Clinical trial NCT05213481
Conditions: Healthy
Keywords: Clinical pharmacology Metabolite Induction of metabolism
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Start date: 2021-12-15; Completion date: 2022-05-06
Enrollment: 18 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study was to assess the effect of multiple doses of carbamazepine on single- dose tepotinib pharmacokinetics in healthy participants. Study details include: Study Duration: up to about 10 weeks; Treatment Duration: single dose of tepotinib on Days 1 and 26, 25 days of treatment with carbamazepine (Days 8 to 32); Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 25 to 29, ambulatory daily visits from Days 5 to 24 and 30 to 33, and one ambulatory visit on Day 39.

Detailed description:

Arms: arm 1: Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 26 in the morning under fed state followed by Carbamazepine 100, 200 or 300mg oral dose under fed state twice daily at the same time each day in the morning and evening from Days 8 to Day 32
Interventions: intervention 1: Tepotinib intervention 2: Carbamazepine
Intervention descriptions: intervention 1: Participants received Tepotinib hydrochloride hydrate film-coated tablet once daily with food on Day 1 and Day 26 in the morning. intervention 2: Carbamazepine 100 mg twice daily at Day 8 and 9, 200 mg twice daily at Day 10 and 11, 300 mg twice daily from Day 12 to 32.

Protocol documents:
Prot_000.pdf: 


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SAP_001.pdf: 
Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 /2 6  
I nte gr ate d A n al ysis Pl a n 
St u d y N u m ber:  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Cli nic al St u d y Pr ot oc ol 
Title:  
P hase I, O pe n -la bel, Si n gle-s e q ue n ce, Cr oss-o v er St u d y of t he 
Effect of 
M ulti ple D os es of Car ba maze pi ne  o n Si n gle -d ose 
Te p oti ni b P har mac o ki netics i n Healt h y Partici pa nts  
St u d y P h ase : 
P hase I  
Merc k C o m p o u n d : 
Te p oti ni b   
Pr ot oc ol V ersi o n:  
0 3  Se p  2 0 2 1 / Versi o n 1. 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or : 
C o or di n ati n g A ut h or  
Bi o st ati sti c s, M er c k  
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
Bi o st ati sti c s, 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n : 
1 1  J a n 2 0 2 2  / Versi o n Fi nal  1 .0  
I nte gr ate d A n al ysis Pl a n 
Re vie wers : 
F u n cti o n  
N a m e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © [2 0 2 1 ] b y M erc k K G a A, D ar mst a dt, Ger m a n y or its a ffili ate. All ri g hts reser ve d. 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 /2 6  
 
 
A p pr o v al  P a ge   
 
I nte gr ate d A n al ysis Pl a n: M S 2 0 0 0 9 5 _ 0 0 5 1   
P hase I, O pe n -la bel, Si n gle-se q ue n ce, Cr oss-o v er St u d y of t he Effect of M ulti ple D oses of 
Car ba maze pi ne  o n Si n gl e -d ose Te p oti ni b P har mac o ki netics i n Healt h y Partici pa nts  
A p pr o val of t he I A P b y all Merc k Data A nal ysis Res p o nsi ble has t o be d oc u me nte d wit hi n E D M S 
via e Si g nat ure. 
Wit h t he a p pr o val, t he Merc k res p o nsi ble f or eac h of t he a nal ysis als o ta kes 
res p o nsi bilit y t h at all re vie wers’ c o m me nts are a d dresse d a d e q uatel y. 
B y usi n g e Si g n at ure, t he si g nat ur e will a p pear at t he e n d of t he d oc u me nt.  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 /2 6  
 
 
1  
T a ble of C o nte nts   
A p pr o val Pa ge  
 ..............................................................................................................2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms  ....................................5  
3  
M o dificati o n Hist or y  ............................................................................6  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  ...............................................6  
5  
O bjecti ves a n d E n d p oi nts  .....................................................................7  
6  
O ver vi e w of Pla n ne d A nal yses  .............................................................7  
7  
C ha n ges t o t he Pla n ne d A nal ys es i n t he Cli nical St u d y Pr ot o c ol  ........7  
8  
A nal ysis Sets a n d S u b gr o u ps  ................................................................8  
8. 1  
Defi niti o n of A nal ysis Sets  ...................................................................8  
8. 2  
S u b gr o u p D efi niti o n a n d Para meterizati o n  ..........................................8  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ............................................8  
9. 1  
Defi niti o n of Bas eli ne a n d C ha n ge fr o m Baseli ne  ...............................9  
9. 2  
St u d y Da y / St u d y I nter v e nti o n Da y  .....................................................9  
9. 3  
Defi niti o n of D urati o n a n d ‘ Ti me Si nce’ Varia bles  .............................9  
9. 4  
I m p utati o n of Missi n g Data ................................................................1 0  
1 0  
St u d y Partici pa nts  ...............................................................................1 0  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................1 0  
1 0. 2  
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ysis Sets  ..........................1 1  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................1 1  
1 0. 2. 2  
Reas o ns Lea di n g t o t he E x cl usi o n fr o m a n A nal ysis Set  ...................1 2  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................1 2  
1 1. 1  
De m o gra p hics  .....................................................................................1 2  
1 1. 2  
Me dical Hist or y  ..................................................................................1 2  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................1 2  
1 2  
Pre vi o us or C o nc o mita nt T hera pies/ Pr oce d ures  .................................1 2  
1 3  
St u d y I nter v e nti o n: C o m plia nce a n d E x p os ure  ..................................1 3  
1 4  
Efficac y A nal yses  ...............................................................................1 3  
1 5  
Safet y A n al yses  ..................................................................................1 4  
1 5. 1  
A d verse E v e nts  ...................................................................................1 4  
1 5. 1. 1  
All A d verse E v e nts  .............................................................................1 4  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 /2 6  
 
 
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Disc o nti n uati o n of St u d y I nter ve nti o n  ...1 5  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ...................................................................................1 6  
1 5. 2. 1  
Deat hs  .................................................................................................1 6  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................1 6  
1 5. 2. 3  
Ot her Si g nifica nt A d verse E ve nts  ......................................................1 6  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................1 6  
1 5. 4  
Vital Si g ns  ..........................................................................................1 7  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................1 7  
1 6  
A nal ys es of Ot her E n d p oi nts/ Esti ma n ds  ............................................1 8  
1 6. 1  
P har mac o ki netics  ................................................................................1 8  
1 6. 1. 1  
Descri pti ve Statistics of P K C o nce ntrati o n Data  ................................1 8  
1 6. 1. 2  
Descri pti ve Statistics of P K Para meter Data  ......................................1 8  
1 6. 1. 3  
Statistical A nal ysi s of P K Para meter Data .........................................1 9  
1 6. 1. 4  
Ge neral S pecificati o ns f or P K C o nce ntrati o n a n d P K Para meter 
Data  .....................................................................................................2 0  
1 6. 1. 5  
Esti mati o n of P har mac o ki netic Para meters  ........................................2 0  
1 6. 1. 5. 1  
Esti mati o n of P har mac o ki netic Para meters i n Plas ma  .......................2 1  
1 6. 1. 6  
Prese ntati o n of P K C o nce ntrati o n a n d P K Para m eter Data  ................2 3  
1 6. 1. 6. 1  
Listi n gs a n d Ta bles  .............................................................................2 3  
1 6. 1. 6. 2  
Gra p hical S u m maries a n d I n di vi d ual pl ots ( P K A nal ysis Set)  ...........2 4  
1 7  
Refere n ces  ...........................................................................................2 5  
1 8  
A p pe n dices  .........................................................................................2 6  
 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 /2 6  
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms  
 
A Da M  
A nal ysis D ata M o del  
A E  
A d verse E v e nt  
A N O V A  
A nal ysis of V A RI A N C E  
B L Q  
Bel o w L o w er Li mit of Q ua ntificati o n  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
CI  
C o nfi de nce I nter val  
C R  
C o m plete Res p o nse  
e C R F 
electr o nic Cas e Re p ort F or m  
C S R  
Cli nical St u d y  Re p ort  
E C G  
Electr ocar di o gra m  
I A P 
I nte grate d A nal ysis Pla n 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
M C A R  
Missi n g C o m pletel y At Ra n d o m  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
P T  
Preferre d Ter m  
P K  
P har mac o ki netics  
S A E  
Seri o us A d verse E v e nt  
 
 
S D T M  
St u d y Data Ta b ulati o n M o del  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T L F  
Ta bles, Listi n gs, a n d Fi g ures  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 /2 6  
 
 
3  
M o dific ati o n Hist or y   
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
Fi n al  1 .0  
1 1 -J a n -2 0 2 1  
 
I niti al v er si o n. 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n   
T he p ur p ose of t his I A P is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns f or t he fi nal a nal ysis 
of data c ollecte d f or pr ot oc ol M S 2 0 0 0 9 5 _ 0 0 5 1 . Res ults of t he a nal yses des cri be d i n t his I A P will 
b e i ncl u de d i n t he C S R . A d diti o nall y, t he pla n ne d a nal yses i de ntifie d i n t his I A P ma y  be i n cl u de d 
i n re g ul at or y s u b missi o ns or f ut ure ma n uscri pts. A n y p ost-h o c, or u n pla n ne d a nal yses perf or m e d 
t o pr o vi de res ults f or i ncl usi o n i n t he CS R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y 
i de ntifie d i n t he CS R.  
T he I A P is base d u p o n Secti o n 9  ( Statistical c o nsi derati o ns ) of t he st u d y pr ot oc ol a n d pr ot oc ol 
a me n d me nts a n d is pre p are d i n c o m plia nce wit h I C H E 9. It d escri b es a n al yses pla n ne d i n t he 
pr ot oc ol a n d pr ot oc ol a m e n d me nts . 
T he w or di n g use d i n t his I A P is c h ose n t o b est matc h t he res pecti ve w or di n g i n t he st u d y pr ot oc ol 
te m plate, t he 
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Re p ort ( C S R) te m plate, 
C DI S C re q uire me nts a n d s pecial 
re q uire me nts f or ta ble la y o uts. T heref ore, t he f oll o wi n g a p pr oac h is use d: 
Ge nerall y, t he ter m ‘ partici pa nt’ will be use d i nstea d of ‘s u bject’ or ‘ patie nt’. H o we v er, i n t a bles 
a n d listi n gs t he ter m ‘s u bject’ will be use d t o matc h C DI S C re q uir e me nts, e x ce pt f or i n -te xt ta bles 
w here ‘ partici pa nt’ will be use d t o mat c h t he C S R a n d pr ot oc ol te m plat es. Si milarl y, t he t er m 
‘st u d y i nter ve nti o n’ will be use d i n t his d oc u me nt i nstea d of ‘treat me nt’ t o matc h pr ot oc ol a n d 
C S R te m plates, h o we ver, ta bles a n d listi n gs will use ‘treat me nt’ f or bre vit y reas o ns. E x ce pti o ns 
fr o m t his r ule are c o m m o nl y use d ter ms li ke “ o n-treat me nt”, “treat me nt-e mer ge nt”, “tr eat me nt 
p olic y”, “s u bject -years”, “ b y -s u bject ”, or na mes of e C R F p a ges li ke “ Treat me nt Ter mi nati o n” 
pa ge.  
P P D




Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /2 6  
 
 
8  
A n al ysis Sets a n d S u b gr o u ps   
8. 1  
Defi niti o n of A n al ysis Sets   
A n al y si s S et  
D e s cri pti o n  
S cr e e ni n g ( S C R)  
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
e nr oll m e nt  a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.  
S af et y ( S A F)  
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n.  
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d.  
P h ar m a c o ki n eti c ( P K ) 
T h e P K A n al y si s S et  i s a s u b s et of t h e S A F, a n d th e P K p o p ul ati o n will i n cl u d e all 
p arti ci p a nt s:  
W h o h a v e c o m pl et e d t h e st u d y wit h o ut a n y r el e v a nt pr ot o c ol d e vi ati o n s a n d f a ct or s 
li k el y t o aff e ct t h e c o m p ar a bilit y of P K r e s ult s. 
Wit h a d e q u at e st u d y i nt er v e nti o n c o m pli a n c e.  
Wit h e v al u a bl e P K d at a, i. e., at l e a st o n e n o n -mi s si n g v al u e f or pri m ar y e n d p oi nt s.  
If p arti ci p a nt s r e c ei v e d pr o hi bit e d c o n c o mit a nt t h er a p y or m e di ci n e s, a s s p e cifi e d i n 
S e cti o n 6. 8 . 3 of t h e C S P , t h e y will b e e x cl u d e d fr o m t h e P K p o p ul ati o n. 
All P K a n al y s e s will b e b a s e d o n t hi s a n al y si s s et.  
 
8. 2  
S u b gr o u p D efi niti o n a n d P ar a meteriz ati o n   
N ot a p plica ble.  
9  
Ge ner al S pecific ati o ns f or D at a A n al yses   
T he res ults of t his st u d y will be re p orte d usi n g s u m mar y ta bles, fi g ures, a n d data listi n gs, as 
a p pr o priate. All dat a will be s u m marize d b y st u d y i nter ve nti o n a n d/ or sc he d ule d ti me p oi nt, as 
a p plica ble.  
Listi n gs  
In t he i n di vi d ual partici p a nt data listi n g  all i n di vi d ual data will be liste d as meas ure d . Re peat e d 
a n d u nsc he d ule d meas ure me nts will be i ncl u de d i n t he listi n gs.  All listi n gs will be s orte d b y s u bject 
I D, st u d y i nter ve nti o n, a n d n o mi nal ti me p oi nt, as a p pr o priate.  
T a bles a n d Descri pti ve St atistics  
All data will be s u m marize d b y st u d y i nter ve nti o n a n d n o mi nal ti me p oi nt, as a p pr o priate. 
Re peate d a n d u nsc he d ul e d meas ure me nts i ncl u d e d i n t he listi n gs will n ot be use d f or statistical 
a nal ys es or s u m maries, u nless t he re peate d m eas ure m e nt was perf or me d d ue t o u nrelia ble 
val ues/tec h nical r eas o ns, e .g ., cl otte d sa m ples.  
U nless ot her wise s pecifi e d, c o nti n u o us varia bles will be s u m marize d usi n g des cri pti ve statistics, 
i.e. t he n u m ber of partici pa nts wit h n o n-missi n g val ues ( n), t he n u m ber of partici pa nts wit h missi n g 
val ues ( n miss), mea n, sta n dar d de viati o n, m e dia n, 2 5t h perce ntile ( Q 1) a n d 7 5t h perce ntile ( Q 3), 
mi ni m u m, a n d ma xi m u m . If t h ere are n o missi n g val ues t he n u m ber of partici pa nts wit h missi n g 
val ues s h o ul d be i n dicate d b y a 0.  M ea n, Me dia n, Q 1, Q 3, Mi n, Ma x will ha ve t he sa me precisi o n 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 /2 6  
 
 
as t he S D T M da ta ( deci mal places). S D will be prese nte d wit h o ne deci mal place m or e t ha n t h e 
mea n.  
Q ualitati ve varia bles will be s u m marize d b y fre q u e nc y c o u nts a n d perce nta ges. U nless ot her wise 
state d t he calc ul ati o n of pr o p orti o ns will be base d o n t he n u m ber of p artici p a nts of t he a nal ysis set 
of i nterest  t h at recei ve d t he res p ecti ve st u d y i nter ve nti o n f or A E a n d P K t a bles a n d f or all ot her 
e val uati o ns  t he a nal ysis set of i nterest [ N]. T heref ore, c o u nts of missi n g o bser vati o ns will be 
i ncl u de d i n t he de n o mi nat or a n d prese nt e d as a s e parate cate g or y.   
St u d y D a y 1 f or t his st u d y is defi n e d as t he start d ate of st u d y i nter ve nti o n. 
T he f oll o wi n g la bels will be use d f or t he st u d y i nter ve nti o ns i n ta bles a n d listi n gs, if n ot state d 
ot her wise:  
Te p oti ni b : 
 
Te p oti ni b: 5 0 0 m g o n Da y 1  
 
Car ba maze pi ne : 
 
Car ba maze pi ne : 1 0 0 
m g  BI D 
o n 
Da ys 8 -9, 2 0 0 
 
 
m g BI D o n Da ys 1 0 -1 1, a n d 3 0 0 m g BI D o n Da ys 1 2 -2 5   
Car ba maze pi ne + T e p oti ni b :  
 
Car ba maze pi ne: 3 0 0 m g Car ba maze pi ne  BI D o n  Da y s 
 
2 6 -3 2  pl us Te p oti ni b: 5 0 0 m g o n  Da y 2 6  
St u d y i nte r ve nti o ns will be or dere d i n ta bles, listi n gs a n d fi g ures as a b o ve. 
All statistical a nal yses will be perf or me d usi n g S A S ®  S oft ware v ersi o n 9. 4  or hi g her . 
9. 1  
Defi niti o n of B aseli ne  a n d C h a n ge fr o m B aseli ne   
If n ot ot her wis e s pecifie d, ‘ bas eli ne’ refers t o t he last sc he d ule d 
meas ure me nt b ef ore 
a d mi nistrati o n of first st u d y i nter ve nti o n. 
H o we ver, if a partici pa nt is missi n g t he b asel i ne c ollecti o n, t he pre vi o us n o n-missi n g e v al uati o n 
c o ul d bec o me t he bas eli ne val ue (e. g. fr o m S cree ni n g). If n o baseli ne or pre vi o us t o baseli ne 
e val uati o ns e xist, t he n t he baseli ne val u e will be treate d as missi n g.  
A bs ol ute c ha n ge s fr o m b aseli ne are defin e d as   
 
a bs ol ute c ha n ge = visit val ue –  baseli ne v al ue  
9. 2  
St u d y D a y / S t u d y Inter ve nti o n D a y   
Da y 1 is t he da y of start of st u d y i nter ve nti o n, t he da y b ef ore is Da y -1 ( n o Da y 0 is defi ne d). St u d y 
da y is defi ne d relati ve t o Da y 1.  
9. 3  
Defi niti o n of D ur ati o n  a n d ‘T i me S i nce’ V ari a bles   
T he f oll o wi n g d efi niti o ns a n d  calc ul ati o ns of d urati o n , as a p plica ble, will be a p plie d:  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /2 6  
 
 
•  D urati o n of a d v erse e ve nt ( A E ) (i n da ys h h: m m) = e n d date a n d ti me - start date a n d ti me of 
t he A E, if missi n g ti me f or eit her t he be gi n ni n g or e n d t he n = e n d date –  start date + 1; i n case 
of m ulti ple rec or ds f or t he sa m e A E, t he d urati o n will be calc ulate d o ver all t hese rec or ds  
•  Da ys h h: m m fr o m d osi n g ( o nset p ost a d mi nistrati o n) = start d ate a n d ti me of t he e ve nt - dat e 
a n d ti me of l ast d ose a d mi nistrati o n of te p oti ni b or Car ba maze pi ne  (calc ulate d f or eac h 
i nter ve nti o n, f or T E A Es), if missi n g ti me f or eit her t he d osi n g or e ve nt t he n da ys h h: m m fr o m 
d osi n g = e ve nt start date –  date of d ose a d mi nistrati o n + 1  
•  Relati ve Da y i n st u d y of A E = start date of t he e ve nt –  date of first ad mi n + 1 (f or A Es o n or 
after t he d a y of d osi n g)  
•  Rel ati ve Da y i n st u d y of A E = start date of t he e ve nt –  date of first ad mi n (f or e ve nts bef ore t he 
da y of d osi n g of t he st u d y o nl y)  
9. 4  
I m p ut ati o n of M issi n g D at a   
I n t his P hase I P K st u d y, missi n g o bser vati o ns will be ass u me d t o be missi n g c o m pletel y at ra n d o m 
( M C A R). N o acti o n will be ta ke n t o ha n dle missi n g dat a. A partici p a nt w h o wit h dra ws pri or t o t he 
last pla n ne d o bser vati o n i n a st u d y peri o d will be i ncl u de d i n t he a n al yses u p t o t he ti me of 
disc o nti n uati o n.  
1 0  
St u d y P artici p a nt s  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g partici pa nt  dis p ositi o n a n d 
st u d y i nter ve nti o n/st u d y disc o nti n uati o ns. 
A d diti o nall y , pr oce d ures f or re p orti n g pr ot oc ol 
de viati o ns are pr o vi d e d.  
1 0. 1  
Dis p ositi o n of P artici p a nt s a n d Disc o nti n u ati o ns  
T he f oll o wi n g will be prese nte d i n a s u m mar y ta bl e: 
•  T otal n u m ber of partici pa nts scree n e d (i.e., p artici pa nts w h o ga ve i nf or me d c o nse nt)  
•  N u m ber of scree n e d partici pa nts w h o disc o nti n ue d fr o m t he st u d y pri or t o first d osi n g o verall  
a n d gr o u pe d b y t he mai n reas o n f or disc o nti n uati o n:  
•  Partici pa nt di d n ot meet all eli gi bilit y criteria  
•  Wit h dre w c o nse nt   
•  Ot her  ( C O VI D-1 9 -relate d a n d C O VI D-1 9 -n o n -relate d)  
•  N u m ber of treate d partici pa nts  
•  N u m ber a n d p erce nta ge of treate d p artici pa nts w h o c o m plete d st u d y  
•  N u m ber a n d perce nt a ge of treate d partici pa nts 
w h o disc o nti n ue d t he st u d y or 
st u d y 
i nter ve nti o n, wit h t he pri mar y reas o n of disc o nti n uati o n:  
•  A d verse e ve nt  
•  L ost t o f oll o w -u p  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /2 6  
 
 
•  Pr ot oc ol n o n -c o m plia nce  
•  Deat h  
•  Wit h dre w c o nse nt  
•  Ot her ( C O VI D -1 9 -relate d a n d C O VI D-1 9 -n o n -relate d) 
T he n u m ber a n d perce nta ge of partici pa nts will be prese nte d b y gr o u p of st u d y i nter ve nti o n a n d 
t otal, w here a p plica ble. Perce nta ges will be prese nte d wit h res pect t o t he n u m ber of tr eate d 
partici pa nts , w here a p pli ca ble. 
A listi n g of disc o nti n u e d partici pa nts will be pr o vi de d.  
A listi n g of p artici pa nts affect e d b y t he C O VI D -1 9 relate d st u d y disr u pti o n b y u ni q u e partici pa nt 
i de ntifier will als o be pr o vi de d. 
1 0. 2  
Pr ot oc ol De vi ati o ns  / E xcl usi o n fr o m A n al ysis Sets   
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns  
Listi n gs of i m p orta nt pr ot oc ol de viati o ns will be pr o vi de d i ncl u di n g t he d ate a n d relati ve da y i n 
relati o n t o first d osi n g i n t he st u d y. A disti ncti o n will be ma de b et wee n i m p orta nt pr ot oc ol 
de viati o ns d ue t o C O VI D -1 9 vers us n ot d ue t o C O VI D -1 9. T he res pec ti ve i m p orta nt pr ot oc ol 
de viati o ns will be fla g ge d acc or di n gl y.  
I m p ort a nt pr ot oc ol d e viati o ns or i m p orta nt e ve nts t hat mi g ht h a ve a n effect o n P K i ncl u de, b ut 
ma y n ot be li mite d t o t he f oll o wi n g:  
•  A d verse e ve nts  li ke diarr hea etc. (t hese i nsta nces will be d isc usse d o n a case-b y cas e basis)  
•  V o miti n g after a d mi nistrati o n f oll o wi n g oral d osi n g (t hes e i nsta nces will be disc usse d i n 
ali g n me nt wit h a p plica bl e re g ulat or y g ui d eli nes o n a case -b y case basis)  
•  Sa m ple pr ocessi n g err ors t hat ma y lea d t o i nacc urate bi oa nal ytical r es ults  
•  I n acc urate d osi n g or d osi n g err ors (e. g. d os e a d mi nistrati o n dela ye d, d ose c ha n ge or misse d 
d oses)  
•  Pre -d ose or tr o u g h s a m ple c ollecte d after t h e act u al d osi n g  
•  N o n -c o m plia nce 
wit h f o o d a n d dri n k re q uire me nts (e. g. n o n -faste d, i nc o m plete meal 
c o ns u m pti o n, caffei n e i nta ke)  
•  C o nc o mita nt me dicati o n, vita mi ns, dietar y or her bal s u p ple me nts  
S h o ul d o ne or m ore of t hese e ve nts b e a v aila ble at t he Data Re vie w M eeti n g, its i m plicati o n f or 
P K e val uati o n will be disc usse d a n d a gree d a m o n gst rele va nt st u d y t ea m me m bers (e. g. S p o ns or 
Cli nical P har mac ol o g y/ Bi ostatistics/ Cli nical P har mac o ki netics 
& P har mac o d y na mics tea m 
re pres e ntati ve). A p pr o priate acti o n will be ta ke n s uc h as fla g gi n g i n di vi d ual val ues t o be e x cl u de d 
fr o m a nal ysis.  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /2 6  
 
 
1 0. 2. 2  
Re as o ns Le a di n g t o t h e E xcl usi o n fr o m a n A n al ysis Set   
If partici pa nts are e x cl u de d fr o m t he P K A nal ysis Set, t he reas o ns f or e x cl usi o n will be liste d.  
Reas o ns f or e x cl u di n g i n di vi d ual P K c o nce ntrati o ns will als o be liste d se paratel y a n d fla g ge d i n 
t he mai n listi n g. 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics   
De m o gra p hics a n d baseli ne c haracteristics will be prese nte d f o r t he S A F.   
1 1. 1  
De m o gr a p hics   
Descri pti ve statistics will be pres e nte d f or a ge, hei g ht, wei g ht, a n d b o d y mass i n de x ( B MI). 
Fre q u e nc y c o u nts a n d perce nta ges will be prese nt e d f or s e x, race, a n d et h nicit y. T he s u m mar y will 
be perf or me d o verall.  
B MI ( k g/ m2) will be deri ve d (i .e., n ot ta ken dir ectl y fr o m t he d ata bas e) acc or di n g t o t h e f oll o wi n g 
f or m ula: 
B MI [k g/ m² ] = 
w ei g ht  [k g ] 
h ei g ht [c m ]2 × 1 0 0 0 0  
1 1. 2  
Me dic al Hist or y   
Me dical hist or y will be c o de d usi n g t he M e dical Dict i o nar y f or R e g ulat or y Acti vities ( Me d D R A), 
m ost c urre nt v ersi o n at ti me of data bas e l oc k , a n d liste d. 
T he me dical hist or y will be liste d b y p artici pa nt i ncl u di n g  preferre d ter m  ( P T) as e ve nt cate g or y 
a n d s yste m or ga n class ( S O C) b o d y ter m as B o d y S yste m cate g or y.   
1 1. 3  
Ot her B aseli ne C h ar acteristics   
Ot her baseli ne meas ur e m e nts, s uc h as vir us scree n, alc o h ol a n d dr u gs of a b use scree n, pre g na nc y 
test i n w o me n, nic oti ne a n d alc o h ol c o ns u m pti o n, will be liste d. 
Baseli ne 
c haracteristics 
wit h 
res pect 
t o 
vital 
si g ns, 
p h ysical 
e x a mi nati o ns, 
a n d 
he mat ol o g y/ bi oc h e mistr y will be part of Secti o n 1 5  ( Safet y A nal ysis ). 
1 2  
P re vi o us  or C o nc o mit a nt T her a pies / Pr oce d ures  
Me dicati o ns will be pres e nte d f or t he S A F . 
Pre vi o us me dicati o ns are defi ne d as a n y m e dicati o n disc o nti n ue d pri or t o t he a d mi nistrati o n of 
first st u d y i nter ve nti o n. C o nc o mita nt me dicati o ns are defi ne d as a n y m e dicati o n ta ke n d uri n g t he 
c o urse of t he st u d y, wit h a starti n g d ate great er t h a n or e q ual t o t h e a d mi nistrati o n of first st u d y 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /2 6  
 
 
i nter ve nti o n, or wit h a starti n g dat e pri or t o t he a d mi nistrati on of first st u d y i nter ve nti o n a n d 
o n g oi n g at t he ti me of t h e first a d mi nistrati o n of st u d y i nter ve nti o n.  
T he W orl d Healt h Or ga niz ati o n Dr u g dicti o nar y ( W H O -D D), m ost c urre nt versi o n at ti me of 
data base l o c k , will be use d f or c o di n g of pri or a n d c o nc o mita nt  me dicati o ns a n d t he y will be 
descri be d usi n g Preferre d Ter m ( P T) as a p plica ble.  
Pre vi o us a n d c o n c o mita nt me dicati o ns will be liste d. C o nc o mita nt pr oce d ures, if a n y, will als o b e 
liste d. 
1 3  
St u d y Inter ve nti o n : C o m pli a nce a n d E x p os ure   
T he d osi n g of eac h p arti ci pa nt is m o nit ore d b y t he st u d y n urse or i n vesti gat or. A listi n g of date 
a n d ti me of eac h dr u g a d mi nistrati o n a n d eac h bl o o d sa m pli n g , i ncl u di n g ti me de viati o ns as well 
as meas ure d plas ma c o n ce ntrati o ns, will be pr o vi de d s orte d b y partici pa nt . I nf or mati o n o n meal 
i nta ke will be liste d b y p artici pa nt, if pr o vi de d. 
1 4  
Effic ac y A n al yses   
N ot a p plica ble . 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /2 6  
 
 
1 5  
S afet y A n al yses   
T his secti o n i ncl u des s pecificati o ns f or s u m mari zi n g safet y e n d p oi nts t h at are c o m m o n acr oss 
cli nical st u dies s uc h as a d verse e v e nts, la b orat or y tests a n d vital si g ns. 
All safet y a nal yses will be perf or me d f or t he Safet y A nal ysis Set a n d will be prese nte d b y  st u d y 
i nter ve nti o n a n d n o mi nal ti me p oi nt, as a p pr o priate.  
Safet y a nal yses will be d o ne acc or di n g t o t he as -tr eate d pri nci ple.  
1 5. 1  
A d verse E ve nts   
All A Es rec or de d d uri n g t he c o urs e of t he st u d y will be c o d e d wit h t h e Me d D R A, latest v ersi o n at 
ti me of data base l o c k, a n d assi g ne d t o a S O C a n d a P T.  
Treat me nt -e mer ge nt A Es ( T E A Es) are t h ose e ve nt s wit h o nset dates o n or after t he first 
a d mi nistrati o n of st u d y i nter ve nti o n  o n Da y 1 . A n y A E occ urri n g b ef ore t he a d mi nistrati o n of 
st u d y i nter ve nti o n o n D a y 1 a n d res ol ve d b ef ore a d mi nistrati o n of st u d y i nter ve nti o n or n ot 
w orse ni n g aft er a d mi nistrati o n  of st u d y i nter ve nti o n o n Da y 1  will be i n cl u de d i n t he A E listi n gs  
b ut will n ot be i ncl u de d i n t he s u m mar y ta bl es ( u nless ot her wise state d). T h ese will be referre d t o 
as “ pre -treat me nt” A Es. A n A E occ urri n g aft er a d mi nistrati o n of a n y st u d y i nter ve nti o n will be 
c o u nte d t o war ds t he last i nter ve nti o n recei ve d bef ore t he o nset, e ve n if t he e ve nt is n ot res ol ve d at 
t he be gi n ni n g of t he f oll o wi n g i nter ve nti o n. A n A E t hat w orse ns after a later i nter ve nti o n peri o d 
will be c o u nte d t o war ds b ot h st u d y i nter ve nti o ns. 
I n case A E-relate d dat es are partial, t he a vaila ble i nf or mati o n will be use d i n a c o nser vati ve 
a p pr oac h t o d eter mi ne w het her t he A E is treat me nt -e mer ge nt.  
All a nal yses d escri b e d i n Secti o n 1 5. 1  will be b ase d o n T E A Es if n ot ot her wise s pecifi e d. T h e A E 
listi n gs will i ncl u de all A Es ( w het h er tr eat me nt-e mer ge nt or n ot). A Es o utsi de t he o n -tr eat me nt 
peri o d will be fla g ge d i n t he listi n gs.  
U nless ot her wise  s pecifie d, T E A Es will be s u m marize d , b y n u m ber a n d perce nta ge of partici pa nts 
wit h t he T E A E i n t he cat e g or y of i nterest , as well as t he n u m ber of e ve nts, i n t otal a n d b y st u d y 
i nter ve nti o n gr o u p, pri mar y S O C a n d P T  i n al p ha betical or der f or S O C a n d decreasi n g o verall 
fre q ue n c y f or P T.  
If a n e v e nt w as re p orte d m ore t ha n o nce d ue t o c h a n ge i n i nte nsit y a n d c ha n ge i n relati o ns hi p, t he 
w orst se verit y a n d t he w orst relati o ns hi p t o trial treat me nt will be ta b ulate d.  
Eac h partici pa nt will be c o u nte d o nl y o nce wi t hi n eac h S O C or P T.  
1 5. 1. 1  
All A d verse E ve nts   
N u m ber of t reat me nt-e mer ge nt A Es a n d n u m ber of p artici pa nts e x peri e nci n g T E A Es will be 
s u m marize d f or Te p oti ni b , Car ba maze pi ne , Car ba maze pi ne + Te p oti ni b  a n d o verall , eac h i n ta bles 
wit h:  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /2 6  
 
 
•  T he n u m ber a n d perce nta ge of partici pa nts wit h a n y T E A E, a n y relat e d T E A E,  a n y te p oti ni b-
relate d T E A E, a n y c ar ba maze pi ne -relate d T E A E, a n y s eri o us T E A E, a n y relate d seri o us T E A E, 
a n y t e p oti ni b-relate d seri o us T E A E, a n y car ba maze pi ne -rel ate d seri o us T E A E, a n y s e vere 
T E A E, a n y relat e d se vere T E A E, a n y te p oti ni b-relate d se v ere T E A E, a n y car ba maze pi ne -
relate d se vere T E A E, a n y A Es of s peci al i nterest ( A E SI), a n y T E A E lea di n g t o deat h, a n y 
relate d T E A E l eadi n g t o deat h, a n y t e p oti ni b-relate d T E A E lea di n g t o deat h, a n y 
car ba m aze pi ne  -relate d T E A E lea di n g t o deat h, a n y T E A E l ea di n g t o st u d y disc o nti n uati o n  
•  T he n u m ber a n d perce nt a ge of partici p a nts wit h at least o ne T E A E a n d t he n u m ber of e ve nts 
b y S O C a n d P T . 
•  T he n u m ber a n d p erce nta ge of partici pa nts wit h T E A Es e x cl u di n g S A Es  a n d t he n u m ber of 
e ve nts , wit h fre q u e nc y ≥ 5 % i n a n y st u d y i nter ve nti o n ar m b y S O C a n d P T 
•  T he n u m ber a n d perce nt a ge of partici p a nts wit h at least o ne T E A E a n d t he n u m ber of e ve nts 
b y se v erit y, S O C, a n d P T  
•  T he n u m ber a n d p erce nt a ge of partici p a nts wit h at least o n e relate d T E A E , te p oti ni b-relate d 
T E A E, car ba maze pi ne  -relate d T E A E a n d t he n u m ber of e v e nts b y S O C a n d P T  
•  T he n u m ber a n d perce nta ge of p artici pa nts wit h at least o ne A E SI rec or de d a n d t he n u m ber of 
e ve nts b y S O C a n d P T.  
U nless ot her wise state d, A Es will be dis pla ye d wit h S O C ter ms  s orte d al p ha beticall y a n d P Ts 
wit hi n eac h S O C ter m s orte d i n desce n di n g o v erall fre q ue n c y.  
F or deter mi ni n g i nci de n ce c o u nts, wit hi n eac h le vel of T E A E ter m, if a partici pa nt e x perie nces 
m ore t ha n o ne occ urre nce, t he partici pa nt will o nl y be c o u nte d o nce f or t h at T E A E.  
A d verse e ve nts relate d t o a n y st u d y i nter ve nti o n  are t h ose e v e nts wit h relati o ns hi p missi n g, 
u n k n o w n or yes.  
I n case a partici pa nt had e ve nts wit h missi n g a n d n o n -missi n g se verit y, t he ma xi m u m n o n -missi n g 
se verit y will be dis pla ye d.  
1 5. 1. 2  
A d verse 
E ve nts 
Le a di n g t o 
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n  
A listi n g of T E A Es lea di n g t o disc o nti n uati o n of st u d y i nter ve nti o n, or disc o nti n uati o n of st u d y, 
if a n y, will be pr o vi de d.   
T he fre q u e nc y ( n u m ber a n d perce nt a ge) of partici pa nts wit h T E A Es lea di n g t o per ma n e nt 
disc o nti n uati o n of eac h st u d y i nter ve nti o n b y st u d y i nter v e nti o n will als o be pr o vi de d i n a ta ble.  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6 /2 6  
 
 
1 5. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts   
1 5. 2. 1  
De at hs   
A listi n g of deat hs, if a n y, will be pr o vi de d . 
1 5. 2. 2  
Seri o us A d verse E ve nts   
A listi n g of seri o us A Es ( S A Es), if a n y, will be pr o vi de d.   
S u m mar y ta ble of t he n u m ber a n d perce nta ge of partici pa nts wit h at least o ne S A E b y S O C a n d 
P T  will als o be pr o vi de d.  
1 5. 2. 3  
Ot her Si g nific a nt A d verse E ve nts   
T he f oll o wi n g A E SI s were defi n e d : 
•  A Es s u g gesti ve of dr u g -i n d uce d li ver i nj ur y i n cl u di n g h e patic/li ver fail ure a n d he p atitis 
( n o ni nfecti o us) are c o nsi dere d A E SIs. 
M ore i nf or mati o n c a n be f o u n d i n t he C S P, S ecti o n 8. 3. 7.  
A E SI s will be i de ntifie d i n t he A E listi n gs. S u m mar y t a ble of t he n u m ber a n d perce nta ge of 
partici pa nts wit h at least o ne A E SI b y S O C a n d P T  will als o be pr o vi de d . 
 
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n   
Listi n gs a n d s u m mar y statistics at eac h assess me nt ti me will be prese nte d usi n g t he S ystè me 
I nter nati o nal ( SI) u nits. N or mal ra n ges will be pr o vi de d b y t h e la b orat or y de part me nt , a n d o ut of 
ra n ge fla gs will be calc ulate d base d o n t he n or mal ra n ges. La b orat or y dat a n ot tra nsferre d fr o m 
t he ce ntr al la b orat or y i n SI u nits will b e c o n v erte d t o SI u nits bef ore pr ocessi n g. B ot h ori gi n al 
u nits a n d SI u nits will be pr o vi de d i n t he S D T M d o mai n.  
Safet y l a b orat or y p ara meters are s e parate d i nt o:  
•  He mat ol o g y (i ncl u di n g c oa g ul ati o n)  
•  Bi oc he mistr y  
•  Uri nal ysis  
•  Ot her tests  
H e mat ol o g y a n d bi oc h e mistr y will be s u m marize d  b y st u d y i nter ve nti o n a n d ti me p oi nt usi n g 
descri pti ve statistics f or baseli ne (see d efi niti o n i n Secti o n 9 ), eac h e val u ati o n d uri n g t he st u d y, 
a n d c ha n ge fr o m bas eli ne t o eac h e val uati o n.  
S u m maries will i ncl u de all assess me nts fr o m scree ni n g o n. 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /2 6  
 
 
Listi n gs of a b n or mal test res ults (l o w a n d hi g h) will als o be pr o vi de d.   
1 5. 4  
Vit al Si g ns   
Vital si g ns data will be s u m marize d b y st u d y i nter ve nti o n a n d ti me p oi nt usi n g descri pti ve statistics 
f or baseli ne (see d efi niti o n i n Secti o n 9 ), eac h e val uati o n d uri n g t he st u d y, a n d c ha n ge fr o m 
baseli ne t o eac h e val u ati o n. Listi n g of vital si g ns data will be pr o vi de d.    
Vital si g n s u m maries will i ncl u de all vital si g n assess me nts fr o m scree ni n g o nwar ds . All vital si g n 
assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n -treat me nt peri o d will be fla g ge d i n 
t he listi n g.  
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns   
Safet y E C G d ata will be s u m marize d b y st u d y i nter ve nti o n a n d ti me p oi nt usi n g descri pti ve 
statistics f or baseli ne (see defi niti o n i n Secti o n 9 ), eac h e v al uati o n d uri n g t he st u d y, a n d c ha n ge 
fr o m baseli ne t o e ac h e v al uati o n. Listi n g of safet y E C G data will be pr o vi de d.  
E C G s u m maries will i ncl u de all E C G assess m e nts fr o m  scree ni n g o nwar ds . All E C G assess me nts 
will be liste d . 
T he a nal ysis of Q T data is c o m plicate d b y t he fact t hat t he Q T i nter val is hi g hl y c orrelate d wit h 
heart rate. Beca use of t his c orrelati o n, f or m ulas are r o uti nel y use d t o o btai n a c orrecte d val ue, 
de n ote d Q Tc, w hic h is i n de pe n de nt of h eart rate. T his Q Tc i n ter val is i nte n d e d t o re prese nt t he Q T 
i nter val at a sta n dar dize d heart rate. Se veral c orrecti o n f or m ulas ha v e bee n pr o p ose d i n t he 
literat ure. T h e Q T i nter val will be c orrecte d f or h eart rate b y t h e Fri derici a’s f or m ula, Q Tc F, is 
defi ne d as   
 , 
w here R R  re pres e nts t he R R i nter val of t he E C G, i n sec o n ds, a n d ca n be esti mate d as 6 0/ Heart 
Rate.   
I n v esti gat or re p orte d i nt er pret ati o n res ults will als o be ta b ulate d b y  st u d y i nter venti o n a n d ti me 
p oi nt  usi n g t he n u m ber a n d perce nta ge of partici p a nt s f or eac h inter pretati o n cate g or y ( N or mal, 
A b n or mal N ot Cli nicall y Si g nifica nt [ N C S], A b n or m al Cli nicall y Si g nifica nt [ C S]).  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /2 6  
 
 
1 6  
A n al yses of Ot her E n d p oi nts/ Esti m a n ds   
1 6. 1  
P h ar m ac o ki netics   
P K e val uati o n will be perf or me d b y 
.   
All statistical a nal ys es a n d descri pti ve s u m maries of P K data will be perf or me d o n t he P K  A nal ysis 
Set . 
1 6. 1. 1  
Descri pti ve St atistics of P K C o nce ntr ati o n D at a   
P K meas ure me nts  of te p oti ni b a n d its meta b olites ( M S C 2 5 7 1 1 0 9 A a n d M S C 2 5 7 1 1 0 7 A) as well 
as car ba maze pi ne a n d its meta b olite car ba maze pi n e -1 0, 1 1 -e p o xi de i n plas ma will be des cri pti vel y 
s u m marize d usi n g n u m ber of n o n-missi n g o bser vati o ns ( n), arit h metic mea n ( Mea n), sta n dar d 
de viati o n ( S D), c o effici e nt of variati o n ( C V %), mi ni m u m ( Mi n), me dia n ( Me dia n) a n d ma xi m u m 
( Ma x).  
Descri pti ve statistics will o nl y be calc ula t e d f or n > 2 i n w hic h a meas ure me nt of bel o w l o wer li mit 
of q ua ntificati o n ( B L Q ) re pres e nts a vali d meas ure me nt a n d will be ta ke n as zer o f or s u m mar y 
statistics of P K c o nce ntrati o n data. 
A n y me a n or me dia n v al ue t hat is bel o w t he  l o wer li mit of q ua ntificatio n  will be s h o w n as B L Q.  
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o ur ce d ata a n d r o u n de d f or re p orti n g p ur p os es o nl y. I n e x p ort datasets, as well as 
i n t he S D T M P C d o mai n, P K c o nce ntrati o ns will be pr o vi de d wit h f ull precisi o n a n d will n ot b e 
r o u n de d. 
T he f oll o wi n g c o n v e nti o ns 
will be a p plie d 
w he n re p orti n g des cri pti ve statistics of P K 
c o nce ntr ati o n data:  
N  
0 deci mal place  
Mea n, Mi n, Me dia n, Ma x:  
3 si g nifica nt di gits  
S D:  
4 si g nifica nt  di gits  
C V %:  
1 deci mal place  
1 6. 1. 2  
Descri pti ve St atistics of P K P ar a meter D at a   
P K para meter data of t e p oti ni b a n d its meta b olites ( M S C 2 5 7 1 1 0 9 A a n d M S C 2 5 7 1 1 0 7 A) o n 
Da y s 1 a n d 2 6  will be descri pti vel y s u m marize d usi n g: n u m ber of n o n -missi n g o bser vati o ns ( n), 
arit h metic mea n ( M ea n), sta n dar d de viati o n ( S D), c oefficie nt of v ariati o n ( C V %), mi ni m u m 
( Mi n), me dia n ( Me dia n), ma xi m u m ( Ma x), ge o metric mea n ( Ge o Mea n), t he ge o m etric c o efficie nt 
o f variati o n ( Ge o C V) a n d t he 9 5 % c o nfi de n ce i nter val f or t he Ge o Mea n ( L CI 9 5 % G M, U CI 9 5 % 
P P D


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /2 6  
 
 
G M). F or P K para meters relate d t o ti me (e. g. t ma x, tla g, tlast), o nl y n, Mi n, Me dia n, a n d Ma x ma y 
be re p ort e d.  
Descri pti ve statistics will o nl y be calc ulate d f or a P K  para meter w he n n > 2.  
P K para met ers rea d directl y fr o m t he m eas ure me nts (i.e. C ma x) will be re p orte d wit h t he sa me 
precisi o n as t he s o urce data. All ot her P K para meters will be re p orte d t o 3 si g nifica nt fi g ures. I n 
e x p ort datasets, as well as i n t he S D T M P P d o mai n, P K para met ers will be pr o vi de d wit h f ull 
precisi o n a n d will n ot be r o u n de d. D escri pti ve statistics of P K para meter d ata will be calc ulate d 
usi n g f ull precisi o n val ues a n d r o u n de d f or re p orti n g p ur p os es o nl y.  
T he f oll o wi n g c o n v e nti o ns will be a p pl ie d w he n re p orti n g des cri pti ve statistics of P K para meter 
data:  
n  
0 deci mal place  
Mea n, Mi n, Me dia n, M a x, Ge o Mea n, 9 5 % CI:  3 si g nifica nt di gits  
S D:  
4 si g nifica nt di gits  
C V %, Ge o C V %:  
1 deci mal place  
1 6. 1. 3  
St atistic al A n al ysis of P K P ar a meter D at a   
A n al ysis  of Pri m a r y E n d p oi nts  
T he  effect of c o -a d mi nistrati o n of Car ba maze pi ne  o n te p oti ni b e x p os ure will be assess e d. A  
ge n eral li near m o del wit h a fi x e d effect f or T R E A T M E N T a n d a ra n d o m effect f or S U BJ E C T  will 
be a p plie d t o t he l o g-tr a nsf or me d P K p ara m eters Cma x , A U C0 -tlast a n d A U C 0 -∞ base d  o n t he P K 
a nal ysis set . Treat me nt differe n ces  o n t he l o g s cale of te p oti ni b wit h Car ba maze pi ne  v ers us 
te p oti ni b al o ne (Da y  2 6  vers us Da y 1 ) will be esti mate d f or t he C ma x , A U C0 -tlast a n d A U C 0 -∞ 
t o get her wit h t heir 9 0 % CIs. P oi nt esti mates a n d CIs will be bac k tr a nsf or me d t o t he ori gi nal scal e 
f or pres e ntati o n. 
T he a nal ysis will be re p eate d wit h b ot h s u bject a n d treat me nt as fi x e d effects.  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
C CI


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /2 6  
 
 
 
1 6. 1. 4  
Ge ner al 
S pecific ati o ns f or 
P K 
C o nce ntr ati o n a n d 
P K 
P ar a meter D at a   
Pre d ose sa m ples t hat occ ur bef ore t he first dr u g a d mi nistrati o n will be assi g ne d a ti me of 0 h o urs, 
as if t he sa m ple ha d bee n ta ke n si m ulta ne o usl y wit h t he st u d y i nter ve nti o n a d mi nistrati o n. Sa me 
a p plies t o t he pre-d os e sa m ple after m ulti ple d oses.  
Pre d ose or tr o u g h s a m ples w hic h ha ve bee n ta ke n after t he s u bse q ue nt d osi n g will b e re p orte d as 
a pr ot oc ol de viati o n. T he res ulti n g c o n ce ntrati o ns will be i ncl u de d i n c o nce ntrati o n listi n gs b ut 
e x cl u de d fr o m descri pti v e statistics of c o nce ntr ati o ns .  
Val ue s B L Q  will be ta ke n as zer o f or s u m mar y st atistics of P K c o nce ntrati o n data, P K p ara met er 
esti mati o n (e. g. A U C) a n d f or gra p hic al pres e ntati o ns.   
Missi n g c o n ce ntrati o ns (e. g. n o s a m ple, i ns uffi cie nt sa m ple v ol u me f or a nal ysis, n o res ult or res ult 
n ot vali d ) will be re p orte d a n d use d ge nerall y as “ N. R.”. A partici pa nt w h o wit h dra ws pri or t o t he 
last pla n ne d o bser vati o n will be i ncl u de d i n t he a nal yses u p t o t he ti me of disc o nti n uati o n if still 
i ncl u de d i n t he P K a nal ysis set. 
If sa m ples are c ollecte d o utsi de of 1 0 % of t he P K sa m pli n g ti me wi n d o ws defi ne d i n t he C S P i n 
secti o n 8. 4, t hese will be i ncl u de d i n t he P K para meter esti mati o n ( N C A) b ut will be e x cl u de d 
fr o m t he c o nce ntrati o n s u m mar y a n d mea n/ me dia n c o nce ntr ati o n pl ots.  
P K c o nce ntr ati o ns w hic h are err o n e o us d ue t o a sa m pli n g pr ocessi n g or a nal ytical err or (as 
d oc u me nte d i n t he bi oa n al ytical re p ort) m a y be e x cl u de d fr o m t he P K a nal ysis if a gree d b y t h e 
S p o ns or. I n t his case t he rati o nale f or e x cl usi o n will be pr o vi de d i n t he C S R. A n y ot h er P K 
c o nce ntr at i o ns t hat a p pear i m pla usi ble t o t he Cli nical P har mac ol o gist/ Cli nical P K/ P D Scie ntist 
will n ot be e x cl u de d fr o m t he a nal ysis. A n y i m pl a usi ble data will be d oc u me nte d i n t he C S R.  
If i m p orta nt pr ot oc ol de viati o ns occ urre d li kel y t o affect t he P K pr ofile of p artici pa nts as s pecifie d 
i n Secti o n 1 0. 2. 1 , t he i m pacte d c o nce ntr ati o ns a n d P K para meters will be e x cl u de d fr o m s u m mar y 
statistics a n d f urt her statistical e val uati o n.  
A n y P K c o nce ntrati o ns or P K para meters e x cl u de d fr o m s u m mar y statistics will be i ncl u de d i n 
partici pa nts listi n gs a n d fla g ge d; a reas o n f or e x cl usi o n will be detaile d i n t he C S R (e. g. a f o ot n ot e 
or a ta ble of e x cl usi o ns). A n y fla gs s h o ul d be i ncl u de d i n t he st u d y s pecific C DI S C data sets.  
P K c o nce ntr ati o ns a n d P K para meters e x cl u de d fr o m s u m mar y statistics will n ot be i ncl u de d i n 
mea n/ me dia n fi g ures. Mea n pl ots will o nl y c o ntai n val ues w here n > 2.  
1 6. 1. 5  
Esti m ati o n of P h ar m ac o ki netic P ar a meters   
T he c o m p uter pr o gra m P h oe ni x ® Wi n N o nli n ® versi o n 6. 4 
 
 
P P D


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1 /2 6  
 
 
) will be use d t o deri ve P K para meters a p pl yi n g n o nc o m part me ntal a nal ysis 
( N C A).  
T he statistical s oft w are S A S ® ( Statistical A nal ysis S yst e m, 
 
wi n d o ws versi o n 9. 1 or hi g her) will  be use d t o ge n erate a d diti o nal P K para meters, pr o d uce t a bles, 
listi n gs a n d fi g ures.  
1 6. 1. 5. 1  
Esti m ati o n of P h ar m ac o ki netic  P ar a meters i n Pl as m a   
P K para meters will be calc ulate d usi n g t he act ual ela pse d ti me si nce d osi n g. I n cas es w here t he 
act ual sa m pli n g ti me is missi n g, cal c ulati o ns ma y b e perf or m e d usi n g t he sc he d ule d ti me. Details 
(e. g. n u m ber of s a m ples, partici pa nts affecte d) will be des cri be d i n t h e C S R. I n cas es act ual d osi n g 
ti me is missi n g, sc he d ul e d ti me mi g ht b e use d f or N C A after perf or ma nce of a de q u ate pl a usi bilit y 
c hec ks a n d a gree m e nt wit h t he s p o ns or. Decisi o n a n d rati o nal s h o ul d be i ncl u de d i n t he C S R. 
Ot her wise, t here will be n o f urt her i m p utati o n of missi n g data.  
T he f oll o wi n g plas ma P K para met ers will be cal c ulate d w here a p pr o priat e f or te p oti ni b a n d its 
meta b olites ( M S C 2 5 7 1 1 0 9 A a n d M S C 2 5 7 1 1 0 7 A ): 
S y m b ol  
D efi niti o n  
A U C 0 -∞ 
T h e A U C fr o m ti m e z er o ( =  d o si n g ti m e) e xtr a p ol at e d t o i nfi nit y, b a s e d o n t h e pr e di ct e d 
v al u e f or t h e c o n c e ntr ati o n at t l a st, a s e sti m at e d u si n g t h e li n e ar r e gr e s si o n fr o m λ z 
d et er mi n ati o n.  
A U C 0 -∞= A U C 0 -tl a st + C l a st pr e d/ λz 
A U C 0 -tl a st 
T h e A U C fr o m ti m e z er o ( =  d o si n g ti m e) t o t h e l a st s a m pli n g ti m e (t l a st) at w hi c h t h e 
c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n. C al c ul at e d u si n g t h e mi x e d 
l o g-li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
A U C 0 -2 4  
T h e A U C fr o m ti m e z er o ( = d o si n g ti m e) t o ti m e p oi nt 2 4 h o ur s. C al c ul at e d u si n g t h e 
mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
A U C 0 -2 4 / D o s e (f or p ar e nt 
dr u g o nl y)  
A U C 0 -2 4  di vi d e d b y a ct u al d o s e.  
C m a x  
M a xi m u m o b s er v e d c o n c e ntr ati o n.  
C m a x / Do s e (f or p ar e nt 
dr u g o nl y)  
C m a x  di vi d e d b y a ct u al d o s e.  
tl a g 
T h e ti m e pri or t o t h e fir st c o n c e ntr ati o n at or a b o v e L L O Q.  
tm a x  
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g 
i nt er v al (t h e 1st o c c urr e n c e i n t h e c a s e of m ulti pl e/i d e nti c al C m a x  v al u e s).  
t1/ 2  
A p p ar e nt t er mi n al h alf -lif e. t1/ 2 = l n ( 2)/ λ z 
λ z 
T er mi n al fir st or d er ( eli mi n ati o n) r at e c o n st a nt. D et er mi n e d fr o m t h e t er mi n al sl o p e of t h e 
l o g-tr a n sf or m e d c o n c e ntr ati o n c ur v e u si n g li n e ar r e gr e s si o n o n t er mi n al d at a p oi nt s of 
t h e c ur v e. 
C L/ F ( p ar e nt dr u g o nl y)  
T h e a p p ar e nt t ot al b o d y cl e ar a n c e of st u d y i nt er v e nti o n f oll o wi n g e xtr a v a s c ul ar 
a d mi ni str ati o n.  
C L/ F = D o s e p o  / A U C 0 -∞. 
V Z / F ( p ar e nt dr u g o nl y) 
T h e a p p ar e nt v ol u m e of di stri b uti o n d uri n g t h e t er mi n al p h a s e f oll o wi n g e xtr a v a s c ul ar 
a d mi ni str ati o n.  
V z/ F = D o s e / (A U C 0 -∞ ×  λ z) f oll o wi n g si n gl e d o s e. 
A U C e xtra % 
T h e A U C fr o m ti m e t l a st e xtr a p ol at e d t o i nfi nit y gi v e n a s p er c e nt a g e of A U C 0 -∞.  
A U C e xtr a %  = ( e xtr a p ol at e d ar e a/ A U C 0 -∞) ×  1 0 0.  
P P D
P P D


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /2 6  
 
 
S y m b ol  
D efi niti o n  
 
 
 
 
  
 
 
 
 
  
 
T he I M P d ose a d mi nistere d is gi ve n f or t he m o n o h y drate h y dr oc hl ori de salt (ie, 5 0 0 m g I M P). A 
c o n versi o n fact or f or t h e free base I M P was cal c ulate d a n d will be a p plie d w he n ‘ d ose is use d i n 
deri vi n g P K p ara met er f or m ulas nee di n g a d ose v al ue ( C L/ F, V z/ F). 
C o n versi o n fact or = M olec ular wei g ht ( M W) of base I M P di vi de d b y M W of salt f or m I M P = 
4 9 2. 5 7 4 g/ m ol / 5 4 7. 0 5 g/ m ol = 0. 9 0 0  
A m o u nt of d ose * c o n versi o n fact or = act ual d ose of I M P:  5 0 0 m g * 0. 9 0 0 = 4 5 0 m g  
T he f oll o wi n g P K para meters will be calc ulate d, w he n a p pr o priate, f or car ba maze pi ne a n d its 
meta b olite car ba maze pi ne -1 0, 1 1 -e p o xi de: 
S y m b ol  
D efi niti o n  
A U C 0 -tl a st 
T h e A U C fr o m ti m e z er o ( =  d o si n g ti m e) t o t h e l a st s a m pli n g ti m e (t l a st) at w hi c h t h e c o n c e ntr ati o n 
i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n.  
C al c ul at e d u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g d o w n). 
C mi n  
T h e mi ni m u m o b s er v e d c o n c e ntr ati o n d uri n g a c o m pl et e d o si n g i nt er v al.  
C m a x  
M a xi m u m o b s er v e d c o n c e ntr ati o n.  
tl a g 
T h e ti m e pri or t o t h e fir st c o n c e ntr ati o n at or a b o v e L L O Q.  
tm a x  
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g i nt er v al (t h e 
1 st  o c c urr e n c e i n t h e c a s e of m ulti pl e/i d e nti c al C m a x  v al u e s).  
A d diti o nal P K para meters ma y be calc ul ate d w here a p pr o pri ate.  
U nits f or P K para meter o ut p ut will be base d o n c o nce ntr ati o n a n d d ose u nits use d i n t he st u d y, 
u nless ot her wise s pecifie d. I n case c o nce ntrati o n data u nits c ha n ge wit hi n t he st u d y, P K para meters 
will be re p ort e d usi n g c o nsiste nt u nits t hr o u g h o ut st u d y o ut p uts. I n s uc h cases, t he S p o ns or will 
s pecif y rel e va nt u nits f or re p orti n g bef ore t he fi n al P K e val uati o n.  
T he para met ers C ma x  a n d t ma x  will be o btai ne d directl y fr o m t he c o nce ntr ati o n -ti me pr ofiles. If Cma x  
occ urs at m ore t ha n o ne ti me p oi nt, t ma x will be assi g ne d t o t he first occ urre n ce of C ma x . 
T he f oll o wi n g r ules mi g ht be a p plie d f or calc ulati o n of partial A U C, aft er a gree me nt wit h t he 
S p o ns or:  
C CI


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /2 6  
 
 
•  I n case s uita ble re gressi o n ca n n ot be perf or me d, p artial areas ma y be calc ul ate d usi n g t he act ual 
sa m pli n g ti me pr o vi de d it is wit hi n 1 0 % of t he act ual sa m pli n g ti me.  
•  I n cases B L Q c o n ce ntrati o ns occ ur at t h e e n d of t he c ollecti o n i nter val, t h ese c o nce ntr ati o ns 
mi g ht be set t o missi n g f or calc ulati o ns of partial A U Cs. T his is a n e x e m pti o n t o t he ge neral 
B L Q ha n dli n g r ul e a n d s h o ul d be a p plie d i n cas e its a p plicati o n w o ul d res ult i n esti mati o n of 
i m pla usi ble partial A U C val ues. I m pl a usi bilit y is c o nsi dere d i n cases p artial A U Cs were greater 
t ha n A U C0 -∞.   
T he f oll o wi n g P K p ara m eters will be calc ulate d f or dia g n ostic p ur p oses a n d liste d, b ut will n ot be 
s u m marize d: 
•  First ( λz l o w) a n d last ( λz u p) ti me p oi nt of t he ti me i nter val of t he l o g -li near re gressi o n t o 
deter mi ne λz.  
•  N u m ber of dat a p oi nts ( N λ) i ncl u de d i n t he l o g -li near re gressi o n a n al ysis t o deter mi ne λz. 
•  G o o d n ess of fit statistic (a dj uste d Rs q) f or calc ulati o n of λz.  
•  A U C fr o m ti me t last e xtra p olate d t o i nfi nit y gi ve n as perce nta ge of A U C 0 -. ( A U Ce xtra %) 
•  S pa n rati o of i nter val o ver w hic h t 1/ 2 was esti mates/t 1/ 2 
T he re gressi o n a nal ysis s h o ul d c o ntai n data fr o m at  least 3 differe nt ti me p oi nts i n t he ter mi nal 
p hase c o nsiste nt wit h t he assess me nt of a str ai g ht li ne o n t he l o g -tra nsf or me d scale. P h oe ni x 
Wi n N o nli n “ best fit” met h o d ol o g y will b e use d as sta n dar d. If warra nte d, f urt her a dj ust me nt ma y 
be ma de b y t h e p har ma c o ki neticist, after a gree me nt wit h t he S p o ns or. T he l ast q ua ntifia ble 
c o nce ntr ati o n > L L O Q s h o ul d al wa ys b e i ncl u de d i n t he re gressi o n a nal ysis, 
w hile t he 
c o nce ntr ati o n at t ma x  a n d a n y c o nce ntrati o ns B L Q w hic h occ ur aft er t he l ast q ua ntifia ble data p oi nt 
> L L O Q s h o ul d n ot be us e d.  
If A U Ce xtra %> 2 0 % a n d/ or t he c oefficie nt of c orrelati o n ( Rs q a dj) of λz is < 0. 8 a n d/ or t he 
o bser vati o n peri o d o ver w hic h t he re gressi o n li ne is esti mate d (s pa n rati o) is less t ha n 2 -f ol d t he 
res ulti n g t1/ 2, t he rate c o nsta nts a n d all deri ve d para meters (e. g. t 1/ 2, A U C0 -, C L etc.) will be  liste d, 
fla g ge d a n d i ncl u de d i n t he para met er o ut p uts. S h o ul d m ore t ha n 1 0 % of s u bjects be fla g ge d f or 
A U Ce xtra a n d/ or Rs q a dj (f or a partic ular a n al yt e), a se nsiti vit y a nal ysis e x cl u di n g fla g ge d  
para meters ma y be p erf or me d after disc ussi o n wit h t he S p o ns or.  
1 6. 1. 6  
Prese nt ati o n of P K C o nce ntr ati o n a n d P K P ar a meter D at a   
1 6. 1. 6. 1  
Listi n gs a n d T a bles   
T he f oll o wi n g P K ta bl es will be pr o d uce d ( P K A n al ysis Set):  
•  Descri pti ve statistics of c o nce ntrati o ns b y a n al yt e, matri x, st u d y i nter ve nti o n (da y )  
•  Descri pti ve statistics of P K para met ers b y a n al yt e, matri x, st u d y i nter ve nti o n ( da y ) 
T he f oll o wi n g P K Listi n gs will be pr o d u ce d ( Safet y A nal ysis Set):  
•  I n di vi d ual c o n ce ntr ati o ns b y a n al yt e, matri x, da y a n d st u d y i nter ve nti o n (d a y ) 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /2 6  
 
 
•  I n di vi d ual P K para meters b y a n al yt e, matri x, da y a n d st u d y i nter ve nti o n (d a y )  
•  P K Sa m pli n g dat e, act ual ti me, n o mi nal ti me, de viati o n fr o m ti me, perce nt a ge ti me d e viati o n  
b y partici pa nt, a nal yte, m atri x a n d st u d y i nter ve nti o n (da y ) s orte d i n c hr o n ol o gical or d er 
•  P h oe ni x Wi n N o nli n N C A C ore O ut p ut  
1 6. 1. 6. 2  
Gr a p hic al S u m m aries a n d I n di vi d u al pl o ts ( P K A n al ysis Set)  
T he f oll o wi n g gra p hical s u m maries a n d i n di vi d ual pl ots will be pr o vi de d  f or te p oti ni b a n d its 
meta b olites ( M S C 2 5 7 1 1 0 9 A a n d 
M S C 2 5 7 1 1 0 7 A) as well as car ba m aze p i ne, if n ot state d 
ot her wise : 
•  O verlai d i n di vi d ual plas ma c o nce ntrati o n v ers us ti me pl ots  o n  li near a n d s e mi-l o g s cale, usi n g 
act ual ti mes;  b y a nal yte a n d st u d y i nter ve nti o n (d a y );  
•  O verlai d i n di vi d ual plas ma c o nce ntrati o n v ers us ti me pl ots b y partici pa nt  an d  a nal yte o n li near 
a n d se mi -l o g scal e usi n g act u al ti mes . If a n y p ost-d ose c o nce ntrati o n is B L Q t he li ne 
re pres e nti n g L L O Q will be a d de d t o t he se mi-l o g pl ots. 
•  Arit h metic mea n c o nce ntrati o n ti me pl ots; li near ( ± S D f or arit h metic mea n) a n d se mi -l o g; usi n g 
sc he d ule d ( n o mi nal) ti me p oi nts b y a n al yt e, matri x a n d st u d y i nter ve nti o n (da y ); if a n y p ost-
d ose c o nce ntrati o n is B L Q t he li ne re prese nti n g L L O Q will be a d de d t o t he se mi -l o g pl ots 
•  B o x pl ots f or pri mar y P K para m eters A U C 0 -∞, A U C 0 -tlast, C ma x  of te p oti ni b  b y st u d y i nter ve nti o n 
(da y) a n d  a nal yte. 
•  S pa g hetti pl ot of pri mar y P K para meters  A U C 0 -∞, A U C 0 -tlast, C ma x  of te p oti ni b  b y st u d y 
i nter ve nti o n ( da y) a n d a n al yte 
 


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /2 6  
 
 
1 7  
Refere nces   
N ot a p plica ble.  


Te p oti ni b  
Te p oti ni b D DI wit h C ar b a m aze pi ne  
M S 2 0 0 0 9 5 _ 0 0 5 1  
Fi n al  1 .0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /2 6  
 
 
1 8  
A p pe n dices   
N ot a p plica ble