Clinical trial NCT02914522
Conditions: Ulcerative Colitis
Sponsor: Gilead Sciences
Start date: 2016-11-14; Completion date: 2020-03-31
Enrollment: 1351 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the efficacy of filgotinib in the induction and maintenance treatment of moderately to severely active ulcerative colitis (UC) in participants who are biologic-naive and biologic-experienced.

Participants who complete the study, or met protocol specified efficacy discontinuation criteria will have the option to enter a separate, long-term extension (LTE) study (Gilead Study GS-US-418-3899: NCT02914535).

Detailed description:

Arms: arm 1: Participants in Cohort A (biologic-naive) received filgotinib 200 milligrams (mg) and placebo-to-match (PTM) filgotinib 100 mg orally once daily for 10 weeks. arm 2: Participants in Cohort A (biologic-naive) received filgotinib 100 mg and PTM filgotinib 200 mg orally once daily for 10 weeks. arm 3: Participants in Cohort A (biologic-naive) received PTM filgotinib 200 mg and PTM filgotinib 100 mg orally once daily for 10 weeks. arm 4: Participants in Cohort B (biologic-experienced) received filgotinib 200 mg and PTM filgotinib 100 mg orally once daily for 10 weeks. arm 5: Participants in Cohort B (biologic-experienced) received filgotinib 100 mg and PTM filgotinib 200 mg orally once daily for 10 weeks. arm 6: Participants in Cohort B (biologic-experienced) received PTM filgotinib 200 mg and PTM filgotinib 100 mg orally once daily for 10 weeks. arm 7: Participants in the Filgotinib 200 mg arm who completed the Induction Study and achieved either Endoscopy/Bleeding/Stool Frequency (EBS) remission or Mayo Clinic Score (MCS) response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive filgotinib 200 mg and PTM filgotinib 100 mg for an additional 47 weeks (up to Week 58). arm 8: Participants in the Filgotinib 200 mg arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive PTM filgotinib orally once daily for an additional 47 weeks (up to Week 58). arm 9: Participants in the Filgotinib 100 mg arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive filgotinib 100 mg and PTM filgotinib 200 mg for an additional 47 weeks (up to Week 58). arm 10: Participants in the Filgotinib 100 mg arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were rerandomized at Week 11 into the Maintenance Study to receive PTM filgotinib orally once daily for an additional 47 weeks (up to Week 58). arm 11: Participants in the Placebo arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive PTM filgotinib for an additional 47 weeks (up to Week 58).
Interventions: intervention 1: Filgotinib intervention 2: PTM filgotinib
Intervention descriptions: intervention 1: Tablet(s) administered orally once daily intervention 2: Tablet(s) administered orally once daily

Protocol documents:
Prot_000.pdf: 
(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
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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

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
Combined Phase 2b/3, Double-Blinded, 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
Name of Test Drug:
Filgotinib
Study Number:
GS-US-418-3898
Protocol Version (Date):
Original: 15 July 2016
Amendment 1: 07 September 2016
Amendment 2: 27 October 2016
Amendment 3: 15 June 2017
Amendment 4: 05 March 2018
Amendment 5: 02 April 2019
Analysis Type:
Final Analysis
Analysis Plan Version:
3.0
Analysis Plan Date:
28 Apr 2020
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


Filgotinib
GS-US-418-3898 Statistical Analysis Plan
Version 3.0
CONFIDENTIAL
Page 2
28 April 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
LIST OF ABBREVIATIONS........................................................................................................................................6
PHARMACOKINETIC ABBREVIATIONS................................................................................................................8
1.
INTRODUCTION ................................................................................................................................................9
1.1.
Study Objectives ......................................................................................................................................9
1.1.1.
Primary Objectives.................................................................................................................9
1.1.2.
Secondary Objectives.............................................................................................................9
1.1.3.
Exploratory Objectives.........................................................................................................10
1.2.
Study Design..........................................................................................................................................11
1.2.1.
Induction Studies (Cohort A Induction Study and Cohort B Induction 
Study)...................................................................................................................................12
1.2.2.
Maintenance Study...............................................................................................................13
1.2.3.
Pharmacokinetics Substudy..................................................................................................14
1.2.4.
Schedule of Assessments......................................................................................................14
1.3.
Sample Size and Power..........................................................................................................................14
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................15
2.1.
Data Monitoring Committee (DMC) Analyses ......................................................................................15
2.1.1.
Safety Analyses....................................................................................................................15
2.1.2.
Futility Analysis ...................................................................................................................15
2.1.3.
Cohorts A and B End-of-Induction Analysis .......................................................................15
2.2.
Final Analysis ........................................................................................................................................15
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................16
3.1.
Analysis Sets..........................................................................................................................................16
3.1.1.
All Randomized Analysis Sets.............................................................................................16
3.1.2.
Full Analysis Set ..................................................................................................................16
3.1.3.
Per-Protocol Analysis Sets ...................................................................................................17
3.1.4.
Safety Analysis Set...............................................................................................................18
3.1.5.
Pharmacokinetic Analysis Sets.............................................................................................18
3.1.6.
Pharmacokinetic Substudy Analysis Set ..............................................................................18
3.1.7.
Biomarker Analysis Set........................................................................................................18
3.2.
Subject Grouping ...................................................................................................................................18
3.3.
Strata and Covariates..............................................................................................................................19
3.4.
Examination of Subject Subgroups........................................................................................................19
3.5.
Multiple Comparisons............................................................................................................................19
3.6.
Missing Data and Outliers......................................................................................................................24
3.6.1.
Missing Data ........................................................................................................................24
3.6.2.
Outliers.................................................................................................................................24
3.7.
Data Handling Conventions and Transformations .................................................................................24
3.8.
Analysis Visit Windows.........................................................................................................................25
3.8.1.
Definitions............................................................................................................................25
3.8.2.
Analysis Visit Windows.......................................................................................................27
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................30
4.
SUBJECT DISPOSITION ..................................................................................................................................31


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4.1.
Subject Enrollment and Disposition.......................................................................................................31
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................33
4.2.1.
Duration of Exposure to Study Drug....................................................................................33
4.2.2.
Adherence to Study Drug.....................................................................................................34
4.3.
Protocol Deviations................................................................................................................................34
5.
BASELINE CHARACTERISTICS....................................................................................................................35
5.1.
Demographics and Other Baseline Characteristics ................................................................................35
5.2.
Baseline Disease Characteristics............................................................................................................35
5.3.
Medical History......................................................................................................................................38
6.
EFFICACY ANALYSES ...................................................................................................................................39
6.1.
General Considerations ..........................................................................................................................39
6.1.1.
Calculations of Mayo Clinic Scores (MCS) and Partial MCS (pMCS) 
with the Subscores................................................................................................................42
6.2.
Primary Efficacy Endpoints ...................................................................................................................42
6.2.1.
Definition of the Primary Efficacy Endpoints......................................................................42
6.2.2.
Statistical Hypotheses for the Primary Efficacy Endpoints..................................................43
6.2.3.
Analysis of the Primary Efficacy Endpoint..........................................................................43
6.2.4.
Sensitivity Analysis of the Primary Efficacy Endpoints ......................................................44
6.2.5.
Subgroup Analysis of the Primary Efficacy Endpoint .........................................................46
6.3.
Secondary Efficacy Endpoints ...............................................................................................................48
6.3.1.
Definition of the Secondary Efficacy Endpoints..................................................................48
6.3.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................49
6.4.
Exploratory Efficacy Endpoints.............................................................................................................49
6.4.1.
Definition of the Exploratory Efficacy Endpoints................................................................49
6.4.2.
Analysis of  Exploratory Efficacy Endpoints.......................................................................50
6.5.
Interim Efficacy Analyses......................................................................................................................54
6.5.1.
DMC Futility Analysis.........................................................................................................54
6.5.2.
DMC Cohorts A and B End-of-Induction Analysis .............................................................54
6.6.
Change from Protocol-Specified Efficacy Analyses..............................................................................55
7.
SAFETY ANALYSES........................................................................................................................................56
7.1.
Adverse Events and Deaths....................................................................................................................56
7.1.1.
Adverse Event Dictionary ....................................................................................................56
7.1.2.
Adverse Event Severity........................................................................................................56
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................56
7.1.4.
Serious Adverse Events........................................................................................................56
7.1.5.
Treatment-Emergent Adverse Events...................................................................................56
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................58
7.1.7.
Adverse Events of Interest ...................................................................................................60
7.1.8.
Additional Analysis of Adverse Events ...............................................................................61
7.2.
Laboratory Evaluations ..........................................................................................................................61
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................62
7.2.2.
Graded Laboratory Values ...................................................................................................63
7.2.3.
Laboratory Evaluations of Interest .......................................................................................65
7.2.4.
Shifts Relative to the Baseline Value ...................................................................................66
7.3.
Body Weight  and Vital Signs................................................................................................................67
7.4.
Prior and Concomitant Medications.......................................................................................................67
7.4.1.
Prior Medications .................................................................................................................68
7.4.2.
Concomitant Medications.....................................................................................................68
7.5.
Electrocardiogram Results .....................................................................................................................69
7.6.
Other Safety Measures ...........................................................................................................................69
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................69


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8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................70
8.1.
PK Sample Collection............................................................................................................................70
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................70
8.2.1.
Estimation of PK Parameters ...............................................................................................70
8.2.2.
PK Substudy.........................................................................................................................70
8.3.
Statistical Analysis Methods ..................................................................................................................72
9.
BIOMARKER ANALYSIS................................................................................................................................73
10.
REFERENCES ...................................................................................................................................................74
11.
SOFTWARE.......................................................................................................................................................75
12.
SAP REVISION..................................................................................................................................................76
13.
APPENDICES ....................................................................................................................................................79
Appendix 1.
Schedule of Assessments........................................................................................................80
Appendix 2.
Biologics for UC Treatment ...................................................................................................85
Appendix 3.
Mayo Scoring System for Assessment of Ulcerative Colitis Activity....................................86
Appendix 4.
Mayo Clinic Score (MCS) Calculation...................................................................................87
Appendix 5.
Study Treatment Failure Rules...............................................................................................92
Appendix 6.
Geboes Histological Score Grades .........................................................................................94
Appendix 7.
PK Parameters ........................................................................................................................95
LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for Induction Study Endoscopic Subscore, and 
Geboes Histologic Score ........................................................................................................27
Table 3-2.
Analysis Visit Windows for Maintenance Study Endoscopic Subscore, and 
Geboes Histologic Score ........................................................................................................27
Table 3-3.
Analysis Visit Windows for Induction Study Stool Frequency, Rectal Bleeding, and 
PGA subscores .......................................................................................................................28
Table 3-4.
Analysis Visit Windows for Maintenance Study Stool Frequency, Rectal Bleeding 
and PGA Subscores................................................................................................................28
Table 3-5.
Analysis Visit Windows for Induction Study QoLs ...............................................................28
Table 3-6.
Analysis Visit Windows for Maintenance Study QoLs..........................................................29
Table 3-7.
Analysis Visit Windows for Induction Study Weight, Vital Signs, ECG, 
Hematology, Chemistry, Lipid Profile, Serum Immunoglobulin, hs-CRP, Fecal 
Lactoferrin and Fecal Calprotectin.........................................................................................29
Table 3-8.
Analysis Visit Windows for Maintenance Study Weight, Vital Signs, ECG, 
Hematology, Chemistry, Lipid Profile, Serum Immunoglobulin, hs-CRP, Fecal 
Calprotectin and Fecal Lactoferrin.........................................................................................29
Table 6-1.
Definitions of Dichotomous Efficacy Endpoints....................................................................39
Table 6-2.
Mayo Clinic Score..................................................................................................................42
Table 8-1.
Study Treatments and Associated Analyte.............................................................................71
Table 8-2.
PK Parameters for Each Analyte............................................................................................71


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LIST OF IN-TEXT FIGURES
Figure 1-1.
Study Schema.........................................................................................................................12
Figure 3-1.
Induction Studies (Cohort A Induction Study and Cohort B Induction Study): 
Testing Strategy for the Primary and Key Secondary Hypotheses.........................................21
Figure 3-2.
Maintenance Study: Testing Strategy for the Primary and Key Secondary 
Hypotheses .............................................................................................................................23


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LIST OF ABBREVIATIONS
AE
adverse event
AEIs
adverse events of interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical drug class
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DMC
data monitoring committee
EBS
endoscopy/bleeding/stool
ECG
electrocardiogram
E-Day
endoscopy day
EQ-5D
EuroQoL (health-related quality of life questionnaire)
ET
early termination
FAS
Full Analysis Set
FDA
Food and Drug Administration
Gilead
Gilead Sciences, Inc.
HCRU
health care resource utilization
HLGT
high-level group term
HLT
high-level term
HRQoL
health-related quality of life
hs-CRP
high-sensitivity C-reactive protein
IBD
inflammatory bowel disease
IBDQ
Inflammatory bowel disease questionnaire
ID
identification
IVRS
interactive voice response system
IWRS
interactive web response system
LLOQ
lower limit of quantitation
LLT
lower-level term
LOCF
last observation carried forward
LOQ
limit of quantitation
LTE
long-term extension
MCS
Mayo Clinic Score composed of subscores from endoscopy, rectal bleeding, stool frequency, 
and physician’s global assessment


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M-Day
maintenance study day
MedDRA
Medical Dictionary for Regulatory Activities
MST
MedDRA search term
MMP-9
matrix metalloproteinase-9
OL
open label
Partial MCS
all components of MCS except for endoscopic subscore
PD
pharmacodynamics 
PGA
Physician’s Global Assessment
PK
pharmacokinetic
PP
Per Protocol
PT
preferred term
PTM
placebo-to-match
Q1, Q3
first quartile, third quartile
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SF-36
short-form 36 health survey
SMQ
Standardised MedDRA Queries
SOC
system organ class
SOP
standard operation procesdure
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
TNFα
tumor necrosis factor-alpha
UC
ulcerative colitis
UCEIS
ulcerative colitis endoscopic index of severity
ULN
upper limit of normal
US
United States
V-Day
visit day
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment 


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PHARMACOKINETIC ABBREVIATIONS
AUClast
the area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration of 
drug
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
Tmax
the time (observed time point) of Cmax


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study Protocol GS-US-418-3898. This SAP is based on the study protocol amendment 5
dated 02 April 2019 and the electronic case report form (eCRF). The SAP will be approved 
before database finalization of the final analysis. Any changes made after the finalization of the 
SAP will be documented in the CSR.
1.1.
Study Objectives
The overall objective of the study is to evaluate the effect of treatment with filgotinib on the 
induction and maintenance of remission in subjects with moderately to severely active ulcerative 
colitis (UC). Subject who are biologic-naïve and biologic experienced will be enrolled in 
Cohort A and Cohort B respectively. Treatment assignments will be randomized within each 
cohort. 
1.1.1.
Primary Objectives
The primary objectives are:
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

To evaluate the efficacy of filgotinib as compared to placebo in establishing 
endoscopy/bleeding/stool (EBS) remission at Week 10
Maintenance Study

To evaluate the efficacy of filgotinib as compared to placebo in establishing EBS remission 
at Week 58
1.1.2.
Secondary Objectives
The key secondary objectives are:
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

To evaluate the efficacy of filgotinib as compared to placebo in establishing Mayo Clinic 
Score (MCS) remission at Week 10

To evaluate the efficacy of filgotinib as compared to placebo in establishing an endoscopic 
subscore of 0 at Week 10

To evaluate the efficacy of filgotinib as compared to placebo in establishing Geboes 
histologic remission at Week 10

To evaluate the efficacy of filgotinib as compared to placebo in establishing MCS remission 
(alternative definition) at Week 10


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Maintenance Study

To evaluate the efficacy of filgotinib as compared to placebo in establishing MCS remission 
at Week 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing sustained EBS 
remission at Week 58, defined as EBS remission at both Weeks 10 and 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing 6-month 
corticosteroid-free EBS remission at Week 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing an endoscopic 
subscore of 0 at Week 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing Geboes 
histologic remission at Week 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing MCS remission 
(alternative definition) at Week 58
The other secondary objectives are:
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

To evaluate the safety and tolerability of filgotinib

To assess the pharmacokinetic (PK) characteristics of filgotinib
Maintenance Study

To evaluate the safety and tolerability of filgotinib

To assess the PK characteristics of filgotinib
1.1.3.
Exploratory Objectives
The exploratory objectives are:
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

To evaluate the efficacy of filgotinib as compared to placebo in improving endoscopic 
appearance as determined by Ulcerative Colitis Endoscopic Index of Severity (UCEIS) 
scoring system at Week 10

To evaluate the association of changes in systemic or localized inflammatory biomarkers 
(including but not limited to C-reactive protein [hs-CRP], fecal calprotectin, fecal lactoferrin, 
and fecal matrix metalloproteinase-9 [MMP-9]) with clinical outcomes 


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
To evaluate stool microbiome

To characterize the association of host genetics and other markers with disease severity, 
disease progression, and treatment response to filgotinib

To evaluate health-related quality of life (HRQoL)

To evaluate the effect of filgotinib on health care resource utilization (HCRU)

To evaluate the efficacy of filgotinib as compared to placebo in achieving novel histologic 
outcomes (eg, resolution of basal plasmacytosis)
Maintenance Study

To evaluate the efficacy of filgotinib as compared to placebo in improving endoscopic 
appearance as determined by UCEIS scoring system at Week 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing sustained MCS 
remission at Week 58, defined as MCS remission at both Weeks 10 and 58

To evaluate the efficacy of filgotinib as compared to placebo in establishing 6-month 
corticosteroid-free MCS remission at Week 58

To evaluate the association of changes in systemic or localized inflammatory biomarkers 
(including but not limited to hs-CRP, fecal calprotectin, fecal lactoferrin, and fecal MMP-9) 
with clinical outcomes 

To evaluate stool microbiome

To characterize the association of host genetics and other markers with disease severity, 
disease progression, and treatment response to filgotinib

To evaluate HRQoL

To evaluate the effect of filgotinib on HCRU

To evaluate the efficacy of filgotinib as compared to placebo in achieving novel histologic 
outcomes (eg, resolution of basal plasmacytosis)
1.2.
Study Design
These are 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 (UC). A schema for this study is in 
Figure 1-1. 


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Figure 1-1.
Study Schema
FIL  filgotinib; PBO  placebo; mg  milligram.
Non responders are subjects who achieve neither EBS remission nor MCS response at Week 10
Subjects in the Maintenance Study who meet disease worsening criteria will be offered open label filgotinib.
1.2.1.
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)
Based on protocol eligibility criteria, subjects will be screened for enrollment in either Cohort A
or Cohort B. Subjects who meet protocol eligibility criteria will be assigned to the respective 
cohort and subsequently randomized in a blinded fashion in a 2:2:1 ratio to 1 of 3 treatments as 
follows:
Treatment Groups (Induction Studies)
Treatment Group 1 (n  260): Filgotinib 200 mg and placebo-to-match (PTM) filgotinib
100 mg, once daily
Treatment Group 2 (n  260): Filgotinib 100 mg and PTM filgotinib 200 mg, once daily
Treatment Group 3 (n  130): PTM filgotinib 200 mg and PTM filgotinib 100 mg, once daily
Note: US and Korea males who have not failed to at least 2 biologic regimens (any TNFα 
antagonist and vedolizumab) will be randomized in a 2:1 ratio to receive either filgotinib 100 mg 
or matching placebo.
Within each cohort, treatment assignments will be stratified according to the following factors:
Stratification Factors (Cohort A, Biologic Naïve Induction Study)

Concomitant use of oral, systemically absorbed corticosteroids (eg, prednisone) at Day 1
(Yes or No)

Concomitant use of immunomodulators (eg, 6-mercaptopurine [6-MP], azathioprine, 
methotrexate [MTX]) at Day 1 (Yes or No)
Biologio-experionced 
(Cohort 8) 
I 
I 
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-
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Biologic-
(CohortA) 
0 
Cl 
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Stratification Factors (Cohort B, Biologic Experienced Induction Study)

Exposure to 1 biologic agent versus more than 1 biologic agent

Concomitant use of oral, systemically absorbed corticosteroids (eg, prednisone) at Day 1
(Yes or No)

Concomitant use of immunomodulators (eg, 6-MP, azathioprine, MTX) at Day 1 (Yes or No)
1.2.2.
Maintenance Study
Subjects in Cohorts A and B who complete the Induction Study and achieve either EBS 
remission or MCS response at Week 10 will be re-randomized into the Maintenance Study at 
Week 11. 
Treatment Assignment in Induction Studies,
Cohorts A and B
Maintenance Study 
Re-randomization:
Treatment 1, filgotinib 200 mg
Treatment 1, 200 mg
Treatment 3, placebo
Treatment 2, filgotinib 100 mg
Treatment 2, 100 mg
Treatment 3, placebo
Treatment 3, placebo
Continue Treatment 3, placebo
Note: Subjects receiving Treatment 1 or 2 in the Induction Study will be randomized in a 2:1 manner to either continue on the 
assigned filgotinib regimen or to placebo for the duration of the Maintenance Study.  
Stratification Factors (Maintenance Study)

Participation in Cohort A or Cohort B

Concomitant use of oral, systemically absorbed corticosteroids (eg, prednisone) at Day 1 
(Yes or No)

Concomitant use of immunomodulators (eg, 6-MP, azathioprine, MTX) at Day 1 (Yes or No)
Subjects who achieve neither EBS remission nor MCS response at Week 10 will have the option 
to enter a separate, Long-Term Extension (LTE) study (GS-US-418-3899). The Maintenance 
Study will run from Weeks 11 to 58 with the primary efficacy assessment at Week 58. Subjects 
who opt out of the LTE study will return 30 days after the last dose of study drug for 
post-treatment safety assessments. Subjects who complete all procedures per protocol, including 
the endoscopy, of the 58-week study will be offered the option to continue into the LTE study. 
Subjects who are eligible and opt to participate in the LTE study can continue into the study 
without post-treatment safety assessments.


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1.2.3.
Pharmacokinetics Substudy
An optional PK substudy will be performed in a subset of subjects (approximately 30 subjects 
each in Cohort A and Cohort B) who provide separate informed consent. In the PK substudy, 
the daily dose of study drug should be administered under supervision in the clinic (at 1 visit 
between Week 2 and Week 10, inclusive), and additional PK samples should be collected 
predose and at 0.5, 1, 2, 3, 4, and 6 hours post dose.
1.2.4.
Schedule of Assessments
Efficacy will be assessed primarily through MCS and partial MCS (all components of MCS 
except for endoscopic subscore). MCS will be assessed at Screening, Week 10, and Week 58. 
Partial MCS will be assessed at all scheduled visits. 
For additional details, please see the Schedule of Assessments in Appendix 1.
1.3.
Sample Size and Power
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)
The sample size was chosen to ensure that a clinically meaningful difference in EBS remission
rate at Week 10 could be detected when comparing filgotinib to placebo within each Induction 
Study. A sample size of 130 subjects in the placebo group and 260 subjects in each filgotinib 
dose (200 mg or 100 mg) group (N  650 per cohort) will provide 90% power for each filgotinib 
dose group comparison to placebo at a 2-sided 0.025 significance level to detect a treatment 
difference in EBS remission rate of 15% (25% on filgotinib and 10% on placebo).
Maintenance Study
Assuming an induction response rate (ie, proportion of subjects achieving either EBS remission 
or MCS response at Week 10) of 55% among subjects receiving filgotinib 200 mg or 100 mg
treatment, approximately 285 subjects from each filgotinib dose group from Cohorts A and B 
Induction Studies combined would be eligible to be re-randomized into the Maintenance Study. 
The sample size was chosen to ensure that a clinically meaningful difference in EBS remission 
rate at Week 58 could be detected when comparing each filgotinib dose group (200 mg or
100 mg) to placebo in the Maintenance Study. A sample size of 95 subjects in the placebo group 
and 190 subjects in the filgotinib group at the same dose level as the induction dose will provide 
more than 85% power for each filgotinib dose group comparison to placebo at a 2-sided 
0.025 significance level to detect a treatment difference in maintenance EBS remission rate 
of 20% (40% on filgotinib and 20% on placebo).


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee (DMC) Analyses
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
described in a mutually agreed upon charter, which defines the DMC membership, 
meeting logistics, and meeting frequency.
2.1.1.
Safety Analyses
An external multidisciplinary DMC will review the progress of the study and perform interim 
reviews of safety data in order to protect subject welfare and preserve study integrity. The DMC 
is to recommend to the sponsor whether the nature, frequency, and severity of adverse events 
(AEs) associated with study treatment warrant the early termination of the study in the best 
interests of study participants, whether the study should continue as planned, or whether the 
study should continue with modifications.  
The initial meeting for each Induction Study will occur after approximately 100 subjects 
complete Week 10 or discontinue from the study. 
After the futility analysis described in Section 2.1.2, routine DMC meetings for safety review 
will be held approximately once every 4 months or at a frequency determined by the DMC.
2.1.2.
Futility Analysis
The second DMC meeting for each Induction Study will include an interim futility analysis and 
occur after approximately 175 subjects complete Week 10 or discontinue from the study. The 
futility analysis will be conducted to evaluate endoscopic efficacy. Overall safety will be 
evaluated at this timepoint as well. Please refer to Section 6.5.1 for details on the futility rule. 
2.1.3.
Cohorts A and B End-of-Induction Analysis
Efficacy and safety analyses will be performed after all subjects in both cohorts complete 
Week 10 or discontinue from the study. Please refer to Section 6.5.2 for details. 
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the study blind will be 
broken and the final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, 
the number and percentage of subjects in each category will be presented; for continuous 
variables, the number of subjects (n), mean, standard deviation (SD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Randomized Analysis Set. Data collected on 
log forms, such as AEs, will be presented in chronological order within subject. The treatment group to 
which subjects were randomized or initially assigned will be used in the listings.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, 
will be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Sets
The All Randomized Analysis Set for each Induction Study (Cohort A Induction Study and 
Cohort B Induction Study) includes all subjects who were randomized on Day 1 into each 
corresponding study. 
The All Randomized Analysis Set for the Maintenance Study includes all subjects who were 
re-randomized into the Maintenance Study (including subjects randomized to the placebo 
treatment group in the Induction Studies who continued on placebo treatment in the Maintenance 
Study).  
The All Randomized Analysis Sets are the primary analysis sets for by-subject listings. 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) for each Induction Study (Cohort A Induction Study and Cohort B 
Induction Study) includes all randomized subjects who took at least 1 dose of study drug in the 
corresponding Induction Study.
The FAS for the Maintenance Study includes all subjects randomized to either the filgotinib 
200 mg or filgotinib 100 mg treatment groups in the Induction Studies who were re-randomized 
in the Maintenance Study and:

Took at least 1 dose of study drug in the Maintenance Study, and

Achieved EBS remission or MCS response at Week 10 as specified in the SAP
The Full Analysis Sets are the primary analysis sets for efficacy analyses.


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3.1.3.
Per-Protocol Analysis Sets
The Per-Protocol (PP) Analysis Set for each Induction Study (Cohort A Induction Study and 
Cohort B Induction Study) includes subjects in the respective FAS who meet the following 
criteria:

Met the following key eligibility criteria:
Documented diagnosis of UC of at least 6 months AND with a minimum disease extent 
of 15 cm from the anal verge. Documentation should include endoscopic and 
histopathologic evidence of UC as follows:
■
The criteria for documentation of UC based on endoscopy will be medical record 
documentation, or an ileocolonoscopy (full colonoscopy with the intubation of the 
terminal ileum) report dated ≥ 6 months before enrollment, which shows features 
consistent with UC, determined by the procedure performing physician
■
The criteria for documentation of UC based on histopathology will be medical record 
documentation of or a histopathology report indicating features consistent with UC as 
determined by the pathologist
Moderately to severely active UC as determined by a centrally read endoscopy score ≥2, 
a rectal bleeding score ≥ 1, a stool frequency score ≥ 1, and PGA of ≥ 2 as determined by 
the Mayo clinic scoring system with endoscopy occurring during screening; total score 
must be between 6 and 12, inclusive.

Dosed at least 80% of both study drugs (filgotinib and PTM) while on-treatment
(see Section 4.2.2) for the Induction Study

Either had sufficient data to evaluate EBS remission at Week 10, or met treatment failure
criteria for Week 10 EBS remission outcome

Never exposed to any biologics listed in Appendix 2 for Cohort A Induction Study, or 
exposed to at least 1 of the biologics listed in Appendix 2 for Cohort B Induction Study
The PP Analysis Set for the Maintenance Study includes subjects in the FAS who meet the 
following criteria: 

Met the key eligibility criteria from Induction Study as stated above

Dosed at least 80% of each study drug type while on-treatment (see Section 4.2.2) for 
Maintenance Study

Met one of following 3 categories:
Had sufficient data to evaluate EBS remission outcome at Week 58, or 
Met treatment failure criteria for Week 58 EBS remission outcome, or 
Discontinued study drug due to protocol-specified disease worsening criterion
The PP Analysis Set is the secondary analysis set for efficacy analyses.


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3.1.4.
Safety Analysis Set
The Safety Analysis Set for each Induction Study (Cohort A Induction Study and Cohort B 
Induction Study) includes all subjects who took at least 1 dose of study drug in the corresponding 
Induction Study.
The Safety Analysis Set for the Maintenance Study includes all subjects who took at least one 
dose of study drug in the Maintenance Study. 
The Overall Safety Analysis Set for the study includes all subjects who took at least one dose of 
study drug from either Induction or Maintenance.
The Safety Analysis Sets are the primary analysis sets for safety analyses.
3.1.5.
Pharmacokinetic Analysis Sets
The primary analysis set for general PK analyses will be defined separately for each individual
study (Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study). For each
study, the PK analysis set includes all randomized subjects who took at least 1 dose of filgotinib 
and have at least 1 nonmissing concentration value for filgotinib and/or its metabolite
GS-829845 by the PK laboratory.
3.1.6.
Pharmacokinetic Substudy Analysis Set
The primary analysis set for intensive PK analyses will be the PK substudy analysis set for each 
Induction Study (Cohort A Induction Study and Cohort B Induction Study), which includes all 
randomized subjects from the corresponding Induction Study who took at least 1 dose of 
filgotinib, participated in the PK Substudy, and have at least 1 nonmissing intensive 
concentration value for filgotinib and/or its metabolite GS-829845 reported by the PK 
laboratory. This is the primary analysis set for detailed PK analysis of intensive PK sampling.
3.1.7.
Biomarker Analysis Set
The Biomarker Analysis Set will be defined separately for each individual study (Cohort A
Induction Study, Cohort B Induction Study, and Maintenance Study). For each study, 
the Biomarker Analysis Set includes all subjects in the respective FAS who have nonmissing 
baseline and at least 1 postbaseline measurement from at least 1 of the 3 biomarkers 
(hs-CRP, fecal calprotectin, and fecal lactoferrin).
3.2.
Subject Grouping
For analyses based on the All Randomized Analysis Sets and FAS, subjects will be grouped 
according to the treatment to which they were randomized. For analyses based on the Safety 
Analysis Sets, PP Analysis Sets, and Biomarker Analysis Set, subjects will be grouped according 
to actual treatment received. The actual treatment received will differ from the randomized 
treatment only when their actual treatment differs from randomized treatment for the entire 
treatment duration. 


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For the PK Analysis Sets, subjects will be grouped according to the actual treatment they 
received.
For the summary of AEs and laboratory abnormalities using the Overall Safety Analysis Set, 
subjects will be grouped according to the actual treatment received across Induction and 
Maintenance studies, if applicable. 
In general, all data will be summarized by treatment group for: 

Cohort A Induction Study

Cohort B Induction Study

Cohort A and B Induction Studies combined (not applicable to efficacy analysis)

Maintenance Study 
3.3.
Strata and Covariates
Subjects will be randomly assigned to treatment groups via the interactive web response system 
(IWRS) using a stratified randomization schedule into each individual study (Cohort A Induction 
Study, Cohort B Induction Study, and Maintenance Study). Details of the randomization ratio 
and stratification variables for each study are provided in Section 1.2. 
If there are discrepancies in stratification factor values between the IWRS and the clinical 
database, the baseline values recorded in the clinical database will be used for analyses. For 
deriving concomitant medication use at Day 1, the start date of such medication should be before 
or on the same date of the first dose of study drug and with either the stop date of such 
medication being on or after the first dose of study drug or with ‘ongoing’ status.
Stratification factors will be used as covariates in evaluating efficacy endpoints, as specified in 
Section 6.
3.4.
Examination of Subject Subgroups
Subgroup analyses for primary efficacy endpoint and adverse events are specified in 
Section 6.2.5 and Section 7.1.8, respectively.
3.5.
Multiple Comparisons
The graphical approach {Bretz 2009} to sequentially rejective multiple test procedures will be 
used to control a family-wise type I error rate (FWER) at 5% (ie, α  0.05) for each individual 
study (Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study). This 
procedure strongly protects the FWER on all the primary and key secondary endpoints. 


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Induction Studies (Cohort A Induction Study and Cohort B Induction Study)
For each individual study (Cohort A Induction Study, Cohort B Induction Study, and 
Maintenance Study), a Bonferroni approach with equal alpha allocation of 0.025 (2-sided) to 
each filgotinib dose group comparison with placebo will be used to control the overall 
study-wide type I error rate at 0.05 within each study. To protect the integrity of the study due to 
the unblinded interim futility analysis planned for each induction study (Cohort A Induction 
Study and Cohort B Induction Study), an alpha of 0.00001 will be spent for each filgotinib dose 
group comparison to placebo within each induction study. As a result, a nominal p-value of less 
than 0.02499 (2-sided) will be needed to declare statistical significance for the final primary 
analysis of each filgotinib dose group when compared to placebo to control the study-wise type I 
error rate at 0.05. If one filgotinib dose group is discontinued for futility at the interim futility 
analysis, the overall alpha error rate stays unchanged at a 2-sided 0.02499 level for the 
continuing filgotinib dose group at the primary analysis. 
The hypotheses to be tested for the induction studies are outlined below. 
The primary null hypotheses to be tested:

H1: The EBS remission rate in the filgotinib 200 mg group is equal to the EBS remission rate 
in the placebo group at Week 10

H2: The EBS remission rate in the filgotinib 100 mg group is equal to the EBS remission rate 
in the placebo group at Week 10
The key secondary null hypotheses to be tested:

H3: The MCS remission rate in the filgotinib 200 mg group is equal to the MCS remission 
rate in the placebo group at Week 10

H4: The MCS remission rate in the filgotinib 100 mg group is equal to the MCS remission 
rate in the placebo group at Week 10

H5: The endoscopic subscore of 0 rate in the filgotinib 200 mg group is equal to the 
endoscopic subscore of 0 rate in the placebo group at Week 10

H6: The endoscopic subscore of 0 rate in the filgotinib 100 mg group is equal to the 
endoscopic subscore of 0 rate in the placebo group at Week 10

H7: The Geboes histologic remission rate in the filgotinib 200 mg group is equal to the 
Geboes histologic remission rate in the placebo group at Week 10

H8: The Geboes histologic remission rate in the filgotinib 100 mg group is equal to the 
Geboes histologic remission rate in the placebo group at Week 10

H9: The MCS remission (alternative definition) rate in the filgotinib 200 mg group is equal 
to the MCS remission (alternative definition) rate in the placebo group at Week 10

H10: The MCS remission (alternative definition) rate in the filgotinib 100 mg group is equal 
to the MCS remission (alternative definition) rate in the placebo group at Week 10


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If the primary null hypothesis is rejected, then the next key secondary hypothesis in the same 
filgotinib dosing regimen will be tested at the same alpha level. Testing of the hypotheses will be 
performed in the order outlined in Figure 3-1 (Induction Studies) in the same filgotinib dosing 
regimen. Once all hypotheses within the same filgotinib dosing regimen are rejected, then the 
respective 0.02499 alpha can be passed on to the other regimen’s hypotheses, that is, all 
hypotheses in the other filgotinib dosing regimen will be tested at 0.04998 (2-sided) for 
Induction Studies. If an endpoint within a filgotinib dosing regimen fails to reach statistical 
significance, then formal sequential testing will stop and only nominal significance will be 
reported for the remaining endpoints within that filgotinib dosing regimen. If not all primary and 
key secondary hypotheses within the same filgotinib dosing regimen can be rejected, all 
hypotheses in the other filgotinib dosing regimen will still be tested at 0.02499 (2-sided) for 
Induction Studies. 
A graphical illustration of the testing strategy for the primary and key secondary hypotheses in 
the Induction Studies is shown in Figure 3-1.
Figure 3-1.
Induction Studies (Cohort A Induction Study and Cohort B Induction 
Study): Testing Strategy for the Primary and Key Secondary 
Hypotheses


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Maintenance Study
Since there is no interim analysis planned for the maintenance study, the significance level for 
the final primary analysis will be at 0.025 (2-sided) level for each filgotinib dose group when 
compared to placebo for the maintenance study.
The hypotheses to be tested for the maintenance study are outlined below.
The primary null hypotheses to be tested:

H1: The EBS remission rate in the filgotinib 200 mg group is equal to the EBS remission rate 
in the placebo group at Week 58

H2: The EBS remission rate in the filgotinib 100 mg group is equal to the EBS remission rate 
in the placebo group at Week 58
The key secondary null hypotheses to be tested:

H3: The 6-month corticosteroid-free EBS remission rate in the filgotinib 200 mg group is 
equal to the 6-month corticosteroid-free EBS remission rate in the placebo group at Week 58

H4: The 6-month corticosteroid-free EBS remission rate in the filgotinib 100 mg group is 
equal to the 6-month corticosteroid-free EBS remission rate in the placebo group at Week 58

H5: The sustained EBS remission rate in the filgotinib 200 mg group is equal to the sustained 
EBS remission rate in the placebo group at Week 58

H6: The sustained EBS remission rate in the filgotinib 100 mg group is equal to the sustained 
EBS remission rate in the placebo group at Week 58

H7: The MCS remission rate in the filgotinib 200 mg group is equal to the MCS remission 
rate in the placebo group at Week 58

H8: The MCS remission rate in the filgotinib 100 mg group is equal to the MCS remission 
rate in the placebo group at Week 58

H9: The endoscopic subscore of 0 rate in the filgotinib 200 mg group is equal to the 
endoscopic subscore of 0 rate in the placebo group at Week 58

H10: The endoscopic subscore of 0 rate in the filgotinib 100 mg group is equal to the 
endoscopic subscore of 0 rate in the placebo group at Week 58

H11: The Geboes histologic remission rate in the filgotinib 200 mg group is equal to the 
Geboes histologic remission rate in the placebo group at Week 58

H12: The Geboes histologic remission rate in the filgotinib 100 mg group is equal to the 
Geboes histologic remission rate in the placebo group at Week 58


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
H13: The MCS remission (alternative definition) rate in the filgotinib 200 mg group is equal 
to the MCS remission (alternative definition) rate in the placebo group at Week 58

H14: The MCS remission (alternative definition) rate in the filgotinib 100 mg group is equal 
to the MCS remission (alternative definition) rate in the placebo group at Week 58
The same approach described for Induction Studies will be applied to the Maintenance Study at 
the alpha level of 0.025 (2-sided) for each filgotinib dose group when compared to placebo.
Graphical illustrations for the testing strategies for the primary and key secondary hypotheses in 
the Maintenance Study are shown in Figure 3-2.
Figure 3-2.
Maintenance Study: Testing Strategy for the Primary and Key 
Secondary Hypotheses


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3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dose date of study drug, imputation rules are described in Section 4.2.1. 
Imputation and calculation rules for missing patient diary data are described in Appendix 4. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2 and for prior 
and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process. All data, 
including outliers, will be included in the data analyses, unless otherwise specified.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the first dosing date of study drug. For screen failures, 
the date the informed consent was signed will be used for age calculation. If only birth year is 
collected on the CRF, “01 July” will be used for the unknown birth day and month for the 
purpose of age calculation. If only birth year and month are collected, “15” will be used for the 
unknown birth day.
Duration of UC (years) is the number of years between the diagnosis date of UC and date of 
first dose of Induction study drug. The partial diagnosis date of UC (if any) will be imputed for 
calculation as follows:

If day and month are missing but year is available, then the imputed day and month will be 
01 Jan.

If day is missing but the month and year are available, then the imputed day will be the 
first day of the month. Partial date will not be imputed if the year is missing.
Non-PK Data that are continuous in nature but are less than the lower limit of quantitation
(LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “x” (where x is considered the LOQ). For example, 
if the values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used 
for calculation of summary statistics. An exception to this rule is any value reported as < 1 or 
< 0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will 
be used for calculation of summary statistics.


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
A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the datum is reported in the 
form of “≤ x” or “≥ x” (where x is considered the LOQ).
Natural logarithm transformation will be used for plasma concentrations and analysis of PK 
parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will be 
presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 0 at 
predose time points, and one-half the value of the LOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
Pharmacokinetic parameters that are BLQ will be imputed as one-half LOQ before log 
transformation or statistical model fitting.
3.8.
Analysis Visit Windows
3.8.1.
Definitions
3.8.1.1.
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)
The First Dosing Date of each Induction Study is defined as the date when subjects take the 
first dose of Induction study drug, as recorded in the Study Drug Administration eCRF. 
The Last Dosing Date of each Induction Study is defined as the date when subjects take the last 
dose of Induction study drug as recorded in the Study Drug Administration eCRF.


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Study Day will be calculated from the first dosing date of study drug and derived as follows:

For days on or after first dosing date: Assessment Date First Dosing Date + 1

For days prior to the first dosing date: Assessment Date First Dosing Date
Therefore, Study Day 1 is the day of the first dose of study drug administration.
Baseline is defined as the last available observation on or prior to the first dosing date, unless 
otherwise specified.
3.8.1.2.
Maintenance Study
The First Dosing Date of Maintenance Study is defined as the date when subjects take the 
first dose of Maintenance Study drug, as recorded in the Study Drug Administration eCRF.
The Last Dosing Date of Maintenance Study is defined as the date when subjects take the 
last dose of Maintenance study drug as recorded in the Study Drug Administration eCRF.
Maintenance Study Day (M-Day) will be calculated from the First Dosing Date of Maintenance 
Study and derived as:

For days on or after First Dosing Date of Maintenance Study: Assessment Date First 
Dosing Date + 1

For days prior to First Dosing Date of Maintenance Study: Assessment Date First Dosing 
Date 
Therefore, M-Day 1 is the first dosing date of the Maintenance Study.
Re-randomization baseline (henceforth referred to as re-baseline) is defined as the last available 
observation on or prior to the first dose date of the Maintenance Study. Re-baseline will be 
considered the baseline of Maintenance Study, unless otherwise specified.
3.8.1.3.
Overall (Induction and Maintenance)
The First Dosing Date is defined as the date when subjects take the first dose of study drug. 
The Last Dosing Date is defined as the date when subjects take the last dose of study drug 
considering both induction and maintenance study drugs.
Study Day will be calculated from the first dose date of study drug and derived as follows:

For postdose study days: Assessment Date First Dosing Date + 1

For days prior to the first dosing date: Assessment Date First Dosing Date 
Therefore, Study Day 1 is the day of first dose of study drug administration.
Baseline is defined as the last available observation on or prior to the first dosing date. 


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3.8.2.
Analysis Visit Windows
Subject visits may not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
For the Induction Studies (Cohort A Induction Study and Cohort B Induction Study), the analysis 
windows for endoscopic subscore and Geboes histologic score are provided in Table 3-1. The 
analysis windows for stool frequency, rectal bleeding, and PGA subscores are provided in
Table 3-3. The analysis windows for HRQoLs are provided in Table 3-5. The analysis windows 
for weight, vital signs, electrocardiogram (ECG), safety laboratory parameters (hematology,
chemistry, lipid profile, and serum immunoglobulin), and key inflammatory biomarkers 
(including hs-CRP, fecal calprotectin, and fecal lactoferrin) are based on study day and provided 
in Table 3-7.
For the Maintenance Study, the analysis windows for endoscopic subscore and Geboes histologic 
score are based on M-Day and provided in Table 3-2. The analysis windows for stool frequency, 
rectal bleeding, and PGA subscores are provided in Table 3-4. The analysis windows for 
HRQoLs are provided in Table 3-6. The analysis windows for weight, vital signs, ECG, safety 
laboratory parameters (hematology, chemistry, lipid profile, serum immunoglobulin), and key 
inflammatory biomarkers (including hs-CRP, fecal calprotectin, and fecal lactoferrin) are 
(defined in Section 3.8.1) provided in Table 3-8.
Table 3-1.
Analysis Visit Windows for Induction Study Endoscopic Subscore, 
and Geboes Histologic Score
Nominal Visit
Analysis Visit
Nominal Day
(Study Day)
Lower Limit 
(Study Day)
Upper Limit
(Study Day)
Screening
Baseline
1
(none)
1
Week 10
Week 10
71
58
minimum of 85 and 
Study Day of 
[Maintenance
first dose date 
(if applicable)]
Note: Anchor day defined in Appendix 4 will be used for analysis visit window calculation of MCS and all efficacy endpoints 
based on MCS; endoscopic day will be used for analysis visit window calculation of endoscopic subscore.
Table 3-2.
Analysis Visit Windows for Maintenance Study Endoscopic Subscore, 
and Geboes Histologic Score
Nominal Visit
Analysis Visit
Nominal Day
(M-Day)
Lower Limit 
(M-Day)
Upper Limit
(M-Day)
Week 10
Re-baseline
1
(none)
1
Week 58
Maintenance 
Week 47
330
303
358
Note: Anchor day defined in Appendix 4 will be used for analysis visit window calculation of MCS and all efficacy endpoints 
based on MCS; endoscopic day will be used for analysis visit window calculation of endoscopic subscore of 0 endpoint.


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Table 3-3.
Analysis Visit Windows for Induction Study Stool Frequency, 
Rectal Bleeding, and PGA subscores 
Nominal Visit
Analysis Visit
Nominal Day
(Study Day)
Lower Limit 
(Study Day)
Upper Limit
(Study Day)
Screening/Day 1
Baseline
1
(none)
1
Week 2
Week 2
15
2
22
Week 4
Week 4
29
23
36
Week 6
Week 6
43
37
57
Week 10
Week 10
71
58
minimum of 85 and 
Study Day of 
[Maintenance first 
dose date 
(if applicable)]
Note: The anchor date for stool frequency and rectal bleeding defined in Appendix 4 will be used to evaluate the analysis visit 
window. The nominal visit date will be used to evaluate the analysis visit window for PGA. 
Table 3-4.
Analysis Visit Windows for Maintenance Study Stool Frequency, 
Rectal Bleeding and PGA Subscores
Nominal Visit
Analysis Visit
Nominal Day
(M-Day)
Lower Limit 
(M-Day)
Upper Limit
(M-Day)
Week 10/Week 11
Re-Baseline
1
None
1
Week 14
Maintenance Week 3
22
2
43
Week 20
Maintenance Week 9
64
44
85
Week 26
Maintenance Week 15
106
86
134
Week 34
Maintenance Week 23
162
135
190
Week 42
Maintenance Week 31
218
191
246
Week 50
Maintenance Week 39
274
247
302
Week 58
Maintenance Week 47
330
303
358
Note: The anchor date for stool frequency and rectal bleeding defined in Appendix 4 will be used to evaluate the analysis visit 
window. The nominal visit date will be used to evaluate the analysis visit window for PGA.
Table 3-5.
Analysis Visit Windows for Induction Study QoLs
Nominal Visit
Analysis Visit
Nominal Day
(Study Day)
Lower Limit 
(Study Day)
Upper Limit
(Study Day)
Screening/Day 1
Baseline
1
(none)
1
Week 10
Week 10
71
58
minimum of 85 and 
Study Day of 
[Maintenance first 
dose date (if 
applicable)]


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Table 3-6.
Analysis Visit Windows for Maintenance Study QoLs
Nominal Visit
Analysis Visit
Nominal Day
(M-Day)
Lower Limit 
(M-Day)
Upper Limit
(M-Day)
Week 10
Re baseline
1
(none)
1
Week 26
Maintenance 
Week 15
106
2
218
Week 58
Maintenance 
Week 47
330
219
358
Table 3-7.
Analysis Visit Windows for Induction Study Weight, Vital Signs, 
ECG, Hematology, Chemistry, Lipid Profile, Serum Immunoglobulin, 
hs-CRP, Fecal Lactoferrin and Fecal Calprotectin
Nominal Visit
Analysis Visit
Nominal Day
(Study Day)
Lower Limit 
(Study Day)
Upper Limit
(Study Day)
Screening/Day 1
Baseline
1
(none)
1
Week 2
Week 2
15
2
22
Week 4
Week 4
29
23
36
Week 6
Week 6
43
37
57
Week 10
Week 10
71
58
For subjects who 
entered Maintenance 
Study: minimum 
of 85 and Study Day 
of [Maintenance 
first dose date]; for 
other subjects: ≥71
Note: ECG, lipid profile, fecal lactoferrin, and fecal calprotectin are collected postbaseline at Weeks 10, 26, and 58 only and the 
corresponding analysis windows will be applied; serum immunoglobulin is collected postbaseline at Weeks 4, 10, 26, and 58
only and the corresponding analysis windows will be applied.
Table 3-8.
Analysis Visit Windows for Maintenance Study Weight, Vital Signs, 
ECG, Hematology, Chemistry, Lipid Profile, Serum Immunoglobulin, 
hs-CRP, Fecal Calprotectin and Fecal Lactoferrin  
Nominal Visit
Analysis Visit
Nominal Day
(M-Day)
Lower Limit 
(M-Day)
Upper Limit
(M-Day)
Week 10/11
Re-Baseline
1
none
1
Week 14
Maintenance  Week 3
22
2
43
Week 20
Maintenance  Week 9
64
44
85
Week 26
Maintenance  Week 15
106
86
134
Week 34
Maintenance  Week 23
162
135
190
Week 42
Maintenance  Week 31
218
191
246
Week 50
Maintenance  Week 39
274
247
302
Week 58
Maintenance  Week 47
330
303
≥330
Note: ECG, lipid profile, fecal lactoferrin and fecal calprotectin are collected postbaseline at Weeks 10, 26, and 58 only and the 
corresponding analysis windows will be applied; serum immunoglobulin is collected postbaseline at Weeks 4, 10, 26, and 58
only and the corresponding analysis windows will be applied.


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3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple, valid, nonmissing, continuous measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed:

In general, the baseline/re-baseline value will be the last nonmissing value on or prior to the 
first dose date of study drug for each individual Induction study, and Maintenance Study, 
respectively, unless otherwise specified. If multiple measurements occur on the same day, the 
last nonmissing value prior to the first dose of study drug will be considered as the baseline 
value. If these multiple measurements occur at the same time or the time is not available, the 
average of these measurements (for continuous data) will be considered the 
baseline/re-baseline value.

For postbaseline visits:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken,
unless otherwise specified.
If multiple, valid, nonmissing, categorical measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed:

For baseline/re-baseline, the last available record on or prior to the date of the first dose of 
study drug for each individual study (Cohort A Induction Study, Cohort B Induction Study 
and Maintenance Study) will be selected. If there are multiple records with the same time or 
no time recorded on the same day, the value with the lowest severity will be selected 
(eg, normal will be selected over abnormal for safety ECG findings).

For postbaseline visits:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the worst severity will be taken
(eg, abnormal will be selected over normal for safety ECG findings), unless otherwise 
specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
For each individual study (Cohort A Induction Study, Cohort B Induction Study, and 
Maintenance Study) and Cohorts A and B Induction Studies combined, a summary of subject 
enrollment will be provided by treatment group for each country, investigator within a country,
and overall. The summary will present the number and percentage of subjects enrolled. For each 
column, the denominator for the percentage calculation will be the total number of subjects 
analyzed for that column.
For each individual study (Cohort A Induction Study, Cohort B Induction Study, and 
Maintenance Study), a similar enrollment table will be provided by randomization stratum. The 
denominator for the percentage of subjects in the stratum will be the total number of enrolled 
subjects. If there are discrepancies in the value used for stratification assignment between the 
IWRS and the clinical database, the value collected in the clinical database will be used for the 
summary. Subjects with discrepancies in the value used for stratification assignment between the 
IWRS and the clinical database at the time of data finalization will be summarized by treatment 
group. A corresponding listing will also be provided. 
The randomization schedule used for each individual study (Cohort A Induction Study, Cohort B 
Induction Study, and Maintenance Study) will be provided as an appendix to the CSR.
Cohort A Induction and Cohort B Induction Studies
A summary of subject disposition will be provided by treatment group for each individual study 
(Cohort A Induction Study, Cohort B Induction Study) and Cohorts A and B Induction Studies 
combined. This summary will present the number of subjects screened, the number of subjects 
who met all eligibility criteria but were not randomized with reasons subjects were not 
randomized, the number of subjects randomized, and the number of subjects in each of the 
categories listed below:

Full Analysis Set

Safety Analysis Set

Per-Protocol Analysis Set

PK Analysis Set

PK Substudy Analysis Set

Biomarker Analysis Set

Completed study drug dosing through Week 10 (indicated in Induction Study Drug 
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
Continuing study drug (for analysis other than the final analysis)

Did not complete study drug up to Week 10 with reasons for premature discontinuation of 
study drug

Completed Induction Study through Week 11

Continuing Induction Study (for analysis other than the final analysis)

Did not complete Induction Study with reasons for premature discontinuation from the study
Maintenance Study
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects who completed the Induction Studies, the number of subjects 
re-randomized, and the number of subjects in each of the categories listed below:

Full Analysis Set

Safety Analysis Set

Per-Protocol Analysis Set

PK Analysis Set

Biomarker Analysis Set

Completed study drug dosing through Week 58

Continuing study drug prior to Week 58 (for analysis other than the final analysis)

Did not complete study drug with reasons for premature discontinuation of study drug

Completed Maintenance Study (defined as completion of protocol-planned duration of the 
study through Week 58)

Continuing Maintenance Study (for analysis other than the final analysis)

Did not complete Maintenance Study with reasons for premature discontinuation from the
study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
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The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation

Reasons for screen failure (will be provided by screening ID number in ascending order)

Lot number and kit ID of assigned study medication
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
Summaries of extent of study drug exposure and adherence will be provided by:

Cohort A Induction Study 

Cohort B Induction Study 

Cohort A and B Induction Studies Combined

Maintenance Study 
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the last study drug dosing date 
is missing, the latest date among the study drug end date, clinical visit date, and laboratory 
sample collection date that occurred during the on-treatment period will be used.
The total duration of exposure to study drug will be summarized for the following using 
descriptive statistics and using the number (ie, cumulative counts) and percentage of subjects 
exposed through the following time periods:

Cohort A Induction Study: 1 day, 2 weeks, 4 weeks, 6 weeks, 10 weeks, and 11 weeks

Cohort B Induction Study: 1 day, 2 weeks, 4 weeks, 6 weeks, 10 weeks, and 11 weeks

Cohort A and B Induction Studies Combined: 1 day, 2 weeks, 4 weeks, 6 weeks, 10 weeks,
and 11 weeks

Maintenance Study: 1 day, 3 weeks, 9 weeks, 15 weeks, 23 weeks, 31 weeks, 39 weeks, and 
47 weeks
Summaries will be provided by treatment group for the Safety Analysis Set.
No formal statistical testing is planned.


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4.2.2.
Adherence to Study Drug
The total number of tablets administered will be summarized using descriptive statistics. 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
4.2.2.1.
On-Treatment Adherence
The level of on-treatment adherence to the study drug regimen will be determined by the total 
amount of study drug administered relative to the total amount of study drug expected to be 
administered during a subject’s actual on-treatment period based on the study drug regimen.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (ie, < 80%, ≥ 80 to < 90%, ≥ 90%) will be provided 
by treatment group for the Safety Analysis Set. 
No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations 
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized. The summary will present the number and percentage of subjects who did not meet 
at least 1 eligibility criterion and the number of subjects who did not meet specific criteria by 
treatment group based on the All Randomized Analysis Set. A by-subject listing will be provided 
for those subjects who did not meet at least 1 eligibility (inclusion or exclusion) criterion. The 
listing will present the eligibility criterion (or criteria if more than 1 deviation) that subjects did 
not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by treatment group for the All Randomized Analysis Set for each individual 
study. A by-subject listing will be provided for those subjects with any important protocol 
deviation.
Total Number of tablets Administered= CI No. of Tablets Dispensed) - CI No. of Tablets returned) 
On-Treatment Adherence (%) 
( 
Total Amount of Study Drng Administered 
) 
l OO 
Study Drng Expected to be Administered on Treatment 
X 


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Other Baseline Characteristics
For the Induction Studies (Cohort A Induction Study and Cohort B Induction Study) and 
Cohorts A and B Induction Studies combined, subject demographic variables will be 
summarized by treatment group and overall using descriptive statistics for continuous variables,
and using number and percentage of subjects for categorical variables. The summary of 
demographic data will be provided for the Safety Analysis Set.

Age (years, on the date of first dose of study drug)

Age group (< 65 years, ≥ 65 years)

Sex at birth (female, male)

Race 

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Geographic region (United States [US], non-US)

Weight

Height

Body mass index (BMI; in kg/m2)

Smoking status (former, current, never)
For the Maintenance Study, the same demographic variables will be summarized by the 
induction dose and respective maintenance dose, and overall. Baseline age from the Induction 
Study will also be used for age in the Maintenance Study. 
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Baseline Disease Characteristics
For the Induction Studies (Cohort A Induction Study and Cohort B Induction Study), Cohorts A 
and B Induction Studies combined, and Maintenance Study, the following baseline disease 
characteristics will be summarized using Safety Analysis Sets by the same grouping as the 
demographic tables, using descriptive statistics for continuous variables, and using number and 
percentage of subjects for categorical variable:

Duration of UC (in years) from date of diagnosis to first dosing date

Duration of UC (< 1 year, ≥ 1 and < 3 years, ≥ 3 and < 7 years, ≥7 years)


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
Have a history of pancolitis (yes, no, unknown)

MCS score (Induction studies only)

MCS score (≤ 8, ≥ 9) (Induction studies only)

Partial MCS score (Induction studies only)

Endoscopic subscore of 3 (yes, no) (Induction studies only)

Participation in Cohort A or Cohort B (Maintenance Study Only)

Fecal calprotectin (μg/g) (re-baseline value for Maintenance Study)

Fecal calprotectin (≤250 μg/g, > 250 μg/g) (Induction studies only)

hs-CRP (mg/L) (re-baseline value for Maintenance Study)

hs-CRP (≤3 mg/L, > 3 mg/L) (Induction studies only)

UC treatment history
Prior use of systemic corticosteroids (yes, no)
Prior use of immunomodulators (yes, no)
Number of prior exposure to biologic agent listed in Appendix 2 (0, 1, 2, ≥ 3) 
Prior use of TNFα antagonist listed in Appendix 2 (yes, no; for Cohort B Induction Study
and Cohorts A and B Induction Studies combined) and for subjects with prior use:
■
Number of TNFα antagonist used
○
1
○
2
○
≥ 3
■
Worst outcome of prior use of TNFα antagonist
○
Treatment failure
○
Intolerance, including both allergic and non-allergic intolerance
○
Other


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Prior use of vedolizumab (yes, no; for Cohort B Induction Study and Cohorts A and B 
Induction Studies combined) and for subjects with prior use:
■
Worst outcome of prior use of vedolizumab
○
Treatment failure
○
Intolerance, including both allergic and non-allergic intolerance
○
Other
Prior use of both TNFα antagonist and vedolizumab (yes, no; for Cohort B Induction 
Study and Cohorts A and B Induction Studies combined)
Note: The worst outcome of a prior treatment is treatment failure, followed by 
intolerance, and then other outcomes.
Prior failure of both TNF-alpha antagonist and vedolizumab (for Cohort B Induction 
Study and Cohorts A and B Induction Studies combined)
■
Yes (dual refractory, defined as those who have failed at least 2 classes of biologic 
therapies [any TNFα antagonist and vedolizumab])
○
US/Korea Males
○
Subjects other than US/Korea Males
■
No 
○
US/Korea Males
○
Subjects other than US/Korea Males

Corticosteroid and Immunomodulator Treatment at baseline (at re-baseline for Maintenance 
Study)
Concomitant use of systemically absorbed corticosteroids and/or immunomodulator at 
baseline/re-baseline, including: a) systemically absorbed corticosteroids only, 
b) immunomodulators only, c) both, and d) neither;
Prednisone equivalent dose for subjects who are on systemically absorbed corticosteroids 
at baseline/re-baseline (mg/day)
Prednisone equivalent dose for subjects who are on systemically absorbed corticosteroids 
at baseline/re-baseline (> 0 to 10 mg/day, > 10 to 20 mg/day, > 20 mg/day)
5-aminosalicylates (yes, no)


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In addition, another baseline disease characteristics table for Maintenance Study using the FAS 
will be generated, including the above baseline characteristics except those marked as 
“Induction studies only” and the following additional variables: 

MCS score at re-baseline 

MCS score at re-baseline (≤ 8, ≥ 9)

Partial MCS score at re-baseline 

Endoscopic subscore of 3 at week 10 (yes, no)

Fecal calprotectin at re-baseline (≤250 μg/g, > 250 μg/g) 

hs-CRP at re-baseline (≤3 mg/L, > 3 mg/L) 

EBS remission at Week 10 (yes, no)  

MCS remission at Week 10 (yes, no)

Endoscopic subscore of 0 at Week 10 (yes, no)  

Geboes histologic remission at Week 10 (yes, no) 
5.3.
Medical History
General medical history and IBD family history data will be collected at screening and listed 
only. General medical history data will be coded using the current version of Medical Dictionary
for Regulatory Activities (MedDRA).


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6.
EFFICACY ANALYSES
6.1.
General Considerations
The efficacy analysis will be conducted on the FAS, defined in Section 3.1.2, unless otherwise 
specified.
The definitions of the dichotomous efficacy endpoints for each individual study (Cohort A 
Induction Study, Cohort B Induction Study, and Maintenance Study) are listed in Table 6-1.
While the endoscopic appearance will be read by both study site investigator and central reader, 
only the centrally-read endoscopic subscore will be used in the calculations of Mayo Clinic 
Score (MCS) and other related efficacy endpoints unless otherwise stated.
Appendix 5 includes a detailed definition of study treatment failure and the corresponding data 
handling rules for efficacy analysis.
Table 6-1.
Definitions of Dichotomous Efficacy Endpoints
Study
Type
Event Endpoint
Definition
Induction 
Primary
EBS remission at 
Week 10
An endoscopic subscore of 0 or 1*, rectal bleeding 
subscore of 0, and at least a 1 point decrease in stool 
frequency from baseline to achieve a subscore of 0 or 
1 at Week 10
Induction
Key 
Secondary
MCS remission at 
Week 10
A MCS of 2 or less and no single subscore higher
than 1 at Week 10
Induction
Key 
Secondary
An endoscopic subscore 
of 0 at Week 10
An endoscopic subscore of 0 at Week 10
Induction
Key 
Secondary
Geboes histologic 
remission at Week 10
Based on the Geboes Scale (Appendix 6), all of the 
following must be met to be considered in Geboes 
histologic remission at Week 10: Grade 0 of ≤0.3, 
Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 
2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 
of 5.0 {Geboes 2000}.
Induction
Key 
Secondary
MCS remission 
(alternative definition) at 
Week 10
Rectal bleeding, stool frequency, and PGA subscore of 
0 and an endoscopic subscore of 0 or 1; overall MCS 
of ≤ 1 at Week 10
Induction
Exploratory
Novel histologic 
outcomes at Week 10
This novel histologic outcome incorporates both 
Geboes and non-Geboes criteria. Based on the Geboes 
Scale (Appendix 6), all of the following must be met 
to achieve the following novel, exploratory histologic 
outcome at Week 10: Grade 0 of ≤ 0.3, Grade 1 of 
≤1.1, Grade 2a of 2A.0, Grade 2b of 2B.0, Grade 3 of 
3.0, Grade 4 of 4.0 and Grade 5 of 5.0, along with the 
absence of basal plasmacytosis.
Induction 
Exploratory
EBS remission 
(alternative definition) at 
Week 10
An endoscopic subscore of 0 or 1*, rectal bleeding 
subscore of 0, and stool frequency subscore of 0 or 1
at Week 10


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Study
Type
Event Endpoint
Definition
Induction 
Exploratory
MCS response at Week 
10
An MCS reduction of ≥ 3 points and at least 30% from 
baseline score with an accompanying decrease in 
rectal bleeding subscore of ≥ 1 point or an absolute 
rectal bleeding subscore of 0 or 1 at Week 10
Induction 
Exploratory
Endoscopic response at 
Week 10
An endoscopic subscore of 0 or 1 at Week 10
Maintenance
Primary
EBS remission at 
Week 58
An endoscopic subscore of 0 or 1* , rectal bleeding 
subscore of 0, and at least a 1 point decrease in stool 
frequency from induction baseline to achieve a 
subscore of 0 or 1 at Week 58
Maintenance
Key 
Secondary
6-month 
corticosteroid-free EBS 
remission at Week 58
EBS remission with no corticosteroid use for the 
indication of UC for at least 6 months prior to Week 
58 among subjects who are on corticosteroid at re-
baseline (baseline of maintenance study).  Subjects 
who weaned off steroids but required re-initiation 
within 6 months prior to Week 58 assessment will be 
considered to have not met this endpoint.
Maintenance
Key 
Secondary
Sustained EBS remission 
at Week 58
EBS remission at both Week 10 and Week 58
Maintenance
Key 
Secondary
MCS remission at 
Week 58
An MCS of 2 or less and no single subscore larger 
than 1 at Week 58
Maintenance
Key 
Secondary
An endoscopic subscore 
of 0 at Week 58
An endoscopic subscore of 0 at Week 58
Maintenance
Key 
Secondary
Geboes histologic 
remission at Week 58
Based on the Geboes Scale (Appendix 6), all of the 
following must be met to be considered in Geboes 
histologic remission at Week 58: Grade 0 of ≤ 0.3, 
Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 
2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 
of 5.0.
Maintenance
Key 
Secondary
MCS remission 
(alternative definition) at 
Week 58
Rectal bleeding, stool frequency, and PGA subscore of 
0 and an endoscopic subscore of 0 or 1; overall MCS 
of ≤ 1 at Week 58
Maintenance
Exploratory
6-month 
corticosteroid-free MCS 
remission at Week 58
MCS remission with no corticosteroid use for the 
indication of UC for at least 6 months prior to Week 
58 among subjects who are on corticosteroid at re-
baseline
Maintenance
Exploratory
Sustained MCS 
remission at Week 58
MCS remission at both Week 10 and Week 58
Maintenance 
Exploratory
Novel histologic 
outcomes at Week 58
This novel histologic outcome incorporates both 
Geboes and non-Geboes criteria. Based on the Geboes 
Scale (Appendix 6), all of the following must be met 
to achieve the following novel, exploratory histologic 
outcome at Week 58: Grade 0 of ≤ 0.3, Grade 1 of 
≤1.1, Grade 2a of 2A.0, Grade 2b of 2B.0, Grade 3 of 
3.0, Grade 4 of 4.0 and Grade 5 of 5.0, alone with the 
absence of basal plasmacytosis.


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Study
Type
Event Endpoint
Definition
Maintenance
Exploratory
EBS remission 
(alternative definition) at 
Week 58
An endoscopic subscore of 0 or 1*, rectal bleeding 
subscore of 0, and stool frequency subscore of 0 or 1
at Week 58
Maintenance
Exploratory
MCS response at Week 
58
An MCS reduction of ≥ 3 points and at least 30% from 
induction baseline score with an accompanying 
decrease in rectal bleeding subscore of ≥ 1 point or an
absolute rectal bleeding subscore of 0 or 1 at Week 58
Maintenance
Exploratory
Endoscopic response at 
Week 58
An endoscopic subscore of 0 or 1 at Week 58
*
Based on centrally read endoscopy.
MCS response will be used as one of the response criteria at Week 10 to decide whether subjects 
are eligible to be re-randomized into Maintenance Study. 
Endoscopic response will be evaluated at the futility analysis at the second DMC meeting. 
Summary of Dichotomous Efficacy Endpoints 
For the Cohort A Induction Study, the Cohort B Induction Study, and the Maintenance Study, 
numbers and percentages of subjects achieving each of the dichotomous efficacy endpoints 
defined above, and numbers and percentages of subjects not achieving those endpoints for the 
following reasons will be summarized by treatment. 
1) Subjects who are observed non-responders;
2) Subjects who are non-responders due to study treatment failure
3) Subjects who are non-responders due to study drug discontinuation led by protocol-specified 
disease worsening (maintenance study only)
4) Subjects who do not have sufficient measurements to determine the endpoint due to study 
drug discontinuation for other reasons
5) Subjects who do not have sufficient measurements to determine the endpoint while on study
drug
Non-Responder Imputation (NRI)
For analysis of all the above defined efficacy endpoints, subjects who do not have sufficient 
measurements to determine the endpoint will be considered non-responders (ie, non-responder 
imputation [NRI]).


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6.1.1.
Calculations of Mayo Clinic Scores (MCS) and Partial MCS (pMCS) with 
the Subscores
The MCS is an instrument designed to measure disease activity in ulcerative colitis (Table 6-2) . 
The MCS system is a composite index of 4 disease activity variables. Each variable is scored 
individually on an integer scale of 0 to 3, inclusive, with higher scores indicating greater disease 
activity. The individual components of the MCS include stool frequency (SF), rectal bleeding
(RB), endoscopic subscore, and the physician’s global assessment (PGA). SF and RB are 
determined using an electronic daily diary, which collects subject reported components directly.  
The efficacy endpoints described in Table 6-1, except for histologic based endpoints, are all 
based on the four individual components. MCS is calculated as the sum of the 4 subscores, 
ranging from 0 to 12. A pMCS is calculated as the sum of the 3 subscores excluding the 
endoscopic subscore, ranging from 0 to 9.  For further information on the MCS and calculation 
rules, reference is made to Appendix 4.
Table 6-2.
Mayo Clinic Score
Variables
Score
0
1
2
3
Endoscopic Findings
Normal or 
inactive
Mild disease
Moderate disease
Severe disease
Rectal Bleeding
None
Streaks of blood in 
stool less than half 
the time
Obvious blood in 
stool half or more 
than half of the 
time
Blood alone passes
Stool Frequency
Normal number 
of daily stools 
for patient
1-2 stools per day 
more than normal
3-4 stools per day 
more than normal
≥5 stools per day 
more than normal
Physician Global 
Assessment
None
Mild disease
Moderate disease
Severe disease
6.2.
Primary Efficacy Endpoints
6.2.1.
Definition of the Primary Efficacy Endpoints
The primary efficacy endpoints are the proportion of subjects achieving EBS remission at 
Week 10 for the Induction Studies (Cohort A Induction Study and Cohort B Induction Study) 
and at Week 58 for Maintenance Study as defined in Table 6-1. MCS subscores collected at 
screening will be used as baseline values for evaluation of EBS remission at both Week 10 and 
Week 58.


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6.2.2.
Statistical Hypotheses for the Primary Efficacy Endpoints
The primary efficacy objective of the Induction Studies (Cohort A Induction Study and Cohort B 
Induction Study) and the Maintenance Study are to evaluate efficacy of filgotinib in establishing
EBS remission at Weeks 10 and 58. These objectives are translated into the following primary 
statistical hypotheses at Weeks 10 and 58:

H1: The EBS remission rate in the filgotinib 200 mg group is equal to the EBS remission 
rate in the placebo group.

H2: The EBS remission rate in the filgotinib 100 mg group is equal to the EBS remission
rate in the placebo group. 
Each null hypothesis is tested against the alternative hypothesis that the EBS remission rate is 
different between the respective filgotinib dose group and the placebo group.
6.2.3.
Analysis of the Primary Efficacy Endpoint
For the individual Induction Studies (Cohort A Induction Study and Cohort B Induction Study), 
a stratified Cochran-Mantel-Haenszel (CMH) test will be used to compare the treatment effect 
between the filgotinib 200 mg group and placebo and between the filgotinib 100 mg group and 
placebo separately. The CMH tests will be stratified by the following factors: 

Concomitant use of oral, systemically absorbed corticosteroids at Day 1

Concomitant use of immunomodulators at Day 1

Exposure to biologic agent as listed in Appendix 2 (≤1, > 1; for Cohort B Induction Study 
only)
For the Maintenance Study, a CMH test will be used to compare the treatment effect between 
filgotinib 200 mg and placebo among the subjects from the Cohort A and B Induction Studies 
combined being treated with filgotinib 200 mg. The CMH test will be stratified by the following 
factors:

Participation in Cohort A or Cohort B

Concomitant use of oral, systemically absorbed corticosteroids at re-baseline

Concomitant use of immunomodulators at re-baseline
Similarly, a CMH test with the same stratification factors will be used to compare the treatment 
effect between filgotinib 100 mg and placebo among the subjects from the Cohort A and B 
Induction Studies combined being treated with filgotinib 100 mg.


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The stratified CMH chi-square p-value will be provided for each of the above comparison. Strata 
with low numbers of subjects might be aggregated for the CMH test. The 2-sided 
95% confidence interval (CI) of EBS remission rate based on normal approximation method with 
a continuity correction will be provided for each treatment group. In addition, non-stratified risk 
difference estimated along with its 2-sided 95% CI using the normal approximation (ie, the Wald 
method) with a continuity correction  for the difference in proportions will be provided. 
Reference Section 3.5 for the significance level that will be used to declare a statistically
significant treatment effect for each filgotinib group. Stratification variables based on the eCRF 
data will be used for the analysis. 
Bar-charts of proportions of subjects achieving EBS remission at Week 10 and Week 58 will be 
provided by treatment group with corresponding p-values. In addition to the primary analysis 
method described above, the proportion of subjects in EBS remission who had a stool frequency
subscore of 0 versus 1 will be calculated and summarized.
6.2.4.
Sensitivity Analysis of the Primary Efficacy Endpoints
Sensitivity analyses of the primary efficacy endpoint will be performed for each individual study 
(Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study). For all of the 
sensitivity analyses, the same statistical method that was used for the primary analysis, will be 
used for the treatment comparison.
6.2.4.1.
Per-Protocol Analyses
To evaluate the impact of study conduct on the primary analysis, the primary endpoint of EBS 
remission rates of each individual study will be analyzed based on the corresponding PP analysis 
sets as defined in Section 3.1.3.
6.2.4.2.
Locally Read Endoscopic Subscore Analyses
To evaluate the potential disparity between centrally read endoscopy scores versus locally read 
scores, the EBS remission rates using locally (ie, investigator) read endoscopic subscore will be 
analyzed based on the FAS. 
6.2.4.3.
Missing Data Imputation Analyses
Subjects who do not meet EBS remission due to study treatment failure or due to meeting 
protocol-specified disease worsening criterion will not be considered as missing in this section,
but will be considered as not achieving EBS remission for the sensitivity analysis listed here.
To explore the distribution of the missing data across cohorts and treatment groups, missing 
EBS, MCS, and pMCS at Week 10 for Induction Studies and at Week 58 for Maintenance Study 
by baseline/re-baseline characteristic and disease status (severity/duration) including variables 
listed from below, in each treatment group will be summarized. 


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Cohort A Induction Study at Baseline

Duration of UC (years)

MCS score

Endoscopic subscore of 3 (yes, no)

Concomitant use of oral, systemically absorbed corticosteroids (yes, no)

Concomitant use of immunomodulators (yes, no)
Cohort B Induction Study at Baseline

Duration of UC (years)

MCS score

Endoscopic subscore of 3 (yes, no)

Concomitant use of oral, systemically absorbed corticosteroids (yes, no)

Concomitant use of immunomodulators (yes, no)

Exposure to biologic agent listed in Appendix 2 (≤ 1, > 1)
Maintenance Study

Duration of UC at baseline (years) 

MCS score at re-baseline

Endoscopic subscore of 3 (yes, no) at re-baseline

Concomitant use of oral, systemically absorbed corticosteroids at re-baseline (yes, no)

Concomitant use of immunomodulators at re-baseline (yes, no)

Participation in Cohort A or Cohort B 
To evaluate the impact from missing data on the EBS remission rates at Weeks 10 and 58, 
the following missing value imputations will be used:
1) Observed-cases only imputation: Observed cases will be used for analysis without any 
imputation. Only subjects in the FAS with both baseline and Week 10 (or Week 58) data will 
be included for analysis.
2) Missing  Success: impute subjects in the FAS who did not have sufficient data to decide on 
EBS remission as achieving the event.


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3) Missing  Success for placebo group and Missing  Failure for filgotinib groups: impute 
subjects in the FAS who did not have sufficient data to decide on EBS remission as achieving 
this event for placebo group and as not achieving this event for filgotinib groups.
4) Using multiple imputation method to impute subjects in the FAS who did not have sufficient 
data to decide on EBS remission status. The EBS remission status for subjects who have 
missing data at Week 10 for Induction Studies or Week 58 for the Maintenance Study will be 
imputed in the multiple imputation procedure. A logistic regression model will be utilized to 
perform the imputation. The baseline values of EBS subscores (endoscopic, rectal bleeding 
and stool frequency subscores), treatment and stratification factors will be used as the 
independent variables in the model.
6.2.4.4.
Analysis Excluding US/Korea Non-Dual Refractory Males
Given the restriction in the US/Korea of only allowing dual refractory males to receive filgotinib 
200 mg, there exists an inherent imbalance in the Cohort B Induction Study between subjects 
randomized to filgotinib 200 mg and the placebo group with respect to US/Korea non-dual 
refractory males who will be present in the placebo group, but not in the filgotinib 200 mg 
group. Recognizing this imbalance and the theoretical potential for non-dual refractory subjects 
to have better disease prognosis and a higher chance of response, a sensitivity analysis excluding 
US/Korea non-dual refractory males from the placebo group in the FAS for Cohort B Induction 
Study will be conducted using the stratified CMH test for the treatment comparison between the 
filgotinib 200 mg and the placebo group on EBS remission at Week 10. This analysis will be the 
primary analysis for evaluating the efficacy of the filgotinib 200 mg dose group in the Cohort B 
Induction Study in support of a Japanese marketing application.
6.2.5.
Subgroup Analysis of the Primary Efficacy Endpoint
The following subgroup analyses will be performed for the primary efficacy endpoints for each
individual study (Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study):
Subgroups based on study stratification include:
Cohort A Induction Study Stratification Factors:

Concomitant use of oral, systemically absorbed corticosteroids at Day 1 (yes, no)

Concomitant use of immunomodulators at Day 1 (yes, no)
Cohort B Induction Study Stratification Factors:

Exposure to biologic agent listed in Appendix 2 (≤ 1, > 1)

Concomitant use of oral, systemically absorbed corticosteroids at Day 1(yes, no)

Concomitant use of immunomodulators at Day 1(yes, no)


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Maintenance Study Stratification Factors:

Participation in Cohort A or Cohort B

Concomitant use of oral, systemically absorbed corticosteroids at re-baseline (yes, no)

Concomitant use of immunomodulators at re-baseline(yes, no)
Other subgroups for each individual study include:

Age group on the date of first dose of the study drug (< 65 years, ≥65 years)

Sex at birth (female, male)

Race (Asian, Black or African American, White, and Other)

Geographic region (the United States [US], non-US) 

Induction baseline hs-CRP (≤3 mg/L, > 3 mg/L)

Induction baseline fecal calprotectin (≤ 250 μg/g, > 250 μg/g)

Duration of UC (years from date diagnosed to first dose date of Induction study drug) 
(< 1 year, ≥ 1 to < 3 years, ≥3 to < 7 years, ≥ 7 years)

Baseline disease activity (based on screening MCS) (6-8, 9-12)

Previous exposure to TNFα antagonist (yes, no) (only for Cohort B Induction Study and 
Maintenance Study)

Prior TNFα antagonist failure (yes, no) (only for Cohort B Induction Study and Maintenance 
Study)

Previous exposure to vedolizumab (yes, no) (only for Cohort B Induction Study and 
Maintenance Study)

Prior vedolizumab failure (yes, no) (only for Cohort B Induction Study and Maintenance 
Study)

Dual refractory (yes, no) (only for Cohort B Induction Study and Maintenance Study)

The following 4 subgroups (only for Cohort B Induction Study and Maintenance Study)
US/Korea males who are dual refractory
US/Korea males who are not dual refractory
Non-US/Korea males (US/Korea females and subjects from countries other than US and 
Korea) who are dual refractory
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For a subject, if the value of the grouping variable cannot be determined, this subject will be 
excluded from the corresponding subgroup analysis. Non-stratified risk difference between 
treatment groups will be evaluated for each of the subgroups using Fisher’s exact test. A forest 
plot will graphically present the non-stratified risk difference and 95% CI using normal 
approximation with a continuity correction on the treatment differences (filgotinib placebo) in 
EBS remission rates for each of the subgroups.
Additional subgroup analyses for geographic region may be added based on the distribution of 
study enrollment prior to study unblinding.
6.3.
Secondary Efficacy Endpoints
6.3.1.
Definition of the Secondary Efficacy Endpoints
The key secondary efficacy endpoints for Induction Studies are:

The proportion of subjects achieving MCS remission at Week 10

The proportion of subjects achieving an endoscopic subscore of 0 at Week 10

The proportion of subjects achieving Geboes histologic remission at Week 10

The proportion of subjects achieving MCS remission (alternative definition) at Week 10
The key secondary efficacy endpoints for Maintenance Study are:

The proportion of subjects achieving MCS remission at Week 58

The proportion of subjects achieving sustained EBS remission, defined as EBS remission at 
both Weeks 10 and 58

The proportion of subjects achieving 6-month corticosteroid-free EBS remission at Week 58

The proportion of subjects achieving an endoscopic subscore of 0 at Week 58

The proportion of subjects achieving Geboes histologic remission at Week 58

The proportion of subjects achieving MCS remission (alternative definition) at Week 58
Please refer to Table 6-1 for detailed definition for all secondary efficacy endpoints for each 
individual study (Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study).


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6.3.2.
Analysis Methods for Secondary Efficacy Endpoints
The same statistical method that was described under Section 6.2.3 for testing the primary 
efficacy endpoint will be utilized for testing the key secondary efficacy endpoints. The key 
secondary efficacy endpoints will be tested in the order listed in Section 3.5. The key secondary 
efficacy endpoints will be tested only after the primary efficacy endpoint is shown to be 
statistically significant at the significance level specified in Section 3.5. Each key secondary 
efficacy endpoint will be tested at the same significance level that is used for the primary 
efficacy endpoint; testing will be stopped after the first failure to reject the null hypothesis of no 
difference for statistical inference. If the null hypothesis testing for the primary efficacy endpoint 
is not rejected, the key secondary efficacy endpoint comparisons will be considered exploratory.
Bar-charts of proportions of subjects achieving each of the key secondary efficacy endpoints by 
treatment group with corresponding p-values will be provided. 
6.4.
Exploratory Efficacy Endpoints
As the exploratory efficacy endpoint comparisons are not part of the gatekeeping strategy 
described under Section 3.5 to control the family-wise type I error, all testing described in this 
section will be done in an exploratory fashion.
Analysis results of biomarkers except for hs-CRP, fecal calprotectin, and fecal lactoferrin, as 
exploratory endpoints, will be included into a separate biomarker analysis report outside of the 
study CSR. Analysis of hs-CRP, fecal calprotectin and fecal lactoferrin is described in Section 9.
6.4.1.
Definition of the Exploratory Efficacy Endpoints
A subset of exploratory efficacy endpoints will be described  in the CSR; for the Induction 
Studies these include:

Change from baseline in HRQoL scores at Week 10

The proportion of subjects achieving novel histologic outcomes at Week 10

The proportion of subjects achieving endoscopic response at Week 10

The proportion of subjects achieving MCS response at Week 10

Change from baseline in MCS at Week 10

Change from baseline in pMCS at Week 10

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A subset of exploratory efficacy endpoints will be described  in the CSR; for the Maintenance 
Study these include:

The proportion of subjects achieving sustained MCS remission, defined as MCS remission at 
both Weeks 10 and 58

The proportion of subjects achieving 6-month corticosteroid-free MCS remission at Week 58

Change from baseline in HRQoL scores at Week 58

The proportion of subjects achieving novel histologic outcomes at Week 58

The proportion of subjects achieving endoscopic response at Week 58

The proportion of subjects achieving MCS response at Week 58

Change from baseline in MCS at Week 58

Change from baseline in pMCS at Week 58

The proportion of subjects achieving EBS remission (alternative definition) at Week 58
Please refer to Table 6-1 and Section 6.1 for detailed definitions of novel histologic outcomes, 
EBS remission (alternative definition), endoscopic response, and MCS response at Weeks 10 and 
Week 58, respectively, sustained MCS remission at Week 58, and 6-month corticosteroid-free 
MCS remission at Week 58 for Maintenance Study.
6.4.2.
Analysis of Exploratory Efficacy Endpoints
6.4.2.1.
Analysis of dichotomous efficacy endpoints
A stratified CMH test will be used to compare the percentage difference of subjects between 
each filgotinib group and placebo group. The CMH chi-square nominal p-value will be provided. 
The 2-sided 95% CI based on normal approximation method will be provided for each treatment 
group. In addition, non-stratified risk difference estimated along with its 95% 2-sided CI with a 
continuity correction will be provided. 
Bar-charts of proportions of subjects achieving the exploratory event type efficacy endpoints will 
be provided by treatment group with corresponding nominal p-values. 
6.4.2.2.
Analysis of MCS and pMCS exploratory endpoints
For calculation of MCS and pMCS, please refer to rules described under Section 6.1.1 for MCS 
and pMCS with subscores. 
MCS at screening will serve as induction baseline MCS. Partial MCS at Day 1 will serve as 
induction baseline pMCS. If pMCS at Day 1 is missing, the screening partial MCS will be used 
as induction baseline.


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MCS at Week 10 will serve as maintenance re-baseline MCS. Partial MCS at Maintenance Day 1 
will serve as Maintenance re-baseline pMCS. Re-baseline values of MCS and partial MCS will 
serve as Maintenance Study baseline for change from baseline calculation. 
As 2 of the 3 partial MCS components (stool frequency and rectal bleeding) will be collected 
through the subject daily diary, partial MCS will be calculated at all visits when PGA is 
scheduled to be assessed.
Descriptive statistics will be used to summarize the absolute values and change from baseline 
values in MCS, endoscopic subscore, stool frequency subscore, rectal bleeding subscore, PGA 
and partial MCS by analysis visit and treatment group for Cohort A Induction Study, Cohort B 
Induction Study, and Maintenance Study. Shift tables of MCS subscores from baseline to 
Week 10 for Induction Studies and from Week 10 to Week 58 for Maintenance Study will be 
provided. 
Difference of mean change from baseline at Week 10 for Induction Studies and difference of 
mean change from re-baseline at Week 58 for Maintenance study between each filgotinib dose 
group and placebo for partial MCS will be tested in an exploratory fashion using an analysis of 
covariance (ANCOVA) model adjusting for stratification factors and baseline or rebaseline 
value, respectively. Last Observation Carried Forward (LOCF) approach will be used to impute 
the missing values. Estimated means of treatment effects and estimated differences in treatment 
effects between each filgotinib treatment group and the placebo group will be presented with 
95% CIs and nominal p-values. Difference of mean change from baseline (or re-baseline) for 
partial MCS at Weeks 2, 4, and 6 for Induction Studies and at Weeks 14, 20, 26, 34, 42 and 
50 for Maintenance Study will be analyzed in the same fashion. The model based estimated 
mean change from baseline (or re-baseline) with 95% CIs will be plotted over all analysis visits 
by treatment group. 
6.4.2.3.
Analysis of exploratory Health-Related Quality of Life (HRQoL) endpoints
HRQoL questionnaires include Short-Form 36 Health Survey (SF-36), Work Productivity and 
Activity Impairment questionnaire (WPAI), EuroQoL (health-related quality of life 
questionnaire) (EQ-5D), and inflammatory bowel disease questionnaire (IBDQ).
HRQoLs will be collected at baseline, Week 10, Week 26, and Week 58. 
SF-36
The SF-36 is a health related quality of life instrument consisting of 36 questions belonging to 
8 domains in 2 components and covers a 4-week recall period:

Physical well-being, 4 domains: physical functioning (10 items), role physical (4 items), 
bodily pain (2 items), and general health perceptions (5 items)

Mental well-being, 4 domains: vitality (4 items), social functioning (2 items), role emotional 
(3 items), and mental health (5 items).


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The remaining item (health transition) is not part of the above domains but is kept separately. 
These scales will be rescaled from 0 to 100 (converting the lowest possible score to 0 and the 
highest possible score to 100), with higher scores indicating a better quality of life. The SF-36 is 
not disease specific and has been validated in numerous health states.
The change from baseline at Week 10 for Cohort A and B Induction Studies and the change from 
re-baseline at Weeks 26 and 58 for Maintenance Study in each of the 8 domains and each of the 
2 components in SF-36 will be analyzed using an ANCOVA model. The model will include 
treatment, stratification factors and baseline/re-baseline score as covariates. LOCF approach will 
be used to impute missing values. Estimated means of treatment effects and estimated 
differences in treatment effects between each filgotinib treatment group and the placebo group 
will be presented with 95% CIs and nominal p-values.
Descriptive statistics will be used to summarize the absolute values and change-from baseline 
(or re-baseline) values for each domain as well as each component by treatment group and 
analysis visit. 
WPAI
The WPAI is a designed to measure the effect of general health and symptom severity on work 
productivity and regular activities during the past seven days.
The questionnaire consists of 6 questions:
Q1:
currently employed, 
Q2:
work time missed due to UC, 
Q3:
work time missed due to other reasons, 
Q4:
hours actually worked, 
Q5:
degree UC affected productivity while working (0-10 VAS; with 0 indicating no 
effect and 10 indicating UC completely prevented the subject from working), 
Q6:
degree UC affected productivity in regular unpaid activities (0-10 VAS; with 
0 indicating no effect and 10 indicating UC completely prevented the subject’s daily 
activities). 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, that is, worse outcomes, as the following domains:

The percentage of work time missed (absenteeism) due to UC: 100xQ2/(Q2+Q4)

The percentage of impairment while working (presenteeism) due to UC: 100xQ5/10

The percentage of overall work impairment (work productivity loss) due to UC: 
100x{Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]}

The percentage of activity impairment due to UC: 100xQ6/10.


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Summary statistics of the absolute and change from baseline (or re-baseline) scores for each of 
the four domains will be displayed by treatment and visit. 
The change from baseline at Week 10 for Cohort A and B Induction Studies and the change from 
re-baseline at Weeks 26 and 58 for Maintenance Study will be analyzed using similar ANCOVA 
models as for SF-36.
EQ-5D
The EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of 
health-related quality of life that can be used in a wide range of health conditions and treatments.
The EQ-5D consists of 2 components: a descriptive system of the subject’s health and a rating of 
his or her current health state using a 0 to 100 VAS. The descriptive system comprises the 
following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension with 5 levels of severity is used for our study: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The VAS records 
the subject’s self-rated health on a vertical VAS in which the endpoints are labeled 
“best imaginable health state” on the top and “worst imaginable health state” on the bottom. 
Higher EQ VAS indicates better health.
The EQ-5D data will be summarized by treatment group and visit as the following:

A health profile: summary statistics will be provided, including number of patients and 
proportions of categorical responses for the 5 dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression)

A self-perceived current health score: calculated from patient level EQ VAS responses 
(continuous variable). The mean, SD, min, median, and max scores will be provided.
The change from baseline at Week 10 for Cohort A and B Induction Studies and the change from 
re-baseline at Weeks 26 and 58 for Maintenance Study will be analyzed using similar ANCOVA 
models as for SF-36.
IBDQ
This disease-specific questionnaire comprises 32 questions divided into four health subscales: 
bowel symptoms (10 questions); systemic symptoms, including sleep disorders and fatigue 
(5 questions); emotional function such as depression, aggression, and irritation (12 questions); 
and social function, meaning the ability to participate in social activities and to work 
(5 questions). 
Summary statistics of the absolute and change from baseline (or re-baseline) scores for IBDQ 
total score and each subscale score will be displayed by treatment and visit. 
The change from baseline at Week 10 for Cohort A and B Induction Studies and the change from 
re-baseline at Weeks 26 and 58 for Maintenance Study will be analyzed using similar ANCOVA 
models as for SF-36.


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6.5.
Interim Efficacy Analyses
6.5.1.
DMC Futility Analysis
After the initial DMC meeting, the second DMC meeting will include an interim futility analysis 
for each Induction Study after approximately 175 subjects reach Week 10 or discontinue from 
study. The futility analysis will be conducted to evaluate endoscopic efficacy. Overall safety will 
be evaluated at this timepoint as well. The proportion of subjects who achieve an 
endoscopic subscore of 0 or 1 for each treatment group will be evaluated. The DMC may 
recommend termination of a filgotinib dose group in the Induction Study that is being evaluated 
if the observed proportion of subjects who achieve endoscopic response in the filgotinib group is 
lower than that in the placebo group. If both filgotinib dose groups meet the futility criteria, the 
DMC may recommend stopping the study (ie, Cohort A Induction Study [biologic naïve], 
Cohort B Induction Study [treatment experienced], or both).
Should the DMC recommend that the study be modified, a Gilead employee (the sponsor 
representative, as defined in the DMC charter) may be provided with unblinded study data in 
order to make a decision about study conduct. Unblinding of specific Gilead personnel will be 
documented per the appropriate standard operation procedures (SOP). 
6.5.2.
DMC Cohorts A and B End-of-Induction Analysis
After all subjects from Cohorts A and B have completed the Week 10 visit or have terminated 
prior to Week 10 and corresponding data entry is complete, an End of Induction safety and 
efficacy analysis will be performed, including cumulative safety analysis and analysis on 
primary endpoint. Gilead Sciences, Inc.’s (Gilead) blinded statistical programmers will provide 
unblinded external statistician, who is independent of Gilead and not a member of Gilead’s 
Study Management Team, with the datasets and programs necessary to complete the analysis. 
The unblinded external statistician will apply the unblinded treatment codes to the datasets and 
generate the unblinded analysis results. 
Both cohorts will be examined independently by DMC:

Taking into account data in Cohort A and Cohort B, if both dosing groups (200 mg and 
100 mg) in both cohorts (independently examined) fail to reach statistical significance 
compared to placebo on EBS remission, the DMC may recommend overall study 
discontinuation. 

If the condition above is not met, the DMC may recommend that the study continue without 
modification. 


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6.6.
Change from Protocol-Specified Efficacy Analyses
Protocol amendment 5 (02 April 2019) Section 8.11, described that a review of the results of all 
primary and key secondary endpoints of Cohort A and B Induction Studies would be performed 
by a Gilead executive team in parallel with the DMC’s review of the end of induction analysis. 
However, this review by a Gilead executive team was not performed due to concerns raised by 
the Voluntary Harmonization Procedure (VHP) during protocol review. No Gilead executive 
team member or GS-US-418-3898 study team member had access to any unblinded study results 
prior to study completion and database finalization/lock. 
EBS remission (alternative definition), endoscopic response, MCS response, changes from 
baseline in MCS and partial MCS at Weeks 10 and 58 are included as exploratory endpoints for 
Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study. The analyses on 
these endpoints are also included as exploratory analyses.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory AEs will be coded using the current version of MedDRA. System organ 
class (SOC), high-level group term (HLGT), high-level term (HLT), preferred term (PT), and 
lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The
missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE case report form 
(CRF) to the question of “Related to Study Treatment.” Relatedness will always reflect the 
investigator assessment of causality rather than the sponsor’s. Events for which the investigator 
did not record relationship to study drug will be considered related to study drug for summary 
purposes. However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAE specified in the study protocol. Serious adverse events captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead
Pharmacovigilance & Epidemiology Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

Any AEs with an onset date on or after the study drug start date for each Induction Study 
(Day 1) and: 
No later than 30 days after the last dosing date of Induction Study, for subjects who did 
not take any study treatment from Maintenance Study, or
Before the first dosing date of Maintenance Study, for subjects who took any study 
treatment in Maintenance Study

Any AEs leading to premature discontinuation of Induction study drug


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Maintenance Study

Any AEs with an onset date on or after the study drug start date for the Maintenance Study 
and up to 30 days after last dosing date of Maintenance Study

Any AEs leading to premature discontinuation of Maintenance study drug
Overall (Induction and Maintenance)

Any AEs with an onset date on or after the study drug start date for the entire study and up to 
30 days after last dosing date of either Induction Study or Maintenance Study, whichever is 
later

Any AEs leading to premature discontinuation of either Induction or Maintenance study drug
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset date 
determine whether an AE is treatment emergent. For first dosing date and last dosing date 
defined for the Induction Studies (Cohort A Induction Study and Cohort B Induction Study), 
Maintenance Study and Overall, please refer to Section 3.8.1. The event is considered treatment 
emergent if both of the following 2 criteria are met:
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

The AE onset date is the same as or after the month and year (or year) of the first dosing date 
of study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 
30 days after the last dosing date of Induction Study, for subjects who did not take any 
treatment from Maintenance, or
the day before the first dosing date of Maintenance Study, for subjects who took any 
study treatment in Maintenance Study
Maintenance Study

The AE onset date is the same as or after the month and year (or year) of the first dosing date 
of Maintenance Study and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after last dosing date of Maintenance Study


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Overall (Induction and Maintenance)

The AE onset date is the same as or after the month and year (or year) of the first dosing date 
of study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after last dosing date of either Induction Study or Maintenance 
Study, whichever is later
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and an incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set for Cohort A 
Induction Study, Cohort B Induction Study, Cohort A and B Induction Studies Combined, 
Maintenance Study, and Overall separately.
No formal statistical testing is planned.
7.1.6.1.
Summaries of AE incidence 
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT, PT, and treatment group. For other AEs described below, summaries 
will be provided by SOC, PT, and treatment group:

TEAEs of Grade 3 or higher (by maximum severity)

TEAEs of Grade 2 or higher (by maximum severity)

All TE treatment-related AEs

TE treatment-related AEs of Grade 3 or higher (by maximum severity)

TE treatment-related AEs of Grade 2 or higher (by maximum severity)

All TE SAEs

All TE treatment-related SAEs 

All TEAEs leading to premature discontinuation of study drug

All TEAEs leading to premature discontinuation of study

All TE SAEs leading to death (ie, outcome of death)

All TEAEs leading to temporary dose interruption of study drug


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A brief, high-level summary of AEs described above will be provided by treatment group 
presenting the number and percentage of subjects who experienced the above AEs. All deaths 
observed in the study will be also included in this summary.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and HLT within each SOC (if applicable), 
and then by PT in descending order of total frequency within each SOC. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study. 
In addition, the following tables will be generated and summarized by PT only, in descending 
order of total frequency:

TEAEs

TEAEs of Grade 3 or higher

TEAEs of Grade 2 or higher

TE SAEs

TE treatment-related AEs

TE treatment-related SAEs

TEAEs leading to premature discontinuation of study drug
Data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs of Grade 3 or higher

All AEs of Grade 2 or higher

SAEs

Deaths

All AEs leading to death (ie, outcome of death)

AEs leading to premature discontinuation of study drug

AEs leading to premature discontinuation of study

AEs leading to dose temporary interruption of study drug


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7.1.7.
Adverse Events of Interest
Adverse events of interest (AEI) include infections, gastrointestinal perforations, herpes zoster, 
malignancies (excluding non-melanoma skin cancers), non-melanoma skin cancers, and 
thromboembolic events. Summaries of the following treatment-emergent AEIs will be produced 
to enhance the analysis of safety data. 

Events of infections, presented in the following subcategories:
AEs of infections, utilizing all AEs in the MedDRA Infections and Infestations SOC
AEs of serious infections, using all AEs in the MedDRA Infections and Infestations SOC 
that are classified as SAEs
AEs of herpes zoster, utilizing a MedDRA search term (MST) list developed by Gilead 
AEs of opportunistic infections (OIs), using a MST list developed by Gilead 

AEs of malignancies, excluding non-melanoma skin cancers, utilizing a MST list developed 
by Gilead 

AEs of non-melanoma skin cancers, utilizing a MST list developed by Gilead

AEs of gastrointestinal perforation, utilizing a MST list  developed by Gilead 

AEs of thromboembolism, presented in the following subcategories:
AEs of venous thrombosis, utilizing a MST list developed by Gilead 
AEs of pulmonary embolism, utilizing a MST list developed by Gilead
AEs of arterial thrombosis, utilizing the embolic and thrombotic events, arterial 
Standardised MedDRA Queries (SMQ)
AEs of cerebrovascular events, utilizing the ischaemic central nervous system vascular 
conditions SMQ
The number and percentage of subjects with a reported event will be summarized for each 
treatment group by PT for each AEI category. Data listings for AEIs will also be provided.


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7.1.8.
Additional Analysis of Adverse Events
TEAE and SAE for the following subgroups of subjects will be summarized by SOC and PT for 
Cohort A Induction Study, Cohort B Induction Study, Cohort A and B Induction Studies 
Combined, Maintenance Study, and Overall separately: 

Age group (< 65 years, ≥ 65 years; on the date of first dose of the study drug)

Sex at birth (female, male)

Race (Asian, Black or African American, White, Other)

Geographic region (US, non-US) 

Prior TNFα antagonist failure (yes, no) (not applicable for Cohort A Induction Study)

Prior vedolizumab failure (yes, no) (not applicable for Cohort A Induction Study)

Prior dual refractory (TNFα antagonist and vedolizumab) (yes, no) (not applicable for 
Cohort A Induction Study)

Concomitant use of systemic corticosteroid and immunomodulator at Day 1 (or re-baseline 
for Maintenance Study), including
Systemic corticosteroid only 
Immunomodulator only 
Both systemic corticosteroid and immunomodulator
Neither systemic corticosteroid nor immunomodulator
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set for Cohort A Induction Study, Cohort B Induction Study, Cohort A and B 
Induction Studies Combined, Maintenance Study, and Overall (treatment-emergent laboratory 
abnormalities tables only for Overall) separately and will include data collected as specified 
below: 
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)

No later than 30 days after the last dosing date of Induction Study, for subjects who did not 
take any study treatment from Maintenance Study, or

On or before the first dosing date of Maintenance Study, for subjects who took any study 
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Maintenance Study 

No later than 30 days after the last dosing date of Maintenance Study
Overall (Induction and Maintenance)

No later than 30 days after the last dosing date of Induction or Maintenance Study, whichever 
is later
The analysis will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. Test results for hemolyzed samples 
will not be included in the analysis, but they will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and time 
point in chronological order for hematology, serum chemistry, urinalysis, lipid profile, and serum 
immunoglobulin separately. Values falling outside of the relevant reference range and/or having 
a severity grade of 1 or higher on the CTCAE severity grade will be flagged in the data listings, 
as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for each laboratory test specified in the 
study protocol within hematology and chemistry panels including creatinine clearance, and also 
laboratory tests from lipids panel including total cholesterol, LDL, HDL, triglycerides, non-HDL 
cholesterol (total cholesterol minus HDL cholesterol), LDL/HDL ratio, and IgA, IgM, IgG, and 
total Ig, as follows for each Induction Study and Cohort A and B Induction Studies Combined:

Baseline values 

Values at each postbaseline time point 

Change from baseline at each postbaseline time point
In addition, descriptive statistics for the laboratory tests described from above will be provided 
by treatment group for the Maintenance Study:

Re-baseline values 

Values at each postbaseline time point after re-baseline

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A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date of first dose of study drug. Change from baseline to a postbaseline visit will be defined as 
the visit value minus the baseline value. A re-baseline laboratory value will be defined as the last 
measurement obtained on or prior to the date of first dose of study drug for the Maintenance 
study, and change from re-baseline will be defined as the visit value minus the re-baseline value. 
The mean, median, Q1, Q3, minimum, and maximum values will be displayed to the reported 
number of digits; SD values will be displayed to the reported number of digits plus 1.
Median (Q1, Q3) of the observed change from baseline (or re-baseline) values for aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, 
serum creatine, creatinine clearance, creatine phosphokinase, white blood cell count, absolute 
neutrophils, absolute lymphocytes, hemoglobin, platelets, total cholesterol, LDL, HDL, total Ig, 
IgG, IgA and IgM, will be plotted using a line plot by treatment group and visit.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The CTCAE Version 4.03 will be used for assigning toxicity grades (0 to 4) to laboratory results 
for analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at 
least Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses 
for each direction (ie, increased, decreased) will be presented separately. 
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, and

No later than 30 days after the last dosing date of Induction Study, for subjects who did not 
take any study treatment from Maintenance Study, or

On or before the first dosing date of Maintenance Study, for subjects who took any study 
treatment in Maintenance Study
Maintenance Study 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from re-baseline at any time point after first dose of maintenance, up to 30 days 
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Overall (Induction and Maintenance)
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline (Day 1) at any postbaseline time point, up to 30 days after 
permanent discontinuation of study drug of Induction or Maintenance study, whichever is later. 
If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent.
7.2.2.2.
Treatment-Emergent Marked Laboratory Abnormalities
Induction Studies (Cohort A Induction Study and Cohort B Induction Study)
Treatment-emergent marked laboratory abnormalities are defined as values that increase at least 
3 toxicity grades from baseline at any postbaseline time point, and

No later than 30 days after the last dosing date of Induction Study, for subjects who did not 
take any study treatment in the Maintenance Study, or

On or before the first dosing date of Maintenance Study, for subjects who took any study 
treatment in the Maintenance Study
Maintenance Study
Treatment-emergent marked laboratory abnormalities are defined as values that increase at least 
3 toxicity grades from re-baseline at any postbaseline time point after the first dose date of 
Maintenance Study, up to 30 days after permanent discontinuation of study drug. 
Overall (Induction and Maintenance)
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
3 toxicity grades from baseline at any postbaseline time point, up to 30 days after permanent 
discontinuation of study drug of Induction or Maintenance study, whichever is later. 
If the relevant baseline laboratory value is missing, any Grade 3 or 4 values observed within the 
timeframe specified above will be considered treatment-emergent marked abnormalities.
7.2.2.3.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline time 
point for Cohort A Induction Study, Cohort B Induction Study, and Cohorts A and B Induction 
Studies combined, and at re-baseline and each schedule time point afterwards for Maintenance 
Study.


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The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group for Cohort A Induction Study, 
Cohort B Induction Study, Cohorts A and B Induction Studies combined, Maintenance Study,
and Overall; subjects will be categorized according to the most severe postbaseline abnormality 
grade for a given lab test:

Graded laboratory abnormalities

Grade 3 or higher laboratory abnormalities

Marked laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values.
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and time point in chronological order. This listing will include all 
test results that were collected throughout the study for the lab test of interest, with all applicable 
severity grades displayed.
7.2.3.
Laboratory Evaluations of Interest
7.2.3.1.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements for Cohort A Induction Study, Cohort B Induction 
Study, Cohorts A and B Induction Studies combined, and Maintenance Study:

AST: (a) > 3 times of the upper limit of normal range (ULN); (b) > 5 x ULN; 
(c) > 10 x ULN; (d) > 20 x ULN

ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
For individual laboratory tests, subjects will be counted once based on the most severe 
postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, subjects 
will be counted once when the criteria are met at the same postbaseline visit date. The 
denominator is the number of subjects in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. A listing of subjects 
who met at least 1 of the above criteria will be provided.


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7.2.3.2.
Complete Blood Count-Related Laboratory Evaluations
Complete blood count (CBC)-related abnormalities such as anemia, leucopenia, neutropenia, 
lymphopenia, and thrombocytopenia after initial study drug dosing will be examined and 
summarized using the number and percentage of subjects who were reported to have the 
following laboratory test values for postbaseline measurements for Cohort A Induction Study, 
Cohort B Induction Study, Cohorts A and B Induction Studies combined, and Maintenance 
Study:

Hemoglobin: (a) postbaseline worsening CTCAE grade from baseline; (b) baseline value of 
less than Grade 3 and increase to Grade 3 or 4 at worst postbaseline; (c) baseline value of less 
than Grade 3 and increase to Grade 4 at worst postbaseline

White blood cell (WBC) count: (a) postbaseline worsening CTCAE grade from baseline; 
(b) baseline value of less than Grade 3 and increase to Grade 3 or 4 at worst postbaseline; 
(c) baseline value of less than Grade 3 and increase to Grade 4 at worst postbaseline

Absolute neutrophil count: (a) postbaseline worsening CTCAE grade from baseline; 
(b) baseline value of less than Grade 3 and increase to Grade 3 or 4 at worst postbaseline; 
(c) baseline value of less than Grade 3 and increase to Grade 4 at worst postbaseline

Lymphocyte count: (a) postbaseline worsening CTCAE grade from baseline; (b) baseline 
value of less than Grade 3 and increase to Grade 3 or 4 at worst postbaseline; (c) baseline 
value of less than Grade 3 and increase to Grade 4 at worst postbaseline

Platelet count: (a) postbaseline worsening CTCAE grade from baseline; (b) baseline value of 
less than Grade 3 and increase to Grade 3 or 4 at worst postbaseline; (c) baseline value of less 
than Grade 3 and increase to Grade 4 at worst postbaseline
For Maintenance Study, re-baseline will be used in the summaries described above. 
7.2.4.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing change in CTCAE grade for hemoglobin, platelet 
count, white blood cell (WBC) count, absolute lymphocyte count, absolute neutrophils, fasting 
triglycerides, and fasting total cholesterol.  
Shift tables will be presented by showing change in lab normal range (low, normal, and high) for 
hematocrit, absolute monocyte count, absolute eosinophil count, and absolute basophil count. In 
addition, shift tables for fasting LDL and HDL will be presented  using the following National 
Cholesterol Education Program (NCEP) ATP III categories {National Cholesterol Education 
Program (NCEP) 2001}:

For LDL (mg/dL): <100, 100-129, 130-159, 160-189, and ≥ 190 

For HDL (mg/dL): < 40, ≥ 40 to < 60, and ≥ 60 


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In all shift tables, the number and proportion of subjects for each category of each laboratory 
result will be summarized by its baseline/rebaseline category for Cohort A Induction Study, 
Cohort B Induction Study, Cohorts A and B Induction Studies combined, and Maintenance 
Study. 
For the Induction Studies, shift tables will be presented for Week 10. For the Maintenance Study, 
shift tables will be presented for Weeks 26 and 58.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by treatment group for body weight, BMI and vital signs
(resting blood pressure [systolic blood pressure and diastolic blood pressure], respiratory rate, 
pulse and temperature) as follows for each Induction Study and combined:

Baseline value

Values at each postbaseline time point 

Change from baseline at each postbaseline time point 
In addition, descriptive statistics will be provided by treatment group for Maintenance Study

Re-baseline values 

Values at each postbaseline time point after re-baseline

Change from re-baseline at each postbaseline time point after re-baseline
A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. A re-baseline value will be defined as the last 
measurement obtained on or prior to the date/time of first dose of study drug for the Maintenance 
Study, and change from re-baseline will be defined as the visit value minus the re-baseline value. 
Body weight and vital signs measured at unscheduled visits will be included for the 
baseline/re-baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. Body weight , height, and BMI will be included in the vital signs listing, if 
space permits. If not, they will be provided separately.
7.4.
Prior and Concomitant Medications
Medications reported at screening and during the study will be coded using the current version of 
the World Health Organization (WHO) Drug dictionary.


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7.4.1.
Prior Medications
Prior medications are defined as any medication taken before a subject took the first study drug
at baseline/re-baseline.
General prior and UC-specific prior medications will be summarized separately by preferred 
name using the number and percentage of subjects for each treatment group and overall. 
A subject reporting the same medication more than once will be counted only once when 
calculating the number and percentage of subjects who received that medication. The summary 
will be ordered by preferred term in descending overall frequency. For drugs with the same 
frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the 
first dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set for Cohort A Induction Study, Cohort B 
Induction Study, Cohort A and B Induction Studies Combined, and Maintenance Study. No 
formal statistical testing is planned.
7.4.2.
Concomitant Medications
General concomitant and UC-specific concomitant medications are defined as medications taken 
while a subject took study drug. Use of concomitant medications will be summarized by 
preferred name using the number and percentage of subjects for each treatment group. A subject 
reporting the same medication more than once will be counted only once when calculating the 
number and percentage of subjects who received that medication. The summary will be ordered 
by preferred term in descending overall frequency. For drugs with the same frequency, sorting 
will be done alphabetically.
First dosing date and last dosing date for Cohort A Induction Study, Cohort B Induction Study, 
and Maintenance Study have been defined in Section 3.8. For the purposes of analysis, any 
medication with a start date prior to or on the first dosing date of study drug and continued to 
take after the first dosing date, or started after the first dosing date but prior to or on the
last dosing date of study drug will be considered concomitant medications. Medications started 
and stopped on the same day as the first dosing date or the last dosing date of study drug will 
also be considered concomitant. Medications with a stop date prior to the date of first dosing date 
of study drug or a start date after the last dosing date of study drug will be excluded from the 
concomitant medication summary. If a partial stop date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) prior to the date of 
first study drug administration will be excluded from the concomitant medication summary. If a 
partial start date is entered, any medication with the month and year (if day is missing) or year 
(if day and month are missing) after the study drug stop date will be excluded from the 
concomitant medication summary. Medications with completely missing start and stop dates will 
be included in the concomitant medication summary, unless otherwise specified. Summaries will 
be based on the Safety Analysis Set. No formal statistical testing is planned.


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All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline
(or re-baseline) values will be presented by treatment group for each Induction Study, Cohort A 
and B Induction Studies Combined, and Maintenance Study using the following categories: 
normal; abnormal, not clinically significant; abnormal, clinically significant. The number and 
percentage of subjects in each cross-classification group of the shift table will be presented. 
Subjects with a missing value at baseline (or re-baseline) or postbaseline will not be included in 
the denominator for percentage calculation. 
No formal statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and time 
point in chronological order.
7.6.
Other Safety Measures
A data listing will be provided for subjects who become pregnant during the study.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection
Sparse plasma PK samples will be collected prior to dose at Weeks 10 and 58, post dose at 
Week 4 (at least 30 minutes and up to 3 hours after dosing), and at any time at Week 26.
An optional PK Substudy will be performed in a subset of subjects. In the PK substudy, the daily 
dose of study drug should be administered in the clinic (at one visit between Week 2 and 
Week 10, inclusive), and additional PK samples should be collected predose and at 0.5, 1, 2, 3, 4, 
and 6 hours post dose to determine the steady-state PK of filgotinib and its metabolite
GS-829845.
8.2.
PK Analyses Related to Intensive PK Sampling
Steady-state PK will be determined in subjects in the PK Substudy analysis set. Concentrations 
of filgotinib and its metabolite GS-829845 in plasma will be determined using validated 
bioanalytical assays.
8.2.1.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to 0. Predose samples may also 
serve as the 24-hour post dose sample if appropriate.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
(τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCinf, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.2.2.
PK Substudy
PK parameters will be generated for all subjects in the PK substudy analysis set. The analyte 
presented in Table 8-1 will be evaluated if data are available


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Table 8-1. 
Study Treatments and Associated Analyte 
Treatment Group 
Treatment 
Analyte 
Treatment I 
Filgotinib (200 mg) tablet 
Filgotinib, GS-829845 
Treatment2 
Filgotinib (100 mg) tablet 
Filgotinib, GS-829845 
The analytes and parameters presented in Table 8-2 will be used to evaluate the PK objectives of 
the study. The primary PK parameters are [AUCtau, and Cmax] of filgotinib and GS-829845. The 
PK parameters to be estimated in this study are listed and defined in the Appendix 7. 
Table 8-2. 
PK Parameters for Each Analyte 
Analyte 
Parameters 
Filgotinib 
AUC1ast, AUC,rn, Cmax, T max, Ctrn, and CLs_JF, if appropriate 
GS-829845 
AUC1ast, AUC3U, Cmax, T max, and Ctlu, if appropriate 
Individual subject concentration data and individual subject PK parameters for filgotinib and 
GS-829845 will be listed and summarized using descriptive statistics by treatment. Smmnary 
statistics (subject number [n], mean, SD, coefficient of variation [%CV], median, min, max, Ql, 
and Q3) will be presented for both individual subject concentration data by time point and 
individual subject PK parameters by treatment. Moreover, the geometric mean, 95% CI, and the 
mean and SD of the natural log-transfonned values will be presented for individual subject PK 
parameter data. 
Individual concentration data listings and smmnaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nomnissing concentration data at that time point. The nmnber of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the lower limit of quantitation (LLOQ) for postdose time points. 
Individual PK parameter data listings and smmnaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nomnissing data for that PK parameter. 
The following tables will be provided for each analyte by treatment: 
• 
Individual subject concentration data and summary statistics 
• 
Individual subject plasma PK parameters and smmnary statistics 
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For the PK Substudy, the following figures may be provided for each analyte by treatment:

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤LLOQ will not be 
displayed in the figures and remaining points connected.
The following listings will be provided:

PK sampling details by subject including actual dosing time and actual draw time, calculated 
time postdose of sample collection, differences in scheduled and actual draw times, sample 
age, and sample concentration
8.3.
Statistical Analysis Methods
For both Pharmacokinetic Analysis Set (sparse PK) and Pharmacokinetic Substudy Analysis Set, 
individual subject concentration data for filgotinib and its metabolite GS-829845 will be listed 
and summarized using descriptive statistics (eg, sample size, arithmetic mean, geometric mean, 
coefficient of variation (%) standard deviation, median, minimum, and maximum) by treatment.
For PK samples collected prior to dose, summary statistics will be generated at nominal visits 
and only the records with PK drawn ≥ 22 hours and ≤26 hours after the prior dose of study drug 
will be included. If the date/time of prior dose of study drug is missing, then the corresponding
concentration records will be excluded from the summary. The number of subjects with 
concentration BLQ will be presented for each time point. For summary statistics, BLQ values 
will be treated as 0 at predose and one-half of the lower limit of quantitation (LLOQ) for 
postdose time points. 
Plasma concentrations over time may be plotted in semi-logarithmic and linear formats as mean 
± standard deviation, and median (Q1, Q3) for PK substudy. 
For PK substudy, individual PK parameters (Cmax, Tmax, Ctau AUClast, AUCtau, and CLss/F, as 
applicable) for both filgotinib and GS-829845 will be listed and summarized using descriptive 
statistics. Molar ratio of GS-829845 to filgotinib exposures (AUClast, AUCtau, Cmax, and Ctau, as 
applicable) will also be calculated and summarized. It can be expreseed as GS-829845 
exposure/filgotinib exposure (425.51/357.43). Moreover, the geometric mean, 95% CI, and the
mean and SD of the natural log-transformed values will be presented for individual subject PK 
parameter data. 
Additional PK analysis may be performed and exposure-response relationships may be explored.


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9.
BIOMARKER ANALYSIS
The biological marker analysis will be conducted on the Biomarker Analysis Set, defined in 
Section 3.1.7.
Serum hs-CRP, fecal calprotectin, and fecal lactoferrin will be listed and summarized for 
Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study separately by 
treatment using descriptive statistics including baseline (or re-baseline) values, values at each 
postbaseline time point, change from baseline (or re-baseline) and percent change from baseline 
(or re-baseline) at each postbaseline time point. The definitions of baseline (or re-baseline) for 
each study are in Section 3.8.1.
Summaries of fecal calprotectin and serum hs-CRP for subjects who have baseline 
(or re-baseline) values satisfying the following criteria will also be provided for Cohort A 
Induction Study, Cohort B Induction study, and Maintenance Study:

Fecal calprotectin > 250 μg/g

Fecal calprotectin ≤250 μg/g

hs-CRP > 3 mg/L

hs-CRP ≤ 3 mg/L
Mean (Q1, Q3) of the observed change from baseline (or re-baseline) values for fecal 
calprotectin, fecal lactoferrin, and serum hs-CRP will be plotted by treatment and visit for 
Cohort A Induction Study, Cohort B Induction Study, and Maintenance Study separately as well.


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10.
REFERENCES
Bretz F, Maurer W, Brannath W, Posch M. A Graphical Approach to Sequentially Rejective 
Multiple Test Procedures. Stat Med 2009;28:586-604.
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lofberg R. A reproducible grading scale for 
histological assessment of inflammation in ulcerative colitis. Gut 2000;47 
(3):404-9.
National Cholesterol Education Program (NCEP). Detection, Evaluation, and Treatment of High 
Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary. 
National Institute of Health  May, 2001.


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11.
SOFTWARE
SAS® Software Version 9.4 (SAS Institute Inc., Cary, NC, USA.) is to be used for all 
programming of tables, listings, and figures.
nQuery Advisor® Version 6.0 (Statistical Solutions, Cork, Ireland.) was used for sample size 
and power calculation.


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12.
SAP REVISION
Revision Date
(DD MMM 
YYYY)
Section
Summary of Revision
Reason for Revision
Original Final Draft 
(07 September 
2016)
27 April 2018
1
Added key secondary objectives of 
establishing MCS remission 
(alternative definition) at Week 10 for 
Cohort A and B Induction Studies and 
at Week 58 for Maintenance Study
To align with Protocol 
Amendment 4
3
Modified definition for Per-Protocol 
Analysis Sets
To better conduct Per-Protocol 
analysis
3, 7
Added Cohorts A and B pooled safety 
summary
To support safety evaluation of 
study drug across Induction 
Studies
3, 7
Clarified overall safety summaries 
only include adverse events and 
laboratory abnormalities including data 
collected across Cohort A Induction 
Study, Cohort B Induction Study and 
Maintenance Study
To support safety evaluation of 
study drug across Induction 
and Maintenance Studies
5
Modified the list of variables to be 
summarized in baseline characteristic 
tables
To provide better 
characterization of the 
investigated patient populations
7
Clarified AEs of interest to be 
summarized
To better address safety 
concerns
7
Added summary of complete blood 
count-related laboratory evaluations
To better address safety 
concerns
7
Removed shift relative to baseline 
tables for laboratory assessment 
including hematology and chemistry
To simplify the analysis
Appendix 1
Update Schedule of Assessments
To align with Protocol 
Amendment 4
Global
Administrative and editorial changes 
have been made throughout the SAP, 
where appropriate
Improve clarity and 
consistency


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Revision Date
(DD MMM 
YYYY)
Section
Summary of Revision
Reason for Revision
28 November 2018
3.5 and 6.1
Changed the testing strategy of 
efficacy endpoints of two filgotinib 
dose groups from separate to 
sequential testing with the proposed 
testing order
In response to comments from 
FDA
4.2.2
Further specified details of adherence 
rate calculation
Improve clarity
5.2
Added variables of baseline 
characteristics
To provide better 
characterization of subjects
6.2.5
Added subgroup analysis regarding 
biologic treatment history for 
Maintenance Study
To better characterize the 
treatment efficacy profile of 
Maintenance Study
7.1.8
Added subgroup summary of AEs and 
SAEs
In response to comments from 
FDA
7.2.4
Added summary of shift change in 
selective laboratory tests
In response to comments from 
FDA
9
Planned summary of additional PK 
parameters
due to data availability
08 April 2019
1.3
Power calculation revised according to 
the current alpha spending strategy
In response to comments from 
FDA
3
Changed the testing strategy of 
efficacy endpoint of two filgotinib 
dose groups to sequentially rejective 
multiple test procedures
In response to comments from 
FDA
Global
Administrative and editorial changes 
have been made throughout the SAP, 
where appropriate
Improve clarity and 
consistency


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Revision Date
(DD MMM 
YYYY)
Section
Summary of Revision
Reason for Revision
28 April 2020
3.2
For Maintenance Study summary, the 
subject grouping would not pool all 
placebo subjects into one group.
Placebo groups not pooled for 
the Maintenance study in 
response to comments from 
FDA on the integrated safety 
analysis SAP and also in 
recognition of different patient
populations of filgotinib 200mg 
induced responders, filgotinib 
100 mg induced responders, 
and placebo induced 
responders
4.1, 4.2, 5.1 
and 5.2
Added enrollment and disposition 
summary for Cohorts A and B 
combined.
To report overall patient 
population and disposition for 
filgotinib UC program
4.1
Added “Per-Protocol Analysis Set”, 
“PK Analysis Set” and “Biomarker 
Analysis Set” into Maintenance Study 
disposition table.
To improve the completeness 
of the Maintenance Study 
disposition table.
6.1 and 6.4
Added exploratory endpoints of EBS 
remission (alternative definition) at 
Week 10 for Induction Studies A and 
B and at Week 58 for Maintenance 
Study
In response to comments from 
FDA
8.2.2 and 8.3
Removed PK parameters Clast, Tlast, t1/2, 
z and Vss/F;  removed listing of 
individual data on determination of the 
plasma half-life and corresponding 
correlation coefficient
To remove parameters that are 
less appropriate/informative to 
characterize the steady state PK
Appendix
Removed Appendix 7 – Appendix 12 
from previous SAP
Appendix 7 – Appendix 12 in 
the previous SAP were MSTs 
for AEI. As internal process 
has evolved and the AEI flags 
are included into the raw 
datasets, those appendixes have 
been removed from the SAP.
Global
Administrative and editorial changes 
have been made throughout the SAP, 
where appropriate
Improve clarity and 
consistency


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13.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
Biologics for UC Treatment
Appendix 3.
Mayo Scoring System for Assessment of Ulcerative Colitis Activity
Appendix 4.
Mayo Clinic Score (MCS) Calculation
Appendix 5.
Study Treatment Failure Rules
Appendix 6.
Geboes Histological Score Grades
Appendix 7.
PK Parameters


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Appendix 1.
Schedule of Assessments
Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PTxa
ET
Week
0
2
4
6
10
11
14
17
20
23
26
30
34
38
42
46
50
54
58
Study Day
-30 
to -1
1
15
29
43
71
78
99
120
141
162
183
211
239
267
295
323
351
379
407
Visit Window
±3
±3
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±3
Written Informed 
Consent 
X
Medical History & 
Demographics
X
Ulcerative Colitis 
Treatment History 
and disease extent
X
12-lead ECG
X
X
X
X
Xb
Review of Inclusion/
Exclusion Criteria
X
X
Complete Physical 
Examc
X
Symptom directed 
physical examc
(as needed)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PTxa
ET
Week
0
2
4
6
10
11
14
17
20
23
26
30
34
38
42
46
50
54
58
Study Day
-30 
to -1
1
15
29
43
71
78
99
120
141
162
183
211
239
267
295
323
351
379
407
Visit Window
±3
±3
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±3
Randomization
X
X
Study Drug 
Dispensing
X
X
X
X
X
X
X
X
X
Colonoscopy/Flexible 
Sigmoidoscopy with 
biopsy
Xd
X
X
Investigator 
Endoscopic Value 
(0,1,2,or 3)e
X
X
X
Mayo Score (Partial)f
X
X
X
X
X
X
X
X
X
X
X
X
Mayo Score 
(Complete)
X
X
X
eDiary instruction & 
reviewg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool for C. diff toxin, 
pathogenic E. coli,
Salmonella spp, 
Shigella spp, 
Campylobacter spp 
or Yersinia spp 
testing
X
Stool O&Ph
X
Stool microbiome
X
X
X
X
Fecal MMP-9
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PTxa
ET
Week
0
2
4
6
10
11
14
17
20
23
26
30
34
38
42
46
50
54
58
Study Day
-30 
to -1
1
15
29
43
71
78
99
120
141
162
183
211
239
267
295
323
351
379
407
Visit Window
±3
±3
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±3
Fecal Lactoferrin, 
Calprotectin
X
X
X
X
Urine drug screeni
X
Urinalysis
X
X
X
X
Pregnancy Testj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TBk  
X
Chest x-ray l
X
HBV, HCV, HIV 
screeningm
X
HBV DNA 
monitoring (Japan)n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV monitoring 
(other regions)n
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid profile
(fasting)o
X
X
X
X
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
immunoglobulin
X
X
X
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PTxa
ET
Week
0
2
4
6
10
11
14
17
20
23
26
30
34
38
42
46
50
54
58
Study Day
-30 
to -1
1
15
29
43
71
78
99
120
141
162
183
211
239
267
295
323
351
379
407
Visit Window
±3
±3
±3
±2
±3
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±3
±3
Blood TCR/BCR 
repertoire samplesp
X
X
X
X
X
Plasma biomarker
sample
X
X
X
X
X
Serum biomarker 
sample
X
X
X
X
X
Blood transcriptome 
sample
X
X
X
X
X
PK collection 
(sparse)q
X
X
X
X
vfPBMCr
X
X
X
X
X
PK substudys
X
HRQoL Surveysu
X
X
X
X
HCRU questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
a
The Post Treatment (PTx) visit should occur 30 days after the last dose of study drug. Only subjects who roll over into the LTE study (GS US 418 3899) will not complete 
PTx assessments.
b
For subjects who terminate prior to Week 10
c
A complete physical examination (PE) including, vital signs, body weight, and height will be performed at screening. (GU exam at investigator discretion). A symptom 
directed PE may be done as needed at other time points.
d
Diary data and other eligibility criteria should be reviewed prior to scheduling endoscopy. Perform the screening colonoscopy/flexible sigmoidoscopy within 2 weeks of 
Day 1 (Day 14 to 1). Subject should meet stool frequency and rectal bleeding requirements based on diary data prior to endoscopy performance.
e
The investigator (ie, local endoscopist) should enter in an endoscopic subscore (0, 1, 2, or 3) based on the Mayo Clinic Scoring System endoscopic scale 
(Protocol Appendix 4); this will be entitled the Investigator Endoscopic Value. The locally read score entered may not be used for eligibility or Mayo Clinic Score calculation 
purposes, and is not a substitute for the centrally read score, but is collected solely for exploratory purposes.
CCI


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f
Includes all parts of the Mayo score except endoscopy
g
Subjects should begin filling out the eDiary the day after their initial screening visit and continue to fill it out throughout the remainder of the study.
h
Stool samples should be collected to rule out infectious causes when disease worsens.
i
Positive cocaine test disqualifies subject; positive amphetamines, barbiturates, benzodiazepines, and opioids require medical monitor review.
j
All females meeting the childbearing potential criteria must have a serum pregnancy testing at screening and a urine pregnancy test must be completed in clinic every 4 weeks 
at a minimum. If any pregnancy test is positive, study drug should be immediately interrupted and the subject should have a serum pregnancy test in clinic.
k
Proof of no active or untreated latent TB at screening. Subjects who are diagnosed with latent TB at screening must initiate an adequate course of prophylaxis as per local 
standard of care for a minimum of 4 weeks prior to randomization. Subject may initiate study drug dosing only after consultation with the medical monitor.
l
Chest x ray (views as per local guidelines) taken at screening or within the 3 months prior to screening (with the report or films available for investigator review) without 
evidence of active or latent TB infection
m
Hepatitis B surface Ag, surface Ab and core Ab, reflex HBV DNA, Hepatitis C Ab, reflex HCV RNA, HIV Ag/Ab, reflext HIV 1/2 Ab at Screening (Protocol Section 6.2.1).
n
In Japan, subjects with negative HBsAg, positive HBcAb and/or positive HBsAb at Screening require HBV DNA monitoring every 4 weeks in accordance with local 
guidelines (Protocol Section 6.2.1). In other regions, subjects with negative HBsAg and positive HBcAb require HBV DNA monitoring every 3 months in accordance with 
local guidelines (Protocol Section 6.2.1)
o
Fasting means no food or drink, except water, for 8 hours 
p
TCR: T cell receptor; BCR: B cell receptor
q
This PK sample at Weeks 10 and 58 are collected at pre dose (within 2 hours prior to dosing).  The PK sample at Week 4 is collected post dose (at least 30 minutes and up to 
3 hours after study drug dosing . For this visit, it is preferred that study drug dosing is in clinic. The PK sample at Weeks 26 can be collected at any time without regard to 
dosing. For these visits, the time of dose taken on the day of and the dose taken prior to the PK sample being drawn will be noted in the eCRF.
r
vfPBMC collection at US and Canadian sites only.
s
Subjects who consent to optional PK substudy will have an additional plasma PK sample at any single visit from Week 2 and 10, collected pre dose and at 0.5, 1, 2, 3, 4 and 
6 hours after supervised dosing in the clinic. For all visits with PK sampling, the time of dose taken prior to and on the day of visit will be noted in the eCRF
u
HRQoLs include SF 36, WPAI, EQ 5D, IBDQ.
CCII 


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Appendix 2.
Biologics for UC Treatment
The drug names of biologics considered as UC treatment are listed below.
No.
Drug Class 
Drug Name
1
TNFα antagonist
Adalimumab
2
TNFα antagonist
Golimumab
3
TNFα antagonist
Infliximab
4
TNFα antagonist
TNFα antagonist biosimilar (to adalimumab, golimumab, or 
infliximab)
5
Integrin receptor antagonist
Vedolizumab


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Appendix 3.
Mayo Scoring System for Assessment of Ulcerative Colitis Activity
Stool Frequency – Each subject serves as his or
her own control to establish the degree of 
abnormality of the stool frequency
0
Normal number of stools for subject
1
1 to 2 stools per day more than normal
2
3 to 4 stools more than normal
3
≥ 5 stools more than normal
Rectal Bleeding - The daily bleeding score 
represents the most severe bleeding of the day
0
No blood seen
1
Streaks of blood with stool less than half the time
2
Obvious blood with stool half or more than half of the 
time
3
Blood alone passes
Endoscopic findings - Assessed by Central 
Reader (include only for MCS assessment)
0
Normal or inactive disease
1
Mild Disease (erythema, decreased vascular pattern)
2
Moderate Disease (marked erythema, lack of 
vascular pattern, friability, erosions)
3
Severe Disease (spontaneous bleeding, ulceration)
Physician’s Global Assessment - The 
physician’s global assessment acknowledges the 
three other criteria, the subject’s daily 
recollection of abdominal discomfort and general 
sense of wellbeing, and other observation, such 
as physical findings and the subject’s 
performance status.
0
Normal
1
Mild disease
2
Moderate disease
3
Severe disease
-
-
-
-
-
-
-
-
-
-


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Appendix 4.
Mayo Clinic Score (MCS) Calculation
Definition of the Mayo Clinic Score and Component Subscores
The Mayo Clinic Score (MCS) is a composite index of 4 disease activity variables; stool 
frequency, rectal bleeding, endoscopic findings, and the physician global assessment (PGA) . 
Each of the 4 variables is assigned an integer subscore from 0-3 as described in Table 6-2.

The MCS is calculated as the sum of the 4 subscores for  stool frequency, rectal bleeding, 
endoscopic findings, and the PGA. 

Partial MCS (pMCS) is the sum of the 3 subscores for stool frequency, rectal bleeding, and 
the PGA.

EBS (Endoscopy, Bleeding, Stool Frequency) is a description of the 3 subscores for 
endoscopic findings, rectal bleeding, and stool frequency.
Calculation of Mayo Clinic Score and Component Subscores
In the GS-US-418-3898 study, subjects report daily stool frequency and rectal bleeding 
symptoms on the study Logpad (an electronic medical diary). The physician reports the PGA at 
specified visits on the study Sitepad. Results of endoscopic evaluation are reported by a central 
reader and site personnel enters the score on the Sitepad.
For the purposes of calculation of the specific MCS and component subscores an anchor date is 
assigned and stool frequency and rectal bleeding records prior to the anchor date are used in the 
calculation of the subscores. 
For screening calculations of MCS and EBS, the anchor date is considered the date of the 
endoscopy. As endoscopic subscore will be only evaluated over screening and not at Day 1 
baseline. Screening MCS and EBS will be used as baseline evaluation. 
For all calculations at other visits, including baseline partial MCS, postbaseline MCS, EBS, and 
partial MCS, the anchor date is the date of the study visit.  
Because the preparation for endoscopy procedure may impact the validity of the diary data, the 
patients reported daily stool frequency and rectal bleeding records collected 1 day prior to, the 
day of, and the day after the procedure will not be used in the calculation of stool frequency and 
rectal bleeding subscores. These above mentioned days are considered as non-evaluable days for 
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Calculation of MCS and EBS at Screening/Baseline 
The calculation of the screening stool frequency subscore and screening rectal bleeding 
subscores for the purposes of calculation of baseline MCS and baseline EBS is as follows:
1) The endoscopic procedure date is defined as the E-Day 1.
2) A 7-day window is defined in which the start of the window begins 7 days prior to the 
endoscopic procedure date and the window ends on the day prior to the endoscopic procedure 
date.
3) The subscore is calculated as the average of the 3 evaluable dairy data entries within the 
7-day window closest to the endoscopic procedure date (discarding the day prior to 
endoscopy) and rounded to the nearest integer.  
4) If a subject does not have 3 evaluable diary day entries within the 7-day window, this subject 
will have a missing subscore and missing baseline MCS and EBS.
5) The PGA subscore used in the baseline MCS is that recorded during the screening period 
(prior to Day1) . 
A schema of this approach (Appendix Figure 1) and examples are included below in 
Appendix Table 1:  
Appendix Figure 1. Stool Frequency and Rectal Bleeding Subscores Calculations at 
Screening
Screening 
1' 
11 E-Day 
1' 
E-Day 
1' 
7-day look back window to calculate 
subscore 
Endoscopy Day 
(E-Day 1) 
(Anchor Day) 
Day l 
1' 


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Appendix Table 1.
Examples of Calculations for the Rectal Bleeding and the Stool 
Frequency Subscores of MCS and EBS at Baseline
Example
Diary Day Looking Back from Endoscopy 
Date
Anchor Day
Days for
Calculation
Average 
Subscore
Final 
Subscore
-7
-6
-5
-4
-3
-2
-1
E-Day 1
3
Jun
4
Jun
5
Jun
6
Jun
7
Jun
8
Jun
9
Jun
10
Jun
Diary 1
M
M
2
M
1
2
X
X
2, 3, 5
1.67
2
Diary 2
M
M
M
M
0
1
X
X
2, 3
Missing
Missing
Diary 3
M
M
M
M
0
M
X
X
3
Missing
Missing
Diary 4
M
2
M
2
1
1
X
X
2, 3, 4
1.33
1
Days are named relative to Anchor Day Endoscopy Date (E Day 1), M  Missing, X  non evaluable
The diary data collected on E Day 1 and E Day 1 will be discarded as endoscopy and its preparation may impact the 
validity of the diary data.
Calculation of Partial MCS at Baseline, and Postbaseline MCS, EBS, and Partial MCS
The calculation of baseline partial MCS and postbaseline MCS, EBS and partial MCS use the 
study visit date as the anchor date. For baseline pMCS, the visit date is the Day 1 visit. The 
calculations are as follows:
1) Subject diary data collected within 7 days prior to the visit day will be used for calculation, 
and some of the days within this 7-day window may be considered non-evaluable due to the 
endoscopy procedure and its preparation (ie, the day of the endoscopy and the day prior to 
the endoscopy). 
2) The average of the 3 evaluable diary day entries within the 7-day window closest to the visit 
day (V-Day 1), rounded to the nearest integer, will be considered the stool frequency and 
rectal bleeding subscore for that visit
3) The PGA subscore used in the calculation of baseline partial MCS is the PGA subscore 
recorded on Day 1. At subsequent visits, the PGA subscore used in calculation of MCS and 
partial MCS is that recorded within the visit window
4)
If there are 2 or less evaluable diary day entries for stool frequency or rectal bleeding within 
the 7-day window, no missing data imputation will be done. MCS, EBS and partial MCS will 
be considered as missing.
5) For MCS, if endoscopic subscore or PGA subscore is missing, MCS will be left as missing. 
For Partial MCS, if PGA is missing, partial MCS will be left as missing.
A schema of this approach and some examples are included below in Appendix Figure 2 and
Appendix Table 2:


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Appendix Figure 2. Stool Frequency and Rectal Bleeding Subscores Calculations at 
Baseline and Postbaseline
Appendix Table 2.
Calculation of Partial MCS at Baseline, and Postbaseline MCS, EBS 
and Partial MCS
Example
Diary Day Looking Back from Visit Date
Anchor
Day
Days for 
Calculation
Average 
Subscore
Final 
Subscore
-7
-6
-5
-4
-3
-2
-1
V-Day 1
3
Jun
4
Jun
5
Jun
6
Jun
7
Jun
8
Jun
9
Jun
10
Jun
Diary 1
E
X
3
M
M
M
0
X
-1, -5
Missing
Missing
Diary 2
4
4
X
E
X
3
3
X
-1, -2, -6
3.33
3
Diary 3
3
X
E
X
1
M
2
X
-1, -3, -7
2
2
Diary 4
2
3
4
4
X
E
X
X
-4, -5, -6
3.67
4
Diary 5
2
M
M
X
E
X
2
X
-1, -7
Missing
Missing
Diary 6
X
E
X
2
3
0
1
X
-1, -2, -3
1.33
1
Diary 7
M
3
X
E
X
M
M
X
-6
N/A
Missing
Days are named relative to Anchor Day (V Day 1 Visit Date), M  Missing, X  non evaluable, E  Endoscopy Day
Sources of Information for Mayo Clinic Score Calculations
The sources of information used for the calculations of MCS and partial MCS are summarized in 
Appendix Table 3 (the calculated MCS and partial MCS from ERT data will not be used for data 
analysis):
V-Day-7 
7-day look back window to calculat 
subscore 
V-Day 1 
(Anchor Day) 
Visit Day 


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Appendix Table 3.
Sources of Information for Calculating MCS and Partial MCS
Variable in Calculation
Data Source
Endoscopy Procedure Date
ENDODAT in ENDO dataset from CRF data for protocol-directed 
endoscopy; ENDODAT in MAYO dataset from ERT data for 
non-protocol-directed endoscopy
Visit Date
VISITDAT in VISDT dataset from CRF data
Stool Frequency Subscore
QSSTRESN in DIARY dataset with QSTESTCD=”SF” from ERT data
Rectal Bleeding Subscore
QSSTRESN in DIARY dataset with QSTESTCD=”RB” from ERT data
Physician Global Assessment
QSSTRESN in MAYO dataset with QSTESTCD=”PGA” from ERT data
Endoscopic Score
MAYO in ENDO ROBARTS dataset from Robarts data
Note: Robarts is the vendor performing endoscopy central scoring; 
ERT is the vendor that electronically collects patient and investigator reported outcomes


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Appendix 5.
Study Treatment Failure Rules
Study treatment failure rules apply to treatment failure that occurs during the course of the study. 
Study treatment failure rules will be applied to all efficacy endpoints unless otherwise specified.
All efficacy data will be censored (set to missing) after treatment failure criteria are met, 
regardless of the observed data. Subjects who do not have sufficient measurements after 
censoring to determine the dichotomized endpoint(s) will be considered non-responder for 
corresponding endpoint(s). Study treatment failure rules override other data handling rules.
Subjects who have any of the following events will be considered a study treatment failure after
the earliest event through the end of the Induction Study (if the event occurred during induction) 
or through the end of the Maintenance Study (if the event occurred during maintenance), 
regardless of the actual efficacy data collected. Induction baseline will be referenced when 
calculating the potentially effective use for induction studies and maintenance baseline 
(re-baseline) will be referenced when calculating the potentially effective use for Maintenance 
Study.
1) Potentially effective steroid use 
Potentially effective corticosteroids, for the purpose of this SAP, are steroids that may impact 
disease under study. Potentially effective steroids include the following steroids when 
administered for an indication of UC: 
a) Commencement of:
Any steroid administered intramuscularly (IM), intravenously (IV),  orally (PO), or rectally 
(PR) at any dose for 7 or more continuous days

This rule applies regardless if a change in drug, dose, or route (from IM to IV to PO or 
PR or vice versa) occurs within the seven continuous days; and it includes oral steroids 
with intended local actions (eg, budesonide)
b) Escalation of concomitant steroid dose above the baseline dose for 7 or more continuous 
days. The baseline steroid dose is defined as the dose at Day 1 of induction if the 
escalation occurs in the Induction Study, or Day 1 of maintenance (re-baseline) if the 
escalation occurs in the Maintenance Study. The prednisone equivalent dose will be used 
to determine escalation of concomitant systemic steroid dose even if there is a change in 
drug or route. For steroids with local actions (eg, budesonide or any rectally administered 
steroid), this rule will apply to scenarios where the post-baseline dose is above the 
baseline dose via the same drug and the same route for 7 or more continuous days. 


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Potentially effective steroid use only includes use of steroids administered via routes that are IM, 
PO, IV, or PR. The below steroids will not be considered potentially effective steroids regardless 
of indication for use:
i)
ocular steroids (ie, eye drops)
ii) topical steroids (eg, cutaneously applied solely to the skin, or topically applied to the
nasal mucosa)
iii) inhaled steroids (eg, inhalational fluticasone for asthma)
iv) intra-articular steroids (steroids administered directly into a joint)
v) neuraxial steroids (steroids administered into the epidural or spinal space)
2) Potentially effective immunomodulator use 
Commencement of a different class of oral, IM, SC, or IV immunomodulator drugs
(where the subject was not previously taking concomitant immunomodulators of the same class 
on Day 1 of induction or maintenance), including but not limited to 6-MP, azathioprine, MTX, 
6-thioguanine, and prohibited immunomodulators including but not limited to cyclosporine, 
leflunomide, tacrolimus, thalidomide regardless of dose, for 7 continuous days. The use of an 
immunomodulator will be considered potentially effective when it is administered for an 
indication of UC. 
3) Potentially effective biologic agent use
Commencement of a biologic agent including but not limited to TNFα antagonists, 
IL-12/23 antagonists, and vedolizumab (or similar agents), regardless of indication for use and 
duration.


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Appendix 6.
Geboes Histological Score Grades
Subgrades
Structural (Architectural Change)
Grade 0
0.0
No abnormality
0.1
Mild abnormality
0.2
Mild or moderate diffuse or multifocal abnormalities
0.3
Severe diffuse or multifocal abnormalities
Grade 1
Chronic inflammatory infiltrate
1.0
No increase
1.1
Mild but unequivocal increase
1.2
Moderate increase
1.3
Marked increase
Grade 2
Lamina propria neutrophils and eosinophils
2A Eosinophils
2A.0
No increase
2A.1
Mild but unequivocal increase
2A.2
Moderate increase
2A.3
Marked increase
2B Neutrophils
2B.0
None
2B.1
Mild but unequivocal increase
2B.2
Moderate increase
2B.3
Marked increase
Grade 3
Neutrophils in epithelium
3.0
None
3.1
< 5% crypts involved
3.2
< 50% crypts involved
3.3
> 50% crypts involved
Grade 4
Crypt destruction
4.0
None
4.1
Probable local excess of neutrophils in part of crypt
4.2
Probable marked attenuation
4.3
Unequivocal crypt destruction
Grade 5
Erosion or ulceration
5.0
No erosion, ulceration, or granulation tissue
5.1
Recovering epithelium + adjacent inflammation
5.2
Probable erosion focally stripped
5.3
Unequivocal erosion
5.4
Ulcer or granulation tissue


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Appendix 7.
PK Parameters
PK parameters evaluated in this study are listed below.
Parameter
Description
AUClast
The area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Cmax
maximum observed concentration of drug in plasma
Ctau
observed drug concentration at the end of the dosing interval
Tmax
time (observed time point) of Cmax
CL/F
apparent oral clearance after administration of the drug:
at single dose: CL/F = Dose/AUCinf , where “Dose” is the dose of the drug
at steady state: CL/F = Dose/AUCtau, where “Dose” is the dose of the drug


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