Clinical trial NCT03158311
Conditions: Asthma
Keywords: QVM149 Asthma Moderate Asthma Severe Asthma ICS/LABA/LAMA ICS/LABA LAMA Adult
Sponsor: Novartis Pharmaceuticals
Start date: 2018-02-05; Completion date: 2019-07-19
Enrollment: 1426 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial was to demonstrate that the efficacy of two treatment arms of the fixed-dose combination product QVM149 was non-inferior to the efficacy of the free combination arm of salmeterol/ fluticasone+ tiotropium in uncontrolled moderate to severe asthmatic patients.

The planned duration of treatment in this study was 24 weeks, followed up by a 7-day follow-up period.

Detailed description:
This study used a randomized, partially-blinded, 24-week, parallel-group, non-inferiority, open-label active controlled design. The study was partially open-label. Investigators and patients had knowledge of treatment allocation between QVM149 and/or comparator, however the QVM149 strength allocation was masked. The global sponsor team responsible for data review and analysis was blinded to all treatment allocations The study consisted of a screening period of up to 1-week, run-in period of 2-weeks, randomized treatment period of 24-weeks, and a follow-up period of 1-week.

At the screening visit, informed consent was obtained, and current and prohibited medications were reviewed. Rescue medication was provided to all patients who met the eligibility criteria and was to be used on an "as needed" basis throughout the study.

At the run-in visit, inclusion and exclusion criteria were reviewed and the patients were supplied with open-label long acting β2-adrenergic agonist/inhaled corticosteroids (LABA/ICS) salmeterol/fluticasone 50/250 μg b.i.d or 50/500 μg b.i.d to match their ICS background medication dose to be stopped at randomization visit.

All patients who met the eligibility criteria were randomized to 1 of 3 treatment arms with a randomization ratio of 1:1:1. The patients were stratified at randomization according to the ICS dose component of background ICS/LABA (medium or high dose) and region.

Treatment period visits were scheduled every 8 weeks. The study used two doses of QVM149 (high dose \[150/50/160 μg\] and a medium dose \[150/50/80 μg\] o.d. delivered via Concept1 inhaler) and a comparator treatment (salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d delivered via Respimat®).

All randomized patients were contacted (by telephone) 7 days following the last dose of study medication or last visit, whichever was later, for Safety Follow-up visit.

Arms: arm 1: QVM149 150/50/80 μg o.d. delivered via Concept1 arm 2: QVM149 150/50/160 μg o.d. delivered via Concept1 arm 3: Salmeterol/fluticasone 50/500 μg b.i.d. delivered via Accuhaler® plus tiotropium 5 μg o.d. delivered via Respimat®
Interventions: intervention 1: QVM149 intervention 2: Salmeterol/fluticasone plus tiotropium
Intervention descriptions: intervention 1: Indacaterol acetate / glycopyrronium bromide / mometasone furoate intervention 2: Free triple arm of salmeterol / fluticasone plus tiotropium

Protocol documents:
Prot_000.pdf: 


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


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


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


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


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


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


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


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


N o v arti s  
C o nfi d e nti al  
P a g e 8 0  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q 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.    


N o v arti s  
C o nfi d e nti al  
P a g e 8 1  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q 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. 


N o v arti s  
C o nfi d e nti al  
P a g e 8 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q 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 


N o v arti s  
C o nfi d e nti al  
P a g e 8 4  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q 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.  


N o v arti s  
C o nfi d e nti al  
P a g e 8 5  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q 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  
P a g e 8 6  
A m e n d e d Pr ot o c ol V er si o n v 0 2/ Cl e a n  
 
    Pr ot o c ol N o.  C Q 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
09-
May-
2017 
Prior 
to 
DB 
lock 
Creation 
of 
draft version 
N/A- First version 
 
14-
Jun-
2017 
Prior 
to 
DB 
lock 
Addressed 
the reviewers 
comments on 
first draft 
version 
Draft- Second version 
2.2.1, 2.3.2, 
2.7.1.1, 2.11.4, 
2.11.5, 2.11.6, 
2.1.1.1, 2.5.3.1 , 
2.6.1, 2.6.2, 
2.11.1, 2.11.4,   
27-
Jun-
2017 
Prior 
to 
DB 
lock 
To make it 
final draft 
version 
Final draft version 
 
14-
Aug-
2017 
Prior 
to 
DB 
lock 
As per 
protocol 
amendment 
1 and 
addressed 
reviewers 
comments 
Final draft version 1.0 
1.1, 1.2.1, 2.5.3 
…. 
Prior 
to 
DB 
lock 
As 
per 
protocol 
amendment 2 
and 
addressed 
reviewers 
comments 
Final draft version 2.0 
 
12-
Sep-
2019 
Prior 
to 
DB 
lock 
As per 
discussion 
with German 
HA team, 
consideration 
of estimand 
and update 
on the 
definitions 
for baseline 
Amendment draft version 1.0 
1.2, 2.5.4, 2.6.1, 
2.6.2, 4 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
and other 
secondary/ 
 
analysis  
17-
Sep-
19 
Prior 
to 
DB 
lock 
Update 
notable 
criteria for 
ECG 
Final Amendment version 2 
5.5 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
1.2.1 
Study Objectives and Endpoints ............................................................. 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 14 
2.2.1 
Subgroup of interest .............................................................................. 15 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 15 
2.3.1 
Patient disposition ................................................................................. 15 
2.3.2 
Patient demographics and baseline characteristics ............................... 15 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 17 
2.5 
Analysis of the primary and key secondary variable ............................................. 17 
2.5.1 
Primary variable .................................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Estimand Analysis ................................................................................. 19 
2.5.4 
Handling of missing values/censoring/discontinuations ....................... 19 
2.5.5 
Supportive and Sensitivity analyses ...................................................... 19 
2.5.6 
Multiplicity adjustment ......................................................................... 20 
2.6 
Analysis of secondary efficacy objective(s) .......................................................... 21 
2.6.1 
AQLQ Score, domains, and responders at each visit ............................ 21 
2.6.2 
ACQ-7 Score and responders at each visit ............................................ 21 
2.6.3 
Spirometry data at each visit ................................................................. 22 
2.7 
Safety analyses ....................................................................................................... 23 
2.7.1 
Adverse events (AEs) ............................................................................ 23 
2.7.2 
Deaths .................................................................................................... 25 
2.7.3 
Serious asthma outcomes ...................................................................... 25 
2.7.4 
Laboratory data ..................................................................................... 25 
2.7.5 
Other safety data ................................................................................... 26 
2.8 
Pharmacokinetic endpoints .................................................................................... 27 


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2.9 
PD and PK/PD analyses......................................................................................... 27 
2.10 
Biomarkers ............................................................................................................. 27 
 
 28 
 
 28 
 
 28 
 
 29 
 
 29 
 
 30 
 
 31 
 
 31 
2.12 
Additional analysis ................................................................................................ 31 
2.13 
Interim analysis ...................................................................................................... 31 
3 
Sample size calculation ..................................................................................................... 32 
4 
Change to protocol specified analyses .............................................................................. 32 
5 
Appendix ........................................................................................................................... 32 
5.1 
Imputation rules ..................................................................................................... 32 
5.1.1 
Study drug ............................................................................................. 32 
5.1.2 
AE date imputation ............................................................................... 32 
5.1.3 
Concomitant medication date imputation ............................................. 32 
5.2 
AEs and Concomitant medications coding/grading .............................................. 33 
5.3 
Data pooling and assessment windows .................................................................. 33 
5.4 
Time Windows ....................................................................................................... 33 
5.5 
Laboratory parameters derivations ........................................................................ 34 
5.6 
Vital signs and ECG – definition of clinically notable values ............................... 35 
5.7 
Statistical methodology and assumptions .............................................................. 36 
5.7.1 
Mixed Model Repeated Measures (MMRM) ........................................ 36 
5.7.2 
Logistic Regression Model via GEE ..................................................... 36 
5.7.3 
ANCOVA Model .................................................................................. 37 
5.7.4 
Cox Regression Model .......................................................................... 37 
5.7.5 
Generalized Linear Model assuming a Negative Binomial 
Distribution ........................................................................................... 37 
5.8 
Rule of exclusion criteria of analysis sets.............................................................. 37 
5.8.1 
Major protocol deviations and other exclusion criteria ......................... 37 
5.9 
Rules to exclude patients using single depot corticosteriod injections: ................ 39 
6 
References ......................................................................................................................... 40 


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List of abbreviations 
ACQ-7 
Asthma Control Questionnaire-7 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AQLQ 
Asthma Quality of Life Questionnaire 
AST 
Aspartate Aminotransferase 
b.i.d 
twice a day 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CM 
Concomitant Medication 
CRF 
Case Report/Record Form (paper or electronic) 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eDiary 
Electronic Diary 
FAS 
Full analysis set 
FEF 
Forced Expiratory Flow 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
GEE 
Generalized Estimating Equation 
GLY 
Glycopyrronium Bromide 
HTA 
Health Technology Assessment 
ICS 
Inhaled Corticosteroid 
IND 
Indacaterol Acetate 
LABA 
Long Acting Beta-2 Agonist 
LFT 
Liver Function Test 
LS 
Least Square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Mometasone Furoate 
MID 
Minimal Important Difference 
MMRM 
Mixed Model for Repeated Measurements 
o.d. 
Once a day 
PD 
Pharmacodynamics 
PEF 
Peak Expiratory Flow 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PT 
Preferred Term  
QTc 
Corrected QT interval 
RAN 
Randomized set 
ROW 
Rest of the World 
SABA 
Short Acting Beta2 Agonist 


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SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SCS 
Systemic Corticosteroids 
 
 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
 


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1 
Introduction 
This document contains details of the statistical methods that will be used in the phase IIIb 
clinical trial CQVM149B2306. This study is designed to demonstrate that the efficacy of two 
strengths of the fixed-dose combination product QVM149 (IND/GLY/MF 150/50/80 μg and 
IND/GLY/MF 150/50/160 μg) is non-inferior to the efficacy of the free combination of 
salmeterol/ fluticasone 50/500 μg + tiotropium 5 μg in patients with uncontrolled asthma. 
Data will be analyzed according to Section 9 of the study protocol.  
Important information is given in the following sections and details are provided, as 
applicable, in section 5: Appendix. 
1.1 
Study design 
This study uses a multicenter, partially-blinded, randomized, 24-week, parallel-group, non-
inferiority, open-label active controlled design (Figure 1). 
Approximately 1251 male and female patients with uncontrolled asthma aged 18 and above 
will be randomized into the three treatment groups in a randomization ratio of 1:1:1, 
expecting approximately 417 patients in each of the treatment groups. It is intended that 
approximately 2085 patients will need to be screened in order to randomize approximately 
1251 patients. Detailed information regarding sample size calculation is provided in section 3. 
This study will enroll multi-nationally and patients will be stratified by previous ICS dose 
component of ICS/LABA therapy (medium or high) and region. Drop-outs after 
randomization will not be replaced. 
No interim analysis for efficacy is planned in this study. An independent Data Monitoring 
Committee (DMC) will not be formed to review any blinded / semi-blinded data. 


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Figure 1 
Study design  
 
The study will consist of a screening period of up to 1-week, run-in period of 2-weeks, 
randomized treatment period of 24-weeks, and a follow-up of period of 1-week.   
1.2 
Study objectives and endpoints 
All objectives will consider the following 2 comparison groups: 
QVM149 150/50/80 μg o.d. delivered via Concept1 compared with open label salmeterol 
xinafoate/fluticasone propionate 50/500 μg b.i.d. delivered via Accuhaler® + tiotropium 5 μg 
o.d. delivered via Respimat®.  QVM149 150/50/160 μg o.d. delivered via Concept1 compared 
with open label salmeterol xinafoate/fluticasone propionate 50/500 μg b.i.d. delivered via 
Accuhaler® + tiotropium 5 μg o.d. delivered via Respimat® 
1.2.1 
Study Objectives and Endpoints 
Table 1-1 
 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective 
• 
To demonstrate non-inferiority of either  
QVM149 
high-dose 
or 
QVM149 
medium-dose to comparator salmeterol/ 
fluticasone + tiotropium in terms of 
Asthma Quality of Life Questionnaire 
(AQLQ) 
Endpoint for primary objective  
• 
Change from baseline in Asthma 
Quality of Life Questionnaire (AQLQ) 
total score after 24 weeks of treatment  


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Objective(s) 
Endpoint(s) 
Secondary Objectives 
• To evaluate efficacy of QVM149 high-
dose 
and 
QVM149 
medium-dose 
compared to salmeterol/ fluticasone + 
tiotropium in terms of Trough FEV1  
• To evaluate efficacy of QVM149 high-
dose 
and 
QVM149 
medium-dose 
compared to salmeterol/ fluticasone + 
tiotropium in terms of Asthma Quality of 
Life Questionnaire  
• To evaluate efficacy of QVM149 high-
dose 
and 
QVM149 
medium-dose 
compared to salmeterol/ fluticasone + 
tiotropium in terms of Asthma Control 
Questionnaire  
• To evaluate efficacy of QVM149 high-
dose 
and 
QVM149 
medium-dose 
compared to salmeterol/ fluticasone + 
tiotropium in terms of lung function  
Endpoints for secondary objectives 
• 
Change from baseline in Trough FEV1 
after 24 weeks of treatment  
• 
Change from baseline in Asthma 
Control Questionnaire (ACQ-7) total 
score over 24 weeks of treatment 
• 
Change from baseline in Asthma 
Quality of Life Questionnaire (AQLQ) 
total score over 24 weeks of treatment 
• 
Percentage of patients achieving the 
minimal important difference (MCID) 
decrease from baseline ACQ-7 ≥ 0.5 
over 24 weeks of treatment (responder 
rate) 
• 
Percentage of patients achieving the 
minimal important difference (MCID) 
change from baseline AQLQ ≥ 0.5 over 
24 weeks of treatment (responder rate) 
• 
Change from baseline in FVC over 24 
weeks of treatment 
• 
Change from baseline in Forced 
Expiratory Flow between 25% and 75% 
of Forced Vital Capacity (FEF25-75) 


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2 
Statistical methods 
2.1 
Data analysis general information 
The most recent version of SAS available in the statistical programming environment will be 
used for the analysis.  
2.1.1 
General definitions  
Study treatment is the treatment administered in treatment period at visit 201. 
The evaluations which have complete date and time values are assigned to pre or post-dose 
assessment based on the actual date/time. However, evaluations with missing date/time are 
assigned to their respective scheduled visit date and time given the visit number and time point 
are non-missing. If an evaluation scheduled as pre-dose is actually performed post-dose, or vice 
versa, the data will not be used for inferential analysis and summary statistics but will be 
included in the summaries of the notable values and extreme values.  
Study day will be defined as the number of days since the date of first dose of study medication. 
The date of first dose of study medication will be defined as Day 1 and the day before the first 
dose of study medication was defined as Day -1.  
Therefore, for a particular date, study day will be calculated as follows: 
• 
for dates on or after the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication + 1; 


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• 
for dates prior to the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication. 
If a patient has no study medication, the randomization date will be used instead of the date of 
first dose of study medication. Then, the randomization date is defined as Day 1 and the day 
prior to randomization is defined as Day -1. 
2.1.1.1 
Baseline definition 
In general, baseline data is defined as the last assessment taken prior to the first dose of study 
drug at Day 1 (Visit 201). 
Checks will be performed to ensure the assessments were indeed taken prior to the first dose of 
study drug on Day 1 (Visit 201). If this assessment is missing or not confirmed to be pre-dose, 
then last available non missing assessment will be used as baseline, if all the assessments prior 
to first drug administration are missing then the baseline will be set to missing without 
imputation. 
Parameter 
Baseline assessment 
Detail 
AQLQ-S 
 
Assessment  on day 1 (Visit 
201) 
If assessment taken on day 
1 (visit 201) prior to 
dosing are missing then 
baseline value will be set 
to missing without 
imputation. 
ACQ-7 
Assessment  on day 1 (Visit 
201) 
If this assessment is 
missing or not confirmed 
to be pre-dose then last 
available non missing 
assessment will be used as 
baseline. If all the 
assessments prior to first 
drug administration are 
missing then baseline 
value will be set to 
missing without 
imputation. 
 


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Lung function (FEV1, FVC, 
FEV1 % predicted and 
FEF25-75) 
Average 
of 
measurements 
taken at 45 min and 15 min 
prior to evening dosing on day 
1 (Visit 201) 
Checks will be performed 
to ensure both values were 
indeed taken prior to the 
first dose of study drug. If 
one of the 45 and 15 min 
values is missing (or is not 
confirmed to be pre-dose) 
then the remaining non-
missing value will be taken 
as the baseline.  
If both measurements are 
missing, then pre-SABA 
assessment on visit 101 
will be used as baseline. 
 


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Laboratory data 
(hematology, clinical 
chemistry, urine analysis) 
Last available assessment prior 
to dosing on day 1 (Visit 201) 
 
Vital signs  
(pulse rate and systolic and 
diastolic blood pressures) 
Last available assessment prior 
to dosing on day 1 (Visit 201) 
 
Height and weight 
Last available assessment prior 
to dosing on day 1 (Visit 201) 
 
ECG 
Last available assessment prior 
to dosing on day 1 (Visit 201) 
 
2.1.1.2 
Post-baseline measurement 
Post-baseline measurements are defined as those assessments after the first dose of study drug. 
When change from baseline is of interest the following formula will be used for each visit and 
time-point where baseline and post-baseline values are both available: 
Change from baseline = post baseline value – baseline value. 
Detail descriptions for calculating post-baseline values are provided in the latter sections. 
2.2 
Analysis sets 
The following analysis sets are defined: 
• The randomized (RAN) set will consist of all patients who were assigned a 
randomization number, regardless of whether or not they actually received study 
medication. Patients in RAN will be analyzed according to the treatment they were 
randomized to. The RAN set will be used for a summary of patient disposition, 
demographics and baseline characteristics. 
• The Full Analysis Set (FAS) will consist of all patients in the RAN set who received at 
least one dose of study medication. Following the intent-to-treat principle, patients will 
be analyzed according to the treatment they were assigned to at randomization. The FAS 
will be used in the analysis of all efficacy variables. 
• The Per-Protocol set (PPS) will include all patients in the FAS who did not have any 
major protocol deviations. The list of major protocol deviations is available in Appendix 
5.8. Patients in the PPS will be analyzed according to the treatment they actually 
received. Patients who have taken ICS alone during the study as a treatment for any AE will be 
excluded from PPS. The PPS will be used for supportive and sensitivity analysis to assess 
robustness of the primary efficacy analysis.  
• The Safety Analysis Set (SAF) will consist of all patients who received at least one dose 
of study medication. Patients will be analyzed according to the treatment they received. 
The SAF will be used in the analysis of all safety variables. 


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Note that the FAS and SAF are the same except that the SAF allows the inclusion of non-
randomized patients who received study drug in error. Also, the FAS assign randomized 
treatment and the SAF assigned received treatment. 
2.2.1 
Subgroup of interest 
The following exploratory subgroup analyses for AQLQ total score at Week 24 using MMRM 
will be performed (using the appropriate interaction term in the model and additional covariate 
as a fixed effect if necessary) for the FAS to explore the treatment effect in: 
• Sex (male, female) 
• Region (Asia, Europe, Latin America and Others) 
• Age categories (18-39 years, 40-64 years and >=65 years) 
• History of asthma exacerbation in the 12 months prior to screening (1, 2, 3, ≥ 4) 
• Patients’ prior therapies for at least 1 month prior to visit 1 (mid or high dose ICS/LABA; 
see Appendix 10 of the study protocol for the definition of ICS dose levels) 
The subgroup analyses for patient's prior therapies prior to visit 1 (mid and high dose 
ICS/LABA) will also be performed for FEV1 at Week 24.  
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number of patients will be summarized by treatment group for the RAN set. Further, for 
each study period (i.e., screening, run-in, randomized treatment phase, post treatment follow-
up), the overall number of patients who entered, completed, and discontinued that phase will 
be summarized including the reasons for discontinuation.  
 
 
Number of patients with protocol deviations will be summarized by deviation category (e.g., 
selection criteria not met, prohibited concomitant medication, key procedures not performed as 
per protocol) and treatment group. Protocol deviations that lead to exclusion from analysis sets 
will be listed by deviation category and treatment group. 
 
The number of patients included in each analysis set will be tabulated by treatment group. 
2.3.2 
Patient demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized by treatment group using the 
RAN set. Summaries will include age, gender, race, ethnicity, height, weight, body mass 
index (BMI), relevant medical history, screening spirometry parameters: (FEV1, FVC, 
FEV1/FVC and FEF25-75), FEV1 reversibility, % of predicted FEV1, duration of asthma, 
history of asthma exacerbations, smoking history, prior concurrent medications (asthma-
related and non-asthma-related), vital signs (systolic and diastolic blood pressure, pulse rate), 
QTc using Fridericia’s correction and baseline AQLQ, ACQ-7, 
. 
 


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Continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, standard deviation, median, first and third quartiles, minimum, and maximum)  and 
categorical variables will be summarized in terms of the number and percentage of patients in 
each category including a category for missing data if any for the treatment group. 
No statistical analyses will be provided for baseline comparability among the treatment group. 
For two patients 2304004 and 2803009, their FEV1 reversibility values will be calculated 
from the last available value at unscheduled visits manually and will be added in the 
summary. 
 
In addition, the following categorizations of continuous variables will be done: 
• Age:  18 – 39, 40 - 64 years, and ≥ 65 years; 
• Region (Asia, Europe, Latin America and Others), 
• BMI:  ≤ 30.0 kg/m2 and > 30.0 kg/m2; 
• Duration of asthma: < 1 year, 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 – 20 
years, and > 20 years; 
• Number of asthma exacerbations in the 12 months prior to the start of the study that 
required treatment: 0, 1, 2, 3, ≥ 4 
• FEV1 reversibility %: <12%, >=12%  
• AQLQ score:   < 0.5, 0.5 - < 1, 1 - < 1.5, 1.5 - < 2, > 2 
• ACQ-7: 1.5- < 2, 2 – < 2.5, ≥ 2.5 (< 1.5 will be added in case of protocol deviations) 
• ICS component of background therapy (mid or high dose ICS/LABA) 
• Baseline eosinophils blood count (low: < 300 cells/µL, high: ≥ 300 cells/µL) 
 
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 
History/conditions will be summarized for the RAN set by primary system organ class and 
preferred term. Verbatim recorded history/conditions will be listed together with the coded 
terms, date of diagnosis/surgery and whether the problem was ongoing at start of the study. 
In addition, medical histories/current medical conditions will be summarized by their status at 
baseline (current medical conditions, past medical conditions) and primary system organ class. 
Current medical conditions are defined as those which were reported as "Ongoing" at baseline. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
2.4.1.1 
Duration of exposure 
Duration of exposure to study treatment will be calculated as the number of days starting from 
the first dose date up to and inclusive the last dose date. The duration of exposure will be 
summarized by treatment group for the safety set as a continuous variable with the standard 
descriptive statistics. In addition, the duration of exposure will be summarized with total 
patient years and the number (%) of patients who were exposed to study drug for the 
following categories <= 29 days, >29 days, >57 days, >85 days, >113 days, –>141 days and > 
169 days. 


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If the patient’s asthma symptoms are well controlled with stable lung function for 3 or more 
months and the patient is not at risk for an exacerbation, Tiotropium may be discontinued only 
in the “free combination” comparator arm (Salmeterol/fluticasone + Tiotropium). The number 
(%) of patients who were exposed to all three components of free triple combination will be 
presented for the time interval categories as described above. 
2.4.2 
Prior, concomitant and post therapies 
Each medication, either an asthma or non-asthma medication, will have the start and end dates 
recorded on the eCRF. Separate tables will be provided for medications which were started and 
stopped prior to the first dose of study drug and medications which were taken concomitantly 
to the study drug (regardless of whether continued or started after the first dose of study drug). 
 
Asthma medications will be summarized by the route of administration, the recorded 
prespecified drug subcategories (including types of combination) and the preferred terms. The 
summary will be repeated by showing ingredients instead of preferred terms. Non-asthma 
medications will be summarized by route of administration and preferred term. The 
summarization will be by treatment group in randomized set. 
 
Surgical and medical procedures (non-drug therapies) will be coded using MedDRA and 
presentations will be done by MedDRA primary system organ class and preferred term, 
separately for prior procedures and those after start of study drug. The summarization will be 
by treatment group in randomized set. 
 
Short acting beta2 agonist (SABA) rescue medication usage (mean number of puffs) during the 
run-in epoch will be summarized. Patients taking prohibited concomitant medications will be 
noted in the summary of protocol deviations. The summarization will be by treatment group in 
randomized set. 
 
The number and proportion of patients who had their background asthma treatment escalated 
will be summarized by treatment group in the safety analysis set. 
 
All summarizations will be by treatment group in the Safety Analysis Set. 
2.5 
Analysis of the primary and key secondary variable 
2.5.1 
Primary variable 
The change from the baseline at week 24 for the AQLQ total score will be used as the primary 
endpoint  
 
AQLQ(S) is a 32-item disease specific questionnaire designed to measure functional 
impairments that are most important to patients with asthma, with a recall time of two weeks 
and each question to be answered on a 7-point scale (1-totally limited/problems all the time, 
7-not at all limited/no problems). It consists of 4 domains: 
• Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items) 


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• Activity limitation = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items) 
• Emotional function = Mean of Items 7, 13, 15, 21, 27 (5 items) 
• Environmental stimuli = Mean of Items 9, 17, 23, 26 (4 items) 
• Total Score = Mean of Items 1 to 32 (32 items) 
 
The AQLQ total score is defined as the mean response to all 32 questions. AQLQ assessment 
will be done at Day 113 and 169 (week 24, primary endpoint). 
2.5.2 
Statistical hypothesis, model, and method of analysis  
2.5.2.1 
Primary variable 
The non-inferiority of QVM149 150/50/160 μg o.d. Versus free combination of salmeterol/ 
fluticasone 50/500 μg + tiotropium 5 μg and QVM149 150/50/80 μg o.d. versus free 
combination of salmeterol/ fluticasone 50/500 μg + tiotropium 5 μg, in terms of change from 
baseline in AQLQ total score, will be assessed by testing the following null hypothesis (H1 & 
H2) versus the alternative hypothesis (Ha1 & Ha2): 
 
H1: QVM149 150/50/160 μg o.d. is inferior to free combination of salmeterol/ fluticasone 
50/500 μg + tiotropium 5 μg in change from baseline for AQLQ total score at Week 24 (μ1 –
μ3 < -0.25) 
       
Ha1: QVM149 150/50/160 is non-inferior to free combination of salmeterol/ fluticasone 50/500 
μg + tiotropium 5 μg in change from baseline for AQLQ total score at Week 24 (μ1 –μ3 ≥ -
0.25) 
 
H2: QVM149 150/50/80 μg is inferior to free combination of salmeterol/ fluticasone 50/500 μg 
+ tiotropium 5 μg in change from baseline for AQLQ total score at Week 24 (μ2 –μ3 < -0.25) 
 
 
Ha2: QVM149 150/50/80 is non-inferior to free combination of salmeterol/ fluticasone 50/500 
μg + tiotropium 5 μg in change from baseline for AQLQ at total score Week 24 (μ2 –μ3 ≥ -
0.25) 
 
where;  
 μ1 = Mean change from baseline for AQLQ total score at week 24 of QVM149 150/50/160 μg 
o.d. treatment; 
μ2 = Mean change from baseline for AQLQ total score at week 24 of QVM149 150/50/80 μg 
o.d. treatment; 
μ3 = Mean change from baseline for AQLQ total score at week 24 of free combination of 
salmeterol/ fluticasone 50/500 μg + tiotropium 5 μg; 
-0.25 = Non-inferiority margin. 
 
The primary variable will be analyzed using a mixed model for repeated measure (MMRM) on 
the FAS. The model will contain treatment, region (Asia, Europe, Latin America and Others), 
visit, background ICS/LABA (medium or high dose), baseline-by-visit interaction and 
treatment-by-visit interaction as fixed effects with baseline AQLQ total score as the covariate, 


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and center nested within region as a random effect. The within-patient correlation will be 
modeled using the unstructured covariance matrix in the mixed model. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom (Kenward and 
Roger,1997). If the model does not converge, then the compound symmetry covariance matrix 
will be used in the mixed model. Restricted maximum likelihood method will be used. 
 
The least squares means of the treatment differences, standard errors, 97.5% (one-sided) CI, 
and one-sided p-values for NI test (adjusted and unadjusted) and nominal two-sided p-values at 
week 24 of each dose QVM149 vs. the combination of salmeterol/ fluticasone50/500 μg + 
tiotropium 5 μg, will be presented. 
 
Non-inferiority of QVM149 will be claimed if the the multiplicity adjusted one-sided p-value 
is < 0.025. 
 
An improvement of 0.5 points in AQLQ score is considered to be the minimally clinically 
important difference (MCID) in asthma. A non-inferiority margin of 0.25 points reduction in 
AQLQ score has been designated for the study based upon 50% of the MCID. If the MCID of 
0.5 points reduction in the AQLQ is considered clinically important, it is reasonable to use a 
non-inferiority margin of one-half of this difference, which is 0.25 points. 
2.5.3 
Estimand Analysis 
The estimand for this study is difference between the effect of initially randomized treatments 
had all patients remained on their randomized treatment throughout the study. The primary 
estimand will quantify the treatment effect based on on-treatment data. The primary estimand 
will account for different post-randomization events as follows: 
• Use of rescue medications: Efficacy data collected during use of rescue medication will 
be used for analysis. 
• Early discontinuation of study drug: The primary analysis will include on treatment data 
from all patients in FAS. Data collected after treatment discontinuation will be 
considered as missing.  
2.5.4 
Handling of missing values/censoring/discontinuations 
The MMRM model, which is used for the analysis of primary variable is based on missing at 
random assumption for the missing values and assesses the treatment effects without explicit 
imputation. No imputation will be used for missing questions or missing total AQLQ score for 
primary analysis. 
 
2.5.5 
 Supportive and Sensitivity analyses 
 
As a sensitivity analysis, the following analyses will be performed: 
• The same MMRM used for the primary objective will be performed with the missing 
values imputed using last observation carried forward (LOCF). The analysis will only 
be performed if there are less than 20% observations missing. 


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• The same MMRM model used for primary objective will be performed with on and off 
treatment data value at week 24/ day 169. 
• The same MMRM used for the primary objective will be performed on the PPS. Primary 
variables will be analyzed using the same MMRM model as that of primary analysis 
using the data from all time-points (i.e. on and available off treatment data) on FAS.  
• The same MMRM used in the primary analysis will be performed on all patients except 
for the patients who are “treatment failures” for whom only the data till the time the 
patient is not a treatment failure will be considered in the analysis while the data 
collected after being treatment failure will be considered as missing. 
• The same MMRM model used in the primary analysis will be performed considering all 
patients in the QVM arms and only those patients in the loose triple arm who  did not 
step down. This analysis will only be performed if more than 5% patients in the loose 
triple arm steps down.  
 
2.5.6 
Multiplicity adjustment 
To control the family-wise type-I error rate at the one-sided 2.5% significance level, a multiple 
testing procedure based on the trimmedSimes test in Brannath et al. (2009) is used. The family 
for the overall type-I error rate control contains total 2 hypotheses for the primary endpoint, 
AQLQ. Denote the two hypotheses for the primary endpoint as H1 and H2  for comparing 
QVM149 150/50/160 µg o.d. Versus free combination of salmeterol/ fluticasone 50/500 μg + 
tiotropium 5 μg and QVM149 150/50/80 µg o.d. versus free combination of salmeterol/ 
fluticasone 50/500 μg + tiotropium 5 μg, in terms of change from baseline in AQLQ total score. 
Below is a brief description of the testing procedure based on the trimmed Simes test in 
Brannath et al. (2009). 
Let p1 and  p2 are the corresponding p-values (1-sided, p-value related to NI hypotheses) of the 
two hypotheses of H1and H2.  
Step 1: Retain both H1 and H2 if ANY pi>=0.975 (i.e.  Loose tripleis performing better than 
QVM) for i=1, 2, stop here; otherwise go to step 2; 
Step 2: Reject H1 and H2 if pi<0.025 for BOTH i=1, 2,and stop here; otherwise go to step 3; 
Step 3: If neither step 1 or 2 applies, perform the Bonferroni test to H1 and H2. Thus reject H1 
if p1<0.0125 and reject H2 if p2<0.0125 and stop. 
For each of the two hypotheses, the corresponding testing statistic (estimated least square mean 
difference) follows normal distribution. Hence for H1 and H2, their corresponding testing 
statistics is assumed to follow jointly bivariate normal distribution. Therefore this testing 
procedure controls the overall type–I error rate at the 1-sided 0.025 level in the strong sense 
regardless if the bivariate normal distributions have positive or negative correlations as shown 
in Brannath et al (2009). 
Other than the two analyses mentioned above for the primary endpoint (primary endpoint using 
FAS and PPS), all other analyses will be performed at the nominal 2-sided 0.05 level (2-sided) 
without multiplicity adjustment. 


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2.6 
Analysis of secondary efficacy objective(s) 
2.6.1 
AQLQ Score, domains, and responders at each visit 
Clinically important differences in scores between any two assessments have been determined 
by the authors of the AQLQ. Changes in scores of 0.5 are considered clinically meaningful; 
changes of 1.0 are considered as moderate and > 1.5 as large changes for any individual domain 
or for the overall summary score (Juniper 1994). 
Change from baseline in Asthma Quality of Life Questionnaire (AQLQ) total score and each of 
the AQLQ domain (symptoms, emotions, exposure to environmental stimuli and activity 
limitation) over 24 weeks of treatment will be analyzed using MMRM model similar to primary 
endpoint. Appropriate baseline AQLQ domain scores will be used as covariate instead of 
baseline AQLQ total score in the model. . 
The between-treatment comparison will be carried out using the adjusted mean (least-square 
mean) difference corresponding to the respective visit. Adjusted mean (LS mean) will be 
displayed for each treatment group along with the estimated treatment differences and the 95% 
confidence intervals and the two sided p-values by visit. 
 
Percentage of patients achieving the minimal important difference (MCID) change from 
baseline AQLQ ≥ 0.5  over 24 weeks of treatment (responder rate) (i.e. increase of AQLQ total 
score of at least 0.5 from baseline) at post-baseline visits will be analyzed using the logistic 
regression model via the generalized estimating equations (GEE). The model will include terms 
for treatment, region, visit, background ICS/LABA (medium or high dose) , baseline-by-visit 
interaction and treatment-by-visit interaction as fixed effects, with baseline AQLQ total score 
as covariates. The within-patient correlation will be modeled using the unstructured covariance 
matrix in the GEE model. The estimated adjusted odds ratios of the treatment comparisons will 
be displayed along with the associated 95% (two- sided) confidence intervals and superiority 
p-values. For odds ratio, binomial distribution with logit link will be used and correlation 
structure will be “Unstructured”. The estimated risk ratios between the treatments will be 
displayed along with the associated 95% (two-sided) confidence intervals and superiority p-
values.For risk ratios, modified Poisson regression model (Zou 2004) will be used in model 
with correlation structure as “unstructured”. This method leads to the robust error variance 
estimation and produce 95% CIS with the correct coverage. 
2.6.2 
ACQ-7 Score and responders at each visit 
ACQ-7 questionnaire consists of five items to assess symptoms and activity limitations, one 
question to assess rescue medication use, and one question to assess airway caliber (FEV1 % 
predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control 
and 6 indicating poor control. The questions are equally weighted and the total score is the mean 
of the seven items. 
 
The first 6 questions of the ACQ-7 should be completed by the patient based on one recall over 
the prior week. The last question should be completed by the investigator at the site using data 
from the MasterScope spirometer. 
The mean will be calculated as the sum of scores divided by the number of questions that were 
answered, as long as there were at least 6 questions answered and the missing question is neither 


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Question 1 ('On the average, during the past week, how often were you woken by your asthma 
during the night?') nor Question 7. Missing ACQ score will not be imputed explicitly. 
Change from baseline in ACQ-7 total score over 24 weeks of treatment will be analyzed using 
the MMRM model similar to primary endpoint with baseline ACQ-7 score will be used as 
covariate instead of baseline AQLQ total score in the model. 
 
Adjusted mean (LS mean), the least squares means of the treatment differences, standard errors, 
95% (two-sided) CI, and superiority p-values at each visit of each dose QVM149 vs. the 
combination of salmeterol/ fluticasone 50/500 μg + tiotropium 5 μg, will be displayed. 
The mean will be calculated as the sum of scores divided by the number of questions that 
were answered, as long as there were at least 6 questions answered and the missing question is 
neither Question 1 ('On the average, during the past week, how often were you woken by your 
asthma during the night?') nor Question 7. 
 
Percentage of patients achieving the minimal important difference (MID) change from baseline 
ACQ-7 ≥ 0.5 decrease over 24 weeks of treatment (responder rate) (i.e. decrease of ACQ-7 
score of at least 0.5 from baseline) at post-baseline visits will be analyzed using the same 
logistic regression model via GEE specified for the AQLQ analysis except that baseline ACQ-
7 score will be used as the covariate in the model, instead of the baseline AQLQ total score. 
The estimated adjusted odds ratios of the treatment comparisons will be displayed along with 
the associated 95% (two- sided) confidence intervals and superiority p-values. For odds ratio, 
binomial distribution with logit link will be used and correlation structure will be 
“Unstructured”. The estimated risk ratios between the treatments will be displayed along with 
the associated 95% (two-sided) confidence intervals and superiority p-values. For risk ratios, 
modified Poisson regression model as described above will be used in model with correlation 
structure as “unstructured”.   
 
 
Percentage of patients achieving the change from baseline ACQ-7 ≥ 0.75 decrease over 24 
weeks of treatment (responder rate) (i.e. decrease of ACQ-7 score of at least 0.75 from baseline) 
at post-baseline visits will be analyzed using the same logistic regression model via GEE 
specified for the AQLQ analysis except that baseline ACQ-7 score will be used as the covariate 
in the model, instead of the baseline AQLQ total score. The estimated adjusted odds ratios of 
the treatment comparisons will be displayed along with the associated 95% (two- sided) 
confidence intervals and p-values. The estimated risk ratios of the treatment comparisons will 
be displayed along with the associated 95% (two-sided) confidence intervals and superiority p-
values. 
 
 
2.6.3 
Spirometry data at each visit 
Change from baseline in Trough FEV1  at week 24 of treatment will be analyzed using the same 
MMRM model as specified for the primary variable on FAS. Trough FEV1 is calculated as 
average of 15 min and 45 min pre-dose measurements.  Baseline FEV1 will be used as covariate 
in the model.  The least squares means of the treatment differences, standard errors, 95% (two-


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sided) CI, and p-values (nominal) at week 24 of each dose QVM149 vs the combination of 
salmeterol/fluticasone 50/500 µg + tiotropium 5 µg will be presented. 
 
Trough FEV1 will also be analyzed using the same MMRM model as specified above, where 
the between-treatment comparison will be carried out using the adjusted mean (least-square 
mean) difference corresponding to the respective visit. Adjusted mean (LS mean) will be 
displayed for each treatment group along with the estimated treatment differences and the 95% 
confidence intervals and the two sided p-values by visit. 
Similar analyses will be performed for FVC and FEF25-75. Change from baseline in the 
spirometry values will be also analyzed using the same MMRM model. 
 
2.7 
Safety analyses 
All safety evaluation will be based on the safety analysis set. 
For safety data, post-baseline measurements comprise recordings up to the last dose of study 
drug + 7 days for laboratory, ECG, vital signs, non-serious AE and up to the last dose of study 
drug + 30 days for SAEs and death.  
2.7.1 
Adverse events (AEs) 
All adverse events including asthma exacerbations, coded with MedDRA using the most actual 
version at the time of database lock, will be listed. In general, summaries will include treatment-
emergent adverse events (TEAEs) only. 
TEAEs are those adverse events starting on or after the time of the first inhalation of study drug 
but not later than 7 days (30 days in the case of SAE) after the last administration of study drug. 
Any adverse events that started during the study before the time of the first inhalation of study 
drug will be classified as a prior adverse event. 
The number and percentage of patients who reported TEAEs will be summarized by primary 
system organ class (SOC) and preferred term (PT), serious adverse events by system organ class 
and preferred term, and adverse events leading to permanent discontinuation of study-drug by 
system organ class and preferred term. The number and percentage of patients with the most 
frequent AEs will be summarized by treatment group for 
• all adverse events  
• all adverse events by maximum severity 
• adverse events suspected to be related to study drug 
• serious adverse events 
• adverse events leading to permanent study drug discontinuation 
• all adverse events by standardized MedDRA query (SMQ) level 
• fatal adverse events, by adjudicated reason for death 
• adjudicated serious cardiovascular and cerebrovascular (CCV) events 
• adjudicated new onset of atrial fibrillation/ flutter 
• adverse events of special interest 


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Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the QVM149 150/50/80 μg treatment. If a patient reported more than one 
adverse event with the same preferred term, the adverse event will be counted only once. If a 
patient reported more than one adverse event within the same primary system organ class, the 
patient will be counted only once at the system organ class level. 
In addition, the most frequent adverse events will be presented by preferred term in descending 
order of frequency in the QVM149 150/50/80 μg treatment. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Serious CCV events will be adjudicated. 
Atrial fibrillation and atrial flutter will be adjudicated according to their onset into: new onset, 
recurrent/persistent, or unknown. 
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of special interest. Selection of appropriate flags in eCRS 
tool will be mentioned in TFL shells. The most recent list of adverse events of special interest 
at the time of database lock will be used. Adverse events of special interest will be summarized 
by risk and preferred term by severity (mild/moderate/severe). 
 
In addition, exposure adjusted analyses of adverse events by preferred term will be performed 
for each treatment group.  
For exposure adjustment, First onset of event will be considered where the exposure is only 
counted up to the time of the first event. The occurrence rate per 100 patient years will be 
calculated as 100*(the total number of patients with the event of interest divided by the total 
number of exposure in patient-years). In the denominator, patients with the event of interest 
will be counted up to the time of the first event while patients without the event of interest will 
be counted with their full exposure. Total patient years will be computed as sum of days of 
exposure over all patients divided by 365.25). 
 
2.7.1.2 
AE reporting for CT.gov and EudraCT 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 2% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• 
a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 


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• 
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.2 
Deaths 
A summary of deaths will be presented by primary system organ class, preferred term, and 
treatment groups regardless of study drug relationship. In addition, deaths will be summarized 
by adjudicated primary cause and treatment group. 
All the deaths in the clinical database will be listed with both the investigator-reported principal 
cause and the adjudicated primary cause presented side by side, but only those between the first 
treatment and (the last dose + 30 days) will be included in summary tables. 
2.7.3 
Serious asthma outcomes 
A composite endpoint of serious asthma outcomes is defined as a) asthma-related 
hospitalization, b) asthma-related intubation, or c) asthma-related death. All serious asthma 
outcomes and deaths occurring from the time of randomization until the 30 days after permanent 
discontinuation of study drug will be adjudicated by an independent external committee to 
determine their asthma relatedness. The composite endpoint as well as each single component 
of it will be analyzed for the number of patients with the event, the time to event and the annual 
rate of events. If a sufficient number of events will occur, similar analyses as described for 
asthma exacerbations will be performed. Otherwise, a purely descriptive analysis will be done 
only. 
2.7.4 
Laboratory data 
All laboratory samples will be processed through the central laboratory. Laboratory data consist 
of hematology, clinical chemistry and urinalysis measurements. All data will be listed with 
abnormal values flagged. Baseline laboratory data is defined in section 2.1.1.1 
Laboratory data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
 
The following analyses will be performed by treatment group: 
• absolute values and change from baseline summarized for continuous laboratory parameters 
by visit  
• frequency table of results for categorical laboratory parameters by visit  
• shift tables relative to the normal reference ranges summarizing the change from baseline 
to post-baseline by visit for each continuous laboratory parameter 
• shift tables from baseline to post-baseline by visit  for categorical laboratory parameters  


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• the number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (see Section 5.5 for definition of notable 
values) summarized by laboratory parameter, scheduled post-baseline visit and additionally 
at any time on treatment considering all post-baseline data from scheduled, unscheduled 
and premature discontinuation visits. 
 
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value that is not clinically notable for that parameter. For a patient to 
meet the criterion of a worsening clinically notable value, the patient needs to have a baseline 
value that is clinically notable and also have a worse post-baseline value. For patients with 
missing baseline value, any post-baseline notable value will be considered as newly occurring. 
A listing of all patients with notable laboratory values will be provided. 
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) will be summarized by treatment and scheduled post-
baseline visit and additionally at any time on treatment considering all post-baseline data from 
scheduled, unscheduled and premature discontinuation visit (if not measured more than 7 days 
after last dose) based on the criteria mentioned in the section 5.4. 
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur at the same time (i.e., within the same sample). A 
case where all criteria are met at a post-baseline time point will be considered as newly 
occurring if the criteria are not met at baseline and will be considered as worsening if the criteria 
are met at baseline and at least one component is worsening from baseline irrespective of 
whether the other(s) are better. 
Listings of patients with clinically notable LFT values will be provided. 
2.7.5 
Other safety data 
2.7.5.1 
ECG  
ECG measurements include ventricular rate, QT interval, RR interval, PR interval, QRS 
duration, and Fridericia’s QTc (calculated as QTcF = QT / 3√ RR (in seconds), where 3√ 
denotes the cube root). Furthermore, an overall interpretation of the central cardiologist will be 
provided as well as a specification of abnormal findings. 
ECG data measured more than 7 days after last inhalation of study drug are regarded as post 
treatment data and will not be summarized, only listed. All data will be included in the analyses 
regardless of rescue medication use. 
The following analyses will be performed by treatment group: 
• absolute values and change from baseline summarized by parameter, and visit  
• the number and percentage of patients with newly occurring or worsening notable QTcF 
values (see Section 5.5 for definition of notable values) summarized by scheduled post-
baseline visit and additionally at any time on treatment considering all post-baseline data 
from scheduled, unscheduled and premature discontinuation visits 
• frequency table of results for overall ECG interpretation (normal, abnormal) by visit and 
with shift tables from baseline to the worst interpretation during treatment 
• the number and percentage of patients with ECG abnormalities summarized by evaluation 
type, abnormality finding, and visit. In addition, the number and percentage of patients with 




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2.12 
Additional analysis 
Apart from the above mentioned primary, secondary, safety 
 analyses, further 
analysis may be performed on a local level for HTA purposes, such as, but not limited to 
responder analysis for patient reported outcomes and subgroup analysis. 
2.13 
Interim analysis 
No interim analysis is performed for this study. 




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5.1.3.1 
Prior therapies date imputation 
Rules for imputing the prior therapies end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details. 
5.1.3.2 
Post therapies date imputation 
Rules for imputing the post therapies end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details. 
5.2 
AEs and Concomitant medications coding/grading 
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. For coding purpose of the concomitant medications, the 
available WHO-DD (World Health Organization- Drug Dictionary) version at the time of 
database lock, will be used. 
5.3 
Data pooling and assessment windows 
Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed. For patients who do not complete the study treatment, the treatment 
discontinuation visit will be an unscheduled visit. 
Clinical laboratory measurements, vital signs and ECG data from unplanned or unscheduled 
visits will only be included in the summaries of the notable values and extreme values. All 
efficacy data from these visits will not be used for missing data imputation unless specified 
otherwise. 
Laboratory, vital signs, and ECG values that have complete data and time values will be slotted 
into pre- or post-dose assessment based on the actual date/time. For values with missing 
date/time, scheduled visit date and time will be used. This rule will be applied to data from 
scheduled visits only. If a measurement scheduled as pre-dose is actually performed post-dose, 
or vice versa, the data will not be used for by time point assessments. 
5.4 
Time Windows 
Below mentioned time windows will be used for week 24 visit (visit corresponding to day 
169).  
• For Treatment Emergent Flag: +7 days , SAE + 30 days 
• For EG, LB, VS : +7days 
• ACQ7, AQLQ: +1 day 
 
 
• ADRESPI (Respiratory): +1 
 
 
• Time to event: +1 days except for adjudicated events(+30) 
 


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5.5 
Laboratory parameters derivations 
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.  
Laboratory parameter (unit) 
Lower bound of 
clinically notable range 
Upper bound of 
clinically notable range 
Hematology 
 
 
Hematocrit (v/v) 
     Male 
     Female 
 
0.37 
0.32 
 
 
Hemoglobin (g/L) 
    Male 
    Female 
 
115 
95 
 
 
Platelets (x10E9/L) 
75  
700 
WBC (x109/L) 
2.8 
16.0 
Chemistry 
 
 
Albumin (g/L)  
 
25 
- 
Alkaline Phosphatase (U/L) 
- 
3xULN 
ALT/SGPT (U/L) 
- 
3xULN 
AST/SGOT (U/L) 
- 
3xULN 
Bilirubin Total (mcmol/L) 
- 
34.2 
BUN (mmol/L) 
- 
9.99 
Creatinine (mcmol/L) 
- 
176.8 
Glucose (mmol/L) 
2.78 
9.99 
Gamma GT (U/L) 
- 
3 x ULN 
Potassium (mmol/L) 
3 
6 
v = volume, ULN = upper limit of normal  
 
Notable liver function test values 
Criterion 
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin > 1 x ULN 
Total bilirubin > 1.5 x ULN 
Total bilirubin > 2 x ULN 
Total bilirubin > 3 x ULN 
ALP > 1.5 x ULN 


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ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP ≤ 2 x ULN (Hy's law) 
ALT or AST > 3 x ULN and (nausea or vomiting or fatigue or general malaise or abdominal pain or (rash and 
eosinophilia))* 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
* Based on the signs/symptoms information as recorded on the liver events eCRF, not the adverse events eCRF. 
5.6 
Vital signs and ECG – definition of clinically notable values 
The following table shows the clinical notable criteria for vital signs. 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of 
clinically notable range 
Notable value considering newly occurring or worsening cases 
Systolic blood pressure (mmHg) 
< 75  
> 200 
Diastolic blood pressure (mmHg) 
< 40 
 
> 115 
Pulse rate (bpm) 
< 40 
> 130 
Notable change from baseline 
Systolic blood pressure (mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20  
≥ 180 and increase 
from baseline by ≥ 20 
Diastolic blood pressure (mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase 
from baseline by ≥ 15 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase 
from baseline by ≥ 15 
Weight (kg) 
Decrease ≥ 7% from 
baseline 
Increase ≥ 7% from 
baseline 
 
The following table shows the clinical notable criteria for QTcF. 
Clinical notable criteria for QTcF (Fridericia's formula) 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTc (msec) 
> 450 (male) 
QTc (msec) 
> 460 (female) 
QTc (msec) 
 > 500 (both)  
Notable change from baseline 






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• OTH 02: Patient was Randomized but no study drug was taken. 
• OTH 05: Patient randomized more than once in the trial. 
• OTH 12: Patient who received study medication before or  without randomization 
Exclusions from Safety Set: 
• INCL01: Informed consent not obtained. 
• 
EXCL14: Clinical significant condition compromising patient safety or compliance 
• OTH 02: Patient was Randomized but no study drug was taken. 
• OTH 04: Patient receiving investigational drug other than study drug during the course 
of the study. 
Exclusion from Randomized Set: 
• INCL01: Informed consent not obtained. 
• OTH 02: Patient was Randomized but no study drug was taken. 
• OTH 12: Patient who received study medication before or  without randomization 
 
 
Exclusions from per-protocol set: 
 
• INCL01: Informed consent not obtained. 
• INCL02: Male and female adult patient ≥ 18 years old. 
• INCL03: No current diagnosis of persistent Asthma of at least 6 months prior to Visit 1. 
• INCL04: Patients are not treated with medium or high dose of ICS/LABA combination 
for at least 3 months and/or not at stable dose 1 month prior to Visit 1. 
• INCL05: Lack of ACQ questionnaire and ACQ score < 1.5 at V101 and/or V201. 
• INCL08: Patient has not demonstrated reversiblity via spirometry test at Visit 101 and 
does not have historical reversibility or bronchoprovocation. 
• INCL08A: Patients without Historical reversibility OR bronchoprovocation according 
to ATS/ERS as per source documentation. 
• EXCL01: Patient has a smoking history of > 20 pack years or missing. 
• EXCL03: Asthma exacerbation within 6 weeks prior to Visit 1 or between Visit 1 and 
Visit 201 prior to randomization. 
• EXCL03A: Asthma attack/exacerbation requiring SCS or hospitalization or ER visits 
within 6 weeks prior to Visit 1. 


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• EXCL08: Respiratory Tract Infection or asthma worsening between screening and 201 
visits. 
• EXCL08A: Respiratory Tract Infection within 4 weeks prior to V1. 
• EXCL09: Chronic condition affecting the upper respiratory tract. 
• EXCL10: Patient has a history of chronic lung diseases other than asthma. 
• EXCL13: Investigational drugs used within  5 half-lives of enrollment, until the 
expected pharmacodynamics effect has returned to baseline, whichever is longer. 
• EXCL 26: Patient is not on maintenance immunotherapy for allergies for at least 3 
months prior to V101. 
• EXCL 29: Unable to use dry powder inhaler device  at V101 and/or V201. 
• EXCL 30: Patient has history of alcohol or other substance abuse that would interfere 
with study conduct. 
• COMD01: Banned asthma related Concomitant medication 
• COMD06: Use of SABA other than rescue medication, not discontinued at visit 1 
• COMD07: Use of parenteral corticosteroids less or unstable OCS dose  than 4 weeks 
prior to visit 101 
• COMD08: Intra muscular corticosteroid less than 3 months prior to visit 101 
• COMD09: Use of biologic less than 3 months prior to visit 1 not in stable dose 
• COMD12: ICS and LABA, not discontinued before required washout period to  visit 
101. 
• OTH 02: Patient was Randomized but no study drug was taken. 
• OTH 03: Patient received wrong treatment or expired drug. 
• OTH 04: Patient receiving investigational drug other than study drug during the course 
of the study. 
• OTH 05: Patient randomized more than once in the trial. 
• OTH 06: Compliance failure of the Patient influencing the safety and efficacy date as 
per investigator judgment 
• OTH 12: Patient who received study medication before or  without randomization 
• OTH 18: Prohibited asthma related medications started in periods different from the 
once stablish in the protocol 
5.9 
Rules to exclude patients using single depot corticosteriod 
injections: 
Patients using below listed single depot corticosteriod injections will be excluded from efficacy 
analysis. 


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Reported Name of Drug, Med, or Therapy 
Standardized Medication Name 
CELESTONE CHRONODOSE 
CELESTONA BIFAS 
celestone(betamethasone acetate +sodium 
phosphate) 
BETAMETHASONE SODIUM 
PHOSPHATE 
CORTEROID RETARD (BETAMETHASONE ACETATO) 
BETAMETHASONE ACETATE 
Corteroid retard. 
BETAMETHASONE 
Diprospan 
BETAMETHASONE 
Methylprednisolone Acetate or Depo-Medrol 
  
 
6 
References 
Elizabeth Juniper (2004). Asthma Control Questionnaire: Background, Administration and 
Analysis 
Brannath et al.(2009). Trimmed weighted Simes’ test for two one-sided hypotheses with 
arbitrarily correlated test statistics. Biometrical Journals  2009; 51(6): 885-898 
 
Kenward MG and Roger JH (1997). Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 53(3):983-97 
Scott L. Zeger; Kung Yee Liang; Paul S. Albert (1988). Models for Longitudinal Data: A 
generalized Estimating Equation Approach. Biometrics, Volume 44, Issue 4, 1049-1060 
Using SAS® Procedures FREQ, GENMOD, LOGISTIC, and PHREG to Estimate Adjusted 
Relative Risks – A Case Study. Jiming Fang, Institute for Clinical Evaluative Sciences, Toronto, 
Ontario, Canada 
Zou, G (2004). A modified poisson regression approach to prospective studies with binary data. 
Am J Epidemiol 159, 702-706. 
Kerstjens HAM, Engle M, Dahl R, et al (2012). Tiotropium in Asthma Poorly Controlled with 
Standard Combination Therapy. N Engl J Med; 367: 1198-1207