Clinical trial NCT05519540
Conditions: Healthy
Keywords: East Asian Japanese Pharmacokinetic Ethnic sensitivity
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Start date: 2022-09-26; Completion date: 2023-04-21
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the pharmacokinetics (PK) of Xevinapant (Debio 1143) and its metabolite D-1143-MET1 as well as safety and tolerability of Xevinapant (Debio 1143) in healthy East Asian participants.

Detailed description:

Arms: arm 1: Xevinapant (Debio 1143) was administered in Healthy Japnaese participants at a dose of 200 milligrams (mg), orally under fasted conditions. arm 2: Xevinapant (Debio 1143) was administered in Healthy Non- Japanese participants at a dose of 200 mg, orally under fasted conditions.
Interventions: intervention 1: Xevinapant (Debio 1143)
Intervention descriptions: intervention 1: All participants (Japanese and non-Japanese) received a single oral dose of 200mg xevinapant (Debio 1143) on Day 1 under fasted condition.

Protocol documents:
Prot_000.pdf: 
Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
Cli nic al St u d y  Pr ot oc ol   
Title P a ge   
Cli nic al St u d y Pr ot oc ol Title:  
A si n gle -d os e, o pe n -l a bel, si n gle ar m st u d y t o 
i n vesti gate P K of x e vi na pa nt a n d its meta b olite, 
D -1 1 4 3 -M E T 1 i n healt h y East Asia n partici pa nts  
St u d y N u m ber:  
M S 2 0 2 3 5 9 _ 0 0 0 4  
Pr ot oc ol V ersi o n:  
1 0  J u n 2 0 2 2/ Versi o n 1. 0  
Merc k  C o m p o u n d:  
Xe vi na pa nt  
Merc k Re gistere d C o m p o u n d N a me i n 
J a p a n : 
N ot A p plica ble  
St u d y P h ase:  
1  
Brief  Title:  
P hase 1 P K St u d y i n Healt h y East Asia n 
Partici pa nts  
Pri nci p al I n vesti g at or : 
 
 
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:  
Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y  
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y  
Fra n kf urter Str asse 2 5 0  
Dar msta dt, 6 4 2 9 3, Ger ma n y  
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:  
E U trial n u m ber : 2 0 2 2 -0 0 2 1 8 2 -1 5  
Ke y w or ds  
•  East Asia n  
•  J a pa nese 
•  P K  
•  Et h nic se nsiti vit y  
 
–  C o nfi d e nti al –  
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot –  i n f ull or p art –  b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 2  b y M er c k K G a A, 
D ar m st a dt, G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.  
Gl o bal Versi o n I D: C CI
P P D


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
T a ble of C o nte nts   
Title Pa ge  
 ..............................................................................................................1  
Ta ble of C o nte nts   ..............................................................................................................2  
1  
Pr ot oc ol S u m mar y  ................................................................................5  
1. 1  
S y n o psis  ................................................................................................5  
1. 2  
Sc he ma  ..................................................................................................6  
1. 3  
Sc he d ule of Acti vities  ...........................................................................7  
2  
I ntr o d u cti o n .........................................................................................1 0  
2. 1  
St u d y R ati o nale  ...................................................................................1 0  
2. 2  
Bac k gr o u n d  .........................................................................................1 0  
2. 3  
Be nefit/ Ri s k Assess me nt ....................................................................1 2  
2. 3. 1  
Ris k Assess me nt  .................................................................................1 3  
2. 3. 2  
Be nefit Assess me nt  .............................................................................1 4  
2. 3. 3  
O verall Be nefit: Ris k C o ncl usi o n  .......................................................1 4  
3  
O bjecti ves a n d E n d p oi nts  ...................................................................1 5  
4  
St u d y Desi g n  .......................................................................................1 5  
4. 1  
O verall De si g n ....................................................................................1 5  
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  ................................................1 7  
4. 3  
J ustificati o n f or D ose ..........................................................................1 8  
4. 4  
E n d of St u d y Defi niti o n  ......................................................................1 8  
5  
St u d y P o p ulati o n  .................................................................................1 8  
5. 1  
I n cl usi o n Criteria ................................................................................1 9  
5. 2  
E x cl usi o n Criteria  ...............................................................................2 2  
5. 3  
Lif est yle C o nsi derati o ns  .....................................................................2 5  
5. 3. 1  
Meals a n d Dietar y Restri cti o ns  ...........................................................2 5  
5. 3. 2  
Caffei ne, Al c o h ol, T o bacc o, a n d Ca n na bi n oi d  ...................................2 6  
5. 3. 3  
Acti vit y  ...............................................................................................2 6  
5. 4  
Scree n Fai l ures ....................................................................................2 6  
5. 5  
Criteria f or T e m p oraril y Dela yi n g E nr oll me nt, Ra n d o mizati o n, 
or A d mi nistrati o n of St u d y I nter ve nti o n .............................................2 6  
6  
St u d y I nter v e nti o n(s) a n d C o nc o mita nt T hera pies  .............................2 7  
6. 1  
St u d y I nter v e nti o n(s) A d mi nistrati o n  .................................................2 7  
6. 2  
St u d y I nter v e nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y  .....................................................................................2 8  
6. 3  
Meas ures t o Mi ni mize Bias: St u d y I nter v e nti o n Assi g n me nt 
a n d Bli n di n g  ........................................................................................2 9  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 /6 6  
 
 
6. 3. 1  
St u d y I nter v e nti o n Assi g n me nt  ..........................................................2 9  
6. 3. 2  
Bli n di n g  ..............................................................................................2 9  
6. 4  
St u d y I nter v e nti o n C o m plia nce  ..........................................................2 9  
6. 5  
D ose M o dificati o n  ..............................................................................2 9  
6. 6  
C o nti n ue d Access t o St u d y I nter ve nti o n After t he E n d of t he 
St u d y  ...................................................................................................2 9  
6. 7  
Treat me nt of O v er d ose  .......................................................................2 9  
6. 8  
C o nc o mita nt T hera p y  .........................................................................3 0  
6. 8. 1  
Per mitte d Me dici nes  ...........................................................................3 0  
6. 8. 2  
Pr o hi bite d Me dici nes  ..........................................................................3 0  
7  
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici p a nt 
Disc o nti n uati o n/ Wit h dra wal  ...............................................................3 0  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................3 1  
7. 2  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ...................3 1  
7. 3  
L ost t o F oll o w -u p  ...............................................................................3 1  
8  
St u d y Assess me nts a n d Pr oce d ures  ....................................................3 2  
8. 1  
Efficac y Assess me nts a n d Pr oce d ures  ................................................3 2  
8. 2  
Safet y Assess me nts a n d Pr oce d ures  ...................................................3 3  
8. 2. 1  
P h ysical E x a mi nati o ns  ........................................................................3 3  
8. 2. 2  
Vital Si g ns  ..........................................................................................3 3  
8. 2. 3  
Electr ocar di o gra ms  .............................................................................3 3  
8. 2. 4  
Cli nical Safet y La b orat or y Tests  ........................................................3 4  
8. 3  
A d verse E v e nts, Seri o us A d verse E v e nts, a n d Ot h er Safet y 
Re p orti n g  ............................................................................................3 4  
8. 3. 1  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts  .................................................................................................3 5  
8. 3. 2  
F oll o w -u p of A d verse E v e nts a n d Seri o us A d verse E ve nts  ...............3 5  
8. 3. 3  
Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts  .................................................................................................3 5  
8. 3. 4  
Pre g n a nc y  ...........................................................................................3 6  
8. 3. 5  
A d verse E v e nts of S peci al I nt erest  .....................................................3 7  
8. 4  
P har mac o ki netics  ................................................................................3 7  
8. 4. 1  
Bl o o d Sa m pli n g a n d Bi o a nal ysis  ........................................................3 7  
8. 4. 2  
P K Para meters  ....................................................................................3 8  
 
 
8. 6  
Bi o mar kers  ..........................................................................................3 9  
Gl o bal Versi o n I D: C CI
C
CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 /6 6  
 
 
8. 7  
I m m u n o ge nicit y Assess me nts ............................................................3 9  
8. 8  
Healt h Ec o n o mics  ...............................................................................4 0  
9  
Statistical C o nsi derati o ns  ....................................................................4 0  
9. 1  
Statistical H y p ot heses  .........................................................................4 0  
9. 2  
Sa m ple Size Deter mi nati o n  ................................................................4 0  
9. 3  
P o p ulati o n f or A nal ys es  ......................................................................4 1  
9. 4  
Statistical A nal yses  .............................................................................4 1  
9. 4. 1  
Efficac y A nal yses  ...............................................................................4 1  
9. 4. 2  
Safet y A nal yses  ..................................................................................4 1  
9. 4. 3  
Ot her A nal yses  ....................................................................................4 1  
9. 4. 3. 1  
P har mac o ki netic A n al ys es  ..................................................................4 2  
9. 4. 4  
Se q ue nce of A nal yses  .........................................................................4 2  
1 0  
Refere n ces  ...........................................................................................4 3  
1 1  
A p pe n dices  .........................................................................................4 4  
A p pe n di x 1  
A b bre viati o ns  ......................................................................................4 5  
A p pe n di x 2  
St u d y G o ver na nce  ...............................................................................4 7  
A p pe n di x 3  
C o ntrace pti o n a n d Barrier Re q uire me nts  ...........................................5 3  
A p pe n di x 4  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g  ................................................5 5  
A p pe n di x 5  
Cli nical La b orat or y Tests  ...................................................................6 2  
 
 
A p pe n di x 7  
S p o ns or Si g nat ure Pa ge  ......................................................................6 5  
A p pe n di x 8  
Pri nci pal I n v esti gat or Si g nat ure Pa ge  .................................................6 6  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 /6 6  
 
 
1  
Pr ot oc ol S u m m ar y   
1. 1  
S y n o psis   
Cli nic al St u d y Pr ot oc ol Title:  A si n gle -d ose, o pe n -la bel, si n gl e ar m st u d y t o i n vesti gate P K 
of xe vi na pa nt a n d its meta b olite, D -1 1 4 3 -M E T 1 , i n healt h y E ast Asia n partici pa nts 
Brief  Title: P hase 1 P K St u d y i n H ealt h y East Asia n Partici pa nts  
R ati o n ale: T his is a n o pe n -la bel, P hase 1 st u d y i n vesti gati n g t he p har mac o ki netics ( P K ) of 
x e vi na pa nt a n d its meta b olite D -1 1 4 3 -M E T 1 as w ell as safet y i n healt h y E ast Asia n 
partici pa nts f oll o wi n g a si n gle d ose of 2 0 0  m g of x e vi na pa nt, w hic h is t he rec o m me n de d 
P hase 3  d ose ( R P 3 D) i n St u d y  M S 2 0 2 3 5 9 _ 0 0 0 6 (f or merl y k n o w n as De bi o 1 1 4 3 
S C C H N -3 0 1 a n d hereaft er referre d t o as Tril y n X), t he o n g oi n g gl o bal P has e 3 i n c o m bi nati o n 
wit h C R T i n u nresecta ble L A S C C H N.  
O bjecti ves a n d E n d p oi nts:   
O bj e cti v e s  
E n d p oi nt s  
R ef. #  
Pri m ar y  
 
T o c h ar a ct eri z e t h e x e vi n a p a nt 
P K aft er a si n gl e 2 0 0  m g d o s e 
i n h e alt h y E a st A si a n 
p arti ci p a nt s a n d i n h e alt h y 
J a p a n e s e p arti ci p a nt s  
X e vi n a p a nt A U C 0 -tl a st, A U C0 -∞, a n d Cm a x   
1  
S e c o n d ar y  
 
T o e v al u at e t h e s af et y a n d 
t ol er a bilit y of a si n gl e 2 0 0 m g 
d o s e of x e vi n a p a nt i n h e alt h y 
E a st A si a n p arti ci p a nt s a n d i n 
h e alt h y J a p a n e s e p arti ci p a nt s  
O c c urr e n c e of T E A E s (i n ci d e n c e, fr e q u e n c y, i nt e n sit y a n d 
c a u s alit y), o c c urr e n c e of c h a n g e s i n s af et y l a b or at or y 
a s s e s s m e nt s, 1 2 -l e a d E C G s, a n d vit al si g n s  
2  
T o d et er mi n e a d diti o n al pl a s m a 
P K p ar a m et er s of x e vi n a p a nt 
aft er a si n gl e 2 0 0  m g d o s e i n 
h e alt h y E a st A si a n p arti ci p a nt s 
a n d i n h e alt h y J a p a n e s e 
p arti ci p a nt s  
X e vi n a p a nt A U C 0 -2 4 , tm a x , t1/ 2 , a p p ar e nt cl e ar a n c e ( C L/ F), a n d 
a p p ar e nt v ol u m e of di stri b uti o n d uri n g t er mi n al p h a s e ( V z/ F)  
3  
T o c h ar a ct eri z e t h e P K of 
m et a b olit e D -1 1 4 3 -M E T 1 aft er 
a si n gl e 2 0 0  m g d o s e i n h e alt h y 
E a st A si a n p arti ci p a nt s a n d i n 
h e alt h y J a p a n e s e p arti ci p a nt s  
D -1 1 4 3 -M E T 1 A U C 0 -tl a st, A U C0 -2 4 , A U C0 -∞, Cm a x , tm a x , a n d t1/ 2 , 
D -1 1 4 3 -M E T 1/ x e vi n a p a nt m ol ar r ati o f or A U C
0 -tl a st, A U C0 -∞, Cm a x  
4  
 
O ver all Desi g n: T his will be a si n gle -d ose, o pe n -la bel st u d y e v al uati n g t he P K a n d safet y of 
x e vi na pa nt i n healt h y East Asia n partici pa nts. At least 1 0 J a pa nese a n d 1 0  n o n -J a pa nese East 
Asia n partici pa nts will be e nr olle d, wit h a pla n ne d t otal d urati o n of t he st u d y f or eac h 
partici pa nt of a p pr o xi matel y 5  w ee ks , i ncl u di n g a n u p t o 4 -wee k Scree ni n g Peri o d, a n 
I n-h o use Peri o d at t he  C R U ( Da y -1 t o D a y 4), a n d a Safet y F oll o w -u p o n Da y 8.  
Brief S u m m a r y:  All partici pa nts will be d ose d o n Da y 1. Gr o u p 1 will e nr oll at least 
1 0  J a pa nese partici pa nts a n d Gr o u p 2 will e nr oll at least 1 0 n o n-J a pa nese E ast Asia n 
partici pa nts. East Asia i n cl u des K orea a n d Great er C hi na, wit h prefera bl y a si milar 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt 
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts 
M S 2 0 2 3 5 9 _ 0 0 0 4 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 /6 6  
 
 
pr o p orti o n of male a n d fe male partici pa nts e nr olle d acr oss gr o u ps if feasi bl e. Partici pa nt s will 
be c o nfi n e d t o t he st u d y site fr o m Da y -1 t o D a y 4 a n d will c o m plete a Safet y F oll o w -u p 
tele visit o n Da y 8. A d verse e ve nts will be f oll o we d fr o m Scree ni n g t hr o u g h t he Safet y 
F oll o w -u p tele visit. Safet y ass ess me nts will i ncl u de p h ysic al e x a mi nati o ns,  vital si g ns, 
electr ocar di o gra ms, a n d cli nical safet y la b orat or y tests. P K a n d 
 sa m ples 
will be o btai ne d.  
N u m ber of P artici p a nts: 2 4 partici pa nts ( 1 2 per gr o u p) will be i nitiall y assi g ne d t o st u d y 
i nter ve nti o n s uc h t hat a p pr o xi matel y 1 0 e val ua ble partici pa nts per gr o u p c o m plete t he st u d y. 
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: Gr o u p 1 will e nr oll at least 1 0 J a pa nese 
partici pa nts. Gr o u p 2 will e nr oll at least 1 0 n o n-J a pa nese E ast Asia n partici pa nts. East Asia 
i ncl u des K orea or Greater C hi na. T he pla n ne d t otal d urati o n of t he st u d y f or eac h p artici pa nt 
will be a p pr o xi matel y 5 wee ks, i ncl u di n g a n u p t o 4- wee k Scree ni n g Peri o d, a n I n- h o use 
Peri o d at t he C R U ( Da y - 1 t o Da y 4), a n d a Safet y F oll o w- u p o n Da y 8.  
D at a a n d S afet y M o nit ori n g / Ot her C o m mittee : N o  
1. 2  
Sc he m a  
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 /6 6  
 
 
1. 3  
Sc he d ule of Acti vities   
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /6 6  
 
 
A s s e s s m e nt s & Pr o c e d ur e s  
S cr e e ni n g  
A d mi s si o n t o C R U  
S F U 
( T el e vi sit) 
N ot e s  
St u d y D a y  
-2 8 t o -3  
-1  
1  
2  
3  
4  
( E o T) 
8  
(-1  / + 2 
d a y s)  
Writt e n i nf or m e d c o n s e nt  
X  
 
 
 
 
 
 
I nf or m e d c o n s e nt t o b e a v ail a bl e 
b ef or e st art of a n y st u d y s p e cifi c 
a s s e s s m e nt s . 
P arti ci p a nt s r e si d e nt at C R U  
 
X  
X  
X  
X  
X  
 
A d mi s si o n t o C R U  i n t h e 
aft er n o o n o n D a y -1 u ntil 
di s c h ar g e o n D a y 4 aft er 
c o m pl eti o n of all st u d y -r el at e d 
a cti viti e s  
I n cl u si o n a n d e x cl u si o n 
crit eri a  
X  
X  
 
 
 
 
 
R e c h e c k cli ni c al st at u s b ef or e 
a d mi ni str ati o n  
D e m o gr a p h y  
X  
 
 
 
 
 
 
I n cl u di n g a g e ( y e ar of birt h), s e x , 
r a c e a n d et h ni cit y 
F ull p h y si c al e x a mi n ati o n  
X  
X  
 
 
 
X  
 
 
M e di c al hi st or y  
X  
 
 
 
 
 
 
 
Pr e g n a n c y  t e st 
X  
X  
 
 
 
X  
 
Pr e g n a n c y t e st u si n g s er u m ( at 
S cr e e ni n g) a n d u si n g uri n e ( o n 
D a y -1 a n d E n d  of  St u d y), t o 
c o nfir m n o n -pr e g n a nt st at u s 
(f e m al e s o nl y) 
F olli cl e sti m ul ati n g h or m o n e  
X  
 
 
 
 
 
 
T o c o nfir m p o st m e n o p a u s al  
st at u s (f e m al e s o nl y)  
S er ol o g y  
X  
 
 
 
 
 
 
HI V, h e p atiti s B a n d C  
S A R S -C o V -2  
Dr u g a n d al c o h ol s cr e e n  
X  
X  
 
 
 
 
 
 
Cli ni c al l a b or at or y t e st s a  
X  
X  
X  
X  
 
X  
 
Aft er at l e a st 1 0 h o ur s f a sti n g,  
D a y 1 s a m pli n g i s pr e d o s e  
S af et y 1 2 -L e a d E C G  
X  
 
X  
X  
 
X  
 
D a y 1: pr e d o s e, 1 h o ur  
p o st d o s e , D a y 2 (2 4 h o ur s 
p o st d o s e), a n d D a y 4 ( 7 2 h o ur s 
p o st d o s e) ( s e e S e cti o n  8. 2. 3  f or 
f urt h er d et ail s) 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 /6 6  
 
 
A s s e s s m e nt s & Pr o c e d ur e s  
S cr e e ni n g  
A d mi s si o n t o C R U  
S F U 
( T el e vi sit) 
N ot e s  
St u d y D a y  
-2 8 t o -3  
-1  
1  
2  
3  
4  
( E o T) 
8  
(-1  / + 2 
d a y s)  
Vit al si g n s  
X  
X  
X  
X  
X  
X  
 
H ei g ht a n d W ei g ht t o b e 
c oll e ct e d at S cr e e ni n g o nl y . 
D a y 1: pr e d o s e, 1, 2, 4, 
1 2  h o ur s; D a y 2: 2 4 h o ur s, 
D a y  3: 4 8 h o ur s, D a y 4: 7 2 h o ur s  
St u d y i nt er v e nti o n  
 
 
X  
 
 
 
 
 
A E & S A E r e vi e w  
X  
X  
X  
X  
X  
X  
X  
 
C o n c o mit a nt m e di c ati o n s 
r e vi e w 
X  
X  
X  
X  
X  
X  
X  
 
P K bl o o d s a m pli n g ( pl a s m a)  
 
 
X  
X  
X  
X  
 
D a y 1: pr e d o s e, a n d 0. 2 5, 0. 5, 
1. 0, 1. 5, 2, 2. 5, 3, 4, 6, 8, a n d 
1 2  h o ur s p o st d o s e; D a y 2: 
2 4  a n d 3 6 h o ur s p o st d o s e; 
D a y  3 : 4 8 h o ur s p o st d o s e, 
D a y  4: 7 2  h o ur s p o st d o s e. S e e 
S e cti o n 8. 4  f or c oll e cti o n 
wi n d o w s a n d f urt h er d et ail s. T h e 
ti m e a n d d at e  of e a c h c oll e cti o n 
t o b e r e c or d e d i n e C R F. 
a Uri n e s a m pl e s will b e c oll e ct e d at S cr e e ni n g a n d ti m e s of ot h er cli ni c al l a b s.
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
2  
I ntr o d ucti o n  
Xe vi na pa nt is a n o vel, orall y a v aila ble a nta g o nist of I A Ps t hat pr o m otes ca ncer cell deat h via 
a p o pt osis. Xe vi na pa nt f osters a ntit u m or i m m u nit y a n d p ote ntiall y se nsitiz es t u m or cells f or 
vari o us c yt ot o xic t hera pies, i ncl u di n g c h e m ot hera p y, ra di ot hera p y a n d / or i m m u n ot hera p y 
(Ser o va 2 0 1 4 , Matzi n ger 2 0 1 5 , Ta o 2 0 1 9 ). 
Detaile d i nf or mati o n o n t he c he mistr y, p har m ac ol o g y, effic ac y, a n d s afet y of  x e vi na pa nt  is i n t he 
I B. 
2. 1  
St u d y R ati o n ale   
T his is a n o pe n -la bel, P h ase 1 st u d y i n v esti gati n g P K of x e vi na pa nt a n d its meta b olite 
D -1 1 4 3 -M E T 1 as w ell as safet y i n healt h y East Asia n partici pa nts f oll o wi n g a si n gle d os e of 
2 0 0  m g of xe vi na pa nt, w hic h is t he rec o m me n d e d P hase 3 d ose ( R P 3 D) i n St u d y 
M S 2 0 2 3 5 9 _ 0 0 0 6 (f or merl y k n o w n as De bi o  1 1 4 3 -S C C H N -3 0 1 a n d hereaft er referre d t o as 
Tril y n X), t h e o n g oi n g gl o bal P hase 3 i n c o m bi nati o n wit h C R T in u nresecta ble L A  S C C H N . 
T he pr o p ose d si n gle d ose of 2 0 0  m g of xe vi na pa nt is t o be a d mi nistere d u n der faste d c o n diti o n, 
t here b y all o wi n g: 
•  E val uati o n of P K of xe vi na pa nt a n d its meta b olite D -1 1 4 3 -M E T 1  i n East Asia n 
partici pa nts i n t he a bse n ce of a n y p ote ntial f o o d effect  
•  C o m paris o n of P K data bet wee n t he h ealt h y East Asia n et h nic s u b gr o u ps  (i ncl u di n g 
J a pa nese) i ncl u de d i n t his st u d y 
•  C o m paris o n of P K data bet wee n t he h ealt h y East Asia n partici pa nts t o be i n ves ti gate d i n 
t his st u d y a n d healt h y Ca ucasia n partici pa nts e val uate d i n earlier st u dies 
( De bi o 1 1 4 3 -1 0 7 , De bi o 1 1 4 3 -1 0 9 ) 
T his cli nical st u d y is part of t he x e vi na pa nt gl o bal de vel o p me nt pr o gra m a n d ai ms t o s u p p ort t he 
partici pati o n of East Asia n s u bjects, i n cl u di n g J a pa nese i n gl o bal P hase 3 trials i n t he tar gete d 
patie nt p o p ulati o ns a n d ass ociate d i n dicati o ns.  
T his cli nical st u d y will be c o n d ucte d i n c o m plia nce wit h t he C S P, G o o d Cli nical Practice 
(I nter nati o nal C o nfere n ce o n Har m o nizati o n [I C H] T o pic E 6, G CP) a n d t he a p plica ble 
re g ulat or y re q uire me nts. 
2. 2  
B ac k gr o u n d   
Hea d a n d n ec k carci n o ma s i ncl u de a variet y of e pit helial t u m ors ori gi nati n g i n t he li p, oral 
ca vit y, h y p o p h ar y n x, or o p har y n x, nas o p har y n x or lar y n x. Hea d a n d nec k ca ncers are t he 7 t h m ost 
c o m m o n ca ncer w orl d wi de wit h a n a n n ual i nci d e nce of a p pr o xi matel y 7 0 0, 0 0 0 a n d a m ortalit y 
rate esti mate d at 3 5 0, 0 0 0 i n 2 0 1 8 (Bra y 2 0 1 8 ). I n t he U S al o ne, 5 0, 0 0 0 ne w cases a n d 
1 0, 0 0 0  deat hs are re p orte d a n n uall y, w hile i n E ur o pe, 1 4 0, 0 0 0 ne w cases are re p ort e d a n n uall y 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
(I gl esias D oca m p o 2 0 1 8 ). A vast maj orit y of t h ese ca ncers ( 9 0 % t o 9 5 %) are S C C H N w hic h are 
cl osel y ass ociate d wit h al c o h ol a n d t o bacc o use. S C C H N of t he or o p har y n x is als o ass ociate d 
wit h H P V, esse ntiall y t y pe 1 6 i nfecti o n. A p pr o xi matel y t w o -t hir d of patie nts are dia g n ose d as 
L A S C C H N ( De nar o 2 0 1 6 ). 
M ulti disci pli nar y treat me nts, i ncl u di n g s ur ger y, R T a n d c he m ot hera p y al o n e or i n c o m bi nati o n 
re pres e nt t he treat me nt o pti o ns f or S C C H N patie nts de pe n di n g o n t he dis ease sta ge. L ocall y 
a d va nce d disease is treat e d wit h c urati ve i nte nt a n d re q uires m ulti m o dal a p pr oac hes i n cl u di n g 
c o m bi ne d C R T eit her as a dj u va nt t hera p y after t u m or resecti o n or as defi niti ve c urati vel y 
i nte n de d treat me nt. 
D ue t o t he pi v otal r ole of R T i n ma n y L A S C C H N setti n gs, a l ot of f o c us is bei n g  p ut o n 
researc h i nt o safe a n d p o werf ul r a di ose nsitizi n g a ge nts. I n a d diti o n, resista nce of t u m or cells t o 
a p o pt osis is a maj or pr o ble m i n c urre nt c a ncer treat me nt.  T heref ore, f urt her de vel o p me nt of ne w 
m olec ular a ntica ncer t hera pies t hat s pecificall y t ar g et r esista nce of ca ncer cells t o a p o pt osis is 
warra nte d ( Nic h ols o n 2 0 0 0 ). 
I A Ps are k e y e n d o ge n o us i n hi bit ors of a p o pt osis, a n d o vere x pressi o n of t hese pr otei ns was 
detecte d i n n u mer o us ca n cers, i ncl u di n g S C C H N. I A Ps ha v e als o b ee n s h o w n t o i nterfere wit h 
t he efficac y of R T (Ta m m 2 0 0 0 ). 
Xe vi na pa nt is a n a nt a g o nist of I A Ps wit h c he m os e nsitizi n g, ra di ose nsitizi n g, a n d 
i m m u n o m o d ulat or y acti vities. N o ncli nical st u dies i n se veral i n vitr o a n d i n vi v o S C C H N m o dels 
de m o nstrate d a n effici e nt a nti pr oliferati ve acti vit y a n d a s y ner gistic e n h a nce me nt of i ntri nsic 
cell ular ra diati o n se nsiti vit y w he n x e vi na pa nt w as c o m bi ne d wit h R T. T he s y n er gistic effect of 
x e vi na pa nt c o m bi ne d wit h R T i n vi v o was a ble t o c ure t u m ors i n  8 of 1 0 x e n o grafte d mice 
wit h o ut a n y a p p are nt t o xicit y w hereas all mice die d wit h R T al o ne ( Matzi n ger 2 0 1 5 ). T h ese 
res ults i n dicate t hat x e vi na pa nt i n c o m bi nati o n wit h R T has a pr o misi n g t h era pe utic p ot e ntial i n 
t he treat me nt of S C C H N.  
Base d o n c urre nt u n derst a n di n g of t he mec h a nis m of acti o n, t he val ue of a d di n g x e vi na pa nt t o 
plati n u m -base d c o n ve nti o nal C R T i n t he treat me nt of pre vi o usl y u ntr eate d patie nts wit h n o n -
resect e d L A S C C H N  has bee n i n vesti gate d i n a P hase 1 -2 st u d y (D e bi o  1 1 4 3 -2 0 1, refer t o I B f or 
f urt her det ails). T he P has e 2 part of De bi o  1 1 4 3 -2 0 1 st u d y ( part B of t he st u d y) was a 
ra n d o mize d, place b o-c o ntr olle d, d o u ble -bli n d st u d y. Efficac y res ults fr o m t he 2 4 -m o nt h pri mar y 
a nal ysis h a ve s h o w n a ntit u m or acti vit y of x e vi na p a nt: patie nts treate d wit h x e vi na pa nt were 
ar o u n d 2. 5 ti mes m ore li kel y t o ha ve l oc ore gi o nal c o ntr ol 1 8 m o nt hs after c o m pleti n g treat me nt, 
c o m pare d wit h patie nts h a vi n g recei ve d a pla ce b o. T he o n g oi n g gl o bal P has e 3 st u d y Tril y n X 
ai ms t o c o nfir m t he  val ue of xe vi na pa nt i n t he treat me nt of pre vi o usl y u ntr eate d L A  S C C H N  
patie nts (i ncl u di n g t h ose fr o m East Asia) wit h h y p o p har y n x, lar y n x a n d/ or H P V -1 6 ne gati ve 
O P C, w h o are s uita ble f or defi niti ve C R T a n d are m ore li kel y t o r ela pse l oc all y.  
Xe vi na pa nt P K has b ee n e val uate d i n cli nical st u dies i n patie nts wit h ca ncer, eit her as 
m o n ot hera p y or i n c o m bi nati o n wit h ot her ca ncer treat me nts, aft er o nce dail y oral a d mi nistrati o n 
o n Da ys 1  t o 5, o n Da ys 1  t o 1 4 of 3 -wee k c ycles a n d o n Da ys 1  t o 1 0 a n d D a y 1 5  t o 2 4  of 
4 -wee k c ycles  (refer t o I B). Xe vi na pa nt w as well a bs or be d wit h tma x  reac he d i n a b o ut 1 t o 
2  h o urs. I n t he m o n ot hera p y tr eat me nt, P K of x e vi na pa nt was d ose -pr o p orti o nal i n t he d ose 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
ra n ge 1 0 0 t o 9 0 0 m g. Half -life (t1/ 2) is a b o ut 6 t o 8 h o urs. I n m o n ot hera p y, n o acc u m ulati o n aft er 
m ulti ple d osi n g was o bser ve d. A p pare nt cleara n ce was l o w, i n dicati n g a li mite d he patic 
e xtracti o n. Re nal cleara n ce was l o w, wit h a b o ut 8 %  t o 1 0 % of x e vi na pa nt rec o vere d u n c ha n ge d 
i n uri ne. I n vitr o bi n di n g of xe vi na pa nt t o h u ma n plas ma pr otei ns was m o derate ( 8 4 % t o 8 8 %). 
D -1 1 4 3 -M E T 1, a m eta b olite wit h n o si g nifica nt a nta g o nistic I A P a cti vit y i n vitr o, is a maj or 
circ ulati n g meta b olite i n h u ma n, wit h plas ma e x p os ure of t he sa m e or der of ma g nit u de as 
x e vi na pa nt. D -1 1 4 3 -M E T 1 f or mati o n fr o m x e vi na pa nt is esse ntiall y e xtra he patic. Xe vi n a pa nt is 
a l o w per mea bilit y dr u g. I n ge neral, i nteri n di vi d ual varia bilit y i n P K dis p ositi o n was lar ge f or 
x e vi na pa nt a n d its maj or meta b olite D -1 1 4 3 -M E T 1 i n ca ncer patie nts (e. g., 5 0  t o 8 0 ge o C V % f or 
x e vi na pa nt A U Cτ), b ut l o wer ( 3 5 ge o C V % f or A U C 0 -t) i n Ca ucasia n healt h y partici pa nts. 
2. 3  
Be nefit/ Ris k Assess me nt   
Alt h o u g h a h ealt h y partici pa nt p o p ulati o n pr o vi des t he o pti mal c o n diti o ns t o ac hie ve t h e P K 
o bjecti ves of t he st u d y, ris k t o partici pa nts m ust be mi ni mize d si nce partici p a nts will deri ve n o 
be nefit fr o m e x p os ure t o t he st u d y me dicati o n. T he i nf or mati o n o btai ne d i n t his st u d y will 
i nf or m t he prescri bi n g i nf or mati o n a n d will be use d f or t he f urt h er m ulti nati o nal cli nical 
de vel o p me nt of x e vi na pa nt.  
As of 3 1 J ul y 2 0 2 1, a t otal of 5 8 healt h y a d ult partici pa nts ha ve bee n e x p ose d t o x e vi na pa nt as a 
si n gle a ge nt i n st u dies De bi o 1 1 4 3 -1 0 7 a n d D e bi o  1 1 4 3 -1 0 9. A m o n g t h e 5 8 healt h y a d ult 
partici pa nts t he m ost fre q ue ntl y re p orte d e ve nts w ere hea dac he ( 5/ 5 8; 8. 6 % partici pa nts), na us ea 
( 3/ 5 8; 5. 2 % partici pa nts), a n d a b d o mi nal pai n u p p er, diarr h ea a n d diz zi ness (eac h i n 2/ 5 8; 
3. 4 %  partici pa nts). All ot her e ve nts w ere re p ort e d i n a si n g le partici pa nt. N o ne of t he T E A Es 
re p orte d i n healt h y p artici pa nts were seri o us or se vere. 
I n x e vi na pa nt st u dies as of 3 1 J ul y 2 0 2 1, a t otal of 3 1 4 partici pa nts wit h a mali g na n c y ha ve 
recei v e d at least 1 d ose of xe vi na pa nt ( u p t o 9 0 0 m g). Si xt y -f o ur p artici pa nts recei ve d 
x e vi na pa nt as si n gle a ge nt, 1 5 0 recei ve d x e vi na p a nt i n c o m bi nati o n wit h c hem ot hera p y or C R T, 
a n d 1 0 0 i n c o m bi nati o n wit h i m m u n ot hera p y. I n a d diti o n, i n a n o n g oi n g P hase 3 st u d y Tril y n X, 
1 0 5  patie nts ha ve recei v e d at least 1 bli n de d d ose of xe vi na pa nt ( 2 0 0  m g/ d a y, D 1 t o 1 4, e ver y 
3  wee ks) / place b o i n c o m bi nati o n wit h C R T. Base d o n t he safet y d ata of t he P hase 1 a n d 
P hase  2 st u dies, x e vi na pa nt d oses of u p t o 2 0 0 m g/ da y were safel y c o m bi ne d wit h eit her 
c he m ot hera p y or C R T (refer t o I B f or f urt h er i nf or mati o n).  
T he p ote ntial se nsiti vit y of xe vi na pa nt t o et h nic fact ors was ass esse d ba se d o n n o ncli nical a n d 
cli nical data mai nl y deri v e d fr o m Ca ucasia n partici pa nts  f oll o wi n g t he g ui d a nce s h o w n i n 
A p pe n di x D of I C H E 5( R 1), a n d t hese a n al ys es s u g geste d t h at t he li keli h o o d t hat race/ et h nicit y 
is a si g nifica nt s o urce of varia bilit y i n P K is lo w.  
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o n a bl y 
a ntici pate d p ote ntial a d v erse e v e nts of  x e vi na pa nt ma y b e f o u n d i n t he  I B. 
Base d o n t h e a vaila bl e  n o ncli nical a n d cli nical  data t o date, t he c o n d u ct of t he st u d y, as s p ecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble. 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
2. 3. 2  
Be nefit Assess me nt   
Healt h y partici pa nts ma y e x pect n o direct be nefit be y o n d t h e t h or o u g h me dical c hec k -u p t hat 
t he y will recei ve fr o m partici pati n g i n t his cli nical st u d y.  
H o we ver, t he i nf or mati o n o btai ne d i n t his st u d y will be use d f or t he f urt her gl o bal cli nical 
de vel o p me nt of x e vi na pa nt.  
2. 3. 3  
O ver all Be nefit: Ris k C o ncl usi o n   
C o nsi deri n g t he f or mer e x perie nce i n healt h y partici pa nts a n d t he meas ures ta ke n t o mi ni mize 
a ntici pate d ris k t o partici pa nts i n t his st u d y, t he c o nte m plate d ris ks i n ass ociati o n wit h t he use of 
x e vi na pa nt are j ustifie d b y t he a ntici pate d be n efits f or t he gl o bal cli nical de vel o p me nt of 
x e vi na pa nt as a ne w treat me nt f or partici pa nts wit h mali g na n cies.  
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
3  
O bjecti ves a n d E n d p oi nts   
O bj e cti v e s  
E n d p oi nt s  
R ef. #  
Pri m ar y  
 
T o c h ar a ct eri z e t h e x e vi n a p a nt 
P K aft er a si n gl e 2 0 0  m g d o s e i n 
h e alt h y E a st A si a n p arti ci p a nt s 
a n d i n h e alt h y J a p a n e s e 
p arti ci p a nt s  
X e vi n a p a nt A U C 0 -tl a st, A U C0 -∞, a n d Cm a x   
1  
S e c o n d ar y  
 
T o e v al u at e t h e s af et y a n d 
t ol er a bilit y of a si n gl e 2 0 0 m g 
d o s e of x e vi n a p a nt i n h e alt h y 
E a st A si a n p arti ci p a nt s a n d i n 
h e alt h y J a p a n e s e p arti ci p a nt s  
O c c urr e n c e of T E A E s (i n ci d e n c e, fr e q u e n c y, i nt e n sit y a n d 
c a u s alit y), o c c urr e n c e of c h a n g e s i n s af et y l a b or at or y a s s e s s m e nt s, 
1 2 -l e a d E C G s, a n d vit al si g n s  
2  
T o d et er mi n e a d diti o n al pl a s m a 
P K p ar a m et er s of x e vi n a p a nt 
aft er a si n gl e 2 0 0  m g d o s e i n 
h e alt h y E a st A si a n p arti ci p a nt s 
a n d i n h e alt h y J a p a n e s e 
p arti ci p a nt s  
X e vi n a p a nt A U C 0 -2 4 , tm a x , t1/ 2 , a p p ar e nt cl e ar a n c e ( C L/ F), a n d 
a p p ar e nt v ol u m e of di stri b uti o n d uri n g t er mi n al p h a s e ( V z/ F)  
3  
T o c h ar a ct eri z e t h e P K of 
m et a b olit e D -1 1 4 3 -M E T 1 aft er a 
si n gl e 2 0 0  m g d o s e i n h e alt h y 
E a st A si a n p arti ci p a nt s a n d i n 
h e alt h y J a p a n e s e p arti ci p a nt s  
D -1 1 4 3 -M E T 1 A U C
0 -tl a st, A U C0 -2 4 , A U C0 -∞, Cm a x , tm a x , a n d t1/ 2 , 
D -1 1 4 3 -M E T 1/ x e vi n a p a nt m ol ar r ati o f or A U C
0 -tl a st, A U C0 -∞, Cm a x  
4  
4  
St u d y Desi g n   
4. 1  
O ver all Desi g n   
St u d y Desi g n  
Si n gle -D ose P K St u d y  
C o ntr ol Met h o d  
N ot a p plica ble  
Si n gle or M ultice nter  
Si n gle ce nt er  
C o ntr ol Gr o u p  
N ot a p plica ble  
St u d y P o p ulati o n T y pe  
Healt h y East Asia n partici pa nts  
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
Le v el a n d Met h o d of 
Bli n di n g  
O pe n -la bel 
Bias Mi ni malizati o n 
Met h o d(s)  
N ot a p plica ble  
St u d y I nter v e nti o n 
Assi g n me nt Met h o d  
N ot a p plica ble, all partici pa nts will recei ve t h e sa me st u d y 
i nter ve nti o n 
Data a n d Safet y 
M o nit ori n g / Ot her 
C o m mittee:  
N o  
St u d y I nter v e nti o n 
Gr o u ps a n d D urati o n of 
St u d y I nter v e nti o n f or 
Eac h Partici pa nt  
1 da y of d osi n g f or all partici pa nts  
Tar get n u m bers of partici pa nts are set f or eac h gr o u p.  
Gr o u p 1 will e nr oll at least 1 0 J a pa nese partici pa nts.  
Gr o u p 2 will e nr oll at least 1 0 n o n -J a pa nese East Asia n 
partici pa nts. East Asia i n cl u des K orea or Great er C hi na.   
Prefera bl y a si milar pr o p orti o n of male a n d fe mal e partici pa nts  
will be e nr olle d acr oss gr o u ps if feasi ble.  
T otal D urati o n of St u d y 
Partici pati o n per 
Partici pa nt  
T he pla n ne d t otal d ur ati o n of t he st u d y f or eac h partici pa nt will be 
a p pr o xi matel y5  wee ks , i ncl u di n g a n u p t o 4 -wee k Scree ni n g 
Peri o d, a n I n -h o use Peri o d at  t he C R U ( Da y -1 t o Da y  4), a n d a 
Safet y F oll o w -u p o n D a y  8.  
Parts of t he St u d y  
N ot a p plica ble  
Met h o d Use d f or D os e 
Escalati o n  
N ot a p plica ble  
A da pti ve As pects of 
St u d y Desi g n  
N ot a p plica ble  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
Scree ni n g, Treat me nt, a n d 
F oll o w -u p Peri o ds:  
Scree ni n g  
Scree ni n g will be perf or me d wit hi n Da y  -2 8 t o D a y -3. If t here are 
n o cli nicall y si g nifica nt fi n di n gs at Scree ni n g a n d t he partici pa nt 
meets all t he pr ot oc ol -defi ne d i ncl usi o n a n d n o ne of t he e x cl usi o n 
criteria, t he p artici pa nt will be c o nsi dere d eli gi ble f or 
partici pati o n i n t he st u d y.  
Tre at me nt peri o d: c o nsists of 4 -da y i n -h o use peri o d. It will 
be gi n at t he a d missi o n t o C R U i n t he after n o o n o n Da y  -1. 
Partici pa nts will recei ve a 2 0 0  m g si n gle d ose of x e vi na pa nt as 
s ol uti o n u n der o ver ni g ht faste d c o n diti o n o n Da y  1 a n d sta y i n t he 
C R U u ntil disc har ge d o n Da y  4 a p pr o xi matel y 7 2 h o urs after 
treat me nt a n d c o m pleti o n of all assess me nts. 
S afet y F oll o w -u p Peri o d: occ urs o n Da y  8.  
I n v ol ve m e nt of S pecial 
C o m mittee(s):  
N o  
Pr o visi o ns f or St u d y 
E xte nsi o n or E ntr y i n t o 
R oll -O ver St u dies  
N ot a p plica ble  
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n   
Cli nical st u dies of x e vi na pa nt ha ve bee n c o n d u cte d mai nl y i n Ca ucasi a ns, t h us t he P K data i n 
Asia n et h nicities is n ot a vaila ble. T h o u g h t he p ossi ble et h nic se nsiti vit y of P K of x e vi na pa nt a n d 
its si g nifica nce o n t he cli nical be nefit/ris k are c o nsi dere d t o be l o w bas e d o n n o ncli nical a n d 
n o n -Asia n cli nical dat a c o nsi dere d i n t he c o nte xt of I C H E 5 pri nci ples, t he i n vesti gati o n of 
x e vi na pa nt P K i n East Asia n healt h y p artici pa nts is c o nsi dere d i nf or mati ve f or t he assess me nt of 
data fr o m t he gl o bal P has e 3 st u dies i n v ol vi n g East Asia n p o p ulati o ns. I n t his c o nte xt, t he 
prese nt P K st u d y is pla n n e d.  
T his is a si n gle d ose st u d y of orall y a d mi nistere d x e vi na pa nt s ol uti o n i n healt h y East Asia n 
partici pa nts (i ncl u di n g J a pa nese) t o e val uate t he P K a n d safet y. T he o verall  safet y a n d P K res ults 
of t his st u d y s h o ul d s u p p ort f urt her gl o bal d e vel o p me nt of x e vi na pa nt, i ncl u di n g f urt h er cli nical 
st u dies a n d re g ulat or y s u b missi o n t o J a pa n a n d ot her East Asia n c o u ntries.  
T his st u d y will be c o n d u cte d i n healt h y male a n d fe male part ici pa nts, prefera bl y wit h a si milar 
pr o p orti o n acr oss gr o u ps, if feasi ble. T h e i ncl usi o n a n d e x cl usi o n criteria are sta n dar d f or a 
P hase  1 st u d y i n healt h y partici pa nts (see Secti o ns 5. 1  a n d 5. 2 ). Healt h y p artici pa nts e ns ure 
h o m o ge n eit y of t h e st u d y p o p ulati o n, a n d a vaila bl e cli nical data i n he alt h y Ca ucasia n 
partici pa nts de m o nstrate d g o o d t olera bilit y after a si n gle 2 0 0 m g d ose. As S C C H N occ urs i n 
b ot h me n a n d w o me n, t his st u d y will e nr oll partici pa nts of b ot h se x es. Se x differe n ces r e gar di n g 
safet y, t olera bilit y, a n d P K are n ot e x pecte d. O nl y w o me n of n o nc hil d beari n g p ote ntial will be 
i ncl u de d. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
T he P K sa m pli n g ti me p oi nts i n t his st u d y c o veri n g u p t o 7 2 h o urs p ost d ose were c h ose n b ase d 
o n data fr o m t he H V st u dies i n Ca ucasia n partici pa nts ( De bi o  1 1 4 3 -1 0 7) t o a p pr o priatel y c o v er 
t he e x pecte d ti me of e x p os ure t o x e vi na pa nt after a si n gle-d ose a d mi nistrati o n (see S o A, 
Secti o n  1. 3 ).  
Cli nical f or m ulati o ns a n d t he d ose ( 2 0 0 m g) t hat h as bee n use d i n h ealt h y p artici pa nts i n H V 
St u d y De bi o  1 1 4 3 -1 0 9 is bei n g us e d i n t he o n g oi n g P hase 3 st u d y (refer t o I B Ta bl e 6 -1 a n d 
6 -4).  
T he safet y of xe vi na pa nt will be assesse d t hr o u g h o ut t he st u d y b y e val u ati n g A Es (i ncl u di n g 
i nci de nce, n at ure, a n d s e verit y), cli nical la b orat or y res ults, vital si g ns meas ure me nts, a n d real 
ti me, l ocall y rea d safet y E C Gs. T he safet y m o nit ori n g pr o p os e d i n t his st u d y is i n acc or da n ce 
wit h t he Be nefit/ Ris k assess me nt (see Secti o n 2. 3 ). 
T he c ollecti o n of plas ma after a si n gle d os e of xe vi na pa nt will als o all o w f urt her c h aracterizati o n 
of t he e x p os ure of t he mai n circ ulati n g m eta b olite D -1 1 4 3 -M E T 1, as w ell as  
 a n al ysis 
of ot her meta b olites, if warra nt e d.  
Details o n x e vi na pa nt de vel o p me nt ca n be f o u n d i n t he I n v esti gat or’s Br oc h ure.  
4. 3  
J ustific ati o n f or D ose   
T he pr o p ose d si n gle d ose of 2 0 0  m g a d mi nistere d u n der faste d c o n diti o ns is i de ntical t o t hat 
use d i n st u dies De bi o  1 1 4 3 -1 0 7 a n d De bi o  1 1 4 3 -1 0 9 i n healt h y Ca u casia n par tici pa nts wit h 
fa v ora bl e t olera bilit y. It is als o t he dail y d ose us e d i n t he o n g oi n g P hase 3 st u d y i n c o m bi nati o n 
wit h C R T i n partici pa nts wit h L A S C C H N.  
F or m ore i nf or mati o n o n t he selecti o n of R P 3 D refer t o A A C R p oster [ A bstract N o. 5 4 2 4. 
Prese nte d at t he A A C R A n n ual Meeti n g 2 0 2 2, A pril 8-1 3, 2 0 2 2; Ne w Orl ea ns, L A, a n d Virt ual].  
4. 4  
E n d of St u d y Defi niti o n   
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last p artici pa nt or t he last 
sc he d ule d pr o ce d ure s h o w n i n Secti o n  1. 3 . 
A partici pa nt has c o m plete d t he st u d y if h e/s he has c o m plete d all st u d y p arts, i ncl u di n g t he last 
vis it or t he last sc he d ule d pr oce d ure s h o w n i n Secti o n  1. 3 . 
5  
St u d y P o p ul ati o n   
T he  p ur p ose  o f t his st u d y is t o assess t he P K a n d safet y  o f x e vi na pa nt  i n h e alt h y E ast Asia n 
partici pa nts, i ncl u di n g h ealt h y J a pa nese p artici pa nts. Acc or di n g ly, J a pa nes e partici pa nts a n d 
n o n -J a pa nese East Asia n partici pa nts will be e nr olle d. 
T he criteri a i n Secti o n s 5. 1  a n d 5. 2  are desi g ne d t o e nr oll o nl y i n di vi d uals w h o are a p pr o priat e 
f or t he st u d y; t here b y, e ns uri n g t he st u d y f ulfills its o bjecti ves. All rele va nt me dical a n d 
n o n me dical c o n diti o ns are c o nsi der e d w he n d eci di n g w h et her a n  i n di vi d ual is s uita ble f or t his 
st u d y. 
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e x cl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
Bef ore perf or mi n g a n y st u d y ass ess me nts t hat are n ot part of t he i n di vi d ual’s r o uti ne me dical 
care, t h e I n vesti gat or will c o nfir m t hat t he i n di vi d ual has pr o vi de d writte n i nf or me d c o nse nt, as 
i n dicate d i n A p pe n di x 2 . 
5. 1  
I ncl usi o n Criteri a  
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:  
C ate g or y  
Criteri o n  
Et h nicit y  
1.  Healt h y  p arti ci pa nt of  J a pa nese or  ot her East Asia n ori gi n.  
a. Gr o u p 1: J a pa nese partici pa nts m ust be first ge n erati o n ( b or n 
i n J a pa n) wit h b ot h bi ol o gic al pare nts a n d all 4 bi ol o gical 
gra n d pare nts bei n g J a pa nese nati ve b or n, li ve d f or < 1 0 years 
o utsi de of J a pa n, a n d ha v e n o si g nifica nt c h a n ge i n lifest yle 
si nce lea vi n g J a pa n. 
b.  Gr o u p 2: Ot her n o n -J a pa nese East Asia n p artici pa nts m ust 
ha ve b ot h bi ol o gic al pare nts a n d 4 bi ol o gical gra n d pare nts of 
East Asia n desce nt, li ve d f or < 1 0 years o utsi de of t heir 
c o u ntries, a n d ha v e n o si g nifica nt c ha n g e i n lifest yl e si nc e 
lea vi n g fr o m t here. East Asia i ncl u des K orea or Greater 
C hi na.  
A ge  
2.  Are 1 8 t o 6 0 years of a ge at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.  
T y pe of Partici pa nt 
a n d Disease 
C haracteristics  
3.  Are o vertl y h ealt h y as deter mi ne d b y m e dical e v al uati o n, 
i ncl u di n g me dical hist or y, p h ysical e x a mi nati o n, la b orat or y tests, 
a n d car di ac m o nit ori n g ( bl o o d press ure, heart rate, a n d 1 2 -lea d 
resti n g E C G). 
Wei g ht  
4 . Ha ve a b o d y wei g ht wit hi n 5 0 a n d 1 1 0  k g  a n d b o d y mass i n de x 
wit hi n t he ra n ge 1 8. 0 t o 3 2. 0  k g/ m 2 (i ncl usi ve). 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
Se x a n d 
C o ntrace pti o n / 
Barrier Re q uir e me nts  
5.  All se x es all o we d.  
T he I n vesti gat or c o nfir ms t hat eac h partici pa nt a grees t o use 
a p pr o priate c o ntrace pti o n a n d barri ers, if a p plica ble. T he 
c o ntrace pti o n, barrier, a n d pre g na nc y t esti n g re q uire me nts are 
bel o w.  
a. Male Partici pa nts:  
•  A gree t o t he f oll o wi n g d uri n g t he st u d y i nter ve nti o n peri o d 
an d f or at least 9 0 da ys fr o m t he last d ose, c o veri n g t he ti me 
nee de d t o eli mi nate st u d y i nter ve nti o n a n d t o c o m plete a f ull 
c ycle of s p er mat o ge n esis after t he l ast d ose of st u d y 
i nter ve nti o n: 
o  Refrai n fr o m d o n ati n g s p er m  
•  Use a male c o n d o m:  
•  
W he n ha vi n g se x ua l i nterc o urse wit h a w o ma n of 
c hil d beari n g p ote ntial , w h o is n ot  c urre ntl y pre g n a nt, a n d 
a d vise her t o use a hi g hl y effecti ve c o ntr ace pti ve met h o d 
wit h a fail ure rate of <  1 % per year, as d escri b e d i n 
A p pe n di x 3  C o ntrace pti o n a n d Barrier Re q uire me nts , 
si nce a c o n d o m ma y brea k or lea k.  
b.  Fe male Partici pa nts:  
•  Are n ot breastfee di n g   
•  Are n ot  pre g na nt, as c o nfir me d b y:  
•  a ne gati ve ser u m (at Scree ni n g) a n d uri ne ( Da y -1) 
pre g na nc y t est, as re q uir e d b y l oc al re g ulati o ns, 
wit hi n 2 4 h o urs bef ore t h e first d ose of st u d y 
i nter ve nti o n. 
•  Are  n ot  a w o m a n of c hil d beari n g p ote ntial (see A p pe n di x 3
 
C o ntrace pti o n a n d Barrier Re q uire me nts ) defi ne d as 
eit her: 
•  At least 1 year  p ost me n o pa usal  (a me n orr hea 
≥ 1 2  m o nt hs a n d F S H ≥ 4 0  mI U/ m L) at Scree ni n g;  
O R  
•  S ur gicall y sterile ( bilateral o o p h orect o m y, 
h ysterect o m y or bilateral sal pi n gect o m y; t u bal li gati o n 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
C ate g or y  
Criteri o n  
al o ne is n ot s ufficie nt) as d oc u me nte d b y me dical 
certificate  
•  A d diti o nal re q ui re me nts f or pre g n a nc y testi n g d uri n g a n d 
after st u d y i nter ve nti o n are i n Secti o n  8. 3. 4 . 
•  T he In vesti gat or re vie ws t he me dical hist or y, me nstr ual 
hist or y, a n d rece nt se x ual acti vit y t o de crease t he ris k f or 
i ncl usi o n of a fe male wit h a n earl y u n d etecte d pre g na n c y 
I nf or me d C o nse nt  
6.  
C a pa ble of gi vi n g si g n e d i nf or me d c o nse nt, as i n dicate d i n 
A p pe n di x 2 , w hic h i ncl u des c o m plia nce wit h t he re q uire me nts 
a n d restricti o ns liste d i n t he I C F a n d t his pr ot oc ol.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
5. 2  
E xcl usi o n Criteri a   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
C ate g or y  
Criteri o n  
Me dical C o n diti o ns  
1.  Hist or y of cli nicall y rele va nt disease of a n y or ga n s yste m 
t hat ma y i nterfere wit h t he o bjecti ves of t he st u d y or 
pr o vi de a ris k t o t he healt h of t he partici pa nt.  
2.  Hist or y of rele v a nt dr u g h y perse nsiti vit y, as certai ne d or 
pres u m pti ve aller g y/ h y p erse nsiti vit y t o t he acti ve dr u g 
s u bsta nce a n d/ or f or m ulati o n i n gre die nts; histor y of 
seri o us aller gic reacti o ns lea di n g t o h os pitalizati o n or a n y 
ot her aller g y reacti o n i n ge n eral, w hi c h t he I n v esti gat or 
c o nsi ders ma y affect t he safet y of t he p artici pa nt a n d/ or 
o utc o me of t he st u d y.  
3.  O n g oi n g or acti ve cli nic all y si g nifi ca nt viral (i ncl u di n g 
S A R S -C o V -2), bacterial or f u n gal i nfecti o n, or a n y maj or 
e pis o de of i nfecti o n re q uiri n g h os pitaliz ati o n or treat me nt 
wit h pare nteral a ntii nfecti ves ≤ 4 wee ks pri or t o or d uri n g 
Scree ni n g Peri o d, or c o m pleti o n of oral a ntii nfecti ves 
≤ 2  wee ks pri or  t o Scree ni n g Visit. Va gi nal ca n di diasis, 
o n yc h o m yc osis, a n d ge nital or oral her p es si m ple x vir us 
c o nsi dere d t o be s ufficie ntl y c o ntr olle d will n ot be 
e x cl usi o nar y. N ote: A n I n vesti gat or m a y use cli ni cal 
j u d gme nt  i n testi n g f or S A R S-C o V -2 i m me diatel y pri or  
t o ra n d o mizati o n de pe n di n g o n t he p artici pa nts’ m e dical 
c o n diti o n. H o we ver, wit hi n 3 t o 5 da ys pri or t o 
ra n d o mizati o n, all partici pa nts s h o ul d be s pecificall y 
q uesti o ne d f or C O VI D -1 9 s y m pt o ms or cl ose c o nt act 
wit h s o me o ne k n o w n t o ha ve S A R S -C o V -2 i nfecti o n t o 
deter mi ne if S A R S -C o V -2 testi n g (acce pte d acc or di n g t o 
l ocal g ui d eli nes) s h o ul d be perf or me d. 
4.  Hist or y of s ple n ect o m y.  
5.  Hist or y of m ali g na n c y ( he mat ol o gic or s oli d t u m or) 
bef ore t h e Scree ni n g Visit, e x ce pt a de q uatel y treat e d 
basal cell or s q ua m o us cell carci n o mas of t he s ki n ( n o 
m ore t ha n 3  lesi o ns re q uiri n g tr eat me nt i n lifeti me) or 
carci n o ma i n sit u/cer vical i ntrae pit helial ne o plasia of t he 
uteri ne cer vi x.  
6.  Hist or y of or a p ositi ve Scree ni n g test f or he p atitis B 
s urface a nti ge n, he p atitis B c ore a nti b o dy, he p atitis C 
a nti b o d y, or h u ma n i m m u n o deficie nc y vir us t y p e I a n d II.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
C ate g or y  
Criteri o n  
Pri or/ C o nc o mita nt 
T hera p y  
7.  Use of a n y prescri be d me dici ne or o ver -t he-c o u nter dr u g 
( ot her t ha n occasi o nal us e of i b u pr ofe n or paraceta m ol 
<  1. 5  g/ d a y b ut i ncl u di n g her bal r e me dies, vita mi ns, a n d 
mi nerals) wit hi n 2 wee ks or 5 ti mes t he half -life of t he 
res pecti ve dr u g, w hic he v er is l o n ger, bef ore t he first d ose 
of st u d y i nter ve nti o n.  
8.  Use of dr u gs a n d h er bal r e me dies wit h e nz y me i n d uci n g 
pr o perties s uc h as tra diti o nal C hi nese me dici ne, St. 
J o h n’s W ort, wit hi n 3 wee ks bef ore t he first d ose of st u d y 
i nter ve nti o n; gra pefr uit or gra pefr uit j uice fr o m 7 2 h o urs 
pri or t o first d osi n g  
9.  Vacci n ati o n wit h a n atte n uate d vir us d uri n g t he last 
3  m o nt hs bef ore t he first a d mi nistrati o n of st u d y 
i nter ve nti o n. 
1 0.  K n o w n h y p erse nsiti vit y t o t he st u d y i nter ve nti o n or t o 
o ne or m ore of t he e x ci pie nts use d  
Pri or/ C o nc urre nt 
Cli nical St u d y 
E x perie nce  
1 1.  Use of a n y i n vesti gati o nal dr u g i n a n y cli nical st u d y 
wit hi n 5  half -li ves fr o m last a d mi nistrati o n 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
C ate g or y  
Criteri o n  
Dia g n ostic Assess me nts  
1 2.  S u pi ne s yst olic bl o o d press ure >  1 4 0  m m H g or 
<  9 0  m m H g or diast olic bl o o d press ure >  9 0  m m H g or 
<  5 0  m m H g at Scree ni n g or Da y  1 pri or t o d osi n g (a n y 
a b n or mal bl o o d press ur e res ults ma y b e re p eate d o nce 
a n d if t he re p eat r es ult is wit hi n t he n or mal ra n ge, it is n ot 
c o nsi dere d t o ha v e met t he e x cl usi o n criteri o n).  
1 3.  P ulse rate >  9 0 or <  5 0 b eats per m i n ute at Scree ni n g or 
Da y  1 pri or t o d osi n g.  
1 4.  1 2 -Lea d E C G rec or di n g wit h si g ns of cli nicall y rele va nt 
pat h ol o g y, i n partic ul ar Q Tc acc or di n g t o Fri deri cia’s 
f or m ula > 4 5 0  ms, P R >  2 1 0  ms, or Q R S d urati o n 
>  1 2 0  ms.  
1 5.  A L T a n d A S T, U L N at Scree ni n g. A n y a b n or mal  val ue 
of t hese para meters ma y be re peate d a n d if t he re p eat 
res ult is wit hi n t he la b orat or y refere n ce ra n ge, it is n ot 
c o nsi dere d t o ha v e met t he e x cl usi o n criteri o n.  
1 6.  Esti mate d gl o mer ular filtrati o n rate acc or di n g t o t he 
C hr o nic Ki d ne y Diseas e E pi de mi ol o g y C olla b orati o n  
Creati ni ne E q uati o n <  8 0  m L/ mi n / 1. 7 3 m2 at Scree ni n g.  
1 7.  Scree ni n g la b orat or y val ues ot her t ha n A S T, A L T f or 
he mat ol o g y, c oa g ulati o n, bi oc he mistr y, or uri nal ysis 
o utsi de t he refere n ce ra n ge. Mi n or de viati o ns fr o m 
n or mal are all o we d if t he y are  n ot cli nicall y si g nifica nt.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
C ate g or y  
Criteri o n  
Ot her E x cl usi o ns  
1 8.  Hist or y of alc o h olis m or dr u g a b use wit hi n t he past 
2  years, or p ositi ve scree n f or alc o h ol or dr u gs of a b use at 
Scree ni n g or a d missi o n.  
1 9.  C o ns u m pti o n of a n a vera ge wee kl y i nta k e of 
>  1 4  dri n ks/ wee k f or me n or >  7 dri n ks/ wee k f or w o me n. 
O ne dri n k is e q ui vale nt t o ( 1 2  g alc o h ol) = 5  o u n ces 
( 1 5 0 m L) of wi ne or 1 2  o u nces ( 3 6 0  m L) of beer or 
1. 5  o u nces ( 4 5  m L) of 4 0 % alc o h ol c o nte nt b y v ol u me of 
distille d s pirits.  
2 0.  K n o w n e x cessi ve c o ns u m pti o n of x a nt hi ne -c o ntai ni n g 
fo o d or be vera ges ( >  5 c u ps of c offee a d a y or e q ui vale nt) 
or i na bilit y t o st o p c o ns u mi n g caffei n e, fr o m 4 8 h o urs 
pri or t o dr u g a d mi nistrati o n u ntil 7 2 h o urs after 
a d mi nistrati o n.  
2 1.  Use of a n y t o ba cc o pr o d ucts (ci garettes, pi pes, ci gars, 
e-ci garettes, or ot he r nic oti ne deli ver y s yst e ms) wit hi n 
9 0  da ys b ef ore t he Scree ni n g Visit. Partici pa nts wit h 
p ositi ve uri ne c oti ni ne le vels d uri n g Scree ni n g or Da y  -1 
will be e x cl u de d.  
2 2.  D o nati o n or l oss of m ore t ha n 4 5 0  m L of bl o o d i n t he 
9 0  da ys pri or t o a d mi nistrati o n of x e vi na pa nt.  
2 3.  I n a bilit y t o c o m m u nicate or c o o perate wit h t he 
I n v esti gat or (e. g., l a n g ua ge pr o ble m, illiterates, p o or 
me ntal stat us) or t o c o m pl y wit h t he re q uire me nts of t he 
e ntire st u d y, i n cl u di n g di etar y restricti o ns.  
2 4.  Ot her fact ors w hic h i n t h e o pi ni o n of t he I n vesti gat or 
ma y i nterfere wit h st u d y c o n d uct.  
5. 3  
Lifest yle C o nsi der ati o ns   
Lif est yle a n d dietar y restricti o ns d uri n g partici pati o n i n t he st u d y, i ncl u di n g dietar y restri cti o ns 
are s pecifie d i n t he e x cl usi o n criteria 1 8 t o 2 1 i n Secti o n 5. 2  a b o ve.  
5. 3. 1  
Me als a n d Diet ar y Restricti o ns   
Partici pa nts will a bstai n f r o m c o ns u mi n g Se ville ora n ges, gra pefr uit or gra p efr uit j uice, p o mel os, 
e x otic citr us fr uits, gr a p efr uit h y bri ds, or fr uit j uic es fr o m 7 2 h o urs pri or t o first d osi n g  u ntil 
disc har ge . 
Partici pa nts will a bstai n fr o m ta ki n g res veratr ol dietar y s u p ple me nts wit hi n 1 4  da ys b ef ore d ose 
a d mi nistrati o n  u ntil after c o m pleti o n of t he f oll o w -u p visit . 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 /6 6  
 
 
All x e vi na pa nt d oses will be gi v e n after a n at least 1 0 -h o ur o ver ni g ht f ast. Fasti n g will be 
mai ntai ne d f or at least 2  h o urs after xe vi na pa nt a d mi nistrati o n. Water c o ns u m pti o n is all o we d a d 
li bit u m (as desire d) e x ce pt f or 1  h o ur bef ore u ntil 1  h o ur after st u d y  i nter ve nti o n i nta ke a part 
fr o m t he water ta ke n wit h t he d ose. 
D uri n g c o nfi ne me nt, p artici pa nts are o nl y per mitte d t o eat meals pr o vi de d b y t he st u d y site. O n 
d osi n g da ys (s ee S o A i n Secti o n 1. 3 ), partici pa nts will recei ve a sta n dar diz e d li g ht meal after 
4  h o urs, a s nac k a p pr o xi matel y 7 h o urs a n d di n ner a p pr o xi matel y 1 0 h o urs after d osi n g.  
Ot her meals will be pr o vi de d at us ual meal ti mes of t he st u d y ce nter.  
Pr o d ucts c o ntai ni n g p o p p y see ds (ca ke, r olls) ma y n ot be c o ns u me d wit hi n 4 8 h o urs bef ore 
Scree ni n g a n d eac h a d missi o n u ntil disc har ge.  
5. 3. 2  
C affei ne, Alc o h ol, T o b acc o , a n d C a n n a bi n oi d  
•  D uri n g t h e d osi n g p eri o d , partici pa nts will a bstai n fr o m i n gesti n g caffei ne - or 
x a nt hi ne -c o ntai ni n g pr o d ucts (e. g., c offee, tea, c ola dri n ks, a n d c h o c olate) f or 4 8  h o urs 
bef ore t h e start of d osi n g u ntil 7 2 h o urs after a d mi nistrati o n . 
•  D uri n g t h e i n-h o use c o nfi ne me nt peri o d , partici pa nts will a bstai n fr o m alc o h ol f or 
3 6  h o urs bef ore t he start of c o nfi ne me nt p eri o d u ntil disc har ge . 
Use of ca n na bi n oi ds a n d ot her dr u gs of a b us e is n ot all o we d d uri n g t h e w h ole st u d y. Partici pa nts 
m ust ha ve a ne gati ve t est f or dr u gs of a b use at Scree ni n g a n d at a d missi o n t o eac h st u d y peri o d.  
Use of t o bacc o pr o d u cts will n ot be all o we d fr o m 9 0 da ys b ef ore t he Scree ni n g Visit u ntil after 
t he disc har ge  (see e x cl usi o n criteri o n 2 1 i n Secti o n 5. 2  a b o ve).  
5. 3. 3  
Acti vit y   
Partici pa nts will a bstai n fr o m stre n u o us e x ercise f or 7 -da ys bef ore eac h bl o o d c ollecti o n f or 
cli nical la b orat or y tests. Partici pa nts ma y p artici p ate i n li g ht recreati o nal a cti vities (e. g., 
watc hi n g tele visi o n or rea di n g).  
5. 4  
Scree n F ail ures   
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y (s cree n fail ure) ma y b e 
rescree ne d.  
5. 5  
Criteri a f or Te m p or aril y Del a yi n g E nr oll me nt , 
R a n d o miz ati o n , or A d mi nistr ati o n of St u d y I nter ve nti o n   
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /6 6  
 
 
6  
St u d y I nter ve nti o n(s)  a n d C o nc o mit a nt T her a pies   
St u d y i nter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), place b o, or 
me dical de vice(s) i nte n d e d t o be a d mi nistere d t o a st u d y p artici pa nt per  t h e st u d y pr ot o c ol. 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistr ati o n   
St u d y I nter ve nti o n(s) A d mi nistere d  
I nter ve nti o n 
N a me  
Xe vi na pa nt  
T y pe  
Dr u g  
D ose 
F or m ul ati o n  
B ottle of  
 oral s ol uti o n c o ntai ni n g 2 0 0 m g x e vi na pa nt 
 
 
U nit D ose 
Stre n gt h(s)  
2 0 0 m g  
D ose  
2 0 0 m g  
D os a ge Re gi me n  
Si n gle d ose  
R o ute of 
A d mi nistr ati o n  
Oral  
Use  
E x peri me ntal  
I M P o r 
NI M P/ A x M P  
I M P 
S o urci n g  
Pr o vi de d ce ntrall y b y t he S p o ns or  
P ac k a gi n g a n d 
L a beli n g  
Xe vi na pa nt will be pr o vi de d i n b ottles. Eac h b ottle will be pac k e d a n d 
la bele d per all a p plica ble re g ulat or y re q uire me nts a n d G M P G ui deli nes. 
F or mer N a m e 
De bi o 1 1 4 3  
 
St u d y Ar m(s)  
Ar m N a me  
•  Gr o u p 1: J a pa nese partici pa nts  
•  Gr o u p 2: n o n -J a pa nese E ast Asia n partici pa nts 
Ar m T y pe  
E x peri me ntal  
Ar m Descri pti o n  Si n gle 2 0 0 m g oral d ose of xe vi na pa nt . Xe vi na pa nt will be a d mi nistere d 
wit h a n oral s yri n ge a n d a gl ass of 2 4 0 m L of water.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 8 /6 6  
 
 
Ass oci ate d 
I nter ve nti o n 
L a bels  
Xe vi na pa nt  
6. 2  
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y   
Xe vi na pa nt will be pr o vi de d i n glass b ottles (f or details, see Secti o n 6. 1 ). 
T he x e vi na pa nt oral s ol uti o n s h o ul d be st ore d u n der a c o ntr olle d te m perat ure at 
 
 
Pac ka g i n g a n d la beli n g of xe vi na pa nt s ol uti o n will be i n acc or da nce wit h a p plica ble re g ulat or y 
re q uire me nts a n d a p plica ble G o o d Ma n ufact uri n g Practice g ui deli nes. T h e i nf or mati o n o n t he 
me dicati o n will be i n acc or da nce wit h a p pr o ve d s u b missi o n d oc u me nts.  
T he In v esti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nt a bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
•  U p o n recei pt of t he st u d y i nter ve nti o n(s), t he In v esti gat or or d esi g n ee will  c o nfir m 
a p pr o priate t e m perat ur e c o n diti o ns ha ve bee n mai ntai ne d d uri n g tra nsit a n d a n y 
discre pa n cies are re p orte d a n d res ol ve d b ef ore use.  Als o, t he res p o nsi ble pers o n will 
c hec k f or acc urate deli ver y.  F urt her g ui da nce a n d i nf or mati o n f or st u d y i nt er ve nti o n 
acc o u nta bilit y are pr o vi d e d i n t he a p plica ble ma n ua l. 
•  O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n(s) a n d o nl y 
a ut h orize d site staff ma y s u p pl y it.  All st u d y i nter v e nti o n(s) will  be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d , a n d m o nit ore d ( ma n u al or a ut o mate d) area, per  t he la bele d 
st ora ge c o n diti o ns, a n d wit h access li mite d t o t he In vesti gat or a n d a ut h orize d site staff.  
•  Dis pe nsi n g will be rec or de d o n t he a p pr o p riate acc o u nta bilit y f or ms s o t hat acc urate 
rec or ds will be a vaila ble f or verifi cati o n at eac h m o nit ori n g visit. 
•  St u d y i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he 
f oll o wi n g: 
o  
C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t h e defi ne d te m p erat ur e ra n ge.  
o  
T he i n ve nt or y pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.  
o  
T he d ose(s) eac h partici p a nt use d d uri n g t he st u d y.  
o  
T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n us e d st u d y i nter ve nti o n(s).  
o  
Dates, q ua ntitie s, batc h n u m bers, b ottle  n u m bers, e x pir y d ates , a n d t h e partici pa nt 
n u m bers.  
•  T he I n vesti gat or site will mai ntai n rec or ds w hi c h a de q uatel y d o c u me nts t hat 
partici pa nts were pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y 
i nter ve nti o n(s) pr o vi de d were f ull y rec o n cile d.  
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 9 /6 6  
 
 
•  U n use d st u d y i nter ve nti o n(s) will  n ot be discar de d or use d f or a n y p ur p ose ot her t ha n 
t he prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y b e 
re dis pe nse d t o a differe nt partici pa nt. 
•  A St u d y M o nit or will pe ri o dicall y c ollect t he st u d y i nter ve nti o n(s) acc o u nt a bilit y 
f or ms. 
•  F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y 
i nter ve nti o n(s) are pr o vi d e d i n t he a p plica ble ma n ual . 
6. 3  
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g   
6. 3. 1  
St u d y I nter ve nti o n Assi g n me nt   
O n Da y 1, partici pa nts will be assi g ne d a u ni q ue n u m ber ( partici p a nt n u m ber) i n asce n di n g 
n u merical or d er at t he st u d y site. T here is o nl y 1 tr eat me nt per gr o u p per et h nicit y, t h us, n o 
ra n d o mizati o n pr oce d ures will be a p plie d. 
6. 3. 2  
Bli n di n g   
Bli n di n g is n ot a p plica bl e as t he st u d y i nter ve nti o n a d mi nistrati o n is o pe n la bel a n d n o ne of t he 
assess me nts is bli n de d.  
6. 4  
St u d y I nter ve nti o n C o m pli a nce   
W he n partici pa nts are d ose d at t he site, t he y will recei ve st u d y i nter ve nti o n directl y fr o m t he 
I n v esti gat or or desi g nee, u n der me dical s u p er visi o n. T he date a n d ti me of eac h d ose 
a d mi nistere d i n t he cli nic will be rec or de d i n t he s o urce d oc u m e nts a n d rec or de d i n t he C R F. A 
me m ber of t he st u d y site staff ot her t ha n t h e pers o n a d mi nisteri n g t he st u d y i nter ve nti o n will 
c o nfir m t he st u d y i nter ve nti o n d ose a n d st u d y partici pa nt i de ntificati o n at t he ti me of d osi n g . 
St u d y site p ers o n nel will e x a mi ne eac h partici pa nt’s m o ut h t o e ns ure t ha t t he st u d y i nter ve nti o n 
was i n geste d.  
6. 5  
D ose M o dific ati o n   
N o d ose m o dificati o ns are pla n ne d i n t his st u d y.  
6. 6  
C o nti n ue d Access t o St u d y I nter ve nti o n A fter t he E n d of t he St u d y  
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o partici pa nts after t he y l ea ve t he st u d y 
beca use s u c h care w o ul d n ot differ fr o m w hat is n or mall y e x pecte d f or healt h y partici pa nts.  
6. 7  
Tre at me nt of O ver d ose   
F or t his st u d y, a n y d ose of st u d y i nter ve nti o n greater t ha n 2 0 0  m g  will be c o nsi dere d a n 
o ver d ose.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /6 6  
 
 
T he S p o ns or has n o s pecific rec o m me n dati o n f or tre ati n g a n o ver d ose. T h e I n v esti gat or will use 
his/ her cli nical j u d g me nt t o ma na ge a n y o v er d ose, c o nsi deri n g t he s y m pt o ms a n d a n y site 
pr oce d ures or sta n dar ds . 
E ve n if n ot ass ociate d wit h a n A E or S A E, a n y o v er d ose is rec or de d i n t he C R F a n d re p ort e d t o 
gl o b al patie nt safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a n  S A E a n d O ver d os e 
Re p ort F or m, f oll o wi n g t he pr oce d ure i n A p p e n di x 4 . 
6. 8  
C o nc o mit a nt T her a p y   
Rec or d i n t he C R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d 
fr o m t he si g ni n g of t h e I C F u ntil c o m pleti o n of t he st u d y at t he ti me p oi nts s pecifie d  i n t he S o A, 
i ncl u di n g a n y c ha n ges. F or prescri pti o n a n d o ver -t he-c o u nter me dici nes, vacci nes, vita mi ns, a n d 
her bal s u p ple me nts, r ec or d t he na me, reas o n f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n.  
F or n o n dr u g i nter ve nti o ns, rec or d t he n a me, t he i n dicati o n, a n d dates a d mi nistere d.  
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n  c o nc o mita nt or pri or t h era p y.  
6. 8. 1  
Per mitte d Me dici nes   
T he o nl y p er mitte d me dici nes are t he f oll o wi n g:  
1.  Paracet a m ol (aceta mi n o p he n) u p t o 1, 5 0 0  m g p er da y  
2.  L ocal treat me nt of a n i n d welli n g ca n n ula i n d uce d t hr o m b o p hle bitis is all o we d, u p o n 
decisi o n b y t he Pri n ci pal I n v esti gat or.  
A n y me di ci nes t hat are c o nsi dere d necessar y t o pr otect t he partici pa nt’s welfare  i n e m er ge n cies 
ma y b e gi ve n at t he I n v esti gat or’s discreti o n , re gar dless if it res ults i n a pr ot oc ol de viati o n. 
6. 8. 2  
Pr o hi bite d Me dici nes   
A n y c o nc o mita nt me dicati o n a part fr o m paraceta m ol/aceta mi n o p he n is c o nsi dere d pr o hi bite d. 
A n y me di cati o n, pres cri pti o n or n o n prescri pti o n (i ncl u di n g vita mi ns a n d di etar y, tra diti o nal 
C hi nese me dici ne or her bal s u p ple me nts), a d mi nistere d wit hi n 2  wee ks or fi ve half -li ves b ef ore 
a d mi nistrati o n of st u d y i nter ve nti o n, w hic he v er is l o n ger, is c o nsi dere d e x cl usi o nar y f or 
partici pati o n i n t he st u d y, u nless, i n t he o pi ni o n of t he I n v esti gat or a n d S p o ns or Me dical 
Res p o nsi ble, t he me dicati o n will n ot i nter fere wit h t he st u d y. 
If a n y pr o hi bite d me dicati o n is a d mi nistere d d uri n g t he st u d y it ma y warra nt e x cl usi o n of f urt her 
partici pati o n i n t he st u d y, s u bject t o S p o ns or Me dical Res p o nsi ble re vie w.  
7  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al   
Disc o nti n uati o n of s pecific sites or of t he e ntire st u d y is s pecifie d i n A p pe n di x 2  St u d y 
G o ver na n ce . 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 1 /6 6  
 
 
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n   
N ot a p plica ble as p artici pa nts will recei ve a si n gl e d ose of xe vi na pa nt of 2 0 0 m g.  
7. 2  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y   
•  T he partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n v esti gat or f o r safet y, b e ha vi oral, c o m plia nce, 
or a d mi nistrati ve reas o ns.  
•  T he partici pa nt ma y b e wit h dra w n b y t he I n vesti gat or d ue t o partici pati o n i n a n ot her cli nical 
st u d y. 
•  If a partici pa nt has faile d t o atte n d sc he d ule d st u d y ass ess me nts, t he I n vesti gat or m ust 
deter mi ne t he reas o ns a n d t he circ u msta nces as c o m pletel y a n d acc uratel y as p ossi ble.  
•  If a partici pa nt m ust be wit h dra w n fr o m t he st u d y, t he S p o ns or Me di cal Res p o nsi ble a n d 
Cli nical St u d y Lea d will be i nf or me d i m me diatel y.  
•  If t here is a me dical r eas o n f or t he wit h dra wal, a p pr o priate me dical care will be pr o vi de d.  
•  At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a disc o nti n uati o n visit will be 
c o n d ucte d, as liste d i n t h e S o A. T he S o A s pecifi es t he data t o c ollect at st u d y disc o nti n uati o n 
a n d f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be c o m plet e d.  
•  If t he partici p a nt wit h dra ws c o nse nt f or f ut ure i n v ol ve me nt i n t he st u d y, a n y dat a c ollecte d u p 
t o t hat p oi nt ma y still be use d, b ut n o f ut ure data ca n be ge n erate d, a n d a n y bi ol o gical 
sa m ples c ollecte d will be destr o ye d.  
•  A partici pa nt has t he ri g ht at a n y ti me t o re q uest d estr ucti o n of a n y bi ol o gical sa m ples ta ke n. 
T he In vesti gat or will d oc u me nt t his i n t he site st u d y rec or ds.  
T he I n vesti gat or will sec ure t he safet y of t he st u d y partici pa nts a n d ma k e e ver y atte m pt t o c ollect 
t he data. 
7. 3  
L ost t o F oll o w -u p   
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o nta cte d b y t he st u d y site. 
T he f oll o wi n g acti o ns will  be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:  
•  T he site will  atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n 
as p ossi ble, c o u nsel t he p artici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n if t he partici pa nt wa nts t o or will  c o nti n ue i n t he st u d y.  
•  Bef ore a p artici pa nt is dee me d “l ost t o f oll o w-u p ”, t he In v esti gat or or d esi g nee will  
ma ke e ver y  eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 
3  tele p h o ne calls; 2) if necessar y, s e n d a certifie d l etter ( or a n e q ui vale nt l o cal met h o d) 
t o t he partici pa nt’s last k n o w n maili n g a d dress, a n d 3) if a partici p a nt has gi ve n t he 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
a p pr o priate c o nse nt, c o nt act t he partici p a nt’s ge neral practiti o ner or careta k er ( w here 
all o we d b y l ocal r e g ulati o ns) f or i nf or mati o n. T hese c o ntact atte m pts will  be 
d oc u me nte d i n t he partici pa nt’s me dical r ec or d.  
•  If t he partici p a nt c o nti n ues t o be u nreac ha bl e, he/s he will be dee me d as “l ost t o 
f oll o w-u p” . 
8  
St u d y Assess me nts a n d Pr oce d ures   
•  St u d y assess me nts a n d pr oce d ures a n d t heir ti mi n g are  s u m marize d i n t he S o A. 
•  N o  pr ot oc ol wai vers or e x e m pti o ns are all o we d.  
•  I m me diat e safet y c o ncer ns are disc usse d wit h t he S p o ns or i m me diatel y u p o n 
occ urre nce or a ware ness t o deter mi ne if t he partici pa nt will  c o nti n ue or disc o nti n ue 
st u d y i nter ve nti o n. 
•  A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d u ct.  
•  All scree ni n g e v al uati o ns will  be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T h e In ve sti gat or will mai ntai n a scree ni n g l o g 
t o rec or d details of all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, 
rec or d reas o ns f or scree ni n g fail ure. 
•  Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici p a nt’s r o uti ne  
me dical care, t he I n v esti gat or will o btai n writte n i nf or me d c o ns e nt as s pecifie d i n 
A p pe n di x 2 . 
•  Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d 
c o u nt) a n d o btai ne d b ef ore si g ni n g of t he I C F ma y be us e d f or s cree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures m et t he pr ot oc ol -s pecifie d criteria, w ere perf or me d 
wit hi n t he ti me fra me defi ne d i n t he S o A , a n d if re vie we d a n d a p pr o ve d b y t he 
S p o ns or . 
•   A p pr o xi matel y 1 1 6. 5  ml of bl o o d will be dra w n t hr o u g h o ut t he st u d y. A ma xi m u m of 
4 7 0  m L of bl o o d t otal m a y b e ta ke n t hr o u g h o ut t h e st u d y. T h ese bl o o d sa m ples will be 
use d f or t he f oll o wi n g p ur p oses: cli nical la b orat or y tests, P K, a n d ge n etics a n d/ or 
 
W here all o we d b y l ocal la w/re g ulati o ns, sa m ples c ollecte d d uri n g t his cli nical st u d y ma y b e 
tra nsferre d t o a bi o ba n k a n d use d f or f ut ure res earc h o utsi de t he cli nical pr ot oc ol w he n a d diti o nal 
c o nse nt f or t his p ur p ose is gi ve n. Tra nsf er t o t he bi o ba n k will be d oc u me nt e d a n d a n y tes ti n g of 
c o de d bi o ba n k sa m ples will n ot  be re p orte d i n t h e C S R.  
8. 1  
Effic ac y Assess me nts a n d Pr oce d ures   
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 3 /6 6  
 
 
8. 2  
S afet y Assess me nts a n d Pr oce d ures   
T he safet y pr ofile of t he st u d y i nter ve nti o n will b e assesse d t hr o u g h t h e rec or di n g, re p orti n g a n d 
a nal ysis of baseli ne me di cal c o n diti o ns, A Es, p h ysical e x a mi nati o n fi n di n gs, vital si g ns, 
electr ocar di o gra m s, a n d l a b orat or y tests. 
C o m pre he nsi ve assess me nt of a n y p ote ntial t o xicit y e x perie n ce d b y eac h p artici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
In v esti gat or will re p ort a n y A Es, w h et her o bs er ve d b y t he I n vesti gat or or re p orte d b y t he 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n 8. 3 . 
8. 2. 1  
P h ysic al E x a mi n ati o ns   
•  A c o m plete p h ysical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he 
car di o vas c ul ar, res pirat or y, g astr oi ntesti nal a n d n e ur ol o gic al s yste ms.  
•  A brief p h ysic al e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular s yste m, a n d a b d o me n (li ver a n d s plee n). 
•  I n v esti gat ors will  pa y s pecial atte nti o n t o cli nical  si g ns relat e d t o pre vi o us seri o us 
ill nesses. 
8. 2. 2  
Vit al Si g ns   
•  Vital si g ns will be meas ure d i n s u pi ne p ositi o n.  
•  Bl o o d press ur e a n d p artici pa nt’s p ositi o n  d uri n g meas ure me nt ; p ulse; res pirat or y rate; 
te m perat ur e a n d l ocati o n of meas ure m e nt , wei g ht, a n d hei g ht (at Baseli ne o nl y) will 
be meas ure d a n d rec or de d.  
•  Bl o o d press ur e a n d p ulse meas ure me nts will  be prece d e d b y at least 5 mi n utes of rest 
f or t he partici p a nt i n a q uiet setti n g with o ut distracti o ns (e. g., tel e visi o n, cell p h o nes)  
a n d meas ure d wit h a n a ut o mate d de vice. M a n ual t ec h ni q ues will be use d o nl y if a n 
a ut o mate d de vice is n ot a vaila ble.  
•  Vital si g ns (t o be ta ke n b ef ore bl o o d c ollecti o n f or la b orat or y tests) will c o nsist of 
1  p ulse a n d 1 bl o o d press ure meas ur e me nt .  
8. 2. 3  
Electr oc ar di o gr a ms   
•  Si n gle 1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he S o A usi n g a n E C G mac hi ne 
t hat a ut o maticall y calc ul ates t he heart rate a n d me as ures P R, R R, Q R S, Q T, a n d Q Tc F 
i nter vals. 
•  T ri plicate  E C Gs are  re q uire d  w he n  a b n or m al  E C G  res ults  are  meas ur e d. If  E C G 
para meters fall o utsi de of cli nical refere n ce ra n ge, i ncl u di n g Q Tc F  >  4 5 0 ms, a re peat 
E C G  is  d o ne. W he n  tri plicate  E C Gs  are  re q uir e d,  3 i n di vi d ual  E C G  traci n gs will  be 
o btai ne d as cl osel y as p ossi ble i n s uccessi o n, b ut n o m ore t h a n 2  mi n utes a p art. T he f ull 
set of tri plicates will  be c o m plete d i n less t ha n 4  mi n utes  a n d will  occ ur i n a resti n g stat e 
wit h o ut pri or pr oce d ure s uc h as bl o o d dra w . Tri plicate me as ure me nts ca n b e perf or me d 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 /6 6  
 
 
base d o n I n vesti gat ors discreti o n. W he n me as ure d as tri plicate, t he a vera ge val ues will 
be c o nsi dere d. A d diti o nal E C Gs d uri n g t he c o urse of t he s t u d y will be at t he discreti o n 
of t he I n vesti gat or.  
8. 2. 4  
Cli nic al S afet y L a b or at or y Tests   
•  Bl o o d a n d uri ne s a m ples will be c ollecte d f or t he cli nical la b orat or y tests liste d i n 
A p pe n di x 5  Cli nical La b orat or y Tests  at t he ti me p oi nts liste d i n t he S o A.  All sa m ples 
will  be clearl y i de ntifie d. T he sa m ples f or s c he d ul e d la b orat or y t ests will be c ollecte d 
i n a faste d state. Partici pa nts will refrai n fr o m f o o d a n d fl ui d wit h t he e x ce pti o n of 
water f or at least 1 0  h o urs pri or t o c ollecti o n. U ns c he d ule d tests ma y n ot re q uire a 
faste d c o n diti o n. 
•  A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y, as d eter mi n e d 
necessar y b y t he In v esti gat or or re q uire d b y l oc al re g ulati o ns.  
•  T he tests will be perf or me d b y t h e l ocal la b orat ori es. 
•  T he S p o ns or will recei v e a list of t he l ocal la b orat or y n or mal ra n ges bef ore s hi p me nt 
of st u d y i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y will be f or war de d 
t o t he S p o ns or. 
•  T he In vesti gat or will  re vi e w eac h la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d 
a n y cli nicall y si g nifica nt c ha n ges occ ur ri n g d uri n g t he st u d y as a n  A E , u nless it d oes 
n ot  meet t he A E defi niti o n, as s pecifie d i n A p p e n di x 4 . T he la b orat or y re p orts will  be 
file d wit h t he s o urce d o c u me nts. 
•  A d diti o nal ser u m or hi g hl y se nsiti ve uri ne pre g na nc y t ests ma y b e c o n d u cte d, as 
deter mi ne d necessar y b y t he I n v esti gat ors or re q uire d b y l ocal r e g ulati o n, t o esta blis h 
t he a bse nce of pre g na nc y at a n y ti me d uri n g t h e st u d y. T o c o nfir m p ost me n o pa usal 
stat us, F S H will be assesse d at Scree ni n g o nl y. 
8. 3  
A d vers e E ve nts , Seri o us A d verse E ve nts , a n d Ot her S afet y 
Re p orti n g   
•  T he defi niti o ns of a n A E a n d S A E are i n A p p e n di x 4 . 
•  T he I n vesti gat or a n d a n y q ualifie d desi g nees (e. g., S u b in vesti gat ors) are res p o nsi ble 
f or detecti n g, d o c u me nti n g, a n d rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or 
S A E. T he I n vesti gat or re mai ns res p o nsi ble f or f oll o wi n g u p A Es t hat are s eri o us , 
c o nsi dere d relate d t o t he st u d y i nter ve nti o n or st u d y pr oce d ures , or t hat c a use d t he 
partici pa nt t o disc o nti n ue t he  st u d y i nter ve nti o n or st u d y, as s pe cifie d i n Secti o n 8. 3. 2 . 
•  Re q uests f or f oll o w -u p will us uall y b e ma de via t h e S p o ns or or Cli nical Researc h 
Or ga nizati o n -desi g n ate d st u d y tea m me m ber , alt h o u g h i n e x ce pti o nal circ u msta nces 
t he gl o bal p atie nt  safet y de part me nt ma y c o nt act t he I n vesti gat or dir ectl y t o o btai n 
f urt her i nf or m ati o n or t o disc uss t he e ve nt. 
•  T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts are i n A p pe n di x 4 . 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 /6 6  
 
 
•  All A Es a n d S A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he f oll o w -u p 
p h o ne call  at t he ti me p oi nts s pecifie d i n t he S o A ( Secti o n 1. 3 ). Be y o n d t his re p orti n g 
peri o d, a n y ne w u ns olicite d S A Es t hat t he I n vesti gat or s p o nta ne o usl y re p orts t o t he 
S p o ns or will be c ollecte d a n d pr ocess e d.  
•  All S A Es will be rec or de d a n d re p ort e d t o t he S p o ns or or desi g nee i m me di atel y a n d 
u n der n o cir c u msta nce will t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x 4 . T he 
I n v esti gat or will s u b mit a n y u p d ate d S A E data t o t he S p o ns or wit hi n 2 4 h o urs of it 
bei n g a vai la ble usi n g t he sa me pr oce d ure t hat w as use d f or t he i nitial re p ort. 
•  I n v esti gat ors are n ot o bli gat e d t o acti vel y s olicit i nf or mati o n o n A Es or S A Es  after t h e 
e n d of st u d y p artici pati o n. H o we ver, if t he In v esti gat or l ear ns of a n y S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he 
c o nsi ders t he e v e nt t o be reas o na bl y relate d t o t he st u d y i nter ve nti o n or st u d y 
partici pati o n, t he I n vesti gat or will  pr o m ptl y n otif y t he S p o ns or.  
8. 3. 1  
Met h o d of Detecti n g A d verse E ve nts  a n d Seri o us A d verse 
E ve nts   
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n .  
Care will be ta ke n n ot t o i ntr o d uce bias w he n d ete cti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d 
n o nlea di n g v er bal q u esti o ni n g of t he p artici pa nt is t he preferre d m et h o d t o i n q uire a b o ut A E 
occ urre nces.  
T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of A E s a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tr a ns mi tti n g S A E re p orts are i n A p pe n di x 4 . 
8. 3. 2  
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts   
After t he i nitial A E/ S A E re p ort, t he In v esti gat or is re q uire d t o pr o acti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All S A Es will be f oll o we d u ntil res ol uti o n, sta bilizati o n, 
t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-u p (as defi ne d i n 
Secti o n  7. 3 ). Reas o na ble atte m pts t o o btai n t his i nf or mati o n will  be ma de a n d d oc u me nte d. It is 
als o t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat a n y n ecess ar y a d diti o nal t hera pe utic me as ures 
a n d f oll o w-u p pr o ce d ures are perf or me d. F urt h er i nf or mati o n o n f oll o w -u p pr oce d ures is i n 
A p pe n di x 4 . 
8. 3. 3  
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse 
E ve nts   
•  Pr o m pt n otificati o n b y t he I n vesti gat or t o t he S p o ns or of a n S A E ( partic ularl y 
life-t hreat e ni n g a nd deat hs) is esse ntial s o t hat le gal o bli gati o ns a n d et hical 
res p o nsi bilities t o war d t he safet y of partici pa nts a n d t he safet y of a st u d y i nter ve nti o n 
u n der cli nical i n vesti gati o n are met.  
•  T he S p o ns or has a le gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 /6 6  
 
 
i n vesti gati o n. T he S p o ns or will c o m pl y wit h c o u ntr y-s p ecific re g ulat or y re q uire me nts 
relati n g t o s afet y re p orti n g t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d In vesti gat ors.  
•  I n di vi d ual Case Safet y R e p orts will be pre pare d f or S U S A Rs acc or di n g t o l ocal 
re g ulat or y re q uire me nts a n d S p o ns or p olic y a n d f or war de d t o I n vesti gat ors wit hi n 
1 5  da ys.  
•  A n I n vesti gat or w h o recei ves a n I n di vi d ual Case S afet y Re p ort des cri b i n g a S U S A R 
or ot her s pecific safet y i nf or mati o n (e. g., E mer gi n g Safet y Iss ue Re p ort, s u m mar y or 
listi n g of S A Es/ S U S A Rs) fr o m t he S p o ns or will rea d it a n d c o nfir m c o m pleti o n of t his  
acti vit y. T his i nf or mati o n will be file d i n t he I n vesti gat or’s Site File, a n d t he I R B/I E C 
will be n otifie d, if a p pr o priate, acc or di n g t o a p pli ca ble l ocal la ws/re g ulati o ns  a n d site 
S O Ps.  
8. 3. 4  
Pre g n a nc y   
•  Details of all pre g n a ncies i n fe male partici pa nts a n d fe male part ners of m ale 
partici pa nts will be c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil 6 m o nt hs 
after t he l ast a d mi nistrati o n of st u d y i nter ve nti o n.  
•  If a pre g na nc y is r e p orte d, t he In v esti gat or will rec or d t he pre g na nc y i nf or mati o n o n 
t he a p pr o priat e f or m a n d s u b mit it t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of t he 
pre g na nc y.  
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y 
c o m plicati o n or electi ve t e r mi nati o n of a pre g na nc y will be re p orte d as a n A E or S A E. 
A d verse  pre g na n c y o utc o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na n c y) are c o nsi dere d a n d re p orte d as S A Es.  A 
s p o nta ne o us a b orti o n ( occ urri n g at < 2 2 wee ks gestati o nal a ge) or still birt h ( occ urri n g 
at > 2 2 wee ks gestati o nal a ge) is al w a ys c o nsi dere d t o be a n S A E a n d will be re p ort e d 
as s uc h.  
•  T he partici pa nt / pr e g na nt fe male part ner will be f oll o we d t o deter mi ne t he o utc o me of 
t he pre g na n c y. T he I n v esti gat or will c ollect f oll o w-u p  i nf or mati o n o n t he 
partici pa nt / pre g na nt fe m ale part ner a n d t he n e o nate, a n d t he i nf or mati o n will be 
f or war de d t o t he S p o ns or. Ge nerall y, f oll o w -u p will n ot be re q uire d f or l o n ger t ha n 
6  t o 8 wee ks be y o n d t he esti mate d deli ver y date f or a healt h y ne w b or n. I n case of a 
c o n ge nital a n o mal y or ot her ill ness of t he ne w b or n, f oll o w -u p will c o nti n ue u ntil t he 
ill ness has res ol ve d or t h ere is a d efi nite o utc o me of t he e ve nt. 
•  A n y p ost  st u d y pre g n a nc y relate d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y 
i nter ve nti o n b y t he I n vesti gat or will be re p orte d t o t he S p o ns or as s pecifie d i n 
Secti o n  8. 3. 3 . W hile t he I n v esti gat or is n ot o bli gate d t o acti vel y s ee k t his i nf or mati o n 
i n f or mer st u d y partici pa nts/ pre g n a nt fe male p art n er, he or s h e ma y lear n of a n S A E 
t hr o u g h s p o nta n e o us re p orti n g. 
•  A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y i nter ve nti o n or be wit h dra w n fr o m t he st u d y. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /6 6  
 
 
•  A b n or mal pre g n a nc y o ut c o mes (e. g., s p o nta n e o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na n c y) are c o nsi dere d S A Es.  
8. 3. 5  
A d verse E ve nts of S peci al I nterest   
A n A E SI is a n ote w ort h y e ve nt of t he partic ular st u d y treat me nts t hat ca n b e a p pr o pri ate t o 
m o nit or cl osel y. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 4  
P h ar m ac o ki netics   
8. 4. 1  
Bl o o d S a m pli n g a n d Bi o a n al ysis   
•  Sa m pl es are c ollecte d o nl y w here all o w e d b y l ocal la w/re g ulati o ns.  
•  T he act ual d ate a n d ti me ( 2 4 -h o ur cl oc k ti me) of:  
o  E ac h sa m ple c ollecti o n  
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 /6 6  
 
 
o  S t u d y i nter ve nti o n a d mi nistrati o n pri or t o sa m ple c ollecti o n 
will be rec or de d i n t he e C R F  t o deter mi ne t he ela pse d ti me of sa m pli n g i n relati o n t o 
t he a d mi nistrati o n of st u d y i nter ve nti o n. 
•  W h ole bl o o d sa m ples of a p pr o xi matel y 2 m L per P K sa m ple c ollecti o n ti me p oi nt will 
be c ollecte d f or meas ure me nt of plas ma c o nce ntr ati o ns of x e vi na pa nt a n d it s 
meta b olite D -1 1 4 3 -M E T 1. C ollecti o n ti mes are s pecifie d i n t he S o A. T he act ual date 
a n d ti me ( 2 4 -h o ur cl o c k ti me) of eac h sa m ple will be rec or de d t o c alc ulate act ual ti me 
ela pse d si nce t h e pri or d ose a d mi nistrati o n. T he sa m pli n g ti mi n g ma y be alt ere d 
d uri n g t he st u d y bas e d o n ne wl y a vaila ble d ata (e. g., t o o btai n data cl oser t o t he ti me 
of pea k plas ma c o nce ntrati o ns) t o e ns ure a p pr o priate m o nit ori n g.  
•  T he q ua ntificati o n of x e vi na pa nt  a n d D-1 1 4 3 -M E T 1  i n plas ma  will be perf or me d 
usi n g a v ali date d assa y m et h o d .  
•  C o nce ntrati o ns will be use d t o e val uate t he P K of x e vi na pa nt a n d its meta b olite 
D -1 1 4 3 -M E T 1.  
•  Re mai ni n g sa m ples c ollecte d f or bi oa n al yti cal meas ure me nts ma y als o b e use d f or 
t of meta b olites of x e vi na pa nt  or  
 bi o mar kers d u ri n g 
or after t h e st u d y. Ret e nti o n ti me a n d p ossi ble a nal ys es of sa m ples aft er t he e n d of 
st u d y are s pecifie d i n t he res pecti ve I C F. 
•  Details o n pr ocess es f or c ollecti o n a n d ha n dli n g of t hese sa m ples are i n t he La b orat or y 
Ma n ual . 
•  F or details o n P K sa m pli n g,  refer t o t he S o A i n Secti o n 1. 3 . 
8. 4. 2  
P K P ar a meters   
•  P K para meters will be deri ve d usi n g n o n c o m part me ntal met h o ds wit h t he vali date d 
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 or hi g h er; Certara, L. P., 
Pri ncet o n, Ne w J erse y, U S A). S A S versi o n 9. 4 or hi g her will be use d t o cal c ulate 
meta b olic rati os.  
•  C o nce ntrati o n data ma y be use d f or i nte grate d d ata a nal yses acr oss st u dies a n d re p orte d 
se parat el y fr o m t he mai n C S R. 
•  T he f oll o wi n g P K para m eters f or x e vi na pa nt  a n d its meta b olite D -1 1 4 3 -M E T 1 will be 
calc ulate d fr o m i n di vi d ual plas ma c o nce ntrati o n-ti me data f or xe vi na pa nt a n d its 
meta b olite(s) , w he n a p pr o priate:  
Ot her P K para meters  ma y be calc ul ate d if a p pr o priate . Details will be i n t he I A P. 
S y m b ol  
D efi niti o n  
A U C 0 -tl a st 
T h e ar e a u n d er t h e c o n c e ntr ati o n -ti m e c ur v 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 (tl 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 - 
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 λz 
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 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 2 4 h o ur s  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 /6 6  
 
 
S y m b ol  
D efi niti o n  
A U C e xtr a %  
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 Ce xtr a  = 
( e xtr a p ol at e d ar e a/ A U C0 -∞) * 1 0 0.  
C L/ F  
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 C0 -∞. 
 
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  
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 
( u nl e s s ot h er wi s e d efi n e d, t a k e t h e 1st o c c urr e n c e i n 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.  
V Z / F 
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 -∞* λz) f oll o wi n g si n gl e d o s e. 
T he e x act date/ti me of sa m ple c ollecti o n a n d st u d y i nter ve nti o n ( 2 4 -h o ur cl oc k ti me) m ust be 
rec or de d i n t he e C R F a n d will be use d i n t he calc ulati o n of P K para meters. T he acce pte d ti me 
de viati o ns fr o m pla n ne d P K ti mes t hat will n ot be c o nsi dere d a pr ot o c ol vi olati o n are liste d 
bel o w:  
Pr o c e d ur e  
Ti m e P oi nt ( R el ati v e Ti m e)  
Wi n d o w All o w a n c e  
P h ar m a c o ki n eti c s  
Pr e d o s e  
- 9 0  mi n  
0. 5 t o 2 h o ur s p o st d o s e  
- / + 2 mi n  
>  2 t o 1 2 h o ur s p o st d o s e  
- / + 5 mi n  
>  1 2 t o 7 2 h o ur s p o st d o s e  
- / + 1 5 mi n  
8. 6  
Bi o m ar kers   
N ot a p plica ble.  
8. 7  
I m m u n o ge nicit y Assess me nts  
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /6 6  
 
 
8. 8  
He alt h Ec o n o mics   
Healt hcare res o urce utilizati o n data are n ot c olle cte d i n t his st u d y.  
9  
St atistic al C o nsi der ati o ns   
9. 1  
St atistic al H y p ot hes es  
N o f or mal statistical h y p ot hesis will be teste d, as t he st u d y is desi g ne d t o b e e x pl orat or y.  
9. 2  
S a m ple Size Deter mi n ati o n   
A ma xi m u m of 3 2 East Asia n partici pa nts will be assi g n e d t o st u d y i nter ve nti o n s uc h t hat 
a p pr o xi matel y 2 0 e val u a ble partici pa nts (at least 1 0 J a pa nese) c o m plete t h e st u d y.  
Alt h o u g h n o h y p ot hesis tests will be perf or me d, t h e sa m ple siz e of t he st u d y s h o ul d be s ufficie nt 
t o esti mate t he P K para m eters i n J a pa nese ( Gr o u p 1) a n d n o n-J a pa nese East Asia n ( Gr o u p 2) 
partici pa nts wit h a de q u ate precisi o n.  
P K data c ollecte d i n st u dies in healt h y Ca u casia n partici pa nts s u g gests t hat t he t otal varia bilit y of 
A U C 0 -tlast, A U C0 -∞ a n d C ma x  is m o derate t o hi g h, wit h a ge o metric C V ra n gi n g fr o m 3 0 % t o 4 0 % 
(refer t o I B Versi o n 1 4). Base d o n t h ese data a sa m ple siz e of 1 0 partici pa nts per gr o u p is  
c o nsi dere d s ufficie nt t o esti mate P K para meters of x e vi na pa nt i n J a pa nese, n o n -J a pa nese East 
Asia n a n d i n all East Asi a n partici pa nts.  
I n a d diti o n, t he rati o of P K para met ers bet w ee n t h e et h nic cate g ories i n Gr o u p 1 vers us Gr o u p 2 
ma y als o be esti mate d. Ass u mi n g C V ( %) of 3 5 % f or P K para meters of x e vi na pa nt, t he precisi o n 
f or t he esti mate d P K para meters rati o t o be ac hie v e d wit h a gi ve n n u m ber of e val ua ble 
partici pa nts is s u m marize d i n Ta ble 1  if 2 0 e val u a ble partici pa nts are i ncl u de d i n t his st u d y 
( 1 0 per gr o u p), a n d t he o bser ve d rati o is 1. 0, t he n t he 9 0 % CI f or t he rati o will, wit h 8 0 % 
pr o ba bilit y, be c o ntai ne d i n 0. 7 4 3 5 t o 1. 3 4 5 1. A f urt her i ncrease  i n sa m ple siz e d oes n ot 
s u bsta ntiall y i m pr o ve t he precisi o n. O n t he ot her h a n d, e ve n wit h a sli g htl y s maller n u m ber of 
c o m plete d partici pa nts, t he precisi o n will n ot be mar ke dl y decrease d.  
T heref ore, 2 4 p artici pa nts ( 1 2 per gr o u p) will be i nitiall y assi g n e d t o st u d y i nter ve nti o n s uc h t hat 
a p pr o xi matel y 1 0 e val u a ble partici pa nts per gr o u p c o m plete t he st u d y, all o wi n g f or a 
1 7 %  dr o p -o ut rat e. If t he n u m ber of c o m pleters is less t ha n 1 0 i n o ne gr o u p, t he n u p t o 
4  a d diti o nal partici pa nts ma y b e i ncl u de d i n e ac h gr o u p ( u p t o 3 2 partici pa nts i n t otal).  
T a ble 1  
9 0 % CI wit h 8 0 % t oler a nce pr o b a bilit y   
N 1  
N 2  
C V = 3 0 %  
C V = 3 5 %  
C V = 4 0 %  
8  
8  
0. 7 4 5 0 -1. 3 4 2 3  
0. 7 1 1 2 -1. 4 0 6 2  
0. 6 7 9 6 -1. 4 7 1 5  
1 0  
1 0  
0. 7 7 4 1 -1. 2 9 1 7  
0. 7 4 3 5 -1. 3 4 5 1  
0. 7 1 4 7 -1. 3 9 9 3  
1 2  
1 2  
0. 7 9 5 1 -1. 2 5 7 7  
0. 7 6 6 8 -1. 3 0 4 0  
0. 7 4 0 2 -1. 3 5 1 0  
CI = c o nfi d e n c e i nt er n al; C V = c o effi ci e nt of v ari ati o n.  
C al c ul ati o n s p erf or m e d i n R v er si o n 4. 0. 1.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 /6 6  
 
 
A s s u m pti o n of N 1  =  N 2  =  1 0 i s b a s e d o n t ot al n u m b er of J a p a n e s e a n d n o n -J a p a n e s e E a st A si a n p arti ci p a nt s p er 
gr o u p t ar g et e d f or t hi s st u d y.  
9. 3  
P o p ul ati o n f or A n al ys es  
T he a nal ysis  p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e x cl u de partici pa nts fr o m a n y 
a nal ysis p o p ulati o n will be ma de d uri n g a d ata re vie w meeti n g pri or t o dat a base l oc k . 
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 
r a n d o mi z ati o n 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 K  
T h e P K A S will c o n si st of all p arti ci p a nt s, w h o r e c ei v e at l e a st o n e d o s e of st u d y 
i nt er v e nti o n, a n d pr o vi d e at l e a st o n e m e a s ur a bl e p o st d o s e c o n c e ntr ati o n. A 
m e a s ur e m e nt B L Q i s c o n si d er e d a v ali d m e a s ur e m e nt. P arti ci p a nt s will b e a n al y z e d p er 
t h e a ct u al st u d y i nt er v e ntio n t h e y r e c ei v e d.  
9. 4  
St atistic al A n al yses   
9. 4. 1  
Effic ac y A n al yses   
N ot a p plica ble.  
9. 4. 2  
S afet y A n al yses   
All safet y a nal yses will be perf or me d o n t he Safet y A n al ysis set. 
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
•  
Pri m ar y  
•  
All pri m ar y s af et y e n d p oi nt s m e a s ur e d t o e v al u at e t h e s af et y of x e vi n a p a nt 
will  b e s u m m ari z e d d e s cri pti v el y b y et h ni c gr o u p a n d o v er all.  
•  
T h e n u m b er a n d p er c e nt a g e of p arti ci p a nt s e x p eri e n ci n g 1 or m or e A E s will 
b e s u m m ari z e d b y et h ni c gr o u p a n d o v er all, r el ati o n s hi p t o st u d y dr u g, s e v erit y, 
a n d s eri o u s n e s s. A E s will b e c o d e d u si n g t h e M e di c al Di cti o n ar y of R e g ul at or y 
A cti viti e s ( m o st r e c e nt v er si o n) t er mi n ol o g y.  
•  
A b s ol ut e v al u e s a n d c h a n g e fr o m b a s eli n e f or l a b or at or y p ar a m et er s a n d 
vit al si g n s will b e s u m m ari z e d u si n g d e s cri pti v e st ati sti c s.  
•  
A b s ol ut e v al u e s a n d c h a n g e s fr o m B a s eli n e i n t h e q u a ntit ati v e p ar a m et er s 
fr o m s af et y E C G r e c or di n g will b e s u m m ari z e d d e s cri pti v el y b y et h ni c gr o u p a n d 
o v er all.  
•  
S e c o n d ar y  
•  
N o s e c o n d ar y s af et y e n d p oi nt s.  
9. 4. 3  
Ot her A n al yses   
Details o n t he P K a nal ys es will be i n t he I nte grat e d A nal ysis Pla n t hat will be fi naliz e d bef ore 
data base l oc k.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
9. 4. 3. 1  
P h ar m ac o ki netic A n al yses   
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
Pri m ar y:  
X e vi n a p a nt A U C 0 -tl a st, 
A U C 0 -∞, a n d Cm a x  
P K p ar a m et er s a n d c al c ul ati o n m et h o d ar e i n S e cti o n  8. 4 . 
S u m m ar y st ati sti c s will b e pr o vi d e d b y et h ni c gr o u p a n d o v er all f or t h e P K a n al y si s 
s et . 
S e c o n d ar y:  
X e vi n a p a nt  A U C 0 -2 4 , tm a x , t1/ 2, 
C L/ F, V z/ F  
P K p ar a m et er s a n d c al c ul ati o n m et h o d ar e i n S e cti o n  8. 4 . 
S u m m ar y st ati sti c s will b e pr o vi d e d b y et h ni c gr o u p a n d o v er all f or t h e P K a n al y si s 
s et . 
S e c o n d ar y:  
D -1 1 4 3 -M E T 1 A U C
0 -tl a st, 
A U C 0 -2 4 , A U C0 -∞ a n d C m a x , 
tm a x , a n d t1/ 2, x e vi n a p a nt: 
D -1 1 4 3 -M E T 1 m ol ar r ati o 
A U C 0 -tl a st, A U C0 -∞, a n d Cm a x  
P K p ar a m et er s a n d c al c ul ati o n m et h o d ar e i n S e cti o n  8. 4 . 
S u m m ar y st ati sti c s will b e pr o vi d e d b y et h ni c gr o u p a n d o v er all f or t h e P K a n al y si s 
s et . 
I n a d diti o n, t he rati o of P K para met ers bet w ee n t h e et h nic cate g ories fr o m t his st u d y a n d fr o m 
hist orical data fr o m h ealt h y partici pa nt st u dies i n n o n -Asia n  partici pa nts m a y als o be esti mate d. 
T hese i nte grat e d a nal ys es acr oss st u dies will be s pecifie d i n a  s e parate I nt e grate d A n al ysis Pla n 
a n d n ot i ncl u de d i n t he C S R.  
9. 4. 4  
Se q ue nce of A n al yses   
All fi nal, pla n ne d a nal ys es i de ntifie d i n t he cli nic al st u d y pr ot oc ol  will be perf or me d o nl y after 
t he last partici pa nt has c o m plete d t he last visit, i.e., F oll o w-u p / Disc o nti n uati o n visit wit h all 
st u d y data i n-h o us e, all d ata q ueries res ol ve d, a n d t he data base l o c ke d.  
T here are n o pla n ne d f or mal i nteri m a nal ys es.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 /6 6  
 
 
1 0  
Refere nce s  
Bra y F, Ferl a y J, S oerj o matara m I, et al. Gl o bal c a ncer st atistics 2 0 1 8: G L O B O C A N esti mates of 
i nci de nce a n d m ortalit y w orl d wi de f or 3 6 ca n cers i n 1 8 5 c o u ntries. C A Ca ncer J Cli n 
2 0 1 8; 6 8( 6): 3 9 4 -4 2 4.  
De nar o N, Merla n o M C, a n d R ussi E G. F oll o w -u p i n Hea d a n d N ec k Ca n cer: D o M ore D o es It 
Mea n D o Better? A S yst e matic Re vie w a n d O ur Pr o p osal Base d o n O ur E x perie nce . Cli nical a n d 
E x peri me ntal Ot or hi n olar y n g ol o g y , 2 0 1 6; 9 ( 4): 2 8 7 -9 7.  
Iglesi as D oca m p o L C, Arraz u bi Arr ula V, Baste R otlla n N, et al. S E O M cli nical g ui deli nes f or t he 
treat me nt of hea d a n d n ec k ca n cer ( 2 0 1 7). Cli n Tra nsl O nc ol. 2 0 1 8; 2 0: 7 5 -8 3.  
Matzi n ger O, Vi ertl D, Ts o uts o u P, et al. T he ra di ose nsitizi n g acti vit y of t h e S M A C -mi metic, 
De bi o 1 1 4 3, i n T N F α -me diate d i n hea d a n d n ec k s q ua m o us cell carci n o ma. Ra di ot her O nc ol 
2 0 1 5; 1 1 6: 4 9 5 -5 0 3.  
Nic h ols o n D W. Fr o m be nc h t o cli nic wit h a p o pt osis -base d t hera pe utic a ge nts. Nat ure 
2 0 0 0; 4 0 7: 8 1 0 -6.  
Ser o va M, Ra balla n d A T, Al bert S, et al. Ef fects of De bi o 1 1 4 3, a n o v el oral I A P i n hi bit or, i n 
m o n ot hera p y a n d i n c o m bi nati o n wit h plati n u m dr u gs i n h u ma n S C C H N t u m or s peci me ns. I n: 
Pr ocee di n gs of t he 1 0 5t h A n n ual Meeti n g of t he A merica n Ass o ciati o n f or Ca ncer Res earc h; 
2 0 1 4 A pr 5 -9; Sa n Die g o, C A.  P hila del p hia ( P A): A A C R; Ca ncer Res 2 0 1 4; 7 4( 1 9): A bstract.  
Ta m m I, K or n bla u S M, Se gall H, et al. E x pressi o n a n d pr o g n ostic si g nifi ca nce of I A P -fa mil y 
ge n es i n h u ma n ca n cers a n d m yel oi d le u ke mias. Cli n Ca ncer Res 2 0 0 0; 6( 5): 1 7 9 6 -8 0 3.  
Ta o Z, Mc Call N S, Wie de m a n n N, et al. S M A C Mi metic De bi o 1 1 4 3 a n d A blati ve Ra diati o n 
T hera p y S y ner gize t o E n ha nce A ntit u m or I m m u nit y a gai nst L u n g Ca n cer. Cli n Ca ncer Res 
2 0 1 9; 2 5( 3): 1 1 1 3 -1 1 2 4.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 /6 6  
 
 
1 1  
A p pe n dices   
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 /6 6  
 
 
A p pe n di x 1  
A b bre vi ati o ns   
A E  
a d verse e ve nt  
A E SI  
a d verse e ve nts of s p ecial i nterest  
A L T  
ala ni ne a mi n otra nsf eras e  
A S T  
as partate a mi n otra nsferas e  
C R F  
case re p ort f or m  
C R T  
c he m ora di ot hera p y  
C R U  
cli nical researc h u nit  
C S R  
cli nical st u d y re p ort  
D L T  
d ose -li miti n g t o xicit y 
D N A  
de o x yri b o n ucleic aci d  
E C G  
electr ocar di o gra m  
E O T  
e n d of st u d y i nter ve nti o n  
G C P  
G o o d Cli nical Practice  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R T  
h or m o ne re place me nt t hera p y  
I A P 
I nte grate d A nal ysis Pla n 
I B 
i n vesti gat or’s br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n 
I E C 
i n de pe n de nt et hics c o m mittee 
I M P 
i n vesti gati o nal me dici nal pr o d uct  
I R B 
i nstit uti o nal re vie w b oar d 
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d v erse 
E ve nts  
NI M P  
n o n -i n vesti gati o nal me di ci nal pr o d uct 
P K  
p har mac o ki netic  
Q Tc F  
c orrecte d  Q T i nter val b y Fri deri cia’ f or m ula  
R T  
ra di ot hera p y 
S A E  
seri o us a d verse e v e nt 
S o A  
sc he d ule of acti vities 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
T E A E  
treat me nt-e mer ge nt a d v erse e x perie nce  
U L N  
u p per li mit of n or mal  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 6 /6 6  
 
 
U K  
U nite d Ki n g d o m  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 7 /6 6  
 
 
A p pe n di x 2  
St u d y G o ver n a nce   
Fi n a nci al Discl os ure  
I n v esti gat ors a n d S u bin vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi n a ncial 
i nf or mati o n, as re q u este d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urat e fi na ncial certificati o n 
or discl os ure state me nts t o t he a p pr o priat e re g ulat or y a ut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1  year after c o m pleti o n of t he st u d y.  
I nf or me d C o nse nt Pr ocess 
•  T he I n vesti gat or or his r e prese n tati ve will e x plai n t he nat ure of t h e st u d yi ncl u di n g t he 
ris ks a n d be nefits, t o t he partici pa nt a n d a ns wer all q uesti o ns o n t he st u d y. 
•  Partici pa nts will  be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  
•  Partici pa nts will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat m eets t he 
re q uire me nts of 2 1 C F R 5 0; t he J a pa nese mi nisterial or di na nce o n G C P; l ocal 
re g ulati o ns; I C H g ui d eli nes; pri vac y a n d d ata pr ot ecti o n re q uir e me nts , w here 
a p plica ble; a n d t h e I R B/I E C or st u d y ce nter.  
•  T he me dical r ec or d will  i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n 
c o nse nt was o btai ne d. T h e a ut h orize d pers o n o btai ni n g t he i nf or m e d c o nse nt will  als o 
si g n t he I C F. 
•  If t he I C F is u p d ate d d uri n g t heir p artici pati o n i n t he st u d y, p artici pa nts will  be 
rec o nse nt e d t o t he m ost c urre nt, a p pr o v e d versi o n. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 /6 6  
 
 
D at a Pr otecti o n  
•  T he S p o ns or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir 
i nf or me d c o nse nt. A n y p artici pa nt rec or ds or d atasets t hat are tr a nsferre d t o t he 
S p o ns or will c o ntai n t he i de ntifier o nl y; p artici pa nt na mes or a n y i de ntifia bl e 
i nf or mati o n will n ot be tra nsferre d. 
•  T he S p o ns or will  i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d d ata will be use d 
per l ocal dat a pr otecti o n a n d pri vac y la ws. T he le vel of discl os ure will  als o be 
e x plai ne d t o t he partici pa nt  a n d pre g na nt part ners (if a p plica ble)  w h o will be re q uir e d 
t o gi ve c o ns e nt f or t heir data t o be use d, as s p ecifi e d i n t he i nf or me d c o ns e nt. 
•  T he partici pa nt will  be i nf or me d t hat his/ her me di cal rec or ds ma y be e x a mi ne d b y 
Cli nical Q ualit y Ass ura n ce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, 
b y a p pr o priate I R B/I E C  me m bers, a n d b y re g ulat or y a ut h orit y i ns pe ct ors. All s uc h 
pers o ns will strictl y mai ntai n partici pa nts’ c o nfi de ntialit y.  
St u d y A d mi nistr ati ve  
T he Pri nci pal I n vesti gat or liste d o n t he title pa ge re prese nts all I n v esti gat ors f or decisi o ns a n d 
disc ussi o ns o n t his st u d y, per I C H G C P. T he Pri nci pal  I n v esti gat or will pr o vi de e x pert me dical 
i n p ut a n d a d vice o n t he st u d y desi g n a n d e x ec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off 
of t he cli nical st u d y re p ort.  
Details of str uct ures a n d ass ociate d pr o ce d ures w ill be defi ne d i n a se p arat e O perati o ns or St u d y 
Refere n ce M a n ual . 
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
•  T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d t he f oll o wi n g:  
o  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i nc l u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga niz ati o ns of Me dical 
Scie nces  I nter nati o nal Et hical G ui deli nes 
o  A p plica ble I C H G C P G ui deli nes  
o  F or st u dies wit h J a pa nes e sites, t he J a pa nese mi nisterial or di na nce o n G C P  
o  A p plica ble la ws a n d re g ulati o ns  
•  T he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I C F, I n v esti gat or Br oc h ure, a n d 
ot her rele va nt d oc u me nts (e. g., a d vertise me nts) will be s u b mitte d t o a n I R B/I E C f or 
re vie w a n d a p pr o ve bef ore t he st u d y is i nitiate d. 
•  A n y pr ot oc ol a me n d me nts ( i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n 
writi n g a n d re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e x ce pt f or 
c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o st u d y p artici pa nts. W he n 
a p plica ble, a me n d m e nts will be s u b mitte d t o t he a p pr o priate Healt h A ut h orities.  
•  T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he 
Healt h A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 /6 6  
 
 
E mer ge nc y Me dic al S u p p ort  
•  T he S p o ns or or desi g n ee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o 
partici pa nts f or use d uri n g t he st u d y. T hes e pr o vi d e t he mea ns f or partici p a nts t o 
i de ntif y t he msel v es as partici pati n g i n a cli nical st u d y. Als o, t hese gi v e healt h care 
pr o vi ders access t o a n y i nf or mati o n  a b o ut t his partici pati o n t hat ma y be n ee de d t o 
deter mi ne t he c o urse of me dical treat me nt f or t he partici pa nt. T he i nf or mati o n o n t he 
E mer ge nc y M e dical S u p p ort car d ma y i n cl u de t he pr ocess f or e mer ge nc y u n bli n di n g 
(if a p plica ble). 
•  T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y I n vesti gat or 
cari n g f or t h e partici pa nt. C o nse q ue ntl y, t he I n v esti gat or a grees t o pr o vi de his or her 
e mer ge n c y c o ntact i nf or mati o n o n t he car d. If t he I n v esti gat or is a vaila ble w he n a n 
e ve nt occ urs, t h e y will a ns wer a n y q u esti o ns. A n y s u bse q u e nt acti o n (e. g., u n bli n di n g) 
will f oll o w t he sta n dar d pr ocess esta blis he d f or I n vesti gat ors.  
W he n t he I n v esti gat or is n ot a vaila ble, t he P hase 1  facilit y will pr o vi de t he a p pr o priate m ea ns t o 
c o ntact a p h ysicia n.  T his i ncl u des t he pr o visi o n of a 2 4 -h o ur c o nt act n u m ber at t he facilit y, 
w here b y t he healt h care pr o vi ders will be gi ve n access t o a n a p pr o priat e p h ysicia n t o assist wit h 
t he me dical e mer ge nc y a n d t o pr o vi de s u p p ort f or t he p ote ntial u n bli n di n g of t he partici pa nt 
c o ncer ne d.  
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts  
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns ur a nce 
c o n diti o ns will  meet g o o d l ocal sta n dar ds, as a p plica ble.  
T he S p o ns or is e ntirel y res p o nsi ble f or A Es t hat are ass ociat e d wit h t his st u d y a n d ca use da ma ge 
t o t he healt h of t he partici pa nts, e x ce pt f or A Es ca use d b y a n i nte nti o nal a n d/ or si g nifica nt 
de viati o n o n t he part of t he I n vesti gat or, t he st u d y site, a n d/ or t he partici pa nt. T he S p o ns or ta kes 
o ut i ns ura nce t o f ulfill t he res p o nsi bilit y.  
Cli nic al St u d y Re p ort  
After st u d y c o m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
Pri nci pal I n v esti gat or a n d a n y Steeri n g C o m mittee or ot her rele va nt st u d y -a p p oi nt e d 
c o m mittees or gr o u ps . 
P u blic ati o n  
•  T he res ults of t his st u d y ma y b e p u blis he d or pres e nte d at scie ntific me eti n gs. If t his is 
f oresee n, t he I n v esti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or 
bef ore s u b missi o n. T his all o ws Merc k t o pr otect pr o prietar y i nf or mati o n a n d t o 
pr o vi de c o m me nts.  
•  T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per 
sta n dar d e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n 
of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site data.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 /6 6  
 
 
•  A ut h ors hi p will be deter mi ne d b y a gree m e nt a n d i n li ne wit h I nter n ati o nal C o m mittee 
of Me dical J o ur nal E dit ors a ut h ors hi p re q uir e me nts.  
Disse mi n ati o n of Cli nic al St u d y D at a  
•  S u m mar y of data will be pr o vi d e d t o w w w. Cli nical Trials. g o v as well as t o t he 
E ur o pea n Cli nical Trial Data base, if a p plica ble. Healt h y partici pa nts mi g ht be 
pr o vi de d wit h t he res ults of t he me dical e x a mi nati o ns at re q uest. Aft er fi naliz ati o n of 
t he st u d y, healt h y p artici pa nts mi g ht be pr o vi de d wit h t he i nf or mati o n p u blis he d o n 
Cli nical Trials. g o v a n d/ or t he E ur o pea n Cli nical Trial Data base  at re q u est.  
•  After c o m pleti o n of t he st u d y, a cli nical st u d y re p ort will be writte n b y t h e S p o ns or i n 
c o ns ultati o n wit h t he Pri nci pal I n vesti gat or f oll o wi n g t he g ui da n ce i n I C H T o pic E 3 
a n d will be s u b mitte d i n acc or da nce wit h l ocal re g ulati o ns.  
•  A n y a n d all scie ntific, c o m mercial, a n d te c h nical i nf or mati o n discl ose d b y t he S p o ns or 
i n t his pr ot oc ol or else w h ere s h o ul d be c o nsi dere d t he c o nfi de ntial a n d pr o prietar y 
pr o pert y of t he S p o ns or. T he I n vesti gat or s hall h ol d s uc h i nf or mati o n i n c o nfi de nce 
a n d s hall n ot discl ose t he i nf or mati o n t o a n y t hir d part y e x ce pt t o s uc h of t h e 
I n v esti gat or’s e m pl o yees a n d staff w h o h a d bee n ma de a w are t hat t he i nf or mati o n is 
c o nfi de ntial a n d w h o are b o u n d t o treat it as s uc h a n d t o w h o m discl os ure is necessar y 
t o e val uate t hat i nf or mati o n. T he I n vesti gat or s hall n ot use s uc h i nf or mati o n f or a n y 
p ur p ose ot her t ha n f or deter mi ni n g m ut ual i nterest i n perf or mi n g t he st u d y a n d, i f t he 
parties deci d e t o pr ocee d wit h t he st u d y, f or t he p ur p ose of c o n d u cti n g t he st u d y.  
•  T he I n vesti gat or u n d ersta n ds t hat t he i nf or mati o n de vel o pe d fr o m t his cli nical st u d y 
will be use d b y t he S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he st u d y 
i nterve nti o n a n d t heref ore ma y be discl ose d as re q uire d t o ot her cli nical I n v esti gat ors, 
t o t he U S F o o d a n d Dr u g A d mi nistrati o n, E ur o pea n Me dici nes A ge n c y , a n d t o ot her 
g o ver n me nt a ge n cies. T he I n vesti gat or als o u n d ersta n ds t hat, t o all o w f or t he use of 
t he i nfor mati o n deri ve d fr o m t he cli nical st u d y, t h e I n vesti gat or has t h e o bli gati o n t o 
pr o vi de t he S p o ns or wit h c o m plete test res ults a n d all data de vel o pe d i n t he st u d y. N o 
p u blicati o n or discl os ure of st u d y res ults will be per mitte d e x ce pt u n der t he ter ms a n d 
c o n diti o ns of a se parate writte n a gree me nt.  
D at a Q u alit y Ass ur a nce  
•  All partici pa nt st u d y d ata will be rec or de d o n pri nt e d or ele ctr o nic C R Fs or 
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e. g., l a b orat or y d ata). T he 
I n v esti gat or is res p o nsi ble for verif yi n g t hat data e ntries are c o m plete, acc urate, 
le gi ble, a n d ti mel y b y p h ysicall y or electr o ni call y si g ni n g t he C R F. Det ails f or 
ma na gi n g C R Fs are i n t h e O perati o ns or S t u d y R efere n ce Ma n u al . 
•  T he I n vesti gat or will  mai ntai n acc urate d oc u m e ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he C R F. 
•  T he I n vesti gat or will  per mit st u d y -relate d m o nit ori n g, q ualit y ass ura n ce a u dits, 
I R B/I E C re vie w, a n d re g ulat or y a ge nc y i ns p ecti o ns a n d pr o vi de direct access t o t he 
st u d y file a n d s o urce d ata. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 /6 6  
 
 
•  Q ualit y t ol era nce li mits will be pre defi n e d a n d d o c u me nte d i n t he Pr oject 
Ma na ge me nt Pla n t o hel p s u p p ort t he i de ntificati o n of s yste m atic iss ues t hat c o ul d 
p ote ntiall y i m pact partici pa nt safet y a n d/ or relia bilit y of st u d y res ults. T hes e 
pre defi n e d para meters will be  m o nit ore d d uri n g t h e st u d y a n d i m p orta nt de viati o ns 
fr o m t he q ualit y t olera nce li mits t hres h ol ds a n d re me dial acti o ns ta ke n will be 
s u m marize d i n t he cli nical st u d y re p ort. 
•  M o nit ori n g details descri bi n g strate g y , i n cl u di n g d efi niti o n of st u d y critical data ite ms 
a n d pr ocess es (e. g., ris k-base d i nitiati ves i n o perati o ns a n d q ualit y s uc h as Ris k 
Ma na ge me nt a n d Miti gati o n Strate gies a n d A nal ytical Ris k -Base d M o nit ori n g), 
met h o ds, res p o nsi bilities a n d re q uir e me nts, i nc l u di n g ha n dli n g of n o n c o m plia nce 
iss ues a n d m o nit ori n g tec h ni q ues (ce ntr al, re m ote, or o n-site m o nit ori n g) are i n t he 
M o nit ori n g Pla n or c o ntr acts.  
•  T he S p o ns or or desi g nee is res p o nsi ble f or data m a na ge me nt of t his st u d y, i ncl u di n g 
q ualit y c h ec ki n g of t he d ata a n d mai ntai ni n g a vali date d data bas e. Data b as e l oc k will 
occ ur o nce q ualit y c o ntr ol a n d q ualit y ass ur a nce pr oce d ures h a ve b ee n c o m plete d. 
Details will be o utli ne d i n data ma na ge me nt  d oc u me nts a n d pr oce d ures.  
•  St u d y M o nit ors will perf or m o n g oi n g s o ur ce data verificati o n t o c o nfir m t hat data i n 
t he C R F are acc urate, c o m plete, a n d verifi a ble; t hat t he safet y a n d ri g hts of 
partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d u cte d per t he c urre ntl y 
a p pr o ve d pr ot o c ol a n d a n y ot her st u d y a gree me n ts, I C H G C P, a n d all a p plica ble 
re g ulat or y re q uire me nts. 
•  T he I n vesti gat or will ret ai n r ec or ds a n d d oc u me nts, i ncl u di n g si g n e d I C Fs, pertai ni n g 
t o t he c o n d uct of t his st u d y f or 1 5 years aft er st u d y c o m pleti o n, u nless l oc al 
re g ulati o ns, i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger ret e nti o n. N o 
rec or ds ma y b e destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he S p o ns or’s writte n 
a p pr o val. N o rec or ds ma y be tr a nsferre d t o a n ot her l ocati o n or part y wit h o ut t he 
S p o ns or’s writte n n otificati o n.  
S o urce D oc u me nts  
•  S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste nce of t he p artici pa nt a n d 
s u bsta ntiate t he i nte grit y of t he data c ollecte d. 
•  T he I n vesti gat or will  mai ntai n s o urce d oc u m e nts t hat s u p p ort t he data rec or d e d i n t he 
C R Fs . 
•  Data rec or de d o n C R Fs t hat are tr a nscri b e d fr o m s o urce d oc u m e nts will  be c o nsiste nt 
wit h t he s o urce d oc u m e nts or t he discre pa n cies will  be e x plai ne d. T he I n vesti gat or 
ma y n ee d t o re q u est pre vi o us me dical rec or ds or tr a nsfer rec or ds, de pe n di n g o n t he 
st u d y. Als o, c urre nt me di cal rec or ds will  be a v aila ble.  
•  S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y t he 
a p plica ble re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic he ver is l o n ger. T he 
I n v esti gat or e ns ures t hat n o destr ucti o n of me dical rec or ds is perf or m e d wit h o ut t he 
S p o ns or’s writte n a p pr o val.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
•  Defi niti o n of w hat c o nstit utes s o urce data a n d its ori gi n is fo u n d i n S o urce Data 
I d e ntificati o n F or m . 
St u d y a n d Site St art a n d Cl os ure  
T he st u d y start date is w he n t he first partici p a nt si g ns t he Inf or me d C o nse nt F or m . 
St u d y a n d Site Cl os ure  
T he I n vesti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca us e a n d 
e n o u g h n otice is gi v e n i n a d va nce of t he i nte n de d cl os ure. 
Reas o ns f or t he earl y cl os ure  of a st u d y site b y t he S p o ns or or I n v esti gat or ma y i ncl u d e:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes. 
•  I n a de q uat e recr uit me nt of partici pa nts b y t he I n v esti gat or. 
•  Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d . 
•  S p o ns or disc o nti n uati o n of t he st u d y d u e t o a n u n acce pta ble ris k, a n y rele v a nt t o xicit y, 
or ne gati ve c h a n ge i n t he ris k/ be nefit assess me nt.  
If t he st u d y is pre maturel y ter mi nat e d or s us pe n d e d, t he S p o ns or will  pr o m ptl y i nf or m t he 
I n v esti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y t hir d-part y ser vice pr o vi d ers of 
t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y re q uire m e nts. 
T he I n vesti gat or will pr o m ptl y i nf or m t he partici p a nts a n d ass ure a p pr o pri ate partici pa nt t hera p y 
a n d/ or f oll o w -u p.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 /6 6  
 
 
A p pe n di x 3  
C o ntr ace pti o n a n d B arrier Re q uire me nts   
W o me n of C hil d be ari n g P ote nti al : 
A w o ma n is of c hil d beari n g p ote ntial (fertile) f oll o wi n g me n arc h e a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile, as s pe cifie d bel o w.  
If fertilit y is u nclear (e. g., a me n orr hea i n a d oles ce nts or at hletes) a n d a me nstr ual c ycle ca n n ot 
be c o nfir me d bef ore t he first d ose of st u d y i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.  
P ost me n o p a use:  
P ost me n o pa use is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical c a use. 
•  A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge m a y b e use d t o c o nfir m a p ost me n o pa usal 
state i n a fe male n ot usi n g h or m o n al c o ntrace pti o n or H R T. H o we v er, i n t he a bse nce of 
1 2  m o nt hs of a me n orr hea, c o nfir mati o n wit h m or e t ha n 1 F S H meas ure me nt is re q uire d.  
•  A fe male o n H R T a n d w h ose  me n o pa usal stat us are i n d o u bt will be re q uir e d t o use o ne of 
t he n o n-estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he wis hes t o 
c o nti n ue her H R T d uri n g t he st u d y. Ot her wise, s h e m ust disc o nti n ue H R T t o all o w 
c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt. 
Per m a ne nt Steriliz ati o n:  
F or t his st u d y, p er ma ne nt sterilizati o n i ncl u des:  
•  D oc u me nte d h ysterect o m y  
•  D oc u me nte d bilateral sal pi n gect o m y  
•  D oc u me nte d bilateral o o p h orect o m y  
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t h e i n di vi d ual’s me dical rec or ds, 
me dical e xa mi nati o n, or me dical hist or y i nter vie w.  
F or i n di vi d uals wit h per ma ne nt i nfertilit y d ue t o a n alter nat e me dical ca us e ot her t ha n t he 
a b o ve, (e. g., M ulleria n a ge n esis, a n dr o ge n i nse nsiti vit y), I n vesti gat or discreti o n a p plies t o 
deter mi ne st u d y e ntr y.  
C o ntr ace pti o n G ui d a nce:  
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:  
Hi g hl y Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y  
•  
I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n  
•  
I U D 
•  
I U S 
•  
Bil at er al t u b al o c cl u si o n  
•  
V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a w o m a n of c hil d b e ari n g p ot e nti al , a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. Ot h er wi s e, 
u s e  a n a d diti o n al hi g hl y eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 
9 0 d a y s.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 4 /6 6  
 
 
Hi g hl y Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt  
•  
C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n  of 
o v ul ati o n  
•  
Or al  
•  
I ntr a v a gi n al 
•  
Tr a n s d er m al  
•  
I nj e ct a bl e 
•  
Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n  
•  
Or al  
•  
I nj e ct a bl e 
•  
S e x u al a b sti n e n c e: a hi g hl y eff e cti v e m et h o d o nl y  if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e 
e nt ir e p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e 
e v al u at e d i n r el ati o n t o t h e d ur ati o n of t h e st u d y a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e p arti ci p a nt.  
Eff e cti v e M et h o d s  
T h e s e m et h o d s h a v e a  f ail ur e r at e of ≥ 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y; t h er ef or e, t h e y d o n ot 
m e et t h e crit eri o n of a hi g hl y eff e cti v e m et h o d.  
•  
Pr o g e st o g e n -o nl y or al h or m o n al c o ntr a c e pti o n w h er e i n hi biti o n of o v ul ati o n i s n ot t h e pri m ar y m o d e of 
a cti o n  
•  
M al e or f e m al e c o n d o m wit h or wit h o ut s p er mi ci d e. M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d 
t o g et h er ( d u e t o ri s k of f ail ur e wit h fri cti o n) 
•  
C er vi c al c a p, di a p hr a g m, or s p o n g e wit h s p er mi ci d e  
•  
A c o m bi n ati o n of m al e c o n d o m wit h eit h er c er vi c al c a p, di a p hr a g m, o r s p o n g e wit h s p er mi ci d e ( d o u bl e-
b arri er m et h o d s)  
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s r e g ar di n g t h e u s e of c o ntr a c e pti v e 
m et h o d s f or t h o s e p arti ci p ati n g i n cli ni c al st u di e s.  
Hi g hl y eff e cti v e m et h o d s h a v e a f ail ur e r at e of <  1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. T y pi c al u s e 
f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
H or m o n al c o ntr a c e pti o n m a y b e s u s c e pti bl e t o i nt er a cti o n wit h t h e st u d y i nt er v e nti o n( s), w hi c h m a y r e d u c e t h e 
effi c a c y of t h e c o ntr a c e pti v e m et h o d. A s s u c h, 1) b arri er m et h o d s ( m al e or f e m al e c o n d o m wit h or wit h o ut 
s p er mi ci d e; c a p, di a p hr a g m, or s p o n g e wit h s p er mi ci d e) i n a d diti o n t o h or m o n al c o ntr a c e pti o n or 2) a 
n o n -h or m o n al i ntr a ut eri n e d e vi c e m u st b e u s e d. If l o c all y re q uir e d, i n a c c or d a n c e wit h C T F G g ui d eli n e s, 
a c c e pt a bl e c o ntr a c e pti v e m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.  
A c c e pt a bl e m et h o d s ar e c o n si d er e d eff e cti v e, b ut n ot  hi g hl y eff e cti v e (i. e., h a v e a f ail ur e r at e of ≥1 % p er y e ar). 
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st -o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d L A M ar e n ot  a c c e pt a bl e m et h o d s of c o ntr a c e pti o n.  
 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 5 /6 6  
 
 
A p pe n di x 4  
A d ver se E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g   
A E Defi niti o n  
A E Defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical st u d y p artici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her c o nsi dere d relate d 
t o t he st u d y i nter ve nti o n or n ot . 
•  A n A E ca n t h eref ore b e a n y u nfa v ora bl e  a n d u ni nt e 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), s y m pt o m, or diseas e ( ne w or e x acer bate d) t e m p orall y 
ass ociate d wit h t he use of st u d y i nter ve nti o n . F or s ur gic al or dia g n ostic pr o ce d ures, 
t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is c o nsi dere d as t h e A E rat her t ha n 
t he pr oce d ure itself. 
E ve nts Meeti n g  t he A E Defi niti o n 
•  A n y a b n or mal la b orat or y test res ults ( e. g., he mat ol o g y , cli nical c he mistr y, or 
uri nal ysis) or ot her safet y ass ess me nts (e. g., E C G, ra di ol o gic al sca ns, vital si g ns 
meas ure me nts), i n cl u di n g t h ose t hat w orse n fr o m baseli ne  a n d are j u d ge d t o  be 
m ore se vere t ha n e x pecte d f or t he partici p a nt’s c o n diti o n per t he I n vesti gat or’s 
me dical a n d scie ntific j u d g me nt, are c o nsi d ere d cli nicall y si g nifica nt i n t he me dical 
a n d scie ntific j u d g me nt of t he In vesti gat or ( e. g., n ot relate d t o pr o gressi o n of 
u n derl yi n g dise ase , b ut ma y b e lea di n g t o st u d y i nter ve nti o n disc o nti n uati o n). 
•  E x acer bati o n of a c hr o ni c or i nter mitte nt pree xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  Ne w c o n diti o ns detect e d or dia g n os e d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve b ee n prese nt bef ore t he start of t he st u d y. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uela e of a s us pecte d dr u g -dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uela e of a s us pecte d o ver d ose of eit her st u d y 
i nter ve nti o n or a c o n c o mita nt me dicati o n. 
•  “ Lac k of efficac y” or “fail ure of e x pecte d p har mac ol o gic al acti o n” p er se will n ot 
be re p ort e d as a n A E or S A E. H o we ver, t h e si g ns, s y m pt o ms, a n d/ or cli nic al 
se q uelae res ulti n g fr o m lac k of effic ac y will be re p orte d as a n A E or S A E if t he y 
f ulfill t he defi niti o n of a n A E or S A E. 
E ve nts N O T  Meeti n g t he A E Defi niti o n  
•  U nless j u d ge d b y t h e In v esti gat or t o b e m ore se v ere t ha n e x pecte d f or t he 
partici pa nt’s c o n diti o n, a n y cl i nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs, ot her 
a b n or mal safet y assess m e nts t hat are ass ociate d wit h t he u n derl yi n g dise ase, t he 
disease/ dis or der bei n g st u die d  wit hi n t he e x pecte d ness f or partici pa nt’s c o n diti o n, as 
j u d ge d b y t he I n vesti gator.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /6 6  
 
 
•  Me dical or s ur gical pr oce d ure (e. g., e n d os c o p y, a p pe n dect o m y): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is t he A E. 
•  Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
•  A ntici pate d da y -t o-d a y  fl uct uati o ns of pree xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n.  
S A E Defi niti o n  
If a n e v e nt is n ot a n A E per t he defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met (e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y, d eat h d ue 
t o pr o gressi o n of diseas e). 
 
A n  S A E is defi ne d as a n y u nt o w ar d me dic al o cc urre nce t h at, at a n y d ose:  
a.  Res ults i n de at h . 
b.  Is lif e-t hre ate ni n g 
T he ter m 'life -t hr eate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e v e nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d o es n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h, if it were m ore se vere.  
c. Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
•  I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n d etai ne d ( us uall y 
i n v ol vi n g at least a n o v er ni g ht sta y) at t he h os pital or e mer ge nc y w ar d f or 
o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he 
p h ysicia n’s office or  o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os pitalizati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitaliz ati o n or f ulfills a n y 
ot her seri o us criteria, t he e ve nt is seri o us. W he n i n d o u bt as t o w het her 
“ h os pitalizati o n” occ urre d or was necessar y, t he A E will  be c o nsi dere d s eri o us.  
•  H os pitalizati o n f or electi ve treat me nt of a pree xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E. 
•  H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitali zati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitaliz ati o n m ust be d oc u me nte d a n d re p orte d as 
S A Es.  
d.  Res ults i n persiste nt dis a bilit y/i nc a p acit y  
T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
T his defi niti o n is n ot  i nte n de d t o i ncl u de e x perie n ces of relati vel y mi n or me dical si g nifica nce 
s uc h as u nc o m plicate d hea dac he, na us ea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de nt al tra u ma 
(e. g., s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt e v er y da y life f u ncti o ns b ut d o n ot 
c o nstit ute a s u bsta ntial disr u pti o n.  
e. Is a c o n ge nit al a n o m al y/ birt h defect. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /6 6  
 
 
f. Ot her sit u ati o ns  
•  Me dical or scie ntifi c j u d g me nt will  be e x ercis e d i n deci di n g w het her S A E re p orti n g 
is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreat e ni n g or res ult i n deat h or h os pitaliz ati o n b ut ma y je o par dize 
t he partici pa nt or 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 d efi niti o n. T hese e ve nts are us uall y c o nsi dere d as 
seri o us. 
•  E x a m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve tr eat me nt 
i n a n e mer ge n c y r o o m or at h o me f or aller gic br o n c h os pas m, bl o o d d ys crasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g d e pe n de nc y 
or dr u g a b use.  
A n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y i nter ve nti o n is als o c o nsi dere d a n 
S A E f or re p orti n g p ur p os es, as s pecifi e d bel o w f or re p orti n g S A Es.  
Rec or di n g a n d F oll o w -u p of A E a n d/ or S A E  
A E a n d S A E Rec or di n g  
•  W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he In v esti gat or t o re vi e w all 
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts) 
relate d t o t he e v e nt. 
•  T he In vesti gat or will t he n rec or d all rele v a nt A E/ S A E i nf or ma ti o n i n t he C R F. 
•  As nee de d, t h e S p o ns or ma y as k f or c o pies of certai n me dical rec or ds (e. g., a ut o ps y re p orts, 
s u p ple me ntal la b re p orts, d oc u me nts o n me dical hist or y/c o nc o mita nt me dicati o ns, 
disc har ge letters), as s u p p orti n g s o ur ce d oc u me nt ati o n. All partic i pa nt i de ntifiers, e x ce pt 
t he partici pa nt n u m ber, will be re dact e d o n t hese c o pies bef ore s u b missi o n t o t he S p o ns or. 
•  T he In vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver possi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
•  S pecific g ui da nce is i n t he C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /6 6  
 
 
 
Assess me nt of I nte nsit y  
T he In vesti gat or will ass ess t he i nte nsit y of eac h A E a n d S A E re p orte d d uri n g t he st u d y a n d 
assi g n it t o 1 of t he f oll o wi n g cate g ories:  
•  Mil d: A t y p e of a d v erse e ve nt t hat is us uall y tr a nsie nt a n d ma y re q uir e o nl y mi ni mal 
treat me nt or t hera pe utic i nter ve nti o n. T he e v e nt d oes n ot ge nerall y i nterfere wit h 
us ual acti viti es of dail y li vi n g.  
•  M o derate: A t y pe of a d v erse e v e nt t hat is us uall y alle viate d wit h a d diti o nal s pecific 
t hera pe utic i nter ve nti o n. T he e ve nt i nterferes wit h us ual acti vities of dail y li vi n g, 
ca usi n g dis c o mf ort b ut p oses n o si g nifica nt or per ma ne nt ris k of  har m t o t h e 
researc h partici pa nt. 
•  Se vere: A t y pe of a d verse e ve nt t hat i nterr u pts us ual acti vities of dail y li vi n g, or 
si g nifica ntl y affects cli nical stat us, or ma y re q uire i nte nsi ve t hera pe utic 
i nter ve nti o n. 
D o n ot c o nf use a n A E t h at is assesse d as se v ere wit h an  S A E. Se vere is a cate g or y use d t o 
rate t he i nte nsit y of a n e v e nt; b ot h A Es a n d S A Es ca n be assesse d as s e vere. A n e ve nt is 
defi ne d as “seri o us” w he n it meets at least 1 of t he pre defi ne d criteria s pecifie d i n t he 
defi niti o n of a n S A E, N O T w h e n it is rate d as s e vere.  
I n v esti gat ors will refere n ce t he N CI -C T C A E, v ersi o n 5. 0 ( p u blicati o n date: 
2 7  N o ve m ber  2 0 1 7 ), a descri pti ve ter mi n ol o g y t hat ca n be use d f or A E re p orti n g. 
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verit y) s cale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere n ce d d o c u me nt, a n d s pecific e v e nt gra d es are als o pr o vi de d.  
If t he se verit y f or a n A E is n ot s pecificall y gra d e d b y N CI-C T C A E, t h e I n v esti gat or is t o use 
t he ge neral N CI-C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra d e 5, usi n g his or her best me dical 
j u d g me nt. 
T he 5 ge neral gra d es are:  
•  Gra de 1 or Mil d  
•  Gra de 2 or M o derate  
•  Gra de 3 or Se vere  
•  Gra de 4 or Life -t hreat e ni n g 
•  Gra de 5 or Deat h  
A n y cli nical A E wit h se v erit y of Gra d e 4 or 5 m ust als o be re p orte d as a n S A E.  H o we v er, a 
la b orat or y a b n or malit y of Gra d e 4, s uc h as a ne mi a or ne utr o p e nia, is c o nsi dere d seri o us o nl y if 
t he c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w. 
If deat h o cc urs, t he pri mar y ca us e of deat h or e v e nt lea di n g t o de at h will  be rec or de d a n d 
re p orte d as a n S A E. “ Fat al” will be rec or de d as t he o utc o me of t his s pecifi c e ve nt a n d d eat h 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 9 /6 6  
 
 
will n ot be rec or de d as se parate e ve nt. O nl y, if n o ca use of deat h c a n be re p orte d (e. g., s u d d e n 
deat h, u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E. 
 
Assess me nt of C a us alit y  
•  T he I n vesti gat or will ass ess t he relati o ns hi p bet w ee n st u d y i nter ve nti o n a n d eac h 
A E/ S A E occ urre nce:  
o  U nrelate d: N ot r eas o na bl y relate d t o t he st u d y i nter ve nti o n. A E c o ul d n ot 
me dicall y ( p har m ac ol o gicall y/ cli nicall y) be attri b ute d t o t he st u d y 
i nter ve nti o n. A reas o na bl e alter nati ve e x pla nati o n will be a vaila ble. 
o  Relate d: Reas o na bl y relate d t o t he st u d y i nter ve nti o n. A E c o ul d me dicall y 
( p har mac ol o gi call y/ cli nicall y) be attri b ute d t o t he st u d y i nter ve nti o n. 
•  A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca us al relati o ns hi p, rat her t ha n a rel ati o ns hi p 
ca n n ot be r ule d o ut.  
•  T he I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
•  Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her 
ris k fact ors, as well as t h e te m p oral r elati o ns hi p of t he e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.  
•  T he I n vesti ga t or will als o c o ns ult t he I B a n d/ or Pr o d uct I nf or m ati o n, f or 
mar kete d pr o d u cts, i n his/ her assess me nt.  
•  F or eac h A E/ S A E, t he I n vesti gat or will  d oc u me nt i n t he me dical n otes t hat 
he/s he has re vi e we d t he A E/ S A E a n d assesse d ca usalit y.  
•  T here ma y b e sit uati o ns w he n a n S A E has o cc urre d , a n d t he I n v esti gat or h as 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he S p o ns or or its desi g nee . 
T o meet t he re p orti n g ti meli ne, t he ca usalit y assess me nt is n ot re q uire d f or t he 
i nitial re p ort. 
•  T he In vesti gat or ma y c h a n ge his/ her ca us alit y ass ess me nt after c o nsi deri n g 
f oll o w-u p i nf or mati o n a n d se n d a n  S A E f oll o w -u p re p ort wit h t he u p date d 
ca usalit y assess me nt.  
•  T he ca us alit y ass ess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uir e me nts. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 0 /6 6  
 
 
F oll o w -u p of A Es a n d S A Es  
•  T he In vesti gat or will perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns, as me dicall y i n dicate d or as re q uest e d b y t he 
S p o ns or  t o el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E, as f ull y as 
p ossi ble. T his ma y i ncl u de a d diti o nal la b orat or y t ests or i n vesti gati o ns, 
hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals.  
•  Ne w or u p d ate d i nf or mati o n will be rec or de d i n t he ori gi n all y c o m plete d C R F.  
•  T he In vesti gat or wi ll s u b mit a n y u p date d S A E d ata t o t he S p o ns or wit hi n 2 4 h o urs of 
recei pt of t h e i nf or mati o n. 
Re p orti n g of S A Es  
S A E Re p orti n g b y a n Electr o nic D at a C ollecti o n T o ol  
•  T he pri mar y mec ha nis m f or re p orti n g a n S A E i n m ultice nter st u dies t o t he S p o ns or or its 
desi g nee will be t he el ectr o nic data c ollecti o n t o ol.  
•  If t he electr o nic s yste m is u na vaila ble, t he n t he sit e will use t he pa per S A E f or m, s pecifie d 
bel o w, t o re p ort t he e ve nt wit hi n 2 4 h o urs.  
•  T he site will e nter i nt o t he electr o ni c s yst e m t he S A E data wit h i n 2 4 h o urs after bec o mi n g 
a ware of t he e ve nt. It is e x pecte d t hat t he I n v esti gat or/ S u bi n vesti gat or si g ns off t his data i n 
t he s yste m a n d a n y rel e v a nt ass ociate d d ata (e. g., a d diti o nal la b orat or y tests, me dical 
rec or ds, dia g n ostic re p orts, hist o pat h ol o gical e x a mi nati o ns, or c o ns ultati o n wit h ot her 
healt h care pr ofessi o nals) will be e ntere d as s o o n as it bec o mes a vaila ble.  
•  After t he st u d y is c o m plete d at a site, t he ele ctr o ni c data c ollecti o n t o ol will be ta ke n off -
li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data.  
•  If a site recei v es a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei v es u p date d data 
o n a pre vi o usl y re p orte d S A E after t he electr o ni c data c ollecti o n t o ol has b ee n ta ke n off -
li ne, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m or t o t he S p o ns or’s 
safet y de p art me nt. 
•  B y e x ce pti o n, a n S A E ( or f oll o w -u p i nf or mati o n) ma y b e re p orte d b y tele p h o ne. T he site 
will c o m plete t he electr o nic S A E data e ntr y i m me diatel y t hereafter.  
S A E Re p orti n g b y a P a per F o r m  
•  S A E re p orti n g  o n a pa p er re p ort f or m ma y b e use d i n si n gle ce nt er st u dies i n a d diti o n t o 
t he sta n dar d el ectr o nic C R F a n d as a b ac k-u p met h o d f or a n E D C s yste m f ail ure. T he f or m 
i ncl u des c o m pleti o n i nstr ucti o ns f or t he I n vesti gat or, na mes, a d dresses, a n d tele p h o ne a n d 
fa x n u m bers. All i nf or mati o n fr o m t he pa per f or m will be tra nscri be d i nt o t he electr o ni c 
f or m as s o o n as t he s yste m bec o mes a vaila bl e. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 1 /6 6  
 
 
•  Facsi mile tra ns missi o n (fa x t o mail) of t he pa per f or m or a n y f oll o w -u p i nf or mati o n is t he 
preferre d m et h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or or its 
desi g nee.  
•  I n rare cir c u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y tele p h o n e 
is acce pta bl e wit h a c o p y of t he f or m se nt b y o ver ni g ht mail or c o uri er ser vice. 
•  I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he I n v esti gat or t o c o m plete 
a n d si g n t he f or m  wit hi n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.  
•  A d diti o nal d oc u me nts (e. g., la b orat or y re p orts, a ut o ps y re p ort, h os pital disc har ge letter) 
a n d rele va nt pa ges  fr o m t he C R F ma y be re q uire d i n a d diti o n (e. g., me di cal hist or y, 
c o nc o mita nt me dicati o n). T he data pr o vi d e d will be c o nsiste nt wit h t he i nf or mati o n i n t he 
C R F.  
Rec or di n g a n d Re p orti n g of D L Ts  
•  Eac h e v e nt t hat meets t he D L T criteri a will be rec or de d i n t he  C R F wit hi n 2 4 h o urs after 
a ware ness of t he e ve nt.  
•  Seri o us D L Ts will be re p orte d i n a n e x pe dite d ma n ner, usi n g t h e S A E re p orti n g pr ocess, as 
s pecifie d a b o v e. 
•  N otificati o n of eac h D L T relate d e v e nt ( n o nseri o us a n d seri o us) will be re p orte d t o t he 
S p o ns or or  its desi g nee wit hi n 2 4 h o urs fr o m t he date of a w are ness. 
Re p orti n g of A E SIs  
•  F or a n o ns eri o us A E SI, t he site will c o m plete t he s pecific A E SI re p ort f or m a n d n otif y t he 
S p o ns or i m me diatel y ( wit hi n 2 4 h o urs), usi n g t he sa me pr ocess f or re p orti n g S A Es, as 
s pecifie d a b o v e. 
•  F or a s eri o us A E SI, t he site will c o m plete a n S A E re p ort f or m, usi n g t he S A E re p orti n g 
pr ocess, s pecifie d a b o v e.  
Re p orti n g of Pre g n a ncies  
•  Pre g n a nc y will be re p ort e d w het her relat e d t o t he st u d y i nter ve nti o n usi n g t he a p plica ble 
pa per f or m . 
•  T he a p plica ble f or m will be use d t o re p ort if a n a b n or mal o utc o me of t he pre g n a nc y o cc urs 
a n d t he c hil d/fet us s ustai ns a n e ve nt.  
•  Facsi mile tra ns missi o n (fa x t o mail) of t he pa per f or m or a n y f oll o w -u p i nf or mati o n is t he 
preferre d m et h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or or its 
desi g nee.  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
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 6  
 
 
A p pe n di x 5  
Cli nic al L a b or at or y Tests   
T he pr ot oc ol -re q uire d cli nical la b orat or y assess me nts are i n t he f oll o wi n g ta ble: 
L a b or at or y A s s e s s m e nt s  
P ar a m et er s  
H e m at ol o g y  
R e d bl o o d c ell c o u nt  
Pl at el et c o u nt  
M e a n 
c or p u s c ul ar 
v ol u m e ( M C V)  
W hit e Bl o o d C ell 
C o u nt wit h 
Diff er e nti al : 
•  
N e utr o p hil s  
•  
L y m p h o c yt e s  
•  
M o n o c yt e s  
•  
E o si n o p hil s  
•  
B a s o p hil s  
H e m o gl o bi n  
M e a n 
c or p u s c ul ar 
h e m o gl o bi n 
( M C H) 
M e a n 
c or p u s c ul ar 
h e m o gl o bi n 
c o n c e ntr ati o n 
( M C H C) 
H e m at o crit  
Bi o c h e mi str y  
Bl o o d Ur e a 
Nitr o g e n  
P ot a s si u m  
A s p art at e 
a mi n otr a n sf er a s e  
Bilir u bi n (t ot al) a  
Cr e ati ni n e  
S o di u m  
Al a ni n e 
a mi n otr a n sf er a s e  
Pr ot ei n  
Gl u c o s e  
C al ci u m  
Al k ali n e 
p h o s p h at a s e  
C r e a cti v e pr ot ei n  
Uri c a ci d  
C hl ori d e  
G a m m a 
Gl ut a m yl 
Tr a n sf er a s e  
L a ct at e 
d e h y dr o g e n a s e  
Ur e a  
M a g n e si u m  
A m yl a s e  
Cr e ati n e Ki n a s e  ( C K)b  
C h ol e st er ol  
I n or g a ni c 
p h o s p h at e  
Li p a s e  
 
Tri gl y c eri d e s  
 
 
 
R o uti n e Uri n al y si s  
•  
S p e cifi c gr a vit y  
•  
p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s,  a n d  l e u k o c yt e s b y di p sti c kc 
•  
Mi cr o s c o pi c e x a mi n ati o n (if bl o o d , pr ot ei n , nitrit e, or l e u k o c yt e s i s 
a b n or m al) .  
Ot h er S cr e e ni n g T e st s  
•  
Uri n e dr u g s cr e e n:  
•  
C o c ai n e, A m p h et a mi n e, M et h a m p h et a mi n e, O pi at e, B ar bit ur at e s, 
B e n z o di a z e pi n e, M et h a d o n e, C a n n a bi n oi d s, Tri c y cli c a nti d e pr e s s a nt s, 
C oti ni n e, 3, 4 -m et h yl e n e di o x y m et h a m p h et a mi n e ( E c st a s y)  
•  
Et h a n ol br e at h t e st  
•  
H e p atiti s B s urf a c e a nti g e n  
•  
H e p atiti s B c or e a nti b o d y  
•  
H e p atiti s C a nti b o d y  
•  
HI V 1/ HI V 2 a nti b o di e s  
•  
S A R s -C o V -2 a c c or di n g t o l o c al r e q uir e m e nt  
•  
F olli cl e Sti m ul ati n g H or m o n e (t o c o nfir m p o st m e n o p a u s al st at u s, 
f e m al e o nl y) 
•  
S er u m or hi g hl y s e n siti v e uri n e h u m a n c h ori o ni c g o n a d otr o pi n  
pr e g n a n c y t e st t o c o nfir m n o n -pr e g n a nt st at u s (f e m al e s o nl y).  
•  
T h yr otr o pi n  
•  
E sti m at e d Gl o m er ul ar  Filtr ati o n R at e b a s e d o n C hr o ni c Ki d n e y 
Di s e a s e E pi d e mi ol o g y C oll a b or ati o n  Cr e ati ni n e E q u ati o n ( 2 0 0 9)  
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 3 /6 6  
 
 
C K = cr e ati n e ki n a s e; HI V = h u m a n i m m u n o d efi ci e n c y vir u s  M C H = m e a n c or p u s c ul ar h e m o gl o bi n; M C H C = m e a n 
c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n  M C V = m e a n c or p u s c ul ar v ol u m e .  
a  I n c a s e of i n cr e a s e d bilir u bi n (t ot al), t h e dir e ct bilir u bi n will b e d et er mi n e d. 
b  I n c a s e of i n cr e a s e d C K, m y o c ar di u m/ br ai n t y p e ( C K-M B) will b e d et er mi n e d; if t h e r ati o of C K/ C K -M B i s a b o v e 6, 
tr o p o ni n will b e d et er mi n e d a s w ell. 
c  O nl y if bl o o d, pr ot ei n, nitrit e, or l e u k o c yt e s ar e p o siti v e o n t h e di p sti c k.  
 
 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 4 /6 6  
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Xe vi na pa nt 
M S 2 0 2 3 5 9 _ 0 0 0 4 
P hase I P K St u d y i n Healt h y East Asia n Partici pa nts 
A p pe n di x 7 
S p o ns o r Si g n at u r e P a ge 
St u d y Titl e: 
A si n gle- d ose, o pe n-la bel, si n gle ar m st u d y t o i n vesti gate 
P K of xe vi na pa nt a n d its meta b olite. D- 1 1 4 3- M E TI 
i n 
healt h y East Asia n partici pa nts 
R e g ul at o r y A g e n c y I d e ntif yi n g 
N u m b e rs: 
E U Trial N u m ber 2 0 2 2- 0 0 2 1 8 2 - 15 
Cli nic al St u d y Pr ot oc ol Versi o n: 
l. O 
I a p pr o v e t he desi g n of t he cli nical st u d y: 
Si g nat ure 
N a me, A c a d e mi c D e gr e e: 
F u ncti o n/ Title: 
I nstit uti o n: 
A d dress: 
Ge ner al Merc k P h o ne 
N u m ber: 
Ge ner al M e r c k F a x 
N u m ber: 
 
Me dical Res p o nsi ble 
Date 
Merc k Healt hcare K Ga A 
Fra n kf urter Strasse 2 5 0 
Dar msta dt , 6 4 2 9 3, Ger ma n y 
 
N ot A p plica ble 
i g nat ure 
C O N F I IJ l ~ N T I A t 
<, 5 /u o 
I N F O R M A TI O N 
Gl o bal V ersi o n J O: 
 
P P D
P P D
P P D
P P D
P P D
C CI


X e vi n a p a nt 
M S 2 0 2 3 5 9 _ 0 0 0 4 
P h as e 1 P K St u d y 111 H e alt h y E ast Asi a n P art 1 c 1 p a nts 
------------------------ - - ---
A p p e n di x 8 
Pri n ci p al I n v esti g at or Si g n at ur e P a g e 
St u d y Titl e: 
A si n gle- d ose, o pe n-la bel, si n gl e a n n st u d y t o m ves L L gate 
P K ol' A. e v 1 n a p a nt a n d its r n ct a b ol 1t e, D- 1 1 4 3- M E Tl 
Ill 
h e alt h y f ast As w n part 1c 1 pa nt <s 
R e g ul at o r y A g e n c y I de nt 1f yr n g 
N u m b e rs: 
E U Tri al N u m b er 2 0 2 2- 0 0 2 1 8 2- 1 5 
Cl mi c al St u d y P r ot o c ol V e rsi o n: 
1 0 
Sit e N u m b e r: 
I a p pr o v e t h e o es 1 g n or L11e e,J m,ca: st uc.:,,·, : m 1 1es p o ns 1 ble t or t he c o n d u ct ot tt 1 e :-it u d y at tl 1 1 s s11c 
a n d u n d erst a n d a n d will c o n d u ct 1t p er t he cl1111cal st u d y pr ot oc ol, a n y t 1 p p 1 o ve d pr ot o c ol 
a m e n d m e nts, I C H G C P ( T o pi c E 6) a n d all a p pli c a bl e H e alt h A ut h orit y r e q uir e m e nts a n d 
nati o nal l a ws 
N a m e, a c a d e mi c tl e g r e e: 
Titl e: 
I nstit uti o n: 
A d d r ess: 
T el e p h o n e n u m b e r. 
F a x n u m b e r: 
E- m ail a d d r ess: 
 
 
 
 
 
 
 
 
N ot A p pli c a bl e 
 
C O N FI D E N TI A L 
I N F O R M A TI O N 
Gl o h al V crs 1 0 n I D 
 
6 6/ 6 6 
P P D
P P D
P P D
P P D
C CI

SAP_001.pdf: 
Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
I nte gr ate d A n al ysis Pl a n  
St u d y N u m ber:  
M S 2 0 2 3 5 9 _ 0 0 0 4  
Cli nic al St u d y Pr ot oc ol 
Title:  
A si n gle -d ose, o pe n -la bel, si n gle ar m st u d y t o i n v esti gate P K of 
x e vi na pa nt a n d its meta b olite, D -1 1 4 3 -M E T 1 i n healt h y E ast 
Asia n partici pa nts  
St u d y P h ase : 
1  
Merc k C o m p o u n d:  
Xe vi na pa nt  
Pr ot oc ol V ersi o n:  
1 0  J u ne 2 0 2 2/ 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  
 
, M er c k 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
, 
 
 
, 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n : 
0 6 Oct o ber 2 0 2 2  / V ersi o n 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  
, M er c k 
 
, M er c k 
 
, M er c k 
, 
M er c k  
O pti o n al: Cli ni c al  Tri al 
L e a d er  
, M er c k 
 
, M er c k 
 
d, M er c k  
M e di c al R e s p o n si bl e, 
M er c k  
, 
M er c k  
St ati sti c al Pr o gr a m mi n g 
Pr oj e ct L e a d, M er c k  
Cli ni c al P h ar m a c ol o g y 
J a p a n, M er c k  
 
 
Gl o bal Versi o n I 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
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k Healt hcare K Ga A, Dar mst a 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 Healt hcare K Ga A, D ar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 2  b y M erc k  He alt hc are  K G a A, D ar mst a dt, Ge r m a n y or its affili ate. All ri g hts reser ve d.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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 2 3 5 9 _ 0 0 0 4  
A si n gle -d os e, o pe n -l a bel, si n gle ar m st u d y t o i n vesti gate P K of xe vi na pa nt a n d its meta b olite 
D -1 1 4 3 -M E T 1 i n healt h y East Asia n 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.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1  
T a ble of C o nte nts   
A p pr o val Pa ge  
 ..............................................................................................................3  
1  
Ta ble of C o nte nts  ..................................................................................4  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms  ....................................6  
3  
M o dificati o n Hist or y  ............................................................................8  
4  
P ur p ose of t he  I nte grate d A nal ysis Pla n ...............................................8  
5  
O bjecti ves a n d E n d p oi nts  .....................................................................8  
6  
O ver vie w of Pla n ne d A nal yses  .............................................................9  
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  ........9  
8  
A nal ysis Sets a n d S u b gr o u ps  ................................................................9  
8. 1  
Defi niti o n of A nal ysis Sets  ...................................................................9  
8. 2  
S u b gr o u p D efi niti o n a n d Para meterizati o n  ........................................1 0  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ..........................................1 0  
9. 1  
Defi niti o n of Bas eli ne a n d C ha n ge fr o m Baseli ne  .............................1 1  
9. 2  
St u d y Da y / St u d y I nter v e nti o n Da y  ...................................................1 1  
9. 3  
Defi niti o n of D urati o n a n d ‘ Ti me Si n ce’ Varia bles  ...........................1 1  
9. 4  
C o n versi o n Fact ors  .............................................................................1 1  
9. 5  
I m p utati o n of Missi n g Data ................................................................1 1  
1 0  
St u d y Partici pa nts  ...............................................................................1 2  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................1 3  
1 0. 2  
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ysis Sets  ..........................1 3  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................1 3  
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 5  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................1 5  
1 1. 1  
De m o gra p hics  .....................................................................................1 5  
1 1. 2  
Me dical Hist or y  ..................................................................................1 5  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................1 5  
1 2  
Pre vi o us or C o nc o mita nt T hera pies/ Pr oce d ures  .................................1 5  
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 6  
1 4  
Efficac y A nal yses  ...............................................................................1 6  
1 5  
Safet y A nal yses  ..................................................................................1 6  
1 5. 1  
A d verse E v e nts  ...................................................................................1 6  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1 5. 1. 1  
All A d verse E v e nts  .............................................................................1 7  
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 7  
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 7  
1 5. 2. 1  
Deat hs  .................................................................................................1 7  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................1 7  
1 5. 2. 3  
Ot her Si g nifica nt A d verse E ve nts  ......................................................1 8  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................1 8  
1 5. 4  
Vital Si g ns  ..........................................................................................1 8  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................1 8  
1 5. 6  
C O VI D -1 9 I m pa ct  ..............................................................................1 8  
1 6  
A nal ys es of Ot her E n d p oi nts  ..............................................................1 9  
1 6. 1  
P har mac o ki netics  ................................................................................1 9  
1 6. 1. 1  
Descri pti ve Statistics of P K C o nce ntrati o n Data  ................................1 9  
1 6. 1. 2  
Descri pti ve Statistics of P K Para meter Data  ......................................1 9  
1 6. 1. 3  
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. 4  
Esti mati o n of P har mac o ki netic Para meters  ........................................2 1  
1 6. 1. 4. 1  
Esti mati o n of P har mac o ki netic Para meters i n Plas ma  .......................2 1  
1 6. 1. 5  
Statistical A nal ysis of P K Para meter Data  .........................................2 3  
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 4  
1 8  
A p pe n dices  .........................................................................................2 5  
 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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 E SI  
A d verse E v e nt  of S pecial Interest  
A U C  
Area u n d er t he c o nce ntr ati o n -ti me c ur ve 
B L Q  
Bel o w t he Li mit of Q ua ntificati o n  
B MI  
B o d y Mass I n d e x  
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  
CI P D  
Cli nicall y I m p orta nt Pr ot oc ol De viati o n  
(e) C R F 
(electr o ni c) Case 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  
E D M S  
Electr o nic D o c u me nt Ma na ge me nt S yste m  
G C P  
G o o d Cli nical Practice  
Ge o C V  
G e o metric C oefficie nt of V ariati o n  
Ge o Mea n  
Ge o metric Mea n  
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 
I P D 
I m p ort a nt Pr ot oc ol De viati o n 
L L O Q  
L o w er Li mit of Q ua ntificati o n  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M W  
M olec ular Wei g ht  
N A  
N ot A p plica ble  
N C A  
N o n -c o m part me nt al A nal ysis  
P D  
Pr ot oc ol De viati o n or P har mac o d y n a mics  
P K  
P har mac o ki netics  
P K A S  
P har mac o ki netic A n al ysis Set  
P T  
Preferre d Ter m  
Q 1  
2 5t h perce ntile  
Q 3  
7 5t h perce ntile  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 
7 /2 5  
 
 
S A E  
Seri o us A d verse E v e nt  
S A F  
Safet y A nal ysis Set  
S C R  
Scree ni n g A n al ysis S et  
S D  
Sta n dar d De viati o n  
S D T M  
St u d y Data Ta b ulati o n M o del  
SI  
S ystè me I nter nati o nal  
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  
U L O Q  
U p per Li mit of Q ua ntificati o n  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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  
1. 0  
0 6 O ct o b er 2 0 2 2  
 
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 2 3 5 9 _ 0 0 0 4 . 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 is pre pare d 
i n c o m plia nce wit h I C H E 9. It d escri bes a n al ys es pla n ne d i n t he pr ot oc ol, wit h t he e x ce pti o n of 
 a n al ysis f or t he effect of 
 varia nts o n t he P K of x e vi na pa nt w hic h will be 
descri be d a n d re p orte d se paratel y.  
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 
Cli nical St u d y 
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 on’ 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.  
5  
O bjecti ves a n d E n d p oi nts   
O bj e cti v e s  
E n d p oi nt s  
I A P s e cti o n 
Pri m ar y  
 
 
T o c h ar a ct eri z e t h e x e vi n a p a nt P K aft er a 
si n gl e 2 0 0 m g d o s e i n h e alt h y E a st A si a n 
p arti ci p a nt s a n d i n h e alt h y J a p a n e s e 
p arti ci p a nt s  
X e vi n a p a nt A U C 0 -tl a st, A U C0 -∞, a n d 
C m a x  
1 6. 1  
S e c o n d ar y  
 
 
Gl o bal Versi o n I D: C CI
P P D
C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
O bj e cti v e s  
E n d p oi nt s  
I A P s e cti o n 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of a 
si n gl e 2 0 0 m g d o s e of x e vi n a p a nt i n h e alt h y 
E a st A si a n p arti ci p a nt s a n d i n h e alt h y 
J a p a n e s e p arti ci p a nt s  
O c c urr e n c e of T E A E s (i n ci d e n c e, 
fr e q u e n c y, i nt e n sit y a n d c a u s alit y), 
o c c urr e n c e of c h a n g e s i n s af et y 
l a b or at or y a s s e s s m e nt s, 1 2-l e a d 
E C G s, a n d vit al si g n s  
1 5  
T o d et er mi n e a d diti o n al pl a s m a P K  
p ar a m et er s of x e vi n a p a nt aft er a si n gl e 2 0 0 
m g d o s e i n h e alt h y e a st A si a n p arti ci p a nt s a n d 
i n h e alt h y J a p a n e s e p arti ci p a nt s 
X e vi n a p a nt A U C 0 -2 4 , tm a x , t1/ 2 , C L/ F, 
a n d V z/ F 
1 6. 1  
T o c h ar a ct eri z e t h e P K of m et a b olit e 
D -1 1 4 3 -M E T 1 aft er a si n gl e 2 0 0 m g d o s e i n 
h e alt h y E a st A si a n p arti ci p a nt s a n d i n h e alt h y 
J a p a n e s e p arti ci p a nt s  
D -1 1 4 3 -M E T 1 A U C
0 -tl a st, A U C0 -2 4 , 
A U C 0 -∞, Cm a x , tm a x , a n d t1/ 2 , 
D -1 1 4 3 -M E T 1/ x e vi n a p a nt m ol ar r ati o 
f or A U C0 -tl a st, A U C0 -∞, Cm a x  
1 6. 1  
6  
O ver vie w of Pl a n ne d A n al yses   
All fi nal, pla n ne d a nal ys es i de ntifie d i n t he I A P will be perf or me d o nl y  after t he last partici p a nt 
has c o m plete d t he last visit, i.e. F oll o w -u p/ Disc o nti n uati o n visit wit h all st u d y d ata i n -h o use, all 
data q ueries res ol ve d, a n d t he data base l o c ke d . 
T here are n o pla n n e d f or mal i nteri m a nal ys es.  
Statistical a nal yses will be perf or me d o n t h e basis of C DI S C S D T M d ata. T hese S D T M dat a 
c o ntai n as cle a n as p ossi ble e C R F data as well as e xter nal data i ncl u di n g p har mac o ki netic d ata.  
A data re vie w me eti n g will be hel d pri or t o a n y data base l oc k. I n a d diti o n, n o data base ca n b e 
l oc ke d u ntil t his I A P has bee n a p pr o ve d (e x ce pt f or e mer ge nc y). 
7  
C h a n ges t o t he Pl a n ne d 
A n al yses i n t he 
Cli nic al 
St u d y  
Pr ot oc ol   
T here are n o c ha n ges t o t he  pla n ne d  a n al ys es i n t he cli nical st u d y pr ot oc ol.  
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   
Sc ree ni n g A n al ysis Set  (S C R)  
T he S cree ni n g A n al ysis Set  i ncl u des all partici pa nt s w h o pr o vi de d si g ne d i nf or me d c o nse nt, 
re gar dl ess of t he partici pa nt’s ra n d o mizati o n a n d st u d y i nter ve nti o n stat us i n t he st u d y. 
Gl o bal Versi o n I D: C CI
C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
S afet y A n al ysis Set  ( S A F) 
T he Safet y A nal ysis Set will i ncl u de all partici pa nts w h o were a d mi nistere d a n y d ose of a n y st u d y 
i nter ve nti o n. A nal yses will c o nsi der partici pa nts as treate d.  
P K A n al ysis Set  ( P KA S)  
T he P K A nal ysis Set will c o nsist of all  partici pa nts , w h o recei ve at least o ne d ose of st u d y 
i nter ve nti o n, a n d pr o vi de at least o ne meas ura ble  p ost d ose c o nce ntrati o n. A meas ure me nt B L Q is 
co nsi dere d a v ali d meas ure me nt. Partici pa nts will be a nal yze d acc or di n g t o t he act ual st u d y 
i nter ve nti o n t he y recei ve d. 
T he f oll o wi n g t a ble s u m marizes t he use of t he a n al ysis sets i n t he differe nt a nal ys es. 
 
A n al y si s S et  
A n al y s e s  
S A F  
P K A S  
B a s eli n e C h ar a ct eri sti c s  
✓ 
 
Pr e vi o u s a n d C o n c o mit a nt T h er a pi e s  
✓ 
 
C o m pli a n c e a n d E x p o s ur e  
✓ 
 
S af et y a n d T ol er a bilit y  
✓ 
 
P K  
 
✓ 
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 data will be s u m marize d b y et h nic gr o u p  (Ja pa nese, n o n -J a pa nese East Asia n a n d 
o verall) a n d/ or s c 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 n t 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 ul e d me as ur e me nts will be i n cl u de d i n t he listi n gs.  All listi n gs will be s orte d b y 
treat me nt, et h nic gr o u p, s u bject I D, a n d/ or n o mi nal ti me p oi nt, as a p pr o priate. Data w hic h are 
meas ure d bef ore a d mi nistrati o n of t he st u d y i nter ve nti o n will be s orte d b y p artici pa nt n u m ber a n d 
n o mi nal ti me p oi nt (if 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 et h nic gr o u p (Ja pa n ese, n o n -J a pa nes e East Asia n a n d  o verall) , da y, 
a n d/ or 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 ule d meas ure me nts i n cl u de d i n 
t he listi n gs will n ot be use d f or s u m mari es, u nless t he re peate d meas ure m e nt was perf or me d d u e 
t o u nrelia ble val ues/tec h nical reas o ns, e.g ., cl otted sa m ples.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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), mea n, sta n dar d de viati o n  ( S D), 
me dia n, 2 5t h perce ntile ( Q 1) a n d 7 5t h perce ntile ( Q 3), mi ni m u m  ( Mi n), a n d ma xi m u m ( Ma x). 
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 heref ore, c o u nts of missi n g o bser vati o ns will be i ncl u d e d i n t he de n o mi nat or a n d 
prese nte d as a se p arate 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 dat e of st u d y i nter ve nti o n. 
All a nal ys es 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 n iti 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 t he 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 aseli 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 b aseli ne val ue (e. g. fr o m scree ni n g/a d missi o n). If n o baseli ne or pre vi o us t o 
baseli ne e val u ati o ns e xist, t he n t he baseli ne val u e will be tre ate d as missi n g.  
C ha n ge fr o m bas eli ne is calc ulate d as p ost -baseli n e 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 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 d a y 
is defi ne d relati ve t o D a 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   
D urati o n s i n da ys will be calc ulate d b y t he differe nce of start a n d st o p date + 1 (e. g. A E d urati o n  
( da ys) = d ate of A E  –  dat e of st u d y i nter ve nti o n a d mi nistrati o n + 1)  if n ot ot her wise s pecifie d. 
T he ti me si nce a n e ve nt (e. g. relati ve da y si nc e first st u d y i nter ve nti o n a d mi nistrati o n ) will be 
calc ulate d as refere nce d ate mi n us date of e v e nt . 
9. 4  
C o n versi o n F act ors   
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years:  
1  wee k = 7 d a ys, 1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.  
9. 5  
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 a t 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 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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 nal yses u p t o t he ti me of 
disc o nti n uati o n.  
Missi n g statistics, e. g. w he n t he y ca n n ot be calc ul ate d, s h o ul d be prese nte d as “ n e”. F or e x a m ple, 
if n = 1, t he meas ur e of varia bilit y ( S D) ca n n ot be c o m p ute d a n d s h o ul d be prese nte d as “ ne”.  
I n c o m plete A E-relate d d ates will be i m p ute d as f oll o ws: 
•  I n cas e t he o nset d ate is missi n g c o m pletel y or missi n g partiall y b ut t he o nset m o nt h a n d year, 
or t he o nset year are e q u al t o t he start of st u d y i nter ve nti o n t he n t he o nset date will be i m p ute d 
b y t he mi ni m u m of start of st u d y i nter ve nti o n a n d A E res ol uti o n date (if n ot missi n g).  
•  I n all ot her cases, t he missi n g o nset da y or missi n g o nset m o nt h will be i m p ute d b y 1.  
•  I n c o m plete st o p dates will be i m p ute d b y t he last da y of t he m o nt h (if da y is missi n g o nl y), if 
n ot res ulti n g i n a date later t ha n t he date of parti ci pa nt’s deat h. I n t he latter cas e, t he dat e of 
deat h will be use d t o i m p ute t he i nc o m plete st o p date.  
•  I n all ot her cases, t he i nc o m plete st o p date will n ot be i m p ute d. 
T here will be n o i m p utati o n f or missi n g or i nc o m plete dates f or pri or or c o n c o mita nt t hera pies.  
F or t he d eri vati o n of pre vi o us  a n d c o nc o mita nt t hera pies t he f oll o wi n g r ules will be a p plie d:  
P re vi o us thera p y:  
•  Start date  ≤ Start of st u d y me d O R  
•  Start date = Missi n g  
C o nc o mita nt t hera p y:  
•  E n d date ≥ Start of st u d y me d. A N D ( Start dat e ≤ E n d of st u d y me d O R Start 
date = Missi n g) O R  
•  E n d date = Missi n g A N D ( Start date ≤ E n d of st u d y me d. O R Start dat e = Missi n g)  
T he deri vati o n is base d o n t he f oll o wi n g pri n ci ples  
•  I m p utati o n lea ds t o ma x. reas o na bl e d urati o n 
•  W orst case: If me dic ati o n is a d mi nistere d t he sa m e da y as start of st u d y me dicati o n , 
me dicati o n is classifie d as c o nc o mita nt a n d pri or  
T here will be n o i m p utati o n f or missi n g or i nc o m plete dates f or date of st u d y i nter ve nti 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.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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 ne d partici pa nts w h o disc o nti n ue d f r o m t he trial pri or t o st u d y i nter ve nti o n 
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  
•  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 nta ge of treate d partici pa nts w h o disc o nti n ue d t he st u d y, wit h t he pri mar y 
reas o n of disc o nti n uati o n b y treat me nt a n d o verall: 
 
A d verse e ve nt  
 
L ost t o f oll o w -u p  
 
Pr ot oc ol n o n -c o m plia nce  
 
Deat h  
 
Wit h dra wal b y s u bject  
 
Ot h er  
A listi n g of disc o nti n ue d partici pa nts will 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 d osi n g. 
I m p ort a nt pr ot oc ol de viati o ns (I P Ds) are pr ot oc ol de viati o ns t hat mi g ht si g nifica ntl y affect t he 
c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y dat a or t hat mi g ht si g nifica ntl y affect a 
partici pa nt's ri g hts, safet y, or well -bei n g.  
I m p ort a nt pr ot oc ol de viati o ns i ncl u de: 
•  Partici pa nts  e nr olle d a n d d ose d o n t he st u d y w h o di d n ot satisf y e nr ol me nt criteria  
•  Partici pa nts t hat de vel o p wit h dra wal criteria w hilst o n t he st u d y b ut are n ot wit h dra w n  
•  Partici pa nts t hat recei ve a n i nc orrect d ose  
•  Partici pa nts t hat recei ve a n e x cl u de d c o nc o mita nt me dicati o n  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
•  Fail ure t o c olle ct data n ecessar y t o i nter pret pri mar y e n d p oi nts  
•  Fail ure t o c olle ct necessar y k e y safet y data  
•  De viati o n fr o m G o o d Cli nical Practice ( G C P)  
•  A n y ot h er pr ot oc ol d e viati o n t hat mi g ht si g nifica ntl y affect t h e c o m plete ness, acc urac y, a n d/ or 
relia bilit y of t he st u d y d ata or t hat mi g ht si g nifica ntl y affect a partici pa nt's ri g hts, s afet y, or 
well -bei n g.  
I m p ort a nt pr ot oc ol de viati o ns will be i de ntifie d f or all partici pa nts b y eit her site m o nit ori n g, 
me dical re vie w pr ocess es or pr o gra m mi n g a n d c o nfir me d pri or t o or at t he Data R e vie w M eeti n g 
at t he latest.  
A n y i m p orta nt pr ot o c ol de viati o n is d oc u me nte d i n S D T M datasets w het her i de ntifie d t hr o u g h sit e 
m o nit ori n g, me dical re vie w or pr o gra m mi n g.  T h e ma na ge me nt of pr ot o c ol de viati o ns is o utsi de 
of t his I A P d oc u m e nt.  
Cli nicall y i m p orta nt pr ot oc ol de viati o ns ( CI P Ds) are a s u bs et of i m p orta nt pr ot oc ol de viati o ns t hat 
c o ul d i m pact t he k e y o bj ecti ves of t h e st u d y  a n d t hat w o ul d lea d t o t he e x cl usi o n of a partici pa nt 
fr o m a n a n al ysis set (s ee S ecti o n 8. 1  Defi niti o n of A nal ysis Sets).  
CI P Ds  ma y be i d e ntifie d d uri n g t he c o urse of t he st u d y b ut will n ot re q uir e a me n d me nts t o t his 
I A P. 
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, diarr hea etc. (t hese i nsta n ces will be disc usse d o n a case -b y case basis)  
•  V o miti n g aft er 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 ose a d mi nistrati o n dela ye d, d ose c ha n ge or misse d 
d oses)  
•  Pre -d ose sa m ple c ollecte d after t he act ual start of d osi n g  
•  I n c o m plete meal c o ns u m pti o n pri or t o d osi n g 
•  C o nc o mita nt me dicati o n vi olati o ns  
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 ue s t o be e x cl u de d 
fr o m a nal ysis. 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1 0. 2. 2  
Re as o ns Le a di n g t o t he 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.  
A fre q u e nc y ta ble or ga ni ze d acc or di n g t o reas o n f or e x cl usi o n fr o m t he P K  A nal ysis Set , as well 
as a listi n g, will be pr o vi de d.  
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 or t he Safet y A nal ysis Set . 
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 b y et h nic gr o u p a n d o verall.  
S pecificati o ns f or c o m p utati o n:  
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 Dicti o nar y f or R e g ulat or y Acti vities ( Me d D R A), 
Versi o n 2 5. 0  or hi g her , a n d liste d. 
1 1. 3  
Ot her B aseli ne C h ar acteristics   
Ot her b aseli ne me as ure m e nts, s uc h as ser ol o g y, al c o h ol a n d dr u gs of a b us e scree n, pre g na nc y test 
a n d f ollicle-sti m ulatin g h or m o ne assess me nt i n w o me 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 E val uati o n). 
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 Safet y A nal ysis Set . 
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 
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 greater t ha n or e q ual t o t h e a d mi nistrati o n of st u d y  
i nter ve nti o n, or wit h a st arti n g d ate pri or t o t he a d mi nistrati o n of 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 he a d mi nistrati o n of st u d y i nter ve nti o n.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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), Versi o n Gl o bal Mar 2 0 2 2 B 3  or 
hi g her , will be use d f or c o di n g of pre vi o us  a n d c o nc o mita nt me dicati o ns a n d t he y will be des cri be d 
usi n g Preferre d Ter m ( P T) as a p plica bl e.  
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   
E x p os ure t o st u d y i nter ve nti o n will be rec or de d i n t he e C R F. T he listi n g of e x p os ure t o t he st u d y 
i nter ve nti o n will i ncl u de t he treat me nt, et h nic gr o u p,  d ose, st u d y i nter ve nti o n a d mi nistere d a n d 
date/ti me of a d mi nistrati o n.  
1 4  
Effic ac y A n al yses   
N ot a p plica ble.  
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 n al ys es will b e perf or me d f or t he Safet y A nal ysis Set a n d will b e pres e nte d b y et h nic 
gr o u p . A n a d diti o nal c ol u m n f or all et h nic gr o u ps ( o verall)  ma y b e prese nt e d w he n s pecifie d.  
1 5. 1  
A d verse E ve nts   
All A Es rec or de d d uri n g t he c o urse of t he st u d y will be c o de d wit h t he Me d D R A, Versi o n 2 5. 0  or 
hi g her , 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 nts wit h o nset dates o n or after t he a d mi nistrati o n 
of st u d y i nter ve nti o n. A n y A E o cc 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 Da 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 after a d mi nistrati o n of 
st u d y i nter ve nti o n will be i ncl 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 bles ( u nless ot her wise state d). T hese will be referre d t o as “ pre-treat me nt ” A Es. 
A n A E of s pecial i nterest ( A E SI) is a n ote w ort h y e ve nt of t he partic ular st u d y treat me nts t hat ca n 
be a p pr o pri ate t o m o nit or cl osel y. A E SIs are n ote d i n t he C R F.  
In 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 ys es descri be d i n t his secti o n will be base d o n T E A Es if n ot ot her wise s pecifie d.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1 5. 1. 1  
All A d verse E ve nts   
Treat me nt -e mer ge nt A Es a n d partici pa nts e x perie nci n g T E A Es will be s u m marize d b y et h nic 
gr o u p  a n d o verall i n ta bles wit h:  
•  T he n u m ber a n d perce nt a ge of partici p a nts wit h a n y T E A E, a n y rel ate d T E A E, a n y seri o us 
T E A E, a n y relate d seri o us T E A E, a n y Gra de ≥3 T E A E, a n y relate d Gra de ≥3 T E A E, a n y 
A E SI s, a n y T E A E lea di n g t o d eat h, a n y rel ate d T E A E lea di n g t o d eat h, a n y T E A E lea 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 p erce nt a ge  of p artici pa nts wit h at least o ne T E A E b y S O C a n d P T , 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 p erce nta ge of partici pa nts wit h at least o ne T E A E a n d t he n u m ber of e v e nts 
b y gra de , 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 relate d 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 perce nt a ge of partici p a nts wit h at least o ne relate d T E A E a n d t he n u m ber of 
e ve nts b y gra d e, 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 a n d P Ts wit hi n eac h S O C ter m 
s orte d al p ha beticall 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 relat e d. 
I n case a partici pa nt ha d 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  
N ot a p plica ble.  
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.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1 5. 2. 3  
Ot her Si g nific a nt A d verse E ve nts   
N ot a p plica ble.  
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 b e pr o vi de d b y t he ce ntr al la b orat or y, 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 d ata n ot tra nsferre d fr o m t he 
ce ntral la b orat or y i n SI u nits will be c o n verte d t o SI u nits bef ore pr ocessi n g. B ot h ori gi nal 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.  
C o nti n u o us cli nical la b orat or y data ( he mat ol o g y, a n d bi oc he mistr y) will be s u m marize d b y et h ni c 
gr o u p  (J a pa nese, n o n-J a pa nese E ast Asia n a n d o v erall) a n d ti me p oi nt usi n g d escri 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 fro m 
baseli ne t o eac h e val u ati o n.  
B o x -a n d-w his ker pl ots f or t he a bs ol ute c ha n ge fr o m baseli ne b y et h nic gr o u p (Ja pa nese, 
n o n -J a pa nese East Asia n a n d o verall) a n d time p oi nt will als o be pr o vi de d.  
Listi n gs of all cli nical la b orat or y d ata f or eac h p artici pa nt  will be pr o vi de d, wit h val ues o utsi de 
t he n or mal ra n ges i n dicat e d. Listi n gs of a b n or mal test res ults (l o w a n d hi g h) will be pr o vi de d.  
1 5. 4  
Vit al Si g ns   
Vital si g ns dat a will be s u m marize d b y et h nic gr o u p  (Ja pa nese, n o n-J a pa nese E ast Asia n a n d 
o verall)  a n d ti m e 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 val uati o n d uri n g t he st u d y, a n d c h a n ge fr o m bas eli ne t o eac h e val uati o n. Listi n g of vital si g ns 
data will be pr o vi de d.  
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 et h nic gr o u p  (Ja pa nese, n o n-J a pa nese East Asia n a n d 
o veral l) 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 val uati o n d uri n g t he st u d y, a n d c h a n ge fr o m bas eli ne t o eac h e val uat i o n. Listi n g of safet y E C G 
data will be pr o vi de d.  
A listi n g of meal det ails will be pr o vi de d . 
1 5. 6  
C O VI D -1 9 I m p act   
A listi n g of all partici pa nts affecte d b y t he C O VI D -1 9 relate d st u d y  disr u pti o n (e. g. A Es/ S A Es, 
misse d visit, misse d d ose, treat me nt/st u d y disc o nti n uati o n, pr ot oc ol de viati o n i ncl u di n g mi n or, 
scree n fail ure, etc.) will b e pr o vi de d. 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1 6  
A n al yses of Ot her E n d p oi nts   
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 t he Cli nical P K/ P D Gr o u p, 
Merc k Healt hcare K Ga A, 
Dar msta dt, Ger ma n y, or b y a C R O sel ecte d b y t he S p o ns or.  
All de scri 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 . All P K data will 
be descri pti vel y s u m mari ze d b y et h nic gr o u p a n d o verall.  
1 6. 1. 1  
Descri pti ve St atistics of P K C o nce ntr ati o n D at a   
P K c o nce ntr ati o ns will be descri pti vel y s u m mariz e d usi n g: n u m ber of n o n -missi n g o bser vati o ns 
( n), arit h metic me a n ( Mea n), sta n dar d d e viati o n ( S D), c oefficie nt of variati o n ( C V %), mi ni m u m 
( Mi n), me dia n ( Me dia n), ma xi m u m ( Ma x). 
Descri pti ve s tatistics will o nl y b e calc ul ate d f or n > 2 i n w hic h a meas ure me nt of B L Q  re prese nts a 
vali d meas ure m e 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 ntr ati o n data.  
I n case n ≤2,  i n di vi d ual d ata  will be pres e nte d ( mi n, ma x) i n  s u m mar y t a bles. 
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 urce d ata a n d r o u n de d f or re p orti n g p ur p oses o nl y.  P K c o nce ntr ati o ns will be 
carri e d o ver wit h f ull precisi o n as pr o vi de d i n t he s o urce data wi t h o ut a n y r o u n di n g a p plie d t o 
C DI S C S D T M P C a n d A Da M P C d o mai ns . 
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 , S D: 
3 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 will b e 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 me a n ( Mea n), sta n dar d d e viati o n ( S D), c oefficie nt of variati 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 
of vari ati 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 M ea n ( 9 5 % CI G e oM ea n ). F or 
P K para meter s relat e d t o ti me (e. g. tma x , tlast), o nl y n, Mi n, Me dia n, a n d Ma x ma y b e re p orte d.  
Descri pti ve statistics 
will o nl y b e cal c ulate d f or a P K para meter 
w he n n > 2 . I n case n 
≤2,  i n di vi d ual data  will be prese nt e d ( mi n, ma x) i n  s u m mar y ta bl es. 
P K para m eters rea d directl y fr o m t he meas ure m e nts (i.e. C ma x ) will be re p orte d wit h t h e sa m e 
precisi o n as t he s o ur ce data. All ot her P K para meters will be re p orte d t o 3 si g nifica nt fi g ures. 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
Descri pti ve statistics of P K para m eter d ata will be calc ulate d usi n g f ull precisi o n a n d r o u n de d f or 
re p orti n g p ur p oses o nl y. 
P K para meters will be pr o vi de d wit h f ull precisi o n, wit h o ut a n y r o u n di n g a p plie d  t o C DI S C S D T M 
P P a n d A Da M P P d o mai ns.  
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 para meter 
d ata: 
n : 
0 deci mal place  
Mea n, Mi n, Me dia n, Ma x , S D, 
Ge o Mea n, 9 5 % CI:  
3 si g nifica nt di gits  
C V %, Ge o C V %:  
1 deci mal place  
1 6. 1. 3  
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 o cc ur bef ore t he dr u g a d mi nistrati o n will be assi g n e 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 dr u g a d mi nistrati o n. 
Val ues bel o w t he l o w er li mit of q ua ntificati o n ( B L Q) 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 dat a, P K para m eter esti mati o n (e. g. A U C) a n d f or gra p hical pres e ntati o ns. It 
is e x pecte d t hat sa m ples wit h c o nce ntrati o ns a b o v e t he U L O Q will be dil ute d a n d ret este d. 
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 n al yses u p t o t he ti me of disc o nti n uati o n. 
Sa m ples t hat are c ollecte d o utsi de t he s pecifie d ti me wi n d o ws s pecifie d i n t he C S P  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 c o nce ntrati o n pl ots.  
P K c o nce ntr ati o ns w hic h are err o ne o us d ue t o a pr ot oc ol vi olati o n (as defi ne d i n t he C S P), 
sa m pli n g pr ocessi n g or a nal yti cal err or (as d oc u me nte d i n t he bi oa nal ytical re p ort) ma y b e 
e x cl u de d fr o m t he P K a nal ysis if a gree d b y t he S p o ns or. I n t his case t he rati o nale f or e x cl usi o n 
m ust be pr o vi de d i n t he C S R. A n y ot her P K c o nce ntrati 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 pla usi ble 
data will be d oc u me nte d i n t he C S R.  
If sa m ples are c ollecte d o utsi de of 1 0 % of its n o mi nal ti me p oi nt, 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 n ce ntrati o n pl ots.  
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 
s u bject 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 ote or 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
a ta ble of e x cl usi o ns). A n y fl a gs s h o ul d be i ncl u d e d i n t he st u d y s pecific S D T M a n d A Da M d ata 
sets. 
P K c o nce ntr ati o ns a n d P K para meters e x cl u de d f or m s u m mar y statistics will n ot be i ncl u de d i n 
c o m bi ne d i n di vi d ual a n d mea n fi g ures. M ea n pl ots will o nl y c o ntai n a v era ges w he n n > 2.  
1 6. 1. 4  
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, or hi g her ( Certara, L. P., Pri ncet o n, 
Ne w J erse y,  U S A) will be use d t o deri ve P K para meters a p pl yi n g n o n -c 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, S A S -I nstit ute, Car y N C, U S A, 
wi n d o ws versi o n 9. 4  or hi g her) ma y b e use d t o ge n erate a d di ti o nal P K para meters, pr o d uce ta bles, 
listi n gs a n d fi g ures. 
1 6. 1. 4. 1  
Esti m ati o n of P h ar m ac o ki netic P ar a meters i n  P l as m a  
P K para meters will be cal c ulate d usi n g t he act ual el a pse d ti me si nc e d osi n g, gi ve n wit h a precisi o n 
of 4 deci mal places  or t he S A S f or mat Best 1 2. I n cases w here t he act ual sa m pli n g ti me is missi n g, 
calc ulati o ns will be perf or me d usi n g t he sc h e d ule d ti me. 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 P K para meters will be calc ulat e d w here a p pr o priat e fr o m x e vi na pa nt a n d its 
meta b olite D -1 1 4 3 -M E T 1 plas ma c o nce ntrati o ns:  
S y m b ol  
Defi niti o n  
A U C 0 -tlast 
T he area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me zer o ( = d osi n g 
ti me) t o t he last sa m pli n g ti me (t last) at w hic h t he c o nce ntr ati o n is at or a b o ve 
t he l o wer li mit of q ua ntificati o n. Calc ulate d usi n g t he mi x e d l o g-li near 
tra pez oi dal r ule (li near u p, l o g d o w n). 
A U C 0 - 
T he A U C fr o m ti me zer o ( d osi n g ti me) e xtra p olate d t o i nfi nit y, base d o n  t he 
pre dicte d val ue f or t he c o nce ntr ati o n at t last , as esti mate d usi n g t he li near 
re gressi o n fr o m λz deter mi nati o n. A U C 0 -∞= A U C 0 -t+ C last pre d/ λz. 
A U C 0 -2 4 
T he area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me zer o ( = dosi n g 
ti me) t o 2 4 h o urs. Calc ulate d usi n g t he mi x e d l o g-li near tr a pez oi dal r ule (li near 
u p, l o g d o w n).  
A U C e xtra %  
T he 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 C e xtra %  = (e xtra p olate d area/ A U C 0 -∞) * 1 0 0. 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
S y m b ol  
Defi niti o n  
C L/ F  
T he a p pare nt t otal 
b o d y cleara n ce 
of st u d y i nter ve nti o n f oll o wi n g 
e xtra vasc ular a d mi nistrati o n, ta ki n g i nt o acc o u nt t he fracti o n of d ose a bs or be d.  
C L/ F  = D ose p. o. / A U C0 -∞ (x e vi na pa nt o nl y).  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n . 
tma x  
T he ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n c ollecte d d uri n g a 
d osi n g i nter val ( u nless ot her wise defi ne d, ta ke t h e 1 st occ urre n ce i n case of 
m ulti ple/i de ntical C ma x  val ues) . 
tlast 
T he last sa m pli n g ti me at w hic h t he c o nce ntr ati o n is at or a b o ve t he l o wer li mit 
of q ua ntificati o n . 
C last 
T he o bser ve d c o nce ntr ati o n at t he last sa m pli n g ti me (t last) at w hic h t he 
c o nce ntr ati o n is at or a b o ve t he l o wer li mit of q ua ntificati o n . 
t1/ 2 
A p pare nt ter mi nal half -life. t1/ 2  = l n ( 2)/ λ z. 
z 
Ter mi nal first or der (eli mi nati o n) rate c o nsta nt. Deter mi ne d fr o m t he ter mi nal 
sl o pe of t he l o g-tra nsf or me d c o nce ntrati o n c ur ve usi n g li near re gressi o n o n 
ter mi nal data p oi nts of t he c ur ve. 
V z/ F 
T he a p p are nt v ol u me of distri b uti o n d uri n g t he ter mi nal p has e f oll o wi n g 
e xtra vasc ular a d mi nistrati o n, base d o n t he fracti o n of d ose a bs or be d. V z/ F = 
D ose/( A U C 0 -∞* λ z) f oll o wi n g si n gle d ose (x e vi na pa nt o nl y).  
M R( A U C
0 -tlast) Meta b olic rati o of A U C
0 -tlast. A U C0 -tlast f or D -1 1 4 3 -M E T 1 
di vi de d b y t he 
A U C 0 -tlast of x e vi na pa nt c orrect e d f or M W.  
M R( A U C
0 -tlast) = A U Cxe vi na pa nt* M W xe vi na pa nt/ A U CD -1 1 4 3 -M E T 1 * M W D -1 1 4 3 -M E T 1  
w here M W
xe vi na pa n t = 5 6 1. 7 1 g/ m ol M W
D -1 1 4 3 -M E T 1  a n d = 4 7 6. 6 1 g/ m ol  
M R( A U C
0 -) 
Meta b olic rati o of A U C
0 -. A U C0 - f or D -1 1 4 3 -M E T 1 di vi de d b y t h e A U C 0 - 
of x e vi na pa nt c orrecte d f or M W.  
M R( A U C
0 -) = A U Cxe vi na pa nt* M W xe vi na pa nt/ A U CD -1 1 4 3 -M E T 1 * M W D -1 1 4 3 -M E T 1  
w here M W
xe vi na pa n t = 5 6 1. 7 1 g/ m ol M W
D -1 1 4 3 -M E T 1  a n d = 4 7 6. 6 1 g/ m ol  
M R( C
ma x ) 
Meta b olic rati o of C
ma x . Cma x  f or D -1 1 4 3 -M E T 1  di vi de d b y t he C ma x of 
x e vi na pa nt  c orrecte d f or M W. 
M R( C
ma x ) = Cma x x e vi na pa nt * M W x e vi na pa nt /C ma x D -1 1 4 3 -M E T 1 * M W D -1 1 4 3 -M E T 1  
w here M W
xe vi na pa n t = 5 6 1. 7 1 g/ m ol M W
D -1 1 4 3 -M E T 1  a n d = 4 7 6. 6 1 g/ m ol  
Partial areas s h o ul d be calc ulate d usi n g t he n o mi nal d osi n g i nter val. T he act ual d osi n g i nter val 
calc ulate d fr o m cas e re p ort f or m ( C R F ) ti me data s h o ul d n ot be use d. 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
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 ( λ z l o w) a n d last (λ z 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 λ z. 
•  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 ness of fit statistic ( a dj uste d Rs q) f or calc ulati o n of λ z. 
•  S pa n rati o . 
T he re gressi o n a nal ysis s h o ul d c o ntai n data fr o m a t 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 be use d as sta n dar d. 
H o we ver, i n s o me cases, f urt her 
a dj ust me nt ma y be ma de b y t he p har mac o ki n eticist, if warra nte d, aft er a gree me nt wit h  t he 
S p o ns or.  T he last q ua ntifia ble c o nce ntrati o n s h o ul d al wa ys b e i ncl u de d i n t he re gressi o n a n al ysis, 
w hile t he c o n ce ntrati o n at t ma x  a n d a n y c o n ce ntrati o ns < L L O Q w hic h occ ur after t he l ast 
q ua ntifia ble data p oi nt s h o ul d n ot be use d.  
If A U Ce xtra %> 2 0 % a n d/ or t he c oefficie nt of c orrelati o n ( R s q a dj) of λ z 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 is less t ha n t w o-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. t1/ 2, A U C 0 -, C L/ F etc.) will be will be liste d, 
fla g ge d a n d i ncl u d e d i n t he para m eter o ut p uts a n d ma y b e e x cl u de d fr o m d escri pti ve statistics . 
I n case pr ofiles ha v e a meas ura ble pre -d ose c o n ce ntrati o n less t ha n or e q ual t o 5 % of its C ma x  
val ue, t he p artici pa nt ’s d ata wit h o ut a n y a dj ust me nts will be i ncl u de d i n all P K meas ure me nts a n d 
calc ulati o ns. If t he pre -d ose val ue is greater t ha n 5 % of t he C ma x , t he partici p a nt will be dr o p pe d 
fr o m all P K e val uati o ns. H o we ver, t his partici pa nt ’s data will be fla g ge d a n d re p orte d. 
1 6. 1. 5  
St atistic al A n al ysis of P K P ar a meter D at a   
N o f or mal statistical a nal ys is of P K para meter dat a is pla n ne d. 
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 w i n g P K ta bl es will be pr o d uce d bas e d o n t he P K  A nal ysis S et: 
•  Descri pti ve statisti cs of c o nce ntrati o ns b y a nal yte  a n d et h nic gr o u p (Ja pa nese, 
n o n -J a pa nese East Asia n a nd o verall)  
•  Descri pti ve statist ics of P K para m eters b y a nal yt e a n d et h nic gr o u p (Ja pa nese, 
n o n -J a pa nese East Asia n a n d o verall) 
T he f oll o wi n g P K l isti n gs will be pr o d uce d bas e d o n t he Safet y A nal ysis Set : 
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
•  I n di vi d ual c o n ce ntr ati o ns b y a n al yt e a n d et h nic gr o u p  
•  I n divi d ual P K para meters b y a n al yt e  a n d et h nic gr o u p  
•  I n di vi d ual dia g n ostic P K para meters b y a nal yte  a n d et h nic gr o u p  
•  P K Sa m pli n g date, act ual ti me, n o mi nal ti me, de viati o n fr o m ti me a n d c o nce ntrati o n b y 
partici pa nt , a nal yte a n d et h nic gr o u p s orte d i n c hr o n ol o gical or der  
•  P h oe ni x Wi n N o nli n N C A C ore O ut p ut  
I n a d diti o n, t he rati o of P K para meters bet wee n t he et h nic cat e g ories fr o m t his st u d y a n d fr o m 
hist orical data fr o m healt h y partici pa nt st u dies i n n o n -Asia n partici pa nts m a y als o be esti mate d. 
T hese i nt e grat e d a nal yses acr oss st u dies will be s pecifie d i n a se p arat e I nt e grate d A nal ysis Pla n 
a n d n ot i ncl u de d i n t he C S R.  
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 ots ( P K A n al ysis Set )  
T he f oll o wi n g P K pl ots  will be pr o d uce d bas e d o n t he P K A nal ysis Set:  
•  O verlai d i n di vi d ual c o nce ntrati o n vers us act ual ti me p ost d ose  pl ots; li near a n d se mi -l o g; 
b y a n al yt e a n d et h nic gr o u p  
•  Arit h metic mea n c o nce ntrati o n ti me pl ots; li near wit h sta n dar d de viati o n a n d se mi -l o g 
wit h o ut sta n dar d d e viati o n ; usi n g s c he d ule d ( n o mi nal) ti me p oi nts b y a n al yte a n d et h nic 
gr o u p (J a pa nes e, n o n -J a pa nese East Asia n a n d o v erall); if a n y p ost-d os e c o nce ntrati o n is 
< L L O 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 P K para met ers ( A U C 0 -tlast, A U C 0 - a n d C ma x ) b y a n al yt e a n d et h nic gr o u p 
1 7  
Refere nces   
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI


Xe vi n a p a nt  
P h ase 1 P K St u d y i n He alt h y E ast Asi a n P artici p a nts  
M S 2 0 2 3 5 9 _ 0 0 0 4  
v 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 5  
 
 
1 8  
A p pe n dices   
N ot a p plica ble.  
 
Gl o bal Versi o n I D: C CI