Clinical trial NCT03717012
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim
Start date: 2018-11-15; Completion date: 2020-06-10
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objectives of this study are:

* Determine the difference in change from baseline in Six Minute Walk Distance (6MWD) when pulmonary rehabilitation (PR) is added to stable underlying nintedanib therapy in patients with idiopathic pulmonary fibrosis (IPF)
* Determine the difference in change in Quality of Life (QoL) when pulmonary rehabilitation (PR) is added to stable underlying nintedanib therapy in patients with idiopathic pulmonary fibrosis (IPF)
* Determine if there is an enduring effect in 6MWD, QoL and lung function from pulmonary rehabilitation (PR) when pulmonary rehabilitation (PR) is added to stable underlying nintedanib therapy in patients with idiopathic pulmonary fibrosis (IPF)

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Nintedanib intervention 2: Pulmonary rehabilitation program
Intervention descriptions: intervention 1: stable dose intervention 2: 12 weeks

Protocol documents:
Prot_000.pdf: 
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

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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27797453-01
BI Trial No.:
1199.324
Title:
Study of Pulmonary Rehabilitation In Nintedanib Treated Patients 
with IPF: Improvements in Activity, Exercise Endurance Time, and 
QoL
Investigational
Product(s):
Nintedanib
Responsible trial 
statistician(s):
Date of statistical 
analysis plan:
18 SEP 2020
Version:
Final
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2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................4
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................5
5.
ENDPOINTS..........................................................................................................5
5.1
PRIMARY ENDPOINT........................................................................................5
5.2
SECONDARY ENDPOINTS ...............................................................................5
5.2.1
Key secondary endpoints ......................................................................................5
5.2.2
Secondary endpoints .............................................................................................5
6.
GENERAL ANALYSIS DEFINITIONS.............................................................9
6.1
TREATMENT(S) ..................................................................................................9
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................10
6.3
SUBJECT SETS ANALYSED ...........................................................................11
6.5
POOLING OF CENTRES..................................................................................11
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................11
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................12
7.
PLANNED ANALYSIS ......................................................................................14
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........14
7.2
CONCOMITANT DISEASES AND MEDICATION......................................14
7.3
TREATMENT COMPLIANCE ........................................................................15
7.4
PRIMARY ENDPOINT......................................................................................15
7.4.1
Primary analysis of the primary endpoint........................................................15
7.4.2
Sensitivity analysis of the primary endpoint.....................................................15
7.5
SECONDARY ENDPOINTS .............................................................................16
7.5.1
Key secondary endpoint......................................................................................16
7.5.2
(Other) Secondary endpoints .............................................................................16
7.7
EXTENT OF EXPOSURE .................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................19
7.8.2
Laboratory data...................................................................................................20
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG ......................................................................................................................20
7.8.5
Others ...................................................................................................................20
8.
REFERENCES ....................................................................................................21
10.
HISTORY TABLE..............................................................................................25


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LIST OF TABLES
Table 6.2: 1
Important protocol deviations...........................................................................10
Table 10: 1
History table .....................................................................................................25


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
6MWT
Six-Minute Walk Test
DLco
Carbon Monoxide Diffusion Capacity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
FVC
Forced Vital Capacity
IPD
Important Protocol Deviation
KBILD
King’s Brief ILD Questionnaire
MMRM
Mixed effect Model for Repeated Measures
Q1
Lower quartile
Q3
Upper quartile
QoL
Quality of Life
SD
Standard deviation
SGRQ
St. George’s Respiratory Questionnaire
SOC
System organ class
SpO2
Oxygen Saturation on Pulse Oximetry
UCSD-SOBQ
University of California, San Diego Shortness-of-Breath Questionnaire
3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, the purpose of this document is 
to provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, and to include detailed procedures for executing the statistical 
analysis of the primary and secondary variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.”
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In writing the core TSAP, these corrections were made to the specifications of the initial 
TSAP:
1. Important protocol deviation (IPD) E1 in Section 6.2 “No post-baseline 6 MWT 
assessments” was clarified to E1 “No post-baseline 6 MWD assessments at 12 weeks”
and E2 “No baseline 6 MWD assessments” to reflect the primary outcome being 
measured at 12 week visit.
2. iPD D2 in Section 6.2 was changed from “Discontinued nintedanib” to “Discontinued 
nintedanib before 12 week visit” to reflect the primary outcome being measured at 12 
week visit. 
3. The Screening trial period in Section 6.1 was changed from “informed consent to 
randomization” to “first informed consent to randomization” to account for re-
consenting of patients.
4. The trial periods defined in Section 6.1 was clarified to make the distinction between 
efficacy analysis and safety analysis.
Following termination of the trial, limited efficacy analysis will be performed for an 
abbreviated CTR.  Primary and secondary endpoints will be limited to descriptive outcome 
measures.  Further endpoints will not be done.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is the change from baseline in Six-Minute Walk Test (6MWT) distance
at 12 weeks.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
There are no key secondary endpoints defined for this trial.
5.2.2
Secondary endpoints
The secondary endpoints are:

Change from baseline in Quality of Life (QoL) (SGRQ, KBILD, UCSD-SOBQ) at 12 
and 24 weeks

Change from baseline in 6MWT distance at 24 weeks

Change from baseline in Forced Vital Capacity (FVC) at 12 weeks and 24 weeks 
using each of
o
Absolute change from baseline of FVC and FVC % predicted
o
Relative change from baseline of FVC and FVC % predicted
o
Absolute categorical change of FVC % predicted (decrease by >5%, increase 
by >5%, and change within ≤ 5%)


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o
Absolute categorical change of FVC% predicted (decrease by >10%, increase 
by >10%, and change within ≤ 10%)

Change from baseline in daily accelerometer activity from baseline at 12 and 24 weeks
o
Score of average Steps/day
o
Score of average VMU/day
Refer to Section 6.7 for baseline value definition.  Refer to Section 6.6 for missing baseline 
assessment.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For treatment specifications, see Section 4 of the CTP.
The following trial periods will be defined with respect to efficacy analyses: Screening, Post-
randomization, Treatment, Post-treatment.

Screening: from first informed consent to randomization

Post-randomization: from randomization to day of first pulmonary rehabilitation (for 
those randomized to Pulmonary Rehabilitation Treatment group)

Treatment:
o
For patients randomized to the Non-Pulmonary Rehabilitation Treatment
group: from randomization to the visit 7 end-of-trial visit
o
For patients randomized to the Pulmonary Rehabilitation Treatment group: 
from first day of pulmonary rehabilitation to the visit 7 end-of-trial visit

Post-treatment: after the visit 7 end-of-trial visit
Efficacy analyses is independent of nintedanib usage: any dose interruption or discontinuation 
has no effect on the efficacy analyses.  Efficacy analyses will be done on the Post-
randomization and Treatment Periods.
The following trial periods will be defined with respect to safety analyses: 
Note: the last day of each of the following periods is excluded.

Screening: from first informed consent to randomization

Post-randomization: from randomization to day of first Nintedanib drug intake
on/after randomization. This period only exists if Nintedanib first drug intake on/after 
randomization occurred at least 1 day after randomization.

Treatment: from first Nintedanib drug intake on/after randomization (or re-start of 
nintedanib if interruption) to last Nintedanib drug intake (or the day before start date 
of interruption if interruption) plus one day.

Off-treatment a: From the start date of Nintedanib interruption to re-start of Nintedanib 
treatment.

Residual-effect a: From the last Nintedanib drug intake plus one day to last Nintedanib 
trial drug intake plus 28 days plus one day.

Post-treatment a: From last trial drug intake plus 29 days.  Note, this period is only 
created if last Nintedanib intake plus 29 days took place before trial completion.

Post-study: from the latest of last trial drug intake plus 29 days or date of trial
completion plus 1 day
a Note: This period is optional insofar as it does not necessarily exist for all patients.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
The following table defines the different categories of important protocol deviations (IPD) to 
be considered. Important efficacy IPDs are those that can potentially influence the primary
endpoint.  No patients will be excluded from the analyses based on those IPDs as no per-
protocol analysis is planned.  However, the frequency of patients with IPDs will be presented.
Table 6.2: 1
Important protocol deviations 
Category / 
Code
Description
Requirements
A
Entrance criteria not met
A1
Inclusion criteria not met
Inclusion criteria not met as specified in the 
protocol.
Automatic PD
A2
Exclusion criteria not met
Exclusion criteria not met as specified in 
the protocol.
Automatic PD
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing
Automatic PD
B2
Informed consent too late
CRF date of informed consent
Automatic PD
B3
Informed re-consent not 
available/not done
Informed re-consent date missing
Manual PD
B4
Informed re-consent too late
CRF date of informed re-consent
Manual PD
B5
Incorrect consent form used or 
other consenting process error
Manual PD
C
Trial treatment and 
randomisation
C1
Incorrect treatment given
Patient assigned to pulmonary rehabilitation 
not prescribed rehab, or patient assigned to 
standard care prescribed rehab
Manual PD with medical review of MQRM 
listings
C2
Non-compliance
Pulmonary Rehabilitation Compliance 
<80% or >120%
Automatic PD with medical review of 
MQRM listings
D
Concomitant medication
D1
Patient received prohibited 
concomitant therapies during 
treatment phase
Manual PD with medical review of MQRM 
listings
D2
Mandatory medication not taken
Discontinued nintedanib before 12 week
visit
Automatic PD
E
Missing data
E1
No post-baseline 6 MWD
assessments at 12 weeks
Automatic PD
E2
No baseline 6 MWD assessments 
Automatic PD
Automatic PDs are those detected via an automatic programming process using SAS.  Manual PDs are those identified during 
the MQRM meeting through patient listings and/or BI CTMS.


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6.3
SUBJECT SETS ANALYSED

Screened set
This patient set includes all patients having signed informed consent and performed 
visit 1.

Randomized set (RS)
This patient set includes all randomized patients, whether treated with pulmonary 
rehabilitation or not

 
 
All analyses will be done on the RS or 
.  Note that the number of patients with available 
data for an endpoint may differ.  For details, see Section 6.6.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, the efficacy analyses as well as safety analyses will be evaluated by observed case
analysis (OC), i.e. using only available data without imputation.
6.6.1 Primary Endpoint
Multiple imputation will be used to handle missing data as a sensitivity analysis for the 
primary endpoint.  Further detail is provided in Section 7.4.2.
6.6.2 Secondary Endpoints
6.6.2.1 Saint George’s Respiratory Questionnaire 
For the SGRQ, the SGRQ manual (7) allows for 25% of missing data per component (i.e., 2


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questions for symptoms, 6 questions for impacts and 4 questions for activities). The rules
defined in the SGRQ manual will be used to derive the SGRQ.
Additionally the responses to questions 5 and 6 (see CTP Section 10.3 for questionnaire) will 
be made consistent to the extent that if the answer to question 5 is 5 (none of the time) and the 
answer to question 6 is non-missing (i.e., length of worst attack specified), then question 6 
will be set to missing. Therefore scores will be calculated ignoring that item. In this case, the 
missing response to question 6 will not be included in the count of missing questions for the 
symptoms component.
6.6.2.2 University of California, San Diego Shortness-of-Breath Questionnaire
If UCSD-SOBQ is not completely answered, the missing questions will not be imputed and 
the score will be set to missing.
6.6.2.3 King’s Brief ILD Questionnaire
For K-BILD, missing item scores are imputed based on the average of the non-missing item 
scores within the domain, rounded to the nearest integer. If the missing items are >50% per 
domain, then the domain score is set to missing. If item 15 is missing, it will be replaced by the 
average of all available items 1-14. If any of the domain scores are missing, the total score is set 
to missing.
6.6.3 Other Endpoints
6.6.3.1 Concomitant therapies
In case of (partially) missing start and end dates of concomitant therapies, the dates will be
imputed so that the extent of exposure to the concomitant therapy is maximal, i.e. the first
day (month) of the month (year) for incomplete start dates and the last day (month) of the
month (year) for incomplete end dates.
6.6.3.2 Safety Endpoints
Information regarding acute IPF exacerbations is collected from AEs and as such, missing or
incomplete start or end dates will be imputed according to BI standards (1).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, last assessment before treatment period start (included) will be used as 
baseline. For patients randomized to the Non-Pulmonary Rehabilitation group treatment 
period starts from randomization. For patients randomized to the Pulmonary Rehabilitation 
group treatment period starts from first day of pulmonary rehabilitation. If the baseline value 
is missing and the screening value is available, then the baseline value will be defined as the 
screening value taken closest to baseline date.
A windowing will be performed in order to assign data to the relevant study visit based on the 
actual day of the assessment. If after windowing of visits at baseline, two values fall within 
the same baseline interval, then the last value will be taken into account. If after windowing of 


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post-baseline visits, two visits fall in the same interval, then the measurement closest to the 
planned visit will be taken into account. In case two measurements are equidistant from the 
planned visit, then the last one will be picked.
Time windowing rules for physical exam, vital signs, and laboratory tests:
Time window of actual day
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-
1
-
2
Baseline
1
2
32
31
3
3 weeks
22
33
63
31
4
6 weeks
43
64
105
42
5
12 weeks
85
106
147
42
6
18 weeks
127
148
-
-
7
24 weeks
169
Time windowing rules for spirometry, six minutes walk test, 
, 
PROactive tool, SGRQ, KBILD, UCSD SOBQ:
Time window of actual day
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned 
day of the 
visit
-
1
-
2
Baseline
1
2
126
125
5
12 weeks
85
127
-
-
7
24 weeks
169
Include for analysis and in average calculation of the ProActive tool scores the following 
measurements.  If a patient does not have at least 5 days of measurements available, no score 
is calculated (except for baseline, noted below).

Baseline = 7 days before and up to actual Visit 2 (excluded).  If a patient does not 
have at least 5 days of measurements within this time window, then use 7 days before 
and up to actual Visit 1 (excluded) (only if 5 days of measurements are available)

12 weeks = 7 days before and up to actual Visit 5 (excluded)

24 weeks = 7 days before and up to actual Visit 12 (excluded)
Note: For accelerometer scores, if a patient has more than one record for a given day, the 
record will not be used for calculation.  For eDiary scores, if a patient has more than one 
record for a given day, the worse answer will be used for calculation.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max.  In descriptive statistics tables, mean and median will be rounded to one additional 
digit than the raw individual value.  SD will be rounded to one additional digit than the mean.
For tables that are provided for endpoints with some extreme data, median,  quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject
set whether they have non-missing values or not). 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers.
The category missing will be displayed only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.2.1 Baseline conditions
A summary of baseline conditions will be provided by treatment group, System Organ Class 
(SOC) and Preferred Term (PT).  SOC will be sorted according to the standard sort order 
specified by EMA and PT by descending frequency over both treatment arms.
7.2.2 Concomitant therapies
Concomitant therapies will be described over several study periods, listed below.

Previous therapies will be defined as treatments with an end date before baseline.

Baseline therapies will be defined as treatments with a start date before baseline and a 
stop date after or on baseline.

On-treatment therapies will be defined as treatments with a start date during the 
nintedanib treatment period defined in Section 6.1.

Post-study drug discontinuation concomitant therapies are defined as treatments with a 
start date during the residual effect, post-treatment or post-study period defined in 
Section 6.1.


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A summary of all on-treatment concomitant therapies (including baseline CTs) will be
provided by treatment group, ATC3 codes and Preferred Name (PN) (sorted by alphabetical
ATC class and decreasing frequency of preferred names in Nintedanib treatment arm within
ATC class).
Relevant groups of therapies have been defined as Special Search Categories (SSC) or
Standardised Drug Groupings (SDG).
A summary of baseline concomitant therapies, on-treatment concomitant therapies will also 
be performed by Special Search Category (SSC) or Standardised Drug Groupings (SDG) and 
Preferred Name (PN) (sorted by alphabetical SSC or SDG and decreasing frequency of 
preferred names within SSC or SDG).
Finally, specific tables for selected concomitant treatments that were restricted during the
study will be provided (by PN):

All on-treatment concomitant therapies (including baseline CTs)

All concomitant therapies (including baseline CTs, on-treatment CTs)
Non-drug therapies will be included as coded items using the current Medical Dictionary for 
Regulatory Activities (MedDRA) version in use at BI at the time of database lock. They will 
be summarised by MedDRA system organ class (SOC) and Preferred Term. The CTR table 
will show the counts of patients with a condition in each SOC present (SOC sorted by 
standard European Medicines Agency (EMA) order) and then the conditions (preferred terms) 
under that SOC in descending order of overall prevalence. 
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
The primary analysis will be conducted on the RS set.  Only descriptive statistics are planned 
for this section of the report.The analysis of the primary endpoint will be conducted in 
accordance with Section 7.3.1 of the CTP.
7.4.2
Sensitivity analysis of the primary endpoint
Multiple imputation will be used to handle missing data as a sensitivity analysis using the RS 
set. All variables included in the analysis model will be included in the imputation model. In
addition, after exploring the missing data mechanism and observed measurements on the 
blinded data additional variables may be included in the imputation model.
When there is no missing baseline information in the imputation model, regression method 
will be used.  When there is missing baseline information in the imputation model, MCMC 
method will be used.  For each imputed complete dataset, the primary analysis model will be 


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used for the analysis.  The results will be pooled following the standard multiple imputation 
procedure.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
(Other) Secondary endpoints
The 12-week and 24-week secondary endpoints will be analyzed on the RS set.  Only 
descriptive statistics are planned for this section of the report.The analyses of these secondary 
endpoints will be conducted in accordance with Section 7.3.2 of the CTP.
The 24-week secondary endpoints will be analyzed on the RS set.  The analysis of these 
secondary endpoints will be conducted in accordance with Section 7.3.2 of the CTP.  In the 
event of non-convergence, the following methods will be attempted (in order) to overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12).
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50.
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations.
4. Include the statement ‘performance nothread’ – this removes multi-threading from the 
calculations.
Secondary endpoints with FVC % predicted will be derived using the following formula:
FVC % Predicted = 100 ×
FVC [L]
FVC Predicted [L],
Where,
FVC Predicted [L]= D 5.76 × Height(m) −0.026 × Age −4.34 if Male
4.43 × Height(m) −0.026 × Age −2.89 if Female
Age will be as collected at Visit 1.  


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7.7
EXTENT OF EXPOSURE
The data will be analysed on the RS.  A summary table showing the duration on pulmonary 
rehabilitation (both mean and frequency, see Section 5.4.3). 
A table displaying the disposition of patients and the conclusion of patients’ participation, and 
a table displaying the primary reason for non-inclusion/randomization will be provided.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the RS.  The analysis will be performed as defined in 
the CTP.   That is, analysis of adverse events will be restricted to nintedanib-related serious 
adverse events, nintedanib-non-related serious adverse events and events of special interest.
Adverse events of special interest include DILI and GI Perforation.
7.8.1
Adverse Events
The analyses of AEs will be descriptive in nature and will be based on BI standards (11).  No 
hypothesis testing is planned. All analyses of AEs will be based on the number of subjects
with AEs and NOT on the number of AEs.
For analysis, multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies:

All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship [investigator defined drug-
relatedness], outcome, AE of special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
For further details on summarization of AE data, please refer to the guideline “Analysis and 
Presentation of Adverse Event Data from Clinical Trials” (11). 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first nintedanib intake on/after 
randomization till 28 days after last nintedanib intake will be assigned to the treatment period. 
All  adverse events occurring before first nintedanib intake will be assigned to ‘screening’ or 
‘post-randomisation’ and all adverse events occurring after last nintedanib intake will be 
assigned to ‘residual effect’, ‘post-treatment’ or ‘post-study’ (for listings only). Also, all 
adverse events occurring between the start of an interruption and the end of interruption will 
be assigned to ‘off-treatment’ period in the listings. For details on the treatment definition, see 
Section 6.1.
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant AEs with (i) ‘action taken = discontinuation’ or 
‘action taken = reduced’, or (ii) marked haematological and other lab abnormalities or lead to 


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significant concomitant therapy as identified by the Clinical Monitor/Investigator at a 
MQRM.
An overall summary of adverse events will be presented.  The frequency of subjects with AEs
will be summarised by treatment, primary system organ class and PT (mention MedDRA 
levels to be displayed in the tables). Separate tables will be provided for subjects with other 
significant adverse events according to ICH E3 (10), for subjects with significant non-serious 
adverse events (only if these are defined for the project) and for subjects with serious adverse 
events (SAEs).
The system organ classes will be sorted by default alphabetically, PTs will be sorted by 
frequency (within SOC). Customized sorting orders may also be used based on trial needs, 
e.g. SOC sorted by frequency.
7.8.2
Laboratory data
Not applicable.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Not applicable.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates “, current 
version, Group “Biostatistics & Data Sciences”, IDEA for CON.
2.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
3.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision 
Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
4.
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & Data 
Sciences”, IDEA for CON.
5.
001-MCS-40-106_RD-03: “Clinical Trial Protocol general template for Phase I-IV”, 
current version, Group “Clinical Operations”, IDEA for CON.
6.
001-MCS-80-606: “Management of Non-Compliances”, current version, Group “Quality 
Medicine”, IDEA for CON.
7.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
8.
001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON.
9.
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, 
and repealing Directive 2001/20/EC, European Commission webpage.
10. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version, EMA webpage.
11. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON
12.
Patel AS, Siegert RJ, Brignall K, Gordon P, Steer S, Desai SR, Maher TM, Renzoni EA, Wells AU, 
Higginson IJ, Birring SS. The development and validation of the King’s Brief Interstitial Lung Disease 
(K-BILD) health status questionnaire. Thorax 2012; 67 (9), 804-810 [R12-4171]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
18-SEP-2020
None
This is the final TSAP