Clinical trial NCT03315936
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-11-02; Completion date: 2018-09-10
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This first-in man trial is designed to investigate the safety and tolerability of BI 894416 in healthy male subjects following oral administration of single rising doses.

Pharmacokinetics (PK) including dose proportionality after single dosing of BI 894416 as oral solution will be explored, the investigation of PK of BI 894416 as tablet formulation and the exploration of relative bioavailability of BI 894416 as tablet formulation compared to oral solution.

Detailed description:

Arms: arm 1: Single Rising Dose (SRD) Part arm 2: SRD Part arm 3: SRD Part arm 4: SRD Part arm 5: SRD Part arm 6: SRD Part arm 7: SRD Part arm 8: SRD Part arm 9: BI 894416 10 mg tablet (tb) / BI 894416 10 mg powder for oral solution (PfOS) / BI 894416 4\*10 mg tablets.

Relative bioavailability (rel BA) part arm 10: BI 894416 10 mg powder for oral solution (PfOS) / BI 894416 10 mg tablet (tb) / BI 894416 4\*10 mg tablets.

Relative bioavailability (rel BA) part.
Interventions: intervention 1: BI 894416 intervention 2: Placebo intervention 3: BI 894416
Intervention descriptions: intervention 1: powder for oral solution intervention 2: Oral solution intervention 3: Tablet

Protocol documents:
Prot_000.pdf: 
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) 
 
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c 1 2 0 9 8 8 1 2
9. 0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c23386906-02
BI Trial No.:
1371-0001
Title:
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)
Including Protocol Amendment 9 [c12098812-09]
Investigational
Product(s):
BI 894416
Responsible trial 
statistician(s):
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
17 OCT 2018 REVISED
Version:
2.0 “Revised”
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoint .....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................23


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7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse events.....................................................................................................23
7.8.2
Laboratory data ..................................................................................................25
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG......................................................................................................................25
7.8.5
Others...................................................................................................................27
8.
REFERENCES....................................................................................................28
10.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, vital signs and ECG................................................................13
Table 6.2: 1
Important protocol deviations...........................................................................14
Table 6.3: 1
Subject sets analysed ........................................................................................16
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........17
Table 10: 1
History table .....................................................................................................31


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA) and SASTM (current Version 9.4, by SAS Institute 
Inc., Cary, NC, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
 
All other analyses described in this TSAP are in accordance with the statistical methods 
described in the revised CTP.
Additionally a sensitivity analysis will be performed for relative bioavailability with subject 
as fixed effect.
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the number of subjects with drug-related AEs in the SRD (single rising 
dose) part of the trial, as defined in Section 5.2.1 of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints of this trial are AUC0-∞and Cmax of BI 894416 in plasma for the SRD 
part and AUC0-tz, AUC0-∞and Cmax of BI 894416 in plasma for rel. BA (relative 
bioavailability) part, as defined in Section 5.5.1.1 of the CTP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated with 
SRD part:

either a single dose of 3, 10, 20, 30, 40, 54 or 70 mg of BI 894416 (test treatments)
or

a single dose of placebo (reference treatment)
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
Rel BA part:

a single dose of 10 mg BI 894416 as tablet formulation (treatment X)
and

a single dose of 10 mg BI 894416 as oral solution formulation (treatment Y)
and

a single dose of 40 mg BI 894416 as tablet formulation (treatment Z)
In treatment periods 1 and 2, the sequence of administration of treatments X and Y is assigned 
in a randomised manner. In the last (third) treatment period, subjects will receive a single dose 
of 40 mg BI 894416 as tablet formulation. This treatment period follows in a fixed sequence 
after the first two treatment periods for all subjects.
Analysis phases for statistical analysis of AEs, safety laboratory data, vital signs and ECG are 
defined for each subject as described in Table 6.1: 1.


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Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, vital signs and ECG
SRD part:
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
Pbo,
3 mg BI,
10 mg BI,
20 mg BI,
30 mg BI,
40 mg BI,
54 mg BI or
70 mg BI,
respectively
Date/time of 
administration of study 
drug
12:00 a.m. on day after 
subject's trial termination date
rel. BA part:
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
10 mg BI tablet
10 mg BI PfOS 
40 mg BI tablet
Date/time of 
administration of study 
drug
Drug administration of study 
drug in next period or 12:00 
a.m. on day after subject's trial 
termination date
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:
SRD:

"Total BI", defined as the total over all on-treatment phases involving BI
rel. BA part:

"Total on-trt", defined as the total over all on-treatment phases 
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening and on-treatment
phases.
Additionally to the totals defined above, the following total will be provided in CTR Section 
16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)


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
"Study Total", defined as the total over all study phases (screening +on-treatment) for the 
SRD and rel. BA part combined (only for disclosure outputs)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the RPM/DBLM. At this meeting, it will be decided whether a 
discrepant data value can be used in analyses or whether it must be corrected in the clinical 
database. Each protocol deviation must be assessed to determine whether it is an IPD. For 
definition of IPDs, and for the process of identification of these, refer to the BI reference 
document " Identify and Manage Important Protocol Deviations (iPD)", " (2).
Table 6.2: 1
Important protocol deviations 
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C5
Improper washout between treatments
C6
Incorrect dose of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
None1
G
Other trial specific important violations
G1
Certain violations of procedures used to measure secondary PK data
Deviations C1, C2 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not IPDs
Source: BI reference document " Identify and Manage Important Protocol Deviations (iPD)", " (2).
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). The table above
contains the categories which are considered to be IPDs in this trial. IPD C5 is only applicable 


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for the SRD part. If the data show other IPDs, this table will be supplemented accordingly by 
the time of the RPM/DBLM.
IPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9 (1). It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one PK parameter 
that was not excluded because of IPDs relevant to the statistical evaluation of PK 
endpoints as defined in Section 7.3 of the CTP.
 
 
 
 
 
 
 
 
 
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline endpoints
X
Primary endpoint
X
 
Other safety parameters
X
Secondary PK endpoints
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal recorded in the CTR.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4).
 
 
 


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Missing data and outliers of PK data are handled according to BI standards (5). CTP: Drug 
concentration data identified with NOS (no sample available), NOR (no valid result), NOA 
(not analysed), BLQ (below the lower limit of quantification), or NOP (no peak detectable) 
will be displayed as such and not replaced by zero at any time point (this rule also applies 
also to the lag phase, including the predose values).
CTP: For the non-compartmental analysis, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ or NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The 
lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
 
 
 


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In all other analyses 
 the last non-missing value 
determined prior to the first dosing of trial medication will be defined as baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
In general, the SRD and rel. BA part will be analysed separately, unless stated otherwise.
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINT
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis of 
the number of subjects with drug related AEs for the SRD part, which is the primary endpoint 
of this trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.


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rel. BA part:
Analysis of relative BA of secondary endpoints AUC0-tz, AUC0-∞and Cmax of BI 894416 in 
plasma will be performed as defined in Sections 7.1.1 and 7.3.2 of the CTP.
The statistical model for the main analysis defined in the CTP is an ANOVA model on the
logarithmic scale including "sequence", "period" and "treatment" as fixed effects and "subject
within sequence" as random effect.
A sensitivity analysis will be performed with the same model as described above but with 
subject as fixed effect.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (7).


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7.7
EXTENT OF EXPOSURE
Only listings are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)


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
The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (8) and "Handling of missing and incomplete AE 
dates" (4). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening or on-treatment phase as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 and for the class of 
AESIs.
CTP: The following are considered as AESIs in this trial:
Hepatic injury, as defined by the following alterations of hepatic laboratory parameters:
○
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
○
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (9), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related (primary 
endpoint) will be summarised separately. Separate tables will also be provided for subjects 
with SAEs, subjects with AESIs and subjects with other significant AEs (according to ICH E3 
(9)). The frequency of subjects with AEs and the frequency of subjects with AEs considered 
by the investigator to be drug related will also be summarised by maximum intensity, primary 
SOC and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency over all treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.


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For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (10).
Analyses will be based on original values.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator. 
 
 


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7.8.5
Others
Clinically relevant physical and 
 findings will be reported as relevant 
medical history/baseline condition (i.e., a condition already existent before intake of study 
drug) or as AE and will be summarised as such. No separate listing or analysis of physical or 
neurological examination findings will be prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trialss, current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; IDEA for CON
3
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
4
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
6
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON
7
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
8
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical 
Trials", current version; IDEA for CON
9
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
10
001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA 
for CON
11
Garnett C, Needleman K, Liu J, Brundage R, Wang Y. Operational characteristics 
of linear concentration-QT models for assessing QTc interval in the thorough QT 
and phase I clinical studies. Clin Pharmacol Ther 2016;100 (2):170-178 [R17-
0553]


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10.
HISTORY TABLE
Table 10: 1
History table
This is a revised TSAP including the following modifications to the final TSAP
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
04-JUL-2018
None
This is the final TSAP without any 
modification
Revised
17-Oct-2018
Sections 
5,6 and 
7
Rel. BA part included and description of 
analysis of rel. BA part added.
IPVs are now iPDs according to new 
SOP