Conditions: Chronic Obstructive Pulmonary Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in subjects with COPD would be efficacious with regards to reducing lung and systemic inflammation and bacterial colonization as potential drivers of airway obstruction, airway destruction, remodeling and exacerbations.

Furthermore, this study provided supportive data to investigate the relationship of COPD phenotype and the response in small airway structure, function, mucus load and spirometry indices as well as in improvement of overall COPD symptoms and quality of life.

Detailed description:
This was a randomized, subject and investigator blinded, parallel-group, placebo controlled study investigating the mode of action (MoA) and preliminary efficacy and safety of QBW251 administered orally twice daily (b.i.d.) for 12 weeks in subjects with moderate to severe COPD (GOLD 2-3).

The study consisted of the following periods: Screening, Baseline / Day 1, Treatment , and End of the Study followed by an additional post-treatment safety phone call. The total duration for each subject in the study is up to approximately 18 weeks.

Arms:
arm 1: Oral use, one capsule twice daily. arm 2: Oral use, one capsule twice daily.

Interventions: intervention 1: QBW251 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsule 300mg intervention 2: Capsule 300mg

Protocol document:
Prot_000.pdf: 


N o v arti s
C o nfi d e nti al
P a g e 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Sit e O p er ati o n s M a n u al ( S O M)
A Site O perati o ns Ma n ual ( S O M) acc o m pa nies t his p r ot oc ol, pr o vi di n g t he o perati o nal details 
f or st u d y pr oce d ures. N ote: T he S O M will n ot be a part of t he Cli nical St u d y Re p ort.


N o v arti s
C o nfi d e nti al
P a g e 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T a bl e of c o nt e nt s
Site O perati o ns Ma n ual ( S O M)........................................................................................... 2
Ta ble of c o nte nts .................................................................................................................3
List of ta bles ........................................................................................................................7
List of fi g ures ......................................................................................................................7
List of a b bre viati o ns ............................................................................................................8
Gl ossar y  of ter ms...............................................................................................................1 2
Pr ot oc ol s u m mar y ..............................................................................................................2 0
1
I ntr o d ucti o n .......................................................................................................................2 6
1. 1
Bac k gr o u n d ............................................................................................................2 6
1. 2
P ur p ose ..................................................................................................................2 8
2
O bjecti ves a n d e n d p oi nts ...................................................................................................2 8
3
St u d y  desi g n ......................................................................................................................3 1
3. 1
St u d y  Visits............................................................................................................3 1
4
Rati o nale ............................................................................................................................3 4
4. 1
Rati o nale f or st u d y desi g n .....................................................................................3 4
4. 1. 1
Rati o nale f or c h oice of bac k gr o u n d t hera p y .........................................3 5
4. 2
Rati o nale f or d ose/re gi me n a n d d urati o n of treat me nt.......................................... 3 6
4. 3
Rati o nale f or c h oice of c o ntr ol dr u gs (c o m parat or/ place b o) or c o m bi nati o n 
dr u gs ......................................................................................................................3 6
4. 4
P ur p ose a n d ti mi n g of i nteri m a nal ys es/ desi g n a da ptati o ns ..................................3 7
4. 5
Ris ks a n d be nefits ..................................................................................................3 7
4. 5. 1
Bl o o d sa m ple v ol u me ............................................................................4 0
5
P o p ulati o n ..........................................................................................................................4 0
5. 1
I ncl usi o n criteria ....................................................................................................4 0
5. 2
E xcl usi o n criteria ...................................................................................................4 1
6
Treat me nt ...........................................................................................................................4 4
6. 1
St u d y  treat me nt......................................................................................................4 4
6. 1. 1
I n vesti gati o nal a n d c o ntr ol dr u gs..........................................................4 4
6. 1. 2
A d diti o nal st u d y  treat me nts ..................................................................4 5
6. 1. 3
Treat me nt ar ms/ gr o u p ...........................................................................4 5
6. 2
Ot her treat me nt(s) ..................................................................................................4 5
6. 2. 1
C o nc o mita nt t hera p y .............................................................................4 5
6. 2. 2
Pr o hi bite d me dicati o n........................................................................... 5 0
6. 2. 3
Resc ue me dicati o n ................................................................................ 5 1
C o m merciall y C o nfi de ntial I nf or mati o n ( C CI)


N o v arti s
C o nfi d e nti al
P a g e 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
6. 2. 4
Restricti o n f or st u d y  s u bjects................................................................5 1
6. 3
S u bject n u m beri n g, treat me nt assi g n me nt, ra n d o mizati o n ....................................5 2
6. 3. 1
S u bject n u m beri n g ................................................................................5 2
6. 3. 2
Treat me nt assi g n me nt, ra n d o mizati o n ..................................................5 2
6. 4
Treat me nt bli n di n g .................................................................................................5 3
6. 5
D ose escalati o n a n d d ose m o dificati o n.................................................................. 5 4
6. 5. 1
D ose i nterr u pti o ns .................................................................................5 4
6. 6
A d diti o nal treat me nt g ui da nce ...............................................................................5 6
6. 6. 1
Treat me nt c o m plia nce ...........................................................................5 6
6. 6. 2
Rec o m me n de d treat me nt of a d verse e ve nts ..........................................5 6
6. 6. 3
E mer ge nc y  brea ki n g of assi g ne d treat me nt c o de..................................5 7
6. 7
Pre parati o n a n d dis pe nsati o n .................................................................................5 7
6. 7. 1
I nstr ucti o n of prescri bi n g a n d ta ki n g st u dy me dicati o n ........................5 8
7
I nf or me d c o nse nt pr oce d ures ............................................................................................5 8
8
Visit sc he d ule a n d assess me nts......................................................................................... 6 0
8. 1
Scree ni n g ...............................................................................................................7 0
8. 1. 1
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures .................................7 0
8. 2
S u bject de m o gra p hics/ ot her baseli ne c haracteristics............................................. 7 1
8. 3
Efficac y  / P har mac o dy n a mics ...............................................................................7 1
8. 3. 1
S pir o metr y .............................................................................................7 1
8. 3. 2
Hi g h Res ol uti o n C o m p ute d T o m o gra p h y ( H R C T) ...............................7 2
8. 3. 3
A p pr o priate ness of efficac y  assess me nts..............................................7 2
8. 3. 4
Fi bri n o ge n .............................................................................................7 2
8. 3. 6
Bacterial l oa d ........................................................................................7 3
8. 4
Safet y .....................................................................................................................7 3
8. 4. 1
La b orat or y  e val uati o ns..........................................................................7 4
8. 4. 2
1 2-lea d Electr ocar di o gra m ( E C G) ........................................................ 7 5
8. 4. 3
Pre g na nc y  a n d assess me nts of fertilit y .................................................7 6
8. 4. 4
C O P D E xacer bati o n ..............................................................................7 6
8. 4. 5
A p pr o priate ness of safet y  meas ure me nts..............................................7 7
8. 5
A d diti o nal assess me nts.......................................................................................... 7 7
8. 5. 1
Cli nical O utc o me Assess me nts ( C O As) ...............................................7 7
8. 5. 2
P har mac o ki netics ..................................................................................8 0
8. 5. 3
Bi o mar kers ............................................................................................8 1
8. 5. 4
Ot her Assess me nts ................................................................................8 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
9
St u d y  disc o nti n uati o n a n d c o m pleti o n ..............................................................................8 2
9. 1
Disc o nti n uati o n ......................................................................................................8 2
9. 1. 1
Disc o nti n uati o n of st u d y  treat me nt.......................................................8 2
9. 1. 2
Wit h dra wal of i nf or me d c o nse nt ...........................................................8 4
9. 1. 3
L ost t o f oll o w -u p................................................................................... 8 4
9. 1. 4
St u d y  st o p pi n g r ules..............................................................................8 5
9. 1. 5
Earl y st u d y ter mi nati o n b y t he s p o ns or .................................................8 5
9. 2
St u d y  c o m pleti o n a n d p ost-st u d y treat me nt ..........................................................8 5
1 0
Safet y  m o nit ori n g a n d re p orti n g........................................................................................8 6
1 0. 1
Defi niti o n of a d verse e ve nts a n d re p orti n g re q uir e me nts ......................................8 6
1 0. 1. 1
A d verse e ve nts ......................................................................................8 6
1 0. 1. 2
Seri o us a d verse e ve nts ..........................................................................8 7
1 0. 1. 3
S A E re p orti n g ........................................................................................8 8
1 0. 1. 4
Pre g na nc y  re p orti n g..............................................................................8 9
1 0. 1. 5
Re p orti n g of st u d y treat me nt err ors i ncl u di n g mis use/a b use ................9 0
1 0. 2
A d diti o nal Safet y  M o nit ori n g................................................................................9 0
1 0. 2. 1
Li ver safet y  m o nit ori n g.........................................................................9 0
1 0. 2. 2
Re nal safet y m o nit ori n g ........................................................................9 1
1 0. 2. 3
Data M o nit ori n g C o m mittee .................................................................9 1
1 1
Data C ollecti o n a n d Data base ma na ge me nt ......................................................................9 2
1 1. 1
Data c ollecti o n....................................................................................................... 9 2
1 1. 2
Data base ma na ge me nt a n d q ualit y  c o ntr ol............................................................9 2
1 1. 3
Site m o nit ori n g ......................................................................................................9 3
1 2
Data a nal y sis a n d statistical met h o ds ................................................................................9 4
1 2. 1
A nal y sis sets ..........................................................................................................9 4
1 2. 2
S u bject de m o gra p hics a n d ot her baseli ne c haracteristics...................................... 9 4
1 2. 3
Treat me nts .............................................................................................................9 4
1 2. 4
A nal y sis of t he pri mar y e n d p oi nt(s)......................................................................9 5
1 2. 4. 1
Defi niti o n of pri mar y  esti ma n d.............................................................9 5
1 2. 4. 2
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis ..........................9 5
1 2. 4. 3
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns .......................9 6
1 2. 4. 4
Se nsiti vit y  a n d S u p p orti ve a nalys es ......................................................9 6
1 2. 5
A nal y sis of sec o n dar y e n d p oi nts...........................................................................9 6
1 2. 5. 1
Efficac y  a n d/ or P har mac o d yna mic e n d p oi nt(s) ....................................9 6
1 2. 5. 2
Safet y  e n d p oi nts....................................................................................9 7
1 2. 5. 3
P har mac o ki netics ..................................................................................9 8


N o v arti s
C o nfi d e nti al
P a g e 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 2. 5. 4 
Patie nt Re p orte d O utc o mes a n d E xacer bati o ns .................................... 9 8
1 2. 6
A nal y sis of e x pl orat or y e n d p oi nts.........................................................................9 9
1 2. 6. 1
Bi o mar kers ............................................................................................9 9
1 2. 7
I nteri m a nalys es .....................................................................................................9 9
1 2. 8
Sa m ple size calc ulati o n........................................................................................ 1 0 0
1 3
Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures ....................................................1 0 0
1 3. 1
Re g ulat or y  a n d et hical c o m plia nce......................................................................1 0 0
1 3. 2
Res p o nsi bilities of t he i n vesti gat or a n d I R B/ I E C................................................1 0 0
1 3. 3
P u blicati o n of st u d y  pr ot oc ol a n d res ults.............................................................1 0 1
1 3. 4
Q ualit y  C o ntr ol a n d Q ualit y Ass ura nce...............................................................1 0 1
1 4
Pr ot oc ol a d here nce ..........................................................................................................1 0 1
1 4. 1
Pr ot oc ol a me n d me nts ...........................................................................................1 0 2
1 5
Refere nces .......................................................................................................................1 0 3
1 6
A p pe n dices ......................................................................................................................1 0 6
1 6. 1
A p pe n di x 1: Cli nicall y  n ota ble la b orat or y val ues a n d vital si g ns.......................1 0 6
1 6. 2
A p pe n di x 2: L i ver e ve nt a n d La b orat or y tri g ger Defi niti o ns a n d F oll o w- u p 
Re q uire me nts .......................................................................................................1 0 7
1 6. 3
A p pe n di x 3: S pecific re nal alert criteria, Acti o ns a n d E ve nt F oll o w - u p.............1 1 1
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Li st of t a bl e s
Ta ble 2 - 1
O bjecti ves a n d relate d e n d p oi nts ..........................................................2 8
Ta ble 6 - 1
I n vesti gati o nal a n d c o ntr ol dr u gs ..........................................................4 4
Ta ble 6 - 2
Me dicati o ns per mitte d u n der certai n c o n diti o ns................................... 4 6
Ta ble 6 - 3
Me dicati o ns w hic h ma y  be c o-a d mi nistere d w it h Q B W 2 5 1 (if n o 
alter nati ve treat me nt is a vaila ble) ......................................................... 4 7
Ta ble 6 - 4
E xa m ples of c o ntrace pti ves n ot rec o m me n de d f or s y ste mic use as 
acce pta ble mea ns of c o ntrace pti o n a s efficac y ma y be 
c o m pr o mise d b y Q B W 2 5 1 a d mi nistrati o n............................................5 0
Ta ble 6 - 5
Pr o hi bite d me dicati o n........................................................................... 5 0
Ta ble 6 - 6
Pr o hi bite d C O P D -relate d me dicati o ns a n d was h o ut peri o d pri or t o 
D a y 1..................................................................................................... 5 1
Ta ble 6 - 7
Bli n di n g Le vels .....................................................................................5 3
Ta ble 8 - 1
Assess me nt Sc he d ule ............................................................................6 0
Ta ble 8 - 2
La b orat or y  e val uati o ns..........................................................................7 5
Ta ble 1 0 - 1
G ui da nce f or ca pt uri n g t he st u d y  treat me nt err ors i ncl u di n g 
mis us e/a b use .........................................................................................9 0
Ta ble 1 6 - 1
Li ver e ve nt a n d la b orat or y  tri g ger defi niti o ns ....................................1 0 7
Ta ble 1 6 - 2
F oll o w u p re q uire me nts f or li ver e ve nts a n d la b orat or y  tri g gers........1 0 8
Ta ble 1 6 - 3
S pecific Re nal Alert Criteria a n d Acti o ns ...........................................1 1 1
Ta ble 1 6 - 4
Re nal E ve nt F oll o w U p .......................................................................1 1 2
Li st of fi g ur e s
Fi g ure 3 -1
St u d y desi g n ..........................................................................................3 1


N o v arti s
C o nfi d e nti al
P a g e 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Li st of a b br e vi ati o n s
A E
A d v er s e E v e nt
A L P
A L k ali n e P h o s p h at a s e
A L T
A L a ni n e a mi n o Tr a n sf er a s e
A N C O V A
A N al y si s of C O V Ari a n c e
A S T
A S p art at e a m i n o Tr a n sf er a s e
A T S
A m eri c a n T h or a ci c S o ci et y
A U C
Ar e a U n d er t h e pl a s m a c o n c e ntr ati o n -ti me C ur v e
A U C 0 -2 4 h
Ar e a U n d er t h e pl a s m a c o n c e ntr ati o n C ur v e o v er 2 4 h o ur s
b.i. d.
bi s i n di e (t wi c e a d a y )
B MI
B o d y M a s s I n d e x
B P
Bl o o d Pr e s s ur e
B U N
Bl o o d Ur e a Nitr o g e n
C A S A - Q
C o u g h a n d S p ut u m A s s e s s m e nt Q u e sti o n n air e
C A T
C O P D A s s e s s m e nt T e st
C D -R O M
C o m p a ct Di s c – R e a d O nl y M e m or y
C F
C y sti c Fi br o si s
C F R
C o d e of F e d er al R e g ul ati o n
C F T R
C y sti c Fi br o si s Tr a n s m e m br a n e C o n d u ct a n c e R e g ul at or
C F U
C ol o n y F or mi n g U nit
C K
Cr e ati ni n e Ki n a s e
C m a x
C o n c e ntr ati o n M a xi m u m
C mi n
C o n c e ntr ati o n Mi ni m u m
C M O & P S
C hi ef M e di c al Offi c e & P ati e nt S af et y
C O
C o u ntr y Or g a ni z ati o n
C O 2
C ar b o n di o xi d e
C O A
Cli ni c al O ut c o m e A s s e s s m e nt s
C O P D
C hr o ni c O b str u cti v e P ul m o n ar y Di s e a s e
C O UI
C o u g h I m p a ct d o m ai n
C O U S
C o u g h S y m p t o m s d o m ai n
C R A
Cli ni c al R e s e ar c h A s s o ci at e
C R F
C a s e R e p ort/ R e c or d F or m ( p a p er or el e ctr o ni c)
C R O
C o ntr a ct R e s e ar c h Or g a ni z ati o n
C R P
C- R e a cti v Pr ot ei n
C S R
Cli ni c al st u d y r e p ort
C V
C o effi ci e nt of V ari ati o n
C Y P 1 A 2
C y t o c hr o m e P 4 5 0 1 A 2 e n z ym e
C Y P 2 B 6
C y t o c hr o m e P 4 5 0 2 B 6 e n z ym e
C Y P 3 A 4
C y t o c hr o m e P 4 5 0 3 A 4 e n z ym e
D B P
Di a st oli c Bl o o d Pr e s s ur e
D M C
D at a M o nit ori n g C o m mitt e e
D N A
D e s o x yri b o -N u cl ei c A ci d


N o v arti s
C o nfi d e nti al
P a g e 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
D R F
D o s e R a n g e Fi n di n g
E C G
El e ctr o c ar di o gr a m
e C O A
El e ctr o ni c Cli ni c al O ut c o m e A s s e s s m e nt
E D C
El e ctr o ni c D at a C a pt ur e
E D D
E x p e ct e d D at a of D eli v er y
E M A
E ur o p e a n M e di ci n e s A g e n c y
E Q -5 D -3 L
E ur o Q u alit y of lif e - 5 Di m e n si o n s - 3 L e v el s
E R S
E ur o p e a n R e s pir at or y S o ci et y
e S A E
El e ctr o ni c S eri o u s A d v er s e E v e nt
E X A C T- P R O 
E X A c er b ati o n s of C O P D T o ol - P ati e nt R e p ort e d O ut c o m e
F D A
F o o d a n d Dr u g A d mi ni str ati o n
F E V 1
F or c e d E x pir at or y V ol u m e i n o n e s e c o n d
F V C
F or c e d Vit al C a p a cit y
G C P
G o o d Cli ni c al Pr a cti c e
G C S
Gl o b al Cli ni c al S u p pl y
G G T
G a m m a -gl ut a m yl  tr a n sf er a s e
G O L D
Gl o b al I niti ati v e f or C hr o ni c O b str u cti v e L u n g Di s e a s e
H
h o ur
H C R U
H e alt h C ar e R e s o ur c e Utili z ati o n
H R C T
Hi g h R e s ol uti o n C o m p ut e d T o m o gr a p h y
h s -C R P
hi g h s e n siti v e -C R e a cti v Pr ot ei n
I A
I nt eri m A n al y si s
I B
I n v e sti g at or' s Br o c h ur e
I C F
I nf or m e d C o n s e nt F or m
I C H
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or 
R e gi str ati o n of P h ar m a c e uti c al s f or H u m a n U s e
I C S
I n h al e d C orti c o St er oi d
I E C
I n d e p e n d e nt Et hi c s C o m mitt e e
I N
I n v e sti g at or N otifi c ati o n
I N D
I n v e sti g ati o n al N e w Dr u g
I N R
I nt er n ati o n al N or m ali z e d R ati o
I R B
I n stit uti o n al R e vi e w B o ar d
I R T
I nt er a cti v e R e s p o n s e T e c h n ol o g y
I U D
I ntr a-Ut eri n e D e vi c e
I U S
I ntr a-Ut eri n e S y st e m
L A B A
L o n g -A cti n g B et a -2 A g o ni st
L A M A
L o n g A cti n g M u s c ari ni c r e c e pt or A nt o g o ni st
L D H
L a ct at e D e h y dr o g e n a s e
L F T
Li v er f u n cti o n t e st
L L O Q
L o w er Li mit Of Q u a ntifi c ati o n
M A R
Mi s si n g At R a n d o m
M e d D R A
M e di c al di cti o n ar y f or R e g ul at or y A cti viti e s


N o v arti s
C o nfi d e nti al
P a g e 1 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
M g
mi lli gr a m( s)
m L
mi llilit er( s)
M M R M
Mi x e d -eff e ct li n e ar M o d el f or R e p e at e d M e a s ur e s
M o A
M o d e of A cti o n
N D A
N e w Dr u g A p pli c ati o n
N Y H A
N e w Y or k H e art A s s o ci ati o n
O A T 3
Or g a ni c A ni o n Tr a n s p ort er 3
O A T P 1 B 1
Or g a ni c A ni o n tr a n s p ort er 1 B 1
O A T P 1 B 3
Or g a ni c A ni o n Tr a n s p ort er 1 B 3
o. d.
O n c e p er d a y
p. o.
p er o s
P D
P h ar m a c o d y n a mi c( s)
P K
P h ar m a c o ki n eti c( s)
P R O
P ati e nt R e p ort e d O ut c o m e s
P T
Pr ot hr o m bi n Ti m e
P T/I N R
Pr ot hr o m bi n Ti m e / I nt er n ati o n al N or m ali z e d R ati o
Q M S
Q u alit y M a n a g e m e nt S y st e m
Q T C
Q T i nt er v al C orr e ct e d
Q T c F
Q T i nt er v al c orr e ct e d b y Fri d eri ci a’ s f or m ul a
R B C
R e d Bl o o d C ell( s)
S A B A
S h ort A cti n g B et a -2 r e c e pt or A g o ni st
S A E
S eri o u s A d v er s e E v e nt
S A P
St ati sti c al A n al y si s Pl a n
S B P
S y st oli c Bl o o d Pr e s s ur e
S D
St a n d ar d D e vi ati o n
S G R Q
S ai nt G e or g e' s R e s pir at or y Q u e sti o n n air e
S m P C
S u m m ar y  of Pr o d u ct C h ar a ct eri sti c s
S M Q
St a n d ar di z e d M e d D R A Q u er y
S o C
St a n d ar d of C ar e
S O M
Sit e O p er ati o n s M a n u al
S U S A R
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
t.i. d
T hr e e ti m e s p er d a y
T m a x
Ti m e  t o r e a c h m a xi m u m ( p e a k) pl a s m a c o n c e ntr ati o n f oll o wi n g dr u g 
a d m i ni str ati o n
U G T
U D P -Gl u c ur o n o s yltr a n sf er a s e
U G T 1 A 1
Uri di n e Di p h o s p h at e -Gl u c ur o n o s yltr a n sf er a s e 1 A 1
U G T 2 B 7
Uri di n e Di p h o s p h at e -Gl u c ur o n o s yltr a n sf er a s e 2 B 7
U L N
U p p er Li mit of N or m al
U L Q
U p p er Li mit of Q u a ntifi c ati o n
V A S
Vi s u al A n al o g u e S c al e
W B C
W h it e Bl o o d C ell( s)
W H O
W o rl d H e alt h Or g a ni z ati o n


N o v arti s
C o nfi d e nti al
P a g e 1 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
W o C
Wi t h dr a w al of C o n s e nt


N o v arti s
C o nfi d e nti al
P a g e 1 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Gl o s s ar y  of t er m s
A d diti o n al 
tr e at m e nt
M e di ci n al pr o d u ct s t h at m a y b e u s e d d uri n g t h e cli ni c al tri al a s d e s cri b e d i n 
t h e pr ot o c ol, b ut n ot a s a n i n v e sti g ati o n al m e di ci n al pr o d u ct ( e. g. a n y 
b a c k gr o u n d t h er a p y )
A s s e s s m e nt
A pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e st u d y
Bi ol o gi c S a m pl e s
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, s er u m), s ali v a, 
ti s s u e, uri n e, st o ol, et c. t a k e n fr o m a st u d y s u bj e ct
C o h ort
A s p e cifi c gr o u p of s u bj e ct s f ulfilli n g c ert ai n crit eri a
C o ntr ol dr u g
A st u d y dr u g ( a cti v e or pl a c e b o) u s e d a s a c o m p ar at or t o r e d u c e a s s e s s m e nt 
bi a s, pr e s er v e bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al st u d y v ali dit y, 
a n d/ or e v al u at e c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g
D o s a g e
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e s u bj e ct i n a ti m e u nit ( e. g. 1 0 0 m g 
o n c e a d a y, 7 5 m g t wi c e a d a y)
El e ctr o ni c D at a 
C a pt ur e ( E D C)
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o ni c a c q ui siti o n of cli ni c al st u d y 
d at a u si n g d at a c oll e cti o n s y st e m s, s u c h a s W e b- b a s e d a p pli c ati o n s, 
i nt er a cti v e v oi c e r e s p o n s e s yst e m s a n d cli ni c al l a b or at or y i nt erf a c e s. 
E D C i n cl u d e s t h e u s e of El e ctr o ni c C a s e R e p ort F or m s ( e C R F s) w hi c h ar e 
u s e d t o c a pt ur e d at a tr a n s cri b e d fr o m p a p er s o ur c e f or m s u s e d at t h e p oi nt of 
c ar e.
E n d of t h e cli ni c al 
tri al
T h e e n d of t h e cli ni c al tri al i s d efi n e d a s t h e l a st vi sit of t h e l a st s u bj e ct or at a 
l at er p oi nt i n ti m e a s d efi n e d b y t h e pr ot o c ol.
E nr oll m e nt
P oi nt/ti m e of s u bj e ct e ntr y i nt o t h e st u d y at w hi c h i nf or m e d c o n s e nt m u st b e 
o bt ai n e d (i. e. pri or t o st arti n g a n y of t h e pr o c e d ur e s d e s cri b e d i n t h e pr ot o c ol)
I n v e sti g ati o n al 
dr u g/tr e at m e nt
T h e st u d y dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y; t hi s d efi niti o n 
i s c o n si st e nt wit h U S C F R 2 1 S e cti o n 31 2. 3 a n d Dir e cti v e 2 0 0 1/ 2 0/ E C a n d i s 
s y n o n y m o u s wit h “i n v e sti g ati o n al n e w dr u g” or “t e st s u b st a n c e”.
M e di c ati o n p a c k 
n u m b er
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h dr u g p a c k a g e i n st u di e s t h at di s p e n s e 
st u d y tr e at m e nt u si n g a n I R T s y st e m
Ot h er tr e at m e nt
Tr e at m e nt t h at m a y b e n e e d e d/ all o w e d d uri n g t h e c o n d u ct of t h e st u d y (i. e. 
c o n c o mit a nt or r e s c u e t h er a p y)
P ati e nt
A n i n di vi d u al wit h t h e c o n diti o n of i nt er e st
P eri o d
T h e s u b di vi si o n s of t h e tri al d e si g n ( e. g.: S cr e e ni n g, Tr e at m e nt, F oll o w -U p) 
w hi c h ar e d e s cri b e d i n t h e Pr ot o c ol. P eri o d s d efi n e t h e st u d y p h a s e s a n d will 
b e u s e d i n cli ni c al tri al d at a b a s e s et u p a n d e v e nt u all y i n a n al y si s.
P er s o n al d at a
S u bj e ct i nf or m ati o n c oll e ct e d b y t h e i n v e sti g at or t h at i s tr a n sf err e d t o N o v arti s 
f or t h e p ur p o s e of t h e cli ni c al tri al. T hi s d at a i n cl u d e s s u bj e ct i d e ntifi er 
i nf or m ati o n, st u d y i nf or m ati o n a n d bi ol o gi c al s a m pl e s.
Pr e m at ur e s u bj e ct 
wit h dr a w al
P oi nt/ti m e w h e n t h e s u bj e ct e xit s fr o m t h e st u d y pri or t o t h e pl a n n e d 
c o m pl eti o n of all st u d y dr u g a d mi ni str ati o n a n d a s s e s s m e nt s; at t hi s ti m e all 
st u d y dr u g a d mi ni str ati o n i s di s c o nti n u e d a n d n o f urt h er a s s e s s m e nt s ar e 
pl a n n e d.
R a n d o mi z ati o n 
n u m b er
A u ni q u e i d e ntifi er a s si g n e d t o e a c h r a n d o mi z e d s u bj e ct, c orr e s p o n di n g t o a 
s p e cifi c tr e at m e nt ar m a s si g n m e nt
S cr e e n F a il ur e
A s u bj e ct w h o i s s cr e e n e d b ut i s n ot tr e at e d or r a n d o mi z e d
S o ur c e 
D at a/ D o c u m e nt
S o ur c e d at a r ef er s t o t h e i niti al r e c or d, d o c u m e nt, or pri m ar y  l o c ati o n fr o m 
w h er e d at a c o m e s. T h e d at a s o ur c e c a n b e a d at a b a s e, a d at a s et, a 
s pr e a d s h e et or e v e n h ar d - co d e d d at a, s u c h a s p a p er or e S o ur c e


N o v arti s
C o nfi d e nti al
P a g e 1 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
St art of t h e st u d y
T h e st art of t h e st u d y i s d efi n e d a s t h e si g n at ur e of t h e i nf or m e d c o n s e nt b y 
t h e fir st s u bj e ct.
St u d y c o m pl eti o n
P oi nt/ti m e at w hi c h t h e s u bj e ct c a m e i n f or a fi n al e v al u ati o n vi sit or w h e n 
st u d y dr u g w a s di s c o nti n u e d w hi c h e v er i s l at er.
St u d y dr u g 
di s c o nti n u ati o n
P oi nt/ti m e w h e n s u bj e ct p er m a n e ntl y st o p s t a ki n g st u d y dr u g f or a n y r e a s o n; 
m a y or m a y  n ot al s o b e t h e p oi nt/ti m e of pr e m at ur e s u bj e ct wit h dr a w al.
St u d y tr e at m e nt
A n y dr u g or c o m bi n ati o n of dr u g s a d mi ni st er e d t o t h e st u d y p arti ci p a nt s a s 
p art of t h e r e q uir e d st u d y pr o c e d ur e s; i n cl u d e s i n v e sti g ati o n al dr u g( s), 
c o ntr ol( s) or b a c k gr o u n d t h er a p y
St u d y tr e at m e nt 
di s c o nti n u ati o n
W h e n t h e s u bj e ct p er m a n e ntl y st o p s t a ki n g st u d y tr e at m e nt pri or t o t h e 
d efi n e d st u d y tr e at m e nt c o m pl eti o n d at e
S u bj e ct
A tri al p arti ci p a nt ( c a n b e a h e alt h y v ol u nt e er or a p ati e nt)
S u bj e ct n u m b er
A u ni q u e n u m b er a s si g n e d t o e a c h s u bj e ct u p o n si g ni n g t h e i nf or m e d 
c o n s e nt. T hi s n u m b er i s t h e d efi niti v e, u ni q u e i d e ntifi e r f or t h e s u bj e ct a n d 
s h o ul d b e u s e d t o i d e ntif y t h e s u bj e ct t hr o u g h o ut t h e st u d y f or all d at a 
c oll e ct e d, s a m pl e l a b el s, et c.
V ari a bl e
A m e a s ur e d v al u e or a s s e s s e d r e s p o n s e t h at i s d et er mi n e d i n s p e cifi c 
a s s e s s m e nt s a n d u s e d i n d at a a n al y si s t o e v al u at e t h e dr u g b ei n g t e st e d i n 
t h e st u d y
Wi t h dr a w al of 
c o n s e nt ( W o C)
Wi t h dr a w al of c o n s e nt fr o m t h e st u d y i s d efi n e d a s w h e n a s u bj e ct d o e s n ot 
w a nt t o p arti ci p at e i n t h e st u d y a n y l o n g er, a n d d o e s n ot w a nt a n y f urt h er 
vi sit s or a s s e s s m e nt s, a n d d o e s n ot w a nt a n y f urt h er st u d y r el at e d c o nt a ct, 
a n d d o e s n ot all o w a n al y si s of alr e a d y o bt ai n e d bi ol o gi c m at eri al


N o v arti s
C o nfi d e nti al
P a g e 1 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
 
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 2 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Pr ot o c ol s u m m ar y
Pr ot o c ol n u m b er
C Q B W 2 5 1 B 2 2 0 2
F ull Titl e
A r a n d o mi z e d, s u bj e ct s a n d i n v e sti g at or bli n d e d, pl a c e b o c o ntr oll e d p ar all el 
gr o u p st u d y  to a s s e s s t h e m o d e of a cti o n of Q B W 2 5 1 i n s u bj e ct s wit h 
C hr o ni c O b str u cti v e P ul m o n ar y Di s e a s e ( C O P D).
Bri ef titl e
St u d y of m o d e of a cti o n of Q B W 2 5 1 i n s u bj e ct s wit h C O P D
S p o n s or a n d 
Cli ni c al P h a s e
N o v arti s , P h a s e II
I n v e sti g ati o n t y p e
Dr u g
St u d y t y p e
I nt er v e nti o n al
P ur p o s e a n d 
r ati o n al e
P ur p o s e
T h e p ur p o s e of t hi s st u d y  is t o d et er mi n e w h et h er p ot e nti ati n g t h e c y sti c 
fi br o si s tr a n s m e m br a n e c o n d u ct a n c e r e g ul at or ( C F T R) wit h Q B W 2 5 1 i n 
a d ult s u bj e ct s wit h C O P D will b e effi c a ci o u s wit h r e g ar d s t o r e d u ci n g l u n g 
a n d s y st e mi c i nfl a m m ati o n a n d b a ct eri al c ol o ni z ati o n a s p ot e nti al dri v er s of  
air w a y o b str u cti o n, air w a y d e str u cti o n, r e m o d eli n g a n d e x a c er b ati o n s. 
T hi s will, pr o vi d e s u p p orti v e d at a t o i n v e sti g at e t h e s af et y  of Q B W 2 5 1, t h e 
r el ati o n s hi p of C O P D p h e n ot y p e a n d Q B W 2 5 1 r e s p o n s e i n s m all air w a y 
str u ct ur e, f u n cti o n, m u c u s l o a d a n d s pir o m etr y  in di c e s a s w ell 
a s i n 
i mpr o v e m e nt of o v er all C O P D s y m p t o m s a n d q u alit y of lif e aft er tr e at m e nt 
wit h Q B W 2 5 1.
R ati o n al e
T h e st u d y  will a s s e s s Q B W 2 5 1 a s a n a d d -o n t o b a c k gr o u n d t h er a p y, i n a d ult 
s u bj e ct s wit h C O P D a s s o ci at e d wit h c hr o ni c br o n c hiti s a n d hi st or y
of 
e x a c er b ati o n s i n t h e 1 2 mo nt h s pri or t o t h e st u dy. C hr o ni c br o n c hiti s, hi st or y 
of fr e q u e nt e x a c er b ati o n s ar e e x p e ct e d t o b e e nri c h m e nt f a ct or s f or s u bj e ct s 
w h o m a y  parti c ul arl y b e n efit fr o m i mpr o v e d a cti vit y ( p ot e nti ati o n) of t h e 
C F T R c h a n n el. A fi bri no g e n l e v el of ≥3 2 0 m g / d L a s w ell a s a s p ut u m s a m pl e 
p o siti v e f or at l e a st o n e p ot e nti all y p at h o g e ni c or g a ni s m at s cr e e ni n g ar e 
f urt h er p o p ul ati o n e nri c h m e nt f a ct or s.
Pri m ar y O bj e cti v e 
T h e pri m ar y o bj e cti v e of t hi s st u d y  is t o a s s e s s t h e eff e ct of Q B W 2 5 1 
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of tr e at me nt o n fi bri n o g e n pl a s m a 
c o n c e ntr ati o n b y  te sti n g t h e h y p ot h e si s: (i) t h er e i s n o r e d u cti o n i n fi bri n o g e n 
fr o m b a s eli n e ( H 0) a n d (ii) t h er e i s a r e d u cti o n i n fi bri n o g e n fr o m b a s eli n e 
( H 1).
S e c o n d ar y 
O bj e cti v e s
O bj e cti v e 1 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of tr e at me nt o n s p ut u m b a ct eri al l o a d b y m e a s uri n g t h e t ot al 
b a ct eri a l o a d of c ol o n y f or mi n g u nit s ( C F U/ m L) of p ot e nti all y p at h o g e ni c 
mi cr o or g a ni s m s i n s p ut u m. 
O bj e cti v e 2 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of  tr e at me nt o n air w a y str u ct ur e a n d f u n cti o n b y  me a s uri n g wit h 
H R C T air w a y w all a n d l u m e n p ar a m et er s al o n g wit h e xt e nt of gl o b al a n d 
r e gi o n al air tr a p pi n g.
O bj e cti v e 3: T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of tr e at me nt o n s pir o m etr y b y  me a s uri n g tr o u g h F E V 1, F V C a n d 
F E V 1/ F V C.


N o v arti s
C o nfi d e nti al
P a g e 2 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
O bj e cti v e 4 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s 
of 
tr e at m e nt o n 
h e alt h 
st at u s
m e a s ur e d 
b y  
EQ- 5 D -3 L 
q u e sti o n n air e.
O bj e cti v e 5 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of  tr e at m e nt o n cli ni c al s y m p t o m s, c o u g h a n d s p ut u m cli ni c al 
s y m p t o m s wit h C A S A Q u e sti o n n air e.
O bj e cti v e 6 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of  tr e at me nt o n C O P D s u bj e ct s s y m p t o m b ur d e n c h a n g e s wit h 
C A T q u e sti o n n air e. 
O bj e cti v e 7 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of tr e at m e nt o n C O P D e x a c er b ati o n s b y  m e a s uri n g:

Ti m e  t o fir st C OP D e x a c er b ati o n

Pr o p orti o n of s u bj e ct s wit h e x a c er b ati o n

A n n u ali z e d r at e of e x a c er b ati o n s a s d efi n e d b y E X A C T -P R O 
q u e sti o n n air e
O bj e cti v e 8 : T o a s s e s s t h e eff e ct of Q B W 2 5 1 c o m p ar e d t o pl a c e b o aft er 
1 2 w e e k s of  tr e at me nt o n c h a n g e s i n h e alt h -r el at e d q u alit y of lif e wit h S G R Q.
O bj e cti v e 9 : T o a s s e s s t h e s af et y a n d t ol er a bilit y of Q B W 2 5 1 i n s u bj e ct s 
wit h C O P D e v al u ati n g E C G i nt er v al s, vit al si g n s, st a n d ar d cli ni c al l a b or at or y 
a n d a d v er s e e v e nt s.
O bj e cti v e 1 0 : T o a s s e s s Q B W 2 5 1 p h ar m a c o ki n eti c s ( P K) i n s u bj e ct s wit h 
C O P D, o n D a y  1, D a y 28, D a y  5 6 a n d D a y 84 (tr o u g h c o n c e ntr ati o n at pr e -
d o s e a n d C m a x p o st d o s e) a s w ell a s C m a x a n d A U C o n D a y  1 a n d D a y 2 8 
i n a s u b s et of s u bj e ct s.
St u d y d e si g n
T hi s i s a r a n d o mi z e d, s u bj e ct a n d i n v e sti g at or bli n d e d, p ar all el -gr o u p, 
pl a c e b o c o ntr oll e d st u d y  in v e sti g ati n g t h e m o d e of a cti o n ( M o A) a n d 
pr eli m i n ary effi c a c y  an d s af et y  of Q B W 2 5 1 a d m i ni st er e d or all y t wi c e d ail y 
( b.i. d.) f or 1 2 w e e k s i n s u bj e ct s wit h mo d er at e t o s e v er e C O P D ( G O L D 2- 3).
A p pr o xi m at el y 1 0 0 s u bj e ct s will b e r a n do m i ze d i n a 1: 1 r ati o t o r e c ei v e eit h er 
Q B W 2 5 1 or pl a c e b o tr e at m e nt. B a s e d o n t h e a s s u m pti o n of a 1 5 % dr o p -o ut 
r at e ( % dr o p o ut b a s e d o n c o m pl et e d pr o of -of -c o n c e pt C O P D 
st u d y 
C Q B W 2 5 1 X 2 2 0 1), it i s e x p e ct e d t o h a v e a p pr o xi m at el y 8 4 s u bj e ct s t o 
c o m pl et e t h e s t u d y.
 
 
T h e st u d y c o n si st s of t h e f oll o wi n g p eri o d s: S cr e e ni n g, B a s eli n e / D a y  1, 
Tr e at m e nt, a n d E n d of t h e St u d y f oll o w e d b y  an a d diti o n al p o st -tr e at m e nt 
s af et y  ph o n e c all. T h e t ot al d ur ati o n f or e a c h s u bj e ct i n t h e st u d y  is u p t o 
a p pr o xi m at el y 1 9 w e e k s.
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 2 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P o p ul ati o n
T h e st u d y p o p ul ati o n will c o n si st of a p pr o xi m at el y 1 0 0 m a l e a n d f e m al e 
s u bj e ct s, a g e d 4 0 y e ar s ol d a n d a b o v e, wit h m o d er at e t o s e v er e C O P D 
( G O L D 2 t o 3) wit h f e at ur e s of c hr o ni c br o n c hiti s, a s m o k i n g hi st or y of at 
l e a st 1 0 p a c k / y e ar s, a n d at l e a st t w o m o d er at e or o n e s e v er e 
e x a c er b ati o n( s) si n c e J a n u ar y 2 0 1 9.. All s u bj e ct s m u st 
h a v e a pl a s m a 
fi bri n o g e n l ev el of ≥ 3 2 0 m g / d L, a C A T s c or e of at l e a st 1 0 a n d h a v e b e e n 
o n L A M A/ L A B A or L A B A/I C S or L A B A/ L A M A/I C S t h er a p y at st a bl e d o s e f or 
at l e a st 3 m o nt h s pri or st u d y st art.
C O P D s u bj e ct s ar e all o w e d t o st a y o n m a cr oli d e s a s b a c k gr o u n d t h er a p y if 
t h e y ha v e br o n c h i e ct a si s a s a s e c o n d ar y di a g n o si s a n d if t h e y ha v e b e e n 
tr e at e d wit h t h e m f or at l e a st 3 m o nt h s at st a bl e d o s e b ef or e st u d y  st art. I n 
a d diti o n, s u bj e ct s' s p ut u m m u st b e c ol o ni z e d wit h
at l e a st o n e p ot e nti all y 
p at h o g e ni c b a ct eri a).
K e y I n cl u si o n 
crit eri a

M al e a n d f e m al e a d ult s a g e d ≥4 0 y e ar s at s cr e e ni n g.

S u bj e ct s wit h st a bl e C O P D, st a g e s G O L D 2 -3, a c c or di n g t o t h e c urr e nt 
G O L D str at e g y ( G O L D 2 0 1 9) at s cr e e ni n g.

S u bj e ct s wit h a p o st -br o n c h o dil at or F E V 1/ F V C < 0. 7 0 at s cr e e ni n g.

S u bj e ct s wit h airfl o w li mit at i o n i n di c at e d b y a p o st-br o n c h o dil at or F E V 1 
≥ 3 0 % a n d F E V 1 < 8 0 % of t h e pr e di ct e d n or m al at S cr e e ni n g w h o 
m u st h a v e h a d at l e a st 2 d o c u m e nt e d m o d er at e or at l e a st 1 
d o c u m e nt e d s e v er e e x a c er b ati o n( s) b et w e e n J a n u ar y 2 0 1 9 a n d st u d y 
s cr e e ni n g.

S u bj e ct s wit h s p ut u m p o siti v e f or at l e a st o n e str ai n of p ot e nti all y 
p at h o g e ni c mi cr o or g a ni s m at s cr e e ni n g ( H i nfl u e n z a e, H 
p ar ai nfl u e n z a e, P a er u gi n o s a, S p n e u m o ni a e, S a ur e u s, M or a x ell a 
c at arr h ali s, E nt er o b a ct eri a c e a e, St e n otr o p h o m o n a s m alt o p hili a, 
B ur k h ol d eri a s p e ci e s, a n d A c hr o m o b a ct er s p e ci e s or a n y p ot e nti al 
b a ct eri a m e a s ur e d b y dil uti o n/ o ut gr o wt h. A n y or g a ni s m t h at i s t o b e 
i n cl u d e d a n d t h at i s n ot i n cl u d e d i n t h e li st of t h e pr ot o c ol d efi n e d 
p at h o g e n s s h o ul d b e di s c u s s e d c a s e b y c a s e b et w e e n t h e Pri n ci p al 
I n v e sti g at or a n d N o v arti s M e di c al E x p ert)

S u bj e ct s w h o h a v e b e e n tr e at e d wit h a c o m bi n ati o n of L A B A/ L A M A or 
L A B A/I C S or L A B A/ L A M A/I C S at a st a bl e d o s e f or t h e l a st 3 m o nt h s 
pri or t o s cr e e ni n g. C O P D s u bj e ct s ar e all o w e d t o st a y o n m a cr oli d e s a s 
b a c k gr o u n d t h er a p y  if t h e y h a v e br o n c hi e ct a si s a s a s e c o n d ary 
di a g n o si s a n d if t h e y ar e tr e at e d wit h t h e m at a st a bl e d o s e 3 m o nt h s 
b ef or e s cr e e ni n g.

S u bj e ct s wit h pl a s m a fi bri n o g e n l e v el ≥ 3 2 0 m g/ d L at s cr e e ni n g.

A C O P D A s s e s s m e nt T e st ( C A T) s c or e of at l e a st 1 0 at s cr e e ni n g.

C urr e nt or e x -s m o k er s w h o h a v e a s m o ki n g hi st or y of at l e a st 1 0 p a c k 
y e ar s ( e. g. 1 0 p a c k y e ar s = 1 p a c k/ d a y x 1 0 y e ar s, or 0. 5 p a c k/ d a y x 
2 0 y e ar s) at s cr e e ni n g.


N o v arti s
C o nfi d e nti al
P a g e 2 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
K e y E x cl u si o n 
crit eri a

S u bj e ct s wit h a hi st or y of l o n g -Q T s y n dr o m e or w h o s e Q T c F i n t er v al at
s cr e e ni n g ( Fri d eri ci a m et h o d) i s pr ol o n g e d ( Q T c F > 4 5 0 m s i n
m a l e s, > 4 6 0 m s i n f e m al e s).

S u bj e ct s w h o h a v e cli ni c all y si g nifi c a nt r e n al, c ar di o v a s c ul ar ( s u c h a s
b ut n ot li mit e d t o u n st a bl e i s c h e mi c h e art di s e a s e, N Y H A Cl a s s III/I V
l eft v e ntri c ul ar f ail ur e, m y o c ar di al i nf ar cti o n), n e ur ol o gi c al, e n d o cri n e,
i m m u n ol o gi c al, p sy c hi atri c, g a str oi nt e sti n al, or h e m at ol o gi c al
a b n or m aliti e s, w hi c h c o ul d i nt erf er e wit h t h e a s s e s s m e nt of t h e effi c a c y
a n d s af et y of t h e st u d y tr e at m e nt, or s u bj e ct s wit h u n c o ntr ol l e d Ty p e II
di a b et e s.

S u bj e ct s wit h a hi st or y of m ali g n a n c y of a n y or g a n s y st e m, tr e at e d or
u ntr e at e d, wit hi n t h e p a st 5 y e ar s w h et h er or n ot t h er e i s e vi d e n c e of
l o c al r e c urr e n c e or m et a st a s e s, wit h t h e e x c e pti o n of l o c ali z e d b a s al
c ell c ar ci n o m a of t h e s ki n. S u bj e ct s wit h a hi st or y of c a n c er a n d 5 y e ar s
or m or e di s e a s e fr e e s ur vi v al ti m e m a y  b e i n cl u d e d i n t h e st u d y b y
a gr e e m e nt wit h N o v arti s M e di c al E x p ert o n a c a s e -b y -c a s e b a si s.

S u bj e ct s w h o d e v el o p a C O P D e x a c er b ati o n t h at r e q uir e d tr e at m e nt
wit h a nti bi oti c s a n d/ or or al c orti c o st er oi d s a n d/ or h o s pit ali z ati o n d uri n g
s cr e e ni n g. R e -s cr e e ni n g i s p er mitt e d aft er a mi ni m u m of 2 w e e k s aft er
t h e r e s ol uti o n of t h e C O P D e x a c er b ati o n (i. e. 2 w e e k s aft er t h e st o p of
S O C t h er a p y f or e x a c er b ati o n).

S u bj e ct s w h o h a v e h a d a r e s pir at or y tr a ct i nf e cti o n wit hi n 4 w e e k s pri or
t o s cr e e ni n g. If a r e s pir at or y tr a ct i nf e cti o n o c c ur s d uri n g s cr e e ni n g,
s u bj e ct s c a n b e r e -s cr e e n e d aft er a mi ni m u m of 2 w e e k s aft er
r e s ol uti o n of t h e r e s pir at ory tr a ct i nf e cti o n.

S u bj e ct s wit h hi st or y of a st h m a or a n y ot h er cli ni c all y r el e v a nt l u n g
di s e a s e s.

S u bj e ct s wit h s u s p e ct e d a cti v e p ul m o n ar y t u b er c ul o si s or c urr e ntl y
b ei n g tr e at m e nt f or a cti v e p ul m o n ar y t u b er c ul o si s.

S u bj e ct s wit h p ul m o n ar y l o b e ct o m y,  l u n g v ol u m e r e d u cti o n s ur g er y,
br o n c h o s c o pi c l u n g v ol u m e r e d u cti o n s, or l u n g tr a n s pl a nt ati o n.

S u bj e ct s p arti ci p ati n g i n or pl a n ni n g t o p arti ci p at e i n t h e a cti v e p h a s e of
a s u p er vi s e d p ul m o n ar y r e h a bilit ati o n pr o gr a m d uri n g t h e tri al.
P arti ci p ati o n i n a m ai nt e n a n c e pr o gr a m i s p er mitt e d.

S u bj e ct s w h o h a v e n ot a c hi e v e d a n a c c e pt a bl e s pir o m etr y r e s ult at
s cr e e ni n g i n a c c or d a n c e wit h A m eri c a n T h or a ci c S o ci et y ( A T S)/
E ur o p e a n R e s pir at or y S o ci et y ( E R S) crit eri a f or a c c e pt a bilit y a n d
r e p e at a bilit y.
St u d y tr e at m e nt
T h e st u d y tr e at m e nt i n cl u d e s:

I n v e sti gati o n al dr u g: c a p s ul e s of Q B W 2 5 1 d o s e of 3 0 0 m g b.i. d.

M at c hi n g pl a c e b o
Effi c a c y 
a n d
P h ar m a c o d y n a mi c 
a s s e s s m e nt s 

Pl a s m a fi bri n o g e n l e v el


B a ct eri al l o a d i n s p ut u m

Air w a y str u ct ur e
 e v al u at e d b y Hi g h R e s ol uti o n 
C o m p ut e d T o m o gr a p h y ( H R C T)

S pir o m etr y

C A S A -Q, C A T, S G R Q, E Q -5 D -3 L a n d E X A C T -P R O q u e sti o n n air e s
C o m merciall y C o nfi de ntial I nf or mati o n
C CI


N o v arti s
C o nfi d e nti al
P a g e 2 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P h ar m a c o ki n eti c 
a s s e s s m e nt s 
P h ar m o c o ki n eti c bl o o d s a m pli n g will b e c oll e ct e d :

I n all s u bj e ct s at pr e a n d p o st-d o s e ( + 3 hr s) o n D a y 1, D a y 2 8, D a y 5 6 
a n d D a y 8 4.

I n a s u b s et of s u bj e ct s ( a p pr o x 3 0 t o 4 0 s u bj e ct s), i n a d diti o n, a s eri al 
s a m pli n g u p t o 8 hr s p o st -d o s e o n D a y 1 a n d D a y 2 8. D u e t o C o vi d a n d 
i n a bilit y/ diffi c ult y of s u bj e ct s r e m ai ni n g at a cli ni c f or 8 + h o ur s, t hi s 
n u m b er m a y  b e r e d u c e d if t h e eff e ct s of t h e C o vi d p a n d e mi c o n sit e 
a n d s u bj e ct li mit ati o n s pr e v e nt s t h e s e ti m e p oi nt s

W h e n a s u bj e ct i s e x p eri e n ci n g a tr e at m e nt -e m er g e nt S A E.
K e y s af et y 
a s s e s s m e nt s
K e y s af et y a s s e s s m e nt s c o n si st i n: 

A d v er s e e v e nt s m o nit ori n g

C O P D e x a c er b ati o n s ( E X A C T -P R O q u e sti o n n air e)

P h y s i c al e x a mi n ati o n

E C G

Cli ni c al O ut c o m e A s s e s s m e nt s: C A T, C A S A -Q, S G R Q, E Q -5 D -3 L
Ot h er a s s e s s m e nt s 
D at a a n al y si s
Pri m ar y e n d p oi nt
A mi x e d -eff e ct li n e ar m o d el f or r e p e at e d m e a s ur e s ( M M R M) will b e fitt e d t o 
t h e c h a n g e s fr o m b a s eli n e i n fi bri n o g e n f or all ti m e p oi nt s u ntil D a y 8 4 vi sit. 
T h e n ull h y p ot h e si s of n o diff er e n c e b et w e e n Q B W 2 5 1 a n d pl a c e b o will b e 
t e st e d at a o n e -si d e d si g nifi c a n c e l e v el of 1 0 % a g ai n st t h e alt er n ati v e 
h y p ot h e si s t h at a diff er e n c e e xi st s b et w e e n Q B W 2 5 1 a n d pl a c e b o i n f a v or 
of Q B W 2 5 1.
K e y s e c o n d ar y p h ar m a c o d y n a mi c e n d p oi nt :

C h a n g e fr o m b a s eli n e i n t h e l o g arit h m of t ot al n u m b er of c ol o n y 
f or mi n g u nit s ( C F U/ m L) of p ot e nti all y p at h o g e ni c mi cr o or g a ni s m s i n 
s p o nt a n e o u s s p ut u m aft er 1 2 w e e k s of tr e at m e nt will b e a n al y z e d 
si mil ar t o t h e pri m ar y a n al y si s.
S e c o n d ar y p h ar m a c o d y n a mi c a n d effi c a c y e n d p oi nt s:

C h a n g e fr o m b a s eli n e i n air w a y w all a n d l u m e n p ar a m et er s al o n g wit h 
e xt e nt of gl o b al a n d r e gi o n al air tr a p pi n g a s m e a s ur e d b y H R C T a n d 
c h a n g e fr o m b a s eli n e i n F E V 1, F V C a n d F E V 1/ F V C m e a s ur e d b y 
s pir o m etr y  aft er 1 2 w e e k s of tr e at m e nt will b e s u m m ari z e d. 
All s pir o m etr y p ar a m et er s a n d H R C T p ar a m et er s i n cl u di n g r e gi o n al 
a n d gl o b al air tr a p pi n g c h a n g e s will b e s u m m ari z e d a s w e ll. 
T h e s u m m ari e s will b e c al c ul at e d at all ti me p oi nt s a s s p e cifi e d i n t h e 
a s s e s s m e nt s c h e d ul e (T a bl e 8- 1 ), a n d s p e cifi c all y  at t h e pri m ar y  tim e  poi nt 
of i nt er e st ( D a y 8 4) c o n si d eri n g pl a c e b o a s t h e r ef er e n c e tr e at m e nt.
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 2 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
K e y w or d s
C O P D, fi bri n o g e n, b a ct eri al l o a d, H R C T
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 2 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1
I ntr o d u cti o n
1. 1
B a c k gr o u n d
C hr o nic o bstr ucti ve p ul m o nar y  disease ( C O P D) is a c hr o nic i nfla m mat or y disease of t he l u n g 
a n d t he t hir d lea di n g ca use of deat h w orl d wi de 
( G B D 2 0 1 5 M ortalit y
a n d Ca uses of 
Deat h 2 0 1 6). S u bjects s uffer fr o m persiste nt res pirat or y sy m pt o ms ( dys p nea, c o u g h, s p ut u m 
pr o d ucti o n) a n d p o orl y r e versi ble airfl o w li mitati o n d u e t o air wa y an d/ or al ve olar a b n or malities 
us uall y  ca use d b y  si gnifica nt e x p os ure t o n o xi o us particles/ gases, i n partic ular ci garette a n d 
bi o mass s m o ke e x p os ure. C hr o nic airfl o w li mitati o n is ca use d b y  a mi xt ure of s mall air wa ys 
disease ( o bstr ucti ve br o nc hi olitis) a n d pare nc h y mal 
destr ucti o n (e m p h yse ma) wit h m ost 
s u bjects ha vi n g s o me c haracteristics of b ot h.
C hr o nic br o nc hitis d ue t o m uc us 
h y persecreti o n wit h 
i ncrease d m uc us 
visc osit y  an d 
d y sf u ncti o nal m uc ociliar y cleara nce c o nstit utes a ke y p he n oty pe i n s u b jects wit h C O P D w hic h 
is c haracterize d b y  fre q ue nt p ul m o nar y  exacer bati o ns, p ul m o nar y  an d s yste mic i nfla m mati o n, 
air wa y bacterial c ol o nizati o n, accelerate d decli ne i n l u n g f u ncti o n, i m paire d healt h -relate d 
q ualit y  of life, a n d p ossi bl y i ncrease d m ortalit y (Ki m et al 2 0 1 2 ). H o we ver effecti ve treat me nt 
o pti o ns are li mite d f or t hese s u bjects.
C O P D e xacer bati o ns are fre q ue nt ca uses of h os pital a d missi o ns a n d i m p orta nt e ve nts i n t he 
nat ural hist or y  of C O P D t hat dri ve m or bi dit y 
a n d m ortalit y  (D o nal ds o n et al 2 0 0 2 ). 
Air wa y i nfla m mati o n is a k e y  fact or c o ntri b uti n g t o p ul m o nar y exacer bati o n. W hile i ncrease d 
le vels of i nfla m mat or y mar kers a n d cells reflecti n g s yste mic a n d p ul m o nar y  infl a m mati o n s uc h 
as fi bri n o ge n, t u m or necr osis fact or-al p ha ( T N F-α), i nterle u ki ns (I L-8, I L-6), le u k otrie ne B 4, 
ne utr o p hils, 
l ym p h oc ytes, 
a n d 
e osi n o p hils 
are 
o bser ve d 
d uri n g 
e xacer bati o ns 
(Beasle y et al 2 0 1 2 ), i n hi biti o n o f i nfla m mati o n b y  in hale d c ortic oster oi ds or t he P D E -4 
i n hi bit or r ofl u milast is ass ociate d wit h a re d ucti o n of C O P D-e xacer bati o n rate. 
F urt her m ore, res pirat or y i nfecti o ns ca use d b y  pote ntiall y  pat h o ge nic bacterial strai ns are 
t h o u g ht t o pla y a maj or r ole i n t he pat h o ge nesis of b ot h sta ble C O P D a n d ac ute e xacer bati o ns. 
Detecti o n rates of bacterial i nfecti o n i n sa m ples c ollecte d d uri n g e xacer bati o ns are hi g h, 
s u g gesti n g t hat ne wl y ac q uire d bacterial strai ns m a y  preci pitate p ul m o nar y  exacer bati o ns 
(Beasle y  et al 2 0 1 2 ). T his is f urt her s u p p orte d b y cli nical data de m o nstrati n g a n i ncrease i n 
rates of s p ut u m c ol o nizati o n fr o m 4 3 -4 8. 3 % i n sta ble s u bjects t o 6 9. 6- 7 6 % d uri n g 
e xacer bati o ns (H ur st et al 2 0 0 5 ), a n d a n i ncrease i n bacterial i nfecti o ns of pr otecte d br us h 
s peci me ns fr o m 2 9 % i n sta ble s u bjects t o 5 4 % d uri n g e xacer bati ons ( R osell et al 2 0 0 5 ).
I n a d diti o n t o ne wl y  ac q uire d bacterial i nfecti o ns, ot her p ote ntial mec ha nis ms tri g geri n g 
e xacer bati o ns are a n i ncrease i n t he l oa d of pree xisti n g or ga nis ms prese nt i n sta ble C O P D 
s u bjects as s u g geste d b y  the data a b o ve, or a c ha n ge i n t he c o m p ositi o n of t he air wa y 
micr o bi o me. H o we ver, data are s parse a n d partl y c o nflicti n g (Set hi a n d M ur p h y  20 0 8 ) a n d 
f urt her st u dies are nee de d t o f ull y el uci date t he r ole of t he air wa y micr o bi o me i n t he 
pat h o ge nesis of C O P D.
N o net heless, t he c o nc urre nce of bacterial c ol o nizati o n, air wa y i nflam mati o n a n d fre q ue nt 
e xacer bati o n is e vi de nt a n d a p pears t o be rele va nt i n t he pat h o ge nesis of C O P D i n t he maj orit y 
of s u bjects prese nti n g wit h a c hr o nic br o nc hitic p he n ot y pe.


N o v arti s
C o nfi d e nti al
P a g e 2 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C urre nt sta n dar d of care i n t he ma na ge me nt of C O P D c o nsists of s h ort a n d l o n g acti n g 
br o nc h o dilat ors ( L A B A/ LA M A) 
+/ - i n hale d c ortic oster oi ds (I C S) i n dicate d i n s u bjects 
e x perie nci n g s y m pt o ms a n d e xacer bati o ns. T he C O P D g ui deli nes ( G O L D 2 0 1 9 ) als o c o nsi der 
macr oli de 
a nti bi otics a n d r ofl u milast as a dditi o nal a d d- o n t hera p y t o tri ple t hera py 
( L A B A + L A M A +I C S) i n s pecific s u b gr o u ps of s u bjects. H o we ver, 3 0 t o 4 0 % of s u bjects 
recei vi n g e ve n tri ple i n hale d t hera p y co nti n ue t o ha ve m o derate or se vere ( h os pitalize d) 
e xacer bati o ns (Vest b o et al 2 0 1 7 , M uller o va
et al 2 0 1 7 ). I n a d diti o n, l o n g-ter m macr oli de 
a nti bi otics are c o m plicate d b y  micr o bial resista nce (P o mares et al 2 0 1 8 ) a n d r ofl u milast, a 
n o n- br o nc h o dilat or ( P D E 4 i n hi bit or) has p o or t olera bilit y  (C h o n g et al 2 0 1 7 ). M uc ol ytics ha ve 
s h o w n s mall a n d i nc o nsiste nt be nefits o n e xacer bati o n re d ucti o n a n d t he efficac y of m uc ol y tics 
o n t o p of ma xi mal i n hale d treat me nt has yet t o be clearl y esta blis he d (We dzic ha
et al 2 0 1 7 ). 
T h us des pite c urre ntl y a vaila ble treat me nts al m ost 7 0 % of s u bjects re mai n si g nifica ntl y li mite d 
b y  breat hless ness ( m M R C ≥ 2) a n d 4 0 % e x perie nce ≥2 m o derate or ≥1 se vere e xacer bati o n per 
ye ar (M uller o va
et al 2 0 1 7 ). Wit h t he e xce pti o n of a nti bi otics, n o ne of t he a vaila ble treat me nts 
tar get bacterial c ol o nizati o n. T heref ore a d diti o nal n o vel t herapies are ur ge ntl y  nee de d.
Researc h i n dicates t hat ci garette s m o ki n g i n d uces a n ac q uire d state of c ystic fi br osis 
tra ns me m bra ne c o n d ucta nce re g ulat or ( C F T R) d y sf u ncti o n i n t he res pirat or y tract 
(Ca nti n et al 2 0 0 6 ; Sl oa ne et al 2 0 1 2 ; Dra nsfiel d et al 2 0 1 3 ), e ve n i n t he a bse nce of C F T R 
m utati o ns (i.e., i n t he wil d t y pe C F T R). T his is h y p ot hesize d t o c o ntri b ute t o t he pat h o ge nesis 
of C O P D. F urt her m ore, c urre nt a n d f or mer s m o kers wit h C O P D ha ve ele vate d s weat c hl ori de 
le vels c o m pare d wit h 
n or mal 
c o ntr ol s u bjects, i n dicati n g re d uce d C F T R 
acti vit y 
(Raj u et al 2 0 1 3 ). C F T R d y sf u ncti o n d ue t o s m o ke e x p os ure a d versel y affects m uc ociliar y 
tra ns p ort a n d is ass ociate d wit h s ym pt o ms of c hr o nic br o nc hitis ( Sl oa ne et al 2 0 1 2 ).
T heref ore, t he m o d ulati o n of C F T R f u ncti o n ma y i m pr o ve air wa y hy d rati o n, decrease m uc us 
visc osit y  an d t h us e n ha nce m uc ociliar y  cleara nce. C F T R als o re g ulates air wa y surface li q ui d 
p H 
b y  bicar b o nate secreti o n, w hic h 
is i m p orta nt i n t he fi g ht a gai nst pat h o ge ns 
(Pezz ul o et al 2 0 1 2 ). He nce, C F T R p ote ntiati o n ma y  be effecti ve i n s u bjects wit h C O P D i n 
re d uci n g air wa y infla m m ati o n/i nfecti o n a n d o bstr ucti o n. A s mall 1 4 d a y  pil ot st u d y wit h 
I vacaft or i n C O P D s u bjects wit h c hr o nic br o nc hitis s h o we d i m pr o ve me nt i n s weat c hl ori de as 
a n i n dicati o n of a u g me ntati o n of C F T R f u ncti o n, i m pr o ve me nt i n s y m pt o ms, b ut di d n ot s h o w 
a differe n ce c o m pare d t o place b o i n l u n g f u ncti o n, t he a ut h ors ar g ue t he st u d y was m ost 
pr o ba bl y  t o o brief t o detect defi niti ve c ha n ges i n l u n g f u ncti o n. (S ol o m o n et al 2 0 1 6 ).
Q B W 2 5 1 is a n o vel p ote ntiat or of t he C F T R c ha n nel t hat was safe a n d well t olerate d i n t he 
st u dies c o n d ucte d i n H Vs a n d s u bjects u p t o n o w.
 
 I n ad diti o n t here was a si g nifica nt re d uctio n of fi bri n o ge n i n bl o o d, a s yste mic 
i nfla m mati o n mar ker, w hic h is c o nsi dere d t o be a pr o g n ostic bi o mar ker f or s u bjects at i ncrease d 
ris k f or all-ca use m ortalit y  or C O P D e xacer bati o n (Ma n ni n o et al 2 0 1 5 ) a n d a p pr o ve d as s uc h 
b y  F D A.
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 2 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T his st u d y is desi g ne d t o pr o vi de e vi de nce o n t he m o de of acti o n of Q B W 2 5 1 i n C O P D. 
1. 2
P ur p o s e
T he p ur p ose of t his st u d y is t o deter mi ne w het her p ote ntiati n g t he c ystic fi br osis tra ns me m bra ne 
c o n d ucta nce re g ulat or ( C F T R) wit h Q B W 2 5 1 i n s u bjects wit h C O P D will be efficaci o us wit h 
re gar ds t o re d uci n g l u n g a n d s yste mic i nfla m mati o n a n d bacterial c ol o nizati o n as p ote ntial 
dri vers of air wa y  o bstr ucti o n, air wa y destr uctio n, re m o deli n g a n d e xacer bati o ns.
F urt her m ore, t his st u d y will pr o vi de s u p p orti ve data t o i n vesti gate t he relati o ns hi p of C O P D 
p he n ot y pe a n d t he res p o nse i n s mall air wa y str uct ure, f u ncti o n
 a n d s pir o metr y 
i n dices as well as i n i m pr o ve me nt of o verall C O P D s ym pt o ms a n d q ualit y of life.
2
O bj e cti v e s a n d e n d p oi nt s
T a bl e 2- 1
O bj e cti v e s a n d r el at e d e n d p oi nt s
O bj e cti v e( s)
E n d p oi nt( s)
Pri m ar y o bj e cti v e( s)
E n d p oi nt( s) f or pri m ar y o bj e cti v e( s)

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n fi bri n o g e n
pl a s m a c o n c e ntr ati o n.

C h a n g e fr o m b a s eli n e i n fi bri n o g e n pl a s m a
c o n c e ntr ati o n.
S e c o n d ar y o bj e cti v e( s)
E n d p oi nt( s) f or s e c o n d ar y o bj e cti v e( s)

K e y s e c o n d ar y o bj e cti v e:
T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n s p ut u m b a ct eri al l o a d.

C h a n g e fr o m b a s eli n e i n t ot al b a ct eri a l o a d of
c ol o n y f or mi n g u nit s ( C F U/ m L)
of p ot e nti all y p at h o g e ni c mi cr o or g a ni s m s i n
s p ut u m.

S e c o n d ar y o bj e cti v e s:
T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n air w a y str u ct ur e a n d
f u n cti o n.

C h a n g e fr o m b a s eli n e i n air w a y w all a n d l u m e n
p ar a m et er s al o n g wit h e xt e nt of gl o b al a n d
r e gi o n al air tr a p pi n g, a s m e a s ur e d b y H R C T.

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n C O P D s u bjects s y m p t o m
b ur d e n c h a n g e s.

C h a n g e fr o m b a s eli n e i n C O P D A s s e s s m e nt
T e st ( C A T) q u e sti o n n air e.
C CI
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 2 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
O bj e cti v e( s)
E n d p oi nt( s)

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n h e alt h st at u s.

C h a n g e s fr o m b a s eli n e i n t h e E ur o Q u alit y of
Lif e -5 Di m e n si o n s -3 L e v el ( E Q-5 D -3 L)
q u e sti o n n air e.

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n c h a n g e s i n h e alt h-r el at e d
q u alit y of lif e.

C h a n g e fr o m b a s eli n e i n St. G e or g e' s
R e s pir at or y Q u e sti o n n air e ( S G R Q) t ot al a n d
d o m ai n s c or e s.

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n C O P D e x a c er b ati o n s.

Ti m e  t o fir st C O P D e x a c er b ati o n

Pr o p orti o n of s u bjects wit h e x a c er b ati o n s

A n n u ali z e d r at e of e x a c er b ati o n s a s
d efi n e d b y E X A C T -P R O q u e sti o n n air e

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n cli ni c al sy m pt o m s, c o u g h
a n d s p ut u m.

C h a n g e fr o m b a s eli n e i n C o u g h a n d S p ut u m
A s s e s s m e n t Q u e sti o n n air e ( C A S A-Q) d o m ai n
s c or e s.

T o a s s e s s t h e s af et y  a n d t ol er a bilit y of
Q B W 2 5 1 i n s u bjects wit h C O P D.

E C G i nt er v al s

Vit al si g n s

St a n d ar d cli ni c al l a b or at or y e v al u ati o n s
( h e m at ol o g y, bl o o d c h e mi str y, a n d
uri n al y si s)

A d v er s e e v e nt s

T o a s s e s s Q B W 2 5 1 p h ar m a c o ki n eti c s
( P K) d uri n g a n d aft er 1 2 w e e k s of
tr e at m e nt.

A s s e s s m e nt of dr u g e x p o s ur e ( Ctr o u g h
c oll e ct e d at pr e -d o s e a n d C m a x at p o st -d o s e)
o n D a y 1, D a y 2 8, D a y 5 6 a n d D a y 8 4.
C m a x a n d A U C o n D a y 1 a n d D a y 2 8 i n a
s u b s et of t h e s u bject p o p ul ati o n ( s eri al
s a m pli n g s u p t o 8 hr).

T o a s s e s s t h e eff e ct of Q B W 2 5 1
c o m p ar e d t o pl a c e b o aft er 1 2 w e e k s of
tr e at m e nt o n s pir o m etr y.

C h a n g e fr o m b a s eli n e i n tr o u g h F E V 1, F V C,
a n d F E V 1/ F V C.
E x pl or at or y o bj e cti v e( s)
E n d p oi nt( s) f or e x pl or at or y o bj e cti v e( s)
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
O bj e cti v e( s)
E n d p oi nt( s)
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
3
St u d y  d e si g n
Fi g ur e 3- 1
St u d y  d e si g n
T his is a ra n do mize d, s u bject a n d i n vesti gat or bli n de d, parallel -gr o u p, place b o -c o ntr olle d st u d y 
i n vesti gati n g t he m o de of acti o n ( M o A) a n d preli mi nar y  efficac y an d safety of Q B W 2 5 1 
a d mi nistere d orall y t wice dail y  ( b.i. d.) f or 1 2 wee ks i n s u bjects wit h m o derate t o se vere C O P D 
( G O L D 2-3). A p pr o xi matel y  1 0 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o t o eit her Q B W 2 5 1 
or place b o. Base d o n t he ass u m pti o n of a 1 5 % dr o p -o ut rate ( % dr o p o ut base d o n c o m plete d 
pr o of -of -c o nce pt C O P D st u d y CQ B W 2 5 1 X 2 2 0 1), it is e x pecte d t o ha ve a p p r o xi matel y 84 
s u bjects t o c o m plete t he st u d y.
T he st u d y co nsists of t he f oll o wi n g peri o ds: Scree ni n g, Baseli ne / Da y  1, Treat me nt, a n d E n d 
of t he St u d y  foll o we d b y  an a d diti o nal p ost -treat me nt safet y ph o ne call. T he t otal d urati o n f or 
eac h s u bject i n t he st u d y is u p t o a p pr o xi matel y 1 9 wee ks.
T he st u d y  desi g n is s u m marize d i n Fi g ure 3 -1 a b o ve.
3. 1
St u d y Vi sit s
S cr e e ni n g (fr o m D -4 2 t o D a y  -1)
I nf or me d c o nse nt m ust be o btai ne d pri or t o i m ple me nti n g a ny st u d y s pecific pr oce d ure.
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Scree ni n g assess me nts ca n be perf or me d o ver a 6 -wee k peri o d ma xi m u m. I ncl usi o n a n d 
e xcl usi o n criteria will be c hec ke d t o c o nfir m s u bject's eli gi bilit y .
T his c hec k i ncl u des me dical hist or y , bac k gr o u n d t hera p y (L A B A/I C S or L A B A/ L A M A or 
L A B A/ L A M A/ I CS or macr oli des), p h ys ical e xa mi nati o ns a n d ot her safet y a n d cli nical tests  i n 
or der t o deter mi ne s u bjects' i nitial eli gi bilit y. D uri n g scree ni n g, i n a d diti o n t o a hist or y  of 
e xacer bati o ns, res ults fr o m a n a nal ys is of bl o o d a n d s p ut u m sa m ples m ust be c ol o nize d wit h at 
least o ne strai n of p ote ntiall y  pat h o ge nic micr o or ga nis m ( H i nfl ue nzae, H parai nfl ue nzae, P 
aer u gi n osa, 
S 
p ne u m o niae, 
S 
a ure us, 
M ora xella 
catarr halis, 
E nter o bacteriaceae, 
Ste n otr o p h o m o nas malt o p hilia, B ur k h ol deria s pecies, a n d Ac hr o m o bacter s pecies or a n y 
p ote ntial pat h o ge nic bacteria meas ure d b y  dil uti o n/ o ut gr o wt h.) A n y or ga nis m t hat is t o b e 
i ncl u de d a n d t hat is n ot i ncl u de d i n t he list of t he pr ot oc ol defi ne d pat h o ge ns s h o ul d b e 
disc usse d case b y case bet wee n t he site PI a n d t he N o vartis Me dical E x pert. 
S p ut u m c ollecti o n a n d a nal ysis as well as fi bri n o ge n c ollecti o n a n d a nal ys is are per mitte d t o be 
re peate d o nce (f or a t otal of t w o res ulte d tests, res pecti vely) d uri n g t he scree ni n g peri o d.  It is 
preferre d t hat t he s u bjects pr o vi de a m or ni n g sa mple at t he cli nic d uri n g t heir st u d y  visit.  It is 
i m p orta nt t o e ns ure sa m ples are c ollecte d at t he sa me ti me of da y t hr o u g h o ut t he st u d y.
At scree ni n g all s u bjects will be pr o vi de d wit h a n electr o nic diar y  (e Diar y) a n d be trai ne d o n 
h o w t o rec or d i nf or mati o n a b o ut t heir st u d y me dicati o n i nta ke (fr o m Da y  1 on war ds), resc ue 
me dicati o n (sal b uta m ol/al b uter ol) a n d h o w t o c o m plete vari o us scales a n d q uesti o n naires. 
A H R C T m ust 
be perf or me d wit hi n t he scree ni n g peri o d t o Baseli ne / Da y  1 bef ore 
ra n d o mizati o n, pr efera bl y to war ds t he e n d of t he scree ni n g peri o d after m ost ot her scree ni n g 
assess me nts ha ve bee n c o m plete d a n d passe d. H R C T data is n ot re q uire d t o defi ne s u bject 
eli gi bilit y.
B a s eli n e / R a n d o mi z ati o n D a y  1
S u bjects w h o meet t he eli gi bilit y criteria at s cree ni n g will g o u n der Baseli ne / Da y 1 safet y a n d 
efficac y eval uati o ns bef ore ra n d o mizati o n. D uri n g baseli ne, s p ut u m sa m ples will be c ollecte d 
at t he sa me ti me of t he d a y  (s p ut u m c ollecti o n pr oce d ure a n d ti mi n g will be detaile d i n t he S O M 
a n d la b orat or y 
ma n ual) 
O nce all baseli ne assess me nts ha ve bee n c o m plete d a n d s u bjects are a gai n c o nfir me d as bei n g 
eli gi ble f or t he st u d y, t he y ca n be ra n d o mize d o n t he sa me d a y  (baseli ne/ ra n d o mizati o n Da y 1).
If s p ut u m sa m ple or ot her assess me nts ca n't be c ollecte d at baseli ne visit f or vari o us reas o ns, 
t he site ca n't ra n d o mize t he s u bject t he sa me da y. A n u nsc he d ule d visit wit hi n 3 da y s nee ds t o 
be 
pla n ne d 
t o c ollect 
s p ut u m 
bef ore 
ra n d o mizati o n 
a n d 
treat me nt 
all ocati o n. 
O nce s p ut u m is c ollecte d, t he s u bject ca n be ra n d o mize d t he sa me da y  of t he u nsc he d ule d visit.
O n Da y 1,  all eli gi ble s u bjects will be ra n d o mize d acc or di n g t o t heir s m o ki n g stat us (c urre nt or 
e x -s m o kers as a stratificati o n criteri o n) t o e ns ure t hat t he n u m ber of s u bjects bei n g s m o kers a n d 
e x -s m o kers are e q uall y distri b ute d i n t he treat me nt a n d place b o gr o u ps.
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Tr e at m e nt p eri o d (fr o m D a y  1 t o D a y 8 4)
O nce eli gi bilit y  has bee n c o nfir me d fr o m Scree ni n g a n d Baseli ne assess me nts, s u bjects will be 
ra n d o mize d i n 1: 1 rati o i nt o o ne of t he t w o treat me nt ar ms: place b o b.i. d. or Q B W 2 5 1 3 0 0 m g 
b.i. d.
T he treat me nt peri o d is 8 4 da y s i n d urati o n, wit h d osi n g t wice dail y . D uri n g t his peri o d, s u bjects 
will ha ve t o ret ur n t o t he site at D a y  28, Da y  56 a n d Da y  84 f or 
 bl o o d/s p ut u m sa m ple 
c ollecti o ns, P K, safety, efficac y assess me nts, a n d e Diar y chec k. At t hese visits, s u bjects will 
ret ur n all use d a n d u n use d st u d y me dicati o n a n d pac ka gi n g. At D a y  14, t he site will call t he 
s u bject t o e val uate c o m plia nce a n d t o c hec k s u bject's well bei n g.
P har mac o ki netic bl o o d sa m pli n g ( pre a n d p ost -d ose) will be d o ne at D a y  1, Da y  28, Da y  56 
a n d D a y  84 visits. A d diti o nall y , a s u bset of a p pr o xi matel y 30- 4 0 s u bjects will u n der g o 
p har mac o ki netic serial sa m pli n g pre a n d u p t o 8 h o urs p ost -d ose o n Da y  1 a n d o n Da y  2 8. 
As a f or mal t h or o u g h Q T assess me nt of Q B W 2 5 1 has n ot bee n c o m plete d, tri plicate E C Gs pre -
a n d p ost -d ose at T ma x will be perf or me d at visits o n Da y  1, Da y  28, Da y  56 a n d Da y  84 (e n d of 
treat me nt). T hese assess me nts will be c o m ple me nte d b y  PK sa m plin g (tr o u g h a n d C ma x) o n 
t he matc hi n g ti me-p oi nts, at visits o n Da y  1, Da y 2 8, Da y 5 6 a n d Da y 8 4.
A sec o n d H R C T will be perf or me d at Da y  84 after t he m or ni n g d ose of st u d y me dicati o n at site. 
If t he H R C T ca n't be perf or me d at Da y 8 4 f or a ny reas o n, t he e xa m nee ds t o be pla n ne d wit hi n 
t he 3 c o mi n g da ys a n d s u bject m ust c o nti n ue t o ta ke st u d y me dicati o n.
S u bjects e x perie nci n g a n e xacer bati o n d uri n g t he treat me nt peri o d will c o nti n ue wit h t he st u d y 
treat me nt al o n g wit h t he sta n dar d of care ( S O C) t hera py f or a m o derate e xacer bati o n 
(i.e. a nti bi otic a n d/ or s yste mic c ortic oster oi ds). Pri or t o t he S O C t hera p y ad mi nistrati o n, 
s u bjects ha ve t o visit t heir st u d y ce nter f or s p ut u m sa m ple c ollecti o n i n or der t o deter mi ne if 
t here are c ha n ges i n pat h o ge n or bacterial l oa d w hic h ma y  ha ve res ulte d i n t he e xacer bati o n.
S u bjects wit h a se vere e xacer bati o n w h o nee d t o be treate d i n t he h os pital will be disc o nti n ue d 
of st u d y treat me nt d uri n g t his ti me wit h t he p ossi bilit y t o restart st u d y treat me nt 2 wee ks after 
t he last S O C t hera p y i nta ke f or t he e xacer bati o n.
E n d of treat me nt assess me nts will be perf or me d at Da y  8 4 visit.
E n d of st u d y  ( E O S) vi sit ( D a y 9 1)
A p pr o xi matel y  one wee k after c o m pleti o n of t he treat me nt peri o d, s u bjects will be i n vite d t o 
t he ce nter f or e n d of st u d y ( E OS) assess me nts.
S af et y  f oll o w- u p c all ( D a y 1 1 4)
A f oll o w -u p tele p h o ne call f or safet y assess me nt will occ ur u p o n st u d y visit c o m pleti o n ( E O S) 
3 0 da y s after last st u d y dose a d mi nistrati o n.  The safety f oll o w- u p i ncl u des a d verse e ve nts 
safety m o nit ori n g.
C CI


N o v arti s
C o nfi d e nti al
P a g e 3 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
S p o nt a n e o u s s p ut u m c oll e cti o n
O n sc he d ule d s p ut u m c ollecti o n visits, at least t w o s p o nta ne o us s p ut u m s peci me ns s h o ul d be 
c ollecte d i n t he m or ni n g at pre -d ose ti me p oi nt a n d bef ore brea kfast. I n case s u bjects ca n’t 
pr o d uce e n o u g h s p ut u m o n t he i n di vi d ual sc h e d ule d visits, t he y ca n c o me bac k t o t he site u p t o 
3 da y s after t he sc he d ule d visit t o tr y t o pr o d uce a s p ut u m sa m ple. If t w o s p o nta ne o us s p ut u m 
c ollecti o n atte m pts are still n ot satisfact or y, i n vesti gat or m a y  ta ke decisi o n t o c ollect s p ut u m 
sa m ple after i n d ucti o n b y t he i n halati o n of sali ne (i n d ucti o n pr ocess will be descri be d i n t he 
S O M).
T he site staff will c hec k t he s p ut u m a p peara nce directl y  after e x pect orati o n t o deter mi ne 
w het her t he y see si g nifica nt sali va a m o u nt.  Once t he s p ut u m q ualit y  has bee n e val uate d a n d 
c o nsi dere d as acce pta ble b y t he site, s p ut u m ca n be pr ocesse d a n d se nt t o t he ce ntral la b orat or y 
f or a nal ys is. If sa m ple is deter mi ne d t o be s u b-o pti mal, a ne w s p ut u m c ollecti o n will be 
re q ueste d by t he site's staff. S p ut u m q ualit y assess me nt a n d pr ocessi n g will be descri be d i n t he 
S O M a n d la b orat or y  ma n ual.
If s p o nta ne o us s p ut u m c ollecti o n is n ot p ossi ble at Da y 8 4, t he site will nee d t o resc he d ule t he 
visit u p t o 3 da y s after D a y  84 a n d s u bject will ha ve t o c o nti n ue t o ta ke st u d y me dicati o n.
Ot her D a y  8 4 assess me nts d o n't nee d t o be re peate d.
F urt her m ore, all s u bjects wit h si g ns of a n e xacer bati o n will ha ve t o c o me t o t he st u d y ce nter 
w here a n a d diti o nal s p ut u m sa m ple al o n g wit h a bl o o d sa m ple f or fi bri n o ge n a n d hs C R P will 
be c ollecte d. T he a nal y sis of t he s p ut u m sa m ple w o ul d hel p t o deter mi ne w het her t he bacterial 
l oa d or c ol o nizati o n ma y c ha n ge wit h a n e xacer bati o n. 
I n case of e xacer bati o n, t he s u bject has t o c o me bac k t o t he site 1 4 d a y s after last a nti bi otics 
i nta ke f or a n ot her s p ut u m/ bl oo d sa m ple c ollecti o n. 
F or a f ull list of assess me nts a n d ti me p oi nts please refer t o t he Assess me nt Sc he d ule (Ta bl e 8- 1).
4
R ati o n al e
4. 1
R ati o n al e f or st u d y  d e si g n
T his ra n d o mize d, d o u ble -bli n d, parallel -gr o u p, a n d place b o -c o ntr olle d desi g n s u p p orts t he 
assess me nt of efficac y as well as safety.
T he st u d y will assess Q B W 2 5 1 as a n a d d- o n t o bac k gr o u n d t hera py,  in a d ult s u bjects wit h 
C O P D ass ociate d wit h c hr o nic br o nc hitis a n d hist or y  of e xacer bati o ns i n t he 1 2 m o nt hs pri or 
t o t he st u d y. C hr o nic br o nc hitis, hist or y  of fre q ue nt e xacer bati o ns are e x pecte d t o be e nric h me nt 
fact ors f or s u bjects w h o ma y  partic ularl y be nefit fr o m i mpr o ve d acti vit y (p ote ntiati o n) of t he 
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C F T R c ha n nel. A fi bri n o ge n le vel of ≥ 3 2 0 m g/ d L as well as a s p ut u m sa m ple t hat is p ositi ve 
f or p ote ntiall y pat h o ge nic bacteria at scree ni n g are f urt her p o p ulati o n e nric h me nt fact ors.
T his st u d y is desi g ne d t o assess the effect of Q B W 2 5 1 o n re d ucti o n of s yste mic a n d l u n g 
i nfla m mat or y bi o mar kers, p ote ntiall y  pat h o ge nic micr o or ga nis ms 
a n d ot her sec o n dar y 
e n d p oi nts c o m pare d t o place b o.
Rati o nale f or ke y  as pects of t his desi g n are as f oll o ws:

St u d y  d urati o n i ncl u des scree nin g ( u p t o 6 wee ks), baseli ne ( 1 da y ), treat me nt ( 1 2
wee ks) a n d a n e n d of t he st u d y visit a p pr o xi matel y 1 wee k after t he last st u d y dr u g
a d mi nistrati o n. A st u d y d urati o n u p t o 1 9 wee ks is of a de q uate ti me i n or der t o c o nfir m
s u bject’s eli gi bilit y a n d sta bilit y bef ore ra n d o mizati o n, as well as, t o pr o vi de data f or
st u d y o bjecti ve(s) a n d t o e ns ure s u bjects safety d uri n g st u d y c o n d uct. I n a d diti o n, t he
st u d y e m pl o ys a safet y f oll o w u p call a p pr o xi matel y 3 0 da ys after t he last st u d y d ose
i nta ke.

T he pri mar y  o bjecti ve, fi bri n o ge n, a n i nfla m mati o n mar ker i n plas ma, is c o nsi dere d
a pr o g n ostic bi o mar ker b y F D A a n d E M A f or s u bjects at i ncrease d ris k f or all -ca use
m ortalit y  or a C O P D e xacer bati o n (Ma n ni n o et al 2 0 1 5 ). S yste mic i nflam mati o n is
ass ociate d wit h w orse cli nical o utc o mes i n C O P D.

T he ke y  sec o n dar y e n d p oi nt assesses a re d ucti o n fr o m baseli ne i n c ol o n y f or mi n g u nits of
p ote ntiall y  pat h o ge nic bacteria a n d micr o or ga nis ms i n s p o nta ne o us s p ut u m. T he re d ucti o n
b y  o ne l o g1 0 u nit is ass ociate d wit h a si g nifica nt re d ucti o n i n ris k of e xacer bati o n b y
a p pr o xi matel y 2 0 % i n s u bjects wit h br o nc hiectasis, w hic h is c o nsi dere d t o be cli nicall y
rele va nt i n C O P D as well (C h al mers et al 2 0 1 2 ). Als o, a st u d y wit h Azit hr o m yci n
mai nte na nce treat me nt i n C O P D wit h t he fre q ue nt e xacer bater p he n ot y pe s h o we d a
si g nifica ntly decrease d e xacer bati o n rate ( Uz u n et al 2 0 1 4 ).
4. 1. 1
R ati o n al e f or c h oi c e of b a c k gr o u n d t h er a p y
T he selecte d bac k gr o u n d t hera py will
c o nsist of s u bject i n di vi d ual i n hale d c o m bi nati o ns 
( L A B A/ L A M A or L A B A/I C S or L A B A/ L A M A/I C S) t hat was ta ke n at a sta ble d ose f or 
3 m o nt hs bef ore st u d y start eit her as a fi xe d c o m bi nati o n or a free c o m bi nati o n gi ve n o nce or 
t wice dail y . S u bjects will c o nti nue ta ki n g t his bac k gr o u n d me dicati o n d uri n g t he trial. G O L D 
strate g y (G O L D 2 0 1 9 ) s u g gests t he decisi o n t o use t he bac k gr o u n d t hera p y s h o ul d be g ui de d 
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
b y  the le vel of s ym pt o ms (e. g. C A T sc ore of at least 1 0) a n d e xacer bati o n fre q ue nc y. I n a d diti o n, 
s u bjects are all o we d t o sta y o n macr oli des at a sta ble d ose if t he y were treate d wit hi n 3 m o nt hs 
bef ore st u d y start a n d/ or if t he y ha ve br o nc hiectasis as a sec o n dar y dia g n osis. Ma n y  CO P D 
s u bjects, es peciall y wit h a sec o n dar y dia g n osis of br o nc hiectasis, are o n a mai nte na nce 
macr oli des t hera p y if t he y s uffer fr o m fre q ue nt e xacer bati o ns.
De pe n di n g o n t he se verit y of C O P D disease it is e x pecte d t hat 2 0 -4 0 % of C O P D s u bjects i n 
t his trial ma y ha ve br o nc hiectasis as a sec o n dar y dia g n osis (Marti nez -Garcia et al 2 0 1 1 ).
4. 2
R ati o n al e f or d o s e/r e gi m e n a n d d ur ati o n of tr e at m e nt
Q B W 2 5 1 is a s mall m olec ule i nte n de d f or oral a d mi nistrati o n. T he half -life of Q B W 2 5 1 
f oll o wi n g a si n gle d ose ra n ges fr o m 1 0 t o 1 6 h o urs. T he t wice dail y d osi n g re gi me n was c h ose n 
base d o n t he half -life a n d t he i nte nt t o ha ve a s ustai ne d effect o n t he i o n c ha n nel. A d diti o nall y, 
a t wice dail y  re gi me n is e x pecte d t o pr o vi de a re d uce d C ma x/tr o u g h fl uct uati o n c o m pare d t o 
o nce dail y  dosi n g. A t wice dail y  re gi me n was als o teste d i n t he pr o of of c o nce pt st u d y 
( C Q B W 2 5 1 X 2 2 0 1) a n d was s h o w n t o be effecti ve i n C O P D s u bjects at 3 0 0 m g b.i. d. T he 
3 0 0 m g b.i. d. is als o selecte d i n ali g n me nt wit h D ose Ra n ge Fi n di n g st u d y  ( C Q B W 2 5 1 B 2 2 0 1) 
wit h d oses u p t o 3 0 0 m g  b.i. d. as t he hi g hest d ose base d o n a rec o m me n dati o n of t he data 
m o nit ori n g c o m mittee t o e ns ure t hat s u bjects' s ys te mic e x p os ures are ge nerall y c o nsiste nt wit h 
a n e x p os ure t hres h ol d A U C 0 - 2 4≥ 9 1' 7 0 0 n g * h/ m L, w hic h was esta blis he d base d o n a ni mal da ta. 
T he 3 0 0 m g b.i. d. re gi me n was well t olerate d i n a n earlier st u d y i n c y stic fi br osis ( C F) s u bjects 
(st u d y C Q B W 2 5 1 X 2 1 0 1) as well.
1 2 wee ks of treat me nt s h o ul d be s ufficie nt t o detect fi bri n o ge n plas ma le vel c ha n ges a n d 
c ha n ges i n bacterial l oa d a n d c ol o nizati o n reflecti ve of t he tar get pr ofile of Q B W 2 5 1. I n the 
P o C st u d y (C Q B W 2 5 1 X 2 2 0 1) re d ucti o n i n fi bri n o ge n i n plas ma a n d bacterial c ol o nisati o n 
were detecte d after 4 w ee ks. A p ositi ve si g nal acr oss t hese e n d p oi nts at t his ti me p oi nt w o ul d 
s u p p ort earl y de cisi o n ma ki n g f or a tra nsiti o n i nt o c o nfir mat or y phase III st u dies. I n ad diti o n, 
1 2 wee ks treat me nt, as c o m pare d t o t he 4 wee ks treat me nt i n t he c o m plete d pr o of of c o nce pt 
st u d y (C Q B W 2 5 1 X 2 2 0 1), e na bles a l o n git u di nal assess me nt. T he pr o p ose d e x p os ure will als o 
i ncrease t he r o b ust ness of t he safety a n d t olera bilit y assess me nt a n d m a y  pr o vi de e x pl orat or y 
i nsi g hts relati ve t o t he effect.
4. 3
R ati o n al e f or c h oi c e of c o ntr ol dr u g s ( c o m p ar at or/ pl a c e b o) or 
c o m bi n ati o n dr u g s
T here is c urre ntl y n o a p pr o ve d C T F R p ote ntiat or f or treat me nt of C O P D o n t o p of i n hale d 
t hera py of L A B A/ L A M A or L A B A/I C S or L A B A/ L A M A/ I CS or macr oli des t hat c o ul d ser ve 
as a c o m parat or. T heref ore, Q B W 2 5 1 is teste d a gai nst place b o o n t o p of bac k gr o u n d t hera p y, 
w hic h is als o i n acc or da nce wit h t he r o b ust met h o d f or t he e val uati o n of a n i n vesti gati o nal a ge nt, 
t o sta n dar ds meeti n g b ot h re g ulat or y re q uire me nts a n d acce pte d scie ntific pri nci ples. T his 
i ncl u des o pti mizi n g t he st u d y desi g n f or hi g h le vels of c o nfi de nce i n t he ri g or a n d vali dit y  of 
t he res ulti n g data, a n d mi ni mizi n g t he ris k of i nc o ncl usi ve res ults.


N o v arti s
C o nfi d e nti al
P a g e 3 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
4. 4
P ur p o s e a n d ti mi n g of i nt eri m a n al y s e s/ d e si g n a d a pt ati o n s
4. 5
Ri s k s a n d b e n efit s
Ri s k s
T he ris ks t o s u bjects i n t his trial will be mi ni mi ze d t hr o u g h c o m plia nce wit h t he eli gi bilit y 
criteria, st u d y pr oce d ures, safet y e val uati o ns, P K data, as well as cl ose cli nical m o nit ori n g. 
P ot e nti al ri s k s of Q B W 2 5 1
P ote ntial ris ks of Q B W 2 5 1 are t he a d verse e ve nts o bser ve d wit h i ncrease d e x p os ure of 
Q B W 2 5 1 as n ote d i n pre vi o us st u dies, c o m prisi n g (refer t o I n vesti gat or Br oc h ure):

Gastr oi ntesti nal e ve nts ( na usea, diarr hea, v o miti n g)

Ner v o us s ys te m dis or ders ( hea dac he, fati g ue a n d dizzi ness)

H y perse nsiti vit y  reacti o ns t o Q B W 2 5 1 ca n n ot be e xcl u de d, b ut ha ve not bee n o bser ve d i n
t he pre vi o us st u dies wit h Q B W 2 5 1.
Ri s k s a s s o ci at e d wit h S o C ( d o u bl e or tri pl e i n h al e d t h er a p y  or m a cr oli d e s)
A d verse e ve nts ass ociate d wit h i n hale d C O P D bac k gr o u n d t hera p y i ncl u de:
Nas o p har y n gitis, h y perte nsi o n, bac k pai n a n d or o p har y n geal pai n, d y s pe psia, gastr oe nteritis, 
c hest pai n, fati g ue, peri p heral e de ma, a n gi oe de ma, ras h/ pr urit us, i ns o m nia, dizzi ness, bla d der 
o bstr ucti o n/ uri nar y  rete nti o n, atrial fi brillati o n, pal pitati o ns, tac hycar dia, u p per a n d l o wer 
res pirat or y tract i nfecti o n, p ne u m o nia, diarr hea, hea dac he, gastr oes o p ha geal refl u x disease, 
h y per gl y ce mia, r hi nitis (a p pr o ve d i nf or mati o n f or Ulti br o Breez haler ® ).
T he m ost c o m m o n a d verse effects ass ociate d wit h tri ple C O P D bac k gr o u n d t hera py are 
hea dac he, bac k pai n, d y s ge usia, diarr hea, c o u g h, or o p har y n geal pai n, nas o p har y n gitis, u p per 
res pirat or y tract i nfecti o n, art hral gia, gastr oe nteritis, a n d oral ca n di diasis (a p pr o ve d i nf or mati o n 
f or Trele g y Elli pta® , Bre o Elli pta® -E U na me Rel var Elli pta ® - a n d I ncr use Elli pta ® ).
T he m ost c o m m o n a d verse effects ass ociate d wit h macr oli de a nti bi otics (e. g. er yt hr o m yci n 
pr o d ucts) are gastr oi ntesti nal. T he y  incl u de na usea, v o miti n g, a b d o mi nal pai n, diarr hea a n d 
a n ore xia. Re versi ble heari n g l oss ass ociate d wit h d oses of er yt hr o m y ci n us uall y  greater t ha n 4 g 
per da y  has bee n re p orte d ( Er yt hr o m yci n U K S m P C).
Pr o c e d ur al ri s k s
Pr oce d ural ris ks ma y  i ncl u de:
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 3 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

L ocal reacti o ns t o ve ni p u nct ure, i ncl u di n g pai n, he mat o mas, fai nti n g, s welli n g, i nfecti o ns,
a n d er yt he ma.

S pir o metr y  ma y be ass ociate d wit h c o u g h, s h ort ness of breat h a n d hea dac he.

H R C T i n v ol ves e x p os ure t o ra diati o n. T he t otal a m o u nt of ra diati o n f or ac q uisiti o n at
scree ni n g a n d Wee k 1 2 H R C T sca ns will be o pti mize d t o be wit hi n t he a n n ual li mits of
e x p os ure defi ne d i n b ot h U S a n d E U g ui deli nes.

H y p e rt o nic sali ne s ol uti o n f or s p ut u m i n d ucti o n mi g ht ca use br o nc h os pas m
Ri s k miti g ati o n
Base d o n t he a b o ve ris k c o nsi derati o ns, cli nical m o nit ori n g i ncl u des t he use of a n electr o nic 
diar y  wit h t he E X A C T-P R O q uesti o n naire t o e na ble dail y s ym pt o ms assess me nt, as well as 
safety assess me nts d uri n g visit da y s at t he i n vesti gati o nal site. T hese i ncl u de a caref ul 
assess me nt of a d verse e ve nts, as well as tri plicate E C Gs, he mat ol o gic a n d cli nical c he mistr y 
la b orat or y assess me nts, uri nal y sis a n d vital si g ns meas ure me nt s. As a f or mal t h or o u g h Q T 
assess me nt of Q B W 2 5 1 has n ot bee n c o m plete d, tri plicate E C Gs pre - a n d p ost -d ose (at t he ti me 
t o reac h ma xi m u m ( C ma x) plas ma c o nce ntrati o n f oll o wi n g dr u g a d mi nistrati o n ( T ma x)) will 
be perf or me d at D a y  1, at D a y  28 ( w he n s u bjects are e x pecte d t o ha ve reac he d stea dy state 
c o nce ntrati o n of t he i n vesti gati o nal dr u g), a n d at Da y 8 4 (e n d of treat me nt). T hese assess me nts 
will be c o m ple me nte d b y  the c orres p o n di n g P K sa m pli n g ( Ctr o u g h a n d C ma x). T he P K 
sa m pli n g is als o part of a m ore gra n ular P K m o nit ori n g, w hic h has bee n p ut i n place t o e ns ure 
t hat s u bject e x p os ures are i n ge neral c o nsiste nt wit h a n e x p os ure t hres h ol d (area u n der t he 
plas ma c o nce ntrati o n c ur ve o ver 2 4 h o urs ( A U C 0-2 4 h) = 9 1 7 0 0 n g × h/ m L) t hat was esta blis he d 
base d o n a ni mal ( m o n ke y) data. As t his t hres h ol d re prese nts a n a vera ge of t he e x p os ures 
o bser ve d i n t h ose a ni mals after 3 9 wee ks of treat me nt wit h Q B W 2 5 1, t his li mit is n ot a bs ol ute, 
t his is a mea n val ue a n d fe w s u bjects are e x pecte d t o e xcee d it. I n pri or Q B W 2 5 1 st u dies,
s u bjects wit h e x p os ures a b o ve t his t hres h ol d re p orte d eit her n o a d verse e ve nts or mil d t o 
m o derate o nes.
I n ad diti o n t o t he sa m pli n g descri be d a b o ve, t he P K m o nit ori n g pla n will ge nerate Ct hr o u g h 
data at all visits a n d a d diti o nal P K sa m ples are re q ueste d t o be ta ke n i n case of 
treat me nt-e mer ge nt seri o us a d verse e ve nts. St u d y  dr u g disc o nti n uati o n a n d st u d y st o p pi n g r ules 
relate d t o e x p os ure are descri be d i n Secti o n 9. 1. 4. 1 .
Fi nall y  a su b- gr o u p of a p pr o xi matel y 30 t o 4 0 s u bjects will u n der g o serial P K assess me nts t o 
f urt her c haracterize t he P K pr ofile of Q B W 2 5 1 i n C O P D s u bjects. 
I n vesti gat ors a n d s u bjects will be i nstr ucte d o n h o w t o react t o w orse ni n g of C O P D s ym pt o ms 
a n d e xacer bati o ns (Sec ti o n 8. 4. 4). F or t he w orse ni n g of C O P D s ym pt o ms, a s h ort -acti n g beta-
2 a g o nist ( S A B A) is pr o vi de d as resc ue me dicati o n. Wit h 
res pect t o t he treat me nt of 
e xacer bati o ns, a s u g geste d t hera py c o nsists of 5 da y s of oral pre d nis ol o ne ( or e q ui vale nt) 4 0 
m g/ da y  an d/ or a n oral 7 d a y  co urse of a m o xicilli n 5 0 0 m g t hree ti mes per d a y  (t.i. d.) 
(alter nati vely a m o xicilli n cla v ula nate 6 2 5 m g  t.i. d. or clarit hr o m yci n 5 0 0 m g b.i. d.), t h o u g h 
i n vesti gat ors are free t o treat C O P D e xacer bati o ns acc or di n g t o t he me dical nee ds of t he 
s u bjects. T he diar y will als o tri g ger alerts t o b ot h s u bjects a n d i n vesti gat ors w he n a n al g orit h m 
detects a deteri orati o n of s ym pt o ms c o m pati ble wit h a n e xacer bati o n. T he i n vesti gat or will 
pr o vi de t he s u bject wit h writte n i nstr ucti o ns t o c o ntact t he m i f s ym pt o ms of C O P D w orse n.


N o v arti s
C o nfi d e nti al
P a g e 3 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
W o me n of c hil d beari n g p ote ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y  in v ol ve 
u n k n o w n ris ks t o t he fet us if pre g na nc y  were t o occ ur d uri n g t he st u d y, a n d a gree t hat i n or der 
t o partici pate i n t he st u d y t h e y must a dhere t o t he c o ntrace pti o n re q uire me nts o utli ne d i n t he 
e xcl usi o n criteria. If t here is a n y q uesti o n t hat t he s u bject will n ot relia bl y c o m pl y, t he y s h o ul d 
n ot be e ntere d or c o nti n ue i n t he st u d y. Base d o n a re pr o d ucti ve t o xicit y st u d y, w o me n of 
c hil d beari n g p ote ntial are all o we d t o e nter t he st u d y as l o n g as t he y are usi n g a n acce pta ble 
effecti ve met h o d of c o ntrace pti o n (see als o e xcl usi o n criteria). T his gr o u p of s u bjects is rele va nt 
f or t he tar gete d disease a n d t heir i ncl usi o n is ali g ne d wit h t he I nter nati o nal C o nfere nce o n 
Har m o nisati o n of Tec h nical Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n Use 
(IC H) M 3 ( R 2) g ui da nce. H o we ver, i n a h or m o nal c o ntrace pti o n st u d y, it was de m o nstrate d 
t hat Q B W 2 5 1 ma y  e n ha nce c yt oc hr o me P 4 5 0 me diate d de gra dati o n of c o ntrace pti ve h or m o nes 
wit h t he c o nse q ue nce t hat h or m o nal c o ntrace pti o n is n ot a n acce pta ble met h o d of c o ntrace pti o n 
i n t he st u d y.
H o we ver, 
efficac y 
of t he i n hale d thera pies 
(s uc h as 
L A B A/ L A M A, 
L A B A/I C S, 
L A B A/ L A M A/ I CS) is n ot e x pecte d t o be i m pacte d d ue t o t he deli ver y  directly t o t he l u n gs. 
I n a d diti o n t o t he i n hale d t hera pies, as a per petrat or, Q B W 2 5 1 is n ot e x pecte d t o ha ve i m pact 
o n t he P K e x p os ure of t he macr oli d es (s uc h as Er y t hr o m yci n a n d Clarit hr o m y ci n) as t he y are 
n o s u bstrates of meta b olite e nz y mes of C Y P 1 A 2, 3 A 4 or U G Ts.
Please refer t o t he res pecti ve la bels of t he bac k gr o u n d t hera py f or a d diti o nal i nf or mati o n o n 
dr u g i nteracti o ns. A n y c o nc o mita nt me dicati o n s s h o ul d be n ote d i n t he e C R F. As a d diti o nal 
i nf or mati o n bec o mes a vaila ble w he n cli nical dr u g i nteracti o n st u dies are c o n d ucte d d uri n g t he 
Q B W 2 5 1 de vel o p me nt pr o gra m, t his i nf or mati o n will be f urt her u p date d a n d reflecte d i n t he 
Q B W 2 5 1 I n vesti gat or Br oc h ur e.
B e n efit s
Wit h res pect t o cli nical be nefits, a pr o of of c o nce pt st u d y  s h o we d a statisticall y si g nifica nt a n d 
cli nicall y rele va nt decrease i n s yste mic i nfla m mati o n (fi bri n o ge n; base d o n e x pert o pi ni o n), 
a n i m pr o ve me nt of p ul m o nar y  f u ncti o n ( F E V 1) a n d a red ucti o n of t he bacterial l oa d of selecte d 
pat h o ge ns after 4 wee ks of treat me nt wit h Q B W 2 5 1 i n C O P D s u bjects. 
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 4 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Fi nall y , a n i n de pe n de nt Data M o nit ori n g C o m mittee will o versee t he de vel o pi n g cli nical 
data base t o s u p p ort e ns uri n g s u bjects' well- bei n g t hr o u g h o ut t he st u d y.
4. 5. 1
Bl o o d s a m pl e v ol u m e
A v ol u me s maller t ha n a t ypical bl o o d d o nati o n (a p pr o xi mati vel y 15 0 m L) is pla n ne d t o be 
c ollecte d d uri n g Scree ni n g, Baseli ne, d uri n g t he 1 2 wee ks of t he treat me nt peri o d a n d at t he 
e n d of t he st u d y , fr o m eac h s u bject. F or s u bset of s u bjects partici pati n g t o serial P K sa m pli n g, 
a p pr o xi mati vel y 3 0 m L will be c ollecte d i n a d diti o n. 
A d diti o nal sa m ples ma y  be re q uired f or safet y m o nit ori n g.
Ti mi n gs of bl o o d sa m ple c ollecti o n are o utli ne d i n t he assess me nt sc he d ule ( Ta ble 8- 1 ).
A s u m mar y bl o o d l o g is pr o vi de d i n t he Site O perati o ns Ma n ual ( S O M). I nstr ucti o ns f or all 
sa m ple c ollecti o n, pr oce ssi n g, st ora ge a n d s hi p me nt i nf or mati o n is als o a vaila ble i n t he S O M 
a n d Ce ntral la b orat or y ma n ual.
See Secti o n 8. 5. 3. 1 o n t he p ote ntial use of resi d ual sa m ples.
5
P o p ul ati o n
T he st u d y po p ulati o n will c o nsist of a p pr o xi mat el y 10 0 male a n d fe male s u bjects, a ge d 4 0 ye ars 
ol d a n d a b o ve, wit h m o derate t o se vere C O P D ( G O L D 2 t o 3) wit h feat ures of c hr o nic 
br o nc hitis, a s m o ki n g hist or y  of at least 1 0 pac k / years, a n d at least t w o m o derate or o ne se vere 
e xacer bati o n(s) bet wee n Ja nuar y  20 1 9 a n d t heir scree ni n g visit. All s u bjects m ust ha ve a plas ma 
fi bri n o ge n le vel of ≥3 2 0 m g/ d L, a C A T sc ore of at least 1 0, a n d ha ve bee n o n L A M A/ L A B A 
or L A B A/I C S or L A B A/ L A M A/ I CS t hera p y at sta ble d ose f or at least 3 m o nt hs pri or st u d y 
start. C O P D su bject s are all o we d t o sta y on macr oli des as bac k gr o u n d t hera p y if t h e y ha ve 
br o nc hiectasis as a sec o n dar y dia g n osis a n d if t he y ha ve bee n treate d wit h t he m f or at least 3 
m o nt hs at sta ble d ose bef ore st u d y start. I n a d diti o n, s u bjects' s p ut u m m ust be c ol onize d wit h 
p ote ntiall y  pat h o ge nic bacteria ( > 0 C F U) at scree ni n g.
5. 1
I n cl u si o n crit eri a
S u bjects eli gi ble f or i ncl usi o n i n t his st u d y  m ust meet all of t he f oll o wi n g criteria:
1.
Patie nts w h o ha ve si g ne d a n I nf or me d C o nse nt F or m pri or t o i nitiati o n of a n y
st u d y-relate d pr oce d ure.
2.
Male a n d fe male a d ults a ge d ≥4 0 y ears at scree ni n g.
3.
Patie nts wit h sta ble C O P D, sta ges G O L D 2 -3, acc or di n g t o t he c urre nt G O L D strate g y
(G O L D 2 0 1 9 ) at scree ni n g.
Patie nts wit h a p ost -br o nc h o dilat or F E V 1/ F V C < 0. 7 0 at scree ni n g
4.
S u perse de d as of a me n d me nt V 0 1
4a. Patie nts wit h airfl o w li mitati o n i n dicate d b y  a p ost-br o nc h o dilat or F E V 1 ≥ 3 0 % a n d
F E V 1 < 8 0 % of t he pre dicte d n or mal at Scree ni n g w h o m ust ha ve ha d at least 2
d oc u me nte d m o derate or at leas t 1 d oc u me nte d se vere e xacer bati o n(s)  bet wee n Ja n uar y
2 0 1 9 t o st u d y  scree ni n g
N otes:


N o v arti s
C o nfi d e nti al
P a g e 4 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

P ost -br o nc h o dilat or refers t o 1 5 t o 3 0 mi n after i n halati o n of 4 0 0 μ g 
sal b uta m ol/ 3 6 0 μ g al b uter ol ( or e q ui vale nt d ose).

E xacer bati o ns are defi ne d as m o derate if lea di n g t o treat me nt wit h s yste mic 
gl uc oc ortic oster oi ds a n d/ or a nti bi otics, a n d as se vere if lea di n g t o h os pital a d missi o n 
or e mer ge nc y  r o o m visit lasti n g > 2 4 h i n a d diti o n t o treat me nt wit h s yste mic 
gl uc oc ortic oster oi ds a n d/ or a nti bi otics.

Patie nts n ot meeti n g t he F E V 1 criteria ma y  be re-scree ne d o nce.
5.
5 a n d 5a: S u perse de d as of a me n d me nt V 0 2
5 b. Patie nts wit h s p ut u m p ositi ve ( > 0 C F U) f or at least o ne strai n of p ote ntiall y 
pat h o ge nic micr o or ga nis m at scree ni n g ( H i nfl ue nzae, H parai nfl ue nzae, P aer u gi n osa, S 
p ne u m o niae, S a ure us, M ora xella catarr halis, E nter o bacteriaceae, Ste n otr o p h o m o nas 
malt o p hilia, B ur k h ol deria s pecies, a n d Ac hr o m o bacter s pecies or a n y  p ote ntial pat h o ge nic 
bacteria meas ure d b y dil uti o n/ o ut gr o wt h. A n y or ga nis m t hat is t o be i ncl u de d a n d t hat is 
n ot i ncl u de d i n t he list of t he pr ot oc ol defi ne d pat h o ge ns will be disc usse d case b y  case). 
S p ut u m sa m ples ma y  be re-c ollecte d a n d re -teste d o nce d uri n g t he scree ni n g peri o d.
6.
Patie nts w h o ha ve bee n treate d wit h a c o m bi nati o n of L A B A/ L A M A or L A B A/I C S or 
L A B A/ L A M A/ I CS at a sta ble d ose f or t he last 3 m o nt hs pri or t o scree ni n g. 
C O P D patie nts are all o we d t o sta y  o n macr oli des as bac k gr o u n d t hera p y if t he y ha ve 
br o nc hiectasis as a sec o n dar y dia g n osis a n d if t he y are treate d wit h t he m at a sta ble d ose 
3 m o nt hs bef ore scree ni n g.
N ote: Fixe d or free c o m bi n ati o ns are acce pt a ble.
7.
S u perse de d as of a me n d me nt V 0 1 
7a. Patie nts wit h plas ma fi bri n o ge n le vel ≥ 3 2 0 m g/ d L at scree ni n g.  Fi bri n o ge n ma y  be 
re-teste d o nce d uri n g t he scree ni n g peri o d.
8.
A C O P D Assess me nt Test ( C A T) sc ore of at least 1 0 at scree ni n g.
9.
C urre nt or e x -s m o kers w h o ha ve a s m o ki n g hist or y of at least 1 0 pac k years (e. g. 1 0 pac k 
ye ars = 1 pac k/ da y x 1 0 years, or 0. 5 pac k/ da y x 2 0 years) at scree ni n g.
N ote: A p ack of ci g arettes is e q u al t o 2 0 ci g arettes. Bi di or ot her si mil ar n o n -filtere d 
ci g arette m ay be c o nsi dere d a p plic a ble t o s m oki n g hist ory. T hey s h o ul d be c o u nte d i n t he 
s a me w ay as st a n d ar d ci g arettes. Occ asi o n al s m oki n g of ci g ars, pi pes, e-ci g arettes, or 
i n h ale d nic oti ne pr o d ucts are n ot relev a nt t o s m oki n g hist ory.
N ote: A n ex -s m oker is defi ne d as a s u bject w h o h as n ot s m oke d f or≥ 6 m o nt hs at 
scree ni n g or at t he ti me of assess me nt.
1 0. Patie nts feat uri n g c hr o nic br o nc hitis, defi ne d as pr o d ucti ve c o u g h t hat occ urs o n m ost 
da y s ( defi ne d as > 5 0 % of da ys) d uri n g at least 3 c o nsec uti ve m o nt hs i n t he y ear pri or t o 
scree ni n g, as assesse d by d oc u me ntati o n of patie nt rec ollecti o n (a na m nesis) or 
d oc u me nte d i n patie nts' rec or ds.
1 1. A ble t o c o m m u nicate well wit h t he i n vesti gat or, t o u n dersta n d a n d c o m pl y wit h t he 
re q uire me nts of t he st u d y. 
5. 2
E x cl u si o n crit eri a
S u bjects meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y .


N o v arti s
C o nfi d e nti al
P a g e 4 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1.
Patie nts wit h a hist or y  of l o n g-Q T s y n dr o me or w h ose Q Tc F i nter val at scree ni n g 
( Fri dericia met h o d) is pr ol o n ge d ( Q Tc F > 4 5 0 ms i n males, > 4 6 0 ms i n fe males).
2.
S u perse de d as of a me n d me nt V 0 1 
2a. Patie nts w h o ha ve a cli nicall y  si g nifica nt * E C G a b n or malit y bef ore ra n d o mizati o n.   
N ote: Cli nic ally si g nific a nt a b n or m alities m ay i ncl u de b ut are n ot li mite d t o t he f oll o wi n g: 
left b u n dle br a nc h bl ock, Wolff -P arki ns o n -W hite sy n dr o me, cli nic ally si g nific a nt 
arr hyt h mi as (e. g., atri al fi brill ati o n, ve ntric ul ar t ac hyc ar di a).
3.
Cli nical la b orat or y  val ues a b n or malities (i ncl u di n g Ga m ma G T, A S T, A L T, t otal bilir u bi n 
or creati ni ne) c o nsi dere d as cl i nicall y si g nifica nt* i n t he o pi ni o n of t he I n vesti gat or at 
scree ni n g. F or a d diti o nal g ui da nce o n he patic para meters see e xcl usi o n criteri o n # 5.
4.
Patie nts w h o ha ve cli nicall y  si g nifica nt * re nal, car di o vasc ular (s uc h as b ut n ot li mite d t o 
u nsta ble isc he mic h eart disease, N Y H A Class III/I V left ve ntric ular fail ure, m y ocar dial 
i nfarcti o n), ne ur ol o gical, e n d ocri ne, i m m u n ol o gical, ps yc hiatric, gastr oi ntesti nal, or 
he mat ol o gical a b n or malities, w hic h c o ul d i nterfere wit h t he assess me nt of t he efficac y  a n d 
safety of t he st u d y treat me nt, or patie nts wit h u nc o ntr olle d T ype II dia betes.
* N ote: Cli nic ally si g nific a nt is defi ne d as a ny dise ase t h at, i n t he o pi ni o n of t he 
i nvesti g at or, w o ul d p ut t he s afety of t he p atie nt at risk t hr o u g h p artici p ati n g, or w hic h 
w o ul d affec t t he effic acy or s afety a n alysis if t he dise ase/c o n diti o n ex acer b ate d d uri n g t he 
st u dy, or w o ul d c o m pr o mise p atie nt c o m pli a nce or precl u de c o m pleti o n of t he st u dy. 
5.
S u perse de d as of a me n d me nt V 0 1
5a. Patie nts wit h a hist or y or c urre nt treat me nt f or he pati c disease i ncl u di n g b ut n ot 
li mite d t o ac ute he patitis, cirr h osis or he patic fail ure. 

Patie nts wit h sta ble c hr o nic he patitis ma y  be i ncl u de d i n t he st u d y b y a gree me nt wit h 
N o vartis Me dical E x pert o n a case -b y -case basis. 

A hist or y  of res ol ve d He patitis A is n ot e xcl usi o nar y. 

Patie nts wit h pr ot hr o m bi n ti me i nter nati o nal n or malize d rati o ( P T/I N R) of m ore t ha n 
1. 5 x U L N at scree ni n g. Patie nts e xcl u de d f or t he P T/I N R of m ore t ha n 1. 5 x U L N ca n 
be re -scree ne d w he n t he val ues ha ve ret ur ne d t o n or mal.  
6.
Patie nts wi t h a hist or y of mali g na nc y of a ny or ga n s y ste m, treate d or u ntreate d, wit hi n t he 
past 5 y ears w het her or n ot t here is e vi de nce of l ocal rec urre nce or metastases, wit h t he 
e xce pti o n of l ocalize d basal cell carci n o ma of t he s ki n. Patie nts wit h a hist or y of c a ncer 
a n d 5 years or m ore disease free s ur vi val ti me ma y  be i ncl u de d i n t he st u d y b y a gree me nt 
wit h N o vartis Me dical E x pert o n a case -b y -case basis.
7.
Patie nts w h o de vel o p a C O P D e xacer bati o n t hat re q uire d treat me nt wit h a nti bi otics a n d/ or 
oral c ortic oster oi ds a n d/ or h os pitalizati o n d uri n g scree ni n g. Re -scree ni n g is per mitte d 
after a mi ni m u m of 2 wee ks after t he res ol uti o n of t he C O P D e xacer bati o n (i.e. 2 wee ks 
after t he st o p of S O C t hera p y f or e xacer bati o n).
8.
Patie nts w h o ha ve ha d a res pirat or y  tract i nfecti o n wit hi n 4 wee ks pri or t o scree ni n g. If a 
res pirat or y tract i nfecti o n occ urs d uri n g scree ni n g, patie nts ca n be re-scree ne d after a 
mi ni m u m of 2 wee ks after res ol uti o n of t he res pirat or y  tract i nfecti o n.
9.
Patie nts wit h hist or y  of ast h ma or a n y ot her cli nicall y rele va nt l u n g diseases.
1 0. Patie nts wit h s us pecte d acti ve p ul m o nar y  t u berc ul osis or c urre ntly bei n g treat me nt f or 
acti ve p ul m o nar y t u berc ul osis.
C
 
 


N o v arti s
C o nfi d e nti al
P a g e 4 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
N ote: P atie nts wit h a hist ory of p ul m o n ary t u berc ul osis c a n be e nr olle d if t hey meet t he 
f oll o wi n g re q uire me nts: hist ory of a p pr o pri ate dr u g tre at me nt f oll o we d by ne g ative 
i m a gi n g res ults wit hi n 1 2 m o nt hs pri or t o scree ni n g s u g gesti n g l o w pr o b a bility of 
rec urre nt active t u berc ul osis.
1 1. Patie nts wit h p ul m o nar y  l o bect o m y, l u n g v ol u me re d ucti o n s ur ger y, br onc h osc o pic l u n g 
v ol u me re d ucti o ns, or l u n g tra ns pla ntati o n.
1 2. Patie nts partici pati n g i n or pla n ni n g t o partici pate i n t he acti ve p hase of a s u per vise d 
p ul m o nar y  re ha bilitati o n pr o gra m d uri n g t he trial. Partici pati o n i n a mai nte na nce pr o gra m 
is per mitte d. N ote: t he s u per vise d p ul m o nar y re ha bilitati o n pr o gra m as a mai nte na nce 
pr o gra m has t o be o n g oi n g f or at least 3 m o nt hs at t he ti me of e nr oll me nt.
1 3. Patie nts wit h a b o d y  mass i n de x ( B MI) of m ore t ha n 4 0 k g/ m2.
1 4. Patie nts recei vi n g a n y m e dicati o ns i n t he classes li ste d i n Ta ble 6- 5 .
1 5. Patie nts recei vi n g a n y C O P D relate d me dicati o ns i n t he classes s pecifie d i n Ta ble 6- 6 , 
u nless t he y  u n der g o t he re q uire d was h o ut peri o d pri or t o scree ni n g a n d f oll o w t he 
a dj ust me nt t o treat me nt pr o gra m.
1 6. Patie nts recei vi n g me dicati o ns i n t he classes liste d i n Ta ble 6- 2 s h o ul d be e xcl u de d u nless 
t he me dicati o n has bee n sta bilize d f or t he s pecifie d peri o d a n d t he state d c o n diti o ns ha ve 
bee n met.
1 7. Use of ot he r i n vesti gati o nal dr u gs (a p pr o ve d or u na p pr o ve d) wit hi n 3 0 da ys or 5 half-li ves 
pri or t o scree ni n g, or u ntil t he e x pecte d p har mac o d y na mic effect has ret ur ne d t o baseli ne 
(e. g., bi ol o gics), w hic he ver is l o n ger; or l o n ger if re q uire d by l ocal re g ulati o ns.
1 8. Pr e g na nt or n ursi n g (lactati n g) w o me n, w here pre g na nc y  was defi ne d as t he state of a 
fe male after c o nce pti o n a n d u ntil t he ter mi nati o n of gestati o n, c o nfir me d by a p ositi ve 
h u ma n c h ori o nic g o na d otr o pi n ( h C G) la b orat or y test.
1 9. W o me n of c hil d -beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of 
bec o mi n g pre g na nt, u nless t he y are usi n g acce pta ble effecti ve met h o ds of c o ntrace pti o n 
d uri n g st u d y partici pati o n. Acce pta ble effecti ve c o ntrace pti o n met h o ds i ncl u de:

T otal a bsti ne nce ( w he n t his is i n li ne w it h t he preferre d a n d us ual lifestyl e of t he 
s u bject). Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s ym pt ot her mal, p ost o v ulati o n 
met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.

Fe male sterilizati o n ( ha ve ha d s ur gical bilateral o o p h o rect o my wit h or wit h o ut 
h y sterect o my), t otal h ys terect o my or bilateral t u bal li gati o n at least 6 wee ks bef ore 
ta ki n g i n vesti gati o nal dr u g. I n case of o o p h orect o m y al o ne, o nly w he n t he 
re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d b y f oll o w u p h or m o ne le vel 
assess me nt.

Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe male s u bjects o n t he 
st u d y, t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat s u bject

Barrier met h o ds of c o ntrace pti o n: c o n d o m or occl usi ve ca p ( dia p hra g m or 
cer vical/ va ult ca ps). F or t he U nite d Ki n g d o m of Great Britai n a n d N ort her n I sla n d 
( U K); wit h s per mici dal f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y.

Place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s ys te m (I U S).

N ote t hat s y ste mic h or m o nal c o ntrace pti o n (e. g. oral c o ntrace pti o n or h or m o ne 
va gi nal ri n g) is n ot a n acce pta ble mea ns of c o ntrace pti o n d ue t o p ote ntial i nfl ue nce of 


N o v arti s
C o nfi d e nti al
P a g e 4 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Q B W 2 5 1 i n decreasi n g t he s y ste mic le vels of t hese h or m o nes a n d t heref ore ma ki n g 
t he m i neffecti ve (see Secti o n 6. 2. 1. 2 )

If l ocal re g ulati o ns de viate fr o m t he c o ntrace pti o n met h o ds liste d a b o ve t o pre ve nt 
pre g na nc y , l ocal re g ulati o ns a p pl y a n d will be descri be d i n t he I C F.
W o me n are c o nsi dere d p ost -me n o pa usal a n d n ot of c hil d beari n g p ote ntial i f t he y ha ve 
ha d 1 2 m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical pr ofile 
(e. g. a ge a p pr o priate hist or y of vas o m ot or sy m pt o ms) or ha ve ha d s ur gical bilateral 
o o p h orect o m y ( wit h or wit h o ut h y sterect o m y), t otal h ysterect o my or t u bal li gati o n at least 
6 wee ks a g o. I n t he case of o o p h orect o my al o ne, o nl y  w he n t he re pr o d ucti ve stat us of t he 
w o ma n has bee n c o nfir me d b y  f oll o w u p h or m o ne le vel assess me nt is s he c o nsi dere d n ot 
of c hil d beari n g p ote ntial.
2 0. Patie nts w h o ha ve n ot ac hie ve d a n ac ce pta ble s pir o metr y res ult at scree ni n g i n acc or da nce 
wit h A merica n T h oracic S ociet y  ( A T S)/ E ur o pea n Res pirat or y S ociety ( E R S) criteria f or 
acce pta bilit y a n d re peata bilit y (refer t o t he S O M a n d ve n d or ma n ual f or S pir o metr y 
G ui da nce).
N ote: o ne re -test m ay be perf or me d i n p atie nts t h at d o n ot meet t he A T S/ E R S criteri a. 
P atie nts w h o h ave f aile d t he test a n d re- test d uri n g scree ni n g peri o d m ay be re-scree ne d 
o nly o nce.
6
Tr e at m e nt
6. 1
St u d y tr e at m e nt
T he st u d y  treat me nt i ncl u des:

I n vesti gati o nal dr u g Q B W 2 5 1 d ose of 3 0 0 m g b.i. d.

Matc hi n g place b o
Details o n t he re q uire me nts f or st ora ge a n d ma na ge me nt of st u d y treat me nt, a n d i nstr ucti o ns t o 
be f oll o we d f or s u bject n u m beri n g, prescri bi n g/ dis pe nsi n g, a n d ta ki n g st u d y treat me nt are 
o utli ne d i n t he S O M.
Refer t o t he Secti o n 6. 2. 4. 1 f or details of d osi n g a n d f o o d i nta ke. 
6. 1. 1
I n v e sti g ati o n al a n d c o ntr ol dr u g s
T a bl e 6- 1
I n v e sti g ati o n al a n d c o ntr ol dr u g s
I n v e sti g ati o n al/ 
C o ntr ol Dr u g
( N a m e a n d 
Str e n gt h)
P h ar m a c e uti c al 
D o s a g e F or m
R o ut e of 
A d mi ni str ati o n
S u p pl y t y p e
S p o n s or ( gl o b al 
or l o c al)
Q B W 2 5 1 3 0 0 m g 
b.i. d
C a p s ul e 1
Or al u s e
D o u bl e -bli n d 
s u p pl y; b ottl e s
N o v arti s P h ar m a 
A G
Q B W 2 5 1 Pl a c e b o 
b.i. d.
C a p s ul e 1
Or al u s e
D o u bl e -bli n d 
s u p pl y; b ottl e s
N o v arti s P h ar m a 
A G


N o v arti s
C o nfi d e nti al
P a g e 4 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
All c a p s ul e s ar e of i d e nti c al a p p e ar a n c e t o e n s ur e bli n di n g
1 Q B W 2 5 1 fi n al p h ar m a c e uti c al d o s a g e f or m i s a H ar d G el ati n C a p s ul e T a b c o nt e nt t o m ai nt ai n 
d o u bl e -bli n d
6. 1. 2
A d diti o n al st u d y tr e at m e nt s
B a c k gr o u n d t h er a p y
I n or der t o be eli gi ble f or t his trial, all s u bjects will be re q uire d t o ha ve bee n o n a sta ble 
bac k gr o u n d t hera p y re gi me n ( L A B A/ L A M A or L A B A/I C S or L A B A/ L A M A/I C S) a n d/ or 
macr oli des f or at least 3 m o nt hs pri or t o scree ni n g. Fr o m scree ni n g o n war ds, s u bjects will 
c o nti n ue wit h t heir bac k gr o u n d t hera p y u ntil e n d of st u d y  visit.
Bac k gr o u n d t hera p y will be ta ke n i n t he m or ni n g a p pr o xi matel y  bet wee n 7 a n d 1 0 a m f or o nce 
dail y  dr u gs a n d, i n a d diti o n t o t he m or ni n g use, a p pr o xi matel y 1 2 h o urs later i n t he e ve ni n g i n 
case of t wice dail y dr u gs. 
Refer t o Ta ble 6- 6 re gar di n g bac k gr o u n d t hera py p ri or t o s pir o metr y assess me nts o n visit da ys.
R e s c u e m e di c ati o n
All s u bjects will be pr o vi de d wit h a s h ort-acti n g beta a g o nist (sal b uta m ol 1 0 0 μ g or al b uter ol 
9 0 μ g or e q ui vale nt d ose). S u bjects will be i nstr ucte d t o use it t hr o u g h o ut t he st u d y on a n as 
nee de d basis. N o ot her resc ue me dicati o n is per mitte d d uri n g t he st u d y. Resc ue me dicati o n will 
be s o urce d l ocall y. ( See Secti o n 6. 2. 3 f or resc ue me dicati o n f urt her i nf or mati o n.)
Sites will be i nstr ucte d t o rec or d t he bac k gr o u n d t hera py i nf or mati o n a n d resc ue me dicati o ns 
i n t he c orres p o n di n g e C R F pa ges.
6. 1. 3
Tr e at m e nt ar m s/ gr o u p
O n Da y  1, s u bjects will be ra n d o mize d t o o ne of t he f oll o wi n g 2 treat me nt ar ms i n a rati o of 1: 1

Q B W 2 5 1 3 0 0 m g b.i. d.

Matc hi n g place b o t o Q B W 2 5 1 b.i. d.
All s u bjects will recei ve t heir res pecti ve Q B W 2 5 1 or place b o ca ps ules f or 1 2 wee ks (fr o m 
D a y 1 t hr o u g h Da y  8 4).
6. 2
Ot h er tr e at m e nt( s)
6. 2. 1
C o n c o mit a nt t h er a p y
All me dicati o ns, pr oce d ures a n d si g nifica nt n o n- dr u g t hera pies a d mi nistere d after t he s u bject 
was e nr olle d i nt o t he st u d y must be rec or de d i n t he c o nc o mita nt me dicati o ns/si g nifica nt 
n o n- dr u g t hera pies or pr oce d ures e C R F pa ge.
Eac h c onc o mita nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bite d 
me dicati o n. Please n ote t hat t he lists pr o vi de d bel o w ma y  not be e x ha usti ve. If i n d o u bt, t he 
i n vesti gat or s h o ul d c o ntact t he N o vartis Me dical 
E x pert bef ore ra n d o mizi n g a s u bject or 


N o v arti s
C o nfi d e nti al
P a g e 4 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
all o wi n g a ne w me dicati o n t o be starte d. If t he s u bject is alrea d y e nr olle d, c o ntact N o vartis t o 
deter mi ne if t he s u bject s h o ul d c o nti n ue partici pati o n i n t he st u d y .
6. 2. 1. 1
P er mitt e d c o n c o mit a nt t h er a p y  r e q uiri n g c a uti o n a n d/ or a cti o n
Ta ble 6- 2 pr o vi des a n o ver vie w of me dicati o ns per mitte d u n der certai n c o n diti o ns, i ncl u di n g 
br o nc h o dilat or me dicati o ns 
w hic h nee d t o be wit h hel d f or certai n ti mefra mes pri or t o 
s pir o metr y assess me nts o n visit da y s, a n d a n o ver vie w re gar di n g acti o ns t o be ta ke n f or 
a nti bi otics.
T a bl e 6- 2
M e di c ati o n s p er mitt e d u n d er c ert ai n c o n diti o n s
R ati o n al e/ Gr o u p
M e di c ati o n
Pr o hi biti o n P eri o d
A cti o n T a k e n
C O P D m ai nt e n a n c e 
b a c k gr o u n d t h er a p y
e. g. Vil a nt er ol, 
U m e cli di ni u m,
I n d a c at er ol
Gl y c o p yrr o ni u m
H ol d tr e at m e nt f or 2 4 
h o ur s ( +/ -2 h o ur s) pri or 
t o e a c h F E V1 / 
s pir o m etr y  
m e a s ur e m e nt o n vi sit 
d a y s f or o n c e d ail y 
i n h al e d b a c k gr o u n d 
t h er a p y a n d 1 2 h o ur s 
( +/-2 h o ur s) f or t wi c e 
d ai l y i n h al e d 
b a c k gr o u n d t h er a p y
I n c a s e t h e w a s h o ut 
crit eri o n i s n ot f ulfill e d, 
r e s c h e d ul e s pir o m etr y 
a c c or di n gl y. Tr o u g h 
s pir o m etr y  (-4 5 mi n a n d -
1 5 mi n a s s e s s m e nt s) 
s h o ul d b e d o n e wit hi n 2 4 
h o ur s f or o n c e d ail y 
i n h al e d b a c k gr o u n d 
t h er a p y s u c h a s 
L A B A/ L A M A or L A B A/I C S 
or L A B A/ L A M A/I C S fr o m 
d o si n g o n t h e pr e vi o u s 
m o r ni n g a n d 
a p pr o xi m at el y 1 2 h o ur s 
f or t wi c e d ail y 
L A B A/ L A M A or L A B A/I C S 
or L A B A/ L A M A/I C S fr o m 
d o si n g o n t h e pr e vi o u s 
e v e ni n g. Ot h er wi s e, 
p o st p o n e vi sit t o t h e n e xt 
d a y w h er e w a s h o ut 
crit eri a c a n b e f ulfill e d
R e s c u e m e di c ati o n 
o nl y
S h ort -A cti n g B et a -2 
A g o ni st s ( S A B A)
H ol d tr e at m e nt at l e a st 6 
h o ur s pri or t o e a c h 
F E V 1 / s pir o m etr y 
m e a s ur e m e nt
If p o s si bl e, p o st p o n e 
s pir o m etr y  m e a s ur e m e nt 
o n t h e s a m e d a y u ntil t h e 
w a s h o ut crit eri o n i s 
f ulfill e d. Tr o u g h 
s p ir o m etr y (-4 5 mi n a n d -
1 5 mi n a s s e s s m e nt s) 
s h o ul d b e d o n e wit hi n 
6 h o ur s aft er l a st r e s c u e 
m e di c ati o n i nt a k e
A nti bi oti c s f or 
tr e at m e nt of 
e x a c er b ati o n s a n d 
m a cr oli d e s a s 
b a c k gr o u n d 
m e di c ati o n
A nti bi oti c s, e. g. 
a m o xi cilli n
M a cr oli d e s, e. g. 
er y t hr o my c i n
S y st e mi c a n d/ or i n h al e d 
a nti bi oti c s ar e all o w e d 
f or tr e at m e nt of a c ut e 
i nf e cti o n s, or ar e 
all o w e d f or t h e 
tr e at m e nt of a c ut e 
e x a c er b ati o n s. 
All d at a will b e s et t o 
mi s si n g d uri n g t h e 
e x a c er b ati o n ti m e(ti m e of 
S o C i nt a k e) a n d f or 
1 4 d a y s t h er e aft er wit h 
t h e e x c e pti o n of 
m a cr oli d e s f or t h o s e 


N o v arti s
C o nfi d e nti al
P a g e 4 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
R ati o n al e/ Gr o u p
M e di c ati o n
Pr o hi biti o n P eri o d
A cti o n T a k e n
P er m a n e nt pr o p h yl a cti c 
tr e at m e nt f or ot h er 
i n di c ati o n s ar e n ot 
all o w e d - wit h t h e 
e x c e pti o n of m a cr oli d e s 
f or C O P D s u bj e ct s wit h 
s e c o n d ar y di a g n o si s of 
br o n c hi e ct a si s if t h o s e 
s u bj e ct s ar e o n st a bl e 
d o s e s of m a cr oli d e s at 
l e a st 3 m o nt h s b ef or e 
s cr e e ni n g a n d 
t hr o u g h o ut t h e st u d y.
T o pi c al tr e at m e nt ( e. g. 
u s e of i ntr a o c ul ar, 
i ntr a c o nj u n cti v al 
a nti bi oti c tr e at m e nt s, 
t o pi c al u s e of cr e a m s, 
et c.) i s p er mitt e d.
C O P D s u bj e ct s wit h a 
s e c o n d ar y di a g n o si s of 
br o n c hi e ct a si s a n d o n 
st a b l e d o s e of m a cr oli d e s 
f or t hr e e m o nt h s b ef or e 
s cr e e ni n g.
Q B W 2 5 1 ma y  in hi bit t he meta b olic cleara nce of c o-me dicati o ns meta b olize d b y  CY P 1 A 2. I n 
a d diti o n, Q B W 2 5 1 is a ti me-de pe n de nt i n hi bit or a n d i n d ucer of C Y P 3 A 4/ 5. Dr u gs t hat are 
se nsiti ve s u bstrates of C Y P 1 A 2 ha ve p ote ntial f or a n i ncrease i n e x p os ure wit h Q B W 2 5 1 d ue 
t o i n hi biti o n of C Y P 1 A 2. T he net effect of Q B W 2 5 1 o n C Y P 3 A 4 is a ntici pate d t o be i n d ucti o n 
base d o n res ults of a n oral c o ntrace pti ve st u d y res ulti n g i n a decrease i n e x p os ure.
Wea k i n vitr o i n hi biti o n of B C R P, O A T 1/ 3, O A T P 1 B 1, O A T P 1 B 3, U G T 1 A 1 a n d U G T 2 B 7 
was als o o bser ve d. Q B W 2 5 1 ma y  increase t he e x p os ure of dr u gs w hic h are s u bstrates of t he 
me nti o ne d pat h wa y s.
T hese dr u gs are liste d i n Ta ble 6- 3 a n d ca n be use d w he n i n dicate d a n d n o alter nati ve treat me nt 
is a vaila ble. Safety a n d efficac y of dr u g s h o ul d be m o nit ore d acc or di n gly.
T he f oll o wi n g lists are n ot c o nsi dere d e x ha usti ve a n d la bels f or i n di vi d ual dr u gs s h o ul d b e 
referre d t o.
T a bl e 6 - 3
M e di c ati o n s w hi c h m a y b e c o -a d mi ni st er e d wit h Q B W 2 5 1 (if n o 
alt er n ati v e tr e at m e nt i s a v ail a bl e)
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 4 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 4 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
6. 2. 1. 2
S y st e mi c c o ntr a c e pti v e s
S y ste mic c o ntrace pti ves s uc h as t h ose liste d i n Ta ble 6- 4 are n ot a n acce pta ble mea ns of 
c o ntrace pti o n (refer als o t o defi niti o n of acce pta ble effecti ve c o ntrace pti o n i n Secti o n 5. 2 ), 
si nce t hese dr u gs ma y be i neffecti ve d ue t o decrease d e x p os ure i n c o m bi nati o n wit h Q B W 2 5 1 
a n d res ult i n c o ntrace pti ve fail ure. T hese dr u gs m a y  be ta ke n f or ot her i n dicati o ns 
(e. g., oste o p or osis pr o p h yla xis); t he efficac y of t he treat me nt ma y be i m paire d b y l o w s ys te mic 
a vaila bilit y, t h o u g h, a n d s h o ul d be m o nit ore d.
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 5 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T a bl e 6- 4
E x a m pl e s of c o ntr a c e pti v e s n ot r e c o m m e n d e d f or s y st e mi c u s e a s 
a c c e pt a bl e m e a n s of c o ntr a c e pti o n a s effi c a c y  m a y  b e c o m pr o mi s e d 
b y  Q B W 2 5 1 a d mi ni str ati o n.
M e di c ati o n
P eri o d d uri n g w hi c h 
c o ntr a c e pti v e eff e ct m a y b e 
c o m pr o mi s e d
A cti o n t a k e n
Dr o s pir e n o n e
Et hi n yl e str a di ol
Et o n o g e str el
L e v o n or g e str el
M e dr o x y pr o g e st er o n e a c et at e
N or el g e str o mi n
N or et hi n dr o n e
N or g e sti m at e
N or g e str el
U s e of t h e s e dr u g s i s n ot 
pr o hi bit e d, b ut i n c o m bi n ati o n 
wit h Q B W 2 5 1 t h e s e m a y  n o 
l o n g er c o n stit ut e m e a n s of 
c o ntr a c e pti o n, a n d t h u s t h eir 
u s e d o e s n ot f ulfill t h e 
r e q uir e m e nt s of c o ntr a c e pti o n 
sti p ul at e d i n t h e e x cl u si o n 
crit eri a ( ri s k of c o ntr a c e pti v e 
f ail ur e). s u bj e ct i s at ri s k t o 
e x p eri e n c e a pr e g n a n c y d u e t o 
t h e i nt er a cti o n b et w e e n 
s y st e mi c c o ntr a c e pti v e a n d 
Q B W 2 5 1.
A v oi d c o n c urr e nt 
a d m i ni str ati o n; f or alt er n ati v e 
m e t h o d s of c o ntr a c e pti o n r ef er 
t o S e cti o n 5. 2
6. 2. 2
Pr o hi bit e d m e di c ati o n
Use of t he treat me nts dis pla y e d i n t he bel o w ta ble is N O T all o we d after t he o nset of t he 
pr o hi biti o n peri o d as i n dicate d i n Ta ble 6- 5 a n d Ta ble 6- 6 . S h o ul d a d mi nistrati o n of o ne of 
t hese dr u gs d uri n g t he c o urse of t he treat me nt e p oc h be re q uire d, st u d y treat me nt s h o ul d b e 
disc o nti n ue d. 
T a bl e 6- 5
Pr o hi bit e d m e di c ati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 5 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T a bl e 6- 6
Pr o hi bit e d C O P D -r el at e d m e di c ati o n s a n d w a s h o ut p eri o d pri or t o 
D a y 1
6. 2. 3
R e s c u e m e di c ati o n
At scree ni n g a n d w he ne ver n ee de d t hereafter, s u bjects will be pr o vi de d wit h a s h ort-acti n g beta 
a g o nist (sal b uta m ol 1 0 0 μ g or al b uter ol 9 0 μ g) i n haler t o use as resc ue me dicati o n o n a n as 
nee de d basis t hr o u g h o ut t he st u d y . N o ot her resc ue me dicati o n is per mitte d.
T he resc ue me dicati o n sal b uta m ol/al b uter ol w hic h is pr o vi de d at scree ni n g f or use d uri n g t he 
st u d will be rec or de d o nce i n t he e C R F at t he be gi n ni n g of t he st u d y. T he resc ue me dicati o ns 
i nta ke s h o ul d n ot be rec or de d o n t he c o nc o mita nt pa ge of t he e C R F, resc ue me dicati o n i nta ke 
bei n g re gistere d i n t he e Diar y .
F or t he use of resc ue me dicati o n or f or t he w orse ni n g of C O P D s ym pt o ms a n d e xacer bati o ns, 
t he s u bject will be i nstr ucte d t o c o m plete t he resc ue me dicati o n i nf or mati o n i n t he e Diar y twice 
dail y  at t he sa me ti me i n t he m or ni n g a n d e ve ni n g, a p pr o xi matel y 12 h o urs a part ( n u m ber of 
p uffs ta ke n i n t he pre vi o us 1 2 h o urs). T his will be c o m plete d pri or t o ta ki n g t he st u d y dr u g.  For 
t he w orse ni n g of C O P D s ym pt o ms please refer t o Secti o n 6. 6. 2 .
T he e Diar y will als o tri g ger alerts t o b ot h t he s u bject a n d t he i n vesti gat or, w he n a n al g orit h m 
( please refer t o Secti o n 8. 4. 4 ) detects a deteri orati o n of s ym pt o ms c o m pati ble wit h a n 
e xacer bati o n. T he i n vesti gat or will pr o vi de t he s u bject wit h writte n i nstr ucti o ns o n h o w t o 
c o ntact t he ce nter if s y m pt o ms of C O P D w orse n.
T he resc ue me dicati o n will be pr o vi de d b y  t he st u d y ce nter a n d rei m b urse d b y N o vartis.
6. 2. 4
R e stri cti o n f or st u d y  s u bj e ct s
F or t he d urati o n of t he st u d y, s u bjects s h o ul d be i nf or me d a n d re mi n de d of t he restricti o ns 
o utli ne d i n t his secti o n.
6. 2. 4. 1
Di et ar y  r e stri cti o n s a n d s m o ki n g
Di et ar y  r e stri cti o n s
T he f oll o wi n g are t he i nstr ucti o ns f or t he i n vesti gati o nal dr u g ( Q B W 2 5 1/ place b o):

it is rec o m me n de d n ot t o ta ke the i n vesti gati o nal dr u g t o get her wit h hi g h- fat meals (refer
t o t he S O M f or details). T he defi niti o n of hi g h-fat meals f oll o w t he defi niti o n s u g geste d
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 5 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
b y  F D A i n t he draft g ui da nce o n Assessi n g t he Effects of F o o d o n Dr u gs i n I N Ds a n d 
N D As ( F D A 2 0 1 9): a meal c o ntai ni n g at least 1 0 0 0 kcal ( 4 1 8 4 kJ), a n d at least 5 0 % of 
t hat e ner g y c o nte nt fr o m fat.
A n e xa m ple of a hi g h fat meal w o ul d be f or a t otal n utriti o nal e ner g y  val ue of 1 0 0 0 kcal:

of w hic h fr o m pr otei ns: 1 5 0 kcal

of w hic h fr o m car b o h y d rates: 2 5 0 kcal

of w hic h fr o m fats: 6 0 0 kcal.

S u bjects ca n dri n k water as nee de d.

S u bjects s h o ul d be i nstr ucte d n ot t o ta ke gra pefr uit, Se ville ora n ges or t heir j uice f or
1 4 da y s pri or t o d osi n g, d uri n g treat me nt a n d u ntil 7 da ys f oll o wi n g t he last d ose as t hese
pr o d ucts are c o nsi dere d i n hi bit ors of C Y P 3 A.
S m o ki n g
S u bjects will be stratif y  b y t heir s m o ki n g stat us (c urre nt or e x-s m o kers).
6. 2. 4. 2
Ot h er r e stri cti o n s
N ot a p plica ble.
6. 3
S u bj e ct n u m b eri n g, tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n
6. 3. 1
S u bj e ct n u m b eri n g
T he s u bject n u m ber assi g ne d t o a s u bject at scree ni n g re mai ns t he u ni q ue i de ntifier f or t he 
s u bject t hr o u g h o ut t he st u d y. F or i nf or mati o n o n s u bject n u m beri n g, please see t he ‘ S u bject 
n u m beri n g’ secti o n i n t he S O M
6. 3. 2
Tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n
U p o n si g ni n g t he i nf or me d c o nse nt f or m, t he s u bject will be assi g ne d t he ne xt se q ue ntial 
n u m ber b y  the i n vesti gat or. T he i n vesti gat or or his/ her staff will c o ntact I R T a n d pr o vi de t he 
re q ueste d i de ntif yi n g i nf or mati o n f or t he s u bject t o re gister t he m i nt o t he I nteracti ve Res p o nse 
Tec h n ol o g y  (IR T).
At D a y  1, all eli gi ble s u bjects will be ra n d o mize d via I RT t o o ne of t he treat me nt ar ms. 
Ra n d o mizati o n will be stratifie d b y s m o ki n g stat us (c urre nt or e x -s m o ker).
T he i n vesti gat or or his/ her dele gate will c o ntact IR T after c o nfir mi n g t hat t he s u bject f ulfills all 
t he i ncl usi o n/e xcl usi o n criteria. I RT will assi g n a ra n d o mizati o n n u m ber t o t he s u bject, w hic h 
will be use d t o li n k t he s u bject t o a treat me nt ar m a n d will s pecif y  a u ni q ue me dicati o n n u m ber 
f or t he first pac ka ge of i n vesti gati o nal treat me nt t o be dis pe nse d t o t he s u bject. 
T he ra n d o mizati o n n u m ber will n ot be c o m m u nicate d t o t he site pers o n nel, b ut will be use d by 
t he IR T s yste m. T he s u bject will retai n t he s u bject n u m ber t hr o u g h o ut t he st u d y as t heir u ni q ue 
i de ntifier. If t he s u bject fails t o be treate d f or a n y reas o n, t he I R T s h o ul d be n otifie d wit hi n 
2 da y s t hat t he s u bject was n ot treate d, a n d t he reas o n will be e ntere d i nt o t he e C R F.


N o v arti s
C o nfi d e nti al
P a g e 5 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T he ra n d o mizati o n n u m bers will be ge nerate d usi n g t he f oll o wi n g pr oce d ure t o e ns ure t hat 
treat me nt assi g n ment is u n biase d a n d c o nceale d fr o m s u bjects a n d i n vesti gat or staff. A s u bject 
ra n d o mizati o n list will be pr o d uce d b y  the I RT pr o vi der usi n g a vali date d s yste m t hat a ut o mates 
t he ra n d o m assi g n me nt of s u bject n u m bers t o ra n d o mizati o n n u m bers. T hese ra n d o mizati o n 
n u m bers are li n ke d t o t he differe nt treat me nt ar ms, w hic h i n t ur n are li n ke d t o me dicati o n 
n u m bers. A se parate me dicati o n list will be pr o d uce d b y or u n der t he res p o nsi bilit y  of N o vartis 
Gl o bal Cli nical S u p pl y  ( G C S) usi n g a vali date d s yste m t hat a ut o mates t he ra n d o m assi g n me nt 
of me dicati o n n u m bers t o pac ks c o ntai ni n g t he st u d y  treat me nt.
T he ra n d o mizati o n sc he me f or s u bjects will be re vie we d a n d a p pr o ve d b y  a me m ber of t he 
Ra n d o mizati o n Office.
F oll o w t he details o utli ne d i n t he Site O perati o ns Ma n ual re gar di n g t he pr ocess a n d ti mi n g of 
treat me nt assi g n me nt a n d ra n d o mizati o n of s u bjects.
6. 4
Tr e at m e nt bli n di n g
S u bjects, i n vesti gat or staff, a n d site pers o n nel perf or mi n g t he assess me nts, will re mai n bli n de d 
t o t he treat me nt fr o m t he ti me of ra n d o mizati o n u nti l data base l oc k, usi n g t he f oll o wi n g 
met h o ds:
( 1) Ra n d o mizati o n data are ke pt strictl y co nfi de ntial u ntil t he ti me of u n bli n di n g, a n d will n ot
be accessi ble b y  an y o ne else i n v ol ve d i n t he st u d y wit h t he f oll o wi n g e xce pti o ns: statisticia n
a n d pr o gra m mer s u pp orti n g t he C Q B W 2 5 1 B 2 2 0 2 st u d y an d u p o n re q uest b y  the D M C f or st u d y
t o u n bli n d all t he D M C me m bers.
( 2) t he i de ntity of t he treat me nts will be c o nceale d b y  the use of st u d y treat me nt t hat are all
i de ntical i n pac ka gi n g, la beli n g, sc he d ule of a d mi nistrati on, a p peara nce, taste a n d o d or.
T he s p o ns or will re mai n bli n de d u ntil st u d y co m pleti o n e xce pt trial statisticia n a n d pr o gra m mer 
w h o will be res p o nsi ble f or i nteri m a nal ys es at a n y ti me f or efficac y an d safety. H o we ver, a n 
i n de pe n de nt statisticia n a n d i n de pe n de nt pr o gra m mer will be u n bli n de d t o s u p p ort all D M C 
re q uire me nts (see Secti o n 1 0. 2. 3 ).
U n bli n di n g t his st u d y to t he s p o ns or will o nl y  ha p pe n i n t he case of s u bject e mer ge ncies t hat 
will be dee me d necessar y b y  t he D M C t o e val uate t he safet y o ut c o me t o safe g uar d all s u bjects.
T he ra n d o mizati o n c o des ass ociate d wit h s u bjects fr o m w h o m P K sa m ples are ta ke n will b e 
discl ose d t o P K a nal y sts w h o will kee p P K res ults c o nfi de ntial u ntil data base l oc k.
U n bli n di n g a si n gle s u bject at site f or safet y reas o ns ( necessar y for s u bject ma na ge me nt) will 
occ ur via a n e mer ge nc y  s yste m i n place at t he site.
T a bl e 6 - 7
Bli n di n g L e v el s
R ol e 
Ti m e  or E v e nt 
R a n d o mi z ati o n 
li st g e n er at e d
Tr e at m e nt 
all o c ati o n a n d 
d o si n g
S af et y e v e nt 
( si n gl e s u bj e ct 
u n bli n d e d)
I nt eri m A n al y si s 
& D M C p ur p o s e s 
S u bj e ct s
B
B
UI
B
Sit e st aff
B
B
UI
B


N o v arti s
C o nfi d e nti al
P a g e 5 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Dr u g S u p pl y a n d 
R a n d o mi z ati o n 
Offi c e
UI
UI
UI
U
U n bli n d e d 
s p o n s or st aff ( s e e 
t e xt f or d et ail s)
B
UI
UI
U
St ati sti ci a n / 
St ati sti c al 
Pr o gr a m m er / 
D at a A n al y st s
B
B
UI
U
I n d e p e n d e nt 
C o m mitt e e u s e d 
f or a s s e s si n g 
i nt eri m r e s ult s
B
B
UI
B*
All ot h er s p o n s or 
st aff n ot i d e ntifi e d 
a b o v e 
B
B
UI
B
B R e m ai n s bli n d e d
B* R e m ai n s bli n d e d u nl e s s s af et y a n d/ or e x p o s ur e c o n c er n s
UI All o w e d t o b e u n bli n d e d o n i n di vi d u al s u bj e ct l e v el
U R e m ai n s u n bli n d e d 
6. 5
D o s e e s c al ati o n a n d d o s e m o difi c ati o n
I n vesti gati o nal treat me nt d ose a dj ust me nts are per mitte d u n der s pecific circ u msta nces 
descri be d i n Secti o n 6. 5. 1 a n d Secti o n 6. 5. 1. 2 . Te m p orar y  dose i nterr u pti o ns are per mitte d 
u n der s pecific circ u msta nces descri be d i n Secti o n 6. 5. 1 .
6. 5. 1
D o s e i nt err u pti o n s
St u d y  dr u g i nterr u pti o ns are n ot per mitte d u nless t he i n vesti gat or c o nsi ders a te m p orar y 
i nterr u pti o n is necessar y f or t he treat me nt of a n a d verse e ve nt. If t he a d verse e ve nt gra de is 
se vere a n d s us pecte d t o be relate d t o t he i n vesti gati o nal st u d y dr u g t he i n vesti gati o nal st u d y 
dr u g s h o ul d be per ma ne ntl y  disc o nti n ue d as descri be d i n Secti o n 9. 1. 1 .
A n y  interr u pti o n of st u d y me dicati o n d uri n g t he treat me nt of a n A E f or m ore t ha n 5 c o nsec uti ve 
da y s d uri n g t he treat me nt peri od s h o ul d be disc usse d wit h t he l ocal N o vartis Me dical E x pert t o 
re vie w t he s u bject’s eli gi bilit y t o c o nti n ue i n t he trial.
T he st u d y dr u g d ose i nterr u pti o ns m ust be rec or de d i n t he D osa ge A d mi nistrati o n Rec or d e C R F.
6. 5. 1. 1
D o s e m o difi c ati o n s
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 5 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
6. 5. 1. 2
Q T c F pr ol o n g ati o n
I n case of Q Tc F > 5 0 0 msec ( or Q Tc F pr ol o n gati o n > 6 0 mse c fr o m baseli ne/ Da y  1):

Assess t he q ualit y  of t he E C G rec or di n g a n d t he Q T val ue a n d re peat, if nee de d

I nterr u pt st u dy i n vesti gati o nal treat me nt

Deter mi ne t he ser u m electr ol y te le vels (i n partic ular f or h y p o kale mia, h y p o ma g nese mia). 
If a b n or mal, c orrect a bn or malities.

C o nsi der c ollecti n g a ti me-matc he d P K sa m ple o n t hat visit (if n ot alrea d y  sc he d ule d per 
Ta ble 8- 1 ) a n d rec or d ti me a n d date of last st u d y treat me nt i nta ke.

If Q Tc F c o nfir me d by t he Ce ntral Rea di n g > 5 0 0 msec: 
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 5 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

Per ma ne ntl y  disc o nti n ue t he st u d y treat me nt (see Secti o n 9. 1 ).

Ta ke a bl o o d sa m ple f or P K a nal y sis. Ti me p oi nt s h o ul d be as cl ose as p ossi ble t o t he 
E C G rec or di n g i n q uesti o n

C o ns ult wit h a car di ol o gist ( or q ualifie d s pecialist)

I ncrease car diac m o nit ori n g as i n dicate d, u ntil t he Q Tc F ret ur ns t o ≤ 4 8 0 msec

Re vie w c o nc o mita nt me dicati o n use f or ot her ca uses f or Q T pr ol o n gati o n (refer t o 
htt p:// w w w. qt dr u gs. or g f or k n o w n Q T pr ol o n gi n g dr u gs), a n d f or dr u gs wit h t he 
p ote ntial t o i ncre ase t he ris k of dr u g e x p os ure relate d Q T pr ol o n gati o n

C hec k t he d osi n g sc he d ule a n d treat me nt c o m plia nce
6. 6
A d diti o n al tr e at m e nt g ui d a n c e
6. 6. 1
Tr e at m e nt c o m pli a n c e
St u d y  dr u g c o m plia nce s h o ul d be assesse d b y  the i n vesti gat or a n d/ or ce nter pers o n nel at all 
visits b y verif y i n g s u bjects' e Diar y. T he I n vesti gat or or desi g nee will c ollect fr o m t he s u bject 
t he use d / u n use d i n vesti gati o nal st u d y dr u g a n d pac ka gi n g at eac h visit a n d at t he E n d of 
Treat me nt ( D a y 84). St u d y  dr u g c o m plia nce will be assesse d fr o m t he ca ps ule c o u nt 
( u n use d me dicati o n) a n d fr o m i nf or mati o n pr o vi de d b y  the s u bject a n d/ or care gi ver i n t he 
e Diar y. T he t otal n u m ber of d oses of i n vesti gati o nal treat me nt a d mi nistere d s h o ul d be ca pt ure d 
i n t he s o urce d oc u me ntati o n, a n d t he start a n d e n d date of i n vestigati o nal st u d y dru g, a n d a n y 
misse d d oses, deri ve d fr o m e Diar y , will be rec or de d o n t he e C R F.
T he n u m ber of p uffs of resc ue me dicati o n i n hale d will be rec or de d t wice dail y  b y the s u bject 
i n t he e Diar y. At scree ni n g, s u bjects will be pr o vi de d wit h t he e Diar y an d t he use of resc ue 
me dicati o n will be disc usse d. T he use of st u d y me dicati o n a n d resc ue me dicati o n will be 
re vie we d at eac h visit a n d data fr o m t he e Diary d o w nl oa de d at eac h visit. W here necessar y, t he 
I n vesti gat or will disc uss c o m plia nce/ d oc u me ntati o n iss ues re gar di n g st u d y dr u g a n d ot her 
me dicati o ns use wit h t he s u bject.
T he C O P D mai nte na nce bac k gr o u n d t hera p y co m plia nce will als o be m o nit ore d at all visits a n d 
i nf or mati o n ca pt ure d i n t he s o urce d oc u me nts at site. I nf or mati o n o n t he start da te, e n d date a n d 
i nterr u pti o ns of m ore t ha n t hree d a y s m ust be ca pt ure d i n t he e C R F. A n y c o m plia nce iss ues 
m ust be disc usse d wit h t he s u bject.
T he i n vesti gat or m ust pr o m ote c o m plia nce b y  instr ucti n g t he s u bject t o ta ke t he st u d y 
treat me nt as prescri be d a nd b y stati n g t hat c o m plia nce is necessar y f or t he s u bject’s safet y a n d 
t he vali dit y  of t he st u d y. T he s u bject m ust als o be i nstr ucte d t o c o ntact t he i n vesti gat or if he/s he 
is u na ble f or a ny reas o n t o ta ke t he st u d y treat me nt as prescri be d. 
6. 6. 2
R e c o m m e n d e d tr e at m e nt of a d v er s e e v e nt s
S u bjects i n t he st u d y ma y de vel o p s ym pt o ms t hat n or mall y  ap pear i n C O P D, h o we ver a n 
i ncrease i n fre q ue nc y an d se verity of t hese s ym pt o ms is n ot e x pecte d. If d uri n g t he st u d y 
s ym pt o ms occ ur t hat are se vere e n o u g h t o i nterfere wit h t he acti vities of dail y  li vi n g of t he 
s u bjects, t he y sh o ul d be treate d acc or di n g t o c urre nt cli nical practice. F or t he w orse ni n g of 
C O P D s ym pt o ms, a s h ort-acti n g beta - 2 a g o nist ( S A B A) is pr o vi de d as resc ue me dicati o n. Wit h 
res pect t o t he treat me nt of e xacer bati o ns, a s u g geste d t hera p y co nsists of 5 da y s of oral 


N o v arti s
C o nfi d e nti al
P a g e 5 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
pre d nis ol o ne ( or e q ui vale nt) 4 0 m g/ da y a n d/ or a n oral 7 da y c o urse of a m o xicilli n 5 0 0 m g t.i. d. 
(alter nati vely a m o xicilli n cla v ula nate 6 2 5 m g  t.i. d. or clarit hr o m yci n 5 0 0 m g b.i. d.), t h o u g h 
i n vestigat ors are free t o treat C O P D e xacer bati o ns acc or di n g t o t he me dical nee ds of t he 
s u bjects.
Me dicati o n use d t o treat a d verse e ve nts ( A Es) m ust be rec or de d i n t he e C R F.
6. 6. 3
E m er g e n c y  br e a ki n g of a s si g n e d tr e at m e nt c o d e
E mer ge nc y  co de brea ks m ust o nl y  be u n derta ke n w he n it is re q uire d t o i n or der t o treat t he 
s u bject safely. M ost ofte n, st u d y treat me nt disc o nti n uati o n a n d k n o wle d ge of t he p ossi ble 
treat me nt assi g n me nts are s ufficie nt t o treat a st u d y su bject w h o prese nts wit h a n e mer ge nc y 
c o n diti o n. E mer ge nc y  treat me nt c o de brea ks are perf or me d usi n g t he I R T. W he n 
t he 
i n vesti gat or c o ntacts t he s yste m t o brea k a treat me nt c o de f or a s u bject, he/s he m ust pr o vi de t he 
re q ueste d s u bject i de ntif yi n g i nf or mati o n a n d c o nfir m t he necessit y t o brea k t he treat me nt c o de 
f or the s u bject. T he i n vesti gat or will t he n recei ve details of t he i n vesti gati o nal dr u g treat me nt 
f or t he s pecifie d s u bject a n d a fa x or e mail c o nfir mi n g t his i nf or mati o n. T he s yste m will 
a ut o maticall y inf or m t he N o vartis m o nit or f or t he site a n d t he st u d y tea m t hat t he c o de has bee n 
br o ke n.
It is t he i n vesti gat or’s res p o nsi bilit y to e ns ure t hat t here is a de pe n da ble pr oce d ure i n place t o 
all o w access t o t he I R T at a n y ti me i n case of e mer ge nc y. T he i n vesti gat or will pr o vi de:

pr ot oc ol n u m ber

site n u m ber

s u bject n u m ber
I n a d diti o n, oral a n d writte n i nf or mati o n t o t he s u bject m ust be pr o vi de d o n h o w t o c o ntact 
his/ her bac k u p i n cases of e mer ge nc y, or w he n he/s he is u na vaila ble, t o e ns ure t hat u n -bli n di n g 
ca n be perf or me d at a n y t i me.
After e mer ge nc y un bli n di n g, t he s u bject will be per ma ne ntl y disc o nti n ue d fr o m t he st u d y 
i n vesti gati o nal treat me nt as descri be d i n Secti o n 9. 1. 1
6. 7
Pr e p ar ati o n a n d di s p e n s ati o n
Eac h st u d y site will be s u p plie d wit h i n vesti gati o nal st u d y dr u g i n pac ka gi n g as descri be d u n der 
i n vesti gati o nal a n d c o ntr ol dr u gs secti o n.
A u ni q ue me dicati o n n u m ber is pri nte d o n t he st u d y me dicati o n la bel.
I n vesti gat or staff will i de ntif y the st u d y me dicati o n kits t o dis pe nse t o t he s u bject b y  co ntacti n g 
t he I RT a n d o btai ni n g t he me dicati o n n u m ber(s). T he st u d y me dicati o n has a 2- part la bel 
( base pl us tear -off la bel). I mme diatel y bef ore dis pe nsi n g t he me dicati o n kit t o t he s u bject, site 
pers o n nel will detac h t he o uter part of t he la bel fr o m t he pac ka gi n g a n d affi x it t o t he s o urce 
d o c u me nt.
I n vesti gati o nal st u d y dr u g c o nsists of oral ca ps ules a n d n o pre parati o n pri or t o dis pe nsati o n is 
re q uire d.


N o v arti s
C o nfi d e nti al
P a g e 5 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Q B W 2 5 1 or place b o will be ta ke n orall y b y  the s u bject at h o me wit h t he e xce pti o n of t he 
f oll o wi n g visits: Da y 1, Da y 2 8, Da y 5 6 a n d Day 8 4 w h e n m or ni n g d ose dr u g i nta ke will occ ur 
at t he st u d y site.
O n t he d a y  of site visits wit h s pir o metr y assess me nts, i n vesti gat ors s h o ul d i nstr uct s u bjects t o 
ha ve site visits al wa ys at a p pr o xi matel y t he sa me ti me ( n o m ore t ha n t w o h o urs differe nt t o t he 
basel i ne visit).
See t he Site O perati o ns Ma n ual f or f urt her details.
6. 7. 1
I n str u cti o n of pr e s cri bi n g a n d t a ki n g st u d y m e di c ati o n
T he f oll o wi n g are t he i nstr ucti o ns f or t he i n vesti gati o nal dr u g ( Q B W 2 5 1/ place b o):

Q B W 2 5 1/ place b o is a n oral ca ps ule.

O ne ca ps ule s h o ul d be ta ke n t wice a da y  at a p pr o xi matel y t he sa me ti me eac h da y, wit h 
a b o ut 1 2 h o urs bet wee n eac h d ose a d mi nistrati o n (a p pr o xi matel y  i n t he m or ni n g bet wee n 
7 a n d 1 0 a. m. a n d i n t he e ve ni n g bet wee n 8 a n d 1 1 p. m.)

Refer t o Secti o n 6. 2. 4. 1 Dietar y  restricti o ns li n ke d t o Q B W 2 5 1 i nta ke.

If v o miti n g occ urs d uri n g t he c o urse of treat me nt, s u bjects s h o ul d be i nstr ucte d n ot t o ta ke 
t he st u d y dr u g a gai n bef ore t he ne xt sc he d ule d d ose.

S u bjects s h o ul d be i nstr ucte d n ot t o ma ke u p f or misse d d oses.

S u bjects s h o ul d be i nstr ucte d t o s wall o w w h ole ca ps ules a n d n ot t o c he w or o pe n t he m.

I nstr ucti o ns f or t he mai nte na nce treat me nt a n d resc ue me dicati o n s h o ul d be acc or di n g t o 
t he res pecti ve pr o d uct la bel.

O n st u d y  visit da ys, s u bjects s h o ul d be re mi n de d n ot t o ta ke eit her t he i n vesti gati o nal dr u g 
( Q B W 2 5 1/ place b o) or t he mai nte na nce t hera py d oses pri or t o t he site visit t o e ns ure 
c o m plia nce wit h t he pre- d ose P K sa m pli n g pr oce d ure a n d s pir o metr y  pre-d ose 
meas ure me nts. T he m or ni n g d ose o n t he vis it da ys s h o ul d be ta ke n after t he pre-d ose P K 
sa m pli n g a n d s pir o metr y assess me nts ha ve bee n c o m plete d, wit hi n 1 5 mi n a p pr o xi matel y.
Of n ote, s pir o metr y  o n visit da ys s hall be c o n d ucte d

1 0- 1 4 h o urs after t he last i nta ke of i n vesti gati o nal dr u g o n t he e ve ni n g bef ore f or b.i. d. 
dr u gs, a n d

2 2- 2 6 h o urs after t he last i n halati o n of dail y  mai nte na nce bac k gr o u n d me dicati o n o n t he 
m or ni n g bef ore o. d. dr u gs (see als o Secti o n 8. 3. 1 ).
7
I nf or m e d c o n s e nt pr o c e d ur e s
Eli gi ble s u bjects ma y  o nl y be i ncl u de d i n t he st u d y after pr o vi di n g ( wit nesse d, w here re q uire d 
b y  la w or re g ulati o n) IR B/I E C -a p pr o ve d i nf or me d c o nse nt.
If a p plica ble, i n cases w here t he s u bject's re prese ntati ve(s) gi ves c o nse nt (if all o we d acc or di n g 
t o l ocal re q uire me nts), t he s ubject m ust be i nf or me d a b o ut t he st u d y to t he e xte nt p ossi ble gi ve n 
his/ her u n dersta n di n g. If t he s u bject is ca pa ble of d oi n g s o, he/s he m ust i n dicate a gree me nt b y 
pers o nall y si g ni n g a n d dati n g t he writte n i nf or me d c o nse nt d oc u me nt.


N o v arti s
C o nfi d e nti al
P a g e 5 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n)
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
I nf or me d c o nse nt m ust b e o btai ne d bef ore c o n d ucti n g a n y s t u d y-s pecific pr oce d ures (e. g. all of 
t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be 
d oc u me nte d i n t he s u bject s o urce d oc u me nts.
N o vartis will pr o vi de t o i n vesti gat ors i n a se parate d oc u me nt a pr o p ose d i nf or me d c o nse nt f or m 
t hat c o m plies wit h t he I C H G C P g ui deli nes a n d re g ulat or y re q uire me nts a n d is c o nsi dere d 
a p pr o priate f or t his st u d y. A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g geste d b y  th e 
i n vesti gat or m ust be a gree d b y N o vartis bef ore s u b missi o n t o t he I R B/I E C.
I nf or mati o n a b o ut c o m m o n si de effects alrea d y k n o w n a b o ut t he i n vesti gati o nal dr u g ca n b e 
f o u n d i n t he I n vesti gat or's Br oc h ure (I B). T his i nf or mati o n will be i ncl u de d i n t he s u bject 
i nf or me d c o nse nt a n d s h o ul d be dis c usse d wit h t he s u bject d uri n g t he st u d y as nee de d. A n y n e w 
i nf or mati o n re gar di n g t he safety pr ofile of t he i n vesti gati o nal dr u g t hat is i de ntifie d bet wee n I B 
u p dates will be c o m m u nicate d as a p pr o priate, f or e xa m ple, via a n i n vesti gat or n otificati o n or 
a n a g gre gate safet y fi n di n g. Ne w i nf or mati o n mi g ht re q uire a n u p date t o t he i nf or me d c o nse nt 
a n d t he n m ust be disc usse d wit h t he s u bject.
W o me n of c hil d beari n g p ote ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y  in v ol ve 
u n k n o w n ris ks t o t he fet us if pre g na nc y  were t o occ ur d uri n g t he st u d y an d a gree t hat i n or der 
t o partici pate i n t he st u d y th e y  must a d here t o t he c o ntrace pti o n re q uire me nts. Male s u bjects 
m ust be i nf or me d t hat if a fe male part ner bec o mes pre g na nt w hile he is e nr olle d i n t he st u d y, 
c o ntact wit h t he fe male part ner will be atte m pte d t o re q uest her c o nse nt t o c ollect pre g na nc y 
o utc o me i nf or mati o n.
 
 
 
 
A c o p y o f t he a p pr o ve d versi o n of all c o nse nt f or ms m ust be pr o vi de d t o N o vartis/s p o ns or after 
I RB/I E C a p pr o val.
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8
Vi sit s c h e d ul e a n d a s s e s s m e nt s
Assess me nt sc he d ule (Ta ble 8- 1 ) lists all of t he assess me nts w he n t he y are perf or me d. All data o btai ne d fr o m t hese assess me nts m ust be 
s u p p orte d i n t he s u bject’s s o urce d oc u me ntati o n.
S u bjects s h o ul d be see n f or all visits/assess me nts as o utli ne d i n t he assess me nt sc he d ule ( Ta ble 8- 1 ) or as cl ose t o t he desi g nate d da y/ti me as 
p ossi ble. Misse d or resc he d ule d visits s h o ul d n ot lea d t o a ut o matic disc o nti n uati o n. S u bjects w h o pre mat urel y disc o nti n ue t he st u d y for a n y 
reas o n s h o ul d be sc he d ule d f or a visit as s o o n as p ossi ble, at w hic h ti me all of t he assess me nts liste d f or t he fi nal E O S visit will be perf or me d. 
At t his fi nal visit, all dis pe nse d i n vesti gati o nal pr o d uct s h o ul d be rec o ncile d, a n d t he a d verse e ve nt a n d c o nc o mita nt me dica ti o ns rec or de d o n 
t he e C R F.
T a bl e 8- 1
A s s e s s m e nt S c h e d ul e
P eri o d
S cr e e ni n g
S cr e e ni n g
Tr e at m e nt
Vi sit N a m e
S cr e e ni n g
B a s eli n e
W e e k 1
Vi sit N u m b er s 1
1
2 0
1 0 0
D a y s
-4 2 t o - 1
1
-3 + 1
1
Ti m e ( p o st -d o s e)
-
-
pr e- d o s e 
d o s e
1 h 
2 h 
3 h 
4 h 
6 h 
8 h
I nf or m e d c o n s e nt
X
I n cl u si o n / E x cl u si o n crit eri a
X
X
X
D e m o gr a p h y
X
P h y si c al E x a mi n ati o n
S
S
S
B o d y H ei g ht
X
B o d y W ei g ht
X
Vit al Si g n s
X
X
X
X
X 2
M e di c al hi st or y/ c urr e nt m e di c al 
c o n diti o n s
X
C O P D e x a c er b ati o n hi st or y
X
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
S cr e e ni n g 
S cr e e ni n g
Tr e at m e nt
Vi sit N a m e
S cr e e ni n g
B a s eli n e
W e e k 1
Vi sit N u m b er s 1
1
2 0
1 0 0
D a y s
-4 2 t o - 1
1
-3 + 1
1
Ti m e ( p o st -d o s e)
-
-
pr e- d o s e 
d o s e
1 h 
2 h 
3 h 
4 h 
6 h 
8 h
C o n c o mit a nt m e di c ati o n s
X
X
X
S pir o m etr y
X
X 3
S m o ki n g st at u s
X
X
X
El e ctr o c ar di o gr a m ( E C G)
X
X
X
Fi bri n o g e n bl o o d c oll e cti o n 7
X
X
Pr e g n a n c y t e st 9
X
X
H e m at ol o g y
X
X
Cli ni c al C h e mi str y 1 0, 7
X
X
Uri n al y si s 1 1
S
S
Hi g h R e s ol uti o n C T of C h e st
X 1 3
C o u g h A n d S p ut u m A s s e s s m e nt 
Q u e sti o n n air e ( C A S A -Q)
X
St. G e or g e' s R e s pir at or y 
Q u e sti o n n air e ( S G R Q) 
X
E Q -5 D -3 L
X
C O P D A s s e s s m e nt T e st ( C A T)
X
E X A C T -P R O Q u e sti o n n air e 1 4
X
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
S cr e e ni n g 
S cr e e ni n g
Tr e at m e nt
Vi sit N a m e
S cr e e ni n g
B a s eli n e
W e e k 1
Vi sit N u m b er s 1
1
2 0
1 0 0
D a y s
-4 2 t o - 1
1
-3 + 1
1
Ti m e ( p o st -d o s e)
-
-
pr e- d o s e 
d o s e
1 h 
2 h 
3 h 
4 h 
6 h 
8 h
Di s p e n s ati o n of st u d y dr u g
X
St u d y dr u g i nt a k e at sit e
X
e- Di ar y 1 6
X
X 
X
P K bl o o d c oll e cti o n
X
X 1 7
X 1 7
X 
X 1 7
X 1 7
X 1 7
A d v er s e E v e nt s
X 1 8
X
S eri o u s A d v er s e E v e nt s
X
T el e p h o n e f oll o w -u p
S af et y F oll o w u p C all
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
Tr e at m e nt
Vi sit N a m e
W e e k 2
W e e k 4
W e e k 8
Vi sit N u m b er s 1
1 1 0
1 2 0
1 3 0
D a y s
1 4
± 2
2 8
± 3
5 6
± 3
Ti m e ( p o st -d o s e)
-
pr e- d o s e 
d o s e
1 h 
2 h 
3 h 
4 h 
6 h 
8 h
pr e- d o s e
I nf or m e d c o n s e nt
I n cl u si o n / E x cl u si o n crit eri a
D e m o gr a p h y
P h y si c al E x a mi n ati o n
B o d y H ei g ht
B o d y W ei g ht
Vit al Si g n s
X
X
X 1 9
X
M e di c al hi st or y/ c urr e nt m e di c al 
c o n diti o n s
C O P D e x a c er b ati o n hi st or y
C o n c o mit a nt m e di c ati o n s
X
X
S pir o m etr y 2 3
X 3
X 3
S m o ki n g st at u s
X
X
El e ctr o c ar di o gr a m ( E C G)
X
X
X
Fi bri n o g e n bl o o d c oll e cti o n 7
X
X
Pr e g n a n c y t e st 9
X
X
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
Tr e at m e nt
Vi sit N a m e
W e e k 2
W e e k 4
W e e k 8
Vi sit N u m b er s 1
1 1 0
1 2 0
1 3 0
D a y s
1 4
± 2
2 8
± 3
5 6
± 3
Ti m e ( p o st -d o s e)
-
pr e- d o s e 
d o s e
1 h 
2 h 
3 h 
4 h 
6 h 
8 h
pr e- d o s e
H e m at ol o g y
X
X
Cli ni c al C h e mi str y 1 0
X
X
Uri n al y si s 1 1
S
S
Hi g h R e s ol uti o n C T of C h e st
C o u g h A n d S p ut u m A s s e s s m e nt 
Q u e sti o n n air e ( C A S A -Q)
X
X
St. G e or g e' s R e s pir at or y 
Q u e sti o n n air e ( S G R Q) 
X
X
E Q -5 D -3 L
C O P D A s s e s s m e nt T e st ( C A T)
E X A C T -P R O Q u e sti o n n air e 1 4
X
X
Di s p e n s ati o n of st u d y dr u g
X
X
St u d y dr u g i nt a k e at sit e
X
e- Di ar y 1 6
X
X
P K bl o o d c oll e cti o n
X
X 1 7
X 1 7
X 
X 1 7
X 1 7
X 1 7
X
A d v er s e E v e nt s
X
S eri o u s A d v er s e E v e nt s
X
T el e p h o n e f oll o w -u p
X
S af et y F oll o w u p C all
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
Tr e at m e nt
Tr e at m e nt C o m pl eti o n F oll o w- U p
Tr e at m e nt C o m pl eti o n F oll o w- U p
U n s c h e d ul e d
Vi sit N a m e
W e e k 8
W e e k 1 2
E O S/ E arl y T er mi n ati o n
S af et y  F oll o w U p c all
U n s c h e d ul e d 2 1
Vi sit N u m b er s 1
1 3 0
1 4 0
1 9 9 9
1 5 0
1 6 0
D a y s
5 6
± 3
8 4
± 3
9 1
± 3
1 1 4
± 3
-
Ti m e ( p o st -d o s e)
d o s e
3 h
pr e- d o s e 
d o s e
3 h
-
-
-
I nf or m e d c o n s e nt
I nf or m e d c o n s e nt 
D N A
I n cl u si o n / E x cl u si o n 
crit eri a
D e m o gr a p h y
P h y si c al E x a mi n ati o n
S
S
B o d y H ei g ht
B o d y W ei g ht
X
Vit al Si g n s
X 
X
X
X
X
M e di c al 
hi st or y/ c urr e nt 
m e di c al c o n diti o n s
C O P D e x a c er b ati o n 
hi st or y
C o n c o mit a nt 
m e di c ati o n s
X
X
X
S pir o m etr y 2 3
X
X 2 4
S m o ki n g st at u s
X
X
El e ctr o c ar di o gr a m 
( E C G)
X 
X
X
X
X
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
Tr e at m e nt
Tr e at m e nt C o m pl eti o n F oll o w- U p
Tr e at m e nt C o m pl eti o n F oll o w- U p
U n s c h e d ul e d
Vi sit N a m e
W e e k 8
W e e k 1 2
E O S/ E arl y T er mi n ati o n
S af et y  F oll o w U p c all
U n s c h e d ul e d 2 1
Vi sit N u m b er s 1
1 3 0
1 4 0
1 9 9 9
1 5 0
1 6 0
D a y s
5 6
± 3
8 4
± 3
9 1
± 3
1 1 4
± 3
-
Ti m e ( p o st -d o s e)
d o s e
3 h
pr e- d o s e 
d o s e
3 h
-
-
-
Fi bri n o g e n bl o o d 
c oll e cti o n 7
X
Pr e g n a n c y t e st 9
X
X
X
H e m at ol o g y
X
X
X
Cli ni c al C h e mi str y 1 0
X
X
X
Uri n al y si s 1 1
S
S
S
Hi g h R e s ol uti o n C T 
of C h e st
X
C o u g h A n d S p ut u m 
A s s e s s m e nt 
Q u e sti o n n air e 
( C A S A-Q)
X
X
St. G e or g e' s 
R e s pir at or y 
Q u e sti o n n air e 
( S G R Q) 
X
X
E Q -5 D -3 L
X
C O P D A s s e s s m e nt 
T e st ( C A T)
X
E X A C T -P R O 
Q u e sti o n n air e 1 4
X
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
P eri o d
Tr e at m e nt
Tr e at m e nt C o m pl eti o n F oll o w- U p
Tr e at m e nt C o m pl eti o n F oll o w- U p
U n s c h e d ul e d
Vi sit N a m e
W e e k 8
W e e k 1 2
E O S/ E arl y T er mi n ati o n
S af et y  F oll o w U p c all
U n s c h e d ul e d 2 1
Vi sit N u m b er s 1
1 3 0
1 4 0
1 9 9 9
1 5 0
1 6 0
D a y s
5 6
± 3
8 4
± 3
9 1
± 3
1 1 4
± 3
-
Ti m e ( p o st -d o s e)
d o s e
3 h
pr e- d o s e 
d o s e
3 h
-
-
-
Di s p e n s ati o n of st u d y 
dr u g
St u d y dr u g i nt a k e at 
sit e
X
X
R e s c u e m e di c ati o n 
u s e a n d r e c or d
X
X
e- Di ar y 1 6
X
X 
X
P K bl o o d c oll e cti o n
X 
X
X
X 2 2
A d v er s e E v e nt s
X
X
X
S eri o u s A d v er s e 
E v e nt s
X
X
T el e p h o n e f oll o w -u p
S af et y F oll o w u p C all
S


N o v arti s
C o nfi d e nti al
P a g e 6 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
X A s s e s s m e nt t o b e r e c or d e d i n t h e cli ni c al d at a b a s e or r e c ei v e d el e ctr o ni c all y fr o m a v e n d or
S A s s e s s m e nt t o b e r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n o nl y
1 Vi sit str u ct ur e gi v e n f or i nt er n al pr o gr a m mi n g p ur p o s e o nl y
2 O nl y  f or s eri al P K s u bj e ct s 
3 tr o u g h F E V 1 
4 I n c a s e t h e fir st t w o att e m pt s w er e n ot s ati sf a ct or y t o o bt ai n s p ut u m, t h e I n v e sti g at or m a y pr o c e e d wit h s p ut u m i n d u cti o n.
5 S a m pli n g c a n b e d o n e at B L or D a y 1 m or ni n g. R e s ult s d o n ot n e e d t o b e a v ail a bl e pri or t o r a n d o mi z ati o n a s b a ct eri al c ol o ni z a ti o n w a s c o nfir m e d 
d uri n g s cr e e ni n g. 
6 I n c a s e of si g n of e x a c er b ati o n a n d 1 4 d a y s aft er l ast S o C ( a nti bi oti c s) i nt a k e, s u bj e ct w o ul d n e e d t o c o m e b a c k t o sit e f or a n a d diti o n al s p ut u m s a m pl e 
c oll e cti o n. S e e S e cti o n 8. 4. 4 f or c o m pl et e d et ail s.
7 I n c a s e of si g n of e x a c er b ati o n a n d 1 4 d a y s aft er l a st S o C i nt a k e, s u bj e ct w o ul d n e e d t o c o m e b a c k t o sit e f or a n a d diti o n al bl o o d s a m pl e c oll e cti o n. 
S e e S e cti o n 8. 4. 4 f or c o m pl et e d et ail s.
9 O nl y  f or w o m e n a s s e s s e d a s b ei n g of c hil d b e ari n g p ot e nti al. At s cr e e ni n g, s er u m pr e g n a n c y t e st ( c e ntr al l a b). Ot h er vi sit s: uri n e pr e g n a n c y t e st (l o c al). 
I n c a s e of p o siti v e t e st i n uri n e, t hi s w o ul d n e e d t o b e c o nfir m e d b y a t e st i n s er u m.
1 1 Di p sti c k t e st c o n d u ct e d o n sit e. If di p sti c k r e v e al s a b n or m al r e a di n g s, a uri n e s a m pl e i s t o b e s u b m itt e d t o t h e c e ntr al l a b or at ory f or a n al y si s.
1 2 O pti o n al D N A c oll e cti o n r e q uir e s a s e p ar at e c o n s e nt. D N A s a m pl e c a n b e c oll e ct e d pri or or aft er r a n d o mi z ati o n or a n y s u b s e q u e nt vi sit s.
1 3 T o b e p erf or m e d, if p o s si bl e, aft er s u bj e ct h a s p a s s e d all ot h er s cr e e ni n g crit eri a. 
1 4 It i s t o b e c o m pl et e d b y t h e s u bj e ct at t h e e n d of e v er y d a y at b e dti m e. 
1 6 e Di ar y will r e c or d a) b a c k gr o u n d t h er a p y a n d r e s c u e m e di c ati o n ( s al b ut a m ol/ al b ut er ol) c a pt ur e d t wi c e d ail y b ef or e t a ki n g st u d y m e di c ati o n; b)  
s u bj e ct s s el f-a s s e s s m e nt s q u e sti o n n air e( s) a n d c) Q B W 2 5 1 m e di c ati o n i nt a k e. T h e e -Di ar y i s t o b e r e vi e w e d at e a c h cli ni c vi sit u ntil st u d y c o m pl eti o n.
1 7 o nl y i n s u b s et of s u bj e ct s 
1 8 D uri n g s cr e e ni n g p eri o d, e x a c er b ati o n( s) will b e r e p ort e d i n A d v er s e E v e nt s e C R F p a g e. N o ot h er a d v er s e e v e nt s will b e c oll e ct e d d uri n g s cr e e ni n g 
p eri o d.
1 9 O nl y  f or s eri al P K s u bj e ct s
2 0 I n c a s e s u bj e ct s c a n’t pr o d u c e e n o u g h s p ut u m o n s c h e d ul e d vi sit s, t h e y c a n c o m e b a c k u p t o 3 d a ys aft er t h e s c h e d ul e d vi sit s t o try t o pr o d u c e 
s p ut u m s a m pl e.
2 1 A n u n s c h e d ul e d vi sit c a n b e pl a n n e d at a n y ti m e b a s e d o n m e di c al n e e d s wit h vit al si g n s, p h y si c al e x a mi n ati o n, h e m at ol o g y, bi o c h e mi str y, uri n e 
pr e g n a n c y t e st, uri n al y si s a n d E C G a s mi ni m u m t o b e a s s e s s e d. I n c a s e of S A E, P K s a m pli n g n e e d s t o b e a d d e d.  Ot h er a s s e s s m e nt s ar e at 
i n v e sti g at or' s di s cr eti o n b a s e d o n t h e p ur p o s e of t h e u n s c h e d ul e d vi sit. 
2 2 A P K a s s e s s m e nt i s o nl y e x p e ct e d i n c a s e t h e u n s c h e d ul e d vi sit o c c ur s d u e t o a S A E s, u nl e s s a pl a n n e d vi sit f or t hi s s u bj e ct i s o c c urri n g wit hi n a 
w e e k ti m e of t h e r e p ort e d S A E ( s c h e d ul e d P K s a m pl e).
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 6 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 (Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
2 3 Br o n c h o dil at or c h all e n g e will o nl y b e p erf or m e d d uri n g s cr e e ni n g s pir o m etr y .
2 4 S pir o m etr y  s h o ul d n ot b e p erf or m e d if t h e u n s c h e d ul e d vi sit i s f or a n e x a c er b ati o n


N o v arti s
C o nfi d e nti al
P a g e 7 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8. 1
S cr e e ni n g
If a s u bject fails t o meet t he eli gi bilit y criteria, re-scree ni n g is all o we d i n t he cases descri be d i n 
Sec ti o n 5 . Re -scree ni n g s h o ul d occ ur after a s u bject has faile d scree ni n g. A ne w s u bject n u m ber 
will be assi g ne d a n d t he site m ust rec or d t he re-scree ni n g i nf or mati o n i n t he c orres p o n di n g 
e C R F a n d i n I R T.
I n t he case w here t he s u bject meets all i ncl usi o n/e xcl usi o n criteria b ut d oes n ot meet s p ut u m
p ositi vit y  for pat h o ge nic bacteria, or t he s p ut u m sa m ple v ol u me is i na de q uate ( < 5 m L), a sec o n d 
s p ut u m c ollecti o n o n a se parate d a y  duri n g scree ni n g is per mitte d t o be perf or me d pri or t o 
ra n d o mizati o n f or f urt her assess me nt of q ualificati o n. Res ults m ust 
be recei ve d bef ore 
ra n d o mizati o n.  
I n t he case w here t he s u bject meets all i ncl usi o n/e xcl usi o n criteria b ut d oes n ot meet ser u m 
fi bri n o ge n re q uire me nt a sec o n d ser u m fi bri n o ge n c ollecti o n o n a se parate da y  is per mitte d t o 
be perf or me d pri or t o ra n d o mizati o n f or f urt her assess me nt of q ualificati o n. Res ults m ust be 
recei ve d bef ore ra n d o mizati o n. 
I n the case w here a safet y la b orat or y assess me nt at scree ni n g is o utsi de of t he ra n ge s pecifie d 
i n t he e x cl usi o n criteria, t he assess me nt ma y  be re peate d o nce pri or t o ra n d o mizati o n. If t he 
re peat val ue re mai ns o utsi de of t he s pecifie d ra n ges, t he s u bject m ust be e xcl u de d fr o m t he 
st u d y a n d c o nsi dere d as scree ne d faile d.
If a s u bject re-scree ns f or t he st u d y, t he n t he s u bject m ust si g n a ne w I C F a n d be iss ue d a ne w 
s u bject n u m ber pri or t o a n y s cree ni n g assess me nt bei n g c o n d ucte d. T he i n vesti gat or/ q ualifie d 
site staff will rec or d if t he s u bject was re-scree ne d o n t he re-scree ni n g e C R F al o n g wit h t he 
scree ni n g n u m ber t he s u bject was iss ue d pri or t o t he c urre nt scree ni n g n u m ber. S u bjects w h o 
ha ve pre vi o usl y scree n faile d o nce or t wice d ue t o s p ut u m C F U le vel bei n g t o o l o w u n der t he 
ori gi nal pr ot oc ol wit h or wit h o ut fi bri n o ge n bei n g t o o l o w, b ut w h o ha d s p ut u m p ositi ve f or at 
least o ne p ote ntiall y pat h o ge nic or ga nis m, m a y  be re-scree ne d f or t he st u d y once usi n g t he 
u p date d i ncl usi o n/e xcl usi o n criteria fr o m t he pr ot oc ol a me n d me nt v 0 2 (i ncl usi ve of versi o n 0 1 
c ha n ges). If t his scree n fail s u bject ha d a H R C T as part of ori gi nal scree ni n g a cti vities, a re peat 
H R C T is n ot re q uire d u nless m ore t ha n 1 2 m o nt hs ha ve passe d si nce t he pri or H R C T.
T he date of t he ne w i nf or me d c o nse nt si g nat ure m ust be e ntere d o n t he i nf or me d c o nse nt e C R F 
c orres p o n di n g t o t he ne w scree ni n g s u bject n u m ber. F or re-scree ni n g, all scree ni n g assess me nts 
m ust be perf or me d per pr ot oc ol.
I nf or mati o n o n w hat data m ust be c ollecte d f or scree ni n g fail ures a n d f urt her i nf or mati o n o n 
re-scree ni n g is o utli ne d i n t he Site O perati o ns Ma n ual.
8. 1. 1
I nf or m ati o n t o b e c oll e ct e d o n s cr e e ni n g f ail ur e s
S u bjects w h o si g n a n i nf or me d c o nse nt b ut fail t o c o nti n ue i nt o t he Baseli ne/ Da y  1 visit f or a n y 
reas o n will be c o nsi dere d a scree n fail ure. T he reas o n f or t he scree ni n g fail ure will be e ntere d 
o n t he scree ni n g dis p ositi o n pa ge. If t he s u bject fails t o be ra n d o mize d, t he I R T m ust be n otifie d 
wit hi n 2 da y s of t he scree n fail t hat t he s u bject was n ot ra n d o mize d.
I nf or mati o n o n w hat data m ust be c ollecte d f or scree ni n g fail ures a n d f urt her i nf or mati o n o n 
re-scree ni n g is o utli ne d i n t he Site O perati o ns Ma n ual.


N o v arti s
C o nfi d e nti al
P a g e 7 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8. 2
S u bj e ct d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s
S u bject de m o gra p hic a n d baseli ne c haracteristic data are t o be c ollecte d o n all s u bjects. 
Rele va nt me dical hist or y /c urre nt me dical c o n diti o n prese nt bef ore si g ni n g t he i nf or me d c o nse nt 
will be rec or de d. I n vesti gat ors will ha ve t he discreti o n t o rec or d a b n or mal test fi n di n gs o n t he 
a p pr o priate e C R F w he ne ver, i n t heir j u d g me nt, t he test a b n or malit y occ urre d pri or t o t he 
i nf or me d c o nse nt si g nat ure.
C o u ntr y -s pecific re g ulati o ns s h o ul d be c o nsi dere d f or t he c ollecti o n of de m o gra p hic a n d 
baseli ne c haracteristics i n ali g n me nt wit h e C R F.
Details are o utli ne d i n t he Site O perati o ns Ma n ual.
8. 3
Effi c a c y  / P h ar m a c o d yn a mi c s
T he efficac y  assess me nts selecte d are sta n dar d f or t his i n dicati o n/s u bject p o p ulati o n.
Bl o o d a n d s p ut u m sa m ples will be c ollecte d a n d e val uate d i n all s u bjects at t he ti me p oi nts 
defi ne d i n t he Assess me nt Sc he d ule (Ta ble 8- 1 ). F oll o w i nstr ucti o ns o utli ne d i n t he Site 
O perati o ns 
Ma n ual 
re gar di n g sa m ple c ollecti o n, n u m be ri n g, pr ocessi n g, a n d s hi p me nt. 
N u m ber of sa m ples/ bl o o d dra ws a n d t otal bl o o d v ol u me c ollecte d will n ot e xcee d t h ose state d 
i n t he pr ot oc ol.
F or all c o m plete d scales/ q uesti o n naire descri be d bel o w, t he I n vesti gat or will be re q uire d t o 
re vie w a n d e xa mi ne resp o nses w hic h m a y  in dicate p ote ntial A Es or S A Es. T he i n vesti gat or 
s h o ul d re vie w n ot o nly t he res p o nses t o t he scale b ut als o f or a ny u ns olicite d c o m me nts writte n 
b y  the s u bject. If t he occ urre nce of A Es or S A Es is c o nfir me d, t he i n vesti gat or / p h y sicia n 
s ho ul d rec or d t he e ve nts as per i nstr ucti o ns gi ve n i n Secti o n 9 .
8. 3. 1
S pir o m etr y
S pir o metr y  testi n g will be perf or me d acc or di n g t o t he A T S/ E R S g ui deli nes ( Miller et al 2 0 0 5a; 
Miller et al 2 0 0 5 b) at scree ni n g t o assess s u bject eli gi bilit y for t he st u d y an d at t he visits detaile d 
i n t he assess me nt sc he d ule i n Ta ble 8- 1 .
T he s pir o metr y eval uati o n s h o ul d be perf or me d at t he site pri or t o t he m or ni n g i n vesti gati o nal 
dr u g i nta ke a n d t he dail y  CO P D 
mai nte n a nce bac k gr o u n d t hera p y, as pre a n d p ost -
br o nc h o dilat or. Refer t o i nstr ucti o ns f or me dicati o n was h o uts i n Ta ble 8- 1 .
Br o nc h o dilat or c halle n ge will o nl y  be perf or me d d uri n g t he scree ni n g visit t o esta blis h data t o 
meet 
i ncl usi o n/e xcl usi o n criteria relate d t o ast h ma. S pir o metr y  
wit h o ut br o nc h o dilat or 
c halle n ge will be perf or me d at all ot her visits.
T he s pir o metr y eq ui p me nt use d d uri n g t he trial will be pr o vi de d t o all st u d y  sites b y a Ce ntral 
S pir o metr y  ve n d or. T he 
e q ui p me nt m ust 
meet 
or 
e xcee d t he mi ni mal 
A T S/ E R S 
rec o m me n dati o ns f or dia g n ostic s pir o metr y e q ui p me nt as defi ne d i n t he g ui deli ne pr o vi de d b y 
t he ve n d or. Cali brati o n of t he s pir o metr y e q ui p me nt is ma n dat or y o n all visit da ys a n d m ust be 
perf or me d bef ore t he first s u bject s pir o metr y test is assesse d. All cali brati o n re p orts a n d s u bject 
s pir o metr y re p orts s h o ul d be st ore d as s o urce data.
T he sa me s pir o metr y eq ui p me nt s h o ul d be use d f or all assess me nts perf or me d b y  a su bject. 
A li mite d n u m ber of q ualifie d staff, as desi g nated b y  t he i n vesti gat or, will e val uate all s u bjects 


N o v arti s
C o nfi d e nti al
P a g e 7 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
at all visits t hr o u g h o ut t he e ntire trial at eac h site. W here p ossi ble t he sa me tec h nicia n s h o ul d 
perf or m all ma ne u vers f or a n i n di vi d ual s u bject. All staff c o n d ucti n g t he s pir o metr y  tests m ust 
ha ve recei ve d a p pr o priate trai ni n g w hic h m ust be d oc u me nte d.
A S pir o metr y  Ma n ual will be pr o vi de d t o all sites as se parate d oc u me nt. 
All s pir o metr y assess me nts will be u n der g oi n g re vie w b y a ce ntral o verrea der. Acce pta bilit y of 
a s pir o metric assess me nt atte m pt de pe n d s o n t he o verrea der's j u d ge me nt f or c o m plia nce wit h 
a n d acce pta bilit y acc or di n g t o t he A T S/ E R S criteria.
8. 3. 2  
Hi g h R e s ol uti o n C o m p ut e d T o m o gr a p h y  ( H R C T)
Hi g h Res ol uti o n C o m p ute d T o m o gra p h y ( H R C T) will be perf or me d at Scree ni n g a n d at Da y 8 4. 
T he H R C T perf or me d d uri n g scree ni n g s h o ul d be perf or me d t o war d t he e n d of t he scree ni n g 
peri o d after m ost or all ot her scree ni n g assess me nts ha ve bee n c o nfir me d. B y  co n d ucti n g t he 
H R C T cl ose t o last i n scree ni n g pr oce d ures, t h ose s u bjects w h o fail scree ni n g will n ot be 
e x p os e d t o u n necessar y  ra diati o n as H R C T w o ul d n o l o n ger be nee de d. T he ac q uisiti o n will 
i ncl u de i ns pirat or y a n d e x pirat or y i ma ge sets at b ot h assess me nt ti me p oi nts. Pr ot oc ol s pecific 
re q uire me nts of t he H R C T a n d mac hi ne setti n gs will be pr o vi de d t o all sites as part of a se parate 
I ma gi n g Ma n ual. A d diti o nall y , t he i ma gi n g ve n d or will pr o vi de ce ntralize d re vie w of t he 
H R C T sca ns. Scree ni n g H R C T data are n ot re q uire d t o defi ne s u bject eli gi bilit y .
I n s u m mar y, e val uati o n of t he H R C T sca ns will be use d t o assess exte nt of:

air wa y str uct ure a n d f u ncti o n f or e val uati o n of c ha n ge fr o m Scree ni n g / Baseli ne 
c o m pare d t o Da y 8 4

N ote: T he c o de d me dical i ma ges will be use d pri maril y  for a nal ys is as descri be d i n t his pr ot oc ol; 
h o we ver, t he i ma ges ma y  als o be use d f or t he de vel o p me nt a n d e val uati o n of ne w a nal ys is 
met h o ds directl y  relate d t o t he area of researc h t hat t his st u d y c o vers.
8. 3. 3
A p pr o pri at e n e s s of effi c a c y  a s s e s s m e nt s
N ot a p plica ble.
8. 3. 4
Fi bri n o g e n
Fi bri n o ge n is a gl yc o pr otei n, w hic h is t he m ost a b u n da nt cl otti n g fact or i n plas ma. Ele vate d 
le vels of fi bri n o ge n a m o n g s u bjects wit h C O P D were f o u n d t o be ass ociate d wit h m ore 
fre q ue nt/ m ore se vere o utc o mes c o m m o nl y use d as e n d p oi nts i n i n vesti gati o ns of C O P D 
(Ma n ni n o
et al 2 0 1 5 ). F or details o n t he c ollecti o n, ha n dli n g a n d st ora ge/s hi p me nt of sa m ples, 
refer t o t he La b orat or y  Ma n ual. Sa m ples will be c ollecte d at t he ti me p oi nts defi ne d i n t he 
Assess me nt Sc he d ule ( Ta ble 8- 1 ).
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 7 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8. 3. 6
B a ct eri al l o a d
S p ut u m sa m ples will be c ollecte d f or a nal ysis of pat h o ge nic bacterial c ol o nizati o n ( C F U/ m L)( H 
i nfl ue nzae, H parai nfl ue nzae, P aer u gi n osa, S p ne u m o niae, S a ure us, M ora xella
catarr halis, E nter o bacteriaceae, Ste n otr o p h o m o nas malt o p hilia, B ur k h ol deria s pecies, a n d
Ac hr o m o bacter s pecies or a n y p ote ntial pat h o ge nic bacteria meas ure d b y  dil uti o n/ o ut gr o wt h. 
A n y  or ga nis m t hat is t o be i ncl u de d a n d t hat is n ot i ncl u de d i n t he list of t he pr ot oc ol defi ne d 
pat h o ge ns s h o ul d be disc usse d o n a case b y case basis wit h t he N o vartis Me dical E x pert.
De pe n di n g o n differe nt la b orat ories, t he u nit of bacterial l oa d C F U/ m L  is c o nsi dere d e q ual t o 
C F U/ g.
I n a d diti o n, 1 6 S s R N A base d a nal ysis will be perf or me d t o pr o vi de micr o bial pr ofili n g. T he 
a nal ys is will be perf or me d o n re mai ni n g s p ut u m sa m ples c ollecte d f or micr o bi ol o g y  assess me nt.
S p o nta ne o us s p ut u m c ollecti o n: o n sc he d ule d s p ut u m c ollecti o n visits, i ncl u di n g Scre e ni n g a n d 
Baseli ne at least o ne s p ut u m s peci me n s h o ul d be c ollecte d i n t he m or ni n g bef ore brea kfast a n d 
at pre -d ose ti me-p oi nt d uri n g t he treat me nt peri o d. I n case s u bjects ca n’t pr o d uce e n o u g h 
s p ut u m o n t he i n di vi d ual sc he d ule d visits, t he y ca n c o me bac k u p t o 3 da y s after t he sc he d ule d 
visits t o tr y  t o pr o d uce s p ut u m sa m ple. If t w o s p o nta ne o us s p ut u m c ollecti o n atte m pts are still 
n ot satisfact or y , a n i n vesti gat or ma y ta ke decisi o n t o c ollect s p ut u m sa m ple after i n d ucti o n b y 
t he i n halati o n of sali ne ( please refer t o t he La b Ma n ual 
Treat me nt e mer gi n g pat h o ge ns will be deter mi ne d at all visits. 
Micr o bi ol o gical a nal yses, i ncl u di n g bacterial c ol o nizati o n a n d bacterial l oa d pr ofili n g, will be 
perf or me d ce ntrall y  at a q ualifie d micr o bi ol o g y la b orat or y.
Fi nall y , all s p ut u m sa m ples m ust be of g o o d q ualit y , acc or di n g t o t he q ualit y  criteri o n as 
s pecifie d i n La b orat or y  Sp ut u m C ollecti o n Ma n ual.
If t he sa m ple is deter mi ne d t o be a s u b-
o pti mal, t he site's staff s h o ul d be c o ntacte d i m me diatel y a n d a re q uest s h o ul d be ma d e f or a 
ne w sa m ple. Details o n t he c ollecti o n a n d s hi p me nt of sa m ples, ge nerati o n of data a n d re p orti n g 
of res ults b y  t he micr o bi ol o g y la b orat or y are pr o vi de d i n t he S p ut u m C ollecti o n Ma n ual. 
8. 4
S af et y
Safet y  assess me nts are s pecifie d bel o w wit h t he assess ment sc he d ule detaili n g w he n eac h 
assess me nt is t o be perf or me d.
F or details o n A E c ollecti o n a n d re p orti n g, refer t o t he A E sec ti o n (Secti o n 1 0. 1. 1 ).
T he met h o ds, assess me nt, s pecificati o n, a n d rec or di n g f or eac h assess me nt will be detaile d i n 
t he S O M.
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 7 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
A s s e s s m e nt
S p e cifi c ati o n
P h y s i c al e x a mi n ati o n
A c o m pl et e p h y si c al e x a mi n ati o n will i n cl u d e t h e e x a mi n ati o n of 
g e n er al a p p e ar a n c e, s ki n, n e c k (i n cl u di n g t h yr oi d), e y e s, e ar s, 
n o s e, 
t hr o at, l u n g s, h e art, 
a b d o m e n, 
b a c k, l y m p h 
n o d e s, 
e xtr e miti e s, v a s c ul ar, a n d n e ur ol o gi c al. If i n di c at e d b a s e d o n 
m e di c al hi st or y a n d/ or s y m p t o m s, r e ct al, e xt er n al g e nit ali a, br e a st, 
a n d p el vi c e x a m s will b e p erf or m e d.
A s h ort p h y si c al e x a m will i n cl u d e t h e e x a mi n ati o n of g e n er al 
a p p e ar a n c e a n d vit al si g n s ( bl o o d pr e s s ur e [ S B P a n d D B P] a n d 
p ul s e). A s h ort p h y si c al e x a m will b e d o n e at all vi sit s st arti n g fr o m 
D a y 1 e x c e pt w h er e a c o m pl et e p h y si c al e x a mi n ati o n i s r e q uir e d 
( s e e a b o v e).
I nf or m ati o n f or all p h y si c al e x a mi n ati o n s m u st b e i n cl u d e d i n t h e 
s o ur c e d o c u m e nt ati o n at t h e st u d y sit e. Cli ni c all y r el e v a nt fi n di n g s 
t h at ar e pr e s e nt pri or t o si g ni n g i nf or m e d c o n s e nt m u st b e r e c or d e d 
o n 
t h e a p pr o pri at e 
e C R F 
t h at c a pt ur e s 
m e di c al 
hi st or y. 
Si g nifi c a nt fi n di n g s m a d e aft er si g ni n g i nf or m e d c o n s e nt w hi c h 
m e et t h e d efi niti o n of a n A d v er s e E v e nt m u st b e r e c or d e d a s a n 
a d v er s e e v e nt.
Vit al si g n s
Vit al si g n s i n cl u d e B P a n d p ul s e m e a s ur e m e nt s. Aft er t h e s u bj e ct 
h a s b e e n sitti n g f or fi v e mi n ut e s, wit h b a c k s u p p ort e d a n d b ot h f e et 
pl a c e d o n t h e fl o or, s y st oli c a n d di a st oli c bl o o d pr e s s ur e will b e 
m e a s ur e d t hr e e ti me s u si n g a n a ut o m at e d v ali d at e d d e vi c e, e. g. 
O M R O N, 
wit h a n a p pr o pri at el y si z e d c uff. T h e r e p e at sitti n g 
m e a s ur e m e nt s will b e m a d e at 1 - 2 m i n ut e i nt er v al s a n d t h e m e a n 
of t h e t hr e e m e a s ur e m e nt s will b e u s e d. I n c a s e t h e c uff si z e s 
a v ail a bl e ar e n ot l ar g e e n o u g h f or t h e s u bj e ct' s ar m cir c u mf er e n c e, 
a s p h y g m o m a n o m et er wit h a n a p pr o pri at el y si z e d c uff m a y  be 
u s e d.
Cli ni c all y n ot a bl e vit al si g n s ar e d efi n e d i n S e cti o n 1 6. 1 .
H ei g ht a n d w ei g ht
H ei g ht 
i n c e nti m et er s ( c m) a n d b o d y  
wei g ht (t o t h e n e ar e st 
0. 1 kil o gr a m ( kg) i n i n d o or cl ot hi n g, b ut wit h o ut s h o e s) will b e 
m e a s ur e d.
8. 4. 1
L a b or at or y  e val u ati o n s
A ce ntral la b orat or y will be use d f or a nal ysis of all s peci me ns c ollecte d. Detai ls o n t he 
c ollecti o ns, s hi p me nt of sa m ples a n d re p orti n g of res ults b y t he ce ntral la b orat or y are pr o vi de d 
t o i n vesti gat ors i n t he La b orat or y Ma n ual. La b orat or y  assess me nts will be perf or me d i n t he 
visits s pecifie d i n Ta ble 8 - 1.
Cli nicall y  si gnifica nt a b n or malities m ust be rec or de d as eit her me dical hist or y  or a d verse e ve nts 
as a p pr o priate. All s u bjects wit h la b orat or y tests c o ntai ni n g cli nicall y si g nifica nt a b n or malities 
s h o ul d be f oll o we d re g ularl y u ntil t he val ues ret ur n t o wit hi n t he n or mal ra n ges or u ntil a vali d 
reas o n ot her t ha n dr u g -relate d a d verse e x perie nces is i de ntifie d, e ve n after t he me dicati o n has 
disc o nti n ue d. Cli nicall y  n ota ble la b orat or y fi n di n gs are defi ne d i n Secti o n 1 6. 1 .
All ab n or mal la b res ults m ust be e val uate d f or criteria defi ni n g a n a d verse e ve nt a n d re p orte d 
as s uc h if t he criteria are met. F or t h ose la b a d verse e ve nts, re peate d e val uati o ns are ma n dat or y 
u ntil n or malizati o n of t he res ult(s) or u ntil t he res ult is n o l o n ger c o nsi dere d t o be cli nicall y 
si g nifica nt.


N o v arti s
C o nfi d e nti al
P a g e 7 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T a bl e 8- 2
L a b or at or y  e v al u ati o n s
T e st C at e g or y
T e st N a m e
H e m at ol o g y
H e m at o crit, H e m o gl o bi n, Pl at el et s, R e d bl o o d c ell s, W h it e bl o o d c ell s, 
Diff er e nti al ( B a s o p hil s, E o si n o p hil s, L y m p h o c y t e s, M o n o c y t e s, N e utr o p hil s)
C h e mi str y
Al b u mi n, Al k ali n e p h o s p h at a s e, A L T, A S T, G a m m a - gl ut a myl -tr a n sf er a s e 
( G G T), 
hi g h -s e n siti vit y 
C- r e a cti v e 
Pr ot ei n 
( h s-C R P), 
L a ct at e 
d e h y dr o g e n a s e ( L D H), Bi c ar b o n at e, C al ci u m, M a g n e si u m, 
P h o s p h or u s, 
C hl ori d e, S o di u m, P ot a s si u m, Cr e ati ni n e, Cr e ati n e ki n a s e, Dir e ct Bilir u bi n, 
I n dir e ct Bilir u bi n, T ot al Bilir u bi n, T ot al C h ol e st er ol, L D L, H D L, T ot al Pr ot ei n, 
Tri gl y c eri d e s, Bl o o d Ur e a Nitr o g e n ( B U N) or Ur e a, Uri c A ci d, A m yl a s e, 
Li p a s e, Gl u c o s e (f a sti n g)
Uri n al y si s
Mi cr o s c o pi c P a n el ( R e d Bl o o d C ell s, W h it e Bl o o d C ell s, C a st s, Cr y st al s 
o nl y if a b n or m aliti e s o n t h e m a cr o s c o pi c p a n el ( di p sti c k) ar e d et e ct e d)
M a cr o s c o pi c P a n el ( Di p sti c k) ( Bl o o d, p H, Pr ot ei n, S p e cifi c Gr a vit y )
C o a g ul ati o n
Pr ot hr o m bi n ti me ( P T) / I nt er n ati o n al n or m ali z e d r ati o [I N R]), P arti al 
t hr o m b o pl a sti n ti m e ( P T T), A cti v at e d p arti al t hr o m b o pl a sti n ti m e ( A P T T)
Pr e g n a n c y T e st 
S er u m / Uri n e pr e g n a n c y t e st (r ef er t o ' Pr e g n a n c y a n d a s s e s s m e nt s of 
f ertilit y' S e cti o n 8. 4. 3 ) 
8. 4. 2
1 2 -l e a d El e ctr o c ar di o gr a m ( E C G)
Tri plicate 1 2 -lea d E C G will be c ollecte d at t he ti me p oi nts i n dicate d i n Ta ble 8- 1 .
P R i nter val, Q R S d urati o n, heart rate, R R i nter val, Q T i nter va l, Q Tc F will be assesse d.
W here cli nical decisi o ns are base d o n t he Q T i nter val, t he le n gt h of t he Q T i nter val is t o be 
calc ulate d acc or di n g t o t he Fri dericia Q T c orrecti o n f or m ula ( Q Tc F).
As a p plica ble, Q Tc F m a y  be calc ulate d at t he cli nical site, u nless a ut o-calc ulate d b y  the E C G 
mac hi ne.
Cli nicall y  si g nifica nt a b n or malities m ust be re p orte d as a d verse e ve nts.
A d diti o nal details pertai ni n g t o E C G c ollecti o n a n d re p orti n g are i ncl u de d i n t he S O M.
T he preferre d se q ue nce of car di o vasc ular data c ollecti o n d uri n g st u d y visits is E C G c ollecti o n 
first, f oll o we d b y  vital si g ns, a n d bl o o d sa m pli n g. A mi ni m u m 3 mi n utes rest peri o d fr o m t he 
be gi n ni n g of E C G assess me nts t o t he start of s pir o metr y ma ne u vers m ust be o bser ve d at all 
ti mes.
F or eac h E C G perf or me d, ori gi na l traces a n d i de ntical d u plicate traces s h o ul d be pri nte d. 
Eac h E C G will be se nt electr o nicall y for ce ntral re vie w directl y  fr o m t he E C G mac hi ne. 
T w o i de ntical d u plicate pri nt -o uts will be ge nerate d a n d ke pt at t he i n vesti gat or site as s o urce 
d oc u me ntati o n a n d as bac k u p f or s u b missi o n t o t he ce ntral la b orat or y i n case of pr o ble ms wit h 
t he electr o nic tra ns missi o n. Eac h pri nt-o ut will be ke pt at t he i n vesti gat or site a n d will be date d 
a n d si g ne d. T he s u bject's n u m ber, t he date, act ual ti me of t he traci n g a n d st u d y co de m ust a p pear 
o n eac h pa ge of t he traci n g. Cli nicall y  si g nifica nt a b n or malities m ust be rec or de d o n t he e C R F 
as eit her me dical hist or y/c urre nt me dical c o n diti o ns or a d verse e ve nts as a p pr o priate.


N o v arti s
C o nfi d e nti al
P a g e 7 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8. 4. 3
Pr e g n a n c y  a n d a s s e s s m e nt s of f ertilit y
See t he Ass ess me nt sc he d ule Ta ble 8- 1 f or ti mi n g of t he pr ot oc ol re q uire d pre g na nc y  testi n g; 
a d diti o nal pre g na nc y  testi n g m a y  be perf or me d t o meet l ocal re q uire me nts. A p ositi ve uri ne 
pre g na nc y  test re q uires i m me diate i nterr u pti o n of st u dy treat me nt u ntil ser u m β- h C G is 
perf or me d a n d f o u n d t o be ne gati ve.
Refer t o Secti o n 1 0. 1. 4 f or details o n Pre g na nc y re p orti n g.
8. 4. 4
C O P D E x a c er b ati o n
S y m pt o m -defi ne d 
C O P D 
e xacer bati o ns 
i de ntifie d b y  the 
E X A C T -P R O 
i nstr u me nt 
( E X A C T-P R O -defi ne d e xacer bati o ns) are defi ne d as a persiste nt i ncrease fr o m baseli ne i n t otal 
E X A C T -P R O sc ore of ≥9 p oi nts f or 3 da y s or ≥1 2 p oi nts f or 2 da y s. W he ne ver 
t he 
E X A C T -P R O diar y  data s u g gest t hat t he s u bject s ym pt o ms are w orse ni n g acc or di n g t o the 
a b o ve defi niti o ns, t he diar y will tri g ger a n alert a d visi n g t he s u bject t o c o ntact t he site.
A healt hcare res o urce utilizati o n ( H C R U)-defi ne d e xacer bati o n is defi ne d as a n ac ute 
w orse ni n g of res pirat or y s ym pt o ms (c o nsisti n g of at least t w o of t he f oll o wi n g s ym pt o ms: 
d y s p nea, c o u g h, s p ut u m v ol u me, s p ut u m p ur ule nce, c hest ti g ht ness or w heeze) t hat re q uires a 
c ha n ge i n treat me nt. H C R U e xacer bati o ns are defi ne d as m o derate if lea di n g t o treat me nt wit h 
s yste mic gl uc oc ortic oster oi ds a n d/ or a nti bi otics, a n d as se vere if lea di n g t o h os pital a d missi o n 
or e mer ge nc y ro o m ( E R) visit lasti n g > 2 4 h i n a d diti o n t o treat me nt wit h 
s yste mic 
gl uc oc ortic oster oi ds a n d/ or a nti bi otics. Mil d 
H C R U e xacer bati o ns are e ve nts t hat ca n be 
ma na ge d wit h a n i ncrease i n us ual me dicati o n a n d wit h o ut t he a d diti o n of s y ste mic t hera p y.
E xacer bati o n t hera p y is at t he discreti o n of i n vesti gat ors. S u g geste d t hera p y i ncl u des 5 da ys of 
oral pre d nis ol o ne ( or e q ui vale nt) 4 0 m g/ da y  a n d/ or a n oral 7 da y c o urse of a m o xicilli n 5 0 0 m g 
t.i. d. (alter nati vely a m o xicilli n/cla v ula nic aci d 6 2 5 m g t.i. d. or clarit hr o m yci n 5 0 0 m g  b.i. d.) 
(G O L D 2 0 1 8 ).
S u bjects w h o de vel o p a C O P D e xacer bati o n bet wee n scree ni n g a n d pri or t o treat me nt will be 
scree n faile d b ut will be per mitte d t o be re-scree ne d after a mi ni m u m of 2 wee ks after 
e xacer bati o n S O C t hera p y has bee n st o p pe d. (see Secti o n 5 ). Sc he d ule d s pir o metr y s h o ul d n ot 
be perf or me d d uri n g a n e xacer bati o n u ntil it has c o m pletel y  res ol ve d, t heref ore a n y sc he d ule d 
visits t hat i ncl u de s pir o metric assess me nt s h o ul d be p ost p o ne d u ntil t he s u bject has rec o vere d. 
Visits t hat d o n ot i ncl u de s pir o metric assess me nt ca n g o a hea d as pla n ne d. Of n ote, b u des o ni de 
a n d fl uticas o ne are se nsiti ve s u bstrates of C Y P 3 A. W here 
a d mi nistere d s yste micall y for a 
C O P D e xacer bati o n, efficac y an d safety of t hese dr u gs s h o ul d be caref ull y m o nit ore d 
(see als o Secti o n 6. 2 f or f urt her details).
I n case of e xacer bati o n alerts, s u bjects will nee d t o visit t he Site as s o o n as reas o na bl y p ossi ble 
a n d be assesse d t o c o nfir m t he e xacer bati o n. T his visit will be c o nsi dere d as a n u nsc he d ule d 
v isit.
 
 
 
 
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 7 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
 
S u bjects e x perie nci n g a m o derate e xacer bati o n d uri n g t he treat me nt peri o d will c o nti n ue wit h 
t heir st u d y treat me nt al o n g wit h t he sta n dar d of care ( S O C) t hera py f or e xacer bati o n (i.e. 
a nti bi otics a n d/ or s yste mic c ortic oster oi ds). I n case s u bjects are treate d wit h a nti bi otics f or t heir 
m o derate e xacer bati o n, s u bjects will ha ve t o c o me bac k t o t he site f or a n ot her u nsc he d ule d visit 
a p pr o xi matel y 2 wee ks after last i nta ke of t heir a nti bi otics, as a f oll o w- u p visit t o pr o vi de 
s p ut u m a n d bl o o d sa m ples. If t he f oll o w-u p visit occ urs wit hi n a p pr o xi matel y  1 wee k fr o m t he 
ne xt st u d y visit, s u bjects ca n c o me bac k directl y t o t he pla n ne d visit as per Asses s me nt sc he d ule 
a n d pr ocee d wit h t he res pecti ve pr oce d ures as per pr o t oc ol f or t his st u d y visit da y.
S u bjects e x perie nci n g a se vere e xacer bati o n w h o nee d t o be treate d i n t he h os pital will be 
disc o nti n ue d of st u d y treat me nt d uri n g t his ti me, wit h t he p ossi bilit y t o restart st u d y treat me nt 
a p pr o xi matel y 2 wee ks after t he last d a y  of t heir a nti bi otics i nta ke f or t heir e xacer bati o n. T h ose 
s u bjects w h o t o o k a nti bi otics s h o ul d als o pr o vi de s p ut u m a n d bl o o d sa m ples bef ore restart wit h 
st u d y treat me nt. S u bjects w h o were n ot treate d wit h a nti bi otics d uri n g t heir h os pital sta y ca n 
restart wit h st u d y dr ug directl y after h os pital sta y.
E xacer bati o n start ti me is c o nsi dere d as t he d a y  the s u bject is pr o vi de d wit h a nti bi otics or 
s yste mic c ortic oster oi ds. E xacer bati o n e n d date is c o nsi dere d as t he da y  after t he last i nta ke of 
a nti bi otics or s yste mic c ortic oster oi ds. I n case of i nta ke of b ot h a nti bi otics a n d s yste mic 
c ortic oster oi ds, start a n d e n d date of t he e xacer bati o n refers t o t he start a n d e n d date of t he 
a nti bi otics i nta ke. 
Fi nall y , if a n e xacer bati o n ha p pe ns after E O S visit, s u bjects will be treate d at t he discreti o n of 
t he s u bject’s p hys icia n. 
F oll o wi n g treat me nt f or t he e xacer bati o n, t he s u bject will be e x pecte d t o c o nti n ue i n t he st u d y 
pr o vi de d t he i n vesti gat or co nsi ders t hat t he s u bject ca n safely ret ur n t o t heir pre -e xacer bati o n 
me dicati o ns.
All H C R U -defi ne d e xacer bati o n e ve nts a n d gi ve n t hera py s h o ul d be rec or de d o n rele va nt e C R F 
pa ges.
8. 4. 5
A p pr o pri at e n e s s of s af et y  m e a s ur e m e nt s
T he safet y assess me nts selecte d are sta n dar d f or t his i n dicati o n/s u bject p o p ulati o n.
8. 5
A d diti o n al a s s e s s m e nt s
8. 5. 1
Cli ni c al O ut c o m e A s s e s s m e nt s ( C O A s)
T he i m pact of C O P D o n a s u bject’s healt h stat us will be assesse d b y  the f oll o wi n g s u bject-
re p orte d o utc o mes q uesti o n naires ( P R Os):

T he C O P D assess me nt test ( C A T) assesses gl o ball y  t he i m pact of C O P D (c o u g h, s p ut u m, 
d y s nea, c hest ti g hte ness) (J o nes et al 2 0 0 9)

C o u g h A n d S p ut u m Assess me nt Q uesti o n naire ( C A S A - Q) meas ures c o u g h a n d s p ut u m 
pr o d ucti o n ( Cra wf or d et al 2 0 0 8 )
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 7 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

T he St. Ge or ge Res pirat or y  Q uesti o n naire ( S G R Q) (J o nes el al 1 9 9 2) pr o vi des healt h 
stat us meas ure me nts

E X A C T -P R O Q uesti o n naire e val uates fre q ue nc y , se verity, a n d d urati o n of e xace r bati o ns.

T he E ur o pea n Q ualit y of Life -5 Di me nsi o n -3 Le vels ( E Q - 5 D-3 L ) e val uates gl o bal healt h 
stat us of s u bjects.
A s u bject’s ref usal t o c o m plete all or a n y part of a P R O meas ure s h o ul d be d oc u me nte d i n t he 
st u d y E D C sys te m a n d will n ot be c o nsi dere d a prot oc ol de viati o n.
S u bject q uesti o n naires will be c o m plete d i n t he la n g ua ge m ost fa miliar t o t he s u bject.
T he site pers o n nel s h o ul d c hec k P R O meas ures f or c o m plete ness a n d as k t he s u bject t o 
c o m plete a n y missi n g res p o nses. T he res p o nses st ore d electr o nicall y o n t he e Diar y will be 
c o nsi dere d t he s o urce file.
C o m plete d meas ures a n d a n y  u ns olicite d c o m me nts writte n b y t he s u bject s h o ul d be re vie we d 
a n d assesse d b y  the i n vesti gat or f or res p o nses w hic h ma y  in dicate p ote ntial A Es or S A Es bef ore 
a n y cli nical st u d y e xa mi nati o ns. T his assess me nt s h o ul d be d oc u me nte d i n t he s u bject's s o urce 
rec or ds. If A Es or S A Es are c o nfir me d, t he st u dy i n vesti gat or s h o ul d n ot e nc o ura ge t he s u bject 
t o c ha n ge res p o nses re p orte d i n t he c o m plete d q uesti o n naires. St u d y i n vesti gat ors m ust f oll o w 
re p orti n g i nstr ucti o ns o utli ne d i n Secti o n 1 0 (e. g. refere nce “ A d verse E ve nts” secti o n) of t he 
st u d y pr ot oc ol.
T he a p pr o priate la n g ua ge versi o n of t he q uesti o n naires will be use d i n eac h partici pati n g 
c o u ntr y. T he sa me la n g ua ge s h o ul d be use d b y  a partic ular s u bject t hr o u g h o ut t he st u d y. 
T he site pers o n nel a d mi nisteri n g t he q uesti o n naire s h o ul d be fa miliar wit h t he meas ures a n d t he 
ass ociate d user g ui des a n d trai ni n g materials pr o vi de d. T he s u bject s h o ul d c o m plete t he 
q uesti o n naires i n a q uiet area a n d be all o we d t o as k q uesti o ns; h o we ver site pers o n nel s h o ul d 
ta ke care n ot t o i nfl ue nce t he s u bject's res p o nses. T he s u bject will be i nstr ucte d t o pr o vi de t he 
tr uest a n d best res p o nse f or t he m.
8. 5. 1. 1
T h e C O P D a s s e s s m e nt t e st ( C A T)
T he C O P D assess me nt test ( C A T) is a s h ort i nstr u me nt use d t o q ua ntif y  the s ym pt o m b ur de n 
of C O P D a n d will be use d t o assess t he healt h stat us of s u bject s i n t his st u d y (J o nes et al 2 0 0 9 ). 
T he assess me nt will be c o m plete d b y  t he s u bject at t he be gi n ni n g of t he visit pri or t o a n y ot her 
assess me nt ta ki n g place, t o a v oi d i nfl ue nci n g s u bject res p o nses. T he C A T will be c o m plete d 
electr o nicall y b y the s u bject at t he i n vesti gat or's site at t he v isit sc he d ule i n dicate d i n Ta ble 8- 1 .
T he assess me nt c o nsists of ei g ht ite ms, eac h prese nte d as a se ma ntic 6 -p oi nt differe ntial scale, 
pr o vi di n g a t otal sc ore o ut of 4 0. A hi g her sc ore i n dicates a w orse healt h stat us. T he res ult is 
i m me diatel y availa ble wit h o ut t he nee d f or a n y  calc ulati o n, a part fr o m s u m mi n g t he sc ores o n 
i n di vi d ual ite ms. Sc ores of 0 - 1 0 ( mil d), 1 1 - 2 0 ( m o derate), 2 1 - 3 0 (se vere) a n d 3 1 - 4 0 
( ver y se vere) re prese nts t he cli nical i m pact of C O P D u p o n t he s u bject.
8. 5. 1. 2
St. G e or g e' s R e s pir at or y  Q u e sti o n n air e ( S G R Q)
T he St. Ge or ge Res pirat or y  Questi o n naire ( S G R Q) will be use d t o pr o vi de t he healt h stat us 
meas ure me nts i n t his st u d y (J o nes el al 1 9 9 2). T he S G R Q will be electr o nicall y c o m plete d b y 
t he s u bject at t he i n vesti gat or's site at t he visits i n dicate d i n t he Assess me nt sc he d ule.


N o v arti s
C o nfi d e nti al
P a g e 7 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T he S G R Q q uesti o n naire s h o ul d al wa ys be c o m plete d bef ore a n y ot her assess me nts (i ncl u di n g 
a n y ot her q uesti o n naires) are ma de t o a v oi d i nfl ue nci n g t he res p o nses. A detaile d g ui de relati n g 
t o t he a d mi nistrati ve pr oce d ures of t he q uesti o n naire is gi ve n i n S O M.
I nstr u me nt sc ori n g a n d ha n dli n g of missi n g ite m data will be c o n d ucte d i n acc or da nce wit h t he 
user g ui de f or t he S G R Q.
T he S G R Q c o ntai ns 5 0 ite ms di v i de d i nt o t w o parts c o veri n g t hree as pects of healt h relate d t o 
C O P D: Part I c o vers " S y m pt o ms" a n d is c o ncer ne d wit h res pirat or y s y m pt o ms, t heir fre q ue ncy 
a n d se verit y;  Part II c o vers " Acti vit y" a n d is c o ncer ne d wit h acti vities t hat ca use or are li mite d 
t o breat hless ness; Part II is als o c o ncer ne d wit h "I m pacts", w hic h c o vers a ra n ge of as pects 
c o ncer ne d wit h s ocial f u ncti o ni n g a n d ps y c h ol o gical dist ur ba nces res ulti n g fr o m air wa ys 
disease. A sc ore will be calc ulate d f or eac h of t hese t hree s u bscales a n d a "T otal" sc ore will 
als o be calc ulate d. I n eac h case t he l o west p ossi ble val ue is zer o a n d t he hi g hest 1 0 0. 
Hi g her val ues c orres p o n d t o greater i m pair me nt of healt h stat us.
8. 5. 1. 3
C o u g h A n d S p ut u m A s s e s s m e nt Q u e sti o n n air e ( C A S A -Q)
T he C A S A -Q is a vali date d q uesti o n naire i nstr u me nt use d t o meas ure c o u g h a n d s p ut u m 
pr o d ucti o n, a n d t heir i m pact i n s u bjects wit h c hr o nic o bstr ucti ve p ul m o nar y  disease ( C O P D) 
a n d/ or c hr o nic br o nc hitis (Cra wf or d et al 2 0 0 8 ). T he assess me nt will be c o m plete d b y  the 
s u bject at t he be gi n ni n g of t he visit pri or t o a n y ot her assess me nt ta ki n g place. T he C A S A -Q 
c o ntai ns a t otal of 2 0 ite ms o n a 5- ste p scale distri b ute d i n f o ur d o mai ns: C o u g h s ym pt o ms 
( C O U S; 3 ite ms), C o u g h i m pact ( C O UI; 8 ite ms), S p ut u m s ym pt o m s ( S P U S; 3 ite ms) a n d 
S p ut u m i m pact ( S P UI ; 6 ite ms).
T here are o nl y d o mai n sc ores a n d n o o verall sc ore. T he sc ore i n eac h d o mai n ra n ges fr o m 0 t o 
1 0 0, wit h l o wer sc ore i n dicati n g m ore se vere s y m pt o ms or a hi g her i m pact.
T he C A S A -Q will be c o m plete d electr onicall y  by t he s u bject at t he i n vesti gat or's site at t he visit 
sc he d ule i n dicate d i n Ta ble 8- 1 .
8. 5. 1. 4
E X A C T -P R O Q u e sti o n n air e
T he E X A C T -P R O is a vali date d 1 4 -ite m electr o nic q uesti o n naire desi g ne d t o detect t he 
fre q ue nc y, se verit y, a n d d urati o n of e xacer bati o ns i n s u bjects wit h C O P D (Lei d y et al 2 0 1 1 ; 
Lei d y et al 2 0 1 4a , Lei d y et al 2 0 1 4 b ). It is t o be c o m plete d b y  the s u bject at t he e n d of e ver y 
da y  at be dti me i n or der t o meas ure t he u n derl yi n g d a y  to d a y  v aria bilit y of C O P D, a n d detect 
w orse ni n g i n dicati ve of a n e xacer bati o n.
Wit hi n t he 1 4- ite m E X A C T -P R O t o ol, t he E val uati n g Res pirat or y  Sy m pt o ms ( E-R S ™) scale 
is base d o n t he 1 1 res pirat or y s ym pt o m ite ms. T hese 1 1 ite ms ge nerate a t otal sc ore, q ua ntif y i n g 
res pirat or y sy m pt o m se verit y overall, a n d 3 s u bscale sc ores assessi n g breat hless ness, c o u g h a n d 
s p ut u m, a n d c hest s ym pt o ms.
T he si n gle q uesti o n naire will be use d f or t w o f u ncti o ns: q ua ntificati o n of res pirat or y s ym pt o ms 
i n usi n g E- R S t otal a n d s u bscale sc ores, a n d t he assess me nt of ac ute e xacer bati o ns usi n g t he 
e ntire E X A C T -P R O i nstr u me nt.


N o v arti s
C o nfi d e nti al
P a g e 8 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8. 5. 1. 5
El e ctr o ni c Di ar y  ( e Di ar y)
At Scree ni n g all s u bjects will be pr o vi de d wit h a n electr o nic diar y  (e Diar y).
e Diar y will rec or d 
 bac k gr o u n d t hera py a n d st u d y dr u g me dicati o ns i nta ke 
( d ose) after ra n d o misati o n, as well as t he st u d y questi o n naires ( E X A C T-P R O ( dail y), C A T, 
C A S A -Q , S G R Q a n d E Q - 5 D-3 L ) at pres pecifie d ti me p oi nts. Refe r t o S O M f or details i n 
differe nt re gistrati o n starti n g ti me-p oi nts (f or bac k gr o u n d t hera p y, 
 
q uesti o n naires, st u d y  dr u g i nta ke).
 
 
Starti n g fr o m Da y 1, s u bjects will be re q uire d t o c o m plete t he 
E X A C T -P R O q uesti o n naire dail y  as well (see Secti o n 8. 5. 1. 4 f or E X A C T -P R O q uesti o n naire). 
T he e Diar y  is t o be re vie we d at eac h cli nic visit u ntil st u d y c o m pleti o n.
Sites a n d s u bjects will recei ve a p pr o priate trai ni n g a n d g ui da nce o n t he use of t he e Diar y de vice.
A list of e Diar y  q uesti o ns is pr o vi de d i n SO M.
8. 5. 1. 6
E Q -5 D -3 L
T he E ur o pea n Q ualit y of Li fe– 5 D i me nsi o ns– 3 Le vel ( E Q- 5 D-3 L ) de vel o pe d b y  the E ur o Q ol 
Gr o u p pr o vi des a sta n dar dize d self-re p orte d meas ure of healt h stat us. It is a si m ple, ge neric 
meas ure of healt h f or cli nical a n d ec o n o mic a p praisal ( E ur o Q ol Gr o u p 1 9 9 0). T he E Q - 5 D-3 L  
c o nsists of t w o pa ges – t he descri pti ve s yste m a n d t he E Q vis ual a nal o g ue scale ( E Q V A S). 
T he descri pti ve s yste m c o m prises fi ve di me nsi o ns ( m o bilit y, self-care, us ual acti vities, 
pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n), eac h wit h t hree le vels: n o pr o ble ms, s o me pr o ble ms, 
a n d e xtre me pr o ble ms. T he s u bject is as ke d t o i n dicate his/ her prese nt healt h state acc or di n g t o 
t he m ost a p pr o priate state me nt f or eac h of t he fi ve di me nsi o ns. T he E Q V A S rec or ds t he 
s u bjects’ self-rate d healt h o n a 2 0 c m vertical, vis ual a nal o g ue scale wit h e n d p oi nts la bele d ‘t he 
best healt h y o u ca n i ma gi ne’ a n d ‘t he w orst healt h y o u ca n i ma gi ne’. T here is n o recall peri o d 
a n d s u bject res p o n ds t o t he prese nt healt h stat us.
T he E Q - 5 D-3 L  will be use d f or t he p ur p os e of t he c o m p utati o n of utilities t hat ca n be use d i n 
healt h ec o n o mic st u dies. 
8. 5. 2 
P h ar m a c o ki n eti c s
Bl o o d sa m ples will be o btai ne d fr o m all s u bjects as per visits a n d ti me p oi nts i n dicate d i n 
Ta ble 8- 1 .
P har mac o ki netic bl o o d sa m plin g ( pre- a n d p ost -d ose) will be d o ne a n d e val uate d i n all s u bjects 
at Da y  1, D a y  28, D a y  56 a n d Da y  84 visit. A d diti o nall y , a s u bset of a p pr o xi matel y 30 t o 
4 0 s u bjects will u n der g o p har mac o ki netic serial sa m pli n g u p t o 8 h o urs p ost -d ose at t he 
be gi n ni n g of
t he treat me nt o n D a y  1 an d Da y  28 as per Ta ble 8 - 1, t o e xa mi ne t he 
ti me-c o nce ntrati o n pr ofiles of Q B W 2 5 1 after si n gle d ose a n d m ulti ple d oses i n C O P D s u bjects.
F urt her m ore, a d diti o nal P K sa m ples will 
be c ollecte d, w here 
p ossi b le, fr o m s u bjects 
e x perie nci n g a treat me nt -e mer ge nt S A E, u nless a sc he d ule d P K sa m pli n g occ urs wit hi n 7 da ys 
of t he start date of t he S A E.
C CI
C CI
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 8 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
W hile 
P K sa m pli n g occ urs als o i n s u bjects recei vi n g place b o, plas ma P K sa m ples will be 
e val uate d o nl y i n s u bjects w h o ha ve bee n a d mi nistere d Q B W 2 5 1. Q B W 2 5 1 will be a nal yz e d 
b y  a vali date d L C-M S/ M S met h o d wit h a n a ntici pate d l o wer li mit of q ua ntificati o n ( L L O Q) of 
1 n g/ m L of Q B W 2 5 1. C o nce ntrati o n bel o w t he L L O Q will be re p orte d as zer o a n d missi n g data 
will be la bele d as s uc h i n t he bi oa nalyt ical re p ort.
F or sta n dar d p har mac o ki netic a b bre viati o ns a n d defi niti o ns see t he list pr o vi de d at t he 
be gi n ni n g of t his pr ot oc ol.
T he f oll o wi n g p har mac o ki netic para meters will be deter mi ne d usi n g t he act ual rec or de d 
sa m pli n g ti mes a n d n o n- c o m part me ntal met h o d(s) wit h P h oe ni x Wi n N o nli n ( Versi o n 6. 4 or 
hi g her): C ma x, T ma x, A U Clast, A U C 0- 8 h, T 1/ 2 fr o m t he plas ma c o nce ntrati o n- ti me data.
8. 5. 3
Bi o m ar k er s
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 8 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
8. 5. 4
Ot h er A s s e s s m e nt s
N ot a p plica ble.
9
St u d y  di s c o nti n u ati o n a n d c o m pl eti o n
9. 1
Di s c o nti n u ati o n
9. 1. 1
Di s c o nti n u ati o n of st u d y tr e at m e nt
Disc o nti n uati o n of st u d y  treat me nt f or a s u bject occ urs w he n st u d y treat me nt is st o p pe d earlier 
t ha n t he pr ot oc ol pla n ne d d urati o n, a n d ca n be i nitiate d b y eit her t he s u bject or t he i n vesti gat or.
T he i n vesti gat or m ust disc o nti n ue st u d y treat me nt f or a gi ve n s u bject if, he/s he belie ves t hat 
c o nti n uatio n w o ul d ne gati vel y  i m pact t he s u bject's well-bei n g.
St u d y  treat me nt m ust 
be per ma ne ntl y disc o nti n ue d f or a s u bject u n der t he f oll o wi n g 
circ u msta nces:

S u bject/ g uar dia n decisi o n

Pre g na nc y

Use of pr o hi bite d treat me nt as per rec o m me n dati o ns i n t he pr o hi bite d treat me nt 
Secti o n 6. 2. 2

A n y  sit uati o n i n w hic h st u d y partici pati o n mi g ht res ult i n a safety ris k t o t he s u bject (e. g. 
h os pitalizati o n)

F oll o wi n g e mer ge nc y u n bli n di n g
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 8 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

E mer ge nce of A E re p orte d as se vere a n d s us pecte d t o be relate d t o i n vesti gati o nal dr u g or 
a n S A E re p orte d a n d s us pecte d t o be relate d t o i n vesti gati o nal dr u g

E mer ge nce of a n S A E n ot s us pecte d t o be relate d t o i n vesti gati o nal dr u g i n a s u bject w it h 
a verifie d e x p os ure a b o ve t he t hres h ol d A U C 0 -2 4 h ≥9 1 ,7 0 0 n g * h/ ml. T he i n vesti gat or 
m ust per ma ne ntl y  disc o nti n ue t he i n vesti gati o nal st u d y dr u g as s o o n as p ossi ble u p o n 
recei pt of t he P K res ults.

A s u bject wit h a verifie d e x p os ure a b o ve t he u p per ra n ge o f t he i n di vi d ual a ni mal 
( m o n ke y) m o del e x p os ure ( A U C 0-2 4 h ≥1 5 9 ,0 0 0 n g * h/ ml). T he i n vesti gat or m ust st o p 
st u d y dr u g  as s o o n as p ossi ble u p o n recei pt of t he P K res ults.

A n y  la b orat or y a b n or malities t hat i n t he j u d g me nt of t he i n vesti gat or, ta ki n g i nt o 
c o nsi derati o n t he s u bject’s o verall stat us, pre ve nts t he s u bject fr o m c o nti n ui n g 
partici pati o n i n t he st u d y

A n y  li ver e ve nt re q uiri n g i m me diate disc o nti n uati o n of st u d y treat me nt, as s pecifie d 
i n Ta ble 1 6 - 2

I ndi vi d ual ser u m creati n i ne i ncrease ≥ 5 0 % c o m pare d t o baseli ne ( m ust be 
c o nfir me d). C o nfir mati o n of t he assess me nt s h o ul d be ma de as q uic kl y as p ossi ble after a n 
a b n or mal res ult is recei ve d. A re nal e ve nt lea di n g t o s u bject disc o nti n uati o n s h o ul d be 
f oll o we d u p u ntil e ve nt res ol uti o n ( Ser u m Cr wit hi n 1 0 % of baseli ne), or e ve nt 
sta bilizati o n ( Ser u m Creati ni ne le vel wit hi n ± 1 0 % varia bilit y o ver last 6 m o nt hs)

St u d y  dr u g ca n be te m p orarily i nterr u pte d as a res p o nse t o t he occ urre nce of a d verse 
e ve nts t hat d o n ot f ulfill t he re q uire m e nts a b o ve descri be d f or per ma ne nt disc o nti n uati o n 
(refer t o Secti o n 6. 5. 1 ).
As a c o nse q ue nce, i n vesti gati o nal st u d y dr u g m ust be per ma ne ntl y disc o nti n ue d i n a s u bject 
e x hi biti n g

a n esti mate d A U C 0-2 4 h > 9 1 ,7 0 0 n g * hr/ ml i n a ss ociati o n wit h a re p orte d S A E
or

a n esti mate d A U C 0-2 4 h > 1 5 9 ,0 0 0 n g * hr/ ml e ve n i n t he a bse nce of a n y S A E ( please see 
m ore details re gar di n g t his t o pic o n Secti o n 6. 5. 1. 1 ) .
If a fe male s u bject of c hil d beari n g p ote ntial w it h dra ws fr o m t he st u d y pre mat urely, t he 
i n vesti gat or s h o ul d rec o m me n d her t o mai ntai n c o ntrace pti ve meas ures f or at least 3 da ys after 
t he last d ose of t he st u dy dr u g.
If per ma ne nt disc o nti n uati o n of st u d y treat me nt occ urs, t he i n vesti gat or s h o ul d ma ke a 
reas o na ble eff ort t o u n dersta n d t he pri mar y  reas o n f or t he s u bject’s pre mat ure disc o nti n uati o n 
of st u d y  treat me nt a n d rec or d t his i nf or mati o n.
T he i n vesti gat or m ust als o c o ntact t he I RT t o re gister t he s u bject’s disc o nti n uati o n fr o m st u d y 
treat me nt.
If dis c o nti n uati o n occ urs beca use treat me nt c o de has bee n br o ke n, please refer t o E mer ge nc y 
brea ki n g of treat me nt c o de Secti o n 6. 6. 3 .
S u bjects w h o ha ve t heir st u d y treat me nt per ma ne ntl y disc o nti n ue d s h o ul d N O T be c o nsi dere d 
wit h d ra w n fr o m t he st u d y UN L E S S t he y wit h dra w t heir c o nse nt (see wit h dra w of i nf or me d 
c o nse nt secti o n). W here p ossi ble, t he y s h o ul d ret ur n f or t he assess me nts i n dic ate d i n t he 


N o v arti s
C o nfi d e nti al
P a g e 8 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
assess me nt sc he d ule i n Ta ble 8- 1 . If t he y fail t o ret ur n f or t hese assess me nts f or u n k n o w n 
reas o ns, e ver y eff ort (e. g. tele p h o ne, e-mail, letter) s h o ul d be ma de t o c o ntact t he s u bject/ pre-
desi g nate d c o ntact as s pecifie d i n t he l ost t o f oll o w -u p secti o n. T his c o ntact s h o ul d prefera bl y 
be d o ne acc or di n g t o t he st u d y  visit sc he d ule. If t he s u bject ca n n ot or is u n willi n g t o atte n d a ny 
visit(s), t he site staff s h o ul d mai ntai n re g ular tele p h o ne c o ntact wit h t he s u bject, or wit h a pers o n 
pre -desi g nate d b y  the s u bject. T his tele p h o ne c o ntact s h o ul d prefera bl y be d o ne ac c or di n g t o 
t he st u d y visit sc he d ule a n d at a mi ni m u m i nf or mati o n o n ne w/ c o nc o mita nt treat me nts a n d 
a d verse e ve nts /seri o us a d verse e ve nts s h o ul d be o btai ne d.
9. 1. 2
Wit h dr a w al of i nf or m e d c o n s e nt
S u bjects ma y  vol u ntaril y  wit h dra w c o nse nt t o partici pate i n t he stu d y  for a n y reas o n at a n y ti me. 
Wit h dra wal of c o nse nt occ urs o nl y w he n a s u bject:

D oes n ot wa nt t o partici pate i n t he st u d y  a n ym ore, a n d

D oes n ot all o w f urt her c ollecti o n of pers o nal data
I n this sit uati o n, t he i n vesti gat or s h o ul d ma ke a reas o na ble eff ort (e. g. tele p h o ne, e-mail, letter) 
t o u n dersta n d t he pri mar y reas o n f or t he s u bject’s decisi o n t o wit h dra w his/ her c o nse nt a n d 
rec or d t his i nf or mati o n.
St u d y  treat me nt m ust be disc o nti n ue d a n d n o f urt her assess me nts c o n d ucte d, a n d t he data t hat 
w o ul d ha ve be e n c ollecte d at s u bse q ue nt visits will be c o nsi dere d missi n g.
F urt her atte m pts t o c o ntact t he s u bject are n ot all o we d u nless safet y fi n di n gs re q uire 
c o m m u nicati n g or f oll o w - u p.
All eff orts s h o ul d be ma de t o c o m plete t he assess me nts pri or t o st u d y wit h dra wal. A fi nal 
e val uati o n at t he ti me of t he s u bject’s st u d y wit h dra wal s h o ul d be ma de as detaile d i n t he 
assess me nt ta ble (Ta ble 8 - 1).
N o vartis will c o nti n ue t o kee p a n d use c ollecte d st u d y inf or mati o n (i ncl u di n g a n y d ata res ulti n g 
fr o m t he a nal ysis of a s u bject’s sa m ples u ntil t he ti me of wit h dra wal) acc or di n g t o a p plica ble 
la w.
F or E U a n d U S: All bi ol o gical sa m ples n ot yet a nal yze d at t he ti me of wit h dra wal will n o l o n ger 
be use d, u nless per mitte d b y  ap plica ble la w. T he y will be st ore d acc or di n g t o a p plica ble le gal 
re q uire me nts.
9. 1. 3
L o st t o f oll o w -u p
F or s u bjects w h ose stat us is u nclear beca use t he y  fail t o a p pear f or st u d y visits wit h o ut stati n g 
a n i nte nti o n t o disc o nti n ue or wit h dra w, t he i n vesti gat or m ust s h o w " d ue dili ge nce" b y  
d o c u me nti n g i n t he s o urce d oc u me nts ste ps ta ke n t o c o ntact t he s u bject, e. g. dates of tele p h o ne 
calls, re gistere d letters, etc. A s u bject s h o ul d n ot be c o nsi dere d as l ost t o f oll o w-u p u ntil d ue 
dili ge nce has bee n c o m plete d.


N o v arti s
C o nfi d e nti al
P a g e 8 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
9. 1. 4
St u d y st o p pi n g r ul e s
9. 1. 4. 1
D o s e R e d u cti o n
9. 1. 4. 3
O v er all st u d y  st o p pi n g r ul e s
E nr oll me nt i n t he st u d y  will be place d o n h ol d if t he S p o ns or c o nsi ders t hat t he n um ber a n d/ or 
se verity of A Es, a b n or mal safet y mo nit ori n g tests, or a b n or mal la b orat or y fi n di n gs j ustif y 
p utti n g t he st u d y  o n h ol d. Relate d criteria are defi ne d i n t he D M C c harter.
T he st u d y ma y res u me f oll o wi n g t he f ull safety re vie w, if t he Pri nci pal I n vesti gat or a n d S p o ns or 
a gree it is safe t o pr ocee d. A n y restart f oll o wi n g a te m p orar y h ol d d ue t o st o p pi n g r ules bei n g 
met will re q uire t he C o m pete nt A ut h orities a n d Et hic C o m mittees t o a p pr o ve t he st u d y to 
pr ocee d, as re q uire d per c o u ntr y  re g ulati o ns.
I n case of si g nifica nt e x p os ure sce nari os, st u d y ma y be st o p pe d after D M C re vie w.  Relate d 
criteria are defi ne d i n t he D M C c harter.  See als o Secti o n 6. 5. 1.
9. 1. 5
E arl y  st u d y t er mi n ati o n b y t h e s p o n s or
T he st u d y  ca n be ter mi nate d b y N ovartis at a n y  ti me f or a n y reas o n. T his ma y i ncl u de reas o ns 
relate d t o t he be nefit/ ris k assess me nt of partici pati n g i n t he st u d y, practical reas o ns (i ncl u di n g 
sl o w e nr oll me nt), or f or re g ulat or y or me dical reas o ns. E x p os ure dri ve n decisi o n r ules are 
descr i be d bel o w i n Secti o n 9. 1. 4. 1 . I n ta ki n g t he decisi o n t o ter mi nate, N o vartis will al wa ys 
c o nsi der t he s u bject welfare a n d safety. S h o ul d earl y ter mi nati o n be necessar y , s u bjects m ust 
be see n as s o o n as p ossi ble. T he I n vesti gat or s h o ul d e ns ure c o ntact is ma de as q uic kl y as 
p ossi ble b y  tele p h o ne a n d/ or e-mail a n d/ or letter. If t he st u d y is st o p pe d f or a c ha n ge i n t he 
be nefit/ris k assess me nt or f or me dical reas o ns, s u bjects m a y  be i nstr ucte d t o st o p ta ki n g t he 
i n vesti gati o nal dr u g Q B W 2 5 1 i m me diatel y. Else, s u bjects m a y  be i nstr ucte d t o c o nti n ue 
Q B W 2 5 1 i nta ke u ntil t he y ca n ret ur n t o t he site f or a fi nal assess me nt. Bac k gr o u n d me dicati o n 
L A B A/ L A M A, L A B A/I C S or L A B A/ L A M A/I C S or macr oli des s h o ul d be c o nti n ue d u ntil t he 
fi nal visit. T he s u bject s h o ul d be treate d as a pre mat urel y  wit h dra w n s u bject a n d u n der g o all 
assess me nts of t he pre mat ure wit h dra wal visit. T he i n vesti gat or ma y  be i nf or me d of a d diti o nal 
pr oce d ures t o be f oll o we d i n or der t o e ns ure t hat a de q uate c o nsi derati o n is gi ve n t o t he 
pr otecti o n of t he s u bject’s i nterests. T he i n vesti gat or or s p o ns or de pe n di n g o n t he l ocal 
re g ulati o n will be res p o nsi ble f or i nf or mi n g I RBs/I E Cs of t he earl y ter mi nati o n of t he trial.
9. 2
St u d y c o m pl eti o n a n d p o st -st u d y  tr e at m e nt
St u d y  co m pleti o n is defi ne d as w he n t he last s u bject fi nis hes t heir e n d of st u d y (E O S) 
c o m pleti o n visit a n d a n y re peat assess me nts ass ociate d wit h t his visit ha ve bee n d oc u me nte d 
a n d f oll o we d -u p a p pr o priatel y  b y t he I n vesti gat or or, i n t he e ve nt of a n earl y st u dy ter mi n ati o n 
decisi o n, t he date of t hat decisi o n (e. g. eac h s u bject will be re q uire d t o c o m plete t he st u d y i n its 
e ntiret y a n d t hereafter n o f urt her st u d y treat me nt will be ma de a vaila ble t o t he m).
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 8 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
U p o n c o m pleti o n of a s u bject's partici pati o n i n t he st u d y, he/s he s h o ul d be treate d acc or di n g t o 
his/ her i n di vi d ual nee ds. It is n ot pla n ne d t o pr o vi de Q B W 2 5 1 t o st u d y partici pa nts after t he 
st u d y is c o m plete d d ue t o t he earl y sta ge of de vel o p me nt. Si nce t his st u d y is a P hase 2 st u d y, 
t he safety pr ofile of t he dr u g has n ot y et bee n esta blis he d t o t he e xte nt c o nsi dere d a de q uate f or 
a pr o visi o n of Q B W 2 5 1 wit h less stri n ge nt safet y m o nit ori n g. 
Ra n d o mize d a n d/ or treate d s u bjects will ha ve a safety f oll o w- u p call c o n d ucte d 3 0 da y s after 
last a d mi nistrati o n of st u d y treat me nt. T he i nf or mati o n c ollecte d is ke pt as s o urce 
d oc u me ntati o n. All S A Es re p orte d d uri n g t his ti me peri o d m ust be re p orte d as descri be d i n 
Secti o n 1 0. 1. 3 a n d i n t he S O M. D oc u me ntati o n of atte m pts t o c o ntact t he s u bject s h o ul d be 
rec or de d i n t he s o urce d oc u me ntati o n.
1 0
S af et y  m o nit ori n g a n d r e p orti n g
1 0. 1
D efi niti o n of a d v er s e e v e nt s a n d r e p orti n g r e q uir e m e nt s
1 0. 1. 1
A d v er s e e v e nt s
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce (e. g. a n y unfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a b n or mal la b orat or y fi n di n gs), s ym pt o m or disease) i n a s u bject 
after pr o vi di n g writte n i nf or me d c o nse nt f or partici pati o n i n t he st u d y. T heref ore, a n A E ma y 
or ma y  not be te m p orall y or ca usall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) 
pr o d uct.
T he i n vesti gat or has t he res p o nsi bilit y for ma na gi n g t he safety of i n di vi d ual s u bject a n d 
i de ntif yi n g A Es.
N o vartis q ualifie d me dical pers o n nel will be rea dil y  a vaila ble t o a d vise o n trial relate d me dical 
q uesti o ns or pr o ble ms.
T he occ urre nce of A Es m ust be s o u g ht b y n o n -directi ve q uesti o ni n g of t he s u bject at eac h visit 
d uri n g t he st u d y. A Es als o ma y  be detecte d w he n t he y are v ol u nteere d b y t he s u bject d uri n g or 
bet wee n visits or t hr o u g h p h y sical e xa mi nati o n fi n di n gs, la b orat or y test fi n di n gs, or ot he r 
assess me nts.
A Es m ust 
be rec or de d u n der t he si g ns, s ym pt o ms, 
or dia g n osis ass ociate d wit h t he m, 
acc o m pa nie d b y  the f oll o wi n g i nf or mati o n (as far as p ossi ble) (if t he e ve nt is seri o us refer 
t o Secti o n 1 0. 1. 2 ):
1.
T he se verit y gra de:
2.
mil d: us uall y  tra nsie nt i n nat ure a n d ge nerall y n ot i nterferi n g wit h n or mal acti vities
3.
m o derate: s ufficie ntl y  disc o mf orti n g t o i nterfere wit h n or mal acti vities
4.
se vere: pre ve nts n or mal acti vities
5.
Its relati o ns hi p t o t he st u d y treat me nt. If t he e ve nt is d ue t o lac k of efficac y or pr o gressi o n 
of u n derl yi n g ill ness (i.e. pr o gressi o n of t he st u d y  i n dicati o n) t he assess me nt of ca usality 
will us uall y  be ‘ N ot s us pecte d.’ T he rati o nale f or t his g ui da nce is t hat t he s ym pt o ms of a 
lac k of efficac y or pr o gressi o n of u n derl yi n g ill ness are n ot ca use d b y t he trial dr u g, t he y 
ha p pe n i n s pite of its a d mi nistrati o n a n d/ or b ot h lac k of efficac y  a n d pr o gressi o n of 


N o v arti s
C o nfi d e nti al
P a g e 8 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
u n derl y i n g disease ca n o nl y be e val uate d mea ni n gf ully b y a n a nal ys is of c o h orts, n ot o n a 
si n gle s u bject
6.
Its d urati o n (start a n d e n d dates) or if t he e ve nt is o n g oi n g, a n o utc o me of n ot 
rec o vere d/ n ot res ol ve d m ust be re p orte d
7.
W het her it c o nstit utes a S A E (see
Secti o n 1 0. 1. 2 f or defi niti o n of S A E) a n d w hic h 
seri o us ness criteria ha ve bee n met
8.
Acti o n ta ke n re gar di n g wit h st u d y  treat me nt
All A Es m ust be treate d a p pr o priatel y. Treat me nt ma y i ncl u de o ne or m ore of t he f oll o wi n g:

D ose n ot c ha n ge

Dr u g i nterr u pte d/ wit h dra w n

its o utc o me (i.e. rec o ver y stat us or w het her it was fatal)
C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or de d i n 
me dical hist or y  of t he s u bject.
A Es (i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d usi n g a dia g n osis 
w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.
A d verse e ve nt m o nit ori n g s h o ul d be c o nti n ue d f or at least 3 0 d a y s f oll o wi n g t he last d ose of 
st u d y treat me nt.
O nce a n a d verse e ve nt is detecte d, it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d t o 
be per ma ne nt (e.g. c o nti n ui n g at t he e n d of t he st u d y), a n d assess me nt m ust be ma de at eac h 
visit ( or m ore fre q ue ntl y, if necessar y) of a n y c ha n ges i n se verit y, t he s us pecte d relati o ns hi p t o 
t he i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me.
I nf or mati o n a b o ut a d verse dr u g reacti o ns f or t he i n vesti gati o nal dr u g ca n be f o u n d i n t he 
I n vesti gat or's Br oc h ure (I B).
A b n or mal la b orat or y val ues or test res ults c o nstit ute A Es o nl y if t h e y fulfill at least o ne of t he 
f oll o wi n g criteria:

t he y i n d uce cli nical si g ns or s ym pt o ms

t he y are c o nsi dere d cli nicall y si g nifica nt

t he y re q uire t hera p y
Cli nicall y  si gnifica nt a b n or mal la b orat or y val ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val ues o utsi de of n or mal ra n ges/cli nicall y nota ble ra n ges, si g nifica nt c ha n ges fr o m 
baseli ne or t he pre vi o us visit, or val ues t hat are c o nsi dere d t o be n o n- t ypical i n s u bjects wit h 
t he u n derl y i n g disease. Alert ra n ges f or la b orat or y an d ot her test a b n or malities are refere nce d 
i n Secti o n 1 6. 1 .
F oll o w t he i nstr ucti o ns f o u n d i n t he Site O perati o ns Ma n ual f or data ca pt ure met h o d ol o g y 
re gar di n g A E c ollecti o n f or s u bjects t hat fail scree ni n g.
1 0. 1. 2
S eri o u s a d v er s e e v e nt s
A n S A E is defi ne d as a n y ad verse e ve nt [a p peara nce of ( or w orse ni n g of a n y pre-e xisti n g)] 
u n desira ble si g n(s), s ym pt o m(s), or me dical c o n diti o ns(s) w hic h meets a n y o ne of t he f oll o wi n g 
criteria:


N o v arti s
C o nfi d e nti al
P a g e 8 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

fatal

life-t hreate ni n g
Life -t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he s u bject was at ris k of 
deat h at t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot heticall y  mi ght ha ve 
ca use d de at h if it were m ore se vere ( please refer t o t he I C H -E 2 D G ui deli nes).

res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y

c o nstit utes a c o n ge nital a n o mal y / birt h defect

re q uires i ns 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, u nless 
h os pitalizati o n is f or: 

r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n

c o n diti o n t hat is u nrelate d t o t he i n dicati o n u n der st u d y  a n d has n ot w orse ne d si nce 
si g ni n g t he i nf or me d c o nse nt

s ocial reas o ns a n d res pite care i n t he a bse nce of a n y  deteri orati o n i n t he s u bject’s 
ge neral c o n diti o n

treat me nt o n a n e mer ge nc y o uts u bject basis f or a n e ve nt n ot f ulfilli n g a ny of t he 
defi niti o ns of a S A E gi ve n a b o ve a n d n ot res ulti n g i n h os pital a d missi o n

is me dicall y si g nifica nt, e. g. defi ne d as a n e ve nt t hat je o par dizes t he s u bject or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o us reacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht 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 mi g ht je o par dize t he s u bject or mi g ht 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o u tc o mes liste d a b o ve. S uc h e ve nts s h o ul d be 
c o nsi dere d as “ me dicall y si g nifica nt.” E xa 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 ro o m or at h o me f or aller gic br o nc h os pas m, bl o o d d y scrasias, 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 de pe n de nc y  or a b use ( please refer t o t he 
I C H-E 2 D G ui deli nes).
All mali g na nt ne o plas ms will be assesse d as seri o us u n der “ me dicall y si g nifica nt” if ot her 
seri o us ness criteria are n ot met an d t he mali g na nt ne o plas m is n ot a disease pr o g ressi o n of t he 
st u d y i n dicati o n.
A n y  s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n i nfecti o us a ge nt is als o c o nsi dere d a 
seri o us a d verse reacti o n.
All re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d seri o us a d verse 
e ve nt irres pecti ve if a cli nical e ve nt has occ urre d.
1 0. 1. 3
S A E r e p orti n g
T o e ns ure s u bject safety, e ver y SA E, re gar dless of ca usalit y, occ urri n g after t he s u bject has 
pr o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da y s after t he last st u d y visit m ust be re p orte d t o 
N o vartis wi t hi n 2 4 h o urs of lear ni n g of its occ urre nce as descri be d bel o w. A n y S A Es 
e x perie nce d after t his peri o d s h o ul d o nl y  b e re p orte d t o N o vartis if t he i n vesti gat or s us pects a 
ca usal relati o ns hi p t o st u d y  treat me nt.


N o v arti s
C o nfi d e nti al
P a g e 8 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Scree n F ail ures: If a s u bject fails scree ni n g (e. g. a s u bject w h o is scree ne d b ut is n ot treate d or 
ra n d o mize d), S A Es occ urri n g after t he s u bject has pr o vi de d i nf or me d c o nse nt u ntil t he ti me t he 
s u bject is dee me d a Scree n Fail ure m ust be re p orte d t o N o vartis.
R a n d o mize d S u bjects w h o disc o nti n ue pre m at urel y : S A Es c ollecte d bet wee n t he ti me a 
s u bject si g ns t he IC F u ntil 3 0 da y s after t he s u bject disc o nti n ue d or st o p pe d st u d y treat me nt, or 
ha d t heir last st u d y visit, w hic h e ver is later s h o ul d be re p orte d t o N o vartis/s p o ns or safety wit hi n 
2 4 h o urs of lear ni n g of its occ urre nce.
All f oll o w -u p i nf or mati o n f or t he S A E i ncl u di n g i nf or mati o n o n c o m plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w- u p t o t he ori gi nal e pis o de 
i m me diatel y, wit h o ut u n d ue dela y , a n d u n der n o circ u msta nces later t ha n  24 h o urs of t he 
i n vesti gat or recei vi n g t he f oll o w-u p i nf or mati o n. A n S A E occ urri n g at a differe nt ti me i nter val 
or ot her wise c o nsi dere d c o m pletel y unrelate d t o a pre vi o usl y re p orte d o ne m ust be re p orte d 
se paratel y as a ne w e ve nt.
If t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I nsert ( ne w 
occ urre nce) a n d is t h o u g ht t o be relate d t o t he st u d y treat me nt, a N o vartis C hief Me dical Office 
a n d s u bject Safet y ( C M O & P S) De part me nt ass ociate ma y  ur ge ntl y req uire f urt her i nf or mati o n 
fr o m t he i n vesti gat or f or healt h a ut h orit y re p orti n g. N o vartis ma y nee d t o iss ue a n I n vesti gat or 
N otificati o n (I N) t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y st u d y wit h t he sa me st u d y treat me nt 
t hat t his S A E has bee n re p orte d.
S u s pecte d U ne x pecte d Seri o us A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o 
t he c o m pete nt a ut h orities a n d rele va nt et hics c o m mittees i n acc or da nce wit h E U G ui da nce 
2 0 1 1/ C 1 7 2/ 0 1 or as per nati o nal re g ulat or y  re q uire me nts i n partici pati n g c o u ntries.
F oll o w t he detaile d i nstr ucti o ns o utli ne d i n t he Site O perati o ns Ma n ual 
re gar di n g t he 
s u b missi o n pr ocess f or re p orti n g S A Es t o N o vartis. N ote: S A Es m ust be re p orte d t o N o v artis 
wit hi n 
2 4 h o urs of t he i n vesti g at or le ar ni n g of its occ urre nce/recei vi n g f oll o w -u p 
i nf or m ati o n.
1 0. 1. 4
Pr e g n a n c y  r e p orti n g
T o e ns ure s u bject safet y, eac h pre g na nc y occ urri n g after si g ni n g t he i nf or me d c o nse nt m ust be 
re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. T he pre g na nc y  sh o ul d b e 
f oll o we d u p t o deter mi ne o u tc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y  t er mi nati o n, details of 
t he birt h, a n d t he prese nce or a bse nce of a n y b irt h defects, c o n ge nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns.
Pre g na nc y  sh o ul d be rec or de d a n d re p orte d b y  the i n vesti gat or t o t he N o vartis C hief Me dical 
Office a n d s u bject Safet y  (C M O & P S). Pre g na nc y f oll o w- u p s h o ul d be rec or de d o n t he sa me 
f or m a n d s h o ul d i ncl u de a n assess me nt of t he p ossi ble relati o ns hi p t o t he i n vesti gati o nal st u d y 
dr u g a n y pre g na nc y o utc o me. A n y S A E e x peri e nce d d uri n g pre g na nc y m ust be re p orte d.
F oll o w u p of pre g na ncies s h o ul d be c o n d ucte d as descri be d bel o w:

At e x pecte d date of deli ver y  ( E D D) + 1 m o nt h: Ma n dat or y t o all pre g na nc y cases; 
pre g na nc y  o utc o me, a n d ot her cli nically rele va nt pre g na nc y data or c ha n ges i n data, 
s h o ul d be c ollecte d.


N o v arti s
C o nfi d e nti al
P a g e 9 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

At E D D + 2 m o nt hs: Ma n dat or y  if n o a ns wer is o btai ne d after re q uest at E D D + 1 m o nt h; 
sa me i nf or mati o n as at E D D + 1 m o nt h s h o ul d be c ollecte d.

At E D D + 3 m o nt hs: Ma n dat or y  f or all cases of li ve birt h/ u n k n o w n o utc o me; stat us of the 
ba b y  3 m o nt hs after deli ver y, a ny de vel o p me nt iss ue or a b n or malit y t hat w o ul d n ot be 
see n at birt h

E D D + 1 2 m o nt hs: Ma n dat or y  f or all cases of li ve birt h/ u n k n o w n o utc o me; i nfa nt healt h 
stat us a n d de vel o p me nt
1 0. 1. 5
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g m i s u s e/ a b u s e
Me dicati o n err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me dici ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, s u bject or 
c o ns u mer ( E M A defi niti o n).
Mis use refers t o sit uati o ns w here t he me dici nal pr o d uct is i nte nti o nall y an d i na p pr o priately use d 
n ot i n acc or da nce wit h t he pr ot oc ol.
A b use c orres p o n ds t o t he persiste nt or s p ora dic i nte nti o nal e xcessi ve use of a me dici nal pr o d uct, 
w hic h is acc o m pa nie d b y har mf ul p h ys ical or psyc h ol o gical effects.
St u d y  treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be rec or de d o n 
t he a p pr o priate C R F irres pecti ve of w het her or n ot ass ociate d wit h a n A E/ S A E a n d re p orte d t o 
Safet y  onl y if ass ociate d wit h a n S A E. Mis use or a b use wi ll be c ollecte d a n d re p orte d i n t he 
safety data base irres pecti ve of it bei n g ass ociate d wit h a n A E/ S A E wit hi n 2 4 h o urs of 
I n vesti gat or’s a ware ness.
T a bl e 1 0 - 1
G ui d a n c e f or c a pt uri n g t h e st u d y  tr e at m e nt err or s i n cl u di n g 
mi s u s e/ a b u s e
Tr e at m e nt err or t y p e
D o c u m e nt i n D o si n g 
C R F ( Y e s/ N o)
D o c u m e nt i n A E 
e C R F
C o m pl et e S A E f or m
U ni nt e nti o n al st u d y 
tr e at m e nt err or
Y e s
O nl y if a s s o ci at e d wit h 
a n A E
O nl y if a s s o ci at e d wit h 
a n S A E
Mi s u s e/ A b u s e
Y e s
Y e s
Y e s, e v e n if n ot 
a s s o ci at e d wit h a S A E
F or m ore i nf or mati o n o n A E a n d S A E defi niti o n a n d re p orti n g re q uire me nts, please see t he 
res pecti ve secti o ns ( A E Secti o n 1 0. 1. 1 , S A E defi niti o n Secti o n 1 0. 1. 2 a n d S A E re p orti n g 
Secti o n 1 0. 1. 3 ).
1 0. 2
A d diti o n al S af et y  M o nit ori n g
1 0. 2. 1
Li v er s af et y m o nit ori n g
T o e ns ure s u bject safet y an d e n ha nce relia bilit y i n deter mi ni n g t he he pat ot o xic p ote ntial of a n 
i n vesti gati o nal dr u g, a sta n dar dize d pr ocess f or i de ntificati o n, m o nit ori n g a n d e val uati o n of 
li ver e ve nts has t o be f oll o we d.
T he f oll o wi n g t w o cate g ories of a b n or malities / a d verse e ve nts ha ve t o be c o nsi dere d d uri n g 
t he c o urse of t he st ud y  (irres pecti ve of w het her classifie d/re p orte d as A E/ S A E):


N o v arti s
C o nfi d e nti al
P a g e 9 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

Li ver la b orat or y  tri g gers, w hic h will re q uire re peate d assess me nts of t he a b n or mal 
la b orat or y para meter

Li ver e ve nts, w hic h will re q uire cl ose o bser vati o n, f oll o w- u p m o nit ori n g a n d c o ntri b uti n g 
fact ors are rec or de d o n t he a p pr o priate C R Fs
Please refer t o Ta ble 1 6- 1 i n Secti o n 1 6. 2 f or c o m plete defi niti o ns of li ver la b orat or y tri g gers 
a n d li ver e ve nts.
E ver y  li ver e ve nt defi ne d i n Ta ble 1 6- 1 s h o ul d be f oll o we d u p b y  the i n vesti gat or or desi g nate d 
pers o n nel at the trial site, as s u m marize d bel o w. A d diti o nal details o n acti o ns re q uire d i n case 
of li ver e ve nts are o utli ne d i n Ta ble 1 6- 2 . Re peat li ver c he mistr y tests (i.e. A L T, A S T, T B L, 
P T/I N R, A L P a n d G -G T) t o c o nfir m ele vati o n.
T hese li ver c he mistr y  re peats will be perf or me d usi n g t he ce ntral la b orat or y. If res ults will n ot 
be a vaila ble fr o m t he ce ntral la b orat or y, t he n t he re peats ca n als o be perf or me d at a l ocal
la b orat or y to m o nit or t he safety of t he s u bject. If a li ver e ve nt is s u bse q ue ntl y re p orte d, a n y 
l ocal li ver c he mistr y tests pre vi o usl y c o n d ucte d t hat are ass ociate d wit h t his e ve nt s h o ul d ha ve 
res ults rec or de d o n t he a p pr o priate e C R F.

If t he i nitial ele vati o n is c o nfir me d, cl ose o bser vati o n of t he s u bject will be i nitiate d, 
i ncl u di n g c o nsi derati o n of treat me nt i nterr u pti o n if dee me d a p pr o priate.

Disc o nti n uati o n of t he i n vesti gati o nal dr u g (refer t o t he Disc o nti n uati o n of st u d y  treat me nt 
secti o n), if a p pr o priate

H os pitalizati o n of t he s u bject if a p pr o priate

Ca usalit y  assess me nt of t he li ver e ve nt

T h or o u g h f oll o w -u p of t he li ver e ve nt s h o ul d i ncl u de 

T hese i n vesti gati o ns ca n i ncl u de base d o n i n vesti gat or’s discreti o n: ser ol o g y tests, 
i ma gi n g a n d pat h ol o g y assess me nts, he pat ol o gist’s c o ns ulta nc y; o btai ni n g m ore 
detaile d hist or y  of s ym pt o ms a n d pri or or c o nc urre nt diseases, hist or y  of c o nc o mita nt 
dr u g use, e xcl usi o n of u n derl y i n g li ver disease
All f oll o w-u p i nf or mati o n, a n d t he pr oce d ures perf or me d m ust be rec orde d as a p pr o priate i n 
t he e C R F. Refer t o t he S O M f or a d diti o nal details.
1 0. 2. 2
R e n al s af et y  m o nit ori n g
Re nal safety m o nit ori n g f or t he i n vesti gati o nal dr u g will be perf or me d i n t he st u d y. T his 
i ncl u des baseli ne meas ure me nts of ser u m creati ni ne, calci u m, p otassi u m a n d uri ne di pstic k a n d 
at s u bse q ue nt visits as i n dicate d i n t he Sc he d ule of Assess me nt s Ta ble 8- 1 .
1 0. 2. 3
D at a M o nit ori n g C o m mitt e e
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 9 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 1
D at a C oll e cti o n a n d D at a b a s e m a n a g e m e nt
1 1. 1
D at a c oll e cti o n
Desi g nate d i n vesti gat or staff will e nter t he data re q uire d b y  the pr ot oc ol i nt o t he Electr o nic 
Case Re p ort F or ms (e C R F). T he e C R Fs ha ve bee n b uilt usi n g f ully vali date d sec ure we b -
e na ble d s oft ware t hat c o nf or ms t o 2 1 C F R Part 1 1 re q uire me nts, I n vesti gat or site staff will n ot 
be gi ve n access t o t he E D C s yste m u ntil t he y ha ve bee n trai ne d. A ut o matic vali dati o n pr o gra ms 
c hec k f or data discre pa ncies i n t he e C R Fs, all o w m o dificati o n a n d/ or verificati o n of t he e ntere d 
data b y t he i n vesti gat or staff.
T he i n vesti gat or/ desi g nee is res p o nsi ble f or ass uri n g t hat t he data (rec or de d a n d e ntere d i nt o 
e C R F) is c o m plete, acc urate, a n d t hat e ntr y a n d u p dates are perf or me d i n a ti mel y ma n ner. T he 
I n vesti gat or m ust certif y t hat t he data e ntere d are c o m plete a n d acc urate.
After fi nal data base l oc k, t he i n vesti gat or will receive c o pies of t he s u bject data f or arc hi vi n g 
at t he i n vesti gati o nal site.
All data s h o ul d be rec or de d, ha n dle d, a n d st ore d i n a wa y  that all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d verificati o n.
1 1. 2
D at a b a s e m a n a g e m e nt a n d q u alit y  c o ntr ol
N o vartis pers o n nel ( or desi g nate d C R O) will re vie w t he data e ntere d b y  in vesti gati o nal staff 
f or c o m plete ness a n d acc urac y. Electr o nic data q ueries stati n g t he nat ure of t he pr o ble m a n d 
re q uesti n g clarificati o n will be create d f or discre pa ncies a n d missi n g val ues a n d se nt t o t he 
i n vesti gati o nal site via t he E D C s yste m. Desi g nate d i n vesti gat or site staff are re q uire d t o 
res p o n d pr o m ptl y t o q ueries a n d t o ma ke a n y necessar y c ha n ges t o t he data.
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data base will be co de d usi n g t he 
W orl d 
Healt h Or ga nizati o n ( W H O) Dr u g Refere nce List, w hic h e m pl o ys t he A nat o mical 
T hera pe utic C he mical classificati o n s yste m. Me dical hist or y /c urre nt me dical c o n diti o ns a n d 
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 9 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
a d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y  for Re g ula t or y Acti vities ( Me d D R A) 
ter mi n ol o g y.
Ra n d o mizati o n c o des a n d data a b o ut all st u d y treat me nt(s) dis pe nse d t o t he s u bject a n d all 
d osa ge c ha n ges will be trac ke d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y (IR T). T he s yste m 
will be s u p plie d b y  a ve n d or, w h o wil l als o ma na ge t he data base. T he data will be se nt 
electr o nicall y t o N o vartis ( or a desi g nate d C R O) at s pecific ti meli nes.
Eac h occ urre nce of a c o de brea k via I R T will be re p orte d t o t he cli nical tea m a n d m o nit or. 
T he c o de brea k f u ncti o nalit y will re mai n a vaila ble u ntil st u d y sh ut d o w n or u p o n re q uest of 
N o vartis.
F or t he H R C T sca ns, a de dicate d i ma gi n g C R O will c ollect all H R C T data fr o m t he sites 
T he a nal ys is res ults will be ge nerate d b y  the i ma gi n g C R O a n d tra nsf or me d i nt o a N o vartis 
f or mat defi ne d b y  a data tra nsfer s pecificati o n. T he tra nsf or me d o ut p ut will t he n be se nt t o 
N o vartis data ma na ge me nt f or i nc or p orati o n i nt o t he C S R. T he i ma gi n g C R O will be 
res p o nsi ble f or all i ma ge data clarificati o n f or ms a n d missi n g data at all sites.
O nce all t he necessar y acti o ns ha ve bee n c o m plete d a n d t he data base has bee n declare d t o be 
c o m plete a n d acc urate, it will be l oc ke d a n d t he treat me nt c o des will be u n bli n de d a n d ma de 
a vaila ble f or data a nal ys is. A n y  cha n ges t o t he data base after t hat ti me ca n o nl y  be ma de after 
writte n a gree me nt b y N o vartis de vel o p me nt ma na ge me nt.
1 1. 3
Sit e m o nit ori n g
Bef ore st u d y initiati o n, at a site i nitiati o n visit or at a n i n vesti gat or’s meeti n g, a N o vartis 
re prese ntati ve will re vie w t he pr ot oc ol a n d data ca pt ure re q uire me nts (i.e. e C R Fs) wit h
t he 
i n vesti gat ors a n d t heir staff. D uri n g t he st u d y, N o vartis e m pl o ys se veral met h o ds of e ns uri n g 
pr ot oc ol a n d G C P c o m plia nce a n d t he q ualit y/i nte grit y of t he sites’ data. T he fiel d m o nit or will 
visit t he site 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 data ca pt ure / data 
e ntr y, t he a d here nce t o t he pr ot oc ol a n d t o G o o d Cli nical Practice, 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 treat me nt is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o 
s pecificati o ns. K e y  st u d y per s o n nel m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese 
visits. C o nti n u o us re m ote m o nit ori n g of eac h site’s data m a y  be perf or me d b y  a ce ntralize d 
N o vartis/ C R A or ga nizati o n. A d diti o nall y , a ce ntral a nal ytics or ga nizati o n ma y  anal yz e data a n d 
i de ntif y ris ks a n d tre n ds f or site o perati o nal para meters, a n d pr o vi de re p orts t o N o vartis cli nical 
tea ms t o assist wit h trial o versi g ht.
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h s u bject i n t he st u d y, c o nsisti n g of 
case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, electr ocar di o gra ms, a n d t he res ults of a n y ot her tests or 
assess me nts. All i nf or mati o n o n e C R Fs m ust be tracea ble t o t hese s o urce d oc u me nts i n t he 
s u bject’s file. T he i n vesti gat or m ust als o kee p t he ori gi nal i nf or me d c o nse nt f or m si g ne d b y t he 
s u bject (a si g ne d c o py is gi ve n t o t he s u bject).
T he i n vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he data ca pt ure a n d/ or data e ntr y. N o vartis m o nit ori n g sta n dar ds re q uire f ull 
verificati o n f or t he prese nce of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n criteria, 
d oc u me ntati o n of S A Es, a n d of data t hat will 
be use d f or all pri mar y  varia bles. 
A d diti o nal c hec ks of t he 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 acc or di n g 


N o v arti s
C o nfi d e nti al
P a g e 9 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
t o t he st u d y-s pecific m o nit ori n g pla n. N o i nf or mati o n i n s o urce d oc u me nts a b o ut t he i de ntit y 
of t he s u bjects will be discl ose d.
1 2
D at a a n al y si s a n d st ati sti c al m et h o d s
T he a nal ys is will be c o n d ucte d o n all s u bject data at t he ti me t he trial e n ds. A n y  data a nal ys is 
carrie d o ut i n de pe n de ntl y b y  the i n vesti gat or s h o ul d be s u b mitte d t o N o vartis bef ore p u blicati o n 
or prese ntati o n.
T he baseli ne val ue is defi ne d as t he last assess me nt pri or t o first d ose a d mi nistrati o n. I n case 
t he sc he d ule d baseli ne assess me nt val ue is missi n g, t he scree ni n g val ue if a vaila ble will be use d 
i nstea d.
N o m ulti plicit y  adj ust me nts will be c o nsi dere d d ue t o t he n o n- c o nfir mat or y nat ure of t his st u dy.
Scree n fail ure s u bject’s data will n ot be re p orte d u nless a n S A E occ urs d uri n g scree ni n g. F or 
S A Es i n scree ni n g, all s u bject data will be re p orte d
1 2. 1
A n al y si s s et s
F or all a nal y sis sets, s u bjects will be a nalyz e d acc or di n g t o t he st u d y treat me nt(s) recei ve d.
T he safet y a nal ys is set will i ncl u de all s u bjects t hat recei ve d a n y st u d y treat me nt.
T he P K a nal ysis set will i ncl u de all s u bjects wit h at least o ne a vaila ble vali d (i.e. n ot fla g ge d 
f or e xcl usi o n) P K c o nce ntrati o n meas ure me nt, w h o recei ve d a n y st u d y dru g a n d e x perie nce d 
n o pr ot oc ol de viati o ns wit h rele va nt i m pact o n P K data.
T he P D a nal ys is set will i ncl u de all s u bjects wit h P D data at b ot h baseli ne a n d at least o ne p ost -
baseli ne assess me nt w hic h are n ot affecte d b y a n y pr ot oc ol de viati o ns.
1 2. 2
S u bj e ct d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s
De m o gra p hic a n d ot her baseli ne data i ncl u di n g disease c haracteristics will be liste d a n d 
s u m marize d descri pti vel y b y treat me nt gr o u p f or t he safet y a nal ys is set.
Cate g orical data will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d.
Rele va nt me dical hist ories a n d c urre nt me dical c o n diti o ns at baseli ne will be s u m marize d b y  
s yste m or ga n class a n d preferre d ter m, b y treat me nt gr o u p .
1 2. 3
Tr e at m e nt s
T he Safet y set will be use d f or t he a nal yses bel o w. Cate g orical data will be s u m marize d as 
fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, 
a n d ma xi m u m will be prese nte d.
T he d urati o n of e x p os ur e t o st u d y treat me nt will be s u m marize d b y  mea ns of descri pti ve 
statistics usi n g t he Safety set.


N o v arti s
C o nfi d e nti al
P a g e 9 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t he 
st u d y treat me nt will be liste d a n d s u m marize d acc or di n g t o t he A nat o mical T hera pe utic 
C he mical ( A T C) classificati o n s y ste m, b y treat me nt gr o u p.
1 2. 4
A n al y si s of t h e pri m ar y  e n d p oi nt( s)
T he pri mar y  o bjecti ve of t he st u d y is t o assess t he c ha n ge fr o m baseli ne o n fi bri n o ge n plas ma 
c o nce ntrati o n le vels after 1 2 wee ks of treat me nt wit h Q B W 2 5 1 c o m pare d t o place b o.
1 2. 4. 1
D efi niti o n of pri m ar y  e sti m a n d
T he pri mar y  esti ma n d, defi ne d bel o w, q ua ntifies a h y p ot hetical effect of 1 2 wee ks treat me nt 
t hat w o ul d ha ve bee n o bser ve d if all s u bjects re mai ne d o n t heir treat me nt f or 1 2 wee ks:

T ar get p o p ul ati o n : s u bjects wit h m o derate t o se vere C O P D wit h feat ures of c hr o nic 
br o nc hitis a n d a hist or y of e xacer bati o ns a n d treate d wit h a n y  of t he c o m bi nati o ns of 
L A B A, L A M A, or I C S al o n g wit h or wit h o ut macr oli des as bac k gr o u n d t hera p y

V ari a bles of i nterest : c ha n ge fr o m baseli ne i n fi bri n o ge n after 1 2 wee ks of treat me nt.

I nterc urre nt e ve nts of i nterest:
1.
Disc o nti n uati o n of st u d y  treat me nt or st u d y partici pati o n bef ore 1 2 wee ks of 
treat me nt
2.
I nta ke of resc ue me dicati o ns or i nta ke of a nti bi otics bef ore 1 2 wee ks of treat me nt

S u m m ar y me as ure: mea n differe nce bet wee n treat me nt gr o u ps ( Q B W 2 5 1 c o m pare d wit h 
place b o).
1 2. 4. 2
St ati sti c al m o d el, h y p ot h e si s, a n d m et h o d of a n al y si s
T he pri mar y  a nalys is will i ncl u de all a vaila ble data fr o m s u bjects i n t he P D a nal ys is set. 
T he fi bri n o ge n sa m ples ta ke n wit hi n 2 wee ks after e xacer bati o n or d uri n g or after last d ose of 
a nti bi otics ot her t ha n macr oli de w o ul d be set t o missi n g if a vali d u nsc he d ule d assess me nt di d 
n ot ha p pe n at t hat ti me p oi nt f or t he pri mar y  a nal ysis.
T he pri mar y  an al ys is will be perf or me d usi n g a o ne -si de d test at al p ha = 0. 1 (t w o-si de d 
8 0 % c o nfi de nce i nter vals) a n d esti mate d treat me nt differe nce ( Q B W 2 5 1-Place b o) at wee k 1 2 
will be re p orte d al o n g wit h ass ociate d 8 0 % c o nfi de nce i nter vals.
T he c o m paris o n of Q B W 2 5 1 t o pl ace b o will be e val uate d b y  testi n g t he f oll o wi n g n ull 
h y p ot hesis ( H 0) vers us t he alter nati ve hy p ot hesis ( H 1):
H 0: T here is n o re d ucti o n i n fi bri n o ge n fr o m baseli ne after 1 2 wee ks of treat me nt i n Q B W 2 5 1 
c o m pare d t o place b o
H 1: T here is a re d ucti o n i n fi bri no ge n fr o m baseli ne after 1 2 wee ks of treat me nt i n fa v or of 
Q B W 2 5 1 c o m pare d t o place b o.
T he c ha n ge fr o m baseli ne i n fi bri n o ge n is ass u me d n or mall y  distri b ute d. A M M R M will be 
fitte d t o t he c ha n ges fr o m baseli ne i n fi bri n o ge n f or all ti me p oi nts u ntil Da y 8 4 visit i ncl u di n g 
t he fi xe d fact ors a n d c o variates b ut are n ot li mite d t o t he f oll o wi n g:

treat me nt gr o u p

visit/ti me


N o v arti s
C o nfi d e nti al
P a g e 9 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

treat me nt gr o u p by visit/ti me i nteracti o n

s m o ki n g stat us

baseli ne fi bri n o ge n val ue b y  visit/ti me i nteracti o n.
If n or malit y ass u m pti o ns are n ot met, t he n t he fi bri n o ge n data ma y be l o g tra nsf or me d.
1 2. 4. 3
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
Esti mates of t he missi n g val ues d ue t o i nta ke of resc ue me dicati o ns or a nti bi otics will be deri ve d 
b y  the m o del u n der t he missi n g at ra n d o m ( M A R) ass u m pti o n. Alter nati ve ass u m pti o ns ma y  be 
e x pl ore d t o i n vesti gate t he r o b ust ness of t he res ults u n der pla usi ble n o n- missi n g at ra n d o m 
sit uati o ns.
1 2. 4. 4
S e n siti vit y a n d S u p p orti v e a n al y s e s
S e n siti vit y a n al y s e s
S u bjects w h ose bacterial l oa d or fi bri n o ge n le vels c ollecte d at t he pla n ne d visits re gar dless of 
t he i nta ke of a nti bi otics ot her t ha n macr oli de or e xacer bate d d uri n g Q B W 2 5 1 treat me nt peri o d 
will be i ncl u de d a n d a nal yse d usi n g re peate d meas ures m o del si milar t o pri mar y  an al y ses. 
T his w o ul d all o w t o assess the r o b ust ness of t he Q B W 2 5 1 treat me nt effect o n fi bri n o ge n a n d 
bacterial l oa d dr o p wit h a n d wit h o ut pr o hi bite d a nti bi otics/e xacer bati o n t hat w o ul d be dee me d 
t o affect t he o utc o me of i nterest.
1 2. 5
A n al y si s of s e c o n d ar y  e n d p oi nt s
1 2. 5. 1
Effi c a c y  a n d/ or P h ar m a c o d yn a mi c e n d p oi nt( s)
K e y  sec o n dar y p har mac o d yna mic e n d p oi nt:

C ha n ge fr o m baseli ne i n t he l o garit h m of t otal n u m ber of c ol o n y f or mi n g u nits ( C F U/ m L ) 
of p ote ntiall y  pat h o ge nic micr o or ga nis ms i n s p o nta ne o us s p ut u m after 1 2 wee ks of 
treat me nt.
T he bacterial l oa d will i ncl u de all a vaila ble data fr o m s u bjects i n t he P D a nal ysis set a n d will 
be a nal yz e d si milar t o t he pri mar y  anal y sis. T he bacterial l oa d sa m ples ta ke n wit hi n 2 wee ks 
after e xacer bati o n or d uri n g or after last d ose of a nti bi otics w o ul d be set t o missi n g if a vali d 
u nsc he d ule d assess me nt di d n ot ha p pe n at t hat ti me p oi nt f or t he pri mar y  a nalys is.
Sec o n dar y p har mac o d y n a mic a n d efficac y e n d p oi nts are as f oll o ws:

C ha n ge fr o m baseli ne i n air wa y wall a n d l u me n para meters al o n g wit h e xte nt of gl o bal 
a n d re gi o nal ai r tra p pi n g as meas ure d by H R C T.

C ha n ge fr o m baseli ne i n F E V 1, F V C a n d F E V 1/ F V C meas ure d b y s pir o metr y after 
1 2 wee ks of treat me nt.
I n or der t o be i ncl u de d i n t he s p ut u m a nal ysis, a s u bject m ust pr o vi de a s ufficie nt s p ut u m sa m ple 
at scree ni n g, a n d/ or at bas eli ne a n d at least o ne p ost-baseli ne visit. T he c ha n ge fr o m baseli ne i n 
t he l o garit h m of t he t otal n u m ber of c ol o n y f or mi n g u nits i ncl u di n g all differe nt 
micr o -or ga nis ms ( C F U) a n d c ha n ge fr o m baseli ne i n t he sec o n dar y efficac y i ncl u di n g gl o bal 
air tra p pin g a n d s pir o metr y para meter will be a nal yze d usi n g t he sa me m o del as f or t he pri mar y 


N o v arti s
C o nfi d e nti al
P a g e 9 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
varia ble of i nterest. C o ntrasts f or treat me nt differe nces will be pr o vi de d t o get her wit h t w o-si de d 
8 0 % C o nfi de nce I nter vals.
All s pir o metr y para meters a n d H R C T para meters i ncl u di n g re gi o nal a n d gl o bal air tra p pi n g 
c ha n ges will be s u m marise d.
T hese will be calc ulate d at all ti me p oi nts as s pecifie d i n t he assess me nt sc he d ule ( Ta ble 8- 1 ), 
a n d s pecifically at t he pri mar y  ti me p oi nt of i nterest ( Da y 8 4) c o nsi deri n g place b o as t he 
refere nce treat me nt.
A n y  correlati o ns bet wee n c ha n ges i n air tra p pi n g a n d t he l u n g f u ncti o n para meters meas ure d 
b y  s pir o metr y w o ul d be e x pl ore d.
1 2. 5. 2
S af et y  e n d p oi nt s
F or all safety a nal ys es, t he safety set will be use d. All listi n gs a n d ta bles will be prese nte d b y  
treat me nt gr o u p.
Safet y  su m maries (ta bles, fi g ures) i ncl u de o nl y data fr o m t he o n- treat me nt peri o d wit h t he 
e xce pti o n of baseli ne data w hic h will als o be s u m marize d w here a p pr o priate (e. g. c ha n ge fr o m 
baseli ne s u m maries). I n a d diti o n, a se parate s u m mar y for deat h i ncl u di n g o n treat me nt a n d p ost 
treat me nt deat hs will be pr o vi de d. I n partic ular, s u m mar y ta bles f or a d verse e ve nts ( A Es) will 
s u m marize o nl y  on- treat me nt e ve nts, wit h a start date d uri n g t he o n- treat me nt peri o d
(treat me nt-e mer ge nt A Es).
T he o n -treat me nt peri o d lasts fr o m t he date of first a d mi nistrati o n of st u d y treat me nt t o 1 wee k 
after t he last act ual a d mi nistrati o n of a n y  st u d y treat me nt.
A d v er s e e v e nt s
All i nf or mati o n o btai ne d o n a d verse e ve nts will be dis pl a ye d b y treat me nt gr o u p a n d s u bject.
T he n u m ber (a n d perce nta ge) of s u bjects wit h treat me nt e mer ge nt a d verse e ve nts (e ve nts starte d 
after t he first d ose of st u d y me dicati o n or e ve nts prese nt pri or t o start of d o u ble -bli n d treat me nt 
b ut i ncrease d i n se verit y base d o n preferre d ter m) will be s u m marize d i n t he f oll o wi n g wa y s:

b y  treat me nt, pri mar y sys te m or ga n class a n d preferre d ter m.

b y  treat me nt, pri mar y sys te m or ga n class, preferre d ter m a n d ma xi m u m se verit y.

b y  treat me nt, Sta n dar dize d Me d D R A Q uer y ( S M Q) an d preferre d ter m.
Se parate s u m maries will be pr o vi de d f or st u d y me dicati o n relate d a d verse e ve nts, deat h, seri o us 
a d verse e ve nts, ot her si g nifica nt a d verse e ve nts lea di n g t o disc o nti n uati o n. A s u bject wit h 
m ulti ple a d verse e ve nts wit hi n a pri mar y  s yste m o r ga n class is o nl y  co u nte d o nce t o war ds t he 
t otal of t he pri mar y sys te m or ga n class.
Vit al si g n s
All vital si g ns data will be liste d b y  treat me nt gr o u p, s u bject a n d visit/ti me, a n d if ra n ges are 
a vaila ble, a b n or malities will be fla g ge d. S u m mar y  statistics will be pr o vi de d b y  treat me nt a n d 
visit/ti me.


N o v arti s
C o nfi d e nti al
P a g e 9 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 2 -l e a d E C G
All E C G data will be liste d b y  treat me nt gr o u p, s u bject a n d visit/ti me, a n d a b n or malities will 
be fla g ge d. S u m mar y  statistics will be pr o vi de d b y treat me nt a n d visit/ti me.
Cli ni c al l a b or at or y  e v al u ati o n s
All la b orat or y data will be liste d b y  treat me nt gr o u p, s u bject, a n d visit/ti me, a n d if n or mal 
ra n ges are a vaila ble, a b n or malities will be fla g ge d. S u m mar y  statistics will be pr o vi de d b y  
treat me nt a n d visit/ti me. 
S hift ta bles usi n g t he l o w/ n or mal/ hi gh/ (l o w a n d hi g h) classificati o n will be use d t o c o m pare 
baseli ne t o t he w orst o n -treat me nt val ue.
1 2. 5. 3
P h ar m a c o ki n eti c s
Descri pti ve statistics of Q B W 2 5 1 plas ma c o nce ntrati o n data will be pr o vi de d b y treat me nt a n d 
visit/sa m pli n g ti me p oi nt, i ncl u di n g t he fre q ue nc y (n, %) of c o nce ntrati o ns bel o w t he l o wer 
li mit of q ua ntificati o n ( L L O Q). S u m mar y statistics of Q B W 2 5 1 plas ma c o nce ntrati o n data a n d 
P K para meters will i ncl u de mea n 
(arit h metic a n d ge o metric), S D, C V (arit h metic a n d 
ge o metric), me dia n, mi ni m u m, a nd ma xi m u m. A n e xce pti o n t o t his is T ma x, w here me dia n, 
mi ni m u m, a n d ma xi m u m will be prese nte d.
C o nce ntrati o ns bel o w L L O Q will be treate d as zer o i n s u m mar y statistics a n d f or P K para meter 
calc ulati o ns. 
1 2. 5. 4
P ati e nt R e p ort e d O ut c o m e s a n d E x a c er b ati o n s
S u bj e ct r e p ort e d o ut c o m e s
C o u g h a n d S p ut u m Assess me nt Q uesti o n naire ( C A S A-Q) a n d St. Ge or ge's Res pirat or y 
Q uesti o n naire 
( S G R Q) d o mai n 
sc ores, C O P D assess me nt test ( C A T), E Q - 5 D-3 L  an d 
E X A C T -P R O q uesti o n naire data will be s u m marize d b y  treat me nt a n d visit. Pres pecif ie d 
s u b-gr o u ps a n d c orrelati o n a nal ysis are pr o vi de d i n t he S A P C O P D e x acer bati o ns base d o n 
E X A C T P R O Q uesti o n naire.
T he f oll o wi n g a nal ys es will be perf or me d t o e x pl ore a n y differe nces i n t he e xacer bati o n e ve nts 
t hat occ ur i n Q B W 2 5 1 vs place b o:
1) Ti m e t o f ir st e x a c er b ati o n
T he ti me-t o-e ve nt a nal yses will be carrie d o ut o nl y  up o n s ufficie nt n u m ber of e xacer bati o n 
e ve nts occ ur d uri n g t he st u d y  t o esti mate t he me dia n i n eit her of t he treat me nt gr o u ps.
T he ti me t o t he first o n- treat me nt e xacer bati o n (e ve nt) is defi ne d as t he start date of first 
e xacer bati o n mi n us 
t he date of ra n d o mizati o n + 1. S u bjects w h o d o n ot e x perie nce a n 
e xacer bati o n or disc o nti n ue d earlier wit h o ut a n e xacer bati o n will be ce ns ore d f or a nal ys es 
p ur p oses.


N o v arti s
C o nfi d e nti al
P a g e 9 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T he hazar d rati os f or Q B W 2 5 1 c o m pare d wit h place b o a n d t heir c orres p o n di n g 8 0 % c o nfi de nce 
i nter vals will be c o m p ute d usi n g Ka pla n -Meier met h o d. T he stratificati o n fact or m a y  incl u de 
n u m ber of e xacer bati o ns. 
T he Ka pla n - Meier esti mates of t he s ur vi val f u ncti o ns f or eac h treat me nt will be pl otte d.
2) A n n u ali z e d r at e of C O P D e x a c er b ati o n s
T he t otal fre q ue nc y of C O P D e xacer bati o ns o ver t he 1 2 wee k treat me nt peri o d will be a nal yze d 
usi n g a ge neralize d li near m o del ass u mi n g a ne gati ve bi n o mial distri b uti o n. T he ti me at ris k f or 
a s u bject is defi ne d as t he le n gt h of ti me t he s u bject is o n treat me nt a n d t he l o g (le n gt h of ti me) 
will be use d as t he offset varia ble i n t he m o del. T he m o del will i ncl u de treat me nt, a nti bi otic use, 
a n d t he n u m ber of e xacer bati o ns i n t he past 1 2 m o nt hs pri or t o scree ni n g as cate g orical varia bles. 
A n esti mate of t he rate rati o t o get her wit h 8 0 % c o nfi de nce i nter vals a n d c orres p o n di n g p -val ue 
will be prese nte d.
3) T h e p er c e nt a g e of s u bj e ct s e x p eri e n ci n g at l e a st a C O P D e x a c er b ati o n
T he pr o p orti o n of s u bjects wit h at least o ne C O P D e xacer bati o n will be a nal yze d usi n g l o gistic 
re gressi o n. T he m o del will i ncl u de treat me nt, a nti bi otic use, a n d t he n u m ber of e xacer bati o ns 
i n t he past 1 2 m o nt hs pri or t o scree ni n g as cate g orical varia bles. T he esti mate d o d ds rati os will 
be dis pla y e d al o n g wit h t he ass ociate d 8 0 % c o nfi de nce i nter vals.
1 2. 6
A n al y si s of e x pl or at or y  e n d p oi nt s
1 2. 7
I nt eri m a n al ys e s
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 0 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 2. 8
S a m pl e si z e c al c ul ati o n
1 3
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s
1 3. 1
R e g ul at or y  a n d et hi c al c o m pli a n c e
T his cli nical st u d y was desi g ne d a n d s hall be i m ple me nte d, e xec ute d a n d re p orte d i n acc or da nce 
wit h t he I nter nati o nal C o nfere nce o n Har m o nisati o n (IC H) Har m o nize d Tri partite G ui deli nes 
f or G o o d Cli nical Practice, w it h a p plica ble l ocal re g ulati o ns (i ncl u di n g E ur o pea n Directi ve 
2 0 0 1/ 2 0/ E C, U S C F R 2 1), a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of 
Helsi n ki.
1 3. 2
R e s p o n si biliti e s of t h e i n v e sti g at or a n d I R B/I E C
Bef ore i nitiati n g a trial, t he i n vesti gat or/i nstit uti o n m ust o btai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (IR B/I E C) f or t he trial pr ot oc ol, 
writte n i nf or me d c o nse nt f or m, c o nse nt f or m u p dates, s u bject recr uit me nt pr oce d ures (e. g. 
a d vertise me nts) a nd a n y ot her writte n i nf or mati o n t o be pr o vi de d t o s u bjects. Pri or t o st u d y 
start, t he i n vesti gat or is re q uire d t o si g n a pr ot oc ol si g nat ure pa ge c o nfir mi n g his/ her a gree me nt 
t o c o n d uct t he st u d y in acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d 
pr oce d ures f o u n d i n t his pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds t o N o vartis 
C o m merciall y C o nfi de ntial I nf or mati o n
C o m merciall y C o nfi de ntial I nf or mati o n


N o v arti s
C o nfi d e nti al
P a g e 1 0 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
m o nit ors, a u dit ors, N o vartis Q ualit y Ass ura nce re prese ntati ves, desi g nate d a ge nts of N o vartis, 
I RBs/I E Cs, a n d re g ulat or y aut h orities as re q uire d. If a n i ns pecti o n of t he cli nical site is 
re q ueste d b y  a re g ulat or y a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis i m me diatel y that t his 
re q uest has bee n ma de.
1 3. 3
P u bli c ati o n of st u d y  pr ot o c ol a n d r e s ult s
T he pr ot oc ol will be re gistere d i n a p u blicl y  accessi ble da ta base s uc h as cli nicaltrials. g o v a n d 
as re q uire d i n E u dra C T. I n a d diti o n, after st u d y  c o m pleti o n a n d fi nalizati o n of t he st u d y re p ort 
t he res ults of t his trial will be s u b mitte d f or p u blicati o n a n d p oste d i n a p u blicl y  accessi ble 
data base of cli nical trial res ults, s uc h as t he N o vartis cli nical trial res ults we bsite a n d all re q uire d 
Healt h A ut h orit y  we bsites (e. g. Cli nicaltrials. g o v, E u dra C T etc.).
F or details o n t he N o vartis p u blicati o n p olic y  incl u di n g a ut h ors hi p criteria, please refer t o t he 
N o vartis p u blicati o n p olic y trai ni n g materials t hat were pr o vi de d t o y o u at t he trial i n vesti gat or 
meeti n gs.
1 3. 4
Q u alit y C o ntr ol a n d Q u alit y  As s ur a n c e
N o vartis mai ntai ns a r o b ust Q ualit y  Ma na ge me nt S y ste m ( Q M S) t hat i ncl u des all acti vities 
i n v ol ve d i n q ualit y  ass ura nce a n d q ualit y c o ntr ol, t o e ns ure c o m plia nce wit h writte n Sta n dar d 
O perati n g Pr oce d ures as well as a p plica ble gl o bal/l ocal G C P re g ulati o ns a n d I C H G ui deli nes.
A u dits of i n vesti gat or sites, ve n d ors, a n d N o vartis s yste ms are perf or me d b y  au dit ors, 
i n de pe n de nt fro m t h ose i n v ol ve d i n c o n d ucti n g, m o nit ori n g or perf or mi n g q ualit y  co ntr ol of t he 
cli nical trial. T he cli nical a u dit pr ocess uses a k n o wle d ge/ris k base d a p pr oac h.
A u dits are c o n d ucte d t o assess G C P c o m plia nce wit h gl o bal a n d l ocal re g ulat or y re q uire me nts, 
p r ot oc ols a n d i nter nal S O Ps, a n d are perf or me d acc or di n g t o writte n N o vartis pr ocesses.
1 4
Pr ot o c ol a d h er e n c e
T his pr ot oc ol defi nes t he st u d y  o bjecti ves, t he st u d y pr oce d ures a n d t he data t o be c ollecte d o n 
st u d y partici pa nts. A d diti o nal assess me nts re q uire d to e ns ure safet y of s u bjects s h o ul d b e 
a d mi nistere d as dee me d necessar y  on a case b y  case basis. U n der n o circ u msta nces i ncl u di n g 
i nci de ntal c ollecti o n is a n i n vesti gat or all o we d t o c ollect a d diti o nal data or c o n d uct a n y 
a d diti o nal pr oce d ures f or a n y p ur p os e i n v ol vi n g a n y in vesti gati o nal dr u gs u n der t he pr ot oc ol, 
ot her t ha n t he p ur p ose of t he st u d y. If des pite t his i nter dicti o n pr o hi biti o n, data, i nf or mati o n, 
o bser vati o n w o ul d be i nci de ntall y collecte d, t he i n vesti gat or s hall i m me diatel y discl ose it t o 
N o var tis a n d n ot use it f or a n y p ur p ose ot her t ha n t he st u d y, e xce pt f or t he a p pr o priate 
m o nit ori n g o n st u d y  partici pa nts.
I n vesti gat ors ascertai n t he y will a p pl y d ue dili ge nce t o a v oi d pr ot oc ol de viati o ns. If a n 
i n vesti gat or feels a pr ot oc ol de viati o n w o ul d i mpr o ve t he c o n d uct of t he st u d y this m ust b e 
c o nsi dere d a pr ot oc ol a me n d me nt, a n d u nless s uc h a n a me n d me nt is a gree d u p o n b y  No vartis 
a n d a p pr o ve d b y  the I R B/I E C a n d Healt h A ut h orities, w here re q uire d, it ca n n ot be i m ple me nte d.


N o v arti s
C o nfi d e nti al
P a g e 1 0 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 4. 1
Pr ot o c ol a m e n d m e nt s
A n y  c ha n ge or a d diti o n t o t he pr ot oc ol ca n o nl y be ma de i n 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  No vartis, healt h a ut h orities w here re q uire d, a n d t he I RB/I E C pri or t o 
i m ple me ntati o n.
O nl y  ame n d me nts t hat are re q uire d f or s u bject safety m a y  be i m ple me nte d i m me diatel y 
pr o vi de d t he healt h a ut h orities are s u bse q ue ntl y notifie d b y  pr ot oc ol a me n d me nt a n d t he 
re vie wi n g I R B/I E C is n otifie d.
N ot wit hsta n di n g t he nee d f or a p pr o val of f or mal pr ot oc ol a me n d me nts, t he i n vesti gat or is 
e x pecte d t o ta ke a n y i m me diate acti o n re q uire d f or t he safet y of a n y s u bject i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re prese nts a de viati o n fr o m t he pr ot oc ol. I n suc h cases, N o vartis s h o ul d 
be n otifie d of t his acti o n a n d t he I RB/I E C at t he st u d y site s h o ul d be i nf or me d acc or di n g t o
l ocal re g ulati o ns.


N o v arti s
C o nfi d e nti al
P a g e 1 0 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 5
R ef er e n c e s
Refere nces are a vaila ble u p o n re q uest
Beasle y  V, J os hi P V, Si n ga na ya ga m A, et al ( 2 0 1 2) Lu n g micr o bi ol o g y  a n d e xacer bati o ns i n 
C O P D. I nt J C hr o n P ul m o n Dis; 7: 5 5 5 - 5 6 9.
Br oe k h uize n R, W o uters E F, Cre utz ber g E C, et al ( 2 0 0 6) Raise d C R P le vels mar k meta b olic 
a n d f u ncti o nal i m pair me nt i n a d va nce d C O P D. T h ora x; 6 1( 1): 1 7- 2 2.
Ca nti n A M, Ha nra ha n J W, Bil o dea u G, et al ( 2 0 0 6) C y stic fi br osis tra ns me m bra ne 
c o n d ucta nce re g ulat or f u ncti o n is s u p presse d i n ci garette s m o kers. A m J Res pir Crit Care 
Me d; 1 7 3( 1 0): 1 1 3 9 - 4 4.
C hal mers J D, S mit h M P, Mc H u g h BJ, et al ( 2 0 1 2) S h ort- a n d l o n g-ter m a nti bi otic treat me nt 
re d uces air wa y a n d s yste mic i nfla m mati o n i n n o n-c ystic fi br osis br o nc hiectasis. A m J Res pir 
Crit Care Me d; 1 8 6( 7): 6 5 7- 6 6 5.
C h o n g J, L e un g B, P o ole P ( 2 0 1 7) P h os p h o diesterase 4 i n hi bit ors f or c hr o nic o bstr ucti ve 
p ul m o nar y  disease. C oc hra ne Data base S yst Re v; 9: C D 0 0 2 3 0 9.
Cra wf or d B, M o nz B, H o hlfel d J, et al ( 2 0 0 8) De vel o p me nt a n d vali dati o n of a c o u g h a n d 
s p ut u m assess me nt q uesti o n naire. Res pir Me d; 1 0 2( 1 1): 1 5 4 5- 5 5.
de T orres J P, C or d o ba- La n us E, L ó pez - A g uilar C, et al ( 2 0 0 6) C-reacti ve pr otei n le vels a n d 
cli nicall y i m p orta nt pre dicti ve o utc o mes i n sta ble C O P D patie nts. E ur Res pir J; 2 7( 5): 9 0 2- 7.
D o nal ds o n G C, See m u n gal T A, B h o w mi k A, et al ( 2 0 0 2) Relati o ns hi p bet wee n e xacer bati o n 
fre q ue nc y a n d l u n g f u ncti o n decli ne i n c hr o nic o bstr ucti ve p ul m o nar y disease. T h ora x; 
5 7( 1 0): 8 4 7 - 5 2.
Dra nsfiel d M T, Wil hel m A M, Fla na ga n B, et al ( 2 0 1 3) Ac q uire d c y stic fi br osis 
tra ns me m bra ne c o n d ucta nce re g ulat or dys f u ncti o n i n t he l o wer air wa ys i n C O P D. C hest; 
1 4 4( 2): 4 9 8 - 5 0 6.
Gl o bal I nitiati ve f or C hr o nic O bstr ucti ve L u n g Disease ( G O L D) G ui deli nes ( 2 0 1 8) Gl o bal 
Strate g y  f or t he Dia g n osis, Ma na ge me nt a n d Pre ve nti o n of C hr o nic O bstr ucti ve P ul m o nar y 
Disease - Gl o bal I nitiati ve f or C hr o nic O bstr ucti ve L u n g Disease, p. 1 -1 2 3. 
htt ps:// g ol dc o p d. or g/arc hi ve d -re p orts/.  Accesse d 2 5- Se p- 2 0 1 9.
Gl o bal I nitiati ve f or C hr o nic O bstr ucti ve L u n g Disease ( G O L D) G ui deli nes ( 2 0 1 9) Gl o bal 
Strate g y  f or t he Dia g n osis, Ma na ge me nt a n d Pre ve nti o n of C hr o nic O bstr ucti ve P ul m o nar y 
Disease - Gl o bal I nitiati ve f or C hr o nic O bstr ucti ve L u n g Disease, p. 1 -1 5 5.  
htt ps:// g ol dc o p d. or g/ w p - c o nte nt/ u pl oa ds/ 2 0 1 8/ 1 1/ G O L D- 2 0 1 9- v 1. 7-FI N A L -1 4 N o v 2 0 1 8 -
W M S. p df. Accesse d 2 5 - Se p- 2 0 1 9.
H urst J R, Perera W R, D o nal ds o n G C, et al ( 2 0 0 5) Relati o ns hi ps a m o n g bacteria, u p per 
air wa y, l o wer air wa y, a n d s yste mic i nfla m mati o n i n C O P D. C hest; 1 2 7: 1 2 1 9-1 2 2 6.
J o nes P W, Har di n g G, Berr y P, et al ( 2 0 0 9) De vel o p me nt a n d first vali dati o n of t he C O P D 
Assess me nt Test. E ur Res pir J; 3 4( 3 ): 6 4 8- 5 4.


N o v arti s
C o nfi d e nti al
P a g e 1 0 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
J o nes P W, Q uir k F H, Ba ve yst oc k C M, et al ( 1 9 9 2) A self-c o m plete meas ure of healt h stat us 
f or c hr o nic airfl o w li mitati o n. T he St. Ge or ge's Res pirat or y Q uesti o n naire. A m Re v Res pir 
Dis; 1 4 5( 6): 1 3 2 1- 7.
Ki m V, Ha n M K, Va nce G B, et al ( 2 0 1 2) T he c hr o n ic br o nc hitic p he n oty p e of C O P D: a n 
a nal ys is of t he C O P D Ge ne St u d y. C hest; 1 4 0( 3): 6 2 6- 6 3 3.
Lei d y N K, M urra y  LT, J o nes P, et al ( 2 0 1 4a) Perf or ma nce of t he E X Acer bati o ns of c hr o nic 
p ul m o nar y  disease t o ol patie nt-re p orte d o utc o me meas ure i n t hree cli nical trials of c hr o nic 
o bstr ucti ve p ul m o nar y  disease. A n n A m T h orac S oc; 1 1( 3): 3 1 6- 2 5.
Lei d y N K, M urra y  LT, M o nz B U, et al ( 2 0 1 4 b) Meas uri n g res pirat or y  s y m pt o ms of C O P D: 
perf or ma nce of t he E X A C T- Res pirat or y  S ym pt o ms T o ol ( E -R S) i n t hree cli nical trials. 
Res pir R es; 1 5: 1 2 4.
Lei d y N K, Wilc o x T K, J o nes P W, et al ( 2 0 1 1) Sta n dar dizi n g meas ure me nt of c hr o nic 
o bstr ucti ve p ul m o nar y  disease e xacer bati o ns. Relia bilit y a n d vali dit y of a patie nt-re p orte d 
diar y . A m J Res pir Crit Care Me d; 1 8 3( 3): 3 2 3- 9.
Ma n ni n o D M, Tal -Si n ger R, L o mas D A, et al ( 2 0 1 5) Plas ma Fi bri n o ge n as a Bi o mar ker f or 
M ortalit y  a n d H os pitalize d E xacer bati o ns i n Pe o ple wit h C O P D. J C O P D F; 2( 1): 2 3 - 3 4.
Marti nez - Garcia M A, de la R osa Carill o D, S oler- Catal u na JJ, et al ( 2 0 1 1). Pr o g n ostic val ue 
of br o nc hiectasis i n patie nts wit h m o derate-t o-se vere c hr o nic o bstr ucti ve p ul m o nar y disease. 
A m J Res pir Crit Care Me d; 1 8 7: 8 2 3- 8 3 1.
M uller o va H, Mas kell J, Meera us W H, et al ( 2 0 1 7) C haracterizati o n of C O P D patie nts treate d 
wit h i n hale d tri ple t hera p y c o ntai ni n g i n hale d c or tic oster oi ds [IC S], l o n g -acti n g beta 2 -
a g o nists [ LA B A], a n d l o n g -acti n g m uscari nic a nta g o nists [ L A M A] i n t he U K. A m J Res p Crit 
Care Me d; 1 9 5: A 4 9 8 6.
Pezz ul o A A, Ta n g X X, H oe g ger MJ, et al ( 2 0 1 2) Re d uce d air wa y  s urface p H  i m pairs 
bacterial killi n g i n t he p orci ne c y stic fi br osis l u n g. Nat ure; 4 8 7( 7 4 0 5): 1 0 9- 1 3.
Raj u S V, Jac ks o n P L , C o ur ville C A, et al ( 2 0 1 3) Ci garette s m o ke i n d uces s yste mic defects i n 
c ystic fi br osis tra ns me m bra ne c o n d ucta nce re g ulat or f u ncti o n. A m J Res pir Crit Care Me d; 
1 8 8( 1 1): 1 3 2 1 - 3 0.
R os ell A, M o ns o E, S oler N, et al ( 2 0 0 5) Micr o bi ol o gic deter mi na nts of e xacer bati o n i n 
c hr o nic o bstr ucti ve p ul m o nar y  disease. Arc h I nter n Me d; 1 6 5( 8): 8 9 1- 8 9 7.
Set hi S, M ur p h y  T F ( 2 0 0 8) I nfecti o n i n t he pat h o ge nesis a n d c o urse of c hr o nic o bstr ucti ve 
p ul m o nar y  disease. N. E n g. J. Me d; 3 2 9: 2 3 5 5 - 2 3 6 5.
Sl oa ne P A, S hastr y  S, Wil hel m A, et al ( 2 0 1 2). A p har mac ol o gic a p pr oac h t o ac q uire d c ystic 
fi br osis tra ns me m bra ne c o n d ucta nce re g ulat or dys f u ncti o n i n s m o ki n g relate d l u n g disease. 
P L o S O N E; 7( 6):e 3 9 8 0 9.
S ol o m o n G M, Hat h or ne H, L i u B, et al ( 2 0 1 6) Pil ot e val uati o n of i vacaft or f or c hr o nic 
br o nc hitis. L a ncet; 4: 3 2 -3 3.


N o v arti s
C o nfi d e nti al
P a g e 1 0 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Uz u n S, Dja mi n R S, Kl u y t ma ns AJ W, et al ( 2 0 1 4). Azit hr o m yci n mai nte na nce treat me nt i n 
patie nts wit h fre q ue nt e xacer bati o ns of c hr o nic o bstr ucti ve p ul m o nar y  disease 
( C O L O M B U S): a ra n d o mise d, d o u ble bli n d, place b o-c o ntr olle d trial. La ncet; 2( 5): 3 6 1 - 3 6 8. 
Vest b o J, Pa pi A, C orra di M, et al ( 2 0 1 7) Si n gle i n haler e xtrafi ne tri ple t hera p y vers us l o n g -
acti n g m uscari nic a nta g o nist t hera p y  f or c hr o nic o bstr ucti ve p ul m o nar y disease ( T RI NI T Y): a 
d o u ble - bli n d, parallel gr o u p, ra n d o mise d c o ntr olle d trial. La ncet; 3 8 9( 1 0 0 8 2): 1 9 1 9- 2 9.
We dzic ha J A, Cal verle y  P M A, Al bert R K, et al ( 2 0 1 7) Pre ve nti o n of C O P D e xacer bati o ns: a 
E ur o pea n Res pirat or y  S ociet y/ A merica n T h oracic Societ y  g ui deli ne. E ur Res pir J; 
5 0( 3) 1 6 0 2 2 6 5.


N o v arti s
C o nfi d e nti al
P a g e 1 0 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 6
A p p e n di c e s
1 6. 1
A p p e n di x 1: Cli ni c all y  n ot a bl e l a b or at or y val u e s a n d vit al si g n s
T he ce ntral la b orat or y will fla g la b orat or y val ues falli n g o utsi de of t he n or mal ra n ges o n t he 
ce ntral la b orat or y re p orts. I n vesti gat ors are res p o nsi ble f or re vie wi n g t hese a b n or mal val ues f or 
cli nical si g nifica nce, si g ni n g t he la b orat or y re p orts t o i n dicate t heir re vie w, a n d re p orti n g val ues 
c o nsi dere d cli nicall y si g nifica nt i n t he a p pr o priate e C R F.
A n y  cli nically si g nifica nt a b n or mal la b orat or y val ue s h o ul d be e val uate d a n d f oll o we d- u p b y 
t he i n vesti gat or u ntil n or mal or a ca use f or t he a b n or malit y is deter mi ne d.
See Secti o n 1 6. 2 f or s pecific li ver e ve nt a n d la b orat or y test tri g ger defi niti o ns a n d f oll o w- u p 
re q uire me nts.
F or E C Gs, a n ota ble Q Tc val ue is defi ne d as a Q Tc F ( Fri dericia) i nter val of ≥ 4 5 0 msec f or 
males or ≥ 4 6 0 msec f or fe males – all s uc h E C Gs will be fla g ge d b y  t he Ce ntral E C G rea di n g 
a n d re q uire assess me nt f or cli nical rele va nce a n d c o nti n ua nce of t he s u bject b y  the I n vesti gat or.


N o v arti s
C o nfi d e nti al
P a g e 1 0 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 6. 2
A p p e n di x 2: Li v er e v e nt a n d L a b or at or y  tri g g er D efi niti o n s a n d 
F oll o w -u p R e q uir e m e nt s
T a bl e 1 6 - 1
Li v er e v e nt a n d l a b or at o r y tri g g er d efi niti o n s
D efi niti o n/ t hr e s h ol d
LI V E R L A B O R A T O R Y T RI G G E R S

3 x U L N < A L T / A S T ≤ 5 x U L N
· 1. 5 x U L N < T B L ≤ 2 x U L N
LI V E R E V E N T S

A L T or A S T > 5 × U L N

A L P > 2 × U L N (i n t h e a b s e n c e of k n o w n b o n e 
p at h ol o g y)

T B L > 2 × U L N (i n t h e a b s e n c e of k n o w n Gil b ert 
s y n dr o m e)

A L T or A S T > 3 × U L N a n d I N R > 1. 5

P ot e nti al H y’ s L a w c a s e s ( d efi n e d a s A L T or A S T > 3 × 
U L N a n d T B L > 2 × U L N [ m ai nl y c o nj u g at e d fr a cti o n] 
wit h o ut n ot a bl e i n cr e a s e i n A L P t o > 2 × U L N)

A n y cli ni c al e v e nt of j a u n di c e ( or e q ui v al e nt t er m)

A L T or A S T > 3 × U L N a c c o m p a ni e d b y ( g e n er al) 
m a l ai s e, f ati g u e, a b d o mi n al p ai n, n a u s e a, or v o miti n g, 
or r a s h wit h e o si n o p hili a

A n y a d v er s e e v e nt p ot e nti all y i n di c ati v e of a li v er 
t o xi cit y*
* T h e s e e v e nt s c o v er t h e f oll o wi n g: H e p ati c f ail ur e, fi br o si s a n d cirr h o si s, a n d ot h er li v er d a m a g e-
r el at e d c o n diti o n s; t h e n o n-i nf e cti o u s h e p atiti s; t h e b e ni g n, m ali g n a nt a n d u n s p e cifi e d li v er 
n e o pl a s m s T B L: t ot al bilir u bi n; U L N: u p p er li mit of n or m al


N o v arti s
C o nfi d e nti al
P a g e 1 0 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
T a bl e 1 6 - 2
F oll o w u p r e q uir e m e nt s f or li v er e v e nt s a n d l a b or at or y  tri g g er s 
Crit eri a
A cti o n s r e q uir e d
F oll o w -u p m o nit ori n g
P ot e nti al H y’ s L a w c a s e a

Di s c o nti n u e t h e st u d y 
tr e at m e nt i m m e di at el y

H o s pit ali z e, if cli ni c all y 
a p pr o pri at e

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o n c
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)
A L T or A S T
> 8 × U L N

Di s c o nti n u e t h e st u d y 
tr e at m e nt i m m e di at el y

H o s pit ali z e if cli ni c all y 
a p pr o pri at e

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o n c
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)
> 3 × U L N a n d I N R > 1. 5

Di s c o nti n u e t h e st u d y 
tr e at m e nt i m m e di at el y

H o s pit ali z e, if cli ni c all y 
a p pr o pri at e

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o n c
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)
> 5 t o ≤ 8 × U L N

R e p e at L F T wit hi n 4 8 
h o ur s

If el e v ati o n p er si st s, 
c o nti n u e f oll o w -u p 
m o nit ori n g

If el e v ati o n p er si st s f or 
m o r e t h a n 2 w e e k s, 
di s c o nti n u e t h e st u d y dr u g

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o n c
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)


N o v arti s
C o nfi d e nti al
P a g e 1 0 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Crit eri a
A cti o n s r e q uir e d
F oll o w -u p m o nit ori n g
> 3 × U L N a c c o m p a ni e d b y  
s y m p t o m sb

Di s c o nti n u e t h e st u d y 
tr e at m e nt i m m e di at el y

H o s pit ali z e if cli ni c all y 
a p pr o pri at e

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o nc
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)
> 3 t o ≤ 5 × U L N ( s u bj e ct i s 
a s y m p t o m ati c)

R e p e at L F T wit hi n t h e n e xt 
w e e k

If el e v ati o n i s c o nfir m e d, 
i niti at e cl o s e o b s er v ati o n of 
t h e s u bj e ct
I n v e sti g at or di s cr eti o n
M o nit or L F T wit hi n 1 t o 4 
w e e k s
A L P (i s ol at e d)
> 2 × U L N (i n t h e a b s e n c e of 
k n o w n b o n e p at h ol o g y)

R e p e at L F T wit hi n 4 8 
h o ur s

If el e v ati o n p er si st s, 
e st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
I n v e sti g at or di s cr eti o n
M o nit or L F T wit hi n 1 t o 4 
w e e k s or at n e xt vi sit
T B L (i s ol at e d)
> 2 × U L N (i n t h e a b s e n c e of 
k n o w n Gil b ert s y n dr o m e)

R e p e at L F T wit hi n 4 8 
h o ur s

If el e v ati o n p er si st s, 
di s c o nti n u e t h e st u d y dr u g 
i m m e di at el y

H o s pit ali z e if cli ni c all y 
a p pr o pri at e

E st a bl i s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o n c
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)
T e st f or h e m ol y si s ( e. g. 
r eti c ul o c yt e s, h a pt o gl o bi n, 
u n c o nj u g at e d [i n dir e ct] 
bilir u bi n)
> 1. 5 t o ≤ 2 × U L N ( s u bj e ct i s 
a s y m p t o m ati c)

R e p e at L F T wit hi n t h e n e xt 
w e e k

If el e v ati o n i s c o nfir m e d, 
i niti at e cl o s e o b s er v ati o n of 
t h e s u bj e ct
I n v e sti g at or di s cr eti o n
M o nit or L F T wit hi n 1 t o 4 
w e e k s or at n e xt vi sit


N o v arti s
C o nfi d e nti al
P a g e 1 1 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
Crit eri a
A cti o n s r e q uir e d
F oll o w -u p m o nit ori n g
J a u n di c e

Di s c o nti n u e t h e st u d y 
tr e at m e nt i m m e di at el y

H o s pit ali z e t h e s u bj e ct

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
A L T, A S T, T B L, Al b, P T/I N R, 
A L P a n d G G T u ntil r e s ol uti o n c
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)
A n y A E p ot e nti all y i n di c ati v e of 
a li v er t o xi cit y*

C o n si d er st u d y tr e at m e nt 
i nt err u pti o n or 
di s c o nti n u ati o n

H o s pit ali z ati o n if cli ni c all y 
a p pr o pri at e

E st a bli s h c a u s alit y

R e c or d t h e A E a n d 
c o ntri b uti n g f a ct or s ( e. g. 
c o n m e d s, m e d h x, l a b) i n 
t h e a p pr o pri at e C R F
I n v e sti g at or di s cr eti o n
a El e v at e d A L T/ A S T > 3 × U L N a n d T B L > 2 × U L N b ut wit h o ut n ot a bl e i n cr e a s e i n A L P t o > 2 × U L N 
b ( G e n er al) m al ai s e, f ati g u e, a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h e o si n o p hili a 
cR e s ol uti o n i s d efi n e d a s a n o ut c o m e of o n e of t h e f oll o wi n g: ( 1) r et ur n t o b a s eli n e v al u e s, ( 2) st a bl e 
v al u e s at t hr e e s u b s e q u e nt m o nit ori n g vi sit s at l e a st 2 w e e k s a p art, ( 3) r e m ai n at el e v at e d l e v el 
aft er a m a xi m u m of 6 m o nt h s, ( 4) li v er tr a n s pl a nt ati o n, a n d ( 5) d e at h.
Base d o n i n vesti gat or’s discreti o n i n vesti gati o n(s) f or c o ntri b uti n g fact ors f or t he li ver e ve nt 
ca n i ncl u de: Ser ol o g y  tests, i ma gi n g a n d pat h ol o g y  assess me nts, he pat ol o gist’s c o ns ulta nc y; 
o btai ni n g m ore detaile d hist or y  of s ym pt o ms a n d pri or or c o nc urre nt diseases, hist or y  of 
c o nc o mita nt dr u g use, e xcl usi o n of u n derl yi n g li ver disease.


N o v arti s
C o nfi d e nti al
P a g e 1 1 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2
1 6. 3
A p p e n di x 3: S p e cifi c r e n al al ert crit eri a, A cti o n s a n d E v e nt 
F oll o w -u p
T a bl e 1 6 - 3 
Sp e cifi c R e n al A l ert Crit eri a a n d Acti o n s
R e n al E v e nt
A ct i o n s
C o nfir m e d s er u m cr e ati ni n e i n cr e a s e 2 5 – 4 9 %

C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s

F oll o w u p wit hi n 2 - 5 d a y s
S er u m cr e ati ni n e i n cr e a s e 5 0 %
+
O R if < 1 8 y e ar s ol d, e G F R 3 5 m L/ mi n/ 1. 7 3 m
2

C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s

R e p e at a s s e s s m e nt wit hi n 2 4 -4 8 h if p o s si bl e

C o n si d er dr u g i nt err u pti o n or di s c o nti n u ati o n 
u nl e s s ot h er c a u s e s ar e di a g n o s e d a n d 
c orr e ct e d

C o n si d er s u bj e ct h o s pit ali z ati o n a n d 
s p e ci ali z e d tr e at m e nt
N e w o n s et di p st i c k pr ot ei n uri a ≥ 3 +
O R
Pr ot ei n -cr e ati ni n e r ati o ( P C R) ≥ 1 g/ g Cr ( or 
m g / m m ol e q ui v al e nt a s c o n v ert e d b y t h e 
m e a s uri n g l a b or at or y)

C o n si d er c a u s e s a n d p o s si bl e i nt er v e nti o n s

A s s e s s s er u m al b u mi n & s er u m t ot al pr ot ei n

R e p e at a s s e s s m e nt t o c o nfir m

C o n si d er dr u g i nt err u pti o n or di s c o nti n u ati o n 
u nl e s s ot h er c a u s e s ar e di a g n o s e d a n d 
c orr e ct e d
N e w o n s et h e m at uri a ≥ 3 + o n uri n e di p sti c k

R e p e at a s s e s s m e nt t o c o nfir m

Di sti n g ui s h h e m o gl o bi n uri a fr o m h e m at uri a

Uri n e s e di m e nt mi cr o s c o p y

A s s e s s s Cr

E x cl u d e i nf e cti o n, tr a u m a, bl e e di n g fr o m t h e 
di st al uri n ar y tr a ct/ bl a d d er, m e n str u ati o n

C o n si d er bl e e di n g di s or d er
+ C orr e s p o n d s t o K DI G O crit eri a f or A c ut e Ki d n e y I nj ur y
A d diti o nal s pecialize d assess me nts are a vaila ble t o assess re nal f u ncti o n or re nal pat h ol o g y .
( N ote: I n exce pti o n al c ases, w he n a ne p hr ol o gist c o nsi ders a re n al bi o psy, it is rec o m me n de d 
t o m ake sli de s peci me n av ail a ble f or ev al u ati o n by t he R S G t o p ote nti ally i de ntify pr oject-wi de 
p atter ns of ne p hr ot oxicity.)
W he ne ver a re nal e ve nt is i de ntifie d, a detaile d s u bject hist or y  an d e xa mi nati o n are i n dicate d 
t o i de ntif y an d p ote ntiall y  eli mi nate ris k fact ors t hat m a y  ha ve i nitiate d or c o ntri b ute d t o t he 
e ve nt:

Bl o o d press ure assess me nt (after 5 -mi n ute rest, wit h a n a p pr o priate c uff size)

Si g ns a n d s y m pt o ms li ke f e ver, hea dac he, s h ort ness of breat h, bac k or a b d o mi nal pai n, 
d y s uria or he mat uria, de pe n de nt or peri or bital e de ma

C ha n ges i n bl o o d press ure, b o d y  wei g ht, fl ui d i nta ke, v oi di n g patter n, or uri ne o ut p ut


N o v arti s
C o nfi d e nti al
P a g e 1 1 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
Pr ot o c ol N o. C Q B W 2 5 1 B 2 2 0 2

C o nc o mita nt e ve nts or pr oce d ures s uc h as tra u ma, s ur gic al pr oce d ures, car diac or he patic 
fail ure, c o ntrast me dia or ot her k n o w n ne p hr ot o xi n a d mi nistrati o n, or ot her diseases or 
ca uses, e. g., de h y drati o n d ue t o deliri u m, t u m or l ysis
T a bl e 1 6 - 4
R e n al E v e nt F oll o w U p
F O L L O W - U P O F R E NA L  E V E N T S

Uri n e di p sti c k a n d s e di m e nt mi cr o s c o p y e vi d e n c e of DI N: cr y st al s, r e d bl o o d c ell s 
( d ys m or p hi c/ gl o m er ul ar v s. n o n -d y s m or p hi c/ n o n -gl o m er ul ar), w hit e bl o o d c ell s, t u b ul ar e pit h eli al 
c ell s

Bl o o d pr e s s ur e a n d b o d y w ei g ht

S er u m cr e ati ni n e, B U N, el e ctr ol yt e s ( s o di u m, p ot a s si u m, p h o s p h at e, c al ci u m), bi c ar b o n at e a n d 
uri c a ci d

Uri n e o ut p ut
R e vi e w a n d r e c or d p o s si bl e c o ntri b uti n g f a ct or s t o t h e r e n al e v e nt ( c o -m e di c ati o n s, ot h er c o -m o r bi d 
c o n diti o n s) a n d a d diti o n al di a g n o sti c pr o c e d ur e s ( M RI et c.) i n t h e C R F

E v e nt r e s ol uti o n: ( s Cr wit hi n 1 0 % of b a s eli n e or P C R < 1 g/ g Cr, or A C R < 3 0 0 m g/ g Cr) or

E v e nt st a bili z ati o n: s Cr l e v el wit h ± 1 0 % v ari a bilit y o v er l a st 6 m o nt h s or pr ot ei n -cr e ati ni n e r ati o 
st a bili z ati o n at a n e w l e v el wit h ± 5 0 % v ari a bilit y o v er l a st 6 m o nt h s.

A n al y si s of uri n e m ar k er s i n s a m pl e s c oll e ct e d o v er t h e c o ur s e of t h e DI N e v e nt

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
QBW251
CQBW251B2202
A randomized, subjects- and investigator blinded, placebo -
controlled parallel group study to assess the mode-of-
action of QBW251 in subjects with Chronic Obstructive 
Lung disease (COPD).
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Final Amendment 1
Release date:
23-Dec-2022
Number of pages:
20
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
ClinicalTrials.gov Identifier: NCT04268823
Personal Protected Data (PPD)


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Commercially Confidential Information (CCI)


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Study No. CQBW251B2202
Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Scope of document ..................................................................................................6
1.2
Study reference documentation ...............................................................................6
1.3
Study objectives.......................................................................................................6
1.4
Study design and treatment......................................................................................8
2
First interpretable results (FIR) ...........................................................................................9
3
Interim analyses...................................................................................................................9
4
Statistical methods: Analysis sets........................................................................................9
5
Statistical methods for Pharmacokinetic (PK) parameters................................................10
5.1
Variables................................................................................................................10
5.2
Descriptive analyses ..............................................................................................10
5.3
Statistical model, assumptions and hypotheses .....................................................11
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................11
6.1
Primary objective...................................................................................................11
6.1.1
Variables ...............................................................................................11
6.1.2
Descriptive analyses..............................................................................12
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.2
Secondary objectives .............................................................................................13
6.2.1
Variables ...............................................................................................13
6.2.2
Descriptive analyses..............................................................................14
6.3
Statistical model, assumptions and hypotheses .....................................................14
6.4
Exploratory objectives...........................................................................................16
6.4.1
Variables ...............................................................................................16
6.4.2
Descriptive analyses..............................................................................16
7
Statistical methods for safety and tolerability data............................................................16
7.1
Variables................................................................................................................17
7.2
Descriptive analyses ..............................................................................................17
Commercially Confidential Information


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List of tables
Table 1-1
Objectives and related endpoints ............................................................6
Figure 1-1
Study design............................................................................................8
Table 4-1
Protocol deviation codes and analysis sets..............................................9
Table 8-1
Biomarkers to be fully reported in CSR................................................19


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Confidential
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Study No. CQBW251B2202
List of abbreviations
AE
Adverse Event
b.i.d.
twice a day
CASA-Q
Cough and Sputum Assessment Questionnaire 
CAT
COPD Assessment Test
CFU
Colony Forming Units
COPD
Chronic Obstructive Pulmonary Disease 
CRF
Case Report Form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
coefficient of variation
DMS
Document Management System
eCRF
Electronic Case Report Form
EQ-5D-3L
Euro Quality of Life-5 Dimensions-3 Level 
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HRCT
High Resolution Computed Tomography 
IA
Interim Analyses
ICS
Inhaled Corticosteroids
LABA
Long-Acting β2-Agonists 
LAMA
Long-Acting Muscarinic Antagonists
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Drug Regulatory Affairs
PD
Pharmacodynamics
PK
Pharmacokinetics
PT
Preferred Term
RAP
Reporting & Analysis Process
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard deviation
SE
Standard error
SOC
System Organ Class
TFLs
Tables, Figures, Listings
ULOQ
Upper limit of quantification
WHO
World Health Organization


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SAP Amendment 1
Study No. CQBW251B2202
1 Introduction
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CQBW251B2202”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
1. Clinical Study Protocol version 02 dated 25-Aug-2021
2. eCRF version 3.0 dated 03-Jul-2020.
1.3
Study objectives
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on
fibrinogen plasma concentration.

Change from baseline in fibrinogen plasma
concentration.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Key secondary objective:
To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on
sputum bacterial load.

Change from baseline in total bacteria load
of colony forming units (CFU/mL)
of potentially pathogenic
microorganisms in  sputum.

Secondary objectives:
To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on airway
structure and function.

Change from baseline in airway wall and
lumen parameters along with extent of
global and regional air trapping, as
measured by HRCT.

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on COPD
subjectsubjects symptom burden changes.

Change from baseline in COPD
Assessment Test (CAT) questionnaire.

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on health
status.

Changes from baseline in the Euro Quality
of Life-5 Dimensions-3 Level (EQ-5D-3L)
questionnaire.

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on
changes in health-related quality of life.

Change from baseline in St. George's
Respiratory Questionnaire (SGRQ) total
and domain scores.

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on COPD
exacerbations.

Time to first COPD exacerbation

Proportion of subjectsubjects with
exacerbations

Annualized rate of exacerbations as
defined by EXACT-PRO questionnaire


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SAP Amendment 1
Study No. CQBW251B2202
Objective(s)
Endpoint(s)

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on
clinical symptoms, cough and sputum.

Change from baseline in Cough and
Sputum Assessment Questionnaire
(CASA-Q) domain scores.

To assess the safety and tolerability of
QBW251 in subjects with COPD.

ECG intervals

Vital signs

Standard clinical laboratory evaluations
(hematology, blood chemistry, and
urinalysis)

Adverse events

To assess the effect of QBW251 compared to
placebo during and after 12 weeks of
treatment on pharmacokinetics.

Assessment of drug exposure (Ctrough
collected at pre-dose and Cmax at post-
dose) on Day 1, Day 28, Day 56 and Day
84.
Cmax and AUC on Day 1 and Day 28 in
subset of subject population (serial
samplings up to 8hr).

To assess the effect of QBW251 compared to
placebo after 12 weeks of treatment on
spirometry.

Change from baseline in trough FEV1,
FVC, and FEV1/FVC.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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SAP Amendment 1
Study No. CQBW251B2202
1.4
Study design and treatment
This is a randomized, subject and investigator blinded, parallel-group, placebo-controlled study 
investigating the mode of action (MoA) and preliminary efficacy and safety of QBW251 
administered orally twice daily (b.i.d.) for 12 weeks in subjects with moderate to very severe 
COPD (GOLD 2-4). Approximately 100 subjects will be randomized in a 1:1 ratio to either 
QBW251 or placebo. Based on the assumption of a 15% drop-out rate (% drop out based on 
completed proof-of-concept COPD study CQBW251X2201), it is expected to have 
approximately 84 subjects to complete the study. Interim analysis plans were discontinued with 
strategic decision to stop this trial prior to completion.
The study consists of the following periods (Figure 1-1) : Screening, Baseline / Day 1, 
Treatment, and End of the Study followed by an additional post-treatment safety phone call. The 
total duration for each subject in the study is up to approximately 19 weeks.
Figure 1-1
Study design
Therefore, CQBW251B2202 study drug dose arms are:

QBW251 

Placebo b.i.d
CCI
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2 First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
3 Interim analyses
4 Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
No screen failure data will be presented.
The safety analysis set will include all subjects that received any study drug.
The pharmacokinetic (PK) analysis set will include all subjects with at least one available valid 
(i.e. not flagged for exclusion) PK concentration measurement, who received QBW251 and 
experienced no protocol deviations with relevant impact on PK data.
The pharmacodynamic (PD) analysis set will include all subjects with PD data at both baseline 
and at least one post-baseline assessment which are not affected by any protocol deviations.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from Safety analysis in case of these 
PDs: 
Exclude subject from 
Safety analysis set 
INCL01
Informed consent was not obtained before any 
assessment
Y
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SAP Amendment 1
Study No. CQBW251B2202
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs:
Exclude subject from PK 
analysis set
INCL01
Informed consent was not obtained before any 
assessment
Y
TRT04
Subject received incorrect dose
Y
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from  PD 
analysis sets
INCL01
Informed consent was not obtained before any 
assessment
Y
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
5 Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables
The Cmax, Tmax, AUClast, AUC0-8h, T1/2 PK parameters will be derived for QBW251 
plasma concentration data for Day 1, Day 28 if feasible in subset of subjects with extensive PK 
collection.
5.2
Descriptive analyses
Plasma concentration data for QBW251 will be listed by treatment, subject and sampling time 
point. Both scheduled and actual times will be included. Descriptive statistics will be provided 
by treatment and scheduled time point, including the number and frequency (n, %) of 
concentrations below the lower limit of quantification (LLOQ), which will be summarized as 
zero and reported as BLQ in the listing. Concentrations will be expressed in mass per volume 
unit.
Summary statistics will include mean (arithmetic and geometric), standard deviation (SD), 
coefficient of variation (CV) (arithmetic and geometric), median, minimum and maximum. If 
zero values occur for the values being summarized due to concentrations below the LLOQ, no 
geometric mean will be calculated. 
Arithmetic mean +/- standard deviations plot of QBW251 plasma concentration will be 
presented by treatment and using schedule sampling times for Day 1 and 28. An overlaying 
individual plot will be presented by treatment.
A box plot will be presented by treatment for pre-dose concentrations on Day 1, Day 28, Day 
56 and Day 84.


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Study No. CQBW251B2202
All PK parameters of QBW251 will be listed by treatment and subject. Summary statistics will 
be displayed by treatment, using the same summary statistics as for the PK concentrations. An 
exception to this is Tmax, where only median, minimum and maximum will be presented. 
All summaries will be based on the PK analysis set, including figures of means. For all listings 
and figures displaying individual data, all subjects will be shown, but subjects not in the PK 
population and values marked as unreliable by the PK Scientist will be flagged.
5.3
Statistical model, assumptions and hypotheses
No model-based statistical analysis will be performed for PK.
6 Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective of the study is to assess the change from baseline on fibrinogen plasma 
concentration levels after 12 weeks of treatment with QBW251 compared to placebo.
6.1.1 Variables
The primary estimand, defined below, quantifies a hypothetical effect of 12 weeks treatment 
that would have been observed if all subjects remained on their treatment for 12 weeks:

Target population: subjects with moderate to severe COPD with features of chronic
bronchitis and a history of exacerbations and treated with any of the combinations of LABA,
LAMA, or ICS LABA/LAMA, LABA/ICS or LABA/LAMA/ICS along with or without
macrolides as background therapy.

Variables of interest: change from baseline in fibrinogen after 12 weeks of treatment.

Intercurrent events of interest:
1. Discontinuation of study treatment or study participation before 12 weeks of
treatment
2. Intake of antibiotics to treat exacerbations (other than macrolides taken as
background medication)
3. Intake of systemic corticosteroids to treat exacerbations.
4.
Use of rescue medications before 12 weeks of treatment with study drug or placebo
is complete

Summary measure: mean difference between treatment groups (QBW251 compared
with placebo).


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Study No. CQBW251B2202
6.1.2 Descriptive analyses
Summary statistics will be provided by treatment group and visit for fibrinogen and will include 
arithmetic mean, standard deviation (SD), coefficient of variation (CV), median, minimum and 
maximum.
6.1.3 Statistical model, assumptions and hypotheses
The primary analysis will include all available data from subjects in the PD analysis set. 
The fibrinogen samples taken within 2 weeks after exacerbation or during or after last dose of 
antibiotics other than chronically administered macrolide would be set to missing if a valid 
unscheduled assessment did not happen at that time point for the primary analysis. 
The primary analysis will be performed using a one-sided test at alpha=0.1 (two-sided 80% 
confidence intervals) and estimated treatment difference (QBW251-Placebo) at week 12 will 
be reported along with the associated 80% confidence intervals.
The comparison of QBW251 to placebo will be evaluated by testing the following null 
hypothesis (H0) versus the alternative hypothesis (H1):
H0: There is no reduction in fibrinogen from baseline after 12 weeks of treatment in     
       QBW251 compared to placebo.
H1: There is a reduction in fibrinogen from baseline after 12 weeks of treatment in favor      
       QBW251 compared to placebo.
The change from baseline in fibrinogen data is assumed to be normally distributed. A MMRM 
will be fitted to the changes from baseline in fibrinogen for all time points until Day 84 visit 
including the fixed factors and covariates but are not limited to the following:

Treatment group

Visit/Time

Treatment group by time interaction

Smoking status

Baseline fibrinogen value by time interaction.
If normality assumptions are not met, then the fibrinogen data may be log transformed.
Sensitivity analyses:
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Study No. CQBW251B2202
Supportive analyses:
Supportive analyses will be performed on subjects whose fibrinogen levels or bacterial load 
collected at the visits during the study based on the different baseline treatments like LABA, 
LAMA, or ICS using repeated measures model similar to primary analyses.
6.1.3.1
Model checking procedures
Estimates of the missing values due to intake of rescue medications or antibiotics will be derived 
by the model under the missing at random (MAR) assumption. Alternative assumptions may be 
explored to investigate the robustness of the results under plausible non-missing at random 
situations. 
6.1.3.2
Graphical presentation of results
Model based plots will be presented for the fibrinogen data. 
6.2
Secondary objectives
The key secondary objective is to assess the effect of QBW251 compared to placebo after 12 
weeks of treatment on sputum bacterial load.
6.2.1 Variables
The key secondary objective endpoint is:

Change from baseline in the logarithm of total number of colony forming units
(log10CFU/mL) of potentially pathogenic microorganisms in sputum after 12
weeks of treatment.
The bacterial load samples taken 2 weeks after exacerbation (after antibiotic intake is finished) 
or during or after last dose of antibiotics would be set to missing if a valid unscheduled 
assessment did not happen at that time point for the primary analysis. 
The other secondary pharmacodynamics and efficacy endpoints are as follows:

Change from baseline in airway wall and lumen parameters along with extent of global
and regional air trapping as measured by HRCT after 12 weeks of treatment.

Change from baseline in FEV1, FVC and FEV1/FVC ratio measured by spirometry after
12 weeks of treatment.

Subject reported outcomes and exacerbations

Changes from baseline in the Euro Quality of Life-5 Dimensions-3 Level (EQ-
5D-3L).

Changes from baseline in Cough and Sputum Assessment Questionnaire (CASA-
Q) domain scores.

Change from baseline in COPD Assessment Test (CAT) questionnaire.

COPD exacerbations

Time to first COPD exacerbation

Proportion of subjects with exacerbations


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SAP Amendment 1
Study No. CQBW251B2202

Annualized rate of exacerbations as defined by EXACT-PRO questionnaire.

Change from baseline St. George’s Respiratory Questionnaire (SGRQ) total and 
domain scores.
In order to be included in the sputum analysis, a subject must provide a sufficient sputum sample 
at screening, and/or at baseline and at least one post-baseline visit. 
6.2.2 Descriptive analyses
Summary statistics will be provided by treatment group and visit for total number of colony 
forming units, all spirometry parameters (FEV1, FVC and FEV1/FVC ratio) and HRCT 
parameters including regional and global air tapping changes will include arithmetic mean, 
standard deviation (SD), coefficient of variation (CV), median, minimum and maximum.  These 
will be calculated at all time points as specified in the assessment schedule (Table 8-1) of CSP 
and specifically at the primary time point of interest (Day 84) considering placebo as the 
reference treatment.
Summary statistics will be provided by treatment group and visit for Cough and Sputum 
Assessment Questionnaire (CASA-Q) and St. George's Respiratory Questionnaire (SGRQ) 
domain scores, COPD assessment test (CAT), EQ-5D-3L and EXACT-PRO questionnaire data.
6.3
Statistical model, assumptions and hypotheses
The secondary objective analysis will include all available data from subjects in the PD analysis 
set.
The change from baseline in the logarithm of the total number of colony forming units including 
all different micro-organisms (log10 CFU) and change from baseline in the secondary efficacy 
including global air trapping and spirometry parameter will be analyzed using the same model 
(MMRM) as for the primary variable of interest. Contrasts for treatment differences will be 
provided together with two-sided 80% Confidence Intervals.
Similarly, other secondary pharmacodynamics and efficacy endpoints (CASA-Q, SGRQ, CAT, 
EQ-5d-3L and EXACT-PRO)  will be analyzed using the same model (MMRM) as for the 
primary variable of interest.
The following analyses will be performed to explore any differences in the exacerbation events 
that occur in QBW251 vs placebo:
1. Time to first exacerbation
The time-to-event analyses will be carried out only upon sufficient number of exacerbation 
events occur during the study to estimate the median in either of the treatment groups. 
The time to the first on-treatment exacerbation (event) is defined as the start date of first 
exacerbation minus the date of randomization +1. Subjects who do not experience an 
exacerbation or discontinued earlier without an exacerbation will be censored for analyses 
purposes.


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Study No. CQBW251B2202
The hazard ratios for QBW251 compared with placebo and their corresponding 80% confidence 
intervals will be computed using Kaplan-Meier method. The stratification factor may include 
number of exacerbations in the last 12 months as <=1 and >1.
The Kaplan-Meier estimates of the survival functions for each treatment will be plotted.
A Cox proportional hazards regression model will be applied in time-to-event analyses to test 
the null-hypothesis H0: λQBW251(t) / λPlacebo(t) = 1, where λ(t) is the hazard function for the 
failure time of subjects treated with QBW251 dose and Placebo, respectively. 
The Cox regression model will be stratified by number of exacerbations in the last 12 months.
The SAS procedure PROC PHREG will be used for analysis. Results will be presented with 
adjusted hazard ratios for treatment group comparisons and associated 80% confidence intervals. 
No check for the validity of proportional hazards assumptions will be done.
2. Annualized rate of COPD exacerbations
The total frequency of COPD exacerbations over the 12-week treatment period will be analyzed 
using a generalized linear model assuming a negative binomial distribution. 
The time at risk for a subject is defined as the length of time the subject is on treatment and the 
log (length of time) will be used as the offset variable in the model. The model will include 
treatment, antibiotic use, and the number of exacerbations in the past 12 months prior to 
screening as categorical variables. An estimate of the rate ratio together with 80% confidence 
intervals and corresponding p-value will be presented.
3. The percentage of subjects experiencing at least a COPD exacerbation
The proportion of subjects with at least one COPD exacerbation will be analyzed using logistic 
regression. The model will include treatment, antibiotic use, and the number of exacerbations 
in the past 12 months prior to screening as categorical variables. The estimated odds ratios will 
be displayed along with the associated 80% confidence intervals.
6.3.1.1
Graphical presentation of results
The mean (+/- SE) and mean change from baseline plots for total number of colony forming 
units, all spirometry parameters (FEV1, FVC and FEV1/FVC ratio) and HRCT parameters 
including regional and global air tapping changes will be presented by treatment.  Plot for the 
estimated treatment differences and associated 80% confidence intervals for change from 
baseline in total number of colony forming units, all spirometry parameters and HRCT 
parameters including regional and global air tapping changes. 


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6.4
Exploratory objectives
6.4.2 Descriptive analyses
7 Statistical methods for safety and tolerability data
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
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Study No. CQBW251B2202
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group for the Safety analysis set.
Other screening/baseline characteristics will be summarized including:

Smoking Status

HRCT

Spirometry (Absolute and percent predicted values of FEV1, FVC)

hsCRP

Fibrinogen plasma concentration

COPD Assessment Test (CAT)

Sputum bacterial load
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.
Subject disposition
A disposition summary will be presented for all subjects. This table will present the number and 
percentage of subjects who completed each study epoch and discontinued early for each epoch, 
along with the reasons for early discontinuation.
The number and percentage of subjects in each analysis set will be summarized for all subjects. 
All analysis set results will be presented in listings by treatment group and subject. A separate 
listing of all subjects excluded from any analysis set and the reasons for their exclusion will be 
provided.
All study epoch completion data will be listed by treatment group and subject.
Treatment
Data for study drug administration, rescue medication and concomitant therapies will be listed 
by treatment group and subject.
Summary statistics will be provided for the duration of exposure to study treatment using the 
safety analysis set.


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Study No. CQBW251B2202
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available, abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time. Shift tables using the low/normal/high (low and high) classification 
will be used to compare baseline to the worst on-treatment value.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
Summary tables for adverse events (AEs) will summarize only on-treatment events, with a start 
date during the on-treatment period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 1week 
after the last actual administration of any study treatment.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Listings will be provided for all AEs, SAEs and fatal AEs. 


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For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 5% 
and on-treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for an individual subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
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