Re vise d t o clarif y t hat it is t he 
I n vesti gat or’s decisi o n t o u n bli n d a 
patie nt.   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 4  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
a c o p y is pr o vi de d t o t he S p o ns or or its 
desi g nee.  T he date a n d reas o n f or t he 
u n bli n di n g is als o e ntere d i n t he st u d y 
electr o nic case re p ort f or m (e C R F) a n d a n y 
ass ociate d A E re p orts.  
I n vesti gat or.  T he ori gi nall y si g ne d c o p y is 
mai ntai ne d i n t he st u d y file at t he site, a n d 
a c o p y is pr o vi de d t o t he S p o ns or or its 
desi g nee.  T he in vesti gat or  s h o ul d f oll o w 
t he ste ps i n t he Me di data Bala nce R T M S 
s yste m an d e nter t he u n bli n di n g date a n d 
reas o n.   T he date a n d reas o n f or t he 
u n bli n di n g is als o e ntere d i n t he st u d y 
electr o nic case re p ort f or m (e C R F) a n d a n y 
ass ociate d A E re p orts.  
5. 3  Pr o hi bite d 
Me dicati o ns  
As a r ule, n o c o m pa ni o n me dicati o n t hat 
has bee n t olerate d a n d is c o nsi dere d 
necessar y b y t he I n vesti gat or f or t he 
treat me nt of t he s u bj ects’ u n d erl yi n g 
disease or c o m or bi dities s hall be wit h hel d 
i n a n y s u bj ect t o f ulfill eli gi bilit y f or t his 
st u d y.   
 
H o we ver, w here p ossi ble, alter nati ve 
treat me nts wit h a l o wer ris k or p ote ntial f or 
i nteracti n g wit h I N S 1 0 0 7 s h o ul d be 
c o nsi dere d.  
As a r ule, n o c o m pa ni o n me dicati o n t hat 
has bee n t olerate d a n d is c o nsi dere d 
necessar y b y t he I n ve sti gat or f or t he 
treat me nt of t he s u bj ects’ u n d erl yi n g 
disease or c o m or bi dities s hall be wit h hel d 
i n a n y s u bj ect t o f ulfill eli gi bilit y f or t his 
st u d y.   
 
Re vise d t o clarif y t hat n o 
me dicati o n s h o ul d be c ha n ge d if it 
is c o nsi dere d necessar y b y t he 
I n vesti gat or.  
5. 4  P er mitte d Me dicati o ns 
a n d Pr oce d ures  
A n y c o nc urre nt o n g oi n g me di cati o ns, 
i ncl u di n g o ver-t he-c o u nter dr u gs a n d 
her bal s u p ple me nts,  are all o we d if n ot 
pr o hi bite d b y t he pr ot oc ol (see Secti o n 
5. 3).   
A n y c o nc urre nt o n g oi n g me di cati o ns, 
i ncl u di n g o ver-t he-c o u nter dr u gs are 
all o we d if n ot pr o hi bite d b y t he pr ot oc ol 
(see Secti o n 5. 3).   
 
Secti o n re vise d t o re m o ve refere nce 
t o her bal s u p ple me nts: 
J ustific ati o n:  Secti o n 5. 3 
ac k n o wle d ges me dici nes f or w hic h 
prescri pti o n is re q uire d.  
5. 4 P er mitte d Me dicat i o ns 
a n d Pr oce d ures  
T a ble 5: Mi ni m u m Ti me 
I nter vals f or Restricte d 
Me dicati o n Use Pri or t o 
Re versi bilit y/ S pir o metr y 
T esti n g  
Mi ni m al Ti me I nter v al fr o m L ast 
M e dic ati o n D ose  
Pre -Br o nc h o dilat or T esti n g  
Mi ni m al Ti me I nter v al fr o m L ast 
M e dic ati o n D ose  
Pri or t o p ost -Br o nc h o dilat or Testi n g  
T he e val uati o n of l u n g f u ncti o n 
para meters is p ost -br o nc h o dil ati o n.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 5  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
6. 2. 2 Visit 3 ( W ee k 2, Da y  
1 5)  
St u d y dr u g dis pe nsi n g a n d re vie w of 
d osi n g diar y  
Re vie w of d osi n g diar y  
N o st u d y dr u g dis pe nsi n g as 
s u bj ects are d ose d m o nt hl y. 
T a ble 6: Sc he d ule of 
E ve nts  
St u d y Dr u g Dis pe nse, 
Acc o u nta bilit y of Ret ur ne d 
Dr u g, a n d Re vie w of 
D osi n g Diar y  
X  
X n  
A d de d f o ot n ote: n N o st u d y dr u g 
dis pe nsi n g at t his Visit  
N o st u d y dr u g dis pe nsi n g re q uire d 
as s u bj ects are d ose d m o nt hl y.  
6. 2. 9 Visit 1 0 ( W ee k 2 8, 
Da y  1 9 7, E n d of St u d y)  
 
 
A d de d: P h ysical E xa mi nati o n  
A d de d: Uri ne pre g na nc y test f or W O C B P  
 
T a ble 6: Sc he d ule of 
E ve nts  
 
Visit 1 0 : P h ysical E xa mi nati o n 
A d de d: Uri ne pre g na nc y test f or W O C B P  
 
6. 1. 1 t hr o u g h 6. 2. 9 Visit 1 
t hr o u g h Visit 1 0 
 
A d de d: S pecial la b orat or y tests ( C -reacti ve 
pr otei n, pr ot hr o m bi n ti me)  
 
T a ble 6: Sc he d ule of 
E ve nts  
 
A d de d t o Visits 1 t hr o u g h 1 0: S pecial 
la b orat or y tests (C -reacti ve pr otei n, 
pr ot hr o m bi n ti me)  
 
T a ble 6: Sc he d ule of 
E ve nts  
A p pe n di x 4:  I nte nse 
P har mac o ki netic S a m pli n g 
Sc he me  
F o ot n ote J: I n a d diti o n, a tr o u g h P K 
sa m ple ( pre d ose of I N S 1 0 0 7) will be 
c ollecte d at Visits 3, 6, 9 a n d 1 0 .   
F o ot n ote J: I n a d diti o n, a tr o u g h P K 
sa m ple ( pre d ose of I N S 1 0 0 7) will b e 
c ollecte d at Visits 3, 6,  a n d 9.  C ollecti o n 
of P K sa m ple  at visit 1 0 will be d o ne 
a n yti me eit her pre - or p ost -d ose d uri n g t he 
visit.  
T o clarif y t hat at visit 1 0 a P K 
sa m ple will b e c ollecte d at a n y 
ti me, as descri be d i n Secti o n 7. 6. 1. 
At visit 1 0 patie nts will ha ve bee n 
off me dicati o n f or 4 wee ks.   
7. 2. 2 P ul m o nar y F u ncti o n 
T est  
P ul m o nar y f u ncti o n test b y s pir o metr y 
( F E V1 , F V C, P E F R, a n d F E F2 5 -7 5) will be 
perf or me d per t he A merica n T h oracic 
S ociet y ( A T S/ E ur o pea n Res pirat or y 
S ociet y [ E R S]) criteria ( Miller et al, 2 0 0 5) 
at Visit 1 ( Scree ni n g), Visit 6, a n d Visit  9 
(refer t o T a ble 6). 
P ost -br o nc h o dilat or p ul m o nar y f u ncti o n 
test b y s pir o metr y ( F E V1 , F V C, P E F R, 
a n d F E F 2 5 -7 5) will be perf or me d per t he 
A merica n T h oracic S ociet y 
( A T S/ E ur o pea n Res pirat or y  S ociet y 
[ E R S]) criteria ( Miller et al, 2 0 0 5) at Visit 
1 ( Scree ni n g), Visit 6, a n d Visit 9 (refer t o 
T a ble  6).  
Secti o n re vise d t o clarif y t he 
pr oce d ures t o perf or m 
br o nc h o dilati o n a n d t he ti mi n g of 
l u n g f u ncti o n tests. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 6  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
S u bj ects s h o ul d be a d vise d t o wit h h ol d 
s h ort-acti n g i n hale d dr u gs (e g, t he β -
a g o nist al b uter ol/sal b uta m ol or t he 
a ntic h oli ner gic a ge nt i pratr o pi u m br o mi de) 
wit hi n 6 h o urs pri or t o t he test.  L o n g -
acti n g β -a g o nist br o nc h o dilat ors ( e.g . 
sal meter ol or f or m oter ol) or l o n g-acti n g 
m uscari nic br o nc h o dilat ors (e g, 
ti otr o pi u m) or oral t hera p y wit h 
a mi n o p h ylli ne or sl o w release β -a g o nists 
s h o ul d be wit h hel d f or 1 2-2 4 h o urs 
de p e n di n g o n t he me dicati o n use d (refer t o 
T a ble 6 ) f or t he mi ni m u m ti me i nter vals 
f or a list of restricte d me dicati o ns) pri or t o 
testi n g. 
S u bj ects s h o ul d be a d vise d t o wit h h ol d 
s h ort-acti n g i n hale d dr u gs (e g, t he β -
a g o nist al b uter ol/sal b uta m ol or t he 
a ntic h oli ner gic a ge nt i pratr o pi u m br o mi de) 
wit hi n 6 h o urs pri or t o t he test.  L o n g -
acti n g β -a g o nist br o nc h o dilat ors ( e.g . 
sal meter ol or f or m oter ol) or l o n g-acti n g 
m uscari nic br o nc h o dilat ors (e g, 
ti otr o pi u m) or oral t hera p y wit h 
a mi n o p h ylli ne or sl o w release β -a g o nists 
s h o ul d be wit h hel d f or 1 2-2 4 h o urs 
de pe n di n g o n t he me dicati o n use d (refer t o 
T a ble 5 ) f or t he mi ni m u m ti me i nter vals 
f or a list of restricte d me dicati o ns) pri or t o 
testi n g. 
P ost -br o nc h o dilat or s pir o metr y tests will 
be perf or me d per t he f oll o wi n g 
i nstr ucti o ns:  
W he n a n i n hale d S h ort Acti n g Beta 2 
a g o nist ( S A B A) is use d, 4 p uffs of 
Al b uter ol, le val b uter ol, or T er b utali ne will 
be a d mi nistere d.  A p ost -br o nc h o dilat or 
P F T will be perf or me d 1 5 t o 3 0 mi n utes 
after t he a d mi nistrati o n of Al b uter ol or 
le val b uter ol.  If a n ot her S A B A is use d, 
I ns me d s ho ul d be c o ntacte d f or f urt her 
directi o ns.  
W he n a n i n hale d S h ort Acti n g M uscari nic 
A nta g o nist ( S A M A) is use d, 4 p uffs of 
I pratr o pi u m will be a d mi nister e d.  A p ost-
br o nc h o dilat or P F T will be perf or me d 3 0 
mi n utes after t he a d mi nistrati o n of 
I pratr o pi u m. 
If a patie nt ca n n ot perf or m a n i n halati o n, 
t he S A B A or S A M A ca n be ne b ulize d. 
P ul m o nar y f u ncti o n tests s h o ul d be 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 7  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
perf or me d 3 0 mi n utes after fi nalizati o n of 
ne b ulizati o n  
If a patie nt use d S A B A i n t he first 
assess me nt of P F Ts, t he sa me S A B A a n d 
m o de of a d mi nistr ati o n s h o ul d be use d i n 
s u bse q ue nt assess me nts.  If a patie nt use d 
S A M A i n t he first assess me nt of P F Ts, t he 
S A M A a n d m o de of a d mi nistr ati o n s h o ul d 
be use d i n s u bse q ue nt assess me nts  
7. 2. 3  Ne utr o p hil Elastase 
C o nce ntrati o n -S p ut u m  
 
S p ut u m sa m ples will be c ollecte d at 
Scree ni n g ( Visit 1), Baseli ne ( Visit 2), a n d 
Visits 4, 6, 9, a n d 1 0 f or meas ure me nt of 
N E c o nce ntrati o ns (refer t o T a ble 6).  
 
 
S p ut u m sa m ples will be c ollecte d at 
Scree ni n g ( Visit 1), Baseli ne ( Visit 2), a n d 
Visits 3 , 4, 6, 9, a n d 1 0 f or me as ure me nt of 
N E c o nce ntrati o ns (refer t o T a ble 6).  
 
 
Re vise d t o a d d Visit 3 t o t he visits 
d uri n g w hic h s p ut u m c ollecti o n is 
re q uire d: J ustific ati o n:  
I nc o nsiste nc y was n ote d bet wee n 
t he secti o n of t he Pr ot oc ol a n d 
T a ble 6: Sc he d ule of E ve nts  
7. 3. 1  Leicester C o u g h 
Q uesti o n naire  
 
A har d c o p y of t he L C Q will be pr o vi de d 
se p aratel y 
 
O nl y electr o nic c o pies will be 
pr o vi de d.  
7. 3. 2  St Ge or ge’s 
Res pirat or y Q uesti o n naire   
A har d c o p y of t he S G R Q will be pr o vi de d 
se p aratel y 
 
O nl y electr o nic c o pies will be 
pr o vi de d.  
7. 3. 3  Ne utr o p hil Elastase 
C o nce ntrati o n -Bl o o d  
Bl o o d sa m ples will be c ollecte d at 
Scree ni n g ( Visit 1),  Baseli ne ( Visit 2), a n d 
Visits 4, 6, 9, a n d  1 0 f or meas ure me nt of 
N E c o nce ntrati o ns (refer t o T a ble 6).  
Detaile d i nstr ucti o n f or t he bl o o d sa m ple 
c ollecti o n, pr ocessi n g a n d s hi p me nt will be 
pr o vi de d i n t he site st u d y bi n d er.  
 
Bl o o d sa m ples will be c ollecte d at B aseli ne 
( Visit 2), a n d Visits 3,  4, 6 , 9, a n d 1 0 f or 
meas ure me nt of N E c o nce ntrati o ns (refer 
t o T a ble 6). 
Detaile d i nstr ucti o n f or t he bl o o d sa m ple 
c ollecti o n, pr ocessi n g a n d s hi p me nt will be 
pr o vi de d i n t he site st u d y bi n d er.  
 
Secti o n re vise d t o c orrect t he 
i nc o nsiste nc y n ote d bet wee n t his 
secti o n of t he Pr ot oc ol a n d T a ble  6: 
Sc he d ule of E ve nts.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 8  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
7. 3. 5  I nfla m mat or y 
Bi o mar ker Le vels -S p ut u m  
 
S p ut u m sa m ples will be c ollecte d at 
Scree ni n g ( Visit 1), Baseli ne ( Visit 2), a n d 
Visits 4, 6, 9, a n d 1 0 f or meas ure me nt of 
N E c o nce ntrati o ns (refer t o T a ble 6).  O nl y 
N E, pr otei nase 3, a n d cat he psi n G will be 
a nal yze d  
 
S p ut u m sa m ples will be c ollecte d at 
Scree ni n g ( Visit 1), Baseli ne ( Visit 2), a n d 
Visits 3, 4, 6, 9, a n d 1 0 f or me as ure me nt of 
N E c o nce ntrati o ns (refer t o T a ble 6).  O nl y 
N E, pr otei nase 3, a n d cat he psi n G will be 
a nal yze d  
Visit 3 a d de d t o t he visits d uri n g 
w hic h s p ut u m c ollecti o n is 
re q uire d: J ustific ati o n:  
I nc o nsiste nc y was n ote d bet wee n 
t he secti o n of t he Pr ot oc ol a n d 
T a ble 6: Sc he d ule of E ve nts  
7. 3. 6  I nfla m mat or y a n d 
Tiss ue De gra dati o n 
B i o mar ker Le vels-Bl o o d 
a n d Uri ne  
Bl o o d a n d uri ne sa m ples will be c ollecte d 
at Scree ni n g ( Visit 1),  Baseli ne ( Visit 2), 
a n d Visits 4, 6, 9, a n d 1 0 f or meas ure me nt 
of i nfla m mat or y a n d tiss ue de gra dati o n 
bi o mar kers (refer t o T a ble 6).  
 
Bl o o d a n d uri ne sa m ples will be c ollecte d 
at Baseli ne ( Visit 2), a n d Visits 3 , 4, 6, 9, 
a n d 1 0 f or meas ure me nt of i nfla m mat or y 
a n d tiss ue de gra dati o n bi o mar kers (refer t o 
T a ble 6).  
 
I nc o nsiste nc y was n ote d bet wee n 
t he secti o n of t he Pr ot oc ol a n d 
T a ble 6: Sc he d ule of E ve nts  
8. 4. 1 P eri o d of 
O bser vati o n f or A d verse 
E ve nts  
F or t he p ur p oses of t his st u d y, t he peri o d of 
o bser vati o n f or c ollecti o n of all A Es will 
be fr o m t he ti me t he s u bj ect si g ns t he I C F 
u ntil 3 0 da ys after t he fi nal d ose of st u d y 
dr u g.  
F or t he p ur p oses of t his st u d y, t he peri o d 
of o bser vati o n f or c ollecti o n of all A Es will 
be fr o m t he ti me t he s u bj ect si g ns t he I C F 
u ntil t he res ol uti o n or sta bilizati o n of t he 
a d verse e ve nts.   
Secti o n re vise d t o clarif y t hat 
patie nts s h o ul d re mai n u n der 
o bser vati o n u ntil t he res ol uti o n or 
c o ns oli dati o n of t he a d verse effects. 
Data base l oc k will occ ur at t he 
desi g nate d ti mes, b ut f oll o w -u p of 
a d verse e ve nts will c o nti n ue u ntil 
res ol uti o n or sta bilizati o n. 
S y n o psis: St atistic al 
M et h o ds  
9. 1 Sa m ple Size  
 
It is e x pecte d t hat p ul m o nar y e xacer bati o ns 
occ ur at a rate of 1. 2 e ve nts per s u bj ect 
year i n t he place b o gr o u p, c orres p o n di n g t o 
4 4. 6 % of t he place b o s u bj ects bei n g e ve nt 
free at 2 4 wee ks.  It is e x pecte d t hat 4 0 % 
m ore e ve nt free s u bj ects will be o bser ve d 
wit hi n t he I N S 1 0 0 7 gr o u ps ( b o t h 1 0 m g a n d 
2 5 m g) c orres p o n di n g t o 6 2. 4 % of t he 
I N S 1 0 0 7 s u bj ects bei n g e ve nt free at 2 4 
wee ks.  T he sa m ple size calc ulati o n is f or 
t he first test i n t he hierarc hical testi n g 
pr oce d ure.  T he hazar d rati o use d i n t he 
Details a d de d t o clarif y t he 
ass u m pti o n be hi n d t he sa m ple size 
calc ulati o n.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 3 9  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
sa m ple size calc ulati o n is 
l n( 0. 6 2 4)/l n( 0. 4 4 6) =0. 5 8 4.  
9. 5. 1. 1 Efficac y A nal ysis   
 
T he o verall si g nifica nce le vel is set at a 
o ne -si de d 0. 1 0 t o de m o nstrate t he 
s u peri orit y of I N S 1 0 0 7 t o place b o.   
T he first ste p is t o te st I N S 1 0 0 7 2 5 m g 
a gai nst place b o at t he o ne -si de d 0. 1 0 le vel 
f or t he pri mar y a nal ysis a n d if statisticall y 
si g nifica nt, I N S 1 0 0 7 1 0 m g will be teste d 
a gai nst place b o at t he o ne -si de d 0. 0 5 le vel 
f or t he pri mar y a nal ysis.   
If I N S 1 0 0 7 2 5 m g is n ot statisticall y 
si g nifica nt a gai nst place b o f or t he pri mar y 
a nal ysis, n o f urt her h y p ot hesis testi n g will 
be c o n d ucte d.  
If o nl y I N S 1 0 0 7 2 5 m g is statisticall y 
si g nifica nt a gai nst place b o f or t he pri mar y 
a nal ysis, t he n t he f o ur sec o n dar y e n d p oi nts 
at t he I N S 1 0 0 7 2 5 m g d ose w ill b e teste d 
a gai nst place b o a n d t he t y pe I err or rate 
will be c o ntr olle d at t he o ne -si de d al p ha 
le vel of 0. 0 5 usi n g t he H ol m-B o nferr o ni 
met h o d.  
If b ot h d oses are statisticall y si g nifica nt 
a gai nst place b o f or t he pri mar y a nal ysis, 
t he n t he f o ur sec o n dar y e n d p oi nts at t he 
I N S 1 0 0 7 2 5 m g d ose will be teste d a gai nst 
place b o a n d t he t y pe I err or rate will b e 
c o ntr olle d at t he o ne -si de d al p ha le vel of 
0. 0 5 usi n g t he H ol m -B o nferr o ni met h o d 
a n d t he f o ur sec o n dar y e n d p oi nts at t he 
I N S 1 0 0 7 1 0 m g d ose will be teste d a gai nst 
place b o a n d t he t y pe I err or rate will b e 
c o ntr olle d at t he o ne -si de d al p ha le vel of 
0. 0 5 usi n g t he H ol m -B o nferr o ni met h o d.  
Details a d de d t o e x plai n t he t y pe I 
err or tec h ni q ues.  
 
  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 0  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
T y pe I err or will n ot be c o ntr olle d f or t he 
e x pl orat or y e n d p oi nts, t he p -val ues 
pr o d uce d f or e x pl orat or y e n d p oi nts will b e 
c o nsi dere d descri pti ve a n d h y p ot hesis 
ge nerati n g.  
9. 5. 1. 2 Pri mar y E n d p oi nt 
A nal ysis  
T he pri mar y efficac y e n d p oi nt is t he ti me 
t o t he first p ul m o nar y e xacer bati o n o ver 
t he 2 4-wee k treat me nt peri o d.  
T he treat me nt c o m paris o n will be ma de 
usi n g t he stratifie d l o g ra n k test f or t he I T T 
p o p ulati o n. T he ti me t o t he first 
e xacer bati o n will als o be a nal yze d usi n g 
C o x re gressi o n m o del t o esti mate hazar ds 
rati o. 
T he pri mar y efficac y e n d p oi nt is t he ti me 
t o t he first p ul m o nar y e xacer bati o n o ver 
t he 2 4-wee k treat me nt peri o d.  A n y 
p ul m o nar y e xacer bati o n i n t he st u d y 
bet wee n Visits 2 t hr o u g h 1 0 will be 
acc o u nte d f or i n t he pri mar y e n d p oi nt, 
re gar dless of w het her it was ass ociate d 
wit h a sc he d ule d or u nsc he d ul e d vis it. 
T he treat me nt c o m paris o n will be ma d e 
usi n g t he stratifie d l o g ra n k test f or t he I T T 
p o p ulati o n. T he ti me t o t he first 
e xacer bati o n will als o be a nal yze d usi n g 
C o x re gressi o n m o del t o esti mate hazar ds 
rati o. 
Details a d de d f or clarificati o n.  
9. 7 Sa m pl e Size 
Reassess me nt  
 
I n or der t o e ns ure t hat t he st u d y has at least 
8 0 % p o wer at t he c o ncl usi o n of t he trial, 
8 7 e ve nts will nee d t o be o bser ve d, 
re gar dless of treat me nt gr o u p.  O nce 7 0 % 
( n= 1 6 8) of t he ra n d o mize d s u bj ects o n trial 
ha ve c o m plete d st u d y treat me nt, I ns me d 
a ntici pates t hat at least 7 0 % of t he re q uire d 
s u bj ects wit h a n e ve nt, or 6 1 s u bj ects wit h 
a n e ve nt, will ha ve occ urre d.  T he f or m ula 
f or t he s u g geste d sa m ple size will b e 𝑌=
6 1
𝑥∗2 4 0  w here Y is t he ne w s u g geste d 
t otal sa m ple size, x is t he o bser ve d n u m ber 
of s u bj ects wit h a n e ve nt o nce 7 0 % 
( n= 1 6 8) of t he ra n d o mize d s u bj ects o n trial 
ha ve c o m plete d st u d y treat me nt, 6 1 is t he 
n u m ber of s u bj ects wit h a n e ve nt t hat was 
e x pecte d t o h a ve occ urre d o nce 7 0 % of t he 
Details a d de d f or clarificati o n.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 1  of 1 5 5  
 
Secti o n  
N u m ber a n d Title  
Ol d Te xt  
Ne w Te xt  
R ati o n ale f or C h a n ge  
ra n d o mize d s u bj ects o n trial ha ve 
c o m plete d st u d y treat me nt, a n d 2 4 0 
re prese nts t he t otal n u m ber of s u bj ects be 
ra n d o mize d base d o n t he ori gi nal sa m ple 
size deter mi nati o n. 
A p pe n di x 4:  I nte nse 
P har mac o ki netic Sa m pli n g 
Sc he me  
I nte nse P K S u b-St u d y Bl o o d S a m pli n g 
Ti mes a n d Ti me Wi n d o ws  
 
Visit  
C ollecti o n 
Ti me Rel ati ve 
t o Dr u g 
A d mi nistr ati o n  
C ollecti o n 
Wi n d o w  
Visit 
1  
0 h o ur ( pre -
d ose)  
-3 0 mi n  
I nte nse P K S u b-St u d y Bl o o d S a m pli n g 
Ti mes a n d Ti me Wi n d o ws  
 
Visit  
C ollecti o n 
Ti me Rel ati ve 
t o Dr u g 
A d mi nistr ati o n  
C ollecti o n 
Wi n d o w  
Visit 
2  
0 h o ur ( pre -
d ose)  
-3 0 mi n  
J ustific ati o n:  I nc o nsiste nc y was 
c orrecte d.  
M ulti ple L ocati o ns 
T hr o u g h o ut t he Pr ot oc ol  
St yle, f or mat, a n d t y p o gra p hic al e dits  
St yle, f or mat, a n d t y p o gra p hic al e dits 
C orrecte d a n y s pelli n g err ors, 
re m o ve d/a d de d p u nct uati o n mar ks 
a n d s paces, a d de d/ use d 
a b bre viati o ns c o nsiste ntl y, a n d 
delete d/re vise d/a d de d p hrases t o 
e ns ure st ylistic c o nsiste nc y 
t hr o u g h o ut t he d oc u me nt. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 2  of 1 5 5  
 
P R O T O C O L S Y N O P SI S  
N a me of S p o ns or: I ns me d I nc or p orate d 
P r ot oc ol N u m ber: I N S 1 0 0 7-2 0 1  
N a me of I n vesti g ati o n al Pr o d uct: I N S 1 0 0 7 
N a me of Acti ve I n gre die nt: ( 2 S)-N -{( 1 S) -1 -c ya n o -2 -[ 4-( 3-met h yl -2 -o x o -2, 3 -di h y dr o -1, 3 -
be nz o xaz ol -5 -yl) p he n yl] et h yl } -1, 4 -o xaze pa ne -2 -car b o xa mi de  
St u d y Title:  
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, M ulti -Ce nter St u d y t o Assess t he 
Efficac y, Safet y a n d T olera bilit y, a n d P har mac o ki netics of I N S 1 0 0 7 A d mi nistere d O nce Dail y f or 
2 4  Wee ks i n S u bjects W it h N o n-C ys tic Fi br osis Br o nc hiectasis –  T he Will o w St u d y.  
St u d y P h ase:   2  
I n dic ati o n U n der I n vesti g ati o n: N o n -c ystic fi br osis br o nc hiectasis  
St u d y O bjecti ves:  
P ri m ar y O bjecti ve:  
T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first p ul m o nar y e xacer bati o n o ver 
t he 2 4-wee k treat me nt peri o d.  
Sec o n d ar y O bjecti ves:  
1.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n q ualit y of life ( Q O L), as assesse d 
b y t he Q ualit y of Life Q uesti o n naire -Br o nc hiectasis ( Q O L -B), Res pirat or y S y m pt o ms D o mai n 
sc ore, o ver t he 2 4-wee k treat me nt peri o d.  
2.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n l u n g f u ncti o n, as meas ure d b y 
f orce d e x pirat or y v ol u me i n 1 sec o n d ( F E V1), o ver t he 2 4-wee k treat me nt peri o d.  
3.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of acti ve 
ne utr o p hil elastase ( N E) i n s p ut u m, as meas ure d b y t he differe nce bet wee n t he pre -treat me nt 
c o nce ntrati o n a n d o n -treat me nt c o nce ntrati o n.  
4.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he rate of p ul m o nar y 
e xacer bati o ns o ver t he 2 4 -wee k treat me nt peri o d.  
E x pl or at or y O bjecti ves:  
1.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assesse d b y t he  Q O L -B 
d o mai ns (e xcl u di n g t he Res pirat or y S y m pt o ms D o mai n) o ver t he 2 4 -wee k treat me nt peri o d.  
2.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assesse d b y t he 
Leicester C o u g h Q uesti o n naire ( L C Q), o ver t he 2 4 -wee k treat me nt peri o d.  
3.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n res pirat or y -relate d healt h stat us, 
as assesse d b y t he St . Ge or ge’s Res pirat or y Q uesti o n naire ( S G R Q), o ver t he 2 4 -wee k 
treat me nt peri o d. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 3  of 1 5 5  
 
4.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of acti ve N E i n 
s p ut u m, as meas ure d b y t he differe nce bet wee n t he pre-treat me nt co nce ntrati o n a n d t he 
c o nce ntrati o ns at Wee ks 2, 4, a n d 2 8.  
5.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of acti ve N E i n 
rea ge nt-sti m ulate d bl o o d, as meas ure d b y t he differe nce bet wee n t he pre-treat me nt 
c o nce ntrati o n a n d t he c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
6.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n s p ut u m c ol or (assesse d b y t he 
s p ut u m c ol or c hart) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
7.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce nt rati o n of acti ve N E i n 
s p ut u m, stratifie d b y Baseli ne s p ut u m c ol or, as meas ure d b y t he differe nce bet wee n t he pre -
treat me nt c o nce ntrati o n a n d t he c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
8.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfl a m mat or y a n d tiss ue 
de gra dati o n bi o mar kers i n s p ut u m ( bi o mar kers w hic h ma y be assesse d are pr otei nase 3 a n d 
cat he psi n G) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
9.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d tiss ue 
de gra dati o n bi o mar ker s i n bl o o d ( bi o mar kers w hic h ma y be assesse d are a bs ol ute ne utr o p hil 
c o u nt [ A N C], pr otei nase  3, a n d cat he psi n  G) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
1 0.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d tiss ue 
de gra dati o n bi o mar kers i n uri ne ( des m osi ne) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8.  
1 1.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g p ul m o nar y 
f u ncti o n para meters as meas ure d b y s pir o metr y (force d vital ca pacit y [ F V C]) o ver t he 2 4 -wee k 
treat me nt peri o d.  
1 2.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g p ul m o nar y 
f u ncti o n para meters as meas ure d b y s pir o metr y (p ea k e x pirat or y fl o w rate [ P E F R]) o ver t he 
2 4 -wee k treat me nt peri o d.  
1 3.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o w i n g p ul m o nar y 
f u ncti o n para meters as meas ure d b y s pir o metr y ( F E F2 5 -7 5) o ver t he 2 4-wee k treat me nt peri o d.  
1 4.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he t otal d urati o n of all 
e xacer bati o ns ( da ys per s u bject) o ver t he 2 4 -wee k treat me nt peri o d.  
1 5.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he n u m ber of e xacer bati o ns per 
s u bj ect o ver t he 2 4-wee k treat me nt peri o d.  
1 6.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first p ul m o nar y 
e xacer bati o n, e xacer bati o n rate, Q O L  meas ures a n d p ul m o nar y f u ncti o n para meters ( F E V
1, 
F V C, P E F R, a n d F E F 2 5 -7 5), stratifie d b y Br o nc hiectasis Se verit y I n de x ( B SI) sc ore at baseli ne, 
o ver t he 2 4 -wee k treat me nt peri o d.  
1 7.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first p u l m o nar y 
e xacer bati o n, e xacer bati o n rate, Q O L meas ures a n d p ul m o nar y f u ncti o n para meters ( F E V 1, 
F V C, P E F R, a n d F E F 2 5 -7 5), stratifie d b y t he prese nce or a bse nce of Pse u d o m o n as aer u gi n os a  
(P a ) at Scree ni n g, o ver t he 2 4 -wee k treat me nt peri o d.   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 4  of 1 5 5  
 
1 8.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he use of resc ue me dicati o ns 
(resc ue me dicati o ns i ncl u de s h ort-acti n g beta a g o nists  [ S A B As], s h ort-acti n g m uscari nic 
a nta g o nists  [ S A M As], ne wl y prescri be d l o n g-acti n g beta a g o nists  [ L A B As], l o n g-acti n g 
m uscari nic a nta g o nists  [ L A M As], a n d o x y ge n) o ver t he 2 4-wee k treat me nt peri o d.  
1 9.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n h os pitalizati o ns f or p ul m o nar y 
e xacer bati o ns o ver t he 2 4 -wee k treat me nt peri o d.  
2 0.  T o assess t he c orrelati o ns a m o n g i nfla m mat or y a n d tiss ue de gra dati o n bi o mar kers, 
c o nce ntrati o n of acti ve N E i n bl o o d, s p ut u m, a n d  uri ne a n d efficac y meas ures.  
S af et y O bjecti ve  
T o assess t he safet y a n d t olera bilit y of I N S 1 0 0 7 relati ve t o place b o base d o n a d verse e ve nts ( A Es), 
vital si g n s a n d electr ocar di o gra m ( E C G) meas ure me nts, p h ysical e xa ms, p ul m o nar y f u ncti o n tests 
( P F Ts), a n d cli nical la b orat or y e val uati o ns. 
P h ar m ac o ki netic O bjecti ves:  
1.  T o e val uate t he p har mac o ki netics ( P K) of I N S 1 0 0 7.  
2.  T o assess t he relati o ns hi p bet wee n P K meas ures  f or I N S 1 0 0 7 a n d efficac y, safet y a n d 
bi o mar ker meas ures (e g, c o nce ntrati o ns of acti ve N E i n s p ut u m a n d rea ge nt -sti m ulate d bl o o d).  
St u d y Desi g n:  
T his is a P hase 2, 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, m ultice nter, 
m ulti -nati o nal st u d y t o assess t he efficac y, safet y a n d t olera bilit y, a n d P K of I N S 1 0 0 7 a d mi nistere d 
o nce dail y ( Q D) f or 2 4 wee ks i n s u bjects wit h n o n -c ystic fi br osis br o nc hiectasis ( N C F B E).  
T his m ulti -ce nter st u d y will be c o n d ucte d at a p pr o xi matel y 1 2 0 sites; e nr oll me nt  is c o m petiti ve acr oss 
all sites.  Acr oss t hese sites, it is pla n ne d t o ra n d o mize a p pr o xi matel y 2 4 0 s u bjects wit h N C F B E.  
S u bj ects will be ra n d o mize d i n a 1: 1: 1 rati o t o 3 treat me nt ar ms ( 8 0/ar m) t o recei ve eit her 1 0 m g or 
2 5  m g of I N S 1 0 0 7 or matc hi n g plac e b o.  Ra n d o mizati o n will be stratifie d base d o n w het her t he 
Scree ni n g s p ut u m is c ult ure p ositi ve f or P a  a n d w het her t he s u bject is o n a mai nte na nce use of 
macr oli des f or pre ve nti n g p ul m o nar y e xacer bati o n.  
T here will be a scree ni n g peri o d of u p t o 6  wee ks p er s u bj ect.   D uri n g t he scree ni n g peri o d, t he 
s u bj ect’s de m o gra p hic i nf or mati o n, me dical hist or y a n d s m o ki n g hist or y will be o btai ne d, a p h ysical 
e xa m, vital si g ns a n d a s p ut u m sa m ple f or s p ut u m c ult ure a n d acti ve N E c o nce ntrati o n will be 
c ollecte d, a n d c he mistr y/ he ma t ol o g y a n d uri nal ysis tests, ser u m pre g na nc y test f or w o me n of 
c hil d beari n g p ote ntial ( W O C B P), E C G, a n d p ul m o nar y f u ncti o n test ( P F T) will be c o n d ucte d.  
S u bj ects w h ose past c hest ra di o gra p hic i ma ge rec or ds are n ot a vaila ble will u n der g o a c hest c o m p ute d 
to m o gra p h y  sca n d uri n g Scree ni n g ( Visit 1).  Peri o d o ntal e xa mi nati o n a n d de ntal clea ni n g pr oce d ures 
f or i ncl usi o n s h o ul d be perf or me d pri or t o ra n d o mizati o n.  S u bjects w h o meet all t he i ncl usi o n b ut 
n o ne of t he e xcl usi o n criteria, e xce pt f or t he de ntal e xcl usi o n criteria, will pr ocee d t o ha ve a de ntal 
e xa mi nati o n f or de ntal criteria scree ni n g.  S u bjects w h o meet all eli gi bilit y criteria will u n der g o a 
peri o d o ntal clea ni n g pr oce d ure pri or t o ra n d o mizati o n.  
S u bj ects will be ra n d o mize d at Visit 2 ( Da y  1) a n d re t ur n t hereafter f or st u d y visits at 2 ( Visit 3), 
4  ( Visit 4), 8 ( Visit 5), 1 2 ( Visit 6), 1 6 ( Visit 7), 2 0 ( Visit 8), 2 4 ( Visit 9) a n d 2 8 ( Visit 1 0) wee ks.  
T here will be a visit wi n d o w of ± 3 da ys f or eac h of t he sc he d ule d visits.  D uri n g eac h visit, all 
assess me nts a n d pr oce d ures will be perf or me d as descri be d i n  Secti o n  6  of t his pr ot oc ol.  St u d y 
treat me nt will occ ur bet wee n Visits 2 a n d 9. 
S u bj ects will be re q uire d t o ha ve a n e n d -of -st u d y ( E O S) visit ( Visit 1 0) at Wee k 2 8 t o c ollect bl o o d, 
s p ut u m, a n d uri ne sa m ples f or bi o mar ker assess me nt a n d pre g na nc y test f or W O C B P a n d t o c ollect 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 5  of 1 5 5  
 
i nf or mati o n o n A Es a n d c o nc o mita nt me dicati o ns use.  A P K sa m ple will be c ollecte d fr o m eac h 
s u bj ect partici pati n g i n t he P K s u b-st u d y. 
P h ar m ac o ki netic S u b -st u d y: 
A P K s u b -st u d y will be c o n d ucte d at a select n u m ber of sites.  S u bjects w h o e nr oll at t he selecte d sites 
will u n der g o i nte nsi ve P K sa m pli n g.  A ma xi m u m of 3 6 s u bjects will be i ncl u de d i n t he P K s u b-st u d y.  
F or s u bjects w h o partici pate i n t he P K s u b -st u d y, t he visit wi n d o w f or Visit 4 will be ± 5 da ys.  
A d diti o nall y, f or s u bj ects n ot partici pati n g i n t he P K s u b -st u d y, s parse P K sa m pli n g will be c o n d ucte d 
i n s u bjects at all sites wit h P K sa m pli n g pr ocessi n g ca pa bilities (see  Secti o n  7. 6. 1 ).  P har mac o ki netic 
sa m ples will be a nal yze d i n batc hes o n a n o n g oi n g basis.  
St u d y P o p ul ati o n:  
A p pr o xi matel y 2 4 0 s u bjects dia g n ose d wit h N C F B E will be ra n d o mize d.  
Tre at me nt D ur ati o n:  
Eac h s u bj ect will recei ve st u d y treat me nt f or 2 4 wee ks.  T he e ntire st u d y is sc he d ule d t o ta ke a 
ma xi m u m of 3 4 wee ks f or eac h i n di vi d ual s u bj ect fr o m Scree ni n g ( Visit 1) t o t he E O S  ( Visit 1 0).  
S u bject Eli gi bilit y Criteri a:  
I ncl usi o n Criteri a: 
S u bj ects w h o ha ve gi ve n t heir si g ne d, i nf or me d c o nse nt, are male or fe male bet wee n 1 8 a n d 8 5 years 
of a ge (i ncl usi ve) wit h a b o d y mass i n de x > 1 8. 5 at S cree ni n g ( Visit 1) a n d ha ve a cli nical hist or y 
c o nsiste nt wit h N C F B E will be eli gi ble f or e nr oll me nt i n t he st u d y.  
F or m ore c o m pre he nsi ve details of t he i ncl usi o n criteria refer t o Secti o n  4. 1. 1  of t his pr ot oc ol.  
E xcl usi o n Criteri a:  
S u bj ects w h o ha ve a pri mar y dia g n osis of c hr o nic o bstr ucti ve p ul m o nar y disease or ast h ma, ha ve 
br o nc hiectasis d ue t o c ystic fi br osis, h y p o ga m ma gl o b uli ne mia, c o m m o n varia ble i m m u n o deficie nc y, 
or α 1 -a ntitr y psi n deficie nc y, are c urre nt s m o kers as defi ne d per Ce nters f or Disease C o ntr ol a n d 
Pre ve nti o n criteria, or c urre ntl y bei n g treate d f or a n o nt u berc ul o us m yc o bacterial l u n g i nfecti o n, 
aller gic br o nc h o p ul m o nar y as per gi ll osis, or t u berc ul osis will n ot be eli gi ble f or e nr oll me nt i n t he st u d y.  
F or m ore c o m pre he nsi ve details of t he e xcl usi o n criteria refer t o Secti o n  4. 1. 2  of t his pr ot oc ol.  
Dr u g Pr o d uct, Stre n gt h, D os a ge F or m, a n d R o ute of A d mi nistr ati o n:  
T he st u d y dr u gs (I N S 1 0 0 7 a n d place b o) will be s u p plie d b y t he S p o ns or.  
P r o d uct N a me  
P r o d uct 
Stre n gt h  
D os a ge F or m  
R o ute a n d F re q ue nc y of 
A d mi nistr ati o n  
I N S 1 0 0 7 
1 0 m g  
r o u n d, bic o n ve x, br o w n, 
fil m c oate d ta blet 
Orall y, o nce dail y bef ore 
brea kfast  
I N S 1 0 0 7 
2 5 m g  
r o u n d bic o n ve x, br o w n, 
fil m c oate d ta blet 
Orall y, o nce dail y bef ore 
brea kfast  
Place b o  
N o acti ve 
i n gre die nt 
r o u n d, bic o n ve x, br o w n, 
fil m c oate d ta blet 
Orall y, o nce dail y bef ore 
brea kfast  
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 6  of 1 5 5  
 
St u d y E n d p oi nts:  
Pri mar y E n d p oi nt:  
T he pri mar y e n d p oi nt is t he ti me t o t he first p ul m o nar y e xacer bati o n o ver t he 2 4 -wee k treat me nt 
peri o d.  
P ul m o nar y e xacer bati o n defi niti o n.   A p ul m o nar y e xacer bati o n i n t his st u d y is defi ne d as ha vi n g 3 or 
m ore of t he f oll o wi n g s y m pt o ms f or at least 4 8 h o urs res ulti n g i n a p h ysicia n’s decisi o n t o prescri be 
a nti bi otics.  
1.  I ncrease d c o u g h  
2.  I ncrease d s p ut u m v ol u me or c ha n ge i n s p ut u m c o nsiste nc y 
3.  I ncrease d s p ut u m p ur ule nce  
4.  I ncrease d breat hless ness a n d/ or decrease d e xercise t olera nce  
5.  Fati g ue a n d/ or malaise  
6.  He m o pt ysis  
S u bj ects o n c hr o nic macr oli de t hera p y w h ose o nl y c ha n ge i n t hera p y is d ose or fre q ue nc y a dj ust me nt 
will n ot meet t he defi niti o n of  e xacer bati o n. 
Sec o n d ar y E n d p oi nts:  
1.  C ha n ge fr o m Baseli ne i n Q O L -B Res pirat or y S y m pt o ms D o mai n sc ore o ver t he 2 4 -wee k 
treat me nt peri o d 
2.  C ha n ge fr o m Scree ni n g i n p ost -br o nc h o dilat or F E V 1 o ver t he 2 4 -wee k treat me nt peri o d  
3.  C ha n ge i n c o nce ntrati o n of acti ve N E i n s p ut u m fr o m pre-treat me nt t o o n-treat me nt 
4.  Rate of p ul m o nar y e xacer bati o ns ( n u m ber of e ve nts per pers o n -ti me) o ver t he 2 4-wee k 
treat me nt peri o d 
E x pl or at or y E n d p oi nts:  
1.  C ha n ge fr o m Baseli ne i n Q O L -B sc ores (all d o mai ns e xcl u di n g t he Res pirat or y S y m pt o ms 
D o mai n) o ver t he 2 4 -wee k treat me nt peri o d  
2.  C ha n ge fr o m Baseli ne i n Q O L as assesse d b y t he L C Q sc ore o ver t he 2 4 -wee k treat me nt 
peri o d  
3.  C ha n ge fr o m Baseli ne i n S G R Q t otal sc ore o ver t he 2 4 -wee k treat me nt peri o d  
4.  C ha n ge i n c o nce ntrati o n of acti ve N E i n s p ut u m f r o m pre-treat me nt t o Wee ks 2, 4, a n d 2 8  
5.  C ha n ge i n c o nce ntrati o n of acti ve N E i n rea ge nt -sti m ulate d bl o o d fr o m pre-treat me nt t o 
Wee ks  2, 4, 1 2, 2 4, a n d 2 8  
6.  C ha n ge fr o m Baseli ne i n s p ut u m c ol or (assesse d b y t he s p ut u m c ol or c hart) at Wee ks 2, 4, 1 2, 
2 4, a n d  2 8   
7.  C ha n ge i n c o nce ntrati o n of acti ve N E i n s p ut u m (stratifie d b y s p ut u m c ol or) at baseli ne fr o m 
pre -treat me nt t o Wee ks 2, 4, 1 2, a n d 2 8 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 7  of 1 5 5  
 
8.  C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d tiss ue de gra dati o n bi o mar ker le vels i n s p ut u m (t he 
bi o mar kers w hic h ma y be a ssesse d are e g, pr otei nase 3 a n d cat he psi n G) at Wee ks 2, 4, 1 2, 2 4, 
a n d 2 8  
9.  C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d tiss ue de gra dati o n bi o mar ker le vels i n bl o o d 
( bi o mar kers w hic h ma y be assesse d are e g, A N C, pr otei nase 3, a n d cat he psi n G) at Wee ks 2, 4, 
1 2, 2 4, a n d 2 8  
1 0.  C ha n ge fr o m Baseli ne i n tiss ue de gra dati o n mar ker le vel i n uri ne ( des m osi ne) at Wee ks 2, 4, 
1 2, 2 4, a n d 2 8  
1 1.  C ha n ge fr o m Scree ni n g i n F V C at Wee ks 1 2 a n d 2 4  
1 2.  C ha n ge fr o m Scree ni n g i n P E F R at Wee ks 1 2 a n d 2 4  
1 3.  C ha n ge fr o m Scree ni n g i n F E F 2 5 -7 5 at Wee ks 1 2 a n d 2 4  
1 4.  T otal d urati o n (i n da ys) of e xacer bati o ns, per s u bject, o ver t he 2 4 -wee k treat me nt peri o d  
1 5.  T otal n u m ber of e xacer bati o ns per s u bject o ver t he 2 4 -wee k treat me nt peri o d  
1 6.  Ti me t o first p ul m o nar y e xacer bati o n, e xacer bati o n rate, Q O L m eas ures , a n d p ul m o nar y 
f u ncti o n para meters ( F E V1, F V C, P E F R, a n d F E F2 5 -7 5), stratifie d b y B SI sc ore at baseli ne, o ver 
t he 2 4-wee k treat me nt peri o d  
1 7.  Ti me t o first p ul m o nar y e xacer bati o n, e xacer bati o n rate, Q O L m eas ures, a n d p ul m o nar y 
f u ncti o n para meters ( F E V1, F V C, P E F R, a n d F E F 2 5 -7 5), stratifie d b y t he prese nce or a bse nce of 
P a  at Scree ni n g, o ver t he 2 4 -wee k treat me nt peri o d  
1 8.  Fre q ue nc y of use of resc ue me dicati o ns (resc ue me dicati o ns i ncl u de S A B As, S A M A s, ne wl y 
prescri be d L A B As, L A M As , a n d o x y ge n) o ver t he 2 4-wee k t reat me nt peri o d  
1 9.  N u m ber of s u bjects h os pitalize d d ue t o p ul m o nar y e xacer bati o ns b y t he e n d of t he 2 4 -wee k 
treat me nt peri o d 
2 0.  Descri pti ve assess me nt of t he c ha n ge i n i nfla m mat or y a n d tiss ue de gra dati o n bi o mar kers a n d 
c o nce ntrati o n of acti ve N E i n bl o o d, s p ut u m, a n d uri ne, o ver t he 2 4 -wee k  treat me nt peri o d 
S af et y E n d p oi nts:  
T he safet y e n d p oi nts will i ncl u de A Es, 1 2 -lea d E C G meas ure me nts, cli nical la b orat or y testi n g res ults, 
vital si g n meas ure me nts, p h ysical e xa mi nati o n res ults, a n d P F T meas ure me nts.  A d verse e ve nts of 
s pecial i nterest t hat will be re p orte d i ncl u de h y per kerat osis, peri o d o ntitis/ gi n gi vitis, a n d ot her 
i nfecti o ns. 
P h ar m ac o ki netic E n d p oi nts:  
T he P K para meters, as esti mate d usi n g n o n -c o m part me ntal a nal ysis met h o ds, will i ncl u de ma xi m u m 
plas ma c o nce ntrati o n ( C ma x ), ti me t o ma xi m u m plas ma c o nce ntrati o n (tma x ), a vera ge plas ma 
c o nce ntrati o n at stea d y state ( C ss), ma xi m u m plas ma c o nce ntrati o n at stea d y state ( C ma x ,ss), ti me t o 
ma xi m u m plas ma c o nce ntrati o n at stea d y state ( tma x,ss ), mi ni m u m plas ma c o nce ntrati o n at stea d y state 
( Cmi nss ), a n d area u n der t he plas ma c o nce ntrati o n c ur ve fr o m 0 t o 8 h o urs ( A U C 0 -8). 
St atistic al Met h o ds:  
S a m ple Size  
It is e x pecte d t hat p ul m o nar y e xacer bati o ns occ ur at a rate of 1. 2 e ve nts per s u bject year i n t he place b o 
gr o u p, c orres p o n di n g t o 4 4. 6 % of t he place b o s u bjects bei n g e ve nt free at 2 4 wee ks.  It is e x pecte d t hat 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 8  of 1 5 5  
 
4 0 % m ore e ve nt -free s u bjects will be o bser ve d wit hi n t he I N S 1 0 0 7 gr o u ps ( b ot h 1 0 m g a n d 2 5  m g) 
c orres p o n di n g t o 6 2. 4 % of t he I N S 1 0 0 7 s u bjects bei n g e ve nt free at 2 4 wee ks.  T he sa m ple size 
calc ulati o n is f or t he first test i n t he hierarc hical testi n g pr oce d ure.  T he hazar d ra ti o use d i n t he sa m ple 
size calc ulati o n is l n( 0. 6 2 4)/l n( 0. 4 4 6) = 0. 5 8 4.  Ass u mi n g t he e xacer bati o n rate i n t he place b o ar m is 
1. 2 e ve nts per s u bject per year, 2 1 6 s u bjects i n t otal, ra n d o mize d i n a 1: 1: 1 rati o t o 3 treat me nt ar ms 
wit h 7 2 c o m pleters per ar m , will yiel d 8 0 % p o wer if t he e x pecte d differe nce i n t he ti me t o t he first 
e ve nt is 4 0 % after 2 4 wee ks of treat me nt wit h a t y pe I err or of 0. 1 u n der a hierarc hical testi n g 
pr oce d ure.  A p pr o xi matel y 2 4 0 s u bjects dia g n ose d wit h N C F B E will be ra n d o mize d t o pr o vi de 
a p pr o xi matel y 2 1 6 s u bjects t o c o m plete t he st u d y, ass u mi n g 1 0 % of t he s u bjects will disc o nti n ue st u d y 
dr u g bef ore c o m pleti n g 2 4 wee ks of treat me nt.  
Effic ac y A n al ysis  
T he pri mar y efficac y e n d p oi nt is t he ti me t o t he first p ul m o nar y e xacer bati o n o ver t h e 2 4-wee k 
treat me nt peri o d.  T he n ull h y p ot hesis ass u mes t hat t he ti me t o t he first e xacer bati o n is i n de pe n de nt of 
treat me nt, a n d t he alter nati ve h y p ot hesis ass u mes t hat t he ti me t o t he first e xacer bati o n is ass ociate d 
wit h treat me nt.  
T he efficac y a nal ysis  of t he ti me t o t he first e xacer bati o n will be perf or me d f or t he i nte nt -t o-treat (I T T) 
p o p ulati o n usi n g Ka pla n Meier c ur ves.  T he treat me nt c o m paris o n will be ma de usi n g t he stratifie d l o g 
ra n k test f or t he I T T p o p ulati o n.  T he ti me t o t he first e xacer batio n will als o be a nal yze d usi n g C o x 
re gressi o n m o del t o esti mate hazar ds rati o. 
A s u p p orti ve a nal ysis of t he pri mar y efficac y e n d p oi nt will be perf or me d f or t he per -pr ot oc ol 
p o p ulati o n usi n g t he sa me met h o ds as f or t he I T T p o p ulati o n.  T he e xacer bati o n rate  will be a nal yze d 
f or t he I T T p o p ulati o n stratifie d b y P a  c ol o nizati o n stat us a n d mai nte na nce use of macr oli des at 
Baseli ne.  
Sec o n dar y e n d p oi nts of Q O L -B, F E V 1, a n d N E will be a nal yze d usi n g a nal ysis of varia nce; t he rate of 
p ul m o nar y e xacer bati o ns will be  a nal yze d usi n g C oc hra n -Ma ntel -Hae nszel statistics.   
S af et y A n al ysis  
S u bj ect dis p ositi o n will be liste d a n d s u m marize d i ncl u di n g t he n u m ber of wit h dra wals a n d t he 
pri mar y reas o n f or wit h dra wal.  S u bjects e xcl u de d fr o m a n y a nal ysis sets will be liste d i ncl u di n g t he 
reas o ns f or e xcl usi o ns.  
All safet y data will be liste d f or eac h s u bject a n d s u m marize d a p pr o priatel y.  A d verse e ve nts will be 
c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities a n d s u m marize d b y s yste m or ga n class 
a n d preferre d ter m.  A d diti o nal s u m maries b y se verit y a n d relati o ns hi p t o st u d y treat me nt will be 
prese nte d.  
All cli nical safet y la b orat or y data a n d vital si g ns will be liste d a n d s u m marize d i ncl u di n g c ha n ges fr o m 
Baseli ne.   A n y o ut of ra n ge la b orat or y meas ure me nts will be fla g ge d i n t he listi n gs.  
Di gital E C G ( d E C G) data will be s m o ot he d, a n d t he heart rate ( H R) a n d correcte d Q T i nter val b y 
Fri dericia  ( Q T c F) will be deri ve d fr o m t he s m o ot he d data at eac h ti me p oi nt.  T he d E C G data will be 
liste d a n d s u m marize d descri pti vel y; o utlier a nal yses f or Q T c F will als o be perf or me d.  
P h ar m ac o ki netic A n al ysis  
F or s u bjects partici pati n g i n t he P K s u b -st u d y, plas ma c o nce ntrati o ns of I N S 1 0 0 7 will be liste d a n d 
s u m marize d b y d ose le vel of I N S 1 0 0 7 o ver eac h sc he d ule d sa m pli n g ti me usi n g descr i pti ve statistics, 
as a p pr o priate.  I n di vi d ual plas ma c o nce ntrati o n data vers us ti me will be prese nte d i n data listi n gs, 
al o n g wit h gra p hical pl ots of i n di vi d ual a n d ge o metric mea n plas ma c o nce ntrati o n -ti me pl ots prese nte d 
i n li near a n d se mi-l o garit h mic scale.  Plas ma P K para meters will be s u m marize d usi n g descri pti ve 
statistics, as a p pr o priate.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 4 9  of 1 5 5  
 
A d diti o nall y, f or s u bj ects n ot partici pati n g i n t he P K s u b -st u d y, s parse P K sa m pli n g will be c o n d ucte d 
i n s u bjects at all sites wit h P K sa m pli n g pr ocessi n g ca pa bilities.  Act ual sa m pli n g ti mes a n d I N S 1 0 0 7 
plas ma c o nce ntrati o ns will be liste d b ut n ot s u m marize d.  
Plas ma c o nce ntrati o n data f or I N S 1 0 0 7 will be p o ole d wit h c orres p o n di n g data fr o m ot her S p o ns or 
st u dies f or p o p ulati o n P K ( PP K) m o delli n g.  T h e met h o ds a n d res ults of a n y PP K a nal yses will be 
descri be d a n d re p orte d se paratel y.  
P h ar m ac o d y n a mic A n al ysis  
T he N E acti vit y i n s p ut u m a n d bl o o d will be calc ulate d as perce nt i n hi biti o n fr o m t he pre -treat me nt 
acti vit y a n d n or malize d b y A N C ( bl o o d o nl y).  Pre -treat me nt val ue is defi ne d as t he mea n val ue of N E 
acti vities at Scree ni n g a n d Baseli ne a n d will be liste d a n d s u m marize d t o get her wit h t he A N C 
meas ure me nts.  
All ot her bi o mar ker le vels at pre - a n d p ost -d ose le vels will be liste d a n d s u m marize d.  
Plas ma c o nce ntrati o n data f or I N S 1 0 0 7 will be p o ole d wit h c orres p o n di n g data fr o m ot her st u dies f or 
p o p ulati o n P K/ P D m o delli n g of t he e x p os ure res p o nse relati o ns hi p.  T he met h o ds a n d res ults of a n y 
p o p ulati o n P K/ P D a nal yses will be descri be d a n d re p orte d se paratel y.  
D at a M o ni t ori n g C o m mittee: 
A n i n de pe n de nt, e xter nal Data M o nit ori n g C o m mittee ( D M C), c o m prise d of at least 2 p h ysicia ns wit h 
p ul m o nar y e x pertise, a n e x pert i n peri o d o ntal disease, a n e x pert i n der mat ol o g y, a n d a statisticia n w h o 
is e x perie nce d i n t he e val uati o n of cli nical safet y data will be set u p t o re vie w all A Es a n d seri o us A Es 
t o e ns ure t he safet y of s u bjects e nr olle d i nt o t his st u d y.  A d diti o nal me m bers ma y be a d de d b y t he 
D M C if it is deter mi ne d t hat a d diti o nal e x pertise is re q uire d t o e val uate t he cli nical safet y data.  T he 
D M C me m bers will re vie w t he data i n a se mi -bli n de d or u n -bli n de d ma n ner at pre deter mi ne d i nter vals.  
If si g nifica nt safet y iss ues arise i n bet wee n sc he d ule d meeti n gs, a d-h oc meeti n gs will be sc he d ule d t o 
re vie w t h ose data.  Base d o n t he safet y i m plicati o ns of t he data, t he D M C ma y rec o m me n d 
m o dificati o n or ter mi nati o n of t he st u d y.  F urt her details of t he D M C will be pr o vi de d se paratel y i n t he 
D M C c harter.  
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 0  of 1 5 5  
 
T A B L E O F C O N T E N T S  
S U M M A R Y O F  C H A N G E S T O A M E N D E D P R O T O C O L V E R SI O N 5. 0 , D A T E D 2 4 
S E P T E M B E R 2 0 1 8  ......................................................................................................4  
S U M M A R Y O F C H A N G E S T O A M E N D E D P R O T O C O L V E R SI O N 4. 0, D A T E D 2 7  
A P RI L 2 0 1 8  ................................................................................................................1 7  
S U M M A R Y O F C H A N G E S T O A M E N D E D P R O T O C O L V E R SI O N 3. 0, D A T E D 1 2  
M A R C H 2 0 1 8  .............................................................................................................2 0  
P R O T O C O L S Y N O P SI S  ..............................................................................................................4 2  
T A B L E O F C O N T E N T S  ...............................................................................................................5 0  
LI S T O F T A B L E S  .........................................................................................................................5 7  
LI S T O F FI G U R E S  .......................................................................................................................5 7  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  ..................................................5 8  
1.  
I N T R O D U C TI O N A N D B A CK G R O U N D I N F O R M A TI O N  ..................................6 2  
1. 1.  
I n v esti gati o nal Pr o d uct(s) ...........................................................................................6 2  
1. 1. 1.  
Na me  ...........................................................................................................................6 2  
1. 1. 2.  
Descri pti o n  ..................................................................................................................6 2  
1. 1. 3.  
I nte n d e d Use U n der I n vesti gati o n ..............................................................................6 2  
1. 2.  
Disease Bac k gr o u n d  ...................................................................................................6 2  
1. 3.  
De vel o p me nt Pr o gra m  ................................................................................................6 3  
1. 3. 1.  
N o ncli nical St u dies  .....................................................................................................6 3  
1. 3. 2.  
Cli nical E x perie nce  .....................................................................................................6 4  
1. 3. 3.  
Cli nical P har mac o ki netics  ..........................................................................................6 5  
1. 4.  
St u d y R ati o nale  ...........................................................................................................6 6  
1. 5.  
Ris ks a n d Be nefits f or St u d y S u bjects  ........................................................................6 7  
1. 5. 1.  
P ote ntial Be nefits  ........................................................................................................6 7  
1. 5. 2.  
Ris ks a n d Ris k Miti gati o n Strate gies  ..........................................................................6 7  
1. 5. 2. 1.  
H y p er kerat osis/ Peri o d o ntitis  .......................................................................................6 7  
1. 5. 2. 2.  
I nfecti o ns ....................................................................................................................6 8  
1. 5. 2. 3.  
Testic ular T o xicit y  ......................................................................................................6 8  
1. 5. 3.  
C o ncl usi o ns o n Ris k -Be nefit  ......................................................................................6 9  
1. 6.  
P o p ulati o n, R o ute, D osa ge, D osa ge Re gi me n, Treat me nt Peri o d  ..............................6 9  
2.  
S T U D Y O BJ E C TI V E S  ..............................................................................................7 0  
2. 1.  
St u d y O bjecti ves  .........................................................................................................7 0  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 1  of 1 5 5  
 
2. 1. 1.  
Pri mar y O bj ecti ve  .......................................................................................................7 0  
2. 1. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................7 0  
2. 1. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................7 0  
2. 1. 4.  
Safet y O bjecti ve  ..........................................................................................................7 2  
2. 1. 5.  
P har mac o ki netic O bje cti ves  .......................................................................................7 2  
3.  
I N V E S TI G A TI O N A L P L A N .....................................................................................7 3  
3. 1.  
O verall St u d y Desi g n a n d Pla n  ...................................................................................7 3  
3. 2.  
St u d y E n d p oi nts  ..........................................................................................................7 6  
3. 2. 1.  
Pri mar y E n d p oi nt  ........................................................................................................7 6  
3. 2. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................7 6  
3. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................7 6  
3. 2. 4.  
Safet y E n d p oi nts  .........................................................................................................7 7  
3. 2. 5.  
P har mac o ki netic E n d p oi nts  ........................................................................................7 8  
3. 3.  
Disc ussi o n of St u d y Desi g n  ........................................................................................7 8  
3. 3. 1.  
N u m ber of S u bjects  ....................................................................................................7 8  
3. 3. 2.  
St u d y D urati o n  ............................................................................................................7 8  
3. 3. 3.  
E n d of St u d y  ...............................................................................................................7 8  
3. 3. 4.  
S t o p pi n g R ules ............................................................................................................7 8  
3. 3. 4. 1.  
St u d y Disc o nti n uati o n  ................................................................................................7 8  
3. 3. 4. 2.  
S u bject Disc o nti n uati o n Criteria  .................................................................................7 9  
3. 4.  
Selecti o n of D oses  ......................................................................................................7 9  
3. 4. 1.  
E x peri me ntal Treat me nts  ............................................................................................7 9  
3. 4. 2.  
C o ntr ol Treat me nts  .....................................................................................................8 0  
3. 5.  
Data M o nit ori n g C o m mittee  .......................................................................................8 0  
4.  
S T U D Y P O P U L A TI O N  .............................................................................................8 1  
4. 1.  
E nr oll me nt  ..................................................................................................................8 1  
4. 1. 1.  
I n cl usi o n Criteria ........................................................................................................8 1  
4. 1. 2.  
E x cl usi o n Criteria  .......................................................................................................8 2  
4. 2.  
Re m o val of S u bjects  ...................................................................................................8 4  
4. 2. 1.  
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n  .........................................................8 4  
4. 2. 2.  
S u bject Re -Scree ni n g Pr oce d ures  ...............................................................................8 5  
5.  
S T U D Y T R E A T M E N T S ............................................................................................8 6  
5. 1.  
I n v esti gati o nal Pr o d ucts ..............................................................................................8 6  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 2  of 1 5 5  
 
5. 1. 1.  
I n v esti gati o nal Pr o d uct ...............................................................................................8 6  
5. 1. 2.  
Matc hi n g Place b o  .......................................................................................................8 6  
5. 1. 3.  
Met h o d of Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g  .......................................8 6  
5. 1. 4.  
U n bli n di n g Pr oce d ures  ...............................................................................................8 6  
5. 1. 5.  
St u d y Dr u g A d mi nistrati o n .........................................................................................8 6  
5. 1. 6.  
Met h o d of Assessi n g Treat me nt C o m plia nce  .............................................................8 7  
5. 1. 7.  
Pac ka gi n g a n d La b eli n g I nf or mati o n  ..........................................................................8 7  
5. 1. 8.  
St ora ge  ........................................................................................................................8 7  
5. 1. 9.  
Dr u g Us a ge a n d Acc o u nt a bilit y ..................................................................................8 8  
5. 2.  
C o nc o mita nt Me dicati o ns  ...........................................................................................8 8  
5. 3.  
Pr o hi bite d Me dicati o ns  ...............................................................................................8 9  
5. 4.  
Per mitte d Me dicati o ns a n d Pr oce d ures  ......................................................................9 2  
6.  
S T U D Y P R O C E D U R E S  ............................................................................................9 5  
6. 1.  
Scree ni n g Peri o d  .........................................................................................................9 5  
6. 1. 1.  
Visit 1 ( Da ys -4 2 t o -1)  ...............................................................................................9 5  
6. 2.  
Treat me nt Peri o d Visits 2 T hr o u g h 9  .........................................................................9 6  
6. 2. 1.  
Visit 2 ( Baseli ne, D a y  1) Ra n d o mizati o n  ...................................................................9 6  
6. 2. 2.  
Visit 3 ( Wee k 2, Da y  1 5)  ............................................................................................9 6  
6. 2. 3.  
Visit 4 ( Wee k 4, Da y  2 9)  ............................................................................................9 7  
6. 2. 4.  
Visit 5 ( Wee k 8, Da y  5 7)  ............................................................................................9 8  
6. 2. 5.  
Visit 6 ( Wee k 1 2, Da y  8 5)  ..........................................................................................9 8  
6. 2. 6.  
Visit 7 ( Wee k 1 6, Da y  1 1 3)  ........................................................................................9 9  
6. 2. 7.  
Visit 8 ( Wee k 2 0, Da y  1 4 1)  ......................................................................................1 0 0  
6. 2. 8.  
Visit 9 ( Wee k 2 4, Da y  1 6 9, E n d of Treat me nt)  ........................................................1 0 0  
6. 2. 9.  
Visit 1 0 ( Wee k 2 8, Da y  1 9 7, E n d of St u d y)  .............................................................1 0 1  
6. 2. 1 0.  
U nsc he d ule d St u d y Visits  .........................................................................................1 0 2  
7.  
S T U D Y V A RI A B L E S A N D M E T H O D S O F A S S E S S M E N T S  .............................1 0 9  
7. 1.  
Pri mar y E n d p oi nt Varia ble  .......................................................................................1 0 9  
7. 1. 1.  
Ti me t o First P ul m o nar y E x acer bati o n  .....................................................................1 0 9  
7. 2.  
Sec o n dar y E n d p oi nt Varia bles  .................................................................................1 0 9  
7. 2. 1.  
Q ualit y of Lif e Q uesti o n naire -Br o nc hiectasis  ..........................................................1 0 9  
7. 2. 2.  
P ul m o nar y F u ncti o n Test  ..........................................................................................1 1 0  
7. 2. 3.  
Ne utr o p hil Elastase C o nce ntrati o n - S p ut u m  ...........................................................1 1 1  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 3  of 1 5 5  
 
7. 2. 4.  
Rate of P ul m o nar y E x acer bati o n  ..............................................................................1 1 1  
7. 3.  
E x pl orat or y E n d p oi nt Varia bles  ...............................................................................1 1 1  
7. 3. 1.  
Lei cester C o u g h Q u esti o n naire  .................................................................................1 1 1  
7. 3. 2.  
St. Ge or ge’s Res pirat or y Q uesti o n naire  ...................................................................1 1 1  
7. 3. 3.  
Ne utr o p hil Elastase C o nce ntrati o n –  Bl o o d  .............................................................1 1 2  
7. 3. 4.  
S p ut u m C ol or  ............................................................................................................1 1 2  
7. 3. 5.  
I nfla m mat or y Bi o mar ker Le v els-S p ut u m  .................................................................1 1 2  
7. 3. 6.  
I nfla m mat or y a n d Tiss ue De gra d ati o n Bi o mar ker Le v els - Bl o o d a n d Uri ne  ..........1 1 3  
7. 3. 7.  
E x acer bati o n D urati o n  ..............................................................................................1 1 3  
7. 3. 8.  
Resc ue Me dic ati o n Use  ............................................................................................1 1 3  
7. 3. 9.  
Healt hcare Res o ur ce Utiliz ati o n  ...............................................................................1 1 3  
7. 4.  
Br o nc hi ectasis Se verit y I n de x  ..................................................................................1 1 3  
7. 4. 1.  
Br o nc hi ectasis Se verit y I n de x Calc ulati o n  ...............................................................1 1 3  
7. 5.  
Ot her St u d y Ass ess me nts  .........................................................................................1 1 4  
7. 5. 1.  
Me dical Hist or y  ........................................................................................................1 1 4  
7. 5. 2.  
S m o ki n g Hist or y a n d Stat us  .....................................................................................1 1 4  
7. 5. 3.  
B o d y Mass I n d e x  ......................................................................................................1 1 4  
7. 5. 4.  
C o m p ute d T o m o gra p h y Sca n  ...................................................................................1 1 4  
7. 5. 5.  
C o nc o mita nt Me dicati o ns a n d Pr oce d ures  ...............................................................1 1 5  
7. 5. 6.  
Esti mate d Gl o mer ular Filtrati o n Rate  .......................................................................1 1 5  
7. 5. 7.  
C hil d -P u g h Sc ore  ......................................................................................................1 1 5  
7. 5. 8.  
T otal Uri ne Pr otei n a n d Uri ne Creati ni ne Q u a ntitati o n  ............................................1 1 6  
7. 6.  
P har mac o ki netic Varia bl es  .......................................................................................1 1 6  
7. 6. 1.  
P har mac o ki netic Sa m pli n g  .......................................................................................1 1 6  
7. 7.  
Safet y Vari a bles  ........................................................................................................1 1 6  
7. 7. 1.  
Vital Si g ns  ................................................................................................................1 1 7  
7. 7. 2.  
P h ysical E x a mi nati o n  ...............................................................................................1 1 7  
7. 7. 3.  
Electr ocar di o gra m  .....................................................................................................1 1 7  
7. 7. 4.  
Cli nical La b orat or y Tests  .........................................................................................1 1 7  
7. 7. 4. 1.  
Pre g n a nc y T est a n d Re pr o d ucti ve Preca uti o ns  .........................................................1 1 9  
7. 7. 5.  
De ntal E x a mi nati o n  ..................................................................................................1 1 9  
7. 7. 6.  
Der mat ol o gical Assess m e nt  ......................................................................................1 2 0  
8.  
A D V E R S E E V E N T S ................................................................................................1 2 2  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 4  of 1 5 5  
 
8. 1.  
Defi niti o n of a n A d verse E ve nt  ................................................................................1 2 2  
8. 2.  
Defi niti o n of a Seri o us A d verse E ve nt  .....................................................................1 2 2  
8. 2. 1.  
Assess me nt of I nte nsit y  ............................................................................................1 2 3  
8. 2. 2.  
Assess me nt of Ca usalit y  ...........................................................................................1 2 4  
8. 2. 3.  
Assess me nt of O utc o me  ...........................................................................................1 2 4  
8. 3.  
A d verse E v e nts of S peci al I nt erest  ...........................................................................1 2 4  
8. 3. 1.  
H y p er kerat osis  ..........................................................................................................1 2 4  
8. 3. 2.  
Peri o d o ntitis/ Gi n gi vitis  .............................................................................................1 2 5  
8. 3. 3.  
Ot her I nfecti o ns  ........................................................................................................1 2 5  
8. 4.  
Re p orti n g Re q uir e me nts  ...........................................................................................1 2 6  
8. 4. 1.  
Peri o d of O bser vati o n f or A d verse E ve nts  ...............................................................1 2 6  
8. 4. 2.  
Seri o us A d verse E v e nts  ............................................................................................1 2 6  
8. 4. 3.  
H y’s La w  ..................................................................................................................1 2 6  
8. 4. 4.  
Ot her Re p orta ble E ve nts  ...........................................................................................1 2 6  
8. 4. 4. 1.  
Pre g n a nc y  .................................................................................................................1 2 6  
8. 4. 4. 2.  
O ver d ose  ...................................................................................................................1 2 7  
8. 5.  
F oll o w -U p of Seri o us A d verse E ve nts  .....................................................................1 2 7  
8. 6.  
Re g ulat or y As pects  ...................................................................................................1 2 7  
9.  
S T A TI S TI C A L M E T H O D S  .....................................................................................1 2 8  
9. 1.  
Sa m ple Siz e  ..............................................................................................................1 2 8  
9. 2.  
Ra n d o mizati o n a n d Stratificati o n  .............................................................................1 2 8  
9. 3.  
A nal ysis P o p ulati o ns  ................................................................................................1 2 8  
9. 3. 1.  
I nte nt-t o-Treat P o p ulati o n  ........................................................................................1 2 8  
9. 3. 2.  
Per -Pr ot oc ol P o p ulati o n  ............................................................................................1 2 9  
9. 3. 3.  
Safet y P o p ulati o n  ......................................................................................................1 2 9  
9. 3. 4.  
P har mac o ki netic P o p ulati o n  .....................................................................................1 2 9  
9. 3. 5.  
P har mac o d y na mic P o p ul ati o n  ..................................................................................1 2 9  
9. 4.  
De m o gra p hics a n d Baseli ne C haract eristics  .............................................................1 2 9  
9. 5.  
Statistical A nal ysis  ....................................................................................................1 2 9  
9. 5. 1.  
Efficac y a n d Safet y  ...................................................................................................1 2 9  
9. 5. 1. 1.  
Efficac y A nal ysis  ......................................................................................................1 3 0  
9. 5. 1. 2.  
Pri mar y E n d p oi nt A nal ysis  .......................................................................................1 3 0  
9. 5. 1. 3.  
Safet y A nal ysis  .........................................................................................................1 3 1  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 5  of 1 5 5  
 
9. 5. 2.  
P har mac o ki netic a n d P har mac o d y na mic A nal ysis  ...................................................1 3 2  
9. 5. 2. 1.  
P har mac o ki netic A n al ysis  ........................................................................................1 3 2  
9. 5. 2. 2.  
P har mac o d y na mic A n al ysis ......................................................................................1 3 3  
9. 5. 2. 3.  
P har mac o ki netic -P har mac o d y n a mic A nal ysis  .........................................................1 3 3  
9. 5. 2. 4.  
P har mac o d y na mic -P har mac o d y na mic A nal ysis  ......................................................1 3 4  
9. 6.  
I nteri m A nal ysis ........................................................................................................1 3 4  
9. 7.  
Sa m ple Siz e Reassess me nt  .......................................................................................1 3 4  
1 0.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  ............................................1 3 5  
1 0. 1.  
S o urce D oc u m e nts  ....................................................................................................1 3 5  
1 0. 2.  
Data C ollecti o n a n d Case Re p ort F or m M o nit ori n g  .................................................1 3 5  
1 0. 3.  
St u d y R ec or ds Rete nti o n  ..........................................................................................1 3 5  
1 1.  
E T HI C A L C O N SI D E R A TI O N S, C O M P LI A N C E S T A T E M E N T A N D 
R E G U L A T O R Y C O M P LI A N C E  ............................................................................1 3 6  
1 1. 1.  
Et hical C o nsi d erati o ns  ..............................................................................................1 3 6  
1 1. 2.  
G o o d Cli nical Practice  ..............................................................................................1 3 6  
1 1. 3.  
Dele gati o n of I n v esti gat or D uties  .............................................................................1 3 6  
1 1. 4.  
S u bject C o nfi de ntialit y  .............................................................................................1 3 6  
1 1. 5.  
I nf or me d C o nse nt Pr oce d ure ....................................................................................1 3 7  
1 1. 6.  
Re g ulat or y C o m plia nce  ............................................................................................1 3 7  
1 2.  
S T U D Y A D MI NI S T R A TI V E  I N F O R M A TI O N .....................................................1 3 9  
1 2. 1.  
Fi na ncial Discl os ur e  .................................................................................................1 3 9  
1 2. 2.  
St u d y R e gistrati o n a n d Res ults Discl os ure  ...............................................................1 3 9  
1 2. 3.  
St u d y Files a n d M aterials  .........................................................................................1 3 9  
1 2. 4.  
Use of St ore d Sa m ples a n d Data  ..............................................................................1 3 9  
1 2. 5.  
Dis p ositi o n of St ore d Sa m ples a n d Data  ..................................................................1 4 0  
1 2. 6.  
St u d y I nitiati o n  .........................................................................................................1 4 0  
1 2. 7 . 
S u bject Rei m b urse me nt, Lia bilit y, a n d I ns ura nce  ....................................................1 4 0  
1 2. 8.  
S u bject I d e ntificati o n a n d C o nfi de ntialit y  ................................................................1 4 1  
1 2. 9.  
St u d y M o nit ori n g  ......................................................................................................1 4 1  
1 2. 1 0.  
Pr ot oc ol A me n d me nts  ..............................................................................................1 4 1  
1 2. 1 1.  
A u dits a n d I ns p ecti o ns  ..............................................................................................1 4 2  
1 2. 1 2.  
P u blicati o n P olic y a n d D ata Usa ge  ...........................................................................1 4 2  
1 3.  
R E F E R E N C E S  .........................................................................................................1 4 3  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 6  of 1 5 5  
 
1 4.  
A P P E N DI C E S  ..........................................................................................................1 4 5  
A P P E N DI X  1.  S P U T U M I N D U C TI O N G UI D E LI N E S  ..........................................................1 4 6  
A P P E N DI X  2.  C A L C U L A TI O N O F B R O N C HI E C T A SI S S E V E RI T Y I N D E X  ...................1 4 9  
A P P E N DI X  3.  C HI L D -P U G H S C O RI N G A N D C L A S S R E F E R E N C E T A B L E S  ................1 5 1  
A P P E N DI X  4.  I N T E N S E P H A R M A C O KI N ETI C S A M P LI N G S C H E M E  ...........................1 5 2  
A P P E N DI X  5.  H Y’ S L A W  .......................................................................................................1 5 4  
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 7  of 1 5 5  
 
LI S T O F T A B L E S  
Ta ble  1:  
Pr o hi bite d Me dicati o ns ( Ma y Ca us e Pal m o pla ntar Kerat o der ma)  .............................8 9  
Ta ble  2:  
List of M o derate a n d Str o n g C Y P 2 D 6 a n d C Y P 2 C 8 I n hi bit ors ( n ot t o be 
C o -A d mi nistere d W it h C Y P 3 A 4/ 5 I n hi bit ors b ut Ot her wise Per mitte d) ...................9 0  
Ta ble  3:  
List of M o derate a n d Str o n g C Y P 3 A 4/ 5 I n hi bit ors ( Per mitte d U nless 
C o m bi ne d Wit h t he A b o ve M o derat e a n d Str o n g C Y P 2 D 6 a n d C Y P 3 C 8 
I n hi bit ors) ...................................................................................................................9 1  
Ta ble  4:  
Pr o hi bite d Me dicati o ns ( C Y P 3 A 4/ 5 I n d ucers)  ...........................................................9 2  
Ta ble  5:  
Mi ni m u m Ti me I nt er vals f or Restricte d Me di cati o n Use Pri or t o 
Re versi bilit y/ S pir o metr y Testi n g  ................................................................................9 4  
Ta ble  6:  
Sc he d ule of E ve nts  ...................................................................................................1 0 3  
Ta ble  7:  
Cli nical La b orat or y Assess me nts  .............................................................................1 1 8  
 
 
LI S T O F FI G U R E S  
Fi g ure  1:  
St u d y Desi g n Dia gra m  ................................................................................................7 5  
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 8  of 1 5 5  
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A b bre vi ati o n  
Defi niti o n  
2 1 C F R  
C o de of Fe deral Re g ulati o ns Title 2 1  
A E  
ad verse eve nt  
A E SI  
ad verse eve nt of special interest  
A L T  
ala ni ne ami n otra nsferase ( S G P T)  
A N C  
abs ol ute n e utr o p hil co u nt  
A S T  
as partate ami n otra nsferase ( S G O T)  
A T S  
A merica n T h oracic S ociet y  
A U C  
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
A U C 0 -8 
area u n der t he plas ma co nce ntrati o n -ti me c ur ve fr o m 0 t o 8 h o urs  
A U C 0 -2 4 
area u n der t he plas ma co nce ntrati o n -ti me c ur ve fr o m 0 t o 2 4 h o urs  
B MI  
b o d y m ass in de x  
B P  
b l o o d p ress ure 
B SI  
Br o nc hiectasis Se verit y I n de x  
C D C  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n  
C F  
cystic fi br osis  
C K D -E PI  
C hr o nic K i d ne y Disease E pi de mi ol o g y Coll a b orati o n e q uati o n  
C ma x  
m a xi m u m plas ma c o nce ntrati o n of dr u g  
C ma x ,ss 
m a xi m u m plas ma c o nce ntrati o n at stea d y state  
C mi n ,ss 
m i ni m u m plas ma c o nce ntrati o n at stea d y state 
C O P D  
c hr o nic o bstr ucti ve p ul m o nar y disease  
C S R  
cli nical st u d y re p ort  
C ss 
avera ge plas ma c o nce ntrati o n at stea d y state 
C T  
co m p ute d t o m o gra p h y  
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
C Y P  
c yt oc hr o me P 4 5 0 e nz y me  
D M C  
Data M o nit ori n g C o m mittee  
d E C G  
d i gital E C G  
D P P 1  
d i pe pti d yl pe pti dase 1 
E C G  
electr ocar di o gra m 
e C R F/ C R F 
(electr o nic) case re p ort for m  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 5 9  of 1 5 5  
 
A b bre vi ati o n  
Defi niti o n  
E D C  
electr o nic d ata ca pt ure 
e G F R 
esti mate d gl o mer ular filtrati o n rate  
E O S  
E n d of St u d y  
E R S  
E ur o pea n T h oracic S ociet y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F E F 2 5 -7 5 
force d ex pirat or y fl o w bet wee n 2 5%  a n d 7 5 % of force d v ital ca pacit y 
F E V 1 
force d ex pirat or y v ol u me i n 1 sec o n d 
F V C  
force d v ital ca pacit y 
G C P  
G o o d Cli nical Practice  
H Bs A g  
h e patitis B surface anti ge n  
H C V  
h e patitis C v ir us 
He p C A b  
h e patitis C a nti b o d y 
HI V  
h u ma n im m u n o deficie nc y v ir us 
H R  
h eart rate 
I B 
I n vesti gat or’s Br oc h ure 
I C F 
inf or me d co nse nt for m  
I C H 
I nter nati o nal C o u ncil f or  Har m o ni sati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I L-1 β  
interle u ki n -1 beta  
I L-6  
interle u ki n -6  
I L-8  
o nterle u ki n -8  
I P 
in vesti gati o nal p r o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
i nte nt-t o-treat 
L A B A  
lo n g -acti n g beta a g o nist  
L A M  
lactati o nal a me n orr hea met h o d 
L A M A  
lo n g -acti n g m uscari nic a nta g o nist 
L C Q  
Leicester C o u g h Q uesti o n naire  
L T B 4  
le u k otrie ne B 4 
M A D  
m ulti ple asce n di n g d ose  
M C P -1  
m o n oc yte c he m otactic pr otei n 1 ( C C L 2)  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 0  of 1 5 5  
 
A b bre vi ati o n  
Defi niti o n  
N C F B E  
n o n -c ystic fi br osis br o nc hiectasis  
N CI  
Nati o nal Ca ncer I nstit ute  
N E  
n e utr o p hil elastase  
N O A E L  
n o -o bser ve d -a d verse -effect le vel  
N S P  
n e utr o p hil seri ne pr otei nase  
P D  
p har mac o d y na mic(s)  
P E F R  
p ea k ex pirat or y fl o w rate 
P F T  
p ul m o nar y fu ncti o n test 
PI  
Pri nci pal I n vesti gat or  
P K  
p har mac o ki netic (s) 
P L S  
Pa pill o n -Lefè vre S y n dr o me  
P P  
per pr ot oc ol  
P P K  
p o p ulati o n P K  
P R O  
p atie nt -re p orte d o utc o me  
Q D  
o nce dail y  
Q O L  
q ualit y of life 
Q O L -B  
Q ualit y of Life Q uesti o n naire -Br o nc hiectasis  
Q T c F  
correcte d Q T inter val b y Fri dericia  
R A N T E S  
re g ulate d o n acti vati o n, n or mal T -cell ex presse d a n d secrete d 
R T S M  
ra n d o mizati o n a n d trial s u p pl y ma na ge me nt  
S A B A  
sh ort -acti n g beta a g o nist 
S A E  
seri o us ad verse eve nt  
S A M A  
sh ort -acti n g m uscari nic a nta g o nist 
S A P  
statistical anal ysis p la n 
S G R Q  
St . Ge or ge ’s Res pirat or y Q uesti o n naire  
S S RI  
selecti ve ser ot o ni n rece pt or i n hi bit or 
T  
b o d y t e m perat ure 
T 3  
trii o d ot h yr o ni ne 
T 4  
t h yr o xi ne 
T B L  
t otal bilir u bi n 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
tma x  
ti me t o m a xi m u m plas ma c o nce ntrati o n  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 1  of 1 5 5  
 
A b bre vi ati o n  
Defi niti o n  
tma x,ss   
ti me t o ma xi m u m plas ma c o nce ntrati o n at stea d y state 
T N F -α  
tu m or n ecr osis fact or al p ha 
T S H  
t h yr oi d-sti m ulatin g  h or m o ne  
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
W O C B P  
w o me n of c hil d beari n g p ote ntial  
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 2  of 1 5 5  
 
1.  
I N T R O D U C TI O N A N D B A C K G R O U N D IN F O R M A TI O N  
1. 1.  
I n vesti g ati o n al Pr o d uct(s) 
1. 1. 1.  
N a me  
T he c he mical na me of I N S 1 0 0 7 is ( 2 S) -N -{( 1 S) -1 -c ya n o -2 - [ 4-( 3-met h yl -2 -o x o -2, 3 -
di h y dr o - 1, 3 -be nz o x az ol -5 -yl) p h e n yl] et h yl } -1, 4 -o x aze pa ne -2 -car b o xa mi de.  
1. 1. 2.  
Descri pti o n  
I N S 1 0 0 7 is a p ote nt, s ele cti ve, c o m petiti ve, a n d re versi ble di pe pti d yl p e pti dase I ( D P P 1 , als o 
k n o w n as cat h e psi n C)  i n hi bit or t hat was s h o w n t o i n hi bit t he f or mati o n of all 3 acti ve ne utr o p hil 
seri ne pr otei nas es (N S Ps ) i n mat uri n g n e utr o p hils i n vitr o a n d i n viv o.   
1. 1. 3.  
I nte n de d Use U n der I n vesti g ati o n 
I N S 1 0 0 7 is i n dicate d f or t he treat me nt of n o n -c ystic fi br osis br o nc hiect asis ( N C F B E ). 
1. 2.  
Dise ase B ac k gr o u n d  
Br o nc hi ectasis is a diseas e c haracterize d b y l ocalize d, irre v ersi ble e nlar ge m e nt of br o nc hi a n d 
br o nc hi oles t hat ma y lea d t o o bstr ucte d breat hi n g ca use d b y a b n or mal m uc us pr o d ucti o n.   
Br o nc hi ectasis s y m pt o ms t y picall y i ncl u de a c hr o nic dr y or wet c o u g h.  Ot her s y m pt o ms i ncl u de 
s h ort ness of breat h, c o u g hi n g u p bl o o d, a n d c h est pai n.  W heezi n g a n d nail cl u b bi n g ma y als o 
occ ur.  Pe o ple wit h t he disease ofte n get fre q ue nt l u n g i nfecti o ns.   
Br o nc hi ectasis, al o n g wit h c hr o nic o bstr ucti ve p ul m o nar y dis ease ( C O P D ), ac ute l u n g i nj ur y, 
ac ute res pirat or y distress s y n dr o me, a n d c ystic fi br osis ( C F) are all c o n diti o ns of se vere 
p ul m o nar y d ysf u ncti o n res ulti n g fr o m a m assi ve i nfla m mat or y res p o nse.  T he hist ol o gical 
c haracteristic of all t hese i nfla m mat or y l u n g dise as es is t he acc u m ulati o n of ne utr o p hils i n t he 
i nterstiti u m a n d al ve oli of t he l u n g.  T h eir acti vati o n lea ds t o t he release of m ulti ple c yt ot o xic 
pr o d ucts i ncl u di n g reacti ve o x y ge n s pecies a n d pr oteases (seri ne, c ystei n e, a n d 
metall o pr oteases).   
Ne utr o p hils c o ntai n 4 mai n t y pes of gra n ules: az ur o p hilic or pri mar y gra n ul es, s pecific or 
sec o n dar y gra n ules, gelati nase or tertiar y gra n ules, a n d secret or y gra n ules.  Az ur o p hilic gra n ul es 
are belie v e d t o be t he first t o f or m d uri n g ne utr o p hil mat urati o n i n t he b o ne ma rr o w a n d are 
c haracteriz e d b y t he e x pressi o n of relate d N S Ps: ne utr o p hil elastase ( N E ), pr otei nase 3, a n d 
cat he psi n G.  T he l ys os o mal c ystei n e D P P 1 is t he pr otei nase t hat acti vates t hese 3 N S Ps b y 
re m o val of t he N-ter mi nal di pe pti de se q ue nces fr o m t heir prec urs ors d uri n g az ur o p hilic gra n ule 
asse m bl y (P ha m et al, 2 0 0 4 ).  Di pe pti d yl pe pti das e 1  is br oa dl y e x presse d i n tiss ues b ut is hi g hl y 
e x presse d i n cells of he m at o p oietic li nea ge s uc h as ne utr o p hils.  
T he 3 N S Ps act i n c o m bi nat i o n wit h reacti ve o x y g e n s pecies t o hel p d e gra d e e n g ulfe d 
micr o or ga nis ms i nsi de p ha g ol ys os o mes.  T h e N S Ps are als o a b u n d a ntl y secrete d i nt o t he 
e xtracell ular e n vir o n me nt u p o n ne utr o p hil acti vati o n at i nfla m mat or y sites.  A fracti o n of t he 
releas e d pr oteas es re m ai ns b o u n d i n a n acti ve f or m o n t he e xter nal s urface of t he plas ma 
me m bra ne s o t hat b ot h s ol u ble a n d me m bra ne -b o u n d N S Ps ca n re g ulate t h e acti vities of a variet y 
of c he m o ki nes, c yt o ki nes, gr o wt h fact ors, a n d cell s urface rece pt ors b y eit her c o n verti n g  t h e m t o 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 3  of 1 5 5  
 
acti ve f or ms or d e gra di n g t he m b y pr ote ol ytic clea va ge.  Secrete d pr oteas es ca n sti m ulate m uc us 
secreti o n a n d i n hi bit m uc ociliar y cleara nce, b ut als o acti vate l y m p h oc ytes a n d clea ve a p o pt otic 
a n d a d hesi o n m olec ules ( Ba n k a n d A ns or ge, 2 0 0 1 ; Me yer -H offert et al, 2 0 0 9 ; P ha m et al, 2 0 0 6 ; 
V o y n o w et al, 2 0 0 8 ).  T h us, t he y p ossess pr o - a n d a nti -i nfla m mat or y acti vities at sites of 
i nfla m mati o n. 
T he p h ysi ol o gic al bala nce bet wee n pr oteas es a n d a nti -pr oteases is re q uire d f or t he mai nte na n ce 
of t he l u n g's c o n necti ve tiss ue, a n d a n i m bala nce i n fa v or of pr oteas es ca n res ult i n l u n g i nj ur y 
(Tetle y, 1 9 9 3 ; U me ki et al, 1 9 8 8 ).  Beca us e of r ol es of N S Ps i n i nfla m mati o n, t he y are p ote ntial 
t hera pe utic tar gets f or c hr o nic i nfla m mat or y l u n g diseases s uc h as br o nc hiectasis.   
I N S 1 0 0 7 is a p ote nt, s ele cti ve, c o m petiti ve, a n d re versi ble in hi bit or of D P P 1 t hat is c urre ntl y 
bei n g d e vel o pe d f or t he treat me nt of N C F B E .  It is h y p ot hesize d t hat I N S 1 0 0 7 will ha ve 
be neficial effects via decreasi n g i nfla m mati o n a n d m uc us h y p ersecreti o n, w hic h will i n t ur n lea d 
t o a decrease i n p ul m o nar y e x acer bati o n  a n d a n i m pr o ve me nt i n l u n g f u ncti o n (c o u g h, s p ut u m 
pr o d ucti o n, a n d f orce d e x pirat or y v ol u me i n 1 sec o n d [ F E V 1]) i n N C F B E s u bjects.  T here is als o 
a p ote ntial be nefit wit h I N S 1 0 0 7 f or m o dif yi n g N C F B E  pr o gressi o n b y re d uci n g t he accelerate d 
rate of l u n g fu n cti o n decli ne or l u n g tiss ue destr u cti o n.    
S u bjects ha vi n g N C F B E  e x perie nce p ul m o nar y e x acer bati o n s wit h a n a vera ge fre q u e nc y ra n gi n g 
fr o m 1. 5 t o 6 per year (C hal mers et al, 2 0 1 4 ; G oe mi n ne et al, 2 0 1 4 ; Kell y et al, 2 0 0 3 ).  
C urre ntl y, t here is n o sta n dar d  of  care f or pr o p h yl actic p har m ac ol o gical treat me nt of N C F B E .  
T he pri mar y g oal of treat me nt is t o treat t he u n derl yi n g ca us e, pre v e nt disease pr o gressi o n, 
ma i ntai n or i m pr o ve l u n g f u ncti o n, a n d i m pr o ve t h e s y m pt o ms a n d q ualit y of life ( Q O L).    
T here is c urre ntl y n o t hera p y a p pr o ve d b y re g ulat or y a ut h orities i n t he U nite d States ( U S) or 
E ur o pe f or t h e treat me nt of N C F B E.  
1. 3.  
De vel o p me nt Pr o gr a m  
1. 3. 1.  
N o ncli nic al St u dies  
I N S 1 0 0 7 is a re versi ble, c o m petiti ve i n hi bit or of D P P 1, wit h hi g h p ote nc y as meas ure d i n vitr o 
usi n g is olate d h u ma n D P P 1 e nz y m e a n d a h e mat o p oietic cell li ne k n o w n t o e x press D P P 1.   
H u ma n pri mar y ne utr o p hil st u dies de m o nstrate d  t hat I N S 1 0 0 7 si g nifica ntl y i n hi bits t he 
acti vati o n of N S Ps, res ulti n g i n  decreas e d elast ol ytic a bilit y of t he cells i n vitr o.  St u dies wit h 
naï ve a n d  li p o p ol ys acc h ari de-i n d uce d p ul m o nar y i nfla m mati o n m o dels i n t he rat s h o we d t h at 
D P P 1 i n hi biti o n wit h oral  I N S 1 0 0 7 tra nsl ates well i n viv o as si g nifi ca nt decreases i n t he 
acti vities of N S Ps were o bser ve d.  
T he sec o n d ar y a n d s afet y p har mac ol o g y of I N S 1 0 0 7 were i n vesti gat e d usi n g b ot h i n vitr o a n d 
i n viv o m o dels.  I n t he i n vitr o m o del , t he c o nce ntr ati o n of t he d r u g ca usi n g a half-ma xi mal 
i n hi bit or y effect (I C 5 0) o n t he h u ma n et her-a -g o -g o  relate d ge n e ( h E R G)-e nc o de d p otassi u m 
c ha n nel w as 1 3. 9 μ M.  I n a si n gle-d ose car di o vasc ular tele metr y st u d y i n d o gs, tra nsi e nt effects 
were s ee n o n heart rate ( H R ), mea n diast olic bl o o d press ure ( B P), mea n B P, Q A i nter val, 
a n d-Q T -i nter val c orrecte d f or H R .  Base d o n t he res ults of t he tele metere d d o g st u d y wit h a 
n o -o bser ve d -a d verse-effect le vel ( N O A E L) of 5 0 m g/ k g a n d a cli nical d ose of 2 5 m g, t he s afet y 
mar gi n d eri ve d fr o m t he ma xi m u m o bser ve d c o nce ntrati o n ( C ma x ) i n plas ma is 4 4 (f or free 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 4  of 1 5 5  
 
I N S 1 0 0 7) a n d 1 9 (f or t otal I N S 1 0 0 7), i n dicati n g a l o w le vel of c o ncer n f or car di o vas c ular 
effects.  
N o effect was o bs er ve d o n eit her t he ce ntral ner v o us or res pirat or y s yste ms i n rats.    
Detail s of n o ncli nical p h ar mac o ki netic ( P K), dr u g meta b olis m, a n d t o xic ol o g y st u dies ca n be 
f o u n d i n t he c urre nt  I N S 1 0 0 7 I n v esti gat or’s Br oc h ure (I B). 
1. 3. 2.  
Cli nic al E x perie nce  
I N S 1 0 0 7 h as bee n assess e d  i n 2 healt h y v ol u nteer st u dies ( D 6 1 9 0 C 0 0 0 0 1 a n d D 6 1 9 0 C 0 0 0 0 3) . 
St u d y  D 6 1 9 0 C 0 0 0 0 1  
St u d y D 6 1 9 0 C 0 0 0 0 1 was a P hase 1, ra n d o mize d, si n gle -bli n d, place b o -c o ntr olle d, m ulti -part 
st u d y i n healt h y a d ult male v ol u nteers.  
Part 1a was a si n gle asce n di n g d ose ( S A D) st u d y i n w hic h 4 5  s u bjects recei ve d eit her place b o 
( 1 5 s u bjects) or I N S 1 0 0 7 ( 5, 1 5, 3 5, 5 0, or 6 5 m g [ 6 s u bjects per d ose le vel]) u n der fasti n g 
c o n diti o ns.  
Part 1 b was a si n gle -d os e f o o d effect st u d y i n w hic h 8 s u bjects ( C o h ort 3 fr o m Part 1a after a 
was h o ut of at least 7 da ys) recei ve d eit her place b o ( 3 s u bjects) or 3 5 m g I N S 1 0 0 7 ( 5 s u bjects) 
after a hi g h -fat br ea kfast.  
Part 2 was a m ulti ple asce n di n g d os e ( M A D) st u d y i n w hic h 3 6 s u bjects ( w h o di d n ot partici pate 
i n Part 1) recei ve d eit her place b o ( 1 2  s u bjects) or I N S 1 0 0 7 ( 6 s u bjects recei ve d 1 0 m g/ da y f or 
2 1  da ys, 8 s u b je cts recei ve d 2 5 m g/ da y f or 2 8 da ys, a n d 1 0 s u bjects recei ve d 4 0 m g/ da y f or 
2 8  da ys) u n der fasti n g c o n diti o ns.  
T he safet y v aria bles f or I N S 1 0 0 7 were a d verse e v e nts ( A Es ); safet y la b orat or y assess me nts 
( he mat ol o g y, cli nical c h e mistr y, uri nal ysis); vital si g ns ( p ulse rate, B P , oral b o d y te m perat ur e 
[ T]); 1 2-lea d pa per a n d di gital electr ocar di o gra m ( E C G, pre -h os pital E C G , a n d di gital  E C G 
[d E C G ]); tele metr y; p h ysical e x a mi nati o n res ults (i ncl u di n g e v al uati o n of gi n gi va a n d t eet h, a n d 
e val uati o n of pal ms a n d s o les).  I n a d diti o n, part 2 la b orat or y ass ess me nts als o i ncl u de d 
ne utr o p hil p ha g o c yt osis, o xi dati ve b urst, s per mat o gra m [fertile male s u bjects partici pati n g i n 
C o h ort 3 a n d o n war d ] a n d re pr o d ucti ve h or m o nes [ C o h ort 3 a n d o n war d ]). 
St u d y  D 6 1 9 0 C 0 0 0 0 3  
St u d y D 6 1 9 0 C 0 0 0 0 3 was a n o pe n -la b el, fi x e d se q ue nce, 3-p eri o d, dr u g -dr u g i nteracti o n (D DI ) 
st u d y of t he effects of c o nc o mita nt vera pa mil ( m o derate C Y P 3 A 4 i n hi bit or) a n d itrac o n az ole 
(str o n g C Y P 3 A 4 i n hi bit or) o n t he si n gle-d ose P K of I N S 1 0 0 7 a n d its t olera b ilit y a n d safet y i n 
healt h y a d ult male v ol u nteers. T he st u d y c o nsiste d of 3  peri o ds wit h at least a 7 -da y was h o ut 
bet wee n Peri o ds 1 a n d 2 a n d at least a 1 4 -da y was h o ut bet wee n Peri o ds 2 a n d 3. D uri n g Peri o d 
1, 1 5 s u bjects recei ve d a si n gle d ose of I N S 1 0 0 7 ( 2 5 m g).  D uri n g Peri o d  2, t he sa me s u bjects 
recei v e d vera pa mil ( 2 4 0 m g, e xte n de d rel ease f or m ulati o n) o n Da ys 1 t hr o u g h 1 0 pl us a si n gle 
d ose of I N S 1 0 0 7 ( 2 5 m g) o n Da y  5.  D uri n g Peri o d 3, t he sa me s u bjects r ecei ve d itrac o n az ole 
( 2 0 0 m g as oral s ol uti o n of 1 0 m g/ m L) t wice o n Da y  1 a n d t he n o nce dail y ( Q D) o n Da ys 2 
t hr o u g h 1 1 pl us a si n gle d ose of I N S 1 0 0 7 ( 2 5 m g) o n Da y  6.  All dr u gs were a d mi nistere d u n der 
fasti n g c o n diti o ns. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 5  of 1 5 5  
 
Safet y v aria bl es i ncl u de d A Es, vital si g ns (s yst olic a n d diast olic B P , p ulse rate a n d te m perat ure), 
electr ocar di o gra ms  ( E C Gs, safet y, a n d d E C Gs ), la b orat or y assess me nts ( he mat ol o g y, cli nical 
c he mistr y, a n d uri nal ysis) a n d p h ysical e xa mi nati o ns (i ncl u di n g e v al uati o n of gi n gi va a n d teet h , 
a n d e val uati o n of p al ms a n d s oles).  Viral s er ol o g y, t u berc ul osis ( T B) scree n a n d uri ne dr u gs of 
a b use, alc o h ol , a n d c oti ni ne were assess e d f or eli gi bilit y.  T h e use of c o nc o mita nt me dicati o ns 
was als o assesse d a n d re p orte d.  
I n b ot h st u dies, I N S 1 0 0 7 was well t olerat e d i n h u ma ns u p t o t he hi g hest d ose le vels assesse d 
(si n gle d os e of 6 5 m g a n d m ulti ple d ose of 4 0 m g/ da y f or 2 8 da ys).  All treat me nt -e mer ge nt 
a d verse e ve nts ( T E A Es) i n t he P hase 1 st u dies were mil d or m o derate.  N o ne of t he re p orte d 
T E A Es were se vere.  I n b ot h st u dies, t he m ost c o m m o n T E A E was hea d ac he ( ge nerall y mil d a n d 
c o nsi dere d relate d t o t he st u d y treat me nt).  N o s u bject die d d uri n g t he st u d y a n d n o s u bject 
e x perie nce d a s eri o us a d verse e v e nt ( S A E).   Treat me nt disc o nti n uati o n d ue t o a T E A E was rare.  
O ne s u bject i n St u d y D 6 1 9 0 C 0 0 0 1 dis c o nti n ue d 2 5  m g/ da y I N S 1 0 0 7 o n Da y  1 3 of a pl a n ne d 
2 8 -da y treat me nt peri o d d ue t o a n A E  of dr u g er u pti o n lic he n, pla n us -li ke. 
Pa pill o n -Lefè vre S y n dr o me ( P L S) is a rare diseas e c haracterize d b y pr of o u n d deficie nc y of 
D P P 1.  T he se q uelae of t his disease are of rele va n ce a n d i m p orta n ce f or ass ess me nt i n t he 
de vel o p me nt pr o gra m f or I N S 1 0 0 7.  T he 2  pri mar y cli nical ma nifestati o ns i n P L S s u bjects w h o 
e x hi bit a s pectr u m of decrease d D P P 1 acti vit y d ue t o m utati o ns i n t he D P P 1 ge n e are 
pal m o pla ntar kerati niz ati o n, c haracterize d b y re d n ess a n d t hic ke ni n g of t he s oles a n d pal ms, a n d 
peri o d o ntal disease, w hi c h ca n be seri o us a n d ca n affect b ot h pri mar y a n d p er ma ne nt teet h.  As 
D P P 1 is t he e nz y me i n hi bite d b y I N S 1 0 0 7 , A Es of t he gi n gi va a n d s ki n of t he pal ms a n d s oles 
we re of s pecial i nterest i n I N S 1 0 0 7 P hase 1 cli nical st u dies.  Mil d gi n gi val blee di n g was 
o bser ve d i n  b ot h  s u bjects ta ki n g I N S 1 0 0 7 a n d t h ose ta ki n g pl ace b o wit h n o o b vi o us differe n ce 
bet wee n acti ve a n d pla ce b o treat me nts.  Mil d s ki n a n d s u bc uta ne o us tiss ue d is or ders were 
o bser ve d i n s u bjects o n I N S 1 0 0 7.   
N o tre n ds were o bser ve d i n cli nical la b orat or y res ults, 1 2 -lea d E C Gs, tele metr y, p h ysic al 
e x a mi nati o n, or s per mat o gra m res ults.  A b n or mal fi n di n gs o bser v e d i n vital si g ns were n ot 
c o nsi dere d t o be cli nicall y si g nifica nt.  Details of P K st u dies ca n be f o u n d i n t he I N S 1 0 0 7 I B . 
1. 3. 3.  
Cli nic al P h ar m ac o ki netics  
P har mac o ki netic  a n al yses of t he first-i n-h u ma n P hase 1  cli nical st u d y of I N S 1 0 0 7 i n healt h y 
s u bjects (D 6 1 9 0 C 0 0 0 0 1 ) i n dicates t hat I N S 1 0 0 7 e x hi bits relati vel y fast oral a bs or pti o n wit h a 
ti me t o ma xi m u m plas ma c o nce ntr ati o n (tma x ) ge nerall y o bs er ve d b et wee n 0. 5  t o 1. 5  h o urs after 
d osi n g.  I N S 1 0 0 7 als o prese nte d  d ose -pr o p orti o nal  stea d y stat e e x p os ures ar o u n d t he a ntici pate d 
t hera pe utic ra n ge of 1 0 t o  2 5  m g .  I N S 1 0 0 7 has a mea n a p pare nt ter mi nal eli mi nati o n half -life 
( T1/ 2) of a p pr o xi matel y 2 5 t o 3 0  h o urs res ulti n g i n acc u m ulati o n i n plas ma ( 2. 3 t o 2. 5 a n d 1. 7 t o 
1. 9 -f ol d acc u m ulati o n f or A U C a n d C ma x , res pecti vel y).  E x creti o n of I N S 1 0 0 7 i n uri ne is 
m o derate ( 1 1 % t o 2 0 % of d ose) f oll o wi n g a si n gle d ose.  F o o d effect data i n dicate t hat 
ad mi nistrati o n of a si n gle 3 5 m g d ose of I N S 1 0 0 7 f oll o wi n g a hi g h-fat br ea kfast res ults i n a 
dela ye d  a bs or pti o n of 3. 2 5 h o urs, a n d decrease d C ma x  of 3 6 % c o m pare d  t o f asti n g.  T he effect of 
f o o d o n A U C is l o w, wit h a decreas e of 9 %.  
T he pri mar y  is oz y mes res p o nsi ble f or P hase 1 meta b olis m of I N S 1 0 0 7 are t he c yt o c hr o me P 4 5 0 
( C Y P) 3 A 4/ 5, a n d t o a lesser e xte nt C Y P 2 C 8 a n d C Y P 2 D 6.  N o u ni q ue h u ma n meta b olites ha ve 
bee n i de ntifie d t o date.  T he ex -viv o plas ma pr otei n bi n di n g of I N S 1 0 0 7 i n h u ma n plas ma was 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 6  of 1 5 5  
 
c o nce ntr ati o n -i n de pe n d e nt at cli nicall y rele va nt c o nce ntrati o ns ( 0.1  t o 1 0 0 µ m ol/ L ) a n d is 
esti mate d t o be 8 7 .2 %.   
B eca use t he cleara nce of I N S 1 0 0 7 is pr e dicte d t o i ncl ude  si g nifi ca nt i n v ol ve me nt of C Y P 3 A 4 
a n d C Y P 3 A 5 , a dr u g-dr u g i nteracti o n cli nical st u d y of I N S 1 0 0 7 ( D 6 1 9 0 C 0 0 0 0 3) was c o n d u cte d 
t o i n vesti gate t he effect of vera p a mil , a mo derat e C Y P 3 A 4/ 5 i n hi bit or , a n d itrac o naz ole , a str o n g 
C Y P 3 A 4/ 5 i n hi bit or , o n t he P K o f I N S 1 0 0 7.  I N S 1 0 0 7 C ma x  a n d A U C were n ot bi oe q ui vale nt 
wit h c o -a d mi nistrati o n of vera pa mil c o m pare d t o I N S 1 0 0 7 a d mi nistrati o n al o ne, wit h 5 3 % ( 9 0 % 
CI  =  1 3 6, 1 7 3) a n d 3 2 % ( 9 0 % CI  =  1 2 2, 1 4 4) i n creases , res pecti vel y.  I N S 1 0 0 7 A U C was 
bi oe q ui vale nt after c o -a d mi nistrati o n wit h itrac o naz ole c o m pare d t o I N S 1 0 0 7 al o ne ( 9 0 % 
CI  =  1 0 5, 1 2 3), h o we v er, C ma x  was si g nifica ntl y d ecrease d b y 3 9 % ( 9 0 % CI  =  5 4, 6 8).   Res ults 
f or itrac o n az ole de m o nstrate t hat t here is n o cli nicall y rele va nt safet y c o n cer n w he n c o-
a d mi nistrati o n I N S 1 0 0 7 wit h str o n g C Y P 3 A 4/ 5 i n hi bit ors.  H o we ver, vera pa mil res ults i n dicate 
t hat ot her n o n-C Y P -relat e d pat h wa ys ma y b e at pl a y a n d t hat f urth er i n vitr o i n vesti gati o ns t o 
el uci date t he me c ha nis m of t he vera pa mil  dr u g -dr u g i nteracti o n are warra nte d.  
I N S 1 0 0 7 d o es n ot i n hi b it a n y of t he maj or C Y P e nz y m es i n i n vitr o C Y P i n hi biti o n e x peri me nts 
(u p t o 3 0  μ m ol/ L ).  T he ge o metric mea n stea d y state t o tal Cma x  i n healt h y  s u bjects fr o m 
st u d y D 6 1 9 0 C 0 0 0 0 1  at 2 5  m g Q D  (t he hi g hest d ose pla n ne d i n t he prese nt  st u d y) was 
0. 5 9 8  µ m ol/ L  ( Cma x , u =  0. 0 7 7  µ m ol/ L ).  Bas e d o n t he d ose a n d re gi me n pla n ne d t o be 
i n vesti gate d i n t his st u d y i n N C F B E s u bjects, I N S 1 0 0 7 pl as ma c o nce ntrati o ns are u nli kel y t o be 
i n t he ra n ge t hat w o ul d i n hi bit t hese C Y P e nz y mes ([I]/ Ki rati o < 0. 1), a n d t heref ore  u nli kel y t o 
preci pitate a si g nifica nt dr u g -dr u g i nteracti o n ( D DI ) via C Y P i n hi biti o n w he n c o -a d mi nistere d 
wit h ot her a ge nts t hat are  s u bstrates f or C Y P e nz y mes.  
I n vitr o st u dies i n dicate t hat I N S 1 0 0 7 is n ot a ti me-de pe n d e nt i n hi bit or  a n d has  l o w ris k of  bei n g 
a per petrat or  of tra ns p ort er -me diat e d dr u g -dr u g i nteracti o ns via O A T P 1 B 1,  B C R P or P -g p .  
Alt h o u g h I N S 1 0 0 7  is a w ea k i n d ucer of C Y P 3 A 4 a n d C Y P 2 B 6 m R N A i n vitr o, data i n healt h y  
s u bjects fr o m st u d y D 6 1 9 0 C 0 0 0 0 1  a p peare d t o i n dicate a t i me-d e pe n de nt i ncreas e i n  plas ma  
A U C b y 5 2 % t o 5 9 % at t he 1 0, 2 5 a n d 4 0 m g d os e le vels.   T hese res ults are n ot c o nsiste nt wit h 
i n d ucti on of C Y P 3 A 4 , a n d t he o bser ve d i ncreas e is t h o u g ht t o be d ue t o a hi g h de gree of 
e xtra p olati o n  i n t he Da y  1 A U C esti mates.  F or t his reas o n, t he ti me i n vari a nce  f or I N S 1 0 0 7 
ca n n ot be r ule d o ut. 
1. 4.  
St u d y R ati o n ale  
I N S 1 0 0 7 is a p ote nt, s ele cti ve, c o m petiti ve a n d re versi ble D P P 1 i n hi bit or t hat was s h o w n t o 
i n hi bit t he f or mati o n of all 3 acti ve N S Ps i n mat uri n g ne utr o p hils i n vitr o a n d i n viv o.   
Acti vati o n of t he 3 N S Ps i n t he mat uri n g ne utr o p hils occ urs via re m o v al of a di pe pti de fr o m t heir 
prec urs ors b y t h e l ys os o mal c ystei n e D P P 1/cat he psi n C (A d kis o n et al, 2 0 0 2 ; P ha m et al, 1 9 9 9 ).  
Di pe pti d yl pe pti dase 1  is br oa dl y e x presse d i n tiss ues b ut is partic ularl y hi g hl y e x presse d i n cells 
of he mat o p oietic li nea ge s uc h as ne utr o p hils.  Ne utr o p hils c o ntai n 4 mai n t y p es of gra n ul es: 
az ur o p hil or pri mar y gra n ules, s pecific or sec o n d ar y gra n ul es, gelati nase or tertiar y gra n ules a n d 
secret or y gra n ules.  Az ur o p hil gra n ules are b elie v e d t o be t he first t o f or m d uri n g t he ne utr o p hil 
mat urati o n i n t he b o ne marr o w a n d are c haracterize d b y t h e e x pressi o n of t he relate d ( ne utr o p hil) 
seri ne pr oteases of N E, pr otei nase 3 a n d cathe psi n G.  Di pe pti d yl pe pti das e 1  al o ne acti vates 
t hese pr oteas es b y re m o vi n g t he N-ter mi nal di pe pti de se q ue nces d uri n g az ur o p hil gra n ule 
asse m bl y (K or k maz et al, 2 0 1 0 ; P ha m et al, 2 0 0 4 ).   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 7  of 1 5 5  
 
It is h y p ot hesize d t hat t he f u ncti o nal i n hi biti o n of N S Ps b y a D P P 1 i n hi bit or s uc h as I N S 1 0 0 7 
will decreas e i nfla m mati o n a n d m uc us h y persecreti o n, lea di n g t o sl o wi n g d o w n l u n g tiss ue 
destr ucti o n, a n d decreasi n g t he e x acer bati o n rate i n s u bjects wit h ne utr o p hili c l u n g c o n diti o ns 
wit h a pr otease -dri ve n p at h ol o g y ( R o ot et al, 2 0 1 6 ) s uc h as N C F B E. 
T his st u d y will e val uate w het her t his h y p ot hesis is c o nfir me d.  
1. 5.  
Ris ks a n d Be nefits f or St u d y S u bjects  
1. 5. 1.  
P ote nti al Be nefits  
T he effects of n  N E  o n air wa y e pit helial cells i ncl u des sl o wi n g of ciliar y b eat fre q ue nc y a n d 
pr o m oti o n of m uc us h y p ersecreti o n ( A mita ni et al, 1 9 9 1 ; V o y n o w et al, 1 9 9 9 ) w hile i m pair me nt 
of o ps o n o p ha g oc yt osis occ urs at  m ulti ple le vels ( T osi et al, 1 9 9 0 ).  I n a rece nt pr o of of c o nce pt 
st u d y, i n hi biti o n of N E de m o nstrate d pr o misi n g si g nals i n C O P D s u bjects wit h c urre nt 
s y m pt o ms of c hr o nic br o nc hitis.  I n t his 3-m o nt h st u d y wit h A Z D 9 6 6 8 (a N E i n hi bit or) 
c o n d ucte d b y Astr a Ze neca, a n i m pr o ve me nt i n F E V 1 ( b ot h pre- a n d p ost -br o nc h o dilat or) was 
o bser ve d i n s u bjects wit h a B C S S sc ore f or c o u g h a n d/ or s p ut u m of ≥ 2  (K u na, 2 0 1 2 ).  T his 
F E V 1 i m pr o ve me nt was n ote d wit hi n a fe w wee ks of d osi n g a n d was a p pr o xi matel y 1 0 0 m L i n 
ma g nit u de ( vers us place b o).  
It is p ost ulate d t hat a d mi nistrati o n of I N S 1 0 0 7 ma y res ult i n be neficial effects f or patie nts 
s ufferi n g fr o m N C F B E via decreasi n g i nfla m mati o n a n d m uc us h y persecreti o n, lea di n g t o a n 
i m pr o ve me nt i n res pirat or y s y m pt o ms (e g, c o u g h a n d s p ut u m pr o d ucti o n) a n d l u n g f u ncti o n (e g, 
F E V 1) a n d a d ecreas e i n e x acer bati o n rate.  Si nce I N S 1 0 0 7 acts u pstrea m of N E a n d i n hi bits 
2  ot her N S Ps re g ulate d b y D P P 1, it ma y h a ve a l ar ger i m pact o n sl o wi n g l u n g da m a ge 
pr o gressi o n i n N C F B E p atie nts c o m pare d t o i n hi biti o n of N E al o ne .   
1. 5. 2.  
Ris ks a n d Ris k Miti g ati o n Str ate gies  
1. 5. 2. 1.  
 
H y per ke r at osis/ Peri o d o ntitis  
Ma n y P L S patie nts  e x perie nce diff us e pal m o pla nt ar kerat osis a n d se vere p eri o d o ntitis, lea di n g t o 
pre mat ure l oss of b ot h t h e deci d u o us a n d p er ma n e nt teet h ( K or k maz et al, 2 0 1 0 ).  Beca us e 
I N S 1 0 0 7 i n hi bits D P P 1, t he e nz y me t h at P L S patie nts lac k, t hese se q uel ae were of i nterest i n t he 
2 P hase 1 st u dies f or I N S 1 0 0 7.  
I n Part 2, t he M A D  p has e,  of St u d y D 6 1 9 0 C 0 0 0 1,  2 healt h y s u bjects w h o recei ve d 2 5 m g of 
I N S 1 0 0 7 e x perie nce d d er mat ol o gical e ve nts: 1  s u bject was dia g n ose d t o h a ve a lic he n oi d dr u g 
reacti o n w hic h was c o nsi dere d p ossi bl y relat e d t o I N S 1 0 0 7 b y t he In vesti gat or a n d res ol ve d aft er 
I N S 1 0 0 7 a d mi nistrati o n was st o p pe d.  T he s u bject ha d pre vi o usl y e x perie n ce d a si milar t y pe of 
e ve nt i n a n ot her cli nical st u d y.  In t he s ec o n d s u bj ect, s ki n e xf oliati o n was n otice d i n t he v olar 
site at t he base of t he fi n gers, a n d t he e ve nt res ol v e d 9 da ys aft er I N S 1 0 0 7 a d mi nistrati o n was 
st o p pe d.  It is t he st u d y S p o ns or’s t h o u g ht t hat t here was a reas o na ble p ossi b ilit y of a ca usal 
relati o ns hi p bet wee n t his e ve nt a n d I N S 1 0 0 7.  
De ntal lesi o ns/ peri o d o ntitis were o bser ve d  i n t he I N S 1 0 0 7 6-m o nt h d o g t o xicit y st u d y i n t he 
hi g hest d ose gr o u p ( 1 4 7 a n d 6 3 -f ol d hi g her e x p os ure t ha n t he hi g hest d ose pla n ne d f or t his st u d y 
base d o n free a n d t otal I N S 1 0 0 7, res pecti vel y ).  I n t he mi d-d ose gr o u p of t his 6 -m o nt h d o g 
t o xicit y st u d y, n o d e ntal lesi o ns/ peri o d o ntitis were o bser ve d ( 2 1 a n d 9 -f ol d hi g her e x p os ure t ha n 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 8  of 1 5 5  
 
t he hi g hest d ose pl a n ne d f or t his st u d y bas e d o n free a n d t otal I N S 1 0 0 7, res pecti vel y).  I n Part 2,  
M A D , of St u d y D 6 1 9 0 C 0 0 0 1 , 3 s u bjects w h o recei ve d I N S 1 0 0 7 a n d 1 s u bject w h o recei ve d 
place b o e x perie n ce d gi n gi val blee di n g t h at were all mil d i n i nte nsit y.   
E ntr y criteria a n d m o nit ori n g pr oce d ures ha v e bee n i nc or p orate d i nt o t he st u d y desi g n t o a v oi d 
i m pairi n g t he a bilit y of t he st u d y t o detect a p ote ntial safet y si g n al a n d t o miti gate a gai nst p utti n g 
s usce pti ble s u bjects at i n a p pr o priate ris k.  T o s pecificall y miti gate t he ris ks relate d t o s ki n 
h y per kerat osis, s u bjects ha vi n g a hist or y of h y per kerat osis or er yt h e ma i n pal ms or s oles will be 
e x cl u de d fr o m t his st u d y.  S u bjects will be cl osel y m o nit ore d t hr o u g h o ut t he st u d y wit h s pecial 
e val uati o n of t he pal ms a n d s oles, b ut als o t he d ors u m of t he ha n ds a n d feet, Ac hilles te n d o n  
area, k n ees, a n d el b o ws.  S u bjects will be disc o nti n ue d fr o m t he st u d y a d mi nistrati o n i n t he case 
of s ki n t hic ke ni n g.  
T o  s pecificall y miti gate ris k s ass ociate d wit h  peri o d o ntitis, s u bjects will u n der g o a de nt al 
e x a mi nati o n d uri n g Visit 1 ( Scree ni n g ).  S u bjects w h o ha ve se v ere p eri o d o ntitis will be e x cl u de d 
fr o m t he st u d y.  Eli gi ble s u bjects will u n der g o a d ee p de ntal clea ni n g d uri n g Scree ni n g bef ore 
e nr oll me nt.  D uri n g t he treat me nt peri o d  ( Visits 2 t hr o u g h 9), s u bj ects’ m o ut h, gi n gi va a n d teet h 
will be e x a mi ne d b y t he Pri nci pal I n v esti gat or (PI ) at eac h visit.  S h o ul d a n y s u bject h a ve a n y 
gi n gi va or t o ot h iss ue or w orse ni n g of t heir pre -e xisti n g c o n diti o n, t he s u bject will be referre d t o 
t he st u d y-d es i g n ate d de ntist f or f urt her e val uati o n.  S u bjects will als o be e xa mi ne d b y t h e st u d y-
des i g nat e d de ntist at Scree ni n g ( Visit 1),  Wee k 8 ( Visit 5),  a n d Wee k 2 4 ( Visit 9) .  S u bjects will 
be disc o nti n ue d fr o m st u d y dr u g a d mi nistrati o n if t he y d e vel o p se vere p eri o d o ntitis.  
1. 5. 2. 2.  
I nfecti o ns 
Beca use N S Ps pla y a dir ect r ole  i n ne utr o p hil res p o nses a gai nst i n va di n g pat h o ge ns, i n hi biti o n of 
N S P acti vati o n mi g ht be c o nsi dere d t o i ncreas e t he ris k of i nfecti o n.  H o we ver, d es pite t he 
se vere d eficie n c y i n N S Ps, t here are n o c o nsiste nt re p orts of ge n eralize d i m m u ne deficie nc y i n 
t hese P L S patie nts .  Rece nt data has  s h o wn  t hat ne utr o p hils fr o m m ost s u bjects wit h P L S 
dis pla ye d n or mal micr o bici dal acti vit y a gai nst E c oli  a n d S a ure us , b ut ne utr o p hils fr o m certai n 
s u bjects were defecti ve i n micr o bial killi n g (P ha m et al, 2 0 0 4 ).  T his cli nical o bser v ati o n 
s u g gests t hat N S Ps were n ot esse ntial a nti micr o bial m olec ules a n d ma y e x plai n w h y o nl y a fe w 
s u bjects wit h P L S de m o nstrate d rec urre nt s yste mi c i nfecti o ns.  Base d o n t h ese o bser vati o ns it is 
e x pecte d t hat s u bj ects gi ve n I N S 1 0 0 7 will ha ve li mite d ris k f or de vel o pi n g i nfecti o ns.  
N o net heless, t o  mi ni miz e a p ote ntial ris k, s u bjects wit h rece nt ac ute i nfecti o ns will be e x cl u de d 
fr o m t he st u d y.  S u bjects will be m o nit ore d c o nti n uall y f or si g ns a n d s y m pt o ms of a n y i nfecti o ns 
a n d will ha ve cli nical safet y la b orat or y tests at eac h st u d y visit.   S u bjects wit h a n a bs ol ute 
ne utr o p hil c o u nt ( A N C) < 1 0 0 0/ m m 3 will be disc o nti n ue d fr o m t he st u d y.   
All seri o us i nfecti o ns a n d all s pecific i nfecti o ns belie ve d t o be ass o ciate d wit h ne utr o pe nia, s uc h 
as s oft tiss ue i nfecti o n, uri nar y tract i nfecti o n s h o ul d be e ntere d i n t he i nfecti o n m o d ule of t he 
electr o nic case re p ort f or m ( e C R F).  
1. 5. 2. 3.  
Testic ul ar T o xicit y  
I n d o gs, testic ular t o xicit y a n d p eri o d o ntal diseas e  were o bs er ve d; s uc h fi n di n g s were n ot 
o bser ve d i n rats.   I n t he 1-m o nt h d o g st u d y,  testic ular t o xicit y was o bser v e d at t he hi g h d ose 
( 7 5 m g/ k g/ da y) , th e testic ular fi n di n gs i ncl u de d s w olle n s per mat oc ytes i n t he testes a n d 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 6 9  of 1 5 5  
 
i ncreas e d cell ular d e bris i n t he e pi di d y mi des  w hic h were  c o m pletel y re v ersi ble after a 1 -m o nt h 
rec o ver y peri o d. 
I n t he 6 -m o nt h re peat -d ose t o xic ol o g y st u d y i n d o gs  at 8 a n d 5 0 m g/ k g/ da y, d ose -de pe n d e nt 
c ha n ges i n t he testis a n d e pi di d y mis were o bser ve d .  T he testic ular fi n di n gs i ncl u de d s w olle n 
s per mat oc ytes i n t he test es a n d i ncrease d cell ular de bris i n t he e pi di d y mi des .   
A pr o p orti o n of t u b ules h a d h y p os p er mat o ge n esis w hic h re prese nts a n i nefficie nc y of 
s per mat o ge nesis i n se g m e nts of s o me t u b ules.  H y p os per mat o ge nesis was c o nsi dere d a n e w 
fi n di n g i n t he hi g h-d ose gr o u p at t he e n d of t h e rec o ver y peri o d, as it was n ot prese nt at t he e n d 
of t he d osi n g p eri o d.  At t he e n d of t he d osi n g peri o d, little  or n o acti ve s per mat o ge n esis was 
prese nt i n t he testes, precl u di n g t he fi n di n g of h y p os per mat o ge nesis.  F oll o wi n g t he rec o v er y 
peri o d, s per mat o ge n esis res u me d i n all 3 rec o ver y d o gs wit h all sta ges of s per m de vel o p me nt 
bei n g prese nt.  H o we ver, t he testes were n ot hist ol o gicall y n or m al, as h y p os per mat o ge nesis was 
prese nt i n le vels a b o v e t h ose see n i n c o nc urre nt c o ntr ols.  T his o bser vati o n was p ossi ble beca use 
acti ve s per m at o ge nesis w as prese nt at t he e n d of t h e rec o v er y p eri o d, de m o nstrati n g rec o ver y of 
t he t u b ular de ge n erati o n/ atr o p h y prese nt at t he e n d of d osi n g.  T h eref ore , t he rec o v er y is 
descri be d as partial.    
T he  fi n di n gs at t he hi g h est d ose of 5 0 m g/ k g/ da y  were p artiall y re v erse d  at t he e n d of t he 
rec o ver y peri o d.  F urt her details of t he res ults i n d o gs i n t he 1 a n d 6 -m o nt h t o xic ol o g y st u dies 
ca n be f o u n d i n t he c urre nt I B.  T he i nf or me d c o nse nt f or m (I C F) f or t he st u d y will descri be t he 
p ote ntial ris ks t o t he male re pr o d ucti ve s yste m.  
1. 5. 3.  
C o ncl usi o ns o n Ris k -Be nefit  
C o nsi deri n g t he p ote ntial be nefits t o s u bjects wit h N C F B E , all t he a vaila ble data f or I N S 1 0 0 7 
fr o m t he n o n cli nical t o xicit y st u dies, t he 2  P hase 1  st u dies, a n d t he ris k miti gati o n strate gies t o 
be p ut i n place, t his st u d y, i n t he o pi ni o n of t he S p o ns or, is c o nsi dere d t o ha ve a fa v ora ble ris k-
be nefit rati o.  
1. 6.  
P o p ul ati o n, R o ute, D os a ge, D os a ge Re gi me n, Tre at me nt Peri o d  
S u bjec ts w h o ha ve gi ve n t heir si g ne d, i nf or me d c o nse nt, are mal e or fe male bet wee n 1 8-8 5 years 
of a ge (i n cl usi ve) wit h a B o d y Mass I n d e x ( B MI) > 1 8. 5 at Visit 1 ( Scree ni n g) a n d ha ve a cli nical 
hist or y c o nsiste nt wit h N C F B E will be eli gi ble f or e nr oll me nt i n t he st u d y.  T he g o al is t o 
ra n d o miz e ap pr o xi matel y 2 4 0  s u bjects dia g n os e d wit h N C F B E.   
I N S 1 0 0 7 will be pr o vi d e d as r o u n d, bic o n ve x, br o w n, fil m-c oate d ta bl ets i n stre n gt hs of 1 0 m g 
a n d 2 5 m g t o be a d mi nistere d orall y Q D  f or 2 4 wee ks of treat me nt. 
Place b o will be i de ntical t o st u d y dr u g as  r o u n d, bi c o n ve x, br o w n, fil m -c oat e d ta blets  wit h o ut 
acti ve st u d y dr u g a n d a d mi nistere d orall y Q D  f or 2 4 wee ks of treat me nt. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 0  of 1 5 5  
 
2.  
S T U D Y O B J E C TI V E S  
2. 1.  
St u d y O bjecti ves  
2. 1. 1.  
Pri m ar y O bjecti ve  
T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n  ti me t o first p ul m o nar y 
e x acer bati o n  o ver t he 2 4 -wee k treat me nt peri o d.  
2. 1. 2.  
Sec o n d ar y O bjecti ves  
1.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assesse d b y t he 
Q ualit y of Lif e Q uesti o n naire -Br o nc hiectasis ( Q O L -B), Res pirat or y S y m pt o ms D o mai n 
sc ore, o ver t he 24 -w ee k treat me nt peri o d  
2.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n l u n g f u ncti o n, as meas ure d 
b y F E V 1, o ver t he 2 4-wee k treat me nt peri o d  
3.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntr ati o n of acti ve 
N E i n s p ut u m, as  meas ur e d b y t h e differe nce bet w ee n t he pre -treat me nt c o nce ntrati o n 
a n d o n-treat me nt c o nce ntrati o n  
4.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he rate of p ul m o nar y 
e x acer bati o ns o ver t h e 2 4 -wee k tr eat me nt peri o d  
2. 1. 3.  
E x pl or at or y O bjecti ves  
1.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assesse d b y t he  
Q O L -B d o mai ns (e x cl u di n g t he Res pir at or y S y m pt o ms D o mai n) o ver t he 2 4 -wee k 
treat me nt peri o d  
2.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assesse d b y t he 
Lei cester C o u g h Q u esti o n naire ( L C Q), o ver t he 2 4 -wee k tr eat me nt peri o d  
3.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n res pirat or y -relate d healt h 
stat us, as assesse d b y t he St. Ge or ge’s Res pirat or y Q uesti o n naire ( S G R Q), o ver t he 
2 4 -wee k tr eat me n t peri o d 
4.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntr ati o n of acti ve 
N E i n s p ut u m, as meas ur e d b y t h e differe nce bet w ee n t he pre -treat me nt c o nce ntrati o n 
a n d t he c o nce ntrati o ns at Wee ks 2, 4, a n d 2 8  
5.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntr ati o n of acti ve 
N E i n rea ge nt -sti m ulate d bl o o d, as meas ure d b y t h e differe nce bet wee n t he pre-treat me nt 
c o nce ntr ati o n a n d t he c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 2 8  
6.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wi t h place b o o n s p ut u m c ol or (assesse d b y 
t he s p ut u m c ol or c hart) at W ee ks 2, 4, 1 2, 2 4, a n d 2 8 
7.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntr ati o n of acti ve 
N E i n s p ut u m, stratifie d b y Baseli ne s p ut u m c ol or, as meas ure d b y t he diffe re nce 
bet wee n t he pre -tr eat me nt c o nce ntrati o n a n d t h e c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, 
a n d 2 8  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 1  of 1 5 5  
 
8.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d tiss ue 
de gra dati o n bi o mar kers i n s p ut u m ( bi o mar kers w hic h ma y b e assess e d are pr otei nase 3 
a n d cat he psi n G) at W ee ks 2, 4, 1 2, 2 4, a n d 2 8  
9.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d tiss ue 
de gra dati o n bi o mar kers i n bl o o d ( bi o mar kers w hi c h ma y be ass esse d are a bs ol ute 
ne utr o p hil c o u nt [ A N C], pr otei nase  3 , a n d cat he psi n G) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8  
1 0.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d tiss ue 
de gra dati o n bi o mar kers i n uri ne ( des m osi ne) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8  
1 1.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h pl ace b o o n t he f oll o wi n g p ul m o nar y 
f u ncti o n para m eters as m eas ure d b y s pir o m etr y (force d vital ca pacit y [ F V C]) o ver t he 2 4 -
wee k treat me nt peri o d  
1 2.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g p ul m o nar y 
f u ncti o n para m eters as m eas ure d b y s pir o m etr y ( p ea k e x pirat or y fl o w rate [ P E F R]) o ver 
t he 2 4-wee k treat me nt p eri o d  
1 3.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g p ul m o nar y 
f u ncti o n para m eters as m eas ure d b y s pir o m etr y (force d e x pirat or y fl o w 2 5 t o 7 5 % [ F E F 2 5 -
7 5]) o ver t he 2 4-wee k treat me nt peri o d  
1 4.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he t otal d urati o n of all 
e x acer bati o ns ( da ys p er s u bject) o ver t h e 2 4 -wee k treat me nt peri o d  
1 5.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he n u m ber of 
e x acer bati o ns per s u bj ect o ver t he 2 4 -wee k tr eat m e nt peri o d  
1 6.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first p ul m o nar y 
e x acer bati o n, e x acer bati o n rate, Q O L m eas ures a n d p ul m o nar y f u ncti o n para meters 
( F E V1, F V C, P E F R, a n d F E F2 5 -7 5), stratifie d b y Br o nc hiectasis Se verit y I n d e x ( B SI) 
sc ore at b aseli ne, o ver t he 2 4-wee k treat me nt peri o d  
1 7.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first p ul m o nar y 
e x acer bati o n, e x acer bati o n rate, Q O L m eas ures a n d p ul m o nar y f u n cti o n para meters 
( F E V1, F V C, P E F R, a n d F E F2 5 -7 5), stratifie d b y t he prese n ce or a bse n ce of Pse u d o m o n as 
aer u gi n os a  (P a ) at Scree ni n g, o ver t he 2 4 -wee k tr eat me nt peri o d   
1 8.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he use of res c ue 
me dicati o ns  (res c ue me di cati o ns i ncl u de s h ort-acti n g bet a a g o nists  [ S A B As], s h ort-acti n g 
m uscari nic a nta g o nists  [ S A M As], ne wl y pres cri b e d l o n g-acti n g beta a g o nists  [ L A B As], 
l o n g-acti n g m us cari nic a nta g o nists  [ L A M As], a n d o x y ge n) o ver t h e 2 4-wee k treat me nt 
peri o d  
1 9.  T o e val uate t he effect of I N S 1 0 0 7 c o m pare d wit h place b o o n h os pitalizati o ns f or 
p ul m o nar y e x acer bati o ns o ver t he 2 4 -wee k tr eat m e nt peri o d  
2 0.  T o assess t he c orrelati o ns a m o n g i nfla m mat or y a n d tiss ue de gra dati o n bi o mar kers, 
c o nce ntr ati o n of acti ve N E i n bl o o d, s p u t u m, a n d, uri ne a n d efficac y meas ures  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 2  of 1 5 5  
 
2. 1. 4.  
S afet y O bjecti ve  
T o assess t he safet y a n d t olera bilit y of I N S 1 0 0 7 relati ve t o place b o bas e d o n A Es, vital si g n s a n d 
E C G meas ure me nts, p h ysica l e x a ms, p ul m o nar y f u ncti o n tests ( P F Ts ), a n d cli nical la b orat or y 
e val uati o ns.  
2. 1. 5.  
P h ar m a c o ki netic O bjecti ves  
1.  T o e val uate t he P K of I N S 1 0 0 7  
2.  T o assess t he rel ati o ns hi p bet wee n P K meas ures f or I N S 1 0 0 7 a n d efficac y, safet y , a n d 
bi o mar ker meas ures ( e g, c o nce ntr ati o ns of acti ve N E i n s p ut u m a n d rea ge nt -sti m ulate d 
bl o o d)  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 3  of 1 5 5  
 
3.  
I N V E S TI G A TI O N A L P L A N 
3. 1.  
O ver all St u d y Desi g n a n d Pl a n  
T his is a P hase 2, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, p arallel -gr o u p, m ultice nter , 
m ulti nati o nal  st u d y t o assess t he effic ac y, s afet y a n d t olera bilit y, a n d P K  of I N S 1 0 0 7 
a d mi nistere d Q D f or 2 4 w ee ks i n s u bjects wit h N C F B E .  
T his m ultice nter st u d y will be c o n d ucte d at a p pr o xi matel y  1 2 0 sites; e nr oll me nt is c o m petiti ve 
acr oss all sites.  Acr oss t hese sites, it is pla n ne d t hat a p pr o xi matel y 2 4 0  s u bjects wit h N C F B E  
will be ra n d o mize d.  S u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 3 treat me nt ar ms ( 8 0 /ar m) t o 
recei v e eit her 1 0 m g or 2 5 m g of I N S 1 0 0 7 or mat c hi n g place b o.  Ra n d o mi zati o n will be 
stratifie d base d o n w h et h er  t he Scree ni n g s p ut u m is c ult ure p ositi ve f or P a  a n d w het her t h e 
s u bject is o n a mai nte na n ce use of m acr oli des f or pre ve nti n g p ul m o nar y e x acer bati o n.  
Eac h s u bject will recei ve st u d y treat me nt f or 2 4 wee ks.  T he e ntire st u d y is sc he d ule d t o ta ke a 
ma xi m u m of 3 4 wee ks f or eac h i n di vi d ual s u bject fr o m Scree ni n g ( Visit 1) t o t he E n d of St u d y 
( E O S, Visit 1 0). 
A P K s u b -st u d y will be c o n d ucte d at a sel ect n u m ber of sites.  S u bjects w h o e nr oll at t he selecte d 
sites will u n der g o i nte nsi ve P K sa m pli n g.  A ma xi m u m of 3 6 s u bjects will be i ncl u de d i n t he P K 
s u b-st u d y.  F or s u bjects w h o partici pate i n t he P K s u b -st u d y, t he visit wi n d o w f or Visit 4 will 
be  ± 5 da ys.  A d diti o nall y, f or s u bjects n ot partici pati n g i n t he P K s u b -st u d y, s parse P K sa m pli n g 
will be c o n d ucte d i n s u bjects at all sites wit h P K sa m pli n g pr ocessi n g ca p a bilities (see 
Secti o n  7. 6. 1 ).  P har mac o ki netic sa m ples will be a nal yze d i n b atc hes o n a n o n g oi n g basis . 
Scree ni n g Peri o d ( Visit 1) 
T here will be a scree ni n g peri o d of u p t o 6 wee ks per s u bject.  D uri n g t he s cree ni n g p eri o d, t he 
s u bject’s de m o gra p hi c i nf or mati o n, me dical hist or y, a n d s m o ki n g hist or y will be o btai ne d ; a 
p h ysical e x a m, vital si g ns , a n d a s p ut u m sa m ple f or s p ut u m c ult ure a n d acti ve N E c o nce ntrati o n 
will be c oll ecte d; a n d c h e mistr y/ h e mat ol o g y a n d uri nal ysis tests, ser u m pr e g na n c y test  f or 
w o me n of c hil d beari n g p ote ntial ( W O C B P) , E C G, a n d P F Ts will be c o n d ucte d.  S u bjects w h ose 
past c hest ra di o gra p hic i ma ge rec or ds are n ot a vaila ble will u n der g o a c h est c o m p ute d 
to m o gra p h y ( C T ) sca n d uri n g Scree ni n g ( Visit 1).  Peri o d o ntal e x a mi nati o n a n d de ntal clea ni n g 
pr oce d ures f or i ncl usi o n s h o ul d be perf or m e d pri or t o ra n d o mizati o n.   
Tre at me nt Peri o d ( Visits 2 T hr o u g h 9)  
O n Da y  1 ( Visit 2), vital si g ns, a n d s p ut u m a n d bl o o d sa m ples f or bi o mar kers will be c ollect e d. 
B l o o d c he mistr y, he mat ol o g y  a n d uri nal ysis tests, E C G, a n d pre g n a nc y test (W O C B P o nl y) will 
be c o n d ucte d.  St u d y sites m ust  c o nfir m s u bject eli gi bilit y base d o n S cree ni n g la b res ults pri or t o 
ra n d o mizati o n.  After re-c o nfir mi n g t h eir eli gi bilit y, s u bjects will be ra n d o mize d via t he 
Me di data Bala nce  ra n d o mizati o n a n d trial s u p pl y ma na ge me nt (R T S M ) s yste m i nt o 1 of 3 ar ms 
t o recei ve eit her 1 0 m g or 2 5 m g of I N S 1 0 0 7 or m atc hi n g pl ace b o i n a 1: 1: 1 rati o. 
Ra n d o mizati o n w ill be stratifie d base d o n t h e f oll o wi n g: 
1.  W het her  S cree ni n g s p ut u m is c ult ure p ositi ve f or P a  
2.  W het her  t he s u bject is o n a mai nte na nce use of m acr oli des f or pre ve nti n g p ul m o nar y 
e x acer bati o n  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 4  of 1 5 5  
 
S u bjects will recei ve a n d be i nstr ucte d o n h o w t o pr o perl y use a  ha n d hel d c o m p uter  ta blet t hat 
will be pre -l oa d e d wit h t he Q O L -B, L C Q, a n d S G R Q q uesti o n naires a n d a d osi n g diar y.  
S u bjects will be re q uire d t o c o m plete all 3 q uesti o n naires aft er t he tr ai ni n g a n d pri or t o t he 
a d mi nistrati o n of t he first d ose of t he ir assi g ne d st u d y dr u g o n Visit 2 ( Da y  1 ).  D uri n g t he 
d urati o n of t he st u d y , s u bjects will c o m plete t he 3  q uesti o n naires at t he s pecifie d ti mes a n d 
rec or d t h eir dail y d ose of st u d y dr u g i n t he d osi n g diar y. 
S u bjects will be pr o vi de d wit h a 5 -wee k s u p pl y of t hei r assi g n e d st u d y dr u g at eac h visit, e xce pt 
Visit 3 a n d Visit 9.  S u bjects will be i nstr ucte d t o c o m plete t heir d osi n g diar y i m me diatel y after 
eac h d ose a n d ret ur n t heir u n use d st u d y dr u g a n d ha n d hel d c o m p uter ta bl et f or dr u g 
acc o u nta bilit y a n d data e ntr y re vie w at eac h st u d y visit.  
S u bjects will be ra n d o mize d at Visit 2 ( Da y  1) a n d ret ur n t hereaft er f or st u d y visits at 2, 4, 8, 1 2, 
1 6, 2 0, 2 4 , a n d 2 8 wee ks.  T here will be a visit wi n d o w of ± 3 da ys f or eac h of t he sc he d ule d 
visits.  
D uri n g t h e treat me nt p eri o d, s u bjects will be re mi n de d a b o ut t he i m p orta nce of birt h c o ntr ol a n d 
de ntal h y gi e ne.  I n a d diti o n t o t he r o uti ne safet y m o nit ori n g, s u bjects will be cl osel y m o nit ore d 
f or h y per kerat osis, peri o d o ntitis/ gi n gi vitis, a n d ot her i nfecti o ns, w hic h will be ca pt ur e d as 
a d verse e ve nts of s p ecial i nterest ( A E SIs) i n t he st u d y.  
F or t h ose s u bjects partici pati n g i n t he P K s u b -st u d y, P K sa m ples will be c ollecte d at t he 
s pecifie d ti me p oi nts detaile d i n Secti o n  7. 6 . 
E n d -of -St u d y Visit ( Visit 1 0)  
S u bjects will be re q uire d t o ha ve a n E O S visit ( Visit 1 0) at wee k 2 8 t o c ollect bl o o d, s p ut u m , a n d 
uri ne sa m ples f or bi o mar ker assess me nt a n d pre g n a nc y test f or W O C B P , a n d t o c ollect 
i nf or mati o n o n A Es a n d c o nc o mita nt me dicati o n use.  A P K sa m ple will be c ollecte d fr o m eac h 
s u bject partici pati n g i n t he P K s u b-st u d y.  
T he st u d y d esi g n is ill ustrate d i n  Fi g ure  1 . 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 2 4  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 5  of 1 5 5  
 
Fi g ure  1 : 
St u d y Desi g n Di a gr a m  
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 6  of 1 5 5  
 
3. 2.  
St u d y E n d p oi nts  
3. 2. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is t he ti me t o t he first p ul m o nar y e x acer bati o n o ver t h e 2 4 -wee k treat me nt 
peri o d.  
P ul m o nar y e x acer bati o n defi niti o n.   A p ul m o nar y e x acer bati o n  i n t his st u d y is defi n e d as ha vi n g 
3  or  m ore of t he f oll o wi n g s y m pt o ms  f or at least 4 8 h o urs res ulti n g i n a p h ysicia n’s decisi o n t o 
prescri be a nti bi otics.  
1.  In crease d c o u g h  
2.  In crease d s p ut u m v ol u me or c ha n ge i n s p ut u m c o nsiste nc y  
3.  In crease d s p ut u m p ur ule nce  
4.  In crease d breat hless ness a n d/ or decreas e d e x ercis e t olera nce  
5.  F ati g ue a n d/ or m alaise  
6.  He m o pt ysis  
S u bjects  o n c hr o nic macr oli de t hera p y w h ose o nl y c ha n ge i n t hera p y is d ose or fre q ue nc y 
a dj ust me nt will n ot meet t he defi niti o n  of e x acer bati o n . 
3. 2. 2.  
Sec o n d ar y E n d p oi nts  
1.  C ha n ge fr o m Baseli ne i n Q O L -B R es pirat or y S y m pt o ms D o mai n sc ore o ver t he 2 4-wee k 
treat me nt peri o d 
2.  C ha n ge fr o m Scree ni n g i n p ost -br o nc h o dilat or F E V 1 o ver t he 2 4 -wee k treat me nt peri o d  
3.  C ha n ge i n c o nce ntrati o n of acti ve N E i n s p ut u m fr o m pre -treat me nt t o o n -tr eat me nt 
4.  Rate of p ul m o nar y e x acer bati o ns ( n u m ber of e ve nts per pers o n -ti me) o v er t he 2 4 -wee k  
treat me nt peri o d 
3. 2. 3.  
E x pl or at or y E n d p oi nts  
1.  C ha n ge fr o m Baseli ne i n Q O L -B sc ores (all d o mai ns e x cl u di n g t he Res pirat or y 
S y m pt o ms D o mai n) o v er t he 2 4 -wee k treat me nt  p eri o d  
2.  C ha n ge fr o m Baseli ne i n Q O L as assess e d b y t he L C Q sc ore o ver t he 2 4 -wee k treat me nt 
peri o d  
3.  C ha n ge fr o m Baseli ne i n S G R Q t otal sc ore o ver t h e 2 4 -wee k treat me nt peri o d  
4.  C ha n ge i n c o nce ntrati o n of acti ve N E i n s p ut u m fr o m pre -treat me nt t o Wee ks 2, 4, a n d 
2 8  
5.  C ha n ge i n c o nce ntrati o n of acti ve N E i n r ea ge nt -sti m ulate d bl o o d fr o m pre-treat me nt t o 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8  
6.  C ha n ge fr o m Baseli ne i n s p ut u m c ol or (assesse d b y t he s p ut u m c ol or c hart) at Wee ks 2, 
4, 1 2, 2 4, a n d 2 8   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 7  of 1 5 5  
 
7.  C ha n ge i n c o nce ntrati o n of acti ve N E i n s p ut u m (stratifie d b y s p ut u m c ol or) at B aseli ne 
fr o m pre-tr eat me nt t o Wee ks 2, 4, 1 2, a n d 2 8 
8.  C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d tiss ue de gra dati o n bi o mar ker le vels i n 
s p ut u m (t he bi o mar kers w hic h ma y be ass esse d are e g, pr ot ei nase 3 a n d cat he psi n G) at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8  
9.  C ha n ge fr o m Baseli ne i n i nfla m mat or y a n d tiss ue de gra dati o n bi o mar ker le vels i n bl o o d 
( bi o mar kers w hi c h ma y be assesse d are e g, A N C, pr otei nase 3, a n d cat he psi n G) at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8  
1 0.  C ha n ge fr o m Baseli ne i n tiss ue de gra dati o n mar k er le vel i n uri ne ( des m osi ne) at Wee ks 
2, 4, 1 2, 2 4, a n d 2 8  
1 1.  C ha n ge fr o m Scree ni n g i n F V C at Wee ks 1 2 a n d 2 4  
1 2.  C ha n ge fr o m Scree ni n g i n P E F R at Wee ks 1 2 a n d 2 4  
1 3.  C ha n ge fr o m Scree ni n g i n F E F 2 5 -7 5 at Wee ks 1 2 a n d 2 4  
1 4.  T otal d urati o n (i n da ys) of e x acer bati o ns, per s u bject, o ver t he 2 4-wee k tr eat me nt peri o d  
1 5.  T otal n u m ber of e x acer bati o ns per s u bject o ver t he 2 4 -wee k treat me nt peri o d  
1 6.  Ti me t o first p ul m o nar y e x acer bati o n, e x acer bati o n rate, Q O L m eas ures, a n d p ul m o nar y 
f u ncti o n para m eters ( F E V1, F V C, P E F R, a n d F E F2 5 -7 5), stratifie d b y  B SI s c ore at 
B aseli ne, o v er t he 2 4 -wee k treat me nt peri o d  
1 7.  Ti me t o first p ul m o nar y e x acer bati o n, e x acer bati o n rate, Q O L m eas ures, a n d p ul m o nar y 
f u ncti o n para m eters ( F E V1, F V C, P E F R, a n d F E F2 5 -7 5), stratifie d b y t he prese nce or 
a bse nce of P a  at Scree ni n g, o ver t he 2 4 -wee k tr eat me nt peri o d  
1 8.  Fre q u e nc y of us e of resc ue me dicati o ns (resc ue m e dicati o ns i ncl u de S A B As , S A M As, 
ne wl y prescri be d L A B As , L A M As, a n d o x y ge n) o ver t he 2 4 -wee k tr eat me nt peri o d   
1 9.  N u m ber of s u bjects h os pitaliz e d d ue t o p ul m o nar y e x acer bati o ns b y t he e n d of t he 
2 4 -wee k tr eat me nt peri o d  
2 0.  Descri pti ve ass ess me nt of t he c ha n ge i n i nfla m mat or y a n d tiss ue de gra d ati o n bi o mar kers 
a n d c o nce ntrati o n of acti ve N E i n bl o o d, s p ut u m, a n d uri ne, o ver t he 2 4 -wee k treat me nt 
peri o d  
3. 2. 4.  
S afet y E n d p oi nts  
T he safet y e n d p oi nts will i ncl u de t he f oll o w i n g: 
1.  A Es  
2.  1 2 -lea d E C G meas ure me nts  
3.  Cli nical la b orat or y testi n g res ults  
4.  Vital si g n meas ur e me nts  
5.  P h ysical e x a mi nati o n res ults  
6.  P F T meas ur e me nts  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 8  of 1 5 5  
 
A E SIs t hat will be re p ort e d  i ncl u de h y per kerat osis, peri o d o ntitis/ gi n gi vitis, a n d ot her i nfecti o ns . 
3. 2. 5.  
P h ar m a c o ki netic E n d p oi nts  
T he P K para m eters, as esti mate d usi n g n o n -c o m p art me ntal a nal ysis met h o ds, will i ncl u de t he 
f oll o wi n g: 
1.  C ma x  
2.  tma x  
3.  A vera ge plas ma c o n ce ntr ati o n at stea d y state ( C ss) 
4.  Ma xi m u m p las ma c o nce ntrati o n at stea d y state ( Cma x ,ss)t 
5.  Ti me t o ma xi m u m plas ma c o nce ntrati o n at stea d y state (t ma x ,ss) 
6.  Mi ni m u m plas ma c o nce ntrati o n at stea d y state ( C
mi n ,ss) 
7.  Area u n d er t he plas ma c o nce ntrati o n c ur ve fr o m 0 t o 8 h o urs ( A U C 0 -8) 
3. 3.  
Disc ussi o n of St u d y De si g n 
3. 3. 1.  
N u m ber of S u bjects  
A p pr o xi matel y 2 4 0 s u bj ects wit h N C F B E will be ra n d o mize d i n a 1: 1: 1 rati o t o 3 treat me nt ar ms 
( 8 0/ar m) t o recei ve eit her 1 0 m g or 2 5 m g of I N S 1 0 0 7 or matc hi n g pl ace b o. 
3. 3. 2.  
St u d y D ur ati o n  
Eac h s u bject will recei ve st u d y treat me nt f or 2 4 wee ks.  T he e ntire st u d y is sc he d ule d t o ta ke a 
ma xi m u m of 3 4 wee ks f or eac h i n di vi d ual s u bject fr o m Scree ni n g ( Visit 1) t o t he 
E O S  ( Visit 1 0), u p t o 6 wee ks f or t he scree ni n g p eri o d, 2 4 wee ks f or t he treat me nt peri o d a n d 
4  wee ks f or t he f oll o w -u p peri o d.   
3. 3. 3.  
E n d of St u d y  
T he E O S is defi ne d as eit her t he date of t he last visit of t he last s u bject t o c o m plete t he p ost -
d osi n g f oll o w -u p ( Visit 1 0), or t he date of recei pt of t he last data p oi nt fr o m t he last s u bject t hat 
is re q uire d f or pri mar y, s ec o n dar y a n d/ or e x pl orat or y a nal ysis, as pre -s pecifie d i n t he pr ot oc ol, 
w hic he ver is t he l ater dat e.  
3. 3. 4.  
St o p pi n g R ules  
3. 3. 4. 1.  
St u d y Disc o nti n u ati o n  
F or reas o na bl e ca us e, t he I n v esti gat or ma y ter mi n ate a s u bject’s partici pati o n i n t he st u d y 
pre mat urel y; if t his occ urs, t he I n v esti ga t or m ust c o ntact t he S p o ns or i m me diatel y.  T h e S p o ns or 
ma y d eci de t o ter mi nat e t he st u d y pre mat urel y.  If t his occ urs, writte n n otificati o n of t he st u d y 
ter mi nati o n is re q uire d t o be se nt t o all t he sites.  S o me c o n diti o ns t hat ma y warra nt st u d y 
ter mi nati on i ncl u de t he f oll o wi n g:  
 Disc o ver y of a n u ne x pecte d, si g nifica nt, or u nacce pta ble ris k t o t he s u bjects i n t he 
st u d y 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 7 9  of 1 5 5  
 
 Decisi o n o n t he part of t h e S p o ns or t o s us pe n d or disc o nti n ue de vel o p me nt of t he 
i n vesti gati o nal pr o d u ct (I P) 
 Decisi o n b y a re g ulat or y a ut h o rit y or t h e S p o ns or t o st o p t he st u d y at a n y ti me, w here 
a p plica ble  
If t he st u d y is pre mat urel y ter mi nat e d, all s u bjects w h o recei ve d a d os e of a n y of t he st u d y dr u gs 
a n d ha ve n ot c o m plet e d t heir st u d y p eri o d will  be disc o nti n ue d fr o m t he st u d y i m me diatel y ; all 
t he safet y pr oce d ures (refer t o safet y pr oce d ures d uri n g Visit 9) re q uire d t o be perf or me d will be 
c o n d ucte d.  All disc o nti n ue d s u bjects will be f oll o we d u p b y a p h o ne call 2 8 da ys  (+/ - 3 d a ys)  
after disc o nti n uati o n f or c ollecti o n of A Es.  
T he S p o ns o r will n otif y t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) a n d a n y ot her R e g ulat or y 
b o dies i n t he res pecti ve c o u ntries re gar di n g t h e reas o n f or ter mi nati n g t he st u d y. 
3. 3. 4. 2.  
S u bject Disc o nti n u ati o n Criteri a  
Detaile d disc o nti n uati o n criteria ca n be f o u n d i n Secti o n  4. 2. 1 . 
3. 4.  
Selecti o n of D oses  
3. 4. 1.  
E x peri me nt al Tre at me nts  
T his st u d y will ha ve 3 treat me nt ar ms of 1 0 m g, 2 5 m g , a n d place b o.  T h e rati o nale f or t he d os e 
selecti o n is base d o n t he safet y, t olera bilit y, a n d p har mac o d y n a mic ( P D) res ults (i n hi biti o n of 
N E acti vit y) o btai ne d fr o m t he P hase 1 si n gle a n d m ulti ple d ose st u d y of I N S 1 0 0 7 i n healt h y 
male v ol u nteers’ a n d res ults of t he 6 -m o nt h t o xicit y st u dies i n t he rat s a n d d o gs.   
T here w ere n o s afet y fi n di n gs fr o m t he I N S 1 0 0 7 P hase 1  si n gle a n d m ulti ple d ose st u d y i n 
healt h y m ale v ol u nteers, w here d os es u p t o 6 5 m g were test e d as a si n gle d ose a n d d oses u p t o 
4 0  m g dail y were teste d as a re p eate d d os e (f or 2 8 da ys) .   
I n t he 6-m o nt h d o g t o xicit y st u d y, 2 m g/ k g/ da y was deter mi ne d t o be t he  N O A E L .  T he e x pecte d 
safet y mar gi n of t h e 2 5-m g d ose of I N S 1 0 0 7 f or area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m 
ti me 0 t o 2 4 h o urs ( A U C0 -2 4) i n plas ma was 3. 9 (f or free I N S 1 0 0 7) a n d 1. 7 (f or t otal I N S 1 0 0 7), 
res pecti vel y.  I n t h e 6-m o nt h rat t o xicit y st u d y, 9  m g/ k g/ da y was d eter mi n e d t o be t he N O A E L.  
T he e x pecte d safet y mar gi n of t he 2 5 -m g d os e of I N S 1 0 0 7 f or A U C 0 -2 4 i n plas ma is 1 2. 4 (f or 
free I N S 1 0 0 7) a n d 2 6 (f or t otal I N S 1 0 0 7). 
I n t he M A D p has e of t he P hase 1 S A D/ M A D st u d y, re peat d osi n g of 1 0 m g, 2 5 m g a n d 4 0 m g of 
I N S 1 0 0 7 d e m o nstrate d a d ose-de pe n d e nt ma xi m u m i n hi bit or y effect o n r elati ve n or malize d N E 
acti vit y i n bl o o d of 3 9 %, 5 3 % a n d 5 9 %, res pecti vel y.    I n patie nts wit h P L S, t he l oss of D P P 1  
acti vit y is ass ociat e d wit h se vere re d ucti o n i n t he acti vit y a n d sta bilit y of  n e utr o p hil -deri ve d 
seri ne pr oteases.  N e utr o p hils deri ve d fr o m P L S p atie nts ha ve bee n descri be d t o ha ve less t ha n 
1 0 % N S P acti vit y of healt h y c o ntr ol ne utr o p hils (P ha m et al, 2 0 0 4 ).  N o ne of t he d oses assess e d 
f or I N S 1 0 0 7 re d u ce d N E acti vit y t o le vels a p pr oac hi n g t h ose s ee n i n P L S s u bjects. 
Gi ve n t he m o dest i ncreas e i n i n hi bit or y effect of 4 0 m g vs. 2 5 m g, t o get her wit h t he safet y 
mar gi n  i nf or mati o n res ulti n g fr o m t he 6-m o nt h d o g st u d y, 2 5 m g was sel ecte d as t he hi g h d os e 
t o be teste d i n t his st u d y.  T o u n dersta n d t he relati o ns hi p bet wee n t he p har mac o d y na mic effect of 
I N S 1 0 0 7 a n d cli nical o ut c o mes, 1 0 m g was als o s electe d t o be assesse d in t his st u d y.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 0  of 1 5 5  
 
T he precli nical a n d cli nic al P K a n d P D data o btai n e d t o date i n dicate t hat I N S 1 0 0 7 is a n orall y 
bi oa vaila ble c o m p o u n d i n h u ma ns.  T he data pr o vi de a de q uat e stea d y state e x p os ures at t he 
pr o p ose d d oses of 1 0 a n d 2 5 m g Q D f or f urt h er e v al uati o n  i n t his P hase 2 st u d y i n a s u bject 
p o p ulati o n wit h N C F B E.  T o e ns ure tar get e n ga ge me nt a n d t o all o w e n o u g h ti me f or t he 
i n hi bit or y effects of t he N S Ps’ acti vities t o be tra nslate d i nt o br o nc hial be neficial effects via 
decreasi n g br o nc hial i nfl a m mati o n a n d  m uc us h y persecreti o n, a d osi n g peri o d of 2 4  wee ks is 
c h ose n, w hic h is s u p p ort e d b y t h e c urre ntl y a vaila ble 6 -m o nt h a ni mal t o xicit y st u dies i n rats a n d 
d o gs.  
3. 4. 2.  
C o ntr ol Tre at me nts  
T his st u d y is pla n ne d t o ha ve 1 place b o c o ntr ol ar m.  T he d osa ge f or m will be i de ntical i n 
a p peara nce t o t he e x peri me ntal dr u gs b ut wit h n o acti ve i n gre die nt.    
3. 5.  
D at a M o nit ori n g C o m mittee  
A n i n de pe n de nt, e xter nal Data M o nit ori n g C o m mittee ( D M C), c o m prisi n g at least 2 p h ysi cia ns 
wit h p ul m o nar y e x pertise, a n e x pert i n peri o d o ntal diseas e, a n e x pert i n der mat ol o g y, a n d a 
statisticia n w h o is e x perie nce d i n t he e val uati o n of cli nical safet y d ata will be set u p t o re vie w all 
A Es a n d S A Es t o e ns ure t he safet y of s u bjects e nr olle d i nt o t his st u d y.  A d diti o nal me m bers ma y 
be a d de d b y t he D M C if  it is deter mi ne d t hat a d diti o nal e x pertise is re q uire d t o e val uate t he 
cli nical safet y dat a.  T he D M C me m bers will re vie w t he data i n a se mi -bli n de d or u n -bli n de d 
ma n ner at pr e deter mi ne d i nter vals.  If si g nifica nt s afet y iss ues aris e i n bet wee n sc he d ul e d 
meeti n gs, a d -h oc me eti n gs will be sc h e d ule d t o re vie w t h ose data.  Base d o n t he safet y 
i m plicati o ns of t he data, t he D M C ma y rec o m me n d m o dificati o n or ter mi nati o n of t he st u d y.  
F urt her details of t he D M C will be pr o vi de d se paratel y i n t he D M C c harter.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 1  of 1 5 5  
 
4.  
S T U D Y P O P U L A TI O N  
4. 1.  
E nr oll me nt  
T he st u d y will e nr oll mal e or fe m ale s u bjects bet w ee n 1 8  a n d 8 5 years of a ge at Scree ni n g 
dia g n ose d wit h N C F B E  (c o nfir me d b y c h est C T) w h o meet all t he i ncl usi o n a n d n o ne of t he 
e x cl usi o n criteria.  
4. 1. 1.  
I ncl usi o n Criteri a 
S u bjects eli gi ble f or e nr oll me nt i n t he st u d y m ust  meet all t he f oll o wi n g criteria:  
1.  Gi ve t heir si g n e d st u d y i nf or me d c o ns e nt t o partici pate   
2.  Are male or fe mal e bet w ee n 1 8 a n d 8 5 years of a ge (i ncl usi ve) at Scree ni n g   
3.  Ha ve a B MI > 1 8. 5 at Scree ni n g   
4.  Ha ve a cli nical hist or y c o nsiste nt wit h N C F B E (c o u g h, c hr o nic s p ut u m pr o d ucti o n a n d/ or 
rec urre nt r es pirat or y i nf ecti o ns) t hat is c o nfir me d b y c h est C T de m o nstrati n g 
br o nc hiectasis affecti n g 1 or m ore l o bes (c o nfir m ati o n ma y b e base d o n pri or c hest C T ).  
S u bjects w h ose past c hest ra di o gra p hic i ma ge rec or ds are n ot a vaila ble will u n der g o a 
c hest C T sca n d uri n g Scree ni n g .  
5.  Are c urre nt s p ut u m pr o d ucers wit h a hist or y of c hr o nic e x pect orati o n, a n d a ble t o pr o vi de 
s p ut u m sa m ple d uri n g Scree ni n g.  If a s u bject is u na ble t o pr o d uce s p ut u m s p o nta ne o usl y 
d uri n g Scree ni n g  ( Visit 1), t he s u bject will be c o nsi dere d a s cree n fail ure.  The s u bject 
ma y n ot u n der g o a s p ut u m i n d ucti o n pr oce d ure  d uri n g Scree ni n g  ( Visit 1) t o meet 
i ncl usi o n criteri o n. 
6.  Ha ve a s p ut u m c ol or at Scree ni n g of m uc oi d p ur ul e nt or p ur ule nt as ass esse d b y t he 
s p ut u m c ol or c hart (M urra y et al, 2 0 0 9 )   
7.  Ha ve at least 2 d oc u me nt e d p ul m o nar y e x acer bati o ns defi ne d b y nee d f or a nti bi otic 
prescri pti o n b y a p h ysici a n f or t he si g ns a n d s y m pt o ms of res pirat or y i nfecti o ns i n t he 
past 1 2 m o nt hs bef ore Scree ni n g  
8.  W o me n m ust be p ost -me n o pa usal ( defi n e 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 us e),  s ur gicall y sterile, or usi n g hi g hl y effecti ve c o ntr ace pti o n 
met h o ds ( ie, met h o ds t hat al o ne or i n c o m bi nati o n ac hie ve  <  1 % u ni nte n de d pre g na nc y 
rates per year) fr o m D a y 1 t o at least 9 0 da ys after t he last d ose.  S uc h  met h o ds i ncl u de 
tr ue a bsti ne nce (refrai ni n g fr o m heter os e x ual i nterc o urse d uri n g t he st u d y); c o m bi ne d 
(estr o gen a n d pr o gest o ge n c o ntai ni n g) or 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 a n d s u p ple me nte d wit h a d o u ble barrier 
( prefera bl y mal e c o n d o m); i ntra uteri ne de vi ces; i ntra uteri ne h or m o n e-releasi n g s yste ms; 
or vasect o miz e d part ner.  All W O C B P  m ust ha ve a ne gati ve pre g na n c y test bef ore 
ra n d o mizati o n. 
N ote:  A bsti ne n ce is o nl y c o nsi dere d  t o be a hi g hl y effecti ve met h o d of c o ntrace pti o n 
w he n t his is t he preferre d a n d us ual lifest yl e of a s u bject.  Peri o dic a bsti ne n ce (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 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 2  of 1 5 5  
 
o nl y, a n d la ctati o nal a me n orr h ea m et h o d ( L A M) are n ot acce pta ble m et h o ds of 
c o ntrace pti o n.  
9.  Males wit h fe male p art ners of c hil d beari n g p ot e ntial m ust be usi n g effecti ve 
c o ntrace pti o n fr o m Da y 1 t o at least 9 0  da ys after t he last d ose.  S uc h met h o ds i ncl u de 
tr ue a bsti ne nce (refrai ni n g fr o m heter os e x ual i nterc o urse d uri n g t he st u d y), 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) or 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, i ntra uteri ne de vices, i ntra uteri ne h or m o ne -
releasi n g s yste ms, or vas ect o mize d part ner.  N ot e: A bsti ne nce is o nl y c o nsi dere d t o be a 
hi g hl y effecti ve m et h o d of c o ntrace pti o n w he n t his is t he preferre d a n d us ual lifest yle  of 
a s u bject.  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 L A M  are n ot acce pt a ble met h o ds 
of c o ntrace pti o n.  
N ote:  M ale s u bjects will be a d vise d of t he p ot e ntial t o xicit y t o s per m o bser ve d i n 
n o ncli nical st u dies a n d will be a d vise d n ot t o partici pate i n t he st u d y if t he y pla n t o fat her 
a c hil d i n t he f ut ure.  
4. 1. 2.  
E xcl usi o n Criteri a  
S u bjects meeti n g a n y of t he f oll o wi n g criteria are t o be e x cl u de d:  
1.  Ha ve a pri mar y dia g n osis of C O P D o r ast h ma as j u d ge d b y t h e I n vesti gat or  
2.  Ha ve br o nc hiectasis d ue t o C F, h y p o ga m ma gl o b uli ne mia, c o m m o n varia bl e 
i m m u n o deficie nc y, or α 1 -a ntitr y psi n deficie nc y  
3.  Are c urre nt s m o kers as d efi ne d per Ce nters f or Disease C o ntr ol a n d Pre v e nti o n ( C D C) 
criteria d etaile d i n t he pr ot oc ol ( Secti o n  7. 5. 2 )  
4.  Are c urre ntl y  bei n g tr eat e d f or a n o nt u b erc ul o us m yc o b acteri al  l u n g i nf ecti o n, aller gi c 
br o nc h o p ul m o nar y as p er gill osis, or t u berc ul osis  
5.  Ha ve a n y ac ute i nfecti o ns (i ncl u di n g res pirat or y i nfecti o ns) t hat r e q uire d a nti bi otic 
treat me nt wit hi n 4 wee ks bef ore Scree ni n g or wit hi n 1 2 wee ks bef ore Scree ni n g if t he 
a nti bi otic prescri pti o n is a macr oli de   
a. If a s u bject s uffers a n e x acer bati o n or i nfecti o n re q uiri n g a nti bi otic treat me nt after t he 
Scree ni n g visit, b ut pri or t o ra n d o mizati o n, t he s u bject will be c o nsi dere d a scree n 
fail ure. 
6.  Are u na ble t o p erf or m tec h nicall y acce pta ble s pir o metr y meeti n g A merica n T h oracic 
S ociet y ( A T S)/ E ur o pea n T h oracic  S oci et y ( E R S) acce pta bilit y criteria wit h at least 
3  acce pta ble fl o w -v ol u me c ur ves wit h at least 2 meeti n g t h e A T S/ E R S re peata bilit y 
criteria f or F E V1 d uri n g Scree ni n g   
a. S u bjects w h o nee d t o re p eat P F T s beca use t he y d o n ot meet  t he e x cl usi o n criteri o n 
ca n re p eat t he test u p t o 2 ti mes wit h o ut bei n g re -s cree n e d. 
7.  Ha ve a n a b n or mal r e nal f u ncti o n test res ult ( esti mate d gl o mer ular filtrati o n rate 
[e G F R ] <  4 5 m L/ mi n b y C hr o nic Ki d ne y Diseas e E pi de mi ol o g y C olla b orati o n 
( C K D-E PI) e q u ati o n ) at Scree ni n g  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 3  of 1 5 5  
 
8.  Ha ve el e vate d li ver f u ncti o n test res ults (ala ni ne a mi n otra nsferas e [ A L T] or as partat e 
a mi n otra nsferase [ A S T] > 2  ×  u p per li mit of n or mal [ U L N]) at Scree ni n g   
9.  Ha ve a bilir u bi n > 1. 5  × U L N (is olate d bilir u bi n > 1. 5  × U L N is acce pta bl e if bilir u bi n is 
fracti o nat e d a n d direct bilir u bi n < 3 5 %) at Scree ni n g  
1 0.  Ha ve a c urre nt or c hr o nic hist or y of li ver disease ( C hil d -P u g h A, B , or C), or k n o w n 
he patic or biliar y a b n or m alities e x ce pt f or Gil bert’s s y n dr o me or as y m pt o matic 
gallst o nes, a n d/ or p ositi v e ser ol o gical tests f or he p atitis B, he patitis C  ( H C V), or k n o w n 
h u ma n i m m u n o deficie nc y vir us ( HI V) i nf ecti o n   
1 1.  Ha ve a w hite bl o o d ce ll c o u nt < l o wer li mit of n or mal at Scree ni n g  
1 2.  Ha ve a n y cli nicall y si g nifica nt a b n or m al la b orat or y val u es at Scree ni n g or diseases or 
dis or ders (e g, car di o v asc ular, p ul m o nar y, gastr oi ntesti nal, li ver, ki d ne y, n e ur ol o gical, 
m usc ul os keletal, e n d ocri ne, meta b olic , ps yc hiatri c, p h ysic al i m pair me nt, or a l u n g 
tra ns pla ntati o n) t hat, i n t he o pi ni o n of t he I n vesti gat or, m a y p ut t he s u bject at ris k b y 
partici pati n g i n t he st u d y, or i nterfere wit h t he s u bj ect’s treat me nt, assess me nt, or 
i nfl ue nce t he res ults of t he st u d y, or ha ve c o m plia nce iss ues wit h t he st u d y   
1 3.  Are ta ki n g c ycli c d oses of a nti bi otics as c hr o nic tr eat me nt f or N C F B E    
1 4.  Are ta ki n g oral or i n hale d a nti bi otics as c hr o nic tr eat me nt f or N C F B E < 6 m o nt hs pri or t o 
Baseli ne , p atie nts o n a nti bi otics as c hr o nic treat me nt s h o ul d be o n s uc h treat me nt f or at 
least 6 m o nt hs pri or t o e nr ol me nt w hile meeti n g all ot her i ncl usi o n a n d e x cl usi o n criteria  
1 5.  Are ta ki n g c o n c o mita nt me dicati o ns t hat ma y ca use h y p er kerat osis (e g, t u m or necr osis 
fact or [T N F -α ] a nta g o nists)  
1 6.  Are n o t o n a sta ble d os e of a n i n hale d c ortic oster oi d f or at least 4 wee ks pri or t o Da y 1 if 
t he s u bject is c urre ntl y o n a n i n hale d c ortic ost er oi d  
1 7.  Are u na ble t o wit h h ol d S A B A or S A M A us e f or at least 6 h o urs pri or t o P F Ts or u na ble 
t o wit h h ol d L A B A or L A M A use o n t he da y P F Ts will be perf or me d u ntil after t he test    
1 8.  Ha ve a hist or y of mali g n a nc y i n t he past 5 years wit h e xce pti o n of n o n -mela n o ma s ki n 
ca ncer  
1 9.  Ha ve a b aseli ne -c orrecte d Q T i nter val b y Fri dericia ( Q Tc F) > 4 5 0 millisec o n ds ( males) 
or 4 7 0 millisec o n ds (fe m ales) or hist or y of c o n ge nital l o n g Q T s y n dr o me, or T orsa des d e 
P oi ntes or ot her a b n or mal E C G at Scree ni n g or Baseli ne ( u nless t he E C G fi n di n gs are n ot 
cli nicall y si g nifica nt a n d are a p pr o ve d b y t he I n vesti gat or a n d d o c u me nte d b y si g nat ur e)   
a. If a s u bject d o es n ot q ualif y d ue t o E C G s t hat d o n ot meet t he q ualit y criteri a, t he 
s u bject ca n re peat t he test u p t o 2 ti mes wit h o ut bei n g re -scree n e d. 
2 0.  Ha ve si g nifica nt h e m o pt ysis ( ≥ 3 0 0 m L or re q uiri n g bl o o d tra nsf usi o n) wit hi n 6 wee ks 
pri or t o Da y  1 ( Visit 2)   
2 1.  Are c urre ntl y partici pati n g i n or sc h e d ule d t o parti ci pate i n a n i nte nsi ve p ul m o nar y 
re ha bilitati o n pr o gra m ( a mai nte na nce re ha bilitati o n pr o gra m is all o we d if t heir sc he d ule 
a n d pr oce d ure will be k e pt c o nsiste nt d uri n g t he d urati o n of t he st u d y)   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 4  of 1 5 5  
 
2 2.  Partici p ate d i n a n y ot her i nter ve nti o nal cli nical st u dies wit hi n 3 m o nt hs bef ore Da y  1 
( Visit 2)  
H a ve t he f oll o wi n g m e dic al c o n diti o ns ass oci ate d wit h t he o nset of n o n -here dit ar y 
p al m o pl a nt ar ker at osis:  
2 3.  H y p ot h yr oi dis m, m y x e de ma, c hr o nic l y m p he de m a, acr oc ya n osis, or li ve d o retic ularis   
N ote: If a s u bject has h y p ot h yr oi dis m b ut is c urre ntl y bei n g treate d, a n d 
t h yr oi d-sti m ulati n g h or m o ne ( T S H) a n d/ or trii o d ot h yr o ni ne ( T 3)/t h yr o xi ne ( T 4) are 
wit hi n n or mal ra n ges, t he s u bject is all o we d i nt o t he trial .   
2 4.  Ha ve ps oriasis  or lic h e n pla n us   
2 5.  Ha ve Reiter's disease/ kerat o der ma, or bl e n n orr h a gic u m, or "reacti ve art hritis"  
2 6.  Ha ve pit yriasis r u bra pilaris, or at o pic der m atitis, or c hr o nic h a n d der matitis, or c hr o nic 
c o ntact der m atitis, or c hr o nic der mat o p h yt osis   
2 7.  Ha ve c hl or ac n e, o r e xte nsi ve verr uca v ul garis, or kerat o der ma cli macteric u m  
2 8.  Perf or m e xtre me r u n ni n g or s wi m mi n g, or ot her c hr o nic, re p etiti ve mec ha nical or water 
da ma ge t o pla ntar e pi der mis  
Peri o d o nt al dise ase (t o be e v al u ate d b y a peri o d o ntis t or de ntist): 
2 9.  Ha ve a n y t o ot h  t hat ca n p ote ntiall y ca use pai n or i nfecti o n as n ote d i n t he oral e xa m 
u nless t he y are c orrecte d bef ore t h e st u d y  
3 0.  Ha ve se v ere p eri o d o ntal disease as defi ne d as wit h p oc ket de pt h meas ure me nts a n d 
attac h me nt l oss ≥ 6 m m o n 2 or m ore teet h  
3 1.  Ha ve Class -3 m o bi lit y or 3  f urcati o n i n v ol ve me nt 
3 2.  Are sc h e d ule d t o ha ve t o ot h e xtracti o n t hat will occ ur d uri n g t he st u d y peri o d  
P a pill o n -Lefè vre S y n dr o me:  
3 3.  Ha ve a cli nical dia g n os is of P L S  
4. 2.  
Re m o v al of S u bjects  
4. 2. 1.  
Re as o ns f or Wit h dr a w al/ E arl y Disc o nti n u ati o n  
A s u bject ma y deci d e t o wit h dra w fr o m t he st u d y at a n y ti me, f or a n y reas o n, wit h o ut prej u dice 
t o s u bse q ue nt care or treat me nt b y t he I n v esti gat or.  W he n t his occ urs, t he s u bject s h o ul d 
c o m plete all t he pr oce d ures at t he Visit 9 ( E n d of Treat me nt) Visit.  S u bjects w h o disc o nti n ue 
t he treat me nt d ue t o A Es  s h o ul d re mai n u n der o bser vati o n u ntil t he res ol uti o n or sta bilizati o n of 
t he A Es . 
A s u bject ma y be disc o nti n ue d fr o m t he st u d y dr u g treat me nt bef ore c o m pl eti o n f or a n y of t he 
f oll o wi n g reas o ns: 
1.  S u bject deat h   
2.  S u bject e x perie nces a n A E(s)/ S A Es t hat warra nts disc o nti n uati o n, as j u d ge d b y t he 
I n v esti gat or a n d/ or I ns m e d 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 5  of 1 5 5  
 
3.  A maj or pr ot oc ol de viati o n, w hic h, i n t he o pi ni o n/ discreti o n of t he I n vesti gat or a n d/ or 
I ns me d c o m pr o mises t he data i nte grit y of t he st u d y  
4.  S u bj ect is n o nc o m plia nt wit h t he st u d y dr u g treat me nt   
5.  Treat me nt c o d e is pre mat urel y br o ke n b y t he I n vesti gat or  
6.  S u bject wit h dra ws c o nse nt   
7.  S u bject decisi o n t o disc o nti n ue  treat me nt 
8.  S p o ns or ter mi nates t he st u d y   
9.  I n v esti gat or discreti o n  
1 0.  S u bject l ost t o f oll o w -u p  
1 1.  S u bject pre g na nc y   
1 2.  Peri o d o ntal criteria met   
1 3.  S ki n criteria met   
1 4.  Seri o us i nfecti o n, defi ne d as life -t hreate ni n g i nfecti o ns, i nfecti o ns re q uiri n g 
h os pitaliz ati o n, or i nfecti o ns re q uiri n g treat me nt wit h i ntra ve n o us a nti bi otics (e x ce pt 
h os pitaliz ati o ns f or e x acer bati o ns, w here t he PI will e val uate w het her it is i n t he best 
i nterest of t he s u bject t o c o nti n ue i n t he st u d y)  
1 5.  S u bject s w h o de vel o p ne utr o pe nia defi n e d as A N C <  1 0 0 0 / m m3 
E x ce pt f or t h ose s u bjects w h o wit h dra w c o ns e nt, die or are l ost t o f oll o w -u p, s u bjects w h o 
disc o nti n ue t heir assi g n e d st u d y dr u g will be e n c o ura ge d t o c o nti n ue t o partici pate i n  t heir 
re mai ni n g s c he d ule d st u d y visits.  E ver y eff ort s h o ul d be ma de b y t he I n v esti gat or t o kee p t hese 
s u bjects i n t he st u d y t hr o u g h Visit 1 0 .  “L ost t o f oll o w -u p ” s h o ul d be mar k e d o nl y i n a n 
e x ce pti o nal case w h e n all d oc u me nte d atte m pts t o reac h t h e s u bject b y t he I n v esti gat or or ot her 
staff me m bers were u ns u ccessf ul. 
4. 2. 2.  
S u bject Re -Sc ree ni n g Pr oce d ures  
S u bjects w h o d o n ot meet eli gi bilit y criteria d uri n g Scree ni n g ma y be re -s cree ne d u p t o 2  ti mes if 
a p pr o ve d b y I ns m e d’s M e dical M o nit or.  
D uri n g S cree ni n g ( Visit 1), if a s u bject d oes n ot q ualif y d u e t o E C Gs t hat d o n ot meet t he q ualit y 
criteria, t he s u bject ca n re peat t he test u p t o 2 ti mes wit h o ut bei n g re -scree ne d. 
S u bjects w h o nee d t o re p eat P F T s beca use t he y d o n ot meet e xcl usi o n criteri o n 6 ( Secti o n  4. 1. 2 ) 
ca n re p eat t he test u p t o 2 ti mes wit h o ut bei n g re -s cree n e d. 
S u bjects w h o are c o nsi dere d a scree n fail ure f or reas o ns n ot relate d t o t he d e ntal e x cl usi o n 
criteria (Secti o n  4. 1. 2 , e x cl usi o n criteria 2 9 t hr o u g h 3 2) d o n ot nee d t o re p eat t he de ntal 
e x a mi nati o n if t he y  are r e-scree ne d wit hi n 3  m o nt hs of t he first Scree ni n g visit.    


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 6  of 1 5 5  
 
5.  
S T U D Y T R E A T M E N T S  
5. 1.  
I n vesti g ati o n al Pr o ducts  
5. 1. 1.  
I n vesti g ati o n al Pr o d uct 
I N S 1 0 0 7 is a fil m-c oate d, oral ta blet a vaila bl e i n d ose stre n gt hs of 1 0 m g a n d 2 5 m g.   T he 
2  stre n gt hs are r o u n d, bic o n ve x, br o w n fil m-c oate d ta blets i de ntical i n size a n d a p peara n ce.  T h e 
ta blets are a n i m me diate-releas e d osa ge f or m wit h ra pi d diss ol uti o n c haract eristics u n der i n vitr o 
test c o n diti o ns. 
Eac h ta blet c o nt ai ns acti ve i n gre die nt I N S 1 0 0 7 a n d t he f oll o wi n g i nacti ve U S 
P har mac o peia/ N ati o nal F or m ular y or E ur o pea n P h ar mac o p o eia c o m pe n di a i n gre di e nts: 
micr ocr ystalli ne cel l ul ose, di basic cal ci u m p h os p hate di h y drate, s o di u m starc h gl yc olat e, silic o n 
di o xi de, a n d gl ycer yl be h e nate.  T he t a blet is fil m c oate d wit h h y pr o mell os e, p ol yet h yl e ne 
gl yc ol, tita ni u m di o xi de, ir o n o xi de re d, ir o n o xi de yell o w, a n d ir o n o xi de blac k.  
5. 1. 2.  
M atc hi n g Pl ac e b o  
T he matc hi n g place b o ta blet c o ntai ns micr ocr ystalli ne cell ul ose a n d s o di u m stear yl f u marate a n d 
is c oate d i de nticall y t o I N S 1 0 0 7 ta blets. 
5. 1. 3.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nts a n d Bli n di n g  
S u bjects will be ra n d o mize d i n a bli n de d fas hi o n via a n R T S M  s yste m i nt o 1 of  3 treat me nt ar ms 
t o recei ve eit her 1 0 m g or 2 5 m g of I N S 1 0 0 7 or m atc hi n g pl ace b o i n a 1: 1: 1 rati o. 
5. 1. 4.  
U n bli n di n g Pr oce d ures  
I n t he cas e of a rare e mer ge n c y w here, i n t he o pi ni o n of t he I n vesti gat or, disc o nti n uati o n of st u d y 
treat me nt is n ot s ufficie nt , a n d t he st u d y tr eat me nt m ust be u n bli n de d t o e val uate f urt h er c o urse 
of acti o n, t he I n v esti gat or ca n u n bli n d st u d y tr eat me nt f or a s pecific patie nt.  It is s u g geste d t hat 
t he I n v esti gat or c o nta ct t he I ns me d Me dical M o nit or or a p pr o pri ate I ns me d st u d y pers o n nel pri or 
t o t he u n bli n di n g.  T he I n vesti gat or m ust be a ble t o c o nfir m t hat u n bli n di n g of t he s u bj ect is 
necessar y a n d dir ectl y i m pacts t he s u bject’s i m me diate me dical ma na ge me nt or welfare of t he 
s u bject.  T he s u bject will be c o nsi dere d disc o nti n ue d fr o m t he st u d y.  
If t his is n ot p ossi ble, t he I n v esti gat or m ust n otif y t he S p o ns or as s o o n as p ossi ble.  T he date a n d 
reas o n f or u n bli n di n g m ust be d oc u me nte d a n d si g ne d b y t h e st u d y I n vesti gat or.  T he ori gi nall y 
si g ne d c o p y is mai ntai ned i n t he st u d y file at t he site, a n d a c o p y is pr o vi de d t o t he S p o ns or or its 
desi g nee.  T he I n vesti gat or s h o ul d f oll o w t he ste ps i n t he Me di data Bala nce R T M S s yste m a n d 
e nter t he u n bli n di n g d ate a n d reas o n.   T he date a n d reas o n f or t he u n bli n di n g is als o e ntere d i n 
t he st u d y e C R F a n d a n y ass ociate d A E re p orts. 
5. 1. 5.  
St u d y Dr u g A d mi nistr ati o n  
I N S 1 0 0 7 is a d mi nistere d orall y, Q D  bef ore brea kfast a n d s h o ul d be ta ke n wit h a glass of water 
o n a n e m pt y st o mac h at a p pr o xi matel y t he s a me ti me e ver y d a y.  Ta blets s h o ul d n ot be br o ke n or 
c he we d.  If a d os e is f or g otte n b ut re me m bere d bef ore mi d ni g ht of t h at da y , t he misse d d ose 
s h o ul d be ta ke n i m me diatel y.  Ot her wise, t he d ose s h o ul d be s ki p pe d f or t h at da y. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 7  of 1 5 5  
 
5. 1. 6.  
Met h o d of Assessi n g Tre at me nt C o m pli a nce  
S u bjects will be a d vise d t o bri n g all t heir u n us e d st u d y dr u g al o n g wit h t heir ha n d hel d c o m p uter 
ta blet t o eac h visit d uri n g t he treat me nt peri o d.  Site staff are res p o nsi ble t o re vie w t he d osi n g 
diar y a n d rec o ncile wit h t he u nta ke n st u d y dr u g.  Dr u g acc o u nta bilit y will be rec or de d i nt o t he 
s o urce d oc u m e nts a n d e C R F at eac h st u d y visit.  
Acc o u nta bilit y f or st u d y dr u g a d mi nistrati o n d uri n g t he st u d y is t he res p o nsi bilit y of t he 
I n v esti gat ors or desi g nees.  T he I n vesti gat ors will d oc u me nt t he n u m ber of ta blets dis pe nse d t o 
a n d ret ur n e d b y eac h s u bject at eac h visit after re vie wi n g t heir d osi n g diar y.  C o m plia nce will be 
defi ne d as ta ki n g b et wee n 8 0 % a n d 1 2 5 % of t h e i nte n de d q ua ntit y of t he st u d y dr u gs.  
5. 1. 7.  
P ac k a gi n g a n d L a beli n g I nf or m ati o n  
La b els will be pre p are d i n acc or da nce wit h G o o d Ma n ufact uri n g Practice A n ne x 1 3 re q uire me nts 
a n d l ocal re g ul at or y g ui d eli nes.  La bel te xt will be tra nslate d i nt o l ocal la n g ua ge.  T he st u d y dr u g 
la bel o n t he b ottle s pecifi es t he a p pr o pri ate st ora ge. 
I N S 1 0 0 7 a n d matc hi n g place b o will be pac ke d i n i n di vi d ual hi g h-de nsit y p ol yet h yle ne b ottles, 
la bele d a n d st ore d as des cri be d bel o w. 
N u m ber  
L a bel Re q uire me nts  
S pecific L a bel I nf o r m ati o n  
1  
P har mace utical d osa ge f or m  
O val, bic o n ve x, br o w n, fil m c oate d 
ta blet 
2  
Q ua ntit y of t he d osa ge u nit  
1 0 m g, 2 5 m g, or place b o  
3  
Pr ot oc ol n u m ber  
I N S 1 0 0 7-2 0 1  
6  
L ot n u m ber  
S u bj ect s pecifie d  
7  
Re -T est/ E x pirati o n date  
As pr o vi de d  
8  
Ca uti o n state me nt  
F or cli nical st u d y use o nl y.  
9  
St ora ge c o n diti o ns  
At r o o m te m perat ure, bel o w 3 0 oC  
1 0  
S p o ns or i de ntificati o n, na me, a d dress a n d p h o ne n u m ber  
I ns me d I nc or p orate d 
1 0 Fi n der ne A ve n ue  
Bri d ge water , NJ 0 8 80 7  
1 1  
Directi o n f or use  
T his pr o d uct s h o ul d o nl y be use d after 
a p pr o priate trai ni n g.   
1 2  
State me nt: “ Kee p o ut of si g ht a n d re ac h of c hil dre n ”  
Kee p o ut of si g ht a n d  reac h of c hil dre n. 
5. 1. 8.  
St or a ge  
All st u d y dr u g s u p plies m ust be st ore d i n acc or da nce wit h t he la bel i nf or mati o n.  U ntil dis pe nse d 
t o t he st u d y s u bjects, t he st u d y dr u gs will be st ore d at r o o m te m perat ur e bet wee n 2 °C a n d 3 0 °C, 
at t he sites i n a sec urel y l oc ke d , li mite d access st ora ge area u n der a p pr o pri ate st ora ge c o n diti o ns, 
accessi ble t o a ut h orize d pers o n nel o nl y.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 8  of 1 5 5  
 
5. 1. 9.  
Dr u g Us a ge a n d Acc o u nt a bilit y  
T he st u d y dr u gs are t o be prescri be d o nl y b y t he I n vesti gat ors or s u b  I n vesti gat ors partici pati n g 
i n t he trial. 
U n der  n o cir c u msta nces will t he I n vesti gat ors all o w t he st u d y dr u gs t o b e use d ot her t ha n as 
directe d b y t his pr ot oc ol.  
W he n a dr u g s hi p me nt is recei v e d, t he I n v esti gat or or desi g nee will c hec k t he a m o u nt a n d 
c o n diti o n of t he dr u g, c h ec k f or a p pr o pri ate l ocal l a n g u a ge i n t he la bel, dr u g e x pirati o n date, a n d 
mai ntai n acc urate rec or ds acc o u nti n g f or t he recei pt of t he st u d y dr u g s u p plies a n d f or t he 
dis p ositi o n of t he st u d y dr u gs o n a n o n g oi n g b asis .  I n a d diti o n, t he I n vesti gat or or desi g nee s hall 
c o ntact I ns me d as s o o n as p ossi ble if t here is a pr o ble m wit h t he s hi p me nt.  
D oc u me ntati o n of t he dis p ositi o n of t he st u d y dr u gs s h o ul d c o nsist of a Site St u d y Dr u g 
Acc o u nta bilit y L o g a n d a S u bject St u d y Dr u g Acc o u nta bilit y L o g.  
 T he st u d y dr u gs dis pe nse d t o t he site will  be rec or de d i n t he Site St u d y Dr u g 
Acc o u nta bilit y L o g ( or e q ui vale nt d oc u me nt a p pr o ve d b y t h e S p o ns or ). 
 T he st u d y dr u gs dis pe nse d t o eac h s u bject will be rec or de d i n t he S u bject St u d y Dr u g 
Acc o u nta bilit y L o g ( or e q ui vale nt d oc u me nt a p pr o ve d b y t h e S p o ns or ). 
T he Site St u d y Dr u g A cc o u nta bilit y L o g s h o ul d i n cl u de i de ntificati o n of all s u bjects b y t heir 
s u bject n u m bers t o w h o m t he st u d y dr u gs are dis pe nse d, t he t otal q ua ntit y a n d date of 
dis pe nsi n g, a n d t he t otal q ua ntit y of use d a n d u n use d st u d y dr u gs.  
T he S u bject St u d y Dr u g Acc o u nta bilit y L o g s h o ul d i ncl u de i de ntificati o n of s u bject b y t heir 
su bject n u m ber  t o w h o m t he dr u g is dis pe ns e d, t he q ua ntit y a n d t he date of dis pe nsi n g, a n d t he 
q ua ntit y of use d st u d y dr u gs.  T his rec or d is i n a d diti o n t o a n y dr u g acc o u nta bilit y i nf or mati o n 
rec or de d o n t he e C R Fs .   
T he Site a n d S u bject St u d y Dr u g Acc o u nta bilit y L o gs will be verifie d b y t he S p o ns or's st u d y 
m o nit or or its desi g nee at eac h m o nit ori n g visit.   
U p o n c o m pleti o n of t he st u d y, t he I n v esti gat ors m ust ret ur n all t he u n use d st u d y dr u gs a n d all 
partiall y dis pe ns e d or e m pt y b ottles t o t he S p o ns or or its desi g nee, or dis p os e of t he m l ocall y per 
a p plica ble l ocal a n d c o u ntr y re g ulati o ns.  A n y use d a n d u n use d st u d y dr u gs will be mai ntai ne d 
b y t he sites u ntil i n ve nt orie d b y t he S p o ns or st u d y m o nit ors or desi g nees bef ore ret ur n or 
dis p osal l ocall y.  Dr u g s u p pl y destr u cti o n m ust be clearl y d oc u m e nte d a n d ke pt i n t he st u d y file 
at sites, a n d a c o p y s h o ul d be pr o vi de d t o t he S p o ns or or its desi g n ee.  T he I n v esti gat ors s hall 
also pr o vi de a writte n e x pla nati o n f or a n y missi n g st u d y dr u gs if it occ urs wit h t he ori gi nal ke pt 
i n t he st u d y file at t he sit es a n d a c o p y t o t he S p o ns or. 
T he ori gi nal Site a n d S u bject St u d y Dr u g Acc o u nt a bilit y L o gs will be a p pr o ve d a n d si g ne d b y 
t he I n v esti gat ors a n d retai ne d at t he st u d y sites a n d a c o p y s u p plie d t o t he S p o ns or or its desi g nee 
after t he st u d y is c o m plet e d.  
5. 2.  
C o nc o mit a nt Me dic ati o ns  
A n y me di cati o ns t he s u bject ta kes ot her t ha n t he st u d y dr u gs fr o m Visit 2 ( Baseli ne, Da y  1) t o 
Visit 1 0 ( E O S, D a y 1 9 7 ) are c o nsi d ere d c o nc o mita nt me dicati o ns a n d will be c ollecte d a n d 
d oc u me nte d i n t he st u d y e C R F.   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 8 9  of 1 5 5  
 
A n y pr oce d ures perf or m e d fr o m Visit 2 ( Baseli ne, Da y  1) t o Visit 1 0 ( E O S, Da y  1 9 7) are 
c o nsi dere d c o nc o mita nt pr oce d ures a n d will be c ollecte d a n d d oc u m e nte d i n t he st u d y e C R F.  
5. 3.  
Pr o hi bite d Me dic ati o ns  
Use of a n y i m m u n o m o d ulat or y a ge nts (e g, b ortez o mi b, i x az o mi b , a n d t hali d o mi de) is  pr o hi bite d 
d uri n g t he st u d y t hr o u g h Visit 1 0 ( E O S).  
C o nti n u o us use of hi g h d ose n o n -ster oi dal a nti-i nfla m mat or y dr u gs is pr o hi bite d d uri n g t he st u d y 
t hr o u g h Visit 1 0 ( E O S) u nless t he use is c o nsi dere d necessar y per I n vesti gat or discreti o n.  
Me dicati o ns t hat ma y ca use a pal m o pla ntar kerat o der ma are pr o hi bite d d uri n g t he st u d y t hr o u g h 
Visit 1 0 ( E O S).  Please refer t o T a ble  1  f or t h e list of me dicati o ns t hat ma y ca use pal m o pla ntar 
kerat o der ma.  
T a ble  1 : 
Pr o hi bite d Me dic ati o ns ( M a y C a use P al m o pl a nt ar Ker at o der m a)  
C o m m o n Ge neric N a me  
Re q uire d W as h o ut P eri o d  
A rse nic  
F o wler’s S ol uti o n f or Ps oriasis  
Di o xi n  
Gl uca n  
T e gaf ur/ Fl u or o uracil  
Ble o m yci n  
H y dr o x y urea  
Lit hi u m  
Ve nlafa xi ne  
Q ui nacri ne  
I mati ni b Mes ylate 
4  Wee ks Pri or t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
T he dr u g -dr u g i nteracti o n cli nical st u d y res ults, St u d y D 6 1 9 0 C 0 0 0 0 3 , i n dicate t hat t here was 
little or n o effect of a str o n g C Y P 3 A 4/ 5 i n hi bit or (itrac o naz ole) o n t he e x p os ures of I N S 1 0 0 7.  
Dr u gs t hat i n hi bit C Y P  is of or ms will be per mitte d d uri n g t his st u d y; h o w e v er, c o -a d mi nistrati o n 
of i n hi bit ors of m ore t ha n o ne I N S 1 0 0 7 eli mi nati o n pat h wa y (e g, C Y P 3 A 4/ 5 wit h C Y P 2 C 8 
a n d/ or C Y P 2 D 6  i n hi bit ors) s h o ul d be a v oi de d, as t here is n o i nf or mati o n o n t heir c o m bi ne d 
dr u g -dr u g i ntera cti o n p ote ntial (refer t o Ta bl e  2  a n d Ta ble  3  for a re prese nt ati ve list of k n o w n 
C Y P 2 C 8 a n d C Y P 2 D 6 i n hi bit ors, a n d a list of C Y P 3 A 4 i n hi bit ors).  
As n o cli nical data e xists o n t he effect of i n d ucers of C Y P 3 A 4/ 5 o n t he P K of I N S 1 0 0 7, 
m o der ate a n d str o n g i n d u cers will n ot be all o we d d uri n g t he st u d y (refer t o Ta ble  4  f or c o m m o n 
C Y P 3 A 4/ 5 i n d ucers).  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 0  of 1 5 5  
 
T a ble  2 : 
List of M o der ate a n d Str o n g C Y P 2 D 6 a n d C Y P 2 C 8 I n hi bit ors ( n ot to b e 
C o -A d mi nistere d Wit h C Y P 3 A 4/ 5 I n hi bit ors b ut Ot her wise Per mitte d)  
C o m m o n Ge neric N a me  
Re q uire d W as h o ut P eri o d  
M o der ate C Y P 2 C 8  I n hi bit ors 
Deferasir o x  
T erifl u n o mi de  
Tri met h o pri m  
4  Wee ks Pri or  t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
Str o n g C Y P 2 C 8  I n hi bit ors 
Cl o pi d o grel  
Ge mfi br ozil  
4 Wee ks Pri or  t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
M o der ate C Y P 2 D 6  I n hi bit ors 
Ci nacalcet  
D ul o xeti ne  
Sertrali ne  
T er bi nafi ne  
4  Wee ks Pri or t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
Str o n g C Y P 2 D 6  I n hi bit ors 
B u pr o pi o n  
Fl u o xeti ne  
Par o xeti ne  
Q ui ni di ne  
4 Wee ks Pri or t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
C Y P  = c yt oc hr o me P 4 5 0 e nz y me . 
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 1  of 1 5 5  
 
T a ble  3 : 
List of M o der ate a n d Str o n g C Y P 3 A 4/ 5 I n hi bit ors ( Per mitte d U nless 
C o m bi ne d Wit h t he A b o ve M o der ate a n d Str o n g C Y P 2 D 6 a n d C Y P 3 C 8 
I n hi bit ors) 
C o m m o n Ge neric N a me  
Re q uire d W as h o ut P eri o d  
M o der ate C Y P 3 A 4/ 5 I n hi bit ors  
A pre pita nt  
Ataza na vir  
Ataza na vir/ Rit o na vir  
Fl uc o naz ole  
Vera pa mil  
Diltiaze m  
A m pre na vir  
Ataza na vir  
Ci pr ofl o xaci n  
Dar u na vir/ Rit o na vir  
F osa m pre na vir  
I mati ni b 
Ci meti di ne  
C ycl os p ori ne  
Fl u v o xa mi ne  
P osac o naz ole  
4 Wee ks Pri or  t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
Str o n g C Y P 3 A 4/ 5 I n hi bit ors  
B oce pre vir  
T ela pre vir L o pi na vir/ R it o na vir  
Sa q ui na vir  
I n di na vir Mi befra dila  
Nelfi na vir  
Clarit hr o m yci n  
T elit hr o m yci n C o ni va pta n Itrac o naz ole 
Ket oc o naz ole P osac o naz ole  
Nefaz o d o ne  
V oric o naz ole  
Gra pefr uit J uice (Als o P o mel o, Gra pefr uit, Se ville 
Ora n ges, Se ville Ora n ge Mar mala d e, or Ot her 
Pr o d ucts C o ntai ni n g Gra pefr uit or Se ville 
Ora n ges )b 
4 wee ks pri or t o Da y 1 t o 2 8 -da y ( +/ - 3 da ys) 
Safet y F oll o w -U p  
C Y P  = c yt oc hr o me P 4 5 0 e nz y me  
a Wit h dra w n fr o m vari o us mar kets s uc h as t he U nite d States  beca use of safet y reas o ns.  
b T he effect of gra p efr uit j uice varies wi del y a m o n g bra n ds a n d is c o nce ntrati o n -, d ose-, a n d pre parati o n- de pe n de nt.  
St u dies ha ve s h o w n t hat it ca n be classifie d as a “str o n g C Y P 3 A i n hi bit or” w he n a certai n pre p arati o n was use d 
(e g, hi g h d ose, d o u ble stre n gt h) or as a “ m o derate C Y P 3 A i n hi bit or” w he n a n ot her pre parati o n was use d ( e g, l o w 
d ose, si n gle stre n gt h).  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 2  of 1 5 5  
 
T a ble  4 : 
Pr o hi bite d Me dic ati o ns ( C Y P 3 A 4/ 5 I n d ucers)  
C o m m o n Ge neric N a me  
Re q uire d W as h o ut P eri o d  
M o der ate C Y P 3 A 4/ 5 I n d ucers  
B ose nta n  
Efa vire nz  
Etra viri ne  
M o dafi nil  
Nafcilli n  
4 Wee ks Pri o r t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
Str o n g C Y P 3 A 4/ 5 I n d ucers  
A vasi mi be a  
P he n o bar bital  
Car ba maze pi ne P he n yt oi n Rifa m pi n  
Rifa b uti n  
St. J o h n’s W ort b 
Tr o glitaz o ne  
4  Wee ks Pri or t o Da y 1 t o 2 8-Da y  ( +/- 3 Da ys ) 
Safet y F oll o w -U p  
a N ot a mar kete d dr u g.  
b T he effect of St J o h n’s W ort v aries wi del y a n d is pre parati o n -de pe n de nt.  
C Y P  = c yt oc hr o me P 4 5 0 e nz y me . 
As a r ule, n o c o m p a ni o n me dicati o n t hat has bee n t olerate d a n d is c o nsi dered necessar y b y t he 
In v esti gat or f or t he treat me nt of t he s u bjects’ u n d erl yi n g dise ase or c o m or bi dities s hall be 
wit h hel d i n a n y s u bject t o f ulfill eli gi bilit y f or t his st u d y.    
If t he use of a n y pr o hi bite d me dicati o ns is necessar y, t he y m a y be all o we d u p o n  c o ns ultati o n 
wit h t he S p o ns or a n d s h o ul d be ta ke n ca uti o usl y u n der cl ose m o nit ori n g.  
5. 4.  
Per mitte d Me dic ati o ns a n d Pr oce d ures  
A n y c o nc urre nt o n g oi n g me dicati o ns, i ncl u di n g o ver -t he-c o u nter dr u gs are  all o we d if n ot 
pr o hi bite d b y t he pr ot oc ol ( see Secti o n  5. 3 ).   
S u bjects s h o ul d c o nti n ue t heir mai nte na nce d oses of oral or i n hale d a nti bi otics or i n hale d 
c ortic oster oi ds  d uri n g t he st u d y.  S u bjects ca n us e L A B A, L A M A, a ntic h oli ner gic 
br o nc h o dilat ors , P D E 4 i n hi bit ors, a n d t heir relie ver me dicati o n ( S A B A , S A M A) d uri n g t he st u d y 
if prescri b e d b y t heir p h ysicia ns.  S u bjects are als o all o we d t o c o nti n ue t heir air wa y cl eara nce 
mai nte na nce tr eat me nt / pr oce d ures s u c h as use of h y p ert o nic sali ne/is ot o nic sali ne, m uc ol ytics, 
a n d p ul m o nar y re h a bilitati o n.  H o we ver, e x ce pt u n der u nf oreseea ble  cli nical circ u msta nces, t he 
air wa y cl eara nce mai nte n a nce tr eat me nt / pr oce d ures a n d p ul m o nar y re h a bilitati o n s h o ul d 
c o nti n ue u nc ha n ge d t hr o u g h o ut t he d urati o n of t he st u d y  t hr o u g h Visit 1 0 ( E O S).  
T he use of sel ecti ve ser ot o ni n rece pt or i n hi bit ors (S S RIs ) is all o we d if t he s u bject has bee n 
recei vi n g t he m f or at least 6 m o nt hs pri or t o t he st u d y.  S u bj ects are n ot all o we d t o start S S RIs 
d uri n g t he st u d y.   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 3  of 1 5 5  
 
T here is a mi ni m u m ti me i nter val restricti o n f or s o me of t he me dicati o n  use bef ore a n d aft er  
s pir o metr y testi n g.  T he mi ni m u m ti me i nter vals of t he restrict e d me dicati o ns are s u m marize d i n 
Ta ble  5 . 
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 4  of 1 5 5  
 
T a ble  5 : 
Mi ni m u m Ti me I nter v als f or Restricte d  Me dic ati o n  Us e Pri o r t o 
Re versi bilit y / S pir o metr y Testi n g 
Me dic ati o n  
Mi ni m al Ti me I nter v al 
F r o m L ast Me dic ati o n 
D ose  
P ri or t o 
P ost -Br o nc h o dil at or 
Testi n g  
I n hale d S A B A  (Sal b uta m ol/ Al b uter ol,  T er b utali ne)  
6  H o urs  
I n hale d L A B A,  I ncl u di n g I C S/ L A B A C o m bi nati o n Pr o d ucts  
1 2  H o urs  
1 2  H o urs  
2 4  H o urs  
2 4  H o urs  
F or m oter ol  
Sal meter ol  
Ol o dater ol  
I n dacater ol 
Oral  β 2-A g o nists:  
S h or t-Acti n g  
L o n g -Acti n g  
6 H o urs 2 4 H o urs  
Tra ns der mal  β 2-A g o nists  
2 4  H o urs  
I n hale d S A M A  (I pratr o pi u m) 
6  H o urs  
I n hale d L A M A,  I ncl u di n g L A M A/ L A B A  a n d I C S/ L A M A 
C o m bi nati o n  Pr o d ucts  
Ac lidi ni u m  
Ti otr o pi u m  
Gl yc o p yrr olate  
U mecli di ni u m  
 
 
1 2 H o urs  
2 4 H o urs  
2 4 H o urs  
2 4 H o urs  
Xa nt hi nes  
T wice Dail y  
O nce  Dail y  
 
1 2 H o urs  
2 4 H o urs  
R ofl u milast  
2 4  H o urs  
E p he dri ne -C o ntai ni n g  Dr u gs  
6  H o urs  
Le u k otrie ne  Rece pt or  A nta g o nists  
All o we d  
I C S =  i n hale d c ortic oster oi d; L A B A  =  l o n g-acti n g beta a g o nist; L A M A  =  l o n g-acti n g m uscari nic a nta g o nist ; 
N A  =  n ot a p plica ble; S A B A  =  s h ort-acti n g beta a g o nist; S A M A  =  s h ort-acti n g m uscari nic a nta g o nist.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 5  of 1 5 5  
 
6.  
S T U D Y P R O C E D U R E S  
A St u d y Sc he d ule of E ve nts is pr o vi de d i n  Ta ble  6 .  
6. 1.  
Scree ni n g Peri o d  
T he scree ni n g peri o d is fr o m Da y  -4 2t o Da y  -1.  D uri n g t h is scree ni n g peri o d, t he pr oce d ures 
a n d assess me nts re q uire d at Visit 1 will be perf or me d.  
6. 1. 1.  
Visit 1 ( D a ys -4 2 t o -1)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Scree ni n g.  
 I nf or me d c o ns e nt 
 Re vie w of eli gi bilit y crit eria  
 De m o gra p hic i nf or mati o n  
 Hei g ht, w ei g ht a n d B MI calc ulati o n  
 S m o ki n g hist or y  
 Rel e va nt me dical hist or y re vie w  
 P h ysical e x a mi nati o n  
 Vital si g ns  ( B P, H R, T, a n d res pirati o n rat e [ R R]) 
 1 2 -lea d E C G  
 P F T b y spir o m etr y  
 C hest C T Sca n (to be perf or me d o nl y if t he s u bject d oes n ot ha ve pri or ra di ol o gical 
c o nfir mati o n of br o n c hie ctasis dia g n osis)  
 Cli nical la b orat or y  tests ( he mat ol o g y, bl o o d c he mistr y a n d uri nal ysis) 
 S pecial la b orat or y t ests ( ie, C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 H e patitis B s urface a nti ge n (H Bs A g ), HI V, a n d He p C A b  
 Ser u m pre g na n c y test f or W O C B P  
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d 
ot her  bi o mar kers . 
 S p ut u m micr o bi ol o g y c ult ure a n d re vie w f or P a  
 eG F R calc ulati o n  
 De ntal e x a mi nati o n  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt me dicati o ns  
 Re vie w a n d d oc u m e nt ati o n of A Es  
 C hil d – P u g h Sc ore ( o nl y f or s u bjects w h ose li ver f u ncti o n tests are a b n or mal a n d 
s us pecte d t o ha ve c hr o ni c li ver disease t o assess f or eli gi bilit y) 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 6  of 1 5 5  
 
6. 2.  
Tre at me nt Peri o d Visits 2 T hr o u g h 9  
6. 2. 1.  
Visit 2 ( B aseli ne, D a y  1) R a n d o miz ati o n  
T he f oll o wi n g pr o ce d ures a n d assess me nts will be perf or me d d uri n g Visit 2.   
 C o nfir m eli gi bilit y pri or t o ra n d o mizati o n  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt me dicati o ns  
 S m o ki n g stat us  
 Vital si g ns  (B P, H R, T, a n d R R)  
 1 2 -lea d E C G   
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis)  
 S pecial la b orat or y t ests ( C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P  
 Re vie w a n d c o nfir mati o n of eli gi bilit y criteria  
 Ra n d o mizati o n b y Me di d ata Bala nce  R T S M  s yste m  
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d  
ot her bi o mar kers  
 Bl o o d a n d u ri ne sa m ple c ollecti o n f or eval u ati n g N E a n d ot her bi o mar kers  
 St u d y dr u g dis pe nsi n g a n d re vie w of d osi n g diar y  
 S G R Q  
 Q O L -B  
 L C Q  
 P ul m o nar y  e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 M e dical R esearc h C o u ncil  Breat hless n ess  Scale assess me nt a n d B SI Calc ul ati o n 
 De ntal h y gi e ne e d ucati o n  
 P K sa m pli n g ( see Ta ble  6 f o ot n ote J f or sa m pli n g details) 
 S p ut u m i n d ucti o n pr oce d ure t o c ollect s p ut u m sa m ple, if nee de d 
6. 2. 2.  
Visit 3 ( Wee k 2, D a y  1 5)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 3.  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 7  of 1 5 5  
 
 Vital si g ns ( B P, H R, T, a n d R R)  
 1 2 -lea d E C G  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C -reacti ve pr otei n a n d pr ot hr o m bi n ti me)   
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d 
ot her bi o mar kers  
 Bl o o d a n d u ri ne sa m ple c ollecti o n f or eval u ati n g N E a n d ot her bi o mar kers  
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d 
 R e vie w of d osi n g diar y  
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 De ntal h y gi e ne ed ucati o n  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
 P K  sa m pli n g (see Ta ble  6 f o ot n ote J f or sa m pli n g details) 
 S p ut u m i n d ucti o n pr oce d ure t o c ollect s p ut u m sa m ple, if nee de d 
6. 2. 3.  
Visit 4 ( Wee k 4, D a y  2 9)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 4.  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  
 Vital si g n s ( B P, H R, T, a n d R R)  
 1 2 -lea d E C G  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P  
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d 
ot her bi o mar kers  
 Bl o o d a n d u ri ne sa m ple c ollecti o n f or eval u ati n g N E a n d ot her bi o mar kers  
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 8  of 1 5 5  
 
 St u d y dr u g dis pe nsi n g a n d re vie w of d osi n g diar y 
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 De ntal h y gi e ne ed ucati o n  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
 P K sa m pli n g (see  Ta ble  6 f o ot n ote J f or sa mpli n g details)  
 S p ut u m i n d ucti o n pr oce d ure t o c ollect s p ut u m sa m ple, if nee de d  
6. 2. 4.  
Visit 5 ( Wee k 8, D a y  5 7)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 5.  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  
 Vital si g ns ( B P, H R, T, a n d R R)  
 1 2 -lea d E C G  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P  
 C ollecti o n  of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d 
 De ntal e x a mi nati o n (ca n be perf or me d ±  7 da ys of visit date)  
 St u d y dr u g dis pe nsi n g a n d re vie w of d osi n g diar y  
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 De ntal h y gi e ne ed ucati o n  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns . 
6. 2. 5.  
Visit 6 ( Wee k 1 2, D a y  8 5)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 6.  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 9 9  of 1 5 5  
 
 S m o ki n g stat us  
 P h ysical ex a mi nati o n  
 Vital si g ns ( B P, H R, T, a n d R R)  
 P F T b y spir o m etr y  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C-reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P  
 Bl o o d a n d u ri ne sa m ple c ollecti o n f or eval u ati n g N E a n d ot her bi o mar kers  
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee ded  
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d 
ot her bi o mar kers  
 St u d y dr u g dis pe nsi n g a n d re vie w of d osi n g diar y  
 S G R Q  
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 De ntal h y gi e ne ed ucati o n  
 Assess me nt of o ral in fecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
 P K  sa m pli n g (see Ta ble  6 f o ot n ote J f or sa m pli n g details) 
 S p ut u m i n d ucti o n pr oce d ure t o c ollect s p ut u m sa m ple, if nee de d  
6. 2. 6.  
Visit 7 ( Wee k 1 6, D a y  1 1 3)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 7.  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  
 Vital si g ns ( B P, H R, T, a n d R R)  
 1 2 -lea d E C G  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 0  of 1 5 5  
 
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d 
 St u d y dr u g di s pe nsi n g a n d re vie w of d osi n g diar y  
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 De ntal h y gi e ne ed ucati o n  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
6. 2. 7.  
Visit 8 ( Wee k 2 0, D a y  1 4 1)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 8.  
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  
 Vital si g ns ( B P, H R, T, a n d R R)  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P  
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d 
 St u d y dr u g dis pe nsi n g a n d re vie w of d osi n g  diar y   
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 De ntal h y gi e ne ed ucati o n  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
6. 2. 8.  
Visit 9 ( Wee k 2 4, D a y  1 6 9, E n d of Tre at me nt)  
T he f oll o wi n g pr oce d ures a n d assess me nts w ill be perf or me d d uri n g Visit 9. 
 Re vie w a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  
 P h ysical e x a mi nati o n  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 1  of 1 5 5  
 
 Vital si g ns ( B P, H R, T, a n d R R)  
 Wei g ht  
 1 2 -lea d E C G  
 P F T b y spir o m etr y  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C -reacti ve pr otei n, pr ot hr o m bi n ti me)  
 Uri ne pre g n a nc y test f or W O C B P   
 Bl o o d a n d u ri ne sa m ple c ollecti o n f or eval u ati n g N E a n d ot her bi o mar kers  
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d 
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d 
ot her bi o mar kers  
 S p ut u m micr o bi ol o g y c ult ure a n d re vie w f or P a  
 e G F R calc ulati o n  
 De ntal e x a mi nati o n (ca n be perf or me d ±  7 da ys of visit date)  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
 R e vie w of d osi n g diar y  
 S G R Q  
 Q O L -B  
 L C Q  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 P K  sa m pli n g (see Ta ble  6 f o ot n ote J f or sa m pli n g details) 
 S p ut u m i n d ucti o n pr oce d ure t o c ollect s p ut u m sa m ple, if nee de d  
6. 2. 9.  
Visit 1 0 ( Wee k 2 8, D a y  1 9 7, E n d of St u d y)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d d uri n g Visit 1 0.  
 Re vie w  a n d d oc u me nt ati o n of A Es  
 Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt  me dicati o ns  
 S m o ki n g stat us  
 Vital si g ns ( B P, H R, T, a n d R R)  
 P h ysical ex a mi nati o n  
 Cli nical la b orat or y tests (h e mat ol o g y, b l o o d ch e mistr y , a n d u ri nal ysis) 
 S pecial la b orat or y t ests ( C-reacti ve pr otei n, pr ot hr o m bi n ti me)  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 2  of 1 5 5  
 
 Uri ne pre g n a nc y test f or W O C B P   
 Bl o o d a n d u ri ne sa m ple c ollecti o n f or eval u ati n g N E a n d ot her bi o mar kers  
 C ollecti o n of uri ne sa m ple f or uri ne pr otei n a n d creati ni ne q ua ntitati ve test t o assess 
re nal f u n cti o n, if nee de d  
 S p ut u m sa m ple c ollecti o n f or s p ut u m c ol or deter mi nati o n a n d e val uati n g N E a n d 
ot her bi o mar kers  
 P ul m o nar y e x acer bati o n s y m pt o m e ntr y a n d re vie w  
 Assess me nt of o ral infecti o n, g i n gi vitis, p eri o d o ntitis, a n d ski n co n diti o ns  
 P K sa m pli n g (see Ta ble  6 f o ot n ote J f or sa m pli n g details) 
6. 2. 1 0.  
U nsc he d ule d St u d y Visits  
S u bjects will be a d vise d t o c o ntact t heir st u d y site s h o ul d t he y feel t heir res pirat or y s y m pt o ms 
are w orse ni n g or if t he y e x perie nce a n A E t hat t h e y m a y c o nsi der relate d t o  t he st u d y dr u g.  T h e 
I n v esti gat or will t he n deci de w het her  t he s u bj ect s h o ul d ha ve a n u nsc h e d ule d st u d y visit t o 
f urt her ass ess t heir res pir at or y s y m pt o ms f or a p ote ntial p ul m o nar y e x acer bati o n or a n y A E 
relate d t o t he st u d y dr u g.  D uri n g t h e u nsc he d ule d visit , it is rec o m me n de d t hat vital si g ns a n d 
safet y la b orat or y tests will be perf or me d; A Es a n d c o nc o mita nt me d icati o ns will be re vie we d; a 
s p ut u m sa m ple will be c ollecte d f or meas uri n g N E c o nce ntr ati o n.  S u bjects will be re mi n de d t o 
c o ntact t he site if s y m pt o ms w orse n a n d  if t he y s us pect t he y ma y be s ufferi n g a p ul m o nar y 
e x acer bati o n.   If p ossi ble, s u bjects will be as ke d t o visit t he site f or a n u nsc he d ule d visit.  If n ot 
p ossi ble, t he I n v esti gat or s h o ul d  e val uate s u bject’s s y m pt o ms b y p h o n e.  
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 3  of 1 5 5  
 
T a ble  6 : 
Sc he d ule of E ve nts  
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y 
Visit  
D a ys -4 2 t o -
1  
D a y  1 
( B aseli ne) 
D a y  1 5  
Wee k 2  
D a y  2 9  
Wee k 4  
D a y  5 7  
Wee k 8  
 
 
D a y  8 5  
Wee k 1 2  
D a y  1 1 3  
Wee k 1 6  
D a y  1 4 1  
Wee k 2 0  
D a y 1 6 9  
Wee k 2 4  
( E O T) 
D a y  1 9 7  
Wee k 2 8  
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 
d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 d a ys ) 
Visit 8  
(±  3 d a ys ) 
Visit 9  
(±  3 d a ys ) 
Visit 1 0  
(±  3 d a ys ) 
O btai n I nf or me d C o nse nt  
X  
 
 
 
 
 
 
 
 
 
De m o gra p hics a n d Me dical 
Hist or y  
X  
 
 
 
 
 
 
 
 
 
S m o ki n g Stat us  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Hei g ht, Wei g ht, a n d B MI 
Calc ulati o n  
X  
 
 
 
 
 
 
 
X a 
 
Vital Si g ns ( B P, H R, T, R R)  
c 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P h ysical E x a mi n ati o n  
X  
 
 
 
 
X  
 
 
X  
X  
P ul m o nar y F u ncti o n Test b y 
S pir o metr y  
X  
 
 
 
 
X  
 
 
X  
 
C hest C T Sca n (if s u bject 
d oes n ot ha ve pri or 
ra di ol o gical c o nfir mati o n of 
br o nc hiectasis dia g n osis)  
X  
 
 
 
 
 
 
 
 
 
1 2 -lea d E C G  
X  
X  
X  
X  
X  
 
X  
 
X  
 
Cli nical La b orat or y Tests 
( He mat ol o g y, Bl o o d 
C he mistr y a n d Uri nal ysis) b,  c 
X  
X c 
X  
X  
X  
X  
X  
X  
X  
X  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 4  of 1 5 5  
 
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y 
Visit  
D a ys -4 2 t o -
1  
D a y  1 
( B aseli ne) 
D a y  1 5  
Wee k 2  
D a y  2 9  
Wee k 4  
D a y  5 7  
Wee k 8  
 
 
D a y  8 5  
Wee k 1 2  
D a y  1 1 3  
Wee k 1 6  
D a y  1 4 1  
Wee k 2 0  
D a y 1 6 9  
Wee k 2 4  
( E O T) 
D a y  1 9 7  
Wee k 2 8  
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 
d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 d a ys ) 
Visit 8  
(±  3 d a ys ) 
Visit 9  
(±  3 d a ys ) 
Visit 1 0  
(±  3 d a ys ) 
S pecial La b orat or y Tests 
( C-Reacti ve Pr otei n a n d 
Pr ot hr o m bi n Ti me)  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
H Bs A g, HI V, a n d He p C A b 
Tests  
X  
 
 
 
 
 
 
 
 
 
Ser u m Pre g na nc y Test d   
X  
 
 
 
 
 
 
 
 
 
Esti mate d Gl o mer ular 
Filtrati o n Rate Calc ulati o n 
per C K D -E PI F or m ula  
X  
 
 
 
 
 
 
 
X  
 
S p ut u m Sa m ple C ollecti o n 
f or S p ut u m C ol or 
Deter mi n ati o n a n d 
E val u ati n g N E a n d Ot her 
Bi o mar kers e 
X  
X  
X  
X  
 
X  
 
 
X  
X  
S p ut u m Micr o bi ol o g y 
C ult ure f or Pse u d o m o nas 
a n d Res ult Re vie w f 
X  
 
 
 
 
 
 
 
X  
 
De ntal E xa mi n ati o n g  
X  
 
 
 
X  
 
 
 
X  
 
Pri or/ C o nc o mita nt 
Me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ra n d o mizati o n h 
 
X  
 
 
 
 
 
 
 
 
Uri ne Pre g na nc y Test d 
 
X  
 
X  
X  
X  
X  
X  
X  
X  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 5  of 1 5 5  
 
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y 
Visit  
D a ys -4 2 t o -
1  
D a y  1 
( B aseli ne) 
D a y  1 5  
Wee k 2  
D a y  2 9  
Wee k 4  
D a y  5 7  
Wee k 8  
 
 
D a y  8 5  
Wee k 1 2  
D a y  1 1 3  
Wee k 1 6  
D a y  1 4 1  
Wee k 2 0  
D a y 1 6 9  
Wee k 2 4  
( E O T) 
D a y  1 9 7  
Wee k 2 8  
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 
d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 d a ys ) 
Visit 8  
(±  3 d a ys ) 
Visit 9  
(±  3 d a ys ) 
Visit 1 0  
(±  3 d a ys ) 
M R C Breat hless ness Scale 
Assess me nt a n d 
Br o nc hiectasis Se verit y 
I n de x Calc ulati o n  
 
X  
 
 
 
 
 
 
 
 
S G R Q C o m pleti o n a n d 
Re vie w i 
 
X  
 
 
 
X  
 
 
X  
 
Q O L -B C o m pleti o n a n d 
Re vie w i 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
L C Q C o m pleti o n a n d 
Re vie w i 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Bl o o d a n d Uri ne Sa m ple 
C ollecti o n f or E val u ati n g 
N E a n d Ot her Bi o mar kers  
 
X c 
X  
X  
 
X  
 
 
X  
X  
P K Sa m pli n g f or I N S 1 0 0 7 j 
 
X  
I nte nse 
P K 
Sa m pli n g  
X  
I nte nse 
P K 
Tr o u g h 
Sa m pli n g  
X  
S parse 
P K a n d 
I nte nse 
P K 
Sa m pli n g  
 
X  
S parse 
P K a n d 
I nte nse 
P K 
Tr o u g h 
Sa m pli n g  
 
 
X  
S parse P K 
a n d 
I nte nse 
P K 
Tr o u g h 
Sa m pli n g  
X  
I nte nse P K 
Sa m pli n g  
St u d y Dr u g Dis pe nse, 
Ac c o u nta bilit y of Ret ur ne d 
Dr u g, a n d Re vie w of D osi n g 
Diar y  
 
X  
X n 
X  
X  
X  
X  
X  
X n 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 6  of 1 5 5  
 
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y 
Visit  
D a ys -4 2 t o -
1  
D a y  1 
( B aseli ne) 
D a y  1 5  
Wee k 2  
D a y  2 9  
Wee k 4  
D a y  5 7  
Wee k 8  
 
 
D a y  8 5  
Wee k 1 2  
D a y  1 1 3  
Wee k 1 6  
D a y  1 4 1  
Wee k 2 0  
D a y 1 6 9  
Wee k 2 4  
( E O T) 
D a y  1 9 7  
Wee k 2 8  
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 
d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 d a ys ) 
Visit 8  
(±  3 d a ys ) 
Visit 9  
(±  3 d a ys ) 
Visit 1 0  
(±  3 d a ys ) 
P ul m o nar y e xac er bati o n 
S y m pt o m E ntr y a n d Re vie w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse E ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
De ntal H y gie ne E d ucati o n k 
 
X  
X  
X  
X  
X  
X  
X  
 
 
Assess me nt of Oral 
I nfecti o n, Gi n gi vitis, 
P eri o d o ntitis, a n d S ki n 
C o n diti o ns (es peciall y 
h y per kerat osis or er yt h e ma 
of pal ms a n d s oles)  l 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
Uri ne Pr otei n a n d Creati ni ne 
Q ua ntitati ve Test a n d Rati o 
Calc ulati o n m  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
C hil d – P u g h S c ore (o nl y f or 
s u bjects w h ose li ver 
f u ncti o n tests are 
a b n or m al a n d s us pect e d t o 
h a ve c hr o nic li v er dis e as e  
t o assess f or eli gi bilit y) 
X  
 
 
 
 
 
 
 
 
 
a W ei g ht o nl y . 
b Cli nical la b orat or y bl o o d sa m ples s h o ul d be c ollecte d i n a faste d state (after a n o ver ni g ht fast f or m or ni n g sa m ple c ollecti o n or at least 4 h o urs wit h o ut f o o d at 
ot her ti mes) if p ossi ble.  Uri nal ysis will be perf or me d usi n g di pstic ks wit h clea n catc h uri n e sa m ples.  
c Vital si g ns a n d cli nical la b orat or y bl o o d sa m ples s h o ul d be c ollecte d pri or t o t he first d ose of t he st u d y dr u g o n Da y  1 . 
d Ser u m a n d uri ne pre g na nc y tests will b e perf or me d f or fe males of c hil d -beari n g p ote ntial o nl y.  
e S u bj ects will be re q u ire d t o pr o vi de a s p ut u m sa m ple d uri n g t he s pecifie d visits.  A s u bj ect ma y n ot u n der g o a s p ut u m i n d ucti o n pr oce d ure d uri n g Scree ni n g 
( Visit 1) t o meet eli gi bilit y (S ecti o n  4. 1. 1 , i ncl usi o n criteri o n 5).  O n Da y  1 , t he s p ut u m sa m ple s h o ul d be c ollecte d pri or t o t he first d osi n g of t he st u d y dr u gs.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 7  of 1 5 5  
 
If a s u bj ect is u na ble t o pr o vi de a s p o nta ne o us s p ut u m sa m pl e d uri n g a n y visit, c hest p h ysi ot hera p y s h o u l d be perf or me d first t o facilitate e x pect orati o n.  If 
c hest p h ysi ot hera p y fails, t he r ec o m me n de d s p ut u m i n d ucti o n pr oce d ure detaile d i n t he pr ot oc ol s h o ul d be perf or me d t o o btai n a s p ut u m sa m ple.   
f S p ut u m micr o bi ol o g y c ult ure f or Pse u d o m o n as  will be per f or me d wit h t he s p ut u m sa m pl e o btai ne d at Scree ni n g.  T he res ult will be re vie we d at B aseli ne a n d 
use d f or ra n d o mizati o n stratifi cati o n.   
g All s u bj ects nee d a de ntal e xa m.  If a s u bj ect states t hat he/s he has n o teet h, a de ntist s h o ul d c o nfir m t hat t he su bj ect has n o teet h a n d/ or i m pla nts s u p p orti n g a 
de nt ure.  A n y de nt ure s ores or a n y ot her pat h ol o g y s h o ul d be n ote d b ut will n ot e xcl u de t he s u bj ect fr o m t he st u d y.  All ot he r s u bj ects w h o meet all i ncl usi o n 
b ut n o ne of t he e xcl usi o n criteria are re q uire d t o ha ve a de nt al e xa mi nati o n t hat i ncl u des a f ull-m o ut h de ntal ra di o gra p h y a n d oral e xa mi nati o n t o e val uate t he 
c o n diti o ns of oral s oft tiss ue, gi n gi va, a n d teet h d uri n g Scre e ni n g.  S u bj ects w h o ha ve t he i ma ges of a f ull -m o ut h de ntal ra di o gra p h y t hat are p erf or me d wit hi n 
6 m o nt hs of Scree ni n g a n d a v aila ble f or re vie w are n ot re q uire d t o ha ve a n ot her de ntal ra di o gra p h y d o ne d uri n g Scree ni n g.  S u bj ects w h o are eli gi ble f or t he 
st u d y will ha ve a de ntal d ee p clea ni n g (scali n g a n d r o ot pla ni n g) bef ore ra n d o mizat i o n.  T he e val uati o n a n d rec or di n g of oral a n d de ntal c o n diti o ns are detaile d 
i n t he st u d y pr ot oc ol.  T he de ntal e xa mi nati o n f or Visits 5 a n d 9 ca n be perf or me d ±  7 da ys of t he visit  date.  
S u bj ects w h o are c o nsi dere d a scree n fail ure f or reas o ns n ot relate d t o t he de ntal e xcl usi o n criteria ( Secti o n  4. 1. 2 , e xcl usi o n criteria 2 9 t hr o u g h 3 2) d o n ot nee d 
t o re p eat t he de ntal e xa mi nati o n if t hey  are  re-scree ne d wit hi n 3 m o nt hs of t he first Scree ni n g visit.  
h Eli gi bilit y s h o ul d be reassesse d pri or t o ra n d o mizati o n at Visit  2 ( Baseli ne).  S u bj ects w h o d o n ot meet all i ncl usi o n/e xcl usi o n criteria will N O T be ra n d o mize d 
a n d will be c o nsi dere d a scree n fail ure.  S u bj ects w h o faile d at Scree ni n g ca n be re-scree ne d u p t o 2 ti mes u p o n S p o ns or a p pr o val. 
i S u bj ects will c o m plete t he S G R Q e ver y 1 2 wee ks a n d t he Q O L -B a n d L C Q e ver y 2  wee ks u ntil Visit  1 0.  S u bj ects will b e re q uire d t o c o m plete all 3 
q uesti o n nai res after t he trai ni n g a n d pri or t o t he a d mi nistrati o n of t he first d ose of t heir assi g ne d st u d y dr u g o n Visit 2 ( D a y  1 ).  T he s u bj ects will c o m plete t he 
q uesti o n naires w hile t he y are i n t he cli nic at eac h of t he st u d y visits a n d at h o me f or t he wee ks i n bet wee n t he st u d y visits.  T he c o m plete d q uesti o n naires 
s h o ul d be re vie we d d uri n g eac h visit.  S u bj ects will be retrai ne d o n h o w t o c o m plete t he q uesti o n naires c orrectl y if nee d e d.   
j F or t he 3 6 s u bj ects w h o partici pate i n t he P K s u b -st u d y, t he P K sa m ples will be c ollecte d t hr o u g h a n i n d welli n g cat heter i nt o vac utai ners wit h K 2E D T A pri or 
t o t he first d ose of t he st u d y dr u gs i n t he m or ni n g o n Da y  1 a n d at 1, 2, 3, 4, 6, 8 h o urs p ost d ose, a n d pri or t o t he m or ni n g d ose d uri n g Visit  4 a n d at 1, 2, 3, 4, 
6, 8 h o urs p ost d ose o n t hat visit  da y; a c ollecti o n ti me wi n d o w of ± 1 0 mi n utes will be per mitte d at eac h ti me p oi nt.  I n a d diti o n, a tr o u g h P K sa m ple ( pre d ose 
of I N S 1 0 0 7) will be c ollecte d at Visits 3, 6, a n d 9.  C ollecti o n of P K sa m ple at visit 1 0 will be d o ne a n yti me eit her pre - or p ost -d ose d uri n g t he visit. F or 
s u bj ects w h o partici pate i n t he P K s u b-st u d y, t he Visit 4 wi n d o w will be ± 5 da ys.  
F or s u bj ects partici pati n g i n t he i nte nsi ve P K s u b st u d y, a meal will be gi ve n after t he 1 -h o ur bl o o d dra w  at Visits 2 a n d 4 (refer t o A p pe n di x 4  f or bl o o d 
sa m pli n g ti mes). 
 F or t he s u bj ects w h o are e nr olle d at sites ha vi n g P K sa m ple pr ocessi n g ca pa bilit y b ut n ot partici pati n g i n t he i nte nsi ve P K s u b -st u d y, 1 P K sa m ple eac h will be 
c ollecte d (eit her pre - or p ost d osi n g o n t he visit da y) at 3 visits of Visits 4, 6, a n d 9, res pecti vel y.  
k De ntal h y gie ne e d ucati o n i ncl u des dail y teet h br us hi n g a n d fl ossi n g.  
l Oral a n d de ntal i ns pecti o n will b e perf or me d b y t he I n vesti gat or at eac h visit.  If t here are a n y si g ns or s y m pt o ms of o ral i nfecti o n, gi n gi vitis, or peri o d o ntitis or 
deteri orati o n of t he pree xisti n g c o n diti o ns t hat warra nt f urt her e val uati o n u p o n I n vesti gat or discreti o n, t he s u bj ect will b e  referre d t o t he st u d y desi g nate d 
de ntist f or f urt her assess me nt.  T he oral a n d de nt al e val uati o n b y t he de ntist f or t he s u bj ect s h o ul d t he n be assesse d t here after o n a n i nter val per t he de ntist 
discreti o n u ntil e n d of t he st u d y.  
 S ki n e xa mi nati o n, es peciall y p al ms a n d s oles, d ors u m of t he ha n ds a n d feet, Ac hilles te n d o n area, k nees, a n d el b o ws,  will be perf or me d b y t he I n vesti gat or at 
eac h visit.  If t here are a n y si g ns or s y m pt o ms of h y per kerat osis or er yt he ma or deteri orati o n of t he pree xisti n g c o n diti o ns t hat warra nt f urt her e val uati o n u p o n 
I n vesti gat or discreti o n, t he s u bj ect will be referre d t o a der mat ol o gist f or f urt her assess me nt.  T he s ki n e val uati o n b y t he der mat ol o gist f or t he s u bj ect s h o ul d 
t he n be assesse d t hereafter o n a n i nter val per t he der mat ol o gist discreti o n u ntil e n d of t he st u d y. 
m  Uri ne pr otei n a n d creati ni ne q ua ntifi cati o n a n d rati o calc ulati o n will be perf or me d o nl y w h e n a s u bj ect is s us pecte d t o ha ve re nal i nj ur y per I n vesti gat or 
d iscreti o n. 
n N o st u d y dr u g dis pe nsi n g at t his Visit . 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 8  of 1 5 5  
 
B P  =  b l o o d p ress ure; B MI =  b o d y m ass in de x; 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 q uati o n; C T  =  co m p ute d to m o gra p h y; 
E C G  =  electr ocar di o gra m; e G F R  =  esti mate d g l o mer ular filtrati o n rate; H Bs A g =  h e patitis  B surface anti ge n; He p C A b  =  h e p atitis C anti b o d y; HI V  =  h u ma n 
im m u n o deficie nc y v ir us; H R  =  h eart rate; L C Q  =  L eicester C o u g h Q uesti o n naire; M R C  =  Me dical Researc h C o u ncil ; N E =  n e utr o p hil elastase; 
P K  =  p har mac o ki netic (s); Q O L -B  =  Q ualit y of Life Q uesti o n naire -Br o nc hiectasis; S G R Q  =  St . Ge or ge’s Res pirat or y Q uesti o n naire ; T = b o d y te m perat ure.


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 0 9  of 1 5 5  
 
7.  
S T U D Y V A RI A B L E S A N D M E T H O D S O F A S S E S S M E N T S  
7. 1.  
Pri m ar y E n d p oi nt V ari a ble  
7. 1. 1.  
Ti me t o Fi rst P ul m o n ar y E x acer b ati o n  
P ul m o nar y e x acer bati o n s y m pt o ms will be c ollect e d a n d re vi e we d t hr o u g h o ut t he st u d y at Visits 
2 t hr o u g h 1 0 (refer t o  Ta ble  6 ).  T he ti me t o first p ul m o nar y e x acer bati o n o ver t he 2 4-wee k 
treat me nt peri o d ( Visits 2 t hr o u g h 9) will be a nal yz e d. 
A p ul m o nar y e x acer bati o n i n t his st u d y is defi n e d as ha vi n g t hree or m ore of t he f oll o wi n g 
s y m pt o ms f or at least 4 8 h o urs res ulti n g i n a p h ysi cia n’s decisi o n t o prescri be a nti bi otics.  
1.  In crease d c o u g h  
2.  In crease d s p ut u m v ol u me or c ha n ge i n s p ut u m c o nsiste nc y  
3.  In crease d s p ut u m p ur ule nce  
4.  In crease d breat hless ness a n d/ o r decreas e d e x ercis e t olera nce 
5.  F ati g ue a n d/ or m alaise  
6.  H e m o pt ysis  
S u bjects o n c hr o nic macr oli de t hera p y w h ose o nl y c ha n ge i n t hera p y is d ose or fre q ue nc y 
a dj ust me nt will n ot meet t he criteria of e x acer bati o n.  
7. 2.  
Sec o n d ar y E n d p oi nt V ari a bles  
7. 2. 1.  
Q u alit y of Life Q ue sti o n n aire-Br o nc hiect asis  
T he Q O L -B is a v ali date d, self -a d mi nistere d p atie nt re p orte d o utc o me ( P R O)  t hat assesses 
s y m pt o ms, f u ncti o ni n g, a n d healt h -rel ate d Q O L f or s u bjects wit h N C F B E (Q uitt ner et al, 2 0 1 5 ; 
Q uitt ner et al, 2 0 1 4 ).  T h e Q O L-B c o nt ai ns 3 7 ite ms i n 8 d o mai ns ( Res pirat or y S y m pt o ms, 
P h ysical F u ncti o ni n g, R ole F u ncti o ni n g, E m oti o nal F u ncti o ni n g, S ocial F u n cti o ni n g, Vitalit y, 
Healt h Perce pti o ns a n d Treat me nt B ur de n).  
T he Q O L -B will be pr o vi de d t o t he st u d y s u bjects i n a n electr o nic f or mat o n a ha n d -hel d  
c o m p uter ta blet aft er ra n d o mizati o n.  S u bjects will be re q uire d t o c o m plete t he Q O L-B  aft er t he 
trai ni n g a n d pri or t o t he a d mi nistrati o n of t he first d ose of t heir assi gne d st u d y dr u g o n Visit  2 
( Da y 1).  S u bjects will c o m plete t he q uesti o n naire directl y o n t h e c o m p uter ta blet e ver y 2  wee ks 
fr o m Visits 2  t hr o u g h 9  (refer t o Ta ble  6 ).  
T he s u bjects will c o m plete t he q uesti o n naire w hil e t he y are i n t he cli nic at eac h of t h e st u d y 
visits a n d at h o me f or t he wee ks i n bet w ee n t he st u d y visits.  It is i m p orta nt f or t he site staff t o 
re mi n d t he s u bjects t o bri n g t heir c o m p uter ta blets wit h t he m t o eac h cli nic visit. 
T he c o m plete d q uesti o n n aires will be re vi e we d d uri n g eac h visit.  S u b jects will be re-trai n e d o n 
h o w t o c o m plete t he q uesti o n naires c orrectl y, if nee de d .  T he Res pir at or y S y m pt o ms D o mai n 
sc ore of t he Q O L-B will be a ssesse d as a sec o n dar y e n d p oi nt.  T he ot h er d o mai n sc ores of t he 
Q O L -B will be assesse d as e x pl orat or y e n d p oi nts . 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 0  of 1 5 5  
 
A har d c o p y of t he Q O L -B a n d t he “ I nstr ucti o ns f or C o m pleti n g t he Q O L -B” will be pr o vi d e d 
se parat el y.  
7. 2. 2.  
P ul m o n ar y F u ncti o n Test  
P ost -br o nc h o dil at or pul m o nar y f u ncti o n test b y s pir o metr y ( F E V 1, F V C, P E F R, a n d F E F2 5 -7 5) 
will be perf or me d p er t he A T S / E R S criteria (Miller et al, 2 0 0 5 ) at Visit 1 ( S cree ni n g), Visit 6, 
a n d Visit 9 (refer t o  Ta bl e  6 ).  S u bjects s h o ul d be pr o vi de d wit h t he detaile d i nstr ucti o n o n h o w 
t o c o n d uct t he F V C ma n e u ver per A T S/ E R S s pir o metr y sta n d ar dizati o n bef ore p erf or mi n g t he 
test.  F orce d ex pirat or y v ol u me i n 1 sec o n d  will be assesse d as a sec o n dar y e n d p oi nt.  T he ot her 
para meters of t he P F T will be assesse d as e x pl orat or y e n d p oi nts.  
S u bjects s h o ul d be a d vise d t o wit h h ol d s h ort -acti n g i n hale d dr u gs (e g, t he β -a g onist 
al b uter ol/sal b uta m ol or t he a ntic h oli ner gic a ge nt i pratr o pi u m br o mi de) wit hi n 6 h o urs pri or t o 
t he test.  L o n g-acti n g β -a g o nist br o nc h o dilat ors ( e g, sal meter ol or f or m oter ol) or l o n g-acti n g 
m uscari nic br o nc h o dilat ors (e g, ti otr o pi u m) or oral t hera p y w it h a mi n o p h ylli ne or sl o w rele ase 
β -a g o nists s h o ul d be wit h hel d f or 1 2 -2 4 h o urs d e pe n di n g o n t he m e dicati o n use d (refer t o  
Ta ble  5 ) f or t he mi ni m u m ti me i nter vals f or a list of restricte d m e dicati o ns) pri or t o t he testi n g.   
S u bjects s h o ul d be a d vise d t o wit h h ol d t he use of t heir i n hale d c ortic oster oi ds at least 2 4  h o urs 
pri or t o t he test.  I n t he e ve nt a s u bject has ta k e n a restricte d me dicati o n d uri n g t he s p ecifie d ti me 
i nter val bef ore t he test, t he test s h o ul d be resc h e d ule d f or a n ot her visit wit hi n t he pr ot oc ol-
s pecifie d visit wi n d o w.  If resc h e d uli n g t he visit is n ot feasi ble f or t h e s u bject, t he test s h o ul d be 
c o n d ucte d as us u al wit h a p pr o priate n ot a ti o n i n t he s o urce d o c u me nts. 
S u bjects s h o ul d be a d vise d t o rest at least 3 0 mi n utes, a n d n ot t o eat a lar ge meal f or at least 
2  h o urs pri or t o t he test.  If a s u bject is sc he d ule d t o ha ve p ul m o nar y re ha bilitati o n o n t he da y of 
t heir visit, t he y s h o ul d be a d vise d t o ha ve t he P F T d o ne bef ore t he re ha bilitati o n o n t hat da y.  
P ost -br o nc h o dilat or s pir o metr y tests will be perf or me d per t he f oll o wi n g i nstr ucti o ns:  
W he n a n i n hale d S A B A is use d,  4 p uffs of al b uter ol, le val b uter ol, or ter b ut ali ne will be 
a d mi nistere d.  A p ost -br o nc h o dilat or P F T will be perf or me d 1 5 t o 3 0 mi n utes after t he 
a d mi nistrati o n of al b uter ol or le val b uter ol.  If a n ot her S A B A is use d, I ns me d s h o ul d be c o ntact e d 
f or f urt her directi o ns. 
W he n a n i n hale d S A M A  is use d, 4 p uffs of ipratr o pi u m will be a d mi nistere d.  A p ost -
br o nc h o dilat or P F T will be perf or me d 3 0 mi n utes after t he a d mi nistrati o n of ipratr o pi u m.  
If a patie nt ca n n ot perf or m a n i n halati o n, t he S A B A or S A M A ca n b e ne b ulize d.  P ul m o nar y 
f u ncti o n tests s h o ul d be perf or me d 3 0 mi n utes after fi nalizati o n of ne b ulizati o n  
If a patie nt use d S A B A i n t he first assess me nt of P F Ts, t he sa me S A B A a n d m o de of 
a d mi nistrati o n s h o ul d be use d i n s u bse q ue nt assess me nts.  If a patie nt use d S A M A i n t he first 
assess me nt of P F Ts, t h e S A M A a n d m o de of a d mi nistrati o n s h o ul d be use d i n s u bse q ue nt 
assess me nts.  
Detaile d i nstr ucti o n o n h o w t o c o n d uct t he s pir o m etr y a n d d oc u me nt t he res ults are pr o vi de d i n a 
se parat e s pir o metr y ma n ual. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 1  of 1 5 5  
 
7. 2. 3.  
Ne utr o p hil El ast ase C o nce ntr ati o n  - S p ut u m  
S p ut u m sa m ples will be c ollecte d at Scree ni n g ( Visit 1), Baseli ne ( Visit 2), a n d Visits 3, 4, 6, 9, 
a n d 1 0 f or me as ure me nt of N E c o nce ntrati o ns (refer t o Ta ble  6 ). 
If a s u bject is u na bl e t o pr o d uce s p ut u m s p o nta ne o usl y d uri n g a n y visit, t he s u bject s h o ul d 
u n der g o a s p ut u m i n d ucti o n pr oce d ure.  T he d etaile d s p ut u m i n d ucti o n pr oce d ure is descri be d i n 
A p pe n di x  1 . 
T he detaile d i nstr ucti o n o n t he s p ut u m sa m ple c ollecti o n, pr ocessi n g a n d s hi p me nt will be 
pr o vi de d i n a se parate la b orat or y ma n ual.  
7. 2. 4.  
R ate of P ul m o n ar y E x a cer b ati o n  
P ul m o nar y e x acer bati o n ( defi n e d b y s y m pt o ms, d urati o n of s y m pt o ms a n d a nti bi otic 
prescri pti o n) will be c oll ecte d a n d re vie we d t hr o u g h o ut t he st u d y at Visits 2 t hr o u g h 1 0 (refer t o 
Ta ble  6 ).  T he rate of p ul m o nar y e x acer bati o ns ( n u m ber of e v e nts per pers o n-ti me) o ver t he 
2 4 -wee k tr eat me nt peri o d will be a nal yze d a n d t h e a nal ysis p o p ulati o n stratifie d b y P a  
c ol o nizati o n stat us a n d mai nte na nce macr oli de a nti bi otic use at Baseli ne.  
P ul m o nar y e x acer bati o ns are defi ne d i n  Secti o n  7. 1. 1 . 
7. 3.  
E x pl or at or y E n d p oi nt V ari a bles  
7. 3. 1.  
Leicester C o u g h Q uesti o n n aire  
T he L C Q is a vali date d P R O q uesti o n naire e val u ati n g c o u g h o n Q O L  i n s u bjects wit h N C F B E  
(M urra y et  al, 2 0 0 9 ).  
T he L C Q c o m prises 1 9 it e ms a n d ta kes 5 t o 1 0 mi n utes t o c o m plete.  Eac h ite m assesses 
s y m pt o ms or t he i m pact of s y m pt o ms o ver t he l ast 2 wee ks o n a 7 -p oi nt Li kert scale.  Sc ores i n 
3  d o mai ns ( p h ysic al, p s yc h ol o gic al a n d social) are calc ul ate d as a m ea n f or eac h d o m ai n (ra n ge  1 
t o 7).  A t otal sc ore (ra n ge 3 t o 2 1) is als o calc ulat e d b y a d di n g t he d o mai n sc ores t o get her.  
Hi g her sc ores i n dicate b etter Q O L . 
T he L C Q will be pr o vi de d t o t he st u d y s u bjects i n a n electr o ni c f or mat o n a ha n d hel d c o m p uter 
ta blet after Ra n d o mizati o n.   S u bjects will be re q uire d t o c o m plete t he L C Q  after t he tr ai ni n g a n d 
pri or t o t he a d mi nistrati o n of t he first d ose of t heir assi g ne d st u d y dr u g o n Vi sit 2 ( Da y 1).   
S u bjects will c o m plete t he q uesti o n naire dir ectl y o n t he c o m p uter ta blet e v er y 2 wee ks fr o m 
Visits 2  t hr o u g h 9  (refer t o Ta ble  6 ).   
T he s u bjects will c o m plete t he q uesti o n naire w hil e t he y are i n t he cli nic at eac h of t h e st u d y 
visits a n d at h o me f or t he wee ks i n bet w ee n t he st u d y visits.   It is i m p orta nt f or t he site staff t o 
re mi n d t he s u bjects t o bri n g t heir c o m p uter ta blets wit h t he m t o eac h cli nic visit. 
T he c o m plete d q uesti o n n aires will  be re vi e we d d uri n g eac h visit.   S u bjects will be re -trai n e d o n 
h o w t o c o m plete t he q uesti o n naires c orrectl y , if nee de d.   
7. 3. 2.  
St . Ge o r ge’s Res pir at or y Q uesti o n n aire  
T he S G R Q is a self -a d mi nistere d P R O wit h 5 0  q uesti o ns desi g ne d t o meas ure a n d q ua ntif y 
healt h -rel ate d healt h stat us i n s u bjects wit h c hr o nic airfl o w li mitati o n (J o nes et al, 1 9 9 1).  T he 
S G R Q ass esses healt h relate d Q O L  b y e val uati n g 3 healt h d o mai ns: S y m pt o ms ( distress  ca use d 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 2  of 1 5 5  
 
b y res pirat or y s y m pt o ms), acti vit y (effects of dist ur ba nces t o m o bilit y a n d p h ysical acti vit y), a n d 
im pact (t he effect of dis ease o n fact ors s uc h as e m pl o y me nt, pers o nal c o n tr ol of o ne’s healt h, 
a n d nee d f or me dic ati o n).  It has b ee n s h o w n t o c orrelate well wit h t he esta blis he d meas ures of 
t he 3 d o mai ns i n s u bjects wit h ast h ma a n d C O P D.  It has als o bee n v ali date d f or use i n N C F B E . 
A c o m p osite t otal sc ore is deri ve d as t he s u m of d o mai n sc ores f or s y m pt o ms, acti vit y, a n d 
i m pact wit h 0 t he best p ossi ble sc ore a n d 1 0 0 t he w orst p ossi ble sc ore.  A re d ucti o n i n sc ore of 
4  u nits is ge nerall y rec o g niz e d as a cli nicall y m ea ni n gf ul i m pr o ve me nt i n Q O L . 
T he S G R Q will be pr o vi de d t o t h e st u d y s u bjects i n a n electr o nic f or mat o n a ha n d hel d c o m p uter 
ta blet after ra n d o mizati o n.   S u bjects will be re q uire d t o c o m plete t he S G R Q after t h e trai ni n g a n d 
pri or t o t he a d mi nistrati o n of t he first d ose of t heir assi g ne d st u d y dr u g o n Visit 2 ( Da y  1) .  
S u bjects will c o m plete t he q uesti o n naire dir ectl y o n t he c o m p uter ta blet at Baseli ne ( Visit 2), 
Wee k 1 2 ( Visit 6) a n d Wee k 2 4 ( Visit 9).  It is i m p orta nt f or t he site staff t o re mi n d t he s u bjects 
t o bri n g t heir c o m p uter ta blets wit h t he m t o eac h cli nic visit.  
T he c o m plete d q uesti o n n aires will be re vi e we d d uri n g eac h visit.  A ns wers t o s o me p ossi ble 
q uesti o ns are pr o vi de d i n t he “ G ui de t o C o m pleti n g t he S G R Q” s ecti o n f oll o wi n g t he 
q uesti o n naire.  T he st u d y c o or di nat or s h o ul d re vi e w t hese g ui deli nes bef or e seei n g s u bj ects t o 
pre pare f or t h eir q uesti o ns.  
7. 3. 3.  
Ne utr o p hil El ast ase C o nce ntr ati o n  –  Bl o o d  
Bl o o d sa m ples will be c ollecte d at Baseli ne ( Visit 2), a n d Visits 3, 4, 6, 9, a n d 1 0 f or 
meas ure me nt of N E c o n ce ntrati o ns (refer t o  T a ble  6 ). 
D etaile d i nstr ucti o n f or t he bl o o d sa m ple c ollecti o n, pr ocessi n g a n d s hi p m e nt will be pr o vi de d i n 
t he site st u d y bi n der. 
7. 3. 4.  
S p ut u m C ol or  
S p ut u m c ol or will b e e val uate d b y t h e In vesti gat or ( m ust be a n M D) a gai nst t he s p ut u m c hart 
de vel o pe d b y M urra y ( M urra y et al, 2 0 0 9 ).  W here p ossi ble, t he sa me I n v esti gat or s h o ul d 
perf or m t he s p ut u m c ol or deter mi nati o n at eac h e v al uati o n f or a s u bject.  T he act ua l c hart will be 
pr o vi de d i n t he site st u d y bi n der.  T he c ol or o n t h e c hart c orres p o n di n g t o t he cl ose st c ol or of t h e 
s p ut u m will be rec or de d i n t he st u d y s o urce d oc u m e nt a n d e C R F.  
S p ut u m sa m ples will be c ollecte d fr o m s u bjects at Visit 1 ( Scree ni n g), Visit  2 ( Baseli ne), Visit s 
3, 4, 6, 9, a n d 1 0 (refer t o  Ta ble  6 ). 
7. 3. 5.  
I nfl a m m at or y Bi o m ar k er Le vels-S p ut u m  
S p ut u m sa m ples will be c ollecte d at Scree ni n g ( Visit 1), Baseli ne ( Visit 2), a n d Visits 3, 4, 6, 9, 
a n d 1 0 f or meas ure me nt of N E c o nce ntrati o ns (refer t o Ta ble  6 : ).  O nl y N E, pr otei nas e 3, a n d 
cat he psi n G will be a n al yze d.  
If a s u bject is u na bl e t o pr o d uce s p ut u m s p o nta ne o usl y d uri n g a n y visit, t he s ubject s h o ul d 
u n der g o a s p ut u m i n d ucti o n pr oce d ure (a s u bj ect ma y n ot u n der g o a s p ut u m i n d ucti o n pr oce d ure 
d uri n g Scree ni n g [ Visit 1] t o meet eli gi bilit y [Secti o n  4. 1. 1 , i ncl usi o n criteri o n 5]).  T he detaile d 
s p ut u m i n d ucti o n pr oce d ure is descri b e d i n A p pe n di x  1 . 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 3  of 1 5 5  
 
D etaile d i nstr ucti o n s o n t he s p ut u m sa m ple c ollecti o n, pr ocess a n d s hi p me nt will be pr o vi de d  i n 
t he site st u d y bi n der 
7. 3. 6.  
I nfl a m m at or y a n d Tiss ue De gr a d ati o n Bi o m a r ker Le vels  - Bl o o d  a n d Uri ne  
B l o o d a n d uri ne s a m ples will be c ollecte d at Baseli ne ( Visit 2), a n d Visits 3, 4, 6, 9, a n d 1 0 f or 
meas ure me nt of i nfla m mat or y a n d tiss ue de gra dati o n bi o mar kers (refer t o Ta ble  6 ). 
N ote:  Sa m ples will o nl y be c ollecte d at sites wit h P K sa m ple pr ocessi n g ca pa bilities.  
T he detaile d i nstr ucti o n f or t he bl o o d sa m ple c ollecti o n, pr ocessi n g a n d s hi p me nt will be 
pr o vi de d i n t he site st u d y bi n der.  
7. 3. 7.  
E x acer b ati o n D ur ati o n  
P ul m o nar y e x acer bati o n s y m pt o ms will be c ollect e d a n d re vi e we d b y t he I n vesti gat or ( m ust be 
a n M D) t hr o u g h o ut t he st u d y at Visits 2 t hr o u g h 1 0 (refer t o Ta ble  6 ).  E x acer bati o ns will be 
defi ne d as d escri be d i n  S ecti o n  7. 1. 1 .  T he t otal d urati o n, i n da ys, of e x acer bati o ns, per s u bject, 
o ver t he 2 4-w ee k tr eat me nt peri o d ( Visits  2  t hr o u g h 9) will be a nal yz e d.   I n vesti gat ors will be 
re mi n de d t o e val uat e t he start a n d e n d dat e of e x acer bati o ns wit h acc urac y, assessi n g t he date 
w he n all t he criteria f or e x acer bati o n were met, a n d t he date w he n a su bject re p ort t hat t heir 
s y m pt o ms ha ve s u bsi de d ( w hic h will n ot c oi nci de wit h t he start a n d e n d date of a nti bi otic 
prescri pti o n i n all cas es) . 
7. 3. 8.  
Resc ue Me dic ati o n Use  
T he fre q u e nc y of res c ue me dicati o ns uses o ver t h e 2 4 -wee k treat me nt peri o d ( Visits  2  t hr o u g h 9) 
will be a nal yze d p er s u bj ect.  Resc ue m e dicati o ns i ncl u de S A B As, S A M As, ne wl y prescri be d 
L A B As, L A M As, a n d o x y ge n (refer t o T a ble  5 ). 
7. 3. 9.  
He alt hc are R es o urce Utiliz ati o n  
Healt hcare res o urce utilizati o n  f or p ul m o nar y e x acer bati o n o ver t he 2 4 -wee k treat me nt peri o d 
( Visits 2 t hr o u g h 9) will be assesse d p er s u bject.  H ealt h care res o urce utilizati o n  will be 
meas ure d b y h os pitaliz ati o ns, i ncl u di n g da y s i n t h e h os pital a n d da ys i n i nte nsi ve care unit s. 
7. 4.  
Br o nc hiect asis Se verit y I n de x  
7. 4. 1.  
Br o nc hiect asis Se verit y I n de x C alc ul ati o n  
Br o nc hi ectasis se verit y i n de x is a sc ori n g s yste m base d o n a c o m bi nati o n of cli nical, ra di ol o gical 
a n d micr o bi ol o gic al feat ures t hat ca n b e use d t o assess s u bjects’ N C F B E  s e verit y.  T he B SI was 
vali date d i n 1 ,3 1 0 s u bjects acr oss 5 E ur o pea n br o nc hiectasis ce nters.  T he B SI has bee n s h o w n 
t o gi ve e x celle nt pr e dicti o ns of m ortalit y a n d h os pital a d missi o ns a n d be pre dicti ve of 
e x acer bati o ns a n d Q O L  gi vi n g a br oa d assess me nt of disease se v erit y (C hal mers et al, 2 0 1 4 ). 
T he B SI sc o re will be cal c ulate d at Baseli ne a n d d oc u me nte d i n t he st u d y s o urce d oc u m e nt a n d 
e C R F.  T he act ual B SI s c ore cal c ulati o n is descri b e d i n A p pe n di x  2 . 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 4  of 1 5 5  
 
7. 5.  
Ot her St u d y Assess me nts  
7. 5. 1.  
Me dic al Hist or y  
Rele va nt me dical hist or y will be o btai ne d fr o m eac h s u bject at Visit 1 ( Scree ni n g) a n d 
d oc u me nte d i n t he st u d y s o urce d oc u m e nt a n d e C R F.  Rele va nt me dical hist or y will i ncl u de 
o n g oi n g me dicati o ns, c o m or bi dities, a n d ot her hist orical diseases or treat m e nts deter mi ne d t o be 
cli nicall y si g nifica nt i n t he o pi ni o n of t he I n vesti gat or.   D uri n g t he st u d y, a n y n e w me dical 
i nf or mati o n dee me d rele va nt t o me dical hist or y b y t he I n v esti gat or will be d oc u me nte d i n t he 
st u d y s o urce d oc u me nt a n d e C R F.  
7. 5. 2.  
S m o ki n g Hist or y a n d St at us  
T he s m o ki n g hist or y a n d stat us f or eac h s u bject will be o btai ne d at eac h st u d y Visit ( 1 t hr o u g h 
1 0).  
S u bject s m o ki n g hist or y will be e val uate d a n d gr o u pe d i nt o t hree cate g ories base d o n t heir 
res p o nse t o t he f oll o wi n g; C urre nt S m o ker, F or mer S m o ker, a n d Ne v er S m o ker (C D C -N C H S, 
2 0 1 7 ).   
S u bjects w h o re p ort s m o ki n g at least 1 0 0 ci garettes i n t heir lifeti me a n d w h o, at t he ti me of t he 
s ur ve y, s m o ke eit her e ver y d a y or occasi o nall y are defi ne d as a C urre nt S m o ker.  S u bjects w h o 
re p orte d s m o ki n g at least 1 0 0 ci garettes i n t heir lifeti me a n d w h o, at t he ti me of t he s ur ve y, d o 
n ot s m o ke at all are d efi n e d as a F or mer S m o ker.  S u bjects w h o re p ort ne v er ha vi n g s m o k e d 
1 0 0  ci garettes are d e fi ne d as Ne ver S m o ker.  S u bjects w h o are deter mi ne d t o be C urre nt 
S m o kers at Visit 1 ( Scree ni n g) are n ot eli gi ble f or partici pati o n i n t he st u d y a n d will be a d de d 
i nt o t he e C R F as a scree n fail ure.   
F or s u bjects w h o are F or mer S m o ker or C urre nt S m o ker, t h eir s m o ki n g hist or y will be ass esse d 
usi n g t he n u m ber of pac k -year criteri a.   
T he pac k -year is calc ulat e d b y m ulti pl yi n g t he n u m ber of pac ks of ci garett es s m o ke d per da y b y 
t he n u m ber of years t he p ers o n has s m o ke d.  F or e x a m ple, 1 pac k year is e q ual t o sm o ki n g 
1  pac k per da y f or 1 year, or 2 pac ks per da y f or half a year.  S u bject s m o ki n g hist or y will be 
d oc u me nte d i nt o t he st u d y s o ur ce d oc u m e nt a n d t he e C R F.  
7. 5. 3.  
B o d y M ass I n de x  
T he B MI f or eac h s u bject will be o btai ne d at Visit 1 ( Scree ni n g) o nl y.  
T he B MI is  a val ue deri v e d fr o m t he mass ( wei g ht) a n d hei g ht of a n i n di vi d ual s u bject.  T he 
B MI is cal c ulate d as t he b o d y mass ( kil o gra m) di vi de d b y t he s q u are of t he b o d y h ei g ht ( meter), 
a n d is e x presse d i n u nits of k g/ m 2. 
7. 5. 4.  
C o m p ute d T o m o gr a p h y Sc a n  
S u bjects w h o were  di a g n ose d t o ha ve N C F B E  b ut u na ble t o pr o vi de t he ra di ol o gical r e p ort or 
t heir hist orical c hest r a di o gra p hic i ma ge are re q uire d t o ha ve a c hest C T sca n at Visit 1 
( Scree ni n g) t o c o nfir m t h e dia g n osis a n d se verit y of t heir N C F B E  (refer t o Ta ble  6 ).  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 5  of 1 5 5  
 
7. 5. 5.  
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  
T he stat us of eac h c o n c o mita nt me dicati o n ( ie, pre -e xisti n g or ne w) will be d oc u me nte d i n t he 
e C R F.  T he f oll o wi n g i nf or mati o n m ust be rec or de d i n t he e C R F f or eac h c o nc o mita nt 
me dicati o n: ge neric n a m e, r o ute of a d mi nistrati o n, start date, st o p date, d os e, re gi me n a n d 
i n dicati o n.  A n y c ha n ges i n t he dosa ge or re gi me n of a c o nc o mita nt me dicati o n m ust be rec or de d 
i n t he e C R F.  
Re vie w a n d d oc u me nt ati o n of pri or a n d c o nc o mita nt me dicati o ns f or eac h s u bject will be 
c ollecte d fr o m Visit 2  ( Baseli ne, Da y 1) t hr o u g h Visit 1 0 ( E O S , Da y 1 9 7 ), a n d rec or de d i n t he 
st u d y s o urce d oc u me nt a n d e C R F.  At eac h visit, t he I n vesti gat or will assess if t he c o nc o mita nt 
me dicati o ns t he s u bject is ta ki n g are part of t he ori gi nal mai nte na n ce/r elie v er me dicati o ns f or 
N C F B E  or w het her  t he s u bject has starte d ta ki n g a d diti o nal c o nco mita nt me dicati o ns.  T he 
f oll o wi n g i nf or mati o n m ust be rec or de d i n t he e C R F f or eac h of t h e me dicati o ns: dr u g na m e, 
start date, o n g oi n g or e n d date, a n d i n dicati o n. 
C o nc o mita nt pr oce d ures will be c ollecte d fr o m Visit 1  ( Baseli ne, Da y 1) t hr o u g h Visit 1 0 ( E O S , 
Da y  1 9 7 ).  All c o n c o mita nt pr oce d ures m ust be rec or de d i n t he st u d y s o urce d oc u me nt a n d 
e C R F.  T he f oll o wi n g i nf or mati o n m ust be rec or de d i n t he e C R F f or eac h of t he me dical 
pr oce d ure: pr oce d ure n a me, o perati o n date a n d i n dicati o n.  
7. 5. 6.  
Esti m ate d Gl o mer ul a r Filtr ati o n R ate  
T he eG F R calc ul ati o n per C K D -E PI e q u ati o n  will be a nal yz e d f or eac h s u bject at Visit 1 
( Scree ni n g) a n d Visit 9 ( E OT ). 
T he C K D -E PI e q u ati o n  descri be d b el o w will be use d t o calc ulate t h e e G F R of creati ni ne 
cleara nce i n m L / mi n.   
G F R  =  1 4 1 × mi n ( Scr/ κ, 1) α × ma x ( Scr/ κ, 1) -1. 2 0 9 × 0. 9 9 3 A ge × 1. 0 1 8 [if fe male] × 1. 1 5 9 [if 
blac k]  
w here:  
Scr  is t he ser u m creati ni ne i n m g/ d L, 
κ  is 0. 7 f or fe males a n d 0. 9 f or males, 
α  is -0. 3 2 9 f or fe mal es a n d -0. 4 1 1 f or males,  
mi n  i n dicates t he mi ni m u m of Scr/ κ or 1,  
m a x  i n dicates t he ma xi m u m of Scr/ κ or 1. 
7. 5. 7.  
C hil d -P u g h Sc ore  
T he C hil d – P u g h sc ore is use d t o assess t he pr o g n osis of c hr o nic li ver disease.  T he sc ore 
e m pl o ys 5  cli nical meas ures of li ver dise ase.  Eac h meas ure is sc ore d 1  t o 3, wit h 3 i n dicati n g 
m ost se vere dera n ge m e nt.  
T he C hil d -P u g h sc ore will be calc ulate d f or t h ose s u bjects w h ose li ver f u ncti o n tests are 
a b n or mal a n d s us pecte d t o ha ve c hr o ni c li ver disease at Visit 1 ( Scree ni n g) f or t he st u d y 
eli gi bilit y.  
T he C hil d -P u g h sc ori n g a n d C hil d -P u g h class ta bles ca n be f o u n d i n A p pe n di x  3 . 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 6  of 1 5 5  
 
7. 5. 8.  
T ot al Uri ne Pr otei n a n d Uri ne Cre ati ni ne Q u a ntit ati o n  
A uri ne pr otei n t o creati ni ne rati o test will be perf or me d b y t h e st u d y d esi g nate d ce ntr al 
la b orat or y f or t h ose s u bjects w h o are s us pect e d b y t he I n v esti gat or of ha vi n g re nal f u n cti o n 
deteri orati o n d uri n g t he st u d y.  If t h e rati o e x cee ds t he n or mal val ue, a re p eat sa m ple will be 
ta ke n t he ne xt da y or as s o o n as p ossi ble.  If t he rati o re mai ns ele vate d, it s h o ul d be c o nsi dere d a 
p ositi ve res ult.   
I nstr u cti o ns f or c ollecti o n, st ora ge, a n d s hi p me nt of t he uri ne sa m ples will be pr o vi de d i n t he 
cli nical la b orat or y ma n u al . 
7. 6.  
P h ar m ac o ki netic V ari a bles  
7. 6. 1.  
P h ar m a c o ki netic S a m pli n g  
A P K s u b -st u d y will be c o n d ucte d at a sel ect n u m ber of sites.  A ma xi m u m of 3 6 s u bjects w h o 
e nr oll i n t he selecte d sites will u n der g o i nte nsi ve P K sa m pli n g.  T he P K sa m ples will be 
c ollecte d t hr o u g h a n i n d well i n g cat heter i nt o vac utai ners wit h K2E D T A pri or t o first d ose of t he 
st u d y dr u gs i n t he m or ni n g at Visit 2 ( Da y 1) a n d at 1, 2, 3, 4, 6, a n d 8 h o urs  p ost -d ose, a n d pri or 
t o t he m or ni n g d ose d uri n g Visit 4 a n d at 1, 2, 3, 4, 6, a n d 8 h o urs  p ost -d ose o n t hat  visit da y; a 
c ollecti o n ti me wi n d o w of ±  1 0  mi n utes will be per mitte d at eac h ti me p oi nt.  F or s u bjects 
partici pati n g i n t he i nte nsi ve P K s u b st u d y, a meal will be gi ve n after t h e 1 -h o ur bl o o d dra w  at 
Visits 2 a n d 4 (refer t o A p pe n di x 4 f or bl o o d sa m pli n g ti mes).  I n a d diti o n, a tr o u g h P K s a m ple 
( pre-d os e of I N S 1 0 0 7) will be c ollecte d at Visits 3, 6, a n d 9 a n d a P K sa m ple will be c ollecte d 
pre -d ose at  Visit 1 0.  F or s u bjects w h o partici pate i n t he P K s u b -st u d y o nl y, t he visit wi n d o w o n 
Visit 4 will be ± 5 da ys.   Bef ore i nte nsi ve P K sa m pli n g is c o n d ucte d, t he site staff will re vie w 
t he d osi n g diar y t o c o nfir m t hat t he s u bject has ta k e n t heir st u d y dr u g dail y f or t he last 5 da ys.  If 
a d ose is misse d i n t he last 5 da ys, t he s u bject s h o ul d ha ve a n ot her visit a rra n ge d wit hi n t he ne xt 
5 da ys f or t he i nte nsi ve P K sa m pli n g o nce t he mi ni m u m 5 -da y d osi n g re q uire me nt has bee n 
f ulfille d.  A d diti o nall y, f or s u bjects n ot partici pati n g i n t he P K s u b-st u d y, s parse P K sa m pli n g 
will be c o n d ucte d i n s u bjects at all sites wit h P K sa m pl i n g pr ocessi n g ca p a bilit ies.  O ne P K 
sa m ple will be c ollecte d at 3 visits  (Visits 4, 6, a n d 9 ).  T he details of t he P K sa m pli n g sc h e me 
are des cri bed i n A p p e n di x  4 . 
All s u bjects will be a d vise d t o d o t heir best t o ta ke t heir st u d y dr u g ar o u n d t he sa me ti me e ver y 
da y.  A p pr o xi matel y 5 m L  of bl o o d f or t he P K sa m ple will be c ollecte d at eac h P K sa m pli n g 
ti me p oi nt.   
P har mac o ki netic sa m ples will be a nal yze d i n b atc hes o n a n o n g oi n g basis, a n d dr u g 
c o nce ntr ati o n data will be a nal yz e d a n d re vie we d as a c o m p o ne nt of b ot h t he peri o dic i nter nal 
safet y a n d D M C r e vie ws t o c o nfir m t hat I N S 1 0 0 7 s u bject e x p os ures are wit hi n t he e x pecte d 
ra n ges. 
Detaile d i nstr ucti o n f or P K sa m ple c ollecti o n, pr o cessi n g, l a beli n g, st ora ge, a n d s hi p pi n g will be 
pr o vi de d i n a P K ma n ual .  
7. 7.  
S afet y V ari a bles  
Safet y v aria bl es t o be ass esse d i n t his st u d y i ncl u d e vital si g ns, p h ysical e xa mi nati o ns, E C Gs, 
he mat ol o g y a n d bl o o d c h e mistr y val u es, de ntal e x a mi nati o n a n d A Es.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 7  of 1 5 5  
 
7. 7. 1.  
Vit al Si g ns  
Vital si g ns will i ncl u de B P, H R, R R , a n d T .  Vital si g ns will be perf or me d after t he s u bject is 
resti n g at sitti n g or se mi-rec u m be nt p ositi o n f or at least 5 mi n utes at Scree ni n g a n d e ver y st u d y 
visit ( Visits 1  t hr o u g h 1 0) as s pecifi e d i n  Ta ble  6 .  Vital si g ns will be rec or de d i n t he st u d y 
s o urce d oc u m e nt a n d e C R F. 
7. 7. 2.  
P h ysic al E x a mi n ati o n  
A c o m ple te p h ysical e x a mi nati o n will be perf or m e d at Visit 1 ( Scree ni n g), Visit 6 , Visit 9, a n d 
Visit 1 0  (refer t o Ta ble  6 ).   
T he fi n di n gs of eac h e x a mi nati o n will be rec or de d o n t he st u d y s o urce d oc u me nt a n d e C R F.  
A n y cli nicall y si g nifica nt a b n or malities o bser ve d at Visit 1 will be rec or de d as me dical hist or y.   
A n y cli nicall y si g nifica nt a b n or malities n ot prese nt at Visit 1 or deteri orati o n of t he c o n diti o ns at 
Visit 1  will be rec or de d as A Es.  T he p h ysical e xa mi nati o n wi ll i ncl u de: wei g ht ( Visit 1 a n d 
Visit  9  o nl y) a n d hei g ht ( Visit 1 o nl y), ge neral a p peara n ce , h ea d, e yes, ears, n ose a n d t hr oat, 
de ntal, res pirat or y, car di o vasc ular .   
Alt h o u g h t he e v al uati o n of gi n gi va, teet h, a n d s ki n (es peci all y o n p al ms a n d s oles ) is c o nsi dere d 
a part of t he p h ysic al e x a mi nati o n, it is of s pecial i nterest f or t his st u d y, a n d t hese areas will be 
e x a mi ne d at eac h visit a n d m o nit ore d cl osel y t hr o u g h o ut t he st u d y.  A n y fi n di n gs i n t hese areas 
will be c o nsi dere d  A E SIs  i n t his st u d y (see Secti o n  8. 3 ). 
7. 7. 3.  
Electr oc a r di o gr a m  
A 1 2 -lea d E C G will be p erf or me d  after t he s u bject has bee n resti n g f or at l east 5 mi n utes i n 
se mi-rec u m be nt or s u pi ne p ositi o n at Visit 1 ( Scree ni n g), Visit 2 ( Bas eli ne ), Visit 3, Visit 4, 
Visit 5, Visit 7, a n d Visit 9 (refer t o Ta ble  6 ). 
T he date a n d i nter pret ati o n ( n or mal; a b n or mal  –  n ot cli nicall y si g nifica nt; a b n ormal  –  cli nicall y 
si g nifica nt) m ust be rec or de d wit hi n t he E C G pa ge of t he e C R F.  A n y a b n or mal –  cli nicall y 
si g nifica nt fi n di n gs at Baseli ne ( Visit 2, Da y 1) a n d a n y c ha n ges fr o m Baseli ne pri or t o first d ose 
at Visit 2 m ust be rec or de d i n t he me dical hist or y/ c urre nt me di cal c o n diti o ns  pa ges of t he e C R F.  
A n y a b n or mal –  cli nicall y si g nifica nt fi n di n gs ma de after t he Baseli ne visit ( Visit 2) t hat meet 
t he defi niti o n of a n A E m ust be rec or de d o n t he A E  pa ge of t h e e C R F.  
7. 7. 4.  
Cli nic al L a b or at or y Tests  
Cli nical la b ora t or y tests of he mat ol o g y, bl o o d c he mistr y a n d uri nal ysis will be perf or me d via t he 
st u d y desi g nate d ce ntr al la b orat or y at Visit 1  ( Scree ni n g) a n d all st u d y Visits 2 t hr o u g h 1 0 (refer 
t o Ta ble  6 ).  Cli nical la b orat or y bl o o d sa m ples s h o ul d be c ollecte d i n t he faste d state if p ossi ble 
after at least 4 h o urs wit h o ut f o o d.  T he cli nical la b orat or y test para meters are liste d i n  Ta ble  7 . 
A d diti o nal safet y la b orat or y s a m ples ma y be c ollecte d if cli nicall y i n dicate d at t he discreti o n of 
t he I n v esti gat ors.  All ret ests are prefera bl y t o be d o ne b y t h e st u d y d esi g n ate d ce ntr al la b orat or y.  
H o we ver, i n case of a n y safet y c o n cer ns a n d ur ge nc y, t h e I n vesti gat or ma y deci de t o perf or m t he 
retest l ocall y per t h e l ocal r ules.  If a retest is d o ne l ocall y, t he date, ti me of retesti n g a n d res ults 
( val ues, u nits a n d refere n ce ra n ges) will be rec or de d i n t he st u d y s o urce d o c u me nt.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 8  of 1 5 5  
 
He patitis B s urface a nti ge n ( H Bs A g), HI V a n d H C V a nti b o d y tests will be perf or me d at Visit 1 
( Scree ni n g) o nl y via t h e st u d y desi g nate d ce ntr al la b orat or y. 
Uri nal ysis will be perf or me d usi n g uri n e di pstic ks wit h mi d -strea m clea n catc h uri ne s a m ples. 
I nstr u cti o ns f or c ollecti o n, st ora ge a n d s hi p me nt of cli nical la b orat or y sa m ples will be pr o vi de d 
i n t he cli nical la b orat or y ma n ual pr o vi de d  i n t he site st u d y bi n der. 
T a ble  7 : 
Cli nic al L a b or at or y Assess me nts  
He m at ol o g y  
Bl o o d C he mistr y  
Uri n al ysis  
S peci al Tests  
R B C C o u nt  
S o di u m  
Di pstic k  
HI V  
He m o gl o bi n  
P otassi u m  
p H  
H Bs A g  
He mat ocrit  
Calci u m  
S pecific Gra vit y  
He p C A b  
Mea n C or p usc ular 
V ol u me  
C hl ori de  
Pr otei n  
Ser u m Pre g na nc y T ests   
Mea n Cell He m o gl o bi n  
Bl o o d Urea Nitr o ge n  
Gl uc ose  
C -Reacti ve Pr otei n   
Mea n C or p usc ular 
He m o gl o bi n 
C o nce ntrati o n  
Creati ni ne  
Ket o ne  
 
C B C Wit h Differe ntial  
Gl uc ose  
He m o gl o bi n  
Pr ot hr o m bi n Ti me  
Platelet C o u nt  
T otal pr otei n  
Bilir u bi n  
 
 
Al b u mi n  
Ur o bili n o ge n  
  
 
Al kali ne P h os p hatase  
Nitrite  
  
 
Creati ni ne Ki nase  
 
 
  
T otal Bilir u bi n  
Le uc oc ytes  
  
  
As partate 
A mi n otra nsferase/ Gl uta mic 
O xal oacetic Tra nsa mi nase  
Uri ne Pr otei n t o 
Creati ni ne 
Q ua ntificati o n a n d Rati o 
Calc ulati o n *  
  
 
Ala ni ne A mi n otra nsferase  
U -Pr otei n *  
 
 
Uric Aci d  
U -Creati ni ne *  
 
 
L D H  
 
 
 
C h olester ol  
 
 
  
Tri gl yceri des  
 
  
 
Ser u m Bicar b o nate  
 
 
* Uri ne pr otei n a n d creati ni ne q ua ntificati o n a n d rati o calc ul ati o n will  o nl y be perf or me d w he n a s u bj ect is s us pecte d 
t o ha ve re nal i nj ur y per PI discreti o n. 
C B C = c o m plete bl o o d c o u nt; H Bs A g = he patitis B s urface a nti ge n; He p C A b = he patitis C a nti b o d y; HI V = h u ma n 
i m m u n o deficie nc y vir us; L D H = lactate de h y dr o ge nase; R B C = re d bl o o d cell. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 1 9  of 1 5 5  
 
7. 7. 4. 1.  
Pre g n a nc y Test  a n d Re pr o d ucti ve Prec a uti o ns  
A ser u m pre g n a nc y test will be perf or me d o n W O C B P  at Visit 1 ( Scree ni n g).  A uri ne pre g na n c y 
test will be perf or me d o n W O C B P  at Visit 2 ( Bas eli ne, pri or t o first d ose), Visit 4, Visit 5, 
Visit  6, V isit 7, Visit 8, Visit 9 ( E O T)  a n d Visit 1 0 .  S u bjects w h o ha ve a p ositi ve pre g n a nc y test 
at scree ni n g are n ot eli gi ble f or partici p ati o n i n t he st u d y a n d will be a d de d i nt o t he e C R F as a 
scree n fail ure. 
Uri ne pre g n a nc y test kits will be o btai ne d b y sites l ocall y.  Pre g n a nc y test f or h u ma n c h ori o nic 
g o na d otr o pi n s h o ul d ha ve se nsiti vit y ≤ 2 5 mI U/ m L . 
I n t he re p eat-d ose t o xicit y st u dies i n d o gs, testic ular t o xicit y was n ote d.   F ertilit y st u dies i n rat 
s h o we d n o effect o n f ertilit y i n mal e a n d fe male rats.  I n e m br y ofetal de vel o p me ntal t o xicit y 
st u dies mi n or malf or mati o ns a n d variati o ns were n ote d i n t he offs pri n g at m ater nal d oses t hat 
res ulte d i n sli g ht mater n al t o xicit y i n r ats, b ut  n o e m br y o -fetal t o xicit y was n ote d i n ra b bits.  
I N S 1 0 0 7 effects o n fertilit y a n d fet us i n h u ma n are u n k n o w n.  T heref ore, e xtre me preca uti o n 
s h o ul d be ta ke n f or birt h c o ntr ol d uri n g t h e st u d y. 
7. 7. 5.  
De nt al E x a mi n ati o n  
All s u bjects nee d a d e ntal e x a m.  If a s u bject states t hat he/s he has n o teet h, a de ntist s h o ul d 
c o nfir m t hat t he s u bject  h as n o teet h a n d/ or i m pla nts s u p p orti n g a de nt ur e.  A n y d e nt ure s ores or 
a n y ot h er pat h ol o g y s h o ul d be n ote d b ut will n ot e x cl u de t he s u bject fr o m t he st u d y.  All ot her 
s u bjects w h o meet all i ncl usi o n b ut n o ne of t he e x cl usi o n criteria e x ce pt t h e de ntal e x cl usi o n 
criteria are re q uire d t o h a ve a de ntal e x a mi nati o n t hat i ncl u des a f ull -m o ut h  de ntal ra di o gra p h y 
a n d oral e x a mi nati o n t o e val uate t he c o n diti o ns of oral s oft tiss ue, gi n gi va a n d teet h b y t h e st u d y 
desi g nat e d l ocal de ntist  ( prefera bl y a p eri o d o ntist) d uri n g Visit 1 ( Scree ni n g).  S u bjects w h o 
ha ve t he i ma ges of a f ull -m o ut h  de ntal ra di o gra p h y t hat are perf or m e d wit hi n 6 m o nt hs of Visit 1  
(Scree ni n g ) a n d a v aila ble f or re vie w at Visit 1 are n ot re q uire d t o ha ve a n ot her de ntal 
ra di o gra p h y d o n e d uri n g Visit 1.  Peri o d o ntal disease will be e val u ate d usi n g t he L o e a n d Sil ness 
Gi n gi val I n d e x a n d a cat e g orical e v al uati o n of blee di n g o n pr o bi n g ( yes/ n o).  
S u bjects w h o ha ve se v ere peri o d o ntitis at Visit 1 are n ot eli gi ble f or t h e st u d y.  Se vere 
peri o d o ntitis i n t his st u d y is defi ne d as “l oss of cli nical attac h me nt a n d pr o bi n g de pt h ≥ 6  m m o n 
2  or m ore teet h ” (Secti o n  4. 1. 2 , e x cl usi o n criteri o n 3 0).  T he e ntr y criteria i n t he st u d y ha v e bee n 
defi ne d t o e x cl u de s u bjects wit h u n derl yi n g se vere peri o d o ntal c o n diti o ns t hat c o ul d i m pair t he 
a bilit y t o detect a p ot e ntial safet y si g nal or mi g ht p ut t he s u bject at i ncreas e d ris k.   S u bjects w h o 
are eli gi ble f or t he st u d y will ha ve a de ntal d ee p cl ea ni n g (scali n g a n d r o ot pla n ni n g) bef ore 
Visit  2 ( R a n d o mizati o n).   
S u bjects w h o are c o nsi dere d a scree n fail ure f or reas o ns n ot relate d t o t he d e ntal e x cl usi o n 
criteria (Secti o n  4. 1. 2 , e x cl usi o n criteria 2 9 t hr o u g h 3 2) d o n ot nee d t o re p eat t he de ntal 
e x a mi nati o n if t he y are  r e-scree ne d wit hi n 3  m o nt hs of t he first Scree ni n g visit. 
D ur i n g t he st u d y: 
N O T E:  A n y s u bject f o u n d t o ha ve de vel o p e d peri o d o ntal disease or w orse ni n g gi n gi vitis d uri n g 
t he st u d y will recei ve sta n dar d of care b y a q ualifi e d de ntist/ peri o d o ntist.   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 2 0  of 1 5 5  
 
 At ea c h st u d y visit, t he I n vesti gat or will perf or m a n oral s oft tiss u e a n d peri o d o ntal 
e x a m t o assess oral i nfecti o n, g i n gi vitis a n d peri o d o ntitis.  T he In vesti gat or will als o 
q uesti o n w het her t he s u bject has ha d a n y bl ee di n g, pai n or s welli n g of t he g u m tiss ue.  
 If t here are a n y si g ns or s y m pt o ms of oral i nfecti o n, gi n gi vitis or peri o d o ntitis or 
deteri orati o n of t he pre -e xisti n g c o n diti o ns t hat warra nt f urt her e val uati o n u p o n 
I n v esti gat or discreti o n, t he s u bject will be referre d t o t he de ntist f or f urt her 
assess me nt.  T he oral a n d de ntal e va l uati o n b y t h e de ntist f or t he s u bject s h o ul d t he n 
be assesse d t hereafter o n a n i n ter val per t he de ntist’s discreti o n u ntil e n d of t he st u d y.  
 At Visit 5 ( Wee k 8) a n d Visit 9 ( Wee k 2 4), wit h a wi n d o w of ± 7 da ys t o c o m plete, 
a n oral s oft tiss ue a n d peri o d o ntal e x a mi nati o n a n d g u m p oc ket meas ure me nts will be 
perf or me d b y a peri o d o ntist or de ntist.  A n y site t hat has a d diti o nal 2 m m or m ore i n 
p oc ket de pt h will be re -meas ure d al o n g wit h attac h me nt le vel meas ure me nt.  
 If f o u n d t o ha v e pr o gresse d o n t he a vera ge of t he 2 meas ures, t he area will be scale d 
(resc u e t hera p y). 
 If m ore t ha n 3 areas ha ve pr o gresse d or if t he s u bj ect has m ore t h a n 2 teet h wit h 
p oc ket de pt h of ≥ 6 m m, t he n t he st u d y dr u g will be disc o nti n ue d.  T he s u bject will 
be m o nit ore d d uri n g t he re mai n der of t h eir st u d y ti me.  
 If t he s u bject has c o m plete d t heir last visit, t he y will be see n after a n a d diti o nal m o nt h 
t o deter mi ne if t he pr o gressi o n of peri o d o ntal disease has st o p pe d. 
7. 7. 6.  
Der m at ol o gic al Assess me nt  
T he e ntr y criteria i n t he st u d y ha v e bee n d efi ne d t o e x cl u de s u bjects wit h u n derl yi n g 
der mat ol o gi c c o n diti o ns t hat c o ul d i m pair t he a bilit y t o detect a p ote ntial safet y si g n al or mi g ht 
p ut t he s u bject at i ncreas e d ris k.  S pecificall y, t he rele va nt e xcl usi o n criteri a are:  
 Ha ve h y p ot h yr oi dis m, or m y x e d e ma, or c hr o nic l y m p he d e ma, or acr oc ya n osis, or 
li ve d o retic ularis.  If a s u bject has h y p ot h yr oi dis m b ut is c urre ntl y b ei n g treate d, a n d 
T S H a n d/ or T 3/ T 4 are wit hi n n or mal ra n ges, t he s u bject is all o we d i nt o t he  trial.   
 Ha ve ps oriasis or lic h e n pla n us  
 Ha ve Reiter's disease/ kerat o der ma, or bl e n n orr h a gic u m, or "reacti ve art hritis"  
 Ha ve pit yriasis r u bra pilaris, or at o pic der m atitis, or c hr o nic h a n d der matitis, or 
c hr o nic c o nta ct der matitis, or c hr o nic d er mat o p h yt o sis 
 Ha ve c hl or ac n e, or e xte nsi ve verr uca v ul garis, or kerat o der ma cli macteric u m  
 Perf or m e xtre me r u n ni n g or s wi m mi n g, or ot her c hr o nic, re p etiti ve mec ha nical or 
water da m a ge t o pla ntar e pi der mis  
 Are ta ki n g c o n c o mita nt me dicati o ns t hat ma y ca use h y p er kerat os is 
(T N F -α  a nt a g o nists)  
D uri n g t he st u d y:  
 At eac h st u d y visit  ( Visits 3  t hr o u g h 1 0), t h e I n vesti gat or will perf or m a caref ul s ki n 
e val uati o n, es peciall y of t he pal mar a n d pla nt ar s urfaces, t he d orsal s urfaces of t he 


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ha n ds a n d feet, t he  A c hilles te n d o n area,  k nees, a n d el b o ws .  If t here are a n y si g ns or 
s y m pt o ms of h y per kerat osis or er yt h e ma or d eteri orati o n of t he pre -e xisti n g 
c o n diti o ns t hat warra nt f urt her e v al uati o n u p o n I n vesti gat or discreti o n, t he s u bject 
will be referre d t o a der m at ol o gist f or f urt her assess me nt.  T he s ki n e val uati o n b y t he 
der mat ol o gist f or t he s u bject s h o ul d t he n be assess e d t hereafter o n a n i nter val per t he 
der mat ol o gist discreti o n u ntil t he e n d of t he st u d y.  
A n y earl y a n d l ocalize d c ha n ges i n t he e pi der mal la yer of s ki n s uc h as scal i n g or t hic ke ni n g wit h 
mi ni mal s y m pt o ms, i n t he a bse nce of b ullae a n d p ur p ura, s h o ul d be e val uat e d a gai n i n 1  wee k, 
a n d s o o ner if t here are s u bsta ntial c ha n ges.   
S ki n e xf oliati o n or si g ns of s ki n t hic ke ni n g i n t he pal ms, s oles, d ors u m of t he ha n ds a n d feet , 
Ac hilles te n d o n area, k nees , or el b o ws s h o ul d al w a ys warra nt e val u ati o n b y t he der mat ol o gist.  
Disc o nti n uati o n decisi o ns will be ma de b y t h e I n v esti gat or after c o ns ulti n g wit h t he 
der mat ol o gist.  U p o n recei vi n g t he d er mat ol o gist’s e val uati o n, t he I n vesti gat or s h o ul d deci de 
w het her t o c o nti n ue t he s u bject i n t he st u d y or i nitiate earl y disc o nti n uati o n of t he s u bject.   


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8.  
A D V E R S E E V E N T S  
T he I n vesti gat or is r es p o nsi ble f or t he detecti o n a n d d oc u me ntati o n of e ve nts meeti n g t he criteria 
a n d defi niti o n of a n A E  or S A E as pr o vi de d i n t his pr ot oc ol  (Secti o n  8. 1  a n d Secti o n  8. 2 , 
res pecti vel y). 
8. 1.  
Defi niti o n of a n A d verse E ve nt  
A n A E  is a n y u n t o war d me dical occ urre n ce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a me dici nal  pr o d uct a n d w hic h d oes n ot necessaril y ha v e t o h a ve a ca usal 
relati o ns hi p wit h t his treat me nt. 
A n A E ca n t h eref ore b e a n y u nfa v ora bl e a n d u ni nt e n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g, f or ex a m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici n al 
pr o d uct, w het her c o nsi dere d rel ate d t o t he me dici n al pr o d uct or n ot. 
E x a m ples of A Es i ncl u de 1 of t he f oll o wi n g or a c o m bi nati o n of 2  or m ore of t hese fact ors:  
 A ne w si g n, s y m pt o m, ill ness, or s y n dr o me  
 W orse ni n g of a c o nc o mit a nt ill ness  
 A n effect of I P, i ncl u di n g c o m p arat or or c o nc o mita nt me dicati o n  
 A n effect of a n i n v asi ve pr oce d ure re q uire d b y t h e pr ot oc ol  
 A n acci d e nt or i nj ur y  
S ur gical pr o ce d ures t he msel ves are n ot A Es; t he y are t hera pe utic meas ures f or c o n diti o ns t hat 
re q uire s ur ger y.  T h e c o n diti o n f or w hic h t he s ur ger y is re q uir e d is a n A E if it occ urs or is 
detecte d d uri n g t he st u d y peri o d.   Pla n ne d s ur gical meas ures per mitte d b y  t he cli nical st u d y 
pr ot oc ol a n d t he c o n diti o n(s) lea di n g t o t hese meas ures are n ot A Es if t he c o n diti o n was k n o w n 
bef ore t h e start of st u d y treat me nt.  I n t hese cas es, t he c o n diti o n s h o ul d be re p orte d as me di cal 
hist or y.  
8. 2.  
Defi niti o n of a Seri o us A d verse E ve nt  
A n S A E  (e x perie nce) or reacti o n is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose: 
 R es ults i n deat h 
 Is life-t hreate ni n g 
 N O T E:  T he ter m "life -t hreate ni n g" i n t he defi niti o n of "seri o us" refers t o a n 
e ve nt i n w h ic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot 
refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if it were m or e 
se vere. 
 R e q uires i n  s u bject h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
 R es ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y  
 Is a c o n ge nital a n o mal y/ birt h defect 


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Me dical a n d sci e ntific j u d g e m e nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her s it uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y 
life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her o ut c o mes liste d i n t he defi niti o n a b o ve.  T hese s h o ul d 
als o us uall y be c o nsi dere d seri o us.  
E x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic 
br o nc h os pas m; bl o o d d ys crasias , or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; or 
de vel o p me nt of dr u g d e p e n de nc y or dr u g a b us e.   A list of S A Es o bser ve d i n s u bjects treate d wit h 
I P i n cli nical st u dies of I N S 1 0 0 7 is pr o vi de d i n t he I B.  I n vesti gat ors s h o ul d refere nce t he c urre nt 
IB w h e n assessi n g t he e x pecte d ness of a d verse reacti o ns f or re p o rti n g t o Healt h 
A ut h orities/I R B/I n de pe n de nt or I nstit uti o nal Et hics C o m mittee ( I E C)/I n vesti gat ors. 
8. 2. 1.  
Assess me nt of I nte nsit y  
Eac h A E will be gra de d per Nati o nal Ca n cer I nstit ute’s ( N CI) C o m m o n Te r mi n ol o g y Criteria of 
A d verse E v e nt versi o n 4 . 0 ( C T C A E v4 . 0).  All ot her la b orat or y a n d cli nical A Es t hat occ ur i n a 
s u bject will be assesse d f or se verit y a n d classifie d usi n g t he cate g ories b el o w.  
 Gr a de 1  ( Mil d): E ve nt r e q uires mi ni mal or n o treat me nt a n d  d oes n ot i nterfere wit h 
t he s u bject’s dail y acti vities. 
 Gr a de 2  ( M o der ate): E ve nt res ults i n a l o w le vel of i nc o n ve nie nce or c o n cer n wit h 
t he t hera pe utic m eas ur es.  M o derate e ve nts ma y ca use s o me i nterfere n ce wit h 
f u ncti o ni n g. 
 Gr a de 3  ( Se vere): E v e nt i nte rr u pts a s u bject’s us u al dail y acti vit y a n d m a y re q uire 
s yste mic dr u g t hera p y or ot her treat me nt.  Se v ere e ve nts are us uall y i n ca pacitati n g.  
 Gr a de 4  ( Lif e t hre ate ni n g): A n y a d verse dr u g e x perie nce t hat places t he s u bject, i n 
t he vie w of t he I n v esti gat or, at i m me diate ris k of d eat h fr o m t he reacti o n as it 
occ urre d (ie, it d oes n ot i ncl u de a reacti o n t hat ha d it occ urre d i n a m ore se vere f or m, 
mi g ht ha ve ca use d d eat h).  
 Gr a de 5  ( De at h): T he In vesti gat or w h o i de ntifies a n A E will deter mi ne t he ca usalit y 
of eac h  A E base d o n t he te m p oral relati o ns hi p t o a d mi nistrati o n of st u d y dr u g a n d 
cli nical j u d g me nt.  T h e d e gree of certai nt y a b o ut ca usalit y will be gra de d usi n g t he 
cate g ories b el o w.  


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8. 2. 2.  
Assess me nt of C a us alit y  
T he I n vesti gat or w h o i d e ntifies a n A E wil l deter mi ne t he ca usalit y of eac h base d o n t he te m p or al 
relati o ns hi p t o a d mi nistrati o n of st u d y dr u g a n d cli nical j u d g me nt.  T h e de gree of cert ai nt y a b o ut 
ca usalit y will be gra d e d usi n g t he cate g ories b el o w.  
 Defi nitel y Rel ate d:  A reacti o n t hat f oll o ws a re as o na ble te m p oral se q u e nce fr o m 
a d mi nistrati o n of st u d y dr u g; t hat f oll o ws a k n o w n or e x pecte d res p o ns e p atter n t o t he 
st u d y dr u g; t hat disa p pears or decreas es o n cess ati o n or re d ucti o n i n st u d y dr u g d os e; 
a n d/ or t hat rea p pears or w orse ns w he n t h e st u d y dru g is a d mi nistere d.  
 Pr o b a bl y Rel at e d:  A reacti o n t hat f oll o ws a reas o na ble te m p oral se q u e nce fr o m 
a d mi nistrati o n of st u d y dr u g  or t hat f oll o ws a k n o w n or e x pecte d res p o nse patter n t o 
t he st u d y dr u g; a n d/ or t h at c o ul d n ot be reas o na bl y e x plai ne d b y ot her fact ors s uc h as 
u n derl yi n g dise ase, c o m plicati o ns, c o nc o mita nt dr u gs, or c o nc urre nt treat me nts.  
 P ossi bl y Rel ate d:  A reacti o n t hat f oll o ws a reas o na ble te m p oral se q u e nce fr o m 
a d mi nistrati o n of st u d y dr u g; t hat f oll o ws a k n o w n or e x pecte d res p o ns e p atter n t o t he 
st u d y dr u g, b ut t hat c o ul d reas o na bl y h a ve bee n pr o d uce d b y se v eral ot her fact ors 
i ncl u di n g u n derl yi n g dise ase, c o m plicati o ns, c o n c o mita nt dr u gs, or c o n c urre nt 
treat me nts. 
 N ot Rel at e d:  A reacti o n f or w hic h s ufficie nt data e xist t o i n dicate t hat t he eti o l o g y is 
u nrelate d t o t he st u d y dr u g.  
8. 2. 3.  
Assess me nt of O utc o me  
T he I n vesti gat or will rec or d t he o utc o me of t he A E as eit her res ol ve d or o n g oi n g o n t he A E p a ge 
of t he e C R F .  A d v erse e v e nts of u n k n o w n o utc o m e will be c o nsi dere d as o n g oi n g f or p ur p oses 
of A E re p o rti n g. 
8. 3.  
A d verse E ve nts of S peci al I nterest  
8. 3. 1.  
H y per ker at osis  
T he s u bjects’ s ki n will be cl osel y m o nit ore d t hr o u g h o ut t he st u d y , es peciall y pal ms a n d s oles, 
d ors u m of t he ha n ds a n d feet, Ac hilles t e n d o n area, k nees, a n d el b o ws .  S u bjects will be a d vise d 
t o self-m o nit or t heir s ki n , i ncl u di n g s ki n e xf oliati o n, a n d re p ort a n y fi n di n gs.   
If t here are a n y si g ns or s y m pt o ms of h y per kerat osis or er yt he ma or d eteri or ati o n of t he 
pre -e xisti n g c o n diti o ns t hat warra nt f urt her e val u ati o n u p o n I n v esti gat or dis creti o n, t he s u bject 
will be referre d t o a der m at ol o gist f or f urt her assess me nt.  T he s ki n e val uati o n b y t he 
der mat ol o gist f or t he s u bject s h o ul d t he n be assess e d t hereafter o n a n i nter val per t he 
der mat ol o gist discreti o n u ntil t he e n d of t he st u d y.  
A n y earl y a n d l o calize d c ha n ges i n t he e pi der mal la yer of s ki n s uc h as scali n g or t hic ke ni n g wit h 
mi ni mal s y m pt o ms, i n t he a bse nce of b ullae a n d p ur p ura, s h o ul d be e val uat e d a gai n i n 1  wee k, 
a n d s o o ner if t here are s u bsta ntial c ha n ges.  
 Disc o nti n uati o n decisi o ns will be ma de b y t h e I n v esti gat or after c o ns ulti n g wit h t he 
der mat ol o gist.   U p o n recei vi n g t he der mat ol o gist’s e val uati o n, t he PI s h o ul d deci de 


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I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
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C o nfi de ntial  
P a ge 1 2 5  of 1 5 5  
 
w het her t o c o nti n ue t he s u bject i n t he st u d y or dis c o nti n ue s uc h s u bject  earl y.  As a 
g ui da n ce, t he f oll o wi n g are e ve nts, i ncl u di n g b ut n ot li mite d t o, t h ose t hat s h o ul d 
tri g ger a der mat ol o gi cal e val uati o n:   
 Si g ns of s ki n t hic ke ni n g i n t he pal ms, s oles, d ors u m of t he ha n ds a n d feet, 
Ac hilles te n d o n area, k nees , or el b o ws.  
 S ki n e xf oliati o n  
8. 3. 2.  
Peri o d o ntitis/ Gi n gi vitis  
S u bjects’ oral s oft tiss ue, gi n gi va , a n d t o ot h m o bilit y will be cl osel y m o nit ore d at eac h st u d y 
visit ( Visits 3  t hr o u g h 1 0).  S u bjects will als o be a d vise d t o c o n d uct self-m o nit ori n g of t heir oral 
s oft tiss ue, gi n gi va, a n d t o ot h m o bilit y, a n d re p ort a n y fi n di n gs.   
Occ urre nce of gi n gi vitis or peri o d o ntitis or t o ot h l o ose ni n g d uri n g t he st u d y will be c o nsi dere d 
a n A E a n d re p orte d t he s a me as ot her A Es.  H o we ver, i n t he cas e of a s e vere 
peri o d o ntitis/ gi n gi vitis j u d ge d b y t h e I n vesti gat or t o be st u d y dr u g -rel ate d, s u bjects will be 
disc o nti n ue d fr o m t he st u d y.  
8. 3. 3.  
Ot her I nfecti o ns  
S u bjects will be m o nit ore d t hr o u g h o ut t he st u d y f or p ote ntial i nfecti o ns.  Occ urre nce of i nfecti o n 
will be c o nsi dere d a n A E a n d re p ort e d t he sa me as ot her A Es.  I n t he case of a seri o us i nf ecti o n 
de fi ne d as life-t hreate ni n g, re q uiri n g h os pitalizati o n, or re q uiri n g treat me nt wit h I V a nti bi otics, 
s u bjects will be disc o nti n ue d fr o m t he st u d y.  
N ote:  P ul m o nar y e x acer bati o ns d o n ot fall i nt o t his A E SI cate g or y.  
All seri o us i nfecti o ns a n d all s pecific i nf ecti o ns belie ve d t o be ass o ciate d wit h ne utr o pe nia, s uc h 
as s oft tiss ue i nfecti o n a n d uri nar y tract i nfecti o n s h o ul d be e ntere d i n t he i nfecti o n m o d ule of t he 
e C R F.   
W he n a uri nar y tract i nfecti o n is s us pecte d, a uri n e c ult ure s h o ul d be p erf or me d f or c o nf ir mati o n. 


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8. 4.  
Re p orti n g Re q uire me nts  
8. 4. 1.  
Peri o d of O bser v ati o n f or A d verse E ve nts  
F or t he p ur p os es of t his st u d y, t he peri o d of o bser vati o n f or c ollecti o n of a n y A Es will be fr o m  
t he ti me t he s u bject si g ns t he I C F u ntil 3 0 da ys aft er t he fi nal d ose of  st u d y dr u g or t o t he date of 
s u bject’s E O S Visit, w hic he ver date is later.   All A Es will be f oll o we d u ntil t he res ol uti o n or 
sta bilizati o n of t he A E s.  All A Es s h o ul d be rec or de d o n t he A Es F or m of t h e e C R F  a n d s h o ul d 
be o bser ve d u ntil t he res ol uti o n or s ta bilizati o n of t he A Es .  I n t he safet y a nal ysis, A Es t hat occ ur 
bet wee n t he ti me t he s u bj ect si g ns t he I C F f or t he st u d y a n d t he ti me w he n t he s u bject recei ves 
his/ her first d ose will be s u m marize d as me dical hist or y a n d n ot as a T E A E u nless t he e ve nt 
meets t he defi niti o n of a n S A E as defi ne d b el o w.  
8. 4. 2.  
Seri o us A d verse E ve nts  
All S A Es, re gar dless of ca usalit y, m ust be re p orte d t o  Pri me Vi gila nce  o n a S A E  Re p ort F or m 
wit hi n 2 4  h o urs of bec o mi n g a w are of t he e v e nt; c orrecti o ns a n d a d diti o ns are re q uire d t o be  
s u b mitte d wit hi n 4 8 h o urs .  St u d y -s pecifi c S A E re p orti n g i nstr ucti o ns will be pr o vi de d i n a 
se parat e S A E re p orti n g ma n ual. 
U ne x pecte d dr u g -relate d S A Es as assesse d b y S p o ns or  or a ut h orize d pers o n q ualif y f or 
e x pe dite d re p orti n g a n d will be re p orte d t o t he  I R B/I E C, re g ulat or y a ut h orities, partici pati n g 
I n v esti gat ors a n d, if cr oss re p orti n g is re q uire d f or s us pecte d u ne x pecte d S A Es , t o ot her 
st u dies/c o u ntries as well.  Deat hs a n d life-t hreate ni n g e v e nts wit h a n y p ossi ble relati o ns hi p t o a 
st u d y i nter ve nti o n m ust be re p ort e d t o t he Re g ulat or y A ge ncies  b y t ele p h o ne or fa x as s o o n as 
p ossi ble, b ut wit hi n 7  cale n dar da ys of n otificati o n t o I ns me d .  T his i nitial re p ort m ust be 
f oll o we d b y a m ore c o m plete writte n re p ort wit hi n 1 5  cale n dar da ys .  S A Es, i ncl u di n g t h ose t hat 
d o n ot meet re q uire m e nts f or e x pe dite d re p orti n g, a n d all ot her A E s will be re p orte d t o t he 
Re g ulat or y A ge nci es  i n t he I n vesti gati o nal Ne w Dr u g a n n ual re p ort a n d t he Dr u g Safet y U p date 
Re p ort , as a p pr o priate. 
8. 4. 3.  
H y’s L a w  
H y's la w is a r ule of t h u m b t h at a dr u g is at hi g h ris k of ca usi n g a fatal dr u g -i n d uce d li ver i nj ur y 
w he n  gi ve n t o a lar ge p o p ulati o n  if it ca use d cas es of li ver i nj ur y t h at satisfie d certai n criteri a 
w he n gi ve n t o a s maller p o p ulati o n.  If a s u bject h as ele vati o n of A S T or A L T ≥ 3 x  U L N 
t o get her wit h t otal bilir u bi n ( T B L) ≥ 2 U L N wit h o ut a n y ot her reas o n t hat ca n be f o u n d t o 
e x plai n t he c o m bi nati o n of i ncrease d A S T/ A L T a n d T B L  d uri n g t he treat me nt, it will be 
c o nsi dere d a H y’s la w case, a n d nee ds t o b e re p orte d as a S A E.  T h e st u d y dr u g  a d mi nistrati o n 
s h o ul d be disc o nti n ue d.   
Please refer t o A p p e n di x  5  f or f urt her i nstr ucti o n o n cases of H y’s la w. 
8. 4. 4.  
Ot her Re p ort a ble E ve nts  
8. 4. 4. 1.  
Pre g n a nc y  
Al t h o u g h pre g na nc y itself is n ot c o nsi dere d a n A E, a n y pre g na n c y, i ncl u di n g t he pre g na n c y of a 
male  s u bject's fe mal e part ner, t hat occ urs after t he s u bject has si g n e d t he I C F a n d occ urs d uri n g 


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a n y p h ase of t h e st u d y m ust be re p orte d t o Pri me Vi gila nce wit hi n 2 4  h o urs of lear ni n g of t he 
pre g na nc y usi n g t he Cli nical St u d y Pre g na n c y F or m . 
T he st u d y tr eat me nt s h o ul d be disc o nti n ue d a n d t he pre g na n c y o utc o me s h o ul d be f oll o we d t o 
ter m.  T he details of a n y pre g na nc y t er mi nati o n m ust als o be re p orte d, i n cl u di n g details of birt h, 
t he prese n ce or a bse nce of birt h defects, c o n ge nital a b n or malities or mater n al a n d ne w b or n 
c o m plicati o ns, or w het her ter mi nati o n was s p o nta ne o us or v ol u ntar y.  
8. 4. 4. 2.  
O ver d ose  
A n o ver d ose is defi ne d as a d ose greater t ha n t h e d ose assi g n e d t o a s u bject i n t his st u d y as 
descri be d i n  Secti o n  5. 1. 1 .  A n o ver d ose itself is n ot a n A E.  H o we v er, if t he o ver d ose res ults i n 
cli nical si g ns a n d s y m pt o ms, it re q uires a n e x pe dite d re p orti n g as if it is a n S A E.  I n t he cas e of 
a n o ver d ose, t h e I n vesti gat or s h o ul d use cli nical j u d g me nt i n treati n g t he o ver d ose, a n d i nf or m 
t he S p o ns or i m me diatel y.  T he I n vesti gat ors s h o ul d refer t o t he rel e va nt d o c u me nts f or detaile d 
i nf or mati o n re gar di n g war ni n gs, pr eca uti o ns, c o ntr ai n dicati o ns, A Es, a n d ot her si g nifi ca nt data 
pertai ni n g t o t he I P us e d i n t he st u d y.  S uc h d oc u me nts ma y i ncl u de, b ut are n ot li mite d t o, t he 
I B of t he I P.  
8. 5.  
F oll o w -U p of Seri o us A d verse E ve nts  
All S A Es, i ncl u di n g t h ose o n g oi n g at E O S , m ust be f oll o we d u ntil res ol uti o n, sta bilizati o n, or 
u ntil ot her wise e x plai ne d.  
8. 6.  
Re g ul at or y As pects  
T he S p o ns or has a le gal r es p o nsi bilit y t o n otif y t h e F D A, Nati o nal C o m pete nt A ut h orities a n d 
Ce ntral Et hics C o m mittees of t he E ur o p ea n U ni o n, a n d all ot her f orei g n re g ulat or y a ge nci es, as 
well as all sites,  a b o ut t he safet y of t h e dr u g.  T he I n v esti gat or has t he res p o nsi bilit y t o n otif y t he 
l ocal Et hics C o m mittee a b o ut S A Es.  
T he I n vesti gat or(s)/i nstit uti o n(s) will per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w 
a n d re g ulat or y i ns pe cti o n(s), pr o vi di n g  direct access t o s o urce data/ d oc u m e nts.  C o pies of t he 
n otificati o n t o t he et hics c o m mittee m ust be se nt t o t he S p o ns or.  


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9.  
S T A TI S TI C A L M E T H O D S  
9. 1.  
S a m ple Size  
It is e x pecte d t hat p ul m o nar y e x acer bati o ns occ ur at a rate of 1. 2 e v e nts per s u bject year i n t he 
plac e b o gr o u p, c orres p o n di n g t o 4 4. 6 % of t he pl ace b o s u bjects bei n g e v e nt free at 2 4 wee ks.  It 
is e x pecte d t hat 4 0 % m ore e ve nt free s u bjects will be o bser ve d wit hi n t he I N S 1 0 0 7 gr o u ps ( b ot h 
1 0  m g a n d 2 5  m g) c orres p o n di n g t o 6 2. 4 % of t he I N S 1 0 0 7 s u bjects bei n g  e ve nt free at 2 4 w ee ks.  
T he sa m ple siz e calc ulati o n is f or t he first test i n t he hierarc hical testi n g pr oce d ure.  T he hazar d 
rati o use d i n t he sa m ple siz e calc ulati o n is l n( 0. 6 2 4)/l n( 0. 4 4 6) = 0 . 5 8 4.  Ass u mi n g t he 
e x acer bati o n rate i n t he place b o ar m is 1 . 2 e ve nts per s u bject per year, 2 1 6 s u bjects i n t otal, 
ra n d o mize d i n a 1: 1: 1 rati o t o 3 treat me nt ar ms wit h 7 2 c o m pleters per ar m, will yi el d 8 0 % 
p o wer if t he e x pecte d differe n ce i n t he ti me t o t he first e ve nt is 4 0 % aft er 2 4 wee ks of treat me nt 
wit h a t y pe  I err or of 0. 1 u n der a hierarc hical testi n g pr oce d ure .  A p pr o xi matel y 2 4 0 s u bjects 
dia g n ose d wit h N C F B E will be ra n d o mize d t o pr o vi de a p pr o xi matel y 2 1 6 s u bjects t o c o m plete 
t he st u d y, ass u mi n g 1 0 % of t he s u bjects will disc o nti n ue st u d y dr u g bef ore c o m pleti n g 2 4 wee ks 
of treat me nt.  
T he ass u me d bac k gr o u n d e x acer bati o n rate fr o m t he literat ure v aries fr o m a p pr o xi matel y 1 t o 
well a b o ve 1 e x acer bati o n per s u bject per year ( Bar ker et al, 2 0 1 4 ; Serisi er et al, 2 0 1 3 ).  Rece ntl y 
p u blis he d res ults ( De S o yza et al, 2 0 1 6 ) wit h a si milar s u bject p o p ulati o n ( 2 e x acer bati o ns i n 
pri or 1 2 m o nt hs), s h o we d a n e x acer bati o n rate of 1. 4 2 e ve nts per s u bject per year.  Base d u p o n 
t hese rece nt res ults a c o nser vati ve e x acer bati o n rate of 1. 2 was sel ecte d, b ut t o e ns ure s ufficie nt 
sa m ple siz e f or t he st u d y a bli n de d assess me nt of t he bac k gr o u n d rate will be perf or me d.  If t h e 
o bser ve d e x acer bati o n rate is s maller t ha n 1. 2, t he sa m ple siz e wil l be reass esse d.  T he decisi o n 
t o i ncrease t h e sa m ple siz e will be ma de b y t he I ns me d st u d y tea m.  T h e sa m ple siz e will n ot be 
decrease d b ase d o n t he s a m ple siz e reassess me nt res ults.  
9. 2.  
R a n d o miz ati o n a n d Str atific ati o n  
T he ra n d o mizati o n n u m bers will be assi g ne d per t he s u bject n u m bers a n d will be ge n erat e d b y 
t he I N C Researc h statisticia n i n c o ns ultati o n wit h a n I ns me d i n-h o use statisticia n.   
T he ra n d o mizati o n will be stratifie d bas e d o n  w het her : 
1.  t he s p ut u m c ult ure at S cree ni n g is p ositi ve f or P a  a n d  
2.  t he s u bject is o n mai nte na nce use of macr oli des. 
T he ra n d o mizati o n will be desi g n e d t o e ns ure t hat t he treat me nt ar ms are b ala nce d wit hi n t he P K 
s u b-st u d y, s parse P K s u bjects a n d re m ai ni n g st u d y s u bjects.  It is e x pecte d t hat m ost sites will  
e nr oll s mall n u m bers of s u bjects, t heref ore site is n ot a desi g n p ara m eter f or t he ra n d o mizati o n.  
T he ra n d o mizati o n will be gl o b al.  
9. 3.  
A n al ysis  P o p ul ati o ns   
9. 3. 1.  
I nte nt-t o-T re at P o p ul ati o n  
All s u bjects w h o are ra n d o mize d will be i ncl u de d i n t he i ntent -t o-treat (I T T) a nal ysis.  


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9. 3. 2.  
Per -Pr ot oc ol P o p ul ati o n  
All s u bjects w h o are ra n d o mize d a n d c o m plete d t he st u d y wit h o ut a n y maj or de viati o ns will be 
i ncl u de d i n t he per pr ot o c ol ( P P)  a nal ysis.  
9. 3. 3.  
S afet y P o p ul ati o n  
All s u bjects w h o recei ve d at least 1  d ose of t he st u d y dr u gs will be i ncl u d e d i n t he safet y 
a nal ysis.  
9. 3. 4.  
P h ar m a c o ki netic  P o p ul ati o n  
T he P K p o p ulati o n  will c o nsist of all s u bjects w h o recei v e t he I P a n d h a ve at least 1  meas ura ble  
plas ma c o nce ntrati o n.   
F or t he n o n -c o m part me nt al P K a nal ysis, i f a n y s u bjects are f o u n d t o be n o n c o m plia nt i n d osi n g 
sc he d ule or wit h i nc o m pl ete data, a decisi o n will be ma de o n a case -b y -case basis as t o t heir 
i ncl usi o n i n t he a nal ysis, b ut t he data will be pres e nte d i n t he s u bject listi n gs.  
9. 3. 5.  
P h ar m a c o d y n a mi c P o p ul ati o n  
A ll s u bjects w h o recei ve d  at least 1  d ose of t he st u d y dr u gs, h a ve at least 1  pre -d ose a n d 1  
p ost -d ose meas ur e me nt f or N E, or pr otei n ase 3 , or cat he psi n G, or ot her bi o mar kers, a n d  ha ve n o 
maj or pr ot oc ol de viati o ns t hat c o nsi dere d t o i m pact o n t he a nal ysis of t he P D data, will be 
incl u de d i n P D a nal ysis .  
F or t he calc ulati o n of ma xi m u m i n hi biti o n a n d ti me t o ma xi m u m i n hi biti o n f or N E,  or 
pr otei nase  3 , or cat he psi n G, or ot her bi o mar kers,  if a n y s u bjects are f o u n d t o be n o nc o m plia nt i n 
d osi n g sc he d ul e or wit h i nc o m plete data, a decis i o n will be ma de o n a case-b y -case b asis as t o 
t heir i ncl usi o n i n t he a nal ysis, b ut t he data will be prese nte d i n t he s u bject listi n gs. 
T he a vaila ble P D data f or a n y s u bjects e xcl u de d fr o m t he P D a nal ysis set will be prese nte d i n s u bject 
listi n gs o nl y.   O n l y s u bjects i n t he P D a nal ysis set will be i ncl u de d i n t he descri pti ve s u m mar y ta bles. 
9. 4.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hic i nf or mati o n will i ncl u de date of birt h, ge n d er, et h nicit y, a n d race.  De m o gra p hics, 
baseli ne c haracteristics a n d d is p ositi o n will be s u m marize d descri pti vel y b y eac h tr eat me nt ar m, 
a n d f or t he e ntire safet y a n d P K p o p ulati o ns.  Hei g ht a n d wei g ht, w hic h are c o nsi dere d b aseli ne 
c haracteristics a n d d o c u me nte d as part of t h e p h ysical e xa mi nati o n perf or me d at Scree ni n g, a n d 
at t he E O T ( w ei g ht o nl y), will be re p orte d wit h t h e de m o gra p hic i nf or mati o n liste d a b o ve.   
9. 5.  
St atistic al A n al ysis  
9. 5. 1.  
Effic ac y a n d S afet y  
A detaile d statistical a nal ysis pla n ( S A P) f or effi cac y a n d safet y al o n g wit h t heir re p orti n g will 
be de vel o pe d.  T h e S A P  will be fi nalize d a n d a p pr o ve d b y si g n at ure pri or t o t he data base l o c k t o 
preser ve t he i nte grit y of t he statistical a nal ysis a n d st u d y c o n cl usi o ns .  


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9. 5. 1. 1.  
Effic ac y A n al ysis  
T he o verall si g nifica nce l e vel is set at a o ne -si de d 0. 1 0 t o de m o nstrate t he s u peri orit y of 
I N S 1 0 0 7 t o pla ce b o.   
T he first ste p is t o test I N S 1 0 0 7 2 5  m g a gai nst place b o at t he o n e -si de d 0. 1 0 le vel f or t he 
pri mar y a nal ysis a n d if st atisticall y si g nifica nt, I N S 1 0 0 7 1 0  m g will be teste d a gai nst place b o at 
t he o ne-si de d 0. 0 5 le v el f or t he pri mary a n al ysis.   
If I N S 1 0 0 7 2 5 m g is n ot statisticall y si g nifica nt a gai nst place b o f or t h e pri mar y a nal ysis, n o 
f urt her h y p ot hesis testi n g will be c o n d ucte d. 
If o nl y I N S 1 0 0 7 2 5 m g is statisticall y si g nifica nt a gai nst place b o f or t he pri mar y a nal ysis, t he n 
t he f o ur sec o n dar y e n d p oi nts at t he I N S 1 0 0 7 2 5 m g d ose will be teste d a gai nst place b o a n d t he 
t y pe I err or rat e will be c o ntr olle d at t he 1 -si de d al p ha le vel of 0. 0 5 usi n g t h e H ol m-B o nferr o ni 
met h o d.  
If b ot h d oses are statisticall y si g nifica nt a gai nst place b o f or t he pri mar y a n al ysis, t he n t he 
4  sec o n dar y e n d p oi nts at t he I N S 1 0 0 7 2 5 m g d ose will be teste d a gai nst place b o a n d t he 
t y pe I err or rat e will be c o ntr olle d at t he 1 -si de d al p ha le vel of 0. 0 5 usi n g t h e H ol m-B o nferr o ni 
met h o d a n d t he 4 sec o n d ar y e n d p oi nts at t he I N S 1 0 0 7 1 0 m g d ose will be t este d a gai nst place b o 
a n d t he t y p e I err or rate will be c o ntr olle d at t he 1 -si de d al p ha le v el of 0. 0 5 usi n g t he H ol m-
B o nferr o ni met h o d.  
T y pe I err or will n ot be  c o ntr olle d f or t he e x pl orat or y e n d p oi nts, t he p -val u es pr o d uce d f or 
e x pl orat or y e n d p oi nts will be c o nsi dere d d escri pti ve a n d h y p ot hesis ge nerati n g .  
9. 5. 1. 2.  
Pri m ar y E n d p oi nt A n al ysis  
T he pri mar y a n al ysis will i ncl u de I T T p o p ulati o n.  A sec o n dar y a nal ysis will i nc l u de t he P P 
p o p ulati o n e x cl u di n g s u bjec ts wit h maj or pr ot oc ol vi olati o ns.  
T he pri mar y effic ac y e n d p oi nt is t he ti me t o t he first p ul m o nar y e x acer bati o n o ver t he 2 4 -wee k 
treat me nt peri o d.  A n y p ul m o nar y e x acer bati o n i n t he st u d y bet w ee n Visits 2 t hr o u g h 1 0  will be 
acc o u nte d f or i n t he pri m ar y e n d p oi nt, re gar dless of w het her it was ass ociate d wit h a sc he d ule d 
or u nsc he d ule d visit.    
T he n ull h y p ot hesis ass u mes t hat t he ti me t o t he first e xacer bati o n is i n de pe n de nt of treat me nt, 
a n d t he alter nati ve h y p ot hesis  ass u mes t hat t he ti me t o t he first e xacer bati o n is ass ociate d wit h 
treat me nt. 
T he effi cac y a nal ysis of t he ti me t o t he first e xacer bati o n will be perf or me d f or t he I T T 
p o p ulati o n usi n g Ka pla n Meier c ur ves.  T he tr eat me nt c o m paris o n will be ma de usi n g t he 
stratifie d l o g ra n k test f or t he I T T p o p ulati o n.  T he stratificati o n will i ncl u de t he stratificati o n 
fact ors use d f or t he ra n d o mizati o n.  T he ti me t o t he first e x acer bati o n will als o be a nal yze d usi n g 
C o x re gressi o n m o del t o esti mate hazar ds rati o.  
A s u p p orti ve a nal ysis of t he pri mar y efficac y e n d p oi nt will be perf or me d f or t he P P p o p ulati o n 
usi n g t he sa me m et h o ds as f or t he I T T p o p ulati o n.  
T he e x acer bati o n rate will be a nal yz e d f or t he I T T p o p ulati o n stratifie d b y P a c ol o nizati o n stat us 
a n d mai nte na nc e use of macr oli des at Baseli ne.  


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F or t he pri mar y o bjecti ve, al p ha will be c o ntr olle d usi n g a hierarc hical testi n g pr oce d ure testi n g 
t he hi g h d ose a gai nst pla ce b o first a n d t he n, if statisticall y si g nifi ca nt, testi n g t he l o w d os e 
a gai nst place b o.  If f or t he pri mar y a n al ysis o nl y 1 d ose is statisticall y si g nifica nt, t he al p ha will 
be s plit, a n d t he sec o n dar y e n d p oi nts will be teste d o nl y f or t h e statisticall y si g nifica nt d ose.  
Al p ha will be c o ntr olle d f or t he sec o n d ar y e n d p oi nts usi n g t he H ol m -B o nferr o ni me t h o d. 
T he a nal ysis of t he pri mar y e n d p oi nt  a n d t he re p orti n g will be descri be d i n m ore detail i n t he 
S A P.  
9. 5. 1. 2. 1.  Sec o n d ar y E n d p oi nt s A n al ysis  
Sec o n dar y e n d p oi nts of Q O L -B, F E V 1, a n d N E will be a nal yze d usi n g a n al ysis of varia nce; t he 
rate of p ul m o nar y e x acer bati o ns will be a nal yze d usi n g C oc hra n-Ma ntel -Hae nszel statistic s a n d 
will be descri be d i n m ore detail i n t he S A P.  
9. 5. 1. 2. 2.  E x pl or at or y E n d p oi nt s A n al ysis  
T he a nal ysis of t he e x pl orat o r y e n d p oi nts a n d t heir re p orti n g will be des cri be d i n m ore detail i n 
t he S A P. 
9. 5. 1. 3.  
S afet y A n al ysis  
All safet y data will be s u m marize d b y  treat me nt r ecei ve d ( w hic h ma y differ fr o m t he ra n d o mize d 
treat me nt ar m) a n d f or t h e e ntire safet y p o p ulati o n usi n g descri pti ve statistics.  
S u bject dis p ositi o n will be liste d a n d s u m marize d i ncl u di n g t he n u m ber of wit h dra wals a n d t he 
pri mar y reas o n f or wit h dra wal.  S u bjects e x cl u de d fr o m a n y a n al ysis sets will be liste d i ncl u di n g 
t he reas o ns f or e x cl usi o ns.  
All safet y data wil l be liste d f or eac h s u bject a n d s u m marize d a p pr o priatel y.  A d verse e ve nts will 
be c o de d usi n g Me dic al Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) a n d s u m marize d b y 
s yste m or ga n class a n d preferre d t er m.  A d diti o nal s u m maries b y se v erit y ( N CI C T C A E) a n d 
relati o ns hi p t o st u d y treat me nt will be prese nte d.  
All cli nical safet y la b orat or y d ata a n d vital si g ns will be liste d a n d s u m marize d i ncl u di n g 
c ha n ges fr o m Baseli ne.  A n y o ut of ra n ge l a b orat or y meas ure m e nts will be fla g ge d i n t he 
listi n gs.  
Di gital E C G ( d E C G) d at a will be s m o ot he d, a n d t he H R a n d Q Tc F will be deri ve d fr o m t he 
s m o ot he d data at eac h ti me p oi nt.  T he d E C G data will be liste d a n d s u m marize d descri pti vel y; 
o utlier a nal yses f or Q Tc F will als o be perf or me d.  
T he a nal ysis of t he safet y e n d p oi nts an d t heir re p orti n g will be des cri be d i n m ore detail i n t he 
S A P.  
9. 5. 1. 3. 1.  A d verse E ve nts  
A d verse e ve nts will be c o de d usi n g Me d D R A  s yste m or ga n class a n d preferre d ter m.  T h e 
se verit y of A Es will be gra de d per t he N CI C T C A E v 4. 0.   
T he n u m ber a n d p erce nt of s u bjects  wit h A Es will be prese nt e d b y treat me nt a n d d ose gr o u p.   
T he se verit y of A Es, t he relati o ns hi p t o  I P, A Es ca usi n g st u d y disc o nti n uati o n, a n d S A Es will be 
si milarl y pres e nte d.  All A Es re p orte d d u ri n g t he st u d y will be liste d.  Treat me nt e mer ge nt a n d 


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treatme nt -relate d A Es will be ta b ulate d b y b o d y s yste m a n d or ga n cl ass.  Place b o fr o m all 
treat me nts will be po ole d a n d descri b e d . 
9. 5. 1. 3. 2.  Cli nic al L a b or at or y Tests  
T h e res ults of he mat ol o g y, bl o o d c h e mistr y , a n d uri nal ysis will be liste d f or eac h s u bject.  
La b orat or y v al ues o utsi de t he n or mal ra n ges will be fla g ge d.  If a p plica ble, s u m mar y statistics 
( mea n, ra n ge, c h a n ge fr o m Baseli ne) b y treat me nt will be pr o vi de d f or eac h ti me p oi nt.  Baseli ne 
is defi ne d b y la b orat or y val ues fr o m bl o o d a n d uri ne sa m ples c ollecte d pri or t o first d ose d uri n g 
t he Bas eli ne visit.  S u m mar y st atistics of cli nical la b orat or y val u es will be ta b ulate d b y treat me nt 
a n d d ose.  
9. 5. 1. 3. 3.  Vit al Si g ns  
S yst olic a n d diast olic B P , H R , R R, a n d T  will be  liste d f or eac h s u bject.  If a p plica ble, s u m mar y 
statistics ( mea n c ha n ge, perce nt a ge  c h a n ge fr o m B aseli ne, a n d a bs ol ute c h a n ge fr o m B as eli ne) 
b y treat me nt at e ac h ti me p oi nt will be pr o vi de d.  Baseli ne is defi ne d b y vit al si g ns  c ollecte d 
pri or t o first d ose o n Da y  1.  
9. 5. 1. 3. 4.  P h ysic al E x a mi n ati o n  
P ost -B aseli ne fi n di n gs of t he p h ysic al e xa mi nati o ns t hat meet t he criteri a of A Es  will be liste d i n 
t he rele va nt A E listi n gs. 
9. 5. 1. 3. 5.  Electr oc a r di o gr a m  
T he res ults of t he safet y E C G will be liste d f or eac h s u bject.   P ost -baseli ne fi n di n gs of t he E C G 
res ults t hat meet t he criteria of A Es will be liste d i n t he rele va nt A E listi n gs.   If a p plica bl e, 
s u m mar y statistics of E C G res ults will be pr o vi de d.  
9. 5. 2.  
P h ar m a c o ki netic a n d P h ar m a c o d y n a mic A n al ysis  
9. 5. 2. 1.  
P h ar m a c o ki netic  A n al ysis  
F or s u bjects p artici pati n g i n t he P K s u b -st u d y, plas ma c o nce ntr ati o ns of I N S 1 0 0 7 will be liste d 
a n d s u m mariz e d b y d ose le vel of I N S 1 0 0 7 o ver eac h sc he d ule d s a m pli n g ti me usi n g des cri pti ve 
statistics (i ncl u di n g arit h metic mea n, S D, me dia n, mi ni m u m a n d ma xi m u m, ge o m etric  mea n, a n d 
perce nt c oefficie nt of variati o n of t he ge o metric m ea n, as a p pr o priate).  I n di vi d ual plas ma 
c o nce ntr ati o n data vers us ti me will be prese nte d i n  data listi n gs, al o n g wit h gra p hical pl ots of 
i n di vi d ual a n d ge o m etric mea n plas ma c o n ce ntr ati o n-ti me pl ots prese nte d i n li near a n d 
se mi-l o garit h mic scale. 
T he mai n P K e n d p oi nts will be t he f oll o wi n g plas ma P K  para meters deri v e d usi n g 
n o n -c o m part me ntal pri n ci ples usi n g P h oe ni x ™ Wi n N o nli n
®  ( Certara, Pri ncet o n NJ): C ma x , C ss, 
C ma xss , Cmi nss , tma x , tma x ,ss, A U C 0 -8.  Ot her a d diti o nal P K para meters ma y b e esti mate d a n d/ or 
re p orte d.   
Plas ma P K para meters will be  liste d a n d s u m marize d usi n g descri pti ve statistics, as a p pr o priate. 
F or s u bjects n ot partici pati n g i n t he P K s u b -st u d y, s parse P K sa m pli n g will be c o n ducte d i n 
s u bjects at all sites wit h P K sa m pli n g pr ocessi n g ca pa bilities.  I N S 1 0 0 7 plas ma c o nce ntrati o n 


I N S 1 0 0 7 
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data fr o m t his st u d y will be p o o le d wit h data fr o m ot her st u dies f or t he p ur p oses of de vel o pi n g a 
p o p ulati o n  P K  ( P P K) m o del.  After a n a de q u ate str uct ura l m o del is i de ntifie d, c o-variate a nal ysis 
ma y b e perf or me d t o e v al uate t he effect of i ntri nsi c a n d e xtri nsic fact ors o n t he P K m o del 
para meters.  
A ct ual sa m pli n g ti mes a n d I N S 1 0 0 7 plas ma c o nce ntrati o ns fr o m s parse s a m pli n g will be liste d 
b ut n ot s u m mariz e d.  T he m o deli n g o ut p ut will be re p ort e d o utsi de of t he cli nical st u d y re p ort 
(C S R ).   
A detail S A P f or t he P K para meters a n d re p orti n g will be de vel o pe d.  T he P K S A P will be 
fi nalize d a n d a p pr o ve d b y si g nat ur e pri or t o t he d ata base l oc k t o preser ve t he i nte grit y of t he 
statistical a nal ysis a n d st u d y c o n cl usi o ns.  
9. 5. 2. 2.  
P h ar m a c o d y n a mi c A n al ysis  
P har mac o d y na mic p ara m eters t hat are pla n ne d t o be a nal yz e d are N E, pr ot ei nase 3, cat he psi n G, 
A N C a n d ot her bi o mar kers (e g, M O P, interle u ki n 8  [I L-8 ], re g ulate d o n activati o n , n or mal T -cell 
e x presse d a n d secrete d [ R A N T E S ], T N F-α, i nterl e u ki n 1 beta [I L-1 β ], le u k otrie ne B 4 [L T B -4 ], 
m o n oc yte c he m otactic pr otei n 1 [ C C L 2] [ M C P -1 ], i nterle u ki n-6 [ I L-6 ], S 1 0 0 A 1 2, M M P 8, a n d 
M M P 9).  
T he res ults of N E, pr otei nase 3, cat h e psi n G acti vities, A N C, a n d ot her bi o mar kers will be liste d 
b y s u bject a n d ti me p oi nt.  N ote t hat A N C will be i ncl u de d i n b ot h safet y a n d P D -relate d 
a nal ys es.  
T he ti me t o ma x i m u m i n hi biti o n a n d ma xi m u m i n hi biti o n f or N E, pr otei nase 3, cat he psi n G 
acti vities, a n d A N C will be calc ul ate d a n d liste d f or eac h s u bj ect.  
T he N E acti vit y i n s p ut u m a n d bl o o d will be calc ulate d as perce nt i n hi biti o n fr o m t he 
pre -treat me nt acti vit y a n d n or maliz e d b y A N C ( bl o o d o nl y).  Pre-treat me nt val ue is defi ne d as 
t he mea n val ue of N E acti vities at Scree ni n g a n d Baseli ne a n d will be liste d a n d s u m marize d 
t o get her wit h t he A N C m eas ure m e nts. 
Descri pti ve statistics f or N E, pr otei nase 3, cat he psi n G acti vities, A N C, a n d deri ve d acti vit y 
para meters ( ma xi m u m i n hi biti o n a n d ti me t o ma xi m u m i n hi bi ti o n) will be prese nte d b y dos e 
le vels of I N S 1 0 0 7 a n d pl ace b o.  
I n di vi d ual fi g ures of N E, pr otei nase 3, cat he psi n G acti vities a n d A N C vers us ti me will be 
prese nte d wit h all s u bjects o verlai d o n t he sa me pl ot f or eac h d ose le vel (s pa g h etti pl ots).   Mea n 
pl ots vers us ti me will als o be prese nt e d wit h all d ose le vels a n d p o ole d pl ace b o o verl ai d o n t he 
sa me pl ot.  
I N S 1 0 0 7 P D dat a fr o m t his st u d y will be p o o le d wit h data fr o m ot her st u dies f or t he p ur p os es of 
de vel o pi n g a  P P K/ P D  m o del.  C o -variate a nal ysis ma y  b e perf or me d t o e v al uate t he effect of 
i ntri nsic a n d e xtri nsic fact ors o n t he P D m o del para meters.  A sta n d-al o ne M o deli n g a n d 
Si m ulati o n a nal ysis pla n will be writte n f or t he P K/ P D a n d P D m o dels.  T he m o deli n g o ut p ut will  
be re p orte d o utsi de of t he C S R.  
9. 5. 2. 3.  
P h ar m a c o ki netic -P h ar m a c o d y n a mic  A n al ysis  
T he relati o ns hi p bet wee n I N S 1 0 0 7 e x p os ure a n d P D mec ha nistic mar kers of D P P 1 i n hi biti o n ( ie, 
N E, pr otei nase 3  a n d cat he psi n G le vels, or ot her bi o mar kers (e g, A N C, M O P, I L-8, R A N T E S, 


I N S 1 0 0 7 
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T N F -α, I L -1 β , L T B-4, M C P -1, I L -6 , S 1 0 0 A 1 2, M M P 8, a n d M M P 9), will be e x pl ore d 
gra p hicall y.  If a p pr o pri ate, li near or n o nli near m o dels ma y b e use d t o f urt h er descri be t he 
relati o ns hi p bet wee n I N S 1 0 0 7 a n d P D bi o mar kers. 
I n a d diti o n t o t he P K -P D a nal ysis , ot her a nal ysis met h o d ol o gies, s uc h as n o nli near mi x e d -effect 
m o deli n g , ma y be e m pl o ye d t o f urt her c haracterize  t he P K/ P D relati o ns hi p of I N S 1 0 0 7.   
9. 5. 2. 4.  
P h ar m a c o d y n a mi c -P h a r m ac o d y n a mic A n al ysis  
T he relati o ns hi p bet wee n I N S 1 0 0 7 P D bi o mar kers of D P P 1 i n hi biti o n (e g, N E, pr otei nase 3 , a n d 
cat he psi n G le vels) a n d o utc o me meas ures (ie, p ul m o nar y e x acer bati o n, F E V 1, etc.) or ot her 
bi o mar kers ( e g, M O P, I L -8, R A N T E S, T N F -α, I L -1 β , L T B-4, M C P -1, I L -6, S 1 0 0 A 1 2, M M P 8, 
a n d M M P 9) will be e x pl ore d gra p hi call y.  If a p pr o priate, li near or n o nli near m o dels ma y be use d 
t o f urt her des cri be t heir relati o ns hi p. 
I n a d diti o n t o t he P D -P D a nal ysis , ot her a nal ysis met h o d ol o gies, s uc h as n o nli near mi x e d -effect 
m o deli n g , ma y be e m pl o ye d t o f urt her c haracterize  t he PD/ P D  relati o ns hi p of I N S 1 0 0 7.   
9. 6.  
I nteri m A n al ysis  
N o i nteri m a nal ysis is pla n ne d d uri n g t he c o n d uct of t his st u d y.  
9. 7.  
S a m ple Size Re assess me nt  
A bli n de d sa m ple siz e reassess me nt is pla n ne d f or t his st u d y.  T his ass ess me nt will c o m pare t he 
o bser ve d e x acer bati o n rate t o ass u me d bac k gr o u n d e x acer bati o n ra te.  If t h e o bser ve d 
e x acer bati o n rate is s maller t ha n 1. 2, t he sa m ple si ze will be reassesse d.  T h e decisi o n t o i ncrease 
t he sa m ple siz e will be ma de b y t he I ns me d st u d y tea m.  T he sa m ple siz e will n ot be decreas e d 
base d o n t he sa m ple siz e reassess me nt re s ults.  T his a nal ysis is n ot i nte n de d t o c ha n ge a n y as pect 
of t he pr ot oc ol ot her t ha n p ossi bl y i n creasi n g t h e sa m ple siz e.  T he sa m ple siz e will be 
reassess e d w he n u p t o 7 0 % ( n  = 1 6 8) of t he ra n d o mize d s u bjects ha ve c o m plete d st u d y 
treat me nt. 
I n or der t o ens ure t hat t h e st u d y h as at least 8 0 % p o wer at t he c o ncl usi o n of t he trial, 8 7 e ve nts 
will nee d t o be o bser ve d, re gar dl ess of treat me nt gr o u p.  O nce 7 0 % ( n  = 1 6 8) of t he ra n d o mize d 
s u bjects o n trial ha ve c o m plete d st u d y treat me nt, I ns me d a ntici pates t hat at least 7 0 % of t he 
re q uire d s u bjects wit h a n e ve nt, or 6 1 s u bjects wit h a n e ve nt, will ha ve o cc urre d.  T he f or m ula 
f or t he s u g geste d s a m ple siz e will be 𝑌 =  
6 1
𝑥∗2 4 0  w here Y is t he ne w s u g geste d t otal sa m ple 
siz e, x is t he o bser ve d n u m ber of s u bjects wit h a n e ve nt o nce 7 0 % ( n  =  1 6 8) of t he ra n d o mize d 
s u bjects o n trial ha ve c o m plete d st u d y treat me nt, 6 1 is t he n u m ber of s u bjects wit h a n e ve nt t hat 
was e x pecte d t o ha ve o cc urre d o nce 7 0 % of t h e ra n d o mize d s u bjects o n trial ha ve c o m plete d 
st u d y treat me nt, a n d 2 4 0 re pres e nts t he t otal n u m ber of s u bjects b e ra n d o mi ze d base d o n t he 
ori gi nal sa m ple siz e deter mi nati o n.  


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1 0.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  
1 0. 1.  
S o urce D oc u me nts  
St u d y d ata will be c ollecte d o n s o urce d o c u me nts.  T he I n vesti gat or is r es p o nsi ble f or ass uri n g 
t hat c ollecte d data are c o m plete a n d acc urat e.  S o urce d oc u m e ntati o n (t he p oi nt of i nitial 
rec or di n g of a piece of data) s h o ul d s u p p ort data c ollecte d o n t he e C R F.  S o urce d oc u m e nts 
i ncl u de all rec or di n gs of o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p orts a n d 
rec or ds n ecess ar y f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y. 
1 0. 2.  
D at a C ollecti o n a n d C ase Re p ort F or m M o nit ori n g  
All data o btai ne d f or t his st u d y will be e ntere d i n a C o de of Fe deral Re g ulati o ns Title 2 1 
(2 1  C F R ) Part  1 1 -c o m pli a nt Data Ma n a ge me nt S yste m pr o vi de d b y I ns me d or its desi g nee.  
T hese data will be rec or de d wit h a n electr o nic d at a ca pt ur e ( E D C) s yste m usi n g e C R Fs.  T h e 
I n v esti gat or will e ns ure t he acc urac y a n d c o m plet e ness of t he data re p orte d t o t he S p ons or.  All 
data e ntr y, m o dificati o n or deleti o n will be rec or de d a ut o maticall y i n a n el ectr o nic a u dit trail.  
T he I n vesti gat or will pr o vi de access t o his/ her ori gi nal rec or ds t o per mit a re pres e ntati ve fr o m 
t he S p o ns or t o verif y t he pr o per tra ns cri pti o n of data.  Data re p orte d i n t he e C R Fs s h o ul d be 
c o nsiste nt wit h a n d s u bsta ntiate d b y t he s u bject’s me dical rec or d a n d ori gi nal s o urce d o c u me nts.  
T he e C R F data will be m o nit ore d b y t he S p o ns or or desi g n ee.  T h e fi nal, c o m plete d e C R F 
Case b o o k f or eac h s u bject m ust be electr o nicall y si g ne d a n d date d b y t he PI wit hi n t he E D C 
s yste m t o si g nif y t h at t he I n v esti gat or has re vie we d t he e C R F a n d certifies it t o be c o m plete a n d 
acc urate.  
T he S p o ns or  will retai n t he fi nal e C R F dat a a n d a u dit trail.  A c o p y of all c o m plete d e C R Fs will 
be pr o vi de d t o t he I n v esti gat or. 
1 0. 3.  
St u d y Rec or ds Rete nti o n  
St u d y d o c u me nts s h o ul d be retai ne d f or a mi ni m u m of 2  years after t he l ast a p pr o val of a 
mar keti n g a p plicati o n i n a n I nter n ati o nal C o u ncil f or Har m o nisati o n (I C H) re gi o n a n d u ntil t here 
are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or at least 2  years ha ve  
ela pse d si nce t h e f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he I P.  T hese d oc u me nts 
s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y l oc al re g ulati o ns.  N o rec or ds  will 
be destr o ye d wit h o ut t he writte n c o nse nt of I ns me d.  It is t he res p o nsi bilit y of I ns me d t o i nf or m 
t he I n v esti gat or w he n t h ese d oc u me nts n o l o n ger nee d t o be retai ne d. 


I N S 1 0 0 7 
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1 1.  
E T HI C A L C O N SI D E R A TI O N S, C O M P LI A N C E S T A T E M E N T 
A N D R E G U L A T O R Y C O M P LI A N C E  
1 1. 1.  
Et hic al C o nsi der ati o ns  
A c o p y of t he pr ot o c ol, I C Fs, ot her i nf or mati o n t o be c o m plete d b y s u bjects, s uc h as 
q uesti o n naires a n d a n y pr o p ose d a d vertisi n g or recr uit me nt materials, will be s u b mitte d t o t he 
re g ulat or y a ut h orit y(i es) a n d E Cs. 
All  s u bse q ue nt a me n d me nts t o t he pr ot oc ol, i nf or me d c o nse nt d oc u me nts, a n d ot her st u d y 
d oc u me ntati o n refere n ce d a b o ve m ust be s u b mitte d a n d a p pr o ve d i n acc or da nce wit h c o u ntr y 
s pecific re q uire me nts. 
Peri o dic st u d y stat us re p orts, as a p plica ble, will b e s u b mit te d t o t he E Cs i n acc or da nce wit h 
c o u ntr y s p ecific re g ulati o ns.  T he PI will be res p o nsi ble f or o btai ni n g E C a p pr o val of t he a n n u al 
c o nti n ui n g re vi e w t hr o u g h o ut t he d urati o n of t he st u d y.  
T he PI will n otif y t he l ocal E Cs of vi olati o ns fr o m t he pr ot oc ol a n d  S A Es.  
S u bjects will be i nf or me d t hat me dical care will n ot be affecte d b y t heir a gree me nt or ref usal t o 
partici pate i n t his st u d y, a n d t hat t he y are free t o wit h dra w fr o m t he st u d y at a n y ti me wit h o ut 
prej u dice t o t he cli nicia n -patie nt relati o ns hi p.  
1 1. 2.  
G o o d Cli nic al Pr actice  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat ha ve 
t heir ori gi n i n t he Declarati o n of Helsi n ki ( Oct o ber 2 0 1 3), t he I C H c o ns oli date d G ui deli ne E 6 f or 
G o o d Cli nical Practice ( G C P) ( C P M P/I C H/ 1 3 5/ 9 5 ), a n d F D A G C P Re g ul ati o ns: C 2 1 C F R, Parts 
1 1, 5 0, 5 4, 5 6 , a n d 3 1 2 as a p pr o priate.  
T he S p o ns or will e ns ure t hat t he st u d y c o m plies wit h all l ocal, fe deral, or c o u ntr y re g ulat or y 
re q uire me nts as a p plica bl e.  T hr o u g h o ut t he st u d y, t he S p o ns or a n d its desi g nee will w or k wit h 
t he I n v esti gat or(s) t o e ns ure pr o per st u d y pr ot oc ol i m ple me ntati o n a n d a d here nce t o re g ul at or y 
re q uire me nts as liste d i n t he st u d y pr ot oc ol. 
1 1. 3.  
Dele g ati o n of I n vesti g at or D uties  
T he PI s h o ul d e ns ure t hat all pers o ns assisti n g wit h t he st u d y are a d e q uatel y q ualifie d, trai ne d, 
a n d i nf or me d a b o ut t he pr ot oc ol, a n y a me n d me nts t o t he pr ot oc ol, t he st u d y treat me nts, a n d t heir 
st u d y rel ate d d uties a n d f u ncti o ns. 
T he PI s h o ul d mai ntai n a list of s u b -I n v esti gat ors a n d ot her a p pr o priatel y q ualifie d pers o ns t o 
w h o m he/s he has dele gat e d si g nifica nt st u d y relat e d d uties.  
1 1. 4.  
S u bject C o nfi de nti alit y  
T he I n vesti gat ors a n d t h e S p o ns or will preser ve t h e c o nfi de ntialit y of all s u bjects ta ki n g p art i n 
t he st u d y, i n acc or da nce wit h G C P a n d l ocal re g ul ati o ns. 
T he S p o n s or will o bser v e t he r ules lai d d o w n i n t he E ur o pea n Data Pr otecti o n Directi ve 
9 5/ 4 6/ E C o n t he pr otecti o n of i n di vi d uals re gar di n g t he pr ocessi n g of pers o nal data a n d t he free 
m o ve me nt of s uc h data.  


I N S 1 0 0 7 
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Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
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T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y  is mai ntai ne d.  O n t he C R F/e C R F or 
ot her d oc u me nts s u b mitte d t o I ns m e d, s u bjects s h o ul d be i de ntifie d b y a u ni q ue s u bject i de ntifier 
as desi g n ate d b y t he s p o ns or.  D oc u me nts t hat are n ot f or s u b missi o n t o I ns me d I C Fs s h o ul d be 
ke pt i n strict c o nfi de nce b y  t he I n vesti gat or. 
I n c o m plia nce wit h fe deral re g ulati o ns/I C H G C P G ui deli nes , it is re q uire d t hat t he I n v esti gat or 
a n d i nstit uti o n per mit a ut h orize d re pres e ntati ves of t he S p o ns or, of t he re g ulat or y a ge nc y(s), a n d 
t he E C direct access t o re vie w t he s u bject’s ori gi n al me dical rec or ds f or verificati o n of st u d y-
relate d pr oce d ures a n d d ata.  T he I n v esti gat or is o bli gate d t o i nf or m t he s u bject t hat his/ her 
st u d y-relate d rec or ds will be re vie we d b y t he a b o v e-na me d re prese ntati ves wit h o ut vi olati n g t he 
c o nfi de ntialit y of t he s u bject. 
1 1. 5.  
I nf or me d C o nse nt Pr oce d ure 
Bef ore a s u bj ect’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o o btai n freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject, or le gall y acce pta ble re prese ntati ve,  after a de q u ate 
e x pla nati o n of t he ai ms, met h o ds, a ntici pate d be n efits, a n d p ote ntial hazar ds of t he st u d y , a n d 
bef ore a n y pr ot oc ol -s p ecific scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  A le gall y 
acce pta ble re pres e ntati ve is a n i n di vi d ual or ot her b o d y a ut h o rize d u n der a p plica ble la w t o 
c o nse nt, o n be half of a pr os pecti ve s u bject, t o t he s u bject’s partici pati o n i n t he cli nical st u d y.   
T he writte n I C F s h o ul d b e pre pare d i n t he l ocal la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n.  
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt, t he I n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y re visi o n(s) s h o ul d be 
a p pro ve d b y t he E C  pri or t o bei n g pr o vi de d t o p ot e ntial s u bjects.  
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be o btai ne d pri or t o his/ her partici pati o n i n t he 
st u d y, a n d s h o ul d be d o c u me nte d i n t he s u bject’s me dical rec or ds, as re q uire d b y 2 1 C F R 
Part  3 1 2. 6 2.  T he I C F s h o ul d be si g ne d a n d pers o nall y dat e d b y t he s u bject, or a le gall y 
acce pta ble re pres e ntati ve , a n d b y t h e pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n ( n ot 
necessaril y t he I n vesti gat or).  T he ori gi nal si g ne d I C F s h o ul d be ret ai ne d i n acc or da nce wit h 
i nstit uti o nal p olic y, a n d a c o p y of t he si g ne d c o ns e nt f or m s h o ul d be pr o vi de d t o t he s u bject or 
le gal re prese ntati ve.  T he date a n d ti me (if a p plica ble) t hat i nf or me d c o ns e nt was gi v e n s h o ul d be 
rec or de d o n t he C R F. 
1 1. 6.  
Re g ul at or y C o m pli a nce  
I ns me d h as a le gal res p o nsi bilit y t o n otif y t he F D A, n ati o nal co m pete nt aut h orities a n d Ce ntral 
Et hics C o m mittees of t he E ur o pea n U ni o n, a n d all ot her f orei g n re g ulat or y a ge ncies, as well as 
all sites, a b o ut t he safet y of t he dr u g.  
T he st u d y pr ot oc ol, s u bje ct i nf or mati o n a n d c o nse nt f or m, t he I B, a n y s u bject diar y car d or 
writte n i nstr ucti o ns t o be gi ve n t o t he s u bject, a vaila ble safet y i nf or mati o n, s u bject recr uit me nt 
pr oce d ures ( e g, a d vertise me nts), i nf or mati o n a b o ut pa y me nts a n d c o m pe ns ati o n a vaila ble t o t he  
s u bjects, a n d d oc u me ntati o n e vi de nci n g t he I n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o 
t he E C  f or et hical r e vie w a n d a p pr o val acc or di n g t o l ocal re g ulati o ns pri or t o t he st u d y start.  T h e 
writte n a p pr o val s h o ul d i de ntif y all d oc u me nts re vie we d b y  na me a n d versi o n.  


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C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P.  
T he I n vesti gat or m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he E C  a nd/ or I ns me d  
f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d c o ns e nt d oc u me nt or 
c ha n ges of t h e i n vesti gati o nal site, facilities or pers o n nel.  T he I n vesti gat or s h o ul d n otif y t he E C  
of de viati o ns fr o m t he pr ot oc ol or S A Es occ urri n g at t he site a n d ot her A E re p orts recei ve d fr o m  
I ns me d, i n acc or da nce wit h l ocal pr oce d ures. 
As re q uire d b y l o cal re g ulati o ns, I ns me d’s Re g ul at or y Affairs gr o u p will e ns ure all le gal as p ects 
are c o v ere d, a n d a p pr o val of t he a p pr o priat e re g ul at or y b o di es o btai ne d, pri or t o st u d y i nitiati o n, 
a n d t hat i m p le me ntati o n of c ha n ges t o t he i nitial pr ot oc ol a n d ot her rele va nt st u d y d oc u me nts 
ha p pe n o nl y after t he a p pr o priate n otificati o n of or a p pr o val b y t he rele va nt re g ulat or y b o dies.  
T he I n vesti gat or(s)/i nstit uti o n(s) will per mit st u d y relate d m o nit ori n g, a u di ts, I R B/I E C re vie w 
a n d re g ulat or y i ns pe cti o n(s), pr o vi di n g direct access t o s o urce data/ d oc u m e nts.  C o pies of t he 
n otificati o n t o t he E C  m ust be se nt t o t he S p o ns or.  


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1 2.  
S T U D Y A D MI NI S T R A TI V E  I N F O R M A TI O N 
1 2. 1.  
Fi n a nci al Discl os ure  
T he discl ose d fi na n cial i nterest of t he PI m ust be c ollecte d bef ore s cree ni n g of t he first st u d y 
s u bject.  T he PI s h o ul d pr o m ptl y u p date t his i nf or mati o n if a n y rele va nt c ha n ges occ ur d uri n g t he 
st u d y peri o d a n d 1 year f oll o wi n g o verall st u d y c o m pleti o n. 
1 2. 2.  
St u d y Re gistr ati o n a n d Res ults Discl o s ure 
T he S p o ns or ma y pr o vi d e st u d y i nf or mati o n f or i ncl usi o n i n nati o nal re gistries per l ocal 
re g ulat or y re q uire me nts. 
Res ults of t his st u d y will be discl ose d per t he rele va nt nati o nal re g ulat or y re q uire me nts.  
1 2. 3.  
St u d y Files a n d M ateri als  
Bef ore t he start of a n y st u d y relate d pr oce d ures, all i nitial d oc u me nts re q uire d b y I C H G C P, 
G o o d P har mac o e pi de mi ol o g y Practice, a n d a p plica ble l ocal r e g ulati o ns m ust be a vaila ble i n t he 
rele va nt files mai ntai n e d b y t he S p o ns or ( or dele gate) a n d t he I n vesti gat or.  A n I n vesti gat or 
St u d y File pre pare d b y t h e S p o ns or ( or dele gate), c o ntai ni n g all a p plica ble d oc u me nts f or use at 
t he st u d y site, will be ma de a vaila ble t o t he I n vesti gat or b ef ore t he start of t he st u d y.  A list of 
pers o n nel a n d or ga niz ati o ns res p o nsi ble f or c o n d uct o f t he st u d y as well as t he list of 
I n v esti gat ors at e ac h site will be i ncl u de d i n t he I n vesti gat or St u d y File.  T h e res pecti ve files will 
be ke pt a n d u p dat e d b y t he S p o ns or ( or dele gate) a n d t he I n vesti gat or, as a p plica ble.  
All st u d y d oc u me ntati o n a n d mate rials mai ntai ne d i n t he I n v esti gat or St u d y File at t he st u d y site 
m ust be a vaila ble f or i ns pecti o n b y t h e S p o ns or’s st u d y m o nit or ( or del e gat e) t o deter mi ne t h at 
all re q uire d d o c u me ntati o n is prese nt a n d c orrect.  
T he st u d y ma y b e a u dite d b y q ualifie d d ele g at es fr o m t he S p o ns or or a c o m pete nt re g ulat or y 
a ut h orit y.  
1 2. 4.  
Use of St ore d S a m ples a n d D at a  
As descri be d i n  Secti o n  7. 6. 1 , plas ma will be st ore d f or P K a nal ysis.  St ore d sa m ples will be 
la bele d wit h st u d y a n d s u bject i nf or mati o n a n d ke pt i n a l oc ke d r o o m wit h li mite d access.  
Electr o nic data will be ke pt i n pass w or d -pr otecte d c o m p uters at t he la b orat or y a n d t he n 
tra nsferre d t o t he S p o ns or or cli nical r esearc h or ga nizati o n ( C R O), as a p plica ble, f or data 
a nal ysis.  Sa m ples a n d c orres p o n di n g data will be trac ke d usi n g t he la b orat or y’s trac ki n g s yste m.  
Pri or S p o ns or a n d I R B a p pr o val are re q uir e d bef ore usi n g or s hari n g st u d y sa m ples or data i n 
wa ys n ot s pecifie d i n t he st u d y pr ot oc ol.  
A n y l oss or u na ntici pate d destr ucti o n of sa m ples (e g, freezer malf u n cti o n) or data (e g, l oss of a 
data s heet wit h i n di vi d uall y i de ntifi a ble i nf or m ati o n) t hat vi olates or c o m pr o mises t he scie ntific 
i nte grit y of st u d y data m ust be re p orte d t o t he S p o ns or a n d t he I R B. 
U nless ot her wise dir ecte d b y t he s u bject, at t he c o m pleti o n (ter mi nati o n) of t he st u d y, sa m ples 
will c o nti n ue t o be st ore d f o r a peri o d of u p t o 2 years, or l o n ger if re q uir e d b y t he i nstit uti o n 
partici pati n g i n t he st u d y.  I n all cases, s a m ples will be st ore d u ntil t he c o m pleti o n (ter mi nati o n) 


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of t he st u d y.  At a n y ti me, s u bjects ma y i nf or m t he I n v esti gat or t hat t he y d o n ot wis h t o ha ve 
t heir sa m ples st ore d be y o n d t he c o m pleti o n (ter mi nati o n) of t he st u d y.  I n t his case, t he 
I n v esti gat or will re q uest t hat all k n o w n re mai ni n g sa m ples be destr o ye d t o S p o ns or a n d re p ort 
t he dis p ositi o n of sa m ples t o t he re q uesti n g s u bj ects a n d t he I R B. 
1 2. 5.  
Dis p ositi o n of St ore d S a m ples a n d D at a  
Access t o st ore d s a m ples will be li mite d b y usi n g a l oc ke d r o o m.  D ata will be ke pt i n 
pass w or d -pr ot ecte d c o m p uters at t he la b orat or y a n d t he n tra nsferre d t o t he ve n d or f or d ata 
a nal ysis.  Sa m ples a n d c orres p o n di n g data ac q uir e d will be trac k e d usi n g t he la b orat or y’s 
s peci me n trac ki n g s yste m. 
I n t he f ut ure, ot her I n vesti gat ors ma y wis h t o st u d y t hese s a m ples a n d/ or d ata.  I n t hat case, I R B 
a p pr o val a n d S p o ns or a p pr o val m ust be o btai ne d bef ore a n y s hari n g of sa m ples a n d/ or data.  A n y 
cli nical i nf or mati o n s hare d a b o ut t he sa m ple w o ul d si milarl y re q uir e pri or S p o ns or a n d I R B 
a p pr o val.  
A n y l oss or u na ntici pate d destr ucti o n of sa m ples (e g, d ue t o freezer m alf u ncti o n) or data (e g, 
l oss of a data s heet wit h i n di vi d uall y i de ntifia ble i nf or mati o n) t hat res ults i n a vi olati o n t hat 
c o m pr o mises t he scie ntific i nte grit y of t h e data c ollecte d f or t he st u d y will be re p ort e d t o t he 
S p o ns or a n d t he I R B.  
At t he c o m pleti o n (ter mi nati o n) of t he st u d y, s a m ples will c o nti n ue t o be st ore d f or a p eri o d of 
u p t o 2 years, or l o n ger if re q uire d b y t he i nstit uti o n partici pati n g i n t he st u d y.  
A d diti o nall y, s u bjects m a y d eci de at a n y p oi nt n ot t o ha ve t heir sa m ples st ore d f or a peri o d of u p 
t o 2 years be y o n d t he d urati o n of t he st u d y.  I n this case, t he PI will re q u est t he destr ucti o n of all 
k n o w n re mai ni n g sa m ples a n d re p ort w h at was d o ne t o b ot h t he s u bject a n d t o t he I R B.  T his 
decisi o n will n ot affect t h e s u bject’s partici pati o n i n t his pr ot oc ol.  
1 2. 6.  
St u d y I niti ati o n  
Bef ore t he start of t he st u d y, t he S p o ns or st u d y m o nit or or dele gate will visit t he st u d y site t o 
e ns ure a d e q uac y of t he facilities a n d t o disc uss res p o nsi bilities re gar di n g st u d y pr ot o c ol 
a d here n ce wit h t he I n vesti gat or a n d ot h er pers o n nel i n v ol ve d i n t he st u d y.  
T he PI m a y n ot e nr oll a n y s u bject i nt o t he st u d y b ef ore t h e S p o ns or has recei ve d writte n 
a p pr o val or a fa v ora ble o pi ni o n fr o m t he I E C or I R B f or c o n d u cti n g t h e st u d y a n d a f or m al 
meeti n g h as bee n c o n d ucte d b y t he S p o ns or’s st u d y m o nit or ( or dele gate) t o i nitiate t he st u d y .  
T his meeti n g will i ncl u de a detaile d re vie w of t he st u d y pla n a n d t he e C R F.  
1 2. 7.  
S u bject Rei m b urse me nt, Li a bilit y, a n d I ns ur a nce  
T he ci vil lia bilit y of t he i n v ol ve d parties wit h res p ect t o fi na ncial l oss d ue t o pers o nal i nj ur y a n d 
ot her da ma ge t h at ma y arise  beca us e of t his st u d y bei n g c o n d ucte d are g o v er ne d b y t he 
a p plica ble le gal re q uire m e nt(s).  
T he S p o ns or will pr o vi de i ns ura nce t o t he I n v esti gat or if re q uir e d b y t he a p plica ble re g ulat or y 
a n d le gal re q uire me nt(s).  


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If re q uir e d b y l ocal la w, s u bjects ta ki n g p art i n t his st u d y will be i ns ure d a gai nst a n y i nj ur y 
ca use d b y t he st u d y i n a cc or da nce wit h t he a p plica ble re g ulat or y a n d le gal re q uire me nt(s).  
1 2. 8.  
S u bject I de ntific ati o n a n d C o nfi de nti alit y  
S u bject na mes will n ot be s u p plie d t o t he S p o ns or.  A s u bject n u m ber  will be rec or de d i n t he 
e C R F, a n d if t he s u bject na me a p pears o n a n y ot h er d oc u me nt (e g, la b orat or y re p ort), it m ust be 
o bliterate d o n t he c o p y of t he d oc u me nt t o be s u p plie d t o t he S p o ns or.  All rec or ds will be ke pt 
c o nfi de ntial t o t he e xte nt pr o vi de d b y  fe d eral, state, a n d l ocal la ws.  T he s u bjects will be 
i nf or me d t hat re prese ntati ves of t he S p o ns or, E C/I R B, or re g ul at or y a ut h orities ma y i ns pe ct t heir 
me dical rec or ds t o verif y t he i nf or mati o n c ollecte d, a n d t hat all pers o nal i nf or mati o n ma de 
a vaila ble for i ns pecti o n will be ha n dle d i n strictest c o nfi de nce a n d i n acc or da nce wit h l ocal data 
pr otecti o n la ws.  
T he PI will mai ntai n a pers o nal s u bject i de ntificati o n list (s u bject n u m bers wit h t he 
c orres p o n di n g s u bject na mes) t o e na ble rec or ds t o be i de ntifie d.  
1 2. 9.  
St u d y M o nit ori n g  
Bef ore st u d y i nitiati o n, at a site i nitiati o n visit or at a n I n vesti gat or’s me eti n g, a S p o ns or 
re pres e ntati ve will re vie w t he pr ot oc ol, e C R F, I B, a n d a n y st u d y relat e d materials wit h t he 
I n v esti gat ors a n d t heir st aff.  D uri n g t h e st u d y, t he st u d y S p o ns or m o nit or or its desi g nee will 
visit t he site re g ularl y t o c hec k t he c o m plete ness of s u bject rec or ds, t he acc urac y of e ntries o n 
t he e C R Fs, a d here nce t o t he pr ot oc ol, a d here nce t o I C H G C P a n d a p plica ble re g ulat or y 
re q uire me nts, t he pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u d y dr u g is bei n g st ore d, 
dis pe nse d, a n d acc o u nte d f or per s p ecificati o ns.  
T he I n vesti gat or m ust gi ve t he m o nit or access t o rele va nt h os pital or cli nical rec or ds t o c o nfir m 
t heir c o nsiste nc y wit h t he e C R F e ntries.  N o i nfor mati o n i n t hese rec or ds a b o ut t he i de ntit y of 
t he s u bjects will lea ve t h e st u d y ce nter.  T h e st u d y S p o ns or m o nit ori n g sta n dar ds re q uir e f ull 
verificati o n f or t he pres e nce of i nf or m e d c o nse nt, a d here n ce t o t he i ncl usi o n/e xcl usi o n criteria, 
d oc u me ntati o n o f S A Es, a n d t he rec or di n g of pri m ar y acti vit y a n d safet y varia bles.  A d diti o nal 
c hec ks of t h e c o nsiste nc y of t he s o urce data wit h t he e C R Fs are perf or me d per t he st u d y s pecifi c 
m o nit ori n g pla n.  
1 2. 1 0.  
Pr ot oc ol A me n d me nts  
A n y s u bsta ntial c h a n ge or a d diti o n t o t his  pr ot oc ol re q uires a writte n pr ot oc ol a me n d me nt t hat 
m ust be a p pr o ve d b y t he S p o ns or, bef ore i m ple me ntati o n.  A me n d me nts si g nifica ntl y affecti n g 
t he safet y of s u bjects, 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, re q uire 
a d diti onal a p pr o val b y t h e a p plica ble re g ulat or y a ut h orit y(ies), ce ntr al E Cs, a n d l ocal I R Bs/ E Cs.  
C o pies of t he a p plica ble writte n a p pr o vals m ust b e gi v e n t o t he site m o nit or or t heir desi g nee.  
T hese re q uire me nts f or a p pr o val s h o ul d i n n o wa y pre ve nt a n y i m me dia te acti o n fr o m bei n g 
ta ke n b y t he I n vesti gat or or b y t he S p o ns or i n t he i nterests of pres er vi n g t he safet y of all s u bjects 
i ncl u de d i n t he st u d y.  If a n i m me diate c ha n ge t o t he pr ot oc ol is felt t o be necessar y b y t he 
I n v esti gat or a n d is i m ple me nte d b y hi m/her f or safet y reas o ns, t he st u d y S p o ns or or its a ge nt 
s h o ul d be n otifie d a n d t he a p plica ble re g ulat or y a ut h orit y(ies)/ ce ntral E Cs/l ocal I R Bs/ E Cs 


I N S 1 0 0 7 
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C o nfi de ntial  
P a ge 1 4 2  of 1 5 5  
 
s h o ul d be i nf or me d wit hi n 1 0 w or ki n g d a ys.  A n y ot her re gi o nal re p orti n g re q uire me nts m ust be 
a d here d t o.  
A me n d me nts affecti n g o nl y a d mi nistrati ve as p ects of t he st u d y d o n ot r e q uire f or mal pr ot o c ol 
a me n d me nts or re g ul at or y a ut h orit y/c e ntral E C/l ocal I R B/I E C a p pr o val, b ut t he re g ulat or y 
a ut h orit y(i es)/ce ntr al E Cs/l ocal I R Bs/ E Cs m ust be ke pt i nf or me d of s u c h a d mi ni strati ve c ha n ges 
i n acc or da nce wit h c o u ntr y s p ecific re q uire m e nts. 
1 2. 1 1.  
A u dits a n d I ns pecti o ns  
D o mestic a n d f orei g n re g ulat or y a ut h orities, t he I R B/I E C, a n d a n a u dit or a ut h orize d b y t he 
S p o ns or ma y re q uest a ccess t o all s o urce d oc u m e nts, C R Fs, a n d ot her st u d y d oc u m e ntati o n f or 
o nsite a u dit or i ns pecti o n.  Direct a ccess t o t hes e d oc u me nts m ust be g u ara ntee d b y t he 
I n v esti gat or, w h o m ust pr o vi de s u p p ort al wa ys f or t hese acti vities.  Me dical rec or ds a n d ot her 
st u d y d oc u me nts ma y b e c o pie d d uri n g a u dit or i ns pecti o n if s u bject na mes are o bliterate d o n t he 
c o pies t o e ns ure c o nfi de ntialit y.  
If a n i ns pecti o n is re q u este d b y a re g ulat or y a ut h orit y, t he I n v esti gat or will i nf or m t he st u d y 
S p o ns or i m me diatel y t hat t his re q uest has bee n m a de.  
1 2. 1 2.  
P u blic ati o n P olic y a n d D at a Us a g e 
A st u d y site ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter p u blicati o n 
has bee n s u b mitte d f or p u blicati o n or u ntil 1  year after t he st u d y has e n de d, w hic he ver occ urs 
first.  T heref ore, t he st u d y site will ha ve t he o p p ort u nit y to p u blis h t he res ults of t he st u d y, if 
I ns me d h as ha d t he o p p ort u nit y t o re vie w a n d c o m me nt o n t he st u d y site’s pr o p ose d p u blicati o n 
pri or t o its bei n g s u b mitte d f or p u blicati o n wit h t h e pri or a d vice of I ns me d Le gal Affairs 
(i ntellect ual pr o pert y c o u ncil) a n d wit h pr o per re gar d t o t he pr ot ecti o n of s u bjects’ i de ntities.  
A n y f or mal prese ntati o n or p u blicati o n of data c ollecte d fr o m t his st u d y will be c o nsi dere d as a 
j oi nt p u blicati o n b y t he I n vesti gat or(s) a n d t he a p pr o priate pers o n nel of t h e st u d y S p o ns or.  
A ut h ors hi p will be deter mi ne d b y a gree m e nt.   
T he st u d y S p o ns or m ust recei v e c o pies of a n y i nte n de d c o m m u nicati o n i n a d va nce of p u blicati o n 
(at least 6 0 w or ki n g da ys f or a n a bstr act or oral pr ese ntati o n a n d 9 0 w or ki n g da ys f or a j o ur n al 
s u b missi o n).  T he st u d y S p o ns or will re vie w t he c o m m u nicati o ns f or acc urac y (t h us a v oi di n g 
p ote ntial discre pa n cies wit h s u b missi o ns t o re g ulat or y a ut h orities), verif y t hat c o nfi de ntial 
i nf or mati o n is n ot bei n g i na d verte ntl y di v ul ge d, a n d t o pr o vi de a n y rel e va nt s u p ple me ntary 
i nf or mati o n.  A ut h ors hi p of c o m m u nicati o ns arisi n g fr o m p o ole d data ma y i ncl u de me m bers 
fr o m eac h of t he c o ntri b uti n g ce nt ers as w ell as t he st u d y S p o ns or pers o n nel. 
After st u d y c o m pleti o n a n d c o m pre he nsi ve d ata a nal ysis, t he res ults of st u d y  will be des cri be d i n 
t he C S R.


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
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1 3.  
R E F E R E N C E S  
A d kis o n A M, Ra ptis S Z, Kelle y D G, P ha m C T. Di pe pti d yl pe pti dase I acti vates 
ne utr o p hil -deri ve d s eri ne pr oteases a n d re g ulat es t he de vel o p me nt of ac ute e x peri me ntal 
art hritis. J Cli n I n vest. 2 0 0 2; 1 0 9: 3 6 3 -7 1.  
A mita ni  R, Wils o n R, R ut ma n A, Rea d R, War d C, B ur nett D, et al. Effects of h u ma n ne utr o p hil 
elastase a n d Pse u d o m o nas aer u gi n osa pr ot ei nases o n h u ma n res pirat or y e pit heli u m. A m J Res pir 
Cell M ol Bi ol. 1 9 9 1; 4( 1): 2 6 -3 2.  
Ba n k U, A ns or ge S. M or e t ha n destr ucti ve: n e u tr o p hil-deri ve d seri n e pr oteases i n c yt o ki ne 
bi oacti vit y c o ntr ol. J Le u k oc Bi ol. 2 0 0 1; 6 9: 1 9 7 -2 0 6.  
Bar ker A F, O’ D o n nell A E, Fl u me P, T h o m ps o n PJ, R uzi J D, de Gracia J, et al. Aztre o na m f or 
i n halati o n s ol uti o n i n s u bjects wit h n o n-c ystic fi br osis br o nc hiecta sis ( AI R-B X 1 a n d AI R -B X 2): 
t w o ra n d o mise d d o u ble-bli n d, place b o -c o ntr olle d p hase 3 trials. La n cet Res pir Me d. 
2 0 1 4; 2( 9): 7 3 8 -4 9.  
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n –  Nati o nal Ce nter f or Healt h Statistics –  A d ult 
T o bacc o Us e I nf or mati o n, 2 0 1 7 [ h o me pa ge o n t h e I nter n et; cite d 2 0 1 7 Ma y 1 1]. A vaila ble fr o m: 
htt ps:// w w w.c dc. g o v/ nc hs/ n his/t o bacc o. ht m/.  
C hal mers J D, G oe mi n ne P, Ali berti S, Mc D o n nell MJ, L o n ni S, Da vi ds o n J, et al. T he 
br o nc hiectasis se v erit y i n de x. A n i nter nati o nal deri vati o n a n d vali dati o n  st u d y. A m J Res pir Crit 
Care Me d. 2 0 1 4 ;1 8 9( 5): 5 7 6 -8 5.  
De S o yza A, A ks a mit T, Ba n del TJ, Cri oll o M, El b or n J S, Kra h n U, et al. Efficac y a n d 
tolera bilit y of ci pr ofl o x aci n d r y p o w der f or in halati o n ( ci pr ofl o x aci n D PI) i n b r o nc hiectasis 
(n o n -C F eti ol o g y): Res ults fr o m t he P hase III R E S PI R E 1 St u d y. C hest. 2 0 1 6; 1 5 0( 4 _ S): 1 3 1 5 A. 
d oi: 1 0. 1 0 1 6/j.c hest. 2 0 1 6. 0 8. 1 4 4 6.  
G oe mi n ne P C, Na wr ot T S, R utte ns D, Se ys S, D u p o nt LJ. M ortalit y i n n o n -c ystic fi br osis 
br o nc hiectasis: a pr os pecti ve treat me nt a nal ysis. Res pir Me d. 2 0 1 4 ; 1 0 8( 2): 2 8 7-9 6.  
I N S 1 0 0 7 I n v esti gat or’s Br oc h ure, I ns m e d I nc or p orate d, Versi o n 2. 0, 3 0 J u ne 2 0 1 7. 
J o nes P W, Q uir k F H, Ba ve yst oc k C M. T h e St Ge or ge’s Res pirat or y Q uesti o n naire. Res pir Me d. 
1 9 9 1 Se p; 8 5 S u p pl B: 2 5 -3 1; disc ussi o n 3 3 -7.  
Kell y  M G, M ur p h y S, El b or n J S. Br o nc hiectasis i n sec o n dar y care: a c o m pre he nsi ve pr ofile of a 
ne gl ecte d disease. E ur J I nter n Me d. 2 0 0 3; 1 4( 8): 4 8 8 -9 2.  
K or k maz B, H or witz M S, J e n ne D E, Ga ut hier F. Ne utr o p hil elastase, pr otei nase 3, a n d 
cat he psi n -G as t hera p e utic tar gets i n h u ma n dis eas es. P har mac ol Re v. 2 0 1 0; 6 2( 4): 7 2 6 -5 9.  
K u na P, J e n ki ns M, O’ Brie n C D, Fa h y W A. A Z D 9 6 6 8, a ne utr o p hil elastas e i n hi bit or, pl us 
o n g oi n g b u des o ni de/f or m oter ol i n patie nts wit h C O P D. Res pir Me d. 2 0 1 2 A pr; 1 0 6( 4): 5 3 1 -5 3 9.  
Me yer -H offert U. Ne utr o p hil -deri ve d seri n e pr oteases m o d ulate i n nate i m m u ne res p o nses. Fr o nt 
Bi osci ( La n d m ar k E d). 2 0 0 9; 1 4: 3 4 0 9 -3 4 1 8.  
Miller M R, Ha n ki ns o n J, Br usas c o V, B ur g os F, Casa b uri R, C oates A, et al; A T S/ E R S Tas k 
F orce. Sta n dar dizati o n of s pir o metr y. E ur Res pir J. 2 0 0 5; 2 6( 2): 3 1 9 -3 8.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 4 4  of 1 5 5  
 
M urra y M P, Pe ntla n d J L, T ur n b ull K, Mac Q uarrie S, Hill A T. S p ut u m c ol o ur: a usef ul cli nical 
t o ol i n n o n-c ystic fi br osis br o nc hiectasis. E ur Res pir J. 2 0 0 9; 3 4( 2): 3 6 1 -4.  
M urra y M P, T ur n b ull K, Mac Q uarrie S, Pe ntla n d J L, Hill A T . Vali dati o n of Leicester C o u g h 
Q uesti o n naire i n n o n -c ystic fi br osis br o nc hiectasis. E ur Res pir J. 2 0 0 9; 3 4( 1): 1 2 5 -3 1.  
P ha m C T. Ne utr o p hil seri ne pr oteases: s pecific re g ulat ors of i nfla m mati o n. Nat Re v I m m u n ol. 
2 0 0 6; 6( 7): 5 4 1 -5 5 0.  
P ha m C T, I va n o vic h J L, Ra ptis S Z, Ze h n ba u er B, Le y TJ. Pa pill o n -Lefè vre s y n dr o me: 
c orrel ati n g t he m ole c ular cell ular a n d cli nical c o ns e q ue nces of cat he psi n C/ di pe pti d yl pe pti dase I 
deficie nc y i n h u ma ns. J I m m u n ol. 2 0 0 4; 1 7 3( 1 2): 7 2 7 7 -8 1.  
P ha m C T, Le y TJ. Di pe pti d yl p e pti dase I is r e q uir e d f or t he pr o cessi n g a n d ac ti vati o n of 
gra nz y mes A a n d B i n viv o. Pr oc Natl Aca d Sci U S A. 1 9 9 9; 9 6( 1 5): 8 6 2 7-3 2.  
Q uitt ner A L, Marciel K K, Salat he M A, O’ D o n n ell A E, G otfrie d M H, Il o wite J S, et al. A 
preli mi nar y q ualit y of life q uesti o n naire –  br o nc hi ectasis: a patie nt -re p orte d o utc o me meas ure 
f or br o nc hie ctasis. C hest. 2 0 1 4; 1 4 6( 2): 4 3 7 -4 8. d oi: 1 0. 1 3 7 8/c hest. 1 3 -1 8 9 1.  
Q uitt ner A L, O’ D o n n ell A E, Salat he M A, Le wis S A, Li X, M o nt g o mer y A B, et al. Q ualit y of 
Lif e Q uesti o n nair e –  Br o nc hiectasis: fi nal ps yc h o metric a nal yses a n d deter mi nati o n of mi ni mal 
i m p orta nt differe n ce sc ores. T h ora x. 2 0 1 5 J a n; 7 0( 1): 1 2-2 0. d oi: 1 0. 1 1 3 6/t h ora xj nl -2 0 1 4 -2 0 5 9 1 8. 
E p u b 2 0 1 4 Oct 1 6.  
R o ot, J, Ber nstr o m J, Clift o n S, Da hl G, D o yl e K, Gar di ner P, et al.  In hi biti o n of n e utr o p hil 
seri ne p r otease a cti vati o n wit h t he re versi ble D P P 1 in hi bit or A Z D 7 9 8 6. A m J of Res pir Crit Care 
Me d . 2 0 1 6; 1 9 3: A 5 8 3 3.  
Serisier DJ, Marti n M L, Mc G uc ki n M A, L o urie R, C he n A C, Brai n B, et al. Effect of l o n g -ter m, 
l o w-d ose er yt hr o m yci n o n p ul m o nar y e x acer bati o ns a m o n g p atie nts wit h n o n -c ystic fi br osi s 
br o nc hiectasis: t he B L E S S ra n d o mize d c o ntr olle d trial. J A M A. 2 0 1 3; 3 0 9( 1 2): 1 2 6 0 -7.  
Tetle y T D. Ne w pers p ecti ves o n basic mec h a nis ms i n l u n g disease. 6. Pr otei nase i m bala nce: its 
r ole i n l u n g dise ase. T h ora x. 1 9 9 3; 4 8( 5): 5 6 0-5.  
T osi M F, Za ke m H, Ber ger M. Ne utr o p hil elast ase clea ves C 3 bi o n o ps o nize d pse u d o m o nas as 
well as C R 1 o n ne utr o p hils t o create a f u ncti o nall y i m p orta nt o ps o ni n rece pt or mis matc h. J Cli n  
I n v est. 1 9 9 0; 8 6( 1): 3 0 0-8.  
U me ki  S, Ni ki Y, S oeji ma R. Elastase/a ntielastase s yste ms i n p ul m o nar y diseases. A m J Me d 
Sci. 1 9 8 8; 2 9 6( 2): 1 0 3 -6.  
V o y n o w J A, Fisc h er B M, Z he n g S. Pr oteases a n d c ystic fi br osis. I nt J Bi oc he m Cell Bi ol. 
2 0 0 8; 4 0( 6 -7): 1 2 3 8 -4 5.  
V o y n o w J A, Y o u n g L R, Wa n g Y, H or ger T , R ose M C, Fisc her B M. Ne utr o p hil elastase 
i ncreas es M U C 5 A C m R N A a n d pr otei n e x pressi o n i n res pirat or y e pit heli al cells. A m J P h ysi ol. 
1 9 9 9; 2 7 6( 5 Pt 1): L 8 3 5 -4 3.  


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I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 4 5  of 1 5 5  
 
1 4.  
A P P E N DI C E S  
 
 


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Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
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C o nfi de ntial  
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A P P E N DI X  1.  S P U T U M I N D U C TI O N G UI D E LI N E S  
C ollecti o n of g o o d s p ut u m sa m ples is critical t o t his  st u d y.  S p ut u m sa m pl es will be c ollecte d at 
t he cli nical site a n d b y t h e s u bjects at h o me.  T o facilitate o btai ni n g g o o d s p ut u m sa m ples d uri n g 
t he st u d y visit at t he st u d y sites, s p ut u m i n d ucti o n will be perf or me d if t he s u bject is u na ble t o 
e x pect orate ap pr o xi matel y 3. 0 m L  of s p ut u m.  
N ote: If a s u bject is u na ble t o pr o d uce s p ut u m s p o nta ne o usl y d uri n g Scree ni n g  ( Visit 1), t he 
s u bject will be c o nsi dere d a scree n fail ure.  T he s u bject ma y n ot u n der g o a s p ut u m i n d ucti o n 
pr oce d ure d uri n g Scree ni n g ( Visit 1) t o meet eli gi bilit y (Secti o n 4. 1 , i ncl usi o n criteri o n 5). 
P ur p ose  
T he p ur p ose of t his g ui deli ne is t o pr o vi de rec o m me n dati o ns t o t he cli nical sites f or o btai ni n g a 
s p ut u m sa m ple b y i n d ucti o n if t he s u bject is u na ble t o e x pect orate a s p ut u m sa m ple o n t heir o w n 
or after c hest perc ussi o n.  
Re q uire d E q ui p me nt  
 Sta n dar d ha n d hel d ne b uli zer use d i n t he site or t he s u bject ca n be as ke d t o bri n g t he 
ne b ulizer t he y us e at h o me f or p ul m o nar y h y gie ne  
 T he ne b ulizer s h o ul d be t h or o u g hl y disi nfecte d t o e ns ure n o cr oss -c o nta mi n ati o n  
 S p ut u m s peci me n c o ntai ners wit h la bel –  s p ut u m c ollecti o n t u be pr o vi de d b y ce ntral 
la b orat or y 
 S o di u m c hl ori de s ol uti o n ( sali ne) –  3 % a n d 7 %, a n d p ossi bl y 1 0 %  
 Sta n dar d cli nic s u p plies ( e g, disi nfecta nt/ ger mici d al/alc o h ol wi pes, tiss ues, pa per 
t owels, etc)  
Pr o ce d ure  
Ge ner al I nstr ucti o ns:  
 At t he st u d y site, s p ut u m i n d ucti o n s h o ul d occ ur i n a pri vate, c o nt ai ne d r o o m. 
S pecific pr ocesses i n place at t he cli nic t o pre ve nt c o nta mi nati o n a n d e ns ure 
steriliz ati o n bef ore a n d after s p ut u m i n d ucti o n s h o ul d be f oll o we d.  
 Cli nic pers o n nel s h o ul d wear gl o ves a n d a mas k d uri n g t he e ntire pr oce d ure.  
 O nl y 1  s u bject s h o ul d be i n d uce d at a ti me. 
 All c ollecti o n c o ntai ners s h o ul d ha ve a s p ut u m c ollecti o n la bel clearl y c o m plete d 
wit h s u bject i de ntifiers, visit na me, da te a n d ti me. 
 T he s u bject s h o ul d ha ve bee n i nstr ucte d n ot t o eat at least wit hi n 1 h o ur of s p ut u m 
i n d ucti o n pr oce d ure.   
 A n e x pla nati o n s h o ul d be pr o vi de d  t o t he s u bject t hat t he p ur p ose of t his pr oce d ure is 
t o hel p hi m/ her c o u g h u p a s p ut u m sa m ple a n d t hat t he s uccess of t he pr oce d ure is 
de pe n de nt o n t he s u bject’s acti ve partici pati o n.  


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I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
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C o nfi de ntial  
P a ge 1 4 7  of 1 5 5  
 
I n h al ati o n a n d C ollecti o n Pr oce d ures: 
 T he i n d ucti o n pr oce d ure s h o ul d start b y utilizi n g eit her 3 % or 7 % s ali ne base d o n t he 
I n v esti gat or’s pr efere nce. 
 A p pr o xi matel y 3  t o 6 m L of t he select e d sali ne s h o ul d be place d i n t he n e b ulizer.  
 T he s u bject s h o ul d be sitti n g u p or i n a s e mi -F o wl er p ositi o n.  
 T he s u bject ma y w ear a n ose cli p d uri n g t h e ne b ulizati o n.  
 T he s u bject s h o ul d breat he sl o wl y a n d dee pl y t hr o u g h t he ne b ulizer m o ut h p iece 
i n hali n g t he salt wat er mist.  Re mi n d t he s u bject n ot t o breat he q uic kl y b ut t o ha ve 
sl o w, dee p breat hs pa usi n g at p ea k i ns pirati o n t o all o w de p ositi o n of particles.  
 T he ne b ulizati o n ti me is 1 0 mi n utes.   
 At t he e n d of t his ti me, t he s u bject s h o ul d t a ke a fe w dee p breat hs, s wall o w t he e xtra 
sali va i n his/ her m o ut h a n d tr y t o c o u g h u p a s p ut u m sa m ple.   
 T he s u bject s h o ul d be e n c o ura ge d t o c o u g h f orcef ull y usi n g t he dee p c o u g hi n g 
met h o d a n d/ or “ h uffi n g” c o u g h m et h o d.  
 All s p ut u m s h o ul d be de p osite d i n t he s peci me n c o ntai ner. T he c o ntai ner s h o ul d n ot 
be o pe ne d u ntil t he s peci me n is rea d y t o be de p osite d. T he c o ntai ner s h o ul d be cl ose d 
i m me diatel y after de p ositi n g t he sa m ple.    
 T he s p ut u m sa m ple s h o ul d be a p pr o xi matel y 3 m L - sli g htl y b el o w t he b ott o m li ne ( 5 
m L) o n t he c ollecti o n c o ntai ner.  
 If a s ufficie nt s p ut u m sa m ple is n ot c ollecte d a n d t he s u bject a p pears t o be t olerati n g 
t he i n d ucti o n pr oce d ure well, t he s u bject ca n c o m plete a n ot her 1 0-mi n ute 
ne b ulizati o n peri o d.  
 If a sec o n d 1 0-mi n ute ne b ulizati o n peri o d is re q uire d, t he rec o m me n dati o n is t o 
i ncreas e t he s o di u m c hl ori de c o nce ntrati o n (ie, if 3 % was use d first t he n 7 % 
s h o ul d be use d f or t he s u bse q ue nt ne b ulizati o n; if 7 % was use d first t he n 1 0 % 
s h o ul d be use d f or t he s u bse q ue nt ne b ulizati o n). 
 Cl osel y  m o nit or t he s u bject f or t olera bilit y iss ues or si de effects.  
 N o m ore t ha n t w o 1 0 -mi n ute ne b ulizati o n peri o ds s h o ul d be c o m plete d.  
 T he s p ut u m sa m ple s h o ul d be refri gerat e d u ntil it is se nt t o t he micr o bi ol o g y 
la b orat or y. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 4 8  of 1 5 5  
 
Si de Effects  
 T he s u bject ma y e x per ie nce si de effects fr o m t he s p ut u m i n d ucti o n pr oce d ure.  T he 
m ost c o m m o n si de effects i ncl u de:  
 c o u g hi n g  
 s ore t hr oat 
 w heezi n g  
 na usea  
 li g ht hea d e d ness 
 hea dac he  
 s h ort ness of 
breat h  
 c hest 
ti g ht ness 
 Ot her p ossi ble si de effects i ncl u de h y p er ve ntilati o n or br o nc h os pas m.  F or 
br o nc h os pas m, e ns ure s u bject recei ves t he necess ar y me dical ma n a ge me nt.  
Miscell a ne o us  
 If t he s u bject ne e ds t o e x pect orate d uri n g ne b ulizati o n, t ur n off t he ne b ulizer a n d 
all o w t he s u bject t o c o u g h u p s p ut u m i nt o t he c o ntai ner.  If a s uff i cie nt s peci me n is 
n ot c ollecte d, t he s u bject s h o ul d t he n res u me t he n e b ulizati o n t o c o m plete t he 1 0 -
mi n ute ne b ulizati o n d urati o n.  
 T he s u bject s h o ul d be e n c o ura ge d t o bl o w his/ her n ose as ofte n as nee d e d d uri n g t he 
i n d ucti o n pr oce d ure t o hel p pre ve nt nas al secti o ns fr o m bec o mi n g mi x e d wit h s p ut u m 
s peci me n. 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 4 9  of 1 5 5  
 
A P P E N DI X  2.  C A L C U L A TI O N O F B R O N C HI E C T A SI S  S E V E RI T Y I N D E X  
Se verit y Criteri a  
0 P oi nt  
1 P oi nt  
2 P oi nt  
3 P oi nt  
4 P oi nt  
5 P oi nt  
6 P oi nt  
A ge ( Years)  
<  5 0  
- 
5 0  t o 6 9  
- 
7 0  t o 7 9  
- 
8 0 +  
B MI ( k g/ m 2) 
>  1 8. 5  
- 
<  1 8. 5  
- 
- 
- 
- 
F E V 1 
( % Pre dicte d) 
>  8 0 %  
5 0  t o 8 0 %  
3 0  t o 4 9 %  
<  3 0 %  
- 
- 
- 
H os pital A d missi o ns i n t he Past 
2  Years  
N o  
- 
- 
- 
- 
Yes  
- 
E xacer bati o n Fre q ue nc y i n Last 
1 2  M o nt hs  
0  t o 2  
- 
3 o r M ore  
- 
- 
- 
- 
M R C  D ys p nea Sc ore  
1 -3  
- 
4  
5  
- 
- 
- 
C ol o nizati o n Stat us  
N ot 
C ol o nize d  
C hr o nic 
C ol o nizati o n  
- 
P a  
C ol o nizati o n  
- 
- 
- 
Ra di ol o gical Se verit y  
<  3 L o bes 
I n v ol ve d 
3 o r M ore 
L o bes o r 
C ystic 
C ha n ges  
 
 
 
 
 
N ote: Esti mate d o utc o mes are t h ose o bser ve d acr oss 5 E ur o pea n treat me nts i n t he ori gi nal deri vati o n a n d vali dati o n st u d y (C hal mers J D et al, 2 0 1 4 ). 
B MI  =  b o d y mass i n de x, F E V 1 =  f orce d e x pirat or y v ol u me i n 1 sec o n d, M R C =  Me dical Researc h C o u ncil ; P a  =  Pse u d o m o n as aer u gi n os a . 
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5 0  of 1 5 5  
 
T H E M E DI C A L R E S E A R C H C O U N CI L  B R E A T H L E S S N E S S S C A L E  
Gr a de  
De gree of Bre at hless ness Rel ate d t o Acti vities  
1  
N ot tr o u ble d b y breat hless ness e xce pt o n stre n u o us e xercise  
2  
S h ort of breat h w he n h urr yi n g o n t he le vel or wal ki n g u p a sli g ht hill  
3  
Wal ks sl o wer t ha n m ost pe o ple o n t he le vel st o ps after a mile or s o, or st o ps after 1 5 mi n utes wal ki n g at o w n pace  
4  
St o ps f or breat h after wal ki n g a b o ut 1 0 0 yar ds or after wal ki n g a fe w mi n utes o n le vel gr o u n d  
5  
T o o breat hless t o lea ve t he h o use, or br eat hless w he n u n dressi n g 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5 1  of 1 5 5  
 
A P P E N DI X  3.  C HI L D -P U G H S C O RI N G A N D C L A S S R E F E R E N C E 
T A B L E S  
C hil d -P u g h Sc ori n g  
Me as ure  
1 P oi nt  
2 P oi nts  
3 P oi nts  
T otal Bilir u bi n , μ m ol/ L ( m g/ d L) 
<  3 4 ( <  2)  
3 4  t o 5 0 ( 2  t o 3)  
>  5 0 ( >  3)  
Ser u m Al b u mi n , g/ d L 
>  3. 5  
2. 8 t o 3. 5  
<  2. 8  
Pr ot hr o m bi n  Ti me , 
Pr ol o n gati o n (s) 
<  4. 0  
4. 0  t o 6. 0  
>  6. 0  
Ascites  
N o ne  
Mil d ( or 
S u p presse d Wit h 
Me dicati o n ) 
M o derate t o Se vere 
( or Refract or y ) 
He patic E nce p hal o pat h y  
N o ne  
Gra de I  t o II 
Gra de III  t o I V 
C hr o nic li ver disease is classifie d i nt o C hil d -P u g h c lass A t o C, e m pl o yi n g t he a d de d sc ore fr o m 
t he C hil d-P u g h Sc ori n g Ta ble a b o ve.  
C hil d -P u g h Cl ass  
P oi nts  
Cl ass  
O ne -ye ar s ur vi v al  
T w o -ye ar s ur vi v al  
5 t o 6  
A  
1 0 0 %  
8 5 %  
7  t o 9  
B  
8 1 %  
5 7 %  
1 0  t o 1 5  
C  
4 5 %  
3 5 %  
 
 


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5 2  of 1 5 5  
 
A P P E N DI X  4.  I N T E N S E P H A R M A C O KI N ETI C S A M P LI N G S C H E M E  
I nte nse P K S u b -St u d y Bl o o d S a m pli n g Ti mes a n d Ti me Wi n d o ws  
 
N ote: S u bj ects will be re mi n de d n ot t o ta ke t heir st u d y dr u gs o n t he da y of t heir visits w he n t heir P K sa m ple(s) will 
be ta ke n.  
N ote: A tr o u g h ( pre -d ose) P K sa m ple will b e c ollecte d at 3 of t he 4 visits of Visits 3, 6,  a n d 9 .  F or visit 1 0, 
c ollecti o n of P K sa m ple s ca n be d o ne at a n y ti me  eit her pre - or p ost -d ose d uri n g t he visit . 
N ote: A P K sa m ple bet wee n 0. 5 t o 4 h o urs p ost -d ose will be c ollecte d at 2 of t he 4 visits of Visits 3, 4, 6, a n d 9.  
Visit  
C ollecti o n Ti me Rel ati v e t o 
Dr u g A d mi nistr ati o n  
C ollecti o n Wi n d o w  
Visit 2  
0 h o ur ( pre -d ose)  
-3 0 mi n  
 
1 hr  
± 1 0 mi n  
 
2 hr  
± 1 0 mi n  
 
3 hr  
± 1 0 mi n  
 
4 hr  
± 1 0 mi n  
 
6 hr  
± 1 0 mi n  
 
8 hr  
± 1 0 mi n  
Visit 3  
Pre -d ose o n t he visit da y  
 
Visit 4  
Pre -d ose o n t he visit da y  
-3 0 mi n  
 
1 hr  
± 1 0 mi n  
 
2 hr  
± 1 0 mi n  
 
3 hr  
± 1 0 mi n  
 
4 hr  
± 1 0 mi n  
 
6 hr  
± 1 0 mi n  
 
8 hr  
± 1 0 mi n  
Visit 6  
Pre -d ose o n t he visit da y  
 
Visit 9  
Pre -d ose o n t he visit da y  
 
Visit 1 0  
A P K sa m ple will be c ollecte d  at a n y ti me d uri n g Visit 1 0 . 
A t otal of 1 8 P K sa m ples will be c ollecte d fr o m eac h s u bject.  


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5 3  of 1 5 5  
 
N ote: At Visits 2 a n d 4, s u bj ects will be fe d after t he 1 -h o ur bl o o d dra w.  
P K = p har mac o ki netic(s).


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5 4  of 1 5 5  
 
A P P E N DI X  5.  H Y ’ S L A W 
D uri n g t h e st u d y, t he I n v esti gat ors will re mai n vi gila nt f or i ncreases i n li ver e nz y mes.  T he 
I n v esti gat ors are res p o nsi ble f or deter mi ni n g w het her a s u bject meet p ote ntial H y’s l a w criteria 
at a n y ti me d uri n g t h e st u d y.  T he I n vesti gat ors t o get h er wit h t h e S p o ns or p h ysicia ns, will 
deter mi ne if H y’s l a w criteria are met or n ot.  T he I n v esti gat ors are res p o nsi ble f or rec or di n g a n d 
re p orti n g H y’s la w cas es per t he safet y re p orti n g re q uire me nt des cri be d bel o w. 
P ote nti al H y’s L a w  
A s u bject’s A S T or A L T ≥ 3  U L N  a n d T B L ≥ 2  U L N at a n y ti me p oi nt d uri n g t he treat me nt 
irres pecti ve of a n y i ncrease of al kali ne p h os p hat as e will be c o nsi dere d t o meet p ote ntial H y’s 
la w.  T he ele v ati o ns of A S T or A L T wit h T B L d o n ot ha ve t o occ ur at t he s a me ti me or wit hi n a 
s pecifie d ti me fra me.   
H y’s L a w  
A s u bject’s A S T or A L T ≥ 3  U L N a n d T B L ≥ 2  U L N at a n y ti me p oi nt d uri n g t he treat me nt 
wit h o ut a n y ot her reas o ns (s uc h as viral h e patitis or a n ot her dr u g or c h olestasis) ot her t ha n t he I P 
will be c o nsi dere d t o meet H y’s la w.  T h e el e vati o ns of A S T or A L T wit h T B L d o n ot ha ve t o 
occ ur at t he s a me ti me or wit hi n a s pecifie d ti me fra me.  
I de ntific ati o n of P ote nti al H y’s L a w C ases 
T o i de ntif y cases of p ot e ntial H y’s la w, it is i m p orta nt t o perf or m a c o m pr e he nsi ve re vie w of 
cli nical la b orat or y d ata f or a n y s u bject w h o meets t he f oll o wi n g criteria i n is olati o n or i n 
c o m bi nati o n:  
A L T ≥ 3  U L N  
A S T ≥ 3  U L N  
T B L ≥ 2  U L N  
T he s u bjects s h o ul d be cl osel y m o nit ore d.  T h eir li ver e nz y m es a n d ser u m bilir u bi n tests will be 
teste d 2 t o 3 ti mes wee kl y.  T he fre q u e nc y of t he t esti n g ca n decrease t o o n ce a wee k or l ess if 
a b n or malities sta biliz e.  T he I n vesti gat ors will re vie w wit h o ut a n y d ela y e ver y ne w cli nical 
la b orat or y re p orts.  T he I n vesti gat ors s h o ul d n otif y S p o ns or if a n y of t he a b o ve criteri a are met, 
a n d deter mi ne w h et her t h e s u bject meets p ote ntial H y’s l a w.  If t h e p ote ntial H y’s la w is met, t he 
I n v esti gat or will i nf or m t he S p o ns or res p o nsi ble p h ysicia n w h o will t he n i nf or m t he e ntire 
S p o ns or st u d y tea m.  T he I n v esti gat or is res p o nsi ble f or pr o vi di n g t he S p o ns or all t he a vaila ble 
rele va nt dat a i n a ti mel y fas hi o n f or re vie w, a n d will disc uss wit h t he S p o ns or t o deter mi ne 
t o get her if t here is a n alter nati ve e x pla nati o n f or m eeti n g p ot e ntial H y’s la w ot her t ha n dr u g 
i n d uce d li ver i nj ur y ca use d b y t he I P.  T he S p o ns or me dical scie n ce dir ect or a n d gl o bal safet y 
p h ysicia n will als o be i n v ol ve d i n t he data re vi e w a n d disc ussi o n t o get her wit h ot her s u bject 
matter e x perts as a p pr o priate t o deter mi ne if H y’s la w is met.  T he I n vesti gat or a n d t he S p o ns or 
wil l a gree o n a n a p pr oac h f or t he sit uati o n.  
T he I n vesti gat or is r es p o nsi ble f or cl osel y m o nit ori n g t he s u bject u ntil his/ her li ver e nz y me 
le vels a n d rel e va nt si g ns or s y m pt o ms ret ur n t o n or mal or at least bas eli ne, or if me dicall y 
i n dicate d.   


I N S 1 0 0 7 
I ns me d I nc or p orate d 
Cli nical St u d y  Pr ot oc ol: I N S 1 0 0 7 -2 0 1  
Versi o n  5. 0 , 24  Se pte m ber 2 0 1 8  
C o nfi de ntial  
P a ge 1 5 5  of 1 5 5  
 
Per t he o utc o me of t he j oi nt re vie w a n d ass ess me nt, t he I n v esti gat or will f oll o w t he i nstr ucti o ns 
bel o w:  
If t here is a n a gree d alter nati ve e x pla nati o n f or t he A L T or A S T a n d T B L ele vati o ns, a 
deter mi nati o n of w het h er t he alter nati ve e x pla nati o n is a n A E will be ma de a n d s u bse q ue ntl y 
w het her t he A E meets t h e criteri a f or a S A E.  If t h e alter nati ve e x pla nati o n is n ot a n A E, rec or d 
t he alter nati ve e x pla nati o n o n t he a p pr o priat e e C R F.  If t he alter nati ve e x pla nati o n is a n 
A E/ S A E, rec or d t h e A E/ S A E i n t he A E e C R F acc or di n gl y .  
If t here is N O a gree d alter nati ve e x pla nati o n t hat w o ul d e x plai n t he A L T or A S T a n d T B L 
ele vati o ns ot her t ha n I P, H y’s l a w is met a n d it s h o ul d be re p orte d as a S A E wit h t he re p orti n g 
ter m of “ H y’s l a w” a n d ca usalit y ass ess me nt of “relate d” s h o ul d be assi g n e d. 

SAP_001.pdf: 
 
Offi ci al Titl e:  A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d, P ar all el -Gr o u p, 
M ulti -C e nt er  St u d y t o A s s e s s t h e Effi c a c y, S af et y a n d T ol er a bilit y, a n d 
P h ar m a c o ki n eti c s of  I N S 1 0 0 7 A d mi ni st er e d O n c e D ail y f or 2 4 W e e k s 
i n S u bj e ct s Wit h N o n -C y sti c  Fi br o si s Br o n c hi e ct a si s – T h e Will o w 
St u d y  
N C T N u m b er:  N C T 0 3 2 1 8 9 1 7  
D o c u m e nt  D at e s: 
S A P V er si o n 1 . 0: 1 0-J a n u ar y -2 0 2 0  
 
 
 


S t atisti c al A n al ysis Pl a n 
 
0 3. 0 0 7 A. 0 3      
 
Pa ge 1 of 7 0  
D oc u me nt T y pe:  
Te m plate  
D oc u me nt I D:  
0 3. 0 0 7 A. 0 3 
Iss u e Date:               0 2 M A Y 2 0 1 6   
Effecti ve Date:       3 0 M A Y 2 0 1 6   
 
S p o ns or N a me:  
I ns me d I nc or p or ate d 
Pr ot oc ol N u m ber a n d Title:  
 
I N S 1 0 0 7-2 0 1 A R a n d o mize d, D o u ble -Bli n d, 
Pl ace b o -C o ntr olle d, P a r allel -Gr o u p, M ulti -Ce nter 
St u d y t o Assess t he Effic ac y, S afet y a n d 
T oler a bilit y, a n d P h ar m a c o ki netics of I N S 1 0 0 7 
A d mi nistere d O nce D ail y f or 2 4 Wee ks i n 
S u bjects wit h N o n -C ystic Fi br osis Br o nc hiect asis 
- T he Will o w St u d y  
Ori gi n al Pr ot oc ol:  
2 1 J u ne 2 0 1 7  
Pr ot oc ol A me n d me nt 
n u m bers a n d d ates  
A me n d me nt 1. 0 , 2 4 A u g ust 2 0 1 7  
A me n d me nt 2. 0 , 1 2 M a rc h 2 0 1 8  
A me n d me nt 3. 0 , 2 7 A p ril 2 0 1 8 
A me n d me nt 4 . 0, 2 4 Se pte m ber 2 0 1 8  
 
 
S y ne os He alt h  Pr oj ect C o de:  
1 0 0 9 1 1 3  
A ut h or(s):  
S A P V ersi o n:  
Versi o n 1. 0  
S A P V ersi o n D ate:  
0 9 -J a n uar y-2 0 2 0  
N otice of C o nfi de nti al a n d Pr o priet ar y I nf or m ati o n: 
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is c o nfi de ntial b el o n gi n g t o I ns me d I nc or p orate d. Acce pta nce of 
t his d oc u me nt c o nstit utes a gree me nt b y t he reci pie nt t hat n o i nf or mati o n c o ntai ne d herei n will be p u blis he d 
or discl ose d wit h o ut pri or writte n a ut h orizati o n fr o m a n official of I ns me d I nc or p orate d.  H o we ver, t his 
d oc u me nt ma y be discl ose d t o a p pr o priate I nstit uti o nal Re vi e w B oar d a n d Et hics C o m mitt ees or d ul y 
a ut h orize d re prese ntati ves of a nati o nal re g ulat or y a ut h orit y u n der t he c o n diti o n  t hat t he y are re q ueste d t o 
kee p it c o nfi de ntial. I n t he e ve nt of a n act ual or s us pecte d breac h of t his o bli gati o n, S y ne os Healt h  s h o ul d be 
n otifie d pr o m ptl y.  








St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 5 of  7 0  
T A B L E O F C O N T E N T S  
C o nte nts  
1.  
G L O S S A R Y O F A B B R E VI A TI O N S  ................................................................. 9 
2.  
P U R P O S E  ...................................................................................................... 1 2  
2. 1.  
R e s p o n si biliti e s  ................................................................................................................. 1 2  
2. 2.  
Ti mi n g s of A n al y s e s  .......................................................................................................... 1 2  
3.  
S T U D Y O B J E C TI V E S  ................................................................................... 1 3  
3. 1.  
Pri m ar y O bj e cti v e  .............................................................................................................. 1 3  
3. 2.  
S e c o n d ar y O bj e cti v e s  ....................................................................................................... 1 3  
3. 3.  
E x pl or at or y O bj e cti v e s  ...................................................................................................... 1 3  
3. 4.  
S af et y O bj e cti v e  ................................................................................................................. 1 5  
3. 5.  
P h ar m a c o ki n eti c O bj e cti v e s  ............................................................................................. 1 5  
3. 6.  
Bri ef D e s cri pti o n  ................................................................................................................ 1 5  
3. 6. 1.  
Scree ni n g P eri o d  ................................................................................................................ 1 6  
3. 6. 2.  
Treat me nt P eri o d ( Visits 2 t hr o u g h 9)  .................................................................................. 1 6  
3. 6. 3.  
E n d -of -St u d y Visit ( Visit 1 0)  .............................................................................................. 1 7  
3. 7.  
S u bject Selecti o n  ................................................................................................................... 1 8  
3. 7. 1.  
Reas o ns f or Wit h dra wal/ Earl y St u d y Disc o nti n uati o n  ........................................................... 1 8  
3. 7. 2.  
Reas o ns f or Earl y Treat me nt Disc o nti n uati o n  ....................................................................... 1 9  
3. 8.  
Deter mi n ati o n of S a m ple Siz e  ............................................................................................... 1 9  
3. 9.  
Tre at me nt Assi g n me nt & Bli n di n g ........................................................................................ 2 0  
3. 1 0.  
St u d y Pr oce d ures a n d Fl o w c h art  .......................................................................................... 2 0  
4.  
E N D P OI N T S  .................................................................................................. 2 1  
4. 1.  
Pri m ar y E n d p oi nt  ................................................................................................................. 2 1  
4. 2.  
Sec o n d a r y E n d p oi nts  ............................................................................................................ 2 1  
4. 3.  
E x pl or at or y E n d p oi nts  ......................................................................................................... 2 1  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 of  7 0  
4. 4.  
S afet y E n d p oi nts  ................................................................................................................... 2 2  
5.  
A N A L Y SI S P O P U L A TI O N S  .......................................................................... 2 4  
5. 1.  
I nte nt-t o-Tre at P o p ul ati o n  .................................................................................................... 2 4  
5. 2.  
Per -Pr ot oc ol P o p ul ati o n  ........................................................................................................ 2 4  
5. 3.  
S afet y P o p ul ati o n  .................................................................................................................. 2 4  
5. 4.  
P h ar m ac o ki netic P o p ul ati o n  ................................................................................................. 2 4  
5. 5.  
P h ar m ac o d y n a mic P o p ul ati o n  .............................................................................................. 2 5  
5. 6.  
Pr ot oc ol De vi ati o ns  ............................................................................................................... 2 5  
6.  
G E N E R A L A S P E C T S F O R S T A TI S TI C A L A N A L Y SI S  ................................ 2 6  
6. 1.  
Ge ner al M et h o ds  .................................................................................................................. 2 6  
6. 2.  
Ke y Defi niti o ns  ..................................................................................................................... 2 6  
6. 2. 1.  
B aseli ne  ............................................................................................................................ 2 6  
6. 2. 2.  
N o mi nal Da y  ..................................................................................................................... 2 6  
6. 2. 3.  
A d verse E ve nts ( A Es) a n d C o nc o mita nt Me dicati o ns ( C Ms)  ................................................. 2 6  
6. 3.  
Missi n g D at a  ......................................................................................................................... 2 7  
6. 4.  
Visit Wi n d o ws ....................................................................................................................... 2 7  
6. 5.  
V ari a bilit y b y Site  ................................................................................................................. 2 7  
7.  
D E M O G R A P HI C S, O T H E R B A S E LI N E C H A R A C T E RI S TI C S A N D 
M E DI C A TI O N  ............................................................................................... 2 8  
7. 1.  
S u bject Dis p ositi o n a n d Wit h dr a w als  ................................................................................... 2 8  
7. 2.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  .......................................................................... 2 8  
7. 3.  
M e dic al a n d S ur gic al Hist or y  ................................................................................................ 2 9  
7. 4.  
Pri or a n d C o nc o mit a nt M e dic ati o n  ....................................................................................... 2 9  
8.  
E F FI C A C Y  ..................................................................................................... 3 0  
8. 1.  
Hier arc h y of e n d p oi nt testi n g  ................................................................................................ 3 0  
8. 2.  
Pri m ar y Effic ac y E n d p oi nt A n al yses a n d  s u m m aries  ........................................................... 3 1  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 7 of  7 0  
8. 2. 1.  
T he ti me t o t he first p ul m o nar y e xacer bati o n o ver t he 2 4 -we e k treat me nt peri o d  ..................... 3 1  
8. 2. 2.  
Se nsiti vit y A nal yses of t he ti me t o t he first p ul m o nar y e xac er bati o n o ver t he 2 4 -wee k treat me nt 
peri o d  3 3  
8. 3.  
Sec o n d ar y Effic ac y E n d p oi nt(s) a n d A n al yses  ....................................................................... 3 4  
8. 3. 1.  
C ha n ge fr o m B aseli ne i n Q O L -B res pirat or y s y m pt o ms sc ore o ver t he 2 4 -wee k treat me nt peri o d
 
3 4  
8. 3. 2.  
C ha n ge fr o m Scree ni n g i n p ost -br o nc h o dilat or F E V 1 o ver t he 2 4 -wee k treat me nt peri o d  ......... 3 5  
8. 3. 3.  
P ul m o nar y e xacer bati o ns o ver t he 2 4 -wee k treat me nt peri o d  ................................................. 3 5  
8. 4.  
E x pl or at or y Effic ac y E n d p oi nt(s) a n d A n al yses  .................................................................... 3 6  
8. 4. 1.  
C ha n ge fr o m B aseli ne i n sc or e of Q O L -B d o mai ns o ver t he 2 4 -wee k treat me nt peri o d  ............ 3 6  
8. 4. 2.  
C ha n ge fr o m B aseli ne i n L C Q sc ore o ver t he 2 4 -wee k treat me nt peri o d  ................................. 3 6 
8. 4. 3.  
C ha n ge fr o m B aseli ne i n S G R Q (t otal) sc ore o ver t he 2 4 -we e k treat me nt peri o d  ..................... 3 6  
8. 4. 4.  
S hift fr o m B aseli ne i n s p ut u m c ol or at W ee ks 2, 4, 1 2, 2 4, a n d 2 8  .......................................... 3 7  
8. 4. 5.  
C ha n ge fr o m Scree ni n g of F V C at W ee ks 1 2 a n d 2 4  ............................................................. 3 7  
8. 4. 6.  
C ha n ge fr o m Scree ni n g of P E F R at W ee ks 1 2 a n d 2 4  ........................................................... 3 7  
8. 4. 7.  
C ha n ge fr o m Scree ni n g of F E F 2 5 -7 5 at W ee ks 1 2 a n d 2 4  ..................................................... 3 7  
8. 4. 8.  
T otal d urati o n of e xacer bati o ns, per s u bj ect, o ver t he 2 4 -wee k treat me nt peri o d  ...................... 3 7  
8. 4. 9.  
T otal n u m ber of e xacer bati o ns per s u bj ect o ver t he 2 4 -wee k treat me nt peri o d  ......................... 3 8  
8. 4. 1 0.  
Ti me t o first p ul m o nar y e xacer bati o n, e xacer bati o n rate, Q O L Meas ures, a n d p ul m o nar y 
f u ncti o n para meters ( F E V 1, F V C, P E F R, a n d F E F2 5- 7 5), stratifie d b y Br o nc hiectasis Se verit y I n de x ( B SI) 
sc ore at baseli ne, o ver t he 2 4-wee k treat me nt peri o d  .......................................................................... 3 8  
8. 4. 1 1.  
Ti me t o first p ul m o nar y e xacer bati o n, e xacer bati o n rate, Q O L Meas ures, a n d p ul m o nar y 
f u ncti o n para meters ( F E V 1, F V C, P E FR, a n d F E F 2 5- 7 5), stratifie d b y t he prese nce or a bse nce of P a  at 
Scree ni n g, o ver t he 2 4 -wee k treat me nt peri o d  .................................................................................... 3 8  
8. 4. 1 2.  
Fre q ue nc y of  use of resc ue me dicati o ns o ver t he 2 4 -wee k tre at me nt peri o d  ........................ 3 8  
8. 4. 1 3.  
N u m ber of s u bj ects h os pitaliz e d d ue t o p ul m o nar y e xacer bati o ns b y t he e n d of t he 2 4 -wee k 
treat me nt peri o d .............................................................................................................................. 3 8  
8. 4. 1 4.  
Ot her e x pl orat or y a nal yses  ............................................................................................. 3 9  
9.  
A N A L Y SI S O F P H A R M A C O KI N E TI C S  ....................................................... 4 1  
1 0.  A N A L Y SI S O F P H A R M A C O D Y N A MI C S  ..................................................... 4 2  
1 1.  S A F E T Y  ......................................................................................................... 4 3  
1 1. 1.  
D ur ati o n of E x p os ure  ............................................................................................................ 4 3  
1 1. 2.  
Tre at me nt C o m pli a nce  ......................................................................................................... 4 3  
1 1. 3.  
A d verse E ve nts  ..................................................................................................................... 4 3  
1 1. 3. 1.  
S u m maries of Treat me nt -e mer ge nt A d verse E ve nts  .......................................................... 4 4  
1 1. 4.  
Cli nic al L a b or at or y E v al u ati o ns  ........................................................................................... 4 5  
1 1. 4. 1.  
T ests  ............................................................................................................................. 4 5  
1 1. 4. 2.  
Deri ve d a n d I m p ute d Data  .............................................................................................. 4 6  
1 1. 4. 3.  
Data S u m marizati o n a n d Prese ntati o n  .............................................................................. 4 6  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 8 of  7 0  
1 1. 5.  
Vit al Si g ns  ............................................................................................................................ 4 7  
1 1. 5. 1.  
Meas ure me nts  ............................................................................................................... 4 7  
1 1. 5. 2.  
Data  S u m marizati o n a n d Prese ntati o n  .............................................................................. 4 7  
1 1. 6.  
E C G  ..................................................................................................................................... 4 7  
1 1. 6. 1.  
Meas ure me nts  ............................................................................................................... 4 7  
1 1. 6. 2.  
Data  S u m marizati o n a n d Prese ntati o n  .............................................................................. 4 7  
1 1. 7.  
De nt al E v al u ati o n  ................................................................................................................. 4 7  
1 2.  I N T E RI M A N A L Y S E S ................................................................................... 4 9  
1 3.  C H A N G E F R O M A N A L Y SI S P L A N N E D I N P R O T O C O L  ............................ 5 0  
1 4.  R E F E R E N C E LI S T  ........................................................................................ 5 1  
1 5.  P R O G R A M MI N G C O N SI D E R A TI O N S  ......................................................... 5 2  
1 5. 1.  
Ge ner al C o nsi der ati o ns  ........................................................................................................ 5 2  
1 5. 2.  
T a ble, Listi n g, a n d Fi g ure F or m at  ........................................................................................ 5 2  
1 5. 2. 1.  
Ge neral  ......................................................................................................................... 5 2  
1 5. 2. 2.  
Hea ders  ......................................................................................................................... 5 2  
1 5. 2. 3.  
Dis pla y Ti tles ................................................................................................................ 5 3  
1 5. 2. 4.  
C ol u m n Hea ders  ............................................................................................................ 5 3  
1 5. 2. 5.  
B o d y of t he Data Dis pla y  ............................................................................................... 5 3  
1 5. 3.  
Deri v ati o n of o ne -si de d P-v al ue  ............................................................................................. 5 6  
1 6.  Q U A LI T Y C O N T R O L .................................................................................... 5 7  
1 7.  M O C K -U P S  .................................................................................................... 5 8  
1 8.  A P P E N DI C E S  ................................................................................................ 5 9  
A P P E N DI X A: S T U D Y S C H E D U L E O F A S S E S S M E N T S  ..................................... 6 0  
A P P E N DI X B: C A L C U L A TI O N O F B R O N C HI E C T A SI S S E V E RI T Y I N D E X  ..... 6 6  
A P P E N DI X C: E X P L O R A T O R Y S T A TI S TI C A L A N A L Y SI S P L A N .................... 6 7  
 
 








St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
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2.  
P U R P O S E  
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o e ns ure t hat t he s u m mar y t a bles, 
data listi n gs, a n d fi g ur es w hic h will be pr o d uce d, a n d t he statistical met h o d ol o gies t hat will 
be use d, ar e c o m plete , re pr o d uci ble, a n d a p pr o pri ate t o all o w vali d c o ncl usi o ns re gar di n g 
t he st u d y o bjecti ves.  A n al ysis of p h ar mac o ki n etics  ( P K), p har m ac o d y na mics ( P D), P K-
P D a n d P D- P D a nal ysis will be descri be d i n a s e p arate a nal ysis pla n.  
2. 1.  
Res p o nsi bilities  
S y ne os H ealt h  will perf or m t he statistical a nal ys es a n d are res p o nsi ble f or t he pr o d ucti o n 
a n d q ualit y c o ntr ol of all ta bles, listi n gs, a n d fi g ures ( T L Fs). 
2. 2.  
Ti mi n gs of A n al yses  
T he pri mar y a n al ysis of safet y , efficac y, p har mac o ki netics , a n d p har mac o d y n a mics is 
pla n ne d after all s u bjects c o m plete t he fi nal st u d y visit  or ter mi nate earl y  fr o m t he st u d y. 
Safet y a nal yses s p ecific t o Data M o nit ori n g C o m mittee (D M C ) will be perf or me d aft er 
2 5 %, 5 0 %, 7 5 % of p atie nts ha ve bee n ra n d o mize d , a n d after t he data b ase l oc k t o s u p p ort 
D M C meeti n gs a p pr o xi matel y 4 t o 6 w ee ks after eac h data b ase s na p s h ot /l o c k. T he details 
of t he safet y a nal yses will be c o ver e d i n a se p arate D M C S A P.    
N o f or mal i nteri m a nal ysis is pla n ne d d uri n g t he c o n d uct of t his st u d y. 
A bli n de d sa m ple size reassess me nt is pla n ne d f or t his st u d y. I n or der t o e ns ure t hat t he 
st u d y has at least 8 0 % p o wer at t he c o ncl usi o n of t he trial, 8 7 e ve nts will nee d t o be 
o bser ve d, r e gar dl ess of tr eat me nt gr o u p.  O nce 7 0 % ( n = 1 6 8) of t he ra n d o mize d s u bjects o n 
trial ha ve c o m plete d st u d y treat me nt, I ns me d a ntici pates t hat at least 7 0 % of t he re q uire d 
e ve nts, or 6 1 e v e nts, will ha ve occ urre d. T he f or m ula f or t he s u g geste d s a m ple size will be 
𝑌𝑌=
6 1
𝑥𝑥∗2 4 0  w here Y is t he ne w s u g geste d t otal sa m ple size, x is t he o bser ve d n u m ber of 
e ve nts o nce 7 0 % ( n = 1 6 8) of t he ra n d o mize d s u bjects o n trial ha ve c o m plet e d st u d y 
treat me nt, 6 1 is t he n u m ber of e v e nts t hat was e x pecte d t o ha v e occ urre d o nce 7 0 % of t h e 
ra n d o mize d s u bjects o n trial ha ve c o m plet e d st u d y treat me nt, a n d 2 4 0 re prese nts t he t otal 
n u m ber of s u bjects be ra n d o mize d base d o n t he ori gi nal sa m ple size deter mi nati o n. T he 
decisi o n t o i ncreas e t he s a m ple size will be ma de b y t he I ns m e d st u d y tea m.  T he sa m ple 
size will n ot be decrease d base d o n t he sa m ple size reass ess me nt res ults.  
T he I ns me d st u d y tea m will be bli n de d a n d n ot a ware of eit her t he act ual treat me nt 
recei v e d n or t he r a n d o mize d treat me nt.  N o u n bli n di n g is necessar y t o c o n d uct t his sa m ple 
size rea dj ust me nt.  I ns me d belie ves t hat n o t y p e I err or c orrecti o n is necessar y to mai ntai n 
t he o verall t y pe I err or rate ( Kieser M et al., 2 0 0 3).   
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 1 3  of  7 0  
3.  
S T U D Y O B J E C TI V E S 
3. 1.  
Pri m ar y O bjecti ve  
T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first p ul m o nar y 
e x acer bati o n o ver t he 2 4- wee k treat me nt peri o d.  
3. 2.  
Sec o n d ar y O bjecti ve s 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n q ualit y of life ( Q O L), 
as assesse d b y t he Q ualit y of Life Q uesti o n naire -Br o nc hi ectasis ( Q O L -B), 
Res pirat or y S y m pt o ms D o mai n sc ore, o ver t he 2 4- wee k treat me nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n l u n g f u ncti o n, as 
meas ure d b y f orce d e x pirat or y v ol u me i n 1 s ec o n d ( F E V 1), o ver t he 2 4- wee k 
treat me nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of 
acti ve ne utr o p hil elastas e ( N E) i n s p ut u m, as meas ure d b y t he differe n ce b et wee n 
t he pre-tr eat me nt c o n ce ntrati o n a n d o n-treat me nt c o nce ntrati o n.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he rate of p ul m o nar y 
e x acer bati o ns o ver t h e 2 4 -wee k treat me nt peri o d . 
3. 3.  
E x pl or at or y O bje cti ves 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assesse d b y 
t he Q O L- B d o mai ns (e x cl u di n g t he Res pirat or y S y m pt o ms D o mai n) o ver t he 2 4-
wee k treat me nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n Q O L, as assess e d b y 
t he Leicester C o u g h Q uesti o n naire ( L C Q), o ver t he 2 4- wee k treat me nt peri o d. 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n res pirat or y- relate d 
healt h stat us, as assesse d b y t he St Ge or ge’s Res pirat or y Q uesti o n naire ( S G R Q), 
o ver t he 2 4- w ee k tr eat me nt peri o d. 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of 
acti ve N E i n s p ut u m, as meas ure d b y t he differe n ce bet w ee n t he pre -treat me nt 
c o nce ntr ati o n a n d t he c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
•  T o e val uate  t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of 
acti ve N E i n r ea ge nt -sti m ulate d bl o o d, as meas ure d b y t h e differe nce bet w ee n t he 
pre -treat me nt c o nce ntrati o n a n d t he c o nce ntrati o ns at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
•  T o e val uate t he eff ect o f I N S 1 0 0 7 c o m pare d wit h place b o o n s p ut u m c ol or 
(assesse d b y t he s p ut u m c ol or c hart) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 1 4  of  7 0  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he c o nce ntrati o n of 
acti ve N E i n s p ut u m, stratifie d b y Baseli ne s p ut u m c ol or, as  meas ure d b y t he 
differe n ce b et wee n t h e pr e -treat me nt c o nce ntrati o n a n d t he c o nce ntrati o ns at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d 
tiss ue de gra dati o n bi o mar kers i n s p ut u m ( bi o mar k ers w hic h ma y b e assesse d are 
pr otei nase 3 a n d cat he psi n G) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d 
tiss ue de gra dati o n bi o mar kers i n bl o o d ( bi o mar kers w hic h ma y be assesse d are 
a bs ol ute ne utr o p hil c o u nt [ A N C], pr otei nase 3, a n d cat he psi n G) a n d uri ne at 
Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n i nfla m mat or y a n d 
tiss ue de gra dati o n bi o mar kers i n uri ne ( des m osi ne) at Wee ks 2, 4, 1 2, 2 4, a n d 2 8. 
•  T o e val uate t he  eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g 
p ul m o nar y f u ncti o n par a meter as meas ure d b y s pir o metr y (f orce d vital ca p acit y 
[ F V C] o ver t he 2 4- wee k treat me nt peri o d . 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g 
p ul m o nar y f u ncti o n par a meter as meas ure d b y s pir o metr y ( pea k e x pirat or y fl o w 
rate [ P E F R]) o ver t he 2 4-wee k treat me nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he f oll o wi n g 
p ul m o nar y f u ncti o n par a meter as meas ure d b y s pir o metr y (f orce d e x pirat or y fl o w 
[ F E F] 2 5- 7 5 % [ F E F 2 5- 7 5] o ver t he 2 4-wee k treat me nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he t otal d urati o n of 
all e x acer bati o ns ( da ys p er s u bject) o v er t he 2 4 -w ee k treat me nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he n u m ber of 
e x acer bati o ns per s u bj ect o ver t he 2 4 -w ee k treat m e nt peri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first 
p ul m o nar y e x acer b ati o n, e x acer bati o n rate, Q O L meas ures a n d p ul m o nar y f u ncti o n 
para meters ( F E V 1, F V C, P E F R, a n d F E F 2 5- 7 5), stratifie d b y Baseli ne 
Br o nc hi ectasis Se verit y I n de x ( B SI) sc ore, o ver t h e 2 4 - wee k treat me nt peri o d. 
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n ti me t o first 
p ul m o nar y e x acer b ati o n, e x acer bati o n rate, Q O L meas ures a n d p ul m o nar y f u ncti o n 
para meters ( F E V 1, F V C, P E F R, a n d F E F 2 5- 7 5), stratifie d b y t he pres e nce or 
a bse nce of P se u d o m o nas aer u gi n osa (P a ) at Scree ni n g, o ver t he 2 4-w ee k treat me nt 
peri o d. 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 1 5  of  7 0  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n t he use of res c ue 
me dicati o ns (res c ue me di cati o ns i ncl u de s h ort-acti n g bet a a g o nists [ S A B As], s h ort-
acti n g m uscari nic a nta g o nists [ S A M As], ne wl y prescri be d l o n g- acti n g beta 
a g o nists [ L A B As], l o n g- acti n g m uscari nic a nta g o nists [ L A M As], a n d o x y ge n) o ver 
t he 2 4-wee k treat me nt p eri o d.  
•  T o e val uate t he eff ect of I N S 1 0 0 7 c o m pare d wit h place b o o n h os pitalizati o ns f or a 
p ul m o nar y e x acer b ati o n o ver t he 2 4- w ee k treat me nt peri o d.  
•  T o assess t he c orrelati o ns a m o n g i nfla m mat or y a n d tiss ue de gra dati o n bi o mar kers, 
c o nce ntr ati o n of acti ve N E i n bl o o d, s p ut u m, a n d, uri ne a n d efficac y meas ures. 
3. 4.  
S afet y O bjecti ve  
T o assess t he saf et y a n d t olera bilit y of I N S 1 0 0 7 relati ve t o place b o bas e d o n a d verse 
e ve nts ( A Es), vital si g n a n d E C G meas ure me nts, p h ysical e x a ms , p ul m o nar y f u n cti o n tests 
( P F Ts) a n d cli nical la b or at or y e val uati o ns.  
3. 5.  
P h ar m ac o ki netic O bjecti ves  
T he p har mac o ki netic o bj ecti ves ar e a d dresse d i n a se parat e P K -P D  S A P.  
•  T o e val uate t he P K of I N S 1 0 0 7. 
•  T o assess t he rel ati o ns hi p bet wee n P K meas ures f or I N S 1 0 0 7 a n d efficac y, safet y 
a n d bi o mar ker m eas ur es (e. g., c o nce ntrati o ns of acti ve N E i n s p ut u m a n d rea ge nt-
sti m ulate d bl o o d) 
3. 6.  
Brief Descri pti o n  
T his is a P hase 2, ra n d o mize d, d o u ble- bli n d, place b o- c o ntr olle d, p arallel - gr o u p, 
m ultice nter, m ulti - nati o nal st u d y t o assess t he effi cac y, safet y a n d t olera bilit y, a n d P K of 
I N S 1 0 0 7 a d mi nistere d Q D f or 2 4 wee ks i n s u bjects wit h N o n -C ystic Fi br osis 
Br o nc hi e ctasis (N C F B E ). 
T his m ultice nter st u d y will be c o n d ucte d at a p pr o xi matel y 1 2 0 sites; e nr oll me nt is 
c o m petiti ve acr oss all sites. Acr oss t hes e sites, it is pla n ne d t hat a p pr o xi matel y 2 4 0 
s u bjects wit h N C F B E will be ra n d o mize d. S u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 3 
treat me nt ar ms ( 8 0 / ar m) t o recei ve eit her 1 0 m g or 2 5 m g of I N S 1 0 0 7 or m atc hi n g 
place b o. Ra n d o mizati o n will be stratifie d base d o n w het her t he Scree ni n g s p ut u m is 
c ult ure p ositi ve f or P a  a n d w het her t he s u bject is o n a mai nte na nce use of m acr oli des f or 
pre ve nti n g p ul m o nar y e x acer b ati o n. 
Eac h s u bject will recei ve st u d y treat me nt f or 2 4 w ee ks. T he e ntire st u d y is sc he d ule d t o 
ta ke a ma xi m u m of 34 wee ks f or eac h i n di vi d ual s u bject fr o m Scree ni n g ( Visit 1) t o t he 
E n d of St u d y ( E O S, Visit 1 0 ). 


St atistic al A n al ysis Pl a n  
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A P K s u b -st u d y will be c o n d ucte d at a sel ect n u m ber of sites. S u bjects w h o e nr oll at t he 
selecte d sites will u n der g o i nte nsi ve P K sa m pli n g. A ma xi m u m of 3 6 s u bjects will be 
i ncl u de d i n t he P K s u b-st u d y. F or s u bjects w h o p artici pate i n t he P K s u b-st u d y, t he visit 
wi n d o w f or Visit 4 will be ± 5 da ys. A d diti o nall y, f or s u bjects n ot partici pati n g i n t he P K 
s u b-st u d y, s parse P K sa m pli n g will be c o n d ucte d i n s u bjects at all sites wit h P K sa m pli n g 
pr ocessi n g ca pa bilities. P har mac o ki netic s a m ples will be a nal yze d i n b atc h es o n a n 
o n g oi n g basis.  
3. 6. 1.  Scree ni n g Peri o d  
T here will be a scr ee ni n g peri o d of u p t o 6 wee ks per s u bject. D uri n g t he s cree ni n g p eri o d, 
t he s u bject’s de m o gr a p hic i nf or mati o n, me dical hist or y a n d s m o ki n g hist or y will be 
o btai ne d, a p h ysical e x a m, vital si g ns a n d a s p ut u m sa m ple f or s p ut u m c ult ure a n d acti ve 
N E c o nce ntrati o n will be c ollecte d, a n d c he mistr y/ he mat ol o g y a n d uri nal ysis tests, ser u m 
pre g na nc y t est f or w o me n of c hil d beari n g p ote nti al ( W O C B P), E C G, P F T, a n d peri o d o ntal 
clea ni n g a n d e x a mi nati o n will be c o n d ucte d. Peri o d o ntal e x a mi nati o n a n d de ntal clea ni n g 
pr oce d ures f or i ncl usi o n s h o ul d be perf or m e d pri or t o ra n d o mizati o n. 
3. 6. 2.  Tre at me nt Peri o d ( Visits 2 t hr o u g h 9)  
O n Da y 1 ( Visit 2), vital si g ns, s p ut u m a n d bl o o d sa m ples f or bi o mar kers will be c o llecte d, 
a n d bl o o d c he mistr y, he mat ol o g y, a n d uri n al ysis tests, E C G, a n d pre g na n c y test ( W O C B P  
o nl y) will be c o n d u cte d. St u d y sites m ust c o nfir m s u bject eli gi bilit y b ase d o n scree ni n g la b 
res ults pri or t o ra n d o mizati o n.  After re -c o nfir mi n g t heir eli gi bilit y, s u bjects will be 
ra n d o mize d via t he Me di data Bala nce ra n d o mizati o n a n d trial s u p pl y ma n a ge m e nt 
( R T S M) s yste m i nt o 1 of 3 ar ms t o recei ve eit her 1 0 m g or 2 5 m g of I N S 1 0 0 7 or matc hi n g 
place b o i n a 1: 1: 1 rati o. 
All eli gi ble s u bjects will be ra n d o ml y assi g ne d t o treat me nt, base d u p o n t h e c o m p uter-
ge n erat e d ra n d o mizati o n list pr o d uce d b y a S y n e os Healt h  i n de pe n de nt u n bli n de d 
bi ostatisticia n i n c o ns ultati o n wit h a n I ns me d  i n- h o use statisticia n.  T w o ra n d o mizati o n 
lists will be ge ner ate d, o ne f or t he i nte nse P K s u b-st u d y a n d t h e ot her f or t he re mai ni n g 
s u bjects.   
S u bjects will recei ve a n d be i nstr ucte d o n h o w t o pr o perl y use a ha n d hel d c o m p uter ta blet 
t hat will be pre-l oa de d wit h t he Q O L- B, L C Q, a n d S G R Q q uesti o n naires a n d a d osi n g 
diar y. S u bjects will be re q uire d t o c o m plete all 3 q uesti o n naires aft er t he trai ni n g a n d pri or 
t o t he a d mi nistrati o n of t he first d ose of t heir assi g ne d st u d y dr u g o n Visit 2 ( Da y 1). 
D uri n g t h e d urati o n of t h e st u d y s u bjects will c o m plete t he 3 q uesti o n naires at t he 
s pecifie d ti mes a n d r ec or d t heir dail y d os e of st u d y dr u g i n t he d osi n g diar y. 
S u bjects will be pr o vi de d wit h a 5- wee k s u p pl y of t heir assi g n e d st u d y dr u g at eac h visit, 
e x ce pt Visits  3 a n d 9. S u bjects will be i nstr ucte d t o c o m plete t heir d osi n g diar y 
i m me diatel y after eac h d ose a n d ret ur n t heir u n us e d st u d y dr u g a n d ha n d h el d c o m p uter 
ta blet f or dr u g acc o u nta bilit y a n d data e ntr y re vie w at eac h st u d y visit. 


St atistic al A n al ysis Pl a n  
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Pa ge 1 7  of  7 0  
S u bjects will be ra n d o mize d at Visit 2 ( Da y 1) a n d ret ur n t hereaft er f or st u d y visits at 2, 4, 
8, 1 2, 1 6, 2 0, 2 4 a n d 2 8 wee ks. T here will be a visit wi n d o w of ± 3 da ys f or eac h of t he 
sc he d ule d visits. 
D uri n g t h e treat me nt p eri o d, s u bjects will be re mi n de d a b o ut t he i m p orta nce of birt h 
c o ntr ol a n d de ntal h y gie n e. I n a d diti o n t o t he r o uti ne safet y m o nit ori n g, s u bjects will be 
cl osel y m o nit ore d f or h y per ker at osis, peri o d o ntitis/ gi n gi vitis, a n d ot her i nfecti o ns, w hic h 
will be ca pt ure d as a d verse e ve nts of s pecial i nterest ( A E SIs) i n t he st u d y. 
3. 6. 3.  E n d - of-St u d y Visit ( Visit 1 0)  
S u bjects will be re q uire d t o ha ve a n E O S visit ( Visit 1 0) at Wee k 2 8 t o c ollect bl o o d a n d 
s p ut u m sa m ples f or bi o mar ker assess me nt a n d t o c ollect i nf or mati o n o n A Es a n d 
c o nc o mita nt me dicati o ns use. A P K sa m ple will be c o llecte d fr o m eac h s u bject 
partici pati n g i n t he P K s u b -st u d y. 
T he st u d y d esi g n is ill ustrate d i n Fi g ure 1.   


St atistic al A n al ysis Pl a n  
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Pa ge 1 8  of  7 0  
Fi g ure  1:  
 
St u d y Desi g n Di a gr a m  
 
3. 7.  
S U B J E C T S E L E C TI O N  
T he st u d y will e nr oll mal e or fe m ale s u bjects bet w ee n 1 8  a n d 8 5 years of a ge at Scree ni n g 
dia g n ose d wit h N C F B E ( c o nfir me d b y c h est c o m p ute d t o m o gra p h y [ C T]) w h o meet all t he 
i ncl usi o n a n d n o ne of t he e x cl usi o n criteria i n t he st u d y pr ot oc ol. 
3. 7. 1.  Re as o ns f or Wit h dr a w al/ E arl y St u d y Disc o nti n u ati o n 
S u bject  earl y st u d y disc o nti n uati o n will be s u m marize d base d o n t he f oll o wi n g reas o ns (as 
pr o vi de d i n t he E n d of St u d y pa ge of t he e lectr o ni c case re p ort F or m [eC R F) ]: 
1.  D eat h; 
2.  A d verse e ve nt  ( A E); 
3.  Pr ot oc ol vi olati o n ; 
4.  N o n -c o m plia nce wit h st u d y dr u g; 
5.  S u bj ect wit h dre w c o nse nt ; 
6.  St u d y ter mi nate d b y S p o ns or; 


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7.  P h ysicia n decisi o n; 
8.  L ost t o f oll o w u p; 
9.  Pre g na nc y ; 
1 0.  Lac k of efficac y ; 
1 1.  Ot her.   
3. 7. 2.  Re as o ns f or E arl y Tre at me nt Disc o nti n u ati o n 
S u bject earl y treat me nt disc o nti n uati o n will be s u m marize d base d o n t he f oll o wi n g reas o ns 
(as pr o vi de d i n t he E n d of Treat me nt p a ge of t h e e C R F): 
1.  Deat h;  
2.  A E; 
3.  Pr ot oc ol vi olati o n;  
4.  N o n -c o m plia nce wit h st u d y dr u g; 
5.  S u bj ect decisi o n t o wit h dra w fr o m st u d y treat me nt; 
6.  St u d y ter mi nate d b y S p o ns or; 
7.  P h ysicia n decisi o n t o wit h dra w S u bject fr o m st u d y treat me nt; 
8.  L ost t o f oll o w u p; 
9.  Pre g na nc y;  
1 0.  Treat me nt c o de pre mat urel y br o ke n b y I n vesti gat or  
1 1.  Ot her.  
3. 8.  
D E T E R MI N A TI O N O F S A M P L E SI Z E  
It is e x pecte d t hat p ul m o nar y e x acer bati o ns occ ur at a rate of 1. 2 e v e nts per s u bject year i n 
t he place b o gr o u p, c orr es p o n di n g t o 4 4. 6 % of t he place b o s u bjects b ei n g e ve nt free at 2 4 
wee ks. It is e x pecte d t hat 4 0 % m ore e v e nt free s u bjects will be o bser ve d wit hi n t he 
I N S 1 0 0 7 gr o u ps ( b ot h 1 0 m g a n d 2 5 m g) c orres p o n di n g t o 6 2. 4 % of t he I N S 1 0 0 7 s u bjects 
bei n g e ve nt fr ee at 2 4 wee ks. T he sa m ple size cal c ulati o n is f or t he first test i n t he 
hierar c hical testi n g pr oce d ure. T he h azar d rati o us e d i n t he sa m ple size calc ulati o n is 
l n( 0. 6 2 4)/l n( 0. 4 4 6) = 0. 5 8 4. Ass u mi n g t he e x acer b ati o n rate i n t he place b o ar m is 1. 2 e ve nts 
per s u bject per year, 2 1 6 s u bjects i n t otal, ra n d o mize d i n a 1: 1: 1 rati o t o 3 treat me nt ar ms 


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wit h 7 2 c o m pleters per ar m, will yi el d 8 0 % p o wer if t he e x pecte d differe nce i n t he ti me t o 
t he first e ve nt is 4 0 % after 2 4 wee ks of treat me nt wit h a t y pe I err or of 0. 1 u n der a 
hierar c hical testi n g pr oce d ure. A p pr o xi matel y 2 4 0 s u bjects dia g n os e d wit h N C F B E will be 
ra n d o mize d t o pr o vi de a p pr o xi matel y 2 1 6 s u bjects t o c o m plete t he st u d y, ass u mi n g 1 0 % of 
t he s u bjects will disc o nti n ue st u d y dr u g b ef ore c o m pleti n g 2 4 wee ks of treat me nt. 
T he ass u me d bac k gr o u n d e x acer bati o n rate fr o m t he literat ure v aries fr o m a p pr o xi matel y 1 
t o well a b o ve 1 e x acer bati o n per s u bject per year ( Bar k er et al, 2 0 1 4; Serisier et al, 2 0 1 3). 
Rece ntl y p u blis he d res ults ( De S o yza et al, 2 0 1 6) wit h a si milar s u bject p o p ulati o n ( 2 
e x acer bati o ns i n pri or 1 2 m o nt hs), s h o we d a n e x acer bati o n rat e of 1. 4 2 e v e nts per s u bject 
per year. Base d u p o n t hese rece nt res ults a c o ns er vati ve e x acer b ati o n rate of 1. 2 was 
selecte d, b ut t o e ns ur e s ufficie nt sa m ple size f or t h e st u d y a bli n de d assess me nt of t he 
bac k gr o u n d r ate will be p erf or me d. If t he o bs er ve d e x acer bati o n rate is s maller t ha n 1. 2, 
t he sa m ple size will be reassesse d. T he d ecisi o n t o i ncreas e t he sa m ple size will be ma de 
b y t he I ns m e d st u d y tea m. T he sa m ple size will n ot be decrease d b ase d o n t he sa m ple size 
reassess me nt r es ults. 
3. 9.  
T R E A T M E N T A S SI G N M E N T  & B LI N DI N G  
All eli gi ble s u bjects will be ra n d o ml y assi g ne d t o treat me nt, base d u p o n t h e c o m p uter-
ge n erat e d ra n d o mizati o n list pr o d uce d b y a n i n de p e n de nt u n bli n de d bi o statisticia n i n 
c o ns ultati o n wit h a n I ns me d i n- h o use statisticia n.  
T w o ra n d o mizati o n lists will be ge n erat e d, o ne f or t he i nte nse P K s u b- st ud y a n d t h e ot her 
f or t he re m ai ni n g s u bjects.   
Ra n d o mizati o n will be stratifie d base d o n t h e f oll o wi n g: 
1.  W het her Scree ni n g s p ut u m is c ult ure p ositi ve f or P a . 
2.  W het her  t he  s u bj ect  is  o n  a  mai nte na nce  use  of  macr oli des  f or  pre ve nti n g  p ul m o nar y 
e xacer bati o n. 
T h e ra n d o mizati o n will be desi g n e d t o e ns ure t hat t he treat me nt ar ms are b ala nce d wit hi n 
t he i nte nse P K s u b-st u d y, s parse P K s u bjects, a n d t he re mai ni n g st u d y s u bjects.  It is 
e x pecte d t hat m ost sites will e nr oll s mall n u m ber s of s u bjects, t heref ore site is n ot a desi g n 
para meter f or t h e ra n d o mizati o n.  T he ra n d o mizati o n will be gl o bal. 
3. 1 0.  
S T U D Y P R O C E D U R E S A N D  F L O W C H A R T  
St u d y s c he d ule of assess me nts is i ncl u de d i n A p pe n di x A: St u d y Sc he d ule of Assess me nts  
 


St atistic al A n al ysis Pl a n  
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4.  
E N D P OI N T S  
T he e n d p oi nts a d dress e d i n t his S A P are descri be d i n t his secti o n. 
4. 1.  
P RI M A R Y E N D P OI N T  
T he pri mar y e n d p oi nt is t he ti me t o t he first p ul m o nar y e x acer bati o n o ver t h e 2 4- wee k 
treat me nt peri o d. 
A p ul m o nar y e x acer b ati o n i n t his st u d y is defi n e d as ha vi n g 3 or m ore of t he f oll o wi n g 
s y m pt o ms f or at least 4 8 h o urs res ulti n g i n a p h ysi cia n’s decisi o n t o prescri be a nti bi otics. 
1.  I n crease d c o u g h; 
2.  I n crease d s p ut u m v ol u me or c ha n ge i n s p ut u m c o nsiste nc y; 
3.  I n crease d s p ut u m p ur ule nce; 
4.  I n crease d br eat hless ness a n d/ or decreas e d e x ercis e t olera nce; 
5.  Fati g ue a n d/ or m alaise;  
6.  He m o pt ysis. 
S u bjects o n c hr o nic macr oli de t hera p y w h ose o nl y c ha n ge i n t hera p y is d ose or fre q ue nc y 
a dj ust me nt will n ot meet t he defi niti o n of  e x acer b ati o n.  
4. 2.  
S E C O N D A R Y E N D P OI N T S  
1.  C ha n ge  fr o m  Baseli ne  i n  Q O L -B  res pirat or y  s y m pt o ms  sc ore  o ver  t he  2 4 -wee k 
treat me nt peri o d. 
2.  C ha n ge  fr o m  Scr ee ni n g  i n  p ost -br o nc h o dilat or  F E V 1  o ver  t he  2 4 -wee k  treat me nt 
peri o d. 
3.  Rate of p ul m o nar y e x acer bati o ns ( n u m ber of e v e nts per pers o n -ti me) o v er t he 2 4-
wee k treat me nt peri o d.  
T he e n d p oi nts ass o ciate d wit h ne utr o p hil elastas e i n s p ut u m are d escri b e d i n a se p arat e 
d oc u me nt, P K/ P D Statistical A nal ysis Pla n .  
 
4. 3.  
E X P L O R A T O R Y E N D P OI N T S  
1.  C ha n ge fr o m Bas eli ne i n sc ore of Q O L -B d o mai ns (e x cl u di n g res pirat or y s y m pt o ms 
d o mai n) o ver t he 2 4- wee k treat me nt peri o d.  


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2.  C ha n ge  fr o m  Baseli ne  i n Q O L  as  assess e d  b y  t he  L C Q  s c ore  o v er  t he  2 4 -wee k 
treat me nt peri o d. 
3.  C ha n ge fr o m Baseli ne i n S G R Q t otal sc ore o ver t h e 2 4 - wee k treat me nt peri o d. 
4.  C ha n ge fr o m Baseli ne i n s p ut u m c ol or (assesse d b y t h e s p ut u m c ol or c hart) at Wee ks 
2, 4, 1 2, 2 4, a n d 2 8. 
5.  C ha n ge fr o m Scr ee ni n g i n F V C at Wee ks 1 2 a n d 2 4. 
6.  C ha n ge fr o m Scr ee ni n g i n P E F R at Wee ks 1 2 a n d 2 4. 
7.  C ha n ge fr o m Scr ee ni n g i n F E F 2 5 -7 5 at Wee ks 1 2 a n d 2 4. 
8.  T otal d urati o n (i n da ys) of e x acer bati o ns, per s u bject, o ver t he 2 4 -w ee k  treat me nt 
peri o d. 
9.  T otal n u m ber of e x acer b ati o ns per s u bject o ver t he 2 4- wee k treat me nt peri o d. 
1 0.  Ti me  t o  first  p ul m o nar y  e x acer b ati o n,  e x acer b ati o n  rate,  Q O L  Meas ures,  a n d 
p ul m o nar y  f u ncti o n par a meters  ( F E V 1,  F V C,  P E F R,  a n d  F E F 2 5 -7 5),  stratifie d b y  
Br o nc hi ectasis Se verit y I n de x ( B SI) sc ore at bas eli ne, o ver t he 2 4 -wee k treat me nt 
peri o d. 
1 1.  Ti me  t o  first  p ul m o nar y  e x acer b ati o n,  e x acer b ati o n  rate,  Q O L  Meas ures,  a n d 
p ul m o nar y f u n cti o n para meters ( F E V 1, F V C, P E F R, a n d F E F 2 5 -7 5), stratifie d b y t he 
prese nce or a bs e nce of P a  at Scree ni n g, o ver t he 2 4 -wee k treat me nt peri o d.  
1 2.  Fre q u e nc y of us e of res c u e me dicati o ns (res c ue me dicati o ns i ncl u de s h ort -acti n g beta 
a g o nists [ S A B As], s h ort -acti n g m uscari nic a nta g o nists [ S A M As], ne wl y prescri be d 
l o n g-acti n g beta a g o nists [ L A B As], l o n g -acti n g m uscari nic a nta g o nists [ L A M As], 
a n d o x y ge n) o v er t he 2 4- wee k treat me nt peri o d.  
1 3.  N u m ber of s u bjects h os pitalize d d ue t o p ul m o nar y e x acer b ati o ns b y t h e e n d of t he 
2 4- wee k tr eat me nt  peri o d. 
4. 4.  
S A F E T Y E N D P OI N T S  
T he safet y e n d p oi nts will i ncl u de t he f oll o wi n g: 
1.  A Es  
2.  1 2- Lea d E C G meas ure m e nts  
3.  Cli nical la b orat or y testi n g r es ults  


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4.  Vital si g n meas ur e me nts  
5.  P h ysical e x a mi nati o n res ults  
6.  P ul m o nar y F u ncti o n  Test ( P F T ) meas ure me nts  
A E SIs t hat will be r e p ort e d i ncl u de h y per k erat osis, peri o d o ntitis/ gi n gi vitis, a n d ot her 
i nfecti o ns as i de ntif y b y t he i n vesti gat or i n t he cas e re p ort f or m .   
 
 
 
 
 


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5.  
A N A L Y SI S P O P U L A TI O N S 
 
5. 1.  
I N T E N T-T O -T R E A T P O P U L A TI O N  
All s u bjects w h o are ra n d o mize d will be i ncl u de d i n t he I nt e nt- t o-treat (I T T) P o p ulati o n. 
S u m maries a n d a nal yses utilizi n g t he I T T P o p ulati o n will s u m marize/a nal yze s u bjects 
acc or di n g t o t heir ra n d o mize d treat me nt. T he I T T P o p ulati o n will be use d f or all a nal yses 
of efficac y e n d p oi nts. 
 
5. 2.  
P E R -P R O T O C O L P O P U L A TI O N  
All s u bjects w h o are ra n d o mize d a n d c o m plete d t he st u d y wit h o ut a n y maj or de viati o ns 
will be i ncl u de d i n t he P er- pr ot oc ol ( P P) P o p ulati o n, w here s u bjects wit h a n a ns wer ‘ Yes’ 
t o t he q uesti o n ‘ Di d t he S u bject c o m plete t he st u d y? ” gi ve n o n t he e C R F will be 
c o nsi dere d as c o m pleti n g t he st u d y.   
S u bjects wit h maj or de viati o ns will be i de ntifie d b y t he I ns m e d St u d y tea m pri or t o 
brea ki n g t he st u d y bli n d.  Maj or de viati o ns ma y i ncl u de, b ut are n ot li mite d t o t he 
f oll o wi n g: 
1.  S u bj ects di d n ot recei ve t he st u d y trea t me nt t o w hic h he/s he was ra n d o mize d  
2.  S u bj ect di d n ot meet I ncl usi o n Criteria 4 or 7. 
3.  S u bj ect met E xcl usi o n C riteria 1, 2, 3, 4, 5, 6, 1 2, 1 3, 1 4, 1 6, 1 7, 2 1, or 2 2. 
4.  S u bj ect di d n ot c o m plete E n d of St u d y Visit ( E O S), e xce pt f or deat h. 
S u m maries a n d a nal yse s utilizi n g t he P P P o p ulati o n will s u m marize/a nal yze s u bjects 
acc or di n g t o t heir ra n d o mize d treat me nt. T he P P p o p ulati o n will be use d f or t he s u p p orti ve 
a nal ysis of t he pri mar y efficac y e n d p oi nt.  
 
5. 3.  
S A F E T Y P O P U L A TI O N  
All s u bjects w h o recei ve d at least 1 d ose of t he st u d y dr u g will be i ncl u de d i n t he S afet y 
P o p ulati o n.  
S u m maries a n d a nal yses utilizi n g t he S afet y P o p ulati o n will s u m marize/a nal yz e s u bjects 
acc or di n g t o t heir act ual treat me nt recei ve d. T he S afet y P o p ulati o n will be use d f or all 
a nal ys es of safet y e n d p oi nts. 
5. 4.  
P H A R M A C O KI N E TI C P O P U L A TI O N  
Please  see t he P K-P D  S A P f or t his defi niti o n . 


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5. 5.  
P H A R M A C O D Y N A MI C P O P U L A TI O N  
Please  see t he P K-P D S A P f or t his defi niti o n .  
5. 6.  
P R O T O C O L D E VI A TI O N S  
Fi nal assess me nt of maj or pr ot oc ol de viati o ns a n d assi g n me nts of s u bjects t o a nal ysis 
p o p ulati o ns will be disc usse d i n a bli n d data re vie w meeti n g pri or t o t he st u d y dat a base 
l oc k. 
 


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6.  
G E N E R A L A S P E C T S F O R S T A TI S TI C A L  A N A L Y SI S  
6. 1.  
G E N E R A L M E T H O D S  
•  
S A S ®  versi o n 9. 4 or hi g her will be use d ( S A S I nstit ute, I nc, Car y, N ort h Car oli na).  
•  
U nless ot her wise s pecifie d, s u m maries will be prese nte d f or eac h treat me nt.  
•  
T he t otal n u m ber of s u bjects i n eac h treat me nt gr o u p ( N) will be use d as t he de n o mi nat or f or 
perce nta ge calc ulat i o ns, u nless state d ot her wise i n t he ta ble s hell.  A r o w f or s u m mar y of missi n g 
o bser vati o ns will be i ncl u de d w here necessar y.  
•  
C o nti n u o us varia bles will be s u m marize d usi n g t he n u m ber of o bser vati o ns ( n), mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, a n d ma x i m u m. Cate g orical varia bles will be s u m marize d usi n g 
n u m ber of o bser vati o ns ( n), fre q ue nc y, a n d perce nta ges of s u bjects wit hi n t he treat me nt gr o u p . 
•  
All s u bjects will be prese nte d i n  t he s u bject data listi n gs if i nf or mati o n is prese nt a n d u nless 
ot her wise n ote d . 
•  
I n ge neral, t he listi n gs will be s orte d b y treat me nt ( place b o/ 1 0 m g I N S 1 0 0 7/ 2 5 m g I N S 1 0 0 7, 
s u bj ect n u m ber, a n d assess me nt date (a n d ti me) if a p plica ble.  
•  
M ulti ple assess me nts at a gi ve n ti me p oi nt ( pla n ne d, re peat) will n ot be i ncl u de d i n s u m mar y 
tables u nless s pecifie d ot her wise, b ut will be i ncl u de d i n t he listi n gs.   
•  
I n ge neral, u nsc he d ule d visit data will be liste d (i n date or der) b ut n ot i ncl u de d i n t he s u m mar y 
ta bles.  
•  
Visit la bels will be i n t he f or mat Scree ni n g, Baseli ne, Wee k 2, Wee k 4, Wee k  8, Wee k 1 2, Wee k 
1 6, Wee k 2 0, Wee k 2 4, E n d of St u d y; all u nsc he d ule d visits will ha ve U N S a d de d. 
 
6. 2.  
K E Y D E FI NI TI O N S  
6. 2. 1.  B aseli ne  
U nless ot her wise s pecifie d, t he baseli ne assess me nt will be t he last a vaila ble meas ure me nt 
ta ke n pri or t o t he first d ose of st u d y dr u g.  
6. 2. 2.  N o mi n al D a y  
N o mi nal da y is t he s c he d ule d da y relati ve t o first d osi n g. Da y 1 is t he da y of first d osi n g.  
T he da y i m me diatel y pri or t o d osi n g is Da y - 1.  
6. 2. 3.  A d verse E ve nts ( A Es) a n d C o nc o mit a nt Me dic ati o ns ( C Ms) 
A treat me nt-e mer ge nt a d verse e v e nt ( T E A E ) is a n y A E t hat b e gi ns d uri n g t he treat me nt-
e mer ge nt peri o d or t he w orse ni n g of a pre- e xisti n g me dical c o n diti o n d uri n g t he treat me nt -
e mer ge nt peri o d. T he tr eat me nt- e mer ge nt peri o d be gi ns w h e n t he s u bject first recei ves 
st u d y dr u g a n d e n ds 3 0 d a ys after t he s u bject last recei ves st u d y dr u g  or t he date of 
s u bject’s E O S visit, w hic he ver is later.   
A Es t hat occ ur b et wee n t he ti me t he s u bject si g ns t he I C F f or t h e st u d y a n d t he ti me w he n 
t he s u bject recei ves his/ h er first d ose will be re p orte d as me dical hist or y a n d n ot as a 
T E A E.  


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C o nc o mita nt me dicati o ns are defi ne d as me di cati o ns ta ke n after t he start of st u d y dr u g 
a d mi nistrati o n or starte d pri or t o t he start of st u d y dr u g a d mi nistrati o n a n d c o nti n ue d after 
t he start of st u d y dr u g a d mi nistrati o n. F or A Es/ T E A Es a n d C Ms, ti me si nce (first) d ose 
will be calc ulate d as t he differe n ce b et wee n t h e e ve nt or me dicati o n start d ate a n d t he d ate 
of t he first d ose. Ti me si nce (first) d os e will be e x presse d i n da ys. Met h o ds f or ha n dli n g 
partial start dates of A E s a n d C Ms are des cri be d i n Secti o n 6. 3 . D urati o n will be calc ulate d 
f or A Es t hat r es ol ve as t h e differ e nce bet wee n t he start date a n d e n d  date a n d w ill be 
e x presse d i n da ys. Ti me si nce (first) d os e a n d d urati o n will o nl y b e calc ulate d w he n b ot h 
dates ar e c o m plete.   
6. 3.  
MI S SI N G D A T A  
A d verse e ve nts  a n d C Ms wit h i nc o m plete start dates will be c o nsi dere d as treat me nt -
e mer ge nt or c o nc o mita nt  u nless t he e n d date precl u des t hat p ossi bilit y.  T h e f oll o wi n g 
al g orit h m  will be utilize d:  
1.  If an A E or  me dicati o n starte d a n d st o p pe d pri or t o t he start of st u d y treat me nt t he 
gi ve n A E or me dicati o n will be c o nsi dere d as pri or. T his will be verifie d usi n g t he 
al g orit h ms bel o w (st e ps 2 t hr o u g h 3).  
2.  O nl y t h e start year is r e p orte d: If t he year is after or t he sa m e as t he year of t he first 
d ose date, t he n t he A E  will  be  c o nsi dere d  treat me nt -e mer ge nt  a n d  t he  me dicati o n 
will be c o nsi dere d as c o n c o mita nt u nless t he e n d d ate precl u des t hat p ossi bilit y.  
3.  O nl y t h e start m o nt h a n d year are re p ort e d: If t he m o nt h/ year is after or t he sa me as 
t he  m o nt h/ year  of  t he  first  d ose  date,  t he n  t he A E  will  be  c o nsi dere d  treat me nt -
e mer ge nt  a n d t he me dicati o n will be c o nsi dere d as c o nc o mita nt  u nless t he e n d date 
precl u des t hat p ossi bilit y. 
 
T here will be n o f urt her i m p utati o n of missi n g data u nless ot her wise n ote d .  
 
6. 4.  
VI SI T WI N D O W S  
Data c ollecte d at u nsc h e d ule d visits t hat occ urre d o utsi de t he ti me wi n d o ws s pecifie d i n 
t he pr ot oc ol (e. g., p ost-d ose cli nical la b orat or y tests d o ne o n da ys n ot s pecifie d i n t he 
pr ot oc ol) will be i ncl u de d i n t he data listi n gs b ut will n ot be i ncl u de d i n t he a nal yses, 
u nless ot her wise s pecifie d. 
6. 5.  
V A RI A BI LI T Y B Y S I T E 
Gi ve n t he lar ge n u m b er of sites, a n d a s mall n u m ber of s u bjects p er site, t here will be n o 
m o del a dj ust me nt f or it.  


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7.  
D E M O G R A P HI C S , O T H E R B A S E LI N E  
C H A R A C T E RI S TI C S  A N D M E DI C A TI O N  
7. 1.  
S U B J E C T DI S P O SI TI O N A N D WI T H D R A W A L S  
Listi n gs of treat me nt assi g n me nts, i ncl u di n g t he ra n d o mizati o n n u m ber, s u bject’s 
i de ntificati o n, date of r a n d o mizati o n, a n d treat me nt gr o u p will be prese nte d.  
T he f oll o wi n g fre q u e nc y of s u bjects ( n u m ber a n d perce nt) will be dis pla ye d b y treat me nt 
gr o u p a n d acr oss treat me nt gr o u ps : s u bjects i n t he Safet y p o p ulati o n b y act ual treat me nt, 
s u bjects i n t he I T T P o p ulati o n b y r a n d o mize d treat me nt, s u bjects i n t he P P  P o p ulati o n b y 
ra n d o mize d treat me nt, s u bjects i n t he PK P o p ulati o n b y act ual treat me nt, s u bjects i n t he 
P har mac o d y na mic P o p ul ati o n b y act ual treat me nt, s u bjects w h o c o m plete d t he st u d y  b y 
ra n d o mize d treat me nt, s u bjects w h o disc o nti n ue d t he st u d y earl y b y ra n d o mize d treat me nt, 
t he pri mar y reas o n f or earl y st u d y disc o nti n uati o n b y ra n d o mize d treat me nt , s u bjects w h o 
c o m plete d t he treat me nt b y r a n d o mize d treat me nt, s u bjects w h o disc o nti n u e d t he treat me nt 
earl y b y r a n d o mize d treat me nt, a n d t he pri mar y reas o n f or earl y treat me nt disc o nti n uati o n 
b y r a n d o mize d treat me nt .  
Listi n gs of st u d y a n d treat me nt c o m pleti o n/ disc o nti n uati o n, i ncl u di n g date of 
c o m pleti o n/ disc o nti n uati o n, last d ose of st u d y dr u g a d mi nistrati o n a n d pri mar y reas o n f or 
disc o nti n uati o n will be prese nte d . 
All i ncl usi o n/e x cl usi o n criteria defi niti o ns will be liste d. I ncl usi o n/e x cl usi o n criteria 
vi olati o ns will be liste d b y s u bject. Pr ot oc ol d e viati o ns will be liste d  a n d t he maj or 
pr ot oc ol de viati o ns will be i de ntifie d i n t he listi n g . 
S u bjects e x cl u de d fr o m a n y a n al ysis p o p ulati o ns will be liste d i ncl u di n g t he reas o ns f or 
e x cl usi o ns. 
7. 2.  
D E M O G R A P HI C S A N D  BA S E LI N E C H A R A C T E RI S TI C S  
De m o gra p hic a n d baseli n e c har acteristics, i ncl u di n g a ge, se x, race, et h nicit y, hei g ht, 
wei g ht, B MI , P a  p ositi ve, mai nte na nce us e of Macr oli des, Br o nc hiectasis Se verit y I n de x 
(B SI ), C T Sca n c o nfir mati o n of Br o nc hiectasis, s m o ki n g stat us, a n d pac k years, t hree or 
m ore e x acer b ati o ns i n pri or 1 2 m o nt hs, h os pitalize d f or e x acer b ati o n i n pri or 2 4 m o nt hs, 
use of i n hale d ster oi ds,  F E V 1 ( % Pre dicte d) < 5 0 %, hist or y of C hr o ni c O bstr ucti ve 
P ul m o nar y Disease ( C O P D) , a n d Ast h ma will be s u m marize d b y treat me nt gr o u p a n d 
acr oss treat me nt gr o u ps usi n g sta n dar d descri pti ve statistics ( n u m ber of s u bjects, 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 f or c o nti n u o us varia bles, a n d 
t he n u m ber a n d p erce nta ge of s u bjects f or cate g orical varia bles) f or all s u bjects i n t he I T T, 
S afet y, P P, P D, a n d P K P o p ulati o n s se paratel y. Patie nts wit h me dical hist or y of c hr o nic 
o bstr ucti ve p ul m o nar y disease, c hr o nic br o n c hitis, p ul m o nar y e m p h ys e ma, br o nc hial 
o bstr ucti o n, a n d br o nc hitis will be c o nsi dere d as h a vi n g a hist or y of C O P D. N o f or mal 
statistical c o m paris o ns bet wee n p o p ulati o ns or treat me nt gr o u ps will be perf or me d.  


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All d e m o gr a p hic data  a n d baseli ne c haracteristics pr o vi de d i n t he ta bles  will als o be liste d 
b y s u bject.   I nf or mati o n r e gar di n g t he B SI (t he B SI s c ore calc ulati o n is des cri be d i n 
A p pe n di x B:  Calc ulati o n of Br o n c hiectasis Se verit y I n de x ), C T sca n c o nfir mati o n of 
Br o nc hi ectasis, a n d s m o ki n g stat us hist or y will be liste d se parat el y f or all s u bjects.  
7. 3.  
M E DI C A L A N D S U R GI C A L HI S T O R Y  
Me dical  a n d s ur gical hist or y will be c o de d usin g Me d D R A 2 2. 0 , s orte d al p ha beticall y b y 
s yste m or ga n class a n d preferre d t er m, s u m marize d b y treat me nt gr o u p a n d acr oss 
treat me nt gr o u ps f or t h e S afet y P o p ulati o n a n d I T T P o p ulati o n a n d liste d f or all s u bjects i n 
t he I T T P o p ulati o n.  
7. 4.  
P RI O R A N D C O N C O MI T A N T M E DI C A TI O N  
Pri or a n d c o nc o mita nt m e dicati o ns will be c o de d usi n g versi o n Se p 1, 2 0 1 8 of t he W orl d 
Healt h Or ga nizati o n dr u g c o des a vaila bl e ( W H O D D E ); t he versi o n us e d will be 
d oc u me nte d i n a f o ot n ote t o t he listi n g. 
Pri or me dicati o ns are d efi ne d as me dicati o ns wit h a st o p date a n d ti me pri or t o t he start of 
st u d y dr u g a d mi nistrati o n. 
Pri or a n d c o nc o mita nt m e dicati o ns will be s u m marize d se paratel y usi n g n ( %) of s u bjects 
f or eac h treat me nt gr o u p a n d acr oss treat me nt gr o u ps b y A T C cl ass ter m ( A T C 4) a n d 
sta n dar d me dicati o n na me f or t he Safet y P o p ulati o n.  S u bjects ma y ha v e m ore t ha n o ne 
me dicati o n per A T C cate g or y a n d sta n dar d me dicati o n na me.  At eac h le vel of 
s u m marizati o n, a s u bject will o nl y b e c o u nte d o n ce if o ne or m ore me dicati o ns are 
re p orte d b y t he s u bject at t hat s u m mar y le v el.  
Pri or a n d c o nc o mita nt m e dicati o ns data will be liste d c hr o n ol o gicall y b y treat me nt gr o u p, 
s u bject, a n d will i ncl u de t he data c ollect e d i n t he e C R F, al o n g wit h t he c o d es. If n o pri or or 
c o nc o mita nt me dicati o ns are r e p orte d, t his will be n ote d i n place of t he listi n g.  
 


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8.  
E F FI C A C Y  
8. 1.  
HI E R A R C H Y O F E N D P OI N T T E S TI N G  
F or all efficac y a n al ys es, I N S 1 0 0 7 1 0 m g a n d 2 5 m g will eac h be c o m pare d se parat el y t o 
place b o.  N o h y p ot hesis t esti n g bet w ee n acti ve treat me nt gr o u ps will be c o n d ucte d.  All p -
val ues will be prese nt e d as  o ne-si de d p-v al ue s.  
T he hierarc h y of t h e a nal ysis is t he f oll o wi n g: pri mar y a nal ysis of I N S 1 0 0 7 2 5 m g a gai nst 
place b o t o test t he s u peri orit y of t he I N S 1 0 0 7 2 5 m g d ose at t he o ne-si de d 0. 1 al p ha le vel, 
t he n t he al p ha is split bet wee n t he I N S 1 0 0 7 2 5 m g sec o n dar y e n d p oi nts a n d t he I N S 1 0 0 7 
1 0 m g pri mar y a nal ysis. If t he s u peri orit y of I N S 1 0 0 7 2 5 m g a gai nst place b o is n ot 
ac hie ve d, t h e n all al p ha is s pe nt, a n d n o f urt her h y p ot hesis testi n g ma y be c o n d ucte d.   
T he sec o n d ar y e n d p oi nts at t he I N S 1 0 0 7 2 5 m g d ose will be teste d f or s u peri orit y a gai nst 
place b o a n d t h e t y p e I err or rate will be c o ntr olle d at t he o ne-si de d al p ha le v el of 0. 0 5 
usi n g t he H ol m- B o nferr o ni met h o d.  If t h e pri mar y a n al ysis of I N S 1 0 0 7 1 0 m g a gai nst 
place b o d oes n ot de m o nstrate t he s u peri orit y of t h e I N S 1 0 0 7 1 0 m g d os e at t he o ne-si de d 
0. 0 5 al p ha le vel, t he n t he 0. 0 5 al p ha is s pe nt, a n d n o f urt her h y p ot hesis testi n g will be 
c o n d ucte d o n t he I N S 1 0 0 7 1 0 m g sec o n dar y e n d p oi nts.   
If t he pri mar y a nal ysis of I N S 1 0 0 7 1 0 m g a gai nst place b o d oes d e m o nstrate t he s u peri orit y 
of t he I N S 1 0 0 7 1 0 m g d ose at t he o ne-si de d 0. 0 5 al p ha le vel, t he n t he 0. 0 5 al p ha is n ot 
s pe nt a n d t he sec o n d ar y e n d p oi nts at t he I N S 1 0 0 7 1 0 m g d ose will be teste d f or s u peri orit y 
a gai nst place b o a n d t he t y p e I err or rate will be c o ntr olle d at t he o ne -si de d al p ha le vel of 
0. 0 5 usi n g t he H ol m- B o nferr o ni met h o d.  
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 1  of  7 0  
 
 
 
F or t he e x pl orat or y e n d p oi nts t he p- val ues will be c o nsi dere d d escri pti ve a n d h y p ot hesis 
ge n erati n g. T y p e I err or will n ot be c o ntr olle d f or t he e x pl orat or y e n d p oi nts .  
 
8. 2.  
P RI M A R Y E F FI C A C Y E N D P OI N T  A N A L Y S E S A N D  
S U M M A RI E S  
8. 2. 1.  T he ti me t o t he first p ul m o n ar y e x acer b ati o n o ver t he 2 4- w ee k tre at me nt 
peri o d  
T he pri mar y efficac y a n al ysis will be c o n d ucte d o n t he I T T P o p ulati o n.  A p ul m o nar y 
e x acer bati o n i n t his st u d y is defi n e d as ha vi n g 3 or m ore of t he f oll o wi n g s y m pt o ms f or at 
least 4 8 h o urs res ulti n g i n a p h ysi cia n’s decisi o n t o prescri be a nti bi otics. S uc h 
e x acer bati o ns will be c o nsi dere d as pr ot o c ol defi n e d e x acer b ati o ns.  
1.  I n crease d c o u g h;  
2.  I n crease d s p ut u m v ol u me or c ha n ge i n s p ut u m c o nsiste nc y;  
3.  I n crease d s p ut u m p ur ule nce;  
Pri m ary E n d p oi nt
2 5 m g vs Pl ac e b o
0. 1 al p h a, o n e -
si d e d
N o f urt h er t esti n g
S u p eri orit y n ot ac hi e v e d
S u p eri orit y ac hi e v e d
Pri m ary E n d p oi nt
1 0 m g vs Pl ac e b o
0. 0 5 al p h a, o n e -
si d e d
S u p eri orit y ac hi e v e d
S ec o n d ary E n d p oi nts
1 0 m g vs Pl ac e b o
0. 0 5 al p h a, o n e -si d e d
H ol m -B o nf err o ni
S ec o n d ary E n d p oi nts
2 5 m g vs Pl ac e b o
0 0 5 al p h a, o n e -si d e d
H ol m -B o nf err o ni
S u p eri orit y n ot ac hi e v e d
N o f urt h er t esti n g


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 2  of  7 0  
4.  I n crease d br eat hless ness a n d/ or decreas e d e x ercis e t olera nce;  
5.  Fati g ue a n d/ or m alaise;  
6.  He m o pt ysis.  
S u bjects o n c hr o nic macr oli de t hera p y w h ose o nl y c ha n ge i n t hera p y is d ose or fre q ue nc y 
a dj ust me nt will n ot meet t he defi niti o n of e x acer b ati o n.   T his c o n diti o n will be satisfie d if 
t he i n vesti gat or res p o n ds “ Y” t o “ Were ne w a nti bi otics prescri be d? ” o n t he res pecti ve 
p ul m o nar y e x acer b ati o n  e C R F pa ge .  
A mi ni m u m of 4 wee ks m ust occ ur bet wee n o ne e x acer bati o n o nset a n d t h e ne xt. A n y 
e x acer bati o ns t hat occ ur less t ha n 4 wee ks fr o m t he pri or e x acer bati o n will n ot be 
c o nsi dere d a ne w e x acer bati o n.  
A n y p ul m o nar y e x acer b ati o n i n t he st u d y b et wee n Visit 2 t hr o u g h E O S  will be i ncl u de d i n 
t he pri mar y e n d p oi nt, re gar dless of w h et her it was ass ociate d wit h a sc h e d ul e d or 
u nsc he d ule d visit. 
T he n ull h y p ot hesis ass u mes t hat t he ti me t o t he first e x acer bati o n is i n de pe n de nt of 
treat me nt, a n d t he alter nati ve h y p ot hesis ass u mes t hat t he ti me t o t he first e x acer bati o n is 
ass ociate d wit h I N S 1 0 0 7 2 5 m g. The h y p ot hesis will be teste d at o ne-si de d al p ha of 0. 1. 
Ka pla n - Mei er pr o d u ct li mit esti mat ors of t he s ur vi v or f u ncti o n ( pr o ba bilit y of sta yi n g 
e ve nt fr ee) will be s u m m arize d f or me dia ns a n d t heir 8 0 % CI, 2 5t h perce ntiles a n d 7 5t h 
perce ntiles , a n d t he mi ni m u m a n d t he ma xi m u m.   
If t he pri mar y a nal ysis of I N S 1 0 0 7 2 5 m g a gai nst place b o s u p p orts t he s u peri orit y of t he 
I N S 1 0 0 7 2 5 m g d ose at t he o ne-si de d 0. 1 al p ha le v el, t he n t he pri mar y  a nal ysis of I N S 1 0 0 7 
1 0 m g a gai nst place b o will be test at o ne-si de d al p ha of 0. 0 5. Ka pl a n -Meier pr o d uct li mit 
esti mat ors of t he s ur vi v or f u ncti o n will be s u m marize d f or me dia ns a n d t heir 9 0 % CI, 2 5t h 
perce ntiles a n d 7 5t h perce ntiles, a n d t he mi ni m u m a n d t h e ma xi m u m .   
T he ti me t o first p ul m o nar y e x acer b ati o n ( da ys) will be calc ulate d as:  t he ti me fr o m date of 
ra n d o mizati o n t o date of first d oc u me ntati o n of e x acer b ati o n, as defi n e d a b o ve. 
T he effi cac y a nal ysis of t he ti me t o t he first e x acer bati o n will be pe rf or me d usi n g t he 
stratifie d l o g ra n k test f or t he I T T P o p ulati o n a n d usi n g Ka pl a n Meier c ur v es . T he 
stratificati o n will be base d o n t he f oll o wi n g stratifi cati o n fact ors: P a  c ol o nizati o n stat us 
a n d mai nte na nce a nti bi otic use at Baseli ne ( Yes/ N o) fr o m t he ra n d o mizati o n. 
S u bjects w h o d o n ot ha ve a p ul m o nar y e x acer bati o n d uri n g t he tri al will be ce ns ore d at t he 
date of last partici p ati o n i n t he trial. T he n u m ber of s u bjects wit h a n e ve nt a n d ce ns ore d 
will be s u m marize d.   
Sa m ple S A S ® c o de is s h o w n bel o w:  
P R O C  LI F E T E S T D A T A = x x x x  M E T H O D = K M O U T S U R V = S U R V A L P H A Q T = < < 0. 2 or 0. 1 > >;  
    TI M E T T F P E * C N S R ( 1);  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 3  of  7 0  
    S T R A T A P A E R O A N TI BI   / G R O U P = T R T P T E S T = L O G R A N K ; 
R U N;  
W here , T T F P E = ti me t o first P E ( da ys), T R T P = ra n d o mize d treat me nt gr o u p, P A E R O = 
Pa c ol o nizati o n stat us, A N TI BI = mai nte n a nce a nti bi otic use at Baseli ne, C N S R( 1) = 
ce ns ori n g i n dicat or v aria ble w here 1 re prese nts ce ns ore d val ues.  
T he pl ot of Ka pla n- M eier esti mates f or t he treat m e nt gr o u ps will als o be prese nte d.   
8. 2. 2.  Se nsiti vit y A n al yses of t he ti me t o t he first p ul m o n ar y e x acer b ati o n o ver t he 
2 4- w ee k tre at me nt peri o d  
T he first se nsiti vit y a n al ysis of t he pri mar y e n d p oi nt, ti me (i n da ys) t o first p ul m o nar y 
e x acer bati o n  is t o assess t he r o b ust ness of t he pri mar y a nal ysis t o t he data sc o pe f or t he 
a nal ysis.  T h e pri mar y e n d p oi nt will be a nal yze d i n t he sa me ma n ner as t he pri mar y 
a nal ysis, b ut usi n g t he P P P o p ulati o n.  
T he sec o n d  se nsiti vit y a n al ysis of t he pri mar y e n d p oi nt, ti me (i n da ys) t o first p ul m o nar y 
e x acer bati o n  is t o assess t he i m pact of t he ra n d o mizati o n stratificati o n fact ors.  T he 
pri mar y e n d p oi nt will be a nal yze d usi n g t he stratifie d C o x Pr o p orti o nal Hazar ds m o del. 
T he m o del will i ncl u de t he ter m f or treat me nt gr o u p wit h P a  c ol o nizati o n stat us, a n d 
mai nte na nce a nti bi otic use at Baseli ne  as t he stratificati o n fact ors. It is c urre ntl y ass u me d 
t hat t he pr o p orti o nal hazar ds ass u m pti o n will be s u p p orte d b y t he data.  If t he pr o p orti o nal 
hazar ds ass u m pti o n is clearl y n ot s u p p orte d b y t he data after o b ser vi n g a statisticall y 
si g nifica nt n o n- zer o c orr elati o n bet wee n t h e Sc h o e nfel d resi d uals a n d t he c orres p o n di n g 
ra n ke d f ail ure ti mes, t he n t he pr o p orti o nal hazar ds res ults will be dee me d i n vali d d ue t o a 
vi olati o n of t he ass u m pti o ns.   
T he I N S 1 0 0 7 2 5 m g vs. place b o hazar d rati o will be prese nt e d wit h 8 0 % CI . T h e I N S 1 0 0 7 
1 0 m g vs. place b o hazar d rati o will be prese nte d wit h 9 0 % CI. O n e -si de d p-val ue will be 
prese nte d f or b ot h t he treat me nt gr o u p effects.  
Sa m ple S A S ® c o de is s h o w n bel o w:  
P R O C P H R E G D A T A = D A T AI N A L P H A = < < 0. 2 or 0. 1 > >  A T RI S K N A M E L E N = 7 0;  
C L A S S T R T P ( R E F = ' Place b o ') P A E R O A N TI BI / O R D E R = I N T E R N A L P A R A M = G L M;  
M O D E L T T F P E * C N S R( 1) = T R T P / RI S K LI MI T S T Y P E 3 RI D GI N G = A B S O L U T E;  
S T R A T A P A E R O A N TI BI;  
L S M E A N S T R T P/ DI F F;  
R U N;  
W here , T T F P E = ti me  t o first P E ( da ys), T R T P = ra n d o mize d treat me nt gr o u p, P A E R O = 
Pa c ol o nizati o n stat us, A N TI BI = mai nte n a nce a nti bi otic use at Baseli ne , C N S R( 1) = 
ce ns ori n g i n dicat or v aria ble w here 1 re prese nts ce ns ore d val ues.  
T he t hir d se nsiti vit y a nal ysis is t o assess t he r o b ust ness of t he m o del t o a d diti o nal 
c o variates. T h e pri mar y e n d p oi nt will be a nal yze d usi n g t he C o x Pr o p orti o nal Hazar ds 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 4  of  7 0  
m o del wit h treat me nt gr o u p as t he mai n effect a n d t he ra n d o mizati o n stratificati o n fact ors 
c o variates, b ut als o i ncl u de o n-st u d y resc u e me dicati o n use as a ( bi nar y) c o variate, w h ere 
resc ue m e dicati o ns i ncl u de S A B As, S A M As, ne wl y pres cri be d L A B As, L A M As, a n d 
o x y ge n  T he val ue of t his bi nar y c o variate will be c o nsi dere d as “ Y” if t he p atie nt uses a n y 
of t he resc u e me dicati o ns w hile o n  t he st u d y, ot her wise it will be c o nsi dere d as “ N”. 
Beca use t he pri mar y effi cac y a nal ysis is e x pecte d t o be hi g hl y p ositi vel y c orrelate d wit h 
t he se nsiti vit y a nal yses of t he pri mar y e n d p oi nt, n o al p ha a dj ust me nts will be ma de. 
8. 3.  
S E C O N D A R Y E F FI C A C Y E N D P OI N T( S ) A N D A N A L Y S E S  
8. 3. 1.  C h a n ge f r o m B aseli ne i n Q O L -B res pir at or y s y m pt o ms s c ore o ver t he 2 4 -
w ee k tre at me nt peri o d  
T he Q ualit y of Life Q uesti o n naire- Br o nc hiectasis  ( Q O L -B) is a v ali date d, self -
a d mi nistere d patie nt re p orte d o utc o me ( P R O) t hat assesses s y m pt o ms, f u n cti o ni n g, a n d 
healt h -rel ate d Q O L f or s u bjects wit h N C F B E ( Q uitt ner et al, 2 0 1 4; Q uitt ner et al, 2 0 1 5).  
T he Q O L - B c o nt ai ns 3 7 ite ms i n 8 d o mai ns ( Res pirat or y S y m pt o ms, P h ysical F u ncti o ni n g, 
R ole F u ncti o ni n g, E m oti o nal F u ncti o ni n g, S ocial F u ncti o ni n g, Vi talit y, H ealt h 
Perce pti o ns , a n d Tr eat me nt B ur de n).  
T he c ha n ge fr o m Baseli n e i n Q O L - B res pirat or y s y m pt o ms sc ore o v er t he 2 4-wee k 
treat me nt peri o d will be c o m pare d b et wee n t h e treat me nts wit h a restri cte d ma xi m u m 
li keli h o o d ( R E M L) bas e d mi x e d m o del f or re peat e d meas ures ( M M R M) a p pr oac h. 
T he m o del will i ncl u de t he fi x e d, cate g orical effects of treat me nt  gr o u p, P a  c ol o nizati o n 
stat us a n d mai nte na nce a nti bi otic use at Baseli ne, visit ( base d o n t he c hr o n ol o gical or d er of 
t he c o m pleti o n of t he q uesti o n naire), a n d treat me nt gr o u p -b y -visit i nteracti o n. S u bject will 
be i ncl u de d i n t he m o del as a ra n d o m effect. A n u nstr uct ure d (c o) varia nce str uct ure will be 
use d t o m o del t he wit hi n- s u bject err ors. If t he c o n ver ge nce is n ot ac hie v e d wit h a n 
u nstr uct ure d varia nce str uct ure t he n varia nce c o m p o ne nt str uct ure will be use d. T he 
Ke n war d R o ger a p pr o xi mati o n will be use d t o esti mate de n o mi nat or de grees of free d o m. 
T he m o del will be fitte d usi n g t he S A S ®/ S T A T pr oce d ure P R O C MI X E D, wit h a 
R A N D O M  state me nt o ver t he visits i ncl ude d a n d t he u ni q ue s u bject i de ntifi er as t he 
S U BJ E C T varia ble i n t he R A N D O M  state me nt. 
Sa m ple S A S ® c o de is s h o w n bel o w: 
P R O C MI X E D D A T A = D A T AI N M E T H O D = R E M L;  
C L A S S T R T P P A E R O A N TI BI;  
M O D E L C H G Q O L B R = T R T P VI SI T N T R T P * VI SI T N P A E R O A N TI BI/ D D F M = 
K E N W A R D R O G E R;  
R A N D O M  VI SI T N / S U BJ E C T = U S U BJI D T Y P E = < U N  or V C > ; 
L S M E A N S T R T P/ C L P DI F F;  
R U N;  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 5  of  7 0  
W here , C H G Q O L B R = c ha n ge fr o m b aseli ne i n Q O L -B res pirat or y s y m pt o ms sc ore t o 
eac h p ost -b aseli ne assess me nt , T R T P = ra n d o mize d treat me nt gr o u p, VI SI T N = visit 
n u m ber ( 1, 2, 3 etc. b ase d o n t he c hr o n ol o gical occ urre n ce of t h e assess me nt ), U S U BJI D = 
u ni q ue s u bject i de ntifier, P A E R O = Pa  stat us, A N TI BI = mai nte na n ce a nti bi otic use at 
Baseli ne.  
Least s q uar es mea ns ( L S mea ns) a n d mea n treat me nt differe nce, st a n dar d err or ( S E), 9 0 % 
CI , 9 5 % CI, a n d p-val u e f or t he treat me nt effect a vera ge d acr oss t he trial, wit h t he sa me 
wei g ht a p plie d t o eac h visit, will be prese nte d. 
8. 3. 2.  C h a n ge f r o m Scree ni n g i n p ost - br o nc h o dil at or F E V 1 o ver t he 2 4-w ee k 
tre at me nt peri o d 
P ost- br o nc h o dilat or p ul m o nar y f u ncti o n test b y s pir o metr y ( F E V 1, F V C, P E F R, a n d 
F E F 2 5 - 7 5) will be perf or me d per t he A merica n T h oracic S ociet y ( A T S/ E ur o pea n 
Res pirat or y S ociet y [ E R S]) criteria ( Miller et al, 2 0 0 5) at Visit 1 ( S cree ni n g), Visit 6  
( Wee k 1 2), a n d Visit 9 (Wee k 2 4 ).   
F E V 1 is a nal yze d usi n g perce nt pre dicte d F E V ( p p F E V 1).  
C ha n ge fr o m Scr ee ni n g i n p ost- br o nc h o dilat or p p F E V 1 at Visit 6 (Wee k 1 2) a n d Visit 9 
(Wee k 2 4 ) se paratel y, will be c o m pare d b et wee n t he treat me nts wit h a n a nal ysis of 
c o varia n ce wit h P a c ol o nizati o n stat us  a n d mai nte na nce macr oli de a nti bi otic use at 
Baseli ne as c o variates . T he c o m paris o n of treat me nts f or c ha n ge fr o m scree ni n g i n 
p p F E V 1 at Visit 6 will be c o nsi der e d as h y p ot hesis ge nerati n g. T he L S mea ns a n d mea n 
treat me nt differe nce, S E, 9 0 % CI, 9 5 % CI a n d p- v al ue f or t he m ea n treat me nt differe n ce 
will be prese nte d. P- val u es f or t he o verall treat me nt effect a n d 2 c o v ariates will als o be 
prese nte d.  
8. 3. 3.  P ul m o n ar y e x a cer b ati o ns o ver t he 2 4 -w ee k tre at me nt peri o d  
P ul m o nar y e x acer bati o n ( defi ne d b y s y m pt o ms, d urati o n of s y m pt o ms a n d a nti bi otic 
prescri pti o n) will be c oll ecte d a n d re vie w e d t hr o u g h o ut t he st u d y bet wee n  ra n d o mizati o n 
t hr o u g h E O S .  
P ul m o nar y e x acer bati o ns are defi ne d i n Secti o n 8. 2. 1  . 
T he rate of p ul m o nar y e x acer b ati o n ( per p ers o n year) o ver t he 2 4- w ee k treat me nt peri o d 
will be calc ulate d f or eac h s u bject as:  
Rate = t otal n u m ber of p ul m o nar y e x acer b ati o n  / t otal f oll o w- u p d urati o n 
W here , t otal f oll o w- u p d urati o n ( years) = ([ date of E O S  – date of ra n d o mizati o n] + 1) / 
3 6 5. 2 5. 
Rate will be r o u n de d t o t w o deci mal places f or dis pla yi n g p ur p os es. 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 6  of  7 0  
T he n u m ber of p ul m o nar y e x acer bati o ns o ver t h e 2 4- wee k treat me nt peri o d , classifie d as 
Yes  or N o de p e n di n g o n t he e x perie nce of p ul m o nar y e x acer bati o n b y t he p atie nt, will be 
a nal yze d usi n g C oc hr a n -Ma ntel -Hae nszel statistics  f or t he I T T P o p ulati o n stratifie d b y P a  
c ol o nizati o n stat us a n d mai nte na nce macr oli de a nti bi otic use at Baseli ne  a n d t he 
c orres p o n di n g p- v al ue will be prese nte d .     
A d diti o nal a nal ys es e x pl ori n g t he tr eat me nt effect base d o n t he p ul m o nar y e x acer bati o ns 
ca n be f o u n d i n A p pe n di x C. 
8. 4.  
E X P L O R A T O R Y E F FI C A C Y  E N D P OI N T( S) A N D A N A L Y S E S  
8. 4. 1.  C h a n ge f r o m B aseli ne i n sc ore of  Q O L - B d o m ai ns o ver t he 2 4-w ee k tre at me nt 
peri o d  
T he act ual a n d c ha n ge fr o m Baseli ne i n sc ore of Q O L - B d o mai ns (e x cl u di n g res pirat or y 
s y m pt o ms d o mai n) will be descri pti vel y s u m mari ze d  o nl y f or t he l atest ass ess me nt b y 
treat me nt gr o u p. A M M R M m o del will be fitte d as descri be d i n s ecti o n 8. 3. 1 a n d t he 
res ults will be prese nte d i n a si milar ma n ner.   
8. 4. 2.  C h a n ge f r o m B aseli ne i n L C Q sc ore o ver t he 2 4 -w ee k tre at me nt peri o d  
T he Leicester C o u g h Q u esti o n naire is a vali date d P R O q uesti o n naire e val u ati n g c o u g h o n 
q ualit y of life i n s u bjects wit h N C F B E ( M urra y et al, 2 0 0 9).  
T he L C Q c o m prises 1 9 it e ms a n d ta kes 5 t o 1 0 mi n utes t o c o m plete.  Eac h ite m assesses 
s y m pt o ms or t he i m pact of s y m pt o ms o ver t he l ast 2 wee ks o n a se v e n- p oi nt Li kert scale.  
Sc ores i n 3 d o mai ns ( P h ys ical, Ps yc h ol o gical a n d S ocial) are calc ulat e d as a mea n f or eac h 
d o mai n (ra n ge 1 t o 7).  A t otal sc ore (ra n ge 3 t o 2 1) is als o calc ulate d b y a d di n g t he 
d o mai n sc ores t o get her.  Hi g her sc ores i n dicate b etter Q O L.  
T he act ual a n d c ha n ge fr o m Baseli ne i n t he L C Q d o mai n a n d t otal will be descri pti vel y 
s u m marize d o nl y f or t he latest assess me nt b y treat me nt.  A M M R M m o del will be fitte d as 
descri be d i n secti o n 8. 3. 1 a n d t he res ults will be prese nte d i n a si milar ma n n er.   
8. 4. 3.  C h a n ge f r o m B aseli ne i n S G R Q (t ot al) sc o re o v er t he 2 4-w ee k tre at me nt 
peri o d  
T he S G R Q is a self -a d mi nistere d q uesti o n naire t h at has bee n v ali date d i n s u bjects wit h 
air wa ys diseas e, s pecificall y i n s u bjects wit h B R (J o nes 1 9 9 1; J o nes, et al. 1 9 9 1; Wils o n, 
et al. 1 9 9 7).  T he S G R Q assesses heal t h-relate d q ualit y of life i n s u bjects wit h c hr o nic 
p ul m o nar y disease b y e v al uati n g 3 h ealt h d o mai ns:  
•  
S y m pt o ms ( distress ca use d b y res pirat or y s y m pt o ms)  
•  
A cti vit y (effects of dist ur ba nces t o m o bilit y a n d p h ysical acti vit y)  
•  
Im pacts (t he effect of disease o n  fact ors s uc h as e m pl o y me nt, pers o nal c o ntr ol of o ne’s 
healt h, a n d nee d f or me dicati o n).  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 7  of  7 0  
A c o m p osite t otal sc ore is deri ve d as t he s u m of d o mai n sc ores f or s y m pt o ms, acti vit y, a n d 
i m pact, wit h 0 t he best p ossi ble sc ore a n d 1 0 0 t he w orst p ossi ble sc ore (J ones P, 2 0 0 9).  
C ha n ge- fr o m- baseli ne will be calc ulate d f or t he S G R Q.  A re d ucti o n i n sc ore of 4 u nits is 
ge n erall y r ec o g nize d as a cli nicall y mea ni n gf ul i m pr o ve me nt i n q ualit y of life.  
N o i m p utati o n of missi n g dat a will be d o ne f or t he S G R Q.  T otal  sc ores will n ot be deri ve d 
f or s u bjects’ wit h m ore t ha n 2, 4 or 6 missi n g  ite ms i n t he s y m pt o ms, acti vit y or i m pacts 
d o mai ns, res pecti vel y, n or will t he d o mai n sc ore b e deri ve d if t h e n u m ber of all o we d 
missi n g ite ms is e x cee de d.   
T he act ual a n d c ha n ge -fr o m-baseli ne f or t otal a n d i n di vi d ual d o mai n sc ores of t he S G R Q 
will be s u m marize d descri pti vel y b y visit  a n d treat me nt gr o u p. 
8. 4. 4.  S hift  f r o m B aseli ne i n s p ut u m c ol or at W ee ks 2, 4, 1 2, 2 4, a n d 2 8  
S hift  fr o m Baseli ne i n s p ut u m c ol or (assesse d b y t he s p ut u m c ol or c hart) at Visit 3 ( Wee k 
2), Visit 4 ( Wee k 4), Visit 6 ( Wee k 1 2), Visit 9 ( Wee k 2 4), a n d Visit 1 0 ( Wee k 2 8) will be 
descri pti vel y s u m marize d b y treat me nt  gr o u p. 
8. 4. 5.  C h a n ge f r o m Scree ni n g of F V C at W ee k s 1 2 a n d 2 4  
F V C is descri be d i n Secti o n  8. 3. 2 8. 3. 2 .   
C ha n ge fr o m Scr ee ni n g of F V C at Visit 6 ( Wee k 1 2) a n d Visit 9 ( Wee k 2 4) will be 
descri pti vel y s u m marize d b y treat me nt  gr o u p. 
8. 4. 6.  C h a n ge f r o m Scree ni n g of P E F R at Wee ks 1 2 a n d 2 4  
P E F R is descri be d i n Secti o n  8. 3. 2 .   
C ha n ge fr o m Scr ee ni n g of P E F R at Visit 6 ( Wee k 1 2) a n d Visit 9 ( Wee k 2 4) will be 
descri pti vel y s u m marize d b y treat me nt  gr o u p. 
8. 4. 7.  C h a n ge f r o m Scree ni n g of F E F 2 5 - 7 5 at Wee ks 1 2 a n d 2 4  
F E F 2 5 - 7 5 is descri b e d i n Secti o n 8. 3. 2 .   
C ha n ge fr o m Scr ee ni n g of F E F 2 5- 7 5 at Visit 6 ( Wee k 1 2) a n d Visit  9 ( Wee k 2 4) will be 
descri pti vel y s u m marize d b y treat me nt  gr o u p. 
8. 4. 8.  T ot al d ur ati o n of e x acer b ati o ns, per s u bject, o ver t he 2 4- w ee k tre at me nt 
peri o d  
E x acer bati o ns ar e  defi ne d i n Secti o n  8. 2. 1 .  T he t otal d urati o n (i n da ys) of e x acer bati o ns, 
s u m me d b y s u bject, b et w ee n Visit 2  ( baseli ne) a n d E O S  will be descri pti vel y s u m marize d 
b y treat me nt  gr o u p. 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 8  of  7 0  
8. 4. 9.  T ot al n u m ber  of e x acer b ati o ns per su bject o ver t he 2 4 -w ee k tre at me nt peri o d  
T otal n u m ber of e x acer b ati o ns o ver t he 2 4- w ee k treat me nt peri o d , defi ne d as t he d urati o n 
bet wee n Visit 2 a n d E O S  per s u bject will be des cri pti vel y s u m marize d b y treat me nt gr o u p.  
8. 4. 1 0.  Ti me t o first p ul m o n ar y e x acer b ati o n, e x acer b ati o n r ate, Q O L Me as ures, a n d 
p ul m o n ar y f u ncti o n p ar a meters ( F E V 1, F V C, P E F R, a n d F E F 2 5 -7 5), str atifie d 
b y Br o nc hiect asis Se verit y I n de x ( B SI) sc ore at b aseli ne, o ver t he 2 4 -w ee k 
tre at me nt peri o d 
F or t he a nal yses stratifie d b y B SI sc ore at Baseli n e, t he B SI s c ore will be cate g orize d i nt o 
3 le vels: ≤4, 5- 8, a n d ≥9 p oi nts. 
Ti me t o first p ul m o nar y e x acer bati o n, as d escri be d i n secti o n 8. 2. 1, will be a nal yze d usi n g 
stratifie d l o g-ra n k test wit h B SI s c ore at baseli ne as a stratificati o n fact or a nd 
c orres p o n di n g o n e- si de d p-val ue will be prese nte d.  
T he rate of p ul m o nar y e x acer b ati o ns o ver t he 2 4 -wee k treat me nt peri o d , as descri be d i n 
secti o n 8. 3. 3, will be a nal yz e d usi n g C oc hra n-M a ntel -Hae nszel statistics stratifie d  b y B SI 
sc ore at b aseli ne a n d t he c orres po n di n g p- v al ue will be prese nte d.  
O bser ve d a n d c ha n ge fr o m baseli ne i n Q O L- B sc ores (all t he d o mai ns)  will be 
descri pti vel y s u m marize d  o nl y f or t h e latest assess me nt f or all t he treat me nt gr o u ps b y 
stratifie d B SI sc ore at b aseli ne . 
O bser ve d a n d c ha n ge fr o m scree ni n g i n p ul m o nar y f u n cti o n para m eters ( F E V 1, F V C, 
P E F R, a n d F E F 2 5 -7 5) will be descri pti vel y s u m marize d f or all treat me nt gr o u ps f or all t he 
a vaila ble visits b y str atifie d B SI sc ore at b aseli ne . 
8. 4. 1 1.  Ti me t o first p ul m o n ar y e x acer b ati o n, e x acer b ati o n r ate, Q O L Me as ures, a n d 
p ul m o n ar y f u ncti o n p ar a meters ( F E V 1, F V C, P E F R, a n d F E F 2 5 -7 5), str atifie d 
b y t he prese nce or a bse nce of P a  at Scree ni n g, o ver t he 2 4 -w ee k tre at me nt 
peri o d  
All t he a nal ys es me nti o n e d i n secti o n 8. 4. 1 0 will be re peate d b y re placi n g stratifie d B SI 
sc ore wit h t he cate g orical varia ble re pres e nti n g prese nce or a bse n ce of Pa at Scree ni n g.  
8. 4. 1 2.  Fre q ue nc y of use of resc ue me dic ati o ns o ver t he 2 4 -w ee k tre at me nt peri o d  
T he fre q u e nc y of res c ue me dicati o ns use bet wee n Visit 2  ( baseli ne) a n d Visit 9 ( Wee k 2 4) 
will be calc ulate d p er s u bject  a n d descri pti vel y s u m marize d b y treat me nt  gr o u p.  Resc ue 
me dicati o ns i ncl u de S A B As, S A M As, ne wl y prescri be d L A B As, L A M As, a n d o x y ge n.   
8. 4. 1 3.  N u m ber of s u bjects h os pit alize d d ue t o p ul m o n ar y e x acer b ati o ns b y t he e n d of 
t he 2 4-w ee k tre at me nt peri o d  
T he n u m ber of s u bjects h os pitalize d d ue t o p ul m o nar y e x acer bati o ns bet wee n Visit 2 
( baseli ne) a n d t he date of E O S will be ta b ulate d b y treat me nt  gr o u p a n d acr oss treat me nt 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 3 9  of  7 0  
gr o u ps.  I n a d diti o n, t he t otal n u m ber of da ys a s u bject s pe nt i n t he h os pital d ue t o 
p ul m o nar y e x acer b ati o ns will als o be s u m marize d b y treat me nt  gr o u p.   
T he n u m ber of s u bjects a d mitte d t o t he I C U d ue t o p ul m o nar y e x acer b ati o ns bet wee n Visit 
2 ( baseli ne) a n d t he date of E O S will be ta b ulate d b y treat me nt  gr o u p a n d acr oss treat me nt 
gr o u ps.  I n a d diti o n, t he t otal n u m ber of da ys a s u bject s pe nt i n t he I C U d u e t o p ul m o nar y 
e x acer bati o ns will als o be s u m marize d b y treat me nt  gr o u p. 
8. 4. 1 4.  Ot her e x pl or at or y a n al yses 
8. 4. 1 4. 1.  
P o ole d I N S 1 0 0 7 A n al yses 
All t he  p-val ues will be prese nte d as o ne -si de d p-v al ues. T hese a nal yses will be ter me d as 
e x pl orat or y a n d n o f or mal al p ha a dj ust me nt will be perf or me d. T he s e nsiti vit y a nal yses 
perf or me d f or t he i n di vi d ual efficac y e n d p oi nts will n ot be perf or me d f or t h e p o ole d 
I N S 1 0 0 7 vs. Place b o c o m paris o ns.  
8. 4. 1 4. 2.  
S u b gr o u p A n al yses of t he ti me t o t he first p ul m o n ar y e x acer b ati o n a n d 
t he r ate of p ul m o n ar y e x acer b ati o n 
A s u b gr o u p a nal ysis of ti me t o first p ul m o nar y e x acer b ati o n will be d o ne usi n g t he 
stratifie d a n d u n-str atifie d C o x P r o p orti o nal Hazar ds. T he I N S 1 0 0 7 2 5 m g vs. Place b o 
hazar d rati o will be pres e nte d wit h 2-si de d 8 0 % CIs a n d I N S 1 0 0 7 1 0 m g vs. Place b o 
hazar d rati o will be pres e nte d wit h 2-si de d 9 0 % CIs. 
A s u b gr o u p a nal ysis of r ate of p ul m o nar y e x acer b ati o n (I N S 1 0 0 7 1 0 m g or 2 5 m g vs. 
Place b o) usi n g a ne gati ve bi n o mial re gressi o n met h o d as descri be d earlier i n secti o n 8. 3. 3 
will be perf or m e d. T he r ate rati o a n d 2 -si de d 9 0 % CIs  will be pr o vi de d f or t he c o m paris o n 
of I N S 1 0 0 7 1 0 m g or 2 5 m g vs. Place b o. 
F oll o wi n g s u b gr o u ps will be e x pl ore d : 
•  A ge : ≥ 6 5 years, < 6 5 years, ≥ 7 5 years ( geriatric), < 7 5 years ( N o n-geriatri c)  
•  P ul m o nar y e x acer bati o ns ( Bas eli ne vari a ble): 0- 2, ≥ 3 
•  Mai nte na nce us e of macr oli des at Baseli ne: Y es, N o  
•  Pa c ol o nizati o n stat us: Yes, N o 
•  Seri o us p ul m o nar y e x acer b ati o n: Yes, N o 
•  Baseli ne N E i n s p ut u m: ≥ 2 0 µ g/ m L, L L O Q t o < 2 0 µ g/ m L , B Q L 
•  Baseli ne B SI sc ore : ≥ 5, < 5 
•  Baseli ne F E V 1 % Pre dicte d : < 5 0 %, ≥ 5 0 % 
•  Ge o gra p hical re gi o n: E ur o pe, N ort h A meri ca , Asi a -pacific , Easter n E ur o pe 
( B ul gari a/ P ola n d) 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 4 0  of  7 0  
8. 4. 1 4. 3.  
Ti me t o first p ul m o n ar y e x acer b ati o n, e x acer b ati o n r ate, Q O L Me as ures, 
a n d p ul m o n ar y f u ncti o n p ar a meters ( F V C, P E F R, a n d F E F 2 5 -7 5), 
str atifie d b y p p F E V 1 res ult  at b aseli ne, o ver t he 2 4-w ee k tre at me nt peri o d  
F or t he a nal yses stratifie d b y p p F E V 1 res ult at Baseli ne, t he p p F E V 1 res ult  will be 
cate g orize d i nt o 2 le vels: < 5 0 % a n d ≥ 5 0 %. 
Ti me t o first p ul m o nar y e x acer bati o n, as d escri be d i n secti o n 8. 2. 1, will be a nal yze d usi n g 
stratifie d l o g-ra n k test wit h p p F E V 1 cate g ories at baseli ne as a stratificati o n fact or a n d 
c orres p o n di n g o n e- si de d p-val ue will be prese nte d.  
T he rate of p ul m o nar y e x acer b ati o ns o ver t he 2 4 -wee k treat me nt peri o d , as descri be d i n 
secti o n 8. 3. 3, will be a nal yz e d usi n g C oc hra n-M a ntel -Hae nszel statistics stratifie d  b y 
p p F E V 1 cate g ories at baseli ne a n d t he c orres p o n di n g p- val u e will be pres e nte d.  
O bser ve d a n d c ha n ge fr o m baseli ne i n Q O L -B sc ores (all t he d o mai ns ) will be 
descri pti vel y s u m marize d o nl y f or t h e latest assess me nt f or all t he treat me nt gr o u ps b y 
stratifie d p p F E V 1 res ult  at baseli ne. 
O bser ve d a n d c ha n ge fr o m scree ni n g i n p ul m o nar y f u n cti o n para m eters ( F V C, P E F R, a n d 
F E F 2 5 -7 5) will be descri pti vel y s u m marize d f or all treat me nt gr o u ps f or all t he a vaila ble 
visits b y str atifie d p p F E V 1 res ult at baseli ne. 
 
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
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0 3. 0 0 7 A. 0 3     
   
Pa ge 4 1  of  7 0  
9.  
A N A L Y SI S O F P H A R M A C O KI N E TI C S  
A nal ys es of p har mac o ki n etics as well as P K - P D a nal ysis will be descri be d i n t he P K-P D  
S A P . 
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 4 2  of  7 0  
1 0.  
A N A L Y SI S O F P H A R M A C O D Y N A MI C S  
A nal ys es of p har mac o d y na mics as well as P D -P D a nal ysis will be d escri be d i n t he P K-P D 
S A P . 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 4 3  of  7 0  
1 1.  
S A F E T Y  
T he p o p ulati o n use d f or s afet y a n al ys es will b e t he S afet y P o p ulati o n.   
1 1. 1.  
D U R A TI O N  O F E X P O S U R E  
S u m mar y statistics will be  pr o vi de d f or t he d urati o n of e x p os ure ( n u m ber of da ys) of st u d y 
dr u g (last k n o w n date p atie nt t o o k st u d y dr u g  - first d ose date + 1) b y treat m e nt  gr o u p. 
Treat me nt a d mi nistrati o n as c ollecte d i n t he eC R F will be liste d c hr o n ol o gi call y b y 
treat me nt gr o u p a n d s u bj ect.   
  
1 1. 2.  
T R E A T M E N T C O M P LI A N C E   
T he per ce nta ge of s u bjects ta ki n g < 8 0 %, 8 0 % - 1 2 5 %, a n d > 1 2 5 % of t he i nte n de d 
q ua ntit y of t he st u d y dr u gs will be s u m marize d b y treat me nt  gr o u p, w h ere i nte n de d 
q ua ntit y is 1 6 8 ta blets ( 1 ta blet per da y x 7 da ys per wee k x 2 4 wee ks of treat me nt). 
Treat me nt c o m plia nce will als o be calc ulate d b ase d o n t he d urati o n of e x p os ure as f oll o ws: 
Treat me nt c o m plia nce  t hr o u g h e n d of treat me nt ( %) = ( nu m b er of act ual t a blets ta ke n / [ 1 
ta blet per da y x d urati o n of e x p os ure]) * 1 0 0.  
 
1 1. 3.  
A D V E R S E E V E N T S  
A d verse e ve nts  will be c o de d usi n g Me d D R A ( versi o n 2 2) s yste m or ga n cl ass a n d 
preferre d t er m. T he se v erit y of A Es will be gr a de d per t he N CI C T C A E v 4. 0. 
If a s u bject h as a n A E wit h u n k n o w n se verit y gra d e, t he n t he A E  will be ass u me d t o be of 
gr a de 3 se v erit y .  If t he r elati o ns hi p t o st u d y dr u g is missi n g a n d t he A E starte d o n or aft er 
t he first d ose of st u d y dr u g, it will be ass u me d t o be “ Defi nitel y Rel ate d” t o st u d y dr u g.  If 
t he relati o ns hi p t o st u d y dr u g is missi n g a n d t he A E be ga n pri or t o t he first d ose of st u d y 
dr u g, it will be ass u me d t o be “ N ot Relate d ” t o st u d y dr u g.  If t he relati o ns hi p t o st u d y 
dr u g is missi n g a n d t he A E be ga n m ore t ha n 3 0 da ys after t h e last d ose of st u d y dr u g, it 
will be ass u me d t o be “ N ot Relate d” t o st u d y dr u g.   
All T E A Es will be s u m marize d b y S O C a n d P T b y t he n u m ber a n d perce nta ge of s u bjects 
e x perie nci n g at least o ne occ urr e nce of t he e v e nt  b y  treat me nt gr o u p, p o ole d I N S 1 0 0 7 
gr o u p a n d acr oss treat me nt gr o u ps.  T h e de n o mi nat or i n t he calc ul ati o n of all T E A E 
perce nt a ges will be t he n u m ber of s u bjects i n t he S afet y P o p ulati o n f or t h e gi ve n treat me nt 
gr o u p.  
All A Es will be liste d b y treat me nt gr o u p, patie nt , a n d t he n c hr o n ol o gicall y b y dat e a n d 
ti me of o nset. T his listi n g will i ncl u de all data c ollecte d i n t he e C R F, al o n g wit h t he 
deri ve d varia bles:  ti me si nce first d ose, d urati o n, a n d t he c o de d v aria bles.  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 4 4  of  7 0  
1 1. 3. 1.  S u m m aries of Tre at me nt -e mer ge nt A d verse E ve nts  
I n ci de nce ta bles pr ese nti n g t he fre q u e nc y a n d p erce nt of A Es b y S O C a n d P T will be 
or dere d al p ha beticall y b y S O C a n d t he n, wit hi n a S O C, b y o verall desce n di n g fre q ue n c y of 
P T.   S u bjects will be c o u nte d o nl y o nce wit hi n eac h S O C a n d P T re p orti n g le vel o n t he 
ta bles.  T he ta bles will pr ese nt t he n u m ber of s u bj ects wit h perce nta ge, a n d t he t otal 
n u m ber of e v e nts per cat e g or y.  
A n o ver vie w of all T E A Es, seri o us T E A Es, a n d T E A Es of S pecial I nt erest will prese nt t he 
n u m ber a n d perce nt a ge of s u bjects i n t he f oll o wi n g cate g ories: 
•  A n y T E A E  
o  Ma xi m u m se verit y: Mil d  
o  Ma xi m u m se verit y: M o d erate  
o  Ma xi m u m se verit y: Se vere  
o  Ma xi m u m se verit y: Life t hreate ni n g  
o  Ma xi m u m se verit y: D eat h  
•  C T C A E gr a de 3 or hi g her 
•  At least o ne rel ate d T E A E  
•  At least o ne seri o us T E A E  
•  S u bject s disc o nti n ue d st u d y d ue t o a T E A E 
•  S u bjects disc o nti n ue d treat me nt d ue t o T E A E 
•  Die d o n st u d y d u e t o T E A E  
S u bjects will be c o u nte d o nce i n eac h of t he a b o ve cate g ories e x ce pt f or ma xi m u m 
se verit y.  S u bjects will be c o u nte d o nl y o nce at t h e hi g h est se verit y re p orte d.  F or e x a m ple, 
if a s u bject has a mil d a n d se vere h ea d ac he a n d a m o derate ras h, t he s u bject will be 
c o u nte d u n der ma xi m u m se v erit y of se v ere o nl y.  
Treat me nt -e mer ge nt ad v erse e v e nt ta bles will prese nt t he data b y treat me nt gr o u p a n d 
acr oss all treat me nt gr o u ps.  I n ci de nce ta bles will be create d f or t he f oll o wi n g gr o u ps of 
T E A Es:  
•  All T E A Es  
•  St u d y dr u g rel ate d T E A Es 
•  T E A Es lea di n g t o  st u d y wit h dra wal 
•  St u d y dr u g  rel ate d T E A Es lea di n g t o st u d y wit h dra wal 
•  All T E A Es b y s e verit y  
•  All T E A Es b y relati o ns hi p t o st u d y dr u g 
•  All seri o us T E A Es  
•  St u d y treat me nt r elate d s eri o us T E A Es 
•  Seri o us T E A Es lea di n g t o st u d y wit h dra w al 
•  St u d y treat me nt r elate d s eri o us T E A Es lea di n g t o st u d y wit h dra w al 
•  Seri o us T E A Es res ulti n g i n deat h 


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•  St u d y treat me nt r elate d s eri o us T E A Es res ulti n g i n deat h 
•  All n o n- seri o us T E A Es 
•  All T E A Es of s pecial i nt erest  
•  All seri o us T E A Es of s pecial i nterest  
•  St u d y treat me nt r elate d T E A Es of s peci al i nterest 
•  T E A Es of s peci al i nterest lea di n g t o st u d y wit h dra wal  
•  St u d y treat me nt r elate d T E A Es of s peci al i nterest lea di n g t o st u d y wit h dra w al 
•  T E A Es of s peci al i nterest res ulti n g i n deat h  
•  St u d y treat me nt r elate d T E A Es of s peci al i nterest resulti n g i n deat h  
 
St u d y treat me nt r elate d A Es are A Es t hat are defi ne d as p ossi bl y, pr o b a bl y or defi nitel y 
relate d t o st u d y treat me nt. 
T he f oll o wi n g A Es will be s u m marize d b y P T f or eac h treat me nt gr o u p a n d o verall. 
•  T E A Es  
•  Seri o us T E A Es  
•  C o m m o n ( > 5 % i n a n y tr eat me nt) N o n -seri o us T E A Es 
T hese ta bles will be s orte d i n t he desce n di n g fre q u e nc y of P T acr oss all  treat me nt gr o u ps. 
If t here ar e n o A Es t o re p ort o n a n y of t he a b o v e ta bles, t he ta ble s h o ul d be creat e d wit h 
t he li ne ‘N o a d verse e v e nts were r e p orte d’ i n t he b o d y of t h e ta ble.  A Es, A Es lea di n g t o 
deat h, seri o us A Es, A Es l ea di n g t o st u d y disc o nti n uati o n, a n d A Es of s pecial i nterest will 
be liste d se parat el y.  
1 1. 4.  
C LI NI C A L  L A B O R A T O R Y E V A L U A TI O N S  
1 1. 4. 1.  Test s 
Cli nical la b orat or y tests  i ncl u de:  
He m at ol o g y : Re d Bl o o d Cell ( R B C) c o u nt, He m o gl o bi n, He mat o crit, Mea n c or p usc ul ar 
v ol u me, Mea n cell he m o gl o bi n, Mea n c or p usc ular he m o gl o bi n c o n ce ntrati o n, C o m plete 
Bl o o d C o u nt ( C B C) wit h differe ntial, Platelet c o u nt.  
Bl o o d C he mistr y : S o di u m, P otassi u m, Calci u m, C hl ori de, Bl o o d urea nitr o ge n, Creati ni ne, 
Gl uc ose, T otal pr otei n, Al b u mi n, Al kali ne p h os p hatase, Creati ni ne ki nas e, T otal bilir u bi n, 
As partate  a mi n otra nsfer ase/ gl uta mic  o x al oacetic  tra nsa mi nase,  Al a ni ne  a mi n otra nsferas e, 
Uric aci d, lactate d e h y dr o ge n ase ( L D H), C h olester ol , Tri gl yceri des, Ser u m bicar b o nate. 
Uri n al ysis:  p H,  S pecific  gr a vit y,  Pr otei n,  Gl uc ose,  Ket o ne,  H e m o gl o bi n,  Bilir u bi n, 
Ur o bili n o ge n,  Nitrite,  Le uc oc ytes,  Uri ne  Pr otei n a n d creati ni ne  q ua ntificati o n  a n d  rati o 
calc ulati o n, U-Pr otei n, U -Creati ni ne ( Uri ne pr ot ei n a n d creati ni ne q ua ntifi cati o n a n d rati o 


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calc ulati o n will o nl y b e perf or me d w he n a s u bject is s us pecte d t o ha v e re nal i nj ur y p er PI 
discreti o n). 
S peci al  Tests:  HI V,  H e patitis  B  s urface  a nti ge n,  he patitis  C  a nti b o d y,  s er u m  pre g n a nc y 
tests, C- reacti ve pr otei n, a n d pr ot hr o m bi n ti me. 
1 1. 4. 2.  Deri ve d a n d I m p ute d D at a  
Cli nical la b orat or y test res ults will be assi g ne d a L o w/ N or mal/ Hi g h ( L N H) classificati o n b y 
t he ce ntral la b orat or y acc or di n g t o w h et her t he v al ue is bel o w ( L: l o w), wit hi n ( N: n or mal), 
or  a b o v e  ( H:  hi g h)  t h e  la b orat or y  p ara meter’s  n or mal  ra n ge;  cate g orical  la b orat or y  test 
res ults will be classifie d as n or mal ( N) or a b n or m al ( A). 
S o me n u meric la b val ues ma y b e re p ort e d as ‘ < n. n’ or ‘ > n. n’; t hese will be a nal yze d i n t he 
s u m mar y  statistics  as  n. n/ 2  a n d  n. n  res pecti vel y.  F or  e x a m ple,  tri gl yceri des  rec or de d  as 
< 0. 5 0  m m ol/ L  w o ul d  b e  s u m marize d  as  0. 2 5  m m ol/ L  a n d  p otassi u m  rec or d e d  as  > 9. 0 
m m ol/ L w o ul d b e s u m marize d as 9. 0 m m ol/ L.  
1 1. 4. 3.  D at a S u m m a riz ati o n a n d Pres e nt ati o n 
C- reacti ve pr otei n, er yt hr oc yt e se di me nt rate, s er u m pre g na n c y test, pr ot hr o m bi n ti me , a n d 
ser ol o g y will be liste d. Assa ys w hic h are o nl y meas ure d if ot her ass a ys are a b n or mal (e. g., 
micr osc o p y) will be liste d, b ut n ot s u m marize d.  
Sta n dar d  descri pti ve  statistics ( n,  mea n,  sta n dar d  de viati o n,  me dia n,  mi ni m u m,  a n d 
ma xi m u m) a n d c ha n ges fr o m baseli ne  will be ta b ulate d b y cli nical l a borat or y p ara m eter a n d 
visit , f or c o nti n u o us la borat or y  par a meters . T he d ata will be s u m marize d b y treat me nt gr o u p 
a n d p o ole d I N S 1 0 0 7 gr o u p  
S hift ta bles (i.e., l o w- n or mal- hi g h at b aseli ne vers us l o w- n or mal- hi g h at f oll o w- u p i n a 3-
b y - 3 c o nti n ge nc y ta ble) will be pr o vi de d t o assess c ha n ges i n la b orat or y v al ues fr o m 
baseli ne t o p ost- baseli ne visits. Refere nce ra n ges esta blis he d b y t he la b will be use d t o 
deter mi ne s hifts.  Deter mi nati o n of cli nical si g nifi ca nce f or all o ut - of-ra n ge la b val ues will 
be ma de b y t he I n v esti gat or. 
Mea n pr ofiles f or eac h cli nical la b orat or y p ara met er will be ge nerate d wit h data pl otte d 
a gai nst ti me b y tr eat me nt gr o u p. 
Cli nical l a b orat or y s a m ple data a n d val ues fr o m cli nical la b orat or y assess me nts will be liste d 
c hr o n ol o gicall y b y treat me nt gr o u p, s u bject, a n d visit.  
N o i nfere ntial tests will b e c o n d ucte d o n l a b data. 


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1 1. 5.  
VI T A L SI G N S  
1 1. 5. 1.  Me as ure me nts  
Vital si g ns will c o nsist of s yst oli c a n d diast olic bl o o d press ure ( m m H g), h eart rate ( b p m), 
res pirati o n rat e ( br eat hs/ mi n), a n d te m perat ure (° C).   
1 1. 5. 2.  D at a S u m m a riz ati o n a n d Pres e nt ati o n 
Vital si g ns data (a bs ol ute val ues , c ha n ge fr o m b aseli ne val ues , a n d p erce nt a g e c h a n ge fr o m 
baseli ne val u es) will be s u m marize d f or eac h para meter a n d visit b y treat me nt  gr o u p a n d 
p o ole d I N S 1 0 0 7 gr o u p . Mea n pr ofiles f or eac h vital si g ns p ara m eter will be ge nerate d wit h 
data pl otte d a gai nst ti me b y treat me nt gr o u p.  Vit al si g ns will be  liste d c hr o n ol o gicall y b y 
treat me nt gr o u p, s u bject, a n d visit.  
1 1. 6.  
E C G  
1 1. 6. 1.  Me as ure me nts  
A 1 2 -lea d E C G will be p erf or me d.   
1 1. 6. 2.  D at a S u m m a riz ati o n a n d Pres e nt ati o n 
E C G  data  (i nter pr etati o n:  N or mal;  A b n or mal – n ot  cli nicall y  si g nifica nt;  A b n or mal – 
cli nicall y si g nifi ca nt) will be ta b ulate d f or eac h para meter a n d visit b y treat me nt  gr o u p a n d 
p o ole d I N S 1 0 0 7 gr o u p . E C G data will be liste d c hr o n ol o gicall y b y treat me nt gr o u p, s u bject, 
a n d visit.  
1 1. 7.  
D E N T A L E V A L U A TI O N  
Oral a n d de ntal i ns pecti o n will be perf or me d b y t he I n v esti gat or at eac h visit.  If t here are 
a n y si g ns or s y m pt o ms of oral i nf ecti o n, gi n gi vitis, or peri o d o ntitis or det eri orati o n of t h e 
pree xisti n g  c o n diti o ns  t hat  warra nt  f urt her  e v al uati o n  u p o n  I n v esti gat or  discreti o n,  t he 
s u bject will be referr e d t o t he st u d y d esi g n ate d de ntist f or f urt her assess me nt.  T he oral a n d 
de ntal  e v al uati o n  b y  t h e  de ntist  f or  t he  s u bj ect  s h o ul d  t he n  be  assess e d  t hereafter  o n  a n 
i nter val per t he d e ntist discreti o n u ntil e n d of t he st u d y.  
De ntal e val u ati o n i n ter ms of t o ot h stat u s a n d t he ra n ges f or P oc ket de pt h , Ce me nt o-e na mal 
j u ncti o n, Au di o li n g ual  a n d Gi n gi val i nfla m mati o n as perf or me d b y t he desi g nate d d e ntist 
will be liste d c hr o n ol o gicall y b y treat me nt  gr o u p, s u bject, a n d visit f or u p per a n d l o wer teet h.  
P oc ket de pt h will b e s u m marize d b y visit b y cat e g or y ( 1 -1 5) a n d n ( n u m ber of o bser vati o ns) 
mea n, S D, S E, 9 5 % CI,  a n d c ha n ge fr o m bas eli ne b y cate g or y ( -1 5 … + 1 5) a n d n ( n u m ber 
of  o bser v ati o ns)  mea n,  S D,  S E,  9 5 % CI.  Gi n gi val  I nfla m mati o n  will  b e  pres e nte d  b y 
treat me nt a n d visit. S u m mar y of S u bjects wit h ch a n ges fr o m Baseli ne of 2  m m a n d m ore i n 
P oc ket De pt h i n 3 or m ore areas will be prese nte d b y Treat me nt b y p ost -b as eli ne visit ( Wee k 


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8 a n d Wee k 2 4).  S u bjects wit h cha n ges of 2  m m a n d m ore i n P oc ket D e pt h i n ≥ 3 areas will 
be liste d se parat el y.  
 
 


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1 2.  
I N T E RI M A N A L Y S E S  
N o f or mal i nteri m a nal ysis will be perf or me d.  


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1 3.  
C H A N G E F R O M A N A L Y SI S P L A N N E D I N P R O T O C O L 
T here are n o c ha n ges fr o m t he a nal ys es pla n ne d i n t he pr ot oc ol. 


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1 4.  
 R E F E R E N C E LI S T  
Bar k er A F, O’ D o n n ell A E, Fl u me P, T h o m ps o n PJ, R uzi  J D, de Gracia J, et al. Aztre o na m 
f or  i n halati o n  s ol uti o n  i n  s u bjects  wit h  n o n-c ystic  fi br osis  br o nc hi ectasis  ( AI R -B X 1  a n d 
AI R -B X 2): t w o ra n d o mise d d o u ble -bli n d, place b o -c o ntr olle d p hase 3 trials. La ncet Res pir 
Me d. 2 0 1 4; 2( 9): 7 3 8- 4 9. 
C hal mers  J D,  G oe mi n ne  P,  Ali berti  S,  Mc D o n n ell  MJ,  L o n ni  S,  D a vi ds o n  J,  et  al.  T he 
br o nc hiectasis s e verit y i n de x. A n i nter nati o nal deri vati o n a n d vali dati o n st u d y. A m J Res pir 
Crit Care Me d. 2 0 1 4; 1 8 9( 5): 5 7 6- 8 5. 
De S o yza  A,  A ksa mit  T,  Ba n del  TJ,  Cri oll o  M,  El b or n  J S,  Kra h n  U,  et  al.  Efficac y  a n d 
T olera bilit y  of  Ci pr ofl o x aci n  Dr y  P o w der  f or  I n hal ati o n  ( Ci pr ofl o x aci n  D PI)  i n 
Br o nc hi ectasis  ( N o n -C F  Eti ol o g y):  Res ults  fr o m  t he  P hase  III  R E S PI R E  1  St u d y.  C hest. 
2 0 1 6; 1 5 0( 4 _ S): 1 3 1 5 A. d oi: 1 0. 1 0 1 6/j.c hest. 2 0 1 6. 0 8. 1 4 4 6. 
J o nes P; St Ge or ge R es pirat or y Q uesti o n naire Ma n ual versi o n 2. 3, J u ne 2 0 0 9, Di visi o n of 
Car diac a n d Vasc ular Sci e nce at St Ge or ge’s, U ni versit y of L o n d o n, U K. 
Kieser M, Frie d e T. T h e Si m ple pr oce d ures f or bli n de d sa m ple size a dj ust me nt t hat d o n ot 
affect t y p e I err or rate. St atistics i n Me dici ne, 2 0 0 3 
Miller M R, Ha n ki ns o n J, Br usas c o V, B ur g os F, Casa b uri R, C oates A, et al; A T S/ E R S Tas k 
F orce. Sta n dar dizati o n of s pir o metr y. E ur Res pir J. 2 0 0 5; 2 6( 2): 3 1 9- 3 8. 
M urra y  M P,  Pe ntla n d  J L,  T ur n b ull  K,  Mac Q u arrie  S,  Hill  A T.  S p ut u m  c ol o ur:  a  usef ul 
cli nical t o ol i n n o n -c ystic fi br osis br o nc hiectasis. E ur Res pir J. 2 0 0 9; 3 4( 2): 3 6 1- 4. 
M urra y M P, T ur n b ull K, Mac Q uarrie S, Pe ntla n d J L, Hill A T. V ali dati o n of Lei cester C o u g h 
Q uesti o n naire i n n o n-c ystic fi br osis br o nc hiectasis. E ur Res pir J. 2 0 0 9; 3 4( 1): 1 2 5- 3 1. 
Q uitt ner A L, M arciel K K, Salat he M A, O’ D o n n ell A E, G otfrie d M H, Il o wite J S, et al. A 
preli mi nar y  q u alit y  of  life  q uesti o n naire – br o nc hiectasis:  a  patie nt -re p orte d  o utc o me 
meas ure f or br o nc hiectasis. C hest. 2 0 1 4; 1 4 6( 2): 4 3 7- 4 8. d oi: 1 0. 1 3 7 8/c hest. 1 3- 1 8 9 1. 
Q uitt ner A L, O’ D o n n ell A E, Salat he M A, Le wis S A, Li X, M o nt g o mer y A B, et al. Q u alit y 
of Lif e Q uesti o n nair e – Br o nc hi ectasis: fi nal ps yc h o metric a n al ys es a n d  deter mi nati o n of 
mi ni mal i m p orta nt differ e nce sc or es. T h ora x. 2 0 1 5 J a n; 7 0( 1): 1 2- 2 0. d oi: 1 0. 1 1 3 6/t h ora xj nl-
2 0 1 4- 2 0 5 9 1 8. E p u b 2 0 1 4 Oct 1 6. 
Serisier DJ, Marti n M L, Mc G uc ki n M A, L o urie R, C he n A C, Brai n B, et al. Effect of l o n g-
ter m, l o w-d ose er yt hr o m yci n o n p ul m o nar y e x acer bati o ns a m o n g patie nts wit h n o n -c ystic 
fi br osis br o nc hiectasis: t h e B L E S S ra n d o mize d c o ntr olle d trial. J A M A. 2 0 1 3; 3 0 9( 1 2): 1 2 6 0 -
7. 


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1 5.  
P R O G R A M MI N G C O N SI D E R A TI O N S 
C o m p uter- ge ner ate d  ta ble,  listi n g  a n d  fi g ure  o ut p ut  will  a d here  t o  t he  f oll o wi n g 
s pecificati o ns.  
1 5. 1.  
G E N E R A L C O N SI D E R A TI O N S  
•  A se par ate S A S pr o gra m will be creat e d f or eac h o ut p ut. 
•  Eac h o ut p ut will be st ore d i n a se parate file. 
•  O ut p ut files will be deli vere d i n W or d f or mat. I n a d diti o n, a c o m pile d file c o ntai ni n g al l 
T L Fs will be ge nerate d.  
•  
N u m beri n g of T F Ls will f oll o w I C H E 3 g ui d a nce.  
 
1 5. 2.  
T A B L E, LI S TI N G, A N D FI G U R E F O R M A T  
1 5. 2. 1.  Ge ner al  
•  All T L Fs will be pr o d uce d i n la n dsca pe f or mat, u nless ot her wise s pecifie d. 
•  All T L Fs will be pr o d uce d usi n g t he C o urier Ne w f o nt, size 8.  
•  T he data dis pla ys f or all T L Fs will ha ve a mi ni m u m 1 -i nc h mar gi n o n all 4 si des. 
•  Hea ders a n d f o oters f or fi g ures will be i n C o urier Ne w f o nt, size 8. 
•  Le ge n ds will be use d f or all fi g ures wit h m ore t ha n 1 varia ble, gr o u p, or ite m 
dis pla ye d. 
•  T L Fs will be i n blac k a n d w hite ( n o c ol or), u nless ot her wise s pecifie d. 
•  S pecialize d te xt st yles, s uc h as b ol di n g, italics , b or ders, s ha di n g, a n d s u p erscri pte d a n d 
s u bscri pte d te xt, will n ot be use d i n t he T L Fs, u nl ess ot her wise s pecifi e d. O n s o me 
occasi o ns, s u pers cri pts 1, 2, or 3 ma y be use d (see bel o w). 
•  O nl y sta n d ar d ke y b o ar d c haracters will be us e d i n t he T L Fs. S pecial c haracters, s uc h as 
n o n- pri nta ble c o ntr ol c h aracters, pri nter-s p ecific, or f o nt- s pecifi c c haracters, will n ot be 
use d. He x a deci mal -d eri v e d c haracters will be use d, w here p ossi ble, if t he y are 
a p pr o priate t o h el p dis pla y mat h s y m b ols (e. g., μ). Certai n s u bscri pts a n d s u perscri pts 
(e. g., c m 2, C ma x) will be e m pl o ye d o n a case-b y -case basis.  
•  Mi x e d case will be use d f or all titles, f o ot n otes, c ol u m n hea ders, a n d pr o gra m mer-
s u p plie d f or mats, as a p pr o priate. 
1 5. 2. 2.  He a ders  
•  All o ut p ut s h o ul d ha ve t he f oll o wi n g h ea der at t he t o p left of eac h pa ge: 
I ns me d I nc or p orate d Pr ot oc ol I N S 1 0 0 7- 2 0 1  
(S y ne os H ealt h  St u d y N u m ber 1 0 0 9 1 1 3)       
          


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I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 5 3  of  7 0  
•  Draft/ Fi n al ( wit h versi o n n u m ber)  All o ut p ut s h o ul d ha ve Pa ge n of N at t he t o p or 
b ott o m ri g ht c or ner of eac h pa ge. T L Fs s h o ul d be i nter nall y p a gi nate d i n relati o n t o t he 
t otal le n gt h (i.e., t he p a ge n u m ber s h o ul d a p pear se q ue ntiall y as p a ge n of N, w here N 
is t he t otal n u m ber of pa ges i n t he ta bl e). 
•  All o ut p ut s h o ul d ha ve C O N FI D E N TI A L i n t he t o p ce nter of eac h pa ge. 
•  T he date  a n d ti me o ut p ut was ge nerate d s h o ul d a p pear al o n g wit h t he pr o gra m na me, 
l ocati o n, a n d datasets use d as a f o oter o n eac h pa ge.  
1 5. 2. 3.  Dis pl a y Titles  
•  Eac h T L F s h o ul d be i de ntifie d b y t he d esi g n ati o n a n d a n u meral. (i.e., Ta bl e 1 4. 1. 1). 
I C H E 3 n u m b eri n g is str o n gl y rec o m me n de d b ut s p o ns or prefere n ces s h o ul d be 
o btai ne d pri or t o fi nal det er mi nati o n (see als o te m plate 0 3. 0 0 7 C “ Ta ble of C o nte nts  
f or Ta bles Listi n gs a n d Fi g ures i n Statistical A nal ysis Pla n”). A d eci mal s yste m ( x. y 
a n d x. y.z) s h o ul d be us e d t o i de ntif y T L Fs wit h rel ate d c o nte nts. T he title is ce ntere d. 
T he a nal ysis p o p ulati o n s h o ul d be i de ntifie d o n t he li ne i m me diatel y f oll o wi n g t he 
title. T he title a n d ta ble desi g nati o n are si n gle s pace d. A s oli d li ne s pa n ni n g t he 
mar gi ns will se parate t h e dis pla y titles fr o m t he C ol u m n hea ders. T here will be 1 bla n k 
li ne bet wee n t he l ast title a n d t he s oli d li ne. 
Ta ble x. y.z  
First Li n e of Title  
Sec o n d Li n e of Title if N ee de d  
I T T P o p ulati o n 
1 5. 2. 4.  C ol u m n He a ders  
•  C ol u m n hea di n gs s h o ul d be dis pla ye d i m me diatel y bel o w t h e s oli d li ne descri be d 
a b o ve i n i nitial u p per- cas e c har acters.  
•  F or n u meri c varia bl es, i ncl u de “ u nit” i n c ol u m n or r o w hea di n g w h e n a p pr o priate. 
•  A nal ysis p o p ulati o n sizes will be prese nte d f or eac h treat me nt gr o u p i n t he c ol u m n 
hea di n g as ( N = x x) ( or i n t he r o w hea di n gs if a p plica ble). T his is disti nct fr o m t he ‘ n’ 
use d f or t he d escri pti ve statistics re prese nti n g t he n u m ber of patie nts i n t he a nal ysis 
p o p ulati o n. 
 
1 5. 2. 5.  B o d y of t he D at a Dis pl a y 
1 5. 2. 5. 1.  
Ge ner al C o n ve n ti o ns 
Data i n c ol u m ns of a ta bl e or listi n g s h o ul d be f or matte d as f oll o ws: 
• 
al p ha n u meric v al ues ar e left -j ustifie d; 
• 
w h ole n u m bers ( e. g., c o u nts) are ri g ht- j ustifie d; a n d 


St atistic al A n al ysis Pl a n  
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Versi o n 1. 0  
S y ne os He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 5 4  of  7 0  
• 
n u m bers c o ntai ni n g fr acti o nal p orti o ns are deci mal ali g ne d. 
 
1 5. 2. 5. 2.  
T a ble C o n ve nti o ns 
•  U nits will be i ncl u de d w here a v aila ble  
•  If t he cate g ories of a para meter are or dere d, t he n all cate g ories bet w ee n t he ma xi m u m 
a n d mi ni m u m cate g or y s h o ul d be prese nte d i n t he ta ble, e ve n if n = 0 f or all treat me nt 
gr o u ps i n a gi v e n cat e g or y t hat is bet wee n t he mi ni m u m a n d ma xi m u m le vel f or t hat 
para meter. F or e x a m ple, t he fre q u e nc y distri b uti o n f or s y m pt o m se v erit y w o ul d a p pear 
as: 
Se verit y 
Rati n g  
N  
se vere 
0  
m o derate  
8  
mil d  
3  
W here per ce nta ges ar e pr ese nte d i n t hese ta bl es, zer o perce nta ges will n ot be prese nt e d 
a n d s o a n y c o u nts of 0 will be prese nte d as 0 a n d n ot as 0 ( 0 %). 
•  If t he cate g ories are n ot or dere d (e. g., Me di cal Hist or y, Reas o ns f or Disc o nti n uati o n 
fr o m t he St u d y, et c.), t he n o nl y t h ose cate g ories f or w hic h t here is at least 1 patie nt 
re pres e nte d i n 1 or m ore gr o u ps s h o ul d be i n cl u de d. 
•  A n U n k n o w n or Missi n g cate g or y s h o ul d be a d de d t o a n y p ara met er f or w hi c h 
i nf or mati o n is n ot a vaila ble f or 1 or m ore patie nts.  
•  U nless ot her wise s pecifie d, t he esti mate d mea n a n d me dia n a n d q uartiles f or a set of 
val ues s h o ul d be pri nte d o ut t o 1 m ore si g nifica nt di git t ha n t he ori gi nal val ues, a n d 
sta n dar d de viati o ns s h o ul d be pri nte d o ut t o 2 m ore si g nifica nt di gits t ha n t he ori gi n al 
val ues. T he mi ni m u m a n d ma xi m u m s h o ul d re p ort t he sa me si g nifica nt di gits as t he 
ori gi nal val u es. F or e x a m ple, f or s yst olic bl o o d press ure: 
N  
  X X  
Mea n  ( S D) 
X X X. X  (X. X X ) 
Me dia n  
X X X. X  
Mi n, Ma x  
X X X , X X X  
•  P- val ues s h o ul d be o ut p ut i n t he f or mat: “ 0. x x x ”, w here x x x is t he val ue r o u n de d t o 3 
deci mal places. A n y p - val ue less t ha n 0. 0 0 1 will be prese nt e d as < 0. 0 0 1. If t he p-val ue 
is ret ur ne d as > 0. 9 9 9 t he n prese nt as > 0. 9 9 9 
•  Perce nta ge val ues s h o ul d be pri nte d t o o ne deci mal place, i n pare nt heses wit h n o 
s paces, o ne s p ace after t he c o u nt (e. g., 7 ( 1 2. 8 %), 1 3 ( 5. 4 %)). Pre- deter mi ne h o w t o 
dis pla y val ues t h at r o u n d d o w n t o 0. 0.  A c o m m o n c o n ve nti o n is t o dis pla y as ' < 0. 1', or 
as a p pr o priat e wit h a d diti o nal deci mal places. U nl ess ot her wise n ote d, f or all 
perce nt a ges, t he n u m ber of patie nts i n t he a nal ysis p o p ulati o n f or t he treat m e nt gr o u p 


St atistic al A n al ysis Pl a n  
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w h o ha ve a n o bs er vati o n will be t he de n o mi nat or. Perce nta ges after zer o c o u nts s h o ul d 
n ot be dis pla ye d a n d perce nta ges e q u ati n g t o 1 0 0 % s h o ul d be prese nt e d as 1 0 0 %, 
wit h o ut a n y deci mal places.  
•  Ta b ular dis pla y of d ata f or me dical hist or y, pri or / c o nc o mita nt me dicati o ns, a n d all 
ta b ular dis pla ys of a d v erse e ve nt data s h o ul d b e prese nte d b y t he b o d y s yst e m, 
treat me nt class, or S O C wit h t he hi g hest occ urre n ce i n t he acti ve treat me nt gr o u p i n 
decreasi n g or der, ass u mi n g all ter ms are c o de d. Wit hi n t he b o d y s yste m, dr u g cl ass a n d 
S O C, me dical hist or y ( b y preferre d t er m), dr u gs ( b y A T C 1 c o d e), a n d a d verse e ve nts 
( b y pref err e d ter m) s h o ul d be dis pla ye d i n decreasi n g or der. If i n ci de nce f or m ore t ha n 
1 ter m is i de ntical, t he y s h o ul d t he n be s orte d al p h a beticall y. Missi n g des cr i pti ve 
statistics or p- val ues w hi c h ca n n ot be esti mate d s h o ul d be re p orte d as “-”.  
•  T he  per ce nta ge  of  patie nts  is  n or mall y  calc ul ate d  as  a  pr o p orti o n  of  t h e  n u m ber  of 
patie nts assesse d i n t he r ele va nt treat me nt gr o u p ( or o verall) f or t he a n al ysis p o p ulati o n 
prese nte d.  H o we ver,  car ef ul  c o nsi derati o n  is  re q uire d  i n  ma n y  i nsta n ces  d ue  t o  t he 
c o m plicate d  nat ure  of  selecti n g  t he  de n o mi nat or,  us uall y  t he  a p pr o priat e  n u m ber  of 
patie nts e x p ose d. Descri be details of t his i n f o ot n otes or pr o gra m mi n g n ot es. 
•  F or cate g or ical s u m mari es ( n u m ber a n d perce nt a ge of patie nts) w here a p atie nt ca n b e 
i ncl u de d i n m ore t ha n o n e cate g or y, d escri b e i n a f o ot n ote or pr o gra m mi n g n ote if t h e 
patie nt s h o ul d be i ncl u de d i n t he s u m mar y statistics f or all rele v a nt cat e g ories or j ust 1 
cate g or y a n d t he criteria f or selecti n g t he criteria.  
•  W here a cate g or y wit h a s u b hea di n g (s uc h as s yste m or ga n class) has t o be s plit o ver 
m ore  t ha n  o ne  pa ge,  o ut p ut  t he  s u b hea di n g  f oll o we d  b y  “(c o nt)”  at  t he  t o p  of  eac h 
s u bse q ue nt  pa ge.    T he  o verall  s u m mar y  statistics  f or  t he  s u b hea di n g  s h o ul d  o nl y  be 
o ut p ut o n t he first rele va nt pa ge. 
1 5. 2. 5. 3.  
Listi n g C o n ve nti o ns 
•  Listi n gs will be s orte d f or prese ntati o n i n or d er of treat me nt s ( place b o/ 1 0 m g 
I N S 1 0 0 7/ 2 5 m g I N S 1 0 0 7), patie nt n u m ber, visit/c ollecti o n da y, a n d visit/c ollecti o n 
ti me. 
•  Missi n g data s h o ul d be r e prese nt e d o n patie nt listi n gs as eit her a h y p he n (“- ”) wit h a 
c orres p o n di n g f o ot n ote ( “- = u n k n o w n or n ot e val uate d”), or as “ N/ A”, wit h t he 
f o ot n ote “ N/ A = n ot a p plica ble”, w hi c he ver is a p pr o priate. 
•  Dates s h o ul d be pri nte d i n S A S ® D A T E 9.f or mat (“ d d M M M y y y y”: 0 1J U L 2 0 0 0). 
Missi n g p orti o ns of dates s h o ul d be re prese nte d o n patie nt listi n gs as das hes ( --
J U L 2 0 0 0). Dates t hat are missi n g beca us e t he y are n ot a p plica ble f or t h e patie nt are 
o ut p ut as “ N/ A”, u nless ot her wise s pec ifie d. 


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0 3. 0 0 7 A. 0 3     
   
Pa ge 5 6  of  7 0  
•  All o bser ve d ti me val ues m ust be prese nte d usi n g a 2 4- h o ur cl o c k H H: M M or 
H H: M M: S S f or mat (e. g., 1 1: 2 6: 4 5, or 1 1: 2 6). Ti me will o nl y be re p orte d if it was 
meas ure d as part of t he st u d y.  
•  U nits will be i ncl u de d w here a v aila ble . 
1 5. 2. 5. 4.  
Fi g ure C o n ve nti o ns 
•  U nle ss ot her wise s pecifie d, f or all fi g ures, st u d y visits will be dis pla ye d o n t he X-a xis 
a n d e n d p oi nt (e. g., mea n c ha n ge fr o m Baseli ne) v al ues will be dis pla ye d o n t he Y- a xis. 
1 5. 2. 5. 5.  
F o ot n ot es 
•  A s oli d li ne s pa n ni n g t he mar gi ns will se parate t h e b o d y of t he data dis pla y fr o m t he 
f o ot n otes.  
•  All f o ot n otes will be left j ustifie d wit h si n gle -li ne s paci n g i m me diat el y b el o w t he s oli d 
li ne u n der neat h t he d ata dis pla y. 
•  F o ot n otes s h o ul d al wa ys be gi n wit h “ N ote:” if a n i nf or mati o nal f o ot n ote, or 1, 2, 3, etc. 
if a ref er e nce f o ot n ote. E ac h ne w f o ot n ote s h o ul d start o n a ne w li ne w h ere p ossi ble. 
•  Patie nt s pecific f o ot n otes s h o ul d be a v oi de d, w here p ossi ble. 
•  F o ot n otes will be use d s p ari n gl y a n d m ust a d d val ue t o t he ta ble, listi n g, or fi g ure. If 
m ore t ha n 6 li nes of f o ot n otes are pla n n e d, t he n a c o ver pa ge ma y be us e d t o dis pla y 
f o ot n otes, a n d o nl y t h ose esse ntial t o c o m pre he nsi o n of t he data will be re p eate d o n 
eac h p a ge.  
•  T he last li ne of t he f o ot n ote secti o n will be a sta n dar d s o urce li ne t hat i n dicates t he 
na me of t he pr o gra m use d t o pr o d uce t he dat a dis pla y, d ate t he pr o gra m w as r u n, a n d 
t he listi n g s o urce, if a p plica ble (i.e., ‘ Dat a S o urce: A D X X, C orres p o n di n g Listi n g x x x x 
Pr o gra m: x x x x.sas Ta ble Ge ner ati o n: d d m m m y y y y or ‘ Pr o gra m: x x x x.sas  Listi n g 
Ge ner ati o n: d d m m m y y y y’) , as w ell as t he l ocati o n of t he pr o gra m  a n d t he datasets 
use d . 
 
1 5. 3.  
D E RI V A TI O N O F O N E -SI D E D P- V A L U E  
T he o ne-si de d p- val ue f or a s u peri orit y test is eit h er P/ 2 or 1 -( P/ 2), w here P is a t w o-si de d 
p- val ue re p orte d b y t he gi ve n S A S pr oce d ure.  
If t he esti mate d statistic ( e. g. h azar d rati o, L S mea n differe n ce etc.) is i n fa v or of t he 
alter nati ve h y p ot hesis (i. e. I N S 1 0 0 7 is better t ha n Place b o) t he n t he o n e- si d e d p-val ue will 
be deri ve d as ( P/ 2).  
If t he esti mate d statistic is i n t he o p p osite directi o n of t he alter n ati ve h y p ot hesis (i.e. 
Place b o is better t ha n I N S 1 0 0 7), t he n t he o ne-si de d p- val ue will be deri ve d as [ 1 - ( P/ 2)].   


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
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1 6.  
Q U A LI T Y C O N T R O L  
S A S pr o gra ms are de v el o pe d t o pr o d uce o ut p ut s uc h as a nal ysis data sets, s u m mar y ta bles, 
data listi n gs, fi g ures or st atistical a nal yses. All S A S pr o gra ms are c hec k e d f or l o gic b y t he 
de vel o per a n d verifi er, if a p plica ble.   
C ha n ges t o a pr o gra m perf or me d aft er t he first release date (i.e. , deli ver y t o t he s p o ns or) are 
d oc u me nte d i n t he hea d er of t he pr o gra m as c ha n ge hist or y ( d o c u me nte d t o get h er wit h date, 
reas o n f or c ha n ge a n d t h e na me of t he pr o gra m m er w h o ma de t h e c ha n ges). 
All  pr o gra ms  f or  pr o d u cti o n  of  S D T M  data  s ets,  a nal ysis  data sets  a n d  T L Fs  are  d o u bl e 
pr o gra m me d  b y  t he  v erifier.    I nitial  pr o gra m mi n g  res ults  a n d  verifi cati o n  pr o gra m mi n g 
res ults are c o m pare d electr o nicall y.  Ta bles a n d listi n gs are d o u ble pr o gra m me d a n d res ults 
of t he i nitial pr o gr a m mi n g a n d t h e verificati o n pr o gra m m i n g are c o m pare d electr o ni call y. 
T he  verificati o n  pr ocess  f or  fi g ur es  ma y  f oll o w  t he  d o u ble -pr o gra m mi n g  pr ocess,  or  b y 
c o nfir mi n g  t hat  data  p oi nts  c o ntai ne d  i n  t he  pl ot  are  c o nsiste nt  a gai nst  a  s o urce  ta ble  or 
listi n g. 
 


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1 7.  
M O C K -U P S  
Attac h me nt: I N S 1 0 0 7- 2 0 1 T L F s hells draft v1 0. d oc x 
    


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1 8.  
A P P E N DI C E S  
 


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0 3. 0 0 7 A. 0 3      
 
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A P P E N DI X A : S T U D Y S C H E D U L E O F A S S E S S M E N T S  
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y Visit  
Da ys -2 8 t o - 1 
 
Da y 1 
( Baseli n e) 
Da y 1 5  
W ee k 2   
Da y 2 9  
W ee k 4   
 
Da y 5 7  
W ee k 8   
 
 
Da y 8 5  
W ee k 1 2   
Da y 1 1 3  
 W ee k 1 6   
Da y 1 4 1  
W ee k 2 0   
Da y 1 6 9  
W ee k 2 4  
( E O T) 
Da y 1 9 7  
W ee k 2 8   
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 da ys ) 
Visit 8  
(±  3 da ys ) 
Visit 9  
(±  3 da ys )  
Visit 1 0  
(±  3 da ys ) 
O btai n I nf or me d C o nse nt  
X  
 
 
 
 
 
 
 
 
 
De m o gr a p hics a n d Me dical 
Hist or y  
X  
 
 
 
 
 
 
 
 
 
S m o ki n g Stat us  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Hei g ht, Wei g ht, a n d B MI 
Calc ulati o n  
X  
 
 
 
 
 
 
 
X a 
 
Vital Si g ns ( B P, H R, T, R R)  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P h ysical E xa mi nati o n  
X  
 
 
 
 
X  
 
 
X  
X  
P ul m o nar y F u ncti o n Test b y 
S pir o metr y  
X  
 
 
 
 
X  
 
 
X  
 
C hest C T Sca n (if s u bject d o es 
n ot ha ve pri or ra di ol o gical 
c o nfir mati o n of br o n c hiectasis 
dia g n osis)  
X  
 
 
 
 
 
 
 
 
 
1 2 -lea d E C G  
X  
X  
X  
X  
X  
 
X  
 
X  
 
S pecial la b orat or y tests ( C -
reacti ve pr otei n, pr ot hr o m bi n 
ti me) 
X  
X  
X 
X  
X  
X 
X  
X 
X 
X  


St atistic al A n al ysis Pl a n  
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0 3. 0 0 7 A. 0 3     
   
Pa ge 6 1  of  7 0  
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y Visit  
Da ys -2 8 t o - 1 
 
Da y 1 
( Baseli n e) 
Da y 1 5  
W ee k 2   
Da y 2 9  
W ee k 4   
 
Da y 5 7  
W ee k 8   
 
 
Da y 8 5  
W ee k 1 2   
Da y 1 1 3  
 W ee k 1 6   
Da y 1 4 1  
W ee k 2 0   
Da y 1 6 9  
W ee k 2 4  
( E O T) 
Da y 1 9 7  
W ee k 2 8   
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 da ys ) 
Visit 8  
(±  3 da ys ) 
Visit 9  
(±  3 da ys )  
Visit 1 0  
(±  3 da ys ) 
Cli nical La b orat or y Tests 
( He mat ol o g y, Bl o o d C h e mistr y 
a n d Uri nal ysis)  b 
X  
X c 
X  
X  
X  
X  
X  
X  
X  
X  
H Bs A g, HI V, a n d He p C A b 
Tests  
X  
 
 
 
 
 
 
 
 
 
Ser u m Pre g na nc y Test d   
X  
 
 
 
 
 
 
 
 
 
Esti mate d Gl o mer ular 
Filtrati o n Rate Calc ulati o n p er 
C K D -E PI F or m ula  
X  
 
 
 
 
 
 
 
X  
 
S p ut u m Sa m ple C ollecti o n f or 
S p ut u m C ol or Deter mi n ati o n 
a n d E val uati n g N E a n d Ot h er 
Bi o mar kers e 
X  
X  
X  
X  
 
X  
 
 
X  
X  
S p ut u m Micr o bi ol o g y C ult ure 
f or Pse u d o m o nas a n d Res ult 
Re vie w f 
X  
 
 
 
 
 
 
 
X  
 
De ntal E xa mi nati o n g  
X  
 
 
 
X  
 
 
 
X  
 
Pri or/ C o nc o mita nt Me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ra n d o mizati o n h 
 
X  
 
 
 
 
 
 
 
 
Uri ne Pre g na nc y Test d 
 
X  
 
X  
X  
X  
X  
X  
X  
X  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 2  of  7 0  
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y Visit  
Da ys -2 8 t o - 1 
 
Da y 1 
( Baseli n e) 
Da y 1 5  
W ee k 2   
Da y 2 9  
W ee k 4   
 
Da y 5 7  
W ee k 8   
 
 
Da y 8 5  
W ee k 1 2   
Da y 1 1 3  
 W ee k 1 6   
Da y 1 4 1  
W ee k 2 0   
Da y 1 6 9  
W ee k 2 4  
( E O T) 
Da y 1 9 7  
W ee k 2 8   
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 da ys ) 
Visit 8  
(±  3 da ys ) 
Visit 9  
(±  3 da ys )  
Visit 1 0  
(±  3 da ys ) 
M R C Breat hless ness Scale 
Assess me nt a n d Br o n c hiectasis 
Se verit y I n de x Calc ulati o n  
 
X  
 
 
 
 
 
 
 
 
S G R Q C o m pleti o n a n d 
Re vie w i 
 
X  
 
 
 
X  
 
 
X  
 
Q O L -B C o m pleti o n a n d 
Re vie w i 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
L C Q C o m pleti o n a n d Re vie w i 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Bl o o d a n d Uri ne Sa m ple 
C ollecti o n f or E val u ati n g N E  
a n d Ot her Bi o mar kers  
 
X c 
X  
X  
 
X  
 
 
X  
X  
P K Sa m pli n g f or I N S 1 0 0 7 j 
 
X 
I nte nse 
P K 
Sa m pli n g  
X 
I nte nse P K 
Tr o u g h 
Sa m pli n g  
X 
S parse P K 
a n d 
I nte nse 
P K 
Sa m pli n g  
 
X 
S parse P K 
a n d 
I nte nse 
P K 
Tr o u g h 
Sa m pli n g  
 
 
X 
S parse P K 
a n d I nte nse 
P K Tr o u g h 
Sa m pli n g  
X 
I nte nse P K 
Tr o u g h 
Sa m pli n g  
St u d y Dr u g Dis pe nse, 
Ac c o u nta bilit y of Ret ur n e d 
Dr u g, a n d Re vie w of D osi n g 
Diar y  
 
X  
X n 
X  
X  
X  
X  
X  
X n 
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 3  of  7 0  
P r oce d ure  
Scree ni n g 
P eri o d  
Tre at me nt P eri o d  
E n d of 
St u d y Visit  
Da ys -2 8 t o - 1 
 
Da y 1 
( Baseli n e) 
Da y 1 5  
W ee k 2   
Da y 2 9  
W ee k 4   
 
Da y 5 7  
W ee k 8   
 
 
Da y 8 5  
W ee k 1 2   
Da y 1 1 3  
 W ee k 1 6   
Da y 1 4 1  
W ee k 2 0   
Da y 1 6 9  
W ee k 2 4  
( E O T) 
Da y 1 9 7  
W ee k 2 8   
Visit 1  
Visit 2  
Visit 3  
(±  3 d a ys ) 
Visit 4  
(±  3 d a ys ) 
Visit 5  
(±  3 d a ys ) 
Visit 6  
(±  3 d a ys ) 
Visit 7  
(±  3 da ys ) 
Visit 8  
(±  3 da ys ) 
Visit 9  
(±  3 da ys )  
Visit 1 0  
(±  3 da ys ) 
P ul m o nar y e xac er b ati o n 
S y m pt o m E ntr y a n d Re vie w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse E ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
De ntal H y gie ne E d u cati o n k 
 
X  
X  
X  
X  
X  
X  
X  
 
 
Assess me nt of Oral I nfecti o n, 
Gi n gi vitis, P eri o d o ntitis, a n d 
S ki n C o n diti o ns (es p eciall y 
h y per kerat osis or er yt h e ma of 
p al ms a n d s oles)  l 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
C hil d – P u g h Sc ore ( o nl y f or 
s u bjects w h ose li ver f u n cti o n 
tests are a b n or mal a n d 
s us pecte d t o ha ve c hr o nic li ver 
disease t o assess f or eli gi bilit y)  
m  
X  
 
 
 
 
 
 
 
 
 
Uri ne Pr otei n a n d Creati ni n e 
Q ua ntitati ve Test a n d Rati o 
Calc ulati o n m  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
a 
Wei g ht o nl y.  
b 
Cli nical la b orat or y bl o o d sa m ples s h o ul d b e c ollecte d i n a faste d state (aft er a n o ver ni g ht fast f or m or ni n g sa m ple c ollecti o n or at least 4 h o urs wit h o ut f o o d at ot her 
ti mes) if p ossi ble.  Uri n al ysis will b e p erf or me d usi n g di pstic ks wit h clea n catc h uri n e sa m ples. 
c 
Vital Si g ns a n d c li nical la b orat or y bl o o d sa m ples s h o ul d b e c ollecte d pri or t o t h e first d ose of t h e st u d y dr u g o n Da y 1.  
d 
Ser u m a n d uri n e pre g n a n c y tests will b e p erf or me d f or fe males of c hil d -b eari n g p ote ntial o nl y.  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 4  of  7 0  
e 
S u bjects will b e re q uire d t o pr o vi d e a s p ut u m sa m ple d uri n g t h e s pecifi e d visits.  A s u bject ma y n ot u n d er g o a s p ut u m i n d ucti o n pr oce d ure d uri n g Scree ni n g ( Visit 
1) t o meet eli gi bilit y.  O n Da y 1, t h e s p ut u m sa m ple s h o ul d b e c ollecte d pri or t o t h e first d osi n g of t he st u d y dr u gs.  If a s u bject is u na ble t o pr o vi de a s p o nta ne o us 
s p ut u m sa m ple d uri n g a n y visit, c h est p h ysi ot h era p y s h o ul d b e p erf or me d first t o fa cilitate e x p ect orati o n.  If c h est p h ysi ot hera p y fails, t he rec o m me n de d s p ut u m 
i n d ucti o n pr o ce d ure d etaile d i n t he pr ot oc ol s h o ul d b e p erf or me d t o o btai n a s p ut u m sa m ple.   
f 
S p ut u m mi cr o bi ol o g y c ult ure f or Pse u d o m o n as  will b e p erf or me d wit h t h e s p ut u m sa m ple o btai n e d at Scree ni n g.  T he res ult will be re vie we d at Baseli ne a n d use d 
f or ra n d o mizati o n stratificati o n.   
g 
All s u bjects n ee d a d e ntal e xa m.  If a s u bject states t h at h e/s h e h as n o  teet h, a d e ntist s h o ul d c o nfir m t h at t he s u bject has n o teet h a n d/ or i m pla nts s u p p orti n g a 
de nt ure.  A n y d e nt ure s ores or a n y ot h er p at h ol o g y s h o ul d b e n ote d b ut will n ot e xcl u d e t h e s u bject fr o m t h e st u d y.   .  .  All ot her s u bjects w h o meet all i ncl usi o n a n d 
e xcl usi o n criteria are re q uire d t o h a ve a d e ntal e xa mi n ati o n t h at i ncl u d es a f ull -m o ut h d e ntal ra di o gra p h y a n d oral e xa mi nati o n t o e val uate t he c o n diti o ns of oral s oft 
tiss ue, gi n gi va, a n d teet h d uri n g Scree ni n g.  S u bjects w h o are c o nsi d ere d a scree n fail ure f or reas o ns n ot relate d t o t he de ntal e xcl usi o n criteria (e xcl usi o n criteria 2 9 
t hr o u g h 3 2) d o n ot n ee d t o re p eat t h e d e ntal e xa mi n ati o n if t h e y are re-scree n e d wit hi n 3 m o nt hs of t h e first Scree ni n g visit. S u bjects w h o ha ve t he i ma ges of a 
f ull-m o ut h d e ntal ra di o gra p h y t h at are p erf or me d wit hi n 6 m o nt hs of Scree ni n g a n d a vaila ble f or re vie w ar e n ot re q uire d t o ha ve a n ot her de ntal ra di o gra p h y d o ne d uri n g 
Scree ni n g.  S u bjects w h o are eli gi ble f or t h e st u d y will h a ve a d e ntal d ee p clea ni n g (scali n g a n d r o ot pla ni n g) b ef ore ra n d o mizati o n.  T he e val uati o n a n d rec or di n g of 
oral a n d d e ntal c o n diti o ns are d etaile d i n t h e st u d y pr ot o c ol.  T h e de ntal e xa mi n ati o n f or Visits 5 a n d 9 ca n b e p erf or me d ± 7 da ys of t he visit  date.  
h 
Eli gi bilit y s h o ul d b e reassesse d  pri or t o ra n d o mizati o n at Visit  2 ( Baseli n e).  S u bjects w h o d o n ot meet all i ncl usi o n/e xcl usi o n criteria will N O T be ra n d o mize d a n d 
will be c o nsi d ere d a scree n fail ure.  S u bjects w h o faile d at Scree ni n g ca n b e re -scree n e d u p t o 2 ti mes u p o n S p o ns or a p pr o val. 
i 
S u bjects will c o m plete t h e S G R Q e ver y 1 2 we e ks a n d t h e Q O L -B a n d L C Q e ver y 2  wee ks u ntil Visit  1 0 .  S u bjects will be re q uire d t o c o m plete all 3 q uesti o n naires 
after t h e trai ni n g a n d pri or t o t h e a d mi nistrati o n of t h e first d ose of t h eir assi g n e d st u d y dr u g o n Visit 2 ( Da y 1). T he s u bjects will c o m plete t he q uesti o n naires w hile t he y 
are i n t h e cli nic at eac h of t h e st u d y visits a n d at h o me f or t h e we e ks i n b et wee n t h e st u d y visits.  T h e c o m plete d q uesti o n naires s h o ul d be re vie we d d uri n g eac h visit.  
S u bjects will b e retrai n e d o n h o w t o c o m plete t h e q u esti o n n aires c orrectl y if n ee d e d.   
j 
F or t h e 3 6 s u bjects w h o p artici p ate i n t h e P K s u b -st u d y, t h e P K sa m ples will b e c ollecte d t hr o u g h a n i n d welli n g cat heter i nt o vac utai ners wit h K 2E D T A pri or t o t he 
first d ose of t h e st u d y dr u gs i n t h e m or ni n g o n Da y 1 a n d at 1, 2, 3, 4, 6, 8 h o urs p ost d ose, a n d pri or t o t h e m or ni n g d ose d uri n g Visit  4 a n d at 1, 2, 3, 4, 6, 8 h o urs 
p ost d ose o n t h at visit  d a y; a c ollecti o n ti me wi n d o w of ± 1 0 mi n utes will b e p er mitte d at eac h ti me p oi nt.  I n a d diti o n, a tr o u g h P K sa m ple ( pre d ose of I N S 1 0 0 7) will be 
c ollecte d at Visits 3, 6, 9 a n d 1 0.  F or s u bjects w h o p artici p ate i n t he P K s u b -st u d y, t h e Visit 4 wi n d o w will b e ± 5 da ys.  
 
F or t h e s u bjects w h o are e nr olle d at sites h a vi n g P K  sa m ple pr o cessi n g ca p a bilit y b ut n ot p artici p ati n g i n t he i nte nsi ve P K s u b-st u d y, 1 P K sa m ple eac h will be 
c ollecte d (eit h er pre - or p ost d osi n g o n t h e visit d a y) at 3 visits of Visits 4, 6, a n d 9, res p ecti vel y.  F or s u bjects p artici pati n g i n t he i nte nsi ve P K s u b st u d y, a meal will be 
gi ve n after t h e 1 -h o ur bl o o d dra w at Visits 2 a n d 4 (refer t o A p p e n di x 4 f or bl o o d sa m pli n g ti mes).  
k De ntal h y gie n e e d u cati o n i n cl u des d ail y teet h br us hi n g a n d fl ossi n g.  
l 
Oral a n d d e ntal i ns p ecti o n will b e p erf or me d b y t h e I n vesti gat or at eac h visit.  If t h ere are a n y si g ns or s y m pt o ms of oral i nfecti o n, gi n gi vitis, or peri o d o ntitis or 
deteri orati o n of t h e pree xisti n g c o n diti o ns t h at warra nt f urt h er e val u ati o n u p o n I n vesti gat or discreti o n, t h e s u bject will be  referre d t o t he st u d y desi g nate d de ntist f or 
f urt her assess me nt.  T h e oral a n d d e ntal e val u ati o n b y t h e d e ntist f or t h e s u bject s h o ul d t h e n b e assesse d t h ereafter o n a n inter val per t he de ntist discreti o n u ntil e n d of t he 
st u d y. 
S ki n e xa mi n ati o n, es p eciall y p al ms a n d s oles , d ors u m of t h e h a n ds a n d feet, Ac hilles te n d o n area, k n ees, a n d el b o ws, will be perf or me d b y t he I n vesti gat or at eac h visit.  
If t here are a n y si g ns or s y m pt o ms of h y p er k erat osis or er yt h e ma or d eteri orati o n of t h e pree xisti n g c o n diti o ns t hat warra nt f urther e val uati o n u p o n I n vesti gat or 
discreti o n, t h e s u bject will b e referre d t o a d er mat ol o gist f or f urt h er assess me nt.  T h e s ki n e val u ati o n b y t h e d er mat ol o gist  f or t he s u bject s h o ul d t he n be assesse d 
t hereafter o n a n i nter val p er t h e der mat ol o gist discreti on u ntil e n d of t h e st u d y.  
m  
Uri n e pr otei n a n d creati ni n e q u a ntificati o n a n d rati o calc ulati o n will b e p erf or me d o nl y w h e n a s u bject is s us pecte d t o ha ve re nal i nj ur y per I n vesti gat or d iscreti o n. 
n N o st u d y dr u g dis p e nsi n g at t his Visit  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 5  of  7 0  
B P  =  bl o o d  press ure;  B MI  =  b o d y  mass  i n d e x;  C K D -E PI  =  c hr o nic  ki d n e y  disease  e pi d e mi ol o g y  c olla b orati o n  e q uati o n  1;  C T  =  c o m p uterize d  t o m o gra p h y; 
E C G = ele ctr o car di o gra m;  e G F R  =  esti mate d  gl o mer ular  filtrati o n  rate;  H Bs A g  =  h e p atitis  B  s urface  a nti ge n;  He p C  A b  =  he patitis  C  a nti b o d y;  HI V  =  h u ma n 
i m m u n o d eficie n c y vir us; H R = h e art rate; L C Q = Leic ester C o u g h Q u esti o n n aire; M R C = Me dical Researc h C o u ncil ; N E = ne utr o p hil elastase; P K = p har mac o ki netic(s); 
Q O L -B =  Q u alit y of Life Q u esti o n n aire -Br o n c hiectasis; S G R Q = St Ge or ge’s R es pirat or y Q u esti o n naire; T = b o d y te m perat ure.  
 
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 6  of  7 0  
A P P E N DI X B:  C A L C U L A TI O N O F B R O N C HI E C T A SI S S E V E RI T Y I N D E X  
Se verit y Criteri a  
0 P oi nt  
1 P oi nt  
2 P oi nt  
3 P oi nt  
4 P oi nt  
5 P oi nt  
6 P oi nt  
A ge ( Years)  
< 5 0 
- 
5 0 t o 6 9  
- 
7 0 t o 7 9  
- 
8 0 + 
B MI ( k g/ m 2) 
> 1 8. 5 
- 
< 1 8. 5 
- 
- 
- 
- 
F E V 1 
( % Pre dicte d) 
> 8 0 % 
5 0 t o 8 0 %  
3 0 t o 4 9 %  
< 3 0 % 
- 
- 
- 
H os pital A d missi o ns i n t he Past 
2 Years  
N o  
- 
- 
- 
- 
Yes  
- 
E xacer bati o n Fre q ue nc y i n Last 
1 2 M o nt hs 
0 t o 2 
- 
3 o r M ore 
- 
- 
- 
- 
M R C D ys p nea Sc ore  
1- 3 
- 
4 
5 
- 
- 
- 
C ol o nizati o n Stat us  
N ot 
C ol o nize d 
C hr o nic 
C ol o nizati o n 
- 
P a 
C ol o nizati o n 
- 
- 
- 
Ra di ol o gical Se verit y  
< 3 L o bes 
I n v ol ve d 
3 o r M ore 
L o bes o r 
C ystic 
C ha n ges 
 
 
 
 
 
N ote: Esti mate d o utc o mes are t h ose o bser ve d acr oss 5 E ur o pea n treat me nts i n t he ori gi nal deri vati o n a n d vali dati o n st u d y (C hal mers J D et al, 2 0 1 4 ). 
B MI  = b o d y mass i n de x, F E V 1 = f orce d e x pirat or y v ol u me i n 1 sec o n d, M R C = Me dical R esearc h C o u ncil ; P a  = Pse u d o m o n as aer u gi n os a . 
 
 
 
 


St atisti c al A n al ysis Pl a n  
I ns m e d I n c or p or at e d Pr ot o c ol I N S 1 0 0 7-2 0 1  
V ersi o n 1. 0  
S y n e os H e alt h # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3      
 
Pa ge 6 7  of 7 0  
A P P E N DI X C: E X P L O R A T O R Y S T A TI S TI C A L A N A L Y SI S P L A N   
 
N ote: T h e e x pl orat or y a nal ys es as descri be d i n t his a p pe n di x 
will b e p erf or me d b y I ns m e d. I nc.  
 
S p o ns or N a me:  
I ns me d I nc or p or ate d 
Pr ot oc ol N u m ber a n d Title:  
 
I N S 1 0 0 7-2 0 1 A R a n d o mize d, D o u ble -Bli n d, 
Pl ace b o -C o ntr olle d, P a r allel -Gr o u p, M ulti -Ce nter 
St u d y t o Assess t he Effic ac y, S afet y a n d 
T oler a bilit y, a n d P h ar m a c o ki netics of I N S 1 0 0 7 
A d mi nistere d O nce D ail y f or 2 4 Wee ks i n 
S u bjects wit h N o n -C ystic Fi br osis Br o nc hiect asis 
- T he Will o w St u d y  
Ori gi n al Pr ot oc ol:  
2 1 J u ne 2 0 1 7  
Pr ot oc ol A me n d me nt 
n u m bers a n d d ates  
A me n d me nt 1. 0 , 2 4 A u g ust 2 0 1 7  
A me n d me nt 2. 0 , 1 2 M a rc h 2 0 1 8  
A me n d me nt 3. 0 , 2 7 A p ril 2 0 1 8 
A me n d me nt 4 . 0, 2 4 Se pte m ber 2 0 1 8  
 
 
A ut h or:  
   
   E S A P Versi o n:  
1. 0  
E S A P Versi o n D ate:  
2 0  Dece m b er 2 0 1 9  
N otice of C o nfi de nti al a n d Pr o priet ar y I nf or m ati o n:  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is c o nfi de ntial b el o n gi n g t o I ns me d I nc or p orate d. Acce pta nce of 
t his d oc u me nt c o nstit utes a gree me nt b y t he reci pie nt t hat n o i nf or mati o n c o ntai ne d herei n will be p u blis he d 
or discl ose d wit h o ut pri or writte n a ut h orizati o n fr o m a n official of I ns me d I nc or p orate d.  H o we ver, t his 
d oc u me nt ma y be discl ose d t o a p pr o priate I nstit uti o nal Re vi e w B oar d a n d Et hics C o m mitt ees or d ul y 
a ut h orize d re prese ntati ves of a nati o nal re g ulat or y a ut h orit y u n der t he c o n diti o n t hat t he y are re q ueste d t o 
kee p it c o nfi de ntial. I n t he e ve nt of a n act ual or s us pecte d breac h of t his o bli gati o n, I ns me d I nc or p orate d 
s h o ul d be n otifie d pr o m ptl y. 
 
 


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 8  of  7 0  
1.  
I ntr o d ucti o n 
T he o bjecti ve of t his E x pl orat or y S A P is t o o utli ne se veral e x pl orat or y a nal ys es t hat assess 
t he rate of e x acer b ati o n as e vi de nce of efficac y of I N S 1 0 0 7 vs. place b o.  
2.  
T ot alit y of e vi de nce  
2. 1.  
T he R ate of e x acer b ati o ns 
T he p ur p ose of t his e x pl orat or y a n al ysis S A P is t o o utli ne h o w t he rate of e x acer bati o ns 
t he a nal ysis o n will be a n al yze d . T he p ossi bilit y t h at I N S 1 0 0 7 is m ore effecti ve i n certai n 
s u b- p o p ulati o ns will be i n vesti gate d. T he stre n gt h of e vi de nce will n ot necessaril y d e pe n d 
o n a n y p- val ues.  
3.  
A n al ysis p o p ul ati o ns  
T he a nal ysi s p o p ulati o ns will i ncl u de t he I T T p o p ulati o n.  
3. 1. 
S u b -p o p ul ati o n of cli nic al rele v a nce  
A s u b gr o u p a nal ysis of r ate of p ul m o nar y e x acer b ati o n (I N S 1 0 0 7 1 0 m g or 2 5 m g vs. 
Place b o) usi n g a ne gati ve bi n o mial re gressi o n met h o d as descri be d earlier i n secti o n 8. 3. 3 
will be perf or me d. T he r ate rati o a n d 2-si de d 9 0 % CIs will be pr o vi de d f or t he c o m paris o n 
of I N S 1 0 0 7 1 0 m g or 2 5 m g vs. Place b o. 
F oll o wi n g s u b gr o u ps will be e x pl ore d: 
•  
A ge: ≥ 6 5 years, < 6 5 years, ≥ 7 5 years ( geriatric), < 7 5 years ( N o n-geriatri c)  
• 
P ul m o nar y e x acer bati o ns ( Bas eli ne vari a ble): 0 - 2, ≥ 3 
• 
Mai nte na nce us e of macr oli des at Baseli ne: Y es, N o  
•  
Pa c ol o nizati o n stat us: Yes, N o 
•  
Seri o us p ul m o nar y e x acer bati o n: Yes, N o 
•  
Baseli ne B SI sc ore: ≥ 5, < 5 
• 
Baseli ne F E V 1 % Pre dicte d: < 5 0 %, ≥ 5 0 % 
•  
Ge o gra p hical re gi o n: E ur o pe, N ort h A meri ca, Asi a- pacific, Easter n E ur o pe 
( B ul gari a/ P ola n d) 
•  Ne utr o p hil elastase i n s p ut u m at baseli ne 2  cate g ories (< 2 0, ≥2 0)   


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 6 9  of  7 0  
•  Oral ster oi ds at bas eli ne Yes or N o  
•  I n h ale d ster oi ds at b aseli ne Yes or N o 
4.  
St atistic al a n al ysis 
 
4. 1. Ge ner al st atistics  
P oi nt esti mates a n d 9 0 % c o nfi de nce i nter vals will be calc ul ate d a n d s u m marize d.  
4. 2. M o deli n g f or t he r ate of e x acer b ati o n  
T he rate of e x acer bati o n will be a nal yze d wit h b ot h ne gati ve bi n o mial distri b uti o n test a n d 
t he An ders o n – Gill m o del test.  
4. 1. 1.  
Ne g ati ve bi n o mi al m o d el 
Ne gati ve bi n o mial m o dels ca n be esti mate d i n S A S usi n g  pr oc ge n m o d. T h e t y p e 3 o pti o n 
is use d t o get t he m ulti-d e gree - of-free d o m test of t he cate g ori cal vari a bles liste d o n 
t he class state me nt, a n d t he dist = ne g bi n o pti o n is use d t o i n dicate t hat a ne gati ve bi n o mial 
distri b uti o n s h o ul d be use d.  
Ne gati ve bi n o mial m o del:  
p r o c  g e n m o d  d a t a = n b ;  
    c l a s s  t r t 0 1 a n  ( R E F  =  ' 1 ' )  M A C R O U S E  S P U T U C U T ;  
    m o d e l  P E X N U M = t r t 0 1 a n  M A C R O U S E  S P U T U C U T  / t y p e 3  d i s t = N B  l i n k = l o g  
o f f s e t = l o g y r s ;  
    e s t i m a t e  " 2 5  m g  v s  P l a c e b o  r a t e  r a t i o "  t r t 0 1 a n   1  0  0  / a l p h a = 0 . 0 5  
e x p ;  
    e s t i m a t e  " 1 0  m g  v s  P l a c e b o  r a t e  r a t i o "  t r t 0 1 a n   0  1  0  / a l p h a = 0 . 0 5  
e x p ;  
     
    l s m e a n s  t r t 0 1 a n  / c l  d i f f  e x p ;  
r u n ;  
W here, trt 0 1a n = tr eat me nt gr o u p (I N S 1 0 0 7 1 0 m g or 2 5 m g vs. Place b o), P E X N U M  = 
N u m ber of p ul m o nar y e x acer b ati o n s, l o g yrs = L o garit h m of Treat me nt D urati o n i n Years.  
4. 1. 2.  
A n ders o n -Gill m o del - d at a pre p ar ati o n 
As a patie nt ca n h a ve rec urre nt e x acer bati o n s, t here will be a d diti o nal se nsiti vit y a nal ysis; 
T he a nal ysis will be perf or me d usi n g t he A n ders e n- Gill, m o difie d C o x re gressi o n 
a p pr oac h, f or 1 0 0 7 v ers us Place b o A n ders o n- Gill m o del.  
Sa m ple S A S ® c o de is s h o w n bel o w:  


St atistic al A n al ysis Pl a n  
I ns me d I nc or p or ate d Pr ot oc ol I N S 1 0 0 7-2 0 1  
Versi o n 1. 0  
S y ne os  He alt h  # 1 0 0 9 1 1 3  
 
0 3. 0 0 7 A. 0 3     
   
Pa ge 7 0  of  7 0  
P R O C  P H R E G  D A T A = a g  C O V M  c o v s ( a g g r e g a t e ) A L P H A  =  0 . 2 ;   
 
c l a s s  t r t 0 1 a n  ( R E F  =  ' 1 ' )  M A C R O U S E  S P U T U C U T / O R D E R  =  I N T E R N A L  P A R A M  = G L M ;  
M O D E L  ( T s t a r t ,  T s t o p )  *  S T A T U S ( 0 )  =  t r t 0 1 a n /  R I S K L I M I T S  T Y P E 3  R I D G I N G  =  
A B S O L U T E ;   
s t r a t a  M A C R O U S E  S P U T U C U T ;  
i d  u s u b j i d ;  
 
R U N ;