Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Rising Oral Doses of BI 894416 in Healthy Male Subjects (Single-blind, Partially Randomised, Placebo-controlled Parallel Group Design)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

0 0 1- M C S - 4 0- 1 0 6-R D - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Cli nic al Tri al Pr ot oc ol
 
D oc u me nt N u m ber:
c 1 2 0 9 8 8 1 2- 0 9
E u dr a C T N o.:
BI Tri al N o.:
2 0 1 6- 0 0 3 4 7 0- 4 0
1 3 7 1- 0 0 0 1
BI I n vesti g ati o n al
Pr o d uct:
BI 8 9 4 4 1 6
Title:
Safet y, t olera bilit y, p har mac o ki netics a n d p har mac o d y na mics of 
si n gle risi n g oral d oses of BI  8 9 4 4 1 6 i n healt h y male s u bjects (si n gle-
bli n d , partiall y ra n d o mise d, place b o-c o ntr olle d parallel gr o u p desi g n) 
L a y Title:
T his st u d y i n healt h y me n tests h o w differe nt d oses of BI 8 9 4 4 1 6 are 
ta ke n u p i n t he b o d y a n d h o w well BI 8 9 4 4 1 6 is t olerate d
Cli nic al P h ase:
I
Tri al Cli nic al M o nit or:
P h o ne:
Fa x: 
Pri nci p al I n vesti g at or:
P h o ne:
Fa x: 
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 8 ))
Versi o n a n d D ate:
Versi o n : 9. 0
Date : 2 5 J ul 2 0 1 8
P a ge 1 of 1 2 2
Pr o priet ar y c o nfi de nti al i nf or m ati o n
© 2 0 1 8 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
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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
N a m e of c o m p a n y:
T a b ul ate d
Tri al Pr ot oc ol
B oe hri n ger I n gel hei m
N a m e of fi nis he d pr o d uct:
N ot a p plica ble
N a m e of acti ve i n gre die nt:
BI 8 9 4 4 1 6
Pr ot oc ol d ate:
Tri al n u m ber:
Re visi o n d ate:
2 5 J U L 2 0 1 8
0 9 A U G 2 0 1 7
1 3 7 1 -0 0 0 1
Title of tri al:
Safet y, t olera bilit y, p har mac o ki netics a n d p har mac o d y na mics of si n gle risi n g oral 
d oses of BI 8 9 4 4 1 6 i n healt h y male s u bjects (si n gle -bli n d, partiall y ra n d o mise d, 
place b o -c o ntr olle d parallel gr o u p desi g n)
Pri nci p al I n vesti g at or :
Tri al site:
Cli nic al p h ase:
I
O bjecti ve s:
T o i n vesti gate safet y, t olera bilit y, p har mac o ki netics a n d p har mac o d y na mics f oll o wi n g 
si n gle risi n g d oses of BI 8 9 4 4 1 6 , t o o btai n p har mac o ki ne tic data of BI 8 9 4 4 1 6 after 
a d mi nistrati o n as ta blet f or m ulati o n a n d t o i n vesti gate relati ve bi oa vaila bilit y of a 
ta blet f or m ulati o n as c o m pare d t o oral s ol uti o n
M e t h o d ol o g y:
1)
Si n gle risi n g d ose ( S R D) part: Si n gle -bli n d , partiall y ra n d o mise d wit hi n d ose 
gr o u ps, place b o -c o ntr olle d, parallel -gr o u p desi g n
2)
Relati ve bi oa vaila bilit y (rel B A) part: O pe n -la bel, ra n d o mise d t wo- wa y 
cr oss o ver f oll o we d b y a fi xe d se q ue nce desi g n
N o. of s u bjects: 
t ot al e ntere d:
7 6 *
e ac h tre at me nt:
1)
S R D part:
8 per d ose gr o u p ( 6 o n acti ve dr u g a n d 2 o n place b o) 
* A d diti o nal s u bjects ma y be e ntere d i n t he S R D part t o all o w testi n g of a d diti o nal 
d oses o n t he basis of e x perie nce gai ne d d uri n g t he trial c o n d uct (e. g. , preli mi nar y P K 
data), pr o vi de d t he pla n ne d a n d a p pr o ve d hi g hest d ose will n ot be e xcee de d. T h us, t he 
act ual n u m ber of s u bjects e ntere d i n t he S R D part ma y e xcee d 6 4 ( ma y e xcee d 76
s u bjects t otal e ntere d i nt o t he trial), b ut will n ot e xcee d 8 0 s u bjects e ntere d i n t he S R D 
part ( will n ot e xcee d 9 2 s u bjects t otal e ntere d).
2)
Rel B A part: 1 2 (all o n acti ve dr u g)
Di a g n osis :
N ot a p plica ble
M ai n criteri a
f or i ncl usi o n:
Healt h y ma le s u bjects, a ge of 1 8 t o 4 5 years, b o d y mass i n de x ( B MI) of 1 8. 5 t o 
2 9. 9 k g/ m 2

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
N a m e of c o m p a n y:
T a b ul ate d
Tri al Pr ot oc ol
B oe hri n ger I n gel hei m
N a m e of fi nis he d pr o d uct:
N ot a p plica ble
N a m e of acti ve i n gre die nt:
BI 8 9 4 4 1 6
Pr ot oc ol d ate:
Tri al n u m ber:
Re visi o n d ate:
2 5 J U L 2 0 1 8
0 9 A U G 2 0 1 7
1 3 7 1 -0 0 0 1
Test pr o d uct s:
1)
S R D part:
BI 8 9 4 4 1 6 as a p o w der f or oral s ol uti o n ( Pf O S  
 
2)
Rel B A part:
BI 8 9 4 4 1 6 as a ta blet f or m ulati o n ( 1 0 m g)
d ose:
1)
S R D part:
3 m g, 1 0 m g, 2 0 m g, 4 0 m g, 5 4 m g (i nteri m d ose
 
3 0 m g (i nteri m d ose  
), 7 0 m g, 
1 1 0 m g, 1 6 0 m g, 2 2 0 m g
2)
Rel B A part: 1 0 m g ( 1 ta blet; treat me nt X ; i n peri o d 1 or 2), 4 0 m g (4 ta blets; 
treat me nt Z ; i n peri o d 3) 
m o de of a d mi n.:
Oral wit h 2 4 0 m L of water after a n o ver ni g ht fast of at least 1 0 h
C o m p ar at or pr o d uct :
1)
S R D part: Place b o s ol uti o n
2)
Rel B A part: BI 8 9 4 4 1 6 as a p o w der f or oral s ol uti o n ( Pf O S  
 
d ose:
1)
S R D part: N ot a p plica ble
2)
Rel B A part: 1 0 m g (treat me nt Y ; i n peri o d 1 or 2)
m o de of a d mi n.:
Oral wit h 2 4 0 m L of water after a n o ver ni g ht fast of at least 1 0 h
D ur ati o n of tre at m e nt:
1)
S R D part: O ne s i n gle d ose per s u bject
2)
Rel B A part: O ne si n gle d ose per s u bject i n eac h treat me nt peri o d ( 3 si n gle 
d oses i n t otal
 
Criteri a f or
p h ar m ac o ki netics:
1)
S R D part:
Sec o n dar y e n d p oi nts: A U C 0- ∞a n d C ma x of BI 8 9 4 4 1 6
 
 
2)
Rel B A part:
Sec o n dar y e n d p oi nts: A U C 0-tz, A U C 0- ∞a n d C ma x of  BI 8 9 4 4 1 6
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
N a m e of c o m p a n y:
T a b ul ate d
Tri al Pr ot oc ol
B oe hri n ger I n gel hei m
N a m e of fi nis he d pr o d uct:
N ot a p plica ble
N a m e of acti ve i n gre die nt:
BI 8 9 4 4 1 6
Pr ot oc ol d ate:
Tri al n u m ber:
Re visi o n d ate:
2 5 J U L 2 0 1 8
0 9 A U G 2 0 1 7
1 3 7 1 -0 0 0 1
 
 
 
Criteri a f or s afet y:
1)
S R D part:
Pri mar y e n d p oi nt t o as sess safet y a n d t olera bilit y of BI 8 9 4 4 1 6 is t he n u m ber [ N ( %)] 
of s u bjects wit h dr u g -relate d a d verse e ve nts.
2)
Rel B A part:
St atistic al m et h o ds:
1)
S R D part:
Descri pti ve statistics f or safet y, P K 
will be 
calc ulate d.
2)
Rel B A part:
Relati ve bi oa vaila bilit y will be esti mate d b y t he rati os of t he ge o metric mea ns (t a blet 
1 0 m g / Pf O S 1 0 m g ) f or t he sec o n dar y e n d p oi nts. A d diti o nall y, t he t wo- si de d 9 0 % 
c o nfi de nce i nter vals ( CIs) will be pr o vi de d. T his met h o d c orres p o n ds t o t he t w o o ne -
si de d t-tests pr oce d ure, eac h at t he 5 % si g nifica nce le vel. Si nce t he mai n f oc us is o n 
esti mati o n a n d n ot testi n g, a n acce pta nce ra n ge was n ot s pecifie d. T he statistical 
m o del will be a n A N O V A o n t he l o garit h mic scale i ncl u di n g effects f or ‘ se q ue nce’, 
‘s u bjects neste d wit hi n se q ue nces’, ‘ peri o d’ a n d ‘treat me nt’. CIs will be calc ulate d 
base d o n t he resi d ual err or fr o m A N O V A.
Descri pti ve statistics will be calc ulate d f or all e n d p oi nts.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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
T A B L E O F C O N T E N T S ...................................................................................9
2.
R A TI O N A L E, O B J E C TI V E S, A N D B E N E FI T - RI S K 
A S S E S S M E N T ......................................................................................... 2 6
2. 1
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 ........................................2 6
2. 1. 4
E x pl or ati o n of rel ati ve bi o a v ail a bilit y ................................................3 3
2. 2
T RI A L O B J E C TI V E S .......................................................................................3 3

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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 .............. 4 3
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 ......................................................4 3
3. 1. 1
A d mi nistr ati ve str uct ure of t he tri al ...................................................4 7
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 ..........................................................................................4 8
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 ......................................................4 9
3. 3. 1
M ai n di a g n osis f or st u d y e ntr y
............................................................4 9
3. 3. 2
I ncl usi o n criteri a...................................................................................4 9
3. 3. 3
E xcl usi o n criteri a ..................................................................................4 9
3. 3. 4
Re m o v al of s u bjects fr o m t her a p y or assess me nts .............................5 1
3. 3. 4. 1
Re m o val of i n di vi d ual s u bjects................................................ 5 1
3. 3. 4. 2
Disc o nti n uati o n of t he trial b y  t he s p o ns or..............................5 2
3. 3. 5
Re pl a ce me nt of s u bjects .......................................................................5 2
4.
T R E A T M E N T S ........................................................................................ 5 3
4. 1
T R E A T M E N T S T O B E A D M I NI S T E R E D ....................................................5 3
4. 1. 1
I de ntit y of BI i n vesti g ati o n al pr o d uct a n d c o m p ar at or 
pr o d ucts .................................................................................................5 3
4. 1. 2
Met h o d of assi g ni n g s u bjects t o tre at me nt gr o u ps
............................5 5
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 s u bject .......5 5
4. 1. 5
Bli n di n g a n d pr oce d ures f or u n bli n di n g ............................................5 7
4. 1. 5. 1
Bli n di n g.................................................................................... 5 7
4. 1. 5. 2
Pr oce d ures f or e mer ge nc y  u n bli n di n g.....................................5 7
4. 1. 6
P ac k a gi n g, l a belli n g, a n d re- s u p pl y ....................................................5 7
4. 1. 7
St or a ge c o n diti o ns .................................................................................5 8
4. 1. 8
Dr u g acc o u nt a bilit y ..............................................................................5 8
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 ...............................................................................................5 9
4. 2. 1
Ot her tre at me nts a n d e mer ge nc y pr oce d ures ....................................5 9
4. 2. 2
Restricti o ns............................................................................................ 5 9
4. 2. 2. 1
Restricti o ns re gar di n g c o nc o mita nt treat me nt .........................5 9
4. 2. 2. 2
Restricti o ns o n diet a n d life st y le.............................................5 9
4. 3
T R E A T M E N T C O M P LI A N C E .......................................................................6 0
5.
V A RI A B L E S A N D T H EI R A S S E S S M E N T ......................................... 6 1
5. 1
E F FI C A C Y - C LI NI C A L P H A R M A C O L O G Y............................................. 6 1
5. 1. 1
E n d p oi nts of effic ac y................................ .............................................6 1
5. 1. 2
Assess me nt of effic ac y ...........................................................................6 1
5. 2
S A F E T Y ..............................................................................................................6 1
5. 2. 1
E n d p oi nts of s afet y ................................................................................6 1
5. 2. 2
Assess me nt of a d verse e ve nts ...............................................................6 2
5. 2. 2. 1
Defi niti o ns of a d verse e ve nts................................................... 6 2
5. 2. 2. 2
A d verse e ve nt c ollecti o n a n d re p orti n g................................... 6 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
5. 4
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 .............................................7 2
5. 5
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 ..................................................................................7 3
5. 5. 1
P h ar m ac o ki netic e n d p oi nts ..................................................................7 3
5. 5. 1. 1
Sec o n dar y  e n d p oi nts................................................................7 3
5. 5. 2
Met h o ds of s a m ple c ollecti o n
...............................................................7 4
5. 5. 2. 1
Plas ma sa m pli n g f or p har mac o ki netic a nalys is.......................7 4
 
5. 5. 3
A n al ytic al deter mi n ati o ns ....................................................................7 8
5. 5. 3. 1
A nal y tical deter mi nati o n of a nalyt e plas ma c o nce ntrati o n ......7 8
6.
I N V E S TI G A TI O N A L P L A N.................................................................. 8 0
6. 1
VI SI T S C H E D U L E ............................................................................................8 0
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 ................8 0
6. 2. 1
Scree ni n g peri o d ....................................................................................8 0
6. 2. 2
Tre at me nt peri o d(s) ..............................................................................8 1
6. 2. 3
E n d of tri al peri o d .................................................................................8 1
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 ......................................................................................... 8 2

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
7. 1 
S T A TI S TI C A L D E SI G N – M O D E L
...............................................................8 2
7. 1. 1
O bjecti ves ...............................................................................................8 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 ..............................................8 2
7. 3
P L A N N E D A N A L Y S E S ....................................................................................8 3
7. 3. 1
Pri m ar y a n al yses ...................................................................................8 3
7. 3. 2
Sec o n d ar y a n al yses ...............................................................................8 3
7. 3. 3
S afet y a n al yses .......................................................................................8 5
7. 3. 4
Preli mi n ar y a n al yses .............................................................................8 6
7. 3. 5
P h ar m ac o ki netic a n al yses ....................................................................8 7
7. 4
H A N D LI N G O F MI S SI N G D A T A ..................................................................8 8
7. 4. 1
S afet y ......................................................................................................8 8
7. 4. 2
Pl as m a 
 dr u g c o nce ntr ati o n - ti me pr ofiles ...............................8 8
7. 4. 3
P h ar m ac o ki netic p ar a meters ...............................................................8 8
7. 5
R A N D O MI S A TI O N ..........................................................................................8 9
7. 6
D E T E R MI N A TI O N O F S A M P L E SI Z E ........................................................8 9
8.
I N F O R M E D C O N S E N T, D AT A P R O T E C TI O N, T RI A L
R E C O R D S ................................................................................................ 9 1
8. 1
S T U D Y A P P R O V A L, S U B J E C T I N F O R M A TI O N, A N D I N F O R M E D 
C O N S E N T ..........................................................................................................9 1
8. 2
D A T A Q U A LI T Y A S S U R A N C E .....................................................................9 1
8. 3
R E C O R D S ..........................................................................................................9 2
8. 3. 1
S o urce d oc u me nts .................................................................................9 2
8. 3. 2
Direct access t o s o urce d at a a n d d oc u me nts................................ .......9 2
8. 3. 3
St or a ge peri o d of rec or ds..................................................................... 9 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 .................................9 3
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 .......................................................9 3
8. 6
C O M P L E TI O N O F T RI A L ..............................................................................9 3

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
2.
R A TI O N A L E, O B J E C TI V E S, A N D B E N E FI T - RI S K 
A S S E S S M E N T
2. 1
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
T his First -i n-Ma n trial is i nte n de d t o start t he cli nical de vel o p me nt of BI 8 9 4 4 1 6  
 
S i n gle-risi n g d ose ( S R D) part
Effects of si n gle risi n g d oses of BI 8 9 4 4 1 6 o n safet y , t olera bilit y, p har mac o ki netics, a n d 
 will be assesse d i n healt h y male v ol u nteers. Wit hi n eac h d ose gr o u p, all 
acti vel y treate d i n di vi d uals will recei ve t he sa me d ose of BI 8 9 4 4 1 6. T he ne xt hi g her d ose 
will o nl y  be a d mi nistere d if t he treat me nt i n t he prece di n g gr o u p was safe a n d s h o we d 
acce pta ble t olera bilit y a n d if t he esti mate d s yste mic e x p os ure of t he ne xt d ose ( g ui de d by 
preli mi nar y  P K a nal ys es) d oes n ot e xcee d t he ma xi m u m acce pta ble sys te mic e x p os ure (f or 
details see Secti o ns 2. 1. 2 , 2. 1. 3 , 3. 1 , 3. 3. 4. 2 a n d 7. 3. 4 ).
Rel ati ve bi oa vaila bilit y (rel B A) part
Oral s ol uti o n f or m ulati o n of BI 8 9 4 4 1 6 is use d i n t he S R D part of t he c urre nt trial, w hereas 
f urt her cli nical trials wit h BI 8 9 4 4 1 6 are pla n ne d f or use wit h a ta blet f or m ulati o n. H o we ver, 
t he relati ve bi oa vaila bilit y of BI 8 9 4 4 1 6 as ta blet f or m ulati o n c o m pare d t o oral s ol uti o n is 
u n k n o w n. I t is n ot e xcl u de d, t hat bi oa vaila bilit y  of BI 8 9 4 4 1 6 as ta blet f or m ulati o n ma y 
differ fr o m oral s ol uti o n. T he ref ore it is re q uire d t o i n vesti gate relati ve bi oa vaila bilit y of 
BI 8 9 4 4 1 6 as ta blet f or m ulati o n i n c o m paris o n t o oral s ol uti o n, i n or der t o pla n t he d oses f or 
f urt her trials.
T he rel B A part will be d o ne after t he 7 0 m g d ose gr o u p was perf or me d i n t he S R D part.
I n t he rel B A part, all s u bjects will be treate d wit h 1 0 m g BI 8 9 4 4 1 6 as ta blet (treat me nt X ) 
a n d as oral s ol uti o n f or m ulati o n (treat me nt Y) i n a t w o-wa y  ra n d o mize d cr oss o ver fas hi o n i n 
visits 2 a n d 3 ( peri o ds 1 a n d 2, res pecti vel y). T he res ulti n g d ata will all o w assess me nt of 
relati ve bi oa vaila bility at  a d ose of 1 0 m g. 
A fter a nal ysis of preli mi nar y P K a n d safety data (see Secti o ns 3. 1 a n d7. 3. 4 ), t he s u bjects t hat 
partici pate i n t he rel B A part will be d ose d i n visit 4 ( peri o d 3) wit h 4 0 m g BI 8 9 4 4 1 6 as 
ta blets (treat me nt Z).
 
 
   
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 2 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
2. 1. 4
E x pl or ati o n of rel ati ve bi o a v ail a bilit y
F or t he rati o nale f or t he relati ve bi oa vaila bilit y  (rel B A) part, please refer t o Secti o n 2. 1 . 
F oll o wi n g t he 7 0 m g d ose gr o u p i n t he S R D part, rel B A will be e x pl ore d i n t he rel B A part. 
First, rel B A is i n vesti gate d i n t w o treat me nt peri o ds (treat me nt X: ta blet 1 0 m g; treat me nt Y : 
o ral s ol uti o n 1 0 m g) i n a n o pe n-la bel, t w o-wa y , ra n d o mize d cr oss o ver fas hi o n. 
T hereafter, s u bjects i n t he rel B A part will be tr eate d i n peri o d 3 wit h 4 0 m g BI 8 9 4 4 1 6 as 
ta blets (treat me nt Z), if all o we d after a nalys is of preli mi nar y P K a n d safety data (se e Secti o ns 
3. 1 a n d 7. 3. 4 ).
2. 2
T RI A L O B J E C TI V E S
T he pri mar y  o bjecti ve of t his trial is t o i n vesti gate t he safety a n d t olera bilit y of BI 8 9 4 4 1 6 i n 
healt h y  male s u bjects f oll o wi n g oral a d mi nistrati o n of si n gle risi n g d oses of 3 m g, 1 0 m g , 
2 0 m g , 4 0 m g, 7 0 m g, 1 1 0 m g, 16 0 m g, a n d 2 2 0 m g .
Sec o n dar y  o bjecti ves are t he e x pl orati o n of t he p har mac o ki netics ( P K) i ncl u di n g d ose 
pr o p orti o nalit y after si n gle d osi n g of BI 8 9 4 4 1 6 as oral s ol uti o n, t he i n vesti gati o n of P K of 
BI 8 9 4 4 1 6 as ta blet f or m ulati o n a n d t he e x pl orati o n of relati ve bi oa vaila bilit y of BI  8 9 4 4 1 6 
as ta blet f or m ulati o n c o m pare d t o oral s ol uti o n.
 
A descri pti o n of t he e n d p oi nts t o be deter mi ne d, a n d t he o bser vati o ns al o n g wit h s pecific 
i nf or mati o n as h o w t o c ollect t he data f or t hat i nf or mati o n, is pr o vi de d i n Secti o n 5 .
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 3 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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 h e si n gle-risi n g d ose part of t he trial is desi g ne d as si n gle-bli n d, partiall y  ra n d o mise d, a n d 
place b o - c o ntr olle d wit hi n parallel d ose gr o u ps.
T he relati ve bi oa vaila bilit y  (rel B A) part of t he trial is desi g ne d as o pe n-la bel, t w o-wa y  
cr oss o ver f oll o we d b y a fi xe d se q ue nce.
A t otal of 7 6 healt h y male s u bjects are pla n ne d t o partici pate i n t he trial, t here of 6 4 i n t he 
S R D part a n d 12 i n t he rel B A part. A d diti o nal d ose gr o u ps ma y be a d de d t o t he S R D part 
(see bel o w). T heref ore t he act ual n u m ber of s u bjects e ntere d i nt o t he trial ma y  e xcee d 76 , b ut 
will n ot e xcee d 9 2 s u bjects e ntere d.
S R D p art
A t otal of 6 4 healt h y male s u bjects is pla n ne d t o partici pate i n t he S R D trial part , acc or di n g t o 
8 se q ue ntial gr o u ps c o m prisi n g 8 s u bjects per gr o u p. H o we ver, a d diti o nal s u bjects ma y  be 
e ntere d t o all o w testi n g of a d diti o nal d oses o n t he basis of e x perie nce gai ne d d ur i n g t he trial 
c o n d uct (e. g. preli mi nar y P K data), pr o vi de d t he pla n ne d a n d a p pr o ve d hi g hest d ose will n ot 
be e xcee de d. T h us, t he act ual n u m ber of s u bjects e ntere d i nt o t he S R D part ma y  e xcee d 6 4,
b ut will n ot e xcee d 8 0 s u bjects e ntere d i n t he S R D part. S uc h c ha n ges m a y  be i m ple me nte d 
via n o n -s u bsta ntial C T P A me n d me nts.
Wit hi n eac h d ose gr o u p, 6 s u bjects are pla n ne d t o recei ve t he acti ve dr u g a n d 2 are pla n ne d t o
recei ve place b o. O nl y o ne d ose is teste d wit hi n eac h d ose gr o u p. Eac h d ose gr o u p will c o nsist 
of 3 c o h orts w hic h will be treate d s u bse q ue ntl y f or safet y reas o ns . T he 1 st a n d 2 n d c o h orts will 
be treate d i n a fi xe d se q ue nce a n d t he 3 r d c o h ort will be ra n d o mise d.
T he d ose gr o u ps t o be e val uate d i n t he S R D part are o utli ne d i n Ta ble 3. 1: 1 bel o w.
Ta ble 3. 1: 1
D ose gr o u ps of t he S R D part
D ose Gr o u p
1
2 
3 
4 
1 1 *
9 * *
5 
6 
7 
8
D ose [ m g]
3 
1 0 
2 0 
4 0 
5 4 
3 0 
7 0 
1 1 0
1 6 0 
2 2 0
N u m ber of s u bjects
8 
8 
8 
8 
8 
8 
8 
8 
8 
8
S u bjects recei vi n g place b o
2 
2 
2 
2 
2 
2 
2 
2 
2 
2
S u bjects recei vi n g acti ve dr u g
6 
6 
6 
6 
6 
6 
6 
6 
6 
6
* I nteri m d ose gr o u p a d de d wit h Gl o bal A me n d me nt N o. 4 f oll o wi n g d ose gr o u p 4 
 
* * I nteri m d ose gr o u p a d de d wit h Gl o bal A me n d me nt N o. 6 f oll o wi n g i nteri m d ose gr o u p 1 1 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
O n t he first st u d y  d a y of eac h d ose le vel of t he S R D part , t he 1st c o h ort will be treate d i n t he 
f oll o wi n g or der: F irst s u bject (acti ve) f oll o we d at least 10 mi n later by t he sec o n d s u bject 
( place b o).
T he 2 n d c o h ort will be treate d n ot earlier t ha n 22 h o urs later ( mi ni m u m ti me i nter val bet wee n 
1 st s u bject of 1 st c o h ort a n d 1 st s u bject of 2 n d c o h ort). I n t he 2 n d c o h ort, a ti me i nter val of at 
least 1 0 mi n will be mai ntai ne d bet wee n d osi n gs of i n di vi d ual s u bjects (acti ve – acti ve). 
T he 3 r d c o h ort will be treate d n ot earlier t ha n 4 6 h o urs later ( mi ni m u m ti me i nter val bet wee n 
1 st s u bject of 2 n d c o h ort a n d 1 st s u bject of 3 r d c o h ort). In t he 3 r d c o h ort, a ti me i nter val of at 
least 1 0 mi n will be mai ntai ne d bet wee n d osi n gs of i n di vi d ual s u bjects ( 3 acti ve, 1 place b o; 
ra n d o mize d or der). 
T he d ose gr o u ps of t he S R D part will be i n vesti gate d c o nsec uti vel y i n asce n di n g or der of 
d ose
 
T he decisi o n t o pr ocee d t o t he ne xt d ose gr o u p will be base d 
u p o n t he safet y, t olera bilit y , a n d p har mac o ki netic data of t he prece di n g d ose gr o u ps. T he ne xt 
d ose will o nl y  be gi ve n if, i n t he o pi ni o n of t he i n vesti gat or a n d t he trial cli nical m o nit or ( or 
a ut h orise d de p uties), n o safety c o ncer ns ar ose i n t he prece di n g d ose gr o u p (i.e. n o d ose -
li miti n g e ve nts occ urre d) a n d if n o ne of t he pre-s pecifie d trial-s pecific st o p pi n g criteria were 
met (refer t o Secti o n 3. 3. 4. 2 ).
A d oc u me nte d Safet y  Re vie w m ust ta ke place pri or t o eac h d ose escalati o n. F urt her m ore, a n 
u nsc he d ule d safet y re vie w meeti n g ca n be re q ueste d a n yt i me f or a n y reas o na ble ca use b y t he 
Pri nci pal I n vesti gat or ( or a n a ut h orise d de p ut y) or t he S p o ns or of t he st u d y,  e. g. beca use of 
a n y u nf oresee n a d verse e ve nts, etc. D ose escalati o n will o nl y be per mitte d if n o safety 
c o ncer ns e xist i n t he o pi ni o n of t he Pri nci pal I n vesti gat or ( or a n a ut h orise d de p ut y ) a n d t he 
trial cli nical m o nit or ( or a n a ut h orise d de p uty). 
 
 
 
     
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
T he i n vesti gat or is all o we d t o alter t he sc he d ule d d ose le vels (e. g. a d d l o w a n d/ or 
i nter me diate d ose le vels) o n t he basis of e x perie nce gai ne d d uri n g t he st u d y, pr o vi de d t he 
pla n ne d a n d a p pr o ve d hi g hest d os e is n ot e xcee de d . In t his case, t he t otal n u m ber of s u bjects 
i n t his trial mi g ht i ncrease. T he i n vesti gat or a n d/ or t he s p o ns or s h o ul d st o p d ose escalati o n i n 
case t he safet y e val uati o n lea ds t o c o ncer ns t hat w o ul d n ot all o w hi g her d osi n g.
A n o ver vie w of a ll rele va nt trial acti vities is pr o vi de d i n t he Fl o w C hart . F or visit sc he d ules 
a n d details of trial pr oce d ures at selecte d visits, refer t o Secti o ns 6. 1 a n d 6. 2 , res pecti vely.
Rel B A p art
A t otal of 12 healt h y male s u bjects is pla n ne d t o partici pate i n t he rel B A trial part. 
T he rel B A trial part will be starte d (i.e., d osi n g i n rel B A part will be starte d) after 
a vaila bilit y of preli mi nar y P K a n d safety data of t he 7 0 m g d ose gr o u p of t he S R D trial part.
T he rel B A part c o nsists of t hree treat me nt peri o ds, a n d all e ntere d s u bjects are pla n ne d t o 
partici pate at all t hree treat me nt peri o ds . Treat me nts are o pe n -la bel. I n peri o ds 1 a n d 2, t he 
s u bjects will recei ve t he treat me nts X ( o ne si n gle d ose of 1 0 m g BI 8 9 4 4 1 6, ta blet 
f or m ulati o n, fasti n g c o n diti o ns) a n d Y ( o ne si n gle d ose of 1 0 m g BI 8 9 4 4 1 6, oral s ol uti o n 
f or m ulati o n, fasti n g c o n diti o ns) i n a ra n d o mize d t w o-wa y  cr oss o ver fas hi o n. T hese t w o 
peri o ds are f oll o we d, after d oc u me nte d re vie w of P K a n d safet y data of peri o ds 1 a n d 2 of t he 
rel B A part, by treat me nt Z ( o ne si n gle d ose of 4 0 m g BI 8 9 4 4 1 6 , ta blet f or m ulati o n, fasti n g 
c o n diti o ns). 
T he s u bjects will be ra n d o ml y  all ocate d t o t he t w o treat me nt se q ue nces ( X - Y-Z or Y- X- Z ).
 
 
 
T he decisi o n t o start treat me nt i n t he rel B A part (i.e. t o a d mi nister treat me nt i n peri o d 1) will 
be base d u p o n t he safet y,  t olera bilit y, a n d p har mac o ki netic data of t he a vaila ble d ose gr o u ps 
of t he S R D part i ncl u di n g als o t he 7 0 m g d ose gr o u p. 
T he decisi o n t o a d mi nister treat me nt i n peri o d 3 of t he rel B A part will be base d u p o n t he 
safety, t olera bilit y, a n d p har mac o ki netic data of t he S R D part i ncl u di n g als o t he 7 0 m g d ose 
gr o u p a n d of peri o ds 1 a n d 2 of t he rel B A part. 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Treat me nt i n t he rel B A part (i.e. treat me nt i n peri o d 1) will o nl y  be starte d if, i n t he o pi ni o n 
of t he i n vesti gat or a n d t he trial cli nical m o nit or ( or a ut h orise d de p uties) , n o safety c o ncer ns 
ar ose i n t he prece di n g d ose gr o u p s of t he S R D part (i.e. n o d ose-li miti n g e ve nts occ urre d) 
a n d if n o ne of t he pre-s pecifie d trial-s pecific st o p pi n g criteria were met (refer t o Secti o n 
3. 3. 4. 2 ).
Treat me nt i n peri o d 3 of t he rel B A part will o nl y be starte d if, i n t he o pi ni o n of t he 
i n vesti gat or a n d t he trial cli nical m o nit or ( or a ut h orise d de p uties) , n o safet y c o ncer ns ar ose i n 
t he prece di n g d ose gr o u ps of t he S R D part or i n peri o ds 1 a n d 2 of t he rel B A part (i.e. n o 
d ose -li miti n g e ve nts occ urre d) a n d if n o ne of t he pre-s pecifie d trial-s pecific st o p pi n g criteria 
were met (refer t o Secti o n 3. 3. 4. 2).
If it is deci de d, base d o n t he criteria a b o ve, t hat treat me nt i n peri o d 3 is n ot gi ve n, n o f urt her 
pr oce d ures i n peri o d 3 are t o be d o ne; 
 
 
A d oc u me nte d Safet y  Re vie w m ust ta ke place pri or t o starti n g treat me nt i n t he rel B A part i n 
peri o ds 1 a n d 3 . F urther m ore, a n u nsc he d ule d safet y  re vie w meeti n g ca n be re q ueste d 
a n yti me f or a n y reas o na ble ca use b y t he Pri nci pal I n vesti gat or ( or a n a ut h orise d de p ut y) or 
t he S p o ns or of t he st u d y , e. g. beca use of a n y u nf oresee n a d verse e ve nts, etc. Treat me nt s will 
o nl y  be starte d if n o safet y c o ncer ns e xist i n t he o pi ni o n of t he Pri nci pal In vesti gat or ( or a n 
a ut h orise d de p ut y) a n d t he trial cli nical m o n it or ( or a n a ut h orise d de p ut y). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
T he i n vesti gat or a n d/ or t he s p o ns or s h o ul d deci de t o st o p treat me nt of s u bjects i n t he rel B A 
part i n case t he safet y e val uati o n lea ds t o c o ncer ns.
A n o ver vie w of all rele va nt trial acti vities is pr o vi de d i n t he Fl o w C hart . F or visit sc he d ules 
a n d details of trial pr oce d ures at selecte d visits, refer t o Secti o ns 6. 1 a n d 6. 2 , res pecti vely.
3. 1. 1
A d mi ni str ati ve str uct ure of t he tri al
T he trial is s p o ns ore d b y B oe hri n ger I n gel hei m ( BI) P har ma G m b H & C o. K G, Ger ma n y.
BI has a p p oi nte d a Trial Cli nical M o nit or, 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 na 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 l ocal cli nical m o nit ors ( C M L), Cli nical 
Researc h Ass ociate s ( C R As), a n d partici pati n g trial sites.
T he trial me dicati o n will be pr o vi de d b y t he Cli nical Trial S u p plies U nit ( C T S U), BI P har ma 
G m b H & C o. K G, Bi berac h, Ger ma n y.
T he trial will be c o n d ucte d at t he H u ma n P har mac ol o g y  Ce ntre ( H P C) of BI P har ma G m b H 
& C o. K G, Bi berac h, Ger ma n y , u n der t he s u per visi o n of t he Pri nci pal I n vesti gat or.
Safet y  la b orat or y tests will be perf or me d by t he l ocal la b orat or y of t he trial site (
 
T he a nal ys es of BI  8 9 4 4 1 6 c o nce ntrati o ns i n plas ma 
 will be perf or me d at 
 
 
 
 
 
T he di gitall y rec or de d 1 2 -lea d E C Gs will be se nt t o a s pecialise d c o ntract researc h 
or ga nisati o n (
) f or e val uati o n.
O n -site m o nit ori n g will be perf or me d by BI or a c o ntract researc h or ga nisati o n a p p oi nte d b y  
BI.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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.
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
F or si n gle -risi n g d ose trials, t he desi g n descri be d i n Secti o n 3. 1 is vie we d fa v o ura ble u n der 
t he pr o visi o n n ot t o e x p ose t he s u bjects i n v ol ve d t o u n d ue ris ks si nce t he mai n st u d y 
o bjecti ve is t o i n vesti gate safet y a n d t olera bilit y o f BI 8 9 4 4 1 6 .
Wit h t he risi n g d ose desi g n, si n gle -bli n d c o n diti o ns re gar di n g t he s u bject’s treat me nt (acti ve 
or place b o) are mai ntai ne d wit hi n eac h d ose gr o u p. H o we ver, t he c urre nt d ose le vel will be 
k n o w n t o s u bjects a n d i n vesti gat ors. T he disa d va nta ge of t his trial desi g n is a p ossi ble 
o bser ver bias wit h re gar d t o t he d ose -de pe n di n g effects as well as ti me effects, b ut it has t he 
virt ue of mi ni mizi n g s u bject ris k by se q ue ntiall y st u d y i n g asce n di ng d oses. As ti me effects 
are e x pecte d t o be s mall relati ve t o t he differe nces bet wee n t he d oses i n t he ra n ge 
i n vesti gate d, u n biase d c o m paris o ns bet wee n treat me nts ca n still be e x pecte d.
It is sta n dar d i n trials i n v ol vi n g healt h y v ol u nteers t o i ncl u de a place b o gr o u p as c o ntr ol f or 
t he e val uati o n of safety, t olera bil it y a n d p har mac o d yna mic effects. Eac h d ose gr o u p c o nsists 
of 8 s u bjects wit h 6 o n acti ve treat me nt, a n d 2 o n place b o. T he place b o c o ntr ol gr o u p 
i ncl u des all s u bjects of all d ose gr o u ps treate d wit h place b o. 6 s u bjects per acti ve treat me nt 
gr o u p are i n ge ne ral c o nsi dere d as s ufficie nt f or t he e x pl orat or y e val uati o n of 
p har mac o ki netics. 
F or t he rel B A part, t hat is desi g ne d t o assess relati ve bi oa vaila bilit y  of ta blet vs. oral s ol uti o n 
f or m ulati o n at a d ose of 1 0 m g BI 8 9 4 4 1 6 a n d t o o btai n p har mac o ki netic da ta at a d ose of
4 0 m g BI 8 9 4 4 1 6 as ta blet f or m ulati o n, t he cr oss o ver desi g n is vie we d fa v o ura ble d ue t o its 
efficie nc y: si nce eac h s u bject ser ves as his o w n c o ntr ol, t he c o m paris o n bet wee n t he 
treat me nts is base d o n a c o m paris o n wit hi n s u bjects rat her t ha n bet wee n s u bjects. T h us t he 
i nter-s u bject varia bilit y is re m o ve d fr o m t he c o m paris o n bet wee n treat me nts [R 9 4 - 1 5 2 9]. T he 
first t w o peri o ds t hat c o m pare 1 0 m g oral s ol uti o n wit h 1 0 m g ta blet f oll o w a t w o-w a y
ra n d o mize d cr oss o ver desi g n, a n d t he t hir d treat me nt peri o d, 4 0 m g BI 8 9 4 4 1 6 as ta blets, 
f oll o ws i n a fi xe d-se q ue nce cr oss o ver desi g n. S u bjects will o nl y be treate d i n t he t hir d 
treat me nt peri o d if all o we d after a nalys is of preli mi nar y P K a n d safet y data of t he prece di n g 
peri o ds . T his desi g n is c h ose n t o e ns ure t hat g Mea n plas ma e x p os ure val ues of BI 8 9 4 4 1 6 i n 
ter ms of Cma x a n d A U C 0- 2 4 i n t he rel B A part d o n ot e xcee d g M ea n plas ma e x p os ure val ues i n 
ter ms of Cma x a n d A U C 0- 2 4 t hat were o bser ve d pre vi o usl y  i n t he S RD part of t he tr ial a n d t hat 
were ass ociate d wit h acce pta ble safet y a n d t olera bilit y . Treat me nts i n t he rel B A part are 
o pe n -la bel, as treat me nts are disti n g uis ha ble a n d P K para meters are n ot e x pecte d t o be 
i nfl ue nce d by k n o wle d ge of treat me nt.   

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 4 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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
It is pla n ne d t hat 7 6 healt h y  male s u bjects will e nter t he st u d y. T he act ual n u m ber of s u bjects 
e ntere d ma y e xcee d t he t otal of 7 6 if a d diti o nal i nter me diate d oses will be teste d i n t he S R D 
part (see Secti o n 3. 1 ), b ut will n ot e xcee d 9 2 s u bjects e ntere d. S u bjects will be recr uite d fr o m 
t he v ol u nteers' p o ol of t he trial site. 
 
 
A l o g of all s u bjects e nr olle d i nt o t he trial (i.e. ha vi n g gi ve n i nf or me d c o nse nt) will be 
mai ntai ne d i n t he I S F at t he i n vesti gati o nal site irres pecti ve of w het her t he y  ha ve bee n treate d 
wit h i n vesti gati o nal dr u g or n ot.
3. 3. 1
M ai n di a g n osis f or st u d y e ntr y 
T he st u d y  will be perf or me d i n healt h y s u bjects.
3. 3. 2
Incl usi o n criteri a
S u bjects will o nl y  be i ncl u de d i nt o t he trial, if t he y meet t he f oll o wi n g criteria:
1.
Healt h y male s u bjects acc or di n g t o t he assess me nt of t he i n vesti gat or , base d o n a 
c o m plete me dical hist or y i ncl u di n g a p h y sical e xa mi nati o n, vital si g ns ( B P, P R), 1 2-lea d 
E C G, a n d cli nical la b orat or y tests 
2.
A ge of 1 8 t o 4 5 ye ars (i ncl.)
3.
B MI  of 1 8. 5 t o 2 9. 9 k g/ m 2 (i ncl.)
4.
Si g ne d a n d date d writte n i nf or me d c o nse nt pri or t o a d missi o n t o t he st u d y  i n acc or da nce 
wit h G C P a n d l ocal le gislati o n
3. 3. 3
E xcl usi o n criteri a
S u bjects will n ot be all o we d t o partici pate if a n y of t he f oll o wi n g ge neral criteria a p pl y :
1.
A n y  fi n di n g i n t he me dical e xa mi nati o n (i ncl u di n g B P, P R or E C G a n d i ncl u di n g t he 
ne ur ol o gical e xa mi nati o n ) is de viati n g fr o m n or mal a n d j u d ge d as cli nicall y rele va nt b y 
t he i n vesti gat or
2.
Re peate d meas ure me nt of s y st olic bl o o d press ure o utsi de t he ra n ge of 9 0 t o 1 4 0 m m H g, 
diast olic bl o o d press ure o utsi de t he ra n ge of 5 0 t o 9 0 m m H g, or p ulse rate o utsi de t he 
ra n ge of 5 0 t o 9 0 b p m
3.
A n y  la b orat or y val ue o utsi de t he refere nce ra n ge t hat t he i n vesti gat or c o nsi ders t o be of 
cli nical rele va nce
4.
A n y  e vi de nce of a c o nc o mita nt disease j u d ge d as cli nicall y rele va nt b y t he i n vesti gat or
5.
Gastr oi ntesti nal, he patic, re nal, res pirat or y , car di o vasc ular, meta b olic, i m m u n ol o gical or 
h or m o nal dis or ders

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
6.
C h olec y stect o m y a n d/ or sur ger y  of t he gastr oi ntesti nal tract t hat c o ul d i nterfere wit h t he 
p har mac o ki netics of t he trial me dicati o n (e xce pt a p pe n dect o my a n d si m ple her nia re pair)
7.
Diseases of t he ce ntral ner v o us s yste m (i ncl u di n g b ut n ot li mite d t o a n y ki n d of seiz ures 
or str o ke), a n d ot her rele va nt ne ur ol o gical or ps yc hiatric dis or ders
8.
Hist or y  of rele va nt ort h ostatic h yp ote nsi o n, fai nti n g s pells, or blac k o uts
9.
C hr o nic or rele va nt ac ute i nfecti o ns
1 0. Hist or y  of rele va nt aller g y or h y perse nsiti vit y  (i ncl u di n g aller g y t o t he trial me dicati o n or 
its e xci pie nts) 
1 1. U se of dr u gs wit hi n 3 0 da y s pri or t o a d mi nistrati o n of trial me dicati o n if t hat mi g ht 
reas o na bly i nfl ue nce t he res ults of t he trial (i ncl. Q T/ Q Tc i nter val pr ol o n gati o n)
1 2. Partici pati o n i n a n ot her trial w here a n i n vesti gati o nal dr u g has bee n a d mi nistere d wit hi n 
6 0 da y s pri or t o pla n ne d a d mi nistrati o n of trial me dicati o n, or c urre nt partici pati o n i n 
a n ot her trial i n v ol vi n g a d mi nistrati o n of i n ves ti gati o nal dr u g
1 3. S m o ker ( m ore t ha n 1 0 ci garettes or 3 ci gars or 3 pi pes per d a y ); 
1 4. I na bilit y t o refrai n fr o m s m o ki n g o n s pecifie d trial da ys
1 5. Alc o h ol a b use ( c o ns u m pti o n of m ore t ha n 3 0 g per da y )
1 6. Dr u g a b use or p ositi ve dr u g scree n i n g
1 7. Bl o o d d o nati o n of m ore t ha n 1 0 0 m L wit hi n 3 0 da ys pri or t o a d mi nistrati o n of trial 
me dicati o n or i nte n de d d o nati o n d uri n g t he trial
1 8. I nte nti o n t o perf or m excessi ve p h y sical acti vities wit hi n o ne wee k pri or t o a d mi nistrati o n 
of trial me dicati o n or d uri n g t he trial
1 9. I na bilit y t o c o m pl y wit h dietar y re gi me n of trial site
2 0. A mar ke d baseli ne pr ol o n gati o n of Q T/ Q Tc i nter val ( s uc h as Q Tc i nter val s t hat are 
re peate dl y greater t ha n 4 5 0 ms) or a n y ot her rele va nt E C G fi n di n g at scree ni n g
2 1. A hist or y  of a d diti o nal ris k fact ors f or Torsa de s de P oi ntes (s uc h as heart fail ure, 
h y p o kal emia, or fa mil y hist or y of L o n g Q T S yn dr o me)
2 2. S u bject is assesse d as u ns uita ble f or i ncl usi o n b y  t he i n vesti gat or, f or i nsta nce, beca use 
c o nsi dere d n ot a ble t o u n dersta n d a n d c o m pl y  wit h st u d y re q uire me nts, or has a co n diti o n 
t hat w o ul d n ot all o w safe partici pati o n i n t he st u d y 
I n a d diti o n, t he f oll o wi n g trial-s pecific e xcl usi o n criteria a p ply:
2 3. Hist or y  of rele va nt ne ur ol o gical disor der affecti n g t he peri p heral or ce ntral ner v o us 
s yste m (this i ncl u des, b ut is n ot li mite d t o: str o ke, e pile ps y, i nfla m mat or y or atr o p hic 
diseases affecti n g t he ner v o us s y ste m, cl uster hea dac he or a n y ca ncer of t he ner v o us 
s yste m) *
2 4. Hist or y  of i m m u n ol o gical disease e xce pt aller g y n ot rele va nt t o t he trial (s uc h as mil d ha y
fe ver or d ust mite aller g y) a n d e xce pt ast h ma i n c hil d h o o d or a d olesce nce
2 5. Hist or y  of ca ncer ( ot her t ha n s uccessf ull y treate d basal cell carci n o ma)
2 6. Wit hi n 1 0 da y s pri or t o a d mi nistrati o n of trial me dicati o n, use of a n y dr u g t hat c o ul d 
reas o na bly i n hi bit platelet a g gre gat i o n or c oa g ulati o n (e. g., acet ylsalic ylic aci d)

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
2 7. Male s u bjects wit h W O C B P part ner w h o are u n willi n g t o use male c o ntrace pti o n 
(c o n d o m or se x ual a bsti ne nce) fr o m ti me p oi nt of a d mi nistrati o n of trial me dicati o n u ntil 
3 0 da y s t hereafter.
* F e brile seiz ures i n c hil d h o o d or a d olesce nce, rec o vere d car pal t u n nel sy n dr o me, rec o vere d 
u nc o m plicate d me ni n gitis, rec o vere d her pes z oster, te nsi o n hea dac he, occasi o nal be ni g n tics 
(e. g. d ue t o stress) or mi n or par- or d y sest hesia (e. g. as a si de effect of pri or bl o o d 
wit h dra wal) d o n ot c o nstit ute a hist or y  of rele va nt ne ur ol o gical dis or der.
F or st u d y restricti o ns, refer t o Secti o n 4. 2 . 2.
3. 3. 4  
Re m o v al of s u bjects fr o m t her a p y or assess me nts
3. 3. 4. 1
Re m o val of i n di vi d ual s u bjects
A n i n di vi d ual s u bject is t o be re m o ve d fr o m t he trial if:
1.
T he s u bject wit h dra ws c o nse nt f or trial treat me nt or trial partici pati o n, wit h o ut t he nee d t o 
j ustif y t he decisi o n
2.
T he s u bject nee ds t o ta ke c o nc o mita nt dr u gs t hat i nte rfere wit h t he i n vesti gati o nal  
pr o d uct or ot her trial me dicati o n
3.
T he s u bject is n o l o n ger a ble t o partici pate f or ot her me dical reas o ns ( s uc h as s ur ger y, 
a d verse e ve nts ( A Es), or diseases)
4.
T he s u bject s h o ws a n ele vati o n of A S T a n d/ or A L T ≥3 -f ol d 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 sa m ple) a n d/ or 
nee ds 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.
I n a d diti o n t o t hese criteria, t he p h ysicia n ma y disc o nti n ue s u bjects at a n y ti me base d o n his 
or her cli nical j u d g me nt.
A s u bject ca n als o be re m o ve d fr o m t he trial if eli gi bilit y criteria are bei n g vi olate d or if t he 
s u bject fails t o c o m pl y wit h t he pr ot oc ol (f or i nsta nce, by n o n- a d here nce t o dietar y r ules, or 
n o n- atte n da nce at st u d y assess me nts).
If a s u bject is re m o ve d fr o m or wit h dra w s fr o m t he trial pri or t o a d mi nistrati o n of trial 
me dicati o n , t he data of t his s u bject will n ot be e ntere d i n t he case re p ort f or m ( C R F ) or trial 
data base a n d will n ot be re p orte d i n t he cli nical trial re p ort ( C T R). 
If a s u bject is re m o ve d fr o m or wit h dra ws fr o m t he trial after first a d mi nistrati o n of trial 
me dicati o n , t his will be d oc u me nte d a n d t he reas o n f or disc o nti n uati o n m ust be rec or de d i n 
t he C R F . I n t his case, t he data will be i ncl u de d i n t he C R F/trial data base a n d will be re p orte d
i n t he C T R. At t he ti me of disc o nti n uati o n a c o m plete e n d of trial e xa mi nati o n will be 
perf or me d if p ossi ble a n d t he i nf or mati o n will be rec or de d i n t he C R Fs. T h ese 
disc o nti n uati o ns will be disc usse d i n t he C T R .

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
3. 3. 4. 2
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 a n y of t he f oll o wi n g reas o ns:
1.
Ne w t o xic ol o gical fi n di n gs or seri o us a d verse e ve nts i n vali date t he earlier p ositi ve 
be nefit -ris k assess me nt. M ore s pecifically, t he trial will be ter mi nate d if m ore t ha n 5 0 % 
of t he acti vel y d ose d s u bjects at o ne d ose le vel s h o w dr u g-relate d a n d cli nicall y rele va nt 
a d verse e ve nts of m o derate or se vere i nte nsit y , or if at least o ne dr u g-relate d seri o us 
a d verse e ve nt is re p orte d.
2.
T he e x pecte d e nr ol me nt g oals o verall or at a partic ular trial site are n ot met
3.
Vi olati o n of G C P or t he C T P b y  a trial site or i n vesti gat or, dist ur bi n g t he a p pr o priate 
c o n d uct of t he trial
4.
T he s p o ns or deci des t o disc o nti n ue t he f urt her de vel o p me nt of t he i n vesti gati o nal 
pr o d uct.
5.
D ose escalati o n will be st o p pe d as s o o n as at least 2 s u bjects at o ne d ose le vel o n acti ve 
dr u g s h o we d rele va nt i n di vi d ual Q T pr ol o n gati o n, i.e. a bs ol ute Q T or Q Tc greater t ha n 
5 0 0 ms w hic h has bee n c o nfir me d b y  a re peat E C G rec or di n g or a Q Tc i ncrease of greater 
6 0 ms fr o m baseli ne i n c o n necti o n wit h a bs ol ute Q T or Q Tc greater t ha n 5 0 0 ms, w hic h 
has bee n c o nfir me d b y  a re peat E C G rec or di n g.
 
 
 
 
 
 
 
 
3. 3. 5
Re pl ace me nt of s u bjects
I n case t hat o ne d ose gr o u p i n t he S R D part of t his trial is c o m plete d b y  less t ha n 4 s u bjects 
o n acti ve treat me nt ( d ue t o e. g. dr o p-o uts or recr uit me nt reas o ns), or i n case t hat t he rel B A 
part of t his trial is c o m plete d b y less t ha n 8 s u bjects ( d ue t o e. g. dr o p -o uts or recr uit me nt 
reas o ns) t he trial cli nical m o nit or t o get her wit h t he trial p har mac o ki neticist a n d t he trial 
statisticia n are t o deci de if a n d h o w ma n y s u bjects will be re place d. A re place me nt s u bject 
will be assi g ne d a u ni q ue st u d y s u bject n u m ber, a n d will be assi g ne d t o t he sa me treat me nt or 
treat me nt se q ue nce as t he s u bject he re places.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
4.
T R E A T M E N T S
4. 1
T R E A T M E N T S T O B E A D M I NI S T E R E D
T he i n vesti gati o nal pr o d ucts ha ve bee n ma n ufact ure d b y  BI P har ma G m b H & C o. K G.
4. 1. 1
I de ntit y of BI i n vesti g ati o n al pr o d uct a n d c o m p ar at or pr o d uct s
S R D p art
T he c haracteristics of t he test pr o d uct are gi ve n bel o w :
S u bsta nce:
BI 8 9 4 4 1 6
P har mace utical f or m ulati o n : P o w der f or oral s ol uti o n
S o urce:
BI P har ma G m b H & C o. K G , Ger ma ny
P os ol o g y :
1- 0- 0
R o ute of a d mi nistrati o n:
p. o.
D urati o n of use:
Si n gle d ose
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Rel B A p art
T he c haracteristics of t he test pr o d uct of t he rel B A part are gi ve n bel o w:
S u bsta nce:
BI 8 9 4 4 1 6
P har mace utical f or m ulati o n: Ta blet
S o urce:
BI P har ma G m b H & C o. K G, Ger ma n y
U nit stre n gt h:
1 0 m g
P os ol o g y :
- 1- 0-0 (treat me nt X ) a n d
- 4- 0- 0 (treat me nt Z )
R o ute of a d mi nistrati o n:
p. o.
D urati o n of use:
O ne si n gle d ose per treat me nt
T he c haracteristics of t he refere nce pr o d uct of t he rel B A part are gi ve n bel o w:
S u bsta nce:
BI 8 9 4 4 1 6
P har mace utical f or m ulati o n: P o w der f or oral s ol uti o n
S o urce:
BI P har ma G m b H & C o. K G, Ger ma n y
P os ol o g y :
 ( 1 0 m g) - 0- 0 (treat me nt Y)
R o ute of a d mi nistrati o n:
p. o.
D urati o n of use:
Si n gle d ose
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
4. 1. 2
Met h o d of assi g ni n g s u bjects t o tre at me nt gr o u ps
Pri or t o t he scree ni n g visit , s u bjects will be c o ntacte d i n writi n g a n d i nf or me d a b o ut t he 
pla n ne d visit dates. 
T he s u bjects willi n g t o partici pate i n t he S R D part will be recr uite d t o d ose gr o u ps a n d 
c o h orts acc or di n g t o t heir te m p oral a vaila bilit y . As s o o n as e n o u g h s u bjects ha ve bee n 
all ocate d t o 1 of t he d ose c o h orts ( 3 c o h orts per d ose gr o u p), t he f oll o wi n g s u bjects will be 
all ocate d t o o ne of t he ot her d ose c o h orts. T heref ore, t he all ocati o n of s u bjects t o d ose 
c o h orts is n ot i nfl ue nce d b y  trial pers o n nel, b ut o nl y b y t he s u bjects’ te m p oral a vaila bilit y. As 
t he st u d y i ncl u des healt h y s u bjects fr o m a h o m o ge n o us p o p ulati o n, rele va nt i m bala nces 
bet wee n t he d ose gr o u ps are n ot e x pecte d. 
T he r a n d o misati o n list wit h st u d y  s u bject n u m bers a n d all ocate d treat me nts ( S R D part) or 
treat me nt se q ue nces (rel B A part) will be pr o vi de d t o t he trial site i n a d va nce. T he all ocati o n 
of s u bjects t o st u d y  s u bject n u m bers will be perf or me d pri or t o t he first a d mi nistrati o n of trial 
me dicati o n. F or t his p ur p ose, t he s u bjects will be all ocate d t o a st u d y  s u bject n u m ber b y 
dra wi n g l ots. O nce a s u bject n u m ber has bee n assi g ne d, it ca n n ot be reassi g ne d t o a n y ot her 
s u bject.
T he ra n d o misati o n pr oce d ure is descri be d i n Secti o n 7. 5 .
 
 
 
 
 
 
 
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 s u bject
T he treat me nts t o be e val uate d are o utli ne d i n Ta ble 4. 1. 4: 1 ( S R D part) a n d 4. 1. 4: 2 (rel B A 
part) bel o w. T he d ose v ol u me f or place b o i n t he S R D part c orres p o n ds t o t he d ose v ol u me of 
t he res pecti ve d ose le vel.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
T he oral s ol uti o ns f or d osi n g (acti ve dr u g a n d place b o) will be pre pare d acc or di n g t o t he 
i nstr ucti o n gi ve n i n A p pe n di x 1 0. 1 b y  p har macists or q ualifie d p har mac y staff me m bers or 
q ualifie d me dical st u d y pers o n nel at t he trial site u n der t he res p o nsi bilit y  of t he i n vesti gat or.
T he trial me dicati o n will be a d mi nistere d t o t he s u bjects, w hile i n a sitti n g or sta n di n g 
p ositi o n, as a n oral d ose t o get her wit h a b o ut 2 4 0 m L of water u n der s u per visi o n of t he 
i n vesti gati n g p hys icia n or a n a ut h orise d desi g nee. T he s o -calle d f o ur-e ye pri nci ple (t w o-
pers o n r ule) s h o ul d be a p plie d f or a d mi nistrati o n of trial me dicati o n a n d – if a p plica ble – its 
pre parati o n (e. g. rec o nstit uti o n), if c orrect d osa ge ca n n ot be e ns ure d ot her wise. 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
A d mi nistrati o n will be perf or me d f oll o wi n g a n o ver ni g ht fast, w hic h is t o start n o later t ha n 
1 0 h bef ore t he sc he d ule d d osi n g. 
 
 
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
T he treat me nts a d mi nistere d i n t he S R D part (acti ve or place b o) will be si n gle-bli n d (t hat is, 
s u bjects will n ot k n o w w het her t he y recei ve acti ve treat me nt or place b o). H o we ver, t he 
c urre nt d ose le vel will be k n o w n t o t he s u bjects. Treat me nts of t he rel B A part will be o pe n -
la bel beca use t he treat me nts are disti n g uis ha ble fr o m eac h ot her , a n d beca use k n o wle d ge of 
treat me nt is n ot e x pecte d t o i nfl ue nce P K para meters .
F or S R D part: Wit hi n t he ce ntral E C G la b, t he staff i n v ol ve d wit h i nter val meas ure me nts will 
be bli n de d wit h res pect t o t he treat me nt a n d als o wit h re gar d t o t he rec or di n g date a n d ti me as 
well as pla n ne d ti me p oi nts of t he E C Gs. T he i nter v al meas ure me nts f or a gi ve n s u bject will 
be perf or me d i n a ra n d o m a n d bli n de d se q ue nce b y  a si n gle tec h nicia n.
F or S R D part: If a n i nteri m safety a nal ys is of E C G data is re q uire d, a part of t he staff of t he 
ce ntral E C G la b ma y be u n bli n de d. T his part of t he staff will be strictl y se parate d fr o m t he 
bli n de d staff me m bers w h o are i n v ol ve d wit h E C G i nter val meas ure me nts a n d assess me nts of 
E C Gs.
F urt her m ore, t he trial bi oa nal ys t, t he trial bi o mar ker a nalys t, t he dr u g meta b olis m scie ntist
a n d trial p har mac o ki neticist ma y  recei ve t he ra n d o misati o n c o des t o perf or m t he preli mi nar y 
P K a nal y sis. He or s he will c o nfir m i n writi n g t hat t he c o des will be treate d c o nfi de ntiall y.
T he data base of t his trial will be ha n dle d o pe n -la bel, beca use n o bias wit h re gar d t o data
clea ni n g o f safety meas ures is e x pecte d.
4. 1. 5. 2
Pr oce d ures f or e mer ge nc y  u n bli n di n g
As t his trial will be c o n d ucte d si n gle-bli n d i n t he S R D part a n d o pe n-la bel i n t he rel B A part, 
t he treat me nt i nf or mati o n will be k n o w n t o t he i n vesti gat or ( S R D part) or t o b ot h i n vesti gat or 
a n d s u bjects (rel B A part) . T heref ore, n o e mer ge nc y e n vel o pes will be pr o vi 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
Dr u g s u p plies will be pr o vi de d b y  t he De part me nt of P har mace utical De vel o p me nt of 
B oe hri n ger I n gel hei m P har ma G m b H & C o. K G, Bi berac h, Ger ma n y .
T he cli nical trial s u p pl y c o nsists of c o ntai ners h ol di n g t he trial me dicati o n w h ic h are la belle d 
wit h trial i de ntificati o n. T he re q uire d i nf or mati o n acc or di n g t o t he Ger ma n Dr u g La w as well 
as A n ne x 1 3/ E U G M P G ui deli ne will be pr o vi de d o n t he c o ntai ners.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
S maller b o xes wit h i n t he cli nical trial s u p pl y c o ntai ners will be la belle d wit h:

BI trial n u m ber

Na me of pr o d uct a n d stre n gt hs or i de ntificati o n c o de

P har mace utical d osa ge f or m, q ua ntit y  of d osa ge u nits 

R o ute a n d m o de of a d mi nistrati o n

Ter m ‘ For C li nical T rial U se’ ( d o mestic la n g ua ge)

S p o ns or na me a n d a d dress

St ora ge c o n diti o ns

Use -b y  date

Me dicati o n
n u m ber (n ot a p plica ble f or ta blets)

Batc h n u m ber
T he tele p h o ne n u m ber of t he s p o ns or a n d na me, a d dress a n d tele p h o ne n u m ber of t he trial 
site are gi ve n i n t he s u bject i nf or mati o n f or m. T he E u dra C T n u m ber is i n dicate d o n t he title 
pa ge of t his pr ot oc ol as well as o n t he s u bject i nf or mati o n a n d i nf or me d c o nse nt f or ms. 
E xa m ples of t he la bels will be a vaila ble i n t he I S F.
4. 1. 7
St or a ge c o n diti o ns
Dr u g s u p plies will be ke pt i n t heir ori gi nal pac ka gi n g a n d i n a sec ure li mite d access st ora ge 
area acc or di n g t o t he rec o m me n de d (la belle d) st ora ge c o n diti o ns. W here necessar y, a 
te m perat ure l o g m ust be mai ntai ne d t o ma ke certai n t hat t he dr u g s u p plies are st ore d at t he 
c orrect te m perat ure. If t he st ora ge c o n diti o ns are f o u n d t o be o utsi de t he s pecifie d ra n ge, t he 
l ocal cli nical m o nit or (as pr o vi de d in t he list of c o ntacts) is t o be i m me diatel y c o ntacte d.
4. 1. 8
Dr u g acc o u nt a bilit y
T he i n vesti gat or will recei ve t he i n vesti gati o nal dr u gs deli vere d b y t he s p o ns or w he n t he 
f oll o wi n g re q uire me nts are f ulfille d:

A p pr o val of t he trial pr ot oc ol b y  t he I RB / et hics c o m mittee

A p pr o val / n otificati o n of t he re g ulat or y  a ut h orit y, e. g. c o m pete nt a ut h orit y

A vaila bilit y  of t he c urric ul u m vitae of t he pri nci pal i n vesti gat or

A vaila bilit y  of a si g ne d a n d date d cli nical trial pr ot oc ol  
O nl y  a ut h orise d pers o n nel as d oc u me nte d i n t he f or m ‘ Trial Staff List’ ma y dis pe nse 
me dicati o n t o trial s u bjects. T he trial me dicati o n m ust be a d mi nistere d i n t he ma n ner 
s pecifie d i n t he C T P. All u n use d me dicati o n will be dis p ose d l ocally b y t he trial site u p o n 
writte n a ut h orisati o n b y  t he cli nical m o nit or. Recei pt, usa ge a n d dis p osal m ust be 
d oc u me nte d o n t he res pecti ve f or ms. Acc o u nt m ust be gi ve n f or a n y discre pa ncies. 
T he i n vesti gat or m ust mai ntai n rec or ds of t he pr o d uct’s deli ver y  t o t he trial site, t he i n ve nt or y 
at t he site, t he use b y eac h s u bject, a n d t he dis p osal of u n use d pr o d ucts. 
T hese rec or ds will i ncl u de dates, q ua ntities, batc h / serial n u m bers, e x pir y  (‘ use-b y ’) dates, 
a n d t he u ni q ue c o de n u m bers assi g ne d t o t he i n vesti gati o nal pr o d ucts a n d trial s u bjects. T he 
i n vesti gat or will mai ntai n rec or ds t hat d oc u me nt a de q uatel y t hat t he s u bjects were pr o vi de d 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 5 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
t he d oses s pecifie d by t he C T P, a n d t hat rec o ncile all i n vesti gati o nal pr o d ucts recei ve d fr o m 
t he s p o ns or. At t he ti me of dis p osal, t he i n vesti gat or m ust verif y  t hat n o re mai ni n g s u p plies 
are i n t he i n vesti gat or’s p ossessi o n.
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
T here are n o s pecial e mer ge nc y  pr oce d ures t o be f oll o we d. N o a d diti o nal treat me nt is 
pla n ne d. H o we ver, i n case of a d verse e ve nts i n nee d of treat me nt, t he i n vesti gat or ca n 
a ut h orise s y m pt o matic t hera p y . I n t h ose cases, s u bjects will be treate d as necessar y a n d, if 
re q uire d, ke pt u n der s u per visi o n at t he trial site or tra nsferre d t o a h os pital u ntil all me dical 
e val uati o n res ults ha ve ret ur ne d t o a n acce pta ble le vel.
4. 2. 2  
Restricti o ns
4. 2. 2. 1 
R estricti o ns re gar di n g c o nc o mita nt treat me nt
I n pri nci ple, n o c o nc o mita nt t hera p y is all o we d . All c o nc o mita nt or resc ue t hera pies will be 
rec or de d (i ncl u di n g ti me of i nta ke o n st u d y d a ys) o n t he a p pr o priate pa ges of t he C R F.
 
 
 
 
 
  
4. 2. 2. 2
Restricti o ns o n diet a n d life st y le
P o p p y -see ds c o ntai ni n g f o o ds s h o ul d n ot be c o ns u me d starti n g 3 da ys bef ore trial dr u g 
a d mi nistrati o n u ntil t he last P K sa m pli n g of t he res pecti ve treat me nt peri o d.
W hile a d mitte d t o t he trial site t he s u bjects are restricte d fr o m c o ns u mi n g a n y  ot her f o o ds or 
dri n ks t ha n t h ose pr o vi de d b y  t he staff. Sta n dar dise d meals will be serve d at t he ti me p oi nts 
descri be d i n t he Fl o w C hart . N o f o o d is all o we d f or at least 4 h after dr u g i nta ke.
Fr o m 1 h bef ore dr u g i nta ke u ntil l u nc h, fl ui d i nta ke is restricte d t o t he water a d mi nistere d 
wit h t he dr u g, a n d a n a d diti o nal 2 4 0 m L  of water ser ve d at 2 h a n d 4 h p ost-d ose ( ma n dat or y  
f or all s u bjects). Fr o m l u nc h o n D a y 1 u ntil 2 4 h p ost-d ose, fl ui d i nta ke is restricte d t o 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
3 0 0 0 m L .
 
Gree n tea , gra pefr uits, Se ville ora n ges (s o ur or bitter ora n ges) a n d t heir j uices, a n d dietar y  
s u p ple me nts a n d pr o ducts i ncl u di n g St. J o h n's w ort ( H y peric u m perf orat u m) are n ot 
per mitte d starti n g 7 d a y s bef ore t he a d mi nistrati o n of trial me dicati o n u ntil after t he last P K 
sa m ple of t he res pecti ve treat me nt peri o d is c ollecte d.
Alc o h olic be vera ges are n ot all o we d starti n g 4 8 h bef ore trial dr u g a d mi nistrati o n u ntil after 
t he last P K sa m ple of t he res pecti ve treat me nt peri o d is c ollecte d.
S m o ki n g is n ot all o we d d uri n g i n -h o use c o nfi ne me nt at t he trial site.
Met h y l xa nt hi ne-c o ntai ni n g dri n ks or f o o ds ( s uc h as c offee, tea, c ola, e ner g y dri n ks, a n d 
c h oc olate) are n ot all o we d d uri n g t he i n -h o use c o nfi ne me nt at t he trial site .
E xcessi ve p h y sical acti vit y (s uc h as c o m petiti ve s p ort) s h o ul d be a v oi de d starti n g 7 da y s 
bef ore t he a d mi nistrat i o n of trial me dicati o n u ntil t he e n d of trial e xa mi nati o n. 
Direct e x p os ure t o t he s u n or e x p os ure t o s olari u m ra diati o n s h o ul d be a v oi de d d uri n g t he 
e ntire st u d y.
4. 3
T R E A T M E N T C O M P LI A N C E
C o m plia nce will be ass ure d b y  a d mi nistrati o n of all trial me dicati o n i n t he st u d y ce ntre u n der 
s u per visi o n of t he i n vesti gati n g p hys icia n or a desi g nee. T he meas ure d plas ma c o nce ntrati o ns 
a n d/ or uri nar y e xcreti o n will pr o vi de a d diti o nal c o nfir mati o n of c o m plia nce.
S u bjects w h o are n o n -c o m plia nt (f or i nsta nce, w h o d o n ot a p p ear f or sc he d ule d visits or 
vi olate trial restricti o ns) ma y  be re m o ve d fr o m t he trial a n d t he C R F will be c o m plete d 
acc or di n gl y (f or f urt her pr oce d ures , please see Secti o n 3. 3. 4. 1 ). 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
5.
V A RI A B L E S A N D T H EI R A S S E S S M E N T
5. 1
E F FI C A C Y - C LI NI C A L P H A R M A C O L O G Y
5. 1. 1 
E n d p oi nts of effic ac y
N o efficac y  e n d p oi nts will be e val uate d i n t his trial.
5. 1. 2
Assess me nt of effic ac y
N ot a p plica ble.
5. 2
S A F E T Y
5. 2. 1
E n d p oi nts of s afet y
S R D p art
Pri mar y  e n d p oi nt t o assess safety a n d t olera bilit y of BI 8 9 4 4 1 6 is t he n u m ber [ N ( %)] of 
s u bjects wit h dr u g -relate d a d verse e ve nts.
Rel B A p art

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
5. 2. 2  
Assess me nt of a d verse e ve nts
5. 2. 2. 1  
Defi niti o ns of a d verse e ve nts
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.
Seri o us a d verse e ve nt
A seri o us a d ver se e ve nt ( S A E) is defi ne d as a n y A E w hic h f ulfils at least o ne of t he 
f oll o wi n g criteria:

res ults i n deat h, 

is life-t hreate ni n g, t his refers t o a n e ve nt i n w hic h t he patie nt was at ris k of deat h at 
t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y  mi g ht ha ve 
ca use d deat h if m ore se vere,

re q uires i n patie nt h os pitalisati 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, 

is a c o n ge nital a n o maly/ birt h defect, 
or 

is t o be dee me d seri o us f or a n y ot her reas o n if it is a n i m p orta nt me dical e ve nt w he n 
base d u p o n a p pr o priate me dical j u d g me nt w hic h ma y  je o par dise t he patie nt a n d ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n 
t he a b o ve defi niti o ns .
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 e ve nts, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be 
i m me diatel y life t hreate ni n g or res ult i n deat h or h os pitalisati on 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 that 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 e ve nt .
A Es c o nsi dere d ‘ Al w a ys Seri o us’
I n acc or da nce wit h t he E ur o pea n Me dici nes A ge nc y  i nitiati ve o n I m p orta nt Me dical E ve nts, 
B oe hri n ger I n gel hei m has set u p a list of f urt her A Es, w hic h b y  t heir nat ure, ca n al wa ys be 
c o nsi dere d t o be ‘seri o us’ e ve n t h o u g h t he y  ma y n ot ha ve met t he criteria of a n S A E as gi ve n 
a b o ve.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
T he latest list of ‘ Al wa y s Seri o us A Es’ ca n be f o u n d i n t he R D C s yste m, a re m ote data 
ca pt ure s ys te m w hic h all o ws t he e ntr y of trial data at t he trial site. T hese e ve nts s h o ul d 
al wa ys be re p orte d as S A Es as descri be d a b o ve.
Ca ncers of ne w hist ol o g y a n d e xacer bati o ns of e xisti n g ca ncer m ust be re p orte d as a seri o us 
e ve nt re gar dless of t he d urati o n bet wee n disc o nti n uati o n of t he dr u g a n d t he occ urre nce of t he 
ca ncer.
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. A E SI 
nee d t o be re p orte d t o t he s p o ns or’s P har mac o vi gila nce De part me nt wit hi n t he sa me 
ti mefra me t hat a p plies t o S A E, please see a b o ve.
T he f oll o wi n g are c o nsi dere d as A E SIs i n t his trial:

He patic i nj ur y , as 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:
o
a n ele vati o n of A S T a n d/ or A L T ≥3 -f ol d 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 sa m ple, a n d/ or
o
mar ke d pea k 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 nts s h o wi n g t hese la b 
a b n 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 SF. I n case of cli nical s y 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.) wit h o ut la b res ults ( A LT, 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 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 pat ic i nj ur y alert, t he pr oce d ures descri be d i n 
t he DI LI c hec klist s h o ul d be f oll o we d.
I nte nsit y of A Es
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) t hat 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
C a us al rel ati o ns hi p of A Es
T he defi niti o n of a n a d verse reacti o n (i.e., a dr u g-relate d a d verse e ve nt) 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 b y t he 
fact 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 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 halle n 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 .

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Ar g u me nts t hat ma y  s u g gest t hat t here is a reas o na ble p ossi bilit y of a ca usal relati 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 har mac 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 class.

A 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.

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 dicall y s o u n d alter nati ve aeti ol o gies t hat c o ul d e x plai n t he e ve nt (e. g. pre -
e 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 -relate d a n d i nfre q ue nt i n t he ge neral p o p ulati 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 reas o na ble p ossi bilit y of a ca usal relati 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 dra 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. 
5. 2. 2. 2
A d verse e ve nt c ollecti o n a n d re p orti n g
A Es c ollecti o n
U p o n e nr ol me nt i nt o a trial, t he s u bject’s baseli ne c o n diti o n is assesse d ( f or i nsta nce, by 
d oc u me ntati o n of me dical hist or y / c o nc o mita nt dia g n oses), a n d rele va nt c ha n ges fr o m 
baseli ne are n ote d s u bse q ue ntl y . 
S u bjects will be re q uire d t o re p ort s p o nta ne o usl y a n y A Es as well as t he ti me of o nset, e n d, 
a n d i nte nsit y of t hese e ve nts. I n a d diti o n, eac h s u bject will be re g ularl y  assesse d b y t he 
me dical staff t hr o u g h o ut t he cli nical trial a n d w he ne ver t he i n vesti gat or dee ms necessar y . As 
a mi ni m u m, s u bjects will be q uesti o ne d f or A Es (a n d c o nc o mita nt t hera pies) at t he ti me 
p oi nts i n dicate d i n t he Fl o w C hart . Assess me nt will be ma de usi n g n o n -s pecific q uesti o ns 
s uc h as ‘H o w d o y o u feel? ’. S pecific q uesti o ns will be as ke d w here ver necessar y  i n or der t o 
m ore precisel y  descri be a n A E.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
A caref ul l y writte n rec or d of all A Es s hall be ke pt b y  t he i n vesti gat or i n c har ge of t he trial. 
Rec or ds of A Es s hall i ncl u de data o n t he ti me of o nset, e n d ti me, a n d i nte nsit y  of t he e ve nt as 
well as a n y treat me nt or acti o n re q uire d f or t he e ve nt a n d its o utc o me.
T he f oll o wi n g m ust be c ollecte d a n d d oc u me nte d o n t he a p pr o priate C R F(s) 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 t hr o u g h t he r esi d ual effect p eri o d ( R E P), 
u ntil a n i n di vi d ual s u bject’s e n d of trial: 
o
A ll A Es (seri o us a n d n o n-seri o us) a n d all A E SIs.
o
T he o nl y  e xce pti o n t o t his r ule are A Es (seri o us a n d n o n -seri o us) a n d A E SIs 
i n P hase I trials i n healt h y v ol u nteers, w he n s u bjects disc o nti n ue fr o m t he trial 
d ue t o scree ni n g fail ures pri or t o a d mi nistrati o n of a n y  trial me dicati o n. I n 
t hese cases, t he s u bjects’ data m ust be c ollecte d at tri al site b ut will n ot be 
e ntere d i n t he C R F or trial data base a n d will n ot be re p orte d i n t he C T R.

After t he i n di vi d ual s u bject’s e n d of trial: 
o
T he in vesti gat or d oes n ot nee d t o acti vel y m o nit or t he s u bject f or A Es b ut 
s h o ul d o nl y re p ort relate d S A Es a n d r elate d A E SIs of w hic h the i n vesti gat or
ma y  bec o me a ware of b y  a n y mea ns of c o m m u nicati o n, e. g. p h o ne call.
T he R E P f or BI  8 9 4 4 1 6, w he n meas ura ble dr u g le vels or P D effects are still li kel y t o be 
prese nt after t he last a d mi nistrati o n, is n ot k n o w n f or t his first-i n-h u ma n trial . T heref ore, all 
A Es re p orte d u ntil t he e n d of trial e xa mi nati o n (last per pr ot oc ol c o ntact) will be c o nsi dere d 
o n treat me nt ; please see S ecti o n 7. 3. 3.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
A E re p orti n g t o s p o ns or a n d ti meli nes
T he I n vesti gat or m ust re p ort S A Es, A E SI s, a n d n o n-seri o us A Es w hic h are rele va nt f or t he 
re p orte d S A E or A E SI, o n t he BI S A E f or m via fa x i m me diatel y ( wit hi n 2 4 h o urs of 
a ware ness ) t o t he s p o ns or’s u ni q ue e ntr y p oi nt (c o u ntr y s pecific c o ntact details will be 
pr o vi de d i n t h e IS F). T he sa me ti meli ne a p plies if f oll o w -u p i nf or mati o n bec o mes a vaila ble. 
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 pfr 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 fa x t he BI S A E f or m.
Wit h recei pt of
a n y f urt her i nf or mati o n t o t hese e ve nts, a f oll o w -u p S A E f or m has t o be 
pr o vi de d. F or f oll o w -u p i nf or mati o n t he sa me r ules a n d ti meli ne a p pl y  as f or i nitial 
i nf or mati o n.
I nf or m ati o n re q uire d
F or eac h A E, 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 a p pr o priate 
C R F pa ges a n d t he BI S A E f or m (if a p plica ble). T he i n vesti gat or s h o ul d deter mi ne t he ca usal 
relati o ns hi p t o t he trial me dicati o n.
T he f oll o wi n g s h o ul d als o be rec or de d as a n ( S) A E i n t he C R F a n d o n t he S A E f or m (if 
a p plica ble):

W orse ni n g of t he u n derl y i n g disease or of ot her pre-e xisti n g c o n diti o ns 

C ha n ges i n vital si g ns, E C G, p h y sical e xa mi nati o n, ne ur ol o gical e xa mi nati o n a n d 
la b orat or y test res ults, if t he y are j u d ge d cli nically rele va nt b y t he i n vesti gat or.
If s uc h a b n or malities alrea d y pre-e xist pri or t o trial i ncl usi o n t he y will be c o nsi dere d as 
baseli ne c o n diti o ns a n d s h o ul d be c ollecte d i n t he C R F o nl y .
All ( S) A Es, i ncl u di n g t h ose persisti n g after i n di vi d ual s u bject’s e n d of trial m ust be f oll o we d 
u p u ntil t he y  ha ve res olve d, ha ve bee n s ufficie ntl y  c haracterise d, or n o f urt her i nf or mati o n 
ca n be o btai ne d.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 6 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
5. 4
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 perf or me d d uri n g t his trial are sta n dar d meas ure me nts a n d will be 
perf or me d i n or der t o m o nit or s u bjects’ safety a n d t o deter mi ne p har mac o ki netic a n d 
 para meters i n a n a p pr o priate wa y . T he sc he d ule d 
meas ure me nts will all o w m o nit ori n g of c ha n ges i n vital si g ns, sta n dar d la b orat or y  val ues, a n d 
E C G para meters t hat mi g ht occ ur as a res ult of a d mi nistrati o n of trial me dicati o n. 
T he safety assess me nts are sta n dar d , are acce pte d f or e val uati o n of safet y a n d t olera bilit y of 
a n oral l y a d mi nistere d dr u g, a n d are wi del y use d i n cli nical trials.
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
T he p har mac o ki netic para meters a n d meas ure me nts o utli ne d i n Secti o n 5. 5 are ge nerall y use d
assess me nts of dr u g e x p os ure. 
 
5. 5
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
Date a n d cl oc k ti me of dr u g a d mi nistrati o n a n d p har mac o ki netic sa m pli n g will be rec or de d.
E xact ti me p oi nts of plas ma sa m pli n g will be deri ve d fr o m t he st u d y ma na ge me nt s yste m 
Cli n Base ™ a n d d oc u me nte d i n t he C R Fs b y  t he me dical pers o n nel or se nt as electr o nic files
t o t he trial data ma na ger. T he act ual sa m pli n g ti mes will be use d f or deter mi nati o n of 
p ha r mac o ki netic para meters.
P K sa m pli n g ti mes a n d peri o ds ma y  be a da pte d d uri n g t he trial base d o n i nf or mati o n 
o btai ne d d uri n g trial c o n d uct (e. g. preli mi nar y  P K data) i ncl u di n g a d ditio n of sa m ples a n d 
visits as l o n g as t he t otal bl o o d v ol u me ta ke n per s u bjec t d oes n ot e xcee d 5 0 0 m L. S uc h
c ha n ges w o ul d be i m ple me nte d via n o n -s u bsta ntial C T P A me n d me nts.
5. 5. 1
P h ar m ac o ki netic e n d p oi nts
T he f oll o wi n g p har mac o ki netic para meters will be deter mi ne d if feasi ble f or BI 8 9 4 4 1 6:
5. 5. 1. 1
Sec o n dar y e n d p oi nt s
S R D p art

A U C 0- ∞(area u n der t he c o nce ntrati o n-ti me c ur ve of t he a nalyt e i n plas ma o ver t he 
ti me i nter val fr o m 0 e xtra p olate d t o i nfi nit y)

C ma x ( ma xi m u m meas ure d c o nce ntrati o n of t he a nal yte i n plas ma)
Rel B A p art

A U C 0- tz (area u n der t he c o nce ntrati o n-ti me c ur ve of t he a nal yt e i n plas ma o ver t he 
ti me i nter val fr o m 0 t o t he last q ua ntifia ble data p oi nt)

A U C 0- ∞

C ma x

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
5. 5. 2
Met h o ds of s a m ple c ollecti o n
5. 5. 2. 1 
Plas ma sa m pli n g f or p har mac o ki netic a nal y sis
F or q ua ntificati o n of BI  8 9 4 4 1 6 plas ma c o nce ntrati o ns, 2. 7 m L  of bl o o d will be ta ke n fr o m 
a n a nt ec u bital or f orear m vei n i nt o a K 3-E D T A (tri p otassi u m et h y le ne dia mi netetraacetic 
aci d)- a ntic oa g ula nt bl o o d dra wi n g t u be at t he ti mes i n dicate d i n t he Fl o w C hart . Bl o o d will 
be wit h dra w n b y mea ns of eit her a n i n d welli n g ve n o us cat heter or b y ve ni p u nct ure wit h a 
metal nee dle .

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
T he E D T A -a ntic oa g ulate d bl o o d sa m ples will be ce ntrif u ge d f or a b o ut 1 0 mi n at a b o ut 
2 0 0 0 g t o 4 0 0 0 g a n d at 4 t o 8 ° C. T w o plas ma ali q u ots will be o btai ne d a n d st ore d i n 
p ol y pr o p yl e ne t u bes. T he first ali q u ot s h o ul d c o ntai n at least 0. 5 m L  plas ma. T he sec o n d 
ali q u ot s h o ul d c o ntai n re mai ni n g plas ma. T he pr ocess fr o m bl o o d c ollecti o n u ntil tra nsfer of 
plas ma a li q u ots i nt o t he freezer s ho ul d be c o m plete d wit hi n 6 0 mi n , wit h i nteri m st ora ge of 
bl o o d sa m ples i n ice water or o n ice . F or eac h ali q u ot the ti me w he n t he sa m ple was place d i n 
t he freezer will be d oc u me nte d. U ntil tra nsfer o n dr y  ice t o t he a nal ytical la b orat or y, t he 
ali q u ots will be st ore d u pri g ht at a b o ut -2 0° C or bel o w at t he trial site. T he sec o n d ali q u ot 
will be tra nsferre d t o t he a nal yt ical la b orat or y after t he bi oa nalys t has ac k n o wle d ge d safe 
arri val of t he first ali q u ot. At t he a nal yt ical la b orat or y t he plas ma sa m ples will be st ore d at 
a b o ut -2 0° C or bel o w u ntil a nal y sis.
At a mi ni m u m, t he sa m ple t u be la bels s h o ul d list t he f oll o wi n g i nf or mati o n: BI trial n u m ber, 
s u bject n u m ber, visit, a n d pla n ne d sa m pli n g ti me. F urt her i nf or mati o n s uc h as matri x a n d 
a nal yt e ma y als o be pr o vi de d . 
After c o m pleti o n of t he q ua ntificati o n of BI  8 9 4 4 1 6 c o nce ntrati o ns i n plas ma sa m ples of 
i n di vi d ual or all v ol u nteers, left -o ver a n d bac k -u p sa m ples of t hese v ol u nteers ca n be use d f or 
a nal ys is of meta bolites of BI 8 9 4 4 1 6 (i ncl u di n g, if a p plica ble, re -a nal ys is of pare nt 
c o m p o u n d).
After c o m pleti o n of t he trial t he plas ma sa m ples ma y be use d f or f urt her met h o d ol o gical 
i n vesti gati o ns, e. g. f or sta bilit y testi n g, assess me nt of meta b olites. H o we ver, o nl y data relate d 
t o t he a nalyt e a n d/ or its meta b olite(s) i ncl u di n g a nti-dr u g a nti b o dies (if a p plica ble) will be 
ge nerate d b y t hese a d diti o nal i n vesti gati o ns. T he st u d y sa m ples will be discar de d after 
c o m pleti o n of t he a d diti o nal i n vesti gati o ns b ut n ot later t ha n 5 ye ars u p o n t he fi nal st u d y  
re p ort has bee n si g ne d.
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
5. 5. 3
A n al ytic al deter mi n ati o ns
5. 5. 3. 1
A nal y tical deter mi nati o n of a nal y te plas ma c o nce ntrati o n
BI 8 9 4 4 1 6 c o nce ntrati o ns i n plas ma will be deter mi ne d b y a vali date d L C -M S/ M S
(li q ui d 
c hr o mat o gra p h y t a n de m mass s pectr o metr y) assa y. All details of t he a nal yt ical met h o d will 
be a vaila ble pri or t o t he start of sa m ple a nal y sis. 
As descri be d i n Secti o n 4. 1. 5 , t he bi oa nalys t will be u n bli n de d d uri n g sa m ple a nalys is.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 7 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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
E xact ti mes of meas ure me nts o utsi de t he per mitte d ti me wi n d o ws will be d oc u me nte d. T he 
acce pta ble ti me wi n d o w s f or scree ni n g a n d e n d- of-trial e xa mi nati o n are gi ve n i n t he Fl o w 
C hart .
St u d y  meas ure me nts a n d assess me nts sc he d ule d t o occ ur ‘ bef ore’ trial me dicati o n 
a d mi nistrati o n o n Da y 1 are t o be perf or me d a n d c o m plete d wit hi n a 3 h- i nter val pri or t o t he 
trial dr u g a d mi nistrati o n (i ncl u di n g bla n k val ues f or P K 
.
I n t he S R D part, the acce pta ble de viati o n fr o m t he sc he d ule d ti me f or vital si g ns, E C G a n d 
la b orat or y tests will be ± 1 5 mi n f or t he first 4 h after trial dr u g a d mi nistrati o n, ± 3 0 mi n 
t hereafter o n da y  1, ± 9 0 mi n o n da y  2, a n d ± 1 2 0 mi n fr o m 4 8 h p ost a d mi nistrati o n 
o n war ds.
I n t he rel B A part, t he acce pta ble de viati o n fr o m t he sc he d ule d ti me f or vital si g ns, E C G a n d 
la b orat or y tests will be ± 4 5 mi n o n da y  1 f or all ti me p oi nts after trial dr u g a d mi nistrati o n, 
± 9 0 mi n o n da y  2, a n d ± 1 2 0 mi n fr o m 4 8 h p ost a d mi nistrati o n o n war ds.
 
Starti n g fr o m 4 8 h p ost a d mi nistrati o n a de viati o n fr o m t he sc he d ule d ti me f or P K  
 
sa m pli n g of ± 1 2 0 mi n is acce pta ble.
If se veral acti vities are sc he d ule d at t he sa me ti me p oi nt i n t he F l o w C hart , E C G s h o ul d be 
t he first a n d meal t he last acti vit y. F urt her m ore, if se veral meas ure me nts i ncl u di n g 
ve ni p u nct ure are sc he d ule d f or t he sa me ti me, ve ni p u nct ure s h o ul d be t he last of t he 
meas ure me nts d ue t o its i nc o n ve nie nce t o t he s u bject a n d p ossi ble i nfl ue nce o n p h y si ol o gical 
para meters.
F or pla n ne d i n di vi d ual plas ma c o nce ntrati o n sa m pli n g ti mes 
 
refer t o t he Fl o w C hart . W hile t hese n o mi nal ti mes s h o ul d be a d here d t o as cl osel y as 
p ossi ble, t he act ual sa m pli n g ti mes will be rec or de d a n d use d f or deter mi nati o n of 
p har m ac o ki netic para meter s.
If a s u bject misses a n a p p oi nt me nt, it will be resc he d ule d if p ossi ble. T he rele va nce of 
meas ure me nts o utsi de t he per mitte d ti me wi n d o ws will be assesse d n o later t ha n at t he Re p ort 
Pla n ni n g Meeti n g.
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 peri o d
After ha vi n g bee n i nf or me d a b o ut t he trial, all s u bjects will gi ve t heir writte n i nf or me d 
c o nse nt i n acc or da nce wit h G C P a n d l ocal le gislati o n pri or t o e nr ol me nt i n t he st u d y.
F or i nf or mati o n re gar di n g la b orat or y  tests (i ncl u di n g dr u g a n d vir us scree ni n g), E C G, vital 
si g ns, p h y sical e xa mi nati o n, a n d 
refer t o Secti o ns 5. 2. 3 t o 5. 2. 5 .  

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
6. 2. 2
Tre at me nt peri o d (s)
Trial me dicati o n will be ta ke n orally b y eac h s u bject u n der direct s u per visi o n of t he 
i n vesti gat or or his desi g nee. Details o n treat me nts a n d pr oce d ures of a d mi nistrati o n are 
descri be d i n Secti o n 4. 1. 4 .
Eac h s u bject t hat partici pates at t he S R D part is e x pecte d t o partici pate i n o ne treat me nt 
peri o d (i.e., visit 2).
Eac h s u bject t hat partici pates at t he rel B A part is e x pecte d t o partici pate i n t hree treat me nt 
peri o ds (i.e., visits 2, 3, a n d 4).
 
 
F or details o n ti me p oi nts a n d pr oce d ures f or c ollecti o n a n d pr ocessi n g of bl o o d
 
sa m ples f or P K
, refer t o Secti o n 5. 5. 2 ( P K) 
 res pecti vel y, a n d 
t o t he Fl o w C hart . 
T he safet y  meas ure me nts perf or me d d uri n g t he treat me nt peri o d are s pecifie d i n Secti o n 5. 2
of t his pr ot oc ol a n d i n t he Fl o w C hart . F or details o n ti me p oi nts f or all ot her trial pr oce d ures, 
refer t o t he Fl o w C hart . A Es a n d c o nc o mita nt t hera py will be assesse d c o nti n u o usl y  fr o m 
scree ni n g u ntil t he e n d of trial e xa mi nati o n.
6. 2. 3
E n d of tri al peri o d 
F or A E assess me nt, la b orat or y tests, recor di n g of E C G a n d vital si g ns, p h ysical e xa mi nati o n
a n d 
d uri n g t he e n d of trial peri o d, see Secti o ns 5. 2. 2 t o 5. 2. 5 .
S u bjects w h o disc o nti n ue treat me nt bef ore t he e n d of t he pla n ne d treat me nt peri o d s h o ul d 
u n der g o t he e n d of trial visit.
All a b n or mal val ues (i ncl u di n g la b orat or y  para meters) t hat are j u d ge d cli nicall y rele va nt b y 
t he i n vesti gat or will be m o nit ore d usi n g t he a p pr o priate tests u ntil a ret ur n t o a me dicall y 
acce pta ble le v el is ac hie ve d. ( S) A Es persisti n g after s u bject’s e n d of trial m ust be f oll o we d 
u p u ntil t he y  ha ve res ol ve d, ha ve bee n s ufficie ntl y c haracterise d, or n o f urt her i nf or mati o n 
ca n be o btai ned. 
T he e n d of t he trial as a w h ole is defi ne d by t he ‘last re g ular v isit c o m plete d b y last s u bject’ 
or ‘e n d date of t he last o pe n A E’ or ‘ date of t he last f oll o w -u p test’ or ‘ date of a n A E has 
bee n deci de d as s ufficie ntl y  f oll o we d-u p’, w h ic he ver is latest.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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
7. 1. 1
O bjecti ves
S R D p art:
T he pri mar y  o bjecti ve of t his trial is t o i n vesti gate t he safety a n d t olera bilit y of BI 8 9 4 4 1 6 b y  
usi n g descri pti ve statistics f or all e n d p oi nts c o m pari n g acti ve d ose gr o u ps t o place b o. T he 
pri mar y  e n d p oi nt is defi ne d i n Secti o n 5. 2. 1 . Infere ntial statistics is n ot pla n ne d (as e x plai ne d 
i n Secti o n 7. 2 ).
S ec o n dar y o bjecti ves are t he e x pl orati o n of p har mac o ki netics ( P K) of BI  8 9 4 4 1 6. E n d p oi nts 
as s pecifie d i n 5. 5. 1 will be a nal ys e d b y descri pti ve statistics.
 
 
 
Rel B A p art
Sec o n dar y  o bjecti ve of t he rel B A part is t o i n vesti gate t he p har mac o ki netics of BI 8 9 4 4 1 6 as 
ta blet f or m ulati o n a n d t o e x pl ore t he relati ve bi oa vaila bilit y of 1 0 m g of BI 8 9 4 4 1 6 ta blet
f or m ulati o n ( Test, T) c o m pare d t o 1 0 m g of BI  8 9 4 4 1 6 oral s ol uti o n f or m ulati o n ( Refere nce, 
R). T he rel B A part is desi g ne d t o all o w i ntra-s u bject c o m paris o ns a n d will be e val uate d 
statisticall y b y use of a n a p pr o priate li near m o del i n a n e x pl orat or y fas hi o n.
 
T he assess me nt of safet y a n d t olera bilit y will be a n a d diti o nal o bjecti ve of t he rel B A part of
t his trial, a n d will be e val uate d b y descri pti ve statistics.
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
Safet y  a n d t olera bilit y of t he differe nt d ose gr o u ps of BI 8 9 4 4 1 6 are t o be deter mi ne d o n t he 
basis of t he i n vesti gate d para meters i n c o m paris o n t o place b o. It is n ot pla n ne d t o test a n y  
statistical h yp ot heses wit h re gar d t o t hese varia bles i n a c o nfir mat or y  se nse. Instea d, t he y  will 
be descri be d i n t heir e ntiret y  a n d eval uate d b y  descri pti ve statistical met h o ds.
C o nfi de nce i nter vals will be c o m p ute d a n d will ha ve t o be i nter prete d i n t he pers pecti ve of 
t he e x pl orat or y c haracter of t he st u d y, i.e. c o nfi de nce i nter vals are c o nsi dere d as i nter val 
esti mates f or effects.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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.
A d here nce t o t he pr ot oc ol (s uc h as i ncl usi o n/e xcl usi o n criteria, ti mes of meas ure me nt, 
c o m plia nce wit h i nta ke of trial me dicati o n, treat me nt dis pe nsi n g err ors, pr o hi bite d 
c o nc o mita nt me dicati o n, c o m plete nes s a n d c o nsiste nc y of data) will be c hec ke d. I m p orta nt 
pr ot oc ol vi olati o ns (I P Vs) will be i de ntifie d n o later t ha n i n t he Re p ort Pla n ni n g Meeti n g a n d 
pr o vi de d i n t he T S A P.
7. 3. 1
Pri m ar y a n al yses
T he pri mar y  safety e n d p oi nt will be e val uate d descri pti vel y, f or f ur t her i nf or mati o n refer t o
t he descri pti o n of A nalys is of safet y a n d t olera bilit y i n Secti o n 7. 3. 3 .
7. 3. 2
Sec o n d ar y a n al yses
T he sec o n dar y  para meters (refer t o Secti o n 5. 5. 1 ) will be calc ulate d acc or di n g t o t he BI  
S ta n dar d O perati n g Pr oce d ure ( S O P) ‘ Sta n dar ds a n d pr ocesses f or a nal yses perf or me d wit hi n 
Cli nical P har mac o ki netics / P har mac o dy na mics’ [ 0 0 1- M C S -3 6- 4 7 2 ].
Plas ma a n d  
c o nce ntrati o n data a n d para meters of a s u bject will be i ncl u de d i n t he 
statistical p har mac o ki netic ( P K) a nalys es if t he y are n ot fla g ge d f or e xcl usi o n d ue t o a 
pr ot oc ol vi olati o n rele va nt t o t he e val uati o n of P K (t o be deci de d n o later t ha n i n t he Re p ort 
Pla n ni n g Meeti n g) or d ue t o P K n o n -e val ua bilit y (as re veale d d uri n g data a nal ys is, base d o n 
t he criteria s pecifie d bel o w). E xcl usi o n of a s u bject’s data will be d oc u me nte d i n t he C T R.
Rele va nt pr ot oc ol vi olati o ns ma y  be

I nc orrect trial me dicati o n ta ke n, i.e. t he s u bject recei ve d at least o ne d ose of trial 
me dic ati o n t he s u bject was n ot assi g ne d t o

I nc orrect d ose of trial me dicati o n ta ke n

Use of restricte d me dicati o ns.
Plas ma a n d  
 c o nce ntrati o ns a n d/ or para meters of a s u bject will be c o nsi dere d as n o n -
e val ua ble, if f or e xa m ple

t he s u bject e x perie nce d e mesis t hat occ urre d at or bef ore t w o ti mes me dia n tma x of t he 
res pecti ve treat me nt ( Me dia n tma x is t o be deter mi ne d e xcl u di n g the s u bjects 
e x perie nci n g e mesis ),

missi n g sa m ples/c o nce ntrati o n data at i m p orta nt p hases of P K dis p ositi o n c ur ve .
T he P K para meter a nal ys is set ( P K S) i ncl u des all s u bjects i n t he Treate d Set ( T S) w h o 
pr o vi de at least o ne P K para meter t hat was n ot e xcl u de d acc or di n g t o t he descri pti o n a b o ve.
Descri pti ve statistics will be pr o vi de d.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Relati ve bi oa vaila bilit y
Relati ve bi oa vaila bilit y is t o be deter mi ne d o n t he basis of t he sec o n dar y p har mac o ki netic 
e n d p oi nts (see Secti o n 5. 5. 1 ) f or t he rel B A part c o m pari n g 1 0 m g  BI 8 9 4 4 1 6 a d mi nistere d as 
ta blet t o Pf O S. T he statistical m o del use d t o assess t he relati ve bi oa vaila bilit y will be a n 
A N O V A (a nal ys is of varia nce) m o del o n t he l o garit h mic scale. T his m o del will i ncl u de 
effects acc o u nti n g f or t he f oll o wi n g s o urces of variati o n: ‘se q ue nce’, ‘s u bjects wit hi n 
se q ue nces’, ‘ peri o d’ a n d ‘treat ment’ . T he effect ‘s u bjects wit hi n se q ue nces’ will be 
c o nsi dere d as ra n d o m, w hereas t he ot her effects will be c o nsi dere d as fi xe d. T he m o del is 
descri be d b y t he f oll o wi n g e q uati o n:
y ij k m = + i + s i m + j + k + e ij k m, 
w here
y ij k m
l o garit h m of res p o nse meas ure d o n s u bject m i n se q ue nce i recei vi n g 
treat me nt k i n peri o d j,

t he o verall mea n,
i
t he it h se q ue nce effect, i = 1, 2,
si m
t he effect ass ociate d wit h t he mt h s u bject i n t he it h se q ue nce, m = 1, 2, ..., 
n i
j
t he jt h peri o d effect, j = 1, 2,
k
t he kt h treat me nt effect, k = 1, 2,
e ij k m
t he ra n d o m err or ass ociate d wit h t he mt h s u bject i n se q ue nce i w h o 
recei ve d treat me nt k i n peri o d j.
7. 3. 3
S afet y a n al yses
Safet y  will be assesse d f or t he e n d p oi nts a n d para meters of i nterest liste d i n Secti o n 5. 2. 1 . All 
treate d s u bjects (t hat is, all s u bjects w h o recei ve d at least o ne d ose of st u d y dr u g ), will be 
i ncl u de d i n t he safety a nal ysis. Safety a nal yses 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.
Treat me nts will be c o m pare d i n a descri pti ve wa y. F or t he S R D part, t he place b o c o ntr ol 
gr o u p i n t he safet y e val uati o n will c o nsist of all place b o treate d s u bjects, re gar dless of t he 
d ose gr o u p i n w hic h t he y were treate d. T reat me nt gr o u ps will be c o m pare d i n a descri pti ve 
w a y . Ta b ulati o ns of fre q ue ncies/ pr o p orti o ns will be use d f or t he e val uati o n of cate g orical 
( q ualitati ve) data, a n d ta b ulati o ns of descri pti ve statistics will be use d t o a nal yse c o nti n u o us 
( q ua ntitati ve) data.
T he a nal ys es will be d o ne b y ‘treat me nt at o nset ’. 
Meas ure me nts (s uc h as E C G, vital si g ns, or la b orat or y  para meters) or A Es will be assi g ne d t o 
treat me nts (see Secti o n 4. 1 ) base d o n t he act ual treat me nt at t he pla n ne d ti me of t he 
meas ure me nt or o n t he rec or de d ti me of A E o nset (c o nce pt of treat me nt e mer ge nt A Es). 
T heref ore, meas ure me nts pla n ne d or A Es rec or de d pri or t o first i nta ke of trial me dicati o n will 
be assi g ne d t o 's cree ni n g', t h ose bet wee n trial me dicati o n i nta ke i n a peri o d u ntil trial 
me dicati o n i nta ke i n t he ne xt peri o d or t he trial ter mi nati o n date will be assi g ne d t o t he 
treat me nt peri o d. T hese assi g n me nts i ncl u di n g t he c orres p o n di n g ti me i nter vals will be 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
defi n e d i n detail i n t he T S A P. Please n ote t hat A Es occ urri n g after t he last per pr ot oc ol 
c o ntact b ut e ntere d bef ore data base l oc k will be re p orte d t o dr u g safet y  o nl y a n d will n ot be 
ca pt ure d i n t he trial data base.
A d diti o nall y , f urt her treat me nt i nter vals (a nal ys i n g treat me nts) ma y be defi ne d i n or der t o 
pr o vi de s u m mar y  statistics f or ti me i nter vals, s uc h as c o m bi ne d treat me nts, o n-treat me nt 
t otals or peri o ds wit h o ut treat me nt effects (s uc h as scree ni n g a n d f oll o w- u p i nter vals).
A d verse e ve nts will be c o de d u si n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). Fre q ue nc y, i nte nsit y a n d ca usal relati o ns hi p of A Es will be ta b ulate d b y  
treat me nt, s yste m or ga n class a n d preferre d ter m. S A Es, A E SIs (see Secti o n 5. 2. 2. 1 ) a n d 
ot her si g nifica nt A Es (acc or di n g t o I CH E 3) will be liste d se paratel y . 
La b orat or y  data will be c o m pare d t o t heir refere nce ra n ges. Val ues o utsi de t he refere nce 
ra n ge as well as val ues defi ne d as cli nicall y rele va nt will be hi g hli g hte d i n t he listi n gs. 
A d diti o na ll y, differe nces fr o m baseli ne will be e val uate d.
Vital si g ns or ot her safet y- 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 d i n gs bef ore start of treat me nt.
T he E C G varia bles Q T, H R, Q Tc F, Q Tc B, P R, Q R S, a n d R R o btai ne d fr o m t he ce ntralise d 
e val uati o n of 1 2 -lea d E C G rec or di n gs will be t he basis f or t he deri vati o n of q ua ntitati ve a n d 
cate g orical E C G e n d p oi nts f or t he S R D part. T hese e n d p oi nts a n d t heir a nal y ses will be 
descri be d i n t he T S A P.
7. 3. 4
Preli mi n ar y a n al yses
Preli mi n ar y P K a n al yses
I n c o ntrast t o t he fi nal P K calc ulati o ns, t he preli mi nar y a nalys is will be base d o n pla n ne d 
sa m pli n g ti mes rat her t ha n o n act ual ti mes, re gar dless of w het her act ual ti mes were wit hi n t he 
ti me wi n d o ws or n ot. T heref ore, mi n or de viati o ns of preli mi nar y a n d fi nal res ults ma y occ ur. 
T he preli mi nar y  a nalys is will pr o vi de i n di vi d ual a n d mea n c o nce ntrati o n-ti me pr ofiles a n d 
s u m mar y statistics of i n di vi d ual val ues. T he preli mi nar y res ults will be distri b ute d t o t he 
I n vesti gat or a n d t he trial tea m. 
De pe n di n g o n t he res ults of a vaila ble preli mi nar y  P K a nal yses, t he t olera bilit y a n d safety of 
t he c o m p o u n d, a n d c ha n ges of d osi n g sc he d ule (e. g. a d diti o nal i nterme diate d oses) a d diti o nal 
P K preli mi nar y  a nalys is ma y be perf or me d base d o n t he re q uest of t he Trial Cli nical M o nit or, 
t he i n vesti gat or, or Trial Cli nical P har mac o ki neticist. N o f or mal preli mi nar y P K re p ort will 
be writte n.
S R D part
A preli mi nar y  a nal ysis of P K para meters ( A U C 0- 2 4 a n d C ma x of BI 8 9 4 4 1 6) pr o vi de d as 
i n di vi d ual val ues a n d ge o metric mea ns will be perf or me d f or eac h d ose le vel bef ore 
pr ocee di n g t o t he ne xt le vel. 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Data fr o m at least 4 acti vel y  d osed s u bjects at t he c urre nt d ose le vel ( d ose le ve l N) are 
re q uire d i n or der t o pr ocee d t o t he ne xt d ose le vel ( d ose le vel N + 1).
F or escalati o n fr o m D ose Gr o u p 1 t o D ose Gr o u p 2, preli mi nar y  P K data are n ot re q uire d.
N o i nfere ntial statistical i nteri m a nal ys is is pla n ne d. H o we ver, after eac h d ose gr o u p t he 
i n vesti gat or ( or his de p ut y) is all o we d t o p ost p o ne f urt her d ose pr o gressi o n u ntil a 
preli mi nar y  a nalys is of t he data alrea d y o btai ne d has bee n perf or me d.
Rel B A part
A preli mi nar y  a nal ysis of P K para meters ( A U C 0- 2 4 a n d C ma x of BI 8 9 4 4 1 6) pr o vi de d as 
i n di vi d ual val ues a n d ge o metric mea ns will be perf or me d f or t he c urre nt d ose gr o u p i n t he 
S R D part bef ore pr ocee di n g t o t he rel B A part (i.e., bef ore d osi n g of s u bjects i n t he rel B A 
part i n peri o d 1). 
I n a d diti o n, a preli mi nar y a nal ys is of P K para meters ( A U C0- 2 4 a n d C ma x of BI 8 9 4 4 1 6) of 
peri o ds 1 a n d 2 of t he rel B A part pr o vi de d as i n di vi d ual val ues a n d ge o metric mea ns will be 
perf or me d bef ore pr ocee di n g t o d osi n g of s u bjects i n peri o d 3 of t he rel B A part.
Data fr o m at least 4 acti vel y  d ose d s u bjects at t he c urre nt d ose le vel of t he S R D part are 
re q uire d i n or der t o pr ocee d t o t he rel B A part, a n d data fr o m at least 6 s u bjects d ose d i n 
peri o ds 1 a n d 2 of t he rel B A part nee d t o be a vaila ble i n or der t o pr ocee d t o d osi n g i n per i o d 
3 of t he rel B A part.
A dj uste d g Mea n rati os will be calc ulate d f or t he preli mi nar y  P K para meters o btai ne d f or 
treat me nt 1 0 m g BI 8 9 4 4 1 6 ta blet c o m pare d t o Pf O S d uri n g treat me nt peri o d 1 a n d 2 base d 
o n t he statistical m o del f or assess me nt of relati ve bi oa vaila bilit y  descri be d i n Secti o n 7. 3. 2 .
F urt her m ore, e x pecte d g Mea n e x p os ure val ues ( C ma x a n d A U C 0- 2 4) will be pre dicte d f or 
treat me nt wit h 4 0 m g BI 8 9 4 4 1 6 ta blet.
N o i nfere ntial statistical i nteri m a nalys is is pla n ne d. H o we ver, t he i n vesti gat or ( or his de p uty) 
is all o we d t o p ost p o ne peri o d 3 of t he rel B A part u ntil a preli mi nar y  a nalysis of t he data 
alrea d y o btai ne d has bee n perf or me d .
 
 
7. 3. 5
P h ar m ac o ki netic a n al yses
T he p har mac o ki netic para meters liste d i n Secti o n 5. 5. 1 f or dr u g BI 8 9 4 4 1 6 will be calc ulate d 
acc or di n g t o t he BI S O P ‘ Sta n dar ds a n d pr ocesses f or a nal ys es perf or me d wit hi n Cli nical 
P har mac o ki netics/ P har mac o d y na mics’ [ 0 0 1- M C S -3 6- 4 7 2 ].

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
S u bjec ts w ho are n ot i ncl u de d i n t he P K S (refer t o Secti o n 7. 3. 1 .) will be re p orte d wit h t heir 
i n di vi d ual plas ma
 c o nce ntrati o ns a n d i n di vi d ual p har mac o ki netic para meters; 
h o we ver, t he y  will n ot be i ncl u de d i n descri pti ve statistics f or plas ma
 c o nce ntrati o ns, 
p har mac o ki netic para meters or ot her statistical assess me nt.
O nl y  c o nce ntrati o n val ues wit hi n t he vali date d c o nce ntrati o n ra n ge a n d act ual sa m pli n g ti mes 
will be use d f or t he calc ulati o n of p har mac o ki netic para meters. C o nce ntrati o ns use d i n t he 
p har mac o ki netic calc ulati o ns will be i n t he sa me f or mat pr o vi de d i n t he bi oa nalyt ical re p ort, 
(t hat is, t o t he sa me n u m ber of deci mal places pr o vi de d i n t he bi oa nalyt ical re p ort).
 
 
 
 
7. 4
H A N D LI N G O F MI S SI N G D A T A
7. 4. 1
S afet y
Wit h res pect t o safet y e val uati o ns, it is n ot pla n ne d t o i m p ute missi n g val ues.
7. 4. 2
Pl as m a 
 dr u g c o nce ntr ati o n - ti me pr ofiles
Ha n dli n g of missi n g P K data will be perf or me d acc or di n g t o t he rele va nt S O P of t he S p o ns or 
[0 0 1- M C S -3 6 - 4 7 2].
Dr u g c o nce ntrati o n data i de ntifie d wit h N O S ( n o sa m ple a vaila ble ), N O R ( no vali d res ult), 
N O A ( n ot a nal y s e d), B L Q ( bel o w t he l o wer li mit of q ua ntificati o n), or N O P ( n o pea k 
detecta ble) will be dis pla ye d as s uc h a n d n ot re place d b y zer o at a n y ti me p oi nt ( t his r ule als o 
a p plies als o t o t he la g p hase, i ncl u di n g t he pre d ose val ues ). 
7. 4. 3
P h ar m ac o ki netic p ar a meters
Ha n dli n g of missi n g P K data will be perf or me d acc or di n g t o t he rele va nt S O P of t he S p o ns or 
[0 0 1- M C S -3 6 - 4 7 2].
F or t he n o n- c o m part me ntal a nal ys is, c o nce ntrati o n data i de ntifie d wit h N O S, N O R or N O A 
will ge nerall y n ot be c o nsi dere d. C o nce ntrati o n val ues i n t he la g p hase i de ntifie d as B L Q or 
N O P will be set t o zer o. All ot her B L Q/ N O P val ues of t he pr ofile will be i g n ore d. T he la g 
p hase is defi ne d as t he peri o d bet wee n ti me zer o a n d t he first ti me p oi nt wit h a c o nce ntrati o n 
a b o ve t he q ua ntificati o n li mit.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 8 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
7. 5  
R A N D O MI S A TI O N
F or t he S R D part, t he first 4 s u bjects per d ose le vel will n ot be ra n d o mise d t o mai ntai n a 
treat me nt se q ue nce of acti ve-place b o -acti ve-acti ve d ue t o safety reas o ns. T he re mai ni n g 4 
s u bjects of eac h d ose le vel will be ra n d o mise d i n a 3: 1 rati o, w hic h reflects t he rati o of 
s u bjects recei vi n g acti ve dr u g t o place b o.
F or t he rel B A part, s u bjects will be ra n d o mise d t o o ne of t he t w o treat me nt se q ue nces i n a 
1: 1 rati o. T he bl oc k size will be d oc u me nte d i n t he C T R.
T he s p o ns or will arra n ge f or t he ra n d o misati o n as well as pa c ka gi n g a n d la belli n g of trial 
me dicati o n. T he ra n d o misati o n list w ill be ge nerate d usi n g a vali date d sys te m, 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 a n d a s u p plie d see d n u m ber s o t hat t he res ulti n g 
all ocati o n is b ot h re pr o d uci ble a n d n o n -pre dicta ble.
T he ra n d o misati o n list will c o ntai n a d diti o nal bl oc ks t o all o w f or s u bject re place me nt (refer 
t o 3. 3. 5 ).
7. 6
D E T E R MI N A TI O N O F S A M P L E SI Z E
A t otal of 7 6 healt h y male s u bjects is pla n ne d t o partici pate i n t he trial, t here of 6 4 i n t he S R D 
part a n d 1 2 i n t he rel B A part. A d diti o nal d ose gr o u ps ma y  be a d de d t o t he S R D part (see 
bel o w). T heref ore t he act ual n u m ber of s u bjects e ntere d i nt o t he trial ma y  e xcee d 76 , b ut will 
n ot e xcee d 9 2 s u bjects e ntere d.
S R D p art
It is pla n ne d t o i ncl u de a t otal of 6 4 s u bjects i n t his trial part . T he pla n ne d sa m ple size is n ot 
base d o n a p o wer calc ulati o n. T he size of 8 s u bjects per d ose gr o u p ( 6 o n acti ve treat me nt, 
a n d 2 o n place b o) is c o m m o nl y use d i n si n gle-risi n g d ose st u dies of t he prese nt t ype a n d is i n 
ge neral c o nsi dere d as s ufficie nt f or t he e x pl orat or y e val uati o n of si n gle d ose safet y a n d 
p har mac o ki netics [ R 9 5 -0 0 1 3 ].
A d diti o nal s u bjects ma y  be e ntere d t o all o w testi n g of a d diti o nal d oses o n t he basis of 
e x perie nce gai ne d d uri n g t he trial c o n d uct (e. g. preli mi nar y P K data), pr o vi de d t he pla n ne d 
a n d a p pr o ve d hi g hest d ose will n ot be e xcee de d. T h us, t he act ual n u m ber of s u bjects e ntere d 
ma y  e xcee d 6 4 , b ut will n ot e xcee d 8 0 s u bjects e ntere d.
Base d o n Gl o bal A me n d me nt N o. 4, f oll o wi n g d ose gr o u p 4 a n i nter me diate d ose gr o u p 1 1 
wit h a d diti o nal 8 s u bjects was a d de d, i.e. pla n ne d sa m ple size of t his trial part is 7 2.
Base d o n Gl o bal A me n d me nt N o. 6, f oll o wi n g d ose gr o u p 1 1 a n i nter me diate d ose gr o u p 9 
wit h a d diti o nal 8 s u bjects was a d de d, i.e. pla n ne d sa m ple size of t his trial part is 8 0.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
Rel B A p art
It is pla n ne d t o i ncl u de a t otal of 1 2 s u bjects i n t his trial part. T he pla n ne d sa m ple size is n ot 
base d o n a p o wer calc ulati o n b ut is j u d ge d t o be a de q uate t o o btai n relia ble res ults a n d t o 
f ulfil t he o bjecti ves a n d re q uire me nts of t his e x pl orat or y trial part. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
8.
I N F O R M E D C O N S E N T, D AT A P R O T E C TI O N, T RI A L
R E C O R D S
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 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 I C H Har m o nise d Tri partite G ui deli ne f or 
G o o d Cli nical Practice ( G C P) a n d rele va nt BI S O Ps.
T he i n vesti gat or s h o ul d i nf or m t he s p o ns or i m me diatel y  of a n y ur ge nt safet y meas ures ta ke n 
t o pr otect t he st u d y s ubjects a gai nst a n y  i m me diate hazar d, a n d als o of a ny seri o us breac hes 
of t he pr ot oc ol or of I CH G C P.
As a ge neral r ule, n o trial res ults s h o ul d be p u blis he d pri or t o fi nalisati o n of t he C T R .
I ns ura nce C o ver a ge: T he ter ms a n d c o n diti o ns of t he i ns ura nce c o vera ge m ust be gi ve n t o 
eac h s u bject a n d are ma de a vaila ble t o t he i n vesti gat or via d oc u me ntati o n i n t he I S F.
8. 1
S T U D Y A P P R O V A L, S U B J E C T I N F O R M A TI O N, A N D I N F O R M E D 
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 vi e 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 men d me nts.
Pri or t o a s u bject’s 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 s u bject ( or t he s u bject’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 s u bject 
i nf or mati o n f or m are t o be retai ne d by t he i n vesti gat or as part of t he trial rec or ds. A c o p y of 
t he si g ne d a n d date d writte n i nf or me d c o nse nt a n d a n y a d diti o nal s u bject i nf or mati o n m ust be 
gi ve n t o eac h s u bject or t he s u bject’s le gally acce pte d re prese ntati ve.
T he s u bject m ust be i nf or me d t hat his/ her pers o nal trial -relate d data will be use d b y 
B oe hri n ger I n gel hei m i n acc or da nce wit h t he l ocal data pr otecti o n la w. T he le vel of 
discl os ure m ust als o be e x plai ne d t o t he s u bject.
T he s u bject m ust be i nf or me d t hat his or her me dical rec or ds ma y be e xa mi ne d b y  a ut h orise d 
m o nit ors ( C li nical M o nit or L ocal /Cli nical Researc h Ass ociate ) or Cli nical Q ualit y Ass ura nce 
a u dit ors a p p oi nte d b y B oe hri n ger I n gel hei m, b y a p pr o priate I R B/I E C me m bers , a n d b y 
i ns pect ors fr o m re g ulat or y a ut h orities.
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 or 
s p o ns or’s desi g nees, b y  I R Bs/I E Cs, 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.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
T he data ma na ge me nt pr oce d ures t o e ns ure t he q ualit y  of t he data are descri be d i n detail i n 
t he trial data ma na ge me nt a n d a nalys is pla n ( T D M A P) a vaila ble i n t he T M F.
8. 3
R E C O R D S
C R Fs f or i n di vi d ual s u bjects will be pr o vi de d by t he s p o ns or . F or dr u g acc o u nta bilit y , refer 
t o Secti o n 4. 1. 8 .
Cli n Base T M
I n t he H u ma n P har mac ol o g y Ce ntre ( H P C) – B oe hri n ger I n gel hei m's P hase I u nit – t he 
vali date d Cli n Base T M s yste m is o perate d f or pr ocessi n g i nf or mati o n a n d c o ntr olli n g data 
c ollecte d i n cli nical st u dies. I n a d diti o n t o its f u ncti o n as a pr oce d ure c o ntr ol s y ste m, 
Cli n Base T M ser ves as data base. I nstea d of bei n g e ntere d i nt o C R Fs, selecte d data are directl y 
e ntere d i nt o t he s ys te m.
8. 3. 1
S o urce d oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he s u bject a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
All d ata re p orte d i n t he C R Fs 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.
Data directl y  e ntere d i nt o Cli n BaseT M (t hat is, wit h o ut pri or writte n or electr o nic rec or d) are 
c o nsi dere d t o be s o urce data. T he place w here data is e ntere d first will be defi ne d i n a trial 
s pecific S o urce Data A gree me nt. T he data i n Cli n Base T M are a vaila ble f or i ns pecti o n at a n y 
ti me.
T he i n vesti gat or m a y  nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g 
o n t he trial.
8. 3. 2
Direct access t o s o urce d at a a n d d oc u me nts
T he i n vesti gat or/i nstit uti o n will per mit trial-relate d m o nit ori n g, a u dits, IR B/I E C re vie w a n d 
re g ulat or y i ns pecti o n, pr o vi di n g direct access t o all relate d s o urce data/ d oc u me nts. C R Fs a n d 
all s o urce d oc u me nts, i nc l u di n g pr o gress n otes (if a p plica ble) a n d c o pies of la b orat or y a n d 
me dical test res ults m ust be a vaila ble at all ti mes f or re vie w b y t he s p o ns or’s cli nical trial 
m o nit or , a u dit or a n d i ns pecti o n b y healt h a ut h orities (e. g. F D A). T he Cli nical Researc h 
Ass oci ate/ o n site m o nit or a n d a u dit or m a y  re vie w all C R Fs, a n d writte n i nf or me d c o nse nts. 
T he acc urac y  of t he data will be verifie d b y re vie wi n g t he d oc u me nts descri be d i n Secti o n 
8. 3. 1.
8. 3. 3
St or a ge peri o d of rec or ds
Trial site:
T he trial site 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 SF) acc or di n g t o t he 
nati o nal or l ocal re q uire me nts ( w hate ver is l o n ger) vali d at t he ti me of t he e n d of t he trial.
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.

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
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 re g ulat or y  re p orti n g o bli gati o n a n d i n acc or da nce t o t he 
re q uire me nts defi ne d i n t his C T P.
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
I n di vi d ual s u bject me dical i nf or mati o n 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. 
S u bject c o nfi de ntialit y will be e ns ure d b y usi n g s u bject i de ntificati o n c o de n u m bers.
Treat me nt data m a y  be pr o vi de d t o t he s u bject’s pers o nal ph y sicia 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 s u bject’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 by 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, i.e. t he C A.
8. 6
C O M P L E TI O N O F T RI A L
T he E C/c o m pete nt a ut h orit y  i n eac h partici pati n g E U me m ber state nee ds t o be n otifi e d a b o ut 
t he e n d of t he trial (last patie nt /s u bject o ut, u nless s pecifie d differe ntl y i n Secti o n 6. 2. 3 of t he 
C T P) or earl y ter mi nati o n of t he trial. 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 9 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 0 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 0 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 0 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
    
 
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2- 0 9
Tri al Pr ot oc ol
P a ge 1 0 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 0 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 0 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 0 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4
 
 
 
 
 
 
 
 

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 0 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 0 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 3 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 4 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 5 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 6 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 7 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 8 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 1 9 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 2 0 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 2 1 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

B oe hri n ger I n gel hei m
2 5 J U L 2 0 1 8
BI Tri al N o.: 1 3 7 1- 0 0 0 1
c 1 2 0 9 8 8 1 2 - 0 9
Tri al Pr ot oc ol
P a ge 1 2 2 of 1 2 2
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 1 8 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 - 1 1 ( 5 0) / Sa ve d o n: 2 5 J u n 2 0 1 4

 
 
 
 
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 2 0 9 8 8 1 2
9. 0
cli nical-trial- pr ot oc ol-re visi o n- 0 8
Safet y, t olera bilit y, p har mac o ki netics a n d p har mac o d y na mics of si n gle risi n g oral
d oses of BI 8 9 4 4 1 6 i n healt h y male s u bjects (si n gle- bli n d, partiall y ra n d o mise d,
place b o-c o ntr olle d parallel gr o u p desi g n)
A ut h or- Trial Statisticia n
2 5 J ul 2 0 1 8 1 7: 0 0 C E S T
A ut h or- Trial Cli nical M o nit or
2 5 J ul 2 0 1 8 1 7: 1 8 C E S T
A p pr o val- T hera pe utic Area Hea d
2 5 J ul 2 0 1 8 1 9: 4 2 C E S T
Verificati o n- Pa per Si g nat ure
C o m pleti o n
2 6 J ul 2 0 1 8 1 2: 0 6 C E S T
A p pr o val- Tea m Me m ber Me dici ne
3 0 J ul 2 0 1 8 1 4: 0 3 C E S T
A ut h or- Trial Cli nical
P har mac o ki neticist
2 0 A u g 2 0 1 8 0 8: 1 4 C E S 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 2 0 9 8 8 1 2
9. 0