A Multicenter, Partially-Blinded, Randomized, 24-Week, Parallel-Group, Non-Inferiority, Open-Label Active Controlled Study to Compare the Efficacy and Safety of QVM149 With a Free Triple Combination of Salmeterol/Fluticasone + Tiotropium in Patients With Uncontrolled Asthma
Phase: PHASE3
Conditions: Asthma
Sponsor: Novartis Pharmaceuticals



N o v arti s  
C o nfi d e nti al  
P a g e 2 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
T a bl e of c o nt e nt s 
 
Ta ble of c o nt e nts ................................................................................................................. 2  
List of ta bles  ........................................................................................................................ 5  
List of fi g ur es  ...................................................................................................................... 5  
List of a b bre viati o ns ............................................................................................................ 6  
Gl ossar y of ter ms  ................................................................................................................. 8  
A me n d me nt 2 ...................................................................................................................... 9  
A me n d me nt 1 .................................................................................................................... 1 0  
Pr ot oc ol s u m mar y .............................................................................................................. 1 2  
1  
I ntr o d u cti 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 bj ecti ves a n d e n d p oi nts ......................................................................................... 1 6  
2. 1  
St u d y O bjecti ves a n d E n d p oi nts  ............................................................................ 1 7  
3  
I n v esti gati o nal pla n ........................................................................................................... 1 8  
3. 1  
St u d y d esi g n ........................................................................................................... 1 8  
3. 2  
Rati o nale f or st u d y desi g n ..................................................................................... 2 0  
3. 3  
Rati o nale f or d ose/r e 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 3  
3. 5  
P ur p ose a n d ti mi n g of i nt eri m a nal yses/ desi g n a d a ptati o ns .................................. 2 3  
3. 6  
Ris ks a n d be nefits .................................................................................................. 2 3  
4  
P o p ulati o n .......................................................................................................................... 2 5  
4. 1  
I n cl usi o n criteria .................................................................................................... 2 5  
4. 2  
E x cl usi o n criteria  ................................................................................................... 2 6  
5  
Treat me nt  ........................................................................................................................... 2 9  
5. 1  
St u d y treat me nt  ...................................................................................................... 2 9  
5. 1. 1  
I n v esti gati o nal a n d c o ntr ol dr u gs .......................................................... 2 9  
5. 1. 2  
A d diti o nal treat me nt  .............................................................................. 3 0  
5. 2  
Treat me nt ar ms  ...................................................................................................... 3 0  
5. 3  
Treat me nt assi g n me nt a n d ra n d o mizati o n  ............................................................. 3 0  
5. 4  
Treat me nt bli n di n g  ................................................................................................. 3 1  
5. 5  
Treati n g t he patie nt  ................................................................................................ 3 1  
5. 5. 1  
Patie nt n u m beri n g ................................................................................. 3 1  
5. 5. 2  
Dis pe nsi n g t he st u d y dr u g ..................................................................... 3 2  
5. 5. 3  
Ha n dli n g of st u d y a n d a d diti o nal treat me nt .......................................... 3 2  

N o v arti s  
C o nfi d e nti al  
P a g e 3 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
5. 5. 4  
I nstr u cti o ns f or prescri bi n g a n d t a ki n g st u d y treat me nt ........................ 3 3  
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 4  
5. 5. 6  
Resc ue me dicati o n  ................................................................................ 3 5  
5. 5. 7  
C o nc o mita nt me dicati o n  ....................................................................... 3 6  
5. 5. 8  
Pr o hi bite d me dicati o ns .......................................................................... 3 6  
5. 5. 9  
E mer ge nc y brea ki n g of assi g ne d treat me nt c o de  .................................. 3 9  
5. 6  
St u d y C o m pleti o n a n d Disc o nti n uati o n ................................................................. 3 9  
5. 6. 1  
St u d y c o m pleti o n, p ost- st u d y treat me nt a n d e n d of trial ...................... 3 9  
5. 6. 2  
Disc o nti n uati o n of St u d y Treat me nt ..................................................... 4 0  
5. 6. 3  
Wit h dra wal of i nf or me d c o nse nt ........................................................... 4 1  
5. 6. 4  
L ost t o f oll o w- u p ................................................................................... 4 1  
5. 6. 5  
Earl y st u d y ter mi nati o n b y t he s p o ns or ................................................. 4 1  
6  
Visit sc he d ule a n d assess me nts  ......................................................................................... 4 1  
6. 1  
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures .................................................. 4 4  
6. 2  
Patie nt de m o gr a p hics/ ot her baseli ne c haracteristics  ............................................. 4 5  
6. 3  
Treat me nt e x p os ure a n d c o m plia nce  ..................................................................... 4 5  
6. 4  
Efficac y  .................................................................................................................. 4 5  
6. 4. 1  
Healt h Stat us ( Patie nt Re p orte d O utc o mes)  .......................................... 4 6  
6. 4. 2  
S pir o metr y  ............................................................................................. 4 7  
 
 4 8  
6. 4. 4  
W orse ni n g of ast h ma ............................................................................. 4 8  
6. 4. 5  
Ast h ma E x acer bati o n  ............................................................................ 4 9  
 
 5 0  
6. 4. 7  
A p pr o priate n ess of efficac y assess me nts  .............................................. 5 1  
6. 5  
Safet y  ..................................................................................................................... 5 1  
6. 5. 1  
P h ysical e x a mi nati o n  ............................................................................ 5 1  
6. 5. 2  
Vital si g ns .............................................................................................. 5 2  
6. 5. 3  
Hei g ht a n d wei g ht ................................................................................. 5 2  
6. 5. 4  
La b orat or y e val uati o ns  .......................................................................... 5 2  
6. 5. 5  
Electr ocar di o gra m ( E C G)  ..................................................................... 5 2  
6. 5. 6  
Pre g n a nc y a n d assess me nts of fertilit y  ................................................. 5 3  
6. 5. 7  
A p pr o priate n ess of safet y meas ure me nts  .............................................. 5 3  
 
 5 3  
 
 5 3  
 
 5 4  
 
 5 4  

N o v arti s  
C o nfi d e nti al  
P a g e 4 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
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 6  
7. 2. 1  
Defi niti o n of S A E ................................................................................. 5 6  
7. 2. 2  
S A E re p orti n g ........................................................................................ 5 7  
7. 3  
Li ver saf et y m o nit ori n g  ......................................................................................... 5 7  
7. 4  
Re p orti n g of st u d y treat me nt err ors i ncl u di n g mis use/a b use ................................ 5 8  
7. 5  
Pre g n a nc y r e p orti n g  ............................................................................................... 5 9  
8  
Data re vi e w a n d d ata bas e ma na ge m e nt  ............................................................................. 5 9  
8. 1  
Site m o nit ori n g  ...................................................................................................... 5 9  
8. 2  
Data c ollecti o n  ....................................................................................................... 6 0  
8. 3  
Data base m a na ge m e 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 n al ysis  ...................................................................................................................... 6 2  
9. 1  
A nal ysis sets  .......................................................................................................... 6 2  
9. 2  
Patie nt de m o gr a p hics a n d ot her baseli ne c haracteristics  ....................................... 6 2  
9. 3  
Treat me nts  ............................................................................................................. 6 3  
9. 4  
A nal ysis of t h e pri mar y v aria ble  ............................................................................ 6 3  
9. 4. 1  
Varia bles  ............................................................................................... 6 3  
9. 4. 2  
Statistical m o del, h y p ot h esis 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 u es/ earl y disc o nti n uati o ns.............................. 6 4  
9. 4. 4  
M ulti plicit y A dj ust me nt ........................................................................ 6 4  
9. 4. 5  
S u p p orti ve a nal ys es ............................................................................... 6 5  
9. 5  
A nal ysis of s ec o n dar y e n d p oi nts ........................................................................... 6 5  
9. 5. 1  
Efficac y vari a bles  .................................................................................. 6 5  
9. 5. 2  
Safet y v aria bl es  ..................................................................................... 6 7  
 
 6 8  
 
 6 8  
 
 6 8  
 
 6 8  
 
 6 8  
9. 7  
I nteri m a nal yses ..................................................................................................... 7 1  
9. 8  
Sa m ple size calc ulati o n  .......................................................................................... 7 1  
1 0  Et hical c o nsi derati o ns ........................................................................................................ 7 1  
1 0. 1  
Re g ulat or y a n d et hical c o m plia nce i nf or me d c o nse nt pr oce d ures ........................ 7 1  

N o v arti s  
C o nfi d e nti al  
P a g e 5 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 0. 2  
I nf or me d c o ns e nt pr oced ures  ................................................................................. 7 2  
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  .................................................. 7 2  
1 0. 4  
P u blicati o n of st u d y pr ot oc ol a n d res ults............................................................... 7 2  
1 0. 5  
Q ualit y C o ntr ol a n d Q u alit y Ass ura n ce ................................................................. 7 2  
1 1  Pr ot oc ol a d here n ce  ............................................................................................................ 7 3  
1 1. 1  
Pr ot oc ol a me n d me nts ............................................................................................. 7 3  
1 2  Refere n ces  ......................................................................................................................... 7 3  
1 3  A p pe n di x 1:  Li ver e v e nt a n d La b orat or y tri g ger Defi niti o ns a n d F oll o w- u p 
Re q uire me nts  ..................................................................................................................... 7 6  
1 4  A p pe n di x 2:  S pir o metr y G ui da nce ................................................................................... 7 8  
1 5  A p pe n di x 3:  I nstr ucti o n f or Use of C o n ce pt 1 .................................................................. 8 1  
1 6  A p pe n di x 4:  I nstr ucti o n f or Use of Acc u h aler ® / Dis k us®  ................................................. 8 5  
1 7  A p pe n di x 5:  I nstr ucti o ns f or Use of t h e Res pi mat ®  ......................................................... 9 0  
 9 3  
1 9  A p pe n di x 7: A Q L Q- S ........................................................................................................ 9 4  
2 0  A p pe n di x 8: A C Q- 7 .......................................................................................................... 9 9  
 1 0 1  
2 2  A p pe n di x 1 0: L o w, me di u m a n d hi g h D ail y D os es of I n hale d Gl u c oc ortic oster oi ds 
f or A d ults1 ....................................................................................................................... 1 0 6  
 
Li st of t a bl e s 
Ta ble 2 - 1 
O bjecti ves a n d relate d e n d p oi nts .......................................................... 1 7  
Ta ble 5 - 1 
St u d y Treat me nts  .................................................................................. 3 4  
Ta ble 5 - 2 
Pr o hi bite d ast h ma- relate d me dicati o ns ................................................. 3 6  
Ta ble 5 - 3 
Pr o hi bite d Me dicati o ns ......................................................................... 3 7  
Ta ble 5 - 4 
Me dicati o ns all o we d u n d er certai n c o n diti o ns ...................................... 3 7  
Ta ble 5 - 5 
Assess me nts f or Patie nts w h o Disc o nti n ue St u d y Treat me nt ............... 4 0  
Ta ble 6 - 1 
Assess me nt sc he d ule  ............................................................................. 4 2  
Ta ble 6 - 2  
Ti me d Assess me nts  ............................... Err or! B o o k m ar k n ot defi ne d.  
Ta ble 7 - 1   
G ui da nce f or ca pt uri n g t he st u d y treat me nt err ors i ncl u di n g 
mis use/a b use ......................................... Err or! B o o k m ar k n ot defi ne d.  
Ta ble 1 3 - 1 
Li ver E ve nt a n d La b orat or y Tri g ger D efi niti o ns .................................. 7 6  
Ta ble 1 3 - 2 
F oll o w U p Re q uire me nts f or Li v er E v e nts a n d La b orat or y Tri g gers ... 7 6  
 
Li st of fi g ur e s 
Fi g ure 3 - 1 
 St u d y d esi g n  ......................................................................................... 2 0  

N o v arti s  
C o nfi d e nti al  
P a g e 6 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Li st of a b br e vi ati o n s 
A C Q -7  
A st h m a C o ntr ol Q u e sti o n n air e -7   
A E  
A d v er s e E v e nt  
A L T  
Al a ni n e A mi n otr a n sf er a s e  
A N C O V A  
A n al y si s of c o v ari a n c e  
A Q L Q ( S) 
A st h m a Q u alit y of Lif e Q u e sti o n n air e  
A S T  
A s p art at e A mi n otr a n sf er a s e  
A T S/ E R S  
A m eri c a n T h or a ci c S o ci et y/ E ur o p e a n R e s pir at or y S o ci et y  
B MI  
B o d y M a s s I n d e x  
B P H  
B e ni g n pr o st ati c h y p er pl a si a  
b.i. d.  
t wi c e a d a y 
C C V  
C ar di o v a s c ul ar a n d C er e br o v a s c ul ar  
C F R  
U S C o d e of F e d er al R e g ul ati o n s  
C O P D  
C hr o ni c O b str u cti v e P ul m o n ar y Di s e a s e  
C P O  
C o u ntr y P h ar m a Or g a ni z ati o n  
C R F  
C a s e R e p ort/ R e c or d F or m ( p a p er or el e ctr o ni c)  
C R O  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
D A L Y s  
Di s a bilit y - A dj u st e d Lif e Y e ar s  
D A R  
D o s e A d mi ni str ati o n R e c or d  
D PI  
Dr y P o w d er I n h al er  
E C G  
El e ctr o c ar di o gr a m  
E D C  
El e ctr o ni c D at a C a pt ur e  
E M A  
E ur o p e a n M e di ci n e s A g e n c y  
E R  
E m er g e n c y R o o m  
E U  
E ur o p e a n U ni o n  
F A S  
F ull a n al y si s s et  
F D C  
Fi x e d d o s e c o m bi n ati o n  
F E F 2 5 -7 5  
F or c e d E x pir at or y Fl o w b et w e e n 2 5 % a n d 7 5 % of F or c e d Vit al C a p a cit y  
F E V 1  
F or c e d E x pir at or y V ol u m e i n 1 s e c o n d  
F V C  
F or c e d Vit al C a p a cit y  
G C P  
G o o d Cli ni c al Pr a cti c e  
G E E  
G e n er ali z e d e sti m ati n g e q u ati o n  
GI N A  
Gl o b al I niti ati v e f or A st h m a  
G LI  
Gl o b al L u n g F u n cti o n I niti ati v e  
G G T/ γ G T  
G a m m a Gl ut a m yl Tr a n sf er a s e  
g M C P  
Gr a p h B a s e d M ulti pl e C o m p ari s o n Pr o c e d ur e s  
H C P  
H e alt h C ar e Pr a ctiti o n er  
 
  
I C H 
I nt er n ati o n al C o nf er e n c e o n H ar m o nis ati o n  of T e c h ni c al R e q uir e m e nt s f or 
R e gi str ati o n of P h ar m a c e uti c al s f or H u m a n U s e  
I B 
I n v e sti g at or Br o c h ur e 
I C S/ L A B A 
C o m bi n ati o n of i n h al e d c orti c o st er oi d a n d l o n g a cti n g b et a a g o ni st  
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 

N o v arti s  
C o nfi d e nti al  
P a g e 7 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
I g E  
I m m u n o gl o b uli n E 
I M 
Intr a m u s c ul ar  
I R B 
I n stit uti o n al R e vi e w B o ar d 
I R T 
I nt er a cti v e R e s p o n s e T e c h n ol o g y 
I UD  
I ntr a ut eri n e d e vi c e 
I U S 
I ntr a ut eri n e s y st e m 
I V 
Intr a v e n o u s  
L A B A  
L o n g -a cti n g β a dr e n o c e pt or a g o ni st s  
L A M A  
L o n g A cti n g M u s c ari ni c A nt a g o ni st  
L F T  
Li v er f u n cti o n t e st  
L T R A  
L e u k otri e n e r e c e pt or a nt a g o ni st s  
M CI D  
Mi ni m al i m p ort a nt diff er e n c e  
M DI  
M et er e d d o s e i n h al er  
M e d D R A  
M e di c al D i cti o n ar y f or R e g ul at or y A cti viti e s  
M M R M  
M o d el f or r e p e at e d m e a s ur e  
NI  
N o n -i nf eri orit y 
O C S  
Or al c orti c o st er oi d  
O C/ R D C  
Or a cl e Cli ni c al/ R e m ot e D at a C a pt ur e  
o. d.  
o n c e a d a y  
P E F  
P e a k E x pir at or y Fl o w  
 
 
p. o.  
or al(l y)  
P P S  
P er pr ot o c ol s et  
P R O  
P ati e nt R e p ort e d O ut c o m e  
Q o L  
Q u alit y of Lif e  
S A B A  
S h ort A cti n g β 2 A g o ni st  
S A E  
S eri o u s A d v er s e E v e nt  
S A M A  
S h ort a cti n g a nti c h oli n er gi c s  
S A P  
St ati sti c al a n al y si s pl a n  
S C S  
S y st e mi c c orti c o st er oi d  
S D D PI  
Si n gl e d o s e dr y p o w d er i n h al er  
 
 
S U S A R  
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s  
T B L  
T ot al bilir u bi n  
T D  
Tr e at m e nt Di s c o nti n u ati o n  
U L N  
U p p er li mit of n or m al  
W H O  
W orl d H e alt h Or g a ni z ati o n  
W o C  
Wit h dr a w al of C o n s e nt  

N o v arti s  
C o nfi d e nti al  
P a g e 8 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Gl o s s ar y of t er m s 
C o ntr ol dr u g  
Dr u g s( s) u s e d a s a c o m p ar at or t o r e d u c e a s s e s s m e nt bi a s, pr e s er v e 
bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al st u d y v ali dit y, a n d/ or 
e v al u at e c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g  
D o s a g e  
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e p ati e nt i n a ti m e u nit ( e. g. 1 0 0 
m g  o. d. , 7 5 m g b.i. d. ) 
El e ctr o ni c D at a C a pt ur e 
( E D C) 
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o ni c a c q ui siti o n of cli ni c al 
st u d y d at a u si n g d at a c oll e cti o n s y st e m s, s u c h a s W e b -b a s e d 
a p pli c ati o n s, i nt er a cti v e v oi c e r e s p o n s e s y st e m s a n d cli ni c al l a b or at or y 
i nt erf a c e s 
E D C i n cl u d e s t h e u s e of El e ctr o ni c C a s e R e p ort F or m s ( e C R F s) w hi c h 
ar e  u s e d t o c a pt ur e d at a tr a n s cri b e d fr o m p a p er s o ur c e f or m s u s e d at 
t h e p oi nt of c ar e 
E 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 ( e. g. 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)  
P eri o d  
 
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 pi c al p eri o d 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   
S y n o n y m o u s wit h t h e t er m “ E p o c h”  
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.” 
M e di c ati o n p a c k n u m b er  
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h i n v e sti g ati o n al dr u g p a c k a g e  
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/ s u bj e ct 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 ati e nt/ s u bj e ct I D    
A u ni q u e  s u bj e ct i d e ntifi c ati o n (I D)  n u m b er a s si g n e d t o e a c h p ati e nt 
u p o n si g ni n g t h e i nf or m e d c o n s e nt  
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  
S o ur c e D at a/ D o c u m e nt  
S o ur c e d at a r ef er s t o t h e i niti al r e c or d, d o c u m e nt, or pri m ar y l o c ati o n 
fr o m w h er e d at a c o m e s. T h e d at a s o ur c e c a n b e a d at a b a s e, a d at a s et, 
a s pr e a d s h e et or e v e n h ar d -c o d e d d at a, s u c h a s p a p er or e S o ur c e.  
St u d y dr u g/ 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), 
pl a c e b o/ c o m p ar at or 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 Tr e at m e nt 
Di s c o nti n u ati o n ( T D)  
W h e n t h e 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 tr e at m e nt pri or t o t h e 
d efi n e d st u d y tr e at m e nt c o m pl eti o n d at e  
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 
Wit h dr a w al of c o n s e nt 
( W o C) 
Wit h dr a w al of c o n s e nt fr o m t h e st u d y i s d efi n e d a s w h e n a p ati e nt d o e s  
n ot w a nt t o p arti ci p at e i n t h e st u d y a n y l o n g er, a n d d o e s n ot w a nt a n y 
f urt h er vi sit s or a s s e s s m e nt s, a n d d o e s n ot w a nt a n y f urt h er st u d y 
r el at e d c o nt a ct, a n d d o e s n ot all o w a n al y si s of alr e a d y o bt ai n e d bi ol o gi c 
m at eri al   

N o v arti s  
C o nfi d e nti al  
P a g e 9 
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
A m e n d m e nt 2 
A m e n d m e nt r ati o n al e  
I n a p o p ulati o n wit h u nc o ntr olle d ast h ma it is t he i n vesti gat or’s res p o nsi bilit y t o e ns ur e t hat 
patie nts are treate d a d e q ua tel y. At t he ti me of ra n d o mizati o n, t he i n vesti gat or nee ds t o ma ke 
a n i nf or me d decisi o n a b o ut t he m ost a p pr o priate treat me nt f or eac h i n di vi d ual patie nt. If t h e 
m ost a p pr o priate tr eat me nt is n ot a  L A B A + L A M A +I C S, t he  patie nt s h o ul d be scree n -faile d 
a n d be treate d acc or di n g t o his/ her i n di vi d ual nee ds. 
T he  p ur p ose  of  t his  a me n d me nt  is  t o  s u p p ort  t his  i nf or me d  decisi o n  ma ki n g  b y  a d di n g 
rele va nt  assess m e nts  at t he r u n-i n  visit,  i.e.  meas ure me nt  of  bl o o d  t otal  Ig E  a n d  a nti ge n - 
s pecific I g E (Im m u n o C A P)  f or c o m m o n pere n nial aer oaller ge ns. 
F urt her m ore , t his  a m e n d me nt  i ncl u des  a  c ha n ge  i n  t he  h y p ot heses  testi n g  strate g y.  T h e  ke y 
sec o n dar y o bjecti ve ( T o e val uate effi cac y of Q V M 1 4 9 hi g h I C S d ose a n d Q V M 1 4 9 me di u m 
I C S d ose c o m pare d t o sal meter ol/ fl uticas one + ti otr o pi u m i n ter ms of Tr o u g h F E V 1 after 2 4 
wee ks of treat me nt) will be treate d as a re g ular sec o n dar y o bjecti ve. T h e testi n g strate g y will 
i ncl u de  o nl y  t h e  pri mar y  o bjecti ve  ( T h e  n o n-i nferi orit y  of  Q V M 1 4 9  hi g h  I C S  d ose  a n d 
Q V M 1 4 9  me di u m  I C S  d ose  c o m p are d  t o  sal meter ol/  fl uticas o ne  +  ti otr o pi u m  free 
c o m bi nati o n  i n  ter ms  of  c ha n ge  fr o m  baseli ne  i n  A Q L Q total  sc ore  after  2 4  wee ks  of 
treat me nt). 
I n a d diti o n, t he a me n d me nt will a d dress c o m me nts recei v e d fr o m t he Et hi cs C o m mittee a n d 
Healt h A ut h orit y i n G er ma n y t o cl arif y s o me pr o ce d ures a n d data pr otecti o n meas ures.  
Recr uit me nt  f or  t he  st u d y  h as  n ot  i nitiate d  as  of  ti me  of  pr ot oc ol  a me n d me nt  fi nalizati o n. 
T hese c ha n ges will n ot i nfl ue nce t he st u d y p o p ul ati o n, t he res ults of t he st u d y n o r is t here a n y 
i m pact t o patie nt safet y. 
I R B s/I E C s 
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 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he  c ha n ges  descri b e d  i n  t his  a me n de d  pr ot oc ol  re q uire  I R B/I E C  a p pr o val  pri or  t o  
i m ple me ntati o n. 
C h a n g e s t o t h e pr ot o c ol  
•  U p date t o t he Pr ot oc ol s u m mar y , Secti o n 4  a n d Secti o n 9. 8  wit h a re d ucti o n i n t he 
n u m ber of patie nts i n t he st u d y p o p ulati o n  
•  Re m o ve d ke y sec o n d ar y o bjecti ve a n d c o nsi deri n g it as o ne of t he sec o n d ar y 
o bjecti ves, Ta ble 2 - 1, O bjecti ves 
•  U p date d patie nt i ncl usi o n criteria  N o. 1 & 6, Secti o n 4. 1  t o e ns ure: 
•  o nl y le gall y c o m p ete nt patie nts ca n be i ncl u d e d i n t he trial ( N o. 1) a n d  
•  t he hist orical se ver e e x acer bati o n is base d o n d oc u me nte d data a n d n ot o n p atie nts 
recall o nl y ( N o. 6)  
•  U p date d patie nt i ncl usi o n criteri o n N o. 8 i n Secti o n 4. 1  t o clarif 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
•  a p ositi ve re versi bilit y test or a hist oric p ositi ve re versi bilit y test perf or me d 
acc or di n g t o A T S/ E R S g ui deli nes will be acce pta ble at V 1 0 1 
•  Pr o vi de d detaile d i nstr ucti o ns f or t he i n vesti gat or re gar di n g t he n ee d t o pa use or 
ter mi nate c o nc o mita nt m e dicati o n f or p atie nt ra n d o mizati o n i nt o t he trial, Secti o n 
5. 5. 8  Pr o hi bite d Me dicati o ns a n d Ta ble 5 - 3 Pr o hi bite d Me dicati o ns 
•  Clarifie d defi niti o n  of t he e n d of t he tri al, Secti o n 5. 6. 1   
•  A d de d ser u m t otal I g E a n d a nti ge n-s pecifi c I g E (I m m u n o C A P) assess me nts at r u n -i n 
p hase Ta ble 6 - 1 Assess m e nt Sc he d ule  
 
•  A d de d s pir o metr y at Tri al Disc o nti n uati o n ( T D) visit as S pir o metr y is part of t he 
A C Q -7  assess me nt , Ta bl e 6 - 1 Assess me nt Sc he d ule  
•  Re m o ve d ce ntr al re vie w of E C Gs b y ce ntral la b orat or y a n d re q uire me nt t o pri nt 
traci n gs i n d u plicate, Secti o n 6. 5. 5  
•  Descri be d m eas ur es f or d ata pr otecti o n t o a v oi d u n a ut h orize d access, t o e ns ure 
c o nfi de ntialit y of rec or ds a n d t o pre ve nt sec urit y breac h Secti o n 8. 2  
•  Re m o ve d t he ke y sec o n d ar y vari a ble (c h a n ge i n tr o u g h F E V 1 fr o m baseli n e t o wee k 
2 4) usi n g o nl y t he pri mar y varia ble f or h y p ot heses testi n g a n d a dj usti n g f or 
m ulti plicit y. Testi n g strat e g y h as bee n c ha n ge d fr o m gl o bal Si mes test t o tri m me d 
Si mes test, Secti o n s 9. 4. 1 , 9. 4. 2 , 9. 4. 3 , 9. 4. 4 ,a n d 9. 4. 5  
•  I n cl u de d t he c h a n ge i n tr o u g h F E V 1 fr o m baseli n e t o wee k 2 4 as o ne of t h e sec o n dar y 
varia ble s a n d t h e c orres p o n di n g a n al ysis, Secti o n 9. 5. 1. 2   
•  C ha n ge d t h e sa m ple size calc ulati o ns a n d p o w er a dj ust me nts base d o n u p date d testi n g 
strate g y of usi n g o nl y t h e pri mar y e n d p oi nt, S ecti o n 9. 8   
•  C orrecte d f or c o nsiste nc y t hr o u g h o ut d oc u me nt; u p date d f or matti n g, t y p o gra p hical 
err ors  
A m e n d m e nt 1 
A m e n d m e nt r ati o n al e  
T he  pri mar y  reas o ns  f or  t his  a me n d me nt  are  t o  e ns ure  c o nsiste nc y  acr oss  secti o ns  of  t he 
pr ot oc ol a n d t o u p date dr u g s u p pl y s o urci n g str ate gies a n d o perati o nal details/ pr ocesses.  
Pr ot oc ol secti o ns  ha ve  b ee n  har m o nize d  wit h  res pect  t o  t he  es calati o n  a n d  de-es calati o n  of 
c o ntr oller  or  mai nte n a n ce t hera p y  all o we d  d uri n g t h e treat me nt  p eri o d. T he  dr u g  s u p pl y 
s o urci n g  strate g y is  u p date d  as l ocal  s ourci n g  f or  t he  c o m parati ve  treat me nt  ar m 
(sal meter ol/fl uticas o ne  a n d  ti otr o pi u m)  a n d  t he  r u n-i n  me dicati o n  (sal meter ol/fl uticas o ne) 
ma y o cc ur, i n a d diti o n t o gl o bal s o ur ci n g.  
Recr uit me nt  f or  t he  st u d y  h as  n ot  i nitiate d  as  of  ti me  of  pr ot oc ol  a me n d me nt  fi nalizati o n. 
T hese c ha n ges will n ot i nfl ue nce t he st u d y p o p ul ati o n, t he res ults of t he st u d y n or is t here a n y 
i m pact t o s u bject safet y. 
C h a n g e s t o t h e pr ot o c ol  
•  C ha n ge d f or matti n g of i n cl usi o n criteria 1 -7 wit h n u meric n u m beri n g of criteria fr o m 
b ullets f or i nter nal c o nsiste nc y ( Secti o n 4. 1). 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
•  C orrecte d  err or f or e x cl usi o n criteria 1 9 , E C G t o be perf or me d at Visit 1 0 1 a n d n ot V 1 
( Secti o n 4. 2).  
•  C orrecte d  t y p o f or e x cl usi o n 2 6, patie nts o n mai nte na nce i m m u n ot hera p y f or aller gies f or 
less t ha n 3 m o nt hs; c ha n ge d “ or” t o “f or” ( Secti o n 4. 2). 
•  A d de d o pe n- l a bel c o m parati ve treat me nts (sal met er ol/fl uticas o ne a n d ti otr o pi u m) a n d 
r u n-i n me dicati o n (sal meter ol/fl uticas o ne) w hi c h ma y b e s o urce d l ocall y fr o m 
c o m mercial s u p plies. ( Secti o n  5. 1. 1 a n d Secti o n 5. 1. 2 ) 
•  Clarifie d  t hat pac k a gi n g wit h 2 part la beli n g is a p plica ble f or gl o ball y s o urce d 
treat me nts; all la beli n g will c o m pl y wit h l ocal re g ulati o ns ( Secti o n 5. 5. 2) 
•  Re m o ve d S m P C ( S u m mar y of  Pr o d uct C haracteristics) as a refere nce f or a p pr o priate us e 
of ste p - u p a n d ste p- d o w n t hera p y; refer t o l ocal a p pr o ve d la bel ( Secti o n 5. 5. 5) 
•  A d de d f o ot n ote t o Ta ble 5 - 4, “ Me dicati o ns all o we d u n der certai n circ u msta nces” t o ali g n 
wit h Secti o n 5. 5. 5 w hic h descri bes t he ste p- u p a n d/ or ste p d o w n of patie nt’s bac k gr o u n d 
me dicati o n (c o ntr oller or mai nte na nce) treat me nt o pti o ns all o we d d uri n g t he treat me nt 
p hase of t he trial. ( Secti o n 5. 5. 8) 
•  Pr o vi de d clarificati o n t hat patie nts will be i nstr ucte d b y I n vesti gat ors t o c o ntact t he trial 
site w he n patie nt recei ves e Diar y n otificati o ns w h e n ast h ma w ors e ni n g crit eria is met. 
( Secti o n 6. 4. 4).   
•  A d de d descri pti o n of t he baseli ne refere nce f or S A B A use i n r u n- i n a n d treat me nt 
peri o ds ( Secti o n 6. 4. 4).   
•  Ali g ne d pr ot oc ol secti o ns wit h u p date d re gi o nal stratificati o n a n d statistical a nal ysis pla n 
( Secti o n 9).  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 M 1 4 9 B 2 3 0 6 
F ull Titl e  
A m ultice nter, partiall y - bli n de d, ra n d o mize d, 2 4-wee k, parallel -
gr o u p, n o n- i nferi orit y, o p e n-la bel acti ve c o ntr olle d st u d y t o c o m pare 
t he efficac y a n d safet y of Q V M 1 4 9 wit h a free tri ple c o m bi nati o n of 
sal meter ol/fl uticas o ne + ti otr o pi u m i n patie nts wit h u nc o ntr olle d 
ast h ma 
Bri ef titl e  
 
Efficac y st u d y of Q V M 1 4 9 i n u nc o ntr olle d ast h ma patie nts  
S p o n s or a n d Cli ni c al 
P h a s e  
N o vartis  
3 b  
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 nter ve nti o nal 
P ur p o s e a n d r ati o n al e  
T he  p ur p ose  of  t his  trial  is  t o  de m o nstrate  t hat  t he  efficac y  of  t w o 
stre n gt hs 
of  t he  fi x e d -d ose  c o m bi nati o n  pr o d uct  Q V M 1 4 9 
(I N D/ G L Y/ M F 1 5 0/ 5 0/ 8 0  μ g  a n d  I N D/ G L Y/ M F  1 5 0/ 5 0/ 1 6 0  μ g)  is 
n o n- i nferi or t o  t he  efficac y  of  t he  free  c o m bi n ati o n  of  sal meter ol 
xi naf oate /fl uticas o ne pr o pi o nate  5 0/ 5 0 0  μ g  +  ti otr o pi u m  5  μ g i n 
u nc o ntr olle d ast h matics.  
Pri m ar y O bj e cti v e( s)  
T o  de m o nstrate  n o n -i nferi orit y  of  eit her  Q V M 1 4 9  hi g h-d ose  or 
Q V M 1 4 9  me di u m -d ose  t o  c o m parat or  sal met er ol  /  fl uticas o ne  + 
ti otr o pi u m after 2 4 wee ks of treat me nt  i n ter ms of Ast h ma Q u alit y of 
Lif e  Q uesti o n naire . 
S e c o n d ar y O bj e cti v e s  
•  T o  e val uate  effi cac y  of  Q V M 1 4 9  hi g h -d ose  a n d  Q V M 1 4 9 
me di u m- d ose c o m pare d t o sal meter ol/ fl uticas o ne + ti ot r o pi u m i n 
ter ms of Tr o u g h F E V1  after 2 4 wee ks of treat me nt .  
•  T o  e val uate  effi cac y  of  Q V M 1 4 9  hi g h -d ose  a n d  Q V M 1 4 9  
me di u m- d ose c o m pare d t o sal meter ol/ fl uticas o ne + ti otr o pi u m i n 
ter ms of Ast h ma Q ualit y of Life  Q u esti o n naire o ver 2 4 wee ks of 
treat me nt.  
•  T o  e val uate  effi cac y  of  Q V M 1 4 9  hi g h -d ose  a n d  Q V M 1 4 9 
me di u m- d ose c o m pare d t o sal meter ol/ fl uticas o ne + ti otr o pi u m i n 
ter ms  of  Ast h ma  C o ntr ol  Q uesti o n naire  o ver  2 4  wee ks  of 
treat me nt.  
•  T o e val uate efficac y of Q V M 1 4 9 hi g h- d os e a n d Q V M 1 4 9 
me di u m- d ose c o m pare d t o sal meter ol/ fl uticas o ne + ti otr o pi u m i n 
ter ms of l u n g f u ncti o n o v er 2 4 wee ks of treat me nt.  
St u d y d e si g n  
T his st u d y  uses  a  m ultice nter,  p artiall y-bli n de d,  ra n d o mize d,  2 4 -

N o v arti s  
C o nfi d e nti al  
P a g e 1 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
wee k,  par allel -gr o u p,  n o n -i nferi orit y,  o pe n-la b el  acti ve  c o ntr olle d 
desi g n.  
T he st u d y will c o nsist of a scree ni n g peri o d of u p t o 1 -wee k, r u n -i n 
peri o d of 2 -wee ks, ra n d o mize d treat me nt peri o d of 2 4- wee ks, a n d a 
f oll o w-u p of peri o d of 1 -wee k.   
P o p ul ati o n  
T he  st u d y  p o p ul ati o n  will  c o nsist  of  a p pr o xi matel y 1 2 5 1 m ale  a n d 
fe male patie nts wit h u nc o ntr olle d ast h ma a ge d 1 8 a n d a b o ve. 
K e y I n cl u si o n crit eri a  
•  Writte n i nf or me d c o nse nt m ust be o btai ne d bef o re a n y st u d y-
relate d ass ess me nt is perf or me d; o nl y f ull y le gall y c o m pete nt 
patie nts ca n be i ncl u d e d.  
•  Male a n d fe male a d ult patie nt ≥ 1 8 years ol d. 
•  Patie nts wit h a dia g n osis of ast h ma f or a peri o d of at least 6 
m o nt hs pri or t o Visit 1 wit h c urre nt ast h ma se v erit y ≥ ste p 4 
( GI N A 2 0 1 7).  
•  Patie nts w h o ha ve use d I C S/ L A B A c o m bi nati o ns f or ast h ma f or 
at least 3 m o nt hs a n d at sta ble me di u m or hi g h d os e of 
I C S/ L A B A f or at least 1 m o nt h pri or t o Visit 1. 
•  Patie nts m ust be s y m pt o matic at scree ni n g des pite treat me nt wit h 
me di u m or hi g h sta ble d oses of I C S/ L A B A as defi ne d b y A C Q- 7 
sc ore ≥ 1. 5 at visits 1 0 1 a n d 2 0 1 (ra n d o mizati o n visit). 
•  Patie nts wit h hist or y of at least o ne se vere ast h ma e x acer bati o n 
(see Secti o n 6. 4. 5 ) w hic h re q uire d me di cal care fr o m a p h ysicia n, 
E mer ge nc y R o o m ( E R) visit ( or l ocal e q ui vale nt str uct ure) or 
h os pitalizati o n i n t he 1 2 m o nt hs pri or t o Visit 1 a n d re q uire d 
s yste mic c ortic oster oi ds ( S C S) treat me nt f or at least 3 da ys 
i ncl u di n g p h ysicia n g ui de d self-ma n a ge me nt treat me nt wit h oral 
c ortic oster oi ds ( O C S) as part of writte n ast h ma acti o n pla n.  
•  Pre -br o nc h o dilat or F E V 1  of < 8 5 % of t h e pre dict e d n or mal 
val ue f or t he p atie nt after wit h h ol di n g br o nc h o dilat ors pri or t o 
s pir o metr y at b ot h Visit 1 0 1 a n d Visit 2 0 1. 
•  Patie nts w h o de m o nstrate a n i ncrease i n F E V 1  of ≥ 1 2 % a n d 2 0 0 
m L.                                                                                          
K e y E x cl u si o n crit eri a  
•  Patie nts w h o ha ve a s m o ki n g hist or y of greater t h a n 2 0 pac k 
years.  
•  Patie nts dia g n ose d wit h C hr o nic O bstr ucti ve P ul m o nar y Diseas e 
( C O P D). 
•  Patie nts w h o ha ve ha d a n ast h ma attac k/e x acer bati o n re q uiri n g 
s yste mic ster oi ds or h os pitalizati o n or e mer ge n c y r o o m visit 
wit hi n 6 wee ks of Visit 1 ( Scree ni n g).  
•  Patie nts treate d wit h a L A M A f or ast h ma wit hi n 3 m o nt hs pri or 
t o Visit 1. 
•  Patie nts w h o ha ve ha d a res pirat or y tract i nfecti o n or cli nical 

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 
I ntr o d u cti o n 
1. 1   B a c k gr o u n d  
Ast h ma  is  a  c hr o nic  i nfla m mat or y  dis or der  of  t he  air wa ys  ass ociate d  wit h  air wa ys  h y per 
res p o nsi ve ness  t hat  lea ds  t o  rec urre nt  e pis o d es  of  w heezi n g,  breat hless ness,  c hest  ti g ht ness, 
a n d  c o u g hi n g,  partic ularl y  at  ni g ht  or  i n  t he  earl y  m or ni n g.  T hese  e pis o des  are  us uall y 
ass ociate d  wit h  wi d es pr ea d  b ut  varia ble  airfl o w  o bstr ucti o n  t hat  is  ofte n re versi ble  eit her 
s p o nta ne o usl y  or  wit h  treat me nt.  Airfl o w  li mitati o n  occ urs  as  a  res ult  of  o bstr ucti o n  or 
narr o wi n g of t he air w a ys, w he n e x p ose d t o preci pitati n g fact ors. E x acer bati o ns of ast h ma are 
e pis o dic w her eas i nfla m mati o n is c hr o nic ( GI N A 2 0 1 7 ). 
Des pite e xisti n g t hera pies t here are still si g nifica nt u n met me dical nee ds  i n ast h ma, wit h a n 
esti mate d  3 0 0  milli o n  pe o ple  affecte d  w orl d wi d e.  T he  Gl o bal  B ur d e n  of  Ast h ma  Re p ort 
esti mates  t hat  1 5  milli o n  disa bilit y– a dj uste d  life  years  ( D A L Ys)  are  l ost  a n n uall y  d ue  t o 
ast h ma,  re prese nti n g  1 %  of  t he  t otal  gl o bal  b ur de n.  A n n u al  w orl d wi de  deat hs  ha v e  b ee n 
esti mate d at 2 5 0, 0 0 0 ( Mas oli, 2 0 0 4 ).  
Ma n y  patie nts  wit h  ast h ma  fail  t o  ac hie v e  a d e q u ate  c o ntr ol  of  s y m pt o ms  a n d  e x acer bati o ns 
w he n treate d wit h i n hale d c ortic oster oi ds (I C S) or c o m bi nati o ns of I C S a n d l o n g -acti n g b eta-
a g o nists  ( L A B A).  Fail ure  t o  res p o n d  t o i n hale d t hera p y  ma y  b e  d ue  t o  m ulti ple  fact ors, 
i ncl u di n g p o or a d h er e nce, i na de q uate i n hal er tec h ni q ue or c ortic oster oi d resista nce. 
T i otr o pi u m ( S piri va ® Res pi mat ®) has bee n a p pr o ve d i n Eur o pea n U ni o n ( E U)  as a n a d d-o n 
mai nte na nce  br o nc h o dilat or  treat me nt  i n  a d ult  patie nts  ( ≥  1 8  years)  wit h  ast h ma  w h o      are 
c urre ntl y  treate d  wit h  t he  mai nte na nce  c o m bi nati o n  of  i n hale d  c ortic oster oi ds  ( ≥  8 0 0 μ g 
b u des o ni de/ da y or e q ui v ale nt) a n d l o n g -acti n g β 2- a g o nists a n d w h o e x perie nce d o n e or m ore 
se vere e x acer b ati o ns i n t he pre vi o us year. 
F oll o wi n g  ti otr o pi u m  re g ulat or y  a p pr o val  i n  ast h ma,  GI N A g ui deli ne  ( 2 0 1 7) rec o m me n ds 
ti otr o pi u m as a ne w a d d-o n o pti o n o n t o p of I C S/ L A B A for ste ps 4 a n d 5 i n patie nts wit h a 
hist or y of e x acer bati o ns  (i n ste p 4 i n t h e list of ot h er c o ntr oller o pti o ns a n d i n ste p 5 i n t h e list 
of pref erre d c o ntr oller c h oice s).   
Q V M 1 4 9  is  a  fi x e d -d ose  c o m bi nati o n  of  i n dacater ol  acetat e  (i n hale d  L A B A  wit h  2 4  h o ur 
d urati o n  of  acti o n),  gl yc o p yrr o ni u m  br o mi de  (i n hale d  L A M A  wit h  2 4  h o urs  d urati o n  of 
acti o n), a n d m o metas o ne f ur oate ( M F, I C S  wit h 2 4 h o ur d urati o n of acti o n) i n de vel o p me nt 
f or o nce-dail y mai nte na n ce treat me nt of ast h ma GI N A ste p ≥ 4. All t hree m o n o -c o mp o ne nts 
ha ve pre vi o usl y b ee n de vel o pe d as i n di vi d ual dr u gs f or eit her C O P D (i n dacater ol maleat e a n d 
gl yc o p yrr o ni u m br o mi de) or Ast h ma ( m o metas o n e f ur oate). N o vartis is de vel o pi n g Q V M 1 4 9 
( L A B A/ L A M A/I C S) fi xe d d ose c o m bi nati o n ( F D C) as a lact ose-ble n d e d i n halati o n p o w der t o 
be  deli vere d  via  C o nce pt 1  ( Breez haler ®),  a  si n gle  d ose  dr y  p o w der  i n haler  ( S D D PI)  f or 
mai nte na nce tr eat me nt f or se ver e ast h ma ( GI N A 2 0 1 7 Ste p ≥ 4). 
D at a fr o m m o n o -c o m p o n e nt s:  
Q V M 1 4 9  is  bei n g  de vel o pe d  i n  parallel  wit h  Q M F 1 4 9  (i n dacater ol acetat e/m o metas o ne 
f ur oate). 
E xisti n g  efficac y  a n d  safet y  d ata  f or  t he  t hree  
m o n o -c o m p o ne nts 
(i n dacater ol/ m o metas o ne/ gl yc o p yrr o ni u m ) of  t he  Q V M 1 4 9  F D C  as  well  as  f or  t he  t w o 

N o v arti s  
C o nfi d e nti al  
P a g e 1 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
c o m bi nati o ns i n dacater ol/ m o metas o ne ( Q M F 1 4 9) a n d gl yc o p y rr o ni u m/i n d acater ol ( Ulti br o ®) 
s u p p ort i n vesti gati o n i n P hase III. 
I n d acat er ol  maleate,  d eli vere d  via  C o nce pt 1,  a  si n gle  d os e  dr y  p o w d er  i n haler  ( S D D PI) 
( O n brez ®  Br eez haler ®),  is  a p pr o ve d  i n  o ver  1 1 0  c o u ntries  w orl d wi de  f or  t he  o nce  dail y 
mai nte na nce br o nc h o dilat or treat me nt of airfl o w o bstr ucti o n i n patie nts wit h C O P D. 
Treat me nt g ui d eli nes stat e t hat L A B As are m ost effecti ve w he n c o m bi ne d wit h a n I C S ( GI N A 
2 0 1 7 ).  T he  P hase  III  cli nical  de vel o p me nt  of  i n dacater ol  maleate  t hat  i ncl u de d  st u dies  i n 
patie nts  wit h  ast h ma  ( w h o  were recei vi n g  bac k gr o u n d  I C S  t hera p y),  de m o nstrate d  t hat 
i n dacater ol maleate was effecti ve a n d well-t olerate d. A st u d y i n a d oles ce nt a n d a d ult patie nts 
wit h m o derate t o se vere persiste nt ast h ma s h o we d t hat d oses of u p t o 6 0 0 μ g o. d. o ver a 2 4-
wee k tr eat me nt p e ri o d ( w he n a d mi nistere d wit h c o nc o mita nt I C S t hera p y) was well-t olerat e d 
a n d  res ulte d  i n  effecti ve  br o nc h o dilati o n  w hic h  was  s u peri or  t o  t hat  pr o vi de d  b y  sal meter ol 
( C Q A B 1 4 9 B 2 3 3 8). St u dies c o m pari n g t he i n dacater ol maleate salt wit h t h e acetate s alt f o u n d 
t hat  t he  alter nati ve  salts  were  ass ociate d  wit h  a  l o wer  i nci de nce  of  p ost-i n halati o n  c o u g h 
( C Q A B 1 4 9 B 2 1 0 2)  
wit h  n o  i m pact  o n  efficac y,  safet y  or  s yste mic  e x p os ure 
( C Q A B 1 4 9 D 2 3 0 1).  
Gl yc o p yrr o ni u m br o mi de ( 5 0 μ g o nce dail y i n a lact ose- b ase d f or m ulati o n) is r e gistere d i n t he 
E U  si nce  2 0 1 2  as  S ee bri ®  Breez haler ®  ( C o nce pt 1)  f or  t h e  treat me nt  of  C O P D.  
Gl yc o p yrr o ni u m  br o mi de  5 0  μ g  has  de m o nstrate d  cli nicall y  m ea ni n gf ul  a n d  statisticall y 
si g nifica nt i m pr o ve m e nts i n l u n g f u ncti o n i n C O P D patie nts w hic h is s ustai ne d o ver 2 4 h o urs 
a n d pr o vi des si g nifica nt s y m pt o matic be nefits wit h a fa v ora ble s afet y a n d t olera bilit y pr ofile.  
T he  fi x e d  d ose  c o m bi n ati o n  of  i n dacater ol  maleate  a n d  gl yc o p yrr o ni u m  br o mi de  is  als o 
registere d i n t he E U as Ulti br o ®  Breez haler ®.   Gl yc o p yrr o ni u m br o mi de has bee n st u die d i n 
a d ults  a n d  de m o nstrat e d  o pti mal  br o nc h o dilati o n  fr o m  t he  first  d ose  a n d  efficac y  w as 
mai ntai ne d o n o nce -dail y d osi n g f or treat me nt p eri o ds of u p t o a year, wit h g o o d s afet y a n d 
t olera bilit y. 
M F is mar k ete d i n i n hal ati o n, nasal, crea m, oi nt me nt a n d l oti o n f or m ulati o ns. T he i n halati o n 
p o w der  f or m ulati o n  w hic h  ma y  be  a d mi nistere d  o nce  or  t wice  dail y  is  mar kete d  as  a  m ulti 
d ose  dr y  p o w der  i n haler  ( M D D PI)  calle d  As ma ne x ®  T wist haler  ®  f or  t he  treat me nt  of 
ast h ma. 
As ma ne x ® T wist haler ®  is c urre ntl y a p pr o ve d i n t he U nite d States f or t he treat me nt of ast h ma 
i n a d ults a n d c hil dre n ≥ 4 years of a ge a n d is a p pro ve d i n o ver 5 5 c o u ntries w orl d wi de f or t he 
treat me nt of ast h ma i n a d ults a n d a d olesce nts ≥ 1 2 years of a ge. 
1. 2   P ur p o s e  
T he p ur p ose of t his trial is t o de m o nstrate t hat t he efficac y of t w o stre n gt hs of t he fi x e d - d ose 
c o m bi nati o n  pr o d uct  Q V M 1 4 9  (I N D/ G L Y/ M F 1 5 0/ 5 0/ 8 0  μ g  a n d  I N D/ G L Y/ M F  1 5 0/ 5 0/ 1 6 0 
μ g) is n o n- i nferi or t o t he efficac y of t he free c o m bi nati o n of sal meter ol/ fl uticas o ne 5 0/ 5 0 0 μ g 
+ ti otr o pi u m 5 μ g i n u nc o ntr olle d ast h matics.   
2 
St u d y o bj e cti v e s a n d e n d p oi nt s  
All  o bjecti ves will c o nsi der t he f oll o wi n g 2 c o m p aris o n gr o u ps: 

N o v arti s  
C o nfi d e nti al  
P a g e 1 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Q V M 1 4 9  1 5 0/ 5 0/ 8 0  μ g  o. d.  deli vere d via  C o n ce pt 1  c o m pare d  wit h  o p e n  la bel  s al meter ol 
xi naf oate/fl uticas o ne pr o pi o n ate 5 0/ 5 0 0 μ g b.i. d. deli vere d via Acc u haler ® + ti otr o pi u m 5 μ g 
o. d. deli vere d via Res pi mat ®  
Q V M 1 4 9  1 5 0/ 5 0/ 1 6 0  μ g  o. d.  deli vere d  via  C o nce pt 1  c o m pare d  wit h  o pe n  la bel  sal meter ol 
xi naf oate/fl uticas o ne pr o pi o nate 5 0/ 5 0 0 μ g b.i. d. deli vere d via Acc u haler ® + t i otr o pi u m 5 μ g 
o. d. deli vere d via Res pi mat ®  
2. 1   St u d y O bj e cti v e s a n d E n d p oi nt s 
T a bl e 2- 1 
O bj e cti v e s a n d r el at e d e n d p oi nt s  
O bjecti ve(s)  
E n d p oi nt(s)  
Pri m ar y O bjecti ve  
•  
T o  de m o nstrate n o n- i nf eri orit y  of  eit her  
Q V M 1 4 9 
hi g h -d ose  
or  
Q V M 1 4 9 
me di u m- d ose  t o 
c o m parat or sal meter ol/ 
fl uticas o ne  +  ti otr o pi u m  i n  ter ms  of 
Ast h ma 
Q ualit y  of L if e  Q uesti o n naire 
( A Q L Q) 
E n d p oi nt  f or pri m ar y o bjecti ve  
•  
C ha n ge fr o m baseli ne i n  Ast h ma Q uali t y 
of  Life  Q uesti o n naire  ( A Q L Q)  t otal 
sc ore after 2 4 w ee ks of treat me nt   
Sec o n d ar y O bjecti ve s 
•  T o  e val uate  efficac y  of  Q V M 1 4 9  hi g h -
d ose  
a n d  
Q V M 1 4 9  
me di u m - d ose 
c o m pare d  t o  sal meter ol/  fl uticas o ne  + 
ti otr o pi u m i n ter ms of Tr o u g h F E V1   
•  T o  e val uate  efficac y  of  Q V M 1 4 9  hi g h -
d ose  
a n d  
Q V M 1 4 9  
me di u m - d ose 
c o m pare d  t o  sal meter ol/  fl uticas o ne  + 
ti otr o pi u m i n ter ms of Ast h ma Q ualit y of 
Lif e Q uesti o n nair e  
•  T o  e val uate  efficac y  of  Q V M 1 4 9  hi g h -
d ose  
a n d  
Q V M 1 4 9  
me di u m - d ose 
c o m pare d  t o  sal meter ol/  fl uti cas o ne  + 
ti otr o pi u m  i n  ter ms  of  Ast h ma  C o ntr ol 
Q uesti o n naire  
•  T o  e val uate  efficac y  of  Q V M 1 4 9  hi g h -
d ose  
a n d  
Q V M 1 4 9  
me di u m - d ose 
c o m pare d  t o  sal meter ol/  fl uticas o ne  + 
ti otr o pi u m i n ter ms of l u n g f u n cti o n  
E n d p oi nts f or sec o n d ar y o bjecti ves  
•  
C ha n ge  fr o m baseli ne  i n  Tr o u g h  F E V 1  
after 2 4 w ee ks of treat me nt   
•  
C ha n ge fr o m baseli ne i n Ast h ma C o ntr ol 
Q uesti o n naire  ( A C Q - 7) t otal sc ore  o ver 
2 4 wee ks of treat me nt  
•  
C ha n ge fr o m baseli ne i n Ast h m a Q ualit y 
of  Life  Q uesti o n naire ( A Q L Q) t otal 
sc ore o ver 2 4 wee ks of treat me nt 
•  
Perce nta ge of patie nts ac hie vi n g t he 
mi ni mal i m p orta nt differe nce ( M C I D) 
decrease fr o m baseli ne A C Q - 7 ≥ 0. 5 
o ver 2 4 wee ks of treat me nt (res p o n der 
rate) 
•  
Perce nta ge of patie nts ac hie vi n g t he 
mi ni mal i m p orta n t differe nce ( MC I D) 
c ha n ge fr o m baseli ne  A Q L Q ≥ 0. 5 o ver 
2 4 wee ks of treat me nt (res p o n der rate) 
•  
C ha n ge fr o m bas eli ne i n F V C o ver 2 4 
wee ks of treat me nt  
•  
C ha n ge fr o m bas eli ne i n F orce d 
E x pirat or y Fl o w b et wee n 2 5 % a n d 7 5 % 
of F orce d Vital Ca pacit y ( F E F 2 5 -7 5 ) 

N o v arti s  
C o nfi d e nti al  
P a g e 1 8  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 his  st u d y  uses  a m ulti ce nter,  p artiall y -bli n de d,  ra n d o mize d,  2 4 -wee k,  parallel -gr o u p,  n o n -
i nferi orit y, o p e n-la b el acti ve c o ntr olle d desi g n.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
T he  st u d y  will  c o nsist  of  a  scr ee ni n g peri o d of  u p  t o  1 -wee k,  r u n -i n  peri o d of  2 -w ee ks, 
ra n d o mize d treat me nt peri o d of 2 4- wee ks, a n d a f oll o w- u p of peri o d of 1 -wee k.   
At  Visit  1,  i nf or me d  c o nse nt  will  be  o btai n e d  bef ore  a n y  st u d y  relat e d  assess me nts  or 
pr oce d ur es  are  p erf or m e d.  All  patie nts  si g ni n g  i nf or me d  c o ns e 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). Ast h m a me dicati o ns  a n d  eli gi bilit y  criteria  will  be 
re vie we d.  All patie nts m ust ha ve use d i n hale d L A B A + I C S f or at least 3 m o nt hs a n d bee n o n 
sta ble me di u m or hi g h d ose L A B A + I C S f or at l east 1 m o nt h pri or t o Visit 1.  If n ecessar y, 
arra n ge me nts will be ma de t o a dj ust c o nc urre nt a n d pr o hi bite d me dicati o ns (Ta ble 5 - 2, Ta ble 
5- 3 ,  a n d T a ble   5- 4)  b ef ore  m o vi n g  f or war d  t o  Visit  1 0 1.    O nce  c o nc urre nt  me dicati o ns 
c o m pl y wit h t he re q uire me nts of t he st u d y patie nts will c o n d uct Visit 1 0 1.  Visit 1 a n d Visit 
1 0 1  ma y  b e  perf or m e d  o n  t he  sa me  d a y  if  c o nc urre nt  me dicati o ns  c o m pl y  wit h  t he 
re q uire me nts of t he st u d y ( L A B A + I C S m ust n ot be use d wit hi n 1 2 h o urs f or t wice dail y a n d 
2 4 h o urs f or o nce dail y b ef ore Visit 1 0 1) .  Visit 1 a n d Visit 1 0 1 s h o ul d be c o n d ucte d as cl ose 
t o get her as p ossi ble base d o n a dj ust me nts of pr o hi bite d me dicati o ns.     
All patie nts t hat meet eli gi bilit y criteria at Visit 1  will be pr o vi de d a s h ort -acti n g β- 2 a g o nist 
(sal b uta m ol)  f or  use  as  a  resc u e  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 res c ue m e dicati o n please refer t o Secti o n 5. 5. 6 .   
At  Visit  1 0 1 all   a d diti o nal scree ni n g ass ess me nts,   i ncl u di n g  a re versi bilit y  test  t o assess  
eli gi bilit y (see  A p pe n di x  2 S pir o metr y), a n d a n E C G   t o e val uate  pati e nts’ car di o vasc ular 
safet y,  m ust  be  c o n d ucte d. Patie nts  w h o  q ualif y   will e nter  a  2-wee k  r u n-i n p eri o d .  
Patie nts will be s u p plie d wit h o pe n- la bel L A B A/I C S sal meter ol /fl uticas o ne 5 0/ 2 5 0 μ g b.i. d. 
or 5 0/ 5 0 0 μ g b.i. d, t o matc h t heir bac k gr o u n d me dicati o n , w hic h will be use d t hr o u g h o ut t he 
R u n- i n a n d st o p pe d at Visit 2 0 1 .  Patie nts  will  al s o be  s u p plie d wit h  a n el ectr o nic di ar y 
(e Diar y) c o m bi ne d wit h Pea k Fl o w meter t o rec or d ast h ma s y m pt o ms, resc ue me dicati o n use, 
a n d P E F.   
U p o n  c o m pleti o n  of  t he  r u n -i n p eri o d  at  Visit  2 0 1  patie nts  will  ret ur n  t o  t he  cli nic.    All 
patie nts w h o meet t he eli gi bilit y criteria will be ra n d o mize d i n a 1: 1 : 1 rati o t o o ne of t he t hree 
treat me nt ar ms (Secti o n 5. 2 ). Patie nts will be stratifie d at Visit 2 0 1 ra n d o mizati o n acc or di n g 
t o t he I C S d ose c o m p o ne nt of bac k gr o u n d I C S/ L A B A ( m e di u m or hi g h d ose) a n d re gi o n. 
T he first d ose of st u d y me dicati o n will be a d mi nistere d at t he cli nic i n t he e ve ni n g ( bet wee n 
5: 0 0 a n d 8: 0 0 p m) at Visit 2 0 1 ( Da y 1). Ra n d o mi ze d pat ie nts will e nter t he 2 4 wee k treat me nt 
peri o d d uri n g w hic h v isits m ust be sc h e d ule d t o all o w ra n d o mize d st u d y treat me nt t o be t a ke n 
i n t he e ve ni n g at t he cli ni c.  Patie nts m ust be i nstr ucte d n ot t o ta ke t heir e v e ni n g d os e of st u d y 
me dicati o n pri or t o all f ut ure cli nic visits, as t hese d oses will be a d mi nistere d i n cli nic after all 
pre -d ose assess me nts ha ve bee n perf or me d.  All treat me nt peri o d visits s h o ul d be c o n d ucte d 
at  a p pr o xi matel y  t he  sa me  ti me  t hr o u g h o ut  t he  st u d y  t o  e ns ure pre- d ose  s pir o metr y  is 
per f or me d a n d st u d y treat me nt is ta ke n at a p pr o xi matel y t he s a me ti me.   
All  ra n d o mize d  patie nts  will  be  c o ntacte d  ( b y  t ele p h o ne)  7  da ys  f oll o wi n g  t he  l ast  d ose  of 
st u d y me dicati o n or l ast visit, w hic he ver is later, f or Visit 3 0 1 ( Safet y F oll o w- u p). 

N o v arti s  
C o nfi d e nti al  
P a g e 2 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Fi g ur e 3- 1   St u d y d e si g n   
 
 
3. 2  R ati o n al e f or st u d y d e si g n  
A m ultice nter, partiall y - bli n de d, ra n d o mize d, 2 4-wee k, parallel -gr o u p, n o n -i nferi orit y, o p e n -
la bel acti ve  c o ntr olle d  st u d y  i n  patie nts  wit h u nc o ntr olle d ast h ma  o n  me di u m  t o  hi g h  d ose 
IC S/ L A B A  was  c h ose n  t o  e val uate  t he  effi cac y  a n d  safet y  of  2 stre n gt hs of  t he  fi x e d  tri ple 
c o m bi nati o n  treat me nt  Q V M 1 4 9  vs  t he  free  tri ple  c o m bi nati o n  treat me nt  sal meter ol/  
fl uticas o ne  +  ti otr o pi u m.  T he  ge n eral desi g n  is  well-esta blis he d  i n  res pirat or y  cli nical  trials 
a n d e na bles t he st u d y treat me nts t o be gi ve n f or a n a p pr o priate a n d practical le n gt h of ti me t o 
assess t he effi cac y a n d s afet y of t he treat me nts. T he st u d y has  a n o p e n-la bel c o m p o ne nt (free 
tri ple c o m bi nati o n of sal meter ol/fl uticas o ne + ti otr o pi u m f or w hic h i n vesti gat ors a n d patie nts 
will ha ve f ull k n o wle d ge of treat me nt all ocati o n.  H o we ver, i n or der t o mi ni mize t he p ote ntial 
i m pact,  meas ures  will  be  ta ke n  t o  bli n d  t he  s p o ns or  tea m  fr o m  k no wle d ge  of  treat me nt 
all ocati o n.  I n a d diti o n, wit hi n t he t w o Q V M 1 4 9 treat me nt ar ms all parties i ncl u di n g patie nts 
a n d  i n vesti gat ors  will  r e mai n  bli n de d t o  t he  act ual  d ose.  T he  i de ntit y  of  t he  Q V M1 4 9 
stre n gt hs will  be  c o nceale d  b y  t he  use  of  st u d y  dr u gs  t hat  are  all  i de ntical  i n  pac ka gi n g, 
la beli n g, sc h e d ule of a d mi nistrati o n, a p peara n ce, taste a n d o d or.  
T he  o pe n -la bel  desi g n  of  t he  st u d y  will  re d uce  t he  b ur de n  of  a  tri ple  d u m m y  treat me nt 
re gi me n f or p artici pati n g patie nts.  
A n  i m pr o ve me nt  of  0. 5  p oi nts  i n A Q L Q sc ore  is  c o nsi dere d t o  be  t h e  mi ni mall y cli nicall y 
i m p orta nt differe n ce ( M CI D) i n ast h ma.  A n o n-i nferi orit y m ar gi n of 0. 2 5 p oi nts re d ucti o n i n 
A Q L Q sc ore  h as bee n desi g nate d f or t h e st u d y bas e d u p o n 5 0 % of t he M CI D.  If t he M CI D of 
0. 5 p oi nts  re d ucti o n i n t he A Q L Q is c o nsi dere d cli nicall y i m p orta nt, it is reas o n a ble t o use a 
n o n- i nferi orit y mar gi n of o ne- half  of t his differe n ce, w hic h is 0. 2 5 p oi nts.    

N o v arti s  
C o nfi d e nti al  
P a g e 2 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
3. 3   R ati o n al e f or 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 
Selecti o n of t he Q V M 1 4 9 c o m bi nati o n pr o d uct stre n gt hs ( 1 5 0/ 5 0/ 8 0 μ g o. d. a n d 1 5 0/ 5 0/ 1 6 0 
μ g  o. d.)  f or  e val u ati o n  i n  t his  P hase  III b  st u d y are t he  sa m e  as  t h ose  use d  i n  t he  P hase  III 
pr o gra m a n d bas e d o n t h e d oses of t he c o nstit ue nt m o n ot hera pies w hic h h a ve bee n a p pr o v e d 
f or eit her C O P D or ast h ma. 
I n d a c at er ol a c et at e: 
I n d acat er ol  maleate  at  a  d ose  of  1 5 0  μ g  o. d.  is  mar kete d  f or  t he  mai nte na nce  treat me nt  of 
C O P D. A d ose -r a n gi n g st u d y of i n dacat er ol maleate i n ast h matic p atie nts de m o nstrate d t hat a 
d ose  of  1 5 0  μ g  o. d.  w as  safe  a n d  effecti ve  ( St u d y  C Q A B 1 4 9 B 2 3 5 7).  T he  acetate  salt  of 
i n dacater ol was f o u n d t o res ult i n a l o wer i nci de nce of t he p ost-i n h alati o n c o u g h, o bs er ve d f or 
i n dacater ol  maleate,  wit h o ut  i m pact  o n  efficac y  or  safet y  C Q A B 1 4 9 D 2 3 0 1.  T he  d ose  of 
i n dacater ol  acetat e  1 5 0  μ g  was  als o  c o nfir me d  i n  St u d y  C Q M F 1 4 9 E 2 2 0 3  i n  a d ult  ast h ma 
patie nts w here i n dacater ol acetate 1 5 0 μ g a n d 7 5 μ g deli vere d via C o nce pt 1 t o place b o were 
i n vesti gate d.  I n d acat er ol acetate 1 5 0 μ g s h o we d p ositi ve tre n ds i n ter ms of tr o u g h F E V1 , P E F 
a n d resc u e me dicati o n use c o m pare d wit h i n dacater ol acet ate 7 5 μ g. I n st u d y Q M F 1 4 9 A 2 2 1 0, 
Q M F 1 4 9 1 5 0/ 1 6 0 μ g o. d. s h o we d be n eficial effects o n ast h ma e x acer bati o ns i n ter ms of t he 
ti me t o first e x acer bati o n a n d t he c u m ulati ve i nci d e nce of s eri o us ast h ma e x acer bati o ns. 
T heref ore, a d ose of i n dacater ol acet ate 1 5 0 μ g o. d. has bee n selecte d f or use i n t he Q V M 1 4 9 
pr o gra m. 
M o m et a s o n e f ur o at e:  
Si nce a vaila ble data f or t he M F c o m p o ne nt e xists i n t he T wist haler ® de vice, a 3 ste p bri d gi n g 
a p pr oac h was c o n d uct e d t o deter mi ne M F d ose f or C o nce pt 1 w hi c h is c o m para ble t o eac h of 
t he re gistere d d ail y d os es of As ma ne x T wist haler ® ( m o metas o ne f ur o ate, i n halati o n p o w der). 
T his is d ue t o differe nce i n de vice perf or m a nce c haract eristics bet wee n t he T wist haler ®  a n d 
C o nce pt 1  de vices.  Ste p  1:  p har mac o ki netic  bri d gi n g  utilizi n g  p har mac o ki netic 
c haracterizati o n  i n  st u d y  C Q M F 1 4 9 E 2 1 0 1  ( Vai d ya  S  et  al,  2 0 1 2)  f oll o w e d  b y  i n -vitr o  fi ne 
particle  mass  a dj ust me nt  (ste p  2)  a n d  fi nall y  p har mac o d y n a mic  e val uati o n  of  efficac y  i n 
ast h ma patie nts i n st u d y C Q M F 1 4 9 E 2 2 0 1 (ste p 3). 
F or  Ste p  1  a n d  2,  t he  d ata  of  st u d y  C Q M F 1 4 9 E 2 1 0 1  ( Vai d ya  S  et  al,  2 0 1 2),  al o n g  wit h  i n 
vitr o fi ne particle m ass a dj ust me nts ha ve le d t o t he selecti o n of 8 0, 1 6 0 a n d 3 2 0 μ g as d os es of 
M F i n C o nce pt 1 de vice t hat are c o m para ble t o t he a p pr o ve d d oses 2 0 0 μ g, 4 0 0 μ g a n d 8 0 0 μ g 
( 2 x 4 0 0 μ g) M F i n T wist haler ®. 
F or  Ste p  3,  t w o  of  t he  M F  d oses  i n  T wist haler ®  a n d  C o nce pt 1  were  f urt her  e val uat e d  f or 
p har mac o d y n a mic a n d cli nical c o m para bilit y i n a 4 -wee k st u d y ( C Q M F 1 4 9 E 2 2 0 1) i n patie nts 
wit h  persiste nt  ast h ma.  M F  d oses  of  8 0  μ g  a n d  3 2 0  μ g  deli vere d  o nce  dail y  via  C o nce pt 1 
s h o we d c o m para ble efficac y i n tr o u g h F E V 1  a n d sli g htl y l o w er s yste mic e x p os ure c o m pare d 
t o  M F  d oses  of  2 0 0  μ g  a n d  8 0 0  μ g  ( 2  x  4 0 0  μ g)  deli vere d  o nce  dail y  via  T wist haler ® 
c o nfir mi n g t h e selecte d d oses f or M F C o nce pt 1 are a p pr o priate f or f urt her Q M F 1 4 9 C o nce pt 1 
de vel o p me nt. 

N o v arti s  
C o nfi d e nti al  
P a g e 2 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
I n s u m mar y, M F d oses of 2 0 0 μ g o. d, 4 0 0 μ g o. d. a n d 4 0 0 μ g b.i. d. deli vere d b y T wist haler ® 
are  c o m para ble  wit h  M F  d oses  of  8 0  μ g  o. d,  1 6 0  μ g  o. d.  a n d  3 2 0  μ g  o. d.,  res pecti vel y  i n 
Q M F 1 4 9 deli ver e d b y C o nce pt 1. 
F or  Q V M 1 4 9  pr o gr a m,  as  a  r es ult  of  a  c o m p o n e nt  i nteracti o n,  a n  i ncrease  i n  t he  M F  fi ne 
particle  mass  ( F P M)  i n  t he  Q V M 1 4 9  c o m bi nati o n  pr o d uct  c o m pare d  t o  t he  c orres p o n di n g 
sa me n o mi nal M F d os e i n Q M F 1 4 9 ( m atc he d t o As ma ne x ® T wist haler ®) was o bser v e d. T o 
a dj ust f or t his, t he n o mi nal d oses of M F has bee n re d uce d t o, 8 0 μ g o. d. a n d 1 6 0 μ g o. d. t o 
e ns ure  t hat  t he  fi n e  particle  mass  ( F P M,  i n -vitr o  aer os ol  p erf or ma nce)  i n  t he  lact ose  ble n d 
f or m ulati o n f or t he tri ple F D C is c o m para ble t o t he n o mi nal M F d oses of 8 0 μ g o. d., 1 6 0 μ g 
o. d.  a n d  3 2 0  μ g  o. d.  f or  Q M F 1 4 9  pr o gra m,  res pecti vel y.  T heref ore  4 0 0  μ g  M F  via 
T wist haler ® is c o m para ble w it h 1 6 0 μ g M F i n Q M F i n C o nce pt 1 a n d wit h 8 0 μ g Q V M 1 4 9 
vi a C o nce pt 1; all pr o vi de si milar fi ne particle mass a n d t here b y e x pecte d t o pr o vi de si milar 
l u n g a n d s yste mic e x p os ure, si nce oral bi oa vaila bilit y of M F is l o w. 
Gl y c o p yrr o ni u m br o mi d e:  
T he  d ose  c h ose n  f or  gl yc o p yrr o ni u m  br o mi de  of  4 4  μ g  (e x presse d  as  d ose  a cti ve  m oiet y 
deli ver y b y t he m o ut h piece of t he i n haler) is t he o ne first a p pr o ve d i n t he E U o n 2 8 - Se p - 2 0 1 2 
f or  t he  i n dicati o n  of  m ai nte na nce  br o nc h o dilat or  treat me nt  t o  relie ve  s y m pt o ms  i n  a d ult 
patie nts wit h C O P D. O utsi de t he E U, t he d ose of See bri ® Bree z haler ® is ge n erall y e x presse d 
as t he d ose of acti ve m oiet y i n t he ca ps ule, i.e. 5 0 μ g. 
E xte nsi ve data fr o m t h e P hase III de v el o p me nt pr o gra m i n C O P D s u p p orts t he efficac y a n d 
safet y of gl yc o p yrr o ni u m br o mi de 5 0 μ g o nce dail y. It has de m o nstrate d cli nicall y mea ni n gf ul 
a n d  statisticall y  si g nifica nt  i m pr o ve me nts  i n  l u n g  f u n cti o n  i n  C O P D  patie nts  w hic h  were 
s ustai ne d o ver 2 4 h o urs a n d pr o vi de d si g nifica nt s y m pt o matic be nefits wit h a fa v ora ble safet y 
a n d  t olera bilit y  pr ofile.  L u n g  f u n cti o n  i m pr o ve me nts  were  c o m para bl e  t o  ti otr o pi u m  1 8  μ g 
a d mi nistere d via Ha n di H aler ®.  
Ti otr o pi u m 5  μ g  o nce d ail y has bee n a p pr o ve d i n E ur o pe f or treat me nt of ast h ma as a d d o n t o 
hi g h d ose L A B A/I C S i n patie nts wit h a hist or y of e x acer bati o ns. T his is e q ui vale nt t o t he d ose 
a p pr o ve d i n  C O P D. It is rec o m me n de d b y GI N A g ui deli ne ( 2 0 1 7) as a n a d d-o n o pti o n ( o n t o p 
of t he pref err e d c o ntr oller c h oice) f or Ste ps 4 a n d 5 i n patie nts wit h a hist or y of e x acer b ati o ns. 
Base d o n h ea d t o hea d c o m parati ve d ata c o n d uct e d i n p atie nts wit h C O P D, it is e x pecte d t hat 
gl yc o p yrr o ni u m  br o mi d e  5 0  μ g  o n ce- dail y  will  pr o vi de  si milar  efficac y  i n  a n  ast h ma 
p o p ulati o n. 
T he t w o L A M As, gl yc o p yrr o ni u m a n d ti otr o pi u m b ot h de m o nstrate si milar ki netic selecti vit y 
f or  M 3  o v er  M 2  rece pt ors,  w hic h  is  i m p ort a nt  f or  t h eir  si milar  l o n g  a n d  s ustai ne d 
br o nc h o dilat or effects ( T esti 2 0 1 4). 
Base d o n t h e a vaila ble d ata gl yc o p yrr o ni u m br o mi de 5 0 μ g is c o nsi dere d a n a p pr o pri ate d os e 
t o  bri n g  f or war d  i nt o  P hase  III/III b  ast h ma  pr o gra m  as  part  of  tri ple  F D C  Q V M 1 4 9 
( L A B A/ L A M A/I C S). 

N o v arti s  
C o nfi d e nti al  
P a g e 2 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
3. 4   R ati o n al e f or c h oi c e of c o m p ar at or 
Sal meter ol/fl uticas o ne  is  wi del y  use d  sta n dar d  of  care  i n  ast h ma  treat me nt.  Sal meter ol 
/fl uticas o ne hi g h d ose 5 0/ 5 0 0 μ g b.i. d. d eli vere d b y D PI ( dr y-p o w der i n h aler) is m ar ket e d as 
Sereti de ® Acc u haler ® or Sereti de ® Dis k us ® de p e n di n g o n t he c o u ntries f or t he treat me nt of 
ast h ma i n a d ults a n d a d ol esce nts 1 2 years a n d ol der. 
Ti otr o pi u m 5  μ g  o. d. has bee n a p pr o v e d i n E ur o p e f or treat me nt of ast h m a as a d d-o n t o hi g h 
d ose  L A B A/I C S  i n  patie nts  wit h  a  hist or y  of  e x acer bati o ns  a n d  is mar kete d  as  S piri va ® 
Res pi mat ®  S oft  Mist ™.  Ti otr o pi u m  is  t he  o nl y  a p pr o v e d  L A M A  f or  t his  i n dicati o n 
w orl d wi de. It is r ec o m me n de d b y GI N A g ui deli n e ( 2 0 1 7 ) as a n a d d-o n o pti o n ( o n t o p of t he 
preferre d c o nt r oller c h oice) f or Ste ps 4 a n d 5.  
T he  i nte nti o n  of t his  trial  is t o  c o m pare a  fi x e d  d ose  c o m bi nati o n  of  L A B A/ L A M A/I C S  i n 
t w o  differe nt d ose  stre n gt hs  wit h  t he  acti ve  c o m parat or  l o ose  c o m bi nati o n  of  t hese  3 
c o m p o ne nts  ( L A B A,  L A M A,  a n d  I C S). T he  acti ve  c o m parat or  is  b ase d  o n  t he  GI N A 
g ui deli ne rec o m me n dati o n s i n t his p o p ulati o n a n d re prese nts t he sta n dar d of care.  T he  acti ve 
c o m parat or free c o m bi nati o n  of sal meter ol/fl uticas o ne  pl us  ti otr o pi u m als o re pres e nts  t he 
m ost  c o m m o nl y  us e d  dr u gs  w hic h  ca n  f or m  t he free tri ple  c o m bi nati o n.   T heref ore , it  is  of 
scie ntific  i nterest  t o  c o n d uct  a  direct  c o m p aris o n  st u d y  t o  de m o nstrate  t hat  t he  fi x e d  tri ple 
c o m bi nati o n Q V M 1 4 9 is n o n -i nferi or t o t he free tri ple c o m bi nati o n of sal meter ol/fl uticas o ne 
pl us ti otr o pi u m.    
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 o i nteri m a nal ysis f or efficac y is pla n ne d. 
3. 6   Ri s k s a n d b e n efit s  
D ual  br o nc h o dilati o n  wit h  I C S  c o ntr oller  w o ul d  be  e x pecte d  t o  ac hie ve  g o o d  s y m pt o m 
c o ntr ol, mi ni mize airfl o w o bstr ucti o n, mi ni mize ris k of e x acer bati o ns, a n d h os pitalizati o ns i n 
t his  p o p ulati o n.  Use  of  m ulti ple,  ofte n  differe nt  de vices  re pres e nts  a  si g nifica nt  b ur de n  f or 
ast h ma  patie nts.  A v aila bilit y  of  t hree  effecti ve  o nce -dail y  c o ntr oller  m e dicati o ns  i n  a  si n gle 
de vice ma y offer a d va nta ges i n ter ms of i m pr o ve d a d here n ce a n d c o n ve ni e nce. 
T h e  a vaila ble  ast h ma  cli nical  trial  data  s u g gest  t hat  a  L A M A  ma y  c o nfer  br o nc h o dilat or 
effects  i n  ter ms  of  i m pr o ve d  l u n g  f u ncti o n  w he n  use d  i n  a d diti o n  t o  I C S  al o ne  or  i n 
c o nj u ncti o n wit h L A B A/I C S (i.e., “free c o m bi nati o n” or “l o ose” tri ple t hera p y) ( Far d o n 2 0 0 7, 
Peters  2 0 1 0,  Bate ma n  2 0 1 1,  Kerstje ns  2 0 1 1,  Kerstje ns  2 0 1 2,  G u yer  2 0 1 3).  A  re vie w 
e val uati n g  t he  efficac y  pr ofile  of  a  L A M A  (ti otr o pi u m)  as  a d d -o n  t hera p y  t o  I C S  or 
L A B A/I C S i n p atie nts wit h u nc o ntr olle d m o derat e t o se v ere persiste nt ast h ma c o ncl u d e d t hat 
t he  a d diti o n  of  a  L A M A  res ulte d  i n  si g nifica nt  i m pr o ve me nts  i n  l u n g  f u ncti o n  ( F E V1   a n d 
pea k e x pirat or y fl o w) ( Befe ka d u 2 0 1 4). 
T he  be nefit  of  a d di n g  a  m uscari nic  a nta g o nist  i n  t he  treat me nt  of u n c o ntr olle d ast h ma  is 
s u p p orte d  b y  t w o  re plicate  st u dies  w hic h  c o m pare d  ti otr o pi u m  t o  place b o  ( Kerstje ns  2 0 1 2). 
Kerstje ns et al s h o we d t h at ti otr o pi u m o n t o p of hi g h d ose I C S/ L A B A i m pr o ve d l u n g f u n cti o n 
a n d si g nifica ntl y pr ol o n ge d ti me t o first s e vere e x acer b ati o n ( K er stje ns 2 0 1 2). T he a d diti o n of 

N o v arti s  
C o nfi d e nti al  
P a g e 2 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
ti otr o pi u m i ncrease d t he ti me t o t he first se vere e x acer bati o n ( 2 8 2 da ys vs. 2 2 6 da ys), wit h a n 
o verall re d u cti o n of 2 1 % i n t he ris k of a se vere e x acer bati o n. 
A d diti o n  of  L A M A  (ti otr o pi u m  5  μ g  Res pi mat ®)  t o  I C S/ L A B A  is  n o w  a  rec o m me n d e d 
treat me nt  o pti o n  i n  GI N A  g ui deli ne  ( 2 0 1 7) f or  ste p  4  o n war ds.  As  gl yc o p yrr o ni u m  a n d 
ti otr o pi u m  ( Ha n di Haler ®)  de m o nstrate d  c o m p ara ble  effi cac y  a n d  safet y  i n  C O P D,  it  is 
reas o na bl e  t o  e x pect  t hat  b ot h  dr u gs  w o ul d  s h o w  si milar  ris k/ be nefit  pr ofiles  i n  ast h ma 
( C ha p ma n 2 0 1 4).  
O verall,  as  c o ncl u d e d  fr o m  t he  cli nical  st u dies  gl yc o p yrr o ni u m  br o mi de  o. d.  was  safe  a n d 
well t olerate d b y t he C O P D patie nts a n d c o m para ble t o o pe n la bel ti otr o pi u m. Re p orti n g rates 
f or k n o w n cl ass effect A Es f or a nti-c h oli ner gic dr u gs w ere l o w a n d ge n erall y c o nsiste nt wit h 
t h ose  e x pecte d  f or  t his  class  (i.e.  c o nsti pati o n,  uri nar y  rete nti o n,  gl a uc o m a,  dr y  m o ut h).  N o 
e n ha nce d ris k of car di o - or cere br o vasc ul ar e ve nts relati ve t o place b o was a p pare nt, a n d t h e 
deat h rat e i n gl yc o p yrr o ni u m br o mi de at all d oses was l o wer t h a n t hat o bser ve d i n t he place b o 
gr o u p. 
I n s u m mar y, as t he be nefit ris k pr ofile of gl yc o p yrr o ni u m br o mi de has s h o w n t o be p ositi ve i n 
C O P D  patie nts  i n  w hic h  t here  are  m ore  c o m or bi dities  t ha n  ast h matic  patie nts.    T he  safet y 
pr ofile  i n a n ast h ma  p o p ulati o n  ( w hic h is  ge nerall y  y o u n ger  wit h  less  c o-m or bi dities)  is 
e x pecte d t o als o be p ositi ve. 
I n  t his  c urr e nt  P hase  III b  st u d y,  t w o  Q V M 1 4 9 stre n gt hs will  be  c o m p are d  t o  s al meter ol/ 
fl uticas o ne + ti otr o pi u m d uri n g 2 4 wee ks of treat me nt. Partici pati n g p atie nts i n t his st u d y will 
be  ra n d o mize d  t o  recei v e  eit her  o ne  of  t he  t w o stre n gt hs/d oses  of  Q V M 1 4 9  or  sal meter ol / 
fl uticas o ne + ti otr o pi u m. 
T he  use  of  ot her  c o ntr oller  me dicati o ns,  i.e.  s ustai ne d  rel ease  t he o p h ylli ne,  le u k otri e ne 
m o difiers a n d a nti I g E ( X olair ®) i n sta ble d oses will be per mitte d d u e t o t he se verit y of t he 
disease a n d p er  treat me nt g ui deli ne ( GI N A 2 0 1 7).  
T he  e x pecte d  p ote ntial  be nefit  f or  t he  patie nt  i ncl u de  a n  i m pr o ve me nt  i n  t he  p ul m o nar y 
f u ncti o n,  better  ast h ma  c o ntr ol s uc h  as re d ucti o ns  i n  s y m pt o ms,  resc ue  me dicati o n  use  a n d 
l o wer fre q u e nc y/ se verit y of ast h ma e x acer b ati o ns, a n d i m pr o ve d q ualit y of life. A t h or o u g h 
me dical  e val u ati o n  of  t he  patie nts’  diseas e  a n d  cl ose  cli nical  m o nit ori n g  f or  t he  d urati o n  of 
t he st u d y will pr o vi de a d diti o nal be nefit t o t he patie nt care.  
Fre q u e nt a n d re g ular c o ntacts will occ ur i n ter ms of cli nic visits a n d tele p h o ne c o ntacts  w he n 
nee de d , t o eac h patie nt t hr o u g h o ut t h e 2 4-w ee k treat me nt. I n a d diti o n, safet y m o nit ori n g (e. g. 
s y m pt o m  c ollecti o n  a n d  resc ue  me dicati o n  use  via electr o nic  diar y),  a n d  P E F  ( dail y) 
meas ure me nts at re g ular i nter vals t hr o u g h o ut t he st u d y will hel p assess stat us of t he patie nt’s 
ast h ma s y m pt o m c o ntr ol. T heref or e, i n vesti gat ors ma y h a ve a n earl y i n dicati o n of w orse ni n g 
s y m pt o ms a n d will be a ble t o m o nitor t he patie nt cl osel y t hr o u g h o ut t he st u d y. 
I n  li ne  wit h  c urre nt  m e dical  treat me nt  g ui deli nes,  all  patie nts  partici pati n g  i n  t h e  st u d y  will 
recei v e  acti ve  “c o ntr oller”  treat me nt  f or  t heir  ast h ma  t hr o u g h o ut  t he  2 4-wee k  treat me nt 
peri o d.  I n a d diti o n, pr o vi d i n g  t he  patie nts  wit h  resc ue  me dicati o n  f or  us e  as  n ee de d  t o  treat 
a n y s u d de n  c o nstricti o n  hel ps miti gate  t hese  ris ks.  At  n o  ti me,  will  a n y  patie nt  be  wit h o ut 
treat me nt f or ast h ma. 

N o v arti s  
C o nfi d e nti al  
P a g e 2 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
T he  ris k  t o  t he  patie nts  i n  t he  st u d y  is  t hat  Q V M 1 4 9  is  u n der  de vel o p me nt  i n  ast h ma a n d 
t heref or e  it  is  p ossi ble  t hat  u ne x pecte d  safet y  iss ues  ma y  be  i de ntifie d  a n d  t he  ris k  will  be 
mi ni mize d b y c o m plia nce wit h t he eli gi bilit y criteria a n d cl ose cli nical m o nit ori n g of patie nts. 
T he  ris ks  of  si de  eff ects  fr o m  t he  st u d y  me dicati o n  are  t h ose  k n o w n  f or  t he  i n di vi d ual 
c o m p o ne nts i n dacat er ol  acetat e,  gl yc o p yrr o ni u m  br o mi de  a n d  m o met as o ne  f ur o ate. N o 
a d diti o nal  ris ks  ha ve  b ee n  i de ntifie d  w hi c h  mi g ht  occ ur  w he n  t h e  t hree  c o m p o n e nts  are 
a d mi nistere d c o nc urre ntl y or fr o m t he sa me i n haler. D etaile d ris k-b e nefit i nf or mati o n ca n be 
o btai ne d fr o m t he Q V M 1 4 9 I n v esti gat or’s Br oc h ure. 
G ui da nce  t o  ma na ge  p ote ntial  w orse ni n g  of  ast h ma  s y m pt o ms  will  be  pr o vi de d  t o 
i n vesti gat ors c o nsiste nt wit h g ui deli ne rec o m me n dati o ns ( GI N A 2 0 1 7 ). Patie nts will receive 
writte n  i nstr ucti o ns  as  t o  h o w  t o  c o ntact  t he  i n vesti gat or  i n  t he  e ve nt  of  w orse ni n g  of  t heir 
ast h ma s y m pt o ms . T he i n vesti gat or s h o ul d disc o nti n ue st u d y treat me nt f or a gi ve n p atie nt if, 
o n bala nce, h e/s he belie v es t hat c o nti n uati o n w o ul d be detri me ntal  t o t he p atie nt’s well- bei n g. 
Patie nts are als o i nstr uct e d t hat t he y ca n disc o nti n ue st u d y treat me nt  at a n y ti me, a n d f or a n y 
reas o n. 
I n s u m mar y, base d o n a v aila ble data of c o m p o ne nts, it is a ntici pate d t hat Q V M 1 4 9 1 5 0/ 5 0/ 8 0 
μ g a n d Q V M 1 4 9 1 5 0/ 5 0/ 1 6 0 μ g wil l ha ve a fa v ora ble be nefit t o ris k pr ofile i n patie nts wit h 
u nc o ntr olle d ast h ma.  
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 2 5 1 m ale  a n d  fe male  patie nts  wit h 
u nc o ntr olle d ast h ma a ge d 1 8 a n d a b o ve. 
It  is  a ntici pate d  t hat  a p pr o xi matel y 2 5 0 0 pati e nts  will  nee d  t o  be  s cree n e d  i n  or der  t o 
ra n d o mize  a p pr o xi matel y 1 2 5 1 patie nts  i nt o  t he  t hree  treat me nt  gr o u ps  of  t he  st u d y  wit h  a 
ra n d o mizati o n rati o of 1: 1: 1, (i.e. a p pr o xi matel y 4 1 7 patie nts i n eac h of t h e treat me nt gr o u ps).  
Dr o p -o uts after ra n d o mizati o n will n ot be re place d. T his st u d y will e nr oll m ulti -nati o nall y a n d 
patie nts will be stratifie d b y pr e vi o us I C S d ose  c o m p o ne nt of I C S/ L A B A t hera p y ( me di u m or 
hi g h) a n d re gi o n. 
4. 1   I n cl u si o n crit eri a 
1.  Writte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y st u d y- relate d assess me nt is 
perf or me d.  O nl y f ull y l e gall y c o m p ete nt patie nts ca n be i ncl u d e d ( patie nts t hat are n ot 
a ble t o c o nse nt ca n n ot be recr uite d i n t his trial). 
2.  Male a n d f e male a d ult patie nt ≥ 1 8 years ol d. 
3.  Patie nts wit h a dia g n osis of ast h ma f or a  peri o d of at least 6 m o nt hs pri or t o Visit 1 wit h 
c urre nt ast h ma se verit y ≥ ste p 4 ( GI N A 2 0 1 7).  
4.  Patie nts w h o ha ve use d I C S/ L A B A c o m bi nati o ns f or ast h ma f or at least 3 m o nt hs a n d at 
sta ble me di u m or hi g h d ose of I C S/ L A B A f or at least 1 m o nt h pri or t o Visit 1  (A p pe n di x 
1 0 ). 
5.  Patie nts m ust be s y m pt o matic at scree ni n g des pite treat me nt wit h m e di u m or hi g h sta ble 
d oses of I C S/ L A B A as d efi ne d  b y A C Q - 7 s c ore ≥ 1. 5 at visits 1 0 1 a n d 2 0 1 
(ra n d o mizati o n visit). 

N o v arti s  
C o nfi d e nti al  
P a g e 2 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
6.  Patie nts wit h  hist or y of at least o ne se vere ast h ma e x acer bati o n ( Secti o n 6. 4. 5 ) w hic h 
re q uire d me di cal care fr o m a p h ysicia n, E R visit ( or l ocal e q ui vale nt str u ct ure) or 
h os pitalizati o n i n t he 1 2 m o nt hs pri or t o Visit 1 a n d re q uire d s yste mic c ortic oster oi d 
( S C S) treat me nt f or at least 3 da ys i n cl u di n g p h ysicia n g ui d e d self-ma n a ge me nt treat me nt 
wit h oral c ortic oster oi ds as part of writte n ast h ma acti o n pla n .  
•  Pre vi o us 
se vere ast h m a  e x acer bati o n  i n  t his  c o nte xt m ust  be  s u p p orte d  b y 
d oc u me ntati o n (i.e.  s uc h  as  i n  s o urce  n otes,  p har mac y  rec or ds,  h os pital  rec or ds,  or 
c hart  r ec or ds)  of  u n pla n ne d  nee d  f or  me dical  care  at  a n y  pri mar y  care  p h ysici a n, 
p ul m o n ol o gist,  e mer ge n c y  r o o m  a n d  h os pital  d ue  t o  a n  a g gra v ati o n  of  ast h ma 
s y m pto ms  a n d  treat me nt  wit h  s yste mic  c ortic oster oi ds  d ue  t o  s e v ere ast h ma 
e x acer bati o n  i ncl u di n g  p h ysicia n  g ui de d  self-ma na ge me nt  treat me nt  wit h  oral 
c ortic oster oi ds as part of writte n ast h ma acti o n pla n . 
7.  Pre -br o nc h o dilat or F E V 1  of < 8 5 % of t h e pre dict e d n or ma l val ue f or t he                                                
patie nt after wit h h ol di n g br o nc h o dilat ors  pri or t o s pir o metr y (Ta ble 5 - 2) at b ot h Visit 1 0 1 
a n d Visit 2 0 1.   
•  Re peat testi n g  is all o w e d o nce at eac h visit ( b y res c he d uli n g t h e visit).  Re peat of 
Visit 1 0 1 s h o ul d be sc he d ule d o n a date t hat w o ul d pr o vi de s ufficie nt ti me t o recei ve 
c o nfir mati o n fr o m t he s pir o metr y ce ntral re vie wer bef ore ra n d o mizati o n.  
•  Re -scree ni n g is all o we d o nce if patie nt fails t o meet t he criteria at t he re peat visit.  
8.    Patie nts w h o de m o nstrate a n i ncreas e i n F E V 1 of ≥ 1 2 % a n d 2 0 0 m L 1 5 t o 3 0 mi n utes 
after a d mi nistrati o n of 4 0 0 μ g sal b uta m ol or 3 6 0 μ g al b uter ol (e q ui val e nt d ose) t hr o u g h a 
s pacer d e vice at Visit 10 1 . Patie nts nee d t o de m o nstrate re v ersi bilit y at V 1 0 1 b y eit her a 
p ositi ve re versi bil it y test or wit h hist orical e vi de nce of re v ersi bilit y or p ositi ve br o nc hial 
pr o v ocati o n test t hat was perf or me d wit hi n 5 years pri or t o Visit 1 a n d acc or di n g t o 
A T S/ E R S g ui deli nes . If r e versi bilit y is n ot de m o nstrate d at Visit 1 0 1 t he re versi bilit y test 
ma y b e re p eate d o n ce.  
If re versi bility is n ot de m o nstrate d at Visit 1 0 1 ( or after re peat ) a n d hist orical e vi de nce of 
re versi bilit y is n ot a vaila ble ( or w as n ot perf or me d acc or di n g t o t he A T S/ E R S g ui deli nes ) 
t he patie nts m ust be scree n faile d.  
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 n cl usi o n i n t his st u d y. N o 
a d diti o nal  e x cl usi o ns  ma y  be  a p plie d  b y  t he  i n vesti gat or,  i n  or d er  t o  e ns ure  t hat  t h e  st u d y 
p o p ulati o n will be re pres e ntati ve of all eli gi ble patie nts.  
1.  Patie nts  w h o ha ve a s m o ki n g hist or y of greater t h a n 20 pac k years ( N ote:  1 pac k is 
e q ui vale nt t o 2 0 ci gar ettes. 1 0 pac k years = 1 p ac k / da y x 1 0 yrs., or ½ pac k/ da y x 2 0 
yrs.).  
2.  Patie nts dia g n ose d wit h C hr o nic O bstr ucti ve P ul m o nar y Diseas e ( C O P D). 
3.  Patie nts w h o ha ve ha d a n ast h ma attac k/e x acer bati o n re q uiri n g s yst e mic ster oi ds or 
h os pitalizati o n or e mer ge nc y r o o m visit wit hi n 6 wee ks of Visit 1 ( Scree ni n g). If patie nts 
e x perie nce a n ast h ma att ac k/e x acer b ati o n re q uiri n g s yste mic ster oi ds or h os pitalizati o n or 
e mer ge n c y r o o m v isit bet wee n Visit 1 a n d Visit 2 0 1 t he y ma y b e re-scree n e d 6 wee ks 
after r ec o v er y fr o m t he e x acer bati o n.  

N o v arti s  
C o nfi d e nti al  
P a g e 2 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
4.  Patie nts w h o ha ve e ver r e q uire d i nt u bati o n f or a s e vere ast h ma attac k/ e x acer bati o n.  
5.  Patie nts w h o ha ve a cli ni cal c o n diti o n w hic h is li kel y t o be w orse n e d b y I C S 
a d mi nistrati o n (e. g. gl a uc o ma, cataract a n d fra gilit y fract ures) w h o are acc or di n g t o 
i n vesti gat or’s m e dical j u d g me nt at ris k p artici pati n g i n t he st u d y. 
6.  Patie nts treate d wit h a L A M A f or ast h ma wit hi n 3 m o nt hs pri or  t o Visit 1.  
7.  Patie nts wit h narr o w -a n gle gla u c o ma, s y m pt o matic be ni g n pr ostatic h y per plasia ( B P H) or 
bl a d der- n ec k o bstr ucti o n or se vere re n al i m pair me nt or uri nar y rete nti o n. B P H patie nts 
w h o are sta bl e  o n treat m e nt ca n be c o nsi dere d . 
8.  Patie nts w h o ha ve ha d a res pirat or y tract i nfecti o n or cli nical si g nifi ca nt ast h ma w orse ni n g 
as defi ne d b y I n vesti gat or  wit h i n 4 wee ks pri or t o Visit 1 or bet wee n Visit 1 a n d Visit 20 1. 
Patie nts ma y be re -s cree ne d 4 wee ks after rec o ver y fr o m t heir res pirat or y tract i nfecti o n or 
ast h ma w orse ni n g.  
9.  Patie nts wit h a n y c hr o nic c o n diti o ns affecti n g t he u p per res pirat or y tract (e. g. c hr o nic 
si n usitis) w hic h i n t he o pi ni o n of t he i n vesti gat or ma y i nterfere wit h t he st u d y e v al uati o n 
or o pti mal partici pati o n i n t he st u d y.  
1 0.  Patie nts wit h a hist or y of c hr o nic l u n g diseases ot her t ha n ast h ma, i ncl u di n g ( b ut n ot 
li mite d t o) sarc oi d osis, i nterstitial l u n g disease, c ystic fi br osis, cli nicall y si g nifica nt 
br o nc hiectasis a n d acti ve t u berc ul osis. 
1 1.  Patie nts wit h u nc o ntr olle d T y pe I or T y p e II dia b etes. 
1 2.  Patie nts w h o ha ve a cli ni call y si g nifica nt la b orat or y a b n or malit y at Visit 1 0 1. 
1 3.  Use of ot her i n v esti gati o nal dr u gs wit hi n 3 0 da ys or 5 half- li ves of e nr oll me nt, u ntil t he 
e x pecte d p har mac o d y na mics effect has ret ur ne d t o baseli ne, w hic he v er is l o n ger.  
1 4.  Patie nts w h o, i n t he j u d g me nt of t he i n vesti gat or, ha ve cli nicall y si g nifica nt c o n diti o n 
s uc h as ( b ut n ot li mite d t o) u nsta ble isc he mic heart disease, Ne w Y or k H eart Ass ociati o n 
( N Y H A) Class III/I V l eft ve ntric ular fail ure, arr h yt h mia, u nc o ntr olle d h y p erte nsi o n, 
cere br o vasc ul ar diseas e, ps yc hiatric diseas e, ne ur o de ge nerati ve diseas es, or ot her 
ne ur ol o gi cal diseas e, u nc o ntr olle d h y p o- a n d h y pert h yr oi dis m a n d ot her a ut oi m m u ne 
diseases, h y p o kale mia, h y p er a dre ner gi c state, or o p ht hal m ol o gic dis or der or patie nts wit h 
a me dical c o n diti o n t hat mi g ht c o m pr o mise patie nt safet y or c o m plia nce, i nterfere wit h 
e val uati o n , or pr ecl u de c o m pleti o n of t he st u d y. 
1 5.  Patie nts wit h par o x ys mal (e. g., i nter mitte nt) atrial fi brillati o n are e x cl 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 r at e c o ntr ol strate g y (i.e., s electi ve beta bl oc k ers, calci u m c ha n nel 
bl oc ker, pace ma k er 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 u c h patie nts, atrial f i brillati o n m ust be prese nt at Visit 1 0 1 
wit h a resti n g v e ntric ular rate < 1 0 0/ mi n.  
1 6.  Patie nts wit h a hist or y of m y ocar dial i nfarcti o n wit hi n 1 2 m o nt hs pri or t o Visit 1 . 
1 7.  C o nc o mita nt use of a ge nts k n o w n t o pr ol o n g t he Q T i nter val u nless it ca n be per ma n e ntl y 
disc o nti n ue d f or t he d ur ati o n of st u d y. 
1 8.  Patie nts  wit h a hist or y of l o n g Q T s y n dr o m e or w h ose Q Tc meas ure d at Visit 1 0 1 
( Fri dericia met h o d) is pr ol o n ge d ( > 4 5 0 msec f or males a n d > 4 6 0 msec f or fe males). 
T hese patie nts s h o ul d n ot be rescree n e 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 9.  Patie nts w h o ha ve a cli ni call y si g nifica nt E C G a b n or malit y at Visit 1 0 1 ( E C G e vi de nce of 
m y ocar dial i nfarcti o n at Visit 1 0 1 s h o ul d be cli nicall y assesse d b y t he i n v esti gat or wit h 
s u p p orti ve d oc u me ntati o n).   
2 0.  Hist or y of m ali g na n c y of a n y or ga n s yste m ( ot her t ha n l ocalize d basal cell carci n o ma of 
t he s ki n or i n-sit u cer vical ca ncer), treate d or u ntreate d, wit hi n t he past 5 ye ars, re gar dless 
of w het her t h ere is e vi d e nce of l ocal rec urre nce or metastases.  
2 1.  Patie nts wit h a hist or y of h y perse nsiti vit y t o lact ose, a n y of t he st u d y dr u gs or its 
e x ci pie nts , or t o si milar dr u gs wit hi n t he cl ass i ncl u di n g u nt o war d reacti o ns t o 
s y m pat h o mi metic a mi nes or i n hale d me dicati o n or a n y c o m p o ne nt t here of. 
2 2.  Patie nts w h o ha ve n ot ac hie ve d a n acce pta ble s pir o metr y res ult at Visit 1 0 1 (c o nfir me d b y 
o ver rea d ) a n d Visit 2 0 1 (s pir o meter) i n acc or da n ce wit h A T S / E R S criteria f or 
acce pta bilit y a n d re peata bilit y.  (R e peat  is all o we d o nce f or eac h visit, sc he d ule d as cl ose 
as p ossi ble b ut n ot o n t he sa me da y). If t he patie nt fails t he re peat assess me nt, t he patie nt 
ma y b e res cree ne d o nce).   
2 3.  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- 3. 
2 4.  Patie nts recei vi n g a n y ast h ma -relat e d me dicati o ns i n t he classes s pecifi e d i n Ta ble 5- 2. 
2 5.  Patie nts recei vi n g me dicati o ns i n t he classes liste d i n Ta ble 5 - 4 s h o ul d be e x cl u de d u nless 
t he me dicatio n has bee n sta bilize d f or t he s pecifie d peri o d a n d t he state d c o n diti o ns ha ve 
bee n met.  
2 6.  Patie nts o n mai nte na nce i m m u n ot hera p y ( dese nsitizati o n) f or aller gies f or l ess t ha n 3 
m o nt hs pri or t o Visit 1 0 1 or patie nts o n Mai nte na n ce I m m u n ot hera p y f or m ore t ha n 3 
m o nt hs pri or t o Visit 1 0 1 b ut e x pecte d t o c ha n ge t hr o u g h o ut t he c o urse of t he st u d y. 
2 7.  Patie nts w h o are ser vi n g a c ust o dial se nte nce, d o n ot ha ve a per ma ne nt resi de nce or w h o 
are det ai ne d u n der l ocal me ntal healt h le gislati o n/re g ulati o ns.  
2 8.  Patie nts w h o are directl y ass ociate d wit h a n y me m bers of t he st u d y tea m or t heir fa mil y 
me m bers.  
2 9.  Patie nts u na ble t o use t he C o nce pt 1 dr y p o w der i n haler, Acc u haler ® / Dis k us ®, Res pi mat ® 
or a meter e d d ose i n haler. S pacer de vi ces are n ot p er mitte d  f or use wit h st u d y treat me nt. 
3 0.  Hist or y of alc o h ol or ot h er s u bsta nce a b use t hat b ase d o n j u d ge me nt of t he i n vesti gat or 
w o ul d i nterfer e wit h st u d y c o n d u ct.   
3 1.  Patie nts wit h a k n o w n hist or y of n o n-c o m plia nce t o me dicati o n or w h o were u na ble t o 
c o m plete a patie nt e Diar y, use electr o ni c Pea k Fl o w  Meter , or c o m plete q uesti o n naires 
( P R Os). 
3 2.  Patie nts w h o d o n ot mai ntai n re g ular d a y/ ni g ht, w a ki n g/slee pi n g c ycles (e. g., i nc o nsiste nt 
ni g ht s hift w or kers).  C o nsiste nt ni g ht s hift w or kers ma y b e c o nsi dere d f or i ncl usi o n.  
3 3.  Pre g n a nt or n ursi n g (lactati n g) w o m e n, w here pre g na n c 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 4.  W o me n of c hil d- beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of 
bec o mi n g pre g na nt, u nless t he y are usi n g hi g hl y effecti ve m et h o ds of c o ntrace pti o n 
d uri n g d osi n g of st u d y tr eat me nt a n d f oll o w- u p p eri o d. 
Hi g hly Effective c o ntr ace pti o n met h o ds i ncl u de: 

N o v arti s  
C o nfi d e nti al  
P a g e 2 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
•  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 
s u bject). Peri o dic a bsti ne nce (e. g., cale n d ar, o v ulati o n, s y m pt o m-t 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 yster ect o m y) , t otal h yst erect o m y or t u b al li gati o n at least si x wee ks bef ore ta ki n g 
st u d y treat me nt. I n cas e of o o p h orect o m y al o n e, o nl y w he n t h e re pr o d ucti ve stat us of 
t he w o ma n has bee n c o nfir me d b y f oll o w u p h or m o ne le vel assess me nt. 
•  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe male s u bjects o n t he 
st u d y, t he vas ect o mize d male part ner s h o ul d be t he s ole part ner f or t hat s u bject. 
•  Use of or al, i njecte d or i m pla nte d h or m o nal met 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 x a 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 ntr a uteri ne de vice (I U D) or i ntra uteri ne s yste m (I U S) .  
I n 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 Visit 2 0 1 ( Ra n d o mizati o n / Start of treat me nt peri o d ). 
W o me n are c o nsi der e d p ost- me n o pa usal a n d n ot of c hil d- beari n g p ot e ntial if t he y h a ve 
ha d 1 2 m o nt hs of nat ural (s p o nta ne o us) a m e n orr h ea wit h a n a p pr o priate cli nical pr ofile 
(e. g. a ge a p pr o pri ate, hist or y of vas o m ot or s y m pt o ms) or ha ve h a d s ur gical bilateral 
o o p h orect o m y ( wit h or wit h o ut h ysterect 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 n e, o nl y w he n t he re pr o d ucti ve stat us of t he w o ma n has 
bee n c o nfir me d b y f oll o w- u p h or m o ne le v el assess me nt is s he c o nsi dere d n ot of 
c hil d beari n g p ote ntial.  
5 
Tr e at m e nt  
5. 1   St u d y tr e at m e nt 
5. 1. 1  I n v e sti g ati o n al a n d c o ntr ol dr u g s 
T he I n vesti gati o nal treat me nts are as f oll o ws:  
•  Q V M 1 4 9 (i n dacater ol acetate/ gl yc o p yrr o ni u m br o mi de/ M F) 1 5 0/ 5 0/ 8 0 μ g o. d. deli vere d 
as p o w der i n har d ca ps ules via C o nce pt 1 
•  Q V M 1 4 9 (i n dacater ol acetate/ gl yc o p yrr o ni u m br o mi de/ M F) 1 5 0/ 5 0/ 1 6 0 μ g o. d. deli vere d 
as p o w der i n har d ca ps ules via C o nce pt 1 
T he C o m parati ve tr eat me nt is:  
•  O pe n la bel sal meter ol xi naf oate  /fl uticas o n e pr o pi o nate 5 0/ 5 0 0 μ g b.i. d. deli vere d as 
p o w der via A cc u h aler ® + ti otr o pi u m 5 μ g o. d deli vere d via Res pi mat ® 
U n der  n o  circ u mst a n ces  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  t he  i n vesti g a ti o n al  or  refere nce  t her a pies  d uri n g  t he  tre at me nt 
peri o d. Q V M 1 4 9 will be pr o vi de d as gl o bal cli nical bli n de d s u p plies a n d will be pac ke d a n d 
la bele d u n der t h e res p o nsi bilit y of N o v artis, Dr u g S u p pl y M a na ge me nt  
•  T he C o m parati ve tr eat me nts, sal meterol xi naf oate  /fl uticas o ne pr o pi o nate 5 0/ 5 0 0 μ g  
deli vere d as p o w der via Acc u hal er ® + ti otr o pi u m 5 μ g deli vere d via Res pi mat ® , will  

N o v arti s  
C o nfi d e nti al  
P a g e 3 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
eit her be s o ur ce d  as l o cal c o m mercial s u p pl y b y N o vartis or pr o vi de d gl o bal l y b y N o vartis 
as cli nical o pe n la b el s u p plies.  
5. 1. 2  A d dit i o n al tr e at m e nt 
Starti n g wit h Visit 1 p atie nts will recei ve s h ort acti n g b eta a g o nist (sal b uta m ol  or al b uter ol ) 
i n haler t o use as r esc ue me dicati o n o n a n “as n ee de d” basis.  At Visit 1 0 1 patie nts will als o be 
s u p plie d wit h o pe n la bel r u n -i n me dicati o n, salmeter ol / fl uticas o ne  5 0/ 2 5 0 μ g b.i. d. or 5 0/ 5 0 0 
μ g b.i. d. t o mat c h t heir b ac k gr o u n d m e dicati o n vi a I R T .  It is re q uire d f or all patie nts t o ta k e 
t he o pe n-la bel r u n-i n me dicati o n, sal meter ol / fl uticas o ne t wice d ail y fr o m Visit 10 1 t o Visit 
2 0 1.   T h e resc u e me di cati o n will be pr o vi de d  as nee de d  t o t he patie nts f or t he d urati o n of t he 
st u d y. M ore d etails re gar di n g res c ue me di cati o n are i n Secti o n 5. 5. 6   
O pe n -la bel  r u n  i n  me dicati o n,  sal meter ol xi naf oate /fl uticas o ne pr o pi o nate  5 0/ 2 5 0  μ g  or 
5 0/ 5 0 0  μ g deli vere d  as  p o w der  via Acc u h aler ®  will  eit her  be  s o urce d  as  l ocal  c o m mercial 
s u p pl y  or  pr o vi de d  as  gl o bal  cli nical  o pe n  l a b el  s u p plies b y  N o vartis. Sal b uta m ol resc ue 
me dicati o n  will eit her be s u p plie d t o t he i n vesti gat or sites l ocall y b y N o vartis or pr o vi de d b y 
t he st u d y ce nter a n d rei m b urse d b y N o vartis. 
5. 2   Tr e at m e nt ar m s 
Patie nts will be ra n d o mize d t o o ne of t he f oll o wi n g t hree treat me nt ar ms i n a rati o of 1: 1: 1 : 
•  Q V M 1 4 9 1 5 0/ 5 0/ 8 0 μ g o. d. deli vere d via C o nce pt 1 
•  Q V M 1 4 9 1 5 0/ 5 0/ 1 6 0 μ g o. d. deli vere d via C o nce pt 1 
•  Sal meter ol  xi naf oate /fl uticas o ne pr o pi o nat e 5 0/ 5 0 0 μ g b.i. d. (i n t he m or ni n g a n d i n t he 
e ve ni n g) deli vere d via A cc u haler ® pl us ti otr o pi u m 5 μ g o. d deli vere d vi a Res pi mat ® 
5. 3   Tr e at m e nt a s si g n m e nt a n d 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  R es p o nse  Tec h n ol o g y 
(I R T) t o o ne of t he 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  t hat  t h e  patie nt  f ulfills  all  t he  i ncl usi o n/e x cl usi o n  criteria.  T h e  I R T  will 
assi g n  a  ra n d o mizati o n  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  u ni q ue  me dicati o n  n u m ber  f or  t he  first  pac ka ge  of 
i n vesti gati o nal treat me nt t o be dis pe nse d t o t he 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 call er.  
T he  ra n d o mizati o n  n u m bers  will  be  ge nerate d  usi n g  t he  f oll o wi n g  pr o ce d ure  t o  e ns ure  t hat 
treat me nt assi g n m e nt is u n biase d a n d c o nceale d fr o m patie nts a n d i n vesti gat or staff. A patie nt 
ra n d o mizati o n  list  will  be  pr o d uce d  b y  t he  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 parat e  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 n a ge m e nt usi n g a v ali 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). 
Ra n d o mizati o n  will  be  stratifie d  b y  pre vi o us  I C S  d ose  of  I C S/ L A B A  t hera p y  ( me di u m  or 
hi g h d ose) a n d r e gi o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 3 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
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  a  me m ber  of  t he 
Ra n d o mizati o n Gr o u p. 
5. 4   Tr e at m e nt bli n di n g  
T he  st u d y  is  partiall y  bli n de d.    T he free tri ple  c o m bi nati o n  of sal meter ol/fl uticas o ne  + 
ti otr o pi u m is  o pe n-la bel  f or  w hic h  i n vesti gat ors  a n d  patie nts  will  ha ve  f ull  k n o wle d ge  of 
treat me nt all ocati o n.  H o we ver, i n or d er t o mi ni mize t he p ote ntial i m pact, meas ures will b e 
ta ke n  t o  bli n d  t he  s p o ns or  tea m,  i ncl u di n g  d ata  a nal ysts,  fr o m  k n o wle d ge  of  treat me nt 
all ocati o n b y  usi n g  t he  f oll o wi n g  met h o ds:  ( 1)  Ra n d o mizati o n  data  a n d  treat me nt  c o des  are 
ke pt  strictl y  c o nfi d e 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 n e 
else i n v ol ve d i n t he st u d y ( 2) Case Re p ort F or ms t hat re veal t he treatme nt ar m  will be bli n de d 
fr o m t he s p o ns or tea m. 
S pecificall y  w it hi n  t he  t w o  Q V M 1 4 9  treat me nt  ar ms  patie nts,  i n vesti gat or  staff,  pers o ns 
perf or mi n g  t h e  ass ess me nts,  a n d  data  a nal ysts  will  re mai n  bli n d  t o  t he  i de ntit y  of  t he 
Q V M 1 4 9  treat me nt  d os e  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  a d diti o nal  met h o d: ( 3) T he  i de ntit y  of  t he  Q V M 1 4 9  treat me nt  d ose  will  be 
c o nceale d b y t he us e of st u d y dr u gs t hat are all i de ntical i n pac k a gi n g, la beli n g, sc h e d ule of 
a d mi nistrati o n, a p pear a n ce,  taste, a n d o d or.  
U n bli n di n g will o nl y occ ur i n t he case of p atie nt e mer ge n cies (s ee Secti o n 5. 5. 9 ) 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  
S p o ns or  q ualifie d  me di cal  pers o n nel  will  b e  rea dil y  a v aila ble  t o  a d vise  o n  trial  rel ate d 
me dica l q uesti o ns or pr o ble ms. 
5. 5. 1  P ati e nt n u m b eri n g  
Eac h  p atie nt  is  u ni q uel y  i d e ntifie d  b y  a  S u bject  N u m ber  w hic h  is  c o m p ose d  b y  t he  site 
n u m ber  assi g ne d  b y  N o vartis  a n d  a  se q u e ntial  n u m ber  assi g ne d  b y  t he  i n vesti gat or.  O n ce 
assi g ne d t o a patie nt, t he S u bject N u m ber will n ot be re use d. 
U p o n si g ni n g t he i nf or m e d c o nse nt f or m, t he patie nt is assi g ne d t h e ne xt se q ue ntial n u m ber 
b y  t he  i n vesti gat or.  T he  i n vesti gat or  or  his/ her  staff  will  c o ntact  t he  I R T  a n d  pr o vi de  t he 
re q ueste d i d e ntif yi n g i nf or mati o n f or t he p atie nt t o re gister t he m i nt o t he I R T s yste m. T he site 
s h o ul d select t he e- Case Re p ort F or m  (e-C R F)  b o o k wit h a matc hi n g S u bject N u m ber  fr o m 
t he E D C s yste m t o e nter data. 
If t he patie nt fails t o be ra n d o mize d f or a n y reas o n, t he  I R T m ust be n otifie d  wit hi n 2 da ys 
t hat t he patie nt was a scr ee ni n g/r u n -i n fail ure. T h e reas o n f or scree ni n g/r u n-i n fail ure will be 
e ntere d  o n  t he a p plica ble St u d y  P eri o d Dis p ositi o n  e C R F.  Re -scree ne d  patie nts  will  be 
assi g ne d a ne w se q ue nti al patie nt n u m ber a n d t he i n vesti gat or or staff will re gister t he m i nt o 
t he I R T s yste m.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
5. 5. 2  Di s p e n si n g t h e st u d y dr u g  
Eac h  st u d y  site  will  be  s u p plie d  b y  N o vartis  wit h  i n vesti gati o nal  treat me nt  i n  pac ka gi n g  of 
i de ntical  a p pear a nce. All 
N o vartis  gl o ball y  s u p plie d  treat me nts  will  ha ve st u d y  dr u g 
pac ka gi n g wit h 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 t hree treat me nt ar ms. I n vesti gat or staff will i de ntif y t h e 
st u d y  dr u g  pac k a ge(s)  t o  dis pe nse  t o  t he  patie nt  b y  c o ntacti n g  t he  I R T  a n d  o btai ni n g  t he 
me dicati 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 ut er  part  of  t h e  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 s u bject n u m ber. 
All st u d y tr eat me nt l a bels will c o m pl y wit h t he le gal re q uire me nts of eac h c o u ntr y, i n cl u di n g 
l ocall y s o ur ce d tr eat me nts. 
5. 5. 3  H a n dli n g of st u d y a n d a d diti o n al tr e at m e nt  
5. 5. 3. 1  H a n dli n g  of st u d y tr e at m e nt  
St u d y treat me nt m ust be recei v e 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 p erl y,  a n d  ke pt  i n  a  sec ure d  l ocati o n  t o  w hic h  o nl y  t he  i n vesti gat or  a n d 
desi g nees  ha v e  access.  U p o n  recei pt,  all  st u d y  treat me nt  m ust  be  st ore d  acc or di n g  t o  t h e 
i nstr ucti o ns s pecifie d o n t he la bels. 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. Tec h nical c o m plai nts are t o be re p orte d t o t he res p ecti v e N o vartis C o u ntr y 
P har ma Or ga nizati o n Q u alit y Ass ur a nce.  
Me dicati o n la bels  will  be  i n  t he  l ocal  la n g u a ge  a n d  c o m pl y  wit h  t he  le gal  re q uire m e 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 st u d y treat me nt b ut n o i nf or mati o n 
a bo ut t he patie nt e x ce pt f or t he me dicati o n n u m ber . 
T he  i n vesti gat or  m ust  m ai 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  st u d y 
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 
m o nit ors d uri n g site visits or r e m otel y a n 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 st u d y  tr eat 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 h e ti me of 
disc o nti n uati o n of st u d y treat me nt.  
At  t he  c o n cl usi o n  of  t he  st u d y,  a n d  as  a p pr o priate  d uri n g  t h e  c o urs e  of  t h e  st u d y,  t he 
i n vesti gat or will r et ur n all u n use d st u d y treat me nt, pac ka gi n g, dr u g l a bels, a n d a c o p y of t he 
c o m plete d dr u g acc o u nt a bilit y l o 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 d er at eac h site. 
5. 5. 3. 2  H a n dli n g of a d diti o n al tr e at m e nt  
T he f oll o wi n g n o n- i n vesti gati o nal treat me nt has t o be m o nit ore d as f oll o ws: 
T he n o n -i n vesti gati o nal treat me nt m ust be recei v e d b y a desi g nat e 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,  a n d  k e pt  i n  a  sec ure d  l ocati o n  t o  w hic h  o nl y  t he 
i n vesti gat or  a n d  desi g n ees  ha v e access.  Cli nical  s u p plies  are  t o  b e  dis pe nse d  o nl y  i n 
acc or d a nce wit h t he pr ot oc ol. 
T he i n vesti gat or m ust m ai 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 t he n o n -
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 unta bilit y will 

N o v arti s  
C o nfi d e nti al  
P a g e 3 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
be  perf or me d  b y  m o nit ors  d uri n g  site  visits  or  re m otel y  a n d  at  t h e  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 n o n - 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  r u n -i n  f or  t h e  r u n-i n  me dicati o n  a n d  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 tr eat me nt f or t h e resc ue m e dicati o n.  
T hese me dicati o ns are:  
•  Sal b uta m ol ( 1 0 0 μ g) or al b uter ol ( 9 0 μ g) us e d as resc ue me dicati o n  
•  Sal meter ol xi naf oate /fl uticas o ne pr o pi o nat e 5 0/ 2 5 0 μ g b.i. d. or 5 0/ 5 0 0 μ g b.i. d. via 
Acc u hal er ® use d as  r u n-i n me dicati o n  
Details are d escri b e d i n t he C R F c o m pleti o n g ui d eli nes.  
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  
At  Visit  1  all  patie nts  will  be  i nstr ucte d  o n  h o w  t o  use  a Met ere d  De vice  I n hal er  ( M DI ) t o 
a d mi nister  res c ue  m e dicati o n,   sal b uta m ol.    Patie nts  will  be  i nstr ucte d  t o  ta ke  resc u e 
me dicati o n  o n  a n  “as  nee de d ”  basis  t hr o u g h o ut  t he  st u d y.    I n  or der  t o  sta n d ar dize 
meas ure me nts, p atie nts will be i nstr ucte d t o a bstai n fr o m ta ki n g res c ue  me dicati o n wit hi n 6 
h o urs of t he start of eac h visit u nless a bs ol utel y n ecessar y.   
At  Visit  1 0 1 patie nts  will  be  trai ne d  o n  h o w  t o  pr o perl y  us e  o pe n -la b el  r u n-i n  me dicati o n 
sal meter ol/fl uticas o ne vi a Acc u h aler ® a n d will be i nstr ucte d t o ta ke  b.i. d. per  instr ucti o ns i n 
A p pe n di x 4 .   
At Visit 2 0 1 patie nts will be trai n e d o n h o w t o pr o perl y use t h e C o nce pt 1 i n haler d e vice or t h e 
Acc u hal er ® pl us Res pi m at ® i n haler d e vices  base d o n t he ra n d o mize d treat me nt ar m pr o vi de d 
b y I R T.  Patie nts w h o are u na ble t o use t he assi g ne d de vice (s) c orrectl y at Visit 2 0 1 will n ot 
c o nti n ue  i n  t he  st u d y.  At  cli nic  visits  t he  i n vesti gat or  s h o ul d  c hec k  t he  patie nt’s  use  of  t he 
i n halati o nal  de vices  t o  e ns ure  t hat  t he y  are  usi n g  eac h  de vice  c orrectl y.  Ad diti o nal  de vice 
trai ni n g s h o ul d be pr o vi d e d as re q uire d. 
Q V M 1 4 9 Tre at me nt ar ms o nce d ail y e ve ni n g d ose: 
Pati e nts will be i nstr ucte d t o i n hale 1 Q V M 1 4 9 ca ps ule usi n g t h e pr o vi de d C o nce pt 1 de vice  
(pac k beari n g o nl y a  m o o n   pict o gra m ) i n t he e ve ni n g bet wee n 5: 0 0 a n d 8: 0 0 p m.  Q V M 1 4 9 
st u d y  tr eat me nt  m ust  o nl y  be ta ke n  o nce  a  d a y  i n  t h e  e v e ni n g.    T h e  first  d ose  will  be 
a d mi nistere d i n t he cli nic at Visit 2 0 1 .  
O pe n l a bel s al meter ol /fl utic as o ne t wice d ail y + ti otr o pi u m o nce d ail y e ve ni n g d ose:  
Patie nts will be i nstr ucte d t o ta ke:  
•  M O R NI N G bet w ee n 5: 0 0 a n d 8: 0 0 a m: 1 i n halati o n fr o m t he Acc u haler ® de vice 
c ontai ni n g sal met er ol/fl uticas o ne ( pac ka ge beari n g b ot h a s u n   a n d m o o n   pict o gra m ) 
•  E V E NI N G b et wee n 5: 0 0 a n d 8: 0 0 p m: 1 i n halati o n fr o m t he Ac c u haler ® d e vice 
c o ntai ni n g sal met er ol/fl uticas o ne  ( pac ka ge beari n g b ot h a s u n   a n d m o o n   pict o gra m )  
f oll o we d directl y b y 2 i n halati o ns fr o m t he Res pi mat ® de vice c o ntai ni n g ti otr o pi u m 
(pac ka ge beari n g o nl y a  m o o n   pict o gra m ).  Ti otr o pi u m via Res pi mat ® m ust o nl y be 
ta ke n o nce a da y i n t he e ve ni n g.   T h e first d ose will be a d mi nistere d i n t he cli nic at Visit 
2 0 1. 
 

N o v arti s  
C o nfi d e nti al  
P a g e 3 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
T a bl e 5- 1 
St u d y Tr e at m e nt s  
Tre at me nt ar m  
M or ni n g  
 
E ve ni n g   
Q V M 1 4 9 1 5 0/ 5 0/ 8 0  µ g  
or  
Q V M 1 4 9 1 5 0/ 5 0/ 1 6 0  µ g  
N o d ose  
 
1 ca ps ule via  C o nce pt 1  
Sal meter ol  xi naf oate/fl uticas o ne  
pr o pi o nate  5 0/ 5 0 0   µ g  
+ 
Ti otr o pi u m 5 μ g o. d  
1 i n halati o n via 
Acc u haler ®   
 
1 i n halati o n via Acc u haler ®   
+ 
2 i n halati o ns via Res pi mat ®  
Patie nts will  be  i nstr ucte d  t o  ri nse  t heir  m o ut h  after  i n halati o n  of  st u d y  dr u g  ( 2  ti mes  wit h 
a p pr o xi matel y  3 0  m L  w ater).  Water  use d  f or  m o ut h  ri nsi n g  s h o ul d  be  s pat  o ut  a n d  s h o ul d 
N O T  be  s w all o we d.  W he n  se q ue ntial  i n halati o ns  of  st u d y  dr u gs  fr o m  t w o  de vices  are 
req uire d,  m o ut h  ri nsi n g  s h o ul d  be  d o ne  after  t he  last  i n halati o n.   Patie nts  will  als o  be 
i nstr ucte d  t o  ta ke  me dicati o n  at  a p pr o xi matel y  t he  sa me  desi g nate d  ti me  w hile  at  h o me  i n 
bet wee n visits.  
I nstru cti o ns  f or  use  of  t he  C o nce pt 1,  Acc u h aler ® ,  a n d  Res pi mat ® de vices  are  gi v e n  i n 
A p pe n di x 3 , A p pe n di x 4 , a n d A p pe n di x 5 . 
T he st u d y treat me nt ca n be ta ke n wit h o ut re gar d t o slee p, meals, a n d ot her acti vities. O n da ys 
of  sc he d ule d  cli nic  visits,  patie nts  s h o ul d  ta ke  t heir  e ve ni n g  d ose  of  st u d y  treat me nt  at  t he 
cli nic.    
T he d ur ati o n of acti ve tr eat me nt is 2 4 wee ks, wit h t he last d os e of st u d y treat me nt o cc urri n g 
at Visit  2 0 4. 
All kits of i n vesti gati o nal treat me nt assi g n e d b y t he I R T will b e rec or d e d i n t he I R T . All use d 
a n d  u n use d  st u d y  me di cati o n/ pac ka gi n g  (e x ce pt  use d  ca ps ules) m ust  be  ret ur n e d  b y  t he 
patie nt at eac h st u d y visit a n d/ or at t he ti me of disc o nti n uati o n.  
T he  i n vesti gat or  s h o ul d  pr o m ote  c o m plia nce  b y  i nstr ucti n g  t he  patie nt  t o  ta ke  t he  st u d y 
treat me nt  e x actl y  as  pres cri be d  a n d  b y  stati n g  t h at  c o m plia nce  is  necessar y  f or  t h e  patie nt’s 
safet y 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 r eas o n t o ta ke t h e st u d y treat me nt as prescri be d. 
If a n y fa ults ar e i de ntifie d wit h eit her t he de vi ce a n d/ or t he blisters, t hese s h o ul d be ret ur ne d 
t o  N o vartis  Dr u g  S u p pl y  Ma na ge me nt  wit h  t he  c o m plete d  De vice  Ret ur n  F or m.  The  f or ms 
will be s u p plie d t o eac h i n vesti gat or site b y t he Fi el d M o nit or. 
5. 5. 5  P er mitt 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  
I n v esti gati o nal  treat me nt  d ose  a dj ust me nts  a n d/ or  i nterr u pti o ns  are  n ot  p er 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 v e nt. A n y 
i nterr u pti o n  of  st u d y  m e dicati o n  s h o ul d  be  f or  t he  s h ortest  ti me  peri o d  p ossi ble. E ver y 
i nterr u pti o n d ue t o a n a d verse e v e nt 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).  I nt err u pti o ns of m ore t ha n 5 da ys f or ot her reas o ns m ust als o 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).  

N o v arti s  
C o nfi d e nti al  
P a g e 3 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Cl a s s of m e di c ati o n  
Mi ni m u m w a s h o ut p eri o d pri or t o S cr e e ni n g ( Vi sit 
1), R u n -i n ( Vi sit 1 0 1) a n d R a n d o mi z ati o n ( Vi sit 
2 0 1) 1, 2, 3  
I ntr a-m u s c ul ar d e p ot c orti c o st er oi d s  
M u st n ot b e u s e d wit hi n 3 m o nt h s pri or t o Vi sit 1 0 1  
1 Tr e at m e nt f or r e c or d e d a st h m a e x a c er b ati o n a s d efi n e d i n S e cti o n 6. 4. 5  i s all o w e d O N L Y u ntil t h e a st h m a 
e x a c er b ati o n i s r e s ol v e d  
2  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 . 
3 T h e s e m e di c ati o n s ar e al s o pr o hi bit e d if a d mi ni st er e d f or ot h er i n di c ati o n s.  
4  St u d y s u p pli e d r e s c u e m e di c ati o n ( s al b ut a m ol/ al b ut er ol r e s c u e m e di c ati o n) pr o vi d e d at Vi sit 1 i s all o w e d d uri n g 
tr e at m e nt b ut s h o ul d b e wit h h el d f or at l e a st 6 h o ur s pri or t o s pir o m etr y m e a s ur e m e nt s at cli ni c vi sit s. Cli ni c vi sit s 
m a y b e r e s c h e d ul e d if r e s c u e m e di c ati o n w er e t a k e n l e s s t h a n 6 h o ur s pri or t o t h e s pir o m etr y a s s e s s m e nt s . 
T a bl e 5- 3 
Pr o hi bit e d M e di c ati o n s  
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 R u n -i n ( Vi sit 
1 0 1)  
N o n -p ot a s s i 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 β – bl o c ki n g a g e nt s  
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  ( e. g. mi z ol a sti n a n d 
t erf e n a di n e) 
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 
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 nt i p s y c h oti c s). C o m bi n ati o n s of a nti p s y c h 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  
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  
S y st e mi c a nti c h oli n er gi c s  
7 d a y s  
Str o n g i n hi bit or s of c yt o c hr o m e P 4 5 0 3 A e. g. 
k et o c o n a z ol e  
7 d a y s  
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  
Ot h er i n v e sti g ati o n al dr u g s  
3 0 d a y s or 5 h alf -li v e s, w hi c h e ver i s l o n g er  
N or a dr e n ali n e r e u pt a k e i n hi bit or s  
7 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  
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. B ef or e st arti n g w a s h -o ut of a n y of t h e li st e d pr o hi bit e d m e di c ati o n s i n t hi s t a bl e, 
t h e i n v e sti g at or h a s t o a s s e s s t h e b e n efit a n d ri s k c ar ef ull y f or e a c h i n di vi d u al p ati e nt. T er mi n ati n g a n y m e di c ati o n 
s ol el y f or t h e p ur p o s e of m e eti n g i n cl u si o n/ e x cl u si o n crit eri a i s n ot a c c e pt a bl e.  
T a bl e 5- 4 
M e di c ati o n s all o w e d u n d er c ert ai n c o n diti o n s  
Cl a s s of m e di c ati o n  
C o n diti o n  

N o v arti s  
C o nfi d e nti al  
P a g e 3 8  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Cl a s s of m e di c ati o n  
C o n diti o n  
M o n o cl o n al a nti b o d y: I g E i n hi bit or s ( e. g. 
o m ali z u m a b), I L -5 i n hi bit or s ( e. g. 
m e p oli z u m a b)  ** 
All o w e d if at st a bl e d o s e f or at l e a st 3 m o nt h s pri or t o 
Vi sit 1  
Or al c orti c o st er oi d s  *  ** 
All o w e d if at st a bl e d o s e f or at l e a st 1 m o nt h pri or t o 
Vi sit 1  
L e u k otri e n e A nt a g o ni st a n d l e u k otri e n e 
s y nt h e si s i n hi bit or s  ** 
All o w e d if at st a bl e d o s e f or at  l e a st 1 m o nt h pri or t o 
Vi sit 1  
L o n g -a cti n g t h e o p h ylli n e ( m et h yl x a nt hi n e) 
pr e p ar ati o n s  ** 
If st a bili z e d f or at l e a st 4 w e e k s pri or t o Vi sit 1 a n d 
t hr o u g h o ut t h e tri al. N ot a d mi ni st er e d wit hi n 2 4  h 
pri or t o st u d y vi sit.  
S h o rt- a cti n g t h e o p h ylli n e ( m et h yl x a nt hi n e) ** 
If st a bili z e d f or at l e a st 4 w e e k s pri or t o Vi sit 1 a n d 
t hr o u g h o ut t h e tri al. N ot a d mi ni st er e d wit hi n 1 2 h 
pri or t o st u d y vi sit.  
M u c ol yti c a g e nt s n ot c o nt ai ni n g 
br o n c h o dil at or s  
If st a bili z e d f or at l e a st 4 w e e k s pri or t o Vi sit 1 a n d 
t hr o u g h o ut t h e tri al 
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 cr o mil, k et otif e n  
If st a bili z e d f or at l e a st 4 w e e k s pri or t o Vi sit 1 a n d 
t hr o u g h out t h e tri al  
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 ( m u st 
h a v e n o d o c u m e nt e d  eff e ct o n a n y ot h er 
n e ur otr a n s mitt er s or ot h er bi ol o gi c al 
p at h w a y s. E. g. m u s c ari ni c p at h w a y)  
Tr e at m e nt r e gi m e n i s st a bl e f or at l e a st o n e m o nt h at 
Vi sit 1  
I n a cti v at e d i nfl u e n z a v a c ci n ati o n, 
p n e u m o c o c c al v a c ci n ati o n 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 st u d y vi sit  
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 4 w e e k s pri or t o Vi sit 1 0 1.  
I n t h e c a s e of a s n e e d e d, pr o vi d e d a n e st a bli s h e d 
p att er n of u s e h a s b e e n d o c u m e nt e d.  
T o pi c al c orti c o st er oi d s f or t h e  tr e at m e nt of 
e c z e m a  
I n r e c o m m e n d e d d o s e s a n d d o s a g e r e gi m e n s 
M ai nt e n a n c e i m m u n ot h er a p y f or all er gi e s  
St a bl e d o s e f or at l e a st 3 m o nt h s pri or t o Vi sit 1 0 1 
a n d t hr o u g h o ut t h e tri al . 
* Or al c orti c o st er oi d s m a y b e c o nti n u e d at a l o w st a bl e d o s e aft er a c o ur s e of st er oi d t a p er f or 
e x a c er b ati o n s at t h e  di s cr eti o n of t h e i n v e sti g at or.  
**D uri n g t h e tr e at m e nt p eri o d, “ st e p u p” or a d d-o n a s w ell a s “ st e p -d o w n” or d e -e s c al ati o n of 
m ai nt e n a n c e  tr e at m e nt s ar e all o w e d , a s d e s cri b e d b el o w a n d i n S e cti o n. 5. 5. 5. T h e s e tr e at m e nt s m u st 
b e u s e d a c c or di n g t o a p pr o v e d l o c al l a b el s .  
If i n dicate d f or t he tr eat me nt of a n ast h ma e x acer bati o n, a n y treat me nt dee me d necessar y b y 
t he treati n g  p h ysicia n  f or  t he  saf et y  of  t he  p atie nt  is  all o we d  fr o m  t he  start  of  t he  ast h ma 
e x acer bati o n e ve nt ( defi n e d as per pr ot oc ol Secti o n 6. 4. 5 ) u ntil t he ast h ma e x acer bati o n e ve nt 
is res ol ve d. If  dee me d  necessar y,  t he  treati n g  p h ysicia n  ma y  “ste p-u p ” patie nt’s bac k gr o u n d 
me dicati o n  a n d/ or  a d d -o n  mai nte na nce  treat me nt  o pti o ns  if  t he y  re m ai n  u nc o ntr olle d  or 
e x perie nce  se v ere  ast h ma  e x acer b ati o ns ,  refer  t o Secti o n  5. 5. 5 .   Patie nts  ma y  N O T  self -
me dicate  ( ot h er  t ha n  a d mi nistrati o n  of  resc u e  me dicati o n)  or  a d j ust  t hera p y  wit h o ut 
per missi o n/ g u i da nce fr o m treati n g p h ysici a n. 

N o v arti s  
C o nfi d e nti al  
P a g e 3 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
5. 5. 9  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 c o d e brea ks  m ust o nl y be u n derta k e n w he n  it is re q uire d t o i n or der t o treat t he 
patie nt  safel y.  M ost  oft e 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 ar e s uffici e nt t o treat a st u d y p atie nt w h o prese nts wit h a n e mer ge nc y 
c o n diti o n.  E mer ge nc y  treat me nt  c o de  brea ks  are  p erf or me d  usi n g  t h e  I R T.  W he n  t he 
i n vesti gat or c o nt acts t he s yste m t o brea k a treat me nt c o de f or a patie nt, h e/s he m ust pr o vi de 
t he re q ueste d p atie nt i de ntif yi n g i nf or mati o n a n d c o nfir m t he necessit y t o brea k t he treat me nt 
c o de  f or  t he  patie nt.  T h e  i n vesti gat or  will  t he n  recei v e  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 m ail c o nfir mi n g t his i nf or mati o n. T he s yst e m 
will a ut o maticall y i nf or m t he N o vartis m o nit or f or t he site a n d t he St u d y Tea m t hat t he c o de 
has bee n br o k e n. 
It is t h e i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t here is a de p e n da ble pr oce d ure i n place t o 
all o w access t o t he I R T/ c o de brea k car ds at a n y ti me i n case of e mer ge n c y. T h e i n vesti gat or 
will pr o vi de: 
•  pr ot oc ol n u m ber 
•  st u d y dr u g na m e  
•  patie nt n u m ber 
I n  a d diti o n, oral a n d writte n i nf or mati o n t o t he  s u bject m ust be pr o vi de d o n h o w t o c o ntact 
his/ her  bac k u p  i n  cases  of  e mer ge nc y,  or  w he n  he/s he  is  u na vaila ble,  t o  e ns ure  t hat  u n -
bli n di n g ca n b e perf or me d at a n y ti me.  
St u d y  tr eat me nt  m ust  be  disc o nti n ue d  if  t he  treat me nt  c o de  of  Q V M 1 4 9  treat me nt  ar m  has 
bee n br o ke n (act ual d ose of Q V M 1 4 9 u n bli n de d) after e mer ge n c y u n bli n di n g or i na d v erte ntl y 
br o ke n.  T his d oes n ot a p pl y t o t he free tri ple treat me nt ar m ( sal meter ol  xi naf oate / fl uticas o ne 
pr o pi o nate + ti otr o pi u m) w hic h is o pe n la bel f or in vesti gat ors a n d p atie nts.       
5. 6   St u d y C o m pl eti o n a n d Di s c o nti n u ati o n  
5. 6. 1  St u d y c o m pl eti o n , p o st -st u d y tr e at m e nt a n d e n d of tri al  
A patie nt will be c o nsi dere d t o ha v e c o m plete d t h e st u d y w he n t he patie nt has c o m plete d t h e 
last visit pla n ne d i n t he pr ot oc ol ( Visit 3 0 1). 
C o nti n ui n g  car e  s h o ul d  be  pr o vi de d  b y  i n vesti gat or  a n d/ or  referri n g  p h ysicia n  b ase d  o n 
patie nt a vaila bilit y.  
F or all ra n d o mize d pati e nts, a safet y f oll o w -u p V isit 3 0 1 s h o ul d be c o n d ucte d b y t ele p h o ne 7 
da ys  after  last  visit . T he  i nf or mati o n  t o  be  c ollecte d  at  t his  f oll o w  u p  visit  i ncl u des a d verse 
e ve nts a n d s ur vi val stat us. 
T he  e ntire  trial  will  be  c o m plete d  w he n  t he  last  ra n d o mize d  patie nt  c o m pletes  t he  last  visit 
( Visit  3 0 1)  of  t his  pr ot oc ol.  I n  case  t he  last  patie nt  ra n d o mize d  disc o nti nues  treat me nt 
pre mat urel y  (see Secti o n  5. 6. 2 )  or v ol u ntaril y  wit h dra ws  c o nse nt  ( see Secti o n  5. 6. 3 )  t he 
fi nalizati o n of t he trial is c o nsi dere d at patie nt’s l ast visit. T he trial will als o e n d if N o vartis is 
ter mi nati n g t he trial d u e t o reas o ns relate d t o be n efit/ris k assess me nt (see Secti o n 5. 6. 5 ).   

N o v arti s  
C o nfi d e nti al  
P a g e 4 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
5. 6. 2  Di s c o nti n u ati o n of St u d y Tr e at m e nt  
Disc o nti n uati o n of st u d y treat me nt f or a patie nt o cc urs w he n st u d y dr u g is st o p pe d earlier t ha n 
t he pr ot oc ol pla n n e d d ur ati o n, a n d ca n b e i nitiate d b y eit her t he patie nt or t he i n vesti gat or. I n 
s uc h cas es t he p atie nt s h o ul d be as ke d t o c o nti n u e i n t he trial t hr o u g h t he sc he d ule d fi n al visit 
i n or der t o e ns ur e t he sci e ntific i nte grit y of t he tri al.    
T he  i n vesti gat or  m ust  disc o nti n ue  st u d y  treat me nt  f or  a  gi ve n  patie nt  if,  o n  bala nce,  h e/s he 
belie ves t hat c o nti n uati o n  of st u d y treat me nt  w o ul d ne gati vel y i m pact t he ris k/ be nefit of trial 
partici pati o n.  
St u d y 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 n ces:  
•  Patie nt wis h  
•  Pre g n a nc y  
•  A n y sit uati o n i n w hic h st u d y treat me nt mi g ht res ult i n a safet y ris k t o t he p atie nt  
If disc o nti n uati o n of st u d y tr eat me nt o cc urs, t he p atie nt s h o ul d N O T b e c o nsi dere d wit h dra w n 
fr o m t he st u d y. F or t his st u d y it is ver y i m p orta nt t o c o nti n ue c ollecti n g data o n all patie nts 
t hat  disc o nti n ue  treat me nt,  es peci all y  f or  pri mar y  e n d p oi nt  a n d  safet y.    The  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,  after  disc o nti n uati o n  of  st u d y  dr u g,  f or  a  st u d y 
treat me nt disc o nti n uati o n visit. Treat me nt disc o nti n uati o n visit assess me nts detaile d i n Ta bl e 
6- 1  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.  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 i n t he E n d of St u d y Tr eat me nt e C R F.   T he i n vesti gat or a n d st u d y staff m ust als o 
disc uss c o nti n ue d partici pati o n wit h t he patie nt.   
Patie nts  w h o  disc o nti n ue  st u d y  treat me nt  pre m at urel y  s h o ul d  c o nti n ue  wit h li mite d st u d y 
assess me nts.  T he y  s h o ul d  ret ur n t o t h e  cli nic  f or eac h  sc h e d ule d  visit  d uri n g  t h e  treat me nt 
peri o d  a cc or di n g  t o  Assess me nt  Sc he d ule T a ble  6 - 1 b ut  o nl y  c o n d u ct  t he assess me nts 
i n dicate d i n Ta ble 5 -5 Assess me nts f or Patie nts w h o Disc o nti n ue St u d y Treat me nt .  Patie nts 
s h o ul d  als o  c o n d uct  t he  safet y  f oll o w-u p  Visit  3 0 1 ( via  tele p h o ne)  after  c o m pleti n g  t he 
i nte n de d treat me nt peri o d.  
T a bl e 5- 5 
A s s e s s m e nt s f or P ati e nt s w h o Di s c o nti n u e St u d y Tr e at m e nt  
A s s e s s m e nt  
A Q L Q 1 
S pir o m etr y 1  
R e c or d  A E s  
R e c or d S A E s  
R e c or d  A st h m a E x a c er b ati o n s  
R e vi e w C o n c o mit a nt M e di c ati o n  
R e vi e w S ur g er y a n d Pr o c e d ur e s  
 
1  P R O s s h o ul d b e c o m pl et e d b ef or e a n y ot h er a s s e s s m e nt .  A Q L Q a n d S pir o m etr y m u st b e p erf or m e d pr e-d o s e 
f or st a n d ar d of c ar e tr e at m e nt.   
T he i n vesti gat or m ust als o c o ntact t he I R T t o re gister t he patie nt’s disc o nti n uati o n fr o m st u d y 
treat me nt.  If st u d y dr u g disc o nti n uati o n occ urs beca use treat me nt c o d e of Q V M 1 4 9 treat me nt 
ar m has bee n br o ke n (act ual d ose of Q V M 1 4 9 u n bli n de d), please refer t o Secti o n 5. 5. 9 . 

N o v arti s  
C o nfi d e nti al  
P a g e 4 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
5. 6. 3  Wit h dr a w al of i nf or m e d c o n s e nt  
Patie nts  ma y  v ol u ntaril y  wit h dra w  c o ns e nt  t o  partici pate  i n  t he  st u d y  f or  a n y  reas o n  at  a n y 
ti me. 
Wit h dra wal of c o ns e nt  ( W o C) occ urs o nl y w h e n a patie nt d o es n ot w a nt t o partici pate i n t h e 
st u d y  a n y m 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  relat e d  c o ntacts  a n d  d oes  n ot  all o w  a nal ysis  of  alrea d y  o btai ne d  bi ol o gic 
material.   A patie nt is N O T c o nsi dere d t o ha ve wit h dra w n c o nse nt if t he y a gree t o f oll o w - u p 
visits.  
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  d eter mi ne  t he  pri mar y  r eas o n  f or  t his  decisi o n  a n d  rec or d  t his  i nf or mati o n.  St u d y 
treat me nt m ust be disc o nti n ue d a n d n o f urt her ass ess me nts c o n d ucte d. All bi ol o gical materi al 
t hat  has  n ot  bee n  a nal yz e d  at  t he  ti me  of  wit h dra wal  m ust  n ot  be  use 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. 6. 4  L o st t o f oll o w -u p  
F or ra n d o mize d patie nts w h o are l ost t o f oll o w -u p (i.e. t h ose patie nts w h ose stat us is u nclear 
beca use he/s he fails 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 ge n ce" b y ma ki n g a p pr o priate eff orts t o re-esta blis h c o nt act 
wit h  patie nt  a n d  atte m pts  t o  c o ntact  t he  patie nt  s h o ul d  be  d oc u me nte d  i n  t he  s o urce 
d oc u me nts, e. g. dates of tele p h o ne calls/e mails, re gistere d letters, etc. If c o ntact has n ot bee n 
re-esta blis he d,  all eff orts s h o ul d still be ma de t o l ocate t he patie nt a n d o btai n i nf or mati o n at 
t he e n d of t he 2 4 wee ks i nte n de d treat me nt  a n d at t he safet y  f oll o w-u p visit ( Visit 3 0 1 ).  A 
patie nt ca n n ot be c o nsi dere d as l ost t o f oll o w -u p u ntil t he ti me p oi nt of his/ her  sc he d ule d e n d 
of st u d y visit has passe d. 
5. 6. 5  E arl y st u d y t er mi n ati o n b y t h e s p o n s or  
T he st u d y ca n be ter mi nate d at a n y ti me f or a n y reas o n b y N o v artis. S h o ul d t his be necessar y, 
t he patie nt 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 uat e  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  r es p o nsi ble  f or  i nf or mi n g  t he  I nstit uti onal  Re vie w  B oar d/I n de pe n d e nt 
Et hics C o m mittee (I R Bs/I E Cs) of t he earl y ter mi n ati 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  
Ta ble  6- 1 lists all t he assess me nts t o be perf or m e d f or t he st u d y a n d i n dicates wit h a n “ X” t h e 
visits at w hic h t he y will be perf or m e d. 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 t o t hat date. Visits d uri n g t he treat me nt pe ri o d s h o ul d be perf or me d 
wit hi n  +/ - 7  da ys  of  t he  desi g nate d  da y  or  as  cl ose  as  p ossi ble.  All  data  o btai ne d  f or  t hes e 
assess me nts m ust be s u p p orte d i n t he patie nts’ s o urce d oc u m e ntati o n. 
T he f oll o wi n g ass ess me nts are sc he d ule d t o be perf or me d i n or der as f oll o ws: Patie nt re p orte d 
o utc o me ( P R O) q u esti o n naires (i.e.  A Q L Q , A C Q, 
), E C G, Vit al si g ns ( p ulse  rat e  
a n d bl o o d press ure),  bl o o d sa m ple/ uri ne sa m ples, f oll o we d b y s pir o metr y i n a ma n ner t hat t he 

N o v arti s  
C o nfi d e nti al  
P a g e 4 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
s pir o metr y  m eas ur e me nts  occ ur  at  t he  sc he d ul e 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 h e d ule d  at  t he  sa me  ti me -p oi nt,  s pir o metr y  m ust  ta ke 
prece d e nce s uc h t hat it occ urs at t he s c he d ule d ti me p oi nt or as near as p ossi ble. As re q uire d, 
ot her assess me nt s ca n be d one after s pir o metr y.  
 
T a bl e 6- 1 
A s s e s s m e nt s c h e d ul e  
 
P eri o d  
S cr e e ni n g  
R u n -i n  Tr e at m e nt  
F oll o w -u p   
St u d y 
C o m pl eti o n  
Vi sit n u m b er  
1  
1 0 1  
2 0 1  
2 0 2  
2 0 3  
2 0 4  
T D  
3 0 1 4 
D a y  
-2 1 t o -1 4  
-1 4  
1  
5 7  
1 1 3  
1 6 9  
 
1 7 6  
W e e k  
- 3 t o -2*  
- 2 
0  
8  
1 6  
2 4  
 
2 5  
O bt ai n I nf or m e d c o n s e nt  
X  
 
 
 
 
 
 
 
C o nt a ct I R T (I V R S/I W R S)  
S  
S  
S  
S  
S  
S  
S  
S  
Pri or  
a n d  
C urr e nt  
m e di c ati o n  
r e vi e w/ a dj u st m e nt 
X  
 
 
 
 
 
 
 
R e vi e w C o n c o mit a nt m e di c ati o n  
 
X  
X  
X  
X  
X  
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  
 
I n cl u si o n/ E x cl u si o n crit eri a r e vi e w 
X  
X  
X  
 
 
 
 
 
R el e v a nt  
M e di c al  
Hi st or y,  
D e m o gr a p h y  
X  
 
 
 
 
 
 
 
Hi st or y of A st h m a E x a c er b ati o n  
X  
 
 
 
 
 
 
 
P h y si c al e x a mi n ati o n  
 
S  
 
 
 
S  
S  
 
S m o ki n g hi st or y a n d st at u s  
X  
 
 
 
 
 
 
 
I s s u e/ c oll e ct r e s c u e  m e di c ati o n  a s 
r e q uir e d a n d r e vi e w u s e  
S  
S  
S  
S  
S  
S  
 
 
Pr e g n a n c y t e st  ( s er u m)1 
 
X  
 
 
 
X  
X  
 
Pr e g n a n c y t e st  ( uri n e)1   
 
 
X  
X  
X  
 
 
 
A nti g e n -S p e cifi c I g E (I m m u n o c a p)  
 
X 
 
 
 
 
 
 
S er u m T ot al I g E  
 
X 
 
 
 
 
 
 
Vit al si g n s  
 
X  
 
 
 
X  
X  
 
E C G  
 
X  
 
 
 
X  
X  
 
H ei g ht  
 
X  
 
 
 
 
 
 
W ei g ht  
 
X  
 
 
 
X  
X  
 

N o v arti s  
C o nfi d e nti al  
P a g e 4 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
P eri o d  
S cr e e ni n g  
R u n -i n  Tr e at m e nt  
F oll o w -u p   
St u d y 
C o m pl eti o n  
Vi sit n u m b er  
1  
1 0 1  
2 0 1  
2 0 2  
2 0 3  
2 0 4  
T D  
3 0 1 4 
D a y  
-2 1 t o -1 4  
-1 4  
1  
5 7  
1 1 3  
1 6 9  
 
1 7 6  
W e e k  
- 3 t o -2*  
- 2 
0  
8  
1 6  
2 4  
 
2 5  
R e v er si bilit y S pir o m etr y t e st( S A B A) 3  
 
X  
 
 
 
 
 
 
S pir o m etr y  
 
 
X  
X  
X  
X  
X  
 
S af et y  
L a b  
a s s e s s m e nt s 
( h a e m at ol o g y, 
cli ni c al  
c h e mi str y, 
uri n al y si s, bl o o d e o si n o p hil c o u nt)  
 
 
X  
 
 
 
X  
X  
 
I s s u e  a n d  tr ai n  o n  e Di ar y  /  
 
 
 
S  
S  
S  
S  
S  
S  
 
R e vi e w e Di ar y / 
 
 
 
S  
S  
S  
S  
S  
 
A c c u h al er ® d e vi c e tr ai ni n g  
 
S  
 
 
 
 
 
 
Di s p e n s e R u n -i n m e di c ati o n vi a I R T 
 
S  
 
 
 
 
 
 
I s s u e R u n -i n m e di c ati o n 
 
X  
 
 
 
 
 
 
R a n d o mi z ati o n vi a I R T  
 
 
S  
 
 
 
 
 
Di s p e n s e st u d y tr e at m e nt vi a I R T  
 
 
S  
S 
S  
 
 
 
C o n c e pt 1  
or 
A c c u h al er ®  
+ 
R e s pi m at ® d e vi c e tr ai ni n g  
 
 
S  
S  
S  
 
 
 
St u d y Tr e at m e nt C o m pli a n c e  
 
 
X 
X 
X 
X 
 
 
St u d y  tr e at m e nt  a d mi ni str ati o n  at 
vi sit 
 
 
X  
X  
X 
X 
 
 
A E s r e c or di n g  
X 2 
X  
X  
X  
X  
X  
X  
X  
S A E s r e c or di n g  
X  
X  
X  
X  
X  
X  
X  
X  
A C Q - 7 
 
X  
X  
 
X  
X  
X  
 
A Q L Q  
 
 
X  
 
X  
X  
X  
 
S ur vi v al St at u s  
 
 
 
 
 
 
 
X  
* Ti m e  b et w e e n  Vi sit  1  a n d  1 0 1  c a n  b e  s h ort e n e d / a d a pt e d  a c c or di n g  t o  t h e  r e q uir e d  w a s h-o ut  fr o m  pr e vi o u s 
a st h m a m e di c ati o n.  
T D: Tri a l di s c o nti n u ati o n 
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  
X: A s s e s s m e nt t o b e r e p ort e d i n t h e cli ni c al d at a b a s e  

N o v arti s  
C o nfi d e nti al  
P a g e 4 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 F or f e m al e s of c hil d -b e ari n g p ot e nti al o nl y u nl e s s s ur gi c all y st eril e.  
2 If p ati e nt i s s cr e e n f ail ur e, a n y n o n-s eri o u s A E s m u st o nl y b e r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n ( S)  
3 If r e v er si bilit y f ail s o n t h e fir st att e m pt at V 1 0 1 , hi st ori c al r e v er si bilit y or br o n c h o pr o v o c ati o n w o ul d b e a c c e pt a bl e 
a s s p e cifi e d i n S e cti o n 4. 1  
4 I nf or m ati o n  a b o ut  p ati e nt s’ st at u s  will b e  o bt ai n e d  b y  a  t el e p h o n e  c all,   7 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 dr u g f or c o m pl et e d p ati e nt s  or at a n y ti m e d uri n g t h e st u d y tr e at m e nt p eri o d w h e n i n di c at e d. F or p ati e nt s 
w h o wit h dr a w e arl y, pl e a s e r ef er t o di s c o nti n u ati o n of st u d y tr e at m e nt a n d pr e m at ur e p ati e nt wit h dr a w al s e cti o n . 
T a bl e 6 -2 Ti m e d A s s e s s m e nt s 
 
Vi sit 
( D a y) 
Ti m e p oi nt 1  
P R O s  
( A Q L Q, A C Q -7,  
) 
S pir o m etr y 4 
( F E V 1 , F V C) 
L a b s  
( H e m at ol o g y, 
C h e mi str y , 
Uri n al y si s ) 
Uri n e 
Pr e g n a n c y 
T e st 3   
E C G  
Vit al s 2  
Vi sit 2 0 1  
( D a y 1) 
> -4 5 mi n   
X  
 
 
X  
 
-4 5 mi n  
 
X  
 
 
 
-1 5 mi n  
 
X  
 
 
 
0 mi n  
E V E NI N G D O S E  
Vi sit 2 0 2  
( D a y 5 7) 
 
> -4 5 mi n  
 
 
 
X  
 
-4 5 mi n  
 
X  
 
 
 
-1 5 mi n  
 
X  
 
 
 
0 mi n  
E V E NI N G D O S E  
Vi sit 2 0 3  
( D a y 1 1 3) 
> -4 5 mi n  
X 
 
 
 
X  
 
-4 5 mi n  
 
X  
 
 
 
-1 5 mi n  
 
X  
 
 
 
0 mi n  
E V E NI N G D O S E  
Vi sit 2 0 4  
( D a y 1 6 9) 
> -4 5 mi n  
X  
 
 
 
X  
- 4 5 mi n  
 
X  
 
 
 
- 4 5 t o -2 0 
mi n  
 
 
X 5, 6  
 
 
-1 5 mi n  
 
X  
 
 
 
0 mi n  
E V E NI N G D O S E  
1  St u d y dr u g ti m e d d o s e s. All st u d y m e di c ati o n d o s e s t o b e a d mi ni st er e d i n t h e cli ni c.  Ti m e r el at e s t o t h e d o s e 
gi v e n fr o m fir st d e vi c e at vi sit .  >- 4 5 r ef er s t o a n y ti m e b ef or e t h e -4 5 s pir o m etr y ti m e p oi nt.  A s s e s s m e nt s 
s c h e d ul e d -4 5 t o -2 0 mi n c a n b e d o n e at a n y ti m e pr e -d o s e if m or e c o n v e ni e nt or effi ci e nt.         
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 (r a di al p ul s e)  
3  Uri n e pr e g n a n c y t e st c a n b e d o n e at a n y ti m e pr e-d o s e if m or e c o n v e ni e nt or effi ci e nt.    
4  A mi ni m u m of 3 mi n ut e s r e st m u st b e o b s er v e d pri or t o t h e st art of s pir o m etr y at e a c h ti m e -p oi nt. A mi ni m u m of 
1 mi n ut e r e st i s t o b e o b s er v e d b et w e e n e a c h s pir o m etr y m a n e u v er.  
5 Uri n e a n al y si s i s t o b e d o n e o nl y if t h e uri n e di p sti c k i s a b n or m al, a n d o nl y d o n e pr e -d o s e  
6 S er u m pr e g n a n c y t e st d o n e wit h s af et y l a b s at Vi sit 2 0 4  
6. 1   I nf or m ati o n t o b e c oll e ct e d o n s cr e e ni n g f ail ur e s 
All patie nts w h o ha v e 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 r u n-i n peri o d will ha v e 
t he scree ni n g dis p ositi o n pa ge f or t he scree ni n g p eri o d , de m o gra p hics, eli gi bilit y criteria, a n d 
seri o us  a d verse  e ve nts  ( S A E)  data  c ollect e d.  A d verse  e ve nts  t hat  are  n ot  S A Es  will  be 
f oll o we d b y t he i n vesti gat or a n d c ollecte d o nl y i n t he s o urce d ata o nl y. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
All  patie nts  w h o  are  e ntere d  i nt o  t he  r u n -i n peri o d of  t he  st u d y  will  a d diti o nall y  ha ve  all 
a d verse e ve nts occ urri n g after i nf or me d c o ns e nt is si g ne d rec or de d o n t he A E pa ge a n d ha ve 
t he r u n-i n dis p ositi o n pa ge f or r u n-i n peri o d c ollecte d.  
6. 2   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  
P ati e nt d e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c d at a t o b e c oll e ct e d o n all p ati e nt s i n cl u d e:  
•  Date of birt h  ( w her e all o we d b y l ocal le gislati o n) 
•  A ge (calc ulate d)  
•  Se x  
•  Race a n d et h nicit y  
•  Patie nts i nitials ( w here all o we d b y l o cal le gislati o n)  
•  Hei g ht a n d Wei g ht 
•  B MI ( calc ulat e d)  
•  Baseli ne p h ysical e x a mi nati o n ( n ot data bases ot her t ha n i n t he c o nte xt of rele va nt me dical 
hist or y) 
•  Vital si g ns  
•  E C G  
•  Date of dia g n osis of ast h ma 
•  Rele va nt me dical hist or y/ c urre nt me dical c o n diti o n prese nt bef ore si g ni n g t he i nf or me d 
c o nse nt 
•  S m o ki n g hist or y a n d st at us 
•  Ast h ma Q ualit y of Life ( A Q L Q)  
•  Ast h ma C o ntr ol ( A C Q- 7)  
 
 
•  Pri or c o nc o mita nt me dicati o n ( B ot h ast h m a relate d a n d n o n- ast h ma relate d)  
•  Pre a n d p ost- br o nc h o dilat or s pir o metr y ( r u n-i n s pir o metr y a n d re versi bilit y testi n g) 
6. 3   Tr e at m e nt e x p o s ur e a n d c o m pli a n c e  
St u d y tr eat me nt c o m plia nce s h o ul d be assess e d b y t he i n vesti gat or a n d/ or site pers o n nel at all 
visits.  W here necessar y, t he I n vesti gat or will disc uss c o m plia nce iss ues wit h t he patie nt.       
6. 4   Effi c a c y 
T he f oll o wi n g assess me nts of efficac y will be perf or me d:  
•  H ealt h Stat us (P R Os: A Q L Q , A C Q - 7, 
) 
•  S pir o metr y  
 
 
 
 
 
 
 
  
 

N o v arti s  
C o nfi d e nti al  
P a g e 4 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
6. 4. 1  H e alt h St at u s ( P ati e nt R e p ort e d O ut c o m e s)  
A patie nt - re p orte d o utc o me ( P R O) is a n y re p ort of t he stat us of a patie nt’s healt h c o n diti o n 
t hat  c o mes  directl y  fr o m  t he  patie nt,  wit h o ut  i nter pretati o n  of  t he  p atie nt’s  res p o nse  b y  a 
cli nicia n or a n y o ne else.  
Patie nt -re p orte d  o utc o m es  ma y  pr o vi de  q u a ntitati ve  i nf or mati o n  f or  patie nts  re gar di n g  t he 
‘i m pact o n dail y life’, w hic h is of ke y i m p orta nce, f or patie nts a n d t heir p h ysicia ns a n d als o 
f or healt h tec h n ol o g y ass ess me nts. 
I n t his st u d y, t he mai n efficac y vari a ble is a P R O t o assess t he i m pact of u nc o ntr olle d  ast h ma 
a n d t he disease’s ma na ge me nt be y o n d l u n g f u ncti o n.  All P R Os s h o ul d al wa ys be c o m plete d 
bef ore  a n y  ot h er  assess me nts  are  perf or me d  t o  a v oi d  i nfl ue nci n g  t he  res p o nses.    W he n 
occ urri n g at t h e sa me visit t he y ar e t o be c o m plete d  i n t he f oll o wi n g or d er:  A Q L Q-S, A C Q - 7, 
     
6. 4. 1. 1  A st h m a Q u alit y of Lif e Q u e sti o n n air e ( A Q L Q -S)  
T he  A Q L Q  is  a  3 2 -ite m ast h ma  s pecific q uesti o n naire  desi g n e d  t o  meas ure  f u n cti o nal 
i m pair me nts  t hat  are  m ost  i m p orta nt  t o  patie nts  wit h  ast h ma  (A p pe n di x  7 ).  It  c o nsists  of  4 
d o mai ns:  s y m pt o ms,  e m oti o ns,  e x p os ure  t o  e n vir o n me ntal  sti m uli  a n d  acti vit y  li mitati o n. 
Patie nts  are  as ke d  t o  recall  t heir  e x perie nces  d uri n g  t he  pre vi o us  2  wee ks  a n d  t o  sc ore  eac h 
ite m  o n  a  7-p oi nt  scale  (J u ni per  1 9 9 2,  J u ni per  1 9 9 3).  T he  o verall  A Q L Q  sc ore  is  t he  m ea n 
res p o nse  t o  all  3 2  q uesti o ns.  Cli nicall y  i m p orta nt  differe nces  i n  sc ores  bet wee n  a n y  t w o 
assess me nts ha ve bee n d eter mi ne d b y t h e a ut h ors of t he A Q L Q. C ha n ges i n sc ores of 0. 5 are 
c o nsi dere d  cli nicall y  mea ni n gf ul;  c h a n ges  of  1. 0  are  c o nsi dere d  as  m o derate  a n d  >  1. 5  as 
lar ge c h a n ges f or a n y i n di vi d ual d o mai n or f or t he o verall s u m mar y sc ore (J u ni per 1 9 9 4). 
A Q L Q s h o ul d be c o m plete d b y t he patie nt (self -a d mi nistere d) at t he cli nic as per Assess me nt 
Sc he d ule Ta ble 6 - 1. 
6. 4. 1. 2  A st h m a C o ntr ol Q u e sti o n n air e ( A C Q -7)  
I n  t his  st u d y,  t he  A C Q-7  ( A p pe n di x 8 )  will  be  use d  t o  assess  i m pr o ve me nts  i n  ast h ma 
s y m pt o m  c o ntr ol.  T he  A C Q-7  (J u ni per  1 9 9 9;  J u ni per  2 0 0 5;  J u ni per  2 0 0 6)  is  a  se ve n -ite m 
disease -s pecific  i nstr u me nt  de vel o pe d  a n d  vali date d  t o  assess  ast h ma  c o ntr ol  i n  patie nts  i n 
cli nical trials as well as i n i n di vi d uals i n cli nical practice. T he A C Q -7 q uesti o n naire will be 
pr o vi de d t o t he site. T h e A C Q -7 q u esti o n naire c o nsists of fi ve ite ms t o assess s y m pt o ms a n d 
acti vit y li mitati o ns, o ne q uesti o n t o assess res c ue me dicati o n use, a n d o ne q uesti o n t o assess 
air wa y cali ber ( F E V 1 % pre dicte d). All se ve n ite ms are sc ore d o n a 7 - p oi nt Li kert scale, wit h 0 
i n dicati n g t otal c o ntr ol a n d 6 i n dicati n g p o or c o ntr ol. T he q uesti o ns are e q uall y w ei g ht e d a n d 
t he  t otal  sc ore  is  t he  mea n  of  t he  se ve n  ite ms.  T he  pr o p orti o n  of  patie nts  w h o  ac hie ve  an  
i m pr o ve me nt  of  at  least  0. 5  i n  A C Q-7  (i.e.  decrease  of  A C Q -7  sc ore  of  at  least  0. 5  fr o m 
baseli ne) at p ost -b aseli ne visits will als o be a nal yz e d.  
T he  first  6  q uesti o ns  of  t he  A C Q-7  s h o ul d  be  c o m plete d  b y  t he  patie nt  b ase d  o n  o ne  recall 
o ver  t he  pri or  wee k.  T h e  last  q uesti o n  s h o ul d  be  c o m plete d  b y  t he  i n v esti gat or  at  t he  site 
usi n g  data  fr o m  t he  s pir o meter.  T he  A C Q -7  s h o ul d  be  c o m plete d  at  t he cli nic  as per 
Assess me nt Sc he d ule Ta ble 6 - 1. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
6. 4. 2  S pir o m e tr y 
T he f oll o wi n g s pir o m etric assess me nts will be ma de:  
•  F orce d e x pirat or y v ol u me i n o ne sec o n d ( F E V 1 ) 
•  F orce d Vital Ca pacit y ( F V C)  
•  F orce d E x pirat or y Fl o w bet wee n 2 5 % a n d 7 5 % of F orce d Vital Ca pacit y ( F E F 2 5 -7 5 ) 
S pir o metric  assess me nts  will  be perf or me d  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. 
Tr o u g h  F E V 1   f or  Q V M 1 4 9  1 5 0/ 5 0/ 8 0  μ g  a n d  Q V M 1 4 9  1 5 0/ 5 0/ 1 6 0  μ g  o. d.  d eli vere d  via 
C o nce pt 1  is  t he  mea n  of  t he  t w o  F E V 1  val ues  meas ures  at -4 5  mi n  a n d -1 5  mi n  pri or  t o 
e ve ni n g d ose.  Tr o u g h F E V 1  f or t he ‘free’ tri ple c o m bi nati o n of sal met er ol/fl uticas o ne 5 0/ 5 0 0 
μ g b.i. d. deli ver e d as p o w der via Acc u haler ® + ti otr o pi u m 5 μ g o. d deli v ere d via Res pi mat ® 
is t he mea n of t he t w o F E V1  val ues meas ures at - 4 5 mi n a n d - 1 5 mi n pri or t o e ve ni n g d os e. 
Please ref er t o t he S pir o metr y G ui d a nce i n A p p e n di x 2 . 

N o v arti s  
C o nfi d e nti al  
P a g e 4 8  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
6. 4. 4  W or s e ni n g of a st h m a  
I n v esti gat ors a n d patie nts will be i nstr ucte d h o w t o deal wit h w orse ni n g of ast h ma s y m pt o ms. 
T he  data  ca pt ure d  i n  t h e  patie nt  di ar y  a n d  site  s pir o meter  will  b e  use d  t o  alert  t he  patie nt 
a n d/ or i n vesti gat or t o p ossi ble si g ns of w orse ni n g ast h ma. T he patie nt e D iar y will i nstr uct t he 
patie nt t o c o ntact t he st u d y site if a n y ast h ma w orse ni n g criteria is met. T he i n vesti gat or will 
i nstr uct  t he  patie nt  t o  c o ntact  t he  i n vesti gat or  if  at  a n y  ti me  d uri n g  t he  trial  fr o m  t he  r u n-i n 
o n war ds o ne or m ore of t he f oll o wi n g criteria of w orse ni n g ast h ma de vel o ps: 
Ast h m a W o rs e ni n g Criteri a : 
1.   > 2 0 % decrease i n F E V 1  fr o m baseli ne val ue (t his criteri o n a p plies t o I n vesti gat or re vie w 
at t he ti me of a st u d y visit or via s pir o metr y re p ort)  
2.  > 5 0 % i ncr ease i n S A B A use a n d > 8 p uffs per da y o n 2 o ut of a n y 3 c o nsec uti ve da ys 
c o mpare d t o bas eli ne 
3.  ≥ 2 0 % decr ease i n m or ni n g ( A M ) or e ve ni n g ( P M ) P E F fr o m baseli ne o n 2 o ut of a n y 3 
c o nsec uti ve da ys c o m par e d t o baseli ne 
4.   < 6 0 % of pr e dicte d or pers o nal best P E F c o m pare d t o bas eli ne 
5.    Ni g ht ti me a w a ke ni n gs r e q uiri n g S A B A us e o n at least 2 o ut of a n y 3 c o nsec uti ve ni g hts  

N o v arti s  
C o nfi d e nti al  
P a g e 4 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
6.    Ur ge nt u nsc he d ul e d cli nic visit d ue t o ast h ma relate d det eri orati o n 
N ote: T he ref ere n ce f or t he w orse ni n g of ast h ma d uri n g t he r u n -i n peri o d w o ul d be t he F E V 1  
a n d P E F ta ke n at Visit 1 0 1 . T he b aseli ne F E V1,  a n d P E F f or t he treat me nt peri o d is ta k e n at 
treat me nt Da y 1 ( Visit 20 1 ). T he b aseli ne f or S A B A use d uri n g t he r u n -i n peri o d will be > 8 
p uffs a n d t he bas eli ne f or t he tr eat me nt peri o d  is t a ke n fr o m t he a vera ge of  t he 7 da ys pri or t o 
V 2 0 1. 
If a n y of t he a b o ve criteria (i ncl u di n g t he alert fr o m e-diar y) are met w hile a p atie nt is i n t h e 
r u n-i n or treat me nt peri o d , t he i n vesti gat or s h o ul d assess t he patie nt’s c o n diti o n. If t his occ urs 
d uri n g  r u n -i n  peri o d a n d  it  is  co nsi dere d  a  cli nicall y  si g nifica nt  ast h ma  w orse ni n g  i n  t he 
i n vesti gat or’s o pi ni o n, t he patie nt s h o ul d be treate d as  a p pr o priate a n d  disc o nti n ue d pri or t o 
ra n d o mizati o n. O nce t he c o n diti o n is res ol ve d, if eli gi bilit y criteria are m et, t he patie nt ma y 
be rec o nsi d ere d f or r escr ee ni n g.  
If  patie nts  de v el o p  a n y  of  t he  a b o ve  criteri a d uri n g  treat me nt,  t he  patie nt  s h o ul d  n otif y  t he 
i n vesti gat or a n d be e v al u ate d b y t he i n vesti gat or a n d treate d as cli nicall y a p pr o priate. 
W orse ni n g  of  ast h ma  s y m pt o ms  ma y  re q uire  u nsc he d ule d  e val uati o n  b et wee n  visits.  St u d y 
site  pers o n nel  m ust  be  a vaila ble  t o  m o nit or  a n d  d oc u me nt  patie nt’s  pr o gress  u ntil  ast h ma 
c o ntr ol is re gai ne d. 
6. 4. 5  A st h m a E x a c er b ati o n  
A se vere ast h m a e x acer bati o n ( Dr aft n ote f or g ui da nce o n cli nical i n vesti gati o n of me d i ci nal 
pr o d ucts f or treat me nt of ast h ma C H M P/ E W P/ 2 9 2 2/ 0 1 Re v. 1) is defi ne d as a n a g gra vati o n of 
ast h ma s y m pt o ms (li ke s h ort ness of breat h, c o u g h, w heezi n g, or c h est ti g ht ness) t hat re q uires 
S yste mic C ortic oster oi d  ( S C S)  f or  at  least  t hree  c o nsec uti ve  d a ys a n d/ or  a  nee d  f or  a n  E R 
visit ( or l ocal e q ui vale nt str uct ure), h os pitalizati o n d ue t o ast h ma or deat h d ue t o ast h ma. 
Start date a n d e n d d ate:  
•  I n case of t he use of S C Ss f or at least t hree da ys, t he first da y of treat me nt will deter mi ne 
t he o nset date of t he e ve nt w hile t he last da y of treat me nt will defi ne t he st o p date.  
•  I n t he e ve nt t hat a n E R visit a n d/ or h os pitalizati o n d ue t o ast h ma e x acer b ati o n were n ot 
ass ociate d wit h a c o urse of S C Ss as descri be d a b o ve, start a n d e n d d ates w o ul d be defi ne d 
b y t he c or r es p o n di n g d ates e ntere d b y t he I n vesti gat or i n t he C R F. 
A m o der ate ast h m a  e x acer bati o n i n t his pr ot oc ol is defi n e d as t he o cc urre nce of t w o or m ore 
of t he f oll o wi n g: 
1. Pr o gr essi ve i ncr ease of at least o ne of t h e ast h ma s y m pt o ms li ke s h ort ness of breat h, c o u g h, 
w heezi n g, or c hest ti g ht ness. T he s y m pt o ms s h o ul d be o utsi de t he patie nt’s us ual ra n ge of 
da y- t o- da y ast h ma a n d s h o ul d last at least t w o c o nsec uti ve da ys. 
2. I n crease d use of “r esc ue” i n hale d br o n c h o dilat ors defi ne d b y:  
•  ≥ 5 0 % i ncreas e i n S A B A use a n d > 8 p uffs o n 2 o ut of a n y 3 c o nsec uti ve da ys 
c o m pare d t o bas eli ne ca pt ure d  
Or  
•  Ni g ht ti me a w a ke ni n gs r e q uiri n g S A B A use o n at least 2 o ut of a n y 3 c o ns ec uti ve 
ni g hts 

N o v arti s  
C o nfi d e nti al  
P a g e 5 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
3. Deteri or ati o n i n l u n g f u ncti o n, w hic h last f or t w o da ys or m ore b ut us u all y n ot se ver e 
e n o u g h t o w arr a nt S C Ss f or m ore t ha n 2 d a ys or h os pitalizati o n. T his deteri orati o n w o ul d 
be defi ne d b y: 
•  ≥ 2 0 % decr ease i n F E V 1  fr o m baseli ne val u e  
Or  
•  ≥ 2 0 % decr ease i n m or ni n g ( A M) or e v e ni n g ( P M) P E F fr o m bas eli ne o n 2 o ut of a n y 
3 c o nsec uti ve da ys c o m p are d t o bas eli ne.  
Or  
•  < 6 0 % of pr e dicte d P E F c o m pare d t o bas eli ne 
A mil d ast h m a  e x acer bati o n is defi ne d as t he occ urre nce of o ne of t he f oll o wi n g criteria: 
1.  Deteri or ati o n of at least o ne ast h ma s y m pt o ms li ke s h ort ness of breat h, c o u g h, w h eezi n g 
or c hest ti g ht n ess.  
2.  I n crease d use of “r esc ue” i n hale d br o nc h o dilat ors 
3.  Deteri or ati o n i n l u n g f u n cti o n, w hic h last f or t w o da ys or m ore b ut us uall y n ot se vere 
e n o u g h t o w arr a nt S C Ss or h os pitalizati o n. T his deteri orati o n w o ul d be d efi ne d b y: 
•  ≥ 2 0 % decr ease i n F E V 1  fr o m baseli ne val u e 
Or  
•  ≥ 2 0 % decr ease i n m or ni n g ( A M) or e v e ni n g ( P M) P E F fr o m bas eli ne o n 2 o ut of a n y 
3 c o nsec uti ve da ys c o m p are d t o bas eli ne.  
Or  
•  < 6 0 % of pr e dicte d P E F c o m pare d t o bas eli ne 
“ Start  a n d  e n d  dates ”  of  eac h  r e p orte d  e ve nt  i n  t he  C R F  will  be  use d  t o  deter mi ne  w het h er 
t w o c o nsec uti vel y re p ort e d e ve nts s h o ul d b e c o nsi dere d as se parate e ve nts or as a pr ol o n ge d 
o ne.  If  a  sec o n d  e x acer bati o n  is  re p orte d  less  t ha n  7  da 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 x acer bati o n wit h t he start date ta k e n 
fr o m  t he  first  e pis o de  a n d  t he  e n d  d ate  fr o m  t h e  sec o n d  or  last  e pis o de.  If  t w o  e ve nts  are 
mer ge d base d o n t his “ 7 da y r ule”, t he hi g hest re p orte d se verit y will be use d t o descri be t he 
o verall se verit y of t he pr ol o n ge d e ve nt. 
T he  treat me nt  of  ast h ma  e x acer bati o ns  i ncl u di n g  t h e  i nitiati o n  of S C S  or  i ncreas e  i n  t he 
mai nte na nce d ose of O C S s h o ul d be d o ne acc or di n g t o i n vesti gat or’s or treati n g p h ysicia n’s 
me dical j u d ge me nt a n d s h o ul d be i n li ne wit h nati o nal a n d i nter nati o nal rec o m me n dati o ns. If 
S C S  are re q uire d, a patie nt ma y r et ur n t o t he st u d y after s uccessf ull y c o m pleti n g a ta p er.  

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6. 4. 7  A p pr o pri at e n e s s of effi c a c y a s s e s s m e nt s  
T he effi cac y assess me nts selecte d are sta n d ar d f or t hi s i n dicati o n/ patie nt p o p ulati o n. 
T he  pri mar y  e n d p oi nt, Ast h ma  Q ualit y  of  Life  ( A Q L Q) , refers  t o  t he  p ercei v e d  i m pact  t hat 
ast h ma has o n t he p atie nt’s q ualit y of life  ( Qo L) . T his e n d p oi nt is wi del y use d i n ast h ma tri als 
a n d i n m ore t ha n si x p u blis he d vali dati o n st u dies c o n d ucte d w orl d wi de a n d has s h o w n ver y 
str o n g m eas ur e me nt pr o p erties.  It is i ncreasi n gl y rec o g nize d t hat t he e v al uati o n of t hera pe utic 
i nter ve nti o ns  s h o ul d  i ncl u de  assess me nt  of  o ut c o mes  t hat  m atter  t o  p atie nts. T he  Q O L  
meas ures  ca n  pr o vi de  u ni q ue  i nf or mati o n  a n d  ca n  t h us  pr o vi de  a  m ore  c o m plet e 
c haracterizati o n  of  t he  st u d y  p o p ul ati o n’s  ast h ma  a n d  of  t he  be nefits  or  dra w bac ks  of 
partic ular i nter v e nti o ns.   
6. 5  S af et y  
T he f oll o wi n g s afet y assess me nts will be perf or m e d:  
•  Me dical hist or y a n d p h ysical e x a mi nati o n  
•  Vital si g ns  
•  He mat ol o g y, Bl o o d c h e mistr y, Uri nal ysis  
•  E C G  
•  A d verse e ve nts i ncl u di n g seri o us a d vers e e v e nts 
•  Pre g n a nc y (fe male p atie nts); a d diti o nal pre g n a nc y testi n g mi g ht be p erf or m e d if re q u este d 
b y l ocal re q uir e me nts  
•  Seri o us ast h ma o utc o mes (ast h ma-relate d h os pitalizati o ns, i nt u bati o ns or deat hs) 
•  C C V e ve nts a n d ne w o ns et of atrial fi brillati o n   
A n i n de pe n d e nt a dj u dicati o n c o m mittee will be esta blis he d t o assess seri o us ast h ma o utc o mes 
(ast h ma-r elate d  h os pitalizati o ns,  i nt u bati o ns  a n d  deat hs), s eri o us  car di o vasc ular  a n d 
cere br o vasc ul ar ( C C V) e ve nts, ne w o ns et of atrial fi brillati o n a n d fl utter as well as all deat hs.  
Refer t o Secti o n 8. 5  f or m ore i nf or mati o n.  
6. 5. 1  P h y si c al e x a mi n ati o n  
A  c o m plete  p h ysical  e x a mi nati o n  will  i ncl u de  t he  e x a 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 o at, l u n gs, heart, a b d o me n, b ac k, l y m p h n o d es, 
e xtre mities ,  vasc ular  a n d  ne ur ol o gical.  If  i n dicate d  bas e d  o n  me dical  hist or y  a n d/ or 
s y m pt o ms, rectal, e xter nal ge nitalia, breast, a n d pel vic e x a ms will be perf or me d as detaile d i n 
Sc he d ule of Assess me nts Ta ble 6 - 1.  
I nf or mati o n f or all p h ysi cal e x a 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 i nf or me d c o nse nt bei n g si g ne d m ust 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  i nf or me d  c o nse nt  ( Visit  1)  is  gi ve n  w hic h  meet  t he 
defi niti o n of a n A d vers e E ve nt m ust be rec or de d o n t he A d verse E ve nt e C R F. 

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6. 5. 2  Vit al si g n s  
S yst olic a n d diast olic bl o o d press ure a n d ra dial p ulse rate ( o ver a 3 0 sec i nter val), perf or m e d 
i n  t he  sitti n g  p ositi o n,  will  be  rec or d e d  at  sc he d ule d visits  as  detail e d  i n  Sc h e d ule  of 
Assess me nts Ta ble 6 - 1.  Vitals ca n be perf or m e d j ust bef ore or j ust after E C G.  
6. 5. 3  H ei g ht a n d w ei g ht  
Hei g ht i n ce nti meters ( c m) will be meas ure d . B o d y w ei 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  acc or di n g  t o  Sc he d ule  of  Assess me nts 
Ta ble 6 - 1. B MI will be calc ulate d bas e d o n hei g ht a n d wei g ht. 
6. 5. 4  L a b or at or y e v al 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  t h e  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 u al. 
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 or malities  s h o ul d  be 
f oll o we d re g ularl y u ntil t he val ues ret ur n t o wit hi n t he n or mal ra n ges or u ntil a vali d reas o n 
ot her  t ha n  dr u g -relate d  a d verse  e x perie nces  is  i de ntifie d,  e ve n  after  t he  me dicati o n  has 
disc o nti n ue d. 
Safet y La b or at or y assess me nts ( he mat ol o g y, cli nical c he mistr y, uri nal ysis ) will be perf or me d 
acc or di n g t o Sc he d ul e of Assess me nts Ta ble 6 - 1. 
6. 5. 4. 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.  
6. 5. 4. 2  Cli ni c al c h e mi str y  
Al b u mi n,  al kali ne  p h os p hatase,  A S T  ( S G O T),  A L T  ( S G P T),  bilir u bi n,  creati ni ne,  γ- G T, 
gl uc ose, p otassi u m, ma g nesi u m, B U N a n d uric aci d will be meas ure d. 
If  t h e  t otal  bilir u bi n  c o nce ntratio n  is  i ncreas e 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. 5. 4. 3  Uri n al y si s  
Di pstic k meas ure me nts f or s pecific gra vit y, p H, pr otei n, gl u c ose a n d bl o o d will be perf or m e d 
acc or di n g t o t he Sc h e d ule of Assess me nts Ta bl e 6 - 1. 
If t he uri ne di pstic k is a b n or mal, t he sa m ple will be se nt t o ce ntral la b orat or y f or a d diti o nal 
testi n g, i ncl u di n g assess me nt of W B C a n d R B C s e di me nts. 
6. 5. 5  El e ctr o c ar di o gr a m ( E C G)  
E C Gs m ust be rec or d e 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 bas eli ne.  
Ce ntralize d E C G e q ui p me nt: 

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E C Gs  will  be  meas ure d  pre -d ose.  All  electr o car 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 be t a ke n f or t h ose patie nts w h o pre mat urel y disc o nti n ue fr o m t he st u d y. 
Eac h E C G will be se nt el ectr o nicall y fr o m  t he E C G mac hi ne t o t he ce ntral la b orat or y. A pri nt  
o ut of  t he  E C G  r ec or d  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 ntat i o n  a n d  as  b ac k-u p  f or  s u b missi o n  t o  t he  ce ntral  la b orat or y  i n  case  of  pr o ble ms 
wit h t he electr o nic tr a ns missi o n. Eac h pri nt o ut will be ke pt at t he i n vesti gat or site a n d will be 
date d a n d si g n e d. T he s u bject's n u m ber, t h e date, act ual ti me of t he traci n g,  a n d St u d y C o d e 
m ust a p pear o n eac h p a ge of t he traci n g. 
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 u al  t o  be  pr o vi de d  b y  t he  ce ntral  la b orat or y  t o  eac h  i n vesti gat or  site.  A 
cli nicall y si g nifica nt a b n or malit y s h o ul d be re p ort e d as a n A E. If necessar y a car di ol o gist ma y 
be c o ns ulte d. 
Cli nicall y  si g nifica nt  E C G  fi n di n gs  at  baseli ne  m ust  be  disc usse d  wit h  t he  s p o ns or  bef ore 
a d mi nistrati o n wit h i n vesti gati o nal treat me nt.  
If  a  patie nt  e x perie nces  a  cli nicall y  si g nifica nt  c ha n ge  i n  car diac  r h yt h m  or  ot her  cli nicall y 
si g nifica nt  car di o vasc ul ar  a b n or malit y,  t he  i n vesti gat or  s h o ul d  c o nsi d er  wit h dra wi n g  t h e 
patie nt fr o m t he st u d y.  
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 rel e 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.  
Ne w cases ( n ot pr ese nt d uri n g scree ni n g/r u n -i n peri o ds) of atrial fi brillati o n re p orte d fr o m t he 
E C G meas ure me nts ( or r e p orte d as a n A E d uri n g t he c o urse of t he st u d y) will be a dj u dicate d. 
A d diti o nal i nf or mati o n re gar di n g t he Atrial Fi brillati o n/ Atrial Fl utter ma y be re q ueste d t o be 
se nt t o t he A dj u dicati o n C o m mittee. All cases of atrial fi brillati o n, re gar dl ess of seri o us ness, 
will be re vie we d b y t h e A dj u dicat i o n C o m mittee. 
6. 5. 6  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  or  s er u m  pre g n a nc y  test  will  be  perf or me d  i n  pre -me n o p a usal  w o me n  w h o  are  n ot 
s ur gicall y  st erile  (t ests  pr o vi de d  b y  t he  Ce ntral  La b orat or y)  per Sc he d ule  of  Assess me nts 
Ta ble 6 - 1. If t he uri ne pr e g n a nc y test is p ositi ve, a plas ma testi n g is t o be d o ne t o c o nfir m t he 
pre g na nc y. A p ositi ve pr e g n a nc y test 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 dy tr eat me nt. Refer t o S ecti o n 5. 6. 2 a n d Secti o n 7. 5  f or m ore details. A d diti o nal 
pre g na nc y t esti n g mi g ht be perf or me d if re q ueste d b y l ocal re q uire me nts .  
6. 5. 7  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 s electe d are sta n d ar d f or t his i n dicati o n/ patie nt p o p ulati o n.  

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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  u nt o war d  me di cal  occ urre nce  (e. g.,  a n y  u nfa 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 y m pt o m or dis ease) i n a s u bject or 
cli nical i n vesti gati o n s u bject 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 u ntil t he e n d of st u d y visit. T heref ore, a n A E ma y or ma y n ot be t e m p orall y or ca usall y 
ass ociate d wit h t he use of a me dici nal (i n v esti gati o nal) pr o d uct.  
I n a d diti o n, all re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d a n 
a d verse e ve nt irr es pecti v e if a cli nical e ve nt has o cc urre d.  
T he occ urre nce of a d v erse e ve nts m ust be s o u g ht b y n o n -directi ve q uesti 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 b e detect e d w he n t he y are v ol u nteere d 
b y t he patie nt d uri n g or  bet wee n visits or  t hr o u g h  p h ysical e x a mi nati o n fi n di n gs, la b orat or y 
test fi n di n gs, or ot her ass ess 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 t he y f ulfill 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 y m pt o ms,  

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•  t he y are c o nsi dere d cli nicall y si g nifica nt,  
•  t he y r e q uire t h era p y.  
Cli nicall y si g nifica nt a b n or mal la b orat or y v al ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val u es o utsi de of n or mal ra n ges/cli nicall y n otable ra n ges, si g nifi ca 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 y pical i n patie nt wit h 
u n derl yi n g diseas e. I n vesti gat ors ha ve t he res p o nsi bilit y f or ma n a gi n g t he s afet y of i n di vi d ual 
patie nt a n d i de ntif yi n g a d verse e ve nts. Al ert ra n ges f or la b orat or y a n d ot h er test a b n or malities 
are i ncl u de d i n A p p e n di x 1. 
A d verse e v e nts m ust be rec or d e d i n t he A d vers e  E ve nts C R F u n der t he si g ns, s y m pt o ms or 
dia g n osis ass oci ate d wit h t he m, acc o m pa ni e d b y t he f oll o wi n g i nf or mati o n: 
•  t he se verit y gra d e 
•  mil d: us uall y tr a nsie nt i n nat ure a n d ge nerall y n ot i nterferi n g wit h n or m al acti vities  
•  m o derate: s uffi cie ntl y dis c o mf orti n g t o i nterfere wit h n or mal acti vities  
•  se vere: pr e ve nts n or mal acti vities 
All a d verse e v e nts m ust be treate d a p p r o priat el y. Treat me nt ma y i ncl u de o ne or m ore of t h e 
f oll o wi n g:  
•  n o acti o n ta ke n ( e. g. f urt her o bser v ati o n o nl y)  
•  [i n vesti gati o nal] treat me nt d osa ge a dj uste d/te m p oraril y i nterr u pte d  
•  [i n vesti gati o nal] 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 her a 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 (see Secti o n 7. 2 ) f or defi niti o n of 
S A E)  
•  its o utc o me ( n ot rec o vere d/ n ot res ol ve d; rec o v ere d/res ol ve d; rec o v eri n g/res ol vi n g, 
rec o vere d/r es 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 v e nt is detecte d, it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d 
t o be per ma ne nt, a n d ass ess me nt m ust be ma de at eac h visit ( or m ore fre q u e ntl y, if necessar y) 
of  a n y  c ha n ges  i n  se v erit y,  t he  s us p ecte d  relati o ns hi p  t o  t he  st u d y  dr u g,  t h e  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 vesti gati o nal dr u g ca n b e 
f o u n d  i n  t he  I n vesti gat or  Br oc h ure  (I B).  T his  i nf or mati o n  will  be  i ncl u de d  i n  t he  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 uri n g t he st u d y as nee de d. A n y 
ne w  i nf or mati o n  re gar di n g  t he  safet y  pr ofile  of  t he  me dici nal  pr o d uct  t hat  is  i de nt ifie d 
bet wee n  I B  u p d ates  will  be  c o m m u nicate d  as  a p pr o priate,  f or  e x a m ple,  via  a n  I n vesti gat or 
N otificati o n or a n A g gre gat e Safet y Fi n di n g. Ne w i nf or mati o n mi g ht re q uire a n u p date t o t he 
i nf or me d c o nse nt a n d h as t he n t o be disc usse d wit h t he patie nt. 
T he i n vesti gat or m ust 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 y o 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 ysicia n,  belie v es 
mi g ht  reas o na bl y  be  rel ate d  t o  st u d y  treat me nt.  T his  i nf or mati o n  m ust  be  rec or d e d  i n  t he 

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i n vesti gat or’s s o ur ce 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 v artis. 
 
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  S A E  is  defi n e d  as  a n y  a d vers e  e v e nt  [a p peara nce  of  ( or  w ors e ni n g  of  a n y pre -e xisti n g)] 
u n desira ble  si g n(s),  s y m pt o m(s)  or  me dical  c o n diti o ns(s)  w hic h  meets  a n y  o n e  of  t he 
f oll o wi n g criteria: 
•  is fatal or life-t hr eate ni n g  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y 
•  c o nstit utes a c o n ge nital a n o mal y/ birt h defect  
•  req 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:  
•  r o uti ne treat me nt or m o nit ori n g of t he st u die d i n di cati 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 h at t his i ncl u des) 
•  electi ve or pre -pla n n e d tr eat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelat e 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 m er ge n c y o ut p atie 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 v e 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 n ce of a n y det eri orati o n i n t he pati e nt’s 
ge n eral c o n diti o n  
•  is me dicall y si g nifica nt, e. g. d efi ne d as a n e v e nt t hat je o par dizes t he patie nt or ma y 
re q uire me di cal 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 ar e n ot met. 
Lif e -t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he p atie nt was at ris k of 
deat h at t he ti me of t he r eacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot h eticall y mi g ht h a ve 
ca use d deat h if it wer e m ore se vere (s ee A n n e x I V, I C H - E 2 D G ui deli ne). 
Me dical  a n d  s cie ntific  j u d g me nt  s h o ul d  be  e x ercise d  i n  deci di n g  w h et h er  ot her  sit uati o ns 
s h o ul d  be  c o nsi dere d  seri o us  reacti o ns,  s uc h  as  i m p orta nt  me dical  e ve nts  t hat  mi g ht  n ot  be 
i m me diatel y  life  t hreat e 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 x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic 
br o nc h os pas m,  bl o o d  d ys crasias  or  c o n v ulsi o ns  t hat  d o  n ot  res ult  i n  h os pitalizati o n  or 
de vel o p me nt of de p e n de nc y or a b use (see A n ne x I V, I C H- E 2 D G ui deli ne).  
A n y s us pect e 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 vers e reacti o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 5 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
7. 2. 2  S A E r e p orti n g  
T o  e ns ure  patie nt  safet y,  e ver y  S A E,  re gar dless  of  ca usalit y,  o cc urri n g  after  t he  patie nt  has 
pr o vi de d  i nf or me d  c o ns e nt  a n d  u ntil  3 0  da ys  after  t he  last  st u d y  visit  m ust  be  re p orte d  t o 
N o vartis saf et y 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  p eri o d  aft er  t he  last  st u d y  visit  s h o ul d  o nl y  be  re p orte d  t o  N o vartis  safet y  if  t h e 
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.  
All f oll o w - u p i nf or mati o n f or t he S A E i n cl u di n g i nf or mati o n o n c o m plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w-u p t o t he ori gi n al e pis o de 
wit hi n 2 4 h o urs of t h e i n vesti gat or recei vi n g t he f oll o w -u p i nf or mati o n. A S A E occ urri n g at a 
differe nt ti me i nter val or ot her wise c o nsi dere d c o m pletel y u nrelat e d t o a pre vi o usl y re p orte d 
o ne m ust be re p orte d s e p aratel y as a ne w e ve nt.  
I nf or mati o n  a b o ut all  S A Es  is  c ollecte d  a n d  rec or de d  o n  t he  Seri o us  A d verse  E ve nt  Re p ort 
F or m; all a p plica ble secti o ns of t he f or m m ust be c o m plete d i n or der t o pr o vi de a cli nicall y 
t h or o u g h  re p ort.  T he  i n v esti gat or  m ust  assess  t he  relati o ns hi p  of  eac h  S A E  t o e ac h  s p ecific  
c o m p o ne nt  of  st u dy  tre at me nt, c o m plete  t he  S A E  Re p ort  F or m  i n  E n glis h,  a n d  s u b mit  t he 
c o m plete d f or m  wit hi n 2 4 h o urs t o N o vartis. Det aile d  i nstr ucti o ns re gar di n g t he s u b missi o n 
pr ocess a n d re q uir e me nts f or si g n at ure are t o be f o u n d i n t he i n vesti gat or f ol der pr o vi de d t o 
eac h site.  
F oll o w- u p  i nf or mati o n  is  s u b mitte d  as  i nstr ucte d  i n  t he  i n vesti gat or  f ol der.  Eac h  re -
occ urr e nce, c o m plicati o n, or pr o gr essi o n of t he ori gi nal e ve nt m ust be re p orte d as a f oll o w - u p 
t o t hat e ve nt re gar dl ess of w he n it occ urs. T h e f oll o w-u p i nf or mati o n s h o ul d descri be w h et her 
t he e ve nt h as r es ol ve d or c o nti n ues, if a n d h o w it was treate d, w h et her t he bli n d was br o ke n or 
n ot, a n d w het her t he p atie nt c o nti n ue d or wit h dre w fr o m st u d y p artici pati o n. 
If  t he  S A E  is  n ot  pre vi o usl y  d oc u me nte d  i n  t h e  I n vesti gat or’s  Br oc h ure  or  Pac k a ge  I nsert 
( ne w  o cc urre nce)  a n d  is  t h o u g ht  t o  be  relat e d  t o  t he  st u d y  treat me nt  a  Dr u g  Safet y  a n d 
E pi de mi ol o g y  D e part me nt  ass ociate  ma y  ur ge ntl y  re q uire  f urt h er  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  n ee d  t o  iss ue  a n  I n v esti gat or 
N otificati o n  (I N)  t o  i nf or m  all  i n vesti gat ors  i n v ol ve d  i n  a n y  st u d y  wit h  t he  sa me  st u d y 
treat me nt t hat t his S A E has bee n re p orte d. S 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 n ce  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   
Li v er s af et y m o nit ori n g 
T o e ns ure patie nt safet y a n d e n ha n ce relia bilit y i n deter mi ni n g t he h e pat ot o xic p ote ntial of a n 
i n vesti gati o nal  dr u g,  a  st a n dar dize d  pr o cess  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 h e st u d y (irres pecti ve of w h et her cl assifie d/re p orte d as ( S) A E): 
•  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 

N o v arti s  
C o nfi d e nti al  
P a g e 5 8  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
•  Li ver e v e nts, w hic h will re q uir e cl os e 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 b ase li ver C R F pa ges  
Please  ref er  t o 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.  
E ver y li ver la b orat or y tri g ger or li ver e ve nt  as d efi ne d i n A p pe n di x 1 s h o ul d be f oll o we d u p 
b y  t he  i n vesti gat or  or  d esi g nat e 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- 1 Li ver E ve nt a n d La b orat or y Tri g ger Defi niti o ns . 
F or t he li ver l a b orat or y tri g ge r: 
•  Re peati n g t h e li ver f u n cti o n test ( L F T) wit hi n t he ne xt wee k t o c o nfir m ele vati o n.  
T he re p eat of L F T s m ust be perf or me d usi n g t he ce ntral la b orat or y , if p ossi ble. If t his 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 t o m o nit or t he safet y of t h e 
patie nt. If a li ver e v e nt is s u bse q ue ntl y re p orte d, a n y l o cal 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 m ust 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 bs er vati o n of t he p atie nt will be i niti ate d, i ncl u di n g 
c o nsi derati o n of tr eat 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 h e L F T t o c o nfir m ele vati o n as a p p r 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 v e nt via e x cl usi o n of alter nati ve ca uses (e. g., disease, 
c o-me dicati o ns)  
•  A n i n vesti gati o n of t he li ver e ve nt w hi c 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  m ust  be  rec or d e d  o n  a p pr o priate eC R F  p a ges,  i ncl u di n g  t he  li ver 
e ve nt o ver vie w e C R F pa ges.  
7. 4   
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
Me dicati o n  err ors  ar e  u ni nte nti o nal  err ors  i n  t h e  prescri bi n g,  dis pe nsi n g,  a d mi nistrati o n  or 
m o nit ori n g  of  a  me dici ne  w hile  u n der  t he  c o ntr ol  of  a  healt hcare  pr ofessi o nal,  patie nt  or 
c o ns u mer ( E M A d efi niti o n).    
Me dicati o n  err ors  are  us uall y  u ni nte nti o nal,  alt h o u g h  a  patie nt  ca n  i nte nti o nall y  ‘c o m mit’  a 
me dicati o n  err or  d u e  t o  a  lac k  of  me dical  k n o wl e d ge  or  s o u n d  j u d g me nt  (e. g.  i nte nti o nall y 
re m o vi n g dr u g fr o m ca ps ule a n d diss ol vi n g i n j uice) or t here is a n acci de ntal dr u g o missi o n 
b y a n H C P).  Me dicati o n err ors are n ot c o nsi d ere d t o be mis use or a b use.    
Mis use  refers  t o  sit uati o ns  w here  t he  me dici nal  pr o d uct  is  i nte nti o nall y  a n d  i na p pr o priatel y 
use d n ot i n acc or d a nce wit h t he pr ot oc ol. 
A b use  c orr es p o n ds  t o  t he  persiste nt  or  s p ora di c,  i nte nti o nal  e x cessi ve  use  of  a  me dici nal 
pr o d uct, w hic h is acc o m pa nie d b y har mf ul p h ysical or ps yc h ol o gical effects. 

N o v arti s  
C o nfi d e nti al  
P a g e 5 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Me dicati o n  err ors wit h ra n d o mize d st u d y treat me nt (st u d y treat me nt err ors ) will be c ollecte d 
o n t he  D A R  ( dose  a d mi nistrati o n  rec or d)  e C R F.    Refer  t o Secti o n  5. 5. 5  f or  i nf or mati o n 
re gar di n g i nterr u pti o ns of st u d y tr eat ment.      
Mis use  or  a b us e 
of  ra n d o mize d  st u d y  treat me nt  will  be  c ollecte d  o n  t he  A E  e C R F  a n d 
re p orte d i n t he safet y dat a base irr es pecti ve of it bei n g ass oci ate d wit h a n A E/ S A E. 
T a bl e 7 -1 G ui d a n c e f or c a pt uri n g t h e st u d y tr e at m e nt err or s i n cl u di n g  mi s u s e/ a b u s e  
Tr e at m e nt err or 
t y p e 
D o c u m e nt i n D o s e 
A d mi ni str ati o n ( D A R) 
e C R F ( Y e s/ N o)  
D o c u m e nt i n A E 
e C R F  
C o m pl et e S A E f or m  
S t u d y tr e at m e nt 
err or  
Y e s  
O nl y if a s s o ci at e d wit h 
a n A E  
O nl y if a s s o ci at e d wit h a n 
S A E  
Mi s u s e/ A b u s e  
Y e s  
Y e s, e v e n if n ot 
a s s o ci at e d wit h A E  
Y e s, e v e n if n ot a s s o ci at e d 
wit h S A E  
7. 5   Pr e g n a n c y r e p orti n g 
T o e ns ure patie nt safet y, eac h pre g na nc y occ urri n g after si g ni n g t he i nf or me d c o nse nt m ust be 
re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre n ce. T he pre g na nc y s h o ul d b e 
f oll o we d u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y t er mi nati o n, details of 
t he  birt h,  a n d  t he  pr ese 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 n e w b or n c o m plicati o ns. 
Pre g n a nc y m ust be rec or de d o n t he P har mac o vi gila nce Pre g n a nc y F or m a n d re p orte d b y t h e 
i n vesti gat or  t o  t h e  l ocal  N o vartis  Dr u g  Safet y  a n d  E pi de mi ol o g y  De p art 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 m e  f or m  a n d  s h o ul d  i n cl u de  a n  assess me nt  of  t he 
p ossi ble relati o ns hi p t o t he st u d y tr eat me n t.  
A n y S A E e x perie nce d d uri n g t he pre g n a nc y a n d u nrelate d t o t he pre g na n c y m ust be re p ort e d 
o n a S A E f or m. 
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  i nitiati 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 v arti s 
re pres e ntati ve  will  r e vie w  t he  pr ot oc ol  a n d  d ata  ca pt ure  re q uire me nts  (i. e.  e S o urce  D D E  or 
e C R Fs)  wit h  t he  i n vesti gat ors  a n d  t heir  staff.  D uri n g  t he  st u d y,  N o v artis  e m pl o ys  se v eral 
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 u alit y/i nte grit y  of t he sites’ d ata. 
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 data ca pt ur e / data e ntr y, t he a d h ere n ce t o t he pr ot oc ol a n d t o G o o d Cli nical Practice, t he 
pr o gress  of  e nr oll me nt,  a n d  t o  e ns ure  t hat  st u d y  treat me nt  is  bei n g  st ore d,  dis pe nse d,  a n d 
acc o u nte d f or acc or di n g t o s pecificati o ns. Ke y st u d y pers o n nel m ust be a v aila ble t o assist t he 
fiel d m o nit or d uri n g t hese visits.  C o nti n u o us re m ote  m o nit ori n g of  eac h site’s data ma y b e 
perf or me d  b y  a  ce ntr a lize d  N o vartis  C R A  or ga nizati o n.  A d diti o nall y,  a  ce ntral  a n al yti cs 
or ga nizati o n ma y a n al yz e data & i de ntif y ris ks & tre n ds f or site o perati o nal para met ers, a n d 
pr o vi de re p orts t o N o v artis Cli nical Tea ms t o assist wit h trial o versi g ht.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
T he i n vesti gat or m ust  mai ntai n s o urce d o c 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 m ati 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 ns e 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 o c u me nts  t o  c o nfir m 
t heir c o 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  pres e 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 x cl usi o n  criteria, 
d oc u me nta ti 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 h e  c o nsiste n c y  of  t he  s o urce  d ata  wit h  t he  C R Fs  are  perf or m e 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 m e nts a b o ut t he i de ntit y of t h e 
patie nts will be discl ose d.  
8. 2   D at a c oll e cti o n  
Desi g n ate d i n vesti gat or site staff will n ot be gi v e n access t o t he s yste m u ntil t he y ha ve b ee n 
trai ne d.  All  data  will  be  ha n dle d  i n  ali g n me nt  wit h  c urre nt  le gislati o n  o n  data  pr otecti o n. 
St u d y d oc u m e nts i ncl u di n g patie nts' files will be st ore d sec ure at cl i nical site. O nl y a pri nci pal 
i n vesti gat or  a n d na me d  st u d y pers o n al will ha ve access t o patie nts'  files. Data tra nsferre d t o 
N o vartis  s yste ms  are  c o de d  a n d  pr otecte d  fr o m  u na ut h orize d  brea k -i n.    I de ntifie d  site  users 
will  recei ve  a n  i n di vi d ual  l o gi n  a n d  p a ss w or d  or  bi o metric  fi n ger pri nt  i de ntificati o n. 
Pass w or ds  use d  t o  access  N o vartis  (a n d  its  ve n d ors)  s yst e ms  nee d  t o  be  of  a p pr o priate 
stre n gt h  a n d  n ee d  t o  be  c ha n ge d  r e g ularl y.  N o v artis  pers o n al  c o m p uters  re q uire  t w o  fact or 
a ut h orizati o ns.  A d diti o nall y  access  t o  all  data  ser ver  r o o ms  use d  t o  st ore  har d w are  a n d 
s oft ware f or t his trial is restricte d o nl y t o t h ose st aff wit h a p pr o priate access ri g hts. Access t o 
s yste ms w hic h are n o l o n ger i n use will be re m o ve d; als o access of users n o l o n ger i n v ol ve d 
i n  t he  c o n d uct  of  t he  st u d y  will  be  re m o ve d.  O n  t he  c o ntrar y,  ne w  staff  will  be  caref ull y 
trai ne d  bef or e  bei n g  all o we d  t o  access  c o nfi d e ntial  or  pers o nal  files  ( o n-site  trai ni n g, 
i n vesti gat or  meeti n g  a n d  ve n d or  s pecific  trai ni n gs).  Staff  m ust  e ns ure  t hat  u na ut h orize d 
pers o ns  ar e  u na ble  t o  vi e w  or  pr ocess  pers o n al  or  se nsiti ve  i nf or mati o n  i n  a  pa per  f or m  or 
dis pla ye d  electr o ni call y.  Pers o nal  data  are  st ore d  ce ntrall y  o nl y  i n  ps e u d o n y m o us  f or m. 
Electr o nic  tr a nsfer  of  data  is  al wa ys  e n cr y pte d  a n d  ta kes  place  via  sec ure  o n -li ne  c h a n nels 
pr o vi di n g t he hi g hest le v el of sec urit y. S pir o meters a n d a n y ot her de vices ca pt uri n g cli nical or 
pers o nal data m ust n ot c o ntai n u na ut h orize d, u nlice nse d or p ers o nall y lice nse d s oft ware. All 
s oft ware m ust be a ut h ori ze d a n d pr oc ure d t hr o u g h N o vartis or its ve n d ors. Electr o nic de vices 
are  sec ure d  b y  u p -t o-d ate  a nti -vir us,  a nti -s p y ware  a n d  pers o n al  fire wall.  O nl y  k n o w n 
mac hi nes are all o we d t o re m otel y access ce ntrall y hel d p ers o nal or se nsiti ve data. I n a d diti o n 
N o vartis as w ell as cli ni cal s ite re g ul ate use of i nf or mati o n a n d c o m m u nicati o n tec h n ol o gies 
b y t heir staff i n or der t o a v oi d u na ut horize d brea k -i n t o t he net w or k. 
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 [ or C R O w or ki n g o n b e half of N o vartis] re vie w t he data e ntere d i nt o t he C R Fs 
b y i n vesti gati o nal staff f or c o m plete ness a n d acc urac y a n d i nstr uct t he site pers o n nel t o ma k e 
a n y  r e 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 

N o v arti s  
C o nfi d e nti al  
P a g e 6 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
electr o nic d ata q u er y. D esi g nate d i n v esti 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 dat a.  
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 n ce  List,  w hic h  e m pl o ys  t he  A nat o mical  T hera p e utic  C he mical  cl assificati o n  s yste m. 
C o nc o mita nt  pr oce d ur es,  n o n -dr u g  t hera pi es  a n d  a d verse  e ve nts  will  b e  c o d e d  usi n g  t h e 
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 , E C G rea di n gs, a n d S pir o metr y rea di n gs will be pr ocesse d ce ntrall y a n d 
t he res ults will be se nt el ectr o nicall y t o N o vartis ( or a desi g nate d C R O). 
Diar y data will be e nt ere d i nt o a n electr o nic diar y b y t h e patie nt a n d patie nts  will fill i n t heir 
P R O  data  i n  a  site  base d  ta blet.  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  d ata base.  T he  data bas e  will  be  se nt  electr o nicall y  t o  N o vartis  pers o n nel  ( or 
desi g nat e 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 dr u g(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 k e d usi n g a n I nt eracti ve Res p o nse Tec h n ol o g y (I R T). T he  s yste m will be 
s u p plie d  b y  a  ve n d or,  w h o  will  als o  ma na ge  t he  data base.  T h e  dat a base  will  be  se nt 
electr o nicall y t o N o v artis ( or a desi g nat e d C R O).  
Eac h  o cc urre nce  of  a  c o de  br ea k  vi a  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 d e brea k f u n cti o nalit y will re mai n a vaila ble u ntil st u d y s h ut d o w n or u p o n re q uest of 
N o vartis.  
T he  occ urre nce  of  rele v a nt  pr ot oc ol  de viati o ns will  be  deter mi ne d.  After  t hese  acti o ns  ha v e 
bee n  c o m plete d  a n d  t he  data base  has  b ee n  decl are d  t o  be  c o m plete  a n d  acc urat e,  it  will  be 
l oc ke d a n d t he treat me nt c o des will be u n bli n de d a n d ma de a vaila ble f or data a nal ysis. A n y 
c ha n ges t o t he data b ase after t h at ti me ca n o nl y be ma de after writte n a gree me nt b y N o vartis 
De vel o p me nt ma na ge me nt. 
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 dj u di c ati o n C o m mitt e e  
A n i n de pe n d e nt a dj u dicati o n c o m mittee will be esta blis he d t o assess seri o us ast h ma o utc o mes 
(ast h ma-r elate d  h os pitalizati o ns,  i nt u bati o ns  a n d  deat hs),  s eri o us  car di o vasc ular  a n d 
cere br o vasc ul ar ( C C V) e ve nts, ne w o ns et of atri al fi brillati o n a n d fl utter as well as all deat hs. 
All seri o us C C V e ve nts occ urri n g fr o m t he ti me of ra n d o mizati o n u ntil t he 3 0 da ys aft er t he 
per ma ne nt disc o nti n uati o n of st u d y dr u g, w here a p plica ble, will be a dj u dicate d. 
T he  c o m mittee  will  c o nsist  of  e x p erts  o utsi de  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,  w h o  will  peri o dicall y  re vie w  bli n de d,  perti ne nt  patie nt  d ata  a n d  t he  s u p p orti n g 
d oc u me ntati o n t o settle t he s pecifie d a dj u dicati o n o bjecti ves.  
F urt her d etails will be pr o vi de d i n t he A dj u dica ti o n C o m mittee C harter. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
9 
D at a a n al y si s  
T he  a nal ysis  will  be  c o n d ucte d  o n  all  s u bject  data  at  t he  ti me  t he  trial  e n ds.  A  detaile d 
Statistical  A nal ysis  Pla n  ( S A P)  will  be  fi nalize d  bef ore  t he  st u d y  data b ase  l oc k.  A n y  dat a 
a nal ysis carrie d o ut i n d e pe n de ntl y b y t he i n v esti gat or s h o ul d be s u b mitte d t o N o vartis bef ore 
p u blicati o n or prese ntati o n.     
9. 1  A n al y si s s et s  
T he f oll o wi n g a nal ysis sets are d efi ne d f or data a nal ysis.  
T he  ra n d o mize d  ( R A N)  set  will  c o nsist  of  all  patie nts  w h o  were  assi g n e d  a  ra n d o mizati o n 
n u m ber,  re gar dless  of  w het her  or  n ot  t he y  act uall y  recei ve d  st u d y  me di cati o n.  Patie nts  i n 
R A N will be a nal yze 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 ysis Set ( F A S) will c o nsist of all patie nts i n t he R A N set w h o recei ve d at least 
o n e d ose of st u d y m e dicati o n. F oll o wi n g t he i nte nt -t o-treat pri nci ple, patie nts will be a nal yze d 
acc or di n g t o t he tr eat me nt t he y w ere assi g n e d t o at ra n d o mizati o n.  
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 w h o di d n ot ha ve a n y m aj or 
pr o t oc ol de viati o ns. Maj or pr ot oc ol de viati o ns will be defi ne d i n t he statistical a nal ysis pla n 
pri or t o data bas e l oc k a n d t he u n -bli n di n g of t he st u d y. Patie nts will be a n al yze d acc or di n g t o 
t he treat me nt t he y r ecei v e d. 
T he Saf et y S et will c o nsist of all p at ie nts w h o recei ve d at least o n e d ose of st u d y me dicati o n. 
Patie nts will be a nal yze d acc or di n g t o t he treat me nt t he y recei v e d.  
T he F A S will be us e d i n t he a nal ysis of all efficac y v aria bles.  T h e R A N s et will be use d f or a 
s u m mar y of patie nt dis p ositi o n, de m o gra p hics a n d baseli ne c haracteristics.  T he P P S will be 
use d f or s u p p orti ve a nal ysis of t he pri mar y a n al ysis o nl y. T he Safet y Set will be use d i n t he 
a nal ysis of all safet y v ari a bles.  
N ote t hat t he F A S a n d Safet y Sets are t he sa me e x ce pt t hat t he Safet y  Set all o ws t he i ncl usi o n 
of  n o n -ra n d o mize d  pati e nts  w h o  recei ve d  st u d y  dr u g  i n  err or.  Als o,  t he  F A S  assi g n 
ra n d o mize d treat me nt a n d t he Safet y Set assi g n e d recei v e d treat me nt. 
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 n e  c har acteristics  meas ure d  bef ore  ra n d o mizati o n  i ncl u di n g  a ge, 
ge n d er,  race,  et h nicit y,  hei g ht,  wei g ht,  b o d y  m ass  i n de x  ( B MI),  rel e va nt  me dical  hist or y, 
scree ni n g  s pir o metr y  para meters:  ( F E V 1 ,  F V C,  F E V1 / F V C  a n d  F E F2 5 -7 5 ),  F E V1  
re versi bilit y,  %  of  pre dicte d F E V 1 ,  d urati o n  of  ast h ma,  hist or y  of  ast h ma  e x acer bati o ns, 
s m o ki n g hist or y, pri or c o nc urre nt m e dicati o ns (ast h ma-relate d a n d n o n-ast h ma-relate d), vital 
si g ns (s yst olic a n d diast olic bl o o d press ure, p ulse rate), Q T c usi n g Fri dericia’s c orrecti o n a n d 
baseli ne A Q L Q - S, A C Q - 7, 
 will be s u m marize d b y treat me nt gr o u p.  
C o nti n u o us varia bles will be s u m marize d usi n g d escri 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 bl es will be s u m marize d i n ter ms of 
t he n u mber a n d perce nta ge of patie nts i n eac h cate g or y f or t he treat me nt gr o u ps.  
Baseli ne  is  d efi ne d  as  t he  last  meas ure m e nt  be f ore  first  d ose  of  st u d y  dr u g. N o  statistical 
a nal ys es will be pr o vi de d f or baseli ne c o m para bilit y a m o n g t he treat me nt gr o u ps. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
H 2 : Q V M 1 4 9 1 5 0/ 5 0/ 8 0 μ g is i nferi or t o free c o m bi nati o n of sal meter ol/ fl uticas o ne 5 0/ 5 0 0 
μ g + ti otr o pi u m 5 μ g i n c ha n ge fr o m b aseli ne f or A Q L Q t otal sc ore at Wee k 2 4 
H a 2 : Q V M 1 4 9 1 5 0/ 5 0/ 8 0 is n o n-i nferi or t o free c o m bi nati o n of sal meter ol/ fl uticas o ne 5 0/ 5 0 0 
μ g + ti otr o pi u m 5 μ g i n c ha n ge fr o m b aseli ne f or A Q L Q at t otal sc ore Wee k 2 4 
T he pri mar y v aria ble will be a nal yz e d usi n g a mi x e d m o del f or re peate d  meas ure ( M M R M) 
o n t he F A S. T h e m o del will c o ntai n treat me nt, re gi o n, visit, bac k gr o u n d I C S/ L A B A ( me di u m 
or hi g h d ose), bas eli ne -b y -visit i nteracti o n  a n d treat me nt -b y -visit i nteracti o n as fi x e d effects 
wit h baseli ne A Q L Q t otal sc ore as t he c o variate, a n d ce nter neste d wit hi n r e gi o n as a ra n d o m 
effect.  T he  wit hi n -patie nt  c orrelati o n  will  be  m o dele d  usi n g  t he  u nstr uct ure d  c o v aria nce 
matri x  i n  t he  mi x e d  m o del.  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 ( Ke n war d a n d R o ger, 1 9 9 7). If t he m o del d oes n ot c o n ver ge, 
t he n t he c o m p o u n d s y m metr y c o v aria n ce matri x will be use d i n t he mi x e d m o del. Restricte d 
ma xi m u m li keli h o o d met h o d will be use d.  
T he least s q uares mea ns of t he treat me nt differe nces, sta n dar d err ors, 9 7. 5 % ( o ne -si de d) CI, 
a n d  o ne-si de d  p- val ues f or  n o n-i nferi orit y  test  (a dj uste d  a n d  u na dj uste d)  a n d  n o mi nal  t w o-
si de d  p-val ues at  wee k  2 4  of  eac h  d ose  Q V M 1 4 9  vs.  t he  c o m bi nati o n  of  sal meter ol/ 
fl uticas o ne 5 0/ 5 0 0 μ g + ti otr o pi u m 5 μ g, will be prese nte d.   
N o n -i nferi orit y of Q V M1 4 9 will be clai me d if t he m ulti plicit y a dj uste d o ne -si de d p-val ue is  
< 0. 0 2 5.    
9. 4. 3  H a n dli n g of mi s si n g v al u e s/  e arl y di s c o nti n u ati o n s   
T he M M R M m o del, w hic h is use d f or t h e a n al ysis of pri mar y v aria ble is b ase d o n missi n g at 
ra n d o m ass u m pti o n f or t he missin g val u es a n d assesses t he treat me nt effects wit h o ut e x plicit 
i m p utati o n.   
T he esti ma n d f or t his st u d y is diff ere n ce b et wee n t he effect of i nitiall y ra n d o mize d treat me nts 
ha d all patie nts re mai ne d o n t heir ra n d o mize d treat me nt t hr o u g h o ut t he st u d y. 
A Q L Q  
T he t otal A Q L Q sc or e is t he mea n res p o ns e t o all 3 2 q uesti o ns; n o i m p utati o n will be use d f or 
missi n g q uesti o ns or missi n g t otal sc ore . 
9. 4. 4  
M ulti pli cit y A dj u st m e nt  
T o  c o ntr ol  t h e  f a mil y -wise  t y pe -I  err or  rate  at  t he o ne-si de d  2. 5 %  si g nifica nce  le vel,  a 
m ulti ple testi n g pr oce d ur e base d o n t he tri m me d Si mes test i n  Bra n nat h et. al. (2 0 0 9)  is use d. 
T he f a mil y f or t he o ver all t y pe -I err or rat e c o ntr ol c o ntai ns t otal 2 h y p ot heses f or t he pri mar y 
e n d p oi nt,  A Q L Q ..  D e n ote  t he  t w o  h y p ot hes es  f or  t he  pri mar y  e n d p oi nt  as  H1  a n d  H 2  f or 
c o m pari n g Q V M 1 4 9  1 5 0/ 5 0/ 1 6 0  µ g  o. d.  Vers us  free  c o m bi nati o n  of  sal meter ol/  fl uticas o n e 
5 0/ 5 0 0  μ g  +  ti otr o pi u m  5  μ g  a n d  Q V M 1 4 9  1 5 0/ 5 0/ 8 0 µ g  o. d.  vers us  free  c o m bi nati o n  of 
sal meter ol/fl uticas o ne  5 0/ 5 0 0  μ g  +  ti otr o pi u m  5  μ g,  i n  ter ms  of c ha n ge  fr o m  baseli ne  i n 
A Q L Q t otal sc or e .  
Bel o w  is  a  brief  des cri pti o n  of  t he  testi n g  pr oce d ure  base d  o n  t he  ge neralize d  Si mes  test  i n 
Bra n n at h  et al (2 0 0 9 ). 

N o v arti s  
C o nfi d e nti al  
P a g e 6 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Let p 1  a n d p2  be t he c orr es p o n di n g p -v al ues ( 1- si de d, p-val ue relate d t o NI h y p ot hes es ) of t he 
t w o h y p ot hes es of H 1  a n dH 2 .  
Ste p 1: Retai n b ot h H 1 a n d H 2  if A N Y p i ≥= 0. 9 7 5(i.e. L o ose tri ple is perf or mi n g better t ha n 
Q V M) f or i = 1, 2st o p h er e; ot her wise g o t o ste p 2; 
Ste p 2: Reject H 1 a n d H 2  if pi< 0. 0 2 5 f or B O T H i = 1, 2, st o p here; ot her wise g o t o ste p 3; 
Ste p 3: If neit her ste p 1 or 2 a p plies, p erf or m B o nferr o ni t est  t o H1 a n d H 2. T h us reject H 1 if 
p 1 < 0. 0 1 2 5 a n d reject H 2 if p2 < 0. 0 1 2 5 a n d st o p. 
F or eac h of t h e t w o h y p ot heses, t he c orres p o n di n g testi n g statistics (esti mate d least s q uare 
mea n differe nce)  f oll o ws n or mal distri b uti o n. He nce f or H 1 a n d H 2 , t heir c orres p o n di n g 
testi n g statistics is ass u me d t o f oll o w j oi ntl y bi v ariate n or mal distri b uti o n. T heref ore t his 
testi n g pr oce d ure c o ntr ols t he o verall t y pe – I err or rate at t he 1-si de d 0. 0 2 5 le vel i n t he str o n g 
se nse re gar dless if t he bi variate n or m al distri b uti o ns ha ve p ositi ve or ne gati ve c orrelati o ns as 
s h o w n i n Bra n n at h et al  ( 2 0 0 9). 
Ot her t ha n t he t w o a nal yses me nti o ne d a b o v e f or t he pri mar y e n d p oi nt, all ot her a n al ys es  will 
be perf or me d at t he n o mi nal 2-si de d 0. 0 5 le vel ( 2- si de d) wit h o ut m ulti plicit y a dj ust me nt. 
9. 4. 5  S u p p orti v e a n al y s e s  
F oll o wi n g s u p p le me ntar y a n al ys es will be perf or me d f or pri mar y. 
T he M M R M m o del use d f or t he a n al ysis of pri mar y varia bles will be perf or me d o n t he P P S. 
P ri mar y vari a bles will be a nal yz e d usi n g t he sa me M M R M m o del as t hat of pri mar y a n al ysis 
usi n g t he data fr o m all ti me - p oi nts (i.e. o n a n d a v aila ble off treat me nt  data ) o n F A S. 
9. 5  A n al y si s of s e c o n d ar y e n d p oi nt s  
 All a nal ys es will be perf or me d o n F A S.  
9. 5. 1  Effi c a c y v ari a bl e s  
9. 5. 1. 1  A Q L Q S c or e, d o m ai n s, a n d r e s p o n d er s at e a c h vi sit  
C ha n ge  fr o m  baseli ne  i n  eac h  of  t he  A Q L Q  d o mai ns  (s y m pt o ms,  e m oti o ns,  e x p os ure  t o 
e n vir o n me ntal  sti m uli  a n d  acti vit y  li mitati o n)  as  well  as  t he c ha n ge  fr o m  baseli ne  i n  t otal 
sc ore  at  p ost-baseli ne  visits  will  be  a nal yze d  usi n g  mi x e d  m o del  of  re peate d  meas ure me nts 
( M M R M)  si milar  t o  pri mar y  varia ble.  A p pr o pri ate  bas eli ne  A Q L Q  d o mai n  sc ores  will  be 
use d as c o variate i nstea d of baseli ne A Q L Q t otal sc ore i n t he m o del. T h e 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  (least -s q uare  mea n)  differe nce 
c orres p o n di n g  t o  t he  res pecti ve  visit.  A dj uste d  mea n  ( L S  m ea n)  will  be  dis pla ye d  f or  eac h 
treat me nt  gr o u p  al o n g  wit h  t he  esti mate d treat me nt  differe n ces  a n d  t h e  9 5 %  c o nfi de nce 
i nter vals a n d t he t w o si de d p-val ues b y visit.  
T he  pr o p orti o n  of  patie nts  w h o  ac hie ve  a n  i m pr o ve me nt  of  at  least  0. 5  i n  t he  c ha n ge  fr o m 
baseli ne i n A Q L Q t otal sc ore (i.e. i ncreas e of A Q L Q t otal sc ore of at least  0. 5 fr o m baseli ne) 
at  p ost -baseli ne  visits  will  be  a nal yze d  usi n g  t he  sa me  l o gistic  re gressi o n  m o del  via  G E E 

N o v arti s  
C o nfi d e nti al  
P a g e 6 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
s pecifie d f or t he AC Q- 7 a nal ysis e x ce pt t hat bas eli ne A Q L Q will b e use d as t he c o v ariate i n 
t he m o del, i nstea d of t he baseli ne A C Q- 7. 
9. 5. 1. 2  S pir o m etr y  
A ll  s pir o metr y  effi cac y  varia bles  will  be  a nal yz e d  f or  t he  F A S,  u nless  ot her wise  s pecifie d. 
S pir o metr y  meas ure m e nts  ta ke n  wit hi n  7  da ys  of  s yste mic  c ortic oster oi d  use d  as  ac ute 
treat me nt  f or  e x acer bati o n,  or  wit hi n  3  m o nt hs  of  si n gle  de p ot  c ortic oster oi d  i njecti o n,  or 
wit hi n  6  h o urs  of  resc ue  me dicati o n,  will  be  set  t o  missi n g  a n d  n ot  be  i m p ute d,  u nless 
s pecifie d ot her wise. 
S pir o met r y d at a at e a c h visit 
C ha n ge fr o m bas eli ne i n tr o u g h F E V 1 at wee k 2 4 will be a nal yze d usi n g a mi x e d m o del f or 
re peat e d  meas ure  (M M R M)  si milar  t o  t he  m o del  use d  f or  pri mar y  v aria ble  o n  t h e  F A S. 
Tr o u g h  F E V 1  is  calc ulate d  as  a vera ge  of  1 5  mi n  a n d  4 5  mi n  pre-d ose  meas ure me nts .  T h e 
m o del  will  i ncl u de  bas eli ne F E V 1 i nstea d  of  baseli ne  A Q L Q  sc ore  as  c o variate.  T h e  least 
s q uares mea ns of t he tr eat me nt differe nces, sta n dar d err ors, 9 5 % (t w o-si de d) CI, a n d p- val ues 
( n o mi nal)  at  wee k  2 4  of  eac h  d os e  Q V M 1 4 9  vs  t he  c o m bi nati o n  of  sal meter ol/fl uticas o ne 
5 0/ 5 0 0 µ g + ti otr o pi u m 5 µ g will be pres e nte d.  
Tr o u g h F E V 1  will als o b e a n al yze d usi n g t he s a m e M M R M m o del as s pecifie d a b o v e,  w here 
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  (least-s q uare 
mea n)  diff ere n ce  c orres p o n di n g  t o  t he  res p ecti v e  visit.  A dj uste d  mea n  ( L S  mea n)  will  be 
dis pla ye d  f or  eac h  tr eat me nt  gr o u p  al o n g  wit h  t he  esti mate d  treat me nt  differe n ces  a n d  t h e 
9 5 % c o nfi de n ce i nter v als a n d t he t w o si de d p- val u es b y visit.  
Si milar  a nal ys es  will  be  perf or me d  f or  F V C  a n d  F E F 2 5 -7 5 .  C ha n ge  fr o m  baseli ne  i n  t h e 
s pir o metr y v al ues will be als o a nal yze d usi n g t he s a me MM R M m o del. 
9. 5. 1. 3  A C Q - 7 S c or e  a n d r e s p o n d er s  at e a c h vi sit  
C ha n ge fr o m baseli ne i n A C Q -7 sc ore at p ost -bas eli ne visits will be a n al yz e d usi n g t he mi x e d 
m o del  of  r e peate d  meas ure me nts  ( M M R M)  si milar  t o  pri mar y  v aria bl e.  Bas eli ne  A C Q -7 
sc ore will be use d as c o v ariate i nstea d of baseli ne A Q L Q t otal sc ore i n t he m o del. 
T he least s q uares mea ns of t he treat me nt differe n ces, sta n dar d err ors, 9 5 % (t w o-si de d) CI, a n d 
p- val ues  at  eac h  visit  of  eac h  d os e  Q V M 1 4 9  vs.  t he  c o m bi nati o n  of  sal meter ol/  fl uticas o n e 
5 0/ 5 0 0 μ g + ti otr o pi u m 5 μ g, will be pres e nte d.   
T he  pr o p orti o n  of  p atie nts  w h o  ac hie v e  a n  i m pr o ve me nt  of  at  least  0. 5  i n  A C Q -7  (i.e. 
decrease of A C Q -7 s c ore of at least 0. 5 fr o m baseli ne) at p ost -baseli ne visits will be a nal yze d 
usi n g  t he  l o gistic  re gressi o n  m o del  via  t he  ge neralize d  esti mati n g  e q uati o ns  ( G E E).  T h e 
m o del will i ncl u de ter ms f or tr eat me nt, re gi o n, visit,  bac k gr o u n d I C S/ L A B A ( me di u m or hi g h 
d ose),  baseli ne -b y -visit  i nteracti o n  a n d  treat me nt -b y -visit  i nteracti o n  as  fi x e d  effects,  wit h 
baseli ne  A C Q -7  as  c o v ariates.  T he  wit hi n -patie nt  c orrelati o n  will  b e  m o dele d  usi n g  t h e 
u nstr uct ure d c o varia n ce matri x i n t he G E E m o del. T he esti mate d a dj uste d o d ds rati os of t he 
treat me nt  c o m paris o ns  will  be  dis pla ye d  al o n g  wit h  t he  ass ociate d  9 5 %  (t w o-  si de d) 
c o nfi de nce i nter vals a n d p- val ues.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
9. 5. 2  S af et y v ari a bl e s  
A d v er s e e v e nt s  
All  st u d y  e mer ge nt  a d verse  e v e nts  i ncl u di n g  ast h ma  e x acer b ati o ns  will  be  liste d.    A d v ers e 
e ve nts  starti n g  o n  or  after  t he  ti me  of  t he  first  i n halati o n  of  st u d y  dr u g  b ut  n ot  later  t ha n  7 
da ys  ( 3 0  da ys i n  t he  case  of  a  S A E)  after  t he  last  a d mi nistrati o n  of  st u d y  dr u g,  will  be 
classifie d as a treat me nt e mer ge nt a d vers e e v e nt.   A n y a d verse e v e 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 st u d y dr u g will be classifie d as a prior a d verse 
e ve nt.  
T he  f oll o wi n g  tr eat me nt  e mer ge nt  a d v erse  e v e nt  s u m maries  will  be  pr o d uce d,  o v erall  b y 
s yste m  or ga n  cl ass  a n d  preferre d  ter m,  o verall  b y  s yste m  or ga n  class,  preferre d  ter m  a n d 
ma xi m u m se verit y, s us pecte d dr u g -relate d a d v erse e ve nts b y s yste m or ga n class a n d preferre d 
ter m,  seri o us  a d v erse  e v e nts  b y  s yste m  or ga n  cl ass  a n d  preferre d  ter m,  a n d  a d verse  e v e nts 
lea di n g t o p er ma ne nt dis c o nti n uati o n of st u d y-dr u g b y s yste m or ga n class a n d preferre d t er m.  
T he  n u m ber  a n d  perce nt a ge  of  patie nts  wit h  t he  m ost  fre q ue nt  A Es  will  be  s u m marize d  b y 
treat me nt. 
El e ctr o c ar di o gr a m ( E C G) a n d vit al si g n s  
Data fr o m t he electr o car di o gra m will be s u m marize d b y treat me nt a n d visit.  
Vital si g ns ( bl o o d pr ess ure a n d  ra dial p ulse  rate) data will be s u m mariz e d b y treat me nt   a n d 
visit.  C ha n ges  fr o m  baseli ne  will  als o  be  s u m marize d  b y  treat me nt.  Wei g ht  will  be 
s u m marize d b y visit a n d treat me nt gr o u p.  
All data will be i ncl u de d i n t he a nal ysis re gar dl ess of resc ue me dicati o n usa ge. T h e n u m ber 
( %) of patie nts wit h p ulse rate of < 4 0 a n d > 9 0 b p m; s yst olic bl o o d press ure of < 9 0 a n d > 
1 4 0 m m H g; diast olic bl o o d press ur e of < 5 0 a n d > 9 0 m m H g will be s u m marize d b y treat me nt 
gr o u p. 
N ota ble val ues f or vital si g ns a n d c ha n ge fr o m b aseli ne will be s u m marize d. A n ota ble val ue 
is defi ne d as f oll o ws: 
S yst olic bl o o d press ure 
“ L o w” criteri o n: < 7 5 m m H g, or ≤ 9 0 m m H g a n d decrease fr o m baseli ne ≥ 2 0 m m H g 
“ Hi g h ” criteri o n: > 2 0 0 m m H g, or ≥ 1 8 0 m m H g a n d i ncrease fr o m baseli ne ≥ 2 0 m m H g 
Diast olic bl o o d press ure 
“ L o w” criteri o n: < 4 0 m m H g, or ≤ 5 0 m m H g a n d decrease fr o m baseli ne ≥ 1 5 m m H g 
“ Hi g h ” criteri o n: > 1 1 5 m m H g, or ≥ 1 0 5 m m H g a n d i ncrease fr o m baseli ne ≥ 1 5 m m H g 
P ulse rate  
” L o w” criteri o n: < 4 0 b p m, or ≤ 5 0 b p m a n d decrease fr o m baseli ne ≥ 1 5 b p m 
“ Hi g h ” criteri o n: > 1 3 0 b p m, or ≥ 1 2 0 b p m a n d i ncreas e fr o m b aseli ne ≥ 1 5 b p m 
N ota ble  Q Tc  val ues  a n d  c ha n ges  fr o m  baseli n e  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 gr eater t ha n 4 5 0 ms ( male), 4 6 0 ms (fe mal e) a n d 5 0 0 ms ( b ot h) at 

N o v arti s  
C o nfi d e nti al  
P a g e 6 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 

N o v arti s  
C o nfi d e nti al  
P a g e 7 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 

N o v arti s  
C o nfi d e nti al  
P a g e 7 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
9. 7  I nt eri m a n al y se s  
N o i nteri m a nal ysis is pla n ne d i n t his st u d y.  
9. 8  S a m pl e si z e c al c ul ati o n  
T he sa m ple size calc ulati o n ta kes i nt o acc o u nt t he f oll o wi n g c o nsi derati o n: 
•  T o ac hie ve at least 9 0 % p o wer ( wit h m ulti plicit y a dj ust me nt) f or pri mar y e n d p oi nt, t o 
de m o nstrate t he n o n-i nf eri orit y of eit her of Q V M 1 4 9 d ose vs. t he free tri ple 
c o m bi nati o n of sal meter ol/fl uticas o ne + ti otr o pi u m i n patie nts wit h u nc o ntr olle d 
ast h ma f or A Q L Q at t he wee k 2 4.  Wit h t he ass u m pti o n of 0. 2 5 f or t he NI mar gi n, 
zer o as t he p oi nt esti mati o n of t he tre at me nt differe nce, o n e- si de d al p h a le v el of 
0. 0 2 5, a n d 0. 8 of t he sta n dar d de viati o n bas e d o n st u dies Q M F 1 4 9 E 2 2 0 3 a n d 
Kerstje ns ( 2 0 1 2);  
If  1 0 %  dr o p o ut  r ate  is  ass u me d,  t he n  t he calc ulati o n  s h o ws  t hat  t he  sa m ple  size  of 1 2 5 1 
patie nts (i.e 4 1 7 /ar m) will pr o vi de 9 9 % p o wer wit h m ulti plicit y a dj ust me nt as gi ve n i n Fi g ure 
9- 1 .  
T he sa m ple size a n d p o w er cal c ulati o ns are p erf or me d i n R 3. 1. 2 wit h pac ka ge g M C P. 
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 i nf or m e d c o n s e nt pr o c e d ur e s 
T his  cli nical  st u d y  was  desi g n e d  a n d  s hall  be  i m ple me nte d,  e x ec ute d  a n d  re p orte d  i n 
acc or d a 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 o cal  r e g ulati o ns  (i ncl u di n g  E ur o p ea n  Directi ve  2 0 0 1/ 2 0/ E C,  U S  C F R  2 1,  a n d 
J a 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 n ci ples lai d d o w n i n 
t he Declarati o n of H elsi n ki. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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/s u bjects  ma y  o nl y  b e  i ncl u d e d  i n  t he  st u d y after  pr o vi di n g  writte n 
( wit nesse d, w her e re q uir e d b y la w or re g ulati o n), I R B/I E C-a p pr o v e d i nf or me d c o nse nt, o nl y 
f ull y le gal c o m p ete nt patie nts ca n b e i ncl u de d  Th e patie nt m ust i n dicat e asse nt b y pers o n all 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 n e d  bef or e  c o n d u cti n g  a n y  st u d y -s p ecific  pr oce d ures  (e. g.  all  of  t he 
pr oce d ur es  des cri be d  i n  t he  pr ot oc ol).  T h e  pr ocess  of  o btai ni n g  i nf or me d  c o nse nt  m ust  be 
d oc u me nte d i n t he 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 C H  G C P  g ui deli ne  a n d  re g ul at or y  re q uire me nts  a n d  is 
c o nsi dere d a p pr o priat e f or t his st u d y. A n y c h a n ges t o t he pr o p ose d c o ns e 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 N o v artis 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 v e 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 R B/I E C a p pr o v al. 
W o me n  of  c hil d  b eari n g  p ot e ntial  m ust  be  i nf or me d  t ha t  t a ki n g  t he  st u d y  treat me nt  m a 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 n c y w ere t o occ ur d uri n g t he st u d y a n d a gree t hat 
i n or der t o partici pat e i n t he st u d y t he y m ust a d h ere t o t he c o ntrace pti o n re q uire me nt f or t h e 
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 he y 
m ust n ot be e ntere d i n t h e st u d y. 
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  m ust  o btai n  a p pr o val/fa v ora ble  o pi ni o n 
fr o m  t he  I nstit uti o nal  Re vie w  B o ar d/I n de p e n de nt  Et hics  C o m mittee  (I R B/I E C)  f or  t he  trial 
pr ot oc ol, i nf or me d c o nse nt f or m, c o nse nt f or m u p dates, s u bject recr uit me nt pr oce d ures (e. g., 
a d vertise me nts) a 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/s u bjects. Pri or t o 
st u d y  start,  t he  i n v esti gat or  is  re q uire d  t o  si g n  a  pr ot oc ol  si g n at ure  p a ge  c o nfir mi n g  his/ her 
a gree m e nt t o c o n d uct t he st u d y i n acc or d a 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 v e  access  t o  a ll  rele v a 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 nat e d a ge nts of 
N o vartis, I R Bs/I E Cs, a n d re g ulat or y a ut 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 r e g ulat or y a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis i m me diatel y t hat 
t his re q uest has bee n m a 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  
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  c o m pleti o n  a n d  fi nalizati o n  of  t he  st u d y  re p ort 
t he  res ults  of  t his  trial  will  be  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 bas e of cli nical trial res ults.  
1 0. 5  Q u alit y C o ntr ol a n d Q u alit y A s s ur a n c e 
N o varti s  mai ntai ns  a  r o b ust  Q ualit y  Ma n a ge me nt  ( Q M)  s yste m  t hat  i n cl u des  all  acti vities 
i n v ol ve d  i n  q ualit y  ass ura nce  a n d  q ualit y  c o ntr ol,  i ncl u di n g  t he  assi g n me nt  of  r oles  a n d 
res p o nsi bilities,  t he  re p orti n g  of  res ults,  a n d  t he  d oc u me ntati o n  of  acti o ns  a n d  escalati o n  of 
iss ues i de ntifie d d uri n g t he re vie w of q ualit y metrics, i nci de nts, a u dits a n d i ns pecti o ns. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
A u dits of i n vesti gat or sit es, ve n d ors, a n d N o vartis s yste ms are perf or me d b y N o v artis P har ma 
A u diti n g  a n d  C o m plia nce  Q ualit y  Ass ura nce,  a  gr o u p  i n de p e n de nt  fr o m  t h ose  i n v ol ve d  i n 
c o n d ucti n g,  m o nit ori n g  or  perf or mi n g  q ualit y  c o ntr ol  of  t he  cli nical  trial.  T he  cli nical  a u dit 
pr ocess uses a k n o wle d ge/ris k base d a p pr oac h. 
A u dits  are  c o n d uct e d  t o  assess  G C P  c o m plia nce  wit h  gl o b al  a n d  l ocal  re g ulat or y 
re q uire me nts, pr ot o c ols a n d i nter nal S O Ps, a n d  are p erf or m e d acc or di n g  t o writte n N o vartis 
pr ocesses.  
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 o bjecti ves, t he st u d y pr oce d ures a n d t he data t o be c ollecte d 
o n  st u d y  partici pa nts.  A d diti o nal  assess me nts  re q uire d  t o  e ns ure  s afet y  of  patie nts/s u bjects 
s h o ul d be a d mi nistere d as dee me d n ecess ar y o n a case b y cas e basis. U n d er n o circ u msta nces 
i ncl u di n g i nci de ntal c oll ecti o n is a n i n vesti gat or all o we d t o c ollect a d diti o nal data or c o n d uct 
a n y  a d diti o nal  pr oce d ur es  f or  a n y  p ur p ose  i n v ol vi n g  a n y  i n v esti gati o n al  dr u gs  u n der  t h e 
pr ot oc ol,  ot her  t ha n  t he  p ur p ose  of  t he  st u d y.  If  des pite  t his  i nter dicti o n,  data,  i nf or mati o n, 
o bser vati o n w o ul d b e i n ci de ntall y c ollect e d, t he i n vesti gat or s h all i m me diatel y dis cl ose it t o 
N o var tis  a n d  n ot  use  it  f or  a n y  p ur p os e  ot her  t ha n  t he  st u d y,  e x ce pt  f or  t he  a p pr o priate 
m o nit ori n g o n st u d y p artici pa nts. 
I n v esti gat ors  ascertai n  t he y  will  a p pl y  d ue  dili ge n ce  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 o c ol de viati o n w o ul d i m pr o ve t he  c o n d u ct of t he  st u d y t his m ust b e 
c o nsi dere d a pr ot oc ol a m e n d me nt, a n d u nless s u c h a n a me n d me nt is a gree d u p o n b y N o vartis 
a n d  a p pr o ve d  b y  t h e  I R B/I E C  a n d  healt h  a ut h orities,  w here  re q uire d,  it  ca n n ot  be 
i m ple me nte d.  
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 b e ma de i n a writte n pr ot o c ol a me n d me nt t hat 
m ust  be  a p pr o ve d  b y  N o vartis,  healt h  a ut h orities  w here  re q uire d,  a n d  t h e  I R B/I E C  pri or  t o 
i m ple me ntati o n.  O nl y  a me n d me nts  t hat  are  i nt e n de d  t o  eli mi nate  a n  a p pare nt  i m me diate 
hazar d t o patie nts/s u bjects ma y b e 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 u e ntl y  n otifie d  b y  pr ot oc ol  a m e n d me nt  a n d  t he  re vie wi n g  I R B/I E C  is  n otifie d. 
N ot wit hsta n di n g  t he  nee d  f or  a p pr o val  of  f or mal  pr ot oc ol  a me n d m e nts,  t he  i n vesti gat or  is 
e x pecte d t o ta ke a n y i m me diate acti o n re q uire d f or t he safet y of a n y pati e nt i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re pres e nts a de viati o n fr o m t he pr ot oc ol. I n s uc 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 ni t ori n g m ust be f oll o we d. 
1 2  R ef er e n c e s  
Refere n ces are a vaila ble u p o n re q uest:  
Bar n es PJ, Casale B, Da hl R et al ( 2 0 1 4) T he Ast h ma C o ntr ol Q uesti o n naire as a cli nical trial 
e n d p oi nt: past e x perie nce a n d rec o m me n d ati o ns f or f ut ure use. J Aller g y Cli n I m m u n ol; 6 9: 
1 1 1 9 – 1 1 4 0. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Bate ma n E D, B o us h e y H A, B o us q u et J et al ( 2 0 0 4) Ca n G ui d eli ne- defi ne d Ast h ma c o ntr ol Be 
Ac hie ve d?  T he Gai ni n g o pti mal Ast h ma C o ntr o l St u d y. A m J Res pir Crit Care Me d; 1 7 0: 8 3 6 -
8 4 4. 
Bate ma n E D, K or n ma n n O, Sc h mi dt P et al ( 2 0 1 1) Ti otr o pi u m is n o n i nferi or t o sal meter ol i n 
mai ntai ni n g  i m pr o ve d  l u n g  f u n cti o n  i n  B 1 6 -Ar g/ Ar g  p atie nts  wit h  ast h ma.  J  Aller g y  Cli n 
I m m u n ol 2 0 1 1; 1 2 8: 3 1 5- 2 2. 
Bea k es D E ( 1 9 9 7) T he use of a ntic h oli ner gics i n ast h ma. J Ast h ma 3 4 ( 5): 3 5 7- 3 6 8).  
Mas oli M, Fa bia n D, H olt S et  al ( 2 0 0 4). T h e gl o b al b ur de n of ast h ma: e x ec uti ve s u m mar y of 
t he  GI N A  Disse mi nati o n  C o m mittee  re p ort,  Gl o bal  I nitiati ve  f or  Ast h ma  ( GI N A)  Pr o gra m. 
A vaila ble fr o m GI N A w e bsite.  
Beasl e y R, La nier B, Var k o n yi I et al ( 2 0 1 2). Safet y of o n ce -d ail y Q M F 1 4 9 i n pa tie nts wit h 
persiste nt ast h ma. E ur Res pir J; 4 0 ( S u p pl 5 6).  
Beasl e y  R,  La nier  B,  M ar k  Z  et  al  ( 2 0 1 2 a). L o n g -ter m  efficac y  of  Q M F 1 4 9  i n  persiste nt 
ast h ma. E ur Res pir J; 4 0 ( S u p pl 5 6).  
Beasl e y  R. , D o n o h ue,  Ja mes  F,  Me hta  R  et  al  ( 2 0 1 5). Effect  of  o nce -dail y  i n dacater ol 
maleate/ m o metas o ne  f ur oate  o n  e x acer bati o n  ris k  i n  a d olesce nt  a n d  a d ult  ast h ma:  a  d o u ble -
bli n d ra n d o mise d c o ntr olle d trial; B MJ O pe n 5:e 0 0 6 1 3 1. d oi: 1 0. 1 1 3 6/ b mj o pe n- 2 0 1 4- 0 0 6 1 3 1 
Bef e ka d u E,  O n ofrei C, C olice G L ( 2 0 1 4) . Ti otr o pi u m i n ast h ma, a s yste mic re vie w.  J A A; 7: 
1 1- 2 1. 
Bra n n at h et al. Tri m me d wei g ht e d Si mes’ test f or t w o o ne -si de d h y p ot heses wit h ar bitraril y 
c orrel ate d test statistics. Bi o metrical J o ur nal 2 0 0 9; 5 1( 6): 8 8 5- 8 9 8 
Bretz F, Ma urer W, Bra n nat h W et al ( 2 0 0 9). A gra p hical a p pr oa c h t o se q ue ntiall y rejecti v e 
m ulti ple test pr oce d ures. Statistics i n Me dici ne; 2 8: 5 8 6 - 6 0 4. 
Bretz  F,  P osc h  M,  Gli m m  E , et  al  ( 2 0 1 1). Gra p hical  a p pr o ac hes  f or  m ulti ple  c o m paris o n 
pr oce d ur es  usi n g  w ei g hte d  B o nferr o ni,  Si mes,  or  para metric  tests.  Bi o m etrical  J o ur nal;  5 3: 
8 9 4- 9 1 3. 
C ha p ma n K R, Bee h K M, Beier J, et al. ( 2 0 1 4) A bli n de d e val uati o n of t he efficac y a n d safet y 
of  gl yc o p yrr o ni u m,  a  o nce -dail y  l o n g -acti n g  m uscari nic  a nta g o nist,  vers us  ti otr o pi u m,  i n 
patie nts wit h C O P D: t he G L O W 5 st u d y. B M C P ul m Me d. 2 0 1 4; 1 4: 4. 
A N O N ,  E ur o pea n  Me dici nes  A ge nc y  ( 2 0 1 3).  N ote  f or  g ui da n ce  o n  cli nical  i n vesti gati o n  of 
me dici nal pr o d ucts f or tr eat me nt of ast h ma. C H M P/ E W P/ 2 9 2 2/ 0 1-re v. 1. 2 7 J u ne 2 0 1 3. 
Far d o n  T,  H a g gart  K,  Lee  D K C  et  al  ( 2 0 0 7)  A  pr o of  of  c o n ce pt  st u d y  t o  e val uate  ste p pi n g 
d o w n t he d ose of fl uticas o ne  i n  c o m bi nati o n  wit h  sal meter ol  a n d  ti otr o pi u m  i n  se vere  
persiste nt  ast h ma. Res pirat or y Me dici ne; 1 0 1: 1 2 1 8- 1 2 2 8. 
Gl o bal  I nitiati ve  f or  Ast h ma  ( GI N A) 2 0 1 7 Gl o bal  Strate g y  f or  Ast h ma  Ma na ge me nt  a n d 
Pre ve nti o n ) htt p:// gi nast h ma. or g/ 2 0 1 7- gi na -re p ort-gl o b al -strate g y-f or-ast h ma-ma na ge me nt -
a n d- pre v e nti o n/ 
G u yer A C, L o n g A A ( 2 0 1 3) L o n g -acti n g a ntic h oli ner gi cs i n t he treat me nt of ast h ma. Aller g y 
Cli n I m m u n ol; 1 3: 3 9 2- 3 9 8 

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
J u ni per  E F,  G u yatt  G H,  Ferrie  PJ,  Griffit h  L E ( 1 9 9 3)  Meas uri n g  q ualit y  of  life  i n  ast h ma. 
A m Re v Res pir Dis.; 1 4 7( 4): 8 3 2- 8 
J u ni per E F, G u yatt G H, Ferrie PJ et al ( 1 9 9 4) D eter mi ni n g a mi ni mal i m p orta nt c ha n ge i n a 
disease -s pecific q ualit y of life q uesti o n naire. J Cli n E pi de mi ol; 4 7: 8 1- 8 7. 
J u ni per  E F,  O’ B yr n e  P M,  G u yatt  G H  et  al  ( 1 9 9 9)  De vel o p me nt  a n d  vali dati o n  of  t he 
q uesti o n naire t o meas ur e ast h ma c o ntr ol. E ur Res p J; 1 4: 9 0 2- 9 0 7. 
J u ni per E F, S ve nss o n K, M or k A C et al. Meas ure me nt pr o perties a n d i nt er pret ati o n of t hree 
s h orte ne d versi o ns of t h e ast h ma c o ntr ol q uesti o n naire. Res pir Me d 2 0 0 5; 9 9: 5 5 3- 8. 
J u ni per  E F,  B o us q u et  J,  A betz  L  et  al  ( 2 0 0 6)  I de ntif yi n g  ‘ well-c o ntr olle d’  a n d  ‘ n ot  w ell -
c o ntr olle d’ ast h ma usi n gt he Ast h ma C o ntr ol Q uesti o n naire. Res pir Me d; 1 0 0: 6 1 6- 2 1. 
Ke n war d M G, R o ger J H. S mall sa m pl e i nfere nce f or fi x e d effects fr o m restricte d ma xi m u m 
li keli h o o d. Bi o metrics 1 9 9 7; 5 3( 3): 9 8 3- 9 7. 
Kerstje ns    H A M,  Disse  B,  Sc hr o der -Ba b o,  W    et  al  ( 2 0 1 1)  Ti otr o pi u m    i m pr o ves    l u n g  
f u ncti o n    i n    patie nts    wit h    se vere  u nc o ntr olle d  ast h ma:  A  ra n d o mize d  c o ntr olle d  trial. J 
Aller g y Cli n I m m u n ol; 1 2 8: 3 0 8- 3 1 4. 
Kerstje ns H A M, E n gle M, Da hl  R, et al ( 2 0 1 2). Ti otr o pi u m i n Ast h ma P o orl y C o ntr olle d wit h 
Sta n dar d C o m bi nati o n T hera p y. N E n gl J Me d; 3 6 7: 1 1 9 8- 1 2 0 7 
Kerstje ns H A M, Casale T, Blec ker E, et al ( 2 0 1 5) Ti otr o p i u m or sal meter ol as a d d-o n t hera p y 
t o  i n hale d  c ortic oster oi ds  f or  patie nts  wit h  m o derate  s y m pt o matic  ast h ma:  t w o  re plicate, 
d o u ble- bli n d, place b o -c o ntr olle d, parallel -gr o u p, acti ve -c o m p arat or, ra n d o mise d trials. La ncet 
Res pir Me d. 3( 5): 3 6 7- 7 6 
Mas oli M et a l ( 2 0 0 4).  T he Gl o bal B ur de n of Ast h ma Re p ort, Gl o bal I nitiati ve f or Ast h ma 
( GI N A). htt p:// gi nast h ma. or g/ 2 0 1 7-gi n a -re p ort- gl o bal-strate g y-f or-ast h ma-ma na ge me nt -a n d-
pre ve nti o n/  
Peters  S P,    K u nsel ma n   J.,  Sicit o vic N et  al  ( 2 0 1 0)  Ti otr o pi u m  br o mi de  ste p -u p  t hera p y  f or 
a d ults wit h u nc o ntr olle d ast h ma. N E n gl J Me d; 3 6 3( 1 8): 1 7 1 5- 1 7 2 6. 
Q ua njer  P H.,  Ta m meli n g,  GJ,  C oites,J E  et  al. ( 1 9 9 3),  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 Part y Sta n d ar dizati o n of L u n g F u n cti o n Tests, E ur o pea n C o m m u nit y 
f or  Steel  a n d  C o al.  Official  State me nt  of  t he  E ur o pea n  Res pirat or y  S o ciet y.  E ur  Res pir  J;  6 
s u p pl. 1 6: 5- 4 0. 
R o h me yer K, Kli n gl m ueller  F,  a n d  B or n ka m p  B  ( 2 0 1 2).  Pac k a ge ‘ g M C P’  gra p h  bas e d 
m ulti ple c o m paris o n pr oce d ures: htt p://cra n.r- pr oj ect. or g/ we b/ pac ka ges/ g M C P/ g M C P. p df.  
Testi 2 0 1 4, W hite Pa per, L o n g Acti n g M uscari nic A ge nt ( L A M A). A ne w Fr o ntier f or C O P D  
a n d Ast h ma Treat me nt. A vaila ble o n w w w. cr o ms o urce.c o m   
Vai d ya  S,  K hi n dri  S,  R o berts o n  J , et  al  ( 2 0 1 2)  P har mac o ki netics  ( P K)  of  si n gl e  d oses  of 
m o metas o ne  f ur oat e  ( M F)  deli vere d  via  t he  Breez haler ®  ( B H)  a n d  T wist haler ®  de vices  i n 
healt h y s u bjects. E ur Res pir J; 4 0 ( S u p pl 5 6): P 3 8 2. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 3  
A p p e n di x 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 
a n d F oll o w -u p R e q u ir 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  
LI V E R L A B O R A T O R Y T RI G G E R S  
•  
3 x U L N < A L T / A S T ≤ 5 x U L N  
•  
1. 5 x U L N < T B L ≤ 2 x U L N  
LI V E R E V E N T S  
•  
A L T or A S T > 5 × U L N  
 
•  
A L P > 2 × U L N (i n t h e a b s e n c e of k n o w n b o n e p at h ol o g y)  
 
•  
T B L > 2 × U L N (i n t h e a b s e n c e of k n o w n Gil b ert s y n dr o m e)  
 
•  
A L T or A S T > 3 × U L N a n d I N R > 1. 5  
 
•  
P ot e nti al H y’ s  L a w c a s e s ( d efi n e d a s A L T or A S T > 3 × U L N a n d 
T B L > 2 × U L N [ m ai nl y c o nj u g at e d fr a cti o n] wit h o ut n ot a bl e 
i n cr e a s e i n A L P t o > 2 × U L N) 
 
•  
A n y cli ni c al e v e nt of j a u n di c e ( or e q ui v al e nt t er m)  
 
•  
A L T or A S T > 3 × U L N a c c o m p a ni e d b y ( g e n er al) m al ai s e, f ati g u e,  
a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h e o si n o p hili a  
 
•  
A n y a d v er s e e v e nt p ot e nti all y i n di c ati v e of a li v er t o xi cit y*  
* T h e s e e v e nt s c o v er t h e f oll o wi n g: h e p ati c f ail ur e, fi br o si s a n d cirr h o si s, a n d ot h er li v er d a m a g e-r el at e d 
c o n diti o n s; t h e n o n -i nf e cti o u s h e p atiti s; t h e b e ni g n, m ali g n a nt a n d u n s p e cifi e d li v er n e o pl a s m s 
T B L: t ot al bilir u bi n; U L N: u p p er li mit of n or m al  
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 dr u 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  
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 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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  
> 3 × U L N 
a c c o m p a ni e d b y 
s y m pt o m s b  
•  
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 pt 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 
dr u g i m m e di at el y  
•  
H o s pit ali z e if cli ni c all y a p pr o pri a t 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 pt 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 err u pti o n or 
di s c o nti n u ati o n  
•  
H o s pit ali z ati o n if cli ni c all y a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
•  
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 
a El e v at e d A L T/ A S T > 3 × U L N a n d T B L > 2 × U L N b ut wit h o ut n ot a bl e i n cr e a s e i n A L P t o > 2 × U L N  
b ( G e n er al) m al ai s e, f ati g u e, a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h e o si n o p hili a  
cR e s ol uti o n  i s d efi n e d a s a n o ut c o m e of o n e of t h e f oll o wi n g: ( 1) r et ur n t o b a s eli n e v al u e s, ( 2) st a bl e v al u e s at 
t hr e e s u b s e q u e nt m o nit ori n g vi sit s at l e a st 2 w e e k s a p art, ( 3) r e m ai n at el e v at e d l e v el aft er a m a xi m u m of 6 
m o nt h s, ( 4) li v er tr a n s pl a nt ati o n, a n d ( 5) d e at h.  
 
 
 
 
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 7 8  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 me nt  
S pir o meters  m ust  meet  t he  s pecificati o ns  a n d  perf or m a nce  criteria  rec o m me n de d  i n  t h e 
A merica n  T h or acic  S oci et y  ( A T S)/ E ur o pea n  Res pirat or y  S ociet y  ( E R S)  Sta n dar dizati o n  of 
S pir o metr y 1. S pir o meters m ust ha ve t he ca pacit y t o 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 m et h o d esta blis he d b y t h e ma n ufact urer. 
C ali br ati o n 
T he s pir o meter s h o ul d b e cali brat e d e ver y m or ni n g bef ore a n y s pir o metri c 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.  
Pre p ari n g t he test s u bject  
O n st u d y da ys w h e n s pir o metr y will be p erf 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 ol ate, c ola a n d ot her caffei ne -c o ntai ni n g be v era ges a n d f o o ds a n d ice-
c ol d be ver a 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 y nc o p e.  W he n p ossi bl e, s pir o metr y s h o ul d be  c o n d ucte d  b y t h e  sa me t ec 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 vari ati 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 m e ti me of da y at eac h visit.  
Perf or mi n g S pir o metr y  
T he s u bject’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 m eter.  It is i m p orta nt t hat 
t he  hei g ht  is  meas ure d  acc ur atel y  at  t he  st u d y  site.  S pir o metr y,  a n  eff ort-de pe n d e nt  test, 
re q uires  caref ul  i nstr ucti o n  a n d  c o o perati o n  of  t he  s u bject.    T he  tec h nicia n  s h o ul d  e ns ure  a 
g o o d  s eal  ar o u n d  t he  m o ut h piece,  a n d  c o nfir m  t hat  t he  s u bject’s  p ost ure  is  c orrect.  T h e 
s u bject 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 b e 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 x erti o n of ma xi mal eff ort. T he res ults of s pir o metr y s h o ul d meet t he A T S/ E R S criteria 
f or acce pta bilit y a n d re p eata bilit y. Acce pta bilit y criteria s h o ul d be a p plie d bef ore re peat a bilit y 
is deter mi ne d.   
N u m ber of tri als  
A mi ni m u m of 3 acce pta ble f orce d vital ca pacit y ( F V C) ma n e u vers s h o ul d be perf or me d. If a 
s u bject  is  u na bl e  t o  p erf or m  a  si n gle  acce pt a ble  ma ne u ver  aft er  8  atte m pts,  testi n g  m a y  b e 
disc o nti n ue d.  
Acce pt a bilit y  
A n acce pta ble ma n e u ver ha s t he f oll o wi n g c haract eristics:  

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C o nfi d e nti al  
P a g e 7 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
•  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 ur e 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 ni m u m e x halati o n ti me  of 6 sec o n ds is 
rec o m me n de d, a n d n o v ol u me c ha n ge f or at least 1 sec o n d), or t h e s u bject ca n n ot 
c o nti n ue t o e x hale f urt her. O verall acce pta bilit y will be deter mi ne d b y e x pert o ver-
rea d b y s pir o metr y v e n d or 
Re pe at a bilit y  
T he  2  lar gest  F E V 1  val ues  fr o m  3  ac ce pta ble  ma ne u vers  s h o ul d  n ot  v ar y  b y  m ore  t ha n 
0. 1 5 0 L.  
Rec 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 bl e  c ur ves  are  rec or de d.  ( T he  hi g h est 
F E V 1  a n d F V C ma y n ot necessaril y res ult fr o m t h e sa me acce pt a ble c ur v e).  
Pre dicte d n or m al  
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  f or  C oal  a n d  Steel 2,  N ha nes3,  E R S  Gl o bal  L u n g  F u n cti o n  I nitiati ve  ( G LI)2  or 
J a pa nese Res pirat or y S ociet y3.  
Re versi bilit y  
All re versi bilit y e v al 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 
A d mi nister 4 0 0 µ g of sal b uta m ol  3 6 0 µ g al b uter ol t hr o u g h a s pacer f oll o wi n g t he c o m pleti o n 
of  t he  baseli ne  assess m e nt.  A  sec o n d  s pir o metr y  assess me nt  is  t he n  perf or me d  1 5  t o  3 0 
mi n utes after a d mi nistrati o n of t he sal b u mat ol/al b uter ol.  
Re versi bilit y is calc ulat e d as:  
1 0 0 x        F E V 1 ( p ost β2 -a g o nists) – F E V 1  ( bas eli ne) 
                                     F E V 1  ( baseli ne) 
S u bjects  will  be  c o nsi dere d  re versi ble  if  a n  i n creas e  of  at  least  1 2 %  (a n d  2 0 0  m L)  is 
de m o nstrate d aft er a d mi nistrati o n of t he br o nc h o dilat or.  
R ef er e n c e s  
1 Miller M R et al, Sta n dar dizati o n of L u n g F u n cti o n Testi n g. E ur Res p J 2 0 0 5; 2 6: 1 5 3- 1 6 1. 
2 Q ua njer  P H  et  al. E R S  Gl o bal  L u n g  F u ncti o n  I nitiati ve. M ulti  et h nic  refere n ce  val ues  f or 
s pir o metr y f or t he 3-9 5 year a ge r a n ge: t he gl o b al l u n g f u ncti o n 2 0 1 2 e q uati o ns. Re p ort of t he 
Gl o bal L u n g F u n cti o n I nitiati ve ( G LI). E R S Tas k F orce t o esta blis h i m pr o ve d L u n g F u n cti o n 
Refere n ce V al ues.  
3K u b ota,  K o b a yas hi,  Q ua njer  P H,  et  al.  Refere nce  val ues  f or  s pir o metr y,  i ncl u di n g  vital 
ca pacit y,  i n  J a pa n ese  a d ults  calc ulate d  wi t h  t he  L M S  met h o d  a n d  c o m p are d  wit h  pre vi o us 

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C o nfi d e nti al  
P a g e 8 0  
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    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
val ues.  Cli nical  P ul m o nar y  F u n cti o ns  C o m mittee  of  t he  J a pa nese  R es pirat or y  S ociet y.   
Res pirat or y I n vesti gati o ns 2 0 1 4: 2 4 2- 2 5 0.    

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C o nfi d e nti al  
P a g e 8 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 5  A p p e n di x 3:  I n str u cti o n f or U s e of C o n c e pt 1 
 
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 dr u g c o ntai ne d 
wit hi n t he ca ps ules b y i n halati o n usi n g t h e i n haler. If y o u ha ve a n y q u esti o ns, please as k t h e 
d oct or or n urse at t he st u d y ce nter.  
 
Y o ur i n h aler a n d c a ps ules  
T he  st u d y  dr u g  pac k a ge  c o nsists  of  b ot h  t he  i n haler  a n d  o ne  or  m ore  blister -pac k a ge d 
ca ps ules.  
•  Ca ps ules are s u p plie d i n blisters. 
•  I n h aler c o nsists of a ca p, m o ut h piece a n d a b ase. 
 
 
Y o ur i n haler is desi g ne d t o deli ver t he me dici ne c o ntai ne d wit hi n t he ca ps ules. 
D o n ot use t he st u d y me dicati o n ca ps ules wit h a n y ot her ca ps ul e i n haler, a n d d o n ot use t he 
i n haler t o ta ke a n y ot h er ca ps ule me dici ne. 
H o w t o use y o ur i n h aler  
 
P ull off c a p.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 
O pe n i n h aler:  
H ol d  t he  base  of  t he  i n haler  fir ml y  a n d  tilt  bac k  t he 
m o ut h piece.  T his o pe ns t he i n haler. 
 
Pre p are c a ps ule:  
I m me diat el y  b ef ore  use,  wit h  dr y  ha n ds,  s e parat e  o ne  of  t he 
blisters fr o m t he blister car d b y teari n g al o n g t he perf orati o ns 
a n d lift t he c or ner of t he f oil. 
 
Re m o ve a c a ps ule:  
Peel a wa y t he f oil a n d re m o ve t he ca ps ule fr o m t he blister.  
 
I nsert c a ps ule: 
Place t he ca ps ule i nt o t he ca ps ule c h a m ber.  
Ne ver pl ace a c a ps ule directl y i nt o t he m o ut h piece.  
 
Cl ose t he i n h aler:  
Y o u s h o ul d hear a “ clic k” as t h e m o ut h piece cl oses o nt o t he 
i n haler base. 

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C o nfi d e nti al  
P a g e 8 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 
Pierce t he c a ps ule:  
•  H ol d t he i n haler u pri g ht wit h t he m o ut h piece p oi nti n g u p. 
•  Pierce t he ca ps ule b y fir ml y pressi n g t o get her b ot h si de 
b utt o ns at t he sa me ti me. D o t his o nl y o nce.  
•  Y o u s h o ul d hear a “clic k ” as t he ca ps ule  is bei n g pierce d. 
 
Rele ase t he si de b utt o ns f ull y.  
 
Bre at he o ut:  
Bef ore  placi n g  t he  m o ut h piece  i n  y o ur  m o ut h,  breat he  o ut 
f ull y. 
D o n ot bl o w i nt o t he m o ut h piece.  
 
I n h ale t he me dici ne 
T o breat he t h e me dici ne dee pl y i nt o y o ur air w a ys: 
•  H ol d t he i n haler as s h o w n i n t he pict ure. T he si de b utt o ns 
s h o ul d be faci n g left a n d ri g ht. D o n ot press t he si de 
b utt o ns. 
•  Place t he m o ut h piece i n y o ur m o ut h a n d cl ose y o ur li ps 
fir ml y ar o u n d it. 
•  Breat he i n ra pi dl y b ut stea dil y a n d as dee pl y as y o u ca n.  
 
N ote:  
As  y o u breat he  i n  t hr o u g h  t he  i n haler,  t he  ca ps ule  s pi ns 
ar o u n d i n t he c ha m ber a n d y o u s h o ul d hear a w hirri n g n oise. 
Y o u will e x perie nce a s weet fla v or as t he me dici ne g oes i nt o 
y o ur l u n gs. 
A d diti o nal i nf or mati o n  
Occasi o nall y, ver y s mall pieces of t he ca ps ule ca n  get past t he 
scree n a n d e nter y o ur m o ut h. If t his ha p pe ns, y o u ma y b e a bl e 
t o feel t hese pieces o n y o ur t o n g u e. It is n ot har mf ul if t hese 

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C o nfi d e nti al  
P a g e 8 4  
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    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
pieces  are  s w all o we d.  T he  c ha n ces  of  t he  ca ps ule  brea k a ge 
will  be  i ncrease d  if  t he  ca ps ule  is  acci de ntall y  pierce d  m ore 
t ha n  o nce  (ste p 7).   T h eref ore  it  is  rec o m me n d e d  t hat  y o u 
f oll o w  t he  st ora ge  directi o ns,  re m o ve  t he  ca ps ule  fr o m  t he 
blister  i m me diatel y  bef ore  use  a n d  pierce  eac h  ca ps ule  o nl y 
o nce.  
If y o u d o n ot hear a w hirri n g n oise: 
T he  ca ps ule  ma y  b e  st uc k  i n  t he ca ps ule  c ha m ber.  If  t his 
ha p pe ns: 
•  O pe n t he i n haler a n d caref ull y l o ose n t h e ca ps ule b y 
ta p pi n g t he b ase of t he i n haler. D o n ot press t he si de 
b utt o ns. 
•  I n h ale t he me dici n e a gai n b y re peati n g ste ps 9 t o 1 1.  
 
H ol d bre at h:  
After y o u ha v e i n hale d t h e me dici ne : 
•  H ol d y o ur breat h f or at least 5- 1 0 sec o n ds or as l o n g as 
y o u c o mf orta bl y ca n w hile ta ki n g t he i n h aler o ut of y o ur 
m o ut h. 
•  T he n breat he o ut. 
•  O pe n t he i n haler t o s ee if a n y p o w der is left i n t he 
ca ps ule.  
If t here is p o w der left i n t he c a ps ule: 
•  Cl ose t he i n haler.  
•  Re peat ste ps  9, 1 0, 1 1 a n d 1 2. 
M ost  pe o ple  are  a ble  t o  e m pt y  t h e  ca ps ule  wit h  o ne  or  t w o 
i n halati o ns. 
A d diti o n al i nf or m ati o n 
S o me  pe o ple  ma y o ccasi o nall y c o u g h  briefl y s o o n after 
i n hali n g t he me dici ne. If y o u d o, d o n’t w orr y. As l o n g as t he 
ca ps ule is e m pt y, y o u ha ve recei ve d y o ur m e dici n e. 
 
 
After y o u h a ve fi nis he d t a ki n g y o ur me dici ne:  
•  Y o u ma y b e directe d b y y o ur p h ysici a n t o ri nse m o ut h 
wit h water a n d s pit it o ut; d o n ot s wall o w t he water.  
•  O pe n t he m o ut h piece a gai n, a n d re m o ve t he e m pt y 
ca ps ule b y ti p pi n g it o ut of t he ca ps ule c ha m ber. P ut t he 
e m pt y ca ps ule i n y o ur h o use h ol d waste. 
•  Cl ose t he i n haler a n d re place t he ca p.  
D o n ot st ore t he c a ps ules i n t he i n h aler.  

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C o nfi d e nti al  
P a g e 8 5  
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    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 
R E M E M B E R:  
•  D o n ot s w all o w c a ps ules. 
•  O nl y use t h e i n haler c o ntai ne d i n t his pac k.  
•  Ca ps ules m ust al wa ys b e st ore d i n t he blister, a n d o nl y re m o v e d i m me diatel y bef ore use. 
•  Ne ver place a ca ps ul e dir ectl y i nt o t he m o ut h piece of t he  i n haler. 
•  D o n ot press t he si de b utt o ns m ore t ha n o nce. 
•  Ne ver bl o w i nt o t he m o ut h piece of t he i n hal er. 
•  Al wa ys release t he p us h b utt o ns bef ore i n halati o n. 
•  Ne ver was h t he i n haler wit h water. Kee p it dr y. See “ H o w t o cl ea n y o ur i n h aler”.  
•  Ne ver ta k e t he i n haler a p art.  
•  T he i n haler s h o ul d be us e d f or a m a xi m u m of 3 0 da ys, t he n re place d wit h a ne w i n haler 
•  Al wa ys use  t he ne w i n haler t hat c o mes wit h y o ur ne w me dicati o n pac k.  
•  D o n ot st ore t he ca ps ules i n t he i n haler. 
•  Al wa ys kee p t h e i n haler a n d ca ps ules i n a dr y place, a n d a v oi d ver y h ot or c ol d 
te m perat ur es. 
H o w t o cle a n y o ur i n h aler 
•  Clea n y o ur i n haler o n ce a wee k.  
•  Wi pe t he m o ut h piece i nsi de a n d o utsi de t o re m o v e a n y p o w der wit h a clea n, dr y li nt- free 
cl ot h. 
•  D o n ot was h y o ur i n haler wit h water. K ee p it dr y. 
•  D o n ot ta ke t he i n haler a part. 
 
 
1 6  A p p e n di x 4:  I n str u cti o n f or U s e  of A c c u h al er ® / Di s k u s® 
 
I n str u cti o n s f or u s e 
F ol l o w t he i nstr ucti o ns b el o w f or usi n g y o ur A cc u haler ®  i n h alati o n de vice. Y o u will bre at he 
i n  (i n h ale)  t he  me dici ne  f r o m  t he Acc u h aler ® . D o  n ot  use  t he A cc u haler ®  u nless  y o ur 
healt hcare pr o vi der has t a u g ht y o u, a n d y o u u n dersta n d e ver yt hi n g. If y o u ha ve a n y q u esti o ns, 
as k t he d oct or, n urs e or p har macist pers o n n el at t h e st u d y 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Fi g ur e 1  
P art s of t h e A c c u h al er ®  
  
Ta ke t he Acc u h aler ®  o ut of t he me dicati o n pac k gi ve n t o y o u. T he A cc u h aler ®  will be i n t he 
cl ose d p ositi o n. T he d ose i n dic at or  o n t he t o p of t he Acc u haler ®  tells y o u h o w ma n y d oses 
are  left.  T h e  d ose  i n dicat or  n u m ber  will  decrease  eac h  ti me  y o u  use  t he Acc u haler ® .  After 
y o u h a ve us e d 5 5 d os es fr o m t he A cc u h aler ® , t h e n u m bers 5 t o 0 will a p pear i n re d t o war n 
y o u t hat t her e are o nl y a fe w d oses left (see Fi g ure 2).  
Fi g ur e 2  
D o s e I n di c at or f or t h e A c c u h al er ®   
 
 
Ta ki n g a d ose fr o m t he Acc u hal er ®  re q uires t he f oll o wi n g 3 ste ps: O pe n, Clic k, I n hal e. 
1. O P E N 
H ol d t he A cc u hal er ®  i n o ne ha n d a n d p ut t he t h u m b of y o ur ot her h a n d o n t he t h um b gri p.   
P us h y o ur t h u m b a w a y fr o m y o u as far as it will g o u ntil t he m o ut h piece a p pears a n d s na ps 
i nt o p ositi o n (see Fi g ure 3). 

N o v arti s  
C o nfi d e nti al  
P a g e 8 7  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Fi g ur e 3  
O p e ni n g t h e M o ut h pi e c e C o v er  
 
2. C LI C K  
H ol d t he A cc u h aler ®  i n a le vel, flat p ositi o n wit h t he m o ut h piece t o war ds y o u. Sli de t he le v er 
a wa y fr o m y o u as f ar as it will g o u ntil it clic ks (see Fi g ure 4). T he A cc u haler ®  is n o w rea d y 
t o use.  
Fi g ur e 4  
Sli di n g t h e L e v er U ntil It Cli c k s  
 
E ver y  ti me  t he le v er is  p us he d  bac k,  a  d os e  is  rea d y  t o  b e  i n hale d.  T his  is  s h o w n  b y  a 
dec rease  i n  n u m b ers  o n  t he  d ose  c o u nter. T o  a v oi d  rele asi n g  or  w asti n g  d oses  o nce  t he 
Acc u h aler ®  is re a d y: 
•  D o n ot cl ose t he Acc u hal er ® . 
•  D o n ot tilt t he Acc u haler ® . 
•  D o n ot pla y wit h t he le v er. 
•  D o n ot m o ve t he le ver m ore t ha n o nce. 
3. I N H A L E  
Bef ore i n hali n g y o ur d os e fr o m t he Acc u haler ® , breat he o ut (e x hale) f ull y w hile h ol di n g t he 
Acc u hal er ®  le v el a n d a wa y fr o m y o ur m o ut h (s ee Fi g ure 5). Re me m ber, ne ver bre at he o ut 
i nt o t he Acc u h aler ®  m o ut h piece.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 8  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Fi g ur e 5  
E x h ali n g  
 
P ut  t he  m o ut h piece  t o  y o ur  li ps  (see  Fi g ure  6).  Breat he  i n  q uic kl y  a n d  dee pl y  t hr o u g h  t h e 
Acc u hal er ® . D o n ot br eat he i n t hr o u g h y o ur n os e. 
Fi g ur e 6  
I n h ali n g 
 
Re m o ve t he Acc u h aler ®  fr o m y o ur m o ut h. H ol d y o ur breat h f or a b o ut 1 0 sec o n ds, or f or as 
l o n g as is c o mf orta ble. Breat he o ut sl o wl y. T he A cc u haler ®  deli vers y o ur d ose of me dici ne as 
a ver y fi ne p o w der. M ost patie nts ca n taste or feel t he p o w der. D o n ot use a n ot her d ose fr o m 
t he Acc u h aler ®  if y o u d o n ot feel or taste t he m e dici ne. 
4. C L O S E 
Cl ose t he Acc u h aler ®  w he n y o u are fi nis he d t a ki n g a d ose s o t h at t he Acc u h aler ®  will 
be  re a d y  f or  y o u  t o  t a ke  y o ur  ne xt  d ose. P ut  y o ur  t h u m b  o n  t he  t h u m b gri p  a n d  sli de  t he 
t h u m b gri p  bac k  t o war ds  y o u  as  far  as  it  will  g o  (see  Fi g ure  7).  T he Acc u haler ®  will  clic k 
s h ut. T he le ver will a ut o maticall y r et ur n t o its ori gi nal p ositi o n. T he A cc u haler ®  is n o w rea d y 
f or y o u t o ta ke y o ur n e xt sc he d ule d d ose, d ue i n a b o ut 1 2 h o urs. ( Re peat ste ps 1 t o 4 at t hat 
ti me). 

N o v arti s  
C o nfi d e nti al  
P a g e 8 9  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
Fi g ur e 7  
Cl o si n g t h e M o ut h pi e c e C o v er  
 
Re me m b er:  
•  Ne ver breat h e i nt o t he A cc u haler ® . 
•  Ne ver ta k e t he A cc u hal er ®  a part.  
•  Al wa ys rea d y a n d use t h e Acc u h aler ®  i n a l e vel, flat p ositi o n. 
•  D o n ot use t he Acc u haler ®  wit h a s pacer de vice.  
•  Ne ver was h t he m o ut h piece or a n y part of t he Acc u haler ® . Kee p it dr y.  
•  Al wa ys kee p t h e Acc u haler ®  i n a dr y place. 
•  Ne ver ta k e a n e xtra d ose, e ve n if y o u di d n ot taste or feel t he m e dici ne.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 9 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 7  A p p e n di x 5:  I n str u cti o n s f or U s e of t h e R e s pi m at ®  
 
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 9 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 
 
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 9 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 

N o v arti s  
C o nfi d e nti al  
P a g e 9 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
1 9  A p p e n di x 7: A Q L Q - S 
( T he s a m pl e pr ovi de d h ere is f or ill ustr ative p ur p oses o nly) 
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 9 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 9 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 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 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 
2 0  A p p e n di x 8: A C Q - 7 
( T he s a m pl e pr ovi de d h ere is f or ill ustr ative p ur p oses o nly) 
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 2  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
 
 
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q V M 1 4 9 B 2 3 0 6                      
 
2 2  A p p e n di x 1 0: L o w, m e di u m a n d hi g h D ail y D o s e s of I n h al e d 
Gl u c o c orti c o st er oi d s f or A d ult s 1  
 
Dr u g  
T ot al D ail y D o s e ( µ g/ d a y)  
L o w  
M e di u m  
Hi g h  
B e cl o m et h a s o n e di pr o pi o n at e –  C F C 2 
2 0 0 -5 0 0  
> 5 0 0 –  1 0 0 0  
> 1 0 0 0  
B e cl o m et h a s o n e di pr o pi o n at e – H F A  
1 0 0 -2 0 0  
> 2 0 0 – 4 0 0  
> 4 0 0  
B u d e s o ni d e - D PI  
2 0 0 -4 0 0  
> 4 0 0 –  8 0 0  
> 8 0 0  
Ci cl e s o ni d e – H F A  
8 0 -1 6 0  
> 1 6 0 – 3 2 0  
> 3 2 0  
Fl uti c a s o n e F ur o at e – D PI 3  
N A  
1 0 0  
2 0 0  
Fl uti c a s o n e pr o pi o n at e – D PI  
1 0 0 -2 5 0  
> 2 5 0 – 5 0 0  
> 5 0 0  
Fl uti c a s o n e pr o pi o n at e – H F A  
1 0 0 -2 5 0  
> 2 5 0 – 5 0 0  
> 5 0 0  
M o m et a s o n e f ur o at e  
1 1 0 -2 2 0  
> 2 2 0 -4 4 0  
≥ 4 4 0  
Tri a m ci n ol o n e a c et o ni d e  
4 0 0 -1 0 0 0  
> 1 0 0 0 –  2 0 0 0  
> 2 0 0 0  
1, 3  C at e g ori e s  b a s e d o n GI N A 2 0 1 7  wit h e x c e pti o n of Fl uti c a s o n e F ur o at e w hi c h i s b a s e d o n t h e S u m m ar y of Pr o d u ct 
C h ar a ct eri sti c s of R el v ar ® Elli pt a ®  
2 B e cl o m et h a s o n e di pr o pi o n at e C F C i s i n cl u d e d f or c o m p ari s o n wit h ol d er lit er at ur e.  
C F C: c hl or ofl u or o c ar b o n pr o p ell a nt; D PI: dr y p o w d er i n h al er; H F A: h y dr ofl u or o al k a n e pr o p ell a nt.