Combined Phase 2b/3, Double-Blind, Randomized, Placebo-Controlled Studies Evaluating the Efficacy and Safety of Filgotinib in the Induction and Maintenance of Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Phase: PHASE3
Conditions: Ulcerative Colitis
Sponsor: Gilead Sciences

(r J GI L E A U 
G al a p a g o s 
S t u dy Titl e: 
S p o n sor: 
I N D Nu m b e r: 
E u d r a C T N u m b e r: 
C li ni c al T ri al s. g ov 
I de ntifier: 
I n di c ati o n: 
P r ot o c ol I D: 
G il e a d S t u dy Di r ect o r 
a n d M e di c al M o nit o r 
P r ot o c ol V e rs i o n/ D at e: 
C LI NI C A L S T U D Y P R O T O C O L 
C o m b i ne d P h ase 2 b /3, D o u bl e - Bli nd, R a n d o mi z e d , 
Pl a c e b o -C o n tr olle d St u dies E v al u ati n g th e Effi c a c y a n d S af et y of 
Fi l g otini b i n t h e I nd u cti o n a n d M a i nte n a n c e of R e mis si on i n S u bj e cts 
wit h M o d er at el y t o S e v er e l y A c ti v e Ul c er ati v e C olitis 
Gi l e a d S ci e n c es , I nc. 
3 3 3 L a k e si d e Dr i v e 
F ost er Ci t y, C A 9 4 4 0 4, U S A 
1 2 9 6 4 7 
2 0 1 6 -0 0 1 3 9 2 -7 8 
N C T 0 2 9 1 4 5 2 2 
Ul c er ati v e C olitis 
G S -U S -4 1 8 -3 8 9 8 
N a m e: 
T e le ph o n e: 
M o bi le: 
E m ail : 
F a x: 
Or i gi nal: 
A m e n d m e nt 1: 
A m e n d m e nt 2: 
A m e n d m e nt 3: 
A m e n d m e nt 4: 
A m e n d m e nt 5: 
P D 
P D 
P D 
P D 
P D 
1 5 J ul y 2 0 1 6 
0 7 S e pt e m b e r 2 0 1 6 
2 7 O ct o b er 2 0 1 6 
1 5 Ju n e 2 0 1 7 
0 5 M a r c h 2 0 1 8 
0 2 A p ril 2 0 1 9 
C O N F I DE N TI A LI T Y  S T A T E M E N T 
T h e i nf o 1 mati o n c on t ai ne d i n t his d o c u m e nt , pa 1t i c ul arl y u n p u bli sh e d d at a , is t h e pr o p e rt y or 
u n d e r c on tr ol of Gil e a d S ci e n ces, I n c., a n d is pr o vi d e d t o y o u i n c on fi d en ce as a n i nv est ig at or , 
p ot e nti al i nv esti g at o r, or c ons u lta nt, f or re vi e w b y y o u, y o ur st aff, a n d a n a p pli c a bl e I nstit uti on al 
R e vi e w B o ar d or I n d e p e n d ent Et hi cs C o m mitt e e. T h e i nf o 1 mati o n is o nl y t o b e us e d b y y o u i n 
c on n e cti on wit h a uth ori z e d cli ni c al st u dies of t h e i nv esti g ati o n al di u g d e s cri b e d i n t h e pr ot o c ol. 
Y o u wi ll n ot dis cl o se a n y of t h e i nf on n a ti o n t o ot h ers wit h o ut wr itt en a u t h oriz ati on fr o m 
Gi le a d S c i e nces , I n c., e x c e pt t o t h e e xt ent n e c es sai y t o o bt a i n i nf on n e d c on s ent fr o m t hos e 
p ers o ns t o w h o m t h e di 11g m a y b e a di ni nister e d . 

Fil g o ti ni b 
Pr ot o c ol G S -U S- 4 1 8 -3 8 9 8 
Gil e a d S ci e n c es , I n c. 
Fi n al 
A m e n d m e nt 5 
T A B L E O F C O N T E N T S 
T A B L E O F C O N T E N T S .............................................................................................................................................. 2 
LI S T O F I N-T E X T T A B L E S ........................................................................................................................................ 5 
LI S T O F I N-T E X T FI G U R E S ...................................................................................................................................... 5 
P R O T O C O L S Y N O P SI S .............................................................................................................................................. 6 
G L O S S A R Y O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S ...................................................... .............. 2 2 
D E FI NI TI O N O F T E R M S .......................................................................................................................................... 2 6 
1. 
I N T R O D U C TI ON .............................................................................................................................................. 2 7 
1. 1. 
B a c k gr o u n d ............................................................................................................................................ 2 7 
1 . 2. 
Fil g oti ni b ( G S-6 0 3 4) .............................................................................................................................. 2 8 
1. 2. 1. 
G e n er al I nf o n n ati o n ............................................................................................................. 2 8 
1. 2. 2. 
Pr e cli ni c al P h a n n a c ol o g y a n d T o xi c ol o g y ........................................................................... 2 8 
1. 2. 3. 
Cli ni c al Tri al s of Fil g oti ni b .................................................................................................. 3 1 
1 . 3. 
R ati o n al e f or T his St u d y ........................................................................................................................ 3 2 
1. 3. 1. 
R ati o n al e f or E n d p oi nt a n d Tir ni n g ...................................................................................... 3 2 
1. 3. 2. 
R ati o n al e f or D o s e ................................................................................................................ 3 3 
1 . 4. 
Ri sk/ B e n efit As sessm e n t f or th e St u d y .................................................................................................. 3 3 
1 . 5. 
C o m pli a n c e ............................................................................................................................................ 3 5 
2. 
O BJ E C TI V E S ..................................................................................................................................................... 3 6 
2. 1. 
C o h o 1t A I n d u cti o n St u d y ...................................................................................................................... 3 6 
2. 2. 
C o h o 1t B I n d u cti o n St u d y ...................................................................................................................... 3 7 
2. 3. 
M ai nt e n a n c e St u d y ................................................................................................................................. 3 8 
3. 
S T U D Y D E SI G N ................................................................................................................................................ 4 0 
3 . 1. 
E n d p oi nt s ............................................................................................................................................... 4 0 
3 . 1. 1. 
C o h o 1t A I n d u cti o n St u d y .................................................................................................... 4 0 
3. 1. 2. 
C o h o 1t B I n d u cti o n St u d y ..................................................................................................... 4 1 
3. 1. 3. 
M ai nt e n a n c e St u d y ............................................................................................................... 4 1 
3. 2. 
St u d y D e s i g n .......................................................................................................................................... 4 3 
3. 3. 
St u d y Tr e at m e n ts ................................................................................................................................... 4 4 
3. 4. 
D ur a tio n of Tr e at m e nt ............................................................................................................................ 4 5 
3. 5. 
Crit eri a f or St u d y Dr n g I nt e n u pti o n or Di sc o nti n u ati o n ........ ................................................................ 4 6 
3 . 5 . 1. 
St u d y T h u g I nte m 1 pti o n C o nsi d er ati o ns ............................................................................... 4 6 
3. 5. 2. 
St u d y T h u g Dis c o nti n u ati o n C o nsi d er ati o ns ........................................................................ 4 6 
3. 6. 
Di se as e W ors e ni n g Crit eri a .................................................................................................................... 4 8 
3. 7. 
E n d of St u d y ........................................................................................................................................... 4 8 
3. 8. 
P o st St u d y C ar e ...................................................................................................................................... 4 9 
3. 9. 
Bi o m ar k er T esti n g .................................................................................................................................. 4 9 
3. 9. 1. 
Bi o m ar k er S a m l es t o A d dr ess t h e St u d o b· e ctive s ............................................ .............. 4 9 
4. 
S U BJ E C T P O P U L A TI O N .................................................................................................................................. 5 1 
4. 1. 
N u m b er of S u b je cts a n d S u bj e c t S el e c ti o n .. .......................... .................................................. .............. 5 1 
4. 2. 
I n d u cti o n St u d y (C o h o 1ts A a n d B) ........................................................................................................ 5 1 
4. 2. 1. 
I n cl usi o n Cri teri a .................................................................................................................. 5 1 
4. 2. 2. 
E x cl usi o n Crit eri a ................................................................................................................. 5 4 
4. 3. 
C o h o 1t A ( Bi ol o gic- nai:v e) I n d u cti o n St u d y ........................................................................................... 5 6 
C O N F I DE N TI A L 
P a g e 2 
0 2 A pril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3
0 2 A pril 2 0 1 9
4. 3. 1.
I ncl usi o n Criteria, C o h ort A O N L Y .....................................................................................5 6
4. 3. 2.
E xcl usi o n Criteria, C o h ort A O N L Y ....................................................................................5 6
4. 4.
C o h ort B ( Bi ol o gic -e x perie nce d) I n d ucti o n St u d y .................................................................................5 7
4. 4. 1.
I ncl usi o n Criteria, C o h ort B O N L Y .....................................................................................5 7
4. 4. 2.
E xcl usi o n Criteria C o h ort B O N L Y .....................................................................................5 8
4. 5.
Mai nte na nce St u d y .................................................................................................................................5 8
4. 5. 1.
I ncl usi o n Criteria..................................................................................................................5 8
4. 5. 2.
E xcl usi o n Criteria .................................................................................................................5 8
5.
I N V E S TI G A TI O N A L M E DICI N A L P R O D U C T S ........................................................................................... 5 9
5. 1.
Ra n d o mizati o n, Bli n di n g a n d Treat me nt C o des ....................................................................................5 9
5. 1. 1.
Pr oce d ures f or Brea ki n g Treat me nt C o des ...........................................................................5 9
5. 2.
Descri pti o n a n d Ha n dli n g of Fil g oti ni b a n d Place b o t o Matc h ( P T M) Fil g o ti ni b..................................5 9
5. 2. 1.
F or m ulati o n ..........................................................................................................................5 9
5. 2. 2.
Pac ka gi n g a n d La beli n g .......................................................................................................6 0
5. 2. 3.
S t ora ge a n d Ha n dli n g...........................................................................................................6 0
5. 3.
D osa ge a n d A d mi nistrati o n ....................................................................................................................6 0
5. 4.
Pri or a n d C o nc o mita nt Me dicati o ns .......................................................................................................6 1
5. 4. 1.
All o we d C o nc o mita nt Me dicati o ns ......................................................................................6 1
5. 4. 2.
Pr o hi bite d C o nc o mita nt Me dicati o ns ...................................................................................6 2
5. 4. 3.
C ortic oster oi d Ta peri n g ........................................................................................................6 3
5. 5.
Vac ci ne G ui deli nes ................................................................................................................................6 3
5. 6.
Acc o u nta bilit y f or St u d y Dr u g ...............................................................................................................6 3
5. 6. 1.
I n vesti gati o nal Me dici nal Pr o d uct Ret ur n or Dis p osal.........................................................6 4
6.
S T U D Y P R O C E D U R E S ....................................................................................................................................6 5
6. 1.
S u bject E nr oll me nt a n d Treat me nt Assi g n me nt .....................................................................................6 5
6. 2.
Pretreat me nt Assess me nts ......................................................................................................................6 6
6. 2. 1.
Scree ni n g Visit .....................................................................................................................6 6
6. 2. 2.
D a y 1 ....................................................................................................................................6 9
6. 3.
Ra n d o mizati o n .......................................................................................................................................7 0
6. 3. 1.
Ra n d o mizati o n a n d St u d y Dr u g A d mi nistrati o n ..................................................................7 0
6. 4.
St u d y Assess me nts .................................................................................................................................7 0
6. 4. 1.
Pri orit y of Assess me nts ........................................................................................................7 0
6. 4. 2.
Efficac y ................................................................................................................................7 0
6. 4. 3.
Safet y ....................................................................................................................................7 1
6. 4. 4.
P har m ac o ki netics Assess me nts ............................................................................................7 3
6. 4. 5.
Bi o mar ker Assess me nts .......................................................................................................7 3
6. 5.
P ost -Treat me nt Assess me nts ..................................................................................................................7 3
6. 6.
Earl y Ter mi nati o n Assess me nts .............................................................................................................7 4
6. 7.
E n d of St u d y ...........................................................................................................................................7 4
6. 8.
P ost St u d y Care ......................................................................................................................................7 4
7.
A D V E R S E E V E N T S A N D T O XI CI T Y M A N A G E M E N T ...............................................................................7 5
7. 1.
Defi niti o ns of A d verse E ve nts, A d verse Reacti o ns, a n d Seri o us A d verse E ve nts .................................7 5
7. 1. 1.
A d verse E ve nts .....................................................................................................................7 5
7. 1. 2.
Seri o us A d verse E ve nts ........................................................................................................7 5
7. 2.
Assess me nt of A d verse E ve nts a n d Seri o us A d verse E ve nts .................................................................7 6
7. 2. 1.
Assess me nt of Ca usalit y f or St u d y Dr u gs a n d Pr oce d ures ...................................................7 6
7. 2. 2.
Assess me nt of Se verit y ........................................................................................................7 6
7. 3.
I n vesti gat or Re q uire me nts a n d I nstr ucti o ns f or Re p orti n g A d verse E ve nts a n d Seri o us 
A d verse E ve nts t o Gilea d .......................................................................................................................7 7
7. 3. 1.
A d verse E ve nts .....................................................................................................................7 7
C CI

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4
0 2 A pril 2 0 1 9
7. 3. 2.
Seri o us A d verse E ve nts ........................................................................................................7 7
7. 4.
Gilea d Re p orti n g Re q uire me nts .............................................................................................................7 9
7. 5.
Cli nical La b orat or y A b n or malities a n d Ot her A b n or mal Assess me nt s as A d verse E ve nts or 
Seri o us A d verse E ve nts ..........................................................................................................................7 9
7. 6.
T o xicit y Ma na ge me nt ............................................................................................................................7 9
7. 6. 1.
Gra des 1 a n d 2 La b orat or y A b n or malit y or Cli nical E ve nt ..................................................8 0
7. 6. 2.
Gra de 3 La b orat or y A b n or malit y or Cli nical E ve nt .............................................................8 0
7. 6. 3.
Gra de 4 La b orat or y A b n or malit y or Cli nical E ve nt .............................................................8 0
7. 7.
S pecial Sit uati o ns Re p o rts......................................................................................................................8 1
7. 7. 1.
Defi niti o ns of S pecial Sit uati o ns ..........................................................................................8 1
7. 7. 2.
I nstr ucti o ns f or Re p orti n g S pecial Sit uati o ns.......................................................................8 1
8.
S T A TI S TI C A L C O N SI D E R A T I O N S................................................................................................................8 3
8. 1.
A na l ysis O bjecti ves a n d E n d p oi nts........................................................................................................8 3
8. 1. 1.
A nal ysis O bjecti ves ..............................................................................................................8 3
8. 1. 2.
Pri mar y E n d p oi nt .................................................................................................................8 6
8. 1. 3.
Sec o n dar y E n d p oi nt .............................................................................................................8 6
8. 1. 4.
E x pl orat or y E n d p oi nts: .........................................................................................................8 7
8. 2.
A na l ysis C o n ve nti o ns.............................................................................................................................8 9
8. 2. 1.
A nal ysis Sets ........................................................................................................................8 9
8. 3.
Data Ha n dli n g C o n ve nti o ns ...................................................................................................................9 0
8. 4.
D e m o gra p hic Data a n d Baseli ne C haracteristics ...................................................................................9 1
8. 5.
Efficac y A nal ysis ...................................................................................................................................9 1
8. 5. 1.
Pri mar y A nal ysis ..................................................................................................................9 1
8. 5. 2.
Sec o n dar y A nal yses .............................................................................................................9 1
8. 5. 3.
M ulti plicit y A dj ust me nts ......................................................................................................9 1
8. 5. 4.
E x pl orat or y A nal yses ...........................................................................................................9 6
8. 6.
Safet y A nal ysis .......................................................................................................................................9 7
8. 6. 1.
E xte nt of E x p os ure ...............................................................................................................9 7
8. 6. 2.
A d ver se E ve nts.....................................................................................................................9 7
8. 6. 3.
La b orat or y E val uati o ns ........................................................................................................9 8
8. 6. 4.
Ot her Safet y E val uati o ns ......................................................................................................9 8
8. 7.
P har m ac o ki netic A nal ysis ......................................................................................................................9 9
8. 8.
Bi o mar ker A nal ysis ................................................................................................................................9 9
8. 9.
Sa m ple Si ze ............................................................................................................................................9 9
8. 9. 1.
I n d ucti o n St u dies ( C o h orts A a n d B) ...................................................................................9 9
8. 9. 2.
Mai nte na nce St u d y .............................................................................................................1 0 0
8. 1 0.
Data M o nit ori n g C o m mittee ................................................................................................................1 0 0
8. 1 1.
E n d of I n d ucti o n I nteri m A nal ysis .......................................................................................................1 0 1
9.
R E S P O N SI BI LI TI E S ........................................................................................................................................1 0 2
9. 1.
I n vesti gat or Res p o nsi bilities ................................................................................................................1 0 2
9. 1. 1.
G o o d Cli nical Practice ........................................................................................................1 0 2
9. 1. 2.
I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee Re vie w a n d 
A p pr o val .............................................................................................................................1 0 2
9. 1. 3.
I nf or me d C o nse nt ...............................................................................................................1 0 2
9. 1. 4.
C o nfi de ntialit y ....................................................................................................................1 0 3
9. 1. 5.
St u d y Files a n d Rete nti o n of Rec or ds ................................................................................1 0 3
9. 1. 6.
Case Re p ort F or ms .............................................................................................................1 0 4
9. 1. 7.
I n vesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y a n d Ret ur n...........................................1 0 5
9. 1. 8.
I ns pecti o ns..........................................................................................................................1 0 5
9. 1. 9.
Pr ot oc ol C o m p lia nce..........................................................................................................1 0 5
9. 2.
S p o ns or Res p o nsi bilities ......................................................................................................................1 0 6
9. 2. 1.
Pr ot oc ol M o dificati o ns .......................................................................................................1 0 6

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5
0 2 A pril 2 0 1 9
9. 2. 2.
St u d y Re p ort a n d P u blicati o ns ...........................................................................................1 0 6
9. 3.
J oi nt I n vesti gat or/ S p o ns or Res p o nsi bilities .........................................................................................1 0 6
9. 3. 1.
Pa y me nt Re p orti n g .............................................................................................................1 0 6
9. 3. 2.
Acces s t o I nf or mati o n f or M o nit ori n g ................................................................................1 0 7
9. 3. 3.
Access t o I nf or mati o n f or A u diti n g or I ns pecti o ns ............................................................1 0 7
9. 3. 4.
St u d y Disc o nti n uati o n ........................................................................................................1 0 7
1 0.
R E F E R E N C E S .................................................................................................................................................1 0 8
1 1.
A P P E N DI C E S ..................................................................................................................................................1 0 9
A p pe n di x 1.
I n vesti gat or Si g nat ure Pa ge ..................................................................................................1 1 0
A p pe n di x 2.
St u d y Pr oce d ures Ta ble ........................................................................................................1 1 1
A p pe n di x 3.
Ma na ge me nt of Cli nical a n d La b orat or y A d verse E ve nts ....................................................1 1 6
A p pe n di x 4.
M a y o Sc ori n g S yste m f or Assess me nt of Ulcerati ve C olitis Acti vit y ..................................1 1 7
A p pe n di x 5.
C T C A E Gra di n g Scale f or Se verit y of A d verse E ve nts .......................................................1 1 8
A p pe n di x 6.
Pre g na nc y Preca uti o ns, Defi niti o n f or Fe male of C hil d beari n g P ote ntial, a n d 
C o ntrace pti ve Re q uire me nts .................................................................................................1 1 9
A p pe n di x 7.
Cli nical La b orat or y Assess me nt Ta ble .................................................................................1 2 2
LI S T O F I N -T E X T T A B L E S
Ta ble 3- 1.
Re -r a n d o mizati o n f or Mai nte na nce St u d y..............................................................................4 5
Ta ble 5- 1.
Pr o hi bite d C o nc o mita nt Me dicati o ns .....................................................................................6 2
Ta ble 7- 1.
Gra di n g of A d verse E ve nt Se verit y ........................................................................................7 7
LI S T O F I N -T E X T FI G U R E S
Fi g ure 3- 1.
St u d y Sc he ma .........................................................................................................................4 3
Fi g ure 8- 1.
I n d ucti o n St u dies ( C o h orts A a n d B): Testi n g Strate g y f or t he Pri mar y a n d Ke y 
Sec o n dar y H y p ot heses ............................................................................................................9 4
Fi g ure 8- 2.
Mai nte na nce St u d y: Testi n g Strate g y f or t he Pri mar y a n d Ke y Sec o n dar y 
H y p ot heses .............................................................................................................................9 6

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6
0 2 A pril 2 0 1 9
P R O T O C O L S Y N O P SI S
Gile a d Scie nces, I nc.
3 3 3 L a kesi de Dri ve
F oster Cit y, C A 9 4 4 0 4
St u d y Title:
C o m bi ne d P hase 2 b/ 3, D o u ble -Bli n d, Ra n d o mize d, Place b o -C o ntr olle d 
St u dies E val uati n g t he Efficac y  a n d Safety of Fil g oti ni b i n t he I n d ucti o n 
a n d Mai nte na nce of Re missi o n i n S u bjects wit h M o deratel y t o Se verel y 
Acti ve Ulcerati ve C olitis
I N D N u m ber:
E u dr a C T N u m ber:
Cli nic al Tri als. g o v 
I de ntifier:
1 2 9 6 4 7
2 0 1 6- 0 0 1 3 9 2- 7 8
N C T 0 2 9 1 4 5 2 2
St u d y Ce nters 
Pl a n ne d:
A p pr o xi matel y  5 0 0 sites gl o bally
O bjecti ves:
T he o verall o bjecti ve of t he st u d y  is t o e val uate t he effect of treat me nt 
wit h fil g oti ni b o n t he i n d ucti o n a n d mai nte na nce of re missi o n i n s u bjects 
wit h m o deratel y t o se verel y acti ve u lcerati ve colitis ( U C). S u bjects w h o 
are bi ol o gic-naï ve a n d bi ol o gic -e x perie nce d will be e nr olle d i n C o h orts A 
a n d B res pecti vel y. Treat me nt assi g n me nts will be ra n d o mize d wit hi n 
eac h C o h ort.
C o h ort A: Bi ol o gic -N aï ve S u bjects, I n d ucti o n St u d y
T he pri mar y  o bjecti ve of C o h ort A I nd ucti o n St u d y  is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g e n d osc o p y/ blee di n g/st o ol ( E B S) re missi o n at Wee k 1 0
T he ke y  sec o n dar y o bjecti ves of C o h ort A I n d ucti o n St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g Ma yo Cli nic Sc ore ( M C S) re missi o n at Wee k 1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g a n e n d osc o pic s u bsc ore of 0 at Wee k 1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g Ge b oes hist ol o gic re missi o n at Wee k 1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g M C S re missi o n (alter nati ve defi niti o n) at Wee k 1 0

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7
0 2 A pril 2 0 1 9
T he ot her sec o n dar y  o bjecti ves of C o h ort A are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b 

T o assess t he p har mac o ki netic ( P K) c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of C o h ort A I n d ucti o n St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
i m pr o vi n g e n d osc o pic a p peara nce as deter mi ne d b y  Ulcerati ve C olitis 
E n d osc o pic I n de x of Se verit y  ( U C EI S) sc ori n g syste m at Wee k 1 0

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d 
i nfla m mat or y bi o mar kers (e g, i ncl u di n g b ut n ot li mite d t o 
C- reacti ve pr otei n [ C R P], fecal cal pr otecti n, fecal lact oferri n, a n d 
fecal matri x metall o pe pti dase-9 [ M M P - 9]) wit h cli nical o utc o mes

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers 
wit h disease se verit y , disease pr o gressio n, a n d treat me nt res p o nse t o 
fil g oti ni b

T o e val uate healt h -relate d q ualit y of life ( H R Q o L)

T o e val uate t he effect of fil g oti ni b o n healt h care res o urce utilizati o n 
( H C R U)

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
ac hie vi n g n o vel hist ol o gic o utc o mes (e g, res ol uti o n of basal 
plas mac y t osis)
C o h ort B: Bi ol o gic -E x perie nce d S u bjects, I n d ucti o n St u d y
T he pri mar y  o bjecti ve of C o h ort B I n d ucti o n St u d y is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g E B S re missi o n at Wee k 1 0
T he ke y  sec o n dar y o bjecti ves of C o h ort B I n d ucti o n St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g M C S re missi o n at Wee k 1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g a n e n d osc o pic s u bsc ore of 0 at Wee k 1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g Ge b oes hist ol o gic re missi o n at Wee k 1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g M C S re missi o n (alter nati ve defi niti o n) at Wee k 1 0

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8
0 2 A pril 2 0 1 9
T he ot her sec o n dar y  o bjecti ves of C o h ort B I n d ucti o n St u d y are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of C o h ort B I n d ucti o n St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
i m pr o vi n g e n d osc o pic a p peara nce as deter mi ne d b y U C EI S sc ori n g 
s yste m at Wee k 1 0

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d 
i nfla m mat or y bi o mar kers (e g, i ncl u di n g b ut n ot li mite d t o C R P, 
fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P- 9) wit h cli nical 
o utc o mes

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers 
wit h disease se verit y , disease pr o gressi o n, a n d treat me nt res p o nse t o 
fil g oti ni b

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
ac hie vi n g n o vel hist ol o gic o utc o mes (e g, res ol uti o n of basal 
plas mac y t osis)
M ai nte n a nce St u d y:
T he pri mar y o bjecti ve of t he Mai nte na nce St u d y  is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g E B S re missi o n at Wee k 5 8
T he ke y  sec o n dar y o bjecti ves of t he Mai nte na nce St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g M C S re missi o n at Wee k 5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g s ustai ne d E B S re missi o n at Wee k 5 8, defi ne d as E B S 
re missi o n at b ot h Wee ks 1 0 a n d 5 8

T o e val uate t he efficac y  of fil g oti ni b as co m pare d t o place b o i n 
esta blis hi n g 6 -m o nt h c ortic oster oi d -free E B S re missi o n at Wee k 5 8 

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g a n e n d osc o pic s u bsc ore of 0 at Wee k 5 8

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9
0 2 A pril 2 0 1 9

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g Ge b oes hist ol o gic re missi o n at Wee k 5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g M C S re missi o n (alter nati ve defi niti o n) at Wee k 5 8
T he ot her sec o n dar y  o bjecti ves of t he Mai nte na nce St ud y  are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of t he Mai nte na nce St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
i m pr o vi n g e n d osc o pic a p peara nce as deter mi ne d b y U C EI S sc ori n g 
s yste m at Wee k 5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
esta blis hi n g s ustai ne d M C S re missi o n at Wee k 5 8, defi ne d as M C S 
re missi o n at b ot h Wee ks 1 0 a n d 5 8

T o e val uate t he efficac y  of fil g oti nib as c o m pare d t o place b o i n 
esta blis hi n g 6 -m o nt h c ortic oster oi d -free M C S re missi o n at Wee k 5 8 

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d 
i nfla m mat or y bi o mar kers (e g, i ncl u di n g b ut n ot li mite d t o C R P, 
fecal cal pr otecti n, fecal lact ofer ri n, a n d fecal M M P-9) wit h cli nical 
o utc o mes

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers 
wit h disease se verit y , disease pr o gressi o n, a n d treat me nt res p o nse t o 
fil g oti ni b

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n 
ac hie vi n g n o vel hist ol o gic o utc o mes (e g, res ol uti o n of basal 
plas mac y t osis)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0
0 2 A pril 2 0 1 9
St u d y Desi g n:
T hese are c o m bi ne d P hase 2 b/ 3, d o u ble -bli n d, ra n d o mize d, 
place b o -c o ntr olle d st u dies e val uati n g t he efficac y a n d safety of fil g oti ni b 
i n t he i n d ucti o n a n d mai nte na nce of re missi o n i n s u bjects wit h 
m o deratel y t o se verel y acti ve ulcerati ve c olitis.
T hese st u dies i ncl u de:

Scree ni n g ( Da y s -3 0 t o -1)

Ra n d o mizati o n ( Da y 1)

Bli n de d I n d ucti o n St u dies ( Da y 1 t o Wee k 1 1) 

C o h orts A a n d B Wee k 1 0 efficac y assess me nts:

At Wee k 1 0, M C S t o assess M C S res p o nse or E B S re missi o n

Bli n de d Bri d ge P hase ( Wee k 1 0 t o 1 1): D osi n g will c o nti n ue i n a 
bli n de d fas hi o n t hr o u g h t he e n d of Wee k 1 0 u ntil 
re-ra n d o mizati o n at Wee k 1 1

Re -ra n d o mizati o n ( Wee k 1 1)

S u bjects i n C o h orts A a n d B w h o c o m plete t he I n d ucti o n St u d y  
a n d ac hie ve eit her E B S re missi o n or M C S res p o nse at Wee k 1 0 
will be re -ra n d o mize d i nt o t he Mai nte na nce St u d y at Wee k 1 1

S u bjects w h o ac hie ve neit her E B S re missi o n n or M C S res p o nse at 
Wee k
1 0 will ha ve t he o pti o n t o e nter a se parate, L o n g -Ter m 
E xte nsi o n ( L T E) st u d y  ( G S-U S -4 1 8 -3 8 9 9)

Bli n de d Mai nte na nce St u d y  ( Wee ks 1 1 t o 5 8)

P ost -Treat me nt ( P T x) safet y assess me nts: 

S u bjects w h o o pt o ut o f t he L T E st u d y ( G S-U S -4 1 8 -3 8 9 9) will 
ret ur n 3 0 da ys after t he last d ose of st u d y dr u g f or P T x safet y 
assess me nts
  
 
 
 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1
0 2 A pril 2 0 1 9

S u bjects w h o c o m plete all pr oce d ures per pr ot oc ol, i ncl u di n g t he 
e n d osc o p y, of t he 5 8 -wee k st u d y  will be offere d t he o pti o n t o 
c o nti n ue i nt o t he LT E st u d y  ( G S-U S - 4 1 8- 3 8 9 9)

S u bjects w h o are eli gi ble a n d o pt t o partici pate i n t he L T E st u d y  
( G S-U S -4 1 8- 3 8 9 9) ca n c o nti n ue i nt o t he st u d y  wit h o ut P T x safet y 
assess me nts
Tre at me nt Re gi me n ( C o h orts A a n d B I n d ucti o n St u dies)
Base d o n pr ot oc ol eli gi bilit y  criteria, s u bjects will be scree ne d f or 
e nr oll me nt i n eit her C o h ort A or C o h ort B.
S u bjects w h o meet pr ot oc ol eli gi bilit y  criteria  will be assi g ne d t o t he 
res pecti ve C o h ort a n d s u bse q ue ntl y ra n d o mize d i n a bli n de d fas hi o n i n a 
2: 2: 1 rati o t o 1 of 3 treat me nts as f oll o ws:
Tre at me nt Gr o u p 1 ( n = 2 6 0): fil g oti ni b 2 0 0 m g  a n d place b o-t o-matc h 
( P T M) fil g oti ni b 1 0 0 m g, o nce dail y
Tre at me nt Gr o u p 2 ( n = 2 6 0): fil g oti ni b 1 0 0 m g  a n d P T M fil g oti ni b 
2 0 0 m g, o nce dail y
Tre at me nt Gr o u p 3 ( n = 1 3 0): P T M fil g oti ni b 2 0 0 m g a n d P T M 
fil g oti ni b 1 0 0 m g, o nce dail y
N ote: U nite d States ( U S) a n d K orea males w h o ha ve n ot faile d at least 
2 bi ol o gic t hera pies (a n y t u m or necr osis fact or-al p ha [ T N F α] a nta g o nist 
a n d ve d oliz u ma b) will be ra n d o mize d i n a 2: 1 rati o t o eit her fil g oti ni b 
1 0 0 m g or matc hi n g place b o.
Wit hi n eac h C o h ort, treat me nt assi g n me nts will be stratifie d acc or di n g t o 
t he f oll o wi n g fact ors i n t he I n d ucti o n a n d Mai nte na nce st u dies:
Str atific ati o n F act or s ( C o h ort A, Bi ol o gic-N aï ve I n d ucti o n St u d y)

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds 
(e g, pre d nis o ne) at Da y  1, ( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors (e g, 6- merca pt o p uri ne 
[ 6-M P], azat hi o pri ne, met h otre xate [ M T X]) at Da y 1,
( Yes or N o)
Str atific ati o n F act ors ( C o h ort B, Bi ol o gic -E x perie nce d I n d ucti o n 
St u d y)

E x p os ure t o o ne bi ol o gic a ge nt vers us m ore t ha n o ne bi ol o gic a ge nt

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds 
(e g, pre d nis o ne) at Da y  1, ( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors (e g, 6- M P, azat hi o pri ne, 
M T X) at Da y  1, ( Yes or N o)

Fil g o ti ni b 
Pr ot o c ol G S -U S- 4 1 8 -3 8 9 8 
Gi le a d S ci e n c es , I n c. 
S u b st u dies : 
N u m b e r of 
S u bj e c ts 
Pl a n n e d : 
C O N F I DE N TI A L 
St r atifi c ati o n F a ct o rs ( M ai nt e n a n c e St u d y) 
• 
P aiiici p atio n i n C o h o 1i A or C o h o 1i B 
Fi n al 
A m e n d m e nt 5 
• 
C o n c omit a n t us e of or al, s yst emi c ally a b s or be d c o1i i c ost er oi ds 
( e g, pr ed ni s on e ) at D a y 1, ( Y es or N o) 
• 
C o n c omit a nt us e of i m m u no m o d ul at ors (e g, 6- M P, a zat hi o pri n e , 
M T X ) at D a y 1, ( Y es or N o) 
R e- r a n d o mi z ati o n f o r M ai nt e n a n c e St u d y at W e e k 1 1 
•  
S ubj e c ts fro m C o h o 1is A a n d B w h o m e et pr o t o c ol-sp e c ifie d 
e ligi b ilit y c riteri a f or t he M a i nten a n ce S t u dy w ill b e r e-r an d o mi z e d t o 
tre at m e nt as f ollo w s: 
T r e at m e nt Assi g n m e nt 
I n d u cti o n S t u di es 
C o h o rts A a n d B 
Tr e at m e nt 1, filg oti ni b 2 0 0 m g 
Tr e at m e nt 2, filg oti ni b 1 0 0 m g 
Tr e at m e nt 3, Pl a c e b o 
M ai nt e n a n c e St u d y 
R e- r a n d o mi z ati o n: 
Tr e at m e nt  1, 2 0 0 m g 
Tr e at me nt 3, P l a ce b o 
Tr e at m e nt 2, 1 0 0 m g 
Tr e at me nt 3, P l a ce b o 
C o nti n u e Tr ea t me nt 3, Pl a c eb o 
N o te: S u bj e cts rec ei vi n g Tr e at m e nt 1 or 2 i n th e I n d u cti o n stu d y w ill b e r a n d o mi z e d i n a 
2: I m a n n er t o eith er c o nti n u e o n t h e as si g ne d fil g oti nib r e gi me n or t o pl a c e b o f or th e d ur ati o n of 
th e M ai n t en a n c e st u d y . 
P h a r m a c o ki n eti c ( P K) S u bst u d y 
A n o pti o n al P K su b st ud y w ill b e p e rf o1 m e d i n a s u b s et of s u bj e cts 
( ap pr o x i mat e l y 3 0 s u bje cts e a c h i n C o h o 1i  A a n d C o h o 1i B) w h o pr o v i de 
a s ep ar a t e i nf o1 me d c o ns e nt. I n t he P K su b st ud y , t he d a ily d os e of s t u dy 
dr n g s h oul d b e a d mi ni stere d u n d er s u p er visi o n i n th e cli ni c (at o n e visit 
b et w e e n W ee k 2 a n d W ee k 1 0 , i n cl usiv e), a n d a d diti o n al P K sa m pl e s 
s h oul d b e c o lle ct e d pr e d os e an d at 0. 5, 1, 2, 3, 4, a n d 6 h o m s p os t dos e. 
A p p r o xim at ely 6 5 0 s u bj e cts f or e a ch C o h o 1i, f or a t ot al of 1 3 0 0 s u bj e cts 
P a g e 1 2 
0 2 A p ril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 3
0 2 A pril 2 0 1 9
Tar get 
P o p ulati o n:
A d ult s u bjects wit h m o deratel y t o se verel y acti ve U C as defi ne d b y a n 
M C S criteria of a ce ntrall y  rea d e n d osc o pic s u bsc ore of ≥2, a rectal 
blee di n g s u bsc ore of ≥1, a st o ol fre q ue nc y  s u bsc ore ≥1 a n d a 
p h y sicia n’s gl o bal assess me nt s u bsc ore ( P G A) of ≥2, wit h a t otal M C S 
of 6 t o 1 2, i ncl usi ve.
D urati o n of 
Treat me nt:
5 8 wee ks
Dia g n osis a n d 
Mai n Eli gi bilit y  
Criteria:
F or a c o m plete list of st u d y  i ncl usi o n a n d e xcl usi o n criteria, please refer 
t o Secti o n 4 .
A s u bject ma y  e nter eit her C o h ort A or C o h ort B base d o n pri or e x p os ure 
t o bi ol o gic t hera py.
M ai n Eli gi bilit y Criteri a ( C o h orts A & B) :
All s u bjects m ust meet all of t he f oll o wi n g criteria t o be eli gi ble f or 
partici pati o n i n eit her t he C o h ort A or B I n d ucti o n St u d y .

Males or n o n -pre g na nt, n o n -lactati n g fe males, a ges 1 8 t o 7 5 ye ars, 
i ncl usi ve base d o n t he date of t he scree ni n g visit

D oc u me nte d dia g n osis of U C of at least 6 m o nt hs A N D wit h a 
mi ni m u m disease e xte nt of 1 5 c m fr o m t he a nal ver ge. 
D oc u me ntati o n s h o ul d i ncl u de e n d osc o pic a n d hist o pat h ol o gic 
e vi de nce of U C as f oll o ws:
a)
T he criteria f or d oc u me ntati o n of U C base d o n e n d osc o p y  will be 
me dical rec or d d oc u me ntati o n of, or a n ile oc ol o n osc o p y 
(f ull c ol o n osc o p y wit h t he i nt u bati o n of t he ter mi nal ile u m) 
re p ort date d ≥6 m o nt hs bef ore e nr oll me nt, w hic h s h o ws feat u res 
c o nsiste nt wit h U C, deter mi ne d b y  t he pr oce d ure perf or mi n g 
p h y sicia n
b)
T he criteria f or d oc u me ntati o n of U C base d o n hist o pat h ol o g y  
will be me dical rec or d d oc u me ntati o n of or a hist o pat h ol o g y  
re p ort i n dicati n g feat ures c o nsiste nt wit h U C as deter mi ne d b y t he 
pat h ol o gist

A s ur veilla nce c ol o n osc o p y  is re q uire d pri or t o scree ni n g i n s u bjects 
wit h a hist or y  of U C f or 8 or m ore years, if o ne was n ot perf or me d i n 
t he pri or 2 4 m o nt hs

M o deratel y t o se verel y acti ve U C as deter mi ne d b y a ce ntrall y rea d 
e n d osc o p y sc ore ≥2, a rectal blee di n g sc ore ≥1, a st o ol fre q ue nc y  
sc ore ≥1, a n d P G A of ≥2 as deter mi ne d b y t he Ma y o cli nic sc ori n g 
s yste m (refere nce A p pe n di x 4 ) wit h e n d osc o p y occ urri n g d uri n g 
scree ni n g; t otal sc ore m ust be bet wee n 6 a n d 1 2, i ncl usi ve

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 4
0 2 A pril 2 0 1 9

Ma y  be recei vi n g t he f oll o wi n g dr u gs (s u bjects o n t hese t hera pies
m ust be willi n g t o re mai n o n st a ble d oses f or t he n ote d ti mes ):
a)
Oral 5 -a mi n osalic ylate ( 5-A S A) c o m p o u n ds pr o vi de d t he d ose 
prescri be d has bee n sta ble f or at least 4 wee ks pri or t o 
ra n d o mizati o n; d ose m ust re mai n sta ble f or t he first 1 0 wee ks
after ra n d o mizati o n
b)
Azat hi o pri ne, 6- M P , or M T X
pr o vi de d t he d ose prescri be d has 
bee n sta ble f or 4 wee ks pri or t o ra n d o mizati o n; d ose m ust re mai n 
sta ble f or t he first 1 0 wee ks after ra n d o mizati o n
c)
Oral c ortic oster oi d t hera p y  ( pre d nis o ne prescri be d at a sta ble d ose 
≤3 0 m g / da y or b u des o ni de prescri be d at a sta ble d ose of 
≤9 m g / da y) pr o vi de d t he d ose prescri be d has bee n sta ble f or 
2 wee ks pri or t o ra n d o mizati o n ; d ose m ust re mai n sta ble f or t he 
first 1 4 wee ks after ra n d o mizati o n

M ust n ot ha ve Cr o h n’s disease, i n deter mi nate c olitis, isc he mic c o litis, 
f ul mi na nt c olitis, is olate d ulce rati ve pr octitis, or t o xic me ga-c ol o n 

M ust n ot ha ve a cti ve t u berc ul osis (T B ) or hist or y  of late nt T B t hat 
has n ot bee n treate d (see i ncl usi o n criteri o n 8 f or f urt her i nf or mati o n)

M ust n ot use a n y
c o nc o mita nt pr o hi bite d me dicati o ns as descri be d i n 
S ecti o n 5. 4. 2
C o h ort A ( Bi ol o gic- N aï ve ) I n d ucti o n St u d y
M ai n Eli gi bilit y Criteri a, C o h ort A O N L Y
S u bjects m us t meet all of t he a d diti o n al f oll o wi n g criteria t o be eli gi ble 
f or partici pati o n i n C o h ort A i n d ucti o n st u d y.

Pre vi o usl y  de m o nstrate d a n i na de q uate cli nical res p o nse, l oss of 
res p o nse t o, or i nt olera nce t o at least 1 of t he f oll o wi n g a ge nts
( de pe n di n g o n c urre nt c o u ntr y treat me nt 
rec o m me n dati o ns/ g ui deli nes):
a) C ortic oster oi ds
i)
Acti ve disease des pite a hist or y  of at least a n i n d ucti o n 
re gi me n of a d ose e q ui vale nt t o oral pre d nis o ne 3 0 m g
dail y  f or 2 wee ks or i ntra ve n o usl y (I V) f or 1 wee k, O R
ii)
T w o faile d atte m pts t o ta per ster oi ds bel o w a d ose 
e q ui vale nt of 1 0 m g dail y  pre d nis o ne, O R
iii)
Hist or y  of ster oi d i nt olera nce i ncl u di n g, b ut n ot li mite d t o, 
C us hi n g’s s y n dr o me, oste o pe nia/ oste o p or osis, 
h y per gl y ce mia, i ns o m nia, seri o us i nfecti o ns, de pressi o n, 
aller gic reacti o ns, m o o d dist ur ba nces, or a n y  ot her 
c o n diti o n t hat c o ntri b ute d t o disc o nti n uati o n of t he a ge nt

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 5
0 2 A pril 2 0 1 9
b) I m m u n o m o d ulat ors
i)
Acti ve disease des pite a hist or y  of at least a 1 2 wee k re gi me n 
of oral azat hi o pri ne ( ≥2 m g / k g/ da y) or 6-M P ( ≥1 m g / k g/ da y),
or M T X ( 2 5 m g s u bc uta ne o usl y [S C ] or i ntra m usc ularl y [I M]
per wee k f or i n d ucti o n a n d ≥1 5 m g I M per wee k f or 
mai nte na nce) O R
ii) Hist or y  of i nt olera nce t o at least o ne i m m u n o m o d ulat or 
i ncl u di n g, b ut n ot li mite d t o, seri o us i nfecti o ns, he pat ot o xicit y, 
c yt o pe nia, pa ncreatitis, t hi o p uri ne met h yltra nsferase (T P M T )
ge netic m utati o n, aller gic reacti o ns, or a n y ot her c o n diti o n t hat 
c o ntri b ute d t o disc o nti n uati o n of t he a ge nt

N o p ri or or c urre nt use of a n y T N F α a nta g o nist i ncl u di n g ( b ut n ot 
li mite d t o) i nfli xi ma b, a dali m u ma b, g oli m u ma b, cert oliz u ma b, or 
bi osi milar a ge nts at a n y ti me

N o p ri or or c urre nt use of ve d oliz u ma b at a n y  ti me
C o h ort B ( Bi ol o gic -E x perie nce d ) I n d ucti o n St u d y
M ai n Eli gi bilit y Criteri a, C o h ort B O N L Y

Pre vi o usl y  de m o nstrate d a n i na de q uate cli nical res p o nse, l oss of 
res p o nse t o, or i nt olera nce of at least o ne of t he f oll o wi n g a ge nts
( de pe n di n g o n c urre nt c o u ntr y treat me nt 
rec o m me n dati o ns/ g ui deli nes):
a)
T N F α A nta g o nists
i)
Acti ve disease des pite a hist or y  of at least 1 i n d ucti o n re gi me n 
of a T N F α A nta g o nist:
○
I nfli xi ma b: Mi ni m u m i n d ucti o n re gi me n of 5 m g / k g at 0, 
2, a n d 6 wee ks (i n t he E ur o pea n U ni o n [ E U ], d urati o n of 
treat me nt of 1 4 wee ks)
○
A dali m u ma b: A n 8 - wee k i n d ucti o n re gi me n c o nsisti n g of 
1 6 0 m g (f o ur 4 0 -m g  i njecti o ns i n o ne da y  or t w o 4 0-m g 
i njecti o ns per da y f or t w o c o nsec uti ve da ys) o n Da y 1, 
f oll o we d by a sec o n d d ose 2 wee ks later ( Da y 1 5) of 
8 0 m g a n d a 4 0 m g d ose 2 wee ks later ( Da y 2 9), f oll o we d 
b y  a 4 0 m g  d ose e ver y ot her wee k u ntil Wee k 8 ( Da y 5 7). 
○
G oli m u ma b: A mi ni m u m i n d ucti o n d urati o n of 6 wee ks 
( 1 2 wee ks i n E U) is re q uire d f or g oli m u ma b, w hic h 
i ncl u des 2 0 0 m g S C i njecti o n at Wee k 0, f oll o we d b y  
1 0 0 m g at Wee k 2, a n d t he n 1 0 0 m g e ver y  4 wee ks O R

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 6
0 2 A pril 2 0 1 9
ii) Rec urre nce of s y m pt o ms d uri n g mai nte na nce t hera p y  wit h t he 
a b o ve a ge nts, O R
iii) Hist or y  of i nt olera nce t o a n y T N F α a nta g o nists i ncl u di n g, b ut 
n ot li mite d t o, seri o us i nfecti o ns, he pat ot o xicit y , heart fail ure, 
aller gic reacti o ns, or a n y ot her c o n diti o n t hat c o ntri b ute d t o 
disc o nti n uati o n of t he a ge nt
b)
Ve d oliz u ma b
i)
Acti ve disease des pite a hist or y  of at least a 1 4- wee k 
( 1 0 wee ks i n E U) i n d ucti o n re gi me n of ve d oliz u ma b 
c o nsisti n g of  3 0 0 m g  IV at Wee ks 0, 2, a n d 6 O R
ii) Hist or y  of i nt olera nce t o ve d oliz u ma b i ncl u di n g, b ut n ot 
li mite d t o, seri o us i nfecti o ns, he pat ot o xicit y, c yt o pe nia, 
aller gic reacti o ns, or a n y ot her c o n diti o n t hat c o ntri b ute d t o 
disc o nti n uati o n of t he a ge nt

M ust n ot ha ve use d a n y T N F α a nta g o nist or ve d oliz u ma b ≤8 wee ks 
pri or t o s cree ni n g or a n y ot her bi ol o gic a ge nt ≤8 wee ks pri or t o 
scree ni n g or wit hi n 5 ti mes t he half-life of t he bi ol o gic a ge nt pri or t o 
scree ni n g, w hic he ver is l o n ger
M ai nte n a nce St u d y 
M ai n Eli gi bilit y Criteri a

C o m pleti o n of C o h ort A or C o h ort B I n d ucti o n St u d y  wit h M C S 
res p o nse or E B S re missi o n base d o n Wee k 1 0 assess me nts
St u d y  
Pr oce d ures/
Fre q ue nc y :
St u d y  visits f or all s u bjects will occ ur at scree ni n g, Da y 1 a n d Wee k 2 t o 
Wee k 1 1 (I n d ucti o n) a n d Wee k 1 4 t o Wee k 5 8 ( Mai nte na nce). 
Scree ni n g assess me nts will i ncl u de c o m plete me dical hist or y a n d 
p h y sical e xa mi nati o n ( P E), vital si g ns, la b orat or y assess me nt, M C S 
assess me nt wit h fle xi ble si g m oi d osc o p y/ c ol o n osc o p y wit h bi o psies, 
pre g na nc y  test (f or fe males of c hil d beari n g p ote ntial as defi ne d by 
A p pe n di x 6 ), s u bject electr o nic diar y (e Diar y), H R Q o L re vie w, sta n dar d 
1 2- lea d electr ocar di o gra m ( E C G), a d verse e ve nts ( A Es) a n d c o nc o mita nt 
m e dicati o n assess me nt.
Ma y o Cli nic Sc ore assess me nt wit h fle xi ble si g m oi d osc o p y /c ol o n osc o py 
a n d bi o psies m ust be perf or me d d uri n g scree ni n g , a n d at t he Wee ks 1 0 
a n d 5 8 visits. If n or mal mar gi ns are n ot a p pare nt fr o m si g m oi d osc o py or 
if pr o xi mal c ol o nic i n v ol ve me nt is s us pecte d, a f ull c ol o n osc o p y s h o ul d 
be perf or me d at all -ti me p oi nts w here e n d osc o pic e val uati o n is 
perf or me d. 
S parse plas ma P K sa m ples will be c ollecte d pri or t o d ose at Wee ks 1 0 
a n d 5 8, p ost d ose at Wee k 4 (at least 3 0 mi n utes a n d u p t o 3 h o u rs after 
d osi n g), a n d at a n y ti me at Wee k 2 6. 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 7
0 2 A pril 2 0 1 9
A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be assesse d at eac h 
visit.
N o n -res po n di n g s u bjects c o m pleti n g all Wee k
1 0 assess me nt s will be 
eli gi ble t o e nter t he L T E st u d y  ( G S-U S - 4 1 8-3 8 9 9). 
S u bjects w h o o pt o ut of t he L T E st u d y  ( G S-U S -4 1 8 -3 8 9 9) will ret ur n 
3 0 da y s after t he last d ose of st u d y dr u g f or P T x safety assess me nts.
S u bjects w h o are eli gi ble a n d o pt t o partici pate i n t he L T E st u d y  
( G S-U S - 4 1 8-3 8 9 9) ca n c o nti n ue i nt o t he st u d y  wit h o ut P T x safet y 
assess me nts.
S u bjects w h o c o m plete t he Wee k 5 8 visit will ha ve t he o pti o n t o c o nti n ue 
st u d y dr u g i n a bli n de d fas hi o n i n t he LT E st u d y  ( G S-U S -4 1 8- 3 8 9 9).
C o nc o mit a nt Ulcer ati ve C olitis Me dic ati o n M a n a ge me nt:
S u bjects o n per mitte d c o nc o mita nt me dicati o ns f or U C t hat are descri be d 
i n t he i ncl usi o n criteria (e g, 5 -A S A, a n d i m m u n o m o d ulat ors ) m ust 
re mai n o n sta ble d oses u ntil Wee k 1 0. Ster oi ds m ust re mai n sta ble t o 
Wee k
1 4.
Starti n g at Wee k 1 4, s u bjects w h o are o n c o nc o mita nt ster oi ds m ust 
be gi n ta peri n g ster oi d t he ra py. T he d ose s h o ul d be re d uce d at a rate 
starti n g at 2. 5 m g  per wee k u p t o 5 m g per wee k ( or e q ui vale nt ta per if 
n ot pre d nis o ne). S u bjects w h o are o n b u des o ni de s h o ul d ha ve t heir dail y 
d ose re d uce d b y 3 m g e ver y  3 wee ks u ntil t he y are c o m pletely off 
steroi ds.  F or s u bjects u n der g oi n g ta per, ster oi ds ma y  be i ncrease d or 
restarte d at d oses u p t o a n d i ncl u di n g t heir baseli ne d ose if ret ur n of 
s ym pt o ms is a p pare nt.  T hese s u bjects will n ot be c o nsi dere d treat me nt 
fail ures.  S u bjects w h o nee d t o restart or i ncrease ster oi d treat me nt at a 
d ose t hat e xcee ds t heir baseli ne d ose of ster oi ds ( d ose ma y  n ot e xcee d 
3 0 m g pre d nis o ne [ or e q ui vale nt ] or b u des o ni de 9 m g/ da y ) will be 
c o nsi dere d treat me nt fail ures f or all cli nical e n d p oi nts b ut will be 
per mitte d t o re mai n i n t he st u d y . 
F or a d diti o nal pr o hi bite d U C me dicati o ns, refere nce Ta ble 5 - 1.
Test Pr o d uct, D ose, 
a n d M o de of 
A d mi nistr ati o n:
Fil g oti ni b 2 0 0 m g oral ta blet, o nce dail y
Fil g oti ni b 1 0 0 m g oral ta blet, o nce dail y
Refere nce T her a p y, 
D ose, a n d M o de of 
A d mi nistr ati o n:
P T M fil g oti ni b 2 0 0 m g oral ta blet, o nce dail y
P T M fil g oti ni b 1 0 0 m g oral ta blet, o nce dail y

Fil g o ti ni b 
Pr ot o c o l G S -U S- 4 1 8 -3 8 9 8 
Gi le a d S ci e n c es , I nc. 
C rit e ri a f o r 
E v al u ati o n: 
Safet y: 
Ef ficac y: 
Fi na l 
A m e n d m e nt 5 
Ass ess m e nt of A E s a n d c o n c omit a nt m e di c atio ns w ill c o nt i n u e 
thr o u g h o ut t he d ur ati o n of t h e st u dy. S af e t y e v al u atio ns i n cl u de 
d o c u m ent ati o n of A Es , P E ( c om plet e or s y mp t om dri v e n ), vi t al si g ns, 
an d cli nic al la b or at o1y e val uat i o ns ( h e mat o lo g y, c h emi stry, uri n alys is) . 
A n E C G w ill b e p e rf o1 me d at s cree ni n g, W e e k 1 0 ( or at E a rly 
T e n ni n atio n ( E T) if s u bje ct t e1 mi n at es pri or t o W e e k 1 0) , W e e k 2 6 a n d 
W e e k 5 8 . 
A data . m oni t ori ng c om mi tte e ( DM C) w ill m e et t o e v al uat e all a v ailabl e 
s af et y d at a a c cu m ul at e d d uri n g t he s t ud y . T h e i niti al m e eti ng f or e a ch 
i nd u c tio n s t u dy ( C oh o 1is A a nd B, s ep ar a t ely) w ill o c c ur a fter 
ap pr o x i mat e l y 1 0 0 s u bj e cts ( 2 0 fro m pl a c eb o gr o u p a n d 4 0 fro m e a ch 
filg o ti nib tre at me nt gr o u p) re ac h W e e k 1 0 . T h e s e c on d m e et i ng f or e a ch 
i nd u ct i o n st u dy w ill i nclu d e a n i nteri m f utilit y an al ys is a n d o c c ur aft e r 
ap p r o xi mat e l y 17 5 s u bj e cts ( 3 5 fro m pl a c eb o gr o u p a nd 7 0 fro m e a ch 
filg o ti nib tre at ment gr o u p) re a ch W e e k  1 0. F o llo w i ng t he i nteri m f utilit y 
a n alys is me eti ng, su b s e qu e nt m e eti ngs w ill o c c ur a p pr o xim at e l y 
o n c e e v e1y  4 m o nt h s or at a freq u e n c y d et en ni n e d b y t h e DM C . 
Pri m ai y effic a c y w ill b e ass ess e d b y E B S r e mi ssi o n, de fi ne d as a n 
e n d os c o pi c s u b s c or e ( b as e d o n ce nt r al re a di ng) of O or 1 (r e fere n c i ng t h e 
M a y o S c o re), rect al bl e e di ng s u b s c or e of 0, a n d at le ast a 1 p o i nt 
d e cre as e i n st o ol fre qu e n c y fro m b ase li ne t o a chi e v e a s u bs c o re of O or 1. 
Ef fic a c y w ill als o b e ass ess e d us i ng t h e f ull M C S c o m p os e d of 
4 s u b- s c ores (st o ol freq u e n c y , re ct al bl ee di n g, e n d os c o pi c fi nd i ngs, a n d 
P G A) , r a ng i ng fro m Ot o 1 2. Ass ess m e nt s duri n g n o n- e n d os c o pi c visi ts 
m a y u s e t he p arti al M C S , whi c h i nclu d es all c o m p o n e nt s e x c ept fle xi b l e 
si g m oid os c o p y/ c o l o nos c o p y. G e b o es h ist olo g ic remi ssi o n will b e 
ass ess e d us i ng t he G e b o es hi st olo g i c s c ores c o m p os e d of 6 d iffer ent 
gr a d es f or e v al u atio n of di s e as e s e v erit y i n U C. 
P h aim ac oki netics: 
Pl as m a c o n c ent r ati o ns of filg ot i ni b a n d i ts m et a b o lit e G S- 8 2 9 8 4 5 
(f o1 m erly G 2 5 4 4 4 5) w ill b e d et e1 mi n ed. 
Bi o m ai·k ers: 
C O N FI D E N TI A L 
Bl o o d s am pl es w ill b e c o lle cte d ( pre d os e , if a ppli c a b le) at D a y 1, a n d 
W e e ks 4, 1 0, 2 6, a nd 5 8 f or ass essm e nt of m ai·k ers of i nfl ai n mati o n, 
i m m u ne sta.t us, p eri p her al bl o o d m o n o n u cl e ar ce ll (P B M C) , a n d t he 
J a nus Ki n as e-Si g n a l Tr a nsd u c er a nd A ct iv at o r of Tr a n s cri ptio n 
(J A K-S T A T) p at h w a y . Hi sto p ath ol o gi c a n d i m m u no h isto c h e mi stiy 
(I HC) ass ess m e nt s will b e p e rf o1 me d o n bi o psi es at s creeni n g a nd 
W e e ks 1 0 a nd 5 8 . Mi cr obi o m e s am  l es w ill b e c o lle cte d at s cre eni n a n d 
W e e ks 1 0 2 6 a nd 5 8 . 
P a g e 1 8 
0 2 A pril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 9
0 2 A pril 2 0 1 9
St atistic al 
Met h o ds:
I n d ucti o n St u dies ( C o h orts A a n d B)
T he pri mar y  a nalys is set f or efficac y a nalys es is t he F ull A nal ys is Set 
(F A S ), w hic h i ncl u des all ra n d o mize d s u bjects w h o recei ve d at least 
1 d ose of st u d y dr u g i n t he c orres p o n di n g i n d ucti o n st u d y  ( Da y 1 t o 
Wee k
1 0).
T he pri mar y  a nalys is will c o m pare eac h fil g oti ni b d ose gr o u p t o place b o 
o n t he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k 1 0. T he 
C oc hra n -Ma ntel -Hae nszel ( C M H) a p pr oac h a dj usti n g f or stratificati o n 
fact ors will be use d f or h y p ot hesis testi n g of t he pri mar y e n d p oi nt. 
T he gra p hical a p pr oac h { Bretz 2 0 0 9 } t o se q ue ntiall y rejecti ve m ulti ple 
test pr oce d ures will be use d t o c o ntr ol a fa mil y-wise t y pe I err or rate 
( F W E R) at 5 % (ie, α = 0. 0 5) f or h y p ot hesis testi n g o n pri mar y a n d ke y 
sec o n dar y e n d p oi nts: O nce all h yp ot heses wit hi n t he sa me fil g oti ni b 
d osi n g re gi me n are rejecte d, t he n t he res pecti ve al p ha ca n be passe d o n t o 
t he ot her re gi me n’s hy p ot heses. See Secti o n 8. 5. 3 f or details a n d t he 
si g nifica nce le vel t hat will be use d t o declare a statistical si g nifica nt 
treat me nt effect f or eac h fil g oti ni b d ose gr o u p w he n c o m pare d t o 
place b o. S u bje cts w h o d o n ot ha ve s ufficie nt meas ure me nts t o deter mi ne 
efficac y e n d p oi nts will be c o nsi dere d fail ures (ie, n o n-res p o n der 
i m p utati o n [ N RI]).
I nteri m F utilit y A n al ysis: I n d ucti o n St u dies ( C o h orts A a n d B)
After 1 7 5 s u bjects ( 3 5 fr o m place b o gr o u p a n d 7 0 fr o m eac h fil g oti ni b 
treat me nt gr o u p) c o m plete Wee k 1 0 assess me nts or disc o nti n ue fr o m t he 
st u d y, a n i nteri m f utilit y a nalys is will be c o n d ucte d t o e val uate 
e n d osc o pic efficac y a n d safety. T he pr o p orti o n of s u bjects w h o ac hie ve 
e n d osc o pic res p o nse (e n d osc o pic s u bsc ore of 0 or 1) f or eac h treat me nt 
gr o u p will be e val uate d. F or eac h fil g oti ni b d ose gr o u p c o m paris o n wit h 
place b o, t he D M C ma y  rec o m me n d t o ter mi nate t hat res pecti ve fil g oti ni b 
d ose gr o u p if t he o bser ve d pr o p orti o n of s u bjects w h o ac hie ve 
e n d osc o p ic res p o nse i n t hat fil g oti ni b d ose gr o u p is less t ha n t hat i n t he 
place b o gr o u p. If b ot h fil g oti ni b d ose gr o u p c o m paris o ns meet t he f utilit y 
criteria, t he D M C ma y rec o m me n d st o p pi n g t he st u d y.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 0
0 2 A pril 2 0 1 9
C o h ort s A a n d B E n d of I n d ucti o n A n al ysis
Efficac y  a n d safety data will be e val uate d b y t he D M C a n d a 
pre -s pecifie d s p o ns or’s e xec uti ve tea m after all s u bjects i n C o h orts A a n d 
B c o m plete Wee k 1 0 d osi n g ( or pre mat urel y disc o nti n ue st u d y  dr u g b ut 
c o m plete P T assess me nts). Data fr o m C o h orts A a n d B (e xa mi ne d 
i n de pe n de ntl y) will be use d t o e val uate t he st u d y o verall f or p ossi ble 
disc o nti n uati o n ( See Secti o n 8. 1 0 a n d Secti o n 8. 1 1 f or details).
M ai nte n a nce St u d y
T he pri mar y  a nalys is set f or efficac y a nalys es is t he F A S, w hic h i ncl u des 
all re-ra n d o mize d s u bjects w h o met t he pr ot oc ol defi niti o n of E B S 
re missi o n or M C S res p o nse at Wee k 1 0, a n d recei ve d at least 1 d ose of 
st u d y dr u g i n t he Mai nte na nce St u d y ( Wee ks 1 1 t o 5 8) .
T he pri mar y  a nalys is will c o m pare eac h fil g oti ni b d ose gr o u p t o place b o 
o n t he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k 5 8. T he 
C M H a p pr oac h a dj usti n g f or stratificati o n fact ors will be use d f or 
h y p ot hesis testi n g of t he pri mar y  e n d p oi nt. See Secti o n 8. 5. 3 f or detai ls 
a n d t he si g nifica nce le vel t hat will be use d t o declare a statistical 
si g nifica nt treat me nt effect f or eac h fil g oti ni b d ose gr o u p w he n c o m pare d 
t o place b o. S u bjects w h o d o n ot ha ve s ufficie nt meas ure me nts t o 
deter mi ne efficac y  e n d p oi nts will be c o nsi dere d fail ures (ie, N RI).
P h ar m ac o ki netics :

Plas ma c o nce ntrati o ns of fil g oti ni b a n d its meta b olite G S -8 2 9 8 4 5 will 
be liste d a n d s u m marize d usi n g descri pti ve statistics.
Sa m ple Size:
I n d ucti o n St u dies ( C o h orts A a n d B)
T he sa m ple size was c h ose n t o e ns ure t hat a cli nicall y  mea ni n gf ul 
differe nce i n E B S re missi o n rate at Wee k 1 0 c o ul d be detecte d w he n 
c o m pari n g fil g oti ni b t o place b o wit hi n eac h I n d ucti o n St u d y . 
A sa m ple size of 1 3 0 s u bjects i n t he place b o gr o u p a n d 2 6 0 s ubjects i n 
eac h fil g oti ni b d ose ( 2 0 0 m g or 1 0 0 m g) gr o u p ( n = 6 5 0 per c o h ort) will 
pr o vi de 9 0 % p o wer f or eac h fil g oti ni b d ose gr o u p c o m paris o n t o place b o 
at a 2-si de d 0. 0 2 5 si g nifica nce le vel t o detect a treat me nt differe nce i n 
E B S re missi o n rate of 1 5 % ( 2 5% o n fil g oti ni b a n d 1 0 % o n place b o).

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 1
0 2 A pril 2 0 1 9
M ai nte n a nce St u d y
Ass u mi n g a n i n d ucti o n res p o nse rate (ie, pr o p orti o n of s u bjects ac hie vi n g 
eit her E B S re missi o n or M C S res p o nse at Wee k 1 0) of 5 5 % a m o n g 
s u bjects recei vi n g fil g oti ni b 2 0 0 m g or 1 0 0 m g  treat me nt, a p pr o xi matel y 
2 8 5 s u bjects fr o m eac h fil g oti ni b d ose gr o u p fr o m C o h orts A a n d B 
I n d ucti o n St u dies c o m bi ne d w o ul d be eli gi ble t o be re-ra n d o mize d i nt o 
t he Mai nte na nce St u d y.
T he sa m ple size was c h ose n t o e ns ure t hat a cli nicall y  mea ni n gf ul 
differe nce i n E B S re missi o n rate at Wee k 5 8 c o ul d be detecte d w he n 
c o m pari n g eac h fil g oti ni b d ose gr o u p ( 2 0 0 m g or 1 0 0 m g) t o place b o i n 
t he Mai nte na nce St u d y.
A sa m ple size of 9 5 s u bjects i n t he place b o gr o u p a n d 1 9 0 s u bjects i n t he 
fil g oti ni b gr o u p at t he sa me d ose le vel as t he i n d ucti o n d ose will pr o vi de 
m ore t ha n 8 5 % p o wer f or eac h fil g oti ni b d ose gr o u p c o m paris o n t o 
place b o at a 2 -si de d 0. 0 2 5 si g nifica nce le vel t o detect a treat me nt 
differe nce i n mai nte na nce E B S re missi o n rate of 2 0 % ( 4 0 % o n fil g oti ni b 
a n d 2 0 % o n placeb o).
T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he g ui deli nes of G o o d Cli nical Practice ( G C P) 
i ncl u di n g arc hi vi n g of esse ntial d oc u me nts.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 2
0 2 A pril 2 0 1 9
G L O S S A R Y O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F  T E R M S
5- A S A
5- a mi n osalic ylate
6- M P
6- merca pt o p uri ne
A D L
Acti vi ties of Dail y li vi n g
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nts
A N O V A
a nal ysis of varia nce
A S T
as partate a mi n otra nsferase
A U C
area u n der t he plas ma/ser u m/ peri p heral bl o o d m o n o n uclear cell c o nce ntrati o n, dr u g vers us 
ti me c ur ve
B A P
Bi o mar ker A nal ysis Pla n
B L Q
bel o w  t he li mit of q ua ntitati o n
B MI
b o d y mass i n de x
C. diff
cl ostri di u m difficile
C C & G
C oc kcr oft -Ga ult
C D
Cr o h n’s Disease 
C D AI
Cr o h n’s Disease Acti vit y I n de x
C E S
Car b o x ylesterase
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
CI A
c olla ge n -i n d uce d art hritis
C K
creati ne ki nase
C m a x
t he ma xi m u m o bser ve d ser u m/ plas ma/ peri p heral bl o o d m o n o n uclear ( P B M C) 
c o nce ntrati o n of dr u g
C M H
C oc hra n -Ma ntel -Hae nszel
C M V
c yt o me gal o vir us
C N S
ce ntral ner v o us s yste m
C P K
creati ne p h os p h o ki nase 
Cr Cl
creati ni ne cleara nce
C R F
case re p ort f or m(s)
C R O
c o ntract ( or cli nical) researc h or ga nizati o n 
C R P
c-reacti ve pr otei n
C S R
cli nical st u d y re p ort
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C Y P
c yt oc hr o me P 4 5 0
D AI
Disease Acti vit y I n de x
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d
D S S
de xtra n s ulfate s o di u m

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 3
0 2 A pril 2 0 1 9
E.c oli
Esc heric hi a c oli
E B S
e n d osc o p y/ blee di n g/st o ol
E C
et hics c o m mittee
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m(s)
E D C
Electr o nic Data Ca pt ure 
e Diar y
electr o nic diar y
E M A
E ur o pea n Me dici nes A ge nc y
E Q -5 D
E ur o Q ol fi ve di me nsi o ns
e S A E
electr o nic S A E s yste m
E T
earl y ter mi nati o n
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n cli nical trials data base
F A S
f ull a nal ysis set
F D A
( U nite d States) F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice ( G ui deli nes)
GI
gastr oi ntesti nal
G SI
Gilea d Scie nces, I nc.
G U
ge nit o uri nar y
H Bc A b
he patitis B vir us c ore a nti b o d y
H Bs A b
he patitis B vir us s urface a nti b o d y
H Bs A g
he patitis B vir us s urface a nti ge n
H B V
he patitis B vir us
H C R U
healt h care res o urce utilizati o n
H C V
he patitis C vir us
H D L
hi g h -de nsit y li p o pr otei n
H D P E
hi g h de nsit y p ol yet h yle ne
h E R G
h u ma n et her -a-g o g o
HI V
H u ma n I m m u n o deficie nc y Vir us
H L G T
Hi g h -Le vel Gr o u p Ter m
H L T
Hi g h -Le vel Ter m
H R Q o L
healt h relate d q ualit y of life
I B
I n vesti gat or Br oc h ure
I B D
i nfla m mat or y b o wel disease
I B D Q
I nfla m mat or y B o wel Disease Q uesti o n naire
I C5 0
c o nce ntrati o n of a n i n hi bit or t hat is re q uire d f or 5 0 -perce nt i n hi biti o n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nis ati o n of  Tec h nical Re q uire me nts f or P har mace uticals 
f or H u ma n Use
I E C
i n de pe n de nt et hics c o m mittee

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 4
0 2 A pril 2 0 1 9
I L-1 2
i nterle u ki n
I M
i ntra m usc ular
I M P
i n vesti gati o nal me dici nal pr o d uct
I N D
i n vesti gati o nal ne w dr u g
I N R
i nter nati o nal n or malize d rati o
I R B
i nstit uti o nal re vie w b oar d
I U D
i ntra uteri ne de vice
I V
intra ve n o us
I W R S
i nteracti ve we b res p o nse s yste m
J A K
Ja n us ki nase
J A K-S T A T
Ja n us Ki nase (J A K)-Si g nal Tra ns d ucer a n d Acti vat or of Tra nscri pti o n ( S T A T)
L A M
lactati o nal a me n orr hea met h o d
L D L
l o w-de nsit y li p o pr otei n
L L O Q
l o wer li mit of q ua ntitati o n
L L T
L o wer -Le vel Ter m
L O C F
Last O bser vati o n Carrie d F or war d
L T E
l o n g-ter m e xte nsi o n
M C S
M a y o Cli nic Sc ore
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M M P - 9
matri x metall o pe pti dase - 9
M T X
met h otre xate
N O E L
n o -o bser ve d -effect -le vels
N RI
n o n- res p o n der i m p utati o n
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u gs
O & P
o va a n d parasites test
O A T
or ga nic a ni o n tra ns p orters
P B M C
peri p heral bl o o d m o n o n uclear cell
P C P
p ne u m oc ystis p ne u m o nia
P D
p har mac o d y na mics
P E
p h ysical e xa mi nati o n
P E G
p ol yet h yle ne gl yc ol
P G A
p h ysicia n’s gl o bal assess me nt
P- g p
p gl yc o pr otei n
PI
pri nci pal i n vesti gat or
P K
p har mac o ki netic
P T M
place b o t o matc h
P T x
p P ost -t Treat me nt
P V E
P har mac o vi gila nce a n d E pi de mi ol o g y
Q 1
1 st q uartile
Q 3
3 r d q uartile

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 5
0 2 A pril 2 0 1 9
R A
r he u mat oi d art hritis
R N A
ri b o n ucleic aci d
R T -P C R
re verse tra nscri pti o n p ol y merase c hai n reacti o n
S A D R
seri o us a d verse dr u g reacti o n
S A E
seri o us a d verse e ve nt
S A P
Statistical A nal ysis Pla n
S C
su bc uta ne o us
S D
sta n dar d de viati o n
S E S -C D
Si m ple E n d osc o pic Sc ore f or Cr o h n’s Disease
S F -3 6
S h ort F or m Healt h S ur ve y
SI
i nter nati o nal s yste m of u nits
S O C
s yste m or ga n class
S O P
sta n dar d o perati n g pr oce d ure
s p p
s pecies
S T A T
si g nal tra ns d ucer a n d acti vat or of tra nscri pti o n
S U S A R
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n
T B
tu berc ul osis
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T gras H 2
tra ns ge nic m o use
T N F α
t u m or necr osis fact or-al p ha
T P M T
t hi o p uri ne met h yltra nsferase
T Y K
t yr osi ne ki nase
U C
ulcerati ve c olitis
U C EI S
ulcerati ve c olitis e n d osc o pic i n de x of se verit y
U G T
u ri di ne 5'-di p h os p h o -gl uc ur o n os yltra nsferase
U L N
u p per li mit of t he n or mal ra n ge
U S
U nite d States
vf P B M C
visi bl y fr oze n peri p heral bl o o d m o n o n uclear cell
W B C
w hite bl o o d cell
W P AI
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 6
0 2 A pril 2 0 1 9
D E FI NI TI O N O F T E R M S
C ortic oster oi d -Free Re missi o n
E B S re missi o n wit h n o c ortic oster oi d use f or at least 6 m o nt hs pri or t o Wee k
5 8 
a mo n g s u bjects w h o are o n c ortic oster oi d at Baseli ne
E B S Re missi o n
A n en d osc o pic s u bsc ore of 0 or 1, rectal b lee di n g s u bsc ore of 0, a n d at least a 
o ne p oi nt decrease i n st o ol fre q ue nc y fr o m baseli ne t o ac hie ve a s u bsc ore of 0 or 1
E n d osc o pic Res p o nse
E n d osc o pic s u bsc ore of 0 or 1
Ge b oes hist ol o gic re missi o n
Base d o n t he Ge b oes Scale, all of t he f oll o wi n g m ust be met t o be c o nsi dere d i n 
Ge b oes hist ol o gic re missi o n.
Gra de 0
≤0. 3
Gra de 1
≤1. 1
Gra de 2a
≤2 A. 3
Gra de 2 b
2 B. 0
Gra de 3
3. 0
Gra de 4
4. 0
Gra de 5
5. 0
M a y o Cli nic Sc o re*
C o m p ose d of s u b -sc ores fr o m e n d osc o p y, rectal blee di n g, st o ol fre q ue nc y, a n d 
P G A
M a y o Cli nic Sc ore Re missi o n
M C S
of ≤2 p oi nts a n d n o i n di vi d ual s u bsc ore > 1 p oi nt
M a y o Cli nic Sc ore Re missi o n 
( Alter nati ve Defi niti o n)
R ectal blee di n g, st o ol fre q ue nc y, a n d P G A s u bsc ore of 0 a n d a n e n d osc o pic 
s u bsc ore of 0 or 1; o verall M C S of ≤ 1
M a y o Cli nic Sc ore Res p o nse
A M a y o Cli nic Sc ore ( M C S) re d ucti o n of ≥3 p oi nts a n d at least 3 0 % fr o m 
b aseli ne sc ore wit h a n acc o m pa n yi n g decrease i n rectal blee di n g s ubsc ore of 
≥1 p oi nt or a n a bs ol ut e rectal blee di n g s u bsc ore of 0 or 1
Partial Ma y o Cli nic Sc ore
C o m p ose d of s u b -sc ores fr o m rectal blee di n g, st o ol fre q ue nc y, a n d P G A
* 
Rectal blee di n g a n d st o ol fre q ue nc y s u bsc ores will be r o u n de d t o t he nearest i nte ger f or deter mi nati o n of eli gi bilit y a n d 
calc ulati o n of e n d p oi nts

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 7
0 2 A pril 2 0 1 9
1.
I N T R O D U C TI O N
1. 1.
B ac k gr o u n d
Ulcerati ve c olitis ( U C) is a c hr o nic, i nter mitte nt, rela psi n g disease c haracterize d b y  i nfla m mati o n 
of t he c ol o nic m uc osa , w hic h is li mite d t o t he c ol o n a n d rect u m. T he di sease c haracteristicall y 
c o m me nces i n t he rect u m a n d ma y e xte n d pr o xi mall y i n a n u ni nterr u pte d patter n i nt o t he c ol o n. 
It can i n v ol ve t he e ntire c ol o n ( pa n -c olitis), t he left c ol o n, or is olate d rect o -si g m oi d disease wit h 
patie nts bei n g e q uall y distri b ute d i n t h ose 3 p he n ot y pes. I n t he U nite d States ( U S), t he 
pre vale nce of U C has bee n esti mate d t o be 2 3 8 per 1 0 0, 0 0 0 a d ults { Ka p pel ma n 2 0 0 7 }. E ur o pe 
has t he hi g hest re p orte d pre vale nce val ues f or i nfla m mat or y b o wel disease 
(I B D; 5 0 5 per 1 0 0, 0 0 0 pers o ns f or U C a n d 3 2 2 f or Cr o h n’s Disease [ C D ]). T he a n n ual 
i nci de nce of U C is 2 4. 3 per 1 0 0, 0 0 0 pers o n -years i n E ur o pe a n d t he i nci de nce is 6. 3 per
1 0 0, 0 0 0 pers o n -ye ars f or U C i n Asia { M ol o dec k y 2 0 1 2 }.  T he i nci de nce a n d pre vale nce of I B D 
a p pear t o be i ncreasi n g o ver ti me gl o ball y . T he hall mar k s y m pt o ms of t he disease are bl o o d y  
diarr hea, rectal ur ge nc y , a n d te nes m us. T he cli nical c o urse te n ds t o wa x a n d wa ne wit h peri o ds 
of re missi o n i nters perse d wit h peri o ds of acti ve disease. Ulcerati ve c olitis ma y als o be ass ociate d 
wit h e xtra -i ntesti nal ma nifestati o ns i ncl u di n g oc ular lesi o ns, s ki n lesi o ns, art hritis, a n d pri mar y 
scler osi n g c h ola n gitis. T he e xact pat h o p h y si ol o g y is n ot k n o w n b ut i n ge neral, ge netic 
pre dis p ositi o n i n c o nj u ncti o n wit h e n vir o n me ntal a n d s ocial fact ors (s uc h as hist or y  of t o bacc o 
use, me dicati o n hist or y , a n d ge o gra p hy)  ma y i m pact de vel o p me nt of disease. Disc o or di nate d 
acti vit y of b ot h i n nate a n d a da pti ve i m m u ne res p o nses i n c o m bi nati o n wit h e pit helial barr ier 
defects a n d d ys bi osis lea d t o a n i nfla m mat or y casca de res ulti n g i n cli nical si g ns a n d sy m pt o ms 
of U C { U n gar o 2 0 1 6 }.  
I n a d diti o n t o a b d o mi nal pai n a n d rectal blee di n g t hat b ot h i m pact acti vities of dail y li vi n g a n d 
q ualit y  of life f or patie nts wit h U C, t he disease als o carries a n i ncrease d ris k of c ol orectal 
ca ncer{ U n gar o 2 0 1 6 }. Wit h p o orl y  c o ntr olle d disease, t he rate of de vel o pi n g c ol orectal ca ncer 
i ncreases wit h ti me. T he ris k of c ol orectal ca ncer i n U C patie nts is decreasi n g o ver ti me partially 
d ue t o better c o ntr ol of i nfla m mati o n a n d c ol o n osc o pic s ur veilla nce { Bea u gerie 2 0 1 5 }. O verall,
U C patie nts still e x perie nce a greater ris k of c ol orectal ca ncer ; i n o ne meta -anal ys is of 
p o p ulati o n base d c o h orts t he ris k was 2. 4 -f ol d { Jess 2 0 1 2}. T h us , U C re prese nts a seri o us, 
life-t hreate ni n g disease f or w hic h ne w t hera pies are nee de d t o i nterr u pt t he i nfla m mat or y pr ocess 
t o pre ve nt disease pr o gressi o n, rest ore q ualit y of life, a n d re d uce t he ris k of c ol orectal ca ncer.
Treat me nt of U C is de pe n de nt o n t he se verit y a n d t he l ocati o n of disease. G oals of treat me nt 
i ncl u de i m pr o ve d q ualit y of life, re d ucti o n i n l o n g-ter m c ortic oster oi d use, a n d mi ni mizati o n of 
ca ncer ris k. Mil d t o m o derate distal c olitis ma y  be treate d wit h oral a mi n osalic ylates, t o pical 
mesala mi ne, or t o pical ster oi ds { K or n bl ut h 2 0 1 0 } . F or m o derate disease, oral c ortic oster oi ds, 
a n d i m m u n o m o d ulat ors s uc h as azat h i o pri ne a n d 6-merca pt o p uri ne ( 6 -M P) ma y  be utilize d 
{ Da nese 2 0 1 1 } . F or m ore m o derate t o se vere disease, patie nts are c o m m o nl y treate d wit h a 
t u m or necr osis fact or-al p ha (T N F α ) a nta g o nist i nf usi o n or i nject i o n s uc h as i nfli xi ma b 
( Re mica de® ), a dali m u ma b ( H u mira® ), a n d g oli m u ma b ( Si m p o ni® ). Ve d oliz u ma b ( E nt yvi o ® ), a n 
i njecta ble i nte gri n α 4 β 7 m o n ocl o nal a nti b o d y, is als o a p pr o ve d f or m o deratel y t o se verel y acti ve 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 8
0 2 A pril 2 0 1 9
disease. Uste ki n u ma b ( Stelara ® , C N T O 1 2 7 5; a n I L-1 2 a n d I L -2 3 m o n ocl o nal a nti b o d y ), 
u pa daciti ni b ( J A K i n hi bit or), etr oliz u ma b ( P R O 1 4 5 2 2 3; m o n ocl o nal a nti b o d y  tar geti n g t he 
β 7 s u b u nit of t he heter o di meric i nte gri ns α 4 β 7 a n d α E β 7), risa n kiz u ma b (I L-2 3 a nti b o d y ) a n d 
oza ni m o d ( R P C 1 0 6 3; selecti ve S 1 P 1 a n d S 1 P 5 rece pt or a g o nist) are c urre ntl y bei n g teste d i n 
P hase 3 cli nical trials . T ofaciti ni b, a J A K 1/ 3 i n hi bit or, was effecti ve i n a P hase 3 U C st u d y
{ Sa n d b or n 2 0 1 7 }.  Le u k oc y ta p heresis t hera py ma y be use d i n Ja pa n { F u k u na ga 2 0 1 2 }. Des pite 
se veral classes of treat me nt o pti o ns f or patie nts wit h U C, t here re mai ns a n u n met me dical nee d, 
partic ularl y i n t he treat me nt of m o deratel y t o se verel y acti ve disease. A ge nts wit h n o vel 
mec ha nis ms of acti o n t hat tar get t he i nfla m mat or y  casca de, with oral d osi n g a n d acce pta ble 
i m m u n o m o d ulat or y a n d he mat ol o gic effects, re mai n t he m ost pr o misi n g o pti o n t o a d dress t hese 
u n met nee ds. 
1. 2.
Fil g oti ni b ( G S- 6 0 3 4)
1. 2. 1.
Ge ner al I nf or m ati o n
Ja n us ki nases (J A Ks) are i ntracell ular c yt o plas mic t yr osi ne ki nases ( T Y Ks) t hat tra ns d uce 
c yt o ki ne si g nali n g fr o m me m bra ne rece pt ors t hr o u g h si g nal tra ns d ucer a n d acti vat or of 
tra nscri pti o n ( S T A T) t o t he n ucle us of cells. J A K i n hi bit ors bl oc k t he si g nali n g of vari o us 
c yt o ki nes, gr o wt h fact ors, a n d h or m o nes, i ncl u di n g t he pr o-i nfla m mator y  c yt o ki ne i nterle u ki n 
(I L)- 6. F o ur differe nt t y pes of J A Ks are k n o w n, J A K 1, J A K 2, J A K 3, a n d T Y K 2 w hic h i nteract 
wit h differe nt sets of me m bra ne rece pt ors. I n hi biti o n of J A Ks is a pr o misi n g t hera pe utic o pti o n 
f or a ra n ge of i nfla m mat or y c o n diti o ns i ncl u di n g r he u mat oi d art hritis ( R A) a n d C D.
Fil g oti ni b ( G S -6 0 3 4, f or merl y  k n o w n as G L P G 0 6 3 4) is a p ote nt a n d selecti ve i n hi bit or of J A K 1. 
T he c o m p o u n d has s h o w n g o o d preli mi nar y  efficac y i n R A a n d C D patie nts i n P hase 2 st u dies.
I n h u ma ns, fil g oti ni b is meta b olize d t o f or m o ne maj or acti ve meta b olite, G S -8 2 9 8 4 5 . T h o u g h 
t he p ote nc y of t his meta b olite is l o wer t ha n t he pare nt m olec ule, t he o verall e x p os ure a n d pea k 
plas ma c o nce ntrati o n i n h u ma ns is hi g her t ha n see n i n all teste d a ni mal s pecies. As a 
c o nse q ue nce, de dicate d p har mac ol o g y  a n d t o xic ol o g y st u dies ha ve bee n perf or me d wit h 
G S - 8 2 9 8 4 5. Res ults fr o m p har mac o d y na mics ( P D) testi n g i n healt h y v ol u nteers s u g gest t hat t he 
cli nical acti vit y of fil g oti ni b c o ul d res ult fr o m t he c o m bi nati o n of t he pare nt m olec ule a n d the 
meta b olite.
F or f urt her i nf or mati o n o n f il g otini b, refer t o t he c urre nt In vesti gat or’s B r oc h ure (IB) .
1. 2. 2.
Precli nic al P h ar m ac ol o g y a n d T o xic ol o g y
Fil g ot i ni b a n d its meta b olite, G S- 8 2 9 8 4 5 ha ve bee n e xte nsi vel y  c haracterize d i n n o ncli nical 
st u dies. T his pr o gra m i ncl u des cell ular assa ys de m o nstrati n g p ote nc y a n d selecti vit y of t he 
c o m p o u n d a gai nst J A K 1; efficac y  st u dies i n rats a n d mice; re peat d ose t o xicity st u dies ( u p t o 
2 6 wee ks i n t he rat a n d 3 9 wee ks i n t he d o g), i n vitr o a n d i n vi v o safet y p har mac ol o g y a n d 
ge netic t o xic ol o g y  st u dies, a n d re pr o d ucti ve t o xic ol o g y st u dies i n rats a n d ra b bits. A d diti o nal 
t o xic ol o g y st u dies c o n d ucte d i ncl u de p h ot ot o xicit y st u dies a n d d ose-ra n ge fi n di n g st u dies i n
s u p p ort of a defi niti ve rat j u ve nile t o xicit y st u d y a n d a 6-m o nt h carci n o ge nicit y  st u d y i n 
tra ns ge nic ( T gras H 2) mice. O n g oi n g st u dies i ncl u de carci n o ge nicit y st u dies i n rats a n d mice, a 
rat pre- a n d p ost- natal de vel o p me nt st u d y, a n d a 4-wee k i m p urit y q ual ificati o n st u d y i n rats.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 2 9
0 2 A pril 2 0 1 9
1. 2. 2. 1.
N o ncli nical P har mac ol o g y 
I n cell ular assa ys, fil g oti ni b i n hi bits J A K 1 si g nali n g wit h t he c o nce ntrati o n of a n i n hi bit or t hat is 
re q uire d f or 5 0 % i n hi biti o n (I C5 0) val ues of ≥ 1 7 9 n M, a n d de m o nstrates 3 0- f ol d selecti vit y o ver 
J A K 2 in a h u ma n w h ole bl o o d assa y. Fil g oti ni b has bee n pr ofile d a gai nst 4 5 1 ki nases a n d it is 
hi g hl y selecti ve f or J A K 1; o nl y 2. 5 % of ki nases were i n hi bite d ≥ 5 0 % at 5 0 -f ol d hi g her 
c o nce ntrati o n t ha n IC 5 0 f or J A K 1. Br oa d rece pt or pr ofili n g ( ~ 7 0 rece pt ors, i o n c ha n nels, 
tra ns p orters a n d e nz ymes) di d n ot re veal a n y  off-tar get lia bilities of t he c o m p o u n d. Fil g oti ni b 
de m o nstrate d hi g h p ote nc y  i n t he rat c olla ge n-i n d uce d art hritis ( CIA) m o del as well as i n t he 
m o use de xtra n s ulfate s o di u m ( D S S)-i n d uce d c olitis m o del, t he latter of w hic h is detaile d bel o w. 
T he maj or h u ma n meta b olite of fil g oti ni b G S- 8 2 9 8 4 5 e x hi bits a si milar J A K 1 selecti vit y pr ofile 
b ut is a p pr o xi matel y  1 0-f ol d less p ote nt as c o m pare d t o pare nt fil g oti ni b i n vitr o.
T he efficac y  of fil g oti ni b was e val uate d i n a pr o p h ylactic setti n g of t he c hr o nic m o use de xtra n 
D S S m o del i n t w o se parate st u dies. B ot h st u dies e val uated oral d ose le vels of 1 0 a n d 3 0 m g / k g 
o nce dail y. I n a d diti o n t o assess me nts of cli nical sc ore ( disease acti vit y  i n de x [ D AI] a n d c ol o n 
lesi o n sc ore), ser u m mar kers of i nfla m mati o n, i m m u n o hist oc he mical a nal ysis, a n d e x pressi o n of 
vari o us c he m o ki nes a n d c yt o ki nes k n o w n t o be altere d i n C D a n d U C patie nts were als o 
e val uate d i n t he distal c ol o n of t hese mice.
I n b ot h st u dies, t he D AI sc ore, w hic h ta kes i nt o acc o u nt b o d y wei g ht l oss, rectal blee di n g, a n d 
st o ol c o nsiste nc y, was re d uce d b y fil g oti ni b i n a d ose-de pe n de nt ma n ner, de m o nstrati n g t hat 
fil g oti ni b pr otecte d mice a gai nst c olitis i n d uce d b y D S S. Hist ol o g y of t he c ol o n re veale d a 
fil g oti ni b-me di ate d d ose -relate d re d ucti o n i n c ol o n lesi o n sc ore, c orrelati ng wit h re d ucti o ns i n 
D AI sc ore.
A d diti o nal e n d p oi nts e val uate d acr oss t he D S S c olitis m o del st u dies c o nfir me d t he s u p pressi o n 
of vari o us i nfla m mat or y  mar kers i ncl u di n g ser u m le vels of C-reacti ve pr otei n ( C R P ) a n d 
m y el o per o xi dase ( M P O ) a n d e x pressi o n of I L -6 a n d T N F α ( b y  re verse tra nscri pti o n p ol ymerase 
c hai n reacti o n [ R T -P C R ]) b y fil g oti ni b. I m m u n o hist oc he mical a nalys is of t he c ol o n c o nfir me d 
i n hi biti o n of t he J A K-S T A T pat h wa y  b y fil g oti ni b as e vi de nce d b y a re d ucti o n of D S S -i n d uce d 
S T A T 3 p h os p h or y lati o n.
1. 2. 2. 2.
Safet y  P har mac ol o g y
Fil g oti ni b a n d G S -8 2 9 8 4 5 ha d n o rele va nt effects o n car di o vas c ular para meters 
( h u ma n et her -a-g o g o [ h E R G] a n d d o g tele metr y  stu dies), a part fr o m a sli g ht n o n -a d verse 
i ncrease i n heart rate a n d arterial press ure wit h G S- 8 2 9 8 4 5 at e x p os ures 8-f ol d t hat of t he pea k 
ser u m c o nce ntrati o n (C ma x ) i n s u bjects wit h C D treate d wit h 2 0 0 m g o nce dail y fil g oti ni b. T here 
were n o rele va nt effects o n electr ocar di o gra m ( E C G) a n d Q T. Fil g oti ni b a n d G S -8 2 9 8 4 5 ha d n o 
effects o n t he res pirat or y  s yste m a n d ce ntral ner v o us s yste m ( C N S).

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 0
0 2 A pril 2 0 1 9
1. 2. 2. 3.
K e y  No ncli nical D istri b uti o n, Meta b olis m, a n d E xcreti o n D ata
Fil g oti ni b de m o nstrates g o o d oral bi oa vaila bilit y  i n mice, rats, d o gs, a n d mi ni-pi gs b ut less i n 
m o n ke y s. Plas ma pr otei n bi n di n g is l o w ( < 7 0 %) i n all s pecies, i ncl u di n g h u ma ns.
T he p har mac o ki netics ( P K) of fil g otini b is ge nerall y d ose pr o p orti o nal wit h o ut ge n der 
differe nces. N o acc u m ulati o n occ urs wit h re peate d d osi n g. T he mea n ter mi nal half-life after oral 
a d mi nistrati o n is 4 h o urs a n d 5 h o urs i n rats a n d d o gs, res pecti vely.
I n t he rat, fil g oti ni b s h o we d a ra pi d a n d e ve n distri b uti o n t hr o u g h o ut t he b o d y. Hi g h 
c o nce ntrati o ns were o bser ve d o nl y  i n t he gastr oi ntesti nal ( GI) tract a n d uri nar y blad der. 
Fil g oti ni b d oes n ot pe netrate i nt o C N S tiss ues. T he distri b uti o n of fil g oti ni b i n dicates s o me 
affi nit y f or mela ni n-c o ntai ni n g tiss ues.
E xcreti o n is nearl y  c o m plete wit hi n 2 4 ho urs (rat) a n d 4 8 ho urs ( d o g) p ost-d osi n g. I n t he rat, 
fecal a n d uri nar y e xcreti o n acc o u nte d f or 4 0 % a n d 5 3 % of t he a d mi nistere d d ose, res pecti vel y, 
wit h a bile secreti o n of a b o ut 1 5 %. I n t he d o g, fecal e xcreti o n was t he pri mar y r o ute of e xcreti o n, 
acc o u nti n g f or 5 9 % of t he a d mi nistere d d ose, wit h uri nar y  e xcreti o n acc o u nti n g f or 2 5 % .
I n vitr o meta b olis m st u dies i n all s pecies re veal e d o ne maj or meta b olite ( G S -8 2 9 8 4 5). T he 
f or mati o n of G S- 8 2 9 8 4 5 is me diate d b y car b o xyl esterases ( C E S) a n d is n ot de pe n de nt o n 
c yt oc hr o me P 4 5 0 ( C Y P).
I n vitr o e x peri me nts ha ve s h o w n t hat dr u g- dr u g i nte racti o ns wit h fil g oti ni b a n d GS- 8 2 9 8 4 5 are 
u nli kel y . T here is n o i n hi biti o n or i n d ucti o n of C Y Ps or 
uri di ne 5’- di p h os p h o -gl uc ur o n os yl tra nsferase (U G Ts ), a n d n o rele va nt i n hi biti o n of ke y  dr u g 
tra ns p orters, i ncl u di n g or ga nic a ni o n tra ns p orters ( O A Ts), b y  fil g oti ni b or G S- 8 2 9 8 4 5. O C T 2 
was i n hi bite d b y  b ot h fil g oti ni b (I C5 0: 8. 7 μ M) a n d G S -8 2 9 8 4 5 (I C 5 0: 6 7 μ M). T he cli nical 
rele va nce of t he I C5 0 val ues f or i n hi biti o n of O C T 2 will be f urt her e val uate d.   M A T E 1 was als o 
wea kl y i n hi bite d b y fil g oti ni b (I C 5 0: 9 4 μ M) a n d G S -8 2 9 8 4 5 (I C 5 0: > 1 0 0 μ M).   Fil g oti ni b was 
f o u n d t o be a s u bstrate of P- gl yc o pr otei n ( P- g p ).
1. 2. 2. 4.
N o ncli nical T o xic ol o g y
I n re peat oral d ose t o xicit y st u dies i n b ot h rats a n d d o gs, t he pri mar y tar get tiss ues i de ntifie d f or 
fil g oti ni b were t he l ym p h oi d tiss ue s w hic h are e x pecte d base d o n t he p har mac ol o g y  of J A K 
i n hi biti o n. A d diti o nal fil g oti ni b-relate d fi n di n gs were o bser ve d i n t he male re pr o d ucti ve or ga ns 
of b ot h s pecies, a n d i n t he i ncis or teet h of rats o nl y. Effects o n t he l y m p h oi d s y ste m were f ull y 
re versi ble. Testic ular t o xicit y de m o nstrate d partial re versi bilit y; h o we ver, s per m c o u nts 
re mai ne d l o w. W he n usi n g t he mea n e x p os ure ( A U C) at t he N O A E Ls f or t he m ost se nsiti ve 
s pecies (t he d o g), t he e x p os ure mar gi ns c o m pare d t o a 2 0 0 m g o nce dail y d ose of fil g oti ni b i n 
C D s u bjects are 2. 5, 1. 9, a n d 3. 6 -f ol d f or t he 2 6-wee k a n d 3 9 -wee k c hr o nic t o xicit y  st u dies a n d 
t he 3 9-wee k tar gete d e x p os ure t o xicit y  st u d y, res pecti vely.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 1
0 2 A pril 2 0 1 9
G S - 8 2 9 8 4 5-relate d fi n di n gs i n t he re peat-d ose t o xicit y  st u dies were ge nerall y si milar t o t h ose of 
t he pare nt fil g oti ni b, h o we ver n o testic ular t o xicit y was n ote d f oll o wi n g a d mi nistrati o n of 
G S - 8 2 9 8 4 5.
Fil g oti ni b a n d G S -8 2 9 8 4 5 were n o n -ge n ot o xic w he n e val uate d i n t he bacterial m uta ge nicit y 
assa y, t he i n vitr o m o use l y m p h o ma m uta ge ni cit y assa y, a n d t he rat b o ne marr o w micr o n ucle us 
assa y.
I n e m br yofetal de vel o p me nt st u dies, fil g oti ni b a n d G S- 8 2 9 8 4 5 ca use d e m br yolet halit y a n d 
terat o ge nicity i n rats a n d ra b bits .  Terat o ge nicit y was o bser ve d at e x p os ures sli g htl y hi g her or
si milar t o t he h u ma n e x p os ure at 2 0 0 m g o nce d ail y  of fil g oti ni b i n s u bjects wit h C D.
A d mi nistrati o n of fil g oti ni b di d n ot affect fe male fertilit y  b ut i m paire d fertilit y was o bser ve d i n 
male rats at e x p os ures a p pr o xi matel y  1 2-f ol d t he h u ma n e x p os ure at 2 0 0 m g of fil g oti ni b i n 
s u bjects wit h C D. G S -8 2 9 8 4 5 di d n ot ha ve a n y effects o n fertilit y para meters i n eit her male or 
fe male rats.
I n a n i n vitr o p h ot ot o xicit y st u d y i n 3 T 3 cells, t he meta b olite G S-8 2 9 8 4 5 was p ositi ve f or 
p h ot ot o xic p ote ntial a n d res ults wit h fil g oti ni b we re e q ui v ocal. A f oll o w-u p i n vi v o rat 
p h ot ot o xicit y  assa y re veale d a lac k of p h ot ot o xic p ote ntial f or b ot h c o m p o u n ds.
1. 2. 3.
Cli nic al Tri als of Fil g oti ni b
A n o ver vie w of e x p os ure a n d cli nical st u dies c o n d ucte d wit h fil g oti ni b is a vaila ble i n t he I B .
1. 2. 3. 1.
P hase 2 S tu d y i n Cr o h n’s Disease (G L P G 0 6 3 4 -C L -2 1 1, FI T Z R O Y)
A P hase 2, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, m ultice nter st u d y wit h fil g oti ni b was
perf or me d i n s u bjects wit h acti ve C D wit h e vi de nce of m uc osal ulcerati o n { Ver meire 2 0 1 7 } . I n
Part 1, a t otal of 1 7 4 s u bjects were ra n d o mize d ( 3: 1) t o recei v e eit her fil g oti ni b 2 0 0 m g 
o nce dail y or place b o f or 1 0 wee ks. Base d o n t heir cli nical res p o nse i n Part 1, s u bjects i n Part 2 
eit her c o nti n ue d t heir c urre nt treat me nt or were reassi g ne d t o a differe nt treat me nt f or a n 
a d diti o nal 1 0 wee ks.
T he efficac y  of fil g oti ni b was assesse d b y e val uati n g cli nical re missi o n ( defi ne d as Cr o h n’s 
Disease Acti vit y  In de x [ C D AI ] sc ore < 1 5 0), cli nical res p o nse ( defi ne d as a decrease i n C D AI of 
at least 1 00 p oi nts fr o m baseli ne), a n d e n d osc o pic res p o nse ( defi ne d as a decrease of at least 
5 0 % fr o m baseli ne i n t he S E S- C D sc ore).
T he pri mar y  e n d p oi nt of t he st u d y was met: at Wee k 1 0, 6 0 of 1 2 8 s u bjects ( 4 6. 9 %) w h o
recei ve d fil g oti ni b ac hie ve d cli nical re missi on vers us 1 0 of 4 4 s u bjects ( 2 2. 7 %) w h o recei ve d
place b o, a differe nce of 2 4. 1 % ( p -val ue = 0. 0 0 7 7). I n a d diti o n, fil g oti ni b treat me nt was 
ass ociate d wit h i ncreases i n t he pr o p orti o n of s u bjects wit h cli nical re missi o n , cli nical res p o nse, 
a n d e n d osc o pic res p o nse c o m pare d wit h place b o.
O verall, t he safet y pr ofile of fil g oti ni b i n C D s u bjects was c o nsiste nt wit h pri or st u dies. 
F or a d diti o nal details a b o ut t he efficac y  a n d safet y of fil g oti ni b i n C D, refere nce is ma de t o t he 
I B.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 2
0 2 A pril 2 0 1 9
1. 3.
R ati o n ale f or T his St u d y
T here re mai ns a s i gnifica nt u n met nee d i n t he treat me nt of m o derate l y t o se verel y acti ve U C
des pite m ulti ple classes of treat me nt re gi me ns.  G oals of treat me nt i ncl u de i m pr o ve d q ualit y of 
life, re d ucti o n i n l o n g-ter m c ortic oster oi d use, m uc osal heali n g , a n d mi ni mizati o n of ris k of 
mali g na nc y . T o date, n o oral a ge nt has bee n a p pr o ve d f or m o derately t o se verel y acti ve U C, a n d 
t he use of c ortic oster oi ds a n d oral i m m u n o m o d ulat ors has bee n i n c o m bi nati o n wit h bi ol o gic 
t hera pies. Patie nt res p o nse t o pri mar y  T N Fα i n hi biti o n is varia ble, a n d t he ris k of sec o n dar y 
bi ol o gic fail ure is si g nifica nt. T h o u g h s ur ger y  ma y be c urati ve, a v oi da nce of s ur gical ris ks is 
e q uall y desira ble. Oral t hera p y wit h efficac y c o m para ble t o T N Fα- i n hi biti o n a n d a nti-i nte gri n 
t hera py is hi g hl y d esira ble. J A K i n hi biti o n wit h fil g oti ni b re prese nts a si g nifica nt o p p ort u nit y  t o 
ac hie ve l o n g-ter m m uc osal heali n g wit h a n acce pta ble safet y pr ofile a n d wit h a d ded ease of oral 
a d mi nistrati o n.
J A K i n hi biti o n as a t hera pe utic m o dalit y  f or U C is s u p p orte d b y precli nical e vi de nce of efficac y  
i n t he D S S-i n d uce d c olitis m o use m o del, P hase 2 cli nical trial res ults i n m o derately t o se verel y 
acti ve C D , a n d by e vi de nce of t ofaciti ni b ( pa n-J A K i n hi bit or) efficac y i n a si milar p o p ulati o n 
wit h m o deratel y t o se verel y ac ti ve U C { Sa n d b or n 2 0 1 7 } . In a well -esta blis he d precli nical m o del 
of U C { C hassai n g 2 0 1 4 } , t he D S S-i n d uce d m o use m o del, fil g oti ni b was efficaci o us at 3 0 m g / k g 
i n pr otecti n g mice fr o m c olitis de vel o p me nt, ne utr o p hil recr uitme nt, a n d macr o p ha ge i nfiltrati o n.  
Mar kers of i nfla m mati o n i ncl u di n g C R P a n d I L- 1 β n or malize d after fil g oti ni b a d mi nistrati o n.
Fi n di n gs wit h t ofaciti ni b { Sa n d b or n 2 0 1 7 } vali date J A K i n hi biti o n as a t hera pe utic i nter ve nti o n 
f or U C a n d c o nse q ue ntly  b ut i n directl y als o s u p p ort de vel o p me nt of fil g oti ni b i n t his p o p ulati o n. 
A d diti o nall y , fil g oti ni b selecti vit y f or J A K 1 wit h c o nse q ue nt mi ni mal effects o n he m o gl o bi n 
( wit h i ncreases u p to 4 % i n P hase 2 b st u dies i n R A a n d i ncreases i n t he C D p o p ulati o n base d o n 
1 0- wee k data ) s u g gests t hat fil g oti ni b ma y de m o nstrate an acce pta ble safety pr ofile i n t he U C 
p o p ulati o n.
1. 3. 1.
R ati o n ale f or E n d p oi nt a n d T i mi n g
Pre vi o us U C i n d ucti o n st u dies ha ve e val ua te d i nitial e n d p oi nts at 8 t o 1 2 wee ks a n d t he prese nt 
st u d y pr o p oses t hat Wee k 1 0 assess me nts f or bi ol o gic naï ve a n d e x perie nce d s u bjects be use d t o 
assess f or c o nti n uati o n i nt o t he mai nte na nce p hase. A Wee k
1 0 i n d ucti o n e n d p oi nt f or U C is 
c o nsi dere d a p pro priate base d o n t he ra pi d a n d s ustai ne d cli nical res p o nses i n d uce d b y  fil g oti ni b 
i n R A a n d C D. Te n wee ks is s ufficie nt ti me f or s o me de gree of m uc osal heali n g t o occ ur a n d f or 
cli nical s ym pt o ms t o i m pr o ve. T he use of e n d osc o p y/ blee di n g/st o ol (E B S ) re missio n , w hic h 
i ncl u des all s u bset of sc ores fr o m t he M C S
b ut e xcl u des t he s u bjecti ve p h ysicia n gl o bal 
assess me nt ( P G A) ma xi mizes o bjecti vit y  i n assess me nt of dr u g effect. Use of ce ntrall y rea d 
e n d osc o p y will f urt her re d uce bias i n assess me nt of e n d osc o pic heali n g. Mai nte na nce
a n d 
d ura bilit y  of res p o nse a n d re missi o n will be e x pl ore d i n t he 4 8- wee k mai nte na nce p hase usi n g a
tra diti o nal m o del of i n d ucti o n-mai nte na nce desi g n.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 3
0 2 A pril 2 0 1 9
1. 3. 2.
R ati o n ale f or D ose
I n P hase 2 trials i n R A, p o ole d data wit h a n e x p os ure- res p o nse a nalys is de m o nstrate d a 
d ose -de pe n de nt i ncrease i n efficac y  u p t o 2 0 0 m g t otal dail y d ose.  I n t he P hase 2 st u d y of C D , 
s ubjects treate d i n t he 2 0 0 m g ar m s h o we d fa v ora ble res p o nse a n d re missi o n rates 
( 47 % re missi o n o ver 23 % place b o a n d 5 9 % res p o nse o ver 4 1 % place b o). T he re missi o n rate at 
Wee k
2 0 f or s u bjects w h o faile d place b o f or t he first 1 0 wee ks a n d c o m me nce d 1 0 0 m g fr om 
Wee ks
1 0 t o 2 0 was sli g htl y l o wer ( 3 2%) t h o u g h t he res p o nse rate was c o m para ble ( 5 9 %) , 
i n dicati n g s o me le vel of efficac y at t he 1 0 0 m g  d ose. T hese res ults are c o nsiste nt wit h t he 
relati o ns hi p o bser ve d bet wee n fil g oti ni b e x p os ures a n d i n hi biti o n of p S T A T 1 acti vati o n 
(e x-vi v o) f oll o wi n g si n gle a n d m ulti ple fil g oti ni b d oses, w here ma xi mal i n hi biti o n of p S T A T 1 
acti vati o n ( ~ 7 8 %) was ac hie ve d at or a b o ve 2 0 0 m g t otal daily d ose a n d inter me diate i n hi biti o n 
( ~ 47 %) at 1 0 0 m g { Na m o ur 2 0 1 5 }. p S T A T 1 data, i n c o nj u ncti o n wit h c o nsi derati o ns ar o u n d t he 
mar gi n f or n o ncli nical testic ular fi n di n gs, s u g gests assessi n g d oses a b o ve 2 0 0 m g is n ot 
i n dicate d. Gi ve n t he a bse nce of defi niti ve data f or fil g oti ni b i n U C, a n d t he prese nce of res p o nse 
i n C D s u bjects i n t he e x pl orat or y 1 0 t o 2 0 wee k ar m of G L P G 0 6 3 4 -C L -2 1 1, a n d st u d y of 
m ulti ple d oses (ie, 1 0 0 m g a n d 2 0 0 m g o nce dail y) i n t he prese nt st u d y will e na ble esta blis h me nt 
of a n a p pr o priate n o mi nal d ose a n d deter mi ne t he d ose wit h t he m ost fa v ora ble ris k/ be nefit 
pr ofile f or U C s u bjects.
T he i n d ucti o n p orti o n of t he st u d y will e val uate 2 d oses of fil g oti ni b . T he p ur p ose of t he 
mai nte na nce p hase is t o e val uate t he a bilit y  of dr u g t o s ustai n re missi o n i n s u bjects w h o ha ve 
res p o n de d at a gi ve n d ose. T heref ore, t he re-ra n d o mizati o n will occ ur i nt o 2 ar ms f or acti ve 
treate d s u bjects: c o nti n uati o n of t he i n d ucti o n d ose or re -ra n d o mizati o n t o place b o.
I n c o ncl usi o n, J A K i n hi biti o n re prese nts a pr o misi n g tar get i n t he treat me nt of m o derate t o 
se vere U C , a n d fil g oti ni b, a safe a n d well t olerate d oral t hera py base d o n P hase 2 data . T he 
prese nt st u d y is i nte n de d t o esta blis h t he safet y a n d efficac y of J A K -selecti ve i n hi biti o n o n a life 
t hreate ni n g disease wit h prese ntly i na de q uate treat me nt o pti o ns. 
1. 4.
Ris k/ Be nefit Assess me nt f or t he S t u d y
U lcerati ve c olitis is a pr o gressi ve a n d p ote ntiall y l ife-t hreate ni n g disease wit h fe w treat me nt
o pti o ns, ma n y  of w hic h res ult i n pri mar y or sec o n dar y n o nres p o nse. I nfla m mat or y b o wel disease
ma y  lea d t o i ncrease d ris k of gastr oi ntesti nal mali g na ncies, i m pair me nt i n q ualit y of life, a n d
ulti mate nee d f or life -alteri n g s ur ger y. C urre nt treatme nt o pti o ns are li mite d i n a bilit y  t o esta blis h
m uc osal heali n g a n d cli nical re missi o n a n d ha ve si g nifica nt safet y a n d efficac y li mitati o ns; f or
e xa m ple, bi ol o gics ha ve si g nifica nt i m m u n o ge nic ris ks a n d ster oi ds are ass ociate d wit h i ncrease d
m or bi dit y  a n d m ortalit y . Re missi o n rates are ge nerall y l o w w he n c o m pare d t o place b o rates
acr oss m ost t hera pies f or I B D. T here re mai ns s u bsta ntial u n met nee d i n I B D, partic ularl y i n
m o derate t o se vere disease. T he lifel o n g nat ure of I B D i ncreases t he pr o ba bilit y t hat s u bjects 
ha ve c y cle d t hr o u g h vari o us t hera pies, lea vi n g fe w a p pr o ve d o pti o ns.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 4
0 2 A pril 2 0 1 9
N o ncli nical st u dies i n rats a n d d o gs i de ntifie d l y m p h oi d tiss ues a n d testes as tar get or ga ns f or
fil g oti ni b i n l o n g-ter m re peat-d ose t o xicit y  st u dies. Alt h o u g h decrease d ly m p h oc y te n u m bers
o bser ve d i n n o ncli nical st u dies ha ve n ot bee n see n i n cli nical st u dies, he mat ol o gical assess me nt
will be perf or me d t hr o u g h o ut t he prese nt st u d y  t o e ns ure t his p ote ntial ris k is a p pr o priatel y 
m o nit ore d. I n b ot h rats a n d d o gs, micr osc o pic fi n di n gs i n t he testes i ncl u de d ger m cell de pleti o n 
a n d de ge nerati o n, wit h re d uce d s per m c o nte nt a n d i ncrease d cell de bris i n t he e pi di d ymis a n d 
re d ucti o n i n fertilit y i n male rats. T he d o g was deter mi ne d t o be t he m ost se nsiti ve s pecies. W he n 
usi n g t he A U C at t he N O A E L s f or d o gs i n t he 2 6- wee k a n d 3 9- wee k c hr o nic t o xicit y  st u dies, 
a n d t he 3 9- wee k tar gete d e x p os ure t o xicit y  st u d y, t he e x p os ure mar gi ns c o m pare d wit h t he 
hi g hest pr o p ose d cli nical d ose of 2 0 0 m g o nce dail y  are 2. 5, 1. 9, a n d 3. 6 -f ol d res pecti vely, i n 
s u bjects wit h C D. A male safet y st u d y is pla n ne d t o e xa mi ne t he p ote ntial effect of fil g oti ni b o n 
s per m/ejac ulate para meters. Pe n di n g t h ose res ults, t he use of 2 0 0 m g i n males i n t he U S a n d 
K orea wit h C D or U C will be li mite d t o s u bjects w h o ha ve faile d at least 2 bi ol o gic t hera pies 
(a n y T N F α a nta g o nist a n d ve d oliz u ma b). Refer t o t he I B f or f urt her i nf or mati o n a b o ut 
n o ncli nical a n d cli nical testic ular fi n di n gs.
Fil g ot i ni b has s h o w n a n i ncrease of e m br yofetal malf or mati o ns i n rats a n d ra b bits at e x p os ures 
si milar t o, or sli g htl y hi g her t ha n, e x p os ures ass ociate d wit h a 2 0 0 m g o nce dail y d ose i n C D 
s u bjects; t he use of hi g hl y  effecti ve c o ntrace pti o n i n t he s u bject p o p ulati o n is e x pecte d t o 
miti gate t his ris k.
J A K i n hi biti o n is e x pecte d t o i ncrease t he ris k of i nfecti o n base d o n mec ha nis m of acti o n.  
Acr oss t he gl o bal st u dies i n fil g oti ni b, i n ge neral, acti ve treate d ar ms ha ve i ncrease d i nci de nces
of i nfecti o n vers us place b o . In t he prese nt pr ot oc ol, treat me nt i nterr u pti o n a n d disc o nti n uati o n 
c o nsi derati o ns s urr o u n di n g i nfecti o ns are i nc or p orate d a n d sites a n d i n vesti gat ors will be trai ne d 
re gar di n g s uc h circ u msta nces. All s u bjects will be scree ne d f or t u berc ul osis (T B ) a n d s u bjects 
wit h cli nicall y  si gnifica nt acti ve i nfecti o ns will be e xcl u de d. Mali g na nc y  has bee n re p orte d i n 
s u bjects o n fil g oti ni b; i n t he prese nt trial, s u bjects will be re q uire d t o ha ve u p t o date c ol orectal 
ca ncer scree ni n g a n d s ur veilla nce a n d s u bjects wit h rece nt mali g na ncies will be e xcl u de d as 
o utli ne d i n t he i ncl usi o n criteria.  F or f urt her details a b o ut i nfecti o ns a n d mali g na ncies, please 
refere nce t he I B.
T he p ote ntial be nefits of J A K i n hi biti o n i ncl u de i m pr o ve me nt i n cli nical s y m pt o ms a n d m uc osal 
a n d e n d osc o pic heali n g. J A K i n hi biti o n ma y  be efficaci o us i n t he treat me nt of I B D base d o n 
res ults fr o m FI T Z R O Y. A l ac k of res p o nse c o nti n ge nc y after Wee k
1 0 will e na ble earl y access 
t o acti ve dr u g w he n cli nicall y i n dicate d. I n FI T Z R O Y, a n i ncrease i n mea n he m o gl o bi n 
c o nce ntrati o n was o bser ve d, wit h o ut differe nce bet wee n fil g oti ni b a n d place b o. N o cli nicall y 
si g nifica nt c ha n ges fr o m baseli ne i n mea n ne utr o p hil c o u nts or li ver f u ncti o n tests were o bser ve d 
at 1 0 wee ks. Fil g oti ni b treate d s u bjects s h o we d a n i ncrease i n H D L a n d n o si g nific a nt c ha n ge i n 
L D L. Li pi d a n d he m o gl o bi n effects re prese nt p ote ntial be nefits i n t his p o p ulati o n.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 5
0 2 A pril 2 0 1 9
A n i n de pe n de nt a n d e x perie nce d data m o nit ori n g c o m mittee ( D M C ) a p p oi nte d t o m o nit or t he 
st u d y will pr o vi de a n a d diti o nal le vel of ris k miti gati o n. T he D M C ma y a d vise t o c o nti n ue t he 
st u d y u nc ha n ge d, t o m o dif y t he st u d y, or t o disc o nti n ue t he st u d y. T he i nitial meeti n g will occ ur 
after a p pr o xi matel y 1 0 0 s u bjects ( 2 0 fr o m place b o gr o u p a n d 4 0 fr o m eac h fil g oti ni b gr o u p)
reac h Wee k 1 0. T he sec o n d meeti n g f or eac h i n d ucti o n st u d y  will i ncl u de a n i nteri m f utilit y 
a nal ys is a n d occ ur after a p pr o xi matel y 1 7 5 s u bjects ( 3 5 fr o m place b o gr o u p a n d 7 0 fr o m eac h 
fil g otini b treat me nt gr o u p) reac h Wee k 1 0. After t he f utilit y  a nalys es, t he D M C meeti n gs f or 
safety re vie w will be he l d a p pr o xi matel y o nce e ver y 4 m o nt hs or at a fre q ue nc y  deter mi ne d b y 
t he D M C. I n a d diti o n, a n e n d of i n d ucti o n a nal ys is will be perf or me d t o e val uate efficac y i n 
i n d ucti o n of b ot h d ose gr o u ps i n b ot h c o h orts.
Ta ki n g all of t hese c o nsi derati o ns i nt o acc o u nt wit h res pect t o t he fil g oti ni b pr o gra m, t he earl y
si g nals f or efficac y de m o nstrate d i n cli nical trials of C D, as well as t he be neficial fi n di n gs i n 
n o ncli nical m o dels of disease a n d t he o verall safet y, t olera bilit y , a n d P K c haracteristics of 
fil g oti ni b t hat ha ve bee n el uci date d t o date, t here is a fa v ora ble be nefit-ris k pr ofile f or t his a ge nt 
i n c o nti n ue d de vel o p me nt as a treat me nt f or U C. T he o verall ris k/be nefit bala nce of t his st u d y  is 
c o nsi dere d fa v ora ble.
F or a d diti o nal i nf or mati o n a b o ut t he ris ks of fil g oti ni b, refere nce is ma de t o t he fil g oti ni b IB.
1. 5.
C o m pli a nce
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t his pr ot oc ol, G o o d Cli nical Practice ( G C P),
a n d all a p plica ble re g ulat or y re q uire me nts.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 6
0 2 A pril 2 0 1 9
2.
O B J E C TI V E S
2. 1.
C o h ort A I n d ucti o n St u d y
T he pri mar y  o bjecti ve of C o h ort A I nd ucti o n St u d y is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g E B S re missi o n 
at Wee k
1 0
T he ke y  sec o n dar y o bjecti ves of C o h ort A I n d ucti o n St u d y are:

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
at Wee k
1 0

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g a n e n d osc o pic 
s u bsc ore of 0 at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pa re d t o place b o i n esta blis hi n g Ge b oes 
hist ol o gic re missi o n at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
(alter nati ve defi niti o n) at Wee k 1 0
T he ot her sec o n dar y o bjecti ves of C o h ort A I n d ucti o n St u d y are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of C o h ort A I n d ucti o n St u d y are:

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n i m pr o vi n g e n d osc o pic 
a p peara nce as deter mi ne d b y U C EI S sc ori n g sys te m at Wee k
1 0

T o e val uate t he ass ociati o n of c ha n ges i n sys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n , a n d fecal M M P - 9) 
wit h cli nical o utc o mes

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , 
disease pr o gressi o n a n d treat me nt res p o nse t o fil g oti ni b 

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n ac hie vi n g n o vel hist ol o gic 
o utc o mes (e g, res ol uti o n of basal plas mac yt osis)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 7
0 2 A pril 2 0 1 9
2. 2.
C o h ort B I n d ucti o n St u d y
T he pri mar y  o bjecti ve of C o h ort B I n d ucti o n St u d y is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g E B S re missi o n 
at Wee k
1 0
T he ke y  sec o n dar y o bjecti ves of C o h ort B I n d ucti o n St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n
at Wee k
1 0

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g a n e n d osc o pic 
s u bsc ore of 0 at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g Ge b oes 
hist ol o gic re missi o n at Wee k
1 0

T o e val ua te t he efficac y of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
(alter nati ve defi niti o n) at Wee k 1 0
T he ot her sec o n dar y  o bjecti ves of C o h ort B I n d ucti o n St u d y are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b 

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y o bjecti ves of C o h ort B I n d ucti o n St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n i m pr o vi n g e n d osc o pic 
a p peara nce as deter mi ne d b y  U C EI S sc ori n g sys te m at Wee k
1 0

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P - 9) 
wit h cli nical o utc o mes

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h o st ge netics a n d ot her mar kers wit h disease se verit y, 
disease pr o gressi o n a n d treat me nt res p o nse t o fil g oti ni b 

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n ac hie vi n g n o vel hist ol o gic 
o utc o mes (e g, res ol uti o n of basal plas mac yt osis)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 8
0 2 A pril 2 0 1 9
2. 3.
M ai nte n a nce St u d y
T he pri mar y  o bjecti ve of t he Mai nte na nce St u d y is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g E B S re missi o n 
at Wee k
5 8 i n s u bjec ts 
T he ke y  sec on dar y  o bjecti ves of t he Mai nte na nce St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g s ustai ne d E B S 
re missi o n at Wee k 5 8, defi ne d as E B S re missi o n at b ot h Wee ks
1 0 a n d 5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g 6 -m o nt h 
c ortic oster oi d -free E B S re missi o n at Wee k
5 8 

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g a n e n d osc o pic 
s u bsc ore of 0 at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g Ge b oes 
hist ol o gic re missi o n at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
(alter nati ve defi niti o n) at Wee k 5 8
T he ot her sec o n dar y  o bjecti ves of t he Mai nte na nce St u d y are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b 

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of t he Mai nte na nce Stu d y  are:

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n i m pr o vi n g e n d osc o pic 
a p peara nce as deter mi ne d b y U C EI S sc ori n g sys te m at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g s ustai ne d M C S 
re missi o n at Wee k 5 8, defi ne d as re missi o n at b ot h Wee ks
1 0 a n d 5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g 6- m o nt h 
c ortic oster oi d -free M C S re missi o n at Wee k
5 8

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P - 9) 
wit h cli nical o utc o mes

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 3 9
0 2 A pril 2 0 1 9

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se ver it y, 
disease pr o gressi o n a n d treat me nt res p o nse t o fil g oti ni b i n s u bjects wit h U C

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n ac hie vi n g n o vel hist ol o gic 
o utc o mes (e g, res ol uti o n of basal plas mac yt osis)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 0
0 2 A pril 2 0 1 9
3.
S T U D Y D E SI G N
3. 1.
E n d p oi nts
3. 1. 1.
C o h ort A I n d ucti o n St u d y
T he p ri mar y e n d p oi nt is :

T he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k
1 0
T he k e y sec o n dar y e n d p oi nts are:

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g a n e n d osc o pic s u bsc ore of 0 at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g Ge b oes hist ol o gic r e missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n (alter nati ve defi niti o n)
at Wee k
1 0
T he ot her sec o n dar y e n d p oi nts are:

P K c haracteristics f or fil g oti ni b a n d its meta b olite G S - 8 2 9 8 4 5 
T he e x pl orat or y  e n d p oi nts are:

C ha n ge fr o m baseli ne i n U C EI S at Wee k
1 0

Ass ociati o n bet wee n c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P - 9)
wit h cli nical o utc o mes

St o ol micr o bi o me assess me nts

Ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , disease pr o gressi o n,
a n d treat me nt res p o nse t o fil g oti ni b

C ha n ge fr o m baseli ne i n H R Q o L  sc ores at Wee k
1 0

H C R U assess me nts at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g n o vel hist ol o gic o utc o mes at Wee k 1 0

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 1
0 2 A pril 2 0 1 9
3. 1. 2.
C o h ort B I n d ucti o n St u d y
T he p ri mar y e n d p oi nt is :

T he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k
1 0
T he k e y  sec o n dar y e n d p oi nts are:

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g a n e n d osc o pic s u bsc ore of 0 at Wee k
1 0

T he pr o p orti o n of s u bje cts ac hie vi n g Ge b oes hist ol o gic r e missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n (alter nati ve defi niti o n)
at Wee k 1 0
T he ot her sec o n dar y  e n d p oi nts are:

P K c haracteristics f or fil g oti n i b a n d its meta b olite G S- 8 2 9 8 4 5
T he e x pl orat or y  e n d p oi nts are:

C ha n ge fr o m baseli ne i n U C EI S at Wee k
1 0

Ass ociati o n bet wee n c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P - 9)
wit h cli nical o utc o mes

St o ol micr o bi o me assess me nts

Ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , disease pr o gressi o n,
a n d treat me nt res p o nse t o fil g oti ni b

C ha n ge fr o m baseli ne i n H R Q o L  sc ores at Wee k
1 0

H C R U assess me nts at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g n o vel hist ol o gic o utc o mes at Wee k 1 0
3. 1. 3.
M ai nte n a nce St u d y
T he p ri mar y e n d p oi nt is :

T he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k
5 8

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 2
0 2 A pril 2 0 1 9
T he k e y  sec o n dar y e n d p oi nts are:

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g s ustai ne d E B S re missi o n, defi ne d as E B S re missi o n at 
b ot h Wee ks
1 0 a n d 5 8

T he pr o p orti o n of s u bjects ac hie vi n g 6- m o nt h c ortic oster oi d -free E B S re missi o n at Wee k
5 8 

T he pr o p orti o n of s u bjects ac hie vi n g e n d osc o pic re missi o n at Wee ks
5 8

T he pr o p orti o n of s u bjects ac hie vi n g Ge b oes hist ol o gic r e missi o n at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n (alter nati ve defi niti o n)
at Wee k 5 8
T he ot her sec o n dar y  e n d p oi nts are:

P K c haracteristics f or fi l g oti nib a n d its meta b olite G S- 8 2 9 8 4 5
T he e x pl orat or y  e n d p oi nts are:

C ha n ge fr o m baseli ne i n U C EI S at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g s ustai ne d M C S re missi o n, defi ne d as M C S re missi o n at 
b ot h Wee ks
1 0 a n d 5 8

T he pr o p orti o n of s u bjects ac hie vi n g 6- m o nt h c ortic oster oi d -free M C S re missi o n at Wee k
5 8

Ass ociati o n bet wee n c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P - 9)
wit h cli nical o utc o mes

St o ol micr o bi o me assess me nts

Ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , disease pr o gressi o n,
a n d treat me nt res p o nse t o fil g oti ni b i n s u bjects wit h U C

C ha n ge fr o m baseli ne i n H R Q o L  sc ores at Wee k
5 8

H C R U assess me nts at Wee k
5 8

T he pr o p o rti o n of s u bjects ac hie vi n g n o vel hist ol o gic o utc o mes at Week 5 8

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 3
0 2 A pril 2 0 1 9
3. 2.
St u d y Desi g n
T hese are c o m bi ne d P hase 2 b/ 3, d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d st u dies e val uati n g 
t he efficac y a n d safet y of fil g oti ni b i n t he i n d ucti o n a n d mai nte na nce of re missi o n i n s u bjects 
wit h m o deratel y t o se verel y acti ve U C . A sc he matic of t his st u d y  is pr o vi de d i n Fi g ure 3- 1 .
Fi g ure 3- 1.
St u d y Sc he m a
FI L = fil g oti ni b; P B O = place b o ; m g = milli gra m.
N o n -res p o n der s are s u bjects w h o ac hie ve n eit her E B S re missi o n n or M C S res p o nse
at Wee k
1 0
S u bjects i n t he Mai nte na nce St u d y t hat meet disease w orse ni n g criteria (see Secti o n 3. 6 ) will be offere d o pe n -la bel fil g oti ni b.
T his st u d y i ncl u des:

Scree ni n g ( Da y s -3 0 t o -1)

Ra n d o mizati o n ( Da y 1)

Bli n de d I n d ucti o n St u dies ( D a y 1 t o Wee k
1 1)

C o h orts A a n d B Wee k
1 0 efficac y assess me nts
■
At Wee k
1 0, M C S t o assess M C S res p o nse or E B S re missi o n

Bli n de d Bri d ge P hase ( Wee k
1 0 t o 1 1): D osi n g will c o nti n ue i n a bli n de d fas hi o n t hr o u g h 
t he e n d of Wee k
1 0 u ntil re -ra n d o mizati o n at Wee k 1 1

Re -ra n d o mizati o n ( Wee k 1 1)

S u bjects i n C o h orts A a n d B w h o c o m plete t he I n d ucti o n St u d y  a n d ac hie ve eit her E B S 
re missi o n or M C S res p o nse at Wee k
1 0 will be re -ra n d o mize d i nt o t he Mai nte na nce 
St u d y at Wee k 1 1

S u bjects w h o ac hie ve n eit her E B S re missi o n n or M C S res p o nse at Wee k
1 0 will ha ve t he 
o pti o n t o e nter a se parate, L o n g - Ter m E xte nsi o n (L T E ) st u d y ( G S-U S -4 1 8 -3 8 9 9)
 
 
 
 
 
 
 
  
   
 
 
 
 
     
    
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 4
0 2 A pril 2 0 1 9

Bli n de d Mai nte na nce St u d y  (Wee ks
1 1 t o 5 8)

P ost -Treat me nt ( P T) safet y  assess me nts: 

S u bjects w h o o pt o ut of t he L T E st u d y (G S -U S - 4 1 8 -3 8 9 9) will ret ur n 3 0 d a y s after t he 
last d ose of st u d y dr u g f or P T x safet y assess me nts

S u bjects w h o c o m plete all pr oce d ures per pr ot oc ol, i ncl u di n g t he e n d osc o p y, of t he 
5 8 -wee k st u d y will be offere d t he o pti o n t o c o nti n ue i nt o t he LT E st u d y 
( G S-U S - 4 1 8- 3 8 9 9)

S u bjects w h o are eli gi ble a n d o pt t o partici pate i n t he L T E st u d y ( G S-U S -4 1 8 -3 8 9 9) ca n 
c o nti n ue i nt o t he st u d y wit h o ut P T x safet y assess me nts
3. 3.
St u d y Tre at me nts
Base d o n pr ot oc ol eli gi bilit y  criteria, s u bjects will be scree ne d f or e nr oll me nt i n eit her C o h ort A 
or C o h ort B.
S u bjects w h o meet pr ot oc ol eli gi bilit y criteria will be assi g ne d t o t he res pecti ve C o h ort a n d 
s u bse q ue ntl y ra n d o mize d in a bli n de d fas hi o n i n a 2: 2 : 1 rati o t o 1 of 3 treat me nts as f oll o ws:
Tre at me nt Gr o u ps (I n d ucti o n St u d y)
Tre at me nt Gr o u p 1 ( n = 2 6 0) : fil g oti nib 2 0 0 m g a n d place b o -t o-matc h ( P T M) fil g oti ni b 
1 0 0 m g , o nce daily
Tre at me nt Gr o u p 2 ( n = 2 6 0 ): fil g oti nib 1 0 0 m g a n d P T M fil g oti ni b 2 0 0 m g , o nce dail y
Tre at me nt Gr o u p 3 ( n = 1 3 0 ): P T M f il g oti ni b 2 0 0 m g a n d P T M fil g oti ni b 1 0 0 m g , o nce dail y
N ote: U S a n d K orea males w h o ha ve n ot faile d at least t w o bi ol o gic t hera pies (a n y T N F α 
a nta g o nist a n d ve d oliz u ma b) will be ra n d o mize d i n a 2: 1 rati o t o eit her fil g oti ni b 1 0 0 m g or 
matc hi n g place b o.
Wit hi n eac h C o h ort, treat me nt assi g n me nts will be stratifie d acc or di n g t o t he f oll o wi n g fact ors i n 
t he In d ucti o n a n d Mai nte na nce st u dies:
Str atific ati o n F act ors ( C o h ort A, Bi ol o gic N aï ve I n d ucti o n St u d y )

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds ( e g, pre d nis o ne) at Da y 1 
( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors ( e g, 6- merca pt o p uri ne ( 6 -M P ), azat hi o pri ne, M T X)
at Da y 1 ( Yes or N o)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 5
0 2 A pril 2 0 1 9
Str atific ati o n F act ors ( C o h ort B, Bi ol o gic E x perie nce d I n d ucti o n St u d y )

E x p os ure t o o ne bi ol o gic a ge nt vers us m ore t ha n o ne bi ol o gic a ge nt

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds ( e g, pre d nis o ne) at Da y 1 
( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors ( e g, 6- M P, azat hi o pri ne, M T X)
at Da y 1 ( Yes or N o)
Str atific ati o n F act ors ( M ai nte n a nce St u d y )

Partici pati o n i n C o h ort A or C o h ort B

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds ( e g, pre d nis o ne) at Da y 1 
( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors ( e g, 6- M P, azat hi o pri ne, M T X)
at Da y  1 ( Yes or N o)

S u bjects fr o m C o h orts A a n d B w h o are eli gi ble f or t he Mai nte na nce St u d y  will be 
re-ra n d o mize d t o treat me nt as f oll o ws:
T a ble 3- 1.
Re -r a n d o miz ati o n f or M ai nte n a nce St u d y
Tre at m e nt Assi g n me nt I n d ucti o n St u dies
C o h orts A a n d B
M ai nte n a nce St u d y
Re -r a n d o miz ati o n:
Treat me nt 1, fil g oti ni b 2 0 0 m g 
Treat me nt 1, 2 0 0 m g
Treat me nt 3, Place b o
Treat me nt 2, f il g oti ni b 1 0 0 m g 
Treat me nt 2, 1 0 0 m g
Treat me nt 3, Place b o
Treat me nt 3, Place b o
C o nti n ue Treat me nt 3, Place b o
N ote : S u bjects recei vi n g Treat me nt 1 or 2 i n t he I n d ucti o n st u d y wi ll be ra n d o mize d i n a 2: 1 ma n ner t o eit her c o nti n ue o n t he
assi g ne d fil g oti ni b re gi me n or t o place b o f or t he d urati o n of t he Mai nte na nce st u d y.
3. 4.
D ur ati o n of Tre at me nt
Ra n d o mize d s u bjects will recei ve a ma xi m u m of 5 8 wee ks of st u d y  dr u g. S u bjects w h o are 
n o n- res p o n ders base d o n t he res ults of t he W ee k 1 0 assess me nts will be offere d t he o pti o n t o 
recei ve o pe n -la bel fil g oti ni b b y  e nteri n g i nt o t he L T E st u d y ( G S-U S - 4 1 8-3 8 9 9 ).
S u bjects meeti n g disease w orse ni n g criteria at Wee k
1 1 or later m ust be disc o nti n ue d fr o m 
bli n de d treat me nt a n d will be offere d t he o pti o n t o recei ve o pe n -la bel fil g oti ni b i n t he LT E st u d y  
( See S ecti o n 3. 6 , Disease W orse ni n g Criteria ).
S u bjects w h o c o m plete t he Wee k 5 8 visit will ha ve t he o pti o n t o c o nti n ue st u d y  dr u g i n a bli n de d 
fas hi o n i n t he L T E st u d y.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 6
0 2 A pril 2 0 1 9
3. 5.  
Criteri a f or St u d y Dr u g Interr u pti o n or D isc o nti n u ati o n
3. 5. 1.
St u d y Dr u g I nterr u pti o n C o nsi der ati o ns
T he Gilea d Me dical M o nit or s h o ul d b e c o ns ulte d pri or t o st u d y dr u g i nterr u pti o n w he n
me dicall y  feasi ble. St u d y dr u g i nterr u pti o n s h o ul d be c o nsi dere d i n t he f oll o wi n g circ u msta nces; 
pri or t o res u m pti o n of st u dy dr u g, t he i nvesti g at or s h o ul d disc uss t he c ase wit h t he 
Gile a d M e dic al M o nit or :

I nterc urre nt ill ness t hat w o ul d, i n t he j u d g me nt of t he i n vesti gat or, affect assess me nts of
cli nical stat us t o a si g nifica nt de gree.

S u bject is sc he d ule d f or electi ve or e mer ge nc y  s ur ger y (e xcl u di n g mi n or s ki n pr oce d ures
u n der l ocal or n o a nest hesia); ti mi n g of st u d y dr u g pa usi n g s h o ul d be deter mi ne d i n
c o ns ultati o n wit h t he Gilea d M e dical M o nit or.

A n y  s u bject w h o de vel o ps a ne w i nfecti o n d uri n g t he st u d y s h o ul d u n der g o pr o m pt a n d
c o m plete dia g n ostic testi n g a p pr o priate f or a n i m m u n oc o m pr o mise d i n di vi d ual, a n d t he
s u bject s h o ul d be cl osely m o nit ore d.
N O T E: D uri n g t he ti me of st u dy dr u g i nterr u pti o n f or a ny of t he a b ove, t he s u bject m ay c o nti n ue 
t o h ave st u dy visits a n d t o t ake p art i n pr oce d ures a n d assess me nts, if dee me d me dic ally 
a p pr o pri ate by t he i nvesti g at or.
3. 5. 2.
St u d y Dr u g D isc o nti n u ati o n C o nsi der ati o ns
T he Gilea d Me dical M o nit or s h o ul d be c o ns ulte d pri or t o st u d y dr u g disc o nti n uati o n w he n
me dicall y  feasi ble.
St u d y  dr u g m ust be per ma ne ntl y  disc o nti n ue d i n t he f oll o wi n g i nsta nces:

A n y  o p p ort u nistic i nfecti o n

A n y  seri o us i nfecti o n t hat re q uires a nti micr o bial t hera py or h os pitalizati o n, or a n y i nfecti o n
t hat meets S A E re p orti n g criteria

Fe brile ne utr o pe nia (te m perat ure > 3 8. 3° C or a s ustai ne d te m perat ure of > 3 8° C f or m ore 
t ha n o ne h o ur) wit h a bs ol ute ne utr o p hil c o u nt of < 1, 0 0 0/ m m3

S y m pt o matic a ne mia (e g, si g ns/s y m pt o ms i ncl u di n g pall or, s h ort ness of breat h, ne w heart 
m ur m ur, pal pitati o ns, let har g y , fati g ue ) wit h he m o gl o bi n < 7. 5 g/ d L , or if tra nsf usi o n is 
i n dicate d re gar dless of he m o gl o bi n val ue

C o m plicate d her pes z oster i nfecti o n ( wit h m ulti -der mat o mal, disse mi nate d, o p ht hal mic, or
C N S i n v ol ve me nt)

E vi de nce of acti ve H C V d uri n g t he st u d y, as e vi de nce d b y H C V R N A p ositi vit y

E vi de nce of acti ve H B V d uri n g t he st u d y, as e vi de nce d b y H B V D N A p ositi v it y

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 7
0 2 A pril 2 0 1 9

U nacce pta ble t o xicit y or t o xicit y  t hat, i n t he j u d g me nt of t he i n vesti gat or, c o m pr o mises t he
s u bject’s a bilit y t o c o nti n ue st u d y-s pecific pr oce d ures or is c o nsi dere d t o n ot be i n t he
s u bject’s best i nterest

S u bject re q uest t o disc o nti n ue f or a n y reas o n

S u bject n o nc o m plia nce

Pre g na nc y  d uri n g t he st u d y; refer t o Secti o n 7. 7. 2. 1

Disc o nti n uati o n of t he st u d y  at t he re q uest of Gilea d, a re g ulat or y a ge nc y or a n i nstit uti o nal
re vie w b oar d or i n de pe n de nt et hics c o m mittee (I R B/I E C)

S u bject use of pr o hi bite d c o nc urre nt t hera p y m ay tri g ger st u d y dr u g disc o nti n uati o n;
c o ns ultati o n s h o ul d be ma de wit h t he Gilea d M e dical M o nit or.

La b orat or y  Criteria : After bec o mi n g a ware of a n y  of t he bel o w descri be d a b n or mal 
la b orat or y c ha n ges occ urri n g at a n y o ne ti me, a n u nsc he d ule d visit (ie, se q ue ntial visit) 
s h o ul d occ ur t o retest wit hi n 3 t o 7 da y s (e xce pt creati ni ne, w hic h s h o ul d be reteste d 7 t o
1 4 da y s a part).

2 se q ue ntial ne utr o p hil c o u nts < 7 5 0 ne utr o p hils/ m m 3 ( SI: < 0. 7 5 x 1 0 9 cells/ L)

2 se q ue ntial platelet c o u nts < 7 5, 0 0 0 platelets/ m m 3 ( SI: < 7 5. 0 x 1 0 9 cells/ L)

2 se q ue ntial as partate a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) 
ele vati o ns > 3 x t he u p per li mit of n or mal ( U L N) a n d at least o ne of t he f oll o wi n g 
c o nfir me d val ues: 
■
t otal bilir u bi n > 2 x U LN 
■
I N R > 1. 5
■
or acc o m pa nie d b y s y m pt o ms c o nsiste nt wit h he patic i nj ur y
F or a n y s u bject wit h a n i niti al A S T or A L T ele vati o n > 3 x t he U L N, at t he ti me of t he 
sec o n d c o nfir m at or y dr a w , a n IN R, pr ot hr o m bi n ti me ( P T) a n d partial t hr o m b o plasti n 
ti me ( P T T) m ust als o be dra w n

2 se q ue ntial A S T or A L T > 5 x U L N

2 se q ue ntial val ues f or esti mate d creati ni ne cleara nce ( Cr Cl) < 3 5 m L/ mi n base d o n t he 
C oc k cr oft Ga ult ( C C & G) f or m ula
Male 
[( 1 4 0 – a ge i n ye ars) × ( wei g ht i n k g)] / [ 7 2 × (ser u m creati ni ne i n m g/ d L)] = 
C L cr ( m L/ mi n)
Fe male [( 1 4 0 – a ge i n years) × ( wei g ht i n k g) × 0. 8 5] / [ 7 2 × (ser u m creati ni ne 
i n m g/ d L)] = C Lcr ( m L/ mi n)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 4 8
0 2 A pril 2 0 1 9

S u bjects are free t o wit h dra w fr o m t he st u d y  at a n y ti me wit h o ut pr o vi di n g reas o n(s) f or 
wit h dra wal a n d wit h o ut prej u dice t o f urt her treat me nt. T he reas o n(s) f or wit h dra wal will be 
d oc u me nte d i n t he electr o nic case re p ort f or m (e C R F).

S u bjects w h o per ma ne ntl y disc o nti n ue st u d y dr u g f or a n y reas o n s h o ul d disc uss t heir 
c o nti n ue d care pla n wit h t heir p h y sicia ns.

S u bjects w h o per ma ne ntl y disc o nti n ue st u d y dr u g f or pre g na nc y s h o ul d n ot c o nti n ue i n t he 
st u d y; if t here are a ny q uesti o ns re gar di n g per ma ne nt disc o nti n uati o n, t hese s h o ul d be 
disc usse d wit h t he S p o ns or.

S u bjects wit h dra wi n g fr o m t he st u d y  s h o ul d c o m plete Early Ter mi nati o n ( E T), f oll o we d b y 
P ost -Treat me nt ( P T x) assess me nts 3 0 da y s after t he last d ose of st u d y dr u g.
Reas o na ble eff orts will be ma de t o c o ntact s u bjects w h o are l ost t o f oll o w -u p. All c o ntacts a n d 
c o ntact atte m pts m ust be d oc u me nte d i n t he s u bject’s file.
T he S p o ns or has t he ri g ht t o ter mi nate t he st u d y  at a n y ti me i n case of safet y c o ncer ns or if
s pecial circ u msta nces c o ncer ni n g t he st u dy me dicati o n or t he c o m pa n y itself occ ur, ma ki n g
f urt her treat me nt of s u bjects i m p ossi ble. In t his e ve nt, t he i n vesti gat or(s) a n d rele va nt a ut h orities
will be i nf or me d of t he reas o n f or st u d y ter mi nati o n.
3. 6.
Dise ase W orse ni n g Criteri a
S u bjects meeti n g t he f oll o wi n g disease w orse ni n g criteria e val uate d starti n g at Wee k
1 1 m ust be 
disc o nti n ue d fr o m bli n de d treat me nt a n d will be offere d t he o pti o n t o recei ve o pe n -la bel 
fil g oti ni b b y  e nteri n g i nt o t he se parate L T E st u d y ( G S-U S - 4 1 8- 3 8 9 9).

Disease w orse ni n g starti n g at 1 1 wee ks of t hera p y  is base d o n t he f oll o wi n g criteria: partial 
M C S sc ore (all c o m p o ne nts of M C S e xce pt f or e n d osc o pic s u bsc ore) i ncrease of ≥3 p oi nts 
t o at least 5 p oi nts fr o m t he Wee k
1 0 val ue o n t w o c o nsec uti ve visits, or a n i ncrease t o 
9 p oi nts o n t w o c o nsec uti ve visits if t he Wee k
1 0 val ue is > 6.

T he disease w orse ni n g visits ma y  i ncl u de u nsc he d ule d visits (e g, a st u dy visit f oll o we d 
b y  a n u nsc he d ule d visit, or 2 se q ue ntial u nsc he d ule d visits a n yti me fr o m Wee k 1 1 
o n war d ).

Disease w orse ni n g t o t he e xte nt t hat t he s u bject cli nicall y re q uires me dicati o ns pr o hi bite d b y 
t he st u d y (at i n vesti gat or discreti o n, wit h disc ussi o n wit h me dical m o nit or if feasi ble); t hese 
s u bjects d o n ot q ualif y f or t he L T E st u d y.
3. 7.
E n d of St u d y
E n d of St u d y  is defi ne d as w he n t he last s u bject has c o m pleted 5 8 wee ks of treat me nt pl us 
3 0 da y s f oll o w-u p.

Fil g o ti ni b 
Pr ot o c o l G S -U S- 4 1 8 -3 8 9 8 
Gil e a d S ci e n c es , I nc. 
3. 8. 
P o st St u dy C a r e 
Fi na l 
A m e n d m e nt 5 
A ll s u bje cts c om pl eti n g all stu d y rel at e d pr o c e dur es i n clu di n g e n d os c o p y at W e e k 5 8 wi ll b e 
off e re d a n o p p ort u n it y t o p a1t i ci p at e i n t h e L T E st u d y ( G S-U S- 4 1 8- 3 8 9 9). F o r t hos e s ubj e cts 
w h o d o n ot p aiti ci p at e i n th e LT E stu d y , aft er t h e s u bje ct h as c om pl et e d t h eir st ud y p aiti c i pati o n, 
th e l o n g-te 1 m cai·e of t h e p aiti c i pa nt wi ll re m ai n th e res p onsi bi lit y of t h eir pr i ma 1 y tr e ati n g 
p h ys icia ns. 
3. 9. 
3. 9. 1. 
Bi o m a r k e r T e sti ng 
Bi o m a r k e r S a m pl e s t o A d d r e ss t he S t u dy O bj e cti v es 
T h e f ollo w i ng bi ol o g ic al s p e ci m ens wi ll b e c o lle ct e d i n thi s st ud y a nd wi ll b e us e d t o e v al uat e 
th e ass o ci ati o n of e x pl or at o1y s yst e mi c a n d/ or tissu e s p e cifi c bi o m ai· kers wit h st u d y d m g 
r es p o ns e, i ncl u di n g effi c a c y a n d/ or A Es a nd t o h el p i nf o1 m  t h e m e c h a n is m of a cti o n a n d 
m e c h a nis m of i ntri nsi c a n d a c q uire d resist an ce t o fil g oti ni b i n U C. T h e s p e cifi c a n al ys es wi ll 
i ncl u d e , b ut wi ll n ot b e li mit e d t o, t h e bi o m ai· ker s a m pl e a n d ass a ys list e d b e lo w. 
• 
C o l o n bi o psi es t o ass ess t h e ass o ciati o n of JA K sig n a li ng, i nfl a m m ati o n, i mm u n e st at us a n d 
cli nic al o ut c o m es. T h e p ot e nti al bi o mai· ker a n alys es i nclu d e t h e e x pr essi on of p S T A T a nd 
M M P- 9, ti ss u e ly m p h o c yt e s ubs ets a n d tran s cri pt o m e. 
• 
St o o l i ni cr o bi o m e t o u n d erst a n d h o w c h a n g es of g ut fl or a c oI Tel at e wit h m u c os al he ali ng, 
im m u n e st at us a n d tre at m e nt eff e ct 
• 
Pl as m a a n d s er n m s a m pl es f or p ot e n ti al a nal ys is of circ ulati ng f a ct ors i n cl u di n g b ut n ot 
li mit e d t o c yt oki n es, mi R N A a n d m et a b o lo m e 
• 
P a x g e n e bl o o d s a m pl es f or leu k o c yt e g e n e e x pr ess i o n a n alys es 
• 
W h ol e bl o o d s a m pl e f or p ot e nti a l B- c ell/ T -c ell r e c e pt or re pe 1t oir e s e q u e n ci ng 
I 
• 
Vi a bl y fr o z en p er i p her al blo o d m o n o n u cleai· c ells ( vf PB M Cs) t o ass ess i nfla m mat o 1 y 
si g n ali n g p at h w a y a n d im m u n e ce ll s ubs et a n al ysis ( vf PB M C s a m pl e c o lle cti o n at U S a n d 
C a n a di an si t es o n l y) 
B e c a us e bi o mai· ker s ci en c e is a r a pi dl y e v ol vi ng ar e a of i nv est ig at i o n, a n d A Es i n p aiti c u lar ai·e 
di ffi c ult t o pr e di ct , it is n ot p ossi bl e t o s p e cif y pr os p e cti v e l y all t ests t hat wi ll b e d o n e o n t h e 
s p e ci m ens pr o v id e d . T h e t esti ng o utli n e d a b o v e is b as e d u p o n t h e c m Tent st at e of s ci en tifi c 
k n o wl e d g e . It m a y b e m o difi e d d uri n g or aft er t h e e n d of t h e st u d y t o r e m o v e t ests n o l on g er 
i ndi c at e d a n d/ o r t o a d d n e w t ests b as e d u p o n t h e gr o wi n g st at e of r ut k n o wl e d g e . 
S p e ci m e ns wi ll b e c oll e ct e d fr o m all s ubj e cts w h o pr o vi d e c on s en t. 
C O N FI D E N TI A L 
P a g e 4 9 
0 2 A pril 2 0 1 9 

Fil g o ti ni b 
Pr ot o c ol G S -U S- 4 1 8 -3 8 9 8 
Gil e a d S c i e nc es , I n c. 
Bi o m ar ker s am pl e c o lle cti on fre q u en c y is list e d i n A p p e n di x 2. 
-
C O N FI D E N TI A L 
P a g e 5 0 
Fi n al 
A m e n d m e nt 5 
0 2 A pril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 1
0 2 A pril 2 0 1 9
4.
S U B J E C T P O P U L A TI O N
4. 1.  
N u m ber of S u bjects a n d S u bject Selecti o n
C o h ort A I n d ucti o n St u d y
A p pr o xi matel y 6 5 0 s u bjects w h o meet eli gi bilit y criteria at scree ni n g will be ra n d o mize d i n a 
bli n de d fas hi o n t o recei ve fil g oti ni b 2 0 0 m g, fil g oti ni b 1 0 0 m g, or matc hi n g place b o i n a 
2: 2 : 1 rati o, res pecti vely.
C o h ort B I n d ucti o n St u d y
A p pr o xi matel y  6 5 0 s u bjects w h o meet eli gi bilit y criteria at scree ni n g will be ra n d o mize d i n a 
bli n de d fas hi o n t o recei ve fil g oti ni b 2 0 0 m g, fil g oti ni b 1 0 0 m g, or matc hi n g place b o i n a 
2: 2 : 1 rati o, res pecti vely. 
M ai nte n a nce St u d y
S u bjects fro m C o h orts A a n d B w h o meet eit her M C S res p o nse
or E B S re missi o n criteria will be 
re-ra n d o mize d at Wee k
1 1 i n a bli n de d fas hi o n i n a 2 : 1 rati o t o eit her t he sa me d ose of fil g oti ni b 
or place b o . Refer t o Secti o n 3. 3 , Ta ble 3- 1 .
I n or der t o ma na ge t he t otal st u d y e nr oll me nt, Gilea d, at its s ole discreti o n, ma y s us pe n d 
scree ni n g a n d/ or e nr oll me nt at a ny site or st u d y- wi de at a n y  ti me.
4. 2. 
I n d ucti o n St u d y ( C o h orts A a n d B)
4. 2. 1. 
I ncl usi o n Criteri a
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or partici pati o n i n eit her 
t he C o h ort A or B I n d ucti o n St u d y.
1)
M ust ha ve t he a bilit y  t o u n dersta n d a n d si g n a writte n i nf or me d c o nse nt f or m, w hic h m ust be 
o btai ne d pri or t o i nitiati o n of st u d y  pr oce d ures
2)
Males or n o n -pre g na nt, n o n -lactati n g fe males, a ges 1 8 t o 7 5 ye ars, i ncl us i ve base d o n t he 
date of t he scree ni n g visit
3)
Fe males of c hil d beari n g p ote ntial (as defi ne d i n A p pe n di x 6 ) m ust ha ve a ne gati ve pre g na nc y  
test at scree ni n g a n d baseli ne
4)
Male s u bjects a n d fe male s u bjects of c hil d beari n g p ote ntial w h o e n ga ge i n heter ose x ual 
i nterc o urse m ust a gree t o use pr ot oc ol s pecifie d met h o d(s) of c o ntrace pti o n as descri be d i n 
A p pe n di x 6

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 2
0 2 A pril 2 0 1 9
5)
D oc u me nte d dia g n osis of U C of at least 6 m o nt hs A N D wit h a mi ni m u m disease e xte nt of 
1 5 c m fr o m t he a nal ver ge. D oc u me ntati o n s h o ul d i ncl u de e n d osc o pic a n d hist o pat h ol o gic 
e vi de nce of U C as foll o ws:
a)
T he criteria f or d oc u me ntati o n of U C base d o n e n d osc o p y  will be me dical rec or d 
d oc u me ntati o n of, or a n ile oc ol o n osc o p y (f ull c ol o n osc o p y wit h t he i nt u bati o n of t he 
ter mi nal ile u m) re p ort date d  ≥ 6 m o nt hs bef ore e nr oll me nt, w hic h s h o ws feat ures 
c o nsiste nt wit h U C, deter mi ne d b y t he pr oce d ure perf or mi n g p h ysicia n
b)
T he criteria f or d oc u me ntati o n of U C base d o n hist o pat h ol o g y  will be me dical rec or d 
d oc u me ntati o n of or a hist o pat h ol o g y  re p ort i n dicati n g feat ures c o nsiste nt wit h U C as 
deter mi ne d b y t he pa t h ol o gist
6)
A s ur veilla nce c ol o n osc o p y  is re q uire d pri or t o scree ni n g i n s u bjects wit h a hist or y of U C f or 
8 or m ore ye ars, if o ne was n ot perf or me d i n t he pri or 2 4 m o nt hs
7)
M o deratel y t o se verel y acti ve U C as deter mi ne d b y a c e ntrall y rea d e n d osc o p y sc ore ≥2, a 
rectal blee di n g sc ore ≥ 1, a st o ol fre q ue nc y  sc ore ≥ 1 a n d P G A of ≥ 2 as deter mi ne d b y t he 
Ma y o cli nic sc ori n g s ys te m (refere nce A p pe n di x 4 ) wit h e n d o sc o py occ ur ri n g d uri n g 
scree ni n g; t otal sc ore m ust be bet wee n 6 a n d 1 2, i ncl usi ve.
8)
Meet o ne of t he f oll o wi n g T B scree ni n g criteria:
a)
N o e vi de nce of acti ve or late nt T B:
i)
A ne gati ve Q ua nti F E R O N ® T B -G ol d I n -T u be test ( or ce ntrall y re p orte d e q ui vale nt 
assa y) at scree ni n g, A N D
ii) A c hest ra di o gra p h ( vie ws as per l ocal g ui deli nes) ta ke n at s cree ni n g or wit hi n t he 
3 m o nt hs pri or t o scree ni n g ( wit h t he re p ort or fil ms a vaila ble f or i n vesti gat or re vie w) 
wit h o ut e vi de nce of acti ve or late nt T B i nfecti o n , A N D
iii) N o hist or y  of eit her untreate d or i na de q uatel y treate d late nt or acti ve T B i nfecti o n
b)
Pre vi o usl y  treate d f or T B: ie, if a s u bject has pre vi o usl y recei ve d a n a de q uate c o urse of 
t hera py as per l ocal sta n dar d of care f or eit her late nt T B ( e g, 9 m o nt hs of is o niazi d i n a 
l ocati o n w here rates of pri mar y m ulti- dr u g resista nt T B i nfecti o ns are < 5 % or a n 
acce pta ble alter nati ve re gi me n) or acti ve T B (acce pta ble m ulti -dr u g re gi me n). I n t hese 
cases, n o Q ua nti F E R O N ® T B- G ol d I n -T u be test ( or ce ntrall y re p orte d e q ui vale nt assa y) 
nee d be o btai n e d, b ut a c hest ra di o gra p h m ust be o btai ne d if n ot d o ne s o wit hi n 3 m o nt hs 
pri or t o scree ni n g ( wit h t he re p ort or fil ms a vaila ble f or i n vesti gat or re vie w). I t is t he 
res p o nsi bilit y of t he i n vesti gat or t o verif y t he a de q uac y of pre vi o us a nti- T B treat me nt 
a n d pr o vi de a p pr o priate d oc u me ntati o n.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 3
0 2 A pril 2 0 1 9
c)
Ne wl y i de ntifie d late nt T B d uri n g scree ni n g: ie, a s u bject w h o has a ne wl y i de ntifie d 
p ositi ve dia g n ostic T B test res ult ( defi ne d as a p ositi ve Q ua nti F E R O N ® T B G ol d i n T u be
test [ or ce ntrall y re p orte d e q ui vale nt assa y]) i n w hic h acti ve T B has bee n r ule d o ut a n d 
f or w hic h a p pr o priate, o n g oi n g, pr o p h yl actic treat me nt f or late nt T B has bee n i nitiate d 
f or a mi ni m u m of 4 wee ks pri or t o t he first a d mi nistrati o n of st u d y me dicati o n. A de q uate 
treat me nt f or late nt T B is defi ne d acc or di n g t o l ocal c o u ntr y g ui deli nes f or 
i m m u n oc o m pr o mise d s u bjects. Q ua ntifer o n testi n g ma y  n ot be re peate d e xce pt i n t he 
case of a si n gle re peat f or i n deter mi nate res ults.
Cases falli n g u n der cate g or y “ b” a n d “c” nee d t o be a p pr o ve d by t he S p o ns or pri or t o
e nr oll me nt i n t he st u d y. N o s u bject wit h c urre ntl y A C TI V E T B ma y  be e nr olle d i n t he st u d y, 
re gar dless of past or prese nt a nti-T B me dicati o n use.
9)
La b orat or y  para meters (s u bjects w h o fail t o meet t he bel o w refere nce la b orat or y tests ma y  be 
re-teste d o nce at discreti o n of i n vesti gat or pri or t o bei n g c o nsi dere d a scree n fail ure):
a)
He patic pa nel ( A S T, A L T, t otal bilir u bi n ) ≤2 ti mes t he U L N
b)
Esti mate d Cr Cl ≥ 4 0 ml/ mi n as calc ulate d b y t he C C & G e q uati o n
c)
He m o gl o bi n ≥ 8 g/ d L
d)
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 × 1 0 9/ L ( 1,5 0 0/ m m 3)
e)
Platelets ≥ 1 0 0 × 1 0 9/ L
f)
W hite bl o o d cells ( W B C ) ≥ 3. 0 x 1 0 9/ L
g)
A bs ol ute L y m p h oc yte c o u nt > 7 5 0/ m m 3
1 0) Ma y  be recei vi n g t he f oll o wi n g dr u gs (s u bjects o n t hese t hera pies m ust be willi n g t o re mai n 
o n sta ble d oses f or t he n ote d ti mes):
a)
Oral 5 -a mi n osalic ylate ( 5-A S A) c o m p o u n ds pr o vi de d t he d ose prescri be d has bee n sta ble 
f or at least 4 wee ks pri or t o ra n d o mizati o n ; d ose m ust be sta ble f or first 1 0 wee ks after 
ra n d o mizati o n
b)
Azat hi o pri ne, 6- M P or M T X pr o vi de d t he d ose prescri be d has bee n sta ble f or 4 wee ks 
pri or t o ra n d o mizati o n; d ose m ust be sta ble f or first 1 0 wee ks after ra n d o mizati o n
c)
Oral c ortic oster oi d t hera p y  ( pre d nis o ne prescri be d at a sta ble d ose ≤3 0 m g / da y or 
b u des o ni de prescri be d at a sta ble d ose of ≤ 9 m g / da y) pr o vi de d t he d ose prescri be d has 
bee n sta ble f or 2 wee ks pri or t o ra n d o mizati o n; d ose m ust be sta ble f or first 1 4 wee ks
after ra n d o mizati o n
1 1)
Willi n g ness t o refrai n fr o m li ve or atte n uate d vacc i nes d uri n g t he st u dy a n d f or 1 2 wee ks 
after last d ose

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 4
0 2 A pril 2 0 1 9
4. 2. 2.
E xcl usi o n Criteri a
S u bjects w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria are n ot t o be e nr oll e d i n eit her t he 
C o h ort A or B I n d ucti o n S t u d y.
1)
Pre g na nt or lactati n g fe males
2)
Males a n d fe males of re pr o d ucti ve p ote ntial w h o are u n willi n g t o a bi de b y pr ot oc ol -s pecifie d 
c o ntrace pti ve met h o ds as defi ne d b y A p pe n di x 6
3)
Fe males w h o ma y  wis h t o bec o me pre g na nt a n d/ or pla n t o u n der g o e g g d o nati o n or e g g 
har vesti n g f or t he p ur p ose of c urre nt or f ut ure fertilizati o n d uri n g t he c o urse of t he st u d y  a n d 
u p t o 3 5 da ys after last d ose of t he st u d y dr u g
4)
Male s u bjects u n willi n g t o refrai n fr o m s per m d o nati o n f or at least 9 0 da y s after last d ose of 
t he st u d y dr u g
5)
K n o w n h y perse nsiti vit y  t o fil g oti ni b, its meta b olites, or f or m ulati o n e xci pie nts
6)
E x hi bit ac ute se vere U C as def i ne d by t he f oll o wi n g criteria:
a)
≥ 6 bl o o d y  st o ols dail y A N D 1 or m ore of t he f oll o wi n g:
i)
B o d y te m perat ure ≥1 0 0. 4 ° F ( or 3 8° C)
ii) P ulse > 9 0 beats per mi n ute
7)
Use of rectal f or m u lati o ns of 5-A S A c o m p o u n ds or rectal c ortic oster oi ds 2 wee ks pri or t o 
scree ni n g
8)
Hist or y of maj or s ur ger y  or tra u ma wit hi n 3 0 da y s pri or t o scree ni n g
9)
Prese nce of C D , i n deter mi nate c olitis, isc he mic c olitis, f ul mi na nt c olitis, is olate d ulcerati ve 
pr octitis, or t o xic me ga -c ol o n
1 0) Pri or s ur gical i nter ve nti o n f or U C (e g, t otal c olect o m y, s u bt otal c olect o my,  partial or 
he mi c olect o m y, ile ost o m y, or c ol ost o m y) or li kel y re q uire me nt f or s ur ger y d uri n g t he st u d y
1 1) De pe n de nce o n pare nteral n utriti o n
1 2) Hist or y  or e vi de nce of i nc o m pletel y resecte d c ol o nic m uc osal d ys plasia
1 3) St o ol sa m ple p ositi ve f or C l ostri di u m difficile (C. diff ) t o xi n, pat h o ge nic Esc heric hi a c oli 
(E. c oli), S al m o nell a s pecies (s p p), S hi gell a s p p, C a m pyl o b acter s p p or Yersi ni a s p p
1 4) St o ol sa m ple p ositi ve f or o va a n d parasites test ( O & P) u nless a p pr o ve d b y t he me dical 
m o nit or

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 5
0 2 A pril 2 0 1 9
1 5) Acti ve cli nicall y si g nifica nt i nfecti o n, or a n y i nfecti o n re q uiri n g h os pitalizati o n or treat me nt 
wit h i ntra ve n o us a nti -i nfecti ves wit hi n 3 0 days  of scree ni n g ( or 8 wee ks of Da y 1); or a n y 
i nfecti o n re q uiri n g oral a nti -i nfecti ve t hera py wit hi n 2 wee ks of scree ni n g ( or 6 wee ks of 
da y 1)
1 6) I nfecti o n wit h HI V, he patitis B or he patitis C
1 7) Prese nce of C hil d - P u g h Class C he patic i m pair me nt
1 8) Acti ve T B or hist or y  of late nt T B t hat has n ot bee n treate d (See i ncl usi o n criteri o n 8 f or 
f urt her i nf or mati o n)
1 9) Hist or y  of mali g na nc y i n t he last 5 years e xce pt f or s u bjects w h o ha ve bee n s uccessf ull y 
treate d f or n o n-mela n o ma s ki n ca ncer or cer vical carci n o ma i n sit u
2 0) Hist or y  of ly m p h o pr oliferati ve dis or der, l y m p h o ma , le u ke mia, myel o pr oliferati ve dis or der, 
or m ulti ple m y el o ma
2 1) Hist or y  of treat me nt wit h l ym p h oc y te-de pleti n g t hera pies, i ncl u di n g b ut n ot li mite d t o 
ale mt uz u m a b, c ycl o p h os p ha mi de, t otal l ym p h oi d irra diati o n, a n d rit u xi ma b
2 2) Hist or y  of c yt a p heresis ≤ 2 m o nt hs pri or t o scree ni n g
2 3) Use of pr o hi bite d c o nc o mita nt me dicati o ns as descri be d i n Secti o n 5. 4. 2 .
2 4) A n y  c hr o nic me dical c o n diti o n (i ncl u di n g, b ut n ot li mite d t o, car diac or p ul m o nar y  disease, 
or s u bsta nce a b use) or ps yc hiatric pr o ble m t hat, i n t he o pi ni o n of t he I n vesti gat or or S p o ns or , 
w o ul d ma ke t he s u bject u ns uita ble f or t he st u d y or w o ul d pre ve nt c o m plia nce wit h t he st u d y 
pr ot oc ol pr oce d ures
2 5) A d mi nistrati o n of a li ve or a tte n uate d vacci ne wit hi n 3 0 da ys of ra n d o mizati o n
2 6) Hist or y  of o p p ort u nistic i nfecti o n or i m m u n o deficie nc y sy n dr o me
2 7) C urre ntl y  o n a n y c hr o nic s yste mic ( oral or i ntra ve n o us) a nti-i nfecti ve t hera p y f or c hr o nic 
i nfecti o n (s uc h as p ne u m oc ystis ( P C P), c yt o me gal o vir us (C M V ), her pes z oster, aty pical 
m y c o bacteria)
2 8) Hist or y  of disse mi nate d St a p hyl oc occ us a ure us
2 9) Hist or y  of sy m pt o matic her pes z oster or her pes si m ple x wit hi n 1 2 wee ks of scree ni n g, or a n y  
hist or y  of disse mi nate d her pes si m ple x, disse mi nate d her pes z oster, o p ht hal mic z oster, or 
ce ntral ner v o us s ys te m z oster

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 6
0 2 A pril 2 0 1 9
4. 3.  
C o h ort A ( Bi ol o gic- n aï v e) I n d ucti o n St u d y
4. 3. 1.
I ncl usi o n Criteri a, C o h ort A O N L Y
S u bjects m ust meet all of t he a d diti o nal f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or 
partici pati o n i n C o h ort A I n d ucti o n S t u dy.
1)
Pre vi o usl y  de m o nstrate d a n i na de q uate cli nical res p o nse, l oss of res p o nse t o, or i nt olera nce 
of at least 1 of t he f oll o wi n g a ge nts ( de pe n di n g o n c urre nt c o u ntr y treat me nt 
rec o m me n dati o ns/ g ui deli nes):
a)
C ortic oster oi ds
i)
Acti ve disease des pite a hist or y  of at least a n i n d ucti o n re gi me n of a d ose e q ui vale nt 
t o oral pre d nis o ne 3 0 m g dail y  f or 2 wee ks or i ntra ve n o usly ( I V) f or 1 w ee k, O R
ii) T w o faile d atte m pts t o ta per ster oi ds bel o w a d ose e q ui vale nt of 1 0 m g dail y  
pre d nis o ne, O R
iii) Hist or y  of ster oi d i nt olera nce i ncl u di n g, b ut n ot li mite d t o, C us hi n g’s s yn dr o me, 
oste o pe nia/ oste o p or osis, h y per gl y ce mia, i ns o m nia, seri o us i nfecti o ns, de pressi o n, 
aller gic reacti o ns, m o o d dist ur ba nces, or a n y  ot her c o n diti o n t hat c o ntri b ute d t o 
disc o nt i n uati o n of t he a ge nt
b)
I m m u n o m o d ulat ors
i)
Acti ve disease des pite a hist or y  of at least a 1 2-wee k re gi me n of oral azat hi o pri ne 
( ≥2 m g / k g/ da y) or 6- M P
(≥1 m g / k g/ d a y), or M T X ( 2 5 m g s u bc uta ne o usl y [S C ] or 
i ntra m usc ularly [I M] per wee k f or i n d ucti o n a n d ≥1 5 m g I M per wee k f or 
mai nte na nce) O R
ii) Hist or y  of i nt olera nce t o at least 1 i m m u n o m o d ulat or i ncl u di n g, b ut n ot li mite d t o, 
seri o us i nfecti o ns, he pat ot o xicit y, c yt o pe nia, pa ncreatitis, t hi o p uri ne 
met h y ltra nsferase (T P M T ) ge netic m utati o n, aller gic reacti o ns, or a n y ot her c o n diti o n 
t hat c o ntri b ute d t o disc o nti n uati o n of t he a ge nt
4. 3. 2.
E x cl usi o n Criteri a , C o h ort A O N L Y
S u bjects w h o meet a n y o f t he f oll o wi n g e xcl usi o n criteria are n ot t o be e nr olle d i n C o h ort A 
I n d ucti o n St u d y.
1)
P ri or use of a ny T N F α a nta g o nist i ncl u di n g ( b ut n ot li mite d t o) i nfli xi ma b, a dali m u ma b, 
g oli m u ma b, cert oliz u ma b, or bi osi milar a ge nts at a n y  ti me
2)
Pri or or c urre nt use of ve d oliz u ma b at a n y  ti me

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 7
0 2 A pril 2 0 1 9
4. 4.
C o h ort B ( Bi ol o gic -ex perie nce d) I n d ucti o n St u d y
4. 4. 1.
I ncl usi o n Criteri a, C o h ort B O N L Y
S u bjects m ust meet all t he a d diti o nal f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or partici pati o n 
i n C o h ort B I n d ucti o n S t u d y.
1)
Pre vi o usl y  de m o nstrate d a n i na de q uate cli nical res p o nse, l oss of res p o nse t o, or i nt olera nce 
of at least o ne o f t he f oll o wi n g a ge nts ( de pe n di n g o n c urre nt c o u ntr y treat me nt 
rec o m me n dati o ns/ g ui deli nes):
a)
T N F α A nta g o nists
i)
Acti ve disease des pite a hist or y  of at least o ne i n d ucti o n re gi me n of a T N F α 
A nta g o nist :

I nfli xi ma b:  Mi ni m u m i n d ucti o n re gi me n of 5 m g / k g at 0, 2, a n d 6 wee ks 
(i n t he E U, d urati o n of treat me nt of 1 4 wee ks)

A dali m u ma b: A n 8 -wee k i n d ucti o n re gi me n c o nsisti n g of 1 6 0 m g (f o ur 4 0- m g 
i njecti o ns i n 1 da y or t w o 4 0- m g i njecti o ns per da y f or 2 c o nsec uti ve da ys) o n 
D a y 1, f oll o we d b y a sec o n d d ose 2 wee ks l ater ( Da y 1 5) of 8 0 m g a n d a 4 0 m g
d ose 2 wee ks later ( D a y 2 9), f oll o we d b y a 4 0 m g d ose e ver y  ot her wee k u ntil 
Wee k
8 ( D a y 5 7).

G oli m u ma b: Mi ni m u m
i n d ucti o n d urati o n of 6 wee ks ( 1 2 wee ks i n E U) is 
re q uire d f or g oli m u ma b, w hic h i ncl u des 2 0 0 m g S C i njecti o n at Wee k
0, 
f oll o we d by 1 0 0 m g at Wee k
2 a n d t he n 1 0 0 m g e ver y 4 wee ks. O R
ii) Rec urre nce of s y m pt o ms d uri n g mai nte na nce t hera p y  wit h t he a b o ve a ge nts, O R
iii) Hist or y  of i nt olera nce t o a n y T N F α a nta g o nists i ncl u di n g, b ut n ot li mite d t o, seri o us 
i nfecti o ns, he pat ot o xicit y, heart fail ure, aller gic reacti o ns, or a ny ot her c o n diti o n t hat 
c o ntri b ute d t o disc o nti n uati o n of t he a ge nt
b)
Ve d oliz u ma b
i)
Acti ve disease des pite a hist or y  of at least a 1 4 wee k ( 1 0 wee ks i n EU) i n d ucti o n 
re gi men of ve d oliz u ma b c o nsisti n g of 3 0 0 m g I V at wee ks 0, t w o, a n d si x, O R
ii) Hist or y  of i nt olera nce t o ve d oliz u ma b i ncl u di n g, b ut n ot li mite d t o, seri o us i nfecti o ns, 
he pat ot o xicit y , c yt o pe nia, aller gic reacti o ns, or a n y ot her c o n diti o n t hat c o ntri b ute d t o 
disc o nti n uati o n of t he a ge nt
2)
M ust n ot h a ve use d a n y T N F α a nta g o nist or ve d oliz u ma b ≤8 wee ks pri or t o scree ni n g or 
a n y ot her bi ol o gic a ge nt ≤8 wee ks pri or t o scree ni n g or wit hi n 5 ti mes t he half -life of t he 
bi ol o gic a ge nt pri or t o scree ni n g, w hic he ver is l o n ger

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 8
0 2 A pril 2 0 1 9
4. 4. 2.
E xcl usi o n Criteri a C o h ort B O N L Y
S u bjects w h o meet t he f oll o wi n g e xcl usi o n criteri o n are n ot eli gi ble t o be e nr olle d i n C o h ort B 
I n d ucti o n St u d y.
1)
Ha ve use d a n y T N F a nta g o nist or ve d oliz u ma b wit hi n ≤ 8 wee ks pri or t o scree ni n g, or a n y  
o t her bi ol o gic a ge nt ≤ 8 wee ks pri or t o scree ni n g or wit hi n 5 ti mes t he half -life of t he 
bi ol o gic a ge nt pri or t o scree ni n g, w hic he ver is l o n ger
4. 5.
M ai nte n a nce St u d y
4. 5. 1. 
I ncl usi o n Criteri a
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or partici pati o n i n t he 
Mai nte na nce S t u d y.
1)
C o m pleti o n of C o h ort A or B i n d ucti o n st u d y wit h M C S res p o nse or E B S re missi o n base d o n 
Wee k
1 0 assess me nts
2)
Willi n g ness t o refrai n fr o m li ve or atte n uate d vacc i nes d uri n g t he st u dy a n d f or 1 2 wee ks 
after last d os e
3)
Ma y  be o n oral c ortic oster oi d t hera p y ( pre d nis o ne prescri be d at a sta ble d ose ≤3 0 m g / da y or 
b u des o ni de at a d ose of ≤9 m g / da y); d ose m ust re mai n sta ble t o Wee k
1 4
4. 5. 2. 
E xcl usi o n Criteri a
S u bjects w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria are n ot t o b e e nr olle d i n t he 
M ai nte na nce S t u d y:
1)
Males a n d Fe males of re pr o d ucti ve p ote ntial w h o are
u n willi n g t o a bi de b y  
pr ot oc ol -s pecifie d c o ntrace pti ve met h o ds as defi ne d b y A p pe n di x 6
2)
Fe males w h o ma y  wis h t o bec o me pre g na nt a n d/ or pla n t o u n der g o e g g d o nati o n or e g g 
har vesti n g f or t he p ur p ose of c urre nt or f ut ure fertilizati o n d uri n g t he c o urse of t he st u d y  a n d 
u p t o 3 5 da ys after last d ose of t he st u d y dr u g
3)
Male s u bjects u n willi n g t o refrai n fr o m s per m d o nati o n d uri n g t he st u d y a n d f or at least 
9 0 da y s after last d ose of t he st u d y  dr u g
4)
Use of pr o hi bite d c o nc o mita nt me dicati o ns as descri be d i n Secti o n 5. 4. 2 .

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 5 9
0 2 A pril 2 0 1 9
5.
I N V E S TI G ATI O N A L  M E DICI N A L  P R O D U C T S
5. 1.
R a n d o miz ati o n, Bli n di n g a n d Tre at me nt C o des
5. 1. 1.
Pr oce d ures f or Bre a ki n g Tre at me nt C o des
I n t he e ve nt of a me dical e mer ge nc y w here brea ki n g t he bli n d is re q uire d t o pr o vi de me dical care 
t o t he s u bject, t he i n vesti gat or ma y o btai n treat me nt assi g n me nt directl y fr o m t he i nteracti ve we b 
res p o nse s yste m (I W R S) f or t hat s u bject. Gilea d rec o m me n ds but d oes n ot re q uire t hat t he 
i n vesti gat or c o ntact t he Gilea d M e dical M o nit or bef ore brea ki n g t he bli n d. Treat me nt assi g n me nt 
s h o ul d re mai n bli n de d u nless t hat k n o wle d ge is necessar y t o deter mi ne s u bject e mer ge nc y 
me dical care. T he rati o nale f or u n bli n di n g m ust be clearl y e x plai ne d i n s o urce d oc u me ntati o n 
a n d o n t he e C R F, al o n g wit h t he date o n w hic h t he treat me nt assi g n me nt was o btai ne d. T he 
i n vesti gat or is re q ueste d t o c o ntact t he Gilea d M e dical M o nit or pr o m ptl y  i n case of a n y 
treat me nt u n bli n di n g.
Bli n di n g of st u d y treat me nt is critical t o t he i nte grit y  of t his cli nical trial; t heref ore, if a s u bject’s 
treat me nt assi g n me nt is discl ose d t o t he i n vesti gat or, t he s u bject will ha ve st u d y treat me nt 
disc o nti n ue d. All s u bjects will be f oll o we d u ntil st u d y  c o m pleti o n u nless c o nse nt t o d o s o is 
s pecifically wit h dra w n b y t he s u bject.
Gilea d P har mac o vi gila nce a n d E pi de mi ol o g y (P V E ) ma y i n de pe n de ntl y u n bli n d cases f or 
e x pe dite d re p orti n g of s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs).
5. 2.
Descri pti o n a n d H a n dli n g of Fil g oti ni b a n d Pl ace b o t o M atc h ( P T M) 
Fil g oti ni b
5. 2. 1.
F o r m ul ati o n
Fil g oti ni b is a vaila ble as 2 0 0 m g a n d 1 0 0 m g stre n gt h ta blets. Fil g oti ni b ta blets, 2 0 0 m g a n d 
1 0 0 m g , are bei ge, de b osse d wit h “ G SI” o n o ne si de a n d “ 2 0 0” or “ 1 0 0” o n t he ot her , 
ca ps ule-s ha pe d, bic o n ve x, fil m-c oate d ta blets f or cli nical use. Eac h ta blet c o ntai ns t he e q ui vale nt 
of 2 0 0 m g or 1 0 0 m g fil g oti ni b free base i n t he f or m of fil g oti ni b maleate. I n a d diti o n t o t he 
acti ve i n gre die nt, fil g oti ni b ta blets c o ntai n t he f oll o wi n g i nacti ve i n gre die nts: micr ocr ystalli ne 
cell ul ose, lact ose m o n o h ydrate, f u maric aci d, pre gelati nize d starc h, silic o n di o xi de, ma g nesi u m 
stearate, macr o g ol/p ol yet h y le ne gl yc ol (P E G ) 3 3 5 0, p ol y vi n y l alc o h ol, talc, tita ni u m di o xi de, 
ir o n o xi de yell o w, a n d ir o n o xi de re d. 
Place b o t o matc h ( P T M) fil g oti ni b 2 0 0 m g a n d 1 0 0 m g ta blets are i de ntical t o t he res pecti ve 
acti ve ta blets, i n a p peara nce. P T M fil g oti ni b 2 0 0 m g a n d 1 0 0 m g ta blets c o ntai n t he f oll o wi n g 
i nacti ve i n gre die nts: micr ocr ystalli ne cell ul ose, lact ose m o n o h ydr ate, cr oscar mell ose s o di u m , 
ma g nesi u m stearate, macr o g ol/ P E G 3 3 5 0, p ol y vi n yl alc o h ol, talc, tita ni u m di o xi de, ir o n o xi de 
ye ll o w, a n d ir o n o xi de re d.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 0
0 2 A pril 2 0 1 9
5. 2. 2.
P a c k a gi n g a n d L a beli n g
Fil g oti ni b a n d P T M fil g oti ni b t a blets are pac ka ge d i n w hite, hi g h de nsit y p ol y et h yl e ne ( H D P E) 
b ottles. Eac h b ottle c o ntai ns 3 0 ta blets, silica gel desicca nt a n d p ol ye ster pac ki n g material. Eac h 
b ottle is e ncl ose d wit h a w hite, c o nti n u o us t hrea d, c hil d -resista nt p ol ypr o p y le ne scre w ca p fitte d 
wit h a n i n d ucti o n- seale d, al u mi n u m -face d li ner.
St u d y  dr u gs t o be distri b ute d t o ce nters i n t he U S, E U a n d ot her partici pati n g c o u ntries s hall be 
la bele d t o meet a p plica ble re q uire me nts of t he U S F D A , E U G ui deli ne t o G o o d Ma n ufact uri n g 
Practice - A n ne x 1 3 (I n vesti gati o nal Me dici nal Pr o d ucts), a n d/ or ot her l ocal re g ulati o ns, as 
a p plica ble.
5. 2. 3.
St or a ge a n d H a n dli n g
Fil g oti ni b a n d P T M fil g oti ni b ta blets s h o ul d be st ore d at c o nt r olle d r o o m te m perat ure of 
2 5° C ( 7 7° F); e xc ursi o ns are per mitte d bet wee n 1 5° C a n d 3 0° C ( 5 9° F a n d 8 6° F). St ora ge 
c o n diti o ns are s pecifie d o n t he la bel. U ntil dis pe nse d t o t he s u bjects, all b ottles of st u d y  dr u gs 
s h o ul d be st ore d i n a sec urel y l oc ke d area, accessi ble o nl y t o a ut h orize d site pers o n nel.
T o e ns ure t he sta bilit y a n d pr o per i de ntifi cati o n, st u d y dr u gs s h o ul d n ot be st ore d i n a c o ntai ner 
ot her t ha n t he c o ntai ner i n w hic h t he y  were s u p plie d. C o nsi derati o n s h o ul d be gi ve n t o ha n dli n g, 
pre parati o n, a n d dis p osal t hr o u g h meas ures t hat mi ni mize dr u g c o ntact wit h t he b o d y . 
A p pr o priate preca u ti o ns s h o ul d be f oll o we d t o a v oi d direct e ye c o ntact or e x p os ure w he n 
ha n dli n g. 
5. 3.
D os a ge a n d A d mi nistr ati o n
T he st u d y me dicati o n will c o nsist of 2 0 0 m g a n d 1 0 0 m g fil g oti ni b ta blets f or oral 
a d mi nistrati o n, a n d P T M 2 0 0 m g a n d 1 0 0 m g fil g oti ni b ta blets f or oral a d mi nistrati o n.
T he f oll o wi n g treat me nts will be e val uate d:

Tre at me nt 1: fil g oti ni b 2 0 0 m g a n d P T M fil g oti ni b 1 0 0 m g , o nce dail y

Tre at me nt 2: fil g oti ni b 1 0 0 m g a n d P T M fil g oti ni b 2 0 0 m g , o nce dail y

Tre at me nt 3: P T M fil g oti ni b 2 0 0 m g a n d P T M fil g o ti ni b 1 0 0 m g , o nce dail y
S u bjects w h o are n o n -res p o n ders base d o n W ee k 1 0 assess me nts will be offere d t he o pti o n t o 
recei ve o pe n-la bel fil g oti ni b b y e nteri n g i nt o t he L T E st u d y ( G S-U S - 4 1 8-3 8 9 9). S u bjects 
meeti n g disease w orse ni n g criteria at Wee k 1 1 or lat er m ust be disc o nti n ue d fr o m bli n de d 
treat me nt a n d will be offere d t he o pti o n t o recei ve o pe n-la bel fil g oti ni b 2 0 0 m g, 
( See Secti o n 3. 6 , Disease W orse ni n g Criteria), e xce pt f or U S a n d K orea males w h o will be
offere d fil g oti ni b 1 0 0 m g u nless t he y  ha ve faile d at least 2 ot her bi ol o gic t hera pies (a n y T N F α 
a nta g o nist a n d ve d oliz u ma b) . S u bjects w h o c o m plete t he Wee k 5 8 visit will ha ve t he o pti o n t o 
c o nti n ue st u d y dr u g i n a bli n de d fas hi o n i n t he L T E st u dy.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 1
0 2 A pril 2 0 1 9
F or misse d d ose(s) of st u d y  me dicati o n, s u bjects s h o ul d be i nstr ucte d t o ta ke t he misse d d ose(s) 
of st u d y  me dicati o n as s o o n as p ossi ble d uri n g t he sa me da y. If t he misse d d ose is n ot ta ke n o n 
t he ori gi nal da y, t he n s u bjects sh o ul d n ot ta ke t he misse d d ose a n d t he misse d d o se s h o ul d be 
ret ur ne d t o t he st u dy dr u g b ottle. S u bjects s h o ul d be ca uti o ne d n ot t o d o u ble t he ne xt d ose 
(ie, ta ki n g t he misse d d ose of st u d y dr u g wit h t hat da y’s d ose).
5. 4.
Pri or a n d C o nc o mit a nt Me dic ati o ns
All me dicati o ns ta ke n u p t o 3 0 da ys pri or t o t he scree ni n g visit t hr o u g h t he e n d of st u d y 
( 3 0 d a y s after t he last d ose of st u d y  dr u g), nee d t o be rec or de d i n t he s o urce d oc u me nts a n d o n 
t he e C R F. At eac h st u d y visit, t he st u d y ce nter will rec or d a n y a n d all me dicati o ns t a ke n b y t he 
s u bject si nce t he last visit or d uri n g t he visit (as a p plica ble). All c o nc o mita nt me dicati o ns 
(prescri pti o n, peri - pr oce d ural me dicati o ns, o ver-t he-c o u nter me dicati o ns, i ncl u di n g vacci nes, 
vita mi ns, her bal , dietar y s u p ple me nts, a n d mi nerals) m ust be rec or de d i n t he c o nc o mita nt 
t hera py secti o n of t he e C R F .
Effecti ve c urre nt t hera pies s h o ul d n ot be disc o nti n ue d f or t he s ole p ur p ose of partici pati n g i n t his 
st u d y. S u bjects ma y recei ve me dicati o ns as s u p p orti ve care or t o treat A Es as dee me d necessary 
b y  t he In vesti gat or or t he s u bject’s p h y sicia n. S h o ul d s u bjects ha ve a nee d t o i nitiate treat me nt 
wit h a n y  e xcl u de d c o nc o mita nt me dicati o n, t he Gilea d Me dical M o nit or s h o ul d be c o ns ulte d 
pri or t o i nitiati o n of t he ne w me dicati o n. I n i nsta nces w here a n e xcl u de d me dicati o n is i nitiate d 
pri or t o disc ussi o n wit h t he S p o ns or, t he In vesti g at or s h o ul d n otif y  Gilea d as s o o n as he/s he is 
a ware of t he use of t he e xcl u de d me dicati o n. 
5. 4. 1.  
All o we d C o nc o mit a nt Me dic ati o ns
T he all o we d c o nc o mita nt me dicati o n(s) f or U C m ust be mai ntai ne d at a sta ble d ose f or t he n ote d 
ti me wit h o ut d osi n g alterati o n or disc o nti n uati o n. 
T he all o we d me dicati o ns f or U C are as f oll o ws:

Oral 5 -A S A c o m p o u n ds pr o vi de d t he d ose prescri be d has bee n sta ble f or at least 4 wee ks 
pri or t o ra n d o mizati o n; d ose m ust be sta ble f or t he first 1 0 wee ks after ra n d o mizati o n

Azat hi o pri ne, 6- M P, or M T X pr o vi de d t he d ose prescri be d has bee n sta ble f or 4 wee ks pri or 
t o ra n d o mizati o n; d ose m ust be sta ble f or t he first 1 0 wee ks after ra n d o mizati o n

Oral c ortic oster oi d t hera p y ( pre d nis o ne prescri be d at a sta ble d ose ≤ 3 0 m g / da y or 
b u des o ni de prescri be d at a sta ble d ose of ≤9 m g / da y) pr o vi de d t he d ose prescri be d has bee n 
sta ble f or 2 wee ks pri or t o ra n d o mizati o n; d ose m ust be sta ble f or t he first 1 4 wee ks after 
ra n d o mizati o n

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 2
0 2 A pril 2 0 1 9
5. 4. 2.
Pr o hi bite d C o nc o mit a nt M e dic ati o ns
T he pr o hi bite d me dicati o ns are as f oll o ws:
T a ble 5- 1.
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
Dr u g Cl ass
A ge nts Dis all o we d 
Pr o hi bite d Peri o d
Str o n g P -g p I n d ucers a
A ntic o n v ulsa nts
P he n o bar bital, p he n y t oi n, car ba maze pi ne
3 0 da y s pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
A nti m yc o bacterials
Rifa b uti n, rifa pe nti ne, rifa m pi n
Her bal/ Nat ural 
S u p ple me nts
St. J o h n’s w ort, da ns he n ( Sal via M ilti orr hiza)
Pr o hi bite d I B D Me dic ati o ns
C ortic oster oi ds
D ose e q ui vale nt t o > 3 0 m g/ da y  of pre d nis o ne
3 0 da y s pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
T N F α a nta g o nist
I nfli xi ma b, a dali m u ma b, g oli m u ma b, 
cert oliz u ma b, or bi osi milar a ge nt
8 wee ks pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
I nte gri n a nta g o nist
Ve d oliz u ma b a n d nataliz u ma b
8 wee ks pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
I nterle u ki n a nta g o nist
Uste ki n u ma b
1 2 wee ks pri or t o scree ni n g t hr o u g h t he e n d 
of t he st u d y
Rectal c o m p o u n ds
Rectal 5 -A S A or rectal c ortic oster oi ds
2 wee ks pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
A nti diarr heal a ge nts
L o pera mi de a n d di p he n o x ylate/atr o pi ne
2 wee ks pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
Ot her ( n o n -bi ol o gic)
C y cl os p ori ne, t hali d o mi de, tacr oli m us, 
lefl u n o mi de, a n d a n y i n vesti gati o nal a ge nt
3 0 da y s pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y
A n y  J A K i n hi bit or
A n y  ti me bef ore a n d t hr o u g h t he e n d of t he 
st u d y
I nv esti gati o nal bi ol o gics
A n y i n vesti gati o nal bi ol o gic a ge nt
8 wee ks pri or t o scree ni n g t hr o u g h t he e n d of 
t he st u d y ( or at least 5 half -li ves)
L y m p h oc yte -de pleti n g 
t hera pies
Ale mt uz u m a b, c ycl o p h os p ha mi de, t otal 
l ym p h oi d irra diati o n, rit u xi ma b, a n d a n y 
ot her l y m p h oc y te de pleti n g t hera p y
A n y  ti me bef ore a n d t hr o u g h t he e n d of t he 
st u d y
Ot her Pr o hi bite d Me dic ati o ns
C hr o nic N o nster oi dal 
A nti -i nfla m mat or y 
Dr u gs ( N S AI Ds) b
As piri n, i b u pr ofe n, na pr o xe n, dicl ofe nac, 
i n d o met haci n, C O X-2 i n hi bit ors
Fr o m scree ni n g t hr o u g h t he e n d of t he st u d y
Ot her bi ol o gics c
A nti b o d y  base d or ot her s yste mic bi ol o gics, 
e g, de n os u ma b, trast uz u ma b
Re q uires me dical m o nit or c o ns ultati o n
a
Ma y decrease st u d y dr u g e x p os ure a n d are e xcl u de d t o a v oi d p ote ntial re d ucti o n i n st u d y dr u g acti vit y. P K res ults i n dicate 
fil g oti ni b is a P-g p s u bstrate, as a si n gle d ose of 2 0 0 m g itrac o naz ole (a p ote nt P -g p i n hi bit or) i ncrease d fil g oti ni b C ma x
b y 
6 4 % a n d A U C i nf b y  4 5 % a n d ha d n o effect o n t he maj or, acti ve meta b olite G S-8 2 9 8 4 5 .
b
Occasi o nal use of N S AI D s f or tra nsie nt s y m pt o ms a n d dail y use of as piri n u p t o 1 6 2. 5 m g f or t he p ur p ose of car di o vasc ular 
pr o p h yla xis are per mitte d
c
Ot her bi ol o gics m a y be all o we d wit h t he a p pr o val of t he me dical m o nit or
 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 3
0 2 A pril 2 0 1 9
5. 4. 3.  
C ortic oster oi d T a peri n g
Starti n g at Wee k
1 4, s u bjects w h o are o n c o nc o mita nt ster oi ds m ust be gi n ta peri n g ster oi d 
t hera py. T he d ose s h o ul d be re d uce d at a rate starti n g at 2. 5 m g per wee k u p t o 5 m g per wee k
( or e q ui vale nt ta per if n ot pre d nis o ne) u ntil s u bject is n o l o n ger o n ster oi ds . S u bjects w h o are o n 
b u des o ni de s h o ul d ha ve t heir dail y  d ose re d uce d b y 3 m g e ver y 3 wee ks u ntil t he y are 
c o m pletel y off ster oi ds.  F or s u bjects u n der g oi n g ta per, ster oi ds ma y be i ncrease d or restarte d at 
d oses u p t o a n d i ncl u di n g t heir baseli ne d ose if r et ur n of s y m pt o ms is a p pare nt. T hese s u bjects 
will n ot be c o nsi dere d treat me nt fail ures. S u bjects w h o nee d t o restart or i ncrease ster oi d 
treat me nt at a d ose t hat e xcee ds t heir baseli ne d ose of ster oi ds (d ose ma y  n ot e xcee d 3 0 m g 
pre d nis o ne [ or e q ui vale nt ] or b u des o ni de 9 m g/ da y) will be c o nsi dere d treat me nt fail ures f or all 
cli nical e n d p oi nts b ut will be per mitte d t o re mai n i n t he st u d y .
5. 5.
V acci ne G ui deli nes

Pri or t o st u d y  partici pati o n, it is rec o m me n de d t hat t he s u bject’s vacci nati o ns be br o u g ht u p 
t o date acc or di n g t o l ocal vacci nati o n sta n dar ds

Li ve or atte n uate d vacci nes (i ncl u di n g, b ut n ot li mite d t o varicella a n d i n hale d fl u vacci ne) 
are pr o hi bite d wit hi n 3 0 da ys of D a y 1, t hr o u g h o ut t he st u d y , a n d f or 1 2 wee ks after t he last 
d ose of st u d y  dr u g

S u bje cts s h o ul d be a d vise d t o a v oi d r o uti ne h o use h ol d c o ntact wit h pers o ns vacci nate d wit h 
li ve/atte n uate d vacci ne c o m p o ne nts. Ge neral g ui deli nes s u g gest t hat a st u d y s u bject’s 
e x p os ure t o h o use h ol d c o ntacts s h o ul d be a v oi de d f or t he bel o w state d ti me peri o ds:

Varicella or atte n uate d t y p h oi d fe ver vacci nati o n – a v oi d c o ntact f or 4 wee ks f oll o wi n g 
vacci nati o n

Oral p oli o vacci nati o n -- a v oi d c o ntact f or 6 wee ks f oll o wi n g vacci nati o n

Atte n uate d r ota vir us vacci ne -- a v oi d c o ntact f or 1 0 da ys f oll o wi n g vacci nati o n

I nhale d fl u vacci ne -- a v oi d c o ntact f or 1 wee k f oll o wi n g vacci nati o n

I nacti vate d vacci nes (s uc h as i nacti vate d fl u vacci nes) s h o ul d be a d mi nistere d acc or di n g t o 
l ocal vacci nati o n sta n dar ds w he ne ver me dically a p pr o priate; h o we ver, t here are n o a vaila ble 
data o n t he c o nc urre nt use of fil g oti ni b a n d its i m pact o n i m m u ne res p o nses f oll o wi n g 
vacci nati o n
5. 6.
Acc o u nt a bilit y f or St u d y Dr u g
T he i n vesti gat or is res p o nsi ble f or e ns uri n g a de q uate acc o u nta bilit y  of all use d a n d u n use d 
st u d y dr u g . T his i ncl u des ac k n o wle d ge me nt of recei pt of eac h s hi p me nt of st u d y dr u g
( q ua ntit y a n d c o n diti o n). All use d a n d u n use d st u d y  dr u g dis pe nse d t o s u bjects m ust be ret ur ne d 
t o t he site.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 4
0 2 A pril 2 0 1 9
St u d y  dr u g acc o u nta bilit y rec or ds will be pr o vi de d t o eac h st u d y site t o:

Rec or d t he date recei ve d a n d q ua ntit y  of st u d y dr u g 

Rec or d t he date, s u bject n u m ber, s u bject i nitials, t he st u d y dr u g n u m ber dis pe nse d

Rec or d t he date, q ua ntit y of use d a n d u n use d st u d y dr u g ret ur ne d, al o n g wit h t he i nitials of 
t he pers o n rec or di n g t he i nf or mati o n. 
5. 6. 1.
I n vesti g ati o n al Me dici n al Pr o d uct Ret ur n or Dis p os al
Please refer t o Secti o n 9. 1. 7 .

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 5
0 2 A pril 2 0 1 9
6.
S T U D Y  P R O C E D U R E S
T he st u d y  pr oce d ures t o be c o n d ucte d f or eac h s u bject e nr olle d i n t he st u d y are prese nte d i n 
ta b ular f or m i n A p pe n di x 2 a n d descri be d i n t he te xt t hat f oll o ws. 
T he i n vesti gat or m ust d oc u me nt a n y de viati o n fr o m pr ot oc ol pr oce d ures a n d n otif y  t he s p o ns or 
or c o ntract researc h or ga nizati o n ( C R O).
6. 1.
S u bject E nr oll me nt a n d Tre at me nt Assi g n me nt
Base d o n pr ot oc ol eli gi bilit y  criteria, s u bjects will be scree ne d f or e nr oll me nt i n eit her C o h ort A 
or C o h ort B.
S u bjects w h o meet t he pr ot oc ol criteria will be assi g ne d t o t he res pecti ve c o h ort a n d 
s u bse q ue ntl y ra n d o mize d in a bli n de d fas hi o n i n a 2: 2: 1 rati o t o 1 of 3 treat me nts as f oll o ws:

Tre at me nt 1 ( n = 2 6 0) : fil g oti nib 2 0 0 m g a n d P T M fil g oti ni b 1 0 0 m g , o nce dail y

Tre at me nt 2 ( n = 2 6 0): fil g oti nib 1 0 0 m g a n d P T M fil g oti ni b 2 0 0 m g , o nce dail y

Tre at me nt 3 ( n = 1 3 0 ): P T M f il g oti ni b 2 0 0 m g a n d P T M fil g oti ni b 1 0 0 m g , o nce dail y
N ote: U S a n d K orea males w h o ha ve n ot faile d at least t w o bi ol o gic re gi me ns (a n y T N F α 
a nta g o nist a n d ve d oliz u ma b) will be ra n d o mize d i n a 2: 1 rati o t o eit her fil g oti ni b 1 0 0 m g or 
matc hi n g place b o.
Wit hi n eac h C o h ort, treat me nt assi g n me nts will be stratifie d acc or di n g t o t he f oll o wi n g fact ors i n 
t he In d ucti o n a n d Mai nte na nce st u dies:
St r atific ati o n F act ors ( C o h ort A , Bi ol o gic-N aï ve I n d ucti o n St u d y)

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds ( e g, pre d nis o ne) at Da y 1 
( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors ( e g, 6- M P, azat hi o pri ne, M T X)
at Da y 1 ( Yes or N o)
Str a tific ati o n F act ors ( C o h ort B, Bi ol o gic-E x perie nce d I n d ucti o n St u d y)

E x p os ure t o o ne bi ol o gic a ge nt vers us m ore t ha n o ne bi ol o gic a ge nt

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds ( e g, pre d nis o ne) at Da y 1 
( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors (e g, 6- M P, azat hi o pri ne, M T X)
at Da y 1 ( Yes or N o)

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 6
0 2 A pril 2 0 1 9
Str atific ati o n F act ors ( M ai nte n a nce St u d y)

Partici pati o n i n C o h ort A or C o h ort B

C o nc o mita nt use of oral, s y ste mically a bs or be d c ortic oster oi ds ( e g, pre d nis o ne) at Da y 1 
( Yes or N o)

C o nc o mita nt use of i m m u n o m o d ulat ors ( e g, 6- M P, azat hi o pri ne, M T X)
at Da y 1 ( Yes or N o)

Refer t o Secti o n 3. 3 , Ta ble 3- 1 f or re-ra n d o mizati o n i n t he Mai nte na nce S t u d y
6. 2.
Pretre at me nt Assess me nts
6. 2. 1.
Scree ni n g Visit
S u bjects will be scree ne d wit hi n 3 0 da y s bef ore ra n d o mizati o n t o deter mi ne eli gi bilit y  f or 
partici pati o n i n t he st u d y . T he f oll o wi n g will be perf or me d a n d d oc u me nte d at scree ni n g:

O btai n writte n i nf or me d c o nse nt

A d diti o nal c o nse nt will be re q uire d fr o m s u bjects partici pati n g i n t he P K s u bst u d y  
 

Re vie w i ncl usi o n/e xcl usi o n criteria a n d ot her pr ot oc ol restricti o ns ( Secti o n 4 )

O btai n me dical hist or y , i ncl u di n g U C disease a n d treat me nt hist or y

C o m plete p h y sical e xa mi nati o n ( P E) i ncl u di n g vital si g ns, b o d y wei g ht a n d hei g ht

Perf or m 1 2 -lea d E C G

Rec or d a n y S A Es a n d all A Es relate d t o pr ot oc ol ma n date d pr oce d ures occ urri n g after 
si g ni n g of t he c o nse nt f or m.

I nstr uct s u bjects t o mai ntai n c o nc o mita nt me dicati o n at a sta ble d ose

Pr o vi de s u bject wit h t he electr o nic diar y (e-Diar y ) a n d i nstr ucti o ns f or dail y d oc u me ntati o n 
of st o ol fre q ue nc y  a n d rectal blee di n g. S u bjects s h o ul d be c o u nsele d t o e nter t he N or m al 
St o ol C o u nt ( N S C) as t he st o ol c o u nt t he s u bject e x peri e nces w he n dise ase free 
(e g, i n re missi o n). If t he s u bject h as ne ver bee n i n re missi o n, t he s u bject s h o ul d e nter i n 
n or m al st o ol c o u nt w he n he alt h y (e g, pri or t o di a g n osis).

C o n d uct p h o ne call a p pr o xi m atel y 4 da ys after scree ni n g visit t o e nc o ura ge c o m plia nce wit h 
dail y  d oc u me ntati o n of st o ol fre q ue nc y a n d rectal blee di n g
C C

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 7
0 2 A pril 2 0 1 9

If warra nte d, base d o n t he re vie w of c o m plia nce a n d a vera ge sc ores fr o m t he s u bject e-Diar y  
re p orts f or rectal blee di n g a n d st o ol freq ue nc y , perf or m fle xi ble si g m oi d osc o p y/c ol o n osc o p y 
a n d bi o ps y d uri n g scree ni n g . If a c ol o n osc o py is perf or me d, fle xi ble si g m oi d osc o p y is n ot 
re q uire d. S u bject di ar y d at a a n d l a b res ults s h o ul d be re vie we d t o e ns ure eli gi bilit y is 
met pri or t o sc he d uli n g e n d osc o p y . E n d osc o p y s h o ul d n ot be perf or me d u nless s u bject 
h as met eli gi bilit y criteri a f or st o ol fre q ue nc y a n d rect al blee di n g.

Rec or d i n vesti gat or e n d osc o pic val ue

S u bjects will nee d a f ull c ol o n osc o p y  o nl y if t he i n vesti gat or c h o oses t o d o s o f or disease
ma na ge me nt 

F o ur bi o ps y sa m ples will be c ollecte d . T hese bi o psies will be se nt t o ce ntral la b orat or y  f or 
st ora ge a n d t he n t o s pecialt y la b orat ories f or s u bse q ue nt a nalys is.

C ollect t he varia bles t o calc ulate c o m plete M C S (refere nce A p pe n di x 4 )

Site c ollects patie nt assess me nts at eac h visit

M C S calc ulate d ce ntrall y after all c o m p o ne nts ha ve bee n ca pt ure d electr o nicall y

T B Assess me nt – M ust ha ve ne gati ve Q ua nti F E R O N
® test ( or ce ntrall y re p orte d e q ui vale nt 
assa y) d uri n g scree ni n g, a n d ne gati ve c hest x- ra y wit hi n 3 m o nt hs of or d uri n g scree ni n g f or 
t h ose wit h n o e vi de nce or hist or y of T B. P ositi ve or ne gati ve res ults m ust n ot be re peate d. A n 
i n deter mi nate res ult s h o ul d be re peate d o nce a n d t he sec o n d res ult (if p ositi ve or ne gati ve) 
will be acce pte d. T w o se q ue ntial i n deter mi nate res ults c o nstit ute a scree n fail ure. S u bjects 
wit h pre vi o usl y  treate d or late nt T B re q uire s p o ns or a p pr o val ( See i ncl usi o n criteri o n 8 f or 
details) . S u bjects w h o are dia g n ose d wit h late nt T B at scree ni n g m ust i nitiate a n a de q uate 
c o urse of pr o p h yl a xis as per l ocal sta n dar d of care f or a mi ni m u m of 4 wee ks pri or t o 
ra n d o mizati o n. S u bject ma y i nitiate st u d y dr u g d osi n g o nly after c o ns ultati o n wit h t he 
Gilea d me dica l m o nit or.

O btai n bl o o d sa m ples ( refere nce St u d y  Pr oce d ure Ta ble i n A p pe n di x 2 )

H C V Scree ni n g G ui deli nes
■
S u bjects wit h p ositi ve H C V a nti b o d y  at Scree ni n g re q uire refle x testi n g f or H C V 
R N A. S u bjects wit h H C V R N A ≥l o wer li mit of q ua ntificati o n ( L L O Q) at Scree ni n g 
will b e e xcl u de d. S u bjects wit h p ositi ve H C V a nti b o d y  b ut H C V R N A < L L O Q are 
eli gi ble.

H B V Scree ni n g a n d S ur veill a nce G ui deli nes
■
S u bjects wit h p ositi ve H B V s urface a nti ge n ( H Bs A g) at Scree ni n g are e xcl u de d.
■
S u bjects w h o are p ositi ve f or H B V s urface a nti b o d y  ( H BsA b) , b ut ne gati ve f or b ot h
H Bs A g a n d H B V c ore a nti b o d y  ( H Bc A b) at Scree ni n g are eli gi ble.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 6 8
0 2 A pril 2 0 1 9
■
S u bjects wit h p ositi ve H Bc A b re q uire refle x testi n g f or H B V D N A. S u bjects wit h 
H B V D N A ≥ L L O Q at Scree ni n g will be e xcl u de d. S u bjects wit h p ositi ve H Bc A b 
a n d H B V D N A < L L O Q are eli gi ble, b ut will re q uire o n g oi n g H B V D N A m o nit ori n g 
e ver y 3 m o nt hs d uri n g t his st u d y . T hese s u bjects ma y re q uire pr o p h ylactic treat me nt 
per i n vesti gat or discreti o n i n acc or da nce wit h l ocal g ui deli nes/sta n dar d of care . 
■
I n Ja pa n a n d w here re q uire d by l ocal g ui deli nes, s u bjects wit h p ositi ve H Bc A b a n d/ or 
p ositi ve H Bs A b will re q uire refle x testi n g f or H B V D N A at S cree ni n g. S u bjects wit h 
p ositi ve H Bc A b a n d/ or H Bs A b b ut wit h H B V D N A < L L O Q at S cree ni n g are 
eli gi ble f or t he st u d y. T hese s u bjects will re q uire o n g oi n g H B V D N A m o nit ori n g 
e ver y 4 wee ks i n acc or da nce wit h l ocal g ui deli nes d uri n g t his st u d y.  
■
A n y  s u bject w h o has H B V D N A ≥ L L O Q d uri n g t he st u d y  will be disc o nti n ue d 
(refere nce Secti o n 3. 5. 2 ).

HI V Scree ni n g G ui deli nes
■
S u bjects w h o ha ve HI V i nfecti o n, re gar dless of vir ol o gic stat us, are e xcl u de d fr o m 
t he st u d y. 

O btai n bl o o d sa m ple f or ser u m pre g na nc y  test (f or fe males of c hil d beari n g p ote ntial o nl y)

O btai n st o ol sa m ple ( refere nce St u d y  Pr oce d ure Ta ble i n A p pe n di x 2 )

A st o ol sa m ple will be o btai ne d f or c ult ure f or pat h o ge nic bacteria, o va a n d parasite 
e val uati o n, a n d C. difficile t o xi n assa y d uri n g scree ni n g f or t he p ur p oses of deter mi ni n g 
eli gi bilit y.

O btai n uri ne sa m ple ( refere nce St u d y  Pr oce d ure Ta ble i n A p pe n di x 2 )

O btai n uri ne sa m ple f or uri ne dr u g scree n (refere nce St u d y  Pr oce d ure Ta ble i n A p pe n di x 2 )
A si n gle retest of scree ni n g la bs is per mitte d o nl y  if t here is reas o n t o belie ve t he retest val ue will 
be wit hi n acce pte d para meters, or if t he i nitial val ue was eit her d ue t o a sa m ple pr ocessi n g err or 
or a n e xte n uati n g circ u msta nce.
S u bjects meeti n g all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria will ret ur n t o t he 
cli nic wit hi n 3 0 da ys after scree ni n g f or ra n d o mizati o n int o t he st u d y. S u bjects ma y be 
ra n d o mize d m ore t ha n 3 0 da ys after i nitial scree ni n g if t he y recei ve per missi o n fr o m t he 
Gi lea d Me dical M o nit or.
If t he s u bject d oes n ot be gi n t he treat me nt wit hi n t his 3 0-da y wi n d o w, 
s pecific scree ni n g e val uati o n pr oce d ures m a y  nee d t o be re peate d at t he directi o n of t he 
Gilea d Me dical M o nit or. N o m ore t ha n o ne re peat scree ni n g visit is all o we d f or eac h s u bject, 
u nless pri or writte n a p pr o val has bee n pr o vi de d b y t he S p o ns or.

Fil g o ti ni b 
Pr o t oc ol G S -U S- 4 1 8 -3 8 9 8 
Gi l e a d S ci e n c es , I nc. 
Fi na l 
A m e n d m e nt 5 
Fr o m t h e tim e of o bt ai n in g i nf on n e d c on s ent th r ou g h t h e first ad mi nistr nti o n of i nv esti g ati o n al 
m e di c i nal pr o du ct, re c ord all S A Es , as w ell as a n y A Es r elat e d t o pr ot o c ol -ma n d at e d pr o c e dur es 
o n t h e ad v ers e e v en ts e C R F. A ll ot h er u n t o w ar d m e di c al o c c m Te n ces o bs er v e d d mi n g t h e 
s cr e en i n g p e ri od, i ncl udi n g e x ac er b ati on or c h a n g es i n m e di c al h ist o1y  ar e t o b e c a ptur e d o n t h e 
m e di c al hi st o1y e C R F . S e e S e cti o n 7 A d v ers e E v e n ts a n d T o x icit y M a n a g e m e nt f or a d diti on al 
d et ai ls. 
6. 2. 2. 
D a y l 
T h e f ollo w i ng t ests a n d pr o c e d ur es m u st b e c o m p let e d pr i or t o r a n d o mi z ati o n a n d 
d osi n g/ dis p e n si n g: 
• 
R e vi e w i n clu si o n/ e x cl usi o n cr it eri a a n d ot h er pr ot o c o l restri cti o ns 
• 
S y m pt o m di r e ct e d P E i nclu di n g b o d y w e i g ht 
• 
O bt a i n b o d y w e i g ht a nd vi t al si g ns (resti ng bl o o d pr essur e, res pir at o1y r at e, p u ls e a n d 
t em p er at ur e) 
• 
R e vi e w A Es a n d c o n c o mit ant m e di c at i o ns 
• 
R e vi e w e- Diai y re p o 1is f or c o m pli an ce a n d s c ores - r emi n d s u bje cts of di ai y i nstr u cti o ns at 
e v er y visit 
• 
C o lle ct t h e vai·ia bles t o c al cul a t e p aiii al M C S (see A p p e n di x 4) 
-
Sit e c o lle cts p at i e nt ass ess m e nts at e a ch visit 
-
M C S ca l c ul at e d c en ti·all y aft er all c om p o n e nts h a v e b e e n c a ptu r ed el e ctr on i c ally 
•  
Ha ve s u bje ct c om pl et e H R Q o L q u esti o n n air es 
• 
A d mi nist er H C R U q u esti o n n air e 
• 
O bt a i n fasti ng bl o o d s ai n pl es (r ef er e nce St u d y P r o c e dur e T a bl e i n A p p e n di x 2) 
• 
O bt a i n bl o o d s ai n pl e f or vf P B M C a n d leu k o c yt e s ubs ets ( U S a n d C a n a di a n sit es o nl y) 
I 
• 
O bt a i n ur i n e s ai n pl e (ref er e nce St u d y P r o c e d ur e T a bl e i n A p p e n di x 2) 
-
S ai n pl e wi ll b e us e d f or ur i nal ys is a n d pre g n a n c y t est (f or fem al es of c hil d beai·i ng 
p ot e nti al o n l y) 
C O N FI D E N TI A L 
P a g e 6 9 
0 2 A pril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 0
0 2 A pril 2 0 1 9
6. 3.
R a n d o miz ati o n
Please refer t o Secti o n 6. 1 .
6. 3. 1.
R a n d o miz ati o n a n d St u d y Dr u g A d mi nistr ati o n

E nter s u bject i nf or mati o n i n t he I W R S t o recei ve ra n d o mizati o n assi g n me nt

Dis pe nse st u d y  dr u g as directe d b y t he I WR S

I nstr uct t he s u bject o n t he pac ka gi n g, st ora ge, a n d a d mi nistrati o n of t he st u d y dr u g

O bser ve t he s u bject t a ki n g t he first d ose of st u d y dru g a n d rec or d t he ti me of first d ose 
6. 4.
St u d y Assess me nts
6. 4. 1.
Pri orit y of Assess me nts
S u bject -re p orte d o utc o mes are rec o m me n de d t o be c o m plete d bef ore a n y  ot her st u d y pr oce d ures. 
I n vasi ve st u d y pr oce d ures s uc h as bl o o d dra ws a n d bi o psies s h o ul d be d o ne at t he e n d of a st u dy 
visit, as m uc h as p ossi ble. I n vesti gat or q uesti o n naires/assess me nts s h o ul d be perf or me d pri or t o 
re vie wi n g s u bject-re p orte d o utc o mes f or t hat visit, as m uc h as p ossi ble. 
6. 4. 2.
Effic ac y
Efficac y  assess me nts will be perf or me d at t he ti me p oi nts i n dicate d i n t he St u d y Pr oce d ures 
Ta ble ( A p pe n di x 2 ). 
6. 4. 2. 1.
Ma y o Cli nic Sc ore ( M C S)
Ma y o Sc ori n g s ys te m f or assess me nt of ulcerati ve c olitis acti vit y. Refer t o A p pe n di x 4 .
6. 4. 2. 2.
3 6- Ite m S h ort F or m Healt h y S ur ve y
T he S F -3 6 is a healt h relate d q ualit y  of life i nstr u me nt c o nsisti n g of 3 6 q uesti o ns bel o n gi n g t o 
8 d o m ai ns i n 2 c o m p o ne nts a n d c o vers a 4 -wee k recall peri o d:

P h y sical well-bei n g , 4 d o mai ns: p h y sical f u ncti o ni n g ( 1 0 ite ms), r ole p h ysical ( 4 ite ms), 
b o dil y  pai n ( 2 ite ms), a n d ge neral healt h perce pti o ns ( 5 ite ms)

M e ntal well -bei n g , 4 d o mai ns: vitalit y  ( 4 ite ms), s ocial f u ncti o ni n g ( 2 ite ms), r ole e m oti o nal 
( 3 ite ms), a n d me ntal healt h ( 5 ite ms).
T he re mai ni n g ite m ( healt h tra nsiti o n) is n ot part of t he a b o ve d o mai ns b ut is ke pt se paratel y . 
T hese scales will be rescale d fr o m 0 t o 1 0 0 (c o n verti n g t he l o west p ossi ble sc ore t o 0 a n d t he 
hi g hest p ossi ble sc ore t o 1 0 0), wit h hi g her sc ores i n dicati n g a better q ualit y  of life. T he S F-3 6 is 
n ot disease s pecific a n d has bee n vali date d i n n u mer o us healt h states.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 1
0 2 A pril 2 0 1 9
6. 4. 2. 3.
W or k Pr o d ucti vit y  a n d Acti vit y Im pair me nt Q uesti o n naire ( W P AI) 
T he W P AI  is a desi g ne d t o meas ure t he effect of ge neral healt h a n d sy m pt o m se verit y  o n w or k 
pr o d ucti vit y  a n d re g ular acti vities d uri n g t he past se ve n da ys.
6. 4. 2. 4.
E Q - 5 D
T he E Q -5 D is a sta n dar dize d i nstr u me nt de vel o pe d b y  t he E ur o Q o l Gr o u p as a meas ure of 
healt h -relate d q ualit y of life t hat ca n be use d i n a wi de ra n ge of healt h c o n diti o ns a n d treat me nts.
6. 4. 2. 5.
I B D Q
T his disease -s pecific q uesti o n naire c o m prises 3 2 q uesti o ns di vi de d i nt o f o ur healt h s u bscales: 
b o wel s y m pt o ms ( 1 0 q uesti o ns); s yste mic s ym pt o ms, i ncl u di n g slee p dis or ders a n d fati g ue 
( 5 q uesti o ns); e m oti o nal f u ncti o n s uc h as de pressi o n, a g gressi o n a n d irritati o n ( 1 2 q uesti o ns); 
a n d s ocial f u ncti o n, mea ni n g t he a bilit y t o partici pate i n s ocial acti vities a n d t o w or k 
( 5 q uesti o ns).
6. 4. 3.
S afet y
Safet y  will be assesse d via A Es, c o nc o mita nt me dicati o ns, p h ysical e xa mi nati o ns (c o m plete a n d 
s ym pt o m -dri ve n), vital si g ns, E C Gs, a n d cli nical la b orat or y  res ults.
6. 4. 3. 1.
Cli nical L a b orat or y E val uati o ns
T he he mat ol o g y , ser u m c he mistr y, c oa g ulati o n la b orat or y, a n d st o ol a nal ys es will be perf or me d 
at a ce ntral la b orat or y. Refere nce ra n ges will be s u p plie d b y t he ce ntral la b orat or y a n d will be 
use d b y  t he i n vesti gat or t o assess t he la b orat or y data f or cli nical si g nifica nce a n d pat h ol o gical 
c ha n ges.
Bl o o d sa m pl es will be c ollecte d b y ve ni p u nct ure ( or o pti o nal i n d welli n g cat heter f or P K 
sa m pli n g da ys) i n t he ar m at t he ti me p oi nts i n dicate d i n t he St u d y Pr oce d ures Ta ble 
(A p pe n di x 2 ). In a d diti o n, uri ne sa m ples f or t he cli nical la b orat or y  assess me nts will be c ollecte d. 
A n o ver ni g ht fast ( n o f o o d or dri n ks, e xce pt water) of at least  8 h o urs will be re q uire d pri or t o 
c ollecti o n of bl o o d sa m ples f or li pi d testi n g.
A st o ol sa m ple s h o ul d als o be c ollecte d at a n y ti me d uri n g t he st u d y f or c ult ure f or pat h o ge nic 
bacteria, o va a n d parasites, a n d C. diff t o xi n assa y w he n a s u bject bec o mes s y m pt o matic, 
i ncl u di n g w orse ni n g or ret ur n of disease acti vit y.
R efer t o A p pe n di x 7 f or ta ble of cli nical la b orat or y tests.
La b orat or y  val ues o utsi de t he n or mal ra n ge will be fla g ge d a n d cli nical rele va nce will be 
assesse d b y t he i n vesti gat or. M ore fre q ue nt sa m pli n g as well as a d diti o nal tests ma y  be 
perf or me d as dee me d necessar y  b y t he i n vesti gat or.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 2
0 2 A pril 2 0 1 9
N ote t hat i n t he case w here cli nicall y si g nifica nt la b orat or y test res ults are a p ote ntial reas o n f or 
disc o nti n uati o n fr o m t he st u d y  dr u g a n d/ or wit h dra wal fr o m t he st u d y, retesti n g of t he affecte d 
para meter(s) s h o ul d be pr o m pt ( wit hi n 3 t o 7 da y s [e xce pt creati ni ne, w hic h s h o ul d be reteste d 
7 t o 1 4 da y s a part]).
T he details of sa m ple ha n dli n g a n d s hi p me nt i nstr ucti o ns will be pr o vi de d i n a se parate 
la b orat or y ma n ual.
6. 4. 3. 2.
Pre g na nc y  Testi n g (f or fe males of c hil d beari n g p ote ntial)
All fe males meeti n g t he c hil d beari n g p ote ntial criteria m ust ha ve a ser u m pre g na nc y  testi n g at 
scree ni n g a n d a n i n-cli nic uri ne pre g na nc y test m ust be c o m plete d e ver y  4 wee ks at a mi ni m u m. 
If a ny pre g na nc y  test is p ositi ve, st u d y dr u g s h o ul d be i m me diatel y i nterr u pte d a n d t he s u bject 
s h o ul d ha ve a ser u m pre g na nc y test i n cli nic t hat will be ce ntrally re p orte d.
6. 4. 3. 3.
Vital Si g ns
Vital si g ns will be meas ure d at t he ti me p oi nts i n dicate d i n t he St u d y  Pr oce dures Ta ble 
(A p pe n di x 2 ).
Vital si g ns s h o ul d be ta ke n after t he s u bject has bee n resti n g i n t he seate d or s u pi ne p ositi o n f or 
at least 5 mi n utes a n d will i ncl u de p ulse rate, res pirat or y rate, sys t olic a n d diast olic bl o o d 
press ure, a n d te m perat ure.
6. 4. 3. 4.
P h y sical E xa mi nati o n
A p h y sical e xa mi nati o n s h o ul d be perf or me d at t he ti me p oi nts i n dicate d i n t he St u d y Pr oce d ures 
Ta ble ( A p pe n di x 2 ). A n y c ha n ges fr o m scree ni n g will be rec or de d. Wei g ht will be meas ure d at 
all visits. Hei g ht will be meas ure d at scree ni n g o nl y . S u bjects s h o ul d be i nstr ucte d t o re m o ve 
s h oes pri or t o meas ureme nt of hei g ht.
At scree ni n g, a c o m plete p h y sical e xa mi nati o n will be perf or me d. A c o m plete p h ysical 
e xa mi nati o n will i ncl u de s o urce d oc u me ntati o n of ge neral a p peara nce a n d t he f oll o wi n g b o d y 
s yste ms: hea d, nec k, a n d t h yr oi d; e yes, ears, n ose, t hr oat, m o ut h a n d t o n g ue; c hest 
(e xcl u di n g breasts); res pirat or y ; car di o vasc ular; l y m p h n o des; a b d o me n; s ki n, hair, nails; 
m usc ul os keletal; a n d ne ur ol o gical. S y m pt o m -dri ve n p h y sical e xa mi nati o ns will be perf or me d at 
all ot her visits base d o n re p orte d si g ns a n d s y m pt o m s.
6. 4. 3. 5.
1 2 -lea d Electr ocar di o gra m
A resti n g 1 2 -lea d E C G will be perf or me d at t he ti me p oi nts i n dicate d i n t he St u d y Pr oce d ures 
Ta ble ( A p pe n di x 2 ).
T he E C G s h o ul d be o btai ne d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at least 
5 mi n utes a n d will i ncl u de heart rate ( H R), i nter- beat ( R R), Q R S, u nc orrecte d Q T, m or p h ol o g y , 
a n d r h yt h m a nal ys is. Electr ocar di o gra ms will be i nter prete d b y t he i n vesti gat or 
( or q uali fie d desi g nee) f or cli nical si g nifica nce a n d res ults will be e ntere d i nt o t he e C R F.

Fil g o ti ni b 
Pr ot o c o l G S -U S- 4 1 8 -3 8 9 8 
Gi le a d S ci e n c es , I nc. 
6. 4. 4. 
P h a r m a c o ki n eti c s As sess m e nts 
Fi na l 
A m e n d m e nt 5 
T h e P K sa m pl e at W e e k 4 is c o llecte d p os t- dos e (at le ast 3 0 mi n ut es a n d u p t o 3 h o ur s after 
st ud y d m g d os i ng) . F o r t his visit, it is pr e f e ne d t h at st u dy d m g d os i ng is d o n e i n cl i nic. T h e P K 
sa m pl e at W e e ks 2 6 ca n b e c o llect e d at a ny ti me wit h o ut r e gar d t o dos i ng. T h e P K sa m pl e at 
W e e ks 1 0 a nd 5 8 ar e c o llecte d at pr e- d os e ( wit hi n 2 h o ur s pr i or t o d os i ng). 
S u bj e c ts w h o c on s ent t o t h e o pt i o n al P K su b st u dy w ill h a v e ad di ti on al pl as m a P K sa m pl es at a ny 
si ngl e visit fro m W e e k 2 t o W e e k 1 0, c o lle cte d pr e- dos e , a n d at 0. 5, 1, 2, 3, 4 a n d 6 h o ur s aft e r 
s up e r vis e d d os i ng i n t he cli nic. If a s u b- st u dy P K sa mpl e is s ch e d ul e d t o b e c o lle ct e d at t h e sa me 
ti me as a s p ar s e P K sa m pl e, o nl y o n e s a m pl e s h oul d b e c o llecte d. 
F o r all visits wit h P K sa mp li ng, t he t i me of d os e t a ke n pr i or t o a n d o n t he d a y of visit w ill b e 
n ot e d i n th e e C R F . Pl asm a c on centr ati ons of filg ot i ni b a nd its met a b o lite ( G S-8 2 9 8 4 5) wi ll b e 
an al yze d. 
6. 4. 5. 
Bi o m a r k e r As sess m e nts 
Bl o o d s am pl es wi ll b e c o lle cte d o n D a y 1 a n d at W e e ks 4, 1 0 , 2 6 , a n d 5 8 . 
Bl o o d s am pl es m a y b e a n alyze d f or ass essm e nt of m ar k ers of i nfl a m matio n, i m m u ne st at us, a n d 
J A K-S T A T p at h w a y a ctiv ati o n. 
-
6. 5. 
P o st- T r e at m e nt As sess m e nts 
A ll s u bj ects m u st c om pl et e t h e P T x assess m e n ts 3 0 d a ys aft e r th e l ast d os e of st ud y d m g. 
S u bj e c ts w h o ent er i nt o t he L T E st ud y ( G S-U S - 4 18- 3 8 9 9) w ill n ot c o m pl et e P T x ass essm e n ts 
ass o ci ate d wit h t his pr ot o c o l. 
T h e f ollo w i ng w ill b e p er f on n e d a n d d o c u m e n te d: 
• 
S y m p t om dir e ct e d P E 
•  
Obt a i n b o d y we i g ht a n d vi t al si g ns (resti ng bl o o d pr essur e, res pir at o1y rate, pul s e a n d 
t em p e r at ure) 
•  
Re vie w A Es a n d c o n c 0 1ni tant m e di c atio ns 
C O N FI D E N TI A L 
P a g e 7 3 
0 2 A pril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 4
0 2 A pril 2 0 1 9

O btai n bl o o d sa m ples ( refere nce St u d y  Pr oce d ure Ta ble i n A p pe n di x 2 )

O btai n uri ne sa m ple (refere nce St u d y  Pr oce d ures Ta ble [A p pe n di x 2 ])

P re g na nc y test (f or fe males of c hil d beari n g p ote ntial o nl y)
6. 6.
E arl y Ter mi n ati o n Assess me nts
T he f oll o wi n g will be perf or me d a n d d oc u me nte d:

S y m pt o m directe d P E

O btai n b o d y  wei g ht a n d vital si g ns (resti n g bl o o d press ure, res pirat or y rate, p ulse a n d 
te m perat ure)

Perf or m 1 2 - Lea d E C G (f or s u bjects w h o ter mi nate pri or t o Wee k 1 0)

Re vie w A Es a n d c o nc o mita nt me dicati o ns

C ollect e -Diar y  bac k fr o m s u bject 

C ollect t he varia bles t o calc ulate partial M C S ( see A p pe n di x 4 )

Site c ollects patie nt assess me nts at eac h visit

M C S calc ulate d ce ntrall y after all c o m p o ne nts ha ve bee n ca pt ure d electr o nicall y

O btai n fasti n g bl o o d sa m ples ( refere nce St u d y  Pr oce d ure Ta ble i n A p pe n di x 2 )

O btai n uri ne sa m ple (refere nce St u d y  Pr oce d ures Ta ble [A p pe n di x 2 ])

P re g na nc y test (f or fe males of c hil d beari n g p ote ntial o nl y)
6. 7.
E n d of St u d y
Please refer t o Secti o n 3. 7 .
6. 8.
P ost St u d y C are
Please r efer t o Secti o n 3. 8 .

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 5
0 2 A pril 2 0 1 9
7.
A D V E R S E E V E N T S A N D T O XI CI T Y  M A N A G E M E N T
7. 1.
Defi niti o n s of A d verse E ve nts, A d verse Re acti o ns, a n d Seri o us A d verse
E ve nts
7. 1. 1.
A d verse E ve nts
A n a d verse e ve nt ( A E ) is a n y u nt o war d me dical occ urre nce i n a cli nical st u d y s u bject 
a d mi nistere d a me dici nal pr o d uct , w hic h d oes n ot necessaril y  ha ve a ca usal relati o ns hi p wit h t he
treat me nt. A n A E ca n t heref ore be a ny u nfa v ora ble a n d / or u ni nte n de d si g n, s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d re late d t o 
t he me dici nal pr o d uct. A d verse e ve nts m a y  als o i ncl u de pre- or p ost -treat me nt c o m plicati o ns t hat 
occ ur as a res ult of pr ot oc ol s pecifie d pr oce d ures, lac k of efficac y , o ver d ose, dr u g a b use/ mis use 
re p orts, or occ u pati o nal e x p os ure. Pree xisti n g e ve nts t hat i ncrease i n se verit y or c ha n ge i n nat ure
d uri n g or as a c o nse q ue nce of partici pati o n i n t he cli nical st u d y  will als o be c o nsi dere d A Es.
A n A E d oes n ot i ncl u de t he f oll o wi n g:

Me dical or s ur gical pr oce d ures s uc h as s ur ger y, e n d osc o p y, t o ot h e xtracti o n, a n d tra nsf usi o n.
T he c o n diti o n t hat le d t o t he pr oce d ure m a y  be a n a d verse e ve nt a n d m ust be re p orte d.

Pre -e xisti n g diseases , c o n diti o ns , or la b orat or y  a b n or malities prese nt or detecte d bef ore t he 
scree ni n g visit t hat d o n ot w orse n

Sit uati o ns w here a n u nt o war d me dical occ urre nce has n ot occ urre d ( e g, h os pitalizati o n f or 
electi ve s ur ger y, s ocial a n d/ or c o n ve nie nce a d missi o ns)

O ver d ose wit h o ut cli nical se q uelae ( See Secti o n 7. 7. 1 )

A n y  me dical c o n diti o n or cli nicall y si g nifica nt la b orat or y a b n or malit y wit h a n o nset date 
bef ore t he c o nse nt f or m is si g ne d a n d n ot relate d t o a pr ot oc ol -ass ociate d pr oce d ure is n ot a n 
A E. I t is c o nsi dere d t o be pre-e xisti n g a n d s h o ul d be d oc u me nte d o n t he me dical hist or y  
e C R F.
7. 1. 2.
Seri o us A d verse E ve nts
A seri o us a d verse e ve nt (S A E ) is defi ne d as a n e ve nt t hat, at a n y d ose, res ults i n t he f oll o wi n g:

D eat h

L ife-t hreate ni n g ( N ote: T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n 
e ve nt i n whic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n 
e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if it were m ore se vere.)

I n-patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

P ersiste nt or si g nific a nt disa bilit y/i nca pacity

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 6
0 2 A pril 2 0 1 9

A c o n ge nital a n o mal y/ birt h defect

A me dicall y i m p orta nt e ve nt or reacti o n: s uc h e ve nts ma y  n ot be i m me diatel y 
life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y  
re q uire i nter ve nti o n t o preve nt o ne of t he ot her o utc o mes c o nstit uti n g S A Es. Me dical a n d 
scie ntific j u d g me nt m ust be e xercise d t o deter mi ne w het her s uc h a n e ve nt is a re p orta ble 
u n der e x pe dite d re p orti n g r ules. E xa m ples of m e dicall y i m p orta nt eve nts i ncl u de i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m; bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; a n d de vel o p me nt of dr u g de pe n de nc y  or 
dr u g a b use. F or t he a v oi da nce of d o u bt, i nfecti o ns res ulti n g fr o m c o nta mi nate d me dici nal 
pr o d uct will be c o nsi dere d a m e dicall y i m p orta nt eve nt a n d s u bject t o e x pe dite d re p orti n g 
re q uire me nts.
7. 2.  
Assess me nt of A d verse E ve nts a n d Seri o us A d verse E ve nts
T he i n vesti gat or or q ualifie d s u b-i n vesti gat or is res p o nsi ble f or assessi n g A Es a n d S A Es f or 
ca usalit y a n d se verit y, a n d f or fi nal re vie w a n d c o nfir mati o n of acc urac y of e ve nt i nf or mati o n 
a n d assess me nts .
7. 2. 1.
Assess me nt of C a us alit y f or St u d y Dr u gs a n d Pr oce d ures
T he i n vesti gat or or q ualifie d s u b-i n vesti gat or is res p o nsi ble f or assessi n g t he relati o ns hi p t o I M P
t hera py usi n g cli nical j u d g me nt a n d t he f oll o wi n g c o nsi derati o ns:

N o : E vi de nce e xists t hat t he a d verse e ve nt has a n eti ol o g y ot her t ha n t he I M P. F or S A Es, a n 
alter nati ve ca usalit y m ust be pr o vi de d (e g, pre -e xisti n g c o n diti o n, u n derl yi n g disease, 
i ntercurre nt ill ness, or c o nc o mita nt me dicati o n).

Yes : T here is reas o na ble p ossi bilit y  t hat t he e ve nt ma y ha ve bee n ca use d b y t he 
i n vesti gati o nal me dici nal pr o d uct.
It s h o ul d be e m p hasize d t hat i neffecti ve treat me nt s h o ul d n ot be c o nsi dere d as ca usally relate d i n 
t he c o nte xt of a d verse e ve nt re p orti n g. 
T he relati o ns hi p t o st u d y  pr oce d ures (e g, i n vasi ve pr oce d ures s uc h as ve ni p u nct ure or bi o psy) 
s h o ul d be assesse d usi n g t he f oll o wi n g c o nsi derati o ns:

N o: E vi de nce e xists t hat t he a d verse e ve nt has a n eti ol o g y ot her t ha n t he st u d y pr oce d ure.

Yes: T he a d verse e ve nt occ urre d as a res ult of pr ot oc ol pr oce d ures (e g, ve ni p u n ct ure)
7. 2. 2.
Assess me nt of Se verit y
T he se verit y of A Es will be gra de d usi n g t he m o difie d C o m m o n Ter mi n ol o g y  Criteria f or 
A d verse E ve nts ( C T C A E ), versi o n 4. 0 3. F or eac h e pis o de, t he hi g hest gra de attai ne d s h o ul d be 
re p orte d.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 7
0 2 A pril 2 0 1 9
If a C T C A E criteri o n d oes n ot e xist, t he i n vesti gat or s h o ul d use t he gra de or a djecti ves: 
Gra de 1 ( mil d), Gra de 2 ( m o derate), Gra de 3 (se vere), Gra de 4 (life-t hreate ni n g) or 
Gra de 5 (fatal) t o descri be t he ma xi m u m i nte nsit y of t he a d verse e ve nt. F or p ur p oses of 
c o nsiste nc y wit h t he C T C A E, t hese i nte nsit y gra des are defi ne d i n Ta ble 7 - 1 a n d A p pe n di x 5 .
T a ble 7- 1.
Gr a di n g of A d verse E ve nt Se verit y
Gr a de
A djecti ve
Descri pti o n
Gra de 1
Mil d
As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d 
Gra de 2
M o derate
L ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -a p pr o priate 
i nstr u me ntal A D L 
Gra de 3
Se vere
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; 
li miti n g self-care A D L 
Gra de 4
Life -t hreate ni n g
Ur ge nt i nter ve nti o n i n dicate d 
Gra de 5
Deat h 
Deat h relate d A E 
*  
Acti vities of Dail y Li vi n g ( A D L) I nstr u me ntal A D L refer t o o pe ni n g pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, 
usi n g t he tele p h o ne, ma na gi n g m o ne y, etc. 
* *
Self -care A D L refer t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g me dicati o ns, a n d n ot 
be dri d de n. 
7. 3. 
I n vesti g at or Re q uire me nts a n d I nstr ucti o ns f or Re p orti n g A d verse E ve nts 
a n d Seri o us A d verse E ve nts t o Gile a d 
Re q uire me nts f or c ollecti o n pri or t o st u d y dr u g i nitiati o n:
After i nf or me d c o nse nt, b ut pri or t o i nitiati o n of st u d y  me dicati o n, t he f oll o wi n g ty pes of e ve nts 
s h o ul d be re p orte d o n t he e C R F: all S A Es a n d a d v erse e ve nts relate d t o pr ot oc ol- ma n date d 
pr oce d ures.
7. 3. 1.
A d verse E ve nts
F oll o wi n g i nitiati o n of st u d y  me dicati o n, all A Es, re gar dless of ca use or relati o ns hi p, u ntil 
3 0 da y s after last a d mi nistrati o n of st u d y  IM P m ust be re p orte d t o t he e C R F data base as 
i nstr ucte d.
All A Es s h o ul d be f oll o we d u p u ntil res ol uti o n or u ntil t he a d verse e ve nt is sta ble, if p ossi ble. 
Gilea d m a y  re q uest t hat certai n A Es be f oll o we d be yo n d t he pr ot oc ol defi ne d f oll o w u p peri o d.
7. 3. 2.
Seri o us A d verse E ve nts
All S A Es, re gar dless of ca use or relati o ns hi p, t hat occ ur s after t he s u bject first c o nse nts t o 
p artici pate i n t he st u d y (ie, si g ni n g t he i nf or me d c o nse nt) a n d t hr o u g h o ut t he d urati o n of t he 
st u d y, i ncl u di n g t he pr ot oc ol-re q uire d p ost treat me nt f oll o w-u p peri o d, m ust be re p orte d t o t he 
e C R F data base a n d Gilea d P V E as i nstr ucte d. T his als o i ncl u des a n y S A Es res ulti n g fr o m 
pr ot oc ol -ass ociate d pr oce d ures perf or me d after i nf or me d c o nse nt is si g ne d.

Fil g o ti ni b 
Pr ot o c o l G S -U S- 4 1 8 -3 8 9 8 
Gil e a d S ci e n c es , I nc. 
Fi na l 
A m e n d m e n t 5 
A n y S A Es a n d d e a t hs t hat o c c ur aft er t h e p ost tr·eat ment f ollo w -u p visit b ut wit hi n 3 0- d a ys of t h e 
last d os e of stu d y I M P, re g ardl ess of c au s alit y, s h o ul d als o b e re p o 1te d . 
I n v esti g at ors ar e n ot o bli g at e d t o a cti v e l y s e ek S A Es aft er t h e pr ot o c ol d efi n e d f ollo w u p p er i o d. 
H o w e v er , if t h e i nv esti g at o r l e ar ns of a n y S A Es t h at o c c ur aft er st ud y p aiti c i pati o n h as 
c on cl u d e d a n d t h e e v e nt is d e e m e d r ele v a nt t o t h e u s e of I M P, h e/ s h e s h o ul d pr o m ptl y d o c u m e nt 
a n d re p ort th e e v ent t o Gi le a d P V E . 
•  
All A Es a n d S A Es wi ll b e re c ord e d i n t h e e C R F d at a b as e wit hi n t h e ti m eli nes o ut li ne d i n t h e 
e C R F c om pl eti o n g u id e li ne. 
• 
At th e tim e of stu d y st art, S A Es m a y b e re p ort e d us i ng a p a p e r s eri o us a d v ers e e v ent 
r e p o1ti n g f o 1 m. Dur i ng t h e st u d y c on d u ct, sit es m a y u-a nsiti o n t o a n electr· on i c S A E ( e S A E) 
s yst em . Gi l e a d wi ll n otif y sit es i n wr iti ng a n d pr o vi d e u-a i ni ng a nd a c c o u nt i nf on n ati o n pr i or 
t o i m ple m en ti n g a n e S A E s yst e m. 
Elec u- o ni c S eri o us A d v ers e E v e nt R e p o1t i ng P r o c ess 
• 
Sit e p ers o n n el r e c or d all S A E d at a i n th e e C R F d at a b as e a n d fr o m t h er e tr·a ns mit th e S A E 
i nf o1m ati o n t o Gi le a d P V E wit hi n 2 4 h o ur s of t h e i nv esti g at or's k n o w le d g e of t h e e v en t. 
D et ai le d i nstr u cti ons c a n b e f o u nd i n t h e e C R F c o m pl eti o n g u id e li nes . 
• If f or a n y r e as on it is n ot p ossi b l e t o r e c or d t h e S A E i nf o1m ati o n el ectr·o ni c all y, ie, t h e e C R F 
d at a b as e is n ot f u ncti on i n g, r e c or d t h e S A E o n th e p a p e r s eri ous a d v ers e e v ent r e p orti ng 
f o 1 m a n d s u b mit wit h i n 2 4 h o urs as d es cr ib e d a b o v e . 
G il e a d S ci e n c e s PV E 
F a x : 
E - m ail: 
P D 
P D 
• 
As s o o n as it is p oss ibl e t o d o s o , a n y S A E re p ort e d vi a p a p er m ust b e tr·a nscrib e d i nt o t h e 
e C R F D at a b as e a c c or di ng t o i nstr u cti o ns i n th e e C R F c o m pl eti on g u i d eli n es. 
• If a n S A E h as b e e n r e p o 1te d vi a a p a p er f on n b e c a us e t h e e C R F d at a b as e h as b e e n l o c k e d, 
n o f uith er a cti o n is n e c ess ai y. 
• 
F o r f at al or life-t hre at e ni n g e v e n ts, c o pi es of h os pit al c as e re p o 1ts, a u t o ps y r e p o1ts, a n d ot h er 
d o c u m e nts ai·e al s o t o b e s ub mitt e d b y e- m ail or f a x w h e n r e qu est e d a n d a p pli c a b l e. 
T ran s missi on of s u c h d o c u m e n ts s h o ul d o c c ur wit h o ut p ers o n al s ubj e ct i d en tifi c ati on, 
m ai nt ai n i ng t h e u-acea bi lit y of a d o c u m e nt t o t h e s ubj e ct i d en tifi ers. 
• 
A d diti o n al i nf on n ati o n m a y b e re qu est e d t o e ns ur e t h e ti m el y c o m p leti o n of a c cur at e s af et y 
r e p o1ts. 
• 
A n y m e di c ati o ns n e c ess ai y f or tr·eat ment of t h e S A E m u st b e r e c or d ed o n t o t h e c on c o mit a nt 
m e di c at i o n s e cti o n of t h e s ubj e ct's e C R F a n d t h e e v ent desc ri pti o n s e cti o n of t h e S A E f on n. 
C O N FI D E N TI A L 
P a g e 7 8 
0 2 A pril 2 0 1 9 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 7 9
0 2 A pril 2 0 1 9
7. 4.
Gile a d Re p orti n g Re q uire me nts
De pe n di n g o n rele va nt l ocal le gislati o n or re g ulati o ns, i ncl u di n g t he a p plica ble U S F D A C o de of 
Fe deral Re g u lati o ns ( C F R), t he E U Cli nical Trials Directi ve ( 2 0 0 1/ 2 0/ E C) a n d rele va nt u p dates, 
a n d ot her c o u ntr y-s pecific le gislati o n or re g ulati o ns, Gilea d m a y  be re q uire d t o e x pe dite t o 
w orl d wi de re g ulat or y  a ge ncies re p orts of S A Es , seri o us a d verse d r u g reacti o ns ( S A D Rs) , or 
S U S A Rs. I n acc or da nce wit h t he E U Cli nical Trials Directi ve ( 2 0 0 1/ 2 0/ E C), Gilea d or a 
s pecifie d desi g nee will n otif y w orl d wi de re g ulat or y a ge ncies a n d t he rele va nt I RB/I E C i n 
c o ncer ne d Me m ber States of a p plica ble S U S A Rs as o utli ne d i n c urre nt re g ulati o ns.
Assess me nt of e x pecte d ness f or S A Es will be deter mi ne d b y  Gilea d usi n g refere nce safet y 
i nf or mati o n s pecifie d i n t he i n vesti gat or's br oc h ure (I B) or rele va nt l ocal la bel as a p plica ble. 
All i n vesti gat ors will recei ve a safet y letter n otif yi n g t he m of rele va nt S U S A R re p orts ass ociate d 
wit h a n y  st u d y IM P . T he i n vesti gat or s h o ul d n otif y t he I R B or I E C of S U S A R re p orts as s o o n as 
is practical, w here t his is re q uire d by l ocal re g ulat or y a ge ncies, a n d i n acc or da nce wit h t he l ocal 
i nstit uti o nal p olic y. 
T o mi ni mize t he p ossi bilit y  of e x p osi n g st u dy s u bjects t o u n us ual ris k, t he safet y i nf or mati o n 
fr o m t his st u d y will als o be re vie we d peri o dically b y  an i n de pe n de nt D M C 
(as descri be d i n Secti o n 8. 1 0 ). T he D M C ma y ha ve access t o partially bli n de d or u n bli n de d data 
a n d will ma ke rec o m me n dati o ns re gar di n g t he st u d y  acc or di n g t o t he D M C c harter. 
7. 5.
Cli nic al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts as 
A d verse E ve nts or Seri o us A d verse E ve nts
La b orat or y  a b n or malities are us ually n ot rec or de d as A Es or S A Es. H o we ver, la b orat or y  
a b n or malities (e g, cli nical c he mistr y, he mat ol o g y, a n d uri nalys is) i n de pe n de nt of t he 
u n derl y i n g me dical c o n diti o n t hat re q uire me dical or s ur gical i nter ve nti o n or lea d t o 
i n vesti gati o nal me dici nal pr o d uct i nterr u pti o n or disc o nti n uati o n m ust be rec or de d as a n A E, as 
well as a n S A E, if a p plica ble. I n a d diti o n, la b orat or y  or ot her a b n or mal assess me nts 
(e g, E C G, x- ra ys, vital si g ns) t hat are ass ociate d wit h si g ns a n d/ or sy m p t o ms m ust be rec or de d as 
a n A E or S A E if t he y meet t he defi niti o n of a n A E ( or S A E) as descri be d i n Secti o ns 7. 1. 1 a n d 
7. 1. 2 . If t he la b orat or y a b n or malit y is part of a sy n dr o me, rec or d t he sy n dr o me or dia g n osis 
(ie, a ne mia) n ot t he la b orat or y  res ult (ie, decrease d he m o gl o bi n).
Se verit y  s h o ul d be rec or de d a n d gra de d acc or di n g t o t he C T C A E Gra di n g Scale f or Se verit y of 
A d verse E ve nts a n d La b orat or y  A b n or malities (A p pe n di x 5 ). F or A Es ass ociate d wit h la b orat or y 
a b n or malities, t he e ve nt s h o ul d be gra de d o n t he basis of t he cli nical se verit y i n t he c o nte xt of 
t he u n derlyi n g c o n diti o ns; t his ma y  or ma y n ot be i n a gree me nt wit h t he gra di n g of t he 
la b orat or y a b n or malit y.
7. 6.
T o xicit y M a n a ge me nt
All cli nical a n d cli nicall y si g nifica nt la b orat or y t o xicities will be ma na ge d acc or di n g t o u nif or m 
g ui deli nes detaile d i n A p pe n di x 3 , a n d as o utli ne d bel o w.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 0
0 2 A pril 2 0 1 9
Refer t o Secti o n 3. 5 , Criteria f or St u dy Dr u g I nterr u pti o n or Disc o nti n uati o n, f or a d diti o nal 
s pecific disc o nti n uati o n criteria. S pecific t o xicit y disc o nti n uati o n criteria i n Secti o n 3. 5
s u perce de bel o w ge neral t o xicit y g ui deli nes, a n d i n ge neral, w here discre pa nc y is prese nt, t he 
m ore c o nser vati ve criteria a p pl y. T he Gilea d Me dical M o nit or s h o ul d be c o ns ulte d pri or t o st u d y  
dr u g disc o nti n uati o n w he n me dicall y  feasi ble.
7. 6. 1.
Gr a des 1 a n d 2 L a b or at or y A b n or m alit y or Cli nic al E ve nt
C o nti n ue st u d y  dr u g at t he discreti o n of t he i n vesti gat or.
7. 6. 2.
Gr a de 3 L a b or at or y A b n or m alit y or Cli nic al E ve nt

F or a Gra de 3 cli nicall y s i g nifica nt la b orat or y a b n or malit y or cli nical e ve nt, IM P ma y  be 
c o nti n ue d if t he e ve nt is c o nsi dere d t o be u nrelate d t o I M P.

F or a Gra de 3 cli nical e ve nt, or cli nicall y si g nifica nt la b orat or y a b n or malit y c o nfir me d b y 
re peat testi n g, t hat is c o nsi dere d t o be relate d t o I M P, IM P s h o ul d be wit h hel d u ntil t he 
t o xicit y ret ur ns t o ≤ Gra de 2.

If a la b orat or y a b n or malit y rec urs t o ≥ Gra de 3 f oll o wi n g re -c halle n ge wit h IM P a n d is 
c o nsi dere d relate d t o I M P, t he n I M P s h o ul d be per ma ne ntl y  disc o nti n ue d a n d t he s u bject 
ma na ge d acc or di n g t o l ocal practice. Rec urre nce of la b orat or y  a b n or malities c o nsi dere d 
u nrelate d t o I M P ma y  n ot re q uire per ma ne nt disc o nti n uati o n.
7. 6. 3.  
Gr a de 4 L a b or at or y A b n or m alit y or Cli nic al E ve nt

F or a Gra de 4 cli nical e ve nt or cli nicall y si g nifica nt Gra de 4 la b orat or y a b n or mal it y 
c o nfir me d b y re peat testi n g t hat is c o nsi dere d relate d t o I M P, I M P s h o ul d be per ma ne ntl y  
disc o nti n ue d a n d t he s u bject ma na ge d acc or di n g t o l ocal practice. T he s u bject s h o ul d be 
f oll o we d as cli nically i n dicate d u ntil t he la b orat or y a b n or malit y ret ur ns t o baseli ne or is 
ot her wise e x plai ne d, w hic he ver occ urs first. A cli nicall y  si g nifica nt Gra de 4 la b orat or y 
a b n or malit y t hat is n ot c o nfir me d b y re peat testi n g s h o ul d be ma na ge d acc or di n g t o t he 
al g orit h m f or t he ne w t o xicit y  gra de.
I n vesti gati o nal me dici nal pr o d uct ma y  be c o nti n ue d wit h o ut d ose i nterr u pti o n f or a cli nicall y 
n o n- si g nifica nt Gra de 4 la b orat or y a b n or malit y (e g, Gra de 4 creati ne ki nase [ C K] after stre n u o us 
e xercise or tri gl yceri de ele vati o n t hat is n o nfasti n g or t hat ca n be me dicall y ma na ge d) or a 
cli nical e ve nt c o nsi dere d u nrelate d t o I M P.
Treat me nt -e mer ge nt t o xicities will be n ote d b y  t he i n vesti gat or a n d br o u g ht t o t he atte nti o n of 
t he Gilea d M e dical M o nit or, w h o will ha ve a disc ussi o n wit h t he i n vesti gat or a n d deci de t he 
a p pr o priate c o urse of acti o n. W het her or n ot c o nsi dere d treat me nt -relate d, all s u bjects 
e x perie nci n g A Es m ust be m o nit ore d peri o dicall y  u ntil s ym pt o ms s u bsi de, a n y  a b n or mal 
la b orat or y val ues ha ve res ol ve d or ret ur ne d t o baseli ne le vels or t he y are c o nsi dere d irre versi ble, 
or u ntil t here is a satisfact or y  e x pla nati o n f or t he c ha n ges o bser ve d.
A n y  q uesti o ns re gar di n g t o xicit y ma na ge me nt s h o ul d be directe d t o t he Gilea d Me dical M o nit or.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 1
0 2 A pril 2 0 1 9
7. 7.
S peci al Sit u ati o ns Re p orts
7. 7. 1.
Defi niti o ns of S peci al Sit u ati o ns
S pecial sit uati o n re p orts i ncl u d e all re p orts of me dicati o n err or, a b use, mis use, o ver d ose, re p orts 
of a d verse e ve nts ass ociate d wit h pr o d uct c o m plai nts , pre g na nc y  re p orts re gar dless of a n 
ass ociate d A E , a n A E i n a n i nfa nt f oll o wi n g e x p os ure fr o m breastfee di n g, a n d a n occ u pati o nal 
e x p os ure wit h a n A E .  
Me dicati o n err or is a ny u ni nte nti o nal err or i n t he prescri bi n g, dis pe nsi n g , or a d mi nistrati o n of a 
me dici nal pr o d uct w hile i n t he c o ntr ol of t he healt h care pr o vi der , s u bject, or c o ns u mer.
A b use is defi ne d as persiste nt or s p ora dic i nte nti onal e xcessi ve use of a me dici nal pr o d uct b y  a 
s u bject.
Mis use is defi ne d as a ny i nte nti o nal a n d i na p pr o priate use of a me dici nal p r o d uct t hat is n ot i n 
acc or da nce wit h t he pr ot oc ol i nstr ucti o ns or t he l ocal prescri bi n g i nf or mati o n .
A n o ver d ose is defi ne d as a n acci de ntal or i nte nti o nal a d mi nistrati o n of a q ua ntit y  of a me dici nal 
pr o d uct gi ve n per a d mi nistrati o n or c u m ulati vel y  w hic h is a b o ve t he ma xi m u m rec o m me n de d 
d ose as per pr ot oc ol or i n t he pr o d uct la belli n g (as it a p plies t o t he dail y  d ose of t he s u bject i n 
q uesti o n). I n cases of a discre pa nc y i n dr u g acc o u nta bilit y, o ver d ose will be esta blis he d o nl y 
w he n it is clear t hat t he s u bject has ta ke n t he e xcess d ose(s). O ver d ose ca n n ot be esta blis he d 
w he n t he s u bject ca n n ot acc o u nt f or t he discre pa nc y  e xce pt i n cases i n w hic h t he i n vesti gat or has 
reas o n t o s us pect t hat t he s u bject has ta ke n t he a d diti o nal d ose(s).
Occ u pati o nal e x p os ure wit h a n A E is defi ne d as e x p os ure t o me dici nal pr o d uct as res ult of o ne's 
pr ofessi o nal or n o n -pr ofessi o nal occ u pa ti o n.
Pr o d uct c o m plai nt is de fi ne d as c o m plai nts arisi n g fr o m p ote ntial de viati o ns i n t he ma n ufact ure, 
pac ka gi n g, or distri b uti o n of t he me dici nal pr o d uct.
7. 7. 2.
I nstr ucti o ns f or Re p orti n g S peci al Sit u ati o ns
7. 7. 2. 1.
I nstr ucti o ns f or Re p orti n g Pre g na ncies
T he i n vesti gat o r s h o ul d re p ort pre g na ncies i n fe male st u d y s u bjects t hat are i de ntifie d after 
i nitiati o n of st u d y  me dicati o n a n d t hr o u g h o ut t he st u d y, i ncl u di n g t he p ost st u d y dr u g f oll o w -u p 
peri o d, t o Gilea d P V E usi n g t he pre g na nc y  re p ort f or m wit hi n 2 4 h o urs of bec o mi ng a ware of 
t he pre g na nc y.
Refer t o S ecti o n 7. 3 a n d t he e C R F c o m pleti o n g ui deli nes f or f ull i nstr ucti o ns o n t he mec ha nis m 
of pre g na nc y  re p orti n g.
T he pre g na nc y  itself is n ot c o nsi dere d a n A E n or is a n i n d uce d electi ve a b orti o n t o ter mi nate a 
pre g na nc y  wit h o ut me dical reas o ns.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 2
0 2 A pril 2 0 1 9
A n y  pre mature ter mi nati o n of pre g na nc y  (e g, a s p o nta ne o us a b orti o n, a n i n d uce d t hera pe utic 
a b orti o n d ue t o c o m plicati o ns or ot her me dical reas o ns ) m ust be re p orte d wit hi n 2 4 h o urs as a n 
S A E. T he u n derl yi n g me dical reas o n f or t his pr oce d ure s h o ul d be rec or de d as t he A E ter m.
A s p o nta ne o us a b orti o n is al wa y s c o nsi dere d t o be a n S A E a n d will be re p orte d as descri be d i n 
Secti o n 7. 3. 2 . F urt her m ore, a ny S A E occ urri n g as a n a d verse pre g na nc y  o utc o me p ost st u d y
m ust be re p orte d t o Gilea d P V E
T he s u bject s h o ul d recei ve a p pr o priate m o nit ori n g a n d care u ntil t he c o ncl usi o n of t he 
pre g na nc y . T he o utc o me s h o ul d be re p orte d t o Gilea d P V E usi n g t he pre g na nc y o utc o me re p ort 
f or m. If t he e n d of t he pre g na nc y occ urs after t he st u d y has been c o m plete d, t he o utc o me 
s h o ul d be re p orte d directl y  t o Gilea d P V E . Gilea d P V E c o ntact i nf or mati o n is as f oll o ws:
E mail: 
 a n d Fa x: 
. 
Pre g na ncies of fe male part ners of male st u d y s u bjects e x p ose d t o Gilea d or ot her st u d y  dr u gs 
s h o ul d als o be re p orte d a n d rele va nt i nf or mati o n s h o ul d be s u b mitte d t o Gilea d P V E usi n g t he 
pre g na nc y  a n d pre g na nc y o utc ome f or ms wit hi n 2 4 h o urs. M o nit ori n g of t he s u bject s h o ul d 
c o nti n ue u ntil t he c o ncl usi o n of t he pre g na nc y . If t he e n d of t he pre g na nc y occ urs after t he 
st u d y has bee n c o m plete d, t he o utc o me s h o ul d be rep orte d directl y t o Gilea d P V E
fa x n u m ber
 or e mail 
 
Refer t o A p pe n di x 6 f or Pre g na nc y  Preca uti o ns, Defi niti o n f or Fe male of C hil d beari n g P ote ntial, 
a n d C o ntrace pti ve Re q uire me nts .
7. 7. 2. 2. 
R e p orti n g Ot her S pecial Sit uati o ns
All ot her s pecial sit uati o n re p orts m ust be re p orte d o n t he s pecial sit uati o ns re p ort f or m a n d 
f or war de d t o Gilea d P V E wit hi n 2 4 h o urs of t he i n vesti gat or bec o mi n g a ware of t he sit uati o n. 
T hese re p orts m ust c o nsist of sit u ati o ns t hat i n v ol ve st u d y IM P
a n d/ or Gilea d c o nc o mita nt 
me dicati o ns , b ut d o n ot a p pl y t o n o n- Gilea d c o nc o mita nt me dicati o ns. 
S pecial sit uati o ns i n v ol vi n g n o n- Gilea d c o nc o mita nt me dicati o ns d oes n ot nee d t o be re p orte d o n 
t he s pecial sit uati o ns re p ort f or m; h o we ver, f or s pecial sit uati o ns t hat res ult i n A Es d ue t o a 
n o n- Gilea d c o nc o mita nt me dicati o n, t he A E s h o ul d be re p orte d o n t he A E f or m. 
A n y  i na p pr o priate use of c o nc o mita nt me dicati o ns pr o hi bite d b y  t his pr ot oc ol s h o ul d n ot be 
re p orte d as “ mis use,” b ut ma y  be m ore a p pr o priatel y d oc u me nte d as a pr ot oc ol de viati o n.
Refer t o S ecti o n 7. 3 a n d t he e C R F c o m pleti o n g ui deli nes f or f ull i nstr ucti o ns o n t he mec ha nis m 
o f s pecial sit uati o ns re p orti n g.
All cli nical se q uelae i n relati o n t o t hese s pecial sit uati o n re p orts will be re p orte d as A Es or S A Es 
at t he sa me ti me usi n g t he A E e C R F a n d/ or t he S A E re p ort f or m. Details of t he s y m pt o ms a n d 
si g ns, cli nical ma na ge me nt, a n d o utc o me will be re p orte d, w he n a vaila ble.
P P D
P P D
P P D
P P D

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 3
0 2 A pril 2 0 1 9
8.
S T A T I S TI C A L C O N SI D E RA T I O N S
8. 1.
A n al ysis O bjecti ves a n d E n d p oi nts
U nless ot her wise s pecifie d, all t he efficac y  e n d p oi nts base d o n M C S will utilize t he ce ntral rea d 
e n d osc o pic s u bsc ore. T he l ocal rea d e n d osc o pic s u bsc ore will be utilize d i nt o t he se nsiti vit y 
a nal ys is wit h details bei n g i ncl u de d i n t he statistical a nalys is pla n (S A P ).
8. 1. 1.
A n al ysis O bjecti ves
C o h ort A I n d ucti o n St u d y
T he pri mar y  o bjecti ve of C o h ort A is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g E B S re missi o n 
at Wee k
1 0
T he ke y  sec o n dar y o bjecti ves of C o h ort A are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
at Wee k
1 0

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g a n e n d osc o pic 
s u bsc ore of 0 at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g Ge b oes 
hist ol o gic re missi o n at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
(alter nati ve defi niti o n) at Wee k 1 0
T he ot her sec o n dar y o bjecti ves of C o h ort A are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b 

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of C o h ort A are:

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n i m pr o vi n g e n d osc o pic 
a p peara nce as deter mi ne d b y U C EI S sc ori n g sys te m at Wee k
1 0

T o e val uate t he ass ociati o n of c ha n ges i n sys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P-9 ) 
wit h cli nical o utc o mes

T o e val uate st o ol micr o bi o me

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 4
0 2 A pril 2 0 1 9

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , 
disease pr o gressi o n , a n d treat me nt res p o nse t o fil g oti ni b

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n ac hie vi n g n o vel hist ol o gic 
o utc o mes (e g, res ol uti o n of basal plas mac yt osis)
C o h ort B I n d ucti o n St u d y
T he p ri mar y o bjecti ve of C o h ort B is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g E B S re missi o n 
at Wee k
1 0
T he ke y  sec o n dar y o bjecti ves of C o h ort B are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
at Wee k
1 0

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g a n e n d osc o pic 
s u bsc ore of 0 at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g Ge b oes 
h ist ol o gic re missi o n at Wee k
1 0

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
(alter nati ve defi niti o n) at Wee k 1 0
T he ot her sec o n dar y o bjecti ves of C o h ort B are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b 

T o as sess the P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of C o h ort B are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n i m pr o vi n g e n d osc o pic 
a p peara nce as deter mi ne d b y  U C EI S sc ori n g sys te m at Wee k
1 0

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n a n d fecal M M P-9) 
wit h cli nical o utc o mes

T o e val uate st o ol micr o bi o me

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 5
0 2 A pril 2 0 1 9

T o c haracterize t he ass ociati o n of h os t ge netics a n d ot her mar kers wit h disease se verit y, 
disease pr o gressi o n , a n d treat me nt res p o nse t o fil g oti ni b

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n ac hie vi n g n o vel hist ol o gic 
o utc o mes (e g, res ol uti o n of basal plas mac yt osis)
M ai nte n a nce St u d y
T he pri mar y o bjecti ve of t he Mai nte na nce St u d y is:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g E B S re missi o n 
at Wee k
5 8 
T he ke y  sec o n dar y o bjectives of t he Mai nte na nce St u d y are:

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g s ustai ne d E B S 
re missi o n at Wee k 5 8, defi ne d as E B S re missi o n at b ot h Wee ks
1 0 a n d 5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g 6- m o nt h 
c ortic oster oi d -free E B S re missi o n at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g a n e n d osc o pic 
s u bsc ore of 0 at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g Ge b oes 
hist ol o gic re missi o n at Wee k
5 8

T o e val uate t he efficac y  of fil g oti ni b as c o m pare d t o place b o i n esta blis hi n g M C S re missi o n 
(alter nati ve defi niti o n) at Wee k 5 8
T he ot her sec o n dar y  o bjecti ves of t he Mai nte na nce St u d y are:

T o e val uate t he safet y a n d t olera bilit y of fil g oti ni b 

T o assess t he P K c haracteristics of fil g oti ni b
T he e x pl orat or y  o bjecti ves of t he Mai nte na nce St u d y  are:

T o e val uate t he efficac y of fil g oti ni b i n i m pr o vi n g e n d osc o pic a p peara nce as deter mi ne d b y 
U C EI S sc ori n g sys te m at Wee k
5 8

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 6
0 2 A pril 2 0 1 9

T o e val uate t he efficac y  of fil g oti ni b i n esta blis hi n g s ustai ne d M C S re missi o n at Wee k 5 8, 
defi ne d as M C S re missi o n at b ot h Wee ks
1 0 a n d 5 8

T o e val uate t he efficac y  of fil g oti ni b i n esta blis hi n g 6- m o nt h c ortic oster oi d -free M C S 
re missi o n at Wee k
5 8 

T o e val uate t he ass ociati o n of c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers 
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P-9 ) 
wit h cli nical o utc o mes 

T o e val uate st o ol micr o bi o me

T o c haracterize t he ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , 
disease pr o gressi o n , a n d treat me nt res p o nse t o fil g oti ni b

T o e val uate H R Q o L

T o e val uate t he effect of fil g oti ni b o n H C R U

T o e val uate t he efficac y of fil g oti ni b as c o m pare d t o place b o i n ac hie vi n g n o vel hist ol o gic 
o utc o mes (e g, res ol uti o n of basal plas mac yt osis)
8. 1. 2.
Pri m ar y E n d p oi nt
C o h ort A I n d ucti o n St u d y

T he pr o p orti o n of s u bject s ac hie vi n g E B S re missi o n at Wee k
1 0
C o h ort B I n d ucti o n St u d y

T he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k
1 0
M ai nte n a nce St u d y

T he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k
5 8
8. 1. 3.
Sec o n d ar y E n d p oi nt
C o h ort A I n d ucti o n St u d y
T he k e y sec o n dar y e n d p oi nts of C o h ort A are:

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g e n d osc o pic s u bsc ore of 0 at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g Ge b oes hist ol o gic r e missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n (alter nati ve defi niti o n)
at Wee k 1 0

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 7
0 2 A pril 2 0 1 9
T he ot her sec o n dar y e n d p oi nt of C o h ort A is:

P K c haracteristics f or fil g oti ni b a n d its meta b olite G S -8 2 9 8 4 5 
C o h ort B I n d ucti o n St u d y
T he k e y  sec o n dar y e n d p oi nts of C o h o rt B are:

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g e n d osc o pic s u bsc ore of 0 at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g Ge b oes h ist ol o gic re missi o n at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n (alter nati ve defi niti o n)
at Wee k 1 0
T he ot her sec o n dar y  e n d p oi nt of C o h ort B is:

P K c haracteristics f or fil g oti ni b a n d its meta b olite G S - 8 2 9 8 4 5 
M ai nte n a nce St u d y
T he k e y  sec o n dar y e n d p oi nts of t he Mai nte na nce St u d y  are:

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g s ustai ne d E B S re missi o n, defi ne d as esta blis hi n g E B S 
re missi o n at b ot h Wee ks
1 0 a n d 5 8

T he pr o p orti o n of s u bjects ac hie vi n g 6- m o nt h c ortic oster oi d -free E B S re missi o n at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g e n d osc o pic s u bsc ore of 0 at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g Ge b oes h ist ol o gic re missi o n at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g M C S re missi o n (alter nati ve defi niti o n)
at Wee k 5 8
T he ot her sec o n dar y  e n d p oi nt of the Mai nte na nce St u d y  is:

P K c haracteristics f or fil g oti n i b a n d its meta b olite G S- 8 2 9 8 4 5
8. 1. 4.
E x pl or at or y E n d p oi nts:
C o h ort A I n d ucti o n St u d y
T he e x pl orat or y e n d p oi nts f or C o h ort A a re:

C ha n ge fr o m baseli ne i n U C EI S at Wee k
1 0

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 8
0 2 A pril 2 0 1 9

Ass ociati o n bet wee n c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers
(e g i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P - 9)
wit h cli nical o utc o mes

St o ol micr o bi o me assess me nts

Ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , disease pr o gressi o n,
a n d treat me nt res p o nse t o fil g oti ni b

C ha n ge fr o m baseli ne i n H R Q o L  sc ores at Wee k
1 0

H C R U assess me nts at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g n o vel hist ol o gic o utc o mes at Wee k 1 0
C o h ort B I n d ucti o n St u d y
T he e x pl orat or y  e n d p oi nts f or C o h ort B are:

C ha n ge fr o m baseli ne i n U C EI S at Wee k
1 0

Ass ociati o n bet wee n c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a nd fecal M M P -9)
wit h cli nical o utc o mes

St o ol micr o bi o me assess me nts

Ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , disease pr o gressi o n,
a n d treat me nt res p o nse t o fil g oti ni b

C ha n ge fr o m baseli ne i n H R Q o L  sc ores at Wee k
1 0

H C R U assess m e nts at Wee k
1 0

T he pr o p orti o n of s u bjects ac hie vi n g n o vel hist ol o gic o utc o mes at Wee k 1 0
M ai nte n a nce St u d y
T he e x pl orat or y  e n d p oi nts f or t he M ai nte na nce st u d y are:

C ha n ge fr o m baseli ne i n U C EI S at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g s ustai ne d M C S re missi o n, defi ne d as M C S re missi o n at 
b ot h Wee ks
1 0 a n d 5 8

T he pr o p orti o n of s u bjects ac hie vi n g 6- m o nt h c ortic oster oi d -free M C S re missi o n at Wee k
5 8

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 8 9
0 2 A pril 2 0 1 9

Ass ociati o n bet wee n c ha n ges i n s ys te mic or l ocalize d i nfla m mat or y bi o mar kers
(e g, i ncl u di n g b ut n ot li mite d t o C R P, fecal cal pr otecti n, fecal lact oferri n, a n d fecal M M P -9)
wit h cli nical o utc o mes

St o ol micr o bi o me assess me nts

Ass ociati o n of h ost ge netics a n d ot her mar kers wit h disease se verit y , disease pr o gressi o n,
a n d treat me nt res p o nse t o fil g otini b

C ha n ge fr o m baseli ne i n H R Q o L  sc ores at Wee k
5 8

H C R U assess me nts at Wee k
5 8

T he pr o p orti o n of s u bjects ac hie vi n g n o vel hist ol o gic o utc o mes at Wee k 5 8
8. 2.
A n al ysis C o n ve nti o ns
8. 2. 1.
A n al ysis Sets
8. 2. 1. 1.
Efficac y
T he pri mar y  a nalys is set f or efficac y is t he F ull A nal ysis Set ( F A S). 

T he F A S f or eac h I n d ucti o n St u d y  ( C o h orts A a n d B) i ncl u des all ra n d o mize d s u bjects w h o 
recei ved at least o ne d ose of st u d y dr u g i n t he c orres p o n di n g I n d ucti o n St u d y (Da y 1 t o 
Wee k
1 0).

T he F A S f or Mai nte na nce St u d y  i ncl u des all re-ra n d o mize d s u bjects w h o met t he pr ot oc ol 
defi niti o n of E B S re missi o n or M C S res p o nse at Wee k
1 0, a n d recei ve d at least o ne d ose of 
st u d y dr u g i n t he Mai nte na nce St u d y (Wee ks
1 1 t o 5 8) .
S u bjects will be a nal y ze d acc or di n g t o t he treat me nt gr o u p t he y were ra n d o mize d t o f or t he 
a nal ys is peri o d.
8. 2. 1. 2.
Safet y
T he pri mar y  a nalys is set f or safet y is t he Safety A nal ysis Set. 

T he S afet y A nal y sis S et f or eac h I n d ucti o n St u d y ( C o h orts A a n d B) i ncl u des all su bjects 
w h o recei ve d at least o ne d ose of st u d y  dr u g i n t he c orres p o n di n g I n d ucti o n St u d y (Da y 1 t o 
Wee k
1 0). 

T he S afet y A nal y sis S et f or t he Mai nte na nce St u d y i ncl u des all s u bjects w h o recei ve at least 
o ne d ose of st u d y dr u g i n t he Mai nte na nce St u d y ( Wee ks
1 1 t o 5 8).

T he O verall S afet y A nal y sis S et f or t he st u d y i ncl u des all s u bjects w h o recei ve d at least 
o ne d ose of st u d y dr u g fr o m Da y 1 t o Wee k
5 8.
S u bjects will be a nal y ze d acc or di n g t o t he st u d y dr u g t he y act ually recei ve d f or t he a nal ysis 
peri o d.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 0
0 2 A pril 2 0 1 9
8. 2. 1. 3.
P har mac o ki netics
8. 2. 1. 3. 1.
P har mac o ki netic S u bst u d y A nal y sis Set
T he pri mar y  a nalys is set f or i nte nsi ve P K a nalys es will be t he P K s u bst u d y a nalys is set f or eac h 
I n d ucti o n St u d y ( C o h orts A a n d B), w hic h i ncl u des all s u bjects i n t he Safet y A nal y sis Set fr o m 
t he c orres p o n di n g I n d ucti o n St u d y w h o ha ve e nr olle d i nt o t he P K s u bst u d y, a n d ha ve i nte nsi ve 
c o nce ntrati o n data t o pr o vi de i nter preta ble res ults f or t he s pecific para meters of i nterest f or t he 
a nal yt e u n der e val uati o n.
8. 2. 1. 3. 2.
P har mac o ki netic A nal y sis Set
T he pri mar y  a nalys is set f or ge neral P K a nal yses will be defi ne d se paratel y f or eac h i n di vi d ual 
st u d y ( C o h ort A I n d ucti o n St u d y, C o h ort B I n d ucti o n St u d y, a n d Mai nte na nce St u d y). F or eac h 
st u d y, t he P K a nal ysis set i ncl u des all s u bjects i n t he c orres p o n di n g Safet y A nal y sis Set w h o 
ha ve at least o ne n o n missi n g plas ma c o nce ntrati o n data f or fil g oti ni b a n d/ or its metab olite 
G S - 8 2 9 8 4 5.
8. 2. 1. 4.
Bi o mar ker A nal ys is Set
T he Bi o mar ker A nal ys is Set will be defi ne d se paratel y  f or eac h i n di vi d ual st u d y 
( C o h ort A I n d ucti o n St u d y, C o h ort B I n d ucti o n St u d y a n d Mai nte na nce St u d y). F or eac h st u dy, 
t he Bi o mar ker A nalys is Set i ncl u des all s u bjects i n t he c orres p o n di n g Safet y  A nalys is Set w h o 
ha ve t he necessar y  baseli ne a n d o n-st u d y meas ure me nts t o pr o vi de i nter preta ble res ults f or t he 
s pecific para meters of i nterest.
8. 3.
D at a H a n dli n g C o n ve nti o ns
Val ues f or missi n g safet y la b orat or y data will n ot be i m p ute d. H o we ver, a missi n g baseli ne res ult 
will be re place d wit h a scree ni n g res ult, if a vaila ble. If n o pre -treat me nt la b orat or y val ue is 
a vaila ble, t he baseli ne val ue will be ass u me d t o be n or mal (ie, n o gra de [ Gra de 0]) f or t he 
s u m mar y of gra de d la b orat or y a b n or malities. If safet y la b orat or y res ults f or a s u bject are missi n g 
f or a ny reas o n at a ti me p oi nt, t he s u bject will be e xcl u de d fr o m t he calc ulati o n of s u m mar y  
statistics f or t hat ti me p oi nt.
Val ues f or missi n g vital si g ns data will n ot be i m p ute d. H o we ver, a missi n g baseli ne res ult will 
be re place d wit h a scree ni n g res ult, if a vaila ble. 
P K c o nce ntrati o n val ues a n d P K para meter val ues bel o w t he li mit of q ua ntitati o n ( B L Q) will be 
prese nte d as “ B L Q” i n t he data listi n gs. B L Q val ues t hat occ ur pri or t o t he first d ose will be 
treate d as 0, B L Q val ues at all ot her ti me p oi nts will be treate d as 1/ 2 of t he l o wer li mit of 
q ua ntit ati o n ( L L O Q).
La b orat or y  data t hat are c o nti n u o us i n nat ure b ut are less t ha n t he L L O Q or a b o ve t he u p per li mit 
of q ua ntitati o n will be i m p ute d t o t he val ue of t he l o wer or u p per li mit mi n us or pl us 
o ne si g nifica nt di git, res pecti vel y ( e g, if t he res ult of a c o nti n u o us la b orat or y test is < 2 0, a val ue 
of 1 9 will be assi g ne d; if t he res ult of a c o nti n u o us la b orat or y test is < 2 0. 0, a val ue of 1 9. 9 will 
be assi g ne d).
Pr oce d ure s f or ha n dli n g missi n g data f or M C S (a n d c o m p o ne nts) will be descri be d i n t he S A P.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 1
0 2 A pril 2 0 1 9
8. 4.  
D e m o gr a p hic D at a a n d B aseli ne C h ar acteristics
De m o gra p hic a n d baseli ne meas ure me nts f or eac h i n di vi d ual st u d y (C o h ort A I n d ucti o n St u d y , 
C o h ort B I n d ucti o n St u d y, a n d Mai nte na nce St u d y) will be s u m marize d se parately b y treat me nt 
gr o u p usi n g sta n dar d descri pti ve statistics ( n, mea n, sta n dar d de viati o n [ S D], me dia n, 1 st q uartile 
[ Q 1], 3r d q uartile [ Q 3], mi ni m u m, ma xi m u m) f or c o nti n u o us varia bles a n d n u m ber a n d 
perce nta ge of s u bjects f or cate g orical varia bles.
De m o gra p hic s u m maries will i n cl u de a ge, se x, race, a n d et h nicit y. Baseli ne c haracteristics m a y
i ncl u de hei g ht, wei g ht, b o d y mass i n de x ( B MI), M C S, n u m ber of years si nce U C dia g n ose d, 
c o nc o mita nt use of oral c ortic oster oi ds, c o nc o mita nt use of i m m u n o m o d ulat ors , fecal 
cal pr otecti n , ser um C R P , a n d ot her varia bles of i nterest.
8. 5.
Effic ac y A n al ysis
8. 5. 1.
Pri m ar y A n al ysis
F or eac h i n di vi d ual st u d y ( C o h ort A I n d ucti o n St u d y , C o h ort B I n d ucti o n St u d y, a n d 
Mai nte na nce St u d y) , the pri mar y  a nalys is will c o m pare eac h fil g oti ni b d ose gr o u p t o place b o o n 
t he pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n at Wee k
1 0 ( I n d ucti o n St u dies, C o h ort A 
a n d B) a n d at Wee k
5 8 ( Mai nte na nce St u d y ), res pecti vely . T he C oc hra n-Ma ntel -Hae nszel 
( C M H) a p pr oac h a dj usti n g f or stratificati o n fact ors will be use d f or hy p ot hesis testi n g of t he 
pri mar y  e n d p oi nt wit hi n eac h st u d y. See Secti o n 8. 5. 3 f or t he si g nifica nt le vel t hat will be use d 
t o declare a statistical si g nifica nt treat me nt effect f or eac h fil g oti ni b d ose gr o u p w he n c o m pare d 
t o place b o f or eac h i n di vi d ual st u d y ( C o h ort A I n d ucti o n St u d y, C o h ort B I n d ucti o n St u d y, a n d 
Mai nte na nce St u d y) . F or e val uati o n of E B S re missi o n at Wee ks 1 0 a n d 5 8, M C S sc ore at 
scree ni n g will be use d as baseli ne val ue.
S u bjects w h o d o n ot ha ve s ufficie nt meas ure me nts t o deter mi ne efficac y e n d p oi nts will be 
c o nsi dere d fail ures (ie, n o n -res p o n der i m p utati o n [ N RI]). Se nsiti vit y  a nalyses will be descri be d 
i n t he S A P.
8. 5. 2. 
Sec o n d ar y A n al yses
T he sa me statistical met h o d s use d f or testi n g t he pri mar y  efficac y e n d p oi nt will be utilize d f or 
testi n g t he ke y sec o n dar y e n d p oi nts i n eac h st u d y ( Co h ort A I n d ucti o n St u d y , C o h ort B 
I nd ucti o n St u d y , a n d Mai nte na nce St u dy) se paratel y . S u bjects w h o d o n ot ha ve s ufficie nt 
meas ure me nts t o deter mi ne t he efficac y  e n d p oi nts will be c o nsi dere d fail ures (ie, N RI) .
8. 5. 3.
M ulti plicit y A dj ust me nts
T he gra p hical a p pr oac h { Bretz 2 0 0 9 } t o se q ue ntiall y rejecti ve m ulti ple test pr oce d ures will be 
use d t o c o ntr ol a fa mil y- wise t y pe I err or rate ( F W E R) at 5 % (ie, α = 0. 0 5) f or eac h i n di vi d ual 
st u d y ( C o h ort A I n d ucti o n St u d y, C o h ort B I n d ucti o n St u d y, a n d Mai nte na nce St u d y). T his 
pr oce d ure st r o n gly pr otects t he F W E R o n all t he pri mar y a n d ke y sec o n dar y e n d p oi nts.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 2
0 2 A pril 2 0 1 9
I n d ucti o n St u dies ( C o h orts A a n d B)
F or eac h i n di vi d ual st u d y ( C o h ort A I n d ucti o n St u d y , C o h ort B I n d ucti o n St u d y, a n d 
Mai nte na nce St u d y), a B o nferr o ni a p pr oac h wit h e q u al al p ha all ocati o n of 0. 0 2 5 ( 2 -si de d) t o 
eac h fil g oti ni b d ose gr o u p c o m paris o n wit h place b o will be us e d t o c o ntr ol t he o verall 
st u d y-wi de t y p e I err or rate at 0. 0 5 wit hi n eac h st u d y . T o pr otect t he i nte grit y  of t he st u dy d ue t o 
t he u n bli n de d i nteri m f utilit y a nalys is pla n ne d f or eac h i n d uc ti o n st u d y ( C o h ort A a n d C o h ort B) 
( details i n S ecti o n 8. 1 0 ), a n al p ha of 0. 0 0 0 0 1 will be s pe nt f or eac h fil g oti ni b d ose gr o up 
c o m paris o n t o place b o wit hi n eac h i n d ucti o n st u d y. As a res ult, a n o mi nal p-val ue of less t ha n 
0. 0 2 4 9 9 ( 2-si de d) will be nee de d t o declare statistical si g nifica nce f or t he fi nal pri mar y  a nal ysis 
of eac h fil g oti ni b d ose gr o u p w he n c o m pare d t o place b o t o co ntr ol t he st u d y -wise t y p e I err or 
rate at 0. 0 5. If o ne fil g oti ni b d ose gr o u p is disc o nti n ue d f or f utilit y at t he i nteri m f utilit y a nalys is, 
t he o verall al p ha err or rate sta ys u nc ha n ge d at a 2-si de d 0. 0 2 4 9 9 le vel f or t he c o nti n ui n g 
fil g oti ni b d ose gr o u p at t he pri mar y a nalys is. 
T he h y p ot heses t o be test e d f or t he i n d ucti o n st u dies are o utli ne d bel o w. 
T he pri mar y  n ull h yp ot heses t o be teste d:

H 1: T he E B S re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he E B S re missi o n rate 
i n t he place b o gr o u p at Wee k 1 0

H 2: T he E B S re missi o n rate i n t he fil g o ti ni b 1 0 0 m g gr o u p is e q ual t o t he E B S re missi o n rate 
i n t he place b o gr o u p at Wee k 1 0
T he ke y  sec o n dar y n ull h yp ot heses t o be teste d:

H 3: T he M C S re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he M C S re missi o n 
rate i n t he place b o gr o u p at Wee k 1 0

H 4: T he M C S re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he M C S re missi o n 
rate i n t he place b o gr o u p at Wee k 1 0

H 5: T he e n d osc o pic s u bsc ore of 0 rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he 
e n d osc o pic s u bsc ore of 0 rate i n t he place b o gr o u p at Wee k 1 0

H 6: T he e n d osc o pic s u bsc ore of 0 rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he 
e n d osc o pic s u bsc ore of 0 rate i n t he place b o gr o u p at Wee k 1 0

H 7: T he Ge b oes hist ol o gic re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he 
Ge b oes hist ol o gic re missi o n rate i n t he place b o gr o u p at Wee k 1 0

H 8: T he Ge b oes hist ol o gic re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he 
Ge b oes hist ol o gic re missi o n rate i n t he place b o gr o u p at Wee k 1 0

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 3
0 2 A pril 2 0 1 9

H 9: T he M C S re missi o n (alter nati ve defi n iti o n) rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual 
t o t he M C S re missi o n (alter nati ve defi niti o n) rate i n t he place b o gr o u p at Wee k 1 0

H 1 0: T he M C S re missi o n (alter nati ve defi niti o n) rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual 
t o t he M C S re missi o n (alter nati ve defi niti o n) rate i n t he place b o gr o u p at Wee k 1 0
If t he pri mar y n ull h yp ot hesis is rejecte d, t he n t he ne xt ke y  sec o n dar y h yp ot hesis i n t he sa me 
fil g oti ni b d osi n g re gi me n will be teste d at t he sa me al p ha le vel. Testi n g of t he h yp ot heses will be 
perf or me d i n t he or der o utli ne d i n Fi g ure 8 - 1 (In d ucti o n St u dies) i n t he sa me fil g oti ni b d osi n g 
re gi me n. O nce all hy p ot heses wit hi n t he sa me fil g oti ni b d osi n g re gi me n are rejecte d, t he n t he 
res pecti ve 0. 0 2 4 9 9 al p ha ca n be passe d o n t o t he ot her re gi me n’s hy p ot heses, t hat is, all 
h y p ot heses i n t he ot her fil g oti ni b d osi n g re gi me n will be teste d at 0. 0 4 9 9 8 ( 2 -si de d) f or 
I n d ucti o n St u dies. If a n e n d p oi nt wit hi n a fil goti ni b d osi n g re gi me n fails t o reac h statistical 
si g nifica nce, t he n f or mal se q ue ntial testi n g will st o p a n d o nl y n o mi nal si g nifica nce will be 
re p orte d f or t he re mai ni n g e n d p oi nts wit hi n t hat fil g oti ni b d osi n g re gi me n. If n ot all pri mar y a n d 
ke y  sec o n dar y hy p ot heses wit hi n t he sa me fil g oti ni b d osi n g re gi me n ca n be rejecte d, all 
h y p ot heses i n t he ot her fil g oti ni b d osi n g re gi me n will still be teste d at 0. 0 2 4 9 9 ( 2-si de d) f or 
I n d ucti o n St u dies. 
A gra p hical ill ustrati o n of t he testi n g strate g y  f or t he pri mar y a nd ke y  sec o n dar y h yp ot heses i n 
t he In d ucti o n St u dies is s h o w n i n Fi g ure 8- 1 .

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 4
0 2 A pril 2 0 1 9
Fi g ure 8- 1.
I n d ucti o n St u dies ( C o h orts A a n d B): Testi n g Str ate g y f or t he 
Pri m ar y a n d Ke y Sec o n d ar y H y p ot hese s
M ai nte n a nce St u d y
Si nce t here is n o i nteri m a nalys is pla n ne d f or t he mai nte na nce st u d y, t he si g nifica nce le vel f or 
t he fi nal pri mar y a nalys is will be at 0. 0 2 5 ( 2-si de d) le vel f or eac h fil g oti ni b d ose gr o u p w he n 
c o m pare d t o place b o f or t he mai nte na nce st u dy. 
T he h y p ot heses t o be teste d f or t he mai nte na nce st u d y  are o utli ne d bel o w.
T he pri mar y  n ull h yp ot heses t o be teste d:

H 1: T he E B S re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he E B S re missi o n rate 
i n t he place b o gr o u p at Wee k 5 8

H 2: T he E B S re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he E B S re missi o n rate 
i n t he place b o gr o u p at Wee k 5 8

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 5
0 2 A pril 2 0 1 9
T he ke y  sec o n dar y n ull h yp ot heses t o be teste d:

H 3: T he 6- m o nt h c ortic oster oi d -free E B S re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is 
e q ual t o t he 6-m o nt h c ortic oster oi d -free E B S re missi o n rate i n t he place b o gr o u p at Wee k 5 8

H 4: T he 6 -m o nt h c ortic oster oi d -free E B S re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr ou p is 
e q ual t o t he 6-m o nt h c ortic oster oi d -free E B S re missi o n rate i n t he place b o gr o u p at Wee k 5 8

H 5: T he s ustai ne d E B S re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he s ustai ne d 
E B S re missi o n rate i n t he place b o gr o u p at Wee k 5 8

H 6: T he s ustai ne d E B S re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he s ustai ne d 
E B S re missi o n rate i n t he place b o gr o u p at Wee k 5 8

H 7: T he M C S re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he M C S re missi o n 
rate i n t he place b o gr o u p at Wee k 5 8

H 8: T he M C S re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he M C S re missi o n 
rate i n t he place b o gr o u p at Wee k 5 8

H 9: T he e n d osc o pic s u bsc ore of 0 rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he 
e n d osc o pic s u bsc ore of 0 rate i n t he place b o gr o u p at Wee k 5 8

H 1 0: T he e n d osc o pic s u bsc ore of 0 rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he 
e n d osc o pic s u bsc ore of 0 rate i n t he place b o gr o u p at Wee k 5 8

H 1 1: T he Ge b oes hist ol o gic re missi o n rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual t o t he 
Ge b oes hist ol o gic re missi o n rate i n t he place b o gr o u p at Wee k 5 8

H 1 2: T he Ge b oes hist ol o gic re missi o n rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual t o t he 
Ge b oes hist ol o gic re missi o n rate i n t he place b o gr o u p at Wee k 5 8

H 1 3: T he M C S re missi o n (alter nati ve defi niti o n) rate i n t he fil g oti ni b 2 0 0 m g gr o u p is e q ual 
t o t he M C S re missi o n (alter nati ve defi niti o n) rate i n t he place b o gr o u p at Wee k 5 8

H 1 4: T he M C S re missi o n (alter nati ve defi niti o n) rate i n t he fil g oti ni b 1 0 0 m g gr o u p is e q ual 
t o t he M C S re missi o n (alter nati ve defi niti o n) rate i n t he place b o gr o u p at Wee k 5 8
T he sa me a p pr oac h descri be d f or I n d ucti o n St u dies will be a p plie d t o t he Mai nte na nce St u d y  at 
t he al p ha le vel of 0. 0 2 5 ( 2-si de d) f or eac h fil g oti ni b d ose gr o u p w he n c o m pare d t o place b o.
Gra p hical ill ustrati o ns f or t he testi n g strate gies f or t he pri mar y a n d ke y sec o n dar y h yp ot heses i n 
t he Mai nte na nce St u d y are s h o w n i n Fi g ure 8- 2 .

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 6
0 2 A pril 2 0 1 9
Fi g ure 8- 2.
M ai nte n a nce St u d y: Testi n g Str ate g y f or t he Pri m a r y a n d Ke y 
Sec o n d ar y H y p ot hese s
8. 5. 4. 
E x pl or at or y A n al yses
T he sa me statistical met h o ds use d f or a nal y zi n g t he pri mar y e n d p oi nt will be utilize d f or 
a nal yz i n g t he e x pl orat or y e n d p oi nts f or pr o p orti o ns i n eac h st u dy ( C o h ort A I n d ucti o n St u d y, 
C o h ort B I n d ucti o n St u d y, a n d Mai nte na nce St u d y) se paratel y . T he differe nce i n pr o p orti o ns 
bet wee n eac h fil g oti ni b d ose gr o u p a n d place b o, al o n g wit h t he c orres p o n di n g 9 5 % 2 -si de d 
c o nfi de nce i nter val ( CI ), will be pr o vi de d.
Differe nce of mea n c ha n ge fr o m baseli ne bet wee n eac h filg oti ni b d ose gr o u p a n d place b o f or 
c o nti n u o us varia bles will be teste d usi n g a n a nal ysis of varia nce ( A N O V A) m o del a dj usti n g f or 
stratificati o n fact ors. Last O bser vati o n Carrie d F or war d ( L O C F) a p pr oac h will be use d t o i m p ute 
t he missi n g val ues. Detaile d a nal ys es will be pr o vi de d i n t he S A P.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 7
0 2 A pril 2 0 1 9
8. 6.
S afet y A n al ysis
Safet y  will be e val uate d b y assess me nt of cli nical la b orat or y tests, p h ysical e xa mi nati o ns, vital 
si g ns meas ure me nts at vari o us ti me p oi nts d uri n g t he st u d y, a n d b y t he d oc u me ntati o n of A Es.
I n d ucti o n St u dies ( C o h orts A a n d B)
All safet y data c ollecte d o n or after t he first d ose of st u d y dr u g a d mi nistrati o n f or eac h I n d ucti o n 
St u d y  (D a y 1) u p t o:

3 0 da ys  after last d ose date, f or s u bjects w h o pre mat urely disc o nti n ue d st u d y dr u g pri or t o or 
at Wee k 1 0 O R

Wee k
1 0, f or s u bjects w h o c o m plete d Wee k
1 0 d osi n g a n d c o nti n ue d o n st u d y  dr u g will be 
s u m marize d b y treat me nt gr o u p acc or di n g t o t he st u d y dr u g recei ved.
M ai nte n a nce St u d y
All safet y data c ollecte d o n or after t he first d ose of st u d y dr u g a d mi nistrati o n f or t he 
Mai nte na nce st u d y ( Wee k
1 1) u p t o 3 0 da y s after per ma ne nt disc o nti n uati o n of st u d y  dr u g will 
be s u m marize d b y  treat me nt gr o u p acc or di n g t o t he stu d y  dr u g recei ve d. 
O ver all (I n d ucti o n a n d M ai nte n a nce)
All safet y data c ollecte d o n or after t he first d ose of st u d y dr u g a d mi nistrati o n f or t he e ntire st u d y 
(D a y 1) u p t o 3 0 da y s after per ma ne nt disc o nti n uati o n of st u d y  dr u g will be s u m marize d b y 
treat me nt gr o u p acc or di n g t o t he st u dy dr u g recei ve d. 
All data c ollecte d d uri n g t he c o urse of st u d y will be i ncl u de d i n data listi n gs.
8. 6. 1.
E xte nt of E x p os ure
A s u bject’s e xte nt of e x p os ure t o st u d y dr u g will be ge nerate d fr o m t he st u d y  dr u g 
a d mi nistrati o n pa ge of t he eC R F . T he n u m ber of d oses a d mi nistere d a n d t he le vel of a d here nce 
will be s u m marize d b y  treat me nt gr o u p.
8. 6. 2.
A d verse E ve nts
A d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y  f or Re g ulat or y Acti vities 
( Me d D R A). Sys te m Or ga n Class ( S O C), Hi g h-Le vel Gr o u p Ter m ( H L G T), Hi g h -Le vel Ter m 
( H L T), Preferre d Ter m ( P T), a n d L o wer- Le vel Ter m ( L L T) will be attac he d t o t he cli nical 
data base.
Treat me nt - e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as 1 or b ot h of t he f oll o wi n g:
I n d ucti o n St u dies ( C o h orts A a n d B)

A n y  A Es wit h a n o nset date of o n or after t he st u d y dr u g start date f or eac h I n d ucti o n st u d y 
(D a y 1) a n d pri or t o:

3 0 da y s after last d ose date, f or s u bjects w h o pre mat urel y disc o nti n ue d st u d y dr u g pri or 
t o or at Wee k 1 0 O R

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 8
0 2 A pril 2 0 1 9

Wee k
1 0, f or s u bjects w h o c o m plete d Wee k
1 0 d osi n g a n d c o nti n ue d o n st u d y  dr u g

A n y  A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g pri or t o Wee k
1 0.
M ai nte n a nce St u d y

A n y  A Es wit h a n o nset date of o n or after t he st u d y dr u g start date for t he Mai nte na nce st u d y  
(Wee k
1 1) a n d u p t o 3 0 da y s after per ma ne nt disc o nti n uati o n of st u d y dr u g.

A n y  A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g after first d ose of st u d y dr u g 
a d mi nistrati o n f or t he Mai nte na nce st u d y  (Wee k
1 1).
O ver all (I n d uc ti o n a n d M ai nte n a nce)

A n y  A Es wit h a n o nset date of o n or after t he st u d y dr u g start date f or t he e ntire st u d y 
(D a y 1) a n d u p t o 3 0 da ys after per ma ne nt disc o nti n uati o n of st u d y  dr u g.

A n y  A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g.
S u m maries ( n u m ber a n d perce nta ge of s u bjects) of T E A Es b y S O C a n d P T will be pr o vi de d b y  
treat me nt gr o u p. T E A Es will als o be s u m marize d b y  relati o ns hi p t o st u d y dr u g a n d se verit y. In 
a d diti o n, T E A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y  dr u g will be s u m marize d a n d 
liste d.
8. 6. 3.
L a b or at or y E v al u ati o ns
Select la b orat or y  data ( usi n g c o n ve nti o nal u nits) will be s u m marize d usi n g o nl y o bser ve d data. 
A bs ol ute val ue a n d c ha n ge fr o m baseli ne at all sc he d ule d ti me p oi nts will be s u m marize d.
Gra de d la b orat or y  a b n or malities will be defi ne d usi n g t he gra di n g sc he me defi ne d i n t he C T C A E 
i n A p pe n di x 5 .
I nci de nce of treat me nt -e mer ge nt la b orat or y a b n or malities defi ne d as val ues t hat i ncrease at least 
1 t o xicit y gra de fr o m baseli ne at a ny ti me p ost baseli ne will be s u m marize d b y  treat me nt gr o u p. 
If baseli ne data are missi n g, t he n a ny gra de d a b n or malit y  (ie, at least a Gra de 1) will be 
c o nsi dere d treat me nt e mer ge nt.
8. 6. 4.
Ot her S afet y E v al u ati o ns
I n di vi d ual data f or p hys ical e xa mi nati o n fi n di n gs, pri or a n d c o nc o mita nt me dicati o ns a n d
me dical hist or y  will be pr o vi de d. T wel ve-lea d E C Gs a n d vital si g ns meas ure me nts will be liste d 
b y  s u bject a n d s u m marize d b y i nci de nce of e ve nts/a b n or malities or descri pti ve statistics as 
a p pr o priate.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 9 9
0 2 A pril 2 0 1 9
8. 7. 
P h ar m ac o ki netic A n al ysis
F or eac h i n di vi d ual st u d y ( C o h ort A I n d ucti o n St u d y , C o h ort B I n d ucti o n St u d y a n d 
Mai nte na nce St u d y), p las ma c o nce ntrati o ns of fil g oti ni b a n d its meta b olite G S - 8 2 9 8 4 5 will be 
liste d a n d s u m marize d b y treat me nt gr o u p usi n g descri pti ve statistics ( e g, sa m ple size, arit h metic 
mea n, ge o met ric mea n, % c oefficie nt of variati o n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d 
ma xi m u m). Plas ma c o nce ntrati o ns o ver ti me ma y als o be pl otte d i n se mi -l o garit h mic a n d li near 
f or mats as mea n ± S D a n d me dia n ( Q 1, Q 3).
F or s u bjects e nr olle d i n t he o pti o nal P K s u bst u d y , p har mac o ki netic para meters of fil g oti ni b a n d 
its meta b olite G S-8 2 9 8 4 5 will be liste d a n d s u m marize d b y  treat me nt; a n d plas ma c o nce ntrati o ns 
of t he fil g oti ni b a n d G S -8 2 9 8 4 5 o ver ti me will be pl otte d i n se mi l o garit h mic a n d li near f or mats 
as mea n ± S D a n d me dia n ( Q 1, Q 3) b y treat me nt.
E x p os ure -res p o nse relati o ns hi ps f or efficac y a n d safety ma y als o be e val uate d.
8. 8. 
Bi o m ar ker A n al ysis
F or eac h i n di vi d ual st u d y ( C o h ort A I n d ucti o n St u d y , C o h ort B I n d ucti o n St u d y a n d 
Mai nte na nce St u d y), descri pti ve statist ics of baseli ne a n d c ha n ge i n bi o mar kers will be pr o vi de d 
at eac h sa m pli n g ti me b y treat me nt. T o e val uate treat me nt effect, a mi xe d -effect a nal ys is of 
varia nce m o del will be use d t o calc ulate a p oi nt esti mate a n d 2- si de d 9 5 % CI f or t he mea n 
perce nt c ha n ge fr o m baseli ne i n bi o mar ker le vel f or eac h treat me nt gr o u p at i n di vi d ual ti me 
p oi nts. T he esti mate a n d 9 5 % CI  of differe nce i n mea n perce nt c ha n ge fr o m baseli ne bet wee n 
eac h fil g oti ni b d ose gr o u p a n d place b o will be pr o vi de d as well. 
E x pl orat or y  a nalys es will als o be perf or me d t o e val uate t he ass ociati o n of i n di vi d ual bi o mar kers, 
i ncl u di n g t he sys te mic or l ocalize d i nfla m mat or y bi o mar kers, or c o m bi nati o n of bi o mar kers wit h 
cli nical o utc o mes.
A d diti o nal e x pl orat or y  a nal yses ma y be descri be d i n t he Bi o mar ker A nal ys is Pla n ( B A P) 
if necessar y .
8. 9.
S a m ple Size
8. 9. 1.
I n d ucti o n St u dies ( C o h orts A a n d B)
T he sa m ple size was c h ose n t o e ns ure t hat a cli nicall y  mea ni n gf ul differe nce i n E B S re missi o n 
rate at Wee k
1 0 c o ul d be detecte d w he n c o m pari n g fil g oti ni b t o place b o wit hi n eac h I n d ucti o n 
St u d y . 
A sa m ple size of 1 3 0 s u bjects i n t he place b o gr o u p a n d 2 6 0 s u bjects i n eac h fil g oti ni b d ose 
gr o u p ( n = 6 5 0 t otal per c o h ort ) will pr o vi de 9 0 % p o wer f or eac h fil g oti ni b d ose gr o u p 
c o m paris o n t o place b o at a 2-si de d 0. 0 2 5 si g nifica nce le vel t o detect a treat me nt differe nce i n 
E B S re missi o n rate of 1 5 % ( 2 5 % o n fil g oti ni b a n d 1 0 % o n place b o).

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 0
0 2 A pril 2 0 1 9
8. 9. 2.
M ai nte n a nce St u d y
Ass u mi n g a n i n d ucti o n res p o nse rate (ie, pr o p orti o n of s u bjects ac hie vi n g E B S re missi o n or 
M C S res p o nse at Wee k
1 0) of 5 5 % a m o n g s u bjects recei vi n g fil g oti ni b 2 0 0 m g of fil g oti ni b 
1 0 0 m g treat me nt , a p pr o xi matel y 2 8 5 s u bjects fr o m eac h fil g oti ni b d ose gr o u p fr o m
C o h orts A a n d B I n d ucti o n St u dies c o m bi ne d w o ul d be eli gi ble t o be re -ra n d o mize d i nt o t he 
Mai nte na nce St u d y.
T he sa m ple siz e was c h ose n t o e ns ure t hat a cli nicall y  mea ni n gf ul differe nce i n E B S re missi o n 
rate at Wee k
5 8 c o ul d be detecte d w he n c o m pari n g eac h fil g oti ni b d ose gr o u p ( 2 0 0 m g or 
1 0 0 m g) t o place b o i n t he Mai nte na nce St u d y . A sa m ple size of 9 5 s u bjects i n t he place b o gr o u p 
a n d 1 9 0 s u bjects i n t he fil g oti ni b gr o u p at t he sa me d ose le vel as t he i n d ucti o n d ose will pr o vi de 
m ore t ha n 8 5 % p o wer f or eac h fil g oti ni b d ose gr o u p c o m paris o n t o place b o at a 2 -si de d 
0. 0 2 5 si g nifica nce le vel t o detect a treat me nt differe nce i n mai n te na nce E B S re missi o n rate of 
2 0 % ( 4 0 % o n fil g oti ni b a n d 2 0 % o n place b o).
8. 1 0.  
D at a M o nit ori n g C o m mittee
A n e xter nal D M C will re vie w t he pr o gress of t he st u d y  a n d perf or m i nteri m re vie ws of safety
data a n d pr o vi de rec o m me n dati o n t o Gilea d w het her t he nat ure, fr e q ue nc y, a n d se verity of 
a d verse effects ass ociate d wit h st u d y  treat me nt warra nt t he early ter mi nati o n of t he st u d y i n t he 
best i nterests of t he partici pa nts, w het her t he st u d y s h o ul d c o nti n ue as pla n ne d, or t he st u d y 
s h o ul d c o nti n ue wit h m o dificati o ns.
T h e i nitial meeti n g f or eac h i n d ucti o n st u d y  will occ ur after a p pr o xi matel y 1 0 0 s u bjects ( 2 0 fr o m 
place b o gr o u p a n d 4 0 fr o m eac h fil g oti ni b gr o u p) reac h Wee k
1 0.
T he sec o n d meeti n g f or eac h i n d ucti o n st u d y  will i ncl u de a n i nteri m f utilit y a nalys is a n d occ ur 
after a p pr o xi matel y 1 7 5 s u bjects ( 3 5 fr o m place b o gr o u p a n d 7 0 fr o m eac h fil g oti ni b treat me nt 
gr o u p) reac h Wee k
1 0. T he f utilit y  a nalys is will be c o n d ucte d t o e val uate e n d osc o pic efficac y 
a n d o verall safet y. T he pr o p ort i o n of s u bjects w h o ac hie ve e n d osc o pic res p o nse 
(e n d osc o pic s u bsc ore of 0 or 1) f or eac h treat me nt gr o u p will be e val uate d. T he D M C ma y 
rec o m me n d t o ter mi nate a fil g oti ni b d ose gr o u p if t he o bser ve d pr o p orti o n of s u bjects w h o 
ac hie ve e n d osc o pic res p o nse i n t he fil g oti ni b gr o u p is l o wer t ha n t hat i n t he place b o gr o u p. If 
b ot h fil g oti ni b d ose gr o u ps meet t he f utilit y  criteria, t he D M C ma y rec o m me n d st o p pi n g t he
st u d y.
After t he f utilit y  a nalys es, D M C meeti n gs f or safet y re vie w will be hel d a p pr o xi matel y 
o nce e ver y 4 m o nt hs or at a fre q ue nc y  deter mi ne d b y t he D M C.
T he D M C’s s pecific acti vities will be defi ne d b y a m ut uall y a gree d c harter, w hic h will defi ne t he 
D M C’s me m bers hi p, c o n d uct a n d meeti n g sc he d ule.
W hile t he D M C will be as ke d t o a d vise Gilea d re gar di n g
f ut ure c o n d uct of t he st u d y, i ncl u di n g 
p ossi ble earl y st u d y ter mi nati o n, Gilea d retai ns fi nal decisi o n -ma ki n g a ut h orit y  o n all as pects of 
t he st u d y.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 1
0 2 A pril 2 0 1 9
C o h orts A a n d B E n d -of -I n d ucti o n A n al ysis
Efficac y  a n d safety data will be e val uate d b y D M C after all s u bjects i n b ot h c o h orts c o m plete 
Wee k
1 0 d osi n g ( or pre mat urel y disc o nti n ue st u d y dr u g b ut c o m plete p ost -treat me nt 
assess me nts).
B ot h c o h orts will be e xa mi ne d i n de pe n de ntl y.

Ta ki n g i nt o acc o u nt data i n C o h ort A a n d C o h ort B, if b ot h fil g oti ni b d ose gr o u ps ( 2 0 0 m g 
a n d 1 0 0 m g) i n b ot h c o h orts (i n de pe n de ntl y e xa mi ne d) fail t o reac h statistical si g nifica nce 
c o m pare d t o place b o o n E B S re missi o n, t he D M C ma y  rec o m me n d o verall st u d y  
disc o nti n uati o n.

If t he a b o ve c o n diti o n a b o ve is n ot met, t he D M C ma y rec o m me n d t hat t he st u d y c o nti n ue 
wit h o ut m o dificati o n .
A d -h oc D M C Meeti n gs
A n a d -h oc c o n ve ni n g of D M C ma y  be tri g gere d b y t he f oll o wi n g c o n diti o ns:

≥ 2 s u bjects de vel o p t he sa me ( b y preferre d ter m) relate d, Gra de 4, u ne x pecte d a d verse e ve nt
( A E) i n t he i nfecti o ns a n d i nfestati o ns s yste m or ga n class

A n y  s u bject de vel o ps a Gra de 5, relate d, u ne x pecte d A E. T he defi niti o n of a n u ne x pecte d A E
will be base d o n t he Refere nce Safet y I nf or mati o n t hat is o n file at t he ti me t he e ve nt occ urs.
8. 1 1.
E n d of I n d ucti o n I nteri m A n al ysis
Aft er all s u bjects fr o m C o h orts A a n d B ha ve c o m plete d t he Wee k 1 0 visit or ha ve ter mi nate d
pri or t o Wee k 1 0 a n d c orres p o n di n g data e ntr y  is c o m plete, a n E n d of I n d ucti o n safety a n d
efficac y a nalys is will be perf or me d i ncl u di n g c u m ulati ve safety a nal ys is t hat has bee n pr o vi de d
f or D M C safety re vie w a n d a nalys es o n pri mar y e n d p oi nt a n d ke y sec o n dar y e n d p oi nts as well 
e n d osc o pic res p o nse a n d M C S res p o nse.
I n parallel wit h D M C re vie w, a pres pecifie d s p o ns or’s e xec uti ve tea m will re vie w t he u n bli n de d 
gr o u p le vel s afet y a nalys is res ults a n d gr o u p le vel efficac y a nalys is res ults fr o m t he I n d ucti o n 
St u dies f or t he p ur p ose of s p o ns or decisi o n ma ki n g a n d f ut ure de vel o p me nt pla n ni n g. Me m bers 
of t he St u d y  Ma na ge me nt Tea m wit h direct i n v ol ve me nt i n t he c o n d uct of t he st u d y will n ot 
ha ve access t o t he u n bli n de d res ults fr o m t he i n d ucti o n st u dies.  
T he u n bli n de d E n d of I nd ucti o n a nal ys is res ults of St u d y G S-U S - 4 1 8-3 8 9 8 will n ot be s hare d 
e xter nall y wit h t he e xce pti o n of Healt h A ut h orit y or D M C re q uests f or i nf or mati o n, u ntil after 
t he Wee k 5 8 data base l oc k is c o m plete d a n d t he st u d y is u n bli n de d.
F oll o w u p acti o ns ma y  be ta ke n base d o n t he data fr o m t his a nal ysis i ncl u di n g st u d y desi g n 
c ha n ge, wit h c o m m u nicati o n wit h re g ulat or y  a ut h orities, if i n dicate d.
F urt her details will be s pecifie d i n t he S A P a n d a n I nteri m A nal ys is C o m m u nicati o n Pla n.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 2
0 2 A pril 2 0 1 9
9.
R E S P O N SI BI LI TI E S
9. 1.
I n vesti g at or Res p o nsi bilities
9. 1. 1.  
G o o d Cli nic al Pr actice
T he i n vesti gat or will e ns ure t hat t his st u d y  is c o n d ucte d i n acc or da nce wit h t he pri nci ples of t he 
Declarati o n of Hel si n ki, I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) g ui deli nes, or wit h t he 
la ws a n d re g ulati o ns of t he c o u ntr y i n w hic h t he researc h is c o n d ucte d, w hic he ver aff or ds t he 
greater pr otecti o n t o t he st u d y  s u bject. T hese sta n dar ds are c o nsiste nt wit h t he E U C li nical Trials 
Directi ve 2 0 0 1/ 2 0/ E C a n d G C P Directi ve 2 0 0 5/ 2 8/ E C.
T he i n vesti gat or will e ns ure a d here nce t o t he basic pri nci ples of G C P , as o utli ne d i n 
2 1 C F R 3 1 2, s u b part D, “ Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors,” 2 1 C F R, part 5 0, a n d 
2 1 C F R, pa rt 5 6 .
T he i n vesti gat or a n d all a p plica ble s u bi n vesti gat ors wil l c o m pl y wit h 2 1 C F R, Part 5 4, pr o vi di n g 
d oc u me ntati o n of t heir fi na ncial i nterest or arra n ge me nts wit h Gilea d, or pr o prietar y  i nterests i n 
t he i n vesti gati o nal dr u g u n der st u d y. T his d oc u me ntati o n m ust be pr o vi de d pri or t o t he 
i n vesti gat or’s (a n d a ny s u bi n vesti gat or’s) partici pati o n i n t he st u d y . T he i n vesti gat or a n d 
s u bi n vesti gat or a gree t o n otif y Gilea d of a ny c ha n ge i n re p orta ble i nterests d uri n g t he st u d y a n d 
f or 1 year f oll o wi n g c o m pleti o n of t he st u d y . St u d y c o m pleti o n is defi ne d as t he date w he n t he 
last s u bject c o m pletes t he pr ot oc ol-defi ne d acti vities.
9. 1. 2. 
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee Re vie w a n d 
A p pr o v al
T he i n vesti gat or ( or s p o ns or as a p pr o priate acc or di n g t o l ocal re g ulati o ns) will s u b mit t his
pr ot oc ol, I C F , a n d a n y acc o m pa nyi n g material t o be p r o vi de d t o t he s u bject 
(s uc h as a d vertise me nts, s u bject i nf or mati o n s heets, or descri pti o ns of t he st u d y  use d t o o btai n 
i nf or me d c o nse nt) t o a n I R B/I E C. T he i n vesti gat or will n ot be gi n a n y st u d y s u bject acti vities 
u ntil a p pr o val fr o m t he I R B/I E C has bee n d oc u me nte d a n d pr o vi de d as a letter t o t he 
i n vesti gat or.
Bef ore i m ple me ntati o n, t he i n vesti gat or will s u b mit t o a n d recei ve d oc u me nte d a p pr o val fr o m 
t he I RB /IE C a n y m o dificati o ns ma de t o t he pr ot oc ol or a n y acc o m pa n yi n g material t o be 
pr o vi de d t o t he s u bject after i nitial I RB/I E C a p pr o val, wit h t he e xce pti o n of t h ose necessar y  t o 
re d uce i m me diate ris k t o st u d y s u bjects.
9. 1. 3.
I nf or me d C o nse nt
T he i n vesti gat or is re s p o nsi ble f or o btai ni n g writte n i nf or me d c o nse nt fr o m eac h i n di vi d ual 
partici pati n g i n t his st u d y after a de q uate e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d 
p ote ntial hazar ds of t he st u d y  a n d bef ore u n derta ki n g a ny st u d y-relate d pr oce d ures. T he 
i n vesti gat or m ust use t he m ost c urre nt I R B/I E C a p pr o ve d c o nse nt f or m f or d oc u me nti n g writte n 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 3
0 2 A pril 2 0 1 9
i nf or me d c o nse nt. Eac h i nf or me d c o nse nt ( or asse nt as a p plica ble) will be a p pr o priatel y si g ne d 
a n d date d b y t he s u bject or t he s u bject’s le gall y a ut h orize d re prese ntati ve a n d t he pers o n 
c o n d ucti n g t he c o nse nt disc ussi o n, a n d als o b y  a n i m partial wit ness if re q uire d b y I R B/I E C or
l ocal re q uire me nts. T he c o nse nt f or m will i nf or m s u bjects a b o ut ge n o mic testi n g a n d sa m ple 
rete nti o n.
9. 1. 4.
C o nfi de nti alit y
T he i n vesti gat or m ust ass u re t hat s u bjects’ a n o ny mit y  will be strictl y mai ntai ne d a n d t hat t heir 
i de ntities are pr otecte d fr o m u na ut h orize d parties. O nl y s u bject i nitials, date of birt h, a n ot her 
u ni q ue i de ntifier (as all o we d b y l ocal la w) a n d a n i de ntificati o n c o de will be rec or de d o n a n y  
f or m or bi ol o gical sa m ple s u b mitte d t o t he S p o ns or, I RB/I E C , or la b orat or y . La b orat or y  
s peci me ns m ust be la bele d i n s uc h a w a y  as t o pr otect s u bject i de ntit y w hile all o wi n g t he res ults 
t o be rec or de d t o t he pr o per s u bject. Refer t o s pecific la b orat or y i nstr ucti o ns or i n acc or da nce 
wit h l ocal re g ulati o ns . N O T E : T he i n vesti gat or m ust kee p a scree ni n g l o g s h o wi n g c o des, a n d 
na me s f or all s u bjects scree ne d a n d f or all s u bjects e nr olle d i n t he trial. S u bject data will be 
pr ocesse d i n acc or da nce w it h all a p plica ble re g ulati o ns.
T he i n vesti gat or a grees t hat all i nf or mati o n recei ve d fr o m Gilea d, i ncl u di n g b ut n ot li mite d t o t he 
I B, t his pr ot oc ol, e C R F, t he I M P, a n d a ny ot her st u d y i nf or mati o n, re mai n t he s ole a n d e xcl usi ve 
pr o pert y of Gilea d d uri n g t he c o n d uct of t he st u d y a n d t hereafter. T his i nf or mati o n is n ot t o be 
discl ose d t o a n y  t hir d part y (e xce pt e m pl oye es or a ge nts directl y i n v ol ve d i n t he c o n d uct of t he 
st u d y or as re q uire d b y la w) wit h o ut pri or writte n c o nse nt fr o m Gilea d. T he i n vesti gat or f urt her 
a grees t o ta ke all reas o na ble preca uti o ns t o pre ve nt t he discl os ure b y  a n y e m pl o yee or a ge nt of 
t he st u d y site t o a ny t hir d part y or ot her wise i nt o t he p u blic d o mai n.
9. 1. 5. 
St u d y Files a n d Rete nti o n of Rec or ds
T he i n vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o e na ble t he c o n d uct of t he st u d y 
t o be f ull y d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d. T hese d oc u me nts s h o ul d 
be classifie d i nt o at least t he f oll o wi n g t w o cate g ories: ( 1) i n vesti gat or’s st u d y file, a n d 
( 2) s u bject cli nical s o urce d oc u me nts.
T he i n vesti gat or’s st u d y file will c o ntai n t he pr ot oc ol/a me n d me nts, eC R F a n d q uer y  f or ms,
I RB/I E C a n d g o ver n me ntal a p pr o val wit h c orres p o n de nce, i nf or me d c o nse nt, dr u g rec or ds, staff 
c urric ul u m vitae a n d a ut h orizati o n f or ms, a n d ot her a p pr o priate d oc u me nts a n d c orres p o n de nce.
T he re q uire d s o urce data s h o ul d i ncl u de se q ue ntial n otes c o ntai ni n g at least t he f oll o wi n g 
i nf or mati o n f or eac h s u bject:

S u bject i de ntificati o n ( na me, date of birt h, ge n der);

D oc u me ntati o n t hat s u bject meets eli gi bilit y criteria, ie, hist or y, P E , a n d c o nfir mati o n of 
dia g n osis (t o s u p p ort i ncl usi o n a n d e xcl usi o n criteria) ;

D oc u me ntati o n of t he reas o n(s) a c o nse nte d s u bject is n ot e nr olle d;

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 4
0 2 A pril 2 0 1 9

Partici pati o n i n st u d y (i ncl u di n g st u d y n u m ber) ;

St u d y  disc usse d a n d date of i nf or me d c o nse nt ;

Dates of all visits ;

D oc u me ntati o n t hat pr ot oc ol s pecific pr oce d ures were perf or me d;

Res ults of efficac y  para meters, as re q uire d by t he pr ot oc ol ;

Start a n d e n d date (i ncl u di n g d ose re gi me n) of I M P, i ncl u di n g dates of dis pe nsi n g a n d ret ur n;

Rec or d of all A Es a n d ot her safet y para meters (start a n d e n d date, a n d i ncl u di n g ca usalit y 
a n d se verit y);

C o nc o mita nt me dicati o n (i ncl u d i n g start a n d e n d date, d ose if rele va nt; d ose c ha n ges);

Date of st u d y c o m pleti o n a n d reas o n f or early disc o nti n uati o n, if it occ urs.
All cli nical st u d y  d oc u me nts m ust be retai ne d by t he i n vesti gat or u ntil at least 2 ye ars or 
acc or di n g t o l ocal la ws, w hic h e ver is l o n ger, after t he last a p pr o val of a mar keti n g a p plicati o n i n 
a n IC H re gi o n (ie, U S , E ur o pe, or Ja pa n) a n d u ntil t here are n o pe n di n g or pla n ne d mar keti n g 
a p plicati o ns i n a n IC H re gi o n; or, if n o a p plicati o n is file d or if t he a p plicati o n is n ot a p pr o ve d 
f or s uc h i n dicati o n, u ntil 2 ye ars after t he i n vesti gati o n is disc o nti n ue d a n d re g ulat or y  a ut h orities 
ha ve bee n n otifie d. I n vesti gat ors ma y  be re q uire d t o retai n d oc u me nts l o n ger if s pecifie d b y  
re g ulat or y re q uire me nts, b y l ocal re g ulati o ns, or b y an a gree me nt wit h Gilea d. T he i n vesti gat or 
m ust n otif y  Gilea d bef ore destr o yi n g a ny cli nical st u d y rec or ds.
S h o ul d t he i n vesti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or m o ve t he m t o a n ot her 
l ocati o n, Gilea d m ust be n otifie d i n a d va nce.
If t he i n vesti gat or ca n n ot pr o vi de f or t his arc hi vi n g re q uire me nt at t he st u d y site f or a n y or all of 
t he d oc u me nts, s pecial arra n ge me nts m ust be ma de bet wee n t he i n vesti gat or a n d Gilea d t o st ore 
t hese rec or ds sec urely a wa y fr o m t he site s o t hat t he y ca n be ret ur ne d seale d t o t he i n vesti gat or 
i n case of an i ns pecti o n. W he n s o urce d oc u me nts are re q uire d f or t he c o nti n ue d care of t he 
s u bject, a p pr o priate c o pies s h o ul d be ma de f or st ora ge a wa y fr o m t he site.
9. 1. 6.
C ase Re p ort F or ms
F or eac h s u bject c o nse nte d, a n e C R F will be c o m plete d b y  a n a ut h orize d st u d y staff me m ber 
w h ose trai ni n g f or t his f u ncti o n is d oc u me nte d acc or di n g t o st u d y  pr oce d ures. T he e C R F s h o ul d 
be c o m plete d o n t he da y  of t he s u bject visit t o e na ble t he s p o ns or t o perf or m ce ntral m o nit ori n g 
of safet y d ata. T he Eli gi bilit y  Criteria e C R F s h o ul d be c o m plete d o nly after all data relate d t o 
eli gi bilit y ha ve bee n recei ve d. S u bse q ue nt t o data e ntr y , a st u d y m o nit or will perf or m s o urce data 
verificati o n wit hi n t he electr o nic data ca pt ure ( E D C ) s yste m. Ori gi nal e ntries as well as a n y 
c ha n ges t o data fiel ds will be st ore d i n t he a u dit trail of t he s y ste m. Pri or t o data base l oc k ( or a n y 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 5
0 2 A pril 2 0 1 9
i nteri m ti me p oi nts as descri be d i n t he cli nical data ma na ge me nt pla n), t he i n vesti gat or will use 
his/ her l o g i n cre de ntials t o c o nfir m t hat t he f or ms ha ve bee n re vie we d, a n d t hat t he e ntries 
acc uratel y reflect t he i nf or mati o n i n t he s o urce d oc u me nts. T he e C R F ca pt ure s t he data re q uire d 
per t he pr ot oc ol sc he d ule of e ve nts a n d pr oce d ures. S y ste m- ge nerate d or ma n ual q ueries will be 
iss ue d t o t he i n vesti gati ve site staff as data discre pa ncies are i de ntifie d by t he m o nit or or i nter nal 
Gilea d staff, w h o r o uti nel y  re vie w t he data f or c o m plete ness, c orrect ness, a n d c o nsiste nc y. T he 
site c o or di nat or is res p o nsi ble f or res p o n di n g t o t he q ueries i n a ti mel y ma n ner, wit hi n t he 
s yste m, eit her by c o nfir mi n g t he data as c orrect or u p dati n g t he ori gi nal e ntr y , a n d pr o vi di n g t he 
reas o n f or t he u p date (e g, data e ntr y  err or). At t he c o ncl usi o n of t he trial, Gilea d will pr o vi de t he 
site wit h a rea d- o nly arc hi ve c o p y of t he data e ntere d b y t hat site. T his arc hi ve m ust be st ore d i n 
acc or da nce wit h t he rec or ds rete nti o n re q uire me nts o utli ne d i n Secti o n 9. 1. 5 .
9. 1. 7.
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y a n d Ret ur n
W here
p ossi ble , I M P s h o ul d be destr oye d at t he site. At t he start of t he st u d y, t he st u d y m o nit or 
will e val uate eac h st u d y ce nter’s I M P dis p osal pr oce d ures a n d pr o vi de a p pr o priate i nstr ucti o n f or 
dis p osal or ret ur n of u n use d I M P s u p plies. If t he site has a n a p pr o priate sta n dar d o perati n g 
pr oce d ure ( S O P) f or dr u g destr ucti o n as deter mi ne d b y Gilea d Scie nces , t he site ma y destr o y 
use d (e m pty or partiall y  e m pt y) a n d u n use d I M P s u p plies as l o n g as perf or me d i n acc or da nce 
wit h t he site’s S O P. T his ca n occ ur o nl y after t he st u d y m o nit or has perf or me d dr u g 
acc o u nta bilit y d uri n g a n o n-site m o nit ori n g visit.
A c o p y of t he site’s I MP Dis p osal S O P or writte n pr oce d ure (si g ne d a n d date d b y  t he Pri nci pal 
I n vesti gat or [PI ] or desi g nee) will be o btai ne d f or Gilea d site files. If t he site d oes n ot ha ve 
acce pta ble pr oce d ures i n place, arra n ge me nts will be ma de bet wee n t he site a n d Gilea d Scie nces 
( or G ilea d Scie nces’ re prese ntati ve) f or ret ur n of u n use d st u d y  dr u g s u p plies.
If I M P is destr oye d o n site, t he i n vesti gat or m ust mai ntai n acc urate rec or ds f or all I M Ps 
destr o y e d. U p o n st u d y c o m pleti o n, c o pies of t he I M P acc o u nta bilit y rec or ds m ust be file d at t he 
site. A n ot her c o py will be ret ur ne d t o Gilea d .
T he st u d y  m o nit or will re vie w I M P s u p plies a n d ass ociate d rec or ds at peri o dic i nter vals.
9. 1. 8.
I ns pecti o ns
T he i n vesti gat or will ma ke a vaila ble all s o urce d oc u me nts a n d ot her rec or ds f or t his trial t o 
Gilea d ’s a p p oi nte d st u dy m o nit ors , t o I RBs/I E Cs , or t o re g ulat or y a ut h orit y or healt h a ut h orit y 
i ns pect ors.
9. 1. 9.
Pr ot oc ol C o m pli a nce
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y  is c o n d ucte d i n acc or da nce wit h t he 
pr oce d ur es a n d e val uati o ns descri be d i n t his pr ot oc ol.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 6
0 2 A pril 2 0 1 9
9. 2. 
S p o ns or Res p o nsi bilities
9. 2. 1. 
Pr ot oc ol M o dific ati o ns
Pr ot oc ol m o dificati o ns, e xce pt t h ose i nte n de d t o re d uce i m me diate ris k t o st u d y  s u bjects, ma y be 
ma de o nl y  b y Gilea d. T he i n vesti gat or m ust s u b mit all pr ot oc ol mo dificati o ns t o t he I RB/I E C i n 
acc or da nce wit h l ocal re q uire me nts a n d recei ve d oc u me nte d I R B/I E C a p pr o val bef ore 
m o dificati o ns ca n be i m ple me nte d.
9. 2. 2.
St u d y Re p ort a n d P u blic ati o ns
A cli nical st u d y  re p ort ( C S R) will be pre pare d a n d pr o vi de d t o t he re g ulat or y age nc y (ies). Gilea d 
will e ns ure t hat t he re p ort meets t he sta n dar ds set o ut i n t he I C H G ui deli ne f or Str uct ure a n d 
C o nte nt of C S Rs (IC H E 3). N ote t hat a n a b bre viate d re p ort ma y  be pre pare d i n certai n cases.
In vesti gat ors i n t his st u d y  m a y c o m m u nicate, orall y  prese nt, or p u blis h i n scie ntific j o ur nals or 
ot her sc h olarl y me dia o nl y after t he f oll o wi n g c o n diti o ns ha ve bee n met:

T he res ults of t he st u d y i n t heir e ntiret y ha ve bee n p u blicl y discl ose d b y or wit h t he c o nse nt 
of Gilea d i n a n a bstract, ma n uscri pt, or prese ntati o n f or m or t he st u d y has bee n c o m plete d at 
all st u d y sites f or at least 2 years

T he i n vesti gat or will s u b mit t o Gilea d a n y  pr o p ose d p u blicati o n or prese ntati o n al o n g wit h 
t he res pecti ve scie ntific j o ur nal or prese ntati o n f or u m at least 3 0 da ys bef ore s u b missi o n of 
t he p u blicati o n or prese ntati o n. 

N o s uc h c o m m u nicati o n, prese ntati o n, or p u blicati o n will i ncl u de Gilea d’s c o nfi de ntial 
i nf or mati o n (See Secti o n 9. 1. 4 ).

T he i n vesti gat or will c o m pl y  wit h Gilea d’s re q uest t o delete refere nces t o its c o nfi de ntial 
i nf or mati o n ( ot her t ha n t he st u d y res ults) i n a n y pa per or prese ntati o n a n d a grees t o wit h h ol d 
p u blicati o n or prese ntati o n f or a n a d diti o nal 6 0 da ys i n or der t o o btai n pate nt pr otecti o n if 
dee me d necessar y .
9. 3.
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities
9. 3. 1.
P a y me nt Re p orti n g
I n vesti gat ors a n d t heir st u d y staff ma y be as ke d t o pr o vi de ser vices perf or me d u n der t his 
pr ot oc ol, e g, atte n da nce at In vesti gat or's Meeti n gs. If re q uire d u n der t he a p plica ble stat ut or y  a n d 
re g ulat or y re q uire me nts, Gilea d will ca pt ure a n d discl ose t o Fe deral a n d State a ge ncies a n y 
e x pe nses pai d or rei m b urse d f or s uc h ser vices, i ncl u di n g a n y cli nical trial pa y me nts, meal, tr a vel 
e x pe nses or rei m b urse me nts, c o ns ulti n g fees, a n d a n y  ot her tra nsfer of val ue.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 7
0 2 A pril 2 0 1 9
9. 3. 2.
Access t o I nf or m ati o n f or M o nit ori n g
I n acc or da nce wit h re g ulati o ns a n d g ui deli nes, t he st u d y  m o nit or m ust ha ve direct access t o t he 
i n vesti gat or’s s o urce d oc u me ntati o n i n or der t o verif y t he acc urac y of t he data rec or de d i n t he 
e C R F.
T he m o nit or is res p o nsi ble f or r o uti ne re vie w of t he e C R F at re g ular i nter vals t hr o u g h o ut t he 
st u d y t o verif y a d here nce t o t he pr ot oc ol a n d t he c o m plete ness, c o nsiste nc y, a n d acc urac y of t he 
data bei n g e ntere d o n t he m. T he m o nit or s h o ul d ha ve access t o a n y s u bject rec or ds nee de d t o 
verif y  t he e ntries o n t he e C R F. T he i n vesti gat or a grees t o c o o perate wit h t he m o nit or t o e ns ure 
t hat a n y pr o ble ms detecte d t hr o u g h a ny t y pe of m o nit ori n g (ce ntral, o n site) are res ol ve d.
9. 3. 3.
Access t o I nf or m ati o n f or A u diti n g or I ns pecti o ns
Re prese ntati ves of re g ulat or y a ut h orities or of Gilea d ma y c o n d uct i ns pecti o ns or a u dits of t he 
cli nical st u d y. If t he i n vesti gat or is n otifie d of a n i ns pecti o n b y a re g ulat or y a ut h orit y t he 
i n vesti gat or a grees t o n otif y t he Gilea d me dical m o nit or i m me diatel y. T he i n vesti gat or a grees t o 
pr o vi de t o re pres e ntati ves of a re g ulat or y a ge nc y or Gilea d access t o rec or ds, facilities, a n d 
pers o n nel f or t he effecti ve c o n d uct of a n y i ns pecti o n or a u dit.
9. 3. 4.
St u d y Disc o nti n u ati o n
B ot h t he s p o ns or a n d t he i n vesti gat or reser ve t he ri g ht t o ter mi nate t he st u d y at a n y ti me. S h o ul d 
t his be necessar y, b ot h parties will arra n ge disc o nti n uati o n pr oce d ures a n d n otif y t he a p pr o priate 
re g ulat or y a ut h ority(i es), IR Bs, a n d I E Cs. I n ter mi nati n g t he st u d y , Gilea d a n d t he i n vesti gat or 
will ass ure t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he s u bjects’ i nterests.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 8
0 2 A pril 2 0 1 9
1 0.
R E F E R E N C E S
Bea u gerie L, Itz k o witz S H. Ca ncers C o m plicati n g Infla m mat or y  B o wel Disease. N E n gl J Me d 
2 0 1 5; 3 7 2 ( 1 5): 1 4 4 1 - 5 2.
Bretz F, Ma urer W, Bra n nat h W, P osc h M. A Gra p hical A p pr oac h t o Se q ue ntia ll y Rejecti ve 
M ulti ple Test Pr oce d ures. Stat Me d 2 0 0 9; 2 8: 5 8 6 - 6 0 4.
C hassai n g B, Ait ke n J D, Malles ha p pa M, Vija y -K u mar M. De xtra n s ulfate s o di u m ( D S S) -
i n d uce d c olitis i n mice. C urre nt Pr ot oc ols i n Im m u n ol o g y  2 0 1 4; 1 0 4.
Da nese S, Fi occ hi C. Ulcerati ve c olitis. N E n gl J Me d 2 0 1 1; 3 6 5 ( 1 8): 1 7 1 3 - 2 5.
F u k u na ga K, Mats u m ot o T. C urre nt stat us a n d f ut ure pers pecti ves of le u k oc yta p heresis f or 
i nfla m mat or y b o wel disease. J Gastr oe nter ol He pat ol 2 0 1 2; 2 7 ( 6): 9 9 7- 1 0 0 3.
Jess T, R u n g oe C, Pe yri n-Bir o ulet L. Ris k of C ol orectal Ca ncer i n Patie nts Wit h Ulcerati ve 
C olitis: A Meta -a nal ysis of P o p ulati o n- Base d C o h ort St u dies. Cli n Gastr oe nter ol 
He pat ol 2 0 1 2; 1 0 ( 6): 6 3 9 - 4 5.
Ka p pel ma n M D, Rifas -S hi ma n S L , Klei n ma n K, Olle n d orf D, B o us var os A, Gra n d RJ, et al. T he 
pre vale nce a n d ge o gra p h ic distri b uti o n of Cr o h n's disease a n d ulcerati ve c olitis i n 
t he U nite d States. Cli n Gastr oe nter ol He pat ol 2 0 0 7; 5 ( 1 2): 1 4 2 4- 9.
K or n bl ut h A, Sac har D B. Errat u m: Ulcerati ve C olitis Practice G ui deli nes i n A d ults: A merica n 
C olle ge of Gastr oe nter ol o g y , Practice Para meters C o m mittee. T he A merica n 
J o ur nal of Gastr oe nter ol o g y 2 0 1 0.
M ol o dec k y N A, S o o n I S, Ra bi D M, G hali W A, Ferris M, C her n off G, et al. I ncreasi n g i nci de nce 
a n d pre vale nce of t he i nfla m mat or y  b o wel diseases wit h ti me, base d o n 
s yste matic re vie w. Gastroe nter ol o g y  2 0 1 2; 1 4 2 ( 1): 4 6-5 4 e 4 2; q uiz e 3 0.
Na m o ur F, Di deric hse n P M, C o x E, Va y ssiere B, Va n der Aa A, Tasset C, et al. 
P har mac o ki netics a n d P har mac o ki netic/ P har mac o d y na mic M o deli n g of Fil g oti ni b 
( G LP G 0 6 3 4), a Selecti ve J A K 1 I n hi bit or, i n S u p p ort of P ha se II B D ose Selecti o n. 
Cli n P har mac o ki net 2 0 1 5; 5 4 ( 8): 8 5 9- 7 4.
Sa n d b or n WJ, S u C, Sa n ds B E, D' Hae ns G R, Ver meire S, Sc hrei ber S, et al. T ofaciti ni b as 
I n d ucti o n a n d Mai nte na nce T hera py f or Ulcerati ve C olitis. N E n gl J Me d 
2 0 1 7; 3 7 6 ( 1 8): 1 7 2 3 - 3 6.
U n gar o R, Me ha n dr u S, Alle n P B, Pe y ri n-Bir o ulet L , C ol o m bel J F. Ulcerati ve c olitis. La ncet 
2 0 1 6: 1 - 1 5.
Ver meire S, Sc hrei ber S, Petr y ka R, K ue h bac her T, He b uter ne X, R o bli n X, et al. Cli nical 
re missi o n i n patie nts wit h m o derate-t o-se vere Cr o h n's disease treate d wit h 
fil g oti ni b (t he FI T Z R O Y st u d y): res ults fr o m a p hase 2, d o u ble-bli n d, 
ra n d o mise d, place b o-c o ntr olle d trial. La ncet 2 0 1 7; 3 8 9: 2 6 6 - 7 5.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 0 9
0 2 A pril 2 0 1 9
1 1.
A P P E N DI C E S
A p pe n di x 1.
I n vesti gat or Si g nat ure Pa ge
A p pe n di x 2.
St u d y Pr oce d ures Ta ble
A p pe n di x 3.
Ma na ge me nt of Cli nical a n d La b orat or y A d verse E ve nts
A p pe n di x 4.
M a y o Sc ori n g S yste m f or Assess me nt of Ulcerati ve C olitis Acti vit y
A p pe n di x 5.
C T C A E Gra di n g Scale f or Se verit y of A d verse E ve nts
A p pe n di x 6.
Pre g na nc y Preca uti o ns, Defi niti o n f or Fe male of C hil d beari n g P ote ntial, a n d 
C o ntrace pti ve Re q uire me nts
A p pe n di x 7.
Cli nical La b orat or y Assess me nt Ta ble

Fil g oti ni b 
Pr ot oc ol G S- U S- 4 1 8- 3 8 9 8 
Fi nal 
Gilea d Scie nces, lnc. 
A m e n d m e nt 5 
A p p e n di x 1. 
I nv es ti g at o r Si g n a t ure P a g e 
GI L E A D S CI E N C E S, I N C. 
3 3 3 L A K E S I DE D RI V E 
F O S T E R C I TY, C A 9 4 4 0 4, U S A 
S T U D Y A C K N O W L E D G E M E N T 
C o m bi n e d P h as e 2 b/ 3, D o u b le- Bli n d, R a n d o mi z e d, Pl a c e b o- C o ntr oll e d St u di es E v al u ati n g t h e 
Effi c a c y a n d S af et y of Fil g oti ni b i n t h e I n d u cti o n a n d M ai nt e n a n c e of R e missi o n i n S u bj e cts 
wit h M o d er at el y t o S e v er el y A cti v e Ul c er ati v e C olitis 
G S- U S- 4 1 8- 3 8 9 8, A m e n d m e nt 5, 0 2 A p ril 2 0 1 9 
T his pr ot o c ol has b e e n a p pr o v e d b y Gil e a d S ci e n c es, I n c. T h e f oll o wi n g si g n at ur e d o c u m e nts 
t his a p pr o v al. 
[ PP D 
( PP D 
f 
P P D 
M e di c al M o nit or/ St u d y Dir e ct or 
o? >- A pr- 2. 0 1 9 
D at e 
I N V E STI G A T O R S T A T E M E N T 
I h a v e rea d t h e pr ot o c ol, i n cl u di n g all a p p e n di c es, a n d I a gr e e t h at it c o nt ai ns all n e c ess ar y 
d et ails f or m e a n d m y st aff t o c o n d u ct t his st u d y as d es cri b e d. I will c o n d u ct t his stu d y as 
o utli n e d h er ei n a n d will m a k e a r e as o n a ble eff ort t o c o m pl et e t h e st u d y wit hi n t h e ti m e 
d esi g n at e d. 
I will pr o vi d e all st u d y p ers o n n el u n d er m y s u p er visi o n c o pi es of t h e pr ot oc ol a n d a c c ess t o all 
i nf or m ati o n pr o vi d e d b y Gilea d S ci e n c es, I n c. I will dis c uss t his m at eri al wit h t h e m t o e ns ur e 
t h at t he y ar e f ull y i nf or m e d a b o ut t h e dr u gs a n d t h e st u d y. 
Pri n ci p al I n v esti g at or N a m e ( Pri nt e d) 
Si g n at ur e 
D at e 
Sit e N u m b er 
C O N FI D E N TI A L 
P a g e 1 1 0 
0 2 A pril 2 0 1 9 
• 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 1
0 2 A pril 2 0 1 9
A p pe n di x 2.
St u d y Pr oce d ures T a ble
Peri o d
Scree n
Tre at me nt
F oll o w -u p
Visit
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0 
1 1 
1 2 
1 3 
1 4 
1 5 
1 6 
1 7 
1 8 
1 9 
2 0
P T x a
E T
Wee k
0 
2 
4 
6
1 0 
1 1 
1 4
1 7
2 0
2 3
2 6
3 0
3 4
3 8
4 2
4 6
5 0
5 4
5 8
St u d y D a y
-3 0 t o - 1 
1
1 5 
2 9 
4 3 
7 1 
7 8 
9 9 
1 2 0 
1 4 1 
1 6 2 
1 8 3 
2 1 1 
2 3 9 
2 6 7 
2 9 5 
3 2 3 
3 5 1 
3 7 9 
4 0 7
Visit Wi n d o w
± 3 
± 3 
± 3 
± 2 
± 3 
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 3 
± 3
Writte n I nf or me d 
C o nse nt 
X
Me dical Hist or y & 
De m o gra p hics
X
Ulcerati ve C olitis
Treat me nt Hist or y
a n d disease e xte nt
X
1 2 -lea d E C G
X
X
X
X
X b
Re vie w of I ncl usi o n/
E xcl usi o n Criteria
X  
X
C o m plete P h y sical 
E xa m c
X
S y m pt o m directe d 
p h y sical e xa mc
(as nee de d)
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vital Si g ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Hei g ht
X
Wei g ht
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A d verse E ve nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C o nc o mita nt 
Me dicati o ns 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Ra n d o mizati o n
X
X

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 2
0 2 A pril 2 0 1 9
Peri o d
Scree n
Tre at me nt
F oll o w -u p
Visit
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0 
1 1 
1 2 
1 3 
1 4 
1 5 
1 6 
1 7 
1 8 
1 9 
2 0
P T x a
E T
Wee k
0 
2 
4 
6
1 0 
1 1 
1 4
1 7
2 0
2 3
2 6
3 0
3 4
3 8
4 2
4 6
5 0
5 4
5 8
St u d y D a y
-3 0 t o - 1 
1
1 5 
2 9 
4 3 
7 1 
7 8 
9 9 
1 2 0 
1 4 1 
1 6 2 
1 8 3 
2 1 1 
2 3 9 
2 6 7 
2 9 5 
3 2 3 
3 5 1 
3 7 9 
4 0 7
Visit Wi n d o w
± 3 
± 3 
± 3 
± 2 
± 3 
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 3 
± 3
St u d y  Dr u g 
Dis pe nsi n g
X  
X
X  
X  
X  
X  
X  
X  
X
C ol o n osc o p y / Fle xi ble 
Si g m oi d osc o p y  wit h 
bi o ps y
X d
X
X
I nvesti gat or 
E n d osc o pic Val ue 
( 0, 1, 2, or 3)e
X
X
X
Ma y o Sc ore ( Partial)f
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
X
Ma y o Sc ore 
( C o m plete)
X
X
X
e Diar y i nstr ucti o n & 
re vie wg
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
St o ol f or C. diff t o xi n, 
pat h o ge nic E. c oli,
S al m o nell a s p p, 
S hi gell a s p p, 
C a m pyl o b acter s p p 
or Yersi ni a s p p 
testi n g
X
St o ol O & P h
X
St o ol micr o bi o me
X
X
X
X
Fecal M M P - 9
X
X
X
X
Fecal Lact oferri n, 
Cal pr otecti n
X
X
X
X

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 3
0 2 A pril 2 0 1 9
Peri o d
Scree n
Tre at me nt
F oll o w -u p
Visit
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0 
1 1 
1 2 
1 3 
1 4 
1 5 
1 6 
1 7 
1 8 
1 9 
2 0
P T x a
E T
Wee k
0 
2 
4 
6
1 0 
1 1 
1 4
1 7
2 0
2 3
2 6
3 0
3 4
3 8
4 2
4 6
5 0
5 4
5 8
St u d y D a y
-3 0 t o - 1 
1
1 5 
2 9 
4 3 
7 1 
7 8 
9 9 
1 2 0 
1 4 1 
1 6 2 
1 8 3 
2 1 1 
2 3 9 
2 6 7 
2 9 5 
3 2 3 
3 5 1 
3 7 9 
4 0 7
Visit Wi n d o w
± 3 
± 3 
± 3 
± 2 
± 3 
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 3 
± 3
Uri ne dr u g scree n i
X
Uri nal ysis
X  
X
X
X
Pre g na nc y Test j
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
T B k
X
C hest x -ra y l
X
H B V, H C V, HI V 
scree ni n g m
X
H B V D N A 
m o nit ori n g (Ja pa n) n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
H B V m o nit ori n g 
( ot her re gi o ns)n
X
X
X
X  
X
He mat ol o g y
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C he mistr y
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Li pi d pr ofile
(fasti n g)o
X
X
X
X
X
C R P
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Ser u m 
i m m u n o gl o b uli n
X  
X  
X
X
X  
X  
X
Bl o o d T C R/ B C R 
re pert oire sa m ples p
X  
X  
X
X
X
Plas ma bi o mar ker 
sa m ple
X  
X  
X
X
X

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 4
0 2 A pril 2 0 1 9
Peri o d
Scree n
Tre at me nt
F oll o w -u p
Visit
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0 
1 1 
1 2 
1 3 
1 4 
1 5 
1 6 
1 7 
1 8 
1 9 
2 0
P T x a
E T
Wee k
0 
2 
4 
6
1 0 
1 1 
1 4
1 7
2 0
2 3
2 6
3 0
3 4
3 8
4 2
4 6
5 0
5 4
5 8
St u d y D a y
-3 0 t o - 1 
1
1 5 
2 9 
4 3 
7 1 
7 8 
9 9 
1 2 0 
1 4 1 
1 6 2 
1 8 3 
2 1 1 
2 3 9 
2 6 7 
2 9 5 
3 2 3 
3 5 1 
3 7 9 
4 0 7
Visit Wi n d o w
± 3 
± 3 
± 3 
± 2 
± 3 
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 3 
± 3
Ser u m bi o mar ker 
sa m ple
X  
X  
X
X
X
Bl o o d tra nscri pt o me 
sa m ple
X  
X  
X
X
X
P K c ollecti o n 
(s parse)q
X  
X
X
X
vf P B M C r
X  
X  
X
X
X
P K s u bst u d ys
X
H R Q o L S ur ve ys u
X
X
X
X
H C R U q uesti o n naire
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
a
T he P ost Treat me nt ( P T x ) visit s h o ul d occ ur 3 0 da ys after t he last d ose of st u d y dr u g. O nl y s u bjects w h o r oll o v er i nt o t he L T E st u d y ( G S -U S -4 1 8 -3 8 9 9 ) will n ot c o m plete 
P T x assess me nts .
b
F or s u bjects w h o ter mi nate pri or t o Wee k 1 0
c  
A c o m plete p h ysical e xa mi nati o n ( PE) i ncl u di n g, vital si g ns, b o d y wei g ht, a n d hei g ht will be perf or me d at scree ni n g. ( G U e xa m at i n vesti gat or discreti o n). A s y m pt o m 
directe d P E ma y be d o ne as nee de d at ot her ti me p oi nts.
d  
Diar y data a n d ot her eli gi bilit y criteria s h o ul d be re vie we d pri or t o sc he d uli n g e n d osc o p y. P erf or m the scree ni n g c ol o n osc o p y/fle xi ble si g m oi d osc o p y wit hi n 2 wee ks of Da y 1
(Da y -1 4 t o -1). S u bject s h o ul d meet st o ol fre q ue nc y a n d rectal blee di n g re q uire me nts base d o n diar y data pri or t o e n d osc o p y perf or ma nce.
e
T he i n vesti gat or (ie, l ocal e n d osc o pist) s h o ul d e nter i n a n e n d osc o pic s u bsc ore ( 0, 1, 2, or 3) base d o n t he Ma y o Cli nic Sc or i n g S yste m e n d osc o pic scale (A p pe n di x 4 ); t his 
will be e ntitle d t he I n vesti gat or E n d osc o pic Val ue. T he l ocall y rea d sc ore e ntere d ma y n ot be use d f or eli gi bilit y or Ma y o Cl i nic Sc ore calc ulati o n p ur p oses, a n d is n ot a 
s u bstit ute f or t he ce ntrall y rea d sc ore, b ut is c ollecte d s olel y f or e x pl orat or y p ur p oses.
f
I ncl u des all parts of t he Ma y o sc ore e xce pt e n d osc o p y
g
S u bjects s h o ul d be gi n filli n g o ut t he e Diar y t he da y after t heir i nitial scree ni n g v isit a n d c o nti n ue t o fill it o ut t hr o u g h o ut t he re mai n der of t he st u d y.
h 
St o ol sa m ples s h o ul d be c ollecte d t o r ule o ut i nfecti o us ca uses w he n disease w orse ns.
i
P ositi ve c ocai ne test dis q ualifies s u bject; p ositi ve a m p heta mi nes, bar bit urates, be nz o diaze pi nes, a n d o pi oi ds re q uire me dical m o nit or re vie w.
j  
All fe males meeti n g t he c hil d beari n g p ote ntial criteria m ust ha ve a ser u m pre g na nc y testi n g at scree ni n g a n d a uri ne pre g na ncy test m ust be c o m plete d i n cli nic e ver y 4 wee ks 
at a mi ni m u m. If a n y pre g na nc y test is p ositi ve, st u d y dr u g s h o ul d be i m me diatel y i nterr u pted a n d t he s u bject s h o ul d ha ve a ser u m pre g na nc y test i n cli nic.
C CI

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 5
0 2 A pril 2 0 1 9
k
Pr o of of n o acti ve or u ntreate d late nt T B at s cree ni n g. S u bjects w h o are dia g n ose d wit h late nt T B at scree ni n g m ust i nitiate a n a de q uate c o urse of pr o p h yla xis as per l ocal 
sta n dar d of care f or a mi ni m u m of 4 wee ks pri or t o ra n d o mizati o n. S u bject ma y i nitiate st u d y dr u g d osi n g o nl y after c o ns ultat i o n wit h t he me dical m o nit or.
l
C hest x -ra y ( vie ws as per l ocal g ui deli nes) ta ke n at scree ni n g or wit hi n t he 3 m o nt hs pri or t o scree ni n g ( wit h t he re p ort or fil ms a vaila ble f or i n vesti gat or re vie w) wit h o ut 
e vi de nce of acti ve or late nt T B i nfecti o n
m
He patitis B s urface A g , s urface A b a n d c ore A b, refle x H B V D N A, He patitis C A b, refle x H C V R N A, HI V A g/ A b, refle xt HI V 1/ 2 A b at Scree ni n g ( Secti o n 6. 2. 1 ).
n
I n Ja pa n, s u bjects wit h ne gati ve H Bs A g, p ositi ve H Bc A b a n d/ or p ositi ve H Bs A b at Scree ni n g re q uire H B V D N A m o nit ori n g e ver y 4 wee ks i n acc or da nce wit h l ocal 
g ui deli nes ( Secti o n 6. 2. 1 ). I n ot her re gi o ns, s u bjects wit h ne gati ve H Bs A g a n d p ositi ve H Bc A b re q uire H B V D N A m o nit ori n g e ver y 3 m o nt hs i n acc or da nce wit h l ocal 
g ui deli nes ( Secti o n 6. 2. 1 )
o
Fasti n g me a ns n o f o o d or dri n k, e xce pt water, f or 8 h o urs 
p
T C R: T -cell rece pt or; B C R: B-cell rece pt or
q
T his P K sa m ple at Wee ks 1 0 a n d 5 8 are c ollecte d at pre -d ose ( wit hi n 2 h o urs pri or t o d os i n g).  T he P K sa m ple at Wee k 4 is collecte d p ost -d ose (at least 3 0 mi n utes a n d u p t o 
3 h o urs after st u d y dr u g d osi n g . F or t his visit, it is preferre d t hat st u d y dr u g d osi n g is i n cli nic. T he P K sa m ple at Wee ks 2 6 ca n be c ollecte d at a n y ti me wit h o ut re gar d t o 
d osi n g . F or t hese visits, t he ti me of d ose ta ke n o n t he da y of a n d t he d ose ta ke n pri or t o t he P K sa m ple bei n g dra w n will be n ote d i n t he e C R F.
r
vf P B M C c ollecti o n at U S a n d Ca na dia n sites o nl y.
s
S u bjects w h o c o nse nt t o o pti o nal P K s u bst u d y will ha ve a n a d diti o nal plas ma P K sa m ple at a n y si n gle visit fr o m Wee k
2 a n d 1 0 , c ollecte d pre-d ose a n d at 0. 5, 1, 2, 3, 4 a n d 
6 h o urs after s u per vise d d osi n g i n t he cli nic. F or all visits wit h P K sa m pli n g, t he ti me of d ose ta ke n pri or t o a n d o n t he da y of visit will be n ote d i n t he e C R F
u
H R Q o Ls i ncl u de S F -3 6, W P AI, E Q -5 D, I B D Q
C CI

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 6
0 2 A pril 2 0 1 9
A p pe n di x 3.
M a n a ge me nt of Cli nic al a n d L a b or at or y A d verse E ve nts
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 8
0 2 A pril 2 0 1 9
A p pe n di x 5.  
C T C A E Gr a di n g Sc ale f or Se verit y of A d verse E ve nts
Please refer t o t he C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) Versi o n 4. 0 3, 
w hic h ca n be f o u n d at:
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6- 1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df .
F or A Es ass ociate d wit h la b orat or y  a b n or malities, t he e ve nt s h o ul d be gra de d o n t he basis of t he 
cli nical se verit y i n t he c o nte xt of t he u n derl yi n g c o n diti o ns; t his ma y or ma y  n ot be i n a gree me nt 
wit h t he gra di n g of t he la b orat or y  a b n or malit y.
T he o nl y  m o dificati o n t o t he C T C A E criteria is t he a d diti o n of a Gra de 1 u p per res pirat or y 
i nfecti o n as f oll o ws:
C T C A E 
v 4. 0 Ter m
Gr a de 1
Gr a de 2  
Gr a de 3  
Gr a de 4
Gr a de 5
C T C A E v 4. 0 3 
A E Ter m 
Defi niti o n
U p per 
res pirat or y 
i nfecti o n
Mil d 
s y m pt o ms; 
s y m pt o matic 
relief 
(e g, c o u g h 
s u p pressa nt, 
dec o n gesta nt)
M o derate 
s y m pt o ms; 
oral 
i nter ve nti o n 
i n dicate d 
(e g, a nti bi otic, 
a ntif u n gal, 
a nti viral)
I V a nti bi otic, 
a ntif u n gal, or 
a nti viral 
i nter ve nti o n 
i n dicate d; 
ra di ol o gic, 
e n d osc o pic, or 
o perati ve 
i nter ve nti o n 
i n dicate d
Life -
t hreate ni n g 
c o nse q ue nces; 
ur ge nt 
i nter ve nti o n 
i n dicate d
Deat h
A dis or der 
c haracterize d b y 
a n i nfecti o us 
pr ocess i n v ol vi n g 
t he u p per 
res pirat or y tract 
( n ose, para nasal 
si n uses, p har y n x, 
lar y n x, or 
trac hea).

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 1 9
0 2 A pril 2 0 1 9
A p pe n di x 6. 
Pre g n a nc y Prec a uti o ns, Defi niti o n f or Fe m ale of C hil d be ari n g 
P ote nti al, a n d C o ntr ace pti ve Re q uire me nts
T he a d mi nistrati o n of fil g oti ni b i n e m br y o- fetal a ni mal de vel o p me nt st u dies res ulte d i n 
decrease d n u m bers of via ble rat fet uses, i ncrease d res or pti o ns, a n d visceral a n d s keletal 
malf or mati o ns.  Si milar effects were n ote d i n t he ra b bit. A safet y mar gi n relati ve t o h u ma n 
e x p os ure has n ot bee n i de ntifie d.  Pre g na nc y  is c o ntrai n dic ate d d uri n g use of fil g oti ni b.
F or partici pati o n i n t his st u d y , t he use of hi g hly effective c o ntrace pti o n is re q uire d as o utli ne d 
bel o w f or all s u bjects w h o are of c hil d beari n g p ote ntial. I n a d diti o n, d uri n g t he st u d y w o me n of 
c hil d beari n g p ote ntial m ust ha ve at a mi ni m u m , a uri ne pre g na nc y  test e ver y 4 wee ks.
1)
Defi niti o ns
a)
Defi niti o n of C hil d be ari n g P ote nti al
F or t he p ur p oses of t his st u d y , a fe male-b or n s u bject is c o nsi dere d of c hil d beari n g p ote ntial 
f oll o wi n g t he i nitiati o n of p u berty ( Ta n ner sta ge 2) u n til bec o mi n g p ost-me n o pa usal, u nless 
per ma ne ntl y sterile or wit h me dicall y d oc u me nte d o varia n fail ure.  W o me n w h o d o n ot meet 
bel o w criteria f or bei n g p ost- me n o pa usal, are n ot per ma ne ntl y sterile, or d o n ot ha ve me dicall y 
d oc u me nte d o varia n fail ure m ust ha ve pre g na nc y testi n g as o utli ne d b y  t he pr ot oc ol. 
W o me n are c o nsi dere d t o be i n a p ost me n o pa usal state w he n t he y  are > 5 4 ye ars of a ge wit h 
cessati o n of pre vi o usl y occ urri n g me nses f or > 1 2 m o nt hs wit h o ut a n alter nati ve ca use.
Per ma ne nt sterilizati o n i ncl u des h ys terect o m y, bilateral o o p h orect o my, or bilateral 
sal pi n gect o m y i n a fe male s u bject of a ny a ge. Bilateral t u bal li gati o n is n ot c o nsi dere d 
per ma ne nt sterilizati o n.
b)
Defi niti o n of M ale Fertilit y
F or t he p ur p oses of t his st u d y , a male-b or n s u bject is c o nsi dere d fertile after t he i nitiati o n of 
p u bert y  u nless per ma ne ntl y sterilize d b y  bilateral orc hi dect o my or has me dical d oc u me ntati o n of 
per ma ne nt male i nfertilit y . Vasect o m y is n ot c o nsi dere d per ma ne nt sterilizati o n.
2)
C o ntr ace pti o n f or Fe m ale S u bjects
a)
St u d y Dr u g Effects o n Pre g n a nc y a n d H or m o n al C o ntr ace pti o n
Fil g oti ni b is c o ntrai n dicate d i n pre g na nc y as t here is a p ossi bilit y  of h u ma n 
terat o ge nicity/ fet ot o xicit y i n early pre g na nc y base d o n n o n -cli nical data. Data fr o m a dr u g -dr u g 
i nteracti o n st u d y of fil g oti ni b a n d h or m o nal c o ntrace pti ves ( G S-U S - 4 1 7- 3 9 1 6) ha ve 
de m o nstrate d c o - a d mi nistrati o n wit h fil g oti ni b di d n ot alter t he p har mac o ki netics of 
re prese ntati ve h or m o nal c o ntrace pti ves, le v o n or gestrel/et hi n yl estra di ol.  

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 2 0
0 2 A pril 2 0 1 9
F or fe male s u bjects, h or m o nal c o ntrace p ti ves will be per mitte d as a f or m of c o ntrace pti o n w he n 
use d i n c o nj u ncti o n wit h a barrier met h o d ( prefera bl y  a male c o n d o m). F or male s u bjects, male 
c o n d o m s h o ul d be use d; f or t heir fe male part ners of c hil d beari n g p ote ntial, a n acce pte d 
c o ntrace pti ve met ho d s h o ul d als o be c o nsi dere d. Details are o utli ne d bel o w.
Please refer t o t he latest versi o n of t he fil g oti ni b I B f or a d diti o nal i nf or mati o n.
b)
C o ntr ace pti o n f or Fe m ale S u bjects of C hil d be ari n g P ote nti al
T he i ncl usi o n of fe male s u bjects of c hil d beari n g p ote ntial re q uires t he use of hi g hl y effecti ve 
c o ntrace pti ve meas ures. W o me n m ust ha ve a ne gati ve ser u m pre g na nc y  test at scree ni n g a n d a 
ne gati v e uri ne pre g na nc y test o n t he D a y 1 visit pri or t o ra n d o mizati o n. Pre g na nc y  tests will be 
perf or me d at m o nt hl y  i nter vals t hereafter. I n t he e ve nt of a dela y e d me nstr ual peri o d 
( > o ne m o nt h bet wee n me nstr uati o ns), a pre g na nc y  test m ust be perf or me d t o r ule o ut pre g na nc y. 
T his is tr ue e ve n f or w o me n of c hil d beari n g p ote ntial wit h i nfre q ue nt or irre g ular peri o ds.
Fe m ale s u bjects m ust a gree t o use o ne of t he f oll o wi n g met h o ds fr o m scree ni n g u ntil 3 5 d a y s 
f oll o wi n g t he last d ose of st u d y dr u g.

C o m plete a bsti ne nce fr o m i nterc o urse of re pr o d ucti ve p ote ntial. A bsti ne nce is a n acce pta ble 
met h o d of c o ntrace pti o n o nl y  w he n it is i n li ne wit h t he s u bject’s preferre d a n d us ual 
lifest yle.
Or

C o nsiste nt a n d c orrect use of 1 of t he f oll o wi n g met h o ds of birt h c o ntr ol liste d bel o w . 

I ntra uteri ne de vice (I U D) wit h a fail ure rate of < 1 % per ye ar

T u bal sterilizati o n

Ess ure micr o -i nsert s yste m ( pr o vi de d c o nfir mati o n of s uccess 3 m o nt hs after pr oce d ure)

Vasect o m y i n t he male part ner ( pr o vi de d t hat t he part ner is t he s ole se x ual part ner a n d 
ha d c o nfir mati o n of s ur gical s uccess 3 m o nt hs after pr oce d ure)
Fe male s u bjects w h o wis h t o use a h or m o nall y base d met h o d , m ust use it i n c o nj u ncti o n wit h a 
barrier met h o d; t he barrier met h o d is t o be use d eit her b y  t he fe male s u bject or b y her male 
part ner . Fe male s u bjects w h o utilize a h or m o nal c o ntrace pti ve as o ne of t heir birt h c o ntr ol 
met h o ds m ust ha ve c o nsiste ntl y  use d t he sa me met h o d f or at least t hree m o nt hs pri or t o st u d y 
d osi n g. H or m o nall y- base d c o ntrace pti ves a n d barrier met h o ds per mitte d f or use i n t his pr ot oc ol 
are as f oll o ws:

or m o nal met h o ds (eac h met h o d m ust be use d wit h a barrier met h o d, prefera bl y  male
c o n d o m)

Oral c o ntrace pti ves (eit her c o m bi ne d estr o ge n/ pr o gesti n or pr o gester o ne o nl y )

I njecta ble pr o gester o ne

I mpla nts of le v o n or gestrel

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 2 1
0 2 A pril 2 0 1 9

Tra ns der mal c o ntrace pti ve patc h

C o ntrace pti ve va gi nal ri n g

Barrier met h o ds (eac h met h o d m ust be us e d wit h a h or m o nal met h o d)

Male or fe male c o n d o m wit h or wit h o ut s per mici de

Dia p hra g m wit h s per mici de

Cer vical ca p wit h s per mici de

S p o n ge wit h s per mici de
All fe male s u bjects m ust als o refrai n fr o m e g g d o nati o n a n d i n vitr o fertilizati o n d uri n g treat me n t
a n d u ntil at least 3 5 da ys after t he last st u d y dr u g d ose.
3)
C o ntr ace pti o n Re q uire me nts f or M ale S u bjects
It is t he oretically p ossi ble t hat a rel e va nt c o nce ntrati o n of st u d y  dr u g m a y  be ac hie ve d i n a 
fe male part ner fr o m e x p os ure t o t he male s u bject’s se mi n al fl ui d. T heref ore, male s u bjects wit h 
fe male part ners of c hil d beari n g p ote ntial m ust use c o n d o ms d uri n g st u d y partici pati o n a n d f or
9 0 da y s after t he last st u d y dr u g d ose . Fe male part ners of male st u d y s u bjects s h o ul d c o nsi der 
usi n g o ne of t he a b o ve met h o ds of c o ntrace pti o n as well . Male s u bjects m ust als o refrai n fr o m 
s per m d o nati o n d uri n g treat me nt a n d u ntil at least 9 0 da y s after t he e n d of st u d y dr u g d osi n g.
4)
U n acce pt a ble Birt h C o ntr ol Met h o ds
Birt h c o ntr ol met h o ds t hat are u nacce pta ble i ncl u de peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n,
s ym pt ot her mal, p ost- o v ulati o n met h o ds), wit h dra wal (c oit us i nterr u pt us), s per mici des o nl y, a n d
lactati o nal a me n orr hea met h o d ( L A M). Fe male c o n d o m a n d male c o n d o m s h o ul d n ot be use d
t o get her.
5)
Pr oce d ures t o be F o ll o we d i n t he E ve nt of Pre g n a nc y
S u bjects will be i nstr ucte d t o n otif y  t he i n vesti gat or if t he y bec o me pre g na nt at a n y ti me d uri n g
t he st u d y, or if t he y bec o me pre g na nt wit hi n 3 0 da ys of last st u d y dr u g d ose. S u bjects w h o
bec o me pre g na nt or w h o s us pect t ha t t he y are pre g na nt d uri n g t he st u dy m ust re p ort t he
i nf or mati o n t o t he i n vesti gat or a n d disc o nti n ue st u d y dr u g i m me diately. S u bjects w h ose part ner
has bec o me pre g na nt or s us pects s he is pre g na nt d uri n g t he st u d y are t o re p ort t he i nf or mati o n t o
t he i n vesti gat or.
I nstr ucti o ns f or re p orti n g pre g na nc y, part ner pre g na nc y, a n d pre g na nc y o utc o me are o utli ne d i n
Secti o n 7. 7. 2. 1 .
6)
Pre g n a nc y Testi n g
All fe males of c hil d beari n g p ote ntial will ha ve uri ne pre g na nc y  testi n g e ver y 4 wee ks (i n cli nic)
d uri n g t heir st u d y partici pati o n. If a uri ne pre g na nc y test is p ositi ve , t he s u bject s h o ul d st o p 
st u d y dr u g i m me diately, c o ntact t he i n vesti gat or, a n d ha ve c o nfir mat or y  ser u m pre g na nc y test i n 
cli nic.

Fil g oti ni b
Pr ot oc ol G S -U S -4 1 8 -3 8 9 8
Fi nal
Gilea d Scie nces, I nc. 
A me n d me nt 5
C O N FI D E N TI A L
Pa ge 1 2 2
0 2 A pril 2 0 1 9
A p pe n di x 7.  
Cli nic al L a b or at or y Assess me nt T a ble
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
H e m at ocrit
H e m o gl o bi n
Platelet c o u nt
Re d bl o o d cell ( R B C) c o u nt
W hite bl o o d cell ( W B C) 
c o u nt
Differe ntials (a bs ol ute a n d 
perce nta ge), i ncl u di n g:
L y m p h oc ytes
M o n oc ytes
Ne utr o p hils
E osi n o p hils
Bas o p hils
Retic ul yte c o u nt
Mea n c or p usc ular v ol u me 
( M C V)
Al kali ne p h os p hatase
As partate a mi n otra nsferase 
( A S T)
Ala ni ne a mi n otra nsferase 
( A L T)
T otal bilir u bi n
Direct a n d i n direct bilir u bi n
T otal pr otei n
Al b u mi n
Bicar b o nate
Bl o o d urea nitr o ge n ( B U N)
Calci u m
C hl ori de
Ser u m creati ni ne
Creati ni ne cleara nce  
C C & G
Gl uc ose
P h os p h or us
Ma g nesi u m
P otassi u m
S o di u m
Creati ne p h os p h o ki nase 
( C P K)
A p peara nce:
Bl o o d
C ol or
Gl uc ose
Le u k oc yte esterase
p H
Pr otei n
Ur o bili n o ge n
Uri ne dr u g scree n f or:
A m p heta mi nes
C ocai ne
Bar bit urates
O piates
Be nz o diaze pi nes
vf P B M Cs *
Le uc oc yte s u bsets *
C- reacti ve pr otei n ( C R P hs)
Q ua nti F E R O N ® T B –
G ol d I n-T u be A nal ysis (if 
re q uire d per i ncl usi o n 
criteria)
R N A
Bi o ps y ( hist ol o g y)
Fecal (st o ol)
Micr o bi o me
Lact oferri n, Cal pr otecti n
M M P - 9
Bacterial St o ol C ult ure
C- Diff T o xi n
O va a n d Parasites ( O & P) 
Plas ma Bi o mar ker
Ser u m Bi o mar ker
P har m ac o ge n o mic ( P G)
P har m ac o ki netics ( P K)
Ser u m I m m u n o gl o b uli n
Pr ot hr o m bi n Ti me ( P T)
Partial t hr o m b o plasti n ti me 
( P T T)
I nter nati o nal N or malize d 
Rati o (I N R)
Ser ol o g y
He patitis B S urface A g 
He patitis B S urface A b
He patitis B C ore A b 
H B V D N A 
He patitis C A b
H C V R N A
HI V
Pre g n a nc y
I n fe m ales of c hil d be ari n g 
p ote nti al:
Ser u m pre g na nc y
Uri ne pre g na nc y
F asti n g Li pi ds
Tri gl yceri des
C h olester ol a n d its
s u bfracti o ns ( hi g h-de nsit y 
li p o pr otei n [ H D L] a n d l o w 
de nsit y li p o pr otei n [ L D L] 
*
vf P B M C a n d Le u k oc yte s u bsets i n N ort h A merica o nl y