A 26-week, Randomized, Double Blind, Parallel-group Multicenter Study to Assess the Efficacy and Safety of QVA149 (110/50 μg o.d.) vs Tiotropium (18 µg o.d.) + Salmeterol/Fluticasone Propionate FDC (50/500 µg b.i.d.) in Patients With Moderate to Severe COPD
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Sponsor: Novartis Pharmaceuticals

Gl o b al M e di c al Aff air s
- G e n er al M e di ci n e
Q V A 1 4 9 (I n d a c at er ol m al e at e/ Gl y c o p yrr o ni u m br o mi d e)
Cli ni c al Tri al Pr ot o c ol  C Q V A 1 4 9 A 2 3 1 6  / N C T 0 2 6 0 3 3 9 3
A 2 6 -w e e k, r a n d o mi z e d , d o u bl e bli n d, p ar all el-gr o u p m ulti c e nt er 
st u d y  t o a s s e s s t h e effi c a c y a n d s af et y  of Q V A 1 4 9 ( 1 1 0/ 5 0  m c g o. d.) 
v s ti otr o pi u m ( 1 8  m c g o. d.) + s al m et er ol/fl ut i c a s o n e pr o pi o n at e F D C 
( 5 0/ 5 0 0 m cg b.i. d.) i n p ati e nt s w it h m o d er at e t o s e v er e C O P D
A ut h or s:
D o c u m e nt t y p e:   
A m e n d e d Pr ot o c ol V er si o n
E U D R A C T n u m b er:
2 0 1 5 ‐ 0 0 0 1 1 4 ‐ 2 2
V er si o n n u m b er:   
v 0 1 (Cl e a n )
D e v el o p m e nt p h a s e:   
I V
R el e a s e d at e:
0 9 -A u g -2 0 1 7
Pr o p ert y of N o v arti s
C o nfi d e nti al
M a y n ot b e u s e d, di v ul g e d, p u bli s h e d, or ot h er wi s e di s cl o s e d 
wit h o ut t h e c o n s e nt of N o v arti s
Cli ni c al Tri al Pr ot o c ol T e m pl at e V er si o n 2. 0, N o v e m b er , 2 0 1 3
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T a bl e of c o nt e nt s
Ta ble of c o nte nts .................................................................................................................2
List of ta bles ........................................................................................................................6
List of fi g ures ......................................................................................................................6
List of a b bre viati o ns ............................................................................................................7
Gl ossar y  of ter ms.................................................................................................................9
A me n d me nt 0 1 ..................................................................................................................1 0
Pr ot oc ol s u m mar y ..............................................................................................................1 1
1  
I ntr o d ucti o n .......................................................................................................................1 5
1. 1   
Bac k gr o u n d ............................................................................................................1 5
1. 2   
P ur p ose ..................................................................................................................1 6
2  
St u d y  o bjecti ves.................................................................................................................1 7
2. 1   
Pri mar y  o bjecti ve...................................................................................................1 7
2. 2   
Sec o n dar y  o bjecti ves.............................................................................................1 7
2. 3   
E x pl orat or y  o bjecti ves...........................................................................................1 7
3  
I n vesti gati o nal pla n ...........................................................................................................1 8
3. 1   
St u d y  desi g n...........................................................................................................1 8
3. 2   
Rati o nale of st u d y  desi g n.......................................................................................2 0
3. 3   
Rati o nale of d ose/re gi me n, r o ute of a d mi nistrati o n a n d d urati o n of treat me nt .....2 1
3. 4   
Rati o nale f or c h oice of c o m parat or....................................................................... 2 1
3. 5   
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 ..................................2 1
3. 6   
Ris ks a n d be nefits ..................................................................................................2 1
4  
P o p ulati o n ..........................................................................................................................2 2
4. 1   
I ncl usi o n criteria ....................................................................................................2 3
4. 2   
E xcl usi o n criteria ...................................................................................................2 3
5  
Treat me nt ...........................................................................................................................2 6
5. 1   
Pr ot oc ol re q ueste d treat me nt................................................................................. 2 6
5. 1. 1   
I n vesti gati o nal treat me nt.......................................................................2 6
5. 1. 2   
Refere nce t hera p y................................ ..................................................2 6
5. 2   
Treat me nt ar ms ......................................................................................................2 6
5. 3   
Treat me nt assi g n me nt, ra n d o mizati o n ...................................................................2 7
5. 4   
Treat me nt bli n di n g .................................................................................................2 7
5. 5   
Treati n g t he patie nt ................................................................................................2 7
5. 5. 1   
Patie nt n u m beri n g................................................................................. 2 7
5. 5. 2   
Dis pe nsi n g t he i n vesti gati o nal treat me nt ..............................................2 8
5. 5. 3   
Ha n dli n g of st u d y  treat me nt..................................................................2 8
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
5. 5. 4   
I nstr ucti o ns f or prescri bi n g a n d ta ki n g st u dy treat me nt ........................2 9
5. 5. 5   
Per mitte d d ose a dj ust me nts a n d i nterr u pti o ns of st u d y  treat me nt ........3 0
5. 5. 6    
Resc ue me dicati o n ................................................................................ 3 0
5. 5. 7   
C o nc o mita nt treat me nt ..........................................................................3 1
5. 5. 8   
Pr o hi bite d Treat me nt .............................................................................3 1
5. 5. 9   
Disc o nti n uati o n of st u d y  treat me nt.......................................................3 3
5. 5. 1 0   
Wit h dra wal of c o nse nt
..........................................................................3 4
5. 5. 1 1   
L oss t o f oll o w -u p .................................................................................. 3 4
5. 5. 1 2   
E mer ge nc y  brea ki n g of assi g ne d treat me nt c o de..................................3 4
5. 5. 1 3   
St u d y  c o m pleti o n a n d p ost-st u d y treat me nt ..........................................3 5
5. 5. 1 4   
Earl y st u d y ter mi nati o n .........................................................................3 5
6  
Visit sc he d ule a n d as sess me nts .........................................................................................3 5
6. 1   
Assess me nt sc he d ule .............................................................................................3 5
6. 2   
Ti me d assess me nts .................................................................................................4 2
6. 3   
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures..................................................4 4
6. 4   
Patie nt de m o gra p hics/ ot her baseli ne c haracteristics .............................................4 4
6. 5   
Treat me nt e x p os ure a n d c o m plia nce .....................................................................4 5
6. 6   
Efficac y ..................................................................................................................4 5
6. 6. 1   
S pir o metr y .............................................................................................4 5
6. 6. 2   
C O P D e xacer bati o ns .............................................................................4 5
6. 6. 3   
Resc ue me dicati o n usa ge ......................................................................4 7
6. 6. 4   
M o difie d Me dical Researc h C o u ncil ( m M R C) D y s p nea Scale ............4 7
6. 6. 5   
C O P D Assess me nt Test ( C A T) .............................................................4 7
6. 6. 6   
St. Ge or ge Res pirat or y  Q uesti o n naire C ( S G R Q-C) .............................4 8
6. 6. 7   
B DI / T DI................................................................................................4 9
6. 6. 8   
e Diar y ....................................................................................................4 9
6. 6. 9   
A p pr o priate ness of efficac y  assess me nts..............................................4 9
6. 7   
Safet y .....................................................................................................................5 0
6. 7. 1   
P h y sical e xa mi nati o n ............................................................................5 0
6. 7. 2   
Vital si g ns ..............................................................................................5 0
6. 7. 3   
P ne u m o nia .............................................................................................5 0
6. 7. 4   
Hei g ht a n d wei g ht .................................................................................5 1
6. 7. 5   
La b orat or y  e val uati o ns..........................................................................5 1
6. 7. 6   
Electr ocar di o gra m ( E C G) .....................................................................5 2
6. 7. 7   
Pre g na nc y  a n d assess me nts of fertilit y .................................................5 3
6. 7. 8   
A p pr o priate ness of safet y  meas ure me nts..............................................5 3
6. 8   
Ot her assess me nts ..................................................................................................5 3
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 8. 1   
Res o urce utilizati o n ...............................................................................5 3
6. 8. 2   
Healt h -relate d Q ualit y of Life...............................................................5 3
6. 8. 3   
P har mac o ki netics ..................................................................................5 3
6. 8. 4   
P har mac o ge netics ..................................................................................5 4
6. 8. 5   
Bi o mar kers ............................................................................................5 4
7  
Safet y  m o nit ori n g..............................................................................................................5 4
7. 1   
A d verse e ve nts .......................................................................................................5 4
7. 2   
Seri o us a d verse e ve nts ...........................................................................................5 5
7. 2. 1   
Defi niti o n of S A E .................................................................................5 5
7. 2. 2   
S A E re p orti n g ........................................................................................5 6
7. 3   
P ne u m o nia .............................................................................................................5 7
7. 4   
Li ver safet y  m o nit ori n g .........................................................................................5 7
7. 5   
Re nal safet y m o nit ori n g .........................................................................................5 8
7. 6   
Pre g na nc y  re p orti n g...............................................................................................5 9
8  
Data re vie w a n d data base ma na ge me nt .............................................................................6 0
8. 1   
Site m o nit ori n g ......................................................................................................6 0
8. 2   
Data c ollecti o n....................................................................................................... 6 0
8. 3   
Data base ma na ge me nt a n d q ualit y  c o ntr ol............................................................6 0
8. 4   
Data M o nit ori n g C o m mittee ..................................................................................6 1
8. 5   
A dj u dicati o n C o m mittee ........................................................................................6 1
9  
Data a nal y sis......................................................................................................................6 2
9. 1   
A nal y sis sets ..........................................................................................................6 2
9. 2   
Patie nt de m o gra p hics a n d ot her baseli ne c haracteristics....................................... 6 2
9. 3   
Treat me nts .............................................................................................................6 3
9. 4   
A nal y sis of t he pri mar y varia ble(s) .......................................................................6 3
9. 4. 1   
Varia ble(s) .............................................................................................6 3
9. 4. 2   
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis ..........................6 3
9. 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 .......................6 4
9. 4. 4   
S u p p orti ve a nal y ses...............................................................................6 5
9. 5   
A nal y sis of sec o n dar y  varia bles ............................................................................6 5
9. 5. 1   
Efficac y  varia bles..................................................................................6 5
9. 5. 2   
Safet y  varia bles.....................................................................................6 6
9. 5. 3   
Res o urce utilizati o n ...............................................................................6 7
9. 5. 4   
P har mac o ki netics ..................................................................................6 7
9. 5. 5   
P har mac o ge netics/ p har mac o ge n o mics .................................................6 7
9. 5. 6   
Bi o mar kers ............................................................................................6 7
9. 5. 7   
P K/ P D ...................................................................................................6 7
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
9. 6   
I nteri m a nalys es .....................................................................................................6 8
9. 7   
Sa m ple size calc ulati o n.......................................................................................... 6 8
1 0
Et hical c o nsi derati o ns ........................................................................................................6 8
1 0. 1 
Re g ulat or y  a n d et hical c o m plia nce........................................................................6 8
1 0. 2 
I nf or me d c o nse nt pr oce d ures.................................................................................6 9
1 0. 3 
Res p o nsi bilities of t he i n vesti gat or a n d I R B/ I E C..................................................6 9
1 0. 4 
P u blicati o n of st u d y  pr ot oc ol a n d res ults...............................................................6 9
1 1
Pr ot oc ol a d here nce ............................................................................................................7 0
1 1. 1 
Pr ot oc ol A me n d me nts ...........................................................................................7 0
1 2
Refere nces .........................................................................................................................7 1
1 3
A p pe n di x 1: Cli nicall y  n ota ble la b orat or y val ues.............................................................7 2
1 4
A p pe n di x 2: S pir o metr y  G ui da nce....................................................................................7 4
1 5
A p pe n di x 3: Patie nt Diar y .................................................................................................7 7
1 6
A p pe n di x 4: I nstr ucti o ns f or use of N o vartis si n gle d ose dr y  p o w der i n haler C o nce pt 
1, Acc u haler a n d Ha n di Haler .............................................................................................7 9
1 7
A p pe n di x 5: G ui deli nes f or A d mi nisteri n g t he S G R Q -C Q uesti o n naire ..........................9 2
1 8
A p pe n di x 6: St. Ge or ge ’s Res pirat or y Q uesti o n naire ( S G R Q-C) .....................................9 5
1 9
A p pe n di x 7: C O P D Assess me nt Test ( C A T) ..................................................................1 0 2
2 0
A p pe n di x 8: m o difie d Me dical Researc h C o u ncil ( m M R C) D y s p nea Scale ..................1 0 3
2 1
A p pe n di x 9: B DI / T DI......................................................................................................1 0 4
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Li st of t a bl e s
Ta ble 5 - 1
Pr o hi bite d treat me nt .............................................................................3 1
Ta ble 5 - 2
Pr o hi bite d C O P D -relate d me dicati o ns d uri n g t he trial........................3 2
Ta ble 5 - 3
Me dicati o n all o we d u n der certai n c o n diti o ns if ta ke n as f oll o ws........ 3 3
Ta ble 6 - 1
Assess me nt sc he d ule .............................................................................3 7
Ta ble 6 - 2
Ti me d assess me nts ................................................................................4 3
Ta ble 7 - 1
S pecific Re nal Alert Criteria a n d Acti o ns .............................................5 9
Ta ble 1 3 - 1   
Li ver E ve nt a n d La b orat or y Tri g ger Defi niti o ns ..................................7 2
Ta ble 1 3 - 2   
F oll o w U p Re q uire me nts f or L i ver E ve nts a n d La b orat or y Tri g gers...7 2
Li st of fi g ur e s
Fi g ure 3 - 1   
St u d y  Desi g n.........................................................................................1 8
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Li st of a b br e vi at i o n s
A E
A d verse E ve nt
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A U C
Area u n der t he c ur ve
B DI
Baseli ne D y s p nea I n de x
b.i. d.
t wice a da y
C C V
Car di o - a n d Cere br o- Vasc ular e ve nts
C F R
U S C o de of Fe deral Re g ulati o ns
C O P D   
C hr o nic O bstr ucti ve P ul m o nar y  Disease
C P O
C o u ntr y  P har ma Or ga nizati o n
C R F
Case Re p ort/ Rec or d F or m ( pa per or electr o nic)
C R O
C o ntract Researc h Or ga nizati o n
C T C
C o m m o n T o xicit y  Criteria
E C G
Electr ocar di o gra m
E D C
Electr o nic Data Ca pt ure
e Diar y   
electr o nic diar y de vice
G C P
G o o d Cli nical Practice
G O L D   
Gl o bal I nitiati ve f or C hr o nic O bstr ucti ve L u n g Disease
F D C
Fi xe d -d ose c o m bi nati o n
F E V 1
F orce d E x pirat or y  V ol u me i n 1 sec o n d
F V C
F orce d Vital Ca pacit y
h C G
h u ma n C h ori o nic G o na d otr o pi n
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n of Tec h nical Re q uire me nts f or 
Re gistrati o n of P har mace uticals f or H u ma n Use
I C S
I n hale d c ortic oster oi d
I E C
I n de pe n de nt Et hics C o m mittee
i. v.
i ntra ve n o us
I RB
I nstit uti o nal Re vie w B oar d
I R T
I nteracti ve Res p o nse Tec h n ol o g y
L A B A   
L o n g acti n g beta 2 a g o nist
L A M A   
L o n g acti n g m uscari nic a nta g o nist
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
L F T
Li ver f u ncti o n test
M DI
Metere d D ose I n haler
Me d D R A   
Me dical dicti o nar y  f or re g ulat or y acti vities
m M R C   
m o difie d Me dical Researc h C o u ncil
N Y H A Class   
Ne w Y or k Heart Ass ociati o n Classificati o n
O C/ R D C   
Oracle Cli nical/ Re m ote Da ta Ca pt ure
o. d.
o nce a da y
P L A
Place b o
p. o.
oral(l y)
P S W
Pre mat ure St u d y  Wit h dra wal
S A B A   
S h ort acti n g beta 2 a g o nist
S A E
Seri o us A d verse E ve nt
S A M A    
S h ort acti n g m uscari nic a nta g o nist
S D D PI   
Si n gle D ose Dr y  P o w der I n haler
S m P C   
S u m mar y  of Pr o d uct C haracteristics
S M Q
Sta n dar dize d Me dical Q ueries
S U S A R   
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns
T D
St u d y  treat me nt disc o nti n uati o n
T DI
Tra nsiti o nal D y s p nea I n de x
W H O
W orl d Healt h Or ga nizati o n
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Gl o s s ar y  of t er m s
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
C o h ort
A gr o u p of n e wl y e nr oll e d p ati e nt s tr e at e d at a s p e cifi c d o s e a n d 
r e gi m e n (i. e. tr e at m e nt gr o u p) at t h e s a m e ti m e
C o ntr ol dr u g
A n y dr u g ( a n a cti v e dr u g or a n i n a cti v e dr u g, s u c h a s a pl a c e b o) 
w hi c h i s u s e d a s a c o m p ar at or t o t h e dr u g b ei n g t e st e d i n t h e tri al
D o s e l e v el
T h e d o s e of dr u g gi v e n t o t h e p ati e nt (t ot al d ail y or w e e kl y  et c.)
E nr oll m e nt
P oi nt/ti m e of p ati e nt 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)
E p o c h
A p orti o n of t h e st u d y w hi c h s er v e s a s p e cifi c p ur p o s e. T y p i c al 
E p o c h s ar e: s cr e e ni n g/r e cr uit m e nt, w a s h -o ut, tr e at m e nt, a n d f oll o w -
u p
I n v e sti g ati o n al dr u g   
T h e 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 3 1 2. 3 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 “i n v e sti g ati o n al 
m e di ci n al pr o d u ct.”
I n v e sti g ati o n al tr e at m e nt   
All i n v e sti g ati o n al dr u g( s) 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 a s w ell a s t h eir a s s o ci at e d tr e at m e nt c o ntr ol s. 
T hi s i n cl u d e s a n y  pl a c e b o s, a n y a cti v e c o ntr ol s, a s w ell a s a p pr o v e d 
dr u g s u s e d o ut si d e of t h eir i n di c ati o n/ a p pr o v e d d o s a g e or t e st e d i n a 
fi x e d c o m bi n ati o n.
I n v e sti g ati o n al tr e at m e nt g e n er all y d o e s n ot i n cl u d e pr ot o c ol -
s p e cifi e d c o n c o mit a nt b a c k gr o u n d t h er a pi e s  w h e n t h e s e ar e 
st a n d ar d tr e at m e nt s i n t h at i n di c ati o n
M e di c ati o n 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 i n v e sti g ati o n al/ st u d y tr e at m e nt
p a c k a g e i n st u di e s t h at di s p e n s e m e di c ati o n u si n g a n I R T s y st e m
Pr ot o c ol
A writt e n a c c o u nt of all t h e pr o c e d ur e s t o b e f oll o w e d i n a tri al, w hi c h 
d e s cri b e s all t h e a d mi ni str ati v e, d o c u m e nt ati o n, a n al yti c al a n d cli ni c al 
pr o c e s s e s u s e d i n t h e tri al.
P art 
A si n gl e c o m p o n e nt of a st u d y w hi c h c o nt ai n s diff er e nt o bj e cti v e s or 
p o p ul ati o n s wit hi n t h at si n gl e st u d y. C o m m o n p art s wit hi n a st u d y 
ar e: a si n gl e d o s e p art a n d a m ulti pl e d o s e p art, or a p art i n p ati e nt s 
wit h e st a bli s h e d di s e a s e a n d i n t h o s e wit h n e wl y -di a g n o s e d di s e a s e
P eri o d
A s u b di vi si o n of a st u d y
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 p ati e nt, 
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
St u d y tr e at m e nt / 
tr e at m e nt
A n y si n gl e 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 p ati e nt 
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), a cti v e dr u g r u n -i n s or b a c k gr o u n d t h er a p y 
St u d y/ i n v e sti g ati o n al 
tr e at m e nt di s c o nti n u ati o n
P oi nt/ti m e w h e n p ati e nt p er m a n e ntl y st o p s t a ki n g 
st u d y/i n v e sti g ati o n al tr e at m e nt  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 p ati e nt wit h dr a w al
P ati e nt 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 p ati e nt w h o e nr oll s i nt o t h e st u d y 
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
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
A m e n d m e nt 0 1
A m e n d m e nt r ati o n al e 
T his pr ot oc ol a me n d me nt was ma de t o pr o vi de t he c orrect n u m ber of patie n ts o n w hic h t he
2 4- h o ur wei g hte d mea n uri ne c ortis ol was deter mi ne d. 
C h a n g e s t o t h e pr ot o c ol
T he n u m ber of patie n ts o n w hic h t he 2 4- h o ur wei g hte d mea n uri ne c ortis ol was deter mi ne d 
was c ha n ge d fr o m a p pr o xi matel y  3 0 0 t o a p pr o xi matel y 3 8 0.
T his c ha n ge is s h o w n i n t he trac k c ha n ges versi o n of t he pr ot oc ol usi n g stri ke t hr o u g h re d f o nt 
f or deleti o ns a n d re d u n derli ne d f or i nserti o ns.
A 
c o p y of t his a me n de d pr ot oc ol will 
be se nt t o t he I nstit uti o nal Re vie w 
B oar d 
(IR Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Pr ot o c ol s u m m ar y
Pr ot o c ol n u m b er   
C Q V A 1 4 9 A 2 3 1 6
Titl e
A 2 6 -w e e k, r a n d o mi z e d, d o u bl e bli n d, p ar all el -gr o u p m u lti c e nt er st u d y  to 
a s s e s s t h e effi c a c y  an d s af et y  of Q V A 1 4 9 ( 1 1 0/ 5 0 μ g o. d.) v s ti otr o pi u m 
( 1 8 µ g o. d.) + s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C ( 5 0/ 5 0 0 µ g b.i. d.) i n 
p ati e nt s wit h m o d er at e t o s e v er e C O P D
Bri ef titl e
E v al u ati o n of t h e effi c a c y a n d s af et y  of Q V A 1 4 9 ( 1 1 0/ 5 0 μ g o. d.) v s 
ti otr o pi u m ( 1 8 µ g o. d.) + s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C ( 5 0/ 5 0 0 
µ g b.i. d.) i n p ati e nt s wit h m o d er at e t o s e v er e 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 I V
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   
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 t h e effi c a c y  an d s af et y 
of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) a n d tri pl e tr e at m e nt wit h ti otr o pi u m ( 1 8 µ g 
o. d.) + s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C ( 5 0/ 5 0 0 µ g b.i. d.) ar e 
c o m p ar a bl e i n p ati e nt s wit h m o d er at e t o s e v er e C O P D wit h o ut a hi st or y 
of fr e q u e nt e x a c er b ati o n s.
Pri m ar y  O bj e cti v e( s)    
T o d e m o n str at e t h e n o n -i nf eri orit y of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) o n tr o u g h 
F E V 1 v s. ti otr o pi u m ( 1 8 µ g o. d .) + s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C 
( 5 0/ 5 0 0 µ g b.i. d.) aft er 2 6 w e e k s of tr e at me nt i n m o d er at e -t o-s e v er e 
C O P D p ati e nt s.
S e c o n d ar y O bj e cti v e s
  
T o e v al u at e t h e eff e ct of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) c o m p ar e d 
wit h ti otr o pi u m ( 1 8 µ g o. d .) + s al m et er ol/fl uti c a s o n e pr o pi o n at e 
F D C ( 5 0/ 5 0 0 µ g b.i. d.) o v er 2 6 w e e k s of tr e at m e nt i n t er m s of:
  
R at e of m o d er at e or s e v er e C O P D e x a c er b ati o n s.
  
R at e of m o d er at e or s e v er e C O P D e x a c er b ati o n s r e q uiri n g
  
S y st e mi c gl u c o c orti c o st er oi d s a n d a nti bi oti c s d uri n g t h e 
tr e at m e nt p eri o d ( m o d er at e e x a c er b ati o n s o nl y).
  
H o s pit ali z ati o n s d uri n g t h e tr e at m e nt p eri o d a n d 
r e h o s pit ali z ati o n wit hi n 3 0 d a y s d uri n g t h e tr e at m e nt p eri o d 
( s e v er e e x a c er b ati o n s o nl y).
  
T o e v al u at e t h e eff e ct of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) c o m p ar e d 
wit h ti otr o pi u m ( 1 8 µ g o. d.) + s al m et er ol/fl uti c a s o n e pr o pi o n at e 
F D C ( 5 0/ 5 0 0 µ g b.i. d.) o n :
  
Tr o u g h F E V 1 a n d F V C o v er 2 6 w e e k s of tr e at m e nt.
  
T ot al s c or e of t h e 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-C) aft er 1 2 a n d 2 6 w e e k s of tr e at m e nt
  
T ot al s c or e of t h e Tr a n siti o n al D y s p n e a I n d e x ( T DI) aft er 1 2  a n d 
2 6 w e e k s of tr e at m e nt
  
M e a n u s e of r e s c u e t h er a p y ( n u m b er of p uff s/ d a y ) a n d t h e 
p er c e nt a g e of d a y s wit h o ut r e s c u e t h er a p y o v er t h e 2 6 w e e k 
tr e at m e nt p eri o d.
  
T o a s s e s s t h e s af et y  ( p arti c ul arl y wit h r e g ar d t o E CG, l a b or at or y 
t e st s, vit al si g n s a n d a d v er s e e v e nt s) a n d t ol er a bilit y 
( di s c o nti n u ati o n d u e t o a d v er s e e v e nt s) of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g 
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
o. d.) v s. ti otr o pi u m ( 1 8 µ g o. d.) + s al m et er ol/fl uti c a s o n e 
pr o pi o n at e F D C ( 5 0/ 5 0 0 µ g b.i. d.) o v er t h e 2 6 w e e k s of 
tr e at m e nt.
  
T o a s s e s s t h e s af et y  of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) v s. ti otr o pi u m 
( 1 8 µ g o. d.) + s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C ( 5 0/ 5 0 0 µ g 
b.i. d.) i n t er m s of H P A a xi s f u n cti o n, a s d et er mi n e d b y 2 4 -h o ur 
w ei g ht e d m e a n uri n e c orti s ol, i n a s u b s et of p ati e nt s.
St u d y d e s i g n
T h e st u d y i s a m u lti c e nt er, r a n d o mi z e d, p ar all el -gr o u p, d o u bl e -bli n d, 
tri pl e-d u m m y st u d y  to a s s e s s t h e effi c a c y of t h e t w o a cti v e tr e at m e nt 
ar m s of  
QV A 1 4 9 
( 1 1 0/ 5 0 μ g o. d.) a n d ti otr o pi u m ( 1 8 μ g o. d) + 
s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C ( 5 0/ 5 0 0 b.i. d ) i n p ati e nt s wit h 
m o d er at e -t o-s e v er e C O P D.
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 0 m a l e a n d f e m al e 
a d ult s ( a g e 4 0 y e ar s a n d gr e at er) wit h a cli ni c al di a g n o si s of st a bl e 
C O P D w h o h a v e m o d er at e t o s e v er e airfl o w o b str u cti o n ( G O L D 2 0 1 4 ) 
a n d 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. Eli gi bl e p ati e nt s will b e 
t h o s e t h at h a v e b e e n m ai nt ai n e d o n tri pl e t h er a p y ( a L A M A pl u s a F D C of 
L A B A/I C S) f or a mi ni m u m of si x m o nt h s, a n d ar e cli ni c all y st a bl e ( d efi n e d 
a s n ot h a vi n g > 1 m o d er at e -s e v er e e x a c er b ati o n wit hi n 
t h e l a st 1 2 
m o nt h s).
I n cl u si o n crit eri a
  
P ati e nt s w h o h a v e si g n e d I nf or m e d C o n s e nt F or m pri or t o 
i niti ati o n of a n y st u d y-r el at e d pr o c e d ur e.
  
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.
  
P ati e nt s wit h m o d er at e t o s e v er e airfl o w o b str u cti o n wit h st a bl e 
C O P D a c c or di n g t o t h e 2 0 1 4 G O L D G ui d eli n e s.
  
P ati e nt s wit h a p o st -br o n c h o dil at or F E V 1 ≥4 0 a n d < 8 0 % of t h e 
pr e di ct e d n or m al v al u e, a n d p o st -br o n c h o dil at or F E V 1 / F V C < 
0. 7 0 at r u n -i n Vi sit 1 0 1. 
(P o st r ef er s t o 1 5 mi n aft er i n h al ati o n of 4 0 0 µ g of s al b ut a m ol).
  
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 ½ 
p a c k/ d a y x 2 0 y e ar s). A n e x -s m o k er i s d efi n e d a s a p ati e nt w h o 
h a s n ot s m o k e d f or ≥ 6 m o nt h s at s cr e e ni n g.
  
P ati e nt s w h o ar e o n tri pl e tr e at m e nt at l e a st f or t h e l a st 6 m o nt h s 
( L A M A + L A B A/I C S).
E x cl u si o n crit eri a
  
K e y e x cl u si o n crit eri a. F ull crit eri a ar e wit hi n t h e pr ot o c ol:
  
P ati e nt s c o ntr ai n di c at e d f or tr e at m e nt wit h, or h a vi n g a hi st or y of 
r e a cti o n s/ h y p er s e n siti vit y t o a n y of t h e f oll o wi n g i n h al e d dr u g s, 
dr u g s of a si mil ar cl a s s or a n y c o m p o n e nt t h er e of:
  
l o n g a n d s h ort a cti n g a nti c h oli n er gi c a g e nt s
  
l o n g a n d s h ort a cti n g b et a-2 a g o ni st s
  
s y m p at h o mi m eti c a mi n e s
  
l a ct o s e or a n y of t h e ot h er e x ci pi e nt s of tri al m e di c ati o n
  
Hi st or y or c urr e nt di a g n o si s of E C G a b n or m aliti e s i n di c ati n g 
si g nifi c a nt ri s k of s af et y f or p ati e nt s p arti ci p ati n g i n t h e st u d y 
s u c h a s:
  
C o n c o mit a nt cli ni c all y si g nifi c a nt c ar di a c arr h yt h mi a s, e. g., 
s u st ai n e d v e ntri c ul ar t a c h y c ar di a, a n d cl i ni c all y si g nifi c a nt 
s e c o n d or t hir d d e gr e e A V bl o c k wit h o ut a p a c e m a k er 
  
Hi st or y of f a mili al l o n g Q T s y n dr o m e or k n o w n f a mil y  hi st or y of 
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T or s a d e s d e P oi nt e s
  
R e sti n g Q T c ( Fri d eri ci a m e t h o d) ≥4 5 0 m s e c f or m al e s a n d 
f em a l e s at Vi sit 1 0 1 .
  
C o n c o mit a nt u s e of a g e nt s k n o w n t o si g nifi c a ntl y pr ol o n g t h e Q T 
i nt er v al u nl e s s t h e y c a n b e p er m a n e ntl y di s c o nti n u e d f or t h e 
d ur ati o n of st u d y.
  
P ati e nt 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), 
arr h yt h mi a ( s e e b el o w f or p ati e nt s wit h atri al fi brill ati 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 s y c hi atri c, 
g a str oi nt e sti n al, h e p ati c, 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.
  
P ati e nt s w h o h a v e h a d m or e t h a n o n e 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 i n t h e 1 2 m o nt h s pri or t o Vi sit 1.
  
P ati e nt s w h o d e v el o p e d a C O P D e x a c er b ati o n of a n y s e v erit y 
eit h er 6 w e e k s b ef or e t h e s cr e e ni n g ( Vi sit 1) or b et w e e n 
s cr e e ni n g ( Vi sit 1) a n d tr e at m e nt ( Vi sit 2 0 1) will n ot b e eli gi bl e 
b ut will b e p er mitt e d t o b e r e -s cr e e n e d aft er a mi ni m u m of 6 
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.
  
P ati e nt s wit h a n y hi st or y of a st h m a.
  
P ati e nt s wit h a bl o o d e o si n o p hil c o u nt > 6 0 0/ m m
3 d uri n g 
s cr e e ni n g ( Vi sit 1 0 1 ).
  
P ati e nt s u n a bl e t o u s e a n el e ctr o ni c p ati e nt di ar y.
  
P ati e nt s u n a bl e t o u s e a dr y p o w d er i n h al er d e vi c e or a 
pr e s s uri z e d M DI (r e s c u e m e di c ati o n) or u n a bl e t o c o m pl y wit h 
t h e st u d y r e gi m e n. S p a c er d e vi c e s ar e n ot p er mitt e d.
  
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 ( ot h er t h a n 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), 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, r e g ar dl e s s of w h et h er 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.
I n v e sti g ati o n al    
a n d 
r ef er e n c e t h er a p y
Q V A 1 4 9 
1 1 0/ 5 0 μ g c a p s ul e s o. d . f or i n h al ati o n, s u p pli e d i n bli st er s 
d eli v er e d vi a N o v arti s si n gl e d o s e dr y  po w d er i n h al er N o v arti s si n gl e 
d o s e dr y p o w d er i n h al er N o v arti s si n gl e d o s e dr y p o w d er i n h al er .
S al m et er ol/fl uti c a s o n e pr o pi o n at e F D C 5 0/ 5 0 0 μ g dr y i n h al ati o n p o w d er 
d eli v er e d vi a A c c u h al er ™.
Ti otr o pi u m 1 8 μ g c a p s ul e s o. d. f or i n h al ati o n, s u p pli e d a s c o m m er ci all y 
a v ail a bl e bli st er s, d eli v er e d vi a H a n di H al er ® .
Effi c a c y  a s s e s s m e nt s
  
P ul m o n ar y F u n cti o n ( S pir o m etr y )
  
C O P D e x a c er b ati o n s
  
R e s c u e m e di c ati o n u s a g e
  
M o difi e d M e di c al R e s e ar c h C o u n cil ( m M R C) D y s p n e a S c al e
  
C O P D A s s e s s m e nt T e st ( C A T)
  
St. G e or g e R e s pir at or y Q u e sti o n n air e C ( S G R Q -C)
  
B DI/ T DI
  
e Di ar y
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
S af et y a s s e s s m e nt s
  
A d v er s e e v e nt s
  
P h y s i c al e x a mi n ati o n
  
Uri n e pr e g n a n c y t e st (f e m al e s of c hil d b e ari n g p ot e nti al)
  
E C G
  
Vit al si g n s
  
P n e u m o ni a
  
2 4 hr uri n ar y c orti s ol (i n a s u b -s et of p ati e nt s)
  
Or o p h ar y n g e al s a m pl e c ult ur e f or c a n di di a si s 
  
L a b or at or y: st a n d ar d bi o c h e mi str y  a n d h e m at ol o g y; uri n al y si s
Ot h er a s s e s s m e nt s
  
R e s o ur c e utili z ati o n
  
Bi o m ar k er s
D at a a n al y si s
T h e pri m ar y  obj e cti v e i s t o d e m o n str at e t h e n o n -i nf eri orit y of Q V A 1 4 9 
( 1 1 0/ 5 0    
µ g    
q. d.)    
c o m p ar e d    
t o    
ti otr o pi u m    
( 1 8    
µ g 
q. d.) + s al m et er ol/fl uti c a s o n e F D C ( 5 0/ 5 0 0 µ g b.i. d) i n t er m s of tr o u g h 
F E V 1 aft er 2 6 w e e k s of  tr e at me nt i n p ati e nt s wit h m o d er at e t o s e v er e 
C O P D .
T h e pri m ar y v ari a bl e i s t h e m e a n c h a n g e fr o m b a s eli n e i n p o st -d o s e 
tr o u g h F E V 1 aft er 2 6 w e e k s of tr e at m e nt. T r o u g h F E V 1 at D a y  18 2 i s 
d efi n e d a s t h e m e a n of t h e t w o F E V 1 v al u e s m e a s ur e d at 2 3 h 1 5 mi n a n d 
2 3 h 4 5 mi n aft er t h e m o r ni n g d o s e t a k e n at sit e o n D a y 1 8 1 . T h e pri m ar y  
effi c a c y  en d p oi nt will b e a n al y z e d u si n g a Mi x e d -Eff e ct M o d el R e p e at e d 
M e a s ur e s 
( M M R M) m o d el. T h e m o d el will i n cl u d e fi x e d, c at e g ori c al 
eff e ct s of  tr e at me nt a n d vi sit, c o u ntr y/r e gi o n, a n d tr e at m e nt-b y -vi sit 
i nt er a cti o n a s w ell a s t h e c o nti n u o u s, fix e d c o v ari at e s of b a s eli n e a n d 
b a s eli n e- b y -vi sit i nt er a cti o n.  If ad diti o n al c o v ari at e s ar e c o n si d er e d t o b e 
r e q uir e d t h e s e will b e pr e d efi n e d a n d i n cl u d e d i n t h e a n al y si s pl a n 
fi n ali z e d pri or t o d at a b a s e l o c k. T h e wit hi n -p ati e nt c orr el ati o n will b e 
m o d el e d 
u si n g 
a n 
u n str u ct ur e d 
c o v ari a n c e m a tri x. T h e 
b et w e e n -
tr e at m e nt c o m p ari s o n will 
b e c arri e d o ut u si n g t h e a dj u st e d m e a n 
diff er e n c e b et w e e n tr e at m e nt s at D a y 1 8 2 a n d 9 5 % c o nfi d e n c e i nt er v al of 
t h e a dj u st e d m e a n diff er e n c e will b e di s pl a y e d.
All ti m e d tr o u gh F E V 1 d at a i. e. d a y  29, d a y  85, d a y 1 8 1 a n d d a y  18 2, 
r e c or d e d p o st -b a s eli n e will b e i n cl u d e d i n t h e pri m ar y M M R M m o d el a n d 
n o i m p ut ati o n will b e a p pli e d t o mi s si n g d at a.
N o n -i nf eri orit y of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) fr o m ti otr o pi u m ( 1 8 µ g o. d.) + 
s al m et er ol/fl uti c a s o n e 
pr o pi o n at e 
F D C 
( 5 0/ 5 0 0 µ g 
b.i. d.) 
will  
b e 
d e m o n str at e d if t h e c o nfi d e n c e i nt er v al f or t h e m e a n D a y  18 2 F E V 1 
diff er e n c e of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) mi n u s ti otr o pi u m ( 1 8 µ g o. d.) + 
s al m et er ol/fl uti c a s o n e pr o pi o n at e F D C ( 5 0/ 5 0 0 µ g b.i. d.) li e s e nt ir el y t o 
t h e ri g ht of ( hi g h er t h a n) – 5 0 m L .
K e y w or d s
C O P D, Q V A 1 4 9, Tri pl e -T h er a p y, D u al Br o n c h o dil ati 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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
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), a c o m m o n pre ve nta ble a n d treata ble 
disease, is c haracterize d b y  persiste nt airfl o w li mitati o n t hat is us uall y pr o gressi ve a n d 
ass ociate d wit h a n e n ha nce d c hr o nic i nfla m mat or y res p o nse i n t he air wa ys a n d t he l u n g t o 
n o xi o us particles or gases. C urre nt treat me nt g ui deli nes f or C O P D rec o m me n d t he use of 
br o nc h o dilat ors f or all se veriti es, eit her o n a n as-re q uire d basis, or re g ular basis (G O L D 2 0 1 4 ). 
I n hale d l o n g-acti n g br o nc h o dilat or t hera p y suc h as β 2 a g o nists ( L A B As, s uc h as f or m oter ol, 
sal meter ol a n d i n dacater ol) a n d m uscari nic a nta g o nists ( LA M As, s uc h as ti otr o pi u m a n d 
gl yc o p yr r o ni u m br o mi de ) are esta blis he d a n d wi del y  use d treat me nt o pti o ns f or C O P D 
(G O L D 2 0 1 4 ).
P u blis he d st u dies (Ma k et al 1 9 9 0 ; Carstairs et al 1 9 8 5 ; I ke da et al 2 0 1 2 ) ha ve s h o w n t hat t he 
mec ha nis ms of acti o n of l o n g-acti n g br o nc h o dilat or t hera py s uc h as L A B As a n d L A M As are 
c o m ple me ntar y due t o t he di ffere ntial de nsit y of β 2 -a dre n oce pt ors a n d M 3 -rece pt ors i n 
ce ntral vers us s maller air wa ys. T h us, L A B As s h o ul d be m ore effecti ve i n rela xi n g s mall 
air wa ys a n d L A M As i n lar ge air wa ys. T here is als o cli nical e vi de nce t hat s u g gests t hat 
c o m bi ni n g br o nc h o dilat o rs fr o m t hese t w o p har mac ol o gical classes res ults i n si g nifica ntly 
greater i m pr o ve me nts i n l u n g f u ncti o n ( F E V 1) c o m pare d wit h t he i n di vi d ual c o m p o ne nts
al o ne (Cazz ola a n d M oli mar d 2 0 1 0 , Wa n g et al 2 0 1 1 ). St u dies t o date ha ve als o s h o w n ot her 
mea ni n gf ul o utc o mes s uc h as i m pr o ve me nt i n i ns pirat or y ca pacit y, re d ucti o n i n d y s p nea, 
i m pr o ve d s ym pt o m sc ores, a n d less resc ue me dicati o n use, as c o m pare d wit h i n di vi d ual dr u gs 
use d al o ne ( Va n der M ole n a n d Cazz ola 2 0 1 2 ).
Q V A 1 4 9 is a fi xe d c o m bi nati o n of a l o n g acti n g β 2 -a g o nist (I n dacater ol maleate – Q A B 1 4 9) 
a n d a l o n g acti n g m uscari nic 
a nta g o nist ( Gl yc o p yrr o ni u m br o mi de –
N V A 2 3 7). 
T his 
c o m bi nati o n pr o d uct will be deli vere d b y  the N o vartis Si n gle D ose Dr y  Po w der I n haler 
( S D D PI).
Q V A 1 4 9 was i n vesti gate d i n a c o m pre he nsi ve p hase III pr o gra m de vel o p me nt c o m prisi n g 
m ore t ha n 1 1, 0 0 0 C O P D patie nts acr oss m ore t ha n 4 0 c o u ntries. D ata fr o m t his Q V A 1 4 9 
P h ase III De vel o p me nt Pr o gra m h a ve de m o nstrate d i m pr o ve me nt i n l u n g f u ncti o n, q ualit y  of 
life, decrease i n C O P D s ym pt o ms a n d decrease i n s h ort-acti n g β 2 a g o nist ( S A B A) use wit h a 
safety pr ofile si milar t o place b o ( V o gel meier et al 2 0 1 3 , Bate ma n et al 2 0 1 3 ).
W he n 
c o m pare d t o c urre nt sta n dar d of care treat me nts li ke fl uticas o ne/sal meter ol or O L  
ti otr o pi u m, Q V A 1 4 9 p hase III st u dies de m o nstrate d si g nifica nt i m pr o ve me nts i n ter ms of 
l u n g f u ncti o n, d y s p nea, s ym pt o ms, q ualit y  of life a n d s h ort-acti n g β 2 a g o nist )- free da ys 
(V o gel meier et al 2 0 1 3 , Bate ma n et al 2 0 1 3 ). A d diti o nal i nf or mati o n ca n be f o u n d i n t he 
Q V A 1 4 9 I n vesti gat or’s Br oc h ure.
T h ese c o m parati ve st u dies ha ve bee n perf or me d i n C O P D p o p ulati o n s wit h c o m para ble sta ge 
a n d cli nical c haracteristics bet wee n t he t reat me nts ar ms.
B uil di n g o n t he stre n gt h a n d val ue of c o m bi nati o n t hera pies, t he cli nical practice of usi n g 
‘tri ple t hera py’ f or C O P D treat me nt has bec o me p o p ular i n rece nt years. T his a p pr oac h 
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
ge nerall y c o nsists of c o m bi ni n g a L A B A a n d a n I C S fi xe d-d ose co m bi nati o n s uc h as 
sal meter ol/fl uticas o ne pr o pi o nate ( S F C) wit h a n a ntic h oli ner gic/ m uscari nic a nta g o nist (i.e., 
l o n g-acti n g ti otr o pi u m br o mi de or s h ort-acti n g i pratr o pi u m br o mi de). T he rati o nale f or usi n g 
t hese c o m p o u n ds t o get her lies i n t he fact t hat t he y ha ve differe nt m olec ular mec ha nis ms of 
acti o n a n d, c o nse q ue ntl y, t heir c o m bi ne d use c o ul d ma xi mize t heir cli nical be nefits f or 
patie nts s ufferi n g fr o m t his de bilitati n g disease ( Sala ma et al 2 0 1 1 ).
Acc or di n g t o G O L D 2 0 1 4 C O P D g ui deli nes l o n g ter m treat me nt wit h i n hale d c ortic oster oi ds 
is rec o m me n de d f or patie nts wit h se vere a n d ver y  se vere C O P D a n d fre q ue nt e xacer bati o ns 
t hat are n ot a de q uatel y c o ntr olle d b y  lo n g -acti n g br o nc h o dilat ors ( E vi de nce A). T hese 
g ui deli ne s als o e m p hasize t hat l o n g-ter m treat me nt c o ntai ni n g i n hale d c ortic oster oi ds s h o ul d 
n ot be prescri be d o utsi de t heir i n dicati o ns, d ue t o t he ris k of p ne u m o nia a n d t he p ossi bilit y  of 
a n i ncrease d ris k of fract ures f oll o wi n g l o n g-ter m e x p os ure. Q V A 1 4 9 o nce da il y pr o vi de d 
cli nicall y rele va nt i m pr o ve me nts i n l u n g f u ncti o n c o m pare d wit h S F C t wice dail y wit h 
si g nifica nt s ym pt o matic be nefits i n patie nts wit h m o derate -t o-se vere C O P D a n d n o hist or y  of 
e xacer bati o n i n t he last year. (V o gel meier et al 2 0 1 3 ). T his st u d y co nfir me d t he s u peri orit y of 
d ual br o nc h o dilat or treat me nt t o a Fi xe d D ose C o m bi nati o n ( F D C) of I C S/ L A B A i n t his 
p o p ulati o n.
C urre nt G O L D 
g ui deli nes (G O L D 2 0 1 4 ) rec o m me n d t he use of tri ple t hera py as a n 
alter nati ve first-li ne c h oice f or t he mai nte na nce treat me nt of o nl y  gr o u p D patie nts. W hile 
c urre nt g ui deli nes s u g gest usi n g L A B As a n d/ or m uscari nic a nta g o nists a n d I CSs i n o nl y  a 
s mall n u m ber of patie nts, t he use of t his tri ple t hera py (i n w hic h a c o m bi nati o n i n haler is 
prescri be d i n c o m bi nati o n wit h a n ot her si n gle dr u g i n haler) is m ore wi del y  use d i n cli nical 
practice t ha n rec o m me n de d (J o nes 2 0 0 9 , Sala ma et al 2 0 1 1 ). I n researc h c o n d ucte d at U S 
pri mar y  care sites, it has bee n f o u n d t hat 2 0 % of Sta ge 1 a n d 3 9 % of Sta ge 2 C O P D patie nts 
are c urre ntl y usi n g I C S (S mall et a l 2 0 1 2) I n fact, t here is e vi de nce of wi des prea d use of tri ple 
t hera py f or C O P D e ve n i n pri mar y  care w here patie nts ha ve pre d o mi na ntl y  mil d disease a n d 
occasi o nal br o nc hitis (Gae bel et al 2 0 1 1 ).
T here is i ns ufficient e vi de nce t o deter mi ne if tri ple t hera py is s u peri or t o d ual br o nc h o dilat or 
t hera py i n patie nts wit h o ut a hist or y  of fre q ue nt e xacer bati o ns (Gae bel et al 2 0 1 1 ). It is als o 
u nclear w het her t hese patie nts c o ul d be ma na ge d j ust as effecti vel y wit h d ual br o nc h o dilat or 
t hera py as tri ple, wit h less c ost a n d i m pr o ve d patie nt c o n ve nie nce.
T he effect of Q V A 1 4 9 vs. tri ple treat me nt wit h L A B A/I C S F D C + L A M A has n ot bee n st u die 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 t he efficac y an d safety of Q V A 1 4 9 ( 1 1 0/ 5 0 
µ g o. d.) a n d tri ple t hera p y wit h ti otr o pi u m ( 1 8 µ g o. d.) + sal meter ol/fl uticas o ne pr o pi o nate 
F D C ( 5 0/ 5 0 0 µ g b.i. d.) are c o m para ble i n patie nts wit h m o derate t o se vere C O P D wit h o ut a 
hist or y  of fre q ue nt e xacer bati o ns ( pri marily G O L D cate g or y B). Data fr o m t his st u d y will 
pr o vi de a d diti o nal efficac y an d safet y data o n Q V A 1 4 9 use i n a patie nt p o p ulati o n i n w hic h 
t he use of i n hale d c ortic oster oi ds a n d he nce tri ple t hera py ma y  be u n necessar y  acc or di n g t o 
c urre nt G O L D g ui deli nes.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
2   
St u d y  o bj e cti v e s
2. 1   
Pri m ar y  o bj e cti v e
T o de m o nstrate t he n o n- i nferi ority of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) o n p ost -d ose tr o u g h F E V 1 vs. 
ti otr o pi u m ( 1 8 µ g o. d.) + sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) after 
2 6 wee ks of treat me nt i n m o derate -t o-se vere C O P D patie nts .
2. 2   
S e c o n d ar y  o bj e cti v e s

T o e val uate t he effect of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) c o m pare d wit h ti otr o pi u m ( 1 8 µ g o. d.) 
+ sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) o ver 2 6 wee ks of treat me nt i n 
ter ms of:

Rate of m o derate or se vere C O P D e xacer bati o ns re q uiri n g

S y ste mic gl uc oc ortic oster oi ds a n d/ or a nti bi otics d uri n g t he treat me nt peri o d 
( m o derate e xacer bati o ns o nl y).

H os pitalizati o ns d uri n g t he treat me nt peri o d a n d re h os pitalizat i o n wit hi n 3 0 da ys 
d uri n g t he treat me nt peri o d (se vere e xacer bati o ns o nl y ).

T o e val uate t he effect of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) c o m pare d wit h ti otr o pi u m ( 1 8 µ g o. d.) 
+ sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) i n ter ms of :

Tr o u g h F E V 1 a n d F V C o ver 2 6 wee ks of treat me nt.

T otal sc ore of t he St. Ge or ge’s Res pirat or y  Q uesti o n naire ( S G R Q-C) after 1 2 a n d 2 6 
wee ks of treat me nt

T otal sc ore of t he Tra nsiti o n al D ys p nea I n de x ( T DI) after 1 2 a n d 2 6 wee ks of 
treat me nt

Mea n use of resc ue t hera p y  ( n u m ber of p uffs/ da y) a n d t he perce nta ge of da ys wit h o ut 
resc ue t hera py o ver t he 2 6 wee ks treat me nt peri o d.

T o assess t he safet y ( partic ularl y wit h re gar d t o E C G, la b orat or y tests, vital si g ns a n d 
a d verse e ve nts) a n d t olera bilit y ( disc o nti n uati o n d ue t o a d verse e ve nts) of Q V A 1 4 9 
( 1 1 0/ 5 0 µ g o. d.) vs. ti otr o pi u m ( 1 8 µ g o. d.) + sal meter ol/fl uticas o ne pr o pi o nate F D C 
( 5 0/ 5 0 0 µ g b.i. d.) o ver t he 2 6 wee ks of treat me nt.

T o assess t he safet y of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) vs. ti otr o pi u m ( 1 8 µ g o. d.) + 
sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) i n ter ms of H P A a xis f u ncti o n, 
as deter mi ne d b y 2 4 -h o ur wei g hte d mea n uri ne c ortis ol, i n a s u b -set of patie nts.
2. 3   
E x pl or at or y  o bj e cti v e s
T o e x pl ore:

T he sc ore c ha n ges fr o m baseli ne i n C A T o ver t he 2 6 wee k treat me nt peri o d a n d m M R C at 
wee k 2 6

Rate of all pr ot oc ol defi ne d e xacer bati o ns

S y m pt o ms re p orte d o ver 2 6 wee ks treat me nt usi n g e -diar y

Or o p har y n geal ca n di diasis e val uati o n b y  p ositi ve or o p har yn geal s wa b sa m ple c ult ure 
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
3   
I n v e sti g ati o n al pl a n
3. 1    
St u d y  d e si g n
T he st u d y is a m ultice nter, ra n d o mize d, parallel -gr o u p, d o u ble -bli n d, tri ple-d u m m y  st u d y to 
assess t he efficac y of t he t w o acti ve treat me nt ar ms of Q V A 1 4 9 ( 1 1 0/ 5 0 μ g o. d.) a n d 
ti otr o pi u m ( 1 8 μ g o. d) + sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 00 b.i. d) i n patie nts wit h 
m o derate -t o-se vere C O P D. 
T he st u d y co nsists of f o ur e p oc hs: scree ni n g ( 1 wee k), r u n-i n ( 4 wee ks), bli n de d treat me nt 
( 2 6 wee ks) a n d f oll o w - u p ( 4 wee ks). See Fi g ure 3 - 1.
Fi g ur e 3 - 1   
St u d y  D e si g n
Scree ni n g e p oc h
At Visit 1 ( Scree ni n g) i nf or me d c o nse nt will be o btai ne d bef ore a n y  st u d y relate d assess me nts 
or pr oce d ures are perf or me d. All patie nts si g ni n g i nf or me d c o nse nt m ust be re gistere d i n t he 
I nteracti ve Res p o nse Tec h n ol o g y  (I R T) s yste m. C O P D me dicati o ns a n d eli gi bilit y criteria 
will be assesse d (as o utli ne d i n Assess me nt Ta ble 6 - 1) a n d if necessar y, arra n ge me nts ma de t o 
a dj ust pr o hi bite d t hera p y (see Ta bl e 5-1 , Ta ble 5 -2 a n d Ta ble 5 - 3).
T he patie nts will als o be pr o vi de d wit h a s h ort acti n g β 2 -a g o nist (sal b uta m ol or al b uter ol) f or 
use as a resc ue i n haler o n a n “as nee de d” basis t hr o u g h o ut t he st u d y; f or m ore details o n 
resc ue me dicati o n please refer t o Secti o n 5. 5. 6 .
I n or der t o assess l u n g f u ncti o n f or i ncl usi o n criteria, t he patie nts m ust be i nf orme d at 
Scree ni n g visit (after ha vi n g si g ne d t he i nf or me d c o nse nt) t o wit h h ol d use of C O P D 
me dicati o n at h o me > 2 4 h o urs f or ti otr o pi u m a n d > 1 2 h o urs f or sal meter ol/fl uticas o ne 
pr o pi o nate F D C bef ore c o mi n g t o t he cli nic o n t he da y  of t he R u n -i n visit ( Visit 1 0 1). C O P D
me dicati o n will be dis pe nse d i n t he cli nic after s pir o metr y testi n g.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
R u n -i n E p oc h
At Visit 1 0 1 ( wee k -4) i ncl usi o n a n d e xcl usi o n criteria will be c hec ke d a gai n a n d ot her 
assess me nts as o utli ne d i n Assess me n t Ta ble 6 - 1 will be perf or me d. I n w o me n of c hil d beari n g 
p ote ntial a pre g na nc y  test will be d o ne.
S pir o metr y  testi n g s h o ul d o nl y  be perf or me d if n o C O P D
me dicati o n was
ta ke n i n t he 
m or ni n g. If n ot, t his visit s h o ul d be resc he d ule d.
D uri n g 
t he r u n-i n e p oc h all patie nts 
will 
be 
gi ve n 
ti otr o pi u m ( 1 8 μ g 
o. d.) 
+ 
sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) treat me nt re gar dless of t heir 
pre vi o us tri ple c o m bi nati o n bef ore st u d y entr y  (Instr ucti o ns wi ll be gi ve n t o t he patie nt o n t he 
c orrect use of t he i n halati o n de vice s). If t he y are alrea d y ta ki n g t his tri ple c o m bi nati o n t he y 
will c o nti n ue t o ta ke t he sa me treat me nt d uri n g t he r u n -i n e p oc h.
T he patie nts will be s u p plie d wit h a n electr o nic diar y  de vice (e Diar y, A p pe n di x 3 ) t o c ollect 
resc ue me dicati o n usa ge a n d s ym pt o m i nf or mati o n bet wee n Visit 1 0 1 (baseli ne r u n-i n, Da y  -
2 8) a n d Visit 2 0 1 ( Ra n d o mizati o n, Da y  1) i n or der t o recei ve baseli ne i nf or matio n. T he 
e Diar y will als o be use d t o c ollect sy m pt o m i nf or mati o n a n d resc ue me dicati o n (sal b uta m ol or 
al b uter ol) usa ge t hr o u g h o ut t he c o urse of t he st u d y treat me nt e p oc h. F or details o n t he e Diar y 
please refer t o Secti o n 6. 6. 4 .
At t he ti me of ra n d o mizati o n patie nts will be ra n d o mize d t o Q V A 1 4 9 or c o nti n ue t o ta ke 
tri ple treat me nt i n a 1: 1 rati o. I n this wa y  possi ble deteri orati o n d uri n g t his peri o d will be 
pre ve nte d.
E n d of R u n -i n E p oc h / St art of Tre at me nt E p oc h ( R a n d o miz ati o n)
Visit 1 0 2 ( R u n -i n) a n d Visit 2 0 1 ( Ra n d o mizati o n) will occ ur o n t he sa me da y.
At Visit 1 0 2 ( Da y 1), t he patie nts will c o me t o t he cli nic i n t he m or ni n g t o c o m plete t he 
q uesti o n naires (e xce pt f or m M R C
q uesti o n naire w hic h is c o m plete d at V isit 1 0 1) as well as 
ha ve eli gi bilit y criteria re vie we d. T his visit s h o ul d occ ur a p pr o xi matel y 2 8 da y s after Visit 
1 0 1. After t he q uesti o n naires are c o m plete d, t he e Diar y sy m pt o m data will be re vie we d a n d 
all ot her ass ess me nts (see Ta ble 6 -1 ) i ncl u di n g s pir o metr y will be perf or me d.
At Visit 2 0 1 ( Ra n d o mizati o n Visit, Da y  1, ta ki n g place ri g ht after V isit 1 0 2), all patie nts w h o 
meet t he eli gi bilit y criteria a n d alrea d y mai ntai ne d o n tri ple treat me nt ( L A B A/I C S + L A M A 
c o m bi nati o n) will be ra n d o mize d i n a 1: 1 rati o t o o ne of t he t w o treat me nt ar ms f or t he 2 6
wee k treat me nt e p oc h. T he st u d y treat me nt will be dis pe nse d (see Secti o n 5. 5. 2 ) a n d 
i nstr ucti o ns will be gi ve n t o t he patie nt o n t he c orrect use of t he i n halati o n de vice a n d st u d y 
treat me nt.
Patie nts m ust be i nf or me d n ot t o ta ke st u d y treat me nt pri or t o A L L f ut ure cli nic visits, as t his 
will be a d mi nistere d i n cli nic after all pre -d ose pr oce d ures a n d assess me nts ha ve bee n 
perf or me d.
I n ot her w or ds, patie nts m ust wit h h ol d sal meter ol/ fl uticas o ne pr o pi o nate F D C > 1 2 h o urs 
pri or t o visits; ti otr o pi u m a n d Q V A 1 4 9 > 2 4 h o urs pri or t o visits.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Tre at me nt E p oc h
Patie nts will atte n d 7 st u d y visits ( u p t o Visit 2 0 8 ) d uri n g t he treat me nt e p oc h. Patie nts s h o ul d 
be see n f or all visits o n t he desi g nate d da y  or as cl ose as p ossi ble f or all Visits fr o m 2 0 2 t o 
2 0 8.
T he i n vesti gat or s h o ul d i nstr uct t he patie nt t o n otif y  the st u d y site a b o ut a n y ne w me dicati o ns 
he/s he ta kes after t he start of t he st u d y. All me dicati o ns a n d si g nifica nt n o n- dr u g t hera pies 
(i ncl u di n g p h y sical t hera p y an d bl o o d tra nsf usi o ns) a d mi nistere d after t he patie nt has starte d 
st u d y treat me nt m ust be liste d o n t he c o nc o mitan t me dicati o ns pa ge of t he e C R F.
All ra n d o mize d patie nts will be c o ntacte d b y tele p h o ne bet wee n t he visits if t he i nter val 
bet wee n t he visits is 4 wee ks or l o n ger t o c hec k if patie nt’s C O P D s ym pt o ms ha ve w orse ne d, 
a n y treat me nt re q uire d a n d e-diar y  c o m plete d acc or di n gl y (see Assess me nt Ta ble 6 - 1). 
Patie nts, w h o disc o nti n ue st u d y  treat me nt earl y, will be as ke d t o c o nti n ue wit h st u d y visit 
t hr o u g h Visit 2 0 7 w hile off st u d y  treat me nt. See Secti o n 5. 5. 9 f or treat me nt disc o nti n uati o n. 
I n case of st u d y wit h dra wal, please refer t o Secti o n 5. 5. 1 0 .
Patie nts will t he n e nter a 3 0 da y  f oll o w-u p e p oc h t o c ollect patie nt safet y  data.
F oll o w -u p E p oc h
All ra n d o mize d patie nts, re gar dless of w het her t he y co m plete d st u d y treat me nt t hr o u g h Wee k 
2 6 or disc o nti n ue d st u d y  treat me nt pri or t o Wee k 2 6 , will be c o ntacte d ( by tele p h o ne) 4 wee ks 
after last st u d y visit/treat me nt f or a Safet y F oll o w-u p Visit 3 0 1.
Patie nts s h o ul d als o be a ware t hat t he y ma y be c o ntacte d i n t he f ut ure if a n y a d diti o nal 
f oll o w- u p i nf or mati o n is re q uire d, f oll o wi n g t he a p pr o priate a p pr o vals a n d i nf or me d c o nse nts 
as re q uire d.
If a patie nt ref uses t o retur n f or a n y assess me nts or is u na ble/ u n willi n g t o d o s o, e ver y eff ort 
( prefera ble at least t hree d oc u me nte d eff orts) s h o ul d be ma de t o c o ntact t he patie nt or a 
k n o wle d gea ble i nf or ma nt t o e ns ure t he safety of t he patie nt. Atte m pts t o c o ntact t he patie nt 
s h oul d be d oc u me nte d i n t he s o urce rec or ds.
I n vesti gat ors will be re q uire d t o f oll o w all pr oce d ures d uri n g t he c o n d uct of t he st u d y.
N o i nteri m a nal ys is is pla n ne d.
3. 2   
R ati o n al e of st u d y  d e si g n
A d o u ble -bli n d, tri ple -d u m m y , t w o-ar m desi g n was selecte d t o pr o vi de scie ntificall y ro b ust 
c o m paris o n data bet wee n treat me nt ar ms. T he p ote ntial c ha n ge i n l u n g f u ncti o n see n i n t h ose 
patie nts treate d wit h Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) will be c o m pare d t o baseli n e a n d t o t he c ha n ge 
i n l u n g f u ncti o n i n t h ose recei vi n g  ti otr o pi u m ( 1 8 µ g  o. d.) + sal meter ol/fl uticas o ne 
pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) treat me nt. T he d urati o n of 2 6 wee ks is c o nsi dere d 
a p pr o priate i n or der t o de m o nstrate t he i m pr o ve me nts i n l u n g f u ncti o n as well as assess t he 
effect o n a variet y of patie nt re p orte d o utc o mes .
We c h ose t his bli n de d a n d parallel desi g n t o mi ni mize t he bias d ue t o differe nt Dr y  Po w der 
I n haler ( D PI) de vices. All patie nts will be usi n g all t hree de vices t hr o u g h o ut t he st u d y eit her 
wit h place b o or wit h a n acti ve pr o d uct.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
3. 3   
R ati o n al e of d o s e/r e gi m e n, r o ut e of a d mi ni str ati o n a n d d ur ati o n 
of tr e at m e nt
T he selecti o n of Q V A 1 4 9 d ose i n t his st u d y (1 1 0/ 5 0 µ g o. d.) was base d o n data fr o m t he 
Q A B 1 4 9 a n d N V A 2 3 7 m o n o -c o m p o ne nt pr o gra ms. T h ose pr o gra ms i de ntifie d t he d oses as 
1 5 0 µ g o nce dail y  for Q A B 1 4 9 a n d 5 0 µ g  once dail y  for N V A 2 3 7. H o we ver, i n f or m ulati n g 
t he Q V A 1 4 9 c o m bi nati o n pr o d uct, a n i ncrease i n fi ne particle (res pira ble) fracti o n was 
o bser ve d f or t he Q A B 1 4 9 
c o m p o ne nt (c o m pare d wi t h t he m o n oc o m p o ne nt). 
As 
a 
c o nse q ue nce, t o e ns ure t hat t he fi ne particle d ose of Q A B 1 4 9 deli vere d t o t he l u n g fr o m t he 
c o m bi nati o n matc hes t hat deli vere d fr o m t he m o n oc o m p o ne nt, t he d ose f or t he Q A B 1 4 9 
c o m p o ne nt of Q V A 1 4 9 has bee n a dj uste d t o 1 1 0 µ g. T he selecti o n of d oses f or ti otr o pi u m 
( 1 8 µ g o. d.) a n d sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) are base d o n t heir 
res pecti ve de vel o p me nt pr o gra ms i n C O P D treat me nt, a n d are a p pr o ve d d oses.
C O P D g ui deli nes iss ue d b y  Co m mittee f or Me dici nal Pr o d ucts f or H u ma n Use ( C H M P) a n d 
ot her healt h a ut h orities s u g gest t hat a n e val uati o n of t he l u n g f u ncti o n as e x presse d b y  FE V 1
meas ures s h o ul d n or mall y  be ma de o ver a peri o d of at least t wel ve wee ks. He nce, patie nts 
will be assesse d at wee k 1 2 a n d u p t o wee k 2 6 i n or der t o de m o nstrate t hat Q V A 1 4 9 is at least 
n o n- i nferi or t o t hera py wit h ti otr o pi u m ( 1 8 µ g o. d.) + sal meter ol/fl uticas o ne pr o pi o nate F D C 
( 5 0/ 5 0 0 µ g b.i. d.) i n ter ms of c ha n ge fr o m baseli ne i n tr o u g h F E V 1.
3. 4   
R ati o n al e f or c h oi c e of c o m p ar at or
Ti otr o pi u m ( 1 8 µ g o. d.) a n d sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) are t he 
m ost wi del y  use d mai nte na nce treat me nts i n C O P D. T hese pr o d ucts ha ve well esta blis he d 
scie ntific data s h o wi n g t heir efficac y an d safet y bot h i n di vi d uall y an d i n c o m bi nati o n wit h 
eac h ot her (tri ple treat me nt) ( Sala ma et al 2 0 1 1 ).
3. 5   
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
N ot a p plica ble .
3. 6   
Ri s k s a n d b e n efit s 
T he ris k t o patie nts i n t his trial will be mi ni mize d b y  co m plia n ce wit h all of t he eli gi bilit y 
criteria a n d b y  cl ose cli nical m o nit ori n g. Alteri n g t he c urre nt C O P D me dicati o n re gi me n 
d uri n g t he r u n-i n peri o d a n d s witc hi n g fr o m o ne tri ple treat me nt t o a n ot her o ne (if t he c urre nt 
tri ple c o m bi nati o n is differe nt t ha n st u d y tri ple c o m bi nati o n) or ra n d o mizi n g t he patie nts 
d uri n g t he st u d y treat me nt eit her t o t he sa me tri ple treat me nt as i n r u n-i n or Q V A 1 4 9 is n ot 
li kel y to p ose a n y ris k of “ u n der-treat me nt”. Alt h o u g h I C S is wit h dra w n i n t he Q V A 1 4 9 ar m 
I C S is n ot rec o m me n de d i n t hese patie nts acc or di n g t o t he c urre nt G O L D C O P D strate g y 
d oc u me nt (G O L D 2 0 1 4 ). T heref ore all patie nts are recei vi n g s ufficie nt C O P D treat me nt i n 
b ot h ar ms, al o n g wit h a p pr o priate resc ue me dicati o n.
Pr o vi di n g t he patie nts wit h resc ue me dicati o n (s h ort acti n g beta a g o nist; S A B A ) a n d acti ve 
treat me nt d uri n g t he scree ni n g, r u n-i n peri o d a n d t hr o u g h o ut t he st u d y 
miti gates a n y 
deteri orati o n ris k. Re petiti ve l u n g f u ncti o n meas u re me nt ma ne u vers d uri n g t he st u d y ca n lea d 
t o c o u g h, s h ort ness of breat h, dizzi ness, or e x ha usti o n. Si nce t he patie nt o nl y  carries o ut 
f orce d ma ne u vers d uri n g cli nic visits ( n ot at h o me), t hese are perf or me d u n der me dical
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
s u per visi o n t o e ns ure a vaila bilit y of i m me diate ai d if re q uire d. T he assess me nts are i nfre q ue nt 
a n d part of t he re g ular me dical assess me nts of t his patie nt p o p ulati o n.
T he ris k of si de effects fr o m t he st u d y me dicati o n are k n o w n f or c o m p o u n ds Q V A 1 4 9, 
Q A B 1 4 9 a n d N V A 2 3 7. T he m ost fre q ue ntly re p orte d si de effects see n f or Q V A 1 4 9 t o date 
are; nas o p har y n gitis, u p per res pirat or y tract i nfecti o n, c o u g h, a n d hea dac he. See Q V A 1 4 9 
I n vesti gat or’s Br oc h ure a n d f or Q A B 1 4 9 a n d N V A 2 3 7 see Q A B 1 4 9 a n d N V A 2 3 7 secti o ns of 
t he Q V A 1 4 9 I n vesti gat or’s Br oc h ure.
T he ris k of si de effects f or t he acti ve c o m parat or sal meter ol/fl uticas o ne 5 0/ 5 0 0 μ g b.i. d) are 
t h ose k n o w n f or sal meter ol a n d fl uticas o ne, s uc h as tre m or, hea dac he, pal pitati o ns, 
p ne u m o nia, br o nc hitis, h y p o kale mia, nas o p har y n gitis, t hr oat irritati o n, si n usitis, m uscle 
cra m ps, tra u matic fract ures, h oarse ness a n d ca n di diasis i n t he m o ut h a n d t hr oat. ( Sereti de 
Acc u haler ® 5 0/ 5 0 0 µ g S m P C).
T he m ost c o m m o n a d verse reacti o ns f or t he ot her acti ve c o m parat or, Ti otr o pi u m ( > 5 % 
i nci de nce i n t he 1- ye ar place b o -c o ntr olle d trials) are u p per res pirat or y tract i nfecti o n, dr y  
m o ut h, si n usitis, p har y n gitis, n o n- s pecific c hest pai n, uri nar y  tract i nfecti o n, d y s pe psia, a n d 
r hi nitis (S piri va Ha n di haler ™ 1 8 µ g S m P C).
T he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) iss ue d a war ni n g c o ncer ni n g l o n g 
acti n g beta - 2 a g o nists ( L A B A). T he war ni n g states t hat L A B As ma y  increase t he c ha nce of 
se vere ast h ma e pis o des a n d ast h ma relate d deat h i n patie nts wit h ast h ma. T he war ni n g was 
base d o n a st u d y that e val uate d t he safety of sal meter ol, w hic h s h o we d a n i ncrease i n ast h ma 
relate d deat hs i n patie nts wit h ast h ma recei vi n g sal meter ol a n d t heir us ual ast h ma me dicati o n.
T his i ncrease d ris k has n ot bee n de m o nstrate d i n patie nts wit h C O P D.
4   
P o p ul ati o n
T he st u d y  p o p ulati o n will c o nsist of a p pr o xi matel y 1 0 0 0 male a n d fe male a d ults (a ge 4 0 y ears 
a n d greater) wit h a cli nical dia g n osis of sta ble C O P D w h o ha ve m o derate t o se vere airfl o w 
o bstr ucti o n ( G O L D 2 0 1 4 ) a n d a s m o ki n g hist or y  of at least 1 0 pac k ye ars. Eli g i ble patie nts 
will be t h ose t hat ha ve bee n mai ntai ne d o n tri ple t hera p y (a L A M A pl us a F D C of L A B A/I C S) 
f or a mi ni m u m of si x m o nt hs
pri or t o Visit 1, a n d are cli nicall y sta ble ( defi ne d as n ot 
ha vi n g > 1 m o derate -se vere e xacer bati o n (see Secti o n 6. 6. 2 ) wit hi n t he last 1 2 m o nt hs pri or t o 
Visit 
1 ). T heref ore 
patie nts w h o 
are c urre ntl y bei n g mai ntai ne d 
o n tri ple t hera p y 
( L A B A/IC S + L A M A) f or at least 6 m o nt hs pri or t o Visit 1 a n d wit h clear d oc u me ntati o n of n o 
m ore t ha n o ne m o derate or se vere e xacer bati o n i n t he last 1 2 m o nt hs pri or t o Visit 1 will be 
recr uite d.
It is a ntici pate d t hat at least 1 4 0 0 patie nts will nee d t o be scree ne d i n or der t o ra n d o mize 1 0 0 0 
patie nts i nt o 2 treat me nt ar ms of t he st u d y wit h a ra n d o mizati o n rati o of 1: 1.
Patie nts will be ra n d o mize d i nt o t he st u d y wit h t he i nte nti o n t hat 7 5 0 patie nts will c o m plete 
t he st u d y. Dr o p o uts will n ot be re place d. T he st u d y will be m ulti-nati o nal.
Patie nts will be stratifie d b y  sm o ki n g stat us (c urre nt/e x-s m o ker) a n d se verit y of airfl o w 
li mitati o n ( usi n g G O L D 2 0 14 classificati o n).
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
4. 1   
I n cl u si o n crit eri a
Patie nts eli gi ble f or i ncl usi o n i n t his st u d y ha ve t o f ulfill all of t he f oll o wi n g criteria:
1.
Patie nts w h o ha ve si g ne d 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.
3.
Patie nts wit h m o derate t o se vere airfl o w o bstr ucti o n wit h sta ble C O P D ( Sta ge 2 or Sta ge 3) 
acc or di n g t o t he 2 0 1 4 G O L D G ui deli nes.
4.
Patie nts wit h a p ost -br o nc h o dilat or F E V 1 ≥4 0 a n d < 80 % of t he pre dicte d n or mal val ue, 
a n d p ost -br o nc h o dilat or F E V 1/ F V C < 0. 7 0 at r u n-i n Visit 1 0 1. 
(P ost refers t o 15 mi n after i n halati o n of 4 0 0 µ g of sal b uta m ol) ( Rea di n gs assesse d by site 
a n d c hec ke d ce ntrall y). 
5.
C urre nt or e x -s m o kers w h o ha ve a s m o ki n g histor 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 ½ pac k/ da y x 2 0 years). A n e x -s m o ker is defi ne d as a 
patie nt w h o has n ot s m o ke d f or ≥ 6 m o nt hs at scree ni n g.
6.
Patie nts w h o are o n tri ple treat me nt at least f or t he last 6 m o nt hs ( LA M A + L A B A/I C S) .
4. 2   
E x cl u si o n crit eri a
Patie nts f ulfilli 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 
a d diti o nal e xcl usi o ns ma y  be a p plie d b y  the i n vesti gat or, i n or der t o e ns ure t hat t he st u d y 
p o p ulati o n will be re prese nt ati ve of all eli gi ble patie nts.
1.
Use of ot her i n vesti gati o nal dr u gs/ de vices (a p pr o ve d or u na p pr o ve d) at t he ti me of 
e nr oll me nt, or wit hi n 3 0 da ys or 5 half-li ves of Visit 1, w hic he ver is l o n ger.
2.
Patie nts c o ntrai n dicate d f or treat me nt wit h, or ha vi n g a hist o r y of reacti o ns/ 
h y perse nsiti vit y  t o a ny of t he f oll o wi n g i n hale d dr u gs, dr u gs of a si milar class or a n y 
c o m p o ne nt t here of:

l o n g a n d s h ort a ntic h oli ner gic a ge nts

l o n g a n d s h ort acti n g beta-2 a g o nists

s ym pat h o mi metic a mi nes

lact ose or a ny of t he ot her e xci p ie nts of trial me dicati o n
3.
Hist or y  or c urre nt dia g n osis of E C G a b n or malities i n dicati n g si g nifica nt ris k of safety f or 
patie nts partici pati n g i n t he st u d y  s uc h as:

C o nc o mita nt cli nicall y  si g nifica nt car diac arr hyt h mias, e. g., s ustai ne d ve ntric ular 
tac hycar dia, a n d cli nicall y si g nifica nt sec o n d or t hir d de gree A V bl oc k wit h o ut a 
pace ma ker

Hist or y  of fa milial l o n g Q T s yn dr o me or k n o w n fa mil y  hist or y of T orsa des de P oi ntes
4.
Resti n g Q Tc ( Fri dericia met h o d ) ≥4 5 0 msec f or males a n d fe males at V isit 1 0 1.
5.
C o nc o mita nt use of a ge nts k n o w n t o si g nifica ntly pr ol o n g t he Q T i nter val u nless it ca n be 
per ma ne ntl y disc o nti n ue d f or t he d urati o n of st u d y .
6.
Patie nts w h o ha ve a cli nicall y  si g nifica nt la b orat or y a b n or mality at Visit 1 0 1 a n d w o ul d 
be at p ote ntial ris k if e n r olle d i nt o t he st u d y.
7.
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 heart disease, N Y H A Class III/I V left ve ntric ular fail ure, m y ocar dial 
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
i nfarcti o n), arr hyt h mia (see bel o w f or patie nts wit h a trial fi brillati o n), ne ur ol o gical, 
e n d ocri ne, i m m u n ol o gical, ps y c hiatric, gastr oi ntesti nal, he patic, 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.
8.
Patie nts wit h par o x ys mal (e. g. i nter mitte nt) atrial fi brillati o n are e xcl u de d. Patie nts wit h 
persiste nt atrial fi brillati o n as defi ne d b y c o nti n u o us atrial fi brillati o n f or at least 6 m o nt hs 
a n d c o ntr olle d wit h a rate c o ntr ol strate g y  (i.e., beta bl oc ker, calci u m c ha n nel bl oc ker, 
pace ma ker place me nt, di g o xi n or a blati o n t hera p y) f or at least 6 m o nt hs ma y  be 
c o nsi dere d f or i ncl usi o n. I n s uc h patie nts, atrial fi brillati o n m ust be prese nt at Visit 1 0 1 
a n d Visit 1 0 2) visits, wit h a resti n g ve ntric ular rate < 1 0 0/ mi n. At visit 1 0 1, atrial 
fi brillati o n m ust be c o nfir me d b y ce ntral rea di n g.
9.
Patie nts wit h narr o w -a n gle gla uc o ma, s y m pt o matic be ni g n pr ostatic h y per plasia or 
bla d der -nec k o bstr ucti o n or m o derate t o se vere re nal i m pair me nt or uri nar y  rete nti o n 
( B P H patie nts w h o are sta ble o n treat me nt ca n be c o nsi dere d).
1 0. Patie nts w h o ha ve n ot ac hie ve d acce pta ble s pir o metr y res ults at Visit 1 0 1 i n acc or da nce 
wit h A T S ( A merica n T h oracic S ociet y)/ E R S ( E ur o pea n Res pirat or y S ociet y) criteria f or 
acce pta bilit y ( o ne retest ma y be perf or me d f or patie nts t hat d on’t meet t he acce pta bilit y  
criteria).
1 1. Patie nts w h o ha ve ha d m ore t ha n o ne 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 i n t he last year pri or t o Visit 1.
1 2. Patie nts w h o de vel o pe d a C O P D e xacer b ati o n of a n y se verity eit her 6 wee ks bef ore t he 
scree ni n g ( Visit 1) or bet wee n scree ni n g ( Visit 1) a n d treat me nt ( Visit 2 0 1) will n ot be 
eli gi ble b ut will be per mitte d t o be re-scree ne d after a mi ni m u m of 6 wee ks after t he 
res ol uti o n of t he C O P D e xacer bati o n.
1 3. 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 
Visit 1.
1 4. Patie nts w h o de vel o p a res pirat or y  tract i nfecti o n bet wee n scree ni n g a n d treat me nt will 
n ot be eli gi ble, b ut will be per mitte d t o be re -scree ne d 4 wee ks after t he res ol uti o n of t he 
res pirat or y tract i nfecti o n.
1 5. Patie nts re q uiri n g l o n g ter m o x y ge n t hera p y prescri be d f or > 1 2 h o urs per da y.
1 6. Patie nts wit h a n y  hist or y of ast h ma.
1 7. Patie nts wit h a bl o o d e osi n o p hil c o u nt > 6 0 0/ m m 3 d uri n g scree ni n g ( Visit 1 0 1 ).
1 8. Patie nts wit h aller gic r hi nitis w h o use a H 1 a nta g o nist or i ntra -nasal c ortic oster oi ds 
i nter mitte ntl y (treat me nt wit h a sta ble d ose or re gi me n is per mitte d).
1 9. Patie nts wit h c o nc o mita nt p ul m o nar y  disease (e. g. l u n g fi br osis, sarc oi d osis, i nterstitial 
l u n g disease, p ul m o nar y h yperte nsi o n, cli nicall y s i g nifica nt br o nc hiectasis).
2 0. Patie nts wit h a dia g n osis of α- 1 a nti -tr ypsi n deficie nc y .
2 1. Patie nts wit h acti ve p ul m o nar y t u berc ul osis .
2 2. Patie nts wit h p ul m o nar y  l o bect o m y or l u n g v ol u me re d ucti o n s ur ger y or l u n g 
tra ns pla ntati o n.
2 3. 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 st u d y ( Mai nte na nce pr o gra m is per mitte d).
2 4. Patie nts recei vi n g a n y m e dicati o ns i n t he classes liste d i n Ta ble 5 - 1.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
2 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 5 - 2
m ust u n der g o t he re q uire d was h o ut peri o d pri or t o Visit 1 0 1 a n d f oll o w t he a dj ust me nt t o 
treat me nt pr o gra m.
2 6. Patie nts recei vi n g me dicati o ns i n t he classes liste d i n Ta ble 5 - 3 s h o ul d be e xcl u de d u nless 
t he me dicati o n has bee n sta ble 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.
2 7. Patie nts u na ble t o use a n electr o nic patie nt diar y .
2 8. Patie nts u na ble t o use a dr y  p o w der i n haler de vice or a press urize d M DI (resc ue 
me dicati o n) or u na ble t o c o m pl y  wit h t he st u d y re gi me n. S pacer de vices are n ot per mitte d.
2 9. Hist or y  of mali g na nc y  of a n y or ga n sys te m ( ot her t ha n l ocalize d basal cell carci n o ma of 
t he s ki n), treate d or u ntreate d, wit hi n t he past 5 years, re gar dless of w het her t here is 
e vi de nce of l ocal rec urre nce or metastases.
3 0. Pre g na nt or n ursi n g (lactati n g) w o me n, w her e pre g na nc y is 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 b y  a p ositi ve h C G 
la b orat or y test.
3 1. 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 nles s t he y are usi n g effecti ve met h o ds of c o ntrace pti o n d uri n g 
d osi n g of st u d y treat me nt. 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 wit h t he preferre d a n d us ual lifest yle of t he 
patie nt . 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 orect o m y wit h or wit h o ut 
h y sterect o my) or t u bal li gati o n at least si x wee ks bef ore ta ki n g st u d y treat me nt.  In 
case of o o p h orect o m y al o ne, o nl y  whe 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 pri or t o scree ni n g). F or fe male patie nt s 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 patie nt

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) wit h s per mici dal f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y  

Use of oral, i njecte d or i m pla nte d h or m o nal me t h o ds of c o ntrace pti o n or ot her f or ms 
of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y (fail ure rate < 1 %), f or 
e xa m ple h or m o ne va gi nal ri n g or tra ns der mal h or m o ne c o ntrace pti o n

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)
In case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n sta ble o n t he sa me pill f or a 
mi ni m u m of 3 m o nt hs bef ore ta ki n g st u d y treat me nt.
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 if 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 s ym 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) or t u bal li gati o n at least si x wee ks a g o. I n t he case of 
o o p h orect o m y al o ne, o nl y  whe 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.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
5   
Tr e at m e nt
5. 1   
Pr ot o c ol r e q u e st e d tr e at m e nt
Si nce t his is a tri ple d u m m y  st u d y patie nts will recei ve me dicati o n kits c o nsisti n g of eit her:

Acti ve Q V A 1 4 9 wit h N o vartis si n gle d ose dr y  p o w der i n haler

P lace b o sal meter ol/fl uticas o ne pr o pi o nate F D C wit h Acc u haler ™ 

Place b o ti otr o pi u m wit h Ha n di H aler ®
O R

Place b o Q V A 1 4 9 wit h N o vartis si n gle d ose dr y  p o w der i n haler.

A cti ve sal meter ol/fl uticas o ne pr o pi o nate F D C wit h Acc u haler ™ 

Acti ve ti otr o pi u m wit h Ha n di H aler ®
5. 1. 1   
I n v e sti g ati o n al tr e at m e nt

Q V A 1 4 9 1 1 0/ 5 0 μ g ca ps ules o. d. f or i n halati o n, s u p plie d i n blisters deli vere d via N o vartis
si n gle d ose dr y p o w der i n haler

Pl ace b o t o sal meter ol/fl uticas o ne pr o pi o nate F D C 5 0/ 5 0 0 μ g will be pr o vi de d as dr y  
in halati o n p o w der via Acc u haler ™

Place b o t o ti otr o pi u m 1 8 μ g will be pr o vi de d as i n halati o n c a ps ules deli vere d via 
Ha n di H aler ®
Q V A 1 4 9 1 1 0/ 5 0 μ g o. d. will be pr o vi de d as i n halati o n ca ps ules. Place b o i n halati o n ca ps ules 
will be e q uall y matc he d i n size, s ha pe a n d c ol or t o Q V A 1 4 9 1 1 0/ 5 0 μ g o. d. i n halati o n 
ca ps ules.
5. 1. 2   
R ef er e n c e t h er a p y

Sal meter ol/fl uticas o ne pr o pi o nate F D C 5 0/ 5 0 0 μ g dr y  i n halati o n p o w der deli vere d via 
Acc u haler ™.

Ti ot r o pi u m 1 8 μ g ca ps ules o. d. f or i n halati o n, s u p plie d as c o m merciall y a vaila ble blisters, 
deli vere d via Ha n di H aler ® .

Place b o t o Q V A 1 4 9 1 1 0/ 5 0 μ g o. d. ca ps ules f or i n halati o n, s u p plie d i n blisters, deli vere d 
via N o vartis si n gle d ose dr y  p o w der i n haler.
U n der 
n o circ u mst a nces is a n alter n ati ve i n h al ati o n de vice t o be use d f or t he 
a d mi nistr ati o n of a n y of t he i n vesti g ati o n al or refere nce t her a pies d uri n g t he tre at me nt 
peri o d.
5. 2   
Tr e at m e nt ar m s
Patie nts will be assi g ne d b y  ra n d o mizati o n t o o ne of t he f oll o wi n g t w o treat me nt ar ms i n a 
rati o of 1: 1 d uri n g t he tri ple d u m m y peri o d.
1.
Q V A 1 4 9 1 1 0/ 5 0 μ g o. d., deli vere d via N o vartis si n gle d ose dr y  p o w der i n haler p l us 
Ti otr o pi u m matc hi n g place b o o. d. deli vere d via t he ma n ufact urer’s Ha n di Haler ® de vice
p l us Fl uticas o ne/sal meter ol pr o pi o nate F D C matc hi n g place b o, b.i. d., deli vere d via t he 
ma n ufact urer’s Acc u haler ® de vice .
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
2.
Q V A 1 4 9 matc hi n g place b o o .d, deli vere d via N o vartis si n gle d ose dr y  p o w der i n haler 
p l us Ti otr o pi u m 1 8 μ g o. d., d eli vere d via t he ma n ufact urer’s Ha n di Haler ®   de vice p l us 
Fl uticas o ne/sal meter ol pr o pi o nate F D C 5 0 0/ 5 0 µ g b.i. d. dr y  i n halati o n p o w der deli vere d 
via t he ma n ufact urer’s Acc u haler ® de vice.
5. 3   
Tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n
At Visit 2 0 1 all eli gi ble patie nts will be ra n d o mize d via I nteracti ve Res p o nse Tec h n ol o g y 
(IR T) t o o ne of t he 2 treat me nt ar ms. T he i n vesti gat or or his/ her dele gate will c o ntact t he I R T 
after c o nfir mi n g at Visit 1 0 2 t hat t he patie nt f ulfills all t he i ncl usi o n/e xcl usi o n criteria. T he 
I R T will assi g n a ra n d o mizati on n u m ber t o t he patie nt, w hic h will be use d t o li n k t he patie nt 
t o a treat me nt ar m a n d will s pecif y a uni 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 patie nt. 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 caller.
T he ra n d o mizati o n n u m bers will be ge nerate d b y  the I R T 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 patie nt 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 Dr u g 
S u p pl y  
Ma na ge me nt 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 i n vesti gati o nal dr u g(s).
T he ra n d o mizati o n sc he me f or patie nts will be re vie we d a n d a p pr o ve d b y N o vartis .
5. 4   
Tr e at m e nt bli n di n g
Patie nts, i n vesti gat or staff, pers o ns perf or mi n g t he assess me nts, a n d data a nal ysts will re mai n 
bli n de d t o t he i de ntit y of t he treat me nt fr o m t he ti me of ra n d o mizati o n u ntil data base l oc k, 
usi n g t he f oll o wi n g met h o ds:

Ra n d o mizati o n data are ke pt strictl y  c o 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 a n y o ne i n v ol ve d i n t he st u d y;

T he i de ntit y  of t he treat me nts will be c o nceale d b y t he use of i n vesti gati o nal treat me nt s
t hat are i de ntical i n pac ka gi n g, la beli n g a n d sc he d ule of a d mi nistrati o n. 
A tri ple -d u m m y  desi g n is use d beca use t he i de ntit y of t he st u d y treat me nts ca n n ot be 
dis g uise d d ue t o t heir differe nt f or ms.
U n bli n di n g will o nl y  occ ur i n t he case of patie nt e mer ge ncies (see Secti o n 5. 5. 1 2 ) a n d at t he 
c o ncl usi o n of t he st u d y.
5. 5   
Tr e ati n g t h e p ati e nt
5. 5. 1   
P ati e nt n u m b eri n g 
Eac h patie nt is u ni q uel y i de ntifie d b y  a Patie nt N u m ber w hic h is c o m p ose d of a 4- di git site 
n u m ber assi g ne d b y  No vartis a n d a se q ue ntial 3- di git se q ue ntial patie nt n u m ber assi g ne d b y  
t he i n vesti gat or. O nce assi g ne d t o a patie nt, t he Patie nt N u m ber will n ot be re use d.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
U p o n si gni n g t he i nf or me d c o nse nt f or m, t he patie nt is 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 dele gate will c o ntact t he I RT a n d pr o vi de t he 
re q ueste d i nf or mati o n f or t he patie nt t o re gister t he m i nt o t he I RT. T he site s h o ul d select t he 
C R F b o o k wit h a matc hi n g Patie nt N u m ber fr o m t he E D C s y ste m t o e nter data.
If t he patie nt fails t o be treate d f or a n y reas o n, t he I RT m ust be n otifie d wit hi n t w o da y s t hat 
t he patie nt was n ot treate d. T he reas o n f or n ot bei n g treate d will be e ntere d o n t he Scree ni n g 
E p oc h St u d y  Dis p ositi o n C R F.
5. 5. 2   
Di s p e n si n g t h e i n v e sti g ati o n al tr e at m e nt
Eac h 
st u d y site will 
be s u p plie d b y  
No vartis wit h 
i n vesti gati o nal treat me nt. T he 
i n vesti gati o nal treat me nt pac ka gi n g has a 2 -part la bel. A u ni q ue me dicati o n n u m ber is pri nte d 
o n eac h part of t his la bel w hic h c orres p o n ds t o o ne of t he 2 treat me nt ar ms a n d a s pecific visit.
I n vesti gat or staff will i de ntif y the i n vesti gati o nal treat me nt pac ka ge(s) t o dis pe nse t o t he 
patie nt b y  co ntacti n g t he I RT a n d o btai ni n g t he me dicat i o n n u m ber(s). I m me diatel y bef ore 
dis pe nsi n g t he pac ka ge t o t he patie nt, i n vesti gat or staff 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 oc u me nt ( Dr u g La bel F or m) f or t hat patie nt’s 
u ni q ue patie nt n u m ber.
5. 5. 3   
H a n dli n g of st u d y  tr e at m e nt
T his secti o n defi nes h o w t o ha n dle t he i n vesti gati o nal me dici nal pr o d uct (I M P) . 
5. 5. 3. 1 
H a n dli n g of i n v e sti g ati o n al tr e at m e nt
I n vesti gati o nal treat me nt m ust be recei ve d b y  a desi g nate d pers o n at t he st u d y site, ha n dle d 
a n d st ore d safel y a n d pr o perl y acc or di n g t o t he i nstr ucti o ns s pecifie d o n t he la bels , a n d ke pt i n 
a sec ure d l ocati o n t o w hic h o nl y  the i n vesti gat or a n d desi g nees ha ve access. Cli nical s u p plies 
are t o be dis pe nse d o nl y i n acc or da nce wit h t he pr ot oc ol. 
Me dicati o n la bels will be i n t he l ocal la n g ua ge a n d c o m pl y wit h t he le gal re q uire me nts of 
eac h c o u ntr y. T he y  will i ncl u de st ora ge c o n diti o ns f or t he i n vesti gati o nal treat me nt b ut n o 
i nf or mati o n a bo ut t he patie nt j ust t he me dicati o n n u m ber.
T he i n vesti gat or m ust 
mai ntai n 
a n acc urate rec or d of t he s hi p me nt a n d dis pe nsi n g of 
i n vesti gati o nal treat me nt i n a dr u g acc o u nta bilit y l o g. M o nit ori n g of dr u g acc o u nta bilit y will 
be perf or me d b y  mo nit ors d uri n g site visits or re m otel y an d at t he c o m pleti o n of t he trial. 
Patie nts will be as ke d t o ret ur n all u n use d i n vesti gati o nal treat me nt a n d pac ka gi n g at t he e n d 
of t he st u d y  or at t he ti me of disc o nti n uati o n of i n vesti gati o nal treat me nt.
At t he c o ncl usi o n of t he st u d y, a n d as a p pr o priate d uri n g t he c o urse of t he st u d y, t he 
i n vesti gat or will ret ur n all u n use d i n vesti gati o nal treat me nt, pac ka gi n g, dr u g la bels, a n d a 
c o p y of t he c o m plete d dr u g acc o u nta bilit y lo g t o t he N o vartis m o nit or or t o t he N o vartis 
a d dress pr o vi de d i n t he i n vesti gat or f ol der at eac h site.
5. 5. 3. 2 
H a n dli n g of ot h er st u d y  tr e at m e nt
N ot a p plica ble.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
5. 5. 4   
I n str u cti o n s f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt
Eac h st u d y site will be s u p plie d b y  No vartis wit h st u d y treat me nt or ga nize d i n u ni q uel y 
n u m bere d me dicati o n kits.

Q V A 1 4 9
1 1 0/ 5 0 μ g o. d., deli vere d via . Matc hi n g place b o o. d., deli vere d via N o vartis 
si n gle d ose dr y p o w der i n haler.

Ti otr o pi u m 1 8 μ g o. d., deli vere d via t he ma n ufact urer’s pr o prietar y  in halati o n de vice 
( Ha n di Haler® ). Matc hi n g place b o o. d., deli vere d via Ha n di Haler ® .

Fl uticas o ne/sal meter ol pr o pi o nate F D C 5 0 0/ 5 0 µ g b.i. d. dr y  in ha lati o n p o w der deli vere d 
via Acc u haler ™ de vice. Matc hi n g place b o, b.i. d., deli vere d via Acc u haler ™.
Eac h patie nt will recei ve t hree kits at eac h dis pe nsi n g vi sit, o ne Q V A 1 4 9 / place b o, o ne 
ti otr o pi u m/ place b o a n d o ne fl uticas o ne +sal meter ol pr o pi o nate / place b o F D C , e xce pt f or Visits 
2 0 5 a n d 2 0 6, w here t he patie nts will recei ve si x kits (t w o eac h of Q V A 1 4 9/ place b o, 
ti otr o pi u m/ place b o a n d fl uticas o ne +sal meter ol pr o pi o nate/ place b o F D C ).
At Visits 2 0 1 ( Ra n d o mizati o n, Da y  1) t hr o u g h 2 0 7 ( Da y 1 4 1 ) st u d y me dicati o n will
be 
a d mi nistere d i n t he cli nic b y  the i n vesti gat or at a desi g nate d ti me bet wee n 0 8: 0 0 A M a n d 
1 1: 0 0 A M (see Ta ble 6 - 2).
Patie nts will be i nstr ucte d t o ta ke at h o me o ne ca ps ule i n t he m or ni n g bet wee n 0 8: 0 0 A M a n d 
1 1: 0 0 A M fr o m eac h of t heir me dicati o n kits a n d o ne ca ps ule i n t he e ve ni n g, i n t he f oll o wi n g 
or der;

A M ( a p pr o xi matel y bet wee n 0 8: 0 0 -1 1: 0 0): o ne i n halati o n fr o m t he Q V A 1 4 9 N o vartis 
si n gle d ose dr y p o w der i n haler) f oll o we d b y o ne i n halati o n fr o m ti otr o pi u m Ha n di Haler ® 
an d o ne fr o m fl uticas o ne/sal meter ol pr o pi o nate F D C Acc u haler ™ de vice .

P M (a p pr o xi matel y  1 2 h o urs after t heir A M d ose +/- 3 0 mi n utes): o ne i n halati o n fr o m 
fl uticas o ne/sal meter ol Acc u haler ™ de vice.
Patie nts s h o ul d als o be i nstr ucte d t o re place eac h blister a n d i n halati o n de vice bac k i nt o t he 
a p pr o priate b o x i m me diatel y after t he y ha ve ta ken t heir d ose.
All use d a n d u n use d st u d y me dicati o n / pac ka gi n g m ust be ret ur ne d b y  the patie nt at eac h 
Visit .
Pat ie nts m ust be i nstr ucte d t o wit h h ol d use of t heir m or ni n g d ose of st u d y me dicati o n at h o me 
o n m or ni n g of cli nic visit da y s as st u d y me dicati o n will be dis pe nse d i n t he cli nic. Patie nts 
m ust als o be i nstr ucte d t o wit h h ol d t he use of s h ort acti n g 2-a g o nists (resc ue me dicati o n) f or 
at least 6 h o urs pri or t o all cli nic visits, u nless t he use is a bs ol utel y necessar y , i n w hic h case 
t he visit is t o be resc he d ule d t o t he ne xt p ossi ble da y.
T he date a n d ti me of t he m or ni n g d ose of st u d y me dicati o n d ose a d mi nistratio n at eac h cli nic 
visit ( Visits 2 0 1- 2 0 7 ) will be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d electr o nic Case 
Re p ort F or m (e C R F).
Patie nts will be i nstr ucte d o n h o w t o use t he st u d y treat me nt i n halati o n de vices . A d diti o nal 
i n halati o n de vices a n d blisters w it h place b o ca ps ules will be pr o vi de d f or trai ni n g a n d 
de m o nstrati o n p ur p oses as nee de d (see A p pe n di x 4 f or t he patie nt i nstr ucti o ns o n h o w t o use 
t he i n halers).
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
All d osa ges prescri be d a n d dis pe nse d t o t he patie nt a n d all d ose c ha n ges d uri n g t he st u d y 
m ust be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d C R F.
T he i n vesti gat or s h o ul d pr o m ote c o m plia nce b y  instr ucti n g t he patie nt t o ta ke t he st u d y 
treat me nt e xactl y as prescri be d a n d b y  stati n g t hat c o m plia nce is necessar y  for t he patie nt’s 
safety a n d t he vali dit y of t he st u d y. T he patie nt s h o ul d 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 n y reas o n t o ta ke t he st u d y treat me nt as prescri be d or err o ne o usl y 
ta kes t he me dicati o n i nc orrectly.
If a n y tec h nical c o m plai nts or fa ults are i de ntifie d wit h eit her t he de vice a n d/ or t he blisters, 
t hese s h o ul d be ret ur ne d t o N o vartis wit h t he c o m plete d De vice Ret ur n F or m. T he f or ms will 
be s u p plie d t o eac h i n vesti gat or site b y t he Fiel d M o nit or.
5. 5. 5   
P er mi tt e d d o s e a dj u st m e nt s a n d i nt err u pti o n s of st u d y tr e at m e nt
St u d y  treat me nt d ose a dj ust me nts a n d/ or 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 n 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 or 
e xacer bati o n (see Secti o n 6. 6. 2 ).
Patie nts w h o e x perie nce a m o derate t o se vere C O P D e xacer bati o n ma y  co nti n ue i n t he st u d y 
(see Secti o n 6. 6. 2 f or defi niti o n a n d m ore i nf or mati o n).
A n y  interr u pti o n of st u d y me dicati o n s h o ul d be f or t he s h ortest ti me peri o d p ossi ble a n d a n y 
i nterr u pti o n of st u d y me dicati o n f or m ore t ha n 5 c o nsec uti ve d a y s d uri n g t he treat me nt e p oc h 
s h o ul d be disc usse d wit h t he N o vartis Me dical M o nit or t o re vie w t he patie nt’s eli gi bilit y to 
c o nti n ue i n t he trial.
T hese c ha n ges m ust be rec or de d i n t he D osa ge A d mi nistrati o n Rec or d C R F (e C R F).
5. 5. 6   
R e s c u e m e di c ati o n
At Visit 1 ( Scree ni n g), all patie nts will be pr o vi de d wit h a s h ort acti n g β 2 -a g o nist (sal b uta m ol 
or a l b uter ol) w hic h t he y will be i nstr ucte d t o use t hr o u g h o ut t he st u d y as resc ue me dicati o n.
Ne b ulize d sal b uta m ol or al b uter ol is n ot per mitte d as resc ue me dicati o n. N o ot her resc ue 
treat me nt is per mitte d d uri n g t he r u n-i n a n d treat me nt e p oc hs.
Sal b uta m ol or al b uter ol is n ot t o be a d mi nistere d wit hi n 6 h o urs of Visit 1 0 1 ( Baseli ne r u n -i n, 
Da y  -2 8) a n d Visit 2 0 1 ( Ra n d o mizati o n, Da y  1), u nless a bs ol utel y necessar y, i n w hic h case 
t he visit is t o be resc he d ule d.
D uri n g t he treat me nt e p oc h sal b uta m ol or al b uter ol s h o ul d be ta ke n as resc ue me dicati o n 
( w he n re q uire d) o nly. I n or der t o sta n dar dize meas ure me nts, f oll o wi n g ra n d o mizati o n patie nts 
s h o ul d be i nstr ucte d t o a bstai n fr o m ta ki n g resc ue me dicati o n (sal b uta m ol or al b uter ol) wit hi n 
6 h o urs of t he start of eac h visit w here s pir o metr y is bei n g perf or me d u nless a bs ol utel y 
necessar y .
F oll o wi n g ra n d o mizati o n, if resc ue me dicati o n is ta ke n wit hi n 6 h o urs pri or t o a s pir o metr y 
visit, t he visit s h o ul d be resc he d ule d t o t he ne xt da y , if p ossi ble. T he i n vesti gat or m ust use 
t heir j u d g me nt w he n deci di n g h o w ma n y ti mes a visit f or a n i n di vi d ual patie nt s h o ul d be 
resc he d ule d.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
I n t he e ve nt t hat a patie nt uses a d ose of resc ue me dicati o n after ta ki n g st u d y me dicati o n at 
a n y visit, t he visit s h o ul d c o nti n ue as pla n ne d. I n t his case t he a p pr o xi mate ti me of resc ue 
me dicati o n i nta ke will be ca pt ure d t hr o u g h t he ce ntral s pir o meter.
Use of resc ue me dicati o n ( n u m ber of p uffs ta ke n i n t he pre vi o us 1 2 h o urs) will be rec or de d 
( o nce i n t he m or ni n g a n d o nce i n t he e ve ni n g) by t he patie nt, i n t he electr o nic patie nt diar y .
5. 5. 7   
C o n c o mit a nt tr e at m e nt
T he i n vesti gat or s h o ul d i nstr uct t he patie nt t o n otif y  the st u d y site a b o ut a n y ne w me dicati o ns 
ta ken after t he patie nt was e nr olle d i nt o t he st u d 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 (i ncl u di n g p h y sical t hera py a n d bl o o d tra nsf usi o ns) a d mi nistere d after t he 
patie nt was e nr olle d i nt o t he st u d y  m ust be rec or de d.
5. 5. 8   
Pr o hi bit e d Tr e at m e nt
T he cl ass of me dic ati o ns liste d i n Ta ble 5- 1 a n d Ta ble 5- 2 are n ot per mitte d t o be t a ke n 
d uri n g t he st u d y tre at me nt peri o d . T he me dicati o ns i n Ta ble 5- 3 are o nl y  per mitte d u n der 
t he circ u msta nces gi ve n. Eac h c o nc 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 a n d t he ta bles bel o w t o see if it is all o we d. 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 m o nit or bef ore ra n d o mizi n g a patie nt or all o wi n g a ne w 
me dicati o n t o be starte d .
T a bl e 5- 1
Pr o hi bit e d tr e at m e nt
Cl a s s of M e di c ati o n 1
Mi ni m u m c e s s ati o n p eri o d pri or t o 
Vi sit 1 0 1 ( B a s eli n e r u n -i n)
N o n -p ot a s si u m s p ari n g di ur eti c s ( u nl e s s a d mi ni st er e d a s 
a fi x e d -d o s e c o m bi n ati o n wit h a p ot a s si u m c o n s er vi n g 
dr u g
7 d a y s
N o n -s el e cti v e s y st e mi c b et a -bl o c ki n g a g e nt s 2
7 d a y s
C ar di a c a nti -arr h yt h mi c s Cl a s s I a
7 d a y s
C ar di a c a nti -arr h yt h mi c s Cl a s s III
7 d a y s, a mi o d ar o n e 3 m o nt h s
Ot h er dr u g s wit h p ot e nti al t o si g nifi c a ntl y pr ol o n g t h e Q T 
i nt er v al
1 4 d a y s or 5 h alf -li v e s, w hi c h e v er i s l o n g er
Tri c y cli c a nti d e pr e s s a nt s ( Pl e a s e n ot e t h at t etr a c y cli c s, 
w hi c h ar e si mil ar i n cl a s s wit h r e g ar d s t o dr u g i nt er a cti o n 
ar e al s o t o b e e x cl u d e d)
1 4 d a y s
All a nti p s y c h oti c a g e nt s (fir st, s e c o n d a n d t hir d 
g e n er ati o n, i n cl u si v e of at y pi c al a nti p s y c h oti c s)
C o m bi n ati o n s of a nti p s y c hi oti c a g e nt s wit h 
a nti d e pr e s s a nt s ar e pr o hi bit e d
1 4 d a y s
S er ot o ni n N or a dr e n ali n e R e u pt a k e I n hi bit or s ( S N RI s)   
1 4 d a y s
Ot h er n or a dr e n ali n e r e u pt a k e i n hi bit or s
1 4 d a y s
M o n o a mi n e -o xi d a s e i n hi bit or s
1 4 d a y s
Li v e att e n u at e d v a c ci n e 
3 0 d a y s 
A nti bi oti c s (l o n g t er m m ai nt e n a n c e) 3
3 0 d a y s
S y st e mi c M a st c ell st a bili z er s ( e. g., cr o m o gl y c at e, 
n e d o cr o mil, k et otif e n)
7 d a y s
S y st e mi c a nti c h oli n er gi c s
7 d a y s
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Cl a s s of M e di c ati o n 1
Mi ni m u m c e s s ati o n p eri o d pri or t o 
Vi sit 1 0 1 ( B a s eli n e r u n -i n)
I g E i n hi bit or s ( e. g., X ol air)
6 m o nt h s 
L e u k otri e n e a nt a g o ni st s a n d l e u k otri e n e s y nt h e si s 
i n hi bit or s
7 d a y s
1 T hi s t a bl e i s n ot c o n si d er e d all -i n cl u si v e. M e di c ati o n s s h o ul d b e a s s e s s e d f or a d h er e n c e t o t h e 
i n di c ati o n a n d ot h er i n cl u si o n/ e x cl u si o n crit eri a.
2 S el e cti v e β 1 bl o c ki n g a g e nt s ar e p er mitt e d.
3 S h ort c o ur s e s of a nti bi oti c s ar e p er mitt e d d uri n g t h e st u d y.
T h e w a s h o ut of t h e s e pr o hi bit e d m e di c ati o n s i s n ot t o b e e n c o ur a g e d.
T a bl e 5- 2
Pr o hi bit e d C O P D -r el at e d m e di c ati o n s d uri n g t h e tri al
Cl a s s of M e di c ati o n 1, 2
Mi ni m u m w a s h o ut p eri o d pri or t o Vi sit 
1 0 1 ( B a s eli n e r u n -i n)
S h ort a cti n g m u s c ari ni c a nt a g o ni st ( S A M A) 2
8 h o ur s
Fi x e d c o m bi n ati o n s of s h ort -a cti n g β 2 a g o ni st s a n d s h ort -
a cti n g m u s c ari ni c a nt a g o ni st ( S A B A/ S A M A)
8 h o ur s
S h ort -a cti n g β 2 a g o ni st s ( S A B A) 3
6 h o ur s
Or al P h o s p h o di e st er a s e -I V i n hi bit or
7 d a y s
X a nt hi n e s ( a n y f or m ul ati o n)
7 d a y s
P ar e nt er al or or al c orti c o st er oi d s
3 0 d a y s
I ntr a-m u s c ul ar d e p ot c orti c o st er oi d s
3 m o nt h s
1 T hi s t a bl e i s n ot c o n si d er e d all -i n cl u si v e. M e di c ati o n s s h o ul d b e a s s e s s e d f or a d h er e n c e t o t h e 
i n di c ati o n a n d ot h er i n cl u si o n/ e x cl u si o n crit eri a. T h e s e m e di c ati o n s ar e al s o pr o hi bit ed if a d mi ni st er e d 
f or ot h er i n di c ati o n s.
2 All of t h e s e m e di c ati o n s ar e p er mitt e d f or t h e tr e at m e nt of a C O P D e x a c er b ati o n d uri n g t h e st u d y 
e x c e pt d e p ot c orti c o st er oi d s. If d e p ot c orti c o st er oi d tr e at m e nt i s r e q uir e d, t h e p ati e nt s h o ul d b e 
wit h dr a w n fr o m t h e st u d y tr e at m e nt.
3 S A B A a n d S A M A pr o hi bit e d wit h e x c e pti o n of st u d y r e s c u e m e di c at i o n ( s e e S e cti o n 5. 5. 6 ).
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T a bl e 5- 3
M e di c ati o n all o w e d u n d er c ert ai n c o n diti o n s if t a k e n a s f oll o w s
Cl a s s of M e di c ati o n 1
C o n diti o n u n d er w hi c h m e di c ati o n i s 
p er mitt e d
S el e cti v e S er ot o ni n R e u pt a k e I n hi bit or s
St a bl e d o s e f or at l e a st 3 0 d a y s pri or t o Vi sit 1 
( S cr e e ni n g) a n d d uri n g t h e tri al.
I ntr a-n a s al c orti c o st er oi d s
St a bl e d o s e f or at l e a st 3 0 d a y s pri or t o Vi sit 1 
( S cr e e ni n g).
H 1 -a nt a g o ni st s 
St a bl e d o s e/r e gi m e n f or at l e a st 5 d a y s pri or t o 
Vi sit 1 ( S cr e e ni n g)   ( E x c e pt mi z ol a sti n or 
t erf e n a di n e)
I n a cti v at e d i nfl u e n z a, p n e u m o c o c c al or a n y  ot h er 
i n a cti v at e d v a c ci n e
N ot a d mi ni st er e d wit hi n 4 8 h o ur s pri or t o a tri al 
vi sit
1 T hi s t a bl e i s n ot c o n si d er e d all -i n cl u si v e. M e di c ati o n s s h o ul d b e a s s e s s e d f or a d h er e n c e t o t h e 
i n di c ati o n a n d ot h er i n cl u si o n/ e x cl u si o n crit eri a.
5. 5. 9   
Di s c o nti n u ati o n of s t u d y tr e at m e nt
I n vesti gati o nal treat me nt m ust be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces:

I n case of a d verse e ve nts f or w hic h c o nti n ue d i n halati o n of t he st u d y treat me nt w o ul d be 
detri me ntal a n d/ or a b n or mal test pr oce d ure res ults i n dicati n g ris k f or t he patie nt o n 
c o nti n ue d i n halati o n of t he st u d y  treat me nt ( patie nt s h o ul d c o nti n ue wit h T D visit).

E mer ge nce of t he f oll o wi n g a d verse e ve nt:
A bs ol ute Q Tc F > 5 0 0 msec, c o nfir me d b y re peat E C G meas ure me nts

Pre g na nc y

Use of pr o hi bite d treat me nt as per Ta ble 5 - 1 a n d Ta ble 5 - 2
If pre mat ure disc o nti n uati o n of st u d y treat me nt occ urs, t he patie nt s h o ul d ret ur n t o t he cli nic 
as s o o n as p ossi ble f or a st u dy treat me nt disc o nti n uati o n ( T D) visit. At t his st u d y treat me nt 
disc o nti n uati o n visit assess me nts s h o ul d be c o m plete d a n d rec or de d i n t he e C R F as per 
Ta ble 6- 1 . T he i n vesti gat or m ust deter mi ne t he pri mar y  reas o n f or t he patie nt’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 o n t he D osa ge A d mi nistrati o n 
e C R F.
T he i n vesti gat or a n d st u d y staff m ust disc uss wit h t he patie nt, t he patie nt’s c o nti n ue d 
partici pati o n i n t he st u d y a n d re q uest patie nts t o c o nti n ue atte n di n g st u d y visits acc or di n g t o 
t he st u d y visit sc he d ule wit h all assess me nts c o m plete d u p t o Visit 2 0 7 . If t he patie nt ca n n ot 
or is u n willi n g t o atte n d a n y visit(s), t he site staff s h o ul d mai ntai n re g ular p h o ne c o ntact wit h 
t he patie nt, or wit h a pers o n pre -desi g nate d b y  the patie nt. T his p h o ne 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. Data will c o nti n ue t o be c ollecte d 
c o ncer ni n g t he patie nt’s healt h stat us, i ncl u di n g i nf or mati o n re gar di ng ne w / c o nc o mita nt 
treat me nts, a d verse e ve nts, a n d vital stat us. T he Wee k 2 6 s pir o metr y assess me nts c o n d ucte d 
at Visit 2 0 7 a n d safety assess me nts at Visit 2 0 7 are t he pri orit y  assess me nts f or patie nts t hat 
pre mat urel y disc o nti n ue st u d y treat me nt. At a mi n i m u m, t he i n vesti gat or s h o ul d ma ke e ver y 
eff ort t o o btai n i nf or mati o n re gar di n g seri o us a d verse e ve nts.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T he a p pr o priate pers o n nel fr o m t he site a n d N o vartis will assess w het her i n vesti gati o nal 
treat me nt s h o ul d be disc o nti n ue d f or a n y patie nt w h ose treat me nt c o de has bee n br o ke n 
i na d verte ntly f or a n y reas 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 patie nt’s disc o nti n uati o n fr o m 
i n vesti gati o nal treat me nt.
At a mi ni m u m, patie nts will be c o ntacte d f or safet y eval uati o ns d uri n g t he 3 0 da y s f oll o wi n g 
t he last st u d y visit or f oll o wi n g t he last a d mi nistrati o n of i n vesti gati o nal treat me nt  if t here are 
p ost -treat me nt f oll o w-u p visits ( w hic he ver is later), i ncl u di n g a fi nal c o ntact at t he 3 0- da y 
p oi nt. D oc u me ntati o n of atte m pts t o c o ntact t he patie n t s h o ul d be rec or de d i n t he s o urce 
d oc u me ntati o n.
5. 5. 1 0  
Wit h dr a w al of c o n s e nt
Patie nts ma y  vol u ntaril y wit h dra w c o nse nt t o partici pate i n t he st u 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 patie nt 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 wa nt a n y f urt her visits or assess me nts a n d d oes n ot wa nt a n y f urt her 
st u d y relate d c o ntacts a n d d oes n ot all o w a nalys is of alrea dy o btai ne d bi ol o gic material.
If a patie nt wit h dra ws c o nse nt, t he i n vesti gat or m ust ma ke e ver y  eff ort (e. g. tele p h o ne, e-mail, 
letter) t o deter mi ne t he pri mar y  reas o n f or t his decisi o n a n d rec or d t his i nf or mati o n i n t he 
s o urce d oc u me ntati 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. F urt her atte m pts t o c o ntact t he patie nt 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.
5. 5. 1 1  
L o s s t o f oll o w -u p
F or patie nts 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 wit h dra w, t he i n vesti gat or s h o ul d s h o w " d ue dili g e nce" b y  co ntacti n g t he 
patie nt, fa mil y or fa mil y p h y sicia n as a gree d i n t he i nf or me d c o nse nt a n d b y  doc 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 patie nt, e. g. dates of tele p h o ne calls, 
re gistere d letters, etc. A patie nt s h o ul d n ot be f ormall y  co nsi dere d l ost t o f oll o w- u p u ntil 
his/ her sc he d ule d e n d of st u d y  visit w o ul d ha ve occ urre d.
5. 5. 1 2  
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  treat me nt c o de brea ks s h o ul d o nl y  be u n derta ke n w he n it is esse ntial t o treat t he 
patie nt safely a n d efficaci o usl y. 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 patie nt w h o prese nts wit h 
a n e mer ge nc y co 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 RT. 
W h e 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 patie nt, he/s he m ust 
pr o vi de t he re q ueste d patie nt i de ntif yi n g i nf or mati o n a n d c o nfir m t he necessit y  to brea k t he 
treat me nt c o de f or t he patie nt. T he i n vesti gat or will t he n recei ve det ails of t he i n vesti gati o nal 
dr u g treat me nt f or t he s pecifie d patie nt 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 i nf or m t he m o nit or f or t he site a n d t he Trial Lea d ( T L) t hat t he c o de 
has bee n br o ke n. T he patie nt will a ut o maticall y be e ntere d as disc o nti n ue d fr o m st u d y 
treat me nt wit hi n t he I R T s y ste m after c o de brea ki n g.
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T he i n vesti gat or (a n d desi g nate d site staff) will ha ve 2 4 hr/ 7 da y  access t o I R T d uri n g t he st u d y, 
a n d will be a ble t o u n bli n d patie nts i n cases of e mer ge nc y .
St u d y  treat me nt m ust be disc o nti n ue d after e mer ge nc y un bli n di n g. St u d y  treat me nt m ust als o 
be disc o nti n ue d f or a n y patie nt w h ose treat me nt c o de has bee n i na d verte ntl y  br o ke n or f or a n y 
n o n- e mer ge nc y reas o n.
5. 5. 1 3  
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 c o m pleti o n f or an i n di vi d ual patie nt will occ ur after he/s he has c o m plete d t hr o u g h t o 
t he fi nal e val uati o n ( Visit 3 0 1). C o m pleti o n of t he st u d y  will be w he n all ra n d o mize d patie nts 
ha ve c o m plete d t hr o u g h t o t he fi nal e val uati o n ( Visit 3 0 1) or ha ve wit h dra w n fr o m t he st u d y.
W he n t he patie nt has c o m plete d all sc he d ule d st u d y assess me nts or pre mat urel y  wit h dra w n 
fr o m t he st u d y, t he i n vesti gat or m ust co ntact t he I R T t o rec or d t he patie nt c o m pleti o n / 
disc o nti n uati o n a n d c o m plete a p plica ble e C R Fs .
T he i n vesti gat or m ust pr o vi de f oll o w- u p me dical care f or all patie nts w h o are pre mat urel y 
wit h dra w n fr o m t he st u d y, or m ust refer t he m f or a p pr o priate o n g oi n g care.
5. 5. 1 4  
E arl y  st u d y t er mi n ati o n
T he st u d y ca n be ter mi nate d at a n y ti me f or a n y reas o n b y No vartis. S h o ul d t h is be necessar y, 
o n g oi n g patie nt s s h o ul d be see n as s o o n as p ossi ble a n d treate d f or a pre mat urel y  wit h dra w n 
patie nt. 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 patie nt’s i nterests. T he 
i n vesti gat or will be res p o nsi ble f or i nf or mi n g 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 (I R Bs/I E Cs) of t he earl y ter mi nati o n of t he trial.
6   
Vi sit s c h e d ul e a n d a s s e s s m e nt s
6. 1   
A s s e s s m e nt s c h e d ul e
T he st u d y will c o nsist of a scree ni n g e p oc h, a r u n-i n e p oc h, a 2 6 wee k bli n de d treat me nt 
e p oc h a n d a f oll o w-u p e p oc h of 3 0 da y s after t he last treat me nt.
Ta ble 6- 1 lists all of t he assess me nts a n d i n dicates wit h a n “ X” or “ S” w he n t he assess me nt(s) 
are perf or me d at t hat visit. Patie nts s h o ul d be see n f or all visits o n t he desi g nate d da y  or as 
cl ose t o it as p ossi ble. T he n u m ber of da y s bet wee n Visit 1 a n d Visit 1 0 1 will de pe n d o n t he 
baseli ne e p oc h ti me f or pr o hi bite d c o nc o mita nt me dicati o n, as descri be d i n Secti o n 5. 5. 7 t he 
mi ni m u m i nter val bet wee n V isit 1 a n d V isit1 0 1 is at least o ne da y ( Patie nts nee d t o si g n 
i nf or me d c o nse nt first bef ore t he y will be as ke d n ot t o ta ke t heir m or ni n g d ose of C O P D 
me dicati o ns o n t he da y  of t he ne xt visit , w he n t he re versi bilit y assess me nt will be d o ne; see 
Secti o n 3. 1 ).All data o btai ne d fr o m t hese assess me nts m ust be re p orte d i n t he patie nt’s s o urce 
d oc u me ntati o n.
Patie nts w h o disc o nti n ue st u d y  treat me nt s h o ul d ret ur n f or t he T D ( Treat me nt Disc o nti n uati o n) 
Visit as s o o n as p ossi ble as n ote d i n Ta ble 6 - 1.
F or all visit s i n w hic h t he y occ ur, the assess me nts liste d bel o w are t o be perf or me d i n t he 
f oll o wi n g or der:
 

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 1 C l e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6

St Ge or ge’s Res pirat or y  Q uesti o n naire (S G R Q - C)

M o difie d Me dical Researc h C o u ncil ( m M R C) D y s p nea Scale

C O P D Assess me nt Test ( C A T)

Baseli ne D y s p n oea I n de x/ Tra nsiti o n D ys p n oea I n de x (B DI/ T DI )

E C G

Vital si g ns: p ulse rate, bl o o d press ure

B l o o d sa m ple/ uri ne sa m ples

S pir o metr y  meas ure me nts m ust al wa ys occ u r at t he sc he d ule d ti me p oi nt (see Ta ble 6 - 2
f or Ti me d Assess me nts)
W he ne ver ot her assess me nts are sc he d ule d at t he sa me ti me- p oi nt, s pir o metr y  m ust ta ke 
prece de nce s uc h t hat it occ urs at t he sc he d ule d ti me p oi nt or as near as p ossi ble. I f necessar y 
ot her assess me nts (e xcl u di n g S G R Q- C, m M R C, C A T, B DI/ T DI) ca n be perf or me d after 
s pir o metr y.
Bl o o ds m ust al wa y s be dra w n after E C G meas ure me nt.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T a bl e 6- 1   
A s s e s s m e nt s c h e d ul e
E p o c h
S cr e e n i n g   
R u n -i n
Tr e at m e nt
F oll o w -u p ( b y p h o n e)
Vi sit n u m b er
1   
1 0 1    
1 0 2  
2 0 1 2 0 2 2 0 3 2 0 4 2 0 5 2 0 6
2 0 7   2 0 8   
2 9 9   
-
3 0 1
Vi sit
S cr e e ni n g
B a s eli n e r u n-i n
R u n-i n
R a n d o mi z ati o n
E n d of tr e at m e nt
P S W
Tr e at m e nt 
di s c o nti n u ati o n 
( T D)
St u d y c o m pl eti o n
W e e k
- 5 t o - 4    
- 4    
1    
1   
2   4   8 
1 2 
2 0  2 6    
2 6
3 0
D a y
-3 5 t o- 2 9    
-2 8   
1    
1  
1 5 
2 9 
5 7 
8 5
1 4 1
1 8 1   
1 8 2
2 1 2
O bt ai n i nf or m e d c o n s e nt
x
D e m o gr a p hi c s
x
I n cl u si o n/ e x cl u si o n crit eri a
x    
x    
x
R el e v a nt m e di c al hi st or y
x
Di s p o siti o n:
                 S cr e e ni n g
x
                      R u n -i n
x   
x*
                  Tr e at m e nt
x    
x
                   F oll o w -u p
x
C O P D e x a c er b ati o n hi st or y    
x
Hi st or y of C V ri s k f a ct or s
x
Hi st or y of p ul m o n ar y di s e a s e s   
x
S m o k i n g hi st ory
x
S m o k i n g st at u s
x
x
x    
x
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
E p o c h
S cr e e n i n g   
R u n -i n
Tr e at m e nt
F oll o w -u p ( b y p h o n e)
Vi sit n u m b er
1   
1 0 1    
1 0 2  
2 0 1 2 0 2 2 0 3 2 0 4 2 0 5 2 0 6
2 0 7   2 0 8   
2 9 9   
-
3 0 1
Vi sit
S cr e e ni n g
B a s eli n e r u n-i n
R u n-i n
R a n d o mi z ati o n
E n d of tr e at m e nt
P S W
Tr e at m e nt 
di s c o nti n u ati o n 
( T D)
St u d y c o m pl eti o n
W e e k
- 5 t o - 4    
- 4    
1    
1   
2   4   8 
1 2 
2 0  2 6    
2 6
3 0
D a y
-3 5 t o- 2 9    
-2 8   
1    
1  
1 5 
2 9 
5 7 
8 5
1 4 1
1 8 1   
1 8 2
2 1 2
Pr e g n a n c y t e st ( uri n e)
s
s
s
R e c or d m e di c al r e s o ur c e u s e   
x    
x
x   
x   
x   x   
x   
x    
x
x
P h y s i c al e x a mi n ati o n
s
s    
s
s
E C G 1, 2
x    
x    
x
x    
x
x
Vit al si g n s ( S y st oli c a n d di a st oli c 
B P a n d r a di al p ul s e) 2
x    
x    
x    
x    
x    
x
x
R e c or d h ei g ht ( vi sit 1 0 1 o nl y) 
a n d w ei g ht
x
x
x
Pri or a n d c urr e nt c o n c o mit a nt 
m e di c ati o n r e vi e w/ a dj u st m e nt
x    
x    
x    
x   
x   
x   x   
x   
x    
x    
x
x
T i otr o pi u m ( 1 8 μ g o. d.) + 
s al m et er ol/fl uti c a s o n e 
pr o pi o n at e F D C ( 5 0/ 5 0 0 µ g 
b.i. d.) r u n-i n
x
R e vi e w s ur g er y a n d pr o c e d ur e s   
x    
x    
x    
x   
x   
x   x   
x   
x    
x    
x
x
S pir o m etr y  ( c e ntr ali z e d)2
(R e v er si bilit y )
x
x    
x    
x    
x    
x
x
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
E p o c h
S cr e e n i n g   
R u n -i n
Tr e at m e nt
F oll o w -u p ( b y p h o n e)
Vi sit n u m b er
1   
1 0 1    
1 0 2  
2 0 1 2 0 2 2 0 3 2 0 4 2 0 5 2 0 6
2 0 7   2 0 8   
2 9 9   
-
3 0 1
Vi sit
S cr e e ni n g
B a s eli n e r u n-i n
R u n-i n
R a n d o mi z ati o n
E n d of tr e at m e nt
P S W
Tr e at m e nt 
di s c o nti n u ati o n 
( T D)
St u d y c o m pl eti o n
W e e k
- 5 t o - 4    
- 4    
1    
1   
2   4   8 
1 2 
2 0  2 6    
2 6
3 0
D a y
-3 5 t o- 2 9    
-2 8   
1    
1  
1 5 
2 9 
5 7 
8 5
1 4 1
1 8 1   
1 8 2
2 1 2
C o nt a ct I R T (I W R S)
S    
S    
S    
S   S  
S  
S   S  
S    S    
S    
S    
S
S
Uri n al y si s ( di p sti c k) 2
x    
x
x    
x
x
H e m at ol o g y 2 /
Bi o c h e mi str y 2
x
x    
x    
x    
x
x
Or o p h ar y n g e al e x a mi n ati o n
3
s
s   
s   
s   s   
s   
s    
s
s
2 4 h uri n e c oll e cti o n ( c orti s ol 
m e a s ur e m e nt) 4
x
x    
x
x
m M R C
5
x
x
C A T
5
x
x    
x    
x
x    
x
S G R Q - C 5
x
x    
x
x
B DI/ T DI 5
x
x    
x
x
I n h al ati o n d e vi c e tr ai ni n g
S
S
A E r e c or di n g 6
x    
x    
x    
x   
x   
x   x   
x   
x    
x    
x    
x    
x
x
S A E r e c or di n g 6
x    
x    
x    
x   
x   
x   x   
x   
x    
x    
x    
x    
x
x
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
E p o c h
S cr e e n i n g   
R u n -i n
Tr e at m e nt
F oll o w -u p ( b y p h o n e)
Vi sit n u m b er
1   
1 0 1    
1 0 2  
2 0 1 2 0 2 2 0 3 2 0 4 2 0 5 2 0 6
2 0 7   2 0 8   
2 9 9   
-
3 0 1
Vi sit
S cr e e ni n g
B a s eli n e r u n-i n
R u n-i n
R a n d o mi z ati o n
E n d of tr e at m e nt
P S W
Tr e at m e nt 
di s c o nti n u ati o n 
( T D)
St u d y c o m pl eti o n
W e e k
- 5 t o - 4    
- 4    
1    
1   
2   4   8 
1 2 
2 0  2 6    
2 6
3 0
D a y
-3 5 t o- 2 9    
-2 8   
1    
1  
1 5 
2 9 
5 7 
8 5
1 4 1
1 8 1   
1 8 2
2 1 2
H o s pit ali z ati o n d u e t o C O P D 
o c c urr e n c e r e c or di n g
x    
x    
x    
x   
x   
x   x   
x   
x    
x    
x    
x    
x
C O P D e x a c er b ati o n r e c or di n g
x    
x    
x   
x   
x   x   
x   
x    
x    
x    
x    
x
Di s p e n s e r e s c u e 
m e di c ati o n/r e vi e w u s e
x    
x    
x    
x   
x   
x   x   
x   
x    
x
X 7
I s s u e/tr ai n o n e Di ar y
S
S
R e vi e w/ u pl o a d e Di ar y 
x    
x   
x   x   
x   
x    
x    
x    
x    
x
A d m i ni st er st u d y  tr e at m e nt at 
vi sit
x   
x   
x   x   
x   
x    
x
Di s p e n s e st u d y tr e at m e nt (I R T)
S    
S  
S   S  
S
R e c or d st u d y tr e at m e nt 
c o m pli a n c e
x   
x   x   
x   
x    
x
x
T el e p h o n e c o nt a ct wit h p ati e nt 8, 9
x 8
x 8
x 9
x 9
x 9
x 9
S ur vi v al f oll o w -u p 1 0
x
T D = St u d y tr e at m e nt di s c o nti n u ati o n ( u n s c h e d ul e d vi sit) P S W = Pr e m at ur e st u d y wit h dr a w al
S = t h e s e a s s e s s m e nt s ar e s o ur c e d o c u m e nt ati o n o nl y a n d will n ot b e e nt er e d i nt o t h e e C R F
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
*f or p ati e nt s n ot eli gi bl e t o c o nti n u e r u n-i n aft er Vi sit 1 0 1
1 . E C G m e a s ur e m e nt s: At Vi sit 1 0 1, a si n gl e E C G will b e p erf or m e d 5 t o 1 5 mi n pri or t o s pir o m etr y
2 . S e e T a bl e 6 - 2 f or d et ail s of ti m e d a s s e s s m e nt s fr o m Vi sit 2 0 1. R e v er si bilit y will b e p erf or m e d at Vi sit 1 0 1 o nl y
3 . Or o p h ar y n g e al e x a mi n ati o n s will b e c o n d u ct e d at Vi sit 1 0 1 a n d all s u b s e q u e nt vi sit s u ntil t h e e n d of t h e st u d y. If a f u n g al i nf e cti o n of t h e m o ut h or t hr o at i s s u s p e ct e d b y eit h er s y m pt o m s or 
dir e ct e x a mi n ati o n, a c ult ur e s h o ul d b e t a k e n a n d s e nt t o t h e c e ntr al l a b f or t e sti n g t o c o nfir m di a g n o si s. T h e p ati e nt s h o ul d b e f oll o w e d a n d tr e at e d a p pr o pri at el y u ntil r e s ol u ti o n. T h e p ati e nt 
m a y c o nti n u e i n t h e st u d y at t h e di s cr eti o n of t h e i n v e sti g at or a n d t h e s p o n s or
4 . Uri n e c orti s ol a n d uri n e cr e ati ni n e will b e p erf or m e d i n s u b-s et of p ati e nt s o nl y
5 . m M R C, C A T, S G R Q-C, a n d B DI/ T DI s h o ul d b e d o n e b ef or e a n y ot h er a s s e s s m e nt s, B DI o nl y at B a s eli n e
6 . A n y r e p ort e d c a s e s of p n e u m o ni a s h o ul d b e c o nfir m e d wit h c h e st X-r a y. A E r e p orti n g st art s fr o m si g ni n g of i nf or m e d c o n s e nt. If a C O P D e x a c er b ati o n o c c ur s d uri n g t h e pr e-s cr e e ni n g/ 
s cr e e ni n g p eri o d, t h e p ati e nt will n ot b e eli g i bl e b ut will b e p er mitt e d t o b e r e-s cr e e n e d aft er a mi ni m u m of 6 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
7 . Di s p e n s ati o n of r e s c u e m e di c ati o n at vi sit T D i s o pti o n al
8 . Sit e t o c all p ati e nt pri or t o V 1 0 1 a n d V 1 0 2 t o r e mi n d t h e m t o st o p t a ki n g r e s c u e m e di c ati o n 6 h ( S A B A) a n d 8 h ( S A M A) pri or t o vi sit s
9 . P ati e nt s will b e c o nt a ct e d b y t el e p h o n e a p pr o xi m at el y 2 w e e k s pri or t o Vi sit 2 04 , 2 05 , a n d a p pr o xi m at el y 3 w e e k s pri or t o Vi sit 2 0 6 a n d 2 0 7 t o c h e c k if p ati e nt’ s C O P D s y m pt o m s h a v e 
w or s e n e d, a n y tr e at m e nt r e q uir e d a n d e-di ar y c o m pl et e d a c c or di n gl y
I n c a s e of a C O P D e x a c er b ati o n, t h e p ati e nt s h o ul d b e e n c o ur a g e d b y t h e sit e t o c o nt a ct it f or a n a d vi c e. If n e c e s s ar y a n u n sc h e d ul e d vi sit t o t h e sit e m a y b e or g a ni z e d.
1 0 . I nf or m ati o n a b o ut a p ati e nt’s s ur vi v al will b e o bt ai n e d b y a t el e p h o n e c all 3 0 d a y s aft er t h e p ati e nt’ s l a st d o s e of st u d y tr e at m e nt or l a st vi sit/ o b s er v ati o n f or p ati e nt s w h o di s c o nti n u e.
1 1 .. 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 2   
Ti m e d a s s e s s m e nt s 
Fr o m Visit 2 0 1 ( Ra n d o mizati o n, Da y  1) on war d, patie nts will be assesse d b ot h pre - a n d p ost -
d ose at t he ti mes s pecifie d i n Ta ble 6 - 2.
F or visits t hat i ncl u de m M R C, C A T, S G R Q -C a n d B DI/ T DI, t he patie nt m ust arri ve earl y 
e n o u g h t o e ns ure t here is a de q uate ti me t o c o m plete t hese q uesti o n naires bef ore ot her 
assess me nts a n d a d here t o sc he d ule d ti mes.
T he q uesti o n naires ha ve t o be c o m plete d i n t he f oll o wi n g or der: S G R Q - C, m M R C, C A T, a n d 
B DI/ T DI. S pir o metr y  meas ure me nts m ust al wa y s occ u r at t he sc he d ule d ti me p oi nt (see Ta ble 
6- 2 f or Ti me d Assess me nts).
W he ne ver ot her assess me nts are sc he d ule d at t he sa me ti me -p oi nt, s pir o metr y  m ust ta ke 
prece de nce s uc h t hat it occ urs at t he sc he d ule d ti me p oi nt or as near as p ossi ble. If necessar y 
ot her assess me nts (e xcl u di n g S G R Q -C, m M R C, C A T, B DI/ T DI) ca n be perf or me d after 
s pir o metr y. Bl o o ds m ust al wa ys be dra w n after E C G meas ure me nt.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T a bl e 6- 2   
Ti m e d a s s e s s m e nt s
Ti m e p oi nt 1
Uri n al y si s   
E C G
Vit al 
si g n s 2
H e m at ol o g y / Bl o o d 
c h e mi str y / 
Bi o m ar k er
S pir o m etr y 3
E n s ur e S G R Q- C , m M R C, C A T a n d B DI/ T DI ar e c o m pl et e d b ef or e ot h er a s s e s s m e nt s st art
Vi sit 2 0 1   
>- 4 5 mi n
X*
X*    
X*
-4 5 mi n
X
-4 5 t o -2 0 
mi n
X
-1 5 mi n
X
0 mi n   
St u d y tr e at m e nt a d mi ni st er e d i n cli ni c
3 0 mi n
X
1 h
X    
X
X
Vi sit 2 0 3   
-4 5 mi n
X
X
-4 5 t o -2 0 
mi n
X
-1 5 mi n
X
0
St u d y tr e at m e nt a d mi ni st er e d i n cli ni c
3 0 mi n
X
1 h
X
X
Vi sit 2 0 5    
>- 4 5 mi n
X
X    
X
-4 5 mi n
X
-4 5 t o -2 0 
mi n
X
-1 5 mi n
X
0 mi n   
St u d y tr e at m e nt a d mi ni st er e d i n cli ni c
3 0 mi n
X
1 h
X    
X
X
Vi sit 
2 0 7 ( or 
T D)
>- 4 5 mi n
X
X    
X
-4 5 mi n
X
-4 5 t o -2 0 
mi n
X
-1 5 mi n
X
0 mi n   
St u d y tr e at m e nt a d mi ni st er e d i n cli ni c
3 0 mi n
X
1 h
X
X
X
Vi sit 2 0 8   
2 3 h 1 5 mi n
X
2 3 h 4 5 mi n
X
* A s s e s s m e nt s ar e c o m pl et e d a s p art of Vi sit 1 0 2 ( E n d of r u n-i n, D a y 1).
1 Ti m e  r el at e s t o t h e d o s e gi v e n fr o m d e vi c e at vi sit u nl e s s ot h er wi s e s p e cifi e d
2 S y st oli c a n d di a st oli c bl o o d pr e s s ur e a n d h e art r at e
3 A m i ni mu m  3 mi n r e st p eri o d fr o m t h e b e gi n ni n g of E C G a s s e s s m e nt s t o t h e st art of s pir o m etr y
m a n e u v er s m u st b e o b s er v e d at all ti m e s
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 3   
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
All patie nts w h o ha ve si g ne d i nf or me d c o nse nt b ut n ot e ntere d i nt o t he ne xt e p oc h will ha ve 
t he st u d y co m pleti o n pa ge f or t he scree ni n g e p oc h, de m o gra p hics, i ncl usi o n/e xcl usi o n, a n d 
seri o us a d verse e ve nt ( S A E) data c ollecte d u p u ntil t he p oi nt t hat t he patie nt is c o nsi dere d t o 
ha ve faile d scree ni n g. A d verse e ve nts t hat are n ot S A Es will be f oll o we d b y  the i n vesti gat or 
a n d c ollecte d o nl y i n t he s o urce data.
F or all patie nts w h o ha ve si g ne d i nf or me d c o nse nt a n d are e ntere d i nt o t he r u n -i n e p oc h of t he 
st u d y will ha ve all a d verse e ve nts occ urri n g after i nf or me d c o nse nt is si g ne d recor de d o n 
t he A d verse E ve nt C R F.
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 me dical hist or y 
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.
6. 4   
P ati e nt 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
Patie nt de m o gra p hic a n d baseli ne c haracteristic data t o be c ollecte d o n all patie nts i ncl u de:

Date of birt h

A ge (calc ulate d)

Se x

Race a n d et h nicit y

Patie nt i nitials ( w here all o we d b y l ocal le gislati o n)

Hei g ht

Wei g ht

Da te of dia g n osis of C O P D

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 i nf or me d 
c o nse nt

S m o ki n g hist or y

S m o ki n g stat us

Healt h Stat us

Pri or c o nc o mita nt me dicati o ns ( b ot h C O P D relate d a n d n o n- C O P D relate d) . Pri or 
c o nc o mita nt me dicati o ns are t h ose pri or t o Visit 1

Pre - a n d p ost-br o nc h o dilat or s pir o metr y  (baseli ne s pir o metr y):

At Visit 1 0 1, F E V 1 a n d F V C pre a n d p ost br o nc h o dilat or i n halati o n (see S pir o metr y  
g ui da nce i n A p pe n di x 2 )

At Visit 2 0 1 F E V 1 a n d F V C pre a n d p ost i n halati o n of i n vesti gati o nal dr u gs

P h y sical e xa mi nati o n ( n ot data base d ot her t ha n i n t he c o ntext of rele va nt me dical hist or y )

La b orat or y  res ults

Vital si g ns

E C 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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 5   
Tr e at m e nt e x p o s ur e a n d c o m pli a n c e
T he ti me of st u d y treat me nt a d mi nistrati o n at eac h i n-office d osi n g visit will be c ollecte d o n 
t he e C R F as well as a n y d osi n g i nterr u pti o ns. F or assess me nts w here s pir o metr y is perf or me d, 
t he ti me of d osi n g is t o be ta ke n fr o m t he s pir o meter.
St u d y  treat me nt c o m plia nce s h o u l d be assesse d b y t he i n vesti gat or a n d/ or desi g nee at all visits. 
T he I n vesti gat or or desi g nee will c ollect, fr o m t he patie nt, t he use d / u n use d i n vesti gati o nal 
me dicati o n a n d pac ka gi n g ( m or ni n g a n d e ve ni n g ca ps ules / blister stri ps a n d i n halati o n 
de vices ) at all dis pe nsi n g visits. St u d y  treat me nt 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 e m pt y blister stri ps ( 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 patie nt a n d/ or care gi ver. T his i nf or mati o n will
be ca pt ure d i n t he s o urce 
d oc u me ntati o n. 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 si nce t he 
last dis pe nsi n g visit will 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 st u d y treat me nt a n d a n y misse d d oses 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  by t he patie nt 
i n t he e Diar y. T he patie nt will be i nstructe d acc or di n gl y at Visit 1 0 1 w he n he/s he is pr o vi de d 
wit h t he e Diar y an d t he use of resc ue me dicati o n is di sc usse d. T he use of 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 Diar y do 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 nt
iss ues re gar di n g resc ue 
me dicati o n use wit h t he patie nt.
6. 6   
Effi c a c y

P ul m o nar y f u ncti o n (S pir o metr y )

C O P D e xacer bati o ns

Resc ue me dicati o n usa ge

M o difie d Me dical Researc h C o u ncil ( m M R C) D y s p nea Scale

C O P D Assess me nt Test ( C A T)

St. Ge or ge Res pirat or y  Q uesti o n naire C ( S G R Q-C)

B DI/ T DI

e Diar y
6. 6. 1   
S pir o m etr y
Please refer t o t he latest versi o n of t he S pir o metr y  Gui da nce, i n A p pe n di x 2 a n d Ta ble 6- 2 f or 
f ull details o n sc he d uli n g a n d perf or mi n g s pir o metr y.
6. 6. 2   
C O P D e x a c er b ati o n s
C O P D e xacer bati o n is defi ne d as:
A w orse ni n g of t he f oll o wi n g t w o or m ore maj or s y m pt o ms f or at least 2 c o nsec uti ve da y s:

d y s p nea

s p ut u m v ol u me

s p ut u m p ur ule nce
O R
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
A w orse ni n g of a n y of t he a b o ve s ym pt o m s t o get her wit h a n i ncrease i n a n y one of t he 
f oll o wi n g mi n or sy m pt o ms f or at least 2 c o nsec uti ve da y s:

s ore t hr oat

c ol ds ( nasal disc har ge a n d/ or nasal c o n gesti o n)

fe ver wit h o ut ot her ca use

c o u g h

w heeze
All C O P D e xacer bati o ns s h o ul d be rec o r de d o n t he C O P D e xacer bati o n e C R F pa ge o nl y.
F or t he p ur p oses of t his st u d y, t he t ype of treat me nt pr o vi de d f or a C O P D e xacer bati o n will 
deter mi ne t he se verity of t he e xacer bati o n a n d h o w t hat se verit y sh o ul d be rec or de d o n t he 
C O P D e xacer bati o n e C R F pa ge :

A w orse ni n g of s ym pt o ms t hat meets t he a b o ve s y m pt o m defi niti o n t hat is n ot treate d wit h 
s yste mic c ortic oster oi ds a n d/ or a nti bi otics will be c o nsi dere d a mil d C O P D e xacer bati o n

A C O P D e xacer bati o n is c o nsi dere d of m o der ate se verity if treat me nt wit h s yste mic 
c ortic osteroi ds or a nti bi otics or b ot h was re q uire d

A se vere C O P D e xacer bati o n re q uires h os pitalizati o n i n a d diti o n t o treat me nt wit h 
s yste mic c ortic oster oi ds a n d/ or a nti bi otics. A n e mer ge nc y r o o m ( E R) visit of l o n ger t ha n 
2 4 h o urs will be c o nsi dere d a h os pitalizati o n. A C O P D e xacer bati o n t hat re q uire d a n 
e mer ge nc y r o o m visit f or less t ha n 2 4 h o urs will be c o nsi dere d t o be of m o derate se verit y, 
pr o vi di n g t he e xacer bati o n was treate d wit h s y ste mic c ortic oster oi ds or a nti bi otics or b ot h
T he criteria f or a pr ot oc ol defi n e d e xacer bati o n are base d o n a w orse ni n g of s ym pt o ms 
occ urri n g after ra n d o mizati o n as c o m pare d t o t he baseli ne t hres h ol d esta blis he d d uri n g t he 
r u n-i n peri o d. T he baseli ne t hres h ol d is deter mi ne d b y  patie nt rec or di n g of dail y  sy m pt o m 
usi n g a n electr o nic di ar y de vice s u p plie d at t he start of t he st u d y .
I n t he e ve nt of a C O P D e xacer bati o n matc hi n g t he a b o ve defi niti o n occ urri n g at a n y ti me 
after si g ni n g of i nf or me d c o nse nt, patie nts s h o ul d be treate d f or t he e xacer bati o n as dee me d 
necessar y  b y t he i n vesti gat or.
A w orse ni n g of s ym pt o ms t hat eit her d o n ot meet t he a b o ve s ym pt o m defi niti o n b ut is treate d 
b y  the i n vesti gat or wit h s yste mic c ortic oster oi ds or a nti bi otics, or t hat meets t he s ym pt o m 
defi niti o n b ut d oes n ot recei ve a nti bi otics a n d/ or s yste mic c ortic ost er oi ds, is n ot c o nsi dere d a 
m o derate or se vere C O P D e xacer bati o n f or t he st u d y. H o we ver, t hese e ve nts s h o ul d be 
ca pt ure d o n t he C O P D e xacer bati o n e C R F as mil d e xacer bati o ns.
T he start date f or a C O P D e xacer bati o n rec or de d i n t he e C R F s h o ul d be t he first da y of 
s ym pt o m w orse ni n g of t w o or m ore maj or s y m pt o ms or of o ne maj or a n d o ne mi n or s y m pt o m, 
as defi ne d a b o ve. T he e n d of a C O P D e xacer bati o n e pis o de is mar ke d b y  the ret ur n t o pre -
e xacer bati o n s ym pt o m stat us. At t he e n d of a n e xacer bati o n t he patie nt m ust atte n d t he cli nic, 
w here p ossi ble, f or assess me nt of t he e pis o de. Mil d C O P D e xacer bati o ns ca n be f oll o we d- u p 
via a tele p h o ne call wit h t he patie nt.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Patie nts 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 
disc o nti n ue d b ut will be per mitte d t o be re-e nr olle d after a mi ni m u m of 6 wee ks a n d after t he 
res ol uti o n of t he C O P D e xacer bati o n (see e xcl usi o n criteria).
If sys te mic c ortic oster oi ds are ta ke n f or a C O P D e xacer bati o n wit hi n 7 da ys pri or t o a n y st u d y 
visit, t he visit m ust be resc he d ule d t o all o w a was h o ut of 7 d a y s ( Patie nt s h o ul d be 
disc o nti n ue d if treate d wit h De p o -Me dr o ne ® 
as disc usse d i n Secti o n 5. 5. 7 ). 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. 
F oll o wi n g treat me nt f or t he e xacer bati o n, t he patie nt will be e x pecte d t o c o nti n ue i n t he st u dy 
pr o vi de d t he i n vesti gat or c o nsi ders t hat t he patie nt ca n safely ret ur n t o t heir pre -e xacer bati o n 
me dicati o ns.
N o s pir o metr y assess me nts s h o ul d be ta ke n u ntil after t he e xacer bati o n has 
res ol ve d.
6. 6. 3   
R e s c u e m e di c ati o n u s a g e
Use of resc ue me dicati o n ( n u m ber of p uffs ta ke n i n t he pre vi o us 1 2 h o urs) will be rec or de d 
m or ni n g a n d e ve ni n g, b y t he patie nt, i n t he e Diar y. T he n u m ber of p uffs ta ke n i n bet wee n a n d 
d uri n g t he cli nic visit will be ca pt ure d i n t he e Diar y. F or m ore i nf or mati o n please refer t o 
Secti o n 5. 5. 6 .
6. 6. 4   
M o difi e d M e di c al R e s e ar c h C o u n cil ( m M R C) D y s p n e a S c al e
T he m o difie d Me dical Researc h C o u ncil ( m M R C) D y s p nea Scale (Fletc her et.al. 1 9 5 9 ), is a 
fi ve-ite m i nstr u me nt ( part of t he B or g scale) t o assess a patie nt’s de gree of breat hless ness i n 
relati o n t o p h y sical acti vit y (Ma hler a n d Wells 1 9 8 8 ). Partici pa nts will be re q uire d t o rea d a 
brief descri pti o n of a n acti vit y an d t he n select a state me nt t hat best descri bes t heir e x perie nce 
wit h d y s p nea at Visit 1 0 1.
T he m M R C will be use d t o c o m pare t he se verity of d y s p nea t hr o u g h o ut t he st u d y. Please see 
A p pe n di x 8 f or t he scale.
6. 6. 5   
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 patie nts i n t his st u d y (J o nes et 
al 2 0 0 9 ). It is c o m plete d b y  the patie nt at t he be gi n ni n g of t he st u d y visit j ust after t he 
S G R Q -C a n d m M R C b ut bef ore a n y ot her assess me nt t o a v oi d i nfl ue nci n g t he res p o nses.
T he C A T is c o m plete d b y  the patie nt at t he i n vesti gat or's site at Visits as per assess me nt 
Ta ble 6- 1 or at t he ti me of disc o nti n uati o n f or patie nts w h o pre mat urel y wit h dra w fr o m t he 
st u d y.
T he C A T c o nsists of ei g ht ite ms. Eac h ite m is 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, 1 1 - 2 0, 2 1 - 3 0 a n d 3 1 - 4 0 re prese nt a mil d, m o derate, se vere or ver y  se vere 
cli nical i m pact of C O P D u p o n t he patie nt.
A n e xa m ple of t he C O P D Assess me nt Test ( C A T) is pr o vi de d i n A p pe n di x 7 .
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 6. 6   
St . G e or g e R e s pir at or y Q u e sti o n n air e C ( S G R Q-C) 
T he St. Ge or ge Res pirat or y  Questi o n naire C ( S G R Q- C) 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 et al 1 9 9 2 ). T he S G R Q -C (refer t o A p pe n di x 6 ) will 
be self-a d mi nistere d b y  the patie nt at t he i n vesti gat or's site at Visits as per assess me nt 
Ta ble 6- 1 or at t he ti me of disc o nti n uati o n for patie nts w h o pre mat urel y  disc o nti n ue fr o m 
st u d y treat me nt ( T D U nsc he d ule d Visit).
T he S G R Q -C 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 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 nistrative 
pr oce d ures of t he q uesti o n naires are gi ve n i n A p pe n di x 5 .
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 patie nt t hr o u g h o ut t he st u d y. T he 
st u d y pers o n 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 patie nt 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 b e all o we d t o as k q uesti o ns; 
h o we ver site staff s h o ul d ta ke care n ot t o i nfl ue nce t he patie nt’s res p o nses. T he patie nt 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. Patie nts s h o ul d date b ut n ot i nitial 
t he q uesti o n naire. T he q uesti o n n aire will be c hec ke d f or c o m plete ness a n d c ollecte d bef ore 
t he patie nt lea ves t he site.
Missi n g data s h o ul d be a v oi de d; t heref ore t he st u d y co or di nat or will c hec k t he q uesti o n naires 
f or c o m plete ness bef ore t he patie nt lea ves t he site, a n d if necessar y , e nco ura ge t he patie nt t o 
c o m plete a n y missi n g res p o nses. At later visits patie nts are n ot all o we d t o re vie w t heir 
pre vi o us res p o nses. T he ori gi nal q uesti o n naire will be ke pt wit h t he patie nt's file as t he s o urce 
d oc u me nt.
I nstr u me nt sc ori n g a n d ha n dli n g of mi ssi 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 -C (A p pe n di x 5 ). Res p o nses will be c ollecte d o n di gital pa per t o 
all o w t he use of a di gital pe n ( O nl y the ori gi nal di gital pa per pr o vi de d ca n be use d f or t he 
di gital pe ns (i.e., t hese pa ges m ust n ot be p h ot oc o pie d). T he c ollecti o n of t his data will be 
ce ntralize d a n d a d diti o nal i nf or mati o n will be s u p plie d.
T he S G R Q -C c o ntai ns 4 0 ite ms di vi 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 " Sy m pt o ms" a n d is c o ncer ne d wit h res pirat or y  sy m pt o ms, t heir fre q ue nc y  
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 b y 
breat hless ness;

Part II is als o c o nc er 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 yc h ol o gical dist ur ba nces res ulti n g fr o m air wa y s 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.
C o m plete d q uesti o n naires will be re vie we d a n d e xa mi ne d b y  the i n vesti gat or, bef ore t he 
cli nical e xa mi nati o n, f or res p o nses w hic h 
ma 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 nl y t he res p o nses t o t he q uesti o ns i n t he q uesti o n naire b ut als o 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
f or a n y u ns olicite d c o m me nts writte n b y  the patie nt. I nvesti gat ors s h o ul d n ot e nc o ura ge t he 
patie nts t o c ha n ge t he res p o nses re p orte d i n t he q uesti o n naire.
If A Es or S A Es are c o nfir me d t he n t he p h y sicia n m ust rec or d t he e ve nts as per i nstr ucti o ns 
gi ve n i n Secti o n 7. 1 a n d Secti o n 7. 2 of t he pr ot oc ol.
6. 6. 7   
B DI/ T DI
Patie nts m ust be i nter vie we d b y  a trai ne d assess or w h o will gra de t he de gree of i m pair me nt 
d ue t o d y s p nea at Visit 1 0 2 ( Baseli ne D y s p nea I nde x, B DI).  The Tra nsiti o nal D y s p nea I n de x 
( T DI) will 
be assesse d at Visits 
as per Assess me nt 
Ta ble 6- 1
a n d at t he ti me of 
disc o nti n uati o n f or patie nts w h o 
pre mat urel y disc o nti n ue fr o m st u d y treat ment
( T D
U nsc he d ule d Visit). T hese assess me nts m ust be u n derta ke n after c o m pleti n g t he S G R Q a n d 
pri or t o t he s pir o metr y  a n d st u d y treat me nt a d mi nistrati o n.
Prefera bl y , t he sa me assess or s h o ul d c o m plete all t he B DI / T DI assess me nts f or a n i n di vi d ual 
patie nt a n d t he y  s h o ul d be bli n de d t o ot her st u d y assess me nts f or t his patie nt.
Details of t he B DI a n d T DI ( Ma hler a n d Wells 1 9 8 8 ) are pr o vi de d i n A p pe n di x 9 .
6. 6. 8   
e Di ar y
At Visit 1 0 1 all eli gi ble patie nts wil l be pr o vi de d wit h a patie nt electr o nic diar y (referre d t o as 
a n e Diar y). T he patie nts will be i nstr ucte d t o r o uti nel y co m plete t he patie nt D iar y twice dail y 
at t he sa me ti me m or ni n g a n d e ve ni n g (a p pr o xi matel y 1 2 h o urs later) .
T he e Diar y will facilitate t he i de ntificati o n of s ym pt o ms t hat meet t he defi niti o n of a C O P D 
e xacer bati o n, as descri be d i n Secti o n 6. 6. 2 , s o it’s ver y  im p orta nt t hat it’s c o m plete d t wice 
dail y .
E ac h m or ni n g a n d e ve ni n g , bef ore ta ki n g st u d y treat me nt , t he patie nt rec or ds

Dail y  cli nical s ym pt o ms: c o u g h, w heezi n g, s h ort ness of breat h, s p ut u m v ol u me a n d 
s p ut u m c ol or, ni g ht ti me a wa ke ni n g, fe ver, s ore t hr oat a n d c ol d

N u m ber of p uffs of resc ue me dicati o n ( n u m ber of p uffs ta ke n i n t he pre vi o us 1 2 h o urs, 
see Secti o n 5. 5. 6 )
M or ni n g a n d e ve ni n g ti me of d ose f or st u d y me dicati o n ta ke n i n bet wee n cli nic visits ( Ti me 
of d ose at t he cli nic will n ot be ca pt ure d i n t he diar y  as t his is rec or de d o n t he e C R F.
Details of t he i nf or mati o n t o be c ollecte d i n t he Patie nt e Diar y  are pr o vi de d i n A p pe n di x 3 .
Sites a n d patie nts 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 electr o nic 
dia r y de vice.
At eac h visit fr o m Visit 1 0 2 o n war ds, site pers o n nel m ust re vie w t he patie nt diar y  data wit h 
t he patie nt.
Please see Secti o n 6. 6. 2 f or t he C O P D e xacer bati o n defi niti o n.
6. 6. 9   
A p pr o pri at e n e s s of eff i c a c y a s s e s s m e nt s
T he efficac y assess me nts ( C O P D e xacer bati o ns, F E V 1, F V C, resc ue me dicati o n usa ge, healt h 
relate d q ualit y of life as assesse d b y  S G R Q-C, patie nt s y m pt o ms as assesse d b y  m M R C , C A T 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
a n d B DI/ T DI,) pla n ne d f or t his st u d y are t he sta n dar d efficac y assess me nts i n C O P D cli nical 
trials.
6. 7   
S af et y

A d verse e ve nts

P h y sical e xa mi nati o n

Uri ne pre g na nc y  test (fe males of c hil d beari n g p ote ntial)

E C G

Vital si g ns

P ne u m o nia

2 4 hr uri nar y  c ortis ol (i n a s u b-set of patie nts)

Or o p har y n geal sa m ple c ult ure f or ca n di diasis .

La b orat or y : sta n dar d bi oc he mistr y, he mat ol o g y  a n d uri nal y sis
6. 7. 1   
P h y si c al e x a mi n ati o n 
A c o m plete p h y sical e xa mi nati o n will be perf or me d as per Assess me nt Ta ble 6- 1 or at st u d y 
treat me nt disc o nti n uati o n visit ( T D). It will i ncl u de t he e xa mi nati o n of ge neral a p peara nce, 
s ki n, nec k (i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, l ym p h 
n o des, e xtre mities, vasc ular, a n d ne ur ol o gical. If i n dicate d base d o n me dical h ist or y an d/ or 
s ym pt o ms, rectal, e xter nal ge nitalia, breast, a n d pel vic e xa ms will be perf or me d.
I nf or mati o n f or all p h ysical e xa mi nati o ns m ust be i ncl u de d i n t he s o urce d oc u me ntati o n at t he 
st u d y site. Si g nifica nt fi n di n gs t hat are prese nt pri or t o t he start of st u d y must be i ncl u de d i n 
t he Rele va nt Me dical Hist or y/ C urre nt Me dical C o n diti o ns scree n o n t he patie nt’s e C R F.
Si g nifica nt fi n di n gs ma de after t he start of st u d y w hic h meet t he defi niti o n of a n A d verse 
E ve nt m ust be rec or de d o n t he A d verse E ve nt scr ee n of t he patie nt’s e C R F.
6. 7. 2    
Vit al si g n s
T y pe Vital si g ns will i ncl u de ra dial p ulse rate ( meas ure d f or 6 0 sec o n ds) a n d s yst olic a n d 
diast olic bl o o d press ure. P ulse rate a n d bl o o d press ure will be assesse d after t he patie nt has 
reste d i n t he sitti n g or s u pi ne p ositi o n f or at least 5 mi n utes. If a n a ut o mate d Bl o o d Press ure 
de vice is use d, it will nee d t o be cali brate d acc or di n g t o t he ma n ufact urer’s g ui deli nes.
T he I nvesti gat or nee ds t o m o nit or t he p ulse rate f or a n y irre g ular beats a n d i n vesti gate f urt her 
usi n g E C G. Vital si g ns will be o btai ne d at t he Visits as per Assess me nt Ta ble 6 - 1.
6. 7. 3   
P n e u m o ni a
P ne u m o nia will be defi ne d as a n e ve nt c haracterize d b y  increase d res pirat or y sy m pt o ms (e. g. 
i ncrease d c o u g h, d y s pnea, w heezi n g, p ur ule nt s p ut u m a n d fe ver) (i.e. b o d y  te m perat ure 
greater t ha n 3 8 ° C) or ple uritic c hest pai n or le u k oc yt osis or ot her cli nical si g ns c o nsiste nt 
wit h p ne u m o nia c o nsi dere d rele va nt i n t he o pi ni o n of t he i n vesti gat or. Ra di o gra p hic i ma gi n g 
(c hest x- ra y or C T sca n), will be re q uire d t o c o nfir m t he dia g n osis. T he dia g n osis of C O P D 
e xacer bati o n will n ot precl u de a dia g n osis of p ne u m o nia. T he i n vesti gat or will use cli nical 
j u d g me nt t o deter mi ne if t he e ve nts are occ urri n g si m ulta ne o usl y.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 7. 4   
H ei g ht a n d w ei g ht
Hei g ht i n ce nti meters (c m) a n d b o d y  wei g ht (t o t he nearest 0. 1 kil o gra m [ k g] i n i n d o or 
cl ot hi n g, b ut wit h o ut s h oes) will be meas ure d at Visit 1 0 1. Wei g ht will be rec or de d a gai n as 
per Assess me nt Ta ble 6 - 1 or at ti me of st u d y treat me nt disc o nti n uati o n.
6. 7. 5   
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. Details 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  the 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. 
Please refer t o Ta ble 6- 1 , f or assess me nt sc he d ule of la b orat or y eval uati o ns a n d Ta ble 6 - 2 f or 
ti mi n g of t h ose assess me nts. All patie nts wit h la b orat or y  tests c o ntai ni n g cli nicall y si gnifica nt 
a b n or malities s h o ul d be f oll o we d re g ularly 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 A p pe n di x 1 .
6. 7. 5. 1 
H e m at ol o g y
He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt wit h differe ntial, a n d 
platelet c o u nt will be meas ure d per Assess me nt Ta ble 6 - 1 a n d Ti me d assess me nts Ta ble 6 -2 .
6. 7. 5. 2 
Cli ni c al c h e mi str y
Al b u mi n, ala ni ne tra nsa mi nase ( A L T), as partate tra nsa mi nase ( A S T), al kali ne p h os p hate, 
t otal bilir u bi n, bl o o d urea nitr o ge n ( B U N), C -reacti ve pr otei n ( C R P), t otal c h olester ol, L D L-C, 
H D L -C, lactate de h y dr o ge nase ( L D H), calci u m, fi bri n o ge n, ma g nesi u m, p h os p hat e, s o di u m, 
p otassi u m, creati ni ne, γ-G T, bl o o d gl uc ose, H b A 1 C , t otal pr otei n will be meas ure d per 
Assess me nt Ta ble 6 - 1 a n d Ti me d assess me nts Ta ble 6 - 2. If t he t otal bilir u bi n c o nce ntrati o n is 
i ncrease d a b o ve 1. 5 ti mes t he u p per li mit of n or mal ra n ge, t otal bilir u bi n s h o ul d be 
differe ntiate d i nt o t he direct a n d i n direct reacti n g bilir u bi n.
6. 7. 5. 3 
Uri n al y si s
Uri ne sa m ples will be ta ke n as per Assess me nt Sc he d ule Ta ble 6- 1 . Testi n g will i ncl u de: 
s pecific gra vit y, p H, pr otei n a n d bl o o d ( via uri ne di pstic k test). A n y  a b n or malities will re q uire 
f urt her a nal ysis b y  the ce ntral la b, w hic h will i ncl u de micr osc o pic e xa mi nati o n i ncl u di n g, 
le u k oc ytes, he m o gl o bi n ( W B C/ H P F, R B C/ H P F,), a n d casts/ H P F. If casts are n ote d, t he t ype 
is t o be s pecifie d. All patie nts wit h la b orat or y tests c o ntai ni n g cli nicall y si g nifica nt a b n ormal 
val ues will be f oll o we d re g ularly u ntil t he val ues ret ur n t o 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 ve nt, is i de ntifie d. 2 4 hr Uri ne c ortis ol will be 
meas ure d i n a s u b -set of a p pr o xi matel y 3 8 0 patie nts. T hese p atie nts will be ra n d o ml y selecte d 
i n a rati o of 1: 1. T he uri ne creati ni ne w o ul d als o be meas ure d t o calc ulate c ortis ol/creati ni ne 
rati o. T he Ce ntral La b orat or y will s u p pl y pr oce d ures f or t he pre parati o n a n d c ollecti o n of 
t hese sa m ples.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 7. 5. 4 
Or o p h ar y n g e al s a m pl e c ult ur e f or c a n di di a si s
Or o p har y n geal s wa b sa m ple c ult ure f or ca n di diasis will be perf or me d per Assess me nt 
Sc he d ule Ta ble 6 - 1. Refer t o Ce ntral La b orat or y  ma n ual f or f urt her details.
6. 7. 6   
El e ctr o c ar di o gr a m ( E C G) 
E C Gs m ust be rec or de d after 1 0 mi n utes rest i n t he s u pi ne p ositi o n t o e ns ure a sta ble baseli ne. 
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, bl o o d sa m pli n g , uri nala n y sis, s pir o metr y an d s ym pt o m 
assess me nts. T he Fri dericia Q T c orrecti o n f or m ula ( Q Tc F) s h o ul d be use d f or cli nical 
decisi o ns.
Cli nicall y  si g nifica nt a b n or malities s h o ul d be rec or de d o n t he rele va nt secti o n of t he me dical 
hist or y / C urre nt me dical c o n diti o ns/ A E C R F / e( C R F) pa ge as a p pr o priate.
E C Gs s h o ul d be free of baseli ne wa n der a n d n oise. Pri or t o a n E C G bei n g perf or me d, t he
E C G o perat or s h o ul d c hec k t he traci n g t o e ns ure t hat it is of hi g h q ualit y .
C e ntr ali z e d E C G E q ui p m e nt
At Visit 1 0 1 a r u n-i n baseli ne E C G will be meas ure d t o test f or eli gi bilit y for trial i ncl usi o n. 
Patie nts w h ose E C G is a b n or mal at r u n-i n baseli ne d ue t o tec h nical/ mec ha nical fa ults ma y  be 
rescree ne d.
Patie nts wit h persiste nt atrial fi brillati o n as defi ne d b y  co nti n u o us atrial fi brillati o n f or at least 
6 m o nt hs a n d c o ntr olle d wit h a rate c o ntr ol strate g y for at least 6 m o nt hs ma y  be c o nsi dere d 
f or i ncl usi o n. I n suc h patie nts, atrial fi brillati o n m ust be prese nt at Visit 1 0 1 (c o nfir me d b y  
ce ntral rea der) a n d Visit 1 0 2 (c o nfir me d b y  local rea der) wit h a resti n g ve ntric ular rate < 
1 0 0/ mi n (if t he i nter pretati o n of atrial fi brillati o n is n ot c o nfir me d b y  ce ntral rea der at Visit 
1 0 2 t he site m ust i nf or m N o vartis). E C Gs will be perf or me d pre a n d p ost d ose per Assess me nt 
Sc he d ule Ta ble 6- 1 a n d Ti me d assess me nts Ta ble 6- 2 . All electr ocar di o gra ms s h o ul d i ncl u de 
1 2 sta n dar d lea ds. A n E C G traci n g will als o be ta ke n f or t h ose patie nts w h o pre mat ur el y 
disc o nti n ue fr o m t he st u d y.
F or eac h E C G perf or me d ori gi nal traces a n d i de ntical d u plicate pri nt -o uts will be pr o d uce d. 
T he ori gi nal trace will be se nt electr o nicall y f or 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 rea der i n case of 
pr o ble ms wit h t he electr o nic tra ns missi o n. T he ‘i de ntical’ d u plicates ke pt at t he i n vesti gat or 
site will be date d a n d si g ne d. T he patie nt'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  C o de m ust a p pear o n eac h pa ge of t he traci n g.
E C Gs m ust be perf or me d o nl y  after patie nts ha ve bee n resti n g i n t he s u pi ne p ositi o n f or at 
least 5 mi n utes. W he n t he E C G rec or di ng ti me c oi nci des wit h vital si g ns, s pir o metr y, a n d 
bl o o d dra ws, t he E C G m ust be perf or me d first, f oll o we d b y  vital si g ns a n d t he bl o o d dra ws 
b ut wit h e n o u g h ti me pla n ne d t o e ns ure t he s pir o metr y is perf or me d at t he pla n ne d ti me p oi nt 
o utli ne d i n Ta ble 6- 2 . S pir o metr y  must be perf or me d as cl ose t o t he sc he d ule d ti me p oi nt as 
p ossi ble.
F ull details of all pr oce d ures relati n g t o t he E C G c ollecti o n a n d re p orti n g will be c o ntai ne d i n 
a n i n vesti gat or ma n ual t o be pr o vi de d t o eac h i n vesti gat or site.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
I n t he e ve nt t hat t he ce ntral car di ol o gist re p orts t hat a n E C G is a b n or mal, t he n t he i n vesti gat or 
m ust c o m me nt as t o w het her t he E C G a b n or malit y is eit her cli nicall y si gnifica nt or cli nicall y 
i nsi g nifica nt. A cli nicall y si gnifica nt a b n or malit y s h o ul d be re p orte d as a n A E. If necessar y  a 
car di ol o gist ma y be c o ns ulte d.
E C Gs s h o ul d be free of baseli ne wa n der a n d n oise. Pri or t o a n E C G bei n g perf or me d, t he 
E C G o perat or s h o ul d c hec k t he traci n g t o e ns ure t hat it is of hi g h q ualit y .
6. 7. 7   
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 
A uri ne pre g na nc y  test will be perf or me d i n pre -me n o pa usal w o me n w h o are n ot s ur gically 
sterile (tests pr o vi de d b y  the Ce ntral La b orat or y) per Assess me nt Ta ble 6- 1 . A p ositi ve 
pre g na nc y  test at Visit 1 0 1 or at a n y ti me d uri n g t he st u d y re q uires t he patie nt t o be 
disc o nti n ue d fr o m t he st u d y  treat me nt. Refer t o Secti o n 5. 5. 9 a n d Secti o n 7. 4 f or m ore details.
6. 7. 8   
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/ patie nt p o p ulati o n.
6. 8   
Ot h er a s s e s s m e nt s
6. 8. 1     
R e s o ur c e utili z ati o n
At 
Visit 
1 0 1 healt h care res o urce
utilizati o n 
i ncl u di n g n u m ber of C O P D -relate d 
h os pitalizati o ns, e mer ge nc y r o o m ( E R) a n d o ut patie nt visits i n t he pre vi o us ye ar will be 
rec or de d as c o m pletel y as p ossi ble.
At eac h s u bse q ue nt sc he d ule d visit t he le vel of C O P D -relate d healt h care res o urce uti lizati o n 
i ncl u di n g n u m ber a n d le n gt h of h os pitalizati o n, n u m bers of E R a n d u nsc he d ule d d oct or’s 
office visits si nce t he pre vi o us sc he d ule d visit will be rec or de d. T he fre q ue nc y  a n d d urati o n of 
a n y in patie nt h os pitalizati o n will 
be rec or de d al o n g wit h 
t he p ri mar y reas o n f or t he 
h os pitalizati o n.
F or eac h h os pitalizati o n t he d urati o n s pe nt i n eac h of t he f oll o wi n g will be rec or de d: i nte nsi ve 
care u nit (IC U), ge neral war d, E mer ge nc y  R o o m ( E R), ot her.
H os pitalizati o ns will be defi ne d as a n y visit t o t he h os pital re q uiri n g a n o ver ni g ht sta y. T he 
fre q ue nc y of o ut patie nt visits will be rec or de d al o n g wit h t he ty pe of p h ys icia n t he patie nt sa w 
a n d t he t ype of visit. A n u nsc he d ule d d oct or’s office visit will be defi ne d as a n y resc he d ule d 
visit t o a me dical practiti o ner n ot re q uiri n g a n o ver ni g ht sta y. I n a d diti o n a n y pr oce d ures 
c o n d ucte d d uri n g t he h os pitalizati o n or u nsc he d ule d d oct or’s office visit will be rec or de d i n 
t he e C R F. If a d verse e ve nts or S A Es are c o nfir me d t he n t he p h y sicia n m ust rec or d t he e ve nts 
as per i nstr ucti o ns gi ve n i n Secti o n 7 of t he pr ot oc ol.
6. 8. 2   
H e alt h -r el at e d Q u alit y of Lif e
See secti o n 6. 6.
6. 8. 3   
P h ar m a c o ki n eti c s
N ot a p plica ble
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
6. 8. 4   
P h ar m a c o g e n eti c s
N ot a p plica ble
6. 8. 5   
B i o m ar k er s
Se veral bi o mar kers ha ve bee n i de ntifie d i n t he literat ure (A g usti a n d Si n 2 0 1 4 ) as bei n g 
i m p orta nt i n C O P D t o pre dict eit her ris k of C O P D e xacer bati o ns, disease pr o gressi o n or deat h.  
I n t his pr ot oc ol ser u m W B C c o u nt, ser u m C R P, a n d fi bri n o ge n will be meas ure d as part of t he 
sta n dar d la b orat or y meas ure me nts per Assess me nt Ta ble 6. 1.   
7   
S af et y  m o nit ori n g
7. 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 unt o war d me dical occ urre nce (i.e., 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 patie nt or 
cli nical i n vesti gati o n patie nt after pr ovi 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 n ot be te m p orall y or ca usally 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 occ urre nce of a d verse e ve nts s h o ul d be s o u g ht b y  n o n-directi ve q ue sti o ni n g of t he patie nt 
at eac h visit d uri n g t he st u d y . A d verse e ve nts als o ma y be detecte d w he n t he y are v ol u nteere d 
b y  the patie nt 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, la b orat or y test, or 
ot her assess me nts.
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y  if the 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 s h o ul d 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 w hic h are c o nsi dere d t o be n o n- t ypical i n patie nt wit h 
u n derl y i n g diseas e. I n vesti gat ors ha ve t he res p o nsi bilit y for ma na gi n g t he safety of i n di vi d ual 
patie nt a n d i de ntif yi n g a d verse e ve nts. Alert ra n ges f or la bs a n d ot her test a b n or malities are 
i ncl u de d i n A p pe n di x 1 .
All pr ot oc ol defi ne d C O P D e xacer bati o ns (as defi ne d i n secti o n 6. 6. 2 ) s h o ul d be rec or de d o n 
t he C O P D e xacer bati o n e C R F pa ge o nl y . All ot her C O P D e xacer bati o ns t hat d o n ot meet t he 
defi niti o n i n secti o n 6. 6. 2 are t o be rec or de d i n t he A E eC R F pa ge o nl y.
A d verse e ve nts s h o ul d be rec or de d i n t he A d verse E ve nts C R F 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  t he f oll o wi n g i nf or mati o n.

t he se verity gra de

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

m o derate: s ufficie ntl y  disc o mf orti n g t o i nterfere wit h n or mal acti vities

se vere: pre ve nts n or mal acti vities
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6

its relati o ns hi p t o t he st u d y treat me nt ( n o/yes), or i n disti n g uis ha ble

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 s h o ul d be re p orte d.

w het her it c o nstit utes a seri o us a d verse e ve nt ( S A E - See S ecti o n 7. 2 f or defi niti o n of S A E)

acti o n ta ke n re gar di n g st u d y treat me nt
All a d verse e ve nts s h o ul d be treate d a p pr o priatel y. Treat me nt ma y  incl u de o ne or m ore of t he 
f oll o wi n g:

n o acti o n ta ke n (i.e. f urt her o bser vati o n o nl y )

stu d y treat me nt d osa ge a dj uste d/te m p oraril y  i nterr u pte d

st u d y treat me nt per ma ne ntl y  disc o nti n ue d d ue t o t his a d verse e ve nt

c o nc o mita nt me dicati o n gi ve n

n o n- dr u g t hera p y gi ve n

patie nt h os pitalize d/ patie nt’s h os pitalizati o n pr ol o n ge d

its o utc o me ( n ot rec o vered/ n ot res ol ve d; rec o vere d/res ol ve d; rec o veri n g/res ol vi n g, 
rec o vere d/res ol ve d wit h se q uelae; fatal; or u n k n o w n)
O nce a n a d verse e ve nt is detecte d, it s h o ul d 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, a n d assess me nt s h o ul d be ma d e 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 verity, t he s us pecte d relati o ns hi p t o t he st u d y treat me nt, 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 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 vestigati o nal dr u g ca n be 
f o u n d i n t he I nvesti gat or Br oc h ure (IB) or will be c o m m u nicate d bet wee n I B u p dates i n t he 
f or m of I n vesti gat or N otificati o ns. T his i nf or mati o n will be i ncl u de d i n t he patie nt i nf or me d 
c o nse nt a n d s h o ul d be disc usse d wit h t he patie nt d u ri n g t he st u dy as nee de d.
T he i n vesti gat or s h o ul d als o i nstr uct eac h patie nt t o re p ort a n y ne w a d verse e ve nt ( be yo n d t he 
pr ot oc ol o bser vati o n peri o d) t hat t he patie nt, or t he patie nt’s pers o nal p h y sicia n, belie ves 
mi g ht reas o na bly be relate d t o st u d y treatme nt. T his i nf or mati o n s h o ul d be rec or de d i n t he 
i n vesti gat or’s s o urce d oc u me nts h o we ver, if t he A E meets t he criteria of a n S A E, it m ust be 
re p orte d t o N o vartis.
7. 2   
S eri o u s a d v er s e e v e nt s
7. 2. 1   
D efi niti o n of S A E
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 one of t he 
f oll o wi n g criteria:

is fatal or life-t hreate ni n g 

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 n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is f or:
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6

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 (s pecif y  w hat t his i ncl u des)

electi ve or pre-pla n ne d treat me nt f or a pre -e xisti n g 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

treat me nt o n a n e mer ge nc y o ut patie nt basis f or a n e ve nt n ot f ulfilli n g a n y 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 

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 patie nt’s 
ge neral c o n diti o n

is me dicall y si g nifica nt, i.e. defi ne d as a n e ve nt t hat je o par dizes t he patie nt or ma y re q uire 
me dical or s ur gical i nter ve nti o n.
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.
Life -t hreate ni n g i n t he c o nte xt of a S A E refers t o a n e ve nt i n w hic h t he patie nt was at ris k of 
deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y  mi ght ha ve 
ca use d deat h if m ore se vere.
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 e ve nts, 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 
patie nt 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 utc o mes liste d a b o ve. 
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.
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 e ve nt.
All A Es (seri o us a n d n o n- seri o us) are ca pt ure d o n t he C R F. S A Es als o re q uire i n di vi d ual 
re p orti n g t o D S & E as per secti o n 7. 2. 2.
7. 2. 2   
S A E r e p orti n g
T o e ns ure patie nt safety,  ever y  SA E, re gar dless of ca usalit y, occ urri n g after t he patie nt 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 wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. A n y S A Es e x perie nce d after t he 3 0 
da y s peri o d s h o ul d o nl y  be 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.
Rec urre nt e pis o des, c o m plicati o ns, or pr o gressi o n of t he i nitial S A E m ust be re p orte d as 
f oll o w- u p t o t he or i gi nal e pis o de, re gar dless of w he n t he e ve nt occ urs. T his re p ort m ust be 
s u b mitte d wit hi n 2 4 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 
t hat is 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 s h o ul d be re p orte d 
se paratel y as a ne w e ve nt.
I nf or mati o n a b o ut all S A Es (eit her i niti al or f oll o w u p i nf or m ati o n) is c ollecte d a n d rec or de d 
o n t he pa per Seri o us A d verse 
E ve nt Re p ort F or m. T he i n vesti gat or m ust 
assess t he 
relati o ns hi p t o e ac h s pecific c o m p o ne nt of st u dy tre at me nt (if st u dy tre at me nt c o nsists of 
sever al dr u gs) c o m plete t he S A E Re p ort F or m i n E n glis h, a n d se n d t he c o m plete d, si g ne d 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
f or m b y  fa x wit hi n 2 4 h o urs after a ware ness of t he S A E t o t he l ocal N o vartis Dr u g Safet y an d 
E pi de mi ol o g y  De part me nt. T he tele p h o ne a n d fa x n u m ber of t he c o ntact pers o ns i n t he l ocal 
de part me nt of Dr u g Safet y  a n d E pi de mi ol o g y, s pecific t o t he site, are liste d i n t he i n vesti gat or 
f ol der pr o vi de d t o eac h site. T he ori gi nal c o p y of t he S A E Re p ort F or m a n d t he fa x 
c o nfir mati o n s heet m ust be ke pt wit h t he case re p ort f or m d oc u me ntati o n at t he st u d y site.
F oll o w - u p i nf or mati o n s h o ul d be pr o vi de d usi n g a ne w pa per S A E Re p ort F or m stati n g t hat 
t his is a f oll o w-u p t o a pre vi o usl y  re p orte d S A E
F oll o w - u p i nf or mati o n pr o vi de d s h o ul d descri be w het her t he e ve nt has res ol ve d or c o nti n ues, 
if a n d h o w it was treate d, w het her t he treat me nt c o de was br o ke n or n ot a n d w het her t he 
patie nt c o nti n ue d or wit h dre w fr o m st u d y partici pati o n. Eac h re-occ urre nce, c o m plicati o n, or 
pr o gressi o n of t he ori gi nal e ve nt s h o uld be re p orte d as a f oll o w- u p t o t hat e ve nt re gar dless of 
w he n it occ urs.
If t he S A E is n ot pre vi o usl y  doc 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 i n vesti gati o nal treat me nt a Dr u g Safet y 
a n d E pi de mi ol o g y  De part me nt ass ociate ma y  ur ge ntly re q 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
i n vesti gati o nal treat me nt t hat t his S A E has bee n re p orte d. S us 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.
7. 3   
P n e u m o ni a
P ne u m o nia will be defi ne d as a n e ve nt c haracterize d b y  increase d res pirat or y sy m pt o ms (e. g. 
i ncrease d c o u g h, d y s p nea, w heezi n g, p ur ule nt s p ut u m a n d fe ver) (i.e. b o d y  te m perat ure 
g reater t ha n 3 8 ° C) or ple uritic c hest pai n or le u k oc yt osis or ot her cli nical si g ns c o nsiste nt 
wit h p ne u m o nia c o nsi dere d rele va nt i n t he o pi ni o n of t he i n vesti gat or. Ra di o gra p hic i ma gi n g 
(c hest x- ra y or C T sca n), will be re q uire d t o c o nfir m t he dia g n osis. T he dia g n osis of C O P D 
e xacer bati o n will n ot precl u de a dia g n osis of p ne u m o nia. T he i n vesti gat or will use cli nical 
j u d g me nt t o deter mi ne if t he e ve nts are occ urri n g si m ulta ne o usl y.
7. 4   
Li v er s af et y  m o nit ori n g
T o e ns ure patie nt safety a n d e n ha nce relia bilit y in 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 u d y:

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 m pleti o n 
of t he sta n dar d base li ver C R F p a ges
Please refer t o Ta ble 1 3- 1 i n A p pe n di x 1 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.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
E ver y  li ver la b orat or y tri g ger or li ver e ve nt as defi ne d i n Ta ble 1 3- 1 of A p pe n di x 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 nal at t he trial site as s u m marize d bel o w. 
Detaile d i nf or mati o n is o utli ne d i n Ta ble 1 3 - 2 i n A p pe n di x 1 .
F or t he li ver la b orat or y  tri g ger:

Re peati n g t he L F T wit hi n t he ne xt wee k t o c o nfir m ele vati o n.
T hese L F T re peats s h o ul d be perf or me d usi n g t he ce ntral la b orat or y if p ossi ble. If this is n ot 
p ossi ble, t he n t he re peats ca n 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 
patie nt. Re peats la b orat or y s h o ul d t he n be perf or me d at ce ntral la b orat or y as s o o n as p ossi ble. 
If a li ver e ve nt is s u bse q ue ntl y re p orte d, a n y l ocal L F Ts 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 be re p orte d o n t he Li ver C R F pa ges.

If t he ele vati o n is c o nfir me d, cl ose o bser vati o n of t he patie nt 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.
F or t he li ver e ve nts:

Re peati n g t he L F T t o c o nfir m ele vati o n as a p pr o priate

Disc o nti n uati o n of t he i n vesti gati o nal dr u g if a p pr o priate

H os pitalizati o n of t he patie nt if a p pr o priate

A ca usalit y assess me nt of t he li ver e ve nt via e xcl usi o n of alter nati ve ca uses (e. g., disease, 
c o-me dicati o n s)

A n i n vesti gati o n of t he li ver e ve nt w hic h nee ds t o be f oll o we d u ntil res ol uti o n
T hese i n vesti gati o ns 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, base d o n i n vesti gat or’s discreti o n. 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 s h o ul d be rec or de d o n a p pr o priate C R F pa ges, i ncl u di n g t he li ver 
e ve nt o ver vie w C R F pa ges.
7. 5   
R e n al s af et y  m o nit ori n g
T o e ns ure patie nt safet y  an d e n ha nce relia bilit y i n deter mi ni n g t he ne p hr 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 
re nal 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 re nal 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 u d y :
1.
Ser u m e ve nt:

c o nfir me d (after ≥ 2 4 h) i ncrease i n ser u m creati ni ne of ≥ 2 5 % c o m pare d t o baseli ne 
d uri n g n or mal h y drati o n stat us
2.
Uri ne e ve nt  Ne w o nset ( ≥1 +) pr otei n uria, he mat uria or gl uc os uria; or

D o u bli n g i n t he uri nar y  al b u mi n-creati ni ne rati o ( A C R) or uri nar y pr otei n-creati ni ne 
rati o ( P C R) (if a p plica ble).
E ver y  re nal la b orat or y tri g ger or re nal e ve nt as defi ne d i n Ta ble 7- 1 s h o ul d be f oll o we d u p b y 
t he i n vesti gat or or desi g nate d pers o n nel at t he trial site as s u m marize d bel o w.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T a bl e 7- 1   
S p e cifi c R e n al A l ert Crit eri a a n d Acti o n s
S er u m E v e nt
S er u m cr e ati ni n e i n cr e a s e
2 5 – 4 9 % c o m p ar e d t o b a s eli n e
C o nfir m 2 5 % i n cr e a s e aft er 2 4 -4 8 h 
F oll o w u p wit hi n 2 - 5 d a y s
A c ut e Ki d n e y I nj ur y: S er u m cr e ati ni n e 
i n cr e a s e 5 0 % c o m p ar e d t o b a s eli n e
F oll o w u p 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 
C o n si d er p ati e nt h o s pit ali z ati o n / s p e ci ali z e d 
tr e at m e nt
Uri n e E v e nt
N e w di p sti c k pr ot ei n uri a ≥ 1 +
Al b u mi n - or Pr ot ei n -cr e ati ni n e r ati o 
i n cr e a s e ≥ 2 -f ol d
Al b u mi n -cr e ati ni n e r ati o ( A C R) ≥ 3 0 m g/ g or 
≥ 3 m g/ m m ol;
Pr ot ei n -cr e ati ni n e r ati o ( P C R ) ≥ 1 5 0 m g/ g 
or > 1 5 m g/ m m ol
C o nfir m v al u e aft er 2 4 -4 8 h
P erf or m uri n e mi cr o s c o p y
C o n si d er dr u g i nt err u pti o n / di s c o nti n u ati o n
N e w di p sti c k gl u c o s uri a ≥ 1 + n ot d u e t o 
di a b et e s
Bl o o d gl u c o s e (f a sti n g)
P erf or m s er u m cr e ati ni n e, A C R 
N e w di p sti c k h e m at uri a ≥ 1 + n ot d u e t o 
tr a u m a
Uri n e s e di m e nt mi cr o s c o p y
P erf or m s er u m cr e ati ni n e, A C R
F or all r e n al e v e nt s:
D o c u m e nt c o ntri b uti n g f a ct or s i n t h e C R F: c o-m e di c ati o n, 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 p erf or m e d
M o nit or p ati e nt r e g ul arl y (fr e q u e n c y at i n v e sti g at or’ s di s cr eti o n) u ntil eit h er:
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 pr ot ei n-cr e ati ni n e r ati o wit hi n 5 0 % of b a s eli n e, 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
7. 6   
Pr e g n a n c y  r e p orti n g
T o e ns ure patie nt safety, eac h pre g na nc y  occ urri n g w hile t he patie nt or male part ner is o n 
st u d y treat me 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 be f oll o we d u p t o deter mi ne o utc o me, incl u di n g s p o nta ne o us or 
v ol u ntar y  ter 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 birt 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  s h o ul d be rec or de d o n t he P har mac o vi gila nce Pre g na nc y  For m a n d re p orte d b y  t he 
i n vesti gat or t o t he l ocal N o vartis Dr u g Safet y a n d E pi de mi ol o g y  De part me nt. 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 rela ti o ns hi p t o t he st u d y treat me nt.
A n y  SA E e x perie nced d uri n g t he pre g na nc y  an d u nrelate d t o t he pre g na nc y  must be re p orte d 
o n a S A E f or m.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
8   
D at a r e vi e w a n d d at a b a s e m a n a g e m e nt 
8. 1   
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 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 patie nt rec or ds, t he acc urac y of e ntries o n t he (e) C R Fs, 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 dy 
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. Ke y  st u dy 
pers 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.  Co nti n u o us re m ote 
m o nit ori n g of eac h site’s data ma 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 n izati o n ma y  a nal yz e data & i de ntif y ris ks & 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 patie nt 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 C R Fs m ust be tracea ble t o t hese s o urce d oc u me nts i n t he 
patie nt'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 patie nt (a si g ne d c o p y is gi ve n t o t he patie nt).
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 co nsiste nc y  wit h t he C R F e ntries. 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 C R Fs are perf or me d acc or di n g 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 
patie nts will be discl ose d t o t he s p o ns or.
8. 2   
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 O C/ R D C 
s yste m. Desi g nate d i n vesti gat or site staff will n ot be gi ve n access t o t he s yste m u ntil t he y 
ha ve bee n trai ne d.
A ut o matic vali dati o n pr oce d ures wit hi n t he s yste m c hec k f or data discre pa ncies d uri n g a n d 
after data e ntr y an d, b y  ge nerati n g a p pr o priate err or messa ges, all o w t he data t o be c o nfir me d 
or c orrecte d o nli ne b y  the desi g nate d i n vesti gat or site staff. T he I n vesti gat or m ust certif y that 
t he data e ntere d i nt o t he electr o nic Case Re p ort F or ms are c o m plete a n d acc urate. After 
data base l oc k, t he i n vesti gat or will recei ve c o pies of t he patie nt data f or arc hi vi n g at t he 
i n vesti gati o nal site.
8. 3   
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 staff [ a n d/or C R O w orki n g o n be h alf of N ov artis ] re vie w t he data e ntere d i nt o t he 
C R Fs b y  in vesti gati o nal staff f or c o m plete ness a n d acc urac y an d i nstr uct t he site pers o n nel t o 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
ma ke a n y re q uire d c orrecti o ns or a d diti o ns. Q ueries are se nt t o t he i n vesti gati o nal site usi n g 
a n electr o nic data q uer y . Desi g nate d i n vesti gat or site staff is re q uire d t o res p o n d t o t he q uer y 
a n d c o nfir m or c orrect t he data. If t he electr o nic q uer y  s yste m is n ot use d, a pa per Data Q uery 
F or m will be fa xe d t o t he site. Site pers o n nel will c o m plete a n d si g n t he fa xe d c op y  an d fa x it 
bac k t o N o vartis staff t hat will ma ke t he c orrecti o n t o t he data base. T he si g ne d c o p y of t he 
Data Q uer y  F or m is ke pt at t he i n vesti gat or site.
C o nc o mita nt me dicati o ns e ntere d i nt o t he data base will be c o de d usi n g t he W H O 
Dr u g 
Refere nce Li st, 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. 
C o nc o mita nt pr oce d ures, n o n- dr u g t hera pies a n d a d verse e ve nts will be c o de d usi n g t he 
Me dical dicti o nar y  f or re g ulat or y acti vities ( Me d D R A) ter mi n ol o g y.
La b orat or y  sa m ples will be pr o cesse d ce ntrall y a n d t he res ults will be se nt electr o nicall y t o 
N o vartis ( or a desi g nate d C R O).
E C G rea di n gs will be pr ocesse d ce ntrall y an d t he res ults will be se nt electr o nicall y to 
N o vartis ( or a desi g nate d C R O).
Diar y  d ata will be e ntere d i nt o a n electr o nic diar y b y  the patie nt. T he s yste m will be s u p plie d 
b y  a ve n d or(s), w h o will als o ma na ge t he data base. T he data base will be se nt electr o nicall y  t o 
N o vartis ( or a desi g nate d C R O).
S pir o metr y  data will be pr ocesse d ce ntrall y a n d t he res ults will be se nt electr o nicall y to 
N o vartis ( or a desi g nate d C R O).
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 patie nt 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 nd or, w h o will als o ma na ge t he data base. T he data base will be se nt 
electr o nicall y t o N o vartis ( or a desi g nate d C R O).
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 b le u ntil st u d y sh ut d o w n or u p o n re q uest of 
N o vartis.
T he occ urre nce of rele va nt pr ot oc ol de viati o ns will be deter mi ne d. After t hese 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 treatme 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 
c ha 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 .
8. 4   
D at a M o nit ori n g C o m mitt e e
N ot re q uire d.
8. 5   
A d j u di c ati o n C o m mitt e e 
T w o i n de pe n de nt e xter nal a dj u dicati o n c o m mittees will be esta blis he d f or t his st u d y. T he 
c o m mittees will c o nsist of e x perts o utsi de of N o vartis w h o are n ot i n v ol ve d i n t he st u d y 
c o n d uct.
A m ortalit y  adj u dicati o n c o m mittee will assess t he ca use of deat h occ urri n g fr o m first 
treat ment u ntil 3 0 da y s after c o m pleti o n of 2 6 wee k st u d y treat me nt e p oc h. T he C o m mittee 
will c o nsist of e xter nal e x perts ( o utsi de of N o vartis) w h o are n ot i n v ol ve d i n t he st u d y 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
c o n d uct. It will i ncl u de a pa nel of at least 3 e x perts, e. g. a p ul m o n ol o gist, a car diol o gist a n d 
a n o nc ol o gist/i nter nist. C o m mittee me m bers will be bli n de d wit h res pect t o t he patie nt’s st u d y 
me dicati o n. At re g ular i nter vals t he C o m mittee will re vie w narrati ves, disc har ge s u m maries 
a n d me dical rec or ds as a vaila ble t o deter mi ne t he m ost li kel y ca use of deat h, i n partic ular 
car di o vasc ular a n d res pirat or y relate d deat hs.
A car di o - a n d cere br o-vasc ular ( C C V) e xter nal a dj u dicati o n c o m mittee will c o nsist of 
e xter nal e x perts ( o utsi de of N o vartis) w h o will re vie w at re g ular i nter vals t he pr o gra m wi de 
selecte d C C V e ve nts t o e ns ure t hat t he e ve nts are c orrectl y classifie d. All t he details of t he 
a dj u dicati o n pr ocess i ncl u di n g t he c o m mittee me m bers will be i ncl u de d i n t he a dj u dicati o n 
c o m mittee c harter. Eac h a dj u dicati o n c o m mittee will ha ve its o w n c harter a n d all details of 
t he a dj u dicati o n pr ocess will be i ncl u de d i n t he rele va nt c o m mittee c harters.
9   
D at a a n al y si s
9. 1   
A n al y si s s et s
T he f oll o wi n g a nal ys is sets are defi ne d f or data a nal ysis.
T he Ra n d o mize d Set ( R A N), will c o nsist of all patie nts w h o were assi g ne d a ra n d o mizati o n 
n u m ber, re gar dless t he y act uall y recei ve d st u d y me dicati o n. It will be use d f or s u m maries of 
patie nt dis p ositi o n a n d a nal ysis sets, a n d listi n gs of maj or pr ot oc ol de viati o ns a n d pre mat ure 
disc o nti n uati o ns.  Patie nts i n R A N will be a nal yz e d acc or di n g t o t he treat me nt t he y were 
ra n d o mize d t o.
T he F ull A nal ys is Set ( F A S) will c o nsist of all patie nts i n t he R A N w h o recei ve d at least o ne 
d ose of st u d y me dicati o n. F oll o wi n g t he i nte nt-t o-treat pri nci ple, patie nts i n t he F A S will be 
a nal yz e d acc or di n g t o t he treat me nt t he y were assi g ne d t o at ra n d o mizati o n. T he F A S will be 
use d t o a nal yz e all efficac y e n d p oi nts, u nless ot her wise state d.
T he Per- Pr ot oc ol set ( P P S) will i ncl u de all patie nts i n t he F A S wit h o ut a n y maj or pr ot oc ol 
de viati o ns. Ma j or pr ot oc ol de viati o ns will be defi ne d i n t he data ha n dli n g pla n pri or t o 
data base l oc k a n d t he u n- bli n di n g of t he st u d y. Patie nts i n t he P P S will be a nal yze d acc or di n g 
t o t he treat me nt gr o u p t he y were ra n d o mize d t o. Patie nts w h o recei ve a n ot her t ha n t heir 
ra n d o mize d treat me nt beca use of a dis pe nsi n g err or will be e xcl u de d fr o m t he P P S.  The P P S
will be use d f or s u p p orti ve a nalys is t o assess r o b ust ness of t he pri mar y a nal ysis.
T he Safet y set will i ncl u de all patie nts w h o recei ve d at least o ne d ose of st u d y me dicati o n 
w het her t he y were ra n d o mize d or n ot. Patie nts will be a nal yz e d acc or di n g t o t he treat me nt 
t he y recei ve d. If patie nts recei ve m ore t ha n o ne treat me nt d uri n g t he st u d y, t he y will be 
a nal yz e d acc or di n g t o t he treat me nt t he y were ra n d o mize d t o. T he safet y set will be use d i n 
t he a nalys is of all safet y e n d p oi nts a n d i n t he listi n gs of certai n n ota ble safet y data.
9. 2   
P ati e nt 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 baseli ne c haracteristics meas ure d bef ore ra n d o mizati o n will be s u m marize d 
b y  treat me nt gr o u p.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics ( mea n, me dia n, sta n dar d 
de viati o n, mi ni m u m, a n d ma xi m u m) a n d cate g orical varia bles will be s u m marize d i n ter ms of 
t he n u m ber a n d perce nta ge of patie nts i n eac h cate g or y.
Baseli ne is defi ne d as t he last meas ure me nt bef ore first d ose of st u d y treat me nt.
N o statistical a nal yses will be pr o vi de d f or baseli ne c o m para bilit y am o n g t he treat me nt 
gr o u ps.
9. 3   
Tr e at m e nt s
St u d y  treat me nt a d mi nistrati o n a n d c o nc o mita nt me dicati o n 
data will 
be liste d a n d 
s u m marize d usi n g Safety set.
T he d urati o n of e x p os ure a n d t he n u m ber of patie nts ra n d o mize d w h o c o m plete d t he st u d y
a n d w h o disc o nti n ue d fr o m st u d y  me dicati o n will be s u m marize d.
Me dicati o ns starte d a n d st o p pe d pri or t o st u d y treatme nt , a n d ta ke n c o nc o mita ntl y will be 
s u m marize d b y treat me nt gr o u p i n se parate ta bles i n t he Safet y Set.
C o nc o mita nt t hera pies will be rec or de d, liste d a n d s u m marize d se parately f or C O P D relate d
me dicati o ns / n o n- dr u g t hera pies a n d ot her me dicati o ns.
S A B A (s h ort acti n g β 2 -a g o nist) usa ge ( n u m ber of p uffs) d uri n g t he scree ni n g peri o d will be 
s u m marize d.
Patie nts ta ki n g pr o hi bite d c o nc o mita nt me dicati o ns will be n ote d i n t he s u m mar y of pr ot oc ol
de viati o ns.
Treat me nt c o m plia nce wit h st u d y  me dicati o n o ver t he st u d y peri o d will be s u m marize d.
9. 4   
A n al y si s of t h e pri m ar y  vari a bl e( s)
T he pri mar y  objecti ve is t o de m o nstrate t he n o n- i nferi ority of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g q. d.)
c o m pare d t o ti otr o pi u m ( 1 8 µ g q. d.) +sal meter ol/fl uticas o ne F D C ( 5 0/ 5 0 0 µ g b.i. d) i n ter ms of 
tr o u g h F E V 1 after 2 6 wee ks of treat me nt i n patie nts wit h m o derate t o se vere C O P D.
9. 4. 1   
V ari a bl e( s)
T he pri mar y varia ble is t he mea n c ha n ge fr o m baseli ne i n p ost -d ose tr o u g h F E V 1 after 2 6
wee ks of treat me nt. T r o u g h F E V 1 is defi ne d as t he mea n of t he t w o F E V 1 val ues meas ure d at 
2 3 h 1 5 mi n a n d 2 3 h 4 5 mi n after t he m or ni n g d ose ta ke n at site o n Da y  18 1.  Baseli ne F E V 1 is 
defi ne d t he a vera ge of t he pre -d ose F E V 1 meas ure d at - 4 5 mi n a n d -1 5 mi n at Da y  1.
9. 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 
c o m paris o n bet wee n 
Q V A 1 4 9  
( 1 1 0/ 5 0 
µ g 
o. d.) 
a n d 
ti otr o pi u m ( 1 8 
µ g 
o. d.) +sal meter ol/fl uticas o ne pr o pi o nate  FD C ( 5 0/ 5 0 0 µ g b.i. d.) i n ter ms of tr o u g h F E V 1 at 
Da y  1 8 2 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 
h y p ot hesis ( Ha) at o ne- si de d 2. 5 % si g nifica nce le vel:

H 0: mea n tr o u g h F E V 1 at Da y 1 8 2 (Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d) ) is i nferi or t o t he mea n 
c ha n ge fr o m baseli ne i n tr o u g h F E V 1 at Da y 1 8 2 (ti otr o pi u m ( 1 8 µ g o. d.) + 
sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.)
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6

H a: mea n tr o u g h F E V 1 at Da y 1 8 2 ( Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) ) is n o n-i nferi or t o t he mea n 
c ha n ge fr o m baseli ne i n tr o u g h F E V 1 at Da y 1 8 2 (ti otr o pi u m ( 1 8 µ g o. d.) + 
sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.)
T he pri mar y  efficac y en d p oi nt will be a nal yze d usi n g a Mi xe d -Effect M o del 
Re peate d 
Meas ures ( M M R M) m o del.
T he m o del will i ncl u de fi xe d, cate g orical effects of treat me nt a n d visit, c o u ntr y/re gi o n, a n d 
treat me nt-b y -visit i nteracti o n as well as t he c o nti n u o us, fi xe d c o variates of baseli ne a n d 
basel i ne-b y -visit i nteracti o n.  If a d diti o nal c o variates are c o nsi dere d t o be re q uire d t hese will 
be pre defi ne d a n d i ncl u de d i n t he a nal ysis pla n fi nalize d pri or t o data base l oc k. T he wit hi n -
patie nt c orrelati o n will be m o dele d usi n g a n u nstr uct ure d c o varia nce m atri x. Restricte d 
ma xi m u m li keli h o o d met h o d will be use d. T he Ke n war d -R o ger a p pr o xi mati o n will be use d t o 
esti mate de n o mi nat or de grees of free d o m.
If t he a nal ys is fails t o c o n ver ge, s patial c o varia nce, c o m p o u n d s ym metr y , or first or der 
a ut ore gressi ve m o del ( A R 1) str uct ure will be use d. T he best m o del fit will be deter mi ne d b y  
t he A kai ke’s I nf or mati o n Criteri o n.
T he bet wee n -treat me nt c o m paris o n will be carrie d o ut usi n g t he a dj uste d mea n differe nce 
bet wee n treat me nts at Da y  1 8 2.
N o n -i nferi ority 
of 
Q V A 1 4 9 
( 1 10/ 5 0 
µ g 
o. d.) 
fr o m ti otr o pi u m ( 1 8 µ g 
o. d.) 
+ 
sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) will 
be de m o nstrate d if t he 
c o nfi de nce i nter val f or t he mea n F E V 1 differe nce of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) mi n us 
ti otr o pi u m ( 1 8 µ g o. d.) + sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) lies 
e ntirel y t o t he ri g ht of ( hi g her t ha n) – 5 0 m L .
9. 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
If a n y of t he - 4 5 mi n a n d - 1 5 mi n val ues c o ntri b uti n g t o t he tr o u g h F E V 1 are c ollecte d wit hi n 
7 da y s of s yste mic c ortic oster oi d use, 6 hr of resc ue me dicati o n , or act ual meas ure me nt ti mes 
are o utsi de t he 2 2 - 2 5 h o ur p ost -m or ni n g d ose ti me wi n d o w t he n t he i n di vi d ual F E V 1 val ue 
will be set t o missi n g.
If o ne of t he t w o val ues is missi n g ( or set t o missi n g) t he n t he re mai ni n g n o n- missi n g val ue 
will be ta ke n as tr o u g h F E V 1. If b ot h val ues are missi n g, or if t he patie nt wit h dre w fr o m t he 
st u d y, re gar dless of t he reas o n f or disc o nti n uati o n, t he n tr o u g h F E V 1 will be re gar de d as 
missi n g i n w hic h case t he missi n g val ue(s) of t he patie nt at t he partic ular visit(s) w o ul d n ot 
directl y  c o ntri b ute t o t he pri mar y a nalys is.
All ti me d tr o u g h F E V 1 data i.e. da y  29, da y  85, da y  18 1 a n d d a y  18 2, rec or de d p ost -baseli ne
will be i ncl u de d i n t he pri mar y  MM R M m o del a n d n o i m p utati o n will be a p plie d t o missi n g 
data. I nstea d of i m p utati o n, i n t he m o del t he pr ofile of eac h patie nt is use d t o a dj ust t he 
esti mates of t he para meters w he n data are n ot a vaila ble (i.e. the p ost -wit h dra wal statistical 
be ha vi or of a patie nt w h o disc o nti n ue d is ass u me d t o be t he sa me as f or a patie nt w h o 
re mai ne d i n t he st u d y an d w h o s hare d t he sa me meas ure me nt hist or y  an d t he sa me c o variates, 
i ncl u di n g treat me nt gr o u p).
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
9. 4. 4   
S u p p orti v e a n al y s e s 
T he f oll o wi n g s u p p orti ve a nal ys es f or tr o u g h F E V 1 will be perf or me d:
1.
T he sa me M M R M m o del use d i n t he pri mar y a nal ysis will be als o perf or me d o n t he P P S.
2.
T o assess t he r o b ust ness of t he pri mar y  res ults i n t he prese nce of missi n g data t he 
f oll o wi n g a nal yses are pla n ne d:

A n a nal ys is of c o varia nce (A N C O V A ) m o del (i ncl u di n g treat me nt, c o u ntr y/re gi o n, a n d 
baseli ne F E V 1) will 
be use d t o a nal yz e c o m plete datasets create d usi n g m ulti ple 
i m p utati o ns u n der var yi n g ass u m pti o ns . F or e xa m ple, missi n g 
F E V 1
val ues after 
disc o nti n uati o n f or patie nts o n Q V A w h o
disc o nti n ue d f or a n y reas o n will be i m p ute d 
base d o n i nf or mati o n fr o m ti otr o pi u m + sal meter ol/fl uticas o ne pr o pi o nate F D C patie nts 
o nl y . T his a nal ysis ass u mes t hat Q V A patie nts after disc o nti n uati o n ha ve a si milar 
res p o nse t o patie nts o n tri ple t hera py. A d d iti o nall y f urt her a nalys es will be perf or me d wit h 
t he p o orest o utc o me assi g ne d t o patie nts wit h missi n g res p o nses a n d t he n i n w hic h t he 
m ost fa v o ura ble res p o nse is assi g ne d t o all s uc h patie nts.

Tr o u g h F E V 1 at Wee k 
2 6 wit h missi n g
data i m p ute d wit h Last O b ser vati o n Carrie d 
F or war d ( L O C F) fr o m Da y  29 will be a nal ys e d usi n g t he A N C O V A m o del as descri be d 
a b o ve.
If t hese a nal ys es pr o vi de i nfere nces c o nsiste nt wit h t he pri mar y  anal ys is met h o d t he n t he 
c o ncl usi o ns will n ot be c o nsi dere d hi g hl y se nsiti ve t o h o w missi n g data are ha n dle d.
3.
All a vaila ble tr o u g h F E V 1 data at Wee k 2 6 ( i ncl u di n g retrie ve d data fr o m patie nts w h o 
pre mat urel y disc o nti n ue treat me nt b ut w h o atte n d s u bse q ue nt sc he d ule d visits) will be 
a nal yz e d usi n g t he A N C O V A m o del descri be d i n p oi nt 2. T o n ot e t his retrie ve d data ma y 
be affecte d b y off -st u d y me dicati o ns.
4.
E x pl orat or y  su b gr o u p a nal yses f or tr o u g h F E V 1 usi n g M M R M will be perf or me d ( usi n g 
t he a p pr o priate i nteracti o n ter m i n t he m o del a n d a n a d diti o nal c o variate as a fi xe d effect 
if necessar y ) f or t he F A S p o p ulati o n. S u b gr o u ps will be defi ne d i n t he a nal ysis pla n pri or 
t o data base l oc k.
9. 5   
A n al y si s of s e c o n d ar y  vari a bl e s
9. 5. 1   
Effi c a c y  vari a bl e s
9. 5. 1. 1 
C O P D e x a c er b ati o n s
I n patie nts wit h m ulti ple e xacer bati o ns, if t he start date of a n e xacer bati o n was less t ha n 7 
d a ys after t he e n d date of a pre vi o us e pis o de, t he n t his will be ass u me d t o be o ne c o nti n u o us 
e xacer bati o n wit h t he start date ta ke n fr o m t he first e pis o de a n d t he e n d date fr o m t he sec o n d 
or last e pis o de. T he w orst se verity of t hese e pis o des will be ta ke n as t he se verit y of t he 
c olla pse d e xacer bati o n.
N u m ber of m o derate or se vere C O P D e xacer bati o ns d uri n g t he treat me nt peri o d will be 
s u m marize d b y  treat me nt gr o u ps, as c o nti n u o us varia bles a n d as cate g orical varia bles 
classifie d i nt o 0, 1, 2, 3, > = 4 e ve nts.
T he rate of m o derate or se vere C O P D e xacer bati o ns d uri n g t he treat me nt peri o d will be 
a nal yz e 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 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
ti me at ris k f or a patie nt is t he le n gt h of ti me e x p ose d t o st u d y treat me nt.  The a nal ys is m o del 
will i ncl u de ter ms f or treat me nt, c o u ntr y/re gi o n, a n d C O P D e xacer bati o n hist or y  (t he n u m ber 
of m o derate or se vere C O P D e xacer bati o ns i n t he ye ar pri or t o scree ni n g). If a d diti o nal 
c o variates are c o nsi dere d t o be re q uire d t hese will be pre de fi ne d a n d i ncl u de d i n t he a nal ys is 
pla n fi nalize d pri or t o data base l oc k. A n esti mate of t he rati o of m o derate or se vere C O P D 
e xacer bati o n rates bet wee n t he treat me nt gr o u ps, t o get her wit h t he 9 5 % c o nfi de nce i nter val, 
will be prese nte d.
T he a b o ve s u m mar y an d a nal ys is will be re peate d f or t he rate of m o derate or se vere C O P D 
e xacer bati o ns re q uiri n g

s yste mic gl uc oc ortic oster oi ds a n d a nti bi otics d uri n g t he treat me nt peri o d ( m o derate 
e xacer bati o ns o nl y)

h os pitalizati o ns d uri n g t he treat me nt peri o d a n d re h os pital izati o n wit hi n 3 0 da ys d uri n g 
t he treat me nt peri o d (se vere e xacer bati o ns o nly).
9. 5. 1. 2 
Tr o u g h F E V 1 a n d F V C, S G R Q -C, T DI, R e s c u e t h er a p y
Tr o u g h F E V 1 c ha n ge fr o m baseli ne o ver 2 6 wee ks of treat me nt will be a nal yze d usi n g t he 
sa me M M R M
m o del descri be d f or t he pri mar y  en d p oi nt.  FV C c ha n ge fr o m baseli ne, 
S G R Q -C t otal sc ore c ha n ge fr o m baseli ne, a n d T DI t otal sc ore o ver 2 6 wee ks of treat me nt 
will be als o a nal yz e d usi n g a si milar M M R M m o del wit h baseli ne F E V 1 re place d b y  the 
c orres p o n di n g baseli ne f or t he e n d p oi nt.  Baseli ne S G R Q -C is t he last n o n -missi n g val ue pri or 
t o t he first d ose of d o u ble-bli n d treat me nt.
T he mea n dail y  nu m ber of p uffs a n d perce nta ge of da y s wit h o ut resc ue me dicati o n usa ge will 
be calc ulate d f or eac h patie nt o ver 2 6 w ee ks. Resc ue use d uri n g t he r u n -i n e p oc h will be use d 
t o calc ulate t he baseli ne. T he mea n dail y  nu m ber of p uffs will be a nal yze d usi n g a li near 
mi xe d m o del wit h fi xe d cate g orical effects of treat me nt a n d c o u ntr y/re gi o n, a n d a fi xe d 
c o nti n u o us c o variate of baseli ne.  If a d diti o nal c o variates are c o nsi dere d t o be re q uire d t hese 
will be pre defi ne d a n d i ncl u de d i n t he a nal ysis pla n fi nalize d pri or t o data base l oc k. 
Perce nta ge of da y s wit h o ut resc ue me dicati o n usa ge will be a nalyz e d usi n g a si milar m o del.
9. 5. 2   
S af et y v ari a bl e s
Baseli ne will be t he last n o n- missi n g val ue pri or t o first d ose of d o u ble -bli n d treat me nt.
9. 5. 2. 1 
A d v er s e e v e nt s
A d verse e ve nts starti n g o n or after t he ti me of t he first i n halati o n of d o u ble -bli n d treat me nt 
b ut n ot later t ha n 7 da y s ( 3 0 d a y s i n t he case of a S A E) after t he last a d mi nistrati o n will be 
classifie d as a treat me nt e mer ge nt a d verse e ve nt. A n y  ad verse e ve nts t hat starte d d uri n g t he 
st u d y bef ore t he ti me of t he first i n halati o n of d o u ble -bli n d treat me nt will be classifie d as a 
pri or a d verse e v e nt.
T he f oll o wi n g treat me nt e mer ge nt a d verse e ve nt s u m maries will be pr o d uce d: o verall b y  
s yste m or ga n class a n d preferre d ter m; o verall b y  sys te m or ga n class, preferre d ter m a n d 
ma xi m u m se verit y; s us pecte d treat me nt-relate d a d verse e ve nts b y  sys te m or ga n class a n d 
preferre d ter m; S A Es b y  s yste m or ga n class a n d preferre d ter m; a n d a d verse e ve nts lea di n g t o 
per ma ne nt disc o nti n uati o n of st u d y -treat me nt b y s yste m or ga n class a n d preferre d ter m.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
9. 5. 2. 2 
L a b or at or y  d at a
All la b orat or y d ata will be liste d wit h a b n or mal val ues fla g ge d. T he la b orat or y val ues a n d t he 
c ha n ge fr o m baseli ne f or c o nti n u o us la b orat or y para meters will be s u m marize d. A fre q ue ncy 
ta ble of res ults f or cate g orical la b orat or y para meters will be pr o d uce d. S hift ta bles relati ve t o 
t he n or mal refere nce ra n ges will s u m marize t he c ha n ge fr o m baseli ne t o p ost baseli ne f or eac h 
la b orat or y para meter.
La b orat or y  data meas ure d m ore t ha n 7 da y s after last i n halati o n of d o u ble -bli n d treat me nt is 
re gar de d as p ost-treat me nt data a n d will n ot be s u m marize d, o nl y liste d.
9. 5. 2. 3 
E C G a n d vit al si g n s
E C G data a n d vital si g ns ( bl o o d press ure, ra dial p ulse a n d wei g ht) will be s u m marize d b y 
treat me nt at eac h ti me p oi nt f or eac h visit se parately. T he ma xi m u m ( Q Tc, s yst olic bl o o d 
press ure, p ulse rate) or mi ni m u m ( diast olic bl o o d pres s ure) val ue p ost baseli ne will als o be 
s u m marize d. C ha n ges fr o m baseli ne will be s u m marize d b y treat me nt. 
N ota ble Q Tc val ues a n d c ha n ges fr o m baseli ne will be s u m marize d. A n ota ble val ue is 
defi ne d as a Q Tc i nter val of greater t ha n 4 5 0 ms f or b ot h se xes. T he cate g ories use d f or t he 
c ha n ge fr o m baseli ne i n Q Tc are less t ha n 3 0 ms, 3 0 t o 6 0 ms, a n d greater t ha n 6 0 ms. C ha n ge 
fr o m baseli ne > 3 0 ms will be c o nsi dere d as a n ota ble c ha n ge.  T he n u m ber of patie nts wit h 
ne wl y  occ urri n g or w orse ni n g n ota ble Q Tc val ues f or p ost baseli ne ti me p oi nts will be 
s u m marize d.
Data meas ure d m ore t ha n 7 da y s after last i n halati o n of d o u ble -bli n d treat me nt is re gar de d as 
p ost -treat me nt data a n d will n ot be s u m marize d, o nl y liste d.
9. 5. 3     
R e s o ur c e utili z ati o n
Data relati n g t o res o urce utilizati o n will be use d f or t he p ur p ose of ec o n o mic e val uati o n 
w hic h will be carrie d o ut a n d re p orte d as a se parate acti vit y .
9. 5. 4    
P h ar m a c o ki n eti c s
N ot a p plica ble
9. 5. 5   
P h ar m a c o g e n eti c s/ p h ar m a c o g e n o mi c s
P h ar m a c o g e n eti c s
N ot a p plica ble
9. 5. 6   
Bi o m ar k er s
As descri be d i n S ecti o n 6. 8. 5 se veral bi o mar kers ha ve bee n i de ntifie d t o be pre dicti ve of 
C O P D e xacer bati o n, disease pr o gressi o n a n d deat h. T he a nal y sis of bi o mar kers is e x pl orat or y. 
T he s u m mar y statistics of t he bi o mar kers at baseli ne a n d eac h visit will be dis pla y e d. M ore 
details wi ll be i ncl u de d i n a nal ys is pla n. 
9. 5. 7   
P K/ P D
N ot a p plica ble .
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
9. 6   
I nt eri m a n al ys e s
N ot a p plica ble .
9. 7   
S a m pl e si z e c al c ul ati o n
T he pri mar y  objecti ve is t o de m o nstrate n o n- i nferi orit y of Q V A 1 4 9 ( 1 1 0/ 5 0 µ g o. d.) vers us 
ti otr o pi u m ( 1 8 µ g o. d.) +sal meter ol/fl uticas o ne pr o pi onate F D C ( 5 0/ 5 0 0 µ g b.i. d.) wit h res pect 
t o p ost -d ose tr o u g h F E V1 after 2 6 wee ks of treat me nt . 
F or tr o u g h F E V 1 it is ass u me d t hat t he esti mate d treat me nt differe nce bet wee n Q V A 1 4 9 a n d
ti otr o pi u m ( 1 8 µ g o. d.) +sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µg b.i. d.) is 0 m L an d 
t he n o n -i nferi ority mar gi n is ass u me d t o be -5 0 m L . T his n o n- i nferi orit y mar gi n is base d o n 
t he treat me nt differe nce bet wee n I C S a n d place b o s u m marize d i n t w o C oc hra ne re vie ws 
(Na n ni ni et al 2 0 0 7 a n d Ya n g et al 2 0 1 2 ) a n d t he TI O S PI R s pir o metr y su b -st u d y (Wise et al. 
2 0 1 3 ). T he selecte d trials were desi g ne d a n d c o n d ucte d i n C O P D patie nts.
Base d 
o n 
t he data 
p o ole d 
fr o m t w o trials
(Na n ni ni 
et al 2 0 0 7 ) i n vesti gati n g 
sal meter ol/fl uticas o ne vers us place b o i n ter ms of tr o u g h F E V 1, t he esti mate d treat me nt 
differe nce bet wee n sal meter ol/fl uticas o ne a n d place b o is 1 6 0 m L  wit h a 9 5 % c o nfi de nce 
i nter val of 1 2 0 t o 2 0 0 m L . Ya n g et al. pr o vi de d s u m mar y data fr o m 6 trials i n vesti gati n g I C S 
d oses of greater t ha n 1 0 0 0 g B D P e q ui vale nt/ da y vers us place b o i n ter ms of pre -d ose F E V 1, 
t he esti mate d treat me nt differe nce bet wee n I C S a n d place b o is 8 0 m L . A reas o na ble a p pr oac h 
t o esta blis h t he n o n-i nferi orit y mar gi n is t o ta ke o ne half of t he l o wer b o u n d of t he c o nfi de nce 
i nter val, w hic h is - 6 0 m L
a n d -4 0 m L res pecti vel y. T he TI O S PI R s pir o metr y su b- st u d y in 
1 3 7 0 C O P D patie nts use d a n o n -i nferi ority ma r gi n of -5 0 m L de m o nstrati n g t he n o n-
i nferi orit y of t he Res pi mat 5 mc g de vice vers us t he Ha n di Haler 1 8 mc g. T w o f or m ulati o ns of 
ti otr o pi u m are si milar i n cli nical efficac y a n d safet y.
A sa m ple size of 3 7 5 e val ua ble patie nts i n eac h treat me nt gr o u p pr o vi des 9 2 % p o wer f or t he 
testi n g of n o n- i nferi ority ass u mi n g a n o n -i nferi orit y mar gi n of -5 0 m L a n d a S D of 2 0 0 m L
( 2. 5 % si g nifica nce le vel, o ne-si de d). T he sta n dar d de viati o n of 2 0 0 m L  is base d o n a re vie w of 
t he res ults of p hase III C O P D st u dies r u n b y  the s p o ns or. T heref ore ass u mi n g a dr o p o ut rate 
of 2 5 % o ver 2 6 wee ks a mi ni m u m sa m ple size of 1 0 0 0 patie nts ( 5 0 0 Q V A 1 4 9 ( 1 1 0/ 5 0 µ g 
o. d.): 5 0 0 ti otr o pi u m ( 1 8 µ g o. d.) + sal meter ol/fl uticas o ne pr o pi o nate F D C ( 5 0/ 5 0 0 µ g b.i. d.) 
has bee n c h ose n.
n Q uer y  ( V 7. 0) has bee n use d t o calc ulate t he sa m ple sizes.
1 0   
Et hi c al c o n si d er ati o n s
1 0. 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 a n d re p orte d i n acc or da nce wit h 
t he I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit 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 Ja pa nese Mi nistr y  of 
Healt h, La b or, a n d Welfare), 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.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 0. 2   
I nf or m e d c o n s e nt pr o c e d ur e s
Eli gi ble patie nts 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 writte n ( wit nesse d, w here 
re q uire d b y  l aw or re g ulati o n), I RB/I E C -a p pr o ve d i nf or me d c o nse nt, or, if i nca pa ble of d oi n g 
s o, after s uc h c o nse nt has bee n pr o vi de d b y  a le gall y acce pta ble re prese ntati ve(s) of t he 
p atie nt. I n cases w here t he patie nt’s re prese ntati ve gi ves c o nse nt, t he patie nt s h o ul d 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 patie nt is 
ca pa ble of d oi n g s o, he/s he s h o ul d i n dicate asse 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 or a se parate asse nt f or m. I nf or me d c o nse nt m ust be o btai ne d 
bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (i.e. 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 s h o ul d be d oc u me nte d i n t he patie nt 
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 CH G C P 
g ui deli ne 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 hi s 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 
t he i n vesti gat or m ust be a gree d t o b y  No vartis bef ore s u b missi o n t o t he I R B/I E C, a n d a c o p y 
of t he a p pr o ve d versi o n m ust be pr o vi de d t o t he N o vartis m o nit or after I RB/I E C a p pr o val.
W o me n of c hil d beari n g p ote ntial s h o ul d be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y 
i n 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 the y  must a d here t o t he c o ntrace pti o n re q uire me nt f or t he 
d urati o n of t he st u d y. If t here is a n y q uesti o n t hat t he patie nt will n ot relia bl y c o m pl y, t hey 
s h o ul d n ot be e ntere d i n t he st u d y.
I n the e ve nt t hat N o vartis wa nts t o perf or m testi n g o n t he sa m ples t hat are n ot descri be d i n 
t his pr ot oc ol, a d diti onal I nstit uti o nal Re vie w B oar d a n d/ or Et hics C o m mittee a p pr o val will be 
o btai ne d.
1 0. 3   
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 s h o ul d 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, patie nt
recr uit me nt 
pr oce d ures (e. g., a d vertise me nts) a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o patie nts. 
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 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 R Bs/IE C s, 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 aut h orit y , t he i n vesti gat or m ust i nf or m N o vartis 
i m me diatel y t hat t his re q uest has bee n ma de.
1 0. 4   
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
N o vartis ass ures t hat t he ke y  desi g n ele me nts of t his pr ot oc ol will be p oste d i n a p u blicl y 
accessi ble data base s uc h as cli nicaltrials. g o v. I n a d diti o n, u p o n st u d y co 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 eit her s u b mitte d f or p u blicati o n 
a n d/ or p oste d i n a p u blicl y accessi ble data base of cli nical trial res ults.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 1   
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 objecti 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 t o e ns ure safet y of patie nts s h o ul d be 
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 s h o ul d a n 
i n vesti gat or c ollect a d diti o nal data or c o n d uct a n y ad diti o nal pr oce d ures f or a n y researc h 
relate d p ur p ose i n v ol vi n g a n y i n vesti gati o nal dr u gs.
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 m pr o ve t he c o n d uct of t he st u d y this m ust be 
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 nd 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 RB/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. All si g nifica nt pr ot oc ol de viati o ns will be rec or de d a n d re p orte d i n t he C S R.
1 1. 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 i nte n de d t o eli mi nate a n a p pare nt i m me diate 
hazar d t o patie nts ma 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 RB/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 safety of a n y patie nt 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, t he re p orti n g 
re q uire me nts i de ntifie d i n secti o n 7 Safet y M o nit ori n g s h o ul d be f oll o we d.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 2   
R ef er e n c e s
Refere nces are a vaila ble u p o n re q uest .
Bate ma n et al ( 2 0 1 3). D ual br o nc h o dilati o n wit h Q V A 1 4 9 vers us si n gle br o nc h o dilat or 
t hera py:  t he S HI N E st u d y. E ur o pea n Res pirat or y  J o ur nal; 4 2( 6): 1 4 8 4 - 9 4.
Carstairs 
J R, Ni m m o 
AJ, 
Bar nes 
PJ ( 1 9 8 5). A ut ora di o gra p hic 
vis ualizati o n of beta -
a dre n oce pt or s u bt y pes i n h u ma n l u n g. A m Re v Res pir Dis; 1 3 2: 5 4 1 - 7.
Cazz ola M, M oli mar d
M ( 2 0 1 0). T he scie ntific rati o nale f or c o m bi ni n g l o n g-acti n g beta 2 -
a g o nists a n d m uscari nic a nta g o nists i n C O P D. P u l m P har mac ol T her; 2 3( 4): 2 5 7- 6 7.
Gae bel K, et al ( 2 0 1 1) Tri ple t hera py f or t he ma na ge me nt of C O P D: A re vie w. C O P D: 
J o ur nal of C hr o nic O bstr ucti ve P ul m o nar y Disease, 8: 2 0 6– 2 4 3.
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] ( 2 0 14 ) Gl o bal strate g y for 
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. 
A vaila ble fr o m w w w. g ol dc o p d.c o m .
I ke da T, A nis uz za ma n A, Y os hi ki H, et al ( 2 0 1 2). Re gi o nal q ua ntificati o n of m uscari nic 
acet yl c h oli ne rece pt ors a n d β- a dre n oce pt ors i n h u ma n air wa ys. Br J P har mac ol; 1 6 6( 6): 1 8 0 4 -
1 4.
J o nes P W, ( 2 0 0 9) Tri ple t hera p y f or c hr o nic o bstr ucti ve p ul m o nar y  disease: trials catc hi n g u p 
wit h cli nical practice? A m J Res pir Crit Care Me d; 1 8 0: 6 8 9 -9 0.
Ma k J C, Bar nes PJ ( 1 9 9 0). A ut ora di o gra p hic vis ualizati o n of m uscari nic rece pt or s u bty pes i n 
h u ma n a n d g ui nea pi g l u n g. A m Re v Res pir Dis: 1 4 1: 1 5 5 9 - 6 8.
Sala ma R, et al ( 2 0 1 1). A d va nces i n dr u g deli ver y : is tri ple t hera py t he f ut ure f or t he 
treat me nt of c hr o nic o bstr ucti ve p ul m o nar y  disease? E x pert O pi n. P har mac ot her. ( 2 0 1 1) 
1 2( 1 2): 1 9 1 3 - 1 9 3 2.
S mall M, et al ( 2 0 1 2). Q ua ntificati o n a n d treat me nt patter ns of real-w orl d patie nts classifie d 
b y  t he G O L D 2 0 1 1 strate g y. ( A bstract N o 2 8 7 8 E R S A n n ual meeti n g).
Va n der M ole n 
T, Cazz ola M 
( 2 0 1 2). Be y o n d l u n g f u ncti o n i n C O P D ma na ge me nt:
effecti ve ness of L A B A/ L A M A c o m bi nati o n t hera p y on patie nt -ce ntre d o utc o mes. Pri m Care
Res pir J; 2 1( 1): 1 0 1 - 8.
V o gel meier et al ( 2 0 1 3). Efficac y  an d safet y of o nce -dail y Q V A 1 4 9 c o m pare d wit h t wice-
dail y  sal meter ol-fl uticas o ne i n patie nts wit h 
c hr o nic o bstr ucti ve p ul m o nar y  disease 
(I L L U MI N A T E): a ra n d o mize d, d o u ble-bli n d, parallel gr o u p st u d y . La ncet ; 1 ( 1): 5 1- 6 0
Wa n g J, Ji n D, Z u o P, et al ( 2 0 1 1). C o m paris o n of ti otr o pi u m pl us f or m oter ol t o ti otr o pi u m 
al o ne i n sta ble c hr o nic o bstr ucti ve p ul m o nar y  disease: a meta - 3 1 0 2 a nal ysis. Res pir ol o g y ; 
1 6( 2): 3 5 0 - 8.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 3   
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
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 3 - 1   
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
D efi niti o n/ t hr e s h ol d
L i v er L a b or at or y T ri g g er 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
L i v er E v e nt 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 m i 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 a bl e 1 3 - 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
 
C o m pl et e li v er 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 γ 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
 
C o m pl et e li v er 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 γ 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
 
C o m pl et e li v er 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 γ 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 or 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  
tr e at m e nt
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ 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 7 3
A m e n d e d Pr ot o c ol V er si o n v 0 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
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
 
E st a bli s h c a u s alit y
 
C o m pl et e li v er C R F
> 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
 
C o m pl et e li v er 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 γ 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 t o ≤ 5 × U L N 
( p ati e nt 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 p ati e nt
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
 
C o m pl et e li v er 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  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
 
C o m pl et e li v er 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 γ 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
( p ati e nt 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 p ati e nt
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
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 p ati e nt
 
E st a bli s h c a u s alit y
 
C o m pl et e li v er 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 γ 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 erru 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
 
C o m pl et e li v er C R F
I n v e sti g at or di s cr eti o n
* 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
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 osi 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 an s pl a nt ati o n, a n d ( 5) d e at h.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 4   
A p p e n di x 2: S pir o m etr y  G ui d a n c e
E q ui p m e nt
S pir o meters m ust meet t he s pecificati o ns a n d perf or ma nce criteria rec o m me n de d i n t he 
A merica n T h oracic S ociet y  (A T S)/ E ur o pea n Res pirat or y  Societ y ( E R S) Sta n dar dizati o n of 
S pir o metr y (Miller et al. 2 0 0 5). S pir o meters m ust ha ve t he ca pacit y to pri nt F V C traci n gs. All 
s pir o metr y val ues s h o ul d be re p orte d at B T P S b y t he met h o d esta blis he d b y t he ma n ufact urer.
C ali br ati o n
T he s pir o meter s h o ul d be cali brate d e ver y mor ni n g bef ore a n y s pir o metric meas ure me nts f or 
t he st u d y are perf or me d. Cali brati o n re p orts s h o ul d be pri nte d a n d st ore d as s o urce data at t he 
site.
Pr e p ari n g t h e t e st p ati e nt
O n st u d y  da ys w he n s pir o metr y will be perf or me d, patie nts s h o ul d refrai n fr o m t he f oll o wi n g:

C offee, tea, c h oc olate, c ola a n d ot her caffei ne -c o ntai ni n g be vera ges a n d f o o ds a n d ice-
c ol d be vera ges  f or 4 h o urs pri or t o s pir o metr y

Alc o h ol f or 4 h o urs pri or t o s pir o metr y

Stre n u o us acti vit y  f or 1 2 h o urs pri or t o s pir o metr y

S m o ki n g wit hi n at least 1 h o ur of testi n g

E x p os ure t o e n vir o n me ntal s m o ke, d ust or areas wit h str o n g o d ors
E ver y  eff ort s h o ul d be ma de t o ass ure c o nsiste nt testi n g c o n diti o ns t hr o u g h o ut t he st u d y.  A 
seate d p ositi o n wit h n ose cli ps is rec o m me n de d t o re d uce ris ks relate d t o dizzi ness or s ync o pe. 
W he n 
p ossi ble, s pir o metr y sh o ul d be c o n d ucte d b y  the sa me tec h nicia n usi n g t he sa me 
s pir o meter. T o mi ni mize t he effects of di ur nal variati o n o n l u n g f u ncti o n, s pir o metr y visits 
s h o ul d start at a p pr o xi matel y t he sa me ti me of da y at eac h visit.
P erf or mi n g S pir o m etr y
T he patie nt ’s a ge, hei g ht a n d ge n der will be e ntere d i nt o t he s pir o meter. It is i m p orta nt t hat 
t he hei g ht is meas ure d acc uratel y at t he st u d y site. S pir o metr y , a n eff ort- de pe n de nt test, 
re q uires caref ul i nstr ucti o n a n d c o o perati o n of t he patie nt.  The tec h nicia n s h o ul d e ns ure a 
g o o d seal ar o u n d t he m o ut h piece, a n d c o nfir m t hat t he patie nt ’s p ost ure is c orrect. T he patie nt
s h o ul d be i nstr ucte d t o perf or m a ma xi mal 
i ns pirati o n, f oll o we d b y ma xi m u m 
f orce d 
e x pirati o n u ntil n o m ore air ca n be e x hale d or f or at least 6 sec o n ds. E x pirati o n m ust be ra pi d 
wit h e xerti o n of ma xi mal eff ort. T he res ults of s pir o metr y sh o ul d meet t he A T S/ E R S criteria 
f or acce pta bilit y (o ne retest ma y  be perf or me d f or patie nts t hat d o n’t meet t he acce pta bilit y 
criteria).
N u m b er of tri al s
A mi ni m u m of 3 acce pta ble f orce d vital ca pacit y  (F V C) ma ne u vers s h o ul d be perf or me d.  If a 
patie nt is u na ble t o perf or m a si n gle acce pta ble ma ne u ver after 8 atte m pts, testi n g s h o ul d be 
disc o nti n ue d.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
A c c e pt a bilit y

A n acce pta ble ma ne u ver has t he f oll o wi n g c haracteristics

N o hesitati o n or false start

A ra pi d start

N o c o u g h, es peciall y  d uri n g t he first sec o n d of t he ma ne u ver

N o gl ottic cl os ure or o bstr ucti o n b y t o n g ue or de nt ures

N o earl y ter mi nati o n of e x halati o n ( mi n i m u m e x halati o n ti me of 6 sec o n ds is 
rec o m me n de d, or n o v ol u me c ha n ge f or at least 1 sec o n d) or t he patie nt ca n n ot c o nti n ue t o 
e x hale f urt her
R e c or di n g of d at a
T he hi g hest F E V 1 a n d F V C fr o m a n y of t he acce pta ble c ur ves are rec or de d. ( T he hi g hest 
F E V 1 a n d FV C ma y  n ot necessaril y res ult fr o m t he sa me acce pta ble c ur ve).
Pr e di ct e d n or m al
F or patie nt s greater t ha n 1 8 ye ars of a ge, t his st u d y will utilize t he s pir o metric pre dicati o n 
e q uati o n sta n dar ds f or t he E ur o pea n C o m m u nit y  for C oal a n d Steel (Q ua njer et al 1 9 9 3 ) or 
N ha nes.
R e v er si bilit y
All re versi bilit y eval uati o ns s h o ul d f oll o w t he rec o m me n dati o ns of t he A T S/ E R S Tas k f orce: 
Sta n dar dizati o n of L u n g F u ncti o n Testi n g ( Miller 
et al. 2 0 0 5). A 
pre -br o nc h o dilat or 
s pir o metr y assess me nt s h o ul d be perf or me d after a was h o ut peri o d of at least:

6 h f or s h ort -acti n g β 2-a g o nists

8 h s h ort -acti n g a ntic h oli ner gics

2 4 h o urs after t he last ( m or ni n g) d ose of t heir L A M A

1 2 h o urs after t he last (e ve ni n g) d ose of t heir L A B A/IC S
P ost -br o nc h o dilat or s pir o metr y assess me nt is perf or me d 1 5 mi n utes after a d mi nistrati o n of 
4 0 0 µ g sal b uta m ol.
Re versi bilit y  is calc ulate d as:
1 0 0 x       F E V 1 ( p ost-br o nc h o dilat or) – F E V 1 ( pre-br o nc h o dilat or)
                                     F E V 1 ( pre-br o nc h o dilat or)
D uri n g re versi bilit y testi n g f or p ost -br o nc h o dilat or F E V 1, if l u n g f u ncti o n deteri orates (i.e. 
t here is a decrease i n p ost br o nc h o dilat or F E V 1 c o m pare d t o pre -br o nc h o dilat or F E V 1 as 
o p p ose d t o a n i ncrease) after a d mi nistrati o n of sal b uta m ol, t he n patie nt nee ds t o be scree n 
faile d.
Patie nts wit h C O P D de m o nstrati n g a hi g h re versi bilit y ma y re q uire f urt her cli nical e val uati o n 
b y  t he i n vesti gat or t o r ule o ut a dia g n osis of ast h ma.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
R ef er e n c e s
Miller M R et al, Sta n dar dizati o n of Lu n g F u ncti o n Testi n g. E ur Res p J 2 0 0 5; 2 6: 1 5 3 - 1 6 1.
Q ua njer P H et al. L u n g v ol u mes a n d f orce d ve ntilat or y  fl o ws, Re p ort W or ki n g Party 
Sta n dar dizati o n of L u n g F u ncti o n Tests, E ur o pea n C o m m u nit y  f or Steel a n d C oal. Official 
State me nt of t he E ur o pea n Res pirat or y s ociety.  E ur Res p J 1 9 9 3; 6: S u p pl. 1 6, 5 - 4 0.
Ha n ki ns o n J L , O de ncra ntz J R, Fe da n K B ( 1 9 9 9) S pir o metric refere nce val ues fr o m a sa m ple 
of t he ge neral U S p o p ulati o n. A m J Res pir Crit Care Me d 1 5 9: 1 7 9 – 1 8 7.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 5   
A p p e n di x 3: P ati e nt Di ar y
T he f oll o wi n g i nf or mati o n will be ca pt ure d t wice dail y  bef ore ta ki n g st u d y me dicati o n:
I n t h e M O R NI N G ( pr e-m e di c ati o n)
I n t h e E V E NI N G ( pr e-m e di c ati o n)
N u m b er of p uff s of r e s c u e m e di c ati o n d uri n g t h e 
p a st 1 2 h o ur s 
N u m b er of p uff s of r e s c u e m e di c ati o n d uri n g t h e 
p a st 1 2 h o ur s 
H o w w o ul d y o u r at e y o ur r e s pir at or y s y m pt o m s 
l a st ni g ht ?
N o w a ki n g d u e t o s y m p t o m s
W o k e u p o n c e d u e t o s y m pt o m s 
W o k e u p m or e t h a n o n c e d u e t o s y m p t o m s
W o k e u p fr e q u e ntl y or c o ul d n ot sl e e p d u e t o 
s y m p t o m s
Di d y o ur r e s pir at or y s y m pt o m s st o p y o u 
p erf or mi n g y o ur u s u al d ail y a cti viti e s t o d a y ?                  
N ot at all
A littl e
Q uit e a l ot 
C o m pl et el y 
H o w w a s y o ur c o u g h d uri n g t h e p a st 1 2 h o ur s ?    
N o n e 
Mil d 
M o d er at e
S e v er e                 
H o w w a s y o ur c o u g h d uri n g t h e p a st 1 2 h o ur s ?
N o n e
Mil d
M o d er at e
S e v er e                
H o w w a s y o ur w h e e z e d uri n g t h e p a st 1 2 h o ur s ?
N o n e 
Mil d 
M o d er at e
S e v er e
H o w w a s y o ur w h e e z e d uri n g t h e p a st 1 2 
h o ur s ?
N o n e
Mil d
M o d er at e
S e v er e
H o w m u c h s p ut u m di d y o u pr o d u c e d uri n g t h e 
p a st 1 2 h o ur s ?
N o n e
L e s s t h a n 5 m L ( 1 t e a s p o o n)
B et w e e n 5 a n d 2 5 m L ( 1 -5 t e a s p o o n s)
M or e t h a n 2 5 m L ( 5 t e a s p o o n s)                  
H o w m u c h s p ut u m di d y o u pr o d u c e d uri n g t h e 
p a st 1 2 h o ur s ?
N o n e
L e s s t h a n 5 m L ( 1 t e a s p o o n)
B et w e e n 5 a n d 2 5 m L ( 1 -5 t e a s p o o n s)
M or e t h a n 2 5 m L ( 5 t e a s p o o n s)                 
W h at c ol or w a s t h e s p ut u m y o u pr o d u c e d d uri n g 
t h e p a st 1 2 h o ur s ?
N o n e
W h it e-gr e y  
Y ell o w
Gr e e n                 
W h at c ol or w a s t h e s p ut u m y o u pr o d u c e d d uri n g 
t h e p a st 1 2 h o ur s ?  
N o n e
W h it e-gr e y
Y ell o w 
Gr e e n               
D uri n g w h at a cti viti e s di d y o u fir st f e el br e at hl e s s 
i n t h e l a st 1 2 h o ur s ?                                          
N e v er or o nl y w h e n r u n ni n g
W h e n w al ki n g u p hill or u p st air s
W h e n w al ki n g o n fl at gr o u n d
At r e st
D uri n g w h at a cti viti e s di d y o u fir st f e el 
br e at hl e s s i n t h e l a st 1 2 h o ur s ?                              
N e v er or o nl y w h e n r u n ni n g
W h e n w al ki n g u p hill or u p st air s
W h e n w al ki n g o n fl at gr o u n d
At r e st
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
P ati e nt Di ar y ( c o nti n u e d)
T he f oll o wi n g i nf or mati o n will be ca pt ure d:
Di d y o u h a v e a s or e t hr o at ?
0) N o
1) Y e s, mil d
2) Y e s, m o d er at e
3) Y e s, s e v er e
Di d y o u h a v e a s or e t hr o at ?
0) N o
1) Y e s, mil d
2) Y e s, m o d er at e
3) Y e s, s e v er e
Di d y o u h a v e a c ol d ( n a s al di s c h ar g e a n d/ or 
n a s al c o n g e sti o n) ?
0) N o
1) Y e s, m il d
2) Y e s, m o d er at e
3) Y e s, s e v er e
Di d y o u h a v e a c ol d ( n a s al di s c h ar g e a n d/ or 
n a s al c o n g e sti o n) ?
0) N o
1) Y e s, mil d
2) Y e s, m o d er at e
3) Y e s, s e v er e
Di d y o u h a v e a f e v er ?
0) N o
1) Y e s, mil d
2) Y e s, m o d er at e
3) Y e s, s e v er e
Di d y o u h a v e a f e v er ?
0) N o
1) Y e s, m il d
2) Y e s, m o d er at e
3) Y e s, s e v er e
Ti m e  of st u d y  tr e at m e nt a d mi ni str ati o n will b e c a pt ur e d i n t h e p ati e nt e Di ar y a n d tr a n sf err e d t o 
N o v arti s.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 6   
A p p e n di x 4 : I n str u cti o n s f or u s e of N o v arti s si n gl e d o s e dr y  
p o w d er i n h al er C o n c e pt 1 , A c c u h al er a n d H a n di H al er
I n str u cti o n s f or u s e of C o n c e pt 1 (i n h al er f or Q V A 1 4 9)

P ur p ose a n d sc o pe
T his d oc u me nt pr o vi des i nstr ucti o n f or use of C o nce pt 1 de vice i n h o me use setti n g. It a p plies 
t o t he bl ue b utt o n versi o n of t he de vice.
T his d oc u me nt versi o n is i nte n de d f or use i n cli nical trials o nl y. T his d oc u me nt o nl y  descri bes 
t he i n haler ha n dli n g a n d n o dr u g pr o d uct relate d i nstr ucti o ns s uc h as c o ntrai n dicati o ns, dr u g 
st ora ge, a d mi nistrati o n etc.
T he i nte n de d use of t he C o nce pt 1 de vice is t o ge nerate a dr y  po w der aer os ol (fr o m t he 
f or m ulati o n c o ntai ne d wit h t he ca ps ule) f or deli ver y of t he dr y  p o w der f or m ulati o n t o t he l u n g.

I nstr ucti o ns f or use
I nstr ucti o ns f or usi n g i n h aler a n d c a ps ules.
D o n ot s w all o w c a ps ules.
F oll o w t he i nstr ucti o ns bel o w f or usi n g y o ur i n haler. Y o u will ta ke t he st u d y treat me nt
c o ntai ne d wit hi n t he ca ps ules b y  in halati o n usi n g t he i n haler. If y o u ha ve a n y q uesti o ns, 
please as k t he d oct or or n urse at t he st u d y  ce nter.
Y o ur I n h al er a n d c a p s ul e s
T h e st u d y tr e at m e nt p a c k a g e c o n si st s of b ot h t h e i n h al er a n d o n e or m or e bli st er -p a c k a g e d 
c a p s ul e s.
C a p s ul e s ar e s u p pli e d i n bli st er c ar d s.
I n h al er c o n si st s of a c a p, m o ut h pi e c e a n d a b a s e.
Y o ur i n h al er i s d e si g n e d t o d eli v er t h e m e di ci n e c o nt ai n e d wit hi n t h e c a p s ul e s.
D o n o t u s e t h e st u d y m e di c ati o n c a p s ul e s wit h a n y ot h er c a p s ul e i n h al er, a n d d o n ot u s e t h e 
i n h al er t o t a k e a n y ot h er c a p s ul e m e di ci n e.
H o w t o u s e y o ur i n h al er
P ull off c a p.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
O p e n i n h al er:
H ol d t h e b a s e of t h e i n h al er fir ml y  a n d tilt b a c k t h e 
m o ut h pi e c e. T hi s o p e n s t h e i n h al er.
Pr e p ar e c a p s ul e:
I m m e di at el y b ef or e u s e, wit h dr y h a n d s, se p ar at e o n e of 
t h e bli st er s fr o m t h e bli st er c ar d b y t e ari n g al o n g t h e 
p erf or ati o n s a n d lift t h e c or n er of t h e f oil.
R e m o v e a c a p s ul e:
P e el a w a y t h e f oil a n d r e m ov e t h e c a p s ul e fr o m t h e 
bli st er.
D o n ot p u s h t h e c a p s ul e s t hr o u g h t h e f oil.
I n s ert c a p s ul e:
Pl a c e t h e c a p s ul e i nt o t h e c a p s ul e c h a m b er.
N e v er pl a c e a c a p s ul e dir e ctl y i nt o t h e m o ut h pi e c e.
Cl o s e t h e i n h al er:
Y o u s h o ul d h e ar a “ cli c k ” a s t h e m o ut h pi e c e cl o s e s o nt o 
t h e i n h al er b a s e.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Pi er c e t h e c a p s ul e:
H ol d t h e i n h al er u pri g ht wit h t h e m o ut h pi e c e p oi nti n g u p.
Pi er c e t h e c a p s ul e b y fir ml y pr e s si n g t o g et h er b ot h si d e 
b utt o n s at t h e s a m e ti m e. D o t hi s o nl y o n c e.
Y o u s h o ul d h e ar a “ cli c k” a s t h e c a p s ul e i s b ei n g 
pi er c e d.
R el e a s e t h e si d e b utt o n s f ull y.
Br e at h e o ut:
B ef or e pl a ci n g t h e m o ut h pi e c e i n y o ur m o ut h, br e at h e 
o ut f ull y.
D o n ot bl o w i nt o t h e m o ut h pi e c e.
I n h al e t h e m e di ci n e
T o br e at h e t h e m e di ci n e d e e pl y i nt o y o ur air w a y s:
H ol d t h e i n h al er a s s h o w n i n t h e pi ct ur e. T h e si d e 
b utt o n s s h o ul d b e f a ci n g l eft a n d ri g ht. D o n ot pr e s s t h e 
si d e b utt o n s.
Pl a c e t h e m o ut h pi e c e i n y o ur m o ut h a n d cl o s e y o ur li p s 
fir ml y ar o u n d it.
Br e at h e i n r a pi dl y b ut st e a dil y a n d a s d e e pl y a s y o u c a n.
N ot e:
A s y o u br e at h e i n t hr o u g h t h e i n h al er, t h e c a p s ul e s pi n s 
ar o u n d i n t h e c h a m b er a n d y o u s h o ul d h e ar a w hirri n g 
n oi s e. Y o u will e x p eri e n c e a s w e et fl a v o ur a s t h e 
m e di ci n e g o e s i nt o y o ur l u n g s.
A d diti o n al i nf or m ati o n
O c c a si o n all y, v er y s m all pi e c e s of t h e c a p s ul e c a n g et 
p a st t h e s cr e e n a n d e nt er y o ur m o ut h. If t hi s h a p p e n s, 
y o u m a y  b e a bl e t o f e el t h e s e pi e c e s o n y o ur t o n g u e. It 
i s n ot h ar mf ul if t h e s e pi e c e s ar e s w all o w e d. T h e 
c h a n c e s of t h e c a p s ul e br e a k a g e will b e i n cr e a s e d if t h e 
c a p s ul e i s a c ci d e nt all y pi er c e d m or e t h a n o n c e ( st e p 7 ).  
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T h er ef or e it i s r e c o m m e n d e d t h at y o u f oll o w t h e st or a g e 
dir e cti o n s, r e m o v e t h e c a p s ul e fr o m t h e bli st er 
i m m e di at el y b ef or e u s e a n d pi er c e e a c h c a p s ul e o nl y 
o n c e.
If y o u d o n ot h e ar a w hirri n g n oi s e:
T h e c a p s ul e m a y  b e st u c k i n t h e c a p s ul e c h a m b er. If t hi s 
h a p p e n s:
O p e n t h e i n h al er a n d c ar ef ull y l o o s e n t h e c a p s ul e b y 
t a p pi n g t h e b a s e of t h e i n h al er. D o n ot pr e s s t h e si d e 
b utt o n s.
I n h al e t h e m e di ci n e a g ai n b y r e p e ati n g st e p s 9 t o 1 1 .
H ol d br e at h:
Aft er y o u h a v e i n h al e d t h e m e di ci n e:
H ol d y o ur br e at h f or at l e a st 5 -1 0 s e c o n d s or a s l o n g a s 
y o u c o mf ort a bl y c a n w hil e t a ki n g t h e i n h al er o ut of y o ur 
m o ut h.
T h e n br e at h e o ut.
O p e n t h e i n h al er t o s e e if a n y p o w d er i s l eft i n t h e 
c a p s ul e.
If t h er e i s p o w d er l eft i n t h e c a p s ul e:
Cl o s e t h e i n h al er.
R e p e at st e p s 9 , 1 0 , 11 a n d 1 2.
M o st p e o pl e ar e a bl e t o e m pt y t h e c a p s ul e wit h o n e or 
t w o i n h al ati o n s.
A d diti o n al i nf or m ati o n
S o m e p e o pl e m a y o c c a si o n all y c o u g h bri efl y s o o n aft er 
i n h ali n g t h e m e di ci n e. If y o u d o, d o n’t w orr y. A s l o n g a s 
t h e c a p s ul e i s e m pt y, y o u h a v e r e c ei v e d y o ur m e di ci n e.
Af t er y o u h a v e fi ni s h e d t a ki n g y o ur m e di ci n e :
O p e n t h e m o ut h pi e c e a g ai n, a n d r e m o v e t h e e m pt y 
c a p s ul e b y ti p pi n g it o ut of t h e c a p s ul e c h a m b er. P ut t h e 
e m pt y  c a p s ul e i n y o ur h o u s e h ol d w a st e.
Cl o s e t h e i n h al er a n d r e pl a c e t h e c a p.
D o n ot st or e t h e c a p s ul e s i n t h e i n h al er.
R E M E M B E R:
D o n ot s w all o w c a p s ul e s.
O nl y u s e t h e i n h al er c o nt ai n e d i n t hi s p a c k.
C a p s ul e s m u st al w a y s b e st or e d i n t h e bli st er, a n d o nl y r e m o v e d i m m e di at el y b ef or e u s e.
N e v er pl a c e a c a p s ul e dir e ctl y i nt o t h e m o ut h pi e c e of t h e i n h al er.
D o n ot pr e s s t h e si d e b utt o n s m or e t h a n o n c e.
N e v er bl o w i nt o t h e m o ut h pi e c e of t h e i n h al er.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
Al w a y s r el e a s e t h e p u s h b utt o n s b ef or e i n h al ati o n.
N e v er w a s h t h e i n h al er wit h w at er. K e e p it dr y. S e e “ H o w t o cl e a n y o ur i n h al er”.
N e v er t a k e t h e i n h al er a p art.
Al w a y s u s e t h e n e w i n h al er t h at c o m e s wit h y o ur n e w m e di c ati o n p a c k. Di s p o s e of e a c h i n h al er 
aft er 3 0 d a y s of u s e.
D o n ot st or e t h e c a p s ul e s i n t h e i n h al er.
Al w a y s k e e p t h e i n h al er a n d c a p s ul e s i n a dr y pl a c e , a n d a v oi d v ery h ot or c ol d t e m p er at ur e s .
D o n ot t a k e t h e i n h al er a p art.
H o w t o cl e a n y o ur i n h al er
N e v er w a s h y o ur i n h al er wit h w at er. If y o u w a nt t o cl e a n y o ur i n h al er, wi p e t h e m o ut h pi e c e i n si d e 
a n d o ut si d e wit h a cl e a n, dr y, li n t-fr e e cl ot h t o r e m o v e a n y p o w d er r e si d u e. K e e p t h e i n h al er dr y.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
I n str u cti o n s f or u s e of t h e Ac c u h al er ®
H o w t o clea n y o ur i n haler
Wi pe t he m o ut h piece of t he Acc u haler wit h a dr y  tiss ue t o clea n it.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
I n str u cti o n s f or u s e of t h e H a n di Hal er ®
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 7   
A p p e n di x 5: G ui d eli n e s f or A d mi ni st eri n g t h e S G R Q -C 
Q u e sti o n n air e
B ef or e t h e Tri al B e gi n s
St u d y  co or di nat ors s h o ul d fa miliarize t he msel ves wit h 
t he q uesti o n naires a n d trai ni n g 
materials i n t he trial, a n d i de ntif y an y  ite ms w here a patie nt’s res p o nse mi g ht hi g hli g ht iss ues 
of p ote ntial c o ncer n.
B ef or e C o m pl eti o n
E x plai n t o t he patie nt w h y t he y are c o m pleti n g t he q uesti o n naires, a n d h o w i m p orta nt it is f or 
us t o u n dersta n d h o w t he y feel a b o ut t heir ill ness a n d t he effect it has o n t heir dail y  life. As k 
t he pa tie nt t o c o m plete t he q uesti o n naires as h o nestl y  as p ossi ble a n d stress t hat t here are n o 
ri g ht or wr o n g a ns wers si m pl y the a ns wer t hat t he patie nt feels a p plies t o t he m. E x plai n t hat 
t he y sh o ul d a ns wer e ver y questi o n a n d t hat s o me o ne will be cl ose at ha n d t o a ns wer a n y 
q ueries.
Patie nts s h o ul d be pr o vi de d wit h t he c orrect q uesti o n naires at t he a p pr o priate visits, a n d i n t he 
a p pr o priate la n g ua ge ( T he sa me la n g ua ge s h o ul d be use d b y  t he patie nt f or all visits).
Patie nts s h o ul d ha ve a de q uate s pace a n d ti me t o c o m plete t he f or ms.
Patie nts s h o ul d be pr o vi de d wit h a fir m writi n g s urface (s uc h as a ta ble or a cli p b oar d) .
Q uesti o n naires s h o ul d be c o m plete d bef ore t he cli nical assess me nts 
D uri n g C o m pl eti o n
T he a d mi nistrat or ma y 
clarif y the q uesti o ns b ut ma y  not i nfl ue nce t he res p o nse. T he 
q uesti o n naires are desi g ne d t o elicit t he patie nt’s o pi ni o n of his/ her healt h, n ot s o me o ne else’s 
o pi ni o n of it. If the s p o use or part ner has acc o m pa nie d t he patie nt t he y s h o ul d be as ke d t o 
wait i n a se parate area. D o n ot all o w pa tie nts t o ta ke t he q uesti o n naires h o me t o be c o m plete d.
E ns ure t here is o nl y  o ne res p o nse f or eac h q uesti o n
Als o see ‘ A d dressi n g Pr o ble ms a n d C o ncer ns’ o n t he ne xt pa ge .
Aft er C o m pl eti o n
C hec k f or c o m plete ness b ut n ot f or c o nte nt .
C hec k f or m ulti ple res p o nses t hat were ma de i n err or 
File c o m plete d q uesti o n naires i n t he patie nt st u d y file n ote b o o ks pr o vi de d f or t he st u d y.
A n y  res p o nse w hic h ma y  directl y im pact o n or reflect t he patie nt’s me dical c o n diti o n (e. g. 
n oti n g of de pressi o n) s h o ul d be c o m m u nicate d b y t he st u d y c o or di nat or t o t he i n vesti gat or.
A d dr e s si n g Pr o bl e m s a n d C o n c er n s
Occasi o nall y a patie nt ma y  h ave c o ncer ns or q uesti o ns a b o ut t he q uesti o n naires a d mi nistere d. 
G ui da nce relate d t o s o me of t he m ost c o m m o n c o ncer ns a n d q ue sti o ns are gi ve n bel o w.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
T he patie nt d oes n ot wa nt t o c o m plete t he q uesti o n naire(s) .
Tell t he patie nt t hat c o m pleti o n of t he q uesti o n naire(s) is v ol u ntar y . T he g oal is t o better 
u n dersta n d t he p h y sical, me ntal, a n d s ocial healt h pr o ble ms of patie nts. E m p has ize t hat t his 
i nf or mati o n is as i m p orta nt as a n y of t he ot her me dical 
i nf or mati o n, a n d t hat t he 
q uesti o n naire(s) is si m ple t o c o m plete. S u g gest t hat t he q uesti o n naire(s) ma y  be differe nt 
fr o m a n yt hi n g t he res p o n de nt has fille d i n t he past. If t he patie nt still decli nes, retrie ve t he 
q uesti o n naires. Rec or d t he reas o n f or t he decli ne, a n d t ha n k t he patie nt.
T he patie nt is t o o ill or wea k t o c o m plete t he q uesti o n naire(s) .
I n these i nsta nces, t he c o or di nat or ma y  obtai n patie nt res p o nses b y  rea di n g o ut l o u d eac h
q uesti o n, f oll o we d b y  the c orres p o n di n g res p o nse cate g ories, a n d e nteri n g t he patie nt’s 
res p o nse. N o hel p s h o ul d be pr o vi de d t o t he patie nt b y  an y  pers o n ot her t ha n t he desi g nate d 
st u d y co or di nat or. T he c o or di nat or s h o ul d n ot i nfl ue nce patie nt res p o nses. T he st u d y 
c o or di nat or ca n n ot tra nslate t he q uesti o n i nt o si m pler la n g ua ge a n d it has t o be rea d ver bati m.
T he patie nt wa nts s o me o ne else t o c o m plete t he q uesti o n naire(s) .
I n n o case s h o ul d t he c o or di nat or or a n y o ne ot her t ha n t he patie nt pr o vi de res p o nses t o t he 
q uesti o ns.
T he patie nt d oes n ot wa nt t o fi nis h c o m pleti n g t he q uesti o n naire(s) .
If n o n- c o m pleti o n is a res ult of t he patie nt ha vi n g tr o u ble u n dersta n di n g partic ular ite ms, as k 
t he patie nt t o e x plai n t he diffic ult y .  Re-rea d t he q uesti o n f or t he m verb ati m , b ut d o n ot 
re p hrase t he q uesti o n. G ui da nce n otes o n q ueries of u n dersta n di n g f or s pecific q uesti o ns fr o m 
t he S G R Q-C User Ma n ual are pr o vi de d bel o w. If t he res p o n de nt is still u na ble t o c o m plete t he 
q uesti o n naire, acce pt it as i nc o m plete. T ha n k t he p atie nt.
T he patie nt is c o ncer ne d t hat s o me o ne will l o o k at his/ her res p o nses .
E m p hasize t hat all res p o nses are t o be ke pt c o nfi de ntial. P oi nt o ut t hat t heir na mes d o n ot 
a p pear a n y w here o n t he q uesti o n naire, s o t hat t heir res ults will be li n ke d wit h a n I D nu m ber 
a n d n ot t heir na me. Tell t he patie nt t hat his/ her a ns wers will be p o ole d wit h ot her patie nts’ 
a ns wers a n d t hat t he y will be a nal yz e d as a gr o u p rat her t ha n as i n di vi d uals. Tell t he patie nt 
t hat c o m plete d f or ms are n ot r o uti nel y share d wit h treati n g staff, a n d t hat t heir res p o nses will 
o nl y  be see n b y  yo u (t o c hec k f or c o m plet e ness), a n d p ossi bl y  the i n vesti gat or. A n y res p o nse 
w hic h ma y  directl y im pact o n or reflect t heir me dical c o n diti o n (e. g. n oti n g of se vere 
de pressi o n) will be c o m m u nicate d b y t he c o or di nat or t o t he p h ysicia n.
T he patie nt as ks t he mea ni n g of a q uesti o n / it e m.
W hile c o m pleti n g a q uesti o n naire, s o me patie nts mi g ht as k t he mea ni n g of s pecific ite ms s o 
t hat t he y ca n better u n dersta n d a n d res p o n d. If t his ha p pe ns, assist t he patie nt b y rerea di n g t he 
q uesti o n f or t he m ver b ati m. If t he patie nt as ks t o i nter pret t he mea ni n g of a n ite m, d o n ot tr y 
t o e x plai n it, b ut s u g gest t hat he/s he use his/ her o w n i nter pretati o n of t he q uesti o n. Patie nts 
s h o ul d a ns wer t he q uesti o ns base d o n w hat t hey t hi n k t he q uesti o ns mea n. H o we ver t here are 
s o me g ui da nce n otes i n t he S G R Q -C Us er Ma n ual 
re gar di n g q ueries relati n g t o s pecific 
q uesti o ns t hat ma y  be of use. T he y are pr o vi de d bel o w:
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
R e s p o n di n g t o a p ati e nt’ s q u eri e s r e g ar di n g c o m pl eti o n of t h e q u e sti o n n air e
If a patie nt as ks f or hel p wit h a q uesti o n, d o n ot pr o vi de a n a ns wer f or t he m. T he 
q uesti o n naire is desi g ne d t o get a n u n dersta n di n g of h o w t he patie nt vie ws his or her ill ness. It 
is a p pr o priate t o clarif y a q uesti o n b ut n ot t o pr o vi de a n a ns wer. Q uesti o ns ma y  be rea d al o u d 
if patie nts ha ve diffic ult y  wit h rea di n g, b ut t he res p o nses m ust be t heirs al o ne. If a patie nt 
gi ves a n a ns wer y o u disa gree wit h it is n ot a p pr o priate t o c halle n ge t heir res p o nse or t o q uer y 
it. It is t heir vie w of t heir c o n diti o n we are i ntereste d i n – n o matter h o w stra n ge t he res p o nse!
T he f oll o wi n g are n ote s t hat ma y hel p yo u e x plai n t o patie nts w hat is re q uire d
1. I n Part 1 of t he q uesti o n naire, e m p hasize t o patie nts t hat y o u are i ntereste d i n h o w m uc h 
c hest tr o u ble t he y ha ve rece ntly. T he e xact peri o d is n ot i m p orta nt. We are l o o ki n g f or a n 
i m pressi o n or perce pti o n of healt h.
2. A n attac k of c hest tr o u ble ( Part 1, Q uesti o n 5) is a n y  e pis o de of w orse s ym pt o ms t hat 
c o nstit utes a n attac k i n t he p atie nt’s o w n j u d g me nt. N ot j ust se vere attac ks as j u d ge d by 
me dical staff.
3. C O P D ca n var y  da y-t o-da y . Part 2 is c oncer ne d wit h t he patie nt’s c urre nt state (i.e. o n 
a vera ge o ver ‘t hese da ys’), n ot necessaril y j ust t o da y.
4. F or Part 1 Q uesti o n 6, e m p hasize t hat y o u are i ntereste d i n t he n u m ber of g o o d da y s t hat 
t he y ha ve ha d.
5. I n Part 2, Q uesti o ns 8 a n d 1 4 re q uire a si n gle res p o nse, b ut Q uesti o ns 9 t o 1 3 re q uire a 
res p o nse t o e ver y q uesti o n. I t ma y be w ort h e m p hasizi n g t his t o t he patie nt.
6. Ma n y patie nts d o n ot e n ga ge i n p h y sical acti vit y. It is i m p orta nt t o deter mi ne w het her t his 
is beca use t he y d o n ot wis h t o (i n w hic h case t he a ns wer w o ul d be ‘ False’) or ca n n ot 
e n ga ge i n t hese acti vities beca use of t heir c hest tr o u ble (i n w hic h case t he a ns wer w o ul d 
be ‘ Tr ue’).
7. Res p o nses t o Q uesti o ns 1 2 a n d 1 3 c o ncer n li mitati o ns d ue t o breat hi n g diffic ulties a n d n ot 
a n y ot her pr o ble ms. If t he patie nt d oes n ot e n ga ge i n a n acti vit y  f or a n ot her reas o n, t he y 
s h o ul d tic k ‘ False’.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 8   
A p p e n di x 6: 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-C)
( T he sa m ples pr o vi de d here are f or ill ustrati ve p ur p oses o nl y) 
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
2 4 
VI A pe 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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
VI A Pe n ® (e Researc h Tec h n ol o g y Gm b H) is a p orta ble data ca pt ure t o ol t hat e na bles t he 
si m ulta ne o us c ollecti o n of data electr o nicall y a n d o n pa per a n d will be use d f or c o m pleti n g 
t he patie nt q uesti o n naires f or t his st u d y. T his mai ntai ns t he ori gi nal vali date d q uesti o n naire 
a n d e na bles t he st u d y t o be set u p wit h o ut c ha n gi n g t he pr ocess f or tra diti o nal P R O c ollecti o n 
tec h ni q ues.
VI A Pe n ® is a di gital a n d a ball pe n i n o ne de vice. T he q uesti o n naires are pri nte d o n e- pa per 
w hic h is pa per wit h c o de d d ot patter n, i n visi ble t o t he na ke d e ye a n d eac h pa ge has a u ni q ue 
patter n.
W hile t he patie nt a ns wers t he q uesti o ns b y  tic ki n g b o xes, circli n g n u m bers or mar ki n g vis ual 
a nal o g scales as o n a us ual pa per wit h a n or mal pe n, t he b uilt -i n i nfrare d ca mera i n t he di gital 
pe n a ut o matica ll y rec or ds t he str o kes a n d t he ti me of t he str o kes.
After t he patie nt has c o m plete d t he q uesti o n naire, t he di gital pe n is d oc ke d i n a cra dle 
attac he d t o a c o m p uter a n d t he VI A Pe n ® s oft ware rea ds t he ca pt ure d data a n d i nter prets t he 
str o kes.
T he i n vesti gator or dele gate c hec ks t he res ults of t he a ut o mate d i nter pretati o n f or acc urac y 
a n d c o m plete ness. D uri n g t his pr ocess t he s oft ware creates a di gital i ma ge a n d a data set a n d 
tra nsfers b ot h i nt o t he ce ntral st u d y data base. A pri nt o ut of t he di gital a ns wers is create d b y  
t he i n vesti gat or bef ore t he data are tra ns mitte d. B ot h t he pri nt o ut as well as t he ori gi nal e-
pa per are file d i n t he s o urce d oc u me ntati o n at t he i n vesti gat or’s site.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
1 9   
A p p e n di x 7: C O P D A s s e s s m e nt T e st ( C A T)
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
2 0   
A p p e n di x 8: m o difi e d M e di c al R e s e ar c h C o u n cil ( m M R C) 
D y s p n e a S c al e
M o difi e d M e di c al R e s e ar c h
C o u n cil Q u e sti o n n air e f or A s s e s si n g
t h e S e v erit y of Br e at hl e s s n e s s
P L E A S E TI C K I N T H E B O X T H A T A P P LI E S T O Y O U        ( O N E B O X 
O N L Y)
m M R C
Gr a d e 0. I o nl y g et br e at hl e s s wit h str e n u o u s e x er ci s e.
m M R C Gr a d e 1. I g et s h ort of br e at h w h e n h urr yi n g o n t h e l e v el   or 
w al ki n g u p a sli g ht hill.
m M R C Gr a d e 2. I w al k sl o w er t h a n p e o pl e of t h e s a m e a g e o n t h e l e v el 
b e c a u s e of br e at hl e s s n e s s, or I h a v e t o st o p f or br e at h w h e n w al ki n g o n 
m y  o w n p a c e o n t h e l e v el.
m M R C Gr a d e 3. I st o p f or br e at h aft er w al ki n g a b o ut 1 0 0 m et er s or aft er a 
f e w mi n ut e s o n t h e l e v el.
m M R C Gr a d e 4. I a m t o o br e at hl e s s t o l e a v e t h e h o u s e or I a m br e at hl e s s 
w h e n dr e s si n g or u n dr e s si n g.
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
2 1   
A p p e n di x 9: B DI/ T DI
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6
 

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 1 Cl e a n
Pr ot o c ol N o. C Q V A 1 4 9 A 2 3 1 6