A Randomized, Subjects and Investigator Blinded, Placebo Controlled Parallel Group Study to Assess the Mode of Action of QBW251 in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Novartis Pharmaceuticals



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