A Phase I, Open-Label, Two-Part Study of the Effect of Multiple-Dose Evobrutinib on Transporter Substrates Digoxin, Metformin, Rosuvastatin, and Sumatriptan Pharmacokinetics in Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 4
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 P hase I, O pe n -La bel, T w o -Part St u d y  of t he 
Effect 
of 
M ulti ple -D ose 
E v o br uti ni b 
o n 
Tra ns p orter 
S u bstrates 
Di g o xi n, 
Metf or mi n, 
R os u vastati n, a n d S u matri pta n P har mac o ki netics 
i n Healt h y Partici pa nts
St u d y N u m ber:
M S 2 0 0 5 2 7 _ 0 0 7 8
Pr ot oc ol Versi o n:
2 4 A u g ust 2 0 2 1/ Versi o n 2. 0
Merc k C o m p o u n d :
E v o br uti ni b ( M 2 9 5 1)
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:
P hase I
S h ort Title:
Dr u g -Dr u g I nteracti o n St u d y  of E v o br uti ni b o n 
Tra ns p orter S u bstrates
Pri nci pal I n vesti gat or:
N u visa n G m b H,
Ne u -Ul m, Ger ma n y
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
S p o ns or:
Affiliates of Merc k K Ga A, Dar msta dt, Ger ma n y
F or all c o u ntries, e xce pt t he U S a n d Ca na da:
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. 2 5 0
6 4 2 9 3, Dar msta dt, 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 dra C T: 2 0 2 1- 0 0 1 9 2 3- 4 2
Ke y w or ds

Cli nical P har mac ol o g y
Pr ot oc ol Hist or y
V er si o n N u m b er
T y p e
V er si o n D at e
1. 0
Ori gi n al Pr ot o c ol
1 3 J ul 2 0 2 1
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D
P P D

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 4
Pr ot oc ol Versi o n ( 2 4- A u g ust - 2 0 2 1)
O ver all R ati o n ale f or t he A me n d me nt
T his pr ot oc ol a me n d me nt was r e q ueste d b y  t he Ger ma n c o m pete nt a ut h orit y an d i n v ol ve d Et hics 
C o m mittees .
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
4. 4 E n d of St u d y 
D efi niti o n
E dit ori al c h a n g e
T o c orr e ct a t y p o.
5 St u d y P o p ul ati o n ;
A p p e n di x 2 St u d y 
G o v er n a n c e
D el eti o n of “ or t h e p arti ci p a nt’ s l e g al / 
hi s/ h er(t h eir) l e g all y a ut h ori z e d
r e pr e s e nt ati v e ( w h er e all o w e d b y l o c al 
l a w s a n d r e g ul ati o n s)”.
It i s n ot all o w e d i n G er m a n y t h at p er s o n s 
wit h a l e g all y a ut h ori z e d r e pr e s e nt ati v e
p arti ci p at e i n t h e st u d y.
5. 2 E x cl u si o n Crit eri a
Mi gr ai n e w a s a d d e d t o e x cl u si o n 
crit eri o n n u m b er 1.
T o cl arif y t h at p arti ci p a nt s wit h a hi st or y of 
di a g n o s e d mi gr ai n e s h o ul d n ot b e i n cl u d e d 
i n t h e st u d y.
I n e x cl u si o n crit eri o n 1 7 it w a s cl arifi e d 
t h at p arti ci p a nt s wit h a m yl a s e a n d li p a s e 
v al u e s o ut of t h e n or m al r a n g e a n d n ot 
a s pr e vi o u sl y gr e at er t h a n 2 × t h e u p p er 
li mit of n or m al w o ul d b e e x cl u d e d fr o m 
t h e st u d y. 
T o mi ni mi z e t h e a d diti o n al ri s k of 
p a n cr e atiti s o b s er v e d wit h r o s u v a st ati n.
8. 3 A d v er s e E v e nt s, 
S eri o u s A d v er s e 
E v e nt s, a n d Ot h er 
S af et y R e p orti n g ; 
A p p e n di x 4 A d v er s e 
E v e nt s: D efi niti o n s a n d 
Pr o c e d ur e s f or 
R e c or di n g, E v al u ati n g, 
F oll o w -u p, a n d 
R e p orti n g
It w a s cl arifi e d t h at s eri o u s a d v er s e 
e v e nt s a n d a d v er s e e v e nt s of s p e ci al 
i nt er e st h a v e t o b e r e p ort e d t o t h e 
S p o n s or or d e si g n e e i m m e di at e l y.
T o m e et t h e r e q uir e m e nt s of t h e G er m a n 
c o m p et e nt a ut h orit y.
8. 4 P h ar m a c o ki n eti c s
T a bl e 4  P K S a m pli n g Ti m e Wi n d o w s: 
“ 5” a d d e d b ef or e “ mi n” u n d er ti m e p oi nt 
> 1 t o 1 2 h o ur s p o st d o s e .
T o c orr e ct a t y p o.
- 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 1 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.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 4
T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
Ta ble of C o nte nts
.............................................................................................................. 3
Ta ble of Ta bles
.............................................................................................................. 6
1
Pr ot oc ol S u m mar y ................................................................................ 7
1. 1
S y n o psis ................................................................................................ 7
1. 2
Sc he ma .................................................................................................. 9
1. 3
Sc he d ule of Acti vities ......................................................................... 1 0
2
I ntr o d ucti o n......................................................................................... 1 4
2. 1
St u d y  Rati o nale................................................................................... 1 4
2. 2
Bac k gr o u n d ......................................................................................... 1 4
2. 3
Be nefit/ Ris k A ssess me nt .................................................................... 1 5
2. 3. 1
Ris k Assess me nt ................................................................................. 1 6
2. 3. 1. 1
P ote ntial Ris ks ass ociate d wit h t he C O VI D -1 9 Pa n de mic Sit uati o n .. 1 9
2. 3. 2
Be nefit Assess me nt ............................................................................. 2 0
2. 3. 3
O verall Be nefit: Ris k C o ncl usi o n ....................................................... 2 0
3
O bjecti ves a n d E n d p oi nts ................................................................... 2 1
4
St u d y  Desi g n....................................................................................... 2 2
4. 1
O verall Desi g n .................................................................................... 2 2
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 2 2
4. 2. 1
Partici pa nt I n p ut i nt o Desi g n .............................................................. 2 3
4. 3
J ustificati o n f or D ose .......................................................................... 2 3
4. 4
E n d of St u d y  Defi niti o n...................................................................... 2 4
5
St u d y  P o p ulati o n................................................................................. 2 4
5. 1
I ncl usi o n Criteria ................................................................................ 2 5
5. 2
E xcl usi o n Criteria ............................................................................... 2 7
5. 3
Lifest y le C o nsi derati o ns..................................................................... 3 1
5. 3. 1
Meals a n d Dietar y  Restricti o ns........................................................... 3 1
5. 3. 2
Caffei ne, Alc o h ol, T o bacc o, a n d Ca n na bi n oi d ................................... 3 2
5. 3. 3
Acti vit y ............................................................................................... 3 2
5. 4
Scree n Fail ures .................................................................................... 3 2
5. 5
Criteria f or Te m p oraril y Dela y i n g t he A d mi nistrati o n of St u dy 
I nter ve nti o n A d mi nistrati o n................................................................ 3 2
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
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6
St u d y  Inter ve nti o n(s) a n d C o nc o mita nt T hera pies............................. 3 2
6. 1
St u d y  Inter ve nti o n(s) A d mi nistrati o n ................................................. 3 3
6. 2
St u d y  Inter ve 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 ..................................................................................... 3 4
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt a n d 
Bli n di n g.............................................................................................. 3 4
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt .......................................................... 3 4
6. 3. 2
Bli n di n g.............................................................................................. 3 5
6. 3. 3
E mer ge nc y  U n bli n di n g....................................................................... 3 5
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 3 5
6. 5
D ose M o dificati o n .............................................................................. 3 5
6. 5. 1
Retreat me nt Criteria ............................................................................ 3 5
6. 6
C o nti n ue d Access t o St u d y  Inter ve nti o n after t he E n d of t he St u d y .. 3 5
6. 7
Treat me nt of O ver d ose ....................................................................... 3 5
6. 8
C o nc o mita nt T hera p y......................................................................... 3 6
6. 8. 1
Resc ue Me dici ne ................................................................................. 3 6
6. 8. 2
Per mitte d Me dici nes ........................................................................... 3 6
6. 8. 3
Pr o hi bite d Me dici nes .......................................................................... 3 6
6. 8. 4
Ot her I nter ve nti o ns ............................................................................. 3 7
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ............................................................... 3 7
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 3 7
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 7
7. 3
L ost t o F oll o w -U p ............................................................................... 3 8
8
St u d y  Assess me nts a n d Pr oce d ures.................................................... 3 9
8. 1
Efficac y  Assess me nts a n d Pr oce d ures................................................ 4 0
8. 2
Safet y  Assess me nts a n d Pr oce d ures................................................... 4 0
8. 2. 1
P h y sical E xa mi nati o ns ........................................................................ 4 0
8. 2. 2
Vital Si g ns .......................................................................................... 4 0
8. 2. 3
Electr ocar di o gra ms ............................................................................. 4 0
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts............................................ 4 0
8. 3
A d verse E ve nts, Seri o us A d verse E ve nts, a n d Ot her Safet y 
Re p orti n g............................................................................................ 4 1
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... 4 2
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
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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 ............... 4 2
8. 3. 3
Re g ulat or y  Re p orti n g Re q uireme nts f or Seri o us A d verse E ve nts ..... 4 2
8. 3. 4
Pre g na nc y ........................................................................................... 4 3
8. 3. 5
Car di o vasc ular a n d Deat h E ve nts....................................................... 4 3
8. 3. 6
Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
Q ualif yi n g as A Es or S A Es ................................................................ 4 3
8. 3. 7
A d verse E ve nts of S pecial I nterest ..................................................... 4 3
8. 4
P har mac o ki netics ................................................................................ 4 5
8. 6
Bi o mar kers .......................................................................................... 4 7
8. 7
I m m u n o ge nicit y Assess me nts ............................................................ 4 7
9
Statistical C o nsi derati o ns .................................................................... 4 7
9. 1
Statistical H y p ot heses ......................................................................... 4 8
9. 3
A nal y ses Sets ...................................................................................... 4 9
9. 4
Statistical A nal y ses ............................................................................. 5 0
9. 4. 1
Efficac y  A nalys es ............................................................................... 5 0
9. 4. 2
Safet y  A nalys es .................................................................................. 5 0
9. 4. 3
Ot her A nal ys es .................................................................................... 5 1
9. 4. 4
Se q ue nce of A nal ys es ......................................................................... 5 2
1 0
Refere nces ........................................................................................... 5 3
1 1
A p pe n dices ......................................................................................... 5 5
A p pe n di x 1
A b bre viati o ns ...................................................................................... 5 6
A p pe n di x 2
St u d y  G o ver na nce............................................................................... 5 8
A p pe n di x 3
C o ntrace pti o n a n d Barrier Re q uire me nts ........................................... 6 3
A p pe n di x 4
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g ................................................ 6 5
A p pe n di x 5
Cli nical L a b orat or y Tests ................................................................... 7 1
A p pe n di x 7
S p o ns or Si g nat ure Pa ge...................................................................... 7 3
A p pe n di x 8
Pri nci pal I n vesti gat or Si g nat ure Pa ge ................................................. 7 4
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 7 4
T a ble of T a bles
Ta ble 1
Part 1: P K Sa m pli n g Sc he d ule ............................................................ 1 1
Ta ble 2
Part 2: P K Sa m pli n g Sc he d ule ............................................................ 1 3
Ta ble 3
S u m mar y  of Dr u g Tra ns p orters a n d T heir I n de x S u bstrates.............. 1 5
Ta ble 4
P K Sa m pli n g Ti me Wi n d o ws ............................................................. 4 6
Ta ble 5
I ntra-S u bject Varia bilit y  ( C V) f or 1 0 m g  Metf or mi n, 0. 2 5 m g 
Di g o xi n, 1 0 m g R os u vastati n a n d 2 5 m g S u matri pta n P K 
Para meters ........................................................................................... 4 8
Ta ble 6
E x pecte d Precisi o n f or t he Esti mate d Rati o of Ge o metric Mea ns ..... 4 9
Ta ble 7
A nal y sis Sets....................................................................................... 4 9
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 7 4
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Title: A P hase I, O pe n -La bel, T w o -Part St u d y  of t he Effect of M ulti ple -D ose 
E v o br uti ni b o n Tra ns p orter S u bstrates Di g o xi n, Metf or mi n, 
R os u vastati n, a n d S u matri pta n 
P har mac o ki netics i n Healt h y  Partici pa nts
S h ort Title: Dr u g -Dr u g I nteracti o n St u d y  of E v o br uti ni b o n Tra ns p orte r S u bstrates
R ati o n ale: T he res ults of n o ncli nical st u dies wit h e v o br uti ni b ha ve i n dicate d t he p ote ntial f or 
e v o br uti ni b t o be a n i n hi bit or of se veral dr u g tra ns p orters (e. g., or ga nic cati o n tra ns p orter 1 
[O C T 1] , P- gl yc o pr otei n [ P-g p ], m ulti dr u g a n d t o xi n e xtr usi o n [M A T E ]1/ M A T E 2 -K, breast ca ncer 
resista nce pr otei n [ B C R P]).
T he i nte nt of t his st u d y is t o pr o vi de i nf or mati o n pertai ni n g t o t he effect of e v o br uti ni b o n 
tra ns p orter acti vit y in h u ma ns usi n g dr u g tra ns p orter s u bstrates. T he selecte d dr u g tra ns p orter 
s u bstrates are well c haracterize d a n d ha ve bee n esta blis he d as sel ecti ve s u bstrates t hat are 
c o m m o nl y use d i n cli nical dr u g -dr u g i nteracti o n (D DI ) st u dies a n d, e xce pt f or s u matri pta n 
( O C T 1), are c o nsi dere d as i n de x s u bstrates i n t he m ost rece nt u p date of t he F o o d a n d Dr u g 
A d mi nistrati o n (F D A ) g ui da nce a n d E ur o pea n Me dicines A ge nc y  ( E M A) g ui deli ne.
Res ults of t his st u d y ma y be use d t o ma ke f ut ure rec o m me n dati o ns re gar di n g t he c o nc o mita nt 
a d mi nistrati o n of s pecific tra ns p orter s u bstrates wit h e v o br uti ni b.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 7 4
O bjecti ves a n d E n d p oi nts:
O bjecti ves
E n d p oi nts
Pri mar y
T o i n vesti gate t he effect of m ulti ple d oses of 
e v o br uti ni b o n si n gle d oses of di g o xi n, 
metf or mi n, a n d r os u vastati n ( Part 1), a n d 
s u matri pta n ( Part 2) P K i n healt h y  partici pa nts

Plas ma tra ns p orter s u bstrates A U C 0 - ∞a n d 
C ma x
Sec o n dar y
T o assess t he safet y a n d t olera bilit y of 
e v o br uti ni b w he n a d mi nistere d t o get her wit h 
di g o xi n, metf or mi n, a n d r os u vastati n ( Part 1), 
a n d s u matri pta n ( Part 2) i n healt h y partici pa nts

Nat ure, o cc urre nce, a n d se verity of 
T E A Es

A bs ol ute val ues a n d c ha n ges i n safety 
la b orat or y tests 

Si n gle 1 2- lea d E C Gs e val uate d b y 
I n vesti gat or, a n d 

V ital si g ns assesse d fr o m ti me of first 
d ose t o en d of st u d y partici pati o n
T o c haracterize t he effect of e v o br uti ni b o n 
di g o xi n, metf or mi n, a n d r os u vastati n ( Part 1), 
a n d s u matri pta n ( Part 2) sec o n dar y  P K 
para meters i n healt h y partici pa nts

Plas ma P K para meter s ( Part 1 a n d Part 2): 
tma x , t½ , a n d A U C0- tlast, C L/ F , a n d V Z / F 

Uri ne P K para meters ( Part 1, metf or mi n 
o nl y ): Ae 0 -3 6 a n d C L R
C L/ F = a p p ar e nt t ot al b o d y cl e ar a n c e , C LR =r e n al cl e ar a n c e, E C G = el e ctr o c ar di o gr a m, P K = p h ar m a c o ki n eti c s, 
T E A E =tr e at m e nt -e m er g e nt a d v er s e e v e nt , VZ / F= a p p ar e nt v ol u m e of di stri b uti o n.
O ver all Desi g n: T his will be a n o nra n d o mize d, o pe n -la bel, si n gle-se q ue nce, t w o-part P hase I 
st u d y i n 4 0 healt h y partici pa nts ( 2 0 per part).
Brief S u m m ar y:
T he p ur p ose of t his st u d y is t o i n vesti gate t he effect of m ulti ple d oses of e v o br uti ni b o n si n gle 
d oses of di g o xi n, metf or mi n, a n d r os u vastati n ( Part 1), a n d s u matri pta n ( Part 2) P K i n healt h y 
partici pa nts . St u d y details i ncl u de:

St u d y  D urati o n: u p t o 6 wee ks f or eac h part

Treat me nt D urati o n: 1 2 da y s ( Part 1), 8 da ys ( Part 2)

Visit Fre q ue nc y : Part 1: Partici pa nts will be resi de nt i n t he Cli nical Researc h U nit ( C R U)
fr o m Da y -1 t o Da y  1 3; Part 2: Partici pa nts will be resi de nt i n t he C R U fr o m Da y  -1 t o 
D a y  9
N u m ber of P artici p a nts: Part 1 : A ma xi m u m of 2 0 partici pa nts will be 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 16 e val ua ble partici pa nts c o m plete t he st u d y. Part 2: A 
ma xi m u m of 2 0 partici pa nts will be assi g ne d t o st u d y inter ve nti o n s uc h t hat a p pr o xi matel y 
1 6 e val ua ble partici pa nts c o m plete t he st u d y .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 7 4
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: 1 2 da y s ( Part 1), 8 da y s ( Part 2), si n gle-se q ue nce 
st u d y (eac h part)
I n v ol ve me nt of S peci al C o m mittee(s): N o
1. 2
Sc he m a
P K = p h ar m a c o ki n eti c.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
1. 3
Sc he d ule of Acti vities
P art 1: Sc he d ule of Assess me nts
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
I nt er v e nti o n P eri o d ( D a ys)
S af et y  
F oll o w -u p
N ot e s
St u d y  D a y
-2 8 t o - 2 
- 1 
1 
2 
3 
4 
5 
6 
7 
8
9
1 0
1 1
1 2
1 3
I nf or m e d c o n s e nt
X
Pri or t o a n y S cr e e ni n g a cti vit y.
P arti ci p a nt s r e si d e nt at C R U
< ----------------------------------------------------------------------------------------------------- >
Eli gi bilit y crit eri a
X 
X
F or r e -c h e c k of eli gi bilit y crit eri a 
o n D a y -1, S e cti o n s 5. 1
a n d 5. 2 ).
D e m o gr a p h y, h ei g ht & 
w ei g ht, m e di c al hi st or y
X
D e m o gr a p h y t o i n cl u d e, at 
mi ni m u m, a g e, s e x, r a c e, a n d 
et h ni cit y.
P h y si c al e x a mi n ati o n
X 
X
X
Bri ef e x a mi n ati o n o n D a y -1 t o 
c h e c k eli gi bilit y.
S er u m pr e g n a n c y t e st
X 
X
X
Vir al s er ol o g y, T S H a n d 
Q u a nti F E R O N ® t e st
X
Cli ni c al l a b or at or y t e st s
X 
X
X
X
D et ail s i n  A p p e n di x 5 .
C oti ni n e, dr u g s cr e e n, 
al c o h ol br e at h t e st, 
S A R S -C o V -2 a n d F S H
X 
X
F S H i n p o st m e n o p a u s al w o m e n 
at S cr e e ni n g o nl y.
E C G & vit al si g n s
X 
X 
X
X
X
Pr e d o s e, 4 a n d 6 h o ur s aft er 
c o c kt ail a d mi ni str ati o n o n D a y s 
1 a n d 1 0.
Di g o xi n, m etf or mi n, 
r o s u v a st ati n a d mi ni str ati o n
X
X
Si n gl e d o s e, f e d c o n diti o n s
(S e cti o n s  5. 3. 1 a n d  6. 1 ).
Bl o o d c oll e cti o n d i g o xi n, 
m etf or mi n, r o s u v a st at i n
X 
X 
X 
X
X 
X 
X 
X
T a bl e 1 a n d S e cti o n  8. 4 .
Uri n e c oll e cti o n f or
m etf or mi n a n al y si s
X 
X
X 
X
T a bl e 1 a n d S e cti o n  8. 4 .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
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
I nt er v e nti o n P eri o d ( D a ys)
S af et y  
F oll o w -u p
N ot e s
St u d y  D a y
-2 8 t o - 2 
- 1 
1 
2 
3 
4
5
6 
7 
8 
9
1 0 
1 1
1 2
1 3
E v o br uti ni b a d mi ni str ati o n
X 
X 
X 
X 
X 
X 
X 
X 
X
T wi c e d ail y, f e d c o n diti o n s 
(S e cti o n s  5. 3. 1 a n d  6. 1 ).
P K bl o o d s a m pl e e v o br uti ni b
X 
X 
X
T a bl e 1 a n d S e cti o n  8. 4 .
A E/ c o n c o mit a nt m e di c ati o n 
r e vi e w 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
X
A E = a d v er s e e v e nt s , C R U = cli ni c al r e s e ar c h u nit, E C G = el e ctr o c ar di o gr a m , F S H =f olli cl e sti m ul ati n g h or m o n e , P K = p h ar m a c o ki n eti c s , S A R S -C o V -2 = s e v er e a c ut e 
r e s pir at or y s y n dr o m e c or o n a vir u s t y p e 2, T S H =t h yr oi d sti m ul ati n g h or m o n e.
T a ble 1
P art 1: P K S a m pli n g Sc he d ule
S a m pl e t y p e
D a y 1
D a y 2
D a y 3
D a y 4
D a y 1 0
D a y 1 1
D a y 1 2
D a y 1 3
Bl o o d s a m pli n g 
ti m e s (tr a n s p ort er 
c o c kt ail)
Pr e d o s e,
0. 3 3, 0. 6 7, 1, 1. 5, 2, 
3, 4, 6, 8, 1 0, 1 2, 
1 6 h o ur s p o st d o s e
2 4, 3 6 h o ur s
p o st d o s e
4 8, 6 0 h o ur s
p o st d o s e
7 2 h o ur s
p o st d o s e
Pr e d o s e
0. 3 3, 0. 6 7, 1, 1. 5, 2, 
3, 4, 6, 8, 1 0, 1 2, 
1 6 h o ur s p o st d o s e
2 4, 3 6 h o ur s
p o st d o s e
4 8, 6 0 
h o ur s
p o st d o s e
7 2 h o ur s
p o st d o s e
Uri n e s a m pli n g 
i nt er v al s
( m etf or mi n)
Pr e d o s e, 
0 t o 4, 
4 t o 8, 
8 t o 1 2 h o ur s 
p o st d o s e
1 2 t o 2 4 , 
2 4 t o 
3 6 h o ur s 
p o st d o s e
Pr e d o s e, 
0 t o 4, 
4 t o 8, 
8 t o 1 2 h o ur s
p o st d o s e
1 2 t o 2 4 , 
2 4 t o 3 6 
h o ur s
p o st d o s e
Bl o o d s a m pli n g 
ti m e s ( e v o br uti ni b)
1 h o ur a
1 h o ur a
1 h o ur a
N ot e: f or a s s o ci at e d s a m pli n g ti m e wi n d o w s s e e S e cti o n  8. 4 (T a bl e 4 ).
a 
P o st m or ni n g e v o br uti ni b d o s e.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D:
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
P art 2: Sc he d ule of Assess me nts
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
I nt er v e nti o n P eri o d ( D a ys)
S af et y  
F oll o w -u p
N ot e s
St u d y  D a y
-2 8 t o - 2 
- 1 
1 
2 
3 
4 
5 
6 
7 
8 
9
I nf or m e d c o n s e nt
X
Pri or t o a n y S cr e e ni n g a cti vit y.
P arti ci p a nt s r e si d e nt i n t h e 
C R U
< --------------------------------------------------------------------- >
Eli gi bilit y crit eri a
X 
X
F or r e -c h e c k of eli gi bilit y crit eri a o n D a y -1, 
S e cti o n s 5. 1 a n d 5. 2 .
D e m o gr a p h y, h ei g ht & 
w ei g ht, m e di c al hi st or y
X
D e m o gr a p h y t o i n cl u d e, at mi ni m u m, a g e, s e x, 
r a c e, a n d et h ni cit y.
P h y si c al e x a mi n ati o n
X 
X
X
Bri ef e x a mi n ati o n o n D a y -1 t o c h e c k eli gi bilit y.
S er u m pr e g n a n c y t e st
X 
X
X
Vir al s er ol o g y, T S H a n d 
Q u a nti F E R O N ® t e st
X
Cli ni c al l a b or at or y t e st s
X 
X
X
X
D et ail s i n  A p p e n di x 5 .
C oti ni n e, dr u g s cr e e n, 
al c o h ol br e at h t e st, 
S A R S -C o V -2 a n d F S H
X 
X
F S H i n p o st m e n o p a u s al w o m e n at S cr e e ni n g o nl y.
E C G & vit al si g n s
X 
X 
X
X 
X
Pr e d o s e
S u m atri pt a n a d mi ni str ati o n
X
X
Si n gl e d o s e, f e d c o n diti o n s (S e cti o n s 5. 3. 1 a n d
6. 1 ).
P K s a m pl e s s u m atri pt a n
X 
X
X 
X
T a bl e 2 a n d S e cti o n 8. 4 .
E v o br uti ni b a d mi ni str ati o n 
X 
X 
X 
X 
X 
X 
X
T wi c e d ail y, f e d c o n diti o n s ( S e cti o n s  5. 3. 1 a n d 
6. 1 ).
P K bl o o d s a m pl e 
e v o br uti ni b
X 
X 
X
T a bl e 2 a n d S e cti o n 8. 4 .
A E/ c o n c o mit a nt m e di c ati o n 
r e vi e w 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
A E = a d v er s e e v e nt s , C R U = cli ni c al r e s e ar c h u nit, E C G = el e ctr o c ar di o gr a m , F S H =f olli cl e sti m ul ati n g h or m o n e , P K = p h ar m a c o ki n eti c s , S A R S -C o V -2 = s e v er e a c ut e 
r e s pir at or y s y n dr o m e c or o n a vir u s t y p e 2, T S H =t h yr oi d sti m ul ati n g h or m o n e.
D oc u me nt N o
O bject N o.
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
T a ble 2
P art 2: P K S a m pli n g Sc he d ule
S a m pl e t y p e
D a y 1
D a y 2
D a y 6
D a y 7
D a y 8
D a y 9
Bl o o d s a m pli n g ti m e 
(s u m atri pt a n )
Pr e d o s e
0. 3 3, 0. 6 7, 1, 1. 5, 2, 3, 4, 
6, 8, 1 0, 1 2, 1 6 h o ur s
p o st d o s e
2 4 h o ur s
p o st d o s e
Pr e d o s e
0. 3 3, 0. 6 7, 1, 1. 5, 
2, 3, 4, 6, 8, 1 0, 
1 2, 1 6 h o ur s
p o st d o s e
2 4 h o ur s
p o st d o s e
Bl o o d s a m pli n g ti m e
( e v o br uti ni b)
1 h o ur a
1 h o ur a
1 h o ur a
N ot e: f or a s s o ci at e d s a m pli n g ti m e wi n d o w s s e e S e cti o n 8. 4 (T a bl e 4 ).
a 
P o st m or ni n g e v o br uti ni b d o s e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
2
I ntr o d ucti o n
E v o br uti ni b is a n oral, selecti ve, irre versi ble i n hi bit or of B T K w hic h is i n cli nical de vel o p me nt 
f or t he treat me nt of a ut oi m m u ne diseases, i ncl u di n g R M S.
Detaile d i nf or mati o n o n t he c he mistr y, p har mac ol o g y , efficac y, a n d safety of e v o br uti ni b is i n 
t he I B.
T here is e xte nsi ve cli nical e x perie nce i n t he use of t he tra ns p orter s u bstrates di g o xi n, metf or mi n, 
r os u vastati n, a n d s u matri pta n selecte d f or t his st u d y (S hi bata 2 0 2 0, St o pfer 2 0 1 8 ). F ull 
i nf or mati o n a b o ut t he p ote ntial si de effects of t hese tra ns p orter s u bstrates a d mi nistrati o n is 
descri be d i n t he S m P Cs f or t he res pecti ve c o m p o u n ds.
2. 1
St u d y R ati o n ale
T he res ults of n o ncli nical st u dies wit h e v o br uti ni b ha ve i n dicate d t he p ote ntial f or e v o br uti ni b 
t o be a n i n hi bit or of se veral dr u g tra ns p orters (e. g., O C T 1, P- g p, M A T E 2 -K, B C R P).
T he i nte nt of t his st u d y is t o pr o vi de i nf or mati o n pertai ni n g t o t he effect of e v o br uti ni b o n 
tra ns p orter acti vit y i n h u ma ns usi n g dr u g tra ns p orter s u bstrates. T he selecte d dr u g tra ns p orter 
s u bstrates are well c haracterize d (St o pfer 2 0 1 8,  S hi bata 2 0 2 0 ) a n d ha ve bee n esta blis he d as 
selecti ve s u bstrates t hat are c o m m o nl y use d i n cli nical D DI st u dies a n d, e xce pt f or s u matri pta n 
( O C T 1) are c o nsi dere d as i n de x s u bstrates i n t he m ost rece nt u p date of t he F D A g ui da nce a n d 
E M A g ui deli ne.
Res ults of t his st u d y ma y be use d t o ma ke f ut ure rec o m me n dati o ns re gar di n g t he c o nc o mita nt 
a d mi nistrati o n of s pecific tra ns porter s u bstrates wit h e v o br uti ni b.
2. 2
B ac k gr o u n d
E v o br uti ni b (als o k n o w n as M 2 9 5 1 a n d M S C 2 3 6 4 4 4 7 C) is a n oral, selecti ve, a n d irre versi ble 
i n hi bit or of B T K. B T K is a cr ucial i ntracell ular ki nase i n t he B cell a nti ge n rece pt or si g nali n g 
pat h wa y . T he m o de of acti o n of e v o br uti ni b a n d n o ncli nical data s u p p ort cli nical de vel o p me nt 
i n a br oa d s pectr u m of a ut oi m m u ne a n d i nfla m mat or y dis or ders i n v ol vi n g a berra nt B cell a n d 
m y el oi d cell acti vit y. In hi biti o n of B T K is e x pecte d t o ac hie ve pr of o u n d B cell sile nci n g. T h us , 
B T K i n hi biti o n c o ul d pr o vi de cli nical be nefit i n t he treat me nt of m ulti ple a ut oi m m u ne diseases 
i ncl u di n g R M S. 
E v o br uti ni b (als o k n o w n as M 2 9 5 1 
a n d M S C 2 3 6 4 4 4 7 C) 
is a n ora l, selecti ve, irre versi ble 
i n hi bit or of B T K . E v o br uti ni b i n hi bits pri mar y  B cell resp o nses ( B C R), s uc h as pr oliferati o n a n d 
a nti b o d y an d c yt o ki ne release, wit h o ut directl y  affecti n g T cells. I n direct effects o n T cells ca n 
be me diate d b y B T K i n hi biti o n b y  bl oc ki n g t he B cell a nti ge n prese ntati o n f u ncti o n. I n a d diti o n, 
B T K i n hi biti o n bl oc k s t he acti vati o n of i n nate i m m u ne cells by i m m u ne c o m ple xes d o w nstrea m 
of Fc rece pt or ( Fc R) acti vati o n. All t hree mec ha nis ms ma y  pl a y a role i n t he pat h o ge nesis of 
vari o us a ut oi m m u ne diseases. T h us, B T K i n hi biti o n c o ul d pr o vi de cli nical be nefit i n t he 
treat me nt of m ulti ple a ut oi m m u ne diseases i ncl u di n g R M S.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
I n cli nical st u dies wit h healt h y  partici pa nts, e v o br uti ni b was ra pi dly a bs or be d wit h a tma x of 0. 5 t o 
1. 5 h o urs u n der faste d c o n diti o ns. E v o br uti ni b de m o nstrate d d ose -pr o p orti o nal P K (i.e. C ma x a n d 
A U C 0- ∞) o ver t he e val uate d d ose ra n ge of 2 5 t o 5 0 0 m g si n gle d ose a n d 2 5 t o 2 0 0 m g o nce -dail y 
m ulti ple d ose. Me dia n t 1/ 2 was a p pr o xi matel y  2 h o urs (ra n ge 1. 8 t o 2. 6 h o urs) at rele va nt plas ma 
c o nce ntrati o ns f oll o wi n g a si n gle oral d ose of 2 5 t o 2 0 0 m g. Acc u m ulat i o n of e v o br uti ni b is 
mi ni mal wit h dail y  d osi n g (refer t o I B).
E v o br uti ni b will be d ose d u n der fe d c o n diti o ns i n t his st u d y. A d mi nistrati o n of e v o br uti ni b t o 
healt h y  partici pa nts 3 0 mi n utes after t he start of a hi g h -fat or l o w- t o m o derate-fat meal res ulted 
i n a 5 0 % t o 7 5 % i ncrease i n e x p os ure (st u dies
, a n d 
a d mi nistrati o n wit h a li g ht meal (t oast a n d c offee) res ulte d i n a 3 8 % i ncrease i n e x p os ure 
(st u d y M S 2 0 0 5 2 7 _ 0 0 7 2). 
Preli mi nar y  data fr o m a rece nt st u d y utilizi n g t he c urrent T F 2 
f or m ulati o n de m o nstrate d t hat a d mi nistrati o n of e v o br uti ni b T F 2 3 0 mi n utes after t he start of a 
hi g h -fat brea kfast res ulte d i n a 6 1 % a n d 1 2 % i ncrease i n A U C a n d C ma x , res pecti vely, relati ve t o 
faste d c o n diti o ns (st u d y M S 2 0 0 5 2 7 _ 0 0 7 7). 
Me dia n 
(ra n ge) tma x
u n der fe d c o n diti o ns was 
1. 5 h o urs ( 0. 5 t o 3 h o urs).
Dr u g tr a ns p orters
D uri n g de vel o p me nt of N M Es, c haracterizati o n of p ote ntial D DI lia bilities wit h i n v ol ve me nt of 
dr u g tra ns p orters is re q uire d ( K ö ni g 2 0 1 3, Giac o mi ni 2 0 1 0, Z ol k 2 0 1 1 ). I n partic ular, re g ulat or y 
a ut h orities re q uest a t h or o u g h assess me nt of t he pr o pe nsit y of a n N M E t o ca use D DI s b y  
i n hi biti o n of t h ose dr u g tra ns p orters wit h c o m pelli n g cli nical e vi de nce f or rele va nce (Hill gre n 
2 0 1 3 ), i ncl u di n g P- g p ( A T P-A B C B 1), O A T P 1 B 1, O A T P 1 B 3, O A T 1, O A T 3, O C T 1, O C T 2, 
M A T E 1, M A T E 2 -K, a n d B C R P ( A B C G 2). Rece ntl y , i nterest i n t he use of t he pr o be dr u g 
c oc ktail a p pr oac h i n tra ns p orter D DI  cli nical trials has i ncrease d c o nsi dera bl y (St o pfer 2 0 1 6 , 
St o pfer 2 0 1 8,  Pr ue ksarita n o nt 2 0 1 7,  Z ha n g 2 0 1 7 ). S uc h c oc ktails all o w si m ulta ne o us 
i n vesti gati o n of t he effect of a n N M E o n t he P K of se veral pr o be dr u gs wit h differe nt tra ns p orter 
s pecificities i n a si n gle trial, t h us re d uci n g t he n u m ber of cli nical D DI  st u dies i n t he de vel o p me nt 
pr o gra m (St o pfer 2 0 1 8 ).
T a ble 3
S u m m ar y of Dr u g Tr a ns p orters a n d T heir I n de x S u bstr ates
Dr u g Tr a n s p ort er
Cli ni c al S u b str at e
P- g p
Di g o xi n
M A T E 1, M A T E 2 - K
M etf or mi n
B C R P
R o s u v a st ati n
O C T 1
S u m atri pt a n
S o ur c e: htt p s:// w w w.f d a. g o v/ dr u g s/ dr u g -i nt er a cti o n s-l a b eli n g/ dr u g-d e v el o p m e nt -a n d -dr u g -i nt er a cti o n s-t a bl e-
s u b str at e s -i n hi bit or s-a n d -i n d u c er s #t a bl e 2-1 (f or di g o xi n, m etf or mi n a n d r o s u v a st ati n); C h u 2 0 1 8 ( s u m atri pt a n).
B C R P = B r e a st C a n c er R e si st a n c e Pr ot ei n, M A T E 1/ 2 = M ulti dr u g a n d T o xi n E xtr u si o n 1/ 2, O C T 1 = Or g a ni c C ati o n 
Tr a n s p ort er 1, P -g p = P -gl y c o pr ot ei n.
2. 3
Be nefit/ Ris k  Assess me nt
E v o br uti ni b
As of 3 1 J ul y 20 2 0, a p pr o xi matel y 1, 3 1 8 a d ult partici pa nts i n 1 4 c o m plete d a n d 4 o n g oi n g 
cli nical st u dies ha ve bee n e x p ose d t o e v o br uti ni b, i ncl u di n g healt h y partici pa nts ( 2 2 7), 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
partici pa nts wit h R M S ( 2 6 1), s yste mic l u p us er yt he mat os us ( 4 5 1), or r he u mat oi d art hritis ( 3 6 3), 
a n d partici pa nts wit h re nal i m pair me nt ( 3 1). E v o br uti ni b was ge nerall y safe a n d well t olerate d 
i n all partici pa nts. T he T E A Es ha ve bee n pri maril y mil d t o m o derate i n se verit y. 
T he e v o br uti ni b treat me nt d urati o n i n t his st u d y will be 9 da ys  (Part 1) or 7 d a y s ( Part 2), wit h 
4 5 m g t wice dail y d osi n g of e v o br uti ni b u n der fe d c o n diti o ns. T his re gi me n was pre vi o usl y 
teste d i n healt h y  partici pa nt st u dies a n d d oes n ot e xcee d e x p os ures reac he d i n first-i n-h u ma n 
cli nical st u d y
 w here si n gle d oses of e v o br uti ni b fr o m 2 5 u p t o 5 0 0 m g a n d 
1 4 da y s of d osi n g wit h 2 5, 7 5, a n d 2 0 0 m g/ da y  were teste d a n d s h o w n t o be well t olerate d.
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 na bly 
e x pecte d a d verse e ve nts of e v o br uti ni b m a y  be f o u n d i n Secti o n 4. 2 a n d t he I B.
Base d o n t he a vaila ble n o ncli nical a n d cli nical data t o date, t he c o n d uct of t he st u d y, as s pecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble.
Tr a ns p orter S u bstr ates
Tra ns p orter s u bstrates are t o be a d mi nistere d at relati vel y lo w d oses a n d are u nli kel y t o ca use 
a n y liste d a d verse e ve nt, w hic h are pr o vi de d f or c o m plete ness ( Secti o n 2. 3. 1 ). 
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 na bly 
e x pecte d a d verse e ve nts of o n t he tra ns p orter s u bstrates ( di g o xi n, metf or mi n, r os u vastati n, a n d 
s u matri pta n) m a y  be f o u n d i n t he res pecti ve S m P Cs.
2. 3. 1
Ris k  Assess me nt
S afet y Ris ks A p plic a ble t o He alt h y P artici p a nts
I d e ntifi e d a n d P ot e nti al 
Ri s k s of Cli ni c al 
Si g nifi c a n c e
S u m m ar y  of D at a/ R ati o n al e
f or Ri s k
Miti g ati o n Str at e g y
E v o br uti ni b
I m p ort a nt i d e ntifi e d ri s k: 
El e v at e d li v er 
tr a n s a mi n a s e s
El e v at e d li v er tr a n s a mi n a s e s h a v e b e e n 
o b s er v e d 
i n p arti ci p a nt s 
tr e at e d wit h 
e v o br uti ni b a cr o s s t h e pr o gr a m a n d i s 
c o n si d er e d a n i m p ort a nt i d e ntifi e d ri s k (f or 
d et ail s r ef er t o c urr e nt I B S e cti o n 6. 1). 
El e v ati o n s of li v er tr a n s a mi n a s e s w er e 
fr e q u e nt, a s y m pt o m ati c, a n d r e v er si bl e, 
a n d 
o c c urr e d 
wit hi n 
6 
m o nt h s 
of 
tr e at m e nt. T hi s h a s n ot b e e n o b s er v e d i n 
h e alt h y p arti ci p a nt s aft er a si n gl e d o s e n or 
i n p arti ci p a nt s r e c ei vi n g s h ort tre at m e nt 
wit h e v o br uti ni b.
P arti ci p a nt s 
wit h 
k n o w n hi st or y of 
h e p ati c di s or d er will n ot b e i n cl u d e d i n 
t h e st u d y. St u d y p arti ci p a nt s will b e 
c o nfi n e d, a n d li v er tr a n s a mi n a s e s will 
b e a d e q u at el y
m o nit or e d d uri n g t h e 
st u d y.
I m p ort a nt p ot e nti al ri s k:
E m br y o -f et al t o xi cit y
B a s e d o n n o n cli ni c al fi n di n g s, e m br y o -
f et al t o xi cit y i s c o n si d er e d a s a n i m p ort a nt 
p ot e nti al ri s k i n w o m e n of c hil d b e ari n g 
p ot e nti al e x p o s e d t o e v o br uti ni b.
F e m al e p arti ci p a nt s of c hil d b e ari n g 
p ot e nti al m u st n ot b e pr e g n a nt, m u st 
h a v e a n e g ati v e pr e g n a n c y t e st at t h e 
ti m e of e nr ol lm e nt 
a n d u s e hi g hl y 
eff e cti v e c o ntr a c e pti o n ( S e cti o n 5. 1 ) 
d uri n g t h e st u d y p eri o d a n d f or 1 2 0 
d a y s aft er t h e l a st d o s e a n d a gr e e n ot  
t o d o n at e 
e g g s 
f or r e pr o d u cti o n 
d uri n g t hi s p eri o d.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
I d e ntifi e d a n d P ot e nti al 
Ri s k s of Cli ni c al 
Si g nifi c a n c e
S u m m ar y  of D at a/ R ati o n al e
f or Ri s k
Miti g ati o n Str at e g y
Di g o xi n ( S m P C)
I m p ort a nt i d e ntifi e d ri s k:
Arr h yt h mi a s
Di g o xi n T o xi cit y a n d 
O v er d o s a g e
Di g o xi n 
i n cr e a s e s t h e a bilit y of h e art 
m u s cl e 
t o 
c o ntr a ct 
b y 
c o m pl e x 
m e c h a ni s m s i n v ol vi n g s o di u m, p ot a s si u m 
a n d c al ci u m i o n s. A n y c h a n g e s i n t h e 
c al ci u m i o n m o bilit y c a n t h er ef or e i m p a ct 
o n h e art b e at r e g ul ati o n.
C o m p ar e d t o a t h er a p e uti c u s e of di g o xi n 
wit h a l o a di n g d o s e of 0. 5 t o 0. 7 5 m g gi v e n 
a s 2 d o s e s 6 h o ur s a p art, o nl y a si n gl e 
d o s e of 0. 2 5 m g i s gi v e n i n t hi s st u d y. T h e 
s y m pt o m s 
a n d 
si g n s 
of 
t o xi cit y ar e 
g e n er all y 
n o n s p e cifi c: 
f ati g u e, bl urr e d 
vi si o n, c h a n g e i n c ol or vi si o n ( e. g. " y ell o w 
vi si o n"), w ei g ht l o s s, n a u s e a (f e eli n g si c k), 
v o miti n g, 
di arr h e a, 
a b d o mi n al 
p ai n, 
h e a d a c h e, 
di z zi n e s s, 
c o nf u si o n, 
a n d 
d eliri u m. It i s al s o a s s o ci at e d wit h irr e g ul ar 
h e art b e at s.
A p pr o pri at e
E C G 
m o nit ori n g 
aft er 
di g o xi n a d mi ni str ati o n, S e cti o n s
1. 3
a n d 8. 2. 3
R o s u v a st ati n ( S m P C)
I m p ort a nt I d e ntifi e d Ri s k: 
R h a b d o m y ol y si s
A s 
wit h 
ot h er 
c h ol e st er ol- l o w eri n g 
m e di ci n e s, a v er y s m all n u m b er of p e o pl e 
h a v e 
e x p eri e n c e d 
u n pl e a s a nt 
m u s cl e 
eff e ct s a n d r ar el y t h e s e h a v e g o n e o n t o 
b e c o m e 
a 
p ot e nti all y 
lif e-t hr e at e ni n g 
m u s cl e 
d a m a g e 
k n o w n 
a s 
r h a b d o m y ol y si s. T hi s h a s b e e n r e p ort e d 
i n ro s u v a st ati n -tr e at e d p arti ci p a nt s wit h all 
d o s e s, a n d i n p arti c ul ar wit h d o s e s m or e 
t h a n 2 0 m g r o s u v a st ati n.
R o s u v a st ati n s h o ul d b e st o p p e d a n d 
m e di c al 
s u p p ort s h o ul d b e s o u g ht 
i m m e di at el y if a n y u n u s u al a c h e s or 
p ai n s i n m u s cl e s o c c ur .
I n cr e a s e d tr a n s a mi n a s e s; 
H e p atiti s; J a u n di c e
I n cr e a s e i n li v er e n z y m e s i n t h e bl o o d h a s 
b e e n o b s er v e d i n 1 t o 1 0 u s er s i n 1 0, 0 0 0. 
T h e li v er pr o bl e m s f oll o wi n g r o s u v a st ati n 
ar e r e p ort e d m or e wit h t h e hi g h e st d o s e 
t h at i s 4 0 m g. J a u n di c e a n d h e p atiti s h a s 
b e e n o b s er v e d i n l e s s t h a n 1 u s er i n 
1 0, 0 0 0.
Bl o o d t e st f or li v er f u n cti o n t e st s h o ul d 
b e 
c arri e d 
o ut 
b ef or e 
a n d 
aft er
tr e at m e nt wit h r o s u v a st ati n. 
I n cr e a s e d tr a n s a mi n a s e s; 
P a n cr e atiti s
S e v er e st o m a c h p ai n ( c a u s e d b y i nfl a m e d 
p a n cr e a s) h a s b e e n o b s er v e d i n 1 t o 1 0 
u s er s i n 1 0, 0 0 0.
R e p ort 
t o tr e ati n g p h y si ci a n 
a n y 
di a g n o si s or s y m pt o m s of p a n cr e atiti s
I n cr e a s e d tr a n s a mi n a s e s; 
M e m or y L o s s
M e m or y l o s s h a s b e e n o b s er v e d i n l e s s 
t h a n 1 u s er i n 1 0, 0 0 0.
M e m or y l o s s i s n ot e x p e ct e d i n t hi s 
st u d y a n d 
p arti ci p a nt s
s h o ul d b e 
p er m a n e ntl y di s c o nti n u e d i n c a s e of 
o c c urr e n c e.
I n cr e a s e d tr a n s a mi n a s e s; 
Pr ot ei n uri a
P arti ci p a nt s tr e at e d wit h hi g h er d o s e s of 
ro s u v a st ati n 
(i n p arti c ul ar 
ro s u v a st ati n 
4 0 m g) ar e li k el y t o d e v el o p i n cr e a s e i n 
t h e a m o u nt of pr ot ei n i n t h e uri n e . T hi s 
u s u all y r et ur n s t o n or m al o n it s o w n 
wit h o ut h a vi n g t o st o p t a ki n g ro s u v a st ati n 
t a bl et s.
R o uti n e 
uri n e 
t e st 
t o 
d et e ct 
pr ot ei n uri a d uri n g t h e f oll o w-u p of 
p arti ci p a nt s 
o n 
hi g h e st 
d o s e 
of 
r o s u v a st ati n i s r e c o m m e n d e d.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
I d e ntifi e d a n d P ot e nti al 
Ri s k s of Cli ni c al 
Si g nifi c a n c e
S u m m ar y  of D at a/ R ati o n al e
f or Ri s k
Miti g ati o n Str at e g y
S u m atri pt a n ( S m P C)
I s c h a e mi c h e art di s e a s e
F oll o wi n g a d mi ni str ati o n, s u m atri pt a n c a n 
b e a s s o ci at e d wit h tr a n si e nt s y m pt o m s 
i n cl u di n g c h e st p ai n a n d ti g ht n e s s w hi c h 
m a y 
b e i nt e n s e a n d i n v ol v e t h e t hr o at. 
W h er e s u c h
s y m pt o m s ar e t h o u g ht t o 
i n di c at e i s c h e mi c h e art di s e a s e, n o f urt h er 
d o s e s of s u m atri pt a n s h o ul d b e gi v e n a n d 
a p pr o pri at e e v al u ati o n s h o ul d b e c arri e d 
o ut. S p e ci al c o n si d er ati o n s h o ul d b e gi v e n 
t o p o st m e n o p a u s al w o m e n 
a n d m al e s 
o v er 4 0 wit h t h e s e ri s k f a ct or s. T h e s e 
e v al u ati o n s,
h o w e v er, m a y
n ot i d e ntif y 
e v er y p ati e nt w h o h a s c ar di a c di s e a s e ,
a n d i n v er y r ar e c a s e s, s eri o u s c ar di a c 
e v e nt s h a v e o c c urr e d i n p ati e nt s wit h o ut 
u n d erl yi n g c ar di o v a s c ul ar di s e a s e.
St u d y 
c o n d u ct e d 
wit h 
h e alt h y 
p arti ci p a nt s 
u n d er 
i n-h o u s e 
m o nit ori n g 
of cli ni c al st at u s at t h e 
C R U.
St u d y  Pr o c e d ur e s
Bl o o d dr a w
Bl o o d dr a w s h a v e t h e p ot e nti al t o c a u s e 
A E s s u c h a s f ai nti n g or h e m at o m a.
A m o u nt of bl o o d dr a w n will b e stri ctl y 
c o ntr oll e d. P arti ci p a nt s will b e i n a 
h o s pit al s etti n g wit h s u p p ort fr o m 
hi g hl y tr ai n e d pr of e s si o n al s.
E C G
C o nt a ct all er gi e s c a n d e v el o p d uri n g 
E C G pr o c e d ur e s.
P arti ci p a nt s wit h k n o w n c o nt a ct 
all er gi e s t o E C G el e ctr o d e s will n ot 
b e i n cl u d e d i n t h e st u d y. 
Ot h er
N ot a p pli c a bl e
A E = a d v er s e e v e nt, C R U = cli ni c al r e s e ar c h u nit, I B =I n v e sti g at or’ s Br o c h ur e, E C G = el e ctr o c ar di o gr a m, 
S m P C = s u m m ar y of pr o d u ct c h ar a ct eri sti c s.
S afet y Ris ks n ot A p plic a ble f or He alt h y P artici p a nts
I d e ntifi e d a n d P ot e nti al 
Ri s k s of Cli ni c al 
Si g nifi c a n c e
S u m m ar y  of D at a/ R ati o n al e
f or Ri s k
Miti g ati o n Str at e g y
M etf or mi n
( S m P C)
I m p ort a nt I d e ntifi e d Ri s k: 
L a cti c a ci d o si s 
L a cti c a ci d o si s i s a r ar e, b ut s eri o u s 
( hi g h d e at h r at e i n t h e a b s e n c e of 
pr o m pt tr e at m e nt), c o n diti o n t h at c a n 
o c c ur d u e t o m etf or mi n 
b uil d u p. 
R e p ort e d c a s e s of l a cti c a ci d o si s i n 
p arti ci p a nt s 
o n 
m etf or mi n 
h a v e 
o c c urr e d 
pri m aril y 
i n 
di a b eti c 
p arti ci p a nt s wit h 
si g nifi c a nt ki d n e y 
f ail ur e a n d i n p arti ci p a nt s wit h ot h er 
a s s o ci at e d ri s k f a ct or s.
All p arti ci p a nt s u n d er m etf or mi n tr e at m e nt 
s h o ul d di s c u s s wit h t h eir d o ct or s if t h e y ar e 
h a vi n g 
m u s cl e 
c r a m p s wit h 
di g e sti v e 
di s or d er s, s u c h a s a b d o mi n al p ai n, a n d 
s e v er e 
a st h e ni a 
( w e a k n e s s / l o s s of 
str e n gt h), 
a s 
t h e s e 
s y m pt o m s 
ar e 
c h ar a ct eri sti c of l a cti c a ci d o si s
I m p ort a nt I d e ntifi e d Ri s k: 
Li v er I n s uffi ci e n c y
It i s n ot i n di c at e d t o u s e m etf or mi n i n 
p arti ci p a nt s wit h li v er i n s uffi ci e n c y.
P arti ci p a nt s wit h li v er i n s uffi ci e n c y s h o ul d 
a v oi d u s e of
m etf or mi n
I m p ort a nt I d e ntifi e d Ri s k: 
H y p o gl y c e mi a
C a uti o n i s a d vi s e d w h e n m etf or mi n i s 
u s e d i n c o m bi n ati o n wit h i n s uli n or 
ot h er 
or al 
a nti di a b eti c s 
( e. g. 
s ul p h o n yl ur e a s 
or 
m e gliti ni d e s) 
i n 
or d er t o a v oi d h y p o gl y c e mi a
W h e n u si n g m etf or mi n i n c o m bi n ati o n wit h 
i n s uli n or ot h er or al a nti di a b eti c s p arti ci p a nt
s h o ul d 
al w a y s 
t a k e t h e e x a ct 
d o s e  
s p e cifi e d b y t h eir p h y si ci a n s. M o nit ori n g of 
bl o o d gl u c o s e i s n e c e s s ar y fr e q u e n tl y.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
I d e ntifi e d a n d P ot e nti al 
Ri s k s of Cli ni c al 
Si g nifi c a n c e
S u m m ar y  of D at a/ R ati o n al e
f or Ri s k
Miti g ati o n Str at e g y
U s e i n p arti ci p a nt s wit h 
ki d n e y i m p air m e nt
D e cr e a s e d ki d n e y f u n cti o n i n el d erl y 
s u bj e ct s i s fr e q u e nt a n d s y m pt o m 
fr e e. El d erl y p arti ci p a nt s s h o ul d a dj u st 
t h e m etf or mi n 
d o s a g e d u e t o t h e 
p ot e nti al 
f or 
d e cr e a s e d 
ki d n e y 
f u n cti o n. It i s n ot i n di c at e d t o u s e 
m etf or mi n i n p arti ci p a nt s wit h ki d n e y 
f ail ur e 
or 
ki d n e y 
d y sf u n cti o n 
( cr e ati ni n e cl e ar a n c e < 6 0 ml/ mi n). 
R e g ul ar a s s e s s m e nt of ki d n e y f u n cti o n i s 
n e c e s s ar y . Cr e ati ni n e cl e ar a n c e ( a m o u nt 
of cr e ati ni n e i n uri n e i n c o m p ari s o n t o t h e 
bl o o d) 
s h o ul d 
b e 
d et er mi n e d 
b ef or e 
i niti ati n g tr e at m e nt a n d r e g ul arl y t h er e aft er
S u m atri pt a n ( S m P C)
S ei z ur e s
S u m atri pt a n 
s h o ul d b e 
u s e d 
wit h 
c a uti o n i n p ati e nt s wit h a hi st or y of 
s ei z ur e s or ot h er ri s k f a ct or s w hi c h 
l o w er t h e s ei z ur e 
t hr e s h ol d, a s 
s ei z ur e s 
h a v e 
b e e n 
r e p ort e d i n 
a s s o ci ati o n wit h s u m atri pt a n .
St u d y c o n d u ct e d wit h h e alt h y p arti ci p a nt s 
u n d er i n -h o u s e m o nit ori n g of cli ni c al st at u s 
at t h e C R U.
C R U = cli ni c al r e s e ar c h u nit, S m P C = s u m m ar y of pr o d u ct c h ar a ct eri sti c s.
2. 3. 1. 1 
P ote nti al Ris ks ass oci ate d wit h t he C O VI D - 1 9 P a n de mic 
Sit u ati o n
As f or t he ge neral p o p ulati o n, t here is a ris k of a S A R S -C o V - 2 i nfecti o n f or st u d y partici pa nts 
as l o n g as t he C O VI D -1 9 pa n de mic sit uati o n is o n g oi n g. 
E v o br uti ni b is a B T K i n hi bit or a n d, as s uc h, w or ks as a n i m m u n o m o d ulat or. T here was s o me 
decre ase i n i m m u n o gl o b uli n M, a n i ncrease i n i m m u n o gl o b uli n A, a n d s o me m o dest c ha n ges i n 
i m m u n o gl o b uli n G f oll o wi n g l o n g-ter m treat me nt wit h e v o br uti ni b; t hese c ha n ges were n ot 
cli nicall y si gnifica nt. I n a d diti o n, d urati o n of t he e v o br uti ni b treat me nt i n t his st u d y will be 
li mite d t o 9 da y s ( Part 1) a n d 7 d a ys (Part 2). Alt h o u g h B T K is n ot re q uire d t o clear viral 
i nfecti o ns, a part fr o m e nter o vir uses, n o i nf or mati o n is a vaila ble re gar di n g B T K i n hi bit ors as a 
class or e v o br uti ni b- s pecifically re gar di n g t he ris k f or eit her c o ntracti n g S A R S -C o V -2 or 
se verity of C O VI D - 1 9 at t his p oi nt. T he p u blis he d data o n a p pr o ve d B T K i n hi bit ors (e. g., 
i br uti ni b a n d acala br uti ni b) use d i n o nc ol o g y  su g gest a pr otecti ve effect of B T K i n hi bit ors f or 
se verity a n d m ortalit y of C O VI D - 1 9 ( Scarf ò 2 0 2 0; T hi ba u d 2 0 2 0 ; Tre o n 2 0 2 0 ).
D uri n g t he e ntire st u d y, all rec o m me n dati o ns iss ue d b y  the R o bert K oc h I nstit ute as well as l ocal 
g ui deli nes wit h res pect t o t he mi ni mizati o n of t he ris k of disease s prea di n g, e. g. s ocial dista nci n g, 
disi nfecti o n, h y gie ne, a n d weari n g of m o ut h -n ose mas ks w ill be f oll o we d. D uri n g t he pa n de mic 
sit uati o n, f urt her meas ures acc or di n g t o rec o m me n dati o ns a n d re q uire me nts fr o m l ocal H ealt h 
A ut h orities ma y  bec o me necessar y  an d will be f oll o we d wit hi n t he c o nte xt of t his st u d y as far 
as a p plica ble, i n or der t o e ns ure f ull i m ple me ntati o n of t he pri nci ples of G C P wit h pri orit y  on 
partici pa nt safety i n t his st u d y als o d uri n g t he C O VI D - 1 9 pa n de mic sit uati o n. T hese meas ures 
are descri be d i n a pre ve nti ve acti o n pla n i m ple me nte d at t he I n vesti gat or site.
I n or der t o mi ni mize t he ris k c o mi n g fr o m a c urre nt i nfecti o n a n d t he ris k of getti n g i nfecte d b y 
ot her partici pa nts d uri n g t he i n-h o use p hase (c o veri n g t he w h ole treat me nt p hase) of t he st u d y, 
t he f oll o wi n g meas ures are i m ple me nte d: O nl y  partici pa nts wit h o ut a n y sy m pt o ms of a 
res pirat or y disease a n d wit h o ut c o ntact t o a n y kn o w n S A R S -C o V -2 p ositi ve patie nt or 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
C O VI D - 1 9 patie nt will be i ncl u de d i nt o t he st u d y. F urt her m ore, as a part of t he cli nical st u d y 
pr oce d ures, partici pa nts will be cl osel y m o nit ore d (i ncl u di n g f or si g ns of C O VI D -1 9) d uri n g t he 
e ntire st u d y d urati o n. C o nti n uati o n of t he st u d y i n case of a S A R S-C o V - 2 i nfecti o n i n t he st u d y 
partici pa nt or a n i de ntifie d c o ntact t o a S A R S-C o V -2 p ositi ve partici pa nt or C O VI D -1 9 patie nt 
will be d o ne at t he I n vesti gat or’s discreti o n a n d a gree me nt wit h t he me dical m o nit ori n g tea m. 
T he S p o ns or will m o nit or t he e ve nts relate d t o a n y SA R S -C o V -2 i nfecti o n re p orte d f oll o wi n g 
e v o br uti ni b re g ularl y a n d u p date t he rec o m me n dati o ns, if necessar y.
2. 3. 2
Be nefit Assess me nt
T he healt h y v ol u nteers partic i pati n g i n t his st u d y will n ot o btai n a n y cli nical be nefit fr o m t he 
treat me nts. T he data o btai ne d fr o m t his st u d y will g ui de f urt her de vel o p me nt of e v o br uti ni b.
2. 3. 3
O ver all Be nefit: Ris k C o ncl usi o n
Ris k mi ni mizati o n meas ures r o uti nely i m ple me nte d i n earl y p has e cli nical st u dies are c o nsi dere d 
a de q uate, i ncl u di n g e xcl usi o n criteria ( Secti o n 5. 2 ), a de q uate bi oc he mical a n d he mat ol o g y  
la b orat or y mo nit ori n g ( Secti o n 8. 2. 4 ), a n d o bser vati o n of vital si g ns a n d E C Gs ( Secti o ns 8. 2. 2
a n d 8. 2. 3 ). E v o br uti ni b will be disc o nti n ue d i n case of e ve nts t hat u nacce pta bl y  en da n ger t he 
safety o f t he partici pa nt ( Secti o n 8. 3 ). Partici pa nts will be a d mitte d t o t he st u d y site f or t he 
d urati o n of t he st u d y  t o all o w c o nti n u o us safet y m o nit ori n g.
C o nsi deri n g t he meas ures ta ke n t o mi ni mize ris k t o partici pa nts i n t his st u d y , t he p ote ntial ris ks 
i de ntifie d i n ass ociati o n wit h e v o br uti ni b a n d t he tra ns p orter s u bstrates di g o xi n, metf or mi n, 
r os u vastati n, a n d s u matri pta n are j ustifie d i n healt h y partici pa nts.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
3
O bjecti ve s a n d E n d p oi nts
O bjecti ves
E n d p oi nts
Pri mar y
T o i n vesti gate t he effect of m ulti ple d oses of 
e v o br uti ni b o n si n gle d oses of di g o xi n, 
metf or mi n, a n d r os u vastati n ( Part 1), a n d 
s u matri pta n ( Part 2) P K i n healt h y 
partici pa nts

Plas ma tra ns p orter s u bstrates A U C 0 -∞
a n d C ma x
Sec o n dar y
T o assess t he safet y a n d t olera bilit y of 
e v o br uti ni b w he n a d mi nistere d t o get her wit h 
di g o xi n, metf or mi n, a n d r os u vastati n ( Part 1), 
a n d s u matri pta n ( Part 2) i n healt h y  
partici pa nts

Nat ure, occ urre nce, a n d se verit y of 
T E A Es

A bs ol ute val ues a n d c ha n ges i n safet y 
la b orat or y tests 

Si n gle 1 2 -lea d E C Gs e val uate d b y 
I n vesti gat or, a n d 

Vital si g ns assesse d fr o m ti me of first 
d ose t o e n d of st u d y partici pati o n
T o c haracterize t he effect of e v o br uti ni b o n 
di g o xi n, metf or mi n, a n d r os u vastati n ( Part 1), 
a n d s u matri pta n ( Part 2) o n sec o n dar y  P K 
para meters i n healt h y partici pa nts

Plas ma P K para meters ( Part 1 a n d 
Part 2): 
tma x , t½ , a n d A U C0- tlast, C L/ F, a n d V Z / F 

Uri ne P K para meters ( Part 1, metf or mi n 
o nl y ): Ae0- 3 6 a n d C L R
C L/ F = a p p ar e nt t ot al b o d y cl e ar a n c e, C L R =r e n al cl e ar a n c e, E C G = el e ctr o c ar di o gr a m , P K = p h ar m a c o ki n eti c s,
T E A E =tr e at m e nt -e m er g e nt a d v er s e e v e nt , VZ / F = a p p ar e nt v ol u m e of di stri b uti o n.
See Secti o n  9. 4 f or t he statistical as pects of t he e n d p oi nts.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
4
St u d y Desi g n
4. 1
O ver all Desi g n
St u d y  Desi g n
N o nra n d o mize d, o pe n -la bel, si n gle-se q ue nce (f or eac h 
part; Secti o ns  1. 2 a n d 1. 3)
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 nter
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 ype
Healt h y partici pa nt s ( Secti o n 5. 1)
Le vel a n d Met h o d of Bli n di n g
N ot a p plica ble
Bias Mi ni malizati o n Met h o d(s)
N ot a p plica ble
St u d y  Inter ve nti o n Assi g n me nt 
Met h o d
N ot a p plica ble
I n v ol ve me nt of S pecial 
C o m mittee(s):
N o
T otal D urati o n of St u d y  
Partici pati o n per Partici pa nt
U p t o 6 wee ks, i ncl u di n g t he Scree ni n g peri o d 
( ma xi m u m 4 wee ks) a n d a ma xi m u m of 2 wee ks of 
i nter ve nti o n peri o d, i ncl u di n g t he Safet y F oll o w-u p o n 
t he da y after t he last d ose of st u d y i nter ve nti o n, Da y 1 3
f or Part 1 a n d Da y 9 f or Part 2 ( Secti o ns 1. 2 a n d 1. 3 ).
Pr o visi o ns f or St u d y  E xte nsi o n or 
E ntr y  i nt o R oll-O ver St u dies
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
A st u d y sc he me a n d a detaile d Sc he d ule of Assess me nts
are pr o vi de d i n Secti o n 1. 2 a n d 
Secti o n 1. 3 , res pecti vely.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T he st u d y desi g n a n d e n d p oi nts are t ypical f or a D DI  st u d y of t his t ype. T he effect of e v o br uti ni b 
o n tra ns p orter acti vities will be i n vesti gate d b y meas ure me nt of t he P K of t he tra ns p orter 
s u bstrates di g o xi n, metf or m i n, r os u vastati n, a n d s u matri pta n. Oral a d mi nistrati o n of t he pr o be 
dr u g tra ns p orter s u bstrates is e x pecte d t o be a se nsiti ve test f or p ote ntial i nteracti o ns wit h dr u g 
tra ns p orters s uc h as P- g p, M A T E 1/ M A T E 2 -K, B C R P, a n d O C T 1 si nce t he y reflect effects o n 
b ot h pres ys te mic a n d s yste mic cleara nce. T he tra ns p orter s u bstrate c oc ktail ( di g o xi n, metf or mi n, 
a n d r os u vastati n) will be a d mi nistere d d uri n g Part 1 of t he st u d y as a refere nce treat me nt o n 
D a y 1 f oll o we d o n D a y  4 thr o u g h D a y  12 b y  multi ple d oses of e v o br uti ni b t wice dail y , wit h a 
sec o n d d ose of s u bstrate c oc ktail gi ve n wit h t he m or ni n g d ose of e v o br uti ni b o n Da y 1 0. D uri n g 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
Part 2, s u matri pta n will be a d mi nistere d o n Da y  1 as refere nce a n d o n Da y  8, a n d e v o br uti ni b 
will be a d mi nistere d t wice dail y  o n Da ys 2 t hr o u g h 8.
A si n gle-se q ue nce desi g n f or Part 1 a n d Part 2 was c h ose n beca use t he e xact mec ha nis m of 
i n hi biti o n of t he tra ns p orters b y e v o br uti ni b a n d t heref ore t he ti me c o urse of o n - / offset of t hese 
effects are n ot k n o w n. T heref ore, e v o br uti ni b will be a d mi nistere d t wice dail y f or 6 da ys bef ore 
t he sec o n d a d mi nistrati o n of tra ns p orter s u bstrates i n eac h st u d y part. 
T he tra ns p orter s u bstrate c oc ktail t o be use d i n Part 1 of t his st u d y (di g o xi n [ 0. 2 5 m g], metf or mi n 
[ 1 0 m g] a n d r os u vastati n [ 1 0 m g]) has be e n o pti mize d as a scree ni n g t o ol f or tra ns p orter 
me diate d D DIs
(Wie be 
2 0 2 0,  St o pfer 2 0 1 8 ) base d o n P K a nal ys es of t he s u bstrates b ot h 
se paratel y a n d i n c o m bi nati o n. T he safety pr ofiles of t he i n di vi d ual s u bstrates of t he c oc ktail are 
well esta blis he d si nce t hese dr u gs are r o uti nely use d i n cli nical practice. St o pfer re p orte d mil d 
or m o derate a d verse e ve nts i n 1 5 of 3 0 partici pa nts (St o pfer 2 0 1 8 ). Si milarl y , f or Part 2, 
s u matri pta n ( 2 5 m g) has bee n rec o m me n de d a n d use d as a s u bstrate f or deter mi ni n g P K effects 
of p ote ntial O C T 1 effect ors (C h u 2 0 1 8 ). T he safet y pr ofile of s u matri pta n is well esta blis he d 
si nce it is r o uti nel y use d i n cli nical practice (S u matri pta n S m P C ). 
Beca use s o me of t he tra ns p orters t o be i n vesti gate d i n t his st ud y  mi ght e xist as p ol y m or p hic 
varia nts, w hic h c o ul d affect t he i nter pretati o n of t he st u d y  res ults, sa m ples f or 
 
 will be c ollecte d a n d a nalyz e d. 
4. 2. 1
P artici p a nt I n p ut i nt o Desi g n
N ot a p plica ble.
4. 3
J ustific ati o n f or D ose
E v o br uti ni b
T he e v o br uti ni b d ose t o be use d i n t his st u d y, 4 5 m g t wice dail y , wit h eac h d ose t o f oll o w a 
sta n dar dize d meal, is t he sa me as f or P hase III st u dies e val uati n g e v o br uti ni b i n partici pa nts wit h 
R M S . T his d ose is a ntici pate d t o be well t olerate d base d o n pri or cli nical e x perie nce a n d is 
a de q uate t o c haracterize e v o br uti ni b P K. 
E v o br uti ni b will be d ose d u n der fe d c o n diti o ns i n t his st u d y. E v o br uti ni b e x p os ure i ncrease d 
w he n gi ve n wit h eit her a hi g h -fat or l o w-fat meal. F oll o wi n g a d mi nistrati o n of t he T F 1 ta blet 
f or m ulati o n, mea n A U C 0 -∞a n d C ma x i ncrease d b y  70 % a n d 2 7 %, res pecti vel y, f oll o wi n g a 
hi g h -fat meal, a n d b y 5 0 % a n d 2 5 %, res pecti vely,  f oll o wi n g a l o w-fat meal. Data fr o m a rece nt 
st u d y utilizi n g t he c urre nt T F 2 f or m ulati o n de m o nstrate d t hat a d mi nistrati o n of e v o br uti ni b T F 2 
3 0 mi n utes after t he start of a hi g h -fat brea kfast res ulte d i n 6 1 % a n d 1 2 % i ncreases i n A U C a n d 
C ma x , res pecti vel y, relati ve t o faste d c o n diti o ns ( St u d y 
MS 2 0 0 5 2 7 _ 0 0 7 7).
A d diti o nall y , 
e v o br uti ni b e x p os ure was i ncrease d b y  ap pr o xi matel y  3 2% 
t o 3 6 % 
w he n a d mi nistere d 
a p pr o xi matel y 2 h o urs after a meal. T he e x p os ure i n t his st u d y is t heref ore e x pecte d t o n ot e x cee d 
t hat of ot her st u dies i n healt h y  partici pa nts, i n w hic h a si n gle d ose u p t o 5 0 0 m g a n d m ulti ple 
d oses u p t o 2 0 0 m g e v o br uti ni b f or 1 4 d a y s were a d mi nistere d a n d well t olerate d. 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
Dr u g tr a ns p orter s u bstr ates
T he d oses f or t he c oc ktail of tra ns p orter s u bstrates di g o xi n ( 0. 2 5 m g ta blet), metf or mi n ( 1 0 m g 
oral s ol uti o n) a n d r os u vasta ti n ( 1 0 m g ta blet) i n Part 1 ha ve bee n c h ose n base d o n t he e xte nsi ve 
e x perie nce wit h t hese dr u gs i n r o uti ne cli nical practice; i.e., di g o xi n i n treat me nt of c o n gesti ve 
car diac fail ure, metf or mi n i n t he treat me nt of t ype 2 dia betes mellit us, a n d r os u vastati n i n t he 
treat me nt of h y perc h olester ole mia. F urt her m ore, c o nsi derati o n was gi ve n t o p u blicati o ns 
s u p p orti n g t he o pti mizi n g of tra ns p orter s u bstrate c oc ktails f or D DI st u dies (St o pfer 2 0 1 8,  
S hi bata 2 0 2 0) . A s u bt hera pe utic metf or mi n d ose is t o be use d beca use of p ote ntial i nteracti o n 
wit h r os u vastati n (t he t y pical cli nical d ose of metf or mi n starts at 5 0 0 m g,  St o pfer 2 0 1 8 ).
T he d ose f or t he O C T 1 tra ns p orter s u bstrate s u matri pta n (r o uti nely use d t o treat mi grai ne) i n 
Part 2 has bee n use d pre vi o usl y  in si milar st u dies (e. g. Cli nical Trials. g o v 
i de ntifier: 
N C T 0 4 3 5 5 8 4 5 ) a n d is c o nsi dere d a de q uate t o assess a n y p ote ntial P K effects o n O C T 1 acti vit y 
d ue t o e v o br uti ni b a d mi nistrati o n.
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 defi ne d as t he date of last c o ntact (relate d t o t his st u d y) wit h t he last 
partici pa nt w h o partici pates i n t his st u d y  (last partici pa nt’s Safety F oll o w -u p Assess me nt) .
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g t he 
Safet y  F oll o w- u p assess me nt s h o w n i n Secti o n 1. 3.
St u d y Ter mi n ati o n Criteri a
T he st u d y  will be ter mi nate d if: 

u nacce pta ble ris k, a n y rele va nt t o xicit y, or a ne gati ve c ha n ge i n t he be nefit /ris k assess me nt 
is i de ntifie d. T his mi g ht i ncl u de t he occ urre nce of A Es w h ose
c haracter, se verit y or 
fre q ue nc y is ne w i n c o m paris o n t o t he e xisti n g ris k pr ofile. 

a n y data deri ve d fr o m ot her cli nical trials or t o xic ol o gical st u dies bec o me a vaila ble w hic h 
ne gati vel y i nfl ue nce t he be nefit /ris k assess me nt.
Ge n eral i nf or mati o n o n st u d y ter mi nati o n is s pecifie d i n A p pe n di x 2 .
5
St u d y P o p ul ati o n
T he criteria 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 partici pa nts, w h o are a p pr o priate 
f or t he st u d y; t here b y, e ns uri n g t he st u d y fulfills 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 deci di n g w het her a partici pa nt is s uita ble f or t his 
st u d y.
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 xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
Bef ore 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 pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will c o nfir m t hat t he partici pa nt 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
A ge
1.
Are bet wee n 1 8 a n d 5 5 (i ncl usi ve) ye ars 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
2.
Are o vertl y healt h y  as deter mi ne d b y  
me dical e val uati o n, 
i ncl u di n g n o cli nicall y si g nifica nt a b n or malit y ide ntifie d o n 
p h y sical e xa mi nati o n or la b orat or y eval uati o n a n d n o acti ve 
cli nicall y si gnifica nt dis or der, c o n diti o n, i nfecti o n, or disease 
t hat w o ul d p ose a ris k t o partici pa nt safety or i nterfere wit h t he 
st u d y e val uati o n, pr oce d ures, or c o m pleti o n.
Wei g ht
3.
Ha ve a b o d y  wei g ht wit hi n 5 0. 0 a n d 1 0 0. 0 k g (i ncl usi ve) a n d 
b o d y  
mass i n de x wit hi n 
t he ra n ge 1 9. 0 a n d 3 0. 0 k g/ m 2 
(i ncl usi ve).
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
C ate g or y
Criteri o n
Se x a n d 
C o ntrace pti o n/ Barrier 
Re q uire me nts
4.
Male or Fe male
T he In 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 
barriers, 
if a p plica ble. 
T he 
c o ntrace pti o n, barrier, a n d pre g na nc y  testi n g re q uire me nts are 
bel o w. 
C o ntrace pti ve use will be c o nsiste nt wit h l ocal re g ulati o ns o n 
c o ntrace pti o n met h o ds f or t h ose partici pati n g i n cli nical st u dies.

Is n ot breastfee di n g

Is n ot pre g na nt (i.e., has a ne gati ve ser u m pre g na nc y  test, as 
re q uire d b y  local re g ulati o ns, wit hi n 2 4 h o urs bef ore t he first d ose 
of st u d y  i nter ve nti o n).

Is n ot a W O C B P.

If a W O C B P, uses a hi g hl y  effecti ve c o ntrace pti ve met h o d (i.e., 
wit h a fail ure rate of < 1 % per ye ar), prefera bl y wit h l o w user 
de pe n de nc y , as descri be d i n A p pe n di x 3 f or t he f oll o wi n g ti me 
peri o ds:
1.
Bef ore t he fir st d ose of t he st u d y i nter ve nti o n(s), if usi n g 
h or m o nal c o ntrace pti o n:

Has c o m plete d at least o ne 4- wee k c y cle of a n oral 
c o ntrace pti o n pill a n d eit her ha d or has be g u n her 
me nses; O R ,

Has use d a de p ot c o ntrace pti ve or e xte n de d- c ycle 
oral c o ntrace pti ve f or least 2 8 da y s a n d has a 
d oc u me nte d ne gati ve pre g na nc y  test usi n g a hi g hl y 
se nsiti ve assa y. 
2.
D uri n g t he st u d y  i nter ve nti o n peri o d
3.
After t he st u d y i nter ve nti o n peri o d (i.e., after t he la st d ose 
of st u d y  i nter ve nti o n is a d mi nistere d) f or at least 1 2 0 da ys
after t he last d ose of st u d y i nter ve nti o n a n d a gree n ot t o 
d o nate e g gs ( o va, o oc y tes) f or re pr o d ucti o n d uri n g t his 
peri o d.
T he In vesti gat or e val uates t he effecti ve ness of t he c o ntrace pti ve 
met h o d i n relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.
T he I n 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 decrease t he ris k f or i ncl usi o n of a fe male 
wit h a n earl y u n detecte d pre g na nc y.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
C ate g or y
Criteri o n
I nf or me d C o nse nt
5.
Ca pa ble of gi vi n g si g ne 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 IC F a n d t his pr ot oc ol.
S m o ki n g
6.
Are 
sta ble n o n- s m o kers f or at least 3 m o nt hs 
prece di n g 
Scree ni n g.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl 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  or prese nce of cli nicall y rele va nt res pirat or y, 
gastr oi ntesti nal, 
re nal, 
he patic, 
he mat ol o gical, 
l ym p hatic, 
ne ur ol o gical, 
car di o vasc ular, 
ps yc hiatric, 
m usc ul os keletal, 
ge nit o uri nar y , i m m u n ol o gical, der mat ol o gical, c o n necti ve tiss ue, 
meta b olic
diseases or dis or ders,
mi grai ne,
or e pile ps y, as 
deter mi ne d b y me dical e val uati o n.
2.
I n di vi d uals wit h dia g n osis of he m oc hr o mat osis, Wils o n´s 
disease, al p ha 1 a ntitr ypsi n deficie nc y , or a n y ot her c hr o nic li ver 
disease i ncl u di n g Gil bert’s disease will be e xcl u de d fr o m t he 
st u d y.
3. 
Pri or hist or y  of c h olec ystect o m y or s ple nect o m y, a n d a n y 
cli nicall y rele va nt s ur ger y wit hi n 6 m o nt hs pri or t o Scree ni n g.
4.
Hist or y  of a n y mali g na nc y.
5.
Hist or y  of c hr o nic or rec urre nt ac ute i nfecti o n or a n y 
bacterial, viral, parasitic or f u n gal i nfecti o ns wit hi n 3 0 da y s pri or 
t o Scree ni n g a n d at a n y t i me bet wee n Scree ni n g a n d a d missi o n, or 
h os pitalizati o n d ue t o i nfecti o n wit hi n 
6 m o nt hs 
pri or t o 
Scree ni n g.
6.
Hist or y  of s hi n gles wit hi n 1 2 m o nt hs pri or t o Scree ni n g.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
C ate g or y
Criteri o n
7.
Hist or y  of dr u g h y perse nsiti vit y , ascertai ne d or pres u m pti ve 
aller g y/ h yperse nsiti vit y  to 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; hist or 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 h y perse nsiti vit y reacti o n i n 
ge neral i ncl u di n g c o ntact h y perse nsi ti vit y to E C G electr o des, 
w hic h m a y  affect t he safet y of t he partici pa nt a n d/ or o utc o me of 
t he st u d y per t he I n vesti gat or’s discreti o n.
8.
Hist or y  of alc o h olis m or dr u g a b use wit hi n 2 ye ars pri or t o 
Scree ni n g, or p ositi ve f or dr u gs of a b use, nic oti ne/c ot i ni ne or 
alc o h ol b y  the la b orat or y assa ys c o n d ucte d d uri n g Scree ni n g a n d 
D a y -1.
9.
Hist or y  of resi de ntial e x p os ure t o t u berc ul osis, or a p ositi ve 
Q ua nti F E R O N ® test wit hi n 4 wee ks pri or t o or at t he ti me of 
Scree ni n g.
1 0.
P ositi ve f or a) he patitis B s urface a nti ge n, he patitis B c ore 
a nti b o d y, he patitis C a nti b o d y, or h u ma n i m m u n o deficie nc y vir us 
I a n d II tests at Scree ni n g; b) S A R S-C o V - 2 at Scree ni n g or Da y -
1.
1 1.
A n y  co n diti o n, i ncl u di n g fi n di n gs i n t he la b orat or y tests, 
me dical 
hist or y , or ot her Scree ni n g assess me nts, t hat i n t he 
o pi ni o n of t he I n vesti gat or c o nstit utes a n i na p pr o priate ris k or a 
c o ntrai n dicati o n f or partici pati o n i n t he st u d y or t hat c o ul d 
i nterfere wit h t he st u d y’s o bjecti ves, c o n d uct, or e val uati o n.
1 2.
A d mi nistrati o n of li ve vacci nes or li ve-atte n uate d vir us 
vacci nes wit hi n 3 m o nt hs pri or t o Scree ni n g. A d mi nistrati o n of 
ot her t ypes of vacci nes (e. g. S A R S -C o V -2 vacci nes, fi nal b o ost) 
is all o we d u ntil 1 wee k bef ore a d missi o n t o C R U.
N ote: I n case of cli nical s ym pt o ms, t he partic i pa nt s h o ul d be 
s ym pt o m -free f or at least 1 wee k pri or t o a d missi o n t o C R U.
Pri or/ C o nc o mita nt 
T hera p y
1 3.
M o derate 
or str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4/ 5 
wit hi n 
4 wee ks 
pri or t o t he first a d mi nistrati o n of st u d y 
i nter ve nti o n.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
C ate g or y
Criteri o n
1 4.
Use of a n y  prescri be d me dici ne or o ver -t he-c o u nter dr u g or 
dietar y  su p ple me nt, i ncl u di n g her bal re me dies, vita mi ns, a n d 
mi nerals, a ntaci ds a n d dietar y  su p ple me nts s uc h as fis h oils 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 ver 
is l o n ger, pri or t o t he first a d mi nistrati o n of st u d y i nter ve nti o n.
Occasi o nal paraceta m ol (aceta mi n o p he n) u p t o 2 g per d a y  or 
h or m o nal c o ntrace pti ves/ H R T) is per mitte d.
Pri or/ C o nc urre nt Cli nical 
St u d y  E x perie nce
1 5.
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 
6 0 d a y s pri or t o St u d y  Da y 1 ad mi nistrati o n, or ha ve use d a n 
e x peri me ntal m o n ocl o nal a nti b o d y wit hi n t he past 1 year pri or t o 
St u d y  Da y 1, or ha ve partici pate d i n a st u d y eval uati n g a B T K 
i n hi bit or wit hi n 6 0 da y s, or are o n e xte n de d f oll o w- u p i n a cli nical 
st u d y, e ve n if last a d mi nistrati o n of a st u d y inter ve nti o n was m ore 
t ha n 6 0 d a y s a g o, or 5 half -li ves of t he i n vesti gati o nal dr u g, 
w hic he ver is l o n ger, pri or t o Scree ni n g.
1 6.
Me dical 
hist or y  an d p h y sical e xa mi nati o n res ults t hat 
i ncl u de a n y o n g oi n g cli nicall y rele va nt fi n di n gs as j u d ge d b y  the 
I n vesti gat or.
Dia g n ostic Assess me nts
1 7.
Cli nicall y  rele va nt fi n di n gs (e xcl u di n g mi n or e xc ursi o ns 
fr o m n or mal ra n ges) at Scree ni n g i n bi oc he mistr y, he mat ol o g y , 
c oa g ulati o n, a n d uri nal y sis e xa mi nati o ns f or t he a ge of t he 
partici pa nt, as j u d ge d b y t he In vesti gat or:

Ala ni ne 
a mi n otra nsferase, as partate a mi n otra nsferase: 
a b o ve U L N

Creati ni ne: a b o ve n or mal li mits

A bs ol ute l ym p h oc y te c o u nt, a bs ol ute ne utr o p hil c o u nt: 
bel o w li mit of refere nce ra n ge
A m y lase a n d li pase o ut of n or mal ra n ge a n d/ or si g ns/s ym pt o ms of 
pa ncreatitis.
1 8.
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 Disease E pi de mi ol o g y  C olla b orati o n Creati ni ne E q uati o n 
( 2 0 0 9) < 9 0 m L / mi n at Scree ni n g. I n case of a b o r derli ne res ult 
bet wee n ≥ 8 0 a n d < 9 0 m L/ mi n, C y stati n C will be deter mi ne d i n 
a d diti o n, a n d t he s u bject will o nl y  be i ncl u de d if t he C y stati n C 
val ue is bel o w t he U L N .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
C ate g or y
Criteri o n
1 9.
Se mi -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, diast olic bl o o d pres s ure > 9 0 m m H g or < 5 0 m m H g, 
a n d p ulse rate > 9 0 or < 5 0 b p m at Scree ni n g. A n y a b n or mal bl o o d 
press ure res ults m a y  be re peate d o nce a n d if t he re peat res 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 ve met t he 
e xcl usi o n criteri o n.
2 0.
1 2- Lea d E C G s h o wi n g a Q Tc F > 4 5 0 ms, P R > 2 1 5 ms, or 
Q R S > 1 2 0 ms.
2 1.
A n y  ot her a b n or mal la b orat or y res ults t hat t he I nvesti gat or 
belie ves s h o ul d precl u de t he partici pa nt’s partici pati o n i n t he 
st u d y.
Ot her E xcl usi o ns
2 2.
C o ns u m pti o n of a n a vera ge wee kl y alc o h ol i nta ke of 
> 1 4 u nits/ wee k f or me n or > 7 u nits/ wee k f or w o me n. O ne u nit 
( 1 2 g) of alc o h ol e q uals ½ pi nt ( 2 8 5 m L ) of beer or la ger, 1 glass 
( 1 2 5 m L ) of wi ne, or 1/ 6 gill ( 2 5 m L ) of s pirits.
2 3.
E xcessi ve c o ns u m pti o n of xa nt hi ne -c o ntai ni n g f o 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 to 
st o p c o ns u mi n g caffei ne, fr o m 4 8 h o urs pri or t o st u d y inter ve nti o n 
a d mi nistrati o n u ntil after c ollecti o n of t he fi nal P K sa m ple.
2 4.
C o ns u m pti o n of alc o h ol fr o m 4 8 h o urs pri or t o first 
a dmi nistrati o n of st u d y  i nter ve nti o n.
2 5.
Her bal s u p ple me nts i ncl u di n g, b ut n ot li mite d t o, St. J o h n’s 
w ort 
( Hy peric u m Perf orat u m), 
gra pefr uit, Se ville 
ora n ges, 
cra n berries, or j uices of t hese fr uits wit hi n 1 4 da y s pri or t o t he first 
a d mi nistrati o n of st u d y i nter ve nti o n.
2 6.
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 
6 0 da y s pri or t o Scree ni n g, d o nati o n of plas ma fr o m 2 wee ks pri or 
t o Scree ni n g, or platelets fr o m 6 wee ks pri or t o Scree ni n g.
2 7.
Tra vel t o a c o u ntr y wit h a hi g h pre vale nce of tr o pical 
diseases wit hi n 3 m o nt hs pri or t o Scree ni n g.
2 8.
I na bilit y to c o m m u nicate relia bly wit h t he I n vesti gat or or 
c o nsi dere d b y  the I n vesti gat or t o be u na ble t o or u nli kel y t o 
c o-o perate wit h t he re q uire me nts of t he st u d y.
2 9.
Site staff, st u d y staff me m bers
a n d fa mily me m bers of t he 
Pri nci pal I n vesti gat or.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
5. 3
Lifest yle C o nsi der ati o ns
5. 3. 1
Me als a n d Diet ar y Restricti o ns
A bstai n fr o m c o ns u m pti o n of t he f oll o wi n g fr o m 1 4 d a y s bef ore t he start of st u d y inter ve nti o n 
u ntil after t he fi nal d ose : Se ville ora n g es, gra pefr uit or gra pefr uit j uice, p o mel os, e x otic citr us 
fr uits, gra pefr uit h ybri ds, or j uices fr o m t hese fr uits.
T he f oll o wi n g ge neral i nstr ucti o ns o n meals a n d dietar y  restricti o ns i ncl u di n g c o m p ositi o n a n d 
ti mi n g of meals a p ply t o b ot h st u d y  parts:

D uri n g t he i n-h o use peri o d at t he C R U f or b ot h parts, partici pa nts s h o ul d start t he 
m o derate -fat/-cal orie brea kfast 3 0 mi n utes pri or t o a d mi nistrati o n of tra ns p orter s u bstrates, 
f oll o wi n g a n o ver ni g ht fast of at least 1 0 h o urs. T he brea kfast s h o ul d be c o nsu me d wit hi n 2 5 
t o 3 0 mi n utes. L u nc h will be pr o vi de d a p pr o xi matel y 4 h o urs a n d di n ner at a b o ut 1 1 h o urs 
after t he m or ni n g d oses of st u d y  i nter ve nti o ns (e v o br uti ni b a n d/ or tra ns p orter s u bstrates). 

Start date a n d ti me a n d st o p ti me of t he brea kfast o n tra ns p orter s u bstrate d osi n g da ys, Da ys 
1 a n d 1 0 i n Part 1 a n d Da ys 1 a n d 8 i n Part 2, will be rec or de d i n t he partici pa nts’ e C R Fs as 
well as w het her t he e ntire brea kfast was c o ns u me d. If t he e ntire meal was n ot c o ns u me d, t he 
perce nta ge of meal c o ns u me d (i n q uartiles) s h o ul d be rec or de d. Start date a n d ti me a n d st o p 
ti me of di n ner o n Da y s 4 t o 1 2 will als o be rec or de d i n t he partici pa nts’ e C R F. All ot her 
meals d uri n g t he i n patie nt sta y at t he st u d y ce nter, will be sta n dar dize d a n d n o d oc u me ntati o n 
of ti me a n d c o m plete c o ns u m pti o n is nee de d.

Sta n dar d m o derate -fat, m o derate -cal orie brea kfasts o n tra ns p orter s u bstrate d osi n g d a y s i n 
t his st u d y are defi ne d as f oll o ws: a p pr o xi matel y 49 0 cal ories c o m p ose d of a p pr o xi matel y 
7 7 g of car b o h y d rates, 2 8 g of pr otei n, a n d 1 3 g of fat (Na derer 2 0 1 5 ).

All tra ns p orter s u bstrates a n d e v o br uti ni b d oses will be a d mi nistere d wit h 2 4 0 m L  water i n 
a sta n di n g p ositi o n. T hereafter, t he partici pa nts will sta y  i n a se mi-rec u m be nt p ositi o n f or at 
least 1 h o ur p ost d ose o n tra ns p orter s u bstrates d osi n g d a y s ( Da y 1 [ Part 1 a n d 2], Da y  8 
[ Part 2] a n d Da y 1 0 [ Part 1]).

O n d osi n g d a y s (see Sc he d ule of Assess me nts i n Secti o n 1. 3 ), partici pa nts ma y  co ns u me 
water a d li bit u m a n d s h o ul d dri n k at least 1. 5 L/ d a y .
D uri n g P a rt 1, st u d y i nter ve nti o ns will be a d mi nistere d u n der fe d c o n diti o ns as f oll o ws:
D a y 1 : Si n gle d ose c ocktail of di g o xi n ta blet ( 0. 2 5 m g), metf or mi n oral s ol uti o n ( 1 0 m g), a n d 
r os u vastati n ( 1 0 m g) ta blet, 0. 5 h o urs after t he start of a sta n dar d m o derate -fat, m o derate -
cal orie brea kfast . Metf or mi n will be a d mi nistere d first f oll o wi n g t he pr oce d ure descri be d b y
St o pfer 2 0 1 8 .
D a ys 4 t o 1 2 : E v o br uti ni b ( 4 5 m g) t wice dail y 0. 5 h o urs after t he start of a sta n dar dize d brea kfast 
a n d wit hi n 1. 5 h o urs of t he start of a sta n dar dize d di n ner.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
D a y 1 0 : Si n gle d oses of 0. 2 5 m g di g o xi n ta blet, 1 0 m g metf or mi n oral s ol uti o n, a n d 1 0 m g  
r os u vastati n ta blet wit h t he sc he d ule d e v o br uti ni b d ose 0. 5 h o urs after t he start of a sta n dar d 
brea kfast. 
D uri n g P a rt 2, st u d y i nter ve nti o ns will be a d mi nistere d u n der fe d c o n diti o ns as f oll o ws:

D a y 1 : Si n gle d ose of s u matri pta n ( 2 5 m g) 0. 5 h o urs after t he start of a m o derate -fat, 
m o derate -cal orie sta n dar d brea kfast.

D a ys 2 t o 8 : E v o br uti ni b ( 4 5 m g) t wice dail y  0. 5 h o urs after t he start of a sta n dar dize d
brea kfast a n d wit hi n 1. 5 h o urs of t he start of a sta n dar dize d di n ner.

D a y 8 : Si n gle d ose s u matri pta n ( 2 5 m g ) wit h t he e v o br uti ni b ( 4 5 m g) m or ni n g d ose 0. 5 h o urs 
after t he start of a m o derate- fat, m o derate -cal orie sta n dar d brea kfast.
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 oid

D uri n g eac h d osi n g peri o d , partici pa nts will a bstai n fr o m i n gesti n g caffei ne- or xa 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 oc olate) f or 4 8 h o urs bef ore t he start 
of d osi n g u ntil after c ollecti o n of t he fi nal P K a n d/ or p har mac o d y na mic sa m ple.

D uri n g eac h d osi n g peri o d , partici pa nts will a bstai n fr o m alc o h ol a n d ca n na bi n oi d -
c o ntai ni n g pr o d ucts f or 2 4 h o urs bef ore t he start of d osi n g u ntil after c ollecti o n of t he fi nal 
P K a n d/ or p har mac o d y na mic sa m ple.

Use of t o bacc o pr o d ucts will n ot be all o we d fr o m S cree ni n g u ntil after t he fi nal f oll o w- u p 
visit.
5. 3. 3
Acti vit y
Partici pa nts will a bstai n fr o m stre n u o us e xercise f or 7 2 h o urs 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 m a y  partici pate i n li g ht recreati o nal acti 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 criteria f or partici pati o n i n t his st u d y (scree n fail ure) will n ot
be rescree ne d.
5. 5
Criteri a f or Te m p or aril y Del a yi n g t he A d mi nistr ati o n of 
St u d y I nter ve nti o n A d mi nistr ati o n
N ot a p plica ble.
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  inter ve nti o n is a n y in vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or 
me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt per t he st u d y pr ot oc ol.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
I nt er v e nti o n 
N a m e
E v o br uti ni b
Di g o xi n
M etf or mi n
R o s u v a st ati n
S u m atri pt a n
T y p e 
Dr u g
Dr u g
Dr u g
Dr u g
Dr u g
D o s e 
F or m ul ati o n
Fil m -c o at e d 
t a bl et ( T F 2)
T a bl et
Or al s ol uti o n
T a bl et
T a bl et 
U nit D o s e 
Str e n gt h
4 5 m g
0. 2 5 m g 
1 0 m g
1 0 m g
5 0 m g
D o s e A m o u nt
4 5 m g, t wi c e 
d ail y, f e d
0. 2 5 m g, f e d
1 0 m g, f e d
1 0 m g, f e d
2 5 m g, f e d
Fr e q u e n c y
T w o d ail y 
t a bl et s (1 2 
h o ur s a p art 
e a c h ), D a y s 4 t o 
1 2 ( P art 1) a n d 
D a y s 2 t o 8 
( P art 2) 
Si n gl e d o s e s o n 
D a y 1 a n d 
D a y 1 0 ( P art 1)
Si n gl e d o s e s o n 
D a y 1 a n d 
D a y 1 0 ( P art 1)
Si n gl e d o s e s o n 
D a y 1 a n d 
D a y 1 0 ( P art 1)
Si n gl e d o s e s o n 
D a y 1 a n d 
D a y 8 ( P art 2)
R o ut e of 
A d mi ni str ati o n
Or al
Or al
Or al
Or al
Or al
U s e
E x p eri m e nt al
E x p eri m e nt al
E x p eri m e nt al
E x p eri m e nt al
E x p eri m e nt al
I n v e sti g ati o n al 
M e di ci n al 
Pr o d u ct (I M P) 
I M P: e v o br uti ni b
I M P: 
Tr a n s p ort er 
s u b str at e
I M P: 
Tr a n s p ort er 
s u b str at e
I M P: 
Tr a n s p ort er 
s u b str at e
I M P: 
Tr a n s p ort er 
s u b str at e
S u p pli er
M er c k 
H e alt h c ar e 
K G a A 
M er c k 
H e alt h c ar e 
K G a A 
M er c k 
H e alt h c ar e 
K G a A 
M er c k 
H e alt h c ar e 
K G a A 
M er c k 
H e alt h c ar e 
K G a A 
P a c k a gi n g a n d 
L a b eli n g
St u d y 
i nt er v e nti o n will 
b e pr o vi d e d i n 
c o nt ai n er s. 
E a c h c o nt ai n er 
will b e l a b el e d 
p er c o u ntr y 
r e q uir e m e nt. 
A d diti o n al 
d et ail s of 
p a c k a gi n g a n d 
l a b eli n g of st u d y 
i nt er v e nti o n will 
b e d efi n e d i n a 
s e p ar at e I M P 
H a n dli n g 
M a n u al.
St u d y 
i nt er v e nti o n will 
b e pr o vi d e d i n 
c o nt ai n er s. 
E a c h c o nt ai n er 
will b e l a b el e d 
p er c o u ntr y 
r e q uir e m e nt. 
A d diti o n al 
d et ail s of 
p a c k a gi n g a n d 
l a b eli n g of st u d y 
i nt er v e nti o n will 
b e d efi n e d i n a 
s e p ar at e I M P 
H a n dli n g 
M a n u al.
St u d y 
i nt er v e nti o n will 
b e pr o vi d e d i n 
c o nt ai n er s. 
E a c h c o nt ai n er 
will b e l a b el e d 
p er c o u ntr y 
r e q uir e m e nt. 
A d diti o n al 
d et ail s of 
p a c k a gi n g a n d 
l a b eli n g of st u d y 
i nt er v e nti o n will 
b e d efi n e d i n a 
s e p ar at e I M P 
H a n dli n g 
M a n u al.
St u d y 
i nt er v e nti o n will 
b e pr o vi d e d i n 
c o nt ai n er s. 
E a c h c o nt ai n er 
will b e l a b el e d 
p er c o u ntr y 
r e q uir e m e nt. 
A d diti o n al 
d e t ail s of 
p a c k a gi n g a n d 
l a b eli n g of st u d y 
i nt er v e nti o n will 
b e d efi n e d i n a 
s e p ar at e I M P 
H a n dli n g 
M a n u al.
St u d y 
i nt er v e nti o n will 
b e pr o vi d e d i n 
c o nt ai n er s. 
E a c h c o nt ai n er 
will b e l a b el e d 
p er c o u ntr y 
r e q uir e m e nt. 
A d diti o n al 
d et ail s of 
p a c k a gi n g a n d 
l a b eli n g of st u d y 
i nt er v e nti o n will 
b e d efi n e d i n a 
s e p ar at e I M P 
H a n dli n g 
M a n u al.
Ti mi n g of tra ns p orter s u bstrates a n d/ or e v o br uti ni b a d mi nistrati o n wit h re gar ds t o f o o d i nta ke 
a n d st u d y d a y is detaile d i n Secti o n 5. 3. 1 .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
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

T he In vesti 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 inter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o nciliati 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 inter ve nti o n(s), t he In vesti gat or or desi g nee will
c o nfir m 
a p pr o priate te m perat ure 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 ncies 
are re p orte d a n d res ol ve d bef 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 inter ve nti o n acc o u nta bilit y are pr o vi de d 
i n t he I MP ha n dli n g ma n ual .

O nl y  partici pa nts e nr olle d i n t he st u d y may recei ve 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 su p pl y  it. All st u d y  i nter ve 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 ual 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 priate 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 verificati o n at eac h m o nit ori n g visit.

St u d y  inter 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:

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 he defi ne d te m perat ure ra n ge.

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.

T he d ose(s) eac h pa rtici pa nt use d d uri n g t he st u d y.

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 use d st u d y i nter ve nti o n(s).

Dates, q ua ntities, batc h n u m bers, c o ntai ner n u m bers, e x pir y dates, a n d t he partici pa nt 
n u m bers.

T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y d oc u me nt 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 inter ve nti o n(s) pr o vi de d were f ully 
rec o ncile d.

U n use d st u d y inter 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 
pre se nt st u dy. 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 be re -dis pe nse d t o 
a differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y c ollect t he st u d y i nter ve nti o n(s) acc o u nta bilit y f or ms.

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal di s p ositi o n of u n use d st u d y i nter ve nti o n(s) are 
pr o vi de d i n t he I M P ha n dli n g 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
N ot a p plica ble as t his is a n o nra n d o mize d st u d y .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
After i nf or me d c o nse nt p r oce d ure, e ver y partici pa nt is gi ve n a scree ni n g n u m ber. O nl y 
partici pa nts w h o c o m pl y wit h all selecti o n criteria (see Secti o ns 5. 1 a n d 5. 2 ) ca n be i ncl u de d 
i nt o t he st u d y. Pri or t o t he first a d mi nistrati o n, t he partici pa nts e nr olle d will be assi g ne d t o a 
u ni q ue 3 -di gits assi g n me nt n u m ber i n asce n di n g n u merical or der. 
T he I n vesti gat or will kee p a rec or d relati n g t he partici pa nt assi g n me nt n u m bers a n d t he na mes 
of all partici pa nts (i ncl u di n g scree ni n g n u m ber a n d t he N u visa n G m b H i de ntificati o n n u m ber) 
w h o ha ve gi ve n t heir i nf or me d c o nse nt, t o all o w eas y c hec ki n g of data i n partici pa nt files, w he n 
re q uire d. T his rec or d will als o i ncl u de t he date of partici pa nt’s e nr oll me nt a n d c o m pleti o n, as 
well as partici pa nts w h o c o ul d n ot be assi g ne d t o st u d y  i nter ve nti o n f or w hate ver reas o n.
6. 3. 2
Bli n di n g
N ot a p plica ble as t his is a n o pe n -la bel st u d y.
6. 3. 3
E mer ge nc y U n bli n di n g
N ot a p plica ble as t his is a n o pe n -la bel st u d y.
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 h e y will recei ve st u d y inter ve nti o n directl y fr o m t he 
I n vesti gat or or desi g nee, u n der me dical s u per 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 me nts a n d rec or de d i n t he C R F.  The d ose of 
st u d y inter ve nti o n a n d st u d y partici pa nt i de ntificati o n will be c o nfir me d at t he ti me of d osi n g b y 
a me m ber of t he st u d y site staff ot her t ha n t he pers o n a d mi nisteri n g t he st u d y inter ve nti o n. St u d y  
site pers o n nel will e xa mi ne eac h partici pa nt’s m o ut h t o e ns ure t hat t he st u d y inter ve nti o n was 
i n geste d.
6. 5
D ose M o dific ati o n
D oses will n ot be m o difie d.
6. 5. 1
Retre at me nt Criteri a
N ot a p plica bl e.
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
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 lea ve t he st u d y 
beca use s uc 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 t he ma xi m u m d ose i n t he st u d y that is 
c o nsi dere d safe a n d well t olerate d wit hi n a 2 4 -h o ur ti me peri o d will be c o nsi dere d a n o ver d ose.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
T he S p o ns or has n o s pecific rec o m me n dati o n f or treati n g a n o ver d ose of e v o br uti ni b. T he 
I n vesti gat or will use his cli nical j u d g me nt t o ma na ge a n y o ver d ose, c o nsi deri n g t he s ym pt o ms 
a n d a n y site pr oce d ures or sta n dar ds.
Rec o m me n dati o n f or treat me nt of a n o ver d ose of di g o xi n, metf or mi n, 
r os u vastati n, or 
s u matri pta n is descri be d i n t he res pecti ve S m P C.
E ve n if n ot ass ociate d wit h a n A E or a S A E, a n y  over d ose is rec or de d i n t he C R F a n d re p orte d 
t o gl o bal 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 S A E a n d O ver d ose 
Re p ort F or m, f ol l o wi n g t he pr oce d ure i n A p pe 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 ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di ng 
a n y cha 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, rec 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.
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 hera p y.
6. 8. 1
Resc ue Me dici ne
N o a nti d ote is a vaila ble s pecifically f or e v o br uti ni b. S ym pt o matic treat me nt will be pr o vi de d i n 
case of a me dical e mer ge nc y .
A n y ki n d of t o xicit y  occ urri n g d uri n g t he st u d y will be treate d sy m pt o maticall y .
F or f urt her i nf or mati o n see t he S m P Cs a n d prescri bi n g i nf or mati o n f or di g o xi n, metf or mi n, 
r os u vastati n, a n d s u matri pta n.
6. 8. 2
Per mitte d Me dici nes
T he o nl y  per mitte d me dici nes are t he f oll o wi n g:
1. Paraceta m ol u p t o 2 g per da y , at t he discreti o n of t he In vesti gat or
2. H or m o nal c o ntrace pti ves a n d H R T (see  A p pe n di x 3 ).
A n y  me dici 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 mer ge ncies
ma y  be gi ve n at t he I n vesti 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. 3
Pr o hi bite d Me dici nes
Pr o hi bite d me dici nes at st u d y  e ntr y are i n dicate d i n t he e xcl usi o n criteria ( Secti o n  5. 2 ).
T he partici pa nts are pr o hi bite d fr o m usi n g prescri pti o n or o ver -t he-c o u nter me dicati o ns (a part 
fr o m t h ose descri be d a b o ve) wit hi n 2 wee ks or 5 ter mi nal half -li ves, w hic he ver is l o n ger, pri or 
t o t he first a d mi nistrati o n of st u d y i nter ve nti o n, d uri n g t he st u d y, a n d u ntil t he Safety F oll o w -u p 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
assess me nt (t his i ncl u des her bal re me dies, vita mi ns, mi nerals, a ntaci ds a n d dietar y s u p ple me nts 
s uc h as fis h oils). 
M o derate 
or str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4/ 5 wit hi n 4 wee ks pri or t o t he first 
a d mi nistrati o n of st u d y i nter ve nti o n u ntil after t he Safet y Foll o w -u p assess me nt are pr o hi bite d. 
Als o, dr u gs mai nl y  meta b olize d b y C Y P 3 A 4/ 5 a n d t hat ha ve a narr o w t hera pe utic i n de x s h o ul d 
be a v oi de d.
6. 8. 4
Ot her I nter ve nti o ns
A d diti o nal restricti o ns t hat st u d y partici pa nts s h o ul d a d here t o fr o m Da y  - 1 u ntil t he Safet y 
F oll o w -u p Assess me nt are detaile d i n Secti o n  5. 2.
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
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
A partici pa nt m ust be wit h dra w n fr o m a d mi nistrati o n of st u d y inter ve nti o n if a n y of t he 
f oll o wi n g occ ur: 

Partici pa nt wit h dra ws c o nse nt. 

A partici pa nt is e nr olle d b ut is s u bse q ue ntl y  disc o vere d n ot t o ha ve met i ncl usi o n/e xcl usi o n 
criteria at Scree ni n g. 

A Es, if disc o nti n uati o n of st u d y inter ve nti o n is c o nsi dere d necessar y  by t he I n vesti gat or 
a n d/ or desire d b y t he partici pa nt. T his i ncl u des i n partic ular A Es of se vere i nte nsit y an d 
S A Es re gar dless of t he relati o ns hi p t o st u d y i nter ve nti o n.

Pre g na nc y (see Secti o n 8. 3. 4) .

Pr ot oc ol n o nc o m plia nce j u d ge d as si g nifica nt b y  the I nvesti gat or (after disc ussi o n wit h t he 
S p o ns or).

Use of a n o n per mitte d c o nc o mita nt dr u g if cli nicall y rele va nt as a gree d b y  Sp o ns or a n d 
I n vesti gat or, as defi ne d i n Secti o n  5. 2, w here t he pre defi ne d c o nse q ue nce is wit h dra wal fr o m 
st u d y i nter ve nti o n.

A n y  e ve nts t hat u nacce pta bl y e n da n ger t he safety of t he partici pa nt. 
If st u d y inter ve nti o n is per ma ne ntl y disc o nti n ue d, t he partici pa nt will re mai n i n t he st u d y to be 
e val uate d f or safet y. T he Sc he d ule of Assess me nts i n dicates data t o be c ollecte d at t he ti me of 
disc o nti n uati o n of st u d y  i nter ve nti o n a n d f oll o w-u p a n d f or a n y  furt her e val uati o ns t hat nee d t o 
be c o m plete d.
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

A partici pa nt m a y  disc o nti n ue 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 at t he 
discreti o n of t he I n vesti gat or f or safet y, be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

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.

A partici pa nt m ust be wit h dra w n if a n y of t he f oll o wi n g occ urs d uri n g t he st u d y :

Pre g na nc y .

A Es, if st u d y disc o nti n uati o n is c o nsi dere d necessar y  by t he I n vesti gat or a n d/ or desire d 
b y  the partici pa nt. T his i ncl u des i n partic ular A Es of se vere i nte nsity a n d S A Es 
re gar dless of t he relati o ns hi p t o st u d y treat me nt.

Use of n o n per mitte d c o nc o mita nt me dicati o ns, as defi ne d i n Secti o n  6. 8 . H o we ver, a ny 
me dicati o ns 
t hat are c o nsi dere d necessar y  for t he partici pa nt’s well bei n g 
(e. g., 
paraceta m ol u p t o 2 g per da y ) ma y be gi ve n at t he discreti o n of t he I n vesti gat or.

Pr ot oc ol 
n o nc o m p lia nce j u d ge d as si g nifica nt b y  the I n vesti gat or, i ncl u di n g 
n o nc o m plia nce t o t he re q uire d st u d y co nsi derati o ns (e. g., f o o d/ diet re q uire me nts), as 
defi ne d i n Secti o ns  5. 1, 5. 2 , 5. 3, 6. 1, a n d 8.

If a partici pa nt has faile d t o atte n d sc he d ule d st u d y assess 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 urately 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 Me dical M o nit or a n d cli nical st u d y 
lea der f or t he S p o ns or will be i nf orme d i m me diatel y .

If t here is a me dical reas 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 st u d y disc o nti n u ati o n, 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 he Sc he d ule of Assess me nts ( Secti o n 1. 3) . T he Sc he d ule of Assess me nts s pecifies 
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 plete d.

If t he partici pa nt re v o kes c o nse nt f or t he st u d y, a n y data 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 nerate d, a n d a n y bi ol o gical sa m ples c ollecte d will be 
destr o y e d.

A partici pa nt has t he ri g ht at a n y ti me t o re q uest destr 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 a n d t he C R F a n d i nf or m t he 
S p o ns or. T he sa m ples will be destr o ye d.
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 ke 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 ntacte d by 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:
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

T he site will atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici 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 s h o ul d c o nti n ue i n t he st u d y .

Bef ore a partici pa nt is dee me d “l ost t o f oll o w-u p ”, t he In vesti gat or or desi 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, se n d a certifie d letter ( or a n e q ui vale nt l ocal 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 pa nt has gi ven t he a p pr o priate c o nse nt, c o ntact t he 
partici pa nt’s ge neral practiti o ner or careta ker ( w here all o we d b y  local re 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 rec or d.

If t he partici pa nt c o nti n ues t o be unreac ha ble, 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 Sc he d ule of 
Assess me nts .

N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.

I m me diate safety c o ncer ns are disc usse d wit h t he S p o ns or i m me diatel y up o n occ urre nce or 
a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y  i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Assess m e nts, is esse ntial a n d re q uire d f or st u dy c o n d uct.

All scree ni n g e val 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 he In vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partic i 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 pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will o btai n writte n i nf or me d c o nse nt a s 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 bef ore si g ni n g of t he I CF m a y  be use d f or scree ni n g or baseli ne p ur p oses pr o vi de d 
t he pr oce d ures met t he pr ot oc ol-s pecifie d criteria a n d were perf or me d wit hi n t he ti me fra me 
defi ne d i n t he Sc he d ule of Assess me nts.

N o m ore t ha n 1 5 0 m L  of bl o o d ma y be dra w n i n a 2 4-h o ur peri o d, a n d n o m ore t ha n 3 0 0 m L  
of bl o o d i n a 4 -wee k peri o d.

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 m a y b e 
tra nsferre d t o a bi o ba n k a n d use d f or f ut ure researc 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 nsfer t o t he bi o ba n k will be d oc u me nte d a n d 
a n y testi n g of c o de d bi o ba n k sa m ples will n ot be re p orte d in t he C S R.

T he l o n g-ter m st ora ge of sa m ples after st u d y c o m pleti o n f or f ut ure researc h m a y  be 
perf or me d wi t h all sa m ple t ypes c ollecte d i n t he st u d y (e. g., P K, 
, 
bi o mar kers, or i m m u n o ge netics) if t he partici pa nt c o nse nts t o o pti o nal f ut ure me dical 
researc h.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

De m o gra p hic data c ollecte d at Scree ni n g will i ncl u de, at mi ni m u m, a ge, se x, race (c ollecte d 
o nl y  w here all o we d b y l ocal la w/re g ulati o ns), a n d et h nicit y.
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
N ot a p plica ble.
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 be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ys is of baseli ne me dical c o n diti o ns, A Es, p h ysical e xa mi nati o n fi n di n gs, vital si g ns, E C Gs, 
a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y p ote nt ial t o xicit y ex perie nce d b y  eac h partici 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 vesti gat or will re p ort a n y AEs, w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  the 
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 y sical 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 vasc ular, res pirat or y, g astr oi ntesti nal a n d n e ur ol o gical s yste ms.

A brief p h y sical 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 ys te m, a n d a b d o me n (li ver a n d s plee n).

I n vesti gat ors will p a y  s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses.
8. 2. 2
Vit al Si g ns

Bl o o d press ure a n d partici pa nt’s p ositi o n; p ulse ; res pirat or y rate; t ym pa nic te m perat ure a n d 
l ocati o n of meas ure me 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 ure a n d p ulse meas ure me nts will be prece de d b y at least 5 mi n utes of rest f or t he 
partici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e. g., tele 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. Ma n ual tec 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.
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 Sc he d ule of Assess me nts usi n g a n 
E C G mac hi ne t hat a ut o maticall y  meas ures heart rate, P R, R R, Q R S, Q T , a n d c orrecte d Q T 
i nter val b y Bazett’s f or m ula or Q Tc F. D oc u me ntati o n of t he Q Tc F is ma n dat or y .

1 2- Lea d E C Gs will be rec or de d i n a s u pi ne p ositi o n f oll o wi n g 5 mi n utes of rest.
8. 2. 4
Cli nic al S afet y L a b or at or y Assess me nts

Bl o o d a n d uri ne sa 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
at t he ti me p oi nts liste d i n t he Sc he d ule of Assess me nts .All sa m ples will be clearl y i de ntifie d. 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

A d diti o nal tests ma y  be perf or me d at a n y ti me d uri n g t he st u d y, as deter mi ne d necessar y b y 
t he In vesti gat or or re q uire d b y  l ocal re g ulati o ns.

T he tests will be perf or me d b y  N u visa n G m b H la b orat or y; t he Q ua nti F E R O N ® Test will be 
perf or me d b y S y nla b, A u gs b ur g, Ger ma n y.

S A R S -C o V -2 tests at Scree ni n g a n d Da y  - 1 will be perf or me d as per l ocal re g ulati o ns.

T he In vesti gat or will re vie 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 urri 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 pe 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 oc u me nts.

Pre g na nc y  testi n g (ser u m or hi g hly se nsiti ve uri ne, as re q uire d b y l ocal re g ulati o ns) will be 
c o n d ucte d at m o nt hl y i nter vals d uri n g st u d y i nter ve nti o n a d mi nistrati o n.

Pre g na nc y  testi n g (ser u m or hi g hly se nsiti ve uri ne, as re q uire d b y l ocal re g ulati o ns) will be 
c o n d ucte d at t he e n d of rele va nt s ys te mic e x p os ure of t he st u dy i nter ve nti o n a n d c orres p o n d 
wit h t he ti me fra me f or fe male partici pa nt c o ntrace pti o n i n Secti o n 5. 1.

A d diti o nal ser u m or uri ne pre g na nc y  t esti n g m a y  be c o n d ucte d at a n y ti me d uri n g t he st u d y 
t o esta blis h t he a bse nce of pre g na nc y , at t he I n vesti gat or’s discreti o n or if l ocal re g ulati o ns 
re q uire t he m.
8. 3
A d verse 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 a S A E are i n A p pe n di x 4 .

T he I n vesti gat or a n d a n y qualifie 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 oc u me nti n g, a n d rec or di n g e ve nts t hat meet t he de fi 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 seri o us, c o nsi dere d relate d t o 
t he st u d y inter ve nti o n or st u d y pr oce d ures, or t hat ca 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 pecifie d i n Secti o n  8. 3. 2.

Re q uests f or f oll o w- u p will us uall y  be ma de via t he S p o ns or or cli nical researc h or ga nizati o n -
desi g nate d st u d y tea m me m ber , alt h o u g h i n e xce pti o nal circ u msta nces t he gl o bal patie nt
safety de part me nt ma y  co ntact t he I nvesti gat or directl y  to o btai n f urt her i nf or mati 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 assessi n g ca usalit y of A Es a n d S A Es a n d t he 
p r oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n A p pe n di x 4 .

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 Safet y F oll o w -u p 
V isit at t he ti me p oi nts s pecifie d i n t he Sc he d ule of Assess me nts ( Secti o n 1. 3 ). Be y o n d t his 
re p orti n g peri o d, a ny n e 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 ocesse d.

All S A Es will be rec or de d a n d re p orte d t o t he S p o ns or or desi g nee i m me diatel y, as i n dicate d 
i n A p pe n di x 4 . T he I n vesti gat or will s u b mit a n y  u p date d S A E data t o t he S p o ns or wit hi n 2 4 
h o urs of i t bei n g a vaila ble usi n g t he sa me pr oce d ure t hat was use d f or t he i nitial re p ort.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

I n vesti gat ors are n ot o bli gate d t o acti vel y s olicit i nf or mati o n o n A Es or S A Es after t he e n d of 
st u d y partici pati o n. H o we ver, if t he In vesti gat or lear 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 ve nt t o 
be reas o na bl y relate d t o t he st u d y inter 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  notif 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 detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d 
n o n- lea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met 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 assessi n g ca usalit y of A E s a n d S A E s a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti 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 vesti gat or is re q uire d t o pr oacti 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 a n d A ESI s (as defi ne d i n Secti o n 8. 3. 7 ) 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 to e ns ure t hat a n y necessar y  ad diti o nal 
t hera pe utic meas ures a n d f oll o w- u p pr oce d ures are perf or me d. F urt her 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  the 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 hreate ni n g 
a n d 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 w ar ds 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 res p o nsi bilit y to n otif y  bot h t he l ocal re g ulat or y a ut h orit y an d ot her 
re g ulat or y age ncies a b o ut t he safet y of a st u d y inte r ve nti o n u n der cli nical 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 pecific re g ulat or y re q uire me nts relati n g t o safety re p orti n g 
t o t he re g ulat or y a ut h orit y, IR B/I E C, a n d In vesti gat ors.
I n di vi d ual Case Safet y Re p orts will
be pre pare d f or S U S A R s 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 In vesti gat ors, as necessar y .
A n In vesti gat or w h o recei ves a n I n di vi d ual Case Safet y  Re p ort descri bi n g a S U S A R or ot her 
s pecific safety 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 re vie w a n d file it i n t he I n vesti gat or’s Site File a n d will 
n otif y  t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
8. 3. 4
Pre g n a nc y

Details of all pre g na ncies i n fe male partici pa nts wil l be c ollecte d after t he start of st u d y 
i nter ve nti o n a n d u ntil Safet y  F oll o w-U p .

If a pre g na nc y  is re p orte d, t he In vesti gat or will rec or d t he pre g na nc y  inf or mati o n o n t he 
a p pr o priate 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 fe male partici pa nt 
pre g na nc y .

W hile pre g na nc 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 nc y c o m plicati o n or 
electi ve ter 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 nc 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 nge nital a n o malies, ect o pic 
pre g na nc 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 wa ys 
c o nsi dere d t o be a n S A E a n d will be re p orte d as s uc h.

T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y . T he I n vesti gat or 
will c ollect f oll o w-u p i nf or mati o n o n t he partici pa nt a n d t he ne 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 b e 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 here is a defi nite o utc o me of t he e ve nt .

A n y  post -st u d y pre g na nc y relate d S A E c o nsi dere d reas o na bly 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 vesti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y 
partici pa nts / pre g na nt fe male part ner , he or s he ma y  lear n of a n S A E t hr o u g h s p o nta ne o us 
re p orti n g.

A n y  fe male partici 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.
8. 3. 5
C ar di o v asc ul ar a n d De at h E ve nts
N ot a p plica ble.
8. 3. 6
Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes 
N ot Q u alif yi n g as A Es or S A Es
N ot a p plica ble.
8. 3. 7
A d verse E ve nts of S peci al I nterest
F or t his st u d y , A E SI(s) i ncl u de o nl y  t he f oll o wi n g:

I nfecti o ns (seri o us, se vere, a n d o p p ort u nistic, ≥Gra de 3) 
As per its mec ha nis m of acti o n, e v o br uti ni b m a y  i m pair B cell f u ncti o n w hic h mi g ht lea d t o 
a decrease d h u m ora l i m m u nit y an d c o nse q ue ntl y a n i ncrease d ris k of i nfecti o n. O verall, i n 
c o m plete d st u dies i n partici pa nts t he Me dical Dicti o nar y  for Re g ulat or y  Acti vities S O C 
i nfecti o n was o ne of t he m ost re p orte d S O Cs (e. g., i n t he M S 2 0 0 5 2 7 _ 0 0 8 6 R M S st u d y 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
a p pr o xi matel y 18 % t o 3 2 % of partici pa nts treate d wit h e v o br uti ni b re p orte d i nfecti o n; a 
si milar rate was re p orte d i n t he place b o gr o u p i n t he 0 t o 2 4 wee k peri o d), t he i n di vi d ual 
e ve nts were of l o w gra de, mai nl y Gra de 1, n o nseri o us a n d di d n ot lea d t o st u d y  i nter ve nti o n 
disc o nti n uati o n. Treat me nt of i nfecti o ns m ust be pr o m pt a n d d o ne i n acc or da nce wit h l ocal 
sta n dar d of care de pe n di n g o n c o nsi derati o ns s uc h as t he nat ure a n d se verit y of t he i nfecti o n 
a n d partici pa nt’s o verall healt h stat us. A n y C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts Gra de ≥3 or S A Es of i nfecti o n a n d o p p ort u nistic i nfecti o n are c o nsi dere d as a n A E SI.

Seiz ures
Seiz ures are m ore c o m m o n i n patie nts wit h M S t ha n i n t he ge neral p o p ulati o n, occ urri n g i n 
2 % t o 3 % of M S patie nts (P oser 2 0 0 3) . C o n v ulsi o ns were o bser ve d i n earl y st u dies of 
e v o br uti ni b i n d o gs, h o we ver t he plas ma c o nce ntrati o n of e v o br uti ni b was a p pr o xi matel y 
1 4 0- f ol d greater t ha n it is pre dicte d f or t he d ose use d i n t his st u d y. O ne partici pa nt wit h R M S 
wit h si g nifica nt brai n lesi o n l oa d re p orte d seiz ure of u nclear cli nical pict ure. T he P K data f or 
t his partici pa nt di d n ot e xcee d t he e x pecte d val ues a n d was si milar t o ot her partici pa nts i n t he 
st u d y. A ntic o n v ulsa nt t hera p y was starte d, a n d t he partici pa nt c onti n ue d treat me nt wit h 
e v o br uti ni b wit h n o re occ urre nce. T he I n vesti gat or di d n ot c o nsi der t he e ve nt t o be relate d t o 
e v o br uti ni b. N o e ve nt of c o n v ulsi o n/seiz ure was re p orte d i n ot her i n dicati o ns. E v o br uti ni b 
has bee n a d mi nistere d t o a p pr o xi matel y 80 0 pati e nts wit h M S, 
rhe u mat oi d art hritis a n d 
sys te mic lu p us er yt he mat os us. M ore o ver, 
a n electr oe nce p hal o gra m st u d y in healt h y 
v ol u nteers di d n ot s h o w a n e pile pt o ge nic p ote ntial f or e v o br uti ni b. A n y  ty pe of 
seiz ures/e pile ps y of a n y gra de or its c o nse q ue nces are classifie d as A E SIs.

Ele vate d li pase, ele vate d a m y lase, pa ncreatitis
As y m pt o matic ele vati o ns i n a m ylase or li pase or b ot h i n partici pa nts treate d wit h e v o br uti ni b 
ha ve bee n o bser ve d at a variet y of ti me p oi nts a n d re p orte d as T E A Es or n ote d as la b orat or y  
a b n or malities. I n R M S St u d y  MS 2 0 0 5 2 7 _ 0 0 8 6, t he i nci de nce of T E A Es of li pase i ncrease d 
was sli g htl y hi gher i n e v o br uti ni b 7 5 m g o nce dail y  an d 7 5 m g  twice dail y  ar ms ( 5 [ 9. 4 %] 
a n d 5 [ 9. 3 %], res pecti vel y) w he n c o m pare d t o ot her ar ms (a p pr o xi matel y bet wee n 4 % t o 6 %). 
H o we ver, s hifts fr o m Baseli ne t o hi g hest gra de o n treat me nt were si milar acr oss all treat me nt 
ar ms f or b ot h a m yl ase a n d li pase. I n ev o br uti ni b st u dies i n ot her i n dicati o ns a n d i n healt h y 
partici pa nts, t he i nci de nce of T E A Es of i ncrease d a m ylase or li pase, or b ot h was i nfre q ue nt 
a n d n o cli nicall y mea ni n gf ul differe nces were o bser ve d acr oss treat me nt ar ms. A n y  ele vati o n 
of > 2 × U L N of li pase or a m y lase a n d a n y ty pe of pa ncreatitis are classifie d as A E SI s.

Li ver relate d e ve nts
T he ele vati o ns of tra n sa mi nases o bser ve d i n partici pa nts treate d wit h e v o br uti ni b were 
fre q ue nt, asy m pt o matic, a n d re versi ble o n disc o nti n uati o n of e v o br uti ni b. T he mec ha nis m is 
u n k n o w n. 
E v o br uti ni b li ver A E SIs will i ncl u de tra nsa mi nases ( > 3 × U L N), bilir u bi n ele vati o ns 
( > 1. 5 × U L N) , bi ol o gical H y ’s La w cases base d o n la b orat or y data, a n y t ype of ac ute or 
c hr o nic he patitis (a ny gra de), s us pecte d dr u g -i n d uce d li ver i nj ur y, ac ute or c hr o nic he patic 
fail ure, fi br osis, cirr h osis, a n d ot her li ver da ma ge-relate d c o n diti o ns.
A E SI s ha ve t o re p orte d i m me diatel y. F or re p orti n g of A E SIs, see A p pe n di x 4 .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
8. 4
P h ar m ac o k i netics
F or details o n P K sa m pli n g refer t o t he Sc he d ule of Assess me nts i n Secti o n 1. 3 a n d Ta ble 1 f or 
P K sa m pli n g d uri n g Part 1 a n d  Ta ble 2 f or P K sa m pli n g d uri n g Part 2.

T he f oll o wi n g P K para meters will be calc ulate d, w he n
a p pr o priate f or t he tra ns p orter 
s u bstrates ( di g o xi n, metf or mi n, r os u vastati n, a n d s u matri pta n):
S y m b ol
D efi niti o n
A U C 0- ∞
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) 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 tl a st, a s e sti m at e d u si n g t h e li n e ar r e gr e s si o n fr o m λ z
d et er mi n ati o n. 
A U C 0- ∞= A U C 0- tl a st + C l a st pr e d/ λz
A U C 0- tl a st
T h e A U C fr o m ti m e z er o ( = d o si n g ti m e) t o t h e l a st s a m pli n g ti m e (t l a st) at 
w hi c h t h e c o n c e ntr ati o n i s at or a b o v e t h e l o w er li mit of q u a ntifi c ati o n. 
C al c ul at e d u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g 
d o w n).
A U C 0- 3 6
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 3 6 h o ur s p o st d o s e ( m etf or mi n 
o nl y) . C al c ul at e d usi n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g 
d o w n).
C 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 (t h e fir st o c c urr e n c e i n t h e c a s e of m ulti pl e/i d e nti c al C m a x
v al u e s) .
t1/ 2
A p p ar e nt t er mi n al h alf -lif e. t1/ 2 = l n ( 2)/ λ z
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- ∞.
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.
A e 0- 3 6
T h e c u m ul ati v e a m o u nt e x cr et e d fr o m ti m e z er o ( = d o si n g ti m e) t o t h e e n d 
of t h e c oll e cti o n i nt er v al aft er d o si n g , c al c ul at e d f or m etf or mi n o nl y.
C L R
R e n al cl e ar a n c e . C L R = A e 0- 3 6 / A U C0- 3 6 , c al c ul at e d for m etf or mi n o nl y.
C l a st pr e d= t h e pr e di ct e d c o n c e ntr ati o n at t h e l a st s a m pli n g ti m e, c al c ul at e d fr o m t h e l o g- li n e ar r e gr e s si o n li n e f or λ z
d et er mi n ati o n .
P art 1

W h ole 
bl o o d sa m ples of a p pr o xi matel y 4 m L  per ti me p oi nt f or meas ure me nt of plas ma 
c o nce ntrati o ns of di g o xi n, metf or mi n, a n d r os u vastati n, will be c ollecte d o n Da ys 1 t o 4 a n d 
D a y s 1 0 t o 1 3 (Ta ble 1 ).

W h ole bl o o d sa m ples of a p pr o xi matel y 2 m L  for meas ure me nt of plas ma c o nce ntrati o ns of 
e v o br uti ni b will be c ollecte d o n Da ys 1 0, 1 1, 1 2 (Ta ble 1 ).

Uri ne will be c ollecte d f or metf or mi n a nal ys is (as it is 1 0 0 % eli mi nate d b y re nal e xcreti o n) 
o n Da y s 1 t o 2 a n d Da y s 1 0 t o 1 1 a n d a n ali q u ot will be ta ke n fr o m eac h c ollecti o n i nter val 
f or c o nce ntrati o n meas ure me nts (Ta ble 1 ). T he v ol u me of uri ne fr o m eac h c ollecti o n i nter val 
will be meas ure d.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
P art 2

W h ole bl o o d sa m ples of a p pr o xi matel y 2 m L  for meas ure me nt of plas ma c o nce ntrati o ns of 
s u matri pta n will be c ollecte d o n Da ys 1 t o 2 a n d Days  8 t o 9 (Ta ble 2 ).

W h ole bl o o d sa m ples of a p pr o xi matel y 2 m L  f or meas ure me nt of plas ma c o nce ntrati o ns of 
e v o br uti ni b will be c ollecte d o n Da y s 6, 7, a n d 8 (Ta ble 2 ).
C ollecti o n ti mes are s pecifie d i n t he Sc he d ule of Assess me nts ( Secti o n 1. 3 ). T he act ual date a n d 
ti me ( 2 4-h o ur cl oc k ti me) of eac h sa m ple will be rec or de d t o calc ulate act ual ti me ela pse d si nce 
t he pri or d ose a d mi nistrati o n. F or uri ne sa m ples, the act ual start a n d e n d date a n d ti me ( 2 4 - h o ur
cl oc k ti me) of eac h uri ne fracti o n, as well as t he v ol u me of eac h uri ne c ollecti o n fracti o n, will 
be rec or de d.

T he q ua ntificati o n of e v o br uti ni b, di g o xi n, metf or mi n, r os u vastati n, a n d s u matri pta n i n 
plas ma sa m ples, a n d metf or mi n i n uri ne sa m ples, will be perf or me d usi n g f ull y vali date d 
assa y met h o ds. C o nce ntrati o ns will be use d t o e val uate t he P K para meters of t he tra ns p orter 
s u bstrates, a n d e v o br uti ni b c o nce ntrati o ns will be s u m marize d.

Re mai ni n g 
sa m ples c ollecte d f or a nal ys es of e v o br uti ni b a n d tra ns p orter s u bstrate 
c o nce ntrati o ns m a y  als o be use d t o e val uate safet y or efficac y as pects relate d t o c o ncer ns 
arisi n g d uri n g or after t he st u d y. A d diti o nall y , re mai ni n g plas ma sa m ples ma y  be use d f or 
i n vesti gati o n of e v o br uti ni b or tra ns p orter s u bstrate meta b olites.

Details o n pr ocesses 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. Rete nti o n ti me a n d p ossi ble a nal ys es of sa m ples after t he E n d of St u d y  are s pecifie d 
i n t he res pecti ve I CF. 

P K para meters will be deri ve d usi n g n o nc 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 her; Certara, L. P., Pri ncet o n , Ne w 
Jerse y, U S A).
T he e xact date a n d ti me of sa m ple c ollecti o n a n d st u d y inter ve nti o n a d mi nistrati 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 sa m pli n g ti mes t hat will n ot be c o nsi dere d a 
pr ot oc ol vi olati o n are liste d i n Ta ble 4.
T a ble 4
P K Sa m pli n g Ti me Wi n d o ws
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
- 6 0 mi n
0. 2 5 t o 1 h o ur s p o st d o s e
± 2 mi n
> 1 t o 1 2 h o ur s p o st d o s e
± 5 mi n
> 1 2 t o 2 4 h o ur s p o st d o s e
± 1 5 mi n
> 2 4 t o 7 2 h o ur s p o st d o s e
± 3 0 mi n
A n y  de viati o n fr o m t he a b o ve-me nti o ne d ti me wi n d o ws re q uires a c o m me nt i n t he e C R F a n d 
ma y  be disc usse d i n t he d ata re vie w m eeti n g. 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
8. 6
Bi o m ar k ers
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.
9
St atistic al C o nsi der ati o ns
All pla n ne d a nal yses defi ne d i n t his pr ot oc ol will be descri be d i n t he I A P t hat will be fi nalize d 
bef ore t he data base l oc k.
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a nal yses, if a n y, will be re p orte d i n t he 
a p pr o priate secti o n of t he I A P a n d i n t he C S R .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
9. 1
St atistic al H y p ot hes es
T he statistical a nal ys is of st u d y data will be p urel y  descri pti ve; n o h y p ot hesis tests will be 
perf or me d. A defi niti o n of pri mar y  an d sec o n dar y objecti ves a n d e n d p oi nts ca n be f o u n d i n 
Secti o n  3.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
9. 3
A n al yses Sets
T he a nal ys is p o p ulati o ns are s pecifie d bel o w i n Ta ble 7 . T he fi nal decisi o n t o e xcl 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 data re vie w meeti n g pri or t o 
data base l oc k.
T a ble 7
A n al ysis Sets
A n al y s i s S et
D e s cri pti o n
S cr e e ni n g 
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
e nr oll m e nt a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.
S af et y ( S A F)
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n. 
A n al y s e s will c o n si d er p arti ci p a nt s a s tr e at e d.
P h ar m a c o ki n eti c ( P K )
T h e P K A n al y si s S et i s a s u b s et of t h e S A F, a n d th e P K p o p ul ati o n will i n cl u d e all 
p arti ci p a nt s:

W h o h a v e c o m pl et e d t h e st u d y wit h o ut a n y r el e v a nt pr ot o c ol d e vi ati o n s a n d 
f a ct or s li k el y t o aff e ct t h e c o m p ar a bilit y of P K r e s ult s.

Wi t h a d e q u at e st u d y i nt er v e nti o n c o m pli a n c e.

Wi t h e v al u a bl e P K d at a, i. e., n o mi s si n g v al u e s f or pri m ar y e n d p oi nt s at e a c h P K 
pr ofil e/ a s s e s s m e nt d a y ( D a y 1, D a y 1 0 f or P art 1; D a y 1 a n d D a y 8 f or P art 2) .
If p arti ci p a nt s r e c ei v e d pr o hi bit e d c o n c o mit a nt t h er a p y or m e di ci n e s, a s s p e cifi e d i n 
S e cti o n 6. 8. 3 , t h e y will b e e x cl u d e d fr o m t h e P K p o p ul ati o n.
All P K a n al y s e s will b e b a s e d o n t hi s a n al y si s s et.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
9. 4
St atistic al A n al yses
Statistical a nal ysis will be perf or me d usi n g t he c o m p uter pr o gra m pac ka ge S A S ® S y ste m 
(release 9. 2 or later versi o n; S A S I nstit ute, Car y  NC, U S A). M ore details o n t he statistical 
a nal ys is will be prese nte d i n t he I A P pri or t o data base l oc k.
T he statistical a nal ys is will n ot be starte d u ntil all data ha ve bee n c orrecte d a n d c hec ke d f or 
pla usi bilit y , a n d u ntil all necessar y c o di n g a n d assess me nts ha ve bee n c o m plete d.
Me dical hist or y  an d A E ter ms will be c o de d wit h t he latest versi o n of t he Me dical Dicti o nar y 
f or Re g ulat or y  Acti vities ( Versi o n 2 3. 0 or later); c o nc o mita nt me dicati o n will be c o de d wit h 
W H O 
Dr u g Dicti o nar y , W H O 
Dr u g Refere nce Li st a n d A nat o mical T hera pe utic C he mical 
Classificati o n S y ste m, latest versi o ns. Versi o ns of dicti o naries use d f or c o di n g will be defi ne d 
i n t he Data Ma na ge me nt Pla n.
All data rec or de d d uri n g t he st u d y will be prese nte d i n i n di vi d ual data li sti n gs.
F or de m o gra p hic (e. g., a ge [ deri ve d], se x, race, et h nicit y, etc.), baseli ne, a n d safety a ssess me nts, 
c o nti n u o us meas ure me nts will be s u m marize d b y  mea ns of descri pti ve statistics (i.e. n u m ber a n d 
perce nta ge of o bser vati o ns, n u m ber a n d perce nta ge of missi n g o bser vati o ns, mea n, S D, me dia n, 
t he first a n d t hir d q uartile [ Q 1 a n d Q 3], Mi n, a n d Ma x), a n d cate g orical data will be s u m marize d 
b y  mea ns of fre q ue nc y ta bles (i.e., c o u nt a n d perce nta ges), if n ot state d ot her wise. 
All data will be e val uate d as o b ser ve d, n o i m p utati o n met h o d f or missi n g val ues. T he ha n dli n g 
of c o nce ntrati o n val ues bel o w t he li mit of q ua ntificati o n will be descri be d i n t he I A P.
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 ys es will be perf or me d o n t he Safet y  A nal y sis p o p ulati o n ( Secti o n 9. 3 ). 
R ef er e n c e
C at e g or y
St ati sti c al A n al y si s
Pri m ar y
N ot a p pli c a bl e.  
N ot a p pli c a bl e.
S e c o n d ar y
N at ur e, o c c urr e n c e, a n d 
s e v erit y of T E A E s
M ai n
A E c o u nt s a n d p arti ci p a nt s wit h A E s will b e s u m m ari z e d f or 
e a c h tr e at m e nt b y S O C a n d P T.
A b s ol ut e v al u e s a n d c h a n g e s 
i n s af et y l a b or at or y t e st s fr o m 
ti m e of fir st d o s e t o e n d of 
st u d y p arti ci p ati o n
M ai n
S af et y l a b or at or y p ar a m et er s will b e li st e d f or e a c h 
p arti ci p a nt i n cl u di n g c h a n g e s fr o m B a s eli n e a n d fl a g s f or 
m e a s ur e m e nt s o ut si d e t h e r ef er e n c e r a n g e s, w h er e 
a p pli c a bl e. 
L a b or at or y p ar a m et er s ( h e m at ol o g y a n d cli ni c al c h e mi str y) 
will b e s u m m ari z e d b y ti m e p oi nt i n cl u di n g b ot h 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.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
R ef er e n c e
C at e g or y
St ati sti c al A n al y si s
Si n gl e 1 2 -l e a d E C G s 
e v al u at e d b y I n v e sti g at or 
fr o m ti m e of fir st d o s e t o e n d 
of st u d y p arti ci p ati o n
M ai n
E C G d at a will b e s u m m ari z e d b y a b s ol ut e a n d c h a n g e s 
fr o m B a s eli n e v al u e s b y tr e at m e nt u si n g d e s cri pti v e 
st ati sti c s. Cli ni c al n ot e w ort h y E C G fi n di n g s f or i n di vi d u al 
p arti ci p a nt s will b e li st e d a n d s u m m ari z e d a s a p pr o pri at e.
Vit al si g n s a s s e s s e d fr o m 
ti m e of fir st d o s e t o e n d of 
st u d y p arti ci p ati o n
M ai n
Vit al si g n s b y p arti ci p a nt, i n cl u di n g c h a n g e s fr o m B a s eli n e, 
will b e li st e d a n d s u m m ari z e d b y tr e at m e nt a n d ti m e p oi nt 
u si n g d e s cri pti v e st ati sti c s .
A E = a d v er s e e v e nt; E C G = el e ctr o c ar di o gr a m; P T = pr ef err e d t er m; S O C = s y st e m or g a n cl a s s; T E A E =tr e at m e nt -
e m er g e nt a d v er s e e v e nt.
9. 4. 3
Ot her A n al yses
P h ar m ac o k inetic A n al yses
Details o n t he P K a nal ys is will be i n t he I AP t hat will be fi nalize d bef ore data base l oc k.
P art 1
A n al ysis of Pri m a r y E n d p oi nts
A ge neral li near m o del wit h a fi xe d effect f or T R E A T M E N T a n d a ra n d o m effect f or S U BJ E C T
will be a p plie d t o l o g -tra nsf or me d P K para meters Cma x a n d A U C 0 -∞base d o n t he P K a nal ysis set
t o assess t he effect of m ulti ple d oses of e v o br uti ni b o n t he P K of t he tra ns p orter s u bstrates 
di g o xi n, metf or mi n, a n d r os u vastati n. Treat me nt differe nces o n t he l o g scale of tra ns p orter 
s u bstrates wit h e v o br uti ni b vs s u bstrates al o ne ( Da y 1 0 vers us Da y 1) will be esti mate d f or C ma x
a n d A U C 0 - ∞t o get her wit h t heir 9 0 % CIs.
P oi nt esti mates a n d CI s will be bac k tra nsf or me d t o t he ori gi nal scale. 
A n al ysis of Sec o n d ar y E n d p oi nts
T he sa me a nal ys is m o del as descri be d f or t he pri mar y  en d p oi nts will be pr o vi de d f or t he 
sec o n dar y e n d p oi nt A U C0-t last of tra ns p orter s u bstrates.
T he sa me a nal ys is m o del as descri be d f or t he pri mar y  en d p oi nts will be pr o vi de d f or t he 
sec o n dar y e n d p oi nt C L R of metf or mi n o nl y .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
P art 2
A n al ysis of Pri m ar y E n d p oi nts
A ge nera l li near m o del wit h a fi xe d effect f or T R E A T M E N T a n d a ra n d o m effect f or S U BJ E C T
will be a p plie d t o l o g -tra nsf or me d P K para meters Cma x a n d A U C 0- ∞base d o n t he P K a nal ysis set
t o assess t he effect of m ulti ple d oses of e v o br uti ni b o n t he P K of t he tra ns p orter s u bstrate 
s u matri pta n. Treat me nt differe nces o n t he l o g scale of s u matri pta n wit h e v o br uti ni b vs 
s u matri pta n al o ne ( D a y 8 vers us D a y  1) will be esti mate d f or C ma x a n d A U C 0- ∞t o get her wit h 
t heir 9 0 % CIs.
P oi nt esti mates a n d CI s will be bac k tra nsf or me d t o t he ori gi nal scale.
A n al ysis of Sec o n d ar y E n d p oi nts
T he sa me a nal ys is m o del as descri be d f or t he pri mar y  en d p oi nts will be pr o vi de d f or t he 
sec o n dar y e n d p oi nt A U C0-t last of s u matri pta n.
9. 4. 4
Se q ue nce of A n al yses
All fi nal, pla n ne d a nal y ses i de ntifie d i n t he cli nical 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 use, all data q ueries res ol ve d, a n d t he data base l oc ke d.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
1 0
Refere nces 
C h u X, Lia o M, S he n H, et al. I nter nati o nal Tra ns p orter C o ns orti u m. Cli nical Pr o bes a n d 
E n d o ge n o us Bi o mar kers as S u bstrates f or Tra ns p orter Dr u g -Dr u g I nteracti o n E val uati o n: 
Pers pecti ves 
Fr o m 
t he I nter nati o nal Tra n s p orter C o ns orti u m. 
Cli n 
P har mac ol 
T her. 
2 0 1 8; 1 0 4: 8 3 6 - 6 4.
Di g o xi n 
S m P C 
Ta blets 
B P 
2 5 0 m g,
Electr o nic 
Me dici ne 
C o m pe n di u m .
htt ps:// w w w. me dici nes. or g. u k/e mc/ me dici ne/ 2 3 9 4 4 # gref. Last accesse d o n 6 Fe b 2 0 2 1 .
Giac o mi ni K, H ua n g S, T wee die D, et al. Me m bra ne tra ns p orters i n dr u g de vel o p me nt. Nat Re v 
Dr u g Disc o v. 2 0 1 0; 9: 2 1 5 -3 6.
Hill gre n K, Ke p pler D, Z ur A, et al. E mer gi n g tra ns p orters of cli nical i m p orta nce: a n u p date 
fr o m t he I nter nati o nal Tra ns p orter C o ns orti u m. Cli n P har mac ol T her. 2 0 1 3; 9 4: 5 2 - 6 3.
K ö ni g J, M ü ller F, Fr o m m M. Tra ns p orters a n d dr u g – dr u g i nteracti o ns: i m p orta nt deter mi na nts 
of dr u g dis p ositi o n a n d effects. P har mac ol Re v . 2 0 1 3; 6 5: 9 4 4 - 6 6.
Metf or mi n 
S m P C
1 0 0 m g/ ml 
Oral 
S ol uti o n , Electr o nic Me dici ne 
C o m pe n di u m ( E M C). 
htt ps:// w w w. me dici nes. or g. u k/e mc/ pr o d uct/ 3 3 6 0/s m pc . Last accesse d o n 7 Fe b 2 0 2 1.
Na derer O, J o nes L S , Z h u J, et al. T he effect of f o o d a n d f or m ulati o n o n t he p har mac o ki netics, 
safety, a n d t olera bilit y  of G S K 1 3 2 2 3 2 2 i n healt h y v ol u nteers. Cli n P har mac ol Dr u g De v. 2 0 1 5;
4( 1): 4 9 - 5 5.
P oser C M , Bri nar V V. E pile ps y  a n d m ulti ple scler osis. E pile ps y  Be ha v. 2 0 0 3; 4( 1): 6- 1 2.
Pr ue ksarita n o nt T, Tat osia n D A, C h u X, et al . Vali dati o n of a micr o d ose pr o be dr u g c oc ktail f or 
cli nical dr u g i nteracti o n assess me nts f or dr u g tra ns p orters a n d C Y P 3 A. Cli n P har mac ol T her .
2 0 1 7; 1 0 1: 5 1 9 -3 0.
R os u vastati n 
S m P C 
1 0 m g 
ta blets. 
Electr o nic 
Me dici ne 
C o m pe n di u m 
( E M C).
htt ps:// w w w. me dici nes. or g. u k/e mc/ pr o d uct/ 7 5 5 9/s m pc . Last accesse d o n 6 Fe b 2 0 2 1.
Scarf ò L, C hatzi k o nsta nti n o u T, Ri g oli n G M, et al. C O VI D -1 9 se verit y a n d m o rtalit y in patie nts 
wit h c hr o nic l y m p h oc y tic le u ke mia: a j oi nt st u d y b y E RI C, t he E ur o pea n Researc h I nitiati ve o n 
C L L, a n d C L L Ca m p us. Le u ke mia. 2 0 2 0; 1 - 1 0.
S hi bata M, T o y os hi ma J, Ka ne k o Y, et al. A dr u g – dr u g i nteracti o n st u d y  t o e val uate t he i m pact 
of pef iciti ni b o n O C T 1- a n d M A T E 1 -me diate d tra ns p ort of metf or mi n i n healt h y  vol u nteers . E ur 
J Cli n P har mac ol. 2 0 2 0; 7 6: 1 1 3 5– 1 1 4 1.
St o pfer P, Giess ma n n T, H o hl K, et al. O pti miz ati o n of a dr u g tra ns p orter pr o be c oc ktail: 
p ote ntial scree ni n g t o ol f or tra ns p orter-me diate d dr u g – dr u g i nteracti o ns. Br J Cli n P har mac ol. 
2 0 1 8; 8 4: 1 9 4 1 - 9.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
St o pfer P, Giess ma n n T, H o hl K, et al . P har mac o ki netic e val uati o n of a dr u g tra ns p orter c oc ktail 
c o nsisti n g of di g o xi n, f ur ose mi de, metf or mi n, 
a n d r os u vastati n. Cli n 
P har mac ol T her. 
2 0 1 6; 1 0 0: 2 5 9 -6 7.
S u matri pta n 
S m P C 
5 0 m g 
ta blets, 
El ectr o nic 
Me dici ne 
C o m pe n di u m. 
htt ps:// w w w. me dici nes. or g. u k/e mc/ pr o d uct/ 7 0 7/s m pc # gref . Last accesse d o n 1 3 Mar 2 0 2 1.
T hi ba u d S, Tre m bla y  D, B halla S, et al. Pr otecti ve r ole of Br ut o n t yr osi ne ki nase i n hi bit ors i n 
patie nts wit h c hr o nic l y m p h oc y tic le u kae mia a n d C O VI D- 1 9. Br J Hae mat ol. 2 0 2 0; 1 - 3.
Tre o n S P, Castill o JJ, S kar b ni k A P, et al. T he B T K i n hi bit or i br uti ni b ma y  protect a gai nst 
p ul m o nar y  i nj ur y i n C O VI D- 1 9-i nfecte d patie nts. Bl o o d. 2 0 2 0; 1 3 5( 2 1): 1 9 1 2- 1 5.
Wie be S, Giess ma n n T, H o hl K, et al. Vali dati o n of a Dr u g Tra ns p orter Pr o be C oc ktail Usi n g 
t he Pr ot ot y pical I n hi bit ors Rifa m pi n, 
Pr o be neci d, Vera pa mil, 
a n d Ci meti di n e. Cli nical 
P har mac o ki net . 2 0 2 0;5 9: 1 6 2 7 - 1 6 3 9.
Z ha n g L, S parre b o o m A. Pre dicti n g tra ns p orter-me diate d dr u g i nteracti o ns: c o m me ntar y on: 
“P har mac o ki netic e val uati o n of a dr u g tra ns p orter c oc ktail c o nsisti n g of di g o xi n, f ur ose mi de, 
metf or mi n a n d r os u vastati n” a n d “Vali dati o n of a micr o d ose pr o be dr u g c oc ktail f or cli nical dr u g 
i nteracti o n assess me nts f or dr u g 
tra ns p orters a n d C Y P 3 A ”. Cli n 
P har mac ol 
T her. 
2 0 1 7; 1 0 1: 4 4 7 - 9.
Z ol k O, Fr o m m M. Tra ns p orter -me diate d dr u g u pta ke a n d effl u x:i m p orta nt deter mi na nts of 
a d verse dr u g reacti o ns. Cli n P har mac ol T her. 2 0 1 1; 8 9: 7 9 8- 8 0 5.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
1 1
A p pe n dices
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
A p pe n di x 1
A b bre vi ati o ns
(e) C R F
( Electr o nic) Case Re p ort F or m
A E
A d verse E ve nt
A E SI
A d verse E ve nts of S pecial I nterest
a P T T
Acti vate d Partial T hr o m b o plasti n Ti me
B C R P
B reast C a ncer R esista nce P r otei n
B T K
Br ut o n’s T yr osi ne K i nase
CI
C o nfi de nce Inter val
C O VI D - 1 9
C or o na vir us D isease 2 0 1 9
C R U
Cli nical Researc h U nit
C S R
Cli nical St u d y  Re p ort
C V
C oefficie nt of Variati o n
C Y P
C y t oc hr o me P 4 5 0
D DI
Dr u g -dr u g Interacti o n
D N A
De o x yri b o n ucleic Aci d
E C G
Electr ocar di o gra m
E u dra C T
E ur o pea n Cli nical Trials Data base
F S H
F ollicle Sti m ulati n g H or m o ne
G C P
G o o d Cli nical Practice
H R T
H or m o ne R e place me nt T hera p y
I A P
I nte grate d A nalys is Pla n
I B
I n vesti gat or’s Br oc h ure
I CF
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 N R
I nter nati o nal N or malize d Rati o
I RB
I nstit uti o nal Re vie w B oar d
M A T E 1/ 2
M ulti dr u g a n d T o xi n E xtr usi o n 1/ 2
M C H
Mea n C or p usc ular He m o gl o bi n
M C V
Mea n C or p usc ular V ol u me
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
M S
M ulti ple
S cler osis
N M E
N e w M olec ular E ntit y
O A T ( P)
O r ga nic A ni o n T ra ns p orter ( P ol ype pti de)
O C T 1  
O r ga nic C ati o n T ra ns p orter 1
P- g p
P -gl yc o pr otei n
P K
P har mac o ki netic (s)
Q Tc F
C orrecte d Q T Inter val b y  Fri dericia’s F or m ula
Q T L
Q ualit y  T olera nce Li mits
R M S
Rela psi n g M ulti ple S cler osis
S A E
Seri o us A d verse E ve nt
S A R S -C o V - 2
Se vere A c ute R es pirat or y Sy n dr o me C or o na vir us T y pe 2
S m P C
S u m mar y  of Pr o d uct C haracteristics
S O C
S y ste m O r ga n C lass
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 - Emer ge nt A d verse E ve nt
U L N
U p per Li mit of N or mal
W O C B P
W o ma n of C hil d beari n g P ote ntial
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
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 vesti gat ors a n d S u b -I n vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate 
fi na ncial i nf or mati o n, as re q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate 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 dy 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/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y 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 meets t he 
re q uire me nts of 2 1 C F R 5 0; l ocal re g ulati o ns; I CH g ui deli nes; Healt h I ns ura nce P orta bilit y 
a n d Acc o u nta bilit y  Act re q uire me nts, w here a p plica ble; a n d t he I RB/I E C or st u d y  ce nter.

T he me dical rec 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 nd t he date t he writte n c o nse nt was o btai ne d. 
T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt will als o si g n t he I C F.

If t he I CF is u p date d d uri n g t heir partici pati o n i n t he st u d y , partici pa nts will be re -c o nse nte d 
t o t he m ost c urre nt, a p pr o ve d versi o n.
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  partici pa nt rec or ds or datasets t hat are tra nsferre d t o t he S p o ns or will c o ntai n 
t he i de ntifier o nly;  partici pa nt na mes or a n y i de ntifia ble 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 data will be use d per 
l ocal data 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 uire d t o gi ve c o nse nt f or t heir 
data t o be use d, as s pecifie d i n t he i nf or me d c o nse nt .

T he partici pa nt will be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y  Cli nical 
Q ualit y  Ass ura nce 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 n el, b y a p pr o priate 
I RB/I E C me m bers, a n d b y  re g ulat or y aut h orit y i ns pect 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 vesti gat ors f or de cisi o ns a n d 
disc ussi o ns o n t his st u d y, per I CH G C P. T he Pri nci pal I nvesti 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 xec 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 C S R .

T he st u d y will be c o n d ucte d at a si n gle ce nter, t he Cli nical P har mac ol o g y  Unit of N u visa n 
G m b H, Ne u -Ul m, Ger ma n y . N u visa n G m b H will be res p o nsi ble f or t he f oll o wi n g acti vities:
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

Cli nical c o n d uct a n d la b orat or y  ser vices

Data ma na ge me nt

Statistical pr o gra m mi n g a n d a nal ys is

P K a nal y sis

Me dical writi n g

I n de pe n de nt m o nit ori n g

Me dical m o nit ori n g

Pr oject ma na ge me nt

Re g ulat or y  ser vices

Cli nical trial s u p plies will be pr o vi de d by T her m o Fis her.

Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate O perati o ns 
Ma 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 ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

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 ncl 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 nizati o ns
of Me dical 
Scie nces I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G C P G ui deli nes

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 CF, I n vesti 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 su b mitte d t o a n I RB/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 xce 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 partici pa nts. W he n a p plica ble, a me n d me 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.
E mer ge nc y Me dic al S u p p ort

T he S p o ns or or desi g nee 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 hese pr o vi de t he mea ns f or partici pa nts t o i de ntif y the msel ves as 
partici pati n g i n a cli nical st u d y. Als o, t hese gi ve 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 nee 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  Me dical S u p p ort car d ma y 
i ncl 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).
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

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 he partici pa nt.  Co nse q ue ntl y , t he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact 
i nf or mati o n o n t he car d. If t he I nvesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y  su bse q ue 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 In vesti gat or is n ot a vaila ble, t he P hase I facilit y will pr o vi de t he a p pr o priate mea ns 
t o c o ntact a p h y sicia n. T his i ncl u des t he pr o visi o n of a 2 4- h o ur c o ntact 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 priate p h y sicia n t o assist 
wit h t he me dical e mer ge nc y an 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 ura nce 
c o n diti o ns will meet g o o d l ocal sta n dar ds, as a p plica ble.
Cli nic al St u d y Re p ort

After st u d y co m pleti o n, t he S p o ns or will write a C S R i n c o ns ultati o n wit h t he Pri nci pal 
I n vesti gat or a n d ot her rele va nt st u d y-a p p oi nte d e x perts of t he S p o ns or a n d N u vis a n G m b H.
P u blic ati o n

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is 
f oresee n, t he I n vesti 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 to 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 vid ual site data.

A ut h ors hi p will be deter mi ne d b y  agree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
Disse mi n ati o n of Cli nic al St u d y D at a

A s u m mar y  of data will be pr o vi de d t o Cli nical Trials. g o v as well as t o t he E ur o pea n Cli nical 
Trial Data base, as a p plica ble, a n d will occ ur 1 2 m o nt hs after t he last cli nic visit of t he fi nal 
st u d y partici pa nt or a n ot her a p pr o priate date t o meet a p plica ble re q uire me nts. 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 xa mi nati o ns at re q uest. After 
fi nalizati o n of t he st u d y, healt h y  partici 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 D ata base at re q uest.

After c o m pleti o n of t he st u d y , a C S R will be writte n b y  t he S p o ns or i n c o ns ultati o n wit h t he 
Pri nci pal I nvesti gat or f oll o wi n g t he g ui da nce i n I CH 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  an d all scie ntific, c o m mercial, a n d tec h nical i nf or mati o n discl ose d b y  the S p o ns or i n t his 
pr ot oc ol or else w here 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 perty 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 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
i nf or mati o n t o a n y thir d part y  exce pt t o s uc h of t he I nvesti gat or’s e m pl o yees a n d staff w h o 
ha d bee n ma de a ware 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  to 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 pur 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 an d, if t he parties deci de 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 ucti n g 
t he st u d y.

T he I n vesti gat or u n dersta 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  the 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 nter ve 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 vesti gat ors, t o t he F D A, E M A, a n d 
t o ot her g o ver n me nt a ge ncies. T he I nvesti gat or als o u n dersta n ds t hat, t o all o w f or t he use of 
t he i nf or mati o n deri ve d fr o m t he cli nical st u dy, t he I n vesti gat or has t he 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 xce 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 data will be rec or de d o n pri nte d or electr 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., la b orat or y d ata). T he I n vesti gat or is res p o nsi ble f or 
verif y i n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y by p h y sicall y or 
electr o nicall y si gni n g t he C R F. Details f or ma na gi n g C R Fs are i n t he Data Ma na ge me nt Pla n .

T he I n vesti gat or will
mai ntai n acc u rate d oc u me 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 nce a u dits, I RB/ I E C 
re vie w, a n d re g ulat or y age nc y  ins pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d 
s ource data.

Q T L s will be pre defi ne d i n t he O perati o nal Ma n ual t o i de ntif y sys te matic iss ues t hat ca n 
i m pact partici pa nt safety a n d/ or relia bilit y of st u d y res ults. T hese pre defi ne d para meters will 
be m o nit ore d d uri n g t he st u d y  a n d i m p orta nt de viati o ns fr o m t he Q T Ls a n d re me dial acti o ns 
ta ke n will be s u m marize d i n t he C S R . 
N ote: Q T Ls will n ot be defi ne d i n t his P hase I  st u d y as neit her t he li mite d n u m ber of pla n ne d 
partici pa nts n or t he s h ort d urati o n of t he st u d y s u p p ort t he c ollecti o n of mea ni n gf ul Q T Ls.

M o nit ori n g details descri bi n g strate g y (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 uire me nts, i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues a n d 
m o nit ori n g tec h ni q ues (ce ntral, 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 .

T he S p o ns or or desi g nee is res p o nsi ble f or D ata M a na ge me nt of t his st u d y, i ncl u di n g q ualit y 
c hec ki n g of t he data a n d mai ntai ni n g a vali date d data b ase. Data base l oc k will occ ur o nce 
q ualit y  co ntr ol a n d q ualit y  ass ura nce pr oce d ures ha ve bee 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  Mo nit ors will perf or m o n g oi n g s o urce 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 verifia ble; t hat t he safety a n d ri g hts of partici pa nts are bei n g 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
pr otecte d; a n d t hat t he st u d y  is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d pr ot oc ol a n d a n y  
ot her st u d y  a gree me nts, 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 retai n r ec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he 
c o n d uct of t his st u d y for 1 5 ye ars after st u d y co m pleti o n, u nless l ocal 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 re te nti o n. N o rec or ds ma y be 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 m a y  be tra 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 de e vi de n ce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d.

T he I n vesti gat or will mai ntai n s o urce d oc u me 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 tra nscri be d fr o m s o urce d oc u me nts will be c o nsiste nt wit h 
t he s o urce d oc u me nts or t he discre pa ncies will be e x plai ne d. T he I n vesti gat or m a y  nee d t o 
re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt 
me dical rec or ds will be a vaila 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  the 
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 vesti gat or e ns ures t hat n o destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he S p o ns or’s 
writte n a p p r o val.

Defi niti o n of w hat c o nstit utes s o urce data is fo u n d i n t he S o urce Data L ocati 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 pa nt si g ns t he I CF.
St u d y a n d Site Cl os ure

T he I nvesti 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 use a n d 
e n o u g h n otice is gi ve 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 vesti gat or ma y  i ncl u de:

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 uire 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 na de q uate recr uit me nt of partici pa nts b y  t he I n vesti 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

If t he st u d y is pre mat urel y  ter mi nate d or s us pe n de d, t he S p o ns or will pr o m ptl y  inf or m 
t he I n vesti gat ors, t he I ECs/I R Bs, t he re g ulat or y aut h orities, a n d a n y t hir d-part y ser vice 
pr o vi ders 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  the a p plica ble 
re g ulat or y re q uire me nts. T he I n vesti gat or will pr o m ptl y  inf or m t he partici pa nts a n d 
ass ure a p pr o priate partici pa nt t hera p y a n d/ or f oll o w - u p.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
A p pe n di x 3
C o ntr ace pti o n a n d B arrier Re q uire me nts
Defi niti o ns:
W O C B P:
A w o ma n is of c hil d beari n g p ote ntial (fertile) f oll o wi n g me narc he 
a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g., a me n orr hea i n a d olesce 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 ca use.

A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge ma y  be 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 nal c o ntrace pti o n or H R T. H o we ver, 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 ore 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 uire 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 he 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, per ma ne nt sterilizati o n i ncl u des:

D oc u me nte d h ys terect 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 he 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 due t o a n alter nate me dical ca use ot her t ha n 
t he a b o ve, (e. g., M ulleria n a ge nesis, 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.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
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 C B P, 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.
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 ntir 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.
[ B arri er M et h o d s (t o b e u s e d i n a d diti o n t o a hi g hl y eff e cti v e m et h o d)

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]
N ot e 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 o n t h e u s e of c o ntr a c e pti v e m et h o d s f or 
cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h 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.
If l o c all y r e 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 ed 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.
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 f or t hi s st u d y. 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 fr o m fri cti o n).
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 /7 4
A p pe n di x 4
A d verse 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 unt o war d me dical occ urre nce i n a patie nt or cli nical st u d y partici pa nt, 
te m p orall y ass ociate d wit h t he use of st u dy 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 heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s ym pt o m, or disease ( ne w or e xacer bate d) te 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 gical or dia g n ostic pr oce 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 he 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  ab n or mal la b orat or y test res ults (he mat ol o g y , cli nical c he mistr y, or uri nal y sis) or ot her 
safety assess me nts (e. g., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), i ncl 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 pa nt’s c o n diti o n are c o nsi dere 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 (i.e., n ot relate d t o p r o gressi o n of u n derl yi n g disease , b ut m a y  
be lea di n g t o st u d y  i nter ve nti o n disc o nti n uati o n).

E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n i ncrease 
i n fre q ue 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 ose 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 bee 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 uelae of a s us pecte d D DI .

Si g ns, s ym pt o ms, or t he cli nical se q uelae 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 nc 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 gical acti o n” per se will n ot be 
re p orte d as a n A E or a S A E.  Ho we ver, t he si g ns, s ym pt o ms, a n d/ or cli nical se q uelae 
res ulti n g fr o m lac k of efficac y will be re p orte d as a n A E or a S A E if t he y fulfil 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  the In vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n diti o n, a n y cli nically 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 safety 
assess me nts t hat are ass ociate d wit h t he u n derl yi n g disease, 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 ga tor.

Me dical or s ur gical pr oce d ure (e. g., e n d osc 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 
occ urre nce 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).
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4

A ntici pate d d a y -t o-d a y  fl uct uati o ns of pre -e 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 ve 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, deat h 
d ue t o pr o gressi o n of disease).
A S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m 'life-t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e ve 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 oes 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 deat 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 detai ne d ( us uall y in v ol vi n g 
at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war 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 y sicia 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 pitalizati o n or f ulfils 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 
seri o us.

H os pitalizati o n f or electi ve treat me nt of a pre -e 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 pitalizati o ns or u n pla n ne d pr ol o n gati o n of a n 
electi ve h os pitalizati 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 nces of relati vely m i n or me dical si g nifica nce 
s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma 
(e. g., s prai ne d a n kle) w hic h m a y  interfere wit h or pre ve nt e ver yd a 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
f.
Ot her sit u ati o ns:

Me dical or scie ntific j u d g me nt will
be e xercise 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  not be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y  je o par dize t he 
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 /7 4
partici pa nt or m a y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts are us uall y c o nsi dere d as seri o us.

E xa 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 treat me nt i n a n 
e mer ge nc y ro o m or at h o me f or aller gic br o nc h os pas m, bl o o d d y scrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de 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 oses, as s pecifie d bel o w f or re p orti n g S A Es or A E SI s.
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 vesti gat or t o re vie 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 ve nt.

T he In vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.

As nee de d, S p o ns or/ desi g nee m a 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 urce d oc u me ntati o n. All partici pa nt i de ntifiers, e xce pt 
t he partici pa nt n u m ber, will be re dacte 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/ desi g nee.

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 b ase d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s ym 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.
Assess me nt of I nte nsit y
T he In vesti gat or will assess 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 an d 
assi g n it t o 1 of t he f oll o wi n g cate g ories:

Mil d: A n e ve nt t hat is easil y tolerate d b y  the partici pa nt, ca usi n g mi ni mal disc o mf ort a n d 
n ot i nterferi n g wi t h e ver yd a y  acti vities.

M o derate: A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal e ver y da y 
acti vities.

Se vere: A n e ve nt t hat pre ve nts n or mal e ver yd a y  acti vities.  Do n ot c o nf use a n A E t hat is 
assesse d as se vere wit h a 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 ve nt; 
b ot h A Es a n d S A Es ca n be assesse d as se 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 he n it is rate d as se vere.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 /7 4
Assess me nt of C a us alit y

T he I n vesti gat or will assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h A E/ S A E 
occ urre nce:

U nrelate d: N ot 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 n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d to t he st u d y inter ve nti o n. A reas o na ble 
alter nati ve e x pla nati o n will be a vaila ble.

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 gically/ 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 usal relati o ns hi p, rat her t ha n a relati 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 y i n g disease(s), c o nc o mita nt t hera py, a n d ot her ris k 
fact ors, as well 
as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y inter 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 gat or will als o c o ns ult t he I B a n d/ or Pr o d uct I nfor mati o n, f or mar kete d 
pr o d ucts, 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 vie we d t he A E/ S A E a n d assesse d ca usalit y.

T here m a y  be sit uati o ns w he n a n S A E has occ urre d , a n d t he I n vesti gat or has 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 m a y  cha n ge his/ her ca usalit y assess 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 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 usalit y  assess 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 uire me nts.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 /7 4
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 ueste d b y  t he S p o ns or/ desi g nee 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 tests 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.

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w-u p 
peri o d, t he I n vesti gat or will pr o vi de t he S p o ns or/ desi g nee wit h a c o p y o f a n y p ost-m orte m 
fi n di n gs i ncl u di n g hist o pat h ol o g y.

Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y  c o m plete d C R F.

T he In vesti gat or will s u b mit a n y up date d S A E data t o t he S p o ns or/ desi g nee i m me diatel y 
after o btai ni n g k n o wle d ge ( wit h o ut u n d ue dela y ).
Re p orti n g of S A Es
S A E Re p orti n g b y a P a per F or m

S A E re p orti n g o n a pa per re p ort f or m m a y  b e use d i n si n gle ce nter st u dies i n a d diti o n t o 
t he sta n dar d electr o nic C R F a n d as a bac k - u p met h o d f or a n Electr o nic Data Ca pt ure
s yste m fail 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, n a 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 nic f or m as s o o n as t he s yste m bec o mes a vaila ble.

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 met h o d f or tra ns missi o n a n d will be d o ne i m me diately t o t he S p o ns or or its 
desi g nee.

I n rare circ 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 ne 
is acce pta ble wit h a c o py of t he f or m se nt by o ver ni g ht mail or c o urier ser vice.

I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he In vesti gat or t o c o m plete 
a n d si g n t he f or m i m me diatel y after bec o m i 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 dical hist or y , 
c o nc o mita nt me dicati o n). T he data pr o vi de d will be c o nsiste nt wit h t he i nf or mati o n i n t he 
C R F.
Re p orti n g of A E SIs

F or a n o nseri 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 the 
S p o ns or i m me diatel y , usi n g t he sa me pr ocess f or re p orti n g S A E s, as s pecifie d a b o ve.

F or a seri 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 ve.
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 /7 4
Re p orti n g of Pre g n a ncies

Pre g na nc y  will be re p orte d w het her relate d t o t he st u d y inter 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 na nc y  occ 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 met 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 .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 /7 4
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
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 h it 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)
H e m at o crit
W h it e Bl o o d C ell C o u nt
R e d bl o o d c ell c o u nt
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
T ot al Bilir u bi n
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
T ot al 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 h ol e st er ol
Uri c a ci d
C hl ori d e
γ - Gl ut a m yl -tr a n sf er a s e
Tri gl y c eri d e s
C- r e a cti v e 
pr ot ei n
I n or g a ni c 
p h o s p h at e
L a ct at e d e h y dr o g e n a s e
A m yl a s e
M a g n e si u m
Cr e ati n e p h o s p h o ki n a s e
Li p a s e
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 ( h e m o gl o bi n), k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, 
l e u k o c yt e e st er a s e b y di p sti c k

Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n or m al wit h p o siti v e di p sti c k) .

N ot e: I n c a s e of a p o siti v e r e s ult f or h e m o gl o bi n, l e u k o c yt e e st er a s e, pr ot ei n or 
nitrit e, a fl o w c yt o m etr y c o u nt a n d cl a s sifi c ati o n will b e p erf or m e d
C o a g ul ati o n

I N R

a P T T
Pr e g n a n c y T e sti n g

S er u m 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 at all ti m e p oi nt s li st e d i n t h e 
S c h e d ul e of A s s e s s m e nt s ( S e cti o n 1. 3 ) ( a s n e e d e d f or a W O C BP)
Ot h er S cr e e ni n g 
T e st s

F S H ( a s n e e d e d if a p o st m e n o p a u s al w o m a n o nl y , at S cr e e ni n g o nl y)

Uri n e dr u g s cr e e n (t o i n cl u d e at mi ni m u m: a m p h et a mi n e s, m et h a m p h et a mi n e s, 
b ar bit ur at e s, e c st a s y, c o c ai n e, o pi at e s, c a n n a bi n oi d s, b e n z o di a z e pi n e s, m et h a d o n e, 
p h e n c y c li di n e, o x y c o d o n e, a n d tri c y cli c a nti d e pr e s s a nt s) ( S cr e e ni n g a n d D a y -1)

S er ol o g y ( h u m a n i m m u n o d efi ci e n c y vir u s I a n d II a nti b o di e s, 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, Q u a nti F E R O N ® T e st, at 
S cr e e ni n g o nl y)

S A R S -C o V -2 t e st  ( S cr e e ni n g a n d D a y -1)

T h yr oi d sti m ul ati n g h or m o n e ( T S H , at S cr e e ni n g o nl y)

C oti ni n e t e st ( S cr e e ni n g a n d D a y - 1)

Al c o h ol br e at h t e st ( S cr e e ni n g a n d D a y -1)

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, S cr e e ni n g o nl y)

C y st ati n C (if a p pli c a bl e), at S cr e e ni n g o nl y)
All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y a c e ntr al l a b or at or y, 
(N u vi s a n’ s cli ni c al l a b or at or y) .
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI

E v o br uti ni b ( M 2 9 5 1 )
Dr u g -Dr u g I nter acti o n St u d y of E v o br uti ni b o n Tr a ns p orter S u bstr ates
M S 2 0 0 5 2 7 _ 0 0 7 8
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 /7 4
D oc u me nt N o.
O bject N o.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

Gl o bal Versi o n I D:
P P D
P P D
P P D
C CI
C CI
C CI
P P D
P P D

Gl o bal Versi o n I D: 
P P D
P P D
P P D
C CI
C CI
C CI
P P D
P P D
P P D