Study of Pulmonary Rehabilitation In Nintedanib Treated Patients With IPF: Improvements in Activity, Exercise Endurance Time, and QoL
Phase: PHASE4
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

C li nic al Tri al Pr ot oc ol
TI T L E P A G E
D oc u me nt N u m ber:
c 1 9 5 5 8 8 0 8- 0 6
E u dr a C T N o.:
E U Tri al N o:
N ot a p plica ble.
BI Tri al N o.:
1 1 9 9- 0 3 2 4
BI I n vesti g ati o n al 
Pr o d uct(s):
N i nte da ni b
Title:
St u d y  of P ul m o nar y Re ha bilitati o n In Ni nte da ni b Treate d 
Patie nts wit h I P F: I m pr o ve me nts i n Acti vit y , E xercise 
E n d ura nce Ti me, a n d Q o L 
L a y Title:
St u d y  of p ul m o nar y re ha bilitati o n i n patie nts wit h Idi o pat hic 
P ul m o nar y  Fi br osis (IP F)
Cli nic al P h ase:
I V
Cli nic al Tri al 
Le a der :
C o or di n ati n g 
I n vesti g at or:
St at us:
Fi nal Pr ot oc ol ( Re vise d Pr ot oc ol base d o n Gl o bal A me n d me nt 
2 )
Versi o n a n d D ate:
Versi o n: 3 . 0
D ate: 1 6 Dec 2 0 1 9
P a ge 1 of 1 0 3
Pr o priet ar y c o nfi de nti al i nf or m ati o n .
2 0 1 9 B oe hri n ger I n gel hei m I nter n ati o n al G m b H or o ne or m ore of its affili ate d c o m p a nies. All ri g hts reser ve d.
T his d oc u me nt ma y n ot - i n f ull or i n part - be passe d o n, re pr o d uce d, p u blis he d or ot her wise use d wit h o ut pri or writte n per missi o n.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
C LI NI C A L T RI A L P R O T O C O L S Y N O P SI S
C o m p a n y n a me
B oe hri n ger I n gel hei m 
Fi nis he d pr o d uct n a me
O F E V
Acti ve i n gre die nt 
n a m e:
Ni nte da ni b
Pr ot oc ol d ate
1 5 A u g 2 0 1 8
Re visi o n d ate
1 6 Dec 2 0 1 9
Tri al n u m ber
1 1 9 9- 0 3 2 4
Title of tri al:
St u d y  of P ul m o nar y Re ha bilitati o n In Ni nte da ni b Treate d Patie nts 
wit h I P F: I m pr o ve me nts i n Acti vit y , E xercise E n d ura nce Ti me, a n d 
Q o L
C o or di n ati n g 
I n vesti g at or:
Tri al site(s):
M ultice nter
Cli nic al p h ase:
I V
O bjecti ve(s):
Deter mi ne t he differe nce i n c ha n ge fr o m baseli ne i n 6 M W D w he n 
p ul m o nar y  re ha bilitati o n ( P R) is a d de d t o sta ble u n derl yi n g 
ni nte da ni b t hera p y i n patie nts wit h i di o pat hic p ul m o nar y fi br osis 
(IP F)
Deter mi ne t he differe nce i n c ha n ge i n Q ualit y of Life ( Q o L ) w he n 
p ul m o nar y  re ha bilitati o n ( P R) is a d de d t o sta ble u n derl yi n g
ni nte da ni b t hera p y i n patie nts wit h i di o pat hic p ul m o nar y fi br osis 
(IP F)
Deter mi ne if t here is a n e n d uri n g effect i n 6 M W D, Q o L a n d l u n g 
f u ncti o n fr o m p ul m o nar y re ha bilitati o n ( P R) w he n p ul m o nar y 
re ha bilitati o n ( P R) is a d de d t o sta ble u n derlyi n g ni nte da ni b t hera py 
i n patie nts wit h i di o pat hic p ul m o nar y fi br osis (I P F)
M e t h o d ol o g y:
M ulti -ce ntre, pr os pecti ve, ra n d o mise d, o pe n la bel cli nical trial
N u m ber of p atie nts 
e ntere d:
2 9 0 ( 9 6 s u b-st u d y)
N u m ber of p atie nts o n 
e ac h tre at me nt:
1 4 5 ( 4 8 s u b-st u d y)
Di a g n osis:
I di o pat hic P ul m o nar y  Fi br osis (IP F) acc or di n g t o A merica n 
T h oracic S ociet y  ( A T S), E ur o pea n Res pirat or y S ociet y ( E R S), 
Ja pa nese Res pirat or y S ociet y  (J R S), a n d Lati n A merica n T h oracic 
Ass ociati o n ( A L A T) criteria p u blis he d i n 2 0 1 1, c o nsiste nt wit h 
I N P U L SI S criteria I ncl usi o n
M ai n i n - a n d e xcl usi o n 
criteri a

A ge ≥ 4 0 y ears. 

F orce d Vital Ca pacit y  ( F V C) ≥ 4 5 % of pre dicte d

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

F E V 1/ F V C greater t ha n/e q ual t o . 7 a n d Car b o n M o n o xi de 
Diff usi o n Ca pacit y ( D L C O ) (c orrecte d f or he m o gl o bi n [ H g b])      
3 0 -7 9 % of pre dicte d

C o nfir me d dia g n osis of I P F acc or di n g t o 2 0 1 1 
A T S/ E R S/J R S/ A L A T g ui deli nes b y  Hi g h Res ol uti o n C o m p ute d 
T o m o gra p h y ( H R C T ) (c o nsiste nt wit h IN P U L SI S criteria) or 
l u n g bi o psy ta ke n wit hi n 2 4 m o nt hs  pri or t o pr o vi di n g 
I nf or me d C o nse nt 

Treate d o n a st a ble d ose of ni nte da ni b f or u p t o 3 0 m o nt hs .
Patie nts w h o ha ve rece ntl y  starte d ni nte da ni b 1 5 0 m g BI D a n d 
ha ve starte d b y t he da y  of ra n d o mizati o n m ust be o n ni nte da ni b 
1 5 0 m g BI D a mi ni m u m of 1 0 da y s b y t he first da y of 
p ul m o nar y  re ha bilitati o n.
E xcl usi o n

Maj or s ur ger y  wit hi n 1 2 wee ks pri or t o ra n d o mizati o n or 
pla n ne d wit hi n 6 m o nt hs after scree ni n g w hic h c o ul d i nterfere 
wit h t he a bilit y  t o partici pate i n p ul m o nar y re ha bilitati o n

Acti ve or s us pecte d mali g na nc y  or hist or y of mali g na nc y wit hi n 
3 y ears pri or t o scree ni n g

C urre ntl y  e nr olle d i n or less t ha n 3 0 da ys si nce e n di n g  a n ot her 
i nter ve nti o nal i n vesti gati o nal de vice or dr u g trial 

W o me n w h o are pre g na nt, n ursi n g, or w h o pla n t o bec o me 
pre g na nt  i n t he trial

Pre vi o us partici pati o n i n p ul m o nar y  re ha bilitati o n pr o gra m 
wit hi n 4 5 da y s pri or t o si g ni n g i nf or me d c o nse nt
Test pr o d uct(s):
ni nte da ni b
d ose:
1 5 0 m g BI D
m o de of 
a d mi nistr ati o n:
oral
C o m p ar at or pr o d ucts:
N o ne
d ose:
N A
m o de of 
a d mi nistr ati o n:
N A
D ur ati o n of tre at m e nt:
2 4 wee ks
E n d p oi nts

Pri m ar y E n d p oi nt
o
C ha n ge fr o m baseli ne i n 6 M W D at 1 2 wee ks

Sec o n d ar y E n d p oi nts
o
C ha n ge fr o m baseli ne i n Q o L  ( S G R Q, K BI L D, U C S D 
S O B Q) at 1 2 a n d 2 4 wee ks 
o
C ha n ge fr o m baseli ne i n 6 M W D at 2 4 wee ks 
o
C ha n ge fr o m baseli ne i n l u n g f u ncti o n ( F V C) at 1 2 wee ks 
a n d 2 4 wee ks u si n g eac h of

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
•
A bs ol ute c ha n ge fr o m baseli ne of F V C a n d F V C % 
pre dicte d
•
Relati ve c ha n ge fr o m baseli ne of F V C a n d F V C % 
pre dicte d
•
A bs ol ute cate g orical c ha n ge of F V C % pre dicte d u p 
t o 1 2 a n d 2 4 wee ks: decrease by > 5 %, i ncrease b y 
> 5 % , a n d c ha n ge wit hi n ≤ 5
•
A bs ol ute cate g orical c ha n ge of F V C % pre dicte d u p 
t o 1 2 a n d 2 4 wee ks: decrease by > 1 0, i ncrease b y 
> 1 0, a n d c ha n ge wit hi n ≤ 1 0
o
C ha n ge fr o m baseli ne i n dail y acceler o meter acti vit y fr o m 
baseli ne at 1 2 a n d 2 4 wee ks 
 
 
 
S afet y criteri a:

Vital si g ns, p h ys ical e xa mi nati o n, wei g ht

Cli nical la b orat or y  tests ( hae mat ol o g y, cli nical c he mistr y, 
a n d uri nal ys is) 

Re p orti n g of a d verse e ve nts

1 2 lea d electr ocar di o gra m
St atistic al m et h o ds:
T he pri mar y  ( 6 M W D at 1 2 wee ks) will be a nalys e d usi n g t he 
A nal y sis of C o varia nce m o del i ncl u di n g i nter ve nti o n as a fi xe d 
cate g orical c o variate a n d baseli ne 6 M W D as c o nti n u o us c o variate
6 M W D will be a nal y se d o n t he ori gi nal scale. 
 
 
all ot her 
assess me nts will be a nal yse d usi n g ori gi nal scales. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
F or sec o n dar y  
 e n d p oi nts, 1 2-wee k e n d p oi nts will 
be a nal ys e d usi n g si milar A N C O V A met h o d ol o g y as t he pri mar y  
e n d p oi nt.  T he 2 4-wee k e n d p oi nts will be a nal y ze d usi n g a mi xe d 
m o del wit h re peate d meas ures.  
Descri pti ve statistics will be s h o w n f or all efficac y a n d safet y 
e n d p oi nts .

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
F L O W C H A R T
* I nf or me d c o nse nt nee ds t o be si g ne d bef ore a n y pr oce d ure relate d t o t he st u d y, all A Es a n d C o nc o mita nt Treat me nts 
occ urri n g after t he I nf or me d c o nse nt ha ve t o be rec or de d.
1 H R C T will be acce pta ble if d o ne wit hi n 2 4 m o nt hs, if n ot a vaila ble patie nt will be se nt f or H R C T bet wee n Visit 1 a n d 2, 
or wit hi n 7 da ys of c o m pleti n g Visit 2.
2 Patie nts will wear t he p h ysical acti vit y m o nit or a n d c o m plete t he e Diar y ( P R Oacti ve T o ol ) 2 4 h o urs e ver y d a y f or 1 wee k 
pri or t o Visits 1, 2, 5 a n d 7 . De vices will be dis pe nse d i n cli nic at Visits 0 a n d 1, a n d will be s hi p pe d t o patie nt or pic ke d 
u p fr o m cli nic at least 1 wee k pri or t o Visits 5 a n d 7.
3
 
 
 
e xercise testi n g ce nter. T he i ncre me ntal a n d practice tests ca n b ot h be d o ne at Visit 1.
5 Access I R T t o ter mi nate if scree n fail at Visit 1 or bet wee n Visit 0 a n d Visit 1 .
Scree ni n g
I nter ve nti o n al Peri o d
Tre at me nt
Visit
0
1
2
3
4
5
6
7 ( E O T)
Wee ks of tre at me nt
- 2
- 1
0
3
6
1 2
1 8
2 4 6
D a y
Ti m e wi n d o w
At least 7 
da ys 
bef ore 
visit 1
≥ 7 d 
bef ore V 2
1
2 2
± 3
4 3
± 3
8 5
± 3
1 2 7
± 3
1 6 9
± 7
I nf or me d c o nse nt
X *
De m o gra p hics/ baseli ne c o n diti o ns
X
Me dical hist or y 
X
I n-/e xcl usi o n criteria
X
X
X
P h ysical e xa mi nati o n 7, vital si g ns
X
X
X
X
X
X
X
La b orat or y test 
X
X
X
X
X
X
X
Pre g na nc y test
X
X
X
X
X
X
X
S pir o metr y ( F V C)
X
X
X
X
S p O 2 ( peri p heral ca pillar y o x y ge n sat urati o n)
X
X
X
X
D L C O
X
X
X
X
H R C T se nt f or o utc o mes re vie w1
X 1
X 1
1 2 -lea d electr ocar di o gra m ( E C G )
X
X
( Practice) Si x-mi n ute wal k test
X
Si x mi n ute wal k test
X
X
X
I nstr uct Patie nt o n Acti vit y M o nit ori n g a n d 
P R Oacti ve t o ol ( e Diar y)2
X
X
X
X
X
Acti vit y M o nit ori n g ( D y na p ort)
X
X
X
X
X
S G R Q, K BI L D , U C S D S O B Q
X
X
X
X
P R Oacti ve T o ol 2, 3
X
X
X
X
X
Ra n d o misati o n
X
Sc he d ule p ul m o nar y re ha b da ys f or assi g ne d 
patie nts 6
X
Rec or d p ul m o nar y re ha b 
X
X
X
IR T
X
X 5
X
A d verse e ve nts , c o nc o mita nt treat me nts
X
X
X
X
X
X
X
C o ncl u de s u bject partici pati o n
X

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
6
Ti me bet wee n visits 2 a n d 3 ma y be e xte n de d f or u p t o  6 wee ks t o all o w sc he d uli n g of t he o nset of p ul m o nar y 
re ha bilitati o n, t he treat me nt peri o d will be gi n o n t he first da y of p ul m o nar y re ha bilitati o n a n d all visits m o ve acc or di n gl y 
t o kee p t he sa me visit sc he d ule.
7 Hei g ht a n d wei g ht t o be c ollecte d at Visit 1 o nl y .

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T A B L E O F C O N T E N T S
TI T L E P A G E ...........................................................................................................................1
C LI NI C A L T RI A L P R O T O C O L S Y N O P SI S .....................................................................2
F L O W C H A R T ........................................................................................................................6
T A B L E O F C O N T E N T S ........................................................................................................8
A B B R E VI A TI O N S ................................................................................................................1 2
1.
I N T R O D U C TI O N...............................................................................................1 5
1. 1
M E DI C A L B A C K G R O U N D .............................................................................1 5
1. 2
D R U G P R O FI L E ................................................................................................1 5
1. 3
R A TI O N A L E F O R P E R F O R MI N G T H E T RI A L .........................................1 5
1. 4
B E N E FI T - RI S K A S S E S S M E N T .....................................................................1 6
2.
T RI A L O B J E C TI V E S A N D E N D P OI N T S ......................................................1 7
2. 1
M AI N O B J E C TI V E S, P RI M A R Y A N D S E C O N D A R Y E N D P OI N T S ........1 7
2. 1. 1
M ai n o bjecti ves ....................................................................................................1 7
2. 1. 2
Pri m ar y e n d p oi nt(s)............................................................................................ 1 7
2. 1. 3
Sec o n d ar y e n d p oi nt(s) ........................................................................................1 7
3.
D E S C RI P TI O N O F D E SI G N A N D T RI A L P O P U L A TI O N .........................1 9
3. 1
O V E R A L L T RI A L D E SI G N A N D P L A N .......................................................1 9
3. 2
DI S C U S SI O N O F T RI A L D E SI G N, I N C L U DI N G T H E C H OI C E O F 
C O N T R O L G R O U P( S) ......................................................................................1 9
3. 3
S E L E C TI O N O F T RI A L P O P U L A TI O N .......................................................1 9
3. 3. 1
M ai n di a g n osis f or
tri al e ntr y ............................................................................2 0
3. 3. 2
I ncl usi o n criteri a................................................................................................. 2 0
3. 3. 3
E xcl usi o n criteri a ................................................................................................2 1
3. 3. 4
Wit h dr a w al of p atie nts fr o m t her a p y or assess me nts.....................................
2 1
3. 3. 4. 1
Wit h dra wal fr o m trial treat me nt
...........................................................................2 2
3. 3. 4. 2
Wit h dra wal of c o nse nt f or trial partici pati o n ........................................................2 2
3. 3. 4. 3
Disc o nti n uati o n of t he trial b y  t he s p o ns or...........................................................2 2
4.
T R E A T M E N T S ...................................................................................................2 4
4. 1
I N V E S TI G A TI O N A L T R E AT M E N T S ...........................................................2 4
4. 1. 1
I de ntit y of t he i n vesti g ati o n al me dici n al pr o d ucts........................................... 2 4
4. 1. 2
Selecti o n of d oses i n t he tri al ..............................................................................2 4
4. 1. 3
Met h o d of assi g ni n g p atie nts t o tre at me nt gr o u ps ...........................................2 4
4. 1. 4
Dr u g assi g n me nt a n d a d mi nistr ati o n of d oses f or e ac h p atie nt...................... 2 4
4. 1. 5
Bli n di n g a n d pr oce d ures f or u n bli n di n g ...........................................................2 5
4. 1. 5. 1
Bli n di n g................................................................................................................. 2 5
4. 1. 5. 2
U n bli n di n g a n d brea ki n g t he c o de ........................................................................2 5
4. 1. 6
P ac k a gi n g, l a belli n g, a n d re- s u p pl y...................................................................2 5

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
4. 2
O T H E R T R E A T M E N T S, E M E R G E N C Y P R O C E D U R E S, 
R E S T RI C TI O N S ................................................................................................2 5
4. 2. 1
Ot her tre at me nts a n d e mer ge nc y pr o ce d ures ..................................................2 5
4. 2. 1. 1
Ma na ge me nt of a d verse e ve nts relate d t o ni nte da ni b ...........................................2 5
4. 2. 1. 2
Ma na ge me nt of ot her a d verse e ve nts ....................................................................2 5
4. 2. 2
Restricti o ns.......................................................................................................... 2 5
4. 2. 2. 1
Restricti o ns o n c o nc o mita nt treat me nt ..................................................................2 5
4. 2. 2. 2
C o nc o mita nt treat me nts all o we d ...........................................................................2 6
4. 2. 2. 3
Restricti o ns o n diet a n d life st y le..........................................................................2 6
4. 2. 2. 4
Restricti o ns re g ar di n g w o me n of c hil d beari n g p ote ntial ......................................2 7
4. 3
T R E A T M E N T C O M P LI A N C E ........................................................................2 7
5.
A S S E S S M E N T S ..................................................................................................2 8
5. 1
A S S E S S M E N T O F E F FI C A C Y ........................................................................2 8
5. 1. 1
E n d p oi nts of effic ac y........................................................................................... 2 8
5. 1. 1. 1
Pri mar y  e n d p oi nt...................................................................................................2 8
5. 1. 1. 2
Sec o n dar y  e n d p oi nts.............................................................................................2 8
5. 1. 2
Assess me nt of effic ac y .........................................................................................2 9
5. 1. 2. 1
6 Mi n ute wal k test .................................................................................................2 9
5. 1. 2. 2
C ha n ge i n q ualit y  of life........................................................................................2 9
5. 1. 2. 3
Assess me nt of l u n g f u ncti o n .................................................................................2 9
5. 1. 2. 4
Dail y  acti vit y m o nit ori n g......................................................................................3 0
5. 1. 2. 6
P R Oacti ve t o ol...................................................................................................... 3 1
5. 2
A S S E S S M E N T O F S A F E T Y .............................................................................3 1
5. 2. 1
P h ysic al e x a mi n ati o n ..........................................................................................3 1
5. 2. 2
Vit al si g ns .............................................................................................................3 1
5. 2. 3
S afet y l a b or at or y p ar a meters ............................................................................3 2
5. 2. 4
Electr oc ar di o gr a m ..............................................................................................3 3
5. 2. 5
Ot her s afet y p ar a meters..................................................................................... 3 3
5. 2. 6
Assess me nt of a d verse e ve nts .............................................................................3 3
5. 2. 6. 1
Defi niti o ns of A Es ................................................................................................3 3
5. 2. 6. 2
A d verse e ve nt a n d seri o us a d verse e ve nt c ollecti o n a n d re p orti n g ......................3 5
5. 2. 6. 3
Re p orti n g t o healt h a ut h orities ..............................................................................3 7
5. 3
D R U G C O N C E N T R A TI O N M E A S U R E M E N T S A N D 
P H A R M A C O KI N E TI C S ...................................................................................3 7
5. 3. 1
Assess me nt of p h ar m ac o ki netics .......................................................................3 7
5. 3. 2
Met h o ds of s a m ple c ollecti o n
.............................................................................3 7
5. 3. 3
A n al ytic al deter mi n ati o ns ..................................................................................3 7
5. 3. 4
P h ar m ac o ki netic – p h ar m ac o d y n a mic rel ati o ns hi p ........................................3 7
5. 4
A S S E S S M E N T O F BI O M A R K E R( S) ..............................................................3 7
5. 5
O T H E R A S S E S S M E N T S ...................................................................................3 8
5. 6
A P P R O P RI A T E N E S S O F M E A S U R E M E N T S ..............................................3 8
6.
I N V E S TI G A TI O N A L P L A N.............................................................................3 9
6. 1
VI SI T S C H E D U L E .............................................................................................3 9

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
6. 2
D E T AI L S O F T RI A L P R O C E D U R E S A T S E L E C T E D VI SI T S .................4 0
6. 2. 1
Scree ni n g a n d r u n -i n peri o d(s) ..........................................................................4 0
6. 2. 2
Tre at me nt peri o d(s) ............................................................................................4 1
6. 2. 3
F oll o w u p peri o d a n d tri al c o m pleti o n ..............................................................4 2
7.
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F
S A M P L E SI Z E ....................................................................................................4 4
7. 1
S T A TI S TI C A L D E SI G N - M O D E L .................................................................4 4
7. 2
N U L L A N D A L T E R N A TI V E H Y P O T H E S E S ...............................................4 4
7. 3
P L A N N E D A N A L Y S E S .....................................................................................4 4
7. 3. 1
Pri m ar y e n d p oi nt a n al yses .................................................................................4 5
7. 3. 2
Sec o n d ar y e n d p oi nt a n al yses .............................................................................4 5
7. 3. 4
S afet y a n al yses .....................................................................................................4 7
7. 3. 5
P h ar m ac o ki netic a n d P h ar m ac o d y n a mic a n al yses.......................................... 4 7
7. 4
I N T E RI M A N A L Y S E S...................................................................................... 4 7
7. 5
H A N D LI N G O F MI S SI N G D A T A ...................................................................4 8
7. 6
R A N D O MI S A TI O N ...........................................................................................4 8
7. 7
D E T E R MI N A TI O N O F S A M P L E SI Z E .........................................................4 8
8.
I N F O R M E D C O N S E N T, T RI A L R E C O R D S, D A T A P RO T E C TI O N, 
P U B LI C A TI O N P O LI C Y, A N D A D MI NI S T R A TI V E S T R U C T U R E ........4 9
8. 1
T RI A L A P P R O V A L, P A TI E N T I N F O R M A TI O N, I N F O R M E D 
C O N S E N T ...........................................................................................................4 9
8. 2
D A T A Q U A LI T Y A S S U R A N C E ......................................................................5 0
8. 3
R E C O R D S ...........................................................................................................5 0
8. 3. 1
S o urce d oc u me nts ...............................................................................................5 0
8. 3. 2
Direct access t o s o urce d at a a n d d oc u me nts..................................................... 5 1
8. 3. 3
St or a ge peri o d of rec or ds................................................................................... 5 2
8. 4
E X P E DI T E D R E P O R TI N G O F  A D V E R S E E V E N T S ..................................5 2
8. 5
S T A T E M E N T O F C O N FI D E N TI A LI T Y A N D P A TI E N T P RI V A C Y ........5 2
8. 5. 1
C ollecti o n, st or a ge a n d f ut ure use of bi ol o gic al s a m ples a n d 
c orres p o n di n g d at a .............................................................................................5 2
8. 6
T RI A L MI L E S T O N E S .......................................................................................5 3
8. 7
A D MI NI S T R A TI V E S T R U C T U R E O F T H E T RI A L................................... 5 3
9.
R E F E R E N C E S ....................................................................................................5 5
9. 1
P U B LI S H E D R E F E R E N C E S ............................................................................5 5
9. 2
U N P U B LI S H E D R E F E R E N C E S ......................................................................5 6
1 0.
A P P E N DI C E S .....................................................................................................5 7
1 0. 1
E X E R CI S E T E S TI N G I N C L U DI N G 6 MI N U T E W A L K T E S T A N D 
W O R K C Y C L E E R G O M E T R Y
.......................................................................5 7
1 0. 1. 1
Ge ner al c o nsi de r ati o ns f or 6 M W T a n d e xercise testi n g .................................5 7
1 0. 1. 2
Si x -mi n ute w al k test ............................................................................................5 9

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 2
M O DI FI E D B O R G S C A L E ( M B S-S) ...............................................................6 7
1 0. 3
S T. G E O R G E’ S R E S PI R A T O R Y Q U E S TI O N N AI R E ( S G R Q) ...................6 8
1 0. 4 
E L E C T R O NI C DI A R Y WI T H D AI L Y P R O A C TI V E T O O L ......................7 7
1 0. 4. 1
T he P R O acti ve T o ol ............................................................................................7 7
1 0. 4. 2
Electr o nic Di ar y – P R O acti ve Q uesti o n n aire................................................... 7 9
1 0. 5
K BI L D ..................................................................................................................8 1
1 0. 6
U C S D M E DI C A L C E N T E R P U L M O N A R Y R E H A BI LI T A TI O N 
P R O G R A M S H O R T N E S S -O F -B R E A T H Q U E S TI O N N AI R E ( U C S D-
S O B Q) ..................................................................................................................8 4
1 0. 7
L U N G F U N C TI O N C RI T E R I A........................................................................8 9
1 1.
D E S C RI P TI O N O F G L O B A L A M E N D M E N T( S) .........................................9 0
1 1. 1
G L O B A L A M E N D M E N T 1 ..............................................................................9 0
1 1. 2
G L O B A L A M E N D M E N T 2 ..............................................................................9 8

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
A B B R E VI A TI O N S
A D R(s)
A d verse Dr u g Reacti o n(s)
A E
A d verse E ve nt
A E SI
A d verse E ve nt of S pecial I nterest
A L A T
Lati n A merica n T h oracic Ass ociati o n
A L T
Ala ni ne A mi n otra nsferase
A N C O V A
A nal y sis of C o varia nce
A S T
As partate A mi n otra nsferase
A T P
A de n osi ne Tri p h os p hate
A T S
A merica n T h oracic S ociet y
b.i. d. / BI D
bis i n die (t wice dail y d osi n g)
ß H C G
Beta H u ma n C h ori o nic G o na d otr o p hi n
C A
C o m pete nt A ut h orit y
C O P D
C hr o nic O bstr ucti ve P ul m o nar y  Disease
C R A
Cli nical Researc h Ass ociate
C R F
Case Re p ort F or m, pa per or electr o n ic (s o meti mes referre d t o as “e C R F”)
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C T L
Cli nical Trial L ea der
C T M
Cli nical Trial Ma na ger
C W R C E
C o nsta nt W or k Rate C y cle Er g o metr y
DI LI
Dr u g I n d uce d Li ver I nj ur y
D Lc o
Car b o n M o n o xi de Diff usi o n Ca pacit y
D O M S
Dela y e d O nset M uscle S ore ness
D -P P A C
Dail y  Assess me nt of P h ysical Acti vit y
d/t
Vel ocit y  ( dista nce/ti me)
E C G
Electr ocar di o gra m
E D C /e D C
Electr o nic Data Ca pt ure
e Diar y
Electr o nic Diar y / Electr o nic Interface
E E L V
E n d -E x pirat or y  Lu n g V ol u me
E O T
E n d of Treat me nt
E R S
E ur o pea n Res pirat or y  S ociet y
E u dra C T
E ur o pea n Cli nical Trial s Data base
f
Breat hi n g Fre q ue nc y
F C
Fl o w C hart
F D A
F o o d a n d Dr u g A d mi nistrati o n
F G F/ R
Fi br o blast Gr o wt h Fact or/ Rece pt or
F L T 3
F ms -li ke T yr osi ne Ki nase- 3
F V C
F orce d Vital Ca pacit y
G C P
G o o d Cli nical Practice
H g b
He m o gl o bi n
H R
Heart Rate
H R Q o L
Healt h Relate d Q ualit y  of Life
H R C T
Hi g h Res ol uti o n C o m p ute d T o m o gra p h y
I C
I ns pirat or y Ca pacit y

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
I C H
I nter nati o nal C o u ncil o n Har m o nizati o n
I E C
I n de pe n de nt Et hics C o m mittee
I L D
I nterstitial Lu n g Disease
I PF
I dio pat hic P ul m o nar y Fi br osis
I RB
I nstit uti o nal Re vie w B oar d
I R T
I nteracti ve Res p o nse Tec h n ol o g y
I SF
I n vesti gat or Site File
J R S
Ja pa nese Res pirat or y S ociet y
K BI L D
Ki n g’s Brief I L D Q uesti o n naire
L D H
Lactic Aci d De h y dr o ge nase
L P D D
Last Patie nt Dr u g Disc o nti n uati o n
M A H
Mar keti n g A ut h orizati o n H ol der
Me d D R A
Me dical Dicti o nar y  f or Dr u g Re g ulat or y Acti vities
N A C
N- Acet y l Cys ti ne
n R T Ks
N o n -rece pt or T yr osi ne Ki nases
O P U
O perati n g U nit
P D G F/ R
Platelet Deri ve d Gr o wt h Fact or/ Rece pt or
P R
P ul m o nar y  Re ha bilitati o n
Q L F
Q ua ntitati ve L u n g Fi br osis Sc ore
Q o L
Q ualit y  of Life
R E M L
Restricte d Ma xi m u m L i keli h o o d 2
R S
Ra n d o mize d Set
R T Ks
Rece pt or T yr osi ne Ki nases
S A D R(s)
Seri o us A d verse Dr u g Reacti o n(s)
S A E
Seri o us A d verse E ve nt
Sa O 2
O x y ge n Sat urati o n
S D
Sta n dar d De viati o n
S O P(s)
Sta n dar d O perati n g Pr oce d ure(s)
S P 0 2
Bl o o d O x y ge n Sat urati o n or peri p heral ca pillar y  o x yge n sat urati o n
Te
E x pirati o n Ti me
Ti
I ns pirati o n Ti me
T L C
T otal L u n g Ca pacit y
T S A P
Trial Statistical A nal y sis Pla n
U C S D S O B Q
U ni versit y  of Calif or nia Sa n Die g o S h ort ness of Breat h Q uesti o n naire
U L N
U p per Li mit of N or mal
U S
U nite d States
V E
Mi n ute Ve ntilati o n
V E G F/ R
Vasc ular E n d ot helial Gr o wt h Fact or/ Rece pt or
V C O 2
Car b o n Di o xi de Pr o d ucti o n
V M U
Vect or Ma g nit u de U nits per Mi n ute
V O 2
O x y ge n C o ns u m pti o n
V T
Ti dal V ol u me
Wca p
Ma xi mal W or k Ca pacit y
W H O
W orl d Healt h Or ga nizati o n
W O C B P
W o m a n of c hil d beari n g p ote ntial
6 M W D
Si x Mi n ute Wal k Dista nce

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
6 M W T
Si x Mi n ute Wal k Test

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1.
I N T R O D U C TI O N
1. 1
M E DI C A L B A C K G R O U N D
I di o pat hic P ul m o nar y Fi br osis (IP F) is a c hr o nic disease of u n k n o w n aeti ol o g y  t hat is 
c haracterize d b y pr o gressi ve fi br otic destr ucti o n of t he l u n g, res ulti n g i n disa bli n g d ys p nea 
a n d p o or gas e xc ha n ge. T he a vera ge life e x pecta nc y  i n I P F patie nts is 3-5 y ears ( U 0 7 - 1 2 4 8-
0 7 ). Ni nte da ni b ( O F E V) is a s mall m olec ule a nti-fi br otic ki nase i n hi bit or ( P D G F/ R [ platelet 
deri ve d gr o wt h fact or/rece pt or], F G F/ R [fi br o blast gr o wt h fact o r/rece pt or], V E G F/ R 
[ vasc ular e n d ot helial gr o wt h fact or/rece pt or]) t hat has bee n de vel o pe d f or t he trea t me nt of 
I PF. T he oretical a n d p har mac ol o gical m o dels s u g gest t hat i n hi biti o n of t hese ki nase rece pt ors 
ma y  i nterfere wit h t he fi br otic si g nali n g casca de.  O F E V was a p pr o ve d as a treat me nt f or I PF 
i n 2 0 1 4. 
1. 2
D R U G P R O FI L E
Ni nte da ni b is a s mall m olec ule t hat i n hi bits m ulti ple rece pt or t yr osi ne ki nases ( R T Ks) a n d 
n o n- rece pt or tyr osi ne ki nases ( n R T Ks). Ni nte da ni b i n hi bits t he f oll o wi n g R T Ks: platelet -
deri ve d gr o wt h fact or rece pt or ( P D G F R) a n d fi br o blast gr o wt h fact or rece pt or ( F G F R) 1 -3, 
vasc ular e n d ot helial gr o w t h fact or rece pt or ( V E G F R) 1-3, a n d F ms -li ke t yr osi ne ki nase- 3 
( FL T 3). A m o n g t he m, F G F R, P D G F R, a n d V E G F R ha ve bee n i m plicate d i n I P F 
pat h o ge nesis. Ni nte da ni b bi n ds c o m petiti vel y  t o t he a de n osi ne tri p h os p hate ( A T P) bi n di n g 
p oc ket of t hese rece pt ors a n d bl oc ks t he i ntracell ular si g nali n g w hic h is cr ucial f or t he 
pr oliferati o n, mi grati o n, a n d tra nsf or mati o n of fi br o blasts re prese nti n g esse ntial mec ha nis ms 
of t he I P F pat h ol o g y . I n a d diti o n, ni nte da ni b i n hi bits t he f oll o wi n g n R T Ks: Lc k, L yn a n d Src 
ki nases. T he c o ntri b uti o n of F L T 3 a n d n R T K i n hi biti o n t o I P F efficac y  is u n k n o w n.
F or a m ore detaile d descri pti o n of t he ni nte da ni b pr ofile please refer t o t he c urre nt a p pr o ve d 
la beli n g (R 1 8 - 1 2 8 9).
1. 3
R A TI O N A L E F O R P E R F O R MI N G T H E T RI A L
P ul m o n ar y re ha bilitati o n ( P R) has bee n defi ne d as a n “e vi de nce-base d, m ulti disci pli nar y , a n d 
c o m pre he nsi ve i nter ve nti o n f or patie nts wit h c hr o nic res pirat or y  disease w h o are 
s ym pt o matic a n d ofte n ha ve decrease d dail y life acti vities.” ( A T S/ E R S State me nt o n 
P ul m o nar y  Re ha bilitati o n). (R 1 3 - 1 5 7 8)  Data s u p p orti n g its use c o me lar gel y  fr o m t he st u d y 
of C O P D (c hr o nic o bstr ucti ve p ul m o nar y disease), i n w hic h P R has bee n s h o w n t o i ncrease 
e xercise e n d ura nce, decrease d ys p nea, i m pr o ve healt h relate d q ualit y of life, a n d re d uce 
healt h -care c ost. Data e xa mi ni n g t he r ole of P R i n i nterstitial l u n g disease (I L D) has bee n less 
v ol u mi n o us a n d nee ds t o be a d dresse d.  St u dies t hat s u p p ort t he use of P R i n I L D ha ve all 
bee n t o o s h ort a n d t o o s mall t o dr a w a n y c o ncl usi o ns.  St u dies t hat ha ve bee n c o m plete d use 
si milar pr ot oc ols t o t he C O P D P R e x perie nce, wit h t otal P R ti me of 1 0 – 1 2 wee ks.  M ost 
ha ve i ncl u de d b ot h a n e xercise a n d e d ucati o nal c o m p o ne nt.  T he rece nt P H Y S A C T O st u d y  
utilize d a n d a d diti o nal c o m p o ne nt of be ha vi o ural m o dificati o n a n d trai ni n g as part of Je a n

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
B o ur bea u’s “ L i vi n g Well wit h C O P D” pr o gra m (P 1 6 - 0 4 4 4 2).  T h us far t here are n o re p orte d 
I L D pr o gra ms t hat ha ve i ncl u de d t his c o m p o ne nt. 
St u dies t hat ha ve bee n d o ne wit h P R f or I L D, ha ve s h o w n s h ort ter m i m pact b ut n o e n d uri n g 
effect i n 6 M W D, Q o L a n d s ym pt o ms ( R 1 8 -1 7 0 4 ).  O ne li kel y ca use of t his o utc o me is t hat 
t he P R has a be nefit, b ut o nce st o p pe d t he patie nt is left wit h a n u n derlyi n g pr o gressi ve 
de bilitati n g disease t hat ca nn ot be a de q uatel y a d dresse d.  T he c o nti n ui n g disease pr o gressi o n 
ma y  accelerate t he l oss of t he i nitial P R be nefit.  Wit h treat me nt a vaila ble t hat sl o ws t he 
u n derl y i n g disease pr o gressi o n, it is reas o na ble t o e val uate w het her t he ni nte da ni b i m pact o n 
pr o gressi o n m a y  e n ha nce a n d e xte n d P R be nefits a n d its e n d ura nce o ver ti me. 
Alt h o u g h ni nte da ni b t hera p y re d uces t he a n n ual rate of F V C decli ne b y 5 0 %, n o c o nsiste nt 
mea ni n gf ul Healt h Relate d Q ualit y  of Life ( H R Q o L) effect was n ote d.  T heref ore t he 
o p p ort u nit y  t o i m pr o ve H R Q o L i n patie nts wit h I P F re mai ns a n i m p orta nt u n met me dical 
ga p. T h us, t he h y p ot hesis is t hat c o m bi ni n g ni nte da ni b a n d P R will re d uce t he rate of F V C 
decli ne a n d i m pr o ve or mai ntai n patie nt f u ncti o nal perf or ma nce a n d H R Q o L
1. 4 
B E N E FI T - RI S K A S S E S S M E N T
T his is n ot a p har mac ol o gic i nter ve nti o nal trial. All patie nts will be treate d wit h ni nte da ni b 
1 5 0 m g BI D (t wice daily) f or u p t o t hirt y m o nt hs .  Patie nts will ha ve bee n all o we d t o ha ve 
d osa ge a dj ust me nt f or ma na ge me nt of a d verse e ve nts b ut wit h res ulta nt c o nti n ua nce of 
ni nte da ni b t hera p y.  T he y will n ot be all o we d t o ha ve c o nc urre nt pirfe ni d o ne or N -acet yl  
c ystei ne ( N A C) t hera p y b ut if treate d wit h eit her dr u g pre vi o usly t he y will n ee d t o c o m plete a 
was h o ut.
Alt h o u g h rare, a p ote ntial f or gastr oi ntesti nal perf orati o n a n d dr u g -i n d uce d li ver i nj ur y
( DI LI) is u n der c o nsta nt s ur veilla nce b y s p o ns ors a n d re g ulat ors. T heref ore, t his trial re q uires 
ti mel y detecti o n, e val uati o n, a n d f oll o w- up of la b orat or y  alterati o ns i n selecte d li ver 
la b orat or y para meters t o e ns ure patie nt s´ safety, see als o secti o n 5. 2. 6, a d verse e ve nts of 
s pecial i nterest.
P ul m o nar y  re ha bilitati o n ( P R) is a sta n dar d t hera pe utic c o m p o ne nt t o t he treatme nt of 
patie nts wit h c hr o nic l u n g disease.  All patie nts are assesse d f or t heir a p pr o priate ness f or P R 
pri or t o i nitiati o n a n d d uri n g t he c o urse of P R.  At a n y p oi nt i n ti me t hat it is deter mi ne d t hat 
t he patie nt is n o l o n ger a p pr o priate f or P R, t he pr o gra m is disc o nti n ue d.  

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
2.
T RI A L O B J E C TI V E S A N D E N D P OI N T S
2. 1
M AI N O B J E C TI V E S, P RI M A R Y A N D S E C O N D A R Y E N D P OI N T S
2. 1. 1
M ai n o bjecti ves
T he f oc us of t his st u d y is t o assess t he be nefit of P R i n IP F patie nts recei vi n g sta ble 
ni nte da ni b t hera p y ( f or u p t o 3 0 m os.) a n d t o deter mi ne w het her t he P R be nefit is mai ntai ne d 
f oll o wi n g cessati o n of P R.  In a d diti o n, t he “ be y o n d t he pill” or patie nt f oc use d i m pact will 
be e val uate d b y meas uri n g t he effects of P R o n patie nt acti vit y le vels a n d H R Q o L .  T he 
e n d uri n g effect of t hese o utc o mes is i m p orta nt t o t he well -bei n g of t he patie nt. C o nce pt uall y  
ni nte da ni b re d ucti o ns i n F V C decli ne m a y  all o w f or an e n d uri n g effect f oll o wi n g P R .
T he mai n o bjecti ves of t his st u d y  are:

D eter mi ne t he differe nce i n c ha n ge fr o m baseli ne i n 6 M W D w he n p u l m o nar y 
re ha bilitati o n ( P R) is a d de d t o sta ble u n derl yi n g ni nte da ni b t hera py i n patie nts 
wit h i di o pat hic p ul m o nar y fi br osis (I P F)

Deter mi ne t he differe nce i n c ha n ge i n Q o L w he n p ul m o nar y  re ha bilitati o n 
( P R) is a d de d t o sta ble u n derl yi n g ni nte da ni b t hera py i n patie nts wit h 
i di o pat hic p ul m o nar y fi br osis (IP F)

Deter mi ne if t here is a n e n d uri n g effect i n 6 M W D, Q o L  an d l u n g f u ncti o n
fr o m p ul m o nar y  re ha bilitati o n ( P R) w he n p ul m o nar y  re ha bilitati o n ( P R) is 
a d de d t o sta ble u n derl yi n g ni nte da ni b t hera p y in patie nts wit h i di o pat hic 
p ul m o nar y  fi br osis (I P F)
2. 1. 2
Pri m ar y en d p oi nt(s)
o
C ha n ge fr o m baseli ne i n 6 M W D at 1 2 wee ks
2. 1. 3 
Sec o n d ar y e n d p oi nt(s)
o
C ha n ge fr o m baseli ne i n Q o L  ( S G R Q, K BI L D, U C S D S O B Q) at 1 2 a n d 2 4 
wee ks 
o
C ha n ge fr o m baseli ne i n 6 M W D at 2 4 wee ks 
o
C ha n ge fr o m baseli ne i n l u n g f u ncti o n ( F V C) at 1 2 wee ks a n d 2 4 wee ks usi n g 
eac h of

A bs ol ute c ha n ge fr o m baseli ne of F V C a n d F V C % pre dicte d

Relati ve c ha n ge fr o m baseli ne of F V C a n d F V C % pre dicte d

A bs ol ute cate g orical c ha n ge of F V C % pre dicte d u p t o 1 2 a n d 2 4 
wee ks: decrease b y > 5 %, i ncrease b y > 5 %, a n d c ha n ge wit hi n ≤ 5

A bs ol ute cate g orical c ha n ge of F V C % pre dicte d u p t o 1 2 a n d 2 4 
wee ks: decr ease b y > 1 0, i ncrease b y  > 1 0, a n d c ha n ge wit hi n ≤ 1 0
o
C ha n ge fr o m baseli ne i n dail y acceler o meter acti vit y at 1 2 a n d 2 4 wee ks 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
3.
D E S C RI P TI O N O F D E SI G N A N D T RI A L P O P U L A TI O N
3. 1
O V E R A L L T RI A L D E SI G N A N D P L A N
T his is a P hase I V, m ulti -ce ntre, pr os pecti ve, ra n d o mise d, o pe n la bel cli nical trial t o 
i n vesti gate t he effect of p ul m o nar y re ha bilitati o n i n patie nts wit h I P F c urre ntl y  treate d wit h 
ni nte da ni b at a d ose of 1 5 0 m g bi d f or u p t o 3 0 m o nt hs .
A t otal of a p pr o xi matel y  2 9 0 patie nts wit h c o nfir me d I P F dia g n osis, alrea d y  usi n g ni nte da ni b 
will be ra n d o mise d, 1 4 5 i n acti ve ar m a n d 1 4 5 i n t he c o ntr ol gr o u p.
After a scree ni n g visit, if t he patie nt c o m plies wit h all i ncl usi o n a n d e xcl usi o n criteria a n d 
pr o vi des i nf or me d c o nse nt, ra n d o misati o n will be perf or me d b y p h o ne or I nter net, usi n g a n 
I nteracti ve p h o ne/ we b Res p o nse S yste m (I RT ). Patie nts will t he n e nter t he treat me nt p hase 
f or 2 4 wee ks. T he treat me nt p hase c o nsists of 1 2 wee ks of p ul m o nar y re ha bilitati o n f or t h ose 
patie nts ra n d o mize d t o t hat ar m, t o ta ke place d uri n g t he first 1 2 wee ks of t he treat me nt 
p h ase.
3. 2
DI S C U S SI O N O F T RI A L D E SI G N, I N C L U DI N G T H E C H OI C E O F 
C O N T R O L G R O U P( S)
T he use of p ul m o nar y  re ha bilitati o n i n IP F has bee n e x pl ore d i n s mall st u dies t hat ha ve 
s h o w n a p ositi ve o utc o me b ut wit h o ut c o ncl usi ve e vi de nce of a n e n d uri n g effect.  It is 
belie ve d t hat t his is i n part d ue t o t he u n derl yi n g pr o gressi ve disease n ot bei n g a d dresse d 
t hr o u g h acti ve treat me nt.  C o nsi derati o n s h o ul d t heref ore be gi ve n t o t he be nefit of 
u n derl y i n g a ntifi br otic t hera p y li miti n g t he rate of l u n g f u ncti o n decli ne a n d all o wi ng t he 
effect of p ul m o nar y re ha bilitati o n t o be m ore e n d uri n g.
T he c o h ort i n t his st u d y  is patie nts t hat are treate d wit h ni nte da ni b f or u p t o 3 0 m o nt hs.  T his 
p ote ntiall y  a d dresses t he c o ncer n t hat patie nts fi nis h p ul m o nar y re ha bilitati o n a n d t he n ret ur n 
to a less acti ve state beca use t he y are still left wit h a n u n derl yi n g c hr o nic pr o gressi ve disease.  
Gi ve n t he fi n di n gs i n t hree pi v otal st u dies t hat ni nte da ni b sl o ws t he rate of decli ne i n l u n g 
f u ncti o n (c 0 2 0 9 8 7 7 5- 0 2, c 0 2 1 5 5 5 7 4- 0 2), t his a p pr oac h wit h t his sta ble c o h ort ma y all o w f or 
a m ore e n d uri n g o utc o me fr o m P R.
3. 3
S E L E C TI O N O F T RI A L P O P U L A TI O N
T his trial will ra n d o mize 2 9 0 patie nts (
 1 4 5
per treat me nt gr o u p 
at a p pr o xi matel y 5 4 sites acr oss t he U nite d States ( U S).
Scree ni n g of patie nts f or t his trial is c o m petiti ve, i.e. scree ni n g f or t he trial will st o p at all 
sites at t he sa me ti me o nce a s ufficie nt n u m ber of patie nts has bee n scree ne d. I n vesti gat ors 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
will be n otifie d a b o ut scree ni n g c o m pleti o n a n d will t he n n ot be all o we d t o scree n a d diti o nal 
patie nts f or t his trial.
A l o g of all patie nt s e nr olle d i nt o t he trial (i.e. w h o ha ve si g ne d i nf or me d c o nse nt) will be 
mai ntai ne d i n t he i n vesti gat or site file (I S F) at t he i n vesti gati o nal site.
Rescree ni n g of patie nts w h o are pre vi o usl y scree n faile d f or t he trial is all o we d wit hi n 1 - 2 
wee ks f or patie nts t hat fail d ue t o F V C, s pir o metr y  m a y be re peate d o nce. Rescree ni n g f or 
a d mi nistrati ve or ot her r eas o ns m ust be disc usse d wit h t he cli nical m o nit or
3. 3. 1
M ai n di a g n osis f or tri al e ntr y
T o q ualif y  f or t he trial, patie nts m ust ha ve a dia g n osis of I di o pat hic P ul m o nar y  Fi br osis (IP F) 
acc or di n g t o A merica n T h oracic S ociet y ( A T S), E ur o pea n Res pirat or y S ociet y ( E R S), 
Ja pa nese Res pirat or y S ociet y (J R S), a n d Lati n A merica n T h oracic Ass ociati o n ( A L A T) 
criteria p u blis he d i n 2 0 1 1 , c o nsiste nt wit h IN P U L SI S criteria. Patie nts m ust als o ha ve bee n 
treate d wit h ni n te da ni b 1 5 0 m g BI D at a sta ble d ose f or u p t o 3 0 m o nt hs .
Please refer t o secti o n 8. 3. 1 ( S o urce D oc u me nts) f or t he d oc u me ntati o n re q uire me nts 
pertai ni n g t o t he i n - a n d e xcl usi o n criteria.
3. 3. 2 
I ncl usi o n criteri a
1.
Patie nts bei n g treate d wit h a sta ble d ose of ni nte da ni b 1 5 0 m g BI D f or u p t o 3 0 m o nt hs. 
Patie nts w h o ha ve rece ntl y starte d ni nte da ni b 1 5 0 m g BI D a n d ha ve starte d b y  t he da y of 
ra n d o mizati o n m ust be o n ni nte da ni b 1 5 0 m g BI D a mi ni m u m of 1 0 da ys b y t he first da y 
of p ul m o nar y  re ha bilitati o n.
2.
A ge ≥ 4 0 years at scree ni n g
3.
W o me n of c hil d beari n g p ote ntial ( W O C B P)1 m ust be rea d y a n d a ble t o use hi g hl y 
effecti ve met h o ds of birt h c o ntr ol per I C H M 3 ( R 2) (R 1 7 - 1 3 9 9) t hat res ult i n a l o w 
fail ure rate of less t ha n 1 % per ye ar w he n use d c o nsiste ntl y a n d c orrectl y. A list of 
c o ntrace pti o n met h o ds meeti n g t hese criteria is pr o vi de d i n t he patie nt c o nse nt f or m
4.
Si g ne d a n d date d writte n i nf or me d c o nse nt i n acc or da nce wit h I CH- G C P (I nter nati o nal 
C o u ncil o n Har m o nizati o n a n d G o o d Cli nical Practice ) a n d l ocal le gislati o n pri or t o 
a d missi o n t o t he trial
5.
C o nfir me d dia g n osis of I P F acc or di n g t o 2 0 1 1 A T S/ E R S/J R S/ A LA T g ui deli nes b y  l u n g 
bi o ps y  or H R C T ( base d u p o n I N P U LSI S criteria (c 0 2 0 9 8 7 7 5- 0 2, c 0 2 1 5 5 5 7 4- 0 2), (if 
bi o ps y  o nly or H R C T d o ne > 2 4 m o nt hs pri or t o scree ni n g, a ne w H R C T t o be d o ne after 
c o nse nt a n d pri or t o or u p t o 7 da ys after Visit 2 f or q ua ntitati ve l u n g fi br osis sc ore ( Q L F) 
f or disease c haracterizati o n)
                                                
1 A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial ( W O C B P) , i.e. fertile, f oll o wi n g me narc he a n d u ntil bec o mi n g p ost-
me n o pa usal u nless per ma ne ntl y sterile. 
Per ma ne nt sterilisati o n met h o ds i ncl u de h ysterect o m y, bilateral sal pi n gect o m y a n d bilateral o o p h orect o m y.
A p ost me n o pa usal stat e is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
6.
F orce d Vita l Ca pacit y ( F V C) ≥ 4 5 % of pre dicte d b y  t he N H A N E S e q uati o n (R 0 4 - 1 0 0 1)
or e q ui vale nt (after disc ussi o n wit h Cli nical M o nit or), hist orical wit hi n past 3 0 da y s ca n 
be u se d. Car b o n m o n o xi de Diff usi o n Ca pacit y  ( D LC O ) (c orrecte d f or he m o gl o bi n [ H g b]) 
3 0- 7 9 % of pre dicte d
7.
F E V 1/ F V C greater t ha n/e q ual t o . 7
8.
P h y sically ca pa ble of perf or mi n g b ot h a 6 mi n ute wal k test a n d 
, m ust s uccessf ully c o m p lete t he practice tests f or t he 6 mi n ute wal k 
test, per t he i nstr ucti o ns
 
3. 3. 3
E xcl usi o n criteri a
1.
Maj or s ur ger y  ( maj or acc or di n g t o t he i n vesti gat or’s assess me nt) perf or me d wit hi n 1 2 
wee ks pri or t o ra n d o mizati o n or pla n ne d wit hi n 6 m o nt hs after scree ni n g, e. g. hi p 
re place me nt w hic h c o ul d i nte rfere wit h t he a bilit y t o partici pate i n p ul m o nar y 
re ha bilitati o n.
2.
A n y  d oc u me nte d acti ve or s us pecte d mali g na nc y or hist or y of mali g na nc y wit hi n 3 years 
pri or t o scree ni n g, e xce pt a p pr o priatel y treate d basal cell carci n o ma of t he s ki n or i n sit u 
carci n o ma of uteri ne cer vi x
3.
Patie nts w h o m ust or wis h t o c o nti n ue t he i nta ke of restricte d me dicati o ns (see Secti o n 
4. 2. 2. 1 ) or a ny dr u g c o nsi dere d li kel y t o i nterfere wit h t he safe c o n d uct of t he trial
4.
Pre vi o us e nr ol me nt i n t his trial (exce pt f or rescree ni n g as descri be d i n Secti o n 3. 3 )
5.
C urre ntl y  e nr olle d i n a n ot her i nter ve nti o nal i n vesti gati o nal de vice or dr u g trial, or less 
t ha n 3 0 da ys si nce e n di n g a n ot her i n vesti gati o nal de vice or dr u g trial(s), or recei vi n g 
ot her i n vesti gati o nal treat me nt(s)
6.
C hr o nic alc o h ol or dr u g a b use or a n y c o n diti o n t hat, i n t he i n vesti gat or’s o pi ni o n, m a kes 
t he m a n u nrelia ble trial patie nt or u nli kel y t o c o m plete t he trial
7.
W o me n w h o are pre g na nt, n ursi n g, or w h o pla n t o bec o me pre g na nt  i n t he trial
8.
Pre vi o us partici pati o n i n p ul m o nar y  re ha bilitati o n pr o gra m wit hi n 4 5 da ys pri or t o 
si g ni n g c o nse nt
3. 3. 4
Wit h dr a w al of p atie nt s fr o m t her a p y or assess me nts
Patie nts ma y  p ote ntially be wit h dra w n fr o m trial treat me nt or fr o m t he trial as a w h ole 
(“ wit h dra wal of c o nse nt”) wit h ver y differe nt i m plicati o ns, please see secti o ns 3. 3. 4. 1 a n d 
3. 3. 4. 2 bel o w.
E ver y  eff ort s h o ul d be ma de t o kee p t he ra n d o mise d patie nts i n t he trial: if p ossi ble o n 
treat me nt, or at least t o c ollect i m p orta nt trial data.
Meas ures t o c o ntr ol t he wit h dra wal rate i ncl u de c aref ul patie nt selecti o n, a p pr o priate 
e x pla nati o n of t he trial re q uire me nts a n d pr oce d ures pri or t o ra n d o mizati o n, as well as t he
e x pla nati o n of t he c o nse q ue nces of wit h dra wal. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T he decisi o n t o wit h dra w fr o m trial treat me nt or fr o m t he w h ole trial as well as t he reas o n 
m ust be d oc u me nte d i n t he patie nt files a n d C R F (case rec or d f or m).
I n t he e ve nt a patie nt or part ner of a patie nt has bec o me pre g na nt pri or t o wit h dra wal fr o m 
t he trial, t he pr oce d ures i n Secti o n 5. 2. 6. 1 s h o ul d be f oll owe d. If a patie nt bec o mes pre g na nt 
d uri n g t he trial, t he prescri bi n g p h ys icia n s h o ul d be n otifie d a n d c o nti n uati o n of ni nte da ni b 
treat me nt a d dresse d by t he prescri bi n g p h ys icia n. C o nti n ue d partici pati o n i n t he trial s h o ul d 
be disc usse d wit h t he cli nical m o nit or.
3. 3. 4. 1
Wit h dra wal fr o m trial treat me nt
A n i n di vi d ual patie nt is t o be wit h dra w n fr o m trial treat me nt if:

T he patie nt wa nts t o wit h dra w fr o m trial treat me nt, wit h o ut t he nee d t o j ustif y t he 
decisi o n.

T he patie nt nee ds t o ta ke c o nc o mita nt treat me nts t hat i nterfere wit h t he re q uire d O F E V 
treat me nt.

T he patie nt ca n n o l o n ger be treate d wit h trial pr oce d ures f or ot her me dical reas o ns (s uc h 
as s ur ger y, a d verse e ve nts, ot her diseases, or pre g na nc y).

T he patie nt has re peate dl y  s h o w n t o be n o n-c o m plia nt wit h i m p orta nt trial pr oce d ures 
a n d, i n t he o pi ni o n of b ot h, t he i n vesti gat or a n d s p o ns or re prese ntati ve, is n ot willi n g or 
a ble t o c o m pl y wit h t he trial re q uire me nts i n t he f ut ure.
Gi ve n t he patie nt ’s a gree me nt, t he patie nt will u n der g o t he pr oce d ures f or ea rly treat me nt 
disc o nti n uati o n a n d f oll o w u p as o utli ne d i n t he Fl o w C hart (F C ) a n d secti o n 6. 2. 3.
F or all patie nt s t he reas o n f or wit h dra wal fr o m trial treat me nt (e. g. a d verse e ve nts) m ust be 
rec or de d i n t he C R F . T hese data will be i ncl u de d i n t he trial data base a n d re p orte d.
3. 3. 4. 2
Wit h dra wal of c o nse nt f or trial partici pati o n
P atie nts ma y  wit h dra w t heir c o nse nt f or trial partici pati o n at a n y ti me wit h o ut t he nee d t o 
j ustif y t he decisi o n.
T his will h o we ver mea n t hat n o f urt her i nf or mati o n ma y be c ollecte d f or t he p ur p ose of t he 
trial a n d ne gati ve i m plicati o ns f or t he scie ntific val ue ma y be t he c o nse q ue nce. F urt her m ore 
it ma y mea n t hat f urt her patie nt f oll o w u p o n safet y ca n n ot occ ur.
If a patie nt wa nts t o wit h dra w c o nse nt, t he i n vesti gat or s h o ul d e x plai n t he differe nce bet wee n 
treat me nt wit h dra wal a n d wit h dra wal of c o nse nt f or trial partici pati o n a n d e x plai n t he o pti o ns 
f or c o nti n ue d f oll o w u p after wit h dra wal fr o m trial treat me nt, please see secti o n 3. 3. 4. 1
a b o ve.
3. 3. 4. 3
Disc o nti n uati o n of t he trial b y  t he s p o ns or
B oe hri n ger I n gel hei m reser ves t he ri g ht t o disc o nti n ue t he trial o verall or at a partic ular trial
site at a n y ti me f or t he f oll o wi n g reas o ns:

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1.
Fail ure t o meet e x pecte d e nr ol me nt g oals o verall or at a partic ular trial site
2.
E mer ge nce of a n y efficac y/safety i nf or mati o n i n vali dati n g t he earlier p ositi ve be nefit -
ris k-assess me nt t hat c o ul d si g nifica ntl y affect t he c o nti n uati o n of t he trial
3.
Vi olati o n of G C P, t he trial pr ot oc ol , or t he c o ntract i m pairi n g t he a p pr o priate c o n d uct of 
t he trial
T he i n vesti gat or / t he trial site will be rei m b urse d f or reas o na ble e x pe nses i nc urre d i n case of 
trial ter mi nati o n (e xce pt i n case of t he t hir d reas o n).

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
4.
T R E A T M E N T S
4. 1 
I N V E S TI G A TI O N A L T R E A T M E N T S
4. 1. 1
I de ntit y of t he in vesti g ati o n al m e dici n al p r o d ucts
N o st u d y  me dicati o n is i ncl u de d i n t his trial, t his trial is a c o m paris o n of p ul m o nar y 
re ha bilitati o n vers us sta n dar d care i n patie nts wit h IP F alrea d y  ta ki n g a sta ble d ose of 
ni nte da ni b. T he acti ve treat me nt ar m will c o nsist of a sta n dar d p ul m o nar y  re ha bilitati o n 
re gi me n t w o or t hree ti mes wee kl y f or 1 2 wee ks. Patie nts assi g ne d t o P R will be referre d t o a 
facilit y c o n ve nie nt f or t he patie nt. T he p ul m o nar y re ha bilitati o n s h o ul d f oll o w t he facility’s 
sta n dar d re gi me n as l o n g as t he re gi me n meets basic sta n dar ds (t o be pr o vi de d i n t he I S F) .  
N o st u d y  s pecific data c ollecti o n is re q uire d b y t he P R facilit y, h o we ver sta n dar d treat me nt 
re p orts m ust be a vaila ble t o t he i n vesti gat or t o d oc u me nt t he atte n da nce a n d pr o gress of P R.
4. 1. 2
Selecti o n of d oses i n t he tri al
Patie nts are re q uire d t o be usi n g t he F D A ( F o o d a n d Dr u g A d mi nistrati o n) a p pr o ve d d ose of 
ni nte da ni b 1 5 0 m g BI D f or u p t o 3 0 m o nt hs t o q ualif y f or t he trial a n d t o c o nti n ue o n 
ni nte da ni b f or t he d urati o n of t he trial. Patie nts w h o ha ve rece ntl y starte d ni nte da ni b 1 5 0 m g 
BI D a n d ha ve starte d b y t he da y of ra n d o mizati o n m ust be o n ni nte da ni b 1 5 0 m g BI D a 
mi ni m u m of 1 0 da y s b y t he first da y of p ul m o nar y re ha bilitati o n. Te m p orar y d ose a dj ust me nt 
f or t he ma na ge me nt of a d verse e ve nts is all o we d d uri n g t he c o n d uct of t he st u d y.
4. 1. 3
Met h o d of assi g ni n g p atie nt s t o tre at me nt gr o u ps
D uri n g visit 2 eli gi ble patie nt s will be ra n d o mised t o eit her c o nti n ue o n ni nte da ni b treat me nt 
al o ne or c o nti n ue o n ni nte da ni b wit h a p ul m o nar y  re ha bilitati o n pr o gra m a d de d i n a 1: 1 rati o 
acc or di n g t o a ra n d o mizati o n pla n. T he assi g n me nt will occ ur via I nteracti ve Res p o nse 
Tec h n ol o g y  (I R T).
4. 1. 4
Dr u g assi g n me nt a n d a d mi nistr ati o n of d oses f or e ac h p atie nt
S u bjects are re q uire d t o be treate d o n a sta ble ( u p t o 3 0 m o nt hs) d ose of ni n te da ni b 1 5 0 m g 
BI D , a d mi nistere d per prescri bi n g i nstr ucti o ns (R 1 8 - 1 2 8 9), t o e nter t he trial a n d t o c o nti n ue 
o n t his d ose t hr o u g h o ut t he trial . Patie nts w h o ha ve rece ntl y starte d ni nte da ni b 1 5 0 m g BI D 
a n d ha ve starte d b y t he da y of ra n d o mizati o n m ust be o n ni nte da ni b 1 5 0 m g BI D a mi ni m u m 
of 1 0 da y s b y t he first da y of p ul m o nar y re ha bilitati o n. Patie nts t hat ha ve ha d a n i nterr u pti o n 
i n ni nte da ni b treat me nt or a te m p orar y d ose re d ucti o n ca n be e ntere d i nt o t he trial w he n t he y 
ha ve ret ur ne d t o a d ose of 1 5 0 m g BI D a n d t heir c o n diti o n is deter mi ne d t o be sta ble b y t he 
i n vesti gat or a n d te m p orar y d ose re d ucti o ns t o treat a d verse e ve nts is per mitte d d uri n g t he 
trial.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
4. 1. 5 
Bli n di n g a n d pr oce d ures f or u n bli n di n g
4. 1. 5. 1 
Bli n di n g
Q ualifie d s u bjects will be ra n d o mize d at Visit 2 t o eit her c o nti n ue wit h t heir us ual treat me nt 
or t o a d d a p ul m o nar y  re ha bilitati o n pr o gra m t o t heir us ual treat me nt. I n t his o pe n-la bel trial, 
treat me nt all ocati o n will n ot be c o nceale d t hr o u g h o ut t he trial. T he C R F will c o ntai n 
i nf or mati o n o n ra n d o mised treat me nt. As patie nts are ra n d o mize d t o eit her n o p ul m o nar y  
re ha bilitati o n or p ul m o nar y re ha bilitati o n, it is n ot p ossi ble t o bli n d t he treat me nts i n t his 
trial.
4. 1. 5. 2
U n bli n di n g a n d brea k i n g t he c o de
N ot a p plica ble , t his trial is n ot bli n de d.
4. 1. 6 
P ac k a gi n g, l a belli n g, a n d re- s u p pl y
N o t a p plica ble, n o st u d y me dicati o n is pr o vi de d i n t his trial.
4. 2  
O T H E R T R E A T M E N T S , E M E R G E N C Y P R O C E D U R E S , 
R E S T RI C TI O N S
4. 2. 1
Ot her tre at me nts a n d e mer ge nc y pr oce d ures
4. 2. 1. 1
Ma na ge me nt of a d verse e ve nts relate d t o ni nte da ni b
A d verse e ve nts relate d t o ni nte da ni b s h o ul d be ma na ge d acc or di n g t o t he c urre nt pac ka ge 
i nsert (R 1 8 - 1 2 8 9) i n c o nj u ncti o n wit h t he prescri bi n g p h ysicia n. 
4. 2. 1. 2
Ma na ge me nt of ot her a d verse e ve nts 
A d verse e ve nts relate d t o t he st u d y  pr oce d ures s uc h as p ul m o nar y re ha bilitati o n, 6 M W T  
 
as well as u nrelate d a d verse 
e ve nts, will be ma na ge d as cli nicall y i n dicate d. If a patie nt e x perie nces a n a d verse e ve nt 
w hic h i m pacts t heir a bilit y t o c o nti n ue wit h p ul m o nar y  re ha bilitati o n (if assi g ne d) or a bilit y 
t o c o nti n ue wit h t he e xercise testi n g, t he cli nical m o nit or s h o ul d be c o ns ulte d re gar di n g 
c o nti n ue d partici pati o n i n t h e trial pri or t o disc o nti n uati o n.
4. 2. 2  
Restricti o ns
4. 2. 2. 1
Restricti o ns o n co nc o mita nt treat me nt
T he f oll o wi n g dr u gs m ust n ot be ta ke n wit hi n 8 wee ks of visit 1: 

Pirfe ni d o ne

A n y  ot her e x peri me ntal I P F t hera p y.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T he f oll o wi n g t hera pies are n ot all o we d d uri n g t he e ntire treat me nt peri o d ( Visit 2- 7). I n case 
a n y of t he f oll o wi n g is me dically i n dicate d d uri n g t he c o urse of t he trial a 4 wee k was h -o ut of 
ni nte da ni b s h o ul d be o bser ve d bef ore t heir use:
Fi bri n ol y sis, f ull-d ose t hera pe utic a ntic oa g ulati o n (e. g. vita mi n K a nta g o nists, da bi gatra n, 
he pari n, hir u di n etc), or hi g h d ose a nti platelet t hera p y . 
T he f oll o wi n g dr u gs are n ot all o we d d uri n g t he st u d y treat me nt e xce pt i n case of ac ute 
e xacer bati o n of I P F or i n case of deteri orati o n at t he discreti o n of t he i n vesti gat or (see secti o n 
4. 2. 2. 2 ):

Azat hi o pri ne, c y cl o p h os p ha mi de a n d c ycl os p ori ne A m ust n ot be ta ke n wit hi n 8 
wee ks of visit 1.

N- Acet y l Cys tei ne ( N A C). M ust n ot be ta ke n wit hi n 2 wee ks of visit 1.

Pre d nis o ne at > 1 5 m g / da y  ( or > 3 0 m g e ver y  2 da ys or e q ui vale nt d ose of ot her oral 
c ortic oster oi d) m ust n ot be ta ke n wit hi n 2 wee ks of visit 1.
4. 2. 2. 2
C o nc o mita nt treat me nts all o we d
F oll o wi n g me dicati o n is all o we d if sta bilize d f or at least 8 wee ks pri or t o visit 1: Pre d nis o ne 
if stea dy d ose ≤ 1 5 m g / da y  ( or ≤ 3 0 m g e ver y 2 da ys) or e q ui vale nt.
I n case of ac ute e xacer bati o ns:
all s u g geste d me dicati o ns (e. g. pre d nis o ne at hi g h d ose, azat hi o pri ne, c y cl o p h os p ha mi de, 
c ycl os p ori ne A or N A C) ca n be freel y i nitiate d or i ncrease d at I n vesti gat or’s discreti o n
exce pt pirfe ni d o ne.
I n case of deteri orati o n of IP F:
Pre d nis o ne at hi g h d ose, azat hi o pri ne, c y cl o p h os p ha mi de, c ycl os p ori ne A or N A C ca n be 
freely i nitiate d or i ncrease d at I n vesti gat or’s discreti o n exce pt pirfe ni d o ne. 
A ≥ 1 0 % decrease i n t he a bs o l ute val ue of F V C % pre dicte d or a ≥1 5 % decrease i n D L C O % 
pre dicte d is c o nsi dere d deteri orati o n ( pr o gressi o n of disease). E xa m ple: a c ha n ge fr o m 5 0 % 
pre dicte d F V C t o 4 0 % pre dicte d F V C re prese nts deteri orati o n. 
Pr o p h y lactic a ntic oa g ulati o n:
Pr o p h y lactic lo w d ose he pari n or he pari n fl us h as nee de d f or mai nte na nce of a n i n d welli n g 
i ntra ve n o us de vice (e. g. e n o xa pari n 4 0 0 0 I. U. s.c. per da y), as well as pr o p h ylactic use of 
a nti platelet t hera p y (e. g. acet yl  salic ylic aci d u p t o 3 2 5 m g/ d, or cl o pi d o grel at 7 5 m g/ d, or 
e q ui vale nt d oses of ot her a nti platelet t hera p y) s h o ul d be all o we d.
4. 2. 2. 3
Restricti o ns o n diet a n d life st y le
T here are n o restricti o ns o n diet a n d life st y le ot her t ha n t h ose re q uire d f or t he e xercise 
testi n g a n d s pir o metr y (A p pe n di x 1 0. 1 a n d Secti o n 5. 1. 2. 3 ).

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
4. 2. 2. 4 
Restricti o ns re gar di n g w o me n of c hil d beari n g p ote ntial 
W o me n of c hil d beari n g p ote ntial m ust use t he c o ntrace pti o n met h o ds descri be d i n
Secti o n 3. 3. 2 a n d f oll o w t he restricti o ns descri be d i n t he patie nt i nf or mati o n f or ni nte da ni b 
(R 1 8 - 1 2 8 9).
4. 3 
T R E A T M E N T C O M P LI A N C E
C o u nsel patie nts o n t he i m p orta nce of ta ki n g bac k gr o u n d me dic ati o n as directe d at eac h visit, 
as well as rei nf orci n g atte n da nce at p ul m o nar y re ha bilitati o n f or t h ose patie nts assi g ne d t o 
t hat treat me nt ar m.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
5.
A S S E S S M E N T S
5. 1  
A S S E S S M E N T O F E F FI C A C Y
5. 1. 1 
E n d p oi nts of effic ac y
5. 1. 1. 1
Pri mar y  e n d p oi nt
o
C ha n ge fr o m baseli ne i n 6 M W D at 1 2 wee ks
5. 1. 1. 2
Sec o n dar y e n d p oi nts
o
C ha n ge fr o m baseli ne i n Q o L ( S G R Q, K BI L D, U C S D S O B Q ) at 1 2 a n d 2 4 
wee ks 
o
C ha n ge fr o m baseli ne i n 6 M W D at 2 4 wee ks 
o
C ha n ge fr o m baseli ne i n l u n g f u ncti o n ( F V C) at 1 2 wee ks a n d 2 4 wee ks usi n g 
eac h of

A bs ol ute c ha n ge fr o m baseli ne of F V C a n d F V C % pre dicte d

R elati ve c ha n ge fr o m baseli ne of F V C a n d F V C % pre dicte d

A bs ol ute cate g orical c ha n ge of F V C % pre dicte d u p t o 1 2 a n d 2 4 
wee ks: decrease b y > 5 %, i ncrease b y > 5 %, a n d c ha n ge wit hi n ≤ 5

A bs ol ute cate g orical c ha n ge of F V C % pre dicte d u p t o 1 2 a n d 2 4 
wee ks: decre ase b y > 1 0, i ncrease b y > 1 0, a n d c ha n ge wit hi n ≤ 1 0
o
C ha n ge fr o m baseli ne i n dail y acceler o meter acti vit y fr o m baseli ne at 1 2 a n d 
2 4 wee ks 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 2 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
5. 1. 2
Assess me nt of effic ac y
5. 1. 2. 1
6 Mi n ute wal k test
T he dista nce meas ure d i n t he 6 Mi n ute Wal k Test at 1 2 a n d 2 4 wee ks will be assess e d
acc or di n g t o t he pr oce d ures descri be d i n A p pe n di x 1 0. 1 .
F o ur 6 M W Ts will be perf or me d d uri n g t he trial ( o ne practice a n d t hree tests).  At Visit 1 a 
practice 6 M W T, als o referre d t o as t he Titrati o n Wal k Test, will be c o n d ucte d t o ac q uai nt t he 
patie nt wit h t he pr oce d ure a n d t o deter mi ne t he le vel of o x y ge n nee de d f or s u bse q ue nt 
testi n g.  As per i ncl usi o n criteri o n #8 , patie nts m ust be p h y sicall y a ble t o perf or m a 6 M W T , 
as per t he i nstr ucti o ns.  Patie nts w h o ca n n ot c o m plete t he Titrati o n Wal k Test will be 
c o nsi dere d a Scree n Fail ure.  T hree 6 M W Ts will be c o n d ucte d d uri n g t he ra n d o mize d 
treat me nt p hase at Visits 2 ( baseli ne), 5 a n d 7 ( E n d of Treat me nt).  D uri n g t he 6 M W T, t he 
B or g Scale will be a d mi nistere d.  Detaile d i nstr ucti o ns f or t he c o n d uct of t he 6 M W T a n d 
B or g Scale are pr o vi de d i n t he I S F a n d A p pe n di x 1 0. 1 a n d 1 0. 2 a n d i n t he distri b ute d 
i nstr ucti o nal vi de o.  It is i m p orta nt t he i nstr ucti o ns are f oll o we d e xactl y.  T he test will be 
perf or me d at a p pr o xi matel y  t he sa me ti me eac h da y fr o m ti me of Visit 2 testi n g.  Patie nts 
w h o ca n n ot c o m plete t he 6 M W T after ra n d o mizati o n will r e mai n i n t he trial.  
5. 1. 2. 2
C ha n ge i n q ualit y  of life
C ha n ge fr o m baseli ne i n Q o L will be meas ure d usi ng t he S G R Q, K BI L D , a n d U C S D-S O B Q 
q uesti o n naires at 1 2 a n d 2 4 wee ks. T he q uesti o n naires are descri be d i n A p pe n di x 1 0. 3 , 1 0. 5
a n d 1 0. 6 . T he q uesti o n naires s h o ul d be c o m plete d first d uri n g t he st u dy visit, pri or t o 
p ul m o nar y  f u ncti o n testi n g a n d ot her pr oce d ures. T he q uesti o n naires will be c o m plete d at 
Visits 1, 2, 5 a n d 7 .
5. 1. 2. 3
Assess me nt of l u n g f u ncti o n
L u n g f u ncti o n will be assesse d at all visits usi n g sta n dar d s pir o metr y , usi n g e q ui p me nt 
pr o vi de d at t he st u d y site a n d t he N H A N E S e q uati o n ( or e q ui vale nt after disc ussi o n wit h 
Cli nical M o nit or ). S pir o metr y meas ure me nts m ust be perf or me d acc or di n g t o A T S/ E R S 2 0 0 5 
g ui deli ne ( P 0 5 -1 2 7 8 2 ), i ncl u di n g daily cali brati o n of t he s pir o meter, a n d re g ular cali brati o n 
of t he cali brati o n p u m p. S pir o metr y  will be c o n d ucte d w hile t he patie nt is i n a seate d 
p ositi o n. T he test will be d o ne i n tri plicate (t hree c ur ves t o be pr o vi de d), a n d t he best res ult 
selecte d acc or di n g t o t he g ui deli nes. T he best of t hree eff orts will be defi ne d as t he hi g hest 
F V C, o btai ne d o n a n y of t he t hree bl o ws meeti n g t he A T S/ E R S criteria wit h prefera bl y a 
ma xi m u m of fi ve ma n oe u vres.
Eff orts s h o ul d be ma de, t o sc he d ule t he s pir o metric meas ure me nts at a p pr o xi matel y t he sa me 
ti me of t he da y, wit h refere nce t o baseli ne meas ure me nt ( Visit 2). O n da ys of cli nic visits, 
patie nts m ust refrai n fr o m stre n u o us acti vit y at least 1 2 h o urs pri or t o p ul m o nar y f u ncti o n 
testi n g. S m o ki n g s h o ul d be disc o ura ge d t hr o u g h o ut t he visit da ys (cli nic visit) a n d will n ot be 
per mitte d i n t he 3 0 -mi n ute peri o d pri or t o s pir o metr y . Patie nts s h o ul d als o a v oi d c ol d 
te m perat ures, e n vir o n me ntal s m o ke, d ust, or areas wit h str o n g o d o urs (e. g. perf u mes). If 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
treate d wit h br o nc h o dilat ors, was h- o ut of 2 4 h o urs f or l o n g acti n g a n d 8 h o urs f or s h ort 
acti n g br o nc h o dilat ors s h o ul d be o bser ve d bef ore s pir o metr y .
C ha n ges fr o m baseli ne i n F V C fr o m baseli ne t o 1 2 a n d 2 4 wee ks of treat me nt will be 
re p orte d as:

A bs ol ute a n d relati ve c ha n ge fr o m baseli ne of F V C a n d F V C % pre d icte d

A bs ol ute cate g orical c ha n ge of F V C % u p t o 1 2 a n d 2 4 wee ks : decrease b y 
> 5, i ncrease b y > 5 a n d c ha n ge wit hi n ≤ 5

A bs ol ute cate g orical c ha n ge of F V C % u p t o 1 2 a n d 2 4 wee ks : decrease b y 
> 1 0, i ncrease b y > 1 0, a n d c ha n ge wit hi n ≤ 1 0
Resti n g S p O 2 s h o ul d be d o ne pri or t o F V C at t he sc he d ule d visits, a n d D Lc o s h o ul d be d o ne 
after t he F V C at t he desi g nate d visits.
F urt her i n f or mati o n o n p ul m o nar y f u ncti o n testi n g ca n be f o u n d i n A p pe n di x 1 0. 7 .
5. 1. 2. 4
Dail y  acti vit y m o nit ori n g
Dail y  acti vit y m o nit ori n g will be c o n d ucte d usi n g t he D yna p ort de vice bet wee n Visits 0 a n d 
1, 1 a n d 2 a n d f or 7 da y s pri or t o Visits 5 a n d 7 ( E n d of Treat me nt - E O T). T he de vice will be 
dis pe nse d t o t he patie nt via eit her pic ki n g u p at t he office or se nt via c o m mercial s hi p pi n g t o 
t he patie nt i n a d va nce of t he sc he d ule d start date. T he patie nt will wear t he de vice f or 7 
c o nsec uti ve da ys, 2 4 h o urs a da y, bet wee n or pri or t o t he sc he d ule d visits a n d bri n g t he 
de vice wit h t he m t o t he visit. T he i nf or mati o n will be d o w nl oa de d b y t he i n vesti gat or at t he 
sc he d ule d visit. F urt her i nf or mati o n a n d i nstr ucti o ns f or t he acti vity m o nit ori n g will be
pr o vi de d i n t he I S F.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
5. 1. 2. 6
P R Oacti ve t o ol
I n t his trial, t he P R Oacti ve t o ol ( D-P P A C) t o get her wit h t he acti vity m o nit or will be use d t o 
c ollect t he P R Oacti ve ite m sc ores.  T he D- P P A C c o nsists of 9 ite ms i n t otal: 7 ite ms fille d 
o ut o n a n electr o nic i nterface (e Diar y) a n d 2 ite ms t o be o btai ne d fr o m t he acti vit y  m o nit or 
(see A p pe n di x 1 0. 4 )  T he ite ms o n t he e Diar y w ill be c o m plete d by t he patie nt at h o me e ver y 
da y  f or 7 da ys bef ore Visits 1, 2, 5, a n d 7 ( E O T) .  Patie nts will recei ve a leaflet wit h detaile d 
i nstr ucti o ns o n h o w t o use it, as well as bei n g gi ve n a de m o nstrati o n at t he st u d y site. 
Data fr o m t he e Diar y f or eac h peri o d will be u pl oa de d t o t he ve n d or’s data base, a n d 
s u bse q ue ntl y tra nsferre d t o t he trial data base.
T he e Diar y a n d t he acti vit y m o nit or data will be u pl oa de d t o t he trial data base f or use i n 
calc ulati n g t he d o mai n sc ores a n d P R Oacti ve t otal a n d d o mai n sc ores .
5. 2  
A S S E S S M E N T O F S A F E T Y
5. 2. 1
P h ysic al e x a mi n ati o n
A c o m plete p h ys ical e xa mi nati o n will be perf or me d at t he ti me p oi nts s pecifie d i n t he 
fl o wc hart. It i ncl u des at a mi ni m u m ge neral a p peara nce, nec k, l u n gs, car di o vasc ular s ys te m, 
a b d o me n, e xtre mities, a n d s ki n. 
Meas ure me nt of h ei g ht a n d b o d y wei g ht will be perf or me d at Visit 1 .
T he res ults m ust be i ncl u de d i n t he s o urce d oc u me nts a vaila ble at t he site. A n y  cli nicall y 
si g nifica nt a b n or malities at Visit 1 will be rec or de d as baseli ne c o n diti o ns i n t he e C R F. A ny 
cli nicall y si g nifica nt c ha n ges at s u bse q ue nt visits will be assesse d a n d re p orte d as a d verse 
e ve nts if t he y meet t he defi niti o ns i n Secti o n 5. 2. 6 . 
5. 2. 2
Vit al si g ns
Vital si g ns will be e val uate d at t he ti me p oi nts s pecifie d i n t he fl o wc hart, pri or t o bl o o d 
sa m pli n g if a p plica ble.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T his i ncl u des s yst olic a n d diast olic bl o o d press ure a n d p ulse rate (electr o nicall y or by 
pal pati o n c o u nt f or 1 mi n ute ) i n a seate d p ositi o n after 5 mi n utes of rest. 
5. 2. 3
S afet y l a b or at or y p ar a meters
La b orat or y  tests
Safet y  la b orat or y testi n g will be c o n d ucte d ( n o n-fasti n g) o n all patie nts at t he scree ni n g visit 
( Visit 1), a n d all st u d y visits ( Visits 2-9). T he la b orat or y  tests at Visit 1 will be c o nsi dere d as 
t he baseli ne meas ure me nts. La b orat or y s peci me ns will be c ollecte d i n t he mor ni n g pri or t o 
t he e xercise testi n g. Patie nts s h o ul d be i nstr ucte d n ot t o d o a n y u nacc ust o me d p h ysical 
e xercise 3 6 h o urs pri or t o la b orat or y  testi n g. 
Hae mat ol o g y , bl o o d c he mistr y, uri nalys is a n d ß-H C G (ser u m h u ma n c h ori o nic g o na d otr o pi n)
will be a nal ys e d b y  t he l ocal la b orat or y of eac h partici pati n g site. La b orat or y data will be 
c ollecte d b ut n ot ca pt ure d i n t he e C R F wit h t he e xce pti o n of he m o gl o bi n.  He m o gl o bi n 
res ults will be rec or de d i n t he e C R F at visits 1, 2, 5 a n d 7 t o all o w calc ulati o n of t he 
c orre cte d D Lc o. It is res p o nsi bilit y of t he i n vesti gat or t o e val uate c ha n ges i n la b orat or y 
val ues a n d re p orti n g of a n y la b orat or y relate d a d verse e ve nt s h o ul d be f oll o we d acc or di n g t o 
t he defi niti o ns o utli ne d i n Secti o n 5. 2. 6 .
Hae mat ol o g y
Hae m o gl o bi n, hae mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt i ncl u di n g differe ntial 
( ne utr o p hils, l ym p h oc y tes, m o n oc ytes, e osi n o p hils, bas o p hils), t otal e osi n o p hil c o u nt a n d 
platelet c o u nt.
Bl o o d c he mistr y
Al kali ne p h os p hatase, L D H, Ga m ma -G T, A L T ( Ala ni ne A mi n otra nsferase), A S T ( As partate 
A mi n otra nsferase) , gl uc ose, calci u m, i n or ga nic p h os p h or us, uric aci d, urea nitr o ge n, 
creati ni ne, t otal pr otei n, p otassi u m, s o di u m, c hl ori de, t otal bilir u bi n, creati ne p h os p h o ki nase.
Uri nal y sis
S pecific gra vit y, p H, gl uc ose, pr otei n, occ ult bl o o d.
Pre g na nc y  Testi n g
A ser u m h u ma n c h ori o nic g o na d otr o pi n ( H C G) test will be perf or me d o n all fe males of c hil d -
beari n g p ote ntial at Visit 1. Uri ne pre g na nc y tests are t o be perf or me d at Visits 2 - 7, as an 
alter nati ve, a ser u m pre g na nc y test ca n be perf or me d at Visits 2-7 if re q uire d b y  site or et hics 
b oar d .
I n case t he criteria f or he patic i nj ur y are met , a n u m ber of a d ditio nal meas ures will be 
perf or me d ( please see Secti o n 5. 2. 6. 1 a n d t he DI LI C hec klist pr o vi de d i n t he I S F or 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
electr o nic data ca pt ure ( e D C) s yste m. T he a m o u nt of bl o o d ta ke n fr o m t he patie nt c o ncer ne d 
will be i ncrease d d ue t o t his a d diti o nal sa m pli n g.
5. 2. 4
Electr oc ar di o gr a m
T he 1 2 -lea d E C Gs will be rec or de d as sc he d ule d i n t he fl o wc hart. T he i n vesti gat or or a 
desi g nee will e val uate w het her t he E C G is n or mal or a b n or mal a n d w het her it is cli nicall y  
rele va nt, if a b n or mal. E C Gs ma y be re peate d f or q ualit y reas o ns a n d t he re peate d rec or di n g 
use d f or a nal y sis. 
A d diti o nal E C Gs ma y  be rec or de d f or safety reas o ns. Date d a n d si g ne d pri nt o uts of E C G 
wit h fi n di n gs s h o ul d be d oc u me nte d i n patie nt’s me dical rec or d.
Cli nicall y  rele va nt a b n or mal fi n di n gs will be re p orte d eit her as baseli ne c o n diti o n (if 
i de ntifie d at t he scree ni n g visit) or ot her wise as a d verse e ve nts as descri be d i n Secti o n 5. 2. 6
a n d will be f oll o we d u p a n d/ or treate d as me dicall y a p pr o priate.
5. 2. 5  
Ot her s afet y p ar a meters
S afet y para meters t o be assesse d d uri n g t he w or k c ycle er g o metr y a n d 6 mi n ute wal k test are 
descri be d i n A p pe n di x 1 0. 1 .
5. 2. 6
Assess me nt of a d verse e ve nts
5. 2. 6. 1
Defi niti o ns of A Es 
A d verse e ve nt
A n a d verse e ve nt ( A E) is defi ne d as a n y  u nt o war d me dical occ urre nce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve 
t o ha ve a ca usal relati o ns hi p wit h t his treat me nt.
A n A E ca n t heref ore be a n y  u nfa v o ura ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y  ass ociate d wit h t he use of a me dici nal 
pr o d uct, w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.
A d verse re acti o n
A n a d verse reacti o n ( A D R) is defi ne d as a res p o nse t o a me dici nal pr o d uct w hic h is n o xi o us 
a n d u ni nte n de d. Res p o nse i n t his c o nte xt mea ns t hat a ca usal relati o ns hi p bet wee n a 
me dici nal pr o d uct a n d a n a d verse e ve nt is at least a reas o na ble p ossi bilit y. A d verse reacti o ns 
ma y  arise fr o m use of t he pr o d uct wit hi n or o utsi de t he ter ms of t he mar keti n g a ut h orisati o n 
or fr o m occ u pati o nal e x p os ure. C o n diti o ns of use o utsi de t he mar keti n g a ut h orizati o n i ncl u de 
off -la bel use, o ver d ose, mis use, a b use a n d me dicati o n err ors.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Seri o us a d verse e ve nt
A seri o us ad verse e ve nt is defi ne d as a n y A E w hic h
-
res ults i n deat h, 
-
is life-t hreate ni n g, 
-
re q uires i n-patie nt h os pitalizati o n, or
-
pr ol o n gati o n of e xisti n g h os pitalisati o n, 
-
res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y, or 
-
is a c o n ge nital a n o maly/ birt h defect 
Life -t hreate ni n g i n t his c o nte xt refers t o a reacti o n i n w hic h t he patie nt was at ris k of deat h at 
t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h yp ot heticall y  mi g ht ha ve ca use d 
deat h if m ore se vere.
Me dical a n d scie ntific j u d ge me nt s h o ul d be e xercise d i n deci di n g w het her ot her sit uati o ns 
s h o ul d be c o nsi dere d seri o us reacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be 
i m me diatel y life t hreate ni n g or res ult i n deat h or h os pitalisati o n b ut mi g ht je o par dise t he 
patie nt or mi g ht re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d a b o ve. 
E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y  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 y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisati o n or 
de vel o p me nt of de pe n de nc y  or a b use. A n y s us pecte d tra ns missi o n via a me dici nal pr o d uct of 
a n i nfecti o us a ge nt is als o c o nsi dere d a seri o us a d verse reacti o n.
A d verse e ve nts of s peci al i nterest ( A E SIs)
T he ter m A E SI relates t o a n y  s pecific A E t hat has bee n i de ntifie d at t he pr oject le vel as bei n g 
of partic ular c o ncer n f or pr os pecti ve safet y m o nit ori n g a n d safet y assess me nt wit hi n t his trial, 
e. g. t he p ote ntial f or A Es base d o n k n o wle d ge fr o m ot her c o m p o u n ds i n t he sa me class. 
T he f oll o wi n g are c o nsi dere d as A E SIs:
Gastr oi ntesti nal perf orati o n
He patic i nj ur y
A he patic i nj ur y  is defi ne d b y t he f oll o wi n g alterati o ns of he patic la b orat or y para meters: 

a n ele vati o n of A S T a n d/ or A L T > 3 f ol d u p per li mit of n or mal ( U L N ) c o m bi ne d wit h 
a n ele vati o n of t otal bilir u bi n > 2 f ol d U L N meas ure d i n t he sa me bl o o d dra w sa m ple, 
a n d/ or

a mi n otra nsferase ( A L T, a n d/ or A S T) ele vati o ns ≥1 0 f ol d U L N
T hese la b fi n di n gs c o nstit ute a he patic i nj ur y  alert a n d t he patie nt s s h o wi n g t hese la b 
a bn or malities nee d t o be f oll o we d u p acc or di n g t o t he “ DI LI c hec klist” pr o vi de d i n t he I S F or 
e C R F. 
I n case of cli nical sy m pt o ms of he patic i nj ur y  (icter us, u ne x plai ne d e nce p hal o pat h y, 
u ne x plai ne d c oa g ul o pat h y , ri g ht u p per q ua dra nt a b d o mi nal pai n, etc.) with o ut la b res ults 
( A L T, A S T, t otal bilir u bi n) a vaila ble, t he i n vesti gat or s h o ul d ma ke s ure t hese para meters are 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
a nal ys e d, if necessar y i n a n u nsc he d ule d bl o o d test. S h o ul d t he res ults meet t he criteria of 
he patic i nj ur y  alert, t he pr oce d ures descri be d i n t he DI LI c hec klist ( pr o vi de d i n IS F or e D C) 
s h o ul d be f oll o wed.
5. 2. 6. 2
A d verse e ve nt a n d seri o us a d verse e ve nt c ollecti o n a n d re p orti n g
T he i n vesti gat or s hall mai ntai n a n d kee p detaile d rec or ds of all A Es i n t heir patie nt files. 
C ollect i o n of A Es
T he st u d y  desi g n is of n o n-i nter ve nti o nal nat ure re gar di n g st u dy me dicati o n a n d t he st u d y is 
c o n d ucte d wit hi n t he c o n diti o ns of t he a p pr o ve d mar keti n g a ut h orisati o n. S ufficie nt data 
fr o m c o ntr olle d i nter ve nti o nal trials are a vaila ble t o s u p p ort t he e vi de nce o n t he safet y a n d 
efficac y of t he st u die d BI dr u g. F or t his reas o n t he f oll o wi n g A E c ollecti o n a n d re p orti n g 
re q uire me nts ha ve bee n defi ne d.
T he f oll o wi n g m ust be c ollecte d b y  t he i n vesti gat or fr o m si g ni n g t he i nf or me d c o nse nt 
o n war ds u ntil t he e n d of t h e st u d y: 
-
all Seri o us A d verse E ve nts ( S A Es) (re gar dless of ca usalit y ), 
-
all N o n-seri o us A D Rs
-
a n d A E SIs
All S A Es, all n o n -seri o us A D Rs, a n d A E SIs i ncl u di n g t h ose persisti n g after st u d y c o m pleti o n 
m ust be f oll o we d u p u ntil t he y  are res ol ve d, ha ve bee n s ufficie ntl y c haracterize d, or n o 
f urt her i nf or mati o n ca n be o btai ne d.
T he i n vesti gat or caref ull y assesses w het her a n A E c o nstit utes a n A D R usi n g t he i nf or mati o n 
bel o w.
Ca usal relati o ns hi p of a d verse e ve nt
T he defi niti o n of a n a d verse reacti o n i m plies at least a reas o na ble p ossi bilit y of a ca usal 
relati o ns hi p bet wee n a s us pecte d me dici nal pr o d uct a n d a n a d verse e ve nt. A n a d verse 
reacti o n, i n c o ntrast t o a n a d verse e ve nt, is c haracterise d by t he fact t hat a c a usal relati o ns hi p 
bet wee n a me dici nal pr o d uct a n d a n occ urre nce is s us pecte d. 
Me dical j u d g me nt s h o ul d be use d t o deter mi ne t he relati o ns hi p, c o nsi deri n g all rele va nt 
fact ors, i ncl u di n g patter n of reacti o n, te m p oral relati o ns hi p, de-c halle n ge or re -c hallen ge, 
c o nf o u n di n g fact ors s uc h as c o nc o mita nt me dicati o n, c o nc o mita nt diseases a n d rele va nt 
hist or y . 
Ar g u me nts t hat ma y  s u g gest a re as o n a ble c a us al rel ati o ns hi p c o ul d be:
•
T he e ve nt is c o nsiste nt wit h t he k n o w n p h ar m ac ol o g y of t he dr u g 
•
T he e ve nt is k n o w n t o be ca use d b y or attri b ute d t o t he dr u g cl ass .
•
A pl a usi ble ti me t o o nset of t he e ve nt relati ve t o t he ti me of dr u g e x p os ure.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
•
E vi de nce t hat t he e ve nt is re pr o d uci ble w he n t he dr u g is re- i ntr o d uce d
•
N o me dic all y s o u n d alter n ati ve eti ol o gi es t hat c o ul d e x plai n t he e ve nt (e. g. 
pree xisti n g or c o nc o mita nt diseases, or c o -me dicati o ns).
•
T he e ve nt is t y picall y dr u g -rel ate d a n d i nfre q ue nt i n t he ge ner al p o p ul ati o n n ot 
e x p ose d t o dr u gs (e. g. Ste ve ns -J o h ns o n s yn dr o me).
•
A n i n dicati o n of d ose -res p o nse (i.e. greater effect size if t he d ose is i ncrease d, s maller 
effect size if d ose is di mi nis he d).
Ar g u me nts t hat ma y  s u g gest t hat t here is n o re as o n a ble p ossi bilit y of a c a us al rel ati o ns hi p
c o ul d be:
•
N o pla usi ble ti me t o o nset of t he e ve nt relati ve t o t he ti me of dr u g e x p os ure is e vi de nt 
(e. g. pre-treat me nt cases, dia g n osis of ca ncer or c hr o nic disease wit hi n da ys/ wee ks of 
dr u g a d mi nistrati o n; a n aller gic reacti o n wee ks after disc o nti n uati o n of t he dr u g 
c o ncer ne d)
•
C o nti n uati o n of t he e ve nt des pite t he wit h d ra wal of t he me dicati o n, ta ki n g i nt o
acc o u nt t he p har mac ol o gical pr o perties of t he c o m p o u n d (e. g. after 5 half- li ves).
Of n ote, t his criteri o n ma y n ot be a p plica ble t o e ve nts w h ose ti me c o urse is pr ol o n ge d 
des pite re m o vi n g t he ori gi nal tri g ger.
•
A d diti o nal ar g u me nts a m o n gst t h ose state d bef ore, li ke alter nati ve e x pla nati o n (e. g.
sit uati o ns w here ot her dr u gs or u n derlyi n g diseases a p pear t o pr o vi de a m ore li kel y
e x pla nati o n f or t he o bser ve d e ve nt t ha n t he dr u g c o ncer ne d).
•
Disa p peara nce of t he e ve nt e ve n t h o u g h t he st u d y  dr u g treat me nt c o nti n ues or re mai ns 
u nc ha n ge d.
I nte nsity of a d verse e ve nt
T he i nte nsit y  of t he A E s h o ul d be j u d ge d base d o n t he f oll o wi n g:
Mil d:
A ware ness of si g n(s) or s y m pt o m(s) w hic h is/are easil y  t olerate d
M o derate:
E n o u g h disc o mf ort t o ca use i nterfere nce wit h us ual acti vit y
Se vere:
I nca pacitati n g or ca usi n g i na bilit y t o w or k or t o perf or m us ual acti vities
Pre g na nc y :
I n rare cases, pre g na nc y mi g ht occ ur i n a st u d y. O nce a s u bject has bee n e nr olle d i nt o t he 
st u d y, after ha vi n g ta ke n ni nte da ni b, t he i n vesti gat or m ust re p ort a n y dr u g e x p os ure d uri n g 
pre g na nc y , w hic h occ urre d i n a fe male s u bject or i n a part ner t o a male s u bject t o t he S p o ns or 
b y  mea ns of Part A of t he Pre g na nc y M o nit ori n g F or m. T he o utc o me of t he pre g na nc y 
ass ociate d wit h t he dr u g e x p os ure d uri n g pre g na nc y  m ust be f oll o we d u p a n d re p orte d b y 
mea ns of Part B of t he Pre g na nc y  M o nit ori n g F or m. 
I n t he a bse nce of a re p orta ble A E, o nly t he Pre g na nc y M o nit ori n g F or m m ust be c o m plete d, 
ot her wise t he NI S A E f or m is t o be c o m plete d a n d f or war de d as well wit hi n t he res pecti ve 
ti meli nes. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
E x pe dite d Re p orti n g of A Es a n d Dr u g E x p os ure D uri n g Pre g na nc y
T he f oll o wi n g m ust be r e p orte d b y t he i n vesti gat or o n t he NI S A E f or m fr o m si g ni n g t he 
i nf or me d c o nse nt o n war ds u ntil t he e n d of t he st u d y: 
T y pe of Re p ort
Ti meli ne
All S eri o us A d verse E ve nts (re g ar dless of 
c a us alit y
i m me diatel y wit hi n 2 4 h o urs
All n o n -seri o us A D Rs ass ociate d wit h 
ni nte da ni b 
7 cale n dar da y s
All pre g n a nc y m o nit ori n g f or ms
7 cale n dar da y s
T he sa me ti meli nes a p pl y  if f oll o w- u p i nf or mati o n bec o mes a vaila ble f or t he res pecti ve 
e ve nts. I n s pecific occasi o ns t he I n vesti gat or c o ul d i nf or m t he S p o ns or u p fr o nt via tele p h o ne. 
T his d oes n ot re place t he re q uire me nt t o c o m plete a n d s u b mit t he NIS A E f or m.
I nf or mati o n re q uire d
F or eac h re p orta ble a d verse e ve nt, t he i n vesti gat or s h o ul d pr o vi de t he i nf or mati o n re q ueste d 
o n t he NIS A E f or m.
5. 2. 6. 3
Re p orti n g t o healt h a ut h orities
A d verse e ve nt re p orti n g t o re g ulat or y  a ge ncies will be d o ne b y t he M A H acc or di n g t o l ocal 
a n d i nter nati o nal re g ulat or y re q uire me nts. 
5. 3
D R U G C O N C E N T R A TI O N M E A S U R E M E N T S A N D 
P H A R M A C O KI N E TI C S
5. 3. 1
Assess me nt of p h ar m ac o ki netics
N ot a p plica ble, t here are n o p har mac o ki netic assess me nts pla n ne d f or t his trial.
5. 3. 2
Met h o ds of s a m ple c ollecti o n
N ot a p plica ble, t here are n o p har mac o ki netic assess me nts pla n ne d f or t his trial
5. 3. 3
A n al ytic al deter mi n ati o ns
N ot a p plica ble, t here are n o p har mac o ki netic assess me nts pla n ne d f or t his trial.
5. 3. 4
P h ar m ac o ki netic – p h ar m ac o d y n a mic rel ati o ns hi p
N ot a p plica ble, t here are n o p har mac o ki netic assess me nts pla n ne d f or t his trial.
5. 4  
A S S E S S M E N T O F BI O M A R K E R ( S)
N ot a p plica ble, t here are n o bi o mar ker assess me nts pla n ne d i n t his trial.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
5. 5  
O T H E R A S S E S S M E N T S
N o ot her assess me nts are pla n ne d f or t his trial.
5. 6
A P P R O P RI A T E N E S S O F M E A S U R E M E N T S
All meas ure me nts c o n d ucte d f or pri mar y  a n d sec o n dar y e n d p oi nts are usi n g sta n dar d 
met h o ds.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 3 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
6.
I N V E S TI G A TI O N A L P L A N
6. 1
VI SI T S C H E D U L E
T his trial c o nsists of t w o parts, a scree n i n g a n d a n i nter ve nti o nal peri o d. T he scree ni n g peri o d 
c o nsists of t he ti me bet wee n si g ni n g c o nse nt a n d ra n d o mizati o n, a n d will last a mi ni m u m of 7 
da y s. T he i nter ve nti o nal peri o d c o nsists of t he ti me fr o m ra n d o mizati o n t hr o u g h t he wee k 2 4 
assess me nt visit. 
T here are t w o scree ni n g visits ( Visit 1, w hic h m ust be prece de d b y a se parate i nf or me d 
c o nse nt V isit 0 ) a n d 6 visits ( Visits 2 t o 7 ) pla n ne d wit hi n t he 2 4 wee k i nter ve nti o nal peri o d .
T here is n o f oll o w u p peri o d i n t his trial. 
After gi vi n g his/ her i nf or me d c o nse nt, t he patie nt will be scree ne d f or i ncl usi o n (see Secti o n 
3. 3. 2 a n d e xcl usi o n criteria (see Secti o n 3. 3. 3 ) f or t he trial at Visits 0, 1 a n d Visit 2 (refer t o
F l o wc hart).
T he patie nt will be dis pe nse d a n acti vit y m o nit or a n d Pr o Acti ve t o ol (e Diar y) at t he c o nse nt 
visit, a n d will wear t he acti vit y  m o nit or a n d use t he e Diar y f or 7 da ys pri or t o Visit 1 f or 
trai ni n g p ur p oses.
Visit 2 ca n be perf or me d o nce t he res ults fr o m l ocal la b orat or y of Visit 1 are o btai ne d a n d t he 
patie nt has w or n t he acti vit y m o nit or a n d c o m plete d t he e Diar y  f or 7 da ys. If f or a n y reas o n 
t he scree ni n g p hase f or a n i n di vi d ual patie nt lasts f or m ore t ha n 6 wee ks, t he n t he la b orat or y 
e xa mi nati o n f or Visit 1 has t o be re peate d bef ore ra n d o mizati o n. T he patie nt will be 
ra n d o mize d at Visit 2 if all i ncl usi o n a n d n o ne of t he e xcl usi o n criteria are f ulfille d. Ce ntral 
H C R T is n ot re q uire d pri or t o ra n d o mizati o n, b ut if hist orical H R C T is n ot a vaila ble t o be 
se nt f or ce ntral calc ulati o n of Q L F, a sca n s h o ul d be o btai ne d after scree ni n g/c o nse nt at t he 
latest 7 da ys after Visit 2.
O n treat me nt visits will be perf or me d at 3, 6, 1 2, 1 8 a n d 2 4 wee ks. Pr oce d ures f or t hese visits 
are o utli ne d i n t he fl o w c hart a n d detaile d i nstr ucti o ns are a vaila ble i n Secti o n 5 , select 
a p pe n dices a n d t he I S F, as a p plica ble.
Visit 7 is t he e n d of treat me nt visit, t here is n o f oll o w u p peri o d. Visit 7 pr oce d ures s h o ul d be 
f oll o we d f or early ter mi nati o n visits if p ossi ble.
If a patie nt misses a visit, t he visit s h o ul d be resc he d ule d as s o o n as p ossi ble. If u na ble t o 
resc he d ule, t he cli nical m o nit or s h o ul d be c o ntacte d.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
6. 2  
D E T AI L S O F T RI A L P R O C E D U R E S A T S E L E C T E D VI SI T S
6. 2. 1
Scree ni n g a n d r u n -i n peri o d(s)
Scree ni n g Peri o d
Visit 0 - I nf or me d c o nse nt (at le ast 7 d a ys bef ore Visit 1)

I nf or me d c o nse nt will be o btai ne d pri or t o patie nt partici pati o n i n t he trial, w hic h 
i ncl u des a ny me dicati o n was h - o ut pr oce d ures or restricti o ns as well as H R C T tra nsfer 
t o ce ntral re vie w. U p o n o btai ni n g i nf or me d c o nse nt, t he patie nt will be i nstr ucte d o n 
t he me dicati o n was h o ut a n d ot her restricti o ns nee de d, a n d dis pe nse d a n e Diar y ( or 
e Diar y a p plicati o n f or o w n de vice) a n d acti vit y m o nit or if t he y meet t he i ncl usi o n a n d 
e xcl usi o n cr iteria at t his ti me.

A preli mi nar y  c hec k of i n-/e xcl usi o n criteria is rec o m me n de d at ti me of i nf or me d 
c o nse nt t o a v oi d u n necessar y pr oce d ures i n n o n-eli gi ble patie nts.
C o nfir mati o n t hat t he patie nt is bei n g treate d wit h  ni nte da ni b f or u p t o 3 0 m o nt hs 
will be c o nfir me d via me dical rec or ds, o bser vati o n of t he patie nt prescri pti o n 
me dicati o n, or me dical rec or ds will be re q ueste d t o c o nfir m. Patie nts w h o ha ve 
rece ntly starte d ni nte da ni b 1 5 0 m g BI D a n d ha ve starte d b y t he da y of ra n d o mizati o n 
m ust be o n ni nte da ni b 1 5 0 m g BI D a mi ni m u m of 1 0 da y s b y t he first da y of 
p ul m o nar y  re ha bilitati o n.

A n H R C T n ot ol der t ha n 2 4 m o nt hs will be se nt f or ce ntral calc ulati o n of Q L F , t o 
assess H R C T patter n f or patie nt c haracterizati o n. Pr o vi de d t he patie nt meets all ot her 
eli gi bilit y criteria, t he H R C T ca n be perf or me d f or t he p ur p oses of partici pati o n i n t he 
trial if t he patie nt d oes n ot ha ve a H R C T wit hi n 2 4 m o nt hs, at t he ti me of t he 
sc he d ule d Visit 2.

Site pers o n nel will perf or m a scree ni n g call i n I R T t o e ns ure acc urat e trac ki n g of trial 
partici pati o n.
Visit 1

De m o gra p hics

Me dical hist or y  i ncl u di n g pre-e xisti n g c o n diti o ns 

Me dicati o n rec or ds nee de d f or c o nfir mati o n t hat t he patie nt has bee n treate d wit h
ni nte da ni b f or u p t o 3 0 m o nt hs will be re vie we d at t his visit if n ot a vaila ble at c o nse nt 
visit . Patie nts w h o ha ve rece ntl y starte d ni nte da ni b 1 5 0 m g BI D a n d ha ve starte d b y 
t he da y of ra n d o mizati o n m ust be o n ni nte da ni b 1 5 0 m g BI D a mi ni m u m of 1 0 da ys 
b y  t he first da y of p ul m o nar y re ha bilitati o n.

A n y  a d verse e ve nts (since c o nse nt, if a p plica ble) 

S G R Q, K BI L D a n d U C S D S O B Q will be c o m plete d b y  t he patie nt, pri or t o a n y 
pr oce d ures

C ollect a n d d o w nl oa d/ re vie w P R Oacti ve T o ol fr o m e Diar y a n d acti vit y m o nit or data

P h y sical e xa mi nati o n i ncl u di n g vital si g ns

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

A resti n g 1 2 -lea d electr ocar di o gra m usi n g site’s o w n e q ui p me nt will be perf or me d 
a n d e val uate d b y t he I n vesti gat or ( if p ossi ble pri or t o bl o o d dra w)

Resti n g S P 0 2

F V C meas ure me nt s will be c o n d ucte d usi n g t he site’s o w n e q ui p me nt, per t he 
i nstr ucti o ns i n Secti o n 5. 1. 2. 3

D L c o meas ure me nt will be c o n d ucte d. F V C meas ure me nt has t o be d o ne first, 
f oll o we d b y patie nt’s rest a n d s u bse q ue nt D Lc o meas ure me nt

Bl o o d a n d uri ne sa m ples (safet y la b a n d ser u m pre g na nc y if w o ma n of c hil d beari n g 
p ote ntial ) will be c ollecte d a n d s u b mitte d t o t he l ocal la b orat or y (f or details refer t o 
Secti o n 5. 2. 3 ). Pri or t o bl o o d dra w a pre-assess me nt of all i ncl usi o n a n d e xcl usi o n 
criteria is hi g hl y rec o m me n de d

Practice 6 mi n ute wal k test

I ncre me ntal a n d practice w or k rate c ycle er g o metr y test perf or me d at t he cli nic at e n d 
of Visit 1 

S e n d H R C T t o ce ntral calc ulati o n of Q L F if a vaila ble, or sc he d ule patie nt f or H R C T 
if n ot a vaila ble

F or patie nts q ualifie d t o e nter t he scree ni n g peri o d, patie nts will be dis pe nse d a n 
e Diar y ( or e Diar y a p plicati o n f or o w n de vice) a n d acti vit y m o nit or a n d i nstr ucte d o n 
t he use of b ot h de vices, wit h s pecific i nstr ucti o ns gi ve n t o use b ot h de vices f or 7 da ys 
pri or t o Visit 2

Visit 2 will be sc he d ule d

If patie nt fails scree ni n g, I R T call t o disc o nti n ue patie nt
6. 2. 2
Tre at me nt peri o d(s)
Treat me nt p hase will be a 2 4 wee k peri o d, be gi n ni n g at visit 2.
Visits are pla n ne d after 3, 6, 1 2, 1 8 a n d 2 4 wee ks after ra n d o mizati o n. If a d diti o nal ti me is 
nee de d after ra n d o mizati o n t o sc he d ule t he p ul m o nar y re ha bilitati o n f or a patie nt ra n d o mize d 
t o t hat gr o u p, t he ti me bet wee n visits 2 a n d 3 ma y be e xte n de d u p t o 6 wee ks. T he visit 
sc he d ule will res u me o n t he da y  of t he first p ul m o nar y re ha bilitati o n visit, a n d all s u bse q ue nt 
visit s will be sc he d ule d acc or di n gl y t o kee p t he ti me bet wee n visits per pr ot oc ol a n d a t otal 
2 4 wee k treat me nt peri o d .
D uri n g all t he visits it is i m p orta nt t hat patie nts’ q uesti o n naires are c o m plete d bef ore a n y 
ot her pr oce d ure. T he or der of t he ot her pr oce d ures t o be f oll o we d is gi ve n bel o w as a n 
i n dicati o n b ut ca n be a da pte d f or practical reas o ns.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Visit 2

S G R Q, K BI L D a n d U C S D S O B Q

A d verse e ve nts a n d c o nc o mita nt t hera p y  assess me nt si nce last visit

D o w nl oa d /re vie w P R Oacti ve T o ol a n d acti vit y m o nit or res ults

P h y sical e xa mi nati o n i ncl u di n g vital si g ns

Resti n g S p O 2

Bl o o d sa m ples f or la b orat or y tests

Uri nar y pre g na nc y  test 

P ul m o nar y  f u ncti o n test i ncl u di n g F V C 

D L C O

Assess me nt of i n/e xcl usi o n criteria

Ra n d o misati o n via I R T 

6 mi n ute wal k test


Sc he d ule patie nt f or p ul m o nar y  re ha bilitati o n if ra n d o mize d t o t hat treat me nt 
gr o u p

Sc he d ule Visit 3

Se n d H R C T f or calc ulati o n of Q L F if n ot pre vi o usl y  a vaila ble.
Visits 3, 4, 5 a n d 6:

A d verse e ve nts a n d c o nc o mita nt t hera p y  assess me nt si nce last visit

C ollect a n d d o w nl oa d/re vie w P R O Acti ve T o ol fr o m e Diar y  a n d acti vit y 
m o nit or data at Visit 5

Re vie w p ul m o nar y  re ha bilitati o n atte n da nce wit h patie nt a n d rec or d 
i nf or mati o n fr o m p ul m o nar y re ha bilitati o n re p orts i nt o e C R F f or patie nts i n 
t he P R treat me nt gr o u p at Visits 3, 4 a n d 5

P h y sical e xa mi nati o n i ncl u di n g vital si g ns

Bl o o d sa m ples f or la b orat or y tests

Uri nar y pre g na nc y  test

S G R Q, K BI L D a n d U C S D S O B Q at Visit 5

P ul m o nar y  f u ncti o n test i ncl u di n g F V C at Visit 5

D L C O  at Visit 5

S P 0 2 at Visit 5

Si x mi n ute wal k test at Visit 5


I nstr uct patie nt o n acti vit y m o nit ori n g a n d e Diar y ( or e Diar y a p plicati o n f or 
o w n de vice) a n d re mi n d patie nt t he y nee d t o pic k u p or will recei ve de vice i n 
t he mail t o all o w 7 da ys of use pri or t o ne xt visit at Visits 4 a n d 6

Sc he d ule ne xt visit. 
6. 2. 3
F oll o w u p p eri o d a n d tri al co m pleti o n

Visit 7/ E n d of Treat me nt ( E O T) or w he n t he patie nt is disc o nti n ue d

A d verse e ve nts a n d c o nc o mita nt t hera p y  assess me nt si nce last visit

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

Re vie w p ul m o nar y  re ha bilitati o n atte n da nce wit h patie nt a n d rec or d i nf or mati o n fr o m 
p ul m o nar y re ha bilitati o n re p orts i nt o e C R F f or patie nts i n t he P R treat me nt gr o u p (f or 
patie nts disc o nti n ue d d uri n g first 1 2 wee ks)

P h y sical e xa mi nati o n i ncl u di n g vital si g ns

S G R Q, K BI L D a n d U C S D S O B Q 

C ollect a n d d o w nl oa d/re vie w P R O Acti ve T o ol fr o m e Diar y a n d acti vit y m o nit or data

Resti n g S p O 2

Resti n g 1 2 -lea d electr ocar di o gra m

Bl o o d sa m ples f or la b orat or y tests

Uri nar y pre g na nc y  test ( d o ne l ocally)

P ul m o nar y  f u ncti o n test i ncl u di n g F V C

D L C O

Si x mi n ute wal k test 


E n d Of Treat me nt pa ge t o be c o m plete d

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
7.
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F
S A M P L E SI Z E
7. 1 
S T A TI S TI C A L D E SI G N - M O D E L
T his is a m ulti -ce ntre, pr os pecti ve, ra n d o mise d, o pe n la bel cli nical trial t o i n vesti gate t he 
effect of p ul m o nar y re ha bilitati o n i n patie nts wit h IP F c urre ntl y treate d wit h ni nte da ni b at a 
d ose of 1 5 0 m g bi d f or u p t o 3 0 m o nt hs .
T he pri mar y  e n d p oi nt is t he c ha n ge fr o m baseli ne i n 6 M W D at 1 2 wee ks.  6 M W D will be 
a nal ys e d o n t he ori gi nal scale usi n g t he A nal ys is of C o varia nce ( A N C O V A) m o del i ncl u di n g 
i nter ve nti o n as a fi xe d cate g orical c o variate a n d baseli ne 6 M W D as a c o nti n u o us c o variate.  
M ore detail is pr o vi de d i n Secti o n 7. 3. 1 .
T he sec o n dar y  a n d f urt her e n d p oi nts are liste d i n Secti o n 5. 1. 1 .  T he 1 2-wee k e n d p oi nts will
be a nal ys e d usi n g si milar A N C O V A met h o d ol o g y as t he pri mar y  e n d p oi nt.  T he 2 4 - wee k 
en d p oi nts will be a nal y ze d usi n g a mi xe d m o del wit h re peate d meas ures.  M ore detail is 
pr o vi de d i n Secti o n 7. 3. 2 .
7. 2
N U L L A N D A L T E R N A TI V E H Y P O T H E S E S
T he o bjecti ve of t his st u d y is t o de m o nstrate t he differe nce of Ni nte da ni b a n d p ul m o nar y  
re ha bilitati o n c o m bi nati o n i nter ve nti o n c o m pare d t o Ni nte da ni b -o nl y  i n t he treat me nt of 
patie nts wit h I P F. T his will be teste d usi n g t he set of h y p ot heses i n dicate d bel o w. T he n ull 
h y p ot hesis is
H 0: N o differe nce i n mea n f or c ha n ge i n 6 M W D at 1 2 wee ks bet wee n Ni nte da ni b a n d 
p ul m o nar y  re ha bilitati o n c o m bi nati o n i nter ve nti o n a n d Ni nte da ni b -o nl y i nter ve nti o n.
T he alter nati ve h y p ot hesis is
Ha: T he mea n f or c ha n ge i n 6 M W D at 1 2 wee ks is differe nt f or patie nts ta ki n g 
Ni nte da ni b a n d p ul m o nar y re ha bili tati o n c o m bi nati o n i nter ve nti o n t ha n i n Ni nte da ni b-
o nl y  i nter ve nti o n.
H 0 will be teste d at t he 5 % le vel (t w o -si de d test).
7. 3
P L A N N E D A N A L Y S E S
All i n di vi d ual data will be liste d. Sta n dar d statistical para meters ( n u m ber of n o n -missi n g 
val ues, mea n, ge o metric mea n, sta n dar d de viati o n ( S D), me dia n, q uartiles, mi ni m u m a n d
ma xi m u m) or fre q ue nc y  ta bles will be calc ulate d w here a p pr o priate. I n ge neral, t hese 
para meters or fre q ue ncies will be calc ulate d se paratel y  f or eac h i nter ve nti o n, b ut j oi ntl y f or 
all st u d y ce ntres.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T he statistical a nal ys is will be base d o n t he f oll o wi n g p o p ulati o ns:
Ra n d o mize d Set ( R S): T he Ra n d o mise d set ( R S) c o nsists of t h ose patie nts w h o were 
ra n d o mize d t o an i nter ve nti o n.
T he efficac y  will be c o n d ucte d o n t he Ra n d o mize d Set . F or efficac y a nal ys is, all 
meas ure me nt s perf or me d wit hi n visits 2 -7 will be use d.
Alt h o u g h t here is n o per pr ot oc ol data set i n t he st u d y , reas o ns f or i m p orta nt pr ot oc ol
vi olati o ns will be s pecifie d i n t he Trial Statistical A nal y sis Pla n ( T S A P). Patie nts wit h
p ote ntial i m p orta nt pr ot oc ol vi olati o ns (t h ose t hat relate t o patie nt safet y or efficac y) will be 
i de ntifie d at Bli n de d Re vie w Pla n ni n g Meeti n gs a n d liste d i n t he cli nical trial.
7. 3. 1
Pri m ar y e n d p oi nt a n al yses
T he pri mar y  a nalys is is a restricte d ma xi m u m li kelih o o d ( R E M L ) base d a nal ysis of 
c o varia nce ( A N C O V A) c o m pari n g t he c ha n ge fr o m baseli ne of 6 M W D after 1 2 wee ks of 
treat me nt wit h a dj ust me nt f or t he c o variates of i nter ve nti o n as a fi xe d cate g orical c o variate 
a n d baseli ne 6 M W D val ue as a c o nti n u o us c o variate.
T he statistical m o del will be as f oll o ws:
   =    +   +     = res p o nse varia ble f or t he s u bject  recei vi n g i nter ve nti o n  = fi xe d effect re gressi o n c oefficie nt of baseli ne effect
  = t he baseli ne meas ure me nt of s u bject ,  = 1, 2, … w here t he baseli ne 
meas ure me nt is c ollecte d o n Da y  1 of t he i nter ve nti o nal peri o d
 = t he fi xe d effect of i nter ve nti o n j, j = 1, 2
  = t he ra n d o m err or ass ociate d wit h t he  s u bject, i de nticall y i n de pe n de nt 
n or mall y  distri b ute d wit h mea n 0 a n d u n k n o w n varia nce   .
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 
a n d a dj ust sta n dar d err ors.  Si g nifica nce tests will be base d o n least -s q uares mea ns usi n g a 
t w o-si de d α = 0. 0 5 (t w o-si de d 9 5 % c o nfi de nce i nter vals).  T he pri mar y i nter ve nti o n
c o m paris o n will be t he least -s q uares mea ns c o ntrast bet wee n i nter ve nti o ns. Pri mar y  e n d p oi nt 
a nal ys es will be d o ne o n c o m plete cases. Secti o n 7. 3. 2 disc uss es pla n ne d se nsiti vit y a nalys is 
t o assess t he i m pact of patie nts missi n g p ost-ra n d o misati o n data.
7. 3. 2
Sec o n d ar y e n d p oi nt a n al yses
T he sec o n dar y  e nd p oi nts i ncl u de t h ose liste d i n Secti o n 5. 1. 1. 2 .  All ot her sec o n dar y 
e n d p oi nts will b e a nal yse d o n t he ori gi nal scales.  

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T he 1 2 - wee k sec o n dar y e n d p oi nts will be a nal y se d e q ui vale ntl y as t he pri mar y e n d p oi nt 
usi n g t he A N C O V A m o del i ncl u di n g i nter ve nti o n as a fi xe d cate g orical c o variate a n d 
baseli ne val ue as a c o nti n u o us c o variate.  
T he 2 4 -wee k sec o n dar y  e n d p oi nts will be a nal y se d wit h a restricte d ma xi m u m li keli h o o d 
( R E M L) base d a p pr oac h usi n g a mi xe d m o del wit h re peate d meas ure me nts ( M M R M) 
c o m pari n g t he c ha n ge fr o m baseli ne after 2 4 wee ks of i nter ve nti o n.  T he a nal ysis will i ncl u de 
t he fi xe d, cate g orical effects of i nter ve nti o n a n d t he fi xe d c o nti n u o us effects of baseli ne at 
eac h visit. Visit will be treate d as t he re peate d meas ure wit h a n u nstr uct ure d c o varia nce 
str uct ure use d t o m o del t he wit hi n-patie nt meas ure me nts.  T he statistical m o del will be as 
f oll o ws:
    =     +    +     ~   ( , )
    = res p o nse varia ble f or t he s u bject  at visit  recei vi n g i nter ve nti o n  ,
  = coefficie nt of baseli ne effect at visit ,
  = t he baseli ne meas ure me nt of s u bject ,  = 1, 2, …
  = t he effect of i nter ve nti o n k at visit j; j = 1, 2 (, 3) a n d k = 1, 2
   = t he ra n d o m err or ass ociate d wit h t he  visit of t he   s u bject, Err ors are 
i n de pe n de nt bet wee n s u bjects,
 = a n u nstr uct ure d c o varia nce matri x.
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 
a n d a dj ust sta n dar d err ors.  Si g nifica nce tests will be base d o n least -s q uares mea ns usi n g a 
t w o-si de d α = 0. 0 5 (t w o-si de d 9 5 % c o nfi de nce i nter vals).  T he pri mar y i nter ve nti o n
c o m paris o n will be t he least -s q uares mea ns c o ntrast bet wee n treat me nts.
A se nsiti vit y  a nalys is of t he pri mar y a nalys is will be perf or me d usi n g m ulti ple i m p utati o n t o 
ha n dle missi n g data.  All varia bles i ncl u de d i n t he a nal ys is m o del will be i ncl u de d i n t he 
i m p utati o n m o del.  In a d diti o n, after e x pl ori n g t he missi n g data mec ha n is m a n d o bser ve d 
meas ure me nts o n t he bli n de d data, a d diti o nal varia bles ma y  be i ncl u de d i n t he i m p utati o n 
m o del, base d o n t heir ass ociati o ns wit h t he o bser ve d e n d p oi nt val ue a n d/ or t he missi n g ness 
mec ha nis m.  T h ose varia bles will be i de ntifie d i n t he T S A P.   F or eac h i m p ute d c o m plete 
dataset, t he pri mar y  a nal ysis m o del will be use d f or t he a nalys is.  T he res ults will be p o ole d 
f oll o wi n g t he sta n dar d m ulti ple i m p utati o n pr oce d ure. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
7. 3. 4
S afet y a n al yses
A nal y sis of a d verse e ve nts will be restricte d t o ni nte da ni b-relate d seri o us a d verse e ve nts, 
ni nte da ni b - n o n-relate d seri o us a d verse e ve nts a n d e ve nts of s pecial i nterest.
A d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y  f or Dr u g Re g ulat or y Acti vities 
( Me d D R A). Sta n dar d BI s u m mar y ta bles a n d listi n gs will be pr o d uce d. A d verse e ve nts wit h 
a n o nset bet wee n start of p ul m o nar y  re ha bilitati o n treat me nt a n d e n d of trial will be assi g ne d 
t o t he o n-treat me nt peri o d f or e val uati o n. All ra n d o mize d patie nts will be i ncl u de d i n t he 
safety a nal ysis.  I n ge neral, safet y a nal ys es will be descri pti ve i n nat ure a n d will be base d o n 
BI sta n dar ds. N o h y p ot hesis testi n g is pla n ne d .
Fre q ue nc y , se verity, a n d ca usal relati o ns hi p of a d verse e ve nts will be ta b ulate d b y s ys te m 
or ga n class a n d preferre d ter m after c o di n g acc or di n g t o t he c urre nt versi o n of t he Me dical 
Dicti o nar y  f or Dr u g Re g ulat or y Acti vities at t he data base l oc k.
Vital si g ns, p hys ical e xa mi nati o ns, or ot her safety -rele va nt data o bser ve d at scree ni n g, 
baseli ne, d uri n g t he c o urse of t he trial a n d at t he e n d - of-trial e val uati o n will be assesse d wit h 
re gar d t o p ossi ble c ha n ges c o m pare d t o fi n di n gs bef ore start of p ul m o nar y re ha bilitati o n.
A nal y sis of la b orat or y data a n d electr ocar di o gra m is n ot pla n ne d.
7. 3. 5 
P h ar m ac o ki netic a n d P h ar m ac o d y n a mic a n al yses
T here is n o p har mac o ki netic a nal ys es pla n ne d f or t his trial.
7. 4 
I N T E RI M A N A L Y S E S
N o i nteri m a nal ys is is pla n ne d.  A re g ular re vie w of safet y data will als o be c o n d ucte d t o 
m o nit or t he safet y of patie nts i n t he trial.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
7. 5
H A N D LI N G O F MI S SI N G D A T A
I n efficac y a nalys es of c o nti n u o us e n d p oi nts missi n g data will n ot be i m p ute d.  M ulti ple 
i m p utati o n will be use d as a se nsiti vit y a nalys is t o ha n dle missi n g data.  Detaile d descri pti o n 
of m ulti ple i m p utati o n will be i ncl u de d i n t he T S A P.
7. 6
R A N D O MI S A TI O N
Patie nts will be ra n d o mize d i n bl oc ks t o p ul m o nar y re ha bilitati o n gr o u ps wit h a n e q ual 
pr o ba bilit y  of assi g n me nt t o eac h treat me nt gr o u p (see Secti o ns 4. 1. 2, 4. 1. 3 a n d 4. 1. 4 f or 
details). BI will arra n ge f or t he ra n d o mi sati o n. T he ra n d o misati o n list will be ge nerate d usi n g 
a n I nteracti ve Res p o nse Tec h n ol o g y (I R T), w hic h i n v ol ves a pse u d o-ra n d o m n u m ber 
ge nerat or s o t hat t he res ulti n g treat me nt will be b ot h re pr o d uci ble a n d n o n -pre dicta ble. 
Access t o t he c o des will be c o ntr olle d a n d d oc u me nte d. T he bl oc k size will be d oc u me nte d i n 
t he cli nical trial re p ort.
7. 7
D E T E R MI N A TI O N O F S A M P L E SI Z E
I n t he 1 1 9 9. 1 8 7 6-m o nt h data, a n u na dj uste d mea n f or a bs ol ute c ha n ge fr o m baseli ne i n 
6 M W T dista nce of 4. 9 meters (s d = 7 6. 5) was o bser ve d f or ni nte da ni b.  T o c o nser vati vely 
esti mate t he sa m ple size, a sta n dar d de viati o n of 8 5. 0 is use d i n esti mati o n.  In t he 2 0 1 4 
C oc hra ne Data base of S yste matic Re vie ws [ R 1 8 -1 7 0 4 ], a mea n f or a bs ol ute c ha n ge fr o m 
baseli ne i n 6 M W T dista nce of 4 4. 3 meters was o bser ve d f or p ul m o nar y re ha bilitati o n f or 
i nterstitial l u n g disease.  T he mi ni mal cli nicall y i m p orta nt differe nce f or t he 6 M W D f or IP F 
patie nts wit h c o m bi ne d treat me nt of ni nte da ni b a n d p ul m o nar y re ha bilitati o n vers us I P F 
patie nts treate d wit h ni nte da ni b o nl y  is 3 0 meters [R 1 8 - 1 7 6 7].
I n li ght of t he a vaila ble e vi de nce, at least 2 5 4 patie nts w o ul d be re q uire d t o pr o vi de 8 0 % 
p o wer t o detect a differe nce i n mea ns of 3 0 meters bet wee n ni nte da ni b a n d p ul m o nar y  
re ha bilitati o n c o m bi nati o n treat me nt vers us ni nte da ni b b y itself wit h a t w o-si de d t ype- I err or 
of 0. 0 5.  Ass u mi n g 1 0 % dr o p o ut, at least 1 4 1 patie nts per ar m, or 2 8 2 patie nts will be 
re q uire d.  Calc ulati o ns were perf or me d usi n g n Q uer y  A d vis or ® 6. 1 statistical pac ka ge by 
Statistical S ol uti o ns L t d. u n der t he fi xe d ter m test of mea ns wit h t w o g r o u ps o pti o n f or 
st u de nt t-test wit h e q ual varia nce.
Differe nce i n 
Mea ns
C o m m o n 
Sta n dar d 
De viati o n
P o wer ( %)
T otal N of 
ra n d o mize d 
patie nts
3 0. 0
7 7. 0
8 0
2 1 0
3 0. 0
8 5. 0
8 0
2 5 4

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 4 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
8.
I N F O R M E D C O N S E N T, T RI A L R E C O R D S, D A T A 
P R O T E C TI O N, P U B LI C A T I O N P O LI C Y, A N D 
A D MI NI S T R A TI V E S T R U C T U R E
T he trial will be carrie d o ut i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples lai d d o w n 
i n t he Declarati o n of Helsi n ki, i n acc or da nce wit h t he IC H Har m o nize d Tri partite G ui deli ne 
f or G o o d Cli nical Practice ( G C P), rele va nt BI Sta n dar d O perati n g Pr oce d ures ( SO Ps),
Sta n dar d me dical care ( pr o p h y lactic, dia g n ostic a n d t hera pe utic pr oce d ures) re mai ns t he 
res p o nsi bilit y of t he treati n g p h ysicia n of t he patie nt .
T he i n vesti gat or will i nf or m t he s p o ns or i m me diatel y  of a n y ur ge nt safety meas ures ta ke n t o 
pr otect t he trial patie nts a gai nst a n y i m me diate hazar d, as well as of a n y s eri o us breac hes of 
t he pr ot oc ol or of I C H G C P.
T he B oe hri n ger I ngel hei m tra ns pare nc y  a n d p u blicati o n p olic y ca n be f o u n d o n t he f oll o wi n g 
we b pa ge : trials. b oe hri n ger-i n gel hei m.c o m. T he ri g hts of t he i n vesti gat or a n d of t he s p o ns or 
wit h re gar d t o p u blicati o n of t he res ults of t his trial are descri be d i n t he i n vesti gat or c o ntract. 
As a r ule, n o trial res ults s h o ul d be p u blis he d pri or t o fi nalizati o n of t he Cli nical Trial Re p ort.
8. 1
T RI A L A P P R O V A L, P A TI E N T I N F O R M A TI O N, I N F O R M ED C O N S E N T
T his trial will be i nitiate d o nl y  after all re q uire d le gal d oc u me ntati o n has bee n re vie we d a n d 
a p pr o ve d b y t he res pecti ve I nstit uti o nal Re vie w B oar d (I R B) / I n de pe n de nt Et hics C o m mittee 
(I E C) a n d c o m pete nt a ut h orit y ( C A) acc or di n g t o nati o nal a n d i nter nati o nal re g ulati o ns. T he 
sa me a p plies f or t he i m ple me ntati o n of c ha n ges i ntr o d uce d b y a me n d me nts.
Pri or t o patie nt partici pati o n i n t he trial, writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h 
patie nt ( or t he patie nt ’s le gall y acce pte d re prese ntati ve) acc or di n g t o I C H / G C P a n d t o t he 
re g ulat or y a n d le gal re q uire me nts of t he partici pati n g c o u ntr y. Eac h si g nat ure m ust be 
pers o nall y date d b y eac h si g nat or y a n d t he i nf or me d c o nse nt a n d a n y a d diti o nal patie nt -
i nf or mati o n f or m retai ne d b y t he i n vesti gat or as part of t he trial rec or ds. A si g ne d c o p y of t he 
i nf or me d c o nse nt a n d a n y a d diti o nal patie nt i nf or mati o n m ust be gi ve n t o eac h patie nt or t he 
patie nt ’s le gally acce pte d re prese ntati ve.”
T he i n vesti gat or m ust gi ve a f ull e x pla nati o n t o trial patie nt s base d o n t he patie nt i nf or mati o n 
f or m. A la n g ua ge u n dersta n da ble t o t he patie nt s h o ul d be c h ose n, tec h nical ter ms a n d 
e x pressi o ns a v oi de d, if p ossi ble. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T he patie nt m ust be gi ve n s ufficie nt ti me t o c o nsi der partici pati o n i n t h e trial. T he 
i n vesti gat or o btai ns writte n c o nse nt of t he patie nt ’s o w n free will wit h t he i nf or me d c o nse nt 
f or m after c o nfir mi n g t hat t he patie nt u n dersta n ds t he c o nte nts. Re -c o nse nti n g ma y bec o me 
necessar y  w he n ne w rele va nt i nf or mati o n bec o mes a vaila ble a n d s h o ul d be c o n d ucte d 
acc or di n g t o t he s p o ns or’s i nstr ucti o ns.
T he c o nse nt a n d re - c o nse nti n g pr ocess s h o ul d be pr o perly d oc u me nte d i n t he s o urce 
d oc u me ntati o n.
8. 2
D A T A Q U A LI T Y A S S U R A N C E
A q ualit y  ass ura nce a u dit/i ns pecti o n of t his trial ma y be c o n d ucte d b y t he s p o ns or, s p o ns or’s 
desi g nees, or b y I RB / I E C or b y  re g ulat or y a ut h orities. T he q ualit y ass ura nce a u dit or will 
ha ve access t o all me dical rec or ds, t he i n vesti gat or’s trial-relate d files a n d c orres p o n de nce, 
a n d t he i nf or me d c o nse nt d oc u me ntati o n of t his cli nical trial.
8. 3
R E C O R D S
C R F s f or i n di vi d ual patie nt s will be pr o vi de d b y t he s p o ns or. 
8. 3. 1
S o urce d oc u me nts
I n acc or da nce wit h re g ulat or y re q uire me nts t he i n vesti gat or s h o ul d pre pare a n d mai ntai n 
a de q uate a n d acc urate s o urce d oc u me nts a n d trial rec or ds t hat i ncl u de all o bser vati o ns a n d 
ot her data perti ne nt t o t he i n vesti gati o n o n eac h trial patie nt . S o urce data as well as re p orte d 
data s h o ul d f oll o w g o o d d oc u me ntati o n practices a n d be attri b uta ble, le gi ble, 
c o nte m p ora ne o us, ori gi nal a n d acc urate . C ha n ges t o t he data s h o ul d be tracea ble (a u dit trail).
Data re p orte d o n t he C R F m ust be c o nsiste nt wit h t he s o urce data or t he discre pa ncies m ust 
be e x plai ne d.
T he c urre nt me dical hist or y  of t he patie nt m a y  n ot be s ufficie nt t o c o nfir m eli gi bilit y f or t he 
trial a n d t he i n vesti gat or ma y  nee d t o re q uest pre vi o us me dical hist ories a n d e vi de nce of a n y 
dia g n ostic tests. I n t his case t he i n vesti gat or m ust ma ke t hree d oc u me nte d atte m pts t o retrie ve 
pre vi o us me dical rec or ds. If t his fails a ver bal hist or y  fr o m t he patie nt , d oc u me nte d i n t heir 
me dical rec or ds, w o ul d be acce pta ble.
D uri n g t he site visit t he s p o ns or’s C R A or a u dit or m ust be gra nte d access t o t he ori gi nal 
patie nt file ( please see secti o n 8. 3. 2). The i n vesti gat or m ust e ns ur e t hat all patie nt i de ntifiers 
(e. g. patie nt’s na me, i nitials, a d dress, p h o ne n u m ber, s ocial sec urity n u m ber ) ha ve pr o perly 
bee n re m o ve d or re dacte d fr o m a ny c o p y of t he patie nts’ s o urce d oc u me nts bef ore se n di n g 
t he m t o t he s p o ns or.
If t he patie nt is n ot c o m plia nt wit h t he pr ot oc ol , a n y c orrecti ve acti o n e. g. re-trai ni n g m ust be 
d oc u me nte d i n t he patie nt file

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
F or t he C R F, data m ust be deri ve d fr o m s o urce d oc u me nts, f or e xa m ple:

Patie nt i de ntificati o n: ge n der, year of birt h (i n acc or da nce wit h l ocal la ws a n d 
re g ulati o ns)

Patie nt partici pati o n i n t he trial (s u bsta nce, trial n u m ber, patie nt n u m ber, date patie nt
was i nf or me d)

Dates of patie nt ’s visits, i ncl u di n g dis pe nsi n g of trial me dicati o n

Me dical hist or y  (i ncl u di n g trial i ndicati o n a n d c o nc o mita nt diseases, if a p plica ble)

Me dicati o n hist or y

A d verse e ve nts a n d o utc o me e ve nts ( o nset date ( ma n dat or y ), a n d e n d date (if 
a vaila ble))

Seri o us a d verse e ve nts ( o nset date ( ma n dat or y ), a n d e n d date (if a vaila ble))

C o nc o mita nt t hera p y (start date, c ha n ges)

Ori gi nals or c o pies of la b orat or y  res ults a n d ot her i ma gi n g or testi n g res ults, wit h 
pr o per d oc u me nte d me dical e val uati o n (i n vali date d electr o nic f or mat, if a vaila ble)

C o m pleti o n of patie nt’s p artici pati o n i n t he trial” (e n d date; i n case of pre mat ure 
disc o nti n uati o n d oc u me nt t he reas o n f or it).

Pri or t o all ocati o n of a patie nt t o a treat me nt i nt o a cli nical trial, t here m ust be 
d oc u me nte d e vi de nce i n t he s o urce data (e. g. me dical rec or ds) t hat t he trial partici pa nt 
meets all i ncl usi o n criteria a n d d oes n ot meet a n y e xcl usi o n criteria. T he a bse nce of 
rec or ds (eit her me dical rec or ds, ver bal d oc u me nte d fee d bac k of t he patie nt or testi n g 
c o n d ucte d s pecific f or a pr ot oc ol) t o s u p p ort i ncl usi o n/e xcl usi o n criteria d oes n ot ma ke 
t he patie nt eli gi ble f or t he cli nical trial.
8. 3. 2  
Direct access t o s o urce d at a a n d d oc u me nts
T he s p o ns or will m o nit or t he c o n d uct of t he trial b y re g ular o n -site m o nit ori n g visits a n d i n-
h o use data q ualit y re vie w. T he fre q ue nc y of site m o nit ori n g will be deter mi ne d b y  assessi n g 
all c haracteristics of t he trial, i ncl u di n g its nat ure, o bjecti ve, met h o d ol o g y a n d t he de gree of 
a n y de viati o ns of t he i nter ve nti o n fr o m n or mal cli nical practice.
T he i n vesti gat or /i nstit uti o n will all o w site trial-relate d m o nit ori n g, a u dits, I R B / I EC re vie w 
a n d re g ulat or y i ns pecti o ns. Direct access m ust be pr o vi de d t o t he C R F a n d all s o urce 
d oc u me nts/ data, i ncl u di n g pr o gress n otes, c o pies of la b orat or y a n d me dical test res ults, w hic h 
m ust be a vaila ble at all ti mes f or re vie w b y t he C R A , a u dit or a n d re g ulat or y i ns pect or 
(e. g. F D A). T h e y  m a y  re vie w all C R Fs a n d i nf or me d c o nse nts. T he acc urac y of t he data will 
be verifie d b y direct c o m paris o n wit h t he s o urce d oc u me n ts descri be d i n secti o n 8. 3. 1. T he 
s p o ns or will als o m o nit or c o m plia nce wit h t he pr ot oc ol a n d G C P.
A n a da pti ve a p pr oac h t o cli nical trial m o nit ori n g 
will be utilise d. T his is i nitiate d b y  a n 
assess me nt of t he ris k ass ociate d wit h t he trial c o m bi ne d wit h i de ntificati o n of critical dat a 
a n d pr ocesses. A n I nte grate d Q ualit y a n d Ris k Ma na ge me nt Pla n
d oc u me nts t he strate gies 
i n v ol ve d wit h t he i m ple me ntati o n of o nsite, offsite a n d ce ntral m o nit ori n g acti vities i n or der 
t o direct f oc us t o t he areas of greatest ris k w hic h ha ve t he m ost p otential i m pact t o patie nt
safety a n d data q ualit y. Trial o versi g ht is ac hie ve d b y  re g ular re vie w of a re p ort of ris k w hic h 
t he n i nfl ue nces a ny m o nit ori n g a da ptati o ns. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
T he i n vesti gat or /i nstit uti o n will all o w o n-site trial-relate d m o nit ori n g, a u dits, IR B/ I EC 
re vie w a n d re g ulat or y i ns pecti o ns. Direct a ccess s h o ul d be gra nte d t o all s o urce d oc u me nts 
(pa per a n d e -rec or ds) i ncl u di n g pr o gress n otes, c o pies of la b orat or y a n d me dical test res ults
T he C R A a n d a u dit or ma y re vie w all C R Fs a n d i nf or me d c o nse nts. T he acc urac y of t he data 
will be verifie d b y direct c o m paris o n wit h t he s o urce d oc u me nts descri be d i n secti o n 
8. 3. 1 . T he s p o ns or will als o m o nit or c o m plia nce wit h t he pr ot oc ol a n d I C H G C P.
8. 3. 3 
St or a ge peri o d of rec or ds
Trial site(s):
T he trial site(s) m ust retai n t he s o urce a n d esse ntial d oc u me nts (i ncl u di n g I S F) acc or di n g t o 
c o ntract or t he l ocal re q uire me nts vali d at t he ti me of t he e n d of t he trial ( w hate ver is l o n ger).
S p o ns or :
T he s p o ns or m ust retai n t he esse ntial d oc u me nts acc or di n g t o t he s p o ns or’s S O Ps.
8. 4 
E X P E DI T E D R E P O R TI N G O F  A D V E R S E E V E N T S
BI is res p o nsi ble t o f ulfil t heir le gal a n d re g ulat or y re p orti n g o bli gati o n i n acc or da nce wit h
re g ulat or y re q uire me nts. 
8. 5
S T A T E M E N T O F C O N FI D E N TI A LI T Y A N D P A TI E N T P RI V A C Y
I n di vi d ual patie nt data o btai ne d as a res ult of t his trial is c o nsi dere d c o nfi de ntial a n d 
discl os ure t o t hir d parties is pr o hi bite d wit h t he e xce pti o ns n ote d bel o w. Patie nt pri vac y will 
be e ns ure d b y usi n g patie nt i de ntificati o n c o de n u m bers.
Data pr otecti o n a n d data sec urit y meas ures are i m ple me nte d f or t he c ollecti o n, st ora ge a n d 
pr ocessi n g of patie nt data i n acc or da nce wit h t he pri nci ples 6 a n d 1 2 of t he W H O G C P 
ha n d b o o k.
Treat me nt data ma y  be gi ve n t o t he patie nt ’s pers o nal p h ysicia n or t o ot her a p pr o priate 
me dical pers o n nel res p o nsi ble f or t he patie nt ’s welfare. Data ge nerate d as a res ult of t he trial
nee d t o be a vaila ble f or i ns pecti o n o n re q uest b y t he partici pati n g p h ys icia ns, t he s p o ns or’s 
re prese ntati ves, by t he I R B / I E C a n d t he re g ulat or y a ut h orities.
8. 5. 1
C ollecti o n, st or a ge a n d f ut ure use of bi ol o gic al s a m ples a n d c orres p o n di n g 
d at a 
Meas ures are i n place t o c o m pl y  wit h t he a p plica ble r ules f or t he c ollecti o n, st ora ge a n d 
f ut ure use of bi ol o gical sa m ples fr o m cli nical trial partici pa nts a n d t he c orres p o n di n g data, i n 
partic ular

A Q ualit y  Ma na ge me nt S yste m has bee n i m ple me nte d t o e ns ure t he a d here nce wit h 
t he Pri nci ples of G o o d Cli nical Practice as o utli ne d i n ' N ote F or G ui da nce O n G o o d 
Cli nical Practice' ( C P M P/I C H/ 1 3 5/ 9 5)

T he BI -i nter nal facilities st ori n g a n d a nalys i n g bi ol o gical sa m ples a n d data fr o m 
cli nical trial partici pa nts as well as t he la b orat ories' acti vities f or cli nical trials 
s p o ns ore d by B oe hri n ger I n gel hei m are re g ularl y a u dite d. T he a nal ytical gr o u ps a n d 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
t he ba n ki n g facility are t heref ore assesse d t o be q ualifie d f or t he st ora ge a n d use of 
bi ol o gical sa m ples a n d data c ol lecte d i n cli nical trials.

Sa m ples a n d data are use d o nl y  if a n a p pr o priate i nf or me d c o nse nt is a vaila ble.
8. 6
T RI A L MI L E S T O N E S
T he st art of t he tri al is defi ne d as t he date w he n t he first patie nt i n t he w h ole trial si g ns 
i nf or me d c o nse nt.
T he e n d of t he tri al is defi ne d as t he date of t he last visit of t he last patie nt i n t he w h ole trial
(“ Last Patie nt O ut” ). 
E arl y ter mi n ati o n of t he tri al is defi ne d as t he pre mat ure ter mi nati o n of t he trial d ue t o a n y 
reas o n bef ore t he e n d of t he trial as s pecifie d i n t his pr ot oc ol.
Te m p or ar y h alt of t he tri al is defi ne d as a ny u n pla n ne d i nterr u pti o n of t he trial b y  t he 
s p o ns or wit h t he i nte nti o n t o res u me it.
S us pe nsi o n of t he tri al is defi ne d as a n i nterr u pti o n of t he trial base d o n a Healt h A ut h orit y  
re q uest.
8. 7
A D MI NI S T R A TI V E S T R U C T U R E O F T H E T RI A L
T he trial is s p o ns ore d by B oe hri n ger I n gel hei m ( BI).
Rele va nt d oc u me ntati o n o n t he partici pati n g ( Pri nci pal) I n vesti gat ors (e. g. t heir c urric ula 
vitae ) will be file d i n t he (I n vesti gat or Site File) I SF. T he i n vesti gat ors will ha ve access t o t he 
BI cli nical trial p ortal ( Cli ner gize) t o facilitate d oc u me nt e xc ha n ge a n d mai ntai n electr o nic 
I SF. 
BI has a p p oi nte d a Cli nical Trial Lea der , res p o nsi ble f or c o or di nati n g all re q uire d acti vities, 
i n or der t o 
-
ma n a ge t he trial i n acc or da nce wit h a p plica ble re g ulati o ns a n d i nter nal S O Ps,
-
direct t he cli nical trial tea m i n t he pre parati o n, c o n d uct, a n d re p orti n g of t he trial,
-
e ns ure a p pr o priate trai ni n g a n d i nf or mati o n of Cli nical Trial Ma na ger s (C T M ), 
Cli nical Resear c h Ass ociates ( C R As), a n d i n vesti gat ors of partici pati n g c o u ntries.
T he or ga nisati o n of t he trial i n t he partici pati n g c o u ntries will be perf or me d b y  t he res pecti ve 
l ocal or re gi o nal BI-or ga nisati o n ( O perati n g U nit, O P U) i n acc or da nce wit h a p plica ble
re g ulati o ns a n d BI S O Ps , or b y  a C o ntract Researc h Or ga nisati o n ( C R O) wit h w hic h t he 
res p o nsi bilities a n d tas ks will ha ve bee n a gree d a n d a writte n c o ntract file d bef ore i nitiati o n 
of t he cli nical trial.
Data Ma na ge me nt a n d Statistical E val uati o n will be d o ne b y BI acc or di n g t o BI S O Ps.
Tas ks a n d f u ncti o ns assi g ne d i n or der t o or ga nise, ma na ge, a n d e val uate t he trial are defi ne d 
acc or di n g t o BI S O Ps. A list of res p o nsi ble pers o ns a n d rele va nt l ocal i nf or mati o n ca n be 
f o u n d i n t he IS F.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
A n I R T ve n d or a n d ot her ce ntral ve n d ors (acti vit y  m o nit or, e Diar y) will be use d i n t his trial. 
Details will be pr o vi de d i n t he I RT Ma n ual a n d ve n d or s pecific ma n uals , a vaila ble i n t he IS F.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
9.
R E F E R E N C E S
9. 1
P U B LI S H E D R E F E R E N C E S
P 0 5 - 1 2 7 8 2
Miller M R, Ha n ki ns o n J, Br usasc o V, B ur g os F, Casa b uri R, C oates A, et. 
al, Sta n dar disati o n of s pir o metr y . E ur Res pir J 2 6 ( 2), 3 1 9-3 3 8 ( 2 0 0 5)
P 1 6 -0 4 4 4 2 
Tr o osters T, B o ur bea u J, Maltais F, Lei d y N, Erze n D, S o usa D de, et. al. 
E n ha nci n g e xercise t olera nce a n d p h ys ical acti vit y i n C O P D wit h c o m bi ne d 
p har mac ol o gical a n d n o n -p har mac ol o gical i nter ve nti o ns: P H Y S A C T O 
ra n d o mize d, place b o-c o ntr olle d st u d y desi g n. B MJ O pe n 6, e 0 1 0 1 0 6 ( 2 0 1 6)
P 1 8 - 0 4 5 9 7
Casa b uri, Ric har d. " Fact ors deter mi ni n g c o nsta nt w or k rate e xercise 
t olera nce i n C O P D a n d t heir r ole i n dictati n g t he mi ni mal cli nicall y 
i m p orta nt differe nce i n res p o nse t o i nter ve nti o ns." C O P D: J o ur nal of 
C hr o nic O bstr ucti ve P ul m o nar y  Disease 2. 1 ( 2 0 0 5): 1 3 1- 1 3 6
R 9 8 - 1 4 8 8  
O’ D o n nell D E, Wee b b K A. E xerti o nal breat hless ness i n patie nts wit h 
c hr o nic airfl o w li mitati o n. T he r ole of l u n g h y peri nflati o n. A m Re v Res pir 
Dis 1 4 8, 1 3 5 1- 1 3 5 7 ( 1 9 9 3)
R 0 4 - 1 0 0 1
Ha n ki ns o n J L , O de ncra ntz J R, Fe da n K B S pir o metric refere nce val ues fr o m 
a sa m ple of t he ge neral U. S. p o p ulati o n. A m J Res pir Crit Care Me d 1 5 9, 
1 7 9- 1 8 7 ( 1 9 9 9)
R 0 6 -2 0 0 2
Maci nt y re N, Cra p o R O, Vie gi G, J o h ns o n D C, Gri nte n C T M va n der, 
Br usasc o V, et. al Sta n dar disati o n of t he si n gle- breat h deter mi nati o n of 
car b o n m o n o xi de u pta ke i n t he l u n g. E ur Res pir J 2 6 ( 4), 7 2 0- 7 3 5 ( 2 0 0 5)
R 1 1 - 4 4 7 1
Bra w ner C A, E hr ma n J K, Al dre d H, Sc hairer J R, Kete y ia n SJ. Q ualit y 
ass ura nce a n d car di o p ul m o nar y  e xercise testi n g i n cli nical trials. J Car d Fail 
1 4 ( 4), 2 8 3 -2 8 9 ( 2 0 0 8).
R 1 3 - 1 5 7 8
Nici L , Z u Wallac k R, W o uters E, D o n ner C F . O n p ul m o nar y  re ha bilitati o n 
an d t he fli g ht of t he b u m ble bee: t he A T S/ E R S state me nt o n p ul m o nar y  
re ha bilitati o n. E ur Res pir J 2 8 ( 3), 4 6 1-4 6 2 ( 2 0 0 6)
R 1 4 -0 9 7 5
Haree n dra n A, Lei d y N K, M o nz B U, Wi n nette R, Bec ker K, Ma hler D A. 
Pr o p osi n g a sta n dar dize d met h o d f or e val uati n g patie nt re p ort of t he 
i nte nsit y of d ys p nea d uri n g e xercise testi n g i n C O P D. Int J C hr o nic 
O bstr uct P ul m Dis 7, 3 4 5 -3 5 5 ( 2 0 1 2)
R 1 6 - 5 3 5 3
Gi mi n o -Sa nt os E, Raste Y, De me y er H, L o u varis Z, J o n g C de, Ra bi n o vic h 
R A, et. al, P R Oacti ve C o ns orti u m. T he P R Oacti ve i nstr u me nts t o me as ure 
p h y sical acti vit y i n patie nts wit h c hr o nic o bstr ucti ve p ul m o nar y disease. 
E ur Res pir J 4 6, 9 8 8 -1 0 0 0 ( 2 0 1 5).

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
R 1 7 - 1 3 9 9
G ui da nce f or i n d ustr y: M 3( R 2) n o ncli nical safet y  st u dies f or t he c o n d uct of 
h u ma n cli nical trials a n d mar keti n g a ut h orizati o n f or p har mace uticals 
(Ja n uar y 2 0 1 0, IC H, re visi o n 1). 
htt ps:// w w w.f da. g o v/ d o w nl oa ds/ g ui da nces/ uc m 0 7 3 2 4 6. p df (access date 1 8 
A pril 2 0 1 7); U. S. De part me nt of Healt h a n d H u ma Ser vices, F o o d a n d 
Dr u g A d mi nistrati o n, Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R), 
Ce nter f or Bi ol o gics E val uati o n a n d Researc h ( C B E R) ( 2 0 1 0)
R 1 8 - 1 2 8 9  
Ofe v ( ni nte da ni b) ca ps ules, f or oral use ( B oe hri n ger I n gel hei m 
P har mace uticals) ( U. S. prescri bi n g i nf or mati o n, re vise d: 1/ 2 0 1 8 ).
R 1 8 - 1 7 0 4  
D o w ma n L, Hill CJ, H olla n d P ul m o nar y  re ha bilitati o n f or i nterstitial l u n g 
disease (re vie w). C oc hra ne Data base S ys t Re v ( 1 0), C D 0 0 6 3 2 2 ( 2 0 1 4).
R 1 8 - 1 7 6 7
Nat ha n S, Al bera C, d u B ois R, Bra df or d W, C osta bel U, Ki n g T, et. Al, 6-
mi n ute wal k test ( 6 M W T) i n patie nts wit h i di o pat hic p ul m o nar y  fi br osis 
(IP F): C o nfir mati o n of t he mi ni mal cli nicall y  i m p orta nt differe nce 
( M CID).' E ur o pea n Res pirat or y  J o ur nal 4 0. S u p pl 5 6 ( 2 0 1 2): P 3 6 5 6.
9. 2
U N P U B L I S H E D R E F E R E N C E S
c 0 2 1 5 5 5 7 4- 0 2
A 5 2 wee ks, d o u ble bli n d, ra n d o mize d, place b o -c o ntr olle d trial e val uati n g 
t he effect of oral Bi B F 1 1 2 0, 1 5 0 m g t wice dail y, o n a n a n n ual F orce d Vital 
Ca pacit y  decli ne, i n patie nts wit h Id o pat hic P ul m o nar y  Fi br osis (IP F) 0 8 
A pr 2 0 1 4.
c 0 2 0 9 8 7 7 5- 0 2
A 5 2 wee ks, d o u ble bli n d, ra n d o mize d, place b o -c o ntr olle d trial e val uati n g 
t he effect of oral Bi B F 1 1 2 0, 1 5 0 m g t wice dail y, o n a n a n n ual F orce d Vital 
Ca pacit y  decli ne, i n patie nts wit h Id o pat hic P ul m o nar y  Fi br osis (IP F) 0 8 
A pr 2 0 1 4.
U 0 7 - 1 2 4 8- 0 7 
 I n vesti gat or's br oc h ure: BI B F 1 1 2 0, I n dicati o n: Idi o pat hic
P ul m o nar y  Fi br osis. 1 1 9 9. P 3. Versi o n 7. 0 9 Dec 2 0 1 1.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0.
A P P E N DI C E S
1 0. 1 
E X E R CI S E T E S TI N G I N C L U DI N G 6 MI N U T E W A L K T E S T A N D 
W O R K C Y C L E E R G O M E T R Y
T o s u p ple me nt t he i nf or mati o n o n t he Si x Mi n ute Wal k Test descri be d i n t his secti o n, 
i nstr ucti o ns a n d a n i nstr ucti o nal vi de o has bee n de vel o pe d. M ore detaile d i nf or mati o n o n t he 
pr oce d ure, o n staffi n g, site a n d e q ui p me nt re q uire me nts, patie nt pre parati o n, I C 
meas ure me nts, a n d calc ulati o ns etc. ca n be f o u n d i n t he i nstr ucti o ns , w hic h is file d i n t he IS F.
1 0. 1. 1
Ge ner al c o nsi der ati o ns f or 6 M W T a n d e xercise testi n g
E xercise perf or m a nce v ari a bility
A n u m ber of p h ys i ol o gical a n d psyc h ol o gical fact ors are k n o w n t o affect e xercise 
perf or ma nce. Lac k of atte nti o n t o c o ntr olli n g t hese e xtra ne o us fact ors ma y  res ult i n a n 
u nacce pta ble de gree of varia bilit y  i n e xercise perf or ma nce. As s uc h, certai n re q uire me nts 
ha ve bee n p ut i n place t o re d uce e xercise perf or ma nce varia bilit y :
P h y si ol o gical:
Pre -e xercise diet: S u bjects are t o be e nc o ura ge d t o eat brea kfast bef ore c o mi n g t o t he cli nic. 
H o we ver, s u bjects s h o ul d n ot eat wit hi n 2 h o urs of e xercise tests.
H y drati o n state: S u bjects are t o be e nc o ura ge d t o mai ntai n a n a de q uate h y drati o n state d uri n g 
t he m or ni n g of t he e xercise tests (i.e., dri n k l ots of water).
E n vir o n me ntal c o n diti o ns (te m perat ure, h u mi dit y ): Te m perat ure a n d h u mi dit y wit hi n t he 
la b orat or y s h o ul d be at c o mf orta ble le vels, a n d s h o ul d be rec or de d eac h tes ti n g da y.
Pre vi o us e xercise:
Fati g ue: S u bjects s h o ul d be e nc o ura ge d t o sta y  well-reste d a n d t o refrai n fr o m a n y stre n u o us, 
fati g ui n g or e x ha usti n g acti vities (e. g., wal ki n g u p hills, wal ki n g u p ma n y fli g hts of stairs, 
r u n ni n g, c ycli n g, s h o velli n g s n o w, s tre n u o us h o use h ol d c h ores) o n t he m or ni n g of e xercise 
tests.
Dela y e d o nset m usc ular s ore ness ( D O M S): Ver y  stre n u o us, hea vy t y pe of acti vities, 
es peciall y acti vities t o w hic h t he s u bject is u nacc ust o me d, ca n lea d t o m uscle s ore ness 2 4 -4 8 
h o urs after t he ac ti vity. S u bjects s h o ul d be e nc o ura ge d t o refrai n fr o m a n y t ype of hea v y 
lifti n g, e x ha usti ve di g gi n g i n t he gar de n etc., f or 2-3 da y s pri or t o eac h cli nic visit, es peciall y 
if t he s u bject has n ot perf or me d t hese acti vities rece ntl y.
Ps y c h ol o gical :
E xter n al m oti vati o nal c ues: m oti vati o nal c ues pr o vi de d t o t he s u bject ca n ha ve pr of o u n d 
effects o n e xercise perf or ma nce. It is i m perati ve t hat e xter nal m oti vati o nal c ues are 
c o ntr olle d acr oss s u bjects a n d acr oss sites.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Ti me of e xercise: N o vis ual c ues re gar di n g t he ti me of e xercise s h o ul d be pr o vi de d t o t he 
s u bject. T he s u bject’s watc h s h o ul d be re m o ve d pri or t o e xercise, a n d all ot her ti me kee pi n g 
de vices (e. g., trial staff watc hes, wall cl oc ks, st o p watc h etc.) s h o ul d be ke pt a wa y  fr o m t he 
s u bject’s vie w.
Fa mili arit y wit h s urr o u n di n gs: Trial staff s h o ul d all o w as m uc h ti me as necessar y f or t he 
s u bject t o bec o me c o mf orta ble wit h t he la b orat or y s urr o u n di n gs.
Distracti o ns: D uri n g t he e xercise tests, access t o t he la b orat or y  s h o ul d be restricte d t o trial 
staff as m uc h as p ossi ble. T he n oise le vel i n t he la b orat or y  s h o ul d be ke pt t o a mi ni m u m, 
e xce pt f or t h ose s o u n ds s pecificall y relate d t o t he c o n d uct of t he test. T his will e ns ure t hat t he 
s u bject is a ble t o c o nce ntrate o n t he tas k at ha n d, a n d will als o e ns ure t hat t he s u bject is 
atte nti ve t o t he ver bal e nc o ura ge me nt pr o vi de d b y t he desi g nate d me m ber of t he trial tea m.
C o mf ort wit h e q ui p me nt: S u bjects s h o ul d be a p pr o priatel y  dresse d f or e xercise (e. g., s h orts 
or trac k pa nts, g y m s h oes, T -s hirt or s weat s hirt), a n d trial staff s h o ul d e ns ure t hat t he s u bject 
is c o mf orta ble wit h t he e q ui p me nt pri or t o starti n g t he e xercise.
Fa miliarit y  wit h test: Bef ore starti n g e xercise, a me m ber of t he trial tea m s h o ul d ma ke s ure 
t hat t he s u bject is c o m pletel y fa miliar wit h t he t ype of e xercise t hat is t o be perf or me d , a 
practice test is e x pecte d pri or t o t he baseli ne test at Visit 2 t o all o w patie nts t o bec o me 
fa miliar wit h t he testi n g pr oce d ures.
Perf or ma nce i nce nti ves: N o e xter nal i nce nti ves f or perf or ma nce (i.e., re war ds f or 
perf or ma nce) s h o ul d be gi ve n t o t he s u bject, pri or t o or at a n y  ti me d uri n g t he e xercise.
Pers o n nel q ualificati o ns :
E xercise c halle n ges s h o ul d be c o n d ucte d b y a de q uatel y trai ne d pers o n nel wit h a basic 
k n o wle d ge of e xercise p h y si ol o g y.
Tec h nicia ns fa miliar w it h n or mal a n d a b n or mal res p o nses d uri n g e xercise a n d trai ne d i n C P R 
s h o ul d be prese nt t hr o u g h o ut t he tests.
Safet y  iss ues:
Car diac ( bra d ya rr hyt h mias, ve ntric ular tac h yc ar dia, m yocar dial i nfarcti o n, heart fail ure, 
h y p ote nsi o n, a n d s h oc k) a n d n o n -car diac ( m usc ul os keletal tra u ma, se vere fati g ue, dizzi ness, 
fai nti n g, b o dy ac hes) c o m plicati o ns of e xercise c halle n ges ha ve bee n re p orte d.
C o nse q ue ntl y d uri n g t he test, st u d y  pers o n nel s h o ul d be alert t o a ny a b n or mal e ve nt.
I n dicati o ns t o st o p t he test m ust be clearl y esta blis he d a n d k n o w n b y t he pers o n nel i n v ol ve d 
i n testi n g.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 5 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
S y m pt o ms s uc h as:
- ac ute c hest pai n,
- s u d de n pall or,
- l oss of c o- or di nati o n,
- me ntal c o nf usi o n,
- e xtre me d ys p n oea.
If t he e xercise test has bee n st o p pe d f or o ne of t hese reas o ns, t he s u bject s h o ul d be m o nit ore d 
i n t he la b orat or y u ntil si g ns / s ym pt o ms / E C G m o dificati o ns ha ve c o m pletel y  cleare d. F ull 
C P R e q ui p me nt s h o ul d be a vaila ble i n t he la b orat or y . F urt her partici p ati o n i n a n y e xercise 
testi n g a n d c o nti n uati o n of t he patie nt i n t he st u d y s h o ul d be disc usse d wit h t he cli nical 
m o nit or.
1 0. 1. 2
Si x -mi n ute w al k test  
A f ull descri pti o n of t he si x mi n ute wal k test will be pr o vi de d i n b ot h t he i nstr ucti o ns a n d 
i nstr ucti o nal vi de o.
Testi n g s h o ul d be perf or me d i n a l ocati o n w here a ra pi d, a p pr o priate res p o nse i n t he e ve nt of 
a n e mer ge nc y is p ossi ble a n d e mer ge nc y i nstr ucti o ns i n t he ma n ual s h o ul d be f oll o we d. 
D uri n g t he 6 -M W T patie nts
will be m o nit ore d f or b ot h H R a n d S p O 2 usi n g p uls e o xi meter.
If S p O2 decreases t o bel o w 8 0 % at a n y ti me after t he patie nts be gi ns wal ki n g , first e ns ure t he 
o xi meter is c o n necte d a n d w or ki n g pr o perl y a n d e ns ure t hat a c o nfi de nt p ulse si g nal is 
ge nerate d.  If S p O 2 is still bel o w 8 0 %, st o p t he st u d y  a n d all o w t he s u bject t o sit a n d rest, t he 
st u d y is c o m plete.
T he dist a nce wal ke d will be meas ure d i n feet (f) a n d will be rec or de d. If t he test is st o p pe d
pre mat urel y, t he dista nce ( f), t he d urati o n ( mi n), a n d t he reas o n f or st o p pi n g will be rec or de d.
Patie nts will be as ke d t o rate t he i nte nsit y of d y s p nea (s h ort ness of breat h) a n d fati g ue usi n g 
t he M o difie d B or g Scale (see Secti o n 1 0. 2 ) as descri be d i n t he i nstr ucti o ns.
Assess me nts will be rec or de d i n a w or ks heet d uri n g t he testi n g, a n d tra nsferre d t o t he e D C 
s yste m. 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9 - 0 3 2 4
c 1 9 5 5 8 8 0 8- 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 2
M O DI FI E D B O R G S C A L E ( M B S-S)
R 1 4 - 0 9 7 5
P A TI E N T I N S T R U C TI O N S
T he B or g Scale is use d t o hel p us u n dersta n d t he i nte nsit y or se verit y of y o ur breat hless ness a n d 
t he i nte nsit y or se verit y of y o ur fati g ue. We will as k y o u t o use t his scale t o rate t he i nte nsit y of 
y o ur breat hless ness a n d y o ur fati g ue bef ore, d uri n g, a n d after y o ur e xercise test.
Please re vie w t he scale t o see t he vari o us le vels fr o m w hic h y o u ca n c h o ose. 
F or breat hless ness ( d ys p nea):
T he t o p of t he scale, “ 0 or n ot hi n g at all,” mea ns n o bre at hless ness at all . 
T he b ott o m of t he scale, “ 1 0 or ma xi mal,” mea ns t he m ost severe bre at hless ness t h at y o u h ave 
ever ex perie nce d or c o ul d i m a gi ne ex perie nci n g .  
F or fati g ue:
T he t o p of t he scale, “ 0 or n ot hi n g at all,” mea ns n o f ati g ue at all .
T he b ott o m of t he scale, “ 1 0 or ma xi mal,” mea ns t he m ost severe f ati g ue t h at y o u h ave ever 
ex perie nce d or c o ul d i m a gi ne ex perie nci n g.  
W he n we as k y o u t o rate t he i nte nsit y of y o ur breat hless ness a n d y o ur fati g ue, please place t he ti p 
of y o ur fi n ger o n t he n u m ber t hat best descri bes t he i nte nsit y t hat y o u are e x perie nci n g at t hat 
m o me nt. Y o u ma y als o place a fi n ger bet wee n 2 n u m bers if t hat better descri bes t he i nte nsit y of 
y o ur breat hless ness or y o ur fati g ue.
Please let us k n o w if y o u ha ve a n y q uesti o ns bef ore we be gi n.
0
N ot hi n g at all
0. 5
Very, very sli g ht (j ust n otice a ble)
1
Very sli g ht
2
Sli g ht 
3
M o der ate
4
S o m e w h at severe
5
Severe 
6
7
Very severe 
8
9
Very, very severe ( al m ost m a xi m al)
1 0
M a xi m al

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
St u dy S pecific I nstr ucti o ns f or t he B or g Sc ale
Pri or t o t he start of e xercise test, eac h s u bject will be t ol d t hat t he y  will be as ke d t o rate t he 
i nte nsit y of 2 se nsati o ns at rest, d uri n g e xercise, a n d at e n d-e xercise. T he 2 se nsati o ns will be 
descri be d t o t he s u bject as: 
- S h ort ness of breat h ( dys p ne a or breat hless ness )
- Fati g ue
Use of t he B or g Scale t o rate t hese se nsati o ns will be e x plai ne d t o t he s u bject. W hile s h o wi n g 
t he scale t o t he s u bject, t he st u d y c o or di nat or or bli n de d tester will e x plai n t hat t he s u bject 
s h o ul d relate t he w or di n g o n t he Bor g Scale t o t he le vel of t he se nsati o n t hat he / s he is 
e x perie nci n g, a n d t he n place t he e n d of a fi n ger o n a n u m ber t hat best descri bes t he i nte nsit y  
of t he se nsati o n - e x plai n t hat placi n g a fi n ger bet wee n 2 n u m bers is all o we d. ( B or g Scale 
n u m bers will be rec or de d t o t he nearest 0. 5 u nits). 
T he st u d y  c o or di nat or or bli n de d tester will a nc h or t he e n d p oi nts of t he scale f or b ot h 
se nsati o ns. T he st u d y c o or di nat or or bli n de d tester will e x plai n t hat f or t he se nsati o n of 
“s h ort ness of breat h”, “ 0 or n ot hi n g at all” c orres p o n ds t o “ n o s h ort ness of breat h” a n d “ 1 0 or 
ma xi mal” c orres p o n ds t o t he “ w orst i ma gi na ble s h ort ness of breat h”. T he st u d y c o or di nat or 
or bli n de d tester will t he n e x plai n t hat f or t he se nsati o n of “ fati g ue”, “ 0 or n ot hi n g at all” 
a gai n c orres p o n ds t o “ n o fati g ue” a n d “ 1 0 or ma xi mal” c orres p o n ds t o t he “ w orst i ma gi na ble 
fati g ue”.
S u bjects are t o be gi ve n n o f urt her i nf or mati o n a b o ut t hese se nsati o ns. If a s u bject re q uests 
f urt her clarificati o n, he/s he will be t ol d t o use his/ her o w n i n di vi d ual i nter pretati o n as t o t he 
mea ni n g of t he se ns or y descri pt ors. T his will e ns ure t hat t he se ns or y  descri pt ors are prese nte d 
t o eac h s u bject i n a sta n dar d f or mat.
1 0. 3 
S T. G E O R G E’ S R E S PI R A T O R Y Q U E S TI O N N AI R E ( S G R Q)
W hat is t he St Ge or ge’s Res pirat or y Q uesti o n naire?
T he S G R Q is desi g ne d t o meas ure healt h i m pair me nt i n patie nts wit h ast h ma a n d C O P D. I t is 
als o vali d f or use i n br o nc hiectasis a n d has bee n use d s uccessf ull y  i n patie nts wit h 
k y p h osc oli osis a n d sarc oi d osis. I t is n ot s uita ble f or c ystic fibr osis. It is i n t w o parts. Part I 
pr o d uces t he S y m pt o ms sc ore, a n d Part 2 t he Acti vit y  a n d I m pacts sc ores. A T otal sc ore is 
als o pr o d uce d.
Part 1 ( Q uesti o ns 1 t o 8) c o vers t he patie nts’ rec ollecti o n of t heir s y m pt o ms o ver a prece di n g 
peri o d t hat ma y  ra n ge 1 m o nt h t o 1 y ear. It is n ot desi g ne d t o be a n acc urate e pi de mi ol o gical 
t o ol; its p ur p ose is t o assess t he patie nt’s perce pti o n of t heir rece nt res pirat or y pr o ble ms. T he 
ori gi nal versi o n was vali date d usi n g a 1 2 -m o nt h recall peri o d. M ore rece ntl y  a 1 m o nth recall 
versi o n (a p pr o priatel y w or de d) has bee n vali date d. T his has sli g htl y wea ker ps yc h o metric 
pr o perties t ha n t he 1 2 - m o nt h versi o n a n d pr o d uces a mar gi nally l o wer S y m pt o m sc ore a n d 
T otal sc ore. A 3 -m o nt h recall peri o d has bee n use d ver y  satisfact oril y. I n s u m mar y, t he 3-
m o nt h a n d 1- ye ar versi o ns pr o vi de t he best pr o perties, wit h n o s pecific a d va nta ges t o eit her. 
T he 1 -m o nt h versi o n s h o ul d o nl y  be use d w he n t he ti me fra me of t he st u d y dictates.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 6 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Part 2 ( Q uesti o ns 9 t o 1 6) a d dresses t he patie nts’ c urre nt s tate (i.e. h o w t he y are t hese da ys). 
T he Acti vit y  sc ore j ust meas ures dist ur ba nces t o patie nt’s dail y p h ysical acti vit y. T he 
I m pacts sc ore c o vers a wi de ra n ge of dist ur ba nces of ps yc h o -s ocial f u ncti o n. Vali dati o n 
st u dies s h o we d t hat t his c o m p o ne nt relates i n part t o res pirat or y sy m pt o ms, b ut it als o 
c orrelates q uite str o n gl y wit h e xercise perf or ma nce ( 6- mi n ute wal ki n g test), breat hless ness i n 
dail y  life ( M R C breat hless ness sc ore) a n d dist ur ba nces of m o o d (a n xiet y a n d de pressi o n). 
T he I m pacts sc ore is, t here f ore, t he br oa dest c o m p o ne nt of t he q uesti o n naires, c o veri n g t he 
w h ole ra n ge of dist ur ba nces t hat res pirat or y  patie nts e x perie nce i n t heir li ves.
H o w s h o ul d it be a d mi nistere d?
T he q uesti o n naire s h o ul d be c o m plete d i n a q uiet area free fr o m distracti o n a n d t he patie nt 
s h o ul d i deall y be sitti n g at a des k or ta ble. E x plai n t o t he patie nt w h y t he y are c o m pleti n g t he 
q uesti o n naire, a n d h o w i m p orta nt it is f or us t o u n dersta n d h o w t he y  feel a b o ut t heir ill ness 
a n d t he effect it has o n t heir dail y life. As k t he patie nt t o c o m plete t he q uesti o n naire as 
h o nestl y  as p ossi ble a n d stress t hat t here are n o ri g ht or wr o n g a ns wers; si m pl y t he a ns wer 
t hat t he patie nt feels a p plies t o t he m. E x plai n t hat t he y m ust a ns wer e ver y q uesti o n a n d t hat 
s o me o ne will be cl ose at ha n d t o a ns wer a ny q ueries.
T he S G R Q is desi g ne d as a s u per vise d self -a d mi nistere d q uesti o n naire. T his mea ns t hat t he 
patie nts s h o ul d c o m plete t he q uesti o n naire t he msel ves b ut s o me o ne s h o ul d be a vaila ble t o 
gi ve a d vice if it is re q uire d. T he patie nt’s res p o nses s h o ul d n ot be i nfl ue nce d b y t he o pi ni o ns 
of fa mil y , frie n ds or me m bers of staff. T he q uesti o n naire is desi g ne d t o elicit t he patie nt’s 
o pi ni o n of his/ her healt h, n ot s o me o ne else’s o pi ni o n of it. If t he s p o use or part ner has 
acc o m pa nie d t he patie nt t he y sh o ul d be as ke d t o wait i n a se parate area. Si milarl y , d o n ot 
all o w patie nts t o ta ke t he S G R Q h o me t o be c o m plete d si nce y o u ca n n ot be s ure t hat it will 
be c o m plete d wit h o ut t he hel p of fa mil y or frie n ds.
It is ver y i m p orta nt, o nce t he patie nt has fi nis he d, t hat yo u c hec k t he q uesti o n naire t o ma ke 
s ure a res p o nse has bee n gi ve n t o e ver y q uesti o n a n d ret ur n it t he patie nt f or c o m pleti o n of 
misse d ite ms, bef ore t he patie nt lea ves.
W hat s h o ul d I  d o a b o ut q ueries re gar di n g c o m pleti o n of t he q uesti o n naire?
If a patie nt as ks f or hel p wit h a q uesti o n, d o n ot pr o vi de a n a ns wer f or t he m. T he p oi nt of t he 
q uesti o n naire is t o get a n u n dersta n di n g of h o w t he patie nt vie ws his or her ill ness. I t is 
a p pr o priate t o clarif y a q uesti o n b ut n ot t o pr o vi de a n a ns wer. Q uesti o ns ma y  be rea d al o u d if 
patie nts ha ve diffic ult y wit h rea di n g, b ut t he res p o nses m ust be t heirs al o ne. If a patie nt gi ves 
a n a ns wer y o u disa gree wit h it is n ot a p pr o priate t o c halle n ge t heir res p o nse or t o q uer y it. It 
is t heir vie w of t heir c o n diti o n we are i ntereste d i n – n o matter h o w stra n ge t he res p o nse!
T he f oll o wi n g are n otes w hic h ma y  hel p y o u e x plai n t o patie nts w hat is re q uire d
1.
I n Part 1 of t he q uesti o n naire, e m p hasise t o patie nts t hat y o u are i ntereste d i n h o w m uc h 
c hes t tr o u ble t he y ha ve ha d o ver t he last year. T he e xact peri o d is n ot i m p orta nt. We are 
l o o ki n g f or a n i m pressi o n or perce pti o n of healt h.
2.
Ast h ma a n d C O P D ca n var y  da y-t o da y. I n Part 2 , we wa nt t o k n o w a b o ut t he patie nt’s 
c urre nt state (t hese da ys). 
3.
A se vere or ver y  u n pleasa nt attac k of c hest tr o u ble ( Part 1, Q uesti o n 5 ) is a n y attac k 
t hat c o ul d be descri be d t hat wa y i n t he patie nt’s o w n j u d ge me nt. N ot ‘se vere’ as defi ne d 
b y  me dical staff.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
4.
F or Q uesti o n 7 e m p hasise t hat y o u are i ntereste d i n t he n u m ber of g o o d da y s t hat t he y 
ha ve ha d.
5.
Q uesti o n 1 0 re gar di n g e m pl o y me nt ca n ca use patie nts s o me pr o ble ms. We are 
i ntereste d i n h o w a patie nt’s c hest tr o u ble affects t heir c urre nt w or ki n g life or h o w it 
affecte d life w he n t he y were w or ki n g. F or e xa m ple, if a patie nt t o o k early retire me nt 
beca use of t heir c hest c o n diti o n, t he res p o nse w o ul d be 1 0a – ‘ My c hest tr o u ble ma de 
me st o p w or k’, if a patie nt’s retire me n t was u nrelate d t o t heir c hest tr o u ble, t heir 
res p o nse w o ul d be 1 0c ‘ M y c hest tr o u ble d oes n ot affect m y w or k’.
6.
Q uesti o ns 1 1 t o 1 6 re q uire a res p o nse t o e ver y  q uesti o n. It ma y be w ort h e m p hasisi n g 
t his t o t he patie nt.
7.
Ma n y  patie nts d o n ot e n ga ge i n ph y sical acti vit y. It is i m p orta nt t o deter mi ne w het her 
t his is beca use t he y d o n ot wis h t o (i n w hic h case t he a ns wer w o ul d be ‘ False’) or 
ca n n ot e n ga ge i n t hese acti vities beca use of t heir c hest tr o u ble (i n w hic h case t he 
a ns wer w o ul d be ‘ Tr ue’).
8.
Me dica ti o n q uesti o ns refer t o me dicati o ns a n d treat me nts gi ve n f or a patie nt´s c hest 
disease a n d ma y  i nterfere wit h t heir life if, f or e xa m ple, t he y are o n o xy ge n s u p p ort a n d 
ha ve t o carr y  it ar o u n d wit h t he m.
9.
It s h o ul d be e m p hasise d t hat res p o nses t o Q uesti on 1 5 are i n ter ms of breat hi n g 
diffic ulties a n d n ot a n y ot her pr o ble ms. If patie nts d o n ot e n ga ge i n acti vities descri be d 
i n certai n ite ms, t he y s h o ul d tic k ‘ False’. Patie nts w h o d o n ot e n ga ge i n t hese acti vities 
beca use t he y  are li mite d b y t heir breat hless ness, s h o ul d tic k ‘ Tr ue’.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
E X A M P L E O F Q U E S TI O N N AI R E

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 4 
E L E C T R O NI C DI A R Y WI T H D AI L Y P R O A C TI V E T O O L
1 0. 4. 1
T he P R O acti ve T o ol
T he P R Oacti ve i nstr u me nt f or t he dail y assess me nt of p h ysical acti vit y ( D -P P A C) will be 
use d i n t he st u d y . T he D-P P A C e xists i n a n electr o nic versi o n.
T he D -P P A C is a ‘ h y bri d’ i nstr u me nt, c o m bi ni n g a s h ort list of P R O ite ms a n d t w o acti vit y  
m o nit or varia bles t o assess p h ysical acti vit y e x perie nce, a n d pr o vi des a si m ple, vali d a n d 
relia ble meas ure of p hys ical acti vit y e x perie nce b y C O P D patie nts [R 1 6 - 5 3 5 3] w hic h ca n 
als o be use d f or ot her res pirat or y diseases.
T he D -P P A C i ncl u des i n t otal 9 ite ms, meas uri n g a p h y sical acti vity ‘ T otal Sc ore’ wit h 2 
d o mai ns (‘a m o u nt’ a n d ‘ diffic ult y ’) (Fi g ure 1 0. 4. 1: 1 ). T he ‘a m o u nt’ d o mai n is c o vere d by 2 
ite ms (a m o u nt of wal ki n g o utsi de a n d c h ores o utsi de) a n d by 2 acti vit y  m o nit or o ut p uts 
( vect or ma g nit u de u nits per mi n ute ( V M U/ mi n) a n d ste ps/ da y). T he ‘ diffic ult y’ d o main is 
c o vere d b y 5 ite ms. 
T he i nstr u me nts re q uire b ot h acti vit y  m o nit or data a n d ite m data o n a dail y basis. A de q uate 
p h y sical acti vit y data are c o nsi dere d f or da ys w here m ore t ha n ei g ht h o urs of weari n g ti me 
( d uri n g t he da y, fr o m getti n g u p i n t he m or ni n g, u ntil g oi n g t o be d i n t he e ve ni n g) is 
a vaila ble. It is p ossi ble t hat da ys wit h acti vit y m o nit ori n g are missi n g or patie nts f or get t o fill 
i n t he dail y P R O i n t he e ve ni n g. 
I n or der t o o btai n t he D- P P A C sc ores (t otal, a m o u nt a n d diffic ult y ), daily meas ure me nts fr o m 
b ot h acti vit y m o nit or a n d q uesti o n naire are mer ge d, a n d dail y  sc ores are calc ulate d. 
T he D -P P A C i nstr u me nt is sc ore d i n a t hree ste ps pr ocess:
•
First, d o mai ns are sc ore d b y  si m ple a d di n g ite ms, w hic h gi ves a val ue f or ‘a m o u nt’ 
bet wee n 0 a n d 1 7, wit h hi g her val ues re prese nti n g a hi g h a m o u nt of acti vit y, a n d a 
‘ diffic ult y’ sc ore fr o m 0 t o 2 0 wit h a hi g h val ue re prese nti n g a lesser de gree of 
diffic ult y . F or t he D- P P A C assess me nt t he val ues are 0-1 7 f or ‘a m o u nt’ a n d 0 -2 0 f or 
‘ diffic ult y’. (Fi g ure 1 0. 4. 1: 1 ) T he ste p c o u nts a n d V M U’s nee d t o be c o n verte d i nt o 
t he a p pr o priate daily sc ore cate g or y.
•
I n t he sec o n d ste p, t he ra w sc ores are scale d t o a sc ore ra n gi n g fr om 0 t o 1 0 0, base d 
o n res ults of Rasc h a nal yses
•
Fi nall y  t he ‘t otal sc ore’ is o btai ne d calc ulati n g t he a vera ge bet wee n t w o d o mai ns. 
T his sc ore has t he sa me scale of t w o d o mai ns, fr o m 0 t o 1 0 0.
After calc ulati n g t he dail y  sc ores, wee kly a vera ges ca n be calc ul ate d.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Fi g ure 1 0. 4. 1: 1
D- P P A C ite ms 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 7 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 4. 2
Electr o nic Di ar y – P R O acti ve Q uesti o n n aire
I N S T R U C TI O N S T O P A TI E N T S D A Y 1:
Patie nts wit h c hr o nic l u n g disease li ke y o u ofte n re p ort t hat t he y  ha ve pr o ble ms d uri n g 
p h y sical acti vit y. B y p h ysical acti vit y, we mea n all acti vities t hat re q uire m o ve me nt of yo ur 
b o d y . E xa m ples are h o use h ol d acti vities, wal ki n g, g oi n g t o w or k, or getti n g dresse d. 
H o we ver, please c o nsi der all acti vities y o u d o, a n d n ot o nl y  t hese e xa m ples. We w o ul d li ke 
t o k n o w h o w yo u e x perie nce d y o ur p h ys ical acti vit y si nce y o u w o ke u p T O D A Y .
Please c o m plete t his q uesti o n naire i n t he e ve ni n g bef ore g oi n g t o be d. Please select t he b o x 
ne xt t o t he res p o nse t hat best a p plies t o y o u T O D A Y.
T here are n o wr o n g a ns wers. We ver y m uc h val ue y o ur res p o nse.
I N S T R U C TI O N S F O R S U B S E Q U E N T D A Y S:
We w o ul d li ke t o k n o w h o w y o u e x perie nce d y o ur p h y sical acti vit y si nce y o u w o ke u p 
T O D A Y. Please c o m plete t his q uesti o n naire i n t he e ve ni n g bef ore g oi n g t o be d. Please select 
t he b o x ne xt t o t he res p o nse that best a p plies t o y o u T O D A Y.
Diffi c ult y s c or e
A m o u nt 
s c or e
H o w m u c h w al ki n g di d y o u d o o ut si d e t o d a y ?
N o n e at all
0
A littl e bit ( u p t o 1 0 mi n ut e s i n t ot al )
1
S o m e ( u p t o 3 0 mi n ut e s i n t ot al )
2
A l ot ( u p t o 1 h o ur i n t ot al )
3
A gr e at d e al ( m or e t h a n 1 h o ur i n t ot al )
4
H o w m a n y c h or e s di d y o u d o o ut si d e t h e h o u s e t o d a y ? S o m e e x a m pl e s 
ar e g ar d e ni n g, t a ki n g t h e r u b bi s h o ut, or d oi n g s m all err a n d s. 
N o n e at all
0
A f e w
1
S o m e
2
A l ot
3
A l ar g e a m o u nt
4
H o w m u c h diffi c ult y di d y o u h a v e g etti n g dr e s s e d t o d a y ?
N o n e at all
4
A littl e bit
3
S o m e
2
A l ot
1
A gr e at d e al
0
H o w oft e n di d y o u a v oi d d oi n g a cti viti e s b e c a u s e of y o ur l u n g pr o bl e m s 
t o d a y ?
N ot at all
4
R ar el y
3
S o m eti m e s
2
Fr e q u e ntl y
1
All t h e ti m e
0
H o w br e at hl e s s w er e y o u i n g e n er al d uri n g y o ur a cti viti e s t o d a y ?
N ot at all
4
A littl e bit
3
M o d er at el y
2
V er y
1
E xtr e m el y
0
H o w tir e d w er e y o u i n g e n er al d uri n g y o ur a cti viti e s t o d a y ?
N ot at all
4

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
A littl e bit
3
M o d er at el y
2
V er y
1
E xtr e m el y
0
H o w oft e n di d y o u h a v e t o t a k e br e a k s d uri n g y o ur p h y si c al a cti viti e s 
t o d a y ?
N ot at all
4
R ar el y
3
S o m eti m e s
2
Fr e q u e ntl y
1
All t h e ti m e
0
P R O a cti v e d ail y st e p s s c or e 
T ot al st e p s p er d a y
D y n a p ort
≤1 9 0 0
1 9 0 1 -3 7 0 0
3 7 0 1 -5 5 0 0
5 5 0 1 -7 3 0 0
> 7 3 0 0
0
0
1
1
2
2
3
3
4
4
P R O a cti v e d ail y V M U s c or e 
D ail y m e a n V M U / mi n
D y n a p ort
≤5 0
5 1 -1 1 0
1 1 1 -1 9 0
1 9 1 -2 7 0
2 7 1 -4 4 0
> 4 4 0
0
0
1
1
2
2
3
3
4
4
5
5
T ot al s c or e s ( s u m a b o v e ) :
diffi c ult y
a m o u nt
Fi g ure 1 0. 4. 2 : 1
Dail y  P R Oacti ve ( D-P P A C ) e-P R O
I T E M S F O R D AI L Y A S S E S S M E N T – Acti vit y m o nit ori n g
Ste ps (t otal dail y  val ue)
0 t o 1 9 0 0 ste ps/ da y
1 9 0 1 t o 3 7 0 0 ste ps/ da y
3 7 0 1 t o 5 5 0 0 ste ps/ da y
5 5 0 1 t o 7 3 0 0 ste ps/ da y
> 7 3 0 1 ste ps/ da y
V M U ( dail y V M U/ mi n)
0 t o 5 0 V M U/ mi n
5 1 t o 1 1 0 V M U/ mi n
1 1 1 t o 1 9 0 V M U/ mi n
1 9 1 t o 2 7 0 V M U/ mi n
2 7 1 t o 4 4 0 V M U/ mi n
> 4 4 1 V M U/ mi n

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 5
K BI L D

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 6
U C S D M E DI C A L C E N T E R P U L M O N A R Y R E H A BI LI T A TI O N 
P R O G R A M S H O R T N E S S -O F -B R E A T H Q U E S TI O N N AI R E (U C S D -
S O B Q)
U C S D M E DI C A L C E N T E R
P U L M O N A R Y R E H A BI LI T A TI O N P R O G R A M
S H O R T N E S S - O F-B R E A T H Q U E S TI O N N AI R E
© 1 9 9 5 T he Re ge nts of t he U ni versit y of Calif or nia
Please rate t he breat hless ness y o u e x perie nce w he n y o u d o, or if y o u were t o d o, eac h of t he 
f oll o wi n g tas ks. D o n ot s ki p a n y ite ms. If y o u’ ve ne ver perf or me d a tas k or n o l o n ger 
perf or m it, gi ve y o ur best esti mate of t he breat hless ness y o u w o ul d e x perie nce w hile d oi n g 
t hat acti vit y. Please re vie w t he t w o sa m ple q uesti o ns bel o w bef ore t ur ni n g t he pa ge t o be gi n 
t he q uesti o n naire.
W he n I d o, or if I were t o d o, t he f oll o wi n g t as ks, I w o ul d r ate m y 
bre at hless ness as:
0
N o ne at all
1
2
3
4
Se vere
5  
Ma xi m al or u na ble t o d o beca use of 
breat hless ness
1.
Br us hi n g teet h ..................................................0 
1 
2
4 
5
Harr y  has felt m o deratel y s h ort of breat h d uri n g t he past wee k w hile br us hi n g his teet h a n d s o 
circles a t hree f or t his acti vit y.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
2.
M o wi n g t he la w n .............................................0 
1 
2 
3 
4
A n ne has ne ver m o we d t he la w n bef ore b ut esti mates t hat s he w o ul d ha ve bee n t o o breat hless 
t o d o t his acti vit y d uri n g t he past wee k. S he circles a fi ve f or t his acti vit y .

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
W he n I d o, or if I were t o d o, t he f oll o wi n g t as ks, I w o ul d r ate m y 
bre at hless ness as:
0
N o ne at all
1
2
3
4
Se vere
5  
Ma xi m al or u na ble t o d o beca use of 
breat hless ness
1.
At rest ..............................................................0 
1 
2 
3 
4 
5
2.
Wal ki n g o n a le vel at yo ur 
o w n pace ..........................................................0 
1 
2 
3 
4 
5
3.
Wal ki n g o n a le vel wit h ot hers 
y o ur a ge ...........................................................0 
1 
2 
3 
4 
5
4.
Wal ki n g u p a hill
.............................................0 
1 
2 
3 
4 
5
5.
Wal ki n g u p stairs .............................................0 
1 
2 
3 
4 
5
6.
W hile eati n g .....................................................0 
1 
2 
3 
4 
5
7.
Sta n di n g u p fr o m a c hair .................................0 
1 
2 
3 
4 
5
8.
Br us hi n g teet h ..................................................0 
1 
2 
3 
4 
5
9.
S ha vi n g a n d/ or br us hi n g hair ...........................0 
1 
2 
3 
4 
5
1 0.
S h o weri n g/ bat hi n g........................................... 0 
1 
2 
3 
4 
5

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
W he n I d o, or if I were t o d o, t he f oll o wi n g t as ks, I w o ul d r ate m y 
bre at hless ness as:
0
N o ne at all
1
2
3
4
Se vere
5  
Ma xi m al or u na ble t o d o beca use of 
breat hless ness
1 1.
Dressi n g ...........................................................0 
1 
2 
3 
4 
5
1 2.
Pic ki n g u p a n d strai g hte ni n g........................... 0 
1 
2 
3 
4 
5
1 3.
D oi n g dis hes ....................................................0 
1 
2 
3 
4 
5
1 4.
S wee pi n g / vac u u mi n g .....................................0 
1 
2 
3 
4 
5
1 5.
Ma ki n g be d ......................................................0 
1 
2 
3 
4 
5
1 6.
S h o p pi n g ..........................................................0 
1 
2 
3 
4 
5
1 7.
D oi n g la u n dr y ..................................................0 
1 
2 
3 
4 
5
1 8.
Was hi n g car .....................................................0 
1 
2 
3 
4 
5
1 9.
M o wi n g la w n ...................................................0 
1 
2 
3 
4 
5
2 0.
Wateri n g la w n ..................................................0 
1 
2 
3 
4 
5
2 1.
Se x ual acti vities ...............................................0 
1 
2 
3 
4 
5

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
0
N o ne at all
1
2
3
4
Se vere
5  
Ma xi m al or u na ble t o d o beca use of 
breat hless ness
H o w m uc h d o t hese li mit y o u i n y o ur d ail y life ?
2 2.
S h ort ness of breat h ..........................................0 
1 
2 
3 
4 
5
2 3.
Fear of " h urti n g m ys elf" b y 
o vere xerti n g .....................................................0 
1 
2 
3 
4 
5
2 4.
Fear of s h ort ness of breat h ...............................0 
1 
2 
3 
4 
5

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 8 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 0. 7
L U N G F U N C TI O N C RI T E R I A
F V C m ust f ulfil t he f oll o wi n g criteria:
o
4 5 % pre dicte d of n or mal ≤ F V C of pre dicte d n or mal
o
Pre dicte d n or mal val ues will be calc ulate d acc or di n g t o N H A N E S
D Lc o m ust f ulfil t he f oll o wi n g criteria:
o
3 0 % pre dicte d of n or mal ≤ D L C O c orrecte d f or H b < 8 0 % pre dicte d of n or mal
F or pre dicte d n or mal val ues, differe nt sites ma y  use differe nt pre dicti o n f or m ulas, base d o n 
t he met h od use d t o meas ure D Lc o. I n a ny case, t he met h o d use d m ust be i n c o m plia nce wit h 
t he A T S/ E R S g ui deli ne o n D Lc o meas ure me nts (R 0 6 - 2 0 0 2), a n d t he pre dicti o n f or m ula 
a p pr o priate f or t hat met h o d. Ra w data ( gas mi xt ure, e q uati o n us e d f or pre dicti o n of n or mal, 
f urt her a dj ust me nts ma de if s o) m ust be trace d.
D L C O c orrecte d f or hae m o gl o bi n ( R 0 6 - 2 0 0 2):
Males:
D Lc o c orrecte d f or H b = D L C O meas ure d x ( 1 0. 2 2 + H b) / 1. 7 H b
Fe males: D Lc o c orrecte d f or H b = D L C O meas ure d x ( 9. 3 8 + H b)/ 1. 7 H b
w here H b is e x presse d i n g· d L- 1.
F or decisi o n o n i ncl usi o n / e xcl usi o n, D Lc o res ults fr o m visit 1 will be c orrecte d f or 
hae m o gl o bi n b y  t he site, if hist orical data wit hi n 3 0 da ys is n ot a vaila ble.
F or a nal y sis of t he trial data, D Lc o res ults fr o m visits 2, 5 a n d 7 will be c orrecte d f or 
hae m o gl o bi n b y  ce ntral data ma na ge me nt. T his mea ns t hat t he site has t o e nter t he D Lc o 
res ult wit h o ut hae m o gl o bi n c orrecti o n i n t he e- C R F, at all visits .
T he val ue t o be e ntere d i n t he e - C R F is t he mea n of t he acce pta ble ma n oe u vers perf or me d 
d uri n g a test. T here s h o ul d be at least t w o acce pta ble tests t hat meet t he re peata bilit y  
re q uire me nt of eit her bei n g wit hi n 3 m L  C O ( S T P D)• mi n-1 • m m H g- 1 ( or 1 m m ol• mi n- 1• k Pa- 1) 
of eac h ot her or wit hi n 1 0 % of t he hi g hest val ue. 
If hi g hest val ue was e ntere d at baseli ne a n d ca n n ot be c orrecte d retr os pecti vel y, t he sa me 
meas ure me nt s h o ul d be rec or de d u ntil t he 2 4 wee k e val uati o n .

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 1.
D E S C RI P TI O N O F G L O B A L A M E N D M E N T( S)
1 1. 1
G L O B A L A M E N D M E N T 1
D ate of a m e n d me nt
3 0 A pr 2 0 1 9
E u dr a C T n u m ber
E U n u m ber
N ot a p plic a ble
BI Tri al n u m ber
1 1 9 9- 0 3 2 4
BI I n vesti g ati o n al Pr o d uct(s)
ni nte d a ni b
Title of pr ot oc ol
St u d y of P ul m o n ar y Re h a bilit ati o n I n 
Ni nte d a ni b Tre ate d P atie nts wit h I P F: 
I m pr o ve me nts i n Acti vit y, E xercise E n d ur a nce 
Ti me, a n d  Q o L
T o be i m ple me nte d o nl y after a p pr o v al of t he I R B / I E C / C o m pete nt A ut h orities                                     
X
T o be i m ple me nte d i m me di atel y i n or der t o eli mi n ate h az ar d –
I R B / I E C / C o m pete nt A ut h orit y t o be n otifie d of c h a n ge wit h re q uest f or 
a p pr o v al
C a n be i m ple me nte d wit h o ut I R B / I E C / C o m pete nt A ut h orit y a p pr o v al as 
c h a n ges i n v ol ve l o gistic al or a d mi nistr ati ve as pects o nl y
Secti o n t o be c h a n ge d
Title P a ge
Descri pti o n of c h a n ge
U p d ate d t he f oll o wi n g:

Tri al Cli nic al M o nit or t o Cli nic al Tri al 
Le a der

Cli nic al Tri al Le a der t o 

C o or di n ati n g i n vesti g at or t o  
 

St at us

Versi o n a n d D ate of Pr ot oc ol
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ges
Secti o n t o be c h a n ge d
Cli nic al Tri al Pr ot oc ol S y n o psis
Descri pti o n of c h a n ge
U p d ate d t he f oll o wi n g:

Re visi o n D ate

C o or di n ati n g i n vesti g at or t o  
 

C h a n ge d i ncl usi o n criteri a fr o m 1 8 
m o nt hs t o 3 0
m o nt hs
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ges.  U p d ate d fr o m 1 8 
m o nt hs t o 3 0 m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.
Secti o n t o be c h a n ge d
Fl o wc h art
Descri pti o n of c h a n ge
 
 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
  
 
 
 
 
 
 
 
 
 
 
R ati o n ale f or c h a n ge
T o pr o vi de m ore cl arific ati o n as t o w he n 
i ncre me nt al c ycle er g o metr y will be c o n d ucte d
a n d t h at t he i ncre me nt al a n d pr actice test c a n 
b ot h be d o ne at Visit 1 .
Secti o n t o be c h a n ge d
A b bre vi ati o ns Secti o n
Descri pti o n of c h a n ge

C orrecte d s pelli n g of w or ds “electr o nic, 
ass oci ati o n a n d i di o p at hic ”.

M o ve d “ C O P D ” t o f oll o w al p h a betic all y.

U p d ate d “ C M L Cli nic al M o nit or L oc al 
a n d T C M Tri al Cli nic al M o nit or t o C T M 
Cli nic al Tri al M a n a ger a n d C T L Cli nic al 
Tri al Le a der.
R ati o n ale f or c h a n ge
T y p o; a d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
3. 1
Descri pti o n of c h a n ge
C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.   U p d ate d fr o m 1 8 
m o nt hs t o 3 0 m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.
Secti o n t o be c h a n ge d
3. 2
Descri pti o n of c h a n ge

C orrecte d s pelli n g of w or d “ p ositi ve ”.

C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs
R ati o n ale f or c h a n ge
T y p o; a d mi nistr ati ve c h a n ge. U p d ate d fr o m 1 8 
m o nt hs t o 3 0
m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.
Secti o n t o be c h a n ge d
2. 1. 1
Descri pti o n of c h a n ge
C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge. U p d ate d fr o m 1 8 
m o nt hs t o 3 0 m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Secti o n t o be c h a n ge d
3. 3. 1
Descri pti o n of c h a n ge

C orrecte d s pelli n g of w or d “ ni nte d a ni b ”

C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs
R ati o n ale f or c h a n ge
T y p o; a d mi nistr ati ve c h a n ge. U p d ate d fr o m 1 8 
m o nt hs t o 3 0 m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.
Secti o n t o be c h a n ge d
3. 3. 2
Descri pti o n of c h a n ge

C orrecte d s pelli n g of w or d “ ni nte d a ni b ”. 

I C 1- c h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs .

I C 8 - a d de d “, per t he i nstr ucti o ns. 
P ote nti al s u b -st u d y p atie nts t h at re q uire 
s u p ple me nt al o x y ge n or c a n n ot c o m plete 
t he i ncre me nt al or pr actice w or k r ate 
c ycle er g o metr y test will n ot p artici p ate 
i n t he s u b-st u d y, b ut will q u alif y f or t he 
m ai n st u d y. ” t o e n d of se nte nce. 
R ati o n ale f or c h a n ge
T y p o; a d mi nistr ati ve c h a n ge. U p d ate d fr o m 1 8 
m o nt hs t o 3 0 m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.
Secti o n t o be c h a n ge d
3. 3. 3
Descri pti o n of c h a n ge
E C 4 - a d de d “(e xce pt f or rescree ni n g as 
descri be d i n Secti o n 3. 3). ” t o e n d of se nte nce.
R ati o n ale f or c h a n ge
T o a d d m ore cl arific ati o n re g ar di n g rescree ns.
Secti o n t o be c h a n ge d
4. 1. 2
Descri pti o n of c h a n ge
C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs .
R ati o n ale f or c h a n ge
U p d ate d fr o m 1 8 m o nt hs t o 3 0 m o nt hs t o 
i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
4. 1. 4
Descri pti o n of c h a n ge
C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs .
R ati o n ale f or c h a n ge
U p d ate d fr o m 1 8 m o nt hs t o 3 0 m o nt hs t o 
i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
4. 2. 2. 1
Descri pti o n of c h a n ge

C h a n ge d “ M ” t o “ m ” i n first a n d t hir d 
b ullet.

Re m o ve d “. ” i n first a n d t hir d b ullet.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
4. 2. 2. 2
Descri pti o n of c h a n ge
Re m o ve d “) ” after N A C a n d “( ” after 
pirfe ni d o ne.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
5. 1. 2. 1
Descri pti o n of c h a n ge

C orrecte d: “ As per i ncl usi o n criteri o n 
# 7, p atie nts m ust be p h ysic all y a ble t o 
perf or m a 6 M W T. ” t o
“ As per i ncl usi o n criteri o n # 8, p atie nts 
m ust be p h ysic all y a ble t o perf or m a 
6 M W T, as per t he i nstr ucti o ns. ”

A d de d h y perli n k t o A p pe n di x 1 0. 1
R ati o n ale f or c h a n ge
T y p o; a d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
5. 1. 2. 5
Descri pti o n of c h a n ge

C orrecte d: “ T he m a xi m al w or k c a p acit y 
( Wc a p) of e ac h p atie nt will be 
deter mi ne d d uri n g a n i ncre me nt al c ycle 
er g o metr y c o n d ucte d at Visit 2, 
acc or di n g t o t he met h o d ol o g y descri be d 
b y O’ D o n nell a n d We b b [ R 9 8 _ 1 4 8 8 ] (see 
A p pe n di x 1 0. 1 ). ” t o 
“ T he m a xi m al w or k c a p acit y ( Wc a p) of 
e ac h p atie nt will be deter mi ne d d uri n g 
a n i ncre me nt al c ycle er g o metr y 
c o n d ucte d at Visit 1, acc or di n g t o t he 
met h o d ol o g y descri be d b y O’ D o n nell 
a n d We b b [ R 9 8 _ 1 4 8 8 ] (see A p pe n di x 
1 0. 1 ). ”

Re pl ace d: “ A pr actice c o nst a n t w or k 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 4 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R ati o n ale f or c h a n ge
T o c orrect as t o w he n i ncre me nt al c ycle 
er g o met r y will be c o n d ucte d a n d t o ali g n wit h 
fl o wc h art.
Secti o n t o be c h a n ge d
5. 2. 1
Descri pti o n of c h a n ge
C h a n ge d: “ Me as ure me nt of hei g ht a n d b o d y 
wei g ht will be perf or me d at t he ti me p oi nts 
s pecifie d i n t he fl o wc h art. ” t o
“ Me as ure me nt of hei g ht a n d b o d y wei g ht will 
be perf or me d at Visit 1. ”
R ati o n ale f or c h a n ge
Cl arific ati o n as t o w he n t his will be perf or me d.
Secti o n t o be c h a n ge d
5. 2. 3
Descri pti o n of c h a n ge
C h a n ge d: “ A ser u m h u m a n c h ori o nic 
g o n a d otr o pi n ( H C G) test will be perf or me d o n 
all fe m ales of c hil d-be ari n g p ote nti al at Visit 1. 
Uri ne pre g n a nc y tests are t o be perf or me d at 
Visits 2 -7. ”t o
“ A ser u m h u m a n c h ori o nic g o n a d otr o pi n 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 5 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
( H C G) test will be perf or me d o n all fe m ales of 
c hil d -be ari n g p ote nti al at Visit 1. Uri ne 
pre g n a nc y tests are t o be perf or me d at Visits 2 -
7, as a n alter n ati ve, a ser u m pre g n a nc y test c a n 
be perf or me d at Visits 2 -7 if re q uire d b y site or 
et hics b o ar d . ”
R ati o n ale f or c h a n ge
Cl arific ati o n t h at a ser u m pre g n a nc y test c a n be 
perf or me d at Visits 2 -7 if re q uire d .
Secti o n t o be c h a n ge d
6. 1
Descri pti o n of c h a n ge

Re m o ve d “s ” i n w or d “ wee ks ”

C orrecte d t y p o t o l oc al fr o m ce ntr al 
re g ar di n g l a b or at or y.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.  O nl y l oc al l a b or at or y is 
bei n g use d.
Secti o n t o be c h a n ge d
6. 2. 1
Descri pti o n of c h a n ge

Visit 0 
o
re m o ve d “ d ” fr o m a n d u n der first 
b ullet
o
c h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs

Visit 1
o
b ullet 1 4, re pl ace d w or d 
“ C o nst a nt ” wit h “ I ncre me nt al 
a n d pr actice ”
o
c h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs
R ati o n ale f or c h a n ge
C orrecte d t y p o.  T o be c o nsiste nt wit h t he 
fl o wc h art a n d t o cl arif y w he n t he i ncre me nt al 
a n d pr actice tests are perf or me d. U p d ate d fr o m 
1 8 m o nt hs t o 3 0 m o nt hs t o i m pr o ve recr uiti n g 
o p p ort u nities.
Secti o n t o be c h a n ge d
7. 1
Descri pti o n of c h a n ge
C h a n ge d 1 8 m o nt hs t o 3 0 m o nt hs.
R ati o n ale f or c h a n ge
U p d ate d fr o m 1 8 m o nt hs t o 3 0 m o nt hs t o 
i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
7. 3
Descri pti o n of c h a n ge
C h a n ge d: “ T he effic ac y will be c o n d ucte d o n t he 
R a n d o mize d Set. F or effic ac y a n al ysis, all 
me as ure me nt s perf or me d wit hi n t he first 3 0
wee ks will be use d. ”
t o
“ T he effic ac y will be c o n d ucte d o n t he 
R a n d o mize d Set. F or effic ac y a n al ysis, all 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 6 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
me as ure me nt s perf or me d wit hi n visits 2 -7 will 
be use d. ”
R ati o n ale f or c h a n ge
U p d ate d t o s pecif y tre at me nt peri o d.
Secti o n t o be c h a n ge d
8. 7
Descri pti o n of c h a n ge

C h a n ge d “ Tri al Cli nic al M o nit or ” t o 
Cli nic al Tri al Le a der ” 

C h a n ge d “ L oc al Cli nic al M o nit or 
( C M L) ” t o Cli nic al Tri al M a n a ger 
( C T M) ”
R ati o n ale f or c h a n ge
A d mi nistr ati ve
Secti o n t o be c h a n ge d
1 0. 1
Descri pti o n of c h a n ge
C h a n ge d: “ T o s u p ple me nt t he i nf or m ati o n o n 
t he Si x Mi n ute W al k Test descri be d i n t his 
secti o n, a M a n u al of pr oce d ures a n d 
i nstr ucti o n al vi de o h as bee n de vel o pe d. M ore 
det aile d i nf or m ati o n o n t he pr oce d ure, o n 
staffi n g, site a n d e q ui p me nt re q uire me nts, 
p atie nt pre p ar ati o n, I C me as ure me nts, a n d 
c alc ul ati o ns etc. c a n be f o u n d i n t his M a n u al, 
w hic h is file d i n t he I S F.
t o
“ T o s u p ple me nt t he i nf or m ati o n o n t he Si x 
Mi n ute W al k Test descri be d i n t his secti o n, 
i nstr ucti ons a n d a n i nstr ucti o n al vi de o h as bee n 
de vel o pe d. M ore det aile d i nf or m ati o n o n t he 
pr oce d ure, o n st affi n g, site a n d e q ui p me nt 
re q uire me nts, p atie nt pre p ar ati o n, I C 
me as ure me nts, a n d c alc ul ati o ns etc. c a n be 
f o u n d i n t he i nstr ucti o ns, w hic h is file d i n t he 
I S F. ”
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ges. 
Secti o n t o be c h a n ge d
1 0. 1. 1
Descri pti o n of c h a n ge
A d de d c ol o ns t hr o u g h o ut t o f or m at.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
1 0. 1. 2
Descri pti o n of c h a n ge
C h a n ge d/ re m o ve d w or d “ m a n u al ” t o 
“i nstr ucti o ns ” t hr o u g h o ut secti o n.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge t o be i n li ne wit h t he w a y 
s u p p orti n g d oc u me nts are n a me d i n t he I S F.
Secti o n t o be c h a n ge d
1 0. 1. 3

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 7 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Descri pti o n of c h a n ge

After fi g ure 1 0. 1. 3: 1, m ai n b ullet 4 –
re m o ve d “ d ” pri or t o t he w or d 
“ d ys p ne a ”.

 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
R ati o n ale f or c h a n ge
 
 
 
Secti o n t o be c h a n ge d
1 0. 3
Descri pti o n of c h a n ge
T he S T. G E O R G E’ S R E S PI R A T O R Y 
Q U E S TI O N N AI R E ( S G R Q) w as u p d ate d t o 
reflect t he m ost c urre nt versi o n.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
1 0. 5
Descri pti o n of c h a n ge
T he Ki n g’s Brief I L D Q uesti o n n aire ( K -BI L D) 
w as u p d ate d t o reflect t he m ost c urre nt versi o n.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
1 0. 7
Descri pti o n of c h a n ge
U p d ate d t o all o w use of hist oric d at a as per 
i ncl usi o n criteri o n 6 a n d c orrecti o n of 
t y p o gr a p hic al err or i n visit n u m ber.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 8 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
1 1. 2
G L O B A L A M E N D M E N T 2
D ate of a m e n d me nt
1 6 Dec 2 0 1 9
E u dr a C T n u m ber
E U n u m ber
N ot a p plic a ble
BI Tri al n u m ber
1 1 9 9- 0 3 2 4
BI I n vesti g ati o n al Pr o d uct(s)
ni nte d a ni b
Title of pr ot oc ol
St u d y of P ul m o n ar y Re h a bilit ati o n I n 
Ni nte d a ni b Tre ate d P atie nts wit h I P F: 
I m pr o ve me nts i n Acti vit y, E xercise E n d ur a nce 
Ti me, a n d  Q o L
T o be i m ple me nte d o nl y after a p pr o v al of t he I R B / I E C / C o m pete nt A ut h orities                                      
X
T o be i m ple me nte d i m me di atel y i n or der t o eli mi n ate h az ar d –
I R B / I E C / C o m pete nt A ut h orit y t o be n otifie d of c h a n ge wit h re q uest f or 
a p pr o v al
C a n be i m ple me nte d wit h o ut I R B / I E C / C o m pete nt A ut h orit y a p pr o v al as 
c h a n ges i n v ol ve l o gistic al or a d mi nistr ati ve as pects o nl y
Secti o n t o be c h a n ge d
Title P a ge
Descri pti o n of c h a n ge
U p d ate d t he f oll o wi n g:

V ersi o n

D ate of Pr ot oc ol

St at us
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ges
Secti o n t o be c h a n ge d
Cli nic al Tri al Pr ot oc ol S y n o psis
Descri pti o n of c h a n ge
U p d ate d t he f oll o wi n g:

Re visi o n D ate

C h a n ge d Incl usi o n C riteri a fr o m “ O n 
st a ble d ose of ni nte d a ni b f or u p t o 3 0 
m o nt hs ” t o “ Tre ate d o n a st a ble d ose of 
ni nte d a ni b f or u p t o 3 0 m o nt hs . P atie nts 
w h o h a ve rece ntl y st arte d ni nte d a ni b 1 5 0 
m g BI D a n d h a ve st arte d b y t he d a y of 
r a n d o miz ati o n m ust be o n ni nte d a ni b 
1 5 0 m g BI D a mi ni m u m of 1 0 d a ys b y 
t he first d a y of p ul m o n ar y 
re h a bilit ati o n. ”

C h a n ge d I ncl usi o n Criteri a F orce d Vit al 
C a p acit y ( F V C) fr o m ≥ 5 0 % of 
pre dicte d t o ≥ 4 5 % of
pre dicte d

C h a n ge d E xcl usi o n Criteri a fr o m 
“ P artici p ati o n i n a p ul m o n ar y 
re h a bilit ati o n pr o gr a m c o m plete d i n t he 
p ast 3 m o nt hs ” t o “ Pre vi o us 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 9 9 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
p artici p ati o n i n p ul m o n ar y 
re h a bilit ati o n pr o gr a m wit hi n 4 5 d a ys 
pri or t o si g ni n g i nf or me d c o nse nt

A d de d s u b b ullet p oi nt s t o sec o n d ar y 
en d p oi nt b ullet # 3 t o be c o nsiste nt wit h 
secti o n  5. 1. 1. 2.
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ges.  U p d ate t he I ncl usi o n 
a n d E xcl usi o n Criteri a t o f urt her i m pr o ve 
recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
Fl o wc h art
Descri pti o n of c h a n ge

 
 
 
 
 
 
 
 
 
 
 
 

U p d ate d F o ot n ote 6 t o “ 6 wee ks ” fr o m 
“ 4 wee ks ”
R ati o n ale f or c h a n ge
T o pr o vi de m ore cl arific ati o n as t o w he n 
i ncre me nt al c ycle er g o metr y will be c o n d ucte d.  
T o i ncre ase t he wi n d o w t o sc he d ule P R.
Secti o n t o be c h a n ge d
1. 4
Descri pti o n of c h a n ge

C h a n ge d “ n ot less t h a n t hree ” t o “ u p t o 
t hirt y ”

A d de d “ g astr oi ntesti n al perf or ati o n ”
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities; t o 
ali g n wit h c urre nt A E SIs i n t he pr o gr a m.
Secti o n t o be c h a n ge d
2. 1. 1
Descri pti o n of c h a n ge
C h a n ge d “f or 3 -3 0 m os ” t o “ f or u p t o 3 0 m os”
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
3. 1
Descri pti o n of c h a n ge
C h a n ge d “c urre ntl y t a ki n g ni nte d a ni b at a d ose 
of 1 5 0 m g bi d f or n ot less t h a n 3 m o nt hs or 
m o re t h a n 3 0 m o nt hs ” t o “ tre ate d wit h 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 0 0 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
ni nte d a ni b at a d ose of 1 5 0 m g bi d f or u p t o 3 0 
m o nt hs. ”
R ati o n ale f or c h a n ge
U p d ate d  t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
3. 2
Descri pti o n of c h a n ge
U p d ate d w or di n g fr o m “T he c o h ort i n t his 
st u d y is p atie nts t h at are o n a st a ble t her a p y 
wit h ni nte d a ni b f or 3- 3 0 m o nt hs. ” t o “ T he 
c o h ort i n t his st u d y is p atie nts t h at are tre ate d 
wit h ni nte d a ni b f or u p t o 3 0 m o nt hs. ”
R ati o n ale f or c h a n ge
U p d ate d  t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
3. 3. 1
Descri pti o n of c h a n ge
C h a n ge d “ bet wee n 3 a n d 3 0 m o nt hs ” t o “ u p t o 
3 0 m o nt hs ”
R ati o n ale f or c h a n ge
U p d ate d  t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
3. 3. 2
Descri pti o n of c h a n ge

C h a n ge d “ C urre ntl y t a ki n g 
ni nte d a ni b 1 5 0 m g BI D, at a st a ble d ose 
f or 3-3 0 m o nt hs ” t o “ P atie nts bei n g 
tre ate d wit h a st a ble d ose of ni nte d a ni b 
1 5 0 m g BI D f or u p t o 3 0 m o nt hs. 
P atie nts w h o h a ve rece ntl y st arte d 
ni nte d a ni b 1 5 0 m g BI D a n d h a ve st arte d 
b y t he d a y of r a n d o miz ati o n m ust be o n 
ni nte d a ni b 1 5 0 m g BI D a mi ni m u m of 1 0 
d a ys b y t he f irst d a y of p ul m o n ar y 
re h a bilit ati o n. ”

Re m o ve d f o ot n ote 2.

C h a n ge d “ F V C fr o m ≥ 5 0 % of 
pre dicte d ” t o “ ≥ 4 5 % of
pre dicte d ”

C h a n ge “ P h ysic all y c a p a ble of 
perf or mi n g b ot h a 6 mi n ute w al k test 
 m ust s uccessf ull y 
c o m plete t he pr actice tests f or b ot h, per 
t he i nstr ucti o ns. P ote nti al s u b-st u d y 
p atie nts t h at re q uire s u p ple me nt al 
o x y ge n or c a n n ot c o m plete t he 
i ncre me nt al or pr actice w or k r ate c ycle 
er g o metr y test will n ot p artici p ate i n t he 
s u b-st u d y, b ut will q u alif y f or t he m ai n 
st u d y.” t o " P h ysic all y c a p a ble of 
perf or mi n g b ot h a 6 mi n ute w al k test 
a n d w or k r ate c ycle er g o metr y (s u b -

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 0 1 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
st u d y p atie nts), m ust s uccessf ull y 
c o m p lete t he pr actice tests f or t he 6 
mi n ute w al k test , per t he i nstr ucti o ns. 
P ote nti al s u b-st u d y p atie nts t h at re q uire 
s u p ple me nt al o x y ge n or c a n n ot c o m plete 
t he i ncre me nt al w or k r ate c ycle 
er g o metr y test will n ot p artici p ate i n t he 
s u b-st u d y, b ut will q u alif y f or t he m ai n 
st u d y.”
R ati o n ale f or c h a n ge
U p d ate d  t o i m pr o ve recr uiti n g o p p ort u nities.   
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
3. 3. 3
Descri pti o n of c h a n ge
C h a n ge d “ P artici p ati o n i n a p ul m o n ar y 
re h a bilit ati o n pr o gr a m c o m plete d i n t he p ast 3 
m o nt hs. ” t o “ Pre vi o us p artici p ati o n i n 
p ul m o n ar y re h a bilit ati o n pr o gr a m wit hi n 4 5 
d a ys pri or t o si g ni n g c o nse nt . ”
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
4. 1. 2
Descri pti o n of c h a n ge

C h a n ge d “ f or 3 t o 3 0 m o nt hs ” t o “f or u p 
t o 3 0 m o nt hs t o q u alif y f or t he tri al a n d 
t o c o nti n ue o n ni nte d a ni b f or t he 
d ur ati o n of t he tri al. P atie nts w h o h a ve 
rece ntl y st arte d ni nte d a ni b 1 5 0 m g BI D 
a n d h a ve st arte d b y t he d a y of 
r a n d o miz ati o n m ust be o n ni nte d a ni b 
1 5 0 m g BI D a mi ni m u m of 1 0 d a ys b y 
t he first d a y of p ul m o n ar y 
re h a bilit ati o n. ”

A d de d “ Te m p or ar y ” i n fr o nt of d ose .
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities. 
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
4. 1. 4
Descri pti o n of c h a n ge
C h a n ge d “ S u bj ects are re q uire d t o be o n a 
st a ble ( 3 t o 3 0 m o nt hs) d ose of ni nte d a ni b 1 5 0 
m g BI D, a d mi nistere d per prescri bi n g 
i nstr ucti o ns ( R 1 8-1 2 8 9), t o e nter t he tri al a n d t o 
c o nti n ue o n t his d ose t hr o u g h o ut t he tri al. ” t o 
“ S u bjects are re q uire d t o be tre ate d o n a st a ble 
( u p t o 3 0 m o nt hs) d ose of ni nte d a ni b 1 5 0 m g 
BI D, a d mi nistere d per prescri bi n g i nstr ucti o ns 
( R 1 8-1 2 8 9), t o e nter t he tri al a n d t o c o nti n ue o n 
t his d ose t hr o u g h o ut t he tri al. P atie nts w h o 

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 0 2 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
h a ve rece ntl y st arte d ni nte d a ni b 1 5 0 m g BI D 
a n d h a ve st arte d b y t he d a y of r a n d o miz ati o n 
m ust be o n ni nte d a ni b 1 5 0 m g BI D a mi ni m u m 
of 1 0 d a ys b y t he first d a y of p ul m o n ar y 
re h a bilit ati o n. ”
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities. 
Secti o n t o be c h a n ge d
5. 1. 2. 5
Descri pti o n of c h a n ge
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
R ati o n ale f or c h a n ge
A d mi nistr ati ve c h a n ge.
Secti o n t o be c h a n ge d
5. 2. 6. 1
Descri pti o n of c h a n ge
A d de d G astr oi ntesti n al perf or ati o n
R ati o n ale f or c h a n ge
T o ali g n wit h pr o gr a m A E SIs
Secti o n t o be c h a n ge d
5. 2. 6. 2

B oe hri n ger I n gel hei m
1 6 Dec 2 0 1 9
BI Tri al N o.: 1 1 9 9- 0 3 2 4
c 1 9 5 5 8 8 0 8 - 0 6
Cli nic al Tri al Pr ot oc ol
P a ge 1 0 3 of 1 0 3
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 9 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S - 4 0- 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
Descri pti o n of c h a n ge
C h a n ge d “f a x ” t o “s u b mit ”
R ati o n ale f or c h a n ge
A d mi nistr ati ve
Secti o n t o be c h a n ge d
6. 2. 1
Descri pti o n of c h a n ge
C h a n ge d Visit 0 a n d Vi sit 1 t o reflect 
u p d ate t o I N C 1 - “f or u p t o 3 0 m o nt hs ” 
a n d a d de d “ P atie nts w h o h a ve rece ntl y 
st arte d ni nte d a ni b 1 5 0 m g BI D a n d h a ve 
st arte d b y t he d a y of r a n d o miz ati o n 
m ust be o n ni nte d a ni b 1 5 0 m g BI D a 
mi ni m u m of 1 0 d a ys b y t he first d a y of 
p ul m o n ar y re h a bilit ati o n. ”
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
6. 2. 2
Descri pti o n of c h a n ge
U p d ate “ 4 wee ks ” t o “ 6 wee ks ”
R ati o n ale f or c h a n ge
T o i ncre ase t he wi n d o w t o sc he d ule P R.
Secti o n t o be c h a n ge d
7. 1
Descri pti o n of c h a n ge
U p d ate d “ c urre ntl y t a ki n g ni nte d a ni b at a d ose 
of 1 5 0 m g bi d f or n ot less t h a n 3 m o nt hs or 
m o re t h a n 3 0 m o nt hs ” t o “ c urre ntl y tre ate d 
wit h ni nte d a ni b at a d ose of 1 5 0 m g bi d f or u p 
t o 3 0 m o nt hs ”
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities.
Secti o n t o be c h a n ge d
1 0. 7
Descri pti o n of c h a n ge
U p d ate d F V C t o 4 5 %
R ati o n ale f or c h a n ge
U p d ate d t o i m pr o ve recr uiti n g o p p ort u nities

 
 
 
 
A P P R O V A L / SI G N A T U R E P A G E 
 
D oc u me nt N u m ber: 
  
Tec h nic al Versi o n N u m ber:
 
D oc u me nt N a me: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Si g n at ures ( o bt ai ne d electr o nic all y) 
 
Me a ni n g of Si g n at ure  
Si g n e d b y 
D ate Si g ne d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c 1 9 5 5 8 8 0 8
6. 0
cli nical-trial- pr ot oc ol- versi o n- 3. 0
St u d y of P ul m o nar y Re ha bilitati o n I n Ni nte da ni b Treate d Patie nts wit h I P F:
I m pr o ve me nts i n Acti vit y, E xercise E n d ura nce Ti me, a n d Q o L
A ut h or- Cli nical Trial Lea der
1 6 Dec 2 0 1 9 1 5: 3 0 C E T
A ut h or- Trial Statisticia n
1 6 Dec 2 0 1 9 1 6: 4 2 C E T
A p pr o val- Me dical 
1 6 Dec 2 0 1 9 2 3: 1 0 C E T
A p pr o val- T hera pe utic Area 
1 6 Dec 2 0 1 9 2 3: 2 0 C E T
A p pr o val- Tea m Me m ber Me dici ne
1 8 Dec 2 0 1 9 1 4: 0 2 C E T
Verificati o n- Pa per Si g nat ure
C o m pleti o n
1 8 Dec 2 0 1 9 1 4: 1 0 C E T

B oe hri n ger I n gel hei m 
P a ge  2 of 2
D oc u me nt N u m ber: 
 Tec h nic al Versi o n N u m ber :
 
 
 
( C o nti n ue d) Si g n at ures ( o bt ai ne d electr o nic all y) 
 
Me a ni n g of Si g n at ure  
Si g ne d b y 
D ate Si g ne d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c 1 9 5 5 8 8 0 8
6. 0