A Phase I, Open-Label Study of the Relative Bioavailability of Evobrutinib Tablet Manufacturing Batches 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)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
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 0  
 
 
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 b el St u d y of t he Rel ati ve  
B i oa vaila bilit y of  E v o br uti ni b T a blet 
Ma n ufact uri n g B at c hes 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 1 3 1  
Pr ot oc ol V ersi o n:  
0 8  Se pte m ber  2 0 2 2 / Versi o n 1. 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 1  
Brief  Title:  
Relati ve Bi oa vaila bilit y of E v o br uti ni b Ta blet 
Batc hes  
Pri nci p al I n vesti g at or:  
 
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:  
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 ntri es, e x ce pt t he U S a n d Ca na d a:  
Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y  
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y  
Fra n kf urter Str asse 2 5 0  
Dar msta dt, 6 4 2 9 3, Ger ma n y  
 
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:  
E u dra C T: 2 0 2 2 -0 0 2 7 5 5 -1 9  
Ke y w or ds : 
P har mac o ki netics  
- C o nfi d e nti al –  
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot –  i n f ull or p art –  b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 2  b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
P P D
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
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 0  
 
 
T a ble of C o nte nts   
Title Pa ge  
 ..............................................................................................................1  
Ta ble of C o nte nts   ..............................................................................................................2  
Ta ble of Ta bl es  
 ..............................................................................................................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  ..................................................................................................8  
1. 3  
Sc he d ule of A cti vities  ...........................................................................9  
2  
I ntr o d u cti o n .........................................................................................1 1  
2. 1  
St u d y R ati o nale  ...................................................................................1 1  
2. 2  
Bac k gr o u n d  .........................................................................................1 1  
2. 3  
Be nefit/ Ris k Assess me nt  ....................................................................1 1  
2. 3. 1  
Ris k Assess me nt  .................................................................................1 2  
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 2  
2. 3. 2  
Be nefit Assess me nt  .............................................................................1 3  
2. 3. 3  
O verall Be nefit: Ris k C o ncl usi o n  .......................................................1 3  
3  
O bjecti ves a n d E n d p oi nts  ...................................................................1 4  
4  
St u d y Desi g n  .......................................................................................1 4  
4. 1  
O verall Desi g n  ....................................................................................1 4  
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  ................................................1 5  
4. 2. 1  
Partici pa nt I n p ut i nt o Desi g n  ..............................................................1 5  
4. 3  
J ustificati o n f or D ose ..........................................................................1 5  
4. 4  
E n d of St u d y Defi niti o n  ......................................................................1 5  
5  
St u d y P o p ulati o n  .................................................................................1 6  
5. 1  
I n cl usi o n Criteria ................................................................................1 7  
5. 2  
E x cl usi o n Criteria  ...............................................................................1 8  
5. 3  
Li fest yle C o nsi derati o ns .....................................................................2 0  
5. 3. 1  
Meals a n d Dietar y Restri cti o ns  ...........................................................2 0  
5. 3. 2  
Caffei ne, Al c o h ol, T o bacc o, a n d Ca n na bi n oi d  ...................................2 1  
5. 3. 3  
Acti vit y  ...............................................................................................2 1  
5. 4  
Scree n Fail ures  ....................................................................................2 1  
6  
St u d y I nter v e nti o n(s) a n d C o nc o mita nt T hera pies  .............................2 1  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
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 0  
 
 
6. 1  
St u d y I nter v e nti o n(s) A d mi nistrati o n  .................................................2 1  
6. 2  
St u d y I nter v e nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y  .....................................................................................2 2  
6. 3  
Meas ures t o Mi ni mize Bias: St u d y I nter v e nti o n Assi g n me nt a n d 
Bli n di n g  ..............................................................................................2 3  
6. 3. 1  
St u d y I nter v e nti o n Assi g n me nt  ..........................................................2 3  
6. 4  
St u d y I nter v e nti o n C o m plia nce  ..........................................................2 4  
6. 5  
D ose M o dificati o n  ..............................................................................2 4  
6. 6  
C o nti n ue d Access t o St u d y I nter ve nti o n After t he E n d of t he 
St u d y  ...................................................................................................2 4  
6. 7  
Treat me nt of O v er d ose  .......................................................................2 4  
6. 8  
C o nc o mita nt T hera p y  .........................................................................2 4  
6. 8. 1  
Resc ue Me dici ne  .................................................................................2 5  
6. 8. 2  
Per mitte d Me dici nes  ...........................................................................2 5  
6. 8. 3  
Pr o hi bite d Me dici nes  ..........................................................................2 5  
6. 8. 4  
Ot her I nter v e nti o ns  .............................................................................2 5  
7  
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici p a nt 
Disc o nti n uati o n/ Wit h dra wal  ...............................................................2 5  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................2 6  
7. 1. 1  
Li ver Cli nical Safet y La b orat or y Tests St o p pi n g Criteria  ..................2 6  
7. 1. 2  
Car diac Safet y St o p pi n g Criteria  ........................................................2 6  
7. 1. 3  
Rec halle n ge  .........................................................................................2 7  
7. 1. 3. 1  
St u d y I nter v e nti o n Restart or Rec halle n ge After Li ver St o p pi n g 
Criteria Are M et  ..................................................................................2 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  ...................2 7  
7. 3  
L ost t o F oll o w -U p ...............................................................................2 7  
8  
St u d y Assess me nts a n d Pr oce d ures  ....................................................2 8  
8. 1  
Efficac y Assess me nts a n d Pr oce d ures  ................................................2 8  
8. 2  
Safet y Assess me nts a n d Pr oce d ures  ...................................................2 8  
8. 2. 1  
P h ysical E x a mi nati o ns  ........................................................................2 9  
8. 2. 2  
Vital Si g ns  ..........................................................................................2 9  
8. 2. 3  
Electr ocar di o gra ms  .............................................................................2 9  
8. 2. 4  
Cli nical Safet y La b orat or y Tests  ........................................................2 9  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
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 0  
 
 
8. 3  
A d verse E v e nts, Seri o us A d verse E v e nts, a n d Ot h er Safet y 
Re p orti n g  ............................................................................................3 0  
8. 3. 1  
Met h o d of Dete cti n g A d verse E ve nts a n d Seri o us A d verse E v e nts  ...3 0  
8. 3. 2  
F oll o w -u p of A d v erse E v e nts a n d Seri o us A d verse E ve nts  ...............3 1  
8. 3. 3  
Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  .....3 1  
8. 3. 4  
Pre g n a nc y  ...........................................................................................3 1  
8. 3. 5  
Car di o vasc ular a n d Deat h E ve nts  .......................................................3 2  
8. 3. 6  
Disease -Rel ate d E ve nts a n d/ or Disease -R elate d O utc o mes N ot 
Q ualif yi n g as A Es or S A Es  ................................................................3 2  
8. 3. 7  
A d verse E v e nts of S peci al I nt erest  .....................................................3 2  
8. 4  
P har mac o ki netics  ................................................................................3 3  
8. 4. 1  
Bl o o d Sa m pli n g a n d Bi o a nal ysis  ........................................................3 3  
8. 4. 2  
P K Para meters  ....................................................................................3 4  
8. 5  
Ge netics a n d/ or P har mac o ge n o mics  ...................................................3 5  
8. 6  
Bi o mar kers  ..........................................................................................3 5  
8. 7  
I m m u n o ge nicit y Assess me nts ............................................................3 5  
8. 8  
Healt h Ec o n o mics  ...............................................................................3 5  
9  
Statis tical C o nsi derati o ns ....................................................................3 5  
9. 1  
Statistical H y p ot heses  .........................................................................3 5  
 
3 5  
9. 3  
A nal ysis Sets  .......................................................................................3 7  
9. 4  
Statistical A nal yses  .............................................................................3 8  
9. 4. 1  
Efficac y A nal yses  ...............................................................................3 8  
9. 4. 2  
Safet y A nal yses  ..................................................................................3 8  
9. 4. 3  
Ot her A nal yses  ....................................................................................3 9  
9. 4. 4  
Se q ue nce of A nal yses  .........................................................................3 9  
1 0  
Refere n ces  ...........................................................................................4 0  
1 1  
A p pe n dice s .........................................................................................4 1  
A p pe n di x 1  
A b bre viati o ns  ......................................................................................4 1  
A p pe n di x 2  
St u d y G o ver na nce  ...............................................................................4 3  
A p pe n di x 3  
C o ntrace pti o n a n d Barrier Re q uire me nts  ...........................................4 9  
A p pe n di x 4  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g  ................................................5 1  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
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 0  
 
 
A p pe n di x 5  
Li ver Safet y: S u g geste d Acti o ns a n d F oll o w -u p Assess me nts  ...........5 5  
A p pe n di x 6  
Cli nical La b orat or y Tests  ...................................................................5 6  
A p pe n di x 7  
Pr ot oc ol A me n d me nt Hist or y  .............................................................5 8  
A p pe n di x 8  
S p o ns or Si g nat ure Pa ge  ......................................................................5 9  
A p pe n di x 9  
Pri nci pal I n v esti gat or Si g nat ure Pa ge  .................................................6 0  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
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 0  
 
 
T a ble of T a bles   
Ta ble 1  
Ti me De viati o ns fr o m P K Sa m pli n g Ti mes  .......................................3 4  
 
 
3 6  
 
 
3 7  
 
Gl o bal Versi o n I D: 
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)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 /6 0  
 
 
1  
Pr ot oc ol S u m m ar y   
1. 1  
S y n o psis   
Cli nic al St u d y Pr ot oc ol Title:  A P has e I, O pe n -La b el St u d y of t he Relati ve Bi oa vaila bilit y of 
E v o br uti ni b Ta blet Ma n ufact uri n g Batc hes i n Healt h y Partici pa nts  
Brief  Title: Relati ve Bi o a vaila bilit y of E v o br uti ni b Ta blet Batc hes  
R ati o n ale: T he p ur p ose of t his st u d y is t o c o m pare e v o br uti ni b P K pr ofiles f or 4 5 -m g ta blet ( T F 2 
f or m ulati o n) batc hes 
 
  
O bjecti ves a n d E n d p oi nts:   
O bj e cti v e s  
E n d p oi nt s  
Pri m ar y  
 
T o c o m p ar e t h e si n gl e -d o s e P K of diff er e nt 
m a n uf a ct uri n g b at c h e s of e v o br uti ni b T F 2 f or m ul ati o n 
r el ati v e t o a r ef er e n c e b at c h u n d er f a st e d c o n diti o n s i n 
h e alt h y p arti ci p a nt s  
A U C 0 -∞,  C m a x   
S e c o n d ar y  
 
T o a s s e s s t h e s af et y a n d t ol er a bilit y of e v o br uti ni b 
a d mi ni st er e d a s a si n gl e or al d o s e of diff er e nt 
m a n uf a ct uri n g b at c h e s of T F 2 f or m ul ati o n u n d er f a st e d 
c o n diti o n s  i n h e alt h y p arti ci p a nt s 
N at ur e, o c c urr e n c e, a n d s e v erit y of tr e at m e nt -e m er g e nt 
a d v er s e e v e nt s ( T E A E s)  
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  
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 
( m or p h ol o g y a n d ti m e i nt er v al s). Li sti n g of t h e E CG 
d e s cri pti o n if cl a s sifi e d a s “ a b n or m al”.  
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  
T o f urt h er c h ar a ct eri z e t h e P K of diff er e nt 
m a n uf a ct uri n g b at c h e s of e v o br uti ni b T F 2 f or m ul ati o n  
A d diti o n al P K p ar a m et er s, e. g. A U C 0 -tla st , tm a x , t½ , C L/ F, 
V z/ F, Fr el 
E C G = El e ctr o c ar di o gr a m, 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, T F 2 = T a bl et f or m ul ati o n 2.  
O ver all Desi g n: 
T his is a ra n d o mize d, o pe n -la bel, 4-peri o d, 4 -se q ue nce, cr oss o ver st u d y 
( Williams desi g n ). 
Brief S u m m a r y:  
T he p ur p ose of t his st u d y is t o c o m pare e v o br uti ni b P K pr ofiles f or 4 5 -m g ta blet ( T F 2 f or m ulati o n) 
batc hes 
 St u d y details i ncl u de: 
• St u d y D urati o n: u p t o 4 6  da ys . 
• Treat me nt D urati o n: Si n gle oral d ose of 4 5 m g e v o br uti ni b  a d mi nistere d i n faste d state at Da y 1 
of eac h p eri o d . 
• T he was h o ut bet w ee n a d mi nistrati o ns of st u d y i nter ve nti o n i n eac h peri o d will be a p pr o xi matel y 
4 8  h o urs . 
Gl o bal Versi o n I D: 
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)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /6 0  
 
 
• Visit Fre q ue nc y: Scree ni n g visit will be wit hi n 2 8 da ys pri or t o first a d mi nistrati o n of st u d y 
i nter ve nti o n. Partici pa nts will be resi de nt i n t he C R U fr o m Da y -1 t o  Da y 8 . 
N u m ber of P artici p a nts: 
 
 
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: Si n gle -d os e, ra n d o mize d, 4 -peri o d , 4-s e q ue n ce, 
4 -wa y cr oss o ver st u d y  ( Willia ms desi g n), u p t o 4 6  da ys.  
D at a a n d S afet y M o nit ori n g / Ot her  C o m mittee : N o  
1. 2  
Sc he m a   
 
B at c h A =  
 (ref er e n c e ), B at c h B = 
 (l o w er di s s ol uti o n b o u n d) , B at c h C = 
 ( u p p er di s s ol uti o n  
b o u n d) , B at c h D = 
 ( h a m m er-mill e d) . 
D o s e s ar e o n D a y s 1, 3, 5, a n d 7, wit h a n a p pr o xi m at e 4 8 -h o ur w a s h o ut b et w e e n d o s e s.  S af et y f oll o w -u p t o b e 
a p pr o xi m at el y 7 -1 0 d a y s aft er st u d y di s c h ar g e.  
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

Evobrutinib (M2951) 
Relative Bioavailability of Evobrutinib Tablet Batches 
MS200527_0131 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/60 
 
 
1.3 
Schedule of Activities  
Assessment 
Screening 
Treatment 
SFU by 
phone 
Comments 
P1 
P2 
P3 
P4 
 
Study Day(s) 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
15 ± 3 Approximate 48-hour washout between doses on Days 1, 3, 5, 
and 7. 
Period-specific 
Day(s) 
-28 to -2 
-1 
1 
2 
1 
2 
1 
2 
1 
2 
Informed consent 
available 
 prior to 
any 
screening 
activity 
 
 
 
 
 
 
 
 
 
 
 
Study Site Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
Inpatient visit (on stay) 
 
 
<==================================
=> 
 
Participants are discharged on Day 8 
Eligibility criteria 
X 
Xa 
 
 
 
 
 
 
 
 
 
a Recheck of healthy state on Day -1. 
Demographics, height, 
and weight 
X 
 
 
 
 
 
 
 
 
 
 
Demography to include, at minimum age (year of birth), sex, 
race, and ethnicity. 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
FSH and TSH levels 
X 
 
 
 
 
 
 
 
 
 
 
FSH only in postmenopausal women. 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
X 
 
Women of childbearing potential must have a negative serum 
pregnancy test at the Screening visit.  Urine pregnancy test 
Day -1 and before discharge on Day 8 will also be performed. 
QuantiFERON test 
X 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
x 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
See Appendix 6. 
Cotinine, alcohol and 
drugs of abuse testing X 
X 
 
 
 
 
 
 
 
 
 
See Appendix 6. 
SARS-Cov-2 
X 
X 
 
 
 
 
 
 
 
 
 
See Appendix 6. 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Global Version ID: 78691_4324367_5428523
Global Version ID: 78691_4387578_5435495

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /6 0  
 
 
A s s e s s m e nt  
S cr e e ni n g  
Tr e at m e nt  
S F U  b y 
p h o n e  
C o m m e nt s  
P 1  
P 2  
P 3  
P 4  
 
S t u d y D a y( s)  
-2 8 t o -2  
-1  
1  
2  
3  
4  
5  
6  
7  
8  
1 5  ± 3  A p pr o xi m at e 4 8 -h o ur w a s h o ut b et w e e n d o s e s o n D a y s  1, 3, 5, 
a n d 7 . 
P eri o d -s p e cifi c 
D a y( s)  
-2 8 t o -2  
-1  
1  
2  
1  
2  
1  
2  
1  
2  
 
 
A d mi ni str ati o n of s t u d y 
int er v e nti o n  
 
 
X  
 
X  
 
X  
 
X  
 
 
W a s h o ut p eri o d of 4 8 h o ur s . 
P h y si c al e x a mi n ati o n  
X  
X  
 
 
 
 
 
 
 
X  
 
A f ull p h y si c al e x a mi n ati o n will b e p erf or m e d at S cr e e ni n g a n d 
b ef or e di s c h ar g e o n D a y 8, a n d a bri ef p h y si c al e x a mi n ati o n will 
b e p erf or m e d o n D a y  -1.  
Vit al si g n s  
X  
X  
X  
 
X  
 
X  
 
X  
X  
 
Vit al si g n s will b e a s s e s s e d o n t h e d a y s of d o si n g ( D a y 1, 3, 5, 
a n d 7) at pr e d o s e a n d at 2 h o ur s p o st d o s e.   
At vi sit s w h er e a s s e s s m e nt ti m e p oi nt s c oi n ci d e wit h e a c h ot h er, 
t h e f oll o wi n g s e q u e n c e of a cti viti e s will b e f oll o w e d: 1 2-l e a d 
E C G f oll o w e d b y vit al si g n s wit hi n 3 0 mi n ut e s b ef or e t h e 
s p e cifi e d ti m e p oi nt pr e c e di n g t h e P K s a m pli n g, w hi c h will b e 
p erf or m e d at t h e s p e cifi e d ti m e p oi nt.  
S af et y E C G  
X  
X  
X  
 
X  
 
X  
 
X  
X  
 
1 2 -l e a d E C G will b e p erf or m e d o n t h e d a y s of d o si n g ( D a y 1, 3, 
5, a n d 7) at pr e d o s e a n d at 2 h o ur s p o st d o s e.  
S e e Vit al si g n s (r o w a b o v e) f or a s s e s s m e nt s t h at c oi n ci d e. 
Cli ni c al l a b or at or y 
s af et y t e st s  
X  
X  
 
 
 
 
X  
 
 
X  
 
O n D a y 5, t e st s  will b e p erf or m e d pr e d o s e.  
Bl o o d s a m pl e s f or t h e cli ni c al l a b or at or y s af et y a s s e s s m e nt s will 
b e c oll e ct e d i n a f a st e d c o n diti o n.  
P K s a m pli n g  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Pl a s m a s a m pl e s f or P K a n al y si s will b e c oll e ct e d o n t h e d a y s of 
d o si n g (i. e. , D a y s 1, 3, 5, a n d 7) at pr e d o s e a n d 0. 2 5, 0. 5, 1. 0, 
1. 5, 2. 0, 2. 5, 3. 0, 4. 0, 6. 0, 8. 0, 1 2. 0, 1 6. 0, a n d 2 4. 0 h o ur s 
p o st d o s e . 
S e e Vi t al s i g n s (r o w a b o v e) f or a s s e s s m e nt s t h at c oi n ci d e.  
Pr e vi o u s m e di c ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
C o n c o mit a nt 
m e di c ati o n m o nit ori n g  
X  
< = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = >  
X  
 
A E m o nit ori n g  
X  
< = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = >  
X  
 
A E = A d v er s e E v e nt , D a y = St u d y D a y,  E C G = El e ctr o c ar di o gr a m, e G F R  = e sti m at e d Gl o m er ul ar Filtr ati o n R at e ;F S H = F olli cl e sti m ul ati n g h or m o n e,  P = P eri o d , 
P K = P h ar m a c o ki n eti c s . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /6 0  
 
 
2  
I ntr o d ucti o n  
E v o br uti ni b is a n oral, selecti ve, irre v ersi 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 safet y of  e v o br uti ni b is i n t he 
I B. 
2. 1  
St u d y R ati o n ale   
T he p ur p ose of t his st u d y is t o c o m pare e v o br uti ni b P K pr ofiles f or 4 5 -m g I R ta blet (T F 2  
f or m ulati o n) batc hes t hat ha ve s h o w n var yi n g diss ol uti o n pr ofiles i n vitr o. T he r elati ve 
bi oa vaila bilit y of t he bat c hes will be assesse d i n refere nce  t o a refere nce b atc h. T he c h oice of t he 
refere nce a n d test bat c h es is base d o n i n vitr o diss ol uti o n pr ofiles: 1 eac h of l o wer a n d u p per 
diss ol uti o n b o u n ds  (ter me d si de batc h es), 1  b atc h a s a refere nce (all 3 batc hes bei n g c o nical sie ve 
mille d),  a n d a 4t h b atc h w hic h is ha m mer -mille d. T his a p pr oac h, referre d t o as ma p pi n g 
met h o d ol o g y, is descri be d i n t he F D A g ui da nce o n diss ol uti o n testi n g f or i m me diate releas e s oli d 
oral d osa ge f or ms  ( G ui d a nce f or in d ustr y, Diss ol uti o n testi n g of im me diate  releas e soli d o ral 
d osa ge for ms , 1 9 9 7). Pri mar y P K para meters assesse d i ncl u de  e v o br uti ni b plas ma C ma x  a n d 
A U C 0 -∞.  
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 v e, 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 f u ncti o ns, s uc h as pr oliferati o n a n d a nti b o d y a n 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 b e me di ate 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 ks t he acti va ti o n of i n nate i m m u ne cells b y i m m u ne c o m ple x es d o w nstrea m of Fc R acti vati o n. 
All 3  mec ha nis ms ma y pl a y a r ole 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. 
2. 3  
Be nefit/ Ris k Assess me nt   
As of 3 1 J ul y 2 0 2 1 , a p pr o xi matel y 2, 0 4 1 a d ult partici pa nts i n 1 6 c o m plete d a n d 5  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 p artici pa nts ( 2 4 3), partici pa nts wit h 
R M S ( 9 4 3 ), s yste mic l u p us er yt h e mat os us ( 4 3 7), 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) a n d he p atic i m pair me nt ( 2 4).  E v o br uti ni b was ge n erall y s afe a n d well 
t olerate d i n all partici pa nts. T he T E A Es ha ve b ee n pri maril y mil d t o m o derate i n se verit y.  
Eac h partici pa nt i n t his st u d y will recei ve u p t o 4  d oses of e v o br uti ni b at 4 5 m g u n der fast e d 
c o n diti o ns, 2  da ys  a p art. T his  re gi me n is n ot e x pecte d t o e x cee d e x p os ures reac he d i n 
first-i n-h u ma n cli nical st u d y E M R 2 0 0 5 2 7 _ 0 0 1, 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 d a ys of d osi n g wit h 2 5, 7 5, a n d 2 0 0 m g/ da y were test e d a n d s h o w n t o be well 
t olerate d.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /6 0  
 
 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o n a bl y 
e x pecte d a d vers e e v e nts of  e v o br uti ni b ma y be f o u n d i n Secti o n 2. 3. 1  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. 
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 a rtici 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  
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 ati e 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). 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, 
g e n er all y mil d ( Gr a d e 1), 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. H o w e v er, m or e 
s e v er e c a s e s w er e r e p ort e d. 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 ati e nt s 
r e c ei vi n g s h ort tr e 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. 
 
 
 
 
 
 
 
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 oll m 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 3 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.  
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 -li k e 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.  
A E  =  a d v er s e e v e nt, 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.  
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 h e ge n eral 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 p a n de mic sit uati o n is o n g oi n g.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /6 0  
 
 
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 
decrease i n I gM , a n i ncrease i n I gA, 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 h a n ges were n ot cli nicall y si g nifica 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 8 da ys. Alt h o u g h B T K is n ot 
re q uire d t o cle ar viral i nf ecti o ns, a part fr o m e nt er 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 pecificall y 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 verit y 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 s u g gest a pr otecti ve effect of B T K 
i n hi bit ors f or se verit y 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 d ati o ns iss ue d b y t he R o bert K oc h I nstit ute as well as l ocal 
g ui deli nes wit h res p ect t o t he mi ni miz ati o n of t he ris k of disease s prea di n g, e. g. s ocial dista n ci n g, 
disi nfecti o n, h y gi e ne, a n d weari n g of m o ut h -n ose mas ks will be f oll o we d. D uri n g t he pa n d e mic 
sit uati o n, f urt her me as ur es acc or di n g t o rec o m m e n dati o ns a n d re q uire m e nts fr o m l ocal Healt h 
A ut h orities ma y bec o m e necessar y a n 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 o n 
partici pa nt safet y i n t his st u d y als o d uri n g t he C O VI D -1 9 pa n d e mic sit uati o n. T hese meas u res 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 m eas ur es are i m ple me nte d: O nl y p artici pa nts wit h o ut a n y s y m pt o ms of a res pir at or y 
disease a n d wit h o ut c o ntact t o a n y k n o w n S A R S -C o V -2 p ositi ve patie nt or 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 p art of t he cli nical st u d y pr oce d ures, partici p a 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 p a 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 v esti gat or’s discreti o n a n d a gree me nt wit h t h e me dical m o nit ori n g t ea m. T he S p o ns or will 
m o nit or t he e ve nts relat e d t o a n y S A 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 partici pa nts partici 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 dat a 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 miz ati o n meas ures r o uti nel y 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 x cl usi o n criteria ( Secti o n 5. 2 ), a de q uat e bi oc he mical a n d he mat ol o g y 
la b orat or y m onit ori n g ( S ecti 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 b e disc o nti n ue d i n case of e ve nts t hat u n acce pta bl y e n da n ger t he s afet y of 
the 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. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /6 0  
 
 
C o n si deri n g t h e me as 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 h e p ote ntial ris ks 
i de ntifie d i n ass ociati o n wit h e v o br uti ni b are j ustifie d i n healt h y partici pa nts. 
3  
O bjecti ves a n d  E n d p oi nts   
O bj e cti v e s  
E n d p oi nt s  
Pri m ar y  
 
T o c o m p ar e t h e si n gl e -d o s e P K of diff er e nt 
m a n uf a ct uri n g b at c h e s of e v o br uti ni b T F 2 f or m ul ati o n  
r el ati v e t o a r ef er e n c e b at c h  u n d er f a st e d c o n diti o n s i n 
h e alt h y p arti ci p a nt s  
A U C 0 -∞,  C m a x   
S e c o n d ar y  
 
T o a s s e s s t h e s af et y a n d t ol er a bilit y of e v o br uti ni b 
a d mi ni st er e d a s a si n gl e or al d o s e of diff er e nt 
m a n uf a ct uri n g b at c h e s  of T F 2  f or m ul ati o n u n d er f a st e d 
c o n diti o n s i n h e alt h y p arti ci p a nt s  
N at ur e, o c c urr e n c e, a n d s e v erit y of tr e at m e nt -e m er g e nt 
a d v er s e e v e nt s ( T E A E s)  
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  
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 
( m or p h ol o g y a n d ti m e i nt er v al s) . Li sti n g of t h e E C G 
d e s cri pti o n if cl a s sifi e d a s “ a b n or m al”.  
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  
T o f urt h er c h ar a ct eri z e t h e P K of diff er e nt 
m a n uf a ct uri n g b at c h e s of e v o br uti ni b T F 2 f or m ul ati o n  
A d diti o n al P K p ar a m et er s : e. g. A U C 0 -tl a st,tm a x , t½ , C L/ F, 
V z/ F, Fr el 
E C G = El e ctr o c ar di o gr a m, T E A = Tr e at m e nt -e m er g e nt a d v er s e e v e nt, T F 2 = T a bl et f or m ul ati o n 2.  
4  
St u d y Desi g n   
4. 1  
O ver all Desi g n   
St u d y D e si g n  
R a n d o mi z e d, o p e n -l a b el, 4 -p eri o d, 4 -s e q u e n c e, cr o s s o v er d e si g n  
C o ntr ol M et h o d  
N ot a p pli c a bl e  
Si n gl e or M ulti c e nt er  
Si n gl e c e nt er  
St u d y P o p ul ati o n T y p e  
H e alt h y p arti ci p a nt s  
L e v el a n d M et h o d of Bli n di n g  
N ot a p pli c a bl e  
Bi a s Mi ni m ali z ati o n M et h o d( s)  
R a n d o mi z ati o n  
St u d y I nt er v e nti o n A s si g n m e nt 
M et h o d  
N ot a p pli c a bl e  
D at a a n d S af et y M o nit ori n g 
/ Ot h er C o m mitt e e: 
N o  
T ot al D ur ati o n of St u d y 
P arti ci p ati o n  p er P arti ci p a nt  
U p t o 4 3  d a y s  
Pr o vi si o n s f or St u d y E xt e n si o n 
or E ntr y i nt o R oll -O v er St u di e s  
N ot a p pli c a bl e  
A d a pti v e A s p e ct s of St u d y 
D e si g n  
N ot a p pli c a bl e  
A st u d y sc h e 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 vel y. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /6 0  
 
 
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n   
T his st u d y will c o m pare t he si n gle -d ose e v o br uti ni b P K of differe nt  ta blet ma n ufact uri n g batc hes  
relati ve t o a refere nce batc h  u n der faste d c o n diti o ns i n healt h y partici pa nts. Res ults of t his st u d y 
are pla n n e d t o pr o vi de data t o s u p p ort o n g oi n g  cli nical de vel o p me nt a n d p ost -a p pr o val  acti vities . 
T he st u d y utilizes a ra n d o mize d cr oss o ver desi g n t o e ns ure all partici pa nts w h o c o m plete t he st u d y 
recei v e eac h treat me nt a n d he n ce all o ws wit hi n partici pa nt  c o m paris o ns, a n d t hat n o bias is 
i ntr o d uce d or c o nf o u n ds t he c o ncl usi o ns of t he st u d y. 
 
 
. 
T he st u d y e n d p oi nts are base d o n t he re g ulat or y g ui da nce of t he F D A ( Bi oa vaila bilit y a nd 
Bi oe q ui vale n ce St u dies S u b mitte d i n N D As or I N Ds —  Ge n eral C o nsi derati o ns , 2 0 1 4) a n d t he 
E M A  ( G ui deli ne on  t he I n vesti gati o n of Bi oe q ui v ale nce, 2 0 1 0). 
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   
T he e v o br uti ni b d ose t o be use d i n t his st u d y  is 4 5  m g u n d er faste d c o n diti o ns . 4 5 m g is t he sa me 
d ose as i n t he P hase 3  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. The P hase 3  d ose 
is bei n g a d mi nistere d u n der fe d c o n diti o ns , w hereas faste d c o n diti o ns are b ei n g use d i n t his st u d y 
as rec o m me n d e d i n t he F D A g ui d a nce f or bi oa vaila b ilit y st u dies. 
T he e x p os ure i n t h is st u d y is 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 da ys were 
a d mi nistere d a n d w ell t olerate d.  
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 (l ast partici pa nt’s Safet y F oll o w -u p Assess me nt).  
A parti ci 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 Crit eri 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 the occ urre n ce of A Es w h ose c h aracter, s e verit y or fre q u e 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.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6 /6 0  
 
 
•  a n y d ata deri v e 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 neral 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 nd 5. 2  are desi g n e d t o e nr oll o nl y i n di vi d uals 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 h e st u d y f ulfills its o bjecti ves. All rele va nt m e 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 n  i n di vi d ual 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 n cl usi o n a n d e x cl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d.  
Bef ore perf or mi n g a n y st u d y assess me nts t hat ar e n ot part of t he i n di vi d ual’s r o uti ne me dical care, 
t he I n v esti gat or will c o nfir m t hat t he i n di vi d ual has pr o vi de d writte n i nf or me d c o nse nt, as 
i n dicate d i n A p pe n di x  2 . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /6 0  
 
 
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 at e g or y  
Crit eri o n  
A g e  
1)  
 Ar e b et w e e n 1 8 a n d 5 5 (i n cl u si v e) y e ar s of a g e at t h e ti m e of si g ni n g t h e 
i nf or m e d c o n s e nt. 
T y p e of P arti ci p a nt a n d 
Di s e a s e C h ar a ct eri sti c s  
2)  
Ar e o v ertl y h e alt h y a s d et er mi n e d b y m e di c al e v al u ati o n, i n cl u di n g n o cli ni c all y 
si g nifi c a nt a b n or m alit y i d e ntifi e d o n p h y si c al e x a mi n ati o n or l a b or at or y 
e v al u ati o n a n d n o  a cti v e cli ni c all y si g nifi c a nt di s or d er, c o n diti o n, i nf e cti o n, or 
di s e a s e t h at w o ul d p o s e a ri s k t o p arti ci p a nt s af et y or i nt erf er e wit h t h e st u d y 
e v al u ati o n, pr o c e d ur e s, or c o m pl eti o n.  
W ei g ht  
3)  
H a v e a b o d y w ei g ht wit hi n 5 0. 0 a n d 1 0 0. 0 k g (i n cl u si v e) a n d B M I wit hi n t h e 
r a n g e 1 9. 0 a n d 3 0. 0 k g/ m2 (i n cl u si v e). 
S e x a n d C o ntr a c e pti o n/  
B arri er R e q uir e m e nt s  
4)  
M al e or f e m al e  
T h e I n v e sti g at or c o nfir m s t h at e a c h p arti ci p a nt a gr e e s t o u s e a p pr o pri at e 
c o ntr a c e pti o n a n d b arri er s, if a p pli c a bl e. T h e c o ntr a c e pti o n, b arri er, a n d pr e g n a n c y 
t e sti n g r e q uir e m e nt s ar e b el o w. 
M al e p arti ci p a nt s: N o c o ntr a c e pti o n n e e d e d.  
F e m al e p arti ci p a nt:  
•  
I s n ot  br e a stf e e di n g.  
•  
I s n ot  pr e g n a nt (i. e., h a s a n e g ati v e s er u m or hi g hl y s e n siti v e uri n e 
pr e g n a n c y t e st,  a s r e q uir e d b y l o c al r e g ul ati o n s, wit hi n 2 4 h o ur s b ef or e 
t h e fir st d o s e of st u d y i nt er v e nti o n). If a uri n e t e st c a n n ot b e c o nfir m e d a s 
n e g ati v e ( e. g., a n a m bi g u o u s r e s ult), a s er u m pr e g n a n c y t e st i s r e q uir e d.  
•  
I s n ot  a W O C B P  
•  
If a W O C B P, u s e s a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d (i. e., wit h a 
f ail ur e r at e of < 1 % p er y e ar), pr ef er a bl y  wit h l o w u s er d e p e n d e n c y, a s 
d e s cri b e d i n A p p e n di x 3  f or t h e f oll o wi n g ti m e p eri o d s: 
1)  
B ef or e t h e fir st d o s e of t h e st u d y i nt er v e nt i o n( s), if u si n g h or m o n al 
c o ntr a c e pti o n:  
H a s c o m pl et e d at l e a st o n e 4 -w e e k c y cl e of a n or al c o ntr a c e pti o n pill 
a n d eit h er h a d or h a s b e g u n h er m e n s e s; O R , 
H a s u s e d a d e p ot c o ntr a c e pti v e or e xt e n d e d -c y cl e or al c o ntr a c e pti v e 
f or l e a st 2 8 d a y s a n d h a s a d o c u m e nt e d n e g ati v e pr e g n a n c y t e st u si n g 
a hi g hl y s e n siti v e a s s a y.  
2)  
D uri n g t h e st u d y i nt er v e nti o n p eri o d  
3)  
Aft er t h e st u d y i nt er v e nti o n p eri o d (i. e., aft er t h e l a st d o s e of st u d y 
i nt er v e nti o n i s a d mi ni st er e d) f or at l e a st 3 0 d a y s aft er t h e l a st d o s e of 
st u d y i nt er v e nti o n a n d a gr e e n ot t o d o n at e e g g s ( o v a, o o c yt e s) f or 
r e pr o d u cti o n d uri n g t hi s p eri o d. 
T h e I n v e sti g at or e v al u at e s t h e eff e cti v e n e s s of t h e c o ntr a c e pti v e m et h o d i n 
r el ati o n s hi p t o t h e fir st d o s e of st u d y i nt er v e nti o n. 
N e g ati v e pr e g n a n c y t e st, a s r e q uir e d b y l o c al r e g ul ati o n s, at S cr e e ni n g a n d 
wit hi n 2 4 h o ur s b ef or e t h e fir st d o s e of st u d y i nt er v e nti o n.  
T h e I n v e sti g at or r e vi e w s t h e m e di c al hi st or y, m e n str u al hi st or y, a n d r e c e nt s e x u al 
a cti vit y t o d e cr e a s e t h e ri s k f or i n cl u si o n of a f e m al e wit h a n e arl y u n d et e ct e d 
pr e g n a n c y.  
I nf or m e d C o n s e nt 
5)  
Ar e c a p a bl e of gi vi n g si g n e d i nf or m e d c o n s e nt, a s i n di c at e d i n 
A p p e n di x  2 , w hi c h i n cl u d e s c o m pli a n c e wit h t h e r e q uir e m e nt s a n d 
r e stri cti o n s li st e d i n t h e I C F a n d t hi s pr ot o c ol. 
S m o ki n g  
6)  
Ar e st a bl e n o n -s m o k er s f or at l e a st 3 m o nt h s pr e c e di n g S cr e e ni n g.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /6 0  
 
 
5. 2  
E xcl usi o n Criteri a   
Partici pa nts are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
C at e g or y  
Crit eri o n  
M e di c al C o n diti o n s  
1.  
Hi st or y or pr e s e n c e of cli ni c all y r el e v a nt r e s pir at or y, g a str oi nt e sti n al, r e n al, 
h e p ati c, h e m at ol o gi c al, l y m p h ati c, n e ur ol o gi c al, c ar di o v a s c ul ar, 
m u s c ul o s k el et al, g e nit o uri n ar y, i m m u n ol o gi c al, d er m at ol o gi c al, c o n n e cti v e 
ti s s u e, p s y c hi atri c ( d u e t o r ar e ri s k of h all u ci n ati o n s, a git ati o n a n d 
a cti v ati o n of p s y c h o si s), a n d ot h er di s e a s e s or di s or d er s, a n d e pil e p s y, a s 
d et er mi n e d b y m e di c al e v al u ati o n.  
2.  
I n di vi d u al s wit h di a g n o si s of h e m o c hr o m at o si s, Wil s o n´ s di s e a s e, al p h a  1 
a ntitr y p si n d efi ci e n c y, or a n y ot h er c hr o ni c li v er di s e a s e i n cl u di n g Gil b ert’ s 
di s e a s e will b e e x cl u d e d fr o m t h e st u d y.  
Pri or hi st or y of c h ol e c y st e ct o m y or s pl e n e ct o m y, a n d a n y cli ni c all y 
r el e v a nt s ur g er y wit hi n 6 m o nt h s pri or t o t h e fir st a d mi ni str ati o n of st u d y 
i nt er v e nti o n. 
3.  
Hi st or y of a n y m ali g n a n c y.  
4.  
Hi st or y of s ei z ur e s . 
5.  
Hi st or y of p h ar m a c ol o gi c all y tr e at e d p s y c hi atri c di s e a s e . 
6.  
Hi st or y of c hr o ni c or r e c urr e nt a c ut e i nf e cti o n or a n y b a ct eri al, vir al, 
p ar a siti c or f u n g al i nf e cti o n s  wit hi n 3 0  d a y s pri or t o S cr e e ni n g a n d at a n y 
ti m e b et w e e n S cr e e ni n g a n d a d mi s si o n, or h o s pit ali z ati o n d u e t o i nf e cti o n 
wit hi n 6  m o nt h s pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n.  
7.  
Hi st or y of s hi n gl e s wit hi n 1 2  m o nt h s pri or t o S cr e e ni n g.  
8.  
Hi st or y of dr u g h y p er s e n siti vit y ( e. g. q ui n ol o n e s a n d a s c ert ai n e d or 
pr e s u m pti v e all er g y/ h y p er s e n siti vit y t o t h e a cti v e dr u g s u b st a n c e a n d/ or 
f or m ul ati o n i n gr e di e nt s); hi st or y of s eri o u s all er gi c r e a cti o n s l e a di n g t o 
h o s pit ali z ati o n or a n y ot h er h y p er s e n siti vit y r e a cti o n i n g e n er al i n cl u di n g 
c o nt a ct h y p er s e n siti vit y t o E C G el e ctr o d e s, w hi c h m a y aff e ct t h e s af et y of 
t h e p arti ci p a nt a n d/ or o ut c o m e of t h e st u d y p er t h e I n v e sti g at or’ s 
di s cr eti o n.  
9.  
Hi st or y of al c o h oli s m or dr u g a b u s e wit hi n 2  y e ar s pri or t o t h e f ir st 
a d mi ni str ati o n of st u d y i nt er v e nti o n, or p o siti v e f or dr u g s of a b u s e, 
ni c oti n e/ c oti ni n e or al c o h ol b y t h e l a b or at or y a s s a y s c o n d u ct e d d uri n g 
S cr e e ni n g a n d D a y  -1.  
1 0.  Hi st or y of r e si d e nti al e x p o s ur e t o t u b er c ul o si s, or a p o siti v e 
Q u a nti F E R O N ® t e st wit hi n 4  w e e k s pri or t o or at t h e ti m e of S cr e e ni n g.  
1 1.  P o siti v e f or a) 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, or HI V  I a n d II t e st s at S cr e e ni n g; b) S A R S-C o V -2 at 
S cr e e ni n g a n d D a y -1 . 
1 2.  A n y c o n diti o n, i n cl u di n g fi n di n g s i n t h e l a b or at or y t e st s, m e di c al hi st or y 
( e. g. h e art f ail ur e, h y p o k al e mi a, f a mil y hi st or y of L o n g Q T S y n dr o m e), or 
ot h er S cr e e ni n g a s s e s s m e nt s, t h at i n t h e o pi ni o n of t h e I n v e sti g at or 
c o n stit ut e s a n i n a p pr o pri at e ri s k or a c o ntr ai n di c ati o n f or p arti ci p ati o n i n 
t h e st u d y or t h at c o ul d i nt erf er e wit h t h e st u d y’ s o bj e cti v e s, c o n d u ct, or 
e v al u ati o n.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /6 0  
 
 
C at e g or y  
Crit eri o n  
1 3.  A d mi ni str ati o n of li v e v a c ci n e s or li v e -att e n u at e d vir u s v a c ci n e s wit hi n 
3  m o nt h s pri or t o D a y 1 . A d mi ni str ati o n of ot h er t y p e s of v a c ci n e s i s 
all o w e d u ntil 1 4  d a y s b ef or e t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n, 
t h er e aft er it i s pr o hi bit e d u ntil t h e e n d of t h e st u d y. H o w e v er, f or S A R S -
C o V -2 m R N A v a c ci n e i s n ot p er mitt e d 4 2 d a y s pri or t o D a y 1 . 
N ot e: I n c a s e of cli ni c al s y m pt o m s, t h e p arti ci p a nt s h o ul d b e s y m pt o m -fr e e 
f or at l e a st 1 w e e k pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n.  
Pri or/ C o n c o mit a nt T h er a p y  
1 4.  M o d er at e or str o n g i n hi bit or s or i n d u c er s of C Y P 3 A 4/ 5 or P g p  wit hi n 
4  w e e k s pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n.  
1 5.  U s e of a n y pr e s cri b e d m e di ci n e or o v er -t h e-c o u nt er dr u g or di et ar y 
s u p pl e m e nt, i n cl u di n g h er b al r e m e di e s, vit a mi n s, a n d mi n er al s, a nt a ci d s 
a n d di et ar y s u p pl e m e nt s s u c h a s fi s h oil s wit hi n 2  w e e k s or 5  ti m e s t h e 
h alf -lif e of t h e r e s p e cti v e dr u g, w hi c h e v er is l o n g er, pri or t o t h e fir st 
a d mi ni str ati o n of st u d y i nt er v e nti o n.  
O c c a si o n al p ar a c et a m ol ( a c et a mi n o p h e n) u p t o 2  g p er d a y or h or m o n al 
c o ntr a c e pti v e s/ H R T i s p er mitt e d. 
Pri or/ C o n c urr e nt Cli ni c al 
St u d y E x p eri e n c e  
1 6.  U s e of a n y i n v e sti g ati o n al dr u g i n a n y cli ni c al st u d y wit hi n 6 0  d a y s pri or t o 
D a y  1 a d mi ni str ati o n, or h a v e u s e d a n e x p eri m e nt al m o n o cl o n al a nti b o d y 
wit hi n t h e p a st 1  y e ar pri or t o D a y  1, or h a v e p arti ci p at e d i n a st u d y 
e v al u ati n g a B T K i n hi bit or wit hi n 6 0  d a y s, or ar e o n e xt e n d e d f oll o w -u p i n 
a cli ni c al st u d y, e v e n if l a st a d mi ni str ati o n of a st u d y i nt er v e nti o n w a s 
m or e t h a n 6 0  d a y s a g o, or 5  h alf -li v e s of t h e i n v e sti g ati o n al dr u g, 
w hi c h e v er i s l o n g er, pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n.  
Di a g n o sti c A s s e s s m e nt s  
1 7.  M e di c al hi st or y a n d p h y si c al e x a mi n ati o n r e s ult s t h at i n cl u d e a n y o n g oi n g 
cli ni c all y r el e v a nt fi n di n g s a s j u d g e d b y t h e I n v e sti g at or.  
1 8.  Cli ni c all y r el e v a nt fi n di n g s ( e x cl u di n g mi n or, n ot cli ni c all y r el e v a nt 
e x c ur si o n s fr o m n or m al r a n g e s, a s j u d g e d b y t h e I n v e sti g a t or) at 
S cr e e ni n g i n bi o c h e mi str y, h e m at ol o g y, c o a g ul ati o n, a n d uri n al y si s 
e x a mi n ati o n s f or t h e a g e of t h e p arti ci p a nt, a s j u d g e d b y t h e I n v e sti g at or:  
•  
Al a ni n e a mi n otr a n sf er a s e, a s p art at e a mi n otr a n sf er a s e: a b o v e U L N  
•  
Cr e ati ni n e: a b o v e n or m al li mit s  
•  
A b s ol ut e l y m p h o c yt e c o u nt, a b s ol ut e n e utr o p hil c o u nt: b el o w li mit of 
r ef er e n c e r a n g e. 
•  
A m yl a s e a n d li p a s e a b o v e n or m al r a n g e s ; mi n or d e vi ati o n s ar e 
all o w e d, if n ot cli ni c all y r el e v a nt.  
1 9.  e G F R  a c c or di n g t o t h e 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) <  9 0  m L/ mi n at S cr e e ni n g. I n 
c a s e of a b or d erli n e r e s ult b et w e e n ≥ 8 0 a n d <  9 0  m L/ mi n, C y st ati n  C will 
b e d et er mi n e d i n a d diti o n, a n d t h e p arti ci p a nt will o nl y b e i n cl u d e d if t h e 
C y st ati n  C v al u e i s b el o w t h e u p p er li mit of n or m al.  
2 0.  S e mi -s u pi n e s y st oli c bl o o d pr e s s ur e >  1 4 0  m m H g or <  9 0  m m H g, di a st oli c 
bl o o d pr e s s ur e >  9 0  m m H g or <  5 0  m m H g, a n d p ul s e r at e >  9 0 or 
<  5 0  b p m at S cr e e ni n g. A n y a b n or m al bl o o d pr e s s ur e  r e s ult s m a y b e 
r e p e at e d o n c e a n d if t h e r e p e at r e s ult i s wit hi n t h e n or m al r a n g e, it i s n ot 
c o n si d er e d t o h a v e m et t h e e x cl u si o n crit eri o n.  
2 1.  1 2 -le a d E C G s h o wi n g a Q T i nt er v al c orr e ct e d f or h e art r at e a c c or di n g t o 
Fri d eri ci a’ s f or m ul a ( Q T c F) >  4 5 0  m s, P R  >  2 1 5  m s, or Q R S >  1 2 0  m s at 
S cr e e ni n g.  
2 2.  A n y ot h er a b n or m al l a b or at or y r e s ult s t h at t h e I n v e sti g at or b eli e v e s s h o ul d 
pr e cl u d e t h e p arti ci p a nt’ s p arti ci p ati o n i n t h e st u d y.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /6 0  
 
 
C at e g or y  
Crit eri o n  
Ot h er E x cl u si o n s  
2 3.  C o n s u m pti o n of a n a v er a g e w e e kl y al c o h ol i nt a k e of >  1 4  u nit s/ w e e k f or 
m e n or >  7  u nit s/ w e e k f or w o m e n. O n e u nit ( 1 2  g) of al c o h ol e q u al s ½  pi nt 
( 2 8 5 m L) of b e er or l a g er, 1  gl a s s ( 1 2 5  m L) of wi n e, or 1/ 6  gill ( 2 5  m L) of 
s pirit s.  
2 4.  E x c e s si v e c o n s u m pti o n of x a nt hi n e -c o nt ai ni n g f o o d or b e v er a g e s 
( > 5  c u p s of c off e e a d a y or e q ui v al e nt) or i n a bilit y t o st o p c o n s u mi n g 
c aff ei n e, fr o m 4 8  h o ur s pri or t o st u d y i nt er v e nti o n a d mi ni str ati o n u ntil aft er 
c oll e cti o n of t h e fi n al P K s a m pl e i n e a c h p eri o d.  
2 5.  C o n s u m pti o n of al c o h ol fr o m 4 8  h o ur s pri or t o fir st a d mi ni str ati o n of st u d y 
i nter v e nti o n.  
2 6.  H er b al s u p pl e m e nt s i n cl u di n g, b ut n ot li mit e d t o, St. J o h n’ s w ort 
( h y p eri c u m p erf or at u m), gr a p efr uit, S e vill e or a n g e s, cr a n b erri e s, or j ui c e s 
of t h e s e fr uit s wit hi n 1 4  d a y s pri or t o t h e fir st a d mi ni str ati o n of st u d y 
i nt er v e nti o n. 
2 7.  D o n ati o n or  l o s s of m or e t h a n 4 5 0 m L of bl o o d i n t h e 6 0  d a y s pri or t o t h e 
fir st a d mi ni str ati o n of st u d y i nt er v e nti o n, d o n ati o n of pl a s m a fr o m 2 w e e k s 
pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n, or pl at el et s fr o m 
6  w e e k s pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n.  
2 8.  Tr a v el t o a c o u ntr y wit h a hi g h pr e v al e n c e of tr o pi c al di s e a s e s wit hi n 
3  m o nt h s pri or t o t h e fir st a d mi ni str ati o n of st u d y i nt er v e nti o n.  
2 9.  I n a bilit y t o c o m m u ni c at e r eli a bl y wit h t h e I n v e sti g at or or c o n si d er e d b y t h e 
I n v e sti g at or t o b e u n a bl e t o or u nli k el y t o c o o p er at e wit h t h e r e q uir e m e nt s 
of t h e st u d y.  
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   
Partici pa nts will a bstai n fr o m c o ns u mi n g  e ner g y dri n ks,  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 (h y p eric u m p erf orat u m), Se ville ora n ges, gra p efr uits, p o mel os, e x otic 
citr us fr uits, gra pefr uit h y bri d s, cra n berries, a n d j uices fr o m t hese fr uits fr o m 1 4 da ys bef ore first 
a d mi nistrati o n of e v o br uti ni b  u ntil after c ollecti o n of t he fi nal P K sa m ple . 
T he f oll o wi n g ge n eral i nstr ucti o ns o n meals a n d dietar y restricti o ns a n d ti mi n g of meals a p pl y t o 
t he st u d y: 
D uri n g t he i n -h o use peri o d at t he C R U, o n d osi n g Da ys 1, 3, 5, 7, partici pa nts s h o ul d f oll o w a n 
o ver ni g ht fast of at least 1 0 h o urs pri or t o e v o br uti ni b a d mi nistrati o n. F o ur h o urs after e v o br uti ni b  
a d mi nistrati o n, a sta n dar dize d l u nc h will be s er ve d. A n a fter n o o n s nac k will be pr o vi de d 
a p pr o xi matel y 8 h o urs a n d di n ner a p pr o xi matel y 1 2 h o urs p ost d ose.  O n ot her da ys p artici pa nts 
will recei ve meals at c ust o mar y ti mes . 
All meals d uri n g t h e 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 nt ati o n 
of ti me a n d c o m plete c o ns u m pti o n is nee de d.  
O n eac h d osi n g d a y, st u d y i nter ve nti o n will be a d mi nistere d wit h 2 4 0 m L of water i n a sta n di n g 
p ositi o n at t he st u d y ce nter foll o wi n g a n o ver ni g ht fast of at least 1 0  h o urs . Partici pa nts will re mai n 
fasti n g u ntil 4  h o urs p ost d ose . Partici pa nts will n ot be all o we d a n y li q ui d fr o m 1  h o ur pre d ose u ntil 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1 /6 0  
 
 
1  h o ur p ost d ose, e x ce pt f or t he 2 4 0  m L water re q uire d t o c o ns u me t he d ose wit h. P artici pa nts 
s h o ul d t hereaft er c o ns u me at least 1. 5  L of water p er da y ( n o d oc u m entati o n of v ol u me is nee de d ). 
5. 3. 2  
C affei ne, Alc o h ol, T o b acc o , a n d C a n n a bi n oi d  
•  D uri n g t h e d osi n g p eri o d partici pa nts will a bstai n fr o m i n gesti n g caffei ne - or x a nt hi ne -
c o ntai ni n g pr o d uct s (e. g., c offee, t ea, c ola dri n ks, a n d c h o c 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 sa m ple.  
•  D uri n g t he d osi n g peri o d partici pa nts will a bstai n fr o m alc o h ol f or 2 4 h o urs bef ore t he start of 
d osi n g u ntil after c ol lecti o n of t he fi nal P K sa m ple. 
•  D uri n g t h e d osi n g p eri o d partici pa nts will a bstai n fr o m ca n n a bi n oi d -c o nt ai 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 sa m ple.  
•  Partici pa nts w h o use t o bacc o pr o d ucts will be i ns tr ucte d t hat use of nic oti ne-c o ntai ni n g 
pr o d ucts (i ncl u di n g nic oti ne patc hes) will n ot be per mitte d fr o m at least 3  m o nt hs prece di n g 
Scree ni n g u ntil after fi nal F oll o w -u p visit  ( p h o ne call). 
5. 3. 3  
Acti vit y   
Partici pa nts will a bstai n fr o m stre n u o us e x ercise f or 7 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 ma y p artici p ate i n li g ht recreati o nal act i vities (e. g., watc hi n g 
tele visi o n or rea di n g). 
O n d osi n g Da ys 1, 3, 5, a n d 7, partici pa nts  will sta y i n a se mi-rec u m b e nt p ositi o n u ntil c o m pleti o n 
of t he 1 -h o ur pr oce d ures. Partici pa nts  are all o we d t o get u p f or g oi n g t o t he bat hr o o m as nee d e d.  
5. 4  
Scree n F ai l ures  
I n di vi d uals w h o d o n ot meet t he criteria f or parti ci pati o n i n t his st u d y (scree n fail ure) will  n ot be 
rescree ne d. 
6  
St u d y I nter ve nti o n(s)  a n d C o nc o mit a nt T her a pies   
St u d y i nter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or me dical 
de vice(s) i nte n d e d t o be a d mi nistere d t o a st u d y p artici pa nt per  t he st u d y pr ot oc ol. 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistr ati o n   
St u d y I nter ve nti o n(s) A d mi nistere d  
I nt er v e nti o n L a b el 
E v o br uti ni b  
I nt er v e nti o n N a m e 
E v o br uti ni b  
I nt er v e nti o n 
D e s cri pti o n  
P arti ci p a nt s will r e c ei v e a 4 5-m g d o s e of e v o br uti ni b o n c e e a c h  o n D a y s 1,  3 , 5, a n d 7. 
St u d y i nt er v e nti o n will b e a d mi ni st er e d wit h 2 4 0  m L of w at er i n a st a n di n g p o siti o n at t h e 
st u d y c e nt er f oll o wi n g a n o v er ni g ht f a st of at l e a st 1 0  h o ur s . P arti ci p a nt s will r e m ai n 
f a sti n g u ntil 4  h o ur s p o st d o s e. D et ail s i n 5. 3. 1 . 
T y p e  
Dr u g  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /6 0  
 
 
D o s e F or m ul ati o n  
T a bl et  ( T F 2) 
U nit D o s e 
Str e n gt h( s)  
4 5 m g  
D o s e  
4 5 m g si n gl e d o s e  
D o s a g e R e gi m e n  
Si n gl e t a bl et o n D a y s 1, 3, 5, 7  
R o ut e of 
A d mi ni str ati o n  
Or al  
U s e  
E x p eri m e nt al  
I M P or NI M P/ A x M P 
I M P 
S o ur ci n g  
Pr o vi d e d b y 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 Ar m(s)  
Ar m N a m e  
E v o br uti ni b  
4 5 m g  
B at c h A  
E v o br uti ni b  
4 5 m g  
B at c h B  
E v o br uti ni b  
4 5 m g  
B at c h C  
E v o br uti ni b  
4 5 m g  
B at c h D  
Ar m T y p 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  
Ar m 
D e s cri pti o n  
Si n gl e d o s e i n e a c h 
tr e at m e nt p eri o d 
Si n gl e d o s e i n e a c h 
tr e at m e nt p eri o d 
Si n gl e d o s e i n e a c h 
tr e at m e nt p eri o d 
Si n gl e d o s e i n e a c h 
tr e at m e nt p eri o d 
A s s o ci at e d 
I nt er v e nti o n 
L a b el s  
E v o br uti ni b  
E v o br uti ni b  
E v o br uti ni b  
E v o br uti ni b  
B at c h A = 
 (r ef er e n c e), B at c h B = 
 (l o w er di s s ol uti o n  b o u n d ), B at c h C = 
 ( u p p er di s s ol uti o n  
b o u n d) , B at c h D = 
 ( h a m m er-mill e d).  
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 h e me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble 
f or st u d y i nter ve nti o n acc o u nta bilit y, rec o ncili ati 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 i nter ve nti o n(s), t he In v esti gat or or desi g n ee will  c o nfir m a p pr o priate 
te m perat ur e c o n diti o ns ha ve bee n mai ntain e 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 v e 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 h er 
g ui da n ce a n d i nf or mati o n f or st u d y i nter ve nti o n acc o u nta bilit y are pr o vi de d i n t he  I M P 
Ha n dli n g M a n ual . 
•  O n l y p artici pa nts e nr olle d i n t he st u d y ma y 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 s u 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 nt all 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 beled st or a ge c o n diti o ns, a n d 
wit h access li mite d t o t he In v esti 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 h e a p pr o priate acc o u nta bilit y f or ms s o t h at 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.  
Gl o bal Versi o n I D: 
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)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /6 0  
 
 
•  St u d y i nt er ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:  
o  
C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m p erat ur e ra n ge.  
o  
T he i n ve nt or y pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.  
o  
T he d ose(s) eac h partici p a nt use d d uri n g t he st u d y.  
o  
T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n us e d st u d y i nter ve nti o n(s).  
o  
Dates, q ua ntities, bat c 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 v esti gat or site will mai ntai n rec or ds w hi c h a de q uatel y d o c u me nts t h at partici pa nts were 
pr o vi de d t he d oses s p ecifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d were f ull y 
rec o ncile d. 
•  U n use d st u d y i nter ve nti o n(s) will  n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he  
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y be re -dis p e nse d t o a 
differe nt p artici 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 nt a bilit y f or ms.  
•  F urt her g ui da n ce a n d i nf or mati o n f or t he fi na l dis p ositi o n of u n use d st u d y i nter ve nti o n(s) are 
pr o vi de d i n t he  I M P Ha n dli ng  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 As si g n me nt  
T his will be a n o pe n -la b el, ra n d o mize d st u d y. Partici pa nts will be ra n d o ml y assi g ne d t o 1  of t he 
f oll o wi n g 4  tr eat me nt se q ue nces, wit h a ma xi m u m of 7  partici pa nts assi g n e d t o eac h treat me nt 
se q ue nce (rati o 1: 1: 1: 1), usi n g a Willia ms desi g n f or a 4 -treat me nt, 4 -peri o d cr oss o ver st u d y: 
S e q u e n c e n o.  
A ct u al S e q u e n c e  
P eri o d  
1  
2  
3  
4  
1  
A -B -C -D  
A  
B  
C  
D  
2  
B -D -A -C  
B  
D  
A  
C  
3  
C -A -D -B  
C  
A  
D  
B  
4  
D -C -B -A  
D  
C  
B  
A  
B at c h A = 
 (r ef er e n c e), B at c h B = 
 (l o w er di s s ol uti o n b o u n d) , B at c h C = 
 ( u p p er di s s ol uti o n 
b o u n d) , B at c h D = 
 ( h a m m er-mill e d).  
After i nf or me d c o ns e nt pr oce d ure, e v er y p artici 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 eli gi bilit y criteria (see Secti o ns 5. 1  a n d Secti o n 5. 2 ) ca n be i ncl u de d i nt o t he 
st u d y.  
O n Da y 1 , pri or t o first a d mi nistrati o n, t he partici pa nts  e nr olle d will be assi g ne d a u ni q ue 3 -di gits 
assi g n me nt n u m b er (ra n d o mizati o n n u m ber) i n asce n di n g n u meri cal or der at t he st u d y site. T h e 
Gl o bal Versi o n I D: 
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)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /6 0  
 
 
ra n d o mizati o n n u m ber e nc o des t he partici pa nt’s assi g n me nt t o 1 of t he 4 treat me nt se q ue n ces of 
t he st u d y, per t he ra n d o mizati o n sc he d ule ge nerate d pri or t o t he st u d y b y 
 C T S 
De part me nt.  
T he I n v esti gat or will kee p a rec or d relati n g t he p artici pa nt assi g n m e nt n u m bers a n d t he n a 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 
 ra n d o mizati 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 h ec ki n g of d ata 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 n e d t o st u d y i nter ve nti o n f or w hat e ver reas o n.  
6. 4  
St u d y I nter ve nti o n C o m pli a nce   
W he n  partici pa nts are d ose d at t he site, t he y will recei ve st u d y i nter ve nti o n directl y fr o m t he 
I n v esti gat or or desi g nee, u n der me dical s u 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 o c u me nts a n d rec or de d i n t he C R F. A me m ber of t h e 
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 i nter ve nti o n will c o nfir m t he st u d y 
i nter ve nti o n d ose a n d st u d y p artici pa nt i de ntificati o n at t he ti me of d osi n g. St u d y site pers o n nel 
will e x a mi ne eac h partici pa nt ’s m o ut h t o e ns ure t h at t he st u d y i nter ve nti o n was i n geste d. 
6. 5  
D ose M o dific ati o n   
D oses will n ot be m o difie d.  
6. 6  
C o nti n ue d Access t o St u d y I nter ve nti o n A fter t he E n d of t he St u d y  
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o partici pa nts after t he y l ea ve t he st u d y b eca 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 os e of e v o br uti ni b  greater t ha n t he m a xi m u m d ose i n t he st u d y t h at 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 v er d ose.  
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 v er d ose of e v o br uti ni b. T he 
I n v esti gat or will use his/ her cli nical j u d g me nt t o ma na ge a n y o ver d ose, c o nsi deri n g t he s y m pt o ms 
a n d a n y site pr oce d ures or sta n dar ds.  
E ve n if n ot ass ociate d wit h a n A E or S A E, a n y o v er d ose is rec or de d i n t h e C R F a n d re p orte d t o 
gl o bal p atie nt safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a n S A E a n d O ver d ose 
Re p ort F or m, f oll 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 si g ni n g of t he I C F u ntil Safet y F oll o w -u p Visit  ( p h o ne call), i ncl u di n g a n y c h a n ges. F or 
prescri pti o n a n d o ver -t he-c o u nter me dici n es, vacci nes, vita mi ns, a n d her bal s u p ple me nts, rec or d 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
P P D
P P D
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /6 0  
 
 
t he na me, reas o n f or us e, dates a d mi nistere d, a n d d osi n g i nf or m ati o n. F or n o n dr u g i nter ve nti o ns, 
rec or d t h e na me, t he i n di cati o n, a n d dates a d mi nistere d. 
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t h era p y.  
6. 8. 1  
Resc ue Me dici ne   
N o a nti d ote is a vaila ble s pecifi call y f or e v o br uti ni b. S y m pt o matic treat me nt will be pr o vi de d i n 
case of a me di cal 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 treat e d 
s y m pt o maticall y. 
6. 8. 2  
Per mitte d Me dici nes   
T he o nl y p er mitte d me dici nes are t he f oll o wi n g:  
1.  Paracet a m ol (aceta mi n o p he n) u p t o 2 g per da y, at t he discreti o n of t he I n v esti 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 m e dici nes t hat are c o nsi dere d necessar y t o pr otect t he p artici pa nt’s welfare i n e mer ge nci es 
ma y b e gi ve n at t he I n v esti gat or’s discreti o n, re gar dless if it res ults i n a pr ot oc ol de viati o n.  
6. 8. 3  
Pr o hi b ite 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 x cl 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 nt er me dicati o ns (a part 
fr o m t h ose d escri be d a b o ve) wit hi n 2 wee ks or 5  t er mi nal half-li ves, w hic h e 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 nt er ve nti o n, d uri n g t he st u d y, a n d u ntil t he Safet y F oll o w -u p 
A ssess me nt (t his i ncl u des her bal re me di es, vita mi ns, mi nerals, a ntaci ds, a n d dietar y s u p ple m e nts 
s uc h as fis h oils). 
I n hi bit ors or i n d ucers of C Y P 3 A 4/ 5 or P-g p 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, a n d u ntil after t he Safet y F oll o w-U p assess me nt, are pr o hi bite 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 p artici 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 d etaile d i n Secti o n  5. 3 . 
7  
Disc o nti n u ati o n 
of 
St u d y I nter ve nti o n 
a n d 
P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al   
Disc o nti n uati o n of s pecific sites or of t he e ntire st u d y is s pecifie d i n A p pe n di x 2 . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /6 0  
 
 
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 i nter 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 i s 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 i nter ve nti o n is c o nsi dere d n ecess ar y b y t h e 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 a n d S A Es 
re gar dl ess of t he relati o ns hi p t o st u d y i nter ve nti o n. 
•  Pre g n a nc y (s ee 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 nifi ca nt b y t h e I n v esti gat or (after disc ussi o n wit h t he 
S p o ns or).  
•  Use of a n o n p er mitte d c o nc o mita nt dr u g if cli nicall y rele va nt as a gree d b y S p o ns or a n d 
I n v esti gat or, as d efi ne d i n Secti o n 6. 8  w here t he pre defi n e d c o nse q u e 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 pt a bl y e n da n ger t he safet y of t he partici pa nt.  
If st u d y i nter 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 t o be 
e val uate d f or safet y. 
T he S o A s pecifies t he data t o c ollect at st u d y i nter ve nti o n 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 st u d y i nter ve nti o n is disc o nti n ue d , t he safet y assess me nts of Da y 8 a n d f oll o w -u p p h o ne call 
s h o ul d be perf or m e d. 
7. 1. 1  
Li ver Cli nic al S afet y L a b or at or y Tests St o p pi n g Criteri a   
T he I n vesti gat or will c o nsi der  disc o nti n uati o n of st u d y i nter ve nti o n f or a b n or mal li ver f u ncti o n 
w he n a partici pa nt me ets o ne of t he c o n diti o ns o utli ne d  i n t he al g orit h m or if t he I n vesti gat or 
belie ves t hat it is i n best i nterest of t he partici pa nt . 
•  All c o nfir me d e v e nts of A L T or A S T ≥ 5  ×  U L N tri g gers st o p pi n g criteria.  
•  All c o nfir me d e ve nts of A L T or A S T ≥ 3  ×  U L N a n d t otal bilir u bi n >  2  ×  U L N tri g gers 
st o p pi n g criteri a.  
T hese e v e nts  will be re p orte d as a n A E SI.  
7. 1. 2  
C ar di ac S afet y St o p pi n g Criteri a   
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i n cl u di n g c ha n ges fr o m b aseli ne i n Q T i nter val 
c orrecte d usi n g Fri derici a’s f or m ula (Q Tc F  >  6 0  ms a n d Q T/ Q T c F  >  5 0 0  ms) after start of st u d y  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /6 0  
 
 
i nter ve nti o n, t he I n vesti gat or or q ualifie d desi g nee will deter mi ne if t he partici pa nt ca n c o nti n ue 
i n t he st u d y a n d if a n y c h a n ge i n partici pa nt ma na ge m e nt is nee de d. T his re vie w of t he E C G at t he 
ti me of c ollecti o n will be d oc u me nte d. A n y ne w cli nicall y rel e va nt fi n di n g is re p orte d as a n A E. 
7. 1. 3  
Rec h alle n ge   
7. 1. 3. 1  
St u d y I nter ve nti o n 
Rest art or 
Rec h alle n ge 
After 
Li ver 
St o p pi n g Criteri a Are Met   
St u d y i nter ve nti o n restart or rec halle n ge after li ver cli nical safet y l a b orat or y test st o p pi n g criteria 
are met b y a n y p artici pa nt i n t his st u d y are n ot all o we 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 ma y disc o nti n ue fr o m t he st u d y at a n y ti me, at t heir o w n re q uest or at t h e 
discreti o n of t he I n vesti gat or f or safet y, be h a vi oral, c o m plia nce, or a d mi nistrati ve reas o ns  (e. g., 
disr u pti o n of o perati o ns d ue t o nat ur al disasters, i nterr u pti o n of la b or facilit y accre ditati o n, 
partici pa nt m o vi n g t o a n ot her c o u ntr y, resi g n ati o n of ke y staff”) . 
•  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 S o A. T he S o A 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 v al uati o ns t hat nee d t o be c o m plete d.  
•  If t he p artici pa nt re v o k es c o nse nt f or t he st u d y, a n y d ata 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 d ata ca n b e ge n erate d, a n d a n y bi ol o gical sa m ples c ollecte d will be 
destr o ye d.  
•  If a p artici pa nt re q uests t he destr ucti o n of a n y bi ol o gical s a m ples still re mai ni n g, t he 
In v esti 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 i nf or m t he S p o ns or. T he sa m ples 
will be destr o ye d.  
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 b y t he st u d y site. 
T he f oll o wi n g acti o ns will  be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uir e d st u d y 
visit:  
•  T he site will  atte m pt t o c o ntact t he p artici pa nt a n d res c 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 will  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 val e nt l ocal met h o d) t o t he partici pa nt’s last k n o wn 
maili n g a d dress , a n d 3) if a p artici pa nt h as gi ve n t h e 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 l ocal re g ul ati o ns) f or 
i nf or mati o n. T hese c o nt act 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 p a nt c o nti n ues t o be u nreac ha bl e, he/s he will be dee me d as “l ost t o f oll o w -u p” . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 8 /6 0  
 
 
8  
St u d y Assess me nts a n d Pr oce d ures   
•  St u d y assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A.  
•  N o  pr ot oc ol wai vers or e x e m pti o ns are all o we d.  
•  I m me diat e safet y c o ncer ns are disc usse d wit h t h e S p o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne if t he partici pa nt w ill c o nti n ue or disc o nti n ue st u d y i nter ve nti o n.  
•  A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t h e S o A, is esse ntial 
a n d re q uir e d f or st u d y 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 ntia l partici pa nts 
meet all eli gi bilit y criteri a. T he In v esti gat or will mai ntai n a scree ni n g l o g t o rec or d d etails of 
all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d reas o ns f or scree ni n g 
fail ure. 
•  Pri or t o perf or mi n g a n y st u d y asse ss me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t h e I n vesti gat or will o btai n writte n i nf or me d c o nse nt as s pecifie d i n A p pe n di x 2 . 
•  Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he I C F ma y b e use d f or scree ni n g or b aseli 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, were perf or me d wit hi n t he ti me fra me defi ne d 
i n t he S o A, a n d if re vie we d a n d a p pr o ved b y t he S p o ns or . 
•  A b o ut  1 6 5  m L  of bl o o d t otal will be ta ke n t hr o u g h o ut t he st u d y. U p t o  a b o ut 4 5 m L  of bl o o d 
ma y b e dra w n at certai n visits. T hese bl o o d sa m ples will be use d f or t he f oll o wi n g p ur p oses:  
P K a n d cli nical la b orat or y te sts. 
W here all o we d b y l oc al la w/re g ulati o ns, sa m ples c ollecte d d uri n g t his cli nical st u d y ma y be 
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 os e 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 i n t h e C S R.  
8. 1  
Effic ac y Assess me nts a n d Pr oce d ures   
N ot a p plica ble.  
8. 2  
S afet y Assess me nts a n d Pr oce d ures   
T he safet y pr ofile of t he st u d y i nter ve nti o n will b e assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ysis of bas eli ne me dical c o n diti o ns, A Es, p h ysical e x a mi nati o n fi n di n gs, v ital si g ns, E C Gs , 
a n d la b orat or y t ests.   
C o m pre he nsi ve assess m e nt of a n y p ote ntial t o xicit y e x perie nce d b y eac h partici pa nt will be 
c o n d ucte d st arti n g w h e n t he p artici pa nts gi ve i nf or me d c o ns e nt a n d t hr o u g h o ut t he st u d y. T h e 
In v esti gat or will re p ort a n y A E s, w het her o bs er ve d b y t h e I n v esti gat or or re p orte d b y t h e 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n 8. 3 . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 9 /6 0  
 
 
8. 2. 1  
P h ysic al E x a mi n ati o ns   
•  A c o m plete p h ysical e x a 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, 
car di o vas c ular, res pirat or y, gastr oi ntesti nal , a n d n e ur ol o gi cal s yst e ms, a n d a b d o me n (li ver a n d 
s plee n). 
•  A brief p h ysical e x a 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, res pirat or y, 
car di o vas c ular s yste m, a n d a b d o me n (li ver a n d s plee n).  
•  I n v esti gat ors will pa y s pecial atte nti o n t o cli nical si g ns relat e d t o pre vi o us seri o us ill nesses. 
8. 2. 2  
Vit al Si g ns   
•  Bl o o d press ur e a n d p artici pa nt’s p ositi o n  d uri n g 
meas ure me nt ; p ulse; res pirat or y rate; 
te m perat ur e a n d l ocati o n of meas ure m e nt , wei g ht, a n d h ei g ht (at b as eli ne o nl y)  will be 
meas ure d a n d rec or de d.  Vital si g ns will be meas ure d i n s u pi ne p ositi o n. T y m pa nic t e m perat ur e 
will be meas ure d.  
•  Bl o o d press ur e a n d p ulse meas ure me nts will  be prece d e d b y at least 5 mi n utes of rest f or t he 
partici pa nt i n a q uiet setti n g wit h o ut distr acti 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 vi ce. 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 -le a 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 m e nts usi n g a n E C G 
mac hi ne t hat a ut o maticall y 
meas ures heart rat e, P R, R R, Q R S, Q T, a n d Q Tc F.  E C G 
a b n or malities will be d oc u me nte d as cli nicall y si g nifica nt or n ot cli nicall y si g nifica nt  i n t he 
e C R F t o get her wit h a d es cri pti o n of t he a b n or malit 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 of rest.  
8. 2. 4  
Cli nic al S afet y L a b or at or y Tests   
•  Bl o o d a n d uri ne s a m ples will be c ollect e d f or t he cli nical la b orat or y tests liste d i n A p pe n di x 6  
at t he ti me p oi nts liste d i n t he S o A.  All sa m ples will  be clearl y i de ntifie d.  
•  A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y, as deter mi n e d necessar y b y t h e 
In v esti gat or or re q uire d b y l oc al re g ulati o ns.  
•  T he tests will be perf or me d b y 
 la b orat or y; t he Q ua nti F E R O N ® Test will be 
perf or me d b y 
. 
•  T he In v esti gat or will  re vie w eac h la b orat or y re p ort, d oc u me nt t his re vi e w, a n d rec or d a n y 
cli nicall y si g nifica nt c h a n ges o cc urri n g d uri n g t h e 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 pecifi e d i n A p pe n di x 4 . T he la b orat or y re p orts will  be fil e d wit h t he s o urce 
d oc u me nts.  
•  Pre g n a nc y t esti n g (ser u m or hi g hl y s e 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 yst e mic e x p os ure of t he st u d y 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 p a nt c o ntrace pti o n i n Secti o n 5. 1 . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
P P D
P P D
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /6 0  
 
 
•  A d diti o nal ser u m or uri ne pre g na n c y testi 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 bs e nce of pre g na nc y, at t h e I n v esti gat or’s discreti o n or if l ocal re g ulati o ns re q uir e 
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 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 q ualifie d d esi 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 v e nts t hat meet t he defi niti o n of a n A E or S A E. T he 
I n v esti 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 relat e d t o 
t he st u d y i nter ve nti o n or st u d y pr oce d ures , or t h at ca use d t he p artici 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 p ecifie d i n Secti o n 8. 3. 2 . 
•  Re q uests f or f oll o w -u p will us uall y b e m a de vi a t he S p o ns or or C R O -d esi g nate d st u d y tea m 
me m ber , alt h o u g h i n e x ce pti o nal circ u msta n ces t he gl o bal p atie nt  safet y de p art me nt ma y 
c o ntact t he I n v esti gat or directl y t o 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 ass essi n g ca usalit y of A Es a n d S A Es a n d t h e 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts are i n A p pe n di x 4 . 
•  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 Safet y F oll o w -u p Visit  
( p h o ne call) at t he ti me p oi nts s pecifie d i n t he S o A ( Secti o n 1. 3 ). Be y o n d t his re p orti n g peri o d, 
a n y n e w u ns olicite d S A Es t hat t he I n v esti gat or s p o nta ne o usl y re p orts t o t he S p o ns or will be 
c ollecte d a n d pr ocess e d.  
•  All S A Es will be rec or de d a n d re p orte d t o t he S p o ns or or desi g n ee i m me diatel y a n d u n der n o 
circ u msta nce will t his e x cee d 2 4 h o urs, as i n dicate d i n A p pe n di x  4  . T he I n 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 it bei n g a vaila ble usi n g t he 
sa me pr oce d ure t hat w as use d f or t he i nitial re p ort. 
•  I n v esti gat ors are n ot o bli gat e d t o acti vel y s olicit i nf or mati o n o n A Es or S A Es  after t he e n d of 
st u d y partici pati o n. H o we ver, if t he In v esti gat or l ear ns of a n y S A E, i n cl 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 relat e d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he I n v esti gat or will  
pr o m ptl y n otif y t he S p o ns or.  
8. 3. 1  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts   
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n .  
Care will be ta k e 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 Es 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 . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 1 /6 0  
 
 
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 E SIs  (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 wis e e x plai ne d, or t h e 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 n a ble atte m pts t o o btai n t his i nf or mati o n will  be ma de a n d 
d oc u me nte d. It is als o t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat a n y n ecessar y a d diti o nal 
t hera pe utic m eas ur es a n d f ollo w -u p pr oce d ures are perf or me d. F urt h er i nf or mati o n o n f oll o w -u p 
pr oce d ures is i n A p pe n di x 4 . 
8. 3. 3  
Re g ul at or y 
Re p orti n g 
Re q uire me nts f or Seri o us 
A d verse 
E ve nts   
•  Pr o m pt n otificati o n b y t h e I n vesti gat or t o t he S p o ns or of a n S A E ( partic ul arl y life -t hreate ni n g 
a n d deat hs) is ess e ntial s o t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war d t he safet y of 
partici pa nts a n d t he safet y of a st u d y i nte r 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 t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safet y of a st u d y i nter ve nti o n u n der cli nical 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 m e nts relati n g t o safet y re p orti n g 
t o t he re g ulat or y a ut h orit y, I R B/I E C, a n d In v esti 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 Rs acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d S p o ns or p olic y a nd f or war de d t o I n v esti gat ors wit hi n 1 5 da ys.  
•  A n I n v esti gat or or S u b in vesti gat or w h o recei v es 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 safet y i nf or mati o n (e. g., E mer gi n g Safet y Iss ue Re p ort, s u m mar y or 
listi n g of S A Es/ S U S A Rs) fr o m t he S p o ns or will rea d it a n d c o nfir m c o m pleti o n of t his  acti vit y. 
T his i nf or mati o n will be file d i n t he I n vesti gat or’s Site File, a n d t he I R B/I E C will be n otifie d, 
if a p pr o priate, acc or di n g t o a p plica ble l ocal la ws/re g ul ati o ns a n d site S O Ps.  
8. 3. 4  
Pre g n a nc y   
•  Details of all pre g na n cies i n fe male partici pa nts a n d  fe male part ners of male partici pa nts will 
be c ollecte d after t he st art of st u d y i nter ve nti o n a n d u ntil 1 2 0 da ys aft er t he last d ose of 
e v o br uti ni b.  
•  If a pre g na n c y is re p ort e d, t he In v esti gat or will rec or d t he pre g na n c y i nf 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 or fe mal e 
part ner of male partici pa nt (after o btai ni n g t he n ecessar y si g ne d i nf or me d c o nse nt fr o m t he 
fe male part ner) pre g n a nc y . 
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n or 
electi ve ter mi nati o n of a pre g n a 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 n e o us a b orti o n, fetal d eat h, still birt h, c o n ge 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 ge stati o n al 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 ort e d as s uc h.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 2 /6 0  
 
 
•  T he partici pa nt /pre g n a nt fe male part ner  will b e f oll o we d t o d eter 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 p artici pa nt  / pre gn a nt 
fe male part ner 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 h e esti mate d 
deli ver y dat e  f or a h ealt h y n e 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 p ost  st u d y pre g n a nc y relate d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y i nter ve nti o n 
b y t he I n vesti gat or will be re p ort e d t o t he S p o ns or as s pecifie d i n Secti o n 8. 3. 3 . W hile t he 
I n v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y partici pa nts 
/ pre g n a nt fe m ale part n er, he or s he ma y lear n of a n S A E t hr o u g h s p o nta n e o us re p orti n g. 
•  A n y fe male partici p a 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 b e 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 h e f oll o wi n g:  
•  I nfecti o ns (seri o us a n d/ or  o p p ort u nistic  a n d/ or ≥ Gra de  3)  
As per its mec h a nis m of acti o n, e v o br uti ni b ma y i m pair B  cell f u ncti o n w hic h mi g ht l ea d t o a 
decrease d h u m or al i m m u nit y a n d c o ns e q ue ntl y a n i ncrease d ris k of i nf ecti o n. O verall, i n 
c o m plete d s t u dies i n partici pa nts, t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities S O C 
i nfecti o n was o ne of t he m ost c o m m o nl y re p ort e 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 a p pr o xi matel y 1 8 % t o 3 2 % of partici pa nts treate d wit h e v o br uti ni b re p orte d i nf ecti 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 n e i n acc or da nce wit h l ocal 
sta n dar d of care de p e n di n g o n c o nsi derati o ns s uc h as t he nat ur e a n d se v erit y of t he i nf ecti 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 nf ecti o n a n d o p p ort u nistic i nfe cti 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 n eral p o p ulati o n, occ urri n g i n 2 % 
t o 3 % of patie nts wit h 
M S (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 m a 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 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 3 /6 0  
 
 
wit h si g nifica nt brai n lesi o n l oa d re p ort e d seiz ure of u nclear cli nical  pict ure. T he P K d ata f or 
t his partici pa nt di d n ot e x cee 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 w as starte d, a n d t he partici pa nt c o nti n ue d treat me nt wit h 
e v o br uti ni b wit h n o re occ urre n ce. T he I n v esti 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 v e 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 8 0 0  patie nts wit h M S, r he u mat oi d art hritis a n d s yste mic 
l u p us er yt he m at os us. M ore o ver, a n 
E C G  st u d y i n healt h y partici pa nts  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 t y p e of seiz ures/e pile ps y of a n y gra de or its 
c o nse q ue nces are classifi e d as A E SIs.  
•  Ele vate d li pase, el e vate d a m ylas e, pa ncreatitis  
As y m pt o matic el e vati o ns i n a m ylas e 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 M S 2 0 0 5 2 7 _ 0 0 8 6, t he i nci de n ce of T E A Es of l i pase i ncrease d 
was sli g htl y hi g h er i n e v o br uti ni b 7 5  m g o n ce d ail y a n d 7 5  m g t wice d ail 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 b et wee n 4 % t o 6 %). 
H o we ver, s hifts fr o m b aseli ne t o hi g hest gra de o n treat me nt w ere si milar acr oss all treat me nt 
ar ms f or b ot h a m ylase a n d li pase. I n e v 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 ncreas e d a m ylas e or li pase, or b ot h was i nfre q u e nt a n d 
n o cli nicall y m ea ni n gf ul differe nc es 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 ylase a n d a n y t y pe of pa ncreatitis are cl assifie d as A E SIs.  
•  Li ver relat e d e ve nts  
T he ele vati o ns of tr a nsa mi nases o bser ve d i n p artici pa nts treate d wit h e v o br uti ni b were fre q u e nt, 
as y m pt o matic, a n d re v ersi ble o n disc o nti n uati o n of e v o br uti ni b. T he mec h a 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 bas e d o n la b orat or y dat a, a n y t y p e of ac ut e or c hr o nic 
he patitis (a n y 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 m a ge-relate d c o n diti o ns. 
A E SIs ha v e t o be re p orte d i m me diatel y ( wit hi n 2 4  h o urs). F or re p orti n g of A E SI s, see A p pe n di x  4 . 
8. 4  
P h ar m ac o ki netics   
8. 4. 1  
Bl o o d S a m pli n g a n d Bi o a n al ysis   
•  Sa m ples are c ollecte d o nl y w here all o we d b y l ocal la w/re g ulati o ns.  
•  T he act ual d ate a n d ti me ( 2 4 -h o ur cl oc k ti me) of:  
o  E ac h sa m ple c ollecti o n  
o  S t u d y i nter ve nti o n a d mi nistrati o n pri or t o sa m ple c ollecti o n  
•  will be rec or de d i n t he e C R F t o deter mi ne t he ela pse d ti me of sa m pli n g i n relati o n t o t h e 
a d mi nistrati o n of st u d y i nter ve nti o n. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 /6 0  
 
 
•  Bl o o d  sa m ples f or meas ure me nts of e v o br uti ni b c o nce ntr ati o ns will be c ollecte d. C ollecti o n 
ti mes are s pecifie d i n t he S o A. 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 1 . 
•   T he q ua ntificati o n of e v o br uti ni b  i n plas ma  will be perf or me d usi n g a vali date d assa y met h o d.  
•  Re mai ni n g sa m ples c ollecte d f or bi oa nal ytical meas ure me nts ma y als o b e use d f or e x pl orat or y 
assess me nt of m eta b olites of e v o br uti ni b  or e x pl orat or y bi o mar kers d uri n g or after t he st u d y. 
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 C F. 
•  Details o n pr ocess es f or c ollecti o n a n d ha n dli n g of t hese sa m ples are i n La b orat or y Ma n u al.  
T a ble 1  
Ti me D e vi ati o ns f r o m P K S a m pli n g T i mes  
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 K  
Pr e d o s e  
- 6 0  mi n  
1 5  mi n  
±  2  mi n  
3 0  mi n  
±  2  mi n  
1  hr  
±  2  mi n  
1. 5  hr  
±  5  mi n  
2  hr  
±  5  mi n  
2. 5  hr  
±  5  mi n  
3  hr  
±  5  mi n  
4  hr  
±  5  mi n  
6  hr  
±  5  mi n  
8  hr  
±  5  mi n  
1 2  hr  
±  5  mi n  
1 6  hr  
±  1 5  mi n  
2 4  hr  
±  1 5  mi n  
A n y de vi ati 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 data re vie w meeti n g.  
8. 4. 2  
P K P ar a meters   
•  T he f oll o wi n g P K p ara m eters f or e v o br uti ni b will be calc ul ate d, w he n a p pr o priate:  
S y m b ol  
D efi niti o n  
A U C 0 -tla 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 ti m e of t h e l a st q u a ntifi a bl e c o n c e ntr ati o n (tl a st). 
A U C 0 -∞ 
T h e A U C fr o m ti m e z er o ( =  d o si n g ti m e) u p t o i nfi nit y wit h e xtr a p ol ati o n of t h e t er mi n al p h a s e.  
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 f oll o wi n g e xtr a v a s c ul ar a d mi ni str ati o 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.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 /6 0  
 
 
S y m b ol  
D efi niti o n  
F r el 
R el ati v e Bi o a v ail a bilit y [ %] of T e st Tr e at m e nt  i n r el ati o n t o R ef er e n c e Tr e at m e nt. 
t1/ 2  
T er mi n al h alf -lif e.  
tl a g 
T h e ti m e pri or t o t h e fir st c o n c e ntr ati o n at or a b o v e L O Q . 
tm a x  
T h e ti m e t o r e a c h t h e C m a x  i n a d o si n g i nt er v al. 
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.  
z  
T er mi n al fir st or d er ( eli mi n ati o n) r at e c o n st a nt.  
L O Q = Li mit of q u a ntifi c ati o n.  
Ot her P K para meters mi g ht be a d de d bas e d o n e mer gi n g d ata. Det ails will be i n t he I A P.  
•  C o nce ntrati o n dat a ma y be use d f or i nte grat e d dat a a n al ys es acr oss st u dies, s uc h as p o p ulati o n 
P K , a n d re p orte d s e parat el y fr o m t he mai n C S R.  
8. 5  
Ge netics a n d/ or P h ar m ac o ge n o mics   
N ot a p plica ble.  
8. 6  
Bi o m ar kers   
N ot a p plica ble.  
8. 7  
I m m u n o ge nicit y Assess me nts  
N ot a p plica ble.  
8. 8  
He alt h Ec o n o mics   
N ot a p plica ble.  
9  
St atistic al C o nsi der ati o ns   
9. 1  
St atistic al H y p ot hes es  
T he statistical a nal ysis of st u d y dat a will be p urel y des cri pti ve; n o h y p ot hesis tests will be 
perf o r me d. 
 
  
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 /6 0  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /6 0  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 3  
A n al ys is Sets   
T he a nal ysis sets are s pecifie d bel o w.  
A n al y si s S et  
D e s cri pti o n  
S cr e e ni n g ( S C R)  
All p arti ci p a nt s, w h o  pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s r a n d o mi z ati o n 
a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.  
S af et y ( S A F)  
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n. A n al y s e s will 
c o n si d er p arti ci p a nt s a s tr e at e d.  
P K  
T h e P K A n al y si s S et  i s a s u b s et of t h e S af et y A n al y si s S et  a n d will c o n si st of all p arti ci p a nt s 
w h o r e c ei v e at l e a st o n e d o s e of a cti v e I M P a n d pr o vi d e at l e a st o n e m e a s ur a bl e p o st d o s e 
c o n c e ntr ati o n. A m e a s ur e m e nt b el o w l o w er li mit of q u a ntifi c ati o n i s  c o n si d er e d a v ali d 
m e a s ur e m e nt. P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e d  
i n e a c h p eri o d. All P K a n al y s e s will b e b a s e d o n t h e P K A n al y si s S et . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 /6 0  
 
 
9. 4  
St atistic al A n al yses   
9. 4. 1  
Effic ac y A n al yses   
N ot a p plica ble . 
9. 4. 2  
S afet y A n al yses   
I n ge n eral, f or t he e v al uati o n of safet y para met ers, t he n u merical val ues will be s u m marize d 
descri pti vel y ( N, arit h metic mea n, me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m val ues). 
Cate g orical v aria bles will be prese nte d i n fre q ue nc y ta bles b y t he n u m ber of o bser vati o ns a n d 
perce nt a ges.  
A d verse E ve nt c o u nts a n d partici pa nts wit h A Es will be s u m marize d f or eac h treat me nt b y s yste m 
or ga n class a n d preferre d ter m. I n a d diti o n, A Es will be ta b ulate d a n d liste d per partici pa nt  a n d 
a nal yze d b y s e verit y a n d relati o ns hi p t o st u d y dr u g.  
Partici pa nts w h o pre mat urel y wit h dre w fr o m t h e st u d y or fr o m treat me nt will be dis pla ye d i n a 
b y -p artici pa nt listi n g a n d s u m marize d b y pri mar y wit h dra wal reas o n f or eac h treat me nt se q ue nce.  
Safet y la b orat or y para m eters will be liste d f or eac h partic i pa nt i ncl u di n g c ha n ges fr o m bas eli ne 
a n d fla gs f or me as ure m e nts o utsi de t he refere nce ra n ges, w here a p plica ble. La b orat or y p ara met ers 
( he mat ol o g y a n d cli nical c he mistr y) will be s u m marize d b y ti me p oi nt i ncl u di n g b ot h a bs ol ute 
val ues a n d c h a n ges fr o m base li ne.  
Vital si g ns b y p artici pa nt, i ncl u di n g c h a n ges fr o m baseli ne, will be liste d a n d s u m marize d b y 
treat me nt a n d ti me p oi nt usi n g des cri pti ve statistics. Electr ocar di o gra m para meters a n d p h ysical 
e x a mi nati o n assess me nts will be liste d f or eac h p artici pa nt.  
All safet y a nal yses will be perf or me d o n t he Safet y A nal ysis set ( Secti o n 9. 3 ) 
 
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
Pri m ar y  
N o pri m a r y s af et y e n d p oi nt s 
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  
T h e n u m b er a n d p er c e nt a g e of p arti ci p a nt s e x p eri e n ci n g at l e a st 1 T E A E will 
b e s u m m ari z e d b y tr e at m e nt a s w ell a s t h e n u m b er of e v e nt s. T a bl e s b y 
r el ati o n s hi p t o st u d y dr u g a n d b y s e v erit y will b e g e n er at e d. A E s will b e c o d e d 
u si n g M e d D R A  t er mi n ol o g y. 
A b s ol ut e v al u e s a n d c h a n g e s i n 
s af et y l a b or at or y t e st s  
All l a b or at or y d at a will b e r e p ort e d wit h SI u nit s. L a b or at or y p ar a m et er s will b e 
s u m m ari z e d u si n g d e s cri pti v e st ati sti c s f or a b s ol ut e v al u e s , c h a n g e s fr o m 
b a s eli n e ( pr e d o s e  f or t h e r e s p e cti v e p eri o d) a n d  d at a li sti n g s of a b n or m aliti e s.  
Si n gl e 1 2 -l e a d 
el e ctr o c ar di o gr a m s ( E C G s) 
( m or p h ol o g y a n d ti m e i nt er v al s 
P R, Q R S, R R, Q T a n d Q T c F ) 
E C G d at a will b e s u m m ari z e d b y c h a n g e s  fr o m b a s eli n e ( pr e d o s e  f or t h e 
r e s p e cti v e p eri o d) 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.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 /6 0  
 
 
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
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  
Vit al si g n s d at a will b e s u m m ari z e d b y c h a n g e s  fr o m b a s eli n e  (pr e d o s e  f or t h e 
r e s p e cti v e p eri o d) v al u e s u si n g d e s cri pti v e st ati sti c s.  
T erti ar y/ E x pl or at or y  
N ot a p pli c a bl e  
9. 4. 3  
Ot her A n al yses   
C at e g or y/ E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
Pri m ar y  
 
A U C 0 -∞ 
C m a x  
P K p ar a m et er s ar e li st e d i n S e cti o n 8. 4 . 
S u m m ar y st ati sti c s will b e pr o vi d e d.  
A li n e ar mi x e d m o d el wit h B A T C H, P E RI O D, a n d S E Q U E N C E a s fi x e d eff e ct s a n d 
S U B J E C T wit hi n S E Q U E N C E a s a r a n d o m eff e ct will b e a p pli e d t o l o g -tr a n sf or m e d 
pri m ar y e n d p oi nt s C m a x , a n d A U C0 -∞ b a s e d o n t h e P K a n al y si s s et. Diff er e n c e s 
b et w e e n b at c h e s o n t h e l o g s c al e f or e a c h c o m p ari s o n will b e e sti m at e d f or t h e 
p ar a m et er s t o g et h er wit h t h eir 9 0 % CI s. P oi nt e sti m at e s a n d CI s will b e b a c k 
tr a n sf or m e d t o t h e ori gi n al s c al e f or pr e s e nt ati o n. 
 
All P K a n al y s e s will b e p erf or m e d o n t h e P K A S.  
 
S e c o n d ar y  
 
P K p ar a m et er s (i n S e cti o n 
8. 4 ) 
S u m m ar y st ati sti c s of P K p ar a m et er s will b e pr o vi d e d.  
All P K a n al y s e s will b e p erf or m e d o n t h e P K A S.  
P K A S = P K a n al y si s s et.  
9. 4. 4  
Se q ue nce of A n al yses   
All fi nal, pla n ne d a nal yses i de ntifie d i n t he cli nical st u d y pr ot o c 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., Safet y F oll o w-u p wit h all st u d y dat a i n-h o use, all 
data q ueries res ol ve d, a n d t he data base l oc ke d.  I nteri m a nal ys es f or earl y decisi o n ma ki n g ma y 
ta ke place wit h restricte d a n d d oc u me nte d access t o t he data a n d res ults, wit h o ut i m pact o n t he 
st u d y desi g n. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /6 0  
 
 
1 0  
Refere nces   
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.   
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 s e verit y a n d m ortalit y i n p atie nts 
wit h c hr o nic l y m p h oc yti c le u ke mia: a j oi nt st u d y b y E RI C, t he E ur o p ea n Researc h I nitiati ve o n 
C L L, a n d C L L Ca m p us. Le u k e mia. 2 0 2 0; 1 -1 0 .  
T hi ba u d S, Tre m bla y D, B halla S, et al. Pr ot ecti 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 ytic l e 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 pr otect a gai nst 
p ul m o nar y i nj ur y i n C O VI D -1 9 -i nf ecte d patie nts. Bl o o d. 2 0 2 0; 1 3 5( 2 1): 1 9 1 2-5.   
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 /6 0  
 
 
1 1  
A p pe n dices   
A p pe n di x 1  
A b bre vi ati o ns   
A E  
a d v er s e e v e nt  
A E SI  
a d v er s e e v e nt s of s p e ci al int er e st  
A L T  
al a ni n e tr a n s a mi n a s e  
A S T  
a s p art at e tr a n s a mi n a s e  
B T K  
Br ut o n’ s tyr o si n e k i n a s e 
C R F  
c a s e re p ort for m  
C R O  
c li ni c al re s e ar c h o r g a ni z ati o n 
C S R  
c li ni c al s t u d y re p ort  
C T  
c li ni c al tri al s 
C V  
C o effi ci e nt of v ari ati o n  
D a y  
St u d y D a y ( u nl e s s ot h er wi s e i n di c at e d) 
D R E  
d i s e a s e-rel at e d e v e nt s  
E C G  
e l e ctr o c ar di o gr a m 
e G F R  
e sti m at e d gl o m er ul ar filtr ati o n r at e  
E M A  
E ur o p e a n M e di c al A g e n c y  
E u dr a C T  
E ur o p e a n Cli ni c al Tri al s D at a b a s e  
F D A  
F o o d a n d Dr u g A d mi ni str ati o n ( U S)  
G C P  
G o o d Cli ni c al Pr a cti c e  
HI V  
h u m a n im m u n o d efi ci e n c y v ir u s 
H R T  
h or m o n e r e pl a c e m e nt t h er a p y  
I A P 
int e gr at e d a n al y si s p l a n 
I B 
I n v e sti g at or’ s Br o c h ur e 
I C F 
inf or m e d c o n s e nt for m  
I C H 
I nt er n ati o n al C o u n cil f or  H ar m o ni z ati o n  
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I F U 
inf or m ati o n f or u s e  
I g 
i m m u n o gl o b uli n 
I M P 
in v e sti g ati o n al m e di ci n al p r o d u ct 
I N R 
int er n ati o n al n or m ali z e d rati o  
I R 
im m e di at e r el e a s e  
I R B 
I n stit uti o n al R e vi e w B o ar d 
I R C 
I n d e p e n d e nt R e vi e w C o m mitt e e 
L O Q  
li mit of q u a ntifi c ati o n 
P K  
p h ar m a c o ki n eti c  
P K A S  
p h ar m a c o ki n eti c  a n al y si s s et   
Q T c F  
c orr e ct e d Q T i nt er v al b y Fri d eri ci a ’ f or m ul a 
R M S  
R el a p si n g m ulti pl e s cl er o si s  
S A E  
s eri o u s a d v er s e e v e nt  
S A F  
s af et y  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 2 /6 0  
 
 
S C R  
s cr e e ni n g  
S o A  
s c h e d ul e of a cti viti e s  
S U S A R  
s u s p e ct e d u n e x p e ct e d s eri o u s a d v er s e re a cti o n 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 s  
T F  
T a bl et f or m ul ati o n  
U L N  
u p p er li mit of n or m a l 
W H O  
W orl d H e alt h Or g a ni z ati o n  
W O C B P  
w o m a n of c hil d b e ari n g p ot e nti al  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 /6 0  
 
 
A p pe n di x 2  
St u d y G o ver n a nce   
Fi n a nci al Discl os ure  
I n v esti gat ors a n d S u bin vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi 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 certifi cati o n 
or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1  year after c o m pleti o n of t he st u d y.  
I nf or me d C o nse nt Pr ocess 
•  T he I n vesti gat or or t h eir re pres e ntati ve will e x plai n t he nat ure of t he st u d yi ncl u di n g t he ris ks 
a n d be nefits, t o t he partici pa nt a n d a ns wer all q uesti o ns o n t he st u d y. 
•  Partici pa nts will  be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  
•  Partici pa nts will be re q uir e d t o si g n a stat e me nt of i nf or me d c o nse nt t hat meets t he re q uire me n ts 
of 2 1 C F R 5 0; l ocal re g ulati o ns; I C H g ui d eli nes; pri vac y a n d data pr otecti o n re q uire me nts , 
w here a p plica ble; a n d t h e I R B/I E C or st u d y ce nter.  
•  T he me dical rec or d will  i ncl u de a state me nt t h at writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o ns e 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 C F is u p date d d uri n g t heir partici pati o n i n t he st u d y, p artici pa nts will  be rec 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 p artici 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 nl y; p artici pa nt na mes or a n y i de ntifia bl e i nf or mati o n will n ot be tra nsferre d. 
•  T he S p o ns or will  i nf or m partici pa nts t hat t heir pers o nal st u d y-rel ate 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 p art ners (if a p plica ble)  w h o will be re q uire d t o gi ve c o ns e nt f or t heir data t o be 
use d, as s pecifi e d i n t he i nf or me d c o ns e nt . 
•  T he partici pa nt will  be i nf or me d t hat t heir me dical rec or ds ma y b e e x a mi ne d b y Cli nical Q ualit y 
Ass ura nc e a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y a p pr o priate I R B/I E C 
me m bers, a n d b y re g ul at or y a ut 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 list e d o n t he title pa ge re prese nts all I n v esti gat ors f or decisi o ns a n d 
disc ussi o ns o n t his st u d y, per I C H G C P. T he Pri nci pal  I n vesti gat or will pr o vi de e x pert me dical 
i n p ut a n d a d vice o n t he st u d y desi g n a n d e x ec uti o n a n d is res p o nsi ble f or t he re vi e w a n d si g noff 
of t he cli nical st u d y re p ort.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 /6 0  
 
 
T he st u d y will be c o n d ucte d at a si n gl e ce nter, t he Cli nical P har mac ol o g y U nit of 
, 
Ger ma n y. 
 will be res p o nsi ble f or t he f oll o wi n g acti vities: 
•  Cli nical c o n d uct a n d la b orat or y ser vi ces  
•  Data ma na ge me nt  
•  Statistical pr o gra m mi n g a n d a nal ysis  
•  P K a nal ysis  
•  Me dical writi n g  
•  I n d e 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 s er vices  
Cli nical trial s u p plies will be pr o vi de d b y T her m o Fis her.  
Details of str uct ures a n d ass ociate d pr o ce d ures will be defi ne d se p arate l y ( 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 u cte d i n acc or da n ce wit h t he pr ot oc ol a n d t he f oll o wi n g:  
o  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he Declarat i o n 
of Helsi n ki a n d CI O M S I nter nati o nal Et hical G ui d eli nes  
o  A p plica ble I C H G C P G ui deli nes  
o  A p plica ble la ws a n d re g ulati o ns . 
•  T he pr ot oc ol, pr ot o c ol a me n d me nts (if a p plica ble), I C F, 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 s u b mitte d t o a n I R B/I E C f or re vie w a n d 
a p pr o ve bef ore t h e st u d y is i nitiate d.  
•  A n y pr ot o c ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e x ce pt f or c h a n ges necessar y t o 
eli mi nate a n i m me diate hazar d t o st u d y p artici pa nts. W he n a p plica ble, a me n d 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 ac c 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 n ee will pr o vi de E mer ge n c y Me dical S u p p ort car ds t o partici pa nts f or use 
d uri n g t h e st u d y. T h es e pr o vi de t he 
mea ns f or partici p a nts t o i de ntif y t h e 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 h at ma y be nee d e d t o d eter mi ne t he c o urse of me dical treat me nt f or t he 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
P P D
P P D
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 /6 0  
 
 
partici pa nt. T he i nf or mati o n o n t he E mer ge nc y M e dical S u p p ort car d ma y i 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). 
•  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 v esti gat or cari n g f or 
t he partici pa nt. C o nse q u e 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 c o ntact 
i nf or mati o n o n t he car d. If t h e I n vesti gat or is a vaila ble w he n a n e v e nt occ urs, t he y will a ns w er 
a n y q u esti o ns. A n y s u 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 v esti gat ors.  
•  W he n t he I n vesti gat or is n ot a vaila ble, t he P hase 1  facilit y will pr o vi de t h e a p pr o priate mea ns 
t o c o ntact a p h ysici a 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 h e healt h care pr o vi ders will be gi ve n access t o a n a p pr o priate p h ysic ia n t o assist wit h 
t he me dical e mer ge nc y a n d t o pr o vi de s u p p ort f or t he p ote ntial u n bli n di n g of t he partici pa nt 
c o ncer ne d.  
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts  
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns 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 c o m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
Pri nci pal I n 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  
 
. 
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 pres e nte d at scie ntific meeti n gs. If t his is f ores ee 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 t o pr o vi de c o m me nts.  
•  T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge n erall y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site data. 
•  A ut h ors hi p will be deter mi ne d b y a gree me nt a n d i n li ne wit h I nter n ati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire m e 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 d ata will be pr o vi de d t o Cli nical Trials. g o v as well as t o t h e E ur o p ea n Cli nical 
Trial Dat a base, as a p plica ble, a n d will occ ur 1 2 m o nt hs after t h e last cli nic visit of t he fi nal 
st u d y p artici pa nt or a n ot her a p pr o priat e 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 x a mi nati o ns at re q u est. Aft er 
fi nalizati o n of t he st u d y, healt h y p artici pa nts mi g ht be pr o vi de d wit h t he i nf or mati o n p u blis he d 
o n Cli nical Trials. g o v a n d/ or t he E ur o pea n Cli nical Trial Data b ase at r e q uest.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: 
P P D
C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 6 /6 0  
 
 
•  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 h e S p o ns or i n c o ns ultati o n wit h t he 
Pri nci pal I n v esti gat or f oll o wi n g t he g ui da nce i n I C H T o pi c E 3 a n d will be s u b mitte d i n 
acc or da nce wit h l ocal re g ulati o ns.  
•  A n y a n d all scie ntific, c o m mercial, a n d tec h ni cal i nf or mati o n discl ose d b y t he S p o ns or i n t his 
pr ot oc ol or else w 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 pert y of t he 
S p o ns or. T he I n vesti gat or s hall h ol d s uc h i nf or m ati o n i n c o nfi de nce a n d s h all n ot discl ose t he  
i nf or mati o n t o a n y t hir d part y e x ce pt t o s u c h of t h e I n vesti gat or’s e m pl o yees a n d st aff w h o h a 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 t o e val uate t hat i nf or mati o n. T he I n vesti gat or s hall n ot use 
s uc h i nf or mati o n f or a n y p ur p ose ot her t ha n f or d eter mi ni n g m ut ual i nterest i n perf or mi n g t he 
st u d y a n d, if t h e parties deci de t o pr ocee d wit h t he st u d y, f or t he p ur p os e of c o n d u cti n g t h e 
st u d y. 
•  T he I n vesti gat or u n derst a n ds t ha t t he i nf or mati o n de vel o pe d fr o m t his cli nical st u d y will be 
use d b y t he S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he st u d y i nter ve nti o n a n d t heref ore 
ma y be discl os e 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 n cies. T he I n vesti 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 d y, t he I n v esti gat or has t he o bli gati o n t o pr o vi d e 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 bl icati o n or 
discl os ure of st u d y res ults will be per mitte d e x ce pt u n der t he ter ms a n d c o n diti o ns of a se parat e 
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 o r 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 yi n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y b y p h ysicall y or 
electr o nicall y si g ni 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 urate d o c 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 v esti gat or will  per mit st u d y -rel ate d m o nit ori n g, q ualit y ass ur a nce a u dits, I R B/I E C 
re vie w, a n d re g ul at or y a ge nc y i ns 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 o urce 
data.  
•  Q T Ls will n ot be pre d efi ne d i n t his st u d y beca use neit her t he li mite d  n u m ber of pla n n e d  
partici pa nts n or t he s h ort d urati o n of t h e st u d y s u p p ort t he c ollecti o n of mea ni n gf ul q ualit y 
t olera nce li mits. 
•  M o nit ori n g details descri bi n g strate g y , i ncl u di n g defi niti o n of st u d y criti cal data ite ms a n d 
pr ocesses (e. g., ris k-bas e d i nitiati ves i n o per ati 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 n cl 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 ntr al, 
re m ote, or o n-site m o nit ori n g) are i n t he M o nit ori n g Pla n or c o ntracts. 
•  T he S p o ns or or desi g nee is res p o nsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g q u alit y 
c hec ki n g of t he d ata a n d mai ntai ni n g a vali date d data base. Data bas e l oc k will occ ur o nce q u alit y 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 7 /6 0  
 
 
c o ntr ol a n d q u alit y ass ur a 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 m e nts a n d pr oce d ures.  
•  St u d y M o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data i n t he C R F 
are acc urat e, c o m plete, a n d verifia ble; t hat t he sa fet y a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y a p 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 m e nts.  
•  T he I n vesti gat or will ret ai n r ec or ds a n d d oc u me nts, i ncl u di n g si g 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 f or 1 5 years after st u d y c o m pleti o n, u nless l ocal r e g ulati o ns, i nstit uti o nal 
p olicies, or t he S p o ns or re q uires a l o n ger ret e nti o n. N o rec or ds ma y be d estr o ye d d uri n g t he 
rete nti o n peri od wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or p art 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 nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. 
•  T he I n vesti gat or will  mai ntai n s o urce d oc u m e nts t hat s u p p ort t he data rec or d e d i n t he C R Fs. 
•  Data rec or de d o n C R Fs t hat are tra ns cri 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 n cies will  be e x plai ne d. T he I n v esti gat or ma y nee d t o re q uest 
pre vi o us me dical rec or ds or tr a nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me 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 by t he a p plica ble 
re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic he ver is l o n ger. T h e 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 pr o val. 
•  Defi niti o n of w h at c o nstit utes s o urce d ata a n d its ori gi n 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 p a nt si g ns t he Inf or me d C o nse nt F or m . 
St u d y a n d Site Cl os ure  
T he I n v esti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t her e is reas o na bl e ca use a n d 
e n o u g h n otice is gi v e n i n a d va nce of t he i nte n de d cl os ure. 
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n v esti gat or ma y i ncl u d e:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he I R B/I E C or 
l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes. 
•  I n a de q uat e recr uit me nt of partici pa nts b y t he I n v esti gat or. 
•  Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d . 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 /6 0  
 
 
•  S p o ns or disc o nti n uati o n of t he st u d y d ue t o a n u nacce pta ble ris k, a n y rele va nt t o xicit y, or 
ne gati ve c h a n ge i n t he ris k/ be nefit assess me nt.  
If t he st u d y is pre mat urel y t er mi nate d or s us p e n de d, t he S p o ns or will  pr o m ptl y i nf or m t h e 
I n v esti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y t hir d-p a rt 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 t he 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 i nf or m t he partici p a nts a n d ass ure a p pr o pri ate partici pa nt t hera p y 
a n d/ or f oll o w -u p.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 /6 0  
 
 
A p pe n di x 3  
C o ntr a ce 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 steril e, 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 ycl e ca n n ot be 
c o nfir me d bef ore t h e 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 no 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 v el i n t he p ost me n o pa usal ra n ge m a y b e use d t o c o nfir m a p ost me n o pa usal state 
i n a fe mal e 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 m e nt  is re q uir e 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 n al 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 m ati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.  
Per m a ne nt steriliz ati o n:  
F or t his st u d y, p er ma ne nt steriliz ati o n i ncl u des:  
•  D oc u me nte d h ysterect o m y  
•  D oc u me nte d bilateral sal pi n gect o m y  
•  D oc u me nte d bilateral o o p h orect o m y  
D oc u me ntati o n ca n c o m e fr o m t he site p ers 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 x a mi nati o n, or me dical hist or y i nter vie w.  
F or i n di vi d uals wit h per ma ne nt i nfertilit y d ue t o a n alter nat e me dical ca us e ot her t ha n t he a b o v e, 
(e. g., M ulleria n a ge nesis, a n dr o ge n i nse nsitivit y), I n v esti gat or discreti o n a p plies t o deter mi ne 
st u d y e ntr y. 
 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 /6 0  
 
 
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 . 
A z o o s p er mi c p art n er ( v a s e ct o mi z e d or d u e t o a m e di c al c a u s e)  
•  
A z o o s p er mi a i s 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 e p art n er i s t h e s ol e s e x u al p art n er of t h e 
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.  
•  
D o c u m e nt ati o n c a n c o m e fr o m t h e sit e p er s o n n el’ s r e vi e w of t h e i n di vi d u al’ s m e di c al r e c or d s,  m e di c al 
e x a mi n ati o n, or m e di c al hi st or y i nt er vi e w.  
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 nt i 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. 
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 Cli ni c al Tri al s F a cilit ati o n Gr o u p g ui d eli n e s, a c c e pt a bl e c o ntr a c e pti v e 
m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.  
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).  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 /6 0  
 
 
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 D efi niti o n  
•  
A n A E i s a n y u nt o w ar d m e di c al o c c urr e n c e i n a p ati e nt or cli ni c al st u d y p arti ci p a nt,  t e m p or all y a s s o ci at e d wit h 
t h e u s e of st u d y i nt er v e nti o n, w h et h er c o n si d er e d r el at e d t o t h e st u d y i nt er v e nti o n or n ot . 
•  
A n A E c a n t h er ef or e b e a n y u nf a v or a bl e a n d u ni nt e n d e d si g n (i n cl u di n g a n a b n or m al l a b or at or y fi n di n g), 
s y m pt o m, or di s e a s e ( n e w or e x a c e r b at e d) t e m p or all y a s s o ci at e d wit h t h e u s e of st u d y i nt er v e nti o n. F or 
s ur gi c al or di a g n o sti c pr o c e d ur e s, t h e c o n diti o n/ill n e s s l e a di n g t o s u c h a pr o c e d ur e i s c o n si d er e d a s t h e A E 
r at h er t h a n t h e pr o c e d ur e it s elf. 
E v e nt s M e eti n g  t h e A E D efi niti o n 
•  
A n y a b n o r m al l a b or at or y t e st r e s ult s (e. g., h e m at ol o g y , cli ni c al c h e mi str y, or uri n al y si s) or ot h er s af et y 
a s s e s s m e nt s ( e. g., E C G, r a di ol o gi c al s c a n s, vit al si g n s m e a s ur e m e nt s), i n cl u di n g t h o s e t h at w or s e n fr o m 
b a s eli n e  a n d ar e j u d g e d t o b e m or e s e v er e t h a n e x p e ct e d f or t h e p arti ci p a nt’ s c o n diti o n p er t h e I n v e sti g at or’ s 
m e di c al a n d s ci e ntifi c j u d g m e nt, ar e c o n si d er e d cli ni c all y si g nifi c a nt i n t h e m e di c al a n d s ci e ntifi c j u d g m e nt of 
t h e In v e sti g at or ( e. g.,  n ot r el at e d t o pr o gr e s si o n of u n d erl yi n g di s e a s e , b ut m a y b e l e a di n g t o st u d y 
i nt er v e nti o n di s c o nti n u ati o n). 
•  
E x a c er b ati o n of a c hr o ni c or i nt er mitt e nt pr e -e xi sti n g c o n diti o n i n cl u di n g eit h er a n i n cr e a s e i n fr e q u e n c y a n d/ or 
i nt e n sit y of t h e c o n diti o n. 
•  
N e w c o n diti o n s d et e ct e d or di a g n o s e d aft er st u d y i nt er v e nti o n a d mi ni str ati o n e v e n t h o u g h it m a y h a v e b e e n 
pr e s e nt b ef or e t h e st art of t h e st u d y.  
•  
Si g n s, s y m pt o m s, or t h e cli ni c al s e q u el a e of a s u s p e ct e d dr u g -dr u g i nt er a cti o n.  
•  
Si g n s, s y m pt o m s, or t h e cli ni c al s e q u el a e of a s u s p e ct e d o v er d o s e of eit h er st u d y i nt er v e nti o n or  a 
c o n c o mit a nt m e di c ati o n.  
•  
“ L a c k of effi c a c y” or “f ail ur e of e x p e ct e d p h ar m a c ol o gi c al a cti o n” p er s e will n ot b e r e p ort e d a s a n A E or S A E. 
H o w e v er, t h e si g n s, s y m pt o m s, a n d/ or cli ni c al s e q u el a e r e s ulti n g fr o m l a c k of effi c a c y will b e r e p ort e d a s a n 
A E or S A E if t h e y f ulfil t h e d efi niti o n of a n A E or S A E.  
E v e nt s N O T  M e eti n g t h e A E D efi niti o n  
•  
U nl e s s j u d g e d b y t h e In v e sti g at or t o b e m or e s e v er e t h a n e x p e ct e d f or t h e p arti ci p a nt’ s c o n diti o n, a n y 
cli ni c all y si g nifi c a nt a b n or m al l a b or at or y fi n di n g s, ot h er a b n or m al s af et y a s s e s s m e nt s t h at ar e a s s o ci at e d wit h 
t h e u n d erl yi n g di s e a s e, t h e di s e a s e/ di s or d er b ei n g st u di e d wit hi n t h e e x p e ct e d n e s s f or p arti ci p a nt’ s c o n diti o n, 
a s j u d g e d b y t h e I n v e sti g a tor.  
•  
M e di c al or s ur gi c al pr o c e d ur e ( e. g., e n d o s c o p y, a p p e n d e ct o m y ): t h e c o n diti o n t h at l e a d s t o t h e pr o c e d ur e i s 
t h e A E. 
•  
Sit u ati o n s i n w hi c h a n u nt o w ar d m e di c al o c c urr e n c e di d n ot o c c ur ( s o ci al a n d/ or c o n v e ni e n c e a d mi s si o n t o a 
h o s pit al).  
•  
A nti ci p at e d d a y -t o-d a y fl u ct u ati o n s of pr e -e xi sti n g di s e a s e( s) or c o n diti o n( s) pr e s e nt or d et e ct e d at t h e st art of 
t h e st u d y t h at d o n ot w or s e n. 
S A E Defi niti o n  
If a n e ve nt is n ot a n A E p er t he defi niti o n a b o ve, t h e n it ca n n ot be a n S A E e v e n if seri o us c o n diti o ns 
are met (e. g., h os pitaliz ati 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 diseas e).  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 2 /6 0  
 
 
A n  S A E i s d efi n e d a s a n y u nt o w ar d m e di c al o c c urr e n c e t h at, at a n y d o s e:  
R e s ult s i n d e at h . 
a)  
I s lif e-t hr e at e ni n g 
T h e t er m 'lif e -t hr e at e ni n g' i n t h e d efi niti o n of ' s eri o u s' r ef er s t o a n e v e nt i n w hi c h t h e p arti ci p a nt w a s at ri s k of d e at h 
at t h e ti m e of t h e e v e nt. It d o e s n ot r ef er t o a n e v e nt w hi c h h y p ot h eti c all y mi g ht h a v e c a u s e d d e at h, if it w er e m or e 
s e v er e.  
b)  R e q uir e s i n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n  
•  
I n g e n er al, h o s pit ali z ati o n si g nifi e s t h at t h e p arti ci p a nt h a s b e e n d et ai n e d ( u s u all y i n v ol vi n g at l e a st a n 
o v er ni g ht st a y) at t h e h o s pit al or e m er g e n c y w ar d f or o b s er v ati o n a n d/ or tr e at m e nt t h at w o ul d n ot h a v e b e e n 
a p pr o pri at e i n t h e p h y si ci a n’ s offi c e or o ut p ati e nt s etti n g. C o m pli c ati o n s t h at o c c ur d uri n g h o s pit ali z ati o n ar e 
A E s. If a c o m pli c ati o n pr ol o n g s h o s pit ali z ati o n or f ulfill s a n y ot h er s eri o u s crit eri a, t h e e v e nt i s s eri o u s. W h e n 
i n d o u bt a s t o w h et h er “ h o s pit ali z ati o n” o c c urr e d or w a s n e c e s s ar y, t h e A E will  b e c o n si d er e d s e ri o u s. 
•  
H o s pit ali z ati o n f or el e cti v e tr e at m e nt of a pr e -e xi sti n g c o n diti o n t h at di d n ot w or s e n fr o m b a s eli n e i s n ot 
c o n si d er e d a n A E.  
•  
H o w e v er, all e v e nt s l e a di n g t o u n pl a n n e d h o s pit ali z ati o n s or u n pl a n n e d pr ol o n g ati o n of a n el e cti v e 
h o s pit ali z ati o n m u st b e d o c u m e nt e d a n d r e p ort e d a s S A E s.  
c)  
R e s ult s i n p er si st e nt di s a bilit y/i n c a p a cit y  
T h e t er m di s a bilit y m e a n s a s u b st a nti al di sr u pti o n of a p er s o n’ s a bilit y t o c o n d u ct n or m al lif e f u n cti o n s.  
T hi s d efi niti o n i s n ot  i nt e n d e d t o i n cl u d e e x p eri e n c e s of r el ati v el y min or m e di c al si g nifi c a n c e s u c h a s 
u n c o m pli c at e d h e a d a c h e, n a u s e a, v o miti n g, di arr h e a, i nfl u e n z a, a n d a c ci d e nt al tr a u m a ( e. g., s pr ai n e d a n kl e) 
w hi c h m a y i nt erf er e wit h or pr e v e nt e v er y d a y lif e f u n cti o n s b ut d o n ot c o n stit ut e a s u b st a nti al di sr u pti o n.  
d)  I s a c o n g e nit al a n o m al y/ birt h d ef e ct . 
e)  
Ot h er sit u ati o n s  
•  
M e di c al or s ci e ntifi c j u d g m e nt will  b e e x er ci s e d i n d e ci di n g w h et h er S A E r e p orti n g i s a p pr o pri at e i n ot h er 
sit u ati o n s , s u c h a s i m p ort a nt m e di c al e v e nt s t h at m a y n ot b e i m m e di at el y lif e -t hr e at e ni n g or r e s ult i n d e at h or 
h o s pit ali z ati o n b ut m a y j e o p ar di z e t h e p arti ci p a nt or m a y r e q uir e m e di c al or s ur gi c al i nt er v e nti o n t o pr e v e nt 
o n e of t h e ot h er o ut c o m e s li st e d i n t h e a b o v e d efi niti o n. T h e s e e v e nt s ar e  u s u all y c o n si d er e d a s s eri o u s.  
•  
E x a m pl e s of s u c h e v e nt s i n cl u d e i n v a si v e or m ali g n a nt c a n c er s, i nt e n si v e tr e at m e nt i n a n e m er g e n c y r o o m or 
at h o m e f or all er gi c br o n c h o s p a s m, bl o o d d y s cr a si a s or c o n v ul si o n s t h at d o n ot r e s ult i n h o s pit ali z ati o n, or 
d e v el o p m e nt of dr u g d e p e n d e n c y or dr u g a b u s e.  
A n y s us p ecte d tra ns missi o n of a n i nf ecti o us a ge nt via a st u d y i nter ve nti o n is als o c o nsi dere d a n 
S A E f or re p orti n g p ur p os es, as s pecifi e d bel o w f or re p orti n g S A Es  a n d A E SIs.  
I n t his cli nical st u d y, a n y late s p o nta ne o us a b orti o n, fetal deat h i n uter o, ect o pic pre g na nc y, c hr o nic 
fetal distress, still birt h, n e o natal d eat h or pre mat urit y-relate d c o m plicati o n m ore t ha n is t y pi cal f or 
pre mat urit y will  be c o nsi dere d as a n S A E.  
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 R e c or di n g  
•  
W h e n a n A E/ S A E o c c ur s, it i s t h e r e s p o n si bilit y of t h e In v e sti g at or t o r e vi e w all d o c u m e nt ati o n ( e. g., h o s pit al 
pr o gr e s s n ot e s, l a b or at or y r e p ort s, a n d di a g n o sti c s r e p ort s) r el at e d t o t h e e v e nt.  
•  
T h e In v e sti g at or will t h e n r e c or d all r el e v a nt A E/ S A E i nf or m a ti o n i n t h e C R F. 
•  
A s n e e d e d, S p o n s or /d e si g n e e  m a y a s k f or c o pi e s of c ert ai n m e di c al r e c or d s ( e. g., a ut o p s y r e p ort s, 
s u p pl e m e nt al l a b r e p ort s, d o c u m e nt s o n m e di c al hi st or y/ c o n c o mit a nt m e di c ati o n s, di s c h ar g e l ett er s), a s 
s u p p orti n g s o ur c e d o c u m e nt ati o n. All p arti ci p a nt i d e ntifi er s, e x c e pt t h e p arti ci p a nt n u m b er, will b e r e d a ct e d o n 
t h es e  c o pi e s b ef or e s u b mi s si o n t o S p o n s or/ d e si g n e e.  
•  
T h e In v e sti g at or will att e m pt t o e st a bli s h a di a g n o si s of t h e e v e nt b a s e d o n si g n s, s y m pt o m s, a n d/ or ot h er 
cli ni c al i nf or m ati o n. W h e n e v er p o s si bl e, t h e di a g n o si s ( n ot t h e i n di vi d u al si g n s/ s y m pt o m s) will b e d o c u m e nt e d 
a s t h e A E/ S A E.  
•  
S p e cifi c g ui d a n c e i s i n t h e C R F C o m pl eti o n a n d M o nit ori n g C o n v e nti o n s.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 /6 0  
 
 
 
A s s e s s m e nt of I nt e n sit y  
T h e In v e sti g at or will a s s e s s t h e i nt e n sit y of e a c h A E a n d S A E r e p ort e d d uri n g t h e st u d y a n d a s si g n it t o 1 of t h e 
f oll o wi n g c at e g ori e s: 
•  
Mil d: A t y p e of a d v er s e e v e nt t h at i s u s u all y tr a n si e nt a n d m a y r e q uir e o nl y mi ni m al tr e at m e nt or t h er a p e uti c 
i nt er v e nti o n. T h e e v e nt d o e s n ot g e n er all y i nt erf er e wit h u s u al a cti viti e s of d ail y li vi n g.  
•  
M o d er at e: A t y p e of a d v er s e e v e nt t h at i s u s u all y all e vi at e d wit h a d diti o n al s p e cifi c t h er a p e uti c i nt er v e nti o n. 
T h e e v e nt i nt erf er e s wit h u s u al a cti viti e s of d ail y li vi n g, c a u si n g di s c o mf ort b ut p o s e s n o si g nifi c a nt or 
p er m a n e nt  ri s k of h ar m t o t h e r e s e ar c h p arti ci p a nt. 
•  
S e v er e: A t y p e of a d v er s e e v e nt t h at i nt err u pt s u s u al a cti viti e s of d ail y li vi n g, or si g nifi c a ntl y aff e ct s cli ni c al 
st at u s, or m a y r e q uir e i nt e n si v e t h er a p e uti c i nt er v e nti o n.  
D o n ot c o nf u s e a n A E t h at i s a s s e s s e d a s s e v er e wit h a n  S A E. S e v er e i s a c at e g or y u s e d t o r at e t h e i nt e n sit y of 
a n e v e nt; b ot h A E s a n d S A E s c a n b e a s s e s s e d a s s e v er e. A n e v e nt i s d efi n e d a s “ s eri o u s” w h e n it m e et s at l e a st 
1 of t h e pr e d efi n e d crit eri a  s p e cifi e d i n t h e d efi niti o n of a n S A E, N O T w h e n it i s r at e d a s s e v er e.  
 
A s s e s s m e nt of C a u s alit y  
•  
T h e I n v e sti g at or will a s s e s s t h e r el ati o n s hi p b et w e e n st u d y i nt er v e nti o n a n d e a c h A E/ S A E o c c urr e n c e:  
o  
U nr el at e d: N ot r e a s o n a bl y r el at e d t o t h e st u d y i nt er v e nti o n. A E c o ul d n ot m e di c all y 
( p h ar m a c ol o gi c all y/ cli ni c all y) b e attri b ut e d t o t h e st u d y i nt er v e nti o n. A r e a s o n a bl e alt er n ati v e 
e x pl a n ati o n will b e a v ail a bl e.  
o  
R el at e d: R e a s o n a bl y r el at e d t o t h e st u d y i nt er v e nti o n. A E c o ul d m e di c all y 
( p h ar m a c ol o gi c all y/ cli ni c all y) b e attri b ut e d t o t h e stu d y i nt er v e nti o n.  
•  
A “r e a s o n a bl e p o s si bilit y” of a r el ati o n s hi p c o n v e y s t h at t h er e ar e f a ct s, e vi d e n c e, a n d/ or ar g u m e nt s t o 
s u g g e st a c a u s al r el ati o n s hi p, r at h er t h a n a r el ati o n s hi p c a n n ot b e r ul e d o ut.  
•  
T h e I n v e sti g at or will u s e cli ni c al j u d g m e nt t o d et er mi n e t h e r el ati o n s hi p.  
•  
Alt er n ati v e c a u s e s, s u c h a s u n d erl yi n g di s e a s e( s), c o n c o mit a nt t h er a p y, a n d ot h er ri s k f a ct or s, a s w ell a s 
t h e t e m p or al r el ati o n s hi p of t h e e v e nt t o st u d y i nt er v e nti o n a d mi ni str ati o n will b e c o n si d er e d a n d 
i n v e sti g at e d. 
•  
T h e I n v e sti g at o r will al s o c o n s ult t h e I B a n d/ or Pr o d u ct I nf or m ati o n, f or m ar k et e d pr o d u ct s, i n hi s/ h er 
a s s e s s m e nt.  
•  
F or e a c h A E/ S A E, t h e I n v e sti g at or will  d o c u m e nt i n t h e m e di c al n ot e s t h at h e/ s h e h a s r e vi e w e d t h e 
A E/ S A E a n d a s s e s s e d c a u s alit y.  
•  
T h er e m a y b e sit u ati o n s w h e n a n S A E h a s o c c urr e d , a n d t h e I n v e sti g at or h a s mi ni m al i nf or m ati o n t o 
i n cl u d e i n t h e i niti al r e p ort t o t h e S p o n s or or it s d e si g n e e. T o m e et t h e r e p orti n g ti m eli n e, t h e c a u s alit y 
a s s e s s m e nt i s n ot r e q uir e d f or t h e i niti al r e p ort.  
•  
T h e In v e sti g at or m a y c h a n g e hi s/ h er c a u s alit y a s s e s s m e nt aft er c o n si d eri n g f oll o w -u p i nf or m ati o n a n d 
s e n d a n  S A E f oll o w -u p r e p ort wit h t h e u p d at e d c a u s alit y a s s e s s m e nt.  
•  
T h e c a u s alit y a s s e s s m e nt i s o n e of t h e crit eri a u s e d w h e n d et er mi ni n g r e g ul at or y r e p orti n g r e q uir e m e nt s.  
F oll o w -u p of A E s a n d S A E s  
•  
T h e In v e sti g at or will p erf or m or arr a n g e f or t h e c o n d u ct of s u p pl e m e nt al m e a s ur e m e nt s a n d/ or e v al u ati o n s, a s 
m e di c all y i n di c at e d or a s r e q u e st e d b y t h e S p o n s or/ d e si g n e e t o el u ci d at e t h e n at ur e a n d/ or c a u s alit y of t h e 
A E or S A E, a s f ull y a s p o s si bl e. T hi s m a y i n cl u d e a d diti o n al l a b or at or y t e st s or i n v e sti g ati o n s, 
hi st o p at h ol o gi c al e x a mi n ati o n s, or c o n s ult ati o n wit h ot h er h e alt h c ar e pr of e s si o n al s.  
•  
If a p arti ci p a nt di e s d u ri n g p arti ci p ati o n i n t h e st u d y or d uri n g a r e c o g ni z e d f oll o w-u p p eri o d, t h e In v e sti g at or 
will pr o vi d e t h e S p o n s or/ d e si g n e e wit h a c o p y of a n y p o st -m ort e m fi n di n g s i n cl u di n g hi st o p at h ol o g y.  
•  
N e w or u p d at e d i nf or m ati o n will b e r e c or d e d i n t h e ori gi n all y c o m p l et e d C R F. 
•  
T h e In v e sti g at or will s u b mit a n y u p d at e d S A E d at a t o t h e S p o n s or/ d e si g n e e  wit hi n 2 4 h o ur s of r e c ei pt of t h e 
i nf or m ati o n. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 4 /6 0  
 
 
Re p orti n g of S A Es  
S A E R e p orti n g b y  a n El e ctr o ni c D at a C oll e cti o n T o ol  
•  
T h e pri m ar y m e c h a ni s m f or r e p orti n g a n S A E i n m ulti c e nt er st u di e s t o t h e S p o n s or or it s d e si g n e e will b e t h e 
el e ctr o ni c d at a c oll e cti o n t o ol.  
•  
If t h e el e ctr o ni c s y st e m i s u n a v ail a bl e, t h e n t h e sit e will u s e t h e p a p er S A E f or m, s p e cifi e d b el o w, t o r e p ort t h e 
e v e nt wit hi n 2 4 h o ur s.  
•  
T h e sit e will e nt er  i nt o t h e el e ctr o ni c s y st e m t h e S A E d at a wit hi n 2 4 h o ur s aft er b e c o mi n g a w ar e of t h e e v e nt. 
It i s e x p e ct e d t h at t h e In v e sti g at or/ S u bi n v e sti g at or si g n s off t hi s d at a i n t h e s y st e m a n d a n y r el e v a nt 
a s s o ci at e d d at a ( e. g., a d diti o n al l a b or at or y t e st s, m e di c al r e c or d s, di a g n o sti c r e p ort s, hi st o p at h ol o gi c al 
e x a mi n ati o n s, or c o n s ult ati o n wit h ot h er h e alt h c ar e pr of e s si o n al s) will b e e nt er e d a s s o o n a s it b e c o m e s 
a v ail a bl e . 
•  
Aft er t h e st u d y i s c o m pl et e d at a sit e, t h e el e ctr o ni c d at a c oll e cti o n t o ol will b e t a k e n of f-li n e t o pr e v e nt t h e 
e ntr y of n e w d at a or c h a n g e s t o e xi sti n g d at a.  
•  
If a sit e r e c ei v e s a r e p ort of a n e w S A E fr o m a st u d y p arti ci p a nt or r e c ei v e s u p d at e d d at a o n a pr e vi o u sl y 
r e p ort e d S A E aft er t h e el e ctr o ni c d at a c oll e cti o n t o ol h a s b e e n t a k e n off-li n e, t h e n t h e sit e c a n r e p ort t hi s 
i nf or m ati o n o n a p a p er S A E f or m or t o t h e S p o n s or’ s s af et y d e p art m e nt. 
•  
B y e x c e pti o n, a n S A E ( or f oll o w -u p i nf or m ati o n) m a y b e r e p ort e d b y t el e p h o n e. T h e sit e will c o m pl et e t h e 
el e ctr o ni c S A E d at a e ntr y i m m e di at el y t h er e aft er.  
S A E R e p orti n g b y a P a p er F or m  
•  
S A E r e p orti n g o n a p a p er r e p ort f or m m a y b e u s e d i n si n gl e c e nt er st u di e s i n a d diti o n t o t h e st a n d ar d 
el e ctr o ni c C R F a n d a s a b a c k -u p m et h o d f or a n E D C s y st e m f ail ur e. T h e f or m i n cl u d e s  c o m pl eti o n 
i n str u cti o n s f or t h e I n v e sti g at or, na m e s, a d dr e s s e s, a n d t el e p h o n e a n d f a x n u m b er s . All i nf or m ati o n fr o m t h e 
p a p er f or m will  b e tr a n s cri b e d i nt o t h e el e ctr o ni c f or m a s s o o n a s t h e s y st e m b e c o m e s a v ail a bl e.  
•  
F a c si mil e tr a n s mi s si o n (f a x t o m ail) of t h e p a p er f or m or a n y f oll o w -u p  i nf or m ati o n i s t h e pr ef err e d m et h o d f or 
tr a n s mi s si o n a n d will b e d o n e wit hi n 2 4 h o ur s t o t h e S p o n s or or it s d e si g n e e.  
•  
I n r ar e cir c u m st a n c e s a n d i n t h e a b s e n c e of f a c si mil e e q ui p m e nt, n otifi c ati o n b y t el e p h o n e i s a c c e pt a bl e wit h 
a c o p y of t h e f or m s e nt b y o v er ni g ht m ail or c o uri er s er vi c e.  
•  
I niti al n otifi c ati o n vi a t el e p h o n e d o e s n ot r e pl a c e t h e n e e d f or t h e In v e sti g at or t o c o m pl et e a n d si g n t h e f or m  
wit hi n 2 4 h o ur s aft er b e c o mi n g a w ar e of t h e e v e nt.  
•  
A d diti o n al d o c u m e nt s ( e. g.,  l a b or at or y r e p ort s, a ut o p s y r ep ort, h o s pit al di s c h ar g e l ett er) a n d r el e v a nt p a g e s 
fr o m t h e C R F m a y b e r e q uir e d i n a d diti o n (e. g.,  m e di c al hi st or y, c o n c o mit a nt m e di c ati o n). T h e d at a pr o vi d e d 
will  b e c o n si st e nt wit h t h e i nf or m ati o n i n t h e C R F.  
Re p orti n g of A E SIs  
•  
F or a n o n s eri o u s A E SI, t h e sit e will c o m pl et e t h e s p e cifi c A E SI r e p ort f or m a n d n otif y t h e S p o n s or i m m e di at el y 
( wit hi n 2 4 h o ur s), u si n g t h e s a m e pr o c e s s f or r e p orti n g S A E s, a s s p e cifi e d a b o v e.  
•  
F or a s eri o u s A E SI, t h e sit e will c o m pl et e a n S A E r e p ort f or m, u si n g t h e S A E r e p orti n g pr o c e s s, s p e cifi e d 
a b o v e.  
Re p orti n g of Pre g n a ncies  
•  
Pr e g n a n c y will  b e r e p ort e d w h et h er r el at e d t o t h e st u d y i nt er v e nti o n u si n g t h e a p pli c a bl e p a p er f or m.  
•  
T h e a p pli c a bl e f or m will b e  u s e d t o r e p ort if a n a b n or m al o ut c o m e of t h e pr e g n a n c y o c c ur s a n d t h e c hil d/f et u s 
s u st ai n s a n e v e nt.  
•  
F a c si mil e tr a n s mi s si o n (f a x t o m ail) of t h e p a p er f or m or a n y f oll o w -u p i nf or m ati o n i s t h e pr ef err e d m et h o d f or 
tr a n s mi s si o n a n d will b e d o n e wit hi n 2 4 h o ur s t o t h e S p o n s or or it s d e si g n e e. 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 5 /6 0  
 
 
A p pe n di x 5  
Li v er S afet y: S u g geste d Acti o ns a n d F oll o w -u p Assess me nts    
T he I n vesti gat or will c o nsi der disc o nti n uati o n of st u d y i nter ve nti o n f or a b n or mal li ver f u ncti o n 
w he n a partici pa nt me ets o ne of t he c o n diti o ns o utli ne d  i n t he al g orit h m or if t he I n vesti gat or 
belie ves t hat it is i n best i nterest of t he partici pa nt.  
All c o nfir me d e v e nts of A L T or A S T ≥ 5  ×  U L N tri g gers st o p pi n g criteria.  
All c o nfir me d e ve nts of A L T or A S T ≥ 3  ×  U L N a n d t otal bilir u bi n >  2  ×  U L N tri g gers st o p pi n g 
criteria.  
All A Es i n v ol vi n g t he li ver or t he gall bla d der will be re p orte d as A E SI acc or di n g t o t he ris k pr ofile 
of e v o br uti ni b.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /6 0  
 
 
A p pe n di x 6  
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: 
All st u d y -re q uire d la b orat or y ass ess me nts will be perf or me d b y a ce ntral la b orat or y.  
L a b or at or y A s s e s s m e nt  
P ar a m et er  
N ot e s  
Bi o c h e mi str y  
Al b u mi n  
 
Al a ni n e A mi n otr a n sf er a s e  
 
Al k ali n e P h o s p h at a s e  
 
A m yl a s e  
 
A s p art at e A mi n otr a n sf er a s e  
 
Bi c ar b o n at e  
 
Bilir u bi n  
 
C -r e a cti v e pr ot ei n 
 
C al ci u m  
 
C hl ori d e  
 
Cr e ati ni n e  
 
C y st ati n C  
 
Gl o m er ul ar Filtr ati o n R at e, E sti m at e d ( b y 
C K D -E pi)  
 
G a m m a Gl ut a m yl Tr a n sf er a s e  
 
Gl u c o s e  
 
L a ct at e d e h y dr o g e n a s e  
 
M a g n e si u m  
 
Li p a s e  
 
P ot a s si u m  
 
S o di u m  
 
Pr ot ei n  
 
Ur at e  
 
C o a g ul ati o n  
Pr ot hr o m bi n I ntl . N or m ali z e d R ati o  
 
H e m at ol o g y  
H e m at o crit  
 
 
H e m o gl o bi n  
 
L e u k o c yt e s wit h Diff er e nti al:  
N e utr o p hil s ( a b s ol ut e/ %)  
L y m p h o c yt e s ( a b s ol ut e/ %)  
M o n o c yt e s ( a b s ol ut e/ %)  
E o si n o p hil s ( a b s ol ut e/ %)  
B a s o p hil s ( a b s ol ut e/ %)  
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /6 0  
 
 
L a b or at or y A s s e s s m e nt  
P ar a m et er  
N ot e s  
Er y. M e a n c or p u s c ul ar h e m o gl o bi n 
( M C H) 
 
Er y. M e a n c or p u s c ul ar v ol u m e ( M C V)  
 
Pl at el et s  
 
Er yt hr o c yt e s  
 
H or m o n al  
F olli cl e s ti m ul ati n g h or m o n e  
F or 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  
T h yr oi d sti m ul ati n g h or m o n 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, 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 s 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).  
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 e rf or m e d. 
Pr e g n a n c y  
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 , uri n e pr e g n a n c y t e st 
C o n d u ct e d at 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  
Al c o h ol a n d Dr u g S cr e e n  
Uri n e dr u g s cr e e n t o i n cl u d e:  
3, 4 -m et h yl e n e di o x y m et h a m p h et a mi n e 
( e c st a s y), a m p h et a mi n e, 
m et h a m p h et a mi n e, b ar bit ur at e, c o c ai n e, 
o pi at e, c a n n a bi n oi d s , b e n z o di a z e pi n e, 
m et h a d o n e, p h e n c y cli di n e, o x y c o d o n e, 
tri c y cli c a nti d e pr e s s a nt s, c oti ni n e 
Et h a n ol br e at h t e st  
S cr e e ni n g a n d D a y -1 o nl y  
S er ol o g y  
HI V a nti b o d y, H e p atiti s B Vir u s S urf a c e 
A nti g e n, H e p atiti s C Vir u s a nti b o d y, 
S A R S -C o V -2 A nti g e n, S A R S -C o V -2 
R N A , a n d Q u a nti F E R O N ® t e st  
S cr e e ni n g o nl y  ( e x c e pt S A R S-C o V -2 
t e st s, al s o D a y -1 ) 
 
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b ( M 2 9 5 1)  
Rel ati ve Bi o a v ail a bilit y of E v o br uti ni b T a blet B atc hes  
M S 2 0 0 5 2 7 _ 0 1 3 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /6 0  
 
 
A p pe n di x 7  
Pr ot oc ol A me n d me nt Hist or y   
T he i nf or mati o n f or t he c urre nt a me n d m e nt is o n t he title pa ge.  
Gl o bal Versi o n I D: 
Gl o bal Versi o n I D: C CI

E v o br uti ni b  ( M 2 9 5 1)
M S 2 0 0 5 2 7  0 1 3 1
R el ati v e  Bi o a v ail a bilit y  of  E v o br uti ni b  T a bl et  B at c h e s
A p p e n di x  8
St u d y  Titl e:
S p o n s or Si g n at ar e P a g e
A P h a s e  I,  O p e n- L a b el  St u d y  of  t h e  R el ati v e
Bi o a v ail a bilit y of E v o br uti ni b Ta bl et M a n uf a ct uri n g
B at c h e s i n H e alt h y P arti ci p a nt s
R e g ul at or y A g e n c y I d e ntif yi n g
N u m b e r s :
E u dr a C T  n u m b er:  2 0 2 2- 0 0 2 7 5 5- 1 9
Cli ni c al  St u d y  Pr ot o c ol  V er si o n:
0 8 S e pt e m b er 2 0 2 2 A ^ er si o n 1. 0
I a p pr ov e t h e d esi g n of t h e cli nic al st u dy:
Si g n at ur e D at e of Si g n at ar e
N a m e, A c a d e mi c D e gr e e:
F u n c ti o n / Ti tl e :
M e di c al  R e s p o n si bl e
M er c k H e alt h c ar e K G a A, D ar m st a dt, G er m a n y a n af ﬁli at e of
M er c k K G a A, D ar m st a dt, G er m a n y
Fr a n kf urt er Str. 2 5 0, 6 4 2 9 3 D ar m st a dt, G er m a n y
Of ﬁc e:  +
I n s ti t u ti o n :
A d d r e s s :
G e n e r al
N u m b e r :
M e r c k
P h o n e
M o bil e:  +
G e n e r a l
N u
m b e r :
M e r c k
F a x  N ot  a p pli c a bl e
C
O
N
F I
D
E
N
T I
A
L
I
N
F
O
R
M
A
T I
O
N
Gl o b al  V er si o n  I D:
5 9/ 6 0
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
C CI
C CI

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