Clinical trial NCT02603393
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: COPD, QVA149
Sponsor: Novartis Pharmaceuticals
Start date: 2015-11-20; Completion date: 2017-07-18
Enrollment: 1053 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate 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

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: QVA149 intervention 2: Tiotropium intervention 3: Salmeterol/fluticasone
Intervention descriptions: intervention 1: QVA149 will be supplied in a capsule form in blister packs for use in the Novartis Concept 1 SDDPI intervention 2: Tiotropium will be supplied as commercially available blisters, delivered via HandiHaler® intervention 3: Salmeterol/fluticasone propionate dry inhalation powder delivered via Accuhaler™

Protocol documents:
Prot_001.pdf: 
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
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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)
 


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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
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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
 


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C o nfi d e nti al
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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
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A m e n d e d Pr ot o c ol V er si o n v 0 1 Cl e a n
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N o v arti s
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A m e n d e d Pr ot o c ol V er si o n v 0 1 Cl e a n
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SAP_000.pdf: 
Clinical Development
QVA149
CQVA149A2316
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
RAP Module 3 – Detailed Statistical Methodology
Author:
Tadhg Guerin, Trial Statistician
Document type:
RAP Documentation
Document status:
Final version 3.0
Release date:
18AUG2017
Number of pages:
36
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Tadhg Guerin, Trial Statistician


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 1
07-Apr-2017
Removed missing data imputation for St. George Respiratory 
Questionnaire C (SGRQ-C) data.
Added COPD GOLD 2011 and 2017 to demographic characteristics.
Added subgroup analyses for trough FEV1 using the same model as 
the primary analysis.
Time-to-first moderate or severe COPD exacerbation analysis is 
included in secondary efficacy analysis instead of exploratory 
efficacy analysis section.
Removed summary and analysis for the COPD assessment test 
(CAT) individual item scores, not reported.
Removed summary and analysis for patients who achieved a 
clinically significant difference or change in health status for at least 
2 in the total CAT score after 26 weeks of treatment, not reported.
Added subgroup analysis by region for the rate of protocol-defined
COPD exacerbations.
Summary of adjudicated MACE and/or CV deaths added.
The rate of pneumonia will be analyzed using the same generalized 
linear model as for the rate of moderate or severe COPD 
exacerbations.
Summary of proportion of patients with oral candidiasis added.
Changed wording in Laboratory data section, 24h urinary cortisol as 
24h urinary free cortisol corrected for creatinine.
For biomarkers section, change from baseline is added.
In Table 2-2, the QTc (msec) >480 notable value will not be 
presented separately.
Added subgroup analyses for all secondary endpoints considering 
blood eosinophilia counts and history of prior COPD exacerbation.
Information about BDI and TDI has been added in Section 2.7.2.
Removed heart rate parameter from vital signs in Section 1.5.2.
Removed ‘#’ in Section 1.5.2.
Amendment 2
18-Aug-2017
Add protocol deviation EXCL10B and INCL04B to Table 2-5 in 
section 2.5


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1
Statistical methods planned in the protocol and 
determination of sample size
1.1
Statistical and analytical plans 
This report and analysis plan (RAP) module describes the statistical analysis methods
specified in Section 9 of the clinical study protocol CQVA149A2316 along with any 
additional analyses, specifications or deviations before database lock. The purpose of this 
study is to determine whether the efficacy and safety of QVA149 (110/50 µg o.d.) and triple 
treatment with tiotropium (18 µg o.d.) + salmeterol/fluticasone propionate FDC (50/500 µg 
b.i.d.) are comparable in patients with moderate to severe COPD without a history of frequent 
exacerbations.
Data will be analyzed according to the data analysis Section 9 of the study protocol which is 
available in Appendix 16.1.1 of the CSR. Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
1.2
Definitions and general strategy
1.2.1
Baseline definitions
Unless otherwise specified, baseline is defined as the last measurement before first dose of 
study treatment in the treatment epoch which will be from Visit 102 or an earlier visit.
1.2.2
Assessment windows
Data from unplanned or unscheduled visits or the early discontinuation visits will be listed.
For patients who complete the study, the end of treatment visit (Visit 208) will be remapped 
to Week 26. For patients who do not complete the study, the premature discontinuation visit 
will not be remapped. Unscheduled visits will be remapped using the repeat visit number 
and/or repeat page number. No other visits will be remapped.
All efficacy data from these visits will not be used for missing data imputation. Lab oratory, 
vital signs and ECG data from these types of visits will only be included in the summaries of 
the notable values and extreme values.
Laboratory, vital signs, and ECG values which have complete data and time values will be 
slotted into pre or post-dose assessment based on the actual date/time. For values with missing 
date/time, scheduled visit date and time will be used. This rule will be applied to data from 
scheduled visits only.
1.2.3
Data collected after treatment discontinuation
Efficacy, laboratory, vital signs and ECG data collected on or after an early discontinuation 
visit will not be analyzed only listed. An exception however is a supportive analysis of the 
primary endpoint (see section 1.4.1.3).


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1.3
Patients and treatments
1.3.1
Analysis sets
The Randomized set (RAN): The RAN will consist of patients who were assigned a 
randomization number; regardless if they actually received the study medication. It will be 
used for summaries of patient disposition and analysis sets, and listings of major protocol 
deviations and premature discontinuations. Patients in the RAN will be analyzed according to 
the treatment they were randomized to.
The Full analysis set (FAS): The FAS will consist of all patients in the RAN who received at 
least one dose of study medication. Following the intent-to-treat principle, patients in the FAS
will be analyzed according to the treatment they are assigned to at randomi zation. The FAS 
will be used to analyze all efficacy endpoints, unless otherwise stated.
The Per-protocol set (PPS): The PPS will include all patients in the FAS without any major 
protocol deviations. Major protocol deviations will be defined in the data review plan prior to 
database lock and the unblinding of the study. Patients in the PPS will be analyzed according 
to the treatment group they were randomized to. Patients who receive treatment other than 
their randomized treatment because of a dispensing error will be excluded from the PPS. The 
PPS will be used for supportive analysis to assess robustness of the primary analysis. Major 
protocol deviations will be defined prior to database lock and unblinding of the study. Non-
compliance to study drug will be regarded a minor protocol deviation.
The Safety set: The Safety set will include all patients who received at least one dose of study 
medication whether they were randomized or not. Patients will be analyzed according to the 
treatment they received. If patients receive more than one treatment during the study, they will 
be analyzed according to the treatment they were randomized to. The Safety set will be used 
in the analysis of all safety endpoints and in the listings of certain notable safety data.
1.3.2
Patient disposition, demographic and other baseline characteristics
1.3.2.1
Patient disposition
The number of patients screened who completed the screening epoch will be given and the 
reasons for not entering the run-in epoch will be summarized for all patients. A similar 
summary for completion of the run-in epoch will also be provided. Patients who screen-failed 
and were re-screened under a new patient number will be counted multiple times in the total 
number of screenings.
The number and percentage of patients in the RAN who completed and discontinued
(including reasons for discontinuation) will be summarized by treatment group for the 
treatment and follow-up epochs.
Completion data for the treatment epoch (including date of last dose, completion status, and 
primary reason for discontinuation) will be listed for the RAN. The date of unblinding will be 
included if applicable. Completion data of the screening, run-in and follow-up epochs will 
also be listed.


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The number of patients with major protocol deviations (see section 2.5) or other criteria which 
cause exclusion from the PPS will be tabulated by category and deviation in the RAN. 
Protocol deviations will be listed with date and study day of occurrence, deviation and 
population codes. Separate summaries for major and minor protocol deviations will be 
provided.
1.3.2.2
Demographics and other baseline characteristics
All demographics or baseline summaries will be done using the RAN. Demographics will be 
collected at Visit 1 and all other measurements will be collected on or prior to Visit 201 (date 
of randomization) unless stated otherwise.
Demographic and baseline characteristics include the following categorical variables:

Gender (Male, Female)

Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other)

Child bearing potential (for females only) (able to bear children, post-menopausal, 
sterile-of child bearing age)

Smoking status (Patient’s usage status: current, former)

Airflow limitation (GOLD 2011) (mild, moderate, severe, very severe)

Severity of COPD (GOLD 2011) (Grade A, Grade B, Grade C, Grade D)

Symptoms/risk of exacerbation (GOLD 2017) (Grade A, Grade B, Grade C, Grade D)

Number of exacerbations in the previous year (0, 1, >1)
Categorical variables will be summarized based on the number and percentages of patients in 
each category.
Demographic and baseline characteristics include the following continuous variables:

Age (in years)

Height (in cm)

Weight (in kg)

Body mass index (BMI) (kg/m2)

Smoking history (Estimated amount consumed on average (pack years))

Duration of COPD (in years)

SGRQ-C score

mMRC score

CAT score

BDI score

Number of exacerbations in the previous year

Baseline spirometry (FEV1, FVC) 

Run-in spirometry (predicted FEV1, FEV1 , % of predicted FEV1 prior to and after 
inhalation of 400 μg of salbutamol, FEV1 reversibility, FVC, FEV1/FVC prior to and 
after inhalation of 400 μg of salbutamol)

Vital signs


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
Laboratory results

ECG
Note: Duration of COPD is calculated as: (date of enrollment – date of diagnosis of COPD + 
1)/365.25. BMI is calculated as: BMI (kg/m2) = Weight (kg) / [Height (m) × Height (m)].
Continuous variables will be summarized by presenting mean, median, standard deviation,
and, minimum and maximum.
1.3.2.3
Medical history/current medical conditions
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most actual version at the time of database lock. 
History/conditions will be summarized for both the RAN and Safety set by primary system 
organ class and preferred term. The summary will include pre-defined cardiovascular events 
and pulmonary diseases. Verbatim recorded history/conditions will be listed together with the 
coded terms, date of diagnosis/surgery and whether the problem was ongoing at start of the 
study.
1.3.3
Study medication
Unless otherwise stated, all analyses will be based on patients in the Safety set.
1.3.3.1
Study drug administration
The extent of exposure will be examined to determine the degree to which safety can be 
assessed for QVA149 (110/50 µg o.d.) and triple treatment with tiotropium (18 µg o.d.) + 
salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.). The extent of exposure to study 
drug will be characterized according to the duration of exposure and the number of patients 
exposed.
Duration of exposure to a treatment will be calculated as the number of days between the first 
dose date and the last dose date exposed to that treatment over the specified period (expressed 
as:
Duration of exposure = Date of last known dose of study drug – Date of first dose of study 
drug + 1).
The duration of exposure (in days) will be summarized by treatment for the Safety set as a 
continuous variable with the standard descriptive statistics. In addition, the duration of 
exposure will be summarized with total patient years and the number (%) of patients who 
were exposed to study drug overall and for each ≥ 2, ≥ 4, ≥ 12, ≥ 26 weeks of treatment.
1.3.3.2
Compliance
Study drug compliance will be assessed by the investigator and/or site personnel at designated 
visits according to the procedures defined in the study protocol.
Compliance will be calculated as the percentage of the number of days where study drug was 
administered as per protocol divided by the duration of exposure (i.e. the number of days 


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between first and last dose). Compliant days will be calculated following instructions given in 
the Appendix Section 2.2.
Compliance will be categorized by < 80 % and 80 % - 100 % and summarized by treatment 
for the Safety set.
1.3.3.3
Prior and concomitant medication
Each medication will have the start and end dates recorded. Prior medications are defined as 
those medications which were taken and stopped prior to the first dose of double-blinded
study drug. Concomitant medications are defined as those medications which were taken after 
the first dose of study drug. Prior concomitant medications are defined as those medications 
which were taken prior to and continued after the first dose of the study drug. All prior
concomitant medications will be summarized as concomitant medications in one table.
Medications started and stopped prior to study drug, and then taken again concomitantly will 
be included in both prior and concomitant summaries separately.
COPD-related medications will be summarized by pre-specified drug categories, route of 
administration, and preferred term, as recorded on the eCRF. The summary will be repeated 
by showing active ingredients instead of preferred terms. Non-COPD related medication will 
be summarized by route of administration and preferred term. Both COPD-related and 
non-COPD related medications will be summarized separately for prior and concomitant 
medications.
Short acting β2-agonist (SABA) usage (number of puffs) during the screening period will be 
summarized.
All summaries will be on the Safety set.
1.4
Efficacy evaluation
1.4.1
Primary efficacy analysis
The primary objective of this study is to demonstrate the non-inferiority of QVA149A 
(110/50 µg o.d.) on post-dose trough FEV1
vs. tiotropium (18 µg o.d.) + 
salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.) in terms of trough FEV1 after 26 
weeks of treatment in moderate-to-severe COPD patients.
The primary variable is the mean change from baseline in post-dose trough FEV1 after 26 
weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at
23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181 (Visit 207). 
Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 
min at Day 1 (Visit 201).
1.4.1.1
Statistical model, hypothesis, and method of analysis
The comparison between QVA149 (110/50 µg o.d.) and tiotropium (18 µg o.d.) + 
salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.) in terms of trough FEV1 at Day 182 


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will be evaluated by testing the following null hypothesis (H 0) versus the alternative 
hypothesis (Ha) at one-sided 2.5% significance level:
H0: mean change from the baseline in trough FEV1 at Day 182 (QVA149 (110/50 µg o.d.)) is 
inferior to the mean change from the baseline in trough FEV1 at Day 182 [tiotropium (18 µg 
o.d.) + salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.)]
Ha: mean change from the baseline in trough FEV1 at Day 182 (QVA149 (110/50 µg o.d.)) is 
non-inferior to the mean change from the baseline in trough FEV1 at Day 182 [tiotropium (18 
µg o.d.) + salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.)]
The primary efficacy endpoint will be analyzed using a Mixed-Effect Model Repeated 
Measures (MMRM) model.
The model will include fixed, categorical effects of treatment and visit, region, and treatment-
by-visit interaction as well as the continuous, fixed covariates of baseline and baseline-by-
visit interaction. The within-patient correlation will be modeled using an unstructured 
covariance matrix. Restricted maximum likelihood method will be used. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.
If the analysis fails to converge, then spatial covariance, compound symmetry, or first order 
autoregressive model (AR1) structure will be used. The best model fit will be determined by 
the Akaike’s Information Criterion.
The between-treatment comparison will be carried out using the adjusted mean difference 
between treatments at Day 182.
Non-inferiority of QVA149 (110/50 μg o.d.) from tiotropium (18 μg o.d.) + 
salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.) will be demonstrated if the 95%
confidence interval for the mean FEV1 difference of QVA149 (110/50 μg o.d.) minus 
tiotropium (18 μg o.d.) + salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.) lies 
entirely to the right of (higher than) –50 mL.
1.4.1.2
Handling of missing values/censoring/discontinuation
If any of the -45 min and -15 min values contributing to the trough FEV1 are collected within 
7 days of systemic corticosteroid use, 6 hr of rescue medication, or actual measurement times 
are outside the 22 - 25 hour post-morning dose time window then the individual FEV1 value 
will be set to missing.
If one of the two values is missing (or set to missing) then the remaining non -missing value 
will be taken as trough FEV1. If both values are missing, or if the patient withdrew from the 
study, regardless of the reason for discontinuation, then trough FEV1 will be regarded as 
missing in which case the missing value(s) of the patient at the particular visit(s) would not 
directly contribute to the primary analysis.
All timed-trough FEV1 data i.e. Day 29, Day 85, Day 181 and Day 182, recorded post -
baseline will be included in the primary MMRM model and no imputation will be applied to 
missing data. Instead of imputation, in the model the profile of each patient is used to adjus t 
the estimates of the parameters when data are not available (i.e. the post-withdrawal statistical 
behavior of a patient who discontinued is assumed to be the same as for a patient who 


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remained in the study and who shared the same measurement history and the same covariates, 
including treatment group).
1.4.1.3
Supportive analyses
The following supportive analyses for trough FEV1 will be performed:
1. The same MMRM model used in the primary analysis will be also performed on the PPS.
2. To assess the robustness of the primary results in the presence of missing data the 
following analyses are planned:

An analysis of covariance (ANCOVA) model (including treatment, region, and 
baseline FEV1) will be used to analyze complete datasets created using multiple 
imputations under varying assumptions. Missing FEV1 values after discontinuation for 
patients on QVA who discontinued for any reason will be imputed based on 
information from tiotropium + salmeterol/fluticasone propionate FDC patients only. 
This analysis assumes that QVA patients after discontinuation have a similar response 
to patients on triple therapy. 

Trough FEV1 at Week 26 with missing data imputed with LOCF from Day 29 will be 
analyzed using the ANCOVA model as described above.
If these analyses provide inferences consistent with the primary analysis method then the 
conclusions will not be considered highly sensitive to how missing data are handled.
3. All available trough FEV1 data at Week 26 (including retrieved data from patients who 
prematurely discontinue treatment but who attend subsequent scheduled visits) will be 
analyzed using the ANCOVA model described in point 2. To note this retrieved data may 
be affected by off-study medications.
4. Exploratory subgroup analyses for trough FEV1 using the same MMRM as the primary
analysis will be performed for the following subgroups:

Blood eosinophils (< 2% vs ≥ 2% and < 150, 150 - <300, >=300 cells/microliter)

COPD exacerbation in the previous year (0 vs 1)

Gender (male vs female)

Airflow limitation - GOLD 2011 (moderate vs severe)

Age group (40-55 vs 56-64 vs >=65)
1.4.2
Secondary efficacy analysis
The secondary endpoints will be summarized by treatment for the FAS. Subgroup analyses 
considering blood eosinophils at baseline (< 2% vs ≥ 2% and < 150, 150 - <300, >=300 
cells/microliter) and COPD exacerbation history (0 vs. 1 exacerbation) will be performed for 
each secondary endpoint described below.
Moderate or severe COPD exacerbations
In patients with multiple exacerbations, if the start date of an exacerbation was less than 7 
days after the end date of a previous episode, then this will be assumed to be one continuous 
exacerbation with the start date taken from the first episode and the end date from the second 


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or last episode. The worst severity of these episodes will be taken as t he severity of the 
collapsed exacerbation
(the merging of multiple exacerbations into one continuous 
exacerbation as defined above).
The number of moderate or severe COPD exacerbations during the treatment period will be 
summarized by treatment groups, as continuous variables and as categorical variables 
classified into 0, 1, 2, 3, ≥ 4 events.
The rate of moderate or severe COPD exacerbations during the treatment period will be 
analyzed using a generalized linear model assuming a negative binomial distribution. The 
time at risk for a patient is defined as the length of time the patient is on double -blind 
treatment and the log (length of time on double-blind treatment) will be used as the offset 
variable in the model. The analysis model will include terms for treatment, region, and COPD 
exacerbation history (the number of moderate or severe COPD exacerbations in the year prior 
to screening). An estimate of the ratio of moderate or severe COPD exacerbation rates 
between the treatment groups, together with the 95% confidence interval, will be presented.
The above summary and analysis will be repeated for the rate of moderate or severe COPD 
exacerbations requiring

systemic glucocorticosteroids and/or antibiotics during the treatment period (moderate 
exacerbations only)

hospitalizations during the treatment period and re-hospitalization within 30 days during
the treatment period (severe exacerbations only).
The time to the first moderate or severe COPD exacerbation during the treatment period will 
be analyzed using a Cox regression model. The model will include the same terms in the rate 
of moderate or severe COPD exacerbations analysis above.
Trough FEV1 and FVC, SGRQ-C, TDI
Change from baseline over 26 weeks of treatment in trough FEV1 will be analyzed using the 
same MMRM model described for the primary endpoint. Trough FEV1 is defined as the 
average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each 
visit with baseline considered the Day 1 (Visit 201) average of pre-dose measurements. 
The analyses of trough FVC change from baseline, SGRQ-C total score change from baseline, 
and Transition Dyspnea Index (TDI) total score over 26 weeks of treatment will also be done 
using a similar MMRM model with baseline FEV1 replaced by corresponding baseline for the 
endpoint. Baseline SGRQ-C is the last non-missing value prior to the first dose of double-
blind treatment.
A graph of trough FEV1 will also be presented by treatment group over time.
Mean use of rescue therapy over 26 weeks
The mean daily number of puffs and percentage of days without rescue medication usage will 
be calculated for each patient over 26 weeks. Rescue use during the run-in epoch will be used
to calculate the baseline. The mean daily number of puffs will be analyzed using a linear
mixed model with fixed categorical effects of treatment and region, a random effect of center 


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nested within region and a fixed continuous covariate of baseline. Percentage of days without 
rescue medication usage will be analyzed using a similar model.
1.4.3
Exploratory efficacy analysis
Total CAT score following 26 weeks of treatment
COPD assessment test (CAT) scores following 4, 12, and 26 weeks of treatment will be 
summarized at each visit and analyzed at these time points using the same MMRM as the 
primary endpoint. The estimated treatment difference on the contrast between QVA149 and 
tiotropium+salmeterol/fluticasone at each visit will be reported along with the associated 95% 
confidence interval and p-value.
Percentage of patients with total CAT scores of 0-10 (mild), 11-20 (moderate), 21- 30 (severe) 
and 31-40 (very severe) clinical impact after 4, 12 and 26 weeks of treatment will be 
summarized descriptively by treatment groups at each visit.
mMRC at Week 26
mMRC will be summarized at each visit (Visit 101 and 207) and change in grade will also be 
presented. An exploratory analysis of the difference between groups in grade and change in 
grade at Day181 will be performed using the Mann-Whitney U test. Change in grade at Day 
181 will be calculated as the change from Visit 101.
Rate of all protocol-defined exacerbations
The rate of protocol-defined exacerbations during the treatment period will be summarized by 
treatment groups, as continuous variables and as categorical variables classified into 0, 1, 2, 3, 
≥ 4 events.
The rate of protocol-defined exacerbations during the treatment period will be analyzed using 
a generalized linear model assuming a negative binomial distribution. The time at risk for a 
patient is defined as the length of time the patient is on double-blind treatment and the log 
(length of time on double-blind treatment) will be used as the offset variable in the model. 
The analysis model will include terms for treatment, region, and COPD exacerbation history 
(the number of moderate or severe COPD exacerbations in the year prior to screening). An 
estimate of the ratio of moderate or severe COPD exacerbation rates between the treatment
groups, together with the 95% confidence interval, will be presented.
Subgroup analysis considering region will be performed for the rate of protocol-defined 
COPD exacerbations. The same analysis model as that without subgroup analysis will be used. 
In this case the interaction term of treatment by region will be further added to the model.
Time to first exacerbation will also be performed and analyzed using a Cox regression model.
The model will include the same terms in the rate of protocol-defined exacerbations analysis 
above.


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Symptom scores
The mean total symptom score and mean individual symptom scores (i.e., scores for 
respiratory symptoms, cough, wheeze, amount of sputum, color of sputum, breathlessness, 
sore throat, cold, and fever) will be calculated for each patient over the baseline and treatment 
periods.
The change from baseline in mean daily symptom scores will be summarized by trea tment 
and will be analyzed similarly as for rescue therapy use with the baseline rescue therapy use 
being replaced by the respective baseline symptom variables in the linear mixed model.
1.5
Safety evaluation
All safety endpoints will be summarized by treatment for patients in the Safety set.
1.5.1
Adverse events
All treatment emergent adverse events (TEAEs), defined as adverse events (AEs) starting on 
or after the time of the first administration of study drug but not later than 7 days (30 days in 
the case of a SAE) after the last administration, will be included in the summaries. All adverse 
events will be listed. Events of COPD exacerbation obtained from the COPD exacerbation 
episode eCRF will be combined with the AE data and reported under the preferred term of 
“chronic obstructive pulmonary disease” together with all other events of the same preferred 
term. As a result COPD exacerbations will be included in all AE outputs.
Any adverse events that started during the study before the time of the first inhalation of study 
drug will be summarized and listed as medical histories.
The following TEAE summaries will be produced: overall by system organ class and 
preferred term; overall by system organ class, preferred term and maximum severity; 
suspected treatment-related adverse events by system organ class and preferred term; SAEs by 
system organ class and preferred term; and adverse events leading to permanent 
discontinuation of study-treatment by system organ class and preferred term.
AEs of special interest will be summarized by category, preferred term and treatment. These
are defined as:

Bladder obstruction, urinary retention

Atrial fibrillation/flutter

Cardio- and Cerebro-Vascular events (CCV) events: Cardiac arrhythmias

CCV events: Cardiac failure

CCV events: Cerebrovascular events

CCV events: Myocardial infarction

CCV events: Ischaemic heart disease

Dry mouth

Constipation

Glaucoma/increased intraocular pressure

Paradoxical bronchospasm


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
QT prolongation

Diabetes mellitus/Hyperglycemia

Pneumonia 

Lower respiratory tract infection

Respiratory composite endpoint
Adjudicated Mortality
Causes of death will be listed by patient and summarized by treatment groups for (1) mortality 
of all causes, (2) mortality of probable cardiovascular cause, (3) mortality of probable 
respiratory cause, (4) mortality of probable cancer cause and (5) mortality of probable other 
causes using the Safety set based on (A) cases reported during the active treatment period and 
(B) cases reported during the active treatment period plus the following 30 days. Mortality of 
the above 4 causes will also be summarized between treatment groups. 
Time to death will be displayed graphically for each treatment group using a Kaplan -Meier 
curve for the Safety set.
Adjudicated serious cardio- or cerebrovascular (CCV) events
All serious CCV events that occurred will be sent to the adjudication committee. Number and 
percentage of patients with serious cardiovascular (CCV) events as adjudicated by 
independent committee will be summarized by category and treatment group with and without 
adjustment by exposure. The CCV events will be adjudicated with categorized outcomes as 
Major adverse cardiovascular event (MACE) with subcategories 
1)
Non-fatal myocardial infraction (MI) 
2)
Unstable angina (USA) requiring hospitalization
3)
Non-fatal stroke 
4)
Heart failure requiring hospitalization
5)
Coronary revascularization (CABG or PCI), 
or as a serious CCV but not MACE event. 
Adjudicated MACE and/or CV deaths will be summarized as above including MACE 
subcategories.
Listing of the CCV adjudicated outcome will be provided. Adjudicated CCV events will be 
summarized as 
1) on treatment (i.e., from the first dose up to the last known dose) 
2) on treatment + 30 days follow up period whether patients completed the study 
treatment period or not.
Pneumonia
Time to first pneumonia will be summarized and analyzed for each treatment group using a 
Kaplan-Meier estimation and log rank test for the Safety set.


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The rate of pneumonia will be analyzed using the same negative binomial model as for the 
rate of moderate or severe COPD exacerbations. 
Serious/non-serious adverse events (SAE/NSAE) and deaths due to SAE
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on on-
treatment/treatment emergent adverse events (TEAEs) which are not serious adverse events 
with an incidence greater than 1% and on TEAEs and SAEs suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set 
population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
1.5.2
Vital signs
Vital signs (blood pressure, radial pulse) will be summarized by treatment at each time point 
for each visit respectively. The maximum (systolic blood pressure, pulse rate) or minimum 
(diastolic blood pressure) post first dosing will also be summarized. Changes from baseline 
will be summarized by treatment. 
All safety data will be included in the analysis regardless of rescue medication use.
Changes from baseline will also be summarized by treatment and visit. The baseline 
measurement will be the last measurement prior to first dose.
The number (%) of patients with pulse rate of < 40 bpm, 40 – 90 bpm, and > 90 bpm; systolic
blood pressure of <90 mmHg, 90 – 140 mmHg, and >140 mmHg; diastolic blood pressure of
<50 mmHg, 50 – 90 mmHg, and >90 mmHg will be summarized by treatment group.
Data measured more than 7 days after last inhalation of study treatment is regarded as post -
treatment data and will not be summarized, only listed.
Notable values for vital signs and change from baseline will be summarized. A notable value 
is defined in Appendix 16.1.9.
1.5.3
ECG
Each patient has two consecutive ECGs at baseline (greater than 45 minutes pre-dose on Day 
1 (Visit 102)) and one ECG at subsequent scheduled time points (1 hour post dose at Day 1
(Visit 201), both greater than 45 minutes pre-dose and 1 hour post dose at Week 12 and Week 


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26). The average of the values at baseline and the value at other scheduled time points will be 
calculated for the quantitative ECG assessments and the analysis.
ECG data will be summarized by treatment at each time point for each visit respectively. For 
ECG parameters, the baseline is defined as the average of the two measurements taken at 
greater than 45 min pre-dose on Day 1. The maximum QTc post first dosing will also be 
summarized. Changes from baseline will be summarized by treatment. All safety data will be 
included in the analysis regardless of rescue medication use.
Notable QTc values will be summarized for Fridericia’s QTc. Data from unscheduled visits 
and from premature discontinuation visits will be included. A listing of all newly occurring or 
worsening abnormalities will be provided. The clinically notable ranges for selected ECG 
parameters and notable changes from baseline are shown in Appendix 16.1.9.
In addition, the ECG overall interpretation of the central interpretation will be presented with 
frequencies per category and time point.
Data measured more than 7 days after last inhalation of study treatment is regarded as post-
treatment data and will not be summarized, only listed.
1.5.4
Oral fungal infections
Number and percentage of patients with oral fungal infections will be summarized by
treatment groups. Oral fungal infections are adverse events identified by the NMQ 
(90000061). Oral and oropharyngeal candidiasis, i.e. all AEs with one of the following 
preferred terms:

Oral candidiasis

Oropharyngeal candidiasis

Candida infection

Fungal pharyngitis

Oral fungal infection

Oropharyngitis fungal

Tongue fungal infection

Tonsillitis fungal
1.5.5
Laboratory data
All the laboratory samples will be processed through a Central Laboratory. Laboratory data 
consist of hematology, biochemistry and urinalysis (including 24hr urinary free cortisol
corrected for creatinine) measurements. Laboratory samples will also include oropharyngeal 
swabs which will be summarized separately. All data will be listed with abnormal values 
flagged. Laboratory data measured more than 7 days after last inhalation of study drug is 
regarded as post-treatment data and will not be summarized, only listed. The following sub-
sections describe the methods of summary.
Summary of absolute values


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For all continuous laboratory parameters, the absolute laboratory values, including the worst 
case post-baseline values (including values from post-baseline unscheduled and premature 
discontinuation visits), will be summarized with standard descriptive statistics by parameter, 
scheduled visit and timepoint, and treatment. The direction of interest for worst case post-
baseline for selected hematology and biochemistry parameters is shown in table given in the 
Appendix 16.1.9. For continuous urinalysis parameters the direction of interest is always high.
For categorical urinalysis laboratory parameters, a frequency table of results will be produced 
by laboratory parameter, scheduled visit and time-point, and treatment. Worst-case post-
baseline values (including values from post-baseline unscheduled and premature 
discontinuation visits) will also be included.
Summary of change from baseline
For continuous laboratory parameters, the change from baseline at each scheduled visit and 
time-point, and the change from baseline to the worst case post-baseline values (including 
values from post-baseline unscheduled and premature discontinuation visits) will be 
summarized by laboratory parameter, scheduled visit and time-point, and treatment with 
standard descriptive statistics.
Shift tables
Shift tables for laboratory parameters will be provided in order to compare a patient’s baseline 
value to the value at each time point at each study visit, relative to the normal reference range 
for each laboratory parameter. For the shift tables, normal reference ranges provided by the 
central lab will be used to evaluate whether a particular laboratory test value for each time 
point at each visit is normal, low, high or non-available relative to the baseline value also 
categorized as normal, low, high, or non-available. These summaries will be presented by 
laboratory test, visit, time point, and treatment group.
In addition, shift tables relative to the normal reference ranges will be used to summarize the 
change from baseline to the most extreme post-dose value for each laboratory parameter. For 
each laboratory test, the patients will be classified into one of the four mutually exclusive 
groups (low, normal, high, and high + low), defined as follows:

Low: at least one post-baseline value below the normal range and none above the normal 
range

High: at least one post-baseline value above the normal range and none below the normal 
range

Normal: all the post-baseline values within the normal range

High + Low: at least one post-baseline value below the normal range and at least one 
above the normal range
Categorical parameters in the urinalysis panel will also be summarized with shift tables 
showing the shift from one categorical result to another.
Notable values
For selected laboratory tests, the number and percentage of patients with newly occurring or 
worsening laboratory abnormalities meeting the clinically notable criteria will be summarized 


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by laboratory parameter, post-baseline visit, time point and treatment. Data from unscheduled 
visits or from premature discontinuation visits will also be included.
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value which is not clinically notable for that parameter. For a patient 
to meet the criterion of a worsening clinically notable value, the patient needs to have a 
baseline value which is clinically notable and also have a worse post-baseline value. For 
patients with missing value in baseline, any post-baseline notable value will be considered as 
newly occurring.
Guidelines for clinically notable criteria for laboratory tests are based on the FDA Guidelines 
for adults in SI units. For those parameters where ranges are available, the criteria for 
clinically notable results are presented in Appendix 16.1.9.
Listings of patients with notable laboratory values will be provided by laboratory parameter, 
treatment group, and patient number.
Liver and renal events
All data relating to liver and renal events will be listed.
1.6
Biomarkers
The analysis of biomarkers (serum WBC count, serum CRP and fibrinogen) will be 
exploratory. Mean, median, SD, minimum and maximum of the biomarkers at each visit
(including change from baseline) will be displayed.
1.7
Interim analyses
Not applicable.
1.8
Other topics
Not applicable.
1.9
Determination of sample size
The primary objective is to demonstrate non-inferiority of QVA149 (110/50 μg o.d.) versus 
tiotropium (18 μg o.d.) + salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.) with 
respect to post-dose trough FEV1 after 26 weeks of treatment.
For trough FEV1 it is assumed that the estimated treatment difference between QVA149 and 
tiotropium (18 μg o.d.)+salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.) is 0 mL and 
the non-inferiority margin is assumed to be -50 mL. This non-inferiority margin is based on 
the treatment difference between ICS and placebo summarized in two Cochrane reviews
(Nannini et al 2007 and Yang et al 2012) and the TIOSPIR spirometry sub -study (Wise et al.
2013). The selected trials were designed and conducted in COPD patients.
Based on the data pooled from two trials (Nannini et al 2007) investigating 
salmeterol/fluticasone versus placebo in terms of trough FEV1, the estimated treatment
difference between salmeterol/fluticasone and placebo is 160 mL with a 95% confidence
interval of 120 to 200 mL. Yang et al. provided summary data from 6 trials investigating ICS


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doses of greater than 1000 g BDP equivalent/day versus placebo in terms of pre-dose FEV1,
the estimated treatment difference between ICS and placebo is 80mL. A reasonable approach
to establish the non-inferiority margin is to take one half of the lower bound of the confidence
interval, which are -60 mL and -40mL respectively. The TIOSPIR spirometry sub-study in
1370 COPD patients used a non-inferiority margin of -50mL demonstrating the non-
inferiority non-inferiority of the tiotropium Respimat 5 μg device versus the tiotropium 
HandiHaler 18 μg. The two. Two formulations of tiotropium are similar in clinical efficacy 
and safety.
A sample size of 375 evaluable patients in each treatment group provides 92% power for the 
testing of non-inferiority assuming a non-inferiority margin of -50mL and a SD of 200mL
(2.5% significance level, one-sided). The standard deviation of 200mL is based on a review of
the results of Phase III COPD studies run by the sponsor. Therefore assuming a dropout rate
of 25% over 26 weeks a minimum sample size of 1000 patients (500 QVA149 (110/50 μg
o.d.): 500 tiotropium (18 μg o.d.)+ salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
has been chosen.
nQuery (V7.0) has been used to calculate the sample sizes.
2
Clinical Study Report -
Appendix 16.1.9 Documentation of statistical methods
This appendix gives details about statistical methods in addition to that provided in the main 
report text. SAS version 9.3 or higher will be used to perform all the statistical analyses in the 
report.
2.1
General data handling strategy
All categorical data will be summarized by frequencies and percentages. The frequencies and 
percentages will also be presented for missing observations.
Continuous data will be summarized with either standard descriptive statistics (i.e. the number 
of non-missing data points, arithmetic mean, standard deviation, minimum, 25% percentiles 
(Q25), median, 75% percentiles (Q75) and maximum), or will be collapsed into categorical 
data and be summarized as categorical data.
2.1.1
Output data precision
Decimal places to be used in displays of demographic, background and duration of exposure 
variables will be as follows:

3 decimal places (p-values; if p-value is less than 0.001, display < 0.001).

2 decimal places (standard errors and standard deviations).

1 decimal place (means, medians).

1 decimal place for min max

1 decimal place (percentages).

If percentage = 100, no decimal is required.


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Decimal places for efficacy and other safety summary tables and listings will be as follows:

4 decimal places (p-values; if p-value is less than 0.001, display < 0.001)

data precision + 2 decimal places (standard errors and standard deviations)

data precision + 1 decimal place (means, medians)

same as data precision (minimums, maximums)

1 decimal place (percentages)

If percentage = 100, no decimal is required.
In outputs containing estimates and p-values for inferential purposes, the means, SEs, SDs and 
confidence intervals will be output to 2 decimal places for all parameters. The p-values will be 
output to 3 decimal places (if a p-value is less than 0.001, it will be displayed as <0.001).
2.2
Compliance derivation
Compliance is presented as the percentage of days where study drug was administered as per 
protocol relative to the duration of exposure (i.e. the number of days between first and last 
dose). This will be derived using the following three eCRF summary pages:

“Dosage Administration Record – Summary – SDDPI (Concept 1)”

“Dosage Administration Record – Summary – Accuhaler” 

“Dosage Administration Record – Summary – Handihaler” 
For a study day to be compliant there must be a summary page for SDDPI (Concept 1), 
Accuhaler and Handihaler with reason for dose recorded “AS PER PROTOCOL” on each 
summary page on that day. 
It may occur that summary pages for a particular device overlap on dates (i.e. one summary 
page ends and the other starts on the same date or two kits are dispensed at a visit and it is 
unknown when one kit stopped and the other began). If this occurs then the rules below will 
be followed:

If dates overlap between summary pages for the same device and the reason for dose is 
recorded “AS PER PROTOCOL” on both pages, then the day is considered “AS PER 
PROTOCOL” for that device and can be compared with other summary pages for 
different devices to decide if the study day is compliant overall.

If dates overlap between summary pages for the same device and the reason for dose on at 
least one page is not recorded “AS PER PROTOCOL”, then the device is not considered 
“AS PER PROTOCOL” and hence the study day is not considered compliant overall.
2.3
Vital signs and ECG – definition of clinically notable values
Table 2-1
Clinically notable criteria for vital signs
Vital sign parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Notable value considering newly occurring or worsening cases
Systolic blood pressure (mm
< 75
> 200


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Hg)
Diastolic blood pressure 
(mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20
≥ 180 and increase from 
baseline by ≥ 20
Diastolic blood pressure 
(mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase from 
baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase from 
baseline by ≥ 15
Weight (kg)
Decrease ≥ 7% from baseline
Increase ≥ 7% from baseline
Table 2-2
Clinical notable criteria for selected ECG parameters
ECG parameter (unit)
Clinically notable range
Notable value considering newly occurring or worsening cases
QTc (msec)
> 450
QTc (msec)
> 500
Notable change from baseline
QTc
30 – 60
QTc
> 60
2.4
Laboratory parameters – direction of interest and definition of 
clinically notable values
The following table shows the direction of interest when analyzing worst case values in form 
of maximum and/or minimum post-baseline values. If the direction of interest is given as 
“high” the maximum value will be calculated and used as worst value, if the direction is given 
as "Low" the minimum value will be taken, and if it is given as "Low and high", both the 
minimum value and the maximum value will be calculated and presented in summary tables.
Table 2-3
Directions of interest for worst case value for laboratory parameters
Laboratory parameter
Direction of interest for worst case value
Hematology
Basophils
High
Eosinophils
High
Hematocrit
Low
Hemoglobin
Low
Lymphocytes
Low and High
Monocytes
High
Neutrophils
Low and High
Platelets
Low
RBC
Low


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WBC total
Low and High
Clinical Chemistry
Albumin
Low
Alkaline Phosphatase
High
ALT/SGPT
High
AST/SGOT
High
Bilirubin
High
Blood Urea Nitrogen (BUN)
High
Creatinine
High
Gamma GT
High
Glucose
Low and High
Sodium
Low and High
Potassium
Low and High
Total protein
Low and High
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.
Table 2-4
Clinical notable criteria for selected laboratory tests
Laboratory parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Hematology
Hematocrit (v/v)
    Male
0.37
    Female
0.32
Hemoglobin (g/L)
    Male
115
    Female
95
Thrombocytes (x10E9/L)
75
700
WBC’s (x109/L)
2.8
16.0
Chemistry
Alkaline Phosphatase (U/L)
-
3xULN
Total Bilirubin (mcmol/L)
-
34.2
Creatinine (mcmol/L)
176.8
Potassium (mmol/L)
3
6
SGOT (U/L)
-
3xULN
SGPT (U/L)
-
3xULN
BUN/Serum Urea (mmol/L)
9.99
Sodium (mmol/L)
125
160
Gamma GT (U/L)
3xULN
Glucose (random) (mmol/L)
2.78
9.99
Protein(total) (g/L)
40
95
Albumin (g/L)
25


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v = volume, ULN = upper limit of normal
2.5
Protocol deviations and associated population codes
All protocol deviations defined at the start of the study are listed with associated population 
codes in Table 2-5. The list will be updated before CDBL.
Table 2-5
List of protocol deviations and associated population codes
Protocol 
Deviation ID
Protocol Deviation Description
Classification
INCL01
Patients have not signed Informed Consent Form prior 
to initiation of any study-related procedure
Exclude from everything
INCL02
Age criteria not met
Exclude from per-protocol
INCL03
Patient is not diagnosed of moderate to severe airflow 
obstruction with stable COPD according to 2014 GOLD 
guidelines
Exclude from per-protocol
INCL04
Patient not with post bronchodilator FEV1 greater than 
or equal to 40 percent and less than 80 percent of the 
predicted normal value or post bronchodilator FEV1/FVC 
less than 0.70 at Baseline Run-in.
Exclude from per-protocol
INCL05
The estimated amount consumed on average is not 
equal to or greater than 10 Pack years
Exclude from per-protocol
INCL06
Patients are not on triple treatment at least for the last 6 
months (LAMA +LABA/ICS)
Exclude from per-protocol
EXCL01
Patients using other investigational drugs/devices  
(approved or unapproved) at the time of enrollment, or 
within 30 days or 5 half-lives of Visit 1, whichever is 
longer
Exclude from per-protocol
EXCL02
Patients contraindicated for treatment with, or having a 
history of reactions/
hypersensitivity to any of the following inhaled drugs, 
drugs of a similar class or any component thereof:
- long and short anticholinergic agents
- long and short acting beta-2 agonists
- sympathomimetic amines
- lactose or any of the other excipients of trial medication
Include in everything
EXCL03
Patient has history or current diagnosis of ECG 
abnormalities indicating significant risk of safety for 
patients participating in the study such as:
- Concomitant clinically significant cardiac arrhythmias, 
e.g., sustained ventricular tachycardia, and clinically 
significant second or third degree AV block without a 
pacemaker
- History of familial long QT syndrome or known family 
history of Torsades de Pointes
Include in everything
EXCL04
Patients with prolonged QTc interval (Frederica) is 
greater than or equal to 450 ms at Baseline Run-in Visit.
Include in everything
EXCL05
Concomitant use of agents known to significantly 
prolong the QT interval unless it can be permanently 
Exclude from per-protocol


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discontinued for the duration of study
EXCL06
Patients has a clinically significant laboratory 
abnormality at Visit 101 and would be at potential risk if 
enrolled into the study
Include in everything
EXCL07
Patients has clinically significant renal or cardiovascular 
or arrhythmia or neurological or endocrine, 
immunological or psychiatric, gastrointestinal or hepatic 
or hematological abnormalities which could interfere with 
the assessment of the efficacy and safety of the study 
treatment
Exclude from per-protocol
EXCL08
Patient has paroxysmal atrial fibrillation or un-controlled 
persistent atrial fibrillation
Include in everything
EXCL09
Patient has narrow angle glaucoma, symptomatic 
BPH/bladder neck obstruction, moderate/severe renal 
impairment or urinary retention
Include in everything
EXCL10
Reversibility test not performed to ATS/ERS standard
Exclude from per-protocol
EXCL11
COPD exacerbation occurred 12 months prior to study 
start that required treatment with Systemic 
corticosteroids, Systemic antibiotics or led to 
Hospitalization
Exclude from per-protocol
EXCL12
Patients developed COPD exacerbation  between 
Screening and Randomization or re-screening is not as 
per protocol
Exclude from per-protocol
EXCL13
Patient has respiratory tract infection  within 4 weeks 
prior to Screening (Visit 1)
Exclude from per-protocol
EXCL14
Respiratory tract infection occurred between Screening 
(Visit 1) and Randomization visit (Visit 201) or is re-
screened within 4 weeks of resolution of Respiratory 
tract infection
Exclude from per-protocol
EXCL15
Long term oxygen therapy of > 12 h per day prescribed 
to patient
Exclude from per-protocol
EXCL16A
Patient has history of asthma
Exclude from per-protocol
EXCL16B
Patient has history of asthma
Exclude from per-protocol
EXCL17
Patients with a blood eosinophil count > 600/mm3 during 
screening (Visit 101)
Exclude from per-protocol
EXCL18
Patient has Allergic rhinitis and using either H1 
antagonist or intranasal corticosteroid intermittently and 
is not on a stable dose or regimen
Include in everything
EXCL19
Patients with concomitant pulmonary disease 
(bronchiectasis and all non-solicited pulmonary 
diseases)
Exclude from per-protocol
EXCL20
Patient with diagnosis of  alpha 1 anti-trypsin deficiency
Exclude from per-protocol
EXCL21
Patient with active tuberculosis
Exclude from per-protocol
EXCL22
Patient has undergone Pulmonary lobectomy or Lung 
volume reduction surgery or lung transplantation
Exclude from per-protocol
EXCL23
Patients plan to or are participating in the active phase 
of a supervised pulmonary rehabilitation programme
Exclude from per-protocol


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EXCL24
Patient receiving prohibited medication
Exclude from per-protocol
EXCL25
Patients receiving any COPD related medications
Exclude from per-protocol
EXCL26
Patients receiving medications in the classes listed in 
Table 5-3 or not been stable on the medications for the 
specified period and stated conditions
Exclude from per-protocol
EXCL27
Patient unable to use an electronic patient diary
Exclude from per-protocol
EXCL28
Patient unable to use inhaler at Run-in and/or at 
Randomization or using Spacer device
Exclude from per-protocol
EXCL29
Patient has active cancer or has been cancer free for 
less than 5 years
Exclude from per-protocol
EXCL30
Subject is Pregnant or nursing (Lactating)
Exclude from per-protocol
EXCL31
Women of childbearing potential not using effective 
methods of contraception during dosing of study 
treatment
Include in everything
COMD01
Banned non-indication Conmed taken
Exclude from per-protocol
COMD02
Banned COPD Conmed taken
Exclude from per-protocol
OTH01
An Adverse Event for oral fungal infection is reported, 
however the presence of the infection was not confirmed 
by the central lab
Include in everything
OTH02
Non-compliance with SAE reporting timelines
Include in everything
OTH04A
Patient randomized in error
Exclude from per-protocol
OTH04B
Patient randomized in error
Exclude from per-protocol
OTH06
Patient randomized more than once into this study or 
also randomized into another study
Exclude from full analysis
TRT01
Patient administered at least one incorrect treatment
Exclude from per-protocol
TRT02
IMP administered instead of run-in medication
Exclude from per-protocol
TRT03
Evening dose from Accuhaler not administered at V207 
(Visit 10) due to site instruction.
Exclude Visit 208 
spirometry from per-
protocol analysis if patient 
is in triple therapy arm
WITH01
Patient pregnant during study and not discontinued from 
study drug treatment
Include in everything
WITH02
Blind broken and study drug not permanently 
discontinued
Exclude from per-protocol
COMD03
Inactivated vaccination taken within 48 hrs prior to a 
study visit
Exclude from per-protocol
EXCL10B*
Reversibility test not performed to ATS/ERS standard
Exclude from per-protocol
INCL04B*
Patient not with post-bronchodilator FEV1 greater than 
or equal to 40 percent and less than 80 percent of the 
predicted normal value or post-bronchodilator 
FEV1/FVC less than 0.70 at Baseline Run-in.
Exclude from per-protocol
*protocol deviations EXCL10B and INCL04B will be created outside of clinical database 
during statistical analysis where deviations will be generated for:

(EXCL10B) patients who do not have acceptable spirometry results, post-bronchodilator 
inhalation, at visit 101.


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
(INCL04B) patients who do not have post-bronchodilator FEV1 greater than or equal to 
40 percent and less than 80 percent of the predicted normal value or do not have post-
bronchodilator FEV1/FVC less than 0.70 at visit 101.
2.6
COPD GOLD
2.6.1
COPD treatment: Gold 2011 Guidelines
Overall Severity
Gold 2011 (or 2014) guidelines grade patients (A-D) based on symptoms, airflow obstruction 
and exacerbation history as follows:

A = Low risk, low symptom burden
Low symptom burden (mMRCof 0-1 OR CAT score < 10) AND
FEV1 of 50% or greater AND low exacerbation rate (0-1/year)

B = Low risk, higher symptom burden
Higher symptom burden (mMRC of 2 or more OR CAT of 10 or more) AND
FEV1 of 50% or greater AND low exacerbation rate (0-1/year)

C = High risk, low symptom burden
Low symptom burden (mMRCof 0-1 OR CAT score < 10) AND
FEV1 < 50% AND/OR high exacerbation rate (2 or more/year)

D = High risk, higher symptom burden
Higher symptom burden (mMRC of 2 or more OR CAT of 10 or more) AND
FEV1 < 50% AND/OR high exacerbation rate (2 or more/year)
Airflow limitation:
Gold Grade
FEV1 (% predicted)
Gold 1 (Mild)
≥80
Gold 2 (Moderate)
50-79
Gold 3 (Severe)
30-49
Gold 4 (Very severe)
<30
2.6.2
COPD treatment: Gold 2017 Guidelines
Gold 2017 guidelines grade patients (A-D) based on symptoms and exacerbation history as 
follows:

A= Low symptom burden (mMRCof 0-1 OR CAT score < 10) AND low exacerbation 
rate (0-1/year)

B= Higher symptom burden (mMRC of 2 or more OR CAT of 10 or more) AND low 
exacerbation rate (0-1/year)


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
C= Low symptom burden (mMRCof 0-1 OR CAT score < 10) AND high exacerbation 
rate (2 or more/year)
D= Higher symptom burden (mMRC of 2 or more OR CAT of 10 or more) AND high 
exacerbation rate (2 or more/year)
2.7
Baseline and post-baseline definitions, missing data handling
2.7.1
Baseline measurements
1) For all FEV1 and FVC endpoints, the baseline value is defined as the average of the 
values taken at 45 and 15 minutes prior to first dose of double-blind drug at Day 1. 
Checks will be performed to ensure both values were indeed taken prior to the first 
dose of double-blind drug. If one of the values from 45 and 15 minutes prior to dose is 
missing (or is not confirmed to be pre-dose) then the remaining non-missing value will 
be taken as the baseline. If both values are missing (or are not confirmed to be pre-
dose), then the pre-bronchodilator measurements taken at the run-in visit-day -28 can 
be used as the baseline. If the FEV1 or FVC measurements are missing both on Day 1 
and at run-in visit, the respective baseline values will be set to missing. Measurements 
taken within 6 hours of rescue use or within 7 days of systemic corticosteroid use will 
be set to missing.
2) FEV1 reversibility is calculated as percentage increase of FEV1 values after sequential 
inhalation of 4 x 21 µg of ipratropium bromide and 4 x 100 µg puffs of salbutamol 
relative to FEV1 values prior to the inhalation. Patients are defined as "Not reversible" 
if post- bronchodilator FEV1 change from pre-bronchodilator value is < 12% or < 200 
mL, and defined as "Reversible" if the increase of FEV1 is ≥ 12% and ≥ 200 mL.
3) For patient diary data (symptoms and rescue therapy use), the baseline values are 
defined as the average from all records taken in the run-in period, which is usually a 
28-day period between run-in visit 101 and up to and including the morning 
assessments at Day 1. All days with data will be used for calculating the baseline value 
without limitation to the 28 days immediately prior to Day 1. For the baseline daily 
individual symptom score, the worst of the morning and evening assessments for the 
particular symptom on each of these days will be averaged (with denominator equal to 
the number of days featuring in the calculation). If either the morning or evening score 
is missing for any symptom then the non-missing value will be taken as the worst and 
used for the derivation of the baseline daily individual symptom scores. If both scores 
for an individual symptom are missing then the daily score for that individual 
symptom will be considered missing (i.e., no imputation performed).
The baseline daily total symptom score will be obtained by adding the daily individual 
symptom scores and averaging over the number of days featuring in the calculation. 
Only the scores of the 6 COPD symptoms (i.e., respiratory symptoms, cough, wheeze, 
production of sputum, sputum color, and feeling of breathlessness) will be used to 
derive the total daily symptom score. For the derivation of the total daily symptom 
score, all 6 scores have to be available at that day. If one or more scores of the 6 
COPD symptoms are missing, a total daily symptom score will not be calculated for 
that day.


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For rescue medication, the baseline value is defined as the average number of puffs 
per day in the run-in period. If the number of puffs is missing for part of the day 
(either daytime or nighttime) then a half day will be used in the denominator. No 
imputation will be used for missing rescue therapy. Any values > 48 for the number of 
puffs of rescue medication in a 12 hour period will be set to missing. These high 
numbers are not realistic and could impact the analyses.
If a patient has less than 7 days with non-missing data, then the respective baseline 
value will be set to missing.
4) Baseline SGRQ-C, BDI and COPD assessment test (CAT) are defined as the 
assessments taken right before the first dose of the double-blind drug on Day 1. 
5) Baseline vital signs (blood pressure, radial pulse) are defined as the assessments taken 
at > 45 minutes pre-dose on Day 1. Checks will be performed to ensure the 
assessments were indeed taken prior to the first dose of double-blind drug on Day 1. If 
this assessment is missing or not confirmed to be pre-dose, the last value taken at the 
run-in Visit 101 or at an unscheduled visit before the first administration of double-
blind drug will be used for baseline.
6) Baseline height and weight are defined as the measurements taken at start of the run-in 
period (Visit 101). Missing baseline will not be imputed.
7) Baseline ECG is defined as the mean of two consecutive ECG (at 1 minute interval) 
readings taken prior to first dose of double-blind drug on Day 1. Checks will be 
performed to ensure the ECG was indeed assessed prior to the first dose of double-
blind drug. If one of the two values is missing (or not confirmed to be pre-dose) then 
the remaining non-missing value will be taken as the baseline. If both values are 
missing (or not confirmed to be pre-dose), then the last value taken at the run-in Visit 
101 or at an unscheduled visit before the first administration of double-blind drug will 
be used for baseline. Otherwise, the ECG baseline will be set missing without 
imputation. The worst interpretation and all findings associated with abnormal 
interpretation(s) of the two consecutive ECGs will be used as baseline.
8) Baseline laboratory data are defined as the assessment taken prior to first dose of 
double-blind drug on Day 1. Checks will be performed to ensure baseline laboratory 
values were indeed assessed pre-dose. If the values are missing (or not confirmed to be 
pre-dose) then the last value taken at the run- in Visit 101 or at an unscheduled visit 
before the first administration of double-blind drug will be used for baseline.
9) ICS use at screening will be derived from the concomitant medication eCRF data by 
selecting medications with route of administration = "Respiratory (inhalation)" and 
pre- specified medication subcategory = "Corticosteroid" or fixed combination type = 
"Inhaled corticosteroid / long-acting beta 2 agonist (ICS / LABA)" or "Inhaled 
corticosteroid / long- acting anticholinergic (ICS / LAMA)". Since ICS is a prohibited 
medication during the run-in period, the status at screening will be analyzed. If at least 
one of the above medications is taken at the screening, i.e. taken at the day of the 
screening visit (i.e. medications starting prior to visit 1 and ending at or after visit 1) , 
then ICS use at screening will be set to "yes", otherwise to "no". Note that this 
derivation of ICS use at screening will be used in all tables and statistical models 
rather than the stratified randomization data from the Interactive Response Technology 


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(IRT) vendor. The same is true for the other two stratified randomization variables 
smoking status (ex-smoker, current smoker) and airflow limitation severity (moderate, 
severe or worse).
10) LABA use at screening will be derived from the concomitant medication eCRF data 
by selecting medications with pre-specified medication subcategory = "Long-acting 
beta 2 agonist" or fixed combination type = "Inhaled corticosteroid / long-acting beta 2 
agonist (ICS / LABA)" or "Long-acting beta 2 agonist / long-acting anticholinergic 
(LABA / LAMA)". Since LABA is a prohibited medication during the run-in period 
(same as ICS), the status at screening will be analyzed. If at least one of the above 
medications is taken at screening , i.e. taken at the day of the screening visit (i.e. 
medications starting prior to visit 1 and ending at or after visit 1)), then LABA use at 
screening will be set to "yes", otherwise to "no".
11) LAMA use at screening will be derived from the concomitant medication eCRF data 
by selecting medications with pre-specified medication subcategory = "Long-acting 
anticholinergic" or fixed combination type = "Inhaled corticosteroid / long-acting 
anticholinergic (ICS / LAMA)" or "Long-acting beta 2 agonist / long-acting 
anticholinergic (LABA / LAMA)". Since all patients will be given tiotropium during 
the run-in period, the status at screening will be analyzed. If at least one of the above 
medications is taken at screening, i.e. taken at the day of the screening visit (i.e. 
medications starting prior to visit 1 and ending at or after visit 1), then LAMA use at 
screening will be set to "yes", otherwise to "no".
12) ICS/LABA use at screening will be derived from the concomitant medication eCRF 
data by selecting medications with fixed combination type = "Inhaled corticosteroid / 
long-acting beta 2 agonist (ICS / LABA)". Since ICS/LABA is a prohibited 
medication during the run-in period, the status at screening will be analyzed. If at least 
one medication is taken at screening, i.e. taken at the day of the screening visit (i.e. 
medications starting prior to visit 1 and ending at or after visit 1), then ICS/LABA use 
at screening will be set to "yes", otherwise to "no".
13) Cardiovascular risk factors at baseline: Seven cardiovascular risk factors are defined.
1. CCV history/condition = at least one out of: Myocardial infarction, Stroke, 
Peripheral arterial disease, Coronary artery bypass graft, or Percutaneous 
transluminal coronary angioplasty, as reported on the eCRF page of "Medical 
History – Protocol solicited events – Cardiovascular events".
2. Hypertension, as reported on the eCRF page of "Medical History – Protocol 
solicited events Cardiovascular events".
3. Hyperlipidemia = at least one out of: Hyperlipidemia, Hypercholesterolemia, as 
reported on the eCRF page of "Medical History – Protocol solicited events –
Cardiovascular events".
4. Diabetes mellitus = Type 1 or Type 2 diabetes mellitus, as reported on the eCRF 
page of "Medical History – Protocol solicited events – Cardiovascular events".
5. Obesity at baseline (i.e., BMI > 30 kg/m2).
6. Age ≥ 65 years.
7. Current smoker at screening.


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2.7.2
Post-baseline measurements
1) FEV1 and FVC measurements taken within 6 hours of rescue use or within 7 days of 
systemic corticosteroid use will be set to missing.
Post dose FEV1 and FVC values, where no morning dose was taken at the 
corresponding visit will be set to missing. If pre-dose measurements are performed 
one day after treatment end date, they will be set to missing if the last dose was not an 
evening dose.
Scheduled pre-dose values which are performed post-dose and scheduled post-dose 
values which are performed prior to morning dose or after evening dose (serial 
spirometry set only) will be set to missing.
The pre-dose trough value is defined as the average of values measured 45 and 15 
minutes prior to the morning dose. If one of the two values is missing (or is not 
confirmed to be pre- dose) then the remaining non-missing value will be used as 
average pre-dose value.
2) The SGRQ-C contains 40 items divided into two parts covering three aspects of health 
related to COPD: Part I covers "Symptoms" and is concerned with respiratory 
symptoms, their frequency and severity; Part II covers aspects of "Activity" and 
"Impacts", "Activity" is concerned with activities that cause or are limited by 
breathlessness and "Impacts" covers a range of aspects concerned with social 
functioning and psychological disturbances resulting from airways disease. A score 
will be calculated for each of these three subscales and a "Total" score will also be 
calculated. In each case the lowest possible value is zero and the highest 100. Higher 
values correspond to greater impairment of health status.
The algorithm below is based on SGRQ-C Manual Version No. 1.2, April 2012, 
updated on 28 September 2012.
Principle of calculation
Each response will be given a unique empirically derived weight between 0 and 100, 
the weights of all responses will be summed up and divided by the maximum possible 
score and expressed as a percentage.
Each component of the questionnaire is scored separately in three steps:
1. The weights for all items with positive responses are summed.
2. The weights for missed items are deducted from the maximum possible weight for 
each component and for the Total score.
3. The score is calculated by dividing the summed weights by the adjusted maximum 
possible weight for that component and expressing the result as a percentage.
Sum of maximum possible weights that could be obtained for the worst possible state 
of the patient for each component and Total:
Symptoms
566.2
Activity
982.9
Impacts
1652.8
Total
3201.9


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Symptoms component is calculated from the summed weights for the positive 
responses to Questions 1-7 (Part 1). The Symptoms component tolerates a maximum 
of 1 missed item.
Activity component is calculated from the summed weights for the positive responses 
to Questions 9 and 12 (13 "true/false" questions, Part 2). The Activity component 
tolerates a maximum of 3 missed items.
Impacts component is calculated from the summed weights for the positive responses 
to Questions 8, 10, 11, 13, 14 (2 "select" questions and 18 "true/false" questions, Part 
2). The Impacts component tolerates a maximum of 5 missed items.
Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire. The 
Total score requires that each of the three component scores has a tolerable number of 
missed items.
Scores for SGRQ-C, calculated as described above, need a small arithmetic adjustment 
to make them directly comparable to those obtained with the SGRQ.
The adjustment is:
Symptoms: SGRQ score = (SGRQ-C x 0.99) + 0.94 units 
Activity: SGRQ score = (SGRQ-C x 0.87) +7.01 units 
Impacts: SGRQ score = (SGRQ-C x 0.88) +2.18 units 
Total: SGRQ score = (SGRQ-C x 0.90) + 3.10 units
3) CAT consists of eight items, each presented as a semantic 6-point differential scale 
(with scores from 0 to 5), providing a total score from 0 to 40 indicating the impact of 
the disease. It is completed by the patient. The total score will be derived as the sum of 
scores on individual items. If more than two responses are missing, a total score will 
not be calculated. When one or two items are missing their scores will be imputed by 
the average of the non-missing item scores for calculation of the total score (Jones et 
al, 2009). Scores of 0 - 10, 11 - 20, 21 - 30 and 31 - 40 represent mild, moderate, 
severe or very severe clinical impact.
4) Rescue medication use and other symptoms will be collected in the patient diary in the 
morning and evening at each day by assessing the past 12 hours. The post-baseline 
treatment period is defined as the period from the evening record of Day 1 up to the 
morning assessment following the day of the last inhalation of double-blind treatment. 
Missing diary data will not be imputed. Post-baseline values will be calculated only if 
a patient has at least 30% of their treatment days and at least 20 days with evaluable 
diary data for that variable in the post- baseline period. Daily individual and total 
symptom scores as well as daily rescue medication use will be derived as described in 
the section of baseline measurements. The mean daily, daytime and nighttime number 
of puffs of rescue medication and individual and total symptom scores will be 
calculated for the whole post-baseline treatment period.
5) Safety measurements include ECG, vital signs, laboratory results, 24 hour urinary 
cortisol (in a subset of patients) and adverse events. All safety data will be included in 
the analysis regardless of rescue medication usage. Post-baseline treatment-emergent 
measurements comprise recordings up to the last dose of double-blind drug + 7 days 
for laboratory, ECG, vital signs, and non-serious AEs and up to the last dose of 


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double-blind drug + 30 days for SAEs and death. ECG, vital signs, laboratory and 24 
hour urinary cortisol values which have complete date and time values are assigned to 
pre or post-dose assessment based on the actual date/time. However, values with 
missing date/time are assigned to their respective scheduled visit date and time given 
the visit number is non-missing.
6) Dyspnea will be measured at baseline using the baseline dyspnea index (BDI) and 
during the treatment period using the transition dyspnea index (TDI), which captures 
changes from baseline. The BDI and TDI each has three domains; functional 
impairment, magnitude of task and magnitude of effort. The BDI domains are rated 
from 0 (severe) to 4 (unimpaired) and the rates are summed for the baseline focal 
score ranging from 0 to 12; the lower the score the worse the severity of dyspnea. The 
TDI domains are rated from -3 (major deterioration) to 3 (major improvement) and the 
rates are summed for the transition focal score ranging from -9 to 9; negative scores 
indicate deterioration. A TDI focal score of 1 is considered to be a clinically 
significant improvement from baseline. 
2.8
Statistical Analysis Outputs
List of statistical analysis outputs were outlined in RAP Module 7 – Section 16.1.9.
2.9
SAS code
Mixed Model for Repeated Measures (MMRM)
The mean change from baseline in post-dose trough FEV1 at Day 182 will be analyzed using 
a Mixed-Effect Model Repeated Measures (MMRM). The model includes the following 
factors:
Change from baseline = intercept + treatment + visit + region + baseline FEV1 + 
treatment*visit + baseline FEV1*visit + error.
The SAS procedure PROC MIXED will be used with the following code:
Proc Mixed data=… order=internal;
where avisitn in (201 202 203 204 205 206 207 208);
class trt georgn avisitn usubjid;
model chg = trt base georgn avisitn trt*avisitn base*avisitn / DDFM=kr;
repeated avisitn / Subject= usubjid type=un rcorr;
lsmeans trt*avisitn / cl diff;
Run;
where 
chg = change from baseline
trt = Treatment (QVA149, Tio+Salm/Flut)
base = baseline value
georgn = region (Africa, Asia, Eastern Europe, Western Europe, Latin and South
America, North America)


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avisitn = visit (include the scheduled visits only, no unscheduled or premature
discontinuation visits)
usubjid = unique subject identifier
Appropriate baseline values and visits will be included for each analysis variable.
The default estimation method for the covariance parameters will be used, which is the 
residual (restricted) maximum likelihood. 
Results will be presented with least squares means and standard errors (SE) for treatment 
effects and least squares mean, SE, associated two-sided 95% confidence interval, and one-
sided p-value for treatment contrast QVA149 – Tio+Salm/Flut at week 26. Regarding 
treatment difference, the two-tailed p-value for the Wald test should be divided by 2 to get the 
approximate p-value for a one-tailed test. Degrees of freedom will be estimated based on 
Kenwards Rogers approximation (DDFM=kr).
If the analysis fails to converge with an unstructured covariance matrix (type=un), either a 
compound symmetry (first choice) or first order autoregressive (AR1) (second choice) 
covariance structure will be used.
ANCOVA analysis using Multiple Imputation (MI)
The mean change from baseline in post-dose trough FEV1 at Day 182 will be analyzed using 
ANCOVA with Multiple Imputation of the missing data. The model includes the following 
factors:
Change from baseline = intercept + treatment + region + baseline FEV1 + error.
The SAS PROC MI procedure carries out multiple imputations creating several “complete” 
versions of the dataset. A key indicator of the efficiency of the imputation is the DF for 
posterior parameter estimates. If the DF for a variable is less than 100, there is excessive 
variability among imputations for that variable, and more imputations are needed to improve 
the efficiency of imputation.
A multiple imputation will be performed based on missing at random (MAR) by treatment 
group for baseline and post-baseline values of trough FEV1 parameter for visits up to the 
primary time point (Week 26) using Markov Chain Monte Carlo (MCMC) method with EM 
algorithm.
Impute the missing values 100 times (NIMPUTE) with a seed=457<studycode> as shown
below:
proc mi data=… out=imputed minmaxiter=10000000 nimpute=100 seed=4572316;
by trt;
var fev1_base fev1_week1-fev1_week26;
mcmc chain=multiple initial=em;
run;
Then PROC MIXED procedure will be used to analyze each imputed dataset as shown below:
proc mixed data=imputed;
ods output lsmeans=lsm;


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where avisitn =208;
class trt georgn;
by _Imputation_;
model chg = trt base georgn;
lsmeans trt;
run;
quit;
where 
chg = change from baseline
trt = Treatment (QVA149, Tio+Salm/Flut)
base = baseline value
georgn = region (Africa, Asia, Eastern Europe, Western Europe, Latin and South
America, North America).
At the last step PROC MIANALYZE procedure will combine data over imputations to 
produce the final results.
proc sort data=lsm; 
by trt; 
run; 
proc mianalyze data=lsm;
ods output parameterestimates=ls_means; 
by trt; 
modeleffects estimate; 
stderr stderr; 
run; 
Results will be presented with least squares means and standard errors (SE) for treatment 
effects and least squares mean, SE, associated two-sided 95% confidence interval, and one-
sided p-value for treatment contrast QVA149 – Tio+Salm/Flut at Week 26. Regarding 
treatment difference, the two-tailed p-value for the Wald test should be divided by 2 to get the 
approximate p-value for a one-tailed test.
Generalized linear model assuming a negative binomial distribution
The rate of COPD exacerbations during the treatment period will be analyzed using a
generalized linear model assuming a negative binomial distribution. The negative binomial 
distribution will often be used as an alternative to the Poisson distribution. It is especially 
useful for discrete data over an unbounded positive range whose sample variance exceeds the 
sample mean. If a Poisson distribution is used to model such data, the model mean and 
variance are equal. In that case, the observations are overdispersed with respect to the Poisson 
model. Since the negative binomial distribution has one more parameter than the Poisson, the 
second parameter can be used to adjust the variance independently of the mean.
The time at risk for a patient is defined as the exposure time and the log(exposure time in 
years) will be used as the offset variable in the model.


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The explanatory variables are: treatment, region, COPD exacerbation history (the number of 
moderate or severe COPD exacerbations in the year prior to screening).
The SAS procedure GENMOD will be used with the following SAS code:
proc genmod data=.... order=internal;
class trt georgn;
model aval = trt georgn exprevyn /
dist=nb link=log offset=logrisk lrci type3 wald;
lsmeans trt / cl diff exp;
run;
where aval = number of COPD exacerbations
trt = treatment (QVA149, Tio+Salm/Flut)
georgn = region (Africa, Asia, Eastern Europe, Western Europe, Latin and South
America, North America)
exprevyn = number of moderate or severe COPD exacerbations during 12 months prior to 
study
logrisk = log (exposure time in years).
It should be noted that the regression model using GEE requires that in a particular level of a 
class factor at least one event in at least one patient must have been occurred to give an 
estimate for that level of a factor, otherwise the model does not converge.
Results will be presented with QVA149/ (Tio+Salm/Flut) ratio of rates and associated 95% 
confidence interval and two-sided p-value.
Cox regression analysis
Time to first COPD exacerbation will be analyzed with a Cox proportional hazards 
regression model. The null-hypothesis will be H0: λQVA(t) / λSFC(t) = 1, where λ
(t) is the hazard function for the failure time of patients treated with QVA149
and Tio+Salm/Flut, respectively. The SAS procedure PHREG will be used with the 
following SAS code:
proc phreg data=.... ;
class trt(order=internal) georgn;
model aval*cnsr(1) = trt georgn exprevyn / rl ties=exact;
hazardratio trt;
contrast "QVA149 vs. Tio+Salm/Flut" trt 1 / estimate=exp;
run;
where aval = time to first COPD exacerbation
cnsr = data are censored if cnsr = 1
trt = treatment (QVA149, Tio+Salm/Flut)
georgn = region (Africa, Asia, Eastern Europe, Western Europe, Latin and South
exprevyn = number of COPD exacerbations during 12 months prior to study.


Novartis
Confidential
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Results will be presented with the hazard ratio for QVA149/ (Tio+Salm/Flut) and associated 
95% confidence interval and two-sided p-value. P-value will be obtained from the Wald chi-
squared statistic testing the null-hypothesis that the parameter estimate for the respective 
treatment effect is 0 (then the hazard ratio is exp(0) = 1). No check for the validity of 
proportional hazards assumptions will be done.
Linear mixed model
A linear mixed ANCOVA model will be used for changes from baseline in daily number of 
puffs of rescue medication use averaged over the 26 weeks of treatment and other related 
variables derived from the patient diary.
Change from baseline = intercept + treatment + baseline + region + center(region) as a 
random effect + error.
The SAS procedure MIXED will be used with the following code:
proc mixed data=… order=internal;
class trt georgn siteid;
model chg = trt base georgn / ddfm=kr;
random siteid(region)/ type=vc;
lsmeans trt / cl diff;
where chg = change from baseline
trt = treatment (QVA149, Tio+Salm/Flut)
base = baseline value
georgn = region (Africa, Asia, Eastern Europe, Western Europe, Latin and South
America, North America)
siteid = study site identifier.
Results will be presented with least squares mean and SE for treatment effects and least 
squares mean, SE, associated two-sided 95% confidence interval and two-sided p-value for
the treatment contrast QVA149 - Tio+Salm/Flut.
Mann-Whitney U test
A Mann-Whitney U test will be performed to explore the difference between treatment groups  
(QVA149 and Tio+Salm/Flut) in mMRC grade and change in grade at week 26 (Day 181).
The SAS procedure PHREG will be used with the following SAS code:
proc npar1way data=… Wilcoxon median;
class trt;
var mmrc;
run;
where mmrc = mMRC Dyspnea Scale (Grade 0, Grade 1, Grade 2, Grade 3, Grade 4)
trt = treatment (QVA149, Tio+Salm/Flut)


Novartis
Confidential
Page 36
RAP Module 3
18-Aug-2017 (7:58)
CQVA149A2316
The WILCOXON option requests the Wilcoxon test for the difference between the groups, 
and the MEDIAN option requests the median test additionally. Results will be presented with 
mean scores and SE for treatment effects, and two-sided p-value for the treatment contrast 
QVA149 - Tio+Salm/Flut.